https://www.makingmolecules.com/blog daily 0.75 2026-03-07 https://www.makingmolecules.com/blog/da-like-reactions monthly 0.5 2025-03-11 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4b136d14-4556-4044-ac69-d894c1024686/01_DA_Intro.png Blog - Diels-Alder-like reactions - A summary of the Diels-Alder reaction. The regioselectivity of the reaction can be predicted by inspecting the polarity of the bonds. The stereochemistry can be predicted by drawing an overlapped transition state that maximizes secondary orbital interactions or favors the endo transition state in which the electron withdrawing group of the dienophile in under the diene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3dd35b14-6e4a-443e-842f-5d409c27ea37/02_catalysis.png Blog - Diels-Alder-like reactions - The effect of a catalyst on the Diels-Alder reaction. Addition of a Lewis acid increases the rate of reaction, allowing reactions to be performed at lower temperatures and with higher selectivity. This version has a 10^5 rate acceleration and the regioselectivity increases for 80% to 97%. The simplest rationale for the acceleration is that the Lewis acid coordinates the dienophile and lowers the LUMO. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c22d9b10-18c1-46fa-bdb0-9620f8491c4a/03_Chiral_DA.png Blog - Diels-Alder-like reactions - An enantioselective Diels-Alder reaction. The copper(II) Lewis acid is complexed to a bisoxazoline, or BOX, ligand. It coordinates with the α-hydroxy ketone to create a rigid chelate with one tert-butyl group blocking approach of the cyclopentadiene from the bottom, so it approaches from the top. This controls the enantioselectivity. The diastereoselectivity arises from the preference for the endo transition state and stereospecificity of cycloadditions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/179e9441-c43d-4844-a108-3679e680d70b/04_Organocatalysis_Chiral_DA.png Blog - Diels-Alder-like reactions - An example of the Diels-Alder reaction accelerated by an organocatalyst. The reaction proceeds by the formation of a charged iminium ion that makes the dienophile more electrophilic. The enantioselectivity is due to the phenyl substituent of the catalyst blocking one face, the Re face, of the alkene. The diene must approach from below. The diastereoselectivity if the reaction is poor, it just favors the exo product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/06282fe7-7d0e-4b87-9013-3983e5804367/05_IMDA.png Blog - Diels-Alder-like reactions - An example of an intramolecular Diels-Alder reaction (IMDA). The regiochemistry is controlled by the length of the linker connecting the diene and the dienophile. The transition state shows the curly arrow mechanism and the overlap of diene and dienophile allows prediction of the relative stereochemistry.Make it stand out https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0cc27a7d-94d6-4080-8aae-76625de01ebd/06_Stenine_IMDA.png Blog - Diels-Alder-like reactions - Make it An example of an intramolecular Diels-Alder reaction taken from the synthesis of stenine. The proposed transition state suggests that reaction proceeds through an endo conformation.stand out https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/29a152b3-9fd9-41b4-96d3-d8b1a90e2f83/07_hDA_IMDA.png Blog - Diels-Alder-like reactions - An example of an intramolecular hetero-Diels-Alder reaction taken from the synthesis of two alkaloids. The reaction is initiated by oxidation of a hydroxamic acid to an acyl nitroso compound. The electron deficient nitroso group acts as a dienophile. An existing stereocenter influences the conformation of the molecule and this biases the diastereoselectivity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4459580-a075-4a01-82b8-8059cf51b739/08_hDA_IMDA.png Blog - Diels-Alder-like reactions - An example of a hetero-Diels-Alder reaction forming dihydropyranones. The diol catalyst activates the aldehyde by hydrogen bonding, this is effectively Lewis acid activation, with the aldehyde being more electron deficient. The electron rich diene attacks and gives the six-membered ring.Make it stand out https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/99470c5a-ac97-47c1-812e-1a668707c494/09_Inverse_MO.png Blog - Diels-Alder-like reactions - This diagram tries to show how changing the electronics of the Diels-Alder reaction can make the reaction more favorable. In the middle is a the reaction of buta-1,2-diene and ethene. This is not a favorable reaction as the HOMO and LUMO are far apart. On the left, there is a representation of the normal demand Diels-Alder reaction. This has an electron donating group on the diene. This raises the HOMO. There is also an electron withdrawing group on the dienophile. This lowers the LUMO. ΔE, the difference in energy between the HOMO and LUMO is small. The reaction is favored. In an inverse demand Diels-Alder reaction the opposite occurs. The LUMO of the diene is lowered by adding electron withdrawing groups to it. The HOMO of the dienophile is raised by adding an electron donating group. The HOMO and LUMO are close in energy and the reaction is fast. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f8ef7ba9-35c6-40f1-b7a0-b4067c72b577/10_Inverse_Example1.png Blog - Diels-Alder-like reactions - An example of an inverse electron demand Diels-Alder reaction. First the electron rich enol ether and the electron deficient diene, the tetrazine participate in the Diels-Alder reaction. This gives a bridged species that undergoes a retro-Diels-Alder reaction that eliminates nitrogen gas. The curly arrows are similar to the Diels-Alder reaction. There are are three moving in a circle. Two σ bonds are broken and thee π bonds created. The resulting diene eliminates methanol to re-aromatize. Elimination probably occurs with methanol leaving to give a carbocation. Elimination of a proton gives an aromatic ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/61518eca-f541-4dc7-8b5a-f9ca2104ac3f/11_Inverse_Example2.png Blog - Diels-Alder-like reactions - An example of an inverse electron demand Diels-Alder reaction for the synthesis of a substituted benzene ring. The reaction involves the addition of an electron rich dienophile in the form of an enamine to an electron deficient diene. It is electron deficient due to conjugation to two carbonyl groups. The resulting cyclohexene ring readily undergoes elimination to give a cyclohexadiene. The proton α to the methyl ester is acidic due to the carbonyl and as it is allylic. The elimination is probably E1cB. There is then a dehydrogenation to give the aromatic ring. Cyclohexadienes are good hydrogen sources for transfer hydrogenation, with the driving force being aromatization. Here the diene probably reduces the enamine. https://www.makingmolecules.com/blog/diels-alder-reaction monthly 0.5 2024-10-22 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/72c1b460-2692-4eb5-95a2-ed071f0c7f99/01_Intro_DA.png Blog - An Introduction to the Diels-Alder Reaction - An example of the Diels-Alder reaction. This shows a cycloaddition reaction occurring between a diene (purple) and a dienophile (green) to form a new six-membered ring. Two new σ bonds are formed (bold grey lines) and a new π bond (bold purple bond). In this example, three new stereocentres are also created. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ea8f5a99-6f5f-4017-ab7b-d5f15c00dd1b/02_DA_examples.png Blog - An Introduction to the Diels-Alder Reaction - Two examples of the Diels-Alder reaction. The new six-membered ring is highlighted as are the three new bonds, two σ bonds and one π bond. Two examples of the Diels-Alder reaction. The new six-membered ring is highlighted as are the three new bonds, two σ bonds and one π bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/647ef220-b62c-4346-adfb-f3665f0aa54e/03_DA_mechanism.png Blog - An Introduction to the Diels-Alder Reaction - The mechanism of the Diels-Alder reaction involves the cyclic movement of six electrons represented with three curly arrows. Each arrow will start from a double bond and it does not matter which direction they flow in. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/64ee87bd-0d6c-4752-afc5-0eefc2888086/04_transition_state.png Blog - An Introduction to the Diels-Alder Reaction - The transition state of the Diels-Alder reaction resembles an aromatic ring with a number of π-electrons spread out over six atoms of a ring. This lowers the energy of the transition state and leads to the reaction being more effective. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3c8e363b-3568-45fd-8685-1740645c08a9/05_FMO_DA_V2.png Blog - An Introduction to the Diels-Alder Reaction - The frontier orbital description of the Diels-Alder reaction. This shows that the HOMO of diene can overlap with the LUMO of the dienophile or the LUMO of the diene can overlap with the HOMO dienophile. In fact, both overlaps are important. The orbital approach is powerful but you can understand the reaction without it. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1462be40-dfde-422d-8df9-a9e1975d9d0c/06_Diene.png Blog - An Introduction to the Diels-Alder Reaction - The diene is one half of a Diels-Alder reaction. It must be conjugated or the Diels-Alder reaction is impossible. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4413c00e-57f4-4838-b2f0-cfdd4560afdb/07_diene_s-cis.png Blog - An Introduction to the Diels-Alder Reaction - One the left is the s-trans and s-cis conformation of butadiene. The s-trans conformation is more stable than the s-cis which effectively matches the anti-periplanar conformation of a hydrocarbon. The s-cis conformation is the only conformation that allows conjugated double bonds to act as dienes in the Diels-Alder reaction. This is confirmed when you look at the two cyclic examples on the right. The first is cyclopentadiene, it has the double bonds locked in the s-cis conformation and it is a good diene. The other, 3-methylenecyclohex-1-ene in red, is locked in the s-trans conformation and it can only behave as a dienophile in the Diels-Alder reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/35a804d3-29ea-4011-911f-35c0fe55e532/08_Dieneophile1.png Blog - An Introduction to the Diels-Alder Reaction - In the Diels-Alder reaction, the dienophile is frequently conjugated to an electron-withdrawing group that activates it. The absence of this group tends to lead to poor reactions that proceed in low yields. The classic example shown at the bottom of the diagram does not give good results with the diene being a better dienophile than ethene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cac7951f-9014-4481-99c8-bf4d485452fe/09_DA_examples.png Blog - An Introduction to the Diels-Alder Reaction - Examples of the Diels-Alder reaction. The diene is in purple and the dienophile in green. The atoms are numbered to show their origin in the newly formed six-membered ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/829b53d5-7537-42f7-a80e-44c73ec9cf5b/10_Regiocontrol_example.png Blog - An Introduction to the Diels-Alder Reaction - The regiochemistry of the Diels-Alder reaction is predictable. As long as the electronics of the system are matched (there is effectively a nucleophile and an electrophile), the regioselectivity will be high. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a69b7dab-0138-4119-9dd6-7b105f04e857/11_Polarization_diene.png Blog - An Introduction to the Diels-Alder Reaction - The polarization of the diene can be predicted by inspecting the resonance structures. This provides a simple method to explain the regioselectivity of the Diels-Alder reaction (but there is a caveat to this, which I’ll mention later). I have only drawn the curly arrows for the resonance/delocalization in a single direction (I think this is clearer than having the reverse arrows on the same diagram). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/25d2b39e-8ba8-4808-bf9b-3d869d92b668/12_Resonance_dienophile.png Blog - An Introduction to the Diels-Alder Reaction - The polarization of the dienophile can be predicted by inspecting the resonance structures. This provides a simple method to explain the regioselectivity of the Diels-Alder reaction (but is not the real/accurate reason). For clarity, I have only drawn the curly arrows for the resonance/delocalization in a single direction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c63db079-c31f-4dc2-9659-7ff31fbc49b3/13_Regioselectivity_answer.png Blog - An Introduction to the Diels-Alder Reaction - The regioselectivity of the Diels-Alder reaction can be predicted by matching the polarization of the two components, the diene and dienophile. The partially negative carbon of the diene will form a new bond to the partially positive carbon of the dienophile and vice-versa. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cbf780e8-2bc2-447e-9f0e-d7bd9477ea22/14_Regioselectivity_ortho.png Blog - An Introduction to the Diels-Alder Reaction - The so-called ortho selectivity in the Diels-Alder reaction of a terminally substituted diene. The diagram also shows the similarity between the transition state and an aromatic ring. This explains why some people call these Diels-Alder reactions ortho selective. At the bottom of the scheme is the resonance structures used to determine the polarization of the diene (just as practice). As always, I've only drawn the curly arrows for the resonance structures left to right. This makes the scheme clearer but there is an argument that resonance structures should always been drawn with the arrows showing the movement of electrons in both directions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7b707000-8017-407e-9644-04dc56b37996/15_Regioselectivity_para.png Blog - An Introduction to the Diels-Alder Reaction - If the electron donating substituent is at the 2-position of the diene the so-called para-selectivity will be observed. An example is shown in the top line. The origin of the name of this selectivity is shown in the second line where the transition state is compared to an aromatic ring. The origin of the selectivity itself can be argued from looking at the polarization of the two components. The resonance structures of the diene is shown at the bottom with only one set of curly arrows. This makes the diagram clearer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c13efa59-02d5-4ce4-83f1-adf21e44f7fc/16_Regioselectivity_MO.png Blog - An Introduction to the Diels-Alder Reaction - Using resonance to predict the polarization of bonds and then matching the electron-rich atoms to the electron deficient atoms does not always give the correct result. To truly understand the Diels-Alder reaction you need to look at the orbitals involved. But that is way more complex than you need for at least the first two years of undergraduate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a6408e92-6913-42f5-8677-7f5142cbf0f4/17_Regioselectivity_summary.png Blog - An Introduction to the Diels-Alder Reaction - The regioselectivity of the ‘normal’ Diels-Alder reaction is summarized above. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/81b63084-5c11-4381-a488-3e1d4b8e16bf/18_Cis_alkenes.png Blog - An Introduction to the Diels-Alder Reaction - The stereospecificity of the Diels-Alder reaction. The concerted nature of cycloadditions means the stereochemistry or geometry of the alkenes is conserved in the final product. Three different representations for the reaction of a cis and a trans alkene are given. The first is the standard reaction scheme. The second shows the frontier molecular orbital overlap, and indicates that as the bonds are created at the same time the relative stereochemistry between the dienophile substituents must remain the same. Finally, the third representation shows a simple method for determining the relative stereochemistry by overlapping the two components. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9a39ccff-8511-4215-a3fa-f3118bc081c7/19_Diene_stereoselectivity.png Blog - An Introduction to the Diels-Alder Reaction - The stereospecificity of the Diels-Alder reaction. The concerted nature of cycloadditions means the stereochemistry or geometry of the alkenes is conserved in the final product. Three different representations for the reaction of a trans,trans and a cis,trans dienes are given. The first is the standard reaction scheme. The second shows the frontier molecular orbital overlap, and indicates that as the bonds are created at the same time the relative stereochemistry between the dienophile substituents must remain the same. Finally, the third representation shows a simple method for determining the relative stereochemistry by overlapping the two components. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/86e405fc-8f3e-44c1-92a5-616fb685dccb/20_Endo_Example.png Blog - An Introduction to the Diels-Alder Reaction - The Diels-Alder reaction is stereoselective. There are two orientations the diene and dienophile can approach each other and this leads to the endo and the exo product. While the exo product looks more stable, with less steric interactions between the coupling partners, the endo is normally preferred. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e3a73475-b4dc-42ab-b996-4f9940cd1524/21_Endo_explanation.png Blog - An Introduction to the Diels-Alder Reaction - The endo selectivity of the Diels-Alder reaction arises due to secondary orbital interactions. There is a stabilizing overlap of the HOMO of the diene with the LUMO of the carbonyl of the activated dienophile in the transition state that leads to the endo product that is absent in the transition state of the exo product pathway. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/10e94d46-185d-42e3-87ea-36a2fcc0785d/22_Reversible.png Blog - An Introduction to the Diels-Alder Reaction - The Diels-Alder reaction of furan is a reversible reaction. This leads to the more thermodynamically stable, exo product, being favored over the normally observed exo product. The reversibility is due to the aromatic characteristics of furan. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/843d6a4e-0b1e-4c4c-b09e-a790a11d5d2a/23_DA_stereochemistry.png Blog - An Introduction to the Diels-Alder Reaction - The relative stereochemistry of the Diels-Alder reaction is easy to predict if you draw the reactants correctly. An electron-withdrawing group or conjugated substituent on the dienophile will sit under the diene to maximize secondary orbital interactions. Once you have this correct, the substituents closest to each other will be on the same face of cyclohexene product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4742cba6-0731-4335-92a1-ffdc8c254601/24_DA_Summary.png Blog - An Introduction to the Diels-Alder Reaction - A summary of the Diels-Alder reaction showing how the regioselectivity and stereoselectivity can be predicted from two normal examples in which the dienophile is electron-deficient and the diene electron-rich. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/65563012-370b-49dc-bc19-0e13f9669a6a/25_More_DA.png Blog - An Introduction to the Diels-Alder Reaction - The Diels-Alder reaction is versatile. The basic principles covered in this summary can be applied to the synthesis of different cyclic molecules. The top row shows an intramolecular Diels-Alder reaction (IMDA) that leads to the formation of a bicyclic system. The middle example is very interesting, it is both an inverse electron demand Diels-Alder reaction (iEDDA), meaning that while the components are still electronically matched, the diene is now electron-deficient and the dienophile is electron-rich. It is also an example of a hetero-Diels-Alder reaction, with one of the carbon atoms of the diene replaced by a nitrogen atom. The middle row also shows a retro-Diels-Alder reaction, an elimination that breaks a six-membered ring and gives a pyridine along with nitrogen gas. The final row shows another hetero-Diels-Alder reaction (HDA). Here an electron-rich diene attacks an aldehyde as the dienophile and leads to a pyran system. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/21d4891d-5a47-4c3e-bb16-4a45893b08a8/26_Cycloaddition.png Blog - An Introduction to the Diels-Alder Reaction - Another example of a cycloaddition reaction. This is a 1,3-dipolar cycloaddition or (3+2)-cycloaddition or [4+2]-cycloaddition depending on how you want to classify it. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f2e36955-b468-4b2a-88b1-57cd7ad87f39/27_Electrocyclic.png Blog - An Introduction to the Diels-Alder Reaction - An example of an electrocyclic reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/18a8766c-67ff-4dbd-909c-3474f0cfbce7/28_Rearrangement.png Blog - An Introduction to the Diels-Alder Reaction - An example of a rearrangement reaction. This is an example of the Ireland-Claisen rearrangement. https://www.makingmolecules.com/blog/enamines monthly 0.5 2024-09-02 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e681ea7a-6d86-445f-bcd7-38936a6fc4f1/01_Enamine_Introduction.png Blog - Enamines - General enamine reaction Alkylation of a ketone proceeding through an enamine. The reaction of pyrrolidine and cyclohexanone leads to the formation of the nucleophilic enamine. This can react with suitable electrophiles to give, after hydrolysis, the alkylated product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/855d985a-fbac-42f6-8fde-b0f07c3b86c8/02_imine_formation.png Blog - Enamines - Imine formation The reaction of a ketone and a primary amine leads to the formation of an imine. This is a condensation reaction that proceeds with the elimination of water. Lose of the N–H proton from the charged iminium species (deprotonation) leads to the neutral imine. This is only possible if a primary amine (or ammonia) is the initial nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ffeadc34-0ec5-4ef7-918a-ba900b71f369/03_enamine_formation.png Blog - Enamines - Enamine formation The reaction of a secondary amine and an aldehyde or ketone leads to an enamine. The mechanism starts the same as imine formation. The amine attacks the polarized carbonyl group in an example of nucleophilic addition. There is a series of proton transfers that leads to the formation of an oxonium leaving group. The water is kicked out to form an iminium species. Unlike with imine formation, there is no N–H bond that can be broken to give a neutral species. Instead it is necessary to deprotonate the α-position leading to an enamine, a species that looks like a enol except with a secondary amine replacing the oxygen. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d56c3ae5-841e-464e-a15c-a75182fa6173/04_reversible_enamine.png Blog - Enamines - Reversibility of enamine formation Just like imine formation, enamine formation is an equilibrium reaction. This means enamines are unstable in the presence of aqueous acid. The mechanism is the reverse of enamine formation. Protonation of the enamine leads to the formation of an iminium cation. Water attacks the charged species leading to a tetrahedral intermediate that resembles an acetal. Protonation of the amine forms a good leaving group that is expelled to give a ketone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f3211e93-d003-4c55-a76d-9d84123792ec/05_Regioselectivity.png Blog - Enamines - Enamine formation of an unsymmetric ketone leads to the thermodynamically more stable, less substituted enamine. This minimizes the interaction between the alkyl groups attached to the nitrogen and the substituents on the C=C double bond. Each step of the reaction is reversible and this explains why the most stable, least sterically congested compound is favored. Enamine formation of an unsymmetric ketone leads to the thermodynamically more stable, less substituted enamine. This minimizes the interaction between the alkyl groups attached to the nitrogen and the substituents on the C=C double bond. Each step of the reaction is reversible and this explains why the most stable, least sterically congested compound is favored. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/28635df4-e3b9-44cb-a5d0-722793189788/06_Delocalization.png Blog - Enamines - Trying to understand why enamines cannot rotate to minimize steric interactions. The lone pair of electrons on the nitrogen is delocalized into the alkene creating double bond-like character. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/068f418d-55ff-45fb-ac55-86d329a853e9/06B_More_Regiocontrol.png Blog - Enamines - The thermodynamic enamine of an acyclic ketone is similar to an enol. It normally favors the more substituted double bond as these are more stable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9ea9069-c311-4b61-82ae-9670d4518205/07_delocalization.png Blog - Enamines - In enamines, the nitrogen lone pair of electrons os delocalized. Both the nitrogen and the α carbon are nucleophiles. Due to the the reduced electronegativity of nitrogen compared to oxygen, the delocalization is more important, and enamines are more nucleophilic than enols.Make it stand out https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6ae2e3ff-e561-44b8-bc30-fd8985f2455d/08_Enamine_alkylation.png Blog - Enamines - The alkylation of an enamine. Enamines are nucleophilic with the electrons of the nitrogen moving to form an iminium cation. As they do this, the electron rich C=C double bond attacks the haloalkane in an example of nucleophilic substitution. The resulting iminium cation is unstable and is normally hydrolysed with weak aqueous acid. This is the reverse of imine formation. It involves nucleophilic addition followed by proton transfers. The amine is eliminated to give an oxonium ion that undergoes a final proton transfer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3b848c35-8022-4349-acd9-3615fa6c8c13/09_Activated_Haloalkanes.png Blog - Enamines - Reactive haloalkanes will be adjacent to a double bond (or heteroatom). They include allylic halides, benzylic halides and halides α-carbonyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2aa1c080-c230-40c1-bd9e-d97f4432b655/10_Michael_Addition.png Blog - Enamines - A Michael or conjugate addition involving an enamine attacking a enoic acid. The soft nucleophile attacks the soft 4-position of the enoic acid resulting in the eventual formation of a 1,5-dicarbonyl compound. The mechanism involves conjugate (nucleophilic) addition followed by proton transfer and then hydrolysis of the iminium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fa96c734-2a77-4fc5-bdb3-cebf56f705a5/11_aldol.png Blog - Enamines - An amine-promoted aldol reaction. The reaction proceeds through the formation of an enamine that participates in nucleophilic attack on an aldehyde to give an iminium ion. Hydrolysis releases both the amine and the product. The interesting feature is that the amine is consumed while water is released at the start and then the amine is released and water consumed at the end. This suggests a catalytic cycle should be possible. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/621656a4-342a-468b-a6ad-ebfce8ceb982/12_aldol_catalytic_cycle.png Blog - Enamines - The amine-mediated aldol reaction can be catalytic in both amine and a weak aqueous acid. The cycle in this reaction shows the consumption of pyrrolidine to form an enamine and its release once the aldol reaction has been performed. Slightly harder to see is water and a hydronium ion keep shuttling backwards and forwards so that neither are consumed in the full reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0b0ca79e-ac46-4eee-9c22-9e82999170e4/13_Proline_Aldol.png Blog - Enamines - Proline catalyzes the reaction of acetone, the nucleolphile, with an aldehyde as electrophile. The reaction only requires 30 mol% of the secondary amine (drawn badly in its non-zwitterionic form) to give a β-hydroxy ketone in good yield and high enantioselectivity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/524f00d9-a605-448e-bfad-0aac2b112bca/14_Proline_Aldol_mechanism.png Blog - Enamines - Catalytic cycle for proline-mediated aldol reaction. A sub-stoichiometric quantity of amine is required. Water is expelled during the condensation step and consumed during the hydrolysis. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ebfdbae1-a02f-44a4-a619-6e2d18cc9940/15_Proline_enamine_confirmation.png Blog - Enamines - The mixture of a ketone, an aldehyde and proline can lead to four different enamines. Two are formed from the aldehyde and are disfavored due to steric interactions between the methyl group of the double bond and proline. The other two are formed from the ketone. The favored conformation has the rigid double bond further away from the bulky carboxylic acid. All of this is important for the chemo- and stereoselectivity. https://www.makingmolecules.com/blog/enolateequivalents monthly 0.5 2024-07-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9c39cab9-af10-4cef-87ad-ff9c523a66ff/Introduction.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The problem with the crossed or mixed aldol reaction is controlling the selectivity. How do you ensure only one substrate acts as the nucleophile? How do you control the regioselectivity of deprotonation and how do you control the stereoselectivity of the resulting β-hydroxy ketone? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4b1c724c-669f-47c6-ba59-193b355b987e/Deprotonation_LDA.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Deprotonation of a methyl ketone with LDA (lithium diisopropylamide) leads to the formation of the lithium enolate. The large difference in pKa means the reaction is essentially irreversible. There are two common representations of lithium enolates, one has a O–Li bond, the other depicts the molecule as ionic (remember that the majority of bonds are somewhere in between the two extremes. Also the structure of lithium enolates is far more complex than indicated in organic textbooks with these species being dimers, tetramers or even larger complexes. There was a fascinating Seebach paper in the late 80s on the subject). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c0e53040-8f3e-45c8-8527-9b93cf75c938/Mixed_aldol.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out An example of a mixed aldol reaction. The enolate is formed prior to the addition of the aldehyde. In this example, I’ve used the Ireland model of deprotonation, which involves a cyclic six-membered transition state. The aldol reaction also proceeds through a cyclic transition state with both the enolate and the aldehyde coordinated to the lithium cation (this is probably incorrect and the complex is more, well complex but it gives a use-able explanation of the observed results, which is that the so called syn-aldol is favored). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/713b41c7-3070-499c-8eb7-faccd8cf65dd/Conformation_deprotonation.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The optimum conformation for the deprotonation of an α-proton and formation of an enolate has the maximum overlap of the C–H σ orbital and the C=O π* antibonding orbital. There are two conformations that permit this overlap. One has an unfavorable interaction between the methyl group and the phenyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d2187a44-2abe-48e2-bfeb-7db858e6b1cc/Kinetic_mixed.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out An example of a crossed aldol reaction that starts with the regioselective formation of the kinetic enolate. LDA is a bulky base and, at low temperature, will preferentially remove the least sterically hindered proton. This is the proton on the least substituted carbon. At low temperature, this reaction is essentially irreversible. This example shows the methyl group causing the hindrance. After enolate formation, an electrophilic aldehyde is added. The reaction proceeds through a cyclic transition state (or at least it can be simplified to this transition state) with the aldehyde approaching from the least sterically demanding side of the enolate (away from the methyl group). The relative stereochemistry can be predicted from the cyclic transition state. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/345f32f9-922e-42eb-9178-94a63cc5218a/Lactone_aldol.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The use of LDA in the crossed or mixed aldol reaction allows ketones, amides and esters to be transformed into nucleophiles prior to the addition of the electrophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bec2e40d-5c9a-41d8-9ce9-211152179e0d/SiylEnolEther1.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Silyl enol ethers can be synthesized by the reaction of a carbonyl containing compound, trimethylsilyl chloride and a weak base, such as triethylamine. There are two possible mechanisms for the reaction. Both are driven by the strength of the Si–O bond. The first involves formation of an oxonium ion. The positively charged carbonyl group is highly polarized and pulls electrons towards it. This increases the acidity of the α-protons and means they are readily deprotonated even with a weak base. Alternatively, the silyl chloride reacts with the minor component of the keto-enol equilibrium to give a protonated oxonium ion. This is readily deprotonated to give the silyl enol ether. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1cf7060b-2812-4ffe-b7b6-0ea91787da8a/SiylEnolEther2.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Silyl enol ethers can also be formed by trapping lithium enolates. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/350e2602-8a69-4621-9bcc-6c473076851b/Thermodynamic_siylenolether.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Formation of the thermodynamic silyl enol ether is favored when a weak base is used. There are two potential mechanisms; one involves elimination of a proton from a cationic intermediate. The more substituted enol ether is favored as the positive charge is stabilized by the inductive effect of an additional substituent. The second mechanism involves the silylation of the more stable, more substituted enol and then deprotonation of the resulting oxonium species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/09cd2547-162a-4eb2-b62f-de4dc999b103/Kinetic_siylenolether.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The regioselective formation of the kinetic silyl enol ether. The reaction is conducted with a strong bulky base at low temperature. The bulky base selectively deprotonates the more accessible, less hindered proton. This forms the least substituted lithium enolate, which is then trapped with a silyl reagent to give the less substituted kinetic enolate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1ea9d818-7245-4115-bab0-1675f60df438/Bromination_silylenolether.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Silyl enol ethers react with halides. The C=C double bond is electron rich due to delocalization of the oxygen lone pair. It acts as a nucleophile and will attack reactive electrophiles. The silyl group is readily removed from the resulting oxonium ion (or the carbocation resonance structure) to give the neutral product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/99ab9a34-e83e-4fcb-b7c7-1af4a8f96538/Alkylation_SilylEnolEther.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Silyl enol ethers can be alkylated. The reaction requires a Lewis base to activate the weakly electrophilic haloalkane. The Lewis acid rips the halide off to give a carbocation, which is sufficiently electrophilic that it will react with a weakly nucleophilic silyl enol ether. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4255f1b0-3a7b-48ae-b63b-1c873d4492b6/Mukiayama.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The general outline of the Mukaiyama aldol reaction. This is a reliable method to perform a crossed or mixed aldol reaction with aldehydes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a74e5c49-f6ea-4d85-9861-ccd919da1453/Mukiyama_aldol_mechanism.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out One possible mechanism for the Mukaiyama aldol reaction. The key step that is common to every version of this mechanism is the activation of the aldehyde with a Lewis acid to give a highly electrophilic oxonium species. After that, whether the silicon is transferred inter- or intra-molecularly or at all (there is an argument that the titanium is coordinated between the two oxygen atoms although bonds strengths would suggest the system would favor a Si–O bond over an Ti–O bond), is up for discussion. Ultimately, activation allows the aldol reaction to occur. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/01f2bc22-26a6-42e4-81b8-e978e87183d3/Crossed_aldol_aldehydes.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out An example of the crossed or mixed aldol reaction of two aldehydes. The partial mechanism on the bottom of the diagram shows that formation of the silyl enol ether prevents self-condensation. An enolate is never formed and the nucleophilic silyl enol ether will only react with an activated aldehyde. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4bf68c45-b159-44ee-85ef-4eaa88cf9eda/Silyl_ketene.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out An example of the formation of a silyl ketene acetal and its aldol reaction with an aldehyde. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a7fd9213-df98-4702-a39d-4484e951b7a0/Boron_enolate_Z.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Formation of the Z-boron enolate is achieved with a small boron reagent. The mechanism involves formation of an oxonium ion prior to deprotonation. The methyl group of the enolate avoids interactions with the bulky phenyl group in the transition state. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/76ec27e3-f5dc-48c6-8cab-7d09faf9cdc7/Boron_enolate_E.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The opposite geometry (stereochemistry) of the boron enolate can be formed using a bulkier boron reagent with a poor leaving group. The mechanism is the same (ignoring whether the halide dissociates or not), it is only configuration of the transition state that changes). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9b52e867-1433-4c4e-b99a-12bbbf1a5721/Boron_aldol_Z.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out Selective formation of the Z-boron enolate followed by crossed or mixed aldol reaction. The reaction forms a new C–C bond and controls the relative stereochemistry of the two new stereocenters. The key to the selectivity is the six-membered chair-like transition state. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2095951c-084d-44a5-8e54-d4aaf518bc88/Boron_aldol_E.png Blog - Lithium enolates &amp; enolate equivalents - Make it stand out The E-enolate favors the formation of the anti diastereomer. The explanation is the same as before; the reaction proceeds through a chair-like transition state and the orientation of the aldehyde is such to minimize 1,3-diaxial interactions. The position of all the other groups is fixed. The fact the geometry of the enolate is different means the favored diastereomer is different. https://www.makingmolecules.com/blog/aldollikereactions monthly 0.5 2024-05-20 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/75753236-5a4d-4822-9ff7-8f5927c1f9ac/General_aldol_like+copy.png Blog - Aldol-like Reactions - Make it stand out A generalization of aldol-like reactions that involve the addition of a nucleophile, formed by the enolization of a suitable functional group, to a carbonyl-containing compound, or its equivalent (in which case it technically isn’t an enolization but the principle is the same). The reaction will result in the formation of a C–C bond and possibly a C=C bond. It will leave the original functional group of the nucleophile unchanged but will lead to the electrophile accepting electrons. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4b63db5e-3e0e-48f2-b7b9-cd3968568165/Claisen_Intro+copy.png Blog - Aldol-like Reactions - Make it stand out The Claisen Condensation of two identical esters. The reaction leads to the formation of a β-keto ester. Standard keto-enol tautomerization favors the compound existing as the conjugated enol form (see HERE for a discussion of this phenomenon). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/89baec3c-b612-458f-8552-38a7d35fd575/Claisen_mechanism+copy.png Blog - Aldol-like Reactions - Make it stand out The mechanism of the Claisen condensation involves enolization of carbonyl-containing functional group (normally aldehyde, ketone or ester) followed by nucleophilic addition to an ester. The resulting tetrahedral intermediate collapses, kicking out an alkoxide. Up to this point, every step of the Claisen condensation is reversible. The next step, deprotonation to form a new stable enolate, drives the reaction forward. To isolate the β-keto ester (or its enol form) requires neutralization or an acid work-up. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2fe6b610-430d-4cc7-aeae-5c348280bfd4/Ketone_vs_ester+copy.png Blog - Aldol-like Reactions - Make it stand out Esters are less acidic than ketones. This means they are harder to deprotonate (the α-proton is harder to remove) but that the resulting enolates are more reactive. The difference in reactivity can be explained by the delocalization of the electrons on the second oxygen atom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/46967c66-0df9-462a-a285-c721b81c7277/Claisen_equilibrium+copy.png Blog - Aldol-like Reactions - Make it stand out The first steps of the Claisen Condensation are in equilibrium and they favor the starting materials. Deprotonation of the β-keto ester is irreversible. This gives a delocalized anion, and it is the stability of this intermediate that drives the reaction forward. To isolate product you need to neutralize the second enolate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d0127d6e-9141-4fce-84af-42d9e5cf695c/Disubstituted_claisen_V2+copy.png Blog - Aldol-like Reactions - Make it stand out The equilibrium prevents the formation of disubstituted β-keto esters as there is no longer an α-proton to be irreversibly deprotonated. This can be overcome if a very strong base is used to drive the initial deprotonation forward. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bf397f7b-3530-404e-891e-c85b9dafe0fe/transesterification+copy.png Blog - Aldol-like Reactions - Make it stand out Transesterification can be an issue in the reaction of any ester with an alkoxide base. The problem is that the base can act as a nucleophile and change the ester through an example of acyl substitution. This can be avoided by using very bulky alkoxides or, more normally, by matching the base to the alkoxy substituent. In the latter case, the transesterification reaction still occurs but as the starting material and product are the same no one notices. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d7dac1bc-ce34-4223-b4bb-715308aea6a2/Mixed_Claisen+copy.png Blog - Aldol-like Reactions - Make it stand out The mixed Claisen condensation can be achieved when only one ester has α-protons and so is the only component that can form the appropriate nucleophile. In this example, only ethyl acetate will form an enolate and this will attack the other ester to form the tetrahedral intermediate. Ideally, one coupling partner should be more electrophilic than the other to avoid self-condensation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b1a53ac8-8bf0-4257-b333-861b3e14ef0b/Mixed_Claisen_ketone_V2+copy.png Blog - Aldol-like Reactions - Make it stand out Another example of a mixed or crossed Claisen condensation. This involves the reaction of a ketone with α protons and a carbonate. The carbonate is a more electrophilic version of an ester as it has an additional electron withdrawing group on it. This is a nice route to β-keto esters. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d162d104-eb7a-4b78-b737-d76c648a8a8b/Summary_Claisen+copy.png Blog - Aldol-like Reactions - Make it stand out A generalization of the Claisen condensation and its mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e269165e-f6a6-4443-a33c-b88e1ae255a2/Dieckmann+copy.png Blog - Aldol-like Reactions - Make it stand out The Dieckmann condensation is the intramolecular variant of the Claisen condensation. The mechanism is identical, with the same limitations, the only difference is that the two esters are now connected and the product is a cyclic molecule. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ebc6c342-c010-44a7-9291-af4a853bb022/Dieckmann2+copy.png Blog - Aldol-like Reactions - Make it stand out An example of the Dieckmann condensation between a ketone and an ester. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6a78a732-b76e-4811-947b-720bafde50de/Mannich_Example_V2+copy.png Blog - Aldol-like Reactions - Make it stand out The ‘classic’ Mannich reaction involves the addition of a ketone to formaldehyde and a secondary amine in the prescence of acid. Formaldehyde is used as it is more electrophilic than a ketone and this ensures the amine condenses with it prior to enolate addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a0622d5f-0fd0-4bef-90b2-743a7bb77b11/Iminium_formation+copy.png Blog - Aldol-like Reactions - Make it stand out The highly reactive aldehyde, formaldehyde, reacts with dimethylamine to give an iminium ion. The mechanism is a condensation reaction. There are a number of variants of this mechanism. The amine will attack formaldehyde prior to protonation but there must be an acid present to form the leaving group for the final step. Sometimes you will see the proton transfers as intramolecular steps and sometimes you’ll see water acting as the base to transfer the proton. All of these mechanisms are acceptable. Proton transfers are rapid and equilibriums so all are probably occurring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9a371c7f-d5b8-40f7-a02b-0586a674770d/Mannich_mechanism1+copy.png Blog - Aldol-like Reactions - Make it stand out Acid-catalyzed keto-enol tautomerization leads to the formation of the nucleophilic enol species. This attacks the highly electrophilic iminium ion in an aldol-like reaction to give an amine. A final proton transfer regenerates the acid catalyst. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3d63bf8a-67e7-4c62-bacf-c3eb251d0f5c/List_Mannich+copy.png Blog - Aldol-like Reactions - Make it stand out In this example of the Mannich reaction there is a condensation between an electron rich aromatic amine (an aniline called p-anisidine) and an electron poor aromatic aldehyde. The proline acts as a catalyst and converts acetone to an enamine, an enol-like reactant that behaves as a nucleophile. The Mannich reaction is followed by hydrolysis of an iminium species to give the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dd2dc3dc-3a66-4386-ade8-7e6c00c752bd/Summary_Mannich+copy.png Blog - Aldol-like Reactions - Make it stand out A generalization of the Mannich reaction and its mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/deae68f9-cc9b-4aeb-9ff0-b9f70c2951d2/Henry_example+copy.png Blog - Aldol-like Reactions - Make it stand out An example of the Henry or nitro-aldol reaction. This the addition of a nitroalkane to an aldehyde to give, initially at least, a β-nitro alcohol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fd89f9e5-c84b-4527-9f35-c3c69bb210a2/Nitro-enolization+copy.png Blog - Aldol-like Reactions - Make it stand out The enolization of a nitroalkane is analogous to that of an aldehyde (or ketone or ester). The resulting species is a good nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/248728f5-ac33-470f-a638-1eaf1af880ba/Henry_mechanism+copy.png Blog - Aldol-like Reactions - Make it stand out An example of the Henry reaction or nitro-aldol reaction. The mechanism is shown. This starts with deprotonation to give the nucleophilic nitronate that attacks the ketone. The resulting alkoxide is sufficiently basic to deprotonate nitromethane to give the product and form more nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/124cfc2a-ce20-454a-b4ae-f00f525d313e/Henry_condensation+copy.png Blog - Aldol-like Reactions - Make it stand out The acidity of the α-protons of a nitro group make addition followed by condensation a common reaction pathway. In the case of aromatic aldehydes the condensation is hard to prevent. The reaction starts with the Henry addition to give the β-nitro alcohol. A second deprotonation gives a nitro-stabilized anion that undergoes elimination, kicking out a hydroxide anion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e69fa56a-4499-4499-a171-590642f63544/Summary_Henry_reaction+copy.png Blog - Aldol-like Reactions - Make it stand out A generalization of the Henry or nitro-aldol reaction and subsequent dehydration leading to a nitroalkene. https://www.makingmolecules.com/blog/aldolintroduction monthly 0.5 2024-04-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ebe1056c-a4e9-42dd-84b6-5ee2fb0ea96f/Aldol_introduction+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The aldol addition of a ketone with an aldehyde gives a β-hydroxyketone. Under the correct conditions this will undergo a second reaction, an elimination reaction or the aldol condensation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0b6fb209-c681-47ac-b249-c0290ee0f5fd/Enolate_aldehyde_equilibrium+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out Deprotonation of an aldehyde leads to an equilibrium in which there is a very small amount of enolate. The equilibrium favors the left-hand side, meaning that there is still a high concentration of aldehyde and only a small quantity of enolate. But this small quantity is enough to give you a mixture of a nucleophilic enolate and an electrophilic aldehyde. A more accurate representation of this diagram should not have the second molecule of aldehyde, and instead should show the aldehyde on the left-hand side and the enolate on the right connected by an equilibrium arrow, but too many students seem to think that this means all the aldehyde has reacted and not that the mixture contains every molecule in the reaction diagram. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/109d4775-1cdb-4e6d-b224-7d71ba51f3c7/Aldol_addition_step2+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out A mixture containing a nucleophile and an electrophile leads to a reaction. The nucleophilic enolate attacks the electrophilic aldehyde to give an addition reaction; all atoms of the starting materials are found in the product. The reaction leads to a β-hydroxy aldehyde. The resulting alkoxide is more basic than hydroxide so will either deprotonate more aldehyde, converting it to enolate or will deprotonate water. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/134a326b-e67c-4496-afd6-a087e976360e/Ketone_aldol+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The aldol reaction of two ketones in the presence of sodium hydroxide. Reaction given in the box at the top while the mechanism is below it. The reaction starts with deprotonation to give an enolate. This participates in nucleophilic attack on the remaining ketone to form a new C–C bond and an alkoxide. A second proton transfer gives the final product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/aeaa672f-bcd5-4f12-9aea-ff936f37c2c4/Aldol_Condensation+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The aldol condensation reaction commences with the aldol addition reaction. This involves formation of an enolate that acts as a nucleophile and attacks the ketone. A proton transfer then gives the product of the aldol addition. A second proton transfer results in the formation of a new enolate. This reforms the ketone with the creation of a double C=C bond and elimination of hydroxide (overall this is loss of water). The reaction is not E2 elimination, it must go through the second enolate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/87762659-0e3f-4a3c-aab0-cbbcf15c2db3/Aldol_Condensation_Aldehyde+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The aldol condensation of an aldehyde can lead to two stereoisomers, the cis and trans (Z & E) forms of the enal. The major product will be the sterically least hindered or more stable compound. The mechanism is exactly the same as described for the ketone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ce93cb83-9a04-4ee9-b08a-feab3da0b687/Acid_catalyzed_aldol+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out Acids can catalyze both the aldol addition and the aldol condensation. The reaction proceeds through acid-catalyzed enol formation and then nucleophilic addition to an activated electrophile, the protonated carbonyl group. After another proton transfer, this leads to the β-hydroxy ketone, the product of the addition reaction. Yet another proton transfer creates a good leaving group in the form of a hydronium ion. This undergoes elimination to give a carbocation. The final proton transfer gives the enone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6cffc83f-64f7-4cc6-b88c-a602fa37d800/Conclusion1+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out A quick summary of the aldol addition and the aldol condensation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3ed0167f-6756-4792-9242-012f3611b71c/Crossed_aldol_intro+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The crossed or mixed aldol addition involves the reaction of two different aldehydes (or ketones). If you do not take any care to control the reaction you can get a complex mixture of products. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/522e473c-d15e-44d6-a54e-0f7cc73d3239/Crossed_aldol_example+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out An example of the crossed aldol reaction taken from an undergraduate laboratory manual. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a44fecea-b414-455d-a44a-a39f52e3edc3/Crossed_Addition_example+copy.png Blog - An Introduction to the Aldol Reaction (addition &amp; condensation) - Make it stand out The mechanism of the crossed aldol condensation is identical to that of a normal aldol condensation. The difference is that there are different aldehydes and ketones. In this example, the ketone will form the nucleophile as it is the only compound with protons in the α position. Without these protons it is impossible to form the enolate. The aldehyde is more electrophilic than the ketone so addition predominantly occurs to this molecule. https://www.makingmolecules.com/blog/enolsenolates monthly 0.5 2024-02-26 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8088a7e6-48b2-4bf4-ba4b-5e2239b286a7/Intro-Carbonyl_electrophile.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The carbonyl group is often an excellent electrophile due to the polarization of the bond and the ease of breaking the double bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c6362263-0a05-4993-9df6-8b515032a5cc/Intro-Carbonyl_nucleophile2.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The carbonyl group can make a good nucleophile. Under neutral or acidic conditions, it can exist in the enol form, which is nucleophilic through the adjacent carbon atom. Under basic conditions, it is converted to an enolate, a more powerful nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fc5f0768-9d89-4cbf-a5d3-eb4fdce91487/keto-enol_tautomerization.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Keto-enol tautomerization describes the equilibrium that exists between functional groups containing a carbonyl group and the enol form where a proton has shifted. The two compounds are structural isomers, not resonance structures. The equilibrium normally favors the carbonyl compound. In the case of acetone, there is only a trace of the enol tautomer, but its existence is still very important. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1f3c51db-f083-49f3-a7d9-d096c2ed067e/Dicarbonyl_favoring_enol.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out In the case of a 1,3-dicarbonyl compound (so named as the carbonyl groups are on the first and third carbons in a row, as shown by the blue numbering), the enol form of one of the carbonyl groups is favored over the keto form. The alkene is stabilized by conjugation with both the benzene ring and the second ketone. The enol is also stabilized by the internal hydrogen bonding. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/855393bf-9c1a-4dc2-9a53-61eb971340e2/Tautomerization_delocalization.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out A second example of a 1,3-dicarbonyl compound in which the enol form is more stable than the keto form. This diagram emphasizes that tautomerization is the movement of a proton and π bonds while delocalization is only the movement of electrons. There are three separate structural isomers shown along with one resonance structure of the last isomer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/821ea06e-3e09-4775-8630-0573a67cc21d/naming_carbons.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Just to make things simple, chemists like to name the carbon atoms next to a carbonyl group using the Greek alphabet. This means the first carbon adjacent to the carbonyl is α and then it keeps going through β, γ, and δ. Chemists also use numbers (as attested by having 1,3-dicarbonyls as well as β-keto carbonyls). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6d778d4d-9ace-4885-ba94-6f03c0098913/deuterization.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out There is a slow exchange of deuterium and hydrogen from D2O and an enolizable carbonyl group. This leads a change in the 1H NMR spectrum over time. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/33d77ddc-33eb-4463-b7d9-1d63e6cb2272/Not_intramolecular.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Keto-enol tautomerization is not an intramolecular process even though this is easier (and lazier) to draw. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/07c0945f-becb-4bcb-ae14-64519d131fc4/Acid-catalyzed-enolization.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Acids will catalyse keto-enol tautomerization through a cation intermediate. The reaction occurs through a protonation and then deprotonation step. The cationic intermediate is delocalized and best represented by two resonance structures. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0535ff6b-096b-4b07-971d-2e3720518b8c/Base-catalyzed-enolization.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Keto-enol tautomerization can also be base catalyzed. Deprotonation, to give the important enolate anion, occurs first, and is then followed by protonation to give the enol. The anionic intermediate, the enolate, is delocalized and best represented by two resonance structures. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/831ec175-11d7-4c9c-84e3-620e50f81924/enolizable_non.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Here are a number of examples of carbonyl-containing compounds. Only those with an α (alpha)-hydrogen are enolizable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/87e9d48b-0e38-4c3b-9dcb-a499c5d3372a/Enol-nucleophile.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Enolization of acetone gives the nucleophilic enol. The resonance structures of the enol show that that carbon atom has partial negative charge and is nucleophilic. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/31db7588-2017-4aba-8f0f-8e690495387d/Racemization-version2.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Enolization of a carbonyl-containing compound with an α-stereocenter can lead to racemization or epimerization. The mechanism for acid-catalysed enolization is shown and the final proton transfer can occur from either face of the enol. This leads to the formation of a mixture of enantiomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/79d50b34-f010-4292-8399-8162593dff5a/Stereochem.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The enol is flat with the carbon atoms being trigonal planar. Protonation can occur from either face (top or bottom in this diagram) and this leads to the different enantiomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c74d0239-7cbc-47cc-9b83-c02452cd5e48/Racemization-version3_base.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Enolization of a carbonyl-containing compound with an α-stereocenter can lead to racemization or epimerization. The mechanism for base-catalyzed enolization is shown and the final proton transfer can occur from either face of the enol. This leads to the formation of a mixture of enantiomers. The process is almost identical to that of acid-catalyzed racemization. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e0d5e68d-faf1-42b7-941b-a3c8cd0be3dc/Acid_catalysed_bromination.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The acid catalyzed bromination of a ketone. This occurs through the formation of an enol, which then behaves as a nucleophile and attacks the bromine. The reaction only occurs once, and leads to the formation of the monobromo ketone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/18b73cf3-0ede-4c29-82ee-223b8dec8c04/Acid-enol-TS.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The positive charge of the oxonium species, the activated carbonyl, is spread over the substrate during the deprotonation. Unfortunately, the bromine is electron withdrawing and disfavors having a partial positive charge near it. This step slows down and it is easy to stop bromination after a single addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fc757a8d-c343-425e-a4a9-be5c08872380/Bromination_of_acid.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Carboxylic acids barely undergo enolization so they are inert to the standard conditions, but if they are converted into the far more reactive acyl halides first, then the reaction readily proceeds. The acid (or an ester or amide) can easily be obtained by reacting the acyl halide with the appropriate nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5acb6fc3-601b-4b6f-b5f7-bf1d3091b39c/Non-symmetrical_example.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The reaction of a non-symmetric ketone can lead to the formation of two regioisomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8f34ed42-0176-49c6-862c-a6aeae71d86b/Zaitsev-enol-profile.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Acid-catalyzed enol formation normally favors formation of the more substituted enol. The reaction is reversible and the more stable or substituted double bond is formed. Alternatively, the transition state leading to this regioisomer is lower in energy as the positive charge is spread over a more substituted system leading to increased stability. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a41cc74b-03a2-498d-a5b0-609fb4915498/More-Substituted_favored.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Acid-catalysed bromination of a non-symmetrical ketone proceeds through the formation of the more stable enol. This corresponds to the Zaitsev product or more substituted alkene. This ultimately leads to the formation of the more substituted bromide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2ae35d71-c206-46fd-af93-0b0adcb7db3c/nitrosation_ketone.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The nitrosation of a ketone followed by hydrolysis to give a 1,2-diketone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3e188921-f26c-4429-be0a-623e13caddf4/nitrosonium_formation.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The formation of the highly electrophilic nitrosonium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c88dfaf5-ae14-45bd-a5cc-e9cc2a60a867/nitroso_mechanisms.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Formation of a nitroso-ketone by the nucleophilic addition of an enol to a nitrosonium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c7fbb847-bd2f-4a5d-9da5-ed964547a2aa/oxime-hydrolysis.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Tautomerization of the nitroso compound gives an oxime that is hydrolysed under acidic conditions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/32e678a0-5d1f-4f84-9ca0-b5e96646a69d/enolate-formation.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The formation of the anionic enolate. This species is a good nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4517425-4f6c-4b81-a086-1f37122806f6/Enolate-Formation-deprotonation.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out It is possible to remove the α-proton next to a carbonyl group as the resulting anion, or conjugate base, is relatively stable. The anion is delocalized over three atoms. It mostly resides on an electronegative oxygen atom and the inductive effect makes the carbanion resonance structure more stable than might otherwise be the case. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4d791661-425b-47ce-9e16-75dc05832e79/pKa.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The ease of deprotonation is influenced by a number of factors including delocalization and electronegativity. The α-proton is more acidic than in an alkane due to delocalization and the possibility that the resulting anion can reside on an electronegative atom. The more electronegative atoms or the more delocalization, the more stable the anion (conjugate base) and the easier the deprotonation is. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d7018295-542c-48d4-825f-d67022fd3384/general-enolate-reaction.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The general reaction of enolates. Deprotonation gives the enolate anion. This is resonance stabilized. The resonance structure with the anion on the oxygen makes a bigger contribution to the structure of an enolate but the enolate normally reacts through the carbon anion. The top version of the reaction shows the two structures an uses the lone pair of electrons on the carbon to react with electrophiles. Most chemists are too lazy to draw the two resonance structures every time and will use the lower simplification. The enolate is drawn as the more stable resonance structure and then the electrons flow through the enolate so that reaction occurs at carbon. Occasionally, you will see the reaction drawn showing only the carbon anion and sometimes you will see the wonderful atom specific curly arrow being used to show the α-carbon reacts. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a44cb2d4-7f37-4513-8609-c65813eef76c/enolate-orbitals.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The frontier orbitals for the allyl anion and an enolate. The allyl anion only contains carbon and is symmetrical, the two ends of the system are the same. The enolate contains an electronegative oxygen atom and this distorts the orbitals. The electrons are pulled towards the oxygen atom meaning there is a large orbital on the π bonding orbital. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6e77b2fe-748c-479f-b1d7-105e2b12f2d0/protonation-enolate.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Enolates are nucleophiles so will readily react with sources of relatively acidic protons. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5036623a-ba4c-480c-8720-fa071accde0a/Haloform_reaction.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Base-mediated bromination of a ketone leads to the haloform (in this case, bromoform) reaction in which a C–C bond is cleaved. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a9ee3122-c31e-4d7d-93ae-483410081a57/Bromoform_part1.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The first stage of the bromoform reaction is exactly as expected, the base deprotonates the ketone to give an enolate that then participates in nucleophilic substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d3e848b9-0d20-4d1e-b23a-c86190c81fb7/Bromoform_part2.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The α-bromoketone formed in the first stage of the reaction is more acidic than the starting material due to the electronegative bromine atom. It is more readily deprotonated to give a new enolate that can be brominated a second time. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b480bc26-3d85-4700-94fd-b53a74eaa8f2/Bromoform_part3.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The dibromoketone is even more reactive than either the starting material or the intermediate. It has two electronegative bromine atoms that can enhance the acidicity of the proton on the α-carbon. As a result, the proton is easily removed to give yet another enolate that then reacts as a nucleophile to give the tribromide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/89effe1e-fe36-46bf-8eb8-b674da255c26/Bromoform_part4.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Once the α-protons have reacted, the hydroxide anion acts as a nucleophile and attacks the carbonyl group to give a tetrahedral intermediate. This collapses expelling the good leaving group the tribrmo-stabilized carbanion. This gives a carboxylic acid and a carbanion that react to form bromoform and a carboxylate anion. The reaction has finished. If you want to isolate the carboxylic acid you need to neutralize the reaction by adding an acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/20c5913a-b054-4777-bfcf-7257b402fe5c/Reversible-attack.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Hydroxide anion will and does attack a carbonyl group. The reaction is normally unproductive as there are no suitable leaving groups so it just reverses and returns the starting materials. In the haloform reaction there is a different leaving group and hence you observe a different reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/da04dd8c-0a70-4ac5-901f-933f8daf75d6/General-Alkylation.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out General reaction equation for the alkylation of an enolate with a haloalkane. The first part of the reaction is deprotonation of the α-proton to form the enolate. The enolate then attacks a haloalkane in an SN2 substitution reaction to give the desired product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/811ad2c1-2d9e-4c3b-ac97-f0c2aec2ae45/Alkylation_beta_ketoester.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The alkylation of a β-keto ester. Enolate formation is relatively easy and can be achieved with sodium ethoxide. The choice of base is very important as you shall see. Otherwise the reaction follows the standard steps of deprotonation to give the nucleophilic enolate followed by nucleophilic substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a69aba2b-e7c7-438b-8776-08813fbb2700/transesterification.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Choosing the wrong alkoxide base can lead to transesterification and formation of a mixture of esters (as well as alkylated compounds). In this example, the methoxide base was used instead of ethoxide and, as a result, a mixture of the desired ethyl ester and methyl ester are formed. The mechanism for the formation of the undesired methyl ester is shown. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9233d21d-8905-4804-b059-a4f6e4e89b8f/Ketone_and_alkoxide.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Alkoxides are not sufficiently strong bases to effectively deprotonate ketones and form a high concentration of enolate. The excess base left in the equilibrium mixture will react as either a base or a nucleophile with the alkyl halides leading to ethers and/or alkenes (depending on the structure of the alkyl halide). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8b5b44ce-86a7-43cd-aa4c-8b57af301a47/Alkylation_decarboxylation.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out One method of controlling regioselectivity and being able to utilize a weak base to form an enolate is to use a β-keto ester. These compounds are readily deprotonated and reliably undergo alkylation. The ester group can be removed through a process of hydrolysis followed by decarboxylation. Normally, the latter step is challenging and requires harsh conditions but the presence of a β-keto group allows the reaction to occur under milder conditions. A six-membered transition state involving the movement of six electrons allows the formation of carbon dioxide and an enol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a6179bed-8c3b-40f8-9d2a-bd9bf2999b88/LDA-deprotonation_mechanism.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Lithium diisopropylamide is a strong, non-nucleophilic base that is often used to deprotonate ketones, esters and amides to form enolates. The mechanism is shown at the bottom of the diagram. I've drawn the deprotonation as a six-membered transition state with the movement of six electrons (three curly arrows) just to show how common this motif is (there is a version of the nucleophilic substitution that also involves a six-membered transition state to give the product and lithium iodide). Lithium amides are very reactive and normally are kept at -78 °C until the electrophile is added. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/23f29ead-95d2-4b1a-9ecf-647893d799f7/LDA-Alkylation_examples.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out Examples of alkylation that can be achieved by the formation of a lithium enolate using LDA. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0d1ef5b9-1c22-4d8f-a26a-78b517d2b5c7/Kinetic_vs_thermodynamic.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out A non-symmetrical ketone can lead to two different regioisomers of enolate. The more stable, more substituted enolate is known as the thermodynamic enolate while the enolate that is formed faster is called the kinetic enolate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f018c279-4bc9-44ce-91cc-79c184f95c54/Kinetic_enolate.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The kinetic enolate can be formed by using a strong, bulky base in excess. The reactions are conducted at low temperature to avoid equilibrium and to favor removal of the more accessible protons. The reactions are performed quickly. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ff1e7bb1-da49-407a-ba41-9741db1e311e/thermodynamic_enolate.png Blog - An Introduction to Enols &amp; Enolates - Make it stand out The thermodynamic enolate can be formed by performing the reaction under conditions that are likely to allow an equilibrium to be established. This includes using sub-stoichiometric quantities of small (often weak) bases, at higher temperatures and leave the enolate for long lengths of time. https://www.makingmolecules.com/blog/eliminations monthly 0.5 2023-11-20 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9ca6afa-7421-4cc8-b69e-5e8c64212760/Intro_substitution_elimination.png Blog - Eliminations - Make it stand out A secondary bromoalkane could react with hydroxide to give either an alcohol, by a substitution reaction, or an alkene by an elimination reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3a201e7f-24ad-48f0-8188-137cc3d291c6/Elimination.png Blog - Eliminations - Make it stand out The elimination of a leaving group (LG) and an adjacent proton (a proton in the α-position) leads to the formation of an alkene. This diagram is bad as it suggests the two groups being eliminated are on the same side of the molecule. As you will see in the coming sections this is not true (well there are examples of syn eliminations but these are rare). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1e73e1ad-b588-43a2-a5ee-90719cc42746/E2-Mechanism-Profile.png Blog - Eliminations - Make it stand out E2 elimination involves the reaction of a base and a substrate to create an alkene. It is a concerted process with all the bonds being made and broken at the same time. This means the rate equation involves both substrate and base. The reaction occurs in a single step and there is a single transition state that has the base, proton and substrate aligned. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6bb02783-4eef-4be5-9d1b-2f523ba38091/Antiperiplanar.png Blog - Eliminations - Make it stand out There is a conformational requirement for E2 elimination. The hydrogen being removed and the leaving group must be antiperiplanar to each other. This is shown in the skeletal form and the Newman projection for the same molecule. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bd5d323d-f72d-4b35-ba8d-f268f6da3b0b/E2-Stereoselective.png Blog - Eliminations - Make it stand out E2 eliminations can be stereoselective if there is a choice of protons that can be eliminated. Invariably, the more stable geometry of alkene will be formed (by more stable, I mean the one that places the largest substituents on opposite sides of the alkene). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6e96ee22-daee-4137-8190-eb4acac6105a/E2-Stereoselective-TS.png Blog - Eliminations - Make it stand out When there is a choice of protons that can be eliminated, E2 reactions progress through the transition state that has less steric interactions between substituents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c7e93031-1cf7-4238-b0c7-41046f431795/E2-Stereospecific.png Blog - Eliminations - Make it stand out E2 eliminations are stereospecific if there is a single proton that can be removed. This means that two diastereomers will give to different geometric alkenes under the same reaction conditions. This is due to the requirement for the proton and the leaving group to be antiperiplanar to each other. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b6e0cbc3-ed4c-4410-90e7-ab15f2347419/Cyclohexane-ring-flipping.png Blog - Eliminations - Make it stand out The chair conformation of a cyclohexane ring places a substituent in one of two positions; it is either equatorial or axial. A change in conformation, known as ring flipping, allows the substituent to swap back and forth between these two positions. When a substituent is equatorial, the only bonds antiperiplanar to it are C–C bonds. These cannot participate in E2 elimination. When the substituent is axial, there are potentially two antiperiplanar C–H bonds. This means only an axial leaving group can participate in E2 elimination. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2d873e12-d9e5-4d7c-98c4-d0f4a40de687/E2-Elimination-bromocyclohexane.png Blog - Eliminations - Make it stand out Cyclohexane derivatives only undergo E2 elimination when both the leaving group and the proton to be removed are parallel to each other in an antiperiplanar conformation. This can only occur if they are both axial. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4fc86f85-f6c1-41a4-bced-179a3ec56416/cyclohexane_diastereomeric.png Blog - Eliminations - Make it stand out Diastereomeric cyclohexane derivatives can give different results in E2 eliminations. In the top example (diastereomer 1), the favored conformation has the isopropyl group in the equatorial position to minimize 1,3-diaxial interactions. This places the chlorine leaving group axial. There are two possible axial protons that can be removed during E2 elimination to give two different alkenes. In the bottom example (diastereomer 2), the favored conformation still has the isopropyl group equatorial but this places the chlorine leaving group in an equatorial position. Equatorial leaving groups cannot react by an E2 mechanism as there are no antiperiplanar protons that can be removed. Before this diastereomer reacts it has to ring flip to the less favored conformation. This takes energy and causes the activation barrier to be larger and slows the rate of reaction. When ring-flipping occurs and the chlorine is axial, there is only one antiperiplanar proton that can participate in the elimination processes and so only one alkene can form. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f73f52c7-c052-4ecd-a1b4-96cf0ae289b4/Substituted_alkenes.png Blog - Eliminations - Make it stand out Alkenes can be classified by the number of substituents (non-hydrogen atoms) attached to the double bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9f93aded-7919-4c56-811b-bbd1d5fd1034/Alkene_stability_orbitals.png Blog - Eliminations - Make it stand out The more substituted a double bond the more stable it is (all other factors being equal). This is a result of the delocalization of the electrons of σ bonds into the π* antibonding orbital of the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/65547785-ce97-417b-b238-bdf5d98a4700/E2-Small_base.png Blog - Eliminations - Make it stand out E2 elimination with a small (sterically non-demanding) base favors formation of the more stable, more substituted alkene. This is sometimes known as the Zaitsev product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3559c74b-46b8-4ce7-ae2a-12853c2ace67/E2-Large_base.png Blog - Eliminations - Make it stand out With E2 eliminations, changing the base can influence the regioselectivity. A large bulky base is slower to react with the internal protons compared to the more acidic, more accessible, methyl protons. This change in rate allows the reaction to favor the formation of the less stable, less substituted, Hofmann product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3d92ed1b-f766-41f1-b9ed-e33ba8908b19/E2-Zaitsev-product-reaction-profile.png Blog - Eliminations - Make it stand out A good leaving group favors the formation of the more substituted, Zaitsev product as the reaction proceeds through a transition state that resembles the alkene. The more stable the alkene the lower the activation barrier and the faster the products is formed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dfc558c8-0105-4849-b1f9-f74551da939b/E2-Hofmann-product-reaction-profile.png Blog - Eliminations - Make it stand out A poor leaving group favors the formation of the less substituted alkene or the Hofmann product. With a poor leaving group there is a build up of negative charge as the proton is attacked earlier. The transition state resembles as anion and these are more stable with fewer electron donating substituents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/71aa0fc7-68e8-4138-b6e5-9e0f64d40f93/Orbitals_E2.png Blog - Eliminations - Make it stand out E2 elimination occurs through the antiperiplanar conformation to maximize the overlap of the C–H σ bond and the C–LG σ* antibonding orbital. These mix to create the new π bond. The synperiplanar conformation is disfavor as it is eclipsed (high energy) and the orbitals are not parallel leading to poor overlap. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e81be3bc-0953-413c-8a98-621cb53090f5/E1-Mechanism-Profile.png Blog - Eliminations - Make it stand out E1 elimination is a unimolecular reaction that is first order with respect to the substrate. This means it is a stepwise reaction, with the first step of the mechanism being ionization to form a carbocation intermediate. The second step is proton transfer which leads to the formation of the alkene. The reaction profile for the two step process is given at the bottom of the diagram. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17bd74a3-b1e2-40a7-b0d7-4ec760c2b20f/E1_competition1.png Blog - Eliminations - Make it stand out Both E1 and SN1 have the first same step (ionization if you ignore the activation of the leaving group in this example) and share a common intermediate, the carbocation. The same substrates favor the dissociation pathway (E1 or SN1 versus E2 & SN2). The difference is the fate of the carbocation and it depends on many factors but an important one is whether the other reactant is a good nucleophile or not. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b4cd9859-0fb9-4ff5-baf9-57749117322e/E1_Stereochemistry1.png Blog - Eliminations - Make it stand out E1 elimination proceeds by lose of the leaving group to give a carbocation that can free rotate. Removal of the proton and formation of the alkene requires the C–H bond to be parallel with the empty 2p orbital of the cation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4a666fb7-80fb-4720-994d-b8b091a159d4/E1-Stereoselectivity-profile.png Blog - Eliminations - Make it stand out In E1 elimination, the only requirement is that the C–H bond of the proton being removed is parallel with the empty 2p orbital. Free rotation of the C–C bond in the cationic intermediate allows the species to adopt a conformation that minimizes steric interaction. This normally results in the E or trans-alkene being favored. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f601cc51-0c3d-4e2c-a253-082c969961ac/E1-Stereoselective_trisubstituted.png Blog - Eliminations - Make it stand out In theory, E1 eliminations should give the same stereoselectivity regardless of the initial diastereomer used. This probably doesn't happen in reality as there are multiple competing reaction pathways (as you will see) and, if I'm honest, I couldn't find an example that had experimental data provided. So take this as an illustrative example but not necessarily true. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/66dade89-c459-41b7-b29c-d198154daa4e/E1-Regioselectivity-Profile.png Blog - Eliminations - Make it stand out E1 eliminations are frequently regioselective and will favor the formation of the more substituted alkene (the Hofmann product). The reason for this is that the transition state that leads to the more stable geometry of alkene normally has the lowest energy so the more substituted alkene is formed faster. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/453af5b4-3d97-42f8-9e5d-e2c1db26b0bf/E2-Substrate.png Blog - Eliminations - Make it stand out All substrates that can undergo elimination can undergo E2 elimination (I know this is a wild generalization that doesn't take into account mechanisms other than E1 & E2 but it is a reasonable starting point). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a3066eb0-69a1-4272-8eab-40b3bd19889e/E1-cations.png Blog - Eliminations - Make it stand out An E1 pathway is only favored when a relatively stable carbocation can be formed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/95e004eb-0e58-4ab5-bc83-cc7c9e342e04/E1_E2_substrates_summary.png Blog - Eliminations - Make it stand out All substrates with the appropriate arrangement of hydrogen and leaving group can undergo E2 elimination but only some of them can follow the E1 pathway. These have to be able to stabilize a carbocation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8379bf52-9fa4-4009-b0e0-a52ff0eafcc1/bases.png Blog - Eliminations - Make it stand out A rough scale of bases. Carbanions are very strong bases. Non-stabilized oxygen and nitrogen anions are strong bases. If they are stabilized by delocalization they are weak bases. Neutral species and the halides are very weak bases. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f164a088-77e2-4620-bbf8-c723e9a07693/Solvent_E1_E2.png Blog - Eliminations - Make it stand out Solvent can influence the mechanism of the reaction by stabilizing the charged intermediates of E1 thus enhancing the rate of E1 elimination. Alternatively, it can solvate the base, making it less reactive and disfavoring E2 elimination. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6086d46e-bbfe-4cb2-91bf-2458938989de/Base_or_nuc.png Blog - Eliminations - Make it stand out The strength of the nucleophile or base can influence which mechanism is operating (and this can be influenced by the solvent). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/009e208c-45f5-425b-b9db-a4de20255e83/Substrate-All_mechanisms.png Blog - Eliminations - Make it stand out Generalization of effect of substrate structure on possible reaction pathway. These aren't rules but a good starting point. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dc3fc88a-d90b-4ab8-baac-c4f374e1bd89/OH_vs_tBuO_V2.png Blog - Eliminations - Make it stand out The size of the reagent can make a difference. Small reactants can easily approach the backside of the carbon and cause substitution. Small reactants are often good nucleophiles. As the reactant gets bigger, it is more sterically demanding and struggles to approach the carbon. It can still attack a small proton found on the outside of the molecule and larger reactants are often basic but not nucleophilic. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/00d065b3-2e8b-4637-b091-5928d9749430/Nucleophiles_bases.png Blog - Eliminations - Make it stand out The rough categorization of common reactants and their favored (but not only) reaction pathway. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d8e87ba6-5c8b-408c-a7bb-3acd86712e1c/Solvents_Summary1.png Blog - Eliminations - Make it stand out Polar protic solvents favor E1 and SN1 pathways. They encourage ionization by solvating both the anion (leaving group) and carbocation. Hydrogen bonding allows them to solvate and reduce the activity of nucleophiles and bases, slowing both E2 and SN2. Polar protic solvents can enhance E2and SN2. They are poor at solvating the nucleophile or base and hence it is stronger or more reactive, which accelerates the two bimolecular mechanisms. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/79754683-7867-4e48-a872-99671321f316/D Blog - Eliminations - Make it stand out Relating the change in Gibbs free energy with enthalpy and entropy. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/057220a4-3775-4fa2-abae-a86e4867316e/Effect_temperature.png Blog - Eliminations - Make it stand out Increasing the temperature favors elimination (E1 or E2) over substitution. There is no change in the number of molecules on either side of a substitution reaction and this means is the change in entropy (disorder) is minimal. As temperature amplifies this term, changing temperature has little effect on the Gibbs free energy of a substitution reaction. Eliminations are different. The overall number of molecules increases and so disorder increases. The entropy term is positive. Any increase in temperature magnifies this making the change in Gibbs free energy for the reaction more negative or more favorable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/de998aa1-f00a-4fc0-bb89-f9a1d73513b3/Summary-mechanisms.png Blog - Eliminations - Make it stand out A brief summary of the mechanisms of elimination. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c273e71f-e7a5-4fd9-b527-581f972697f3/Summary_all.png Blog - Eliminations - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://www.makingmolecules.com/blog/substitution monthly 0.5 2023-10-30 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ff8cb81d-3c62-475c-a091-8b54e78fd5cc/Acyl_substitution.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out A simplified mechanism for acyl substitution. It shows that overall a nucleophile replaces a suitable leaving group (the substitution) but that the reaction mechanism proceeds by nucleophilic attack on the carbonyl group and then collapse of the tetrahedral intermediate. This expels the leaving group and gives the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4c9bf4d-507f-4e21-a8ea-1bfd57ad69e1/Introduction_substitution.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Substitution at a saturated carbon atom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/97ee1bd5-b9ac-4084-9825-18d7f6e46a47/Hydrolysis_bromides.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Hydrolysis of a bromoalkane is an example of a substitution reaction. Different bromoalkanes react at different rates. What is interesting is that the two structural extremes react the fastest. This suggests that there are two different mechanisms operating. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/765aad7e-c41e-4a23-9803-e27af1253108/Positions.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Substrates can be classified depending on the number of alkyl groups attached to the carbon that is bonded to a functional group or heteroatom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cdb0f4db-fd9b-4f76-b85d-e2ec3454e2b5/SN2_mechanism_rate.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The mechanism of an SN2 substitution involves the concerted formation of the new C–nuc bond and breaking of the C–LG bond. There are two molecules in the rate determining step. This is a single elementary step, meaning the mechanism cannot be broken down into any other reaction and there is no intermediate. This is represented by two curly arrows. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eeeeddbe-afab-4431-a101-bd97dd2ef29c/SN2_reaction_profile.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out A reaction profile for a typical SN2 substitution showing the transition state with partial bonds between carbon and both the nucleophile and leaving group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7e169fd4-2f9f-4689-b458-b72514b8b133/Inversion_example.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out SN2 substitution occurs with inversion of stereochemistry (should the electrophilic carbon be a stereocenter). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d4b21984-8ca9-4454-9e88-dc8e6bc38277/Sn2_orbitals.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The frontier molecular orbital approximation of an SN2 substitution. It shows the HOMO of the nucleophile overlap with the LUMO of the electrophile, which leads to the formation of a new σ bond and the breaking of an old σ bond. Bonding forming and breaking passes through a transition state in which the carbon atom is approximately trigonal planar and the electrons of the nucleophile, substrate and leaving group are shared through a p orbital. The only way this achievable is if the incoming nucleophile and the outgoing leaving group are on opposite sides or are 180° to each other. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0225f46e-520b-4665-b07e-15a32af4622a/Sn1_mech_rate.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The mechanism of the second substitution reaction. This is SN1 substitution and is a stepwise process that involves the elimination of the leaving group prior to the nucleophile attacking. The first step is the rate determining step. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/de854966-dfac-4519-b8d2-913938724b68/SN1_reaction_Profile_Mechanism.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The SN1 substitution is a stepwise process that involves elimination and then addition. The first step, the lose of the leaving group (elimination) is the slow, rate rate determining step due to the size of the activation energy. Addition of the nucleophile is rapid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7b1a5841-0518-4bd6-95af-b0e40738f2ef/Racemate_formation.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out When the substrate is chiral and the leaving group is on the stereocenter, the SN1 mechanism can give rise to a racemate. Once the leaving group departs, you are left with a trigonal planar carbocation. This flat intermediate can be attacked from either side leading to a mixture of enantiomers. This diagram tries to show the flat intermediate by placing all the substituents in the dark grey plane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/78d560b3-f244-41a2-bff7-1cca30a1cfa4/Tight_ion_pairs.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Chemistry is rarely as simple as your lecturer will make out. This even includes SN1, one of the first reactions covered in many courses (but not my own I hasten to add, and will argue why it should be at long length given half the chance), is more tricky than made out. It is always stated that the reaction occurs with lose of stereochemical information and formation of a racemate if a chiral substrate was used. This isn't always true. Tight (intimate) ion pairs form, meaning that the nucleophile attacks before the leaving group has completely departed. This means that you normally observe a little more inversion than might be expected. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b320862c-4af3-404b-8cb5-8bd798a50501/Sn1_vs_SN2.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The two substitution mechanisms discussed in this summary (there are more), differ by the timing of the leaving group departing from the substrate. It either occurs before the nucleophile attacks or as the nucleophile attacks. This means the difference between the two mechanisms often comes down to the stability of the carbocationic intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d8e85c56-7b2b-4593-a3c3-952463bfa94b/Cation_stability.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The stability of simple carbocations is determined by hyperconjugation or the inductive effect (two names for the same concept). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0c977ec3-1a6c-4b27-a1cb-2900d99247c3/hyperconjugation.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Hyperconjugation is the delocalization of σ electrons by the overlap of σ bonds. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b7f523e8-c17b-4560-bc34-eb0139af6913/Delocalization.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Substitution of a halide on a benzylic position can be either SN1 or SN2. Both mechanisms are enhanced through conjugation. A primary halide, such as the one in this example, is probably SN2 due to the rapid attack on the primary position (although, I have muddied the waters by using a poor nucleophile). If the halide had been either secondary or tertiary then more SN1 would be observed. In these two examples, there is a deprotonation step to give the neutral final product. This step is rapid and makes no difference to the rate of reaction or mechanism. Almost certainly, the base would actually be the alcohol and not the chloride shown but I've used the chloride to balance the equation (this is one of the many ways chemistry tries to confuse students). Solvent will play a role in determining mechanism but that is a subject for another day. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/402b583b-d831-4e20-aeb3-5dd874024de9/Delocalization_SN2_1st.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Conjugation stabilizes the transition state of SN2 substitution. The π electrons are delocalized onto the partially positive carbon. This lowers the energy of the transition state and the rate of reaction increases. This means delocalization can aid both reaction mechanisms. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6cdaa39b-2cca-4965-9b34-6c67788239f4/Sterics2.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out For an SN2 reaction the nucleophile must approach from 180° to the leaving group. This is easy for methyl and primary substrates but when the leaving group is on a tertiary position there is so much steric bulk that the nucleophile finds it hard to approach. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a3208f14-02d5-4c6c-8106-a1fddaf47376/steric_congestion.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The substituents on the electrophilic carbon atom can influence the reaction in multiple ways. One factor that is often over looked is the change in bond angle. SN2 is disfavored if there are multiple substituents as the transition state involves bringing multiple groups closer together while bulky groups accelerate the SN1 mechanism as the transition state of the rate determining step allows groups to move apart. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/270bdaca-93c5-4348-879b-ca633c0ea9cd/Example-Substitution1.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out An example of a challenging substitution. Which mechanism is operating? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b9c10d47-acc9-408b-ab09-302a84f3a666/SN1_bad.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out SN1 substitution next to a carbonyl group is disfavored as the formation of a carbocation next to a highly polarised carbon with a partial positive charge is energetically unfavorable (the transition state will be high energy). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3e40fbae-d71a-4553-ab06-0594831ec4ed/alpha-carbonyl.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out A halide adjacent to a carbonyl group is around reacts ~100,000 times faster than the analogous primary halide. The reason for this is the conjugation of the antibonding orbitals leads to a lower energy LUMO. This reacts faster with nucleophiles and can offset other issues ... https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5f99069a-68d9-4eae-bc06-2efb7a1ce29a/Answer_SN1_vs_SN2.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out For this question, the answer is that the reaction proceeds by an SN2 mechanism. The reaction will be slow, as the steric hindrance of a tertiary position will slow the reaction considerably, but it is still more favorable to have SN2 than SN1 as there is no cationic intermediate and α-halides react by SN2 faster than normal. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/106ad685-91db-4414-9d34-7e9c903618a7/Rates_leaving_group.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Rate equations showing that the leaving groups is involved in the rate determining step of both substitution mechanisms. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/36de13cc-a434-4e66-b3bc-b71ccd2f33ed/Leaving_groups.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Good leaving groups form weak bases when they are eliminated from the substrate. Iodides are better leaving groups than fluorides (the C–F bond is the strongest single bond in common organic compounds and normally only behaves as a leaving group in nucleophilic aromatic substitution). Elimination of a neutral species will be better than formation of an anionic species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0be68e45-07b5-4e73-9e45-18999b0d9690/hydroxide-Not_LG.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The hydroxide anion is never a leaving group in SN1 and SN2 reactions. It is a strong base so is a poor leaving group. Also the proton of an alcohol is relatively acidic and will be attacked by any nucleophile sufficiently strong to attempt substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ca8bdcf0-1b0d-43a7-99f9-c74aff7b2884/Substitution_protonated_alcohols.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Alcohols can be converted into good leaving groups by treating with acid. The resulting protonated oxonium ion is a good leaving group and will participate in both SN1 and SN2 reactions depending on the substrate structure. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f64dcd38-3ea1-4a7d-a523-a5ccdcb2f952/Sulfonate_synthesis.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The synthesis of the common sulfonate esters. The products are shown in skeletal representation and abbreviated, using the organic elements Ms, Ts, and Tf to represent mesylates, tosylates and triflates. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2541cfef-3f03-4127-a339-8b5e3e31c873/Substitute_sulfonates.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The substitution of sulfonate esters. The top shows the substitution of a tosylate while the bottom shows the substitution of a mesylate. The top reaction proceeds through an SN1 mechanism while the bottom is SN2; this change in mechanism is not due to altering the sulfonate ester but rather changes in the substrate structure. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9e3c218e-c2d1-4f3d-8231-b145262c20a3/Anion_vs_neutral.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Anions are invariably better nucleophiles than neutral species (although it would be better to write that the conjugate base is always the stronger nucleophile so that you don't start comparing an anion of one species with a the neutral form of a completely different molecule). When comparing nucleophilicity, you can use pKa as a starting point, remembering that a good nucleophile is often a good base and so you are looking for the species with the high pKa for the conjugate acid. But two things that trip the unwary, first, make sure you are comparing the conjugate acids, and secondly, pKa is not a guide if the nucleophilic atoms are in different rows so be careful. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/584bc1f6-0c1e-4a5c-b6bb-2c6317362667/Electronegativity_row.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out As you move across a row of the periodic table the nucleophilicity decreases as the electronegativity increases. This effectively matches the ease of donation of a lone pair of electrons. More electronegative elements hold on to the lone pair more and so it is harder for it to be shared; the species is less nucleophilic. This allows you to use pKa as a predictor, but only as you move across a row. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/49a96cbc-a4e2-4df3-a031-c1e45866ce10/pKaH_nucleophilicity_O.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Basicity (and acidity) can act as a predictor for relative nucleophilicity but should not be relied upon. It works across a row of the periodic table and with the same atoms ... most of the time but it should always be remembered that acidity is a thermodynamic effect (measured by an equilibrium constant) while nucleophilicity is a rate effect (how fast a reagent attacks another). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f6a6da57-9232-4432-9e5e-f8778e168cae/Sterics_basicity_nucleophilicity.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Steric hindrance influences nucleophilicity but has little effect on basicity. Less hindered compounds are better nucleophiles as they can attack the carbon more readily. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e34400fd-322d-4a6e-8d24-5c2726791bf0/Down_Group.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out When comparing the nucleophilicity of atoms in the same group, size or polarizability is more important the basicity. The larger the atom, the more electrons and the polarizable it is. There are more electrons and they are further from the nucleus so they are readily unevenly distributed and more readily donated to an electrophile. With increasing size of an atom the HOMO is raised and becomes closer to the LUMO of the electrophile; the reaction is easier. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6ee1ea8f-dc85-495d-b1b0-b6546bad7dd9/nucleophiles.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Summary of relative nucleophile strengths (ignoring solvation). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ec70325f-fc30-4446-b0d6-6012bc7f6767/Solvents-scale.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Solvents can be divided into two categories, non-polar and polar solvents, although it should always be remembered that this a scale with some solvents being more polar than others (a rough rule of thumb involves water solubility; it if dissolves in water it is polar, if it doesn't it isn't, but this is very crude). Polar solvents can be further subdivided into protic (hydrogen bond donors) and aprotic (not hydrogen bond donors). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a2e0189d-b695-4420-8f4f-a27b0e1f652e/polar_non-polar_solvents.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Examples of polar and non-polar solvents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c395476e-c488-467b-b29c-f4933327a8ec/moderately_polar.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Examples of borderline polar/non-polar solvents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ee58a9d7-026c-4935-80d0-8800b26218c6/polar_protic.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Examples of polar protic solvents https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7dd4b5fd-1914-41a3-b0e1-6ba7fcea20ac/polar_Aprotic.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Examples of polar aprotic solvents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/391d61be-413c-4c69-be27-a23c5384af88/Solvent_SN1.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Polar solvents stabilize the cationic intermediate. This means it is easier to form the intermediate and the activation energy is lower. Substitutions occurring by an SN1 will be faster in polar solvents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fb5147db-8349-41b3-a1ee-2a1f96f07479/Solvent_SN2.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Polar solvents are normally required to dissolve both the substrate and the nucleophile, with the latter frequently being an anion with a metal counter cation. Polar protic solvents disfavor SN2 substitution as they can hydrogen bond to the anion and create a solvent shell that hinders the approach of the nucleophile and electrophile. Polar aprotic solvents generally favor SN2 substitutions. They are capable of dissolving the reactants but form only weak interactions with nucleophile. They are said to leave the nucleophile naked, which makes it highly reactive and capable of easily attacking the electrophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1e15e132-7b9e-45c5-9425-4c170c0addd9/Example1.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out An example of a SN1 substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1af60f2d-96e7-4ed6-9a60-983cb63c67ed/Example2.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out An example of a SN2 substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f98ccd77-4ea9-4f7f-9914-a544a136a47d/Example3.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out The effect of acid on the reaction of a tertiary alcohol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2195f86-bb9a-4430-a512-d80df3307d41/Example4.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Conversion of an alcohol into an alkyl halide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4080077a-4516-4b43-ba9e-c56baa5325d7/Example5.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Substitution of allylic bromides (leaving group next to a alkene). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f5628cf8-e33f-46e7-800d-365e9d836738/Example6.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Synthesis of a MOM-protected alcohol by an SN1 process. Acetal formation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2cd9817-da60-45c1-84e3-7e4d761dd24d/Summary.png Blog - Substitution Reactions (on Saturated Carbons) - Make it stand out Summary of factors influencing mechanism of reaction. It is important to remember that these are not rules and that all factors must be considered. Additionally, it does not cover all eventualities, you could have a secondary allylic position or the dreaded neopentyl group, a primary leaving group that is a poor substrate for both SN1 and SN2. https://www.makingmolecules.com/blog/ratesreaction monthly 0.5 2023-09-11 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6544661f-ce41-476b-80d5-4b2bf239bce9/Burning_iooctane.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The combustion of isooctane is thermodynamically favorable, with the equilibrium far are on the right-hand side. But the reaction does not spontaneously occur at any appreciable rate. It is said to be kinetically stable. We must put energy into the reaction to promote it. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/febc2d30-78d0-442f-9696-df9a0e325d22/Just_energy.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A reaction is thermodynamically favorable if the products have less energy than the starting materials. This is shown on the left. A product is thermodynamically less favorable (or disfavored) if the products have more energy. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f6c0d9af-e52c-4425-be16-df50f7db663d/Activation_energy_1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out On an energy profile, the line connecting reactants and products is related to the energy changes in the system as a reaction progresses. The higher the energy barrier, the saddle point between the reactants and products, the slower the reaction will be. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/110d4370-32f0-4153-9a50-8ddbabb40e2b/Pushing_block.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out An analogy for activation energy. A block balanced vertically is not in its most stable state but it will stay balanced. If you give it a weak push, it will wobble, but it will not fall over. There is a minimum amount of energy you must supply before it falls over and reaches its most stable state. This is its activation energy. Molecules behave in the same manner. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c243dae8-7e55-426a-9e14-022916859283/Kinetic_vs_thermodynamic_energy_diagram.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A reaction profile showing both where we learn about thermodynamics, with the energy of the reactants and products determining the position of the equilibrium, and kinetics, the activation barrier that controls the rate of reaction. Organic chemists can be quite vague/lazy/imprecise about energy (hence the lack of a plimsole °) sometimes using E as energy, G as Gibbs free energy and H as enthalpy. These don’t actually mean the same thing and it must be really annoying for physical chemists. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d3e7ce22-aca0-4c95-afd2-b9196cc2bb53/Rate_speed.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Speed is a measure of movement or a change in distance per unit of time (commonly in either km per hour or miles per hour). The rate of a reaction is a similar measurement. It is the change in concentration of a reactant or product per unit time. In this example, the measurement is of the disappearance of reactant (blue circle). As a result, we have had to add a minus sign to the equation. This ensures that the rate is positive (negative rate doesn’t make sense … it is like saying a car is traveling at -30 kph, it is meaningless). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7d0ca7dd-cd86-4e0e-8d97-2c07cda5a941/Simple_General_reaction_V2.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A simplified general reaction involving two reactants. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/294b0fad-2712-4cd1-a41e-9c03a9359024/Simple_rate_proportionally_equationV1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The rate of reaction is proportional to the concentration of reactants A and B. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fc0597f1-43c6-44d5-a4b7-2a8fc8c0c6c8/Pool_analogyV2.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Collision theory treats reactions a little like snooker or pool. For a reaction to occur, two balls (molecules) must collide at the correct orientation and with sufficient energy. If either of theses conditions is not met, the molecules collide but do not react. Obviously, there are differences between collision theory and pool. The main one being that more than one 'shot' is occurring at any moment. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/74991053-058c-429a-9bce-560bb74696b9/HBr_orientation.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Not all collisions are successful. Molecules must collide with the correct orientation for a reaction to occur. This can be pictured if you consider protonation of an alkene. For reaction to occur, the hydrogen must interaction with the π bond of the alkene. Any other clash will lead to the two molecules simply bouncing off each other. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/78f4ebef-d0ae-4f99-831b-1ed0247c84c2/Simple_rate_with_constant.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A simple version of the rate equation (not complete yet ... see later), where k is the rate constant and [A] & [B] are the concentrations of the reactants A & B. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f4af0dca-227c-416a-b799-0ada5b4010a6/increase_concentration_increase_rate_equation.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out If you increase the concentration of one of the reactants, the rate equation shows that rate must also increase. As you shall see later, this isn't always true and isn't always straight forward but it gives a good point to jump off in our discussion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/caf58a31-4849-496c-88d9-87bb1bfb811c/Collisions_concentration.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Reducing the concentration of reactants reduces the frequency of collisions, successful or otherwise. A lower frequency of collisions (fewer collisions per unit time) leads to a slower reaction or a reduced rate of reaction. Increasing the concentration of reactants increases the frequency of molecules colliding and there will be more successful and unsuccessful reactions, the reaction will be faster or the rate of reaction increases. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a0e722b6-e3a8-43c8-baba-8ca34e2e008c/Collisions_temperature2.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out At low temperatures, molecules are moving slowly and there are only a few collisions per unit time. Not all of these are successful, the reaction is slow. At higher temperatures, the molecules have more energy and are moving faster. The frequency of collisions increases and this leads to an increased frequency of successful collisions. The rate of reaction increases. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0c30d461-dcf3-4ad7-8956-e45e9e556d1d/Molecules_with_sufficient_energy.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out As the temperature of a reaction is raised so the number of molecules with sufficient energy to overcome the activation barrier increases. The more molecules that have sufficient energy, the higher the frequency of successful collisions and the rate of reaction increases. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/304965f6-31db-496a-99fa-3d3abe14aaa8/Boltzmann_distribution.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Not all molecules will have the same energy, and there is a distribution of energies that favors moderate or average (surprise) energy while there are fewer molecules with very high or very low energy. The shape of the curve is derived from maths/equations that you can get from a physical chemist (if you need it). Area under the curve is related to the number of molecules with that energy. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a28464ee-524d-42eb-a599-ff9fc71e7058/Boltzmann_distribution_Plus_Activation_barrier.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The area under the curve to the left of the activation energy represents the molecules with insufficient energy to react. It is the majority of the molecules. To the right are those that have sufficient to cause a reaction. It is normally a smaller portion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c196620c-dabf-470d-80b3-f033a39949ff/Boltzmann_distribution_Plus_Activation_barrier_increase_temperature.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Increasing the temperature, increases the proportion of molecules that have enough energy to overcome the activation barrier and react. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/662189be-da33-47dc-8906-2d737d03255b/Arrhenius.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The Arrhenius equation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fcf9765b-f7fe-49f7-991c-b80bc4f230b5/Activation_Barrier_vs_rate.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A lower activation barrier means a faster reaction as more molecules will have enough energy to react. It is possible to lower the activation barrier by adding a catalyst. Such species change the reaction pathway and can add additional steps but all these steps will have a lower activation barrier than the original pathway. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d903bfa8-6e77-47ad-ba44-f333242bb139/Elementary_vs_Mechanism.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A reaction mechanism describes the sequence of elementary steps (or elementary reactions) that lead from the reactants to the product. An elementary reaction is a single step that cannot be broken down into a series of reactions. It is a direct transformation of reactants to products without an intermediate. A reaction mechanism is a composite of elementary steps with one, or more, intermediates formed along the sequence. Transition states frame each intermediate. And boy, do I dislike the curve of the far right! https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cecd44be-512f-4411-bef7-bbb6c1e5c4fb/TransitionStateTheory.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Transition state theory views each elementary step in the same way. There is a state where the molecules are neither starting materials or products. This is known as the active complex or transition state (there is a subtle difference, I think, between these two with the transition state being the apex of the curve while an active complex is the top portion of the curve (so there is a little more flexibility)). It is the saddle point of an elementary step meaning it has the maximum energy and is a transient species with no appreciable lifetime. Formation of the active species is reversible and it can break apart to give either the starting materials or the product. The rate of the reaction depends on the concentration of the active species, how easily it breaks apart and in which direction it breaks apart. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d26f3909-5268-4fdb-beca-cf4cc177ad95/Hammond_postulate.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The Hammond Postulate states that the structure of the transition state resembles the structure of either the preceding or subsequent stable species along the reaction profile that it is is closest in energy to. In other words, in the examples above the transition state resembles the structure of the reactants if they are closer in energy to the transition state than the products (the left-hand side). Alternatively, if the transition state is closer in energy to the products, its structure will resemble that of the products. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fe3fccd8-d1f1-4344-8a16-d24f1acce8cf/An_intermediate.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Stepwise reactions involve the formation of intermediates. These are local energy minima and represent real species that, while reactive, exist and in rare examples, can be isolated. There are two different activation energies for the reaction of an intermediate, the one overcome to form the intermediate and the one that must be overcome so that it transforms into product. The largest (highest) activation barrier will control the rate of reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c20e5bf4-505c-45ac-848a-fdfcf474af69/Rate_equation_Example1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The rate equation for a reaction involving two reactants that are converted to products by a single elementary step. The rate is proportional to the concentration of both reactants and the rate constant applies a correction factor that takes into account the temperature and the probability of a successful collision. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d7a6de1e-c677-4844-905c-3cd5ed20e672/Rate_equation_Single+molecule_Example2.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Simple rate equation for a reaction involving a single molecule being converted into product. The order of the reaction x has not been specified. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bb91c540-bf60-4b10-908f-9714d2e9cf56/Zero_order_V4.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out In a zero-order reaction, the rate of reaction is independent of the concentration of reactant. This is not common in organic chemistry but the situation frequently arises in enzyme catalyzed processes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/82fbd4c9-7838-49ee-b0cd-d912ffb7e5b2/First_order_V1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out In a first order reaction, there is one molecule of reactant in the rate determining step. If the concentration of the reactant is doubled, so the rate of the reaction will double. If the concentration is halved so the rate of reaction is halved. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1d71cd2c-dc6e-49f1-b630-4dd3990918e5/Second_order_V1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out In a second order reaction, there are two molecules of reactant in the rate determining step. If the concentration of the reactant is doubled, so the rate of the reaction will quadruple. If the concentration is halved so the rate of reaction is quartered. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fa4c14f8-62ed-4e30-a9f2-3100174c78c6/Cyanohydrin_formation.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Cyanohydrin formation is a typical organic reaction. It involves two elementary steps, the first is nucleophilic addition of a cyanide anion to a carbonyl group and the second is a proton transfer. The first step is the rate determining step. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2049fba2-7e0e-4439-8390-a82b37fb10a2/Cyanohydrin_Formation_rate.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Cyanohydrin formation and the rate equation for the simple, textbook, version of the reaction mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8d1305ae-9b8b-481a-a667-3864324acc0f/Overall_Order_general.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The overall order of the reaction is the sum of the superscripts (or exponents) but you can also talk about the order of the reaction with respect to anyone of the reactants. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ba8f22ac-68f4-4a56-8807-d481b2e490f4/Cyanohydrin_formation_Energy_Profile.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Compared to most steps, proton transfers are fast, they have a low activation barrier. They are rarely the rate determining step and organic chemists can be annoyingly inconsistent about where and when they add the proton transfer (and between which species). Ultimately, this is not a problem (as they are so fast). This example shows cyanohydrin formation with cyanide anion attacking a ketone followed by protonation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e3d3f5c3-ba9e-4e36-9219-a844807b08ee/Rate_amide_hydrolysis.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The base-mediated hydrolysis of an amide is a third order reaction involving the amide and two molecules of hydroxide, but this doesn't mean what you might (at this stage at least) think it does. In fact, hydroxide doesn't even appear in the rate determining step. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1392006e-fb70-4a31-815d-bff9dc05d25d/Amide_hydrolysis_V1.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A reaction profile for base-mediated hydrolysis of an amide (incomplete mechanism as there is a proton transfer from water to the amide anion (ammonia anion) NH2– that hasn't been included as it comes after the rate determining step and isn't important). This shows that the rate determining step is first order, involving the collapse (or elimination) of the dianion of the tetrahedral intermediate. This enables the amide anion, which is a poor leaving group, to be eliminated. It is a contentious mechanism (and not the one I included in my summary on the reaction of carboxylic acid derivatives) but it is useful in showing how we can use rate equations and how they can mislead the unwary. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7718cb83-2d84-40b1-b862-3b8b6094ad9a/Third_order_equation.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out You can determine the rate equation in terms of the starting reactants even when they are not involved in the rate determining step. This achieved by assuming that the earlier, faster steps, are equilibria processes (their activation energy is lower so this isn't an awful assumption), and then using the equilibrium expressions to give the concentration of the key intermediate in terms of the reactants. This can lead to third order expressions like the one found for this hydrolysis experiment. This example was pinched from the Clayden, Greaves & Warren Organic Chemistry textbook (which if you like organic chemistry you should buy it … I have two copies so don't feel massively guilty in using one of their examples (and I've now referenced them)). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ec2cdefc-7153-4d20-be3c-24f994fd7566/Summary1_Collision_theory.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out The three criteria for a successful reaction in collision theory. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a61b5b91-7582-4bad-a1f8-22d5210a8157/Summary2_Increasing_rate.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out According to collision theory there are a number of ways of increasing the rate of a reaction. You can in crease the concentration and this will increase the frequency of collisions. You can increase the temperature and this will increase the frequency of collisions and the proportion of successful collisions by giving more molecules sufficient energy to overcome the activation energy. Finally, you can add a catalyst and this lowers the activation energy so that more molecules have sufficient energy and therefore there are more successful collisions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1075d501-abe9-44ef-8823-4ea01af1e80a/Summary3-reaction_profile.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out A reaction profile showing the progress of a reaction. The top example shows a reaction that has two elementary steps. It passes through an intermediate, a chemical species that exists and can potentially be observed or even isolated. Each elementary step has a transition state. This is the perfect arrangement of atoms for a reaction and it has a definitive structure involving the partial formation and cleavage of bonds. It has no lifespan and a reaction only passes through a transition state. The difference in energy between a species and the transition state is the activation energy. This is the barrier to a reaction. The largest activation energy corresponds to the rate determining step. The Hammond postulate gives an idea of possible structure of a transition state. It states that the transition state resembles the structure of the stable species (reactant, intermediate or product) that it is closest in energy to. If it is closest to the starting materials it is known as an early transition state, if it is closer to the product then it is a late transition state. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cc111560-a58f-4e7e-a8fb-7eaa68402b64/Summary4_General_rate_equation.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f899b036-0cc9-4525-beaf-e48d410cf883/Summary5_First_order.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out In a first order reaction, the rate of reaction is directly proportional to the concentration of only one reactant. This can occur when there is only a single reactant that does not interact with any other molecule in the rate determining step (on the left) or when the rate determining step only includes one of the molecules found in the reaction and any other molecules present in the balanced equation reaction with an intermediate (on the right). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c87a2379-01d9-44ba-8afe-4b9cbee73dfb/Summary6_second_order.png Blog - Simplified Rates of Reaction from an Organic Chemist - Make it stand out In second order reactions there are two molecules in the rate determining step. These can be two identical reactant as on the left or two different molecules, as on the right. In the reaction on the right, the overall reaction is second order but the reaction is first order with respect to A and first order with respect to B. https://www.makingmolecules.com/blog/conjugate monthly 0.5 2023-08-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9ca232d1-6e5c-4bcb-9468-5eb6c347abda/Intro-Aromatics.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Aromatic rings such as benzene are normally nucleophilic but, by the addition of electron withdrawing groups it is possible to make them into the electrophile and they can be attacked by a suitable nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bf9953af-483a-43cf-a331-f356c2e18846/Intro-Alkenes_both.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Like aromatic rings, alkenes can be either nucleophiles or electrophiles. Like aromatic rings they are nearly always nucleophiles (even the α,β-unsaturated ester above will react with bromine), but if they have electron withdrawing groups attached they can be electrophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9e409d5-e723-42f8-b6b1-d02c466cc5d0/Examples_conjugate_addition.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Three examples of Michael additions or conjugate additions or 1,4-additions. The key to each reaction is that the alkene is in conjugation with a carbonyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1c736fd2-6eaa-4af0-b3c8-560a1e1570c1/terminology.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Conjugated alkenes have a number of different names. They can be called α,β-unsaturated carbonyl compounds as the alkene, the double bond or unsaturated (doesn't have the maximum number of hydrogen atoms possible) is between the α and β carbon atoms. If the alkene was one atom along, a β,γ-unsaturated system it would not reacted in a Michael addition as it would not be conjugated. Alternatively, the atoms can be numbered from the higher priority oxygen. This makes the β-carbon that is attacked by the nucleophile, carbon 4. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5df022ec-c3de-4267-94ea-f15570b70350/Addition_Step1.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Step 1 of the conjugate addition is nucleophilic addition to the activated alkene. This leads to an enolate (or similar species). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42e1f19b-2cc1-4f38-9dc2-f8933989eea0/Protonation_enolate.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The second step of conjugate addition involves proton transfer. In this example this is required to deprotonate the ammonium cation and protonate the enolate. In many examples, step 2 is simply the protonation of the enolate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eff2acf5-2760-4cb8-88fd-b52f8f11e859/Enol_tautomerization.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Yet another mechanism to form the product involves protonation of the oxygen to give an enol. The enol undergoes tautomerization (and let's be honest, there are multiple mechanisms for this process as well) to give the product. This just adds extra steps and seems totally unnecessary unless ... https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/be3110e6-80cf-4943-8eac-a3480091a182/Acid_promoted_chlorination.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Some conjugate additions can be accelerated by the addition of acid. This leads to protonation of the electrophile with the new, cationic species, being more electrophilic. Addition occurs as normal to give the enol directly. A series of proton transfers cause tautomerization and the formation of the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/82a1f19d-2a54-4f2d-a3e2-c7e94cd7e713/Resonance_part.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The resonance structures of a typical enone show why the alkene is polarized and activated towards nucleophilic attack at the β-carbon (4 position). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a57ce40b-dd24-4775-9d0d-e7df3d416157/General_mechanism.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The general mechanism for a conjugate addition involves two steps. The first is addition of the nucleophile to form an enolate. The second step is a proton transfer that returns a neutral species with the strong carbonyl group intact. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8dd766cc-e6de-4951-88b8-7a1db195e3ba/1_2_vs_1_4_addition.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The conjugated carbonyl group polarizes the alkene and makes it electrophilic but it also adds a second electrophilic center to the molecule. The resonance structures show that the molecule has two electrophilic centers, the carbon of the carbonyl group (carbon 2) and the β-carbon of the alkene (carbon 4). A nucleophile can add directly to the carbonyl group to give the product of 1,2-addition or it can participate in conjugate addition to give the 1,4-addition product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6224bfdd-14d5-4f0f-987b-11433e2cb9ca/Kinetic_plot.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out A cartoon plot showing the difference between the kinetic and thermodynamic product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56bfa20a-0d3f-45bb-a24f-dce351b79484/Cyanide-Two_products.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out At low temperature the addition of cyanide to an enone favors formation of the cyanohydrin. At higher temperatures, the initial reaction becomes reversible and the thermodynamically more favored molecule becomes the predominate product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/809e4833-e7bd-4dc3-aded-7ae720439b83/Cyanohydrin_reversible.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Heat the reaction of an enone with the cyanide anion and there is sufficient energy to make cyanohydrin formation reversible. Now the slow, but irreversible 1,4-addition becomes more important. Given sufficient time, the majority of compound will be syphoned down this pathway to give the thermodynamic product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/91aa75e6-057f-4a43-9a2a-23503df927b0/1%2C2-Addition_BuLi.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out A nucleophile that is a strong base (it has a weak conjugate acid) will undergo irreversible direct addition to the carbonyl group or 1,2-addition. This is an example of a reaction under kinetic control. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d7f59d84-1d13-4a14-bd58-6719df3b4400/1%2C4-Addition_ROH.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The addition of alcohols, which are weak bases, predominantly gives the product of 1,4-addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/41ca8c77-09f5-42dc-bb2a-c5e2f50244fe/Addition_beta_keto_ester.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The conjugate addition of a resonance stabilized nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2fbbde6-e7b0-47e0-8df6-8c2cf04cc610/Grignard-Cuprate.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out A Grignard reagent is a hard nucleophile and it is involved in 1,2-addition to give an alcohol. Add copper to the reaction and you create an organocopper reagent. These are soft nucleophiles and they participate in conjugate addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3e79aa5e-4a2a-40d0-a89d-da556fbb7c15/Carbonyl_structure.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Changing the carbonyl-containing functional group can alter the 1,2- versus 1,4-addition selectivity. More reactive carbonyl groups, like aldehydes encourage 1,2-addition while less reactive carboxylic acid derivatives, such as amides, encourage 1,4-addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b207ffe5-224a-4805-b1d9-c960c060e7b7/Addition_nitro_alkene.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out An example of the conjugate addition of a nucleophilic to a nitroalkene. The mechanism is the same as the addition to an enone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6497e6ab-5858-4017-b433-0ff4b244a343/nitroalkene_resonance.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Resonance structures of a nitroalkene showing that the β-carbon is the electrophilic carbon due to the π electrons being dragged towards the electronegative oxygen atoms. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d99dad98-2cfd-40d1-9d7d-aeda26496e51/Addition_nitrile_alkene.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The addition of a nucleophilic amine to an electrophilic alkene activated by being in conjugation with a nitrile group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9c288cc6-a707-4df9-9d8c-2f774e1cd07c/Addition_Vinylsulfone.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The addition of a nucleophilic thiol to an electrophilic vinylsulfone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/50cc61f2-eb36-4411-8baf-01eb1b6ad067/butadiene.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The π orbitals for 1,3-butadiene. On the left is the 'electron in a box' representation that shows the wavefuntion. In the middle is the more 'normal' representation used by organic chemists then there is a 'top down' view that tries to show the relative size of the coefficient on each atom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1292ff16-4c71-4f2b-a4fc-9a2394ff7eb5/LUMO_enal.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The frontier molecular orbitals of an enal are very similar to those of 1,3-butadiene (except the HOMO is now the non-bonding lone pairs of electrons and are not shown in this diagram). The other difference is that the polarization of the bond changes the size of the coefficients of the orbitals (a good background to this can be found in Ian Fleming’s excellent textbook). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1cc0876e-adf5-4291-ae9e-7c1862500ccb/Orbital_overlap.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out The HOMO of the nucleophile will overlap with the LUMO of the electrophile. Soft nucleophiles will have a large coefficient on their HOMO as the charge is diffuse, this will overlap with the carbon with the largest coefficient in the LUMO of the Michael acceptor. This is on the β-carbon (carbon 4). Hard nucleophiles, with a smaller coefficient will overlap the slightly smaller coefficient on the carbon of the carbonyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9d935aef-bd2a-44a0-b71b-3d68dae29023/Summary_Michael_acceptors.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Examples of Michael acceptors. These are conjugated alkenes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8ebaff9c-8d5b-4a9f-b965-29d2d16025ff/nucleophiles.png Blog - Conjugate Addition (1,4- or Michael Addition) - Make it stand out Examples of nucleophiles for conjugate additions. https://www.makingmolecules.com/blog/benzyne monthly 0.5 2023-07-24 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/53a789b4-f29e-452a-b0f4-2aa2cbcb4f05/Intro-Other_substitutions.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Two possible reactions that bring about nucleophilic aromatic substitution. The top reaction is classical nucleophilic aromatic substitution involving an activated benzene ring that has a leaving group either ortho or para to an electron withdrawing group. The reaction proceeds by an addition-elimination mechanism and the Meisenheimer complex. The second reaction is closer to SN1 substitution. It starts from a diazonium salt that eliminates to give an aryl cation. This is trapped by the nucleophile in an elimination-addition mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/03d70695-44e0-4a3b-bd0b-0a4e5aa9276d/Phenol_synthesis_intro.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The synthesis of phenol from chlorobenzene. Nucleophilic substitution occurs through an elimination-addition mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/93350d29-ab3a-427c-b7d9-ce05faad4134/Formation_meta_para_aniline.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The reaction of p-bromotoluene with sodamide to give 4-methylaniline (para-toluidine) and 3-methylaniline (meta-toluidine). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/afb15bf0-eb0f-4b92-8651-bd3d13314870/Benzyne_formation.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The formation of benzyne by deprotonation ortho to a leaving group and then elimination (step 1). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/155b88c7-e4fb-4b99-9381-ea0e2fa595cd/Benzyne_structure.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The structure of benzyne. Benzyne has a triple bond or alkyne in the ring. This is made up of a σ bond, and two π bonds, one of which is 'normal' being formed from the overlap of 2p orbitals. The other is 'abnormal', it is made from the weak or poor overlap of two sp2 orbitals that are splayed away from each other. This puts the new π bond outside the ring and perpendicular to the π system that gives the ring its aromaticity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f82a961f-f1d1-4873-965d-f8ccf8560fce/Benzyne-resonance.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Potential resonance structures for benzyne. These reveal that the triple bond is more electrophilic than normal alkynes. While the resonance structures are useful, the structure of benzyne is closer to a triple bond, just a very weak triple bond! https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c915446d-d177-454a-a791-a1d0cf62cdf6/Benzyne-Addition_step.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The second step of the process is the addition of the nucleophile to the benzyne. This gives an aryl anion that is protonated to give the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/35a216c2-75f6-4c2e-9817-4ac1d021b63a/Deprotonation-protonation.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The formation of benzyne requires strongly basic conditions. This means any acidic protons will undergo deprotonation. At the end of the reaction it is necessary to neutralize the reaction mixture with acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e0db7cdc-7388-4e07-94fa-9eb1da2e6267/Two_regioisomers.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The formation of the two isomers of toluidine (methylaniline) can be explained by the aryne intermediate. The nucleophile can attack either end of triple bond to give the two different isomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dc7394ac-1a74-4ec1-b7a5-931eb86860fb/Complete_mechanism.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The complete mechanism for nucleophilic aromatic substitution proceeding through a benzyne/aryne intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dc11d1d2-71fa-4957-a3fb-fd7019f04ad6/benzyne_vs_aryne.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Benzyne is derived from benzene. Arynes are all the other aromatic derivatives. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/05a9fc04-ae6b-494f-aa15-311e7434d8c4/Example_inductive_effect.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The strong electron-withdrawing effect of the trifluoromethyl substituent slightly encourages the formation of the para substituted isomer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e83e4adf-bb8e-4b69-aeb2-c252f91f3ec5/CF3_directing.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The slightly selectivity in this substitution reaction can be understood by considering the stability of the anionic intermediate formed on addition of the nucleophile. If the nucleophile adds to the meta position the anion is as far from the stabilizing effect of the trifluoromethyl group as it is possible to get. If the addition occurs at the para position, the anion will be meta and this is closer to the inductive effect caused by the fluorines. It is more stable and is favored. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0382bce7-3dba-443e-ba8c-f45964fd43bf/Steric_effects_reaction.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Substitution of ortho-bromoanisole with tert-butoxide gives predominantly the meta product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/aa256997-e24b-4298-9cd9-ffc4dc958d40/Inductive_explanation_2.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out The meta selectivity can be justified by the inductive argument. The nucleophile adds to form the anion closest to the electronegative oxygen atom as this is the more stable anion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4e0fd97e-a9c1-49b3-8149-7a99a6c581b9/Steric_explanation_2.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Steric hindrance can also influence the regioselectivity of nucleophilic attack. The nucleophile avoids interaction with the ether if it attacks at the meta position. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4ffaf351-05d3-48b8-b9b4-625daf7b7bdf/Summary_Substitution.png Blog - Benzyne, Arynes &amp; Nucleophilic Aromatic Substitution - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://www.makingmolecules.com/blog/nucleophilicaromaticsubstitution monthly 0.5 2023-07-10 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b8a2b256-38e7-4ff8-94b1-42ae92bb187a/Bromination_Intro.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Benzene is a reasonable nucleophile and will attack activated electrophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17b0d0db-eb2d-43ca-8447-b45a1962bf76/Impossible_substitution.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Direct substitution of the bromide with a hydroxide anion is impossible as the aromatic ring is electron rich and repels the nucleophile and because it is impossible for the nucleophile to approach the σ* antibonding orbital due to the presence of the ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ab9f505e-8f33-47a0-af78-c6a7b83d599a/Example_SNAr.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Nucleophilic aromatic substitution involving hydroxide anion attacking the electrophilic aryl chloride. The substitution occurs by an addition-elimination mechanism. In this example an extra neutralization step is necessary as the phenol will be deprotonated by the nucleophile (base). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/86510282-b6a3-41fd-a7c1-6bb892131348/Chlorine_substitution_intro.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The hydroxide anion substitutes the chlorine atom through an addition-elimination mechanism. Step 1 involves the addition of the nucleophile to the electron poor (two electron withdrawing groups) aromatic ring. The electrons flow out of the ring onto the nitro oxygen atoms. Step 2 is an elimination. The electrons flow back into the ring, regenerating the aromatic ring. The extra electrons are removed on a suitable leaving group. In this example, the basic conditions would also lead to deprotonation of the product and it would be necessary to neutralize the reaction to get the desired product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/12f9452c-e3da-4d9b-9854-cce4b01a1d5e/General_mechanism.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The mechanism of nucleophilic aromatic substitution. This is a two step process. Step 1 is nucleophilic addition with the nucleophile attacking the electron deficient aromatic ring. This ring invariably has at least two electron withdrawing substituents. The electrons must flow out of the ring and onto one of the electron withdrawing groups. Step 2 is elimination. The electrons flow back into the ring and onto the leaving group that can then take them away. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/49893aca-4a82-43bf-b812-82797a2f6ca0/Meisenheimer_complex.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The first step of nucleophilic aromatic addition is addition of the nucleophile to the an electron poor aromatic ring. This step adds two electrons to the molecule and breaks the aromaticity. This is energetically disfavored as there is a lose in aromatic stabilization. The resulting anion is stabilized by resonance and is sometimes called the Meisenheimer complex. This is the anionic equivalent of the cationic intermediate in electrophilic aromatic substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6ce480b7-c58e-4f6d-ab84-72223d4a5da3/Similarities_cation_anion.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The similarities between nucleophilic aromatic substitution and electrophilic aromatic substitution should be apparent. The first step involves nucleophilic addition either of a nucleophile to the ring or of the ring to a suitable electrophile. This step destroys the aromaticity so is slow and disfavored. The resulting anionic or cationic intermediate is stabilized by resonance but is still higher in energy than an aromatic or fully delocalized system. The next step will be similar for both ... https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/454e0b4c-4036-4047-8dbe-4f820d489f53/Sulfone-EWG.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Sulfones are good electron withdrawing groups for nucleophilic aromatic substitution. The amine attacks the electron poor ring and the electrons flow out of the aromatic ring and onto the electronegative oxygen atom of the sulfone. In the last step the electrons flow back into the ring and restore aromaticity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2fdf2c9d-1eb7-4f04-88f3-d9cbe45aecbf/Leaving_grou_sulfone.png Blog - Nucleophilic Aromatic Substitution - Make it stand out A sulfone can be a leaving group in electrophilic aromatic substitution. It is slightly electron withdrawing (which activates the ring) and forms a resonance stabilized conjugate base (stable anion). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a0ee548e-67e0-4fe3-a713-c55b52020915/Leaving_grou_fluoride.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The electronegative fluorine activates the ring to nucleophilic addition in step 1. It makes the ring more electron deficient. It is then ok to kick it out in the second step as it can stabilize an anion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dffefa03-f43d-4fcb-9c7f-8080a1c159a3/Position.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The leaving group and the electron withdrawing activating group must be either ortho or para to each other. This pattern allows the incoming electrons of the nucleophile to be pushed out onto the activating group giving the anionic intermediate extra stability. If the substituents are meta, then the electrons are only stabilized within the ring, which is less favorable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c29c0314-9c73-4c3f-81ff-832eb278100e/DNP.png Blog - Nucleophilic Aromatic Substitution - Make it stand out 2,4-Dinitrophenylhydrazine or DNP can be synthesized by nucleophilic aromatic substitution. Step 1 involves the nucleophilic addition of hydrazine to an aryl chloride leading to an anionic intermediate with the negative charge stabilized outside the ring. After a proton transfer, step 2 is the elimination, where the electrons flow back into the ring and kick out the chloride anion. The process is addition and elimination. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dfe69acd-cf7b-484f-901d-a0b2990a1063/Diazonium-Substitution_example1.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The formation of phenol from a diazonium salt by nucleophilic aromatic substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4b1e6b0b-ef5a-463c-8cb7-5eade3f8b257/nitrosonium.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Formation of the powerful electrophile, the nitrosonium ion. The nitrite anion undergoes a series of protonations, first to give nitrous acid, then a cationic species that loses water to give the nitrosonium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/761d8861-2a58-4aef-8c2b-1fec50e9bfb7/diazotization.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The mechanism for diazotization or formation of the diazonium salt looks long but is relatively straight forward and involves reaction steps you have seen many times before. The first step is nucleophilic addition to the activated electrophile, the nitrosonium ion. There are then a series of proton transfers that create an oxonium ion. Finally, this is eliminated to give thee diazonium species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/87564211-15ff-48f3-b1ea-8bb6b83e4518/Mechanism_diazo_substitution.png Blog - Nucleophilic Aromatic Substitution - Make it stand out The mechanism of nucleophilic aromatic substitution of diazonium compound involves the elimination of nitrogen gas to give an aryl cation. This is a powerful electrophile which is rapidly attacked by a nucleophile. Proton transfer (in this case) then gives the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8382e92f-f948-4cb6-8b55-87119de66340/Diazo_scope.png Blog - Nucleophilic Aromatic Substitution - Make it stand out Diazonium salts readily loss nitrogen to give a cation that can then react with the appropriate nucleophile to give nucleophilic aromatic substitution. If the nucleophile is a copper(I) reagent then the reaction is probably related to the Sandmeyer reaction and proceeds by a radical mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ad3fd95e-b61d-4891-89a9-a11e23b1cd3c/Sandmeyer_V1.png Blog - Nucleophilic Aromatic Substitution - Make it stand out One mechanism for a Sandmeyer-like reaction involves the copper(I) salt reducing the diazonium salt. This causes the copper(I) to be oxidised to copper(II). The copper(II) species probably picks up a counterion. The neutral diazo radical undergoes an elimination to give the aryl radical. This adds directly to the copper(II) species to add the ‘nucleophile’ and regenerate copper(I). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/30491c9e-d2bf-497e-b88b-084a5344d588/Sandmeyer_V2.png Blog - Nucleophilic Aromatic Substitution - Make it stand out A second potential mechanism starts in the same manner. Once the aryl radical is formed, it adds to the copper salt to give a copper(III) species or organocuprate. This undergoes reductive elimination to give the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5c5e59f2-1b6d-41c8-9399-7b3c123c70ef/Example_use_Sandmeyer.png Blog - Nucleophilic Aromatic Substitution - Make it stand out An example of the Sandmeyer reaction being used in the synthesis of a pharmaceutical. https://www.makingmolecules.com/blog/electrophilic-aromatic-substitution monthly 0.5 2023-06-19 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cbb790ca-7d9f-4579-8dfe-4bbf586d5712/Bromination_alkene_intro.png Blog - Electrophilic Aromatic Substitution - Make it stand out The stepwise bromination of an alkene involves the nucleophilic alkene attacking bromine to give a bromonium ion. This is attacked by the bromide anion to give the product of anti addition. All atoms of the starting materials are included in the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fec14bfb-c935-4b89-91ae-916574be5590/Non-Reaction_PhH_intro.png Blog - Electrophilic Aromatic Substitution - Make it stand out Benzene does not react with bromine (on its own). Again, this shows why you must be careful when you look at Lewis structures (or resonance structures), they do not always tell the whole story. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/65bdf102-5ec4-4edb-8e34-e50943e921bf/Bromination_intro.png Blog - Electrophilic Aromatic Substitution - Make it stand out The bromination of benzene in the presence of a Lewis acid occurs to give the product of a substitution reaction not an addition (atoms are exchanged between the reactants). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f69c7e2c-e5ba-472d-a559-d4ac531a0794/Bromination_balanced_eq.png Blog - Electrophilic Aromatic Substitution - Make it stand out Highlighting the substitution of a hydrogen atom by bromine during electrophilic aromatic substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6c0908c3-4036-4e28-86c1-4c584f13d927/Bromine_activation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Step 0 - The activation of bromine with a Lewis acid (AlBr3). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/46325b74-8f78-43f4-9d7a-7d2e57e71951/Bromination_nuc_addition_V2.png Blog - Electrophilic Aromatic Substitution - Make it stand out Step 1 - Nucleophilic addition. The nucleophilic aromatic ring attacks the activated electrophile to form a cationic intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/586183dd-9cf4-4254-a9ec-98c5d3fe8ed1/Bromination_intermediate.png Blog - Electrophilic Aromatic Substitution - Make it stand out The arenium ion, σ complex or Wheland intermediate. This is not aromatic due to the sp3 carbon. The charge is stabilized by delocalization but you should remember that it is focused at the three carbons indicated in the resonance structures rather than just spread everywhere (the resonance hybrid). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fec35869-9671-44e4-8269-9c36e79c4e57/Step3-deprotonation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Step 2 - deprotonation (or proton transfer) removes a proton and re-forms the aromatic ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/62f328df-161b-4509-a674-61792a4ce688/Complete_bromination_mechanism.png Blog - Electrophilic Aromatic Substitution - Make it stand out The complete mechanism for the bromination of benzene. There are three steps: Step 0 is activation of bromine, the electrophile. Steps 1 & 2 are electrophilic aromatic substitution (SeAr) with Step 1 being nucleophilic addition to give the cationic intermediate. Step 2 is deprotonation or proton transfer, which returns the aromatic ring. Overall, a bromine atom has substituted a hydrogen atom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6375594d-53bf-400d-9123-7fa1bfc52cd5/Orbital_bromination.png Blog - Electrophilic Aromatic Substitution - Make it stand out The frontier orbitals (or valence bond model) for the bromination of benzene. This shows the formation of the π-complex followed by the addition step that leads to breaking of aromatic ring and the synthesis of the cationic σ-complex. The lowest drawing shows proton transfer to reform the aromatic ring and lead to the product of substitution. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77cdfd9e-7c5a-4ede-9830-1ea56dfbd0f6/positions.png Blog - Electrophilic Aromatic Substitution - Make it stand out Naming the positions around a benzene ring relative to a substituent. The positions are either given the names ortho, meta, and para, or are numbered (given in blue inside the ring with the original substituent being position 1 and then other substituents having the lowest possible numbers). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c4a2984a-5ea8-4a3c-8ae9-cdd7fdeb0468/Bromination_Phenol.png Blog - Electrophilic Aromatic Substitution - Make it stand out The bromination of phenol occurs at room temperature without the addition of a Lewis acid. It is virtually impossible to stop multiple additions at this temperature. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/32cf3ada-d1cc-4e3f-8a49-5f5c04874042/Bromination1_Phenol.png Blog - Electrophilic Aromatic Substitution - Make it stand out The bromination of phenol occurs at room temperature without any Lewis acid to activate the electrophile. It starts with bromination of the para position through the standard two step electrophilic substitution mechanism with nucleophilic addition followed by proton transfer. But the reaction does not stop here … https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/977c7ac4-299c-46af-b1ae-3501327db9f7/bronination2_phenol.png Blog - Electrophilic Aromatic Substitution - Make it stand out Delocalization of the oxygen lone pair is such a good activating group that bromination does not stop after a single reaction but proceeds until three bromine atoms have added to the aromatic ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ed17f613-c0b1-4cc4-86c8-38066a91495c/Phenol_resonance.png Blog - Electrophilic Aromatic Substitution - Make it stand out The resonance structures of phenol show that there is an increased concentration of electrons on three carbon atoms. This means those three carbon atoms at more electron rich and hence are more nucleophilic. Reaction with an electrophile occurs here. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/010240b5-8998-4932-a004-aa391a39e277/Bromination_aniline.png Blog - Electrophilic Aromatic Substitution - Make it stand out Aniline is even more reactive than phenol, due to nitrogen being less electronegative. It is brominated three times even at low temperatures. It is virtually impossible to stop multiple bromination simply by changing the reaction conditions and it is necessary to change the structure of the molecule. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4dfa68a9-3a68-4858-850d-c768079be131/Bromination_anilide.png Blog - Electrophilic Aromatic Substitution - Make it stand out By converting aniline into an amide, its nucleophilicity is reduced. Now the nitrogen lone pair is also delocalized over the carbonyl group. This means it is less available to activate the aromatic ring and bromination only occurs once. The addition is in the para position for steric reasons. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4c6e09e3-c073-4cdf-9127-686d31bba139/Bromination_toluene.png Blog - Electrophilic Aromatic Substitution - Make it stand out The bromination of toluene is faster than that of benzene. Alkyl groups are activating groups. They are ortho,para-directing. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42a67c64-2124-4007-aeef-e4af3e72359a/Bromination_toluene_orhto_para.png Blog - Electrophilic Aromatic Substitution - Make it stand out The methyl group of toluene is an o,p-directing group. The preference for attack in these two positions can be explained by the stability of the cationic intermediate and that attack at these two positions allows the cation to be drawn on the tertiary position. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cd35e74d-6338-462f-a8a7-bf6feb94fe1a/bromination_meta.png Blog - Electrophilic Aromatic Substitution - Make it stand out Bromination at the meta position lacks stabilization of the intermediate carbocation on the tertiary position. This means it is less favored (disfavored even). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/340104a0-6c87-4af1-8e53-cec9b39283bb/Hyperconjugation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Hyperconjugation of the σ electrons activates the ring by making it more electron rich. The effect occurs over a short distance and the ortho position is more activated than the para position. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cfb015f2-3daa-4a39-8f77-56e16dedbeb1/Hyperconjugation_stabilized_cation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Alkyl groups can stabilize the cationic intermediate if a resonance structure places on the adjacent carbon (gives a tertiary carbocation). This can occur if substitution occurs in either the ortho or para positions. If the electrophile adds to the meta position then there are no resonance structures in which the empty 2p orbital can overlap with a σ bond of the alkyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/55c4221c-5377-4e08-b8e7-7451ccee1947/Bromination_nitrobenzene.png Blog - Electrophilic Aromatic Substitution - Make it stand out The bromination of nitrobenzene occurs under forcing conditions (the reaction is heated over 100 °C), and bromination occurs at the meta position. Both the deactivation of the ring and the directing effect are due to the electron withdrawing nature of the nitro group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/96525164-0977-418d-b995-60ecf87d13ad/Nitrobenzene_resonance.png Blog - Electrophilic Aromatic Substitution - Make it stand out The nitro group is electron withdrawing and deactivating. The resonance structures of nitrobenzene reveal that the positive charge can be distributed over three carbon atoms, the ortho and para positions. The resonance hybrid at the bottom highlights the most electron rich (meta) carbon atoms. These will act as nucleophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e8579b67-7f98-4b3d-940f-401f13f104c4/Bromination-Nitro-regio.png Blog - Electrophilic Aromatic Substitution - Make it stand out Electron-withdrawing groups can also be considered ortho,para-avoiding groups instead of meta-directing groups. If you inspect the various resonance structures that can be drawn for the cationic intermediate, it becomes clear that only the ones formed from reaction in the meta position avoid the disfavored interaction of having the cation adjacent to the electron withdrawing group (or in this example having two positive charges on adjacent carbon atoms). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9408026e-a0ba-48ba-bc86-ce24bd79627d/Halogen-directing.png Blog - Electrophilic Aromatic Substitution - Make it stand out Halogens are the odd exception to our normal guidelines. They are electron-withdrawing groups that deactivate the ring by an inductive effect, but they are also ortho,para-directing through delocalization. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f446fd50-51c5-4a6f-a5d2-a18e3af95b0e/Directing_summary.png Blog - Electrophilic Aromatic Substitution - Make it stand out A chart summarizing the various effects of adding substituents to a benzene ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/70ed710b-0930-47cd-a257-080b733280d8/General_Rct.png Blog - Electrophilic Aromatic Substitution - Make it stand out Electrophilic aromatic substitution is a general reaction. There are invariably three steps. The first (step 0) is activation of the electrophile, this is necessary for all but the most activated benzene derivatives. Step 1 (of the actual substitution reaction) is nucleophilic addition in which the aromatic ring attacks the electrophile. This breaks the aromaticity of the ring and creates a cation intermediate. Step 2 is deprotonation or proton transfer and this regenerates the aromatic ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c7cde12b-e157-4909-beaf-acf30722302f/Nitration_reaction.png Blog - Electrophilic Aromatic Substitution - Make it stand out Nitrobenzene can be formed by nitration of benzene with a mixture of nitric and sulfuric acids. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9916e52c-7384-49f6-b293-0441c53819be/Nitration_activation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Nitric acid is activated by protonation with a stronger acid, most commonly sulfuric acid. A dehydration process occurs to give a nitronium cation, the activated electrophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e5b84026-3fc4-447f-bc15-58fd95883da0/Nitration-Mechanism.png Blog - Electrophilic Aromatic Substitution - Make it stand out The nitration mechanism is another standard example of electrophilic aromatic substitution. The electrophile is activated in a prior step, this is followed by nucleophilic addition with the aromatic ring attacking the nitronium ion. The cationic intermediate is deprotonated in the second step to regenerate the aromatic ring and give the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/844a6a09-2329-484e-90fb-aea53a90dfeb/nitro-reduction.png Blog - Electrophilic Aromatic Substitution - Make it stand out The nitro group can be reduced to an amine and this provides a useful way to introduce the nitrogen atom onto an aromatic ring. It also offers opportunities to alter directing effects. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6351c06a-ba9c-4d2b-b6e0-c708caa3201b/Sulfonation_benzene.png Blog - Electrophilic Aromatic Substitution - Make it stand out The sulfonation of benzene to synthesize benzenesulfonic acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2856d666-e1e3-481e-a844-5fe69b170557/Complete_sulfonation_mechanism.png Blog - Electrophilic Aromatic Substitution - Make it stand out One of the possible mechanisms for sulfonation of benzene involves protonation of sulfur trioxide to create the activated electrophile. This participates in the standard electrophilic aromatic substitution mechanism. Arguably, sulfur trioxide is already sufficiently activated to take part in this reaction without prior activation. To draw this mechanism simply add step 0 the proton transfer to the end of the reaction sequence and protonate the sulfonate anion formed by nucleophilic attack on sulfur trioxide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/db4ad627-5cfb-4df9-bcde-464279ce9e86/Sulfonation_reversible.png Blog - Electrophilic Aromatic Substitution - Make it stand out The sulfonation of aromatic rings is an equilibrium process, that is the reaction can go both forwards (addition of the sulfonic acid) and in reverse (removal of the sulfonic acid). The position of the equilibrium can be controlled by the reaction conditions. Fuming sulfuric acid leads to sulfonation. Use of dilute sulfuric acid leads to removal of the sulfonic acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d5decbb3-8043-4c12-9f9c-e37fa6047c92/General_Friedel-Crafts.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Friedel-Crafts alkylation is the reaction of an alkyl chloride with an aromatic ring to give a new C–C bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/abd5dde5-d663-43c9-9283-f3e40a7d0fb5/Friedel-Crafts_alkylation_activation.png Blog - Electrophilic Aromatic Substitution - Make it stand out First the electrophile must be activated (Step 0). This is achieved by the formation of a carbocation (or complex that behaves as a carbocation). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ffdf816d-95a7-4583-bcfc-ec93d96910d6/Friedel-Carfts_Alkylation-mechanism.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Friedel-Crafts alkylation is another example of electrophilic aromatic substitution. The mechanism is identical to all the previous examples. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cb0d1d62-66b2-4121-9913-a32cc5535c05/Mulitple-Additions.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Friedel-Crafts alkylation adds an electron-donating alkyl group. The inductive effect (or hyperconjugation) feeds electrons onto the ring making it more nucleophilic and making the second addition faster. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a1f14fb8-545c-42d0-a3c2-ed6d1ecbf49c/Rearrangement-reaction.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Friedel-Crafts reaction of primary alkyl halides is notoriously problematic due to the instability of primary carbocations. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ddf27476-ef9b-4504-bb61-a5ca90da3e4e/Not_primary_cation.png Blog - Electrophilic Aromatic Substitution - Make it stand out Primary cations are hard to form and the Friedel-Crafts alkylation is more likely to occur through direct displacement of the appropriate Lewis acid adduct. I have called step 1 a nucleophilic addition so that it looks the same as all the other reactions (it is the same), but the reaction is technically a substitution as the aromatic ring replaces the metal complex … but this then confuses people as the reaction is still an addition-elimination (deprotonation) process. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ea920f0b-1dc3-42bd-9d82-69e66b22478f/Rearrangement_then_attack.png Blog - Electrophilic Aromatic Substitution - Make it stand out The precursors to primary carbocations can rearrange to give secondary (or tertiary) cations. This will happen prior to electrophilic aromatic substitution and leads to the major product of reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5fc1035a-62f9-491b-824c-3d1cfd849e48/Friedel-Crafts_acylation.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Friedel-Crafts acylation gives aromatic ketones (and carboxylic acid derivatives). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a0505955-4927-4c1d-bf00-b72d62dc6c3f/Friedel-Crafts_acylation_mechanism.png Blog - Electrophilic Aromatic Substitution - Make it stand out The mechanism for Friedel-Crafts acylation follows the same pattern as before. There is activation of the electrophile followed by nucleophilic attack and proton transfer. The advantage of the Friedel-Crafts acylation is that the acylium ion is stabilized so there is no rearrangement and the addition of a carbonyl group to the aromatic ring deactivates the ring to subsequent reactions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/37aa0554-ab4e-4a21-8252-230b76a520f0/Clemmensen.png Blog - Electrophilic Aromatic Substitution - Make it stand out The Clemmensen reduction converts ketones into alkanes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/62efc6f0-0a80-4e83-9bf9-adedf1c863fb/Complementary_directing.png Blog - Electrophilic Aromatic Substitution - Make it stand out Two substituents can direct reaction to occur at the same position. Such groups are complementary. Note now the name of the positions around the ring changes depending on the which group we are referring to. The ortho,para position is relative to the phenol hydroxyl group while the meta positions is relative to the aldehyde that causes this directing effect. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/874e46bf-59af-4278-bb41-7bba4f9839cb/Competitive_directing.png Blog - Electrophilic Aromatic Substitution - Make it stand out Both groups activate the ring to electrophilic aromatic substitution and both are ortho,para-directing relative to their own positions. The phenol directs the reaction as it is a stronger activating group, and bromination is ortho to the hydroxyl group and meta to the alkyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cf92e910-c8ce-4dfb-b4ce-5e692cf8b7a5/Activating_and_deactivating.png Blog - Electrophilic Aromatic Substitution - Make it stand out The strongest activating group, the one that donates more electron density into the ring will control the reaction. It controls the reaction as it encourages substitution. In the example above the phenol directs reaction to occur at either the ortho or para positions. The ortho position wins due to steric hindrance. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ea36361a-9775-4dfd-8bd8-c6b3a5de7afc/Nitration_anisole.png Blog - Electrophilic Aromatic Substitution - Make it stand out The nitration of anisole occurs predominantly at the para position due to steric hindrance slowing addition at the ortho position. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b3e33be5-aacb-4e7e-bb95-d110c618a6d0/Nitration_anisole_blocking_group.png Blog - Electrophilic Aromatic Substitution - Make it stand out Sulfonic acids can be used as a blocking group that prevents reaction at specific positions but can be removed at a later stage. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/025fe965-616a-486f-b855-566de6da17f9/Two_isomers_chloroaniline.png Blog - Electrophilic Aromatic Substitution - Make it stand out How could you selectively make each of these regioisomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1302e5e5-4f84-4583-8304-695e4660a7aa/Synthesis_p-chloroaniline.png Blog - Electrophilic Aromatic Substitution - Make it stand out The para-isomer is synthesized by first forming the amide. This prevents over chlorination and promotes chlorination at the para position as the amide is weakly activating, ortho,para-directing but the bulk of the acetamide hinders approach to the ortho positions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56fdd429-1e56-48e5-a1e6-5c2673468471/Synthesis_m-chloroaniline.png Blog - Electrophilic Aromatic Substitution - Make it stand out The synthesis of the meta-regioisomer starts from nitrobenzene. The electron withdrawing nitro group is meta directing, so delivers the chlorine to the correct carbon atom. Selective reduction of the nitro group (annoyingly, aryl halides can be reduced with metals in weak acids, so you must choose the correct combination, which can be determined from standard electrode potentials (something I hope I never have to discuss on here!)) gives the desired isomer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f0fb3e57-4c68-4e54-8b29-a6fc3b75bc3b/Friedel-Crafts-Directing_effects.png Blog - Electrophilic Aromatic Substitution - Make it stand out Switching between a ketone and an alkyl group allows control of regiochemistry. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/36a648e9-f03a-4947-b6cd-47adf16c5986/Summary1.png Blog - Electrophilic Aromatic Substitution - Make it stand out The common examples of electrophilic aromatic substitution and useful functional group interconversions of the resulting products. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ea5e814d-cb48-4fbf-ad7a-2d5039bbe6bb/Summary3.png Blog - Electrophilic Aromatic Substitution - Make it stand out A summary of activating and deactivating groups along with the position they direct reaction to. https://www.makingmolecules.com/blog/asymhydroboration monthly 0.5 2023-05-02 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/02f5ae62-7e4b-4478-a836-48a6d4cab802/Intro-Hydroboration-Oxidation.png Blog - Asymmetric Hydroboration - Make it stand out An example of hydroboration-oxidation. The reaction is regioselective and stereospecific. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/236663d4-6e3b-405e-971d-3c4f8c2ad01c/intro-Sterics.png Blog - Asymmetric Hydroboration - Make it stand out The transition state for hydroboration. For steric reasons, the boron adds to the least hindered end of the alkene. This avoids unfavorable repulsive interactions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1c837728-87a0-42ea-9ced-f5045878017a/hydroboration-pineneV2.png Blog - Asymmetric Hydroboration - Make it stand out The borane adds to the least hindered face of pinene. This is opposite the two methyl groups (shaded in grey), which block approach to the top of the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/089ec73e-835b-4547-a078-f6512b033f3c/Pictures_Pinene2.png Blog - Asymmetric Hydroboration - Make it stand out Representations of the three-dimensional structure of pinene and the alcohol that is formed on hydroboration-oxidation ((+)-Isopinocampheol). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/72aee5de-306f-48ea-91fe-fb4a3c0c6f30/Allylic-strain_propene.png Blog - Asymmetric Hydroboration - Make it stand out The two extreme conformations of propene. The favored conformation minimises A1,2 strain but at the expense of A1,3 strain. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2aa068f5-ef12-4b4b-944c-14db318d1add/but-1-ene.png Blog - Asymmetric Hydroboration - Make it stand out The main conformations of but-1-ene. The most stable conformation has the smallest allylic substituent eclipsing the hydrogen at the 3-position. The least favored conformations suffer from A1,2 strain with these substituents being eclipsed. It also shows that A1,3 strain can be important. Barriers to rotation are relative to 0 kJ mol^–1 for the most stable conformation and are taken from J. Am. Chem. Soc. 1985, 107, 5035. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ece8db2c-8bda-4683-8f96-cbe162de3ea1/pent-2-ene.png Blog - Asymmetric Hydroboration - Make it stand out The important conformations of Z-pent-2-ene. The relative energies are taken from David Evans' Chem 206 lectures (found HERE), with the exception of the gauche conformation, which is an approximation. The key interactions are now the A^1,3 strain between the allylic position and the methyl group on the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3d47da9a-d954-43d3-97d7-a4809ba14e13/Stable_pentene.png Blog - Asymmetric Hydroboration - Make it stand out Favored conformation of Z-pent-2-ene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ec940d99-39f1-403e-b871-10e08ac6230d/2-methylbut-1-ene.png Blog - Asymmetric Hydroboration - Make it stand out A^1,2 strain controls the barrier to rotation in 2-methylbut-1-ene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f5d0136e-4614-4a7a-9f34-d7772d7cd2d9/Monensin.png Blog - Asymmetric Hydroboration - Make it stand out The hydroboration-oxidation of an intermediate in the synthesis of monesin. The three most important conformations are shown as Newman projections. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/79553b33-883a-48da-bdc2-b4c1daf17ffb/General_A13_hydroboration.png Blog - Asymmetric Hydroboration - Make it stand out A summary of A1^,3 strain controlling the diastereoselectivity of hydroboration of an alkene with an allylic stereocenter. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cfe7832a-2466-447d-bd18-cfc0e933288e/ionomycin.png Blog - Asymmetric Hydroboration - Make it stand out Diastereoselective hydroboration-oxidation of ionomycin is an example of A^1,2 control and reagent control. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4735adbd-ba03-4d78-9ae1-b4bae3cf80d9/A1%2C2_strain_BH3_Example.png Blog - Asymmetric Hydroboration - Make it stand out A^1,2 strain controls the reaction of a 1,1-disubstituted alkene and a small borane. The disfavored conformation has an interaction between the larger hydroxyl group and the methyl group. The favored conformation places the hydrogen outside, effectively eclipsing the methyl group. The hydrogen is small and this interaction is unimportant. This does place the hydroxyl group inside but the small size of the borane means this is acceptable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/96026d86-27f6-4fc3-a6b1-86d4d727ef1b/A1%2C2_strain_BIG_BHR2_Example.png Blog - Asymmetric Hydroboration - Make it stand out When a larger organoborane is used A^1,2 strain is not the most important interaction and now the interaction between the inside group and the reagent becomes important. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/60bbc0c0-c52f-4ec6-8f17-9ddb0171f3da/11Alkene-A12_Strain_summary.png Blog - Asymmetric Hydroboration - Make it stand out A summary of the effect of changing organoborane on the hydroboration of 1,1-disubstituted alkenes with an allylic stereocenter. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/86539d8b-5763-4fac-8139-632ed28a1be6/Reagents.png Blog - Asymmetric Hydroboration - Make it stand out The two classic chiral hydroboration reagents, ipc2BH and ipcBH2. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9f24939a-7f1a-452a-bf1e-69b3d8c4e078/Tylonolide_example.png Blog - Asymmetric Hydroboration - Make it stand out Synthesis of two diastereomers of an alcohol. The choice of enantiomer of the organoborane determines which diastereomer is isolated. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/631c5e7f-69c5-4e02-a481-47e03a1fbf28/ipcBH2-addition.png Blog - Asymmetric Hydroboration - Make it stand out The smaller ipcBH2 reagent approaches a trans-alkene so that the boron adds to the least hindered end of the alkene and the isopinocampheyl unit is anti to other alkene substituent. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/707a5423-4a9f-4352-af48-8df3567ce9d4/Conformation_ipcBH2.png Blog - Asymmetric Hydroboration - Make it stand out A Newman projection showing the relative sizes of the substituents on the stereocenter attached directly to the boron atom. This gives an idea of the steric environment around the reactive BH2 center. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b5a41a90-b59e-4d05-9419-a3540c29d796/Conformation_TS_Addition_ipcBH2.png Blog - Asymmetric Hydroboration - Make it stand out The preferred face of hydroboration is controlled by the interaction between the ipc moiety and the R^E substituent of the alkene substrate. The favored conformation places the least sterically demanding part of the organoborane (the hydrogen atom) close to the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6d861bc2-193e-4b5c-8de5-916560b43654/Conformation_TS_Addition_ipcBH2_Cis_alkene.png Blog - Asymmetric Hydroboration - Make it stand out There is no selectivity with cis alkenes as the substituent is on the opposite side of the alkene to the reagent. If the reagent cannot interact with the alkene there is no communication of stereochemical information. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/787d1acb-cd15-4ade-ac26-8f3560f49a9f/icp2BH_conformation.png Blog - Asymmetric Hydroboration - Make it stand out This diagram attempts to show the conformation of ipc2BH in the transition state during addition to an alkene. This is not the ground state conformation of this molecule. I have tried to show that the C–H bond is eclipsing the large substituent of the isopinocampheyl ring, while the two medium sized substituents are eclipsed. One of the isopinocampheyl rings projects its bulk downwards while the other has the hydrogen in this position. This second ring behaves as if it had less steric bulk. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/620c7cda-6b84-49ff-9c50-3b25ca9ffdc1/ipc2BH-alkene-addition.png Blog - Asymmetric Hydroboration - Make it stand out The approach of ipc2BH and an alkene minimizes steric interactions. The interaction of the large isopinocampheyl ring with the alkene is minimized. As a result, reaction with the Z-alkenes tend to be more efficient as this allows the large ring and the substituents on the alkene to be anti. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e7575b1c-4e10-4b98-8d90-ecda4eb91975/Conformation_TS_Addition_Z-alkene_ipc2BH.png Blog - Asymmetric Hydroboration - Make it stand out The enantioselectivity is determined by which face of the alkene the organoborane approaches. This is determined by the minimization of steric interactions. The substituents of the alkene will be close to the so-called small ring of organoborane. The alkene will attack so that the hydrogen atom of the isopinocampheyl ring is in the inside position. https://www.makingmolecules.com/blog/antimarkovnikov monthly 0.5 2023-02-27 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3ee4b025-4465-4a7d-a139-4e05045e7a28/Intro_reactions.png Blog - Anti-Markovnikov Addition - Make it stand out Hydrohalogenation and acid-catalyzed hydration of alkenes favors Markovnikov addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77813d9c-2e25-463b-b255-7627a5a2ebab/Anti-Markovnikov_HBr_Addition_Version2.png Blog - Anti-Markovnikov Addition - Make it stand out When the addition of H–Br is performed in the presence of a radical initiator, such as a peroxide, the anti-Markovnikov product is favored. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/18cf1a8e-39c9-4d36-b0ea-945c810bfc5f/Initiation_Step.png Blog - Anti-Markovnikov Addition - Make it stand out The first step of a radical chain reaction is initiation. This is formation of the initial radical and creation of the radical chain carrier, the species the will propagate (perform) the productive part of the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/de9c2dc5-ad44-4946-b1c4-6ae80a65f873/Propagation_Steps.png Blog - Anti-Markovnikov Addition - Make it stand out The second set of steps are the propagation steps. These are the reaction steps that make the product. The chain carrier adds to the alkene to give a carbon-centered radical. The product is formed by hydrogen abstraction. This also regenerates the chain carrier, which then repeats the steps until all starting material is consumed or a termination step occurs. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7b730152-7d4f-4dfc-89b0-a0d3ac620be7/termination_steps.png Blog - Anti-Markovnikov Addition - Make it stand out Termination steps remove radicals from the chain reaction. These are just some of the possibilities. The initiator could also be involved. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ca6ae6de-45fa-4137-ae93-573bdf0c50dd/General_Chain_Reaction.png Blog - Anti-Markovnikov Addition - Make it stand out The complete radical chain mechanism for the anti-Markovnikov addition of HBr to an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/568254ac-89cf-4aee-8490-28645d5ec84d/radical_stability.png Blog - Anti-Markovnikov Addition - Make it stand out Factors influencing the stability of radicals, which are electron deficient species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4f845882-2e3f-4158-9ff0-d5fdd3ea47a4/Radical_regioselectivity.png Blog - Anti-Markovnikov Addition - Make it stand out Addition of the bromine radical can occur to either end of the alkene but favors formation of the more stable tertiary radical intermediate over formation of the less stable primary radical. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/574d63d4-2527-4701-8fd2-01e68c86559e/Ionic_vs_radical.png Blog - Anti-Markovnikov Addition - Make it stand out Obtaining either the Markovnikov or anti-Markovnikov product. In both reactions the regioselectivity is determined by the stability of the electron deficient intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1f4da261-0000-41f2-8a14-d4aea5426267/Hydroboration_Example1.png Blog - Anti-Markovnikov Addition - Make it stand out The hydroboration-oxidation of this cyclohexene derivative gives a racemic mixture of two alcohols, the products of anti-Markovnikov addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a307313a-ff16-4d0b-b3c1-47a79757dc63/boranes.png Blog - Anti-Markovnikov Addition - Make it stand out Common (organo)boranes used in organic synthesis. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e2fba54e-2a5f-4b4c-b8bd-3e18d185e098/hydroboration_mechanism.png Blog - Anti-Markovnikov Addition - Make it stand out Hydroboration is a concerted reaction that leads to syn addition. The transition state is a four-membered ring that has the boron atom sitting over the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0166fbe4-d906-4dfe-a325-37683da3d4d9/Regioselectivity_9BBN.png Blog - Anti-Markovnikov Addition - Make it stand out Steric hindrance influences the regioselectivity of hydroboration. The bulkier the boron reagent the greater the preference for the anti-Markovnikov product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77947295-423d-4aa2-adbc-76e484dc305f/Multiple_hydroboration.png Blog - Anti-Markovnikov Addition - Make it stand out Borane can add to three alkenes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e1231b08-e23f-4871-86c8-3d23b5b4199d/Oxidation.png Blog - Anti-Markovnikov Addition - Make it stand out The oxidation of an organoborane with basic hydrogen peroxide is stereospecific, occurring with retention of stereochemistry. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a80a3326-874b-494b-a6d5-7c7dc34156e6/Oxidation_mechanism.png Blog - Anti-Markovnikov Addition - Make it stand out The oxidation of organoboranes occurs with the retention of stereochemistry due to the migration or alkyl shift. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2e31cb38-5784-416e-ac6d-79d36a41025d/Oxidation_transition_state.png Blog - Anti-Markovnikov Addition - Make it stand out The transition state of the alkyl shift or migration shows that there are partial C–B and the C–O bonds. This leads to the retention of stereochemistry. If one bond broke before the other started to form it is likely that there would be lose of stereochemical information. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/334c045b-f265-4f56-a6dd-348404127d65/Orbitals_Hydroboration.png Blog - Anti-Markovnikov Addition - Make it stand out The orbital interactions involved in hydroboration. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5d7f6431-f9ae-47f9-9d77-a113f9e8443f/Oxidation_orbitals.png Blog - Anti-Markovnikov Addition - Make it stand out The migration or alkyl shift during oxidation occurs with retention of stereochemistry. Effectively, the C–B σ bond slides across into the O–O σ* antibonding orbital. https://www.makingmolecules.com/blog/alkenenucleophiles1 monthly 0.5 2023-02-06 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e1421ec1-fb75-4274-af55-bea6b5f6cf9f/General_HX_v2.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out General reaction for the addition of H–X to an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/424bb188-361e-4f4c-9dd6-3826c1eaace4/Mechanism_HX_addition.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The mechanism for the addition of HX to an alkene is a two step process involving proton transfer and then nucleophilic addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f7df70ad-7005-403a-8d25-50bd780b5712/Regioselectivity_example1.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Non-symmetrical alkenes can lead to a mixture of regioisomers but invariably one isomer is favored. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c56c0870-1266-4322-aa53-ad987b0fea77/HX_regioselectivity_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The regioselectivity of the addition of H–X to an alkene can be understood by the stability of the intermediate carbocation formed during the initial protonation step. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/689ffeb4-aef6-4948-adf2-0cdb9e0d6451/Cation_stability.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The stability of simple carbocations is determined by hyperconjugation or the inductive effect (two names for the same concept). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/55673699-1923-49a6-85c9-a8298667f0d8/hyperconjugation.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Hyperconjugation is the delocalization of σ electrons by the overlap of σ bonds. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9f07dd3-019b-428d-af48-e87224fb8fcf/Markovnikov-resonance_reaction.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Markovnikov's rule cannot predict the major product of this addition reaction but you can if you understand the mechanism of the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b089b4da-9498-4358-a3ea-db8f9798c6de/Markovnikov_resonance_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Delocalization of the carbocation favors formation of the the top alkyl bromide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fd805b31-db20-44dc-bd72-82eb54c9fb92/curly_arrows.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Different ways of representing the redistribution of electrons during the proton transfer step so that it is clear which carbon atom retains a share of the electrons. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6864d0c0-f0b1-4d94-93fc-a4b387ee1d30/orbitals-HX_addition.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The frontier orbitals involved in the addition of H–X across an alkene. The two steps involve different orbital interactions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5f81e3c8-e594-47e3-9cf0-db8e8d40a316/Alkene_hydration.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The acid catalyzed hydrogenation of an alkene. The reaction is similar to hydrohalogenation and shows the same regioselectivity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c78dd7fc-4e89-4484-81b0-d5291474e6ee/Hydration_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Mechanism for the acid catalyzed hydration of an alkene. The acid adds one step (the second proton transfer), otherwise it is identical to hydrohalogenation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c85bc3f1-c9c6-45d3-ac03-00c58f4a90d1/Reversible.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Hydration of an alkene is a reversible reaction. Using dilute acid, so that there is an excess of water, leads to hydration. Using concentrated acid, with no water present (concentrated sulfuric acid is a drying reagent), leads to elimination and conversion of an alcohol into an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/46aa23bd-7720-46b4-8797-03e8b21b011c/oxymercuration.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Oxymercuration-reduction (or oxymercuration-demercuration) results in the Markovnikov addition of water across an alkene. The reaction is milder than acid-catalyzed hydration and does not involve the formation of a carbocation that could undergo rearrangement. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c12a526e-fffa-4cef-824f-1f8c20a62e70/mercuration_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Oxymercuration involves formation of a charged mercuronium ion followed by attack of a nucleophile to give an organomercury species. Reduction leads to demercuration and the formation of the Markovnikov product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/11652462-cc52-43cb-aa26-d41fd2f445d8/Bromination.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The bromination of alkenes was a standard test for alkenes. A red-brown solution of bromine (either neat or in solution) would go colorless when added to a solution containing an alkene. The reaction is an addition reaction with bromine adding across the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8e3d59fb-747d-4ad3-913c-742f4a14f15f/Anti-addition.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The anti-addition of bromine to the two diastereoisomers of an alkene will give different stereoisomers. Addition to the E-alkene leads to a single compound, the achiral dibromide while addition to the Z-alkene gives two enantiomers of the dibromide as a racemic mixture. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b50d117e-7796-4541-bd80-64115a126c23/meso_dibromide.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Changing the conformation of the dibromide reveals that it has an internal plane of symmetry. Molecules with a plane of symmetry cannot be chiral. As the molecule has two stereocenters yet is achiral it is known as meso. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/272a2ca3-71b5-43cf-8eac-71383b6cad75/Bromination_step1.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The first step of the addition of bromine to an alkene is formation of a bromonium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/657a664f-6fc8-44cf-ba8d-114f70558218/Polarization_Bromine.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The polarization of bromine by interaction with an electron rich alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5d905517-1425-4940-a217-eb479500e3b5/Bromination_step2.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The second step of the addition reaction is nucleophilic attack of the bromide on the bromonium ion. This occurs from the opposite face to the first bromine atom and leads to the anti-dibromide. This is shown in three different representations above. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c82ec2e2-6a25-4cbe-b15c-74f4ccbbc2ea/Bromination_making_enantiomers.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The formation of enantiomers is the result of the bromide anion attacking either end of the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7546967e-9327-4cfc-b4f4-f03b27b56adb/Bromination_complete.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The two step mechanism for the addition of bromine to an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2c775b25-59a5-4486-aae6-a9e2f0ca84d0/Not_Bromination_Mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The bromination of an alkenes does not proceed via the formation of a carbocation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56cee9ff-39a5-4bba-b460-7004719edd38/orbitals_br2_Step1.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The orbital representation of bromonium ion formation. The HOMO of the alkene attacks the bromine while the LUMO of the alkene is attacked by the bromine. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8f60c9ed-cc3a-4ae1-aad6-9f1d1d8b2c13/orbitals_br2_Step2.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The orbital interactions for the second step of bromination, nucleophilic attack by the bromide on the bromonium species, explain why anti-addition is observed. The nucleophile must approach at 180° to the C–Br bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f551d414-5b84-4666-96e3-ebc92548f86d/Brominating_reagent.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Kinetic experiments suggest that the brominating reagent is bromonium ion formed from the reaction of two equivalents of bromine. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/68d5576b-1f44-43f7-b4e4-29b628bc42df/Bromohydrin_formation_Example1.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out A mixture of bromine and water will add to an alkene to give a bromohydrin. The reaction is stereospecific for the anti-diastereoisomer and regioselective for addition of the alcohol to the most substituted end of the alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e13b6577-22a4-48f2-ae65-642dc8e96759/Bromohydrin_formation_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The mechanism for bromohydrin formation is the same as bromination except that there is an additional proton transfer step. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b023f6f0-1e44-4605-90c6-959a117e38b3/Partial_cahrges.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The regioselectivity can be explained by considering that the C–Br starts to break before the nucleophile attacks. This leads to the build up of a partial positive charge on a carbon atom. The carbon atom that best stabilizes a carbocation, in this case the tertiary carbon, best stabilizes the partial positive charge. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/86f6973f-7beb-4d5f-a4d5-ffdeb795e7c2/Partial_charge_resonance.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out It is possible (but I don't like it) to argue the selectivity with 'resonance' structures. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a3c76f46-045e-4e6d-bace-4b2e98ba0189/Regioselectivity_Transition_State.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The regioselectivity can be explained by considering the transition state of the reaction, this has a charge being redistributed across two atoms. One transition state allows this transfer to occur via the more stable tertiary position while the other requires the build up of positive charge on a disfavored primary position. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8584095b-db3c-4cf5-a0e5-d917f0634bbe/Rate_bromohydrin.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out When the rate of reaction of four different alkenes is compared, you can see that the more substituted the alkene the more reactive is due to increased nucleophilicity. The tetra-substituted alkene is almost 2 million times more reactive than the unsubstituted alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/916f7b45-abad-4211-9a13-38397eb310ad/BromoLactonisation.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out An example of bromolactonization. This is exactly the same as the bromohydrin reaction above. The alkene is activated by formation of a bromonium ion then the nucleophilic carboxylate anion participates in nucleophilic attack, opening the bromonium species and giving the cyclic ester or lactone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bfb49aef-39e9-4bc0-8f42-2d8369a02055/Expoxidation_general.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out An example of epoxidation with a peracid, in this case the common reagent meta-chloroperoxybenzoic acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/60b23a25-a2a0-4f9e-9a4e-f3de160251e9/epoxidation_acyclic.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The peracid-mediated epoxidation of acyclic alkenes occurs with retention of stereochemistry as the reaction is concerted. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/be21189b-7b51-4b40-90a6-a58a8452e9ab/Epoxidation_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Peracid-mediated epoxidation is a one step, concerted reaction, with all the bonds made and broken at the same time. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9aab7b01-9c48-4fa6-b642-7b65284bb8f7/Rate_Epoxidation.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The more substituted the alkene, the more electron rich it is, and the more nucleophilic. The more nucleophilic the alkene the faster the epoxidation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/807aac8b-1613-4598-b2d1-77ad20c928ed/orbitals-epoxidation.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The orbital interactions for the formation of an epoxide with a peracid are almost identical to those found in the formation of the bromonium ion. The same concepts and patterns are used repeatedly in chemistry and there isn’t half as much to remember/understand as many students think. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c63e9a0b-5053-4db9-a4e0-9d46f793b072/Real_curly_arrows_epoxidation.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The real curly arrows for epoxidation should probably be drawn more like this. The key difference is that the oxygen lone pair of electrons is used to form the second C–O bond of the epoxide. The arrows also reveal another dirty secret of organic chemistry, the orbital alignment of the σ bonds means they can’t form the π bond so we need more arrows. The simplified version is much nicer and no one ever said curly arrows were real! https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cb9f4475-1701-468a-9db6-3f59777130e9/Dihydroxylation-general.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out Dihydroxylation with osmium tetroxide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/28845132-9062-4a7f-bd6d-3f739f21e91c/Syn-addition-diol.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The dihydroxylation of an alkene with OsO4 is stereospecific but it gives the opposite results to bromination. Dihydroxylation gives a racemic mixture with the E-alkene while bromination gave the racemic mixture from the Z-alkene. Dihydroxylation is a syn addition while bromination is an anti addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c17d3854-dbb5-4508-93f4-03d39f8178d0/Dihydrolyation_mechanism.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out A simplified version of the mechanism for syn-dihydroxylation of alkenes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/136a8e77-4a73-4eb6-a258-1bd80f44d47d/General_conclusion.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out The first step of all these reactions involves the alkene behaving as a nucleophile and attacking another reagent. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5882d0db-b315-4a47-badd-1a8547be1fd6/Conclusion.png Blog - Alkenes as nucleophiles: Part 1 - Make it stand out A summary of the reactions covered in this summary (so a summary of a summary) https://www.makingmolecules.com/blog/acylsubstitution monthly 0.5 2022-12-20 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/08d3de4b-f5dd-47a6-bc4e-71c8ade2624b/General_reaction.png Blog - Nucleophilic Acyl Substitution - Make it stand out Nucleophilic acyl substitution is a reversible reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e632d7fb-dfcd-426f-948d-7c81ab7c5ffd/Carboxylic_acid_derivatives.png Blog - Nucleophilic Acyl Substitution - Make it stand out Carboxylic acid derivatives and their relative reactivity, which to large extent is based on leaving group ability. This, in turn, is related to base strength and the pKa of the conjugate acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/516687aa-8014-4b3c-b2e7-4b91c95323c6/Reactivity.png Blog - Nucleophilic Acyl Substitution - Make it stand out The reactivity of various carboxylic acid derivatives (and aldehydes and ketones as a sort of baseline) can be explained by either balancing polarization and delocalization or leaving group ability. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c1adc7d4-a9ba-461b-86c4-7bdb2257ecc6/Problem_with_acids.png Blog - Nucleophilic Acyl Substitution - Make it stand out Carboxylic acids have an acidic proton than can interfere in nucleophilic acyl substitution reactions. The nucleophile (or base) can deprotonate the acid resulting in the formation of a carboxylate anion. Carboxylate anions are the least reactive carboxylic acid derivatives as they are electron rich. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42317022-6856-4374-be17-83ab1f5b63ca/General_mechanism_Anion.png Blog - Nucleophilic Acyl Substitution - Make it stand out Nucleophilic acyl substitution with an anion nucleophilic occurs by an addition-elimination mechanism or written out in full, nucleophilic addition followed by loss of a leaving group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0865acb7-ea4e-4b3e-8f57-02d62aa2821c/General_mechanism_Neutral.png Blog - Nucleophilic Acyl Substitution - Make it stand out Nucleophilic acyl substitution with a non-charged nucleophile. The reaction still involves nucleophilic addition and loss of the leaving group but it now has a proton transfer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/abed35db-51f5-49b1-8607-5785346f33b8/General_mechanism_Acid_catalysis.png Blog - Nucleophilic Acyl Substitution - Make it stand out Acid-catalyzed nucleophilic acyl substitution with a non-charged nucleophile (the nucleophile can't be an anion otherwise it would be destroyed by the acid). The reaction still involves nucleophilic addition and loss of the leaving group but it now there are four proton transfer steps. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1a712fee-4d66-4ed0-9fb0-bdd32e0f2216/reversible.png Blog - Nucleophilic Acyl Substitution - Make it stand out Nucleophilic acyl substitution is reversible and an equilibrium will be established that favors formation of the more stable leaving group unless perturbed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/002e91fb-6c13-42a8-8def-428c8ab9c678/Acyl_Chloride_formation.png Blog - Nucleophilic Acyl Substitution - Make it stand out Carboxylic acids can be converted into acyl chlorides by reaction with thionyl chloride (SOCl2). The reaction follows the standard acyl substitution reaction with a nucleophilic addition step and a loss of a leaving group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56154b15-03d4-4c1f-926d-743610f35c46/Not_Acyl.png Blog - Nucleophilic Acyl Substitution - Make it stand out Acyl chlorides cannot be made by reacting carboxylic acids with hydrochloric acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/60bdc5fa-8765-4be5-90e2-143dd6a5aa1b/Esterification.png Blog - Nucleophilic Acyl Substitution - Make it stand out The acid-catalyzed esterification or formation of an ester from the reaction of a carboxylic acid and an alcohol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5c40bf64-be8c-4907-a541-de1497445762/salt_formation.png Blog - Nucleophilic Acyl Substitution - Make it stand out Amines behave as bases not nucleophiles when they react with carboxylic acids. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77c25f4f-7264-4c94-bd58-d4daca3e495c/Chloride_water.png Blog - Nucleophilic Acyl Substitution - Make it stand out Hydrolysis of an acid chloride to a carboxylic acid is another example of nucleophilic acyl substitution. The water is the nucleophile and attacks the carbonyl group before the chloride is eliminated. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ae4e96e8-32f7-43c7-a22f-1085c0e3e8ac/Chloride_to_ester.png Blog - Nucleophilic Acyl Substitution - Make it stand out Esterification by the reaction of an acyl chloride with an alcohol. In this example a base, triethylamine, has been added to neutralize the acid formed in the reaction so that it does not damage the product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/23f22d7c-c9a3-4be7-81ae-b3226ebe6608/Chloride_to_amide.png Blog - Nucleophilic Acyl Substitution - Make it stand out Formation of an amide from an acyl chloride. Follows the same mechanism as all the reactions of an acyl chloride. There are three steps, nucleophilic addition, loss of a leaving group and a proton transfer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c4fc1b27-f5fe-4acc-9e61-8fbc4f56fd94/Anhydride_formation.png Blog - Nucleophilic Acyl Substitution - Make it stand out One method to prepare (mixed) anhydrides. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cbebe44b-3eb6-4f0d-8e29-a12fa952acea/Reaction_anhydride.png Blog - Nucleophilic Acyl Substitution - Make it stand out The reaction of an anhydride with an alcohol to give an ester. This follows the standard nucleophilic acyl substitution reaction. Reactions of water and amines are exactly the same. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a245386e-bcbf-4ad9-a3e7-0faf61c44edb/Reaction_anhydride_more.png Blog - Nucleophilic Acyl Substitution - Make it stand out Reactions of anhydrides to give a variety of different products. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ba5d875f-5166-479f-a89a-ff6cdcefaf02/Ester_amide.png Blog - Nucleophilic Acyl Substitution - Make it stand out Reaction of an ester with an amine to give an amide. In this version of the mechanism, elimination occurs before proton transfer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/698e217a-0234-4d38-b9d5-b34e015168bd/ester_hydrolysis_acid.png Blog - Nucleophilic Acyl Substitution - Make it stand out Acid catalyzed hydrolysis of an ester to give a carboxylic acid is the reverse of esterification. The mechanism is exactly the same. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/88938d71-7aeb-4c66-951f-edb2863555ce/Base_mediated_ester_hydrolysis.png Blog - Nucleophilic Acyl Substitution - Make it stand out Base-mediated hydrolysis of an ester is an irreversible process. The carboxylic acid is only an intermediate and it is deprotonated in an irreversible step to give a carboxylate anion. This species is not electrophilic so the reverse reaction is no longer possible. The carboxylic acid can only be isolated by neutralizing the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/531b175f-42fb-4097-8de8-5863534cbb86/Acid_Amide_hydrolysis.png Blog - Nucleophilic Acyl Substitution - Make it stand out Acid-mediated amide hydrolysis follows the standard nucleophilic acyl substitution reaction with additional proton transfer steps. The reaction is irreversible due to the protonation of the amine, which makes it non-electrophilic. This also means that at least one equivalent of acid is required for the reaction to proceed fully. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fa496a59-82ee-4200-8869-cd5ee7559efc/Base_Amide_hydrolysis.png Blog - Nucleophilic Acyl Substitution - Make it stand out Base-mediated amide hydrolysis is an irreversible process due to deprotonation of the carboxylic acid and formation of a non-electrophilic carboxylate anion. Isolation of the acid requires neutralization of the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c4d053dd-7d3a-4b43-8b4f-40380e3a95b9/Acid_table.png Blog - Nucleophilic Acyl Substitution - Make it stand out The interconversion of carboxylic acid derivatives. https://www.makingmolecules.com/blog/condensation monthly 0.5 2022-12-05 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8eb768a6-0dc3-40da-b865-41d9092db292/Hydrate_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Hydrate formation by nucleophilic addition to an aldehyde. The mechanism is shown in the white box. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/64c3fef1-40bb-4e03-9c91-5478e937863b/Hydrate_formation_catalysed.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The mechanism of acid-catalysed hydration of an aldehyde. The order of the proton transfers has changed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/aad910e7-d7f3-4180-9c20-fa0b60db948a/Acetal_Formation_intro.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The acid catalyzed addition of an alcohol to an aldehyde does not give the ‘expected’ hemiacetal but leads thee substitution of the oxygen atom and the formation of an acetal. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c450e1d6-2e1a-4ea9-b674-525ef33934fc/General_acetal_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The general reaction for acetal formation has two equivalents of alcohol adding to the carbonyl group to substitute the oxygen atom and give an acetal and water. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eb2221d5-c8c3-472f-81be-4bb519f62f7f/Hemiacetal_Formation1.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Hemiacetal formation. This involves two proton transfers and nucleophilic attack on the highly reactive oxonium ion. The original carbonyl oxygen has been highlighted. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6e5b607d-de90-438c-92cf-8ccb866d0f7f/Acetal_formation_part2.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The second half of the acetal formation mechanism. The hemiacetal is protonated to create a leaving group. This is lost to give a highly activated oxonium ion, which is a good electrophile and is attacked by more alcohol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/30d5d7f2-2278-4dfd-b031-5e5c72e72289/Compare_oxonium.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Comparing the two oxonium species. Both are activated carbonyl groups. One can be lose the charge by simple proton transfer, the other must undergo a reaction (nucleophilic addition) before it loses its charge. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2f9b0a9d-6792-41fb-b585-4dcf14c1a850/Acetal_formation_complete.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The complete mechanism of acetal formation. It involves a proton transfer to activate the carbonyl group. This is followed by nucleophilic addition and a second proton transfer to form a neutral hemiacetal. A third proton transfer forms the leaving group, which is eliminated to give an activated oxonium ion. A second nucleophilic attack and a final proton transfer give the acetal. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9e4ba96d-8f0e-4e64-b8fc-67ca5e8cf2b8/Wrong_mechanism.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Addition of the second alcohol molecule is not a substitution reaction. There must be an elimination to form the oxonium ion first, then the alcohol adds to the cationic species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ab0398a7-b5c2-44de-8a49-80a8c72768f6/Remove_water.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Acetal formation is made irreversible by removing water from the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4956b818-5ab3-4187-b02a-cdb979f581ec/Acetal_hydrolysis.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Hydrolysis of an acetal to give the carbonyl compound, aldehyde or ketone, is normally achieved with an excess of water. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6b5df988-02ae-44a5-bf82-19c91c941d5f/Protecting_group.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Acetal formation protects the ketone from nucleophilic attack (it no longer has a carbonyl group so is no longer electrophilic). The ester reacts and then acetal hydrolysis allows the ketone to be regenerated. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/332a0594-9f3f-4ce2-8831-65215b5e280a/Acetal_example1.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The formation of an acetal from an aldehyde and two equivalents of ethanol. This acetal is actually known simply as acetal and is a major flavoring in distilled drinks, such as whisky. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/775b373e-e16a-43ab-ba48-ce281dc55596/Acetal_Example2.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Diols normally give cyclic acetals. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/84b87621-104c-4e30-818b-691757ee88bf/Acetal_example3.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Synthesis of the fungicide, propiconazole, which contains a cyclic acetal. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8958f3de-93f9-45ec-8195-d3b1e1b205ce/Olean_synthesis.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The synthesis of olean, another acetal. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8a50e519-0c13-4671-9151-3fb5076d9730/Dithiane_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Thiols, the sulfur equivalent of an alcohol, behaves in the same manner and will form thioacetals by the same mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42ac496f-3bec-4720-8ed4-71f7d2450db3/Use_dithiane.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The chemistry of dithianes is different to oxygen-based acetals and allows for a variety of different reactions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/37d4dc96-fd86-4ff5-9b19-508f7bb8bb70/Imine_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The reaction of an aldehyde or ketone with a primary amine results in the formation of an imine. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a7053689-3859-46e3-8f8d-770b24c19e3f/Hemiaminal_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The first stage of imine formation involves formation of the hemiaminal. This is analogous to formation of the hemiacetal. The only difference is that order of the proton transfers has been changed. Here nucleophilic attack occurs before proton transfer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2704afc-38d8-45f8-a115-2d94c79cbd50/Iminium_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Iminium formation. This is identical to formation of the oxonium ion during acetal formation. The oxygen is protonated and then eliminated to give the charged double bond species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e614887b-0fd0-4ce2-a569-e74add59b738/Iminium_deprotonation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Nucleophilic addition to an oxonium ion versus deprotonation of an iminium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/43862bd1-84a7-4ca3-851d-3a0908c9c283/Imine_formation_full.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The complete reaction mechanism for the formation of an imine (Schiff base reaction) from an aldehyde or ketone and a primary amine (or a whole host of other nitrogen-containing compounds). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/577db308-b09d-4734-9031-7a479a4a40a8/oxime.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out Formation of imine-like compounds. Oximes are made from hydroxylamine and hydrazones are made from hydrazine. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/68ea11ba-010b-440f-8383-c825a2e9ac95/Enamine_formation.png Blog - Condensation reactions of aldehydes &amp; ketones: substituting the carbonyl oxygen atom - Make it stand out The reaction of an aldehyde or ketone with a secondary amine results in the formation of an enamine by the mechanism in this diagram. https://www.makingmolecules.com/blog/diastereoselectiveaddition monthly 0.5 2022-11-21 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1eeb55b2-cef3-418b-a980-2dd1570f3185/New_stereocentre.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Addition to a carbonyl group can create a new stereocenter depending on the substituents and the nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/05cde855-1ab3-4939-8167-5aeaf99c2078/Diastereotopic_facesV2.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out This summary introduces the different models for predicting or rationalizing which diastereotopic face of a chiral aldehyde or ketone is preferentially attacked by an achiral nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/20a52c9f-d244-4457-a438-79f7b8cd0164/BD_Angle.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The Bürgi-Dunitz angle is based on the observation that nucleophiles approach the carbonyl group at an obtuse angle of approximately 107°. The separation of nucleophile and oxygen atom is maintained throughout the reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/220c64a9-1768-4182-8bcc-e4cc13c8c13e/Flippin_lodge_angle.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The Flippin-Lodge angle describes the deviation of the nucleophiles approach from the idealized 90° to the carbonyl group. It is influenced by the substituents on the carbonyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/477b6f77-7ce1-43e5-808b-f8c2084b34f1/Conformation_of_addition.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Representing the trajectory of the approaching nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3aa33324-a156-4348-a0e9-45a90d4317a0/Standard_representation.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The standard representation for a nucleophile approaching along the Bürgi-Dunitz trajectory. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fc0aa7da-42c9-4a14-95ed-13467c07a664/Types_nucleophile.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Nucleophiles that involve a nucleophilic σ bond or lone pair of electrons will be covered in this summary. Those that involve a nucleophilic double bond will not. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1674acb8-9eef-4b90-8b6a-b6bab602aaa3/nucleophiles.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Most organic chemists are happy to simplify nucleophiles to an anion, R–. This is what I'll be doing for the rest of the summary. It misses both the beauty of the real structures and can lead to mistakes (as in the case of organoborane reducing reagents). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ff30ec3a-020a-40a2-9003-566ee14a6a51/TS_FA_reduction.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The Felkin-Anh model of stereochemical addition to chiral aldehydes and ketones is based on minimizing non-bonding interactions between the incoming nucleophile and the substituents of the α-stereocenter. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a3d731bf-6dc8-4b1b-b428-a3f93ac31580/Reduction_FA.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Reduction of the chiral ketone is diastereoselective. The bigger the reductant the greater the selectivity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fff870e1-79e5-4bac-b632-a6ecfd2bfaa6/General_FA.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out General diagram representing the Felkin-Anh model of stereoselective addition to aldehydes or ketones with an α-stereocenter. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/159c3806-eb8c-415f-a3a7-fe8a63a87c95/Reduction_Chloro.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Reduction of the ketone above favors the anti-Felkin-Anh product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/04608d6c-d8a6-4857-97a3-c1b3684d7835/Hyperconjugation.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Hyperconjugation or delocalization of the π* C=O and σ* C–Cl orbitals leads to stabilization of the conformation with the most electronegative group anti to the incoming nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3fe0bf24-3e29-4cfe-959d-d3de3d36a1d2/General_polar_FA.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out General diagram representing the polar Felkin-Anh model of stereoselective addition to aldehydes or ketones with an electronegative group, Z, on the α-stereocenter. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4bbd3d07-2ff5-4d1c-b1e9-635f9f8201e2/Modified_Cornfirth_Example.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The reduction of a ketone with an electronegative α-substituent. The diastereoselectivity can be rationalized by the modified Cornforth model. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6fa2c4b1-616c-4c1c-90ea-c39d5f858655/Boron_example.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The modified Cornforth model correctly predicts the outcome of the organoborane-mediated reduction while the polar Felkin-Anh model would give the wrong answer. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c3656ba7-0e2a-4487-bce4-19926ce8f6be/General_Cornforth.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The modified Cornforth model is based on the minimization of electrostatic effects (minimize the dipoles of the electronegative substituent and the carbonyl group or the incipient alkoxide). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0950abad-5023-40c9-8927-a920e196059b/Cram_example1.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Chelation can reverse the normal selectivity of a reaction by restricting the conformation of the substrate. This is known as Cram chelation control. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/745a61b6-ed99-4db1-8946-136c3054b847/Cram_Substrate_Example2.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The diastereoselectivity of the reduction can be reversed depending on the protecting group. The silyl ether prevents chelation and the stereoselectivity is rationalized with the polar Felkin-Anh model. With an acetal protecting group, chelation is possible and Cram chelation control predicts the product outcome. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b808824d-9b65-4b25-bea0-f16781cc6c0d/General_Cram.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out A generalization of the Cram chelation model, where Z is a Lewis base (has a lone pair of electrons). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9dc9f328-ff1e-463b-82e0-b48880a08766/Evans_general.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out Choice of reactant permits both diastereoisomers to be formed selectively. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3efc13cf-620d-4952-acda-47bc8ff7bf29/Evans_Intramolecular.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The 1,3-syn product is formed when a Lewis acid that can tie the carbonyl and β-alcohol together. The chelate sits in a conformation that places the substituents pseudo-equatorial, and the nucleophile approaches in an intermolecular fashion to give the chair-like intermediate, not the twisted boat intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/44c62154-d94b-42d1-89f2-689aeacefc94/Evans_intramolecule.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out The 1,3-anti product is formed when the reaction is intramolecular, with internal delivery of a hydride through a chair-like transition state. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f02fce9c-789c-4b8e-949f-91cbb89b6af2/Summary.png Blog - Diastereoselective addition to aldehydes &amp; ketones - Make it stand out A brief summary of the most common models for diastereoselective nucleophilic addition to aldehydes or ketones. https://www.makingmolecules.com/blog/nucleophilicaddition monthly 0.5 2022-11-07 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/66cde54b-6ee9-4c99-937b-82b666d7ac12/carbonyl_group.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The carbonyl group, the acyl group and functional groups containing the carbonyl group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eb01a627-0c7c-43de-b87a-4d01598060b1/addition_plus_reactions.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The tetrahedral intermediate formed on addition of a nucleophile to a carbonyl-containing compound can lead to a number of different functional groups depending on the nature of the nucleophile or carbonyl substituent (Z). In this summary, I am just interested in a single addition followed by protonation (white box). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/47bac2dc-3860-4828-b897-df3adad06f08/polarisation.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Polarization and delocalization of the carbonyl group make the carbon highly electrophilic. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3f930545-7d25-4e69-b8e1-be1dfd90c58a/Bond_strength.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Comparison of the physical properties of a carbonyl C=O bond and an alkene C=C bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/020fe015-bed7-4881-9214-7e40b24f2573/General_reaction.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The general reaction for nucleophilic addition (of a nucleophile called nuc-) to an aldehyde or ketone followed by protonation. The groups acting as a nucleophile are in purple while the electrophiles are in green. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/951973ee-731c-4b61-9ea9-530e1a30e8d4/Nucleophilic_addition_step1.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The first step in nucleophilic addition. The nucleophile attacks the electrophilic carbonyl group to form a new bond and the tetrahedral intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/569828ca-bb6f-4289-a3df-c871a940a360/Proton_Transfer_step2.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Proton transfer from a hydronium ion to the tetrahedral intermediate (anion). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8c116f9c-daf8-4213-ab0e-3b0a2a012c5b/Elimination.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Nucleophilic addition to form the tetrahedral intermediate (blue arrows on the left) or elimination, kicking out the nucleophile as a leaving group (the red arrows on the right). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8f4a36a4-ab61-4c54-aa9e-e6fc468b15a2/Electronic_reactivity.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out A carbonyl group is highly polarized and electrophilic on the carbon atom. Adding electron donating groups pushes electron density onto the carbon and reduces the electrophilicity. Two groups have a bigger effect than a single group. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d91dd796-52af-4b98-826a-f005c5a4372f/Steric_reaction.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The steric argument for the reduced reactivity of ketones; some form of interaction between incoming nucleophile and the bulk of the molecule is unavoidable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3ee70298-b2f1-4da8-b063-ab4fd8a85d4b/BuLi_addition.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The addition of butyllithium to acetone followed by the addition of water gives an alcohol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bce9e0db-0c1c-4d4c-a6f5-ce632bc37163/Grignard_both_versions.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Two versions of the mechanism for the addition of a Grignard reagent (organomagnesium nucleophile). Both are simplifications of what is “really” happening as the reactions almost certainly involve at least two equivalents of the Grignard reagent and solvent molecules. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f508b3a0-d0fa-462b-97d6-d970c0519ab5/Two_Organometallic_additions.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Two, of the many, different ways of writing the reaction of an aldehyde or ketone with an organometallic reagent. The key is that the organometallic reagent and the proton source cannot be mixed together. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/628b0e2a-5870-477a-8e36-d3fd3782d0da/Organometallic_Plus_water.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Proton sources can destroy many organometallic reagents. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/434d64e8-953f-48c9-ab79-5b18e6dd5e76/Non-reversible.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The addition of an organometallic reagent to an aldehyde is irreversible as there is no suitable leaving group to allow the carbonyl bond to reform. This can be seen from comparison of the strength of the bases (or conjugate acids). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/de442a87-6376-455a-b9e6-6af01341f966/General_Reduction.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The reduction of aldehydes and ketones with lithium aluminium hydride or sodium borohydride. Both reagents will reduce both aldehydes and ketones. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0b773337-629d-4cd3-8478-afce3a199457/LAH_reduction.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The mechanism for the lithium aluminium hydride reduction of a ketone. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/074ec615-5c2b-4383-84e8-860311bb75c8/Destroying_LAH.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The first step in the reaction of lithium aluminium hydride and water. More reactions occur after this, none desirable to most organic chemists. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0bd8d3e3-bae1-4132-b160-1b665224886d/H-_version.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The common simplification for hydride reducing regents. It is not correct! https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/15ed8ddb-9615-453e-b687-de40abbe6217/Borohydride_reduction.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Reduction of a ketone with sodium borohydride. The reduced nucleophilicity of sodium borohydride permits the use of protic solvents that also act as the source of protons in the second step of the nucleophilic addition mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2b4a492b-aaab-401e-82e0-b2b6465b4cdb/Hydrate_formation.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Water can add to an aldehyde by nucleophilic addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6bf43bbf-88e5-4288-9ba5-a894cac9f4c3/Hydrate_mechanism.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The mechanism for hydrate formation is identical to that of the addition of organometallic reagents with one important exception, the reaction is now reversible. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4543a16b-20ef-486a-847c-3627b07fab90/ProtonTransfer_variants.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Alternative mechanisms for proton transfer (all are correct so don't panic). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/919cee3f-cfa2-4a43-a592-b2bcf536d1de/Elimination_hydrate.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Elimination from water from the tetrahedral intermediate. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/befa2556-54be-48bd-8fd7-d279927a79c7/Hemiacetal_formation.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Formation of hemiacetals by the nucleophilic attack of an alcohol on an aldehyde or ketone. Mechanism shown below the overall reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d4f71177-ccb6-4b41-8a4a-9926d071c62c/Cyclic_hemiacetal.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Intramolecular hemiacetal formation. Occurs when alcohol and carbonyl are in the same molecule. The resulting cyclic hemiacetal is more stable than the acyclic version. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ee570903-8a8c-436d-9e3f-7e22467ee70c/Glucose.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Intramolecular hemiacetal formation is favored for many carbohydrates or sugars. This diagram shows two different representations of glucose cyclizing to form the hemiacetal. The wiggly line at the hemiacetal (anomeric) position indicates that I'm not defining the stereochemistry. This is because that would be a summary in its own right. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e6dd50f6-65a4-4e0b-9eb0-c56096a261be/Hemiacetal_Base_catalysis.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out The base-catalyzed formation of hemiacetals. This mechanism works for the formation of hydrates as well (as they are the same reaction for all intents-and-purposes). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/53217b9e-6069-432f-a687-6824a74aa63e/Cyanohydrin_formation.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Cyanohydrin formation and mechanism. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5b707bee-8921-4d97-85fb-2b64c5521309/Protonate_carbonyl.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Nucleophilic attack on the polarized carbonyl group versus protonation to enhance the electrophilicity, followed by nucleophilic addition. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a77d26cc-f793-494d-9f70-8ffd02fcfe43/hydrate_formation_acid.png Blog - Nucleophilic Addition to Aldehydes &amp; Ketones - Make it stand out Acid-catalyzed hydrate formation. An addition step activates the aldehyde to nucleophilic attack. https://www.makingmolecules.com/blog/curlyarrow monthly 0.5 2022-10-24 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/67e1edb3-cf64-4d9d-8725-a64315cbe238/Intro_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out An example of how an organic chemist might represent the addition of cyanide to acetone to give a cyanohydrin. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/00f0cc62-db52-4648-af07-e4053ca49ea2/Ionic_vs_radical_reactions.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Ionic (or polar) reactions versus radical reactions. Ionic reactions involve heterolytic bond formation and breaking through the movement of a pair of electrons while radical reactions involve homolytic bond formation and cleavage with one electron coming from each atom. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/85831030-f196-4686-9337-5fa68800590a/ionic_substitution.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out An ionic reaction showing a nucleophilic lone pair of electrons attacking the electrophilic carbon of iodoethane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/76087651-74ea-481c-9127-4e02483fea48/radical_addition.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The radical addition of bromine to an alkene to give a new carbon-centered radical. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a6f355af-2ba1-423e-9bf6-69b19433b1a9/Addition_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Cartoon of an addition reaction followed by an example of an addition reaction, the bromination of an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9a543eed-1027-4002-9ae2-ac61973cbc8e/Elimination_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out An elimination reaction involves a reactant splitting into multiple molecules. It is is the opposite of an addition reaction. Here hydrobromic acid is eliminated from an alkyl bromide to give an alkene. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1ac805a7-7a74-4838-b1a9-88f977abc337/substitution_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out A substitution reaction involves reactants swapping groups to make new products. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/22e345b1-8abd-4248-afe3-0befa6383d11/rearrangement_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out A rearrangement reaction. This is an example of an oxy-Cope rearrangement and there should be an additional rearrangement (tautomerization) to give an aldehyde not a enol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ec232140-6d46-4d96-983d-424519f8b7a7/Protonation_as_Addition.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Protonation of an alkene as an addition reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17ac71f3-d4f1-45ad-bd8e-0b4b175bb3a5/Protonation_as_Substitution.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Protonation of an alkene shown as a substitution reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9d37b9db-c89d-4bf2-b932-2ac6b6f5e239/Anion_nucleophile_V2.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Anions are nucleophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2e11a2d-49a9-4ecf-8b49-36564151553f/LonePair_nucleophile_V2.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out A lone pair of electrons acting as a nucleophile. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6545fe1e-0a96-4163-8479-4ee2a35bc4df/Pi_bond_nucleophileV2+copy.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Alkenes, alkynes and aromatic rings have nucleophilic π bonds. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5497520e-f227-45dc-bf48-618fc6657117/SigmaBond_nucleophileV2.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Polarized sigma (σ) bonds can be nucleophiles. The more electronegative atom will be the nucleophilic atom (and the reaction above is not a good example as there are a number of side reactions that can occur but that is a story for another day). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/593a1f7c-1c1a-45ab-82c4-0a6d387947c4/Base_vs_nuc.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The same reagent, in this case a hydroxide anion, can be both a nucleophile and a base depending on where it reacts in a molecule. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/70fcee92-a970-4bbe-8bbf-b69c8840a0d7/Anion_v_neutral.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/35a8904c-8ecd-4bc4-b0be-5660f52a40ee/Nucleophilicyt_vs_electronegativity.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56795dcb-cb7a-4ef6-85b5-6d9a8cca143e/Nucleophilicity_down_a_group.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b495ad83-da65-443f-b7cd-a7e457b112ab/Electrophile_proton.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Protons are good electrophiles (although arguably it is the oxonium adduct that is the real electrophile and this should be listed in a different category … don’t you love chemistry?) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2fc730fe-72ac-4cb7-ac5f-c2c05d2c3065/Electrophile_carbocation.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Carbocations only have six valence electrons and an empty 2p atomic orbital, they are good electrophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/90a45159-438e-492a-90b7-5a0845264a58/Electrophile_Borane.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Group 13 elements form neutral species while still having an atom with only six valence electrons. They are electrophilic. Add electron withdrawing or electronegative elements like fluorine and you will increase the electrophilicity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/13707e66-20f0-4c35-83e3-b9b59d44c3e4/Electrophile_carbonyl.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The electronegative oxygen atom polarizes the carbonyl group leaving the carbon atom partially positively charged. The δ+ carbon is an electrophilic site. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/54586f07-ee2e-410c-86ad-abbe897368e4/Electrophile_C-X.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Bonds to electronegative atoms leave the carbon atom partially positively charged (δ+) and make it an electrophilic site. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7fbc9daf-0266-4ba6-ae72-ba2418ce418e/Electrophilicity_charge.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The charged species is more electrophilic than the neutral species. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/96be3983-afe1-4cee-8898-b542cc2f6ae9/Electrophilicity_inductive_effect_cation.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Electron donating groups, such as alkyl groups, can reduce the electrophilicity of an electron poor site. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/abb6dfbd-5394-4d3c-b6f8-8a94ac9e55cc/Electrophilicity_resonance_cation.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The delocalization of electrons will influence electrophilicity. The allyl cation is less electrophilic than a simple secondary carbocation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/62050633-5478-4247-b0bb-24cf81dce7ff/Electrophilicty_neutral_carbonyl.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Both inductive effects and the delocalization of electrons can alter the electrophilicity of a reactive site. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3b7b5046-331e-4141-827e-e55c4fdcdf0d/Summary_Nuc_elec+copy.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out A summary of nucleophiles and electrophiles. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/74334921-cfc2-4086-8ebc-f7eb7e530abc/resonance_vs_reaction.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The difference between resonance and reaction curly arrows. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c24fbb74-552e-4d5c-8b57-c5a0c1a56129/Different_curly_arrows.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Different conventions for drawing curly arrows. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1d476629-cb12-40cf-87c0-fb041d82f020/LP_bond_V2.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/44310a9b-a2fa-4c9c-9d7f-39f0c319234b/Bond_LP.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fcacba1f-b50d-4d30-9b2a-873e5fcdf727/bond_bond_V2.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/36337f1c-9255-4e9c-890d-bd7cf29f8a62/nucleophilic_attack.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a1110e52-f15a-46c1-9aa4-c6734ef14357/Proton_transfer.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/61d19fc6-1bc4-4b7a-a1fa-f84595feb4f7/Leaving_group.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/efc345e6-af54-41de-ba85-56b371be0992/rearrangement.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56365447-70ce-4645-87f0-7c2418dc7ad5/Steps.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out A reaction mechanism can involve multiple steps or ‘mini’ reactions that bring about the overall transformation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1ce911bd-7cd3-400a-b84a-7b9e034f3e32/Number_steps_important.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out The number of steps is important. Don’t try to fit all curly arrows on a single diagram (unless the reaction is concerted e.g. epoxidation with a peracid). Hemiacetal formation is stepwise (although it could have been drawn one step shorter with an internal proton transfer but I was trying to make a point). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dc4eb87a-6702-46b2-806d-415cbccd46dc/Nucleophilic_attack_combinations.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7198b11b-a123-4ef5-a8d9-57a4a14d5151/Question.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/02ce4bfb-67dc-4743-9215-83dfd4fe91fc/Answer1-polarisation.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17dda28a-4377-4270-9640-a5d1c9c576ab/Answer2-nucleophile.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e8363fe2-5bdd-442c-ace1-4ffcd3fb07f7/Answer3-Arrows.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/88aced30-f6ab-4494-bc99-7b09eb424b1e/Answer4-elimnination+.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/da99dfc6-536c-47e9-9a38-a3328914b371/Answer5-deprotonation.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d8a6d392-0fff-4fec-a47d-23a6538b78b5/Answer6-total.png Blog - Reaction Mechanisms &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://www.makingmolecules.com/blog/chirality monthly 0.5 2022-10-06 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/469c2f76-00ea-45b6-a459-e2d9a0828257/Chiral_mirror_images_V1.001.png Blog - An Introduction to Chirality - Make it stand out Chiral and achiral objects. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/66d2b167-6cfc-48f9-a57e-7abffde2ac8f/Chiral_3D_cubes.png Blog - An Introduction to Chirality - Make it stand out Chiral objects are not identical to their mirror image. Chiral objects cannot have a plane of symmetry, inversion center or axis of improper rotation (wow that got technical fast). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/60586d7a-c460-45a7-8b6c-43521305a090/Achiral_Cubes.png Blog - An Introduction to Chirality - Make it stand out An achiral object is identical to its mirror image. It will have either a plane of symmetry, an inversion center or a rotation/reflection axis. The above example has two planes of symmetry shown in red. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/536e28e1-3c86-4b5b-aad9-dc41db0f580c/Chiral_Snail.png Blog - An Introduction to Chirality - Make it stand out A snail is chiral due to the helix of the shell. The shell has no symmetry. If you are really interested, something like 90% of all snails are right-handed helices although this number is both species and population dependent. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b867779c-befa-41ca-9761-277998523bf8/Achiral_cutlery.png Blog - An Introduction to Chirality - Make it stand out Cutlery (ignoring hallmarks & other engravings) are achiral. The fork and spoon have a plane of symmetry coming vertically out of the plane of the picture while the knife, as drawn, has a plane of symmetry parallel to the picture. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/84b932fe-d6fb-4097-bee4-df5adae6a83d/1-dimension_achiral.png Blog - An Introduction to Chirality - Make it stand out An achiral object in one dimension. The point of reflection should also be in one dimension so should be a point of reflection but to make it easier to see (but technically incorrect) I have drawn a mirror. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9605dc0-1185-45f4-9049-f60057cb4cd2/1-dimension_chiral.png Blog - An Introduction to Chirality - Make it stand out A one-dimensional chiral object. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/653044a9-53fb-484c-a9f9-d315bd10ba39/1-dimension_symmetry.png Blog - An Introduction to Chirality - Make it stand out An achiral object will have an element of symmetry. Chiral objects don't (when we're looking at more dimensions that can have rotational symmetry but no elements with reflective symmetry. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ff80fa48-fdd2-4627-bcb0-446d2adf7518/2-dimension_achiral.png Blog - An Introduction to Chirality - Make it stand out An achiral object in two dimensions. Now rotations are allowed but no flips. Again, I shouldn’t have drawn a 3D mirror and the reflection should take place along a mirror line (as we are in two dimensions). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8a2ddb61-4dfd-44e4-a136-d5b33e1c7ace/2-dimension_achiral_2Dots.png Blog - An Introduction to Chirality - Make it stand out An equilatoral triangle with two different colored corners is still achiral. Simple rotation of the reflection (which should have occurred along a line of reflection not a plane as drawn) allows the two objects to coincide. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/87faa5de-e637-4fbd-af83-4c9184768dfe/2-dimension_chiral_3Dots.png Blog - An Introduction to Chirality - Make it stand out A triangle with three different corners is chiral. It is impossible to move the reflection (yes,it should have been reflected along a line) of triangle in two dimensions so that all the corners match with the original triangle. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/990e8d2e-0de1-40ce-83b0-337dc350954a/2-dimension_symmetry.png Blog - An Introduction to Chirality - Make it stand out Achiral objects will have at least one mirror line in two dimensions. Chiral objects have no line of symmetry in two dimensions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/af76991d-3116-4cbd-bcc4-27db08674f0b/Tetris+copy.png Blog - An Introduction to Chirality - Make it stand out Tetris tiles can be split into achiral and chiral tiles. ‘I’, ‘O’ and ‘T’ are achiral as they have at least one internal line of symmetry (shown as a mirror above). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e9f6bdd9-3ded-40b9-99ab-26b289f79fd9/3-dimensional-achiral.png Blog - An Introduction to Chirality - Make it stand out Chirality in three dimensions. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/04498c80-8f7c-4516-b911-48a43dbb7442/Catching_different_balls.png Blog - An Introduction to Chirality - Make it stand out The interaction between either mirror image of an achiral object and a chiral object is the same. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/98620b58-4d88-4da7-a26e-d9ead45abfec/Catching_Balls_different_hands.png Blog - An Introduction to Chirality - Make it stand out The interaction between either mirror image of a chiral object and an achiral object is the same. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a686828e-6ed6-45b0-b176-b94bd5eaaf48/gloves_chirality+copy.png Blog - An Introduction to Chirality - Make it stand out The mirror images of chiral objects behave differently in the presence of other chiral objects. Mirror images are different. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/16b92ec7-fbdb-4988-8945-d952d5d37089/Nut_Bolt_mirror.png Blog - An Introduction to Chirality - Make it stand out Nuts and bolts are chiral. The two mirror images of a bolt are different and only one will interact (screw into) a nut. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e43d975c-4f71-4af7-bb44-c4fb26a39e86/Achiral%2Bchiral.png Blog - An Introduction to Chirality - Make it stand out The two mirror images of an achiral object will have the same interactions with a chiral object. The resulting combined objects will be mirror images as a result of the original chiral object. The interaction of two mirror images of a chiral object with a second chiral object will be different. The resulting adducts will be different, they will not be mirror images. The interactions of chiral objects with chiral objects is different. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/45408462-062f-46ce-8e03-500f1007e74a/Tetris_achiral_cropped.png Blog - An Introduction to Chirality - Make it stand out An achiral ’T’ piece and its mirror image both fit in the gap (and complete the line). This is no surprise as the mirror image of an achiral object is identical to the object. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/586c980b-44a0-4033-afc1-a49bbe64fe86/Tetris_chiral_cropped.png Blog - An Introduction to Chirality - Make it stand out The ’S’ piece is chiral. It is different to its mirror image, the ‘Z’ piece. Only one of the two mirror images will fit into the slot in this chiral board. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/94955d84-2a17-4db8-8624-261d872ed902/Chiral_achiral_molecules.png Blog - An Introduction to Chirality - Make it stand out Achiral and chiral molecules have the same properties as achiral and chiral objects. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/24183db9-e308-40b2-81b0-19b5cf7dabbd/stereoisomers.png Blog - An Introduction to Chirality - Make it stand out Chiral molecules are a type of stereoisomer. Non-identical mirror images are called enantiomers while non-mirror image stereoisomers are called diastereomers. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/389de333-dbf0-474e-9977-1f4b035b2e25/plane_symmetry.png Blog - An Introduction to Chirality - Make it stand out Achiral molecules will have at least one other element of symmetry beyond an axis of rotation. Most commonly, this is a plane of symmetry. Chiral molecules, at most, have an axis of rotation or no symmetry at all. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/017dfde5-7bb3-46eb-82de-7e09f17b2e0d/Enantiopure.png Blog - An Introduction to Chirality - Make it stand out Molecules can be chiral, substances made up of chiral molecules are either enantiomerically pure, enantiomerically enriched or racemic. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c3ba68cd-c1d3-493f-8616-80faa9f79d0b/Optical_rotation_Use.png Blog - An Introduction to Chirality - Make it stand out Cartoon of a polarimeter and the rotation of plane polarized light by an enantiomerically pure compound. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/637f7c65-c636-4321-8f43-980b38e3e3d0/Different_rotations.png Blog - An Introduction to Chirality - Make it stand out If you know how much a pure enantiomer rotates plane polarized light you can determine the purity of a mixture by measuring the size of the optical rotation/specific rotation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eaa25ebc-f0b0-4e57-944b-7bdbee49ee20/Biological_activity.png Blog - An Introduction to Chirality - Make it stand out Different enantiomers can have different biological activities. R & S describes the stereochemistry in the molecule. A detailed explanation can be found in a previous summary HERE. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4b4c7a95-df3d-4e13-8530-d1a858a614fb/tartaric_acid.png Blog - An Introduction to Chirality - Make it stand out Enantiomerically pure substances can have different properties to mixtures of enantiomers of the same compound. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ab0132a6-6ca2-426f-9ad8-35c499836f0b/Stereocentre.png Blog - An Introduction to Chirality - Make it stand out A cartoon showing that there must be four different groups coming off a tetrahedral atom for it to be a stereocenter and be chiral. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9c95bbaa-1321-48eb-9b86-c518ad151a7d/tartaric_acid_meso.png Blog - An Introduction to Chirality - Make it stand out Some molecules with multiple stereogenic centers are still achiral. These are known as meso compounds. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f4ef0b08-cede-4a1d-bc59-b588ea121ae1/Other_chirality.png Blog - An Introduction to Chirality - Make it stand out Chiral molecules that do not contain a stereogenic center. https://www.makingmolecules.com/blog/predicting-acids monthly 0.5 2023-05-08 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a57f0b03-a3a7-438e-ba2a-daf05d23b477/General_acid_base_V2.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The general reaction of an acid and a base. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a365ff0f-47d4-4153-85e8-7a860a514f2b/Factors.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Factors influencing the stability of the conjugate base A-. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a8f02429-1394-44a8-8316-b44dea18790c/electronegativity.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Effect of electronegativity on the stability of the conjugate acid as you move across a row of the periodic table. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/14ca253c-0d0d-44d0-a2bd-4aa5103b85b4/Size.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Effect of the size of an ion or the strength of the bond on acidity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/46937bf3-7511-469b-9cfb-a363cfbcc937/Size_bonds.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out A cartoon representing poor overlap. The bigger the difference in size of atoms the weaker the bond connecting them. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fade1cfe-641a-47f4-bd00-992459ab71d2/Ranking_Q1.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/41ebda6f-4f6a-4267-b355-b7a747593b13/Ranking_Q1_answerV2.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out By comparing the thiol to the alcohol and the alcohol to the amine, it is possible to determine the order of acidity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bb2cef03-b0a2-41ef-ab7b-d1440104c62b/Ranking_Q1_Answer2.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The correct order of the compounds along with approximate pKa values (for most similar compounds). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/eed5ca1e-7aba-4cb7-8f14-39e0c4a2fcbb/chloric_acid_delocalization.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The effect of increasing delocalization of charge in the conjugate base. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0c167f59-26e5-4c52-9c43-111bcea8d81c/acid_delocalization.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out * this is the pKa for methanol, the pKa of ethanol will be slightly higher but probably not much (see inductive effect). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/47187ffd-afc3-472f-a291-5402c34e269a/Acetic_acid_vs_Phenol.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Delocalization in phenol and acetic acid. Spreading the charge over electronegative oxygen atoms has a greater effect than spreading the charge of multiple carbon atoms (and the inductive effect described later is also important). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/892c3579-5dd1-403f-9735-d81016b8b0fa/p-Nitro-phenol.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Increased delocalization lowers the pKa of phenol but not by as much as you might think. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/09a141bd-0fca-4850-9684-412b251d4260/Nitro_phenols.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Resonance stabilization is only possible if the nitro group is ortho or para. It is not possible with a meta substituent. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a3fd6418-7e80-414d-9c68-d19938654f0d/Ranking_Q2_Question.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4bcc87ba-7cfa-4fe1-a2fc-a2a18f1cb9d1/Ranking_Q2_answer.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The allylic proton is more acidic due to delocalization. * approximate pKa values for similar molecules. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/32f08dfa-847e-4966-92d5-cd64dffc1edf/Fluoro_acids.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The inductive effect explains the increasing acidity of fluoroacetic acid derivatives compared to acetic acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42f24a1e-e36e-48b9-8c32-0980f3d7314b/Chloro-Phenols.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Proximity of an electronegative element, or electron withdrawing group, effects the acidity of the phenol. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d32ba6bd-35a4-4c2d-8e66-52264f716bfc/Amine_base.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out The inductive effect can destabilize a base and make the compound more basic (or the conjugate acid less acidic). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9ea9315b-6569-4f6f-910e-9f35269f9efa/Ranking_Q3_Question.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1bab3003-d7dc-448c-ada2-e3588db1fd44/Ranking_Q3_Answer.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ca5cb69f-fd93-4369-b3d2-da0fbb1d5e1b/alkyne_vs_rest.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Why is the proton on an alkyne more acid than that of either an alkene or alkane? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9a995c47-5d31-46d1-a04f-b3092f00a7e7/alkyne_acidity.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Effect of hybridization on stability of conjugate base. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/08ff4d54-f9e6-4e9b-a12e-224a80d90165/acetontrile.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/93c97cf3-6f95-402d-8e95-d249c6e3a3b8/acetontrile_answer.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d86a9f08-b246-40fa-9b80-7c6d22b4e01d/solvent.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Solvent will influence the ease of dissociation or deprotonation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4c8464e-da32-4211-9bc6-f45ff1868522/reaction.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out Sodium amide is a sufficiently strong base to deprotonate an alkyne. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b50673e5-0ebe-4999-8429-0156a94bcc3c/General_reaction2_the_end.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out General acid base reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/43228dff-05ed-4d46-90c9-df7751d0b4ed/Simple_deprotonation.png Blog - Predicting the relative strengths of acids (or bases) - Make it stand out An example of an acid base reaction. https://www.makingmolecules.com/blog/acidsbases monthly 0.5 2022-08-22 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f8a24d63-3b3a-47c2-862a-906321faccfb/hydronium_ion.png Blog - Acids &amp; Bases - Make it stand out While seen in organic reaction mechanisms, H+ or a proton, does not exist and will always be associated with another molecule. If the reaction is in water then it will be a hydronium ion. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/28ef430b-c23f-42fe-9643-db66742b2d58/Acid_base1.png Blog - Acids &amp; Bases - Make it stand out A typical acid base reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f27d45bc-c80d-424b-8119-c368deff6a49/General_Acid_Base.png Blog - Acids &amp; Bases - Make it stand out General form of the acid-base reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fad7e726-48c7-4ebc-991b-5a55c7f0706b/Strength_acid_V2.png Blog - Acids &amp; Bases - Make it stand out A generalized acid-base reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8fca69db-4a63-4be7-870b-004bf0235d0d/Strong_General_acid.png Blog - Acids &amp; Bases - Make it stand out A strong acid fully dissociates and will favor the right-hand side. It will have a large equilibrium constant (> 10^2). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6c815e38-060c-46c0-ab17-926e2366af8a/Weak_General_acid.png Blog - Acids &amp; Bases - Make it stand out A strong acid does not dissociate much. The equilibrium favors the left-hand side. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/205222c2-3d2b-4d11-b383-d7ad00af34ab/Ka_Acid_Base.png Blog - Acids &amp; Bases - Make it stand out Acid-Base equilibrium in water. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/082b63e5-ceef-4fc7-9424-3433f9a7295a/HCl_strong_acid_V3.png Blog - Acids &amp; Bases - Make it stand out Hydrochloric acid has a large Ka and is effectively fully dissociated. The orange dot represents HCl while the black dots are the ions Cl– and H+. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77a6cc69-5fc3-4c0b-be52-69e593b4b941/AcOH_Weak_acid_V3.png Blog - Acids &amp; Bases - Make it stand out Acetic acid is a weak, organic acid, with a small Ka. Only a small number of molecules have dissociated as represented by the black dots (the ions H+ and AcO–). The orange dots represent protonated acetic acid. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8abfc4c6-1795-4a56-9429-d2276b5925c2/pKa.png Blog - Acids &amp; Bases - Make it stand out The relationship between Ka and pKa. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/11de6920-5465-40f5-b91e-a0b4024b25ab/pKa_Scale.png Blog - Acids &amp; Bases - Make it stand out A simplified pKa scale. The boxes above give an idea of the scale of proton dissociation (black dot dissociated conjugate base - orange dot, the non-dissociated acid). Values are approximations (as there are multiple values available online). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3ed2361c-f95f-4eeb-9456-e9baae1f9ed2/strong_acid_pka.png Blog - Acids &amp; Bases - Make it stand out Pictorial summary of a strong acid, which will have low (small or negative) pKa. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/04d0ce27-0c21-43b5-b000-96da8df8784a/Weak_acid_pKa.png Blog - Acids &amp; Bases - Make it stand out Pictorial summary of a weak acid, which will have high pKa. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/82b5bbd9-80aa-4c54-9a0a-8346698c6a70/meaningless_reaction.png Blog - Acids &amp; Bases - Make it stand out A meaningless reaction. Absolute fantasy but here to make a point (without any subtlely). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f0ac0f28-fdfa-4e98-b7bb-c018f4b1bf1e/BasicityV2.png Blog - Acids &amp; Bases - Make it stand out Using pKa to assess basicity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/35957ab0-4fcb-45a1-b5ba-d094a28c1421/pH_formula.png Blog - Acids &amp; Bases - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/01910f0f-64b3-4913-9787-ce82677d742a/Water_dissociation.png Blog - Acids &amp; Bases - Make it stand out Water reacting as both an acid and a base. The small value of K shows the equilibrium favors the left-hand side. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/15575536-f57e-477b-b6ae-5a3c25a59a18/pH%3D7.png Blog - Acids &amp; Bases - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9888e00d-5d99-4084-a211-219c2e98c2b0/pH_ScaleV2.png Blog - Acids &amp; Bases - Make it stand out The pH scale. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a91c1105-ebae-4118-bc49-b40fc5a01858/pH%3DpKa.png Blog - Acids &amp; Bases - Make it stand out The relationship between the pKa of a molecule, the pH of a solution and whether a molecule is protonated or not. If the pH < pKa then the majority of the compound will be protonated. If the pH > pKa then the majority of the molecule will not be protonated. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/087cde15-77fc-402e-90d2-8bdef67cb6ee/Favoured_reaction.png Blog - Acids &amp; Bases - Make it stand out Reactions always favor the weaker acid and base. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/48b10b67-73f3-423d-adb9-107c2213ce83/fentanyl_citrate.png Blog - Acids &amp; Bases - Make it stand out The salt, fentanyl citrate, is more water soluble than fentanyl. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d048a5ad-a16a-411c-b4b8-8567891e61e8/protonating_drugsH.png Blog - Acids &amp; Bases - Make it stand out Protonation of amines at physiological pH. If the pKa of the conjugate acid (pKaH) is lower than the pH, the majority of the amine will be unprotonated. If it is higher, then the majority is protonated. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ce0fe01a-1f7d-4ad9-be1c-a4c846445393/SeparationH2O.png Blog - Acids &amp; Bases - Make it stand out Separation of a mixture of compounds by acid-base extraction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9e47ce45-68b8-4fac-a661-7a8e8a512f74/Summary.png Blog - Acids &amp; Bases - Make it stand out A summary. https://www.makingmolecules.com/blog/equilibria2 monthly 0.5 2022-08-05 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/88287d67-c5bf-49cc-a1b2-85a4fd9dc4de/SeeSaw.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out See-saw acting as an analogy for Le Chatelier’s Principle - if the equilibrium is perturbed, the reaction counters the change to restore balance. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/527a6480-f7e2-4c0b-8948-75858e324b05/General_Reaction_pictorial.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/14b2a7c8-6f16-48d4-89ef-7d2c8697002d/Change_Concentration.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Increasing the concentration of a reactant on one side of the reaction will cause the equilibrium to shift in favor of the opposite side, increase the left side and the reaction shifts to the right. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fc73d784-c89b-4440-bd85-241d7c92bbd0/Conc_Change_explanation.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out The equilibrium constant must remain constant (if temperature unchanged), and reaction shifts to counteract any changes. Addition of starting material results in reaction moving forward. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dad63d9b-416f-4eb1-a600-b5f051502a84/Change_Concentration2.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Decreasing the concentration of a reactant on one side of the reaction will cause the equilibrium to shift in favor of that side as the reaction tries to counter the change - remove reactant from the left and the reaction shifts to the left. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c97d7694-932a-4b56-8acf-b5450c8295a7/Conc_Change_Remove_explanation.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out The equilibrium constant must remain constant at a fixed temperature. Removing starting materials decreases the denominator. To counter this the numerator must get smaller and more of the denominator (starting materials) must be formed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a1610361-85f8-4cf5-a1b1-0a71e7d720d1/Increase_pressure.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Increasing the pressure favors the side of the reaction with fewer moles of gas - this counters the change by reducing pressure. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0d36c6f9-7b7c-4013-a2fb-991dead86caf/decrease_pressure.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Decreasing pressure leads to the equilibrium shifting to the side with more moles of gas - this counters change by increasing pressure. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b7186384-f44f-4502-a180-ddcf7a66ee0d/Exo_and_endo.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Simplified way of thinking about exothermic and endothermic reactions in equilibrium processes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dafbfef2-fa14-42f7-8d74-1fa584b54dd2/Heating_reaction.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Heating a reaction shifts the equilibrium to favor the endothermic reaction, while cooling a reaction will favor the side that releases heat, the exothermic reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/caa568ae-084a-49f2-8445-cc8674920e03/Using_equilibrium.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out You can deliberately perturb the equilibrium in order to force the reaction to deliver the desired product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2dd7b077-e412-4364-8852-d2c3fbe0b0b1/esterification_Change_original.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Esterification is the forward reaction while hydrolysis is the reverse or backward reaction. The equilibrium constant is approximately 1 (possibly as high as 4). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/62ac682f-f703-47eb-a990-18cb5ee63ee6/Add_alcohol_V2.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Adding alcohol causes the concentration of carboxylic acid to decrease and the concentrations of ester and water to increase in order to maintain a Kc close to 1. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ea01fb57-d387-4533-bbb1-041784a2052f/LeChatelier_Summary.png Blog - Le Chatelier’s Principle: Stressing Equilibria - Make it stand out Controlling the equilibrium using Le Chatelier’s Principle. https://www.makingmolecules.com/blog/equilibria1 monthly 0.5 2022-07-29 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1def6729-8a02-4a95-b1b3-6798f1a5019b/Initial_reaction.png Blog - Equilibria (by a synthetic chemist) - Make it stand out The initial reaction proceeds in a single direction (as indicated by the single black arrows) as there are no molecules of the product to react in reverse direction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/16ee18b4-c1f7-461c-b03b-846cdbe2301d/Reaction_at_equilibrium.png Blog - Equilibria (by a synthetic chemist) - Make it stand out When at equilibrium, the rate of the forward reaction is the same as the rate of the reverse reaction (same number of single arrows going in both directions). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2adf329a-13f6-4c77-b030-426109d6800f/Reaction_at_equilibrium_different_amounts.png Blog - Equilibria (by a synthetic chemist) - Make it stand out In a reaction at equilibrium, the rate of forward reaction and backward reaction are the same but the amounts of each reagent do not need to be the same. Here, there is more product than starting materials. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f9b63937-ebcf-4c2a-9473-701a56cc6637/general_reaction.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/91b48e3f-05ac-4e48-9a3e-7838a0cc07cb/Equilibrium_Equation.png Blog - Equilibria (by a synthetic chemist) - Make it stand out [A] = concentration of A in M (or mol/L). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5588848a-330d-4114-9178-3605e0d5fd78/Kc_greater_1.png Blog - Equilibria (by a synthetic chemist) - Make it stand out If Kc > 1, the reaction favors the products or right-hand side of the equation (there will be more product than starting materials). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e7d620b0-ccb8-4157-aa81-cd1b12f11c02/Equilibrium_clarification_V2.png Blog - Equilibria (by a synthetic chemist) - Make it stand out It is important to remember that an equilibrium reaction contains a mixture of both sides of the reaction equation, the amount of which is dependent on the equilibrium constant. If the equilibrium constant is > 10^2 then over 99% of the mixture is product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4a01d8b6-c3c0-49af-8c3c-fe1cf28db2aa/Esterification_V3.png Blog - Equilibria (by a synthetic chemist) - Make it stand out If Kc is close to 1 there will be equal amounts of the reactants and the products, neither side of the reaction is favored to any great extent. This is true of any reaction with a Kc between 10^-2 and 10^2. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/94de7af9-b58d-4f00-b95c-2e2318744381/Water_Kc_V3.png Blog - Equilibria (by a synthetic chemist) - Make it stand out If Kc < 1 then the left-hand side, or starting materials is favored. Kc = 10^2 and only 1% products. The reaction does not appear to proceed. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a2d5639b-26b3-4744-87dd-8cf3b6b3fb9a/Spontaneous_ReactionV3.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Reaction favors formation of the products as it releases energy (G is negative). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/09a580ec-f3b3-4312-b4d0-db89421d52f6/Change_in_Gibbs.png Blog - Equilibria (by a synthetic chemist) - Make it stand out As reaction proceeds (in either direction) so the Gibbs free-energy falls until it reaches a minimum. At this point the reaction requires energy to go in either direction. It is now at equilibrium. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6dd58d9b-6f8c-4eb7-a91a-ad2e1c8cd520/Gibbs_Kc.png Blog - Equilibria (by a synthetic chemist) - Make it stand out The connection between the Gibbs free-energy change and the equilibrium constant. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0f1b278e-b1bc-4e0d-a416-b83ecf06582c/DG_Meaning.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Gibbs free energy and the position of the equilibrium. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b69708d6-b7b6-4651-8d94-719e95855bfd/Methylcyclohexane.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Determining the strain energy of axial methylcyclohexane based on the population of the two conformations. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bf646864-0748-4ec9-ba6d-8b985832aac1/tert_butylcyclohexane.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Determining the population of two conformations from the difference in strain energy. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/295d36c2-8ade-4559-861f-c021c0f06641/DG%3DDH.png Blog - Equilibria (by a synthetic chemist) - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/63246af2-3639-478d-a68b-6bf3ff187991/Exothermic.png Blog - Equilibria (by a synthetic chemist) - Make it stand out An exothermic reaction releases heat (energy) and the products are more stable than the starting materials. The bonds of the product are stronger. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3465fb28-866a-4c25-8a50-e4caacf30ca5/Endothermic.png Blog - Equilibria (by a synthetic chemist) - Make it stand out An endothermic reaction takes in heat (energy). The products are less stable than the starting materials and they will have weaker bonds. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/98cbd4a2-5bcd-47fa-a57e-6f3a8c6f74c1/Entropy.png Blog - Equilibria (by a synthetic chemist) - Make it stand out A simple view of entropy. In the top reaction, the number of molecules increases so the disorder increases and S is positive. The opposite is shown at the bottom. In an addition reaction the number of molecules decreases and S is negative. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dec7644f-0006-486d-804d-41c633a6cc27/Favoured_reactions.png Blog - Equilibria (by a synthetic chemist) - Make it stand out There are two ways to achieve a negative G and thus a favourable reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e86145bb-87fa-4247-834b-22062baf3777/Kc_Summary1.png Blog - Equilibria (by a synthetic chemist) - Make it stand out The equilibrium constant Kc of a reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8899809a-b654-493d-9d22-e007e209e897/Kc_Summary2.png Blog - Equilibria (by a synthetic chemist) - Make it stand out The position of the equilibrium. The relationship between Gibbs free-energy change and the equilibrium constant. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/325128c0-1092-4fe9-a912-52130fc8a1cb/Kc_Summary3.png Blog - Equilibria (by a synthetic chemist) - Make it stand out The components of the Gibbs free-energy change of a reaction, enthalpy (stability or bond strength) and entropy (disorder/randomness as a simplification). https://www.makingmolecules.com/blog/planar monthly 0.5 2022-07-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4d5c2f02-ed5f-4c8e-8a0b-83447a747850/PC_tetrahedron.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out The configuration of [2.2]paracyclophane based on a stereogenic centre or a tetrahedron. The plane, a & b, forms one edge of the tetrahedron and the out-of-plane atoms y & z are another. The priorities are a > b > y > z. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/467777f1-c15d-4301-a5af-105cb59a9291/PC_tetrahedron_assignment.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Method of assigning stereochemistry based on drawing a tetrahedron on the cyclophane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/64b91dc4-998f-47cf-907f-c6e20f3f8828/Identify_plane.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a5746748-c9f5-43f2-9c91-a6c6239e8c67/Pilot_atom.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ec2429ad-1760-4413-a6d8-ece8e75955f7/number_atoms.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2707af98-4fe6-4f4c-a98a-e035fa198737/Cyclophane_configuration.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7eafdd48-d684-4231-8090-df21b06c5c5c/cyclocphane_example.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Assign the configuration of this [2.2]paracyclophane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/54b62323-c6f1-4f4c-aef6-8bfa31545f46/Cyclophane_Example1_Answer.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out The steps to determining the stereochemical descriptor for a planar chiral cyclophane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2f42967f-8649-474c-af8c-d9144646e83b/cyclophane_helix1.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Describing a cyclophane as a helix. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b6cc2d25-117a-4b7d-8413-f494e00588cc/cyclophane_helix2.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Using a Newman projection to determine the helical descriptor of a cyclophane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2fe03a67-5f8c-4b09-b13a-aa798d7fd67d/Metallocene_pilot_atom.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/21550e31-7a2f-4abd-8277-e57cf2822217/Metallocene_number_atoms.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e84b180f-59bb-44cb-b77a-d59cb04d82c2/Metallocene_Assign_stereochem_recommended.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dd21dc73-9dc4-4da3-b3ac-72ed3617c519/Metallocenes_Planar_chiral_idenitfy_plane.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d69c92ff-2dde-4066-beac-49f31b139940/Metallocenes_Planar_chiral_idenitfy_pilot.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/72ce4427-def6-4dd2-a478-e539a451c5a1/Metallocenes_Planar_chiral_idenitfy_groups.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f9f3afc5-c8bd-4018-98dc-c9312786f0cc/Metallocenes_Planar_chiral_Assign_configuration.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/362a3452-e869-45a3-abdc-e535e6fe7cf5/Josiphos_central_chirality.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out Assigning the stereochemical descriptor to the stereogenic plane of Josiphos using the recommended convention. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7ae9b89b-879d-4621-a8bc-bea32345d59d/Josiphos_planar_chirality.png Blog - Stereochemical descriptors 3: Assigning a descriptor to a stereogenic plane - Make it stand out The older naming convention gives the opposite stereochemical descriptor. https://www.makingmolecules.com/blog/helical-axial monthly 0.5 2022-07-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7baca069-6dae-48d1-a1df-493b0bc9e3fd/atomic_number.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7876f7ba-e4ee-4674-a69d-abf264261416/Move_Chain.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/67577b52-e692-45bf-acfc-ef319538f941/Multiple_bonds.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/32924c9f-6b92-47d9-9b4f-4ff7e084a7db/atomic_mass.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b0ab27b2-8d70-4462-86f5-aeee6a493fc9/geometry.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c1b6fbde-faae-41a2-9cd8-70d946a08b19/Configuration.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e5f50cf7-392f-427d-9634-367150dcb73a/Nearer2.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c32ebf65-e275-4a2b-bd97-44ff99a75e80/6Helicene.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Determining the configuration of [6]helicene - looking along the axis of the helix, if rotation is anticlockwise as you move away (front to rear) then the configuration is S. If it is clockwise then it is P. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/decdf1d4-0acb-49d0-8b8a-10df220a3efe/arrows_helix.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f8e6525b-9e42-4dfd-9ce5-24c5af08bcf0/P_M_descriptors.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e95b5df8-2e85-4fd1-a970-2280d157e119/Conformation_butane.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Differentiating the two gauche conformers of butane by defining the stereochemical descriptor of the helix. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b0dcd467-51bc-4ca6-ab2d-f6b57f2965af/Axis_1st_examples.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Examples of determining the stereochemical descriptor of an axis of chirality by considering it as an elongated tetrahedron. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3cace95c-9189-4540-ad08-ef3dd160cdeb/Axis_example2.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Simplified determination of the stereochemical descriptor for an axis. The direction the axis is viewed from is immaterial as long as the nearest groups take priority. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/80e11c6a-1ad6-4fd2-a2b2-9ae799e10d3b/axis_example3.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out Simplified determination of the stereochemical descriptor for a stereogenic axis in a chiral biaryl compound. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/840919e0-a69e-495a-9f45-6bfb485f7a88/Axis_PM_V2.png Blog - Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality - Make it stand out A stereogenic axis can be treated as a helix and the configuration assigned the descriptor P or M. https://www.makingmolecules.com/blog/cyclohexane monthly 0.5 2022-06-16 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/181ff637-215d-4d8f-9873-9d9bcc0d76e1/Ring_strain_plot.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Strain in cycloalkanes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d587e457-7781-4268-9a7e-a65dffc2b1a5/ethane_cyclopropane2.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Torsional strain in ethane and one component of the strain in cyclopropane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/baa6312c-2180-4cfc-a995-271272a9df60/Cyclopropane_VB.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Cyclopropane - forcing a tetrahedron into a triangle. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4062e57f-ba99-447e-a9a0-abc997c86de8/Cycloalkanes.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Cyclobutane and cyclopentane reduce torsional strain at the expense of ring or angle strain. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/82716985-957c-41a7-be28-ae66933e6f3c/Cyclohexane_First_diagram.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The chair conformation of cyclohexane (& ball and spoke model for clarity). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c0d96461-06d3-422e-914d-785681fc4724/Axial_Equatorial.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The skeletal representation of cyclohexane showing hydrogen pointing towards viewer (up) as bold wedges and downward hydrogen as hashed lines. The forced perspective representation of the ring shows three axial hydrogen are up and three down. Three equatorial hydrogen are up and three down. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f11e9199-9abe-4a3b-8b4c-4974bd0562c6/Draw_cyclohexane.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4e3a977e-9fe8-4a0e-ba52-565bd7972e5a/Adding_Axial_bonds.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/49ba2248-4c5c-43cb-9c75-47ae046334c5/Adding_equatorial_bonds.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e5254a2e-1e67-4a6f-8ffc-f2998b10c8c7/Reverse_chair_ring.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The chair can slope in the opposite direction, just start with the V falling to the left. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4d752fec-585f-4ed1-99f6-c090c5c71d5b/Permitted_drawings.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out By convention, it is assumed that the chair conformation forces perspective onto a drawing. The use of bold wedges and hashed lines is not encouraged. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cd5b0e17-9d79-4c38-a425-7eae214eabe6/Crap_drawings.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Poor drawings all lecturers have seen far too many times. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/913cd0ec-a27a-46cb-bdeb-c74d274e1f37/Methyl_cyclohexane.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The two conformations of methylcyclohexane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fff4975e-88c3-4726-ad8c-0f9fddd203ee/Chair_flipping_with_arrows.gif Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out An animation showing ring flipping in cyclohexane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a45cb9a4-5197-4aae-99ce-f35c1e8d3b35/Not_ring_flipping.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Rotating the molecule versus rotating bonds or ring flipping cyclohexane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5fa129d0-d968-44aa-aff6-c0297c47730f/Two_ring_flips_V2.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Two approaches to drawing the two conformations of cyclohexane: top is ‘more’ correct & the bottom is ‘easier’. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2fa18f7-34ad-4204-9a30-faee98ba29e4/DIaxial_Me_finished.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out 1,3-Diaxial interactions disfavor the axial conformation and only 5% of the molecules reside in this conformation at any one time. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cb0744a8-5a08-472b-8e2b-cbf0b571f09e/DIaxial_tBu_finished.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The larger tert-butyl group causes more steric or 1,3-diaxial interactions when in the axial position than a methyl group. It is rare to see a tert-butyl group adopt the axial conformation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9d65f62b-7877-4616-8373-11720b445407/Newman-13-Diaxial.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Newman projection showing axial substituents suffer from gauche steric interaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9500c2df-8f34-4569-97a2-241d8f2e72a8/Mapping.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Mapping substituents from the skeletal representation to the chair conformation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/14e25558-809b-4f59-987d-ba719ca458be/Draw-disubstituted1.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Drawing one of the chair conformations of a disubstituted cyclohexane ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2fca530a-e3a8-47c4-8d55-4cd36aa0bf2b/Draw-disubstituted2.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Drawing the other chair conformation of a disubstituted cyclohexane ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a147ea18-f64f-4cc3-ad9f-7e6ab1c691be/Alternative_conformation_drawing.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out A second way to draw the other conformation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2b21bd1a-fe57-43b3-bfc3-b2e5d052a7ec/Two-Conformations.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out The two conformations with the most stable, the one with the largest group equatorial, highlighted. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ccc07a7b-2171-43c7-b0ef-c27aff5496d8/cis-trans.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Cis and trans diastereomers and their two conformations. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/53c33c08-7824-4932-8d94-bff650f7ede3/Heterocycles.png Blog - An Introduction to the Conformation of Cyclohexane - Make it stand out Six-membered saturated heterocycles behave similar to cyclohexane. https://www.makingmolecules.com/blog/9hy2qo78989yu1tqr06vifinbeu91u monthly 0.5 2022-06-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f84fae0a-4f8a-41d1-a9b5-163b754d3f93/Conformation_analogy2.png Blog - Conformations of simple acyclic alkanes - Make it stand out Analogy comparing conformations and configurations to the human body https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f7c6bd06-0c7b-4d19-806c-69a1f2cf1f70/Rotate_single_bond2.png Blog - Conformations of simple acyclic alkanes - Make it stand out Rotation around a single σ bond has no effect on the orbital https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/097e7e63-4e45-4bf5-a78b-53bc1808ccc5/rotate_pi_bond1.png Blog - Conformations of simple acyclic alkanes - Make it stand out Rotation of a π bond would cause the 2p atomic orbitals to become skewed & no longer overlap. The bond would break. You cannot rotate a π bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a2027769-ab19-423f-ab0c-9ca4a989f5e0/Representaitons.png Blog - Conformations of simple acyclic alkanes - Make it stand out Three representations of a molecule all showing the same conformation. One atom is marked with an asterisks for clarity. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/76cb45a5-08f8-42ba-be71-48ee5b4d031e/Skeletal_Sawhorse_rotating.png Blog - Conformations of simple acyclic alkanes - Make it stand out Rotating a molecule between skeletal, sawhorse and Newman projections (then nudging the Newman projection to one side to highlight the relationship between Newman & sawhorse). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d26be2d3-51cf-4778-913f-610f27136b8e/skeletal_Newman_traditional.png Blog - Conformations of simple acyclic alkanes - Make it stand out The traditional way to convert between a skeletal representation and the Newman projection. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/944c8b01-9c4c-43a4-ad88-720615fe9e5a/Newman_skeletal.png Blog - Conformations of simple acyclic alkanes - Make it stand out Converting a Newman projection to a skeletal drawing via a sawhorse representation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3ebafbb1-6f26-429f-8e3e-03356536f8fe/3D_molecules_V3.png Blog - Conformations of simple acyclic alkanes - Make it stand out Two drawings of a natural product taken from the work of David Proctor at the University of Manchester, UK https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b7a79290-7a64-485c-a6a5-77a7b2b42e0a/Staggered3.png Blog - Conformations of simple acyclic alkanes - Make it stand out The three representations (& the ball and spoke model) of the favored, staggered, conformation with the analogy of a comfortable person https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/20c3a216-c0d8-471c-8f76-97b1618869ad/eclipsed4.png Blog - Conformations of simple acyclic alkanes - Make it stand out The three representations of the disfavored eclipsed conformation (& ball and spoke model) with the analogy of an uncomfortable person. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a8a30387-20b0-4a53-8b12-90eb6c9c4965/Barrier_analogy1.png Blog - Conformations of simple acyclic alkanes - Make it stand out An analogy for the barrier to rotation. Standing up takes energy. This is equivalent to the high energy disfavored conformation. It is the barrier to moving between conformations. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/25c31c09-f49c-40c9-aece-d4e7441cbeeb/barrier_analogy2.png Blog - Conformations of simple acyclic alkanes - Make it stand out A second analogy showing a marble being pushed up a hill. The top of the hill is the barrier and is equivalent to the least favored conformation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2167dfb9-15da-40f5-b37e-3e0eedb79d88/%2312-Ethane_energy_profile_V1+copy.png Blog - Conformations of simple acyclic alkanes - Make it stand out Energy profile for the rotation of the C–C bond of ethane (sorry the style doesn’t match the rest of the pictures but I didn’t feel like re-plotting the data so just pinched the excel plot I use at first year). https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/37765e83-3562-407f-8071-b77d8c2bc275/torsional_strain2.png Blog - Conformations of simple acyclic alkanes - Make it stand out Torsional strain, the repulsion between electrons of a bond, causes the eclipsed conformation to be less stable. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b90a0d4d-86f3-43a1-a4ed-416f4cdae4dd/hyperconjugation.png Blog - Conformations of simple acyclic alkanes - Make it stand out The staggered formation is more stable due to interactions between the σ bonding orbital and the adjacent σ* antibonding orbital due to better alignment of the orbitals. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/55ff9ed5-f3c6-4361-a349-24924b2566be/Examples_rotation.png Blog - Conformations of simple acyclic alkanes - Make it stand out Structural features alter the barrier to rotation. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4f52c554-51ba-4396-8222-9c2166718f36/Propane.png Blog - Conformations of simple acyclic alkanes - Make it stand out The conformations of propane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/69376837-5157-4787-8755-add5b5b0eba2/butane.png Blog - Conformations of simple acyclic alkanes - Make it stand out The conformations of butane https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8cbde980-71ef-43c1-b7dd-75bf48904635/butane-gauche.png Blog - Conformations of simple acyclic alkanes - Make it stand out Gauche conformation of butane showing steric hindrance. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5e4cc671-53a0-48c4-8a8c-3c22087ba82b/pentane.png Blog - Conformations of simple acyclic alkanes - Make it stand out The conformations of pentane. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/31062cc4-f5e6-45c9-8c82-e062be3bb1be/pentane_stable.png Blog - Conformations of simple acyclic alkanes - Make it stand out The most stable conformation of pentane, drawn as a skeletal representation, an extended sawhorse and the Newman projection along the C3–C4 bond. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/38511a24-80bf-4ad9-9430-c4c176b02c54/Conformation_question.png Blog - Conformations of simple acyclic alkanes - Make it stand out What is the most stable and least stable conformation around the bond highlighted in blue? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a96d004c-ced4-4fdb-9fc4-05c39b0f690e/Answer_Draw_Newman.png Blog - Conformations of simple acyclic alkanes - Make it stand out To answer the question you need to draw the Newman projection. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d1913a8b-1731-45bf-997a-fcdb61b0c06a/Answer_compare_staggered_Newman.png Blog - Conformations of simple acyclic alkanes - Make it stand out The largest groups on each atom are marked in red. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/427d7e4c-95b1-4ef6-a6ab-59b7824f3fe2/Answer_compare_eclipsed_Newman.png Blog - Conformations of simple acyclic alkanes - Make it stand out The least favored conformation has the the most steric interactions - here it is the largest substituent on each atom eclipsed. https://www.makingmolecules.com/blog/3ghoexnqn3c23tsv2x8jzlk35atc6b monthly 0.5 2022-06-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/38131874-9747-40ae-89d3-8c6238030b5d/Isomer_Flow_Chart_Full_1.png Blog - Isomer Flowchart - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ae6729b0-6afc-4c01-832e-c7606fe8c0a6/Isomer_Flow_Chart_Simplified_1.png Blog - Isomer Flowchart - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/71a8dd6e-7a3c-46e0-99b5-4aa544d4b9a4/Pictorial_Isomers_A4.png Blog - Isomer Flowchart - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/705eb2fb-a0a5-42fe-9d47-938ce27f806b/Notes.001.png Blog - Isomer Flowchart - Make it stand out First working drafts https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/96e26fc4-42f2-4442-b066-fa75c61b4e4d/Notes.002.png Blog - Isomer Flowchart - Make it stand out Working sketch https://www.makingmolecules.com/blog/7d9hspx9lt7gneed6mz4exsxg91ll4 monthly 0.5 2022-06-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8d356b96-80bd-4bf3-a1cc-c7e7d1a3e243/Plus_minus.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out The use of (+) and (–) to describe the optical properties of stereoisomers https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1cfe7dd1-ca0f-4f35-99af-7ca2e07c4f29/Phenylalanine_Glyceraldehyde.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out D & L enantiomers and their connection to glyceraldehyde https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/18ee2da0-7900-4fa9-a5a8-8ccc4a7c231c/Rank_Groups.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/11747dd5-a7af-482d-a347-4719fac36c44/Rank_Groups2.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/21255ff3-d813-4173-9ee6-c6f40b16e856/Rank_Groups5.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/97df9942-622c-432a-a66c-d6c5b44ad4e9/Rank_Groups4.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b4812a71-0d2e-400d-92f1-17ca4570996f/Rank_Groups6.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/16f7d3ef-f2e0-4619-a606-0e168ea83d2d/Rank_Groups7.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out You must ensure that the lowest priority group points away from you https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/748d60d5-8750-4cec-ac61-1394dd9f73b5/Example1.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Working through an example to determine the stereochemical descriptor of carvone https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b197190d-9781-4c33-a737-850dab2509cd/Alkene_Examples1.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Consider each carbon atom separately https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/12fd0b37-a59b-492c-a71e-c96f549bcae3/Alkene_Example2.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Ranking substituents of an alkene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5d11fa88-6e15-47c1-a451-41356586973c/Alkene_Example3.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Alkene stereochemical descriptors https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/717c4c0e-37ba-49a0-9592-007c852bedc8/Reflection1.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Enantiomers with the mirror to the right of the original molecule https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4e119c29-d5c6-4540-8ad8-d4caa422f00f/Reflection2.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Enantiomers reflected in the screen https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/65a5d931-f1be-4433-9a5d-50190a629a69/Reflection3.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Enantiomers reflected in the screen (right) and forced perspective drawing of this process (left) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4d2b7e23-dfb9-4dd2-bf4c-0984897b1cc6/Wobble-atom.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out ‘Wobbling’ a bond - if you keep the atoms in the same place the stereocentre remains a bold wedge https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7821e7eb-220c-4275-bd1d-ebe8fc093cb4/Bond_rotationcdx.png Blog - Stereochemical Descriptors: Naming Molecules - Make it stand out Rotating a bond by swapping the position of the groups and reversing wedge/hash https://www.makingmolecules.com/blog/tpyjoy313mzi7wp3oqmpfsuwzs5fwl monthly 0.5 2022-06-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b5bcdbc0-4846-4cbd-ac89-bfa575d9ec65/cis_trans_alkenes.png Blog - An Introduction to Stereochemistry - Make it stand out The two stereoisomers of butenedioic acid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6f829852-85af-46a1-ad18-a8f653289bcb/alkene-stereocentes.png Blog - An Introduction to Stereochemistry - Make it stand out The two stereocentres of an alkene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ba525b9e-e53e-4c2f-b2c2-5676590bd8ea/alanine2.png Blog - An Introduction to Stereochemistry - Make it stand out The two stereoisomers (enantiomers) of alanine https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2ce97b37-3ee2-467d-b64c-ded3dc386370/Alanine3Dv2.png Blog - An Introduction to Stereochemistry - Make it stand out A 3D model of D-alanine https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a8a979b5-9ad8-434d-9d3f-8f7ed7ba55d7/stereocentres.png Blog - An Introduction to Stereochemistry - Make it stand out Three examples of sp3 carbon stereocentres https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7120dfef-f182-4b09-b134-395b04b43e59/plane.png Blog - An Introduction to Stereochemistry - Make it stand out Chiral objects have no plane of symmetry. Achiral objects have a plane of symmetry. In this example, the plane is the same as the screen and cuts through atom 1, the central black dot and atom 2. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4a6d9a98-afb6-4735-ae84-1376bc3c50c9/diastereomers.png Blog - An Introduction to Stereochemistry - Make it stand out Diastereomers are different compounds https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/aa4ea36e-a9fd-4370-90f4-32c7d50dfc7d/tartaric_acid1.png Blog - An Introduction to Stereochemistry - Make it stand out A diagram of tartaric acid showing the two stereocentres. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3be2dfaa-b851-4250-ac8b-fa0c51c7a514/tartaric_acid_enantiomers.png Blog - An Introduction to Stereochemistry - Make it stand out The enantiomers of tartaric acid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f2b05b43-1453-4831-b007-d3ddfe02bccb/tartaric_acid_diastereomers.png Blog - An Introduction to Stereochemistry - Make it stand out Stereoisomers of tartaric acid, showing both enantiomers and diastereomers https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/90437602-6b9a-4ec4-8cc2-c3d3d4434bc7/2n_stereoisomers.png Blog - An Introduction to Stereochemistry - Make it stand out Various stereoisomers of simple sugars https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b7edabd4-eb27-4a07-847e-014dea1455dd/meso.png Blog - An Introduction to Stereochemistry - Make it stand out Two depictions of tartaric acid are not diastereomers but the same, achiral compound (the same molecule drawn differently) https://www.makingmolecules.com/blog/wlp2w18z0bsehupxg3waq6wspjufh9 monthly 0.5 2024-12-04 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6873e07f-4fe3-4570-9692-7f82da517ba3/Dipole_and_Bp.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out The effect of dipole-dipole interactions on boiling point (bp) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c4440da0-9627-4121-b131-0f42a9e50eab/H-Bonding_bp.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out The effect of hydrogen bonding on boiling point https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/257d41fc-ff72-4572-b7fd-c9fe811fb86c/dispersion_bp.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out The influence shape of a molecule on dispersion forces and boiling point https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/26ce9b67-eda4-4ec9-9af7-d059d88ad65f/Oils_fats_V2.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out The difference between oils and fats can partially be explained by dispersion interactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b40a7cdc-42b4-45da-80b9-29eb1332dd56/Miscibility-cartoon.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out A cartoon showing why polar molecules mix with polar molecules https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c844911d-e9a5-4357-b5bc-04ab244f7344/salt%2Bwater.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out Sodium chloride dissolves in water due to strong non-covalent interactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/04f60246-d80b-4615-aa0b-664e2b0be206/acetone%2Bwater.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out Acetone is miscible in water due to strong non-covalent interactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a2fd6e19-88b5-4fcc-a56e-9f8ba1718567/hexane%2Bwater.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out Hexane is not miscible in water as there are little non-covalent interactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/81c1e116-c751-4f86-a1e7-dfa1fb27f672/Acids.png Blog - Polarity Part 2: Intermolecular Interactions &amp; Physical Properties - Make it stand out The miscibility of simple organic acids in water https://www.makingmolecules.com/blog/ujan99dhistpi879lrjzwpfq8pxru5 monthly 0.5 2024-12-04 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ce839d3a-5b3b-4098-9157-7ef328d67197/Polar_Bonds.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Polar bonds and the two standard conventions for depicting polarization https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/94bcc75e-aea5-4b1a-91e4-62a14fdff0fc/Inductive_effect.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out The inductive effect exerts an influence over several bonds although its strength rapidly drops off (has less effect) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6a04c3de-af2e-4873-8edd-46241439a6b8/phenol.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out The mesomeric effect - delocalization of electrons and the resulting polarization of the resonance hybrid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0a668606-092d-4fc3-b23f-4732483d6a10/HCl2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Diatomic molecule showing the polar bond (bond dipole) and the molecular dipole https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9c11a35b-04d6-4413-9892-ce4c40217a18/non-polar_polar.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out The importance of shape on molecular dipoles and polarity https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/699cc889-2d5e-4521-b9e5-98a09d063727/CCl4_CHCl3.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Comparison of carbon tetrachloride (non-polar) and chloroform (polar) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a823beac-67f7-4284-adf4-d4f589b4b873/Zones.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Molecules can have polar and non-polar areas https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/47bc3ced-acdd-47ea-8850-7595b6e20566/non-covalent_interactions.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out A summary of the common non-covalent interactions (there are more but as an undergraduate this is all you need) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77f76afc-174a-46a3-9db9-19b8aa741a44/Salt_dissolving2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Ion-dipole interactions between cation and anion in water https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7ff45120-1826-4efb-aaf3-5e367838720b/ion-induced_dipole2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out An ion (the green cation above) can induce a dipole in a non-polar compound that temporarily causes an attraction before dissipating https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d72554dd-697b-45fa-b87d-5ec17ea528fc/dipole-dipole2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Diagram showing the two favored orientations of a dipole-dipole interaction https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b6a0ab31-2743-43bc-b977-3bc50238d815/H-Bonding2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out A cartoon of hydrogen bonding and examples showing optimum arrangement of atoms and lone pairs of electrons https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0afd0c40-dbec-4ae0-ba97-4ef9838190b8/dipole-induced_dipole+copy2.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Permanent dipole–induced dipole interaction with a polar molecule inducing a temporary dipole in a non-polar compound https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4e8c4173-8756-4f0e-8bc4-c4399047d3ed/dispersion_forces.png Blog - Polarity &amp; Non-Covalent Interactions Part 1 - Make it stand out Cartoon showing the origin of dispersion forces https://www.makingmolecules.com/blog/guqjbda7wm3p68z1p4elcjhwga68s3 monthly 0.5 2022-04-28 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/766b64be-8ad7-495e-a597-ff3740b9d9e3/Benzene_box.png Blog - Aromatic Molecules - Make it stand out Resonance structures of benzene and the resonance hybrid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d0cb4293-b863-444f-abcb-29c07d3d7c7b/Examples.png Blog - Aromatic Molecules - Make it stand out Examples of aromatic, non-aromatic and anti-aromatic compounds https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/486cddd4-c888-4df4-be32-16b52e2a0363/cyclic_box.png Blog - Aromatic Molecules - Make it stand out Benzene is cyclic so can be aromatic, hexatriene is acyclic and cannot be aromatic https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d4df785a-6b86-48ee-a02c-65d5d491bb8b/benzene_2p_box.png Blog - Aromatic Molecules - Make it stand out The non-hybridized 2p orbitals of benzene overlap around the ring and show an unbroken ring of conjugation https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dbd31551-f1ca-48f3-b56b-fa3996072c87/Cyclopentadiene_box.png Blog - Aromatic Molecules - Make it stand out Cyclopentadienyl anion is aromatic with an unbroken ring of 2p orbitals. Cyclopentadiene is not aromatic due to the sp3 carbon breaking the ring of 2p orbitals. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c890847c-a0e0-4cf6-b323-efbe972f81d6/Cyclopentadienyl_resonance_box.png Blog - Aromatic Molecules - Make it stand out The delocalization of the cyclopentadienyl anion (top) and the resonance structures for cyclopentadiene highlighting that the π electrons are never delocalized on the carbon https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1a1123f8-458b-4faf-b348-918bd9ec6303/pyrolle_full_box.png Blog - Aromatic Molecules - Make it stand out Pyrrole has an unbroken circle of delocalized π electrons https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cbe57daf-8dc5-47ea-bc01-4701c231c34e/Cycloheptatriene_cation.png Blog - Aromatic Molecules - Make it stand out The cycloheptatrienyl cation is aromatic, with an unbroken circle of π electrons https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/66b60098-98e4-4cb0-9dd3-642f9fc8c306/aromatic_antiaromatic.png Blog - Aromatic Molecules - Make it stand out The anion of cyclopentadienyl is aromatic, the cation is anti-aromatic https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/91859f7f-e3d6-48b4-a830-4cb73726e6b7/Huckel_box.png Blog - Aromatic Molecules - Make it stand out Aromatic and anti-aromatic compounds (and one non-aromatic compound) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1f9745a9-aa7e-40c6-8d33-9fc4239b98b0/cyclooctatetraene_shape_box1.png Blog - Aromatic Molecules - Make it stand out Shape of cyclooctatetraene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/549d7e17-aaf3-4440-950f-dea156196ed1/pyridine_resonance.png Blog - Aromatic Molecules - Make it stand out The lone pair of the nitrogen of pyridine is not involved in the aromatic ring and can react https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/61d206ac-f290-4ed4-aa57-18e79fd011d2/pyridine_2p_box.png Blog - Aromatic Molecules - Make it stand out Valence bond model showing the lone pair of pyridine https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8be857bf-a1e4-4fd9-9890-814754ce647a/pyrrole_lone_pair.png Blog - Aromatic Molecules - Make it stand out The lone pair on nitrogen of pyrrole is delocalized and a part of the aromatic ring. It is not basic. https://www.makingmolecules.com/blog/pokq0okaxq5sfal0lgzgw0if9rgfj6 monthly 0.5 2022-04-21 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/419efb1d-2cce-4e43-a5a2-73883792ca37/Curly_arrow.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out What does a (resonance) curly arrow show? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e133ca4f-496e-4d11-ac78-3e24710076d6/Example1_no_arrows.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Add a curly arrow to connect the left-hand resonance structure with the right-hand resonance structure. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/739cf8ce-c487-4b0d-944e-279dbe602cb8/Example1_arrows.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out The curly arrow connecting the two resonance structures of an allyl cation https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/38bca814-5614-4de4-a596-92e62a85ead5/Example2_no_arrows.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Add curly arrows to connect the left-hand resonance structure with the right-hand resonance structure https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e592e8bb-d697-46e0-9d60-f7380f2cca4e/Example2_arrows.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out The curly arrow connecting these two resonance structures https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ef75fe9c-e978-4bfc-8e7f-a05dfdb5c71b/Start_arrow.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c8fbf128-a0ae-42ca-b9ce-84d6dfad8519/End_arrow.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5562d66f-53e0-4c6b-92ba-7ce5c662bc23/Octet_rule.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ba0e67bd-57a7-4be1-b655-0b33c26d2f5c/Breaking_sigma_bonds.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f368cd4e-89e2-4ffe-88e0-f6d84465114b/Charge.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2e6f0934-0270-4edb-86cc-6fe0e6074dcc/Dont_skip.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f27089ca-6d1a-4b84-9374-2667f9cbe06a/bond_lone_Pair.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17712f35-afe6-4627-bf55-e3e02f621a47/lone_pair_to_bond.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d3a854ff-c49a-4970-9dec-b12966281338/bond_bond.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b28fc5fd-dd52-4439-8b34-e489d2b26cb5/Example3_no_arrows.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Add curly arrows to connect each of these resonance structures (moving left to right) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d40c265a-3cd8-4bd3-a74f-7531df6ccf9c/Example3_arrows1.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out The curly arrows connecting the first resonance structure to the middle structure https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8711a97d-5d46-4f69-9848-01208d7a978a/Example3_arrows2.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out The curly arrows connecting the second two resonance structures https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c21f9d32-933e-4ff4-984e-32af86a8496b/Example4_question.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Use curly arrows to help determine other resonance structures https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/de85d67b-b15d-4e2b-9c61-ecd7aa8c0d4c/Example4_answer1.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out A potential answer - a less important resonance structure https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e596fcb6-e19f-4b12-acbc-6ad2ecab60c1/Example4_answer2.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out A second resonance structure - more favorable as the formal charges are separated https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/10979ef3-bf37-4f91-90fd-994858d64338/Example4_answer3.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Two more resonance structures, including the second largest contributor to the resonance hybrid (far right-hand side) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/95ec5271-c470-4555-a1e1-7af416d592ab/Example4_answer4.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out The best answer https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/082e49e6-9196-482d-8e32-0258fa6d8456/Example4_answer5.png Blog - Resonance Structures &amp; the Curly Arrow - Make it stand out Some of the many resonance structures - not all of them play any meaningful contribution to the resonance hybrid https://www.makingmolecules.com/blog/jj5gyk89y6z7pxie9l9q4yvphbdp9t monthly 0.5 2022-04-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/882d016c-1a90-4a4c-a3d7-9be2c7976d4d/Conjugation.png Blog - Delocalization &amp; Resonance - Make it stand out Examples of conjugation and non-conjugation https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c0f52630-c328-4904-af09-d534fd59c88e/buta-1%2C3-diene.png Blog - Delocalization &amp; Resonance - Make it stand out Resonance structures of buta-1,3-diene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2a609f6b-3043-45db-9b63-e301a3978b52/enol_ether.png Blog - Delocalization &amp; Resonance - Make it stand out Resonance structures of an enol ether (1-methoxyprop-1-ene) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/777bf98d-333c-4b9b-b0a5-4325048930a5/curly_arrow.png Blog - Delocalization &amp; Resonance - Make it stand out Curly arrows connecting allowable resonance structures https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e854f19b-4cdc-488a-8754-ef11b3f796a8/Overlap.png Blog - Delocalization &amp; Resonance - Make it stand out Representing resonance structures and the resonance hybrid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8e9f3a5b-52e2-4874-911c-4503a6344ac6/Favoured.png Blog - Delocalization &amp; Resonance - Make it stand out Examples of the importance of various resonance structures https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8d2e443a-ddc8-4a12-b4be-be398fc8849e/Delocalisation_%26_VB.png Blog - Delocalization &amp; Resonance - Make it stand out Incorrect assignment of hybridization in a delocalized system https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1f35ac55-9d48-470d-9bd9-b94533d587e3/Delocalisation_%26_VB_Correct.png Blog - Delocalization &amp; Resonance - Make it stand out The correct assignment of hybridization in a delocalized system https://www.makingmolecules.com/blog/formalcharges monthly 0.5 2024-10-01 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4d661467-32e6-4d8b-b907-6e2ab9d3acb5/Formal_Charge1.png Blog - Formal Charges - Make it stand out The diagram above shows how you can look at the bonding to determine formal charge https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/84dc5ecd-268b-463b-a409-cbcb95873155/Formal_Charge2.png Blog - Formal Charges - Make it stand out Formula to determine the formal charge from line diagram https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7fd5f683-b24c-4c0b-88a6-e51ea75ecce0/Formal_Charge3.png Blog - Formal Charges - Make it stand out Determining the formal charges on the atoms of nitric acid https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/049286b4-4875-42d0-ae71-533a13863216/Formal_Charge4.png Blog - Formal Charges - Make it stand out Standard number of bonds for common elements in organic molecules https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3bae2e31-c31f-4e76-87aa-dab43cc904fe/Formal_Charge5.png Blog - Formal Charges - Make it stand out Bonds to oxygen - normally it has 2 bonds; more or less and it will have a formal charge https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1302e16d-15ee-4b01-b36f-76c513a3d2b4/Formal_Charge6.png Blog - Formal Charges - Make it stand out A carbon with three bonds can either have a formal positive or negative charge https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7b961830-4af6-4c43-8f35-1e59f8ffebda/Formal_Charge7.png Blog - Formal Charges - Make it stand out Elements of the third row can have different numbers of bonds and still have no formal charge https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9cd52eea-bece-4593-bb18-5084dc862473/Formal_Charge8.png Blog - Formal Charges - Make it stand out Determining the number of lone pairs of electrons from the formal charge https://www.makingmolecules.com/blog/0wo4bhz7eca6vvcx6ql3e7vi10opp8 monthly 0.5 2022-04-03 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a9ccfcb8-2495-4fb7-83dd-f3a1dcc8ab0a/Name.png Blog - Naming Molecules - Make it stand out Parts of an organic molecule’s name https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/713e411b-373a-49eb-947d-3b1305eb0e83/Major_FG.png Blog - Naming Molecules - Make it stand out The major functional groups and naming suffix https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0c3ce20e-421b-4c34-b354-06562ca51d52/Priorities.png Blog - Naming Molecules - Make it stand out Order of priority of the functional groups https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1224886a-972a-4e98-bc85-1e000e7a132a/Parent_name.png Blog - Naming Molecules - Make it stand out Parent name based on number of carbon atoms https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4432a1a7-51e9-4004-9324-b9a8ff0248ad/Minor_FG.png Blog - Naming Molecules - Make it stand out Minor functional groups and their prefixes https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b05f82eb-916d-4580-a5c6-92f668a4852a/example-full_name.png Blog - Naming Molecules - Make it stand out The steps to name an organic compound https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/617a8a8d-0bf4-4905-97c1-19fc6b9b45b8/Mono_benzene.png Blog - Naming Molecules - Make it stand out Naming monosubstituted benzene derivatives https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/67025e81-10a9-48ec-8900-751fd3976203/Benzene_positions.png Blog - Naming Molecules - Make it stand out Positions on a multiply substituted benzene ring https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/755b07f2-3842-4c14-b87a-f6eb94e414f9/Name-to-molecule.png Blog - Naming Molecules - Make it stand out Draw the structure of 4-amino-5-methylhex-5-en-2-one. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648863614435-JNU07TGBLJY64QHPE2W3/Example-Suffix.png Blog - Naming Molecules - Example: What are the major functional groups in the following molecules? https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648864318843-BUJTIZD56NPNKHQ2WIJD/Examples-parent.png Blog - Naming Molecules - Example: Identify the parent carbon chain in these molecules: https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648864466858-R46TDOSVK4WAOWVY9MBU/example-numbering.png Blog - Naming Molecules - Example: Number the parent chain: https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648864828947-80Y6ACIL9P2H9S9O1XBI/example-substituents.png Blog - Naming Molecules - Example: Identify the substituents on these molecules and list their prefixes. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648865160530-SK3ET85SPVM791RT4EP6/Example-alkenes.png Blog - Naming Molecules - Example of an alkene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648865337982-S0TQ1OOEZ6JBZ7CWXZAC/Example-Multiples.png Blog - Naming Molecules - Examples of multiple identical functional groups https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1648952682977-JS1SNVW72LZ0OOVXFMJF/Example-cycloalkanes.png Blog - Naming Molecules - Examples: Naming cyclic non-aromatic compounds https://www.makingmolecules.com/blog/arazfyh7cqeqromqhtcjmymk5nyr7f monthly 0.5 2022-03-27 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b3d7e745-4b63-459d-900e-f108446acbaa/Leucine_representationscdx.png Blog - Drawing Molecules - Make it stand out Various representations of L-leucine (naughtily drawn in non-zwitterionic or uncharged form) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8adc7cfa-f02a-4182-aab2-bcb650c3c2f2/Structural_to_skeletal.png Blog - Drawing Molecules - Make it stand out Converting a structural representation into a skeletal or line diagram https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fb680129-89e0-46b0-94e9-446499a2a689/multiple_bonds.png Blog - Drawing Molecules - Make it stand out Common errors when drawing multiple bonds https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2a04c243-9fe4-44b4-9a1f-9eb2a9712b2b/A_skeletal_drawing.png Blog - Drawing Molecules - Make it stand out Understanding a skeletal drawing https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/734f558c-6f3f-4e96-af1b-652038cfd22d/Line_to_structural.png Blog - Drawing Molecules - Make it stand out Converting a line diagram into a structural diagram https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c10c675a-d502-4da7-849b-9f2510795b2d/Good_and_Bad.png Blog - Drawing Molecules - Make it stand out Three poor and two acceptable molecular representations https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/21491cf6-b002-49e4-bb3b-c579870dfb6a/condensed_formula.png Blog - Drawing Molecules - Make it stand out Expanding condensed formula - you cannot add extra atoms https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f103e56a-74b4-4337-a988-7a81842f5992/Sparteine.png Blog - Drawing Molecules - Make it stand out Representations of sparteine and morphine https://www.makingmolecules.com/blog/functional-groups monthly 0.5 2022-03-25 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d83b9392-e02d-4822-8ab4-d14ad8deed8f/Alkanes_1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c21f57b3-54ea-4b4d-bc95-041337e4469c/Alkanes2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/548ea9a5-d052-4e7f-b9e0-a822ddbd071d/Alkenes1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/88fb9507-b784-449c-8bc8-c1dfaa6ee56c/Alkenes2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/dde7734c-6aaa-4aab-af4a-81235dadd40c/Alkynes.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8ac8f47a-fd84-43d7-93b9-097e6caf1123/Alkynes2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/22d32fce-1c59-41d2-bcae-098b1ad19a92/arene1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bdf0866c-6fde-4399-8279-a96dd2fd619c/arene2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8f02bc61-d0a6-4cb8-9ce2-a7c3bef88bbd/amines1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6639fef7-6ef5-4612-a7ff-24abba8900f9/amines2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/23083601-33f7-4dd7-a906-c29cb061081f/alcohols1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3b75dd74-9710-4058-a596-4e9d0a0df19f/alcohols2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/09f975d4-4900-42e6-892b-0cd26b347c41/halide1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/00bfcc9e-048c-4048-b0ab-33faed1f8ce9/halides2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17db2f23-fbb1-4760-8b9c-3765a6fd2160/thiols1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/781dfc8e-6660-4c4a-8545-9f51fb1ede6a/thiol2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5704c0d8-bd2c-4655-a492-0387072a4d0b/aldehyde1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e37dabb2-31f8-4d54-a891-7dabb1bd8566/Aldehydes2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77783e6b-729f-4031-b875-46cfe70067a7/ketones1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/70b2432b-6e0c-4ec4-8cf0-a9c3d28db9a8/ketones2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6711c4c9-ef50-49ff-b157-2e8074a3c99e/acids1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c65d779f-faf0-4660-9018-f8eb83a35341/acids2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/773ebbd4-5fd6-4d4e-8cb9-7d7a35cea3ba/amide1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/790d00b6-1a6c-4e8d-98ce-67765ef2f945/amides2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/82926dbf-9df5-4950-8ceb-2d553692a21c/Ester1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1a79644b-7782-42e7-8fc0-2cfc458e617f/esters2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7f1ee9f1-fbfa-40dd-96ee-6e4d76b6baa8/nitro1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/782418b8-8cf8-4ed0-9156-01bae61c0a09/nitro2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/661153e5-eaae-49e8-aa91-12042126a2fa/ethers1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/30f31679-90e6-42d2-91cf-e051dd2c8657/ethers2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4ea9974-f2d6-4e77-b8c9-d953ffd96309/Sulfide1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/19ec3f08-6cb7-4fb7-b126-b918e4f5c186/Sulfide2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/14e33962-787b-4d27-b66a-6008f86e39a5/Disulfide1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/507287ac-6d87-4859-af92-11ad526134a2/Disulfide2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/6689618d-b9f4-4cf6-b9de-d90cb47f3ea7/Acetal1.png Blog - Functional Groups - 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Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/965e1e5f-cca6-42bd-84b0-42d77408bbde/Acyl_chlorides1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/98b7c312-23c1-49d9-b44e-1915b2c6b64e/Acyl_chlorides2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a1b347d1-5a86-4f08-a466-0b53b06247fb/Anhydrides1.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/68bdaa04-36b4-4cc1-9f0c-9009f8ac6159/Anhydrides2.png Blog - Functional Groups - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://www.makingmolecules.com/blog/hybrid-atomic-orbitals-amp-valence-bond-theory monthly 0.5 2022-03-23 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d859ed46-1227-4edd-a0db-09e697937409/Atomic_orbitals.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Important atomic orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/7f02bb94-faea-4fb9-a35b-13fc7e424041/methane_wrong.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out The wrong structure for methane https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/92a39d90-90c0-4dc4-9fe3-6ada72e2c5e5/Table1.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Hybrid atomic orbitals formed from the combination of a 2s orbital with 2p orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fe63f5ac-0942-4b49-9293-354240d7ab83/Table2.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Examples of hybrid atomic orbitals and the geometry of molecule https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b842d774-721a-400d-bfef-ab9626878ff6/Hybridisation.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Hybridisation of atomic orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/37fc570a-33bd-4547-a38b-b3bbc0a7eb69/sigma_bond.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Formation of σ (sigma) bond by head-to-head overlap of orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f5468c56-3cff-4297-987c-47e91622fd1e/sigma-Bonds2.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Six flavours of carbon-carbon σ bond depending on which hybrid atomic orbitals overlap https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4cc8f983-f34a-4351-9de6-f0ff36189f28/pi_bond.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out π bond formed by the side-to-side overlap of two non-hybridised 2p orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/25c86d6f-4177-46bc-a4b8-dfdb6b7d434e/VB_model.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Flow diagram to determine valence bond model of a molecule https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/afecffbe-049d-48ba-b8dc-3ce8843b53fb/VB_model_allyl_alcohol.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/26683f46-a418-427a-ba22-1efbd497aadd/VB-Allyl_Alcohol.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Valence bond model of allyl alcohol https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/94d3a923-305d-4d50-a37f-b593b4cca14f/trimethylamine.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Hybridisation of a nitrogen atom in an amine https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b441a8ae-2c90-4d92-a568-868f6fd545e8/Amide-hybridisation.png Blog - Hybrid Atomic Orbitals &amp; Valence Bond Theory - Make it stand out Hybridisation of a nitrogen atom in an amide - two resonance structures https://www.makingmolecules.com/blog/thin-layer-chromatography-tlc monthly 0.5 2022-03-17 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ae0ac124-338d-42f5-90e3-3597bea3c123/TLC-set-up.png Blog - Thin Layer Chromatography (TLC) - Make it stand out Cartoon of running a TLC plate https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/69413547-94b1-4032-bdaf-e0532dee8f7a/Following_reaction.png Blog - Thin Layer Chromatography (TLC) - Make it stand out Following a reaction by TLC. From left to right: Before running the TLC all spots are on the baseline. Second diagram shows the TLC plate for a reaction that still has starting material and an intermediate present. The reaction has not gone to completion. The final diagram shows a reaction in which all starting material has been consumed and converted to product. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/650834e2-8bc1-4d4e-9d52-a1fd4f02132b/Rf_value.png Blog - Thin Layer Chromatography (TLC) - Make it stand out Determining the R_f value of a sample https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/974bcad7-99e9-4dd2-ac4b-e4533516ff72/TLC_examples.png Blog - Thin Layer Chromatography (TLC) - Make it stand out Examples of TLC plates - frequently a single spot is a pure compound but occasionally you can be unlucky and two different compounds have the same Rf value. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2581cd44-f932-48af-805e-d88612bbb901/TLC_attractions.png Blog - Thin Layer Chromatography (TLC) - Make it stand out Interactions between silica stationary phase and sample cause separation https://www.makingmolecules.com/blog/3cp6ta6b6ohqvg2onpfoylgh7b3h2w monthly 0.5 2022-03-09 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/483b5879-4782-41a4-8aba-28a60ca9072d/Atom_structure.png Blog - Lewis Structures - Make it stand out Simplified representation of an atom (the Bohr model) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/97f3da6e-765a-4dfd-af04-0d0a1fe81be9/Groups_valence_electrons.png Blog - Lewis Structures - Make it stand out Number of valence electrons along the second row of the periodic table https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/0bab022a-2846-4e2a-961d-eb381e547cc3/ionic_bond.png Blog - Lewis Structures - Make it stand out An example of an ionic bond https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/19982bfa-267e-4f17-bc17-594bbbccbcc0/covalent_bonds.png Blog - Lewis Structures - Make it stand out Examples of covalent bonds as found in hydrogen and methane 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https://www.makingmolecules.com/handouts daily 0.75 2024-08-26 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3895adbf-7348-4fac-9480-d51525da5f03/Lewis_structures.png Handouts Lewis structure summary https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2710aee5-f800-4bbb-b674-ed52c5c74457/TLC.png Handouts TLC summary https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/06a5e96f-4d3b-49c2-8b55-d2c3f6290d2a/TLC_Repair2_1.png Handouts Updated version of the TLC summary - now with added silica gel https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8c8bdf58-60f2-4d9f-9437-7c53a5804cd0/Orbitals.png Handouts Valence Bond Theory and Hybrid Atomic Orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/fd20a189-907b-4e57-8528-5eaafb14f23c/FG_1Pager.png Handouts Common Functional Groups 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https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/872c634a-225f-4639-9e1c-06939f21ed5d/LeChatelier_Animation_AddReagentsV2Medium.gif Handouts Animation Showing Effect of Adding Reactant https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9bde19e8-0e2a-49ba-a7be-4bbae1c065ec/LeChatelier_Animation_RemoveReagentsV2Medium.gif Handouts Animation showing the effect of removing a reactant https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9e5ad3e7-9978-4281-bf68-2c2bcec0293c/LeChatelierEndothermic_medium.gif Handouts Animation showing the effect of heating an endothermic reaction https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f4c22cf2-7dc5-48d8-b4f8-2cc555a8487c/LeChatelierHeat_medium.gif Handouts Animation showing the effect of heating an exothermic reaction https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c9b3ada6-b1e9-4afb-8d37-3bbecb82d29d/LeChatelierPressure_Medium.gif Handouts Animation showing the effect of changing the pressure on a reaction containing gas molecules https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2b52044-c21a-4899-a259-ba79a4a14164/Chair_flipping_with_arrows.gif Handouts Animation of ring-flipping in cyclohexane https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2f7f811d-bb1a-4f08-93ff-91f47f427cfb/MM22_AcidsBase%28c%29Pg47.png Handouts Acids, bases, pKa and pH https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d6fd1570-fb99-46c3-a5e1-c24dd4412841/MM23-pKa_water.png Handouts pKa Scale in Water https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/9dec1f71-187e-4cfe-bd67-9491aec6c828/MM24_pKa_DMSO_1.png Handouts pKa scale in DMSO https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a9ffa655-97ac-4bfa-948c-5372b139b3d6/MM25_Relative_Acidity%28c%29Pg27.png Handouts Predicting Relative Acidity https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c7152a3f-bbf3-4a09-be42-827f653687f5/MM26_pKa_MeCN.png Handouts pKa Scale in MeCN https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b39181f7-ad8b-4198-8032-b14ecccbdf07/MM27_Chirality%28c%29Pg47.png Handouts Introduction to Chirality https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/bb1d9c8f-1cfc-4dc6-8fa3-d4c0b74ecf21/MM28_IntroReactionsV3%28c%29Pg47.png Handouts Curly arrows and reaction mechanisms https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/42462241-9af0-4dab-9319-9910afff40b8/MM29_NucleophilicAddition_%28c%29Pg47.png Handouts Nucleophilic addition to aldehydes & ketones https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5c672eb1-28f2-4ede-af25-8c757ff348db/MM30_SubstrateControl_Carbonyl%28c%29Pg47_1.png Handouts Diastereoselective addition to Carbonyl https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b856fd33-d58e-4e9b-b790-83c9a657dea6/MM31_Condensation_%28c%29Pg47.png Handouts Condensation reactions of carbonyl group https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/56cac6e5-14f6-4e76-b73d-12ea17515582/MM31B_Condensation2_%28c%29Pg47.png Handouts Mechanism of condensation Reaction with lone pairs https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a4d11163-1ac1-4006-8f95-534a1c47c223/MM32_Acyl_Substitution_%28c%29Pg47_1.png Handouts Nucleophilic acyl substitution https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d9492bd2-7071-4bbc-b10e-5334837c341b/MM33_PiNuc_Part1%28c%29Pg47V2.png Handouts Alkenes as nucleophiles Part 1 - mechanisms https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/92c7d2ef-3b34-4ebd-953b-76e92a98f316/MM34_Pi_Nuc_Orbitals_%28c%29Pg47_1.png Handouts Frontier orbitals & reactions of alkenes https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/142ca186-8618-47d5-bdd7-f41fe72c1775/MM35_AntiMarkovnikov%28c%29_Pg47.png Handouts Anti-Markovnikov addition of HBr and H2O to an alkene https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3fffec69-7eed-4cc8-82c7-4b11babfb79a/MM36-Asym_Hydroboration_%28c%29_Pg47-2.png Handouts Asymmetric Hydroboration both substrate and reagent control https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e00ad09c-4e7d-477f-844c-efc3280f876e/MM37A_SEAr_Summary_%28c%29_Pg47.png Handouts Electrophilic Aromatic Substitution Summary https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/910605af-ad69-4e22-b2f5-815895ead4c2/MM37-Electrophilic_Ar_Substitution_%28c%29_Pg47_V2_1.png Handouts Electrophilic aromatic substitution https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/53f6d95e-b920-4cb3-8730-f031eb19c4fc/MM38_SEAr_activation_direction_%28c%29_Pg47.png Handouts Electrophilic aromatic substitution - directing effects https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b790c126-ad0c-456d-bef1-4688f29a1aee/MM39-Nucleophilic_Ar_Substitution_%28c%29_Pg47.png Handouts Nucleophilic Aromatic Substitution - Addition-Elimination https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e4064f65-f68a-41ef-814c-f6f6872129d5/MM40_Nucleophilic_sub_diazo_%28c%29_Pg47.png Handouts Nucleophilic Aromatic Substitution 2 - Diazonium salts https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b3e08494-0ad4-4d08-b597-aa27c6709d19/MM41_Substitution_Arynes_%28c%29_Pg47_V2.png Handouts Benzyne: Nucleophilic Aromatic Substitution https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4597fd65-da71-4c40-9f06-d003906c0a85/MM42_Nucleophilic_Aromatic_Summary_%28c%29_Pg47.png Handouts Summary of the Summaries of Nucleophilic Aromatic Substitution https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/c2d7f44b-8364-44c9-a0d2-8ee87d1ba333/MM43_Conjugate_Addition_%28c%29_Pg47V2.png Handouts Conjugate Addition https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ff63a01b-5ae8-479d-9546-1b9066a8a1a1/MM44_Rates-Collision_Theory_%28c%29_Pg47_V2.png Handouts Collision Theory https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/867705ed-bc39-4899-aa39-8c5eaf0c106b/MM45_Rates-Reaction_mechanism_%28c%29_Pg47.png Handouts Rates of reaction 2: Mechanisms https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/69239e9a-a0e2-4526-bee9-7ea828593887/MM46_Substitution_Pg47.png Handouts Substitution reactions (SN1 & SN2) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/f6751a08-5c60-4157-8c45-f0552976d36c/MM47_Elimination_%28c%29Pg47.png Handouts Elimination (E1 & E2) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3f5ee3a1-e68a-44c2-a179-c81e6f88acb2/Last_cover.png Handouts Last Playlist https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d3891fe8-2d77-46e1-9824-8f2f53c45bf7/MM48_WhichMechanismSummary_%28c%29_Pg47.png Handouts Summary of the four common UG mechanisms (SN1, SN2, E1, E2) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b1c3191e-4a75-4583-be12-ad5e561a3273/MM49_Enol_%28c%29Pg47.png Handouts Formation of Enols and Their Reactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d65fb66f-459b-4eff-b98c-a993e0a9a5c0/MM50_Enolate_%28c%29_Pg47.png Handouts Summary of enolate formation and simple reactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/14e36abf-bef7-40b0-b749-5c9004f66391/MM51_Aldol_%28c%29_Pg47.png Handouts Intro to the aldol reaction https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/4cd90452-08f9-4352-8b43-64258c09415d/MM52_Aldol-like_%28c%29_Pg47.png Handouts Aldol-like reactions https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/986ca812-ab3e-40c8-bd2f-425005f042e7/MM53A_Aldol-Like_Summary_%28c%29_Pg47.png Handouts Summary of Aldol-like Reactions Version 1 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d44fb7c5-79de-44ca-b8b6-3b8f8e778c21/MM53B_Aldol-Like_Summary_%28c%29_Pg47.png Handouts Summary of Aldol-like Reactions Version 2 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8abf75b3-67f2-44ae-aef1-63d5824a6933/MM54_EnolateEquivalents_%28c%29_Pg47_1.png Handouts Lithium enolates and enolate equivalents https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/ba1bebe9-3d8b-4e79-9c7b-d5941286bdce/MM55_Enamines_%28c%29_Pg47.png Handouts Enamines - formation, reaction and hydrolysis https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/534006ae-42d7-4125-9a5a-40d56d814fb9/MM01_Enamines_%28c%29_Pg47_24.png Handouts Lewis structure summary (reformatted) https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/77016046-b4d7-4b25-9949-810a7c784649/MM03-Naming-%28c%29_Pg47_MM2024.png Handouts Naming simple organic molecules https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/36ae0d25-125a-41cb-ac64-e152c6a9966f/MM05-FG_%28c%29_Pg47_2024.png Handouts A table of organic functional groups https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/15c35068-418e-438a-ae17-85b3342da316/%E2%80%8EMM06_Formal_Charges_MM.png Handouts Formal Charges https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/17b1a7ff-8481-46ce-8ab3-821a61ef98b7/MM56_Diels-Alder_%28c%29_Pg47_1.png Handouts An introduction to the Diels-Alder reaction. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/a0d4988a-28fe-467d-b748-ad5db673beab/MM57_DA-Like_%28c%29_Pg47.png Handouts Summary of Diels-Alder-like reactions https://www.makingmolecules.com/gin-tonic-analogy daily 0.75 2022-03-14 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8b8fa363-451d-4e2c-a4ff-65e2fc897c52/G%26T1sp3.png Gin & Tonic Analogy - Make it stand out Mixing four identical gin and tonics is the equivalent of forming four sp^3 hybrid atomic orbitals https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/12041f18-efa9-4d11-87b0-c04d66853258/G%26T2sp2.png Gin & Tonic Analogy - Make it stand out Mixing three identical gin and tonics is the equivalent of forming three sp^2 hybrid atomic orbitals - something is left-over https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/d36fb5bf-3400-4b66-a743-be227aaefa81/G%26T3sp.png Gin & Tonic Analogy - Make it stand out Mixing two identical gin and tonics is the equivalent of forming two sp hybrid atomic orbitals https://www.makingmolecules.com/drawing-other-cycloalkanes daily 0.75 2022-06-15 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/e47abbc9-f729-4854-aafd-cfc95c61aa24/Drawing_cyclobutane.png Drawing Other Cycloalkanes - Make it stand out Drawing cyclobutane from a six-membered ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/87c93f52-9458-422b-9904-66339934d004/Drawing_cyclopentane.png Drawing Other Cycloalkanes - Make it stand out Drawing cyclopentane from a six-membered ring. https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/cbe682f7-c02b-4e65-9dde-36918b5bf41e/Drawing_cycloheptane.png Drawing Other Cycloalkanes - Make it stand out Drawing cycloheptane. https://www.makingmolecules.com/the-carbonyl-group-and-spectroscopy daily 0.75 2022-11-01 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/3e7bc273-38f3-4522-ab9b-c27a996a699a/IR-carbonyl.png https://www.makingmolecules.com/orbital-nucleophilic-addition daily 0.75 2022-11-02 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/1c639a68-da44-48f0-97d0-663acbb51baa/Carbonyl-Orbitals.png https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/2106526c-4463-48cc-8482-2483adef0798/Reaction_orbital_view.png https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/b2b13f32-5311-446b-aa97-92888e71bb9e/Burgi-Dunits.png https://www.makingmolecules.com/the-orbital-approach-to-the-addition-of-organometallic-reagents daily 0.75 2022-11-04 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/5e43ef9e-e8a4-4794-907c-8e02c2708328/CH3Li_orbitals.png https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/beff84c1-d2d1-438f-b63f-ab2c57be01fa/Borohydride_orbitals2.png https://www.makingmolecules.com/addition-of-water-or-cyanide daily 0.75 2022-11-04 https://images.squarespace-cdn.com/content/v1/62185f3b81809a6fd03ddbb5/8cd6b207-ed50-433d-a006-28e392e83237/Reversible_orbitals.png