Nobel Prize in Chemistry 2021 Part 1, Asymmetric Organocatalysis, Enantioselective Organic Chemistry
17.3 هزار بار بازدید -
3 سال پیش
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An introduction to asymmetric catalysis,
An introduction to asymmetric catalysis, enantioselective reactions and asymmetric organocatalysis through a discussion of the proline catalysed aldol reaction. The video is pitched at an undergraduate chemistry level for those already familiar with general carbonyl reactivity in organic chemistry. 3D transition state models are used to show how certain enantiomers and/or diastereomers of organic products are formed selectively.
#chemistry #nobelprize #chemnobel
A combination of kinetic control and thermodynamic control in organic chemistry means that you can use enamines in diastereoselective and enantioselective reactions. Using an enamine as an enolate equivalent allows it to act as a nucleophile alpha to the parent carbonyl group and with acid activation can be used to react with other carbonyls, such as aldehydes and ketones. The proline-catalysed aldol reactions was one of the first major steps to developing a general asymmetric (enantioselective) catalytic reaction for strategic bond formation, in this case a very useful carbon-carbon bond and up to two new stereogenic centres.
Proline is a commonly occurring amino acid as both enantiomer in nature and so it is a very cheap catalyst to use. Its combination of functional groups of a secondary amine in a ring structure with restricted flexibility and a carboxylic acid mean that it is a bifunctional catalyst. It can both form an enamine with an aldehyde or a ketone, but also it carries with it an acidic proton that can be used to activate an electrophile for the new nucleophile to react with. More so than that, it can activate another carbonyl by hydrogen bonding and setting up an essentially intramolecular reaction via a 9-membered ring. That ring size does not have sufficient low energy specific conformations, but the presence of a well-placed nitrogen atom sets up a further hydrogen bond, and so essentially making a 6,5-bicyclic ring system for a reaction transition state. The lowest energy transition state will, as ever, be the one that minimises 1,3-diaxial interactions, resulting in a preference for big groups to be positioned in pseudo-equatorial arrangements.
In the video, I explain how one of four possible stereoisomers of aldol product can be formed in preference to the others. I go on to show how other chemistry can be done by replacing the electrophile in the organised transition state. An enantioselective and diastereoselective Mannich reaction is also possible for creating a specific enantiomer of a 1,3-syn Mannich reaction product. You can also use nitroso compounds (such as PhNO) as oxygen-electrophiles, as the hydrogen bonding in the transition state is stronger with a nitrogen lone pair rather than with an oxygen lone pair. Hence, the normal electrophilic at nitrogen reactivity of nitroso compounds is not observed, and we have access to a mild and easy-to-handle oxygen electrophile without needing, for example, peracids or peroxides that will react easily with many other sensitive functional groups in both simple and complex molecules.
The chemistry further extends to desymmetrisation reactions. I finish the video explaining an intramolecular diastereoselective desymmetrisation reaction using proline organocatalysis. This is the synthesis often called the Hajos–Parrish–Eder–Sauer–Wiechert reaction (or in some books just the Hajos–Parrish reaction), and is a classic example of early use of amino acids directly in both asymmetric catalysis in organic chemistry but also is one of the cornerstones of enantioselective organocatalysis.
#chemistry #nobelprize #chemnobel
A combination of kinetic control and thermodynamic control in organic chemistry means that you can use enamines in diastereoselective and enantioselective reactions. Using an enamine as an enolate equivalent allows it to act as a nucleophile alpha to the parent carbonyl group and with acid activation can be used to react with other carbonyls, such as aldehydes and ketones. The proline-catalysed aldol reactions was one of the first major steps to developing a general asymmetric (enantioselective) catalytic reaction for strategic bond formation, in this case a very useful carbon-carbon bond and up to two new stereogenic centres.
Proline is a commonly occurring amino acid as both enantiomer in nature and so it is a very cheap catalyst to use. Its combination of functional groups of a secondary amine in a ring structure with restricted flexibility and a carboxylic acid mean that it is a bifunctional catalyst. It can both form an enamine with an aldehyde or a ketone, but also it carries with it an acidic proton that can be used to activate an electrophile for the new nucleophile to react with. More so than that, it can activate another carbonyl by hydrogen bonding and setting up an essentially intramolecular reaction via a 9-membered ring. That ring size does not have sufficient low energy specific conformations, but the presence of a well-placed nitrogen atom sets up a further hydrogen bond, and so essentially making a 6,5-bicyclic ring system for a reaction transition state. The lowest energy transition state will, as ever, be the one that minimises 1,3-diaxial interactions, resulting in a preference for big groups to be positioned in pseudo-equatorial arrangements.
In the video, I explain how one of four possible stereoisomers of aldol product can be formed in preference to the others. I go on to show how other chemistry can be done by replacing the electrophile in the organised transition state. An enantioselective and diastereoselective Mannich reaction is also possible for creating a specific enantiomer of a 1,3-syn Mannich reaction product. You can also use nitroso compounds (such as PhNO) as oxygen-electrophiles, as the hydrogen bonding in the transition state is stronger with a nitrogen lone pair rather than with an oxygen lone pair. Hence, the normal electrophilic at nitrogen reactivity of nitroso compounds is not observed, and we have access to a mild and easy-to-handle oxygen electrophile without needing, for example, peracids or peroxides that will react easily with many other sensitive functional groups in both simple and complex molecules.
The chemistry further extends to desymmetrisation reactions. I finish the video explaining an intramolecular diastereoselective desymmetrisation reaction using proline organocatalysis. This is the synthesis often called the Hajos–Parrish–Eder–Sauer–Wiechert reaction (or in some books just the Hajos–Parrish reaction), and is a classic example of early use of amino acids directly in both asymmetric catalysis in organic chemistry but also is one of the cornerstones of enantioselective organocatalysis.
3 سال پیش
در تاریخ 1400/06/03 منتشر شده
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