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Asymmetric induction
Asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer (enantioinduction) or diastereoisomer (diastereoinduction) over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.
Asymmetric induction was introduced by Hermann Emil Fischer based on his work on carbohydrates. Several types of induction exist.
Internal asymmetric induction makes use of a chiral center bound to the reactive center through a covalent bond and remains so during the reaction. The starting material is often derived from chiral pool synthesis. In relayed asymmetric induction the chiral information is introduced in a separate step and removed again in a separate chemical reaction. Special synthons are called chiral auxiliaries. In external asymmetric induction chiral information is introduced in the transition state through a catalyst of chiral ligand. This method of asymmetric synthesis is economically most desirable.[clarification needed]
Several models exist to describe chiral induction at carbonyl carbons during nucleophilic additions. These models are based on a combination of steric and electronic considerations and are often in conflict with each other. Models have been devised by Cram (1952), Cornforth (1959), Felkin (1969) and others.
The Cram's rule of asymmetric induction named after Donald J. Cram states In certain non-catalytic reactions that diastereomer will predominate, which could be formed by the approach of the entering group from the least hindered side when the rotational conformation of the C-C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center. The rule indicates that the presence of an asymmetric center in a molecule induces the formation of an asymmetric center adjacent to it based on steric hindrance (scheme 1).
The experiments involved two reactions. In experiment one 2-phenylpropionaldehyde (1, racemic but (R)-enantiomer shown) was reacted with the Grignard reagent of bromobenzene to 1,2-diphenyl-1-propanol (2) as a mixture of diastereomers, predominantly the threo isomer (see for explanation the Fischer projection).
The preference for the formation of the threo isomer can be explained by the rule stated above by having the active nucleophile in this reaction attacking the carbonyl group from the least hindered side (see Newman projection A) when the carbonyl is positioned in a staggered formation with the methyl group and the hydrogen atom, which are the two smallest substituents creating a minimum of steric hindrance, in a gauche orientation and phenyl as the most bulky group in the anti conformation.
The second reaction is the organic reduction of 1,2-diphenyl-1-propanone 2 with lithium aluminium hydride, which results in the same reaction product as above but now with preference for the erythro isomer (2a). Now a hydride anion (H−) is the nucleophile attacking from the least hindered side (imagine hydrogen entering from the paper plane).
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Asymmetric induction
Asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer (enantioinduction) or diastereoisomer (diastereoinduction) over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.
Asymmetric induction was introduced by Hermann Emil Fischer based on his work on carbohydrates. Several types of induction exist.
Internal asymmetric induction makes use of a chiral center bound to the reactive center through a covalent bond and remains so during the reaction. The starting material is often derived from chiral pool synthesis. In relayed asymmetric induction the chiral information is introduced in a separate step and removed again in a separate chemical reaction. Special synthons are called chiral auxiliaries. In external asymmetric induction chiral information is introduced in the transition state through a catalyst of chiral ligand. This method of asymmetric synthesis is economically most desirable.[clarification needed]
Several models exist to describe chiral induction at carbonyl carbons during nucleophilic additions. These models are based on a combination of steric and electronic considerations and are often in conflict with each other. Models have been devised by Cram (1952), Cornforth (1959), Felkin (1969) and others.
The Cram's rule of asymmetric induction named after Donald J. Cram states In certain non-catalytic reactions that diastereomer will predominate, which could be formed by the approach of the entering group from the least hindered side when the rotational conformation of the C-C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center. The rule indicates that the presence of an asymmetric center in a molecule induces the formation of an asymmetric center adjacent to it based on steric hindrance (scheme 1).
The experiments involved two reactions. In experiment one 2-phenylpropionaldehyde (1, racemic but (R)-enantiomer shown) was reacted with the Grignard reagent of bromobenzene to 1,2-diphenyl-1-propanol (2) as a mixture of diastereomers, predominantly the threo isomer (see for explanation the Fischer projection).
The preference for the formation of the threo isomer can be explained by the rule stated above by having the active nucleophile in this reaction attacking the carbonyl group from the least hindered side (see Newman projection A) when the carbonyl is positioned in a staggered formation with the methyl group and the hydrogen atom, which are the two smallest substituents creating a minimum of steric hindrance, in a gauche orientation and phenyl as the most bulky group in the anti conformation.
The second reaction is the organic reduction of 1,2-diphenyl-1-propanone 2 with lithium aluminium hydride, which results in the same reaction product as above but now with preference for the erythro isomer (2a). Now a hydride anion (H−) is the nucleophile attacking from the least hindered side (imagine hydrogen entering from the paper plane).