Overview

The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an achiral 2-butanone yields the chiral enantiomers of (R)-2-butanol and (S)-2-butanol. Here, the achiral reactant that can be converted into a chiral product by altering just one substituent group is known as prochiral.

Mechanistically speaking, the chiral configuration of the product depends on the orientation of the incoming hydride group that adds to the sp²-hybridized carbon. Since each face of the molecule is unique, they can be assigned unique names. This follows the Cahn–Ingold–Prelog system, where priorities are assigned to the substituents at the trigonal carbon center based on their atomic numbers at the first point of difference. The face of the molecule is then labeled depending on whether the sequence of groups is clockwise or counterclockwise. A clockwise sequence in the face is labeled as “re,” while the counterclockwise face is labeled “si.” Here, the chiral agent plays a key role. In the absence of chiral reagents, the incoming group can attach to the molecule from either face, resulting in a racemic mixture of the product. Conversely, chiral catalysts or enzymes can dictate the formation of one of the enantiomers over the other. These reactions are accordingly referred to as enantioselective reactions.

Further classification of the substituents on the prochiral carbon as homotopic, diastereotopic, and enantiotopic is significant and probed. For example, the different hydrogen substituents in (+)-2,6-dimethylcyclohexanone are individually classified. As depicted in Figure 1(a), the two hydrogens in blue are homotopic, the two hydrogens colored green in Figure 1(b) are enantiotopic, and the red hydrogens in Figure 1(c) are diastereotopic.

Figure 1: The classification of substituents on prochiral carbon of (+)-2,6-dimethylcyclohexanone - (a) Homotopic, (b) Enantiotopic, and (c) Diastereotopic

Procedure

Prochirality refers to the concept of two or more achiral molecules reacting to give rise to chiral products.

For example, consider the reduction of 2-butanone to 2-butanol. Here, the achiral molecules 2-butanone and sodium borohydride react to generate an equimolar mixture of the chiral enantiomers (R)-2-butanol and (S)-2-butanol.

Achiral molecules that can be converted to chiral products by changing only one substituent are referred to as prochiral.

In trigonal prochiral molecules, the chiral configuration of the product depends on whether the incoming group adds to the sp²-hybridized center from the top face or the bottom face of the molecule.

As such, each face of the butanone molecule is unique and should have its own distinct name, which can be assigned with the Cahn–Ingold–Prelog system.

Similar to the naming of chiral molecules, priorities are assigned to the substituents at the trigonal carbon atom based on their atomic numbers at the first point of difference. The faces of the molecule are then labeled depending on whether the one-two-three sequence is clockwise or counterclockwise.

If the sequence is clockwise, the face is labeled as “re”. If the sequence is counterclockwise, the face is labeled as “si”.

In the case of 2-butanone, if the hydride group adds from the “re” face of 2-butanone, (S)-2-butanol is obtained. In contrast, addition of the hydride ion from the “si” face generates (R)-2-butanol.

In the absence of chiral reagents, the hydride group is equally likely to attach to the molecule from either face, and a racemic mixture of the product is obtained.

However, chiral catalysts or enzymes can be used to favor the formation of one enantiomer, which makes the reaction ‘enantioselective’ for that enantiomer.