Stereochemistry of Reactions - Addition of H₂O to an Achiral and Chiral Alkenes | Chemistry Optional Notes for UPSC PDF Download

Stereochemistry of Reactions - Addition of H₂O to an Achiral Alkene

• Most of the biochemical reactions that take place in the body, as well as many organic reactions in the laboratory, yield products with chirality centers. For example, acid-catalyzed addition of H₂O to 1-butene in the laboratory yields 2-butanol, a chiral alcohol. What is the stereochemistry of this chiral product? If a single enantiomer is formed, is it R or S? If a mixture of enantiomers is formed, how much of each? In fact, the 2-butanol produced is a racemic mixture of R and S enantiomers. Let’s see why.
  
• To understand why a racemic product results from the reaction of H₂O with 1-butene, think about the reaction mechanism. 1-Butene is first protonated to yield an intermediate secondary carbocation. Because the trivalent carbon is sp²-hybridized and planar, the cation has a plane of symmetry and is achiral. As a result, it can react with H2O equally well from either the top or the bottom. Reaction from the top leads to (S)-2-butanol through transition state 1 (TS 1) in Figure 8.13, and reaction from the bottom leads to (R)-2-butanol through TS 2. But the two transition states are mirror images, so they have identical energies, form at identical rates, and are equally likely to occur.
  Figure 8.13: Reaction of H₂O with the carbocation resulting from protonation of 1-butene. Reaction from the top leads to S product and is the mirror image of reaction from the bottom, which leads to R product. Because they are energetically identical, they are equally likely and lead to a racemic mixture of products. The dotted C···O bond in the transition state indicates partial bond formation.
• As a general rule, the formation of a new chirality center by achiral reactants always leads to a racemic mixture of enantiomeric products. Put another way, optical activity can’t appear from nowhere; an optically active product can only result by starting with an optically active reactant or chiral environment.
• In contrast to laboratory reactions, enzyme-catalyzed biological reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to (Z)-aconitate (usually called cis-aconitate) to give isocitrate.
  
• Even though cis-aconitate is achiral, only the (2R,3S) enantiomer of the product is formed. Cis-aconitate is a prochiral molecule, which is held in a chiral environment by the aconitase enzyme during the reaction. In this environment, the two faces of the double bond are chemically distinct, and addition occurs on only the Re face at C2.

Stereochemistry of Reactions - Addition of H₂O to a Chiral Alkene

• The reaction discussed in the previous section involves an addition to an achiral reactant and forms an optically inactive, racemic mixture of two enantiomeric products. What would happen, though, if we were to carry out the reaction on a single enantiomer of a chiral reactant? For example, what stereochemical result would be obtained from addition of H₂O to a chiral alkene, such as (R)-4-methyl-1-hexene? The product of the reaction, 4-methyl-2-hexanol, has two chirality centers and so has four possible stereoisomers.
  
• Let’s think about the two chirality centers separately. What about the configuration at C4, the methyl-bearing carbon atom? Since C4 has the R configuration in the starting material and this chirality center is unaffected by the reaction, its configuration is unchanged. Thus, the configuration at C4 in the product remains R (assuming that the relative rankings of the four attached groups are not changed by the reaction).
• What about the configuration at C2, the newly formed chirality center? As shown in Figure 8.14, the stereochemistry at C2 is established by reaction of H2O with a carbocation intermediate in the usual manner. But this carbocation doesn’t have a plane of symmetry; it is chiral because of the chirality center at C4. Because the carbocation is chiral and has no plane of symmetry, it doesn’t react equally well from the top and bottom faces. One of the two faces is likely, for steric reasons, to be a bit more accessible than the other, leading to a mixture of R and S products in some ratio other than 50 : 50. Thus, two diastereomeric products, (2R,4R)-4-methyl-2-hexanol and (2S,4R)-4-methyl-2-hexanol, are formed in unequal amounts, and the mixture is optically active.
  Figure 8.14: Stereochemistry of the acid-catalyzed addition of H₂O to the chiral alkene, (R)-4-methyl-1-hexene. A mixture of diastereomeric 2R,4R and 2S,4R products is formed in unequal amounts because reaction of the chiral carbocation intermediate is not equally likely from top and bottom. The product mixture is optically active.
• As a general rule, the formation of a new chirality center by a chiral reactant leads to unequal amounts of diastereomeric products. If the chiral reactant is optically active because only one enantiomer is used rather than a racemic mixture, then the products are also optically active.