Formation of Diastereomers

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Chapter: Organic Chemistry : Stereochemical and Conformational Isomerism

Diastereomers are defined as compounds which have the same molecular formula and sequence of bonded elements but which are nonsuperimposable, non – mirror images.


Diastereomers are defined as compounds which have the same molecular formula and sequence of bonded elements but which are nonsuperimposable, non – mirror images. While Z,E isomers are one subclass of diastereomers which are achiral, the majority of diastereomeric compounds are chiral compounds which have more than one chiral center. Furthermore it is important to recall that for a compound with n chiral centers there will be 2n stereoisomers. These will be divided into 2n /2 pairs of enantiomers, and each pair of enantiomers will be diastereomeric with the other pairs of enantiomers. This was reviewed earlier in this chapter.

One of the most direct ways to produce diastereomers is by addition reactions across carbon – carbon double bonds. If the structure of the olefin substrate is such that two new chiral centers are produced by the addition of a particular reagent across the double bond, then diastereomers will result. For example, the addition of HBr to Z-3-chloro-2-phenyl-2-pentene produces 2-bromo-3-chloro-2-phenylpentane as a mixture of four diastereomers. Assuming only Markovnikov addition, the diastereomers are produced by the addition of a proton to C-3 followed by addition of bromide to the carbocation intermediate at C-2. Since the olefin precursor is planar, the proton can add from either face, and since the carbocation intermediate is also planar and freely rotating, the bromide can add to either face to give diastereomeric products. The possibilities are delineated schematically (but not mechanistically) below.

Now even though there are four possible stereoisomers that can be produced, they will not necessarily be formed in equal amounts. Diastereomers are not equal in terms of their energies; consequently, reactions which produce diastere-omers reflect these energy differences in the various transition states and therefore proceed at different rates. Thus diastereomers are normally formed in unequal amounts. This is a very important concept since it provides the kinetic basis for the stereoselectivity found in many different organic reactions. Restating this idea, if reactions produce diastereomers and thus proceed via diastereomeric transition states, then the energy barriers for the formation of individual diastereomers will be different, the rates of formation of individual diastereomers will be different, and they will be formed in unequal amounts. The greater are the differences in the energy barriers, the greater will be the differences in rates and the more stereoselective will be the reaction. In contrast to HBr addition, which gives a mixture of diastereomers, there are a variety of other olefin addition reactions which yield a single diastereomer from a starting olefin of defined stereochem-istry. Furthermore a starting olefin with a different stereochemistry will give a different single diastereomer. Such reactions are described as being stereospecific or highly stereoselective.

The diastereoselectivity for any process is often reported as a diastereomeric excess (de%), which is analogous to the optical purity reported for mixtures of enantiomers. The de% is given by de% = % major diastereomer − % minor diastereomer. For diastereospecific reactions in which a single diastereomer is produced, de = 100%, while for reactions in which there is no selectivity and diastereomers are produced in equal amounts, de = 0%.

A typical example of a stereospecific olefin addition reaction is the addition of bromine to olefins. If cis - 2 - pentene is used as the substrate, only the 2R,3R and 2S,3S pair will be produced (they are enantiomers) .

Because the addition of bromine is stereospecifically trans or anti, one bromine atom adds to each face of the olefin and can go to either carbon. If t rans - 2 - pentene is used as the substrate, then only the 2R,3S and 2S,3R pair is produced (they are also enantiomers.) . However, the pair from cis - 2 - pentene is diastereomeric with the pair from trans - 2 - pentene.

The stereospecificity observed in olefin bromination is only possible if the inherent facial relationship of the olefinic bond is maintained throughout the addition process and only one bromine atom adds to each face. In bromination, the electrophilic addition leads to a bridged bromonium ion which not only maintains the initial olefin geometry but also forces the second bromine to add from the opposite direction (anti) .

(Contrast this to the addition of HCl or water to a double bond where the intermediate is free to rotate so that the olefin geometry is lost and both the proton and the nucleophile can add to either face).

Other olefin additions which proceed via bridged intermediates should show similar stereospecificity and addition should occur anti. Chlorination of olefins  is an obvious analogy to bromination, but the addition of sulfenyl chlorides, oxymercuration, and expoxidation/hydrolysis all give stereospecific anti addition across the double bond because bridged intermediates are involved.

There are other stereospecific olefin addition processes which occur with cis or syn stereochemistry. Common examples include catalytic hydrogenation, hydroboration/oxidation, and dihydroxylation using osmium tetroxide. The stere-ospecificity of these syn additions requires that the facial properties of the olefinic bond be maintained throughout the addition process and that both new bonds are formed to the same face of the olefin. This is normally accomplished by a concerted syn addition to the π system.

Stereospecificity in hydrogenation is gained by a surface-mediated delivery of the hydrogen atoms to one face of the olefin. Stereospecificity in both hydrobora-tion/oxidation and osmium tetroxide/reduction results from a concerted addition to one face of the π system. This mode of addition guarantees that both new bonds are formed on the same face of the olefin. Although the reagents can add to either face of the olefin, this leads only to enantiomers of a single diastereomer. The concerted addition is the key feature which assures syn selectivity.

Another type of stereoselectivity is possible when a new chiral center is pro-duced in a molecule which already contains one or more chiral centers. A typical example of such a process would be addition to an aldehyde or ketone which already contains a chiral center.

To understand the stereoselectivity that might be observed, it is first necessary to delineate the stereochemical possibilities. The existing chiral center can be either R or S or both. Addition to the carbonyl group can potentially occur from either face since it is planar. Thus, if the existing chiral center is of the R config-uration, the products of addition will have either the R,R or R,S configurations and are diastereomers. If the starting material has only the R configuration, each diastereomer is optically active because only one enantiomer is produced. If the existing chiral center is of the S configuration, the products of addition can be either S,S or S,R diastereomers. Each diastereomer will be optically active, and they are enantiomers of the diastereomeric pair formed from the R configura-tion of the precursor. If the starting material is a racemic mixture, then all four stereoisomers will be produced —two sets of enantiomeric diastereomers. (That is, the R will give R,R and R,S and the S will give S,S and S,R.) The product mixture will be optically inactive.

A given chirality of the starting material gives two diastereomers, and it is normal to find that these two diastereomers are not produced in equal amounts. Because the two diastereomeric products are of different energies, the diastere-omeric transition states leading to them will be of different energies, the rates of their formation will be different, and they will be produced in unequal amounts. If one diastereomer is produced in excess of the other, the reaction is diastereos-elective. If only one diastereomer is produced, the reaction is diastereospecific or highly diastereoselective. The same analysis would apply if the starting material is racemic. The reaction would still produce two diastereomers and each would be formed as a pair of enantiomers, and the same diastereoselectivity would be observed.

As stated previously, the addition of nucleophiles to chiral carbonyl com-pounds is a very common type of reaction which produces diastereomeric mix-tures. The diastereoselectivity varies with the reagents and conditions. Some examples are

By analogy, the formation of diastereomers is observed for additions to other trigonal systems, such as olefins, which have a chiral center elsewhere in the molecule. In these cases, if optically active starting materials are used, then the diastereomers will be optically active. If racemic starting materials are employed, the diastereomeric mixture will be optically inactive. In either case it is common to find different amounts of the two diastereomers.

The formation of diastereomers is also possible when two new chiral cen-ters are produced from achiral starting materials. A pertinent example is found in aldol-type reactions between enolates and carbonyl compounds. The achi-ral enolate and the achiral aldehyde or ketone gives a product with two new chiral centers. Thus there can be two diastereomers produced, syn and anti, and because there is no initial chirality, each diastereomer will be produced as a racemic mixture of enantiomers. The syn and anti diastereomers will usually not be produced in equal amounts.

Factors which influence the stereoselectivity of organic reactions have been under intense investigation recently because of the increasing requirement and profitability of producing stereoisomerically pure compounds. A great deal of progress has been made, but even more remains to be accomplished. The specific contributors to stereoselectivity in individual reactions will be discussed as they are encountered. At this point it is important to be aware of the stereochemical variations that are possible.

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