Stereoselectivity of Organometallic Addition Reactions

Addition, Condensation and Substitution Reactions of Carbonyl Compounds 

The stereochemistry of organometallic additions with carbonyl compounds fits into the general pattern for nucleophilic attack discussed in Chapter 2. With 4-7-butylcyclohexanone there is a preference for equatorial approach, but the selectivity is low. Enhanced steric factors promote stereoselective addition. 

The stereochemistry of organometallic additions in acyclic carbonyl compounds has also been examined. Additions of Grignard reagents to ketones and aldehydes was one of the reactions that led to the formulation of Cram s rule (see p. 179). Many ketones and aldehydes have subsequently been subjected to studies to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 7.5. These data show consistent agreement with Cram s rule and the Felkin TS, as discussed in Section 2.4.I.2. 

The role of chelation has been investigated both experimentally and computationally. In experimental studies, it was found that an a-methoxy group increases the rate of addition of dimethylmagnesium to propiophenone approximately 2000-fold. ° The rate acceleration indicates that chelation not only controls stereochemistry but also facilitates the addition step. The methyl group adds from the less hindered face of the chelate. The reaction gives a greater than 99 1 preference for chelation-controlled addition. 

An a-benzyloxy group was found to cause rate acceleration of more than 100, relative to a nonchelating a-trimethylsiloxy group. On the other hand, a 4-benzyloxy group in 2-butanone ((i-substitution) caused only a 20% rate increase. 

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