Carbonyl compounds with nucleophiles

Reactions of Co-ordinated Carbonyl Compounds with Nucleophiles... 

The typical reaction of carbonyl compounds with nucleophiles is the addition (Section 9.1 and Chapter 10) the C=0 bond disappears ... 

The stereochemistry of the reactions of chiral carbonyl compounds with nucleophiles has been a topic of considerable theoretical and synthetic interest since the pioneering study by Cram appeared in 1952. The available predictive models focus entirely on the conformational and stereoelectronic demands of the chiral carbonyl substrate, the implicit assumption being that the relative stabilities of the competing transition states are determined only by stereoelectronics and the minimization of nonbonded interactions between the substituents on the chiral center and the nucleophile. These models totally ignore the possibility, however, that the geometric requirements of the nucleophile may also have an effect on reaction diastereoselectivity. Considerable evidence is now available, particularly in the reactions of Type I (Z)-crotylboronates and Z(0)-metal enolates, that the stereochemistry of the nucleophile is indeed an important issue that must be considered when assessing reaction diastereoselectivity. 

There is a wealth of literature information over the past centuiy in relation to mechanisms of acid-catalysed processes sueh as hydrolyses or solvolyses. In particular, the seminal work of Bell, Eigen and Jencks, clearly delineated all the mechanistic options for the reaction of carbonyl compounds with nucleophiles, and established the key criteria that influence specific and general acid-catalysed processes. In the following two sections, we overview only recent examples of homogeneous acid-catalysed reactions. 

The rates and equilibrium constants of reactions of carbonyl compounds with nucleophiles such as semicarbazide are affected significantly by variations in the pH of the reaction medium. This may be understood by examining the results of protonating the reactants. 

First, consider the effect that protonation of the carbonyl function has on the rate of reaction of a carbonyl compound with nucleophiles. The addition of a proton to the oxygen atom of a carbonyl group produces 6 (Eq. 13.5). The carbonyl carbon atom in 6 is much more electrophilic than in the unprotonated compound because the partial positive charge on the carbon atom is increased, as shown by consideration of the two resonance structures for 6. Since the rate-determining step for the formation of semicarbazones is the nucleophilic attack of semicarbazide (1) on the carbonyl carbon atom of the substrate, the enhanced electrophilicity of 6 increases the rate of formation of the semicarbazone. 

A variant of these reactions was optimized based on the Hosomi-Miyaura borylation of a,P-unsaturated carbonyl compounds with nucleophilic boryl copper, providing 2-alkoxycarbonyl (as well as 2-acyl- and 2-cyano) allylboronates such as 40 in high stereoselectivity (Equation 22) [60]. The resulting 2-alkoxycarbonyl reagents react with aldehydes to provide a-methylene-y-butyrolactones. 

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