Predicting the Site of Cleavage for Acyl Transfers from Esters

3 Predicting the Site of Cleavage for Acyl Transfers from Esters 

Another method for analysis is to examine stereogenic centers at the ester group [RCO(OR )]- Addition-elimination leads to retention of the stereochemistry of the ester R group, while Sn2 attack inverts the stereochemistry of the ester R group. 

Acyl transfer reactions are susceptible to many different forms of catalysis, including acid, base, and nucleophilic. We will look at each type here. 

One of the most common methods to catalyze acyl transfers is the addition of a nucleophile, particularly when using acid halide reactants. For example, consider the reaction of an alcohol or water with an acid halide, but with the addition of triethyl amine. We add the tri-ethylamine to neutralize the HX produced in this reaction, but it also significantly enhances the rate of the reaction (Eq. 10.109 also see Section 9.2.5 for a discussion of nucleophilic catalysis). Initial attack of the amine is faster than attack by the less nucleophilic alcohol or water, creating an intermediate with a positive charge. This is a highly reactive carbonyl that now adds nucleophiles faster than the starting acid halide. 

Several pieces of data support the role of certain amines as nucleophiles and others as general-base catalysts in this reaction. First, non-nucleophilic amines follow Bronsted relationships, but those amines that are small enough to be nucleophiles are markedly more active. Furthermore, solvent isotope effects are significantly different for the nucleophilic and general-base pathways. The small nucleophilic amines do not show solvent isotope effects, whereas the amines that act as general-base catalysts do show solvent isotope effects. 

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