Size-Driven Inversion of Selectivity in Esterification Reactions: Secondary Beat Primary Alcohols

Relative rates for the Lewis base-mediated acylation of secondary and primary alcohols carrying large aromatic side chains with anhydrides differing in size and electronic structure have been measured. While primary alcohols react faster than secondary ones in transformations with monosubstituted benzoic anhydride derivatives, relative reactivities are inverted in reactions with sterically biased 1-naphthyl anhydrides. Further analysis of reaction rates shows that increasing substrate size leads to an actual acceleration of the acylation process, the effect being larger for secondary as compared to primary alcohols. Computational results indicate that acylation rates are guided by noncovalent interactions (NCIs) between the catalyst ring system and the DED substituents in the alcohol and anhydride reactants. Thereby stronger NCIs are formed for secondary alcohols than for primary alcohols.