Direct O-Acylation of Small Molecules Containing CO2(1-)---HN<--HO Units by a Distorted Amide: Enhancement of Amine Basicity by a Pendant Carboxylate in a Serine Protease Mimic

Article abstract of DOI:10.1021/ja00186a045

The kinetics of the reaction of two series of amino alcohols (ethanol amines and 2-hydroxymethylimidazoles) with a distorted amide were studied as models for the acylation of the serine proteases.The pH/logk₂^max profiles plateau above the amine pK_a, indicating the basic form is active.In all cases, the reactions proceed by initial O-acylation to produce esters.With primary or secondary ethanolamines, subsequent O-->N acyl transfer occurs to give amides.In each series, a Bronsted relationship exists relating the increasing amine pK_a with an increasing second-order rate constant for O-acylation.Amino alcohols containing a pendant carboxylate (e.g., serine and the 4(5)-<α,α-dimethylacetic acid> derivative of 2-hydroxymethylimidazole) fit on the Bronsted plots exactly, which suggests the amine pK_a controls the reactivity.The role of the carboxylate is to enhance the amine basicity by electrostatic/inductive means.This is particularly effective in solvents of reduced polarity (40percent and 80percent v/v, EtOH/H2O) since the above effects counteract the normal drop in amine pK_a exhibited by the other amino alcohols that do not possess the CO2(1-).Both series exhibit low kinetic solvent isotope effects of between 1 and 2.In the imidazole alcohol series, as the amine pK_a increases the kinetic solvent isotope effect tends to 1.0.This is discussed in terms of a possible involvement of direct nucleophilic attack of an ammonium alkoxide zwitterion on 1.