peri-Dimethylamino substituent effects on proton transfer at carbon in α-naphthylacetateesters: a model for mandelate racemase

Abstract

The rate constants for exchange of hydrogen for deuterium at the α-CH₂ positions of 8-(N,N-dimethylaminonaphthalen-1-yl)acetic acid tert-butyl ester 1 and naphthalen-1-ylacetic acid tert-butyl ester 2 have been determined in potassium deuteroxide solutions in 1 : 1 D₂O : CD₃CN, in order to quantify the effect of the neighbouring peri-dimethylamino substituent on α-deprotonation. Intramolecular general base catalysis by the (weakly basic) neighbouring group was not detected. Second-order rate constants, k_DO, for the deuterium exchange reactions of esters 1 and 2 have been determined as 1.35 × 10⁻⁴ M⁻¹ s⁻¹ and 3.95 × 10⁻³ M⁻¹ s⁻¹, respectively. The unexpected 29-fold decrease in the k_DO value upon the introduction of a peri-dimethylamino group is attributed to an unfavourable steric and/or electronic substituent effect on intermolecular deprotonation by deuteroxide ion. From the experimental k_DO values, carbon acid pK_a values of 26.8 and 23.1 have been calculated for esters 1 and 2.