A catalyst for ester hydrolysis showing electrostatic and hydrophobic binding properties

The steroid 17β-(4-imidazolyl)-5α-androstane-3β,11β-diamine, 1a, R = H, acts as a catalyst for the hydrolysis of aryl esters. For a series of aryl acetates, 2a–h, at 1 M ionic strength, log k2 for 1a catalyzed hydrolysis is linearly related to log k2 for imidazole catalyzed hydrolysis, with only 2d, 4-acetoxy-3-nitrobenzoate, deviating: at zero ionic strength, all anionic substrates show positive deviations, and a cationic substrate shows a negative deviation. This is interpreted in terms of a stringent geometrical requirement for strong electrostatic catalysis. With favorable geometry, a 1:1 electrostatic attraction can lead to a 15 fold rate enhancement (μ = 0). For a series of arylpropionate esters 3a–c, rate constants for 1a catalyzed hydrolysis show a small but progressive increase with increasing size of the aryl group: after correcting for substrate reactivity and electrostatic interactions, this hydrophobic effect is independent of the leaving group. 1b (R = isopropyl) was prepared to determine the rate of reaction at N-3 of the steroidal imidazole ring: this is the more hindered nitrogen but also the more suitable for hydrophobic binding. 1b was markedly less reactive than 1a, but showed larger hydrophobic effects. Detailed analysis suggests that the potential hydrophobic rate enhancement for the interaction of a phenanthryl group with the lower surface of a steroid is about 160-fold. This study provides guidelines for the design of enzyme models of greater catalytic efficiency.