Fidelity in Hapten Design:  How Analogous Are Phosphonate Haptens to the Transition States for Alkaline Hydrolyses of Aryl Esters?

• Published in: Journal of organic chemistry 1999-04, Vol.64 (9), p.3066-3076
• Main Authors: Tantillo, Dean J, Houk, K. N
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo982335t

Is antibody catalysis of hydrolysis reactions limited by imperfect mimicry of transition states by haptenic analogs? This question was explored by comparison of calculated transition states for the hydrolyses of aryl esters and the haptens intended to mimic them. The addition−elimination reaction of phenyl acetate and hydroxide ion in the gas phase was examined using ab initio calculations at the RHF/6-31+G(d)//RHF/6-31+G(d) and MP2/6-31+G(d)//RHF/6-31+G(d) levels of theory. Although transition states for both addition and elimination were located, the barrier to elimination disappeared when zero point energy or electron correlation was included. The reaction is therefore concerted, and the transition state for addition is the only relevant transition state in the gas phase. When aqueous solvation is considered through PCM and SCI-PCM calculations, the barrier to addition is shown to increase dramatically, and a stepwise addition−elimination pathway is predicted. A single transition state for the analogous reaction with p-nitrophenyl acetate was also located, and this reaction is predicted to be concerted in both the gas phase and in solution. The calculated geometries, CHELPG atomic charges, and electrostatic potential surfaces of stationary points involved in hydrolysis were compared with those of model phosphonate and phosphinate haptens. The haptens are better mimics of the two transition states and the tetrahedral intermediate than of the reactants or productsexactly the situation desired for catalyst generationyet they are more analogous to the tetrahedral intermediate and the transition state for elimination than to the rate-determining addition transition state. In addition, the hydrogen-bonding pattern and asymmetry of the stationary points are not faithfully reproduced by the haptens. These considerations suggest that catalysis may be improved by hapten redesign or antibody mutagenesis.