Control of Modes of Intramolecular Imidazole Catalysis of Ester Hydrolysis by Steric and Electronic Effects

The various mechanisms by which a neighboring imidazolyl nitrogen base (both neutral and anionic) or the conjugate acid imidazolium cation may participate in the hydrolysis of an acetyl ester of a weakly basic or strongly basic phenol have been evaluated (pH 0-13). For this purpose 0-acetyl esters of 2 4 2 ’ and 4‘-hydroxypheny1)imidazoles were prepared (Ia, b, 11, IIIa, b, and IV). Lyate species access to the ester carbonyl carbon is quite similar for Ia, b, 11, and IV as shown by their nearly identical specific acid rate constants (k l , Table 111). For 11 the imidazole is para to the ester bond and therefore anchimeric assistance of hydrolysis is not possible. For esters IIIa and IIIb which possess bulky rert-butyl groups ortho to the ester bond, access by lyate species to the ester carbonyl group is greatly restricted as shown by the fact that the specific acid rate constant is -lo3 less than that determined for the other esters. At low pH (2-4) intramolecular participation by the o-imidazole function of esters Ia and Ib is evidenced by a plateau in the pH-log k o b s d profiles. Arguments presented favor general acid assistance to HzO attack by the neighboring imidazolium cation representing rate enhancements of 25and 150-fold for esters Ia and Ib, respectively. At neutrality a second plateau is observed for esters la, b, IIIa, and IV and is attributed to general base catalyzed H20 attack at the ester bond by neutral imidazole. The discussion correlates this mechanism with the like mechanism proposed elsewhere for the isomeric imidazolyl compound V and also for aspirin. Thus, a nearly 104-fold rate enhancement is seen over the uncatalyzed hydrolysis of Ia and similarly for Ib, IIIb, and IV. At alkaline pH (9-11) additional plateaus in the pH-log k o b s d profiles for esters Ib and IIIb are observed and present evidence for intramolecular acetyl group transfer to the imidazole anion with subsequent hydrolysis of the acetylimidazole intermediate. In the case of IIIb this intermediate is directly observable. Therefore the alkaline plateau regions and the ascending limbs of the pH-log k o b s d profiles in the most alkaline region represent rate-limiting specific base hydrolysis of acetylimidazole intermediates (AH and A, respectively of Scheme 11) derived from Ib and IIIb. The only pathway operable in the hydrolysis of IIIa in the pH range studied (811 5 ) is uia specific base attack on the corresponding acetylimidazole intermediate AH (Scheme 11). For esters Ia, 11, and IV (where IV cannot form an imidazole anion), specific base catalyzed hydrolysis of the ester bond is the preferred mechanism. Thus, depending upon the substituent groups on the phenyl acetate ring, three modes of intramolecular imidazole catalysis of ester hydrolysis can occur: (1) general acid assisted H20 attack, (2) general base assisted HzO attack, and (3) 0-N acetyl transfer to imidazole anion with subsequent hydrolysis of the intermediate acetylimidazole. All three modes of catalysis attain in the single ester Ib. The electronic and steric factors which mediate these different modes are discussed in detail. he implication of an imidazolyl group in the mechaT nism of catalysis by the serine esterases2 has led to extensive investigations of imidazole catalysis of ester hydrolysis. In intermolecular reactions involving phenyl acetates as substrates, bimolecular nucleophilic displacement of phenoxide (eq 1) is the exclusive pathway until the pK, of the conjugate acid of the leaving group exceeds that of imidazolium ion by (ApK,) Ei 3.0. When ApK, > 3 (with phenyl esters) general base assistance of the attack of imidazole by imidazole (eq 2) becomes of importance. When ApK, >> 3 (aliphatic esters), general base assistance of the attack of water by imidazole (eq 3) is the sole mechanism for catalysis of hydrolysis. In eq 1-3 the arrows are for bookkeeping purposes. The actual timing of proton transfer and covalent bond making and breaking processes is of much present concern.4 The changes of mechanism from eq 1 to 2 to 3 on increase in ApK, may be viewed as arising through the necessity of generating a nucleophilic species which is, in basicity, comparable to the leaving group.5 (1) A portion of the material submitted by G. A. Rogers in partial fulfillment of the requirements for the Ph.D. in Chemistry, University of Califorina at Santa Barbara. (2) T. C. Bruice and S. J. Benkovic, “Bioorganic Mechanisms,” Vol. I. W. A. Benjamin, New York, N. Y., 1966, Chapter 11. (3) (a) M. L. Bender and T. W. Turnquist, J. Amer. Chem. SOC., 79, 1956 (1957); (b) T. C. Bruice and G. L. Schmir, ibid., 79, 1663 (1957); (c) see Chapter 1 of ref 2 for a review. (4) W. P. Jencks, Chem. Reo., 72,705 (1972). The dependence of mechanism upon ApK, for intramolecular displacement reactions is amended by steric considerations. Thus, although acetate ion is incapable of displacing phenolate ion directly if ApK, > 2.6,6 in intramolecular reactions the COOgroup may directly displace alkoxide ions (ApK, 10) if a cyclic anhydride is formed and the alkoxide leaving group departs from the acyl product.’,* On the other hand, if the leaving group and COOmoiety are part of a single molecule, as in acetyl salicylate, direct nucleophilic displacement gives way to COOgeneral base catalyzed attack of H 2 0 when ApK, > 0.9 Though intramolecular imidazole catalysis of ester hydrolysis has received less attention than carboxylate intramolecular catalysis, the mechanistic requirements would seem to be similar. Thus, for phenyl esters of y-(4-imidazolyl) butyrate, direct nucleophilic displacement is a very facile process yielding the bicyclic lactam intermediate.l0.l1 For the acetyl ester,12 and presumably sub( 5 ) A tenet of the anthropomorphic rule: W. P. Jencks and J. E. Reimann, J . Amer. Chem. SOC., 88, 3973 (1966). (6) V. Gold, D. G. Oakenfull, and T. Riley, J . Amer. Chem. Soc., 90, 515 (1968). (7) J. W. Thanassi and T. C. Bruice, J . Amer. Chem. SOC., 88, 747 (1966). (8) If steric compression in the ground state is great, displacement may occur when ApK, S 12: A. J. Kirby, J. Chem. SOC., Chem. Commun., 834 (1972). (9) A. R. Fersht and A. J. Kirby, J. Amer. Chem. SOC., 90, 5818, 5826 (1968). Rogers, Bruice 1 Imidazole Catalysis of Ester Hydrolysis