Kinetics and Mechanism of Hydrolysis of Labile Quaternary Ammonium Derivatives of Tertiary Amines

Abstract

The kinetics and mechanism of hydrolysis of N-(4-hydroxy-3,5-dimethylbenzyl)pyridinium bromide and similar quaternary derivatives of niacinamide, N,N-dimethylaniline, and trimethylamine were investigated. pH-Rate profiles at 25 degrees for formation of tertiary amine and 4-hydroxymethyl-2,6-dimethylphenol indicated that the zwitterionic quaternary phenoxide was the reactive species in alkaline solution. The apparent rate of hydrolysis was strongly inhibited by addition of small amounts of product tertiary amine, which is consistent with the presence of an intermediate in the reaction pathway. A mechanism was proposed for the hydrolysis and methanolysis of these compounds involving the reversible formation of the quinone methide, 4-methylene,-2,6-dimethyl-2,5-cyclohexadien-1-one, followed by a trapping reaction with solvent or nucleophiles. Replacement of the phenolic hydrogen with methyl or acetyl groups greatly stabilized the molecule which is in agreement with the proposed mechanism. For the ester, the rate of amine release was limited by specific base catalyzed hydrolysis of the ester group. Compounds of this type may be useful in prodrug design for tertiary amines. The possibility of quinone methine intermediates in the degradation of structurally similar drugs, such as epinephrine, was discussed.