The reaction mechanism of the nonenzymatic transmethylation of catechol by S-adenosylnethionine (AdoMet, as modeled by sulfonium ion) has been elucidated using ab initio and semiempirical quantum mechanical methods. The gas phase reaction between catecholate and sulfonium is extremely fast, involving no overall barrier. The reaction profile to some extent resembles a typical gas phase S(N)2 reaction. However, in aqueous solution, this reaction is very slow with a predicted barrier of 37.3 kcal/mol. The calculated (k(H)/k(D))(alpha), k(12)/k(13), k(16)/k(18), and k(32)/k(34) are 0.80, 1.06, 1.003, and 1.010, respectively. Previously, Schowen and co-workers measured (k(H)/k(D))(alpha) and k(12)/k(13) to be 0.83 +/- 0.05 and 1.09 +/- 0.05 for the catechol O-methyltransferase (COMT)-catalyzed methylation of 3,4-dihydroxyacetophenone by AdoMet. This good agreement between the calculated kinetic isotope effects for the model reaction and the measured kinetic isotope effects for the enzymatic reaction seems to suggest that the structure of the enzymatic transition state is very similar to that of the nonenzymatic reaction. Factors that modulate the catalytic efficacy of catechol O-methyltransferase were discussed in light of the present study on the nonenzymatic reaction and the recently solved X-ray crystal structure.