Computational Study of the Aminolysis of Esters. The Reaction of Methylformate with Ammonia Sonia Ilieva, † Boris Galabov, † Djamaladdin G. Musaev, ‡ Keiji Morokuma, ‡ and Henry F. Schaefer III* ,§ Department of Chemistry, University of Sofia, Sofia 1164, Bulgaria, Emerson Center for Scientific Computations and Department of Chemistry, Emory University, Atlanta, Georgia 30322, and Center for Computational Quantum Chemistry, University of Georgia, Athens, Georgia 30602 hfsiii@uga.edu Received August 30, 2002 The aminolysis of esters is a basic organic reaction considered as a model for the interaction of carbonyl group with nucleophiles. In the present computational study the different possible mechanistic pathways of the reaction are reinvestigated by applying higher level electronic structure theory, examining the general base catalysis by the nucleophile, and a more comprehensive study the solvent effect. Both the ab initio QCISD/6-31(d,p) method and density functional theory at the B3LYP/6-31G(d) level were employed to calculate the reaction pathways for the simplest model aminolysis reaction between methylformate and ammonia. Solvent effects were assessed by the PCM method. The results show that in the case of noncatalyzed aminolysis the addition/elimination stepwise mechanism involving two transition states and the concerted mechanism have very similar activation energies. However, in the case of catalyzed aminolysis by a second ammonia molecule the stepwise mechanism has a distinctly lower activation energy. All transition states in the catalyzed aminolysis are 10-17 kcal/mol lower than those for the uncatalyzed process. Introduction The aminolysis of esters is a basic organic reaction considered as a model for the interaction of carbonyl group with nucleophiles. The process can be studied easily by kinetic methods since for many pairs of reagents it can take place with sufficient rate at ambient temper- ature. The reaction can also be viewed as a model process for the formation of peptide bonds. There are numerous kinetic and mechanistic studies on the ester aminolysis. 1-11 The rich kinetic data form a solid basis for studying the mechanism of this reaction. In the absence of experimen- tal data concerning the structure of reaction intermedi- ates and transition states, several possible reaction paths have been discussed, all of which conform to the available kinetic results. Three principle schemes have been considered: 12 (a) a stepwise mechanism through zwitter- ionic intermediates; (b) a stepwise path through neutral intermediates; and (c) a concerted pathway involving simultaneous cleavage of the C-O single bond and formation of a C-N bond. The catalytic influences of solvents such as water and general base catalysis by the amine as well as the overall influence of the media have also been studied. 2,5 It has been shown that in aqueous solution the ester aminolysis proceeds predominantly by a general base-catalyzed attack of free amine. 2,4 The selection between the different possibilities for the mechanism of the reaction became possible only after theoretical studies of the reaction by applying semiem- pirical and ab initio electronic structure theory. 12-16 Yang and Drueckhammer studied 12 the aminolysis of ethyl thioacetate by applying molecular orbital calculations. Their results support a stepwise mechanism through neutral intermediates involving water-catalyzed proton transfer. Transition states initially found through AM1 computations were reoptimized by HF/6-31+G(d) com- putations. The energy profiles for aminolysis reactions of ethyl acetate and ethyl thioacetate have been obtained at MP2/6-31+G(d) and MP2/6-31G(d,p) levels of theory. Notably, the theoretical results showed similar values for the energy of the transition states for the stepwise and the concerted pathways. More pronounced differences in TS energies for the two schemes were obtained after considering a specific catalytic role for the water solvent. † University of Sofia. ‡ Emory University. § University of Georgia. (1) Bunnett, J. F.; Davis, G. T. J. Am. Chem. Soc. 1960, 82, 665. (2) Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 675. (3) Bruice, T. C.; Mayahi, M. F. J. Am. Chem. Soc. 1960, 82, 3067. (4) Blackburn, G. M.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 2638. (5) Jencks, W. P.; Gilchrist, M. J. Am. Chem. Soc. 1966, 88, 104. (6) Bruice, T. C.; Donzel, A.; Huffman, R. W.; Butler, A. R. J. Am. Chem. Soc. 1967, 89, 2106. (7) Rogers, G. A.; Bruice, T. C. J. Am. Chem. 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