SN2 reactions at amide nitrogen - theoretical models for reactions of mutagenic N-acyloxy-N-alkoxyamides with bionucleophiles

The reactions of N-formyloxy-N-methoxyformamide 4 with ammonia 2 and methanethiol 3 have been modeled at the AM1, HF/6-31G* and Density Functional computational levels. The reaction process is similar geometrically and electronically to classical SN2 reactions at carbon. Near-linear transition states reveal extensive charge separation and partial nitrenium ion character at the formamide nitrogen indicative of a non-synchronous process involving early stretching of the formate-formamide nitrogen bond. Activation energies, computed from pBP/DN* energies of HF/6-31G* ground state and transition state geometries, are in the range of experimental values and a strong solvation effect is predicted. Evidence for anomeric weakening of the N-formate bond by the geminal alkoxyl oxygen was obtained from a comparison of the reactions of ammonia with 4 and N-formyloxy-N-methylformamide 5. An N-alkyl group leads to a much larger activation energy in accordance with the experimental findings for N-acyloxy-N-alkylamides, which are resistant to attack by nucleophiles and are non-mutagenic.