Amide bond dissociation enthalpies: Effect of substitution on N-C bond strength

The amide group plays an important role in the structure of proteins and is one of the major functional groups in organic chemistry. Although a large number of investigations were devoted to understanding the chemical character of the amide bond, little is known about the N-C bond dissociation enthalpies (BDEs), which represent one of the fundamental sets of chemical thermodynamic data. In this study, the homolytic N-C BDEs have been calculated for 55 amides and the effect of substituents on the strength of N-C bond has been investigated using the Gaussian-4 (G4) method. The atomization reaction and isodesmic reaction procedures were used for accurate evaluations of enthalpies of formation of parent molecules and radicals derived from them by the breaking of the amide bond. It is demonstrated that the G4 method reproduces the experimental data with high accuracy in most cases. The large discrepancies between experimental and theoretical values revealed in some cases could be due to possible experimental errors. More reliable enthalpies of formation are recommended for 10 molecules and 9 radicals based on quantum chemical calculations. The accurate and internally consistent values of enthalpies of formation of amide molecules and corresponding radicals were used to calculate the N-C BDEs. The trends observed in BDEs are associated with substituents on nitrogen and carbonyl. The electron-donating substituents (-C(O)-, -NHC(O)-, -O-, -N-3) on carbonyl increase the BDE; these groups, therefore, have stabilizing effect on amide bond. However, the methyl and phenyl substituents on nitrogen result in a decrease of 10-90 kJ/mol in BDEs on going from primary to tertiary amides and, therefore, cause the amide bond to weaken. The observed BDE trends correlate with the N-C bond lengths. Nitrogen atomic charges and second-order stabilization energy estimates obtained by NBO analysis can be also used to uncover trends in BDEs and build qualitative descriptions. (C) 2012 Elsevier B.V. All rights reserved.