Comment on “Penicillin’s catalytic mechanism revealed by inelastic neutrons and quantum chemical theory” by Z. Mucsi, G. A. Chass, P. Ábrányi-Balogh, B. Jójárt, D.-C. Fang, A. J. Ramirez-Cuesta, B. Viskolczc and I. G. Csizmadia, Phys. Chem. Chem. Phys., 2013, 15, 20447

Abstract

The nature of amide resonance in the β-lactam ring of β-propiolactams and penicillin type structures has been evaluated by the Mucsi hydrogenation method on the one hand, and isodesmic trans-amidation (TA) and the carbonyl substitution nitrogen atom replacement (COSNAR) methods on the other hand. The discrepancy between the two approaches points to two errors, one arithmetic and the other conceptual, in the manner in which the hydrogenation method is applied to β-lactams and which leads to much lower resonance stabilisation and amidicities than found by the TA and COSNAR methodologies. Correction of these errors yields amidicities in line with the TA and COSNAR results demonstrating that amide bonds in simple β-propiolactams are not weakened by strain relative to normal amides such as N,N-dimethylacetamide. Mucsi's results for penicillin are similarly in error, critically so in light of their use of the drastically reduced resonance in rationalising their proposed mechanism of reaction of the antibiotic with transpeptidase. Correction of the errors in application to penicillin-models points to other difficulties in applying the methodology to complex molecules. A detailed analysis of penicillin-type structures has been carried out using the reliable TA and COSNAR methods, which both point to relatively modest reductions in amidicity or resonance stabilisation in accordance with the known stability of the penam-type structures. At the very least, penicillin retains about 60% the resonance of N,N-dimethylacetamide in stark contrast to the erroneous −36% reported from the hydrogenation method.