INFLUENCE OF INTER AND INTRAMOLECULAR HYDROGEN BONDS ON THE TAUTOMERISM OF BETHA-KETOAMIDES: AN NMR AND THEORETICAL STUDY

LAURELLA S.; SPALTRO A., RUIZ D. ALLEGRETTI P.

Villa Carlos Paz, Córdoba

Conferencia; 13a Conferencia Latinoamericana de Físico-Química Orgánica; 2015

-ketoamides are useful pro-drugs (involved in treatment of inflammatory diseases including cystic fibrosis and emphysema) as well as versatile intermediates in the synthesis of heterocycles (3-acetyltetramic acids and related antibiotics, lactames, syrolactames, etc.) [1,2]. Even when they have been described exclusively as a unique structure,we have carried out a study on eleven -ketoamides [3] and we have found out that they exist mainly as two tautomeric forms: ketoamide and Z-enolamide (other tautomeric forms concentrations are negligible). All structural determinations in solution were carried out by means of 1HNMR and 13CNMR in CDCl3 and DMSO-d6. Enol/keto rate appears to be affected by solvent polarity, substituents (electronic and steric effects), concentration and temperature. We have determined ΔH and ΔS for all eleven compounds. We have suggested that equilibrium shifts and thermodynamic parameters are strongly affected by intramolecular hydrogen bonds, which can be established only in these two isomers. Intermolecular hydrogen bonds are suggested in order to explain the differences observed in DMSO. Our aim in this work is to support the structures previously proposed using theoretical calculations in solution.We carried out the study on eleven ketoamides (bearing H-, CH3-, Ph-, p-ClPh, p-CH3OPh- subtituents in several positions). All geometries have been optimized in vacuum using B3LYP density functional and the re-optimized in CHCl3 and in DMSO. We calculated the shielding tensors corresponding to each one of these molecules using two different methods: B3LYP/6-31G(d,p) and mPW1PW91/6-311+G(2d,p). We calculated all 1H and 13C chemical shifts by substracting TMS and using scaling factors [4]. Energy differences were calculated as well.The best results in chloroform were obtained using the method mPW1PW91/6-311+G(2d,p) followed by the application of scaling factors (RMSE from the experimental values of 0.246 for the enol hydroxylic H and 0.064 for the keto metinic H). In DMSO the results were not satisfactory by neither of the previous methods. When we added explicit DMSO molecules (in order to form the supposed hydrogen bonds) the results regarding energies and chemical shifts turned out excellent (RMSE of 0.357 for the enol hydroxylic H and 0.069 for the keto metinic H). We think that these results can be very helpful for the structure determination of new molecules.