Tautomeric Equilibrium in 1-Benzamidoisoquinoline Derivatives

In this study, the tautomeric equilibrium of a sequence of 1-benzamidoisoquinoline derivatives was investigated with the tools of NMR spectroscopy and computational chemistry. The equilibrium between different tautomers in these systems could be controlled via the substitution effect, and the relative content of the amide form varied from 74% for the strong electron-donating NMe2 substituent to 38% for the strong electron-accepting NO2 group in the phenyl ring. In contrast to the previously investigated 2-phenacylquinoline derivatives, the most stable and thus most abundant tautomer in the 1-benzamidoisoquinoline series except the two most electron-accepting substituents was an amide. The intramolecular hydrogen bond present in the enol tautomer competed with the intermolecular hydrogen bonds created with the solvent molecules and thus was not a sufficient factor to favor this tautomer in the mixture. Although routinely computational studies of tautomeric equilibrium are performed within the continuum solvent models, it is proven here that the inclusion of the explicit solvent is mandatory in order to reproduce the experimental tendencies observed for this type of system, facilitating strong intermolecular hydrogen bonds.

Automated summary

The tautomeric equilibrium of a series of 1-benzamidoisoquinoline derivatives was investigated using NMR spectroscopy and computational chemistry. The substitution effect could control the equilibrium between different tautomers, with the relative content of the amide form varying depending on the substituent. Unlike 2-phenacylquinoline derivatives, the most stable tautomer in the 1-benzamidoisoquinoline series was an amide, except for the two most electron-accepting substituents. The inclusion of explicit solvent was necessary to reproduce the experimental tendencies observed in this system, particularly for the formation of strong intermolecular hydrogen bonds.