Joint gas-phase electron diffraction and quantum chemical study of conformational landscape and molecular structure of sulfonamide drug sulfanilamide

Abstract

Conformational composition and molecular structure of sulfanilamide (para-aminobenzenesulfonamide, SA) has been investigated by means of gas electron diffraction (GED) and quantum chemical (QC) calculations. Conformations with eclipsed orientation of the S=O and the N–H bonds in the sulfonamide moiety have been found to be predominant in vapor at the average temperature of the GED experiment of 184(5) °C. The structural parameters of the most stable conformer are the following (rh1 in A and ∠h1 in ° with 3σ in parenthesis): r(C=C) av = 1.410(4), r(S=O)av = 1.433(4), r(C–S) = 1.763(6), r(S–N) = 1.649(6), ∠CSN = 104.7(15), (∠CSO)av = 109.0(8). The orientation of the S–N bond of the sulfonamide group about the anilinic ring plane has been found to be different from orthogonal by about 13°. It has been shown that QC calculations tend to overestimate the values the S=O bond lengths as well as are not always accurate in the prediction of mutual orientation of the sulfonamide group and the anilinic ring plane. While in the gas phase, low energy conformations are found to be the most abundant; the molecular structure of SA in the crystal phase resembles a high energy conformation with staggered orientation of the N–H and the S=O bonds for all polymorph modifications. The mechanisms of mutual transformations of different SA conformers into each other have also been considered and discussed.