Chiral Thiophene Sulfonamide—A Challenge for VOA Calculations

Abstract

Two enantiomers of 2-methyl-N-(1-thien-2-ylethyl)propane-2-sulfonamide (TSA) were synthesized, and their VCD, ROA, IR, and Raman spectra were registered. The solved (S)-TSA X-ray structure shows a disorder connected to the presence of two TSA conformers differing by a slight rotation of the thiophene ring. Two molecules in the unit cell of the monoclinic P2 crystal form a net of NH···OS and C*H···OS hydrogen bonds. Out of a series of computational levels tested to interpret the spectra, the B3LYP functional combined with the def2TZVP basis set satisfactorily reproduces the experimental VCD and ROA spectra. To simulate the VCD spectra of TSA enantiomers in KBr pellets, dimers and tetramers, with two different positions of the thiophene ring, were considered. The VCD spectra measured in CDCl are completely different from those taken in KBr due to the conformational freedom of TSA in chloroform. Seven TSA conformers fall into two groups of opposite configurations at the pyramidal N atom forming the additional stereogenic center. However, the barriers between conformers in each group are lower than the energy of thermal motions at 300 K. Thus, all conformers, but the most stable in each group, are likely to be metastable states. The calculated IR, VCD, Raman, and ROA spectra of the conformers depend not only on the type of stereogenic N atom but also on the thiophene ring rotation. Yet, they are likely to coexist because of low barriers between them. Three approaches were tested to reproduce the chiroptical spectra in solution using PCM and hybrid solvation models. As a consequence, it was found that a model in which all conformers contribute to the spectra with equal population factors seems to best reproduce the experimental data. Such a result suggests that in a dissolved state in 300 K TSA occurs in a very shallow potential well and all of its conformers coexist.

The Vibrational Circular Dichroism Pattern of the ν(C=O) Bands in Isoindolinones

“…We have recently observed that VCD spectra measured in KBr pellets are much more intense than those measured in solutions . However, VCD spectra measured in solution were completely different from those taken in KBr.…”

“…We have recently observed that VCD spectra measured in KBr pellets are much more intense than those measured in solutions. [11] However, VCD spectra measured in solution were completely different from those taken in KBr. This dichotomy results from differences between conformational freedom in solution and in the crystal phase.…”

IR, Raman, and Vibrational Optical Activity Spectra of Methyl Glycidate in Chloroform and Water: The Clusters‐in‐a‐liquid Solvation Model

“…This is in part due to the significant developments in the associated instrumentation, and ab initio density functional theory (DFT), treatment in the last two decades. More recently, the applications of these two chiroptical techniques have extended to studies of intermolecular interactions directly in solution, in particular chiral solute‐solvent interactions ,,. These studies pointed out the importance of both explicit and implicit solute‐solvent interactions in modelling solvent effects, for example for solvents which can serve as a hydrogen (H)‐bond donor/acceptor to a solute.…”

“…More recently, the applications of these two chiroptical techniques have extended to studies of intermolecular interactions directly in solution, in particular chiral solute-solvent interactions. [7,8,9] These studies pointed out the importance of both explicit and implicit solutesolvent interactions in modelling solvent effects, for example for solvents which can serve as a hydrogen (H)-bond donor/ acceptor to a solute. For many common solvents, such as chloroform and dimethyl sulfoxide (DMSO), one can adequately account for solvent effects by constructing small solute-solvent H-bonded complexes and placing them in a bulk solvent which is commonly modelled by the polarizable continuum model (PCM).…”

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

“…Further examples are an intermediate in the synthesis of an phthalazine-based p38 MAP kinase inhibitor ( 16 ), the aroma compound 2,5-dimethyl-4-methoxy-3­(2 H )-furanone 17 and several of its derivatives; the 2,6-bis­(2-butyl)-4-methylpyridine 18 and its N -oxide; aromatase-sulfatase inhibitor 19 , for which no suitable crystals could be obtained; the α-(trifluoromethyl)-tryptamine 20 ; the chiral sulfonamide 21 ; a new calcium channel blocker 22 ; products of the newly developed biocatalytic reduction of the corresponding imines to sulfur containing cyclic amines such as 23 ; the monoamine oxidase inhibitor 24 ; the phenothiazine-based derivative 25 ; the acetonide 26 ; and the dihydronaphthalene 27 , which is chiral by isotopic labeling only.…”