Conformational analysis of N-isopropylbenzohydroxamic acids: crystal structure, DFT, and NMR studies

Abstract

X-ray crystal structure determinations together with density functional theory (DFT) calculations in vacuo and NMR studies in solution have been carried out for 4-MeOC 6 H 4 CONPr i OH 2a and 3,5-(NO 2 ) 2 C 6 H 3 CONPr i OH 2b. The results were compared with that for the respective N-methyl benzohydroxamic acids. For crystal structures as well as for DFT-optimized geometries of 2 (both isomers) in vacuo, the effect of substituents in aromatic ring manifested by changing of charges is inconspicuous. Studies of potential energy surfaces showed that libration barrier around x 1 = 0°is low enough to make electron conjugation feasible, and that for 2b rotation barrier around C(O)N bond is higher by 6 kcal/mol and additionally, that rotation around N-C bond is hindered. A careful analysis of lowtemperature 1 H NMR spectra confirmed the greater stability of Z-2a, the greater rigidity of E-2b and the influence of solvent on both isomers population. Despite solventdependent conformational alteration, both 2a and 2b crystallize exclusively as E isomers from ethyl acetate solution. Correlations of absolute 1 H, 13 C, and 15 N shielding calculations with experimental data were also analyzed.Keywords Hydroxamic acids Á X-ray structure Á DFT calculations Á Substituent effects Á Conformations Á Absolute nuclear shieldings Electronic supplementary material The online version of this article (

Conformational analysis of a secondary hydroxamic acid in aqueous solution by NOE spectroscopy

“…All signals appeared to be singlets. 1 H NMR peaks for hydroxamic acids are often broad around 300 K because of conformational exchange . Data were therefore collected at 281 K to obtain maximum signal resolution and minimize exchange.…”

“…Analysis of hydroxamic acids by NOE spectroscopy is complicated by conformational interconversion. Polarization created in one form can be carried into the other form, with the result that chemical exchange NOEs may be observed . Because chemical exchange NOEs would grow in at later times than direct NOEs, build‐up curves were prepared to differentiate direct from chemical exchange NOEs.…”

“…The hydroxamic acid is a naturally occurring metal ligand with high affinity for ferric iron. The relevance of hydroxamic acids to medicine, microbial iron harvesting, and industrial metal‐binding applications has prompted the development of various model systems . Hydroxamic acids favor two conformations, the so‐called E and Z (antiperiplanar and synperiplanar; Fig.…”

“…Computational studies of differential stabilities of E and Z have also been used to support assignment of major and minor conformations . One report has used NOE studies to assign conformations . Some inconsistencies exist in E and Z assignments, however.…”

Interplay of thermochemistry and Structural Chemistry, the journal (volume 19, 2008) and the discipline

“…Hydroxamic acids have a diverse biological activity, and so Przychodzeń and Chojnacki [220] report conformational analysis of the X-ray structure, DFT calculations and NMR studies of 4-MeOC 6 H 4 CONPr i OH and 3,5-(NO 2 ) 2 C 6 H 3 CONPr i OH and compared results to those of N-methyl benzohydroxamic acids. For crystal structures as well as for DFT-optimized geometries of both isomers in vacuo, the substituent effect in the aromatic ring manifested by changing of charges is negligible.…”