Study on Conformation Interconversion of 3-Alkyl-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines from Dynamic NMR Experiments and ab Initio Density Functional Calculations

Abstract

Variable-temperature NMR experiments and ab initio density functional calculations were carried out to investigate the conformation interconversion of novel chiral 3-alkyl-3,4-dihydro-2H-benzo[1,4]oxazine derivatives. With CDCl 3 as the solvent, the coalescence temperatures of H 2 , H 3 , H 11 , and H 19 of product 1 are about 289, 304, 292, and 316 K, with the corresponding activation free energies at 58.0 ( 6.7, 60.9 ( 7.1, 58.3 ( 6.8, and 59.6 ( 6.9 kJ‚mol -1 , respectively. When dimethyl sulfoxide (DMSO-d 6 ) was used as the solvent, 1 H and 13 C NMR signals were completely assigned at 375 K. The effects of solvent and temperature were investigated through a polarizable continuum model. At each theoretical level (MP2 or B3LYP), the changing tendencies of the calculated activation free energies and interconversion rates agree well with those of the NMR results. In addition, the interconversion rate at each specified temperature was calculated to be about 1.5 times faster in DMSO-d 6 than in CDCl 3 . Accordingly, we failed to observe the coalescence phenomena of H 3 and H 19 in DMSO-d 6 by NMR measurements from 296 to 375 K. The substitution effect at the R 1 -R 5 positions was considered using density functional calculations, with the activation barriers decreasing as follows: product 6 > 3 > 1 > 7 > 2. This sequence is consistent with that of the reaction heats, except for product 7, implying that the interconversion processes may be thermodynamically controlled. Surprisingly, the substituted groups near the acetyl group in product 2 and 7 do not elevate the activation barrier but, instead, lower it somewhat, with the possible reasons for this provided in the paper.

The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study

“…All density functional calculations were performed using the Gaussian03 suite of programs. 40 As in previous works in the literature, [41][42][43][44] the structures were optimized using the B3LYP density functional 45,46 and the standard 6-31G(d) basis set. The neutral and zwitterionic isomers of BA were also optimized at the B3LYP/6-311++G(d,p) level of theory.…”

“…As to the implicit solvation models, the selfconsistent isodensity polarizable continuum model (SCI-PCM) of self-consistent reaction field (SCRF) 47 was used. 42,48 The default dielectric constant of 78.0 was adopted for water.…”

Noncovalent Interactions of Fluorine with Amide and CH2 Groups in N-Phenyl γ-Lactams: Covalently Identical Fluorine Atoms in Nonequivalent Chemical Environments

“…Apparently, large 19 F chemical shift differences in CDCl 3 solution required high rotation rates to unify the separated 19 F NMR signals in compound 4 . In such a dynamic system, faster rotation rates were generally achieved at higher temperatures …”

Resolute italian study in all comers

“…To further clarify the chiral recognitions with NA proteins, the relative energies of BL stereoisomers are obtained, under different environments. The energies in aqueous solutions are calculated by the SCI‐PCM model as previously [18, 39, 41]. The BL1z stereoisomer represents the lowest energy and is used as the energy benchmark.…”

“…Note that the N1H1 distances in the zwtterions are fixed at 1.030 Å due to their structural instabilities [19, 38, 39]. In accord with the previous studies [18, 39, 41], the solvent effects of the BL x stereoisomers were accounted by the self‐consistent isodensity polarizable continuum model (SCI‐PCM) of self‐consistent reaction field [42, 43].…”