NMR Spectroscopy and Theoretical Calculations in the Conformational Analysis of 1-Methylpyrrolidin-2-one 3-Halo-derivatives

Abstract

This study reports the results of ab initio and density functional theory (DFT) electronic structure calculations as well as (3)J(HH) experimental and calculated coupling constant data obtained in the investigation of the conformational equilibrium of 3-halo-derivatives of 1-methylpyrrolidin-2-one. The five-membered ring assumes an envelope conformation owing to the plane of formation of the O═C-N-R bond, with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between positions above and below the amide plane. The α-carbonyl halogen assumes two positions: a pseudo-axial and a pseudo-equatorial. In the gaseous phase, the calculations indicate that the pseudo-axial conformer is more stable and preferable going down the halogen family. Natural bond orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the conformational equilibrium. When the solvated molecule was taken into account, the pseudo-equatorial conformer population increased with the relative permittivity of the solvent. This variation was strong in the fluoro derivative, and the preference was inverted. In the chlorine derivative, the two populations became closer in methanol and acetonitrile. In the bromine and iodine derivatives, the percentage of pseudo-equatorial conformer increased only slightly owing to the dipole moment of the conformation: the pseudo-equatorial conformation has a greater dipole moment and thus is stable in media with high relative permittivity.

Conformational Isomerism of 3-Chalcogenomethyl-N-Methyl-2-Pyrrolidinones: Insights from NMR Spectroscopy and Molecular Modeling

“…When the relative permittivity of the medium is increased, the pseudo-equatorial conformer becomes progressively more stable, mainly for fluorine and chlorine derivatives, while for bromine and iodine, electronic delocalization in the pseudo-axial conformer is so strong that the conformational equilibrium is practically insensitive to solvation. These statements are valid both for R = H and Me. , …”

“…Previous work of our research group showed that the 3-halosubstituted N -methyl-2-pyrrolidinones exist as an equilibrium between two conformations: one with the substituent in a pseudo-axial position ( p -ax) and the other, due to the pseudo-rotation of the five-membered ring, at the pseudo-equatorial position ( p -eq) (Figure ). Assuming that 3-chalcogenomethyl derivatives have the same conformational behavior, the stereochemical dependence of the spin–spin coupling constants can be used to gather information on the conformational preference of these compounds.…”

“…The 3-substituted N -methyl-2-pyrrolidinone derivatives were synthesized by methodologies already employed in our research group or by adapting literature procedures. ,,− The detailed procedure for each derivative is available in the Supporting Information (Section B) along with the 1 H and 13 C NMR characterizations (Section C).…”

“…Our research group investigated the conformational behavior of several cyclic compounds and how the substituents affect it. One interesting series was the 3-halo-derivatives of N -methyl-2-pyrrolidinones (Figure ), where an intricate balance between electrostatic repulsion and hyperconjugative interactions (electronic delocalization) governed the conformational preference. , …”

Validation of Computational Methods Applied in Molecular Modeling of Caffeine With Epithelial Anticancer Activity: Theoretical Study of Geometric, Thermochemical and Spectrometric Data

“…A general analysis of table 8 Good results for NMR data calculated with the DFT/B3LYP method have been also obtained, such as reported in works with 4', 7-dihydroxy-8-prenylflavan, 38 as well as 1-methylpyrrolidine-2-one-3-Halo-derivatives. 39 Here, the HF method used with basis set 6-31G** has also shown good results for NMR data prediction, with B classification.…”