Data: Rotational Dynamic of Methylen-Group in Benzylic Derivatives: Intramolecular Non-covalent Bindings Driven Conformational Restriction

Published: 13 June 2025| Version 1 | DOI: 10.17632/yjkdhtcdr6.1
Contributor:
Angel Romero

Description

Herein we provided a general and consistent perspective of the rotational dynamic of methylene-group in benzylic derivatives from experimental and theoretical analysis. Different conformational states including the most stable conformation were recognized from DFT-calculations. Further calculations showed that the most stable conformation of the benzylic-amine and benzylic-alcohol compounds was defined by the existence of an intramolecular binding between the benzylic-amine substitution and ortho- substitution such as halogen, hydrogen or nucleophile-π binding. Neither type of intramolecular interaction was identified from benzyl-bromide compounds. Energetically, the rotational barrier of the methylene-group was increased as function of the nature of the ortho-substitution as follows: 2,6-dibrominated˃˃ 2-iodinated ~ 2-brominated˃ 2-arylated≥ 2,6-unsubstituted˃ 2-fluorinated. Experimentally, in solid-state, structural aspects such as the most preferred conformation state or intramoelcular binding were supported by X-ray studies. In solution, scalar correlations between the methylene-hydrogens with the vicinal ortho- or meta-protons from a simple 1H/1H-COSY measurement allowed us to confirm the most stable conformation for the studied benzylic compounds as well as to give a general draw about the rotational dynamic of the methylene-group in these benzylic compounds. From the benzyl-amines, the 2,6-dibrominated showed the strongest H-H correlations, followed by the 2-iodinated and 2-brominated compounds, whereas the 2-arylated, 2,6-unsubstituted and 2-fluorinated showed a discrete or null H-H correlations. All studied benzyl-bromides did not show H-H correlations. All these findings revealed that the rotation of the methylene-group is restricted by steric hindrance derived from ortho-substituent as well as by the existence of an intramolecular binding involving the benzyl-substituent, being this last the most determinant factor, although the co-existence of both factors restricted even more the free rotation of methylene-group. The data include a detailed theoretical output concerning structure optimization, conformational analysis (scans), NBO calculations, X-ray data and NMR data for most of 40 compounds. Some figure and graphic, which are found in the manuscript and supporting Information material, can be found.

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Theoretical Calculation. All theoretical calculations, in the gas phase, were performed M06-2X/def2TZVP approach in Gaussian. The geometries of the 2,6-unsubstituted 1a-g, 2-brominated 2a-g, 2,6-dibrominated 3a-g, 2-iodinated 4a-g, 2-fluorinated 5a-g, 2-arylated 7a-g and 2,6-diiodinated benzylic compounds 8a-g were optimized. All structures were optimized in the ground state without restrictions, using tight optimization criteria and an ultrafine grid in the computation of two-electron integrals and their derivatives. The geometries of the conformers for different dihedral C2Ar-C1Ar-CH2-X angle were optimized under structural restriction in gas phase.For conformational analysis, under the same M06-2Xdef2TZVP approach, calculations were performed using SCAN commando with following parameters: RMS gradient normalization, 0.000311 hartree/Bohr; scan coordinate, 4.4567; maximum force, 0.000046; RMS force, 0.000014; maximum displacement, 0.001759; RMS displacement, 0.000627; predicted energy change, -2.85×10−8 hartree. Further analysis to identify the occurrence of non-covalent interaction was performed on Multiwfn software, version 3.8,47 which allowed us to obtain the corresponding NCI (Non-covalent interaction) plots, RDG (Reduced Density Gradient) isosurfaces and ELF (Electron-localization Function) maps for the optimized structures for all studied benzylic compounds. NCI plots and RDG isosurfaces were generated on electron density isosurface of 0.05 a.u. X-Ray Data Collection and Structural Determination. Light orange and yellow block-shaped crystals of compounds 1c, 2c, 2e and 7i were obtained after slow evaporation of acetonitrile, ethyl acetate and chloroform solutions for 10 days. X-ray diffraction intensities were collected (ω scans with ϑ and κ offsets), integrated, and scaled with the CrysAlisPro 26 suite of programs. The unit cell parameters were obtained by least-squares refinement (based on the angular settings for all collected reflections with intensities larger than 7 times the standard deviation of measurement errors) using CrysAlisPro. Data were corrected empirically for absorption employing the multiscan method implemented in CrysAlisPro. The structures were determined by the intrinsic phasing procedure implemented in SHELXT, and the corresponding non-H molecular model was refined by a full matrix least-squares method on F2 with anisotropic displacement parameters employing SHELXL.50 Crystallographic structural data for the four structures have been deposited at the Cambridge Crystallographic Data Centre (CCDC) with reference numbers 2434177(1c), 2434176(2c), 2434178 (2e) and 2434179 (7i). NMR measurements. The 1H/1H-COSY spectra of 1a-g, 2a-f, 3c-d, 4d-e and 7a-g were recorded from CDCl3 (5-10 mg/0.5mL).1H/15N-HMBC spectra of 1d, 2d and 3c were recorded from acetone-d6 solutions (5-10 mg/0.5mL). NOE experiments were performed irradiating the benzylic peak positioned between 3.3 and 3.7 ppm in 1H-NMR spectrum.

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Organic Chemistry, Computational Organic Chemistry, Chemical Bonding

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