EXPLICIT SOLVENT AND CONFORMATIONAL DYNAMICS PLAY A ROLE FOR J-COUPLING CALCULATIONS

Identifying stable conformations and their populations, as well as the stereoelectronic interactions influencing conformational stability is crucial in studying organic molecules. NMR spectroscopy can be employed for conformational analysis due to the direct relationship between the magnitude of the scalar spin-spin coupling constant (J-coupling) and the dihedral angle between coupled nuclei.(1) When conformers interconvert rapidly due to low energy barriers, only averaged NMR signals are detected, making it difficult to determine individual populations without known J-couplings for each conformer. However, quantum mechanical calculations can reliably estimate J-couplings for stable conformers of small molecules, enabling accurate conformational analysis when combined with experimental data.(2) Nevertheless, solute-solvent interactions and conformational dynamics are often overlooked to save computational resources. However, these effects can play a role in conformational equilibria, which would be reflected in J-coupling.(3) In this work, we use ab initio metadynamics simulations combined with DFT calculations, to highlight the importance of explicitly considering solvation and addressing the energy barriers involved in the interconversion of conformers for a comprehensive understanding of experimental ³J_HH of trans- and cis-3-halo-2-methoxy-tetrahydro-pyrans.  The dynamic treatment of the explicit solvent has been shown to improve the sampled conformer structures, thereby contributing to a more reliable calculated J-coupling. It was noted that the energy barriers for interconversion between conformers are low enough to permit a substantial population of intermediate structures in the conformational equilibria. Consequently, the accuracy of the calculated ³J_HH for the cis isomer is influenced not only by the most stable conformers (i.e., chair axial-equatorial and equatorial-axial) but also by significant contribution from the boat and skew-boat conformers. In contrast, the energy barriers in the trans isomer are slightly higher than those in the cis isomer, leading to the predominance of the chair conformers (i.e., axial-axial and equatorial-equatorial).

REFERENCES

(1) Contreras, R.H, Peralta, J.E. Prog. Nucl. Magn. Reson. Spectrosc., 2000, 37, 321.

(2) Tormena, C.F. Prog. Nucl. Magn. Reson. Spectrosc., 2016, 96, 73.

(3) Chiari, C., et.al. Org. & Biomol. Chem., 2024, 22, 2580.

Acknowledgements: We thank FAPESP grant #2021/09687-5; #2023/00531-8; #2020/10246-0; CAPES grant #88887.654054/2021-00; CNPq grant #134270/2024-0; Coaraci Supercomputer (FAPESP grant #2019/17874-0) and SDumont Supercomputer for HPC facilities.