A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

This protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. Experimental H-1 and/or C-13 NMR spectral data and its proper interpretation for the compound of interest is required as a starting point. The approach involves the following steps: ( i) using molecular mechanics calculations (with, e. g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFT) calculations (with, e. g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e. g., fewer than similar to 10 non-H atoms or up to similar to 180 a.m.u. and similar to 20 conformers), this protocol can be completed in similar to 2 h of active effort over a 2-d period; for more complex molecules (e. g., fewer than similar to 30 non-H atoms or up to similar to 500 a.m.u. and similar to 50 conformers), the protocol requires similar to 3-6 h of active effort over a 2-week period. To demonstrate the method, we have chosen the analysis of the cis-versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). The protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience.