title: A guide to small-molecule structure assignment through computation of (¹H and ¹³C) NMR chemical shifts.
abstract: 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 ¹H and/or ¹³C 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 ∼10 non-H atoms or up to ∼180 a.m.u. and ∼20 conformers), this protocol can be completed in ∼2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ∼30 non-H atoms or up to ∼500 a.m.u. and ∼50 conformers), the protocol requires ∼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.
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Willoughby
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Jansma
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hoye
mesh_terms: D004852:Epoxy Compounds / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry*; D011083:Polycyclic Compounds / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D013141:Spiro Compounds / Q000737:chemistry
chemical_list: D004852:Epoxy Compounds; D009930:Organic Chemicals; D011083:Polycyclic Compounds; D054852:Small Molecule Libraries; D013141:Spiro Compounds; C469535:hexacyclinol; C543843:vannusal B