The potential utility of predicted one bond carbon-proton coupling constants in the structure elucidation of small organic molecules by NMR spectroscopy.

Chandrasekhar Venkata,Mark J Forster,Peter W A Howe,Christoph Steinbeck

doi:10.1371/journal.pone.0111576

Chandrasekhar Venkata, Mark J Forster + Show 2 more

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https://doi.org/10.1371/journal.pone.0111576

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Abstract

NMR spectroscopy is the most popular technique used for structure elucidation of small organic molecules in solution, but incorrect structures are regularly reported. One-bond proton-carbon J-couplings provide additional information about chemical structure because they are determined by different features of molecular structure than are proton and carbon chemical shifts. However, these couplings are not routinely used to validate proposed structures because few software tools exist to predict them. This study assesses the accuracy of Density Functional Theory for predicting them using 396 published experimental observations from a diverse range of small organic molecules. With the B3LYP functional and the TZVP basis set, Density Functional Theory calculations using the open-source software package NWChem can predict one-bond CH J-couplings with good accuracy for most classes of small organic molecule. The root-mean-square deviation after correction is 1.5 Hz for most sp3 CH pairs and 1.9 Hz for sp2 pairs; larger errors are observed for sp3 pairs with multiple electronegative substituents and for sp pairs. These results suggest that prediction of one-bond CH J-couplings by Density Functional Theory is sufficiently accurate for structure validation. This will be of particular use in strained ring systems and heterocycles which have characteristic couplings and which pose challenges for structure elucidation.

Highlights

NMR (Nuclear Magnetic Resonance) spectroscopy remains the most popular method of determining both the covalent structure and conformation of small organic molecules in solution, owing to the detailed chemical information that can be obtained from NMR spectra acquired on sub-milligramme amounts of material [1]
Proton and 13C chemical shifts provide information about the chemical environment of atoms, proton-proton and proton-carbon J-couplings provide information about the connectivity between atoms, and proton integrals provide information about the multiplicity of groups of atoms. These principal sources of information can be supplemented by 15N chemical shifts, by nuclear Overhauser effect or rotating frame Overhauser effect data, and by proton-carbon residual dipolar couplings where a sufficient amount of the substance is available
Carbon chemical shifts can be predicted with reasonable accuracy using literature data or ab initio using Kohn-Sham Density Functional Theory (DFT) methods while prediction of proton shifts has much lower accuracy owing to their dependence on solvent and through-space interactions such as hydrogen bonding and ring current effects [5]

Summary

Introduction

NMR (Nuclear Magnetic Resonance) spectroscopy remains the most popular method of determining both the covalent structure and conformation of small organic molecules in solution, owing to the detailed chemical information that can be obtained from NMR spectra acquired on sub-milligramme amounts of material [1]. Proton and 13C chemical shifts provide information about the chemical environment of atoms, proton-proton and proton-carbon J-couplings provide information about the connectivity between atoms, and proton integrals provide information about the multiplicity of groups of atoms These principal sources of information can be supplemented by 15N chemical shifts, by nuclear Overhauser effect (nOe) or rotating frame Overhauser effect (rOe) data, and by proton-carbon residual dipolar couplings where a sufficient amount of the substance is available. These different pieces of information can be interpreted by experienced scientists, or by automated structure determination software, to determine the structure of an unknown molecule [2]. Several possible structures are consistent with the observed chemical shifts so choosing which is correct can become an exercise of judgement involving knowledge of the synthetic scheme or biosynthetic pathway, interpretation of through-space information from nOe or rOe spectra, or consideration of the magnitude of long-range proton-carbon J-couplings

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