Improved Quantum Chemical NMR Chemical Shift Prediction of Metabolites in Aqueous Solution toward the Validation of Unknowns

A quantum-chemistry based protocol, termed MOSS-DFT; is presented for the prediction of C-13 and H-1 NMR chemical shifts of a wide range of organic molecules in 5 aqueous solution, including metabolites. Molecular motif-specific linear scaling parameters, are reported for five different density functional theory,(DFT) methods (B97-2/pcS-1, B97-2/pcS-2, B97-2/pcS-3, B3LYP/pcS-2, and BLYP/pcS-2), which were applied to a large set of 176 metabolite molecules. The chemical shift root-mean-square deviations (RMSD) for the best method, B97-2/pcS-3, are 1.93 and 0.154 ppm for P C-13 and H-1 chemical shifts, respectively: Excellent results have been obtained for chemical shifts of methyl and aromatic C-13 and H-1 that are not directly :bonded to a heteroatom (O, N, S, or P) with RMSD values of 1.15/0.079 and 1.31/0.118 ppm, respectively: This study not only demonstrates how NMR chemical shift in aqueous environment can be improved over the commonly used global linear scaling approach, But alsO allows for motif-speCific error estimates, which are useful for an improved chemical shift-based verification of metabolite, Candidates of metabolomics samples containing unknown components.