Evaluating the accuracy of theoretical one-bond 13C–13C scalar couplings and their ability to predict structure in a natural product

This study explores the feasibility of using a combination of experimental and theoretical one-bond 13C-13C scalar couplings (1JCC) to establish structure in organic compounds, including unknowns. Historically, nJCC and nJCH studies have emphasized two and three-bond couplings, yet 1JCC couplings exhibit significantly larger variations. Moreover, recent improvements in experimental measurement and data processing methods have made 1JCC data more available. Herein, an approach is evaluated in which a collection of theoretical structures is created from a partial NMR structural characterization. Computed 1JCC values are compared to experimental data to identify candidates giving the best agreement. This process requires knowledge of the error in theoretical methods, thus the B3LYP, B3PW91 and PBE0 functionals are evaluated by comparing to 27 experimental values from INADEQUATE. Respective errors of ± 1.2, ± 3.8 and ± 2.3 Hz are observed. An initial test of this methodology involves the natural product 5-methylmellein. In this case, only a single candidate matches experimental data with high statistical confidence. This analysis establishes the intramolecular hydrogen bonding arrangement, ring heteroatom identity and conformation at one position. This approach is then extended to hydroheptelidic acid, a natural product not fully characterized in prior studies. The experimental/theoretical approach proposed herein identifies a single best-fit structure from among 26 candidates and establishes, for the first time, one configuration and three conformations to complete the characterization. These results suggest that accurate and complete structural characterizations of many moderately sized organic structures (< 800 Da) may be possible using only 1JCC data.