Gary E. Martin

Members of the broad family of Strychnos alkaloids have been the favorite molecules for the development and evaluation of new NMR methods for many years, including the establishment of the ¹H-¹⁵N two-dimensional NMR methods. The present study is an effort to computationally evaluate the ¹⁵N chemical shift behavior of eight members of this structurally diverse group of indole alkaloids. The molecules range from relatively “simple” strychnine and brucine and their respective N-oxides to molecules as complex as vinorelbine, a synthetic analog used in cancer chemotherapy, and sungucine, a naturally occurring complex dimeric member of the family. The 20 ¹⁵N chemical shifts in this study afforded a CMAE of 2.96 ppm and an RMSD of 3.50 ppm, with the data affording a correlation coefficient, r = 0.997.

It is demonstrated that by using modern computational methods, it is possible to identify potential structural misassignments for even molecules as complex as cryptospirolepine. While methods that rely on anisotropic nuclear magnetic resonance (NMR) methods can also be used to offer a powerful orthogonal means of structure elucidation and verification, the present computational study should be feasible in most chemistry departments with access to sophisticated computational facilities. From the overall correlations calculated against experimental ¹H and ¹³C NMR chemical shifts in the series of thirteen Cryptolepis alkaloids, it follows that, generally, they provide a very high level of correlation. The corrected mean absolute error (CMAE) is found to be at the level of 0.13 and 1.5 ppm for, proton and carbon chemical shifts, respectively, which is only about 2 and 1% of their ranges. Based on the performed calculations, some spectral reassignments are suggested, and a number of missing (unknown) experimental chemical shifts are predicted.

Early NMR studies of several heterohelicenes containing an annular nitrogen atom and a thiophene ring in their structure suggested the possibility of the lengthening of the carbon–carbon bonds in the interior of the helical turn of the molecule based on the progressive upfield shift of ¹³C resonances toward the center of the helical turn. We now report a comprehensive analysis of the optimized geometry and a comparison of the calculated vs. observed ¹H and ¹³C NMR chemical shifts of nineteen representative benzothienoquinoline heterohelicenes. As was initially hypothesized on the basis of the progressive upfield shift of carbon resonances toward the center of the interior helical turn, the present computational study has demonstrated that carbon–carbon bonds indeed have more sp3 character and are longer than normal sp² bonds to accommodate the helical twist of the molecule, as expected.

Density functional theory (DFT) benchmark studies of ¹H and ¹³C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured ¹H and ¹³C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for ¹H and ¹³C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for ¹H and 0.5 to 2.9 for ¹³C. Maximum deviations were less than 0.5 and 6.5 ppm for ¹H and ¹³C, respectively.