A number of computational schemes based on different Density Functional Theory (DFT) functionals in combination with a number of basis sets were tested in the calculation of 1H and 13C NMR chemical shifts of strychnine, as a typical representative of the vitally important natural products, and used as a challenging benchmark and a rigorous test for such calculations. It was found that the most accurate computational scheme, as compared with experiment, was PBE0/pcSseg‐4//pcseg‐3 characterized by a mean absolute error of 0.07 ppm for the range of about 7 ppm for 1H NMR chemical shifts and that of only 1.13 ppm for 13C NMR chemical shifts spread over the range of about 150 ppm. For more practical purposes, including investigation of larger molecules from this series, a much more economical computational scheme, PBE0/pcSseg‐2//pcseg‐2, characterized by almost the same accuracy and much less computational demand, was recommended.

A combined theoretical and experimental study revealed that the nature of the upfield (shielding) protonation effect in 15N NMR originates in the change of the contribution of the sp(2)-hybridized nitrogen lone pair on protonation resulting in a marked shielding of nitrogen of about 100 ppm. On the contrary, for amine-type nitrogen, protonation of the nitrogen lone pair results in the deshielding protonation effect of about 25 ppm, so that the total deshielding protonation effect of about 10 ppm is due to the interplay of the contributions of adjacent natural bond orbitals. A versatile computational scheme for the calculation of 15N NMR chemical shifts of protonated nitrogen species and their neutral precursors is proposed at the density functional theory level taking into account solvent effects within the supermolecule solvation model.

The calculation of (15)N NMR chemical shifts of 27 azoles and azines in 10 different solvents each has been carried out at the gauge including atomic orbitals density functional theory level in gas phase and applying the integral equation formalism polarizable continuum model (IEF-PCM) and supermolecule solvation models to account for solvent effects. In the calculation of (15)N NMR, chemical shifts of the nitrogen-containing heterocycles dissolved in nonpolar and polar aprotic solvents, taking into account solvent effect is sufficient within the IEF-PCM scheme, whereas for polar protic solvents with large dielectric constants, the use of supermolecule solvation model is recommended. A good agreement between calculated 460 values of (15)N NMR chemical shifts and experiment is found with the IEF-PCM scheme characterized by MAE of 7.1 ppm in the range of more than 300 ppm (about 2%). The best result is achieved with the supermolecule solvation model performing slightly better (MAE 6.5 ppm).

A number of computational schemes for the calculation of N andP NMR chemical shifts and shielding constants in a series of azoles, phospholes, and phosphazoles was examined. A very good correlation between calculated at the CCSD(T) level and experimental N andP NMR chemical shifts was observed. It was found that basically solvent, vibrational, and relativistic corrections are of the same order of magnitude and alternate in sign, being, on average, of about 2-3 ppm in absolute value but, being much larger (up to 14 ppm) in the case of solvent molecules explicitly introduced into computational space. At the DFT level, the performance of nine exchange-correlation functionals including six conventional gradient functionals and three hybrid functionals was studied. The most accurate results were reached with the OLYP and Keal-Tozer's family of functionals, KT1, KT2, and KT3, while the most popular B3LYP and PBE0 functionals showed the most unreliable results. On the basis of these data, we highly recommend OLYP and KT2 functionals for the computation of N andP NMR chemical shifts at the DFT level in the diverse series of nitrogen- and phosphorus-containing heterocycles. Benchmark calculations of N andP NMR chemical shifts in a series of larger nitrogen- and phosphorus-containing heterocycles were performed at the DFT level in comparison with experiment and revealed the OLYP functional in combination with the aug-pcS-3/aug-pcS-2 locally dense basis set scheme as the most effective computational scheme.

The main factors affecting the accuracy and computational cost of the gauge-independent atomic orbital density functional theory (GIAO-DFT) calculation of (15)N NMR chemical shifts in the representative series of key nitrogen-containing heterocycles--azoles and azines--have been systematically analyzed. In the calculation of (15)N NMR chemical shifts, the best result has been achieved with the KT3 functional used in combination with Jensen's pcS-3 basis set (GIAO-DFT-KT3/pcS-3) resulting in the value of mean absolute error as small as 5 ppm for a range exceeding 270 ppm in a benchmark series of 23 compounds with an overall number of 41 different (15)N NMR chemical shifts. Another essential finding is that basically, the application of the locally dense basis set approach is justified in the calculation of (15)N NMR chemical shifts within the 3-4 ppm error that results in a dramatic decrease in computational cost. Based on the present data, we recommend GIAO-DFT-KT3/pcS-3//pc-2 as one of the most effective locally dense basis set schemes for the calculation of (15)N NMR chemical shifts.