On the Use of Deuterated Organic Solvents without TMS to Report 1H/13C NMR Spectral Data of Organic Compounds: Current State of the Method, Its Pitfalls and Benefits, and Related Issues.

The quite popular, simple but imperfect method of referencing NMR spectra to residual 1H and 13C signals of TMS-free deuterated organic solvents (referred to as Method A) is critically discussed for six commonly used NMR solvents with respect to their δH and δC values that exist in the literature. Taking into account the most reliable data, it was possible to recommend 'best' δX values for such secondary internal standards. The position of these reference points on the δ scale strongly depends on the concentration and type of analyte under study and the solvent medium used. For some solvents, chemically induced shifts (CISs) of residual 1H lines were considered, also taking into account the formation of 1:1 molecular complexes (for CDCl3). Typical potential errors that can occur as a result of improper application of Method A are considered in detail. An overview of all found δX values adopted by users of this method revealed a discrepancy of up to 1.9 ppm in δC reported for CDCl3, most likely caused by the CIS mentioned above. The drawbacks of Method A are discussed in relation to the classical use of an internal standard (Method B), two 'instrumental' schemes in which Method A is often implicitly applied, that is, the default Method C using 2H lock frequencies and Method D based on Ξ values, recommended by the IUPAC but only occasionally used for 1H/13C spectra, and external referencing (Method E). Analysis of current needs and opportunities for NMR spectrometers led to the conclusion that, for the most accurate application of Method A, it is necessary to (a) use dilute solutions in a single NMR solvent and (b) to report δX data applied for the reference 1H/13C signals to the nearest 0.001/0.01 ppm to ensure the precise characterization of new synthesized or isolated organic systems, especially those with complex or unexpected structures. However, the use of TMS in Method B is strongly recommended in all such cases.

Spirostanol Sapogenins and Saponins from Convallaria majalis L. Structural Characterization by 2D NMR, Theoretical GIAO DFT Calculations and Molecular Modeling.

Two new spirostanol sapogenins (5ß-spirost-25(27)-en-1ß,2ß,3ß,5ß-tetrol 3 and its 25,27-dihydro derivative, (25S)-spirostan-1ß,2ß,3ß,5ß-tetrol 4) and four new saponins were isolated from the roots and rhizomes of Convallaria majalis L. together with known sapogenins (isolated from Liliaceae): 5ß-spirost-25(27)-en-1ß,3ß-diol 1, (25S)-spirostan-1ß,3ß-diol 2, 5ß-spirost-25(27)-en-1ß,3ß,4ß,5ß-tetrol 5, (25S)-spirostan-1ß,3ß,4ß,5ß-tetrol 6, 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 7 and (25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 8. New steroidal saponins were found to be pentahydroxy 5-O-glycosides; 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-ß-galactopyranoside 9, 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-ß-arabinonoside 11, 5ß-(25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 5-O-galactoside 10 and 5ß-(25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 5-O-arabinoside 12 were isolated for the first time. The structures of those compounds were determined by NMR spectroscopy, including 2D COSY, HMBC, HSQC, NOESY, ROESY experiments, theoretical calculations of shielding constants by GIAO DFT, and mass spectrometry (FAB/LSI HR MS). An attempt was made to test biological activity, particularly as potential chemotherapeutic agents, using in silico methods. A set of 12 compounds was docked to the PDB structures of HER2 receptor and tubulin. The results indicated that diols have a higher affinity to the analyzed targets than tetrols and pentols. Two compounds (25S)-spirosten-1ß,3ß-diol 1 and 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-galactoside 9 were selected for further evaluation of biological activity.

13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization.

Tautomerization of 2-phenylimidazolecarbaldehydes has not been studied in detail so far, although this process is a well-known phenomenon for imidazole derivatives. That is why we focus our study on a series of 2-phenylimidazolecarbaldehydes and their parent alcohols that were synthesized and studied by detailed 1H and 13C NMR in solution and in the solid state. The apparent problem is that the fast tautomerization impedes the full structural description of the compounds by conventional 13C NMR measurements. Indeed, the 13C NMR spectra in solution exhibit poor resolution, and in most cases, signals from the imidazole ring are not detectable. To avoid this problem, we used 13C CP-MAS NMR as an alternative spectroscopic method for unambiguous spectroscopic characterization of the studied series of 2-phenylimidazoles. The data were analyzed in combination with quantum chemical DFT-GIAO methods by considering the tautomerization process and the intermolecular interactions. The DFT (B3LYP/6-31G(d,p)) calculations allowed to identify and suggest the preferred tautomer in the gas phase and in DMSO solvent, which for alcohols are (2-phenyl-1H-imidazol-4-yl)methanol and its analogs, and for the aldehydes are the 2-phenyl-1H-imidazole-5-carbaldehydes. The gas-phase calculated energy differences between the two possible tautomeric forms are in the range 0.645-1.415 kcal/mol for the alcohols and 2.510-3.059 kcal/mol for the aldehydes. In the DMSO solvent, however, for all compounds, the calculated energy differences go below 1.20 kcal/mol. These data suggest that both tautomeric forms of the studied 2-phenylimidazoles can be present in solution at room temperature. Our data from detailed 2D NMR measurements in the solid state (1H-13C HETCOR and 1H-1H double-quantum coherence MAS NMR) suggested that also in the solid state both tautomers coexist in different crystalline domains. This fact does not obscure the 13C CP-MAS NMR spectra of the studied 2-phenyl substituted imidazoles and suggests this spectroscopic method as a powerful tool for a complete structural description of tautomeric systems with aromatic conjugation.

DFT computational schemes for 15 N NMR chemical shifts of the condensed nitrogen-containing heterocycles.

A systematic density functional theory (DFT) study of the accuracy factors (functionals, basis sets, and solvent effects) for the computation of 15 N NMR chemical shifts has been performed in the series of condensed nitrogen-containing heterocycles. The behavior of the most representative functionals was examined based on the benchmark calculations of 15 N NMR chemical shifts in the reference set of compounds. It was found that the best agreement with experiment was achieved with OLYP functional in combination with aug-pcS-3(N)//pc-2 locally dense basis set scheme providing mean absolute error of 5.2 ppm in the range of about 300 ppm. Taking into account solvent effects was performed within a general Tomasi's polarizable continuum model scheme. It was also found that computationally demanding supermolecular solvation model computations essentially improved some "difficult" cases, as was illustrated with phenanthroline dissolved in methanol. Based on the performed calculations, some 200 unknown 15 N NMR chemical shifts were predicted with a high level of confidence for about 50 real-life condensed nitrogen-containing heterocycles, which could serve as a practical guide in structural elucidation of this class of compounds.

Substitution effects in the 15 N NMR chemical shifts of heterocyclic azines evaluated at the GIAO-DFT level.

A systematic study of the accuracy factors for the computation of 15 N NMR chemical shifts in comparison with available experiment in the series of 72 diverse heterocyclic azines substituted with a classical series of substituents (CH3 , F, Cl, Br, NH2 , OCH3 , SCH3 , COCH3 , CONH2 , COOH, and CN) providing marked electronic σ- and π-electronic effects and strongly affecting 15 N NMR chemical shifts is performed. The best computational scheme for heterocyclic azines at the DFT level was found to be KT3/pcS-3//pc-2 (IEF-PCM). A vast amount of unknown 15 N NMR chemical shifts was predicted using the best computational protocol for substituted heterocyclic azines, especially for trizine, tetrazine, and pentazine where experimental 15 N NMR chemical shifts are almost totally unknown throughout the series. It was found that substitution effects in the classical series of substituents providing typical σ- and π-electronic effects followed the expected trends, as derived from the correlations of experimental and calculated 15 N NMR chemical shifts with Swain-Lupton's F and R constants.

GIAO-DFT calculation of 15 N NMR chemical shifts of Schiff bases: Accuracy factors and protonation effects.

15 N NMR chemical shifts in the representative series of Schiff bases together with their protonated forms have been calculated at the density functional theory level in comparison with available experiment. A number of functionals and basis sets have been tested in terms of a better agreement with experiment. Complimentary to gas phase results, 2 solvation models, namely, a classical Tomasi's polarizable continuum model (PCM) and that in combination with an explicit inclusion of one molecule of solvent into calculation space to form supermolecule 1:1 (SM + PCM), were examined. Best results are achieved with PCM and SM + PCM models resulting in mean absolute errors of calculated 15 N NMR chemical shifts in the whole series of neutral and protonated Schiff bases of accordingly 5.2 and 5.8 ppm as compared with 15.2 ppm in gas phase for the range of about 200 ppm. Noticeable protonation effects (exceeding 100 ppm) in protonated Schiff bases are rationalized in terms of a general natural bond orbital approach.

On the long-range relativistic effects in the 15 N NMR chemical shifts of halogenated azines.

Long-range ß- and γ-relativistic effects of halogens in 15 N NMR chemical shifts of 20 halogenated azines (pyridines, pyrimidines, pyrazines, and 1,3,5-triazines) are shown to be unessential for fluoro-, chloro-, and bromo-derivatives (1-2 ppm in average). However, for iodocontaining compounds, ß- and γ-relativistic effects are important contributors to the accuracy of the 15 N calculation. Taking into account long-range relativistic effects slightly improves the agreement of calculation with experiment. Thus, mean average errors (MAE) of 15 N NMR chemical shifts of the title compounds calculated at the non-relativistic and full 4-component relativistic levels in gas phase are accordingly 7.8 and 5.5 ppm for the range of about 150 ppm. Taking into account solvent effects within the polarizable continuum model scheme marginally improves agreement of computational results with experiment decreasing MAEs from 7.8 to 7.4 ppm and from 5.5 to 5.3 ppm at the non-relativistic and relativistic levels, respectively. The best result (MAE: 5.3 ppm) is achieved at the 4-component relativistic level using Keal and Tozer's KT3 functional used in combination with Dyall's relativistic basis set dyall.av3z with taking into account solvent effects within the polarizable continuum solvation model. The long-range relativistic effects play a major role (of up to dozen of parts per million) in 15 N NMR chemical shifts of halogenated nitrogen-containing heterocycles, which is especially crucial for iodine derivatives. This effect should apparently be taken into account for practical purposes.

13 C and 15 N NMR spectra of high-energy polyazidocyanopyridines.

13 C and 15 N NMR spectra of high-energy 2,4,6-triazidopyridine-3,5-dicarbonitrile, 2,3,5,6-tetraazidopyridine-4-carbonitrile and 3,4,5,6-tetraazidopyridine-2-carbonitrile are reported. The assignment of signals in the spectra was performed on the basis of density functional theory calculations. The molecular geometries were optimized using the M06-2X functional with the 6-311+G(d,p) basis set. The magnetic shielding tensors were calculated by the gauge-independent atomic orbital method with the Tao-Perdew-Staroverov-Scuseria hybrid functional known as TPSSh. In all the calculations, a polarizable continuum model was used to simulate solvent effects. This approach provided accurate predictions of the 13 C and 15 N chemical shifts for all the three compounds despite complications arising due to non-coplanar arrangement of the azido groups in the molecules. It was found that the 15 N chemical shifts of the Nα atoms in the azido groups of 2,4,6-triazidopyridines correlate with the 13 C chemical shifts of the carbon atoms attached to these azido groups. Copyright © 2016 John Wiley & Sons, Ltd.

On the accuracy factors and computational cost of the GIAO-DFT calculation of 15 N NMR chemical shifts of amides.

The main factors affecting the accuracy and computational cost of Gauge-independent Atomic Orbital-density functional theory (GIAO-DFT) calculation of 15 N NMR chemical shifts in the benchmark series of 16 amides are considered. Among those are the choice of the DFT functional and basis set, solvent effects, internal reference conversion factor and applicability of the locally dense basis set (LDBS) scheme. Solvent effects are treated within the polarizable continuum model (PCM) scheme as well as at supermolecular level with solvent molecules considered in explicit way. The best result is found for Keal and Tozer's KT3 functional used in combination with Jensen's pcS-3 basis set with taking into account solvent effects within the polarizable continuum model. The proposed LDBS scheme implies pcS-3 on nitrogen and pc-2 elsewhere in the molecule. The resulting mean average error for the calculated 15 N NMR chemical shifts is about 6 ppm. The application of the LDBS approach tested in a series of 16 amides results in a dramatic decrease in computational cost (more than an order of magnitude in time scale) with insignificant loss of accuracy.

A theoretical and experimental study of the NMR spectra of 4,5,6,7-tetrafluorobenzazoles with special stress on PCM calculations of chemical shifts.

The chemical shifts and several (19)F-(19)F, (13)C-(19) F and (1)H-(19)F spin-spin coupling constants (SSCSs) of eight 4,5,6,7-tetraflurobenzazoles (three benzimidazoles, three benzimidazolinones and two indazoles) have been determined. The chemical shifts were discussed using gauge including atomic orbital-density functional theory calculations taking into account solvent effects (polarizable continuum model) and, for the solid state, hydrogen bonds (clusters up to three molecules).

Theoretical and experimental study of 15N NMR protonation shifts.

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.

Theoretical and experimental (15)N NMR study of enamine-imine tautomerism of 4-trifluoromethyl[b]benzo-1,4-diazepine system.

The tautomeric structure of 4-trifluoromethyl[b]benzo-1,4-diazepine system in solution has been evaluated by means of the calculation of (15)N NMR chemical shifts of individual tautomers in comparison with the averaged experimental shifts to show that the enamine-imine equilibrium is entirely shifted toward the imine form. The adequacy of the theoretical level used for the computation of (15)N NMR chemical shifts in this case has been verified based on the benchmark calculations in the series of the push-pull and captodative enamines together with related azomethynes, which demonstrated a good to excellent agreement with experiment.

On the accuracy of the GIAO-DFT calculation of 15N NMR chemical shifts of the nitrogen-containing heterocycles--a gateway to better agreement with experiment at lower computational cost.

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.

Solvent effects in the GIAO-DFT calculations of the 15N NMR chemical shifts of azoles and azines.

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).

Towards the versatile DFT and MP2 computational schemes for 31P NMR chemical shifts taking into account relativistic corrections.

The main factors affecting the accuracy and computational cost of the calculation of (31)P NMR chemical shifts in the representative series of organophosphorous compounds are examined at the density functional theory (DFT) and second-order Møller-Plesset perturbation theory (MP2) levels. At the DFT level, the best functionals for the calculation of (31)P NMR chemical shifts are those of Keal and Tozer, KT2 and KT3. Both at the DFT and MP2 levels, the most reliable basis sets are those of Jensen, pcS-2 or larger, and those of Pople, 6-311G(d,p) or larger. The reliable basis sets of Dunning's family are those of at least penta-zeta quality that precludes their practical consideration. An encouraging finding is that basically, the locally dense basis set approach resulting in a dramatic decrease in computational cost is justified in the calculation of (31)P NMR chemical shifts within the 1-2-ppm error. Relativistic corrections to (31)P NMR absolute shielding constants are of major importance reaching about 20-30 ppm (ca 7%) improving (not worsening!) the agreement of calculation with experiment. Further better agreement with the experiment by 1-2 ppm can be obtained by taking into account solvent effects within the integral equation formalism polarizable continuum model solvation scheme. We recommend the GIAO-DFT-KT2/pcS-3//pcS-2 scheme with relativistic corrections and solvent effects taken into account as the most versatile computational scheme for the calculation of (31)P NMR chemical shifts characterized by a mean absolute error of ca 9 ppm in the range of 550 ppm.

Theoretical prediction of 13C NMR spectrum of mixed triglycerides by mean of GIAO calculations to improve vegetable oils analysis.

This pioneering study based on GIAO-DFT methods is aimed to the best prediction of 13C Nuclear Magnetic Resonances (NMR) arising from triglycerides (and also glycerols), known to be the main component of vegetable oils. Provided that fatty esters bound to the glycerol moiety are not affected by the other esterification chains, and slightly affected by their own esterification position (2- internal, or 1/3- external), eight natural molecules are first optimized despite the challenging presence of many non-hydrogen atoms and the large conformational freedom. This preliminary study sheds light on the total chemical shift prediction concerning five fatty esters (Oleic, Palmitic, Linoleic, Stearic and Linolenic) either present in internal or external positions (ten fragments in total); these results display a very good matching to the experimental profile recorded for several vegetable oils chosen as natural mixtures of glycerides. In order to further improve the theoretical to experimental matching, ten simplified triglycerides with the mentioned fatty esters in the two different esterification positions, and flanked by acetyl esters, were studied and optimized. Beyond the best matching reached so far, we notice that the theoretical rationalisation of the overcrowding in the 28.7-29 ppm spectral region in unable to decode the necessary resolution, nonetheless the same theoretical prediction can still drive the appropriate assignments (as for the fifth and sixth carbon attribution of every chain) even against actual misleading reports.

GIAO-DFT-NMR characterization of fullerene-cucurbituril complex: the effects of the C60@CB[9] host-guest mutual interactions.

Magnetic shielding constants for an isolated fullerene C60, cucurbituril CB[9], and the host-guest complex C60@CB[9] were calculated as a function of separation of the monomers. Our results in the gas phase and water indicate a significant variation of the magnetic properties for all atoms of the monomers in the complex and after liberation of fullerene C60 from the interior of the CB[9] cavity. The interaction between the two monomers results in a charge transfer that collaborates with a redistribution of electron density to deshield the monomers. Graphical Abstract NMR spectroscopy alteration on C60@CB[9] host-guest mutual interactionsᅟ.

Structural determination of complex natural products by quantum mechanical calculations of (13)C NMR chemical shifts: development of a parameterized protocol for terpenes.

Nuclear magnetic resonance (NMR) spectroscopy is one of the most important tools for determining the structures of organic molecules. Despite the advances made in this technique, revisions of erroneously established structures for natural products are still commonly published in the literature. In this context, the prediction of chemical shifts through ab initio and density functional theory (DFT) calculations has become a very powerful tool for assisting with the structural determination of complex organic molecules. In this work, we present the development of a protocol for (13)C chemical shift calculations of terpenes, a class of natural products that are widely distributed among plant species and are very important due to their biological and pharmacological activities. This protocol consists of GIAO-DFT calculations of chemical shifts and the application of a parameterized scaling factor in order to ensure accurate structural determination of this class of natural products. The application of this protocol to a set of five terpenes yielded accurate calculated chemical shifts, showing that this is a very attractive tool for the calculation of complex organic structures such as terpenes.