Conformation and configuration of tertiary amines via GIAO-derived (13)C NMR chemical shifts and a multiple independent variable regression analysis.

The (13)C chemical shifts of six tertiary amines of unambiguous conformational structure are compared to predicted (13)C NMR chemical shifts obtained via empirically scaled GIAO shieldings for geometries from MM3 molecular mechanics calculations. An average deviation, absolute value of Deltadelta(av), of 0.8 ppm and a maximum deviation, absolute value of Deltadelta(max), of 2.8 ppm between predicted and experimental (13)C shifts of the six tertiary amines of unambiguous structure are found. In several cases of tertiary amines subject to rapid exchange, where experimental (13)C shifts at room temperature are weighted averages of multiple conformers, a comparison of calculated (13)C shifts of all reasonable MM3 predicted conformers with experimental (13)C shifts via a multiple independent variable regression analysis provides an efficient method of determining the major and minor conformers. The examples presented are 2-methyl-2-azabicyclo[2.2.1]heptane and 1,6-diazabicyclo[4.3.1]decane, which each have two expected contributing structures, and 2-(diethylamino)propane and 1,8-diazabicyclo[6.3.1]dodecane, where ten and seven low-energy conformers, respectively, are predicted by MM3 calculations.     

Performance validation of neural network based (13)c NMR prediction using a publicly available data source

The validation of the performance of a neural network based 13C NMR prediction algorithm using a test set available from an open source publicly available database, NMRShiftDB, is described. The validation was performed using a version of the database containing ca. 214,000 chemical shifts as well as for two subsets of the database to compare performance when overlap with the training set is taken into account. The first subset contained ca. 93,000 chemical shifts that were absent from the ACD\CNMR DB, the "excluded shift set" used for training of the neural network and the ACD\CNMR prediction algorithm, while the second contained ca. 121,000 shifts that were present in the ACD\CNMR DB training set, the "included shift set". This work has shown that the mean error between experimental and predicted shifts for the entire database is 1.59 ppm, while the mean deviation for the subset with included shifts is 1.47 and 1.74 ppm for excluded shifts. Since similar work has been reported online for another algorithm we compared the results with the errors determined using Robien's CNMR Neural Network Predictor using the entire NMRShiftDB for program validation.     

Comprehensive parameter set for the prediction of the 13C-NMR chemical shifts of sp3-hybridized carbon atoms in organic compounds

A parameter set is described for prediction of the carbon-13 chemical shifts of sp³-hybridized carbon atoms based on a simple linear additivity relationship. It was tested against 88 692 known chemical shift values. Many of the previously reported parameters were amended and new parameters added. With this parameter set, the chemical shifts in 99.7% of the 88 692 cases can be estimated with an overall standard deviation of 5.6 ppm for the predicted values relative the the experimental ones. The additivity parameters reported here can be used per se or in connection with a recent computer program for the estimation of carbon-13 chemical shifts, which automatically selects and applies additivity rules appropriate for the individual carbon atoms of the chemical constitution entered.     

Computational studies of 13C NMR chemical shifts of saccharides

The (13)C NMR chemical shifts for alpha-D-lyxofuranose, alpha-D-lyxopyranose (1)C(4), alpha-D-lyxopyranose (4)C(1), alpha-D-glucopyranose (4)C(1), and alpha-D-glucofuranose have been studied at ab initio and density-functional theory levels using TZVP quality basis set. The methods were tested by calculating the nuclear magnetic shieldings for tetramethylsilane (TMS) at different levels of theory using large basis sets. Test calculations on the monosaccharides showed B3LYP(TZVP) and BP86(TZVP) to be cost-efficient levels of theory for calculation of NMR chemical shifts of carbohydrates. The accuracy of the molecular structures and chemical shifts calculated at the B3LYP(TZVP) level is comparable to those obtained at the MP2(TZVP) level. Solvent effects were considered by surrounding the saccharides by water molecules and also by employing a continuum solvent model. None of the applied methods to consider solvent effects was successful. The B3LYP(TZVP) and MP2(TZVP)(13)C NMR chemical shift calculations yielded without solvent and rovibrational corrections an average deviation of 5.4 ppm and 5.0 ppm between calculated and measured shifts. A closer agreement between calculated and measured chemical shifts can be obtained by using a reference compound that is structurally reminiscent of saccharides such as neat methanol. An accurate shielding reference for carbohydrates can be constructed by adding an empirical constant shift to the calculated chemical shifts, deduced from comparisons of B3LYP(TZVP) or BP86(TZVP) and measured chemical shifts of monosaccharides. The systematic deviation of about 3 ppm for O(1)H chemical shifts can be designed to hydrogen bonding, whereas solvent effects on the (1)H NMR chemical shifts of C(1)H were found to be small. At the B3LYP(TZVP) level, the barrier for the torsional motion of the hydroxyl group at C(6) in alpha-D-glucofuranose was calculated to 7.5 kcal mol(-1). The torsional displacement was found to introduce large changes of up to 10 ppm to the (13)C NMR chemical shifts yielding uncertainties of about +/-2 ppm in the chemical shifts.     

THE CALCULATION OF CHEMICAL SHIFTS IN DISUBSTITUTED NAPHTHALENES

<正> The principle and method for calculating the chemical shifts of substituted benzenes have been extended to the calculation of chemical shifts in disubstituted naphthalenes. We have set up a series of empirical parameters for the calculation of chemical shifts. The calculated results of 439 8 values from 78 compounds show that the standard deviation between the calculated and the experimental values is 0.08 ppm. The combination of this calculation with that of the coupling constants can be used to provide a criterion .for the determination of molecular structure in disubstituted naphthalenes as well as to assign NMR parameters for the experiment of proton simulated spectra of disubstituted naphthalenes.     

A computer program for the prediction of 13-C-NMR chemical shifts of organic compounds

A computer program is described for the estimation of carbon-13 chemical shifts. It automatically selects and applies the additivity rules appropriate for the individual carbon atoms of the structure entered. Besides connectivity, the configuration and conformation can be entered and evaluated for some types of structure. All rule parameters (base values and increments) can be extended or modified by the user. New rules based on the corresponding linear relationships can also be added. A test against 168 807 known chemical shifts shows that the implemented rules cover roughly 97% of all cases. The standard deviation of the predicted values relative to the experimental values is 5.5 ppm.     

THE CALCULATIOM OF CHEMXCAL SHIFTS IN SUBSTITOTED PYRIDINES

<正> The principle and method for the calculation of chemical shifts of substituted benzenes have been extended to calculation of the cheiiical shifts in substituted pyridines. We have set up a series of empirical parameters for calculation of the chemical shifts. The calculated results of 154 δ values frou 54 compounds show that the standard deviation between the calculated and the experimental values is 0 . 09 ppm. The combination of the coupling constants can be used to provide a criterion for the determination of molecular structure in substituted pyridines and to assign NMR parameters for the experiment of proton simulated spectra of substituted pyridines.     

13C-NMR-Spektren isomerer Diazaphenanthrene

The ¹³C chemical shifts of eleven isomeric diazaphenathrenes (1.5-? 1.10-, 2.7-, 4.5-? 4.7-, and 5.6-DAP) have been determined and iteratively assigned by means of comparison with suitable model compounds. The data obtained (132 points) were used to test the relationship between ¹³C chemical shifts and HMO charge densities. The best correlation with a standard deviation S(E) = 4.8 ppm was found for the chemical shifts, relative to phenanthrene, of tertiary carbons. The different slopes for correlations of tertiary and quarternary carbons (275–300 vs 540–550 ppm/electron) are most probably due to different ΔE values for both types of carbons.     

Prediction of the ~(13)C NMR Chemical Shifts of 9,10-Dihydrophenanthrene Analogues by the GIAO Method

After the geometry optimizations at the B3LYP/6-31+G(d,p) level, the NMR calculations of a series of 9,10-dihydrophenanthrene analogues have been carried out by GIAO method at the HF/6-31+G(d) level. The calculated 13C NMR chemical shifts are in agreement with the observed values. By a series of linear correlation equations (δpred = a + bδcal.c) of the 13C chemical shifts, accurate prediction of 13C chemical shifts was achieved for the new 9,10- dihydrophenanthrene compound, for which the predicted 13C NMR chemical shifts are in quite good agreement with the experimental values. The linear correlation between δpred and δexptl is excellent, and the square of correlation coefficient, r2, is up to 0.9973. The maximum absolute difference between δpred and δexptl, Δδ, is 4.5 ppm, and the rms error between δpred and δexptl is 2.55 ppm. In the meantime, according to the theoretical predicted result, we could confirm that the new 9,10-dihydrophenanthrene analogue is erianthridin (2,7-dihydroxy-3,4-dimethoxy-9,10-dihydro-phenanthrene).     

(67)Zn NMR chemical shifts and electric field gradients in zinc complexes: a quantum chemical investigation

We have used quantum chemical methods to predict 67Zn NMR chemical shifts as well as quadrupole coupling constants (CQ) in a series of biomimetic and inorganic zinc complexes. The 67Zn chemical shifts are predicted with an R2 = 0.975, corresponding to a 24.3 ppm or 6.7% error over the entire 365 ppm 67Zn chemical shift range. The 67Zn CQ values are predicted with an R2 = 0.991, corresponding to a 1.17 MHz or 3.0% error over the entire 38.75 MHz range. The 67Zn NMR shifts in a series of complexes containing N,O ligands are, in general, highly correlated with the number of oxygen ligands. The ability to compute 67Zn NMR shifts as well as CQ values opens up the possibility of using both of these properties in structure determination or refinement in proteins.     

15N NMR chemical shifts for the identification of dipyrrolic structures

A variety of dipyrromethanes and dipyrromethenes have been prepared, and their 15N NMR chemical shifts have been measured by two-dimensional correlation to 1H NMR signals. The nitrogen atoms in five examples of dipyrromethanes consistently exhibit chemical shifts around -231 ppm, relative to nitromethane. Seven examples of hydrobromide salts of meso-unsubstituted dipyrromethenes consistently display 15N chemical shifts around -210 ppm, while their corresponding zinc(II) complexes exhibit chemical shifts around -170 ppm. The presence of electron-withdrawing substituents on one of the pyrrolic rings of dipyrromethenes affects the chemical shifts of both of the nitrogen nuclei in the molecule. Boron difluoride complexes of meso-unsubstituted dipyrromethenes display 15N chemical shifts around -190 ppm. Two examples of free-base dipyrromethenes bearing substituents at the meso-position exhibit 15N chemical shifts at approximately -156 ppm, and for the zinc complexes of these compounds at -162 ppm. One-bond nitrogen-hydrogen coupling constants, when measurable, were consistently in the range of -96 Hz. Since the measured 15N chemical shifts have such a high regularity correlated to structure, they can be used as diagnostic indications for identifying the structure of dipyrrolic compounds.     

Accurate prediction of proton chemical shifts. I. Substituted aromatic hydrocarbons

Forty‐five proton chemical shifts in 14 aromatic molecules have been calculated at several levels of theory: Hartree–Fock and density functional theory with several different basis sets, and also second‐order Møller–Plesset (MP2) theory. To obtain consistent experimental data, the NMR spectra were remeasured on a 500 MHz spectrometer in CDCl₃ solution. A set of 10 molecules without strong electron correlation effects was selected as the parametrization set. The calculated chemical shifts (relative to benzene) of 29 different protons in this set correlate very well with the experiment, and even better after linear regression. For this set, all methods perform roughly equally. The best agreement without linear regression is given by the B3LYP/TZVP method (rms deviation 0.060 ppm), although the best linear fit of the calculated shifts to experimental values is obtained for B3LYP/6‐311++G**, with an rms deviation of only 0.037 ppm. Somewhat larger deviations were obtained for the second test set of 4 more difficult molecules: nitrobenzene, azulene, salicylaldehyde, and o‐nitroaniline, characterized by strong electron correlation or resonance‐assisted intramolecular hydrogen bonding. The results show that it is possible, at a reasonable cost, to calculate relative proton shieldings in a similar chemical environment to high accuracy. Our ultimate goal is to use calculated proton shifts to obtain constraints for local conformations in proteins; this requires a predictive accuracy of 0.1–0.2 ppm. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1887–1895, 2001     

Geometric dependence of the B3LYP-predicted magnetic shieldings and chemical shifts

We perform a systematic investigation of how the B3LYP/6-311+G(2d,p) calculated 13C nuclear magnetic shielding constants depend on the 6-31G(d)-optimized geometries for a set of 18 molecules with various chemical environments. For absolute shieldings, the Hartree-Fock (HF)-optimized geometries lead to a mean absolute deviation (MAD) of 5.65 ppm, while the BLYP- and B3LYP-optimized geometries give MADs of 13.07 and 10.14 ppm, respectively. For chemical shifts, the HF, BLYP and B3LYP geometries lead to MADs of 2.36, 5.80, and 4.43 ppm, respectively. We find that the deshielding tendency of B3LYP can be effectively compensated by using the HF-optimized geometries. When we apply the B3LYP//HF protocol to versicolorin A and 5alpha-androstan-3,17-dione, MADs of 1.86 and 1.41 ppm, respectively, are obtained for chemical shifts, in satisfactory agreement with the experiment.     

How reliable are GIAO calculations of 1H and 13C NMR chemical shifts? A statistical analysis and empirical corrections at DFT (PBE/3z) level

Reliability of calculated (1)H and (13)C NMR chemical shifts for various classes of organic compounds obtained with gauge-invariant atomic orbital (GIAO) approach has been studied at the PBE/3ζ level (as implemented in PRIRODA code) using linear regression analysis with experimental data. Empirical corrections for the calculated chemical shifts δ(H,calc) = δ(PBE/3ζ) - 0.08 ppm (RMS 0.18 ppm, MAD 0.66 ppm) and δ(C,calc) = δ(PBE/) (3) (ζ) - 6.35 ppm (RMS 3.09 ppm, MAD 9.42 ppm) have been developed using the sets of 263 and 308 experimental values for (1)H and (13)C chemical shifts, respectively. The confidence intervals of NMR chemical shifts at 95% confidence probability are δ(H,calc) ± 0.35 ppm for (1)H and δC,calc) ± 6.05 ppm for (13)C.     

A solid state 13C NMR, crystallographic, and quantum chemical investigation of chemical shifts and hydrogen bonding in histidine dipeptides

We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the 13C NMR chemical shifts of the imidazole group in histidine-containing dipeptides. The chemical shift ranges for Cgamma and Cdelta2 seen in eight crystalline dipeptides were very large (12.7-13.8 ppm); the shifts were highly correlated (R2= 0.90) and were dominated by ring tautomer effects and intermolecular interactions. A similar correlation was found in proteins, but only for buried residues. The imidazole 13C NMR chemical shifts were predicted with an overall rms error of 1.6-1.9 ppm over a 26 ppm range, by using quantum chemical methods. Incorporation of hydrogen bond partner molecules was found to be essential in order to reproduce the chemical shifts seen experimentally. Using AIM (atoms in molecules) theory we found that essentially all interactions were of a closed shell nature and the hydrogen bond critical point properties were highly correlated with the N...H...O (average R2= 0.93) and Nepsilon2...H...N (average R2= 0.98) hydrogen bond lengths. For Cepsilon1, the 13C chemical shifts were also highly correlated with each of these properties (at the Nepsilon2 site), indicating the dominance of intermolecular interactions for Cepsilon1. These results open up the way to analyzing 13C NMR chemical shifts, tautomer states (from Cdelta2, Cepsilon1 shifts), and hydrogen bond properties (from Cepsilon1 shifts) of histidine residue in proteins and should be applicable to imidazole-containing drug molecules bound to proteins, as well.     

Temperature dependence among the grant and Paul parameters as derived from 13C NMR polymer spectra

Improvements in the ¹³C NMR Grant and Paul parameters as applied to polymers have been obtained by noting that the “corrective terms” can be temperature-sensitive. A corresponding temperature sensitivity was not observed for the primary parameters, α through ?. Results are given for a hydrogenated polybutadiene and six different ethylene–1-olefin copolymers where the standard deviation between calculated and observed chemical shifts has been improved from 1.04 to 0.30 ppm. Since the “corrective terms” in the Grant and Paul empirical analyses of chemical shifts reflect the conformational character of polymers, it is shown that values for these terms can best be obtained directly from the system under study.     

Empirically predicted 13C NMR chemical shifts for 8-hydroxyflavone starting from 7,8,4'-trihydroxyflavone and from 7,8-dihydroxyflavone

8-Hydroxyflavone is not found in nature. While the (13)C chemical shifts of 8-hydroxyflavone have been reported previously, the observed (13)C chemical shifts were not assigned. A previously reported empirical predictive tool has been applied in reverse in order to deconvolute the (13)C chemical shifts for 8-hydroxyflavone from each of those of 7,8,4'-trihydroxyflavone and 7,8-dihydroxyflavone together with those of 7-hydroxyflavone, 4'-hydroxyflavone, and flavone. The two sets of calculated (13)C chemical shifts for 8-hydroxyflavone are in good agreement with each other in that the average absolute difference is 0.4 ppm. The previously reported but unassigned (13)C chemical shifts for 8-hydroxyflavone have been assigned by matching them with the averages of the two sets of calculated (13)C chemical shifts for 8-hydroxyflavone such that the minimum average absolute difference is 0.63 ppm. The assigned (13)C chemical shifts of 8-hydroxyflavone may be used, along with the (13)C chemical shifts of the remaining monohydroxyflavones, as part of a predictive tool to rapidly assess the (13)C NMR spectra of C8-hydroxylated flavonoids.     

Modified MINDO/3 13C chemical shift calculations for simple hydrocarbons

Calculations of ¹³C chemical shifts in some simple hydrocarbons have been carried out using the GIAO approach in the MINDO/3 semiempirical formalism. In order to achieve reasonable agreement with experiment it is necessary to modify (increase) the vacant orbital energies in the MINDO/3 calculation in order to reduce the magnitude of the paramagnetic contribution, and to also modify this dominant term by generally reducing it as a function of the number of hydrogen and carbon atoms bonded to the resonant nucleus in question. For a set of 34 resonant nuclei of the simpler hydrocarbons, agreement with experiment of the order of 7.8 ppm is attained; however, pathological cases such as cyclopropane and some simple allenes continue to cause problems, increasing the standard deviation of the full set to 12.5 ppm. Our results indicate that the MINDO/3 approach is as viable for ¹³C chemical shift calculations as other semiempirical approaches, all of which seem currently to be limited to a standard deviation of the order of 10 ppm.     

Exploring new 129Xe chemical shift ranges in HXeY compounds: hydrogen more relativistic than xenon

Among rare gases, xenon features an unusually broad nuclear magnetic resonance (NMR) chemical shift range in its compounds and as a non-bonded Xe atom introduced into different environments. In this work we show that (129)Xe NMR chemical shifts in the recently prepared, matrix-isolated xenon compounds appear in new, so far unexplored (129)Xe chemical shift ranges. State-of-the-art theoretical predictions of NMR chemical shifts in compounds of general formula HXeY (Y = H, F, Cl, Br, I, -CN, -NC, -CCH, -CCCCH, -CCCN, -CCXeH, -OXeH, -OH, -SH) as well as in the recently prepared ClXeCN and ClXeNC species are reported. The bonding situation of Xe in the studied compounds is rather different from the previously characterized cases as Xe appears in the electronic state corresponding to a situation with a low formal oxidation state, between I and II in these compounds. Accordingly, the predicted (129)Xe chemical shifts occur in new NMR ranges for this nucleus: ca. 500-1000 ppm (wrt Xe gas) for HXeY species and ca. 1100-1600 ppm for ClXeCN and ClXeNC. These new ranges fall between those corresponding to the weakly-bonded Xe(0) atom in guest-host systems (δ < 300 ppm) and in the hitherto characterized Xe molecules (δ > 2000 ppm). The importance of relativistic effects is discussed. Relativistic effects only slightly modulate the (129)Xe chemical shift that is obtained already at the nonrelativistic CCSD(T) level. In contrast, spin-orbit-induced shielding effects on the (1)H chemical shifts of the H1 atom directly bonded to the Xe center largely overwhelm the nonrelativistic deshielding effects. This leads to an overall negative (1)H chemical shift in the range between -5 and -25 ppm (wrt CH(4)). Thus, the relativistic effects induced by the heavy Xe atom appear considerably more important for the chemical shift of the neighbouring, light hydrogen atom than that of the Xe nucleus itself. The predicted NMR parameters facilitate an unambiguous experimental identification of these novel compounds.     

Theoretical predictions of 31p NMR chemical shift threshold of trimethylphosphine oxide absorbed on solid acid catalysts

The 31P NMR chemical shifts of adsorbed trimethylphosphine oxide (TMPO) and the configurations of the corresponding TMPOH+ complexes on Br?nsted acid sites with varying acid strengths in modeled zeolites have been predicted theoretically by means of density functional theory (DFT) quantum chemical calculations. The configuration of each TMPOH+ complex was optimized at the PW91/DNP level based on an 8T cluster model, whereas the 31P chemical shifts were calculated with the gauge including atomic orbital (GIAO) approach at both the HF/TZVP and MP2/TZVP levels. A linear correlation between the 31P chemical shift of adsorbed TMPO and the proton affinity of the solid acids was observed, and a threshold for superacidity (86 ppm) was determined. This threshold for superacidity was also confirmed by comparative investigations on other superacid systems, such as carborane acid and heteropolyoxometalate H3PW12O40. In conjunction with the strong correlation between the MP2 and the HF 31P isotropic shifts, the 8T cluster model was extended to more sophisticated models (up to 72T) that are not readily tractable at the GIAO-MP2 level, and a 31P chemical shift of 86 ppm was determined for TMPO adsorbed on zeolite H-ZSM-5, which is in good agreement with the NMR experimental data.