Long-range deuterium isotope effects on (13)C chemical shifts of intramolecularly hydrogen-bonded N-substituted 3-(cycloamine)thiopropionamides or amides: a case of electric field effects

A series of intramolecularly hydrogen-bonded N-substituted 3-(piperidine, morpholine, N-methylpiperazine)thiopropionamides and some corresponding amides have been studied with special emphasis on hydrogen bonding. The compounds have been selected in order to vary and to minimize the N...N distance. Geometries, charge distributions, and chemical shifts of these compounds are obtained from DFT-type BP3LYP calculations. 1H and 13C 1D and 2D NMR experiments were performed to obtain H,H coupling constants, 13C chemical shifts assignments, and deuterium isotope effects on13C chemical shifts. Variable-temperature NMR studies and 2D exchange NMR spectra have been used to describe the rather complicated conformational behavior mainly governed by the ring flipping of the piperidine (morpholine) rings and intramolecular hydrogen bonding. Unusual long-range deuterium isotope effects on 13C chemical shifts are observed over as far as eight bonds away from the site of deuteriation. The isotope effects are related to the N...N distances, thus being related to the hydrogen bonding and polarization of the N-H bond. Arguments are presented showing that the deuterium isotope effects on 13C chemical shifts originate in electric field effects.     

Intramolecular hydrogen bonding of novel o-hydroxythioacetophenones and related compounds evaluated by deuterium isotope effects on 13C chemical shifts

A new class of compounds, the 2-hydroxythioacetophenones, and related compounds have recently been synthesized. The hydrogen-bond system has been characterized by NMR chemical shifts and deuterium isotope effects on these as well as by DFT calculations. Use of solid-state (13)C NMR has enabled measurements of the intrinsic deuterium isotope effects of the most abundant tautomer of beta-thioxoketones. The compounds show very interesting long-range deuterium isotope effects on the thiocarbonyl carbon. The intramolecular hydrogen bonds of o-hydroxythioacetophenones are found to be slightly stronger than those of the corresponding acetophenones. The reactivity and stability of the compounds can be related to hydrogen bonding and to the presence of electron donating substituents.     

Conformational and long-range low field steric deuterium isotope effects on carbon chemical shifts

Comparison of the room and low temperature (203 K) ¹³C NMR spectra of 3-cis-bicyclo[4.4.0]decanone and its 2,2,4,4-tetradeuterio isotopomer provides information about the deuterium isotope effect on the conformational equilibrium in this compound. Four-bond low field deuterium isotope effects on some carbon chemical shifts are observed. These effects can be used for unambiguous assignment of the ¹³C lines to carbon atoms in alicyclic compounds.     

Principal component analysis of the 13C NMR spectra of enamino ketones

The ¹³C NMR spectra of eleven 3-N,N-dialkylamino-5,5-dimethylcyclohex-2-en-1-ones have been determined. The chemical shifts of the three sp² carbons and of the two methylene carbons on the cyclohexenone moiety have been subjected to factor analysis. Two factors are necessary and sufficient to account for more than 93% of the total variance. The more important axis (79%) corresponds to a factor closely related to the inductive and steric effects of the alkyl nitrogen substituents. The second parameter is more difficult to interpret and could correspond to the ‘ipso effects’ of amino groups.     

NMR,MP2, and DFT study of thiophenoxyketenimines (o‐thio‐Schiff bases): Determination of the preferred form

Five new thiophenoxyketinimines have been synthesized. ¹H and ¹³C NMR spectra as well as deuterium isotope effects on ¹³C chemical shifts are determined, and spectra are assigned. DFT and MP2 calculations of both structures, chemical shifts, and isotope effects on chemical shifts are done. The combined analysis reveals that the compounds are primarily on a zwitterionic form with an NH⁺ and a S⁻ group and with a little of the neutral form mixed in. Very strong intramolecular hydrogen bonding is found and very high NH chemical shifts are observed. The theoretical calculations show that calculations at the MP2 level are best to obtain correct “C═S” chemical shifts.     

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.     

Deuterium isotope effects on 13C chemical shifts of negatively charged NH…N systems

Deuterium isotope effects on ¹³C chemical shifts are investigated in anions of 1,8‐bis(4‐toluenesulphonamido)naphthalenes together with N,N‐(naphthalene‐1,8‐diyl)bis(2,2,2‐trifluoracetamide) all with bis(1,8‐dimethylamino)napthaleneH⁺ as counter ion. These compounds represent both “static” and equilibrium cases. NMR assignments of the former have been revised. The NH proton is deuteriated. The isotope effects on ¹³C chemical shifts are rather unusual in these strongly hydrogen bonded systems between a NH and a negatively charged nitrogen atom. The formal four‐bond effects are found to be negative indicating transmission via the hydrogen bond. In addition, unusual long range effects are seen. Structures, ¹H and ¹³C NMR chemical shifts and changes in nuclear shieldings upon deuteriation are calculated using density functional theory methods. Copyright © 2013 John Wiley & Sons, Ltd.     

Variable-temperature NMR study of the enol forms of benzoylacetones

The enol forms of the beta-diketones, benzoylacetones, have been studied using long-range carbon-hydrogen couplings involving the chelate OH proton, O1H chemical shifts, 13C chemical shifts and deuterium isotope effects on 13C chemical shifts. Studies were done in the temperature range from 268 to 181 K. The compounds are shown to be tautomeric, in opposition to a more symmetrical, delocalised, close to one-potential well structure as found in the solid at very low temperature. The same is true for dibenzoylmethane. The isotope effects on chemical shifts are very sensitive gauges of structure in these almost symmetrical systems. Equilibrium constants are determined and related to other similar compounds.     

Unusual deuterium isotope effects in 13C NMR spectra of trans-stilbene

A detailed analysis of the ¹³C NMR spectra of trans-stilbene and ten deuteriated trans-stilbenes has been undertaken. Some unusual deuterium isotope effects on carbon–hydrogen spin–spin coupling constants could not be explained by the ordinary primary and secondary isotope effects. The positive and negative changes of ⁿJ(CH) were interpreted in terms of a steric effect, the vibrational influence of the C? D bond and the para-effect induced by deuterium. In this respect, deuterium behaves as a real substituent with electronic properties different from those of hydrogen. The deuterium isotope effects on ¹³C NMR chemical shifts and carbon–deuterium coupling constants have also been determined.     

13C isotope effects on 1H chemical shifts: NMR spectral analysis of 13C‐labelled D‐glucose and some 13C‐labelled amino acids

The one‐ and two‐bond ¹³C isotope shifts, typically ?1.5 to ?2.5 ppb and ?0.7 ppb respectively, in non‐cyclic aliphatic systems and up to ?4.4 ppb and ?1.0 ppb in glucose cause effects that need to be taken into account in the adaptive NMR spectral library‐based quantification of the isotopomer mixtures. In this work, NMR spectral analyses of some ¹³C‐labelled amino acids, D ‐glucose and other small compounds were performed in order to obtain rules for prediction of the ¹³C isotope effects on ¹H chemical shifts. It is proposed that using the additivity rules, the isotope effects can be predicted with a sufficient accuracy for amino acid isotopomer applications. For glucose the effects were found strongly non‐additive. The complete spectral analysis of fully ¹³C‐labelled D ‐glucose made it also possible to assign the exocyclic proton signals of the glucose. Copyright © 2009 John Wiley & Sons, Ltd.     

New deuterium isotope effects on C and F chemical shifts across intramolecular hydrogen bonds of non-resonance assisted systems

A series of thioanilides and corresponding anilides, some of which contain fluorinated phenyl rings, have been synthesized as model compounds. They all contain rather strong intramolecular hydrogen bonds, the strength of which varies. Deuterium isotope effects on ¹⁹F and ¹³C chemical shifts due to deuteriation at the NH proton show interesting new long-range isotope effects on chemical shifts that may be related to the existence of an intramolecular hydrogen bond and to transmission of the isotope effect due to an electric field effect. Deuterium isotope effects on chemical shifts report on variations in hydrogen bonding, for example, as a function of changes in substituents or temperature. Deuteriation leads to a strengthening of the hydrogen bond.     

Schiff bases of gossypol: an NMR and DFT study

Schiff bases of gossypol with benzylamine, methylamine, 4-aminoacetophenone and 4-fluoroaniline have been synthesized and characterized by NMR spectroscopy. All the Schiff bases of gossypol are in the enamine form according to (3)J(HC,NH) and (1)J(N,H) coupling constants. The spectra are basically unchanged by change of solvent (CD(2)Cl(2), THF-d(8) and CD(3)OD) and by variation of temperature. For the derivative of benzylamine, deuterium isotope effects on (13)C chemical shifts are determined. They support strongly the enamine form and serve as a reference for other tautomeric Schiff bases. Structures and NMR nuclear shieldings of model compounds (the second monomer is replaced by a 2-hydroxybenzene ring) have been calculated by density functional theory (DFT) methods. A good correlation is observed between calculated (13)C nuclear shieldings of the enamine form and observed (13)C chemical shifts.     

Tautomerism of sterically hindered schiff bases. Deuterium isotope effects on 13C chemical shifts

A series of sterically hindered o-hydroxy Schiff bases derived from o-hydroxyaceto- and benzophenones with very short intramolecular hydrogen bonds were described qualitative and quantitatively by deuterium isotope effects on (13)C chemical shift, (n)DeltaC(XD), (n)DeltaF(XD), (1)J(N,H) coupling constants, deltaNCH(3) chemical shifts and UV spectra. All the investigated compounds are found to be tautomeric. The tautomeric character is described by the signs of the deuterium isotope effects on the (13)C chemical shifts. For the 3-nitro-5-chloro derivatives at low temperature, the equilibrium is shifted almost fully toward the proton transferred form in CD(2)Cl(2). Intrinsic deuterium isotope effects on chemical shifts of these compounds as well as (1)J(N,H) coupling constants suggest that a zwitterionic resonance form is dominant for the proton transferred form. Structures, (1)H, (19)F, and (13)C chemical shifts, and deuterium isotope effects on (13)C chemical shifts are calculated by ab initio methods. The potential energy functions and the total deuterium isotope effects are calculated, and they are shown to correspond well with the experimental findings.     

NMR isotope shifts in the 2-methyl-2-bicyclo[2.1.1]hexyl cation and related systems

NMR isotope shifts at ¹³C nuclei due to deuteriation in the 2-methyl-2-bicyclo[2.1.1]hexyl cation are reported. Comparisons are made to the 2-methyl-2-bicyclo[2.2.1]heptyl and 2-methyl-2-bicyclo[2.2.2]octyl cations, and also to neutral molecules containing the bicyclo[2.1.1]hexyl framework. The combination of isotope effects with temperature dependence of ¹³C chemical shifts allows predictions of the shapes of the energy surfaces along the bending coordinate corresponding to bridging in these cations.     

Structure validation of natural products by quantum-mechanical GIAO calculations of 13C NMR chemical shifts

Geometry optimization and GIAO (gauge including atomic orbitals) (13)C NMR chemical shift calculations at Hartree-Fock level, using the 6-31G(d) basis set, are proposed as a tool to be applied in the structural characterization of new organic compounds, thus providing useful support in the interpretation of experimental NMR data. Parameters related to linear correlation plots of computed versus experimental (13)C NMR chemical shifts for fourteen low-polar natural products, containing 10-20 carbon atoms, were employed to assess the reliability of the proposed structures. A comparison with the hybrid B3LYP method was carried out to evaluate electron correlation contributions to the calculation of (13)C NMR chemical shifts and, eventually, to extend the applicability of such computational methods to the interpretation of NMR spectra in apolar solutions. The method was tested by studying three examples of revised structure assignments, analyzing how the theoretical (13)C chemical shifts of both correct and incorrect structures matched the experimental data.     

35Cl/37Cl isotope effects on 13C chemical shifts. Assignment of carbon-13 NMR lines of polychlorinated hydrocarbons

An isotope effect of about 0·1 Hz at 25 MHz (0·004 ppm) on the ¹³C chemical shifts due to directly bonded chlorine has been observed at ?50°C for hexachloropropene, hexachlorobutadiene and tetrachlorobutenyne. This effect yields an unambiguous assignment of ¹³C NMR lines to specific carbon atoms in these polychlorinated hydrocarbons.     

NMR spectroscopy of organolithium compounds. XXVI--The aggregation behaviour of methyllithium in the presence of LiBr and LiI in diethyl ether and tetrahydrofuran

1H, 6Li and 13C NMR spectroscopy were used to determine the structure of aggregates formed in mixtures of methyllithium, H3CLi, and lithium bromide and iodide in diethyl ether and tetrahydrofuran. From the chemical shifts, the signal intensity distribution and the isotope shifts observed for partially deuterated systems, it was shown that generally tetrameric structures with different halogen contents dominate. For methyllithium-lithium bromide (1:1) in THF a considerable concentration of an H3CLi-LiBr dimer was found. For the first time, deuterium-induced 6Li isotope shifts over four bonds were observed.     

Effets isotopiques du deutérium en RMN 13C,measure du marquage isotopique des alcools allylques.

Primary and secondary deuterium isotope effects on ¹³C NMR chemical shifts for trigonal carbons are reported for twelve allylic alcohols. The secondary DIECCS is used for an accurate measurement of the deuterium labeling of variously substituted allylic alcohols.     

A (13)C INADEQUATE and HF-GIAO study of C(60)H(2) and C(60)H(6) identification of ring currents in a 1,2-dihydrofullerene

The hydrofullerenes C(60)H(2) (1) and C(60)H(6) (2) have been prepared in (13)C-enriched form and 2D INADEQUATE NMR spectra were measured. These spectra have provided unambiguous (13)C assignments for 2, and nearly unambiguous assignments for 1. In both cases, the most downfield resonances are immediately adjacent to the sp(3) carbons, despite the fact that these carbons are the least pyramidalized carbons in the molecule. Typically, (13)C chemical shifts move downfield with increasing pyramidalization (THETA(p)), but in these systems there is no strong correlation between THETA(p) and delta. HF-GIAO calculations are able to predict the chemical shifts, but provide little chemical insight into the origin of these chemical shifts. London theory reveals a significant paramagnetic ring current in 1, a feature that helps explain the (1)H shifts in these compounds and may contribute to the (13)C chemical shifts as well.     

Carbon-13 chemical shifts of substituted nortricyclenes

¹³C NMR spectra of a series of substituted nortricyclene derivatives have been measured, and the ¹³C chemical shifts interpreted in terms of α, β, γ and δ-effects. The nature of these substiuent shifts is discussed together with some analytical possibilities. The substituent shifts provide valuable data about the steric effects in strained molecules and can be used as increments for structural analysis, particularly for the determination of orientations of substituent groups.