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.     

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.     

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.     

Factor analysis of deuterium isotope effects on 13C NMR chemical shifts in Schiff bases

We have analyzed deuterium isotope effects on (13)C chemical shifts in a series of o-hydroxy Schiff bases by applying factor analysis. Two orthogonal factors were obtained that explain about 80 and 10 % of the variance of the data. The numerical values of these factors can be related to 1H NMR chemical shifts of the proton involved in the intramolecular bonds delta(XH) (X = O or N). Such a relation allows one to identify clusters of compounds with different tautomeric forms of hydrogen bonding. Application of a similar approach to solution 13C NMR chemical shifts produces three important factors, which have a different structure to factors describing isotope effects. This illustrates well the different nature of chemical shifts and isotope effects. The three factors explain about 54, 15, and 13 % of variance. They can be rationalized and are strongly related to the electronic properties and location of substituents.     

NMR studies of solvent-assisted proton transfer in a biologically relevant Schiff base: toward a distinction of geometric and equilibrium H-bond isotope effects

The tautomeric equilibrium in a Schiff base, N-(3,5-dibromosalicylidene)-methylamine 1, a model for the hydrogen bonded structure of the cofactor pyridoxal-5'-phosphate PLP which is located in the active site of the enzyme, was measured by means of 1H and 15N NMR and deuterium isotope effects on 15N chemical shifts at variable temperature and in different organic solvents. The position of the equilibrium was estimated using the one-bond 1J(OHN) and vicinal 3J(H(alpha)CNH) scalar coupling constants. Additionally, DFT calculations of a series of Schiff bases, N-(R1-salicylidene)-alkyl(R2)amines, were performed to obtain the hydrogen bond geometries. The latter made it possible to investigate a broad range of equilibrium positions. The increase of the polarity of the aprotic solvent shifts the proton in the intramolecular OHN hydrogen bond closer to the nitrogen. The addition of methanol and of hexafluoro-2-propanol to 1 in aprotic solvents models the PLP-water interaction in the enzymatic active site. The alcohols, which vary in acidity and change the polarity around the hydrogen bond, also stabilize the equilibrium, so that the proton is shifted to the nitrogen.     

NMR study of 5-substituted pyrazolo[3,4-c]pyridine derivatives

Substituted pyrazolopyridines are potent inhibitors of phosphodiesterases and cyclin-dependent kinases. In this study, NMR was used to investigate the potential N1-H and N2-H tautomerism of 5-substituted pyrazolo[3,4-c]pyridine derivatives. Six compounds were fully characterized by using (1)H, (13)C, and (15)N chemical shifts and indirect (1)H--(13)C and (1)H--(15)N coupling constants. The (1)H NMR spectra were measured over a broad range of temperatures. All of the compounds were shown to exist predominantly in the N1-H tautomeric form. Complementary quantum-chemical calculations of the chemical shieldings and indirect spin-spin couplings support the structural conclusions drawn.     

Investigations of intramolecular hydrogen bonding in three types of Schiff bases by 2H and 3H NMR isotope effects

Hydrogen bonding within the structures of three Schiff bases (1-3), obtained by condensation of 4-methoxy-, 5-methoxy- and 4,6-dimethoxysalicylaldehyde with methylamine, was investigated by measuring deuterium and tritium NMR isotope effects. The primary deuterium and tritium isotope effects (delta(XH)-delta(XD/T)) and secondary one-bond nitrogen deuterium effect appear to be very useful parameters for defining the character of intramolecular hydrogen bonds. The tritium isotope effects were also determined for nitrogen-hydrogen one-bond coupling constants for both 4-methoxy and 4,6-dimethoxy derivatives. These parameters are seen to be highly sensitive to hydrogen bond characteristics and can be used to distinguish localized and tautomeric hydrogen bonds.     

Non-empirical calculations of the nuclear magnetic resonance spectra of imidazole and hydrated imidazole

The magnetic shielding constants of the ¹H, ¹³C and ¹⁵N nuclei of imidazole are calculated for the isolated and hydrated molecules. The results show that the hydrogen bonds produce not only large variations of the chemical shifts for the nitrogen nuclei and the NH proton which are directly involved in the intermolecular bonding, but also measurable shifts for the carbon nuclei. The calculated shielding constants and their variation with hydration are discussed in relation to experimental results concerning imidazole, the 5-membered ring of the purine bases and the imidazole ring of histidine. The calculated values of the spin-spin coupling constants confirm that it is possible to study the tautomeric equilibrium of the imidazole ring from the measurement of these coupling constants and that spin-spin coupling constants are not very sensitive to solvent effects.     

13C and proton NMR spectra of 2(1H)pyrazinones

¹³C and proton NMR spectra data are given for eleven 2(1H)pyraziones. Assignments of chemical shifts were made by methods which included: deuterium exchange with certain protons of 3-alkyl substituents; change of chemical shifts of certain carbon atoms with change in pH; the use of long-range coupling constants for ¹³C to protons; and various correlations among assigned spectra.     

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.     

A Spectroscopic Overview of Intramolecular Hydrogen Bonds of NH…O,S,N Type

Intramolecular NH…O,S,N interactions in non-tautomeric systems are reviewed in a broad range of compounds covering a variety of NH donors and hydrogen bond acceptors. ¹H chemical shifts of NH donors are good tools to study intramolecular hydrogen bonding. However in some cases they have to be corrected for ring current effects. Deuterium isotope effects on ¹³C and ¹⁵N chemical shifts and primary isotope effects are usually used to judge the strength of hydrogen bonds. Primary isotope effects are investigated in a new range of magnitudes. Isotope ratios of NH stretching frequencies, νNH/ND, are revisited. Hydrogen bond energies are reviewed and two-bond deuterium isotope effects on ¹³C chemical shifts are investigated as a possible means of estimating hydrogen bond energies.     

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.     

Characterization of fluxional hydrogen-bonded complexes of acetic acid and acetate by NMR: geometries and isotope and solvent effects

1H, (2)H, and (13)C NMR spectra of enriched CH(3)(13)COOH acid without and in the presence of tetra-n-butylammonium acetate have been measured around 110 K using a liquefied Freon mixture CDF(3)/CDF(2)Cl as a solvent, as a function of the deuterium fraction in the mobile proton sites. For comparison, spectra were also taken of the adduct CH(3)(13)COOH.SbCl(5) 1 and of CH(2)Cl(13)COOH under similar conditions, as well as of CH(3)(13)COOH and CH(3)(13)COO(-) dissolved in H(2)O and D(2)O at low and high pH at 298 K. The low temperatures employed allowed us to detect several well-known and novel hydrogen-bonded complexes in the slow hydrogen bond exchange regime and to determine chemical shifts and coupling constants as well as H/D isotope effects on chemical shifts from the fine structure of the corresponding signals. The measurements show that self-association of both carboxylic acids in Freon solution gives rise exclusively to the formation of cyclic dimers 2 and 3 exhibiting a rapid degenerate double proton transfer. For the first time, a two-bond coupling of the type (2)J(CH(3)COOH) between a hydrogen-bonded proton and the carboxylic carbon has been observed, which is slightly smaller than half of the value observed for 1. In addition, the (1)H and (2)H chemical shifts of the HH, HD, and the DD isotopologues of 2 and 3 have been determined as well as the corresponding HH/HD/DD isotope effects on the (13)C chemical shifts. Similar "primary", "vicinal", and "secondary" isotope effects were observed for the novel 2:1 complex "dihydrogen triacetate" 5 between acetic acid and acetate. Another novel species is the 3:1 complex "trihydrogen tetraacetate" 6, which was also characterized by a complex degenerate combined hydrogen bond- and proton-transfer process. For comparison, the results obtained previously for hydrogen diacetate 4 and hydrogen maleate 7 are discussed. Using an improved (1)H chemical shift-hydrogen bond geometry correlation, the chemical shift data are converted into hydrogen bond geometries. They indicate cooperative hydrogen bonds in the cyclic dimers; i.e., widening of a given hydrogen bond by H/D substitution also widens the other coupled hydrogen bond. By contrast, the hydrogen bonds in 5 are anticooperative. The measurements show that ionization shifts the (13)C signal of the carboxyl group to low field when the group is immersed in water, but to high field when it is embedded in a polar aprotic environment. This finding allows us to understand the unusual ionization shift of aspartate groups in the HIV-pepstatin complex observed by Smith, R.; Brereton, I. M.; Chai, R. Y.; Kent, S. B. H. Nature Struct. Biol. 1996, 3, 946. It is demonstrated that the Freon solvents used in this study are better environments for model studies of amino acid interactions than aqueous or protic environments. Finally, a novel correlation of the hydrogen bond geometries with the H/D isotope effects on the (13)C chemical shifts of carboxylic acid groups is proposed, which allows one to estimate the hydrogen bond geometries and protonation states of these groups. It is shown that absence of such an isotope effect is not only compatible with an isolated carboxylate group but also with the presence of a short and strong hydrogen bond.     

1H and 13C NMR study of the enol–enolic tautomerism of some cyclic β-ketoaldehydes

Aldehyde (δCH) and enolic (δOH) proton chemical shifts, the corresponding spin–spin coupling constants (JCH,OH) and the ¹³C chemical shifts (δC) have been measured for three cyclic β-ketoaldehydes as a function of temperature. A tautomeric equilibrium has been shown to exist between the aldo–enol ( A ) and hydroxymethylene ketone ( B ) forms. The chemical shifts δCH δOH and δC for the two pure tautomeric forms A and B have been calculated. The enthalpy changes ΔH in the tautomeric process A ? B and the percentages of the tautomeric forms have been determined.     

Chiral recognition of the Schiff bases by NMR spectroscopy in the presence of a chiral dirhodium complex. Deuterium isotope effect on 13C chemical shift of the optically active Schiff bases and their dirhodium adducts

The dirhodium method has been successfully applied in chiral recognition of the optically active Schiff bases, derivatives of ortho-hydroxyaldehydes existing in the NH-form. or at tautomeric equilibrium. The position of the equilibrium of Schiff bases as well as their adducts has been established on the basis of measurements of deuterium isotope effects on 13C chemical shifts. The presence of the proton transfer equilibrium or NH-tautomer has promoted the adduct formation. At the equilibrium state, formation of the adducts has shifted the proton transfer equilibrium towards the NH-form. The binding site was the oxygen atom of the proton donor group.     

Solid-state NMR study of Schiff base derivatives of 2-hydroxynaphthaldehyde. Deuterium isotope effects on 15N chemical shifts in the solid state

Schiff base derivatives of 2-hydroxynaphthylaldehyde were studied by means of 13C and 15N cross-polarization magic angle spinning NMR spectroscopy and deuterium isotope effects on 15N chemical shifts, deltaN(D), in the solid state. DeltaN(D) in the solid state provided evidenced for the presence of a dynamic proton transfer equilibrium in the solid state at the room temperature.     

Deuterium isotope effects on 13C nuclear shielding as a measure of tautomeric equilibria

Large deuterium isotope effects of both signs have been observed on the ¹³C nuclear shielding in proton-chelating tautomeric forms of β-thioxoketones, and small isotope effects of both signs have been found in related forms of Schiff's bases of salicylaldehydes. These effects are interpreted in terms of shifts in the tautomeric equilibria on deuterium substitution of the enolic proton. The observation of deuterium isotope effects is suggested as a useful method for the detection of fast tautomeric equilibria in systems of the following type. .     

19F and 1H NMR spectra of halocarbons

19F NMR chemical shifts and coupling constants are reported for 215 compounds. For 77 of these compounds, 1H NMR spectral data are also given. Long-range couplings, including 8J(F,F) and 5J(F,H), are reported. The complexity of halocarbon spectra owing to the presence of rotational isomers, asymmetric centers, long-range couplings, and chlorine isotope effects are illustrated, and the methods used for analyzing such complex spectra are briefly discussed.     

Deuterium isotope effects in 13C NMR spectroscopy: Stereochemical assignment of monodeuteriated allylic alcohols.

Vicinal deuterium isotope effects on 13C NMR chemical shifts, ³ΔC (Φ) are given for ten monodeuteriated allylic alcohols. The relationship found for nine of them: 3ΔC(0°) ≅ 5/3 x ³ΔC(180°) allows the stereochemical assignement of their deuterium labeling. This assignment is in agreement with that from the Karplus-type relationship of vicinal coupling constants, ³J_C-D(Φ).     

Indirect nuclear 57Fe-13C and 57Fe-1H spin-spin coupling in ferrocenes and cyclopentadienyliron complexes: measurements and DFT calculations

Several 57Fe-labeled ferrocene derivatives and other cyclopentadienyliron complexes were studied by 57Fe and 13C NMR with respect to isotope-induced chemical shifts 1Delta12/13C(57Fe) and the magnitude and sign of coupling constants 1J(57Fe,13C) and 2J(57Fe,1H). The geometries of the complexes were optimized by DFT methods [B3LYP/6-311+G(d,p)] and chemical shifts (GIAO) and coupling constants were calculated at the same level of theory. The trends in calculated 57Fe nuclear shielding agree well with the experimental data and, in the case of coupling constants 1J(57Fe,13C) and 2J(57Fe,1H), both sign and magnitude are correctly reproduced.