Exploiting natural abundance 13C–15N coupling as a method for identification of nitrogen heterocycles: practical use of the HCNMBC sequence

In this paper, we detail the results of ¹H–¹⁵N correlation data obtained via ¹³C–¹⁵N coupling at natural abundance on a number of classes of azoles including pyrazoles, imidazoles and triazoles. The experiment produces data that is highly complementary to direct ¹H–¹⁵N HMBC type correlations in that it can provide ¹⁵N chemical shift data for nitrogen that may not show up in the HMBC. This is particularly advantageous in the triazoles where ¹⁵N chemical shift can be diagnostic of regiochemistry. Because of the consistency in J_CN values among the azoles, the experiment produces distinctive correlation patterns that can be used for identification of regiochemistry. The experiment can also be used to directly measure ¹³C–¹⁵N coupling constants. Copyright © 2015 John Wiley & Sons, Ltd.     

Analysis of fine splittings in the fourier transform 1H magnetic resonance spectra of some 15N labeled borazine derivatives

Proton NMR spectra are reported for ¹⁵N enriched borazine and a series of ¹⁵N enriched derivatives: N-methyl-borazine, N,N′-dimethylborazine and a new photochemical product, 1-methyl-2-aminoborazine. Chemical shifts for the ring (¹⁵N? H) protons have been measured. Using a Fourier transform spectrometer, fine structure in the ¹⁵N? H doublet is resolved. Ortho and meta ring proton and three-bond ¹⁵N to H coupling constants have been determined. Substituent effects on chemical shifts and coupling constants for borazine derivatives are compared with those for analogous benzene derivatives.     

High resolution NMR spectroscopy of heteroaromatic cations. I. 13C?1H coupling constants in the pyridinium cation

High-resolution ¹H? {¹⁴N} and proton-coupled natural-abundance ¹³C? {¹⁴N} double resonance spectra have been recorded for pyridinium tetrafluoroborate dissolved in CD₃CN. Iterative analysis of these spectra has provided the accurate values and relative signs of all possible long-range ¹³C—¹H coupling constants. These are compared with the respective values in pyridine and pyridine-N-oxide and discussed in terms of the relationship with the electronegativity of the N-substituent. Experimental conditions allowing the observation of well-resolved proton-coupled ¹³C NMR spectra of charged heteroaromatics are also presented.     

Electron spin resonance spectra of α-sulfonyl iminoxy radicals

Syn- andanti-α-sulfonyl iminoxy radicals have been generatedin situ by lead tetra-acetate oxidation of α-oximino sulfones. The ESR spectra of the geometrical isomers have been assigned and the¹⁴N and¹H hyperfine splitting constants are discussed in terms of the proposed structures.     

13C NMR: The stereochemical dependence of 15N?13C coupling constants in pyrazoles

Geminal ¹⁵N? ¹³C coupling constants have been measured in a series of ¹⁵N-enriched 1?phenyl?3,5?dialkyl-substituted pyrazoles. The importance of the orientation of the nitrogen lone-pair in determining the magnitude of ²J(¹⁵N¹³C) values is reflected in the enhanced coupling observed for those carbon atoms lying close in space to the lone-pair electrons.     

NMR studies in the heterocyclic series XXIV—1H, 13C and 15N study of 15N labelled indazoles

The ¹⁵N chemical shifts and ¹H? ¹⁵N and ¹³C? ¹⁵N coupling constants of nine monolabelled indazoles were measured and assigned. The experimental values are discussed in terms of the indazolic and iso-indazolic structures, and compared with literature data for other related heterocycles. All the results are consistent with an N-1(H) tautomeric structure for indazole in DMSO-d₆.     

Structural assignments in isomeric pyrazoles based on 3J(15NH) coupling constants

Vicinal ¹⁵N–H coupling constants are used to characterize the isomeric pyrazoles obtained from the condensation of phenylhydrazine, ¹⁵N-enriched at the amino nitrogen atom, with various 1,3-diketones.     

A natural abundance 15N NMR investigation of bilirubin IX-α

Natural abundance ¹⁵N NMR spectra have been obtained for bilirubin IX-α using polarization transfer via the INEPT and SINEPT-2 techniques. The resonances for all four nitrogens are clearly resolved. ¹⁵N chemical shifts and ¹⁵N? ¹H coupling constants over one and three bonds are reported. Heteronuclear chemical shift correlation between ¹⁵N and ¹H for the four NH groups has been established by means of the SINEPT-2 pulse sequence.     

Proton polarization transfer in natural abundance 15N NMR studies of E- and Z-isomers of N-alkylformamides

Proton polarization transfer has been used for the convenient observation of proton coupled natural abundance ¹⁵N NMR spectra of the E- and Z-isomers of N-methylformamide at 10.14 MHz. Second-order spectral analysis is required to determine the ¹⁵N? H coupling constants, at least for the E-isomer of secondary formamides. An useful stereospecificity is observed for both the one- and two-bond ¹⁵N? H coupling constants.     

Derivatives of pyrazinecarboxylic acid: 1H, 13C and 15N NMR spectroscopic investigations

NMR spectroscopic studies are undertaken with derivatives of 2‐pyrazinecarboxylic acid. Complete and unambiguous assignment of chemical shifts (¹H, ¹³C, ¹⁵N) and coupling constants (¹H,¹H; ¹³C,¹H; ¹⁵N,¹H) is achieved by combined application of various 1D and 2D NMR spectroscopic techniques. Unequivocal mapping of ¹³C,¹H spin coupling constants is accomplished by 2D (δ,J) long‐range INEPT spectra with selective excitation. Phenomena such as the tautomerism of 3‐hydroxy‐2‐pyrazinecarboxylic acid are discussed. Copyright © 2009 John Wiley & Sons, Ltd.     

1H and 13C NMR studies on 1,3,2-dioxarsolanes

The ¹H and ¹³C NMR spectra of a series of 1,3,2-dioxarsolanes have been obtained at 2.1 T and some at 9.4 T. The chemical shifts and spin-spin coupling constants have been obtained from complete spectral analyses of the ¹H and proton-coupled ¹³C spectra. The spectral data are interpreted on the basis of two rapidly interconverting half-chair conformers with a pseudoaxial substituent at arsenic. Unique assignment of syn/anti or cis/trans geometries have been made from ¹H or ¹³C NMR spectroscopy alone. The syn and trans isomers of the 4-methyl- and 4,5-dimethyl-1,3,2-dioxarsolanes, respectively, appear to be conformationally biased towards the forms with pseudoequatorial methyl groups. The general trends in the geminal and vicinal ¹H? ¹H and ¹³C? ¹H coupling constants are interpreted in terms of stereospecific, electronegativity and lone-pair effects of the oxygen heteroatoms and conformational factors. The NMR data on the 1,3,2-dioxarsolanes are discussed with reference to related 1,3-dithoxa- and 1,3-dithia- five-membered rings with As, P, S or C at the 2-position.     

Synthesis of 3-aminomethyl-substituted pyrazoles and isoxazoles

A series of new 3-(aminomethyl)pyrazoles and 3-(aminomethyl)isoxazoles was synthesized along a route involving the formation as key intermediates of esters of 5-substituted 1H-pyrazole-3-carboxylic and 1H-isoxazole-3-carboxylic acids. All compounds obtained were characterized by physicochemical constants, IR, ¹H, ¹³C NMR, and mass spectra.     

15N-NMR. Studies of Aminopyridines,Aminopyrimidines and of Some Diazine N-Oxides

¹⁵N-NMR. spectra of mono- and diaminopyridines, and mono-, di- and triaminopyrimidines including trimethoprim and other dihydrofolate reductase inhibitors have been studied in neutral and acidic media. Complete chemical shift assignments are given. Ring-nitrogen shifts are discussed in terms of β-, χ- and δ-substituent effects of amino and alkyl groups. Protonation states in TFA- and FSO₃H-solution and protonation increments for the ¹⁵N-shifts of ring and amino N-atoms are determined. A linear correlation is observed between amino substituent effects (Δδ(¹⁵N)) on the ring N-atom in aminopyridines and corresponding Δδ (¹³C) values in aminobenzenes and, similarly, between Δδ(¹⁵N) values in aminopyrimidines and Δδ(¹³C) values in aminopyridines. Assignment of the ¹⁵N-NMR. spectra of pyrimidine N-oxides, pyrazine N-oxides and pyridazine N-oxides is achieved by comparison with ¹⁴N-NMR. data and with the aid of Yb(fod)₃-induced shifts. One-bond ¹⁵N, ¹H-coupling constants are reported for aminopyridines and aminopyrimidines and discussed in terms of conjugative interaction between NH₂-group and ring system.     

Trans‐Hydrogen‐Bond Scalar Couplings as a Source of Structural Constraints in NMR of Proteins: DFT Analysis

The conformational dependences of ¹⁵N,¹⁵N and ¹H,¹⁵N trans‐H‐bond spin‐spin scalar couplings, ^h2J(N,N) and ^h1J(N,H), have been investigated by sum‐over‐states density‐functional‐perturbation theory. The distance and angular dependence of the ^h2J(N,N) and ^h1J(N,H) coupling constants in the H‐bonded arrangement between acetylethylamine and imidazole molecules were examined for a wide range of mutual orientations. These molecules were used to model a structurally important H‐bond between the amide backbone of Arg7 and the remote imidazole side chain of His106 in the 44 kDa trimeric enzyme chorismate mutase from Bacillus subtilis. The magnitude of ^h1J(N,H) is relatively insensitive to the sampled rotations around three orthogonal axes centered on the tertiary N‐atom of the imidazole, whereas values of ^h2J(N,N) demonstrated a strong dependence on the value of the cone angle θ aligned with the amide group involved in the H‐bond. Simple functional approximations have been generated, enabling back calculations of the N⋅⋅⋅N distance and angle θ of the H‐bond, provided that the experimental values of both ^h2J(N,N) and ^h1J(N,H) coupling constants are available.     

Electron spin resonance spectroscopy of iron nitrosyl complexes with organic ligands

ESR spectra of liquid and frozen solutions of nitrosyl iron complexes formed in aqueous solution with a variety of mercaptans, dithiocarbamates and azoles have been studied. The hyperfine ¹⁴N splittings from nitrosyl groups and azole nitrogen as well as ¹H splittings in the case of nitrosyl mercaptan complexes have been observed. Structures of these complexes are suggested on the basis of the ESR spectral parameters.     

One-bond 1J(15N,H) coupling constants at sp2-hybridized nitrogen of Schiff bases,enaminones and similar compounds: A theoretical study

¹J(¹⁵N,H) coupling constants for enaminones and NH-forms of intramolecularly hydrogen-bonded Schiff bases as model compounds for sp²-hybridized nitrogen atoms are evaluated using density functional theory (DFT) to find the optimal functionals and basis sets. Ammonia is used as a test molecule and its one-bond coupling constant is compared with experiment. A methylamine Schiff base of a truncated molecule of gossypol is used for checking the performance of selected B3LYP, O3LYP, PBE, BHandH, and APFD density functionals and standard, modified, and dedicated basis sets for coupling constants. Both in vacuum and in chloroform, modeled by the simple continuum model of solvent, the modified basis sets predict significantly better the ¹J(¹⁵N,H) value in ammonia and in the methylamine Schiff base of a truncated molecule of gossypol than the standard basis sets. This procure is then used on a broad set of intramolecularly hydrogen-bonded molecules, and a good correlation between calculated and experimental one-bond NH coupling constants is obtained. The ¹J(¹⁵N,H) couplings are slightly overestimated. The calculated data show for hydrogen-bonded NH interatomic distances that the calculated values depend on the NH bond lengths. The shorter the bond lengths, the larger the ¹J(¹⁵N,H). A useful correlation between ¹J(¹⁵N,H) and NH bond length is derived that enables realistic predictions of one-bond NH coupling constants. The calculations reproduce experimentally observed trends for the studied molecules.     

Selective population transfer in 15N and 13C NMR: Signs of 15N?H and 15N?13C coupling constants in secondary amide and iminium salts

The selective population transfer method has been applied to the study of a secondary amide and of the corresponding iminium salt. Important signal-to-noise enhancements were accessible in both fully coupled and proton decoupled ¹⁵N and ¹³C spectra. Moreover, the resolving power of the method was exploited for the accurate determination of long range ¹⁵N¹H coupling constants. Experiments in which the selective inversion of transitions pertaining to the ¹⁵N satellite spectrum of multiplets which themselves constitute the ¹³C satellite spectrum of the main proton resonances could be carried out. The influence of a change from the amide to the iminium structure on the magnitudes and the signs of various ¹⁵N¹H and ¹⁵N¹³C coupling constants is discussed.     

A 15N NMR study of some azoles

¹⁵N NMR data are reported for 42 azoles, taken mostly at a standard concentration and in a common solvent (0.5 M dimethyl sulfoxide with a 0.01 M increment of Cr(acac)₃ for each nitrogen atom present). Signal assignments were assisted by comparison with ¹⁴N line widths, the use of ²J(¹⁵N¹H) couplings, and shielding calculations obtained by the INDO/S–SOS approach. The generally large differences in nitrogen-shielding changes permitted rather facile shift assignments.     

Etude des Signes des Constantes de Couplage 3J(P?X?C?H) et 4J(F?P?X?C?H) dans les Diaza-, Dioxa- et Dithiaphospholanes Fluores

The NMR spectra of the trivalent fluorophospholanes ( 1, 2, 3 ) have been analysed at length. The absolute signs of the ³J(P? H) and ⁴J(F? H) coupling constants have been referred to the known negative sign of the ¹J(P? F) coupling constant from selective heteronuclear double resonance experiments. The ³J(P? O? C? H) and ³J(P? N? C? H) coupling are positive. The weak values observed for ³J(P? S? C? H) have opposite signs, the larger being positive. All the ⁴J(F? P? X? C? H) coupling constants are positive showing a lack of stereospecificity.     

Constantes de couplage vicinales à travers deux hétéroatomes: III—Calculs théoriques et mesures expérimentales dans les hydrazides enrichies en 15N

Different calculations, among them those utilizing the finite perturbation theory with INDO wave functions, have been effected to calculate the value of the ³J(¹H ? N? N? ¹H ) coupling constant in hydrazides as a function of the dihedral angle. Experimental coupling constants have been compared with calculated ones in order to determine the conformation around the N? N bond. The first example of a ²J(¹H ? N? ¹⁵N ) coupling is described.