Protonation of trimipramine salts of maleate, mesylate and hydrochloride observed by 1H, 13C and 15N NMR spectroscopy

Protonation of the tricyclic antidepressant drug trimipramine with maleic acid, methanesulfonic acid and hydrochloric acid was studied using 1H, 13C and 15N NMR spectroscopy at natural abundance. The effect of counter ions on the protonation was compared under identical conditions of solvent, concentration and temperature using homonuclear and heteronuclear one- and two-dimensional experiments. Differential protonation of the terminal tertiary amine nitrogen is determined from the indirect spin-spin couplings, chemical shifts, 13C relaxation data and variable-temperature experiments. In the maleate salt, only one of the acidic protons is involved in protonation, the other being associated with the anion moiety. 15N chemical shifts of the protonated nitrogens are nearly linearly related to the pK(a) of the constituent acid.     

Effects of protonation and co-anion on the 1H and 13C chemical shifts of 2r,6c- diphenylpiperidin-4-ones: evidence for the formation of ion pair

(1)H and (13)C NMR spectra have been recorded for 2r,6c-diphenylpiperidin-4-one (1a), 3t-alkyl-2r,6c-diphenylpiperidin-4-ones 1b-d, 3t-alkyl-2r,6c-diphenyl-4-oxopiperidinium nitrates 2b and 2d, 3t-alkyl-2r,6c-diphenylpiperidin-4-one hydrochlorides 3a-c and 3t-methyl-2r,6c-diphenyl-4-oxopiperidinium picrate 4b in DMSO-d(6). For 1b, 2b and 3b, (1)H and (13)C NMR spectra have been recorded in CH(3)OD also. For 1b, 1d, 2b, 2d, 3b and 4b, 2D spectra have also been recorded. In DMSO-d(6) the protons of the piperidine ring and the ortho protons of the phenyl groups are markedly deshielded due to protonation. Protonation shields all the carbons of the piperidine ring and the ipso carbons of the phenyl groups markedly but deshields the other aromatic carbons slightly. The deshieldings on H-3a, H-5a and the ortho protons of the phenyl groups are less in the nitrate and picrate than in the corresponding hydrochloride. The effects on (13)C chemical shifts are not influenced by the co-anion. These observations suggest that the nitrates and pictrate exist as ion pairs in DMSO-d(6) and the nitrate and picrate ions shield, H-3a, H-5a and the ortho protons by magnetic anistropic effect. In CH(3)OD for 2b and 3b in addition to the ion-pair containing free ions two ion-pairs containing solvated ions are also present. The effects of protonation in the ion pairs containing the solvated ions are significantly different from those in the ion-pair containing free ions.     

Complete 1H and 13C assignments of 8-C-beta-D-[2-O-(E)-p-coumaroyl]glucopyranosyl-2-(2-hydroxy)propyl-7-methoxy-5-methylchromone

1H and 13C NMR spectra of 8-C-beta-D-[2-O-(E)-p-coumaroyl] glucopyranosyl-2-(2-hydroxy)propyl-7-methoxy-5-methylchromone were completely assigned by 2D NMR observations. Especially the 1H assignments of the glucosyl and hydroxyl protons were achieved by utilizing HMQC, HMBC, 1H-1H COSY and DEPT techniques together with a heavy water exchange 1H NMR experiment.     

NMR Investigations of Inclusion Complexes between β-Cyclodextrin and Naphthalene/Anthraquinone Derivatives

A ¹H and ¹³C NMR study on the inclusion complex between β-cyclodextrin and naphthalene, 1,5-dichloronaphthalene and 9,10-anthraquinone was carried out in order to define the stoichiometry of the association and the possible conformations. The upfield variation of the chemical shifts from the protons locate inside the cavity (H-3, H-5) coupled with the downfield variation of the other protons which locate outer sphere of the β-CD (H-1, H-2, H-4 and H-6,6′) provided clear evidence of the inclusion phenomena. The NMR spectra revealed the formation of 1:1 inclusion complex in which aromatic ring of the guest is tightly held by the host cavity. The signal degeneration of ¹H & ¹³C NMR spectra still exist for naphthalene and 1,5-dichloronaphthalene upon complexation revealed a symmetrical conformation of the guest molecules in the cavity of β-cyclodextrin, respectively. However, in 9,10-anthraquinone, the signal degeneration of ¹H & ¹³C NMR spectra was removed upon complexation which revealed an unsymmetrical conformation of the guest molecule inside the cavity. According to theoretical calculations and NMR studies, the possible conformations of the inclusion complexes are given here.     

Complete and unambiguous assignments of 1H and 13C chemical shifts of new arylamino derivatives of ortho-naphthofuranquinones

Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).     

An addition to the oxoacid family: H2B12(OH)12

The acid H(2)B(12)(OH)(12) can be isolated as a crystalline solid by protonation of the hydroxylated borane anion, B(12)(OH)(12)(2)(-). This acidic compound has low solubility in water, conducts protons in the solid state, and has thermal stability to a temperature of 400 degrees C. The conductivity mechanism is a Grotthuss mechanism with a low activation enthalpy (9-13 kcal/mol). This new acid represents an addition to the class of oxoacids, of which sulfuric and phosphoric acid are the most prominent examples.     

Precise Molecular Weight Determination and Structure Characterization of End-functionalized Polymers: An NMR Approach via Combination of One-dimensional and Two-dimensional Techniques

We present here the application of one-dimensional and two-dimensional NMR techniques to characterize the structure of methoxyl end-functionalized polystyrenes (PS).The peaks in 1H-NMR spectra corresponding to main-chain,side-chain and chain-end groups are assigned by 1H-1H gCOSY,1H-13C gHSQC and gHMBC spectra.For the first time,the spin-lattice relaxation time (T1) of protons of the chain-ends is revealed to be affected more by polymer molecular weight (MW) than by the protons of the main-chains and the side-chains (almost independent from MW).As a result,a much higher delay time (d1) for chain-ends (d1 ＞ 20T1) is needed for quantitative NMR measurement when using end-group estimation method to obtain the MW of PS,which is in accordance with the value estimated by GPC.An improved method for the polymer MW determination is established,by combination of different NMR techniques to distinguish the peaks,and a large dl setting to achieve quantitative NMR analysis.     

Solution-state NMR spectroscopy of famotidine revisited: spectral assignment, protonation sites, and their structural consequences

Multinuclear one (1D-) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic investigations of famotidine, the most potent and widely used histamine H₂-receptor antagonist, were carried out in dimethyl sulfoxide-d₆ (DMSO-d₆) and water. Previous NMR assignments were either incomplete or full assignment was based only on 1D spectra and quantum-chemical calculations. Our work revealed several literature misassignments of the ¹H, ¹³C, and ¹⁵N NMR signals and clarified the acid–base properties of the compound at the site-specific level. The erroneous assignment of Baranska et al. (J. Mol. Struct. 2001, 563) probably originates from an incorrect hypothesis about the major conformation of famotidine in DMSO-d₆. A folded conformation similar to that observed in the solid-state was also assumed in solution, stabilized by an intramolecular hydrogen bond involving one of the sulphonamide NH₂ protons and the thiazole nitrogen. Our detailed 1D and 2D NMR experiments enabled complete ab initio ¹H, ¹³C, and ¹⁵N assignments and disproved the existence of the sulphonamide NH hydrogen bond in the major conformer. Rather, the molecule is predominantly present in an extended conformation in DMSO-d₆. The aqueous acid–base properties of famotidine were studied by 1D ¹H- and 2D ¹H/¹³C heteronuclear multiple-bond correlation (HMBC) NMR-pH titrations. The experiments identified its basic centers including a new protonation step at highly acidic conditions, which was also confirmed by titrations and quantum-chemical calculations on a model compound, 2-[4-(sulfanylmethyl)-1,3-thiazol-2-yl]guanidine. Famotidine is now proved to have four protonation steps in the following basicity order: the sulfonamidate anion protonates at pH = 11.3, followed by the protonation of the guanidine group at pH = 6.8, whereas, in strong acidic solutions, two overlapping protonation processes occur involving the amidine and thiazole moieties.     

Assignments of 1H and 13C NMR spectral data for ondansetron and its two novel metabolites, 1-hydroxy-ondansetron diastereoisomers

Assignments of 1H and 13C NMR chemical shifts were made by means of heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments for ondansetron, and by means of 1H-1H correlation spectroscopy (1H-1H COSY) and two-dimensional nuclear Overhauser effect spectroscopy (NOESY) experiments for two novel metabolites (M1 and M2) of ondansetron. These two metabolites were isolated for the first time from Mucor circinelloides.     

Chemical inequivalence behavior of the protons attached to the same carbon in ethylene-propylene copolymer（EPC）

Six ethylene-propylene copolymer samples with different structural parameters were analyzed by ^1H NMR,^13C NMR and ^1H-^13C COSY in this paper.With the aid of the ^1H-^13C COSY spectra of ethylene-propylene copolymer,the chemical inequivalence behavior of the protons attached to the same carbon in the ethylene-propylene copolymer could be observed. Four basic types of chemical bonds were divided,and two kinds of main conformations were proposed to explain this phenomenon. Based on the calculation of conformation distribution,it can be proved that the explanation of this phenomenon was reasonable.     

Paramagnetic 1H NMR spectrum of nickel(II) pseudoazurin: investigation of the active site structure and the acid and alkaline transitions

The paramagnetic (1)H NMR spectrum of Ni(II) pseudoazurin [(PA)Ni(II)] possesses a number of resonances exhibiting sizable Fermi-contact shifts. These have been assigned to protons associated with the four ligating amino acids, His40, Cys78, His81, and Met86. The shifts experienced by the C(gamma)H protons of the axial Met86 ligand are unprecedented compared to other Ni(II)- and Co(II)-substituted cupredoxins (the C(gamma)(1)H signal is found at 432.5 ppm at 25 degrees C). The large shift of protons of the axial Met86 ligand highlights a strong Ni(II)-S(Met) interaction in (PA)Ni(II). The paramagnetic (1)H NMR spectrum of (PA)Ni(II) is altered by decreasing and increasing the pH value from 8.0. At acidic pH a number of the hyperfine-shifted resonances undergo limited changes in their chemical shift values. This effect is assigned to the surface His6 residue whose protonation results in a structural modification of the active site. Increasing the pH value from 8.0 has a more significant effect on the paramagnetic (1)H NMR spectrum of (PA)Ni(II), and the alkaline transition can now be assigned to two surface lysine residues close to the active site of the protein. The effect of altering pH on the (1)H NMR spectrum of Ni(II) pseudoazurin is smaller than that previously observed in the Cu(II) protein indicating more limited structural rearrangements at the non-native metal site.     

Analysis of human urine metabolites using SPE and NMR spectroscopy

Nuclear magnetic resonance (NMR) spectroscopic analysis of metabonome/metabolome has widespread applications in biomedical science researches. However, most of NMR resonances for urinary metabolites remain to be fully assigned. In the present study, human urine samples from two healthy volunteers were pre-treated with C18 solid-phase extraction and the resultant 5 sub-fractions were subjected to one- and two-dimensional NMR studies, including 1H J-Resolved, 1H-1H COSY, 1H-1H TOCSY, 1H-13C HSQC, and HMBC 2D NMR. More than 70 low molecular weight metabolites were identified, and complete assignments of 1H and 13C resonances including many complex coupled spin systems were obtained.     

Complete 1H and 13C NMR assignment of trans,trans-2,3-divinylfuran derivatives

1H and 13C NMR spectra of trans, trans-2,3-divinylfuran derivatives (1-4) in CDCl3 were fully assigned using one- and two-dimensional NMR techniques. The 1H NMR resonances of ethylenic protons in position 2 with regard to the corresponding protons in position 3 of the furan ring are discussed.     

Protonation of carbon single-walled nanotubes studied using 13C and 1H-13C cross polarization nuclear magnetic resonance and Raman spectroscopies

The reversible protonation of carbon single-walled nanotubes (SWNTs) in sulfuric acid and Nafion was investigated using solid-state nuclear magnetic resonance (NMR) and Raman spectroscopies. Magic-angle spinning (MAS) was used to obtain high-resolution 13C and 1H-13C cross polarization (CP) NMR spectra. The 13C NMR chemical shifts are reported for bulk SWNTs, H2SO4-treated SWNTs, SWNT-Nafion polymer composites, SWNT-AQ55 polymer composites, and SWNTs in contact with water. Protonation occurs without irreversible oxidation of the nanotube substrate via a charge-transfer process. This is the first report of a chemically induced change in a SWNT 13C resonance brought about by a reversible interaction with an acidic proton, providing additional evidence that carbon nanotubes behave as weak bases. Cross polarization was found to be a powerful technique for providing an additional contrast mechanism for studying nanotubes in contact with other chemical species. The CP studies confirmed polarization transfer from nearby protons to nanotube carbon atoms. The CP technique was also applied to investigate water adsorbed on carbon nanotube surfaces. Finally, the degree of bundling of the SWNTs in Nafion films was probed with the 1H-13C CP-MAS technique.     

Determination of multiple torsion-angle constraints in U-(13)C,(15)N-labeled peptides: 3D (1)H-(15)N-(13)C-(1)H dipolar chemical shift NMR spectroscopy in rotating solids

We demonstrate constraint of peptide backbone and side-chain conformation with 3D (1)H-(15)N-(13)C-(1)H dipolar chemical shift, magic-angle spinning NMR experiments. In these experiments, polarization is transferred from (15)N[i] by ramped SPECIFIC cross polarization to the (13)C(alpha)[i], (13)C(beta)[i], and (13)C(alpha)[i - 1] resonances and evolves coherently under the correlated (1)H-(15)N and (1)H-(13)C dipolar couplings. The resulting set of frequency-labeled (15)N(1)H-(13)C(1)H dipolar spectra depend strongly upon the molecular torsion angles phi[i], chi1[i], and psi[i - 1]. To interpret the data with high precision, we considered the effects of weakly coupled protons and differential relaxation of proton coherences via an average Liouvillian theory formalism for multispin clusters and employed average Hamiltonian theory to describe the transfer of (15)N polarization to three coupled (13)C spins ((13)C(alpha)[i], (13)C(beta)[i], and (13)C(alpha)[i - 1]). Degeneracies in the conformational solution space were minimized by combining data from multiple (15)N(1)H-(13)C(1)H line shapes and analogous data from other 3D (1)H-(13)C(alpha)-(13)C(beta)-(1)H (chi1), (15)N-(13)C(alpha)-(13)C'-(15)N (psi), and (1)H-(15)N[i]-(15)N[i + 1]-(1)H (phi, psi) experiments. The method is demonstrated here with studies of the uniformly (13)C,(15)N-labeled solid tripeptide N-formyl-Met-Leu-Phe-OH, where the combined data constrains a total of eight torsion angles (three phi, three chi1, and two psi): phi(Met) = -146 degrees, psi(Met) = 159 degrees, chi1(Met) = -85 degrees, phi(Leu) = -90 degrees, psi(Leu) = -40 degrees, chi1(Leu) = -59 degrees, phi(Phe) = -166 degrees, and chi1(Phe) = 56 degrees. The high sensitivity and dynamic range of the 3D experiments and the data analysis methods provided here will permit immediate application to larger peptides and proteins when sufficient resolution is available in the (15)N-(13)C chemical shift correlation spectra.     

Synthesis and NMR spectral studies of some 2,6-diarylpiperidin-4-one O-benzyloximes

Variously substituted 2,6-diarylpiperidin-4-one O-benzyloximes were synthesized by the direct condensation of the corresponding 2,6-diarylpiperidin-4-ones with O-benzylhydroxylamine hydrochloride. All the synthesized compounds are characterized by IR, Mass and NMR spectral studies. NMR spectral assignments are made unambiguously by their one-dimensional (1H NMR and 13C NMR) and two-dimensional (1H-1H COSY, NOESY, HSQC and HMBC) NMR spectra. All the synthesized compounds are resulted as single isomer, i.e., exclusively E isomer (9-14). The conformational preference of 2,6-diarylpiperidin-4-one oxime ethers with and without alkyl substituents at C-3 and C-5 has also been discussed using the spectral studies. The observed chemical shifts and coupling constants suggest that compounds 8-13 adopt normal chair conformation with equatorial orientation of all the substituents while compound 14 contributes significant boat conformation along with the predominant chair conformation in solution. The effect of oximination on ring carbons, their associated protons, alkyl substituents and ipso carbons are studied. Every proton in the piperidone ring of the oxime ether is observed as distinct signal due to oximination. The order of chemical shift magnitude in compound 8 is H-2a>H-6a>H-5e>H-3e>H-3a>H-5a. For 9-12, the order is H-6a>H-5e>H-2a>H-3a>H-5a, for 13, H-6a>H-2a>H-5e>H-3a>H-5a and for 14, the order is H-2a>H-6a>H-5e>H-3a>H-5a while the 13C chemical shift magnitude for 8-14 due to oximination is C-2>C-6>C-3>C-5.     

Microenvironmental and conformational structure of triblock copolymers in aqueous solution by 1H and 13C NMR spectroscopy

1H and 13C nuclear magnetic resonance (NMR) spectra of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers in D2O solutions have been systematically investigated. The detailed assignments of various 1H and 13C NMR signals are presented. The hyperfine structure of PO -CH2- protons was clearly assigned, the arising reason of this hyperfine structure was attributed to the influence of the chiral center of -CHCH3- groups and the direct coupling between the PO -CH2- and -CH3 protons. The external standard 2,2-dimethyl-2-silapentane-5-sulfonate sodium salt (DSS) was firstly applied in this system. Accurate chemical shift values referenced to the external standard DSS were obtained. 1H NMR chemical shift of PO -CH2- and -CH3 signals shows a larger decrease in ppm values than that of EO -CH2- signal with the increase of PPO/PEO ratio or temperature indicating that PO segments exist in a more hydrophobic microenvironment. A new resonance signal assigned to the PO -CH2- protons appeared when the temperature is above the CMT, which is attributed to the breakdown of the intra-molecular (C-H)...O hydrogen bond between the PO -CH2- protons and the ester oxygens. The breakdown of this intra-molecular hydrogen bond may result in a decrease of gauche conformers of the PPO chain. The increase of 13C NMR chemical shift of block copolymers validates this conformational change assumption. It can be inferred that the amount of gauche conformers decreases whereas that of trans conformers increases in both PO and EO chains when elevating the PPO/PEO ratio or temperature. The observed 13C NMR chemical shifts of PO segments show a bigger increase than those of EO segments, supporting the formation of a nonpolar microenvironment around PO segments.     

1H and 13C NMR study of 5-substituted-4- (arylidene)amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 6-aryl-3-(D-gluco- pentitol-1-yl)-7H-1,2,4-triazolo[3,4-b] [1,3,4]thiadiazines

Five 5-substituted-4-(arylidene)amino-2,4-dihydro-3H-1, 2,4-triazole-3-thiones (2a-2e) and seven 6-aryl-3-(D-gluco-pentitol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (3a-3g) were synthesized. The complete 1H and 13C NMR chemical shift assignments were analyzed on one- and two-dimensional NMR techniques, including DEPT, NOE-DIF, COSY, gHMBC, and gHSQC.     

1H and 13C NMR spectra of N-substituted morpholines

(1)H and (13)C NMR data for N-substituted morpholines 1-20 were measured using 1D (DEPT, 1D NOE difference) and 2D NMR spectroscopic methods including (1)H-(1)H COSY, long-range (1)H-(1)H COSY, NOESY, gHMBC and gHMQC experiments. At room temperature the (1)H NMR spectra of protonated compounds 2 and 9 show the chair conformation for the morpholine ring. Spin-spin coupling constants were deduced from the resolution-enhanced proton spectra.     

1H and 13C NMR spectral study of some 3-aryl-5r-aryl-6t-carbethoxycyclohex-2-enones-a study of four-bond 1H-1H couplings

Nine 3-aryl-5r-aryl-6t-carbethoxycyclohex-2-enones 2a-2i have been synthesized. For all these compounds, (1)H and (13)C NMR spectra have been recorded. For two compounds, 2D spectra have been recorded. The spectral data suggest that these compounds adopt sofa conformation in solution with H-5, H-6 and H-4t occupying axial-like positions and H-4c occupying equatorial-like positions. In 3-phenyl-5r-(o-chlorophenyl)-6t-carbethoxycylohex-2-enone (2b), the o-chlorophenyl group is oriented such that the chlorine atom is in between H-4c and H-5. Allylic coupling of H-2 is observed only with H-4t. Evidence has been obtained for four-bond coupling between 1,3-diaxial and 1,3-axial-equatorial protons.