CAST/CNMR: highly accurate C NMR chemical shift prediction system considering stereochemistry

Accurate, practical prediction of ¹³C NMR chemical shifts has been achieved with a new system, CAST/CNMR, taking account of stereochemistry. The CAST/CNMR system has solved the critical problem of the accurate distinction of differences and similarities in stereochemical structures around a specific carbon, which has not yet been achieved by any other database-oriented system for prediction of ¹³C NMR chemical shifts. CAST/CNMR uses a three-dimensional structural database together with a ¹³C NMR spectral database. Absolute/relative configurational and conformational structural information are described by the CAST (CAnonical-representation of STereochemistry) coding method. This paper provides an overview of the CAST/CNMR system, and describes its application to two natural products as examples.     

13C, 15N and 113Cd NMR and Molecular Orbital Studies of Novel Bile Acid N-(2-aminoethyl)amides and Their Cd2+-complexes

Lithocholic acid N-(2-aminoethyl)amide (1) and deoxycholic acid N-(2-aminoethyl)amide(2) have been prepared and characterized by¹H, ¹³C and ¹⁵N NMR. The accurate molecular masses of 1 and 2 have been determined by ESI MS. The formation of the Cd²⁺-complexes (1+Cd and 2+Cd) in CD₃OD solution have been detected by ¹H,¹³C, ¹⁵N and ¹¹³Cd NMR. The ¹³C NMR chemical shift assignments of 1 and 2 and their Cd²⁺-complexes are based on DEPT-135 and z-GS ¹H,¹³C HMQC experiments as well as comparison with the assignments of the related structures. The ¹⁵N NMR chemical shiftassignments of the ligands and theirCd²⁺-complexes are based on z-GS¹H,¹⁵N HMBC experiments. ¹³C NMR chemical shift differences between 1and its 1:1 Cd²⁺-complex based on ab initiocalculations at Hartree-Fock SCI-PCM level using3-21G(d) basis set are in agreement with theexperimental shift changes observed onCd²⁺-complexation.     

First experimental determination of two-bond C isotopic effects on H NMR chemical shifts

For the first time, a simple NMR methodology is proposed for the accurate determination of the effect of the substitution of ¹²C by ¹³C on the chemical shifts of protons separated by two-bonds in small molecules in their natural abundance.     

Structural revision of peribysins C and D

Structural revision of the cell-adhesion inhibitory eremophilane sesquiterpenoid peribysins C and D is reported. A CAST/CNMR system is utilized in the reinvestigation of ¹³C NMR chemical shift values and structures, and geometric analyses with molecular and quantum mechanics calculations, and revalidation of NMR data support the revised structures.     

Nuclear magnetic resonance of donor atoms as a tool for determination of the structure of platinum metal complexes in solutions

Data on the NMR spectroscopy of C, N, O, Si, P, and Sn donor atoms of platinum metal complexes in solutions are surveyed. The chemical shift of a donor atom mainly depends on the ligand in the trans-position (due to the trans-effect). The chemical shift of a donor atom on a particular coordinate of the complex (coordinate shift, CSh) is an attribute of this coordinate and can be used to identify such a coordinate in platinum metal complexes and to determine the structures of complexes. Based on the known data, CSh diagrams were composed for ¹H, ¹³C, ¹⁴N, ¹⁷O, ¹⁹F, ³¹P, and ¹¹⁹Sn. Examples of using the CShs for determining the structures of platinum metal complexes in solutions are presented.     

Use of13C chemical shift/charge density linear relationship for ranking chemical structures

A novel approach to molecular structure elucidation based on ranking chemical structures in agreement with the¹³C NMR chemical shift/charge density linear relationship is suggested. The structure having the lowest standard approximation error (SAE) is considered to be the correct one. Each ranked structure is additionally tested for the¹³C chemical shift equivalence corresponding to its constitutional symmetry (in terms of the charge densities).This paper is Part VI of the series Automatic assignment of¹³C NMR signals. For Part V see ref. [1].     

Effects of different GIAO and CSGT models and basis sets on 2-aryl-1,3,4-oxadiazole derivatives

The direct molecular structure implementations of the gage-including atomic orbital (GIAO), individual gages for atoms in molecules (IGAIM) and continuous set of gage transformations (CSGT) methods for calculating nuclear magnetic shielding tensors at both the Hartree-Fock (HF) and density functional (B3LYP) levels of theory with 6-31G(d), 6-311G(d), 6-31++G(d,p), 6-311++G(d,p), and 6-311++G(df,pd) basis sets are presented. Dependence on the ¹H and ¹³C NMR chemical shifts on the choice of method and basis set have been investigated. Also, these chemical shifts of 2-aryl-1,3,4-oxadiazoles 5a–g have been performed related to dihedral angles (C4–C3–C2–O) of two conformers. The optimized molecular geometries and ¹H and ¹³C chemical shift values of 2-aryl-1,3,4-oxadiazoles 5a–g in the ground state have been obtained. The linear correlation coefficients of ¹³C NMR chemical shifts for these molecules were given. The new nuclear magnetic shielding tensors of tetramethylsilane (TMS) were calculated. The data of 2-aryl-1,3,4-oxadiazole derivatives display significant molecular structure and NMR analysis. Also, these provide the basis for future design of efficient materials having the 1,3,4-oxadiazole core.     

Structural Refinement of Carbimazole by NMR Crystallography

The characterization of the three-dimensional structure of solids is of major importance, especially in the pharmaceutical field. In the present work, NMR crystallography methods are applied with the aim to refine the crystal structure of carbimazole, an active pharmaceutical ingredient used for the treatment of hyperthyroidism and Grave’s disease. Starting from previously reported X-ray diffraction data, two refined structures were obtained by geometry optimization methods. Experimental ¹H and ¹³C isotropic chemical shift measured by the suitable ¹H and ¹³C high-resolution solid state NMR techniques were compared with DFT-GIPAW calculated values, allowing the quality of the obtained structure to be experimentally checked. The refined structure was further validated through the analysis of ¹H-¹H and ¹H-¹³C 2D NMR correlation experiments. The final structure differs from that previously obtained from X-ray diffraction data mostly for the position of hydrogen atoms.     

Correlation between C and O chemical shifts and torsional strain in spiroacetals

The relationship between the ¹³C and ¹⁷O NMR chemical shifts and the dihedral energies (non-bonding interactions) of 1,4-dioxaspiro[4.4]nonane, 1,4-dioxa- and 6,10-dioxaspiro[4.5]decane, 1,4-dioxa- and 6,11-dioxaspiro[4.6]undecane, 1,5-dioxaspiro[5.5]undecane, 1,5-dioxa and 7,12-dioxaspiro[5.6]dodecane and 1,6-dioxaspiro[6.6]tridecane were analyzed. These data showed correlation of the non-bonding interactions with the chemical shift of the spiranic carbon, as well as a linear relationship between ¹³C and ¹⁷O.     

Chloroscabrolides, chlorinated norcembranoids from the Indonesian soft coral Sinularia sp.

Chemical analysis of the Indonesian soft coral Sinularia sp. (order Alcyonacea, family Alcyoniidae) afforded two known and three new C-4 norcembranoids, named chloroscabrolides A (3) and B (4) and prescabrolide (5). Chloroscabrolide A is a pentacyclic norcembranoid including an unprecedented THF-type ring to connect C-13 and C-15; furthermore, it is only the second chlorinated cembranoid derivative to be reported in the literature. The relative configuration of chloroscabrolide A has been established on the basis of a comparison between experimental ¹³C NMR data and DFT-calculated ¹³C NMR chemical shifts. All the isolated norcembranoids have been evaluated for iNOS protein inhibition.     

13C NMR study of the influence of the Aerosil surface charge on the short-chain surfactant adsorption

¹³C NMR chemical shift measurements have been used to study the adsorption of short-chain ionic surfactants on the Aerosil surface from aqueous solutions. The investigations were carried out in a wide concentration range above and below the critical micelle concentration value. The values and the character of the chemical shift changes of Δδ are mainly determined by the surface charge, which is generally assumed to change with the initial pH value of the silica aqueous dispersion. Most sensitive to changes of the surface charge are the ¹³C NMR parameters of the first and second carbon atoms in the hydrophobic chain of the surfactant molecules. This allows investigating the influence of the Aerosil surface charge on the structure of the adsorbed aggregates.     

Site-specific C content by quantitative isotopic C Nuclear Magnetic Resonance spectrometry: A pilot inter-laboratory study

Isotopic ¹³C NMR spectrometry, which is able to measure intra-molecular ¹³C composition, is of emerging demand because of the new information provided by the ¹³C site-specific content of a given molecule. A systematic evaluation of instrumental behaviour is of importance to envisage isotopic ¹³C NMR as a routine tool. This paper describes the first collaborative study of intra-molecular ¹³C composition by NMR. The main goals of the ring test were to establish intra- and inter-variability of the spectrometer response. Eight instruments with different configuration were retained for the exercise on the basis of a qualification test. Reproducibility at the natural abundance of isotopic ¹³C NMR was then assessed on vanillin from three different origins associated with specific δ¹³C_i profiles. The standard deviation was, on average, between 0.9 and 1.2‰ for intra-variability. The highest standard deviation for inter-variability was 2.1‰. This is significantly higher than the internal precision but could be considered good in respect of a first ring test on a new analytical method. The standard deviation of δ¹³C_i in vanillin was not homogeneous over the eight carbons, with no trend either for the carbon position or for the configuration of the spectrometer. However, since the repeatability for each instrument was satisfactory, correction factors for each carbon in vanillin could be calculated to harmonize the results.     

1H, 13C,and 14N NMR study of 3-methylfurazans with nitrogen-containing substituents at position 4

3-Methylfurazans with nitrogen-containing substituents at position 4 were studied by ¹H, ¹³C, and ¹⁴N NMR spectroscopy. A correlation between the chemical shifts in ¹³C NMR spectra of these furazans and monosubstituted benzenes with the same substituents was found. The increments for a number of furazan-containing substituents were determined for the first time.     

Evaluation of <Superscript>13</Superscript>C NMR spectra of cyclopropenyl and cyclopropyl acetylenes by theoretical calculations

A convenient methodology was developed for a very accurate calculation of ¹³C NMR chemical shifts of the title compounds. GIAO calculations with density functional methods (B3LYP, B3PW91, PBE1PBE) and 6-311+G(2d,p) basis set predict experimental chemical shifts of 3-ethynylcyclopropene (1), 1-ethynylcyclopropane (2) and 1,1-diethynylcyclopropane (3) with high accuracy of 1–2 ppm. The present article describes in detail the effect of geometry choice, density functional method, basis set and effect of solvent on the accuracy of GIAO calculations of ¹³C NMR chemical shifts. In addition, the particular dependencies of ¹³C chemical shifts on the geometry of cyclopropane ring were investigated.     

Solid state13C NMR spectra of metal carbonyl clusters

The solid state¹³C NMR spectra of four¹³CO enriched carbonyl clusters having a tri-iron metallic core have been analyzed to provide structural and dynamic information. In Fe₃(CO)₁₂ (1), the high temperature spectra suggest the occurrence of large amplitude motions of the CO groups around their position at the vertexes of the coordination polyhedron in addition to the motion involving the Fe₃-triangle previously detected in the VT-¹³C MAS spectra.¹³C and³¹P NMR data of Fe₃(CO)₁₁PPh₃ (2) indicates the presence of one molecule in the asymmetric unit in apparent disagreement with the previously reported X-ray data. Furthermore, we show that structural information can be obtained from the chemical shift tensor components readily available from the analysis of the spinning sideband manifold.     

The increment scheme for the prediction of13C NMR chemical shifts in polychlorinated dibenzo-p-dioxins

A topological method for the calculation of¹³C NMR chemical shifts was developed for polychlorinated dibenzo-p-dioxins (PCDD). Based on previous results for polychlorinated benzenes and polyhydroxybenzenes, the collective influence of the substituents on carbon chemical shifts is presented as the sum of two-particle increments. The increments only of two new monosubstituted graphs have to be added to those known for PCDD spectra: 1-Cl-DD and 2-Cl-DD. All structural situations in the¹³C NMR chemical shifts of the whole class of 75 PCDD can be covered with a few model compounds. The coefficients of the increment scheme are independent of the change of CDCl₃ for acetone-d₆, so it may be a new reliable criterion for recognizing PCDD by¹³C NMR, in spite of the close resemblance of NMR spectra of aromatic compounds.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 280–284, February, 1995.     

Quantitative determination of mebeverine HCl by NMR chemical shift migration

Quantitative ¹H NMR spectroscopic methods are not frequently reported, but current NMR instrumentation allows ready access to such data. Mebeverine HCl is an attractive molecule for NMR spectroscopy teaching purposes as it possesses a variety of simple but significant functional groups; we fully assign its ¹H and ¹³C NMR spectra. Using mebeverine HCl, we show that concentration changes, in water as a solvent, can lead to significant changes in the ¹H chemical shifts of non-exchangeable aromatic protons and to a lesser extent to aromatic methoxy protons. An important observation is that different protons migrate to different extents as the concentration of the solute is varied, and thus the ¹H NMR spectra are concentration-dependent across a useful range. This chemical shift variation of selected protons was therefore analyzed and applied in the quantitative determination of mebeverine HCl in a medicine (Colofac IBS) formulated as a tablet. Self-association phenomena in water could account for these observed chemical shift migration effects as shown by determining the hydrodynamic radius from the modified form of the Stokes-Einstein equation, and thence the apparent hydrodynamic volume, V_H, for mebeverine HCl in D₂O solution which is 10-fold greater than that seen in either CDCl₃ or CD₃OD.     

Nitropyrazoles

The structures of substitutedN-aminonitropyrazoles and 1- and 2-amino-4-nitro-1,2,3-triazoles as well as the site of protonation of 1-aminopyrazole were determined based on the¹H,¹³C, and¹⁵N (¹⁴N) NMR spectra. The¹³C NMR spectra were recorded under conditions of¹³C-{¹H,¹⁴N} triple resonance. Effects of substituents in the pyrazole ring on the¹³C and¹⁴N chemical shifts were studied. The¹³C,¹H and¹⁵N,¹H spin-spin coupling constants, obtained using techniques of [¹H]¹³C and [¹H]¹⁵N polarization transfer (SPT, INEPT), were measured, fully assigned, and discussed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2181–2186, November, 1995.For Part 8, see Ref. 1.     

Conditions to obtain precise and true measurements of the intramolecular C distribution in organic molecules by isotopic C nuclear magnetic resonance spectrometry

Intramolecular ¹³C composition gives access to new information on the (bio) synthetic history of a given molecule. Isotopic ¹³C NMR spectrometry provides a general tool for measuring the position-specific ¹³C content. As an emerging technique, some aspects of its performance are not yet fully delineated. This paper reports on (i) the conditions required to obtain satisfactory trueness and precision for the determination of the internal ¹³C distribution, and (ii) an approach to determining the “absolute” position-specific ¹³C content. In relation to (i), a precision of <1% can be obtained whatever the molecule on any spectrometer, once quantitative conditions are met, in particular appropriate proton decoupling efficiency. This performance is a prerequisite to the measurement of isotope fractionation either on the transformed or residual compound when a chemical reaction or process is being studied. The study of the trueness has revealed that the response of the spectrometer depends on the ¹³C frequency range of the studied molecule, i.e. the chemical shift range. The “absolute value” and, therefore, the trueness of the ¹³C NMR measurements has been assessed on acetic acid and by comparison to the results obtained on the fragments from COOH and CH₃ by isotopic mass spectrometry coupled to a pyrolysis device (GC-Py–irm-MS), this technique being the reference method for acetic acid. Of the two NMR spectrometers used in this work, one gave values that corresponded to those obtained by GC-Py–irm-MS (thus, the “true” value) while the other showed a bias, which was dependent to the range covered by the resonance frequencies of the molecule. Therefore, the former can be used directly for studying isotope affiliations, while the latter can only be used directly for comparative data, for example in authenticity studies, but can also be used to obtain the true values by applying appropriate correction factors. The present study assesses several key protocol steps required to enable the determination of position-specific ¹³C content by isotopic ¹³C NMR, irrespective of the NMR spectrometer: parameters to be adjusted, performance test using [1,2-¹³C₂]acetic acid, generation of correction factors.