Carbon-proton Coupling Constants Research Articles

Long-range proton–carbon coupling constants for the determination of the stereochemical structure of organic compounds.

A new methods for elucidating stereochemistry of organic compounds was developed on the basis of long-range proton–carbon coupling constants (2,3JC,H) and interpreting spin-coupling constants (3JH,H). Reaction of compound containing pyrin ring with nucleophile reagent was done to open the ring. HSQC-TOCSY experiments one of the new NMR spectroscopy method used to measure this values of spin-coupling constants and elucidating the stereochemistry of the product.

How to measure long-range proton-carbon coupling constants from 1 H-selective HSQMBC experiments.

Heteronuclear long-range scalar coupling constants (n JCH ) are a valuable tool for solving problems in organic chemistry and are especially suited for stereochemical and configurational analyses of small molecules and natural products. This tutorial will focus on the step-by-step implementation of several 2D 1 H frequency selective HSQMBC experiments for the easy and accurate measurement of either the magnitude or both the magnitude and the sign of long-range n JCH couplings. The performance of these experiments will be showcased with several scenarios in a range of different experimental conditions.

Synthesis of new cyano-substituted analogues of Tröger's bases from bromo-derivatives. A stereochemical dependence of long-range (n JHH , n=4, 5, and 6) proton-proton and proton-carbon (n JCH , n=1, 2, 3, 4, and 5) coupling constants of these compounds.

A free-catalyst microwave-assisted cyanation of brominated Tröger's base derivatives (2a-f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a-e, I) in very good yields. Complete assignment of 1 H and 13 C chemical shifts of 2a-f, I and 3a-d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton-proton coupling constants n JHH (n=4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the 1 H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and 1 H-15 N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon-proton coupling constants n JCH (n=2, 3, and 4) and for assignment of 15 N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6-311+G(d,p) basis sets. For calculation of 1 H and 13 C chemical shifts, n JHH (n=2, 3, 4, 5, and 6), and n JCH (n=1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range n JHH (n=4, 5, and 6) and n JCH (n=1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tröger's bases.

1JCH NMR Profile: Identification of Key Structural Features and Functionalities by Visual Observation and Direct Measurement of One-Bond Proton-Carbon Coupling Constants.

A user-friendly NMR interface for the visual and accurate determination of experimental one-bond proton-carbon coupling constants (1JCH) in small molecules is presented. This intuitive 1JCH profile correlates directly to δ(1H), and 1JCH facilitates the rapid identification and assignment of 1H signals belonging to key structural elements and functional groups. Illustrative examples are provided for some target molecules, including terminal alkynes, strained rings, electronegative substituents, or lone-pair-bearing heteronuclei.

Perfect 1JCH-resolved HSQC: Efficient measurement of one-bond proton-carbon coupling constants along the indirect dimension

A versatile 1JCH-resolved HSQC pulse scheme for the speedy, accurate and automated determination of one-bond proton-carbon coupling constants is reported. The implementation of a perfectBIRD element allows a straightforward measurement from the clean doublets obtained along the highly resolved F1 dimension, even for each individual 1JCHa and 1JCHb in diastereotopic HaCHb methylene groups. Real-time homodecoupling during acquisition and other alternatives to minimize accidental signal overlapping in overcrowded spectra are also discussed.

Native and modified chitosan-based hydrogels as green heterogeneous organocatalysts for imine-mediated Knoevenagel condensation

A variety of methylenemalononitriles and ethyl cyanoacrylates derived from both aromatic and heteroaromatic aldehydes were synthesized by Knoevenagel condensation catalysed with native and modified chitosan-based heterogeneous catalysts. The efficiency of our hydrogel organocatalysts, chitosan hydrogel beads and ureidyl-chitosan derivative hydrogel disks, was evaluated as function of pH, temperature and catalyst concentration by considering reaction rates, conversions, E/Z stereoselectivities, and kinetic studies of a model reaction between 4-nitrobenzaldehyde and ethyl cyanoacetate. An unprecedented study by solid state 13C CP MAS NMR of the employed catalyst when reaction was quenched after a 50% of conversion, has demonstrated that an imine-chitosan intermediate is formed during this process. Analysis of E/Z ethyl cyanoacrylate isomer mixtures for determining the corresponding stereoselectivity was carried out by NMR measuring carbon-proton coupling constants (3JC,H) using a novel CLIP-HSQMCB experiment. Additionally, DFT calculations let us rationalise the observed E/Z stereoselectivities as well as to evaluate the role of ureidyl moiety on interaction with aldehydes and imine intermediate formation with chitosan derivative.

The potential utility of predicted one bond carbon-proton coupling constants in the structure elucidation of small organic molecules by NMR spectroscopy.

NMR spectroscopy is the most popular technique used for structure elucidation of small organic molecules in solution, but incorrect structures are regularly reported. One-bond proton-carbon J-couplings provide additional information about chemical structure because they are determined by different features of molecular structure than are proton and carbon chemical shifts. However, these couplings are not routinely used to validate proposed structures because few software tools exist to predict them. This study assesses the accuracy of Density Functional Theory for predicting them using 396 published experimental observations from a diverse range of small organic molecules. With the B3LYP functional and the TZVP basis set, Density Functional Theory calculations using the open-source software package NWChem can predict one-bond CH J-couplings with good accuracy for most classes of small organic molecule. The root-mean-square deviation after correction is 1.5 Hz for most sp3 CH pairs and 1.9 Hz for sp2 pairs; larger errors are observed for sp3 pairs with multiple electronegative substituents and for sp pairs. These results suggest that prediction of one-bond CH J-couplings by Density Functional Theory is sufficiently accurate for structure validation. This will be of particular use in strained ring systems and heterocycles which have characteristic couplings and which pose challenges for structure elucidation.

Bisindole Alkaloids with Neural Anti-inflammatory Activity from Gelsemium elegans

Three new trace bisindole alkaloids geleganimines A and B (1, 2) and geleganamide (3) were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by spectroscopy, particularly from their carbon-proton coupling constants, and electronic circular dichroism. Compounds 1-3 are the first bisindole alkaloids discovered from the genus Gelsemium. Geleganimine B exhibited anti-inflammatory activity indirectly by suppressing lipopolysaccharide-induced pro-inflammatory factors in BV2 microglial cells with an IC50 value of 10.2 μM. These findings confirm the importance of bioactive trace components in medicinal plant research.

On the interference of J(HH) modulation in HSQMBC‐IPAP and HMBC‐IPAP experiments

The effects of phase modulation due to homonuclear proton-proton coupling constants in HSQMBC-IPAP and HMBC-IPAP experiments are experimentally evaluated. We show that accurate values of small proton-carbon coupling constants, (n)J(CH), can be extracted even for phase-distorted cross-peaks obtained from a selHSQMBC experiment applied simultaneously on two mutually J-coupled protons. On the other hand, an assessment of the reliability of (n)J(CH) measurement from distorted cross-peaks obtained in broadband IPAP versions of equivalent HMBC and HSQMBC experiments is also presented. Finally, we show that HMBC-COSY experiments could be an excellent complement to HMBC for the measurement of small (n)J(CH) values.

CLIP-HSQMBC: easy measurement of small proton–carbon coupling constants in organic molecules

A user-friendly 2D NMR approach denoted as CLIP-HSQMBC is proposed for the very easy, direct and accurate measurement of long-range proton-carbon coupling constants in organic molecules and natural products. The J value can be extracted directly from the analysis of resolved in-phase (1)H multiplets that show an additional splitting arising from the proton-carbon coupling. In cases of unresolved peaks, a simple fitting analysis using the internal satellite lines as a reference is performed. Addition of a spin-lock period results in a CLIP-HSQMBC-TOCSY experiment that is suitable for the measurement of very small coupling values or to observe correlations from overlapped resonances.

P.E.HSQMBC: Simultaneous measurement of proton–proton and proton–carbon coupling constants

A long-range optimized P.E.HSQC experiment, named P.E.HSQMBC, is proposed for the simultaneous measurement of a complete set of homonuclear and heteronuclear coupling constants from a single 2D cross-peak. The sign and the magnitude of proton–proton coupling constants are measured along the direct dimension from the relative E.COSY-type multiplet pattern displacement due to the passive one-bond coupling constant splitting generated in the indirect dimension. On the other hand, long-range proton–carbon coupling constants are independently determined in the detected dimension from a traditional fitting analysis of antiphase multiplet patterns or, more conveniently, from the IPAP multiplet displacement obtained from extended HSQMBC experiments.

Efficient measurement of the sign and the magnitude of long‐range proton‐carbon coupling constants from a spin‐state‐selective HSQMBC‐COSY experiment

A spin state-selective Heteronuclear Single-Quantum Multiple-Bond Connectivities (HSQMBC-COSY) experiment is proposed to measure the sign and the magnitude of long-range proton-carbon coupling constants ((n)J(CH); n > 1) either for protonated or for non-protonated carbons in small molecules. The simple substitution of the selective 180° (1)H pulse in the original selHSQMBC pulse scheme by a hard one allows the simultaneous evolution of both proton-proton and proton-carbon coupling constants during the refocusing period and enables a final COSY transfer between coupled protons. The successful implementation of the IPAP principle leads to separate mixed-phase α/β cross-peaks from which (n)J(CH) values can be easily measured by analyzing their relative frequency displacements in the detected dimension.

The relative signs of NMR proton–carbon coupling constants in quinolines

The relative signs of spin–spin coupling constants are of practical significance in spectral analysis and in structural elucidation. The signs, however, cannot be obtained directly from usual NMR spectra. In the present study, we measured 1H and 13C NMR spectra of three quinolines and used the Selective Population Transfer (SPT) to determine the relative sign of their proton–carbon coupling constants. For the determination of the relative signs of JCH, hetero-nuclear SPT experiments accompanied with proton decoupling were applied to systems in which a carbon nucleus couples with four or more protons. SPT was applied to the lowest or highest field 13C satellite of the 1H spectrum. The value of 2JH3C2 of 6-chloro-2-methyl-quinolines (1) was determined to be +2.2 Hz by hetero-nuclear SPT with the decoupling of CH3 protons. Similarly, 2JH6C7 of 7-chloro-8-methylqionoline (2) and 2JH7C8 of 8-hydroxyquinoline (3) were determined to be −2 and −4.0 Hz with the decoupling of CH3 protons of Compound (2) and H4 of Compound (3), respectively.

Accurate measurement of small heteronuclear coupling constants from pure-phase α/ β HSQMBC cross-peaks

A simple proton-selective α/ β-HSQMBC experiment is proposed for the accurate measurement of long-range proton–carbon coupling constants ( n J CH) in small molecules without need for an individualized and time-consuming post-processing fitting procedure. The method acquires two pure-phase In-phase (IP) and Anti-phase (AP) multiplets completely free of any phase distortion due to the absence of J HH evolution. Accurate n J CH values can be directly measured analyzing the relative displacement of the resulting IPAP cross-peaks. Discussion about signal intensity dependence and cross-talk is made for a range of experimental conditions. The robustness of the method is evaluated by comparing the n J CH value measured from the analysis of the three available IP, AP and IPAP multiplet patterns. Multiple-frequency and region-selective versions of the method can also be efficiently recorded provided that excited protons are not mutually coupled.

Measurement of long‐range proton–carbon coupling constants from pure in‐phase 1D multiplets

The SELective INverse detection of carbon-proton CORrelation pulse sequence that yields a 1D spectrum of a proton directly bonded to a selected carbon resonance has been converted into a proton and carbon double-selective variant that provides a (1)H spectrum of a selected proton that is long-range coupled to a specific carbon resonance. The resulting 1D proton multiplet exhibits a pure absorptive in-phase lineshape for precise measurement of specific long-range proton-carbon coupling constants in small organic molecules at natural abundance.

Prorocentrol, a Polyoxy Linear Carbon Chain Compound Isolated from the Toxic Dinoflagellate Prorocentrum hoffmannianum

A polyoxy linear carbon chain compound, prorocentrol (1), was isolated from cultured cells of the dinoflagellate Prorocentrum hoffmannianum, which produces a polyether carboxylic acid, okadaic acid. The structure of 1 was elucidated by detailed analyses of 2D NMR spectra. Compound 1 possesses 30 hydroxy groups, 1 ketone, and 8 double bonds on the C65-linear carbon chain. Its partial relative configuration was deduced by the proton-proton and long-range carbon-proton coupling constants, and compound 1 showed moderate cytotoxicity and antidiatom activity.

Determination of 29Si−1H Spin−Spin Coupling Constants in Organoalkoxysilanes with Nontrivial Scalar Coupling Patterns

Application of polarization transfer techniques such as DEPT and INEPT in (29)Si NMR investigation of bridged silane polymerization requires knowledge of indirect (29)Si-(1)H scalar coupling constants in the silane system. However, the fully coupled (29)Si NMR spectra of these molecules, specifically those containing ethylene bridging groups, are too complicated to measure the coupling constants directly by visual inspection. This is because unlike hydrocarbon systems where one-bond proton-carbon coupling constants exceed other coupling constants by an order of magnitude, in silanes the closest proton-silicon pairs are separated by two bonds and all coupling coefficients (both homonuclear and heteronuclear) are of similar magnitude. In these systems, theoretical tools are required to interpret the spectra of even simple molecules. Here, we determine density functional theory estimates of (29)Si-(1)H scalar coupling constants and use these along with homonuclear coupling constant estimates to resolve the nontrivial nature of these spectra. We also report a Karplus equation consistent with the dihedral angle dependence of the three-bond homo- and heteronuclear coupling in the ethylene bridge. By thermal averaging of DFT coupling constants, a good initial guess of the coupled (29)Si spectral pattern is made, which is easily refined by curve fitting to determine estimates of all coupling constants in the system.

Residual dipolar coupling investigation of a heparin tetrasaccharide confirms the limited effect of flexibility of the iduronic acid on the molecular shape of heparin

The solution conformation of a fully sulfated heparin-derived tetrasaccharide, I, was studied in the presence of a 4-fold excess of Ca2+. Proton–proton and proton–carbon residual dipolar couplings (RDCs) were measured in a neutral aligning medium. The order parameters of two rigid hexosamine rings of I were determined separately using singular value decomposition and ab initio structures of disaccharide fragments of I. The order parameters were very similar implying that a common order tensor can be used to analyze the structure of I. Using one order tensor, RDCs of both hexosamine rings were used as restraints in molecular dynamics simulations. RDCs of the inner iduronic acid were calculated for every point of the molecular dynamics trajectory. The fitting of the calculated RDCs of the two forms of the iduronic acid to the experimental values yielded a population of 1C4 and 2So conformers of iduronic acid that agreed well with the analysis based on proton–proton scalar coupling constants. The glycosidic linkage torsion angles in RDC-restrained molecular dynamics (MD) structures of I are consistent with the interglycosidic three-bond proton–carbon coupling constants. These structures also show that the shape of heparin is not affected dramatically by the conformational flexibility of the iduronic acid ring. This is in line with conclusions of previous studies based on MD simulations and the analysis of 1H-1H NOEs. Our work therefore demonstrates the effectiveness of RDCs in the conformational analysis of glycosaminoglycans.

Improved NMR methods for the direct 13C‐satellite‐selective excitation in overlapped 1H‐NMR spectra

Improved pulsed-field gradient echo methods are presented and discussed for the direct selective excitation of the (13)C-satellite lines in overcrowded (1)H NMR spectra of small molecules. Sensitivity enhancements in (13)C spin-state selection can be achieved by combining multiple-proton-frequency excitation and Hadamard phase encoding. Several satellite-selective (SATSEL) NMR experiments are proposed and exemplified by measuring the sign and the magnitude of small, long-range proton-carbon coupling constants for (1)H resonances showing several levels of signal overlapping.

Optimum spin-state selection for all multiplicities in the acquisition dimension of the HSQC experiment

Most conventional heteronuclear spin-state-selective (S 3) NMR experiments only work for a specific multiplicity, typically IS spin systems. Here, we introduce a general and efficient IPAP strategy to achieve S 3 editing simultaneously for all multiplicities in the acquisition dimension of the HSQC experiment. Complementary in-phase (HSQC-IP) and anti-phase (HSQC-AP) data are separately recorded with a simple phase exchange of two 90° proton pulses involved in the mixing process of the F2-coupled sensitivity-improved HSQC pulse sequence. Additive and subtractive linear combination of these IP/AP data generates simplified F2-α/β-spin-edited HSQC subspectra for all IS, I 2S, and I 3S spin systems and combines enhanced and optimized sensitivity with excellent tolerance to unwanted cross-talk contributions over a considerable range of coupling constants. Practical aspects such as pulse phase settings, transfer efficiency dependence, inter-pulse delay optimization, and percentage of cross-talk are theoretically analyzed and discussed as a function of each I n S multiplicity. Particular emphasis on the features associated to spin-editing in diastereotopic I 2S spin systems and application to the measurement of long-range proton–carbon coupling constants are also provided.