A simple method for measuring long-range 1H-13C coupling constants in organic molecules

This study presents a simple method for measuring long-range heteronuclear coupling constants between protons and proton-bearing carbons. The approach involves recording two conventional 1D-TOCSY experiments in which the offset of the selective proton pulse is set on the low- and high-frequency 13C satellites of an isolated proton signal, Hi. Long-range heteronuclear coupling values between the 13Ci bonded to Hi and the protons Hj,k...n that belong to the same spin system were easily determined from the relative displacement of the relayed Hj,k...n signals in the satellite-selective TOCSY spectra. The sense of the displacement indicated the sign of the coupling constants.     

Geminal 2JCCH spin-spin coupling constants as probes of the phi glycosidic torsion angle in oligosaccharides

Two-bond (13)C-(1)H NMR spin-spin coupling constants ((2)J(CCH)) between C2 and H1 of aldopyranosyl rings depend not only on the relative orientation of electronegative substituents on the C1-C2 fragment but also on the C-O torsions involving the same carbons. The latter dependencies were elucidated theoretically using density functional theory and appropriate model pyranosyl rings representing the four relative configurations at C1 and C2, and a 2-deoxy derivative, to probe the relationship between (2)J(C2,H1) magnitude and sign and the C1-O1 (phi, phi) and C2-O2 (alpha) torsion angles. Related calculations were also conducted for the reverse coupling pathway, (2)J(C1,H2). Computed J-couplings were validated by comparison to experimentally measured couplings. (2)J(CCH) displays a primary dependence on the C-O torsion involving the carbon bearing the coupled proton and a secondary dependence on the C-O torsion involving the coupled carbon. These dependencies appear to be caused mainly by the effects of oxygen lone pairs on the C-H and C-C bond lengths along the C-C-H coupling pathway. New parameterized equations are proposed to interpret (2)J(C1,H2) and (2)J(C2,H1) in aldopyranosyl rings. The equation for (2)J(C2,H1) has particular value as a potential NMR structure constraint for the C1-O1 torsion angle (phi) comprising the glycosidic linkages of oligosaccharides.     

19F n.m.r. spectrum of hexafluoroquinazoline long-range inter-ring F?F coupling constants

The ¹⁹F n.m.r. spectrum of hexafluoroquinazoline has been analyzed giving the signs and magnitudes of all but two of the coupling constants, and supporting the analyses of the ¹⁹F n.m.r. spectra of heptafluoroquinoline and heptafluoroisoquinoline. Long range F? F inter-ring coupling constants are a guide for assessing π-electron delocalization pathways. In addition, nitrogen in the β position enhances the distant F-5, F-7 meta-coupling constant, implying a π-contribution to J(FF)meta. A rationalization of changes in peri-coupling constants is also presented. The observed changes appear to be the sum of two effects: (i) ring contraction by the insertion of shorter C? N bonds into the aromatic ring and (ii) a secondary effect which is dependent on the existence of a β-nitrogen, adjacent to the peri nuclei.     

13C-detected IPAP-INADEQUATE for simultaneous measurement of one-bond and long-range scalar or residual dipolar coupling constants

The sensitivity of cryoprobes, which are rapidly becoming available, means that the measurement of coupling constants involving 13C, 13C pairs at the natural abundance of 13C can now, in principle, be done by using tens rather then hundreds of milligrams of compounds. However, a robust method that would yield reliable values of small long-range carbon--carbon coupling constants is still missing. In this Communication, we describe a novel 13C-detected incredible natural-abundance double-quantum transfer experiment (INADEQUATE) experiment for simultaneous correlation of one-bond and long-range 13C- 13C pairs and the measurement of both types of coupling constants in 13C natural abundance samples. This method yields accurate values of one-bond and long-range coupling constants by manipulation of pure phase in-phase (IP) and antiphase (AP) doublets, and is referred to as 13C-detected IPAP-INADEQUATE. It is illustrated by the measurement of interglycosidic (3)J(CCOC) coupling constants in a disaccharide molecule providing important information about the conformation of the glycosidic linkage. Owing to the simplicity of INADEQUATE spectra the carbon-carbon coupling constants are particularly suitable for studies of partially oriented molecules through the measurement of carbon-carbon residual dipolar couplings (RDCs). An example of this approach is presented. We expect the method to find a variety of applications in the conformational analysis of small molecules, determination of diastereoisomers and enantiomers, and studies of molecules in aligned media.     

Interbenzylic 19F,19F spin-spin coupling constants in bis(fluoromethyl) arenes

Five- to eleven-bond F,F spin coupling is observed in bis(fluoromethyl)arenes. According to INDO MO calculations, these couplings are transmitted mainly via the aromatic π-system. The low preference of 1,4-(CH₂F)₂-benzene for the conformation in which the C? F bonds are perpendicular to the aromatic ring is shown by the strong increase of⁷J(FF) upon double ortho-substitution.     

Measurement of 1H-1H residual dipolar coupling constants for structural studies of medium size molecules.

Residual dipolar coupling constants (RDCs) are being increasingly applied to elucidate the configuration and conformation of small organic molecules, peptides and oligosaccharides. In this paper we describe a set of robust 1D NMR methods for accurate and precise measurement of proton-proton RDCs of small and medium size molecules. The performance of these techniques is not impeded by the presence of overlapping and broad (1)H multiplets that are typically observed for such molecules in weakly aligned media. The use of these techniques provides access to a large pool of proton-proton RDCs opening new avenues for the solution structure elucidation of medium size molecules by NMR. The techniques are illustrated on the determination of the alignment tensor of the reducing monosaccharide ring of cellobiose and the determination of the relative configuration of sodium cholate.     

Signs of proximate 31P, 19F and 19F, 19F spin–spin coupling constants in 2-trifluoromethylphenyldifluorophosphine

In 2-trifluoromethylphenyldifluorophosphine the proximate couplings ⁴J(¹⁹F³¹P) and ⁵J(¹⁹F¹⁹F) are + 68.3 and + 8.3 Hz, respectively. ¹J(¹³C³¹P) is ?57.0 Hz, ²J(¹³C-1, ¹⁰F) is + 9.9 Hz and ²J(¹³C-6, ¹³C-6, ³¹P) is + 10.1 Hz. The trifluoromethyl substituent induces substantial changes in some coupling constants, particularly those between the ³¹P and ring ¹³C nuclei.     

Measurement of long-range 1H-1H dipolar couplings in weakly aligned proteins

Measurement of 1H-1H dipolar couplings in macromolecules, weakly oriented by a dilute liquid crystalline medium, is generally limited to the largest such interactions. By removing dipolar couplings to nearest neighbors, either by decoupling, deuteration, or both, more remote interactions become accessible. The approach is demonstrated for measurement of amide-amide interactions in the proteins calmodulin and ubiquitin and permits observation of direct dipolar couplings between protons up to 7 A apart. Quantitative evaluation of 1H-1H dipolar couplings measured in ubiquitin shows excellent agreement with its solution structure.     

19F NMR of five polyfluoronaphthalenes. Inter-ring FF coupling constants

Analyses of the ¹⁹F and ¹H spectra of 1,2,3,4,5-pentafluoro-, 1-bromo-4,5,6,7,8-pentafluoro-, 1,2,3,4,5,6-hexafluoro-, and 1-bromo-3,4,5,6,7,8-hexafluoro-naphthalene are presented, and it is observed that the Fermi contact mechanism does not, simply, account for the long range couplings. Calculations of the carbon-carbon polarizability part of the Fermi contact term do, however, imply that inter-ring F,F couplings should be almost constant from difluoro- to heptafluoro-naphthalene. Within the limits of this study, the inter-ring F,F couplings, excluding peri F,F couplings, do not vary substantially. The steric effect of substituting an α-hydrogen with bromine, at a peri position and adjacent to fluorine, is to increase the F,F coupling at the opposed peri position by 20 Hz, an unusually high increase in J(FF)peri.     

19F chemical shifts, coupling constants and conformational preferences in monosubstituted perfluoroparacyclophanes

In the process of studying the chemistry of perfluoro[2.2]paracyclophanes (PFPCs), a novel class of compounds, it became necessary to identify some disubstituted products. To achieve this goal, we characterize in this work some monosubstituted PFPCs, identifying their (19)F-(19) F coupling patterns, and establishing a methodology for the assignment of their (19)F chemical shifts. The pattern of coupling constants indicates a skewed geometry in which the upper deck moves towards or away from the substituent, depending on the substituent electron-donor character and size. Quantum chemical calculations, performed at the HF/6-311 + G(d,p)//B3LYP/EPR-III level of theory, confirmed the conformations inferred from coupling constants and reproduced well the values of the couplings. Transmission mechanisms for the FC term of four- and five-bond (19)F-(19) F couplings are discussed in detail. Understanding the conformational preferences of PFPCs and how they are reflected by the coupling constants facilitates the assignment of (19)F chemical shifts in monosubstituted PFPCs and the identification of the disubstituted products.     

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.     

The effects of substituents on the 5J long-range spin-spin coupling constants in substituted benzaldehydes

Proton magnetic resonance spectra of several mono- and disubstituted benzaldehydes were studied using CW, INDOR and double resonance techniques. It was verified that substitution in the para position has no effect on the long-range coupling of the aldehydic proton with the ring protons five bonds away. Substitution in the ortho and meta positions (with the exception of 2,4-dinitrobenzaldehyde) follows closely the additivity rule effects of the substituents.     

Spin-spin coupling constants of 13C-1H and 1H- 1H in 4-substituted pyridines

The spin-spin coupling constants (SSCC) of ¹³C-¹H and ¹H-¹H in 4-substituted pyridines, C₅H₄NX [X=,CN, COCH₃, COOCH₃, N(CH₃)₂, NO₂, OCH₃, Cl, Br], were investigated. To determine the constants, the proton-coupled NMR spectra of ¹³C and ¹³C-satellites in the PMR spectra of the compounds, recorded for monomolecular solutions of 4-substituted pyridines in DMSO-D₆, were analyzed. The interrelationship of the SSCC of ¹³C-¹H and ¹H-¹H in 4-substituted pyridines with the analogous constants in monosubstittued benzenes were obtained. The correlations of the constants with the F- and R-parameters of the substituents are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 948–952, July, 1984.     

Comparison of 1H–19F two‐dimensional NMR scalar coupling correlation pulse sequences

The effectiveness of hetero‐COSY, HETCOR, HMQC, and HSQC two‐dimensional NMR pulse sequences for detection of ¹⁹F–¹H correlations by scalar coupling was evaluated on monofluorinated and polyfluorinated test compounds. All four of these sequences were effective in observing ¹H–¹⁹F correlations, using either ¹⁹F or ¹H as the observe nucleus. All four sequences were amenable, to some degree, to adjustment to observe larger or smaller couplings preferentially. A 1/2J echo filter was effectively applied to remove artifacts from ²J_FF strong coupling. The HETCOR experiments afforded the best overall combination of sensitivity, resolution and selectivity for J_HF. Copyright © 2014 John Wiley & Sons, Ltd.     

19F n.m.r spectra of polyfluoroquinolines. Long range inter-ring 19F?19F coupling constants and 19F chemical shifts

The signs and magnitudes of every fluorine–fluorine coupling constant in perfluoroquinoline ( 1 ), 2,4-dichloropentafluoroquinoline ( 2 ) and 2-bromohexafluoroquinoline ( 3 ) have been determined by ¹⁹F n.m.r. These provide an unambiguous assignment of the spectrum of the first compound and its derivatives. Inter-ring fluorine–fluorine coupling constants were found to be positive over an odd number of bonds and negative over an even number of bonds, similar to that observed in proton–proton coupling constants in multicyclic systems. The ¹⁹F chemical shifts of perfluoroquinoline and its protonated salt are reported and directly correlated with SCF MO calculated π-electron densities at both fluorine and bonded carbon atoms.     

19F n.m.r spectra of heptafluoroisoquinoline and hexafluoro-1-methoxyisoquinoline. Long-range inter-ring coupling constants

An analysis of the ¹⁹F n.m.r. spectra of heptafluoroisoquinoline and hexafluoro-1-methoxyisoquinoline is presented. As in heptafluoroquinoline, the inter-ring F? F coupling constants alternate in sign and magnitude and are positive over an odd number of bonds. They correlate with SCFMO carbon–carbon polarizabilities and this infers that the long-range coupling mechanism is dominated by the contribution from the π-electron system.     

Laccase-catalyzed phenol oxidation. Rapid assignment of ring-proton deficient polycyclic benzofuran regioisomers by experimental 1H-13C long-range coupling constants and DFT-predicted product formation

Laccase-catalyzed oxidation of substituted catechols followed by reaction with 4-hydroxy-pyrone/-benzopyrone afforded substituted benzofuran regioisomers whose structures with only two aromatic protons in total prevent a rapid structural assignment. Based on the evaluation of (1)H-(13)C long-range coupling constants a rule of thumb could be deduced for an easy and unambiguous differentiation between the possible regioisomers formed. DFT frontier orbital calculations of the reactants offer an interesting tool to explain the regioselectivity of the key reaction.     

15N chemical shifts and long-range 1H-15N coupling pathways of selected strychnos alkaloids

The Strychnos alkaloids have been the focal point of considerable synthetic and spectroscopic effort. We now report the ¹⁵N chemical shifts and long-range ¹H-¹⁵N coupling pathways of strychnine, brucine, and holstiine at natural abundance. Long-range coupling pathways were established using a gradient-enhanced HMQC sequence optimized for the observation of ¹H-¹⁵N long-range couplings.     

1H-1H scalar coupling across two stacked aromatic rings: DFT calculations and experimental proof

1H-1H scalar coupling across two stacked (parallel and eclipsed) aromatic rings has been revealed through the 1D and 2D 1H NMR analysis of a [2,2]paracyclophane and rationalized by means of density functional theory (DFT) calculation of the J values.