Heteronuclear Shift Correlation Research Articles

Development of 19 F-detected 1,1-ADEQUATE for the characterization of polyfluorinated and perfluorinated compounds.

Polyfluorinated and perfluorinated compounds in the environment are a growing health concern. 19 F-detected variants of commonly employed heteronuclear shift correlation experiments such as heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) are available; 19 F-detected experiments that employ carbon-carbon homonuclear coupling, in contrast, have never been reported. Herein, we report the measurement of the 1 JCC and n JCC coupling constants of a simple perfluorinated phthalonitrile and the first demonstration of a 19 F-detected 1,1-ADEQUATE experiment.

Simplifying LR-HSQC spectra using a triple-quantum filter: The LR-HTQC experiment.

Long-range heteronuclear single quantum correlation (LR-HSQC) experiments may be applied for detecting long-range correlations but suffer from two disadvantages, common to all heteronuclear long-range correlation experiments: (i) The information density in LR-HSQC spectra may be too high to be used directly without "filtering out" shorter range correlations, and (ii) often, substantial differences in intensity among cross peaks exist, potentially hampering the visualization of weak, often crucial cross peaks. In this contribution, we propose a modified LR-HSQC experiment, the LR-HTQC experiment (Long-Range Heteronuclear Triple Quantum Correlation) that partially solves the problems aforementioned. We show theoretically and experimentally that the LR-HTQC experiment removes the intense cross peaks of CH spin pairs, substantially reduces the medium intensity of cross peaks originating from CHH' spin systems, whereas the typically weak intensity of cross peaks of CHH'H″ and C(H)n, n > 3 spin systems is less affected. Consequently, the LR-HTQC experiment affords simplified long-range heteronuclear shift correlation spectra and scales down large intensity differences among different types of cross peaks, although a certain general reduction of signal intensities has to be accepted.

The impact of LR-HSQMBC very long-range heteronuclear correlation data on computer-assisted structure elucidation

The impact of LR-HSQMBC very long-range (n)JCH heteronuclear shift correlation data as a supplement to HMBC data as input for the computer-assisted structure elucidation program, Structure Elucidator(®), is assessed for the first time. The severely proton-deficient xanthone antibiotic cervinomycin A2 and the alkaloid staurosporine were employed as a model compounds.

NMR Structure Elucidation of Small Organic Molecules and Natural Products: Choosing ADEQUATE vs HMBC

Long-range heteronuclear shift correlation methods have served as the cornerstone of modern structure elucidation protocols for several decades. The (1)H-(13)C HMBC experiment provides a versatile and relatively sensitive means of establishing predominantly (3)J(CH) connectivity with the occasional (2)J(CH) or (4)J(CH) correlation being observed. The two-bond and four-bond outliers must be identified specifically to avoid spectral and/or structural misassignment. Despite the versatility and extensive applications of the HMBC experiment, it can still fail to elucidate structures of molecules that are highly proton-deficient, e.g., those that fall under the so-called "Crews rule". In such cases, recourse to the ADEQUATE experiments should be considered. Thus, a study was undertaken to facilitate better investigator understanding of situations where it might be beneficial to apply 1,1- or 1,n-ADEQUATE to proton-rich or proton-deficient molecules. Equipped with a better understanding of when a given experiment might be more likely to provide the necessary correlation data, investigators can make better decisions on when it might be advisible to employ one experiment over the other. Strychnine (1) and cervinomycin A2 (2) were employed as model compounds to represent proton-rich and proton-deficient classes of molecules, respectively. DFT methods were employed to calculate the relevant (n)J(CH) heteronuclear proton-carbon and (n)J(CC) homonuclear carbon-carbon coupling constants for this study.

Synthesis, NMR spectroscopic characterization and structure of a divinyldisilazane-(triphenylphosphine)platinum(0) complex: observation of isotope-induced chemical shifts 1 Δ12/13 C(195 Pt)

Tetramethyldivinyldisilazane-(triphenylphosphine)platinum(0) was prepared, characterized in solid state by X-ray crystallography and in solution by multinuclear magnetic resonance spectroscopy ((1)H, (13)C, (15)N, (29)Si, (31)P and (195)Pt NMR). Numerous signs of spin-spin coupling constants were determined by two-dimensional heteronuclear shift correlations (HETCOR) and two-dimensional (1)H/(1)H COSY experiments. Isotope-induced chemical shifts (1)Δ(12/13)C((195)Pt) were measured from (195)Pt NMR spectra of the title compound as well as of other Pt(0), Pt(II) and Pt(IV) compounds for comparison. In contrast to other heavy nuclei such as (199)Hg or (207)Pb, the "normal" shifts of the heavy isotopomers to low frequencies are found, covering a range of >500 ppb.

On the Solution Behaviour of Benzyllithium⋅(−)-Sparteine Adducts and Related Lithium Organyls - A Case Study on Applying7Li,15N{1H} HMQC and Further NMR Methods, Including Some Investigation into Asymmetric Synthesis

2D (7)Li,(15)N heteronuclear shift correlation through scalar coupling has successfully been applied to several lithium organyls consisting of polydentate N ligands such as N,N,N',N'-tetramethylethylenediamine (tmeda), N,N,N',N',N''-pentamethyldiethylentriamine (pmdta) and (-)-sparteine. Structural insights on the conformation of benzyllithium·pmdta (5) in a toluene solution and the strength of ion pairing in combination with PGSE NMR measurements, (1)H,(1)H-NOESY and (1)H,(7)Li-HOESY experiments are presented. By studying in detail the formation of 5 in solution, a transient species has been observed for the first time and assigned to a pre-complex of nBuLi and pmdta. In addition, the solution behaviour of the complex formed between benzyllithium and (-)-sparteine (8) has been studied by PGSE and multinuclear NMR spectroscopy. The straightforward synthesis and first applications in asymmetric lithiations are also reported, which show that the new system benzyllithium·(-)-sparteine (8) provide poorer enantioselective induction than the classical nBuLi·(-)-sparteine (6). The results were supported by deprotonation experiments confirming that the formation of 8 relies on two relevant factors, namely temperature and lithiating reagent. The existence of 8 may thus interfere with the asymmetric induction when the system nBuLi· (-)-sparteine is used in the enantioselective deprotonations of N-Boc-N-(p-methoxyphenyl)-benzylamine conducted in toluene.

X-ray topography, photopyroelectric and two-photon absorption studies on solution grown benzimidazole single crystal

Benzimidazole (BMZ) is an organic nonlinear optical material, and it is possible to grow it in the laboratory by a slow evaporation solution growth technique using methanol as the solvent. Its nonlinear optical harmonic generation efficiency is 4.5 times higher than that of standard potassium dihydrogen phosphate (KDP) single crystal. It crystallizes with orthorhombic structure, which is noncentrosymmetric in nature, with lattice parameters a=13.58 A, b=6.85 A, c=6.97 A. The functional groups of the grown specimen are confirmed by heteronuclear chemical shift correlation (HETCOR) analysis and it is found that other elements are not incorporated in the compound. The crystalline perfection is examined by high resolution X-ray diffraction (HRXRD), and its topographic image was recorded for the as-grown single crystal indicates the presence of some grain boundaries in the grown specimen. Thermal parameters such as thermal diffusivity (α), thermal conductivity (k), thermal effusivity (e), and heat capacity (cp) have been determined by a photopyroelectric thermal wave method. In addition, piezoelectricity, birefringence, and third-order nonlinear optical properties have been examined. The two-photon absorption coefficient of the title compound is determined by the open-aperture Z-scan technique.

Structural Characterization of a Phenoxazine Analog Formed as a By-product of the Synthesis of a 3-Amino-N,N-dimethylsalicylamide

A highly colored impurity formed at low levels during the preparation of 3-amino N,N-dimethyl salicylamide was isolated and identified as 2-amino-N,N,N′,N′-tetramethyl-3-oxo-3H-phenoxazin-4,6-dicarboxamide using mass spectrometry and two-dimensional NMR methods that included long-range 1H-15N heteronuclear chemical shift correlation data to assemble the proton-deficient “right-half” of the 2-aminophenoxazin-3-one nucleus. The structure was independently confirmed using computer-assisted structure elucidation methods and by synthesis.

ChemInform Abstract: Heteronuclear Shift Correlation Spectroscopy

AbstractReview: 21 refs.

Characterization and structural determination of 3A-amino-3A-deoxy-(2AS, 3AS)-cyclodextrins by NMR spectroscopy

The proton and carbon NMR resonances have been assigned for 3A-amino-3A-deoxy(2AS,3AS)-α-, β- and γ-CyDs (3α, 3β and 3γ). In these CyDs, a glucose residue has been replaced by an altro-pyranose unit with an axial hydroxyl group. Assignments were made with one-dimensional NMR and COSY, TOCSY, ROESY and CHSHF (heteronuclear shift correlation) spectra. Titration by NMR shift changes gave amino-group pKa values of 7.73 and 8.84 for 3β (left) and 6A-amino-6A-deoxy-β-CyD (6β, right), respectively.

Posaconazole: Application of HSQC-ADEQUATE from General Indirect Covariance Processing

Posaconazole is a structurally complex triazole antifungal agent that, by virtue of its structural complexity, provides a good test molecule for the evaluation of NMR structure elucidation methodologies. Although GHMBC and related long-range 1H–13C heteronuclear shift correlation techniques are extremely powerful, at the same time, when dealing with unknowns, they can be problematic in that there is no way to readily differentiate adjacent (2 JCH) correlations from longer range correlations, e.g., 3JCH and nJCH, n > 3. The 1,1-ADEQUATE experiment, in contrast, provides unequivocal experimental access to adjacent carbon–carbon correlation information, albeit with a sensitivity penalty, as the experiment involves an adjacent 13C–13C out-and-back magnetization transfer. In part, the sensitivity penalty can be overcome by using unsymmetrical indirect covariance or general indirect covariance processing methods. The application of these methods through the coprocessing of multiplicity-edited GHSQC and 1,1-ADEQUATE data to generate an HSQC-ADEQUATE correlation plot is demonstrated for posaconazole.

1H,89Y HMQC and Further NMR Spectroscopic and X‐ray Diffraction Investigations on Yttrium‐Containing Complexes Exhibiting Various Nuclearities

2D (1)H,(89)Y heteronuclear shift correlation through scalar coupling has been applied to the chemical-shift determination of a set of yttrium complexes with various nuclearities. This method allowed the determination of (89)Y NMR data in a short period of time. Multinuclear NMR spectroscopy as function of temperature, PGSE NMR-diffusion experiments, heteronuclear NOE measurements, and X-ray crystallography were applied to determine the structures of [Y(5)(OH)(5)(L-Val)(4)(Ph(2)acac)(6)] (1) (Ph(2)acac=dibenzoylmethanide, L-Val=L-valine), [Y(2)(OTf)(3)] (3), and [Y(2)(4)(OTf)(5)] (5) (2: [(S)P{N(Me)N=C(H)Py}(3)], 4: [B{N(Me)N=C(H)Py}(4)](-)) in solution and in the solid state. The structures found in the solid state are retained in solution, where averaged structures were observed. NMR diffusion measurements helped us to understand the nuclearity of compounds 3 and 5 in solution. (1)H,(19)F HOESY and (19)F,(19)F EXSY data revealed that the anions are specifically located in particular regions of space, which nicely correlated with the geometries found in the X-ray structures.

HSQC-1,n -ADEQUATE: a new approach to long-range 13 C13 C correlation by covariance processing

Long-range, two-dimensional heteronuclear shift correlation NMR methods play a pivotal role in the assembly of novel molecular structures. The well-established GHMBC method is a high-sensitivity mainstay technique, affording connectivity information via (n)J(CH) coupling pathways. Unfortunately, there is no simple way of determining the value of n and hence no way of differentiating two-bond from three- and occasionally four-bond correlations. Three-bond correlations, however, generally predominate. Recent work has shown that the unsymmetrical indirect covariance or generalized indirect covariance processing of multiplicity edited GHSQC and 1,1-ADEQUATE spectra provides high-sensitivity access to a (13)C-(13) C connectivity map in the form of an HSQC-1,1-ADEQUATE spectrum. Covariance processing of these data allows the 1,1-ADEQUATE connectivity information to be exploited with the inherent sensitivity of the GHSQC spectrum rather than the intrinsically lower sensitivity of the 1,1-ADEQUATE spectrum itself. Data acquisition times and/or sample size can be substantially reduced when covariance processing is to be employed. In an extension of that work, 1,n-ADEQUATE spectra can likewise be subjected to covariance processing to afford high-sensitivity access to the equivalent of (4)J(CH) GHMBC connectivity information. The method is illustrated using strychnine as a model compound.

Assignment of the 15N resonances of the antifungal agent posaconazole

The structurally complex antifungal agent posaconazole has been well characterized by conventional 1H- and 13C-NMR studies. In contrast, 15N resonance assignments have never been reported. We now wish to report the assignment of the eight 15N resonances of posaconazole using two-dimensional long-range 1H-15N GHMBCAD NMR data. The 15N resonance assignments were undertaken to facilitate the evaluation of the impact of 1H-15N heteronuclear shift correlation data in the Computer-Assisted Structure Elucidation (CASE) of complex molecular structures. J. Heterocyclic Chem., (2011).

Long‐range 1H15N heteronuclear shift correlation across wide F1 spectral windows

Long-range (1)H-(15)N heteronuclear shift correlation experiments at natural abundance are becoming more routinely utilized in the characterization of unknown chemical structures from a diverse range of sources including natural products and pharmaceuticals. Apart from the inherent challenges of the low gyromagnetic ratio and natural abundance of (15)N, investigators are also occasionally hampered by having to deal with the wide spectral range inherent to various nitrogen functional groups, which can exceed 500 ppm. Earlier triple resonance cryoprobe designs typically provided 90° (15)N pulses in the range of 35-40 µs, which did not allow the uniform excitation of wide F(1) spectral ranges for (1)H-(15)N GHMBC spectra. We report the results obtained with a newly designed Bruker 600 MHz triple resonance TCI Micro CryoProbe™ using methyl orange as a model compound, in which the (15)N resonances are separated by >450 ppm.

NMR study of the spatial structure of synthetic pyrethroids

The spatial isomers of the new synthetic analogs of ethyl permithrinic ether and permethrin were investigated by NMR (1H, 13C, DEPT (distortionless enhancement by polarization transfer), COSY (correlation spectroscopy), CHCORR (heteronuclear (C, H) shift correlation spectroscopy), ROESY (rotating-frame Overhauser effect spectroscopy)). Several tendencies were revealed in the 1H and 13C chemical shifts of the α atoms of the substituents in the 2nd and 3rd positions of the cyclopropane ring. For substituents cis-orientated relative to the ester group, the spectra show a paramagnetic shift of the 1H signals and the diamagnetic shift of the 13C signals relative to the trans-orientated substituents. The 1H and 13C chemical shifts of the α atoms of the substituents in the 2nd and 3rd positions of the cyclopropane ring permit an unambiguous determination of the stereochemistry of ethyl permethrinic ether and permethrin analogs.

Inverse H‐C ex situ HRMAS NMR experiments for solid‐phase peptide synthesis

The growing importance of solid-phase peptide synthesis (SPPS) has necessitated the development of spectroscopic experiments that can be used to obtain structural and conformational information on resin-bound peptides. Despite the utility of two-dimensional high-resolution magic angle spinning (HRMAS) NMR experiments that provide homonuclear shift correlations, experiments that provide heteronuclear shift correlations are necessary for complex conformational and structural elucidatory problems. Here we report the optimization and implementation of non-gradient inverse NMR experiments for acquiring the 1H-13C shift correlations of resin-bound peptides. The use of non-gradient experiments is advantageous as many magic angle spinning (MAS) probes do not possess gradient coils. An HRMAS BIRD-HMQC experiment with a reduced 1JCH constant has proven very suitable for obtaining one-bond correlations. Long-range correlations can be interpolated by using a non-gradient HRMAS CT-HMBC-1 experiment where the resulting data is processed with forward linear prediction. It has been shown that removing the effects of 1H-1H J-modulation is crucial in order to view cross peaks that correspond to long-range correlations. Additionally, both experiments prove extremely useful over routine one-dimensional 13C HRMAS experiments for extracting carbon chemical shift data. The non-gradient HRMAS BIRD-HMQC and CT-HMBC-1 experiments can be used to assist in conformational analysis and to identify and deconvolute situations where accidental equivalence and seemingly correlated isochronous signals arise.

Application of biselective refocusing soft pulses to the simplification of heteronuclear correlation spectra

The biselective spin echo technique allows the signals of coupled proton pairs to be extracted from crowded liquid state proton NMR spectra. Its use as a preparation sequence in heteronuclear chemical shift correlation experiments requires the removal of the heteronuclear coupling interaction during the biselective echo time. The discrimination between coupled and uncoupled protons signals is achieved by double quantum filtration, which delivers antiphase magnetization states. The latter are not directly compatible with the design of an HSQC-like pulse sequence. The conversion of antiphase to in-phase magnetization states by a second biselective echo sequence solves this problem. The optimization of spin echo delays is also discussed. Lastly, the article presents modified HSQC and HMBC pulses sequences in which information is obtained solely for the biselectively selected proton pairs. A peracetylated trisaccharide was used as a test molecule.

Phosphorus−Nitrogen Compounds. 14. Synthesis, Stereogenism, and Structural Investigations of Novel N/O Spirocyclic Phosphazene Derivatives

The reactions of hexachlorocyclotriphosphazatriene, N3P3Cl6, with N/O donor-type N-alkyl-o-hydroxybenzyl- and o-hydroxynaphthylamines result in novel mono- (3a, 4a and 4b), di- (5a and 5b), and tri- (3b, 6a, and 6b) spirocyclic phosphazene derivatives. The tetrakis-pyrrolidinophosphazene, 3b, has been obtained from the reaction of partly substituted compound 3a with the excess pyrrolidine in tetrahydrofuran. The relationship between the endocyclic NPN (alpha) and exocyclic NPO (alpha') bond angles of the analogous spirocyclic phosphazenes with the deltaP shifts of NPO phosphorus atoms have been presented. It was observed that there is a linearity between alpha angles and deltaP shifts, while no linear relationship has been observed for alpha' angles. In addition, we have found the correlation between Delta(P-N) and deltaNPO shifts, which implies a linear relationship. Delta(P-N)=(a-b), where a and b are the average lengths of two adjacent P-N bonds. The structural investigations of all of the compounds have been made by elemental analyses; mass spectrometry; Fourier transform infrared spectroscopy; one-dimensional 1H, 13C, and 31P NMR; distortionless enhancement by polarization transfer; and two-dimensional correlation spectroscopy, heteronuclear shift correlation, and heteronuclear multiple-bond correlation homo- and heteronuclear correlation techniques. The solid-state structures of 3a, 4a, 4b, and 5a have been determined by X-ray crystallographic techniques. The asymmetric units of compounds 3a and 4a contain two independent molecules, and 3a has strong intermolecular N-H...N hydrogen bonds linking three phosphazene rings. The molecular structure of 6a looks like a propeller where the chemical environment of P1 is different from that of P2 and P3. On the other hand, compounds 5a and 5b are expected to exist as cis- or trans-geometric isomers and to be in cis (meso) or trans (racemic) configurations. The crystallographic and preliminary chiral solvating agents results show that both of them are trans (racemic). In addition, 6a and 6b are also expected to exist as cis-trans-trans- and cis-cis-cis-geometric isomers; both of them are found to be in cis-trans-trans geometries. According to the two-dimensional spectroscopic data, the possible conformations of 3a and 4a in CDCl3 are the same with the solid-state structures.

13C‐15N Connectivity networks via unsymmetrical indirect covariance processing of 1H‐13C HSQC and 1H‐15N IMPEACH spectra

Abstractmagnified imageLong‐range 1H‐15N heteronuclear shift correlation methods at natural abundance to facilitate the elucidation of small molecule structures have assumed a role of growing importance over the past decade. Recently, there has also been a high level of interest in the exploration of indirect covariance NMR methods. From two coherence transfer experiments, A→B and A→C, it is possible to indirectly determine B⟷C. We have shown that unsymmetrical indirect covariance methods can be employed to indirectly determine several types of hyphenated 2D NMR data from higher sensitivity experiments. Examples include the calculation of hyphenated 2D NMR spectra such as 2D GHSQC‐COSY and GHSQC‐NOESY from the discrete component 2D NMR experiments. We now wish to report the further extension of unsymmetrical indirect covariance NMR methods for the combination of 1H‐13C GHSQC and 1H‐15N longrange (GHMBC, IMPEACH‐MBC, CIGAR‐HMBC, etc.) heteronuclear chemical shift correlation spectra to establish 13C‐15N correlation pathways.