Observation of potentially troublesome 2 J CC correlations in 1,1-ADEQUATE spectra

Magnetic Reson in Chemistry

Cohen

et al. 2018

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Recently, it has been reported that large J correlations can sometimes be observed in 1,1-ADEQUATE spectra with significant intensity, which opens the possibility of structural misassignment. In this work, we have focused on pyrimidine-based compounds, which exhibit multiple bond correlations in the 1,1-ADEQUATE experiment as a consequence of J coupling constants greater than 10 Hz. Results are supported by both the experimental measurement of J coupling constants in question using J-modulated-ADEQUATE and density functional theory calculations.

Section: Introductionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Observation of untoward ³J_cc correlations in 1,1‐ADEQUATE spectra of pyrimidine analogs: Avoiding potential interpretation pitfalls

Kim

Magnetic Reson in Chemistry

Cohen

et al. 2018

Self Cite

Advances in NMR‐Based Characterization of Drug Substances, Impurities, Degradants, and Drug Metabolites

Burger's Medicinal Chemistry and Drug Discovery

Reibarkh

Williamson

et al. 2021

In the approximately 70 years since the first reports of experiments that led to what is now known as nuclear magnetic resonance or NMR spectroscopy, the technique has become the cornerstone of molecular structure characterization. From the isolation of strychnine to the confirmation of its complex structure in a total synthesis reported by Woodward consumed a century and a half. In contrast, using a modern 600 MHz NMR instrument equipped with a 1.7 mm MicroCryoProbe™, that task can now be accomplished in 24 hours, including the acquisition of 15 N chemical shift information on a few milligrams of sample. Such is the magnitude of the advances that have been made in the discipline. This article is not intended to make NMR spectroscopists out of a practicing medicinal chemistry; rather, the article is intended to acquaint the reader with recent advances in NMR techniques that are making it possible to successfully and unequivocally characterize ever increasingly more complex structures being synthesized in the laboratory as potential drug candidates or isolated from nature. Our goal was to augment the NMR knowledge of the medicinal chemist, better equipping him or her to more effectively interact with the NMR spectroscopy staff at the chemist's facility. The article begins with a discussion of new experimental methods that allow the acquisition of broadband decoupled 1 H NMR spectra that resemble an 1 H‐decoupled 13 C spectrum, with every proton resonance reduced to a singlet. Pure‐shift heteronuclear shift correlation methods are described next, followed by new long‐range heteronuclear chemical shift correlation experiments and then hyphenated techniques to identify components of complex, overlapped proton homonuclear spin systems. Techniques are also described for the unequivocal identification of vicinal neighbor carbon resonances that can be invaluable when dealing with complex impurities or degradation products. Covariance NMR data processing methods that allow 2D NMR experiments to be treated as large numerical matrices that can be manipulated using matrix algebraic operations are briefly discussed. Finally, anisotropic NMR methods are considered, which afford investigators the means of orthogonally verifying chemical structure constitution and configuration without investigator bias that often can lead to erroneously assigned structures. The latter eventuality, of course, can slow development timelines or could potentially have devastating patent protection consequences and regulatory implications.

A Comprehensive Discussion of HMBC Pulse Sequences: 4. Establishing Two‐Bond Correlations from HMBC and Related Experiments

Concepts Magnetic Resonance

Martin

Furrer

2015

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The utility of the HMBC experiment for structure elucidation is unquestionable, but the nature of the coupling pathways leading to correlations in an HMBC experiment creates the potential for misinterpretation. This misinterpretation potential is intimately linked to the size of the long‐range heteronuclear couplings involved, and may become troublesome in those cases of a particularly strong 2JCH correlation that might be mistaken for a 3JCH correlation or a 4JCH correlation of appreciable strength that could be mistaken for a weaker 3JCH correlation. To address these potential avenues of confusion, work from several laboratories has been focused on the development of what might be considered “coupling pathway edited” long‐range heteronuclear correlation experiments that are derived from or related to the HMBC experiment. The first example of an effort to address the problems associated with correlation path length was seen in the heteronucleus‐detected XCORFE experiment described by Reynolds and co‐workers that predated the development of the HMBC experiment. Proton‐detected analogs of the HMBC experiment intended to differentiate 2JCH correlations from nJCH correlations where n = 3, 4, include the 2J,3J‐HMBC, HMBC‐RELAY, H2BC, edited‐HMBC, and HAT H2BC experiments. The principles underlying the critical components of each of these experiments are discussed and experimental verification of the results that can be obtained using model compounds are shown. This contribution concludes with a brief discussion of the 1,1‐ADEQUATE experiments that provide an alternative means of identifying adjacent protonated and non‐protonated carbon correlations by exploiting 1JCC correlations at natural abundance.