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

Abstract

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.

Why is HMBC superior to LR‐HSQC? Influence of homonuclear couplings JHH′ on the intensity of long‐range correlations

“…Heteronuclear long‐range correlation experiments correlate protons and heteronuclei exploiting n J HX long‐range couplings. The experiments are essential to connect structural fragments across nonprotonated carbons or heteroatoms . Prior to the introduction of proton‐detected NMR methods, experiments such as long‐range heteronuclear correlation (HETCOR) and FLOCK were used for this purpose .…”

“…The combination of CT‐HMBC, sensitivity enhanced HMBC, an efficient low‐pass J filter (for suppressing unwanted 1 J XH artifacts), and of the acceleration by sharing adjacent polarization (ASAP) building block, that significantly enhances the sensitivity and allows reducing the measurement time, has led to the improved and accelerated constant‐time HMBC experiment (IMPACT‐HMBC), which is probably the most useful and efficient sequence derived from the classical HMBC . Most of these methods have been discussed in a number of reviews, and the interested reader is referred to these for a more in‐depth treatment of long‐range heteronuclear correlation methods …”

D‐HMBC versus LR‐HSQMBC: Which experiment provides theoretically and experimentally the best results?

“…Strychnine is readily available and has been used as a standard in many NMR studies. [6,15,[30][31][32] Although the intensities of corresponding long-range correlation cross peaks are in most cases higher in the D-HMBC spectrum compared with the LR-HSQMBC, the results are also inconsistent and highly dependent on the number and size of the involved couplings and on the experimental parameters as theoretically predicted. This is corroborated in Figures 10 and 11, where LR-HSQMBC exhibits long-range correlations that are significantly weaker in the D-HMBC spectrum and viceversa.…”

“…We utilized strychnine (Figure ) as the classical model compound to compare the performance of the LR‐HSQMBC and the D‐HMBC sequences (Figures and S3–S8). Strychnine is readily available and has been used as a standard in many NMR studies …”

The use of indirectly bonded 13C‐1H (INCH) shift correlation spectra for ab initio structure elucidation of natural products and other complex organic compounds; A personal and historical perspective

“…In an attempt to overcome this problem, several pulse sequences have been developed. 48 I will discuss four in particular. They all rely, in different ways, on a common, generally valid, assumption, ie, that 3 J HH ≫ 4 J HH.…”