Measurement and Applications of Long‐Range Heteronuclear Scalar Couplings: Recent Experimental and Theoretical Developments

Abstract

The use of long-range heteronuclear couplings, in association with (1)H-(1)H scalar couplings and NOE restraints, has acquired growing importance for the determination of the relative stereochemistry, and structural and conformational information of organic and biological molecules. However, the routine use of such couplings is hindered by the inherent difficulties in their measurement. Prior to the advancement in experimental techniques, both long-range homo- and heteronuclear scalar couplings were not easily accessible, especially for very large molecules. The development of a large number of multidimensional NMR experimental methodologies has alleviated the complications associated with the measurement of couplings of smaller strengths. Subsequent application of these methods and the utilization of determined J-couplings for structure calculations have revolutionized this area of research. Problems in organic, inorganic and biophysical chemistry have also been solved by utilizing the short- and long-range heteronuclear couplings. In this minireview, we discuss the advantages and limitations of a number of experimental techniques reported in recent times for the measurement of long-range heteronuclear couplings and a few selected applications of such couplings. This includes the study of medium- to larger-sized molecules in a variety of applications, especially in the study of hydrogen bonding in biological systems. The utilization of these couplings in conjunction with theoretical calculations to arrive at conclusions on the hyperconjugation, configurational analysis and the effect of the electronegativity of the substituents is also discussed.

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

“…It turns out that 1D 13 C‐selective HMBC experiments can used for accurately measuring long‐range coupling constants of any size. The 1D experiment is most advantageously if only a few n J CH values for structural elucidation, have to be determined, as described and demonstrated elsewhere …”

Measurement of long‐range heteronuclear coupling constants using the peak intensity in classical 1D HMBC spectra

“…The most effective methods have been reviewed first by Marquez et al . and more recently by Suryaprakash, Parella and Espinosa, and Butts et al . Hereafter, we will refer exclusively to 1 H– 13 C coupling constants, but the discussed methods can be applied implicitly to other heteronuclei.…”

“…During the last 30 years, a large number of 1D and 2D NMR methods have been proposed for the measurement of these coupling constants in small molecules in solution. The most effective methods have been reviewed first by Marquez et al [4] and more recently by Suryaprakash, [5] Parella and Espinosa, [6] and Butts et al [7] Hereafter, we will refer exclusively to 1 H-13 C coupling constants, but the discussed methods can be applied implicitly to other heteronuclei.…”

CSSF-CLIP-HSQMBC: measurement of heteronuclear coupling constants in severely crowded spectral regions

“…Long-range heteronuclear scalar couplings contain important information about molecular relative conguration, structure identity and structural conformation. [1][2][3][4] The size of these couplings are in the same range as proton-proton scalar couplings, 0-15 Hz, but are generally more complicated to measure accurately. There is a large number of different pulse sequences available for the measurement of long range heteronuclear scalar couplings, mainly divided into TOCSY basedand HMBC/HSQMBC-based methods.…”