Crews' rule—Still useful but often misquoted

Unequivocal identification of two-bond heteronuclear correlations in natural products at nanomole scale by i-HMBC

“…Accurate measurement of 2-n Δ 1 H( 13/12 C) isotope shift by i-HMBC Considering that the natural isotopic abundance of NMR active 13 C is approximately 1.1%, the two-bond (H a to C b ) and three-bond (H a to C c ) HMBC correlations in a C a H-C b -C c spin system are principally comprised of the isotopomers, 12 C a H- 13 C b - 12 C c and 12 C a H-12 C b - 13 C c , respectively, while the H a signal in the 1 H NMR spectrum is dominated by the 12 C a H- 12 C b -12 C c isotopomer. Comparing the chemical shifts of H a in the HMBC correlation versus the 1 H spectrum, a two-bond isotope shift 2 Δ 1 H a ( 13/12 C) and a three-bond isotope shift 3 Δ 1 H a ( 13/12 C) would be expected for the two-and three-bond HMBC correlations, respectively.…”

“…However, this limitation is problematic for proton-deficient compounds with a preponderance of quaternary carbons or heteroatoms, and has led to frequent "guesswork" to elucidate the carbon skeleton from HMBC correlations, due to the inability to differentiate the number of bonds between atoms. This tedious and errorprone workflow has frequently yielded inconclusive or misassigned structures, leading to the heuristic "Crews rule"a low ratio of H/C (<1:1) could complicate or even prevent unequivocal structure elucidation using the conventional suite of 2D NMR experiments (e.g., COSY/TOCSY, HSQC, HMBC, and NOESY/ROESY) [10][11][12][13] .Recent advancements of NMR techniques have led to the unambiguous structure elucidation of proton-deficient compounds that meet Crews' rule. Particularly, the atom connectivity of a C a H-C b spin system, where C b is a quaternary carbon, can be directly determined using the 1,1-ADEQUATE experiment, which utilizes 1 J CH and 1 J CC 14-19 .…”

“…However, this limitation is problematic for proton-deficient compounds with a preponderance of quaternary carbons or heteroatoms, and has led to frequent "guesswork" to elucidate the carbon skeleton from HMBC correlations, due to the inability to differentiate the number of bonds between atoms. This tedious and errorprone workflow has frequently yielded inconclusive or misassigned structures, leading to the heuristic "Crews rule"a low ratio of H/C (<1:1) could complicate or even prevent unequivocal structure elucidation using the conventional suite of 2D NMR experiments (e.g., COSY/TOCSY, HSQC, HMBC, and NOESY/ROESY) [10][11][12][13] .…”

“…However, both methods have notable limitations. 1,1-ADEQUATE, which relies on magnetization transfer through two consecutive 13 C nuclei at natural abundance, is inherently about two orders of magnitude less sensitive than HMBCbased approaches for compounds without 13 C labeling. Thus, it usually requires several milligrams of material in combination with the use of a cryogenically-cooled NMR probe.…”

Ominoxanthone—The First Xanthone Linearly Fused to a γ-Lactone from Cortinarius ominosus Bidaud Basidiomata. CASE- and DFT-Based Structure Elucidation

“…The so-called Crews’ rule foresees that NMR-based structure elucidation is at high risk of being inaccurate when the ratio of H/C atoms is less than one, as it is the case here [ 15 ]. The scarce information available from the NMR data of such structures is likely to result in several possible candidates, and it is therefore important to ensure that all possibilities have been duly considered [ 16 ].…”