Additional pitfalls of using 1,1-ADEQUATE for structure elucidation

Abstract

1,1-ADEQUATE is a powerful and robust NMR experiment to establish carbon-carbon connectivities using modest sample quantities when cryogenic probe technology is available. Yet potential pitfalls of applying this method are not widely appreciated, such as weak or missing J correlations in strongly coupled C- C AB spin systems and unusually large multi-bond ( J ) correlations associated with particular functional groups. These large J correlations observed in 1,1-ADEQUATE spectra could be mistaken for J correlations. Copyright © 2016 John Wiley & Sons, Ltd.

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

“…In this report, we will show examples of commercially available pyrimidine analogs with different electronegative substituents to illustrate that relatively large 3 J CC correlations from position 2 to position 5 can be observed in 1,1‐ADEQUATE spectra with considerable intensity. The present study further expands our understanding of potential untoward n J CC correlations that may be observed in 1,1‐ADEQUATE spectra …”

“…The intensities of correlations observed in the ADEQUATE spectra acquired for small molecules are primarily governed by the congruence of the actual carbon–carbon coupling constant and the delay optimization for the 1 J CC transfer, which is typically in the range of 40 to 60 Hz. As previously reported, large multiple‐bond correlations can give rise to observable correlations in 1,1‐ or 1,1‐HD‐ADEQUATE spectra . For aromatic compounds, such as pyrimidine derivatives, a good optimization delay for the 1 J CC transfer step would be 60 Hz due to the aromatic nature of the molecule.…”

“…We have reported, for instance, that large 2 J CC across carbonyls can be seen in 1,1-ADEQUATE spectra or that large 3 J CC may be observed in pyrazine-like compounds. [15,16] In the former case, a 2 J CC correlation was observed across the carbonyl as shown for the natural product cryptospirolepine (structure 1). [9] Even though the small quantity of the alkaloid available precluded the measurement of the coupling constant, the density functional theory (DFT)-calculated 2 J CC coupling constant was 15.6 Hz.…”

“…If data acquisition parameters are not carefully considered, observation of these correlations could lead to a potential structural misassignment and thereby to incorrectly reported structures. We have reported, for instance, that large 2 J CC across carbonyls can be seen in 1,1‐ADEQUATE spectra or that large 3 J CC may be observed in pyrazine‐like compounds …”

“…3 J CC correlations were later observed in pyrazine analogs obtained from photocatalyzed C─H hydroxymethylation reactions whose structural characterization required the acquisition of 1,1‐ADEQUATE spectra . Nitrogen‐containing compounds, such as pyrazines, pyrimidine, and purine derivatives, have been widely exploited in drug discovery programs over the years .…”