How and why do substituents affect 1JCC couplings?

The molecular complexity of organic compounds (natural or synthetic) leads to spectroscopic challenges in the assignment of their structure. Quaternary carbons and hydrogen-deficient moieties are particularly challenging due to the scarcity of correlations in classical 2D experiments (e.g., HSQC, COSY, HMBC) used for structure elucidation. Structure elucidation of hydrogen-deficient molecules requires use of more complicated and time-consuming experiments, such as 1,n-ADEQUATE and its variations.[1]
Pulse sequences of these experiments contain delays that must be optimized based on the 1JCC (or nJCC) to obtain spectral data suitable for unambiguous interpretation. Wrong delays could lead either to the absence of some 1JCC correlations or to the presence of additional apparent 1JCC correlations that are in fact nJCC. Both scenarios could easily lead to erroneous structural assignments. Understanding relevant 1JCC values is therefore necessary in order to properly set up and acquire experiments of the ADEQUATE family.
Recently developed J-modulated 19F- and 1H-detected dual-optimized inverted 1JCC 1,n-ADEQUATE experiments [2] revealed a significant difference in 1JCC values between 4-(dimethylamino)phthalonitrile and 4-(dimethylamino)-3,5,6-trifluorophthalonitrile. Experimental data indicate that 1JCC coupling is up to 30% larger in the fluorinated molecule compared to its non-fluorinated analog.[2]
Our present work is aimed at developing understanding and rationalizing the impact of fluorine and other typical substituents (i.e., withdrawing or electron-donating groups) on 1JCC coupling constants. Our theoretical investigation suggests that this difference is due to the s character in the CC-bond, which can be rationalized in terms of Bent’s rule.
[1] a) Sørensen, Ole W., et. al. J. Magn. Reson. 1982;46:180-184; b) Reibarkh, Mikhail et al., J. Magn. Reson. 2013;236;126-133; c) Raab, Jeffrey, et al. Magn. Reson. Chem. 2021;59:628–640.
[2] Crouch, Ronald C., et al. Magn. Reson. Chem. 2023;61:169–179.
We thank Merck and Co. for their partnership and experimental measurements, and CAPES, PROEX, FAEPEX, and FAPESP (2020/10246-0) for financial support.