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RESEARCH HIGHLIGHTS Nature Reviews Chemistry | https://doi.org/10.1038/s41570-020-0211-2 | Published online 7 July 2020 ELECTRONIC INTERACTIONS nitro group — usually considered to be strongly electron withdrawing — could exert an influence similar to that of an electron-donating group Feeling the effects when it was oriented to point back- wards over a biaryl ring. Similarly, When studying reaction mechanisms, were far more important than many the classical electron-donating the effects of small changes in sub- had thought. We were keen to see influence of methoxy or hydroxyl Our expecta- strate structure on reaction outcome whether we could reproduce this substituents could be switched off, tions derived and rate are often rationalized by in an experimental model in the or even inverted by twisting the considering the electron-donating presence of a solvent.” orientation of the substituent. “These from simple or electron- withdrawing properties Cockroft and co-workers studied observations can only be rationalized textbook of a particular substituent. Indeed, a series of 25 ‘molecular balances’ if through- space electrostatic field electron these terms are a key component in which the electronic effect of effects dominate over through- bond donation/ of undergraduate teaching in substituents can be measured by its contributions,” he continues. organic chemistry. They are usually influence on the conformational Terms such as ‘electron donating’ withdrawal considered almost entirely as being equilibrium of a nearby formamide. and ‘electron withdrawing’ have considerations through- bond effects, but recently A substituent inducing a positive proved highly useful in teaching were turned questions have been raised about electrostatic potential would the basic principles of organic on their head the relative importance of simple favour a conformation in which chemistry, but this work shows that through- space interactions. Now, the electron- rich oxygen atom they can often be mechanistically Scott Cockroft and co-workers from of the carbonyl group was in closest misleading when going beyond the University of Edinburgh have proximity to the substituent, while simple textbook examples. “These built a series of molecules that enable a substituent inducing a negative terms should be strictly reserved for the direct experimental study of electrostatic potential would true delocalization influences such through- space effects and reached repel the oxygen. Similarly, they as resonance and hyperconjugation, some surprising conclusions. studied the N- methylation reactivity but even then we must consider, for “In 2008, Wheeler and Houk of a series of 17 phenylpyridine example, that much of the influence reported a seminal computational molecules. “It is a challenge to design of a nitro group is manifested study on the interactions between a system in which through-bond via electric fields, not by electron substituted benzenes,” explains influences are removed — there delocalization,” says Cockroft. Cockroft. “They showed that the sum are always bonds between the Beyond just improving mechanis- of isolated electrostatic potentials of substituent and the site where its tic understanding, however, Cockroft the ring and substituents provided a effects are manifested,” explains and co- workers see real applications remarkably good approximation of Cockroft. “We reasoned that a biaryl of these effects. “The through-space the interactions and thus suggested system would allow us to have effects of two nearby methoxy groups that through- space interactions substituents pointed ‘backwards’ can have a larger overall electronic towards the site where the effect effect than a conjugated nitrogen was measured and this would help lone- pair without any attendant H O minimize through- bond effects problem of side reactions,” he says. N and thus ensure that any measured “One might imagine such effects X effect would be largely the result of being exploited in ligand design F through- space electrostatics.” for catalysis.” Cockroft admits to being Stephen G. Davey X sceptical of the Wheeler–Houk model but was rapidly convinced ORIGINAL article Burns, R. J. et al. Quantifying through- space substituent effects. Angew. Chem. by the data they were able to collect. Int. Ed. https://doi.org/10.1002/anie.202006943 Me “Our expectations derived from (2020) N X N X RelateD article Wheeler, S. E. & Houk, K. N. k simple textbook electron donation/ Substituent effects in the benzene dimer are due withdrawal considerations were to direct interactions of the substituents with turned on their head,” he explains. the unsubstituted benzene. J. Am. Chem. Soc. 130, X X 10854–10855 (2008) Credit: Stephen G. Davey/Springer Nature Limited Nature Davey/Springer G. Stephen Credit: They found, for example, that a NATURE REVIEWS | CHEMISTRY VOLUME 4 | AUGUST 2020 | 385.

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