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One Step at Time: Most Nucleophilic Aromatic Substitutions are Concerted

A new NMR-based method for determining kinetic isotope effects (KIEs) in fluorination reactions overturns the textbook picture of nucleophilic aromatic substitutions (SNAr).

Go to the profile of Eugene Kwan
Jul 16, 2018
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The paper in Nature Chemistry is here: https://www.nature.com/articles/s41557-018-0079-7

The discovery of nucleophilic aromatic substitution (SNAr) pathways dates back to the early 20th century, yet, despite all the extraordinary advances in cross-coupling and related reactions, SNAr remains by some measures the second most frequently used reaction class in medicinal chemistry. For decades, textbooks have described the mechanism as a two-step sequence with an intervening Meisenheimer intermediate:

This depiction persists despite extensive computational work that predicts one-step, or “concerted,” SNAr pathways. In 2016, the Ritter group provided compelling experimental evidence that certain nucleophilic aromatic fluorinations indeed proceed by concerted mechanisms. This fascinating study led us to ask just how general concerted SNAr reactions might be.

To study some representative reactions, we applied a method we recently developed for the accurate measurement of 12C/13C kinetic isotope effects (KIEs) at fluorine-bearing carbons. We first studied reaction A, which had been established previously to proceed via a stepwise mechanism:

The anionic intermediate is thermodynamically stabilized by two electron-withdrawing nitro groups and kinetically stabilized towards elimination by two poor leaving groups (fluoride and methoxide). Both the predicted and measured KIEs at the carbon undergoing substitution were found to be small, consistent with a stepwise mechanism with rate-determining elimination.

In contrast, the predicted and measured KIEs for reaction B are large:

The putative Meisenheimer complex is now much less stable because the substituent on the ring is only moderately electron-withdrawing. The complex is also more reactive because it contains an excellent leaving group (bromide). Elimination becomes so fast that it happens simultaneously with addition—a concerted mechanism.

The excellent agreement between the theoretical and experimental KIEs for both the stepwise and concerted reactions validates DFT calculations as an accurate probe of SNAr mechanisms. We proceeded to model 120 additional SNAr reactions spanning a range of typical ring types, nucleophiles, and leaving groups. We found that stepwise mechanisms occur only 17% of the time, and only when a NO2 ring substituent is present and fluoride is the leaving group. Heterocycles, which are the most common substrates for substitutions in medicinal chemistry, were found to follow exclusively concerted pathways.

Concerted substitutions on the sp2 centers of aromatic rings are usually thought to be disfavored because the antibonding orbital of the breaking bond is inaccessible. However, in SNAr reactions, rehybridization can occur as the nucleophile approaches, tilting the breaking bond out of planarity and aligning it for cleavage. The result is a non-aromatic “Meisenheimer transition state.”

The measurement of carbon KIEs at natural abundance is a powerful mechanistic tool, but applications have been hampered by technical factors. Here, we have developed an ultrasensitive method for measuring KIEs at carbons that are adjacent to fluorine: multiple-quantum-filtration (MQF). MQF makes it possible to measure KIEs with only 10 mg of natural abundance material in a single overnight run! We hope our method will enable the study of other reactions that involve C–F bond formation or cleavage.

Interested in applying our methods? Software and detailed tutorials are freely available at www.github.com/ekwan/PyKIE.

Written by Eugene Kwan and Eric Jacobsen

Go to the profile of Eugene Kwan

Eugene Kwan

Researcher, Harvard University

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