Upending a fundamental reaction in organic chemistry—discovery of a new nucleophilic substitution reaction

by School Of Physical And Mathematical Sciences, Nanyang Technological University , School of Physical and Mathematical Sciences, Nanyang Technological University

Schematics of the textbook SN2 nucleophilic substitution reaction, and the newly-discovered SN2X reaction. Credit: School of Physical and Mathematical Sciences, Nanyang Technological University

Nucleophilic substitution is a class of chemical reactions encountered throughout organic chemistry, including those used to manufacture common petrochemical and pharmaceutical products. Its underlying mechanism was discovered 82 years ago by the British chemists Edward Hughes and Christopher Ingold, who showed that an electron-rich chemical species, called a nucleophile, "attacks" and replaces an electron-poor fragment of an organic molecule, called a leaving group.

One of the main types of nucleophilic substitution reactions, called S N 2, involves the nucleophile attacking and the leaving group departing at the same time. Hughes and Ingold first made the observation, subsequently confirmed by generations of chemists, that S N 2 reactions all seemed to occur via "backside attack," whereby the nucleophile joins the organic molecule at a location opposite to the leaving group.

Although S N 2 reactions were believed to be understood, a new variant has been found by a group of scientists in Singapore. In an upcoming paper due to be published in the journal Science, a research group led by Professor Choon-Hong Tan of Nanyang Technological University (NTU) reports that SN2 reactions can also occur via "frontside attack," whereby the nucleophile approaches the molecule on the same side as the leaving group.

One of the key characteristics of a standard S N 2 reaction is that the nucleophile, in attempting a backside attack, is blocked by other parts of the molecule. This phenomenon, called "steric hindrance," imposes strict limits on how rapidly S N 2 reactions can happen. By contrast, the newly discovered reaction, which the researchers call S N 2X, occurs via frontside attack and is not prone to steric hindrance.

The discovery of the S N 2X reaction involved a considerable amount of chemical detective work. "We had to design our experiment to exclude the possibilities of several other types of reactions, as well as carefully checking that the reaction byproducts were consistent with our interpretation," commented Xin Zhang, an NTU graduate student who was the first author on the paper.