Zuerch Lab
Zuerch Lab

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New paper out: Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N–Aryl Azacycle Photomediated Ring Contractions
Feb 21 2024

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In our most recent joint work between organic chemistry and photochemistry, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

This research not only advances the synthetic utility of photomediated ring contraction but also sheds light on the mechanistic and photophysical aspects of photochemical systems. This work was jointly done between the Sarpong group, colleagues from Merck and Abbvie, and our group.

Published manuscript in the Journal of the American Chemical Society:

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