Ultrafast Formation of Aza-Quinone Methides from Suitably Substituted o-Hydroxymethylanilines Involves Higher Excited States

Su, Yifan; Došlić, Nađa; Martinović, Manuel; Glavaš, Mladena; Draženović, Josip; Ma, Jiani; Basarić, Nikola (2026) Ultrafast Formation of Aza-Quinone Methides from Suitably Substituted o-Hydroxymethylanilines Involves Higher Excited States. Journal of the American Chemical Society, 148 (17). pp. 17662-17674. ISSN 0002-7863

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Abstract

Aza-quinone methides (aza-QMs) are important intermediates for the synthesis of aza-heterocycles, yet mild methods for their generation remain scarce. Here, we combine experimental and theoretical studies to guide the rational design of aza-QM precursors in efficient photoreactions. Photochemical elimination of H2O from 2-aminobenzyl alcohol (1) serves as a promising starting point. We show that aza-QM formation from 1 is a relatively slow, multistep process involving heterolytic cleavage on the first singlet excited state (S1), formation of a contact ion pair, relaxation to the ground state (S0), and final deprotonation. In the newly designed N-Boc-O-Ac-aminobenzyl alcohol (5), the Boc group increases NH acidity and enforces a reactive conformation, while replacement of OH with an acetyl group introduces a low-energy nπ* state. Benzylic C–O bond elongation stabilizes this state, promoting OAc elimination and enabling a highly efficient pathway. Aza-QM generation from 5 is an ultrafast, intermediate-free process that proceeds via conical intersections from 5 (S1) to the aza-QM in S0. Notably, in 5, and possibly in 1, the benzylic C–O bond cleavage ultimately occurs along their respective dissociative nσ* states. We hope that these mechanistic insights will enable rational design of aza-QM precursors in multistep organic synthesis and in biological applications, where precise control of reactive intermediates is essential to avoid undesired interactions with biomolecular substrates.

Item Type:	Article
Uncontrolled Keywords:	aza-quinone methides; nonadiabatic surface hopping molecular dynamics simulations; quantum calculations; transient absorption spectroscopy
Subjects:	NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Theoretical Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions:	Division of Physical Chemistry
Depositing User:	Martina Žugaj
Date Deposited:	29 May 2026 09:45
URI:	https://fulir.irb.hr:/id/eprint/12001
DOI:	10.1021/jacs.5c21621

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