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Lookup NU author(s): Dr Patrick Higgs, Dr Antonio Ruiz-Sanchez, Milene Dalmina, Dr Ben Horrocks, Professor David Fulton
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Royal Society of Chemistry, 2019.
For re-use rights please refer to the publisher's terms and conditions.
© 2019 The Royal Society of Chemistry. The capacity of hydrazone bonds to readily undergo component exchange processes sees their extensive utilization in dynamic combinatorial chemistry. The kinetics of hydrazone exchange are optimal at pH ∼4.5, which limits the use of hydrazone-based dynamic combinatorial libraries, particularly for biological targets which are only stable at near-neutral pH values. It would thus be advantageous if hydrazone exchange proceeded with faster rates at pH values closer to neutral. We experimentally and computationally evaluated the hypothesis that hydrazones possessing neighbouring acidic or basic functional groups within the carbonyl-derived moitety of the hydrazone would enhance exchange rates. Our work suggests that judiciously placed N- or O-hydrogen bond acceptors within the carbonyl-derived moiety of the hydrazone stabilize transition states via hydrogen bonding interactions, providing a valuable boost to exchange kinetics at near-neutral pH values. We anticipate these findings will be of interest in dynamic combinatorial chemistry, dynamic covalent polymers/materials, functionalized nanoparticles and interlocked molecules, all of which may benefit from hydrazone exchange processes able to operate at near-neutral pH values.
Author(s): Higgs PL, Ruiz-Sanchez AJ, Dalmina M, Horrocks BR, Leach AG, Fulton DA
Publication type: Article
Publication status: Published
Journal: Organic and Biomolecular Chemistry
Year: 2019
Volume: 17
Issue: 12
Pages: 3218-3224
Online publication date: 26/02/2019
Acceptance date: 25/02/2019
Date deposited: 24/04/2019
ISSN (print): 1477-0520
ISSN (electronic): 1477-0539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/C9OB00058E
DOI: 10.1039/c9ob00058e
PubMed id: 30840013
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