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Enhancing the kinetics of hydrazone exchange processes: An experimental and computational study

Lookup NU author(s): Patrick Higgs, Dr Antonio Ruiz-Sanchez, Milene Dalmina, Dr Ben Horrocks, Dr David Fulton

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Royal Society of Chemistry, 2019.

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Abstract

© 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.


Publication metadata

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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