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

Higgs, PL, Ruiz-Sanchez, AJ, Dalmina, M, Horrocks, BR, Leach, AG and Fulton, DA (2019) Enhancing the kinetics of hydrazone exchange processes: an experimental and computational study. Organic & Biomolecular Chemistry. ISSN 1477-0520

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Royal Society of Chemistry (RSC)
Date Deposited: 19 Mar 2019 10:09
Last Modified: 20 Mar 2019 12:21
DOI or Identification number: 10.1039/c9ob00058e
URI: http://researchonline.ljmu.ac.uk/id/eprint/10363

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