Paper
Organic & Biomolecular Chemistry
also the mechanistically similar processes of imine and oxime
formation.
Conflicts of interest
There are no conflicts of interest.
Conclusion
Acknowledgements
We have demonstrated that the judicial placement of neigh-
bouring hydrogen-bond acceptors within the carbonyl-derived
moiety of a hydrazone does lead to enhancements in rates of
hydrazone exchange. Computational modelling identified a
likely reaction pathway for this process whose energetics were
consistent with experimentally determined exchange rates.
Modelling supported the hypothesis that the rate-determining
step in hydrazone exchange was nucleophilic attack on the pro-
tonated hydrazone, which is an important distinction between
hydrazone exchange and hydrazone formation, where the rate-
limiting step is collapse of the carbinolamine tetrahedral inter-
mediate. Crucially, modelling indicated that the origin of the
observed rate enhancements lies in the ability of neighbouring
functional groups to form a stabilizing hydrogen bonds within
the transition state, and that geometries where 6-membered
ring intramolecular hydrogen bonding interactions can be
adopted are particularly important. Our confidence in this
model was demonstrated by its prediction that a benzoDHP
group – containing a very weakly basic but optimally placed
oxygen atom that acts as a hydrogen-bond acceptor – displayed
fast exchange kinetics, which was gratifyingly supported by
experimental observation. Preliminary experiments revealed
that chroman-8-carbaldehyde (from which BenzoDHP 1g was
derived) also catalyses rapid hydrazone formation. Surprisingly,
chroman-8-carbaldehyde was found to react 15-fold faster than
previously reported quinoline-8-carbaldehyde,6a despite its lack
of an acidic/basic group. These observations suggest that the
inclusion of hydrogen-bond acceptor moieties within the alde-
hyde component may also play an important role in catalysing
hydrazone formation, alongside the previously reported6a–d cata-
lytic effect of proximal acid/base groups. At neutral pD,
benzoDHP 1g was observed to afford an 2-fold enhancement in
the rate of hydrazone exchange, compared to that of quinoline
1a, and was 10-fold faster than control hydrazone 1d. With
regards to our own interest in dynamic combinatorial chemistry,
our work suggests that valuable gains in rate of exchange can be
made that would allow the design of a polymer-scaffolded
DCLs12 operating with reasonable kinetics at near-neutral pH –
a crucial requirement for interfacing DCLs with biomacro-
molecules.13 Furthermore, given the importance of hydrazone
exchange within dynamic covalent polymers,14 materials,15 sur-
faces,16 molecular machines,17 interlocked molecules,18 cages19
and functionalized nanoparticles,20 where component exchange
processes endow structural adaptivity, we speculate this work
will offer insight to the design and optimization of new
systems. We also anticipate our work will benefit the develop-
ment of new organocatalysts for hydrazone/oxime formation
and exchange processes, indicating that computational studies,
on account of their ability to ‘pick winners’, might minimise
tedious preliminary screenings for catalytic activity.
The authors wish to thank Dr Rachael Dack (Newcastle
University) and Dr Jackie Mosely (Durham University) for
assistance with HRMS.
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