Cationic Multidentate Halogen-Bond Donors in Halide Abstraction Organocatalysis: Catalyst Optimization by Preorganization

In contrast to hydrogen
bonding, which is firmly established in
organocatalysis, there are still very few applications of halogen
bonding in this field. Herein, we present the first catalytic application
of cationic halogen-bond donors in a halide abstraction reaction.
First, halopyridinium-, haloimidazolium-, and halo-1,2,3-triazolium-based
catalysts were systematically tested. In contrast to the pyridinium
compounds, both the imidazolium and the triazolium salts showed promising
potency. For the haloimidazolium-based organocatalysts, we could show
that the catalytic activity is based on halogen bonding using, e.g.,
the chlorinated derivatives as reference compounds. On the basis of
these studies, halobenzimidazolium organocatalysts were then investigated.
Monodentate compounds featured the same trends as the corresponding
imidazolium analogues but showed a stronger catalytic activity. In
order to prepare bidentate versions which are preorganized for anion
binding, a new class of rigid bis­(halobenzimidazolium) compounds was
synthesized and structurally characterized. The corresponding syn
isomer showed unprecedented catalytic potency and could be used in
as low as 0.5 mol % in the benchmark reaction of 1-chloroisochroman
with a silyl enol ether. Calculations confirmed that the syn isomer
may bind in a bidentate fashion to chloride. The respective anti isomer
is less active and binds halides in a monodentate fashion. Kinetic
investigations confirmed that the syn isomer led to a 20-fold rate
acceleration compared to a neutral tridentate halogen-bond donor.
The strength of the preorganized halogen-bond donor seems to approach
the limit under the reaction conditions, as decomposition is observed
in the presence of chloride in the same solvent at higher temperatures.
Calorimetric titrations of the syn isomer with bromide confirmed the
strong halogen-bond donor strength of the former (K ≈ 4 × 106 M–1, ΔG ≈ 38 kJ/mol).