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).

与在有机催化（organocatalysis）中已得到广泛应用的氢键（hydrogen bonding）不同，卤键（halogen bonding）在该领域的应用仍极为有限。在此，我们首次报道了阳离子型卤键给体在卤离子抽提反应中的催化应用。首先，我们系统测试了基于卤代吡啶鎓（halopyridinium）、卤代咪唑鎓（haloimidazolium）以及卤代1,2,3-三唑鎓（halo-1,2,3-triazolium）的催化剂。与吡啶鎓（pyridinium）类化合物不同，咪唑鎓（imidazolium）盐与三唑鎓（triazolium）盐均展现出可观的催化活性。对于卤代咪唑鎓类有机催化剂，我们以氯代衍生物作为参比化合物，证实其催化活性源于卤键作用。基于上述研究，我们进一步探究了卤代苯并咪唑鎓（halobenzimidazolium）类有机催化剂。单齿型化合物的活性变化趋势与对应咪唑鎓类似物一致，但催化活性更强。为制备预组织化以结合阴离子的双齿型催化剂，我们合成了一类新型刚性双(卤代苯并咪唑鎓)化合物，并对其结构进行了表征。该类化合物的顺式（syn）异构体展现出前所未有的催化活性，在1-氯异色满（1-chloroisochroman）与硅烯醇醚（silyl enol ether）的基准反应中，其使用量可低至0.5 mol%。计算结果证实，顺式异构体可通过双齿模式与氯离子结合。对应的反式（anti）异构体活性更低，仅以单齿模式结合卤离子。动力学研究表明，与中性三齿卤键给体相比，顺式异构体可使反应速率提升20倍。在该反应条件下，预组织型卤键给体的强度似乎已接近极限——在相同溶剂中、较高温度下与氯离子作用时，该催化剂会发生分解。对顺式异构体与溴离子的量热滴定（calorimetric titrations）实验证实了其优异的卤键给体能力，其结合常数K≈4×10^6 M⁻¹，吉布斯自由能变化ΔG≈38 kJ/mol。