Multidentate Halogen-Bond Donors as Lewis Acidic Activators or Catalysts in Halide Abstraction Reactions

Abstract

Although halogen bonds share many similarities with hydrogen bonds, they have so far found virtually no application in organic synthesis. This account summarizes our efforts to use multidentate halogen-bond donors (halogen-based Lewis acids) in formal halide abstraction reactions. Following a first proof-ofprinciple study, we recently reported the first halogen-bond-based organocatalytic carbon-carbon bond-forming reaction.Hydrogen bonds are ubiquitous in Nature. As arguably the most important type of non-covalent interactions, they are crucial for various processes of life, for example, the specific binding of substrates in enzyme pockets. 1 Mimicking Nature, hydrogen-bond donors such as thiourea derivatives have, in the last 15 years, been established as potent non-covalent organocatalysts. 2 Although it has been known for a long time 3 that certain halogen substituents form similar non-covalent interactions with Lewis bases (LB; Figure 1, a), these so-called 'halogen bonds' 4 have so far found very little use in synthetic organic chemistry. Figure 1Halogen bonding: a) general definition (X = F, Cl, Br, I; LB = Lewis base); b) charge-transfer interaction; c) electrostatic potential (red = negative potential, blue = positive potential) of CF 3 I (violet = iodine, grey = carbon, cyan = fluorine) illustrating the σ-hole (in blue) on the iodine substituent Traditionally, halogen bonds have predominantly been described as n→σ* charge-transfer interactions (Figure 1, b), 5 while in recent years, the electrostatic contribution to the overall interaction energy has been more in focus. 6 The latter is often visualized by the 'σ-hole', a region of positive electrostatic potential on the halogen substituent ( Figure 1, c). 6a Strong halogen-bond donors (halogenbased Lewis acids) R-X are obtained for X = I > Br > Cl, and very electron-withdrawing (or highly polarizable) 7a R substituents. In contrast to hydrogen bonds, halogen bonds invariably feature a high directionality, with an R-X···LB angle of approximately 180°. 4,7b,c In the last two decades, halogen bonds have mostly found applications in the solid state, especially for crystal engineering. 8 With few exceptions, 9 studies in solution have only started to appear in the last few years. 10 In addition to fundamental investigations, 11 further examples include trans-membrane anion transport, 12 catenanes and rotaxanes, 13 and anion receptors. 14 In the field of organocatalysis, there are only two reports in which the involvement of halogen bonds has been postulated (Scheme 1). 15 In both cases, it was shown that typical halogen-bond donors (a perfluoroiodoalkane or iodine trichloride) acted as catalysts. The exact mode of activation was not elucidated, however, and it cannot be ruled out that traces of acid are responsible for part of the observed activity. Similar Stefan M. Huber (3 rd from left) studied chemistry at the FriedrichAlexander University of Erlangen-Nuremberg, Germany. He obtained his PhD in 2007 in the group of Prof. Robert Weiss, working on...