TOPICS
For an overview on halogen bonding in organocatalysis, see:
Chem. Eur. J. 2016, 22, 14434-14450.
Introduction: Halogen Bonding and Chalcogen Bonding
Halogen bonding is the attractive non-covalent interaction between electrophilic halogen atoms in compounds R-X (X = Cl, Br, I) and Lewis bases [Chem. Rev. 2016, 4, 2478]:
Figure 1: Definition of halogen bonding
(R= organic or inorganic group; X= Cl, Br, I; D= Lewis-Base with N, O, S, X, ... donor atom)
Reasonably strong halogen bonds (“XBs“) are only obtained when a strongly electronegative substituent R is bound to the halogen atom. Although they have been known for a long time, XBs have only received increased interest since the early 1990s, mostly in solid state investigations (“crystal engineering”). Applications in solution are still rare.
A related interaction is chalcogen bonding, in which electrophilic chalcogen substituents (typically S, Se, Te) act as Lewis acids:
Figure 2: Definition of chalcogen bonding
(Ch= chalcogen)
Chalcogen bonding is even less explored than halogen bonding, with only a handful of studies on intermolecular chalcogen bonding in solution having been published.
Halogen and chalcogen bonds share many similarities with hydrogen bonds but also feature some distinct advantages: a softer interacting atom, a higher directionality, a better tunability, and in some cases a markedly higher hydrophobicity.
Halogen Bonding in Organocatalysis
Our primary goal is to develop new applications of XBs in organic synthesis and organocatalysis, e.g. via the non-covalent activation of electrophiles. Towards this end, a special focus of our research is on the rational design of novel multidentate XB donors.
In several proof-of-principle cases, we could demonstrate that cationic XB donors which are based on haloimidazolium, halopyridinium, or halotriazolium moieties are able to activate a carbon-heteroatom bond. In each case, and for the first time, the activity could be clearly linked to halogen bonding [Angew. Chem. Int. Ed. 2011, 50, 7181]. Using neutral polyfluorinated XB donors like the terphenyl derivative shown in Scheme 1, we could realize an XB-based organocatalytic halide abstraction reaction [Angew. Chem. Int. Ed. 2013, 52, 7028]:
Scheme 1: Organocatalysis by neutral multidentate halogen-bond donors
Subsequently, this concept could also be extended towards the activation of neutral organic substrates like carbonyl compounds (Scheme 2) [Chem. Commun. 2014, 50, 6281]:
Scheme 2: XB-Catalyzed Diels-Alder reaction
Based on systematic studies, isothermal titrations, and quantum-chemical calculations, we are further optimizing the catalyst structures. As an interesting structural variation, we could also demonstrate for the first time that hypervalent iodine(III) compounds may act as Lewis acidic organocatalysts through halogen bonding (see the iodolium derivatives in Figure 3) [Angew. Chem. Int. Ed. 2018, 57, 3892].
Figure 3: Hypervalent iodine(III) derivatives as halogen bonding organocatalysts
Ongoing projects in this area are mostly dealing with XB-catalyzed enantioselective transformations. A further goal is the combination of halogen bonding with other modes of activation in bifunctional or multifunctional catalysts.
Overall, we envision that a second class of non-covalent interactions will complement the ubiquitous hydrogen bond, which already finds frequent use in organocatalysis (e.g. in thiourea derivatives). Because of the different electronic nature of the interaction, different substrate scopes and selectivities are to be expected in comparison to the classical, hydrogen-bond based organocatalysts.
Halogen Bonding in Molecular Recognition
Currently, there are very few examples of halogen-bond complexes which are bound by multipoint interactions, i.e. the interaction of several XB donor sites on one molecule with several Lewis basic sites on a second molecule. However, true multipoint interactions are the basis of molecular recognition and are the ideal basis of strong and rigid materials. As a first step towards this goal, we introduced the first three-point halogen-bonded complex (Figure 4) between a polyfluorinated and -iodinated quaterphenyl and an orthoamide [J. Am. Chem. Soc. 2014, 136, 16740]. This represents the first case of halogen-bond-based molecular recognition, as other amines are bound markedly weaker by this XB donor.
Subsequently, we could show in a cooperation with the Waldvogel group in Mainz that the same XB donor detects acetone in the gas phase, even in the presence of an excess of water [Chem. Commun. 2015, 51, 2040]. Ongoing projects aim to extend this concept to more complex recognition processes, aiming also at enantioseparation and -detection.
Figure 4: Three-point halogen bonding
Halogen-Bond-Based Supramolecular Assemblies
In this line of research, we want to either assemble complex supramolecular architectures by halogen bonding linkers or to modify existing supramolecular systems with multiple XB donating sites. In the mid- and long-term, we also aim to utilize halogen bonding as a further level of hierarchy in the assembly of supra-molecular structures.
Chalcogen Bonding in Organocatalysis
Parallel to our work on halogen bonding, we also strive to establish chalcogen bonding as a viable tool in non-covalent organocatalysis. In a proof-of-principle case study, we could show for the first time that selenium-based Lewis acids may be used as activators and that their mode of action is very likely based on chalcogen bonding (Scheme 3) [Angew. Chem. Int. Ed. 2017, 56, 12009].
Scheme 3: First proof-of-principle for selenium-based chalcogen bonding Lewis acidic activators
While this first application still required a stoichiometric use of the Lewis acid, we could subsequently also establish the first use of organoselenium derivatives as non-covalent organocatalysts [Chem. Eur. J. 2017, 23, 16972].
Currently we are extending these lead results towards enantioselective processes and towards processes which utilize the unique feature of chalcogen bonding: the presence of two electrophilic axes.
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