Applications of halogen bonding in solution

Andreas Vargas Jentzsch 1
  • 1 Laboratory of Macromolecular and Organic Chemistry, Institute of Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands
Andreas Vargas Jentzsch

Abstract

Halogen bonding is the noncovalent interaction where the halogen atom acts as an electrophile towards Lewis bases. Known for more than 200 years, only recently it has attracted interest in the context of solution-phase applications, especially during the last decade which was marked by the introduction of multitopic systems. In addition, the small yet rich collection of halogen-bond donor moieties that appeared in this period is shown to be versatile enough as to be applied in virtually any solvent system. This review covers the applications of halogen bonding in solution during the past ten years in a semi-comprehensive way. Emphasis is made on molecular recognition, catalytic applications and anion binding and transport. Medicinal applications are addressed as well with key examples. Focussing on the major differences observed for halogen bonding, as compared to the ubiquitous hydrogen bonding, it aims to contribute to the design of future solution-phase applications.

Introduction

In recent years, the concept of halogen bonding has become less of a mystery. While most articles published in general literature still include a short description, this situation is slowly moving forward, in part due to its similarities with hydrogen bonding.

As it stands, the halogen bond is the attractive interaction between the positive region of a halogen atom and an electron-rich molecular entity. Its nature, for a long time subject to debate, has evolved from a mainly electrostatic model [1, 2] to be better understood as the interplay of electrostatics, orbital interactions and polarization. This is most evident in the work of Hunter and co-workers who demonstrate that, in contrast to a pure electrostatic model, some halogen bonds can retain their strength over a large range of solvent polarities, due to charge-transfer interactions [3].

Nevertheless, the electrostatic model has one important advantage: based on this almost naïve concept, it is easy to have a good general understanding. Many concepts can be derived from the nature of the electrostatic interaction. Consider for instance one of the prototypical examples that helped significantly in the development of halogen bonding: the electrostatic surface potentials of the family CF4, CF3Cl, CF3Br and CF3I (Fig. 1a). The presence of a positive region at 180° to the carbon–halogen bond is evident; moreover, its size and magnitude can clearly be noticed to decrease steadily from iodine to fluorine. The nature of this positive region, baptized as σ-hole, has attracted considerable attention and inspired seemingly endless literature in the past 20 years with some great reviews summarizing well the general concepts [1, 4–10]. A simple description is given in the following.

Fig. 1
Fig. 1

(a) Electrostatic potential surfaces of CF4, (top left) CF3Cl, CF3Br and CF3I (bottom right) red represents electron-rich and blue electron-poor regions. (b) Schematic representation and preferred geometries of the possible interactions of a typical halogen in a halocarbon towards Lewis acid and bases. (c) Simplistic representation of halogen-bond formation.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The σ-hole

The concept of σ-hole has its origin in pure quantum mechanical calculations, as it can be traced back to the observation of a positive region, much like those presented in Fig. 1a in the surface potential of molecules as simple as tetrachloromethane [11]. Building on this observation, extensive research would follow, notably by Legon, Murray, Politzer, Clark and co-workers, which was summarized recently [4, 6, 7]. It is important to realize that the σ-hole exists even in absence of a bond to the halogen, it is a consequence of the anisotropy of the electronic distribution.

In the simplest case, if a halogen is bound to another atom, even more so if this other atom is electron withdrawing, some electronic density will vacate the halogen, resulting in a more pronounced expression of the already present anisotropy. The bonding itself will take place with the half-full p-orbital. Its electronic density participating to the bounding event, the direct opposite side is vacant and depleted in electronic density; this vacant p-orbital is, roughly speaking, the σ-hole. The other p-orbitals remain populated and are the basis for the negative belt that can be observed in Fig. 1a [1].

The consequence of this forced anisotropy localized among the orbitals gives rise to an important difference with hydrogen bonding: Lewis acids can interact with the negative belt giving halogens a dual Lewis acid and base character of the halogen (Fig. 1b).

It should be noted that the concept of σ-hole is not exclusive to halogens as it has been observed systematically with groups IV–VI of the periodic table.

Definition of halogen bonding

The definition of halogen bonding involved several steps. Presumably, halogen bonding was first observed more than 200 years ago in iodine. Indeed, the color change observed when titrating ammonia into iodine is due, formally, to halogen bond formation [12]. More recently, the Nobel prize winner Prof. Hassel observed the complex formed between, for instance, dioxane and bromine [13]. With the boom of X-ray crystallography, halogen bonding was observed in an increasing number of situations. A survey of the crystallographic database revealed many of the common characteristics of this noncovalent interaction [14].

Given the need of a definition, an IUPAC task group was appointed and proposed the following definition: “A halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity” [15] which is by necessity wide.

To have a practical understanding of halogen bonding, particularly in the context of solution-phase, it is useful to return to the electrostatic potentials shown in Fig. 1a.

As halogen bonding includes an important electrostatic component, any Lewis base can act as halogen-bond acceptor (Fig. 1c). The extent in which a Lewis base is a good halogen-bond acceptor is not straightforward and relates to the concept of basicity scales [16, 17]; indeed, the affinity of a given Lewis acid, take a hydrogen-bond donor or AlCl3 for instance, towards a Lewis base like a carbonyl oxygen, is not necessarily the same, as the interaction taking place can have different natures. In the case of halogen bonding, the electrostatic nature shared with hydrogen bonding gives a good indication to this end, but should be handled with care [18].

The directionality of the halogen bond is to be considered as well. Here again, pure electrostatic considerations help to understand this phenomenon, yet not necessarily to explain it completely: the presence of a negative residual region at 90° from the carbon–halogen bond suggests significantly less angular freedom as compared to the all “positive” hydrogen [1, 19]. As the σ-hole is affected naturally by the interaction with a Lewis base, the linearity of the halogen bond is better explained by charge-transfer interactions and lone pair repulsion [20]. The higher directionality of halogen bonding is often referred to and significant pieces of evidence exist for crystals; indeed, the overall angle observed for halogen bonds in the crystal database show that it is geometrically less flexible than hydrogen bonding [21]. In solution-like media, this geometrical preference is difficult to investigate and only a few examples could be related to the higher directionality of halogen compared to hydrogen bonding [22].

Applications of halogen bonding

Since the rediscovery of halogen bonding, it has mainly been applied in the solid state. Extensively exploited in crystal engineering for the past 20 years, it is hardly new for that community anymore. As this field is not covered here, the reader is referred to some recent reviews [10, 21, 23–25]. Applications include surface chemistry, where its directionality was intelligently exploited for the assembly of molecular monolayers [26, 27] and liquid crystals [28] among others [29].

Concerning halogen bonding in solution, two recent reviews have been published recently focusing on the methods used to investigate halogen bonding in solution [30], and the intrinsic thermodynamics and emerging applications [31]. The applications in solution will be discussed in detail in the following.

Scope

This review aims to summarize the applications of halogen bonding in solution-phase that have been reported during the past 10 years. With the exception of the monovalent binding events, i.e., one-to-one binding between a monovalent halogen-bond donor and a Lewis base, progress in the solution-phase is almost comprehensively restraint to the past decade.

The fields of anion receptors, molecular recognition, catalysis and anion transport are covered in a comprehensive way, while the applications in medicinal chemistry are addressed partially with representative examples.

Halogen bond in molecular recognition

Molecular recognition represents the main focus of supramolecular chemistry and is greatly dominated by hydrogen bonding. This is not surprising as it is the interaction of choice in natural systems. It is not used exclusively, additional interactions, notably hydrophobic interactions, play capital roles as well. In such a context, it is surprising how little attention halogen bonding has attracted in spite of sharing several properties, like strength and directionality, with this ubiquitous interaction.

Here we present examples of halogen bonding applied in molecular recognition; while the focus is, in accordance with this field of research, aimed to explore the possibility to apply this less common interaction in situations where hydrogen bonding is not favored, to this date most examples are intended to provide a fundamental understanding of this promising tool in supramolecular chemistry.

The study of molecular recognition is by no means new and several methods exist that allow for a correct evaluation of affinity constants and energetic estimations [32]. The most common methods being currently employed to study halogen bonding in solution are the subject of an excellent tutorial review and are not being discussed here [30]. It should be noted that NMR spectroscopy (notably 19F NMR), electrospray ionization mass spectrometry (ESI-MS) and isothermal titration calorimetry (ITC) represent the most frequently applied.

Using these methods, the fundamental nature of simple one-to-one recognitions, which were the only examples before 2005, have been explored and their thermodynamic parameters investigated. This thermodynamic information in solution-phase and its interpretation was reviewed recently [31].

It is probably best to address first the original and always latent question of how it compares to hydrogen bonding. One of the original and most noteworthy examples which address this question in molecular recognition, although not explicitly in solution, is the competition study of hydrogen bonding and halogen bonding towards determining the conformation of a four-stranded DNA junction. Ho and co-workers engineered known DNA sequences, which form the stacked-X structure of the DNA Holliday junction [33] with brominated uracil nucleobases. While the original non-halogenated-DNA strands are isoenergetic, the brominated variation uses halogen bonding in one isomer and hydrogen bonding for the other (Fig. 2). Hence, a comparison of the strength of both interactions in this “biological” environment can be obtained. The read-out being the distribution of the isomers in the solid state, the situation in solution was only implied to be the same. In a later study, the direct correlation to the situation in solution was confirmed. The halogen-bonded isomer was more stable with a calculated gain in stability of ca. 2 kcal·mol–1 per halogen bond [34, 35].

Fig. 2
Fig. 2

(a) Crystal structures of the four-stranded DNA H-isomer (hydrogen bonding) and the X-isomer (halogen bonding) studied by Ho and co-workers [34]. (b) Schematic representation of the X-isomer. Copyright (2007) National Academy of Sciences, USA.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

While this example is extremely specific, it represented a breakthrough for the upcoming applications of halogen bonding in solution and solid state.

Interlocked structures

The construction of interlocked structures has attracted the chemists’ attention since several years, not only from the purely proof-of-concept point of view, but also because of the numerous potential applications of nano-mechanical structures [36]. Nowadays, a substantial number of reports exist in the fields of nanomachines, nano-scale switches and nanoelectronics [37, 38].

An excellent example of how interlocked structures can be applied is substrate sensing. The unmatched ability of natural systems in substrate recognition is partially due to the existence of perfectly adapted pockets to recognize the substrate of interest. A similar situation can be reached with interlocked structures; especially, structures that use templates for their assembly are particularly well suited as receptors later on [39, 40].

Halogen bonding having similar characteristics to hydrogen bonding, yet being intrinsically more directional, its application could lead to more selective systems. Interlocked structures, pseudorotaxanes, rotaxanes and catananes, assembled partially and exclusively by halogen bonding, have been explored by the Beer group over the past 5 years. In that period of time, not only the possibility to access such constructs via halogen bonding was proven, but it has been used also in anion sensing applications [41, 42].

The natural first step was the pseudorotaxane formation by anion-templated assembly. The use of a halogen-functionalized imidazolium thread component 2 with isophthalamide macrocycle 1 in the presence of chloride anions gave access to the desired pseudorotaxane 3 (Fig. 3). While the use of halogens other than bromide was not reported, the replacement of bromine by hydrogen had an impairing effect on the affinity constants. Additionally, the methylated version, which showed similar affinities, was confirmed by 1H, 1H ROESY NMR spectroscopy to adopt an inverted conformation for stearic reasons stressing the strong linear tendency of halogen bonds [43].

Fig. 3
Fig. 3

Pseudorotaxane employing halogen bonding reported by Beer and co-workers.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The assembly of the first rotaxane employing halogen bonds followed shortly after. Towards this goal, the 5-iodo-1,2,3-triazolium group was used as halogen-bond donor. Several model compounds (4a–d, Fig. 4) were evaluated for pseudorotaxane formation with the isophthalamide macrocycle 1 by means of NMR titrations. A preference for the bromide anion was observed with a 2-fold increase in affinity as compared to chloride and a 4-fold increase in the case of iodide. The 1,2,3-triazolium variant showed decreased yet detectable affinity, and the use of non-coordinating BF4 lead to barely detectable associations with macrocycle 1.

Fig. 4
Fig. 4

Rotaxane assembly by anion-halogen bond templation.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The assembly of rotaxane 7 was achieved using 5-iodo-1,2,3-triazolium axle bromide 6 and bisvinyl-functionalized compound 5 with Grubbs’ second-generation catalyst in CH2Cl2 (Fig. 4). The formation of the rotaxane was confirmed by 1H,1H ROESY NMR spectroscopy, ESI-MS and single crystal X-ray diffraction [44].

Anion exchange with NH4PF6 gave access to a bromide anion receptor with affinities in the range of >104 M–1 in a 1:1 MeOH/CHCl3 mixture, which were significantly higher than those reported before for the hydrogen bond variant [45]. The affinity of rotaxane 7 in a competitive water media was explored next and affinities >103 M–1 in MeOH/CHCl3/H2O (45:45:10) were observed for bromide and iodide with a preference for the latter. This selectivity was attributed to steric constraints.

The preparation of a concatenated structure being promising towards an enhancement of the steric, electronic, and lipophilic properties of the potential anion-binding pocket was attempted using the simplest version in the form of a [2]catenane. In this example, the authors employed bromo-4,5-methylimidazolium derivative 8, which mixed in equimolar quantities with the bromide version form a 2:1 complex with the bromide anion. Further reaction under ring-closing metathesis conditions with Grubbs’ second-generation catalyst yielded catenane 9 (Fig. 5). The catenane formation was confirmed by NMR spectroscopy and mass spectrometry [46].

Fig. 5
Fig. 5

[2]Catenanes assembled by halogen-bond formation.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The presence of naphthalene units in the catenane precursor, and thus the catenane itself, was shown to report by fluorescence on the complexation of anions. Indeed, removal of the bromide template by anion exchange with NH4PF6 gave a receptor selective for chloride (Ka > 106 M–1) and bromide (Ka > 105 M–1) in CH3CN. The observed selectivity, 10 times better for chloride than bromide and the virtually non-affinity for other anions was attributed to the specificity of the binding pocket.

The assembly of [2]catenane structures was further explored by using pyridine-containing macrocycle 13. This approach was interesting because no anion templation was necessary and the main directing interaction was designed to be halogen bonding. The formation of the pseudorotaxane between macrocycle 13 and thread components 10a–b and 11a–c confirmed the expected increase stability with increasing polarizability (e.g., derivatives from iodine were better than from bromine), a preference to form the pseudorotaxane by halogen bonding over the less favorable hydrogen bonding and an increased stability with pyridinium over triazolium compounds, probably due to more favorable aromatic donor-acceptor interactions [47].

With the most promising candidate, the iodopyridinium derivative 11c, the catenane formation was explored, leading to catenane 14 as confirmed by NMR spectroscopy and mass spectrometry.

Similarly, the formation of pseudorotaxanes and catenanes was explored with the isophthalamide 1 used before for the first pseudorotaxane, leading to catenanes 12a–b. As their assembly is based on the anion-templation strategy, anion-binding affinities were investigated, but only weak associations were observed (e.g., 340 M–1 for 12b and iodide in 1:1 MeOH/CHCl3). The preference towards iodide over the smaller halides was in line with that observed for rotaxane 7, albeit for the rotaxane better affinities were observed.

The possibility to use exclusively halogen bonding to assemble interlocked structures with receptor/sensor capabilities was addressed by using the all-new design depicted in Fig. 6. A combination of bis-iodo-1,2,3-triazole 16 macrocycle precursor and bis-iodo-1,2,3-triazolium axle 15 under Stewart-Grubbs’ metathesis conditions in presence of chloride as template gave access to rotaxane 17 as confirmed by NMR spectroscopy and solid-state crystal structures. The rhenium(I) bipyridyl center was included in the macrocycle component to report on anion binding by fluorescence [48].

Fig. 6
Fig. 6

Components and resulting [2]catenane assembled purely by halogen bonding.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The binding affinities, as reported by fluorescent quenching in competitive media, i.e., H2O/CH3CN up to 50 %, were as high as 105 M–1 with a higher affinity towards iodide and only weak binding to oxo-anions. While binding affinities decreased steadily with increasing water content, the selectivity between anions was naturally accentuated due to the hydration free energies. The observed binding affinities are the highest observed for halide-sensing interlocked structures, underlining the suitability of halogen bonds in this field.

Anion receptors

When considering the nature of halogen-bond donors, it is obvious that such interaction should give rise to, if any, anion receptors. Indeed, the formation of one-to-one complexes of several halogen-bond donors with Lewis bases has been reported repeatedly. Most notably, the discovery of halogen bonding is often traced back to the titration of iodine in aqueous ammonia in the 19th century [12].

In this review we will not cover monovalent receptors such as iodine or perfluoroiodobenzene. Particularly, iodine has been exhaustively studied and the formation of complexes in solution and solid state are included in the more than 200 years of research [49]. In the context of halogen bonding, it is worth pointing to the research in the field of the diiodine basicity scale [18]. It establishes a quasi-orthogonality of the diiodine basicity scale with the better known hydrogen-bond, dative-bond or cation basicity scales. This is of paramount importance for the design of supramolecular systems employing halogen bonding in solution and solid state. Similar studies exist for other dihalogens [16, 17].

Monovalent organic halogen-bond donors have been characterized in solution for their affinities towards Lewis bases; examples including iodoalkynes [50], 2-iodo imidazolium salts [51], and perfluorinated haloalkanes and arenes have been reported [52] and recently reviewed [31]. Importantly, computational methods are becoming increasingly reliable for the study of molecular affinities in this context [53].

Ironically, the first multivalent “receptor” using halogen bonding was a cation receptor; halogen bonding was employed to enhance the receptor affinity in presence of a suitable anion. It was reported in 2005 by Resnati, Metrangolo and co-workers [54].

This receptor used a tertiary amine as scaffold: the tris[2-(2-hydroxyethoxy)ethyl]amine was functionalized with a iodoperfluorophenyl or perfluorophenyl units to yield receptors 18a–b (Fig. 7). On itself the tris[2-(2-hydroxyethoxy)ethyl]amine scaffold can complex cations in virtue of its structure that is, not surprisingly, similar to the family of crown and aza-crown ethers. It was hypothesized that upon substitution of the terminal alcohols with strong halogen-bond donors, i.e., a iodoperfluorophenyl unit, the cation binding would be enhanced by the peripheral coordination of halide anions.

Fig. 7
Fig. 7

Anion receptors based on perfluorinated iodoarenes by Metrangolo, Resnati, Taylor and co-workers [54–56].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

It was observed that cation coordination with cations such as Na+, K+ and Cs+ was indeed taking place, as evidenced by ESI-MS. In addition, crystal structures for the heteroditopic receptor for NaI were also resolved showing the expected Na+ coordination by the heteroatoms and halogen-bond formation in the periphery.

The affinity constants were measured by 19F NMR spectroscopy using the well characterized [18]crown-6 as reference, and the apparent association constant Ka(1) showed a 20-fold increase over Ka(2). This is the first reported example of a multidentate receptor based on halogen bonding and to report on association constants.

Interestingly, a high selectivity for iodide was observed. This was not surprising at that time, as it was incorrectly considered to be the “natural” strength scale in solution for halogen bonding [54]. It has since been established that the halide anion strength scale is similar to the one for hydrogen bonding, which is Cl > Br > I under non-biased conditions in solution [57].

During the following years, there were no reports on receptors using halogen bonding until 2010, when Taylor and co-workers reported a series of compounds (19–22, Fig. 7), among which receptor 22 was the first receptor using exclusively halogen-bond donors to achieve good anion-binding affinity (1.9 × 104 M–1 in acetone) by a real multidentate coordination. The chosen halogen-bond donor, 2,3,4,5-tetrafluoro-6-iodobenzylester, had the advantage of providing a convergent multidentated binding and, moreover, it allowed following the binding event by 19F NMR spectroscopy. As usual for receptor studies, anion bindings were determined and a 1:1 binding stoichiometry was in support of the proposed complex formation. The increase in binding affinities by increasing the number of halogen-bond donors and significantly lower associations in absence of the iodine provided conclusive evidence for this breakthrough example [55].

Several new bidentated and tridentated receptors were reported later based on the same halogen-bond donor unit and, whereas no better affinities were observed, it was clearly established that the strong directionality of halogen bonding is a key parameter to consider in the design of supramolecular structures using halogen bonding [58]. Moreover, it was reported that the use of perfluoroiodoalkanes and arenes to achieve binding results in a positive entropic contribution to binding [58, 59].

The possibility of combining hydrogen- and halogen-bond donors in receptors, not unlike other naturally occurring interactions, is attractive and was explored with compounds 23–25 (Fig. 7). The urea unit was used as primary binding interaction and the influence of potential halogen-bond donors in proximity was investigated [56].

Systematic structural changes in receptor 23a–b to assess the linker size and rigidity effect concluded that a short and flexible linker was best due to, on the one hand, the entropic penalty of a longer linker and the larger deviations from the ideal linear geometry of the halogen-bond formed with the phenyl linker, on the other hand.

While the contribution to binding by the halogen-bond formation could be assessed in all cases, the contribution of anion-π interactions had to be investigated for possible interference [60–62]. Receptors 24a–c were used to gain insights into this additional interaction. Affinities towards oxoanions were observed with phenolate anion being the best, with an affinity Ka = 1.9 × 105 M–1 in CH3CN for 24a. Careful analysis of the data revealed that halides are recognized significantly better with the halogen-bond donors than with only the anion-π contribution (i.e., comparing 24a–24b).

Finally, receptors 25a–b were investigated; in this case, the halogen-bond geometries were predicted to be less penalized, and a higher contribution to binding (up to 2.0 ± 0.1 kcal·mol–1) was measured due to halogen bonding. While phenolate remained the preferred guest, the halide anions showed a 30-fold increased affinity when comparing 25a–25b, confirming the major role of halogen bonding [56].

Perfluorohalo arenes and alkanes are by far the most exploited moieties in the halogen-bonding field and, not surprisingly, the first to be employed in solution applications, as well. Alternatives exist and were notably exploited by Beer and co-workers [23, 41, 51].

Taking into account the usefulness of the imidazolium unit as a hydrogen-bond donor and previous reports where halogen-bond formation was observed with 2-iodo- and bromoimidazolium, the possibility to use a 2-haloimidazolium unit to achieve anion binding was explored [63–65]. Imidazoliophanes 26a–b were investigated first: one important difference between imidazoliophanes 26a and 26b is evident by the possibility to isolate syn and anti conformers of 26a; Receptor 26b exists as a mixture of isomer due to the fast exchange at room temperature. For the binding studies, the two conformers had to be differentiated. It became evident from crystal structures and NMR titration experiments that the syn-26a was capable of binding simultaneously with both bromoimidazolium units leading to overall higher affinities [66].

These higher affinities were observed with syn-26a and bromide (889 ± 37 M–1), followed by iodide, with undetected affinity for chloride, while 26b showed a relatively constant affinity for all three anions (ca. 100 M–1) in 9:1 CHCl3/H2O. This selectivity highlights not only the usefulness of the bromoimidazolium as halogen-bond donor but also demonstrates one of the fundamental differences between hydrogen and halogen bonds: the steric demands which in this case allow for the preorganization of receptor 26a in the syn configuration and account for both the higher affinity and selectivity.

The same binding geometry was later exploited in imidazoliophane receptors 27a–d that incorporate naphthalene in the macrocyclic framework to serve as fluorescent reporter. Due to the larger macrocycle and the reduced steric demands, only iodoimidaliophane 27d was isolated as syn and anti conformers. A significant higher selectivity and affinity was observed with these receptors: out of the five receptors, only 27c and syn-27d would show changes in the fluorescent spectrum upon titration with a range of potential anions. Moreover, only bromide and iodide were suitable guests for these receptors with selectivity for bromide (27c) and iodide (syn-27d) with a ca. 20-fold preference for one anion over the other. With affinities close to 106 M–1 in competitive 9:1 MeOH/H2O media, both receptors are exceptional. It is remarkable that 27c can rearrange to its syn-conformer upon anion binding with no significant penalization to the binding affinity. The counterintuitive and opposed selectivity for iodide or bromide is most likely explained by a competition between favorable binding geometries and solvation [67].

Synthetically easily to access, triazoles are promising neutral halogen-bond donors and have been explored with iodotriazole and triazole zinc(II)-metalloporphyrin receptors 28a–b (Fig. 8). A major advantage of such a system is the possibility to monitor binding following the changes of the absorption spectrum, namely the Soret band. Significant bathochromic shifts of the Soret band upon titration in CHCl3 with tetrabuthylammonium (TBA) halide salt were observed with both receptors 28a–b, which was confirmed additionally by NMR titrations. Interestingly, oxoanions like acetate, hydrogenphosphate and sulfate showed similar shifts with significantly higher, over 100-fold, affinity constants [68].

Fig. 8
Fig. 8

Anion receptors reported by Beer and co-workers.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

While halide binding was best with the iodotriazole variant (halogen bonding), oxoanions show the opposite trend having better affinities with the triazole version (hydrogen bonding). A preference in binding of tetrahedral over trigonal anions was observed as well.

In other solvents, like acetonitrile and acetone, the affinity constants increased dramatically showing Kas > 106 M–1 for most anions with the noteworthy exception of iodide. Remarkably, the observed affinities only showed poor correlation with typical solvent parameters, especially in the case of 28b. The authors found a good correlation with the Guttmann acceptor number [69] which is an empirical measure of the Lewis acidity of the solvent. This is important as solvent effects on halogen bonding are still little explored and the available data suggest that significant differences exist as compared to hydrogen bonding [57, 59, 70]. Overall, halide recognition was better with halogen bonding, and oxoanions were best recognized with hydrogen bonding in this example [68].

Although not explicitly included in this section, due to their other functional properties, interlocked structures (e.g., 17) catalysts (e.g., 36) and anion-transporters (e.g., 60) are ipso facto anion receptors with affinities as high as 105 M–1 even in water competitive media. Importantly, studies exist where functional structures like 43a–b were investigated in detail for their anion affinities largely confirming their binding properties [20]. Interlocked structures are most interesting with regards to anion receptors, because their receptor pockets are reminiscent of natural phosphate and sulfate receptors [42].

Further examples on molecular recognition

The formation of host-guest complexes by multivalent halogen bonding is greatly dominated by the complexation of anions while the complexation of molecules, much like the interlocked structures prior to mechanical fixation, has received less attention. Two examples by Navarro-Vazquez, Rissanen and their respective co-workers describe in detail the formation of host-guest complexes. Additional NMR spectroscopic evidence confirms the existence of these complexes in solution [71, 72].

The work of Erdélyi and co-workers on the symmetry of halogen bonding has provided the community with significant insights that have potential applications in organic chemistry. They used pyridine-based halogen-bond acceptors and notably rigid bis-pyridines to assess the symmetry of the halogen bond formed with iodous and bromous halogen-bond donors.

Studied by a combination of NMR spectroscopy exploiting the method of isotopic perturbation of equilibrium processes [73] and computational methods, it was demonstrated that, in contrast to hydrogen bonding, halogen bonding is symmetric in solution [70, 74, 75].

Halogen bonding in catalysis

The development of organocatalysis depends intrinsically on the types of interactions that are possible or available. Typically, the field is dominated by Lewis base type catalyst, while Lewis acid type came later into the scientific landscape [76, 77]. For less common non-covalent interaction it is difficult to enter such a field, and examples of, for instance, cation-π and anion-π are either scarce or limited to intrinsically complicated biological systems [78–81]. The same holds true for halogen bonding; in spite of sharing several characteristics with hydrogen bonding, only a handful of examples have appeared in the last years.

Similarly to anion receptors based on halogen-bond donors, a single example for catalysis with halogen bonding appeared before 2010 by the Bolm group. In this example, the transfer hydrogenation reaction of a series of quinolines (29) by Hantzsch ester to the respective 1,2,3,4-tetrahydroquinolines (30) was used as a model reaction (Fig. 9) [82].

Fig. 9
Fig. 9

Model reaction employed by Bolm and co-workers to explore catalysis with halogen-bond donors [82].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

It was shown that the presence of 1–10 % loading of perfluorooctyliodide as activator/catalyst was enough to promote up to 98 % product formation for 2-phenylquinoline. Under the same reaction conditions in absence of the halogen-bond donor, no trace of product was observed. The reaction was postulated to proceed by C=N activation promoted by halogen-bond formation. The N-halo interaction was confirmed by small shifts on the 13C NMR signals for both the donor and acceptor and the 19F NMR signals for the halogen-bond donor.

The use of perfluorobromo alkanes proved to be less efficient, in line with the weaker halogen bond formed, and the elongation of the perfluorinated chain resulted in better overall yields. One exception was perfluorodecyliodide, most likely due to solubility issues. The scope of the reaction demonstrated that electronic effects had an influence, i.e., electron-rich quinolines gave decreased yields, when steric effects had only a marginal impact.

In 2014, the Tan group used the transfer hydrogenation of quinolines, as described above, and imines to investigate a series of bidentate dihydroimidazolines as catalysts (35–40, Fig. 10) [83]. Their bidentate catalysts/receptors are interesting not only for their catalytic activities, but also because they introduce a new motif for charge-assisted halogen-bond donors to complement the ones used by Huber, Beer and co-workers [43, 84].

Fig. 10
Fig. 10

Model reactions and catalysts employed by Tan and co-workers to explore catalysis with multidentated halogen-bond donors [83].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

Similar as before, under the reaction conditions used, only traces of the 1,2,3,4-tetrahydroquinoline product were observed. In presence of 10 mol% of 36, the reaction proceeded to completion within 1 h. Conversion was observed, albeit significantly slower, with 35 and 3739. These catalysts represented the hydrogen-bonding (35), iodobenzimidazolium (37), the neutral non-methylated imidazoline (38) and the monodentate iodohydroimidazolium (39) versions. The only halogen-bond donor tested that was unable to catalyze the reaction was iodoimidazolium 40, which is surprising as it is known to form strong halogen bonds [84]. It was suggested that the activation by halogen-bond donors follows the “goldilocks” principle, i.e., a too weak or too strong binding inhibits the function [85].

It was further possible to reduce the quantity of catalyst 36 down to 2 mol%, which gave a conversion of over 90 % for a variety of quinolines. Only small influence on the quinoline substitutions was observed. Moreover, phenantrolines and inactivated pyridines reacted under similar condition and gave good conversions.

The transfer hydrogenation of imine derivatives was tried next with catalyst 36 (Fig. 10). The catalyst loading could be lowered to 0.2 mol% and over 90 % yields were observed. Only with strong electron-withdrawing substituents the reaction was inhibited. Halogen-bond formation was confirmed by NMR spectroscopy and binding constants with bromide were measured by ITC. 37 with a Ka = 4.57·105 M–1 in CH3CN was the best receptor displaying a 10-fold stronger binding as compared to 36 and in line with the proposed over-binding hypothesis.

The main group involved in the development of catalysis using halogen bonding is the Huber group [84]. Their first contributions were aimed to demonstrate the intrinsic usefulness of halogen-bond donors to activate a carbon-halogen bond. Upon formation of the formal complex, either the abstraction of the halide takes place generating a carbocation or the carbon-halogen bond is weakened to allow for a nucleophilic substitution.

In order to explore the first alternative, benzhydryl bromide (41) was used in wet acetonitrile. On abstraction of bromine the generated carbocation reacts with the solvent in a Ritter-like solvolysis to yield amide 42. The activation by simple halogen-bond donors not being strong enough, the use of multidentate systems was the natural option (Fig. 11).

Fig. 11
Fig. 11

Ritter-like solvolysis and catalysts explored in the context of halogen-bond activation of carbon-halogen bonds by Huber and co-workers [86–89].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The first multidentate halogen-bond donor was a bis(iodoimidazolium) (43a). In presence of this activator over 80 % of amide 42 is formed in a four days time at room temperature. Extensive control experiments were carried out notably to dismiss the possibility of catalysis by traces of acid. Importantly, the bisimidazolium, i.e., the hydrogen-bonding analogue, showed only a negligible conversion. Additionally, the para-substituted version was tested along with the bromoimidazolium, and in all cases significant lower yields were observed [86].

The next generation of cationic multidentated halogen-bond donors explored the possibility of using iodopyridinium. The azo-bridged bipyridinium compound 44a was prepared and subsequently tested with the same reaction. With activation by halogen bonding, better yields were observed and controls experiments were consistent with this hypothesis [87].

Triazolium-based multidentated halogen-bond donors like 45a were studied next. Here it was the first time a tridentated activator was introduced allowing to better realize the importance of multivalency; indeed, the activation of substrate 41 increases with the number of halogen-bond donors. A conversion of over 95 % was observed for 45a while the control 45b gave a modest 8 % after 48 h. The importance of the counteranion became more evident in this case; the yield decreased on replacing triflate by hexafluophosphate [88].

For all three cases, the formation of halogen bonds was confirmed by NMR, and crystal structures where obtained showing the short contacts between the halogen and the oxoanions. Although the three charge-assisted halogen-bond donor moieties are related, it is remarkable that their similarities are function-wise.

The use of cationic activating agents not always being convenient, the neutral activator 46a was prepared. It uses iodoperfluorophenyl units, since these are commonly accepted to be among strongest non-ionic halogen-bond donors, and the geometry was selected to be similar to 44a, i.e., prepared as an azo-compound. Unfortunately, only marginal activation of the carbon-halogen bond was observed. This was explained mainly by the strength of the interaction that should be weaker with these units as seen from the calculated positive electrostatic potential of the σ-hole [89].

In all the previous examples, stoichiometric amounts of the activating agent were required, most likely, due to the coordination of the liberated bromide; indeed, affinity for the anion is supposed to largely exceed the affinity for a halocarbon. To circumvent this problem, the reaction of 1-chloroisochroman (47) with silyl ketene acetal (48) was proposed. In this reaction, the liberated chloride forms tert-buthyldimethylsilyl chloride preventing the inhibition of the catalyst (Fig. 12a). This reaction is well known and asymmetric organocatalytic versions exist [93].

Fig. 12
Fig. 12

Model reactions and catalysts employed by Huber, Coulembier and co-workers to explore halogen-bond catalysis [90–92].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

A new series of neutral multidentated halogen-bond donors was prepared (50a–b and 51a–b, Fig. 12) and tested towards the activation of the said chloroisochroman 47. Yields of over 90 % were obtained for tritopic catalyst 51a in sharp contrast to the virtually non-conversion observed for the hydrogen-bonding variant 51b. Bidentate versions like 50a in either meta or para configurations gave yields of 17–52 % under similar conditions. Curiously, in this case the para configuration seemed to be slightly better, probably due to different geometrical demands as compared to the previous situation. All necessary controls to dismiss acid traces and to confirm anion binding, in this case by ITC, support the hypothesis of a catalytic activation of the carbon-halogen bond. Moreover, thiourea 56 was included as a reference for a typical organocatalyst and while slightly better binding affinities towards anions where observed by ITC, it was outperformed by the new catalysts [90].

Their most recent contribution concerns a classical reaction for organocatalysis: a Diels-Alder reaction. The activation of a dienophile triggered by Lewis acids often entails improvements in stereo- and regioselectivity.

The use of cationic catalyst 43a to catalyze the model reaction depicted in Fig. 12b was unsuccessful showing essentially no difference with the blank reaction. It was postulated that triflate coordination could be the origin of this inhibition of activation. Replacement of triflate with the non-coordinating [B[3,5-(CF3)2C6H3]4], often referred as BarF4, changed the situation and a modest yet significant increase from 24 % to 63 % using 20 mol% of catalyst was observed. Furthermore, coordination to the carbonyl oxygen was confirmed by NMR spectroscopy. Importantly, thiourea catalyst 56 displayed catalytic activity, but to a lesser extent, showing only 38 % yield under the same conditions [91].

The last reported example for catalysis with halogen bonding concerns the sole example of inorganic halogen-bond donors acting as catalysts. In his report from 2010, Coulembier and co-workers demonstrated that the ring-opening polymerization of l-lactide (57) can be catalyzed by iodine trichloride (ICl3, Fig. 12c). The polymerization reaction of L-lactide initiated by 11-bromo-1-undecanol (58) in presence of ICl3 in catalytic amounts (2 mol%) can reach up to 22 % conversion; with 10 mol% of the catalyst 86 % conversion with a polydispersity index (PDI) of 1.4 was observed [92].

The catalytic mechanism in this case was postulated to be a dual activation of the hydroxy-initiator and the L-lactide monomer; the former by the Lewis base and the latter by the Lewis acid character of the catalyst. The coordination of ICl3 to the initiator was confirmed by NMR spectroscopy and, in a similar way, the interaction with L-lactide was demonstrated. Additionally, FT-IR confirmed the carbonyl group interaction with ICl3.

Anion transport with halogen bonds

Ion transport is a fundamental process of life and ubiquitously present in all organisms. It has been subject of extensive research for at least 50 years and it is understood at many levels. More recently, interest was centered to the creation of artificial ion transport systems. In 1982, the first example of a synthetic ion channel was reported by the group of Prof. Tabushi [94], which successfully started three decades of exploration in the field of ion channels [95].

Anion transport was explored as well, due to certain diseases known to be related to anion transport deficiencies such as cystic fibrosis [96–98], but drifted from the concept of ion channels rapidly; indeed, whereas cation transport is mainly achieved by means of channel proteins, anion transport is not uncommonly related to small-molecules transport in nature, i.e., by ion carriers.

The main motivation for using halogen bonding to transport anions through the lipid bilayer membrane can be explained by the nature of halogen-bond donors: while having similar strength and directionality to hydrogen bonds, it displays an increased lipophilicity. On paper, such characteristics are most desirable for the design of anion transport systems [99].

Moreover, ion transport has been recently achieved with other uncommon interactions such as anion-macrodipoles [100] and anion-π interactions [101, 102].

Characterization of ion transport systems

The characterization of ion transport systems was one of the original bottlenecks in the research of ion transport systems. Indeed, detection of ion transport and the kinetics of such a process required the development of new methods. Those methods not being usually encountered, as compared to NMR titrations or ESI-MS spectroscopy, a brief introduction is given below of the most common ones. For detailed descriptions the reader is directed to the specialized literature [103, 104].

Large unilamellar vesicles

Probably the most common method to assess synthetic ion channels nowadays; it consists of using large unilamellar vesicles (LUVs). For this experiment, LUVs are formed by various methods (dialysis, extrusion, etc.) with defined lipid composition, typically dipalmitoyl phosphatidylcholine or dioleoyl phosphatidylcholine or the naturally occurring mixture “Egg yolk” phosphatidylcholine, and defined content dispersed in an aqueous solution of equal or similar composition.

An ion gradient is generated by the addition of a base, typically NaOH, and upon the addition of a putative ion transporter the evolution of the ionic species of interest can be followed by several methods: ion selective electrodes [96, 105], fluorescence [106], etc.

Fluorogenic LUVs are particularly interesting as they can be used in virtually any laboratory because no special equipment is required. The most versatile fluorophore used in fluorogenic LUVs is 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) [107] which is used in the so-called HPTS assay [103]. HPTS is a pH-sensitive fluorophore and measures the efflux or influx of anions or cations by the concomitant change in pH due to proton or OH- transport (Fig. 13a). The HPTS assay cannot, a priori, discriminate between the different processes and mechanisms that lead to a pH-change, and as such it is the ideal method to be used in initial screening studies. Variations exist that allow the discrimination of symport and antiport transport mechanisms, anion versus cation selectivities, etc. These more specific experiments are described elsewhere [103, 109].

Fig. 13
Fig. 13

The most common methods to characterize synthetic ion transport systems. (a) The HPTS assay, a typical experiment with fluorogenic vesicles. (b) Typical fluorescent trace for a single HPTS experiment. (c) Typical dose-response curve to determine the effective molarity needed to obtain 50 % transport activity (EC50) and the Hill coefficient (n). (d) Typical set-up for planar bilayer conductance experiments. (e) Current flow changes in response to a carrier anion transporter. Adapted from reference [108] with permission, © 2012 Nature Publishing Group.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

In a typical experiment, Egg yolk phosphatidylcholine LUVs loaded with HPTS (EYPC-LUVs⊃HPTS) are subjected to, first, a NaOH pulse followed by the addition of the putative transporter and finally the equilibration of the system by adding a detergent to calibrate for the maximal emission (Fig. 13b). The fluorescence is recorded at two different excitation wavelengths in order to determine the ratiometric fluorescence kinetic trace which can be directly correlated to ion transport. If the fractional transport value, i.e., the highest relative value before addition of the detergent, is reported as a function of the transporter concentration, the dose-respond curve (DRC, Fig. 13c) of the transporter is obtained. This transporter-specific DRC reports the effective molarity needed to obtain 50 % transport activity (EC50) and the Hill coefficient (n) which can give information regarding the number of molecules required to achieve transport [103]. Other fluorophores can be used in a similar manner to address membrane stability, i.e., carboxyfluorescein [103], or to detect specific anions like chloride with lucigenin [110].

Conductance experiments in planar bilayer membranes

These experiments were the first used to characterize ion channels and are still the basis to define a compound as an ion “channel.” Ion channels are defined by their function as “compounds that feature single-molecule currents in planar bilayer conductance experiments” [111, 112].

The principle of planar bilayer conductance experiments has not changed significantly since its conception. It consists of two chambers, called cis and trans for historical raisons, filled up with a buffer and separated by a wall. A small hole with a diameter of approx. 200 μm is covered with a lipid bilayer membrane (Fig. 13d). If a potential is applied between both chambers, no current can be observed since the lipid membrane act as an insulator. This situation is different in presence of an ion transporter which allows the electrolytes to move across the membrane, and a current, typically pA, can be observed. This current is directly related to the ion-transport capabilities of the compound [104].

The fact that this method is still considered the gold standard for the determination of ion channels is due to the large amount of information such a measurement can provide. Indeed, in the case of ion channels, information like the channel inner-pore size or the cation/anion permeability can be obtained [103]. For an ion carrier, a steady increase in current before reaching saturation is the typical situation (Fig. 13e).

Anion transport with anion-π interactions and halogen bonding

Shortly after the first reports on anion receptors using halogen-bond donors, the possibility to exploit this noncovalent interaction to transport anions across the lipid bilayer membrane was explored. The first anion transport system reported was designed to allow for multitopic binding to anions. The calix[4]arene scaffold was selected in order to take advantage of the coordination of the tetramethylamonium (TMA) cation to the upper rim by cation-π interactions. Perfluoro-m-iodophenyl groups were employed as halogen-bond donors, while the fully fluorinated aromatic version was used as control (60, 63, Fig. 14) [113].

Fig. 14
Fig. 14

Calix[4]arenes decorated with halogen-bond donors and anion-π surfaces to achieve anion transport in bilayer membranes; proposed binding of tetramethylammonium (TMA) cation and chloride are shown.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

Good anion transport in the HPTS assay with calix 63 as compared to the almost negligible activity of calix 60 was attributed to favorable anion-π interactions for the former and excessive binding of the latter. Both situations have been reported in the literature: anion-π interactions have been used to achieve anion transport in comparable simpler systems [101, 114], and inhibition by excessive binding is known as the goldilocks principle [85].

Weaker halogen-bond donors with calix 61 or a less favorable conformation (62) resulted in significant improvement in the anion transport activities. Further affinity investigations by 19F NMR spectroscopy confirmed binding by halogen bond formation and the proposed one-to-one stoichiometry for all receptors/transporters except calix 62 with a one-to-two stoichiometry. Additional evidence for the proposed involvement of halogen bonding was implied by the significant anion selectivity of the transport system.

Anion transport with halogen-bond donors

Only moderate transport activities with calix-based transporters and less than favorable binding geometries observed by DFT models suggested that, on the one hand, the calix[4]arene scaffold was detrimental for the activity and, on the other hand, perfluorinated iodoarenes halogen-bond donors were nicely suited for the task in hand.

The possibility to achieve anion transport using exclusively halogen-bond donors in absence of a pre-organizing scaffold was investigated next. Several perfluorinated halogen-bond donors (64–73, Fig. 15a), were tested in the HPTS assay, and surprisingly high activities were observed. Contributions from anion-π type interactions were safely excluded with transporters 64–69 where no π-surface exist. Also were excluded effects originated from perfluorinated materials (74) and pure anion-π interactions (75). Weaker halogen-bond donors (75, 78) were inactive as was the stronger yet too hydrophilic diiodopyridinium 77 [108].

Fig. 15
Fig. 15

(a) Halogen-bond donors explored in the context of transmembrane anion transport. (b) Top, proposed structure responsible for anion-translocations; bottom, ball-and-stick model of chloride bound to six perfluoro-1-iodobutane by DFT simulations. Adapted from reference [108] with permission, © 2012 Nature Publishing Group.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

Additional experiments performed with variations of the HPTS assay confirmed high anion selectivity, high dependence on membrane viscosity and thus suggested an anion antiport mechanism ruling the transport.

The observed activities with small molecules were astonishing. While anion transport has been reported with simple molecules [115], encounting molecules like trifluoroiodomethane (6), which is a gas at room temperature (b.p. –22 °C) that was bubbled directly through the suspension of EYPC-LUVs⊃HPTS to activate anion transport and represents the smallest organic anion transport system reported, was intriguing and required further confirmation.

Conductance experiments in planar bilayer membranes confirmed the existence of transport by a carrier mechanism (Fig. 13e) and revealed high anion selectivity.

The proposed mechanism of transport implies the formation of an unstable hexa-coordinated complex with the anion in the middle (Fig. 15b), which in virtue of the hydrophobicity of the outer shell shuttles through the lipid bilayer and exchanges the anion for a hydroxide. This is supported by the observed requirement of a minimum of five molecules to achieve transport in the HPTS assay.

Halogen-bond donor channels

The last available contribution by Matile and co-workers was the development of the family of anion transporters depicted in Fig. 16. To maximize anion transport, a formal channel, i.e., a molecule or ensemble of molecules capable to promote anion translocation without moving significantly, was proposed. The p-octaphenyl scaffold has been reported before, using hydrogen bonding to achieve proton transport by an ion-hopping mechanism [116]. It was hypothesized that a similar process could take place with halogen bonding.

Fig. 16
Fig. 16

Halogen-bond cascades explored for channel-like anion transport in bilayer membranes; arrows show the proposed mechanism of action.

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The transport activity of rigid rods 79–82 was investigated in the HPTS assay and an over 2300-fold increase in transport activity compared to the simple pentafluoroiodobenzene (70) was observed. Moreover, the observed activity per halogen-bond donor increased faster than exponentially with a cooperativity coefficient [117] of 3.37, a cooperativity coefficient that strongly support the proposed anion-hopping mechanism. Indeed, purely multivalent systems like polymeric constructs typically show cooperativity coefficients between 1 and 2 [118].

Additionally, the anion-π analogue, i.e., the fully fluorinated version, showed significantly lower activities confirming the suitability of halogen bonding for anion transport and the generality of the p-octaphenyl scaffold as applied to ion transport. Additional experiments confirmed anion selectivity and membrane stability, as well. The proposed mechanism involves the perpendicular arrangement in the lipid membrane of at least one rigid rod and subsequent hopping of the anion from one halogen-bond donor to the next.

With detectable transport activity at lipid/transporter ratios as high as 20 000:1 for 82, high selectivity, even with incredibly small systems like 69 and having explored most transport mechanism (i.e., sym- and antiport carriers and channels), halogen bonding is confirmed as a valuable and reliable noncovalent interaction to achieve anion transport.

Halogen bonding in medicinal chemistry

One of the main fields of chemistry where halogen bonding has found applications is medicinal chemistry, specifically for the enhancement of small-molecules binding affinities with proteins. Curiously, their influence in binding and specificity has not been recognized until recently. So far, most examples of applications of halogen bonds are serendipitous and a consequence of the typical lead optimization procedure in drug discovery, as opposed to lead discovery where by their high molecular weight higher halogens are typically absent.

Since the first survey for halogen-bond contacts in the available crystal-structure database, which confirmed an important number of short contacts already present in the literature to be attributed to halogen bonding, there has been an evident interest to consider halogen bonding for drug discovery and optimization. An important number of reviews on the subject published recently stress this fact [119–121]. Also, significant work towards improving docking software to account for polarization and halogen bond formation has appeared [122–124]. Hence, only a few examples are presented here.

In a typical example, a specific inhibitor for the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4) employing halogen bonding has recently been reported. It represents a variation of the Bauerine C (83, Fig. 17), originally isolated from blue-green alga Dichithrix baueriana. Inhibitor 84, with similar structure and engineered to prevent the ATP-mimetic binding mode, was synthesized and tested. A high IC50 (i.e., 16.5 ± 6) for CLK1 was observed. The co-crystals were resolved and confirmed the presence of halogen bonding [125].

Fig. 17
Fig. 17

Molecules investigated as CDC2-like kinase inhibitor, stabilizer of the p53 mutant Y220C and AR inhibitor, which display halogen bonding for binding [125, 126].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

While halogen bonding clearly plays a major role in this molecular recognition, its use is coincidental.

Another approach is the use of halogen-enriched libraries for lead discovery. Such method has been successfully applied to stabilize the p53 mutant Y220C. Boeckler and co-workers employed a halogen-enriched library of fragments built by replacing the classical molecular weight criterion by a numerical limit of heavy atoms. Screening of the p53 mutant by differential scanning fluorimetry (DSF) and secondary screenings by NMR and ITC resulted in the discovery of lead fragment 85. Traditional computer-assisted lead optimization improved the affinities with compounds 86–89 (Fig. 17), notably yielding a 10-fold increase with compounds 86 and 87. In addition, the effect of halogen exchange was assessed showing significant and gradual decrease in affinity when using bromo and chloro derivatives [119].

The binding mode during each step of optimization was confirmed by X-ray diffraction of the co-crystals. Studies in human cancer cells confirmed apoptosis only for the mutant Y220C.

Systematic studies aimed to unveil the importance of halogen bonding and to achieve more active molecules have been reported. To the best of our knowledge, the first systematic study on halogen bonding in protein-ligant interaction was reported by Danner, Haap, Diederich and co-workers. Based on proline derivatives acting as human Cathepsin L (hCatL) inhibitors previously reported, which bind covalently in the S1 pocket, a typical and extensive lead optimization was carried out, focusing notably on the roles of halogens. Some examples are presented in Fig. 18 (92a–f); the effect of increasing the polarizability of the halogen is evident and very systematic, showing the best IC50s for the most polarizable iodine. The binding geometries were confirmed to be similar across the series by X-ray crystallography [127].

Fig. 18
Fig. 18

Inhibitors of hCatL and MEK1 kinase studied systematically to unveil halogen-bonding effects [127–129].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

While the previous example takes place in a polar environment, the same trend can be observed in apolar media. The series of inhibitors of MEK1 kinase 93a–e show that better affinities are obtained with highly polarizable halogens, even in the highly hydrophobic media of the back pocket of MEK1 kinase [128, 129].

Whereas applying halogen bonding concepts to obtain better affinities and thus better inhibition may seem straightforward, in reality it requires the an ideal situation to work. To help to predict the usefulness of halogen bonding in medicinal chemistry, computational methods are being developed intensively. This is not trivial, given that contributions from binding, solvation, dynamics and others have to be considered in large molecular systems [130]. One example was reported in the design of aldose reductase (AR) inhibitors: their design was inspired on the reported IDD388 (90b) inhibitor; changes to explore the strength of the formed halogen bond not only exchanging the halogen, but also addressing the electron withdrawing strength of the arene by varying the number and position of fluorinations. The family of inhibitors 90a–90g was investigated computationally and experimentally. While the observed correlations were not perfect, the major role of halogen bonding could be confirmed indicating that good approximations are accessible in-silico [126].

With the recognition of the applicability of halogen bonding in this field and the steady improvement of computational methods, medicinal applications of halogen bonding should become the norm much like it happened before with cation-π interactions, for instance.

Other applications in solution

Not all examples can be assigned into the previous categories; here, we try to highlight some of these less standard applications, which most often consist of single examples. Additionally, applications at the solid-liquid interface are considered partially due to their fundamental recognition, which takes place, formally, in solution-phase.

Halogen-bonded gels

Gel formation is a widespread application of supramolecular chemistry. The use of noncovalent chemistry has the additional advantage to give self-healing properties and to reversibly trigger gel formation by external stimuli [131, 132].

The first proof-of-the-concept example where halogen bonding is used to trigger gel formation was reported recently [133]. Formation of two-component gels was possible using compounds 94 and 95 in presence of halogen-bond linker 98 in competitive methanol/water mixtures upon rapid cooling. Similarly, with gelator 96 it was possible to trigger gelation by addition of TBACl or 4,4′-bipyridine (97) in DMSO/water. Equimolar mixtures of 94 and 96 also formed gels in DMSO/water. The microscopic structure of all three gels differed significantly: there was loss of organization, which was highest for the first case, and increasingly thinner fibers for the latter two.

These examples prove the possibility to form gels either by the use of gelators including the halogen-bond forming groups or by introducing partners of gelation.

Halogen bond-assisted electron transfer

A kinetic study of the redox reaction of halogenated methane, namely tetrabromomethane and tribromonitromethane, with electron donor N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD) has shown that electron transfer in this case proceeds by an inner-sphere electron-transfer mechanism as opposed to the electron transfer of the same acceptor with decamethylferrocene, which occurs by an outer-sphere electron transfer [134].

Such a situation should be considered in systems where electron transfer is important, like photosystems [135].

Assembly of gold nanoparticles on quartz and silicon surfaces

It has been demonstrated that functionalization of gold nanoparticles with halogen-bond donors (99, Fig. 19) leads to aggregation of the nanoparticles in the presence of a linker accepting halogen bonds (101). Aggregation of gold nanoparticles was easily followed by changes in the surface plasmon absorption band: in absence of the ditopic halogen-bond acceptor or with monotopic capper 104 no changes in the absorption spectrum were observed. In a similar way, using perfluorophenyl 100, which lacks the halogen-bond donor, only minor changes were observed. These observations were further confirmed by transmission electron microscopy (TEM) [136].

Fig. 19
Fig. 19

Gelators and halogen-bond linkers explored by Resnati, Metrangolo and co-workers; Molecules applied to the functionalization of gold nanoparticles [133, 136, 137].

Citation: Pure and Applied Chemistry 87, 1; 10.1515/pac-2014-0807

The same strategy was applied to functionalize silicon and quartz surfaces. Indeed, quartz and silicon functionalized with monolayers of terminal-pyridine organic compounds can interact with gold nanoparticles functionalized as described before. Subsequent growth of the gold nanoparticles layer was accomplished in presence of different linkers, (102–104) showing significant differences when employing linear (102), 2D (103) and 3D (104) linkers, confirming that molecular geometry influences, while not transferring, the aggregation patterns as confirmed mainly by atomic force microscopy (AFM) [137].

The possibility to use halogen bonding in this context suggests the orthogonal application in surface patterning. It also indicates that the formation of well-defined nanoparticles-based assemblies is possible.

Purification of iodoperfluoroalkanes by halogen bonding

Halogen bonding between iodoperfluoroalkanes and chloride has been used to separate the former from hexane. Using strong ion exchange, that is silica functionalized with 3-hydroxy-N,N,N-trimethylpropan-1-aminium chloride, it was possible to separate iodoperfluoroalkanes, mono- and diiodo, methane to dodecane, from hexane in a column like set-up [138].

Further evidence confirming the binding and selective extraction of analytes was provided by UV/Vis, Raman and NMR spectroscopy. This system was applied to the recovery of iodoperfluoroalkanes in soil samples and showed good performance in the selective recovery of diiodo compounds with ng·g–1 accuracy.

Conclusions and future perspectives

The past 10 years mark the take-off for the applications of halogen bonding in solution and in spite of a noticeable inclination to mimic hydrogen bonding, its characteristic properties have quickly been noticed and exploited.

When comparing hydrogen to halogen bonding there are two important differences: the steric demands and the directionality of the noncovalent bond. These important differences are evident, for instance, for anion receptors where completely different selectivities are observed with hydrogen and halogen bonds. Moreover, the possibility of mechanically fix conformations, that would otherwise be dynamic with hydrogens while preserving bonding possibilities, offers an additional tool for supramolecular design.

Importantly, while hydrogen and halogen bonding can be rationalized to have a common origin, it has been shown that its basicity scales are not identical; moreover, the influence solvent has on one or the other is significantly different. Exploiting these not obvious disparities can lead to molecular systems where hydrogen and halogen bonding have orthogonal roles.

In sharp contrast with the ubiquitous hydrogen bonds, halogen bonding requires relatively large fragments, e.g., an iodopyridinium hexafluorophosphate, to form a single bond. This situation is probably the origin of its delayed introduction in functional systems; the newly reported moieties, albeit in small number, should inspire future applications.

As a matter of fact, cationic halogen bond donors are ideal as receptors in aqueous environment, giving high affinities and being readily available. Neutral triazole and perfluorinated materials are compatible with hydrophobic media, a situation most uncommon with hydrogen-bond donors that are, by definition hydrophilic and typically require extensive hydrophobic domains to compensate, e.g., ion channels.

The main field where relevant applications of halogen bonding are expected to appear is in medicinal chemistry. Indeed, applications in this domain are different: strong halogen-donors are virtually absent and have almost exclusivity for the use of iodoarenes as halogen-bond donors. It is apparent that a medium to weak interaction is sufficient and eliminates the need for stronger halogen-bond donors, a situation dramatically different from other applications in solution-phase.

This review, by its context, has overlooked the significant contributions of theoretical chemistry and computer-assisted modeling despite the fact that they have been playing a major role in the rediscovery and late development of halogen bonding. It should be underscored here that rational design, be it for protein-ligand interaction or supramolecular system conception, will require significant support by these disciplines.

The author is confident that while halogen bonding is not to remain a field on its own but to be dispersed into other domains of science as we learn to understand it better, the path to be covered is exciting and hopefully reserves still unforeseen surprises.

Acknowledgments

The author apologizes to all authors of unintentionally overlooked contributions. The IUPAC is acknowledged for the prize and the opportunity of writing this review. The author would specially like to express his gratitude towards his PhD advisor Prof. Stefan Matile for his guidance and support. All collaborators, whose names appear in the references, are warmly acknowledged.

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  • View in gallery

    (a) Electrostatic potential surfaces of CF4, (top left) CF3Cl, CF3Br and CF3I (bottom right) red represents electron-rich and blue electron-poor regions. (b) Schematic representation and preferred geometries of the possible interactions of a typical halogen in a halocarbon towards Lewis acid and bases. (c) Simplistic representation of halogen-bond formation.

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    (a) Crystal structures of the four-stranded DNA H-isomer (hydrogen bonding) and the X-isomer (halogen bonding) studied by Ho and co-workers [34]. (b) Schematic representation of the X-isomer. Copyright (2007) National Academy of Sciences, USA.

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    Pseudorotaxane employing halogen bonding reported by Beer and co-workers.

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    Rotaxane assembly by anion-halogen bond templation.

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    [2]Catenanes assembled by halogen-bond formation.

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    Components and resulting [2]catenane assembled purely by halogen bonding.

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    Anion receptors based on perfluorinated iodoarenes by Metrangolo, Resnati, Taylor and co-workers [54–56].

  • View in gallery

    Anion receptors reported by Beer and co-workers.

  • View in gallery

    Model reaction employed by Bolm and co-workers to explore catalysis with halogen-bond donors [82].

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    Model reactions and catalysts employed by Tan and co-workers to explore catalysis with multidentated halogen-bond donors [83].

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    Ritter-like solvolysis and catalysts explored in the context of halogen-bond activation of carbon-halogen bonds by Huber and co-workers [86–89].

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    Model reactions and catalysts employed by Huber, Coulembier and co-workers to explore halogen-bond catalysis [90–92].

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    The most common methods to characterize synthetic ion transport systems. (a) The HPTS assay, a typical experiment with fluorogenic vesicles. (b) Typical fluorescent trace for a single HPTS experiment. (c) Typical dose-response curve to determine the effective molarity needed to obtain 50 % transport activity (EC50) and the Hill coefficient (n). (d) Typical set-up for planar bilayer conductance experiments. (e) Current flow changes in response to a carrier anion transporter. Adapted from reference [108] with permission, © 2012 Nature Publishing Group.

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    Calix[4]arenes decorated with halogen-bond donors and anion-π surfaces to achieve anion transport in bilayer membranes; proposed binding of tetramethylammonium (TMA) cation and chloride are shown.

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    (a) Halogen-bond donors explored in the context of transmembrane anion transport. (b) Top, proposed structure responsible for anion-translocations; bottom, ball-and-stick model of chloride bound to six perfluoro-1-iodobutane by DFT simulations. Adapted from reference [108] with permission, © 2012 Nature Publishing Group.

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    Halogen-bond cascades explored for channel-like anion transport in bilayer membranes; arrows show the proposed mechanism of action.

  • View in gallery

    Molecules investigated as CDC2-like kinase inhibitor, stabilizer of the p53 mutant Y220C and AR inhibitor, which display halogen bonding for binding [125, 126].

  • View in gallery

    Inhibitors of hCatL and MEK1 kinase studied systematically to unveil halogen-bonding effects [127–129].

  • View in gallery

    Gelators and halogen-bond linkers explored by Resnati, Metrangolo and co-workers; Molecules applied to the functionalization of gold nanoparticles [133, 136, 137].