Halogen bonding in water results in enhanced anion recognition in acyclic and rotaxane hosts Matthew J. Langton 1 , Sean W. Robinson 1 , Igor Marques 2 , Vítor Félix 2 and Paul D. Beer 1 * Halogen bonding (XB), the attractive interaction between an electron-deficient halogen atom and a Lewis base, has undergone a dramatic development as an intermolecular force analogous to hydrogen bonding (HB). However, its utilization in the solution phase remains underdeveloped. Furthermore, the design of receptors capable of strong and selective recognition of anions in water remains a significant challenge. Here we demonstrate the superiority of halogen bonding over hydrogen bonding for strong anion binding in water, to the extent that halide recognition by a simple acyclic mono-charged receptor is achievable. Quantification of iodide binding by rotaxane hosts reveals the strong binding by the XB-rotaxane is driven exclusively by favourable enthalpic contributions arising from the halogen-bonding interactions, whereas weaker association with the HB-rotaxanes is entropically driven. These observations demonstrate the unique nature of halogen bonding in water as a strong alternative interaction to the ubiquitous hydrogen bonding in molecular recognition and assembly. A halogen bond is the highly directional, intermolecular attractive interaction between a Lewis-acidic halogen atom and a neutral or negatively charged Lewis base 1,2 . The Lewis-acidic electropositive region, termed the sigma-hole, is greatest in the heavier, more polarizable halogens and is enhanced by a covalently attached electron-withdrawing group (Fig. 1a). Although the utilization of halogen bonding (XB) in solid-state crystal engineering has been extensively explored 3–7 , its application in solution-phase molecular recognition and self-assembly remains underdeveloped, despite the obvious analogy with the ubiquitous hydrogen bond 8 . It is only very recently that seminal applications of XB to the fields of molecular recognition and assembly 9,10 , anion binding 11–16 and membrane transport 17 , catalysis 18 , structural biology 19 and medicinal chemistry 20 have resulted in an explosion of interest in this non-covalent intermolecular interaction. Surprisingly, however, experimental data quantifying this increasingly important interaction remain limited and confined merely to selected measurements in organic solvents 8,21–24 . To the best of our knowledge, a quantitative and systematic comparison of XB and hydrogen bonding (HB) interactions in water has yet to be reported, despite the importance of developing functional supramolecular systems for applications in this biologically and environmentally relevant solvent medium. The recognition of anions in such highly competitive media is non-trivial 25 and remains a key challenge for supramolecular chemistry, as a conse- quence of the fundamental role of anions in many biological, medical, environmental and chemical processes 26 . For example, chloride is found in high concentrations in extracellular fluids, with its misregulation being linked to diseases such as cystic fibrosis 27 , whereas iodide is necessary for hormone biosynthesis by the thyroid gland 28 . However, although there are a plethora of receptors capable of anion recognition in organic or organic–aqueous solvent mixtures, there are relatively few examples that can function in highly competitive water solutions 23 . Typically, such hosts are highly charged and involve multiple protonation equilibria, restricting the anion binding function to a narrow pH window 25 . Designing synthetic anion receptors that achieve the degree of affinity and selectivity observed in natural anion-binding proteins remains a difficult challenge 29,30 , despite extensive research over past decades. Interlocked molecules (in which two or more mol- ecules are mechanically interlocked but not covalently linked) such as rotaxanes and catenanes have been reported to be effective anion receptors, utilizing the unique three-dimensional binding cavity formed between the interlocked components to encapsulate the anion 31,32 . To date, however, anion recognition in pure water by such interlocked molecules has been thwarted by a lack of aqueous solubility of such receptors 33 . Here, we demonstrate the superior ability of XB over HB for strong anion binding in water, by comparing structurally related XB- and HB-donor bis-triazole pyridinium receptors, solubilized with β-cyclodextrin functionality (Fig. 1b) and integrated within both simple acyclic and interlocked rotaxane-based structural frameworks (Fig. 1c,d). We demonstrate an enhancement in anion binding affinity of up to two orders of magnitude mediated by halogen bonds in water. The extent of enhancement is such that rec- ognition of halide anions in water by a simple acyclic mono-charged XB receptor is achievable. Results and discussion Rotaxane receptor design and synthesis. Bis-prototriazole pyridinium receptors recognize anions through two convergent polarized C–H HB donors 34 . By replacing the triazole protons with iodine atoms, an analogous receptor that binds anions via two convergent halogen bonds is obtained, thus enabling a direct comparison of the strength of the two intermolecular interactions (Fig. 1c). Permethylated β-cyclodextrins impart aqueous solubility upon the anion receptors and act as bulky stopper groups for the axle components (Fig. 1d, blue) that prevent the macrocycle (Fig. 1d, red) de-threading from the rotaxane. Furthermore, permethylation renders the cyclodextrin soluble in organic solvents, facilitating synthetic manipulation and anion-templated synthesis of the rotaxanes in organic solvents such as dichloromethane. Bis-prototriazole pyridinium 1 and bis-iodotriazole pyridinium 2 were prepared from 3,5-diethynyl pyridine and azido-functiona- lized permethylated β-cyclodextrin (Supplementary Section 1). 1 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK, 2 Departamento de Química, CICECO and Secção Autónoma de Ciências da Saúde, Universidade de Aveiro, 3810-193 Aveiro, Portugal. *e-mail: paul.beer@chem.ox.ac.uk ARTICLES PUBLISHED ONLINE: 17 NOVEMBER 2014 | DOI: 10.1038/NCHEM.2111 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 1 © 2014 Macmillan Publishers Limited. All rights reserved.