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Submerging a Biomimetic Metallo‐Receptor in Water for Molecular Recognition

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Submerging a Biomimetic Metallo‐Receptor in Water for Molecular Recognition A Journal of Accepted Article Title: Submerging a Biomimetic Metallo-Receptor in Water for Molecular Recognition: Micellar Incorporation or Water Solubilization? A Case Study Authors: Solène Collin, arnaud parrot, Lionel Marcelis, emilio Brunetti, ivan jabin, gilles Bruylants, Kristin Bartik, and Olivia Reinaud This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201804768 Link to VoR: http://dx.doi.org/10.1002/chem.201804768 Supported by Chemistry - A European Journal 10.1002/chem.201804768 FULL PAPER Submerging a Biomimetic Metallo-Receptor in Water for Molecular Recognition: Micellar Incorporation or Water Solubilization? A Case Study Solène Collin,[a] Arnaud Parrot,[a] Lionel Marcelis,[b] Emilio Brunetti,[b,c] Ivan Jabin,[c] Gilles Bruylants,[b] Kristin Bartik,*[b] and Olivia Reinaud*[a] Abstract: Molecular recognition in water is an important topic but solvents, stem from the intrinsic properties of this solvent.[2] challenging task due to the very competitive nature of the medium. Indeed, it provides a very competitive medium for electrostatic The focus of this study is the comparison of two different strategies interactions, and particularly for the directional H-bonding for the water solubilization of a biomimetic metallo-receptor based on interactions. It is thus necessary to associate other types of the poly(imidazole) resorcinarene core. The first one relies on a new stabilizing effects in order to extract analytes from water. The synthetic path for the introduction of hydrophilic substituents on the hydrophobic effect[3] can be exploited for analytes that present an receptor, at a remote distance from the coordination site. The second apolar component in their structure.[4,5] For highly polar one consists in the incorporation of the organosoluble metallo- compounds, such as small anions,[6,7] coordination to a metal receptor into dodecylphosphocholine (DPC) micelles that mimics the cation[8–10] can provide an efficient way to shift the equilibria proteic surrounding of the active site of metallo-enzymes. The towards the formation of a host-guest adduct, i.e. a metal resorcinarene ligand can be transferred into water via both strategies complex.[11] However, water is also a strong competitor in the case where it binds ZnII over a large pH window. Quite surprisingly, very of metal-coordination due to its good donor ability in its neutral similar metal ion affinity, pH response and recognition properties were form or as hydroxide. In Nature, and in particular in the case of observed with both strategies. The systems, behave as remarkable proteins, this problem is circumvented[12] as the metallo active receptors for small organic anions in water, near physiological pH. sites are generally associated to a well-defined hydrophobic These results show that, provided the biomimetic site is well cavity that also plays a major role in substrate recognition. structured and presents a recognition pocket, the micellar Inspired by this design, we are developing biomimetic cavity- environment has very little impact on both metal ion binding and guest based metal complexes as a tool for molecular recognition.[13] hosting. Hence, micellar incorporation represents an easy alternative These so-called “funnel” or “bowl” complexes have in common the to difficult synthetic work, even for the binding of charged species presence of a hydrophobic cavity in the vicinity of a coordinated (metal cations or anions), which opens new perspectives for metal ion that act in synergy for guest binding. The funnel Manuscript molecular recognition in water, either for sensing, transport or complexes, based on the flexible calix[6]arene core, have been catalysis. shown to display remarkable recognition properties towards neutral guests presenting both, good donor ability for metal ion binding and good shape complementarity to the cone cavity (Figure 1, left).[14–17] Surprisingly, most of these complexes were Introduction observed to be reluctant to anion binding, which made them unusually selective.[18] This was attributed to electrostatic The study of molecular recognition processes in water is a field of repulsion by the oxygen-rich narrow rim as a second coordination great interest, not only for the elaboration of efficient and selective sphere. In contrast, the rigid bowl-shaped resorcinarene-based sensors for environmental analyses or the development of green metal complexes, offering very different second coordination [1] catalysts, but also for the elucidation of biological processes. sphere and shape, display strong affinity to small anionic The major difficulties encountered in water, compared to organic guests.[19] Our most recently described bowl complex, based on the new [20] ligand Rim4, is depicted in Scheme 1. In this system, the [a] S. Collin, A. Parrot, and O. Reinaud resorcinarene is functionalized at its large rim with four imidazole Laboratory of Pharmacological and Toxicological Chemistry and II Biochemistry arms of which three firmly hold the Zn ion at the entrance of the Université Paris Descartes bowl-shape cavity, whereas the fourth is hemilabile. We showed 45, rue des Saints-Pères / 75006 Paris / FRANCE that this hemilabile arm assists the deprotonation of a neutral Accepted E-mail: [email protected] guest molecule, which can then bind as an anion to the metal [b] L. Marcelis, E. Brunetti, G. Bruylants, and K. Bartik Engineering of Molecular Nanosystems center. It was also shown to promote the selective base-catalyzed Université Libre de Bruxelles hydration of acetonitrile into acetamide, thus coined as “a third Avenue F. D. Roosevelt 50, CP165/64, B-1050 Brussels / BELGIUM degree of biomimetism”.[20] In our quest towards more E-mail: [email protected] biomimetism, the following aspects were then considered: i) the [b] E. Brunetti, and I. Jabin. Laboratory of Organic Chemistry solvent for the natural systems, i.e. enzymes, is water; and ii) in Université Libre de Bruxelles soluble enzymes, the active site is surrounded by a large proteic Avenue F. D. Roosevelt 50, CP160/06, B-1050 Brussels / BELGIUM structure, mostly hydrophobic in its heart, whereas a polar surface Supporting information for this article is given via a link at the end of insures its water-solubility. the document. This article is protected by copyright. All rights reserved. Chemistry - A European Journal 10.1002/chem.201804768 FULL PAPER II (-) Scheme 1. Schematized structure and general host-guest behavior of complex Rim4Zn in MeCN. G stands for an anionic guest ligand and S stands for a solvent or water molecule. To face this new aspect of biomimetism, two different strategies amines in water.[21,22] The second strategy relies on the II have been considered for the water-solubilization of the Rim4Zn incorporation of the organo-soluble metal complex into micelles. system. The first strategy consists in the implementation of This has been exemplified previously for a metallo-receptor with hydrophilic moieties to the macrocyclic structure. This requires an uranyl-salophen complex for anion binding.[23,24] More recently, careful synthetic design to avoid interaction between the we have reported the successful incorporation of a calix[6]arene hydrophilic moieties and the metal ion and often leads to laborious ZnII funnel complex in DPC micelles and have shown that the synthetic work. Such a strategy has been previously successfully system keeps its hosting properties towards amines at applied to various funnel complexes as illustrated by physiological pH. However, none of these funnel complexes tris(imidazole)ZnII-based and trenCuII-based calix[6]arene recognize anions, even lipophilic ones.[25] systems that behave as selective receptors for lipophilic primary Manuscript Figure 1. Left: A water-soluble funnel complex. Right: two strategies for water solubilizing a resorcinarene-based ZnII receptor, subject of this article. Here, we report a study that compares the two different strategies Synthesis of the water-soluble ligand WRim4 for the water-solubilization of a resorcinarene-based metallo- We have recently described a strategy to transform an organo- receptor (Figure 1, right) for the recognition of small organic soluble ligand based on a resorcinarene macrocycle presenting [26] guests that bind in their anionic form t (Figure 1, right): direct three imidazole groups (so-called Rim3) into a water-soluble water-solubilization of the ligand into water, which will then one thanks to the introduction of quaternary ammonium groups Accepted [27] surrounds the metallo receptor, or encapsulation into a zwiterionic as “feet”. The synthesis of WRim4 followed a similar strategy micelle that will mimic the hydrophobic environment provided by (Scheme 2), but using pyridinium as water-solubilizing feet, the proteic backbone of natural systems. according to a procedure adapted from one previously reported by Rebek et al. for deep cavitands.[28] The tetrabromoderivative
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