Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Tetrathiafulvalene (TTF)-Annulated Calix[4]pyrroles: Chemically Switchable Systems with Encodable Allosteric Recognition and Logic Gate Functions Published as part of the Accounts of Chemical Research special issue “Supramolecular Chemistry in Confined Space and Organized Assemblies”. Jung Su Park*,† and Jonathan L. Sessler*,§ Downloaded via UNIV OF SOUTH DAKOTA on September 11, 2018 at 14:15:28 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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Department of Chemistry, Sookmyung Women’s University, 100 Cheongpa-ro 47-gil, Yongsan-gu, Seoul 04310, Republic of Korea Department of Chemistry, The University of Texas at Austin, 105 East 24th Street-Stop A5300, Austin, Texas 78712-1224, United States
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CONSPECTUS: Molecular and supramolecular systems capable of switching between two or more states as the result of an applied chemical stimulus are attracting ever-increasing attention. They have seen wide application in the development of functional materials including, but not limited to, molecular and supramolecular switches, chemosensors, electronics, optoelectronics, and logic gates. A wide range of chemical stimuli have been used to control the switching within bi- and multiple state systems made up from either singular molecular entities or supramolecular ensembles. In general, chemically triggered switching systems contain at least two major functional components that provide for molecular recognition and signal transduction, respectively. These components can be connected to one another via either covalent or noncovalent linkages. Of particular interest are switchable systems displaying cooperative or allosteric features. Such advanced control over function is ubiquitous in nature and, in the case of synthetic systems, may allow the capture and release of a targeted chemical entity or permit the transduction of binding information from one recognition site to another. Allosterically controlled complexation and decomplexation could also permit the amplification or deamplification of analyte-specific binding affinity, lead to nonlinear binding characteristics, or permit a magnification of output signals. Our own efforts to develop chemically driven supramolecular switches, advanced logic gates, and multifunction cascade systems have focused on the use of tetrathiafulvalene (TTF) annulated calix[4]pyrroles (C4Ps). These systems, TTF-C4Ps, combine several orthogonal binding motifs within what are conformationally switchable receptor frameworks. Their basic structure and host−guest recognition functions can be controlled via application of an appropriate chemical stimulus. Homotropic or heterotropic allosteric molecular recognition behavior is often seen. This has allowed us to (1) produce self-assembled structures, (2) control switching between bi- and multistate constructs, (3) generate chemical logic gates performing chemicalbased Boolean logic operations, (4) create ionically controlled three-state logic systems that release different chemical messengers and activate disparate downstream reactions, and (5) encode a variety advanced functional operations into what are relatively simple molecular-scale devices. Looking to the future, we believe that exploiting allosteric control will expand opportunities for supramolecular chemists and allow some of the complexity seen in biology to be reproduced in simple constructs. Of particular appeal would be a capacity to release chemical messengers at will, perhaps after a prior capture and chemical modification step, that then encode for further downstream functions as seen in the case of the small molecules, such as neurotransmitters and pheromones, used by nature for the purpose of intraentity communication. Molecular scale logic devices with allosteric functions are thus the potential vanguard of a new area of study involving interactions between multiple discrete components with an emphasis on functional outcomes.
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INTRODUCTION Molecular scale recognition and signaling processes are routinely found in nature. The elegance of these processes continues to provide an inspiration to create supramolecular and self-assembled architectures that display complex functional behavior.1 To date, a large number of noncovalent © XXXX American Chemical Society
interactions have been explored in an effort to mimic in rudimentary fashion the often-complex hierarchical ensembles seen in nature.2,3 These noncovalent interactions include but Received: June 26, 2018
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DOI: 10.1021/acs.accounts.8b00308 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research
is only observed in this form. However, in the absence of an anion, C4Ps generally exist in a 1,3-alternate conformation (Figure 1). Anion recognition thus serves to effect a direct switching between forms that have very different structures and recognition features.
are not limited to electrostatic, hydrogen bonding, cation−π, π−π stacking, CH−π, anion−π, donor−acceptor, and metal− ligand interactions.1−4 Their strength, directionality, and inherent structural limitations can have a tremendous influence on the resulting supramolecular constructs and their function.5 The reversible nature of many noncovalent interactions has allowed the construction of dynamic systems that are susceptible to external stimuli. In certain cases, reversible switching between bistable or multiply stable states displaying different chemical or physical properties can be achieved by application of a photochemical or redox stimulus.6,7 Such stimulus-induced changes between states is a key characteristic of many functional materials, including molecular and supramolecular switches, chemosensors, optoelectronic devices, and molecular-scale logic gates.6−8 Switching also underlies many biological and artificial information processing systems. In recent years, we have developed a number of molecular switches based on tetrathiafulvalene (TTF)annulated calix[4]pyrroles (TTF-C4Ps) that display allosteric recognition features. Our progress along these lines is summarized in this Account. A molecular switch may be defined as any chemical system that allows reversible and controlled access to two or more quasi-stable states upon application of an appropriate external stimulus or stimuli. Since the seminal report of a Boolean AND logic operation in a fluorescent chemosensor switch for Na+ and H+ by de Silva and co-workers, artificial molecular and supramolecular switches, as well as information processing systems, have attracted ever-increasing attention within the research community.9 A number of very elegant systems are now known. External stimuli that have been used to control switching between the states, include light, temperature, electrochemical, magnetic, and various chemical reagents.10 Chemically driven molecular switches displaying allosteric behavior are of particular interest. Allosteric recognition is common in nature and is one of the more elegant strategies used to regulate precisely a variety of biochemical processes.11 In allosteric systems, an initial binding event involving a receptor generally induces conformational changes that either enhance or diminish the magnitude of subsequent substrate recognition events. Receptors demonstrating allosteric binding behavior are attractive in the context of molecular switch design because they may permit the effects of an external stimulus to be amplified or deamplified. This provides an additional element of control. As detailed below, TTF-C4Ps have allowed us to create chemically driven supramolecular switches, stimulus responsive self-assembled constructs, controllable logic gates, and multicomponent cascade systems.
Figure 1. Two representative conformations of the calix[4]pyrrole framework as determined by single crystal X-ray diffraction analyses of meso-octamethyl calix[4]pyrrole and its chloride bound form.
The controllable nature of the molecular motions, specifically the anion-induced switching between conformational forms, seen for C4Ps makes these systems attractive as potential allosteric receptors. To be effective as an allosteric receptor, a recognition system typically needs to not only possess dynamic features but also express two or more binding sites capable of recognizing multiple guests and in a disparate manner. Simple, unfunctionalized C4Ps display the requisite dynamic features. However, to use C4Ps in the context of allosteric recognition, additional binding motifs must be introduced. We and others have pursued the development of C4P derivatives with multiple recognition features along two generalized lines.12−16 The first involves functionalization at the meso positions and the second replacement of the βpyrrolic protons with synthetically more elaborate substituents.13−15 While the first approach has proved highly effective for the preparation of second- and third-generation ion receptors, we felt that the second option would prove more useful in the context of creating systems that display allosteric recognition features. With such a view in mind and in conjunction with collaborators from Odense, we created a series of TTF-bearing pyrrolic building blocks.17,18 These were then used to prepare a number of TTF-annulated calix[n]pyrroles19−21 and other oligopyrrolic macrocyles.22,23 The smallest members of this family, the TTF-C4Ps, have proved capable of binding a variety of guest molecules in organic media. Often allosteric binding is observed. To date, three TTF-annulated pyrroles with different aromatic rings, specifically the bis-S-propyl, benzannulated, and thiophene derivatives 1−3, have been used as precursors for the preparation of TTF-calix[n]pyrroles (Figure 2).20,21 Standard condensation methods provided the TTF-C4Ps 9− 11 along with higher order products in certain instances. These three C4P products are considerably more electron rich than the parent system. Moreover, the presence of π-electron rich TTF “arms” was expected to lead to the production of frameworks capable of stabilizing donor/acceptor, charge-, or electron-transfer complexes with a variety of electron deficient substrates. The TTF subunits were also expected to support redox reactions that would not be expected in the case of simple C4Ps. As true for simpler C4Ps, the TTF-C4Ps 9−11 were found to bind small, Lewis basic anions, including halides and various oxo-anions.20,21 Most studies were carried out in halogenated solvents using the tetrabutylammonium (TBA+) salts of the anion in question. As in the case of unsubstituted C4Ps, anion
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CONFORMATIONAL PROPERTIES AND ALLOSTERIC NATURE OF TTF-CALIX[4]PYRROLE RECEPTORS Calix[n]pyrroles are oligopyrrolic macrocycles wherein each pyrrole unit is connected covalently through sp3 hybridized meso carbon bridges. The smallest member of the series, calix[4]pyrrole (C4P), was first reported as an anion receptor in 1996.12 Since then, many derivatives have been prepared for the purpose of recognizing, sensing, and extracting both anionic substrates and ion pairs.13,14 Anion recognition is typically the result of concerted hydrogen bonding interactions between the pyrrolic N−H protons and a bound Lewis basic anion. These concerted interactions are enhanced in the case of the so-called cone conformation, and typically anion binding B
DOI: 10.1021/acs.accounts.8b00308 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research
Figure 2. Aromatic-annulated TTF-pyrrolic building blocks (a) and tetrathiafulvalene−calix[4]pyrrole derivatives (b).
binding was accompanied by a conformational change from the most stable 1,3-alternate to the corresponding anion-bound cone conformation. This conformational change leads to formation of a concave cavity defined by the four substituted TTF subunits. Relative to the parent C4P, significantly higher binding affinities were observed for all anions tested under otherwise identical measurement conditions. This enhancement was ascribed to the inductive effect of the sp2 hybridized S atoms of the annulated TTF subunits on the pyrrolic N−H protons. X-ray crystallographic analyses revealed that the smaller tetraalkylammonium cation such as tetraethylammonium (TEA+) were encapsulated within the bowl-shaped electronrich TTF cavity, while larger cations such as tetraphenylphosphonium were found bound external to the cavity (Figure 3).24 Initial studies of 9 also led to the finding that the chloride anion binding affinities were correlated with the size of the tetraalkylammonium counter cations (TEACl = 1.5 × 107 M−1, TBACl = 7.8 × 105 M−1, THACl = 1.8 × 105 M−1, where THA+ = the tetrahexylammonium cation).25 The significantly higher Ka values seen for TEA+ vs THA+ led to the consideration that the smaller tetraalkylammonium cations were acting as positive allosteric regulators for chloride anion binding. Viewed in a different way, the counter cations, as well as the anions, could be considered as separate control elements
Figure 3. X-ray crystal structures of the chloride anion bound form of 10 with two different sized counter cations, tetraethylammonium (TEA+) (a) and tetraphenylphosphonium (b). Note the sizedependent encapsulation behavior.
that may be exploited to regulate the structure and recognition function of the TTF-C4Ps 9−11. Four limiting classes of allosteric behavior typically govern the chemistry of artificial supramolecular receptors with more than one binding site.11 Negative allosteric systems are ones where the binding of a first guest, or regulator, serves to reduce the affinity for the binding of one or more subsequent guests. Depending on whether the same or different guests are involved, the allosteric effects are defined as either homotropic or heterotropic. In contrast, in simple positive heterotropic allosteric systems the binding of a first guest serves to increase C
DOI: 10.1021/acs.accounts.8b00308 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Accounts of Chemical Research
Figure 4. X-ray crystallographic analyses of (a) TNB2⊂10, (b) TNP2⊂10, and (c) proposed origin of the positive homotropic cooperative binding observed for these guests.
the affinity for a second, different guest. The TEACl recognition discussed above falls into this category. Finally, and most challenging from the perspective of receptor design, are systems displaying positive homotropic allosteric behavior. In this case, the binding of a first substrate serves to amplify the binding of further identical guests. Such positive cooperative effects are ubiquitous in nature as exemplified by the dioxygen binding of dioxygen to hemoglobin. However, they are not commonly observed in synthetic systems, particularly in the context of neutral guest recognition. A particular appeal of the TTF-C4Ps is that they display positive homotropic allosteric behavior in the case of certain electron deficient guests. The discovery that TTF-C4Ps can display positive homotropic allosteric binding behavior came in studies involving three trinitroaromatic explosives, namely, 1,3,5trinitrobenzene (TNB), 2,4,6-trinitrotoluene (TNT), and 2,4,6-trinitrophenol (TNP). These substrates are small and were expected to intercalate into the cleft-like cavities defined by the TTF walls in the tweezers-like 1,3-alternate conformations of 9−11.19 In all cases, a 1:2 stoichiometry binding between the TTF-C4P receptors and the electron deficient guests was seen, as inferred from Job plots and X-ray diffraction analyses (cf. Figure 4). Based on an analysis of the binding isotherms using the Hill equation (Hill coefficient >1), Adair equation (K1 < K2), and the upward curvature seen in the Scatchard plots, it was concluded that the binding was subject to positive homotropic allostery. The greatest cooperativity was seen in the case of the thiophene-TTF-calix[4]pyrrole 11, followed by benzo-TTFcalix[4]pyrrole 10, and the S−Pr-TTF-C4P 9. This finding is consistent with the order of the overall binding constants. We ascribe the origin of the positive homotropic cooperative binding seen in the case of TNB, TNT, and TNP to the fact that recognition of a first neutral guest helps fix the conformation of the TTF-C4P in the 1,3-alternate conformation. It is also thought to induce polarization of the pyrrolic N−H protons within the second tweezers-like cleft. The net result is systems that show a dramatic response to nitroaromatic explosives. Easy-to-discern color changes are seen
upon simple mixing the TTF-C4P receptors with these deficient analytes. These colorimetric changes are ascribed to the appearance of charge-transition bands involving partial charge transfer from the HOMOs of the TTF-pyrroles to the LUMOs of the bound explosive. In addition to the colorimetric response observed in solution, significantly enhanced sensitivity and improved detection limits were achieved through incorporation of receptor 11 into a polymer microcantilever with an integrated deflection-sensing element; this gave a TNB detection limit of
