Self-Assembled Tetrahedral Hosts As Supramolecular Catalysts
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Article Cite This: Acc. Chem. Res. 2018, 51, 2447−2455 pubs.acs.org/accounts Self-Assembled Tetrahedral Hosts as Supramolecular Catalysts Published as part of the Accounts of Chemical Research special issue “Supramolecular Chemistry in Confined Space and Organized Assemblies”. Cynthia M. Hong, Robert G. Bergman,* Kenneth N. Raymond,* and F. Dean Toste* Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States Department of Chemistry, University of California, Berkeley, California 94720, United States CONSPECTUS: The field of supramolecular chemistry has its foundation in molecular recognition and selective binding of guest molecules, often with remarkably strong binding affinities. The field evolved to leverage these favorable interactions between the host and its guest to catalyze simple, often biomimetic transformations. Drawing inspiration from these early studies, self-assembled supramolecular hosts continue to capture a significant amount of interest toward their development as catalysts for increasingly complex transformations. Nature often relies on microenvironments, derived from complex tertiary structures and a well-defined active site, to promote reactions with remarkable rate acceleration, substrate specificity, and product selectivity. Similarly, supramolecular chemists have become increasingly intrigued by the prospect that self-assembly of molecular components might generate defined and spatially segregated microenvironments that can catalyze complex transformations. Among the growing palette of supramolecular catalysts, an anionic, water-soluble, tetrahedral metal−ligand coordination host has found a range of applications in catalysis and beyond. Early work focused on characterizing and understanding this host and its various host−guest phenomena, which paved the path for exploiting these features to selectively promote desirable chemistries, including cyclizations, rearrangements, and bimolecular reactions. Although this early work matured into achievements of catalysis with dramatic rate accelerations as well as enantioenrichment, the afforded products were typically identical to those produced by background reactions that occurred outside of the host microenvironment. This Account describes our recent developments in the application of these anionic tetrahedral hosts as catalysts for organic and organometallic transformation. Inspiration from natural systems and unmet synthetic challenges led to supramolecular catalysis displaying unique divergences in reactivity to give products that are inaccessible from bulk solution. Additionally, these tetrahedral assemblies have been shown to catalyze a diverse range of transformations with notable rate acceleration over the uncatalyzed background reaction. The pursuit of complexity beyond supramolecular catalysis has since led to the integration of these tetrahedral catalysts in tandem with natural enzymes, as well as their application to dual catalysis to realize challenging synthetic reactions. Downloaded via UNIV OF CALIFORNIA BERKELEY on February 6, 2019 at 01:22:33 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Variation in the structure, including size and charge, of these tetrahedral catalysts has enabled recent studies that provide insights into connections between specific structural features of these hosts and their reactivities. These mechanistic studies reveal that the solvent exclusion properties, hydrophobic effects, confinement effects and electrostatic effects play important roles in the observed catalysis. Moreover, these features may be leveraged for the design of supramolecular catalysis beyond those described in this Account. Finally, the supramolecular chemistry detailed in this Account has presented the opportunity to emulate some of the mechanisms nature engages to achieve catalysis; however, this relationship need not be entirely unidirectional, as the examples describe herein can stand as simplified model systems for unravelling more complex biological processes. ■ INTRODUCTION parameters and yield the intended outcome, which constrains The canonical reaction within a flask limits synthetic chemists’ the scope of transformations performed in synthetic chemistry. fi control over reactivity to macroscopic parameters: temperature, Supramolecular assemblies with well-de ned cavities present solvent, reagent concentrations, and the exclusion of circum- a rare opportunity for synthetic chemists to surpass these stantially deleterious components (e.g., water, oxygen, and light). This necessitates that all individual mechanistic steps and Received: July 3, 2018 reaction intermediates must be amendable to the chosen Published: October 1, 2018 © 2018 American Chemical Society 2447 DOI: 10.1021/acs.accounts.8b00328 Acc. Chem. Res. 2018, 51, 2447−2455 Accounts of Chemical Research Article limitations by generating internal microenvironments that are distinct from bulk solution. Upon encapsulation, guests are influenced by the host at the molecular level via these microenvironments, not parameters defined at the macroscopic level. Common manifestations of this control include (i) segregation of guests from solvent and nonencapsulated constituents, (ii) conformational control over the guest, (iii) shifts in equilibria to generate reactive species, and (iv) dramatic increases in effective concentrations upon binding multiple guests. These phenomena, among others, control the relative Figure 1. (a) Crystal structure of tetrahedral host 2. (b) Schematic energetics of the ground and transition states of substrates and representation of host 2 [K12(Ga416)]. ultimately grant new opportunities to achieve a wealth of homogeneous applications including catalysis,1 reactive inter- 13 2 3 substitution pattern in 1 (Figure 1b). While several III and IV mediate stabilization, chemical sensing, and the mimicry of oxidation state metal hosts have been prepared, Ga(III) is most biological processes such as signal transduction,4 multicatalytic commonly used to generate 2 [K12(Ga416)]. Because each cascades,5 configurationally adaptive binding,6 and information − 7 Ga(III) triscatecholate has a formal trianionic charge, 2 is transfer. overall dodecaanionic. By virtue of this high charge, the host is Supramolecular chemists draw inspiration from nature’s 8 soluble in water and polar organic solvents. In terms of size, the precise chemistry. In biological systems, complex reactions host falls just within the nanoscale regime, measuring about 13 Å ffi featuring high uncatalyzed energetic barriers proceed e ciently from vertex to vertex. with excellent selectivities, despite limited temperature control For catalysis, the most pertinent feature of the host is the ’ and an abundance of reactive species. Enzymes exquisite microenvironment within. Like many enzymatic active sites, this command over substrates is achieved by the isolation of microenvironment excludes the bulk solution by virtue of the substrates into customized active sites. The parallels between tightly geared hydrocarbon walls. The 1,5-substitution pattern of enzymatic active sites and the microenvironments of supra- the naphthalene in 1 sets the metal-binding catecholamide molecular hosts are self-evident, as both rely on molecular (CAM) moieties apart, enabling the arene walls of 2 to “breathe” recognition, substrate isolation, and conformational control. via amide bond rotation about the C−N bond to accommodate Thus, the development of supramolecular chemistry neces- guests of variable sizes and shapes, including spherical, prolate, sitates the interpretation and application of insights gleaned and cylindrical, as evidenced by NMR spectroscopy, high from enzymatic catalysis. resolution mass spectrometry, UV−vis spectroscopy, and single- The broad range of supramolecular architectures applied to crystal X-ray diffractometry.12 Below the size exclusion limit, catalysis spans from early covalent structures to self-assembled 8−11 cationic guests are often strongly bound (log Ka up to 4.61) due systems constructed via a number of assembly motifs. In this to electrostatic enthalpic and solvation-related entropic driving Account, we survey recent advancements within a fruitful forces, while neutral guests are bound by the hydrophobic collaboration between the Toste, Raymond, and Bergman effect.14,15 The exceptional flexibility of 2 bears consequences − groups studying self-assembled metal ligand tetrahedra with for the kinetics and mechanism of host−guest association. Guest fi well-de ned, isolated cavities. In contrast to previous topical encapsulation and self-exchange are known to proceed through reviews, we focus on the divergent reactivities achieved, as well an aperture dilation mechanism, rather than host rupture by as the development of complex multicatalytic systems and partial ligand dissociation.16 This mechanism constitutes an mechanistic probes. To demonstrate the strategies employed in additional parallel with biological systems, wherein enzymes our pursuit of catalysis, we begin with a discussion of the accommodate their substrates by architectural deformation and structural characteristics of the tetrahedron and revisit select configurationally adaptive binding. − host guest studies to give context to crucial insights regarding A useful metric for studying enzyme structures is the rates of ff the e ects of encapsulation. We then connect lessons learned amide hydrogen−deuterium exchange. These exchange kinetics