Proton-Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

Abstract

Synthetic supramolecular assemblies able to encapsulate guest molecules often impart unique reactivity on the encapsulated guests. Although much less complex than the active sites of enzymes, synthetic host molecules have been developed that can carry out complex reactions within their cavities.Over the last decade, the Raymond group has developed a series of self-assembled supramolecules able to encapsulate small guest molecules. This Account details recent collaborative work between the Raymond and Bergman groups focusing on chemical catalysis stemming from the encapsulation of protonated guests and expanding to acid-catalysis in basic solution.We initially investigated the ability of a self-assembled supramolecular host molecule to encapsulate protonated guests. Our study of encapsulated protonated amines revealed a rich array of host-guest chemistry. Guest exchange studies established that the rates of encapsulated protonated amines were dependent on the steric bulk of the amine rather than its basicity. The purely-rotational T symmetry of the host molecule effectively desymmetrized the geminal N-methyl groups and allowed for the observation and quantification of the barriers for nitrogen inversion followed by bond rotation. In further screening of amine guests, small nitrogen heterocycles such as N-alkylaziridines, -azetidines and -pyrrolidines were found to be encapsulated as proton-bound homodimers or homotrimers. Expanding 3 the study of protonated amines to investigate the thermodynamic stabilization of protonated amines showed that encapsulation makes the encapsulated amines more basic and raises the effective basicity of the protonated amines by up to 4.5 pK a units.The thermodynamic stabilization of protonated guests was translated into chemical catalysis by applying the stabilization of protonated species to reactions proceeding through monocationic protonated intermediates. Orthoformates, which are generally stable in neutral or basic solution, were found to be suitable substrates for catalytic hydrolysis by the assembly. Orthoformates small enough to undergo encapsulation were readily hydrolyzed by the assembly in basic solution with observed rate accelerations of up to 3900 when compared to the uncatalyzed reaction. Furthering the analogy to enzymes that obey Michaelis-Menten kinetics, competitive inhibition was demonstrated with the inhibitor NPr 4 + , thereby confirming that the interior cavity of the assembly was the active site for catalysis. Mechanistic studies revealed that the assembly is intimately required for catalysis and that the rate limiting step of the reaction is proton-transfer from hydronium to the encapsulated substrate.Encapsulation in the assembly changes the orthoformate hydrolysis mechanism from an A-1, in which decomposition of the protonated substrate is the rate limiting step, to an A-S E 2 mechanism in which proton transfer is the rate limiting step. The study of hydrolysis reactions in the assembly was next extended to acetals, which were also catalytically hydrolyzed ...

External and Internal Guest Binding of a Highly Charged Supramolecular Host in Water: Deconvoluting the Very Different Thermodynamics

“…[16][17][18] The [Ga 4 L 6 ] 12-assembly (Figure 1, 1) has received the most attention and is used exclusively in the present study. The hydrophobic interior cavity of 1 can encapsulate a variety of hydrophobic monocationic 19 and neutral guest molecules.…”

Does Size Really Matter? The Steric Isotope Effect in a Supramolecular Host–Guest Exchange Reaction

“…We attribute the KIEs observed in the host-guest exchange process to differences in the relative C-H and C-D ZPEs resulting from an increase in guest C-H/D vibrational force constants at the sterically strained transition state. The dramatic guest stabilization and catalysis previously observed in this host [17,18] has much to do with guest binding and exchange. The latter occurs through dilation of the host aperture and this study has shown that the exquisite dependence on guest architecture at the transition state for exchange leads to a significant isotope effect.…”

“…[11,12] The host assembly 1 has a hydrophobic interior cavity that can encapsulate a variety of monocationic [13,14] and neutral [15,16] guest molecules, and has been shown to mediate the chemical reactivity of encapsulated guests. [17,18] Guest molecules can exchange between the interior and exterior of the host assembly via one of four C 3 -symmetric apertures (Figure 1) in the ligand framework, which expand and contract to accommodate guest exchange without Ga-L bond breakage (Figure 2). [19] Due to the large distortion of the host framework required for guest exchange, drastically different exchange rates are observed for guests of different size and shape.…”

“…This orientation, along with the rigid structure of 2-d n , maximizes contact between the host walls and guest C-H/D bonds and is thus expected to accentuate any KIEs in the exchange process. 18 The calculated transition state (left) and energy profile (right) for the displacement process are shown. The increase in energy after guest ejection (>18 Å) is due to charge separation in the gas phase.…”

Hierarchical assembly of discrete copper(ii) metallo-structures from pre-assembled dinuclear (bis-β-diketonato)metallocycles and flexible difunctional co-ligands

“…8,9 Despite considerable advances in the development of such materials, their synthesis to yield predictable multinuclear architectures still often remains a challenge. 3 We, and others, have found that ligands incorporating more than one β-diketone motif react with selected metal ions to yield an array of metallo-supramolecular architectures with the products in many instances exhibiting a significant degree of predictability.…”