Catalysis in a Cationic Coordination Cage Using a Cavity-Bound Guest and Surface-Bound Anions: Inhibition, Activation, and Autocatalysis

Abstract

The Kemp elimination (reaction of benzisoxazole with base to give 2-cyanophenolate) is catalyzed in the cavity of a cubic ML coordination cage because of a combination of (i) benzisoxazole binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage-based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2-cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface.

Coordination‐Cage‐Catalysed Hydrolysis of Organophosphates: Cavity‐ or Surface‐Based?

“…We could obtain crystal structures of the H⋅ (dichlorvos) 1.56 and H ⋅DICP complexes by immersing pre‐formed crystals of H (as its tetrafluoroborate salt) in a methanolic solution of the appropriate guest for two hours, which resulted in uptake of the guest without loss of crystallinity, in a manner analogous to the “crystalline sponge“ method used by Fujita and co‐workers and which we have also found effective . The crystal structure of the cage/guest complex of H⋅( dichlorvos) 1.56 is shown in Figures and Figure .…”

“…The crystal structure of H⋅ DICP is in Figure and Figure . The process of treating crystals of H with DICP has clearly generated traces of HCl from hydrolysis of DICP as several of the fluoroborate anions have been replaced by chloride in addition to the guest being taken up into the cavity (we have noted before that anion‐exchange can also be performed on single‐crystalline samples of H without loss of crystallinity) . Although there is the usual disorder of anions, the site occupancies of the anions that could be located suggest the presence of eight tetrafluoroborate and nine chloride ions per complete cage.…”

“…On the basis of the ion‐pairing model we proposed for the catalysed Kemp elimination, we predicted that the high local concentration of hydroxide ions around the cage cavity at modest pH values should result in accelerated hydrolysis of dichlorvos: the expected products from this are the dimethyl phosphate anion and dichloroethanal, both of which are too small and hydrophilic to bind significantly in the cage cavity. This means that the products should readily dissociate from the cavity into the aqueous phase, affording the possibility of catalytic turnover .…”

“…The cavities of self‐assembled molecular container molecules provide a fertile environment for the study of catalysis in confined spaces . The relatively rigid, hydrophobic cavities arise from the self‐assembly process of relatively simple metal and ligand components into hollow, pseudo‐spherical arrays and show some similarities to the binding pockets of enzyme active sites.…”

“…The catalysis was attributed to the accumulation of hydroxide ions from aqueous solution around the highly positive surface of the cage, such that the bound benzisoxazole experiences a very high local concentration of base even when the bulk pH is relatively low. This ion‐pairing effect also allows other anionic bases (phenolates) to participate in the cage‐catalysed Kemp elimination as they are less well solvated than hydroxide ions and so preferentially accumulate around the cage surface . Related examples come from Raymond and Bergman using a tetrahedral cage with tris‐catecholate vertices that has a 12− charge: the high negative charge on the host facilitated protonation of bound guests, such that acid‐catalysed reactions can occur in the cage cavity even under basic conditions …”