Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

Abstract

The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests . We report here a new example (catalysis of the Kemp elimination -reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. Firstly, the rate enhancement is amongst the largest so far observed: at pD 8.3, kcat/kuncat is 2 x 10 5 , due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Secondly, the catalysis is based on two orthogonal interactions: (i) hydrophobic binding of benzisoxazole in the cavity, and (ii) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments. Hundreds of turnovers occur with no loss of activity due to expulsion of the hydrophilic, anionic product. 2Since the realisation that hollow molecular container molecules can accommodate guest molecules in their central cavities, 1-3 their ability to modify the reactivity of their bound guests has been of great interest. [4][5][6][7][8] Well known examples include Cram's stabilisation of highly-reactive cyclobutadiene; 4 Fujita's 'ship-in-a-bottle' synthesis of cyclic silanol oligomers; 5 Nitschke's stabilisation of P4 in a tetrahedral cage; 6 and the demonstration of unusual regioselectivity in a Diels-Alder reaction when the two reacting molecules are co-confined in a host cavity. 7 The ultimate expression of this behaviour is efficient catalysis of a reaction occurring in the cavity of a container molecule. 8 These synthetic systems have the potential to achieve the selectivity and catalytic rate enhancements displayed by biological systems. For example, artificial container molecules provide relatively rigid and hydrophobic central cavities that may mimic binding pockets in enzymes. These containers may be purely organic hydrogen-bonded assemblies (such as Rebek's 'softball' dimer) 9 or may be metal-ligand polyhedral coordination cages [such as Fujita's Pd6/tris(pyridyl)triazine cage]. 10 Coordination cages offer particular promise in this field because of the ease with which they can be formed by a self-assembly process from very simple component parts, using the predictable coordination geometries of metal ions to provide the three-dimensional ordering of the components which generates the necessary cavity. [1][2][3]8,11,12 In order for a container molecule to act as an efficient catalyst it needs to (i) recognise and bind the guest(s); (ii) accelerate the reaction by increasing the local concentration of reactants and/or stabilising the transition state; and (iii) expel the product to allow catalytic turnover. 8 Guest binding in cage cavities has been very well studied and is becoming a mature field, 1 to the extent that a modeling tool for quantitative prediction of guest binding has recently been reported by us. 13 For a reaction of t...

Guest Binding and Catalysis in the Cavity of a Cubic Coordination Cage

“…This is explained by the idea that the chloride ions accumulate around the cage surface preferentially to the surface-bound DO ¹ ions, because they are more easily desolvated than hydroxide. 16 Again, this preferential binding of chloride ions to cationic surfaces compared to HO ¹ /DO ¹ anions is known in cationic micelles. 17b,18 As well as being one of the best examples of catalysis by a coordination cage in terms of rate acceleration and turnover, 3 this example is of particular interest because of its potential generality.…”

“…Overall, when the bulk solution is at pD 8.5, the benzisoxazole molecule in the cage cavity is in a local environment equivalent to the bulk solution at pD 13.8 due to the accumulation of DO ¹ anions around the cage surface. 16 As the cavity provides a microenvironment that is less effective at solvating anions than water, the surface hydroxide is even more effective than 0.1 M DO ¹ in promoting the reaction. Such an accumulation of anions around cationic surfaces is known in cationic vesicles and micelles, 17 and indeed the Kemp elimination has been shown to be accelerated by a factor of 800 in cationic vesicles for this reason.…”

“…16 Importantly, as the pK a of 2-cyanophenol is 6.9, the product exists as the 2-cyanophenolate anion at pD 10.2. This means that it is expelled from the cavity as the anion is hydrophilic, and this change in charge provides the basis for achieving catalytic turnover as well as rate acceleration.…”

“…To this end, we prepared a modified ligand L w , which bears CH 2 OH groups at the C 4 position of every pyridyl ring (Figure 1b 16 (Figure 3b) which, by virtue of the twenty-four hydroxyl groups on the external surface, is now water-soluble, and this has been the focus of our recent guest binding studies. 7 The importance of the hydrophobic effect on guest binding was immediately apparent on comparing binding properties of the same guests in the original MeCN-soluble cage and the new water-soluble cage: for example, the binding constant for coumarin increases by two orders of magnitude from 78(«20) M ¹1 in MeCN to 7600(«900) M ¹1 in D 2 O.…”

Highly selective CO2vs. N2 adsorption in the cavity of a molecular coordination cage

“…[46][47][48][49][50][51][52] The ligand L may be unsubstituted (L o : R = H in the figure) in which case the cages are soluble in polar organic solvents; 47,48 or may be substituted (L w : R = CH 2 OH in the figure) to make the cages water-soluble. [49][50][51][52] These cages have been shown to bind a wide range of organic guests in the central cavity. In organic solvents guest binding is partly driven by hydrogen-bonding of electron-rich regions of guests to H-bond donor pockets located on the interior surface of the cage, in regions of high positive electrostatic potential; this affords binding constants in the range 10 2 -10 3 M À1 .…”