Cofactor-Mediated Nucleophilic Substitution Catalyzed by a Self-Assembled Holoenzyme Mimic

Abstract

A self-assembled Fe4L6 cage is capable of co-encapsulating multiple carboxylic acid containing guests in its cavity, and these acids can act as cofactors for cage-catalyzed nucleophilic substitutions. The kinetics of the substitution reaction depend on the size, shape, and binding affinity of each of the components, and small structural changes in guest size can have large effects on the reaction. The host is quite promiscuous and is capable of binding multiple guests with micromolar binding affinities while retaining the ability to effect turnover and catalysis. Substrate binding modes vary widely, from simple 1:1 complexes to 1:2 complexes that can show either negative or positive cooperativity, depending on the guest. The molecularity of the dissociative substitution reaction varies, depending on the electrophile leaving group, acid cofactor, and nucleophile size: small changes in the nature of substrate can have large effects on reaction kinetics, all controlled by selective molecular recognition in the cage interior.

Supramolecular Catalysis of the oxa‐Pictet–Spengler Reaction with an Endohedrally Functionalized Self‐Assembled Cage Complex

“…As such, we investigated the binding affinities of the substrates 4 , 5 and some of the products 6 with 1 by UV/vis absorbance titrations. This is an effective method of interrogating binding in porous hosts such as 1 and 2 , which show rapid in/out exchange of neutral guests [9, 10, 17] . Guests were titrated into a CH 3 CN solution of 1 , and absorbance changes at 300 nm and 330 nm were fitted using the Nelder‐Mead method with both 1:1 and 2:1 binding models, [18] to determine the affinity and stoichiometry of the process.…”

No, Not That Way, the Other Way: Creating Active Sites in Self-Assembled Host Molecules

“…Cage 13 cannot promote the thioetherification reaction by itself at all, and the acid ligand L15 is an extremely poor catalyst, but when they are combined, significant reactivity was observed (Scheme 12, a). 71 It is getting repetitive to say that this was surprising at this point, but this system is the gift that keeps on giving.…”

“…a) Combination of unfunctionalized cage 13 and acid ligand L15 accelerates thioetherification reactions; b) molecular models of the host-guest complex between cage 13 and two molecules of L15, and the complex between 13, L15, electrophile TPM, and nucleophile PrSH; c) host-guest processes present in the cofactor-mediated reaction. 71 As shown in Scheme 11 (b), the reaction of TPM with PrSH when catalyzed by 5% 13/30% L15 occurs at ca. 25% the rate of the reaction catalyzed by acid cage 14, which is still a 50-fold increase over that of L15.…”

“…In the case of L15, the binding was highly cooperative ( (4K 2 /K 1 ) = 51), presumably due to favorable H-bonding in the cage. 71 The reaction rate was highly variable, depending on the nature of the cofactor and electrophile. Different acid cofactors of essentially identical pK a (e.g., benzoic acid, naphthoic acid, anthroic acid) gave reaction rates that varied by up to fourfold, depending on the binding in the host.…”

Supramolecular Catalysis of the oxa‐Pictet–Spengler Reaction with an Endohedrally Functionalized Self‐Assembled Cage Complex

“…This is an effective method of interrogating binding in porous hosts such as 1 and 2, which show rapid in/out exchange of neutral guests. [9,10,17] Guests were titrated into a CH 3 CN solution of 1, and absorbance changes at 300 nm and 330 nm were fitted using the Nelder-Mead method with both 1:1 and 2:1 binding models, [18] to determine the affinity and stoichiometry of the process. The results are shown in Table 2.…”