Acid Catalysis in Basic Solution: A Supramolecular Host Promotes Orthoformate Hydrolysis

Abstract

Though many enzymes can promote chemical reactions by tuning substrate properties purely through the electrostatic environment of a docking cavity, this strategy has proven challenging to mimic in synthetic host-guest systems. Here we report a highly-charged, water soluble, metal-ligand assembly with a hydrophobic interior cavity that thermodynamically stabilizes protonated substrates and consequently catalyzes the normally acidic hydrolysis of orthoformates in basic solution, with rate accelerations of up to 890-fold. The catalysis reaction obeys Michaelis-Menten kinetics, exhibits competitive inhibition, and the substrate scope displays size selectivity consistent with the constrained binding environment of the molecular host.Synthetic chemists have long endeavored to design host molecules capable of selectively binding slow-reacting substrates and catalyzing their chemical reactions. While synthetic catalysts are often site-specific and require certain properties of the substrate to insure catalysis, enzymes are often able to modify basic properties of the bound substrate such as pK a in order to enhance reactivity. Two common motifs used by nature to activate otherwise unreactive compounds are the precise arrangement of hydrogen-bonding networks and electrostatic interactions between the substrate and adjacent residues of the protein.(1) Precise arrangement of hydrogen bonding networks near the active sites of proteins can lead to well-tuned pK a -matching,(2) and can result in pK a shifts of up to eight units, as shown in bacteriorhodopsin.(3) Similarly, purely electrostatic interactions can greatly favor charged states and have been responsible for pK a shifts of up to five units for acetoacetate decarboxylase.(4) Attempts have been made to isolate the contributions of electrostatic versus covalent interactions to such pK a shifts; however this remains a difficult challenge experimentally. This challenge emphasizes the importance of synthesizing host molecules that, like enzyme cavities, can enhance binding of small molecular guests and, in a few cases, catalyze chemical reactions. (5-7) Supramolecular assemblies with available functional groups have been used to generate solution-state pK a shifts of up to two pK a units (8-11) and to catalyze chemical reactions.(12, 13) Synthetic hosts often rely on hydrogen-bonding or ion-dipole interactions for guest inclusion, and numerous studies have investigated the effects of charge on guest binding affinities in supramolecular host-guest systems.(14, 15) We report here a synthetic supramolecular host assembly that relies exclusively on electrostatic and hydrophobic interactions for thermodynamic stabilization of protonated substrates. As nature has exploited pK a shifts to activate otherwise unreactive substrates toward catalysis, this stabilization is exploited to promote acid-catalyzed hydrolyses in strongly basic solution.During the past decade, the Raymond group has reported the formation and guesthosting properties of supramolecular assemblies of the...

Structural Consequences of Anionic Host−Cationic Guest Interactions in a Supramolecular Assembly

“…26 The same types of size selectivities have been observed when using the assembly as a catalyst for the hydrolysis of acid-sensitive substrates. 12,28 In the hydrolysis of orthoformates, only substrates smaller than tri-n-pentyl orthoformate are able to enter the assembly to undergo hydrolysis. Similarly, for the hydrolysis of acetals, small acetals are readily hydrolyzed inside of the assembly whereas larger acetals are not.…”

Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled “Nanozyme”

“…For example, the acid-catalyzed hydrolysis of acetals and orthoformates is catalyzed by 1 in basic solution by lowering the pK a of the encapsulated substrate. 29 Several encapsulated transition metal complexes can participate in stoichiometric and catalytic organometallic reactions in which 1 imposes strict limits on the size and shape of substrates that will react. [30][31][32] Pericyclic reactions are popular targets in supramolecular catalysis because encapsulation by itself can enforce the geometries necessary for enhanced reactivity, even in the absence of accelerating functional groups within the cavity.…”

Spin Equilibria in Monomeric Manganocenes: Solid-State Magnetic and EXAFS Studies

“…49 We have recently reported the ability of 1 to greatly favor the protonated form of encapsulated substrates such as amines, with pK a shifts of up to 4.5 pK a units, and have exploited this stabilization for the catalysis of orthoformates and acetals in basic solution. 44,50 Herein we expand upon our initial report of orthoformate hydrolysis to include a detailed study of the mechanism of hydrolysis in 1. …”