Analysis of Host‐Assisted Guest Protonation Exemplified for p‐Sulfonatocalix[4]arene—Towards Enzyme‐Mimetic pK_a Shifts

Abstract

The pD dependence of the complexation of p-sulfonatocalix[4]arene (CX4) with the azoalkanes 2,3-diazabicyclo[2.2.1]hept-2-ene (1), 2,3-diazabicyclo[2.2.2]oct-2-ene (2), 2,3-diazabicyclo[2.2.3]non-2-ene (3), and 1-methyl-4-isopropyl-2,3-diazabicyclo[2.2.2]oct-2-ene (4) in D(2)O has been studied. The pD-dependent binding constants, determined by (1)H NMR spectroscopy, were analyzed according to a seven-state model, which included the CX4 tetra- and penta-anions, the protonated and unprotonated forms of the azoalkanes, the corresponding complexes, as well as the complex formed between CX4 and the deuteriated hydronium ion. The variation of the UV absorption spectra, namely the hypsochromic shift in the near-UV band of the azo chromophore upon protonation, was analyzed according to a four-state model. Measurements by independent methods demonstrated that complexation by CX4 shifts the pK(a) values of the guest molecules by around 2 units, thereby establishing a case of host-assisted guest protonation. The pK(a) shift can be translated into improved binding (factor of 100) of the protonated guest relative to its unprotonated form as a result of the cation-receptor properties of CX4. The results are discussed in the context of supramolecular catalytic activity and the pK(a) shifts induced by different types of macrocyclic hosts are compared.

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

“…[27][28][29][30] Synthetic chemists have also used assemblies which preferentially encapsulate charged guests to try to emulate the hydrolytic efficiency of enzymes. Other supramolecular systems have demonstrated the ability of the interior cavity or periphery of the host to shift the pK a of encapsulated guests by up to 2 pK a units [31][32][33][34] and we have shown shifts of up to 4.5 pK a units. 35 This type of stabilization should also affect the transition states of reactions which have highenergy protonated species on the reaction coordinate.…”

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

“…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)(6)(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)(9)(10)(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.…”

A photoinduced pH jump applied to drug release from cucurbit[7]uril

“…For example, pH-dependent binding of guests is well known for calixarenes [15][16][17] and, in particular, for cucurbiturils (CBs). [18][19][20] CBs have received much attention in recent years, 21 which has led to versatile applications, including the stabilisation of dyes and drugs, 8,13,22 chemosensing and monitoring, 5,23-25 the implementation of logic gates, 20 and the use as nanoreactors.…”