Bis(alkylguanidinium) receptors for phosphodiesters: effect of counterions, solvent mixtures, and cavity flexibility on complexation

Abstract

Four bis(guanidinium) receptors have been synthesized in which the guanidinium groups are spatially preorganized by an octahydroacridine (meso-3 and d,l-3) or hexahydrodicyclopenta [b,e\pyridine (meso-4 and d,l-4) spacer to complement a phosphodiester. These structures are designed to mimic the active site of staphylococcal nuclease and, thereby, form four hydrogen bonds to a bound phosphodiester with little reorganization of the host structures. The syntheses involve two parts: construction of the spacer and formation of the aminoimidazoline groups via an intramolecular cyclization between an amine and a thiouronium salt. Binding constants between the receptors and dibenzyl phosphate range from 4.0 X 10* 123 to 10 M~' in highly competitive solvent systems such as aqueous DMSO. Each receptor forms both a 1:1 and 2:1 phosphate to host complex. The methods for determining K\ and K2 are discussed in detail and involve both 31P and *H NMR titration experiments followed by a linear treatment of the data. Binding in pure DMSO is worth 3-4 kcal/mol, but the addition of water significantly decreases the degree of complexation. When the guanidinium counterions are tetraphenylboron, the meso forms of the hosts are the best receptors due to preorganization of the guanidinium groups on the same face of the spacer. When the counterions are chloride, the d,l forms can be the best receptors due to a specific ion effect where a chloride is involved in the host-guest complex. Addition of chloride salts increases binding, possibly due to a chaotropic "salting-out" phenomenon. The structures of the host-guest complexes of meso-4 with dibenzyl phosphate and phenyl phosphate have been determined by X-ray analysis. The structures demonstrate the chloride-counter ion assistance and confirm the four hydrogen bonds between the host and the guest. Near-identical structures to the crystal structures are calculated by molecular mechanics for the complex formed between dimethyl phosphate and meso-3 and meso-4. meso-3 has been found to act as an RNA hydrolysis catalyst and is the first step toward the optimization of a functional RNA-cleaving artificial enzyme.

Supramolecular recognition: On the kinetic lability of thermodynamically stable host–guest association complexes

“…Addition of solutions of the guest molecules to yellow solutions of 9 results in the immediate development of a deep red color, suggesting host-guest association. In the case of 9-methylanthracene (9-MA; 12), its association with 9 (L ϭ Cl) in acetonitrile solutions was measured by the 1 H NMR titration method at 21°C (13,(15)(16)(17). Two equilibrium (association) constants were obtained,…”

Experimental and theoretical investigation of the complexation of methacrylic acid and diisopropyl urea

“…NMR titration, a relatively common method in host-guest chemistry, was used to determine binding constants where host and guest are mixed in different ratios and the NMR spectrum of the mixture is measured. NMR titration is often used to understand complexation phenomena in macrocycle chemistry 7,8,9 , molecular imprinting 10,11 and receptors 12,13 . Due to fast-exchange correlation the NMR signals of the complexes and the initial compounds do not appear separately but as their average.…”

Challenges and breakthroughs in recent research on self-assembly

“…pH 7) because of the essential cooperative function of the neutral and protonated histidines. Figure 10C illustrates a molecular-cleft-type artificial enzyme, which was developed by Anslyn and coworkers, where guanidinium residues connected to a rigid backbone could immobilize an RNA phosphodiester moiety [98][99][100]. Imidazole in solution activated 2 -OH groups with subsequent nucleophilic attack at the phosphate group.…”