Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

Abstract

The guanosine hydrazide 1 yields a stable supramolecular hydrogel based on the formation of a guanine quartet (G-quartet) in presence of metal cations. The effect of various parameters (concentration, nature of metal ion, and temperature) on the properties of this gel has been studied. Proton NMR spectroscopy is shown to allow a molecular characterization of the gelation process. Hydrazide 1 and its assemblies can be reversibly decorated by acylhydrazone formation with various aldehydes, resulting in formation of highly viscous dynamic hydrogels. When a mixture of aldehydes is used, the dynamic system selects the aldehyde that leads to the most stable gel. Mixing hydrazides 1, 9 and aldehydes 6, 8 in 1:1:1:1 ratio generated a constitutional dynamic library containing the four acylhydrazone derivatives A, B, C, and D. The library constitution displayed preferential formation of the acylhydrazone B that yields the strongest gel. Thus, gelation redirects the acylhydrazone distribution in the dynamic library as guanosine hydrazide 1 scavenges preferentially aldehyde 8, under the pressure of gelation because of the collective interactions in the assemblies of G-quartets B, despite the strong preference of the competing hydrazide 9 for 8. Gel formation and component selection are thermoreversible. The process amounts to gelation-driven self-organization with component selection and amplification in constitutional dynamic hydrogels based on G-quartet formation and reversible covalent connections. The observed self-organization and component selection occur by means of a multilevel self-assembly involving three dynamic processes, two of supramolecular and one of reversible covalent nature. They extend constitutional dynamic chemistry to phase-organization and phase-transition events.

Figure 6

Fig. 1.

Guanine derivatives self-assemble to G-quartets in the presence of metal ions.

Fig. 2.

Hydrogel formed from 1.(a) Picture showing that the sample does not flow when the vial is inverted at 15 mM, 23°C in 0.5 M sodium acetate buffer at pH 6.0. (b) Transmission electron microscopy images of fibers forming the gel.

Fig. 3.

Temperature of gelation T_gel determined visually as a function of hydrazide 1 concentration in buffer (0.5 M) of the acetates of various cations as follows. (♦), Na⁺;(▪), K⁺;(▴), NH₄⁺;(⋄), Me₄N⁺.(a) T_gel values (in °C for 10 and 50 mM, ion): (33, 65, Na⁺), (59, 87, K⁺), (45, 73, NH₄⁺), and (54, 79, Me₄N⁺). (b) T_gel of an aqueous solution of 1 (15 mM) as a function of K⁺ concentration (in mM, °C): (15, 41), (30, 51), (45, 61), (60, 61), and (90, 61).

Fig. 4.

Investigation of the gelation of 1 (15 mM, ²H₂O) by ¹H-NMR spectroscopy. (a) Fraction of free 1 (▴), 1 engaged in the gel (▵) as function of K⁺ concentration (lines drawn through the experimental data points). (b) Fraction of free 1 in the presence of 90 mM KCl as a function of temperature. Experimental data points and the calculated best fit to a sigmoidal curve are given. (Inset) Derivative curve giving the transition temperature T_t

Fig. 5.

Reversible decoration of guanosine hydrazide 1 and of its G-quartet assembly Q₁ by condensation with various aldehydes (2-8).

Fig. 6.

Viscosity of the gels formed from the acylhydrazone derivatives obtained by reacting guanosine hydrazide 1 with the aldehydes 7 (▴) and 8 (▵).

Fig. 7.

Generation of a dynamic library of acylhydrazones C, D and of the acylhydrazone G-quartets A and B from hydrazides 1, 9 and aldehydes 6 and 8.

Fig. 8.

Distribution of the acylhydrazones A-D in the CDL generated from a mixture of the hydrazides 1, 9 and the aldehydes 6 and 8 (all 15 mM, sodium acetate buffer, pD 6 in ²H₂O) as a function of temperature after reaching equilibrium, as calculated from integration of the CH═N ¹H-NMR signals. At 25°C: A, 8%; B, 39%; C, 42%; D, 11%; at 55°C: A, 15%; B, 35%; C, 35%; D, 15%; at 80°C: A, 22%; B, 28%; C, 28%; D, 22%.

Fig. 9.

Dynamic library of acylhydrazones C-F generated from hydrazides 9, 10 and aldehydes 6 and 8.