Catalytic Gels for a Prebiotically Relevant Asymmetric Aldol Reaction in Water: From Organocatalyst Design to Hydrogel Discovery and Back Again

Abstract

This paper reports an investigation into organocatalytic hydrogels as prebiotically relevant systems. Gels are interesting prebiotic reaction media, combining heterogeneous and homogeneous characteristics with a structurally organized active “solid-like” catalyst separated from the surrounding environment, yet in intimate contact with the solution phase and readily accessible via “liquid-like” diffusion. A simple self-assembling glutamine amide derivative 1 was initially found to catalyze a model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, but it did not maintain its gel structure during reaction. In this study, it was observed that compound 1 could react directly with the benzaldehyde to form a hydrogel in situ based on Schiff base 2 as a low-molecular-weight gelator (LMWG). This new dynamic gel is a rare example of a two-component self-assembled LMWG hydrogel and was fully characterized. It was demonstrated that glutamine amide 1 could select an optimal aldehyde component and preferentially assemble from mixtures. In the hunt for an organocatalyst, reductive conditions were applied to the Schiff base to yield secondary amine 3, which is also a highly effective hydrogelator at very low loadings with a high degree of nanoscale order. Most importantly, the hydrogel based on 3 catalyzed the prebiotically relevant aldol dimerization of glycol­aldehyde to give threose and erythrose. In buffered conditions, this reaction gave excellent conversions, good diastereo­selectivity, and some enantio­selectivity. Catalysis using the hydrogel of 3 was much better than that using non-assembled 3demonstrating a clear benefit of self-assembly. The results suggest that hydrogels offer a potential strategy by which prebiotic reactions can be promoted using simple, prebiotically plausible LMWGs that can selectively self-organize from complex mixtures. Such processes may have been of prebiotic importance.

Supramolecular assemblies of a 1,8-naphthalimide conjugate and its aggregation-induced emission property

“…Recently, several emerging properties 26,[36][37][38][39][40][41][42][43] of planar fluorophores have been observed in mixed solvents. One of them is supramolecular gelation [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] . It is clear from the gelation table that the gelator is insoluble in water and soluble in DMSO.…”

Catalysis in Supramolecular Systems: the Case of Gel Phases

“…More recently, Smith et al using a glutanamide derivative (GluC 12 ) to catalyse the aldol reaction between p-nitrobenzaldehyde and cyclohexanone in aqueous solution, observed that reagents addition induced the formation of a gel-like phase (Scheme 7). [19] Deep investigation of the observed phenomenon demonstrated that gel phase resulted from the formation of the reversible imine intermediate between GluC 12 and p-nitrobenzaldehyde. This adduct behaved as a supergelator, being able to induce gel phase formation at concentration lower than 0.1 % w/vol.…”

Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self‐Healing Supramolecular Gel

“…Based on the design criteria above, we selected our recently disclosed two‐component gelation system ( 1 ) as a potentially suitable LMWG . [ 18 ] This system assembles into gels when a glutamine amide derivative and benzaldehyde are mixed together in a 1:1 ratio, with a reversible reaction between the two‐components giving rise to Schiff base 1 , which is responsible for self‐assembly and gelation ( Figure 1 ). We reasoned this gelator was an ideal candidate for drug delivery applications as the Schiff base should be non‐persistent over long timescales in vivo as a result of hydrolysis, potentially limiting the deposition of any self‐assembled material on repeated administration.…”

“…We have also previously shown that gels can still effectively be formed using only 0.7 equiv. of benzaldehyde, [ 18 ] and using this approach, effectively all of the benzaldehyde is immobilized within the solid‐like gel nanofibers. We were therefore comfortable that this two‐component gel constituted a reasonable platform for further investigation as a nasal delivery system and that the impact of benzaldehyde could be minimized.…”

“…This hydrogel was characterized in some detail in our previous report, [ 18 ] but it was important here to demonstrate that the gel had suitable rheological properties to make it a candidate for nasal delivery. Rheology was performed using a parallel plate geometry and as expected for a gel, G ′ > G ′′, demonstrating that the solid‐like characteristics dominate ( Figure 2 a ).…”