Anion-Responsive Fluorescent Supramolecular Gels.

Three novel bis-urea fluorescent low-molecular-weight gelators (LMWGs) based on the tetraethyl diphenylmethane spacer-namely, L1, L2, and L3, bearing indole, dansyl, and quinoline units as fluorogenic fragments, respectively, are able to form gel in different solvents. L2 and L3 gel in apolar solvents such as chlorobenzene and nitrobenzene. Gelator L1 is able to gel in the polar solvent mixture DMSO/H2O (H2O 15% v/v). This allowed the study of gel formation in the presence of anions as a third component. An interesting anion-dependent gel formation was observed with fluoride and benzoate inhibiting the gelation process and H2PO4-, thus causing a delay of 24 h in the gel formation. The interaction of L1 with the anions in solution was clarified by 1H-NMR titrations and the differences in the cooperativity of the two types of NH H-bond donor groups (one indole NH and two urea NHs) on L1 when binding BzO- or H2PO4- were taken into account to explain the inhibition of the gelation in the presence of BzO-. DFT calculations corroborate this hypothesis and, more importantly, demonstrate considering a trimeric model of the L1 gel that BzO- favours its disruption into monomers inhibiting the gel formation.

Minimizing Polymorphic Risk through Cooperative Computational and Experimental Exploration.

We combine state-of-the-art computational crystal structure prediction (CSP) techniques with a wide range of experimental crystallization methods to understand and explore crystal structure in pharmaceuticals and minimize the risk of unanticipated late-appearing polymorphs. Initially, we demonstrate the power of CSP to rationalize the difficulty in obtaining polymorphs of the well-known pharmaceutical isoniazid and show that CSP provides the structure of the recently obtained, but unsolved, Form III of this drug despite there being only a single resolved form for almost 70 years. More dramatically, our blind CSP study predicts a significant risk of polymorphism for the related iproniazid. Employing a wide variety of experimental techniques, including high-pressure experiments, we experimentally obtained the first three known nonsolvated crystal forms of iproniazid, all of which were successfully predicted in the CSP procedure. We demonstrate the power of CSP methods and free energy calculations to rationalize the observed elusiveness of the third form of iproniazid, the success of high-pressure experiments in obtaining it, and the ability of our synergistic computational-experimental approach to "de-risk" solid form landscapes.

Tuning Gel State Properties of Supramolecular Gels by Functional Group Modification.

The factors affecting the self-assembly process in low molecular weight gelators (LMWGs) were investigated by tuning the gelation properties of a well-known gelator N-(4-pyridyl)isonicotinamide (4PINA). The N-H∙∙∙N interactions responsible for gel formation in 4PINA were disrupted by altering the functional groups of 4PINA, which was achieved by modifying pyridyl moieties of the gelator to pyridyl N-oxides. We synthesized two mono-N-oxides (INO and PNO) and a di-N-oxide (diNO) and the gelation studies revealed selective gelation of diNO in water, but the two mono-N-oxides formed crystals. The mechanical strength and thermal stabilities of the gelators were evaluated by rheology and transition temperature (Tgel) experiments, respectively, and the analysis of the gel strength indicated that diNO formed weak gels compared to 4PINA. The SEM image of diNO xerogels showed fibrous microcrystalline networks compared to the efficient fibrous morphology in 4PINA. Single-crystal X-ray analysis of diNO gelator revealed that a hydrogen-bonded dimer interacts with adjacent dimers via C-H∙∙∙O interactions. The non-gelator with similar dimers interacted via C-H∙∙∙N interaction, which indicates the importance of specific non-bonding interactions in the formation of the gel network. The solvated forms of mono-N-oxides support the fact that these compounds prefer crystalline state rather than gelation due to the increased hydrophilic interactions. The reduced gelation ability (minimum gel concentration (MGC)) and thermal strength of diNO may be attributed to the weak intermolecular C-H∙∙∙O interaction compared to the strong and unidirectional N-H∙∙∙N interactions in 4PINA.

Construction of supramolecular hydrogels using photo-generated nitric oxide radicals.

Photo-generated nitric oxide radicals (NO˙) derived from sodium nitroprusside dihydrate (SNP) are employed for the construction of supramolecular hydrogels based on an amino acid derivative precursor, N-fluorenylmethyloxycarbonyl tyrosine phosphate (FYP), which through dephosphorylation produces the gelator, N-fluorenylmethyloxycarbonyl tyrosine (FY). Self-assembly of the amphiphilic gelator yields high-aspect ratio nanofilaments that entangle to form self-supporting, viscoelastic hydrogels. The presence of photolyzed SNP yields periodically twisted nanofilaments with opposite chirality to filaments formed through conventional hydrogelation routes.

Pushing Technique Boundaries to Probe Conformational Polymorphism.

We present an extensive exploration of the solid-form landscape of chlorpropamide (CPA) using a combined experimental-computational approach at the frontiers of both fields. We have obtained new conformational polymorphs of CPA, placing them into context with known forms using flexible-molecule crystal structure prediction. We highlight the formation of a new polymorph (ζ-CPA) via spray-drying experiments despite its notable metastability (14 kJ/mol) relative to the thermodynamic α-form, and we identify and resolve the ball-milled η-form isolated in 2019. Additionally, we employ impurity- and gel-assisted crystallization to control polymorphism and the formation of novel multicomponent forms. We, thus, demonstrate the power of this collaborative screening approach to observe, rationalize, and control the formation of new metastable forms.

Stimuli-Responsive Nucleotide-Amino Acid Hybrid Supramolecular Hydrogels.

The ability to assemble chemically different gelator molecules into complex supramolecular hydrogels provides excellent opportunities to construct functional soft materials. Herein, we demonstrate the formation of hybrid nucleotide-amino acid supramolecular hydrogels. These are generated by the silver ion (Ag+)-triggered formation of silver-guanosine monophosphate (GMP) dimers, which undergo self-assembly through non-covalent interactions to produce nanofilaments. This process results in a concomitant pH reduction due to the abstraction of a proton from the guanine residue, which triggers the in situ gelation of a pH-sensitive amino acid, N-fluorenylmethyloxycarbonyl tyrosine (FY), to form nucleotide-amino acid hybrid hydrogels. Alterations in the supramolecular structures due to changes in the assembly process are observed, with the molar ratio of Ag:GMP:FY affecting the assembly kinetics, and the resulting supramolecular organisation and mechanical properties of the hydrogels. Higher Ag:GMP stoichiometries result in almost instantaneous gelation with non-orthogonal assembly of the gelators, while at lower molar ratios, orthogonal assembly is observed. Significantly, by increasing the pH as an external stimulus, nanofilaments comprising FY can be selectively disassembled from the hybrid hydrogels. Our results demonstrate a simple approach for the construction of multicomponent stimuli-responsive supramolecular hydrogels with adaptable network and mechanical properties.