Primary Ammonium Monocarboxylate Research Articles

Hydrogen bonded network of 1,1-cyclobutanedicarboxylic acid (CBD) salts: Effect of amine backbone on supramolecular assembly

A new series of salts containing 1,1-cyclobutanedicarboxylic acid (CBD) and amines with a diverse backbone (aliphatic, alicyclic, aromatic, and heterocyclic) were designed and synthesized. Twelve new salts (CBD-1 to CBD-12) were prepared and characterized by various physicochemical techniques such as FT-IR, 1H NMR, and X-ray crystallography (9 out of 12 salts). Various hydrogen-bonded motifs present in CBD salts were assigned graph set representation and compared with the known CBD salts (using CSD search) to discover the similarity/dissimilarity between packing in these salts and to understand the role of amine backbone on the hydrogen-bonded network in these salts. The quantitative analysis of non-covalent interaction in CBD salts was carried out using Hirshfeld surface analysis. Hydrogen bonded network of salts (CBD-1 to CBD-3, CBD-5, CBD-6, CBD-9 to CBD-12) displayed a plethora of supramolecular synthons and graph set representation ranging from conventional graph set representation R22(8) and R44(12) frequently observed in PAM (Primary ammonium monocarboxylate) and PAD (Primary ammonium dicarboxylate) salts to unconventional R44(16), R22(14),R12(6), etc. Hirshfeld surface analysis establishes the van der Waals interaction as the most significant non-bonded interaction to control the overall supramolecular assembly in CBD salts.

Design, synthesis, and application of a new series of organogelator using crystal engineering approach and solvent parameter study: A synergetic approach

A new series of organic salts (A1B1-A1B6) based on pivalic acid and primary amine (alicyclic, aromatic, aliphatic) has been designed and synthesized for its potential organogelation behavior. A simple strategy of synthesizing 1-D hydrogen bonded network of PAM (primary ammonium monocarboxylate) leads to the discovery of five new gelators. All the synthesized salts (gelator/non-gelator) were subjected to single crystal X-ray studies to support the hypothesis that 1-D hydrogen bonded networks favor gelation. A detailed study of solvent parameters like dielectric constants, Kamlet-Taft parameters, Hansen parameters, etc. was carried out to get an insight into the role of solvents on the thermal stability and gelation performance of these salts. Organogelation behavior of Salts (A1B1-A1B5) is found to be dependent upon bulk solvent properties such as dielectric constant (ε), polarity index (P′) and a strong correlation between multi-component solvent parameters such as (β) and polar cohesive energy (δp) is observed. Gel network of salt A1B3 (in Acetonitrile solvent) has been used as a template for synthesis of silver nano particles owing to its rectangular hollow xerogel fibers.

A series of memantine based salts with various aromatic and aliphatic carboxylic acids: Crystallographic analysis, Hirshfeld surfaces and dissolution study

Memantine.HCl (MEM.HCl), an adamantane based amine is a clinically useful drug for the treatment of various neurological disorders. Surprisingly, applications of MEM salts/cocrystals in crystal engineering, as a supramolecular motif, are rarely reported in literature, in spite of opportunity that MEM salts (primary ammonium monocarboxylate, PAM and primary ammonium dicarboxylate, PAD) provide to study the reliability and stability of various non-bonded interactions such as C–H⋯O, C–H⋯N, van der Waals, etc. in presence of strong ionic hydrogen bonds (N+ –H…O−, O–H⋯ O, etc.). In the present study, a new series of 12 salts with MEM and varied carboxylic acid backbones (aliphatic and aromatic) were synthesized and characterized by various physicochemical techniques such as IR, NMR and single crystal X-ray studies. The focus was also directed to understand the supramolecular synthons present in these salts and establish a structure-property relationship among them. Qualitative (graph set analysis) and quantitative (Hirshfeld surface analyses) approaches were also employed to analyse all the single crystal structures of salts (1A-1K) to gain an insight regarding the supramolecular assemblies formed and some subtle variation in the well-established PAM and PAD supramolecular synthons. Additionally, all the synthesized salts were subjected to solubility studies in water and compared with the standard MEM. HCl salt. All synthesized salts displayed a range of solubility in water from high to medium to low as compared with MEM. HCl salt. Efforts were also directed to understand the possible cause of high and low solubility of newly synthesized MEM salts in water with respect to the carboxylic acid backbone, ratio of acid/amine (present in salts) and the supramolecular synthons present in the single crystal structures. Moreover, supramolecular isomerism of 1D PAM to 0D PAM, with bulky group substituted carboxylic acid (pivalic acid and 4-methylbenzoic acid), suggests bright future prospects of designing new materials from crystal engineering point of view.

Supramolecular Gels Derived from Simple Organic Salts of Flufenamic Acid: Design, Synthesis, Structures, and Plausible Biomedical Application.

Following supramolecular synthon rationale in the context of crystal engineering, a nonsteroidal-anti-inflammatory-drug (NSAID), namely flufenamic acid (FA) and its β-alanine monopeptide derivative (FM), were converted to a series of primary ammonium monocarboxylate (PAM) salts. Majority of the PAM salts (∼90%) showed gelation with various solvents including water and methyl salicylate (important solvents in topical gel formulation). Structure-property correlation studies based on single-crystal X-ray diffraction (SXRD) and powder X-ray diffraction (PXRD) data provided intriguing insights into the structure of the gel network. Furthermore, one of the gelator salts (S7) displayed anticancer activity on a highly aggressive human breast cancer cell line (MDA-MB-231) ,as revealed by MTT, PEG2, and cell migration assays.

Exploring Orthogonal Hydrogen Bonding towards Designing Organic-Salt-Based Supramolecular Gelators: Synthesis, Structures, and Anticancer Properties.

A series of primary ammonium monocarboxylate (PAM) salts derived from β-alanine derivatives of pyrene and naphthalene acetic acid, along with the parent acids, were explored to probe the plausible role of orthogonal hydrogen bonding resulting from amide⋅⋅⋅amide and PAM synthons on gelation. Single-crystal X-ray diffraction (SXRD) studies were performed on two parent acids and five PAM salts in the series. The data revealed that orthogonal hydrogen bonding played an important role in gelation. Structure-property correlation based on SXRD and powder X-ray diffraction data also supported the working hypothesis upon which these gelators were designed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell migration assay on a highly aggressive human breast cancer cell line, MDA-MB-231, revealed that one of the PAM salts in the series, namely, PAA.B2, displayed anticancer properties, and internalization of the gelator salt in the same cell line was confirmed by cell imaging.

Supramolecular Synthon Approach in Developing Anti-Inflammatory Topical Gels for In Vivo Self-Delivery.

A new series of tertiary-butyl ammonium (TBA) salts of various nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized and characterized. Nearly 90 % of the NSAID-derived primary ammonium monocarboxylate (PAM) salts displayed remarkable gelation ability with various solvents including methyl salicylate. Single crystal X-ray diffraction data (SXRD) revealed the existence of 1D PAM synthon in the gelator salts. Structure-property correlation studies based on SXRD and powder X-ray diffraction (PXRD) data established the presence of the 1D PAM synthon in the bulk salts as well as in the corresponding xerogels. A parallel series of salts derived from TRIS (2-amino-2-(hydroxymethyl)-1,3-propanediol) and the same set of NSAIDs displayed poor gelation ability; only 33 % of the salts in the series displayed gelation ability. A few selected gelator salts of both TBA and TRIS were found to be biocompatible (MTT assay with RAW 264.7 cell line) and two of the selected salts (FLR.TBA and FLR.TRIS) possessed anti-inflammatory properties equal to the parent drug FLR (flurbiprofen). Finally a methyl salicylate topical gel derived from FLR.TRIS was successfully delivered in a self-delivery fashion to treat inflamed skin conditions in the mice model. Histological studies of the dorsal tissues of the untreated and treated mice clearly demonstrated the effect of topical gels in such treatment.

Rationally Developed Organic Salts of Tolfenamic Acid and Its β-Alanine Derivatives for Dual Purposes as an Anti-Inflammatory Topical Gel and Anticancer Agent.

A new series of primary ammonium monocarboxylate (PAM) salts of a nonsteroidal anti-inflammatory drug (NSAID), namely, tolfenamic acid (TA), and its β-alanine derivatives were generated. Nearly 67 % of the salts in the series showed gelling abilities with various solvents, including water (biogenic solvent) and methyl salicylate (typically used for topical gel formulations). Gels were characterized by rheology, electron microscopy, and so forth. Structure-property correlations based on single-crystal and powder XRD data of several gelator and nongelator salts revealed intriguing insights. Studies (in vitro) on an aggressive human breast cancer cell line (MDA-MB-231) with the l-tyrosine methyl ester salt of TA (S7) revealed that the hydrogelator salt was more effective at killing cancer cells than the mother drug TA (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay); displayed better anti-inflammatory activity compared with that of TA (prostaglandin E2 assay); could be internalized within the cancer cells, as revealed by fluorescence microscopy; and inhibited effectively migration of the cancer cells. Thus, the easily accessible ambidextrous gelator salt S7 can be used for two purposes: as an anti-inflammatory topical gel and as an anticancer agent.

Multidrug-Containing, Salt-Based, Injectable Supramolecular Gels for Self-Delivery, Cell Imaging and Other Materials Applications.

Both molecular and crystal-engineering approaches were exploited to synthesize a new class of multidrug-containing supramolecular gelators. A well-known nonsteroidal anti-inflammatory drug, namely, indomethacin, was conjugated with six different l-amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table-top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature-dependent 1 H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single-crystal X-ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen-bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self-delivery) applications for future multidrug-containing injectable delivery vehicles.

An Easy Access to Organic Salt-Based Stimuli-Responsive and Multifunctional Supramolecular Hydrogels.

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β-alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table-top rheology and dynamic rheology. FTIR, variable-temperature (1) H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π-π stacking in hydrogelation. Single-crystal X-ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide-amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli-responsive and were capable of sensing ammonia and adsorbing water-soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.

Supramolecular Gels by Design: Towards the Development of Topical Gels for Self-Delivery Application.

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well-known non-steroidal anti-inflammatory drug (NSAID) ibuprofen. A well-studied gel-inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts (S1-S7) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single-crystal and powder X-ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts (S2, S3, S6, and S7) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE2 assays) revealed that all of the salts (except S3 and S7) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6, displayed anti-inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self-delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.

Easy Access to Supramolecular Gels of the Nonsteroidal Anti-inflammatory Drug Diflunisal: Synthesis, Characterization, and Plausible Biomedical Applications.

By exploiting salt formation, a new series of primary ammonium monocarboxylate salts of a nonsteroidal anti-inflammatory drug, namely, diflunisal, was synthesized. The majority of the salts thus synthesized turned out to be good gelators of various solvents, including the solvents (e.g., methyl salicylate and pure water) typically used for topical gel formulation. Single-crystal X-ray diffraction studies of a few gelator and nongelator salts in the series revealed details of the hydrogen-bonding networks present in the salts. Furthermore, one such gelator salt, namely, the diflunisal salt of serinol, was found to be biocompatible (MTT assay), and its anti-inflammatory (PGE2 assay) response turned out to be as good as that of the parent drug, which is indicative of its potential in biomedical applications.

Exploiting supramolecular synthons in designing gelators derived from multiple drugs.

A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.

Crystal Engineering Approach toward Selective Formation of an Asymmetric Supramolecular Synthon in Primary Ammonium Monocarboxylate (PAM) Salts and Their Gelation Studies

A crystal engineering approach assisted by Cambridge Structural Database (CSD) analyses was adopted in synthesizing a new series of primary ammonium monocarboxylate (PAM) salts derived from variously substituted phenylacetic acid (PA) and chiral amines (R)- and (S)-1-phenylethyl amines (PEA) with the aim of ascertaining an asymmetric one-dimensional (1D) PAM synthon (designated as synthon W) over the other symmetric possibility (synthon X). Characterization of 32 such PAM salts by single crystal X-ray diffraction (SXRD) revealed the exclusive formation of synthon W. The results suggested that the chiral ammonium components must have played a crucial role in generating exclusive formation of synthon W. Interestingly, about 28% of the PAM salts thus synthesized herein displayed gelation ability thereby emphasizing the role of 1D PAM synthon W in gelation.

Primary Ammonium Monocarboxylate Synthon in Designing Supramolecular Gels: A New Series of Chiral Low‐Molecular‐Weight Gelators Derived from Simple Organic Salts that are Capable of Generating and Stabilizing Gold Nanoparticles

The primary ammonium monocarboxylate (PAM) synthon has been exploited to generate a new series of PAM salts from the free amine of L-phenylalanine-3-pyridyl amide, (S)-2-amino-3-phenyl-N-(pyridine-3-yl)propanamine (designated as "B"), and various substituted benzoic acids (designated as "A(R)"; R=4-Me, 4-Cl, 4-Br, 4-NO2, 3-Me, 3-Cl, 3-Br, 3-NO2, 2-Me, 2-Cl, 2-Br, 2-NO2). The 4- and 3-substituted benzoate salts showed moderate-to-excellent gelation ability with a number of polar and apolar solvents. The gels were characterized by DSC, rheology, SEM and TEM, FTIR spectroscopy, etc. Structure-property studies based on single-crystal powder X-ray diffraction (PXRD) and FTIR data provided insights into the role of the PAM synthon in the formation of the gel networks. Interestingly, some of the gels were capable of forming and stabilizing gold nanoparticles at room temperature without the use of any exogenous reducing agents.

Supramolecular Synthon Transferability and Gelation by Diprimary Ammonium Monocarboxylate Salts

Earlier studies revealed that primary ammonium dicarboxylate (PAD) salts possessed gelling ability, and many such salts displayed a 1D columnar hydrogen bonded network (observed in primary ammonium monocarboxylate (PAM) salts) on either side of the dicarboxylate end of the anion. In the present study, a new series of diprimary ammonium monocarboxyate (DPAM) salts have been prepared with the aim of achieving supramolecular synthon transferability (the same 1D columnar hydrogen PAM bonded network on either side of the diammonium cation) in these salts. Single crystal X-ray diffraction studies revealed that, in 47% of the DPAM salts, such supramolecular synthon transferability indeed took place. Some of the DPAM salts also showed gelation ability. The gels were characterized by DSC, rheology, electron microscopy, and atomic force microscopy. Structure property correlation using single crystal and powder X-ray diffraction data on a selected gel was also attempted.

Supramolecular Synthons in Designing Low Molecular Mass Gelling Agents: L‐Amino Acid Methyl Ester Cinnamate Salts and their Anti‐Solvent‐Induced Instant Gelation

Easy access to a class of chiral gelators has been achieved by exploiting primary ammonium monocarboxylate (PAM), a supramolecular synthon. A combinatorial library comprising of 16 salts, derived from 5 L-amino acid methyl esters and 4 cinnamic acid derivatives, has been prepared and scanned for gelation. Remarkably, 14 out of 16 salts prepared (87.5 % of the salts) show moderate to good gelation abilities with various solvents, including commercial fuels, such as petrol. Anti-solvent induced instant gelation at room temperature has been achieved in all the gelator salts, indicating that the gelation process is indeed an aborted crystallization phenomenon. Rheology, optical and scanning electron microscopy, small angle neutron scattering, and X-ray powder diffraction have been used to characterize the gels. A structure-property correlation has been attempted, based on these data, in addition to the single-crystal structures of 5 gelator salts. Analysis of the FT-IR and (1)H NMR spectroscopy data reveals that some of these salts can be used as supramolecular containers for the slow release of certain pest sex pheromones. The present study clearly demonstrates the merit of crystal engineering and the supramolecular synthon approach in designing new materials with multiple properties.

New Series of Organogelators Derived from a Combinatorial Library of Primary Ammonium Monocarboxylate Salts

A crystal engineering approach has been adopted to generate a combinatorial library of 40 primary ammonium monocarboxylate salts derived from 10 cinnamic acid derivatives and 4 n-alkyl primary amines, as potential organic gelators. It is observed that 4-Cl, 4-Me, and 4-Br cinnamate salts of CH3(CH2)n−NH2 (n = 15) are gelators. A systematic study of 4-Br cinnamate salts of n-alkylamine with varying chain lengths indicates that the alkyl chain length has a profound effect on gelation. A structure−property correlation study has been attempted on the basis of single-crystal and powder X-ray diffraction data of the salts.