Organic Salts as Supramolecular Hosts with Various Applications

Abstract

Brønsted salts are an integral part of everyday activities in various research areas. This article is on hydrogen-bonded assemblies of host–guest complexes of organic salts referred to as ionic cocrystals. Proton transfer from an organic conjugate acid to a base provides salts, which participate in self-assembly with one or more neutral parent components or guests, providing ionic cocrystals. At first sight, such salts appear like the simplest among all other compounds; they have a large scope as medicine, energy materials, and fertilizers in a native form or as ionic cocrystals. The host systems of Brønsted salts have numerous utilities as materials used in diverse sectors and molecular recognition. The ionic cocrystals have the prospect to control bioavailability, degradation, and specific delivery of one or more components. The compositions and types of salt cocrystals are illustrated to explain the different key structural features. The fundamental issue of their utility in the self-recognition of one of the components is analyzed. Their perspectives on their applications in energy, medicine, the environment, and materials are presented.

Introduction

Solid-state assemblies of Brønsted salts have key roles in biology, , drugs, − environment, , and material sciences. − Their multicomponent systems show better solubility and different melting temperatures than the parent components. − To accrue advantages from their supramolecular chemistry, one has to rely on the proton transfer, and reversible assembling properties. The adequate design allows for the mimicry of enzyme activity and sensing. − The acid–base properties of assemblies contribute to the understanding of physiological and pathophysiological changes in pH and cellular metabolism. The ionic liquids find uses as electrolytes. They find importance in solid-state photochemistry, excited state chemistry, and mechanochemical reactions. The hydrogen-bonded ionic liquids are widely studied for different applications. − Their proton transfer and importance in the hydrogen evolution reaction of fuel cells are reported in the literature. Long-range proton transfer between donor–acceptor (such as −SO₃H groups with −NH₂ groups) in metal–organic frameworks improves the proton conductance. The pK _a difference between conjugate acid and base has been widely used to depict the proton transfer between acid and base. , Hydrogen bonds between acid and base, with or without a proton transfer, create platforms to design various multicomponent assemblies, as illustrated in Figure . Proton transfers provide hydrogen-bonding sites for the formation of charge-assisted hydrogen bonds. Those hydrogen bonds have energy between 5 and 35 kcal/mol. There are many ternary assemblies of salts with their neutral acid or base counterparts. − The possibility to form multicomponent assemblies by hydrogen bond compatibility, hierarchical effects of weak interactions, and to control the formation of structural inequivalence of similar pairs are some challenging aspects to be dealt with by a supramolecular chemist. − Reversible assembly, disassembling, or dynamic equilibria between different species/forms add advantages and disadvantages to having a stable form of an assembly consistently crystallized in a desired manner. Above these issues, many scopes arise from the solvate, polymorph, tautomer of solvated assemblies, or in multicomponent assemblies, making it a challenging topic for future developments.

1.

Assemblies of conjugate acid–base with a third component.

Structural Features and Self-Recognition

An organic carboxylic acid and amine occasionally accommodate neutral acid, base, or guest molecules (Figure ) in their assemblies; thereby, the salt serves as a host. A carboxylate salt accommodating the same carboxylic acid can be termed as self-recognition, the same is true for an ammonium salt, including the same amine as a guest, as shown in Figure a–c. A salt also serves as a host for a neutral molecule by complementary interactions, as illustrated in Figure d. While accommodating a molecule of a neutral acid or a neutral base, the corresponding template of the acid and base molecules serves as a host template. Alternatively, a ternary system may result in the formation of 1:2 or 2:1 cocrystals between the carboxylate and amine, as shown in Figure e,f. The difference in energy between the ternary assembly, having a charge-assisted hydrogen bond, and the one formed by the sharing of a hydrogen atom is usually small. The ones with proton transfer from an acid to base at one or more sites of the cocrystals are referred to as ionic cocrystals. There remains a challenge to crystallize in neutral or ionic forms of such multicomponent assemblies. Further difficulties arise from the location of the exact position of a labile proton participating in a hydrogen bond. A small but inappropriate orientation of the projections of the hydrogen bond donor and acceptor affects the hydrogen bonds. Photoelectron spectroscopy , and solid-state NMR spectroscopy , are often used as tools to distinguish the proton-shared or proton-transferred forms in self-assemblies of an acid with an amine.

2.

(a–d) Different types of assemblies of a monocarboxylate through proton transfer to provide salts as hosts (ionic part is marked in red color) and (e, f) 1:2 and 2:1 cocrystals.

The ionic cocrystal of imidazolium salt of 5-chlorosalicylate with 5-chlorosalicylic acid is an example of self-recognition. The acid molecules and the anions of the acid formed a cyclic structure as illustrated in Figure , where the imidazolium ions are linked at the intervening hydrogen bonds between the acid and anion. Such self-recognition of an acid by its salt is found in many other assemblies and is a general phenomenon.

3.

Assembled 5-chlorosalicylate anion with imidazolium cation serving as a host template for guest 5-chlorosalicylic acid.

The N-phthaloyl glycine was self-recognized in the host template formed by the salt of N-phthaloyl glycinate with 8-hydroxyquinoline, as shown in Figure . In this case, the bipolar phthalimide and quinoline rings guided the π-stacking patterns.

4.

Two examples of hydrogen-bonded glycine/glycinate combination (ionic part is marked in red color).

Classification of Ionic Cocrystals and Scope

The classification of organic ionic crystals between Brønsted acid and base requires an assertion on the proton transfer and the type of conjugate partner molecules. However, the ones where the host salt, such as metal salts, are involved may be classified based on factors like charges of the ionic counterparts and partnering guests. The complexity is large, and we present only examples within a class without making a generalized approach. To suggest the wide scopes in delineating different ionic cocrystals from di, tri, and tetracarboxylic acids available in the literature, some examples are presented in Figure . The 1-amino-3,5-benzenedicarboxylic acid forms a monoanion to form the ionic cocrystal shown in Figure a. It holds 4,6-dimethylpyrimidin-2-ammonium cation on one side, having a carboxylate group, and neutral 4,6-dimethylpyrimidin-2-amine on the other side as illustrated in Figure a. In such examples, confirmation of proton transfer from a structural study or evidence by physical measurements only suggests whether it is a 1:2 ionic cocrystal or not. On the other hand, neutral dicarboxylic acid with a monoanionic dicarboxylate holds neutral dicarboxylic acid and the cation, as in the case of fumaric or succinic acid, providing ionic cocrystals with 2,3- or 3,5-lutidine. Those assemblies have a monodeprotonated acid and a lutidinium ion as the host with a neutral acid molecule as a guest, as shown in Figure b. These assemblies have grid-like structures, where the cations are held. , The self-recognition in these cases stemmed from the accessible voids in the grids for the neutral counterparts to get encapsulated.

5.

(a–d) Examples of poly carboxylic acid holding cations of nitrogen-based compounds and multicomponent assembly of salts (ionic part in each case is shown in red color).

A tetracarboxylic acid has a large scope to prepare different ionic cocrystals; two examples are given in Figure c,d. The ionic cocrystal 2,2′-bipyridine with benzene-1,2,4,5-tetracarboxylic acid reported in the literature is an assembly of neutral and dianionic acid with two monoprotonated 2,2′-bipyridinium cations as shown in Figure d. , The X-ray photoelectron spectrum (PES) of the salt was used to confirm the proton transfer.

6.

(a, b) Two different assemblies of 2,5-dihydroxybenzoic acid with 4,4′-bipyridine (ionic part in each case is marked red). (c) Two crystallographic symmetry-independent assemblies (shown in red and violet colors) within an assembly, one unit having proton transfer other not.

It showed two peaks (N 1s) with equal intensities, where the ionization energies of the two peaks were different from each other by ∼2 eV. The new peak of the salt appeared as a consequence of protonation of one of the nitrogen atoms, which carries a positive charge of the bipyridinium part. The occurrence of these two peaks for the nitrogen atoms in the PES showed the nonequivalent environments at the two pyridine sites. In this interesting composition, 2,2′-bipyridinium­[1,2,4,5-benzenetetracarboxylate^(2‑)]_0.5′ (1,2,4,5-benzenetetracarboxylic acid)_0.5 has the syn-conformation 2,2′-bipyridiium cations, and it serves as a proton sponge.

The proton transfers are stimulus-dependent processes, occurring upon application of 3.1 GPa pressure on the cocrystal of malonic acid with the 4,4′-bipyridine. In this example, the cocrystal transforms to a new P2₁/c space group at this pressure due to a change in the packing pattern after proton transfer. By reducing the pressure from 3.1 to 2.4 GPa, the crystals adopted the C2/c space group; hence, an ionic cocrystal may have different forms under different conditions. Coformers guide the packing of cocrystals, so they influence their mechanical properties, such as the modulus of elasticity and bending abilities.

The ionic cocrystals may have neutral guest molecules, such as the 4,4′-dinitro 2,2′,6,6′-tetracarboxybiphenyl (H₄dntcb), which form quaternary assemblies with acridine and polyaromatic compounds. In this case, there were two protons transferred from the tetracarboxylic acid to form a host salt with acridine (acrd). The host accommodated the anthracene (anth) or phenanthrene (phn) guest molecule to provide ionic cocrystals. The salt (Hacrd)₂(H₂dntcb) formed 1D chains, which embedded the polyaromatic guests by π–π and cation···π interactions. These cocrystals showed guest-dependent emission in the visible region, could distinguish the polyaromatics, and provide a large scope to study them for switching and detection. From the above discussions, it is clear that the cocrystals and salts are like two sides of a coin; they occasionally crystallize concomitantly. To add as a further example, the 2:1 ionic cocrystal of 2,5-dihydroxybenzoic acid with a 4,4′-bipyridine molecule adds a new recipe, as it was obtained as two different crystals from the same solution to make distinctions between the properties of a cocrystal and an ionic cocrystal of the same composition from the same components as shown in Figure a,b. The cocrystal had hydrogen-bonded chain-like arrangements, whereas the ionic cocrystal was formed by a proton transfer to one of the nitrogen atoms of the 4,4′-bipyridine. The ionic cocrystal had a twisted geometry due to the nonparallel orientations of the two pyridine rings.

The acidic compounds, such as phenols, form ionic cocrystals. The ammonium phenolates form cocrystals with phenols through self-recognition. Different salts of phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol, recognizing the phenolic counterpart as a guest, are reported in the literature. Some examples are listed in Table . The strength of the PhO-H··· ^– OPh hydrogen bond is appoximately three times stronger than the phenol–phenol hydrogen bond; hence, the phenol easily gets attached to a phenolate. In these examples, the pK _a value of the phenols is in a range of 8–10, and the pK _b of the amines is approximately ∼13. Thus, proton transfer is less predictable.

1. Some Self-Recognizing Phenolic Assemblies.

The self-recognition of a partner molecule in a cocrystal of salt is due to the ability of the neutral species to remain hydrogen-bonded to the salt, serving as a host template. The proton disorders are an outcome of nonrigidity, unequal sharing, or partial proton transfer in ill-matched orientations between the hydrogen bond donor and acceptor. The self-recognition process allows the modulation of composition and physical and chemical properties.

Proton Disorder in Salts and Consequences

When the pK _a values of acid–base counterparts are similar, it is difficult to predict the crystallization of an ionic cocrystal from a conventional one. The challenges in the classification of ionic cocrystals also come when the proton sharing between electronegative atoms participating in hydrogen bonds is greater than zero but less than one. Nevertheless, the intriguing issue is to isolate a cocrystal or a salt under reproducible conditions. Such partial proton transfer was observed in the cocrystals of squaric acid (H₂squ) with 4,4′-bipyridine (44′bipyr), depending on the extent of proton transfer, it could form three forms as shown in Figure . The formation of each form was dependent on the crystallization conditions. Slow crystallization at room temperature provided the 1:1 salt [H44′bipyr]⁺[Hsqu]⁻, whereas crystallization from solution treated at higher temperatures provided a salt [H₂44′bipyr]²⁺[squ]^2– (Figure a) and another form (Figure b). The latter one had proton disorder, as illustrated in Figure c. The proton of the hydrogen bond was shared with 0.82:0.18 occupancies for ⁺N–H···O^– and N···H–O forms as illustrated in Figure c. Each of these salts had a distinguishable shape and color of its respective crystal. Another example is two polymorphs of 4-hydroxy-benzoic acid, which comprise two molecules in the asymmetric unit. They have packing differences due to the sequence of arrangements among the R² ₂(8) type homosynthons of carboxylic acids in lattices. The synchrotron microcrystal diffraction technique, on the one of the polymorphs, had established a proton disorder in the homodimer of 4-hydroxybenzoic acid. The proton disorder in the hydrogen-bonded homodimer of 3,5-dinitrobenzoic acid was also established from X-ray diffraction data recorded at different temperatures, and these data also tallied with the neutron diffraction data. These examples depict that the accuracy of determining the electronic aspects of hydrogen bonds is complicated, but it is necessary to obtain the intrinsic structural information.

7.

(a–c) Three different cocrystals of squaric acid with 4,4′-bipyridine, the third form is with proton disorder.

Assembling of Nucleobases

The nucleobases are the principal components in genetic transcription, and they generally form base pairs through complementary hydrogen bonds. However, the nucleobases have multiple sites (faces) for protonation to combine among them to form assemblies by different or the same type of protonated species. The combinations may be between neutral and ionic species. Orderly arrangement of the numbers of ions of nucleobases in a particular sequence is essential to design properties. The hydrogen-bonded chains of the protonated adenine (ade) or cytosine (cyt) were stabilized by metal­(II) bis-2,6-pyridinedicarboxylate (pdc), namely, by [Cu­(pdc)₂]^2– or [Mn­(pdc)₂(H₂O)]^2– anions, as shown in the Figure b. Protonated hydrogen-bonded dimers of adenine were stabilized as [1H,9H-ade]­[3H,7H-ade] pairs with [Cu­(pdc)₂]^2– as a trihydrate, illustrated in Figure a. Whereas cytosinium ions form a hydrogen bond with neutral cytosine, such assembly was stabilized by a seven-coordinated manganese­(II)­complex, [1H,3H-cyt]₂[Mn­(pdc)₂(H₂O)]·2cyt·6H₂O. The assembling unit is shown in Figure b. Transition metal oxalate (ox) also stabilized charge-assisted hydrogen-bonded assemblies of protonated nucleobases. Examples of assemblies of cytosinium cations in the complexes (1H,3H-cyt)₂[M­(ox)₂(H₂O)₂] M­(II) = Mn, Co, Cu, and Zn) were reported; the assemblies had one-dimensional hydrogen-bonded ribbon-like aggregates of the protonated cytosine molecules that were held within the layers of metal-oxalate anions. Similar complexes of 1H,9H-adeninium assembly were stabilized by anionic complexes. The differences among such assemblies were from the complementary hydrogen-bonded schemes, as the protonation sites were different. The protonated adenine or thymine hydrogen bonds with polyoxometalate, providing self-assembled nanostructures. Some of those assemblies were redox-active and served as functional nanoscale hybrid materials. The composite prepared from protonated nucleobases, namely, phosphomolybdic acid/adenine/[AuCl₄]⁻, has shown anticancer activity

8.

Assembling of two forms of (a) adeninium cations in [1H,9H-ade]­[3H,7H-ade]­[Zn­(pdc)₂]^2–·3H₂O and (b) cytosine-cytosinium cation in [1H,3H-cyt]₂[Mn­(pdc)₂(H₂O)]·2cyt·6H₂O. (Red portion represents the host).

The nucleobases have a large potential to organize in designed and desired manners to understand their implications. One of the ways would be to look for a new template that will provide size and shape-selective stabilization of different sequences of base pairs.

Miscellaneous Examples

The tetrahydrate perchlorate salt of N-[2-(4-methoxy-phenyl)-ethyl]-2-(quinolin-8-yloxy)­acetamide (mpeqa) exchanges protons between perchloric acid and water to provide two different self-assemblies. A hydroxide salt with perchloric acid and water, as shown in Figure a, was observed. In solution, it is the perchlorate salt or a hydrogen-bonded assembly without proton transfer. Solvent-dependent emission properties of mpeqa in solution were observed. The emission at 395 nm in the benzene solution was quenched with an increasing concentration of perchloric acid, whereas a new emission peak at 493 nm and quenching at 395 nm were observed upon the addition of perchloric acid in methanol. In this case, a proton transfer from methanol to quinoline was observed.

9.

(a) The structure of the hydrate cocrystal of mpeqa with perchloric acid. (b) A ternary assembly of pyridine N-oxide, 4-nitrobenzoic acid, with Mn­(OH)₂(H₂O)₄ (ionic part is shown in red color).

The factors, like the nature of metal ions and solvent, guide either to form a metal complex with a ligand or a cocrystal with the ligand. The proton transfer in an anhydrous cocrystal has differences from the corresponding hydrated cocrystal due to the interference of lattice water molecules in proton transfer. The complex [Mn­(H₂O)₄(OH)₂] forms an ionic cocrystal with pyridine N-oxide and 4-nitrobenzoic acid in aqueous methanol with a 1:1:1 composition, as shown in Figure b, whereas a coordination polymer of N-oxide was obtained from a solution of the reactants in dry methanol. Generally, the extent of proton transfer from a polytopic acid or base is decided by a third component, as well as crystallization conditions. − In a recent study, it was shown that the assembly of ditopic amine with pyridine dicarboxylic acids depends on the position of the carboxylic acid groups on the pyridine ring. In fact, by changing crystallization conditions, different compositions with altogether different interaction schemes could be achieved. − It is also possible to stabilize unconventional zwitterionic anions within such assemblies.

There are examples of the use of a combination of charge-assisted and conventional hydrogen bonds to construct multicomponent assemblies, thereby adding further scope to study them as constituents of multicomponent systems. Trimesic acid (H₃tma) forms a multicomponent ionic cocrystal together with 2-aminopyrimidine (amp), pyrimethamine (Clpyr), and trimethoprim (tmp), together with 4,4′-bipyridine (44′bipyr), with a composition (HClpyr)⁺(Htmp)⁺(Hamp)^2–·(44′bipyr)·H₂O is known. This quaternary ionic assembly has the assembly between Htmp⁺ cation, HClpyr⁺ cation, Hamp^2– dianion, and (amp) as the host template recognized a neutral 44′bipy. The assembly of the components, excluding the water molecules of crystallization, is depicted in Figure .

10.

Different components and structure of the ionic assembly of (HClpyr)⁺(Htmp)⁺(Htma)^2–·(44′bipyr)·H₂O.

Fluoride is a relatively small-sized anion; it has a higher charge-to-size ratio, it forms HF₂ ^– species, and provides multicomponent assemblies. As an example, fluoride salt of cysteine is comprised of a neutral cysteine molecule as a guest, which assembles with a host template composed of two cations of cysteine holding an HF₂ ^– and F^– anion, as shown in Figure a. The cysteine adopts a zwitterionic form and becomes involved in charge-assisted hydrogen bonds. This aspect was reflected in the short O···F distance (d_D···A = 2.34 Å) of the O–H···F bond. The short hydrogen bond donor–acceptor distance reflects a strong hydrogen bond. There are also examples of ionic assemblies of fluoride salt with a particular tautomeric form of a compound. For instance, the keto-oxime form of α-hydroxy-nitroso phenol formed an assembly with tetrabutylammonium fluoride to provide a hemihydrate, which is shown in Figure b. The respective C=O (1.24 Å) and C=N (1.35 Å) bond distances established the assigned tautomer. Different forms of phosphoric acid stabilized on designed receptors have relevance as proton conductors. For example, the host template of salt, having a monoanion of phosphoric acid, recognized a neutral acid molecule, as illustrated in Figure a.

11.

Host templates in the ionic cocrystals of (a) cysteine with fluoride ions and (b) tetrabutyl ammonium fluoride salt with keto-oxime form of 8-hydroxy quinoline (ionic part in each case is shown in red color).

12.

(a) Assembly of biphosphate and phosphoric acid and (b) a water tetramer stabilized in an ionic assembly of diaryl phosphate.

The triethylammonium salt of 2,6-(diphenylmethyl)-4-isopropyl-phenylphosphate diester was a host template to stabilize water tetramers. Two hosts were held together by a water tetramer, as illustrated in Figure b. Functionalized sulfamic acids, another class of molecules, were used to prepare cocrystals through proton transfer to 4,4′-bipyridyl and bipyridyl-ethane. , Those cocrystals had higher solubility than the individual parent components to maintain a tightly packed structure and a self-recognition of neutral.

These miscellaneous examples are indicative of possible new openings by changing the templates and partner molecules. On the other hand, there is a necessity to have a design to modulate compositions for self-recognitions as well as for multicomponent synthesis.

Applications

NLO and Electrical Properties

Glycine forms an ionic cocrystal with sulfamic acid, shown in Figure . It has a zwitterion of glycine and a cation of glycine, together with a sulfamate ion. The ionic cocrystal of glycine showed a longitudinal piezoelectricity of ∼2 pC/N. DFT calculations revealed that this was due to an ionic deformation. It may be noted that the α form of the polymorphs of glycine is nonpiezoelectric, but the γ-polymorph is noncentrosymmetric and with a salt that shows piezoelectric response up to 10 pC/N. The ionic cocrystal showed nonlinear optical (NLO) property with a mean effective longitudinal value of second harmonic generation of 0.57 pm/V, which is comparable to a value of 0.38 pm/V shown by potassium dihydrogen phosphate. Another intriguing aspect of assemblies of ionic cocrystals is controlling the formation of zwitterions in assemblies. For example, zwitterionic triglycine sulfate shows ferroelectric characteristics and interesting optical properties in the presence of another amino acid, also used in asymmetric catalysis. This article describes ionic cocrystals, whereas a very closely related class of compounds, namely, organic salts , and ionic-liquids that have also applications in ionic conductors, are not included here.

13.

Ionic cocrystal of glycine with sulfamic acid.

Separations

The ionic cocrystals have self-recognition ability and have the scope to modulate guest recognition. As for illustration, theophylline (tp) is a natural and medicinal compound from salt with 1,2,3-benzenetricarboxylic acid (H₃123bta) (Htp)⁺·(H₂123bta)⁻·2H₂O, through selective deprotonation of the acid. The structure of the salt is shown in Figure a, which has a monoanion of the tricarboxylic acid holding a cation. The monodeprotonation being at a selective site indicates the possibility for studying molecular recognition.

14.

(a) Hydrate of monoanionic salt of theophylline with 1,2,3-benzenetricarboxylic acid. (b) Recognition of phenylenedicarboxylate by an imidazolium functionalized cavitand.

Polytopic ionic host templates are used in the separation of compounds by selective crystallization, and they are recovered by disassembly with or without a stimulus. Such recognitions require the compatible sizes and steric and electronic factors between the host and the guest. For example, 1,4-phenylenediacetic acid was recognized among several dicarboxylic acids by the cavitand illustrated in Figure b. The recognition was due to the size of the anion and charge-assisted hydrogen bonds.

Supramolecular Catalysis

Supramolecular host templates of salts are catalysts for asymmetric induction and for organic reactions. The acid-catalyzed hydride-transfer reaction from NADH to 3,3′-bis­(2,4,6-trisopropylphenyl)-1,1′-binaphthyl-2,2′-diylhydrogen phosphate shown in Figure a is an example of the use of ionic cocrystal as a catalyst. The intermediate of the reaction was depicted through ¹H, ¹⁵N, and ³¹P NMR studies as an ion pair shown in Figure b. Based on a theoretical calculation, as well as NMR coupling between P-atom with N-atom and P-atom with H-atom, the distances between active hydrogen with electroactive atoms (N–H, O–H) were determined. In the solid-state case, the ternary ion pair as an intermediate was also observed. The structure of one such intermediate is shown in Figure c. It had the reactants hydrogen-bonded to the catalyst. A recent example of a charge-assisted hydrogen-bonded intermediate of organocatalyzed asymmetric induction was reported by a crystallographic study. In this example, a hydrogen-bonded dimer of diols of chiral N-oxide was isolated and was suggested to be an intermediate. Here, a prochiral diol was self-assembled as shown in Figure d. The chiral form of the dimer was recognized by a chiral carbene-bound acyl azolium intermediate, and subsequently, enantioselective transformations occurred. Besides these, the salts of alkaloid-based molecules such as cinchonine provide a suitable geometry for chiral inductions. So, there are large prospects of ionic cocrystals as catalysts, and they have definite scope to revisit the reactions catalyzed by ordinary salts.

15.

(a) Phosphorus-based acid catalyst; (b) a binary ion pair as intermediate in asymmetric catalysis of imine to amine; (c) a ternary ion pair as an intermediate in optical inductions established by crystal structure; (d) a hydrogen-bonded dimer of N-oxide involved in chiral induction.

Superconductors

The ionic assemblies designed from hydroxy or carboxylic derived tetrathiafulvalene, shown in Figure a are organic superconductors, whereas the ones shown in Figure b are semiconductors at room temperature and atmospheric pressure but metallic under pressure. The assembly of the triethylamine (tea), ethylenedioxy-tetrathiafulvalene dicarboxylic acid (H₂edattf), and oxalic acid (H₂ox) with a composition (Htea)­(Hedattf)₂·2­(H₂ox) is an organic superconductor. This assembly has an onset T _C of 4.0 K. This has provided a 0.06 fraction of +ve charge on the thiafulvalene ring of each molecule. The tetrathiafulvalene part is assembled in a one-dimensional manner, forming ionic π-conducting layers in the cocrystal. Such a layer is embedded by two other layers formed by hydrogen-bonded acids, one above and the other below, as illustrated in Figure c. The planar tetrathiafulvalene derivative had symmetric intramolecular hydrogen bonds. One set of stacked rings was organized along the crystallographic a-axis, and another was organized along the b-axis. The π-orbitals were organized in such a manner that they avoid strong local interactions. This arrangement was an insulator above 187 K. In the self-assembly, the hydrogen bond between the Hedattf and its dicarboxylate counterpart, whereas the protons of the oxalic acid, were found to be disordered at low temperature, and they had 0.94 and 0.06 occupancies at two positions between the two oxygen atoms participating in the hydrogen bond. In this arrangement, the radicals were organized in an orderly and unidirectional manner, as shown on the right side of Figure d. Hence, upon cooling, the stacked arrangements were turned to a charge-ordered state. This was accomplished by a crystal-to-crystal transformation of the crystals from the C2/c space group to P-1. The arrangements between the rings in the packing of the molecule that crystallized in the P-1 space group were charge-ordered, and it showed metallic conductivity. The changes in the resistivity and magnetic susceptibility profiles by cooling to liquid helium temperature are shown in Figure . The sudden stiff change in magnetic susceptibility and resistance near liquid helium temperature indicates superconducting behavior. Similarly, 1,2-dihydroxybenzene-functionalized tetrathiofulvalene self-assembles to provide radicals and undergoes structural changes with temperature to provide charge-aligned stacking, which enables it to serve as a metallic conductor under pressure. , As a specific example, the selenium derivative shown in Figure b showed a room-temperature electrical conductivity of ∼180 S cm^–1 at 2.2 GPa. When the measurements were carried out by applying pressure above 1.3 GPa and lowering the temperature, the electrical resistivity was decreased until 150 K. A study using deuterated compounds had established the involvement of π-radical electrons localized on individual molecules. ,

16.

(a, b) Two thiafulvalene derivatives; (c) assembling of [(Htea)­(Hedattf)₂·2­(H₂ox)] (the Htea is omitted for clarity); (d) orderly stacks of thiafulvalene rings with random and with aligned electron spins.

17.

(a) Electrical resistivity of (Htea)­(Hedattf)₂·2­(H₂ox) at different temperature. The superconducting transition is shown in the inset. (b) The dc-magnetic susceptibility of (Htea)­(Hedattf)₂·2­(H₂ox), under a field of 5000 Oe at different temperatures; the inset is the dc-magnetic susceptibility under fields of 10, 100, and 1000 Oe in the field-cooled conditions. Reproduced after modification from ref , Copyright 2023 Royal Society of Chemistry.

Frameworks and Enzyme Mimic

In recent days, there has been an interest in generating charge-assisted hydrogen-bonded frameworks Hydrogen bonds between cations and anions are extended to construct charge-assisted hydrogen-bonded frameworks. Some common acid–base counterparts suitable for the construction of charge-assisted frameworks are given in Figure a–d. The combination of tetrakis­(4-aminophenyl)­methane and 2,6-naphthalenedisulfonic acid provided a rigid framework that encapsulated an anion. The enclosure of one unit of the framework is shown in Figure e. These frameworks are used as recyclable Brønsted acid catalysts. Tetraphenylethene decorated amidinium cation with terephthalate anion provides an ionic framework showing aggregation-induced emission. Figure f shows a subunit of a charge-assisted hydrogen-bonded framework of cations of bis-amidinium hydrogen-bonded with disulfonated derivatives. There are also examples of phosphates attached to bis-amidinium cations. ,

18.

(a, b) Examples of cationic, and (c, d) anionic linkers; (e, f) subassemblies of charge-assisted hydrogen-bonded frameworks.

Hydrogen-bonded organic frameworks provide enclosures to enzymes, such encapsulation helps to increase durability and improve catalytic activity of the enzyme. As an example, two enzymes encapsulated by a charge-assisted hydrogen-bonded framework derived from triamidinium and tricarboxylate are illustrated in Figure . The catalytic activity of the catalase enzyme was studied to degrade hydrogen peroxide by the enzyme alone as well as by the encapsulated enzyme. The decomposition was significantly enhanced by the encapsulated enzyme. Similarly, the α-amylase was encapsulated in the charge-assisted hydrogen-bonded framework. This enzyme in the encapsulated form was able to improve the catalytic transformation of amylum to glucose. In these examples, the negatively charged enzyme surfaces were interacting with the positively charged triamidinium units to form an enzyme-encapsulated assembly, where the enzyme had served as the central portion. This enhancement of reactivity was due to the easy rupture of hydrogen bonds and could also be used to reassemble the enzyme within. Hence, the ionic framework had protected the enzyme from degradation under acidic or basic conditions and could also keep the enzyme activity intact up to 10 sequential catalytic cycles. The catalytic decomposition of encapsulated anions such as oxalate in cationic cages by an oxidizing agent such as potassium permanganate resulted easy formation of carbon dioxide under ordinary conditions. In such reactions, the specific anions are recognized through complementary hydrogen bonds with the ionic receptor. The association of the anion with the cation as a host molecule changes the influence of the anionic nature of permanganate ions. This happens by forming partially or completely neutral anion-encapsulated species, which enables us to overcome the electrostatic repulsions of the permanganate that was originally there in the free state. This has facilitated the decomposition of the oxalic acid by MnO₄ ^–. Moreover, such research introduces the encapsulation of an anionic substrate by a cationic cage as a new mechanism for catalysis in water. This molecular recognition approach inverts the charges of the substrates and overcomes electrostatic repulsions, showing a strategy to design catalysts to perform in water. A protonated or a zinc complex of porphyrin-fullerene conjugate linked by hydrogen bonds between amidinium and carboxylate is shown in Figure . This facilitated charge separation between two radical species in the self-assembly. The stability of the porphyrin radicals with a nanosecond lifetime from a radical at fullerene was observed.

19.

Enzyme encapsulated in a charge-assisted hydrogen-bonded ionic framework and its catalytic activities. Modified with permission from ref , Copyright 2025 Royal Society of Chemistry.

20.

A porphyrin and C₆₀ conjugate held together by charge-assisted hydrogen bonds.

It is evident from the discussion that the orderly arranged charges with orderly packing contribute significantly to changing the conducting properties of organic semiconductors. The solid-state phase transitions brought out by stimuli guided crystal transformations and allowed equilibration between different states to show switching properties. The enhancement of enzyme activity in ionic assembly has a higher prospect for designing water-soluble catalysts.

Medicines

The primary benefit of transforming a drug into an ionic cocrystal is the ability to have multiple components in one pill to decrease the number of pills to be taken by a patient. This serves several purposes at once and enhances the physicochemical properties. Solubility and biological performance of many insoluble drugs are improved by forming salt cocrystals, and this happens without an adverse effect on biological activities. Some such drug formulations have dual roles to increase bioavailability and control their release.

For example, the solubility of the drug fluoxetine hydrochloride, an antidepressant drug, was enhanced by preparing an ionic cocrystal with benzoic acid whose structure is shown in Figure . The self-assembly has protonated drug molecules linked by benzoic acid and chloride ions through hydrogen bonds. Similarly, the hydrated ionic cocrystal of isoniazid with 2,5-dihydroxybenzoic acid or 2,4-dihydroxycinnamic acid had better aqueous solubility than the parent drug molecule.

21.

Hydrogen-bonded assembly of fluoxetine hydrochloride with benzoic acid (ionic part is shown in red color).

Ciprofloxacin and enrofloxacin, shown in Figure a–c, have a similar skeleton with different substituents; one common point is that they are monocarboxylic acid derivatives. Each forms cocrystals with a series of dicarboxylic acids listed in Figure d. The drug Pefloxacin forms an ionic cocrystal with fumaric acid, which is an assembly of the protonated drug molecule with fumarate and fumaric acid in a 1:0.5:0.5 molar ratio. This ionic cocrystal had a solubility about 10 times higher than that of the parent drug. It may be noted that the succinate salt of the drug at pH 1.2, which is the pH of the intestine during gastric bypass, showed higher solubility than the parent drug, and it also showed improved solubility at pH 7, which is a normal biological condition during intestinal passage in the human body. The salts with different dicarboxylic acids are used as medicinal formulations without adverse effects. Divalproex sodium, an anticonvulsant, which is used in the treatment of epilepsy, formulation is consisting of sodium valproate and valproic acid. The salt cocrystals of the drugs such as ciprofloxacin (cip), and enrofloxacin (enro) with α,ω-dicarboxylic acids listed in Figure provide cocrystals or gel. Among those multicomponent ionic assemblies, (Henrofloxacin)₂(adipate)^2–·adipic acid·CH₃CN and (enrofloxacin)₂(adipate)^2–·adipic acid·CH₃CN have higher solubility in water than the parent drug molecules. There are several other examples of nitrogen-based drug molecules forming ionic cocrystals with dicarboxylic acids. ,

22.

Structures of pefloxacin, ciprofloxacin, enrofloxacin, and coformer α,ω-dicarboxylic acids.

The drug ponatinib hydrochloride has an interesting hydrogen-bonded assembly, comprising a hydrochloride salt holding a neutral ponatinib (Figure a). Ponatinib hydrochloride is a multicomponent ionic crystal with an unusual stoichiometry. The assembly of the salt is a trihydrate, which has one monocation, the ponatinib hydrogen bonding to a dication of the ponatinib molecule and three chloride ions. The chloride ions are ionic and do not interact with the organic components. The structure was ascertained by X-ray crystal structure determination as well as by ¹³C CP/MAS spectroscopy.

23.

Assembling of (a) ponatinib hydrochloride with ponatinib; (b) assembly of salt cocrystal of pyrimethamine with succinimide and benzoic acid.

The pyrimethamine is an antimalarial drug that forms varieties of multicomponent salt cocrystals with coformers such as imides and carboxylic acids. The structure of the 2:1:1 salt cocrystal among pyrimethamine, succinimide, and benzoic acid is shown in Figure b. Cocrystals were also obtained from the same constituent molecules under different conditions. For example, a mechanochemical crystallization or sublimation or ball milling had yielded independent forms from the same reactants.

Cis and trans isomers of dicarboxylic acids, namely, maleic as well as fumaric acid, form salt cocrystals with marbofloxacin (mbf, Figure a). It forms an ionic cocrystal (Hmbf·Hfa·H₂fa) with fumaric acid (H₂fa) as shown in Figure b. Whereas with maleic acid (H₂ma), the cis isomer of saltHmbf·Hma was observed. The two geometrical isomers formed independent compositions due to the difference between the pK _{a 1} and pK _{a 2} values of the isomers. The cis isomer of the coformer maleic acid forms a stable intramolecular hydrogen-bonded monoanion; hence, dianion was not formed in this case. The ionic crystal with fumaric acid has a grid-like assembly, as illustrated in Figure c. The grids within the assembly are formed by cations and anions; the neutral acid molecules are held in the grid. The salt mbf·ma had a higher solubility and permeation rate than the ionic cocrystal Hmbf·Hfa·H₂fa. The salt had higher in vitro bacterial inhibitory activity assays against Gram-negative and Gram-positive bacterial strains than the salt cocrystal and the parent marbofloxacin.

24.

(a) Marbofloxacin (mbf), (b) ionic cocrystal Hmbf·Hfa·H₂fa, and (c) its self-assembly.

The promethazine drug forms an ionic cocrystal with fumaric and hydrochloric acid. This is an example of a medicinal compound having a mineral and an organic acid in the cocrystal; the structure is illustrated in Figure . Betrixaban is an anticoagulant drug. It forms 1:1 salt as well as a 1:3 ionic cocrystal with maleic acid. The betrixaban has an imidazole part, which forms a cooperative hydrogen bond with maleic acid. The ionic cocrystal hydrate formed in a 1:3 ratio had 10 times lower solubility as compared to its salt, as illustrated from the solubility profiles of the powdered samples of the two forms in Figure . It was suggested that the common-ion effect caused the lower solubility of the salt.

25.

Structure of the ionic cocrystal of promethazine hydrochloride.

26.

(a) Structure of Betrixaban; Dissolution with time of the powder samples of (b) salt and (c) 1:3 cocrystals of betrixaban with maleic acid in aqueous buffers (i) pH 1.2, and (ii) pH 6.8. Modified from ref , Copyright 2021, American Chemical Society.

The sulfamethazine formed a hydrated 2:2 salt cocrystal with 4-biphenylcarboxylic acid. The cocrystal was comprised of two parts. It had neutral as well as protonated sulfamethazine molecules. The neutral part of this salt cocrystal had the sulfamethazine hydrogen-bonded to a neutral carboxylic acid, whereas the other part was the salt, which had a protonated sulfamethazine forming a charge-assisted hydrogen bond with a carboxylate ion. There are also ionic cocrystals of quinoline carbaldoximes with carboxylic acid, which can modulate the compositions of oxime-based drugs.

From these discussions, it is clear that modulation of the composition of a drug to enhance bioactivity can be achieved through a self-recognition method of its salt. They are safe to deal with, as the host template has the original drug molecules in the assemblies with biocompatible partners.

Explosives

Among the Brønsted salts, ammonium nitrate and ammonium perchlorate are high-energy materials with potential as rocket fuels. Various ammonium nitrate and perchlorate-based assemblies are prepared and explored as new salt cocrystals for explosives. − The ammonium nitrate with a urea cocrystal modulates carbon dioxide release under ambient conditions and serves as an explosive material under detonating conditions. The positive oxygen balance is an important criterion for the performance of explosives. The cocrystals of the ammonium nitrate salt with energetic molecule 5,5′-dinitro-2H,2H′-3,3″-bi-1,2,4-triazole in a 2:1 molar ratio exhibited a positive oxygen balance during combustion, showing its improved quality as a detonator. This ionic cocrystal does not undergo a solid-state phase transition. The different components and salt cocrystal of the explosive are illustrated in Figure .

27.

5,5′-Dinitro-2H,2H′-3,3′-bi-1,2,4-triazole, ammonium nitrate, and their cocrystal.

Another such example of an explosive salt cocrystal is the 2:1 salt cocrystal of ammonium dinitride with 5,5′-dinitro-2H,2H′-3,3″-bi-1,2,4-triazole, which shows a high oxygen balance. The composition is shown in Figure . The nitro barbituric acid and 7H-[1,2,4]­triazolo­[4,3-b]­[1,2,4]­triazole-3,6,7-triamine (tato) nitro barbituric acid (nba) form a 1:2 cocrystal. It is a high-energy ionic salt and has a composition tato′2­(nba)′2.5H₂O; the structural components are shown in Figure . It has high impact and friction sensitivity comparable to those of trinitrotoluene. The explosive property of properties of the cocrystal concerning TNT and RDX are compared with RDX and are listed in Table . There are many other salt cocrystals of energetic molecules, formed either by the combination of an explosive with a nonexplosive component or with another high-energy component to control the release of energy during the explosion and modify the activation energy required for an explosion. The recent studies have shown that solvation and cocrystal formation influence the explosion efficiency of trinitrotoluene and nitramines.

28.

Structure of the tato′2­(nba)′5H₂O.

2. Comparison of Explosion Parameters of an Ionic Cocrystal with RDX and TNT .

material	T d (°C)	DP [GPa]	VOD [ms–1]	IS [J]	FS [N]
tato′2(nba). 5H2O	239	19.7	7521	>40	>360
RDX	210	34.9	8878	7.5	120
TNT	295	19.5	6881	15	360

^a T _d: decomposition temperature; DP: detonation pressure; VOD: detonation velocity; IS: impact sensitivity; FS: friction sensitivity, modified from ref with permission, Copyright 2023, American Chemical Society.

These assemblies have provided wider scopes to modify the properties of explosives for specific purposes. The design of stable energetic supramolecular assemblies is a direction to look forward to for alternative energy sources.

Control N₂O and CO₂ Emissions

There is a concern that extensive use of nitrogen-based fertilizers causes a rise in the concentration of toxic nitrous oxide (N₂O) in the atmosphere, which warrants adjusting the emission of N₂O from agricultural soil. , It was observed that with fulvic acid with urea matrix in cotton guided controlled release of fertilizer. It helped in nutrition as well as controlled the amounts of urea decomposition over time. To obtain information about the possible control of such emissions from urea, the ionic cocrystal of urea is promising. Assessments of N₂O fluxes carried out independently have suggested positive data with promise, but much needs to be done with more examples. Otherwise, by comparing the water solubility of the ionic cocrystal CaSO₄·3­(urea)·H₂O and ZnSO₄·(urea)·2H₂O concerning urea in 24 h showed that the molar solubility of urea was six times higher than the zinc sulfate ionic cocrystal, whereas it was 8.2 times higher than the calcium sulfate urea ionic cocrystal. , These data are suggestive of the fact that the lower solubilities of the parent compound and controlled release can be a way to control the decompositions and regulate the toxic emissions from fertilizers.

Future Directions and Conclusions

There is a large paucity in laying out the list of different ionic cocrystals due to the diversity and unsystematic data in the literature that deters systematic classifications. Hence, the open-ended possibilities to prepare ionic assemblies for applications to create fertile land using ecofriendly fertilizers are emerging. The scope to study ionic cocrystals is vast, ranging from energy and medicine to materials; each domain has its merit and potential. The search for new systems for high-temperature superconductors, ferroelectrics, and nonlinear optical materials will continue with interest. The mechanical properties, such as bending and jumping properties, of cocrystals, require due consideration as the pressure-induced proton transfer and coformers influence the elastic modulus and hardness of crystals. Multicomponent ionic cocrystals as porous assemblies and designed ionic cocrystals with macromolecules will offer solutions to modulate compositions and align assemblies to develop green technologies. Access to new tools for mechanochemical synthesis and the use of new characterization tools, such as synchrotron techniques for characterization, photoelectron spectroscopy, and solid-state NMR, and advanced energy and pollution measuring tools will accelerate the development of new, reliable systems with enhanced stability.

Biographies

Prof. Jubaraj B. Baruah received his Ph.D. degree (1989) in Chemistry from the Indian Institute of Science, Bangalore, under the supervision of Prof. Ashoka G. Samuelson. During 1993-1994, he worked as a UNESCO fellow at Tokyo Institute of Technology, Japan, in the research group of Prof. T. Yamamoto and Prof. K. Osakada. He, also visited the same laboratory as a visiting Professor for a brief period in 1999. After working as a Lecturer at Guahati University, India during 1989 to 1995, he joined the Department of Chemistry, Indian Institute of Technology Guwahati, from the day of inception, where he is currently holding the position of a highest academic grade Professor. He is a recipient of E. Corey Memorial Award (1999) and the Bronze medal from the Chemical Research Society of India (2005). He has authored independently or with co-workers more than 320 scientific publications, has also published book chapters and books. As an active researcher in supramolecular chemistry, he has participated in different International scientific activities.

Abhay Pratap Singh received his M.Sc. in Chemistry from Indian Institute of Technology Bhubaneswar, India, in 2019. He received his Ph.D. in Chemistry in 2025 from the Indian Institute of Technology Guwahati under the supervision of Prof. Jubaraj B. Baruah. His dissertation was focused on the design and applications of salt, ionic cocrystals, and hydrates. Dr. Singh has published 10 research articles during his Ph.D. He is a keen racquet sports, along with cricket.

The authors declare no competing financial interest.