Supramolecular Reagent Research Articles

Covalent Assisted Supramolecular Synthesis: The Influence of Crystallization Conditions on Co-Crystals of “Masked” Isoniazid Derivatives

Eight co-crystals of covalently modified isoniazid were synthesized, using either 3- or 4-hydroxybenzoic acid as the co-former. It was demonstrated that, for the co-crystallization of “masked” isoniazid by benzophenone derivatives, a small change in reaction or crystallization conditions played a large role in the outcome of the resulting supramolecular structure, whereas the addition of either one or two methyl substituents to the benzophenone rings did not affect the supramolecular structure of the resulting co-crystals. Changing the reflux time for the supramolecular synthesis resulted in stoichiometric variation. Adding larger quantities of one of the starting supramolecular reagents as “additives” resulted in polymorphism. Using a catalyst for the covalent modification of isoniazid during one-pot supramolecular synthesis prevented the formation of a solvate.

Binary and ternary co-crystals and molecular salts of 3,5-dinitrobenzoic acid: A many-faceted supramolecular reagent

The co-crystallization of 3,5-dinitrobenzoic acid (DNBA) to form binary and ternary complexes is reported. Binary complexes (DNBA) (flouranthene) (1), (DNBA) (9-bromoanthracene) (2), (DNBA) (9-methylanthracene) (3) and (DNBA) (9-anthroic acid) (4) are all sustained by charge-transfer interactions. By introducing three different pyridine complexes, the ternary complexes (DNBA) (flouranthene) (5-nitro-2-aminopyridine) (5), (DNBA) (9-anthracenecarboxylic acid)∙(3-bromo-2-aminopyridinium) (6) and (DNBA) (9-anthroic acid) (3-nitro-2-aminopyridine) (7) were synthesized utilizing an additional classical hydrogen bond from the DNBA to the pyridine. Compound 6 formed a molecular salt via proton exchange between the DNBA and 3-bromo-2-aminopyridine, whereas all other complexes are neutral (co-crystals).

Supramolecular assembly of copper(II) halogenobenzoates with nicotinamide into hydrogen-bonding networks

Nicotinamide has been employed as a supramolecular reagent in the synthesis of ten copper(II) chloro-, bromo-, fluoro-, iodo-, and dichlorobenzoate complexes. Compound structures were determined by single-crystal X-ray diffraction structural analysis. All ten compounds are monomeric complexes with a square-bipyramidal coordination sphere around the Cu2+ ion. The two polymorphs of [Cu(2,6-Cl2bz)2(nia)2] are examples of coordination compounds which are conformation and supramolecular isomers. The molecules of all compounds are connected by N–H…O and O–H…O hydrogen bonds from NH2 groups of nicotinamide and water molecules which create supramolecular hydrogen-bonding-coordination chains and networks.

Self-assembly hydrogen-bonded supramolecular arrays from copper(II) halogenobenzoates with nicotinamide:Structure and EPR spectra‡

Nicotinamide was employed as a supramolecular reagent in the synthesis of six new copper(II) bromo-, iodo-, fluoro- and dibromobenzoate complexes. Structures of [Cu(2-Brbz)

Covalent Assistance to Supramolecular Synthesis

The similarity of crystal engineering to organic synthesis has been noted by Desiraju and many concepts and strategies have been successfully transferred. We aim to combine the two fields of research into one new concept called "Covalent Assistance to Supramolecular Synthesis". The supramolecular reagent isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes (Lemmerer at al., 2010). Due to the covalent reaction of the carbohydrazide functional group with simple ketones and aldehydes, the hydrogen bonding functionality of isoniazid can be modified, where two of the hydrogen bond donors are replaced with hydrogen bonding "inert" hydrocarbons (Lemmerer et al., 2011). The "modifiers" bonded to the isoniazid then give a measure of control of the outcome of the supramolecular synthesis with various carboxylic acids depending on the identity and steric size of the modifier used. The steric size itself can be used to shield or to "mask" the remaining hydrogen bonding functionality of isoniazid such that common homomeric and heteromeric interactions are prevented from taking place.

Supramolecular hydrogen-bonding networks constructed from copper(II) chlorobenzoates with nicotinamide: Structure and EPR

Nicotinamide (nia) has been employed as a supramolecular reagent in the synthesis of four copper(II) chloro- and dichlorobenzoate (Clbz/Cl2bz) complexes. The structures of the compounds [Cu(2-Clbz)2(nia)2(H2O)2] (1), [Cu(4-Clbz)2(nia)2(H2O)2] (2), [Cu(3,5-Cl2bz)2(nia)2(H2O)2] (3), and [Cu(2,5-Cl2bz)2(nia)2(H2O)]·H2O (4) were determined. All the investigated compounds 1–4 reveal water molecules as coordinated. Their structures show distorted octahedral chromophores CuIIN2O2O′2, though some are better described as square-planar or square-pyramid due to a large deviation of the axial ligand away from the octahedral z-axis along with different Cu⋯O(axial) lengths. The equatorial positions are occupied in all four cases by two nitrogen (nia-py) atoms and two carboxylate oxygen atoms of two Clbz/Cl2bz ligands, while the axial positions are occupied by water molecules. The EPR spectra reveal for all 1–4 compounds a spin state of S = ½, mostly with axial symmetry of the spectra. Their resolution is clearly dependant to the crystal symmetry related equivalence of the magnetic sites. The coordination molecules of all compounds are connected by N–H⋯O and O–H⋯O H-bonds from nicotinamide NH2 groups, carboxylate anions and/or water molecules, which create supramolecular chains or further H-bonded into 2D sheets. Steric hindering of the chlorine atoms of the Clbz/Cl2bz, especially seen at the coordination of the water molecules, demonstrates its role at the coordination sphere appearance. Despite this influence, the water molecules in 1–4 always assist at the similar supramolecular H-bonded network, almost at the same manner.

A cooperation molecular recognition study: syntheses and analysis of supramolecular assemblies of tetrafluoroterephthalic acid with some aza compounds

A series of new molecular complexes, both co-crystals and salts, constructed by tetrafluoroterephthalic acid with various aza compound moieties, 3-hydroxypyridine, 2-aminopyrimidine, 4-dimethylaminopyridine, 4,4′-bipyridine, 2,5-bis(4-pyridyl)-1,3,4-oxadiazole, o-phenanthroline, and imidazole have been analyzed with respect to synthons presented in the crystal structures. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). A family of supramolecular reagents containing different binding sites were allowed to react with tetrafluoroterephthalic acid in order to assemble individual molecules into larger architectures with precise intermolecular interactions, using a combination of hydrogen- and halogen-bonds. Single crystal X-ray diffraction studies show that, the –COOH/–COO− group acceptor consistently seeks out the basic co-former donor generating the most important intermolecular interaction in all organic complexes. The hydrogen bond patterns exhibited with the aza compounds were found to depend on the nature and position of the substituents. The results can be rationalized through a hierarchical view of intermolecular interactions based upon observed structural pattern preferences, and they also show the reliability of tetrafluoroterephthalic acid as an effective supramolecular tool, even in the presence of other potential disruptive hydrogen-bonding donor–acceptor moieties. These results also illustrate how two different noncovalent interactions can be employed side-by-side in the reliable construction of extended molecular networks with predictable connectivity and dimensionality. With o-phenanthroline forming hydrates, the water molecule plays a central role in synthon formation and crystal packing. After the formation of 1–8, the melting points are dramatically different, and thermal stabilities of these compounds have been investigated.

Stoichiometric variation in two molecular salts of the anti-tuberculosis drug isoniazid with 2-butynoic acid

The supramolecular reagent isoniazid is a molecule capable of undergoing a number of different heteromeric interactions to form neutral co-crystals. By choosing a suitably acidic carboxylic acid molecule, we have been able to form two molecular salts by altering the ratio of the two reactant molecules by both solution crystallization and mechanochemical means. The two stoichiometric salts are formed by using both similar and different hydrogen bonded interactions to those encountered previously in co-crystals.

Adventures in co-crystal land: high Z′, stoichiometric variations, polymorphism and phase transitions in the co-crystals of four liquid and solid cyclic carboxylic acids with the supramolecular reagent isonicotinamide

The supramolecular reagent isonicotinamide (isonico) was used to co-crystallize with three liquid carboxylic acids, cyclopropanecarboxylic acid (C3A), cyclobutanecarboxylic acid (C4A) and cyclopentanecarboxylic acid (C5A), and a solid carboxylic acid, cyclohexanecarboxylic acid (C6A). A total of six co-crystal structures resulted, which are an illustration of the co-crystal space observed in the ever-expanding research on co-crystallization of multiple molecular components. Co-crystal 1, (C3A)·(isonico), has a crystal structure with one of the highest reported Z′ values. 12 acid and 12 isonico molecules combine in the asymmetric unit to give a Z′ = 12, all forming 1-D ribbons. Co-crystals 2a and 2b, both having a formula of (C4A)2·(isonico), having, respectively, a Z′ of 1 and 2, illustrate both stoichiometric variation as well as polymorphism, resulting in different packing architectures. Co-crystals (C5A)·(isonico) 3 and (C6A)·(isonico) 4 have isostructural structures at low temperature, and both show phase transitions above room temperature. For (C6A)·(isonico), we determined the structure of both the low temperature phase, 4a, as well as a high temperature phase, 4b, by single crystal X-ray diffraction, and monitored the transition of 3 by variable temperature powder X-ray diffraction. In all of the compounds reported here, synthesized from two components that are not necessarily solids at ambient conditions and which we have called co-crystals, the primary hydrogen bonded interaction is the carboxylic acid⋯pyridine hydrogen bond.

Covalent assistance in supramolecular synthesis: in situ modification and masking of the hydrogen bonding functionality of the supramolecular reagent isoniazid in co-crystals

The supramolecular reagent isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes. Due to the covalent reaction of the carbohydrazide functional group with simple ketones and aldehydes, the hydrogen bonding functionality of isoniazid can be modified, where two of the hydrogen bond donors are replaced with hydrogen bonding “inert” hydrocarbons. The ketones used are propanone, 2-butanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, 4′-methylacetophenone and benzophenone and the aldehyde 4′-methylbenzaldehyde. The “modifiers” bonded to the isoniazid then give a measure of control of the outcome of the supramolecular synthesis with 3-hydroxybenzoic acid depending on the identity and steric size of the modifier used. The steric size itself can be used to shield or to “mask” the remaining hydrogen bonding functionality of isoniazid such that common homomeric and heteromeric interactions are prevented from taking place. This process of covalent assistance to supramolecular synthesis has been carried out in a one-pot covalent and supramolecular reaction to make six unhydrated co-crystals 2–7 and five hydrated co-crystals 8–12.

One-pot covalent and supramolecular synthesis of pharmaceutical co-crystals using the API isoniazid: a potential supramolecular reagent

The synthon approach has been applied to synthesizing pharmaceutical co-crystals using the anti-tuberculosis drug isonicotinic acid hydrazide (ISONIAZID). Isoniazid has the potential to be a supramolecular reagent and so far has been put to very limited use in making co-crystals. In this report, we co-crystallize isoniazid with the dicarboxylic acids malonic (1), succinic (2), glutaric (3), adipic (4) and pimelic acid (5), and the monocarboxylic acids 4-hydroxybenzoic acid (6) and 2,4-dihydroxybenzoic acid (7). By surveying the literature through the Cambridge Structural Database, we identified the possible homosynthons and heterosynthons that are likely to form in the co-crystallization of isonizaid with carboxylic acids. The dominant interaction is the COOH⋯N hydrogen bond, which is used in all seven co-crystals. In addition, we present an example in which both a covalent and supramolecular synthesis occurs without affecting the vital supramolecular co-crystal forming synthon, the carboxylic acid⋯pyridine pair functionality, by reacting isoniazid with 2-butanone and acetone while co-crystallizing it with 3-hydroxybenzoic acid (8 and 9) in a one-pot synthesis.

Controlling hydrogen-bond preferences in bipyridines with competing binding sites

The design and synthesis of a family of supramolecular reagents (SRs) based on ethynyl-spaced substituted bipyridines are described, and their potential use as molecular ‘hubs’ for the predictable construction of binary and ternary co-crystals is explored. Each SR was synthesized in good yields through consecutive Pd-catalyzed Sonogashira cross-coupling reactions. Crystal structures of three binary co-crystals are presented with each structure clearly illustrating how accurate supramolecular assembly control can be achieved by increasing/decreasing the strength of the participating hydrogen-bond interactions.

Using Lewis acidity differences in chelating ligands to control molecular structure and supramolecular assembly of Cu(II) complexes

The electronic effects of the fluorine atoms in hfacac (hexafluoroacetylacetonato) compared with acac (acetylacetonato) in Cu(II) complexes are used to control the molecular and supramolecular structure of Cu(II) compounds. While bis(acac)Cu(II) (acac = acetylacetonato) is known to be able to have a fifth-position coordination, bis(hfacac)Cu(II), (hfacac = hexafluoroacetylacetonato) may have two extra ligands. This, together with the reliable “supramolecular reagent” isonicotinamide, as the additional ligand, are used to go from a zero-dimension structure, with Cu-acac, to an extended supramolecular two-dimension network, with Cu-hfacac. The molecular and crystal structure of bis(acetylacetonato- O, O′)-(isonicotinamide- N) copper(II), 1, and bis(hexafluoroacetylacetonato- O, O′)- trans-bis(isonicotinamide- N) copper(II), 2, are reported.

Supramolecular synthesis based on a combination of hydrogen- and halogen bonds.

A family of supramolecular reagents containing two different binding sites, pyridine and amino-pyrimidine, were allowed to react with iodo- or bromo-substituted benzoic acids in order to assemble individual molecules into larger architectures with precise intermolecular interactions, using a combination of hydrogen- and halogen-bonds. The hydrogen-bond based amino-pyrimidine/carboxylic acid or amino-pyrimidinium/carboxylate synthons are responsible for the assembly of the primary structural motif in every case (7/7 times, 100% supramolecular yield), while Icdots, three dots, centeredN, Brcdots, three dots, centeredN, and Icdots, three dots, centeredO, halogen bonds play a structural supporting role by organizing these supermolecules into extended 1-D and 2-D architectures (5/7 times, 71% supramolecular yield). These results illustrate how two different non-covalent interactions can be employed side-by-side in the reliable construction of extended molecular solid-state networks with predictable connectivity and dimensionality.

Balancing Hydrogen-Bond Donors and Acceptors in a Family of Bifunctional Aromatic N-Heterocycles

A series of bifunctional pyridine-aminopyrimidine/aminopyridine supramolecular reagents (SRs) have been synthesized through palladium-catalyzed cross-coupling reactions and characterized by single-crystal X-ray crystallography. 3-(2-Amino-4-methylpyrimidin-6-yl)pyridine 1, 4-(2-amino-4-methylpyrimidin-6-yl)pyridine 2, and 4-methoxy-3-(2-amino-4-methylpyrimidin-6-yl)pyridine 3 were synthesized via Suzuki-Miyaura cross-coupling conditions in good yields, whereas 1-(2-amino-4-methylpyrimidin-6-yl)-2-(3-methoxypyridin-5-yl)ethyne 4, 1-(2-aminopyrid-5-yl)-2-(pyrid-3-yl)ethyne 5, and 1-(6-amino-3-pyridyl)-2-(4-{benzimidazol-1-yl}phenyl)ethyne 6 were synthesized through conventional Sonogashira cross-coupling conditions. The primary hydrogen-bonding motif in solid-state structures 1–5 is a self-complementary amino-pyrimidine N–H···N/N···H–N synthon, whereas adjacent molecules in the structure of 6 are connected via aminopyridine-benzimidazole N–H···N hydrogen bonds. Secondary anti-amino proton/pyridyl N–H···N hy...

Peptide Ligation Catalyzed by Functionalized Gold Nanoparticles

Trimethylammonium functionalized gold nanoparticles are demonstrated as templates for the assembly of peptide fragments and their subsequently promoted ligation. This system displays the use of organically tailored nanoparticles as effective supramolecular reagents for catalyzing bond-forming reactions and may also serve as a model for prebiotic conditions where charged surfaces may have promoted the polymerization of the early biopolymers.

Constructing, deconstructing, and reconstructing ternary supermolecules

A hypothesis-driven protocol comprising precise and predictable molecular recognition events based upon an electrostatic view of competing hydrogen-bond interactions is proposed and subsequently employed in the construction of ternary co-crystals.

Syntheses and Crystal Structures of (N-Pyridylmethylene)Aminobenzamides: New Building Blocks for Binary and Ternary Co-Crystals

The syntheses of four supramolecular reagents (SRs) based on (N-pyridylmethylene)aminobenzamides are reported. The crystal structure of 4′-(N-4-pyridylmethylene) aminobenzamide is dominated by an amide-py N–H…N hydrogen bond and an amide–carbonyl N–H…O hydrogen bond. The crystal structure of 4′-(N-3-pyridylmethylene)aminobenzamide contains the same N–H…N interaction but this time it is accompanied by an amide-imine N–H…N hydrogen bond. Finally, the crystal structure of 3′-(N-3-pyridylmethylene) aminobenzamide contains a well-known amide-amide ribbon constructed from two inequivalent N–H…O hydrogen bonds. The hydrogen-bond interactions in these three similar compounds are very different which indicates a structural flexibility that may be beneficial for successful co-crystallization reactions.

Balancing supramolecular reagents for reliable formation of co-crystals

The rational design and synthesis of a supramolecular reagent (SR) composed of two distinct hydrogen bonding sites (pyrazole-benzamide), and four co-crystals resulting from reactions between this SR and a variety of carboxylic acids are described; the observed primary intermolecular interaction is consistent and predictable in each case.

Syntheses and Crystal Structures of Versatile Supramolecular Reagents Based upon [(Benzimidazol-1-yl)methyl]-benzamides

A new family of supramolecular reagents based upon [(benzimidazol-1-yl)methyl]-benzamides and geared toward the assembly of binary and ternary cocrystals have been synthesized and characterized. Single-crystal structure determinations of four of these compounds demonstrate that the carboxamide moieties engage in either dimeric or catemeric self-complementary hydrogen bonds, as well as in a N−H···N hydrogen bond involving the anti proton of the amide moiety (the hydrogen-bond donor) and a heterocyclic nitrogen atom (the hydrogen-bond acceptor). The crystal structures of two binary cocrystals illustrate that [(benzimidazol-1-yl)methyl]-benzamides are capable of coexisting within a crystalline lattice with a suitable partner, and this fact, coupled with their wide ranging solubility, makes them into versatile and, potentially, very useful supramolecular reagents.