Multi-component Molecular Complexes Research Articles

Structure Guiding Supramolecular Assemblies in Metal-Organic Multi-Component Compounds of Mn(II): Experimental and Theoretical Studies

Two multi-component coordination compounds of Mn(II), viz. [Mn(H2O)6](2-Mepy)2(4-NO2bz)2·2H2O (1) and [Mn(H2O)6][Mn(2,3-PDCH)3]2 (2) (where, 2-Mepy = 2-methylpyridine, 4-NO2bz = 4-nitrobenzoate, 2,3-PDC = 2,3-pyridinedicarboxylate), have been synthesized and characterized using elemental, spectroscopic (FT-IR and electronic), TGA and single-crystal X-ray diffraction analyses. Complex 1 is a co-crystal hydrate of Mn(II) involving uncoordinated 2-Mepy, 4-NO2bz and water molecules; while compound 2 is a multi-component molecular complex salt of Mn(II) comprising cationic [Mn(H2O)6]2+ and anionic [Mn(2,3-PDCH)3]−complex moieties. The uncoordinated 2-Mepy and 4-NO2bz moieties of 1 are involved in lone-pair (l.p)-π and C–H⋯π interactions which stabilize the layered assembly of the compound. The crystal structure of compound 2 has been previously reported. However, we have explored the unusual enclathration of complex cationic moieties within the supramolecular host cavities formed by the molecular assembly of complex anionic moieties. The supramolecular assemblies obtained in the crystal structure have been further studied theoretically using DFT calculations, quantum theory of atoms-in-molecules (QTAIM) and non-covalent interaction plot (NCI plot) computational tools. Theoretical studies reveal that the combination of π-staking interactions (l.p-π, π-π and C–H···π) have more structure-guiding roles compared to the H-bonds. The large binding energy of π-stacking interactions in 2 is due to the antiparallel orientation of aromatic rings and their coordination to the metal centers, thereby increasing the contribution of the dipole–dipole interactions.

New hydrate cocrystal of l-proline with 4-acetylphenylboronic acid obtained via mechanochemistry and solvent evaporation: An experimental and theoretical study

In this work, we present the formation of a new multi-component molecular complex by targeting the boronic acid moiety (-B(OH)2) of 4-acetylphenylboronic acid with the carboxylate group (-COO-) of l-proline using two different techniques: mechanochemistry and solvent evaporation. The experiments produced efficiently a new cocrystal named L-PRO4APBA. It was characterised to study its structural properties by X-ray powder diffraction (XRPD), infrared spectroscopy (FTIR), single-crystal X-ray diffraction (SCXRD), and quantum chemical methods based on QTAIM. Also, its thermal behaviour was analysed using a simultaneous DSC/TGA experiment. The results showed that L-PRO4APBA comprises discrete molecular units held together mainly by O–H⋯O and N–H⋯O hydrogen bonds. However, C–H⋯O, C–H⋯π, and other non-conventional interactions gave further stabilisation. Moreover, SCXRD showed that the asymmetric unit contains five independent molecules: two of l-proline (PRO1 and PRO2), two of 4-acetylphenylboronic acid (4APBA1 and 4APBA2) and one of water. PRO1 and PRO2 adopted different conformations with their carboxylate groups in equatorial and axial positions, respectively. This feature produced two independent helical chains running along the 21 screw axis in which 4APBA1 and 4APBA2 bound through the expected -B(OH)2···−OOC- heterosynthon. Surprisingly, the presence of water molecules in the lattice did not disrupt the formation of this motif. However, water molecules played an essential role for the stabilisation of the 3D structure. These findings would set up the structural basis to continue exploring the formation of new cocrystals by combining l-proline with boronic acids.

Growth and characterization of l-histidinium – 4-nitrobenzoate (1:1) multi-component molecular complex

A novel phase by reaction of l-histidine with 4-nitrobenzoic acid (4NBA) was obtained by solvent assisted grinding (SAG). The complex was crystallized from aqueous solution and characterized by X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (SCXRD), infrared spectroscopy (FTIR) and thermal analysis (DSC/TGA). Additionally, the non-linear optical (NLO) properties were assessed for second harmonic generation (SHG). XRPD confirmed that a new phase was obtained, and this can be obtained pure from solution. However, when the complex appeared in SAG experiments, it was always in equilibrium with the precursors. The crystal structure of the complex revealed that a proton transfer took place from the carboxylic acid group of 4NBA to the unprotonated nitrogen atom in the imidazole ring of l-histidine to yield l-histidinium – 4-nitrobenzoate (LH4NBE) molecular complex. The FTIR spectroscopy depicted accurately the molecular characteristics of LH4NBE and the thermal analysis showed that it is stable up to 190 °C. Unfortunately, the complex displayed poor NLO properties and the sample suffered damage upon laser excitation.

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.

From Evaporative to Cooling Crystallisation: An Initial Co-Crystallisation Study of Cytosine and Its Fluorinated Derivative with 4-chloro-3,5-dinitrobenzoic Acid

Two new multi-component molecular complexes of cytosine and 5-fluorocytosine with 4-chloro-3,5-dinitrobenzoic acid are presented. Materials synthesis was achieved initially by evaporative crystallisation and the crystal structures determined. The process was then successfully transferred into a controlled small scale cooling crystallisation environment, with bulk samples shown to be representative of the multi-component product phase, by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) methods. Turbidity measurements are shown to be a valuable process analytical technology probe for characterising the initial stages of molecular complex formation in solution. The significance of these findings for scale-up of crystallisation of multi-component molecular materials and for future transfer into continuous cooling crystallisation is discussed.

Turning colour on and off using molecular disorder and proton transfer in multi-component molecular complexes

Three pairs of molecular complexes based around 4-iodoaniline and 3,5-dinitrobenzoic acid are reported. Within each pair, one complex is colourless and one red; the influences on the colour are discussed including the role of molecular disorder and proton transfer.

An on-demand four-way junction DNAzyme nanoswitch driven by inosine-based partial strand displacement

A DNA four-way junction device capable of junction expansion and contraction cycles using an inosine-based partial strand displacement scheme is reported. These nanoscale positioning capabilities are used to provide on-demand activation and deactivation of a pair of split E6 DNAzymes on the device. The device also demonstrates a combined catalytic rate significantly higher than the original E6 DNAzyme under similar operational conditions. This approach can provide structural organization and spatially control other multicomponent molecular complexes.

A Supramolecular Assembly Formed by Heteroassociation of Ciprofloxacin and Norfloxacin in the Solid State: Co-Crystal Synthesis and Characterization

The interaction in the solid state between ciprofloxacin (CIP) and norfloxacin (NOR) was investigated and a new multicomponent molecular complex (COP) was obtained and characterized. It is composed of equimolar quantities of both compounds, according to TLC and 1H NMR data. As single-crystal X-ray analysis showed, COP crystallizes in the triclinic system, space group P(1). The asymmetric unit comprises three independent zwitterions (A, B, and C) with contributions of both CIP and NOR, as well as 14.6 water molecules. At the zwitterion A site, the occurrence is about 37% (CIP), 63% (NOR); at the B site, there is predominantly CIP (70%); and at the C site the occurrence is about 43% (CIP) and 57% (NOR), yielding an overall 1:1 CIP-NOR ratio in the crystal. TG data evidenced a one-step loss of solvent (about 18% per COP zwitterion) below 110 °C, confirming the presence of water molecules. The propensity for heteroassociation between CIP and NOR, under the conditions described herein, originated a co-crystal...

Covalent assistance to supramolecular synthesis: modifying the drug functionality of the antituberculosis API isoniazidin situ during co-crystallization with GRAS and API compounds

The anti-tuberculosis molecule isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes and also allows for its biological activity to be improved and modified by a simple covalent reaction. The low temperature crystal structures of both isoniazid (1) and the related N′-(propan-2-ylidene)isonicotinohydrazide molecule (2), the latter known to be a more effective agent against Mycobacterium tuberculosis, are reported. In addition, these two molecules were then co-crystallized with the same three Generally Regarded As Safe (GRAS) molecules, succinic acid, 4-hydroxybenzoic acid and 2-hydroxybenzoic acid, to produce the following pharmaceutical co-crystals: (isonicotinic acid hydrazide)2·(succinic acid) 3, (N′-(propan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 4, (isonicotinic acid hydrazide)·(4-hydroxybenzoic acid) 6, (N′-(propan-2-ylidene)isonicotinohydrazide)·(4-hydroxybenzoic acid) 7, (isonicotinic acid hydrazide)·(2-hydroxybenzoic acid) 8, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-hydroxybenzoic acid) 9. In addition, a co-crystal using 2-butanone as a modifier is also reported, (N′-(butan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 5. Drug–drug co-crystals were also made with the anti-HIV compound 2-chloro-4-nitrobenzoic acid: (isonicotinic acid hydrazide)·(2-chloro-4-nitrobenzoic acid) 10, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-chloro-4-nitrobenzoic acid) 11. All the co-crystals use the carboxylic acid⋯pyridine hydrogen bond to connect the GRAS or drug molecule to the pyridine ring. In general, the co-crystals with the modified isoniazid feature the C(4) homosynthon, and those with the original isoniazid a variety of homo- and heterosynthons. By comparing the melting points of the co-crystals that use isoniazid and those that use the modified isoniazid, a reduction in melting point is observed.

Paracetamol Form II: An Elusive Polymorph through Facile Multicomponent Crystallization Routes

A simple route to crystallization of the pharmaceutically important paracetamol form II is reported. The method is based around multicomponent crystallization techniques, involving various second components containing carboxylic acid groups and a range of solvents. These crystallization experiments do not produce multicomponent molecular complexes, but instead they provide the conditions in which the metastable paracetamol form II is reliably produced in 100% yields and with stability of greater than one year. To date, batches of paracetamol form II have been produced easily on the 100 mg scale with clear potential for bulk production.

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.

Advantages of cocrystallization in the field of solid-state pharmaceutical chemistry: l-Proline and MnCl 2

Cocrystallization (formation of a “ cocrystal”) is an emerging method to optimize physico-chemical properties of pharmaceutically active compounds. One elegant technique used to obtain such cocrystals is grinding the components together, either alone or in the presence of a small amount of solvent (so called solvent-drop grinding). Dry grinding has been used here to obtain cocrystals (actually a hydrated salt) of l-Proline and MnCl 2. In that context, a new crystalline structure of a multicomponent molecular complex composed of l-Proline and MnCl 2 is here reported. The complex was characterized by powder and single-crystal X-ray diffraction and differential scanning calorimetry. This study underlines the interest of grinding as a method to synthesize original solid-state complexes. It also emphasizes the advantage of combining calorimetric and X-ray diffraction to characterize the newly formed solids. Finally, our work provides structural basis for the role that l-Proline can play within multicomponent solid-state molecular complexes, in particular as a potential cocrystal former acting by both ionic and H-bond interactions when combined to molecules of pharmaceutical interest.

From electron microscopy to X-ray crystallography: molecular-replacement case studies.

Multi-component molecular complexes are increasingly being tackled by structural biology, bringing X-ray crystallography into the purview of electron-microscopy (EM) studies. X-ray crystallography can utilize a low-resolution EM map for structure determination followed by phase extension to high resolution. Test studies have been conducted on five crystal structures of large molecular assemblies, in which EM maps are used as models for structure solution by molecular replacement (MR) using various standard MR packages such as AMoRe, MOLREP and Phaser. The results demonstrate that EM maps are viable models for molecular replacement. Possible difficulties in data analysis, such as the effects of the EM magnification error, and the effect of MR positional/rotational errors on phase extension are discussed.