Formation Of Synthons Research Articles

Influence of Polar Protic Solvents on Urea Morphology: A Combination of Experimental and Molecular Modeling

The modification of crystal shapes is used intensively in designing particles with desired properties to ensure the efficiency of the manufacturing processes. In this work, urea crystals grew in various polar protic solvents by cooling crystallization that produced α-form urea. The aspect ratios of the crystals were found to be in the range from 14.77 to 1.44, grown in the following solvents: water > methanol > ethanol > isopentanol > isobutanol > pentanol > butanol > propanol > isopropanol. An attempt to establish a correlation between the nonbonded energy, solvent molecule size, binding energy, and the change in morphology revealed that the aforementioned factors could not accurately predict the aspect ratios of the urea crystals. The solvent-surface binding energy showed the {111} and {001} capping facets recorded the highest strength (most negative energy), while the {110} facet was the lowest. The inhibition of the solvent molecules on the {001} and polar {111} facets stopped the growth along the c-axis by stopping the formation of synthon A and synthon B, while the growth along the a-axis was halted by stopping the formation of synthon B. The transformation from elongated cuboid to prismoidal shape of urea was governed by the {111}/{110} energy ratio, i.e., it must be <1.78.

The Role of Solvent Hydroxyl Functional Groups on the Interaction Energy and Growth of Form I Paracetamol Crystal Facets

The morphology of a crystal grown in a solvent can change depending on the solvent used during the crystallization process. Modification of the morphology of a crystal can be engineered based on information conferred by the functional groups of the facets of interest and the functional groups of the solvent. This study aims to predict the effect of the alcoholic functional group of amyl alcohol, benzyl alcohol, and phenol on the {002}, {011}, and {110} facets of Form I paracetamol. Prediction and simulation studies were carried out using an embedded tool available in Material Studio. The interaction between the solvents (phenol, benzyl alcohol, and amyl alcohol) and the surfaces used in this study revealed that the {011} facet had the most negative nonbonded energy, followed by the {110} and {002} facets. Overall, the nonbonded interactions between the solvents and the facets were dominated by Coulombic interactions, accounting for more than 90% of the energies, which is within the range from −2566 to −3613 kcal/mol. The binding energy for amyl and benzyl alcohols on the facets of the crystal, ranked from the strongest to the weakest, was in the order {002} > {110} > {011}, while for phenol, the rank was {002} > {011} > {110}. This result is in line with the observed crystal morphology of Form I paracetamol crystallized in a polar protic solvent, in which the most favorable solvent binding on the {002} facets delayed the growth of the elongated hexagonal morphology along the c-axis and formed prismatic-like morphology. Using benzyl alcohol as a case study, an assessment of synthon formation on facets {002} and {011} showed that synthon B is an important synthon for the growth of units of these facets, while synthon F is an important building block synthon for the {110} facet.

Formation of supramolecular synthons in the crystalline structure of the dinitrosyl iron complexes with aliphatic thiourea ligands.

By means of quantum-chemical calculations using Density Functional Theory, Quantum Theory of Atoms in Molecules, and Natural Bond Orbitals, theoretical modeling of intermolecular interactions has been performed for eight nitrosyl iron complexes with aliphatic thiourea ligands, which was aimed at discovering the presence of the NO…NO intermolecular interactions and at studying the possibility of the NO…NO supramolecular synthon formation in their crystalline structure for explaining their unusual magnetic properties. Such interactions were shown to be either stacking or T-like interactions, depending on the relative position of nitrosyl ligands and energetically corresponding to Van der Waals bonds. Mainly LP(O), π (NO), and π*(NO) orbitals in various combinations participate in their formation, with π (FeN), π(FeО), and LP(N) orbitals hardly being participants. The involvement of the NO bond orbitals results in quenching the orbital moment of the NO groups. If NO groups are isolated from intermolecular interactions, they can preserve the unquenched orbital moment.

Recurrent motifs in pharmaceutical cocrystals involving glycolic acid: X-ray characterization, Hirshfeld surface analysis and DFT calculations

Crystallization studies on some pyridinecarboxamides and methylated xanthines with glycolic acid as coformer, were carried out on formation of synthons and their influence on stability and solubility, the energy landscape and stabilization energies.

Multicomponent Supramolecular Assemblies of Melamine and α-Hydroxycarboxylic Acids: Understanding the Hydrogen Bonding Patterns and Their Physicochemical Consequences

The reaction of 1,3,5-triazine-2,4,6-triamine (melamine, me) with alpha-hydroxycarboxylic acids, namely, glycolic acid (H2ga) and mandelic acid (H2ma), provided three ionic multicomponent crystal structures (MCSs) of composition: [(Hme+)(Hga–)]·1/2H2O (I), [(Hme+)(Hma–)]·dioxane·2H2O (II), and [(Hme+)(Hma–)]·(me)·DMSO·3H2O (III). Those MCSs revealed the typical propensity of “me”, and particularly of its monoprotonated form (Hme+), to form supramolecular aggregates such as linear and crinkled tapes and molecular ribbons. The energetic landscape of those assemblies has been explored with the use of density functional theory calculations of various models of Hme+ and “me” hydrogen-bonded aggregates. The stabilization energies of Hme+-based adducts are for the first time rationalized within the context of the anti-electrostatic hydrogen bonding concept. In addition, we discussed the supramolecular arrangement of I–III in terms of synthon formation and explored structural peculiarities imparted by hydration a...

Investigation of non-covalent and hydrogen bonding interactions on the formation of crystalline networks and supramolecular synthons of a series of α-aminophosphonates: Crystallography and DFT studies

α-Aminophosphonates have been rarely explored in the field of crystal engineering. These organic molecules are capable of forming reliable and reproducible supramolecular synthons through non-covalent interactions that can be employed for designing high dimensional supramolecular architectures. Here, we systematically study the influence of conventional and unconventional hydrogen bonding interactions on the formation of these synthons and stability of the crystal packing. The theoretical studies were employed to further confirm the presence of these synthons by comparing the stabilization energies of the dimers and monomers. The dependence of the stability of NH⋯O hydrogen bonds to the aromatic substituents were investigated using NBO analysis. The most stable compound was determined by comparing the HOMO-LUMO energy gap of all compounds and compared with NBO analysis.

Using Electron Density to Predict Synthon Formation in a 4-Hydroxybenzoic Acid: 4,4′-Bipyridine Cocrystal

Experimental charge density distribution studies complemented by quantum mechanical theoretical calculations of 4-hydroxybenzoic acid (4HBA) (1), 4,4′-bipyridine (44BP) (2), and one polymorphic form of the cocrystal containing 4HBA and 44BP molecules in a 2:1 ratio (3), have been carried out via high resolution single-crystal X-ray diffraction. Synthon formation was found to be the main driving force for crystallization in both (1) and (3) with a carboxylic acid homosynthon present in (1) and a heterosynthon in (3) comprised of a carboxylic acid from 4HBA and a pyridine nitrogen and aromatic hydrogen from 44BP. Topological analysis revealed the bonding in the homosynthon to be stronger than the heterosynthon (305.88 versus. 193.95 kJ mol–1) with a greater number of weak interactions in (3) helping to stabilize the structure. The distance from the hydrogen and hydrogen bond acceptor to the bond critical point (bcp) was also found to be a significant factor in determining bond strength, potentially having a...

First-line antituberculosis drug, pyrazinamide, itspharmaceutically relevant cocrystals and a salt.

A few pyrazinamide (Pyz) cocrystals involving hydroxybenzoic/cinnamic acid derivatives [2,4-dihydroxybenzoic acid (24DHBA); 2,6-dihydroxybenzoic acid (26DHBA); 3,5-dihydroxybenzoic acid (35DHBA) and nutraceutical molecule ferulic acid (FRA)] and the first example of a molecular salt with p-toluenesulfonic acid (pTSA) have been prepared and characterized using various solid-state techniques. A high-temperature cocrystal polymorph of Pyz·FRA has been characterized from the endothermic peaks observed using differential scanning calorimetry. The presence of substituent groups carrying hydrogen bond donors or acceptors and their influence on supramolecular synthon formation has been investigated using a Cambridge Structural Database search. Equilibrium solubility of all the binary complexes of Pyz follows the order of their coformer solubility, i.e. Pyz+·pTSA- > Pyz·35DHBA > Pyz > Pyz·26DHBA > Pyz·24DHBA > Pyz·FRA. A twofold enhancement in solubility of Pyz+·pTSA- molecular salt compared with the parent drug suggests a potential drug formulation for the treatment of tuberculosis.

Structural and Energetic Analysis of Molecular Assemblies in a Series of Nicotinamide and Pyrazinamide Cocrystals with Dihydroxybenzoic Acids

Four new cocrystals of pharmaceutically active N-donor compounds, pyrazinamide (P) and nicotinamide (N), with a series of dihydroxybenzoic acids, i.e., 2,3-dihydroxybenzoic acid (23DHB), 2,4-dihydroxybenzoic acid (24DHB), and 2,6-dihydroxybenzoic acid (26DHB), were synthesized and structurally evaluated in order to study basic recognition patterns and crystal lattice energetic features. The literature-reported structures of this kind, i.e., N:24DHB, N:25DHB and N:26DHB (the last two were crystallized and remeasured by us at 100 K) and P:25DHB, completed the series. The analysis of interaction networks in the examined cocrystals reflects the relative affinity of the COOH and OH groups toward N-donor compounds. A major factor that governs the primary synthon formation is the basic character of the proton acceptors in the heterocyclic compounds. In a crystal lattice, the more rigid pyrazinamide tends to form its primary structural motifs, and hence is less influenced by the molecular surrounding than nicotin...

Testing the limits of synthon engineering: salts of salicylic and sulfosalicylic acid with nucleobases and derivatives

Synthon engineering concepts were tested by using nucleobases and derivatives, namely adenine, cytosine, benzimidazole and fluorocytosine when crystallized with salicylic acid and 5-sulfosalicylic acid. These bases were selected to investigate how the hydrogen bond donor and acceptor groups would influence the crystal structure. Salicylic acid was selected to investigate N–H⋯O hydrogen bonding and synthon formation, while its derivative, 5-sulfosalicylic acid, was selected to see how the sulfonate group would enhance or disrupt these features. Each of the seven complexes obtained was characterized by single crystal X-ray diffraction, which showed that acid–base pairing favored salt formation. All the salicylic acid complexes adopt similar hetero supramolecular synthons, while 5-sulfosalicylic acid forms more complex structures with more than one type of synthon present. Crystal formation using cytosine or fluorocytosine did not result in the predicted synthon formation. This unexpected outcome highlights the current limitations of synthon engineering.

Cysteine as a ligand platform in the biosynthesis of the FeFe hydrogenase H cluster

Hydrogenases catalyze the redox interconversion of protons and H2, an important reaction for a number of metabolic processes and for solar fuel production. In FeFe hydrogenases, catalysis occurs at the H cluster, a metallocofactor comprising a [4Fe-4S]H subcluster coupled to a [2Fe]H subcluster bound by CO, CN(-), and azadithiolate ligands. The [2Fe]H subcluster is assembled by the maturases HydE, HydF, and HydG. HydG is a member of the radical S-adenosyl-L-methionine family of enzymes that transforms Fe and L-tyrosine into an [Fe(CO)2(CN)] synthon that is incorporated into the H cluster. Although it is thought that the site of synthon formation in HydG is the "dangler" Fe of a [5Fe] cluster, many mechanistic aspects of this chemistry remain unresolved including the full ligand set of the synthon, how the dangler Fe initially binds to HydG, and how the synthon is released at the end of the reaction. To address these questions, we herein show that L-cysteine (Cys) binds the auxiliary [4Fe-4S] cluster of HydG and further chelates the dangler Fe. We also demonstrate that a [4Fe-4S]aux[CN] species is generated during HydG catalysis, a process that entails the loss of Cys and the [Fe(CO)2(CN)] fragment; on this basis, we suggest that Cys likely completes the coordination sphere of the synthon. Thus, through spectroscopic analysis of HydG before and after the synthon is formed, we conclude that Cys serves as the ligand platform on which the synthon is built and plays a role in both Fe(2+) binding and synthon release.

Charge density and optical properties of multicomponent crystals containing active pharmaceutical ingredients or their analogues.

Active pharmaceutical ingredients (APIs), through their favourable donor/acceptor spatial distribution and synthon formation flexibility, are attractive building blocks in modern materials crystallography. The optical properties of a crystal strongly depend on two factors, i.e. the spatial distribution of molecules in the crystal structure and the electronic properties of molecular building blocks (dipole moments, polarizabilities, hyperpolarizabilities). Although the latter are easy to predict through ab initio calculations, the former are not. Only a combination of experimental and theoretical charge density studies together with prediction and measurement of optical properties enable full analysis of the obtained functional material in terms of its usefulness in practical applications. This article presents design strategies of optical materials based on selected pharmaceutical molecules. Factors that contribute to molecular recognition in the four selected polar/chiral crystal phases (derived through charge density and Hirshfeld surfaces analysis) have been determined. Theoretically predicted optical properties of the molecular/ionic building blocks as well as bulk effects have been confirmed experimentally. This research is a first step in the design of novel optical materials based on push-pull molecules and APIs.

X-ray crystallographic and EPR spectroscopic analysis of HydG, a maturase in [FeFe]-hydrogenase H-cluster assembly

Hydrogenases use complex metal cofactors to catalyze the reversible formation of hydrogen. In [FeFe]-hydrogenases, the H-cluster cofactor includes a diiron subcluster containing azadithiolate, three CO, and two CN(-) ligands. During the assembly of the H cluster, the radical S-adenosyl methionine (SAM) enzyme HydG lyses the substrate tyrosine to yield the diatomic ligands. These diatomic products form an enzyme-bound Fe(CO)x(CN)y synthon that serves as a precursor for eventual H-cluster assembly. To further elucidate the mechanism of this complex reaction, we report the crystal structure and EPR analysis of HydG. At one end of the HydG (βα)8 triosephosphate isomerase (TIM) barrel, a canonical [4Fe-4S] cluster binds SAM in close proximity to the proposed tyrosine binding site. At the opposite end of the active-site cavity, the structure reveals the auxiliary Fe-S cluster in two states: one monomer contains a [4Fe-5S] cluster, and the other monomer contains a [5Fe-5S] cluster consisting of a [4Fe-4S] cubane bridged by a μ2-sulfide ion to a mononuclear Fe(2+) center. This fifth iron is held in place by a single highly conserved protein-derived ligand: histidine 265. EPR analysis confirms the presence of the [5Fe-5S] cluster, which on incubation with cyanide, undergoes loss of the labile iron to yield a [4Fe-4S] cluster. We hypothesize that the labile iron of the [5Fe-5S] cluster is the site of Fe(CO)x(CN)y synthon formation and that the limited bonding between this iron and HydG may facilitate transfer of the intact synthon to its cognate acceptor for subsequent H-cluster assembly.

Exploring the structural landscape in nia derivatives and their Cd(II) complexes

Constant need for design of new materials with desired and pre-determined bulk properties necessitates much improved understanding of competition and balance between non-covalent interactions. In order not to rely on serendipity when targeting synthesis of new solids with pre-determined connectivity and topology, as this offers a path towards the design of materials with pre-determined bulk properties, it is imperative to map out the reliability and robustness of supramolecular synthons. In this contribution, we want to delineate the effect of the counter ion accommodation in the supramolecular assembly on the synthon formation. We opted for positively charged pyridine-based organic molecules that are encoded with two functionalities, caboxamide and carboxylic acid moieties, which both proved as robust and reliable self-complementary reagents, accompanied with one of the three halide counter ions (Cl-, Br-, I-). The study thus focuses on the competition and hierarchy of supramolecular synthons in organic systems of the ligands themselves as well as in the Cd(II)-containing architectures (upon the ligand coordination) depending on the polarizability of the present halide ion. Furthermore, the most prominent intermolecular contacts in the crystal structures will be visualized by Hirshfeld surface analysis and their contributions to the Hirshfeld surface area will be determined. Bader's QTAIM (Quantum Theory of Atoms in Molecules) analysis will be used to characterize the nature and strength of intermolecular interactions based on the DFT calculations started from X-ray determined geometries. The computationally determined data will be compared with the experimental results to get unbiased analysis about the role of specific intermolecular interactions on crystal packing of examined compounds.

Charge Density and Optical Properties of Multicomponent Crystals Containing APIs

Technological progress forces improved material performance therefore controlling synthesis of new crystal phases requires moving from the trial-and-error method to comprehensive solutions. Active Pharmaceutical Ingredients (API) are of particular interest in crystal engineering [1]. Molecular flexibility reflected in many polymorphic forms and appropriate spatial distribution of hydrogen bond donors and acceptors make many known drugs useful for designing optically active materials [2]. The effective correlation between properties and structural features of a given material is possible through quantitative crystal engineering combined with in silico crystal engineering. Quantitative crystal engineering utilizes modern charge density analysis and properties calculations, whereas in silico crystal engineering assesses synthon formation capability probing weak interactions existing within the crystal phases. Optical properties of a crystal strongly depend upon spatial distribution of molecules in the crystal structure, as well as on the electronic properties of molecular building blocks (dipole moments, polarizabilities, hyperpolarizabilities)[3]. Recently we have investigated materials based on pharmaceutically active ingredients: barbiturates, antiarrhythmic drugs, alkaloids, combined with organic molecules and/or transition metal salts. Partial results of our research have already been published [2]. Factors that contribute to molecular recognition in the selected polar/chiral crystal phases (derived through charge densityand Hirshfeld Surfaces Analysis) have been determined. The predicted values of refractive indices were confirmed experimentally using the immersion oil method. Second Harmonic Generation efficiency was assessed using a modified Kurtz-Perry technique [2].

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.

Dihydropyrrolo[1,2-b]pyrazoles: withasomnine and related compounds

In the paper we indicate the increasing importance of derivatives containing a dihydropyrrolo[1,2-b]pyrazole (DPP) core. We try to show our synthetic approach based on an improved Kulinkovich method as well as our new synthetic pathway. A complex methodology involving the preparation of substituted DPPs focuses on withasomnine and the synthesis of several structurally related compounds. The developed reaction protocols enable the preparation of the mentioned bicyclic system with broadly diverse substitution. Thus, we are able to prepare systems with aliphatic, aromatic, polyaromatic, heteroaromatic, TMS, and even adamantane substitution with known biologically active properties. The reaction protocol, consisting of two multi-step synthetic pathways, includes Sonogashira and Suzuki–Miyaura cross-coupling reactions, allenyl synthon formation, Kulinkovich cyclopropanation, ring transformations, and nonsymmetrical homoallenyl azines cycloadditions. Moreover, we prepared compounds with a resemblance to other bioactive species: fadrozole, nagstatine, an antitumor agent LY2109761 and a mixed lineage kinase 7 inhibitor DHP-2.

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.

ChemInform Abstract: Enantioenriched Formation of Synthons of 1,5‐Hexadiene Bis‐Epoxides for Construction of Nonracemic cis‐ and trans‐2,5‐Disubstituted Tetrahydrofurans.

AbstractThe pathway to the enantioenriched bis‐epoxides includes the Sharpless asymmetric epoxidation of heptadienol and the mild epoxidation of the resulting epoxy alkenes (I) as the key step via high asymmetric induction by using the Katsuki titanium salalen catalyst.

Enantioenriched Formation of Synthons of 1,5-Hexadiene Bis-epoxides for Construction of Nonracemic cis- and trans-2,5-Disubstituted Tetrahydrofurans

Enantioenriched Formation of Synthons of 1,5-Hexadiene Bis-epoxides for Construction of Nonracemic cis- and trans-2,5-Disubstituted Tetrahydrofurans