Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.

X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.     

Toward rational and modular molecular design in soft matter engineering

This essay discusses some preliminary thoughts on the development of a rational and modular approach for molecular design in soft matter engineering and proposes ideas of structural and functional synthons for advanced functional materials. It echoes the Materials Genome Initiative by practicing a tentative retro-functional analysis(RFA) scheme. The importance of hierarchical structures in transferring and amplifying molecular functions into macroscopic properties is recognized and emphasized. According to the role of molecular segments in final materials, there are two types of building blocks: structural synthon and functional synthon. Guided by a specific structure for a desired function, these synthons can be modularly combined in various ways to construct molecular scaffolds. Detailed molecular structures are then deduced, designed and synthesized precisely and modularly. While the assembled structure and property may deviate from the original design, the study may allow further refinement of the molecular design toward the target function. The strategy has been used in the development of soft fullerene materials and other giant molecules. There are a few aspects that are not yet well addressed:(1) function and structure are not fully decoupled and(2) the assembled hierarchical structures are sensitive to secondary interactions and molecular geometries across different length scales. Nevertheless, the RFA approach provides a starting point and an alternative thinking pathway by provoking creativity with considerations from both chemistry and physics. This is particularly useful for engineering soft matters with supramolecular lattice formation, as in giant molecules, where the synthons are relatively independent of each other.     

A survey of tellurium-centered secondary-bonding supramolecular synthons

The crystal structures of tellurium compounds frequently display intermolecular contacts between the chalcogen and atoms possessing lone pairs of electrons. Analysis of the data deposited in the Cambridge crystallographic database shows that the shortest secondary bonding interactions (SBIs) are formed when oxygen, nitrogen or chlorine are the donor atoms for SBIs. In addition, these SBIs are shortest when they occur opposite to a bond between tellurium and oxygen, nitrogen, fluorine, chlorine or the nitrile functional group. The structural motifs assembled in these systems fall within eight general categories, from single to multiple bonded supramolecular synthons. The use of multiple points of attachment between molecules leads, in principle, to stronger and more directional supramolecular synthons. The overall structures assembled by the most important tellurium-based supramolecular synthons and prospects for their application in crystal engineering are discussed.     

Correspondence between molecular functionality and crystal structures. Supramolecular chemistry of a family of homologated aminophenols

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C6H4-(CH2)n-C6H4-NH2 (n = 1 to 5) and both OH and NH2 in a para position; (b) compounds 1a, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5,1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH2 groups: the tetrameric loop or square motif, the infinite N(H)O chain, and the beta-As sheet. These three synthons are not completely independent of each other but interrelate, with the structures tending toward the more stable beta-As sheet in some cases. Compounds 1-5 show an alternation in melting points, and compounds with n = even exhibit systematically higher melting points compared to those with n = odd. The alternating melting points are reflected in, and explained by, the alternation in the crystal structures. The n = odd structures tend toward the beta-As sheet as n increases and can be considered as a variable series whereas for n = even, the beta-As sheet is invariably formed constituting a fixed series. Substitution of a methylene group by an isosteric S-atom may causes a change in the crystal structure. These observations are rationalized in terms of geometrical and chemical effects of the functional groups. This study shows that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available.     

Co-crystallization of glycine anhydride with the hydroxybenzoic acids: Controlled formation of dimers via synthons cooperation and structural characterization

The results of crystallographic analyses on 1:1 and 1:4 well-defined co-crystals formed between glycine anhydride and each of 4-hydroxybenzoic acid and 3,5-dihydroxybenzoic acid are described. Neutral molecules are connected via heteromeric O-H···O and N-H···O contacts leading to different packing arrangements of supramolecular chains. On the basis of the molecular structures of glycine anhydride and carboxylic acid guests, the hydrogen bonds are arranged to give centrosymmetric synthons V and VII which are noteworthy for their robustness. Hydrogen-bond interactions between glycine anhydride and aromatic acid provide sufficient driving force to direct molecular recognition and crystal packing. Utilization of the orientation of functional groups of the building blocks, the acidity, and weak interactions provides a route for the creation of novel supra- molecular architectures in the crystal lattice. Both two co-crystals contain the expected hydrogen-bonded motifs, and there has been no proton transfer from either of the two carboxylic acids to the aza compound moiety. This demonstrates that glycine anhydride is very capable of affecting the construction of binary co-crystals in a predictable and rationale manner. It is noted that synthons VⅢ and IX are fairly large, but the real challenge in crystal engineering is to find a big enough synthon that occurs often enough. Thermal stability of these compounds has been investigated by thermogravimetric analysis (TGA) of mass loss.     

Solution and nanoscale structure selection: implications for the crystal energy landscape of tetrolic acid

Solution and growth effects are in many cases critical in determining which crystal structure (polymorph) a molecule will adopt. Contemporary crystal structure prediction (CSP) rarely address formation and growth in a systematic way, relying instead on bulk thermodynamic stabilities. In this study, it is shown that analysis of simulated solutions of tetrolic acid in combination with calculation of stabilities for nanoscale clusters cut from bulk structures can distinguish between four computationally predicted crystal structures, including the two known forms and two speculative forms, rationalizing the formation of one structure rather than another on grounds other than bulk lattice energies. It is concluded that modelling of both solution-based supramolecular species and nanocrystal stabilities are necessary to explain the selection of one structure over another during crystal formation, and that they are sufficient for the specific case of tetrolic acid.     

Identification of an Overlooked Halogen-Bond Synthon and Its Application in Designing Fluorescent Materials

Research on new supramolecular synthons facilitates the progress of materials design. Herein, the ability of sp² carbonyl oxygen atoms to act as halogen-bond acceptors was established through cocrystallization. Four sets of carbonyl compounds, including aldehydes, ketones, esters, and amides, were selected as halogen-bond acceptors. In the absence of strong hydrogen bonds, 14 out of 16 combinations of halogen-bond donors and acceptors could form cocrystals, whereby the supramolecular synthon C=O ⋅⋅⋅ X acts as the main interaction. Further, the geometric parameters of the C=O ⋅⋅⋅ X interaction were statistically revealed on the basis of the crystallographic database. The bifurcated interaction mode that has been observed in other halogen-bond synthons rarely occurs in the case of C=O ⋅⋅⋅ X. The robustness of C=O ⋅⋅⋅ X makes its application in crystal engineering possible and opens up new opportunities in designing multicomponent fluorescent materials, as indicated by multicolor emission of cocrystals D through C=O ⋅⋅⋅ X interactions.     

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion-corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol⁻¹) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher-order molecular ICCs with functional properties.     

Supramolecular synthons in fluorinated and nitrogen-rich <Emphasis Type="Italic">ortho</Emphasis>-diaminotriazoles

5-Substituted 3,4-diamino-1,2,4-triazoles can be obtained in moderate to good yields in a one-pot reaction starting from a carboxylic acid and dimethylaminoguanidine monohydrochloride in polyphosphoric acid (PPA) at 120 °C. Several triazoles and bistriazoles have been prepared in this way, with substituents ranging from alkyl to aryl, including perfluoroaryl or perfluoroalkyl substituents. The crystal structure analysis of three perfluorinated diaminotriazoles has evidenced a most stable R₂² (8) R_{2}^{2} (8) H bonding synthon, involving the amino CNH₂ donor and the adjacent nitrogen ring acceptor; additionally, two new synthons consisting of chains of rings have been identified. The relevance of the short F⋯F intermolecular contacts found in the structures is also discussed.     

A systematic study of ligand intermolecular interactions in crystals of copper(II) complexes of bidentate guanidino derivatives

The synthesis and X-ray structures of four neutral copper(II) complexes and one cationic complex incorporating bidentate alkyl N-(4-oxo-5,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)imidocarbamate ligands are reported. The neutral complexes, which possess potential doublet (DA) hydrogen bonding motifs, form supramolecular structures based on synthons involving hydrogen bonding or phenyl embraces. The formation of sheets within the crystal through combination of these synthons, and the occurrence of guest molecules trapped in cavities between the sheets, are described. The cationic complex forms an extended hydrogen-bonded structure that incorporates nitrate ions. The structures of the five complexes are compared with others reported previously for complexes of related ligands.     

Crystals at a Carrefour on the Way through the Phase Space: A Middle Path

Multiple supramolecular functionalities of cyclic α-alkoxy tellurium-trihalides (including Te---O, Te---X (X = Br, I) and Te---π(C=C) supramolecular synthons) afford rich crystal packing possibilities, which consequently results in polymorphism or Z’ > 1 crystal structures. Example of three crystal forms of cyclohexyl-ethoxy-tellurium-trihalides, one of which combines the packing of two others, affords a unique model to observe the supramolecular synthon evolution at the early stages of crystallization, when crystals on the way find themself at a carrefour between the evolutionally close routes, but fail to choose between two energetically close packing patterns, so taking the “middle path”, which incorporates both of them (and results in two crystallographically independent molecules). In general, this allows a better understanding of the existing structures, and an instrument to search for the new polymorphic forms.     

Graph theory of synthons

A graph-theory model of synthons is suggested. A synthon is a special kind of the molecular graph in which some vertices are distinguished from other ones, and they are called the virtual vertices. The most important property of the synthons is that the constraint of strict stoichiometry is removed and the virtual vertices formally correspond to functional groups that are not closely specified.     

Combinatorial Crystal Synthesis: Structural Landscape of Phloroglucinol:1,2‐bis(4‐pyridyl)ethylene and Phloroglucinol:Phenazine

A large number of crystal forms, polymorphs and pseudopolymorphs, have been isolated in the phloroglucinol‐dipyridylethylene (PGL:DPE) and phloroglucinol‐phenazine (PGL:PHE) systems. An understanding of the intermolecular interactions and synthon preferences in these binary systems enables one to design a ternary molecular solid that consists of PGL, PHE, and DPE, and also others where DPE is replaced by other heterocycles. Clean isolation of these ternary cocrystals demonstrates synthon amplification during crystallization. These results point to the lesser likelihood of polymorphism in multicomponent crystals compared to single‐component crystals. The appearance of several crystal forms during crystallization of a multicomponent system can be viewed as combinatorial crystal synthesis with synthon selection from a solution library. The resulting polymorphs and pseudopolymorphs that are obtained constitute a crystal structure landscape.     

Probing the Crystal Structure Landscape by Doping: 4‐Bromo, 4‐Chloro,and 4‐Methylcinnamic Acids

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4‐bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4‐methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4‐chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl‐doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of π⋅⋅⋅π interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.     

Probing the Crystal Structure Landscape by Doping: 4‐Bromo, 4‐Chloro,and 4‐Methylcinnamic Acids

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4‐bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4‐methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4‐chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl‐doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of π???π interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.     

A mathematical model of realistic constitutional chemistry. A synthon approach. I: An algebraic model of a synthon

A mathematical model of a synthon is suggested. The synthon is modelled by a special so-calledS-matrix. The notion of isomeric synthons on the set of atoms A and that of a Family of Isomeric SynthonsFIS (A) is introduced. The chemical reaction is represented by a matrix equation and it is modelled by the so-calledSR-matrix. The notion of the reaction distance (RD) between two isomeric synthons is defined. A mathematical theory of the S andSR-matrices is developed.     

New hydrogen-bonded donor-acceptor pairs between dipyridylacetylenes and 2,5-dichloro-3,6-dihydroxyl-1,4-benzoquinone

[structure: see text] The crystalline donor-acceptor hydrogen-bonding complexes between 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid) and dipyridylacetylenes (DPA) [2,2'-DPA, 3,3'-DPA, and 4,4'-DPA] were prepared, and crystal structures were revealed by X-ray analysis. The structures of the complexes are formed by intermolecular hydrogen-bonding interactions and demonstrate three supramolecular architectures based on a new common supramolecular synthon, which allows the formation of a different stacking arrangement and ionicity.     

利用二次球形配位构筑亲水型隧道框架结构

质子化N,N,N’,N’-四苄基乙二胺可与[Fe(CN)6]3－, [SnCl6]2－和[TeCl6]2－二次球形配位分别形成可容纳客体分子的包结物晶体(1～3). 晶体1通过NH＋…NC－, NH＋…p(NC)和CH…p(NC)组合合成子, 构筑了亲水性层柱隧道结构, 孔径尺寸为1.03 nm×1.12 nm, 两个乙醇分子和两个水分子填充于隧道中; 晶体2通过CH…Cl－合成子, 构筑了亲水性层间隧道结构, 孔径尺寸为0.94 nm×0.73 nm, 三个水分子和两个氯离子填充于隧道中; 晶体3的结构与晶体2相似, 也是通过CH…Cl－合成子, 构筑了层间亲水性隧道结构, 孔径尺寸为0.94 nm×0.72 nm, 两个水分子填充于隧道中.     

Toxicity-indicating structural patterns

We describe a toxicity alerting system for uncharacterized compounds, which is based upon comprehensive tables of substructure fragments that are indicative of toxicity risk. These tables were derived computationally by analyzing the RTECS database and the World Drug Index. We provide, free of charge, a Java applet for structure drawing and toxicity risk assessment. In an independent investigation, we compared the toxicity classification performance of naive Bayesian clustering, k next neighbor classification, and support vector machines. To visualize the chemical space of both toxic and druglike molecules, we trained a large self-organizing map (SOM) with all compounds from the RTECS database and the IDDB. In summary, we found that a support vector machine performed best at classifying compounds of defined toxicity into appropriate toxicity classes. Also, SOMs performed excellently in separating toxic from nontoxic substances. Although these two methods are limited to compounds that are structurally similar to known toxic substances, our fragment-based approach extends predictions to compounds that are structurally dissimilar to compounds used in the training set.     

Multicomponent Crystal of Metformin and Barbital: Design,Crystal Structure Analysis and Characterization

The formation of most multicomponent crystals relies on the interaction of hydrogen bonds between the components, so rational crystal design based on the expected hydrogen-bonded supramolecular synthons was employed to establish supramolecular compounds with desirable properties. This theory was put into practice for metformin to participate in more therapeutic fields to search for a fast and simple approach for the screening of candidate crystal co-formers. The prediction of intermolecular synthons facilitated the successful synthesis of a new multicomponent crystal of metformin (Met) and barbital (Bar) through an anion exchange reaction and cooling crystallization method. The single crystal X-ray diffraction analysis demonstrated the hydrogen bond-based ureide/ureide and guanidine/ureide synthons were responsible for the self-assembly of the primary structural motif and extended into infinite supramolecular heterocatemeric structures.