The separations of picoline isomers by enclathration

The chemical and physical properties of isomers make them difficult to separate using conventional methods. This renders the separation of isomers one of the more challenging obstacles in chemistry. In these cases, the supramolecular phenomenon of host-guest chemistry may be used in order to achieve separation. In this investigation, the preferences of three TADDOL (α,α,α’,α’-tetraphenyl-l,3-dioxolane4,5-dimethanol) - derived host compounds towards the isomers of methyl-pyridines (picolines) were studied. Crystals of ten novel inclusion compounds were synthesised and their structural properties were further characterised using an array of techniques. Thermal analysis was also conducted on these and other TADDOL-derived inclusion compounds. Binary competition experiments were performed with varying mole fractions of guests in the starting solution and detailed selectivity curves were generated. It was apparent that all three hosts discriminate between the picoline isomer guests. Notably, the three hosts display different preferences towards the picoline isomers and these results were rationalised by their resulting crystal structures, packing analysis, solubilities and correlated to their DSC results. DSC results showed a correlation between the thermal stability of an inclusion compound and the preference of the host towards the certain isomer involved in the inclusion complex. Further discussion on the selectivity preferences with regard to solubilities and crystal growth times was conducted

Fine tuning of crystal architecture by intermolecular interactions: synthon engineering

There has been a long time effort to influence or favourably fine tune structural properties by introduction of substituents or guest molecules of different sizes, shapes and chemical composition to consequently alter physico-chemical properties of the respective crystals. These attempts require the recognition, understanding and application of intermolecular interactions, crystallographic and, in case of occurrence, non-crystallographic symmetries. It brings us to the field of crystal engineering, which aims to produce new substances with required properties based on the knowledge of the structural properties of already characterised solids. A series of calixarene crystal structures are presented where the crystal packing is determined by spatial or by electrostatic effects. A series of laterally substituted calixarenes where both steric requirements and electrostatic forces play a role in the crystal architecture shows how the supramolecular synthon can be engineered

Polymorphism of Sildenafil: A New Metastable Desolvate

A new anhydrous polymorph of the free base of sildenafil and two solvates (acetonitrile and propanenitrile) have been discovered and fully characterized. The new polymorph can be considered a desolvate of the acetonitrile solvate and is related to the most stable form I by morphotropism. The new polymorph can only be obtained by desolvation of the acetonitrile solvate. Thus, this study is a new example of the importance of this multicomponent family of solid forms in the discovery of new polymorphs of active pharmaceutical ingredients

Assessment of the host potential of TETROL [(+)-(2R,3R)-1,1,4,4- tetraphenylbutane-1,2,3,4-TETROL] for the separation of isomers and related compounds

In this study, we investigated the potential of a host compound, (+)-(2R,3R)-1,1,4,4- tetraphenylbutane-1,2,3,4-tetrol (TETROL), for use in the separation of isomers and related compounds using host-guest chemistry. The synthesis of this host was carried out using a standard Grignard procedure, reacting naturally-occurring optically active tartaric acid with phenylmagnesium bromide. The feasibility of this host for separating isomers and structurally-related compounds was investigated by recrystallizing it from various potential cyclic, aromatic and aliphatic guest compounds. The extent of host inclusion and guest separation were determined using 1H-NMR spectroscopy and GCMS analyses. Competition studies were conducted to establish the selectivity of TETROL for the various guest species and whether this host would be able to discriminate between them. In this instance, the host was recrystallized from equimolar amounts of binary, ternary, quaternary or quinary mixtures of the guests present in each target study. Subsequent binary or ternary competitions were conducted where the molar ratios of the guest species were varied beyond equimolar, and the guest selectivity of TETROL thus evaluated by means of selectivity profiles. Further analyses included single crystal X-ray diffraction (SCXRD), thermal analysis and Hirshfeld surface analysis. Any crystalline inclusion complex formed between host and guest, with suitable crystal quality, was analysed using SCXRD in order to determine the nature of any significant host–guest interactions present. Thermogravimetric and differential scanning calorimetry experiments provided further insight into complex stability by analysing the thermal events experienced by the complexes as they were heated at 10 °C/min. The data obtained from Hirshfeld surface analyses were used to determine whether host selectivity and/or thermal stability of the complexes were related to the number and types of interactions, observed from SCXRD, between host and guest. The ability of TETROL to discriminate between related compounds was favourable. This host proved to have selective preference for aniline over its methylated derivatives, N-methylaniline and N,N-dimethylaniline. It was also selective for cyclohexylamine over cyclohexanol and cyclohexanone, and discriminated against the pyridine, piperidine and dioxane heterocyclics in favour of morpholine. Furthermore, this host was successful in the selective separation of isomers; for example, it selectively showed discrimination between the three toluidine isomers (p-toluidine > m-toluidine > o-toluidine) and the cresols (p-cresol > m-cresol > o-cresol). Each guest mixture was selected based on data from experiments using either the industrial significance of its separation or because the mixture would add to the knowledge base of the host compound’s preferences and selectivities. In a separate study, TETROL and its derivative, (–)-(2R,3R)-2,3-dimethoxy-1,1,4,4- tetraphenylbutane-1,4-diol (DMT), were also allowed to compete for the inclusion of the guest cyclohexanone, where TETROL demonstrated superior ability. This host, in addition, showed potential for the separation of cis- and trans- 2-methylcyclohexanol

Piezochromism in Nickel Salicylaldoximato Complexes: Tuning Crystal-Field Splitting with High Pressure

The crystal structures of bis(3-fluoro-salicylaldoximato)nickel( II) and bis(3-methoxy-salicylaldoximato) nickel(II) have been determined at room temperature between ambient pressure and approximately 6 GPa. The principal effect of pressure is to reduce intermolecular contact distances. In the fluoro system molecules are stacked, and the Ni Ni distance decreases from 3.19 Å at ambient pressure to 2.82 Å at 5.4 GPa. These data are similar to those observed in bis(dimethylglyoximato) nickel(II) over a similar pressure range, though contrary to that system, and in spite of their structural similarity, the salicyloximato does not become conducting at high pressure. Ni-ligand distances also shorten, on average by 0.017 and 0.011 Å for the fluoro and methoxy complexes, respectively. Bond compression is small if the bond in question is directed towards an interstitial void. A band at 620 nm, which occurs in the visible spectrum of each derivative, can be assigned to a transition to an antibonding molecular orbital based on the metal 3d(x 2-y 2) orbital. Time-dependent density functional theory calculations show that the energy of this orbital is sensitive to pressure, increasing in energy as the Ni-ligand distances are compressed, and consequently increasing the energy of the transition. The resulting blueshift of the UV-visible band leads to piezochromism, and crystals of both complexes, which are green at ambient pressure, become red at 5 GPa

Structures and thermal stability of selected organic inclusion compounds

Includes bibliographical references.The crystal structures of 1,1 ,6,6-Tetraphenyl-hexa-2,4-diyne-1 ,6-diol and 5-(3,5- Dicarboxyphenylethynyl)-isophthalic acid hosts with various guests have been elucidated. Depending on their structural properties and the way in which the host components pack, the guests may become trapped in spaces or voids, stacked in channels or sandwiched between layers of hosts. The crystal structures are stabilised by hydrogen bonding networks created by host-guest intermolecular interactions. The host hydroxy moieties adopt a trans conformation in 1,1 ,6,6-Tetraphenyl-hexa-2,4-diyne-1 ,6- diol host-guest inclusion componds. Host-guest hydrogen bonding in 5-(3,5- Dicarboxyphenylethynyl)-isophthalic acid salts occurs via the carboxylate group of the host anion. Hydrogen bond formation was the directing force determining the form of a host-guest array. The crystal structures of four inclusion compounds with 1,1 ,6,6-Tetraphenyl-hexa-2,4- diyne-1 ,6-diol host and six hydrated salt structures with 5-(3,5-Dicarboxyphenylethynyl)isophthalic acid host were solved using the single crystal X-ray diffraction technique. In addition the thermal stability and the structural properties of all compounds were investigated by thermal analysis techniques, including differential scanning calorimetry, thermogravimetry and hot-stage microscopy

Structural chemistry of metal coordination complexes at high pressure

The application of pressures of up to about 10 GPa may induce significant geometric, configurational, conformational and packing changes in molecular solids. This review highlights and describes recent advances in high pressure studies of coordination complexes, many of which have been conducted at synchrotrons or other central facilities. The main focus is on the wide range of geometric changes which occur with pressure. In some cases these changes have associated physical effects, and the review describes materials exhibiting negative linear compressibility, spin cross-over phenomena, magnetism and molecular conduction, as well as detailing the exciting possibilities for future developments in this area of research

Computational prediction of organic crystal structures

Crystal Structure Prediction (CSP) is used by the pharmaceutical industry to assess whether other polymorphs of active pharmaceutical ingredients (API) might cause problems during manufacturing processes. In the 7th Blind Test of CSP, organized by the Cambridge Crystallographic Data Centre (CCDC), one of the targets (XXX) was to predict the possible stoichiometries of two co−crystals of cannabinol (CBN) and tetramethylpyrazine (TMP). This thesis describes the methodology used for the submission of predicted structures of these co−crystals, concluding that the likely stoichiometries were 1CBN:1TMP and 1CBN:2TMP, as these were more stable than the component structures and had plausible crystal packings. Following submission, this thesis analysed the crystal structures of TMP and have proposed starting points for the crystal structure refinement of a structure (MPYRAZ03) on the Cambridge Structural Database (CSD) that has no atomic coordinates. The CBN search failed to find the Z’=2 experimental crystal structure (CANNOL) that is on the CSD, which has a high energy molecular conformation. This failure was found to be due to the limits on the structure generation program (Sobol sequence and density setting) and was exacerbated by the point charge model failing to model the CANNOL hydrogen bonding adequately. Alternative strategies to find the experimental structure were proposed, but they were deemed too expensive to run a full search. As this thesis was being completed, experimental co−crystal structures were provided by CCDC. After comparing with experimental structures, there was no experimental co−crystal structure in co−crystal CSP searches used in this thesis. This problem was caused by the folded pentane tail instead of the hydroxyl group

Synthesis and Characterization of Copper(I) Halide and Nitrate Complexes of Heterocyclic Thioureas

This thesis aims to characterize several novel copper(I) thiourea complexes of the form (CuIX)x(RNHCSNHR\u27)y (X = Cl, Br, I, or NO3; R = 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, thiazole or benzothiazole; and R\u27 = phenyl or methyl; R = R\u27 = 2-pyridyl or 3-pyridyl). The synthesis and characterization of the novel heterocyclic thioureas from heterocyclic amines with phenyl- or methylisothiocyanate or CS2 used in the copper(I) thiourea complexes mentioned above are also described. The chemical identity of each copper thiourea complex is verified by elemental analysis and/or X-ray crystallography. All complexes are analyzed for elemental analysis of copper, and several are also analyzed for carbon, hydrogen and nitrogen content. Additionally, many crystal structures are discussed, but due to difficulty in consistently obtaining X-ray quality crystals, not all complexes discussed have a known structure. X-ray crystal structures of seven new heterocyclic thioureas and nine new copper(I) thiourea complexes are reported

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

International audienceThe physicochemical properties of a 33 isomer grid of mono-chlorobenzamides (Clxx) are reported with comprehensive studies of their crystal structures and interaction environments (Clx = para-/meta-/ortho-chlorobenzoyl and x = para-/meta-/ortho-aminopyridine substitutions). The nine compound Clxx series was synthesised from the three p-/m-/o-chlorobenzoyl chlorides and three p-/m-/o-aminopyridine isomers using standard synthetic procedures. Clxx exhibits some similarities to the related Fxx and Brxx congeners e.g. the isomorphous behaviour of Clpp (para-Chloro-N'-(para-pyridyl)benzamide) with several close relatives, and there are five isomorphous pairs of Clxx and Brxx crystal structures. Notably Clmp and Clpm both crystallise with Z'=4 in space group P but show important differences. The overall lack of isomers crystallising with solvate molecules is noteworthy, except for Clmm(H 2 O). In all Clxx crystal structures, strong N-H…N hydrogen bonds form, however, Clpo also crystallises as the unexpected Clpo_O polymorph with N-H…O=C intermolecular hydrogen bonding. The Clxo triad (with ortho-pyridines) exhibits the expected cyclic N-H…N dimer formation with R 2 2 (8) hydrogen bonded rings. The H C atom type, forming weak C-H…Cl hydrogen bonds, is the only favoured interaction partner of chlorine in Clxx. Conformational analyses (gas phase) together with crystal contact enrichment studies place Clxx in context and at the interface of hydrogen and halogen bonding interactions, though strong hydrogen bonding dominates. In Clxx the interaction energies with nearest neighbours are shown to contribute to most of the lattice electrostatic energies. The melting temperatures T m show correlation with both molecular symmetry (Carnelley's rule) and total electrostatic energy of the weak interactions; in addition, these T m values can be well predicted from a linear fit combining both descriptors. In Clxx, N-H…N hydrogen bonds dominate, largely in the absence of solvates, and with five Clxx forming isomorphous pairs with Brxx analogues; Clpp being isomorphous with several close benzamide relatives. Analysis of T m reveals correlations involving both symmetry and electrostatic energies