Yes / Derivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed "tribochromism". We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies. A number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2 -one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb - which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb. Our studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice. Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).

Yes / Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmaceutical and specialty fine chemicals manufacturing. In this contribution, we systematically examine the mechanical properties of dimorphic forms, Forms I and II of 1:1 caffeine-glutaric acid cocrystal on multiple faces using nanoindentation to fully understand their mechanical anisotropy and mechanical stability under applied load. Higher hardness, H, and elastic modulus, E, of stable Form II has been rationalized based on its corrugated layers, higher interlayer energy, lower interlayer separation, and presence of more intermolecular interactions in the crystal structure compared to metastable Form I. Our results show that mechanical anisotropy in both polymorphs arises due to the difference in orientation of the same 2D structural features, namely the number of possible slip systems, and strength of the intermolecular interactions with respect to the indentation direction. The mechanical properties results suggest that 1:1 caffeine-glutaric acid cocrystal, metastable form (Form I) could be a suitable candidate with desired tablet performance to that of stable Form II. The overall, it demonstrates that the multiple faces of nanoindentation is critical to determine mechanical anisotropy and structure- mechanical property correlation. Further, the structural-mechanical property correlations aids in the selection of the best solid phase for macroscopic pharmaceutical formulation.

Yes / The creation of co-crystals as a route to creating new pharmaceutical phases with modified or defined physicochemical properties is an area of intense research. Much of the current research has focused on creating new phases for numerous active pharmaceutical ingredients (APIs) to alter physical properties such as low solubilities, enhancing processability or stability. Such studies have identified suitable co-formers and common bonding motifs to aid with the design of new co-crystals but understanding how the changes in the molecular structure of the components are reflected in the packing and resulting properties is still lacking. This lack of insight means that the design and growth of new co-crystals is still a largely empirical process with co-formers selected and then attempts to grow the different materials undertaken to evaluate the resulting properties. This work will report on the results of a combination of crystal structure database analysis with computational chemistry studies to identify what structural features are retained across a selection of families of co-crystals with common components. The competition between different potential hydrogen bonding motifs was evaluated using ab initio quantum mechanical calculations and this was related to the commonality in the packing motifs when observed. It is found while the stronger local bonding motifs are often retained within systems, the balance of weaker long-range packing forces gives rise to many subtle shifts in packing leading to greater challenges in the prediction of final crystal structures.

Crystal engineering is defined as “the understanding of intermolecular interactions in the context of crystal packing and in the utilisation of such understanding in the design of new solids with desired physical and chemical properties”. If crystals are the supramolecular equivalents of molecules, then crystal engineering is the supramolecular equivalent of organic synthesis. The subject considers both crystal structure analysis and design of new structures with targeted properties. The concept of “Supramolecular Synthons” was introduced by G. R. Desiraju in this context, for the rational design of structures. Supramolecular synthons are the smallest reducible structural units that contain geometrical and chemical information required for recognition between functional groups in molecular solids. Crystal engineering has grown very fast after the introduction of this idea in 1995 and engineered solids were found to be useful for application in many diverse fields, from structural chemistry to drug design. Because of the great significance of supramolecular synthons, their identification and analysis in terms of crystallographic, spectroscopic, and computational methods is essential. Single crystal X-ray diffraction (SCXRD) is a widely used technique for the identification of synthon structure. But the technique has its own limitations like requirement of good quality, suitably sized single crystals, longer times associated with the process which further restricts high throughput analysis. Practically, there is no other way for identification of synthons on a regular basis. In this situation a simple, accurate, and fast method will be of significance; not only for basic studies, but also to scan different solid state phases in pharmaceutical industries. Due to this reason, I have studied IR spectroscopy to find marker bands for different synthons in the first part of the thesis. In chapter 2, I have analyzed a variety of C–H···X based weak synthons. For identification of each synthon, two sets of compounds were taken. In one set the synthon exists and in the other set it does not. Comparison and verification of IR characteristics helps to establish marker bands. Such markers are used to get information on synthon patterns in compounds with unknown crystal structures. The next challenge is whether or not such an IR method can distinguish different geometries of a same interaction. To address this question, different geometries of NO2···I halogen bonded synthons are investigated in chapter 3. This synthon exists in three geometries P, Q and R based on angular and distance criteria. The identification process is divided into five steps. The first step identifies IR signatures from very similar compounds, but with different topologies. The second step verifies earlier features and establishes IR marker bands. In the next step a graded IR protocol is formulated for stepwise discrimination of unknown systems. Such a graded method is applied for clarification of synthon ambiguities and in the identification of synthons in new compounds. Till now synthon information from crystal structures is used as a basis for IR study. Spectroscopy provides chemical information on intermolecular interactions. Is it possible to use such chemical information for crystal engineering? Chapter 4 deals with this aspect. Here, IR investigation is performed on the acid···amide heterodimer synthon. The initial analysis shows contradictory outcomes for synthon formation. According to IR, the N–H···O interaction is significantly destabilized in this synthon. Why then does the acid···amide synthon form? It is found that the answer lies in the higher stability of the other interaction, O–H···O, in the synthon. In other words, dimer formation will be preferred when the O‒H···O interaction is favoured. This is possible when the acidity of H-atom and the basicity of carbonyl O-atom is high. Based on this, a combinatorial study is performed varying the chemical nature of molecules, electron donating or withdrawing. Four quadrants are generated with different combinations of the molecular nature. The result of the combinatorial study shows different acid–amide oriented synthon preferences from different quadrants. A combination of all the observed synthons creates a structural landscape for the acid–amide system. A particular synthon associated with a specific quadrant is found to be responsible for the mechanical property of the synthesized cocrystals. Analysis on the structural aspects of mechanical properties allows for the formulation of models for property engineering. Can it be possible to use these models for targeted property design, other than serendipitous results? Crystal engineering is associated with three aspects, structure analysis, structure design and property engineering. Structure analysis is the first step in any crystal engineering exercise. It also explains the way by which the subject was started in the early days to correlate structure with property. This is the first phase or generation of crystal engineering. The second generation considers rational design of crystal structure which is facilitated by the concept of the supramolecular synthon. This phase has seen in the incorporation of different synthon based strategies to build a variety of supramolecular architectures. However, there is no prediction of a property which is the ultimate aim of crystal engineering. If one can achieve a desired property by predesign, then crystal engineering will see the final and higher stage which is termed third generation crystal engineering in chapter 5. The second part of the thesis discusses work is this direction, where mechanical properties are targeted and achieved by design using models from previous work. Chapter 6 discusses the engineering of elastic crystals from initial brittle precursors. A capping based model is proposed and used to prepare systems that can adopt the desired structure type. Among many other requirements, the crystals need some structurally buffering regions to show elasticity. Type-II electrostatic halogen bonds are used to construct such buffering regions. When the crystals are obtained according to the model type, they show reversible elastic deformation. σ-Hole based halogen bonds are crucial to the synthesis. But, during the project some adverse effects were noticed/realized for the use of halogen bonds. This suggests the need for an alternative methodology. A synthon that can mimic both the geometrical and chemical nature of σ-hole based halogen bonds would be useful to replace the earlier one. A search in this respect results in π-hole oriented orthogonal synthons based on C=O···C=O and NO2···NO2 interactions. A stepwise replacement procedure is applied to see and carry forward structural modularity in the new systems. Cocrystal systems are chosen for easy replacement by changing the constituents. Halogen bonds in cocrystals of the first step are partially substituted by a π-hole mimicking synthon in the second step and completely substituted in the third step. All the structures in the different steps are found to retain the same property, namely elasticity, although they possess dissimilar synthons. These aspects are discussed in chapter 7. Chapter 8 deals with the design of hand twistable helical crystals which are known to result during natural growth. Helical shape crystals are highly impactful for application in metamaterials and lithographic techniques, but at the same time occurrence of such morphology is unpredictable. Such shape generates from the periodic bending of crystals and thus needs multiple deformation directions. Here, a multistep crystal engineering procedure is adopted to get two directionally (2D) plastically bendable crystals, starting from one directional (1D) plastic crystals. Halogen bonds again play a major role in the design. The route follows the order 1D plastic crystals → 1D elastic crystals → 2D elastic crystals → 2D plastic crystals. These 2D plastic crystals are used to obtain hand-twisted helical crystals. Here, different properties namely elastic and plastic are seen in identically structured compounds. Once again, problems in using halogens are noticed. To address the issue of halogens, chapter 9 uses halogen bond/hydrogen bond equivalence to replace halogen bonds by geometrically and chemically similar hydrogen bonds. However, the first designed molecule in this respect did not result in the desired structure. The obligations are removed by applying the molecular/supramolecular equivalence strategy on the earlier molecule. Such an attempt gives another completely hydrogen bonded system that can now adopt the model structure and show a similar 2D plasticity. Crystals of this compound are also hand twistable. Third generation crystal engineering needs predesign models for targeted property engineering. In this context some differently structured elastic crystals are compared with common brittle crystals to identify and ascertain the structural requirements. This analysis helps in constructing different models for future engineering of elastic crystals. It also tabulates the structural and interaction differences in obtaining different mechanical properties namely shearing, plastic, elastic and brittle. In summary, these two major aspects for doing crystal engineering are highlighted in my thesis. One is the identification of robust synthons and the other is the use of synthon based structure design for property engineering. The first part of the thesis discusses the IR spectroscopic method for identification of synthons and then uses the spectral information for crystal structure engineering. The second part is related to deliberate crystal property engineering and uses structure-property relationships from the previous chapters and the literature to formulate predesign models and strategy. Achieving crystal properties in this way is expected to initiate the fast progress of the third generation crystal engineering.

This thesis covers a range of methodologies to provide an account of the current (2010-2014) state of the art and to develop new methods for solubility prediction. We focus on predictions of intrinsic aqueous solubility, as this is a measure commonly used in many important industries including the pharmaceutical and agrochemical industries. These industries require fast and accurate methods, two objectives which are rarely complementary. We apply machine learning in chapters 4 and 5 suggesting methodologies to meet these objectives. In chapter 4 we look to combine machine learning, cheminformatics and chemical theory. Whilst in chapter 5 we look to predict related properties to solubility and apply them to a previously derived empirical equation. We also look at ab initio (from first principles) methods of solubility prediction. This is shown in chapter 3. In this chapter we present a proof of concept work that shows intrinsic aqueous solubility predictions, of sufficient accuracy to be used in industry, are now possible from theoretical chemistry using a small but diverse dataset. Chapter 6 provides a summary of our most recent research. We have begun to investigate predictions of sublimation thermodynamics. We apply quantum chemical, lattice minimisation and machine learning techniques in this chapter. In summary, this body of work concludes that currently, QSPR/QSAR methods remain the current state of the art for solubility prediction, although it is becoming possible for purely theoretical methods to achieve useful predictions of solubility. Theoretical chemistry can offer little useful additional input to informatics models for solubility predictions. However, theoretical chemistry will be crucial for enriching our understanding of the solvation process, and can have a beneficial impact when applied to informatics predictions of properties related to solubility.

Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.

The knowledge of the packing behaviour of small organic compounds in crystal lattices is of great importance for industries dealing with solid state materials. The properties of materials depend on how the molecules arrange themselves in a crystalline environment. Crystal structure prediction provides a theoretical approach through the application of computational strategies to seek possible crystal packing arrangements (or polymorphs) a compound may adopt. Based on the chemical diagrams, this thesis investigates polymorphism of several small organic compounds. Plausible crystal packings of those compounds are generated, and their lattice energies are minimised using molecular mechanics and/or quantum mechanics methods. Most of the work presented here is conducted using two software packages commercially available in this field, Polymorph Predictor of Materials Studio 4.0 and GRACE 1.0. In general, the computational techniques implemented in GRACE are very good at reproducing the geometries of the crystal structures corresponding to the experimental observations of the compounds, in addition to describing their solid state energetics correctly. Complementing the CSP results obtained using GRACE with isostructurality offers a route by which new potential polymorphs of the targeted compounds might be crystallised using the existing experimental data. Based on all calculations in this thesis, four new potential polymorphs for four different compounds, which have not yet been determined experimentally, are predicted to exist and may be obtained under the right crystallisation conditions. One polymorph is expected to crystallise under pressure. The remaining three polymorphs might be obtained by using a seeding technique or the utilisation of suitable tailor made additives.

<p>Primary cell walls are a composite of cellulose microfibrilsand hemicelluloses. Xyloglucan is the principal hemicelluloseof primary cell walls of dicotyledons. Xyloglucanendotransglycosylases (XETs) cleave and religate xyloglucanpolymers in plant cell walls. A XET (PttXET16A) from hybridaspen has been heterologously expressed and characterized inour lab.</p><p>To study XETs enzymology on a molecular level a series ofnovel xyloglucan oligosaccharides (XGOs) have been synthesized.The chromogenic 2-nitrophenol XGO and fluorogenic XGOs havebeen used as kinetic probes for PttXET16A. The first 3-Dstructure of the XET and of the enzyme-substrate complexrevealed new insights into the requirements fortransglycosylation.</p><p>Cellulose fibers are an important raw material for manyindustries. In a novel chemo-enzymatic approach, thetransglycosylating activity of XET was used for biomimeticfiber surface modification. The aminoalditol XGO derivate wasused as key intermediate to incorporate novel chemicalfunctionality into xyloglucan. TheXGO derivatives wereintegrated into xyloglucan with PttXET16A. The resultingmodified xyloglucan was used as a versatile tool fiber surfacemodification.</p>

<p>Crystal structure, morphology and crystallization kinetics of melt-crystallized polypropylene and poly(propylene-stat-ethylene) fractions with 2.7 to 11.0 mol% of ethylene were studied by differential scanning calorimeter, wide- and small-angle X-ray scattering, polarized light microscopy, transmission electron microscopy and infrared spectroscopy. With increasing ethylene content the poly(propylene-stat-ethylene) fractions showed unchanged crystallinity, increased unit cell volume and constant crystal thickness in combination with a shortened helix length. This indicated that a fraction of ethylene defects were incorporated into the crystal structure. During the isothermal crystallization both α- and γ-crystals could be formed. The γ-crystal fraction increased with increasing ethylene content and increasing crystallization temperature. For samples with α- and γ-crystal contents, multimodal melting was observed and a noticeable γ- to α-crystal conversion was observed on slow heating. The spherulitic structure of the copolymers was coarser than that for the homopolymer.</p><p>The crystalline lamellae in copolymers exhibited profound curvature in contrast to the straighter cross-hatched α-crystals typical to the homopolymer. Area dependence of electrical breakdown strength was studied for thin polypropylene homopolymer films. The measurements were performed with an automatic measurement system equipped with a scanning electrode arm. Five different electrodes having areas between 0.045 cm2 and 9.3 cm2 were used and typically 40-80 breakdowns per sample and electrode area were collected. All measurements were performed on dry samples in air at room temperature. The data was analyzed statistically and the Weibull function parameters α and β, the first one related to 63% probability for the sample to break down and the second one to the width of the distribution were fitted to the obtained data. Different features concerning the measurement system and conditions, e.g. criteria for the automatic detection of the breakdowns, effect of electrode edge design, partial discharges, DC ramp speed and humidity were critically analyzed. It was concluded that the obtained α-parameter values were stable and repeatable over several years of time. The β-parameter values, however, varied ± 10-30%, more for the large than the small electrodes, and were also sensitive to the changes both in the sample itself and in the measurement conditions.</p><p>Breakdown strengths of over 50 capacitor grade polypropylene films were analyzed. The obtained α-parameter values were between 450 and 850 V/μm, depending on the film grade and electrode area. In addition to the high breakdown strengths, reflected by the obtained α-values, another, sparse distribution consisting of low breakdown strengths was revealed when the amount of measurement points was high enough. This means that more than one Weibull distribution could be needed to describe the breakdown strength behavior of a polypropylene film. Breakdown values showed decreasing area dependence with decreasing electrode area. Breakdown strengths for larger sample areas were predicted from the small area data by area- and Weibull extrapolation. The area extrapolation led to predicted α-values 50% higher than measured at 4 m² whereas the Weibull extrapolation showed an accuracy of ±15 % when predicted and measured values were compared.</p><p>Breakdown strengths were also extrapolated for film areas similar to those in impregnated power capacitors. It turned out that the power capacitors, tested at the factory, performed much better than predicted by the extrapolation. However, a few weak spots with very low breakdown values were also found. For the poly(ethyelene terephtalate) dielectric, which is not swelled by the impregnation liquid, the large area breakdown strength was predictable. This indicates that for polypropylene film processing and impregnation led, in addition to the improved large area breakdown performance, also to sparse weak spots with low breakdown probabilities. Different Weibull distributions were responsible for the breakdown strengths for the processed and impregnated polypropylene than for the dry film samples.</p>

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