Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Enantiospecific approaches to komarovispiranes” describes the utility of the monoterpene α-campholenaldehyde as chiral starting material in the enantiospecific synthesis of a variety of bi- and tricyclic compounds, and enantiospecific first total synthesis of spiro diterpenes komarovispiranes. For convenience the results are described in two different sections, viz., (a) Chiral synthons from α-campholenaldehyde; and (b) Enantiospecific synthesis of a komarovispirane. In the thesis, the compounds are sequentially numbered (bold) and the references are marked sequentially as superscripts and listed in the last section of the thesis. Complete details of the experimental procedures and the spectroscopic data were provided in the experimental section. A brief introduction is provided wherever appropriate to keep the present work in proper perspective. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. Monoterpenes are widely used as chiral auxiliaries, but their potential as chiral synthons has not been properly exploited. In the present thesis, utility of α-campholenaldehyde, which is readily available from α-pinene in two steps, as chiral synthon has been demonstrated in the enantiospecific synthesis of a few bi- and tricarbocyclic frameworks as well as spiroditerpenes komarovispiranes. To begin with, synthesis of several bi- and tricyclic compounds, namely bicyclo[3.3.0]octan-3-one; bicyclo[3.2.1]octan-2-one; bicyclo[3.2.1]octan-3-one; 3-cyclopentylcyclopentanone; bicyclo[4.3.0]non-3-one; spiro[4.4]non-2-one; tricyclo[6.3.0.02,6]undecan-6-ol; and spiro[4.5]decan-2-one; have been accomplished employing an intramolecular rhodium carbenoid C-H insertion, intramolecular type II carbonyl ene cyclisation, intramolecular acid catalysed diazoketone cyclisation reactions and ring-closing metathesis (RCM) reaction as the key steps. Komarovispirone is a tricyclic spiro diterpene isolated from Dracocephalum komarovi Lipsky, a perennial semishrub available in Uzbekistan and exhibits trypanocidal activity. The novel diterpene containing an unusual carbon framework, cyclohexane spiro fused to bicyclo[4.3.0]nonane, coupled with the potential biological activity have made komarovispirone, and its analogues interesting and challenging synthetic targets. Initially, as a model study, enantiospecific synthesis of a bis-norkomarovispirane was developed employing 7,8,8-trimethylbicyclo[3.3.0]oct-6-en-3-one as the starting material, which was readily available from campholenaldehyde. A Claisen rearrangement and RCM reaction based methodology was developed for the spiroannulation of a cyclohexane ring at the C-3 position of the bicyclo[3.3.0]octan-3-one. For the enantiospecific first total synthesis of komarovispiranes, the AB-trans ring system was generated via ring expansion of 7,8,8-trimethylbicyclo[3.3.0]oct-6-en-3-one employing ozonolytic cleavage followed by an intramolecular aldol condensation reaction of the resultant keto aldehyde. For the generation of the ABC ring system of the komarovispiranes, initially, a Claisen rearrangement and intramolecular type II carbonyl ene reaction based methodology was developed for the spiroannulation of a cyclohexane ring at the C-8 position of the bicyclo[4.3.0]nonan-8-one. Subsequently, an alternate Claisen rearrangement-RCM reaction based methodology was also developed for the spiroannulation, and extended it to the first total synthesis of a komarovispirane.

Les sécoiridoïdes sont des monoterpènes hautement fonctionnalisés utilisés comme matières premières chirales renouvelables en hémisynthèse, lorsqu'ils sont abondants au sein des végétaux. Un nouveau procédé vert d'extraction aqueuse et de purification utilisant des résines et la chromatographie de partage centrifuge a permis l'isolement de plus de 100 g d'oleuropéine des feuilles d'Olea europaea et d'une douzaine de grammes de sécologanoside et de sweroside des feuilles de Lonicera tatarica. L'ouverture de la lactone du perpivaloylsweroside a été effectuée en milieu organique apolaire par le TMSONa. Cette réaction a été étendue à 8 lactones commerciales et 5 lactones de sécoiridoïdes. Une approche mécanistique de cette nouvelle réaction a été établie sur la γ-butyrolactone à l'aide d'une étude cinétique. Cette réaction a été utilisée pour la conversion du sweroside en sécologanoside en quatre étapes. Cette approche séquentielle a été appliquée avec succès sur les dérivés du sweroside. Quatre nouveaux analogues du sécologanoside et 9 synthons chiraux originaux ont ainsi été isolés. De plus l'étude de la réactivité de l'oleuropéine a permis l'obtention de 4 nouveaux synthons et un analogue isomérique du sécologanoside. Ces analogues de sécologanoside sont précurseurs de nouveaux alcaloïdes indolo-monoterpèniques. Enfin la double liaison exocyclique du sweroside a pu être sélectivement ozonolysée et épimérisée pour conduire à la formation d'un synthon clé pour la synthèse de diterpènes cytotoxiques marins de types xénicanes.

Crystal engineering is widely applied in the design of new solids with desired physical and chemical properties based on an understanding of intermolecular interactions in terms of crystal packing. The understanding of such structure-property correlations increased my interest in the modulation of macroscopic properties of solid compounds. Establishing connections between structure and macroscopic properties is a classical aspect of materials science and engineering. With the advent of the nanoindentation technique, it is now possible to make such a link between micro-level structures with mechanical properties of molecular solids - in other words, between chemistry and engineering. Nanoindentation is a quantitative probe for the assessment of mechanical behavior of small volume materials. In this technique, applied load and indenter depth penetration are measured simultaneously for a molecular crystal specimen, with high precision and resolution. From this data, one can obtain the elastic modulus and hardness of molecular crystals. Being able to accordingly assess the relative strengths of intermolecular interactions, such a technique has become relevant to the subject of crystal engineering. We have used nanoindentation to study the packing anisotropy of molecular crystals and to establish structure-property relationships. This thesis demonstrates that nanoindentation is a state-of-the-art technique to probe the mechanical properties of molecular crystals and assists the development of the subject of crystal engineering towards property design. Chapter 1 gives an overview of the development of crystal engineering from solid state organic chemistry and a brief introduction of the nanoindentation technique which has become relevant to the subject of crystal engineering to establish structure-property relationships. The study of the mechanical properties of molecular solids as a function of their crystal structures is a very active branch of crystal engineering. Chapter 2 explores the insights of well-known odd-even alternative mechanical, physical and thermal properties of α,ω-alkanedicarboxylic acids such as elastic modulus, hardness and melting temperature through nanoindentation technique. These properties are well correlated with their crystal structure packing. The odd acids were found to be softer and lower melting temperature as compared to the even ones, possibly due to the strained molecular conformations in the odd acids in easier plastic deformation. Shear sliding of molecular layers past each other during indentation is a key to the mechanism for plastic deformation in the molecular crystals. Relationships between structural features such as interplanar spacing, interlayer separation distance, molecular chain length and signatures of the nanoindentation responses, discrete displacement bursts have also been discussed in this chapter. Chapter 3 explores the use of the nanoindentation measurement as a signature response to study the microstructure that exists in a single crystal of organic solids. The analysis of microstructure through X-ray crystallography can be misleading. This is because crystal structures as determined from the single-crystal diffractometer data represent only space- and time-averaged structures. Thus, due to higher spatial resolution of the nanoindentation technique compared to X-ray diffraction (XRD) it become a local probe, which allows for discrimination between different microstructure or domains in the single crystal. Chapter 4 attempts to explore an understanding of the underlying relationship between crystal structure and the mechanical properties of molecular crystals which are relevant for the systematic design of organic solids with a desired combination of mechanical properties such as elasticity and hardness through crystal engineering. Elastic properties in molecular solids are largely determined by the isotropy of crystal packing. By using the techniques of crystal engineering, seven halogenated N-benzylideneanilines (Schiff bases) crystals have been systematically designed and observed common underlying structural features which lead to high flexibility and elasticity. Elasticity in those crystals arises from a criss-cross packing of molecular tapes in isotropic structures with energetically comparable halogen bonds (Cl···Cl or Cl···Br). The chapter also demonstrates that the solid solution strengthening can be effectively employed to engineer hardness of organic solids. High hardness can be attained by increasing lattice resistance to shear sliding of molecular layers during plastic deformation. Chapter 5 demonstrates the broad applications of mechanical properties of molecular solids in the context of the pharmaceutical industry, which can be understood through nanoindentation. Crystal engineering is applied in designing active pharmaceutical ingredients (APIs) so as to obtain materials that exhibit optimum combinations of important physicochemical properties such as solubility, dissolution rate, and bioavailability. In the context of industrial-scale pharmaceutical manufacturing, it can also be used to tune mechanical properties such as grindability and tabletability, which often determine the processing steps that are adopted. Hence, there is always interest in the crystal structure−mechanical property correlations of APIs. The study of the mechanical properties of polymorphic drugs is an important for developing an understanding of their stability in the solid state. Overall, the main aim of this thesis is to explore an understanding for establishing structure-mechanical properties correlations of molecular crystals with recent advances in the nanoindentation technique and to gain knowledge for the design and synthesis of new materials using the crystal engineering approach. Nanoindentation of molecular crystals provides insights related to crystal packing, interaction characteristics, polymorphism and topochemistry.

Crystal engineering offers a rational way of analyzing crystal structures and designing new structures with properties. The supramolecular synthon concept was introduced in 1995 and has shown versatility and utility in the design of molecular solids. Chapter 1 gives a general introduction about the development of the concept of supramolecular synthons over the years which has seen a transition from synthesis to structures and dynamics. This thesis focuses on the later phase of the development of the concept of supramolecular synthons. Chapter 2 introduces the idea of structural landscape and describes a structural landscape of a conformationally flexible molecule, orcinol, and explores the synthon preferences of this particular molecule towards cocrystal formation. Chapter 3 explores a combinatorial matrix to show both global and local features of a structural landscape. Chapter 4 takes a component of this landscape namely 4,4'-bipyridine and 4-hydroxybenzoic acid and shows the occurrence of synthon polymorphism in cocrystals which originates from the interplay of geometrical and chemical factors. Chapter 5 introduces a four step method for the identification of multiple synthons by FTIR spectroscopy. Along with, it shows that the rarity of synthon polymorphism is not a case of overlooking of crystals in the process of selecting good looking crystals. Chapter 6 takes a series of dihalogenated phenols and indicates that the Br prefers type II. This chapter also explains elastic bending on the basis of halogen bonds. Chapter 7 attempts to explore the Cl/Br isostructurality in the light of type I and type II contacts and concludes that Cl/Br isostructurality arises from a geometrical model and therefore it is quite similar to Cl/Me isostructurality. Chapter 8 attempts to analyze the class of trichlorophenols and reveals structural modularity in this class of compounds. The modularity of 3,4,5-trichlorophenol is explored in crystal design in chapter 9 in terms of LSAM (Long Range Synthon Aufbau Module) A subsequent study in solution by NMR reveals the presence of LSAM in solution and establishes a hierarchy of the dissociation of its components. The concept of supramolecular synthon has come a long way from being a tool in a crystal engineer’s toolbox to a structural unit responsible for crystallization and therefore offer multiple possibilities both in terms of structures and dynamics. This thesis attempts to explore some of these possibilities based mainly on the concepts of structural landscape and halogen bonds which are blended with the concept of supramolecular synthons.

Les propriétés exceptionnelles des composés fluorés ont entrainées un développement considérable de la chimie du fluor depuis les années 1950. Aujourd'hui les substances fluorées se retrouvent dans la plupart des domaines tels que la chimie thérapeutique ou l'agrochimie. L'atome d'azote étant ubiquitaire en chimie médicinale, le développement de voies synthétiques permettant l'obtention de fluoroamines est donc essentiel.Au laboratoire, une étude a précédemment été menée sur la réaction de bromofluoration de composés azotés insaturés en milieu superacide de type HF/SbF5. Le NBS utilisé comme donneur d'ion broménium, après activation par polyprotonation, a permis d'accéder à des composés azotés bromofluorés difficiles à obtenir en milieux classiques. Cependant l'ion bromonium s'isomérise rapidement conduisant aux produits difluorés. Les ions chloroniums ayant une réactivité différente de celle des ions bromoniums, ce travail porte sur l'étude des ions chloroniums dans des systèmes dicationiques générés en milieu superacide.Dans un premier temps l'impact des paramètres expérimentaux a été étudié par analyse des produits de réaction et par des expériences de RMN in situ. L'étude a ensuite été étendue à un panel de substrats afin de mesurer l'impact de la structure du substrat sur la réaction de chlorofluoration. Enfin l'effet de substituants halogènes sur la double liaison carbone-carbone a été étudié. Ces travaux ont permis de mettre en lumière le mécanisme réactionnel impliqué dans cette réaction, puis d'appliquer la méthode pour la préparation de composés biologiquement actifs. / Exceptional properties of fluorinated compounds led to a considerable development of fluorine chemistry since the 1950's. Nowadays, fluorinated products have a key role in many domains going from medicinal chemistry to agricultural chemistry. As nitrogen atom is ubiquitous in pharmaceuticals, the development of new synthetic ways for the preparation of fluorinated nitrogen containing compound is of relevant interest.Previously, the superacid team developed a bromofluorination reaction of unsaturated nitrogen containing compounds in superacidic media HF/SbF5. The reaction was performed by using the NBS as halenium ion donor, activated through polyprotonation, permitting the access to bromofluorinated nitrogen containing compounds difficult to be obtained under classical organic conditions. Nevertheless the resulting bromonium ion isomerizes quickly to produce difluorinated products. Chloronium ions show different reactivities than the bromonium ones; so this study is focused on the reactivity of chloronium ion in dicationic systems generated by the use of superacidic media.The first step of the study was focused on the evaluation of the impact of experimental conditions by reaction products analysis and in situ NMR experiments. Then the influence of substrate structure on the reaction course was investigated. Finally the halosubstitution on the carbon-carbon double bound was studied. This work allowed us to highlight the chlorofluorination reaction mechanism and then to extend this method to bioactive compounds synthesis.

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.

The thesis entitled “Organic fluorine in crystal engineering: Consequences on molecular and supramolecular organization” consists of six chapters. The main theme of the thesis is to address the role of substituted fluorine atoms in altering the geometrical and electronic features in organic molecules and its subsequent consequences on crystal packing. The thesis is divided into three parts. Part I deals with compounds that are liquids under ambient conditions, crystal structures of which have been determined by the technique of in situ cryocrystallography. Part II demonstrates the utilization of in situ cryocrystallography to study kinetically trapped metastable crystalline phases that provide information about crystallization pathways. In part III, crystal structures of a series of conformationally flexible molecules are studied to evaluate the consequences of fluorine substitution on the overall molecular conformation. The genesis and stabilization of a particular molecular conformation has been rationalized in terms of variability in intermolecular interactions in the crystalline state. Part I. In situ cryocrystallography: Probing the solid state structures of ambient condition liquids. Chapter 1 discusses the crystal structures of benzoyl chloride and its fluorinated analogs. These compounds have been analysed for the propensity of adoption of Cl···O halogen bonded dimers and catemers. The influence of conformational and electronic effects of sequential fluorination on the periphery of the phenyl ring has been quantified in terms of the most positive electrostatic potential, VS,max (corresponding to σ-hole) on the Cl-atom. It is shown that fluorine also exhibits “amphoteric” nature like other heavier halogens, particularly in presence of electron withdrawing groups. Although almost all the derivatives pack through C–H···O, C–H···F, C–H···Cl, Cl···F, C–H···π and π···π interactions, the compound 2,3,5,6-tetrafluorobenzoyl chloride exhibited a not so commonly observed Cl···O halogen bonded catemer. On the other hand, the proposed Cl···O mediated dimer is not observed in any of the structures due to geometrical constraints in the crystal lattice. Chapter 2 presents the preferences of fluorine to form hydrogen bond (C–H···F) and halogen bonds (X···F; X= Cl, Br, I). Crystal structures of all three isomers of chloro-, bromo-and iodo-fluorobenzene have been probed in order to gain insights into packing interactions preferred by fluorine and other heavier halogens. It has been observed that homo halogen…halogen (Cl···Cl, Br···Br and I···I) contacts prevail in most of the structures with fluorine being associated with the hydrogen atom forming C–H···F hydrogen bond. The competition between homo and hetero halogen bonds (I···I vs I···F) is evident from the packing polymorphism exhibited by 4-iodo fluorobenzene observed under different cooling protocols. The crystal structures of pentafluoro halo (Cl, Br, I) benzenes were also determined in order to explore the propensity of formation of homo halogen bonds over hetero halogen bonds. Different dimeric and catemeric motifs based on X···F and F···F interactions were observed in these structures. Chapter 3 focuses on the effect of different cooling protocols in generating newer polymorphs of a given liquid. The third polymorph (C2/c, Z'=6) of phenylacetylene was obtained by sudden quenching of the liquid filled in capillary from a hot water bath (363 K) to the nitrogen bath (< 77 K). Also, different polymorphs were obtained for both 2¬fluoro phenylacetylene (Pna21, Z'=1) and 3-fluoro phenylacetylene (P21/c, Z'=3) when crystallized by sudden quenching in contrast to the generally followed method of slow cooling which results in isostructural forms (P21, Z'=1). The rationale for these kinetically stable “arrested” crystalline configurations is provided in part II of the thesis. Part II. Tracing crystallization pathways via kinetically captured metastable forms. Chapter 4 explains the utilization of the new approach of sudden quenching of liquids (detailed in chapter 3) to obtain kinetically stable (metastable) crystalline phases that appear to be closer to the unstructured liquids. Six different examples namely, phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorobenzoyl chloride, 3-chloro fluorobenzene and ethyl chloroformate are discussed in this context. In each case, different polymorphs were obtained when the liquid was cooled slowly (100 K/h) and when quenched sharply in liquid nitrogen. The relationship between these metastable forms and the stable forms (obtained by slow cooling) combined with the mechanistic details of growth of stable forms from metastable forms provides clues about the crystallization pathways. Part III. Conformational analysis in the solid state: Counterbalance of intermolecular interactions with molecular and crystallographic symmetries. Chapter 5 describes the crystal structures of a series of conformationally flexible molecules namely, acetylene and diacetylene spaced aryl biscarbonates and biscarbamates. While most of the molecules adopt commonly anticipated anti (transoid) conformation, some adopt unusual cisoid and gauche conformations. It is shown that the unusually twisted conformation of one of the compounds [but-2-yne-bis(2,3,4,5,6¬pentafluorocarbonate)] is stabilized mainly by the extraordinarily short C–H···F intermolecular hydrogen bond. The strength of this rather short C–H···F hydrogen bond has been authenticated by combined single crystal neutron diffraction and X-ray charge density analysis. It has also been shown that the equi-volume relationship of H-and F-atoms (H/F isosterism) can be explored to access various possible conformers of a diacetylene spaced aryl biscarbonate. While biscarbonates show variety of molecular conformations due to absence of robust intermolecular interactions, all the biscarbamates adopt anti conformation where the molecules are linked with antiparallel chains formed with N–H···O=C hydrogen bonds. Chapter 6 presents a unique example where the commonly encountered crystallographic terms namely, high Z' structure, polymorphism, phase transformation, disorder, isosterism and isostructuralism are witnessed in a single molecular species (parent compound benzoylcarvacryl thiourea and its fluorine substituted analogs). The origin of all these phenomenon has been attributed to the propensity of formation of a planar molecular dimeric chain mediated via N–H···O [R2 (12)] and N–H···S [R2 (8)] dimers.

Polyketide products are useful compounds to research and industry but can be difficult to access due to their richness in stereogenic centers. Type I polyketide synthases offer unique engineering opportunities to access natural stereocontrol and resultant complex compounds. The development of a controlled in vitro platform based around type I polyketide synthases is described. It has been used to produce a small library of polyketide fragments on an unprecedented and synthetically-relevant scale and explore polyketide synthase enzymology. / text