Crystal engineering studies: polymorphs and co-crystals

We review the key topics of one of the areas with the biggest impact of the last years in the chemical and pharmaceutical industry that is Crystal Engineering. The relevance of polymorphs and co-crystals from different points of view is been highlighted and broadly illustrated by means of several recent examples of studies carried out in this field. In addition, the most suitableinstrumental techniques and the intellectual property implications are reviewed.

Synthesis and characterisation of novel nitrogen and fluorine containing spirobifluorene derivatives for electronic applications and crystal engineering

Among organic materials, spirobifluorene derivatives represent a very attractive class of materials for electronic devices. These compounds have high melting points, glass transitions temperatures and morphological stability, which makes these materials suitable for organic electronic applications. In addition, some of spirobifluorenes can form porous supramolecular associations with significant volumes available for the inclusion of guests. These molecular associations based on the spirobifluorenes are noteworthy because they are purely molecular analogues of zeolites and other microporous solids, with potential applications in separation, catalysis, sensing and other areas.

Crystal engineering using functionalized adamantane

We performed a first-principles investigation on the structural, electronic and optical properties of crystals made of chemically functionalized adamantane molecules. Several molecular building blocks, formed by boron and nitrogen substitutional functionalizations, were considered to build zinc blende and wurtzite crystals, and the resulting structures presented large bulk moduli and cohesive energies, wide and direct bandgaps, and low dielectric constants (low-kappa materials). Those properties provide stability for such structures up to room temperature, superior to those of typical molecular crystals. This indicates a possible road map for crystal engineering using functionalized diamondoids, with potential applications ranging from space filling between conducting wires in nanodevices to nano-electromechanical systems.

Crystal Engineering of an Anti-HIV Drug Based on the Recognition of Assembling Molecular Frameworks

A rational strategy was employed for design of an orthorhombic structure of lamivudine with maleic acid. On the basis of the lamivudine saccharinate structure reported in the literature, maleic acid was chosen to synthesize a salt with the anti-HIV drug because of the structural similarities between the salt formers. Maleic acid has an acid-ionization constant of the anti first proton and an arrangement of their hydrogen bonding functionalities similar to those of saccharin. Likewise, there is a saccharin-like conformational rigidity in maleic acid because of the hydrogen-bonded ring formation and the Z-configuration around the C=C double bond. As was conceivably predicted, lamivudine maleate assembles into a structure whose intermolecular architecture is related to that of saccharinate salt of the drug. Therefore, a molecular framework responsible for crystal assembly into a lamivudine saccharinate-like structure could be recognized in the salt formers. Furthermore, structural correlations and structure-solubility relationships were established for lamivudine maleate and saccharinate. Although there is a same molecular framework in maleic acid and saccharin, these salt formers are Structurally different in some aspects. When compared to saccharin, neither out-of-plane SO(2) oxygens nor a benzene group occur in maleic acid. Both features could be related to higher solubility of lamivudine maleate. Here, we also anticipate that multicomponent molecular crystals of lamivudine with other salt formers possessing the molecular framework responsible for crystal assembly can be engineered successfully.

Crystal Engineering of bright luminescent copper iodide clusters with phosphorus and nitrogen-based ligands

Copper(I) halide clusters are recently considered as good candidate for optoelectronic devices such as OLEDs . Although the copper halide clusters, in particular copper iodide, are very well known since the beginning of the 20th century, only in the late ‘70s the interest on these compounds grew dramatically due their particular photophysical behaviour. These complexes are characterized by a dual triplet emission bands, named Cluster Centred (3CC) and Halogen-to-Ligand charge transfer (3XLCT), the intensities of which are strictly related with the temperature. The CC transition, due to the presence of a metallophylic interactions, is prevalent at ambient temperature while the XLCT transition, located preferentially on the ligand part, became more prominent at low temperature. Since these pioneering works, it was easy to understand the photophysical properties of this compounds became more interesting in solid-state respect to solution with an improvement in emission efficiency. In this work we aim to characterize in SS organocopper(I)iodide compounds to valuate the correlation between the molecular crystal structure and the photophysical properties. It is also considered to hike new strategies to synthesize CuI complexes from the wet reactions to the more green solvent free methods. The advantages in using these strategies are evident but, obtain a single crystal suitable for SCXRD analysis from these batches is quite impossible. The structure solution still remains the key point in this research so we tackle this problem solving the structure by X-ray powder diffraction data. When the sample was fully characterized we moved to design and development of the associated OLED-device. Since copper iodide complexes are often insoluble in organic solvents, the high vacuum deposition technique is preferred. A new non-conventional deposition process have also been proposed to avoid the low complex stability in this practice with an in-situ complex formation in a layer-by layer deposition route.

A reverse crystal Engineering approach

The enormous impact of crystal engineering in modern solid state chemistry takes advantage from the connection between a typical basic science field and the word engineering. Regrettably, the engineering aspect of organic or metal organic crystalline materials are limited, so far, to descriptive structural features, sometime entangled with topological aspects, but only rarely with true material design. This should include not only the fabrication and structural description at micro- and nano-scopic level of the solids, but also a proper reverse engineering, a fundamental discipline for engineers. Translated into scientific language, the reverse crystal engineering refers to a dedicated and accurate analysis of how the building blocks contribute to generate a given material property. This would enable a more appropriate design of new crystalline material. We propose here the application of reverse crystal engineering to optical properties of organic and metal organic framework structures, applying the distributed atomic polarizability approach that we have extensively investigated in the past few years[1,2].

Charge density analysis for crystal engineering

This review reports on the application of charge density analysis in the field of crystal engineering, which is one of the most growing and productive areas of the entire field of crystallography. While methods to calculate or measure electron density are not discussed in detail, the derived quantities and tools, useful for crystal engineering analyses, are presented and their applications in the recent literature are illustrated. Potential developments and future perspectives are also highlighted and critically discussed.

Crystal engineering of co-crystals and host-guest systems for environmentally friendly applications: sunscreens stabilization, pollutant sequestering and herbicide reformulation.

Solid state engineered materials have proven to be useful and suitable tools in the quest of new materials. In this thesis different crystalline compounds were synthesized to provide more sustainable products for different applications, as in cosmetics or in agrochemistry, to propose pollutants removal strategy or to obtain materials for electrocatalysis. Therefore, the research projects presented here can be divided into three main topics: (i) sustainable preparation of solid materials of widely used active ingredients aimed at the reduction of their occurrence in the natural environment. The systems studied in this section are cyclodextrins host-guest compounds, obtained via mechanochemical and slurry synthesis. The first chemicals studied are sunscreens inclusion complexes, that proved to have enhanced photostability and desired photoprotection. The same synthetic methods were applied to obtain inclusion complexes of bentazon, a herbicide often found to leach in groundwaters. The resulting products showed to have desired water solubility properties. The same herbicide was also adsorbed on amorphous calcium phosphate nanoparticles, to obtain a biocompatible formulation of this agrochemical. This herbicide could benefit by the adsorption on nanoparticles for what concerns its kinetic release in different media as well as its photostability. (ii) Sustainable synthesis of co-crystals based on polycyclic aromatic hydrocarbons, for the proposal of a sequestering method with a resulting material with enhanced properties. The co-crystallization via mechanochemical means proved that these pollutants can be sequestered via simple solvent-free synthesis and the obtained materials present better photochemical properties when compared to the starting co-formers. (iii) Crystallization from mild solvents of nanosized materials useful for the application in electrocatalysis. The study of compounds based on nickel and cobalt metal ions resulted in the obtainment of 2D and 1D coordination polymers. Moreover, solid solutions were obtained. These crystals showed layered structures and, according to preliminary results, they can be exfoliated.

Crystal engineering strategies against antimicrobial resistance: a solid contribution to a contemporary problem

This PhD thesis sets its goal in the application of crystal engineering strategies to the design, formulation, synthesis, and characterization of innovative materials obtained by combining well established biologically active molecules and/or GRAS (generally recognized as safe) compounds with co-formers able to modulate specific properties of the molecule of interest. The solid-state association, via non-covalent interactions, of an active ingredient with another molecular component, a metal salt or a complex, may alter in a useful way the physicochemical properties of the active ingredient and/or may allow to explore new ways to enhance, in a synergistic way, the overall biological performance. More specifically this thesis will address the threat posed by the increasing antimicrobial resistance (AMR) developed by microorganisms, which call for novel therapeutic strategies. Crystal engineering provides new tools to approach this crisis in a greener and cost-effective way. This PhD work has been developed along two main research lines aiming to contribute to the search for innovative solutions to the AMR problem. Design, preparation and characterization of novel metal-based antimicrobials, whereby organic molecules with known antimicrobial properties are combined with metal atoms also known to exert antimicrobial action. Design, preparation and characterization of co-crystals obtained by combining antibacterial APIs (active pharmaceutical ingredients) with natural antimicrobials.

Crystal design approaches for the synthesis of paracetamol co-crystals

Crystal engineering principles were used to design three new co-crystals of paracetamol. A variety of potential cocrystal formers were initially identified from a search of the Cambridge Structural Database for molecules with complementary hydrogen-bond forming functionalities. Subsequent screening by powder X-ray diffraction of the products of the reaction of this library of molecules with paracetamol led to the discovery of new binary crystalline phases of paracetamol with trans-1,4- diaminocyclohexane (1); trans-1,4-di(4-pyridyl)ethylene (2); and 1,2-bis(4-pyridyl)ethane (3). The co-crystals were characterized by IR spectroscopy, differential scanning calorimetry, and 1H NMR spectroscopy. Single crystal X-ray structure analysis reveals that in all three co-crystals the co-crystal formers (CCF) are hydrogen bonded to the paracetamol molecules through O−H···N interactions. In co-crystals (1) and (2) the CCFs are interleaved between the chains of paracetamol molecules, while in co-crystal (3) there is an additional N−H···N hydrogen bond between the two components. A hierarchy of hydrogen bond formation is observed in which the best donor in the system, the phenolic O−H group of paracetamol, is preferentially hydrogen bonded to the best acceptor, the basic nitrogen atom of the co-crystal former. The geometric aspects of the hydrogen bonds in co-crystals 1−3 are discussed in terms of their electrostatic and charge-transfer components.

Preparation of new crystal forms via photochemical, mechanochemical and sol-gel methods

This work of thesis involves various aspects of crystal engineering. Chapter 1 focuses on crystals containing crown ether complexes. Aspects such as the possibility of preparing these materials by non-solution methods, i.e. by direct reaction of the solid components, thermal behavior and also isomorphism and interconversion between hydrates are taken into account. In chapter 2 a study is presented aimed to understanding the relationship between hydrogen bonding capability and shape of the building blocks chosen to construct crystals. The focus is on the control exerted by shape on the organization of sandwich cations such as cobalticinium, decamethylcobalticinium and bisbenzenchromium(I) and on the aggregation of monoanions all containing carboxylic and carboxylate groups, into 0-D, 1-D, 2-D and 3-D networks. Reactions conducted in multi-component molecular assemblies or co-crystals have been recognized as a way to control reactivity in the solid state. The [2+2] photodimerization of olefins is a successful demonstration of how templated solid state synthesis can efficiently synthesize unique materials with remarkable stereoselectivity and under environment-friendly conditions. A demonstration of this synthetic strategy is given in chapter 3. The combination of various types of intermolecular linkages, leading to formation of high order aggregation and crystalline materials or to a random aggregation resulting in an amorphous precipitate, may not go to completeness. In such rare cases an aggregation process intermediate between crystalline and amorphous materials is observed, resulting in the formation of a gel, i.e. a viscoelastic solid-like or liquid-like material. In chapter 4 design of new Low Molecular Weight Gelators is presented. Aspects such as the relationships between molecular structure, crystal packing and gelation properties and the application of this kind of gels as a medium for crystal growth of organic molecules, such as APIs, are also discussed.