Basics of “crystal engineering”: supramolecular interactions, polymorphy, temperature and pressure

Our research group has a long tradition in both supramolecular chemistry and polymorphy studies. Isostruturality indices were introduced, morphotropy was described, and the first examples of morphotropy induced by supramolecular effects were revealed by our group. Combining all these knowledge we show how to fine tune structural properties by gradual chemical change. We demonstrate how the well balanced spatial and electrostatic forces play role in the arrangement of packing motifs in the crystals. Our research interest is extended on supramolecular interactions of one and multicomponent systems under ambient and non-ambient conditions.

Performing crystal engineering, e.g. fine tuning of crystal architecture requires the recognition, understanding and application of supramolecular interactions, crystallographic and in case of occurrence, non-crystallographic symmetries. The diversity and scope of intermolecular interactions in the solid state are investigated. The main emphasis is made on the relationship of secondary interactions and polymorphy. An improved understanding of supramolecular interactions at ambient and extreme conditions is in our interest in context of polymorphism, and the assembly of molecular crystals. We focus our work on crystal engineering, supramolecular chemistry of one and more component systems of biologically relevant organic molecules, organometallic compounds and metal coordination complexes. The focal points: how far the molecular conformation and the packing arrangement can be preserved in respond to chemical changes, e.g. sterical and electrostatical aspects.

Granted by :

Support for the use of international and domestic research infrastructures, 2021-4.1.2-NEMZ_KI-2022-00022 (2023-2024)

Title: Investigation of the effect of high pressure on crystallization and crystal structure
Principal Investigator: Tamás Holczbauer
Members from the research group: Sourav De
Summary: Crystallization in nature is a self-organizing process striving for a minimum of energy. We can observe strong and weak attractive (and repulsive) interactions between the atoms, ions, and molecules that make up the crystal. We can also observe weak interactions between the molecules that make up the living organism, and single-crystal diffraction is suitable for examining the molecular lattice formed from them. The X-ray diffraction method can be used to examine the spatial location of atoms, their electron density, the relative distances and bond angles of atoms and molecules. In the crystal, the changes (conformations) of the spatial structure of the molecules and the alignment of the molecules with each other aim to maximize weak interactions and gain energy. During the crystallization conditions, the conformations and interactions of the molecules are formed, which will then be true for the crystal as a whole. There are many methods for influencing crystallization (temperature, auxiliary materials), but relatively few have investigated the effect of pressure on both crystallization and the structure of crystals. By increasing the pressure, new structures can be created, which can create new materials with properties that have not been experienced before. Examining the effect of pressure can bring important insights for industry as well. In the pharmaceutical industry, for example, the different dissolution and absorption of different crystalline substances in the body is an important parameter to be investigated. Choosing the right crystal form results in a smaller amount of active ingredient or less return to the environment. For example, the durability and possible transformation of the paint material is also crucial for the paint industry.

OTKA KH 129588 (2018-2021)

Title: Supramolecular chemistry in the solid phase
Principal Investigator: Petra Bombicz
Members from the research group: Holczbauer Tamás, Nagyné Bereczki Laura, May Nóra Veronika
Summary: Supramolecular chemistry is a highly interdisciplinary field of science covering chemical, physical and biological features. The supramolecular interactions are responsible for the self-assembly of molecules in liquid and solid states. Study of noncovalent interactions is crucial in understanding of many biological processes. A crystal bears the collective properties of molecules moderated by intermolecular interactions. Exploring the secondary interactions is important to the development of new pharmaceutical therapies by understanding the interactions at a drug binding site, in protein-protein interactions and also in drug stability, encapsulation and targeted release mechanism. Knowledge of supramolecular interactions is necessary in nanotechnology, catalysis, material sciences, polymer sciences, in understanding of transport phenomena, development of molecular sensors, molecular switches, in the chemistry at interfaces etc. The aim of the project is to contribute to the knowledge driven supramolecular architecture, and to contribute to the design and development of new materials with desired properties. The results of the project will be published in international scientific journals and will be presented on international and national conferences. An additional aspect is the involvement of students and young researchers to the project disseminating synthetic and crystallographic learning. Regarding the development of human capital and resources, the project will afford significant skills and knowledge transfer.

OTKA K 124544 (2017-2022)

Title: Principles in crystal engineering: supramolecular interactions, polymorphy, temperature and pressure
Principal Investigator: Petra Bombicz
Members from the research group: Tamás Holczbauer, Sourav De, Nóra Veronika May, Gyula Tamás Gál, Laura Nagyné Bereczki
Summary: Crystal engineering, mastering the macroscopical properties of the material can be performed by fine tuning of structural properties. Our aim is the manipulation of supramolecular packing architecture. The expected result of this project is the deeper understanding of intermolecular interactions and their effect on the arrangement of molecules in the solid phase influenced by temperature and pressure. Increasing knowledge on the principles of supramolecular chemistry contributes to the crystal engineering and prediction ability and brings us closer to be able to prepare novel materials with desired properties. It encompasses the study of crystals with the application in solid state chemistry, material science, catalysis, polymer sciences, molecular sensors and switches, etc. Supramolecular chemistry contributes to the understanding of nanotechnology and biological systems, important to the development of new pharmaceutical therapies. The project facilitates the establishment of high pressure single crystal X-ray diffraction in Hungary. The completion of the microscopes with advanced software increases its performance in imaging and documentation. The polarizing attachment facilitates the twin screening at different temperatures reducing the diffraction measuring time.

OTKA K 100801 (2012-2016)

Title: The role of supramolecular interactions in the construction of single- and multi-component solid phase systems
Principal Investigator: Petra Bombicz
Members from the research group: Alajos Kálmán, Tamás Holczbauer, Nóra Veronika May
Summary: Investigation of non-covalent interactions takes us beyond the molecule to organised mono- and polymolecular systems. Our aim is the systematic design of novel supramolecular materials with increasing predictability of properties. We plan to achieve deeper knowledge of intermolecular interactions and their effect on the arrangement of molecules in solid phase. It has importance in pharmaceutical, biological, chemical and materials sciences. Four series of compounds are planned to be investigated: inclusion compounds of calixarenes and of wheel-and-axle type organic or organometallic hosts, clathrates of a bibenzimidazole derivative, and co-crystals of fullerenes. The extent of the flexibility of the solid crystal systems will be investigated by fine tuning of intermolecular interactions in order to influence the physico-chemical properties of the crystals, to keep isostructurality or promote morphotropic and polymorphic transition, and/or to achive chiral separation. These studies give insights on the mechanisms by which a great variety of processes take place, such as molecular recognition, guest inclusion phenomena, chiral discrimination etc. The results will be published in ten-twelve publications in international journals, and presented regularly on conferences. Students will be involved to the research work. A hot stage is planned to be purchased to the microscope to investigate thermal stability what would greatly improve our research infrastructure needed to investigate multicomponent systems.

Development of crystallization processes for creating solid state molcular associations.

Our goal is to obtain and determine the structures of new polymorphic or isostructural crystal forms of small organic molekules, particularly active pharmaceutical ingredients (APIs) by single crystal X-ray diffraction and several thermal analytic methods. It includes the development of laboratory crystallization processes to grow single crystals of one- or two-component systems, clathrates, inclusion complexes and co-crystals. Physico-chemical properties can be gradualy modified e.g. solidity that is related to the formulation, solubility that is connected to bioavailability in human body and stability that infulences the durability.

Granted by

MTA Infrastructure grants at 2014, 2015 and 2016

OTKA PD 128504 (2018-2022)

Title: Supramolecular interactions and polymorphy, effect of temperature and pressure
Principal Investigator: Tamás Holczbauer
Summary: The aim of the project was to investigate important new materials from various fields (e.g. catalysis, medicinal substances, energetics, etc.); to identify polymorphs, solvatomorphs and co-crystals, and to explore their structural properties and secondary interactions, using the Single-crystal X-Ray Diffraction (SXRD) method. Thiourea and borane organocatalysts were examined, which are more advantageous for environmental protection and sustainability than metal-containing catalysts. Organocatalysts crystallization with different substrates can contribute a better understanding of their mechanism of action. Drugs were examined (e.g.: drotaverine, nitrofurazone) and metal-containing (Cu and Ru and Rh “half-sandwich”) complexes (under development) to explore the relationship between structure and biological effect. We found a new highly porous crystal-forming metal-free organic frameworks (not MOFs, iHOFs). Organic frameworks can be used in many fields, such as separation, storage, sensing, heterogeneous catalysis or drug delivery. Highly porous crystals were formed by different functional groups on the same frame. The structure of aromatic – non-aromatic systems were also investigated, it can be used in the field of energy storage and solar cell systems. The effect of different functional groups on chiral separations were also examined: chiral organophosphorus compounds were separated using spiro-TADDOL.

Structural investigation of bioactive organic molecules and their metal complexes

In diverse fields of clinical practices, metal complexes of small biomolecule are frequently used as bioactive compounds eg. drugs, imaging agents, or chelators. X-ray diffraction method is one of the most powerful technique for the investigation of single crystals of these organic compounds and their complexes. Though crystallographic method can offer detailed and accurate data on the structure of metal-bioligand complexes, it is limited only for solid states. In order to establish any structure-stability-activity relationships for these bioactive compounds the knowledge of the speciation, and the most plausible chemical forms, in aqueous solution is mandatory. Electron paramagnetic resoncance (EPR) spectroscopy is able to detect paramagnetic metal complexes in solution equilibrium systems. Such a structural comparison obtained at different phases can disclose interesting features of the intramolecular and intermolecular interactions of the complexes, and reveal possible structural transformations which can be crucial both for their biological functions and pharmaceutical formulations.

Granted by

Support for the use of international and domestic research infrastructures 2021-4.1.2-NEMZ_KI-2022-00016 (2022-2024)

Title: Investigation of the effect of high pressure on crystallization and crystal structure
Principal Investigator: Tamás Holczbauer
Members from the research group: Sourav De
Summary: Crystallization in nature is a self-organizing process striving for a minimum of energy. We can observe strong and weak attractive (and repulsive) interactions between the atoms, ions, and molecules that make up the crystal. We can also observe weak interactions between the molecules that make up the living organism, and single-crystal diffraction is suitable for examining the molecular lattice formed from them. The X-ray diffraction method can be used to examine the spatial location of atoms, their electron density, the relative distances and bond angles of atoms and molecules. In the crystal, the changes (conformations) of the spatial structure of the molecules and the alignment of the molecules with each other aim to maximize weak interactions and gain energy. During the crystallization conditions, the conformations and interactions of the molecules are formed, which will then be true for the crystal as a whole. There are many methods for influencing crystallization (temperature, auxiliary materials), but relatively few have investigated the effect of pressure on both crystallization and the structure of crystals. By increasing the pressure, new structures can be created, which can create new materials with properties that have not been experienced before. Examining the effect of pressure can bring important insights for industry as well. In the pharmaceutical industry, for example, the different dissolution and absorption of different crystalline substances in the body is an important parameter to be investigated. Choosing the right crystal form results in a smaller amount of active ingredient or less return to the environment. For example, the durability and possible transformation of the paint material is also crucial for the paint industry.

Mobility support for international research projects, MTA-FWO PROJEKT2017-16 (2018-2019)

Title: Structural analysis of copper-drug complexes relevant for chelation therapy
Principal Investigator: Nóra Veronika May
Members from the research group: Gyula Tamás Gál, Tamás Holczbauer
Summary: An excess of redox-active heavy metals can cause severe oxidative stress to the human body. Chelation therapy can remove these toxic metal ions by complexation of the metal by a suitable chelating drug molecule. The design and screening of possible chelator drugs requires detailed insight in their physicochemical properties, the structural aspects of their metal complexation, and their toxicity. The current project focuses on the copper complexation of chelators derived from hydroxypyridine-carboxylic acids (HPC), a well-known drug used in chelation therapy. Using a unique combination of pulsed electron paramagnetic resonance methods and single-crystal X-ray diffraction, the formation of different isomers will be studied both in solution and in the solid state. The experimental data will be corroborated with density-functional theory computations to gain insight in the intra- and intermolecular interaction that govern the copper complex formation in solution and in the solid state.

OTKA K 115762 (2015-2018)

Title: Structure determination of bioligands and their functional metal complexes in solid and solution phases
Principal Investigator: Nóra Veronika May
Members from the research group: Petra Bombicz, Tamás Holczbauer, Gyula Tamás Gál, Laura Nagyné Bereczki
Summary: Many transition metal ions, such as copper, iron and zinc, are essential for all living organisms, as they participate in a wide variety of biochemical processes in the cells. Homeostasis of metal ions is crucial for life and is maintained within strict limits. Nowadays it appears that the copper excess causes significant health problems. The objective of chelation therapy is removal of toxic metal ions from human body or attenuation of their toxicity by transforming them into less toxic compounds. In the field of anticancer research, the well-known platinum-containing anticancer drug, cisplatin, is still recognized as the most prominent compound in treatment of various types of cancers and used successfully in clinical treatments. However the inefficiency of these compounds against platinum-resistant tumours and the frequently observed severe side effects still strongly motivate the investigation of new compounds offering novel modes of actions. Under this project we will investigate a new class of compounds which contains copper ions instead of platinum, complexed with thiosemicarbazone type of molecules which have anticancer properties themselves. In both cases, the design of these complexes must be developed on the basis of specific physico-chemical properties which are usually fine-tuned by sophisticated methods. During this project, we intend to investigate of these two families of prosperous drug candidates by the help of powerful structure determination techniques: single crystal X-ray diffraction and electron paramagnetic resonance spectroscopy.

Research collaborations

Within RCNS:

Institute of Material and Environmental Chemistry

Plasma Chemistry Research Group
Polymer Chemistry Research Group
Renewable Energy Research Group
Green Chemistry Research Group
Functional Nanoparticles Research Group
Biological Nanochemistry Research Group

Institute of Organic Chemistry

Organocatalysis Research Group
Functional Organic Materials Research Group

Within HUN-REN:

HUN-REN Mechanism of Complex Homogeneous and Heterogenous Phase Chemical Reactions
HUN-REN Centre for Energy Research, Surface Chemistry and Catalysis Department
HUN-REN Wigner Research Centre for Physics, Institute for Solid State Physics and Optics

National:

Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics

Department of Inorganic and Analytical Chemistry
Department of Chemical and Environmental Process Engineering
Department of Organic Chemistry and Technology

ELTE Faculty of Science

Institute of Chemistry, Laboratory of structural chemistry and biology

Faculty of Science and Informatics, University of Szeged

Department of Molecular and Analytical Chemistry and MTA-SZTE Lendület Functional Metal Complexes Research Group
Department of Molecular and Analytical Chemistry
Department of Physical Chemistry and Material Science, MTA-SZTE “Lendület” Biocolloids Research Group

Faculty of Pharmacy, University of Szeged

Department of Pharmacognosy

Faculty of Science and Technology, University of Debrecen

Department of Inorganic and Analytical Chemistry
Department of Physical Chemistry

International:

Italy, Department of Chemical Sciences, University of Padova
Belgium, Antwerpen Department of Chemistry, University of Antwerp
Portugal, Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa
Ireland, Centre of Applied Science and Health, Tallaght Campus, TU Dublin
USA, Department of Chemistry, University of West Florida
Slovak Republik, Department of Inorganic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology
Uzbekistan, National University of Uzbekistan named after Mirzo Ulugbek

Industry partners:

Richter Gedeon NyRT
CEVA-Phylaxia
EuroAPI