Quantitative scale for halogen bonding and hydrogen bonding: a foundation for self-assembly

This project will provide quantitative experimental data on interactions between molecules that will underpin future research in self-assembly. The pre-eminent class of intermolecular interaction is the hydrogen bond. More recently established are halogen bonds, highly important interactions which parallel hydrogen bonds.

The atoms within molecules are usually held together by strong chemical bonds (150-1000 kJ/mol), but their molecular structures are often strongly influenced by forces that are about 10 times weaker, of which the most famous is the hydrogen bond. It is the hydrogen bond that provides the means for DNA to encode genetic information and for proteins to acquire their specificity. These weaker forces also underlie interactions between molecules, and hence determine how small molecules assemble into larger structures. Self-assembly is the process of forming the larger structures: it pervades research and technology in areas ranging from materials chemistry to catalysis to structural biology. For instance, it is the interaction of a drug with a protein that determines its activity, or the interaction of a catalyst with a substrate that determines its specificity.

When strong chemical bonds are formed, for instance between nitrogen and hydrogen atoms, the electrons are distributed unevenly; the nitrogen acquires a slight negative charge and the hydrogen acquires a slight positive charge. A hydrogen bond is formed when a hydrogen atom with a slight positive charge interacts with another atom with a slight negative charge: e.g. N-H...OC, where O has a partial negative charge. In this project we will also focus on the halogen bond, in which the role of the hydrogen is replaced by a halogen (iodine, bromine or chlorine) with the partial positive charge. This situation arises when these halogens are attached to other groups that pull the electrons away, for instance fluorine-containing groups.

In 2004, Hunter presented a quantitative approach to understanding the impact of molecular interactions that has unified all classes of intermolecular interaction in all solvents. The basic principles have now been experimentally validated for simple systems that form hydrogen bonds, but the challenge is to implement this approach in systems that are more complicated and feature different types of intermolecular interaction. The research programme will examine hydrogen bonds to transition metal complexes and halogen bonds in general. The resulting quantitative measurements will be placed on a common scale with existing knowledge of organic hydrogen bonds.

The dominant techniques for quantitative probing of molecular interactions in solution will be nuclear magnetic resonance spectroscopy (especially appropriate to the transition metal compounds) and automated ultraviolet/visible spectroscopy (especially for the organic molecules). The interaction energies will often be determined at many temperatures, giving a full range of energetic information. The geometry of the interactions will be studied by X-ray crystallography, supported by solid-state nuclear magnetic resonance. The experimental studies will be underpinned by computational methods based on quantum mechanics that can predict the site of interaction and its strength.

The Brammer-Hunter-Perutz team bring great experience of studying intermolecular interactions and an established record of collaboration. The project is divided into three sections: (A) studies of transition metal compounds, (B) studies of interactions of organic molecules, (C) development of quantitative scales for hydrogen-bond and halogen-bond donor and acceptor strengths. Brammer provides the lead in crystallography, Perutz in NMR spectroscopy especially of transition metal complexes, and Hunter in automated UV/visible spectroscopy of organic molecules. Hunter also is the leader in data analysis methods and in computational methods.

Although this project is fundamental research, it has the potential to impact on many current research problems across the science and technology area. The aim is to establish a general model for the prediction of the properties of non-covalent interactions for an unprecedented range of molecular species, both organic and inorganic. The physical properties as well as most of the functional properties of molecular systems in chemistry, biology and materials science are all governed by non-covalent interactions. Although computational methods can now begin to make useful predictions about structure, especially for biopolymers that have evolved to adopt a single well-defined conformation, our ability to make predictions about thermodynamic properties lags far behind. The proposed development of a quantitative relationship between chemical structure and the thermodynamics of non-covalent interactions will unlock the doorway to a new era in rational molecular design in many areas where trial and error or random screening currently represent the state of the art, e.g. drug design, catalysis, sensors and smart materials. There are many apparently simple but important problems that one can imagine tackling from first principles based on chemical structure, e.g. mixing and solubility, but currently more empirical approaches are the state of the art. If molecular engineering is to become a reality in the 21st century, the development of any genuine form of synthetic non-biological nanotechnology will require an intimate appreciation of the specifications of the basic building materials, i.e. we must learn the relationship between chemical structure, non-covalent interactions and properties. The insights arising from this research programme will therefore be directly applicable in fields like organocatalysis, biocatalysis, transition metal catalysis, process chemistry, drug design, sensor design, molecular machines, smart polymers and nanotechnology to name a few areas where there is much current activity.

The project will produce two scientists with training and expertise that spans the traditional disciplines of organic, inorganic, physical and theoretical chemistry, with experience of working in a collaborative team. The interdisciplinary nature of the work will equip the appointees for work at the interfaces with other disciplines, which is where they are likely to have to most impact in their future research careers. A knowledge of non-covalent chemistry underpins almost all of the chemical industries: pharmaceutical, agrochemicals, dyes, liquid crystals and polymers, including basic R&D, chemical engineering, manufacturing and process chemistry. The applicants collaborate with a range of pharmaceutical, agrochemical and computational drug discovery companies, so there is plenty of potential for knowledge transfer and industrial input to the project through these interactions.