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1.1.1 Molecular recognition

Molecular recognition¹ i.e. the way in which molecules interact and communicate with each other through non-covalent intermolecular forces² is essential in biological systems as well as in areas of pharmaceutics, materials science and polymer chemistry.

According to Jean-Marie Lehn, recognition involves complementarity interactions between associating partners, i.e. the information content of a receptor with respect to a given substrate.¹ In essence, the recognition process extends over energetic features as well as over geometrical ones, which has being eloquently illustrated by Emil Fischer’s concept of the steric fit “lock and key” model.^1,3 Further illustrating Lehn concept that recognition is binding with a purpose, similarly receptors are ligands with a purpose¹ Figure 1.1.

Figure 1.1 Example of selective molecular recognition.

Thus it is important to have a comprehensive understanding of non-covalent interactions, in order to reliably predict molecular organization, assembly and connectivity in the solid state as this will ultimately aid in controlling physical properties of bulk materials.⁴

1.1.2 Generation of complementarity through self-assembly

Self-assembly is a process of organizing molecular units into ordered structures through non-covalent interactions thereby generating supermolecules.⁵ It is a powerful

strategy for the generation of structural and functional complexity. Several studies have shown that extended supramolecular architectures can be synthesized with the aid of complementary intermolecular interactions.⁶ Most of these supramolecular synthetic strategies employed are based on the combination of functional groups located on different molecules that prefer to interact with each other rather than with themselves.^7,8

Furthermore, the organization of different functional groups results from the molecular information stored in the component and from the active groups, which they bear. Thus generating molecular order is based on recognition-directed spontaneous assembly of one functional group from complementary molecular components, each of which presents two identical recognition sites,⁹ Figure 1.2.

Figure 1.2 Schematic representation of the formation of an ordered structure through molecular-recognition assembly of two different molecular units.⁹

The most famous and well-known example of self-assembly is the DNA double helix, a self-assembly of two complementary helical strands, held together through hydrogen bonding between base pairs,¹⁰ Figure 1.3.

Figure 1.3 Example of self-assembly.

Other examples of self-assembly include inorganic and hydrogen-bonded multicomponent entities.¹¹ Furthermore, these examples provide us with more insight into controlling molecular recognition and self-assembly, thereby allowing for further construction of supermolecules.

1.1.3 Hydrogen bond in crystal engineering

Hydrogen bonding, the master key for molecular recognition,¹² is the most reliable directional interaction in supramolecular construction, and is highly significant in crystal engineering;¹³ the latter has been defined as “…the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desirable physical and chemical properties.”¹⁴

The field of crystal engineering is greatly indebted to the pioneering work of Etter and co-workers who began to focus attention on the ability of hydrogen bonds to help control molecular crystallizations.¹⁵ Moreover, this early work revealed that reliable hydrogen-bonding motifs are formed by many elementary functional groups frequently encountered in simple molecules. Together, these observations along with the bond rules provide useful information about preferred connectivity patterns, hydrogen-bond selectivity, and stereoelectronic properties.¹⁶

The hydrogen-bond rules proposed by Etter are very useful and can be applied to organic hydrogen-bonded structures. The general rules state:

1. all acidic hydrogens available in a molecule will be used in hydrogen bonding in the crystal structure of that compound.¹⁷

2. all good acceptors will be used in hydrogen bonding when there are available hydrogen-bond donors.¹⁸

3. the best hydrogen-bond donor and the best hydrogen-bond acceptor will preferentially form hydrogen bonds to one another.¹⁹

These guidelines have set the stage for important advances in crystal engineering where structures are built from more sophisticated molecules, specifically designed to incorporate multiple sites of hydrogen bonding and oriented in arrays favoring the assembly of networks with predictable architectures,²⁰ Figure 1.4.

Figure 1.4 Formation of a hexagonal network, broken lines represent directional intermolecular interactions.²¹

Hydrogen bonds are usually written as D-H…A and normally involve an electronegative atom such as O or N as the acceptor (A) and an atom, as the donor (D) where D is more electronegative than A.²² Normal hydrogen bonds typically range in strength from approximately 4-60 kJ mol^-1, although certain highly acidic compounds such as HF2- have hydrogen bond energies of up to 120 kJ mol^-1.²³ Whereas, the typical hydrogen bond distances are 2.50-2.80 Å (H…A), interactions in excess of 3.0 Å may also be significant.²³

The design step of crystal engineering utilizes the knowledge of non-covalent forces that mediate the formation of supramolecular synthons, which are “structural units within supermolecules which can be formed and/or assembled by known or conceivable intermolecular interactions.”²⁴

Hydrogen-bonded supramolecular synthons are commonly used in crystal engineering, and an improved understanding of their geometries, and their frequency of occurrence in the presence of other hydrogen-bonding groups, will allow us to design and synthesize novel cocrystals. Supramolecular synthons are divided into two categories;

homosynthons,²⁵ which are composed of self-complementary functional groups, as exemplified by the carboxylic acid dimer 1 and the amide-amide dimer 2, and heterosynthons,^25,26 which are composed of different but complementary functional groups 3-6, Figure 1.5.

Figure 1.5 Few examples of supramolecular synthons selected from the recent literature: homosynthons (1-2) and heterosynthons (3-6).^25,26

1.1.4 Co-crystallization a tool for probing intermolecular interaction

Co-crystallization plays a vital role in probing intermolecular interactions between different molecules; these involve the deliberate bringing together of different molecular species within the same crystalline lattice without making or breaking covalent bonds.²⁷ The overall aim of a co-crystallization reaction is to obtain a heteromeric compound, rather than a homomeric species (recrystallization), Figure 1.6.

Figure 1.6 Recrystallization (homomeric intermolecular forces dominates) and co-crystallization (heteromeric intermolecular forces dominates).

Obtaining a heteromeric compound is easier said than done, because molecules by nature are inherently selfish and tend to stick with themselves. However, by developing

new systematic strategies we can increase the chances of obtaining a heteromeric product. With this in mind, one of the major goals of this dissertation is to probe for intermolecular recognition by conducting systematic studies on series of cocrystals. A cocrystal is a “structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts.”^27,28 Two examples of a cocrystal are shown in Figure 1.7.

(a) (b)

Figure 1.7 Two examples of a cocrystal (a) 3-(acetaminomethyl)pyridine succinic acid (1:1),¹¹ (b) N,N'-1,6-hexanediylbis-4-pyridinecarboxamide suberic acid (1:1).²⁹

1.1.5 Molecular electrostatic potential as a tool for ranking hydrogen/halogen bond donor and acceptor strength

According to one of Etter’s rules “the best hydrogen bond donor and the best hydrogen-bond acceptor will preferentially form hydrogens to one another.”¹⁹ Therefore, it begs the question, how do we determine the strength of a given donor or acceptor molecule in order to determine the best donor and best acceptor?

Hunter has shown that hydrogen bonding mainly involves electrostatic interactions and the molecular electrostatic potentials (MEP) of a given functional group which can be determined using low level of theoretical calculations provides a useful method for ranking different donors/acceptors.³⁰ The association constants (K) have been measured for a wide variety of intermolecular interactions both in the gas phase and in solution. Furthermore, simple molecules such as benzoic acid or amino benzoic acid can be analyze in terms of pair-wise hydrogen-bonding interactions between the functional groups. These results can then be accounted for by the following relationship, Equation 1.³⁰

log K = c1α2H

β2H + c2 Equation 1

“Where c1 and c2 are constants that depend on the solvent and α2H and β2H are functional group constants that relate to the hydrogen-bond donor and hydrogen-bond acceptor properties of the molecules.”³⁰

Therefore equation 1 can be correlated to the electrostatics of the hydrogen-bonding interaction.³¹ Moreover, computed molecular properties such as atomic charge and electrostatic potential have been correlated to the values obtained for α2H and β2H.³²

Furthermore, AM1 molecular electrostatic potential calculations carried out by Hunter, established that values obtained for α2H and β2H can be correlated with the experimentally determined values. Additionally, values of α (hydrogen bond donor) and β (hydrogen bond acceptor) can be calculated from the MEP by dividing by a correction factor of 52 kJ mol^-1 resulting in:

α = Emax/52 kJ mol^-1 = hydrogen bond donor constant β = -Emin/52 kJ mol^-1 = hydrogen bond acceptor constant.³⁰

Hence MEPs can be used to rank the strength of hydrogen-bond donors and acceptors of a variety of functional groups, thus allowing us to probe the best-donor/best-acceptor hypothesis.

1.2 Halogen bonding as a complement to hydrogen bonding in crystal