In supramolecular chemistry or the “chemistry beyond the molecules” non-covalent interactions play a major role in the formation and the properties of supramolecular systems. Formation occurs via self-assembly and the resulting structure often possess the ability to form so-called host-guest complexes.
Non-covalent Interactions
Non-covalent interactions are attractive forces between different molecules or different groups within one molecule.[3] They are categorized into electrostatic attraction, hydrogen bonds, π-π stacking interactions, Van-der-Waals forces and hydrophobic effects (see Figure 1.5). In contrast, to covalent bond with bond energies of 300-400 kJ·mol−1, non-covalent interactions are significantly weaker. One of the strongest interactions with bond energies of 50-250 kJ·mol−1 are electrostatic interactions, which occur between charged ions or dipoles (e.g. ion-ion, ion-dipole, and dipole-di-pole). Hydrogen bonds are formed between polarized “acidic” hydrogens and an electron pair donor atom. Although the binding energy of one single hydrogen bond is low (10-30 kJ·mol−1), the pres-ence of several hydrogen bridges can add up to high bond energies and systems containing multi-ple hydrogen bonds show high stability (e.g. DNA). In aromatic systems, π-π stacking interactions can be found with bond energies of up to 50 kJ·mol−1. One of the weakest interaction are Van-der-Waals forces with energies of less than 5 kJ·mol–1. They include London forces (between induced dipoles), Debye forces (interactions between permanent dipoles and induces dipoles) and disper-sion forces (attractive interaction between non-polarized molecules). Furthermore, under specific conditions metal coordination is considered a non-covalent interaction. On the one hand, the formed complex needs to be thermodynamically stable with the system in its lowest energy state with its environment. On the other hand, the metal-ligand bonds should be kinetically labile, to allow ligand exchange in the formation process (see Self-assembly in Chapter 1.2.2). Therefore, transi-tion metals, alkaline, earth alkaline or lanthanide metal catransi-tions are frequently used in metallo-su-pramolecular chemistry.[28]
Figure 1.5 Non-covalent interactions: a) ion-ion b) hydrogen bonding c) π-π and CH-π stacking.
While the bond energy of a typical covalent bond is around ~350 kJ·mol−1, non-covalent interactions are usually weaker ranging from 5 kJ·mol−1 for dispersion forces to 250 kJ·mol−1 for ion-ion interac-tions (see Table 1.1).[3] Despite the low binding energy, rather stable systems can be formed due
5 to an interplay of different interactions and the sum of individual contributions. Non-covalent inter-actions are highly reversible and can be broken easily, which is important in the formation of su-pramolecular assemblies (see Chapter 1.2.2).
Table 1.1 Supramolecular interaction and their energy contribution.[2]
Interaction E [kJ·mol−1]
Supramolecular systems are often built with the help of molecular self-assembly.[28] Thereby, pre-existing components arrange themselves spontaneously into one ordered structure. The self-as-sembled product is stabilized through non-covalent interactions, which are highly reversible.[29] This reversibility is important in the formation process, because any error that may have occurred during the assembly can be corrected immediately (“self-healing”). Less stable products or mismatched bonds are broken in favor of more stable ones. During self-assembly processes, many reversible reactions may occur simultaneously until the system reaches equilibrium and a thermodynamic product is formed in nearly quantitative yield. The used starting compounds are often quite simple and the resulting product can be of complex architecture and topology. Via self-assembly chemists were able to form fascinating structures,[30] whose synthesis was difficult or unsuccessful by the utilization of traditional organic synthesis. Examples of supramolecular assemblies are links and knots (see Chapter 1.1), Platonic and Archimedean solids,[31],[32] micelles and vesicles[33] as well as capsules[34] and cages (see Chapter 1.3 for more details). Despite sophisticated planning of reac-tion condireac-tions and starting components, supramolecular chemists are often surprised by their self-assembled products. Due to the reversibility and the weakness of the non-covalent interactions, a precise prediction of the formed structure can be difficult.
Self-assembly processes are distinguished into two types (see Figure 1.6).[35] The most common one is strict self-assembly, where all added compounds are directly used in the formation of the supramolecular aggregate. Whereas, in the directed self-assembly process, another species or template (e.g.: counter ions, cations or solvent molecules) accompanies the formation. The tem-plate can be essential for the assembly of one discrete species or drive the assembly to a product, that is inaccessible by strict self-assembly (see Figure 1.6).
Figure 1.6 Types of self-assembly: a) strict self-assembly and b) directed (templated) self-assembly.
The driving force of supramolecular assemblies is controlled by thermodynamics. Based on the Gibbs-Helmholtz equation ΔG = ΔH−TΔS enthalpic (ΔH) and entropic (ΔS) contributions have to be considered for the total free energy of the system. The enthalpic contribution is the deliberation of energy by forming non-covalent interactions within the supramolecular aggregate. The assembly of one highly organized species out of several individual components gives the idea, that the en-tropic contribution is less favorable. However, the release of solvent molecules, organized around the starting components, needs to be considered as well. This dissociation process is so prominent, that the disfavored contribution of the formation process may be negligible and the overall entropic contribution is in favor of the supramolecular assembly process.
Host-Guest Chemistry
Besides the synthesis of unique supramolecular structures with exceptional topologies and archi-tectures, chemists are further interested in investigating the host-guest chemistry of these sys-tems.[2,7,36] Supramolecular assemblies are often able to incorporate smaller molecules or ions in their structure. The larger supramolecular aggregate is referred to as “host” (abbreviated H), while the encapsulated molecule is named “guest” (G). The resulting structure is the host-guest complex [G@H] (see Figure 1.7).[2] Driving force for the encapsulation process is an attractive interaction between the guest and the interior of the host molecules based on electrostatic attractions and/or solvophobic effects (see Chapter 1.2.1).
Figure 1.7 Schematic representation of a supramolecular host, which can encapsulate another molecule in its cavity and form a host-guest complex.
Requirement for the formation of the host-guest complex is the presence of a sizeable central cavity of the supramolecular assembly. Researchers found numerous supramolecular systems, which are able to incorporate guests such as (in)organic anions, cations, or even larger neutral guest mole-cules.[2,36] Among these, cages and capsules are of particular interest due to their ability to host, protect, transport and release guest molecules (for further information about supramolecular cages
7 see Chapter 1.3). Furthermore, guest molecules can act as a template in the self-assembly process of the supramolecular structure (see Chapter 1.2.2). Charged molecules are usually used as tem-plates, due to their directional electrostatic interactions, which help to organize the starting mole-cules prior to the final assembly.
Due to the stabilization of the host-guest complex through non-covalent interactions, the formation is reversible and the complex is in equilibrium with its starting components (see Figure 1.7). The association- or binding constant Ka expresses the thermodynamic stability of the host-guest com-plex:
𝐾𝑎 = [𝐆@𝐇]
[𝐆] · [𝐇]= 𝑘1 𝑘−1
A high binding constant correlates to a high equilibrium concentration of the host-guest complex [G@H] in comparison to free host and guest. The binding constant can be expressed via the rate constant of the complexation (k1) and decomplexation (k−1) process. Determination of Ka is possible via NMR-, UV/Vis-, fluorescence spectroscopy, ITC or any other technique whose response signals correlates to the concentration of the involved components.[37]
Some supramolecular assemblies are able to incorporate more than one guest molecule. This bind-ing of several guest molecules towards a supramolecular host can occur in an allosteric fashion with positive or negative cooperativity (see Figure 1.8).
Figure 1.8 Schematic representation of positive and negative allosteric effect.
In case of positive cooperativity, the binding of the first guest molecule enhances the binding affinity of the second uptake, resulting in a higher value for the second association constant Ka2. Negative cooperativity decreases the association affinity for further guest binding, resulting in a lower value for the second association constant. In nature, positive cooperativity is observed for example in the binding of dioxygen towards hemoglobin. Binding of one oxygen molecule to one of hemoglobin’s four binding sites induces a structural change, which increases the binding affinity towards another oxygen molecule.[5]