Host-guest assemblies

Host-guest assemblies are the complexes that are composed of two or more molecules or ions held together in a unique structural relationship by non-covalent forces.52 A necessary requirement to classify complexes as host-guest assembly is that the host and the guest are distinguishable from one another. Generally in a host-guest assembly, the larger component forms an array which includes the guest molecules. In host-guest complexes two different types of arrangements are observed.

1. The tunnel type inclusion complexes.53 2. The clathrate type host-guest arrangement.54

In the first type the guests are included in the tunnels formed by the host molecules and can be in mutual contact with one another. In the second type the guest molecules are separated from one another while being included in the cages formed by the host molecules.

In both the tunnel and clathrate types, the interactions between the host compounds can be divided into two types: (i) in which the host molecules interact through directional hydrogen- bonding interactions; (ii) complexes in which the host molecules interact through non- directional van der Waals interactions. Similar types of interaction can be observed between the host and the guest molecules. In host-guest assemblies, the host network can be made up of one or two components with other components occupying the guest positions.

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1.5.8.1. Tunnel type inclusion complexes with directionally bonded hosts

The first among the tunnel type inclusion complexes are the crystalline adducts formed by urea.55 Urea forms crystalline hexagonal complexes with a series of homologous n-paraffins32 and rhombohedral complexes56 with other bulkier guests. However, depending on the crystallisation conditions, urea forms both hexagonal and rhombohedral complexes with certain guests. Examples of guests which form hexagonal inclusion complexes with urea include57 n-paraffins, alcohols, ketones, ethers, thioethers, esters, carboxylic acids. Rhombohedral inclusion complexes of urea are less common when compared to the hexagonal structure types. Dioxane, trioxane, acetone, 2,15-dimethylhexadecane, 2,18- dimethylnonadecane and 2,19-dimethyleicosane are among the guest molecules which form rhombohedral inclusion complexes with urea. Thiourea58 and selenourea59 form isostructural rhombohedral complexes similar to that of urea, with guest molecules such as n-paraffins, alcohols, ketones and halogen-containing compounds.60 The structures of the inclusion complexes of urea are based on forming a hexagonal cross-section with the urea molecules forming four hydrogen bonds between the N-H and C=O groups. The structure types of compounds formed though directional interactions are called tectons.61

One example of a molecular tecton formed though hydrogen bonding interactions is the structure shown in Scheme 1.14. The results demonstrate that the 3-D porous hydrogen- bonded network remains intact upon exchange of the guest molecules.

N N N NH2 NH₂ C 4

Scheme 1.14: Molecular structure of a compound forming a hydrogen-bonded framework.

1.5.8.2. Tunnel type inclusion complexes with van der Waals bonded hosts

There are many examples of channel type inclusion complexes formed by cleft and tweezer shaped molecules. Deoxycholic acid (DCA) is an example of a cleft molecule. 2,6- Dimethylbicyclo[3.3.1]nonane-exo-2,exo-6-diol and Trogers base (Scheme 1.15) are examples of tweezer shaped molecules which form inclusion complexes with different guest molecules.

26 HO H3C OH CH3 H3C O HO CH3 CH3 OH HO H

2,6-dimethylbicyclo[3.3.1]nonane-2,6-diol deoxycholic acid

N N

Trogers base

Scheme 1.15: Molecular structures of 2,6-dimethylbicyclo[3.3.1]nonane-2,6-diol (a), deoxycholic acid (b), Trogers base (c).

DCA forms orthorhombic, tetragonal and hexagonal inclusion complexes with a variety of guests which include organic acids, aliphatic and aromatic hydrocarbons, alcohols, alkaloids, and methyl orange. The host network in these complexes is stabilised through van der Waals interactions. In addition to the DCA molecules, some substituted bicyclo[3.3.1]nonane compounds form host networks which are stabilised through van der Waals interactions. The molecular shape of the substituted bicylco[3,3,1] compounds is suitable for the molecules to form supramolecular inclusion channels type structures.62 Based on these biclyclic molecules, analogous compounds like Trogers base have emerged as a valuable building block for the construction of a number of chiral host systems for molecular recognition studies.63

1.5.8.3. Tunnel type two-component host network

Robust tunnel type inclusion complexes resulting from two-component host-networks are rare. The 1:1 co-crystal of caffeine and succinic acid forms a host network in which different guest molecules occupy the void space to form a host-guest assembly as shown in Figure 1.7. The structure determined by single crystal X-ray diffraction shows that the caffeine and succinic acid molecules form layers held together though O-H···O, O-H···N and pairs of C- H···O hydrogen bonds. The channels are occupied by the different guest molecules existing in stoichiometric or non-stoichiometric ratios.64

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Figure 1.7: Host-guest arrangement in a caffeine–succinic acid co-crystal.62

1.5.8.4. Clathrate inclusion compounds

The term clathrate was coined by H. M. Powell in 1948.65 Clathrates are molecular complexes formed by host molecules which pack in crystal structures such that they leave cavities between them. The cavities produced by the host molecules are occupied by guest molecules. In clathrate structures the guest is entirely enclosed in a framework formed by the host molecules. These molecular complexes can be divided into three types depending on the type of interaction observed between the host molecules.

1. Directionally hydrogen-bonded hosts: The complexes formed by hydroquinone (quinol) belong to this category of clathrate complexes. There are three known polymorphs of quinol (α, β, γ). Among the three polymorphs only the β-polymorphic arrangement is known to form clathrate type complexes. The β-quinol clathrates are structurally isomorphous but are known to crystallise in three space groups depending on the guest molecules and the interactions between them. The guest molecules enclosed by the β-quinol clathrates include Ar, Kr, Xe, HCOOH, CO2, HBr, C2H2, CH4, SO2, etc.

2. Host networks formed by a combination of van der Waals interactions and hydrogen bonds: Host networks formed by phenol and related compounds belong to this class of clathrates. The crystals formed by the phenol clathrate networks crystallise in the rhombohedral space group 𝑅3̅, containing small guest molecules like HCl, HBr, HI, H2S, SO2, CO2, etc. In addition to the phenol molecules, Dianin’s compound is known

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to form clathrate complexes with many organic compounds Scheme 1.16.

X R8 R7 R6 YH CH3 R2' R2

Scheme 1.16: Molecular structure of Dianin’s compound. (R2, R2’, R6, R7, R8 are CH3 or H. While X and Y can be O or S).

3. Van der Waals linked hosts: Tetraphenylene (Scheme 1.17) is known to form clathrate complexes with dioxane, pyridine, CCl4, benzene, CHCl3 and acetone as guests.

tetrabenzo[a,c,e,g] cyclooctatetraene

Scheme 1.17: Molecular structure of tetraphenylene.

1.6. Co-crystals or molecular complexes in the context of the pharmaceutical industry