Supramolecular chemistry

Supramolecular chemistry deals with non-covalent interactions between molecules: hydrogen bonding, ion–dipole forces, permanent dipole forces, London forces and π–π stacking. Each is much weaker than a covalent bond, but several acting together can give strong, selective binding.

In host–guest chemistry, a larger host molecule has a cavity or cleft that fits a smaller guest. The strength of binding is given by an equilibrium constant:

with units of dm^3 mol^{-1}. A larger K_a means stronger binding.

Crown ethers are rings of -\text{CH}_2\text{CH}_2\text{O}- units. The oxygen lone pairs point inwards and bind a metal ion by ion–dipole attraction, while the hydrocarbon outside makes the complex soluble in organic solvents. Ring size gives selectivity: 12-crown-4 suits Li^+, 15-crown-5 suits Na^+ and 18-crown-6 suits K^+, because the ion fits the hole.

Cyclodextrins are rings of glucose units (six, seven or eight, called α-, β- and γ-cyclodextrin). They are shaped like a hollow truncated cone with a water-loving outside and a greasy inside, so they hold non-polar guests in water. The odour-neutralising ingredient in some fabric sprays is a cyclodextrin trapping smelly molecules.

The chelate effect links this to transition metals. Replacing six ammonia ligands on Ni^{2+} with three ethane-1,2-diamine ligands is favoured because it releases more free particles:

Four particles become seven, so \Delta S is positive and, with \Delta H close to zero, \Delta G is negative.

Thermodynamics of binding

For 1:1 binding, \Delta G^\circ = -RT\ln K_a, so at 298 K each tenfold increase in K_a is worth about 5.7 kJ mol^{-1}. K_a is measured by titrating guest into host and following a property that changes on binding: NMR chemical shifts, UV–vis absorbance, fluorescence, or heat released in isothermal titration calorimetry (ITC). Non-linear fitting of the binding isotherm gives K_a; ITC also gives \Delta H^\circ directly, hence T\Delta S^\circ.

Preorganisation and the macrocyclic effect

A host that already has the shape of its bound state pays no entropic or conformational penalty on binding. This preorganisation explains a clear series for K^+ in methanol: an open-chain polyether binds weakly, 18-crown-6 much more strongly, and the bicyclic [2.2.2]cryptand, which encloses the ion in three dimensions, more strongly still. The extra stability of a macrocycle over its open-chain analogue is the macrocyclic effect, an extension of the chelate effect. Solvation matters too: binding is always a competition with the solvent, so a host that binds K^+ well in methanol binds far less well in water, where the ion is strongly hydrated.

Water and the hydrophobic effect

In water, cyclodextrins and cucurbit[n]urils bind non-polar guests partly because poorly hydrogen-bonded "high-energy" water is released from the cavity. Cucurbit[7]uril binds some cationic guests with K_a above 10^{12} dm^3 mol^{-1}, rivalling biotin–streptavidin.

Self-assembly and templating

Reversible bonds let a system correct mistakes and settle at the thermodynamic minimum. Metal–ligand self-assembly uses fixed coordination angles: combining square-planar Pd^{2+} with bent or linear pyridyl ligands gives squares, cages and spheres with predictable stoichiometry. Template synthesis uses a guest to organise reactants: Sauvage made a [2]catenane by threading two phenanthroline ligands around Cu^+ before closing the rings, then removing the copper. A rotaxane is a ring trapped on an axle by bulky stoppers; if the axle has two binding stations, the ring can be shuttled between them by a chemical, redox or light stimulus, the basis of molecular switches.

Supramolecular chemistry has moved from studying single host–guest pairs to designing systems whose function emerges from many weak interactions at once. Key directions:

Molecular machines away from equilibrium. Switches flip between states, but a machine must do work, which needs a ratchet driven by an energy source. Feringa's light-driven overcrowded-alkene motors rotate unidirectionally, and chemically fuelled rotaxane and catenane pumps now move rings uphill against a concentration gradient. Coupling such motion to macroscopic effects, such as contraction of gels and polymers, is an open challenge.

Cages and confinement. Metal–organic cages from Pd_nL_{2n} assembly and imine-based porous organic cages are used to stabilise reactive species (white phosphorus has been held in air inside a cage), to catalyse reactions inside cavities with enzyme-like rate enhancements, and to separate gases and isomers. Predicting which cage forms from a set of components is still largely trial and error, though computational screening is catching up.

Systems chemistry. Dynamic combinatorial libraries (disulfides, imines, hydrazones) let a template amplify its best binder from a mixture; self-replicating macrocycles and fuel-driven transient assemblies are studied as models for the origin of life.

Materials and medicine. Supramolecular polymers based on quadruple hydrogen-bonding motifs heal after damage. Host–guest chemistry already reached the clinic: sugammadex, a modified γ-cyclodextrin, reverses the muscle relaxant rocuronium by encapsulating it. Mechanically interlocked molecules are being explored in batteries and molecular electronics.

A persistent methodological issue is binding analysis: fitting titrations to the wrong stoichiometry or using too narrow a concentration range gives unreliable constants, and global fitting of full data sets is now encouraged over the old Job plot.