Supramolecular Chemistry: Crown Ethers, Cryptands and Host–Guest Binding

What makes it supramolecular

Ordinary molecular chemistry concerns covalent bonds within a molecule. Supramolecular chemistry concerns what happens between molecules, using interactions that are individually weak but collectively decisive: hydrogen bonding, ion–dipole attraction, pi stacking, dispersion forces and the hydrophobic effect.

Because these interactions are reversible at ordinary temperatures, supramolecular assemblies form and dissociate readily, which is exactly what biological systems require. Enzyme–substrate recognition, the base pairing of DNA and the assembly of cell membranes are all supramolecular.

Crown ethers and the size-match principle

A crown ether is a macrocyclic polyether. The naming convention is x-crown-y, where x is the total number of atoms in the ring and y the number of oxygen atoms. So 18-crown-6 has an eighteen-membered ring containing six oxygens, which means the ring is built from six repeating OCH₂CH₂ units.

The oxygen lone pairs point into the cavity. A metal cation sitting there is surrounded by ion–dipole interactions from every oxygen at once, and the binding is strongest when the ion fits the cavity closely — too small and it cannot touch all the donors, too large and it sits above the ring instead of inside it.

Cryptands and the cryptate effect

A cryptand is a bicyclic ligand containing both nitrogen bridgeheads and oxygen donors, so it wraps around the ion in three dimensions rather than encircling it in a plane. The notation [2.2.2]-cryptand counts the oxygen atoms in each of the three bridges linking the two nitrogens.

Because the ion is fully enclosed, binding constants are several orders of magnitude larger than for the corresponding crown ether. The additional stabilisation on going from a macrocycle to a three-dimensional cage is called the cryptate effect.

Where the extra stability comes from

The macrocyclic effect is the observation that a cyclic ligand binds much more strongly than an open-chain analogue with the same donor atoms. Two contributions are usually cited, and a complete answer names both.

• Entropy. An open-chain ligand has many accessible conformations and must be frozen into one to bind. A macrocycle is already pre-organised, so less conformational freedom is lost on complexation and the entropic penalty is smaller.
• Enthalpy. The donor atoms in a ring are held close together and already partly desolvated, so less energy is spent removing solvent from the ligand before binding.

Pre-organisation is the general principle: the more a host already resembles its bound form before the guest arrives, the more strongly it binds.

Phase transfer catalysis

This is the classic application and the one most often examined. Potassium permanganate does not dissolve in benzene, so it cannot oxidise a substrate dissolved there. Add 18-crown-6 and the picture changes.

The crown ether wraps the potassium ion in a shell whose exterior is entirely hydrocarbon, so the complexed cation becomes soluble in the organic phase. The permanganate anion must follow to preserve charge balance, and it arrives poorly solvated and therefore highly reactive. The resulting purple benzene solution is a standard lecture demonstration.

Other systems worth knowing by name

• Cyclodextrins are cyclic oligomers of glucose with a hydrophilic exterior and a hydrophobic interior cavity. They bind non-polar guests in water and are used to solubilise and stabilise drugs and to trap volatile flavours.
• Calixarenes are cup-shaped phenol-derived macrocycles whose rim can be functionalised, which makes them versatile hosts for both ions and neutral molecules.
• Rotaxanes and catenanes are mechanically interlocked assemblies — a ring threaded on an axle with bulky stoppers, and two interlocked rings respectively. Their components cannot separate without breaking a covalent bond even though no bond joins them, and they form the basis of molecular machines.
• Ionophores such as valinomycin are the natural counterpart. Valinomycin selectively transports potassium across cell membranes by the same size-match principle, which is why it is an effective antibiotic.

The field was recognised with the 1987 Nobel Prize to Pedersen, Cram and Lehn, and again in 2016 to Sauvage, Stoddart and Feringa for molecular machines built from these interlocked systems.

Frequently asked questions

What does the name 18-crown-6 mean?

The first number is the total number of atoms in the macrocyclic ring and the second is the number of those atoms that are oxygen. So 18-crown-6 is an eighteen-membered ring containing six oxygen donors, built from six OCH2CH2 units.

Why does 18-crown-6 bind potassium better than sodium?

Its cavity diameter of roughly 260 to 320 pm closely matches the ionic diameter of potassium at 276 pm. Sodium is too small to make good contact with all six oxygens simultaneously, so the binding is weaker. The selectivity is geometric rather than electronic.

What is the macrocyclic effect?

The observation that a cyclic ligand binds a metal ion much more strongly than an open-chain ligand with the same donor atoms. The main contribution is entropic, because the ring is pre-organised and loses less conformational freedom on binding, with a smaller enthalpic contribution from partial desolvation.

How does a crown ether act as a phase transfer catalyst?

It encapsulates the cation in a shell with a hydrocarbon exterior, making the ion pair soluble in an organic solvent. The anion is carried across with it and arrives largely stripped of solvent, so it is considerably more reactive than it would be in water.

Are supramolecular assemblies held together by bonds?

Not by covalent bonds. They are held by hydrogen bonding, ion–dipole and dipole–dipole attractions, pi stacking, dispersion forces and the hydrophobic effect. Individually these are weak, but many acting together give assemblies that are stable and highly selective while remaining reversible.