Molecules in quarantine

Intermediate compounds are often produced during a chemical reaction, but they are too short-lived to be easily observed. It seems that a molecular pyramid can persuade them to stick around for a little longer.

The path from starting materials to products in chemical reactions often involves many steps. Intermediate compounds are the resting stages along this path, but they exist in vanishingly small concentrations and can rarely be observed. The methods used to see them all require isolation of the intermediates — a sort of quarantine that keeps them from encountering other molecules and so prevents them from continuing along the reaction pathway.

Several methods have been developed to enforce this isolation. For example, reaction intermediates in the gas phase at very low pressures can be kept apart long enough for them to be observed by spectroscopy. Alternatively, exotic solvents such as liquid helium droplets or frozen argon matrices can isolate intermediates at temperatures near absolute zero. But the segregation of reaction intermediates at room temperature, in a reactive solvent such as water, is far more difficult. That is just what Dong et al.¹ have done, as they report in the Journal of the American Chemical Society.

The authors isolated intermediates for a widely used type of reaction that is catalysed by amine compounds. They did this by surrounding the intermediates with a capsule that temporarily protects them from further reaction. The capsule is a tetrahedron-shaped complex of four gallium ions (at the corners) and six organic molecules (along the edges; Fig. 1). This forms spontaneously from its constituent parts and is stable in water; its overall negative charge provides an ideal nanoenvironment for positively charged molecules that can fit inside.

Figure 1: Trapping reactive intermediates.

Molecular tetrahedra (1) form spontaneously in water from four gallium ions (red) and six organic molecules (only one of these molecules is shown for simplicity; their positions are represented as blue lines). Dong et al.¹ used these tetrahedra to trap iminium ions (green) that form fleetingly in water from their starting materials (R, R¹ and R² represent hydrocarbon groups).

The intermediates isolated by Dong et al. are positively charged iminium ions, which form when amines react with ketone molecules (Fig. 1). The concentration of these intermediates in water is tiny, as they react rapidly with water to regenerate the starting materials. The authors¹ found that merely mixing the reaction components — capsule, amine and ketone — in water was enough to generate encapsulated iminium ions in good yields. The yields varied depending on the molecular size of the amines and ketones used, but typically 30–90% of the capsules were occupied by iminium ions. The trapped intermediates were detected directly by nuclear magnetic resonance (NMR) spectroscopy. The magnetic environment inside the capsule is unusual because of the many aromatic rings that enclose it. Encapsulated molecules thus show profoundly altered NMR signals compared with free molecules in solution, and so are easily distinguished from their unrestrained counterparts.

Given a choice of competing iminium ions with different sizes and shapes, the capsule preferentially traps the ion with the best fit, in a process known as molecular recognition. But although such competition experiments¹ go some way to defining the space inside the capsule, questions still remain. Given the flexibility of the larger iminium ions and the sizeable holes in the capsule's structure, it is impossible to say conclusively how much space there is and what fraction of it is occupied. Moreover, not all iminium ions are stabilized by this capsule, with the shape and size of the amine starting material being particularly limiting.

The same researchers have previously used their capsule as a catalyst for a different kind of reaction². In this case, the captured starting material (an enammonium ion) underwent a molecular rearrangement, generating iminium ions. These particular ions were not held tightly by the capsule and so escaped, whereupon they were cleaved by the water solvent to yield two products. This overall process shows some of the essential features of enzymatic catalysis, such as selective recognition of starting materials and rapid product release. Indeed, there are many parallels between the encapsulation technique and enzymatic processes: reversible encapsulation can recognize, amplify³ and stabilize⁴ reactive intermediates and accelerate reactions under mild equilibrium conditions, just as enzyme active sites do. Product release from capsules is often difficult, but even that problem has been overcome in specific reactions⁵. And, like enzymes and other natural receptors, synthetic cavities have been fashioned that create an asymmetric environment; this should allow the recognition and control of molecular asymmetry in reactions, which is essential for preparing compounds that have biological activity.

The encapsulation technique also has implications for nanoscience. Capsules with huge cavities⁶, capable of holding eight molecules, have been analysed, and polymeric capsules that self-assemble⁷ have been discovered. These represent new ways of arranging molecules and might find applications in information storage. The ability to organize molecules within molecules within molecules is also an exciting prospect for researchers seeking to build materials from the inside out.

The reaction of amines with ketones is one of the most useful transformations in an organic chemist's repertoire, so Dong and colleagues' isolation of the elusive iminium intermediates is big news. The authors hope to design and prepare different capsules, so that other fleeting reaction intermediates can be stabilized and studied. It may even be possible to develop chemical reactions that were previously unthinkable in aqueous solution. The future of encapsulation chemistry seems assured.