Reactions of Folded Molecules in Water

The chemistry of confined molecules is a relatively new undertaking, and this Account describes the effects of certain host container compounds on the behavior of molecules held as guests within. The containers are known as cavitands, which have one open end that allows small molecules to go in and out. The containers are amphiphilic: they feature aromatic surfaces that create a hydrophobic space inside but their peripheries are polar and permit solubility in water. The tension between the inner space of the cavitand and the outer space of the medium is experienced by the guest molecules. Two kinds of cavitand, a cylindrical and a cone-like methylated cavitand, are presented here, and they bind guests in somewhat different depths. The cylindrical cavitand typically has its aromatic panels closer to the guests and when a suitable guest is inside, two cylindrical cavitands can form a capsule through hydrogen bonding between their rims. Halogen bonding may also occur between the aromatic faces of the cavitands and the "sigma hole" of appropriate halides. Long-chain organic compounds of suitable size form host/guest complexes through hydrophobic forces on brief sonication with both cavitands in water. The container's shape acts on flexible guests and deforms them in order to fill the space properly. NMR spectroscopy reveals that many long-chain guests assume U- or J-shaped conformations within the cavitands. The J-shaped conformations are dynamic and undergo "yo-yo" like motions in the cavitand. An inevitable consequence of a folded chain is that its ends are closer together. Accordingly, these guests are prone to cyclization processes. The cavitands act as templates and were applied as chaperones for the synthesis of several classes of large-ring heterocycles, many of which were previously unknown compounds. Functional groups that are remote in extended, long-chain molecules act independently; when folded in cavitands, the functions are brought into proximity and affect each other's reactivities. Such communication introduces the concept of "entanglement" to chemistry. The concept was applied to the monofunctionalization of symmetrical long chain diesters, diazides, and diisocyanates. For the diisocyanates, macrocyclic urea formation followed the desymmetrization. Folding flexible molecules in a predictable way can also offer new reaction pathways for remote chemical functionalization. Most such processes involving C-H activation proceed through 6-membered transition states; folding promises alternative ring sizes but has yet to be shown. These results should encourage applications using more accessible container molecules such as cyclodextrins, cucurbiturils, and pillarenes.