Trapping A Transient Intermediate

Using a bowllike cavitand molecule, chemists have managed to catch and stabilize a fragile and reactive chemical intermediate that would otherwise be extremely short-lived (Science 2007, 317, 493). The cavitand was designed and synthesized by Julius Rebek Jr., Tetsuo Iwasawa, and Richard J. Hooley of Scripps Research Institute, La Jolla, Calif.

In this case, the cavitand stabilizes a tetrahedral hemiaminal, thereby allowing direct observation of this intermediate, which forms during the reaction of an aldehyde with an amine en route to an imine. The cavitand first sequesters a primary alkyl amine from solution. It then orients the molecule so the amine nitrogen is held closely to an aldehyde functional group that's covalently tethered to the cavitand's rim and oriented into the cavity. The amine then attacks the aldehyde, forming a hemiaminal.

Usually, hemiaminals quickly dehydrate in the presence of either acid or base, making them too transient to be directly observed. But thanks to the protective isolation provided by the cavitand, the normally transient species becomes stable for up to three hours—long enough to be characterized by nuclear magnetic resonance spectroscopy.??

"The cavitand is in several ways reminiscent of an enzyme active site, comprising a hydrophobic cavity, a secondary amide scaffold, and inwardly directed functional groups folded around the substrate," the researchers note in their Science paper. These cavitand systems could be generally useful for trapping reactive intermediates, thereby allowing for more direct studies of reaction mechanisms, the researchers suggest.