New Twist On Amide Activation

The amide bond can be activated for cleavage under mild, neutral conditions by chemical derivatization, a British group has demonstrated (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201107117).

Amide bonds are notoriously tough to break. Under mild, neutral-pH conditions, reaction times for bond cleavage are more than 100 years. The only way to activate amide bonds for faster breakdown without resorting to acids, bases, and catalysts is to twist them physically, for example by incorporating them into a constrained ring system.

Guy C. Lloyd-Jones and Kevin I. Booker-Milburn of the University of Bristol, in England, and coworkers now find that the breakdown of amide bonds (–CO–NH–) can be accelerated by attaching an electron-withdrawing group (R) to an α carbon (right next to the carbonyl carbon) and bulky substituents (R') to the nitrogen. The groups induce the α carbon to lose a proton and the nitrogen to become protonated. The resulting zwitterion intermediate (R–HC^––CO–HN⁺–R'₂) expels the bulky nitrogen group (HN–R'₂), cleaving the amide bond.

The remaining fragment then likely rearranges into a ketene intermediate, which reacts with the methanol solvent to produce an ester. The researchers demonstrated the fast reaction in several types of amides.

The method may help explain the workings of some cellular enzymes that break amide bonds and could make it easy to carry out some amide-based reactions. “The ability to take a functional group that resists hydrolysis for hundreds of years in neutral water and permit it to react in minutes is such a remarkable rate enhancement” that the study is also interesting from a fundamental perspective, says synthetic chemist Jeff Aubé of the University of Kansas.

The amide bond persists because its flat conformation permits a stabilizing interaction between the lone pair of electrons on the amide nitrogen and π electrons of the adjacent carbonyl. The bond becomes more reactive when distorted from planarity, such as by making it part of a bicyclic lactam or other constrained ring. This strategy has been used to reduce reaction time for amide hydrolysis from centuries to less than a minute. The new approach accomplishes that more easily.

Organic mechanism specialist Anthony Kirby of the University of Cambridge says that “it is hard to see potential synthetic applications of this neat reaction” because the requirement for polar and bulky substituents is a significant synthetic constraint.

Amide hydrolysis expert Robert Stan Brown of Queen’s University, in Kingston, Ontario, comments that the main interest of the work is not the new technique’s synthetic potential but instead the proposal of a novel mechanism for amide cleavage. “A lot of people have looked at the mechanistic decomposition of sterically hindered amides and esters, ourselves included, but no one thought to include the possibility” that strategic derivatization could “change the normal mechanism.”

Brown agrees with Kirby that the new reaction’s “generality will be limited to carefully crafted substrates. This means it will not be completely general for drug synthesis” and other synthetic applications. But he notes that twisting amides in rings is even more confining synthetically, whereas the new approach is “a more general way to enhance cleavage.” In addition, “clever chemists will expand on the utility of the mechanism in creative ways to expand the scope of substrates that can be cleaved,” he says.

Twisted-amide specialist Shinji Yamada of Ochanomizu University, in Tokyo, calls the new strategy a breakthrough that he believes could be useful for syntheses of carboxylic acid derivatives, protecting groups, degradable polymers, and drug delivery systems, among other applications.