news of the week D EC E MBE R 1 2, 20 1 1 EDITED BY WILLIAM G. SCHULZ & SOPHIA L. CAI
NEW TWIST ON AMIDE ACTIVATION CHEMICAL SYNTHESIS:
Strategically placed substituents cause bond to break
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
HE 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 GROUP EFFORT An electron-withdrawing group (R) and a bulky group (such as the ring acids, bases, and catalysts is to shown here) added to or present on the substrate help break the amide bond. twist them physically, for example by incorporating them into a H HH HH H constrained ring system. H _ CH OH Elimination OCH3 Guy C. Lloyd-Jones and N N 3 R R R + C R Kevin I. Booker-Milburn of the O O O O University of Bristol, in EngH land, and coworkers now find Amide substrate Zwitterionic Ketene Ester N intermediate that the breakdown of amide R = Electron-withdrawing group bonds (–CO–NH–) can be accelerated by attaching an electron-withdrawing group (R) to an α carbon (right next of a novel mechanism for amide cleavage. “A lot of to the carbonyl carbon) and bulky substituents (R') to people have looked at the mechanistic decomposition the nitrogen. The groups induce the α carbon to lose a of sterically hindered amides and esters, ourselves inproton and the nitrogen to become protonated. The re- cluded, but no one thought to include the possibility” sulting zwitterion intermediate (R–HC––CO–HN+–R'2) that strategic derivatization could “change the normal expels the bulky nitrogen group (HN–R'2), cleaving the mechanism.” amide bond. Brown agrees with Kirby that the new reaction’s “genThe remaining fragment then likely rearranges into erality will be limited to carefully crafted substrates. This a ketene intermediate, which reacts with the methanol means it will not be completely general for drug synthesolvent to produce an ester. The researchers demonsis” and other synthetic applications. But he notes that strated the fast reaction in several types of amides. twisting amides in rings is even more confining synthetiThe method may help explain the workings of some cally, whereas the new approach is “a more general way cellular enzymes that break amide bonds and could to enhance cleavage.” In addition, “clever chemists will make it easy to carry out some amideexpand on the utility of the mechanism in based reactions. “The ability to take a creative ways to expand the scope of subfunctional group that resists hydrolysis strates that can be cleaved,” he says. “Clever for hundreds of years in neutral water Twisted-amide specialist Shinji Yachemists will and permit it to react in minutes is such a mada of Ochanomizu University, in Toexpand on the remarkable rate enhancement” that the kyo, calls the new strategy a breakthrough study is also interesting from a fundamen- utility of the that he believes could be useful for tal perspective, says synthetic chemist Jeff mechanism in syntheses of carboxylic acid derivatives, Aubé of the University of Kansas. protecting groups, degradable polymers, creative ways.” The amide bond persists because its and drug delivery systems, among other —ROBERT STAN BROWN, flat conformation permits a stabilizing QUEEN’S UNIVERSITY applications.—STU BORMAN
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DECEMBER 12, 2011
