Aniline Catalyzes Imine Formation

The mild organic base aniline speeds the formation of imines in water under mild conditions, opening the door to wider use of such reactions in synthetic and combinatorial chemistry.

Associate professor of cell biology and chemistry Philip E. Dawson of Scripps Research Institute and coworkers report that aniline strongly catalyzes aqueous reactions of aldehydes and ketones with amines to form stable imines (RR'C=NR'') such as hydrazones (RR'C=NNR'') and oximes (RR'C=NOR'') (Angew. Chem. Int. Ed. 2006, 45, 7581).

In a second paper, they report that aniline also catalyzes aqueous transiminations (J. Am. Chem. Soc., DOI: 10.1021/ja067189k). Transiminations are reversible reactions of amines with imines that yield new compounds with exchanged substituents. The paper demonstrates the use of catalytically formed hydrazone and oxime linkages to combine and exchange unprotected peptides.

"Aniline is a nucleophilic catalyst—basically, it is a reagent that isn't consumed by the reaction," Dawson says. "It has worked on everything we've tried so far. In water at pH 4 to 7, rate enhancements are up to 400-fold." The ability to work at neutral pH "may be especially important for biomolecular and cellular applications."

Imines are "routinely used in bioconjugation and ligation reactions and represent one of the most studied systems for dynamic combinatorial chemistry [DCC]," he says. In addition, "the diverse uses of transimination reactions suggest this approach will be widely applied."

"As far as we can determine, aniline is the only aqueous catalyst of imine formation or transimination that has been demonstrated," Dawson adds. A transimination catalyst that works only in organic solvents was reported last year, and "we anticipate we will see catalytic effects for aniline in organic solution as well."

Chemistry professor Stephen B. H. Kent of the University of Chicago comments that the ability of aniline to catalyze oxime formation "is potentially quite significant" for oxime-forming ligation, a peptide ligating technique that works very slowly. "Being able to do things in a few hours with aniline catalysis rather than a few days," he says, "would change it from something you would use only when forced to do so to something that would be convenient to use." For example, Kent says, aniline-catalyzed oxime-forming ligation might be very useful for making synthetic erythropoietin. One synthetic route to this glycoprotein drug involves attaching glycans to the polypeptide backbone via oxime links.

Jeremy K. M. Sanders, chemistry department head at the University of Cambridge, in England, comments that DCC "using imines and hydrazones has many potential applications in organic and biological chemistry, but very slow kinetics places severe constraints on what can be done. These papers appear to give us benign catalysts that speed up equilibrium without interfering in the outcomes."

The use of aniline to speed transimination-based DCC reactions "is a welcome departure that we are surely going to witness being employed more and more often in the future," adds J. Fraser Stoddart, a professor of nanosystems sciences at the University of California, Los Angeles.

Dawson's Scripps colleague, chemistry professor M. G. Finn, is not necessarily a dispassionate observer but nevertheless says he believes that the Dawson group's findings "have the same kind of potential impact as proline-type organocatalysis, in applications that go well beyond small-molecule synthesis. They will be of use to anybody who makes hydrazone or oxime connections under demanding circumstances, does DCC, or uses Mannich-type reactions."