In 1919, Hermann Staudinger, future Nobel Laureate and forefather of polymer chemistry, described a room-temperature reaction that could be performed in water to convert a phosphine and an azide to a corresponding primary amine and phosphine oxide (Fig. 1a). A useful reaction, but why has this German chemist's 90-year-old discovery gotten so much attention lately?

Figure 1: Schematics of: (a) The classic Staudinger reaction, (b) the Bertozzi group's modified Staudinger ligation.
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Ph, phenyl.

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“It always fascinated me as a chemical transformation, because... it's a really mild, very selective way of converting azides to amines,” says Berkeley chemist Carolyn Bertozzi. Her group had been investigating methods to tag sugar molecules on cell surfaces, and a key consideration for developing such in vivo tags is the principle of bio-orthogonality — that functional groups being introduced neither interfere with endogenous cellular functions nor be inappropriately recognized by the host.

The Staudinger reaction relies on two synthetic functional groups — the azide and the phosphine — that do not seem to engage in any inappropriate interactions within the cell. However, the classical reaction produces separate molecules, so Bertozzi's team had to modify the reaction to generate a covalent linkage. They found that adding a methyl ester to the reacting phosphine produces a stable, covalent amide bond connecting the two reactants (Fig. 1b). This modified reaction, known as the Staudinger ligation, has since shown strong potential for cell modification and other biochemical tagging strategies (see above).

Bertozzi cites the in vivo–friendly reaction conditions as a major benefit to this technique, and adds, “there aren't too many other reactions that have that level of selectivity, where the reacting partners see only each other and ignore everybody else in the room, and this is one of those few.”