Come On, Allene! The Crabbé Reaction

Readers: This post was written in response to Rachel Pepling’s call for submissions to the IYC2011 Chemistry Carnival over at CENtral Science

Have you ever been in love?

Has a single, chance moment changed your outlook on life?

Did you ever have the burning desire to . . . add one little methylene group to the end of an alkyne?

I’m an organic chemist, and our emotions tend to track directly with the success of our bench work. In my third year of graduate school, I felt down in the dumps.  My methodology project had no traction; heck, I couldn’t even make the (relatively simple) allene substrates I needed in less than five steps! Such was life when, during my group meeting presentation, a voice chimed in from one of the postdocs sitting in the far corner of the room:

“I think there’s a reaction for this.  Haven’t you tried the Crabbé?”

Credit: scenicreflections.com

(At first, I stared agog, since the name made it sound like he was ordering seafood in a fancy French restaurant, so I thought he was joking, but he wasn’t!)

Turned out, there was a “chemical shortcut” to do just what I needed: the Crabbé takes a terminal alkyne under Mannich-like conditions (di-isopropylamine, formaldehyde, dioxane) – with a dash of copper (I) bromide for good measure – and adds a methylene (=CH₂) unit to form an allene (see scheme). Why make allenes, you ask?  The two alkenes in this three-carbon synthon are orthogonal (at a 90^o angle), which twists their pi-electron clouds away from one another. Thus, each olefin can react independently in reactions like metal coordination or electrophile addition.

The reaction mechanism made me scratch my head for a while, just as it did Crabbé’s researchers working at U. Missouri in the early 1980s. These chemists propose that, after the initial Mannich adduct forms, a copper atom wiggles into coordination between the amine and the alkyne. When you crank up the heat, the amine kicks out a hydride (H^-) from an isopropyl group, which then migrates to the copper. This copper hydride spins around, delivers its hydride payload to the alkyne, and kicks out an imine leaving group. 

Credit: Carl Sagan's Dance Party Blog

It’s a fairly chemoselective reaction, meaning you can use it late in the game in a synthesis (assuming your compound can survive heating in dioxane for a few hours with copper!). My favorite part? I enjoy watching the autumnal palette that evolves during the reaction, from birch-tree yellow to maple-leaf red. Different starting materials lend different shades. And, as most organic chemists will tell you, one-pot preps you can set up and forget about are the reactions we love.