Sunday, April 7, 2013

Twisted Olefins in "Click" Chem?

Everyone digs the copper-catalyzed "click" reaction between azides and alkynes - its fruits have ripened into applications for protein labeling, drug analogs, and green synthetic approaches.

Science Express just released an intriguing read from the Fokin group, which uses reaction calorimetry (how hot? how fast?) and mass spec isotopic enrichment studies (where'd that atom come from?) to study the copper-catalyzed click. Using calorimetry, Fokin's group determines that two copper atoms must cooperate to form the desired triazole; the uncatalyzed reaction limps along (~7%) in the same amount of time that the catalyzed reaction - which gives off a brief burst of heat - reaches completion (>96%). 

To try and tease out which copper does what, the team synthesized an isotopically-enriched 63Cu catalyst, which they added to a "normal" (63Cu / 65Cu) isotope blend of a copper-bound acetylide. Time-of-flight mass spec showed isotopic enrichment of copper in the resulting isolated copper species. How the heck can that happen?!? 

Well, it can't. . . unless, of course, there's an intermediate where the two copper atoms interchange. Enter the crazy, wild world of gem-dimetalation, a concept several groups (Fürstner, Blum,  Gagnéhave recently studied for a variety of d10 metals (Pd, Ag, Au). Even more crazy, the enrichment indicates that an NHC ligand "jumps" between the two copper atoms, hardly usual behavior for such a strong donor ligand. To explain these results, Fokin constructs a modified catalytic cycle, shown below:
Source: Science | Fokin group, Scripps
Check out that prism-shaped intermediate in the lower left. Anything seem strange about it?

Think, for a moment, about axial chirality. What comes to mind? BINAP, certainly, or the M and P descriptors for allene (cumulated double bonds) chemistry. Well, unless I'm missing something, this intermediate may be the first representation of olefinic axial chirality I've seen. To invoke this intermediate, the alkene in question must really be something special, since the azide has to be disposed roughly 90 degrees out-of-plane! 

Usually, alkenes like to sit in sp2 -hybridized space - flat, like a sheet of paper. Rotational energy barriers exist to interchange E to Z olefins, but they usually need lots of energy (heat, light) or a charged intermediate. Here, we have an almost-room-temp, neutral, 3D alkene intermediate: a rare duck indeed.


  1. So they're basically claiming a more or less classical "two electron, three centered" bonding, a la boranes? (Sorry, I don't have a computer with proper creds to read the article this weekend, just going by what you have in your post.)

    Orbitally, I don't think this is crazy. I also don't think you have to break the classical pi bond of the olefin so you don't need to invoke high energy (or magic). It's just transition metals being transition metals.

    1. It's not that side I'm worried about, it's the other one (the C-N bond). If that double bond is really a double bond (and not a strange metal-destabilized or ylide form), then it has to be angled roughly orthogonally to the rest of the (flat) pi system. No?

    2. The 3-centered bond I'm talking about is the C-Cu-Cu, making that carbon sp-hybridized so you still have allene-like geometry. The problem is they are drawing the C-Cu bonds solid line, making your inference that the carbon is sp2 understandable.

      If you consider it sp, and then line up the Cu-Cu bond with the empty p orbital on the carbon atom, the geometry all works out and makes sense. But the way it's drawn is misleading.

    3. As drawn, the system should not have allenic character. The Cu-C-Cu angle is (roughly) 120 degrees as shown, which places it firmly within the sp2 regime. If we had another carbon stuck in the middle, I'd say OK, but since we don't, it more closely approximates an olefin with a 90 degree twist.

    4. Andre - What if I'm seeing it backwards? What if it's actually the Cu atoms donating electron density into the antibonding orbitals of the pi bond? That would be wild, but would also destabilize the bond for the azide closure...

    5. Oops. 3-D fail on my part. Sorry, it's early. That made it very confusing.

      The empty p orbital would not line up with the Cu-Cu bond, but would be perpendicular to it. The pi bond of the C=C would line up with the Cu-Cu bond and the empty p orbital would be available for donation from the N (which is needed to get the bond to form in the next step anyway.

      Or think about it this way (this would be another extreme on the continuum): the carbon is sp2 and it is a vinylic carbocation. The bond from the double bond goes to both Cu atoms (like it goes to the [Cu] in the next intermediate, but it's a three centered bond in this case). The Cu-Cu complex is cis to the R1 and trans to the N3. This leaves the vinylic carbocation ready for attack from the nitrogen.

  2. Think of the alkene part with the two copper atoms as a bridging vinylidene ligand (R2C=C:) and then you will find an 'empty' p orbital that is orthogonal to the pi system for the C=C double bond. then there is no problem.

    There are compounds very much like the copper acetylide intermediate that has a second atom coordinated to the C-C triple bond known - they're ruthenium acetylides with a copper coordinated to the alkyne functionality of the acetylide ligand. (work by Michael Bruce I think).

    on a side note, alkenes are almost never twisted or trans-bent but it is extremely commonplace for heavier alkene analogues with silicon, germanium or tin atoms. this is because the singlet/triplet gap in the monomers (R2E:) is much lower than in the case of carbon. the heavy alkene are more of a dimer of the two singlet carbene-like fragments, where as alkenes themselves are a dimer of the two triplet carbene fragments.