It’s Clickalicious
May 16th, 2008 by excimerThis is click chemistry.
I’m pretty sure this isn’t, though.
[1] But that isn’t stopping Larock and friends from calling it click chemistry, right in the title, no less. Before I start ranting, let’s go over some of those criteria K. Barry Sharpless wrote in stone and brought down from Mt. Nobel:
- Really fucking efficient.
- Atom economical. All parts of the reactants should be part of the product. (Catalysts and byproducts that are benign are okay.)
- Inert to solvent, and neat is nice. You should be able to do them in water. If the word “ionic liquid” hits your lips, Barry will smite you.
- The reaction should be (one of my favorite words) bioorthogonal. This word also describes CBC- orthogonal to biology.
- Thermodynamically downhill like whoa. Sharpless calls them “spring-loaded reactions.” One might also call them “bam,” particularly if one is Emeril Lagasse.
Okay, then. So the “click reaction,” the copper-catalyzed Huisgen [3+2] cyclization, is the clickiest reaction around. All you need is some copper, some vitamin C, an azide and an alkyne. And they just come and stick together like white on rice. And it almost always works, hooray. You can imagine how nice an idea this is for materials- if all you want to do is stick two things together covalently, starting from simple precursors, then there’s a protocol that’ll work more often than not. Lots of materials chemists have used them for a variety of purposes, and biologists have done some insanely cool things with it, too. There’s a reason it’s rather hyped- it’s cause non-organic chemists are making this reaction useful at a rate previously unheard of. It’s clicktastic.
But Larock’s example, while cool, is bit of a stretch on the clicky dogma. Now the cycloaddition between benzyne and an azide is clicky- of course, it’s thermodynamically downhill, and it doesn’t even need a catalyst to go, owing to the ridiculous reactivity of benzyne.
But it’s the MAKING of benzyne that makes it not very clicky. Okay, first, you start with o-(trimethylsilyl)phenyl triflate. So how do you make that? You’ll likely need some butyllithium and some triflic anhydride. So it’s not terribly clicky to make the precursor. The formation of benzyne itself is a really, really cool reaction: take your precursor and treat it with fluoride at room temperature. Then add your azide, wait, and whee! A benzotriazole you get, in good yield.
But is it clicky? I don’t think so, mostly cause you have to make that benzyne using chemistry that isn’t very clicky. On the other hand, how do you make azides and alkynes for the copper catalyzed click chemistry? With non-click chemistry. Sodium azide? Nasty shit. Alkynes? Probably not going to be clickable much in the making, either.
I mean, don’t get me wrong, it’s the idea that’s important, and a worthwhile goal to achieve. And the chemistry is still very much in its infancy. Regardless, even though those one (or two) click reactions have been utilized in many different ways, we shouldn’t be limiting ourselves to them necessarily- unless, of course, it gets you funding. Then I would recommend you take your science and click the shit out of it.
[1] I wish all graphical abstracts were as awesome as these. Floating Head Barry should make more appearances in the literature.
Shi, F., Waldo, J.P., Chen, Y., Larock, R.C. (2008). Benzyne Click Chemistry: Synthesis of Benzotriazoles from Benzynes and Azides. Organic Letters DOI: 10.1021/ol800675u
Thanks anyway for pointing out the Clicky Criteria. More often than not, people think “click reaction” = “Huisgen cycloaddition”, which isn’t entirely true.
I think the benzyne reaction is a pretty cool idea, although I’m sure you can’t run it inside an enzyme
Can I haz benzyne DNA clevage?
I propose naming all falsely-named click reactions as klick reactions. All in favor?
Nice – I’ll take it one step further: if you see someone misusing the term ‘click chemistry’ in a seminar, you must shout out die ist nicht Klickenchemie!
THAT’S what I needed to get mine to work…
Jack Daniels and Sharpless’s head floating around.
1) Sharpless got a Nobel for his work on asymmetric epoxidation/dihydroxylation of olefins, not click chemistry. ZOMG stereocenters and nonplanar moleculez! Run for your lives!
2) Larock pwns face. If he wants to call this a click reaction, it’s a click reaction. Also, he puts nBuLi and Tf2O in his coffee to give it a little kick. Pd trembles at the sound of his name. He can make benzyne by glaring at cyclohexane.
Yes, I know what he won it for. But I think it’s no coincidence that he started advocating the idea after winning his Nobel- his notoriety helped push the idea into the mainstream. Didn’t hurt that Meldal and him developed the CuAAC reaction around the same time, either.
Larock is kind of a goofy guy. He recently gave a seminar here which I titled “1001 uses of iodine monochloride.” When he started talking about clicky stuff, you could feel the groan the audience was holding back. He is, however, like 6′5. And that monstrosity of a book he wrote… well. Hardly a task for an ordinary human.
He was giving lectures about click chemistry 5 years before he won the nobel prize. of course everyone knew he would win someday anyway
Sexy iodine is via US Pat 3992424, namely I(CF3)7. It should be gaseous at or just above room temp. With MW = 609.946 a 2-liter drink bottle of it would weigh an extra 50 grams, 21 times as dense as air. Fluxional! F-19 NMR for a rearrangement kinetics happy run.
Analytical chemists use ICl to titrate Crisco. Feh.
Larock’s cycloaddition isn’t exactly bioorthogonal – it isn’t like there is a shortage of nucleophiles under biological conditions, and nucleophiles and benzynes will probably short-circuit the click. Also, the specificity in a biological system might be low – Huisgen cycloadditions are useful for tagging because they’re selective for alkynes and azides, which aren’t normally present in cells or proteins, while benzynes will probably not be very site-selective for nucleophiles, because they can react with many nucleophiles. It can’t be run neat, unless you want aryl fluorides or dibenzocyclobutadienes (or a large mess). It isn’t very atom-economical (though lots of chemistry isn’t). It’s definitely downhill from silylaryl triflate, so far downhill that it is probably going to be unselective (and hence inefficient). It’s inert to methylene chloride, THF, etc. but not alcohols or water. Sorry…no clicky for Prof. Larock. His group has done other nice Pd-cyclization work, though (I think they or Lautens started the use of norbornene to move Pd reactions around aryl halides) although I’m not very fond of benzyne reactions. I bought his name reaction book in grad school, and I think I’ve used it…thrice (in 15 years).
As a side note, does anyone feel an allergic reaction coming on when they see “benzotriazole” in print? I’ve seen more than enough Katrizky Bt papers to start screaming, particularly when his group uses two Bt groups to add one carbon (at which point I can’t silence the screaming in my head, “ATOM ECONOMY! OMG! OMG!”
It’s Katritzky.
Sorry.
1) Leukemogenic benzene in ground water.
2) Larock
3) Carbon credits!
It’s all about ruby slippers and a hero’s journey. Click ‘em high! Why not benzyne from anthranilic acid? Grape flavoring is Green! O-(Trimethylsilyl)phenyl triflate is Officially icky poo-poo. ACS Project SEED (expensively rescuing the top 10% of the bottom 10%) dusky heroines must not be burdened with historic abusive patriarchal nomenclature.
Actually, making azides can be pretty “clicky”. Sodium azide in DMSO (0.5 M) will scare off pretty much any leaving group quite quickly (it’s an excellent nucleophile). Extract into ether, wash with water, dry, and you’re done. Handling the neat organic azide is another story altogether, though.
You had me right up until DMSO.
…Yeah, I’d imagine that sodium azide in DMSO would maybe scare off a few click-happy biologists too.
Don’t worry about it, they have sodium azide in their proteins and even in their sucrose as a preservative.
I knew they used it for something.
I just like to make fun of them.
Ah…Barry Sharpless. Who can forget the aimless, eccentric, inspired and delightfully pointless romp that he indulged in in a seminar here. I for one sincerely loved it, no really, although critics may toss out trivialities like “It doesn’t help”
the tetramethyguanidinium azide in acetonitrile is very lovely also. (Until you make the mistake of using a chlorinated solvent in the reaction and blow up your rotovap).
The term :click chemistry” and its “rules” were determined after the fact by Sharpless. I don’t think Larock should be held to criteria created artificially. He uses the term because he forms a 5-membered ring with 3 contiguous Nitrogen atoms which is reminiscent of the chemistry that K. Barry has been exploiting with his collaborator Dr Fokin.
I don’t think Larock should be held to criteria created artificially.
Yes he should in this case. If he chooses it call it click chemistry, it better follow the criteria. This reaction doesn’t.
Sharpless had one definition what it means click chemistry (bench stable springloaded substrates that can be made to react under mild conditions ortogonally to lots of other chemistry) when he introduced the word but for better or worse click chemistry became synonymous with 1,2,3-triazoles made from azides and acetylenes. Its like word “retarded” or “moron” or “asylum” which originated as completely technical and neutral words, in fact they have been introduced as inoffensive alternative to more demenaing words.
Hmmm, from what I’ve seen in my lab (not my own work … but anyway I trust the guy) The whole click reaction is a bit overhyped. I mean, sure it’s nice that it works most of the time, but for the person who did this got a lot of issues with the click chemistry … A LOT. Perhaps due to coordination of his materials with Cu … but anyways, not that much of 100 % in pure water …
otherwise nice blog
!! First time im reading it…
[...] As bioorthogonal as CBC is, we still have some respect to biofolk.[1] See, these people won’t be anywhere without chemistry. The sun of Barry Sharpless shines real close to me and burns me with the hot fire of click chemistry.[2] While the initial message was directed at medchem people as a new way to think about creating diversity, the reliable reactions that work on any scale is something that everyone likes. Even biologists, with their inability to step outside of the Eppendorfs full of hella dilute and sensitive stuff. Especially biologists. This is why our lab looked into what makes The Click Reacion fail on biological substrates, and how to prevent it in ways other than making unhappy compounds resembling the wild dreams of the neophytes who don’t know any better. The result, in my view, is quite impressive. You’d better agree. [...]
What kind of nerds get this humor?