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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Finding New Reactions By Looking For Them | Main | Big Sirtuin News »

September 21, 2011

Pulling Molecules Apart, For Fun

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Posted by Derek

Now here's an odd reaction, done in an odd way. Organic chemists will all be familiar with the azide/acetylene cycloaddition to form triazoles. In its copper-catalyzed variant, it's become a sensation, and is used as a convenient linker to do all kinds of interesting things. The reverse reaction, taking a triazole back to the starting materials, just isn't feasible. If you heat up one of the triazoles enough to get it to do anything, which takes some pretty serious heat, it just gives you a handful of decomposition products.

But what if you grabbed each side of the ring and just pulled on it? A paper in Science does just that, though having polymeric chains attached. If you subject that to ultrasound, the cavitation bubbles that form are violent enough to pull and jerk the molecular chains around - and when they try that on a triazole-linked molecule, they can see reversion to the acetylene and the azide. This only happens with long-chain polymers - the effect increases with polymer molecular weight, and small-molecule analogs aren't cleaved at all. It also appears that the effect works best when the triazole is near the midpoint of the polymer, not out towards one end. These are just what you would expect for this sort of "mechanosynthesis", and strong evidence for the proposed effect.

This could lead to some rather unusual reactions being discovered. Some sort of cleavable tether that stands up under sonication might allow you to put on "mechanosynthetic handles" that you could then take off again, as if they were protecting groups. Silyl ethers, maybe? Which functional groups can take the stress, and which will pull apart to give something new?

Comments (14) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. John Spevacek on September 21, 2011 12:38 PM writes...

YES! Finally your in my area (polymers), but NO! I don't have access to the article!

If the effect works best with the triazole in the middle and not the end, then it looks like you are working with dilute polymers (i.e., there is no overlap between the random globule of one polymer coil with the next). If it is that dilute, I wonder about the economic efficiency - that is a lot of water to have to rid oneself of at the end.

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2. imatter on September 21, 2011 2:21 PM writes...

Imagine windows that shatter in a controlled manner using sonic waves, etc. The army would fund that. Send checks my way.

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3. milkshake on September 21, 2011 3:32 PM writes...

I have my doubts about this - according to Fokin and Sharpless the triazole formation is hugely exothermic, to the tune of 50-65 kcal/mol. If you sono-cavitate and put that much energy into the system, what else also breaks?

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4. Algirdas on September 21, 2011 3:34 PM writes...

#2 imatter

"Imagine windows that shatter in a controlled manner using sonic waves, etc. The army would fund that."

Well, I know what you saying, but ... people have been shattering windows using sonic waves since invention of the gunpowder. Note that it was usually done in a very controlled manner: "Windows will stay intact around here until I apply this here torch to the fuse on yon powder keg." The twentieth century saw many refinements to this technique, such as, e.g., HE munitions.

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5. Derek Lowe on September 21, 2011 5:46 PM writes...

Milkshake - the thermodynamics of this process make for an interesting question. The authors of the paper say that the mechanical stress destabilizes the ground state, which I can well believe, but unless the process leads through a different transition state, you do still have those 50 kcal/mol to make up. And on grounds of microscopic reversibility, you'd have to assume that the transition state is the same - but does that apply when one reaction is thermal and the other one is mechanical? Maybe there's one bond that goes before the others, though some sort of radical intermediate. Odd stuff to think about, for sure. . .

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6. Doug on September 21, 2011 7:34 PM writes...

Todd Martinez has done modeling of these systems which seem to indicate that the reactant, product, and transition state geometries are all altered by mechanical force. (http://pubs.acs.org/doi/abs/10.1021/ja8095834)

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7. barry on September 21, 2011 7:45 PM writes...

we've known for years that one can initiate a radical chain reaction by mechanically grinding a cross-linked polymer in the reaction flask. What's new is designing the weak link. It's not hard to think of some Diels-Alders that are only slightly exothermic in the cyclcoaddtion direction that are great candidates for ripping asunder mechanically.

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8. milkshake on September 21, 2011 7:52 PM writes...

According to Fokin uncatalyzed Huisgen reaction of terminal acetylenes with alkyl azides has about +25 kcal/mol activation bareer. (He blames mismatched HOMO and LUMO energy levels for high activation bareer of the uncatalyzed reaction but I don't care). Even if you invoke some weird recoil - biradical mechanism with much lower bareer you are still more than 50kcal/mol in the hole. I think the mechanism must be different, not just a simple reversal. (By the way, the name click was supposed to signify a highly exothermic cycloaddition reaction that snaps into place and stays put)

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9. NHR_GUY on September 21, 2011 8:43 PM writes...

Only glanced at the paper, but I will go back and check, but if the energy (forward reaction) to make the bonds is different then the energy to break the bonds(reverse reaction), then you have two different mechanisms at work here. Pretty cool stuff though. Interesting thought here:
if the reaction is due to polymers on either end of the triazole, could you do the same thing for bio-polymers? Would be cool to see if you could do it w/o denaturing the proteins. Could be a cool catch and release method.

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10. Ludite on September 22, 2011 7:27 AM writes...

Is it just me or has "Science" lowered the bar for accepting chemistry papers, although maybe I am just missing the signifigance of this and the recent Hartwig publication?

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11. Am I Lloyd peptide on September 22, 2011 2:52 PM writes...

milkshake: He blames mismatched HOMO and LUMO energy levels for high activation bareer of the uncatalyzed reaction but I don't care

Apparently the molecule does.

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12. Hap on September 22, 2011 4:39 PM writes...

Aren't you throwing a ton of energy into the system by sonicating it? If the bubbles formed on sonication are reaching plasma temperatures, then there's an awful lot of energy to play with. Since 1) you're not really talking preparative scale here and 2) the molar mass of the polymers is so large that 50 kcal buys a lot of broken polymer, I don't think that the energetics is that much of a hindrance, or am I missing something?

I'm assuming that "energies to break/make bonds" is referring to kinetic barriers and not thermodynamics (which shouldn't change however the reaction goes)?

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13. Doug on September 23, 2011 8:20 AM writes...

Hap: Yes you are throwing a ton of energy into the system by sonicating, and the interior of the bubbles can get quite warm. However, the polymer/mechanophore likely doesn't enter the bubble. In general, the sonication is kept cool and controls are run with low molecular weight polymer or polymer + small molecule to make sure it's not just a thermal effect. The theory is that as the bubbles collapse, the fluid flow toward the collapsing bubble pulls the polymer chains along. Longer chains provide larger lengths to pull against and cleavage rates generally go up.

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14. Hap on September 23, 2011 9:18 AM writes...

Mostly duh - sorry (if the polymers entered the bubbles, they'd be tar rather than discrete products). The only caveat is while a lot of the energy from sonication is going out as heat, some of it is not (I assumed that the heat was the product of motions of the bubbles) - if there's enough energy in the motion to be converted to temperatures that high in the bubbles, there's plenty lying around to harness for the chemistry observed.

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