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Mechanochemistry Lets Scientists Tug On Molecules

In covalent mechanochemistry, chemists are discovering new reactivity by subjecting molecules to mechanical force

by Bethany Halford
October 1, 2012 | APPEARED IN VOLUME 90, ISSUE 40

Pulling on a dioxetane-based mechanophore gives off light.
Pulling on a dioxetane-based mechanophore gives off light.

When it comes to manipulating molecules, there’s a new force to be reckoned with—literally. Heat, light, and electricity have long been the standard tools chemists use to turn one molecule into another. But in the past few years, researchers have discovered that subjecting certain molecules to mechanical force can bring about transformations that aren’t observed under other conditions.

Taking advantage of this phenomenon could lead to new materials that strengthen under stress and strain or materials that signal, through a color change or by giving off light, when they are close to failing. It might also give synthetic chemists a new tool for building molecules. Those exploring the power of mechanical force in chemistry say there is plenty of exciting science out there for experimentalists and theorists alike.

The burgeoning field is known among its practitioners as covalent mechanochemistry or, sometimes, polymer mechanochemistry. The adjectives are important, explains Dominik Marx, a theoretical chemist at Ruhr University, in Bochum, Germany, because mechanochemistry generally refers to nonselective approaches that involve physically grinding chemicals together, such as in ball-milling experiments.

“The term covalent mechanochemistry means we manipulate covalent bonds and break them or rearrange molecules in terms of the molecular skeleton,” Marx says. “This is done very specifically at the molecular level in a controlled fashion.” Together with Jordi Ribas of Spain’s Barcelona University, he recently published a review on the subject (Chem. Rev., DOI: 10.1021/cr200399q).

Polymer mechanochemistry is sometimes used instead because to apply mechanical force to molecules, researchers often covalently tether these molecules—known as mechanophores—to long polymer chains on either side.

To tug on those chains, researchers turn to ultrasound. When chemists use ultrasound on a chemical solution, the sonic waves cause bubbles to form, grow, and implode in the liquid. Polymer mechanochemists think that the collapsing bubbles created by ultrasound pull on the polymer chains. This causes the polymer to elongate and puts stress on its backbone. Experiments have shown that polymers subjected to ultrasound tend to break at their midpoint, which is why chemists place the mechanophore there.

Ultrasound isn’t the only way to apply mechanical force to a molecule. Chemists have also used single-molecule spectroscopy. But, explains Jeffrey S. Moore, a chemistry professor at the University of Illinois, Urbana-Champaign, “the problem with single-molecule experiments is that you never get to see what structural changes took place.” It’s not possible to cleave the molecule in question off the atomic force microscope and then analyze it using nuclear magnetic resonance.

“We needed a tool that would allow us to use mechanical energy and then be able to collect the sample and do some traditional kinds of analysis,” Moore continues. The obvious choice was polymers, he says. Just put the molecule in the solid state and pull on it. But that still didn’t address the structural elucidation problem.

Mechanical force results in only one ring-opened product, even though orbital symmetry rules indicate there should be two.
Mechanical force results in only one ring-opened product, even though orbital symmetry rules indicate there should be two.

After scouring the literature, Moore struck upon the idea of using ultrasound on polymers in solution to do the job. Rint P. Sijbesma, a chemistry professor at Eindhoven University of Technology, in the Netherlands, was thinking along similar lines at the same time—around 2004 and 2005.

“It looked perfect as a means of providing the polymer with mechanical energy,” Moore notes. “Then we could just collect the sample and do a bulk analytical measurement to see if what had happened was what we expected or something different.” Plus, he says, the technique was easy and required relatively inexpensive equipment.

Using ultrasound on polymers is, in fact, a fairly old technique, Moore points out. But until recently, all the work was focused on the degradation of polymers through mechanical means. “If we put our stamp on some change of thinking in the field, it was this: Force doesn’t have to just be degradative,” Moore says.

In 2007, Moore’s group showed they could apply mechanical force to both the cis and trans isomers of benzocyclobutene and wind up with just one ring-opened product: the E,E-diene (Nature, DOI: 10.1038/nature05681). This was a surprise because the Woodward-Hoffmann rules of orbital symmetry dictate that the cis and trans isomers should lead to different products. And light and heat produce both the E,E- and the E,Z-dienes from a mixture of cis- and trans-benzocyclobutene. Essentially, Moore’s team had shown they could use force to perform a formally disallowed electrocyclic ring opening.

This paper turned out to be an inspiration to organic chemists and polymer chemists alike, mechanochemistry researchers tell C&EN. It got them thinking: What could mechanical force do to molecules that heat, light, and electricity could not?

Application of force results in a long-lived diradical transition state, which collapses to the cis isomer.
Application of force results in a long-lived diradical transition state, which collapses to the cis isomer.

“Polymer chemistry has benefited greatly from organic chemistry,” says Christopher W. Bielawski, a chemistry professor at the University of Texas, Austin. But until Moore’s paper, it had been hard to find examples where synthetic organic chemists rely on polymers to make molecules. “Mechanochemistry opens up avenues to do chemistry you just can’t do any other way,” says Stephen L. Craig, a materials chemist at Duke University. In 2010, working with Stanford University theoretical chemist Todd J. Martinez, Craig showed that force could be used to trap a reaction’s diradical transition state (Science, DOI: 10.1126/science.1193412).

The team was working with a polymer containing a mixture of cis- and trans-difluorocyclopropyl groups. When they subjected the polymer to ultrasound, the trans groups converted to cis stereochemistry, despite the fact that the trans structure is more thermodynamically stable. “It’s as though you take a rubber band, pull on it, and it shortens,” Martinez says.

The act of physically pulling on the difluorocyclopropyl group was resulting in a diradical transition state that persists for an unusually long time—on the order of nanoseconds. In fact, the researchers were able to trap it with a radical reagent. “You can take a molecule, pull it into a conformation that corresponds to a transition state, and hold it there for long enough to allow it to do reactions,” Craig explains. These reactions take the molecule somewhere different from where it was headed on its reaction pathway before force was applied. In this case, applying and then removing force makes it energetically more favorable for the diradical to form the cis-difluorocyclopropyl structure.

Only force can cyclorevert 1,2,3-triazoles into alkynes and azides.
Only force can cyclorevert 1,2,3-triazoles into alkynes and azides.

Bielawski demonstrated another transformation using mechanochemistry that chemists had been unable to perform using either light or heat. Last year, his team managed to unclick the most popular of the so-called click reactions, tugging a 1,2,3-triazole apart into an alkyne and an azide (Science, DOI: 10.1126/sci​ence.1207934).

And this year, Bielawski’s group showed they could de-racemize BINOL with mechanical force (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201107937). It was, Bielawski says, a crazy idea he had on a plane ride; he remembers doodling it on an airline cocktail napkin. They covalently linked both ends of a racemic mixture of the molecule to polymer chains via ester bonds and then pulled on the chains with ultrasound. Cholesterol esterase is known to stereoselectively hydrolyze esters of (S)-BINOL, so they added the enzyme to the reaction flask. When the ultrasound pulled the BINOL into its S conformation, the enzyme selectively cleaved (S)-BINOL from the polymer.

Meanwhile, theorists have begun trying to figure out what makes mechanical force special. In 2009, Marxand Martinez both showed that mechanical force can significantly change the potential energy surface for a reaction (J. Am. Chem. Soc., DOI: 10.1021/ja8095834 and Angew. Chem. Int. Ed., DOI: 10.1002/anie.200900673). For example, if one thinks of a reaction pathway as traveling from one valley to another over a mountain, mechanical force can, in some cases, alter that landscape so the mountain becomes a valley.

“I am looking for the rules that allow us to predict what happens if you stretch a molecule,” Marx says. “This is, in some modest way, similar to the Woodward-Hoffmann rules that help us understand photochemistry.”

The idea that stress or strain could lead to chemical changes offers some intriguing possibilities in terms of applications, too. Polymers that respond to stress or strain in some fashion seem logical. Moore, along with his University of Illinois colleague Nancy R. Sottos, showed in 2009 that by covalently attaching a mechanophore to a solid polymer, they could create a material that changes color under a certain amount of strain (Nature, DOI: 10.1038/nature07970).

A one-pot method for de-racemizing BINOL involves polymer mechanochemistry and an enzyme reaction.
A one-pot method for de-racemizing BINOL involves polymer mechanochemistry and an enzyme reaction.

This year, Sijbesma’s group at Eindhoven reported a mechanophore based on a 1,2-dioxetane group that results in two ketones, one of which is in an excited state and gives off light. “It’s a useful diagnostic to see when and where materials fail or threaten to fail,” Sijbesma says.

And there are plenty of other ideas floating around. What if, for example, you could develop a material that becomes stronger as it’s stressed, just as bones and muscles do?

Moore, a marathon runner, says such a material could revolutionize running shoes. “It would be really cool to have a shoe that would be able to sense according to all of the specifications unique to you—your weight distribution, the exact shape of your foot, and your running form—the mechanical load that it’s being subjected to, and undergo modification and adaptation that will be more suitable to you and the way you run,” he says.

Of course, mechanochemistry mavens caution that the field is only just starting out. “There are a lot of potential applications that haven’t been disproven but that haven’t been proven either,” Craig says. “Much of the emphasis now is on understanding exactly what the limits of polymer mechanochemistry are.”

For example, most covalent mechano­chemical transformations reported to date involve opening a ring. “Are ring systems special in terms of being able to exist at the level where they’re controllable?” Martinez wonders. Something is going to happen if you pull hard enough on any molecule, but it won’t be selective, he says. “The whole thing that has made mechanochemistry so interesting is the ability to induce selectivity. We don’t know what the range of molecules is where some kind of selectivity is achievable with respect to mechanically induced processes.”

Bielawski sees a different limitation: atom economy. “You have two huge polymer chains attached to one mechanophore, which is relatively small, and what you’re really interested in is that mechanophore.”

Bielawski envisions that one could solve this problem by coming up with a polymer that attaches and detaches in situ so that only a catalytic amount of polymer is needed. “Once that happens, I can see commercial applications in the near future,” he says.

“We can’t promise too much,” Moore cautions. Whether mechanochemistry is going to deliver a critical application is still uncertain. But, he says, nature provides good inspiration in the form of bones and muscles as mechanically adaptive materials. “As chemists,” he adds, “we need to find materials that follow suit.”



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