ICES researcher Dmitrii Makarov finds atomic prodding can strengthen chemical bonds instead of break them

Dmitrii Makarov, ICES researcher and chemistry professor, has developed a computational molecular model that predicts how perturbing certain atoms in molecules affects the reaction rate. Here, Makarov and collaborators discuss research developments while surrounded by articles. Pictured from right to left: Dmitrii Makarov; John Brantley, graduate student; Sai Konda, graduate student; Stanislav Avdoshenko, post-doctoral researcher.

The field of atomic scale mechanochemistry is literally pushing chemistry to new places.

Using high-frequency sound pulses, researchers are able to physically move the atoms that make up molecules, potentially changing reaction outcomes. Recent research has focused on speeding up chemical reactions, with chemical intuition guiding experimentalists in this young field on just what particular atoms to pull to make a reaction move along.

Dmitrii Makarov, a researcher at ICES Center for Computational Molecular Sciences, has a different, less selective approach —try everything. By computationally modeling the outcome of perturbing every possible atomic pairing in a selection of molecules, Makarov and his collaborators have helped reveal new mechanochemical insights. One of the most interesting, says Makarov, is the ubiquitous presence of catch bonds, bonds that strengthen under force, impede chemical reaction, and are a rarity in the natural world.

His research was published last fall in the Journal of the American Chemical Society. His co-authors are Sai Sriharsha Konda, John Brantley, Bibin Varghese, Kelly Wiggins, all chemistry graduate students at UT, and Christopher Bielawski, a UT chemistry professor.

Controlling chemicals

The appeal of mechanochemistry lies in its potential to give humans unprecedented control over chemical reactions, said Makarov. While conventional methods of chemistry act on the entire chemical system, mechanochemisits influence reactions by applying precise forces to specific atomic targets

“Mechanochemistry allows you to control reactions in a different way because, unlike pressure or temperature, force is a vector. So you can push your chemical system towards a desired pathway,” said Makarov.

Precisely controlling chemical reactions is of particular interest for materials research, says Makarov, with “mechanomaterials” potentially gaining different attributes when subjected to different degrees of force. For example Makarov notes an elastic material, developed by Nancy Sottos and collaborators at The University of Illinois, that changes color under stress, and returns to its original hue when stress is removed. It's a material with great potential in devices that gauge tension, such as ropes and suspension cables.

While materials are a large research motivator, most science is still in the investigative stage, with researchers trying to understand the fundamentals of how different forces applied to different atoms in certain molecules influence chemical reactions.

Makarov’s models were made with these basic research questions in mind. However, while other researchers often test reactivity by pulling on one set of atoms at a time through experimental methods, Makarov was able to test all possible atom pairings in six different mechanophores (molecules that have proven reactive to mechanical manipulation) through simulation. The force applied to the atoms in the model was in the piconewton and nanonewton range, or about a trillionth of the force required to break an egg.

“We chose molecules that are known to be responsive to force. What we changed is applying the force to different locations, not where everybody has tried it,” said Makarov. “We just wanted to look at if you try and pry a molecule apart in every possible way what are the outcomes.”

Generally, simulating how forces applied to every possible pairing of atoms affect the whole molecule would be out of reach because of the great cost for the computational power involved, said Makarov. But Makarov has developed a technique that, by examining molecules at zero force, is able to predict how the molecule react when force is applied to a select atomic perturbation.

“So if you know everything about the reaction at zero force we can do it at finite force, and thus it allows us to analyze every possible way to pull on it,” said Makarov.

Results with a catch

Many of Makarov’s simulations produced findings similar to experimental results, with forces inducing “slip bond” behavior, breaking bonds, and causing a faster reaction. A graphic depicting the reaction of the Dials-Alder adduct mechanophore under different mechanical stresses. When the two atoms in the top representation were perturbed, a slip bond was broken and the reaction proceeded toward the products. However, as depicted in the bottom representation, when one of the stressed atoms was swapped for a different, nearby atom, stressed bonds strengthened, exhibiting catch bond behavior, and preventing the reaction toward proceeding toward the products. However, just as often, pulling on atoms caused “catch bond” behavior, strengthening bonds and suppressing chemical reactions. The 50-50 distributions of slip bonds to catch bonds held across all examined molecules even as reaction details differed, said John Brantley, a chemistry graduate student in the Bielawski group.

“This trend held regardless of what the transformation was, whether it was an isomerization, or an electrocyclic ring opening, regardless of whether we had heteroatoms present, regardless of the size of the scaffold. We always saw that there were large numbers of instances where exerting force on the molecules would suppress any associated reactivity,” said Brantley.

Catch-bonds have been documented in biology enabling E.Coli and white blood cells to adhere to different materials, and their presence predicted by other computational models. But “slip bonds tend to be the rule,” said Makarov. However, Makarov’s simulations show that in covalent mechanochemistry catch bonds may not only be possible but an important and frequent player.

Guiding Experimentalists

Simulations are applied to predictive scenarios in many spheres, from weather to manufacturing. But in mechanochemistry they’re usually only applied to illustrate hypothesized experimental mechanisms after-the-fact, said Makarov, offering a limited data pool, imprecise experimental force application, and a disconnect between experimentalists and theorists, as reasons.

In contrast to this trend, one of Makarov’s simulations directly guided experiential design, a likely first for mechanochemistry.

“Our study is the first example, I believe, of rational mechanophores design where the experiment was guided not by chemical intuition but by precise predictions and calculations,” said Makarov.

Because of current experimental constraints (some of the atomistic pulling that Makarov simulated are “strictly thought experiments”), one mechanophore was chosen to examine experimentally. In a previous experiment, the mechanophore exhibited slip bond behavior when a pair of atoms was perturbed, but in an alternate pulling arrangement simulated by Makarov the bond was fortified into a catch bond.

“We actually took a molecule that is well studied and well understood where we have a slip bond and what we found was that if you change one of the pulling points in a very subtle and non-intuitive way, then you find that there’s basically a reversal of the effect,” said Makarov.

When Makarov’s simulation was recreated in the lab, the reaction was suppressed—evidence supporting catch-bond formation and meshing with the model’s predictions.

“It was really interesting because it seemed to defy chemical intuition,” said Brantley. “If I had been presented with the two molecules and asked to predict if one would activate and one wouldn’t, or whether they would both activate, I would have guessed that they would both activate [when perturbed].”

In this particular research, the products produced by the molecular bond breaking are more proof-of-concept than useful material. But understanding where and why catch bonds occur, scientists can be cued in on what molecules may be good candidates for the mechanomaterials of the future.

“We know that catch bonds could lead to very interesting viscoelastic behavior,” said Makarov. “So you could potentially create a material that has very interesting mechanical properties, and that’s one of the main reasons there is a lot of interest in mechanochemistry.”

Brantley agrees, saying that the discovery of catch bond frequency has jumpstarted research into reactions that take it slow.

“When you think about pulling on a molecule you don’t think about suppressing bond breaking, you think about breaking things. So that was the recent mindset in the field of mechanochemistry. But now, in the mechanochemical world at least, this idea of suppressing reactivity is starting to become a hot topic,” said Brantley. “So we’re really lucky to be at the forefront of that wave of new research.”

Furthering his mechanochemical work, Makarov, jointly with graduate student Sai Sriharsha Konda and ICES postdoctoral researcher Stanislav Avdoshenko, published a paper in The Journal of Chemical Physics this month developing computational methods that can be used to track how pathways of chemical transformations are altered in response to mechanical forces.

Article by Monica Kortsha

Posted: March 27, 2014