‘Chemical Thermometer’ Factors In Local Environment Of A Cobalt Molecule
By Deborah Borfitz
June 23, 2022 | The concept of mimicry—making molecules that “do cool things that other molecules do”—is foundational to chemistry. But the discovery of a cobalt-based molecule engineered to be a noninvasive chemical thermometer for detecting tiny temperature changes, one of the signposts of injury and disease as well as the true edges of a cancerous tumor, opens the door to a new approach where the mimicking is focused on manipulating a molecule’s quantum aspects rather than its reactivity, according to Joseph Zadrozny, assistant professor of chemistry at Colorado State University.
For the past several years, Zadrozny has been fascinated with metal ion nuclear magnetic resonance (NMR), a field of study that admittedly experienced its final renaissance in the 1990s. It was a perfectly logical path for the physical scientist whose passions bridge the worlds of chemistry, magnetism, and quantum computing.
One of Zadrozny’s current fascinations is with the “magnetic moments” of a metal ion-containing cobalt molecule whose nucleus acts like an electron, as recently described in the Journal of the American Chemical Society (DOI: 10.1021/jacs.2c03115). As the temperature in the environment rises, so do the magnetic fields on the molecule because its electrons start to become unpaired—a technique analogous to using radiofrequency waves to flip the alignment of nuclear spins, he explains.
This, in turn, makes the NMR signal exhibit a temperature dependence “on par with what you might see if you were studying just a single electron,” continues Zadrozny. But unlike an electron, the molecule in this quantum superposition state—where its magnetic nucleus exists in multiple orientations in a magnetic field simultaneously, much like multiple soundwaves heard by the ear as a single chord—is relatively stable.
The molecule’s “robust coherence” is a promising peculiarity for something that interacts so strongly with the environment, he notes. An entire area of research is devoted to understanding how to make that superposition state persist longer.
“I am trying to flip that design strategy on its head,” Zadrozny says. “If this superposition state is really fragile, can we exploit that [environmental] sensitivity to make new types of sensing agents?” Since superposition is a function of nuclear magnetism, perhaps NMR (using radiation frequency) or magnetic resonance imaging (MRI, using radiation intensity) could be the means to generate clinically useful information, he reasons.
The temperature sensitivity of cobalt molecules is related to the nuclei’s multiple orientations, or wave functions, that have an energy associated with them, he adds. So, it is possible to pump in radiant energy to move the system between the different orientations, which is a fundamental NMR principle.
Zadrozny’s long-term goal with the designer molecule are “magnetic imaging probes” with extreme temperature sensitivity that can weather clinical use. This is likely many years off still, since the cobalt molecule as-is would probably fall apart or otherwise be rendered useless if introduced into the oxygenated, aqueous environment of a human.
But the impact could one day be sweeping. Imagine doctors being able to detect the minutest temperature shifts around a still-invisible tumor, for example, or an in-office thermal ablation procedure that could precisely kill off only diseased tissue, Zadrozny says. It may even become possible for a temperature-sensing probe to be injected or ingested to communicate temperature signals from the body.
Additionally, the envisioned magnetic probe would work at room temperature. Electron-based probes would need to be much colder and would in any case be dangerous for humans since exploiting their magnetism requires microwaves, says Zadrozny.
The most important temperature range Zadrozny and his team are interested in is close to that that of the human body, where small fluctuations could herald clinically meaningful insights. Creation of the compounds is step one, “an important proof of concept” that must now be translated into magnetic design principles to inch closer to clinical utility, he says.
The nucleus of the cobalt compound made in Zadrozny’s lab has two orientations and “the spacing of energy between them is changing a lot as a function of temperature,” he explains. As shown in the study, radio waves were applied to the molecule in the NMR spectrometer until researchers found the frequency where the system responded.
Magnetic nuclei will typically respond to changing frequencies with minute temperature changes, less than 1 parts per million per degree Celsius (ppm/°C), he says. But for the compounds reported on in the published paper, temperatures were changing by 100 or 150 ppm/°C, making it a substantial advance over existing sensing agents where the fluctuations are driven by small changes in bond distances or molecular geometry that alter the local electron distribution.
Zadrozny says he hasn’t abandoned the study of “cobalt compounds that don’t have that weird kind of paired/unpaired electron transition [aka “spin crossover”],” which also show a lot of promise in enhancing the capabilities of bioimaging. His lab continues to look at those more traditional molecules, which are highly chemically stable, with an eye toward structural changes that can give them higher temperature sensitivities.
His lab shifted gears to molecules with the spin crossover based on the interests of postdoctoral researcher Ökten Üngör who designed the cobalt molecule and tested its temperature sensitivity using a 500-megahertz NMR spectrometer.
So, what is the significance of measuring temperature via NMR or MRI? Excepting run-of-the-mill thermometers placed under the tongue or in one’s ear, measuring temperature in vivo tends to be highly invasive—e.g., a surgically inserted metal probe used during thermal ablation procedures, Zadrozny says.
More broadly, it might be deployed for other focused challenges and imaging of chemical signals, including pH balance in the body, which are barometers of health. “There are way more types of chemistry going on in the body than just exchanges of protons, flow of oxygen, movement of water, and adenosine triphosphate [principal molecule for storing and transferring energy in cells],” he says, adding that “we clearly don’t have a complete picture of why the body works [or doesn’t] the way it does.”
Outside of the medical realm, the magnetic probe may well find application in enhancing quantum computing, says Zadrozny. The dichotomy here is that it is necessary to stop molecular quantum bits from interacting with the environment to obtain the longest-lived superposition states holding the most stable information for the longest amount of time, which doesn’t reflect the reality of how the technology gets deployed in the real world.
The analogy in regular computing would be one transistor sitting by itself in the corner of the room, rather than having multiple ones linked together on a chip to enable communication, he says. “The fact of the matter is that stable data [flow] seems to be directly in conflict with whether or not a qubit can interact with anything else.”
The new temperature-sensing probe is part of a larger effort by Zadrozny and his team to understand how quantum objects interact with one another—and which ones might be strong but also not interfere with the lifetime of the superpositions. “We need to stop measuring and studying compounds in these special engineered environments that are analogous to the [lone] transistor.” Only by considering what is happening in the local environment of a molecule can scientists hope to design parts of that molecule so it can better hold its own.