Molecular Locks and Keys: Three Studies Decipher the Secrets of Ionic Bonds

Understanding how molecules interact with ions is the basis of chemistry and has applications ranging from contamination detection and cleaning to drug delivery. In a series of new studies led by Girafero and Professor Matthias Weber, Professor of Chemistry at the University of Colorado, the researchers investigated how a specific ion receptor called octamethylcalix (4)pyrrole (OMC4P) binds to different anions such as fluoride and nitrate.

These findings, published in the Journal of the American Chemical Society, The Journal of Physical Chemistry Letters, and The Journal of Physical Chemistry B, provide basic insights into molecular bonding that can help advance areas such as environmental science and synthetic chemistry.

“The main problem with understanding these interactions is that there is a competition between ionic binding to a particular receptor and the same ions that want to be surrounded by solvent molecules,” explains Weber. “This competition affects how effective and specific ion receptors are. We don’t understand them enough to design better ion receptors for applications. This has been a problem for decades and we can try to solve them by taking a different perspective.”

Looking at the ion receptor

The test molecule in question, OMC4P, is a prototype anion receptor that has been of much interest for nearly 30 years, and is a macrocyclic molecule with a cup-like structure designed to capture negatively charged ions (anions). Its rigid yet adaptable cavity contains four NH groups that form hydrogen bonds with incoming ions, making it an ideal system for investigating how different anions interact with molecular hosts.

What makes OMC4P particularly interesting is its peculiarity. The binding pocket has a specific size and shape, so simple anions such as fluoride and chloride fit very tightly. However, when larger or more complex anions enter, such as nitrates or formation, their shape breaks down the pocket structure, and the ions protrude into the surrounding solvent. At the same time, some ions bind tightly to the NH group, thus binding strongly to OMC4P despite their relatively large size.

Understanding these variations in binding is important for designing selective receptors. If receptors can distinguish closely related anions, they could greatly help advance applications such as water purification, medical diagnostics, and industrial sensing.

“These studies help us understand what receptors are selective,” explains Zilla graduate student Lane Terry, who was the first author of the paper. “If we can fine-tune that structure, we can create target ion sensors for real applications.”

First Step: Simple Halogenation

The team’s first study, published in the Journal of the American Chemical Society, focused on halide ions in simple spherical shapes, in fluoride, chloride and bromide.

“We started because halides are the simplest. They act as a single point charge,” explains Terry.

To analyze how these anions interacted with OMC4P, the researchers used cryogenic ion vibrational spectroscopy (CIVS) to employ “snapshots” of molecules showing interactions occurring in the sample. CIVS is a technique that investigates ionized molecules that have been cooled to low temperatures, reducing movement and separating vibrations. Ions are fired with infrared photons, and the ions absorb certain wavelengths based on how the atoms are arranged and vibrational.

This allows researchers to measure how receptors interact with different ions, in combination with quantum chemistry calculations, without interfering with external factors such as solvent molecules.

After multiple CIVS measurements, the team validated the measurements with measurements predicted by density functional theory (DFT), a computational method that predicts how the molecular structure of complexes is calculated and interacted.

“DFT helps compare experimental data with theoretical models,” explains Terry.

Through this process, the team discovered that fluoride formed the strongest hydrogen bonds and remained firmly bound in solution, but chloride and bromide have a weaker proton affinity, resulting in weaker ion-receptor interactions and thus more susceptible to solvent interactions.

“This is important because most of these ion receptors are used in aqueous environments,” notes Terry. “This means that fluoride binding is more stable at these ion receptors than other halides.”

Added complexity: Unique binding of nitrates

The team built on this foundation investigated the nitrate anion binding to OMC4P, detailed in the Journal of Physical Chemistry Letters detailed in the second study. Unlike halides, nitrates are polyatomic. That is, multiple atoms are arranged in a Y-shaped shape in this case.

Using the CIVS Plus DFT method, researchers found that nitrates prefer a binding mode in which only one of the three oxygen atoms interacts with the NH group of OMC4P. This was a surprising result, as it is possible that two oxygen atoms could be expected to bond symmetrically.

“There are multiple possible configurations of nitrates, but I strongly support one,” Terry says. “The shape of the ions and charge distribution make a huge difference, especially in aqueous environments.”

Most complex cases: formation and isomers

The final study published in the Journal of Physical Chemistry B addresses the most complex binding behavior to date (HCOO⁻), a small but asymmetric anionic bond that binds to OMC4P. Unlike nitrates, formation was observed to have multiple binding configurations (a process known as isomerism) to ion receptors.

“Formation actually isomers, even in extremely low isomers, isomers with sufficient energy to detect multiple isomers,” explains Terry.

The researchers observed that unlike nitrates that settle into one stable structure, the formation shifts between different compositions. Interestingly, the most stable formation configuration was not symmetric and defied traditional expectations. In contrast, highly symmetric structures allow for predictability, whereas in contrast, asymmetry can lead to unexpected behavior affecting ion receptor selectivity and stability.

After analyzing these findings, the team is currently investigating the modified OMC4P with the addition of a structural “wall” to deepen the binding cavity and alter ionic interactions. This adds even more complexity to the experiment.

Beyond the basics

These studies focus on basic chemistry, but their meaning goes far beyond the lab. Environmental surveillance, drug delivery, and chemical sensing all rely on understanding ion interactions at the molecular level.

Terry said, “We work closely with the organic chemists who design these molecules. Our findings help us build better ion receptors with improved selectivity.”

Whether they detect contaminants in the water or design a better drug carrier, their discoveries take them a step closer to harnessing chemistry for greater benefits.