Molecular lock and key: Three studies decode the secrets of ion binding

Understanding how molecules interact with ions is a cornerstone of chemistry, with applications from pollution detection and cleanup to drug delivery. In a series of new studies led by JILA Fellow and University of Colorado Boulder chemistry professor Mathias Weber, researchers have explored how a specific ion receptor called octamethyl calix[4]pyrrole (omC4P) binds to different anions, such as fluoride or 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 fundamental insights into molecular binding that could help advance fields such as environmental science and synthetic chemistry.

“The main issue with understanding these interactions is that there is a competition between an ion binding to a certain receptor and that same ion wanting to be surrounded by solvent molecules,” Weber explains. “This competition impacts how effective and specific an ion receptor can be, and we currently don’t understand it sufficiently well to design better ion receptors for applications. This has been a problem for decades, and we can now try to solve it by taking a different perspective.”

Looking at ion receptors

The test molecule in question, omC4P, is a prototypical anion receptor that has received much interest for nearly 30 years, 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 especially interesting is its specificity. Because its binding pocket has a particular size and shape, simple anions like fluoride or chloride fit quite snugly. However, when larger or more complex anions enter, like nitrate or formate, their shapes can disrupt the pocket structure, and the ions stick out into the surrounding solvent. At the same time, some ions bind strongly to omC4P even though they are relatively large, because they bind tightly to the NH groups.

Understanding these variations in binding is crucial for designing selective receptors. If a receptor can differentiate between closely related anions, it could help significantly in advancing applications such as water purification, medical diagnostics, or industrial sensing.

“These studies help us figure out what makes a receptor highly selective,” elaborates JILA graduate student Lane Terry, the papers’ first author. “If we can fine-tune its structure, we can create targeted ion sensors for real-world applications.”

First step: Simple halides

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

“We started with halides because they are the simplest—they act as just a single point charge,” Terry explains.

To analyze how these anions interacted with omC4P, researchers used cryogenic ion vibrational spectroscopy (CIVS) to take a molecular “snapshot” showing the interactions happening in the sample. CIVS is a technique that investigates ionized molecules cooled to low temperatures, which reduces their movement and isolates their vibrations. Ions are then bombarded with infrared photons, causing the ions to absorb specific wavelengths based on how their atoms are arranged and how they vibrate.

This, in combination with quantum chemical calculations, allows researchers to measure how the receptor interacts with different ions without interference from external factors like solvent molecules.

After multiple CIVS measurements, the team verified their measurements with those predicted by Density Functional Theory (DFT), a computational method that calculates the molecular structure of complexes to predict how they interact.

“DFT helps us compare our experimental data with theoretical models,” Terry explains, “so we can confirm what we’re seeing and refine our understanding of ion binding.”

Through this process, the team discovered that fluoride formed the strongest hydrogen bonds, remaining tightly bound even in solution, whereas chloride and bromide showed weaker ion-receptor interactions due to weaker proton affinities, and thus, were more susceptible to solvent interaction.

“This is important because most of these ion receptors are used in aqueous environments,” Terry notes. “Meaning that fluoride’s binding will be more stable with these ion receptors than the other halides.”

Adding complexity: Nitrate’s unique binding

Building on this foundation, the team then explored the nitrate anion binding to omC4P, detailed in their second study, in The Journal of Physical Chemistry Letters. Unlike halides, nitrate is polyatomic, meaning it has multiple atoms, in this case, arranged in a Y-shape.

Using the CIVS plus DFT method, the researchers found that nitrate prefers a binding mode where only one of its three oxygen atoms interacts with the omC4P’s NH groups. This was a surprising result, as one might expect two oxygen atoms to bind symmetrically.

“Even though nitrate has multiple possible configurations, it strongly favors just one,” Terry says. “The ion shape and charge distribution make a big difference, especially when in an aqueous environment.”

The most complex case: Formate and isomerism

The final study, published in The Journal of Physical Chemistry B, tackled the most intricate binding behavior yet—formate (HCOO⁻), a small but more asymmetric anion binding to the omC4P. Unlike nitrate, formate was observed to have multiple binding configurations—a process known as isomerism—to the ion receptor.

“Formate actually isomerizes at a low enough energy that we detect multiple isomers, even at cryogenic temperatures,” Terry explains.

The researchers observed that the formate shifted between different configurations, unlike nitrate, which settled into one stable structure. Interestingly, the most stable formate configuration was not symmetrical at all, defying conventional expectations. While highly symmetrical structures often allow for predictable, in contrast, asymmetry can lead to unexpected behaviors that influence selectivity and stability in ion receptors.

After analyzing these findings, the team is now investigating modified omC4P with added structural “walls” to deepen the binding cavity and alter ion interactions, which will add further complexity to their experiment.

Beyond fundamentals

While these studies focus on fundamental chemistry, their implications extend far beyond the lab. Environmental monitoring, drug delivery, and chemical sensing all rely on understanding ion interactions at the molecular level.

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

Whether detecting contaminants in water or designing better drug carriers, their discoveries bring us one step closer to harnessing chemistry for the greater good.