Scientists have developed a computational method to quantify and generate 3D maps of stereoscopic effects. The technique is more accurate than existing approaches, and tests have shown it to work in a wide range of cases, including atropoisomerism, coordination chemistry, and organocatalytic enantioselectivity.

Steric effects are nonbonding interactions that affect both reaction outcome and molecular structure. Interference, or blocking, is the most commonly encountered steric effect and occurs when you try to force two atoms to occupy the same space. However, the analysis and visualization of stereoscopic effects remains difficult, and despite their ubiquity and importance, they are often described only qualitatively, without explicit spatial or quantitative details.

now, Eric Enonfrom the University of Reims-Champagne-Ardenne and colleagues across France have developed a new method that allows them to quantify and visualize steric effects directly from quantum calculations.

This method, called the steric exclusion localization function (Self), is based on the Pauli exclusion principle, a quantum effect that prohibits two electrons with the same spin from occupying the same space. “This exclusion constraint comes at a cost in extra kinetic energy,” Henon explains. Self calculates additional kinetic energy that is closely correlated with steric effects.

This method can generate 3D maps showing exactly where steric interactions play a role. “It’s important that it’s not just a measurement of the geometric distance between approaching molecules, but is based on actual quantum mechanical calculations.”

robert paytonThe method, said the computational organic chemist at Colorado State University in the US, “moves us towards a more accurate grasp of three dimensions… It stands out in that it creates a three-dimensional map rather than just giving energy values.”

In fact, a number of methods exist to investigate steric effects, including energy-based quantum mechanical methods, geometric methods, and classical methods, but each has its limitations. Although energy-resolved analysis and symmetry-adapted perturbation theory can quantify Pauli repulsion, they are often imprecise in indicating where exactly steric interactions are occurring and which atoms are involved. Also, while simple, geometric methods tend to treat atoms like hard spheres of fixed size, and are unable to provide a realistic picture.

“There are various approaches to quantifying steric effects, most of which are socialized by showing correlations with other descriptors already in use.” Natalie FayeResearch at the University of Bristol in the UK includes computational studies of synthetically relevant organometallic catalysts. “But the application to such diverse problems – organocatalysis, atropoisomerization – and the comparison of the Tolman parameter (which, by the way, is well known to be flawed and somewhat tedious to determine) with reasonable results is interesting. Easy visualization is also always helpful.”

Hénon’s team tested Self in a classic example in which steric interactions are often invoked to explain different outcomes. For example, they investigated organocatalytic reactions in which the selectivity for one product is due to steric collisions between the mesityl groups in the catalyst and the catalyst. p-methoxyphenyl moiety of the reaction substrate. This hypothesis was self-confirmed, and in addition, less obvious steric interactions were revealed.

Another system developed by the Self team was a series of Ni-phosphine complexes in which steric interactions often limited the access of the lone pair of electrons in the phosphine ligand. The researchers found that their results correlated well with the Tolman angle, the traditional method of studying this, but they also showed that the interaction between the nickel center and the ligand was smaller than the Tolman analysis suggested.

These insights could be useful to chemists. Paton said: “You can also imagine using this tool to compare many different ligands in a library and use it to, for example, characterize and understand performance or even design ligands. Ultimately, you can think about how to design better and more efficient systems and reactions.”

Enon emphasizes that the “self” operates not only between molecules but also within them. “Previous methods were designed to bring two separate molecules closer to each other. But what about rotational barriers within a single molecule? That’s intramolecular steric repulsion, and Self deals with it naturally. Other methods struggle with this greatly. This opens up new perspectives.”

But Fay is cautious about the future impact of this research. “Time will tell, but for now it’s promising due to its theoretical rigor and ease of visualization, but it may take some time to see if this really adds value, as the Tolman parameter, for example, is very well established for organometallic catalysts.”