A groundbreaking development in molecular science has emerged from an international team spearheaded by researchers at the University of Vienna. This pioneering work introduces a novel experimental technique capable of directly measuring partial charges within molecules, a feat long deemed unattainable. Published recently in the esteemed journal Nature, this advancement promises to revolutionize our understanding of molecular interactions, providing a tangible window into the electrostatic landscapes that dictate chemical behavior and biological functionality.
At the core of every molecular interaction lie electrostatic forces—attractive and repulsive influences arising from uneven electron distributions among atoms. These delicate imbalances manifest as partial charges, subtle yet critical contributors to molecular structure, reactivity, and function. For decades, these partial charges have remained confined to theoretical models, inferred through computational algorithms rather than observed firsthand. The new method developed by the University of Vienna’s team now transcends these theoretical boundaries, allowing scientists to observe and quantify these charges with unprecedented precision.
This breakthrough hinges on the sophisticated use of electron diffraction, an analytical approach that exploits the charged nature of electrons to probe the internal electrostatic potential of crystals. By directing a finely focused electron beam onto a minuscule crystalline sample, the team recorded the minute deflections caused by interactions with the atoms’ partial charges. Unlike traditional X-ray diffraction, which primarily reveals atomic positions and electron density, electron diffraction’s sensitivity to electrostatic potential enables an unparalleled glimpse into the charge distributions within molecules.
The technological leap was achieved in part due to a cutting-edge camera developed at the Paul Scherrer Institute in Switzerland. This detector’s heightened resolution and sensitivity allowed for the precise capture of electron scattering patterns, which, when combined with an innovative analytical framework known as ionic scattering factor modeling (iSFAC), yielded quantifiable partial charge values. The iSFAC method models each atom as both neutral and charged species simultaneously, refining its simulation against the experimental data to extract the most accurate partial charge assignment.
Historically, partial charges were approximated via computational chemistry methodologies, each with their own inherent assumptions and limitations. Popular approaches such as electrostatic potential-derived charges (ESP charges) rely on fitting atomic charges to reproduce calculated electrostatic fields, while others partition electron density to assign charges to individual atoms. These computational methods often generated inconsistent results depending on the algorithm and parameters applied, leading to uncertainty and debate within the scientific community. The direct experimental assessment provided by this new electron diffraction method introduces an objective standard for validating and improving these theoretical models.
The researchers demonstrated the robustness and versatility of their technique across a broad spectrum of molecular types. Their experimental repertoire spanned crystalline industrial catalysts like ZSM-5, biologically relevant amino acids including tyrosine and histidine, organic acids such as tartaric acid derived from Austrian wine, and critical pharmaceuticals like Ciprofloxacin. In the latter case, a molecule of significant medical importance classified by the World Health Organization as an essential medicine, the analysis revealed notable environmental modulation of charge distribution: the chloride ion (Cl⁻) within the Ciprofloxacin hydrochloride salt carried only about 40% of a full negative charge, indicative of complex intermolecular influences on local electronic environments.
In addition to quantifying charges, this technique penetrates the intricate relationship between molecular geometry, electrostatic potential, and functional behavior—a nexus vital for drug discovery and materials design. Partial charges govern how molecules recognize and bind to targets, influence reaction mechanisms, and dictate the macroscopic properties of materials through subtle electronic effects. The capacity to observe these charges experimentally equips chemists and biologists with a powerful tool to fine-tune molecules for increased efficacy and reduced adverse effects in pharmaceuticals, alongside engineering advanced materials with tailored electronic properties.
The implications extend even further. By bridging the gap between theoretical predictions and experimental realities, this development promises to enhance computational modeling across disciplines, from quantum chemistry to structural biology. Researchers can now calibrate their algorithms against experimentally derived partial charges, fostering more reliable simulations and accelerating the rational design of molecules. Furthermore, the ability to experimentally resolve electrostatic potentials in crystalline states opens new avenues for investigating molecular dynamics under varied environmental conditions.
The involvement of the University of Vienna’s Core Facility for Crystal Structure Analysis has been instrumental in advancing electron crystallography methods that now transcend mere atomic localization. Their continuous innovation in combining state-of-the-art instrumentation with sophisticated data analysis has enabled this leap from structural to electronic characterization at atomic resolution. The collaboration with international experts and cutting-edge research infrastructures like the Paul Scherrer Institute underscores the multidisciplinary nature of this achievement.
This milestone arrives during an era where deepening our mechanistic understanding of molecular behavior is paramount. Complex biological systems, novel therapeutic agents, and next-generation materials all hinge on subtle electron redistributions that were previously inaccessible. By unlocking direct measurement of partial charges, the scientific community gains a potent new lens to discern and harness these subtleties, potentially reshaping approaches to chemistry and biomedicine for years to come.
In summary, the experimental determination of partial charges through electron diffraction signifies a monumental advance in molecular science. By revealing the nuanced electronic features that govern molecule-to-molecule interactions, it offers a concrete pathway to enhance theoretical models, refine pharmaceutical design, and engineer sophisticated materials. As this technique matures, its influence will undoubtedly permeate across scientific disciplines, enriching our molecular understanding and capability.
Subject of Research: Experimental measurement of partial atomic charges in molecules using electron diffraction.
Article Title: Experimental determination of partial charges with electron diffraction.
News Publication Date: 20-Aug-2025
Web References: DOI: 10.1038/s41586-025-09405-0
Image Credits: Gruene/Schroeder
Keywords: Electron diffraction, partial charges, molecular interactions, electrostatic forces, ionic scattering factor modeling, molecular crystallography, drug development, materials science, computational chemistry validation, electrostatic potential, molecular structure, pharmaceutical design
