January 22, 2026 -- Inserting, removing or swapping individual atoms from the core of a molecule is a long-standing challenge in chemistry. This process, called skeletal editing, can dramatically speed up drug discovery or be applied for upcycling of plastics. Consequently, the field is witnessing a surge of interest spanning from fundamental chemical research to applications in the pharmaceutical industry. A group of researchers have now extended the scope of skeletal editing to the scale of just a single molecule. Such a level of precision in skeletal editing is unprecedented, and this may open a new route to obtain elusive molecules.

The team of researchers are active at Chalmers University of Technology, Sweden; IBM Research Europe – Zurich, Switzerland; and CiQUS at the University of Santiago de Compostela, Spain. In a recent article published in the Journal of the American Chemical Society they demonstrate how, in a controlled manner, they can selectively remove a single oxygen atom from an organic molecule using the sharp tip of a scanning probe microscope.

Skeletal editing is a field of research that has rapidly emerged over the past few years. The idea in skeletal editing is to insert, delete or swap individual atoms from the core of molecules. An important context is drug discovery, which involves synthesising (that is, creating complex chemical compounds through chemical reactions of simpler starting materials) slightly different versions of a promising molecular skeleton to impact drug potency or toxicity. Skeletal editing could also be applied to modify polymer backbones, enabling the upcycling of plastics and helping reduce waste.

“We have demonstrated that it is possible to modify single molecules with atomic precision. The process is similar to an atomic Lego where selected atoms are removed or swapped,” says Henrik Grönbeck, Professor at the Department of Physics at Chalmers University of Technology.

Changing the molecular skeleton

The physicochemical properties of an organic molecule depend on two aspects. First, the molecule’s core, which is the set of linked atoms that define the molecular skeleton. Second, the presence of functional groups, which are atoms or a group of atoms situated at the periphery that are linked to the molecular skeleton.

It is relatively straightforward to induce changes at the molecular periphery (termed peripheral editing) by adding or modifying functional groups. For example, a molecular skeleton can be made soluble in water by installing hydrophilic functional groups at the periphery – something that is done routinely.

However, it is difficult to change the molecular skeleton itself once it is formed. In drug discovery, the difference between two versions of a molecular skeleton could sometimes be the presence or absence of just one atom. Driven by this problem, there is currently a large interest in skeletal editing, which enables insertion, removal or swapping of individual atoms at precise locations within a pre-formed molecular skeleton, thereby avoiding the need to synthesise a new skeleton from scratch each time.

Chemistry under the microscope

To achieve the removal of a single oxygen atom from an organic molecule, the team designed a precursor molecule whose skeleton contained twenty carbon atoms and one oxygen atom. The precursor molecules were then sublimed under ultrahigh vacuum onto a copper surface covered by two-atom thick films of sodium chloride and housed inside a combined scanning tunneling and atomic force microscope apparatus operating at a temperature of –268 °C.

The team then zoomed onto single precursor molecules and by applying voltage pulses through the tip of the microscope, they could controllably remove the oxygen atom from the core – leaving the carbon atoms intact and resulting in the formation of a different skeleton. This atom ‘deletion’ constitutes one of the fundamental classes of skeletal editing reactions. By imaging the product molecules with atomic resolution, the team further discovered that in most cases the ‘deleted’ oxygen atom went from the skeleton to the periphery, while in few cases, the oxygen atom was completely removed. Moreover, the team explained the mechanism and selectivity of the reaction using quantum mechanical calculations.

A powerful route to synthesise single molecules

“The results have uncovered a powerful route to synthesise single molecules with atomic precision,” says Shantanu Mishra, Assistant Professor at the Department of Physics at Chalmers University of Technology.

The team also expects that the precision with which specific atoms can be removed could be used to locally modify the chemical and electronic properties of organic nanostructures.

“By combining tip-induced atom deletion and the cold, confining and ultrahigh vacuum environs of the microscope, we plan to synthesise and study elusive molecules that are too unstable to be prepared by solution-phase chemistry,” continues Shantanu Mishra.