Selectivity in tip-induced skeletal editing via heteroatom substitution

arXiv:2606.22677 · cond-mat.mes-hall · Submitted 2026-06-21 · Read on arXiv

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Introduction to the show: ident: Quantum Radio. Generated commentary on the latest quantum physics and condensed matter papers.

Kai: Today's paper: "Selectivity in tip-induced skeletal editing via heteroatom substitution".

Mira: Skeletal editing enables precise structural modifications of molecules at late stages of a synthetic sequence, with applications in drug discovery and materials science.

Kai: First, who's behind it and why it matters.

Paper summary: Kai: To summarize this paper, "Selectivity in tip-induced skeletal editing via heteroatom substitution," the main idea is that you can perform precise structural modifications to molecules at a late stage of synthesis by using a scanning probe tip. They claim that the key to controlling *which* atom gets edited lies in choosing the right heteroatom within the molecular skeleton.

Mira: The paper explores skeletal editing, which involves inserting, deleting, or exchanging individual atoms in a molecule's structure. What they specifically investigate is whether this can be done reliably at the single-molecule level through tip-induced chemistry. They focus on dinaphtho

eighteen-bc:one',eight'-ef: oxepine (DNO) and its sulfur analog, DNT, to test this concept <ref:2606.22677#pg1,dinaphtho 1,8-bc:1',8'-ef oxepine (DNO>.

Lev: From a researcher's viewpoint, the significance lies in overcoming the limitations of solution-phase chemistry when it comes to achieving highly specific molecular modifications. If you can target an individual molecule with a tip and control the outcome atom by atom, that capability becomes incredibly valuable for designing complex functional units.

Kai: Exactly. The paper shows that by comparing DNT and DNO, they found a strong preference for sulfur deletion when using this method on a specific surface setup involving bilayer NaCl films. This isn't just about making a product; it’s about demonstrating control over the reaction pathway based on the chemical makeup of the molecule itself.

Mira: The paper claims that tip-induced reactions of DNT predominantly lead to sulfur deletion, accounting for ninety-four percent of successful reactions, which is a high degree of selectivity compared to other possible outcomes like ring-contraction rearrangement <ref:2606.22677#pg0>. This selectivity is theoretically supported by DFT calculations showing lower activation barriers for the sulfur elimination pathway.

Lev: If the DFT data holds up under experimental conditions, it suggests that this method offers a predictable mechanism for structural manipulation, which would be a huge plus when trying to scale up any molecular assembly process, even if only for small units initially.

Kai: So, essentially, they’re proving that combining tip-induced chemistry with careful heteroatom selection gives us a tool capable of achieving single-molecule skeletal editing with atomistic precision. This moves the field forward by showing a new way to access elusive molecular structures directly.

Mira: It matters because it shows how fundamental structural decisions—like which atom is removed—can be dictated by the system's inherent chemistry, rather than just brute-force reaction conditions in solution chemistry. It provides a blueprint for designing targeted molecular transformations.

Conclusion: Kai: Reflecting on "Selectivity in tip-induced skeletal editing via heteroatom substitution," it really comes down to this: they’ve established a powerful method for making specific atomic deletions on molecules at the single-molecule scale by cleverly choosing the heteroatom involved. The authors, including Mishra, Svensson, Malave, Albrecht, VilasVarela, Grönbeck, Gross and Peña—they’ve mapped out how to use tip chemistry to achieve this level of atomistic control.

Mira: Their implication is that we can design molecular scaffolds with pre-determined structural features by controlling the reaction based on the heteroatom's nature. This means we are no longer limited to synthesizing molecules through sequential chemical steps where you hope for a certain outcome; instead, we dictate the structure during the reaction itself.

Lev: For error correction researchers like myself, this is intriguing because it suggests a pathway to creating molecular components with highly tailored electronic properties from scratch, which could be useful in designing next-generation quantum systems that need extremely specific structural configurations.

Kai: Right. It’s about realizing that we can use the probe to guide the chemistry toward a very specific structural change, rather than just observing what happens in a bulk solution. This capability speaks to accessing molecular complexity with unprecedented control over structure and composition.

Mira: The core implication is shifting the focus from synthesizing molecules entirely through chemical reactions to selectively modifying existing molecular frameworks using localized, controlled probes like this tip-induced chemistry. This opens up new avenues for targeted material design and drug discovery applications where precise structural changes are needed.

Lev: If we can reliably execute these kinds of atom-specific manipulations, it means we might be able to engineer molecular architectures with properties that are optimized for specific physical tasks, which is exactly what we need when designing functional components for hardware.

Kai: So the takeaway from this paper is that this work validates a method where the combination of tip-induced chemistry and heteroatom selection allows for selective and atomically precise skeletal editing of carbon frameworks. It’s a demonstration of powerful control over molecular structure at the single-molecule level.

Department of Physics and Astronomy, Chalmers University of Technology · Competence Centre for Catalysis, Chalmers University of Technology · Center for Research in Biological Chemistry and Molecular Materials, and Department of Organic Chemistry, University of Santiago de Compostela · IBM Research Europe – Zurich · Oportunius, Galician Innovation Agency

cond-mat.mes-hall

Submitted: 2026-06-21

Updated: 2026-06-21

Comments: Manuscript: 8 pages and 4 figures; Supporting Information: 10 pages and 11 figures

DOI: 10.1021/jacs.6c12567

License: http://creativecommons.org/licenses/by/4.0/

Importance score: 77/100

The gist: Skeletal editing enables precise structural modifications of molecules at late stages of a synthetic sequence, with applications in drug discovery and materials science.

Key concepts

Skeletal Editing: This involves making precise changes to a molecule's structure by adding, removing, or exchanging individual atoms at late stages of synthesis. It aims to create specific molecules without needing to synthesize the entire structure from scratch, which is useful for drug discovery.
Tip-Induced Chemistry: This technique uses the sharp tip of a microscope (STM/AFM) to deliver precise energy or chemical reactions directly onto single molecules adsorbed on a surface. This allows chemists to perform chemistry on a single molecule rather than in bulk solution, enabling single-molecule control over reactions.
Heteroatom Selection: This refers to the strategic choice of which atom within a molecule (like sulfur or oxygen) is targeted for deletion during skeletal editing. The study showed that selecting sulfur leads to atom deletion, while oxygen leads to different outcomes like ring contraction.
DFT Calculations: Density Functional Theory calculations are used as a theoretical tool to predict reaction pathways and energy barriers between different chemical possibilities (like deleting sulfur versus oxygen). These calculations confirmed why sulfur deletion is favored in DNT over oxygen deletion.

Terminology

Core — 11× in this paper · explained in 2 episodes
Density Functional Theory — 7× in this paper
Ab Initio — 6× in this paper · explained in 1 episode
DFT Calculations — 5× in this paper · explained in 2 episodes
Density Functional Theory (DFT) — 2× in this paper · explained in 2 episodes
APEX — 1× in this paper · explained in 1 episode
Hysteresis — 1× in this paper · explained in 3 episodes

Summary

Skeletal editing enables precise structural modifications of molecules at late stages of a synthetic sequence, with applications in drug discovery and materials science. The tip-induced reactions of dinaphtho[1,8-bc:1',8'-ef]thiepine (DNT) adsorbed on NaCl predominantly lead to sulfur deletion, demonstrating that the combination of tip-induced chemistry and heteroatom selection is a powerful strategy for single-molecule skeletal editing.

The Core Concept

Skeletal editing refers to the late-stage modification of a molecular skeleton through insertion, deletion or exchange of individual atoms (Scheme 1a). This field is gaining attention as a means of reducing the need for de novo synthesis, and precise structural transformation of molecules, with potential applications in drug discovery, green chemistry, and materials science. Conventionally performed via solution-phase chemistry, extension to the single-molecule scale via tip-induced chemistry could enable the synthesis of elusive molecules. The central question addressed is whether selective skeletal editing of a heterocyclic core can be achieved by an appropriate choice of the heteroatom.

Experimental Setup and Observation

The study explored tip-induced reactions on dinaphtho[1,8-bc:1',8'-ef]oxepine (DNO) and its sulfur analog, DNT. DNT was synthesized via solution-phase chemistry and deposited onto a single-crystal Cu(111) surface partially covered by bilayer NaCl films. Individual molecules of DNT adsorbed on both Cu(111) and NaCl adopt a geometry where the sulfur atom points toward the surface. STM and AFM imaging revealed that for DNT adsorbed on bilayer NaCl, two diagonally-opposite benzenoid rings appear bright in AFM imaging due to their upward tilt, while the sulfur atom was not visible.

Reaction Selectivity via Heteroatom Choice

The key finding contrasts DNT with its oxygen analog, DNO. When voltage pulses were applied to individual DNT molecules adsorbed on bilayer NaCl at step edges of third-layer NaCl islands, Sulfur deletion was the predominant reaction in successful cases, accounting for 16/17 reacted molecules (94%). This resulted in the generation of perylene as the major product (14/17 cases, 82%), and in a minority of cases, perylenyl radical. Notably, there was no ring-contraction rearrangement observed for DNT, in contrast to DNO where it was the dominant reaction.

Theoretical Validation

To elucidate these experimental observations, gas-phase Density Functional Theory (DFT) calculations were performed comparing DNT and DNO. The calculations showed that the activation energy barrier for "chalcogen elimination from Int1 and Int2 for sulfur compared to oxygen, along with the similar ΔE‡ values for the reaction Int3 → P1 for sulfur and oxygen (the difference being only 0.12 eV), results in the high selectivity for atom deletion in DNT. This confirms that Perylene results from atom deletion and is the predominant product of tip-induced reactions of DNT."

Conclusion on Selectivity

The researchers conclude that they demonstrate that selective skeletal editing of a heterocyclic core can be achieved through a judicious choice of the heteroatom. By combining single-molecule scanning probe experiments and DFT calculations, they show that tip-induced reactions of dinaphtho[1,8-bc:1',8'-ef]thiepine adsorbed on NaCl predominantly leads to atom deletion, enabling selective and atomically precise skeletal editing of heteroatom-containing carbon frameworks at the single-molecule scale.

The gist

Tip-induced reactions of dinaphtho[1,8-bc:1',8'-ef]thiepine adsorbed on NaCl predominantly lead to sulfur deletion, demonstrating that the combination of tip-induced chemistry and heteroatom selection is a powerful strategy for single-molecule skeletal editing.

How it works

Voltage pulses are applied by the tip of a combined scanning tunneling microscope (STM) and atomic force microscope (AFM) to individual DNT molecules adsorbed on NaCl at stabilized step edges of third-layer NaCl islands.
The tip is retracted, and voltage is increased to trigger skeletal editing reactions, such as atom deletion.
DFT calculations are used to compare the reaction landscapes of DNT and DNO, showing that the lower C–S bond dissociation energy relative to the C–O bond promotes heteroatom deletion over ring-contraction rearrangement.
The resulting products, such as perylene, are characterized using STM (revealing LUMO density) and AFM imaging (showing structural changes like non-planarity in radical species).

How it works

The study compares the reaction outcomes of DNT (sulfur) versus DNO (oxygen).

Improvements for AI systems

Based on the scientific paper provided, here are specific improvements that could be made to AI systems, and what those improved systems could achieve:

The development of a more accurate predictive model for selective chemical reactions based on heteroatom substitution in molecular design.
The creation of an AI system capable of predicting whether a specific heteroatom (e.g., Sulfur vs. Oxygen) will favor atom deletion or ring-contraction rearrangement during tip-induced skeletal editing reactions on single molecules, given the molecular structure and surface environment (e.g., NaCl vs. Cu(111)).
The integration of Density Functional Theory (DFT) calculations directly into a generative AI framework to guide the design of molecules that are predisposed to a specific type of skeletal transformation (e.g., designing molecules with lower C–S bond dissociation energy to favor sulfur deletion).
The creation of an AI system for automated experimental planning that optimizes parameters (voltage pulses, tip retraction distances) for achieving a desired skeletal editing outcome (e.g., maximizing the yield of perylene formation and minimizing ring-contraction rearrangement).
The development of a high-fidelity image processing AI capable of distinguishing between different reaction products (e.g., perylene vs. pylenyl radical) based on subtle changes in surface topography, charge state bistability, and electronic structure signatures (LUMO density).

These improved AI systems can achieve the following:

The ability to rapidly screen vast chemical libraries to identify molecular scaffolds that are optimized for a desired single-molecule transformation (e.g., finding the ideal heterocyclic core for specific sulfur deletion).
The design of novel synthetic routes that bypass lengthy, traditional synthesis by predicting the precise, late-stage atomic surgery required to achieve a target structure directly.
The autonomous execution and refinement of single-molecule experiments, ensuring that experimental conditions are tuned in real-time to favor the desired reaction pathway (e.g., automatically adjusting voltage pulses until perylene formation is maximized).
The accurate identification and characterization of fleeting reaction intermediates or side products on a single molecule with high confidence, allowing for deeper mechanistic understanding of complex chemical processes at the single-molecule scale.

Abstract

Skeletal editing enables precise structural modifications of molecules at late stages of a synthetic sequence, with applications in drug discovery and materials science. We recently demonstrated skeletal editing on the single-molecule scale. Voltage pulses applied by the tip of a scanning probe microscope to an oxygen-containing seven-membered heterocycle led to both oxygen deletion and ring-contraction rearrangement reactions. An open question is whether selective skeletal editing of a heterocyclic core can be achieved by an appropriate choice of the heteroatom. Here, we show that tip-induced reactions of an analogous sulfur-containing seven-membered ring results in sulfur deletion in virtually all cases. Our results demonstrate that the combination of tip-induced chemistry and heteroatom selection in the molecular design is a powerful strategy for single-molecule skeletal editing, with the potential to enable diverse structural transformations of heterocyclic frameworks.