From Synthesis Pathways to Digital Lab Execution: An Overview of Closed-Loop Automation
In many research laboratories, a gap persists between planning a synthesis and executing it. Traditionally, chemists design routes on paper, conduct experiments manually, and analyze results to determine next steps. This segmented workflow introduces delays and inconsistencies. Closed-loop automation seeks to eliminate these gaps by creating a continuous cycle of design–make–test. By tightly integrating artificial intelligence (AI) for planning with robotic equipment for synthesis and analysis, autonomous laboratories can conduct iterative experiments with minimal human intervention. The ultimate vision is a self-driving chemistry lab: given a target molecule, the system designs a pathway, executes it in hardware, evaluates outcomes, and updates its plan in rapid succession.
From Digital Pathway to Physical Experiment
At the core of closed-loop automation lies retrosynthesis software. Tools such as SYNTHIA® can propose detailed reaction sequences to reach a target molecule. The challenge is translating this digital plan into machine-executable instructions, and though automated synthesis platforms narrow the gap—bringing users closer to closed loop integration—human intervention is still required to review the pathway and establish individual reaction steps for execution by the automated synthesis platform.A notable example is the linkage between SYNTHIA and the Synple automated synthesizer. In this setup, SYNTHIA generates a route that specifies building blocks and reactions, while Synple—a benchtop cartridge-based robot—executes the steps with minimal manual involvement.
This integration exemplifies how digital and physical systems can merge. The software provides a network of viable routes and a human operator decides which to carry out; directing a robot to do so. It is important to note that Synple does not carry out a selected pathway but a single reaction at a time with human intervention between each step.
By linking planning and execution, the time between molecular design and laboratory testing is significantly reduced.
Benefits of Closed-Loop Automation
When retrosynthesis output flows directly into robotic execution, several advantages emerge:
- Faster turnaround: Automated systems can run reactions continuously, including overnight, and perform immediate analysis, accelerating exploration of chemical space.
- Consistency and reproducibility: Robots follow instructions exactly, reducing human error and ensuring standardized outcomes.
- Reduced hands-on labor: Case studies demonstrate dramatic reductions in manual effort. In one two-step synthesis, manual execution required 7.25 hours, whereas the automated route took only 0.5 hours of active time—a 93% reduction—with comparable yields (~49% vs 46%). In another example, the working time was reduced by 61% for a more complex molecule, while maintaining efficiency.
These results highlight how closed-loop automation not only accelerates discovery but also frees chemists from routine tasks, allowing them to focus on strategic experimental design.
Real-Time Data and Feedback
A defining feature of closed-loop systems is their ability to learn from outcomes. After each reaction, results are analyzed—commonly with techniques such as LC/MS or NMR—to determine product identity and yield. If a reaction fails or delivers suboptimal performance, the AI can revise the pathway, selecting alternative reagents or routes. In advanced implementations, robotic systems perform real-time optimization by inserting condition screens between steps, improving yields before advancing.
This feedback-driven cycle creates a self-correcting loop. Each round of experimentation informs the next, leading to increasingly effective synthetic strategies. Platforms such as SynFini, developed by SRI International, already demonstrate this adaptive capacity by optimizing conditions on the fly.
Synthia and Closed-Loop Automation
SYNTHIA® is well suited for closed-loop workflows because it allows chemists to tailor retrosynthetic outputs for automation. For example, if an automated platform specializes in certain reaction types, SYNTHIA can prioritize those in its proposed routes. The software outputs detailed reagent lists and conditions, which can then be translated into robotic instructions.
Merck has reported that integrating SYNTHIA with Synple created a “groundbreaking solution that streamlines the synthesis process, significantly reducing time and effort while enhancing precision and efficiency.” This capability enables workflows where design, execution, and evaluation occur seamlessly, moving toward a truly digital laboratory.
Closing Thoughts on Closed-Loop Automation
Closed-loop automation represents a significant shift in how chemistry is practiced. By connecting retrosynthesis planning tools with robotic execution and real-time feedback, laboratories can operate in a continuous design–make–test cycle. This approach reduces manual labor, improves reproducibility, and accelerates discovery. As platforms like SYNTHIA continue to integrate with automated synthesizers, the concept of the self-driving chemistry lab moves closer to reality—empowering scientists to focus on innovation while letting machines handle execution and analysis.
References
- Chen, J.; Xu, Q. Artificial intelligence-driven autonomous laboratory for accelerating chemical discovery. Chem. Synth. 2025, 5, 76. https://dx.doi.org/10.20517/cs.2025.66
- Gao W, Raghavan P, Coley CW. Autonomous platforms for data-driven organic synthesis. Nat Commun. 2022 Feb 28;13(1):1075. doi: 10.1038/s41467-022-28736-4
- SelectScience. Automated synthesis with SYNTHIA retrosynthesis software.
