The desire to perform chemical synthesis quickly and without tedious manual manipulations has long driven the development of automated chemical synthesizers. In a paper in Nature, Chatterjee and colleagues1 report an automated approach that they describe as radial synthesis. In their system, individually accessible compartments for performing reactions are arranged around a central hub that coordinates reagent delivery, product sampling and chemical analysis, and the temporary storage of compounds produced as intermediates. The authors’ approach not only promises to reduce manual manipulation, but also eliminates the need to customize a synthesizer for each target molecule.

Read the paper: Automated radial synthesis of organic molecules

The synthesis of structurally complex organic molecules is the first task in the discovery of functional compounds needed for new technologies, including those in medicine and flexible electronics. Starting with relatively simple, purchasable reactants, the process involves sequences of chemical reactions in which the complexity of the molecules produced gradually increases with each step towards the final target. The sequences can be linear, or convergent (different parts of the target molecule are made in separate sequences and then joined together). To ensure that large amounts of the final product are prepared, each synthetic step must be high-yielding and reproducible, and must generate few side products.

Conventional chemical synthesis is performed ‘in batch’ (in a flask). However, this requires multiple manual interventions from chemists to prepare, run and stop each reaction, and to isolate the desired product from any by-products that cannot be tolerated in subsequent steps. An approach known as flow chemistry2 has therefore been developed to address this problem. Flow chemistry can also increase the productivity of synthetic routes compared with batch procedures, and is safer for syntheses that involve potentially hazardous components.

In flow chemistry, a continuous stream of reactants is pumped through a heated or cooled reactor (typically, a tube) to form the product. To carry out multistep synthesis, multiple reactor units are usually connected in series, so that the output of one reactor becomes — along with any further reagents — the input to the next (Fig. 1a). In-line separation systems can be added to purify intermediate compounds or to switch solvents.

Figure 1 | Linear and radial flow systems for chemical synthesis. a, Multistep routes for synthesizing organic molecules can be carried out in a continuous flow of solvent. A solution of reagents is typically passed through a series of reactors; further reagents are introduced as needed. A different reaction occurs in each reactor, the product of which becomes the input for the next reactor. A solution of target molecules is produced as the output of the flow system. However, reactors and other modules in these systems often need to be manually replaced to optimize the platform for each synthetic route. b, Chatterjee et al.1 report a flow platform in which a central hub is surrounded by individually accessible reactors. The hub coordinates reagent delivery to the reactors in any sequence, thereby allowing the most suitable reactor to be used for any particular reaction (black dots indicate ports through which solutions are passed from or to the hub). This removes the need to customize the system manually for each synthetic route.

The mass flow must be balanced so that the flow exiting each reaction or separation step equals the sum of the input flows from the previous step and from any added reagents and solvents, minus any diverted streams (which occur when compounds are extracted from one solvent into another). This mass-flow constraint means that different reactor types and volumes are needed to achieve the best-possible product yield in each step: slow reactions require large reactors, whereas fast reactions need small reactors.

Because reaction rates increase with temperature, flow-reactor temperatures can sometimes provide flexibility in the choice of reactor sizes. For example, high temperatures can make relatively slow reactions fast enough to enable the use of a small reactor. However, high temperatures can also promote side reactions, including those that cause decomposition of the desired product. Therefore, the need to balance mass flow often dictates a specific sequence of reactor volumes and temperatures for a particular multistep synthesis. This, in turn, means that the platforms used for flow chemistry must be reconfigured — reactors must be replaced with others that are more appropriately sized — for each new target molecule, decreasing flexibility and increasing the development time (the time needed to optimize the platform and chemistry for each new synthesis).

Chatterjee and colleagues’ radial synthesizer is designed to overcome this issue. A master controller in the central hub of their system uses multi-positionable valves to direct reagents to different reactor modules around it (Fig. 1b), so that each reaction in a synthesis can be performed at optimal conditions — for example, at the best temperature and concentration of reagents, and in the most appropriate reactor type. The effluent from each reactor returns to the central hub for in-line analysis and subsequent distribution to the next synthesis step, which could be in the same reactor unit or in a different one. This process repeats for each reaction step until the target molecule has been synthesized (in three steps, for most of the examples reported by Chatterjee and co-workers).

The system allows both linear and convergent synthesis — in the latter case, intermediate products are stored and then joined together in the final step. But the key advance of Chatterjee and colleagues’ radial synthesizer is that it decouples the steps by directing reagents to an appropriate module for each reaction, independently of the other steps. This eliminates the mass-flow constraints and the need to reconfigure the platform for different synthetic sequences, reducing the development time.

The need to store intermediate compounds produced from different steps until they are required for the next reaction increases the overall process time and the total volume of the flow platform, compared with linear sequences in conventional flow synthesis. The longer process times are likely to be offset by the shorter development times when synthesizing many different compounds in laboratory quantities (milligrams to grams). However, longer process times could be a disadvantage in the commercial synthesis of individual organic compounds, for which productivity per unit volume of the flow system matters.

The need to store intermediates also limits applications in which the intermediates are potentially hazardous — a disadvantage compared with conventional flow-chemistry platforms, which contain only small amounts of intermediates at any given time. For such cases, the radial synthesizer would need to be configured without interim storage and to have a short transfer time between successive reactor units, effectively creating a conventional linear system.

A cure for catalyst poisoning

Previously reported automated synthesis platforms have been designed so that standardized reactors and other modules (such as those used for extractions) can be easily plugged into and taken out of reconfigurable linear sequences by hand, enabling simple customization for different syntheses3,4. More recently, a system has been reported5 in which machine learning is combined with a chemist’s expert knowledge to plan the synthesis of a target compound. The synthesis is automatically converted into a robotically assembled flow system that prepares the compound. Automated multistep reaction sequences can also be carried out in robotically controlled batch reactors integrated with liquid handlers, purification and analytical systems6. And a robotic system that uses conventional laboratory apparatus, such as round-bottomed flasks, and which uses a standardized approach (the ‘chemputer’) to translate chemical-synthesis methods into physical operations, was reported last year7.

Such automated systems ensure reproducibility, because a given instruction set for a synthesis will be carried out in exactly the same way on an identical system at another location, assuming that the input materials are of the same quality. Furthermore, these systems make it feasible for potentially dangerous compounds, such as potent pharmaceuticals or radioactively labelled compounds used for medical diagnostics, to be made without exposure to humans. Automated systems could also be used to generate reaction data — such as the reagents used, yields and conditions — for machine learning in organic chemistry. However, this will require further miniaturization of existing systems, which are currently too large, and therefore too slow to produce sufficient data (equivalent to tens of thousands of experiments) in a useful time frame (weeks) to enable machine learning. Modules for analysing reactions will also need to be incorporated into flow systems to produce such data.

Chatterjee and co-workers’ radial synthesizer and other automated platforms go a long way towards eliminating tedious manual operations from chemical synthesis. Nevertheless, challenges remain, particularly in the handling of solids — whether solid reagents or solids formed during reactions. Solids can be suspended in slurries by stirring reaction vessels, but the transfer of slurries through tubes (or even more problematically, through valves) leads to clogging.

Another problem is how to seamlessly integrate purification, isolation and analytical procedures. Robotic systems and the radial synthesizer offer opportunities to develop hybrid platforms that integrate the best elements of flow and batch technologies with purification and analytical methods. This would enable automated synthesis that incorporates state-of-the-art reactions and can produce more-complex molecular structures than have been achieved so far. As the hardware matures, the emphasis will shift to developing the control and artificial-intelligence infrastructure necessary to generate and implement chemical syntheses5 — freeing chemists from carrying out routine procedures, so that they can focus on discovering new chemical reactions.