Automated Organic Synthesis Goes Radial

Automated synthesis has become a routine task in many organic chemistry laboratories. Automated platforms combine, react, and even purify and analyze chemicals, all without human involvement. For syntheses with several reaction steps, this works best with continuous flow systems where the reagents flow through a series of tubular reactors until the final product leaves the machine. This linear design is now being challenged by a new, radial platform type. This design adds loops, is more flexible, and overcomes drawbacks such as relying on a constant flow rate or volume limitations.

Everything Flows …

Automation means chemists don’t have to perform their reactions manually. The researcher does the planning and configuring, but most of the benchwork is left to the machine. Flow systems, the most common type of automated synthesizers, consist of a continuous tube with inflow and outflow valves. Inside this tube, the reagents linearly flow through a series of internal reactors, much like food being processed as it passes through our various digestive organs. Of course, the end product of chemical synthesis should be a pure chemical compound; food digestion has a different purpose.

Linearity has the advantage that, once the stage is set and the reaction started, the synthesis will proceed continuously in a fixed order, and it is relatively easy to play around with parameters such as temperature, dilution, catalyst, or sequence of steps. With that being said, however, it is not easy to change the duration of individual reactions, the volume or mass of the intermediates, the individual flows, or even just to repeat some reaction steps.

With all that in mind, Kerry Gilmore and colleagues from the Max-Planck-Institute of Colloids and Interfaces, Potsdam, Germany, have come up with a different design. Instead of pushing the flow in only one direction, they installed a hub, which they called central switching station (CSS), and all the flows run through this.

… and Flows Back to the Reactor

With this construction, only a very small number of reactors are needed because the reagent stream can run in circles. The CSS may guide the products of one reaction to another section called reagent delivery system (RDS), where they are stored while something else is undergoing reaction in the reaction vessel. The products from this reaction may be combined with the products of the first reaction, going on to the next reaction step in the same reactor, but under different reaction conditions.

The researchers demonstrated the operability of the radial synthesizer by comparing two routes for synthesizing the antiepileptic drug rufinamide, a benzylic triazole derivative. One was a linear three-step procedure from a fluorinated benzyl bromide, the other a convergent process where the fluorinated benzyl bromide and methyl propiolate are transformed independently to intermediate products, which are then combined to give the final product.

The radial synthesizer could perform both routes, but the scientists found that the convergent route was easier to optimize and provided a higher yield. Such a convergence could not be achieved with a linear synthesizer. The researchers also used the radial synthesizer to create a small library of rufinamide derivatives.

The study shows that the radial design is more versatile than the usual linear systems. It means one reaction vessel can be used multiple times in one reaction sequence, under different conditions. This is useful, for example, to build up a larger volume or mass of one intermediate or simply to add molecular units to a growing chain like in biopolymer synthesis.

One disadvantage, however, is that multistep synthesis takes more time using this radial method than using linear systems. In the linear system, the synthesis proceeds at a constant speed, whereas in the radial one, intermediates are left to wait in the storage unit until the reactor is free again—similar to the way ruminants push their cud back into their mouths. While the cow is chewing the cut, it cannot eat more. This disadvantage means that while radial architecture adds some intriguing new options to automated synthesis, it will be a while before it can replace linear systems.