C3PU: An autonomous portable platform

Everything started back in 2012, a conference discussion resulted in the idea of 3D printing reactors where we can perform chemistry and potentially give us control over the reactivity. The term of reactionware was created. This blog was written by Hsin Wang with some edits from Lee Cronin.
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    C3PU: An autonomous portable platform
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But what is reactionware? Well, this concept has evolved over the years along with 3D printing capabilities and the groups’ expertise, going from simple reactors controlling the chemical outcome depending on their morphology1, through reactors with embedded catalysts2, all the way to linearly interconnected reactors for the multi-step synthesis of organic compounds3-8. So, I guess now we can define reactionware as “A series of discrete physical reactor modules that are designed to perform linear operations (filtration, evaporation, reaction, and separation) that result in the synthesis of the targeted molecule.” (Figure 1)

Figure 1. Reactionware timeline.

But what is the downside of these systems? (Hint: It is not 3D printing them!) Reactionware still requires manual intervention despite its convenience of miniaturizing laboratory glassware.

Now, how do we solve this problem? Exactly! Automate it!!!!

Nowadays, it is not surprising to have robotic systems in labs anymore, but it is still a developing field, so platforms can be limited, specific for some types of chemistry, and/or they can occupy a large amount of space. In addition, the systems must be run by dedicated personnel for hardware, software, and not to mention chemical handling – all of which must occur in highly specialised laboratory environments, and yet these systems are nowhere near able to tackle general batch chemistry and often produce unpurified materials.

If only there was a way to minimize space (compact), synthesize molecules from code (chemputation) in a single unit?

Well, it seems that reactionware fits these requirements, and that is how C3PU (Compact, Chemputing, Chemical processing unit), a portable system that could synthesize known molecules anywhere, on-demand, and in a fully automated way was born. C3PU uses χDL (a Chemical Description Language)9-11 coupled ChemSCAD3 (python code to generate reactionware systems) to produce a reactor and executable files based on literature procedures.

All the reaction processes that are already telescoped into reactionware monoliths can be operated in C3PU, where the platform only requires to minimal operations like heat, cool, and liquid handling. However, to control the liquid transfer within the reactors, a manifold, along with a pressure sensor were implemented. For every operation (filtration, transfer, evaporation) we can track any pressure change to detect if it the process been completed.

We used C3PU to prepare five different active pharmaceutical ingredients (APIs: phenelzine sulphate, an antidepressant drug; isoniazid, an antibiotic drug for tuberculosis; dihydralazine, an antihypertensive drug); lomustine, an alkylating agent used in chemotherapeutic cancer treatments; and umefenivor, an antiviral medication for the treatment of influenza), 4 oligonucleotides, and 4 oligopeptides in good yield and purity.

C3PU can hold up to 32 reagents/solvents at the same time, so we can pre-load all the precursors needed for the synthesis of multiple APIs such as phenelzine sulphate, lomustine, isoniazid, and dihydralazine (Figure 2). In this way, to prepare all targets, the only change in between the synthesis is loading a new reactor without any platform reconfiguration.

The automation of reactionware contains the process of a complete synthesis procedure solving the problem of minimizing human inputs and space. This is what we call lab in a C3PU! The number of chemical syntheses a C3PU can perform, is time saved for focusing the work on a different task. The portability of C3PU implies that we can access molecules not only on-demand, but also on-site.

Of course, there is room for improvement, and we are currently working on it, but for now C3PU is the only compact platform capable of doing a wide range of chemistries, comparable to big, expensive platforms. All of this is possible thanks to the reactionware systems, but maybe it is time to move away from plastic prototypes into glassware analogues. (Figure 2)

Figure 2. Various reactionware cartridge used for different synthesis and the graph for each connection.

References

  1. Symes, M. D.; Kitson, P. J.;  Yan, J.;  Richmond, C. J.;  Cooper, G. J. T.;  Bowman, R. W.;  Vilbrandt, T.; Cronin, L., Integrated 3D-printed reactionware for chemical synthesis and analysis. Nature Chemistry 2012, 4 (5), 349-354.
  2. Kitson, P. J.; Symes, M. D.;  Dragone, V.; Cronin, L., Combining 3D printing and liquid handling to produce user-friendly reactionware for chemical synthesis and purification. Chemical Science 2013, 4 (8), 3099-3103.
  3. Hou, W.; Bubliauskas, A.;  Kitson, P. J.;  Francoia, J.-P.;  Powell-Davies, H.;  Gutierrez, J. M. P.;  Frei, P.;  Manzano, J. S.; Cronin, L., Automatic Generation of 3D-Printed Reactionware for Chemical Synthesis Digitization using ChemSCAD. ACS Central Science 2021, 7 (2), 212-218.
  4. Kitson, P. J.; Glatzel, S.;  Chen, W.;  Lin, C.-G.;  Song, Y.-F.; Cronin, L., 3D printing of versatile reactionware for chemical synthesis. Nature Protocols 2016, 11 (5), 920-936.
  5. Kitson, P. J.; Marie, G.;  Francoia, J.-P.;  Zalesskiy, S. S.;  Sigerson, R. C.;  Mathieson, J. S.; Cronin, L., Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals. Science 2018, 359 (6373), 314-319.
  6. Kitson, P. J.; Marshall, R. J.;  Long, D.;  Forgan, R. S.; Cronin, L., 3D Printed High-Throughput Hydrothermal Reactionware for Discovery, Optimization, and Scale-Up. Angewandte Chemie International Edition 2014, 53 (47), 12723-12728.
  7. Lin, C.-G.; Zhou, W.;  Xiong, X.-T.;  Xuan, W.;  Kitson, P. J.;  Long, D.-L.;  Chen, W.;  Song, Y.-F.; Cronin, L., Digital Control of Multistep Hydrothermal Synthesis by Using 3D Printed Reactionware for the Synthesis of Metal–Organic Frameworks. Angewandte Chemie International Edition 2018, 57 (51), 16716-16720.
  8. Zalesskiy, S. S.; Kitson, P. J.;  Frei, P.;  Bubliauskas, A.; Cronin, L., 3D designed and printed chemical generators for on demand reagent synthesis. Nature Communications 2019, 10 (1), 5496.
  9. Hammer, A. J. S.; Leonov, A. I.;  Bell, N. L.; Cronin, L., Chemputation and the Standardization of Chemical Informatics. JACS Au 2021, 1 (10), 1572-1587.
  10. Wilbraham, L.; Mehr, S. H. M.; Cronin, L., Digitizing Chemistry Using the Chemical Processing Unit: From Synthesis to Discovery. Accounts of Chemical Research 2021, 54 (2), 253-262.
  11. Mehr, S. H. M.; Craven, M.;  Leonov, A. I.;  Keenan, G.; Cronin, L., A universal system for digitization and automatic execution of the chemical synthesis literature. 2020, 370 (6512), 101-108.

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