Later, in , Alan Bard filed a US patent priority where it is taught how an integrated chemical synthesizer could be constructed from a number of microliter-capacity microreactor modules, most preferably in a chip-like format, which can be used together, or interchangeably, on a motherboard like electronic chips , and based upon thermal, electrochemical, photochemical, and pressurized principles [12].
Following this, a pioneering experiment conducted by Salimi-Moosavi and colleagues introduced one of the first examples of electrically driven solvent flow in a microreactor used for organic synthesis.
An electro-osmotic-controlled flow was used to regulate mixing of reagents, p -nitrobenzenediazonium tetrafluoroborate AZO and N,N -di-methylaniline, to produce a red dye [13]. One of the first microreactor-based manufacturing systems was designed and commissioned by CPC in for Clariant [14]. Microreactor systems have since evolved from basic, single-step chemical reactions to more complicated multistep processes. Belder et al. The microfluidic chip fabricated from fused silica as seen in Figure 1.
The authors reported a separation of enantiomers within 90 s, highlighting the high throughput of such devices. The chip was the first example of synthesis, separation and analysis combined on a single device. Source : Photograph courtesy of Professor D. Belder with permission. Early patents in microreactor engineering have been extensively reviewed by Hessel et al. From to , the number of research articles published on microreactor technology rose from 61 to per annum Figure 1.
The number of patent publications produced was also highest in the United States of America; the data are given in Figure 1. The number of patent publications is highest in the field of inorganic chemistry, but of particular interest, organic chemistry comes second out 18 fields of chemical applications investigated [16].
Source : Images reprinted from Ref. Microreactor technology has been widely employed in academia and is also beginning to be used in industry where clear benefits arise and are worthy of new financial investment. To place microreactors clearly within an historical context, we can relate the emergence of such devices to their nearest neighbors, these being from the wider field of microfluidics, which includes the flow of gases. Schmidt, H. Gebauer, H.
Conference on Catalysis, , Grenada, Spain; d R. Maurer, C. Claivaz, M. Fichtner, K. Schubert, A. Ketalization reaction of cyclohexanone. Mayer, M. Fichtner, D. Wolf, K. Ehrfeld, Springer, Berlin, Germany, , wide universe of chemical reactions.
In Acknowledgement p. Tonkovich, J. Zilka, many cases better yields and higher selec- The authors would like to thank their col- M. Powell, C. We elsewhere aims at unraveling and exploit- turization: 2nd International Conference are most grateful for the following research ing steeper energy gradient synthesis Preprints, Eds.
Ehrfeld, I. Another part of [3] a E. Ditzsche, D. Fichtner, development and manufacturing of func- the ongoing research that is partially reported K. Schubert, G. As the technology was herein is funded by the Deutsche Bundesstiftung Umwelt. Walter, E. Joannet, M. Schiel, I.
Kanazawa, T. Tokoroyama, Synthesis Boullet, R. Phillips, M. Woodward, Pure Appl. Buu-Hoi Ng, J. Katritzky, Adv. Kah, D. Armstrong, J. Beau, S. Cheon, [31] B. Shull, T.
Sakai, J. Christ, H. Fujioka, W. Ham, L. Jin, S. Kang, Y. Kishi, M. McWhorter, M. Nakata, A. Stutz, F. Talamas, M. Ley, I. Tino, K. Ueda, J. Uen- , 1, May 27—30, , Strasbourg, France, p. White, M. Yonaga, J. Zheng, F. Jones, J. Fang, T. Cui, Soc. Kleemann, J. Engel, B.
Kutscher, D. Corey, Angew. Seebach, Angew. Schiewe, W. Ehrfeld, V. Haverkamp, V. Hessel, H. Wille, M. Altvater, R. Trost, Angew. Rietz, R. Morrison, R. Krummradt, U. Kopp, J. Watts, C. Haswell, E. Microreaction Technology, Proceedings of Fletcher, S. Ehrfeld, Springer, B. Warrington, P. Watts, S. Wong, Berlin, Germany, Germany, , p. Zhang, Tetrahedron , 58, Schwalbe, K. Sahin, Scaling in chemi- plus , 4, 28; c V.
Richter, A. Haswell, R. Middleton, B. O'Sulli- Wolf, Chem. Watts, P. Styring, [6] V. Skelton, G. Greenway, S. Haswell, Chem. Styring, D. Morgan, S. Becker, G. Domschke, E. Fischer, K. Gewald, R. Mayer, D. Pavel, H. Schmidt, K. There are phenomena in this reaction that prevent complete conversion to complete by a long way, probably azide-consuming side reactions or lack of activity of the substrate, lack of acid catalysis, or a combination of these reasons.
Additionally, the substitution pattern of the substrates led to an unexpected outcome of the reaction. Procedure I [ 23 ]: Sodium azide mmol, 13 g was dissolved in water 30 mL. Then tetrabutylammonium hydroxide mmol, 26 g was added and the mixture was stirred at room temperature for 90 min. Dichloromethane 50 mL was added and stirring was continued for 10 min. The organic layer was separated and dried over magnesium sulfate. Finally the solvent was removed under reduced pressure and the product was dried for 24 h under vacuum.
Procedure II [ 24 — 25 ]: Sodium azide 79 mmol, 5. Dry THF 70 mL was added and stirring continued for 15 min. The reaction mixture was filtered and the solvent in the filtrate was removed under reduced pressure. The product was heated under vacuum for 2 h to remove some DMF. Yields for these reactions cannot be given as the solvents could not be removed completely from the product.
A twin syringe pump KDSCE was charged with two 5 ml Hamilton syringes, one containing tetrabutylammonium azide 3 mmol, mg in dry acetonitrile 3. The outlets were connected by standard HPLC tubing to a T-junction, after 30 cm tubing a second T-junction was connected to the third syringe containing the substrate aldehyde 1 mmol in dry acetonitrile 2. The third syringe was loaded on a separate syringe pump.
The flow rate was adjusted to an overall flow rate of 7. The source of heating for the reaction was a PEG oil bath. The combined organic phases were separated, dried over magnesium sulfate and the solvent removed under reduced pressure. Phenylcarbamoyl azide 4a 0. Then n -BuLi 0. After the addition the cooling bath was removed and the flask was allowed to warm to r.
Then ethylacetate 60 mL was added, the organic layer separated and dried over magnesium sulfate. Yield: 14 mg quant.
We thank Dr. Robert Richardson, Cardiff University, for discussions and for performing the calculations. National Center for Biotechnology Information , U. Beilstein J Org Chem. Published online Jun Johan C Brandt 1 and Thomas Wirth 1. Find articles by Johan C Brandt. Find articles by Thomas Wirth. Andreas Kirschning, Guest Editor. Author information Article notes Copyright and License information Disclaimer. Corresponding author.
Thomas Wirth: ku. Received Mar 23; Accepted Jun 4. This article has been cited by other articles in PMC. Abstract Aromatic aldehydes have been converted into the corresponding carbamoyl azides using iodine azide. Keywords: azide, flow chemistry, hazardous reagents, microreactor, rearrangement. Introduction Microstructured devices have already found their way into organic synthesis, because they offer various advantages over traditional large-scale chemistry performed in flasks or vessels [ 1 — 2 ].
Results and Discussion The radical addition of azide to aldehydes 1 initially forms acyl azides 2 which directly rearrange in a Curtius rearrangement to the corresponding isocyanates 3.
Open in a separate window. Scheme 1. Azide addition to aldehydes and formation of carbamoyl azides.
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