Esperanza de vida sana

to be directly transferred into the next (fl ow) reactor. With the cyanohydrin synthesis, we were the fi rst to report on a two-step fl ow process in which a biphasic mixture containing an enzyme lysate was successfully separated.

7.2. Considerations and limitations

Part of the challenges encountered in multistep fl ow synthesis, like solvent incompatibilities and intermediate purifi cation, were successfully addressed in a few illustrative examples. The issues of dilution eff ects and fl ow rate control, however, still remain. One possible (partial) solution to excessive dilution might be the distillation device

as described by Hartman et al.7,8 _{Although this module was only reported for replacing}

low boiling for high boiling solvents, excess solvent could potentially also be removed. Flow rate control on the other hand will always be a challenge since for each additional reaction step, a fl ow of reagents or building blocks has to be pumped into the system. With a fi xed channel length, this means that the second reaction has to be completed in shorter residence times compared to the fi rst reaction. Alternatively, when elongating the channel to obtain suffi cient residence times, pressure drop problems will be encountered. It goes without saying that every additional reaction step of such a continuous multistep process leads to an even more complex system.

When sett ing up a fl ow process the dimensions of all individual modules (e.g. pumps, reactors, work-up and analysis modules, and backpressure regulators) need to operate in the same fl ow regime. Currently available modules range from μL/h to mL/min and do not always exist in the required operating window.

With the development of multistep fl ow processes, the question was raised if fl ow systems could be automated and (time consuming) product handling could be reduced to a minimum by using online and inline analysis procedures. Many diff erent research groups and companies picked up this request and manufactured diff erent online and inline analysis apparatus in diff erent fl ow regimes. We and others proved the added value of online and inline analysis by optimizing reactions containing highly reactive, in situ formed intermediates (e.g. Chapter 4). Additionally, one example is known in which a fully automated optimization set-up was built where the computer directly communicates

with the pumps and temperature controller.9

In some instances, a fl ow process is not possible at all. First, reactions in which solids are present or formed cannot be performed in fl ow due to fouling and/or clogging

of the system.10 _{It was estimated by Roberge et al. that 50% of all reactions performed}

at Lonza would benefi t from fl ow chemistry, however, 63% of these reactions cannot be carried out in a microreactor due to the presence of solids.11 _{Secondly, reactions that} require very long reaction times (order of multiple hours or days) cannot be performed in fl ow. The enormous length of channels required will take up a large amount of space (larger than a batch reactor of the same production rate) and tremendous pressure drops will be encountered in the system.

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Chapter 7

associated with building a continuous fl ow set-up. As was described in Section 1.2.6, the manufacturing costs of microreactors are higher than for batch reactors. Additionally, a batch reactor can be applied for multiple purposes while a continuous fl ow set-up is dedicated to one process. This means that the profi t margins on a possible fl ow process need to be suffi cient to compensate for the investment.

7.3. Outlook

Overall, I am convinced that continuous fl ow chemistry has a considerable potential for future applications. It certainly is a valuable tool for the organic chemist in addition to the traditional batch chemistry. The decision as to whether to run a reaction in a fl ask/ reactor or in a microreactor must be made on a case-by-case basis. The advantages and limitations as stated above, in previous chapters, and in literature12 _{will help elucidating} the pros and cons of continuous fl ow microreactors for every individual case.

With the research described in this thesis, we contributed to the concept and applicability of fl ow chemistry in organic synthesis. However, considering the technological aspects of fl ow chemistry, chemists and engineers will have to bundle their expertise. By joining forces, more complicated fl ow reactions and processes will be made possible addressing the issues of dilution, incompatible fl ow modules, and solid handling. Additionally, fully automated optimization in continuous fl ow has to be explored more extensively. In conclusion, I expect that fl ow chemistry will progress from academic curiosity and proof of concept to mainstream applications: implementation in industrial research, process development and manufacturing of pharmaceutical and fi ne chemical companies.

7.4. References and notes

1. Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. ChemSusChem, 2013, 6,

746-789.

2. Boswell, C. April 30th 2009 “Microreactors gain popularity among producers”, htt p://

www.icis.com/Articles/2009/05/04/9211877/microreactors+gain+popularity+amon g+producers.html, (accessed Nov 24, 2013)

3. Sahoo, H. R.; Kralj, J. G.; Jensen, K. F. Angew. Chem. Int. Ed. 2007, 46, 5704-5708.

4. Mason, B. P.; Price, K. E., Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.

Rev. 2007, 107, 2300-2318.

5. Section 1.4.2 of this thesis describes this continuous work-up module.

6. For an overview of multistep processes, see: Wegner, J.; Ceylan, S.; Kirschning, A.

Adv. Synth. Catal. 2012, 354, 17-57.

7. Hartman, R. L.; Sahoo, H. R.; Yen, B. C.; Jensen, K. F. Lab Chip 2009, 9, 1843-1849.

8. Hartman, R. L.; Naber, J. R.; Buchwald, S. L.; Jensen, K. F. Angew. Chem. Int. Ed.

2010, 49, 899-903.

9. MacMullen, J. P.; Jensen, K. F. Org. Process Res. Dev. 2011, 15, 398-407.

10. Hartman, R. L. Org. Process Res. Dev. 2012, 16, 870-887.

11. Roberge, D. M.; Ducry, L.; Bieler, N.;Crett on, P.; Zimmermann, B. Chem. Eng.

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