Continuous Flow Olefin Metathesis Using a Multijet Oscillating Disk

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Continuous Flow Olefin Metathesis using a MultiJet Oscillating Disk Reactor as the Reaction Platform Hans-René Bjørsvik, and Lucia Liguori Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500223e • Publication Date (Web): 02 Oct 2014 Downloaded from http://pubs.acs.org on October 3, 2014

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Organic Process Research & Development

Continuous Flow Olefin Metathesis using a Multi-Jet Oscillating Disk Reactor as the Reaction Platform Hans-René Bjørsvik* and Lucia Liguori# Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway

Abstract. The multi-jet oscillating disk (MJOD) flow reactor is a relatively new technology for continuous flow synthesis. This technology is still under investigation as an all-round platform for flow synthesis. In this article, findings are disclosed from a project where a MJOD flow reactor rig (reactor volume of ≈ 50 mL) was investigated as the reaction platform for ring closing metathesis and cross (self) metathesis reaction, using reaction mixture volumes down to only ≈ 5 mL. The Hoveyda-Grubbs 2nd generation catalyst was used without an inert atmosphere. The results of the flow synthesis provided excellent selectivity and high yield. For comparison purposes, the syntheses conducted in the MJOD reactor were compared with similar literature experiments performed with other flow technologies and batch conditions.

Introduction During the last two decades, continuous flow synthesis has by means of a constantly expanding armoury of flow chemistry devices been developed into an outstanding tool for both laboratory organic synthesis1 and organic process applications.2 Despite great success with this technology, there remain several application areas that need to be developed or further improved; examples of such applications include (1) two-phase reactions, (2) narrow operating temperature ranges, typically 0150 °C, although some few recent reports describe processes that use cryogenic temperature, 3 (3) small throughputs, that however can be solved with a huge "number-up"4 to even provide multi-metric tons scale processes, 5 , 6 (4) the micro-reactor is generally unsuitable to perform reaction processes that involve slurries. With the aim of coping with some of the limitations of the micro-reactor (often synonymous flow reactor), a decade ago we launched a project with the goal to design, realize, develop, and investigate a novel flow chemistry approach that could reduce or even eliminate some of the limitations of the “classical micro-reactor”. Recently, we disclosed herein a report that described a novel approach in flow chemistry that we called a multi-jet oscillating disk flow reactor or shortly a MJOD flow reactor. 7 In this previous account, a series of classical organic reactions were explored, a study that also included preliminary studies dedicated to phase transfer catalysis (PTC), assisted two-phase reactions and reactions involving formation of slurries during the course of the reaction. Subsequently, a study demonstrated an organocatalyzed oxidation process that utilized molecular oxygen (liquid-gas phase reaction) as the terminal oxidant where a series of olefins were converted to epoxides.8 A further investigation involved the MJOD

reactor platform suitable for reactions under cryogenic conditions (a cryoMJOD reactor).3a The latter study also demonstrated the capability of the MJOD flow reactor as a platform for telescoped processes (operated on a kg × day-1 scale). This equipment and the established phenylboronic acid process were later compared to other similar processes in a highlight article.3b In this report, we reveal results achieved in a study involving the MJOD flow reactor platform that we used to execute ruthenium catalyzed olefin metathesis reactions. 9 The MJOD reactor rig we utilized for this study possessed a net flow reactor volume of Vnet ≈ 50 mL, while the experiments we conducted used a total reaction mixture volume of 520 mL. Successful reactions under such a set-up and conditions might confirm our preliminary findings,7 which revealed that the MJOD flow reactor operates without substantial back-mixing, 10 an important feature for multi-step telescoped syntheses and processes, and for the purpose of conducting reactions with the highest possible reaction rate. Method and Result The flow reactor. The MJOD flow reactor has been previously thoroughly described in this journal,7 and thus only a brief description of how it is constructed and operates will be given here. The MJOD flow reactor body is constructed as shown in the 3D drawing of Figure 1. The multi-jet oscillating disk assembly that is placed in the centre of the reactor tube is composed of a number of multijet disks (Ddisk=10 mm, thickness = 4 mm) and disk spacers (L=12 mm) , that together with the wall of the reactor tube form reactor cavities (Vcavity ≈ 0.63 mL). Each of the multi-jet disks (in total 80 pcs) is furnished with four jets each (Djet=1.25 mm) equally distributed around the disk.

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The input section is furnished with four equally distributed input lines . The input lines are connected to piston pumps (FMI Fluid Metering Inc.) that are furnished with one-way valves (Idex Corp. / Upchurch Scientific®) between the reactor and output of the feeding pump.

Figure 1. 3D drawing of the MJOD flow reactor shows: the oscillator unit, the output section, the reactor body, and the input section. A part of the heat exchanger chamber is enlarged and shown in transparent view (on the right hand side of the figure). The MJOD assembly is composed of alternate perforated discs and spacers that are attached firmly to the oscillator piston shaft. This MJOD assembly is placed in the center of the reactor tube and extends along the entire length of the reactor tube. This MJOD unit is connected to the oscillator unit that is placed on the top of the reactor. The oscillator unit transfer an oscillating vertical movement of this “multi-headed” piston. A reactor cavity, indicated by the rectangle (sketched with dashed line type), corresponds to the volume bounded by the tube wall, two discs and the “piston shaft/spacer” (Vcavity ≈ 0.63 mL). Each disc is furnished with four jets equally distributed around the disk. The input section is provided with four input ports for the supply of the reactants to the MJOD flow reactor.

This MJOD reactor possess a net volume of Vnet ≈ 0.63 mL cavity-1 × 79 cavities ≈ 50 mL. The oscillator with a cam mechanism , Figure 1, was used as the motive power for the piston motion, which provides the vertical up-down movement of the MJOD unit. This motion was performed with a frequency of f = 1.6 Hz and an amplitude of A = 0.5 mm. Heating and temperature control were acomplished by means of a circulation pump with heater and thermostat (Haake) connected to the heating/cooling circuit (heat-exchanger) of the MJOD reactor system. Olefin metathesis. The MJOD reactor rig described above was utilized as reaction platform for a series of experiments involving olefin metathesis. 11 , 12 Previously, only a few studies involving olefin metathesis in continuous flow have been disclosed using micro-reactors / flow reactors.13 As part of our exploration of the properties and suitability of the MJOD reactor as a platform for organic synthesis, we aimed in the present study to examine in addition to the title reaction three important aspects of the reactor system:

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(1) A standard MJOD platform (Figures 1-3) is constructed with a net reactor volume in the range 50-100 mL. In cases where the total volume of the substrate and reactants in solution is small (in the range 5-20 mL), it is a requirement that the MJOD flow reactor operates as a plug flow reactor in order to avoid back-mixing and thus dilution of the reaction mixture. We wanted to acertain whether this rather large net MJOD reactor volume could work with small reaction volumes. A sketch of how this is thought to operate is shown in Figure 4. (2) The MJOD platform is mainly constructed of stainless steel (316), except for the multi-jet disks that are produced in Teflon. Due to the intimate contact between reactants and the stainless steel surfaces during the entire passage through the reactor system, we wanted to conduct and evaluate processes that involve organometallic complexes (catalyst). On the basis of these experiments, we wanted to establish whether the construction material of the reactor had a detrimental effect on the reactions. We decided to perform NHC-Ru catalyzed olefin metathesis experiments for this purpose. (3) It was also of interest to examine the residence time when a reaction was carried out in our MJOD reactor system and compare this with the demanded residence time in the corresponding batch mode process and with other types of flow reactors. The olefin metatheis experiments. Some of the dienes that were submitted to the various metathesis conditions are commonly exploited for the purpose of investigating new and modified olefin catalysts. The selected substrates allow one to perform ring-closing metathesis (RCM) and self-metathesis (cross metathesis, CM). The chemical literature provides data from a series of studies dedicated to these dienes. Synthesis of diethyl cyclopent-3-ene-1,1dicarboxylate 2 via ring closing metathesis. The very first olefin metathesis experiment that we conducted in continuous flow mode using the MJOD reactor rig was a ring closing metathesis reaction using diethyl 2,2-diallylmalonate 1 as the diene.14 Two precision feeding pumps, P1 and P2, Figure 3, were utilized to feed the substrate 1 and the Rucatalyst from the reservoirs R1 and R2 and dispense accurately volumes/quantities at the input section of the MJOD reactor body. The substrate 1 was dissolved in toluene and pumped at a rate of r1 = 3.33 mL min.-1 The Hoveyda-Grubbs 2nd generation catalyst was dissolved in toluene and pumped at a rate of rcat = 0.67 mL min.-1 The overall reactor volume-time flow with these setting was rtot = 4 mL min,-1 and a residence time of 15 min. The experiments were conducted at two different temperatures, at 30 oC and 45 oC, respectively.


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Figure 3. Process flow diagram for the MJOD flow reactor system utilized for the metathesis reactions. R1-R5: reservoirs, P1-P3: pumps, M1/O1: electrical motor and cam mechanisms that constitute the oscillator for the “MJOD piston”, C/HE1: cooler/heat exchanger composed by a cooling/heater and a circulator pump. MJOD: the multi-jet oscillating disk flow reactor.

The initial RCM experiments for the preparation of diethyl cyclopent-3-ene-1,1-dicarboxylate 2 were conducted using a low catalyst loading, only 0.02%. Both the batch mode and the MJOD flow reactor experiments provided similar low yields, only 14% and 17%, respectively. When the Ru-catalyst loading was augmented to 1%, much improved identical results were obtained for the two reactor approaches. Initially, it was somewhat surprising to note that the good mixing properties 15 of the MJOD flow reactor had no influence on the yield/time. The batch mode and the flow mode experiments provided identical yields of 80% using a reactor residence time of 15 min., see Scheme 1. Scheme 1. Ring closing metathesis in continuous flow for the synthesis of diethyl cyclopent-3-ene-1,1-dicarboxylate 2 using the Hoveyda-Grubbs 2nd generation catalyst.

Figure 2. The photo shows a standard MJOD flow reactor platform. The reactor body has length of L=1000 mm, and is composed of two feeding pumps and feeding reservoirs . Laboratory aggregates (power supplies) are used to control the pumping rate (pumps ) and to control the oscillating rate of the oscillator . In this photo, the output section is furnished with a vacuum filter allowing removal of (semi-continuously) solids in the post-reaction stream.

a

0.02 mol-%: 5 mg catalyst in 10 mL toulene and 0.2 mol-% 50 mg catalyst in 10 mL toluene


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Figure 4. A MJOD flow reactor set-up used to evaluate whether the MJOD flow system works with reaction volumes (Vrx.mix) that is less than the net reactor volume (Vnet), Vrx.mix 95% and quantitative yields, respectively, although, under prolonged residence times. Scheme 2. Ring closing metathesis in continuous flow synthesis of 1-tosyl-2,5-dihydro-1H-pyrrole 4 using Hoveyda-Grubbs 2nd generation catalyst.

Self-metathesis - 1,4-dibromobut-2-ene 6. A selfmetathesis experiment was elaborated and adapted for the MJOD flow reactor on the basis of a previously disclosed batch protocol.17,18 The substrate 5 (26 µL, 0.30 mmol) and the Hoveyda-Grubbs 2nd generation catalyst (19 mg, 0.030 mmol, 10 mol-%) was dissolved in acetone (2.00 mL). The mixture was pumped into the MJOD reactor at a rate of r = 0.40 mL min.-1 When the reservoir of the reaction mixture was emptied, pure solvent was pumped into the reactor at a rate of r = 0.85 mL min.-1 thus providing a total residence time of 60 min. The reactor heat exchanger was kept at a temperature of 25 oC. For the purpose of benchmarking the capability and properties of the flow process, similar experiments were conducted using the corresponding batch protocol. The achieved experimental results are summarized in Scheme 3. Scheme 3. Self metathesis in continuous flow synthesis of 1,4dibromobut-2-ene 6 using Hoveyda-Grubbs 2nd generation catalyst.

a The reaction conditions were adapted with the basis in the protocol leading to compound 8.17 The yield values were estimated by means of 1H NMR spectroscopy.

Scheme 4. Self metathesis in continuous flow synthesis of but-2ene-1,4-diol 8 using Hoveyda-Grubbs 2nd generation catalyst.

a b

See reference 17 The reaction was performed under argon.

a See reference 17. The results from the MJOD experiment was estimated by means of 1H NMR spectroscopy.


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Self metathesis - but-2-ene-1,4-diol 8. A flow chemistry protocol leading to 8 was elaborated on the basis of a previously disclosed batch protocol.17 The substrate prop-2-en-1-ol 7 (20 µL, 0.30 mmol) and the Hoveyda-Grubbs 2nd generation catalyst (19 mg, 0.030 mmol, 10 mol-%) were dissolved in acetone (2.00 mL). The mixture was transferred to a reservoir and pumped into the MJOD reactor at a rate of r = 0.40 mL min.-1 When the reactant/catalyst reservoir was emptied, pure solvent (acetone) was pumped into the -1 MJOD reactor body at a rate r = 0.85 mL min. to provide a total residence time of 60 min. The temperature of the MJOD reactor body was controlled at a temperature of 25 oC using the heat exchanger (circulator) throughout the whole reaction experiment. Conclusion We have assembled a MJOD flow reactor platform to successfully conduct various olefin metathesis experiments. The achieved results were benchmarked with other reaction platforms, revealing the MJOD flow reactor to be better or at least equivalent in productivity when compared to the other approaches. Moreover, the investigation revealed that the MJOD flow reactor platform can operate satisfactorily even when the volume of the reaction mixture is only a fraction of the net reactor volume, which demonstrates that the MJOD flow reactor may be operated as a plug flow reactor. Exerimental Section General methods. Starting materials, reagents, catalyst and solvents were purchased commercially and used without further purification. GLC analyses were performed on a capillary gas chromatograph equipped with a fused silica column (L 25 m, 0.20 mm i.d., 0.33 µm film thickness) at helium pressure of 200 kPa, split less /split injector and flame ionization detector. Mass spectra were obtained on a GC-MS instrument, using a gas chromatograph equipped with fused silica column (L 30 m, 0.25 mm i.d., 0.25µm film thickness) and He as carrier gas. Structure control by using 1H-NMR spectra were recorded on a NMR spectrometer operating at 400 MHz. Chemical shifts was referenced to internal TMS. The obtained synthesis products were compared with authentic samples. The flow reactor. A multi-jet oscillating disk (MJOD) flow reactor system with a net volume Vnet≈50 mL (L = 1000 mm, di=10 mm) furnished with N=80 pcs. of 4-jets disks was used for all experiments in the present study. The input section is furnished with four inlet points, whereof two or three were connected to precision feeding pumps. The non-used input-lines were plugged during the reaction experiments. See the process flow diagram in Figure 2 and a 3D drawing of the MJOD flow reactor in Figure 1. The tubular volume (reactor jacket) surrounding the reactor tube was used for circulating temperature controlled water in order to keep the reaction temperature at theo desired level (selected in the temperature range T=20−60 C). The oscillator was adjusted to provide oscillations on the MJOD unit with an amplitude of A=5 mm at a frequency of f ≈ 1.6Hz. Synthesis of diethyl cyclopent-3-ene-1,1-dicarboxylate 2. Diethyl 2,2-diallylmalonate 1 (1 g, 4.16 mmol) was dissolved in toluene (50 mL) and placed in reservoir R1. The Hoveyda-Grubbs 2nd generation catalyst (52 mg or

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260 mg) was dissolved in toluene (10 mL) and placed in the reservoir R2. The reservoir R3 was filled with pure toluene (V≈250 mL). The pump R3 was used to fill the MJOD flow reactor with toluene. The reactor tube was heated by passing temperature-controlled water (30 oC or 45 oC) through the reactor jacket using a circulating pump. Two precision feeding pumps, P1 and P2, were utilized to feed the substrate 1 and the Ru-catalyst from the reservoirs R1 and R2 and dispense accurately volumes/quantities at the input section of the MJOD flow reactor body. The substrate -11 solution was pumped using a rate of r = 3.33 mL min. The Hoveyda-Grubbs 2nd generation catalyst solution was pumped with a rate r = 0.67 mL min.-1 The overall reactor volume-time flow corresponded to 4 mL min-1 and provided a reactor residence time of 15 min. The reaction experiments were conducted at temperatures of 30 oC or 45 oC. 1-Tosyl-2,5-dihydro-1H-pyrrole 4. N,N-diallyl-4-methylbenzenesulfonamide 3 (0.261 g, 1.04 mmol) was dissolved in methylenechloride (5 mL) that was added the HoveydaGrubbs 2nd generation catalyst (31 mg), that corresponded to 5 mol-% of the catalyst. This mixture was transferred to the reagent reservoir R1. The reservoir R3 was filled with toluene (≈250 mL). The pump R3 was used to fill the MJOD reactor with toluene. The jacketed reactor tube of the MJOD reactoro was heated by circulating water at a temperature of 40 C by means of a circulator pump. The reaction was conducted switching on the pump P1 that furnished the MJOD flow reactor with reaction mixture at a flow rate of r = 1.00 mL min.−1 When reservoir R1 was emptied, the feeding pump P3 was switched on to provide an pure solvent plug at a rate of r=0.85 mL min.−1 This configuration provided a reactor residence time of 60 min. 1,4-dibromobut-2-ene 6. The substrate 5 (26 µL, 0.30 mmol) and the Hoveyda-Grubbs 2nd generation catalyst (19 mg, 0.030 mmol, 10 mol-%) was dissolved in acetone (2.00 mL) and transferred to reservoir R1. The mixture was pumped (P1) into the MJOD reactor at a rate r = 0.40 mL min.-1 When the reservoir of the reaction mixture (R1) was emptied, pure solvent (R3) was pumped (P3) into-1 the MJOD flow reactor with a rate of r = 0.85 mL min. to provide a total residence time of 60 min. The reactor heat exchanger was maintained at a temperature of 25 oC. But-2-ene-1,4-diol 8. Prop-2-en-1-ol 7 (20 µL, 0.30 mmol) and the Hoveyda-Grubbs 2nd generation catalyst (19 mg, 0.030 mmol, 10 mol-%) was dissolved in acetone (2.00 mL). The mixture was transferred to reservoir R1 (see Figure 2) and pumped (P1) into the MJOD flow at a rate of r = 0.40 mL min.-1 When reservoir R1 of the reaction mixture was emptied, pure solvent (acetone) that was placed in reservoir R3 was pumped (P3) into the -1MJOD flow reactor body with a rate r = 0.85 mL min. that provide a total residence time of 60 min. The temperature of the MJOD reactor body was controlled at T=25 oC using the heat exchanger (circulator) throughout the whole reaction experiment.

Author Information Corresponding Author * Phone: +47 55 58 34 52. Fax: +47 55 58 94 90. E-mail: [email protected] Present address # Nordahl Griegs secondary high school, Bergen, Norway Notes The Authors declare no competing financial interest. Acknowledgements Fluens Synthesis are gratefully acknowledged for placing the MJOD flow reactor rig at our disposal.


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Wirth, T. (ed.) Microreactors in Organic Synthesis and catalysis. Wiley-VCH, Weinheim, 2008. (a) Ehrfeld, W.; Hessel, V. ; Löwe, H. Microreactors New Technology for Modern Chemistry. Wiley-VCH, Weinheim, 2000. (b) Hessel, V.; Hardt, S.; Löwe, H. Chemical Micro Process Engineering. Fundamentals, Modelling and Reactions. Wiley-VCH, Weinheim, 2004. (c) V. Hessel, H. Löwe, A. Müller, G. Kolb. Chemical Micro Process Engineering. Processing and Plant. Wiley-VCH, Weinheim, 2005. a) Sleveland, D.; Bjørsvik, H.-R. Org. Process Res. Dev. 2012, 16, 1121-1130. b) Desai, A. A. Angew. Chem. Int. Ed. 2012, 51, 9223-9225. Laird, T. Org. Proc. Res. Dev. 2001, 5, 612 (a) Reintjens, R.; Pöchlauer, P.; Kotthaus, M.; Vorbach, M.; Bohn, L.; Kraut, M.; Wenka, A.; Schubert, K. How to implement a micro reactor in a large-scale production. Lecture at 25th SCI Process Development Symposium, Churchill College, Cambridge, UK, December 5-7, 2007. (b) Poechlauer, P.; Vorbach, M.; Kotthaus, M.; Braune, S.; Reintjens, R.; Mascarello, F.; Kwant, G. Micro reactor plant for the large-scale production of a fine chemical intermediate: a technical case study. In Hessel, V. (ed.) Micro Process Engineering 2009, 3, 249-254. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−4048. (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048−4050. c) Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. Liguori, L.; Bjørsvik, H.-R. Org. Process Res. Dev. 2011, 15, 997–1009. Spaccini, R.; Liguori, L.; Punta, C.; Bjørsvik, H.-R. ChemSusChem 2011, 5, 261-265. Previously, introductory results were presented as a oral conference contribution: Bjørsvik, H.-R.; Liguori, L. Olefin Metathesis in Continuous Flow using the Novel MJOD milli-reactor Technology (O-5). 18th International Symposium on Olefin Metathesis and Related Chemistry, Leipzig, Germany, 2-7 August 2009. “Back-mixing” is an undesirable feature in a chemical reactor. When back-mixing occur in a reactor, the product of the desired chemical reaction mixes with unreacted feed in the reactor. Such a feature is in contrast to a plug or piston flow that is an desired property of any flow reactor. Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012-3043 (a) Grubbs, R. H. (ed.) Handbook of Metathesis Vol 1−3. Wiley-VCH, Weinheim, 2003. (b) Cossy, J.; Arseniyadis, S.; Meyer, C. (Eds.). Metathesis in Natural Product Synthesis. Wiley-VCH: Weinheim, 2010 Some example: (a) Ahmed-Omer, B.; Barrow, D. A.; Wirth, T. ARKIVOC 2011, (iv), 26-36. (b) Selva, M.; Guidi, S.; Perosa, A.; Signoretto, M.; Licence, P.; Maschmeyer, T.Green Chemistry 2012, 14, 2727-2737. (c) Duque, R.; Oechsner, E.; Clavier, H.; Caijo, F.; Nolan, S. P.; Mauduit, M.; Cole-Hamilton, D. J. Green Chemistry 2011, 13, 1187-1195. (d) Skowerski, K.; Wierzbicka, C.; Grela, K. Current Organic Chemistry 2013, 17, 2740-2748. (e) Skowerski, K.; Czarnocki, S. J.; Knapkiewicz, P. ChemSusChem 2014, 7, 536542. Som few litterature examples: (a) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318–9325. (b) Ledoux, N.; Linden, A.; Allaert, B.; Vander Mierde, H.; Verpoort, F. Adv. Synth. Catal. 2007, 349, 1692-1700. (c) Shao, M.; Zheng, L.; Qiao, W.; Wang, J.; Wanga, J. Adv. Synth. Catal. 2012, 354, 2743-2750. Previous MJOD flow reactor versus batch reactor comparison studies, we have shown large differences in residence time in order to acheive similar outcomes of otherwise identical reaction experiments. These differences can only be explained by divergent mixing efficiency. For example, the study disclosed in reference 8 reveals an aerobic oxidation that utilize molecular oxygen as the terminal oxidant. The batch process and the MJOD flow process reveals substantially different residence times for similar yields. While the batch mode process required 24-48 h, the flow mode process required only 1-2h. Several other reactions demonstrate similar large differences between the batch and MJOD flow mode, see reference 7. Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508−3509. Binder, J. B.; Blank, J. J.; Raines, R. T. Org. Lett. 2007, 9, 4885–4888. Halbach, T. S.; Mix, S.; Fischer, D.; Maechling, S.; Krause, J. O.; Sievers, C.; Blechert, S.; Nuyken, O.; Buchmeiser, M. R. J. Org. Chem. 2005, 70, 4687−4694.


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Continuous Flow Olefin Metathesis Using a Multijet Oscillating Disk

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