Name: Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations (Video) | JoVE Journal
Uploaded: 2018-01-04T14:00:00.000+00:00
Duration: 13 min 9 s
Description: Learn to screen organic reactions using a stop-flow micro-tubing reactor platform combining continuous flow and batch advantages. This green, safe method improves efficiency for small-scale reaction screening.

ai_agent_IP

ai_agent

maintenance

instantTrialDurationMinutes

isBiopharma

enableNewMyJoveSectionDesign

educationFeatures

seoMetaApi

ai_copilot_institution_blacklist

ai_chat_institution_blacklist

freeAccessWindow

ssoRoleCapture

scheduledMaintenanceBanner

joveLabsFeatures

disable_autoplay_for_bots

extended_trial_duration

5 minutes

&#160;We are grateful for the financial support provided by the National University of Singapore (R-143-000-645-112, R-143-000-665-114) and GSK-EDB (R-143-000-687-592).

Refer to all relevant material safety data sheets (MSDS) before handling any possible toxic and carcinogenic chemicals. Conduct appropriate risk assessments before starting any reactions, including the use of engineering controls, such as fume hoods and gas cylinders, as well as wearing sufficient personal protective equipment. Proper training should be conducted before using any highly flammable gas to avoid any accidents caused by mishandling of the gas cylinders.
1. Gas-involved Reaction2
<ol>
	<li>Preparation of acetylene tank 
	Set gas regulator of acetylene tank to 20 psi (137895 Pa), above the desired back-pressure of 5 psi (34474 Pa) used in the system. 
	Note: Refer to Figure 1 on more details of the gas regulator set up. 
	Note: Back-pressure regulator (BPR) is set at the end of the tubing, refer to Figure 2 and 3 for more details on the SFMT set-up.</li>
	<li>Preparation of 4-iodoanisole solution
	<ol>
		<li>Add a 10 mm magnetic stir bar into a 10 mL round-bottom flask.</li>
		<li>Measure 58.5 mg 4-iodoanisole with a weighing balance and transfer to the round-bottom flask. 
		Caution: Aryl halides are irritants and can be harmful. Consult the relevant MSDSs before proceeding.</li>
		<li>Add 8.5 mg Pd(PPh3)2Cl2, 1.0mg copper(I) iodide, 21.0 mg 1, 3, 5-trimethoxybenzene (internal standard) and 80 µL N,N-Diisopropylethylamine (DIPEA) into the same round-bottom flask. Add approximately 2.5 mL of dimethyl sulfoxide (DMSO) to the round-bottom flask. 
		Caution: Pd(PPh3)2Cl2, copper(I) iodide, DIPEA are irritants and can be harmful. Consult the relevant MSDSs before proceeding. 
		Caution: 1, 3, 5-trimethoxybenzene are flammable and volatile. Keep away from ignition sources. 
		Caution: DMSO is a toxic chemical. Consult the relevant MSDSs before proceeding.</li>
		<li>Seal the round bottom flask with a rubber septum and mixture was stir on a heat plate at room temperature and pressure until all the solid have dissolved. 
		Note: Further sonication can be done to ensure a homogenous solution.</li>
		<li>Degas the reaction mixture with argon-filled balloon for approximately 15 min while maintaining a constant stirring on heat plate. Remove both needles after 15 min to ensure an inert environment within the round-bottom flask. 
		Note: Refer to Figure 4 for details on degas procedure.</li>
	</ol>
	</li>
	<li>Mixing of liquid-gas layer in SFMT reactor
	<ol>
		<li>Extract all the reaction mixture from the round bottom flask with a 8 mL stainless steel syringe connected to a long needle via a needle connector through the rubber septum. Remove the needle and attach the stainless steel syringe to the syringe pump. Connect the syringe to High purity Perfluoroalkoxy alkanes (HPFA) tubing (O.D. 1/16", I.D. 0.03", 300 cm, volume = 1.37 mL) via a T-connector. 
		Note: Use a needle connector to connect both the stainless steel and long needle, refer to Figure 5 for more details on using the needle connector. 
		Note: All air bubbles should be remove from the stainless steel syringe before attaching to the syringe pump. 
		Note: Ensure that all the tubing are tighten before connecting the reaction mixture to the set-up to reduce exposure of air, refer to Figure 2 and 3 on the connections for the tubing.</li>
		<li>Set flow rate of the syringe pump to 300 µL/min for the reaction mixture to be pumped into the HPFA tubing. Adjust the flow rate of acetylene with the needle valve to about 1:1 liquid:gas ratio along the plugs. Equilibrated ratio was maintained until the HPFA tubing is filled with gas/liquid slug reagents. 
		Caution: Acetylene is highly flammable. Keep away from ignition sources. 
		Note: BPR is placed in acetone vial before purging the tubing with acetylene gas. 
		Note: Purge the tubing with acetylene gas first until bubble is observed in the acetone vial for the BPR to ensure that the pressure is built up within the SFMT reactor before pumping the reaction mixture into the SFMT reactor. Refer to Figure 6 for better illustration of the liquid:gas ratio.</li>
		<li>Close the valve at the end when all the liquid had been injected into the HPFA tubing or when liquid start to leak from the BPR. Pump in more acetylene until the liquid stops moving in the tubing in order to maintain the pressure within the tubing. Close the valve at the start point and close the needle valve once complete. Transfer the whole set-up into the oil bath and incubate for 2 hours. 
		Note: The valves are kept above the oil bath to prevent contamination from the silicon oil. 
		Note: Pre-heat the oil bath to the desired temperature before transferring the SFMT reactor to it.</li>
		<li>After 1 hour, pump the reaction mixture into a 10 mL vial using a 8 mL stainless steel syringe. Fill an 8 mL stainless steel syringe with diethyl ether (approximately 4.0 mL) to wash out any residue in the tubing. 
		Caution: Diethyl ether is highly flammable. Keep away from all ignition sources. 
		Note: Hexane could be used to wash away the silicon oil before proceeding to avoid contamination for subsequent steps.</li>
		<li>Saturated NH4Cl aqueous solution (4.0 mL) was added to the combined organic layer, followed by a liquid-liquid extraction with 1.5 mL diethyl ether, with the aid of a separatory funnel. 
		Caution: NH4Cl may be harmful. Consult the relevant MSDSs before proceeding.</li>
		<li>Conduct a gas chromatography mass spectrum (GC-MS) analysis with the organic layer to determine the yield. 
		Note: 1, 3, 5-trimethoxybenzene was added in step 1.2.3 as an internal standard. 
		Note: An internal standard calibration curve was plot with different mass of the product to derive a linear regression curve. The yield of the product is interpolated from the linear regression curve. Refer to Ref. 2 for more details on the calibration curve.</li>
	</ol>
	</li>
</ol>
2. Photo-mediated Reaction5
<ol>
	<li>Add 30.8 mg benzylidenemalonitrile, 4.1 mg 9-mesityl-10-methylacridinium perchlorate, 67.3 mg tetramethylethylene and 2.0 mL dichloroethane into a 10 mL silicon septa vial. 
	Caution: Benzylidenemalonitrile, 9-mesityl-10-methylacridinium perchlorate, tetramethylethylene and dichloroethane are highly flammable. Keep away from all ignition sources.</li>
	<li>Degas for about 15 minutes with argon-filled balloon. Remove both needles after 15 min to ensure an inert environment within the vial. 
	Note: Refer to Figure 4 for details on degas procedure.</li>
	<li>Purge the HPFA tubing (O.D. 1/16", I.D. 0.03", 340 cm, volume = 1.5 mL) with argon gas for approximately 5 min by direct connection of the SFMT reactor to the argon gas cylinder with an Union body PEEK. Close both valves to entrap the argon gas within the HPFA tubing after reaching the indicating time of 5 min. 
	Note: Refer to Figure 5 for more details on using the Union body PEEK.</li>
	<li>With a 3 mL disposable syringe attached with a long needle, extract the reaction mixture from 10 mL silicon septa vial. Remove the needle and connect the disposable syringe to the HPFA tubing via a syringe connector. Open both valves to pump in the reaction mixture manually. Close both valves again once the HPFA tubing has been filled with the reaction mixture. 
	Note: Refer to Figure 5 for more details on using the syringe connector. 
	Note: Mix the reaction mixture well with the syringe to ensure a homogenous solution before pumping into the HPFA tubing. 
	Note: There may be excess solvent that will exceed the tubing volume. Place the tubing end on a waste can to collect any overflowed reaction mixture.</li>
	<li>Place the SFMT reactor in the middle of the blue LED (λmax = 425 nm, 2 m, 20 W) stripe to ensure equal exposure of the HPFA tubing. The HPFA was exposed for irradiation for approximately 5-48 hours. 
	Note: The length of the blue LED stripe is set to 2 meters to provide enough energy for the reaction to proceed.</li>
	<li>Pump out the reaction mixture with 3 mL disposable syringe into a clean round-bottom flask with a syringe connector piece. Wash out any residue with excess diethyl ether using a 3 mL disposable syringe into the same round-bottom flask. 
	Note: Refer to Figure 5 for more details on using the syringe connector.</li>
	<li>Measure 0.06 mmol of 1, 3, 5-trimethoxybenzene (internal standard) and add to combined organic mixture. Remove excess solvent under reduced pressure with a rotavap machine.</li>
	<li>Measure 0.6 mL of deuterated chloroform with 1 mL disposable syringe attached with long needle and add to the concentrated crude product. Transfer the deuterated mixture into a clean NMR tube for crude 1H NMR analysis. 
	Note: The integral (x) for internal standard at 6.10 ppm is used to calculate the conversion rate by comparing the integral (y) of product formed at 3.38 ppm. 
	<img alt="Yield equation: Integral of y over x times 100%." src="/files/ftp_upload/56897/56897eq1v2.jpg" data-altupdatedat="1788250015000" data-alt="Equation 1"></li>
</ol>
3. Photo-mediated Gas-involved Reaction2
<ol>
	<li>Preparation of acetylene tank 
	Set the gas regulator of the acetylene tank to about 20 psi (137895 Pa) which is above the desired back-pressure of 5 psi (34474 Pa) in the system. 
	Note: Refer to Figure 1 on more details of the gas regulator set up. 
	Note: Back-pressure regulator (BPR) is set at the end of the tubing, refer to Figure 2 and 3 for more details on the SFMT set-up.</li>
	<li>Preparation of bromopentafluorobenzene solution
	<ol>
		<li>Under inert atmosphere, add 74.1 mg bromopentafluorobenzene , 2.8 mg Ir(ppy)2(dtbbpy)PF6 and 46.8 mg 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) into a 10 mL silicon septa. Add 3.0 mL of acetonitrile into the same 10 mL glass vial to dissolve all the reagents. 
		Caution: Bromopentafluorobenzene and acetonitrile are highly flammable and volatile. Keep away from all ignition sources. 
		Caution: Ir(ppy)2(dtbbpy)PF6 and TEMPO may be harmful. Consult the relevant MSDSs before proceeding.</li>
		<li>Degas the reaction mixture with argon-filled balloon carefully for 10 minutes in an ice bath. Remove both needles from the septa to ensure an inert atmosphere in the vial. 
		Note: Refer to Figure 4 for details on degas procedure.</li>
		<li>Add 56.0 µL of DIPEA into the mixture with a 1 mL syringe and degas for another 5 minutes in an ice bath similar to step 3.2.2.</li>
	</ol>
	</li>
	<li>Mixing of liquid-gas layer in SFMT reactor
	<ol>
		<li>With a 8 mL stainless steel syringe attached with long needle via a needle connector, extract the reaction mixture from the silicon septa vial. Remove the needle and attach the syringe to the syringe pump. Connect the outlet to T-connector. 
		Note: Use a needle connector to connect both the stainless steel and long needle, refer to Figure 5 for more details on using the needle connector. 
		Note: All gas should be remove from the stainless steel syringe before attaching to the syringe pump. 
		Note: Ensure that all the tubing are tighten before connecting the reaction mixture to the set-up to reduce exposure of gas, refer to Figure 2 and 3 on the connections for the tubing.</li>
		<li>Set the flow apparatus' flow rate to 100 µL/min and pump the reaction mixture into the HPFA tubing (O.D. 1/16", I.D. 0.03", 300 cm, volume = 1.37 mL). Adjust the flow rate of acetylene with the needle valve until 2:1 gas/liquid ratio is observed in the plug. The ratio plugs was determine via estimation in the clear tubing. 
		Note: BPR is placed in acetone vial before purging the tubing with acetylene gas. 
		Note: Purge the tubing with acetylene gas first until bubble is observed in the acetone vial for the BPR to ensure that the pressure is built up within the SFMT reactor before pumping reaction mixture into the SFMT reactor. 
		Note: Refer to Figure 6 for better illustration of the liquid:gas ratio but take note that the volume of the gas should be double the volume of the liquid in the plug by visual estimation.</li>
		<li>Close the valve at the end when all the liquid had been injected into the SFMT reactor (total volume 0.65 ml, 0.065 mmol) or when liquid started to leak from the BPR. Pump in more acetylene until the liquid stop moving in the tubing. Close the valve at the start point and close the needle valve once done. Transfer the whole set-up to a water bath pre-heated to 60°C, and allowed to react for 3 h under blue LED light (λmax = 425 nm, 3 m, 30 W). 
		Note: The valves are left above the water bath to prevent any contamination. 
		Note: The length of the blue LED stripe is set to 3 meters to provide enough energy for the reaction to proceed.</li>
		<li>Pump the reaction mixture from the HPFA tubing with a 8 mL stainless syringe into a round-bottom flask. Wash out the residues from the tubing reactor with excess diethyl ether into the same round-bottom flask. Concentrate the mixture under reduced pressure with a rotavap machine. 
		Note: Carefully reduce the pressure as the starting material and products are highly volatile.</li>
		<li>Add 0.6 mL of deuterated chloroform via a 1 mL disposable syringe into the round-bottom flask to dissolve the concentrated crude mixture. Transfer the deuterated mixture into an NMR tubing for 19F NMR analysis. 
		Note: The 19F NMR spectrums of the starting material (bromopentafluorobenzene) and the 2 products (2, 3, 4, 5, 6-Pentafluorostyrene and pentafluorobenzene) were analysed to find a significant peak for each chemical. The crude 19F NMR spectrum is used to compare the integral of these 3 significant peaks in order to determine the ratio of product formed. Refer to Ref. 2 for more details on the calculation of the product conversion and product ratio.</li>
	</ol>
	</li>
</ol>

<ol><li>Mallia, C. J., Baxendale, I. R. <a target="_blank" href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00222">The Use of Gases in Flow Synthesis.</a> Organic Process Research & Development. 20 (2), 327-360 (2016).</li>
<li>Xue, F., Deng, H., Xue, C., Mohamed, D. K. B., Tang, K. Y., Wu, J. <a target="_blank" href="http://pubs.rsc.org/en/content/articlelanding/2017/sc/c7sc00408g#!divAbstract">Reaction discovery using acetylene gas as the chemical feedstock accelerated by the &#34;stop-flow&#34; micro-tubing reactor system.</a> Chemical Science. 8 (5), 3623-3627 (2017).</li>
<li>McTeague, T. A., Jamison, T. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Photoredox+Activation+of+SF6+for+Fluorination%5BTitle%5D)+AND+%22Angewandte+Chemie+International+Edition%22%5BJournal%5D)">Photoredox Activation of SF6 for Fluorination.</a> Angewandte Chemie International Edition. 55 (48), 15072-15075 (2016).</li>
<li>Mohamed, D. K. B., Yu, X., Li, J., Wu, J. <a target="_blank" href="http://www.sciencedirect.com/science/article/pii/S0040403916309297">Reaction screening in continuous flow reactors.</a> Tetrahedron Letters. 57 (36), 3965-3977 (2016).</li>
<li>Zhou, R., Liu, H., Tao, H., Yu, X., Wu, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Metal-free+direct+alkylation+of+unfunctionalized+allylic%2Fbenzylic+sp3+C-H+bonds+via+photoredox+induced+radical+cation+deprotonation%5BTitle%5D)+AND+%22Chemical+Science%22%5BJournal%5D)">Metal-free direct alkylation of unfunctionalized allylic/benzylic sp3 C-H bonds via photoredox induced radical cation deprotonation.</a> Chemical Science. 8 (6), 4654-4659 (2017).</li>
<li>Prier, C. K., Rankic, D. A., MacMillan, D. W. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Visible+Light+Photoredox+Catalysis+with+Transition+Metal+Complexes%3A+Applications+in+Organic+Synthesis%5BTitle%5D)+AND+%22Chemical+Reviews%22%5BJournal%5D)">Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis.</a> Chemical Reviews. 113 (7), 5322-5363 (2013).</li>
<li>Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V., Noël, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Applications+of+Continuous-Flow+Photochemistry+in+Organic+Synthesis%2C+Material+Science%2C+and+Water+Treatment%5BTitle%5D)+AND+%22Chemical+Reviews%22%5BJournal%5D)">Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.</a> Chemical Reviews. 116 (17), 10276-10341 (2016).</li>
<li>Straathof, N. J. W., Su, Y., Hessel, V., Noel, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Accelerated+gas-liquid+visible+light+photoredox+catalysis+with+continuous-flow+photochemical+microreactors%5BTitle%5D)+AND+%22Nat.+Protocols%22%5BJournal%5D)">Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors.</a> Nat. Protocols. 11 (1), 10-21 (2016).</li>
<li>Robards, K., Haddad, P. R., Jackson, P. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((High-performance+Liquid+Chromatography%E2%80%94Instrumentation+and+Techniques%5BTitle%5D)+AND+%22Principles+and+Practice+of+Modern+Chromatographic+Methods%22%5BJournal%5D)">High-performance Liquid Chromatography—Instrumentation and Techniques.</a> Principles and Practice of Modern Chromatographic Methods. 5, 227-303 (1994).</li>
<li>Linder, V., Sia, S. K., Whitesides, G. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Reagent-Loaded+Cartridges+for+Valveless+and+Automated+Fluid+Delivery+in+Microfluidic+Devices%5BTitle%5D)+AND+%22Analytical+Chemistry%22%5BJournal%5D)">Reagent-Loaded Cartridges for Valveless and Automated Fluid Delivery in Microfluidic Devices.</a> Analytical Chemistry. 77 (1), 64-71 (2005).</li>
<li>Terao, K., Nishiyama, Y., Tanimoto, H., Morimoto, T., Oelgemöller, M., Morimoto, T. <a target="_blank" href="http://akademiai.com/doi/abs/10.1556/JFC-D-12-00005">Diastereoselective [2+2] Photocycloaddition of a Chiral Cyclohexenone with Ethylene in a Continuous Flow Microcapillary Reactor.</a> Journal of Flow Chemistry. 2 (3), 73-76 (2012).</li>
<li>Qian, D., Lawal, A. <a target="_blank" href="http://www.sciencedirect.com/science/article/pii/S0009250906005604">Numerical study on gas and liquid slugs for Taylor flow in a T-junction microchannel.</a> Chemical Engineering Science. 61 (23), 7609-7625 (2006).</li>
<li>Hamilton, D. S., Nicewicz, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Direct+Catalytic+Anti-Markovnikov+Hydroetherification+of+Alkenols%5BTitle%5D)+AND+%22Journal+of+the+American+Chemical+Society%22%5BJournal%5D)">Direct Catalytic Anti-Markovnikov Hydroetherification of Alkenols.</a> Journal of the American Chemical Society. 134 (45), 18577-18580 (2012).</li>
<li>Singh, A., Teegardin, K., Kelly, M., Prasad, K. S., Krishnan, S., Weaver, J. D. <a target="_blank" href="http://www.sciencedirect.com/science/article/pii/S0022328X14005208">Facile synthesis and complete characterization of homoleptic and heteroleptic cyclometalated Iridium(III) complexes for photocatalysis.</a> Journal of Organometallic Chemistry. 776, 51-59 (2015).</li>
</ol>

The authors have nothing to disclose.

The newly developed SFMT reactor is a modification of the continuous-flow system by adding shut-off valves to the micro-tubing2. In this system, the flow rate of a desired volume of reagents can be halted at will, simulating a batch reactor but in micro-tubing2,10,11. These valves aid in the trapping of desired amount of reagents in the HPFA or stainless steel tubing while...

Flow chemistry is well poised towards the movement of green and sustainable processes1,2. In contrast to batch reactors, continuous flow reactors possess significant advantages, such as improved thermal management, enhanced mixing control, and internal pressure regulation. These advantages greatly reduce the formation of by-products in the continuous flow system. Furthermore, continuous-flow enhances the biphasic gas-liquid reactions within the micro-tubing due to the excellent interfacial surface area of the reagents in different states. Continuous flow reactors also provide a good platform for photosynthesis due to the enhanced and uniform light illumination across the micro-tubing3.
Despite success in continuous-flow technology, there are still limitations in reaction screening for parameters that involve catalysts, solvents and reagents2. Changes made to the pressure in the flow system will drastically affect the flow equilibrium. Moreover, a classic continuous flow system generally is limited to one reaction screening at a time, making it time consuming for efficient parallel reaction screening. The reaction time in continuous flow synthesis is also limited by its micro-tubing reactor size. Furthermore, continuous flow screening is prone to cross-contamination at higher temperature, even though carrier medium is employed between different reactions4.
Hence, to address the difficulty of screening discrete parameters in continuous-flow systems, we developed a stop-flow micro-tubing (SFMT) reactor system for reaction screening that involves gaseous reagents and/or photo-mediated reactions2. SFMT reactors comprise elements of both batch reactors and continuous flow reactors. The introduction of shut-off valves entraps the reagents within the micro-tubing, a concept that is similar to a batch reactor, and when the system is pressurized, the SFMT behaves as a miniature high-pressure reactor. The SFMT can then be submerged into a water or oil bath, introducing heat to the reactor system. Visible lights can also be shone on the micro-tubing during the reaction period to facilitate photo-mediated reactions.
In SFMT, flammable or toxic gases, such as ethylene, acetylene, and carbon monoxide, can be utilized to generate valuable chemicals in a safer way compared to batch reactors1,2,4. It is an asset to use such reactive gases as they are inexpensive chemical feedstocks and can be readily removed after reactions are completed, providing a cleaner procedure2. On the contrary, most reaction development carried out in batch reactors tends to exclude the use of reactive gases due to its inconvenience and risk of explosion at elevated pressure and temperature. If gaseous reagents are employed, they are usually introduced into batch reactors via bubbling or balloons. This generally gave lower reproducibility or reactivity due to the low mixing efficiency at the interface. Although high-pressure vessels are commonly applied to enhance reactivity and solubility of gases, they are laborious with a risk of explosion, especially with flammable gases. In addition, the opaque surface of those commonly used high-pressure reactors made it unsuitable for photo-mediated reactions. Hence, reactions that consist of gaseous reagents and photo-mediated reactions are generally left unexplored. In this context, SFMT reactors provide an ideal platform because the gaseous reagents can be utilized within the micro-tubing with the assistance of a back pressure regulator (BPR) to regulate the internal pressure in a safe and convenient manner2. Apart from reactions that involve gaseous reagents, visible-light promoted synthesis also displays great promises for organic synthesis5,6. However, one of the greatest downfall of visible-light mediated reactions is the scalability in conventional batch reactors due to the attenuation effect of photon transport in large vessels7. If high-power light sources are used, over-irradiation may result in by-product formation. Moreover, gaseous reagents have seldom been applied in photo-chemical reactions mainly due to the complex apparatus system when using gas-phase reactants at high pressure2. Through the introduction of a narrow channel, like SFMT, a high-pressure gas environment can be easily achieved under light irradiation.
Hence, this detailed video aims to help more scientists understand the advantages and the procedure of using SFMT for condition screening of gas-involved transformations and light-mediated reactions.

<table><tbody><tr><td>Acetylene Cylinder</td><td>Chem Gas PTE LTD (Singapore)</td><td></td><td></td></tr><tr><td>Logato 200 series Syringe pumps</td><td>KD Scientific Inc</td><td>788200</td><td></td></tr><tr><td>Blue LED Strips</td><td>Inwares Pte Ltd (Singapore)</td><td>3528 FlexiGlow LED Strips</td><td></td></tr><tr><td>PFA Tubing High Purity 1/16&quot; OD x .030&quot; ID x 50ft</td><td>IDEX Health&amp;amp;Science</td><td>1632-L</td><td>Depending on diameter of tubings needed</td></tr><tr><td>KDS Stainless Steel Syringe</td><td>KD Scientific Inc</td><td>780802</td><td></td></tr><tr><td>Shut-Off Valve Tefzel (ETFE) with 1/16&quot; Fittings</td><td>IDEX Health&amp;amp;Science</td><td>P-782</td><td></td></tr><tr><td>BPR Assembly 20 psi</td><td>IDEX Health&amp;amp;Science</td><td>P-791</td><td></td></tr><tr><td>Luer Adapter Female Luer - Female Union</td><td>IDEX Health&amp;amp;Science</td><td>P-628</td><td>Known as syringe connector in this paper</td></tr><tr><td>1/4-28 Female to Male Luer Assy</td><td>IDEX Health&amp;amp;Science</td><td>P-675</td><td>Known as needle connector in this paper</td></tr><tr><td>Union Body PEEK .020 thru hole, for 1/16&quot; OD&quot;</td><td>IDEX Health&amp;amp;Science</td><td>P-702-01</td><td></td></tr><tr><td>Super Flangeless Ferrule w/SST Ring, 1/4-28 Flat-Bottom, for 1/16&quot; OD</td><td>IDEX Health&amp;amp;Science</td><td>P-250X</td><td></td></tr><tr><td>PEEK Low Pressure Tee Assembly 1/16&quot; PEEK .020 thru hole</td><td>IDEX Health&amp;amp;Science</td><td>P-712</td><td>Known as T-connector in this paper</td></tr><tr><td>Super Flangeless Nut PEEK 1/4-28 Flat-Bottom, for 1/16&quot; &amp;amp; 1/32&quot; OD</td><td>IDEX Health&amp;amp;Science</td><td>P-255X</td><td></td></tr><tr><td>Micro Metering Valve Assembly, 1/4-28 Flat-Bottom, for 1/16&quot; OD</td><td>IDEX Health&amp;amp;Science</td><td>P-445NF</td><td>Known as Needle valve in this paper</td></tr><tr><td>Shut Off Valve Assembly PEEK .020</td><td>IDEX Health&amp;amp;Science</td><td>P-732</td><td></td></tr><tr><td>Terumo Syringe without needle</td><td>Terumo medical</td><td></td><td>1 mL and 3 mL depending on the volume needed</td></tr><tr><td>Terumo needle</td><td>Terumo medical</td><td></td><td>22G X 1&amp;frac12;&amp;rdquo;&lt;br/&gt; (0.70 X 38 mm)</td></tr><tr><td>Sterican needle</td><td>B | Braun Sharing Enterprise</td><td></td><td>21G X 4&amp;frac34;&amp;rdquo;&lt;br/&gt; (0.80 X 120 mm)</td></tr><tr><td>Bruker ACF300 (300 MHz)</td><td></td><td></td><td>For 300 MHz NMR scanning</td></tr><tr><td>AV-III400 (400 MHZ)</td><td></td><td></td><td>For 400 MHz NMR scanning</td></tr><tr><td>AMX500 (500 MHz)</td><td></td><td></td><td>For 500 MHz NMR scanning</td></tr><tr><td>Merck 60 (0.040-0.063 mm) mesh silica gel</td><td>Merck</td><td></td><td></td></tr><tr><td>4-Iodoanisole</td><td>Sigma Aldrich</td><td>I7608-100G</td><td></td></tr><tr><td>412740 ALDRICH&lt;br/&gt; Bis(triphenylphosphine)&lt;br/&gt; palladium(II) dichloride&lt;br/&gt; &amp;ge;99% trace metals basis</td><td>Sigma Aldrich</td><td>412740-5G</td><td></td></tr><tr><td>Copper(I) iodide&lt;br/&gt; purum, &amp;ge;99.5%</td><td>Sigma Aldrich</td><td>03140-100G</td><td></td></tr><tr><td>N,N-Diisopropylethylamine</td><td>Tokyo Chemical Industry Co., Ltd</td><td>D1599</td><td></td></tr><tr><td>1, 3, 5-trimethoxybenzene</td><td>Tokyo Chemical Industry Co., Ltd</td><td>P0250</td><td></td></tr><tr><td>2,3-Dimethyl-2-butene&lt;br/&gt; &amp;ge;99%</td><td>Sigma Aldrich</td><td>220159-25ML</td><td></td></tr><tr><td>Bromopentafluorobenzene&lt;br/&gt; 99%</td><td>Sigma Aldrich</td><td>B75158-10G</td><td></td></tr><tr><td>TEMPO Green Alternative&lt;br/&gt; 98%</td><td>Sigma Aldrich</td><td>214000-25G</td><td></td></tr><tr><td>Acetonitrile</td><td>Sigma Aldrich</td><td>271004-1L</td><td></td></tr><tr><td>Diethylether</td><td>Sigma Aldrich</td><td>346136-1L</td><td></td></tr><tr><td>Dimethyl sulfoxide</td><td>VWR chemical</td><td>23500.322- 25L</td><td></td></tr><tr><td>1,2-Dichloroethane</td><td>Sigma Aldrich</td><td>284505-1L</td><td></td></tr><tr><td>9-mesityl-10-methylacridinium perchlorate</td><td></td><td></td><td>Refer to Ref. &lt;sup class=&quot;xref&quot;&gt;8&lt;/sup&gt; for synthesis</td></tr><tr><td>Ir(ppy)&lt;sub&gt;2&lt;/sub&gt;(dtbbpy)PF&lt;sub&gt;6&lt;/sub&gt;</td><td></td><td></td><td>Refer to Ref. &lt;sup class=&quot;xref&quot;&gt;9&lt;/sup&gt; for synthesis</td></tr></tbody></table>

utilization of stop-flow micro-tubing reactors for the development of organic transformations

Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations

A new reaction screening technology for organic synthesis was recently demonstrated by combining elements from both continuous micro-flow and conventional batch reactors, coined stop-flow micro-tubing (SFMT) reactors. In SFMT, chemical reactions that require high pressure can be screened in parallel through a safer and convenient way. Cross-contamination, which is a common problem in reaction screening for continuous flow reactors, is avoided in SFMT. Moreover, the commercially available light-permeable micro-tubing can be incorporated into SFMT, serving as an excellent choice for light-mediated reactions due to a more effective uniform light exposure, compared to batch reactors. Overall, the SFMT reactor system is similar to continuous flow reactors and more superior than batch reactors for reactions that incorporate gas reagents and/or require light-illumination, which enables a simple but highly efficient reaction screening system. Furthermore, any successfully developed reaction in the SFMT reactor system can be conveniently translated to continuous-flow synthesis for large scale production.

In this study, SFMT is used to carry out transformations that include gaseous reagents ( Table 1), light-mediated reactions (Table 2), and reactions that involves both gaseous reagents and photo-catalysis (Table 3).
Figure 1 displays a typical set-up for the gas regulator to be connected to the gas cylinder so as to regulate the pressure of the gas being pumped into the SFMT system.
Figure 2 represents the ...

A protocol for organic reaction screening using stop-flow micro-tubing (SFMT) reactors employing gaseous reactants and/or visible-light mediated reactions is presented.

A new reaction screening technology for organic synthesis was recently demonstrated by combining elements from both continuous micro-flow and conventional ...

utilization-stop-flow-micro-tubing-reactors-for-development-organic

Research

JoVE Journal

Chemistry

Millifluidic devices are utilized for controlled synthesis of nanomaterials, time-resolved analysis of reaction mechanisms and continuous flow catalysis.

Millifluidics for Chemical Synthesis and Time-resolved Mechanistic Studies

Real-time monitoring allows for fast optimization of reactions performed using continuous-flow processing. Here the preparation of 3-acetylcoumarin is used as an example. The apparatus for performing in-situ Raman monitoring is described, as are the steps required to optimize the reaction.

Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example

Lab-in-a-drop reaction systems allow the versatile implementation of complex reactions in a microfluidic scale. An automated actuation platform consisting of a 3 x 3 matrix of electromagnetic coils was developed and successfully used to merge two 10 µL microreactors and thereby initiate an enzymatic reaction in the resulting liquid marbles.

Aqueous Droplets Used as Enzymatic Microreactors and Their Electromagnetic Actuation

This paper describes the operation procedure for the flow tube reactor and related data collection. It shows the protocols for setting the experiments, recording data and generating the number-diameter distribution as well as the particle mass information, which gives useful information about chemical and physical properties of the organic aerosols.

Production and Measurement of Organic Particulate Matter in a Flow Tube Reactor

Flow chemistry carries environmental and economic advantages by leveraging superior mixing, heat transfer and cost benefits. Herein, we provide a blueprint to transfer chemical processes from batch to flow mode. The reaction of diphenyldiazomethane (DDM) with p-nitrobenzoic acid, conducted in batch and flow, was chosen for proof of concept.

Continuous Flow Chemistry: Reaction of Diphenyldiazomethane with p-Nitrobenzoic Acid

A detailed protocol for the concurrent operation of 48 parallel cell cultures under varied conditions in a microbioreactor system is presented. Cell culture process, harvest and subsequent antibody titer analysis are described.

Use of High-Throughput Automated Microbioreactor System for Production of Model IgG1 in CHO Cells

The fabrication process of a PDMS-based, multilayer, microfluidic device that allows in vitro transcription and translation (IVTT) reactions to be performed over prolonged periods is described. Furthermore, a comprehensive overview of the hardware and software required to automate and maintain these reactions for prolonged durations is provided.

A Multilayer Microfluidic Platform for the Conduction of Prolonged Cell-Free Gene Expression

Here, we present a detailed procedure to run a Design of Experiment in an automated micro-bioreactor followed by cell harvest and protein quantification using a Protein A column.

Process Optimization using High Throughput Automated Micro-Bioreactors in Chinese Hamster Ovary Cell Cultivation

A detailed scalable continuous flow protocol is presented to synthesize an aryl fluoride from an aryl amine through the Balz-Schiemann reaction.

A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor

The targeted synthesis of new metal-organic frameworks (MOFs) is difficult, and their discovery depends on the knowledge and creativity of the chemist. High-throughput methods allow complex synthetic parameter fields to be explored quickly and efficiently, accelerating the process of finding crystalline compounds and identifying synthetic and structural trends.

Discovery and Synthesis Optimization of Isoreticular Al(III) Phosphonate-Based Metal-Organic Framework Compounds Using High-Throughput Methods

This protocol presents a microfluidic system for studying the microbial precipitation of manganese oxide minerals. Biomineral formation is measured in situ with optical microscopy and image analysis. This approach can be adapted to investigate the precipitation of other distinctively colored biogenic minerals in porous environments.

A Microfluidic Platform to Investigate Microbial Precipitation of Metal Oxides in Porous Media

Learn to screen organic reactions using a stop-flow micro-tubing reactor platform combining continuous flow and batch advantages. This green, safe method improves efficiency for small-scale reaction screening.

Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations

Explore More Videos