Name: utilization of stop-flow micro-tubing reactors for the development of organic transformations
Uploaded: 2018-01-04T14:00:00
Description: Watch this Scientific Journal Video about Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations at JoVE.com

&#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 Reaction<sup ...

<ol>
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F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Photoredox+Activation+of+SF6+for+Fluorination.">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.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reaction+screening+in+continuous+flow+reactors.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metal-free+direct+alkylation+of+unfunctionalized+allylic/benzylic+sp3+C-H+bonds+via+photoredox+induced+radical+cation+deprotonation.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Visible+Light+Photoredox+Catalysis+with+Transition+Metal+Complexes:+Applications+in+Organic+Synthesis.">Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis.</a> Chemical Reviews. 113 (7), 5322-5363 (2013).</li><li>Cambi&#233;, D., Bottecchia, C., Straathof, N. J. W., Hessel, V., No&#235;l, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Applications+of+Continuous-Flow+Photochemistry+in+Organic+Synthesis,+Material+Science,+and+Water+Treatment.">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. 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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&#34; OD x .030&#34; ID x 50ft</td>
			<td>IDEX Health&#38;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&#34; Fittings</td>
			<td>IDEX Health&#38;Science</td>
			<td>P-782</td>
			<td></td>
		</tr>
		<tr>
			<td>BPR Assembly 20 psi</td>
			<td>IDEX Health&#38;Science</td>
			<td>P-791</td>
			<td></td>
		</tr>
		<tr>
			<td>Luer Adapter Female Luer - Female Union</td>
			<td>IDEX Health&#38;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&#38;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&#34; OD&#34;</td>
			<td>IDEX Health&#38;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&#34; OD</td>
			<td>IDEX Health&#38;Science</td>
			<td>P-250X</td>
			<td></td>
		</tr>
		<tr>
			<td>PEEK Low Pressure Tee Assembly 1/16&#34; PEEK .020 thru hole</td>
			<td>IDEX Health&#38;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&#34; &#38; 1/32&#34; OD</td>
			<td>IDEX Health&#38;Science</td>
			<td>P-255X</td>
			<td></td>
		</tr>
		<tr>
			<td>Micro Metering Valve Assembly, 1/4-28 Flat-Bottom, for 1/16&#34; OD</td>
			<td>IDEX Health&#38;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&#38;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&#189;&#8221; 
			(0.70 X 38 mm)</td>
		</tr>
		<tr>
			<td>Sterican needle</td>
			<td>B | Braun Sharing Enterprise</td>
			<td></td>
			<td>21G X 4&#190;&#8221; 
			(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 
			Bis(triphenylphosphine) 
			palladium(II) dichloride 
			&#8805;99% trace metals basis</td>
			<td>Sigma Aldrich</td>
			<td>412740-5G</td>
			<td></td>
		</tr>
		<tr>
			<td>Copper(I) iodide 
			purum, &#8805;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 
			&#8805;99%</td>
			<td>Sigma Aldrich</td>
			<td>220159-25ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Bromopentafluorobenzene 
			99%</td>
			<td>Sigma Aldrich</td>
			<td>B75158-10G</td>
			<td></td>
		</tr>
		<tr>
			<td>TEMPO Green Alternative 
			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. 8 for synthesis</td>
		</tr>
		<tr>
			<td>Ir(ppy)2(dtbbpy)PF6</td>
			<td></td>
			<td></td>
			<td>Refer to Ref. 9 for synthesis</td>
		</tr>
	</tbody>
</table>

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 ...

Watch this Scientific Journal Video about Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations at JoVE.com

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

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 ...

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