Name: a scalable balz-schiemann reaction protocol in a continuous flow reactor
Uploaded: 2023-02-10T12:55:00
Description: Watch this Scientific Journal Video about A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor at JoVE.com

We would like to thank the support of Shenzhen Science and Technology Program (Grant No. KQTD20190929172447117).

CAUTION: Carefully check the properties and toxicities of the chemicals described here for the appropriate chemical handling of the relevant material as per the material safety data sheets (MSDS). Some of the chemicals used are detrimental to health, and special care must be taken. Avoid inhalation and contact with skin of these materials. Please wear the proper PPE during the whole process.
1. Preparation of feeds for continuous flow protocol
<ol>
	<li>Purchase BF3</su...

<ol>
	<li>Alexander, J. C., Stephen, G. D., Paul, M. R., James, E. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Beyond+the+Balz-Schiemann+reaction:+The+utility+of+Tetrafluoroborates+and+Boron+Trifluoride+as+nucleophilic+fluoride+sources.">Beyond the Balz-Schiemann reaction: The utility of Tetrafluoroborates and Boron Trifluoride as nucleophilic fluoride sources.</a> Chemical Reviews. 115 (2), 566-611 (2014).</li><li>Mo, F., Qiu, D., Zhang, L., Wang, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+development+of+Aryl+Diazonium+chemistry+for+the+derivatization+of+aromatic+compounds.">Recent development of Aryl Diazonium chemistry for the derivatization of aromatic compounds.</a> Chemical Reviews. 121 (10), 5741-5829 (2021).</li><li>Riccardo, P., Maurizio, B., Alessandra, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flow+chemistry:+Recent+developments+in+the+synthesis+of+pharmaceutical+products.">Flow chemistry: Recent developments in the synthesis of pharmaceutical products.</a> Organic Process Research &amp; Development. 20 (1), 2-25 (2016).</li><li>Ball, N. D., Sanford, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+and+reactivity+of+a+Mono-&#963;-aryl+Palladium(iv)+fluoride+complex.">Synthesis and reactivity of a Mono-&#963;-aryl Palladium(iv) fluoride complex.</a> Journal of the American Chemical Society. 131 (11), 3796-3797 (2009).</li><li>Griffete, N., Herbst, F., Pinson, J., Ammar, S., Mangeney, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preparation+of+water-soluble+magnetic+nanocrystals+using+aryl+diazonium+salt+chemistry.">Preparation of water-soluble magnetic nanocrystals using aryl diazonium salt chemistry.</a> Journal of the American Chemical Society. 133 (6), 1646 (2011).</li><li>Stefan, A., Gunther, S., Matthew, J. F., Heinz, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+one-pot+Diazotation-Fluorodediazoniation+reaction+and+fluorine+gas+for+the+production+of+fluoronaphthyridines.">A one-pot Diazotation-Fluorodediazoniation reaction and fluorine gas for the production of fluoronaphthyridines.</a> Organic Process Research &amp; Development. 18 (8), 993-1001 (2014).</li><li>Carl, T., Alexandre, L., Rajeev, S. B., R&#233;jean, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Concise+and+efficient+synthesis+of+4-Fluoro-1H-pyrrolo[2,3-b]pyridine.">Concise and efficient synthesis of 4-Fluoro-1H-pyrrolo[2,3-b]pyridine.</a> Organic Letters. 5 (26), 5023-5025 (2003).</li><li>Nicolas, O., Erwan, L. G., Fran&#231;ois, X. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Handling+diazonium+salts+in+flow+for+organic+and+material+chemistry.">Handling diazonium salts in flow for organic and material chemistry.</a> Organic Chemistry Frontiers. 2 (5), 590-614 (2015).</li><li>Fortt, R., Wootton, R., Mello, A. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous-flow+generation+of+anhydrous+diazonium+species:+Monolithic+microfluidic+reactors+for+the+chemistry+of+unstable+intermediates.">Continuous-flow generation of anhydrous diazonium species: Monolithic microfluidic reactors for the chemistry of unstable intermediates.</a> Organic Process Research &amp; Development. 7 (5), 762-768 (2003).</li><li>Liu, Y., Zeng, C., Wang, C., Zhang, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous+diazotization+of+aromatic+amines+with+high+acid+and+sodium+nitrite+concentrations+in+microreactors.">Continuous diazotization of aromatic amines with high acid and sodium nitrite concentrations in microreactors.</a> Journal of Flow Chemistry. 8 (3-4), 139-146 (2018).</li><li>Arlene, B., Aisling, L., Alex, C. P., Marcus, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Forgotten+and+forbidden+chemical+reactions+revitalised+through+continuous+flow+technology.">Forgotten and forbidden chemical reactions revitalised through continuous flow technology.</a> Organic &amp; Biomolecular Chemistry. 19 (36), 7737-7753 (2021).</li><li>Jianli, C., Xiaoxuan, X., Jiming, L., Zhiqun, Y., Weike, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Revisiting+aromatic+diazotization+and+aryl+diazonium+salts+in+continuous+flow:+highlighted+research+during+2001-2021.">Revisiting aromatic diazotization and aryl diazonium salts in continuous flow: highlighted research during 2001-2021.</a> Reaction Chemistry &amp; Engineering. 7 (6), 1247-1275 (2022).</li><li>Li, B., Widlicka, D., Boucher, S., Hayward, C., Young, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Telescoped+flow+process+for+the+syntheses+of+N-Aryl+pyrazoles.">Telescoped flow process for the syntheses of N-Aryl pyrazoles.</a> Organic Process Research &amp; Development. 16 (12), 2031-2035 (2012).</li><li>Zhi, Y., Yan, L., Chuan, Y., Wei-ke, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous+flow+reactor+for+Balz-Schiemann+reaction:+a+new+procedure+for+the+preparation+of+aromatic+fluorides.">Continuous flow reactor for Balz-Schiemann reaction: a new procedure for the preparation of aromatic fluorides.</a> Tetrahedron Letters. 54 (10), 1261-1263 (2013).</li><li>Li, B., Steven, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+flow+processes+for+the+syntheses+of+N-aryl+pyrazoles+and+diethyl+cyclopropane-cis-1,2-dicarboxylate.">Development of flow processes for the syntheses of N-aryl pyrazoles and diethyl cyclopropane-cis-1,2-dicarboxylate.</a> Acs Symposium. 1181 (14), 383-402 (2014).</li><li>Zhiqun, Y., Hei, D., Xiaoxuan, X., Jiming, L., Weike, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous-Flow+diazotization+for+efficient+synthesis+of+Methyl+2-(Chlorosulfonyl)benzoate:+An+example+of+inhibiting+parallel+side+reactions.">Continuous-Flow diazotization for efficient synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An example of inhibiting parallel side reactions.</a> Organic Process Research &amp; Development. 20 (12), 2116-2123 (2016).</li><li>Jiming, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous-flow+double+diazotization+for+the+synthesis+of+m-difluorobenzene+via+Balz-Schiemann+reaction.">Continuous-flow double diazotization for the synthesis of m-difluorobenzene via Balz-Schiemann reaction.</a> Journal of Flow Chemistry. 10 (4), 589-596 (2020).</li><li>Zhiqun, Y., Yanwen, L., Chuanming, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Continuous+kilogram-scale+process+for+the+manufacture+of+o-Difluorobenzene.">A Continuous kilogram-scale process for the manufacture of o-Difluorobenzene.</a> Organic Process Research &amp; Development. 16 (10), 1669-1672 (2012).</li><li>Hathaniel, H. P., Timothyl, J. S., Stephen, L. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+synthesis+of+aryl+fluorides+in+continuous+flow+through+the+Balz-Schiemann+reaction.">Rapid synthesis of aryl fluorides in continuous flow through the Balz-Schiemann reaction.</a> Angewandte Chemie International Edition. 55 (39), 11907-11911 (2016).</li><li>David, R. S., Fran&#231;ois, L., William, J. M., John, R. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+improved+Balz-Schiemann+reaction+enabled+by+ionic+liquids+and+continuous+processing.">An improved Balz-Schiemann reaction enabled by ionic liquids and continuous processing.</a> Tetrahedron. 75 (32), 4261-4265 (2019).</li><li>He, G., Wang, D., Liang, C., Chen, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Theoretical+study+on+thermal+safety+of+preparing+fluorobenzene+by+the+Balz-Schiemann+reaction+and+fluorodenitration+reaction.">Theoretical study on thermal safety of preparing fluorobenzene by the Balz-Schiemann reaction and fluorodenitration reaction.</a> Journal of Chemical Health &amp; Safety. 20 (1), 30-34 (2013).</li><li>Schotten, C., Leprevost, S. K., Yong, L. M., Hughes, C. E., Browne, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+the+thermal+stabilities+of+diazonium+salts+and+their+corresponding+triazenes.">Comparison of the thermal stabilities of diazonium salts and their corresponding triazenes.</a> Organic Process Research &amp; Development. 24 (10), 2336-2341 (2020).</li><li>Sharma, Y., Nikam, A. V., Kulkarni, A. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Telescoped+sequence+of+exothermic+and+endothermic+reactions+in+multistep+flow+synthesis.">Telescoped sequence of exothermic and endothermic reactions in multistep flow synthesis.</a> Organic Process Research &amp; Development. 23 (2), 170-176 (2018).</li></ol>

A continuous flow protocol of the Balz-Schiemann reaction has been successfully performed through a combination of a micro-channel flow reactor and a dynamically mixed flow reactor. This strategy features several advantages compared with the batch process: (i) it is safer with controlled diazonium salt formation; (ii) it is more amenable to a higher reaction temperature, 10 &#176;C versus -20 &#176;C; and (iii) it is more efficient without isolation of the diazonium intermediate, two steps in one continuous process. Spec...

The Balz&#8722;Schiemann reaction is a classic method for replacing the diazonium group with fluorine by heating ArN2+BF4&#8722; without a solvent1,2. The reaction can be applied to a wide variety of aryl amine substrates, making it a generally applicable approach to synthesize aryl amines, which are frequently utilized for advanced intermediates in pharmaceutical or fine chemical industries2,3. Unfortunately, harsh reaction conditions are often employed in the Balz-Schiemann reaction, and the reaction generates potentially explosive aryldiazonium salts4,5,6,7,8. Other challenges associated with the Balz-Schiemann reaction are the formation of side products during the thermal decomposition process and its modest yield. In order to minimize the side product formation, thermal dediazotization can be performed in nonpolar solvents or using neat diazonium salts9,10, which means the aryldizanium salts should be isolated. However, the diazotization of aromatic amines is generally exothermic and fast, which is a risk associated with the isolation of the explosive diazonium salt, especially in large-scale production.
In recent years, continuous flow synthesis technologies have helped to overcome the safety issues associated with the Balz-Schiemann reactions11,12. Although there are some examples of diazotization of aromatic amines using continuous microreactors for deamination at positions para to aryl-chlorides, 5-azodyes, and chlorosulfonylation, these contributions were only reported on a laboratory scale13,14,15,16,17. Yu and co-workers developed a continuous kilo-scale process for the synthesis of aryl fluorides18. They have shown that the improved heat and mass transfer of a flow system would benefit both the diazotization process and the fluorination process. However, they used two separate continuous flow reactors; therefore, the diazotization and thermal decomposition processes were investigated separately. A further contribution was published by Buchwald and co-workers19, where they presented a hypothesis that if the product formation was proceeding through the SN2Ar or SN1 mechanism, then the yield may be improved by increasing the concentration of the fluoride source. They developed a flow-to-continuous stirred tank reactor (CSTR) hybrid process in which the diazonium salts were generated and consumed in a continuous and controlled manner. However, the heat and mass transfer efficiency of a CSTR is not good enough as a tube flow reactor, and a large CSTR cannot be expected to be used with explosive diazonium salts in large-scale production. Subsequently, Naber and co-workers developed a fully continuous flow process to synthesize 2-fluoroadenine from 2,6-diaminopurine20. They found that the exothermic Balz-Schiemann reaction was easier to control in a continuous flow manner and that the tubing dimensions of the flow reactor would influence the heat transfer and temperature control aspects - a tube reactor with large dimensions shows a positive improvement. However, the tube reactor&#39;s scaled-up effect will be notable, and the poor solubility of the polar aryl diazonium salt in organic solvents is troublesome for static tube reactors, which face a blockage risk. Even though remarkable progress has been established, there are still some problems associated with large-scale Balz-Schiemann reactions. Thus, the development of an improved protocol that would provide rapid and scalable access to aryl-fluorides is still significant.
The challenges associated with large-scale Balz&#8722;Schiemann reaction processing include the following:(i)the thermal instability of an accumulated diazonium intermediate over a short time period21; (ii) the long processing times; and (iii) the non-uniform heating or the presence of water in the diazonium fluoroborate, leading to uncontrollable thermal decomposition and increased by-product formation22,23. Additionally (iv) in some flow processing modes, an isolation of the diazonium intermediate is still required due to its low solubility14, which is then fed into a uncontrolled rate decomposition reaction. The risk of handling a large quantity of in-line diazonium salt cannot be avoided. Thus, there is significant benefit in developing a continuous flow strategy to solve the abovementioned problems and avoid both the accumulation and the isolation of the unstable diazonium species.
In order to establish an inherently safer production of chemicals in pharmaceuticals, our group has focused on multi-step continuous flow technology. In this work, we apply this technology to the Balz&#8722;Schiemann synthesis on a kilogram scale in a way that eliminates the isolation of aryl diazonium salts, while facilitating efficient fluorination.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>2-Methylpyridin-3-amine</td>
			<td>Raffles Pharmatech Co. Ltd</td>
			<td>C2021236-SM5-H221538-008</td>
			<td>HPLC: &#62;98%, Water by KF &#8804;0.5%</td>
		</tr>
		<tr>
			<td>316L piston constant flow pump</td>
			<td>Oushisheng (Beijing) Technology Co.,Ltd</td>
			<td>DP-S200</td>
			<td></td>
		</tr>
		<tr>
			<td>BF3.Et2O</td>
			<td>Whmall.com</td>
			<td>B802217</td>
			<td></td>
		</tr>
		<tr>
			<td>Citric acid</td>
			<td>Titan Technology Co., Ltd</td>
			<td>G83162G</td>
			<td></td>
		</tr>
		<tr>
			<td>con.HCl</td>
			<td>Foshang Xilong Huagong</td>
			<td>1270110101601M&#160;&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Dynamically mixed flow reactor</td>
			<td>Autichem Ltd</td>
			<td>DM500</td>
			<td>316L reator with 500 mL of internal volume</td>
		</tr>
		<tr>
			<td>Heptane</td>
			<td>Shenzhen Huachang</td>
			<td>HCH606</td>
			<td>Water by KF &#8804;0.5%</td>
		</tr>
		<tr>
			<td>Micro flow reactor</td>
			<td>Corning Reactor Technology Co.,Ltd</td>
			<td>G1 Galss AFR</td>
			<td>Glass module with 9 mL of internal volume</td>
		</tr>
		<tr>
			<td>PTFE piston constant flow pump</td>
			<td>Sanotac China</td>
			<td>MPF1002C</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium hydroxide</td>
			<td>Foshang Xilong Huagong</td>
			<td>1010310101700</td>
			<td></td>
		</tr>
		<tr>
			<td>tert-Butyl methyl ether</td>
			<td>Titan Technology Co., Ltd</td>
			<td>01153694</td>
			<td></td>
		</tr>
		<tr>
			<td>tert-Butyl nitrite</td>
			<td>Whmall.com</td>
			<td>XS22030900060</td>
			<td></td>
		</tr>
		<tr>
			<td>Tetrahydrofuran</td>
			<td>Titan Technology Co., Ltd</td>
			<td>1152930</td>
			<td>Water by KF &#8804;0.5%</td>
		</tr>
	</tbody>
</table>

a scalable balz-schiemann reaction protocol in a continuous flow reactor

The demand for aromatic fluorides is steadily increasing in the pharmaceutical and fine chemical industries. The Balz-Schiemann reaction is a straightforward strategy for preparing aryl fluorides from aryl amines, via the preparation and conversion of diazonium tetrafluoroborate intermediates. However, significant safety risks exist in handling the aryl diazonium salts when scaling up. In order to minimize the hazard, we present a continuous flow protocol that has been successfully performed at a kilogram scale that eliminates the isolation of aryl diazonium salts while facilitating efficient fluorination. The diazotization process was performed at 10 &#176;C with a residence time of 10 min, followed by a fluorination process at 60 &#176;C with a residence time of 5.4 s with about 70% yield. The reaction time has been dramatically reduced by introducing this multi-step continuous flow system.

The model reaction is shown in Figure 2. 2-Methylpyridin-3-amine (compound 1 in Figure 2) was chosen as the starting material to prepare 2-methylpyridin-3-fluoride (compound 3 in Figure 2) via the Balz-Schiemann reaction. The experimental parameters were systematically investigated by varying reaction temperature and residence time. Feed A is 0.35 M 2-methylpyridin-3-amine in THF. Feed B is pure BF3&#183;Et2...

Watch this Scientific Journal Video about A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor at JoVE.com

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

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

The demand for aromatic fluorides is steadily increasing in the pharmaceutical and fine chemical industries. The Balz-Schiemann reaction is a ...

Our protocol is a straightforward strategy for preparing aryl fluoride from aryl amine in a continuous flow manner. The is safe, controllable, and efficient. This measure could provide an insight into the fine chemical and the pharmaceutical industry, which could make a safe and a reliable process.Please be careful and attentive will performing this technique. First, read all the steps and figure out the details of operating before you try this technique. To perform the Balz-Schiemann reaction in a continuous flow system, prepare two modules of the microflow reactor with an internal reaction volume of nine milliliters, and one dynamic mixing tube reactor with an internal reaction volume of 500 milliliters.Also, prepare one constant flow pump with a PTFE pump head, and three constant flow pumps with the 316 L stainless steel pump head. Assemble the equipment as described in the manuscript. Check the mechanical integrity of all the connections between pumps, pipelines, and flow reactors before use.Set the flow rates of the pumps. Then set the jacket outlet, temperature of the premixing and diazonium salt formation zone at minus five degrees Celsius and the jacket outlet temperature of the thermal decomposition zone at 60 degrees Celsius to maintain the temperature regulation. To check equipment safety and leakage, first place the dosing pipeline of pumps A, B, C and D into the feed E bottle.And discharging pipeline into the waste collecting bottle. Then start the pumps and slowly regulate the back pressure up to three bars. Observe the stability of each pump and check all the joints, pipelines, and reactors for any solvent leakage.Also, check if the jacket inlet and outlet temperature of each zone and the current inlet pressure of each pump are within the target ranges. Then, stop pumps after 10 minutes of steady state equilibrium. To begin the reaction process, place the dosing pipeline's A, B, C and D into the corresponding feeds, and put the discharging pipeline into the waste collection bottle.Start pumps A and B simultaneously and record the time. Then start pump C after 30 seconds and pump D after 8 minutes. After 10 minutes of steady state equilibrium, place the discharging pipeline into the product collection vessel.Observe and record the temperature of each zone and the pressure of each pump. Once feed B pumping is complete, insert the dosing pipeline B into feed E.Then put the discharging pipeline into a waste collection bottle. And dosing pipeline's, A, C and D into the feed E bottle.Turn off pumps A, B, C, and D after 10 minutes of washing. A continuous flow reactor was successfully applied to the Balz-Schiemann reaction on a model substrate. The reaction temperature of the flow experiments was successfully controlled at 10 degrees Celsius with 70%crude product purity, which was higher than what was obtained in batch processing.Almost 98%of conversion was reached in 600 seconds of the resident's time. When the flow rate was 50 milliliters per minute in the diazotization zone, and 5.4 seconds in the thermal decomposition zone, at 100 milliliters per minute flow rate. Increasing the flow rate leaves a large amount of starting material in the reaction and reducing the flow rate may completely consume the starting material, but limit production efficiency.The crude product was further purified and analyzed using mass spectroscopy, proton-NMR and fluorine-NMR. It's important to show the reactors are pumps according to the chemical property and absorbability of substances, especially for those who highly or for those reactions with solid formation. Reactions that have a liquid effect and faster reaction rate can be carried out effectivity using a continuous flow system.In addition, it can cause reaction that may or may not result in the formation of a solid.

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