We would like to thank Corning for the gift of the glass flow reactor.

Health Warnings and Specification of Reagents 
Benzophenone Hydrazone: May cause irritation of the digestive tract. The toxicological properties of this substance have not been fully investigated. May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated. May cause skin irritation and eye irritation18.
Activated manganese oxide (MnO2): (Health MSDS rating of 2) Hazardous in case of skin contact, eye contact, ingestion, and inhalation19.
Dibasic potassium phosphate (KH2PO4): (Health MSDS rating of 2) Hazardous in case of skin contact, eye contact, ingestion, and inhalation20.
Dichloromethane: (Health MSDS rating of 2, Fire rating of 1) Very hazardous in case of eye contact (irritant), of ingestion, of inhalation. Hazardous in case of skin contact (irritant, permeator). Inflammation of the eye is characterized by redness, watering, and itching21.
1. Synthesis of Diphenyldiazomethane (DDM):
<ol>
	<li>Before beginning synthesis of DDM, ensure all necessary materials listed are present as well as necessary reagents to ensure that proper synthesis can be conducted.</li>
	<li>Add 10 g (.72 equivalent) of anhydrous KH2PO4 and 31 g of activated manganese dioxide, MnO2 (3.5 equivalents) to a 250 mL 3-neck round bottom flask (1), and a magnetic stirrer.</li>
	<li>Add 20 g of benzophenone hydrazone into a separate 100-mL 2-neck round bottom flask (2), a magnetic stirrer, and store at room temperature.</li>
	<li>Add 67 mL of dichloromethane (DCM) and equip both flasks (1 and 2) with stoppers, thermometer, and thermocouple.</li>
	<li>After purging both flasks with inert gas for 15 min, apply an ice bath to the KH2PO4 and MnO2 solution (flask 1). Ensure that the temperature of the solution stays constant at 0 &#176;C for at least 30 min.</li>
	<li>After 30 min of constant temperature reading, transfer the benzophenone hydrazone (flask 2) into the flask containing KH2PO4 and MnO2 (flask 1). Carry out the reaction for 24 h to reach completion.</li>
</ol>
2. Purification of DDM:
<ol>
	<li>After 24 h, add 120 mL of pentane to the reaction mixture (a deep, red purple solution).</li>
	<li>Filter the solution rapidly through neutral silica gel (50 - 200 &#181;m). It is important that the contact time of the product with the silica does not exceed 5 min. DDM is acid sensitive; significant decomposition will occur with longer contact time22.
	<ol>
		<li>Carry out the filtration with a medium porosity sintered glass funnel, attached to a vacuum filtration system or a fume hood vacuum system.</li>
	</ol>
	</li>
	<li>Transfer the filtrate and remove solvent with a rotary evaporator in vacuo. The resulting crude product is a deep-purple oil.
	<ol>
		<li>Wrap aluminum foil around the flask to keep light away from DDM. DDM is light sensitive.</li>
	</ol>
	</li>
	<li>After covering the flask with aluminum foil, store pure DDM in the freezer, sealed and under an atmosphere of inert gas.</li>
	<li>Monitor for crystallization to occur, which usually takes 2 - 3 days. Remove the flask from the freezer and allow it to reach room temperature. A further purification step is necessary. Add 200-proof ethyl alcohol to the flask, filter and then use a rotary evaporator to remove the remaining solvent. At this point, most impurities remaining should be removed.
	<ol>
		<li>Analyze the resulting deep, reddish purple crystals of DDM by UV spectroscopy. The experimental molar absorptivity was measured to be (&#949;) 94.8, which matched literature values. 
		CAUTION: Below are the relevant health warnings and specifications of reagents for the proper and safe handling of carrying out the reaction protocol for DDM. When dealing with these substances, ensure proper PPE at all times and working conditions under a fume hood. 
		 
		DDM: Prolonged or repeated exposure may cause allergic reactions in certain sensitive individuals23. 
		p-nitrobenzoic acid: (MSDS health rating of 2) ensure that reagent is kept away from heat. Keep away from sources of ignition. Empty containers pose a fire risk; evaporate the residue under a fume hood. Ground all equipment containing material. If ingested, seek medical advice immediately and show the container or the label. Avoid contact with skin and eyes24. 
		Ethyl Alcohol, 200 Proof: (MSDS health rating of 2, Health Rating of 3) Hazardous in case of skin contact, eye contact, and inhalation. Ethanol rapidly absorbs moisture from the air, and can react vigorously with oxidizers25. 
		Toluene: (MSDS health rating of 2, Health Rating of 3) Hazardous in case of skin contact (irritant), of eye contact (irritant), of ingestion, and of inhalation. Slightly hazardous in case of skin contact (permeator). Highly flammable26. 
		o-xylene: (MSDS health rating of 2, Health Rating of 3) possibility of developing teratogenic effects, developmental toxicity to reproductive system in males, and toxic if ingested to kidneys, liver, upper respiratory tract, skin, eyes, and central nervous system. Keep away from skin contact (irritant, permeator), eye contact (irritant), or&#160;ingestion&#160;and inhalation27.</li>
	</ol>
	</li>
</ol>
3. Preparing Solution of DDM for Continuous Flow:
<ol>
	<li>Rinse a 100 mL volumetric flask with ethanol.</li>
	<li>Tare a 6-dram vial on an analytical balance, and add .1942 g of DDM into the dram vial. Add anhydrous ethanol (5 mL) to the vial in 2 to 3 increments until all the DDM goes into solution. With a pipette, transfer the solution from the 6-dram vial into the clean 100 mL volumetric flask.
	<ol>
		<li>Carefully add ethanol until the minimum point of the meniscus aligns with the line denoted on the volumetric flask.</li>
		<li>Add 1 mL of toluene, the internal standard, into the flask. The volumetric flask can now be capped and stored until both the DDM solution and p-nitrobenzoic acid solution are ready for the continuous flow reaction.</li>
	</ol>
	</li>
</ol>
4. Preparation of 0.1 M Stock Solution of p-nitrobenzoic Acid:
<ol>
	<li>Rinse the 250 mL volumetric flask multiple times with anhydrous ethanol.</li>
	<li>Tare a 6-dram vial on an analytical balance. Add 4.1780 g of p-nitrobenzoic acid into the dram vial. After adding the acid, add anhydrous ethanol (5 mL) into 2 to 3 increments to the vial until all the p-nitrobenzoic acid goes into solution.
	<ol>
		<li>With a pipette, transfer the solution from the 6-dram vial into the clean 250 mL volumetric flask.</li>
		<li>Carefully add ethanol until the minimum point of the meniscus aligns with the line of the volumetric flask.</li>
		<li>Add 1 mL of o-xylene, the internal standard, into the flask. The volumetric flask can now be capped and stored as needed.</li>
	</ol>
	</li>
</ol>
5. Preparation of the Continuous Flow Reactor:
<ol>
	<li>Check that the transducer is connected to the pump controller in portal A for both ISCOs, and empty collecting beakers at the end of each exit tube to collect reaction solutions, waste, and solvent.
	<ol>
		<li>Set-up and check both ISCO 1 (p-nitrobenzoic acid) and ISCO 2 (DDM), as shown in Figure 9.</li>
		<li>Set-up each ISCO pump with its own controller to independently control reagent streams. This allows for the flow rates to be independently adjusted as necessary.</li>
	</ol>
	</li>
	<li>In a separate beaker, add 400 mL of ethanol. This will be utilized to flush the reactor.
	<ol>
		<li>Turn the inlet HIP valve counter-clockwise until the valve is fully open (denoted as valve A and B, respectively). Press &#34;Constant Flow&#34; on the pump controller, and then &#34;A&#34;, which denotes the inlet which the transducer is linked to the ISCO. This action prompts the user to enter the desired flow rate.</li>
		<li>Enter a flowrate of &#34;70&#34;, and press &#34;Enter&#34;. When ready, hit &#34;Refill&#34; to communicate to the system to draw up the solution at a rate of 70 mL/min.</li>
		<li>Begin drawing the ethanol solvent through the inlet tube. Note that if the flow rate is drawing the solvent in, the flow rate on the ISCOs should read -70.000 mL/min. The solvent level in the flask will begin to decrease. 
		&#8203;NOTE: It is perfectly normal if the volume of solvent does not match the volume that is shown on the controller. Air will be partially drawn into the system as well.</li>
	</ol>
	</li>
	<li>When both ISCO 1 and ISCO 2 have been completely filled and the controller indicates this by reading &#34;Cylinder Full&#34; and &#34;Stopped&#34;, turn the inlet valve A and B completely closed by turning the valve fully clockwise.</li>
	<li>Open the outlet valve which operates similarly to the inlet valve, which is the valve leading to the reactor, by turning it counterclockwise. The outlet valve feeds through the filter, past the one-way valve, and from there past the pressure relieve valve and into the flow reactor.</li>
	<li>At this point, change the flow rate. The maximum total flow rate recommended on a single run should not exceed 30 mL/min.
	<ol>
		<li>Clean each ISCO separately, running each at a flow rate of 30 mL/min.</li>
	</ol>
	</li>
	<li>Press &#34;A&#34; on the ISCO that is currently set up to run the ethanol through the system. Change the flow rate by entering the desired flow rate of &#34;30&#34;, &#34;Enter&#34;, and finally &#34;Run&#34;. This communicates to the system to run at a rate of 30 mL/min. 
	&#8203;NOTE: As the flow equilibrates, the solvent begins flowing through the system.
	<ol>
		<li>Monitor the reactor for leakage or blockage, and that there is solvent flowing throughout the whole reactor. Once both ISCOs have been cleaned 2 - 3 times, the system is now ready to run the experiment.</li>
	</ol>
	</li>
</ol>
6. Setting Up the .01 M DDM ISCO 2 Pump:
<ol>
	<li>Place the inlet feed in the 100-mL volumetric flask of DDM. Open the inlet valve B (Feed 2 in Figure 9).</li>
	<li>Set the ISCO to a flow rate of 70 mL/min. Begin drawing the solution up until all of it is taken up into the syringe by hitting &#34;Refill&#34;.</li>
	<li>Note that the volume of solution in the ISCO and the original volume of solution in the flask can be slightly different. Air is also pulled in the ISCO pump.
	<ol>
		<li>If there is leftover DDM after the ISCO has reached max volume after the uptake of solution, press &#34;Run&#34; to push out the air that was drawn along with the flask from the inlet. Once DDM begins pushing out, hit &#34;Stop&#34;, and then &#34;Refill&#34; to begin refilling the ISCO.</li>
		<li>Keep repeating these steps until all DDM has been taken up (this will be applied to p-nitrobenzoic acid as well).</li>
		<li>Flow about 1 mL of DDM from pump. ISCO 2 pump is now ready to be run. The solvent level is in line and ready to begin flowing through the continuous flow reactor.</li>
	</ol>
	</li>
	<li>Close inlet valve B by turning the HIP valve clockwise until it cannot be turned further, and open the outlet valve which feeds into the continuous flow reactor by turning the valve counter clockwise until it is fully open. Transfer the 1 mL of DDM and toluene solution into a cuvette for UV-Vis analysis.</li>
	<li>Set the flow rate to 1.42 mL/min. Do not hit &#34;Run&#34; until the p-nitrobenzoic acid ISCO 1 has been set-up by the same protocol at a flow rate of 3.58 mL/min and is ready to be run in tandem.</li>
</ol>
7. Setting Up the .1 M p -nitrobenzoic Acid ISCO 1 Pump:
<ol>
	<li>Open the inlet valve A of ISCO 1 pump, with the 250 mL volumetric flask of p-nitrobenzoic acid at the end of the feeding tube.</li>
	<li>Once the feed tube is completely submerged in the volumetric flask, set the ISCO to a flow rate of 70 mL/min. Again, check to see if the flow rate on the controller reads 70.00 mL/min upon hitting &#34;Refill&#34;.</li>
	<li>Begin drawing the solution up until all of it is taken up into the syringe, using the same technique listed above to get all of the solution into the system.</li>
	<li>Close the inlet valve by turning the HIP valve clockwise until it is fully closed. Open the outlet valve which feeds into the continuous flow reactor by turning the valve counter clockwise until it is fully open.</li>
	<li>Set the flow rate to 3.58 mL/min. The total flow rate including the 1.42 mL/min of DDM will be 5.00 mL/min, for a total residence time within the reactor of approximately 11 minutes with a ratio of 10:1 p-nitrobenzoic acid to DDM.</li>
</ol>
8. Conducting the Reaction in Flow with 10:1 Molar Equivalence of p-nitrobenzoic acid and DDM:
<ol>
	<li>Once each pump is ready with the reagent&#39;s solutions, the valves properly adjusted, and the correct flow rates have been entered, hit &#34;Run&#34; on both pumps. After the one-way valve pressure has equilibrated, the reagent&#39;s solutions will begin flowing into the reactor modules.
	<ol>
		<li>Monitor flow. DDM&#39;s feed enters at module 1, p-nitrobenzoic acid&#39;s feed into module 2, and mixing take place at module 3. The residence time is approximately 11 minutes.</li>
		<li>Monitor color change (indicative of reaction progress). The color in module 2, prior to mixing, is strong pink. The color intensity decreases, it becomes fainter pink in module 3, and pale pink in module 4. The modules thereafter are colorless.</li>
	</ol>
	</li>
</ol>
9. Cleaning the Continuous Flow Reactor:
<ol>
	<li>Once both runs of DDM and p-nitrobenzoic acid are completed, fill a beaker with 400 mL ethanol. This will be used to clean the reactor and the ISCO pumps.</li>
	<li>Turn the inlet HIP valve counter-clockwise until the valve is fully open.</li>
	<li>Set the flow rate to 70, press &#34;Enter&#34; and &#34;Refill&#34; to begin drawing the ethanol solvent through the inlet tube (note that if the flow rate is drawing the solvent in, the flow rate on the ISCOs should read 70 mL/min).</li>
	<li>Once the ISCOs have been filled, the ISCOs will automatically stop, and the controller will read &#34;Cylinder Full&#34; and &#34;Stopped&#34;. At this point, turn the inlet valve completely closed, by turning the valve clockwise until the HIP valve cannot be turned further.</li>
	<li>Open the outlet valve which operates similarly to the inlet valve, by turning it counterclockwise. The outlet valve feeds through the filter, passes the one-way valve, and from there flows through the pressure relieve valve and into the flow reactor.</li>
	<li>Adjust the flow rate to not exceed 30 mL/min.</li>
	<li>Press &#34;A&#34; on the ISCO that is currently set up to run the ethanol through the system. Change the flow rate by entering the desired flow rate of &#34;10&#34;, hit &#34;Enter&#34;, and then hit &#34;Run&#34;. Check the system to see there is no leakage or blockage, and that there is solvent flowing throughout the whole system. 
	NOTE: Once both ISCOs have been cleaned 2 times with ethanol and once with just air following procedures noted above, the system is now ready to run for future experiments.</li>
</ol>

<ol>
	<li>Jimenez-Gonzalez, C., 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=Engineering+Research+Areas+for+Sustainable+Manufacturing:+A+Perspective+from+Pharmaceutical+and+Fine+Chemicals+Manufacturers.">Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers.</a> Org Process Res Dev. 15 (4), 900-911 (2011).</li><li>Constable, D. J. C., 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=Key+green+chemistry+research+areas+-+a+perspective+from+pharmaceutical+manufacturers.">Key green chemistry research areas - a perspective from pharmaceutical manufacturers.</a> Green Chem. 9 (5), 411-420 (2007).</li><li>Plutschack, M. B., Pieber, B., Gilmore, K., Seeberger, P. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Hitchhiker's+Guide+to+Flow+Chemistry.">The Hitchhiker's Guide to Flow Chemistry.</a> Chem Rev. , (2017).</li><li>Dallinger, D., Kappe, C. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Why+flow+means+green+-+Evaluating+the+merits+of+continuous+processing+in+the+context+of+sustainability.">Why flow means green - Evaluating the merits of continuous processing in the context of sustainability.</a> Curr Opin Green Sustain Chem. 7, 6-12 (2017).</li><li>Movsisyan, M., 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=Taming+hazardous+chemistry+by+continuous+flow+technology.">Taming hazardous chemistry by continuous flow technology.</a> Chem Soc Rev. 45 (18), 4892-4928 (2016).</li><li>Hessel, V., Ley, S. V. <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+in+Europe.">Flow Chemistry in Europe.</a> J Flow Chem. 6 (3), 135-135 (2016).</li><li>Mascia, S., 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=End-to-End+Continuous+Manufacturing+of+Pharmaceuticals:+Integrated+Synthesis,+Purification,+and+Final+Dosage+Formation.">End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation.</a> Angew Chem Int Edit. 52 (47), 12359-12363 (2013).</li><li>Newman, S. G., Jensen, K. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+role+of+flow+in+green+chemistry+and+engineering.">The role of flow in green chemistry and engineering.</a> Green Chem. 15 (6), 1456-1472 (2013).</li><li>Watts, P., Haswell, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+application+of+micro+reactors+for+organic+synthesis.">The application of micro reactors for organic synthesis.</a> Chem Soc Rev. 34 (3), 235-246 (2005).</li><li>Wiles, C., Watts, P. <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+reactors:+a+perspective.">Continuous flow reactors: a perspective.</a> Green Chem. 14 (1), 38-54 (2012).</li><li>Roberge, D. M., 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=Microreactor+technology+and+continuous+processes+in+the+fine+chemical+and+pharmaceutical+industry:+Is+the+revolution+underway.">Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: Is the revolution underway.</a> Org Process Res Dev. 12 (5), 905-910 (2008).</li><li>Degennaro, L., Carlucci, C., De Angelis, S., Luisi, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flow+Technology+for+Organometallic-Mediated+Synthesis.">Flow Technology for Organometallic-Mediated Synthesis.</a> J Flow Chem. 6 (3), 136-166 (2016).</li><li>Roberts, J. D., Watanabe, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Kinetics+and+Mechanism+of+the+Acid-Catalyzed+Reaction+of+Diphenyldiazomethane+with+Ethyl+Alcohol.">The Kinetics and Mechanism of the Acid-Catalyzed Reaction of Diphenyldiazomethane with Ethyl Alcohol.</a> J Am Chem Soc. 72 (11), 4869-4879 (1950).</li><li>Roberts, J. D., Watanabe, W., Mcmahon, R. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Kinetics+and+Mechanism+of+the+Reaction+of+Diphenyldiazomethane+and+Benzoic+Acid+in+Ethanol.">The Kinetics and Mechanism of the Reaction of Diphenyldiazomethane and Benzoic Acid in Ethanol.</a> J Am Chem Soc. 73 (2), 760-765 (1951).</li><li>Roberts, J. D., Watanabe, W., Mcmahon, R. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Kinetics+and+Mechanism+of+the+Reaction+of+Diphenyldiazomethane+with+2,4-Dinitrophenol+in+Ethanol.">The Kinetics and Mechanism of the Reaction of Diphenyldiazomethane with 2,4-Dinitrophenol in Ethanol.</a> J Am Chem Soc. 73 (6), 2521-2523 (1951).</li><li>Roberts, J. D., Regan, C. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Kinetics+and+Some+Hydrogen+Isotope+Effects+of+the+Reaction+of+Diphenyldiazomethane+with+Acetic+Acid+in+Ethanol.">Kinetics and Some Hydrogen Isotope Effects of the Reaction of Diphenyldiazomethane with Acetic Acid in Ethanol.</a> J Am Chem Soc. 74 (14), 3695-3696 (1952).</li><li>Oferrall, R. A., Kwok, W. K., Miller, S. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Medium+Effects+Isotope+Rate+Factors+++Mechanism+of+Reaction+of+Diphenyldiazomethane+with+Carboxylic+Acids+in+Solvents+Ethanol+++Toluene.">Medium Effects Isotope Rate Factors + Mechanism of Reaction of Diphenyldiazomethane with Carboxylic Acids in Solvents Ethanol + Toluene.</a> J Am Chem Soc. 86 (24), 5553 (1964).</li><li>Aldrich, 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> Material Safety Data Sheet: Benzophenone Hydrazone. 4.2, 3-6 (2014).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet: Manganese dioxide MSDS. , (2005).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet: Potassium phosphate dibasic MSDS. , 1-5 (2005).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet: Methylene Chloride MSDS. , 3-5 (2005).</li><li>Smith, L. I., Howard, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diphenyldiazomethane.">Diphenyldiazomethane.</a> Org. Synth. 3 (351), (1955).</li><li>Capot Chemical Co. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet, diphenyldiazomethane. 2017, (2010).</li><li>Science Lab. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet: P-nitrobenzoic acid MSDS. , 3-5 (2005).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet Ethyl Alcohol 200 proof MSDS. , (2005).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet Toluene MSDS. , 4-5 (2005).</li><li>Science Lab Chemicals &amp; Laboratory Equipment. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Material Safety Data Sheet o-Xylene MSDS. , 3-5 (2005).</li><li>Zheng, J., 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=Cross-Coupling+between+Difluorocarbene+and+Carbene-Derived+Intermediates+Generated+from+Diazocompounds+for+the+Synthesis+of+gem-Difluoroolefins.">Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gem-Difluoroolefins.</a> Organic Letters. 17, 6150-6153 (2015).</li><li>Reimlinger, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=1,5-Dipolar+cyclizations,+I.+Definition+and+contributions+to+the+Imidazide/Tetrazole+tautomerism.">1,5-Dipolar cyclizations, I. Definition and contributions to the Imidazide/Tetrazole tautomerism.</a> Chem. Ber. 103, 1900 (1970).</li><li>Baumann, M., Garcia, A. M. R., Baxendale, I. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Flow+synthesis+of+ethyl+isocyanoacetate+enabling+the+telescoped+synthesis+of+1,2,4-triazoles+and+pyrrolo-[1,2-c]+pyrimidines.">Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c] pyrimidines.</a> Org Biomol Chem. 13 (14), 4231-4239 (2015).</li><li>Baumann, M., Baxendale, I. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+synthesis+of+active+pharmaceutical+ingredients+(APIs)+using+continuous+flow+chemistry.">The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry.</a> Beilstein J Org Chem. 11, 1194-1219 (2015).</li><li>Pastre, J. C., Browne, D. L., Ley, S. V. <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+syntheses+of+natural+products.">Flow chemistry syntheses of natural products.</a> Chem Soc Rev. 42 (23), 8849-8869 (2013).</li><li>Pirotte, G., 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+Polymer+Synthesis+toward+Reproducible+Large-Scale+Production+for+Efficient+Bulk+Heterojunction+Organic+Solar+Cells.">Continuous Flow Polymer Synthesis toward Reproducible Large-Scale Production for Efficient Bulk Heterojunction Organic Solar Cells.</a> Chemsuschem. 8 (19), 3228-3233 (2015).</li><li>Kumar, A., 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+Synthesis+of+Regioregular+Poly(3-Hexylthiophene):+Ultrafast+Polymerization+with+High+Throughput+and+Low+Polydispersity+Index.">Continuous-Flow Synthesis of Regioregular Poly(3-Hexylthiophene): Ultrafast Polymerization with High Throughput and Low Polydispersity Index.</a> J Flow Chem. 4 (4), 206-210 (2014).</li><li>Helgesen, M., 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=Making+Ends+Meet:+Flow+Synthesis+as+the+Answer+to+Reproducible+High-Performance+Conjugated+Polymers+on+the+Scale+that+Roll-to-Roll+Processing+Demands.">Making Ends Meet: Flow Synthesis as the Answer to Reproducible High-Performance Conjugated Polymers on the Scale that Roll-to-Roll Processing Demands.</a> Adv Energy Mater. 5 (9), 1401996 (2015).</li><li>Grenier, F., 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=Electroactive+and+Photoactive+Poly[lsoindigo-alt-EDOT]+Synthesized+Using+Direct+(Hetero)Arylation+Polymerization+in+Batch+and+in+Continuous+Flow.">Electroactive and Photoactive Poly[lsoindigo-alt-EDOT] Synthesized Using Direct (Hetero)Arylation Polymerization in Batch and in Continuous Flow.</a> Chem Mater. 27 (6), 2137-2143 (2015).</li><li>Pollet, P., 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=Production+of+(S)-1-Benzyl-3-diazo-2-oxopropylcarbamic+Acid+tert-Butyl+Ester,+a+Diazoketone+Pharmaceutical+Intermediate,+Employing+a+Small+Scale+Continuous+Reactor.">Production of (S)-1-Benzyl-3-diazo-2-oxopropylcarbamic Acid tert-Butyl Ester, a Diazoketone Pharmaceutical Intermediate, Employing a Small Scale Continuous Reactor.</a> Ind Eng Chem Res. 48 (15), 7032-7036 (2009).</li><li>Flack, K., 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=Al(OtBu)(3)+as+an+Effective+Catalyst+for+the+Enhancement+of+Meerwein-Ponndorf-Verley+(MPV)+Reductions.">Al(OtBu)(3) as an Effective Catalyst for the Enhancement of Meerwein-Ponndorf-Verley (MPV) Reductions.</a> Org Process Res Dev. 16 (3), 1301-1306 (2012).</li><li>Aponte-Guzman, J., 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=A+Tandem,+Bicatalytic+Continuous+Flow+Cyclopropanation-Homo-Nazarov-Type+Cyclization.">A Tandem, Bicatalytic Continuous Flow Cyclopropanation-Homo-Nazarov-Type Cyclization.</a> Ind Eng Chem Res. 54 (39), 9550-9558 (2015).</li><li>Liotta, C. 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=Synthetic+Transformations+Employing+Continuous+Flow.">Synthetic Transformations Employing Continuous Flow.</a> ACS- Fall 2013.Synthetic Transformations Employing Continuous Flow. , (2013).</li></ol>

None of the authors within this protocol have any competing financial interests or conflict of interest.

Flow chemistry has gained much attention recently with an average of about 1,500 publications on the topic annually in research areas of Chemistry (29%) and Engineering (25%). Many successful processes have been conducted in flow. In numerous cases, flow chemistry was demonstrated to exhibit superior performances to batch for many applications such as the preparations of pharmaceutically active ingredients30,31, natural products32, and spe...

Green chemistry and engineering are creating a culture change for the future direction of industry1,2,3,4. Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer, and cost savings through the &#34;scaling out&#34; strategy as opposed to the traditional &#34;scaling up&#34;5,6,7,8,9,10.
Although the industries producing high-value products like the pharmaceutical industry have long favored batch processing, the advantages of flow technology have become attractive due to mounting economic competition and commercial production benefits11. For example, when scaling up batch processes, pilot scale units must be built and operated to ascertain accurate heat and mass transfer mechanisms. This is hardly sustainable and subtracts substantially from the marketable patent life of the product. In contrast, continuous flow processing allows for the advantages of scale out, eliminating the pilot-plant phase and engineering associated with production scale-a significant financial incentive. Beyond the economic impact, continuous technology also enables atomic and energy efficient processes. For instance, enhanced mixing improves mass transfer for biphasic systems, leading to improved yields, catalyst recovery strategies, and subsequent recycling schemes. Additionally, the ability to accurately manage the reaction temperature leads to precise control of reaction kinetics and product distribution12. The enhanced process control, quality of product (product selectivity) and reproducibility are impactful both from environmental and financial standpoints.
Flow reactors are available commercially with a wide variety of sizes and designs. In addition, customization of reactors to meet process needs can easily be achieved. Herein, we report experiments conducted in a glass continuous flow reactor (Figure 1). The assembly of microstructures (161 mm x 131 mm x 8 mm) made of glass is compatible with a wide range of chemicals and solvents and is corrosion-resistant over a wide range of temperatures (-25&#8211;200 &#176;C) and pressures (up to 18 bar). The microstructures and their arrangement were designed for multi-injection, high-performance mixing, flexible residence time, and precise heat transfer. All of the microstructures are equipped with two fluidic layers (-25&#8211;200 &#176;C, up to 3 bar) for heat exchange on either side of the reaction layer. Heat transfer rates are proportional to the heat transfer surface area and inversely proportional to its volume. Thus, these microstructures facilitate an optimum surface-to-volume ratio for improved heat transfer. There are two types of microstructures (i.e. modules): &#34;mixing&#34; modules and &#34;linear&#34; modules (Figure 2). The heart-shaped &#34;mixing&#34; modules are designed to induce turbulence and maximize mixing. In contrast, the linear modules provide additional residence time.
As proof of concept, we selected the well-described reaction of diphenyldiazomethane with carboxylic acids13,14,15,16,17. The reaction scheme is shown in Figure 3. The initial transfer of the proton from the carboxylic acid to the diphenyldiazomethane is slow and is the rate-determining step. The second step is rapid and yields the reaction product and nitrogen. The reaction was initially investigated to compare relative acidity of organic carboxylic acids in organic solvent (aprotic and protic). The reaction is first-order in the diphenyldiazomethane and first-order in carboxylic acids.
Experimentally, the reaction was conducted in presence of large excess of carboxylic acid (10 molar equivalents). As a consequence, the rate was pseudo first order with respect to the diphenyldiazomethane. The second order rate constant can then be obtained by dividing the experimentally obtained pseudo first order rate constant by the initial concentration of the carboxylic acid. Initially, the reaction of diphenyldiazomethane with benzoic acid (pKa = 4.2) was investigated. In batch, the reaction appeared to be relatively slow, reaching about 90% conversion in 96 minutes. As the reaction rate is directly proportional to the acidity of the carboxylic acid, we chose as a reaction partner the more acidic carboxylic acid, p-nitrobenzoic acid (pKa =3.4) to shorten the reaction time. The reaction of p-nitrobenzoic acid with diphenyldiazomethane in anhydrous ethanol was thus investigated in batch and flow (Figure 4). The results are provided in detail in the following section.
When the reaction is carried out in ethanol, three products can be formed: (i) benzhydryl-4-nitrobenzoate, which results from the reaction of p-nitrobenzoic acid with the diphenylmethane diazonium intermediate; (ii) benzhydryl ethyl ether that is obtained from reaction of the solvent, ethanol, with the diphenylmethane diazonium; and (iii) nitrogen. The product distribution was not studied as it is well documented in literature; rather we focused our attention to the technology transfer of the batch reaction to continuous flow13,14,15. Experimentally the disappearance of the diphenyldiazomethane was monitored. The reaction proceeds with a vivid color change, which can be visually observed by UV-Vis spectroscopy. This results from the fact that the diphenyldiazomethane is a strongly purple compound whereas all other products from the reaction are colorless. Therefore, the reaction can be visually monitored on a qualitative basis and quantitatively followed by UV spectroscopy (i.e. disappearance of the diphenyl diazomethane absorption at 525 nm). Herein, we first report the reaction of diphenyldiazomethane and p-nitrobenzoic acid in ethanol in batch as a function of time. Secondly, the reaction was successfully transferred and carried out into the glass flow reactor. The progress of the reaction was ascertained by monitoring the disappearance of diphenyldiazomethane using UV-spectroscopy (in batch and flow modes).

<table style="border-collapse:collapse;width:1075pt" width="1433">
	<colgroup>
		<col style="width:189pt" width="252" />
		<col style="width:188pt" width="251" />
		<col style="width:81pt" width="108" />
		<col style="width:617pt" width="822" />
	</colgroup>
	<tbody>
		<tr height="22" style="height:16.5pt">
			<td class="xl16" height="22" style="width:189pt;height:16.5pt" width="252">Thermometer</td>
			<td class="xl17" style="width:188pt" width="251">HB-USA/ Enviro-safe</td>
			<td class="xl17" style="width:81pt" width="108"></td>
			<td class="xl17" style="width:617pt" width="822">Any other instrument scientific company provider works</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Benzophenone hydrazone</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Store at 2-8 &#176;C, 96% purity</td>
		</tr>
		<tr height="26" style="height:19.5pt">
			<td class="xl18" height="26" style="width:189pt;height:19.5pt" width="252">Activated MnO2</td>
			<td class="xl19" style="width:188pt" width="251">Fluka</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">&#8805; 90% purity, harmful if inhaled or swallowed. Refer to MSDS for more safety precautions</td>
		</tr>
		<tr height="26" style="height:19.5pt">
			<td class="xl18" height="26" style="width:189pt;height:19.5pt" width="252">Dibasic KH2PO4</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Serious eye damage, respiratory irritant. Refer to MSDS for more safety precautions</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Dichloromethane (DCM)</td>
			<td class="xl19" style="width:188pt" width="251">Alfa Aesar</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">&#8805; 99.7% purity, argon packed</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Rotovap</td>
			<td class="xl19" style="width:188pt" width="251">B&#252;chi</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">accessory parts include Welch self-cleaning dry vacuum model 2027, and Neuberger KNP dry ice trap&#160;</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Bump trap</td>
			<td class="xl19" style="width:188pt" width="251">Chemglass</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other instrument scientific company provider works&#160;</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Neutral Silica Gel (50-200 mM)</td>
			<td class="xl19" style="width:188pt" width="251">Acros Organic/ Sorbent Technology</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Respiratory irritant if inhaled, refer to MSDS for more safety precautions</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Inert Argon Gas</td>
			<td class="xl19" style="width:188pt" width="251">Airgas</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Always ensure proper regulator is in place before using</td>
		</tr>
		<tr height="43" style="height:32.25pt">
			<td class="xl18" height="43" style="width:189pt;height:32.25pt" width="252">Medium Porosity Sintered Funnel Glass Filter</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other instrument scientific company provider works</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Aluminum Foil</td>
			<td class="xl19" style="width:188pt" width="251">Reynolds Wrap</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other company works. Used to prevent photolytic damage towards DDM</td>
		</tr>
		<tr height="26" style="height:19.5pt">
			<td class="xl20" height="26" style="width:189pt;height:19.5pt" width="252">Para-NO2 benzoic acid</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Skin contact irritant, eye irritant, respiratory irritant. Refer to MSDS for more safety precautions</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Pure ethyl alcohol (200 proof)</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">&#8805; 99.5% purity, anhydrous. Highly flammable</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Toluene</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">&#8805; 99.8% purity, anhydrous. Skin permeator, flammable</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl20" height="22" style="width:189pt;height:16.5pt" width="252">Ortho-xylene</td>
			<td class="xl19" style="width:188pt" width="251">Sigma-Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">99% purity, anhydrous. Toxic to organs and CNS. Adhere to specifications dictated within MSDS</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Diphenyl diazo methane</td>
			<td class="xl19" style="width:188pt" width="251">Produced in-house</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Respiratory irritant, refer to MSDS for more safety precautions</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Corning reactor</td>
			<td class="xl19" style="width:188pt" width="251">Corning Proprietary</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Manufactured in 2009. model number MR 09-083-1A</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Stop watch</td>
			<td class="xl19" style="width:188pt" width="251">Traceable Calibration Control Company</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other company that provides monitoring with laboratory grade accredidation works</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Analytical balance</td>
			<td class="xl19" style="width:188pt" width="251">Denver Instruments</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Model M-2201, or any analytical balance that has sub-milligram capabilities</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Dram vials</td>
			<td class="xl19" style="width:188pt" width="251">VWR</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">2 dram, 4 dram, and 6 dram vials&#160;</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Micropipettes</td>
			<td class="xl19" style="width:188pt" width="251">Eppendorf</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">2-20 &#956;L and 100-1000 &#956;L micropipettes work</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Glass pipettes</td>
			<td class="xl19" style="width:188pt" width="251">VWR</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other instrument scientific company provider works</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">GC-MS</td>
			<td class="xl19" style="width:188pt" width="251">Shimadzu GC</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Software associated: GC Real Time Analysis</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">GC vials</td>
			<td class="xl19" style="width:188pt" width="251">VWR</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Any other providing company works</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Beakers</td>
			<td class="xl19" style="width:188pt" width="251">Pyrex</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">500 mL beakers&#160;</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Syringe pumps</td>
			<td class="xl19" style="width:188pt" width="251">Sigma Aldrich</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Teledyne Isco Model 500D</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Relief valve</td>
			<td class="xl19" style="width:188pt" width="251">Swagelok</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">Spring loaded relieve valve&#160;</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">One-way valves</td>
			<td class="xl19" style="width:188pt" width="251">Nupro&#160;</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">10 psi grade</td>
		</tr>
		<tr height="22" style="height:16.5pt">
			<td class="xl18" height="22" style="width:189pt;height:16.5pt" width="252">Two-way straight valves</td>
			<td class="xl19" style="width:188pt" width="251">HiP</td>
			<td class="xl19" style="width:81pt" width="108"></td>
			<td class="xl19" style="width:617pt" width="822">15,000 psi grade</td>
		</tr>
	</tbody>
</table>

continuous flow chemistry: reaction of diphenyldiazomethane with p-nitrobenzoic acid

Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer and cost savings through the &#34;scaling out&#34; strategy as opposed to the traditional &#34;scaling up&#34;. Herein, we report the reaction of diphenyldiazomethane with p-nitrobenzoic acid in both batch and flow modes. To effectively transfer the reaction from batch to flow mode, it is essential to first conduct the reaction in batch. As a consequence, the reaction of diphenyldiazomethane was first studied in batch as a function of temperature, reaction time, and concentration to obtain kinetic information and process parameters. The glass flow reactor set-up is described and combines two types of reaction modules with &#34;mixing&#34; and &#34;linear&#34; microstructures. Finally, the reaction of diphenyldiazomethane with p-nitrobenzoic acid was successfully conducted in the flow reactor, with up to 95% conversion of the diphenyldiazomethane in 11 min. This proof of concept reaction aims to provide insight for scientists to consider flow technology&#39;s competitiveness, sustainability, and versatility in their research.

Batch Reaction 
Diphenyldiazomethane was prepared according to literature28,29. The compound was crystallized from petroleum ether:ethyl acetate (100:2) and the purple crystalline solid was analyzed by H1 NMR, melting point, and MS. The analyses were consistent with the structure and reported literature values.
The reaction of diphenyldia...

Watch this Scientific Journal Video about Continuous Flow Chemistry: Reaction of Diphenyldiazomethane with p-Nitrobenzoic Acid at JoVE.com

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

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

Continuous flow technology has been identified as instrumental for its environmental and economic advantages leveraging superior mixing, heat transfer and ...

continuous-flow-chemistry-reaction-diphenyldiazomethane-with-p

Research

Education

JoVE Journal

JoVE Core

Chemistry

Organic Chemistry

Unit 1

Carboxylic Acids

Chemical Kinetics

SCIENTISTS IN ACTION

11.3K Views.  Georgia Institute of Technology. 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.

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

Preparation of Silica Nanoparticles Through Microwave-assisted Acid-catalysis

Microwave-assisted synthetic techniques were used to quickly and reproducibly produce silica nanoparticle sols using an acid catalyst with nanoparticle diameters ranging from 30-250 nm by varying the reaction conditions. Through the selection of a microwave compatible solvent, silicic acid precursor, catalyst, and microwave irradiation time, these microwave-assisted methods were capable of overcoming the previously reported shortcomings associated with synthesis of silica nanoparticles using microwave reactors. The siloxane precursor was hydrolyzed using the acid catalyst, HCl. Acetone, a low-tan &#948; solvent, mediates the condensation reactions and has minimal interaction with the electromagnetic field. Condensation reactions begin when the silicic acid precursor couples with the microwave radiation, leading to silica nanoparticle sol formation. The silica nanoparticles were characterized by dynamic light scattering data and scanning electron microscopy, which show the materials&#39; morphology and size to be dependent on the reaction conditions. Microwave-assisted reactions produce silica nanoparticles with roughened textured surfaces that are atypical for silica sols produced by St&#246;ber&#39;s methods, which have smooth surfaces.

Silica nanoparticles were prepared using acid-catalysis of a siloxane precursor and microwave-assisted synthetic techniques resulting in the controlled growth of nanomaterials ranging from 30-250 nm in diameter. The growth dynamics can be controlled by varying the initial silicic acid concentration, time of the reaction, and temperature of reaction.

Microwave-assisted synthetic techniques were used to quickly and reproducibly produce silica nanoparticle sols using an acid catalyst with nanoparticle ...

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family of easy accessible, very cheap, and air stable, but highly active and universally applicable C-C cross-coupling catalysts with an excellent functional group tolerance. Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1), the least stable complex within this series towards protons; e.g. in the form of water, allows an eased nanoparticle formation and hence, proved to be the most active Heck catalyst within this series at 100 &#176;C and is a very rare example of an effective and versatile catalyst system that efficiently operates under mild reaction conditions. Rapid and complete catalyst degradation under work-up conditions into phosphonates, piperidinium salts and other, palladium-containing decomposition products assure an easy separation of the coupling products from catalyst and ligands. The facile, cheap, and rapid synthesis of 1,1',1"-(phosphinetriyl)tripiperidine and 1 respectively, the simple and convenient use as well as its excellent catalytic performance in the Heck reaction at 100 &#176;C make 1 to one of the most attractive and greenest Heck catalysts available.
We provide here the visualized protocols for the ligand and catalyst syntheses as well as the reaction protocol for Heck reactions performed at 10 mmol scale at 100 &#176;C and show that this catalyst is suitable for its use in organic syntheses.

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) is an easy accessible, cheap, and air stable, but highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products in very high yields.

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family ...

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

By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible to ensure consistent product quality over time using this technique. We here show how to interface a commercially available flow unit with a Raman spectrometer. The Raman flow cell is placed after the back-pressure regulator, meaning that it can be operated at atmospheric pressure. In addition, the fact that the product stream passes through a length of tubing before entering the flow cell means that the material is at RT. It is important that the spectra are acquired under isothermal conditions since Raman signal intensity is temperature dependent. Having assembled the apparatus, we then show how to monitor a chemical reaction, the piperidine-catalyzed synthesis of 3-acetylcoumarin from salicylaldehyde and ethyl acetoacetate being used as an example. The reaction can be performed over a range of flow rates and temperatures, the in-situ monitoring tool being used to optimize conditions simply and easily.

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.

By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible ...

Synthesis and Reaction Chemistry of Nanosize Monosodium Titanate

This paper describes the synthesis and peroxide-modification of nanosize monosodium titanate (nMST), along with an ion-exchange reaction to load the material with Au(III) ions. The synthesis method was derived from a sol-gel process used to produce micron-sized monosodium titanate (MST), with several key modifications, including altering reagent concentrations, omitting a particle seed step, and introducing a non-ionic surfactant to facilitate control of particle formation and growth. The resultant nMST material exhibits spherical-shaped particle morphology with a monodisperse distribution of particle diameters in the range from 100 to 150&#160;nm. The nMST material was found to have a Brunauer-Emmett-Teller (BET) surface area of 285 m2g-1, which is more than an order of magnitude higher than the micron-sized MST. The isoelectric point of the nMST measured 3.34 pH units, which is a pH unit lower than that measured for the micron-size MST. The nMST material was found to serve as an effective ion exchanger under weakly acidic conditions for the preparation of an Au(III)-exchange nanotitanate. In addition, the formation of the corresponding peroxotitanate was demonstrated by reaction of the nMST with hydrogen peroxide.

The surfactant mediated sol-gel synthesis of nanosized monosodium titanate is described, along with preparation of the corresponding peroxide modified material. An ion-exchange reaction with Au(III) is also presented.

This paper describes the synthesis and peroxide-modification of nanosize monosodium titanate (nMST), along with an ion-exchange reaction to load the ...

Post Column Derivatization Using Reaction Flow High Performance Liquid Chromatography Columns

A protocol for the use of reaction flow high performance liquid chromatography columns for methods employing post column derivatization (PCD) is presented. A major difficulty in adapting PCD to modern HPLC systems and columns is the need for large volume reaction coils that enable reagent mixing and then the derivatization reaction to take place. This large post column dead volume leads to band broadening, which results in a loss of observed separation efficiency and indeed detection in sensitivity. In reaction flow post column derivatization (RF-PCD) the derivatization reagent(s) are pumped against the flow of mobile phase into either one or two of the outer ports of the reaction flow column where it is mixed with column effluent inside a frit housed within the column end fitting. This technique allows for more efficient mixing of the column effluent and derivatization reagent(s) meaning that the volume of the reaction loops can be minimized or even eliminated altogether. It has been found that RF-PCD methods perform better than conventional PCD methods in terms of observed separation efficiency and signal to noise ratio. A further advantage of RF-PCD techniques is the ability to monitor effluent coming from the central port in its underivatized state. RF-PCD has currently been trialed on a relatively small range of post column reactions, however, there is currently no reason to suggest that RF-PCD could not be adapted to any existing one or two component (as long as both reagents are added at the same time) post column derivatization reaction.

A protocol for the use of reaction flow high performance liquid chromatography columns for methods employing post column derivatization (PCD) is presented.

A protocol for the use of reaction flow high performance liquid chromatography columns for methods employing post column derivatization (PCD) is ...

Synthesis of High Purity Nonsymmetric Dialkylphosphinic Acid Extractants

We present the synthesis of (2,3-dimethylbutyl)(2,4,4&#39;-trimethylpentyl)phosphinic acid as an example to demonstrate a method for the synthesis of high purity nonsymmetric dialkylphosphinic acid extractants. Low toxic sodium hypophosphite was chosen as the phosphorus source to react with olefin A (2,3-dimethyl-1-butene) to generate a monoalkylphosphinic acid intermediate. Amantadine was adopted to remove the dialkylphosphinic acid byproduct, as only the monoalkylphosphinic acid can react with amantadine to form an amantadine&#8729;mono-alkylphosphinic acid salt, while the dialkylphosphinic acid cannot react with amantadine due to its large steric hindrance. The purified monoalkylphosphinic acid was then reacted with olefin B (diisobutylene) to yield nonsymmetric dialkylphosphinic acid (NSDAPA). The unreacted monoalkylphosphinic acid can be easily removed by a simple base-acid post-treatment and other organic impurities can be separated out through the precipitation of the cobalt salt. The structure of the (2,3-dimethylbutyl)(2,4,4&#39;-trimethylpentyl)phosphinic acid was confirmed by 31P NMR, 1H NMR, ESI-MS, and FT-IR. The purity was determined by a potentiometric titration method, and the results indicate that the purity can exceed 96%.

A protocol for the synthesis of high purity nonsymmetric dialkylphosphinic acid extractants is presented, taking (2,3-dimethylbutyl)(2,4,4&#39;-trimethylpentyl)phosphinic acid as an example.

We present the synthesis of (2,3-dimethylbutyl)(2,4,4&#39;-trimethylpentyl)phosphinic acid as an example to demonstrate a method for the synthesis of high ...

Combustion Chemistry of Fuels: Quantitative Speciation Data Obtained from an Atmospheric High-temperature Flow Reactor with Coupled Molecular-beam Mass Spectrometer

This manuscript describes a high-temperature flow reactor experiment coupled to the powerful molecular beam mass spectrometry (MBMS) technique. This flexible tool offers a detailed observation of chemical gas-phase kinetics in reacting flows under well-controlled conditions. The vast range of operating conditions available in a laminar flow reactor enables access to extraordinary combustion applications that are typically not achievable by flame experiments. These include rich conditions at high temperatures relevant for gasification processes, the peroxy chemistry governing the low temperature oxidation regime or investigations of complex technical fuels. The presented setup allows measurements of quantitative speciation data for reaction model validation of combustion, gasification and pyrolysis processes, while enabling a systematic general understanding of the reaction chemistry. Validation of kinetic reaction models is generally performed by investigating combustion processes of pure compounds. The flow reactor has been enhanced to be suitable for technical fuels (e.g. multi-component mixtures like Jet A-1) to allow for phenomenological analysis of occurring combustion intermediates like soot precursors or pollutants. The controlled and comparable boundary conditions provided by the experimental design allow for predictions of pollutant formation tendencies. Cold reactants are fed premixed into the reactor that are highly diluted (in around 99 vol% in Ar) in order to suppress self-sustaining combustion reactions. The laminar flowing reactant mixture passes through a known temperature field, while the gas composition is determined at the reactors exhaust as a function of the oven temperature. The flow reactor is operated at atmospheric pressures with temperatures up to 1,800 K. The measurements themselves are performed by decreasing the temperature monotonically at a rate of -200 K/h. With the sensitive MBMS technique, detailed speciation data is acquired and quantified for almost all chemical species in the reactive process, including radical species.

An investigation of the oxidative combustion chemistry of novel biofuels, fuel components, or jet fuels by comparison of quantitative speciation data is presented. The data can be used for kinetic model validation and enables fuel assessment strategies.This manuscript describes the atmospheric high-temperature flow reactor and demonstrates its capabilities.

This manuscript describes a high-temperature flow reactor experiment coupled to the powerful molecular beam mass spectrometry (MBMS) technique. This ...

Fabricating High-viscosity Droplets using Microfluidic Capillary Device with Phase-inversion Co-flow Structure

The generation of monodisperse droplets with high viscosity has always been a challenge in droplet microfluidics. Here, we demonstrate a phase-inversion co-flow device to generate uniform high-viscosity droplets in a low-viscosity fluid. The microfluidic capillary device has a common co-flow structure with its exit connecting to a wider tube. Elongated droplets of the low-viscosity fluid are first encapsulated by the high-viscosity fluid in the co-flow structure. As the elongated low-viscosity droplets flow through the exit, which is treated to be wetted by the low-viscosity fluid, phase inversion is then induced by the adhesion of the low viscosity droplets to the tip of the exit, which results in the subsequent inverse encapsulation of the high-viscosity fluid. The size of the resultant high-viscosity droplets can be adjusted by changing the flow rate ratio of the low-viscosity fluid to the high-viscosity fluid. We demonstrate several typical examples of the generation of high-viscosity droplets with a viscosity up to 11.9 Pas, such as glycerol, honey, starch, and polymer solution. The method provides a simple and straightforward approach to generate monodisperse high-viscosity droplets, which may be used in a variety of droplet-based applications, such as materials synthesis, drug delivery, cell assay, bioengineering, and food engineering.

A phase-inversion co-flow device is demonstrated to generate monodisperse high-viscosity droplets above 1 Pas, which is difficult to realize in droplet microfluidics.

The generation of monodisperse droplets with high viscosity has always been a challenge in droplet microfluidics. Here, we demonstrate a phase-inversion ...

Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction

Antibody-drug conjugates (ADCs) used nowadays in clinical practice are mixtures of antibody molecules linked to a varying number of toxins at different positions. Preclinical studies have shown that the therapeutic index of these traditional ADCs can be improved by the site-specific linkage of toxins. However, current approaches to produce homogeneous ADCs have several limitations, such as low protein expression and slow reaction kinetics. In this protocol we describe how to set up an expression system to incorporate a cyclopropene derivative of lysine (CypK) into antibodies using genetic code expansion. This minimal bioorthogonal handle allows rapid conjugation of tetrazine derivatives through an inverse-demand Diels-Alder cycloaddition. The expression system here reported enables the facile production and purification of trastuzumab bearing CypK in each of the heavy chains. We explain how to link the antibody to the toxin monomethyl auristatin E and characterize the immunoconjugate by hydrophobic interaction chromatography and mass spectrometry. Finally, we describe assays to assess the stability in human serum of the dihydropyridazine linkage resulting from the conjugation and to test the selective cytotoxicity of the ADC for breast cancer cells with high levels of HER2 receptor.

Incorporating a cyclopropene derivative of lysine into antibodies allows the site-specific, rapid and efficient linkage of tetrazine-bearing molecules to generate antibody-drug conjugates.

Antibody-drug conjugates (ADCs) used nowadays in clinical practice are mixtures of antibody molecules linked to a varying number of toxins at different ...

Extending the Lifespan of Soluble Lead Flow Batteries with a Sodium Acetate Additive

In this report, we present a method for the construction of a soluble lead flow battery (SLFB) with an extended cycle life. By supplying an adequate amount of sodium acetate (NaOAc) to the electrolyte, a cycle life extension of over 50% is demonstrated for SLFBs via long-term galvanostatic charge/discharge experiments. A higher quality of the PbO2 electrodeposit at the positive electrode is quantitatively validated for NaOAc-added electrolyte by throwing index (TI) measurements. Images acquired by scanning electron microscopy (SEM) also exhibit more integrated PbO2 surface morphology when the SLFB is operated with the NaOAc-added electrolyte. This work indicates that electrolyte modification can be a plausible route to economically enable SLFBs for large-scale energy storage.

A protocol for the construction of a soluble lead flow battery with an extended lifespan, in which sodium acetate is supplied in the methanesulfonic electrolyte as an additive, is presented.

In this report, we present a method for the construction of a soluble lead flow battery (SLFB) with an extended cycle life. By supplying an adequate ...