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>

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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 specialty, high-value chemicals like high-performance polymers33,34,35,36. We leveraged and reported continuous flow processes for the preparation and reaction of diazoketone37, Meerwein-Ponndorf-Verley reduction of ketone and aldehydes to alcohols38 and metal-catalyzed Homo-Nazarov cyclization39. Especially interesting is the example of the preparation and reaction of thermally unstable and highly reactive anhydride in the reaction of diazoketone, tert-butyl (S)-(4-diazo-3-oxo-1-phenylbutan-2-yl) carbamate (Figure 11)37,40.
Because of the enhanced temperature control and mixing, the flow technology was demonstrated to be superior to batch process for the following criteria: (i) the implementation of a less expensive mixed anhydride, (ii) the use of the relatively safer trimethyl silyldiazomethane than diazomethane, (iii) the temperature, 4 &#176;C in flow instead of -20 &#176;C in batch with consistent 100% yield, (iv) shortened reaction time (10 min), and (v) significant reduction in waste-stream (atomic economy).
Herein, we have provided a blueprint for the successful transfer of diphenyldiazomethane with p-nitrobenzoic acid reaction from batch mode to continuous flow. Our blueprint emphasizes that it is critical to conduct studies in batch mode to establish accurate reaction rate, the reaction profile as a function of time, and the optimum concentration and temperature. These parameters are essential to take into consideration prior to transferring the reaction to continuous flow technology. The design of the reactor was described in detail and was tailored to be amenable with regards to the reaction characteristics. Finally, the reaction was successfully conducted in flow and monitored qualitatively by visual observation (i.e. loss of color). Quantitative assessment of the progress of the reaction (e.g. disappearance of diphenyldiazomethane) was obtained by UV-Vis. About 94% consumption was achieved with 11 min residence time in flow at 21 &#176;C.
Limitation and considerations 
The formation of solids (i.e. precipitates) during the reaction is an important parameter when considering flow processes. In those instances, one must consider: (i) modifying the protocol in batch-mode to maintain homogeneity throughout the reaction (i.e. changing reagents, solvent, temperature, etc.) or (ii) design the reactor to allow for the processing of slurries. The second option may be viable with optimization and tailored reactor design. In practice, the two most limiting factors for flow processes are (i) viscous solutions: the ability to pump viscous liquids and the resulting pressure drop are often prohibitive and (ii) using heterogeneous (solid/liquid) feeding streams. It is difficult to consistently and effectively pump fine suspensions (for example in the cases of heterogeneous catalyst). In addition, accumulation of particles in the reactor can lead to blockage, and ultimately failure.
Overall, flow chemistry has been demonstrated to be superior (to batch processes) for synthetic transformations that (i) require precise temperature control (i.e. avoid hot spot, competitive reaction, etc.) (ii) involve the formation of highly reactive or unstable intermediates, or (iii) require enhanced mixing with multi-liquid phases for example. The resulting increase of product quality and reproducibility (via enhanced and precise control of the process parameters) is impactful both from an environmental and a financial standpoint. Flow technology may not be the universal solution but can open new avenues for chemical pathways that were deemed not viable in batch (i.e. too reactive or too unstable intermediates) as well as provide process optimization in terms of energy consumption, atom economy and downstream-purification. To conclude, it is a powerful tool to effectively conduct multi-step processes for high-value added chemicals.

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><tbody><tr><td>Thermometer</td><td>HB-USA/ Enviro-safe</td><td></td><td>Any other instrument scientific company provider works</td></tr><tr><td>Benzophenone hydrazone</td><td>Sigma-Aldrich</td><td></td><td>Store at 2-8 &amp;deg;C, 96% purity</td></tr><tr><td>Activated MnO&lt;span class=&quot;font6&quot;&gt;&lt;sub&gt;2&lt;/sub&gt;&lt;/span&gt;</td><td>Fluka</td><td></td><td>&amp;ge; 90% purity, harmful if inhaled or swallowed. Refer to MSDS for more safety precautions</td></tr><tr><td>Dibasic KH&lt;sub&gt;2&lt;/sub&gt;PO&lt;sub&gt;4&lt;/sub&gt;</td><td>Sigma-Aldrich</td><td></td><td>Serious eye damage, respiratory irritant. Refer to MSDS for more safety precautions</td></tr><tr><td>Dichloromethane (DCM)</td><td>Alfa Aesar</td><td></td><td>&amp;ge; 99.7% purity, argon packed</td></tr><tr><td>Rotovap</td><td>B&amp;uuml;chi</td><td></td><td>accessory parts include Welch self-cleaning dry vacuum model 2027, and Neuberger KNP dry ice trap&amp;nbsp;</td></tr><tr><td>Bump trap</td><td>Chemglass</td><td></td><td>Any other instrument scientific company provider works&amp;nbsp;</td></tr><tr><td>Neutral Silica Gel (50-200 mM)</td><td>Acros Organic/ Sorbent Technology</td><td></td><td>Respiratory irritant if inhaled, refer to MSDS for more safety precautions</td></tr><tr><td>Inert Argon Gas</td><td>Airgas</td><td></td><td>Always ensure proper regulator is in place before using</td></tr><tr><td>Medium Porosity Sintered Funnel Glass Filter</td><td>Sigma-Aldrich</td><td></td><td>Any other instrument scientific company provider works</td></tr><tr><td>Aluminum Foil</td><td>Reynolds Wrap</td><td></td><td>Any other company works. Used to prevent photolytic damage towards DDM</td></tr><tr><td>Para-NO&lt;sub&gt;2&lt;/sub&gt; benzoic acid</td><td>Sigma-Aldrich</td><td></td><td>Skin contact irritant, eye irritant, respiratory irritant. Refer to MSDS for more safety precautions</td></tr><tr><td>Pure ethyl alcohol (200 proof)</td><td>Sigma-Aldrich</td><td></td><td>&amp;ge; 99.5% purity, anhydrous. Highly flammable</td></tr><tr><td>Toluene</td><td>Sigma-Aldrich</td><td></td><td>&amp;ge; 99.8% purity, anhydrous. Skin permeator, flammable</td></tr><tr><td>Ortho-xylene</td><td>Sigma-Aldrich</td><td></td><td>99% purity, anhydrous. Toxic to organs and CNS. Adhere to specifications dictated within MSDS</td></tr><tr><td>Diphenyl diazo methane</td><td>Produced in-house</td><td></td><td>Respiratory irritant, refer to MSDS for more safety precautions</td></tr><tr><td>Corning reactor</td><td>Corning Proprietary</td><td></td><td>Manufactured in 2009. model number MR 09-083-1A</td></tr><tr><td>Stop watch</td><td>Traceable Calibration Control Company</td><td></td><td>Any other company that provides monitoring with laboratory grade accredidation works</td></tr><tr><td>Analytical balance</td><td>Denver Instruments</td><td></td><td>Model M-2201, or any analytical balance that has sub-milligram capabilities</td></tr><tr><td>Dram vials</td><td>VWR</td><td></td><td>2 dram, 4 dram, and 6 dram vials&amp;nbsp;</td></tr><tr><td>Micropipettes</td><td>Eppendorf</td><td></td><td>2-20 &amp;mu;L and 100-1000 &amp;mu;L micropipettes work</td></tr><tr><td>Glass pipettes</td><td>VWR</td><td></td><td>Any other instrument scientific company provider works</td></tr><tr><td>GC-MS</td><td>Shimadzu GC</td><td></td><td>Software associated: GC Real Time Analysis</td></tr><tr><td>GC vials</td><td>VWR</td><td></td><td>Any other providing company works</td></tr><tr><td>Beakers</td><td>Pyrex</td><td></td><td>500 mL beakers&amp;nbsp;</td></tr><tr><td>Syringe pumps</td><td>Sigma Aldrich</td><td></td><td>Teledyne Isco Model 500D</td></tr><tr><td>Relief valve</td><td>Swagelok</td><td></td><td>Spring loaded relieve valve&amp;nbsp;</td></tr><tr><td>One-way valves</td><td>Nupro&amp;nbsp;</td><td></td><td>10 psi grade</td></tr><tr><td>Two-way straight valves</td><td>HiP</td><td></td><td>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 diphenyldiazomethane (1.0 mM) with benzoic acid (10 mM) in anhydrous ethanol was carried out at 21 &#176;C in dry ethanol. The progress of the reaction was monitored using UV-Vis spectrometry (&#955;max = 525 nm). After 96 minutes, about 90% of the diphenyldiazomethane was consumed. The pseudo-first order rate constant was calculated to be 0.0288 min-1 and the resulting second rate constant to be 0.58 mol-1.min-1.L. The second-order rate constant is in agreement with literature values (~ 0.7 mol-1.min-1.L at 26 &#176;C)17. The reaction was then investigated with the more acidic p-nitrobenzoic acid. The reaction of diphenyldiazomethane (1 mM) with p-nitrobenzoic acid (10mM) in anhydrous ethanol was conducted at 21 &#176;C and monitored in-situ by UV-Vis at &#955; = 525 nm (Figure 5). UV-vis spectra were taken at 1.5 minutes intervals. Figure 6 shows a representative spectrum of the UV-absorbance of diphenyldiazomethane as a function of the progression of the reaction with p-nitrobenzoic acid in anhydrous ethanol.
Figures 7 and 8 show the concentration of DDM as a function of time and the pseudo-first order ln(Abs/Abs0) as a function of time. From the latter plot, an apparent first-rate of reaction of 0.135 min-1 was obtained, which corresponds to a second order rate constant of 1.80 mol-1.min-1.L. The data are consistent with reported literature values17. Importantly, the reaction reaches about 94% completion within 20 min (Figure 8), which is amenable to the flow reactor. The next step was to transfer the reaction to the glass flow reactor.
Flow reaction 
The schematic and photograph of the flow process used herein is shown in Figure 9. The two reactant streams are introduced into a pre-heating/cooling module (1 and 2 in Figure 9). Modules 1 and 2 allows to control the temperature of each incoming feeds. The mixing of the two reactant feeds occurs at the module 3 (Figure 9) before proceeding into three mixing modules (4, 5, &#38; 6 in Figure 9) and two linear modules (7 &#38; 8 in Figure 9). Each reactant stream was independently controlled and introduced via syringe pumps. The reactant solutions were each prepared with internal standards (1vol% toluene/ortho-xylene) to measure accurately the concentrations of reactant. The residence times of the reactions are controlled by changing the total flow rate. For example, residence times of 1 min 52 s, 3 min 44 s, and 11 min 12 s corresponded to total flow rates of 30 mL/min, 15 mL/min, and 5 mL/min.
Operationally, two stock solutions were prepared: (1) A solution of diphenyldiazomethane in anhydrous ethanol (0.02M) and (2) A solution of p-nitrobenzoic acid (0.1 M). Both solutions were fed into the reactor (Feeds 1 &#38; 2 in Figure 9) at rate of 1.42 mL/min of and 3.58 mL/min respectively. Accounting for the initial concentrations of diphenyldiazomethane and p-nitrobenzoic and their respective flow-rate, the molar ratio of diphenyldiazomethane to p-nitrobenzoic acid was 1 to 10. Experimentally, the total flow rate was approximately 5 mL/min leading to a residence time of 11 minutes. Aliquots were taken as a function of time and analyzed by GC-FID (gas chromatography with flame ionization detector) and by UV-Vis spectroscopy. GC-FID analyses were used to measure the accurate concentration ratio of reagents using internal standards. Toluene was used as the internal standard (0.107 M) in the diphenyldiazomethane solution and ortho-xylene was present in the p-nitrobenzoic acid (0.072 M). The UV-Vis analyses quantitatively measured the progress of the reaction by monitoring the disappearance of diphenyldiazomethane as a function of time (the method was established and described for the batch reaction).
The results shown in Figure 10 shows that 95% completion is reached within the 11 min residence time. To reach complete conversion, the residence time can be extended to 33 min or less. Operationally, full conversion can be obtained with slower flow rate (as shown) or by increasing residence time (additional microstructures/modules) and/or increase of temperature. However, the proof of concept shows that the reaction can successfully be conducted in flow with 95% conversion in 11 min.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/56608/56608fig1.jpg" /> 
Figure 1: Schematic of continuous flow microstructures.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56608/56608fig2.jpg" /> 
Figure 2: Mixing (left) and linear (right) microstructures.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/56608/56608fig3.jpg" /> 
Figure 3: Reaction of diphenyldiazomethane with an acid (X-H).&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/56608/56608fig4.jpg" /> 
Figure 4: Reaction of diphenyldiazomethane with p-nitrobenzoic acid in anhydrous ethanol.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/56608/56608fig5.jpg" /> 
Figure 5: Reaction of diphenyldiazomethane (1eq) with ethanol and p-nitrobenzoic acid (10 eq).&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/56608/56608fig6.jpg" /> 
Figure 6: Absorbance as a function of wavelength for the reaction of diphenyldiazomethane with p-nitrobenzoic acid. The maximum absorbance for diphenyldiazomethane is 525 nm. Each line represents one spectra taken at different time intervals (each 1.5 min) from time = 0.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/56608/56608fig7.jpg" /> 
Figure 7: pseudo-first order reaction (ln(Abs/Abs0) vs. Time (min) as a function of time for the reaction of diphenyldiazomethane and p-nitrobenzoic acid at 21 &#176;C in ethanol in batch.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig7large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/56608/56608fig8.jpg" /> 
Figure 8: Concentration of diphenyldiazomethane as a function of time for the reaction of diphenyldiazomethane and p-nitrobenzoic acid at 21 &#176;C in ethanol in batch.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig8large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 9" class="xfigimg" src="/files/ftp_upload/56608/56608fig9.jpg" /> 
Figure 9: Schematic of the continuous flow reactor.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig9large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 10" class="xfigimg" src="/files/ftp_upload/56608/56608fig10.jpg" /> 
Figure 10: Concentration of diphenyldiazomethane as a function of time for the reaction of diphenyldiazomethane and p-nitrobenzoic acid at 21 &#176;C in ethanol in flow.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig10large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 11" class="xfigimg" src="/files/ftp_upload/56608/56608fig11.jpg" /> 
Figure 11: Reaction of diazoketone, tert-butyl (S)-(4-diazo-3-oxo-1-phenylbutan-2-yl) Carbamate.&#160;<a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56608/56608fig11large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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

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11.4K Views.  Georgia Institute of Technology. Stroom chemie draagt milieu en economische voordelen door leveraging superieure mengen, warmteoverdracht en kosten voordelen. Hierin bieden we een blauwdruk voor het overbrengen van chemische processen van batch naar stroom modus. De reactie van diphenyldiazomethane (DDM) met p- nitrobenzoic zuur, uitgevoerd in batch en stroom, werd gekozen voor bewijs van concept.

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

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 ...

Ethylene Polymerizations Using Parallel Pressure Reactors and a Kinetic Analysis of Chain Transfer Polymerization

We demonstrate a method for high-throughput catalyst screening using a parallel pressure reactor starting from the initial synthesis of a nickel &#945;-diimine ethylene polymerization catalyst. Initial polymerizations with the catalyst lead to optimized reaction conditions, including catalyst concentration, ethylene pressure and reaction time. Using gas-uptake data for these reactions, a procedure to calculate the initial rate of propagation (kp) is presented. Using the optimized conditions, the ability of the nickel &#945;-diimine polymerization catalyst to undergo chain transfer with diethylzinc (ZnEt2) during ethylene polymerization was investigated. A procedure to assess the ability of the catalyst to undergo chain transfer (from molecular weight and 13C NMR data), calculate the degree of chain transfer, and calculate chain transfer rates (ke) is presented.

A protocol for the high-throughput analysis of polymerization catalyst, chain transfer polymerizations, polyethylene characterization, and reaction kinetic analysis is presented.

We demonstrate a method for high-throughput catalyst screening using a parallel pressure reactor starting from the initial synthesis of a nickel ...

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. The complexes were tested for catalytic activity in arylation and Suzuki-Miyaura reactions. For each reaction investigated, at least one of the four complexes successfully catalyzed the reaction.

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

[(DPEPhos)(bcp)Cu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the activation of a broad variety of organic halides, including unactivated ones. These can then participate in various radical transformations such as reduction and cyclization reactions, as well as in the direct arylation of several (hetero)arenes. These transformations provide a straightforward access to a range of small molecules of interest in synthetic chemistry, as well as to biologically active natural products. Altogether, [(DPEPhos)(bcp)Cu]PF6 acts as a convenient photoredox catalyst which appears to be an attractive, cheap and complementary alternative to the state-of-the-art iridium- and ruthenium-based photoredox catalysts. Here, we report a detailed protocol for the synthesis of [(DPEPhos)(bcp)Cu]PF6, as well as NMR and spectroscopic characterizations, and we illustrate its use in synthetic chemistry for the direct arylation of (hetero)arenes and radical cyclization of organic halides. In particular, the direct arylation of N-methylpyrrole with 4-iodobenzonitrile to afford&#160;4-(1-methyl-1H-pyrrol-2-yl)benzonitrile and the radical cyclization of N-benzoyl-N-[(2-iodoquinolin-3-yl)methyl]cyanamide to afford natural product luotonin A are detailed. The scope and limitations of this copper-based photoredox catalyst are also briefly discussed.

[DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Detailed and general protocols are presented for the synthesis of [(DPEPhos)(bcp)Cu]PF6, a general copper-based photoredox catalyst, and for its use in synthetic chemistry for the direct arylation of C-H bonds in (hetero)arenes and radical cyclization of organic halides.

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the ...

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.

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 ...

Molecular Orbital (MO) Theory

Source: Tamara M. Powers, Department of Chemistry, Texas A&#38;M University
This protocol serves as a guide in the synthesis of two metal complexes featuring the ligand 1,1&#39;-bis(diphenylphosphino)ferrocene (dppf): M(dppf)Cl2, where M = Ni or Pd. While both of these transition metal complexes are 4-coordinate, they exhibit different geometries at the metal center. Using molecular orbital (MO) theory in conjunction with 1H NMR and Evans method, we will determine the geometry of these two compounds.

Molecular Orbital MO Theory: Predicting Geometry of Transition Metal Complexes

Source: Tamara M. Powers, Department of Chemistry, Texas A&#38;M University
This protocol serves as a guide in the synthesis of two metal complexes ...

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Inorganic Chemistry

Carboxylic Acids to Methylesters: Alkylation using Diazomethane

Carboxylic acids react with diazomethane in an ether solvent via alkylation at the carboxylate oxygen atom to give methyl esters of the corresponding acid with excellent yields.
<img alt="Esterification reaction: carboxylic acid with diazomethane formula, chemical process diagram." src="/files/ftp_upload/12349/12349_PT_Figure_1.svg" style="text-align: center; height: 60px;" data-altupdatedat="1747908711000" data-alt="Figure1">
Diazomethane is a yellow gas having a boiling point of −23 °C. It is conveniently prepared by the action of a base on N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulphonamide.
The esterification mechanism involves the protonation of diazomethane by the carboxylic acid to yield a carboxylate salt and methyldiazonium cation. The methyldiazonium cation is highly unstable due to the presence of N≡N, which functions as an excellent leaving group.
<img alt="Chemical reaction, Curtius rearrangement equations, molecular transformation diagram." src="/files/ftp_upload/12349/12349_PT_Figure_2.svg" style="text-align: center; height: 72px;" data-altupdatedat="1747908711000" data-alt="Figure2">
In the final alkylation step, an SN2 attack on the methyldiazonium ion by the carboxylate anion produces a methyl ester, along with the elimination of N2 gas.
<img alt="SN2 reaction mechanism diagram; nucleophile attack on carbonyl, forming new bond, expelling N2." src="/files/ftp_upload/12349/12349_PT_Figure_3.svg" style="text-align: center; height: 70px;" data-altupdatedat="1747908711000" data-alt="Figure3">
However, diazomethane is a potentially explosive gas and requires precautions during its handling and storage. It undergoes spontaneous detonation upon contact with rough or scratched surfaces. Therefore, flame-polished glassware and a blast shield are often recommended in reactions involving diazomethane. Moreover, diazomethane is highly toxic as well as carcinogenic.
Diazomethane decomposes in the presence of heat or light to generate carbenes and eliminate nitrogen.
<img alt="Chemical reaction diagram; azide decomposition to form methylene and nitrogen under heat or light." src="/files/ftp_upload/12349/12349_PT_Figure_4.svg" style="text-align: center; height: 52px;" data-altupdatedat="1747908711000" data-alt="Figure4">

Carboxylic acids react with diazomethane in an ether solvent&#160;via alkylation at the carboxylate oxygen atom&#160;to give&#160;methyl esters of the ...

KEY TERMS AND CONCEPTS

Hydrolysis of Chlorobenzene to Phenol: Dow Process

Simple aryl halides do not react with nucleophiles under normal conditions. However, the reaction can proceed under drastic conditions involving high temperatures and high pressure&#160;to give the substituted products. For example,&#160;chlorobenzene is converted to&#160;phenol using&#160;aqueous sodium hydroxide at 350 &#176;C&#160;under high pressure by the Dow process. The reaction follows an elimination-addition mechanism involving a benzyne intermediate. Here, the chloride ion is eliminated to generate the benzyne intermediate. The benzyne intermediate then reacts with the base, followed by&#160;an acid workup that&#160;generates phenol as the final product.

Simple aryl halides do not react with nucleophiles under normal conditions. However, the reaction can proceed under drastic conditions involving high ...

Reactions of Aromatic Compounds

Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions

Arenediazonium substitution reactions occur when the diazonium group is substituted by various functional groups such as halides, hydroxyl, nitrile, etc. For instance, arenediazonium salts react with copper(I) salts of chloride, bromide, or cyanide to form corresponding aryl chlorides, bromides, and nitriles. These reactions are named Sandmeyer reactions. Although the mechanism of this reaction is complicated, as illustrated in Figure 1, they are believed to progress via an aryl copper intermediate.
<img alt="Figure1" src="/files/ftp_upload/12539/12539-PT_Figure_1.svg" style="text-align: center; height: 275px;" />
Figure 1. The formation of aryl halides and nitriles via the Sandmeyer reaction
The hydrolysis of aryl nitriles into carboxylic acids is very facile. In this context, the Sandmeyer reaction plays a crucial role in converting aryl amines to substituted benzonitrile, as shown in Figure 2.
<img alt="Figure2" src="/files/ftp_upload/12539/12539-PT_Figure_2.svg" style="text-align: center; height: 85px;" />
Figure 2. The conversion of aryl amines to substituted benzonitrile.
Sandmeyer reactions are not used to prepare aryl fluorides and aryl iodides. For aryl fluorides, the arenediazonium salts react with fluoroboric acid to give diazonium fluoroborate in the form of a precipitated salt. As depicted in Figure 3, these residues are isolated, dried, and heated until they decompose to form the corresponding aryl fluorides. Such reactions are named Schiemann reactions. Similarly, arenediazonium salts react with potassium iodide to form aryl iodides.
<img alt="Figure3" src="/files/ftp_upload/12539/12539-PT_Figure_3.svg" style="text-align: center; height: 90px;" />
Figure 3. The formation of aryl fluoride via the Schiemann reaction.

Arenediazonium substitution reactions occur when the diazonium group is substituted by various functional groups such as halides, hydroxyl, nitrile, etc. ...

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

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