The overall goal of this experiment, is to screen reactions using a stop-flow micro-tubing reactor platform that combines elements from both continuous flow and batch reactors. We invented this technology to overcome the problems that the continuous micro-tubing flow system is not an efficient for small scale reaction as well as reaction screening. The difference between our stop-flow micro-tubing reactor system and continuous micro-tubing reaction system, is that there are two valves before and after each micro-tubing in our system.
The main advantages of this technique are that it is green, safe, easy to use for reaction screening, and more efficient than conventional bench reactors, but does involve organic transformation. To prepare a stop flow micro-tubing reactor, wrap 300 centimeters of high-purity, PFA tubing into a narrow ring. Secure the tubing with zip ties.
And attach a shut-off valve to each end. It's easy to construct a SFMT reactor, therefore we just prepare a SMFT reaction for each condition to be screened. Connect The Reactor to a 20 psi back pressure regulator and a low-pressure T-fitting connected to an acetylene gas tank, via a needle valve.
Submerge the end of the back-pressure regulatory outfit in acetone. Next, place 58.5 milligrams of 4-iodoanisole, in a 10 ml round-bottom flask with a stir bar. Add to the flask, 8.5milligrams of Bis(triphenylphosphine)palladium chloride, 1 milligram of copper iodide, 80 micro-liters of DIPEA, and 2.5 milliliter of dimethyl sulfoxide.
Stopper the flask with a rubber septum, and begin stirring the mixture at room temperature. Use an aragan-filled balloon to de-gas the mixture for 15 minutes while stirring. When de-gassing has finished, remove the venting needle, followed by the balloon assembly.
Then, use a short length of high-purity PFA tubing and a luer needle fitting to equip an eight-milliter stainless steel syringe with a long needle. Insert the needle through the septum to the bottom of the flask. And draw the reaction liquid into the syringe.
Disconnect the syringe from the needle. Secure the syringe in a syringe pump, and connect the syringe to the T-fitting joining the SMFT reactor and the acetylene gas. Purge the tubing with acetylene gas until bubble are observed at the back-pressure regulator.
Then, start loading the reaction mixture into the reactor at 300 micro-liters per minute. Use the needle valve to adjust acetylene flow rate until the liquid-to-gas ratio between the T-fitting and the reactor inlet shut-off valve is one-to-one. Close the reactor outlet shut-off valve once the entire reaction mixture has been loaded into the tubing and the mixture begins leaking from the back-pressure regulator outlet.
Pressurize the reactor with acetylene until the reaction mixture is immobile in the reactor. Then, close the reactor inlet shut-off valve and the needle valve. Disconnect the reactor from the system and place it in a silicone oil bath, heated to the desired reaction temperature, being careful to keep the shut-off valves clear of the oil.
Leave the reactor in the oil-bath for one hour. Then, use hexine to rinse the silicone oil from the reactor. Use an eight-milliliter stainless steel syringe to push reaction mixture from the reactor into a 20 milliliter vial.
Flush the residue into the vial with four milliliter of diethyl ether. Wash the mixture with four milliliters of an aqueous-saturated ammonium chloride solution, and extract the product into 1.5 milliliters of diethyl ether. Determine the yield with GC-MS.
To clean the system, use the syringe pump to wash the tubing with a solvent to be used in the next reaction. Dry the system with nitrogen gas for 20 minutes. To construct the SFMT reactor, wrap 340 centimeters of high-purity PFA tubing into a ring and fit the ends with shut-off valves.
Then, combine the reagents for the reaction in a 10-milliliter vial and seal the vial with a silicone septum end cap. Degas the mixture for 15 minutes with an aragan balloon. Remove the needles after degassing.
Connect the reactor to an argan gas line using a peak union body, and purge the reactor argon for five minutes. Then, close both reactor shut-off valves to preserve the argon atmosphere. Next, equip a three-milliliter syringe with a long needle.
Pierce the septum of the vial and draw the pre-mixed reaction mixture into the syringe. Then, invert the syringe and gently tap the plunger until all bubbles are expelled, leaving only the reaction mixture in the syringe. Gently shake the syringe to ensure homogeneity.
Use a luer adaptor to connect the syringe to the SFMT reactor. Open both shut-off valves and introduce the reaction mixture into the reactor, either manually or using a syringe pump. Close both shut-off valves, and place the reactor in the center of a blue LED strip.
Eradiate the mixture for five to 48 hours, as desired. Then, use a three-milliliter syringe to push the reaction mixture into a clean round-bottom flask. Rinse the residue into the flask with excess diethyl ether to obtain the crude product.
Concentrate the product and determine the conversion rate with proton NMR analysis, by adding appropriate amount of 1, 3, 5 trimethoxybenzene as the internal standard. First, wrap 300 centimeters of high-purity PFA tubing into a narrow ring, and fit the ends with shut-off valves. Connect the reactor to a back-pressure regulator, and to a T-fitting in series with the needle valve and an acetylene gas tank.
Next, under an inert atmosphere, dissolve the reagents and three milliliters of acetonitrile, in a 10-milliliter vial. Seal the vial with a cap and a silicone septum. Degas the reaction mixture with argon in an ice bath for 10 minutes.
Then, remove the gas and vent needles, and 56 micro-liters of DIPEA to the mixture. Degas the mixture in an ice bath for another five minutes. Remove the needles when finished.
Next, draw the reaction mixture into an eight-milliliters stainless steel syringe fitted with a long needle. Attach the syringe to a syringe pump, and connect the syringe to the T-fitting of the SFMT assembly. Purge the tubing with acetylene gas.
Then, start pumping the mixture into the tubing at a 100 micro-liters per minute. Adjust acetylene flow-rate to achieve a two-to-one, gas-to-liquid ratio, and the tubing between the T-fitting, and the reactor inlet shut-off valve. Once the reaction mixture has been fully loaded into the reactor, close the reactor outlet shut-off valve.
Pressurize the reactor until the mixture is immobilized in the tubing. Then, close the reactor inlet shut-off valve and the needle valve. Transfer the reactor to a heated water-bath positioned under blue LED lights, keeping the valve above the water.
Allow the mixture to react for three hours. Then, transfer the reaction mixture to a round-bottom flask, and rinse the tubing with excess diethyl ether. Concentrate the reaction mixture to obtain the crude product.
Determine the product ratio with fluorine 19 MNR analysis. Sonogashira couplings of four ayoto anisole with acetylene gas, was evaluated under 11 different conditions using multiple SFMT reactors and parallel The optimal SMFT conditions resulted in better conversion and selectivity than were obtained with the conventional batch-reactor. Further, the SFMT screening was completed in less than three hours.
The photo mediated transformation of tetramethylethylene and benzylidinemelanitrile was performed in batch, in SFMT reactors. The SFMT reaction was completed in only five hours, while the batch reaction took 18 hours. This reduction in reaction-time could be the result of enhanced homogeneous lights scattering to the reagents in the micro-tubing.
The utilization of acetylene gas as a feed-stock for photo-redox Catalysis, was tested in batch, in SFMT reactors. Less than five percent conversion was served in the batch reaction, whereas 97%conversion was observed in SFMT reaction. This was attributed to the increase solubility of acetylene gas and acyto nitrile at the higher temperature attained in the sealed micro-tubing reactor.
The SFMT is a of best reactor using micro-tubing as the reaction container. Pumps are used to introduce the reagents to these reactors. With this technique, the reaction time is not limited by the length of the micro-tubing.
Any successful SFMT reaction, can be easily converted to continues-flow velocity and production. SFMT only need small amount of reagent for the enhanced efficiency with guess and light promote of transformation. It also enable safer flammable gases, especially under high-pressure conditions.
There's many benefits SFMT reactors provides accessible conditions of batch reactors and avoid many limitations from continuous-flow reactors. Therefore, proves to be an important complementary method for labs.
