Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

This protocol allows students of any level to perform the synthesis of air-sensitive compounds, for example, carbenes, or their dimers, or free radicals using a Schlenk line and cannulas for filtration. Filter cannulas allow for the isolation of very, very sensitive compounds with minimal effort and a very low risk of contamination of the product. What's important to remember is the use of dry and degassed solvents, dry glassware, and properly cycling the glassware when connected to the Schlenk line.

A visual guideline is especially useful when navigating the workflow of, for example, the Schlenk technique or filter cannula techniques. To begin, quickly transfer a hot, oven-dried 100 milliliter Schlenk flask into a dinitrogen-filled glove box. Weigh out iminium salt 1prot and KHMDS.

And combine both in the 100 milliliter Schlenk flask. Equip the Schlenk flask with a magnetic stir bar and cap the flask with a rubber septum. Then, transfer the flask to a Schlenk line by connecting the Schlenk flask valve with one of the hoses of the Schlenk line.

To another hose of the Schlenk line, connect a second hot, oven-dried 100 milliliter Schlenk flask capped with a rubber septum. Additionally, connect a Straus flask containing dry, degassed diethylether to the Schlenk line. Turn the Schlenk line valves to evacuate and wait for the manometer to show a vacuum around 10 to the power of minus 2 millibar.

Refill the connecting hoses with dinitrogen by turn the Schlenk line valve. The bubbler then starts bubbling due to overpressure. This procedure removes any traces of water and air from the hoses.

After evacuating and refilling the connecting hoses three times, place the flask with the reagents in an isopropanol slush bath at minus 88 degrees Celsius to cool for three minutes. During cooling, the Schlenk flask is kept under a slight overpressure of dinitrogen as provided from the Schlenk line. Use the Straus flask containing diethylether to purge a syringe three times to remove traces of air.

Via the syringe, add 20 milliliters of this solvent along with the cold flask wall over the course of three minutes. Place the flask on a stir plate and stir the suspension for 10 minutes. Once the mixture reaches room temperature, discontinue stirring and allow the potassium tetrafluoroborate salt to settle.

Then, obtain a steel cannula and wind PTFE tape around one end of the cannula to obtain an overall diameter of about 0.6 centimeters. Fit a glass microfiber filter to that end by winding further PTFE tape around. With a small needle which has a smaller diameter than the cannula, perforate a septum and subsequently push the filter cannula through the tiny hole.

Remove the rubber septum of the Schlenk flask containing the crude carbene connected to dinitrogen. Under a gently flow of dinitrogen, swiftly exchange this septum with the septum of the cannula. Keep the glass microfiber filter attached to the cannula, pointing into the flask.

Purge the cannula for at least one minute with dinitrogen. Use a small needle to perforate the septum, capping a second empty Schlenk flask as well. And introduce the other end of the steel cannula.

Additionally, insert a thin needle through the septum of the empty flask for overpressure release. Close the Schlenk valve connecting this flask to the Schlenk line to stop dinitrogen flow. Lower the filter cannula into the overlying solution to start filtration of the solution containing the free carbene into the second Schlenk flask using slight dinitrogen overpressure provided by the Schlenk line.

Eventually, also lower the filter cannula into the suspension with the settled salt at the bottom of the flask. After quantitative transfer of the carbene, reopen the stopcock of the second Schlenk flask to the Schlenk line for dinitrogen supply. Remove the small needle as well as the steel cannula and seal the perforated septum of the Schlenk flask with adhesive tape.

Remove the solvent as well as the volatile hexamethyldisilazane in vacuo by applying vacuum from the Schlenk line to obtain 1.53 grams of free carbene 1 as a colorless to slightly yellow and greasy solid. Transfer the Schlenk flask containing the carbene under vacuum to a glove box for storage. After synthesis of carbene 2, transfer a Schlenk flask with iminium salt 1prot and the free carbene tube to the Schlenk line.

Additionally, connect one Straus flask to the Schlenk line containing dry and degassed tetrahydrofuran. Evacuate and refill the connecting hoses with dinitrogen three times. Purge a syringe on the flask as previously.

And add 30 milliliters of dry and degassed tetrahydrofuran along the flask wall via the syringe. Stir for 10 minutes. Swiftly replace the perforated septum by a well-greased glass stopper.

Stir the reaction mixture for at least 12 hours at room temperature. After the salt has settled, swiftly exchange the glass stopper by a septum with a filter cannula to remove the supernatant solvent from the yellow powder. Via a clean syringe, add 20 milliliter of dry tetrahydrofuran to wash the residue in the Schlenk flask.

Stir for 15 minutes to obtain a fine suspension. Remove the supernatant washing solution by a filter cannula. Exchange the perforated septum along with the filter cannula by a well-greased glass stopper.

Open the stopcock to vacuum on the Schlenk line to dry the residue and afford the protonated heterodimer quantitatively as an off-white powder. Transfer the Schlenk flask containing 3prot to the glove box for storage. To synthesize compound 4, connect a Schlenk flask containing silver trifluoromethanesulfonate and compound 3, as well as a second hot, oven-dried empty 20 milliliter Schlenk flask to the Schlenk line Additionally, connect a Straus flask containing tetrahydrofuran to the Schlenk line.

After evacuating and refilling the connecting hoses with dinitrogen three times, add 5 milliliters of dry and degassed tetrahydrofuran into the flask via a purged syringe to obtain a deep maroon mixture. Then, filter the solution into the second empty Schlenk flask using a filter cannula as previously done. Obtain the stable radical quantitatively as a yellow-brown powder after removing the solvent in vacuo.

Transfer the Schlenk flask containing compound 4 to a glove box for storage. Carbenes 1 and 2 are isolated at room temperature and do not dimerize as evidenced by the signals of the carbene carbon atom in the C-13 NMR spectrum at 313.9 ppm and 216.9 ppm respectively. The absence of a signal around 100 ppm confirms the efficient exclusion of air using the filter cannula technique.

The stability of carbene 1 is largely due to the sterically demanding diisopropylphenyl substituent at the nitrogen atom which prevents dimerization. The proton NMR spectrum of 3prot shows a characteristic singlet at 5.02 ppm belonging to the proton at the carbene position of the CAAC scaffold. The proton NMR spectrum of compound 3 reveals a significant upfield shift of the NHC-methyl groups to 2.53 ppm and 1.39 ppm in relation to the starting material 3prot.

This shift is indicative for the elimination of the positive charge on the NHC nitrogen atom and the formation of the olefin 3. The Carbon-13 NMR spectrum unambiguously proves the formation of an olefinic dimer by the absence of the carbene signal. The most important thing to remember is the proper organization of the sequence of events.

For example, one must use care and concentration when exchanging the stoppers, adjusting valves, and of course working with needles and syringes. All reagents and solvents are potentially hazardous, therefore, all synthetic efforts should be conducted in a well-ventilated fume hood.