Palladio

The aim of this video is to show you detailed and generalized protocols for the synthesis and purification of benzimidazolium salts, and subsequently, their palladium n-heterocyclic carbene complexes. The video also aims to show you detailed and generalized protocols for testing the catalytic activity of the synthesized complexes in carbon-carbon bond-forming reactions, such as arylation, and Suzuki-Miyaura cross-coupling. After watching this video, you should have a good understanding of how to synthesize and purify these compounds, as well as how to test the catalytic activity of the complexes in arylation and Suzuki-Miyaura reactions.

Protocol demonstration will start with the generalized method for the synthesis and purification of benzimidazolium salts. This will be followed by the generalized method for the synthesis and purification of palladium n-heterocyclic carbene complexes. Finally, the generalized methods for testing the catalytic activity of the complexes in arylation and then Suzuki-Miyaura reactions will be shown.

Warning:many volatile solvents are used as part of the protocols presented, so carry out all experiments in a working fume hood. Wear appropriate personal protective equipment throughout, and consult the MSDS of each reagent before use. The generalized method for the synthesis and purification of benzimidazolium salts will now be demonstrated.

Clamp a 100 mil Schlenk tube upright and put a stirrer bar, one millimole of benzimidozole, one millimole of potassium hydroxide, and 60 mils of ethyl alcohol as the solvent into it. Place the Schlenk tube into an oil bath for even and safe heating of the reaction mixture during the stirring steps to come. Attach the tube to a condenser to prevent solvent evaporation during stirring.

Make sure that the glass fitting parts are sufficiently greased and well-fitted. Stir the reaction mixture at 25 degrees Celsius for one hour to allow for complete dissolution of all the solids, as well as the breaking of the nitrogen-hydrogen bond in benzimidazole molecules. After one hour, detach the Schlenk tube from the condenser and slowly add one millimole of your chosen aryl halide to the mixture.

Reattach the Schlenk tube to the condenser and reflux the mixture at 78 degrees Celsius for six hours to allow the reaction to reach completion. Let the mixture cool down to 25 degrees Celsius after refluxing is finished. Detach the Schlenk tube from the condenser and wipe the grease off the tube's mouth.

Then filter the reaction mixture using a funnel and filter paper to remove the potassium chloride precipitate that formed during the reaction. Collect the filtrate in a beaker. Transfer the filtrate, which contains the n-alkyl benzimidazolium product, to a clean Schlenk tube.

Seal the tube with a greased stopper and remove the ethyl alcohol solvent in the filtrate with vacuum. Once all of the solvent is removed, unseal the Schlenk tube and add five mils of diethyl ether to wash the n-alkyl benzimidazole product left behind. Gently shake the tube to perform washing.

After washing is done, wipe the grease off the tube's mouth and decant the ether into a beaker. Repeat this washing step a few times, adding five mils of diethyl ether and decanting it each time. After the final washing step, seal the Schlenk tube with a greased stopper and dry your washed n-alkyl benzimidazole product with vacuum.

After drying, wipe the grease off the tube's mouth and then transfer your product to a small vial for use in the next reaction. Clamp a clean Schlenk tube upright and expel the air inside it by purging it with argon gas. Introduce the gas from the side arm of the tube and keep the mouth of the tube unsealed during this process.

Argon is heavier than air, so it will expel the air by filling the tube from the bottom up. Keep purging the tube with argon while adding the reagents in the next step. This purging operation is important, as the reaction to come needs to be carried out in an inert atmosphere.

Slowly add a stirrer bar, one millimole of your n-alkyl benzimidazole, one millimole of your chosen alkyl halide, and four mils of anhydrous DMF as the solvent to the Schlenk tube. Once all the reagents are added, quickly seal the mouth of the tube with a greased stopper, then seal its side arm by turning the stopcock, and the turn off the argon gas. Place the sealed Schlenk tube into an oil bath and stir the reaction mixture at 80 degrees Celsius for 24 hours to allow the reaction to reach completion.

After 24 hours, remove part of the DMF solvent in the mixture with vacuum. Approximately one to two minutes of vacuuming should be sufficient. If you want, you can remove all of the DMF solvent from your grease-like mixture, but this is not necessary.

Unseal the Schlenk tube and add 15 mils of diethyl ether. Stir the mixture until your benzimidazolium salt product precipitates out. After precipitation occurs, remove the diethyl ether using an appropriate filtering method.

We have used a special glass tube with a side arm, an internal filter, and two open ends to which Schlenk tubes can be attached. Since the side arm on this tube and those on the Schlenk tubes can be attached to vacuum, this filtering tube provides immense convenience for filtering after the precipitation step, as well as the washing steps to come, and drying after the washing steps. If you're using something similar, attach the filled Schlenk tube to one end of the filtering tube and an empty Schlenk tube to the other end.

Then attach the empty Schlenk tube to vacuum and carefully and gradually invert the apparatus so that the diethyl ether passes through the filter to this empty Schlenk tube. If, however, you cannot find such a tube, other methods, such as filtration with a funnel and filter paper, can also be used. Wash your salt product with 15 mils of diethyl ether and remove the diethyl ether using the same filtration method you used earlier.

Repeat this washing step a few times, using 15 mils of diethyl ether and filtering it each time. After the final washing step, dry your washed salt product. Here, we have dried it inside the filter tube with vacuum.

Collect your product for further purification through recrystallization. For recrystallization, add your salt and a 12 mil to four mil ethyl alcohol diethyl ether mixture to a clean Schlenk tube. Heat the mixture using a heat gun until the salt dissolves completely.

Afterwards, seal the tube with a greased stopper and clamp it in an almost horizontal position. Leave your salt to recrystallize at room temperature. Once the salt has recrystallized, wipe the grease off the tube's mouth and then filter the mixture using a funnel and filter paper to separate the salt crystals.

Wash your salt crystals while they're still on the filter paper in the funnel with 15 mils of diethyl ether. Repeat this washing step a few times. After the final washing step, allow the crystals to dry in air on the filter paper.

Collect your purified salt for characterization and the synthesis of your palladium n-heterocyclic carbene complex. The synthesized benzimidazolium salts were white or cream colored solids and had yields ranging from 62%to 97%The generalized method for the synthesis and purification of palladium n-heterocyclic carbene complexes will now be demonstrated. Clamp a 75 mil Schlenk tube upright and add a stirrer bar, one millimole of your chosen benzimidazolium salt, one millimole of palladium chloride, five millimoles of potassium carbonate as a base, and three mils of 3-chloropyridine into it.

Seal the tube with a greased stopper and place it into an oil bath. Stir the reaction mixture at 80 degrees Celsius for 16 hours to allow the synthesis of the palladium n-heterocyclic carbene complex to reach completion. After 16 hours, allow the mixture to cool down to room temperature and unseal the tube.

You can add 10 mils of dichloromethane to the mixture to improve the efficiency of the filtering steps to come, but this is optional and can be skipped if desired. Use a glass filtering tube without a top to assemble a pad of celite and silica gel, which will be used to remove the unreacted palladium chloride and benzimidazolium salt from the reaction mixture. First, add four spatulas of celite into the tube to make a celite layer above the filter that is in the middle of the tube.

Then, add four spatulas of silica gel above the celite layer. Finally, squeeze a small cotton wad above the silica gel layer, such that the celite and silica gel layers are fixed in place between the filter and the cotton wad. To filter the reaction mixture through the pad of celite and silica gel, first attach the Schlenk tube containing the reaction mixture to the glass filtering tube such that the Schlenk tube faces the end of the filtering tube with the cotton wad.

Then, attach an empty Schlenk tube to the other end of the filtering tube. Connect the empty Schlenk tube to vacuum and carefully and gradually invert the apparatus so the reaction mixture gets filtered through, in order, the cotton, silica, celite, and filter layers. The unreacted palladium chloride and benzimidazolium salt will be retained in the layers, while the filtrate containing your palladium n-heterocyclic carbene complex will enter the empty Schlenk tube.

If you added dichloromethane to the reaction mixture, it can contribute some pressure inside the filtering tube, and this may cause liquid to seep out from the connecting part between the filled Schlenk tube and the filtering tube upon inversion. To prevent his, it is important to connect the empty Schlenk tube to vacuum before inversion of the apparatus, as shown, so that upon inversion, the reaction mixture does not have enough time to seep out from the connecting part. Detach the Schlenk tube containing your filtrate from the filtering apparatus above and seal it with a greased stopper.

Remove the solvent in the filtrate with vacuum. Once all of the solvent is removed, unseal the Schlenk tube and add 5 mils of diethyl ether to wash the palladium n-heterocyclic carbene complex product left behind. Gently shake the tube to perform washing.

After washing is done, wipe the grease off the tube's mouth and decant the ether into a beaker. Repeat this washing step a few times, adding five mils of diethyl ether and decanting it each time. After the final washing step, seal the Schlenk tube with a greased stopper and dry your washed palladium n-heterocyclic carbene complex product with vacuum.

After drying, wipe the grease off the tube's mouth and then collect your product for further purification through recrystallization. For recrystallization, find an appropriate solvent for your specific palladium n-heterocyclic carbene complex and follow the same steps shown earlier for the salts. The solvent should be one that the complex does not readily dissolve in at room temperature, but does so upon heating.

After purification, collect your complex for characterization. The synthesized palladium n-heterocyclic carbene complexes were yellow or cream colored solids and had lower yields than the salts, ranging from 25%to 60%The four palladium complexes were tested for catalytic activity in arylation and Suzuki-Miyaura cross-coupling reactions. Now, the generalized method for testing the catalytic activity of the synthesized complexes in arylation reactions will be demonstrated.

Carry out all catalytic reactions under air in a fume hood and use the purchased reagents without further purification. Clamp a 25 mil Schlenk tube upright and add a stirrer bar, two millimoles of 2-n-butylthiophene or 2-n-butylfuran, and one millimole of your chosen aryl bromide into it. Then add one millimole of potassium acetate, 0.01 millimole of your chosen palladium n-heterocyclic carbene complex, and two mils of n, n-dimethylacetamide into the tube.

Seal the tube with a greased stopper and place it into an oil bath. Stir the reaction mixture for various times and at various temperatures to find a the time and temperature conditions leading to maximum product yield for the given reaction. Once the reaction is complete or has run for the desired amount of time, remove the solvent in the reaction mixture with vacuum, using heat to aid if necessary.

Unseal the Schlenk tube and add a 10 mil to two mil hexane-diethyl ether mixture into it. This solvent mixture will be your mobile phase for flash column chromatography in the steps to come. Shake the mixture vigorously to ensure that your product dissolves in the mobile phase and is not left behind in the tube.

Use a glass dropper to assemble a flash chromatography column for purification of your product. First, insert a small wad of cotton into the dropper and push it in until it rests firmly just where the glass chamber starts to thin out. Then, add silica gel on top of the cotton wad such that 2/3 of the dropper's thick section is filled.

Clamp your silica gel column upright and use a glass dropper to gradually transfer your reaction mixture into it. Elute your mixture through the column and collect the eluant containing your purified product in a clean beaker or test tube. Transfer your eluant to a clean tube that can be attached to vacuum and seal the tube with a greased stopper.

Remove the solvent in your eluant with vacuum. Once all of the solvent is removed, unseal your tube and add 1.5 mils of dichloromethane. Gently shake the tube to dissolve your product and thereby allow its analysis with gas chromatography.

Representative results are shown for the catalytic effect of the palladium n-heterocyclic carbene complexes on the arylation reactions studied. The reaction between 2-n-butylthiophene and 4-bromoacetophenone was given as an example to highlight the poor results obtained in arylation reactions in the absence of an appropriate catalyst. For catalysis of the reaction between 2-n-butylfuran and 4-bromoacetophenone, complex six was a good candidate, while complexes seven and eight performed particularly well.

Complex seven was an excellent catalyst for the reaction between 2-n-butylfuran and bromobenzene. The positive effect of increased temperature on yield for this reaction shows that if the reaction is catalyzed by an appropriate complex, modifying other reaction conditions such as temperature can help maximize the yield. For the reaction of 2-n-butylthiophene with bromobenzene, complex eight was an excellent catalyst, while for the reaction between 2-n-butylthiophene and 4-bromoanisole, complex five performed quite well as a catalyst.

Overall, each of the arylation reactions studied was catalyzed well by at least one of the four complexes synthesized. Further work can be done to potentially increase the yield values for these reactions by modifying reaction conditions such as time and temperature. Now, the generalized method for testing the catalytic activity of the synthesized complexes in Suzuki-Miyaura cross-coupling reactions will be demonstrated.

Clamp a 25 mil Schlenk tube upright and add a stirrer bar, 1.5 millimole of phenylboronic acid or your choice of boronic acid derivative, one millimole of your chosen aryl chloride, and two millimole of sodium tert-butoxide as a base into it. Then add 0.01 millimole of your chosen palladium n-heterocyclic carbene complex and a two mil to two mil DMF-water mixture into the tube. Seal the tube with a grease stopper and place it into an oil bath.

Stir the reaction mixture for various times and at various temperatures to find the time and temperature conditions leading to maximum product yield for the given reaction. Once the reaction is complete or has run for the desired amount of time, allow the mixture to cool down to room temperature. Unseal the Schlenk tube and add a five mil to one mil hexane-ethyl acetate mixture to your reaction mixture.

Reseal the tube and shake the new mixture vigorously for a few minutes to allow the migration of the synthesized product to the hexane-ethyl acetate phase. Clamp the Schlenk tube upright and let the mixture settle into two distinct phases over the course of a few minutes. Use a glass dropper to carefully extract the top organic phase and transfer it to a clean beaker containing one gram of anhydrous magnesium sulfate.

The magnesium sulfate powder will help remove any residual water from your extracted organic phase. Repeat the entire extraction process at least once to maximize the extraction of your synthesized product. Assemble a silica gel column as before to purify your product with flash column chromatography.

This time, the hexane-ethyl acetate mixture present in your extracted organic phase will serve as the mobile phase. Collect the eluant containing your purified product in a clean beaker or test tube and then analyze your product using gas chromatography. The catalytic effect of the complexes on the studied Suzuki-Miyaura reactions between boronic acid derivatives and aryl chlorides was variable.

Here, the aim was to compare the performance of the four complexes in catalysis of these reactions. So, for each of the reactions studied, the other reaction conditions were kept constant. Namely, a 2 mil to 2 mil DMF-water mixture was used as a solvent, sodium tert-butoxide was used as the base, reactions were run for two hours, and reaction temperature was kept at 80 degrees Celsius.

Under these conditions, complexes five to seven proved to be a good candidate, while complex eight did not perform well for catalysis of the reaction between 2, 5-dimethoxyphenylboronic acid and 4-methoxy-1-chlorobenzene. For the reaction of 4-tert-butylphenylboronic acid and 4-chlorotoluene under these conditions, all four complexes proved to be excellent catalysts. Finally, for the reaction of thianaphthene-2-boronic acid with 1-chloro-4-nitrobenzene under these conditions, complexes five and six did not perform well as catalysts, while complexes seven and eight showed some promise.

Overall, each of the Suzuki-Miyaura reactions studied was catalyzed well by at least one of the four complexes synthesized. For those cases where the chosen complex performed well in catalyzing the given reaction, further work can be done to potentially increase conversion and yield values by varying reaction conditions like time, temperature, solvent composition, and the base used. In summary, this video has shown the detailed and generalized protocols for the synthesis and purification of benzimidazolium salts and, subsequently, the palladium n-heterocyclic carbene complexes.

The video has also shown the detailed and generalized protocols for testing the catalytic activity of the complexes in various arylation and Suzuki-Miyaura cross-coupling reactions. After mastering these protocols, you should be able to easily adapt them for the synthesis, purification, and testing of the catalytic activity of many other palladium n-heterocyclic carbene complexes.