Hello all, hope youre having a nice day. Lets say you want to do a 1 mol scale synthesis of the 2-phenyl cyclohexanone as this is a reasonable amount to do at a time. If you want to do more then invest in a 2nd set of glassware and just do 2 at a time as youll need a dean stark aparatus to remove water. The first step will be formng an enamine of cyclohexanone using Cyclohexanone, anhydrous Para-Tolusulfonic acid and Pyrrolidine.
First youll need to set up glassware. First, youll need a 500ml 3 neck round bottom flask and a heating mantle that can stir. In one neck, have a gas line for flushing the reaction vessel with N2 or Ar, on the middle neck place a dean stark aparatus with a spout to remove water from the bottom of the trap, and in the third neck place a funnel to add your reagents and have a rubber septum on hand to replace the funnel once theyve been added. Fill the dean stark trap fully with toluene until it slighly overflows into the RBF. Youll also need a vaccum distilation setup including a pump for water and generating the vaccum.
1) Add 350ml of toluene into the 500ml rbf and turn on low heating. Add 120g of pyyrolidine, 100 grams of Cyclohexanone and 15 grams of p-TSA into the reaction vessel and after this, swap the funnel for a rubber septum and start the gas flow into the reaction vessel. After the argon or nitrogen flow had been turned on, the reaction is brought to a reflux and left to stir. As the reaction takes place, the water will be driven out of the reaction and into the dean stark aparatus so this means youll need to remove the water from the dean stark as its generated, wait till a few ml of water is generated before removing as you dont want to take any of the toluene out with it. Leave this reaction to reflux for 2 hours before swapping out the gas line for a stopper and then is left to reflux for another 22 hours.
2) You will know when the reaction has taken place as the reaction mix will stop producing water in the dean stark aparatus aswell as the reaction mix willl have gone from a very light yellow to a dark orange. After the 24 hours, turn the heating off and let cool to room temperature. Try to limit the reaction mixes contact with the air as the eneamine will be easily oxidized by atmospheric conditions, this is why the rubber septum is used, so take your syringe and draw out all the reaction mix and transfer into a vaccum distilation setup. The first fraction that boils over will be a mix of toluene and pyyrolodine however after this has come off, your 1-pyrrolidino-1-cyclohexene will start to come over with some of the cyclohexane. This cyclohexane wont react with any chemical in the next step so for the time being, separation of the 2 compounds isnt neccicary. While it is a pain, i reccomend you distill till there is no liquid left in your first distilation flask as this will give the highest yeilds, being nearly quantitative if all water is removed. Once the pyrrolindo has been isolated and moved to an air tight flask, we can move onto the next step.
3)Due to the enamine formation with cyclohexane, the molecule will undergo an enamine-imine tautomerism similar to an keto enol tautomerism allowing for the carbon one carbon left or right of the carbonyl to become very nucleophilic therefore an electrophilic attack can take place with a molecule like iodobenzene with iodine acting as the electrophile. Now, add all your freshly brewed 1-pyrrolidino-1-cyclohexene to a 1 neck 1L flask with 250ml of cyclohexane and 204 grams of Iodobenzene. Place the 1L rbf onto a heating mantle and add a reflux condensor with water pumping through, bring this reaction to a boil and leave it to react for another 24 hours.
4) Finally, youll be left with a white powder, if the powder has generated before the full 24 hours has been up then just turn off the heating and start the work up. Stop the heat and take the refux condenser off the rbf so replace it with a stopper. Once the flask has cooled down, take off the stopper and add roughly 300ml of distilled water to destroy any remaining enamine, this will convert it back to its cyclohexanone and pyyrolidine. Recap the flask and shake vigerously, you want all the powder to be gone. Add a solution of 10% sulpuric acid to destory any remaining pyyrolidine. Pour the reaction mix into a 1L sepratory funnel and wait for both layers to separate. Both the bottom aqeous layer and top organic layer should be poured into different beakers and saved while you repour the aqueous into the sep funnel with 250ml of DCM. Once again, this mix should be shaken well to extract any of the final 2-phenylcyclohexanone to the DCM layer. The aqueous layer is discarded while both organic layers are combined and washed with a sodium thiosulfate and dried over magnesium sulphate. Finally, evaporate off all of the organic solvent to leave you with roughly 140 grams of crude product. Perform a recystalisaition using IPA to recieve a white powder with a rough yeild of 60-70%
I will be writing an experimental guide to alkylation using triphenylaluminium however id rather perform the reaction before creating a replicatable writeup. If anyone has questions id be more than happy to help
First youll need to set up glassware. First, youll need a 500ml 3 neck round bottom flask and a heating mantle that can stir. In one neck, have a gas line for flushing the reaction vessel with N2 or Ar, on the middle neck place a dean stark aparatus with a spout to remove water from the bottom of the trap, and in the third neck place a funnel to add your reagents and have a rubber septum on hand to replace the funnel once theyve been added. Fill the dean stark trap fully with toluene until it slighly overflows into the RBF. Youll also need a vaccum distilation setup including a pump for water and generating the vaccum.
1) Add 350ml of toluene into the 500ml rbf and turn on low heating. Add 120g of pyyrolidine, 100 grams of Cyclohexanone and 15 grams of p-TSA into the reaction vessel and after this, swap the funnel for a rubber septum and start the gas flow into the reaction vessel. After the argon or nitrogen flow had been turned on, the reaction is brought to a reflux and left to stir. As the reaction takes place, the water will be driven out of the reaction and into the dean stark aparatus so this means youll need to remove the water from the dean stark as its generated, wait till a few ml of water is generated before removing as you dont want to take any of the toluene out with it. Leave this reaction to reflux for 2 hours before swapping out the gas line for a stopper and then is left to reflux for another 22 hours.
2) You will know when the reaction has taken place as the reaction mix will stop producing water in the dean stark aparatus aswell as the reaction mix willl have gone from a very light yellow to a dark orange. After the 24 hours, turn the heating off and let cool to room temperature. Try to limit the reaction mixes contact with the air as the eneamine will be easily oxidized by atmospheric conditions, this is why the rubber septum is used, so take your syringe and draw out all the reaction mix and transfer into a vaccum distilation setup. The first fraction that boils over will be a mix of toluene and pyyrolodine however after this has come off, your 1-pyrrolidino-1-cyclohexene will start to come over with some of the cyclohexane. This cyclohexane wont react with any chemical in the next step so for the time being, separation of the 2 compounds isnt neccicary. While it is a pain, i reccomend you distill till there is no liquid left in your first distilation flask as this will give the highest yeilds, being nearly quantitative if all water is removed. Once the pyrrolindo has been isolated and moved to an air tight flask, we can move onto the next step.
3)Due to the enamine formation with cyclohexane, the molecule will undergo an enamine-imine tautomerism similar to an keto enol tautomerism allowing for the carbon one carbon left or right of the carbonyl to become very nucleophilic therefore an electrophilic attack can take place with a molecule like iodobenzene with iodine acting as the electrophile. Now, add all your freshly brewed 1-pyrrolidino-1-cyclohexene to a 1 neck 1L flask with 250ml of cyclohexane and 204 grams of Iodobenzene. Place the 1L rbf onto a heating mantle and add a reflux condensor with water pumping through, bring this reaction to a boil and leave it to react for another 24 hours.
4) Finally, youll be left with a white powder, if the powder has generated before the full 24 hours has been up then just turn off the heating and start the work up. Stop the heat and take the refux condenser off the rbf so replace it with a stopper. Once the flask has cooled down, take off the stopper and add roughly 300ml of distilled water to destroy any remaining enamine, this will convert it back to its cyclohexanone and pyyrolidine. Recap the flask and shake vigerously, you want all the powder to be gone. Add a solution of 10% sulpuric acid to destory any remaining pyyrolidine. Pour the reaction mix into a 1L sepratory funnel and wait for both layers to separate. Both the bottom aqeous layer and top organic layer should be poured into different beakers and saved while you repour the aqueous into the sep funnel with 250ml of DCM. Once again, this mix should be shaken well to extract any of the final 2-phenylcyclohexanone to the DCM layer. The aqueous layer is discarded while both organic layers are combined and washed with a sodium thiosulfate and dried over magnesium sulphate. Finally, evaporate off all of the organic solvent to leave you with roughly 140 grams of crude product. Perform a recystalisaition using IPA to recieve a white powder with a rough yeild of 60-70%
I will be writing an experimental guide to alkylation using triphenylaluminium however id rather perform the reaction before creating a replicatable writeup. If anyone has questions id be more than happy to help
