January 26, 2023

This is the final part of the series, where the p-aminophenol is converted to the acetaminophen.

This is the sixth and final installment of this video series getting to this point has kind of been a journey and i want to recap everything i’ve done so far the aspirin was first extracted then it was hydrolyzed decarboxylated nitrated and reduced this left me with a molecule called pea amino phenol which needs to be accelerated to form the final paracetamol so

In terms of chemicals there isn’t much that i need on the right i have the p amino phenol from the previous video and on the left i have some acetic anhydride acetic anhydride is commonly used to make illegal drugs so its sale is pretty heavily controlled at least in north america though you can get a small amount from ebay but it comes at a pretty hefty price

The procedure that i’m using for this video is sound on line and i’ll provide a link to it in the description to start things off all of the pme know phenol was added to a flask along with a little bit of water pme no phenol is not very soluble in water and what we want here is an evenly mixed suspension once i felt like i had a nice even suspension i added the

Acetic anhydride after it’s added the p amino phenol should quickly dissolve the stir bar wasn’t doing a great job at mixing things so i decided to do it manually the procedure that i was following said it would take about two minutes for a precipitate to form but in my case it took about five in this reaction the pme know phenol is being assimilated to form our

Final paracetamol this type of reaction is known as an acetylene and in the final product we form an amide bond which i’ve marked in red in terms of the mechanism the first step is the attack of the carbonyl by the primary amine the reason this occurs is because the nitrogen has a free electron lone pair that can attack the partial positive of the carbonyl this

Leads to the formation of this intermediate molecule and the new carbon nitrogen bond the proton from the nitrogen is then intermolecular li transferred to the oxygen electrons on the negatively charged oxygen then moved to reform the carbonyl a carbon oxygen bond is broken which leads to the formation of the final paracetamol as well as a molecule of acetic acid

So coming back to the preparation it took about five minutes for some solid to start forming the solar that’s precipitating out is our desired paracetamol and as i continue to mix it it seems like more appears it’s then mix for the next 15 minutes or so to make sure that the reaction goes to completion so 15 minutes later the reaction should be more or less done

And i move on to filtering i turned on the vacuum to pull away the brown liquid and i wash the flask out a few times with cold water the water helps get out any paracetamol that remained in the flask and it also washes the stuff that’s already in the filter it should help wash away contaminants side products and unreacted starting material with that being said

Paracetamol is slightly soluble in water so a minimal amount should be used here so once i was done with the washing steps i used a metal spatula to scrape off the product i keep the vacuum on to dry it up as much as possible and i’m eventually left with a powder that looks a lot like the pea amino phenol that i started with pure paracetamol is white or colorless

So what we have here must be pretty dirty luckily it should be pretty easy to clean this up and i just need to recrystallize it from water the dirty paracetamol is placed back into the small flask and i add a little bit of activated charcoal activated charcoal is very good at getting out colored impurities so it should help us get rid of this brown color i then

Added a somewhat arbitrary amount of water mix things around and turned on the heating i also quickly made a hog filtration set up because the activated charcoal needs to be filtered off i let the solution boil for about 30 seconds and then i filtered it off it might be hard to see but the liquid coming through is nearly colorless so it’s looking good so far once

Everything is filtered through i wash the flask with a little bit of water i waited for everything to pass through the filter and then i boiled things down a little bit to get it more concentrated i did a time-lapse and as it cools we can see the crystals forming the crystals are unfortunately still brown but on a positive note there are a lot cleaner than before

Once it cooled to room temperature i put it in the fridge to fully crystallize about an hour in the fridge i think it precipitated as much as a paracetamol as possible the crystals were then isolated by vacuum filtration and i washed them a few times with ice-cold water i kept the vacuum going to dry them up and using a metal spatula i scraped them off the filter

The crystals were transferred to a filter paper and although they’re not super brown here they’re still evidently discolored when i tested the melting point it was way off from the theoretical so i did another recrystallization after the second recrystallization the melting point was much closer to the theoretical but it was still discolored so to purify it even

Further i carried out a third recrystallization after the third one i was left with a very clean product i tested the melting point and this time it was pretty much exactly the theoretical a very nice friend of mine then ran a hydrogen and amara on the product so from the data in the graph and from the melting point i can confirm that i do have paracetamol the

Nmr here is also quite clean so the product i have is probably pretty pure i am only detecting hydrogen’s here though and it’s not going to pick up inorganic things like metals at some point during the preparation i use palladium on carbon so it’s possible for the final product to contain some palladium but it’s not going to show up here with that being said i’m

Going to go over this nmr and nmr in general in more detail but i’m going to do that in a separate video so in the end the yield was 0.21 grams which represents a killer percent yield of 18 percent the major reason for the low yield is because i did multiple recrystallization each recrystallization gave a more pure product but i lost quite a bit in each one it’s

Very normal to lose some product when you recrystallize but i think i lost a little bit more than i should have because i used way too much water to get the efficiency of the series i multiply out the individual efficiency of each reaction to get an overall percentage of 0.26 percent so with this amazing method i was able to convert about a hundred extra-strength

Aspirin tablets to one regular strength paracetamol in the end though this was mostly just for fun and to explore the chemistry i never really expected to get a great yield an inherent problem with synthetic pathways like this is that the yield is sequentially whittled down with each step that you have no matter how efficient your steps are unless there are a

Hundred percent efficient you’re going to lose something with each one even if i got an 80 percent yield for every single step my final percent yield would only be 26% this is just one reason among many why when you’re synthesizing something you want to use the fewest steps possible anyway i guess that’s all i have to say about this reaction this was the first

Real series that i’ve done on this channel and it’s been pretty well received so i think i’ll do another one at this moment besides nile red i don’t have any particular ideas in mind so if you have any please leave them in the comments alongside this video or shortly after i’m going to upload the nmr video that i mentioned earlier i decided to separate it off

Into its own video because i thought it might be nice to do a little introduction into nmr i’m going to do my best to not make it too technical because i want everyone to be able to follow along the next video that i’ll be posting is the cannizzaro reaction of benzaldehyde what i do want you guys to do though is vote for the next video that you want me to film i

Have a decently large list at the end of the video so please take a look at it and let me know in the comments as usual i’d like to thank everyone who’s supporting me on patreon anyone who supports me with $5 or more will get their name at the end of the video like you see here if i made a mistake with your name or i forgot to include you here please let me know

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Transcribed from video
Aspirin to Acetaminophen – Part 6 of 6: Acetaminophen from p-aminophenol By NileRed