At one point, acetanilide was sold as a fever and pain reducing medication under the brand name Antifebrin. However, due to toxicity issues, it was eventually taken off the market. Nowadays, Antifebrin and other related medications have been completely replaced by acetaminophen. Also known as paracetamol or Tylenol. It was eventually discovered that acetanilide and many of the other an aniline based pain relievers were not themselves effective, and they were simply being metabolized to acetaminophen. However, they were also being broken down into many toxic side products that could have quite severe effects. By using acetaminophen directly, a lot of the nasty and potentially fatal side effects were reduced or eliminated. Although acetaminophen is still somewhat toxic, it’s not nearly as bad as the stuff that it replaced. The history of how these analine based pain relievers were discovered and developed is actually pretty interesting. If you guys are interested in knowing more, I have a short video on my other channel “NileBlue”, which I’ll link in the description. Nowadays, acetanalide is mostly used as a chemical precursor to dyes and pharmaceuticals, or is an inhibitor of hydrogen peroxide decomposition. I plan to use it to make the dye para red as well as the antibiotic sulfanilamide. Although penicillin was the first true antibiotic to be discovered, sulfanilamide and a related drug Prontosil were the first antibiotics to be mass-produced. So in terms of chemicals, this is what I need; from left to right I have aniline, acetic anhydride, muriatic acid (also known as hydrochloric acid), and sodium acetate. The sodium acetate and the hydrochloric acid are pretty easy to get, but the others aren’t. For this prep, I ordered aniline online from a chemical company, but in the past I made it from scratch. If you’re interested in seeing how I did this, there are some links in the description. The acetic anhydride is the hardest to get because it’s dangerous and difficult to make, and it’s also a restricted chemical. I’m never going to make it myself— but if you’re interested in seeing how it can be made— Doug over at “Doug’s Lab” has done it before and I’ll provide some links in the description. Over time and prolonged storage, aniline tends to degrade, so before I get started, it’s a good idea to check the quality of it. When aniline is pure it’s either colorless or slightly yellow, but the stuff I have here is brown. Unfortunately, this means it has degraded quite a bit, and before proceeding on I need to purify it. To do this, it’s pretty simple. I just pour everything into a large round bottom flask and then I carry out a vacuum distillation. It’s not absolutely necessary to do it under vacuum, but because aniline degrades in the presence of oxygen, it just makes things a little bit cleaner. I turn on the heating in the vacuum, and the first thing to come off is gonna just be water. When we take a look at the other end of the distillation setup, you can see that I’m using my 3-way cow adapter. In the beginning I’m just collecting water, but at some point when the aniline starts to come over. I need to swap out the receiving flask. If I didn’t have this, it’s also possible to remove the vacuum, change the flask, and then re-pull the vacuum— but it’s kind of a pain. I continue collecting things in the middle flask until I’m sure there’s no more water coming over. When I think it looks good and water free, I turn it again to collect everything in the large one. It’s now just a matter of waiting until everything distills over. It’s eventually done when there’s only a small amount left in the distillation flask. So, this is what was left. A little bit of aniline mixed in with a whole bunch of polymerized junk. Because aniline is relatively toxic this needs to be dealt with properly and added to a waste container and not poured down the drain or something. In the first collection flask, we have a mixture of aniline and water, and this can be included in the waste as well. The second one is kind of a judgement call because it’s mostly aniline, but it is wet with some water. I decided to not tarnish my main supply, so I dumped this in the waste as well. The now relatively pure and dry aniline was poured back into the same bottle that I had cleaned in the meantime. Okay, so now let me know that the aniline is good, I can proceed on to the reaction. To start things off, I add distilled water to a beaker, turn on the stirring, and dump in some sodium acetate. This is going to take a couple minutes to dissolve. I come back about five minutes later, and I have a nice clear solution. I don’t need this immediately and it’s temporarily placed on the side. Then, into another beaker, I add some distilled water. I turn the stirring and I slowly pour in some hydrochloric acid. Once all of the acid is added, I can start to pour in the aniline. Under normal conditions, aniline is insoluble in water. In this case though, the water is acidic and aniline is a base. So it’s going to undergo an acid-base reaction. This leads to the formation of aniline hydrochloride which is a salt and soluble in water. So I just continue stirring and wait for all of the aniline to react. When it does, I should be left with a completely clear solution. With everything dissolved, I then dumped in the acetic anhydride. The reaction is quite quick, and it’s more or less done within 30 seconds. However, nothing precipitates out and all of the product is still dissolved in the solution. To get it out, I dump in the sodium acetate solution from earlier. Almost immediately, a whole bunch of acetanilide falls out of solution. Okay, so now to talk about what’s going on here so as I said before the aniline first reacts with the hydrochloric acid to form aniline hydrochloride. This allows it to dissolve in water, but in this form, it can’t react with acetic anhydride. The key step in getting the reaction going is the addition of the sodium acetate. When the sodium acetate is added it forms an equilibrium reaction with the aniline hydrochloride. The acetate ion can pick up one of the hydrogen’s on the nitrogen which leads to the formation of aniline, acetic acid, and sodium chloride. The forward reaction isn’t very strongly favored though, so only a little bit of aniline is liberated at any given time. When the aniline is free it quickly reacts with the acetic anhydride to form acetanilide, which is insoluble in water and precipitates out. This reaction is a good example of how equilibriums can be manipulated. Even though only a small amount of aniline is present at any time, It’s immediately picked up and sequestered. The equilibrium keeps trying to establish balance by making more aniline, but it just keeps getting picked up. Eventually, all of the aniline hydrochloride is converted back to aniline and the reaction is pushed to completion. In terms of the mechanism, it’s not too complicated, and it’s just a couple steps. So the first thing that happens, is a lone pair of electrons on the nitrogen of aniline – attacks one of the carbonyls of acetic anhydride. The double bond of the carbonyl is opened, and then immediately reformed and the carbon oxygen single bond is broken. Then there’s a proton transfer where the extra hydrogen on the nitrogen is given to the acetate ion. This leads to the formation of our final acetanilide as well as acetic acid as a side product. To reduce the solubility of acetanilide, and precipitate as much as possible, it now needs to be cooled to around 0°C. I decided to do this using an ice bath, but it’s also possible to just put it in the freezer for a little bit. I let it sit for a couple hours, and at this point It should be done. All of the acetanilide is then separated using just a coffee filter. I wash the beaker and the stuff in the filter a few times with some distilled water. I left it out for a day or so, but it didn’t really seem like things were drying very well. So I picked up everything out of the strainer and manually squeezed out excess water. I opened up the filter paper, and then I broke apart the acetanilide. The stuff I have at this point is technically still crude, but I imagine the purity is pretty decent. Although it’s probably fine, I want to purify it a little bit more, and I’m going to do this by recrystallization. So, all of it was added back into the same beaker as before, which I had cleaned in the meantime. I add around 200 milliliters of distilled water, and then I turn on the stirring and the heating. I broke things up using the glass rod, and I continued to add water. The bottom part eventually clears up, but there’s still a whole bunch of solid floating on top. I keep adding water until everything dissolves, and when I get to this point, I add an extra hundred milliliters. The glass rod is washed with a little bit of water, and the beaker is taken off the hot plate. The top is covered with plastic wrap to reduce evaporation, and I wait for the crystals to form. As the solution cools, the solubility of acetanilide will slowly decrease, and we should start to see something precipitate out. I took a time-lapse, and this is what happened over the course of about two or three hours. When it was done, there was a very nice layer of crystals at the top. I shook it around to knock everything to the bottom, and then I cooled it to about 5°C for a few hours. By cooling it, I’m further decreasing the solubility of the acetanilide, and it should help to get out a little bit more. When I think that everything is crystallized, I move on to filtering it. When everything was transferred, I washed the beaker and the stuff in the filter paper a couple times with distilled water. I mix it around a little to help the water filter through, but I was very careful to not break any of the crystals. It was relatively dry after a few hours, so I transferred the filter to a piece of paper. I continue to let it dry over the course of a couple days, and this is what I was left with. The
final yield of nice acetanilide crystals is 21.4 grams, which corresponds to a percent yield of 74%. I picked out some of the nice crystals, and zoomed in as much as I could. When it’s tilted on the side, and I’m able to catch the light, we can see the surface texture of the crystal. I honestly don’t have too much to say about this. I just thought the close-up was kind of cool. Anyway, I think that’s about it for acetanilide. Like I said before, in the future I’ll be using it to make sulfanilamide and para red, and both of these videos should be posted in the next couple months. I ran a giveaway in the last video and now it’s time to say who won. So the way that it works, is the website randomly generates a number, which corresponds to one of the entires. When I did this, I got the number 2 3 2 2, so the winner is “Juyoung” from Ohio. Anyway, in general, this giveaway was pretty successful, and I’m thinking of maybe doing it once a month. A big thanks goes out to all of my supporters on Patreon. Anyone who supports me will see my videos 24 hours before I post it to YouTube, and they’ll also be able to directly contact me. Anyone who supports me with $5 or more, will also get their name at the end of the video like you see here.