Transcription
Today, I'm going to show you three ways to make the extremely important chemical methylamine. Methylamine is the simplest primary amine, and as such, its use in organic chemistry is pervasive. For example, methylamine is used extensively in the synthesis of accelerants, propellants, pharmaceuticals, insecticides, fungicides, and surfactants. It's also used as a fuel additive, a polymerization inhibitor, a component in paint strippers, a solvent, a water treatment agent, and a photographic developer. However, like some of the other most ubiquitous and commonplace lab chemicals you could imagine, methylamine is regulated by the US government as a precursor chemical, which makes it tough to purchase. For reference, here are just some of the other many commonplace lab chemicals scheduled as precursors.
This video took me months to actually release because I heard so often that this chemical was under particular scrutiny. But in reality, these chemicals are all identical in the eyes of the law. And that said, you'd have a hard time finding a video on my channel where I don't use at least one scheduled precursor. So in the end, I decided to just say "screw it" and make the list a little longer anyway.
The first method I'm going to show today is the reaction between formaldehyde and ammonium chloride. This route is by far the easiest, but it's very messy, time-consuming, and requires a large amount of formalin, which is not an easy chemical for many people to get. To get started, I went ahead and added 125 g of ammonium chloride and 250 ml of 37% formalin to a three-neck round-bottom boiling flask. I then connected a distillation head to one of the necks, a thermometer to another, and capped the third. Notice here that the thermometer is immersed in the solution, as I want to monitor the temperature of the reaction mixture and not the vapor temperature. I turned my heating mantle to max and waited until the temperature reached around 104° C.
Now, as the temperature increases, a set of reactions begin to occur that eventually result in the formation of the chloride salt of methylamine, which is much easier to collect and weigh than free-base methylamine. The first reaction that occurs is a direct condensation of formaldehyde and ammonium chloride, yielding water, hydrogen chloride, and the unsaturated compound methylamine. This reaction happens spontaneously near ambient temperatures, but as the temperature increases, methylamine, water, and another molecule of formaldehyde react to form methylamine and formic acid. This is technically a redox reaction wherein water is being oxidized by methylamine, which itself is being reduced. In the final reaction step, the free-base methylamine generated in the previous step will react with hydrogen chloride, forming the target methylamine hydrochloride. As for the reaction byproducts, the formic acid produced is, for the most part, oxidized to carbon dioxide and water as the reaction mixture heats up. However, formalin solutions are stabilized with 10 to 15% methanol in order to prevent oxidation or polymerization of the formaldehyde, and some of the formic acid will react with this methanol, forming methyl formate and the acetyl methylol, which both have very low boiling points and will distill off early in the reaction.
Anyway, once the temperature reaches 104° C, I cut the heat and fiddled with it a bit until the temperature stabilized between 100 and 105° Celsius. This temperature is held for about 3 hours while slowly distilling away water and the formic byproducts. At a certain point, the distillation slows to a virtual stop and can't continue without raising the temperature. The issue, though, is that raising the temperature would favor the formation of undesired byproducts, and as low as even 115° C, the formation of dimethylamine is favored, especially if excess formaldehyde is present. To fix this, I go ahead and connect a vacuum to the distillation apparatus and vacuum distill away as much as I can until ammonium chloride begins to crash out of solution. At this point, I cut the heat completely, allow my solution to cool to room temperature, and then transfer it to an ice bath until it's cooled to 0° C. I then pass the solution through vacuum filtration to collect the ammonium chloride, which can be recrystallized and reused. I then add my solution back to my boiling flask and continue heating at 105° C and repeat the previous step once the distillation had again slowed to a crawl. At this point, the reaction is virtually complete, and most of the unreacted ammonium chloride has been removed. To this end, I go ahead and move my boiling flask back to the heat and continue heating until the mixture had reached around 160° C in order to drive off as much water as possible. This is then poured into a beaker while still hot, and I went ahead and rinsed the flask with some methanol to make sure all my crude methylamine made it into the beaker. This immediately began to harden, as methylamine hydrochloride has a relatively high melting point.
To begin purifying my crude product, I first needed to dissolve it in a minimal amount of hot methanol, which took around 70 ml in my case. Now, while methylamine hydrochloride is very soluble in hot methanol, ammonium chloride isn't, and virtually all the remaining ammonium chloride can now be removed by passing this mixture through vacuum filtration. The resulting solution is left overnight to crystallize, and when I came back the next day, some beautiful methylamine crystals had formed. As a final step, I put this beaker into an ice bath for a few hours to crystallize out as much as possible and then pass the resulting solution through vacuum filtration to collect mostly pure methylamine hydrochloride. These crystals are rinsed with a bit of ice-cold methanol, followed by some ice-cold dichloromethane to remove any dimethylamine hydrochloride that might have formed, and then vacuum desiccated for a few hours. Vacuum desiccation is extremely important here, as methylamine hydrochloride is one of the most aggressively hygroscopic chemicals I've ever handled and will pull enough moisture out of the air to liquefy itself at 40% relative humidity in just a few hours. Anyway, once my methylamine hydrochloride was allowed to dry completely, I weighed it, giving me a final mass of 16.96 g. After this, I was able to crystallize out another 10 g along with 30 g of ammonium chloride. However, this second batch was visibly lower purity, with a melting point of 195° C and not ideal if purity is required.
To calculate percent yield, I decided to use ammonium chloride consumed as my limiting reagent. If I was left with 30 grams of ammonium chloride recrystallized, then 95 grams were consumed, and my percent yield would be 49.9% out of the theoretical 53.97 g. This yield would actually be considered quite good based on the literature I've read, but given the quantity of starting reagents, it still feels bad. With that said, I don't really love this method. It requires valuable and very toxic formalin, yields are pretty low, and it's very messy, smells horrendously of rotten fish, and produces a lot of formate waste along with a lot of unreacted ammonium chloride, which can obviously be reused but requires a recrystallization if you want to use it for anything else. As a side note, I did read on one forum that this reaction can produce yields in excess of 91% if vacuum reflux and distillation is used exclusively and the reaction temperature is never allowed to exceed 90° C. I found this out after I finished filming, so I didn't try it out, and I'm kind of skeptical of it, but I might give it a shot in the future.
Now, the second method for making methylamine is basically analogous to the first, but rather than building methylamine from ammonia and formaldehyde, the methylamine produced here is formed by the decomposition of the more complex molecule hexamine. To get started on method number two, I added just under 70 g of hexamine fuel tablets to a beaker along with 170 ml of distilled water. This solution was brought to a boil under constant stirring until the tablets had completely dissolved, and then the solution was poured into a three-neck round-bottom boiling flask. I then measured out 230 ml of 32% hydrochloric acid and poured it into an addition funnel, which was connected to the center neck of the boiling flask. The stopcock was opened slightly to allow the hydrochloric acid to drip onto the hexamine solution dropwise under constant stirring until it was all added. This was done because allegedly dissolving hexamine directly in hydrochloric acid would result in a much more aggressive reaction that almost exclusively forms ammonium chloride instead. The desired reaction here is the hydrolysis of the hexamine by hydrochloric acid to form four molecules of ammonium chloride and six molecules of formaldehyde. The resulting solution, if this reaction proceeds favorably, should be nearly identical to the solution used in the first synthesis. And so, once all the hydrochloric acid had been added, all you have to do is set this up for a distillation and process it exactly the same as before. This included another round of slow distillation at 104° C, vacuum distillation to crash out excess ammonium chloride, filtration to remove the salt, repeat to remove more ammonium chloride, heat to 160° C, dissolve in methanol, filter, recrystallize, filter again to collect the product, and dry.
However, while my footage here catches up to my lazy explanation, I want to highlight a key difference in this reaction compared to the first method. Now, if you'll remember, I mentioned that the formalin solution used in the first method was stabilized with a significant quantity of methanol, which produced methyl formate as a primary byproduct. Since there is no methanol here and the solution is far more acidic, the primary byproduct will be formic acid. Not only that, but the formation of formic acid here is favorable, while in the first process the oxidation of formic acid to carbon dioxide was strongly favored. As a result, the distillate here contains a significant amount of surprisingly pure formic acid, which I do collect in the end and will likely purify later on. Anyway, once the reaction is complete and the resulting methylamine hydrochloride thoroughly processed and dried like before, I went ahead and weighed the final product for a final mass of 25.97 g of pure methylamine hydrochloride and another 9.25 g of the impure stuff. This time I was able to recrystallize 21 g of ammonium chloride, and since 16.84 g were generated by the hydrolysis of hexamine, this means 85.8 g were used in the reaction, giving me a theoretical yield of 48.77 g. This means my percent yield this time was 72.2%, although I might knock a few points off as I don't think I dried my methylamine completely in this second run. Overall, I definitely prefer this method to the first, mostly because the reagents are way cheaper and easier to get for me. I consistently get higher yields than I do with the first method for some reason, and the byproduct formic acid is, in of itself, much more useful to me than methyl formate.
Now, the third and final method I have for making methylamine is by a Hofmann rearrangement of acetamide. This route is by far the most interesting, the fastest, and the cleanest. The only caveat here is that this method is more formally done using bromine, and instead I used hypochlorite, as it's worked for me in the many past Hofmann rearrangements I've done on this channel. However, my yield ended up excessively low despite the reaction conditions being controlled very carefully. And that said, I believe that either my acetamide was too impure or bromine is required for this reaction to ever be truly efficient. If there is sufficient interest, I can retry this process using bromine and spend a bit more time verifying the purity of my acetamide. But in the meantime, here's how the hypochlorite route went.
I began by dissolving 45.2 g of 73% calcium hypochlorite bleaching powder, representing 33 g of calcium hypochlorite, in a minimal volume of water. This is then filtered to leave me with a reasonably clean solution of calcium hypochlorite and then placed in the freezer to cool down to well below 0° C. I then use a bit of heat to melt down some acetamide I made a few weeks ago by reacting acetic acid and urea in order to transfer 20 g to a beaker, which is then dissolved in around 40 ml of water and also placed in the freezer to cool down as much as possible. After a few hours, these are both removed from the freezer and placed on ice. I transfer about 105 g of this ice to a large beaker and then put that on ice as well. I then go ahead and salt the ice to make it colder by lowering its melting point, and then I pour my acetamide solution into the ice-slush beaker. I then wait until the temperature reads well below 0° C, at which point I begin to slowly add small splashes of my hypochlorite solution while stirring as much as I can, making sure the temperature is well below 0° C before adding any more. This reaction is highly exothermic and very heat-sensitive. That said, if it heats up even above 10° C, you need to scrap everything and start over. An addition funnel might have actually been an even better idea here, but for some reason, I figured it wasn't worth the extra step. In any case, as the hypochlorite is added, you'll notice a lot of bubbling, which I didn't really expect. My assumption is that this was dichloramine that was produced when the hypochlorite reacted with ammonium acetate impurities in my acetamide. This bubbling ceased after about a third of my hypochlorite had been added, and if this really is the result of acetamide impurity, this accounts for at least a third of my loss. Alternatively, there could have been such a high concentration of hydroxide ions in my hypochlorite that the reaction went to completion, generating carbon dioxide, but I'm not sure this is possible this fast and at such low temperatures.
Anyway, the way this should work is that when acetamide is treated with an alkaline source of bromine or chlorine, they will react to form N-bromoacetamide or, in this case, N-chloroacetamide. This is a two-step reaction where first the amine group is deprotonated by the hydroxide, which then undergoes an alpha substitution reaction with chlorine, yielding the chloroacetamide. Once the reaction was complete, I went ahead and poured my reaction mixture into a three-neck round-bottom boiling flask and quickly added my sodium hydroxide solution, which resulted in even more bubbling. In this step, the additional hydroxide abstracts the remaining amide proton to give the chloroamide anion. The chloroamide anion rearranges as the methyl group attached to the carbonyl carbon migrates to the nitrogen at the same time the chloride ion leaves, giving an isocyanate. The isocyanate then reacts with water in a nucleophilic addition step to yield a carbamic acid, which spontaneously loses carbon dioxide, yielding the amine product. This reaction is also very exothermic, but not enough to sustain itself starting from 0° C. With that said, to drive the reaction to completion, I gently heat the mixture to around 60° C, at which point it begins to bubble. At this point, the reaction will be able to generate enough heat to sustain itself, so I remove it from the heat and allow it to rest. During this time, the reaction mixture heats itself to the point that it climbs to nearly 70° C, and if it were to go beyond this temperature, I would recommend placing the flask in an ice bath. Once the reaction mixture begins to cool, the reaction is complete. I then put the boiling flask back on the heating mantle and heat at 100° C. This will cause methylamine to boil out of solution, which is assisted by excess hydroxide in the solution. The methylamine gas will then travel through this apparatus I've constructed and into cold water where it will readily dissolve into solution.
Now, a couple side notes while this happens. I want to first clarify that the reason my reaction mixture turned white after the addition of the hydroxide was due to the formation of insoluble calcium hydroxide, and if you were to use sodium hypochlorite or bromine, the reaction mixture would be a pale yellow. Second, methylamine is aggressively soluble in its free-base form, much more so than even ammonia, and that said, reflux is a genuine concern here, which is the main purpose of the receiving flask I connected to the end of my short-path apparatus. If reflux were to happen, it would simply reflux into the collection flask and not ruin the entire reaction. Third, this methylamine gas can also be fed into hydrochloric acid to yield methylamine hydrochloride rather than the free base. This reaction, however, is extremely aggressive, and if you choose to go this route, I would recommend suspending the funnel above the hydrochloric acid rather than in it, as I've done with the water here. Anyway, getting back to my reaction here, you can test if it's working by testing the pH of the receiving water with some litmus paper, which should turn blue as methylamine is very alkaline. This reaction is continued for about 30 minutes until I feel no more methylamine gases coming over, and then I disconnect my apparatus before turning off my heat. This step reminded me to reiterate that this should all be done under a fume hood, as I caught a whiff of the absolutely foul gaseous methylamine. Not only is methylamine one of the most terrible-smelling chemicals out there, it's also quite toxic, along with most of the potential byproducts of this reaction.
Anyway, that's the entire process, and in the end, I'm left with a solution of free-base methylamine of unknown purity or strength. To try and get an idea of how much methylamine I actually synthesized, I needed to make this into the hydrochloride salt and then isolate it. To this end, I first neutralized my crude methylamine solution with hydrochloric acid and boiled it down until the remaining liquid was around 145° C. I then dissolved the residue in a minimal amount of anhydrous methanol and passed it all through vacuum filtration. This caught a significant amount of what I can only assume is ammonium chloride, which is discarded. The filtrate is then transferred to a beaker and allowed to cool so that methylamine hydrochloride can begin to crystallize out. Make sure to pay attention to the shape of the crystals during this step, as methylamine crystals will form these translucent feathery crystals while ammonium chloride will form smaller opaque white crystals. Honestly, that's something you should look out for in the previous two methods as well. This is actually the only footage I bothered trying to get of methylamine hydrochloride actually crystallizing, and since many of you seem to enjoy watching these, I'm just going to give this a few more seconds to play before I resume the procedure.
Anyway, once this is chilled below freezing to allow the methylamine to fully crystallize, I collected it by vacuum filtration and rinsed the crystals in a minimal amount of chloroform and ice-cold methanol to remove any impurities. I dried the methylamine hydrochloride further under a full vacuum for a few hours and then weighed them to get a final mass of just under 3 g, or roughly a 13% yield. I was able to more than double this by desperately crystallizing out the rest of the much more impure methylamine from the filtrate, but even this new 27.8% yield isn't very good. As I said earlier, I'm nearly positive that my acetamide must have just been very impure. This is likely negligence on my part, as I figured the Hofmann rearrangement would be the hard part while the synthesis of the acetamide itself was basically idiot-proof. Uh, this is clearly not the case, and I might try this again using bromine and some genuinely pure acetamide.
In any case, that's all I have for today. I hope you found this video interesting, and as always, I want to thank all my incredible patrons for their generous contributions. Your support is vital and very appreciated. This video was done on behalf of multiple Patreon requests, and do remember that I will eventually get to every Patreon request I've gotten; it just might take a while. To everyone else, if you'd like to see more content like this, consider subscribing on TikTok, YouTube, Instagram, or even by becoming a patron yourself. Thank you all so much for watching, and I'll see you next time.