Methylamine hydrochloride synthesis. Large scale.

G.Patton

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Introduction

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Many chemists are making a methylamine out of hexamine and HCl acid. I think it's very time-consuming and HCl is pretty nasty. Thus, I have found that one can easily make lots of good quality methylamine from ammonium chloride and formaldehyde (formalin). The only drawback with this method is that one must have good quality formaldehyde. It may have paraformaldehyde sediment in the bottom, it doesn't hurt, not even a bit, but Formaldehyde has to be strong and not some diluted shit, 35-40% is fine. Now to the more-less foolproof method. If you do like said below, you get around 600-750 g of pretty pure dimethylamine-free methylamine hydrochloride, which is perfect for Al/Hg reductive aminations.

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Appearance: white powder;
Boiling Point: 225-230 °C/15 mmHg;
Melting Point: 231-233 °C;
Molecular Weight: 67.52 g/mol.


Safety note: hold all manipulations in pull out probe or under exhaust hood; methylamine is a rather toxic substance, do not let its vapors enter the respiratory tract. Using respiratory mask is required. Inhalation of methylamine causes severe skin irritation, eyes and upper respiratory tract. Firstly, leads to excitement and then to depression of the central nervous system. Death can occur from respiratory arrest. Using chemical glass, gloves, chemical coat and respiratory mask is required.

Equipment and glassware:

  • Three naked round bottom flasks 5 L x2;
  • Round bottom flask with cap 5 L;
  • Beakers 5 L x2, 2 L x2;
  • Liebig condenser and water pump system (for condencer cooling) or water flow;
  • Retort stand and clamp for securing apparatus;
  • Connection tube;
  • Distillation adapter with vacuum tap;
  • Receiver flask 1 L;
  • Laboratory grade thermometer (0 °C to 200 °C) with flask adapter;
  • Conventional funnel for dry substances (d 15 cm) and liquids (d 15-20 cm);
  • Laboratory scale (1 - 5000 g is suitable);
  • Heater;
  • Large Buchner funnel Ø 25 cm (or Shott filter) and flask 5 L;
  • Pyrex dish 5 L;
  • Water-jet aspirator;
  • Ice bath (0 °C);
  • Glass rod;
  • Magnetic stirrer;
  • Drying tube x2;
  • Spatula;
  • Vacuum desiccator (large);
  • Paper filter.

Reagents:

  • 4 kg (3711 ml, 47-53 moles) Technical formaldehyde (35-40 %; d 1.078 g/ml at 20 °C);
  • 2 kg (37 moles) Technical ammonium chloride;
  • ~1600 ml of absolute Ethanol or n-Butyl Alcohol.

Procedure

In a 5 liter three naked round bottom flasks, fitted with a stopper holding a condenser set for downward distillation and a thermometer which will extend well into the liquid, are placed 4 kg (3711 ml, 47-53 moles) of technical formaldehyde (35-40 %; d 1.078 g/ml at 20 °C) and 2 kg (37 moles) of technical ammonium chloride. The mixture is heated on the steam bath until no more distillate comes over and then over a flame until the temperature of the solution reaches 104 °C. At about 90 °C, an exothermic reaction kicks in (it needs to be cooled in a water bath once in a while at the beginning in order to keep temperature below 104-106 °C).
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The temperature is held at this point until no more distillate comes over (four to six hours).
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The distillate, which consists of by-products such as methylal (bp 42-43 °C), methylformate and water, which may be treated with NaOH solution to recover methylal (dimethoxymethane) and sodium formate. The contents of the reaction flask are cooled to room temp and the ammonium chloride which separates are filtered off on a large Buchner funnel. You should get a clear yellowish filtrate like in this picture.
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The mother liquor (in three naked round bottom flasks 5 L) is concentrated on the steam bath under reduced pressure to 2500 ml, and again cooled to room temp, whereupon a second crop of ammonium chloride separates. The total recovery of ammonium chloride up to this point amounts to 780-815 g. The mother liquor is again concentrated under reduced pressure until crystals begin to form on the surface of the solution (1400-1500 ml). It is then cooled to room temperature, and a first crop of methylamine hydrochloride, containing some ammonium chloride, is obtained by filtering the cold solution. The Methylamine solutions in all steps should be cooled rapidly to promote smaller crystal formation. At this point, 625-660 g of crude product is obtained. The mother liquor is now concentrated under reduced pressure to about 1000 ml, and cooled, and a second crop of methylamine hydrochloride (170-190 g) is then filtered off. This crop of crystals is washed with 250 ml of cold chloroform, and filtered to remove most of the dimethylamine hydrochloride which is present. After the washing, the product weighs 140-150 g. The original mother liquor is then evaporated under reduced pressure, as far as possible, by heating on a steam bath, and the thick syrupy solution (about 350 ml) which remains are poured into a beaker and allowed to cool, with occasional stirring, in order to prevent the formation of a solid cake, and the crystals obtained are washed with 250 ml of cold chloroform, the solution is filtered yielding 55-65 g of product. There is no advantage in further concentrating the mother liquor, which contains mostly tetramethylmethylenediamine hydrochloride, but no trimethylamine hydrochloride. The total yield of methylamine hydrochloride is 830-850 g.

Purification

The product contains water, ammonium chloride and some dimethylamine hydrochloride. In order to obtain a pure product, the impure methylamine hydrochloride is recrystallized from absolute ethanol (solubility 0.6 g/100ml at 15 °C), or preferably butyl alcohol (even less soluble). Purification of the Methylamine HCl is in order now, so transfer all of the crude product to a 5 L rb flask and add either ~1600 ml of absolute Ethanol or, ideally, n-Butyl Alcohol. Heat at reflux with a Calcium Chloride dry tube for 30 minutes. Allow the undissolved solids to settle (Ammonium Chloride) then decant the clear solution through a paper filter and cool quickly to precipitate out Methylamine HCl. Filter rapidly on the vacuum Buchner funnel and transfer crystals to a vacuum desiccator. Repeat the reflux-settle-cool-filter process four more times if using absolute Ethanol, or two more times if using n-Butyl Alcohol. The recovery of ammonium chloride amounts to 100-150 grams, making the total recovery 850-950 g. The yield of recrystallized methylamine hydrochloride is 600-750 g (45-51% of theory, based on the used up ammonium chloride).

A standard run, from 250 g ammonium chloride and 500 g 37% formaldehyde (containing 15% methanol), gives 100-134 g methylamine hydrochloride, 27 grams dimethylamine hydrochloride and 81 grams of recovered ammonium chloride. The distillate contains methylal (formaldehyde dimethyl acetal) and methyl formate, which after treatment with NaOH can yield 25 g of sodium formate and 30 grams of methylal, as the compound cannot be separated by fractional distillation, neutralization is the way to go. Ammonium chloride is very sparingly soluble in a concentrated solution of methylammonium chloride, making the separation of the compounds pretty sharp.
 
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WundaBearz41

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Thank you so much for posting this! This is pretty spectacular. Do you know what equipment is needed for the "A standard run" synthesis?
 

MadHatter

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I'm actually interested in the hexamine/HCl-route. These precursors are abundant to me.
 

MadHatter

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NVM. Found it on Rhodium. This is it, I guess the part you think is time-consuming is the filtering step?

1. 140 grams hexamine (1 mole) was slowly dissolved in 400 ml water and 400ml 37% HCl (4 moles) was added. If the hydrochloric acid is added directly to the HMTA, a lot of it is lost, as ammonium chloride starts to separate almost immediately.

2. The mixture was heated on a temperature controlled heating plate, and the contents was slowly distilled while the temperature slowly rose from 100°C to 109°C during 1-2 hours, during which time a lot of CO2 was evolved, and approx 75ml of formaldehyde-smelling distillate was collected.

3. The solution was concentrated under vacuum until a lot of solids precipitated, which were filtered off, and the solution was further concentrated, filtered etc until everything was crystallized. The last crop of crystals was very hard to crystallize, and care must be taken not to burn the contents of the flask, it must not be allowed to rise over, say 75°C.

4. The white solids were placed in 150ml warm methanol (or ethanol), and was filtered. The insoluble portion was recrystallized from water, to give 40 grams of pure ammonium chloride, which looked like very large snowflakes.

5. The methanol solution was evaporated, recrystallized from methanol and washed with acetone, to give a deliquescent crystalline mass, which was dried in a desiccator over CaCl2, to give methylamine hydrochloride as a fluffy soft powder.
 

cockysavage

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how to make methylamine a.q solution from methylamine hcl ?
 

UWe9o12jkied91d

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Yes, methylamine hydrochloride will turn into methylamine freebase in the presence of NaOH sol. After all methylamine has dissolved and the organic layer formed is no longer getting bigger the layers separated, top layer is your freebase amine.You take that weight it and mix it with water
 

mejdubulok

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Jesus Christ! I love this forum. this is the most valuable information. everything is available, everything is clear. Oh, god bless you, @G.Patton I have to try it. I will definitely write about the results. a million likes. 👍❤️🙏
 

Frit Buchner

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Someone I know nothing of, is 1/2 way through this synthesis one scale equal to the scale you give figures on ( 250g/500g) he was hoping to use methanol he probably didn't distill out if a gallon if windshield washed fluid instead of butyl or abs.ethyl. how much is he going to need? He probably didn't react 2 gallons of bleach with...400 ml of acetone either. Both of these things probably don't need to be redistilled, but if so, how much chloroform is he going to need also? For this 259g/500g batch. He may not have enough formaldehyde to do it one more time ( but he probably doesn't)I hope someone can't help this guy I don't even know because he's not knee deep in it right now and probably knows exactly what he is doing. @G.Patton
About how much do you think it takes?
 

G.Patton

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Someone I know nothing of, is 1/2 way through this synthesis one scale equal to the scale you give figures on ( 250g/500g) he was hoping to use methanol he probably didn't distill out if a gallon if windshield washed fluid instead of butyl or abs.ethyl. how much is he going to need? He probably didn't react 2 gallons of bleach with...400 ml of acetone either. Both of these things probably don't need to be redistilled, but if so, how much chloroform is he going to need also? For this 259g/500g batch. He may not have enough formaldehyde to do it one more time ( but he probably doesn't)I hope someone can't help this guy I don't even know because he's not knee deep in it right now and probably knows exactly what he is doing. @G.Patton
About how much do you think it takes?
Frit BuchnerHello, I don't understand part of your speech about washed fluid and bleach. Can you please write clearly? There is the list of reagent. You need to get them in a pure form. For sure, distill them.
 

Frit Buchner

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Hello, I don't understand part of your speech about washed fluid and bleach. Can you please write clearly? There is the list of reagent. You need to get them in a pure form. For sure, distill them.
G.PattonYes I made it quite cryptic. basically I would like to know how much chloroform and methanol I will need to clean the product of a reaction between 250 ml of ammonium chloride and 500 g formaldahyde. I am having to make these chemicals so I don't want to waste resources making more than I need
 

G.Patton

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Yes I made it quite cryptic. basically I would like to know how much chloroform and methanol I will need to clean the product of a reaction between 250 ml of ammonium chloride and 500 g formaldahyde. I am having to make these chemicals so I don't want to waste resources making more than I need
Frit BuchnerThere are numbers in the article, count them proportionately for your batch scale.
 

Frit Buchner

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Unfortunately I've failed this synth twice. I lost several dollars. There's just too much guess work. I'm looking at the nitromethane reaction now, it seems more straight forward. I'm discouraged by this route
 

Mo0odi

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Can this procedure be done in a pressure cooker for cooking?
 

FENTAMAS

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@Frit Buchner, this synthesis is over a century year old (Marvel et al., 1923, Org. Synth.) and confirmed to be working by many independent chemists, including me.
Moreover, every publication in that journal should be peer reviewed, so it is one of the most trusted source for practical organic chemist.
Link for the original document - https://www.orgsyn.org/demo.aspx?prep=CV1P0347
If you fail, then you definitely doing something very wrong or your reagents are not what you expect it are.

Chloroform could be substituted by DCM, but anyway it is not necessary.
If you want good results better to use paraformaldehyde, not formaldehyde with methanol, the more MeOH the more colored RM in my experience.
Without methanol you not need to distill reaction mixture, just hold temperature below 100C, it works even at lover t, just take more time.
You absolutely need aspirator vacuum for distilling portions of water if you want nice white product.
The key for a good purity is fractional crystallizations, the more the better result.
I used 5-6 times, a little bit more than in the original procedure and got fantastic results.
So after 6+ hours of 100C, distill some water under vacuum, cool down, suction filter, and repeat.
First 2-3 fractions will be ammonium chloride. Then methylamine*hcl with crystal structure clearly different from first batches, more like hygroscopic shiny flakes.
The last mother liquor will contain mostly dimethylamine*hcl and should be discarded if don't need it.
The final step is multiply crystallization from hot abs. ethanol or methanol as described. But it also is not necessary for many synthesis, it just for removing last traces of water, NH3*HCl and Me2NH*HCl.

So as you can see it is time consuming, many days of working, but you can start with pretty large batch and prepare non-trackable pure Methylamine for month or years.
 

Frit Buchner

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@Frit Buchner, this synthesis is over a century year old (Marvel et al., 1923, Org. Synth.) and confirmed to be working by many independent chemists, including me.
Moreover, every publication in that journal should be peer reviewed, so it is one of the most trusted source for practical organic chemist.
Link for the original document - https://www.orgsyn.org/demo.aspx?prep=CV1P0347
If you fail, then you definitely doing something very wrong or your reagents are not what you expect it are.

Chloroform could be substituted by DCM, but anyway it is not necessary.
If you want good results better to use paraformaldehyde, not formaldehyde with methanol, the more MeOH the more colored RM in my experience.
Without methanol you not need to distill reaction mixture, just hold temperature below 100C, it works even at lover t, just take more time.
You absolutely need aspirator vacuum for distilling portions of water if you want nice white product.
The key for a good purity is fractional crystallizations, the more the better result.
I used 5-6 times, a little bit more than in the original procedure and got fantastic results.
So after 6+ hours of 100C, distill some water under vacuum, cool down, suction filter, and repeat.
First 2-3 fractions will be ammonium chloride. Then methylamine*hcl with crystal structure clearly different from first batches, more like hygroscopic shiny flakes.
The last mother liquor will contain mostly dimethylamine*hcl and should be discarded if don't need it.
The final step is multiply crystallization from hot abs. ethanol or methanol as described. But it also is not necessary for many synthesis, it just for removing last traces of water, NH3*HCl and Me2NH*HCl.

So as you can see it is time consuming, many days of working, but you can start with pretty large batch and prepare non-trackable pure Methylamine for month or years.
FENTAMASI followed the original synth the first time and I the second time I followed one I was given by one of the experts here. I refluxed under vacuum for 4 hours and distilled under vacuum for 2 hours. The temps never Reached the target level though, perhaps my vacuum is stronger than they were using in 1910. That's what I assumed.The second time the methylamine hcl and the product I made with it looked exactly like everyone's pictures the methylamine hcl even produced flammable gas when neutralized with NaOH and water. But the product has no cns action.
I have here a liter of technical grade formaldehyde with 5%methanol and I'm going to try again but do I need to distill the methanol off to start? I'm going to read some more, it's true my ammonium chloride is fertilizer grade not technical grade could that be the problem? How do you decide when "a round" of reducing the volume of the rm is done? I was measuring it and stopping every time I halved the volume but only get 4 rounds that way and 4 batches of crystals. Would the methanol I use at the end not being dry enough cause it? I can't imagine that was the problem though because I distilled it twice and put in 100% w/w, 3a sieve for several days
 
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FENTAMAS

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I followed the original synth the first time and I the second time I followed one I was given by one of the experts here. I refluxed under vacuum for 4 hours and distilled under vacuum for 2 hours. The temps never Reached the target level though, perhaps my vacuum is stronger than they were using in 1910. That's what I assumed.The second time the methylamine hcl and the product I made with it looked exactly like everyone's pictures the methylamine hcl even produced flammable gas when neutralized with NaOH and water. But the product has no cns action.
I have here a liter of technical grade formaldehyde with 5%methanol and I'm going to try again but do I need to distill the methanol off to start? I'm going to read some more, it's true my ammonium chloride is fertilizer grade not technical grade could that be the problem? How do you decide when "a round" of reducing the volume of the rm is done? I was measuring it and stopping every time I halved the volume but only get 4 rounds that way and 4 batches of crystals. Would the methanol I use at the end not being dry enough cause it? I can't imagine that was the problem though because I distilled it twice and put in 100% w/w, 3a sieve for several days
Frit Buchner
I refluxed under vacuum for 4 hours
What? That has no sense refluxing under vacuum, you should hold near 100C, or even 60-80C day or so. If time is limited you can interrupt and continue next time, nothing bad will happen. So please just control reaction mixture temperature.
But the product has no cns action.
WAT??
How do you decide when "a round" of reducing the volume of the rm is done?
Distill each time 10-15% of the RM volume under vacuum.
fertilizer grade
there may be some other shit.
 

Frit Buchner

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What? That has no sense refluxing under vacuum, you should hold near 100C, or even 60-80C day or so. If time is limited you can interrupt and continue next time, nothing bad will happen. So please just control reaction mixture temperature.

WAT??

Distill each time 10-15% of the RM volume under vacuum.

there may be some other shit.
FENTAMASThere's a large advantage in refluxing under vacuum in that the ratio of monomethylamine to di and trimethylamine is much higher as outlined in
Jones, H. I., & Wheatley, R. (1918). THE PREPARATION OF METHYLAMINE. Journal of the American Chemical Society, 40(9), 1411–1415. doi:10.1021/ja02242a007
10.1021/ja02242a007
Highlights include;
A study of these equations of Werner’s makes it plain that if we could hold down the temperature and at the same time hasten the decomposi- tion of the formic acid as it is formed, that we could in this way pull the equilibrium to the right in the first case, Equations I and 2, and thus get the monomethylamine as almost the sole product, this being the valuable thing and the one that we are after.
In Expt. 4 the procedure differed only in that the reaction was refluxed at 20 mn. pressure. for 4 hours, or until no more carbon dioxide was given off. The reaction product was then distilled in a vacuum as before, 2 hours being consumed in the distillation.
tabulation of results brings out several facts clearly:
I. The vacuum refluxing and distillation plainly decreases the amount of ammonium chloride left unused, lowers the temperature and therefore decreases the yield of dimethylamine and other higher methylated bodies, which agrees with Werner's theory, and it increases the acidity of the distillate, the loss of carbon dioxide and the weight of methylamine pro- duced.

Monomethylamine, a valuable reagent and the member of the
series most often desired, is best made by the vacuum reflux method.
Link to the document
 

FENTAMAS

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There's a large advantage in refluxing under vacuum in that the ratio of monomethylamine to di and trimethylamine is much higher as outlined in
Jones, H. I., & Wheatley, R. (1918). THE PREPARATION OF METHYLAMINE. Journal of the American Chemical Society, 40(9), 1411–1415. doi:10.1021/ja02242a007
10.1021/ja02242a007
Highlights include;


tabulation of results brings out several facts clearly:



Link to the document
Frit BuchnerThat effort do not worth it.
And that's just authors' speculation about vacuum, which itself likely cannot influence selectivity, as is with formic acid excess too.
Maybe it is just effect of reduced temperature, more effective stirring of RM by bubbling and more full conversion of NH3*HCl, etc.
Later authors don't use vacuum reflux, moreover it is quite uncommon method even nowadays.
Reduced boiling temperature also will be in the case of excess of MeOH in formalin, because of esterification of formic acid and forming low boiling methyl formate and other by-products, but as I already noted, try to avoid it.
 

Frit Buchner

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That effort do not worth it.
And that's just authors' speculation about vacuum, which itself likely cannot influence selectivity, as is with formic acid excess too.
Maybe it is just effect of reduced temperature, more effective stirring of RM by bubbling and more full conversion of NH3*HCl, etc.
Later authors don't use vacuum reflux, moreover it is quite uncommon method even nowadays.
Reduced boiling temperature also will be in the case of excess of MeOH in formalin, because of esterification of formic acid and forming low boiling methyl formate and other by-products, but as I already noted, try to avoid it.
FENTAMASThat's a fair point. I'll have to read it again with that in mind (that the vacuum lowers the temperature and makes the stir bar turn easier, ect.) This document was linked to me by one of the site experts so I didn't scrutinize it heavily. Even if I decide it isn't proven that the vacuum itself is the reason they achieved a higher yield I might decide that the cause doesn't matter and the effect does. We consider gravity and magnetism effect and plan for it every day even though the mechanism is debatable. Buying formaldehyde is stressful because I'm not a taxidermist or farmer. I have more spare time than money or bravery to buy formaldehyde without a legitimate use. It's not free. I'll probably choose to maximize my yield over convenience. I'll have $33 in this formaldehyde whether I get a kg of methylammonium chloride or a gram from it. It can't be bought legally here and there is no end to the amount I can use
 
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