HaCKeRz KrOnIcKLeZ 3/HaCKeRz_KrOnIcKLeZ.iso/drugs/faq-methylamine

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Newsgroups: alt.drugs.chemistry
From: [e-mail] (Eleusis)
Subject: The Methylamine FAQ v2.0 - Final!
Message-ID: <3skaea$[e-mail]>
Date: Sun, 25 Jun 1995 18:38:02 GMT

After I made my Request for Comments, I received a couple of excellent
ones. Everything basically checks out, and the chemistry is solid, so have
at it and let me know any successes and failures out there (anonymous,
though, I don't want to know too much about you <g>).

The Methylamine Data Sheet v1.0 (non-beta)
---------------------------------------------------------------------

Table of Contents
-----------------
1) Introduction
2) Methylamine via Hoffman (Hypohalite version)
3) Methylamine HCl via Formaldehyde
4) Acetamide from Acetic Acid & Urea
5) Absolute Ethanol


1) Introduction
---------------
Methylamine is one of the "trickier" chemicals to come by which is a
necessary ingredient for all sorts of organic syntheses. For those of
you too disinclined to find this information yourself <g>, I have
compiled a treatise on various methods of producing this compound from
more "banal" chemical precursors. Some of the precursors are useful for
other syntheses as well, so do what you like. Sources are provided for
those of you who doubt my credibility (and you *should*, since you
don't know me from the proverbial Adam). I have basically pirated them
from the credited texts with modifications to verbiage and such to make
it more 20th century and/or practical. Feel free to applaud or flame me:
[e-mail] and be sure to get my check out my other various
and sundry FAQs on Hydrobromic Acid, Sassafras Oil (new release) and
more to come.


 *                   *                   *

2) Synthesis of Methylamine/Methylamine HCl via Hoffman Reaction
----------------------------------------------------------------
This Hoffman reaction takes an Amide and treats it with a Hypobromite
or Hypochlorite solution to produce an Amine of similar composition
to the original Amide but minus one Carbonyl (CO) group. In this case,
Acetamide is the primary Amide, which is of formula CH3CONH2. We
merely strip the CO off without damaging the structure too much and
voilla, we get Methylamine, a volatile nasty gas of formula CH3NH2.
See the similarities here. Alright, the unbalanced reaction is:

CH3CONH2 + Ca(OCl)2 ----> (CH3CONCl)2Ca++ + H2O   then

(CH3CONCl)2Ca++ + NaOH ----> CH3NH2 + Na2CO3

We'll skip the theory normally present at this point, and merely
interject that because we are introducing Methylamine into an aqueous
solution, it will dissolve into the water rather than escape into the
room to poison us all. This leads to the actual, hold your hand
directions. Fantastic! One caveat. You can scale these reactions up or
down within reason. What does that mean? I can't tell you, it depends.
It is safe to say that doubling or halving will have no effect.
Multiplying by ten times? Maybe. The key problems with scaling
reactions like this have to do with heat gradients in the flask and
inadequate stirring, such that secondary products form (like, say,
dimethylamine or ammonium chloride). Use your best judgement. One
reference to keep in mind (Thanks to J. Smith for sending this one)
concerns the conversion of Acetamide to Chloracetamide via the
addition of Calcium Hypochlorite and the time to get an effective
yield. The original reference claims it only takes a few minutes
whereas the reference below begs to differ. Either way, it can't hurt
to let it sit for a long time, so you might as well.


Whitmore and Thorpe, J. of the Amer. Chemical Society, Vol 63, April
1941, p1118

"It was necessary to allow several hours for the formation of the
N-chloroamide before heating to degradation temperature.  With this
modification it was possible to prepare methylamine...consistently in
78% yield."


Prepare an ice bath with water and Calcium Chloride to bring the
temperature down to -15C or so. Setup glassware for simple distillation
with magnetic stirring. Dissolve 82g of Calcium Hypochlorite in 250mL
water in a beaker or flask. Swirl vigorously, though not all will
dissolve. Place in the ice bath and add 50g of crushed ice. In a
separate beaker/flask, dissolve 50g of Acetamide in 100mL water. Add
500g of crushed ice to this solution and swirl vigorously. Place a
thermometer into the Acetamide soln. then add the Hypochlorite soln.
slowly, in several small parts with gentle swirling. Make sure the
temperature stays close to 0C because if it rises above 10C the solns.
must be discarded. Allow the mixed soln. to remain in the ice bath for
15 minutes (or several hours...), gently swirling occasionally. All of
the Acetamide will have converted to the methylisocyanate by this time.
Now pour the mixture into the distilling flask (I like to put a long
stem glass funnel into the top of the three-way adapter). Follow this
with a solution of 120g NaOH in 200mL water at room temperature. Heating
this mixture is the trickiest part of the synthesis. The thermometer
should be positioned in the solution and the flask heated as rapidly
as possible to 60C while being stirred magnetically (see Note 1 for my
method on this). When it hits 60C, the rearrangement will commence with
considerable heat evolved. Remove the heat while still stirring to allow
the solution to react in the temperature range of 70C to 80C. If it
appears it will head past 80C, quickly cool with ice or a cold water
bath (See Note 1). The reaction completes within 15 minutes (the
temperature will drop off). Before distilling this mixture, you need to
choose between the aqueous or Hydrochloride form. In either case, heat
to a gentle boil with stirring to liberate the methylamine as a gas.

For the aq. soln.: String two air traps in tandem comprised of an
Erlenmeyer flask with a two hole stopper and 175mL of chilled water.
In one hole of the stopper, a glass tube should extend nearly to the
bottom. Connect this tube to the condenser (I connect to the vacuum
nipple on the receiver adapter, and use a receiver flask to catch any
condensed liquid). The other hole connects to either the second trap
or vents to the atmosphere (beware, if the soln. saturates in both
traps, you will be exposing yourself to Methylamine, which is a highly
unpleasant chemical in the least). The primary contaminant will be a
slight amount of Ammonia. To purify...

For the HCl salt: Do exactly as above except use 175mL each of 6N
(normal) Hydrochloric Acid. The primary contaminant in this case is
Ammonium Chloride (makes sense, eh). Mix the contents of the two
traps and evaporate to dryness. Add 75ml of water and 48mL 10% NaOH
soln. and heat gently to a boil with constant motion until dense white
fumes appear. This will remove the Ammonium Chloride. Remove from heat
while stirring as it cools down. Pulverize the dry residue, then reflux
with absolute Ethanol for several minutes. Filter the refluxed soln. on
a heated Buchner or Hirsch funnel, then distill the alcohol off the
filtrate until crystals just begin to form. Allow the soln. to cool
naturally to room temperature, then cool further in an ice bath. Filter
the solution on a chilled Buchner funnel with suction. The yield of
Methylamine Hydrochloride should be around 55% of the theoretical.

Note 1 - A convenient way of alternating hot and cold water in a
water bath, while still allowing magnetic stirring, requires two
small bilge pumps, two buckets, a "Y" valve", a non-ferrous stainless
steel water bath and some tubing. Mount a bilge pump in each bucket, one
for hot water and one for cold. Connect the discharge side of both pumps
to either "head" of the Y-valve, the tail connects to the inlet side of
the water bath (the lower tube). The discharge side connects to the tail
of another Y-valve, with each head going to each bucket. This allows you
to quickly switch the water in the bath without hassle, just flick both
valves at once. The magnetic stirrer should still be able to stir though
the non-ferrous stainless steel bath (works for me).

References:
Journal of Chemical Education, v14, pg542


3) Synthesis of Methylamine HCl from Formaldehyde and Ammmonium Chloride
------------------------------------------------------------------------
Place 4kg of 37% Formaldehyde solution into a 5L RB flask  along with
2kg of Ammonium Chloride. Rig the flask for simple distillation with a
Claisen adapter, a thermometer long enough to extend into the reaction
mixture, and a Liebig or West condenser. Heat the mixture on the steam
bath until no more distillate comes over, then turn up the heat using
a burner and hold the reactant temperature at 104C until, once again,
nothing else comes over. This should take from 4 to 6 hours. The
distillate may contain interesting things, so check out footnote 1 for
details on what to do with it. Next, the reaction flask should be
cooled rapidly to room temperature by immersion into first a warm
water bath (60C) switled, and then an ice bath. Ammonium Chloride
crystals will precipitate which the original text calls for
centrifugation to remove. Personally, I would just filter with a
chilled Buchner funnerl several times, cooling the solution down more
each time. After this, concentrate the "mother liquor" (ie - the
filtered reaction flask contents) under medium vacuum (water
aspirator) and steam bath heat until the volume drops to approximately
2.5L. Repeat the above mentioned crystallisation/filtration process
again to remove a second batch of Ammonium Chloride crystals. The
total recovered Ammonium Chloride should be around 780 - 815g.

We now move on to the extraction of the good stuff, Methylamine
Hydrochloride, with the principal contaminants Ammonium Chloride
(Still? Damn that stuff) and Dimethylamine Hydrochloride.
Concentrate the reaction flask contents once again under medium vacuum
on the steam bath until crystals form on the surface (at around 1.4 -
1.5L of volume). Cool the reaction flask rapidly, as above, and cold
filter (for genuine draft taste) the crystals. Approximately 600 -
650g of crude product should be obtained, at which point you
concentrate the mother liquor once more on the steam bath with reduced
pressure to a volume of 1L and repeat to yield an additional 170 -
190g. Wash with 250mL of cold Chloroform then filter and "centrifuge"
(if you are bothering). This removes most of the Dimethylamine HCl,
leaving around 150g of Methylamine HCl and Ammonium Chloride. The
original mother liquor is concentrated once again, on the steam bath,
under reduced pressure (do I sound like a broken record yet?) until
there is around 350mL left. Pour this out into a beaker which is
situated in an ice bath and stir to prevent the formation of a solid
cake. Centrifuge this paste (or, possibly, Buchner it) then wash the
resulting crystals (170-190g) with 250mL cold Chloroform. Filter this
solution then centrifuge to yield an additional 55-65g of Methylamine
Hydrochloride. Your combined yield of crude product should be
approximately 830-870g (620g + 180g + 60g) which contains as impurites
water, Ammonium Chloride and Dimethylamine Hydrochloride.

To purify this, you need to reflux with an alcohol for approximately
1/2 hour. Ideally, you should use n-Butyl Alcohol as the solubility of
Ammonium Chloride in it is neglible. More practically, though, you
will be using absolute Ethyl Alcohol (Ethanol with the water extracted
- see how to do this later on in the FAQ). Place the crude product
into a 5L RB flask, add 2L of Alcohol, fit an Allihn or Liebig
condenser vertically and finally attach a Calcium Chloride filled
drying tube to the top (a standard "dry" reflux setup). Reflux at boil
for half an hour. Let the contents settle, then decant the liquid off,
leaving undissolved junk in the bottom (the Ammonium Chloride). You
should rapidly cool the supernatant, precipitating out Methylamine
Hydrochloride. Recover the alcohol by filtering the crystals out on
the Buchner, then repeat the whole process at least 4 more times. In
the flask should remain approximately 150g of Ammonium Chloride,
making it's total recovery 850-950g. Your yield of Methylamine
Hydrochloride is 600-750g which is 41-51% of the theoretical.

Footnote 1 - The byproducts of the first step are Dimethoxymethane and
Sodium Formate.

Footnote 2 - The Methylamine solutions in all steps should be cooled
rapidly to promote smaller crystal formation.

Footnote 3 - According to the original document, centrifuging is the
only satisfactory method of drying products because of the
deliquescent nature of them. As a suggestion, try placing the products
into a vacuum dessicator to dry, instead.

Footnote 4 - The solubility of Ammonium Chloride in absolute Ethanol
is 0.6g/100g at 15C. The solubility in n-Butyl Alcohol is neglible,
even at its boiling point. If you use n-Butyl Alcohol, you will only
need to perform 3 reflux/filter operations to obtain sufficiently pure
Methylamine Hydrochloride.

References to this section:
Sharp & Solomon, J. Chem. Soc. 1477 (1931)
Werner, J. Chem. Soc. 850 (1917)
Sommelet, Compt. rend. 178, 217 (1924)
Hofmann, Ann. 79, 16 (1851)


4) Synthesis of Acetamide from Acetic Acid and Urea
---------------------------------------------------

Urea is conveniently obtained as a constituent of many fertilizers
and so it is easily obtained. Sources have indicated that a 50lb bag
can be purchased for $15 in the US. It is of less than ideal purity
from this source, so some washing will be in order (with what?).
Glacial Acetic Acid is easily obtained from photographic supply
stores in high purity and for cheap as well. This reaction produces
Acetamide with such purity that the product does not even need to be
recrystallized (the reaction goes to completion with no side products).
The reaction is:

CH3COOH + NH2CONH2 ----> CH3CONH2 + CO2 + 2NH3

Place 125g Urea and 125g of Acetic Acid in a 500mL round bottom flask
in preparation for simple refluxing with magnetic stirring and without
cooling water. Attach condenser, claisen adapter and place thermometer
so that the bulb is around 1cm from the bottom, fully immersed. Heat on
an oil bath gently to bring the temperature of the mixture to 150C in
20 minutes. The mixture should be refluxing in the condenser, and
probably subliming in it as well. Push any deposited crystals back
into the adapter as necessary. Continue refluxing until temperature
can be raised to 195-200C (approximately 1.5 hours) Allow to cool,
then rearrange the condenser for distilling (once again, in free
air). Heat until the Acetamide just begins to reach the condenser
(200C or greater) then it is most practical to have another condenser
on hand to quickly replace the first. This is not so convenient with
ground glass jointware, in which case it might be best to just stop
distilling completely until cleaning out the condenser or switching
it. Continue heating to collect nearly pure Acetamide starting at 200C
with most coming over from 214-216C. If the product smells strongly of
mice (as in the rodents), then recrystallization from warm methanol is
in order. To recrystallize, take 50g of Acetamide, dissolve in 40mL
warm Methanol, add 100mL Ether and allow to stand. If your product is
only faintly odorous and is colourless, then it is considered pure.
Melting point is 80.5C.


5) Preparation of Absolute Ethanol from "Everclear" or Rectified Spirits
------------------------------------------------------------------------

Absolute, or 99.5% water-free, Ethanol is frequently necessary in many
Organic operations. It is quite easy to prepare from the azeotrope with
water such as "Everclear" brand grain alcohol, "moonshine" or "Rectified
Spirits" (an old term for the same thing).

Dehydrate 100g of fresh anhydrous Calcium Oxide in a vacuum dessicator
for 24 hours (a bit redundant, I know). Setup glassware for simple
refluxing with water-cooled condenser and a Calcium Chloride guard
tube. Place 500mL of Ethanol into the flask, quickly add the Calcium
Oxide and reflux gently on the water bath for 6 hours. Allow the
reflux mixture to stand overnight, then distill off the alcohol,
discarding the first few ml (it may be more convenient to just vent
the condenser to the atmosphere for the first couple of minutes after
distillation has commenced).

    - [e-mail] - The Methylamine FAQ v2.0 Final - 06/24/95 -

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