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IndoleAmine
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Wed Apr 13, 2005 5:45 am |
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...for example for thinking about important things like:
Where in the following lines can you see a possibility for making methylamine:
1) ammonia + formic acid -> ammonium formate
2) ammonium formate + formic acid + heat -> formamide
3) formamide + HCl + heat -> ammonia
...I'm asking because this are the only reagents involved in your proposed synthesis protocol you linked to, and you seem to agree with me that these rxns all will happen, as soon you mix the needed reagents, or heat them together!?
what I'm trying to say is: all these three rxns work for sure like described; you know it, and I know it.
And therefore no methylamine will be formed, no matter in which order you heat, distill and stir those reagents together.
Now my last word:
- For making methylamine, you will need formaldehyde and ammonia, the former is made from hexamine fuel tabs or paraformaldehyde ("mildewcide") for example
- you need to purify the methylamine made this way by separating unreacted ammonium and product methylamine salts as the hydrochlorides,
- then you need to make methylammonium formate from your MeAm by liberating it as a gas and reacting with formic acid (in drescher bottles if you like them),
- then you have to heat and distill under strong vacuum to get NMF,
- then distill that again 2x to purify,
and then you can start thinking about making ketone maybe....
i_a |
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loki
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Thu Apr 14, 2005 8:47 am |
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http://newjournal.kcsnet.or.kr/main/j_search/j_download.htm?code=B020134
this reference, if you would actually read it, says that with heat, toluene and collecting water that boils out, with an amine and formic acid, generates a formylated amine.
It does not boil, it decomposes, as you say, but the temperature it does this at is 180 degrees, and it liquifies at 116 degrees (celsius of course).
| Quote: |
The effect of changing the solvent was studied with 1.2
equivalents of formic acid. When the reaction was carried
out in benzene, the formamide was obtained in only 40%
yield (entry 5). The yield was improved to 98% when the
reaction was run in either toluene or xylene (entries 4, 6).
The best result was obtained with 1.2-2.0 equiv. of formic
acid in refluxing toluene using Dean-Stark trap (entries 3, 4).
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I am not saying that this reference says 'it will work', however, it works with all the primary and secondary amines, with yields between 80 and 99%. However, the method's simplicity and efficiency begs the question of whether it might work. Remember, this method is new, the document is dated late 2001. Also, they tested 1.2 - 2 molar equivalents in these reactions. It would be very simple indeed to test this idea, one only needs a small amount of toluene/xylene and formic acid and ammonia.
It is my opinion that the reaction will work at a 1:1 ratio as i described but it may require an excess of formic acid to work. The reaction is a simple dehydration, or condensation, thus it probably needs something to kick it along, which may mean a small amount of formic acid.
I am of the opinion that this reaction *will* work. I am going to nut out the possible reaction pathways to see if i can find out what the proper molar ratio is, my feeling at this point is it will be 1:1.5
As you can read clearly in the pdf i have linked to, the reaction works, and is very efficient, with primary and secondary amines. If the same principle applies here, then this could be very useful. |
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IndoleAmine
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Thu Apr 14, 2005 9:37 am |
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Hey, thats a pretty nice find - but remember that methylamine is gaseous at room temp., contrary to other primary amines. It will vaporize when heat is applied, hell even at room temp. if you don't cool it to below -23°C.....
(its very difficult to heat the toluene to reflux and still make that MeAm stay in there...  )
Further, you cannot use this dehydration method with methylamine to make a formamide, because NMF is miscible with water in any proportion.
This makes the use of a dean-stark a bit difficult, I would say - since you will loose all NMF to the aequous layer in your dean-stark....
You can use a dean-stark trap in the Leuckart rxn itself though, since the formyl amine intermediate produced with the leuckart reaction
a) is not miscible with water (so you can dehydrate the leuckart rxn, without loosing any formyl intermediate)
b) doesn't evaporate as easy as methylamine (you can heat the leuckart at atmospherical pressure, without vaporizing the starting material before it can react)
My advice: try to use the technique described in your article with the leuckart rxn, not for making formamide, and you will have good dreams.... 
(of course no toluene is needed in leuckart rxns; since in the beginning the ketone acts as a solvent, and when things have progressed, the freshly made formyl amine intermediate does this job instead..)
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n00dle
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Thu Apr 14, 2005 8:30 pm |
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| IndoleAmine wrote: |
To make NMF, just bubble your methylamine gas into formic acid, heat, then distill under reduced pressure to get a partially dehydrated mixure, then gas the distillate again with some methylamine, distill again - and you will be left with a mixture of ~90% NMF, some methylamine and some formic, along with traces of water.
This mixture is ideally suited for the shitty, crap-yielding leuckart rxn.
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Why's this crap yeilding? What are the yeilds for leuckarts with p2p/mdp2p?
I think the issue here isnt an astounding yeild, but more the fact that leuckarts are probably easier to do bulk rather than al/hging which in time consuming in that you're fairly limited with scaling up before things get messy and hairy.
In the alternate route that one uses formamide in a leuckart with the ketone to the non-methylated whatever, on rhodium's page it shows that you can then al/hg that 'phetamine to methylate it again with formaldeyhde i believe.. if this step could be done in bulk ie if one could methylate an existing compound without al/hg it'd probably be better, no?
Ie. amphetamine to methedrine page on rhodium.
just gotta get rid of that pesky al/hg. lah and NaBH and such reducers would be canceled out because if one is trying to form methylformamide by hand chances are they can't get thier hands on a lot of stuff.
Stripped of crap: Is it possible leuckart amphetamine to methylate it? Instead of al/hg? (dont think so... but worth a shot) |
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IndoleAmine
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Fri Apr 15, 2005 6:16 pm |
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Its possible, but not worth the shot maybe; you're better off making methylamine and reductively aminating your ketone directly with it (either with n-methylformamide/hydrolysis or through imine formation/hydrogenation).
The leuckart is no adequate alternative to Al/Hg, since yields are very differing (10% to 90% have been reported) and a scale-up can easily lead to just as much product as you would've got with using less starting amounts in a Al/Hg (a leuckart can give 10g of product from 20g or 200g of starting material with the same conditions!)...
And this holds even more true when you make primary amine via leuckart and then methylate with Al/Hg and HCHO...
If hydration reducing agents like LAH or NaBH4 can't be obtained, there's always the possibility of making the oxime and reducing that to arrive at primary amines.
For secondary amines, it is preferable to go via red.amination of ketones with alkylamines directly, as said. (less losses on the way, compared to a 2-step procedure)
i_a
Last edited by IndoleAmine on Sat Apr 16, 2005 10:18 am; edited 1 time in total |
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loki
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Sat Apr 16, 2005 5:52 am |
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| IndoleAmine wrote: |
Hey, thats a pretty nice find - but remember that methylamine is gaseous at room temp., contrary to other primary amines. It will vaporize when heat is applied, hell even at room temp. if you don't cool it to below -23°C.....
(its very difficult to heat the toluene to reflux and still make that MeAm stay in there... )
Further, you cannot use this dehydration method with methylamine to make a formamide, because NMF is miscible with water in any proportion.
This makes the use of a dean-stark a bit difficult, I would say - since you will loose all NMF to the aequous layer in your dean-stark....
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Nice to see you actually read it at last :/
er...
1. that reaction specifies that the acid equals or exceeds the molarity of the base. If i am not mistaken, methylamine *will* form a salt, as it does with hydrochloric acid, via ionic bonding (methylammonium formate) and thus it will not go anywhere.
2. the NMF will not get to the dean stark trap because NMF boils at 204 (or somesuch near that number) - and unless they are azeotropic (water and NMF), which is highly unlikely considering an over 100 degree boiling point difference, then... well, basically, it should work. If it turns out that tolly and NMF are azeotropic (i doubt it) then this is no biggie, they have to be separated anyway and the only other thing in the dean-stark is water. The only question about this reaction method is whether or not it can be done with ammonia formate in the first place.
3. the toluene is not heated to reflux, it is heated to 100 degrees C. It will barely collect toluene in the dean stark trap, but this should be borne in mind of course. For this reason, xylene may be more desirable, but I don't see it being a big problem.
This is how I see it proceeding:
In the first reaction step, dehydrating ammonia formate, the ammonia formate itself should not decompose at water's boiling point, which is the temperature of the reaction - in fact i think i stated the decomposition temperature of ammonium formate previously (190?) However, the water will boil and be caught in the dean-stark trap. So unless there's some special condition relating to starting with ammonia as the amine in the reaction system (none of which I can think of), at the end of it you end up with formamide.
Second step, separating toluene and formamide - Does formamide dissolve in toluene? If so, simple distillation should work pretty much, with a goodly difference between BP's otherwise, or to be thorough, fractionation would be required. If it does not, so much the better.
Third step, with our methanol and hydrochloric acid, I may be wrong, but won't the hydrochloric acid prevent the amine from boiling out? Isn't this a critical element to the HCl/methanol de-formylation used in the leukart rxns?
Fourth step, you have to turn the methylamine into methylamine formate + extra formic acid, can you now see why it has to be done by bubbling it out and catching it in formic acid solution? It will come out of the reaction as MeAm.HCl, which we don't want.
Fourth step, methylamine formate + a little extra formic acid, if it works for ammonia, then it should work for methylamine exactly the same way, in fact it may be a little better in the respect of methylamine having a higher boiling point than ammonia. The product may be miscible in water, but as i said above, it's boiling point is way way higher, so it should be possible to have the water entirely driven off the NMF by the use of the dean stark apparatus. I really should look up whether tolly does dissolve nmf or formamide, if it does, that's quite helpful, and from looking at the reaction, i suspect this is why it works so well, but for the formamide and NMF it may not be so good, but if solubility in toluene of these chems is low, then i guess this means use more toluene.
And then at this point you have NMF, which binds to a ketone simply by heat and reflux and enough time given, followed by the methanol/HCl de-formylation to leave us with the methylaminated ketone.
Anyway, some day, in a parallel dimension, someone who is not me will acquire the required equipment and make formic acid, and test this out. In the mean time, someone who is not you (good reader) who happens to have a dean stark, formic acid and ammonia, could possibly stand to see, at least qualitatively, whether this even works at all, and if it does, what caveats to look out for. |
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loki
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Sat Apr 16, 2005 5:57 am |
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interesting - formic acid, in these conditions, will be boiling. I am surprised at this actually, but one big implication - it means that even if they start with 2x equivalents as described in that paper, all the formic acid is going straight into the trap. Which implies that equimolar, 1:1 salts of the amine and formic acid are what will do the trick. I probably should read that paper a bit more deeply, but I don't recall them talking about the fact that any excess formic acid is going up directly with the water. seems kinda obvious when you look at the msds of formic acid.
I stand corrected, it states 'heated at reflux', which means, for toluene, 110, and for xylene, 140. I read the paper more thoroughly this time, and i still see no reason why it won't work with straight ammonia formate, and I am also puzzled as to why they did not try it.
chemfinder says that ammonia formate liquifies at 115 and boils at 180 (decomposition is not stated but I know this is the case)
Last edited by loki on Sat Apr 16, 2005 6:12 am; edited 1 time in total |
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IndoleAmine
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Sat Apr 16, 2005 6:09 am |
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methylamine *will* form a salt, as it does with hydrochloric acid, via ionic bonding (methylammonium formate)
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, and this salt will be turned into methylammonium carbonate and sublime, clogging your dean-stark... 
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it means that even if they start with 2x equivalents as described in that paper, all the formic acid is going straight into the trap. Which implies that equimolar, 1:1 salts of the amine and formic acid are what will do the trick.
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Whatta bullshit (sorry, but you don't seem to understand me as long as I'm friendly..)! 
If the formic is gonna go into the trap at all, it can't hold back any amine as any salt anymore. You should decide for the formic holding back the amine or evaporating, leaving it in free form - that would be the minimum requirement for me to discuss this topic any further with you.
And moreover, the formic collecting in the trap (if it does) will mix up the phases and make separation of any H2O impossible. And what do you mean with a ratio of amine salt to formic acid salt of 1:1? 
And the MSDS of methylamine tells you much more than the one for formic that the chemical it describes is gonna evap waaay sooner when heat is applied, dude!! |
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IndoleAmine
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Sat Apr 16, 2005 6:12 am |
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| Quote: |
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unless they are azeotropic (water and NMF), which is highly unlikely considering an over 100 degree boiling point difference, then... well, basically, it should work. If it turns out that tolly and NMF are azeotropic (i doubt it) then this is no biggie, they have to be separated anyway and the only other thing in the dean-stark is water.
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They distill azeotropic, and further they are miscible with each other in any proportion. The fact that their bp differs by more than 100°C doesn't mean anything, this is also the case with phenylacetone and you can steam distill it like a beauty. Your dean-stark will remove all NMF that will be formed (if any will be made at all) instead of drying it.
I don't understand why you think you would need to convince everybody with your revolutionary findings, although I keep telling you the friendly way that it will most probably not work. I suspect you don't accept me as knowledgable enough, and respect that.
I give up.
Do what you think.
i_a
Last edited by IndoleAmine on Sat Apr 16, 2005 6:36 am; edited 2 times in total |
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loki
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Sat Apr 16, 2005 6:16 am |
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| IndoleAmine wrote: |
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methylamine *will* form a salt, as it does with hydrochloric acid, via ionic bonding (methylammonium formate)
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, and this salt will be turned into methylammonium carbonate and sublime, clogging your dean-stark...
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oh... are you sure that methylammonium formate will form methylamine carbonate? that does kinda wreck the whole thing. Not to mention (N methyl) formamide being azeotropic with water...
RATS  |
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IndoleAmine
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Sat Apr 16, 2005 6:21 am |
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You mean I'm sure that formic turns into carbon dioxide upon heating?
This happens when making methylamine from HCHO/NH4Cl, and the whole theory of the leuckart rxn is based on that fact too.
I thought you'd read the MSDS for formic??
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loki
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Sat Apr 16, 2005 9:19 am |
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| *slinks back into the corner, chastened* |
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IndoleAmine
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Sat Apr 16, 2005 10:15 am |
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Head up, at least you know now how to properly use a dean stark, and are familiar with reductive methylation and leuckart reductive amination reactions.
At least you learned something useful! 
And to your satisfaction, the synthetikal research department has started the following experiment: a handful of ACS ammonium formate is currently "dehydrated" in a dean-stark apparatus at toluene reflux temp (110°C), the heat was just cranked up and results will be in shortly.
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IndoleAmine
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Sat Apr 16, 2005 11:09 am |
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First result: its strongly advised to use a big fat excess of formic acid when working with gaseous/volatile amines, since a 1:1 ratio ammonia/formic results in development of much NH3, apparently. What a luck there are hose takeoff adapters and long hoses to vent out the fumes through the window... (cough) and after about one hour rxn time, 2.8ml H2O have settled in the trap. The two phases look a bit cloudy though.
Hmm..
(think it will be left unattended for at least 8 hours, since I'm tired right now. To be continued...)
EDIT: now the trap content is 4.1ml with 0.9ml at the bottom filled with - ammonium carbonate crystals... |
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IndoleAmine
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Sat Apr 16, 2005 10:49 pm |
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Ok, after 10h rxn time, the trap contained about 2cm3 of crystalline material floating in ~9ml of H2O.
The toluene was stripped on the rotovap at 12mmHg, leaving about 0.5ml of yellowish residue.
Since the chemist doesn't believe that all ammonium formate has simply vaporized into nothing but water, he adds the trap content to the recovered residual toluene, and starts rotovapping away the solvent again.
He's left with a viscous aequous phase being definitely much more than 9ml (15ml to be more exact), and thinks: "hm, looks like the dean-stark has removed the formamide too".
As said, formamide and H2O form an azeotrope, and formamide is only slightly soluble in toluene - but very miscible with H2O..
The experiment is now repeated at twice the scale, in hope to get enough formamide to be able to vacuum distill it (and dry it this way).
Conclusion: using a dean-stark trap to make formamides from amines is only of advantage if the product formamide and starting material amine are both water-immiscible and, preferrably, not volatile.
For ammonia as the starting material, better heat 1mol ammonium formate + 0.1mol formic acid to 115°C in normal distillation apparatus until water/formic flow has ceased, then distill out the formamide directly under vacuum, and distill again to purify.
(what did I say? No need to reinvent the wheel here... ) |
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