NMF synthesis for secondary amine via leukart?

loki · guinea pig

looking at http://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/ONR234.htm i got thinking about how to use this rxn in methylamination type rxns

what i came up with was:

paraformaldehyde + ammonia formate + formic acid -> N-Methyl formamide

this reaction *should* go to methylamine if there is too much formic acid, but that's not what we want here anyway. NMF is the reagent to use to make a ketone into a methylaminated ketone.Technically this reaction is called Eschweiler-Clarke reaction, because it's done with formaldehyde. The ratios of ammonia formate and paraformaldehyde have to be fairly exact otherwise one gets secondary or tertiary amines which we don't want. Using paraformaldehyde makes this fairly easy because it's easier to measure (just weigh it)

I'm just not entirely clear on what molar ratios to use or what kind of yields from this. I'm not sure why this hasn't been suggested before, but i'm sure i will be informed as to why soon enough.

So then, the next step would be to take the NMF and formic acid and one's ketone thusly:

ketone + NMF + formic acid -> N-Methyl - whatever

in this step, we do want formation of the straight methylamine so an excess of formic acid is required.

Via modifications, one could use this to produce dimethyl amines as well, or using other aldehydes or ketones to produce other novel N-substituted amines (eg if one could get indole 3 acetaldehyde somehow, or 3,4,5 phenylacetaldehyde edit: scratch the indole thing)

bio · Working Bee

Probably easier to just bubble MeNH2 through the HCOOH to make your
N-MethylFormamide followed by fractionating carefully.

IndoleAmine · Dreamreader Deluxe

Throwing together several rxns and trying to perform them in the same vessel is generally no good idea.

- You can make methylamine from paraformaldehyde and ammonium formate (additional formic does no good in this rxn btw)

- You can make NMF from methylamine and formic acid, but only when heating and distilling out the formed NMF, followed by fractionation (as bio said)

- and finally you can use NMF/formic to aminomethylate ketones with a so-called leuckart-wallach rxn, followed by hydrolysis of the intermediate formamide....

But you cannot use praformaldehyde, ammonium formate and formic acid one-pot with a ketone and hope to get pure monomethylated amine ..- Rolling Eyes

it most probably won't work at all and just give a huge mess, please don't try.

My advice:

Take your time, perform all steps separately, you will be rewarded for your patience. Or overhaste it, try to take heaps of shortcuts and throw all reagents together - and you will become very disappointed..

i_a

loki · guinea pig

i didn't think i was saying do them in one pot, first was make nmf then purify and then nmf + formic + ketone -> methylaminated hydrocarbon

edit: ok i see it, ammonia formate and formaldehyde will make nmf. we do *not* want it to reduce. The formaldehyde should be able to be fractionated out of the post reaction mixture, and remaining ammonium formate will separate by adding water and distilling the NMF out (or somesuch, maybe extraction into an appropriate solvent)

in any case my idea was to get to this point with relatively pure NMF, and then use already well established methods i found in documents i found on rhodium (NMF and mdp2p --acidic hydrolysis-->mdma):
http://rhodium.moppy.net/www.rhodium.ws/chemistry/mdp2p.leuckart.txt

loki · guinea pig

http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/eschweiler-clarke.htm

if you look at that diagram you see it's going to make methylamine from formaldehyde

making NMF is an extra step in the reaction system but it *can* be done. That eschweiler-clarke rxn is most likely going to produce methylamine formate because there's an abundance of formic acid around. If i am not mistaken, one could then distill off the excess formic acid and water, and then attach a dean-stark to the flask and dehydrate the methylamine formate and get N methyl formamide, which then must be distilled out from the rest of it. It might help to recrystallise the methylamine formate before dehydrating it.

Does this sound right?

The only downside of this reaction is the yield is a bit miserable, 40% at the bottom end. However, formic acid is not difficult to make, and ammonia is cheap.

Another possible rxn system is to take ammonia and formic acid (well, ammonia formate i guess) and reflux it mixed with toluene (see below) with a dean stark to produce the formamide, and then reduce the formamide with HCl/methanol, yielding methylamine HCl, and then repeating the formylation rxn with the formed methylamine... except one has to liberate the methylamine from the chloride first... which means stinky methylamine gas, i don't think that the toluene formylation method will work with the HCl around. It should be possible to do this by basifying the methylamine HCl and sucking the methylamine gas out through a bubbler with formic acid in it (using a vacuum aspirator on a bubbler bottle perhaps).

fyi, here is the formylation method i am referring to:

http://newjournal.kcsnet.or.kr/main/j_search/j_download.htm?code=B020134

I think this last described method is probably the highest yielding synth for NMF that one could conceive, according to that pdf the formylation produces 98% yields, and the reduction of the formamide to methylamine is practically quantitative.

The advantage of using this reaction system is that it reduces the total number of reagents required and everything involved is very much OTC, if you coupled this protocol with the aldol condensation/baeyer villiger oxidation route from the benzaldehyde, which can be made via the manganese(2)sulphate oxidation from toluene, this is your reagents list:

Hydrochloric acid
Methanol
Toluene
Oxalic acid
Glycerol (this and the previous for the formic acid synth)
ammonia
methyl ethyl ketone
sulphuric acid
manganese dioxide

and the equipment required is a set of drescher bottles and appropriate HCl resistant hose, reflux, distillation and dean-stark apparatus. The oxalic acid/glycerol method of making formic acid possibly could be replaced by an oxidation protocol on the methanol, but is probably more difficult. At this point oxalic acid and glycerol are easy enough to get and the synthesis is high yielding.

IndoleAmine · Dreamreader Deluxe

IndoleAmine · Dreamreader Deluxe

By the way: everything else about making formic, benzaldehyde and baeyer-villiger is correct so far - so you're on the right way!

Just improve on your MeAm + NMF synth knowledge maybe, and there you go.. Wink

i_a

loki · guinea pig

i think i specifically say 'ammonia formate' and 'methylamine formate' in both steps of the proposed NMF synthesis, and by those terms i specifically mean the 1:1 salts made by titration, or as i describe for methylamine, by bubbling it through dilute solutions of formic acid, in a sequence (3 or 4 drescher bottles in a row) that have had the amounts of formic acid in them specifically calibrated to ensure that they do not end up with too much of one or the other in them. Given an equimolar amount of formic acid and an amine one merely needs to heat at about 100 degrees and the water boils out. The method using toluene/xylene and a dean-stark apparatus has a stated 98% yield, because, obviously, when the (methyl)ammonium formate is heated to the point of decomposition the first thing that happens is dehydration, and you get formyl (methyl) ammonia, or (N methyl) formamide.

The second part of my previous post seems the most likely route after much consideration, and uses equimolar amine and formic.

loki · guinea pig

i think that the multiple bubber idea could be used for making the ammonia and formic acid salts equimolar too, get formic acid solution in a big heavy container and a bubbler after it with strong hydrochloric acid solution after it to absorb any excess, and an anhydrous ammonia generator, and either push air through one or suck it out through the other end, for this, a vacuum aspirator would be good for ensuring that you don't get any ammonia stink. same goes for the methylamine formate generation system.

Or, one could deliberately overshoot on the ammonia and catch the excess by vacuum and boiling the ammonia out as the water is removed.

getting the amine and formate ratio exactly 1:1 is critical to getting the best possible result.

loki · guinea pig

Here is a summary of the protocol I have conceived from end to end. I have not yet done stochiometry on it, I will finish that later once the protocol is 'approved' by my peers Wink

https://m0c.no-ip.org/writing/amphet.html

IndoleAmine · Dreamreader Deluxe

come on...
stop talking about it - do experiments - continue talking if you like to.

No offense, but it doesn't sound as if it would work from all I know, and I can also explain to you why it won't, if you like me to.

But I guess you'll have to find out for yourself, then do so..

Only please don't try to defend this "route" unless you can prove it will work. It just sounds too, well - ridiculous.

MeAm synth + NMF synth one-pot = impossible

..and unless you can prove the opposite, either through experimentsl data or through providing literature refs, I would say you should shut up and instead read up on this one. Please take it not as offence, but as kind of an advice, Very Happy

I would be glad to hear about, for example, a reference for this step you describe in the document you linked to:

loki · guinea pig

http://www.pharm.unifi.it/Gr_Moroni/2004_Farm_Costantino.pdf page 95

IndoleAmine · Dreamreader Deluxe

First of all, you said that you would make formamide from ammonium formate and then hydrolyze to METHYLamine - and in fact the result will be AMMONIA.

But thats a minor error.

Come on - you don't have to invent things by your own... Very Happy

Methylamine syntheses already are out there, more than I can count with both hands.

Making methylamine as the formate salt presents no advantage if you bubble it into anything as a gas - you have a more difficult rxn and still have to neutralize that formate moiety afterwards - why not make the HCl salt like is common, then you can recrystallize the methylamine and purify it that way....

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.

You cannot use a dean-stark at atmospherical pressure in hope te get NMF. Since the NMF will decompose before reaching reflux, further all reagents are water-miscible, further methylamine will simply evaporate when you start heating, no matter if you distill or use a dean-stark - so you have to re-gas anyway)....(!)

Of course you can interject several unnecessary steps somewhere in between (like make MeAm, make NMF, hydrolyze to MeAm, make NMF again... Question

)

- but I strongly doubt that it will help in ANY way.

Oh, and lastly and since I'm tired in short:

How should this be related to nmf?? Its not even a secondary amide and for sure no n-methylformamide AFAICS...

i_a

IndoleAmine · Dreamreader Deluxe

Heads up lad!

Its not all lost: just exchange ammonia with hexamine (those red brand camping fuel tabs, you know... *hint*), add more muriatic and everclear to your ingredients list - and you're still in biz and can make MeAm easy and OTC without the need of synthing formic for it, and then you can easily proceed with gassing the MeAm into your self-made, therefore precious formic acid, like you described, to make NMF (just don't mess around with a dean-stark here) and do that leuky thingie you're talking about ... Laughing

https://synthetikal.com/synthforum/viewtopic.php?t=350#

(and thinking about it, it could really be that hydrolyzing NMF would give methylamine like you said; but anyway: you want NMF I thought - why destroy it once you finally have some, instead of purifying and using it?? Question

)

i_a[/b]

IndoleAmine · Dreamreader Deluxe

And please, please:

There are LOTS of procedures available for anything you describe (including all that glycerol, oxalic and formic stuff), if you ask kind enough I can also help you finding them - but you didn't post anything new here, and further you put up things in the wrong order in your plan.

So please don't try to convince us that you've found something special, new or unknown. I don't want to cause desperation here, but in this case you have helped noone so far with your posts, we all know already what you just "discovered"..

Since we try to keep the content of our posts useful, I want to kindly ask you to think about it next time before posting such things. Please don't take it as offense.

Oxalic acid is available otc as household cleaner btw, better leave those poor plants alive and save your energy for more important things.. Wink

Greets

i_a