04-21-00 00:18
No 108403
      Aminomercuration-demercuration question: -ReFlux
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Author  Topic:   Aminomercuration-demercuration question: 
Member   posted 06-23-98 09:00 PM          
So the subject of hypothetical Aminomercuration-demercuration of our favourite olefin safrole has been widely discusssed on this board. I'd now like to get to some specifics, so here are a few questions that are on my mind:
1. What is the ideal solvent for this reaction? Most journal refs call for THF, but the problem with THF is its perpensity for formation of explosive peroxides upon distilling that can make it go BOOM! Also, it is relativley expensive. How about 1,2-Dichloroethane (DCE) or methylene chloride (DCM)? Factors to consider are solubility of Safrole in the solvent, solubility of the Amine source in the solvent, and non-reactivity of the solvent.

2. For creation of secondary aminated product (MDMA) what form should the amine source (MeNH2) be in? The journal refs call for it to be used in aq. solution, but can a solution of the hydrochloride salt (MeNH2.HCL) be used somehow?

3. For creation of primary aminated product (MDA) what amine source can be used? Ammonum Acetate is not very soluble in THF or DCE, however, this should only slow down the speed of the creation of the organomercurial complex. More important to consider is will the formed complex dissolve in these solvents? What other sources for NH3 can be used? Perhaps aq. ammonium?

4. What species of Mercury II salt should be used? Mercuric Acetate is widely used in oxymercuration reactions, but is less reactive than Mercuric Nitrate or Chlorate. It appears that speed of reactivity with amine source to form organomercurial complex is the only main issue, and as such, can the acetate salt be used with MeNH2?

5. What is the best procedure for issolation of the resulting amines (MDA/MDMA)? It is important to carefully issolate the product from the rxn. mix so as to avoid any possible mercury contamination. Are standard solvent extractions, acid-base washings enough?

6. How to issolate pontential anti-Markownikoff aminated product? According to some journal refs, though most of the product from these rxns will proceed with Markownikoff addition of the amine, some anti-addition products can occur. How can these be seperated/issolated from the product ?

The refs that I have looked into for researching this method are:
J Org Chem Vol 44, 20. Pg. 3581 (1979)
Tett Vol 40, 7. Pg. 1199 (1984)


Member   posted 06-24-98 09:52 AM          
ReFlux, a while ago I got interested in that specific reaction too. I did a little reading and would like to share my thoughts with you:
1)THF is probably the best solvent you can get. If you want to substitute, why don't you use diethyl ether? That's an ether too. I wouldn't use chlorinated hydrocarbons like DCM or DCE, cuz they might react with the Hg-salt. Distilling THF is not a problem if you throw in some reducing agent to take care of the peroxides, and then distilling.
2)I've asked the same questions as you a while back. Ziggy answered to me, that you have to use methylamine freebase.
3)For primary amines, why don't you use benzylamine. You'll make the N-benzylamine, which can be split off by hydrogenation with Pd/C. This aminomercuration is actually suited better to make secondary amines, like MDMA.
4)After the aminomercuration, you'll pour in some NaOH solution to make the mixture basic, then reduction with NaBH4. This'll reduce the Hg2+ to Hg(l). Mercury isn't soluble in water, so you can separate the layers. I guess acid-base extraction are sufficient to prevent mercury-contamination.
5)This bothered me too, until I read in PIHKAL, that the anti-Markovnivkov product, 1(3,4-methylenedioxyphenyl)-3-propylmethylamine, is a known under the name GAMMA and is an active compound. So why bother removing it?

I hope I've helped you a little with this. This is a very interesting reaction, so if you find anything good, keep me posted OK? Lr/

Member   posted 06-24-98 09:55 PM          
Great reply Labrat! You and I are on the same wavelength!
I REALLY like your benzyl-substituted amine idea, (Check out my new post: A substitute for MeNH2 in various Synths.) although I think you meant Aniline for MDA as Benzylamine gives MDMA.

As for the anti-markownikoff product, GAMMA is the MDA anti-addition product (gamma-3,4-methylendioxy-phenylproplyamine), and though it is active, it didn't seem to have a desirable effect (see PIHKAL). Any info on the MDMA anti-product? In any case I think we should think of ways to remove them.

BTW: is Ziggy the person who originally posted the aminomerc. method for MDMA in Lyeaum?



Member   posted 06-25-98 10:15 AM          
Reflux: no, I didn't mean aniline, I did mean benzylamine. Hydrogenation with Pd-C is known to split off benzyl groups, just check out the literature to remove benzyl groups from benzyl alcohols. What GAMMA is gamma-3,4-methylendioxy-phenylproplyamine, not the methylamine? Damn, my mistake. But I still think it's active. And I would just use it as is. Otherwise you'll be forced to use chromatography to separate the anti-Markovnikoff from the Markovnikoff compound. Ziggy is indeed the guy who posted the aminomercuration method for MDMA.
I've done some reading too. I've read the JOC 44:3580('79) again and found some interesting leads.

It's stated that:"In all cases, rapid formation of amine-mercury complexes was observed prior to addition of olefin". Hmm, what would happen if one would try aqueous MeNH2 here? Will there be formation of amine-mercury complex? If there is, one could use aqueous methylamine. You probably have to use Hg(ClO4)2 instead of Hg(NO3)2.
They also state:"We have observed that the aminomercuration can be performed in aqueous or anhydrous THF...this means hydroxide ion does not compete successfully with ethylamine as a nucleophile for the intermediate mercurinium ion or a direct addition of amine-mercury complex is involved". Hmm, I'm guessing that you could probably use aqeous methylamine solution.

Then I also read another good article:
Chem.Het.Compounds. 11:4('75)
This is actually about INTRAMOLECULAR not intermolecular aminomercuration, but they give some properties of the reaction:
-nature of the anion on Hg is important
-the reaction has an IONIC character:
first a pi-complex between the olefin and the mercury salt is formed, then the amine adds to give the Markovnikoff addition product
-reduction with NaBH4 has an radical OR an ionic mechanism. If the mechanism is ionic, then during the reduction aziridinium ion is formed, which explains the presence of the two isomeric amines.
Remember when reading this article, that intramolecular aminomercuration is a lot easier to accomplish then intermolecular aminomercuration and that with intermolecular aminomercuration more hydroxymercuration occurs.

Well, that's it for today. I'm gonna find some more refs on this very interesting reaction and would like to communicate with you on it. Lr/

Member   posted 06-25-98 02:55 PM          
Labrat- I'm confused now. Aniline HAS a benzyl group doesn't it? (just one less methyl group before the amine when compared to Benzylamine) Or is a Benzyl group the benzene ring plus a single methyl (essentially a toluene less one H)? Please clarify.
As to rxns. w/ aq. MeNH2, I too believe that it would work fine. In J Org Chem Vol 44, 20. Pg. 3581 (1979) they used aq. EtNH2 w/ m-methoxyallylbenzene & Hg(ClO4)2 and produced then ethylaminated product in high yields (87%)

Can one make an aq. MeNH2 sol'n from MeNH2.HCL? If it were to be disolved in H20, and then the sol'n basified w/ NaOH, would that not result in MeNH2 (g) which would stay disolved in the H20 plus NaCL?

I'll continue digging ... I look forward to further discussion with you on this topic.


Member   posted 06-26-98 10:17 AM          
Reflux, aniline is phenylamine, benzylamine is like toluene with an -NH2 group substituted for a -H! Basic chemistry me boy!
Using aqueous methylamine is indeed a very viable option, although you have to heat the mercury salt/aqueous MeNH2 mixture to 60 C to expedite formation of the amine-mercury complexes. If the Labrat remembers correct, the bp of an 40% aqueous solution is about 50 C (correct?). I wonder if refluxing the amine-mercury mixture will take care of the complex formation. Have any thoughts on this?

Making aqueous methylamine is easy! Just put your MeNH2.HCl in a flask, attach a distillation setup to it and fill a dropping funnel with 50% aqueous NaOH. Now slowly drip the alkalic solution on the salt to create MeNH2 gas. Now bubble the gas into a water mixture until it has gained the proper amount of weight to get aqueous MeNH2! You could neutralise it as you described, but you'll have NaCl contamination. I don't know what this will do to the yield.

Keep digging, I'll do the same! Lr/

unregistered   posted 06-26-98 12:42 PM           
i previously posted a lot of ref and notes from ziggy on the rxn on this board.
elf has posted attempts with aminomercuration but with the MeNH HCl salt which is definitely bad. I noticed that in one of the major ref for this rxn in JOC uses ethylamine as one of their variable amines and in methods they mention that it is used as a 70% solution (but i dont remember if it was aqueous of alcoholic) but this example made me think that aq methylamine would work. question is: is 40% enough and will much be lost during reflux. ziggys suggestions to over come this problem was doing rxn in a presurized container of sorts.
i think this rxn has a lot of potential, someone just has to ave the balls to dream about it a few times to perfect a procedure.
my guess is that HgAc and HgNO3 salts will work, and that HgNO3 and Hgperchloriate would be best (based on the articles i have read-they seem to use these the most)

Member   posted 06-29-98 06:25 AM          
I don't think that the % of Aq. sol'n of the amine (ethyl-methyl) is that important. 70% aq. EtNH2 & 40% aq. MeNH2 are standard concentrations and that is probably why the JOC paper used the 70% soln.
As for the heating of reaction mix to 60-65 degrees C to "speed up the formation of the intermediate organomercurials", I believe that here again the researchers in the JOC paper chose this temp as it just below the BP of THF (66 C). The paper did not call for refluxing the mix, but simple stirred heating.

The paper also indicates that "In all cases, rapid formation of amine-mercurcy complexes was observed prior to the addition of the olefin substrate. The rate of aminomercuration proved to be a sensitive function of the mercuric salt employed."

This indicates to me that there is no need for any refluxing or pressurized/sealed reaction vessels. The amine source is converted almost immediately into an amine-mercury complex which is dissolved in the THF. Simply add the 40% aq. methylamine to the stirring Mercuric salt in THF soln. Then add the Safrole, heat to say 60 C, and leave stirring for prolonged period of time (72 to 96 hrs.) until all of the safrole is converted to an organomercurial intermediate.

As for the species of Mercuric salt used, only dreaming will tell! As far as I can tell, Hg(NO3)2 would be ideal, but Hg(OAC)2 is easier to aquire. Also, no need to worry about the hyrdated state of your HG salt (mono-hydrate, tri-hydrate etc.) Use whatever type is easiest/cheapest to aquire and then adjust the amount used in reaction so that it is used in the correct molar ratios.

Just a few more musings...will continue the search!

PS Labrat-I found the BP of 40% Aq. Methylamine at 48 C. Looked it up in Acros catalog.


Member   posted 06-29-98 10:32 AM          
ReFlux, thanx for the comments. It's good to discuss this with a fellow chemist, cuz it seems we agree on a lot of things here. So we should definitely use 40% aqueous methylamine and we don't have to heat it to reflux (but I think it's better to speed up the complex formation).
I think that when using aqueous methylamine it's better to use Hg(ClO4)2 then Hg(NO3)2 and you can definitely forget Hg(OAc)2. That anion is very important for the course of the reaction. That anion is the nucleophile that has to compete with hydroxide and methylamine nucleophiles, so you'd better choose the right anion. It's easy to prepare those salts from HgO, just by dissolving this mercuryoxide in e.g. perchloric acid you'll end up with Hg(ClO4)2. I'll try to find the intricate details for this. Lr/

Member   posted 06-30-98 02:50 PM          
Labrat-I've been doing some more research into this and here's what I've come up with:
In Tet. Vol. 40,7 (1984) pg. 1199-1204 they discuss reversibility in aminomercuration. They found that aminomerc. w/ Mercury(II) Acetate is an irreversible process while w/ Mercury (II) salts derived from strong acids (Hydrochloric, Nitric, Perchlorate etc) it is reversible. Could this pose a problem? The only main differnce is the rate of the rxn. which I think would be fine with acetate salt. Nucleophility (sp?) is not an issue as hydroxy mercuration never occurs even with very weak nucleophilic amines and mercuric acetate. However, yeilds can be affected by weaker salts, though I wonder if that is because the reactions just aren't given enough time to complete?

In Tet. Vol 34 (1978) pg. 1943-1950 they discuss using a catalytic amount of concentrated (70%) perchloric acid sol'n w/ mercury (II) acetate which results in greater yields and much accelerated reaction time. My french really sucks, so If yours is any better maybe you could look up this ref. as it has a lot of info on the process and mechanisms of aminomercuration.

Also, won't using a strong acid based salt will result in highly acidic conditions in the reaction mix after aminomercuration is complete? The anion will turn the aq. sol. acidic will it not, which could damage the methylenedioxy ring structure, no?

Just a few more thoughts for us to ponder, though I really think many of these issues would be resolved with a little dreaming!


Member   posted 06-30-98 03:12 PM          
Just one more point, I don't see the point in having a 2.67X molar excess of amine to mercury salt as suggested by the JOC ref. Since in the first part of the reaction, there is a near immediate formation of organomercurial complex (before addition of the olefin) then what is the point in having all that highly nucleophilic (as in the case of MeNH2) excess amine floating around in the reaction mix.
I would suggest equimolar or if not then just a slight excess of amine (1.1X maybe? relative to the mercury salt), while still maintaining the excess of mercury salt relative to olefin ratio (1.5X). What are your thoughts?


Member   posted 07-02-98 04:48 PM          
Labrat-On a related note, how about using an aq. Ammonia sol'n for hypothetically creating MDA in this reaction. Any thoughts?

Member   posted 07-06-98 11:20 AM          
ReFlux - sorry it took a while to answer this, but my computer got fucked. I tried to post the answers Friday, but no good. I'll try it again today:
>Tet. Vol 34 (1978) pg. 1943-1950
This is a real goldmine! I'll translate the most important things for you:

They used 15 molar excess of water compared to the amine and got NO oxymercuration products!

They added the olefin to a aniline/Hg-Ac mixture in dry THF, then added water. They obtained uniquely aminomercurations compounds. When they added water to Hg-Ac in THF, then added the amine, the oxymercuration products were obtained. This means it's important to have the amine in the mix BEFORE the alkene is added.

Mercury has a greater affinity for nitrogen (N) then for oxygen (O). In the reaction conditions used, there is competition between two nucleophiles: the amine and water. Since no oxymercuration product was found, they concluded amines are better and stronger nucleophiles then water.

Aminomercuration is a compromise between the nucleophilicity of the amine and the weak stability of the amino-mercury complex. There's always complex formation, that's why you have to use at least 4 moles of amine to 1 moles of Hg-salt. In the case of intermolecular aminomercuration the stability of the complex formed between the amine and the mercury salt plays a dominant role in determining the rate of the reaction. In reactions with strongly basic amines (like ammonia, methylamine) a reaction time of several days is necessary to get a decent yield.

The absence of a reversible binding of the complex mercury salt-olefin makes nucleophilic attack on the carbon atom possible even for weak nucleophiles.

Well, this post got kinda long, so onto the next one! Lr/

Member   posted 07-06-98 11:30 AM          
Now onto the questions:
>Also, won't using a strong acid based salt will result in highly acidic conditions in the reaction mix after aminomercuration is complete? The anion will turn the aq. sol. acidic will it not, which could damage the methylenedioxy ring structure, no?
=>No! The salt of a strong acid is by definition a very weak base! Theory me boy!

>I would suggest equimolar or if not then just a slight excess of amine (1.1X maybe? relative to the mercury salt), while still maintaining the excess of mercury salt relative to olefin ratio (1.5X). What are your thoughts?
=>In Tet 34:1943('78) they're talking about complex formation between the amine and the Hg-salt is a competing reaction with complex formation of the Hg-salt with the alkene. With aniline, two molecules of aniline complex with one molecule of Hg-salt. I don't know whether more basic amines like ammonia will complex with even more amines per Hg-salt. This means the excess amine IS NECESSARY. Otherwise the reaction will be slowed down.

>On a related note, how about using an aq. Ammonia sol'n for hypothetically creating MDA in this reaction.
=>Great idea! That way you won't have to go through all that trouble making aqueous methylamine. I guess it'll work. Otherwise, bubble dry NH3 into a mixture of dry THF and a mercury salt, drip in the alkene. If an insoluble complex forms, add a little perchloric acid and watch it dissolve. The water in the mix is used to make the amine-mercury complex less stable. Lr/

Member   posted 07-06-98 11:38 AM          
I've done a little literature searching on aminomercuration and found some more refs:
Synth.Comm.26:4279-88 and 1507-16('96)
=>Here they're talking about creating an mercurinium ion between mercury and the olefin, which is trapped with a nucleophile, like amines. So no direct addition of the amine-mercury complex to the double bond as mentioned in JOC 44:3580('79)

J.Organomet.Chem. 78:177-84('74)
=>not so interesting, dealing mainly with the stereochemistry of aminomercuration

TL 51:5165-8('67) + C.R. 262:1591('66)
=>using NaBH4 instead of LAH produces less anti-Markownikoff compound.

Synthesis 375('81) + 919('82)
=>reduction and deaminomercuration are always competitive processes
=>use of dichloroethane as a solvent for the aminomercuration reaction

JOC 37:3069('72)
=>not worth looking up, just mentioning it.

Well, this'll keep you busy for a while. Lr/

Member   posted 07-06-98 01:13 PM          
I understand exactly what you mean about the excess of amine needed, since more than one amine complexes per mercury, even though only one gets added on, and since all the complex formation is at the begininng, excess of amine is required.

Now, as to the anion of the mercuric salt, I'm a little confused (picture ReFlux scratching his head!) If, for example, Mercuric Perchlorate is used; when it is dissolved in H20:THF sol'n. you have mercury ions and perchlorate ions, correct? Now when the amine is added and it complexes with the mercury, what happens to the perchlorate ions?

I too have faith in the Aq. NH3 route and wish to use it as a test bed for initial dreaming about this reaction. (No sense in wasting hypothetical MeNH3 on working out the bugs in our system, cause even in dreams, MeNH3 is hard to get!!)

I'll check out the synthesis and synth. comm. refs that you posted. They both seem very interesting! You know I've been looking for an alternative to THF for this reaction from the begining!

Also, do you have any info on solubility of MeNH3 and ammonia in THF / DCE ? Ideas on where to look?

Well, I'll bee sorting through some final details here, but I sense some dreaming coming on pretty soon! Talk to you soon.


Member   posted 07-07-98 09:38 AM          
ReFlux - I've read the article you mentioned:
Tetrahedron 40:1199-1204('84)
And I guess you're right what the reversibility of the aminomercuration concerns: if you use the mercury salt of a strong acid, the aminomercuration is reversible.

The authors in this article mention the contradictory results of Perie and Lattes(BSCF 583('70) and Griffith et al (JOC 44:3580('79) concerning the rate of aminomercuration with use of the various mercury-II-salts. I'd follow the instructions of Griffith et al, since they've tried it on allylbenzenes.

The authors state that: "..aminomercuration is reversible only when the mercury(II)salt derives from a strong acid. By the contrary the aminomercuration of olefins with mercury(II)acetate has been found an irreversible process which only leads to the kinetically controlled products." It's very worthwhile to consider using mercury-II-acetate. You'll have to expect a reaction time of several days/weeks to get a decent yield of product. Refluxing will speed up the process.

In the article I read that: "The rate of aminomercuration increases with the ionic character of the mercury salt and the polarity of the solvent, but the extent to which the deaminomercuration takes place largely depends on temperature and reaction time"

Hmmm, I wonder, what if we used mercury(II)acetate in combination with a little perchloric acid as done in
Tetrahedron 34:1943-50('78)?? Probably the aminomercuration will proceed with a faster rate and higher yield. Well, let's do it then!

I'm very curious what will happen if somebody used the above mentioned protocol to brew some MDA. It's probably best to use dry ammonia for starters, you can always add a little perchloric acid (or water) if a insoluble complex precipitates. I'd certainly consider using mercury(II)acetate, since this gives irreversible aminomercuration.

Keep me posted on the results, OK. Lr/

Member   posted 07-08-98 09:53 AM          
ReFlux - I forgot to answer your question yesterday. So I'll do it today:
>If, Mercuric Perchlorate is used; when it is dissolved in H20:THF sol'n. you have mercury ions and perchlorate ions, correct? Now when the amine is added and it complexes with the mercury,what happens to the perchlorate ions?
=>I thought you were an organic chemist, like I am. The amine just complexes with the mercury salt, while the anions stay on the mercury! That's complexation. In the reaction however, the mercury salt has to be ionised (HgX+) to react with the alkene and this is the rate-determining step. That's the only time when the mercury salt loses it's anion temporarily. Otherwise the anions can be exchanged for other anions, but that's it. No amine will exchange for the anions!!!

>Also, do you have any info on solubility of MeNH3 and ammonia in THF / DCE ? Ideas on where to look?
=>You might something useful in the Merck. And I think you mean MeNH2 instead of MeNH3. Hope this helps. Lr/

Member   posted 07-08-98 01:54 PM          
Labrat, please excuse my sometimes naive questions. But where the source of my confusion derived from is that in these reactions (aminomerc-demerc.) metailic Mercury percipitates along with the desired product after reduction. That's why I was wondering what would happen to the anion.

Member   posted 07-09-98 05:42 AM          
Labrat- Got those additional refs and am peering over them for more insights into this process. I think I'm about ready to devise a hypothetical experimental protocol for MDA using THF/Hg(OAc)2. Some questions first:
1) Do you think we should first refine the protocol between ourselves (via email) before posting it? You and I seem to be the main participents in this discussion 
2) Should we both dream about the experiments concurrently and then compare results? Are you in a dream-ready state vis-a-vis the req'd chems, etc.
3) what scale should we dream in? I really haven't found too much on the scalability of these reactions, though the conditions would seem to indicate that they should scale-up easily. For initial dreams, I would suggest 0.1 mol scale, and once perfected, scale-up to 10 mol scale.
Just some more thoughts...


Member   posted 07-09-98 09:39 AM          
ReFlux - he partner, how're doing?
I see you got some questions, so I'll answer them first:
1)Yes, let's continue this story via email. Nobody else seems to care for this reaction or doesn't understand what we're talking about, so we might as well do it a little more private.

2)Currently, I'm switching habitat, if you get my drift. The house we're moving into needs a little work, so I'll be busy with solvents, allright. But to make the paint thinner, not something else unfortunately! So if you could start, I'll dream up some results as soon as possible.

3)Yes, always start out on a small scale, especially if you're not following literature procedures. First see if it works, then scale up. It would be a terrible waste to see 10 moles of perfectly good safrole go down the drain because the reaction was fucked up!

So, we're going to continue this discussion via email. I think it would be a good idea to encrypt this with e.g. PGP5.0. Do you happen to have a copy? I'm already searching for it, since OP also wants to have this, but I can't seem to find a good place to download it from. I'm already looking forward to this. Lr/

Member   posted 07-09-98 02:33 PM          
Right on Partner!
Yes, I have PGP. You can get the latest (and most robust) version of PGP (version 5.53i) from  Grab a copy then we'll exchange keys.

I too am very excited about this project!


Member   posted 07-10-98 09:21 AM          
Thanks for the URL! I've been looking for at least half an hour and only found shitty sites to download previous versions of PGP. This is the latest version! OP, if you read this, get the latest version of PGP at  .
ReFlux, I'll be gone for the weekend, so I'll see you back monday. Have a nice weekend! Lr/

Member   posted 07-10-98 09:22 AM          
Thanks for the URL! I've been looking for at least half an hour and only found shitty sites to download previous versions of PGP. This is the latest version! OP, if you read this, get the latest version of PGP at  .
ReFlux, I'll be gone for the weekend, so I'll see you back monday. Have a nice weekend! Lr/

unregistered   posted 07-12-98 06:13 AM           
Sir,I have asked several times here this question and can't get a civilized answer perhaps you will help since you sound like well like a bro...
I need help with my mercuryII triflouralacetate, I have 10 grams and 10 gallons of raw nutmeg oil, have THF and other things needed but no RXN,anyhelp will be rewarded somehow......

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