Sciencemadness Discussion Board - Mercury-free Clemmensen reduction?

Mercury-free Clemmensen reduction?

Melgar - 30-9-2016 at 13:35

This PDF seems to claim that mercury isn't necessary at all for Clemmensen reduction of ketones into methylene compounds:

https://www.thevespiary.org/library/Files_Uploaded_by_Users/...

The source doesn't seem especially reliable, but so far my searches haven't turned up much, regarding the role that mercury plays in the reduction process. Presumably galinstan (Ga/In/Sn alloy) wouldn't work as a substitute, since going by electronegativity, gallium seems like it would react before zinc would. Field's metal (indium/bismuth/tin) seems to have the lowest melting point of any fusible alloy that doesn't have any toxic metals or metals that are more reactive than zinc in it. Its melting point is 80C or so though, and adding zinc seems to raise that melting point considerably.

Cryolite. - 30-9-2016 at 14:57

Zinc's standard reduction potential (corresponding to Zn -> Zn2+ + 2e-) is 0.76 volts, while gallium's potential (corresponding to Ga -> Ga3+ + 3e-) is 0.53 volts. Thus, zinc is capable of reducing gallium out of its salts. I'm pretty sure galinstan (or even pure gallium) would work as a mercury replacement for Clemmensen reductions.

Maroboduus - 30-9-2016 at 16:21

Am I missing something here? Why would the melting point of the metal matter?

CuReUS - 1-10-2016 at 02:49

Quote: Originally posted by Maroboduus

Why would the melting point of the metal matter?

Quote:

the reaction mixture is boiled vigorously for twenty-five to thirty hours

http://www.orgsyn.org/demo.aspx?prep=cv2p0499

[Edited on 1-10-2016 by CuReUS]

Maroboduus - 1-10-2016 at 07:33

Quote: Originally posted by CuReUS

Quote: Originally posted by Maroboduus

Why would the melting point of the metal matter?

Quote:

the reaction mixture is boiled vigorously for twenty-five to thirty hours

http://www.orgsyn.org/demo.aspx?prep=cv2p0499

[Edited on 1-10-2016 by CuReUS]

Yes, I am aware of what a Clemmensen reduction is, but the initial poster seemed to be looking for low melting alloys to use in preference to other metal combinations. Not avoiding them.

The thread seems to be involve an assumption that a metal or alloy which is liquid at room temperature , or of very low melting point, is somehow desirable for making a metallic couple for this reaction. This is what I was asking about.

[Edited on 1-10-2016 by Maroboduus]

Magpie - 1-10-2016 at 07:58

As I understand it the mercury, sometimes in the form of mercuric chloride (HgCl2), serves to dissolve the oxide coating on the Zn, making it more "active."

This confuses me a bit as my mossy zinc (chunks) with obvious oxide coating will dissolve readily in 6M H2SO4 giving off copious amounts of H2.

Maroboduus - 1-10-2016 at 14:34

I believe the mercuric chloride deposes a layer of mercury on the Zinc, forming an amalgamated surface. Similar to the deposition of mercury on aluminum on some of the aluminum foil based reductions that Alexander Schulgin was so fond of.

(Never could figure out why a guy with access to LAH and sodium borohydride and a Parr bottle and catalysts as well insisted on using mercury to do so many reductions on things he was actually going to eat and give to his friends. If I were gonna actually feed anything I made to somebody, I'd damn sure avoid the heavy metals!)

I have seen similar treatments for zinc where copper is deposited on it for reducing methoxynitrostyrenes with a zinc/copper couple. (this was a proprietary industrial process and might not be in the literature)

It's actually possible to depose the mercury from its metallic state on mossy zinc by just putting the two in a flask together with some HCl and good stirring, but I suspect this gives a more variable amalgam if you're just 'winging it' and not following some accepted procedure. But I know that some people do it that way to avoid having to work with, or obtain, mercuric chloride.

My impression was that the original post was about either doing without the mercury, or replacing it with those other alloys as a coating for the zinc.

I myself find metal/acid reductions somewhat confusing. There are so many different ones, and it seems that many of them can achieve a tremendous number of different things under varying conditions. If anybody knows any good broad reviews of this field, I'd love to hear about it. I'm especially interested in the potential of Zinc/copper(with various mineral and organic acids), as it seems to be quite versatile and doesn't involve any really nasty ions. Iron/Ferrous Sulphate/Sulphuric acid combinations are something else I've heard good things about, but few nuts and bolts details.

aga - 1-10-2016 at 15:02

I can never work out why supposedly amateur chemists don't just try things and find out for themselves.

Much easier to speculate on web forums than Do anything Real i guess.

Maroboduus - 1-10-2016 at 17:08

Quote: Originally posted by aga

I can never work out why supposedly amateur chemists don't just try things and find out for themselves.

Much easier to speculate on web forums than Do anything Real i guess.

I'm surprised you tolerate these web forum discussions of theory as graciously as you do. After all, with your winning ways and sophisticated demeanor you must have constant demands on your time from your many admirers, and I feel truly fortunate that you deign to give me the benefit of your oh so valuable opinions.
Especially since it means tearing yourself away from not only what must be many social demands on your august personage, but also your truly groundbreaking work on activating charcoal by pouring calcium chloride on it.

BromicAcid - 1-10-2016 at 17:38

"A couple of months in the laboratory can frequently save a couple of hours in the library. " - Frank Westheimer

Darkstar - 2-10-2016 at 21:38

Quote: Originally posted by Maroboduus

Never could figure out why a guy with access to LAH and sodium borohydride and a Parr bottle and catalysts as well insisted on using mercury to do so many reductions on things he was actually going to eat and give to his friends. If I were gonna actually feed anything I made to somebody, I'd damn sure avoid the heavy metals!

Shulgin's intent was often to design practical syntheses that could be replicated by non-professionals in an amateur setting. One way he accomplished this was by making use of the kind of reagents that would actually be available to those in amateur settings.

laserlisa - 7-10-2016 at 23:47

Quote: Originally posted by Darkstar

Quote: Originally posted by Maroboduus

I never heard that Shulgin had this intention, and his procedures are often far from OTC or anything like that. I would rather think that he used mercury because he was old school. But what do I know.

Darkstar - 8-10-2016 at 23:57

Quote: Originally posted by laserlisa

Shulgin and his wife (a psychedelic therapist) were both very openly anti-War on Drugs, especially when it came to the criminalization of psychedelic drugs. Both adamantly believed that everyone should have access to psychedelics for the purpose of self-exploration (which they felt to be quite beneficial), and that many psychedelic drugs also have legitimate therapeutic potential for use in fields like psychotherapy.

The reason Shulgin made the second half of PiHKAL (and then later TiHKAL) freely available online for non-commercial reproduction and distribution was to guarantee that the public would always have access to information on the various psychedelic substances he studied, information like their chemical structure and nomenclature, detailed, step-by-step instructions on their preparation and isolation, various different sources for obtaining the necessary reagents and precursors, their recommended dosages and effects and so on. The idea was, in part, to encourage a kind of civil disobedience among underground chemists, which is why he often used somewhat unorthodox (but easy to obtain) reagents like aluminum amalgam.

From Psychedelic Frontier:

Quote:

The Shulgins believed that information about psychedelic drugs should be freely available, so the chemical overview sections of PiHKAL and TiHKAL have been published online (here and here). As Sasha once put it, everyone has “the license to explore the nature of his own soul.” [. . .] The influence of these books, together with Shulgin’s many scientific papers, cannot be overstated. He was an open-source chemist, freely sharing the synthesis steps for the hundreds of new compounds that he created. His methods focused on easily obtainable precursors, presumably to help underground chemists replicate his work. Shulgin’s synthesis of MDMA, for example, is still widely used.

From Wikipedia:

Quote:

While the reactions described are beyond the ability of people with a basic chemistry education, some tend to emphasize techniques that do not require difficult to obtain chemicals. Notable among these are the use of mercury-aluminum amalgam (an unusual but easy to obtain reagent) as a reducing agent and detailed suggestions on legal plant sources of important drug precursors such as safrole.

Through PIHKAL (and later TIHKAL), Shulgin sought to ensure that his discoveries would escape the limits of professional research labs and find their way to the public; a goal consistent with his stated beliefs that psychedelic drugs can be valuable tools for self-exploration. The MDMA ("ecstasy") synthesis published in PIHKAL remains one of the most common clandestine methods of its manufacture to this day.

Melgar - 9-10-2016 at 04:05

Al/Hg is just really easy, and he'd probably done it enough times that he understood it better than he did other reduction methods. Though, he does also seem to like using LiAlH a lot too, so I don't think his primary goal was OTC preparation, so much as ingesting as many different drugs as possible before someone stopped him. I suppose I don't blame him.

Looking up the standard reduction potentials, I guess there doesn't seem to be any reason the Clemmensen reduction wouldn't take place using gallium or galinstan instead of mercury. The chloralkali process would probably also work, for that matter. And considering gallium is going for like $20 for 100g if you don't mind waiting on international shipping, it's competitive with Hg for the amateur chemist. Indium is more expensive, but tin is basically free if you have any lead-free solder laying around.

Mush - 12-11-2016 at 07:27

Quote: Originally posted by Melgar

This PDF seems to claim that mercury isn't necessary at all for Clemmensen reduction of ketones into methylene compounds:

https://www.thevespiary.org/library/Files_Uploaded_by_Users/...

The source doesn't seem especially reliable, but so far my searches haven't turned up much, regarding the role that mercury plays in the reduction process. Presumably galinstan (Ga/In/Sn alloy) wouldn't work as a substitute, since going by electronegativity, gallium seems like it would react before zinc would. Field's metal (indium/bismuth/tin) seems to have the lowest melting point of any fusible alloy that doesn't have any toxic metals or metals that are more reactive than zinc in it. Its melting point is 80C or so though, and adding zinc seems to raise that melting point considerably.

I have doubts about Mr. Bulavka's work. I googled his name. Only ECSO conferences keep poping up pretty much nothing else. If what he found is breakthrough ragarding Hg free Clemmensen reduction why he hasn't published them in the well known journals (not even the Russian ones)?
I also like these "The reaction mixture was monitored with TLC", but no further details were given.

Just to compare:
Zinc, ether, HCl, on -15 C
MODIFIED CLEMMENSEN REDUCTION: CHOLESTANE
Org. Synth. 1973, 53, 86
DOI: 10.15227/orgsyn.053.0086
http://www.orgsyn.org/demo.aspx?prep=CV6P0289

This is also another piece that looks good on paper.

"Comparative study of classical and modified Clemmensen reduction of anthraquinone and alizarin with amalgamated and non-amalgamated zinc: what “hexahydroanthracene” Clemmensen have obtained?"
http://www.usc.es/congresos/ecsoc/11/hall_aGOS/a028/index.ht...

V. N. Bulavka. Reduction of anthraquinones with non-amalgamated zinc by modified Clemmensen reaction. 9th Scientific School-conference on Organic Chemistry. (Moscow – Zvenigorod, 11-15.12.2006). Abstracts of Reports. Moscow, 2006, Abstract C-39, p.92.

This presentation would be the most relevant to this topic. I don't think we ever find this unless some contact him.

V. N. Bulavka, A. N. Shchavlinskii, O. N. Tolkachev. Zinc dust as a novel reduction agent for 2'-nitrostyrenes, formamides and acetophenones. 10th Int. Conf. Org. Synth. (ICOS-10). Bangalore, 1994. Abstract P-WED-70.

macckone - 12-11-2016 at 14:39

Devada's alloy can be used for some reactions. It is more reducing than the clemsen reduction.

clearly_not_atara - 12-11-2016 at 17:42

Not quite the same thing but:

https://erowid.org/archive/rhodium/chemistry/zn-ni.couple.ht...

bipolar - 24-3-2019 at 17:03

About 2 years ago I was curious whether or not non-amalgamated zinc could reduce aldehyde group. So I ran Bulavka's procedure for ketones on a 2,5-dimethoxybenzaldehyde (2,5-DMBA) and unsubstituted one.

Unsubstituted benzaldehyde gave yellow liquid with a density of >1 g/cm3, but there was definetely some toluene in it (judging by the smell). 2,4-DNPH test was negative.
Steam distillation was carried out in attempt to separate PhMe from said obtained liquid. First small fraction of distillate was containing colorless liquid with a density of <1 g/cm3 and strong smell of toluene. Shortly after, a heavier liquid started to distill (probably mix of toluene + some major impurity) and there was lots of crystalls in the condenser. At this point distillation was abandoned, after cooling there was visible crystalls in the distillation flask.
The crude yield of [presumably] toluene was around 15-20%, IIRC.

Later, smarter comrade gave me a clue, that those crystalls were probably hydrobenzoin, as this procedure I did is actually method for synthesizing it, with a good yield also.

(I have a reference for it, but it's in russian)

2,5-DMBA gave a red sticky resin (sticked to unreacted zinc); it was becoming liquid with action of strong acids. No signs of aldehyde with 2,4-DNPH test.
Steam distillation gave some (not more than ~10% yield) of colorless liquid with a strong aroma, quite pleasant one. After extraction, drying, evaporating of the solvent it gave a yellowish liquid that solidifies in the freezer but becoming liquid again at RT°. Strangely, it also had blue fluorescence in direct sunlight. Yes, 2,5-DMBA itself is known to have fluorescent properties, but 2,4-DNPH test was negative.
I think it might was impure 2,5-dimethoxytoluene judging by melting point (lit. mp. ~20°C); unfortunately, I had no other analytical tool at the time, and there was too little volume of said compound to run a distillation.

trying my best to write in english ;P

[Edited on 25-3-2019 by bipolar]

[Edited on 25-3-2019 by bipolar]

[Edited on 25-3-2019 by bipolar]

draculic acid69 - 26-3-2019 at 04:27

Quote: Originally posted by BromicAcid

"A couple of months in the laboratory can frequently save a couple of hours in the library. " - Frank Westheimer[/r

I like it.thats a good one.

Monoamine - 13-10-2021 at 18:14

Quote: Originally posted by Melgar

Nice find! Hope they are right.

macckone - 14-10-2021 at 07:08

one of the things mercury does, is regulate the reaction.
the mechanism isn't clear to me but it increases the yields for some reactions.
and it isn't just removing the oxide coating.

There is probably a paper out there that discusses possible reaction mechanisms.
In the clemmensen reduction mercury is not 'necessary' as the HCl will dissolve zinc just fine without it.
But it does improve yields.

One possible mechanism is reducing bubble size which would lead to better contact with the substrate being reduced. Another possible mechanism is actually interacting with the substrate in some manner. I am sure there are more.

S.C. Wack - 14-10-2021 at 16:06

It's not clear exactly when no-Hg does or does not give the desired products. It's been mentioned that sometimes no mercury is needed, in https://doi.org/10.1021/ja01500a029 (don't blink), my scan of Organic Reactions vol. 1 (at the end), and less briefly in https://doi.org/10.1246/bcsj.45.264; it seems that all anyone talks about in amalgam/Clemmensen reductions is anything but the role of Hg. Some reasons for Hg which have been floated are cleaning metal surfaces or lowering the rate of dissolving or influencing potential or the surface in some way (https://doi.org/10.1021/ja01653a034, https://doi.org/10.1016/S0040-4020(01)90501-0), but I wonder if amalgam reductions are different from many other dissolving metal and mercury cathode reductions, and the mercury is transiently directly involved in forming bonds.

Quote: Originally posted by Maroboduus

(Never could figure out why a guy with access to LAH and sodium borohydride and a Parr bottle and catalysts as well insisted on using mercury

Did Shulgin have a Parr, or use much hydrides after Dow? Maybe he went with what he was familiar with and had at hand.

Whoever was writing for "Psychedelic Frontier" and wikipedia probably has no clue.

Some things in his writing are not his experimentals and are straight from the literature (e.g. MDP2P) and I do wonder where the amalgam w/IPA reductive amination of same originated from exactly (ethanol is used in a French meth patent which itself is an extension of an older German patent) but it's probably in there because it was convenient for him. It's certainly inexpensive.