Organic Reagents

By James Ashenhurst

Reagent Friday: Zinc Amalgam (Zn-Hg)

Last updated: January 29th, 2020 |

Zinc Amalgam (Zn-Hg)

In a blatant plug for the Reagent Guide and the Reagents App for iPhone, each Friday  I profile a different reagent that is commonly encountered in Org 1/ Org 2. 

What it’s used for: For our purposes, zinc amalgam (Zn-Hg) has one important use: in the Clemmensen reduction of ketones to alkanes.

Similar to: The reagent has essentially the same effect as the Wolff-Kishner reaction, although it is done under acidic conditions.

Examples: 

Zinc amalgam (Zn-Hg) is most commonly used in the Clemmensen reduction, which takes ketones adjacent to aromatic rings down to the alkane. This can be useful in, say, after the Friedel-Crafts acylation when you want to obtain a straight chain alkane that would otherwise rearrange.

use-of-zinc-amalgam-in-clemmensen-reduction-of-ketones

Note that the Clemmensen isn’t as effective on ketones that aren’t adjacent to aromatic systems, a sign that the reaction is probably proceeding through a carbocation or other electron-deficient intermediate that is stabilized through resonance with the aromatic ring.

How it works:

Amalgams are alloys of mercury and other metals. They are among the oldest of reducing agents, but their precise mode of action remains somewhat mysterious. I remember reading at some point that their mode of action is not unlike that of an electrochemical cell. In the Clemmensen, addition of acid protonates the ketone, and electrons from the Zn(Hg) are delivered to the carbon; the new hydrogens come from the acid, while the oxygen is eventually expelled as water.

Real life tips: Although I’ve never prepared zinc amalgam, for a good time, try making sodium amalgam through dropping liquid Hg into a beaker of molten Na in mineral oil. Watch that you don’t get splattered. Shulgin uses aluminum amalgam as the reductant of choice for taking ketones and aldehydes to alcohols. In PIKHAL I recall him describing the preparation of aluminum amalgam through cutting conventional aluminum foil into small squares and adding a solution of mercuric chloride in water.


P.S. You can read about the chemistry of Zn(Hg) and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF. The Reagents App is also available for iPhone, click on the icon below!

Notes:


(Advanced) References And Notes

  1. γ-PHENYLBUTYRIC ACID
    L. Martin Org. Synth. 1935, 15, 64
    DOI: 10.15227/orgsyn.015.0064
    A reliable, tested procedure for a simple Clemmensen Reduction that demonstrates how this reaction can be used to reduce a ketone in the presence of a carboxylic acid.
  2. Elrik Clemmensen: Reduktion von Ketonen und Alahyden su den entspcechenden Kohlenwaaserstoflbn unter Anwendung von amalgamiertem Zink und Salesaure.
    Clemmensen, E. Chem. Ber. 1913 46 (2), 1837-1843
    DOI: 10.1002/cber.19130460292
    The original paper by Clemmensen on the reduction of aldehydes and ketones with Zn metal in acid. Note that even though this was submitted to a German journal and written in German, Clemmensen was working at Parke-Davis, in the U.S.Two reviews on the Clemmensen Reduction:
  3. THE CLEMMENSEN REDUCTION
    Martin, E. L. React. 1942, 1, 155
    DOI: 10.1002/0471264180.or001.07
  4. CLEMMENSEN REDUCTION OF KETONES IN ANHYDROUS ORGANIC SOLVENTS
    Vedejs, E. React. 1975, 22, 401
    DOI: 10.1002/0471264180.or022.03
  5. Stereoselective total synthesis of (–)-pumiliotoxin C by an aqueous intramolecular acylnitroso Diels–Alder approach
    Masaichi Naruse, Sakae Aoyagi and Chihiro Kibayashi
    Chem. Soc., Perkin Trans. 1, 1996, 1113-1124
    DOI: 10.1039/P19960001113
    Clemmensen reductions can be used in total synthesis due to the mild conditions – in this case 34 to 35 is a Clemmensen reduction that selectively reduces a ketone in the presence of an amide.

 

Comments

Comment section

21 thoughts on “Reagent Friday: Zinc Amalgam (Zn-Hg)

  1. Wow, is like you’re doing all the reagents I’ve learned this semester, thanks for reminding me of this one for my final.

  2. I’ve actually performed traditional Clemmensen reductions a couple of times. They are very straightforward experimentally. Sometimes they work, and sometimes they don’t. That is organic synthesis in a nutshell. If we are talking about reducing aromatic ketones down to the alkane, I’ve had much better success with either Wolff-Kishner or with alane (AlH3 – prepared in situ from LAH and AlCl3).

    Regarding the mechanism for Clemmensen, it is indeed elusive. I’m fairly certain however that protonation of the ketone is NOT the first step. You would expect the alcohol as an intermediate (partially reduced ketone) if that was the case. It has been shown numerous times that a) not even trace amounts of alcohol are produced and b) alcohols when subjected to Clemmensen conditions are not reduced down to the alkane, which tells us that the mechanism is something else. I think that the foremost candidate today is a zinc-carbene intermediate, as depicted here. N.B. the single-electron transfer in the first step.

    Other than that, great post. Any student must know you cannot take any exam in organic chemistry, at any level, not knowing about Clemmensen. It’s one of those reactions you absolutely must know of. (But not the exact mechanism, because it is still unknown.)

    1. Cool! That’s strange, like I said I would have definitely expected the alcohol as a byproduct. I guess that means that benzylic alcohols wouldn’t be good substrates for the Clemmensen?

    2. What is the advantage of the Clemmensen/Wolff-Kishner reductions over the Mazingo reaction? Since the Mazingo reaction doesn’t impose acidic or basic conditions, it seems to be the more utilitarian choice on paper (have never run any of the reactions myself).

      Well, aside from the smell from the dithiol…

  3. My link above appears to be defunct; here is the full path to the proposed zinc-carbene mechanism again
    http://www.organic-chemistry.org/namedreactions/clemmensen-reduction.shtm

    Yes, I am quite sure that benzylic alcohols are inert towards Zn(Hg). To reduce these down to the alkane, one popular two-step method is i) conversion to the chloride with SOCl2 (which you just wrote about!) followed by ii) reduction with Raney-Ni/H2.

    Alternatively i) oxidation to the ketone followed by ii) Zn(Hg) or ii) Wolff-Kishner or ii) AlH3

    1. Benzyl alcohol can be converted to benzyl chloride with nothing but hydrochloric acid. If you don’t believe me, try mixing the two. With strong ventilation, of course.

      I don’t know if zinc amalgam would reduce benzyl chloride to toluene, or which if any other benzylic alcohols would similarly be converted to chlorides, but benzyl chloride would definitely form under those conditions.

  4. Can you tell that what happens if pyruvic acid is treated with Zn-Hg . Or for that matter what happens when any carboxylic acid is treated with Zn-Hg?

  5. Hi I don’t know why but for some Reason when I go and click the icon for the app for the IPhone it does not take me to the Application Do you know why?

    1. Amalgams are not unique to Zn, they can be made from many different metals (aluminium is an easy one to make, as is sodium). They are an alloy of mercury with various other metals and all have slightly different reduction potentials. Here we just keep things simple by using Zn amalgam for the Clemmensen. I’ve seen aluminum amalgam used to reduce ketones and sodium amalgam used to reduce sulfonamides for example.

  6. thanks for the information…
    Please tell me how does zn dust forms alkene(i came to know about difference in reaction for higher alkene but not sure if it is right)

    1. Zn dust forms alkenes in the haloether reduction. Essentially it reduces a C-X bond and then the lone pair of electrons gained by the carbon become a new pi bond with expulsion of an alkoxide leaving group.

  7. So if Zn-Hg contains mercury, does that mean it’s fairy toxic to work with? And what exactly is the proper way to dispose of it?

    1. Filter it off and put in a dedicated mercury waste container. Most labs have mercury waste receptacles and dispose of it through their department. In our lab, for instance, mercury thermometers would break from time to time, and we’d have a mercury waste container in which we’d place all the mercury as well as waste from making amalgams, etc.

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