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I was reading some reactions of ethers and I came across Zeisel determination. Later that day, I was asked to determine the products of the reaction :

enter image description here

And I made the product:

enter image description here

This reaction is standard Kucherov Reaction

Now my doubt is that ether linkage can get hydrolyzed under acidic conditions, so why can't the below product be formed?

enter image description here

Zeisel's method follows this mechanism, so then why can't it happen in this case?

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    $\begingroup$ Strongly acidic and a good nucleophile like $\ce{I-}$. $\endgroup$
    – Mithoron
    Jan 3 at 15:57
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    $\begingroup$ Aromatic methyl ethers are very robust and need specialist condtions to cleave them. 48% HBr in refluxing AcOH for example. $\endgroup$
    – Waylander
    Jan 3 at 16:09
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    $\begingroup$ @Buttonwood Ok yes I had an intutuion of this in my spine ,while I was reading the very first comments on this question. I am thankful for clarification of this and Please submit this comment as an answer and I will accept it $\endgroup$ Jan 4 at 1:17
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    $\begingroup$ @Buttonwood the ketone will do a neucleophilic addition reaction with HI I think.UNder these conditions right?? $\endgroup$ Jan 4 at 1:21
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    $\begingroup$ @Damstridium Pretty much yes. There is an explanation of the process in this paper chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/… $\endgroup$
    – Waylander
    Jan 4 at 7:44

2 Answers 2

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The Zeisel reaction as described here reads like submitting the substrate to refluxing $\ce{HI}$ with $\ce{HOAc}$. This seems much more aggressive than the oxymercuration conditions in the first scheme, where you need a bit of $\ce{H+}$ to transfer the intermediate enol into the more stable ketone by keto-enol tautomerism. Compare e.g., with an entry on Organic Synthesis:

enter image description here

(credit to Org. Synth. 1973, 53, 94)

which, in the case of acetylenic bonds looks like this:

enter image description here

(credit to Wikipedia)

Thus, in your case:

enter image description here

My anticipation (though speculation) is, the reaction conditions to cleave off the methyl ether easily knock-down the enolizable ketone.

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    $\begingroup$ Hydration of the triple bond is opposite that of the original example, which is the likely site of hydration. Mercuric ion hydration of triple bonds is catalytic, not stoichiometric. NaBH4 is not needed. Hydration of double bonds is stoichiometric and requires NaBH4 reduction. NaBH4 here would reduce any ketone present. $\endgroup$
    – user55119
    Jan 4 at 15:25
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    $\begingroup$ @user55119 Thanks for spotting that the other side was used. But based on the protocol by Org. Syn., are $\ce{C#C}$ triple bonds so much more susceptible to oxymercuration than $\ce{C=C}$ double bonds? I agree for the point of reduction of the ketone by $\ce{NaBH4}$. $\endgroup$
    – Buttonwood
    Jan 4 at 18:04
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    $\begingroup$ The story I heard, perhaps apocryphal, was that the hydration reaction was discovered by the accidental breakage of a mercury thermometer while stirring a vessel containing an alkyne and aqueous sulfuric acid lending credence to the catalytic nature of the reaction. BTW: A gold catalyst shows 100% regioselectivity for this substrate in favor of the anisole end. [DOI:10.1039/d1cc01837j ] $\endgroup$
    – user55119
    Jan 5 at 0:26
  • $\begingroup$ Teflon, the tube that was clogged; post-it, the super-glue that did not stick; penicillin, the Petri dish left on the desk; saccharin, the sweet taint on Fahlberg's coat when performing a coal analysis; LSD and Hofman's famous bicycle ride in Basle; nitroglycerine allegedly administered to Alfred Nobel (not as explosive, but to treat an angina); there are plenty finds not anticipated. «You can plan research, but not the results of research.» (Dieter Seebach in Angewandte Chemie, doi 10.1002/anie.199013201) $\endgroup$
    – Buttonwood
    Jan 5 at 9:03
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Demethylation of phenolic ethers generally requires some pretty extreme conditions. In verifying the structure of vanillin Tiemann and Haarmann (page 620) demethylated it successfully with dilute hydrochloric acid at up to 200°C. To illustrate the "usual" extreme conditions for demethylation, the authors first tried fuming hydroiodic acid at up to 130°C, but that gave an "amorphous, iodine-containing, black" decomposition product.

More recent work by Bomon et al. successfully used catalytic dilute HCl in an autoclave at up to 250°C to demethylate various phenolic ethers. The authors also give a very good review of demethylation reagents/techniques for comparison.

  • Tiemann and Haarmann, Ber., 7, 608 (1874)
  • Bomon et al., Green Chem., 23, 1995 (2021)

Funny how little has changed in those almost 150 years!

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