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formation of tetrazoles from ketones

Normally in Schmidt reaction of ketones, amides are formed however for some reason here further reaction takes place and a tetrazole is formed. Here is my try for this reaction mechanism (if my mechanism attempt is wrong please point out the mistakes and the proper mechanism):

reaction mechanism attempt

Relating to the mechanism, I have the following doubts:

  • Is this a special case of reaction or are tetrazoles formed with many different ketone reactions? If not, what makes this case special?

  • What are the driving forces in each step? Is the aromaticity the main reason?

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  • $\begingroup$ One particular question comes to mind. Do lactams react with HN3? You might check the stoichiometry in the Schmidt reaction. $\endgroup$
    – user55119
    Sep 28, 2020 at 19:58
  • $\begingroup$ Stoichiometry is fine I checked. It is reacting with HN3 after all. What about the mechanism I wrote? Does it seem ok? Or do you have a source with actual mechanism $\endgroup$ Sep 29, 2020 at 1:42
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    $\begingroup$ Hydrazoic acid, a weak acid, is usually prepared in H2SO4 from sodium azide. The initially formed amide (lactam) forms a nitrilium ion via the enol of the amide that is protonated with loss of water. Whether the addition of hydrazoic acid is stepwise or "electrocyclic" is at issue. Take a look. here: organicreactions.org/index.php/Schmidt_reaction_(2) $\endgroup$
    – user55119
    Sep 29, 2020 at 3:16
  • $\begingroup$ i understand the nitrilium ion formation. but you have presented 2 pathways one is electrocyclic and other is stepwise. i dont seem to get what mechanisms you have implied here. i tried drawing a mech where the N(-) part of hydrazoic acid attacks the nitrilium ion followed by a cyclic rearrangement(after a nucleophilic attack on the N in the cycle by -NH of hydrazoic acid. which one of your mechanisms is that? and what is the other one you think is possible. $\endgroup$ Sep 29, 2020 at 3:53
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    $\begingroup$ Stepwise means a terminal nitrogen of hydrazoic acid adds to the nitrilium cation then the nitrogen of the ring adds to the other terminus to close the ring. Some double bond migration will likely be necessary. Perhaps someone will speak to the hybridization of N3 in the ring closure. You can see the problem in your third to last structure. BTW, the synthesis of losartan employs trioctyltinazide or tritylazide addition to a nitrile. Probably electrocyclic in this case. patents.google.com/patent/US7915425B2/en $\endgroup$
    – user55119
    Sep 29, 2020 at 12:01

1 Answer 1

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It is true that normally in the Schmidt reaction of ketones, amides are formed as the major product (Ref.1). However, the products from the Schmidt reaction is highly depeends on the conditions used. The other byproducts include tetrazole and urea derivatives (Ref.2).

The mechanism for tetrazole formation given by OP is acceptable but it need harsh conditions such as the presence of $\ce{NaN3}$ and $\ce{POCl3}$ as the solvent at high temperature (e.g., Ref.3). Actually, during the Schmidt reaction of ketones, the formation of terazole should be taken place even before formation of the corresponding amide. According to the mechanism (Ref.4), there should be a nitrilium ion $(\ce{R1-C#N^+-R2})$ formation, which can be considered as a N-alkylated nitrile structure:

The mechanism for the Schmidt reaction

We all knows that a nitrile reacts with hydrazoic acid $(\ce{HN3})$ in the presence of sulfuric acid to give corresponding tetrazole (Ref.5). Thus, it can be envisioned that the additional hydrazoic acid molecule may react with the nitrilium ion to produce tetrazole compound as depicted in Ref.3:

The mechanism for tetrazole formation

Is this a special case of reaction or are tetrazoles formed with many different ketone reactions?

It is not a special case of tetrazole formation with cyclohexanone alone. As shown in the mechanism, it is possible to prepare a tetrazole from all kind of ketones (REf.2). However, it is note worthy that Hjelte and Agback have discussed that the formation of only tetrazole with $\alpha$-tetralone even with 1:1 ketone to hydrazoic acid ratio is due to the ring size (resistance to rearrange more stable six-membered to less stable seven membered). The have isolated $45\%$ of $\alpha$-tetralone unreacted (Ref.6).

References:

  1. Karl Friedrich Schmidt, “Process of making derivatives of hypothetical imines including amines and their substitution products,” U.S. Patent 1,564,631, 1925.
  2. G. I. Koldobskii, V. A. Ostrovskii, and B. Z. Gidaspov, "Application of the Schmidt reaction for the preparation of tetrazoles (review)," Chemistry of Heterocyclic Compounds 1975, 11, 626–635 (DOI: https://doi.org/10.1007/BF00959947).
  3. Rajendran Sribalan, Andiappan Lavanya, Maruthan Kirubavathi, and Vediappen Padmini, "Selective synthesis of ureas and tetrazoles from amides controlled by experimental conditions using conventional and microwave irradiation," Journal of Saudi Chemical Society 2018, 22(2), 198-207 (DOI: https://doi.org/10.1016/j.jscs.2016.03.004).
  4. Peter A. S. Smith, “The Schmidt Reaction: Experimental Conditions and Mechanism,” J. Am. Chem. Soc. 1948, 70(1), 320–323 (DOI: https://doi.org/10.1021/ja01181a098).
  5. Robert M. Herbst and Charles F. Froberger, “Synthesis of Iminotetrazoline Derivatives as Trichomonacidal and Fungicidal Agents,” J. Org. Chem. 1957, 22(9), 1050–1053 (DOI: https://doi.org/10.1021/jo01360a013).
  6. Nils S. Hjelte and Tamara Agback, “Benzocycloalkanones in the Schmidt Reaction,” Acta Chem. Scand. 1964, 18(1), 191-194 (DOI: 10.3891/acta.chem.scand.18-0191)(PDF).
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