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Author: Subject: Thiocyanation of Vanillin using Cu(ii) Advice
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[*] posted on 13-6-2018 at 13:35
Thiocyanation of Vanillin using Cu(ii) Advice

A long time ago I came across this interesting procedure in Shulgin:


o an ice cold and well stirred solution of 15 g vanillin and 20 g sodium thiocyanate in 150 mL acetic acid there was added, dropwise over the course of 15 min, a solution of 16 g elemental bromine in 40 mL acetic acid. This was followed by the addition of 30 mL of 5% HCl and 300 mL EtOH, and stirring was continued for an additional 30 min. The mixture was heated to its boiling point, and filtered while hot. The mother liquor was diluted with an equal volume of H2O, which initiated the crystallization of crude 5-formyl-7-methoxy-2-oxo-1,3-benzoxathiole as a flocculant yellow solid. On filtration and air-drying, this weighed 12.5 g. After recrystallization from EtOH, the product was white and had a mp of 164 °C sharp.

Using Scifinder, I only came up with two references for this type of reaction, both in German. Fantastic.

Derivatives of 2-hydroxy-3-methoxybenzaldehyde
Archive of Pharmacy and Reports of the German Pharmaceutical Society (1964), 297, (4), 226-35. CODES: APBDAJ ISSN: 0376-0367.

I don't really want to work with bromine. If I understand the mechanism of the reaction, the bromine and thiocyanate ion produce thiocyanogen, which then reacts immediately with vanillin, and then undergoes an intramolecular cyclization: the phenol acts as a nucleophile and forms the benzoxathiole?

Well, Cu(SCN)2 also produces thiocyanogen. It is easy to prepare, & reasonably stable when dry- but when hot and wet it readily disproportionates. The attached paper describes using this as a thiocyanogen source. It isn't efficient- but I bought some thiocyanate essentially just for this kind of reaction, and I have a l o t of copper sulfate.

If anyone has experience with this sort of reaction, how worried should I be about any of the thiocyanogen producing HCN?

Attachment: The Aromatic Thiocyanation of 1-Alkoxynaphthalene by the Copper(II) Thiocyanate Method.pdf (357kB)
This file has been downloaded 11 times

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[*] posted on 13-6-2018 at 19:08

Very interesting stuff! Never thought or heard about using thiocyanates that way.

It has to be more reactive than bromine, otherwise the vanillin would be brominated, as bromine attacks vanillin already at quite low temperatures in acetic acid.
Thiocyanogen should be highly sensitive to water, so you have to work in quite dry GAA for good yields! Test it's melting point before using it!
(SCN)2 + H2O --> HSCN + HOSCN
I personally don't see a high risk of HCN production under the usual conditions I can imagine, but I would handle thiocyanogen with the same care as bromine due its reactivity.

2 SCN- - 2 e- --> (SCN)2
If you don't wan't to use bromine, why not using a waterfree but safer oxidising agent which should be stable enough in GAA, like sodium perborate, sodium persulphate, oxone, MnO2,.... Maybe it works even better and cleaner as no bromination-side-reaction could occur.
(EDIT: After a few minutes of googling I luckily found Syn. Comm., 31(19), 3041-3045 (2001) - They were using sodium perborate and ammonium thiocyanate in HOAc for thiocyanation with good results)

As vanillin is cheap, I wonder if you could make your target via the bromide (easily made from vanillin + alkalibromide like NaBr + oxidant like H2O2) and then swapping the -Br to -SCN with sodium thiocyanate using a PTC under reflux, like it's done for laboratory scale production of 4-fluorobenzaldehydes and 2-fluorbenzaldehydes (check US Patent 6,166,242 for instance).
Less elegant as it's a two-stage way and needs long reflux times, but maybe avoids some dangers. Just an idea ;)

[Edited on 14-6-2018 by EilOr]

[Edited on 14-6-2018 by EilOr]
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