Sciencemadness Discussion Board

Thiocyanation of Vanillin using Cu(ii) Advice

myristicinaldehyde - 13-6-2018 at 13:35

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

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.

https://doi.org/10.1002/cber.19620950731

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 415 times

EilOr - 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]

Gl3n - 30-6-2018 at 13:49

While I have never even taken organic chem I have picked some up through years of higher education and reading of things e.g. PiHKAL, very recently I was wondering about the possibility of using a thiocyanate as opposed to a halogen in the same sort of thing as it is a pseudo halogen. I would have to dig the references up but as it was only a week ago or so I should probably be able to find them. But one ref in particular seemed to indicate KSCN could be employed to transform a bromo substituted phenylalkylamine into a SCN group. I came across some online posts stating Br/KSCN had been attempted to no benefit. I seem to recall the journal article I saw applying to a finished phenylalkylamine and will try to find the original article as soon as I get the time at work.

myristicinaldehyde - 1-7-2018 at 07:51

I tried 2 thiocyanations, a Tetrahedron Letters article claimed I2/MeOH would work (it did not) and the decomposition of Cu(II) thiocyanate- which might have worked- but the workup is extremely tedious: the Cu(I) salt clogs and passes through the filters I have. I yielded a tiny, tiny amount of the flocculant yellow solid. It could be thiocyanogen is not quite reactive enough to add to vanillin, or more likely I botched the workup.

Any ideas on generating dry Br2 or Cl2 in acetic acid?

wildfyr - 1-7-2018 at 08:19

This is a bit of an ugly answer, but pyridine can be used to extract copper salts. Usually its done the other way around, copper sulfate is used to extract pyridine.

If you end up with some pyridine in the product from the wash, you can do a clean aqueous copper sulfate wash at the end.

myristicinaldehyde - 10-7-2018 at 12:03

An update: I prepared a putative Br2 solution using TCCA in glacial acetic acid, which was then filtered and dropwise added to NaSCN & vanillin.

Some notes so far:
- I used too little acetic acid for the NaSCN/vanillin which tends to form a bit of a paste (30mL).
- This paste impeded stirring.
- There is a marked color change, to a rich orange color (not bromine orange), and quite a bit of solid, which is probably a mixture of unreacted thiocyanate (see above) and NaBr as well as polymers and other junk.
- If any HCN is produced, it's not enough to kill me (yet).
Right now, the flask is in the heating before filtering step in Shulgin's procedure- this is to remove any polymers and waste which would crash out with our product if I were to add the flask contents straight away into water.