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Old Dec 10th 2017, 06:45 PM   #1
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Wink Schmidt reaction - advice on solvents

The question is about the chemistry of the carbon-carbon bond. My friend and I want to try a Schmidt reaction starting with an alkyl carboxylic acid and converting to an intermediate azide then hydrolysis of this via an intermediate isocyanate to the corresponding primary amine.

This is the 'Schmidt Reaction' if the process commences with the carboxylic acid directly, but there is an alternative 'Curtius Reaction' commencing with the acid chloride. The 'Curtius Rearrangement' seems to be the middle step from the carboxylic azide intermediate to the isocyanate (common to both reactions).

Safety-wise we think it's viable provided everything is kept chilled and dilute (<5% theoretical hydrazoic acid). We did a small experiment with a small amount of dilute (5%) chilled aqueous sodium azide and adding a little dilute HCl to see what the fumes were like. There's no sign of any fumes using ventilation but on allowing the reaction mixture to come up to room temperature you can detect a slight pungent aroma rather like 'metallic formic acid' coming from the mixture. It's powerful and even the slightest sniff does generate a slight 'alkyl nitrite esque' lightheadedness. So chilled and dilute and with good ventilation is clearly the way.

To give the game away the substrate we were looking to work with was actually ibuprofen. It's a isobutyl substituted 2-phenylpropionic acid derivative and so there are no other functional groups which should interfere. We don't have a use for the primary amine product; it just seems like an interesting and different reaction to try and something a bit challenging to get right and safely.

Time for some references; OrgSyn is always a good place to look at practical examples and learn:

Org. Synth. 1967, 47, 28 covers a preparation of cyclobutylamine from cyclobutanecarboxylic acid. This seems like a fairly archetypal reaction schema, but it's a non-aqueous reaction and uses chloroform as a solvent and with concentrated sulfuric acid + sodium azide.

On Google we found a very useful PDF entitled "4.4 Degradation Reactions by Takayuki Shiori" (obviously from a book / collection, but not sure which) which actually talks about 3-phenylpropionic acids (pretty similar) reacting readily via Schmidt and yielding the primary amine. Again, they suggest chlorinated solvents.

In fact most references we can find about performing this reaction use not an aqueous solution but a chlorinated organic solvent. There are some which refer to using aqueous hydrochloric acid however. For ibuprofen, water alone won't work for us since the substrate just isn't soluble.

So the questions:

1. Are chloroform / 1,2-dichloroethane etc. really safe to use with azides both in terms of explosion risk in dilute solution and in terms of reactivity? We read lots of horrific things about azides and dichloromethane and there are plenty of examples out there about azides reacting readily with chloro groups in compounds. Any other non-reactive non-aqueous solvents which might be safer?

2. We could try an alcohol/water mixture as a co-solvent if we can get the ibuprofen / sodium azide to dissolve - initial experiments suggest unlikely but we could keep trying. Or does the presence of lots of water somehow mess up this reaction? Water is after all generated as a byproduct of the reaction to form the isocyanate, but perhaps someone here knows better?

Any advice appreciated,kynix.
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