Rich_Insane - 6-12-2012 at 20:52
I've been trying to manipulate oximes to synthesize amides lately, with little success. I was wondering this: How stable are oximes towards heat in
neutral (neither acidic nor basic) conditions? My procedure requires me to heat the flask containing the oxime to 110oC with a catalyst, but my most
recent trial involved formation of the oxime first, then addition of the catalyst five minutes following addition of a base and hydroxylamine
hydrochloride to the aldehyde.
I won't go into to much detail about my exact protocol, I'm basically more worried about the integrity of the oxime. Do oximes readily form the
dreaded "tars" so often talked about by organic chemists?
DJF90 - 7-12-2012 at 07:31
Have you checked by TLC for purity of starting materials? 0.5% CuCl2 in MeOH is a good stain for oximes. It looks to me like you're doing a Beckmann
rearrangement... Can you provide further details of the substrate/methodology? Given that caprolactam is made by this methodology on multi-tonne
scale, I have a hard time believing (at least in the case of this substrate) that this is a messy reaction.
SM2 - 7-12-2012 at 13:47
I'm just surprised Nico didn't move this to the Quick Questions forum!
Rich_Insane - 8-12-2012 at 15:02
I do not have access to TLC, unfortunately. All starting materials excepting the substrate (aldehyde substrate was purchased from a perfumery
supplier, sold as 99% pure however). My general procedure is to first prepare the oxime using hydroxylamine and sodium acetate. This is all solvent
free, but I do sometimes add ~5 ml of toluene to make things a bit more uniform. I then add a catalytic amount of copper sulfate pentahydrate and
rapidly bring the heat to 110oC in an oil bath. By the end of the reaction, I'm left with a brown liquid that quickly solidifies upon cooling to room
temperature. But not completely. It's much like a tar. Extraction with ethyl acetate followed by evaporation yields some absolute gunky gunk. A tarry
semi-solid that looks like a cross between motor oil and molasses.
This procedure follows pretty much everything from this particular paper: Tetrahedron Letters 53 (2012) 1413–1416.
I've found papers that suggest that copper sulfate does not work for this reaction (Tetrahedron Letters, 52 (33), pp. 4252-4255), instead suggesting
copper acetate.
kristofvagyok - 8-12-2012 at 15:16
Aldoximes on heating usually lost a molecule of water and they form nitriles. Here this also happens (check out the catalytic circle).
For making amides from aldehydes it much easier any cheaper to oxidize it to a carboxylic acid and bubble some ammonia through a solution of it and be
happy with the high end yield.
And just an advice: do not work with hydroxylamine without solvents, it could easily explode, especially if you make larger amounts.
Rich_Insane - 8-12-2012 at 15:37
According to that reference, the nitrile is a part of a catalytic cycle in which the copper (II) cation somehow destabilizes both the oxime and the
nitrile. So nitrile formation and dehydration of the aldoxime is fully intended.
As for the hydroxylamine, I knew it was highly reactive, but I did not know it was such a hazard. These people in the reference did not use a solvent
in the end, but they were working with amounts on the order of 1 mmol. I'll use a small amount of toluene as a solvent then.
kristofvagyok - 8-12-2012 at 16:52
I never ever belive 1mmol reactions. And according to your results it is not true. Both the amide, oxime and the nitrile is nearly colorless
crystalline and not a like a tar.
And use methanol as a solvent for the oxime formation, it is the best for this(:
Rich_Insane - 8-12-2012 at 17:33
Well here's what I'm doing with the last of my reagents (sadly I started before your reply):
Instead of CuSO4 straight up, I mixed CuSO4 (pentahydrate) with an equimolar amount of NaOAc (I know that Cu(OAc)2 would need 2 mol eq of NaOAc to
completely transform the CuSO4). Added a very small amount of water. Observed the pleasant opaque blue (lighter than the sulfate) coloration of
Cu(OAc)2. Upon addition of the hydroxylamine, I observed a thick oily white crystal form. As of now, I am seeing a white colored crystals (flakes)
form on the side of the flask. It could be anything (oxime, NaOAc or whatnot), but I take it as a good sign. I am not heating it consistently. I take
10 minute "cool" breaks. My hotplate is a cooking stove, so there is no temp. control. I want to avoid going beyond 120oC. I noticed heavy evolution
of something even before the BP of either water or toluene was reached.
There's also a strong, irritating odor of acetic acid. Not sure if that's a good sign or not.
[Edited on 9-12-2012 by Rich_Insane]
kristofvagyok - 8-12-2012 at 17:42
Hydroxylamine.HCl reacts with the NaOAc to form hydroxylamine base and acetic acid, that's the smell what you have noticed.
I would like to advice to ignore the one pot reaction, because this type of "mix everything and hope best" usually ends up with a gunk. Make the
oxime, purify it and then make the rearrangement.
Rich_Insane - 8-12-2012 at 17:45
I'll keep that in mind for next time. You're right, the one-pot does usually end up a mess. What solvent would you recommend for isolation and
recrystallization of aliphatic oximes?
kristofvagyok - 8-12-2012 at 17:50
Methanol, ethanol, THF/water, little acetone/much water.
Rich_Insane - 8-12-2012 at 17:55
OK, I will definitely do that next.
The reaction mixture is turning kind of red-brown. There's a bottom layer with a lot of tan/light colored crystals and a top layer that is liquid. I
continuously add more toluene to both cool down the reaction and ensure uniformity.
Since I do not have TLC, when should I stop the reaction?