[daker]

Hey everyone!

I am currently working on a project regarding the synthesis of variously substituted isatins using the Sandmeyer methodology, involving the condensation of chloral hydrate, hydroxylamine and substituted aniline (in this case the 4-ethylaniline) to nitrosoacetanilide with following cyclization under strongly acidic conditions to give the isatin.

However, I seem to be stuck on the condensation reaction due to the prevalent formation of a tarry material which I have been unable to wash off, and which seems to cause problems in the cyclization-step, giving lower yields of sticky, impure product. If I follow the synthesis described in the following preparation: http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1p0327, I get an immediate formation of insoluble creme/brownish crystals upon addition of the aniline, which i assume is the aniline sulfate. However, after heating of the reaction mixture, the tar seems to form on/in the crystals. How can I prevent the precipitation of the aniline sulfate, to allow the acetanilide to precipitate, and could the precipitation of the aniline sulfate be the cause of the tarry compound?

[Dan]

Are you following the procedure exactly - i.e. heating to reflux over a period of 45 min, allowing reflux for 2 min and then cooling?
 
There is not much to go on from your description, but there is probably some detail that you've changed or there is something wrong with your reagents (check their purity) - OrgSyn preps are generally rock solid. If you are using a burner to heat the mixture, you need to keep any precipitate mobile with efficient stirring. The temperature of the vessel can become much higher than the solution and any residue that gets stuck to it might decompose. I would recommend a more controlled heating method, such as a thermostatically controlled oil bath. I might be tempted to try running the reaction at lower temperature for longer and monitor by TLC.

[daker]

Thanks a lot for the quick reply, good to have a second set of eyes/brain cells on this. 

I am not following the procedure exactly. In fact I am actually using an oil bath, as we generally don't use burners in my lab.
The round-bottomed flask I use for the reaction is equipped with a magnetic stirrer, but due to the great amount of precipitate it is quite difficult to prevent crystals from "clinging" to the side of the flask.
I am using an internal thermometer to monitor the reaction temperature, and I heat the reaction mixture to 60-80°C for 2-2,5 hours.
I use TLC for monitoring the reaction (eluent system: EtOAC/heptane 1:1), and it indicates the formation of 2 products with no trace of the aniline.
My starting aniline has been destilled under vacuum to give a yellow, clear liquid, rather than the almost black "pure" aniline.

The problem I am having is that I have seen pictures of other peoples reactions, and they all start out with a clear reaction mixture with the nitrosoacetanilide slowly precipitating, and I have an immediate formation of a large amount of crystals which does not go into solution again. See for instance how the reaction progresses in this video: http://www.youtube.com/watch?v=vprOtSxHNw8 (just pictures, at around 1:48).

[Dan]

Maybe try using the conditions in the video you posted

[daker]

I tried that as well, but the precipitation still occurred upon addition of the aniline. I have been working with this synthesis for almost a month now, and ¹H-NMR and LC/MS both show that I do indeed produce the correct product, albeit not pure enough to be used in the cyclization step. So far I have only tried the 4-ethylaniline, but I have access to a number of other anilines with far greater solubility in water than the ethyl compound. I currently have 3 ideas for further work:

1. Use a smaller amount of Na₂SO₄, or add it to the reaction mixture during heating.
2. Purify my isonitrosoacetanilide using column chromatography, however the tarry material is not easy to work with, and I would generally prefer not to do this.
3. Use a different starting material. I was thinking of trying 4-iodoaniline, as I was going to introduce some aromatic sidegroups by means of Suzuki coupling at some later stage anyway. Would I be able to synthesize the ethyl-analogue using a Suzuki coupling (if all else fails), and in that case which catalyst would be preferred?

[Dan]

So far I have only tried the 4-ethylaniline

I see now that you did mention this in your first post, but I missed it. Not all cakes are baked at the same temperature for the same amount of time. It should not be surprising that 4-ethylaniline behaves a bit differently compared to aniline and that the conditions will need tweaking. Look up a procedure for the preparation of the exact compound you intend to make - it is a known compound.

Maybe it would be a good idea to purify the oxime intermediate by recrystallisation before cyclisation?

[daker]

Look up a procedure for the preparation of the exact compound you intend to make

I have, and they generally use the same basic reaction conditions, albeit a bit lower temperature/longer reaction time. The 60-80°C I mentioned above actually comes from a preparation of 5-ethylisatin specifically, refluxing the mixture just produces a larger amount of tar. Lower temperatures generally give very low yields. I even tried using ethanol as a co-solvent and letting it slowly evaporate during the reaction, but no luck.
I also considered recrystallizing the oxime, however the tarry substance is apparently just as soluble as the oxime in ethanol and they both go in and out of solution at around the same time and temperature.

Like I said, I've been juggling with this synthesis for a bit, and I feel like I have examined and tested all variations of temperatures and reaction times.

Not all cakes are baked at the same temperature for the same amount of time

That's a pretty nice quote right there, I might just steal it...