Author Topic: Hofmann Rearrangement Yields  (Read 3632 times)

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #120 on: September 14, 2011, 01:28:53 PM »
Recrystalised and completely dry chloroamide (supposedly) failed in rearrangement, yielding the same crystaline white powder as previous runs. Im starting to get the feeling I dont have the chloroamide at all to begin with and the minute amount of amine I yielded last time was as a result of some residual minor chloroamide mixed into this unknown white substance im getting out of the TCCA reaction.

Whilst doing some research I came across this:
hxxp://www.sciencemadness.org/talk/viewthread.php?tid=4201&page=3#pid138509

A hofmann rearrangement with TCCA in one step without isolation of the chloroamide, very interesting indeed... I'll be surely giving this a run.

What I also noted was the use of cooling in the formation of the chloroamide, as per the standard hofmann rearrangement using hypochlorite. Interestingly, the reference I have used thus far, DOI: 10.1081/SCC-200066703, makes no mention of the need to cool the reaction. This makes me wonder if heat is the issue in the TCCA reaction and whether it needs to be kept cool, I can certainly tell you the reaction is fast if all the TCCA is dumped in at once and is quite exothermic. If I succeed with running the procedure as outlined in the SM link, i'll try forming and isolating the chloroamide again by doing the following:

-Dissolve amide in MeOH and into RB
-Cool solution to 0-10c
-Dissolve TCCA in MeOH and into dropping funnel
-Drip TCCA solution into amide maintaining 0-10c

If both are a success, a comparison of the yields will tell us if its worthwhile isolating the chloroamide or whether the one step rearrangement is just as good and saves time and energy. Though I dont want to get too far ahead of myself..
« Last Edit: September 14, 2011, 01:32:21 PM by dingbow »

b6baddawg

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Re: Hofmann Rearrangement Yields
« Reply #121 on: September 16, 2011, 03:14:58 AM »
reading that lots a bit confusing theres a few methods there.
AFAIK run like twodogs is good for 20% my dog never got more than 15, usually 5-10%
the tcca in methanol at the time was good to 35-40% cant remember what else added gave at best another 5%


the bisulphite hoffman ran dilute hit a sweet spot though

like in the patent, 3c is good temp to cool everything too prior to commencing
note heat is evolving as reaction commences, keep it down, had to add icecubes to keep temp below 3c. dont go too low and stop the reaction yet. after several hours the heat evolution ceases and solution temp drops.. NOW go to -9 -10c.
leave it stirring until the precipitate at the bottom turns from white to a yellow colour, might be 24 hour, might be 72hour (had a problem with naocl concentration which prolonged the reaction my dogs went longer due to this)
solution at this point should be golden yellow almost taking hint of orange.
allow to return to room temp on own accord.
add bisulphite to quench excess bleach. give a few hours for oil to fall out of solution.
separate the thick red sometimes slightly brown crude mda oil (you know how to work that up n recover unreacted amide yeah) its slightly yellow when done.

um the solution drip in the naoh 75c allow 15-20 mins from final addition before allowing to cool. n work up. screaming blinding white product
lie and say the yields shit, share the extra with friends
i just added the bits i thought might be missing from your practical whats killing yields
i hope that makes sense as in fills in a few gaps.

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #122 on: September 16, 2011, 03:24:27 AM »
The hofmann with TCCA works!

I ran this:
-5g amide
-1.9g TCCA
-250ml 10% NaOH solution

I had a somewhat different experience then the post at SM, temperature control seems to be quite important.

My solution seemed to level out ~8c in an ice bath, there was no change in colouration with the addition of TCCA to the basic solution. This could possibly be because I cleaned my TCCA of any CuSO4 before use.

It took some time and heavy stirring to dissolve the TCCA, even then not all of it dissolved, especially the larger chunks, which is something to consider next time.

At ~8c there was no visible sign that any of the amide was converting to the chloroamide and dissolving. Raising the temperature had a dramatic impact on this though and the solution cleared and visually it looked like 90%+ of the amide had dissolved, I assume because it had converted to the chloroamide. From here more heat was applied and rearrangement occured quite nicely, albiet at ~75c, rather then the 65c noted on SM.

Final work up is yet to be complete, but visually it speaks for itself! For a 5g amide run, I have never seen so many droplets of oil swirling around the flask, not only that but the reacion is soo much cleaner then a hypochlorite hofmann. No tar was formed at all. I have some high expectations for the final yield, which I will post once work up is complete..

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #123 on: September 16, 2011, 03:26:56 AM »
thanks for the info b6baddawg. I managed ~25% on my best run with the twodogs method, allowing 4hrs for chloroamide formation, then heating quickly for rearrangement.

WazOne

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Re: Hofmann Rearrangement Yields
« Reply #124 on: September 17, 2011, 01:58:35 AM »
that method seems to yeild no better than say 70-80 c.
Yeah i know that, but its pretty simple and doesn't need any fancy schmancy stuff like decadent hot plates and thermometers :D

I don't find workup difficult, my only sep funnel is 100ml, so i'm separating layers more manually from beaker to beaker... just clean the result as i mentioned.

I'd love to know what Waz is doing right to get those 50% + w/w yields... running 200g batches or something?

Shaking the fuck outta it.. And giving it the time it deserves to seperate. Remember once after waz added his 200ml of hcl to his xylene(40g batch) Based slowly over a few hours and let that sit till the next morning to find a good 5millimetres thick of honey coloured oil. Got 31g outta that batch.
Note: there has been times of complete failure.
The key is to be thorough and take your time.

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #125 on: September 19, 2011, 01:23:47 PM »
Final workup on the TCCA hofmann has been completed and the yield from a 5g amide batch is 2.4g amine.HCl or 46% molar. The non polar solution containing the amine was only gassed once, so I would imagine there might be a bit more in it, but not much.

I was hoping for a higher yield, but this is the best I have so far achieved with the hofmann and it gives a much cleaner product. I think theres a few things to try differently and see how it affects yields.

i'll probably trying isolating the chloroamide one last time, this time keeping control of the reaction temperature.

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #126 on: September 19, 2011, 01:38:56 PM »
One question though, looking at these two links:
hxxp://www.youtube.com/watch?v=mibv4bUarpE
hxxp://en.wikipedia.org/wiki/Hofmann_rearrangement

It seems to me that a hydroxide ion is necessary for the formation of the chloroamide. Given that "DOI: 10.1081/SCC-200066703" makes no use of NaOH in its reactions, does mean that the solvent is providing the hydroxide ion?

atara

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Re: Hofmann Rearrangement Yields
« Reply #127 on: September 20, 2011, 06:57:20 PM »
Hydroxide isn't necessary -- you can run a water-free Hoffman using NCS or NBS (N-chloro/bromo succinimide) in methanol. You do need a base though, and strong nucleophiles are bad.

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #128 on: September 21, 2011, 10:21:11 AM »
so the base is required for the deprotonation right, the reference I mention makes no use of a base so I dont understand how the chloroamide would be formed?!

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #129 on: September 21, 2011, 10:32:22 AM »
I'm not sure if this is the video I watched or not, if it is, it will show you the role the base plays. I can't play it right now to verify, but I'm almost positive that's the one.

hxxp://www.youtube.com/watch?v=mibv4bUarpE
"Ego is a structure that is erected by a neurotic individual who is a member of a neurotic culture against the facts of the matter. And culture, which we put on like an overcoat, is the collectivized consensus about what sort of neurotic behaviors are acceptable."
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dingbow

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Re: Hofmann Rearrangement Yields
« Reply #130 on: September 21, 2011, 11:24:26 AM »
Yeap, thats the one. As far as I can tell it clearly shows that deprotonation needs to occur before the chloroamide is formed, so im confused as to how its done in "DOI: 10.1081/SCC-200066703".

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #131 on: September 26, 2011, 11:27:47 AM »
I have now run the TCCA hofmann three times in total, with my last attempt yielding 3.9g amine.HCl from 5g amide, or 75% molar yield, in 2hrs total reaction time. I think at a larger scale, yields will improve slightly if only through minimised mechanical losses, but I think theres another few percent in the reaction parameters to be had.
VERY happy with this result :)

Through trial and error and some chance, the parameters of this reaction have become clearer. Temperature control is most important and interestingly for this particular amide, it seems that the temperatures requirements are quite different then was is written in any of the literature/references I have read to date.

I have abandoned the quest to isolate the chloroamide, this seems good enough to me. Monomethylation is the next goal. Thanks to everyones input, this thread has achieved what I wanted 8)
« Last Edit: September 26, 2011, 11:31:50 AM by dingbow »

letters

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Re: Hofmann Rearrangement Yields
« Reply #132 on: September 26, 2011, 04:24:18 PM »
can you please input the exact methodology you used so it can be replicated and tested?
75% without a co-solvent seems like a fantasy, and if you are using methanol as a solvent, then most likely you are getting a mixture of carbamate and free amine. I am willing to test the exact conditions you use and report back to the community

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #133 on: September 27, 2011, 02:00:33 AM »

oh people are still interested in this, thought I was posting to myself :D

In the spirit of sharing information and giving back to the community (im not a follower of the secrecy thing), here it is:

5g amide Batch
1.2 molar equivalent of TCCA
10% 250ml NaOH solution

-Cool solution of NaOH down to ~20c, if necessary.
-Add TCCA, stir vigorously until FULLY dissolved, this is important. Some very slight foaming will occur. Do no proceed until it is all dissolved.
-Add amide, continue stirring vigorously, while SLOWLY raising the temp to around ~25-30c. You know the chloroamide is forming when the solution is becoming clearer over time, this took about an hour.
-Once the solution is free of any solids and appears a somewhat opaque but still clear solution, raise temperature rapidly to 75c. Once this temperature is reached, hold for 30min.


Extract and workup as usual.

letters

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Re: Hofmann Rearrangement Yields
« Reply #134 on: September 27, 2011, 05:59:03 AM »
thanks. will try it as you suggest and report back.

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #135 on: September 27, 2011, 06:55:49 AM »
I don't think it's secrecy that keeps most people's lips sealed. I did at one time, but I have a different take on it now. I think it's more that people loathe the idea of someone who has not put forth any effort at all taking their hard work and reaping the benefits. Via pm I don't think I've came across a single person who was not willing to tell me anything they knew or had figured out. Of course there have been very few times when I asked anyone for that kinda help, but when I did, they were always very forthcoming and more than willing to share.

Anyway, I just thought I'd throw that out there lol.
"Ego is a structure that is erected by a neurotic individual who is a member of a neurotic culture against the facts of the matter. And culture, which we put on like an overcoat, is the collectivized consensus about what sort of neurotic behaviors are acceptable."
— Terence McKenna

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #136 on: September 27, 2011, 07:26:40 AM »
I can understand where they are coming from, no one wants a repeat of the hive saga and the effects on the supply of certain materials occurring again.

Having said that, I think we all take from the community in some way, I certainly wouldn't be here if it weren't for certain members who opened up some possibilities to me and i'm sure many many others. For that reason I feel obliged to share, on a give and take basis, even though complete anonymity used to be what I thought completely necessary.

I also realise theres many lurkers who will simply leach, but that's the nature of the game and I would not want it to detract from the concept of sharing and community.

fries

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Re: Hofmann Rearrangement Yields
« Reply #137 on: September 30, 2011, 04:18:33 PM »
Has anyone done any more runs with this tcca procedure? I'm wondering if yields are consistently good and if its easy to fuck up? If its robust and easy to get decent yields, i might give this one a go.

b6baddawg

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Re: Hofmann Rearrangement Yields
« Reply #138 on: October 01, 2011, 06:17:40 AM »
ah yes youve ran a dilute hoffman dingbow, nice yield. ive not seen it run with tcca
can i ask did you notice byproduct formation, eg yellow/orange floaties?  or tar?
im curious if after the tcca was dissolved with the naoh, before you added the amide did you cool the solution right down (2-5c) before beginning addition of amide and not raise temps till all was in solution?

if you scale that up have icecubes handy because amide addition is thermal as the scale increases and can become a yield killer.

(i base that suggestion on the hypochlorite not the tcca hoffman, i guess it will still apply)

the 2-5c comment is from various patents suggesting 0-5c as optimum addition of amide temperature. as i understand it with tcca the tcca must be dissolved slowly in solution at temp above 15c but am unsure if it can then be lowered as far as 0-5c afterwards and brought back up without smoking/runaway once the amide is in solution as the effect may be catalysed at 15c or thereabouts.
i hope that makes sense.
it will answer whether the amide all in solution in the dilute hoffman was what gave the good yield or the temps you used. the tcca yield i mentioned previously in a post had undissolved amide.
« Last Edit: October 01, 2011, 06:52:54 AM by b6baddawg »

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #139 on: October 02, 2011, 01:34:56 AM »
can i ask did you notice byproduct formation, eg yellow/orange floaties?  or tar?..

..im curious if after the tcca was dissolved with the naoh, before you added the amide did you cool the solution right down (2-5c) before beginning addition of amide and not raise temps till all was in solution?

if you scale that up have icecubes handy because amide addition is thermal as the scale increases and can become a yield killer.

...the 2-5c comment is from various patents suggesting 0-5c as optimum addition of amide temperature..

There were floaties, but it was mostly amine. One one occasion yielding close to 50% the amine was so clean it appeared as light yellow blobs of oil. On the highest yielding occasion, the amine was darker probably from some slight tar. It all dissolved easily in the non polar extraction though. No solid tar ever obtained, like I used to get with the hypochlorite.

Nope, it was never cooled down that far. I used to cool it down to ~8c, that seemed to be an equilibrium temperature that was reached with the amide added, cooled on an ice bath.

Unfortunately for me I have gotten to your post too late, as I tried scaling it up a bit and had some major problems! I scaled up without increasing solvent volumes and it seemed to have a dramatic effect. After adding the amide and leaving the reaction to allow the chloroamide to form, I returned to see how it was going expecting to see a somewhat clearer solution. Instead what I saw was an orange/red milky solution with a lot of solids undissolved, the temperature had risen to ~28c from around ~18c when I first added the amide.

I continued as usual knowing things had not gone well. Let me tell you, I have never seen so much tar in my life! I lost count how many filtrations and separations I had to do, not to mention I had to do 2x A/B as the final non polar extract was as black as the night. The A/B helped a lot and I now have a non polar extract which is much cleaner, ready for final work up (yet to be done, will post yield when complete).

The previous 3 reactions with TCCA yielded such a clean product that the extract could be converted to the hydrochloride without any clean up, only a final recrystalisation. Oh well, lesson learnt. Im guessing the smaller solvent to amide ratio meant the net effect on the temperature of the reaction was rather quite large and killed it.

Correct, thats what all the patents say. I dont know if its because they all use hypochlorite? But even when I ran with the hypochlorite, I never got a clear solution to indicate full conversion to the chloroamide when I ran it that cold. I can tell you right now that with TCCA, <10c the chloroamide is way too slow to form and is completely unnecessary.
« Last Edit: October 02, 2011, 01:37:13 AM by dingbow »