Author Topic: Hofmann Rearrangement Yields  (Read 3630 times)

dingbow

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Hofmann Rearrangement Yields
« on: July 30, 2011, 07:57:25 AM »
hello all,

After some experimentation with the rearrangement of an amide, I thought I might try my luck and see if I could get some guidance around increasing yields.

When I first attempted this reaction, yields were around 3-4% and the reaction did not run very clean at all and a lot of work up was required post reaction. After experimentation, I have finally ended up around the 25% mark with a much cleaner product, but this is still leaving me rather unsatisfied! Much amide is going to waste..

Anyway, the highest yielding reaction has been run something like this:
-add 1.2 molar excess of hypochlorite to an RB
-dissolve ~1 molar eq. of NaOH in RB
-Bring temperature down to  0-10ºc, then add all the amide
-add DH2O as required to allow good stirring
-maintian temp and stir for ~4hrs
-prepare a hot solution with 1 mole eq. of NaOH, and add to RB
-bring temp of reaction up to ~75ºc, maintain temp for ~20min
-extract with NP solvent, workup as usual

Now I recently tried to run it much like the below referenced patent, which basically encompassed 2 changes. One was to neutralise the excess hypochlorite with a 10% NaHSO3 solution, which actually gave a MUCH cleaner reaction (no polymerised looking goop to be seen) and the second change was dripping the reaction mixture onto a solution of hot NaOH. The latter change was not entirely possible, as the amide never fully dissolved like it does in the patent (even though I left it for 8hrs this time), so instead it was poured in portions from a beaker onto the hot NaOH solution. Now, whilst this was by far the cleanest reaction, the yield had in fact dropped from ~25% to ~10%. The other problem though, was that upon the completed reaction being let to stand, ~45% of the original amide crashed out and was recovered (some has always crashed out but I had not previously weighed it).

From this I concluded one of two things was happening, either the recovered amide had never been converted to the intermediate isocyanate, or alot of the formed isocyanate was reversing back to an amide during the rearrangement. I have no idea if the latter is even possible, but I made the assumption that the isocyanate was not forming explaining why it never completely dissolved in the solution.

So, can anyone provide some guiance on what could be done to bring up the yields :). I have seen on other forums claims of 60% being made, though I was unable to replicate it by following their procedure.

Any help is appreciated.

Reference: US Patent 7205440
« Last Edit: July 30, 2011, 08:12:24 PM by Enkidu »

jon

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Re: Hofmann Rearrangement Yields
« Reply #1 on: July 30, 2011, 09:39:19 AM »
i'm thinking if you can find a solvent for this you might be able to get better yeilds just a hunch.
there is an equilibrium between the isocyante and the cyanate.
i think if you dial in your temp a little higher to say 80 instead of 75 you can keep that equilibrium going.
i would use the rate of co2 generation as an indicator to what the optimal reaction temperature is.
what happens is the cyanate can polymerize into trimers.
« Last Edit: July 30, 2011, 09:42:59 AM by jon »

poisoninthestain

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Re: Hofmann Rearrangement Yields
« Reply #2 on: July 30, 2011, 06:46:57 PM »
EtOH or anothor polar alcohol of your choosing can better solvate the amide since the solubility of it in water is shotty. I have only experimented with EtOH and had a yield increase from 5-10% post workup. Temp control is the biggest factor i've found. With the colsolvent EtOH workup is a bit messier but worth it if you just got a buchner. sodium hypochlorite and calcium hypochlorite give roughly identical yields if done under proper conditions but the downside of bleach is that you gotta use a fresh bottle or yields are variable.  Perhaps try a PTC found in your favorite fabric softener i've heard good things.  This particular amide takes some tweaking to reach a 50% mark.

Enkidu

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Re: Hofmann Rearrangement Yields
« Reply #3 on: July 30, 2011, 07:42:33 PM »
Gene A. Hiegel, Tyrone J. Hogenauer
"Preparation of Methyl N-Substituted Carbamates from Amides through N-Chloroamides"
Synthetic Communications Volume 35, Issue 15, 2005 pp. 2091-2098 DOI: 10.1081/SCC-200066695
Quote
Amides are chlorinated on the nitrogen using trichloroisocyanuric acid, and the N?chloroamides are then rearranged to the corresponding methyl N?substituted carbamates by sodium methoxide in methanol.

If anyone one has a paper like the one above that doesn't use an alkoxide (I thought I had one), please post it.

Also,

Quote
Preparation and Diels-Alder reaction of a 2-amido substituted furan

http://www.orgsyn.org/orgsyn/prep.asp?prep=v78p0202

C. tert-Butyl N-(3-methyl-3-butenyl)-N-(2-furyl)carbamate. In a flame-dried, 500-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar and reflux condenser are placed  4.0 g (21.8 mmol) of furan-2-ylcarbamic acid tert-butyl ester  and  150 mL of toluene   (Note 11) under an argon atmosphere. To this solution are added  3.1 g (76.4 mmol) of freshly ground powdered sodium hydroxide  ,  6.04 g (43.7 mmol) of potassium carbonate  , and  1.48 g (4.4 mmol) of tetrabutylammonium hydrogen sulfate   (Note 12). The solution is heated at 80°C for 25 min with vigorous stirring and then  3.9 g (26.2 mmol) of freshly distilled 4-bromo-2-methyl-1-butene   is added as a solution in  10 mL of toluene  over a 30-min period. After being heated at 80°C for 30 min, the solution is charged with an additional  0.98 g (6.6 mmol) of 4-bromo-2-methyl-1-butene  . The mixture is heated at 80°C for an additional 1 hr. After the reaction is cooled to room temperature, it is quenched by the addition of 200 mL of water and the aqueous phase is extracted three times with  100-mL portions of dichloromethane  . The combined organic phase is dried over  magnesium sulfate   and the solvent is removed with a rotary evaporator at aspirator vacuum. The crude residue is purified by silica gel chromatography (  10% ethyl acetate-hexane  ) to give 5.0 g (91%) of  tert-butyl N-(3-methyl-3-butenyl)-N-(2-furyl)carbamate  as a colorless oil (Note 13).

The PTC isn't required, though you may have to tweak the ratios.

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #4 on: July 31, 2011, 12:28:52 AM »
i'm thinking if you can find a solvent for this you might be able to get better yeilds just a hunch...
i think if you dial in your temp a little higher to say 80 instead of 75 you can keep that equilibrium going.
i would use the rate of co2 generation as an indicator to what the optimal reaction temperature is.
Ive been thinking along the same lines, the problem is finding a suitable co-solvent. When I ran the reaction according to the patent I did actually dial in 80-85 degrees, since the patent said the higher temps were preferable to the rearrangement.

EtOH or anothor polar alcohol of your choosing can better solvate the amide since the solubility of it in water is shotty. ..Perhaps try a PTC found in your favorite fabric softener i've heard good things.  This particular amide takes some tweaking to reach a 50% mark.
The reason I havent used alcohol as a co-solvent is because it would seem to me that it would be oxidised to chloroform and consume the hypochlorite. Interesting that you note a yield increase, i'll give this a run and see what happens.

I actually tried using benzalkonium chloride as a PTC, with no change in yield unfortunately. Havent tried fabric softener yet, maybe I should look into that..

If anyone one has a paper like the one above that doesn't use an alkoxide (I thought I had one), please post it.

See attached, example 4. They replace the alkoxide with soda ash, bubble in the chlorine.
« Last Edit: July 31, 2011, 12:31:59 AM by dingbow »

dingbow

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Re: Hofmann Rearrangement Yields
« Reply #5 on: July 31, 2011, 12:44:10 AM »
Thought this was interesting, just reading the attached file to this post, they add the bisulfite seemingly after the rearrangement, where as in the US patent its clearly done before.

Enkidu

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Re: Hofmann Rearrangement Yields
« Reply #6 on: July 31, 2011, 04:45:01 AM »
Yeah, here's the one I have, which is a revision of the patent you posted. Of course there is a more facile method to prepare the N-chloroamide than working with Cl2.
« Last Edit: July 31, 2011, 05:39:06 AM by Enkidu »

letters

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Re: Hofmann Rearrangement Yields
« Reply #7 on: August 03, 2011, 04:41:56 PM »
dioxane is the solvent of choice in hofmann rearrangements. THF can work sometimes if the intermediate chloramide is reactive enough to undergo rearrangement at THF's reflux temps

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #8 on: August 03, 2011, 09:13:25 PM »
The method I was told to try by someone, I have yet to see posted anywhere. I'm running it now and will post my results. Being the first reaction of this nature I have ever ran I would be hard pressed to blame a bad yield on the parameters of the reaction, it's more likely due to my inexperience. However, I've had pretty good luck with every other reaction once I understood what it was doing and changed it around a little to suit my situation better.

The method I am trying now starts not unlike the op's. Reactants chilled to around -10c and the amide added after. The difference is I will never add heat and also I'm willing to give it a couple days. We'll see what happens.

Here it is as we speak. I don't think a single ice cube has melted and it's been almost 6 hours. Chemical wise I have all sorts of 'ines' and solvents too. I got plenty of amide to play with as well. I don't care about losing it, the experimentation is just too fucking awesome.
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jon

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Re: Hofmann Rearrangement Yields
« Reply #9 on: August 04, 2011, 12:29:47 AM »
hmmm drugs not food? man can't live on mda alone.
makes sense you want the chloramide to go to completion before you reflux it in base to the isoocyante.
remember bhopal?
methyl isocyanate nasty stuff.
25000 dead.
luckily it hydrolyses as fast as it's formed.

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #10 on: August 04, 2011, 01:20:03 AM »
You know better than to think I have any idea what I'm doing. The way this has went so far is, I have followed instructions to the letter, it has somehow failed everytime. I have then been able to apply that hands on knowledge to better understanding the reactions, make small but significant changes to better suit my situation and then I have pretty good luck. I'm doing the same thing this time, following instructions to the letter. We'll see what happens. I kept the food out of view from the camera. I eat people and I don't want any of you guys to recognize one of my meals.
"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

jon

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Re: Hofmann Rearrangement Yields
« Reply #11 on: August 04, 2011, 03:05:03 AM »
we don't care as long as it's mexican food we need the jobs.

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #12 on: August 04, 2011, 11:57:20 PM »
Does this look like amine to you guys in the bottom of the flask?
"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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akcom

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Re: Hofmann Rearrangement Yields
« Reply #13 on: August 05, 2011, 03:38:38 AM »
Looks like what I got when I tried (and failed) with OTC bleach.  Finally resorted to generating my own solution with much better results

jon

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Re: Hofmann Rearrangement Yields
« Reply #14 on: August 05, 2011, 04:16:21 AM »
he failed to mention he only stirred it and never refluxed it.
the hoffman rxn can't go without heat.
ohh and letters did you know most detergents
(liquid detergents) contain dioxane...
so it must be a handy solvent.
so according to akcom your going to have to bubble cl2 gas into NaOH
Cl2 gas is no fun to work with.
you can neutralize the overflow with a sodium bisulfite solution, of course you need a trap in line to the wash solution.
« Last Edit: August 05, 2011, 04:22:18 AM by jon »

Enkidu

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Re: Hofmann Rearrangement Yields
« Reply #15 on: August 05, 2011, 04:20:14 AM »
Yeah, that's a mixture of the amide and the N-chloroamide. The amine will be liquid.

jon

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Re: Hofmann Rearrangement Yields
« Reply #16 on: August 05, 2011, 04:23:14 AM »
indeed a yellow liquid with a sweet odor and taste.

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #17 on: August 05, 2011, 01:25:47 PM »
Okay, so holding true to form, my first try using these notes I have has yielded nothing (with the exception of the beckmann which showed me much love). I will try again today using heat.

jon, I was expecting a red oil, based on the notes I have. If I got a yellow oil I would probably stick a straw down in it in the bottom of my flask and just drink it all, right then and there.

Sorry to take a thread about a general reaction and bend it specifically to suit my needs, but then again I assume me and the op are doing the same thing.

Edit: jon, I did mention that I wasn't using heat.
The method I am trying now starts not unlike the op's. Reactants chilled to around -10c and the amide added after. The difference is I will never add heat and also I'm willing to give it a couple days. We'll see what happens.

akom, what do you make of what java said here?
http://www.psychonaut.com/post-34173.html?f=43&sid=312eea648a32530bbe629c0a8e1e46da&start=165#p216021
Quote
.and now to the hoffman . as i blindly tried the reaction, as i coined it the "cold method", in the cold with 50 % yield with some slight heating at the end to put the base into solution....other wise the amine base i've noticed is that brown powder that sits at the end when the hoffman is allowed to return to RT.
« Last Edit: August 05, 2011, 03:47:08 PM by reDEEMed »
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letters

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Re: Hofmann Rearrangement Yields
« Reply #18 on: August 05, 2011, 09:18:28 PM »
jon, i did not know commercial detergents contain dioxane. only bummer about dioxane is that it is next to impossible to distill it away from the reaction mixture in most cases, so it is not recyclable. THF can be used multiple times, since although it forms an azeotrope and is impossible to distill to dryness by itself, the wet THF that comes out of the rotavapor is suitable for reaction.
Regarding "active halogen" sources - bubbling Cl2 into NaOH just prior to reaction used to be the method of choice. I find that generating large amounts of chlorine needed for large scale is not my cup of tea. Liquid bromine is a suitable source and if the initial addition of amide to OBr(-) solution is slow enough yields are comparable. Still, liquid bromine is also not very nice to work with. it creeps through almost anything. normal glass joints do not hold bromine well.
There are other way to generate the active species insitu, all of them are easily accessible in the main journals. Think of the reagents used to halogenate aromatics nowadays. almost all of them are capable of producing the required oxidating species in the right conditions.
Since when i download articles they are tagged with an identifier i will not upload the refs, but here is a list of some interesting articles :
1. Amines Related to 2,5-Dimethoxyphenethylamine, Richard Baltzly, Johannes S. Buck, ,J. Am. Chem. Soc., 1940, 62 (1), pp 164–167, DOI: 10.1021/ja01858a047.
2. New Method for Direct Conversion of Amides to Amines. ,G. Marc Loudon et. al. J. Org. Chem., Vol. 44, No. 10, 1979, DOI: 0022-3263/79/1944-1746$01.00/0.
3. A Re-examination of Limitations of the Hofmann Reaction. Ernest Magnien, Richard Baltzly, J. Org. Chem., 1958, 23 (12), pp 2029–2032, DOI: 10.1021/jo01106a630.
4. Development of the Hofmann Rearrangement of Nr-Tosylasparagine through Calorimetric and NMR Analysis. Joseph S. Amato et. al., J. Org. Chem. 1998, 63, 9533-9534, 10.1021/jo980799l CCC: $15.00.
5. Nature of N-Bromosuccinimide in Basic Media: The True Oxidizing Species in the Hofmann Rearrangement. Chris H. Senanayake et. al., J. Am. Chem. SOC. 1994, 11 6, 7947-7948, 0002-7863/941/5 16-7947$04.50/0.
6. A Versatile Modification of the Hofmann Rearrangement. Radlick and Brown, Synthesis, 290-292, April, 1974.

Depending on the choice of amide and procedure, yields in a properly run rearrangement should exceed 80%. In the lit. you will many times see 60% and lower, this is due to no optimization done. Check out the industrial example in the articles, it gives a good insight into large scale.
Common yield killers in the hofmann -
instability of the reactants - your basically fucked unless you can find something mild enough, or choose a different route.
solubility issues - when the amide does not dissolve it can not react! when it dissolves it is either as a deprotonated species, or as is in an appropriate organic solvent. If there is not enough solvent, or no solvent at all, and the water solubility is low enough, the cyanate and amine will coextract each other into their phase and give you urea like products. this is very common when not using organic solvents!
inactivity of the oxidizing species - commercial bleach solution, even industrial ones are sometimes no good. some of them are old, others contain stabilizers, and others contain inactive surfacatants which can retard the progress of reaction. When using OX(-) it is best to make your own.

another option to increase the yields is to generate the carbamate instead of free amine, and the find a suitable way to deprotect. methyl carbamate are very easy to make, but are also very hard to cleave. LiOH in the microwave works well, but thats out of reach for most amateur drug cookers. a right choice of alcohol as solvent can give you an easily cleaved carbamate. benzyl alcohol comes to mind. never tried it, but im sure any reaction protocol can be tweaked to work with it. the product would be the benzyl carbamate, or CBZ, which is easily cleaved via CTH. yields in the carbamate synthesis are usually stellar!
« Last Edit: August 05, 2011, 09:27:31 PM by letters »

reDEEMed

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Re: Hofmann Rearrangement Yields
« Reply #19 on: August 05, 2011, 09:20:10 PM »
It sure looks like the same results to me and I have people telling me the precipitate is the shit it just needs to be extracted more thoroughly (shaken better) or allowed to sit and it will congeal into a single 'puddle'.

5.5gms of NaOH in 110mls of water were chilled to 0C. To this was added 11gms of amide and solution stirred until all of the amide was thoroughly mixed, it did not dissolve, of course. 138gms (145.25ml) of 6% bleach (chlorox) at room temperature was then added with stirring and heat started on 3. Solution went from grey to black to purple. Thirty eight minutes after heat was first applied the solution turned white (64C), four minutes after that light brown (milk coffee as it was once called), shortly after that (didn't record time) a dark crimson red. Finally, one hour fifteen minutes in the solution hit 80C. It was immediately removed from the hot plate and sat in a bucket of room temperature sand to cool.

It looks almost identical to what was given the first time. The only difference being a very slightly darker red at the end and a slightly darker precipitate. If there was any difference in the yield it was tiny, I would even say negligible.
"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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