Sciencemadness Discussion Board - Hofmann Rearrangement of 3,4,5-trimethoxybenzamide

Hofmann Rearrangement of 3,4,5-trimethoxybenzamide

DrDevice - 24-12-2015 at 23:02

Another experiment in a series to obtain various phenylhydrazines, this time with a benzamide as a starting material.

Drawing heavily on the procedure outlined in "The Hofmann Rearrangement Using Household Bleach : Synthesis of 3-Nitroaniline"(Monk, Mohan 1999), I attempted the reaction using 3,4,5-trimethoxybenzamide. There are other procedures in the literature for this compound (see note below), but the ease of using household bleach was a preferred approach.

Dissolve 3.2g (0.08mol) NaOH in 24ml of 12.5% w/v sodium hypochlorite solution. I calculated this to be 1.7M, but made no attempt to titre this more accurately. 24ml = 0.04mol NaOCl.

This solution was placed in an ice bath, 40g ice added & 40ml cold water. To this was added 8.0 g (0.038 mol) of 3,4,5-trimethoxybenzamide, with stirring.

(I initially tried this step without the ice cooling, but the reaction was quite exothermic and a black gunk resulted. Referring to the other papers, ice was used and then heating afterwards, and this approach seemed successful.)

Temperature was then slowly increased to 60C over 1 hour. After 1 hour, a solution of 5g NaOH in 5ml water was added, and the temperature raised to 70C with stirring continuing for another hour.

During this time, precipitate begins to form. On removal from heat, a mass of crystals form. This was filtered and washed with ice cold water. I believe some product did still dissolve during this washing, but no attempt was made to recover any dissolved product.

After drying 4.16g material was obtained. MW of 3,4,5-trimethoxyaniline is 183.2, so yield of 22.7mmol ie 60%, compared to the 80% yield in the referenced paper.

I didn't add the NaHSO₃ that was in the paper, as it seemed there was copious yield. I will attempt the experiment again with this step at some point to see what difference it makes ie to improve yield. I will also attempt recrystallization from ethanol.

I used this material in a later diazo experiment and it reacted in the typical way with sodium nitrite and sodium sulfite, so I am reasonably confident I obtained the desired result.

I have just gone looking for the exact reference to other papers - I thought was in OrgSyn, but buggered if I can find it now. I'll keep looking & will post it if I find it.

aga - 25-12-2015 at 01:31

http://www.prepchem.com/synthesis-of-3-nitroaniline/ ?

SunriseSunset - 24-1-2016 at 11:21

Nice workup! You said it yourself, you probably lost a little bit of yield through the filter wash. Why not just extract into a solvent then dry and salt out or evaporate to residue?

[Edited on 25-1-2016 by SunriseSunset]

DrDevice - 27-1-2016 at 02:37

Thanks for the comment. Yes, next time I will try a solvent approach. Ethanol has worked well for me in the past in other hydroxy and methoxy substituted anilines.

It's just been too damn hot to get back into the workshop...

byko3y - 27-1-2016 at 06:54

In nature there cannot exist 12,5% NaOCl solution. There can be "approx 10% solution", "I've just measured it to be a 7.3% solution", or "week ago it was a 5.7% solution".
You provided neither melting point measurement, nor crystalls, nor any other proof that you've obtained the correct compound. I believe you've got a mixture of carbamate and benzoate. I have no idea what's the purpose of the second portion of NaOH you've used, but I can definitely say the purpose of NaHSO3 - to hydrolyze the carbamate and destroy any chlorine left in the solution. You know, you can't just a add table salt instead of sodium nitrite into the reaction and hope the result will be the same.

DrMethyl - 27-1-2016 at 13:20

Hello, nice work indeed !

Dont worry, you often have less yield than in the paper.. byko3y is right take care about the conc. of NaOCl. Because Im lazy about bleach titration I always use calcium hypochlorite to be sure.

Did you check your final compound ? Did you try to dissolve into dil HCl to see wheter it dissolves ?

chemrox - 27-1-2016 at 14:15

@byko3y: what is the "bleaching powder" of commerce?

SunriseSunset - 27-1-2016 at 22:00

Would using calcium hypochlorite actually work?! I wondered about that but assumed it wont. Haven't got a chance to try it.

SunriseSunset - 27-1-2016 at 22:23

Quote: Originally posted by byko3y

I believe you've got a mixture of carbamate and benzoate. I have no idea what's the purpose of the second portion of NaOH you've used, but I can definitely say the purpose of NaHSO3 - to hydrolyze the carbamate and destroy any chlorine left in the solution. You know, you can't just a add table salt instead of sodium nitrite into the reaction and hope the result will be the same.

I'm curious why you'd say this when there's a decent number of references i could cite for you using simply a 2nd portion of NaOH or KOH.

They all pretty much start off with 2 part NaOH and 1 part NaOCl 1 part amide, then the writeups either include NaOH, KOH or 10% aq NaHCO3.

So unless I'm mistaken, he used the 2nd portion of NaOH to compensate the role of the NaHCO3. Which should of worked fine.

byko3y - 28-1-2016 at 08:48

chemrox, I don't understand your question, did you want to ask something like "what is in fact sold as bleaching powder?"? Sodium and calcium hypochlorites degrade over time, so when it says on the label "12,5% sodium hypochlorite" - it means "not higher than 12,5% hypochlorite". In fact in our shops the labels say "higher than 15% sodium hypochlorite", that means "it was higher than 15% sodium hypochlorite few month ago". AFAIK, the only non-gaseous product of decomposition of sodium hypochlorite is NaCl.
SunriseSunset, you are right, heating the carbamate with alkali hydroxide will hydrolyze the carbamate, but there was no rationalization in the OP's message.
Both calcium hypochlorite and sodium hypochlorite work the same, but they both decompose over time.

DrDevice - 29-1-2016 at 02:50

An influence on my procedure was the OrgSyn article on the preparation of 4-aminoveratrole, which in the second step also involves a Hofmann rearrangement, where a second amount of NaOH is added.

That procedure generates NaOCl directly with chlorine passed into NaOH solution - however, it was easier to do my home experiment with a bleach solution, and hence my use of the first referenced paper. No, I don't know what the purpose of the second NaOH addition in the 4-aminoveratrole paper is for.

byko3y, your point regarding bleach molarity is taken, and I'll be titrating next time. And adding NaHSO3.

Regarding the verification of the product, no I don't have a melting point etc. My evidence is indirect - a diazotization with NaNO2 was performed, with strong colours developing on addition of the nitrite. A near-exact amount of nitrite was required for the amount of aniline (as tested by starch/iodide), as is typical for a diazotization.

Subsequent addition of sodium sulfite resulted in a strongly yellow coloured precipitate typical of a diazosulphonate.

I'm just learning here, guys. My professional/educational background is electrical engineering and I'm only just getting back into a chemistry hobby I abandoned decades ago. Mostly developing lab technique right now and only gradually picking up the deeper theory...

DrDevice - 7-3-2016 at 02:34

I followed up on a couple of comments made in an earlier part of the thread, and repeated the experiment.

I titrated the bleach & determined it was 0.97M, and used an amount accordingly.

I built a melting point apparatus (a block of aluminium with a hole to place a thermometer into, heated with my heater/stirrer) and measured a quite sharp melting point of 110C (lit 110 - 114).

Subsequent diazotization & addition of sulfite to form a diazosulfonate worked smoothly, as before, as did a following reduction to the sulfonic acid using sodium dithionite. I'll post a procedure sometime.

I'm pretty sure I ended up with what I intended

Nicodem - 7-3-2016 at 08:39

Thanks for sharing. I would very much like to see it posted in the Prepublication forum section, once you get all the data and write a report.

chemrox - 23-3-2016 at 20:05

Quote: Originally posted by byko3y

chemrox, I don't understand your question, did you want to ask something like "what is in fact sold as bleaching powder?"?

I didn't want to digress so much. This is an actual organic chemistry thread and a good one. I would buy 3,4,5-trimethoxy benzaldehyde because I can and have. But this is about a rearrangement and I'd like to see it proceed and get optimized. But your question was what was I asking so here: I don't know bleaching powder. What is it? (I just learned from you it is Ca-hypochorite) why can't it be a solid, i.e. why is it so unstable? How much Ca-hypochorite is in "bleaching powder? So what I'm asking here is why is Ca-hypochorite unstable? But this is off-topic so if you want to say it could be in general chemistry or u2u. Thanks.

byko3y - 23-3-2016 at 21:12

Calcium hypochloride is as unstable as any hypochlorite is. It is less unstable when mixed (dilluted) with CaCl2 and kept at low temperature, also some compounds are more stable than others, still they degrade over time if stored at r.t./water vapors/light.

solo - 24-3-2016 at 06:32

Reference Information

The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline
Keith A. Monk and Ram S. Mohan
J. Chem. Educ.
1999, 76 (12), p 1717
DOI: 10.1021/ed076p1717

Abstract
The Hofmann rearrangement is an important example of a rearrangement reaction that is discussed in most sophomore organic chemistry texts. Yet very few examples of this reaction can be found in lab texts. We have developed a simple experiment that involves the Hofmann rearrangement of 3-nitrobenzamide to give 3-nitroaniline using household bleach. The synthesis of 3-nitrobenzamide by nitration of benzamide and the subsequent Hofmann rearrangement can be carried out in two-and-a-half hours, making this a new and simple two-step reaction sequence for the organic laboratory.

Attachment: The Hofmann Rearrangement Using Household Bleach- Synthesis of 3-Nitroaniline.pdf (16kB)
This file has been downloaded 1038 times

Boffis - 8-4-2016 at 08:19

Sorry I'm a bit late to the party but while researching something completely different (purpurogallin) I came across a detailed synthetic account of exactly the OP's requirement. If anyone is still interested check out:

J. Chem. Soc, [1951] p1318-1325; Critchlow et al; Purpurpogallin VI; The Mechanism of oxidation of pyrogallol

In the experimental section they describe the preparation of various starting materials in detail including exactly the OP's requirement and its conversion to 1,2,3-trimethoxy-5-iodobenzene via diazotization. So all the details you need; even the preparation of sodium hypochlorite from KMnO4 and HCl!!! What more could you desire?

DrDevice - 15-4-2016 at 22:20

Thanks for the further information, Boffis. However, I am actually pursuing hydrazines, rather than (eg) 3,4,5-trimethoxybenzaldehyde, so the amine was what I was after to form a diazo then reduce to a phenylhydrazines. And the use of liquid bleach is easier than faffing around with gaseous chlorine.

I'll put up my subsequent phenylhydrazine sulfonic acid prep some time Real Soon now...

The comments about the stability of calcium hypochlorite are interesting. Is the stability concern for solutions or the solid state? Calcium hypochlorite solid I thought was stable for years, and thus (as per DrMethyl's comment) safer to rely on for OCl- content. All the doomsday preppers out there swear by the long-term stability of solid calcium hypochlorite for water purification, and who are we to argue with them

BTW, I've put a tidied up version of the procedure in Prepublications.

Boffis - 16-4-2016 at 04:38

@DrDevice, you need to read the experimental section as it describes specifically the hofmann degradation you are trying to carry out ie the preparation of the trimethoxyaniline never mind the title subject. If you don't read you won't learn much.