Sciencemadness Discussion Board

Chloroacetic acid from glycine or another bullshit patent?

NaK - 3-8-2020 at 11:51

Looking around for a more convenient chloroacetic acid preparation I found a german patent posted on this board claiming that it was possible to produce chloroacetic acid with a 50% yield from glycin when reacted with a 50/50 mixture of nitric acid and hydrochloric acid. Under nitrogen release chloroacetic acid is supposed to form which is extracted with ether and then distilled.

Compared to the nasty photolytic chlorination that sounds almost too good to be true, the price of glycine considered.

Can someone more experienced in organic chemistry comment on the general plausibility of this reaction? It kind of looks like a strange sandmeyer, then again they are using nitric acid and not nitrous acid so it might be someting else entirely?


Attachment: DE348671C.pdf (130kB)
This file has been downloaded 503 times

[Edited on 3-8-2020 by NaK]

Pumukli - 3-8-2020 at 12:17

I think this is a very good patent and what it describes is true.

You can see that the reaction is not simply between the amino acid and the nitric acid though! Always (in the examples) mixes nitric acid with concentrated HCl or HBr, so the reaction is between nitrosyl-halide and the amino acid!

The yields are probably tried and true.

What little I know about this type of reaction is this: use as high halide-ion excess in the solution as you can, because it improves yield (to a degree, of course). There's a marked increase in yield of bromo-propionic acid in the reaction between beta-alanine, NaNO2, H2SO4 and NaBr depending on the molar excess of NaBr to the amino acid. (There's a supporting paper around here somewhere on SM, I think I requested years ago. :) )
Also, glycine is the worst (lowest yielding) substrate, the longer chain amino acids all give higher yields. :)

NaK - 3-8-2020 at 13:07

Oh that makes sense, nitrosyl chloride formed in situ from hydrochloric and nitric acid. I looked around a bit more and found that chemplayer tried to make this work with nitrite and hcl, a more direct way to nitrosyl chloride and produced an unidentified unstable blue liquid. Maybe the presence of nitrite was causing this?

I think I will try this reaction on very small scale to see what happens

Fery - 3-8-2020 at 14:01

Pity that trichlorethylene was banned already years ago, its hydrolysis gives very pure monochloroacetic acid.

NaK - 3-8-2020 at 14:29

But what I still don't understand are the following things:
1. Why is there so much more nitric acid than hydrochloric? Should it not be the other way around (HNO3 + 3 HCl --> NOCl + Cl2 + H2O and the displacement of the diazo group also consumes HCl)?
2. How are they extracting with ether from a nitric acid solution and distilling afterwards without creating an indoor firework?
3. Why do they need to extract when they could just distill directly from the reaction mixture.

I'm not convinced yet....

clearly_not_atara - 3-8-2020 at 16:00

The stoichiometric reaction is not the physical reaction. The physical reaction is more like:

NO3- + HCl <> NO2Cl + OH-

NO2Cl + NO3- <> N2O5 + Cl-

N2O5 <> 2 NO2 + 1/2 O2 <> N2O3 + O2 <> 2 NO + 3/2 O2

2 NO2Cl <> 2 NO2 + Cl2

2 NO2 + Cl- <> NOCl + NO3-

2 NO2 <> N2O4 = NO+*NO3- "nitrosyl nitrate"

Aqua regia is used with a high concentration of Cl- to dissolve metals because Cl- acts as an effective ligand for heavy metal ions. Here ligation is irrelevant and chlorine evolution is undesirable. The ability of N2O4 to act as "nitrosyl nitrate" may also be relevant because N2O4 is already effective for diazotization:

https://pubs.acs.org/doi/pdf/10.1021/ja01689a027

and NO2 is significantly less volatile than NOCl. Overall, this means that the reaction with a higher proportion of HNO3 may be less inconvenient and dangerous, although probably not by much.

Also, it is not a 1:1 molar ratio. It is a 1:1 volumetric ratio of konzentrierter Salzsäure and konzentrierter Saltpetersäure as understood by German chemists from the Gilded Age. The konzentrierter Salzsäure is probably azeotropic, while the concentration of Saltpetersäure is actually indicated by its Gewicht of 1.4 which you may have guessed is specific gravity. However the specific gravity of WFNA is 1.51 so it turns out konzentrierter Saltpetersäure is not "concentrated" by the modern definition. The SG of 1.4 actually corresponds more closely to azeotropic nitric acid, 68% w/w. Additional work is required to find the true stoichiometry used in the patent.

The other problem I see here is that glycine may not be as conveniently available in the quantities desired by people making chloroacetic acid, which means that this and similar Sandmeyer-type preparations would not be preferred. The highly exothermic nature of the Sandmeyer reaction creates the potential to rapidly produce foam and release toxic gases, which makes it a relatively unpopular reaction, even for otherwise attractive targets like GBL.

Quote:
2. How are they extracting with ether from a nitric acid solution and distilling afterwards without creating an indoor firework?
3. Why do they need to extract when they could just distill directly from the reaction mixture.


While the combination of nitric acid and organic solvents is always dangerous, ether should not detonate spontaneously with sufficiently dilute nitric acid at sufficiently low temperatures. Most of the nitric acid should be consumed by rxn with HCl and the amino acid by the time you get to work-up. However, your concern is warranted, and the other reason is that in 1919 they didn't care as much about safety as we do in 2020. I would not recommend using ether for this workup; instead chlorobenzene or DCM may be a safe choice.

http://blogs.nature.com/stepwise/2013/10/01/caution-dont-mix...

draculic acid69 - 3-8-2020 at 17:55

Quote: Originally posted by NaK  
Oh that makes sense, nitrosyl chloride formed in situ from hydrochloric and nitric acid. I looked around a bit more and found that chemplayer tried to make this work with nitrite and hcl, a more direct way to nitrosyl chloride and produced an unidentified unstable blue liquid. Maybe the presence of nitrite was causing this?

I think I will try this reaction on very small scale to see what happens


Is this the liquid smurf your talking about

RadicallyStabilized - 3-8-2020 at 22:24

I have done this reaction and it runs well. The problem, as stated in the patent, is the isolation of the chloroacetic acid.

There are no especially noxious gases, however, the evolved nitrogen carries away some HCl so this need scrubbing or ventilation. There is definitely no blue side product like what chemplayer produced. That leads me to think that nitrosyl chloride may not be involved in this reaction. A very simple theory that arose from my limited understanding would be this:

The amino group of glycine is protonated making its carbon more delta-positive which is then nucleophilically attacked by Cl-. Ammonia is not that good of a leaving group but can be replaced by chloride, forming ammonium nitrite with nitrous acid which immediately decomposes into nitrogen and water at low pH and when heated. This is the step that drives the equilibrium towards the product.

Now this theory may be somewhat primitive but it is at least consistent with my observations so far. It also explains that the concentration of Cl- should be fairly high to increase the reaction rate. The patent stated yields to be quantitative but I found that there was still some glycine left after a few hours. One could try to add more HCl after some time.

I extracted with DCM and got a yield of about 40 % (on glycine) of the crude product. I didn't isolate it in pure form, however, and made a few mistakes along the way... Ether may be a better extraction solvent but I didn't have any. I only very recently found that a mixture of 10 - 15 % of IPA with a halocarbon solvent (DCM/chloroform) is supposed to be the most polar extraction solvent that is still immiscible with water, so for the next run I'd definitely try that.

There may be other possible improvements like concentrating the solution before extraction, partially neutralizing the stronger acids, direct distillation or whatever.

NaK - 4-8-2020 at 08:35

I just wonder why they extracted at all. I suspect side reactions from heating (vaccum distillation?) or tar formation. We'll see...

clearly_not_atara - 4-8-2020 at 13:20

"unstable blue liquid" sounds an awful lot like N2O3

Extraction is just easier; it was 1919, vacuum distillation equipment wasn't as good.

Jackpot

NaK - 9-8-2020 at 13:57

I got around to trying this experiment. I think it's awesome and if the workup goes as well as this then it really is great!


Here's what happened: Upon addition of the acid the mix got warm and a small amount of bubbling occured. After heating to around 90C it really took off with vigorous bubbling. I just let it sit on a hotplate until there was a distinct chlorine smell and I decided it was enough. Curiously the yellow color of aqua regia, which disappeared immediately after the addition, reappeared. So I think we even have a good color indicator for start and end of the reaction.

The real magic happened when I let it sit it for cooling and came back 30 minutes later: There was a really strange smell, a combination of sweat and vinegar and the contents of the beaker turned into solid lumb of crystals. I performed this experiment at 30 gram scale in a large beaker (beware the foam!) so the heat and nitrogen was enough to drive of quite a sígnificant amount of water (and HCl gas, caution!), which probably helped quite a bit and also means that it is possible to drive of the water/acids without any vacuum.


Verifying that what I had was actually the product and not just glycin I heated it up again. Lo and behold the crystals melted just around the 60C mark.


I'm really not used to experiments going better than expected so I am really excited to see if removing the rest of the acid/water is going to be as easy as this reaction. If it is...then this is just the one synthesis of chloroacetic acid: Cheap and available reagents, really quick, no dichlorinated product and very high in yield. And that without any vacuum distillation!

[Edited on 9-8-2020 by NaK]

[Edited on 9-8-2020 by NaK]

RadicallyStabilized - 14-8-2020 at 06:49

Very well done. How about a little more detailed writeup including quantities and yield? I'd like to do this reaction again, maybe we can find out how to optimize it.

Mush - 14-8-2020 at 16:01

DE348671C great patent!

Example 1.
Glycine to chloroacetic acid with 50% yield.

Example 2.
Leucine to 2-chloro-4-methylpentanoic acid (2-Chloroisocaproic acid), 90 % yield.

Example 3.
Leucine to 2-bromo-4-methylpentanoic acid , 85 %

Example 4.
Aspartic acid to 2-chloro-butanedioic acid (2-Chlorosuccinic acid), quantitative yield

The author also states that sodium chloride and bromide can be used to form hydrogen chloride and bromide in situ.

To understand the reaction mechanism see this study:

The Reaction of Nitrosyl Chloride with Aliphatic Primary Amines

Attachment: The Reaction of Nitrosyl Chloride with Aliphatic Primary Amines.pdf (370kB)
This file has been downloaded 508 times

NaK - 15-8-2020 at 08:53

Quote: Originally posted by RadicallyStabilized  
Very well done. How about a little more detailed writeup including quantities and yield? I'd like to do this reaction again, maybe we can find out how to optimize it.


When I'm done streamlining the process and extraction I will post a whole writeup

Meanwhile for everyone trying this: On larger scale always use a flask and a funnel style basic trap for the acid vapors. Especially chloroacetic acid vapors are really irritating for your lungs even in very low concentrations. It is most important to keep the time of exposure very short.



[Edited on 15-8-2020 by NaK]

[Edited on 15-8-2020 by NaK]

Mancival - 18-8-2020 at 17:24

NaK, how long do you keep the reaction going at 90 celsius, before workup? I seem to have many nitrogen bubbles developing even after 3h..

NaK - 19-8-2020 at 15:19

Well I suspect there is some decomposition going on, also boiling water, etc. My experience was the same and just picked some time to stop, I noted that the solution had turned slightly yellow. I have been out of town since I posted the long thing and have not been able to do a real workup yet, therefore no real writeup. Is it crystallizing on cooling?

Mancival - 24-8-2020 at 13:43

I think the crystallization on cooling is just a (possibly hydrated) nitrate or chloride salt of unreacted glycine, not the Chloroacetic Acid. The Chloroacetic Acid is in solution and needs extraction. With a partition coefficient Log(Kow)=0.22, it should be extracted quite easily with the right solvent. I used DCM and I obtained a 10% yield of MCAA after 3h heating at 90c (no reflux condenser, I was left with half initial volume). Huge amount of unreacted glycine salt crystallyzed upon cooling. Not sure if increasing time/temperature or adding a reflux condenser would improve yield. Patent is super vague.

NaK - 2-9-2020 at 08:02

Quote: Originally posted by Mancival  
I think the crystallization on cooling is just a (possibly hydrated) nitrate or chloride salt of unreacted glycine, not the Chloroacetic Acid. The Chloroacetic Acid is in solution and needs extraction. With a partition coefficient Log(Kow)=0.22, it should be extracted quite easily with the right solvent. I used DCM and I obtained a 10% yield of MCAA after 3h heating at 90c (no reflux condenser, I was left with half initial volume). Huge amount of unreacted glycine salt crystallyzed upon cooling. Not sure if increasing time/temperature or adding a reflux condenser would improve yield. Patent is super vague.


Yeah you're right, chloroacetic acid couldn't possibly crystallize with that much water around.

I found that in the run that I distilled water/acid off at atmospheric pressure there is a smaller amount of crystals, so increasing heating, time and also concentration of nitric (removal of water) seems to be beneficial.

The extraction yield could surely be improved by distilling off the water first, either at atmospheric or vacuum. Atmospheric obviously easier to set up, but from small experiments I think that the glycin salt would decompose before chloroacetic acid boiling point

The thing that I am struggeling with is the question, if this reaction could become an explosion hazard at any time, heating nitric and organics seems always like a bad idea. There is absolutely no information on the topic though.

For now I filtered off the crystals and vacuum distilled off the nitric and water. Now I am extracting with DCM just to see if I can extract any usable quantity. The glycin salt seems to be absolutely insoluble in DCM (which is good), so I added a bit of water again to break up the crystals. We'll see....

NaK - 2-9-2020 at 08:50

I just distilled off the dcm and I have crystals but they are brown and ugly. So long hot reaction also causes degradation. Looking at the prices just buying it seems much more worthwhile. The reaction definitely works but I don't think I have much time to explore it further.

[Edited on 2-9-2020 by NaK]