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Thecriscoking
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[*] posted on 11-8-2014 at 17:34
Oxidative decarboxylation with TCCA


Hello all,

I would first like to say that this is my first post to this forum, though I have been lurking for quite some time. I was not quite sure where to post this, so the beginning section seemed proper. As I am fairly knew to this, if one finds any error in my calculations for preparing solutions, please let me know.

So, I'll dive right in.

Oxidative decarboxylation of phenylalanine with TCCA to phenylacetonitrile


References
An Insight of the Reactions of Amines with Trichloroisocyanuric Acid

Experimental from reference
The reported procedure is representative: L -Phenylalanine (1.20 g, 7.6 mmol) was dissolved in an aq solution of 2 N NaOH (3.8 mL) and treated with TCCA (1.17 g, 5.1 mmol) at 25 °C. After 10 min, when TLC analysis showed the complete absence of the L -phenylalanine, the reaction mixture was treated with HCl (15 mL), followed by an aq solution of 3 N HCl (2.5 mL). After 10 min the mixture was extracted twice with Et2O (15 mL). The organic layers were washed with H2O (10 mL), dried on Na2SO4 , filtered and concentrated in vacuo to yield 2-phenylacetonitrile (20, 0.87 g, 98%)

Actual Experiment

A 2N NaOH solution was prepared beforehand by dissolving 4 grams of NaOH into 50mL of distilled water and allowed to cool to 5°C. A 10mL solution of 3N HCl was prepared by diluting 2.9mL of conc. HCl to the specified 10mL. 1.2g of Phenylalanine was placed into a 10mL vial to which 3.8mL of the NaOH solution was added. The solution containing Phenylalanine was allowed to sit at RT with manual stirring every few minutes until completely dissolved. The solution was placed in the fridge until it was once again 5°C, to which it was taken out and placed in an ice bath. 1.1g of 99% TCCA was added in portions as to prevent any runaway reactions. About half-way through adding portions of TCCA, no signs of runaway occurred, so the remaining half was dumped into the solution. Some gas evolved, smelling of chlorine and (I believe) faintly CO2. This mixture was kept on an ice bath for roughly one hour with manual stirring every few minutes. The mixture was removed from the ice bath and 4mL of conc. HCl was added to the solution and the entire contents of the vial was transferred to a 125mL flask (as it was all I have to work with). The remaining 11mL of conc. HCl (to total 15mL as suggested in the reference) was added to the 125mL flask, with some used to rinse the 10mL vial. The solution was treated with 2.5mL of 3N HCl and allowed to sit for about twenty minutes. Since no Et2O was available, toluene (2x30mL, much higher than the references suggests) was used in place to extract from the mixture. The toluene was then dried over Na2SO4, decanted off into another 125mL flask.

This is my progress thus far, I simply need to recover the phenylacetonitrile from the toluene (granted the reaction took place).

Notes
-This was a small scale test to get the reaction down, ideally this could be scaled up with no issue.
-I have also read the WD thread pertaining to this exact experiment, but as far as I could tell, the chemist did not bother isolating the final product.
-The phenylalanine used was both the D/L- isomers, not the L-isomer used by the reference. I felt this wouldn't be a problem, as the nitrile formed is planar (?), void of chirality. Please let me know if this is false.
-Upon adding TCCA, I was unsure if much of it dissolved into solution. If I am not mistaken, there should be deposits of cyanuric acid when it has reacted? Would someone please clarify this for me.
-After total addition of the acid and the evolution of gas ceased, the smell took on a very familiar aromatic smell. Hard to explain, but it reminded me slightly of benzaldehyde.
-Upon extracting with toluene, the toluene took on a rich-piss looking color. Very yellow. When dried, it was transparent and looked like apple juice.
-Attached are some pictures during.

After partial addition of TCCA


Complete addition of TCCA


Close-up of solution in 125mL flask after acid addition (yellow oily substance floating about)


Precipitate after addition of acid


Some questions
-Since Et2O was unavailable, would toluene be a suitable alternative? I have read that nitriles will dissolve well in nonpolars, but I was not certain.

-I now, presumably, have a solution of BzCN in toluene. My next plan is to simply boil off the toluene, as it's B.P. is at least 100C less. Does this seem like a liable route?

-I understand that the NaOH was used to react the TCCA with the amine, but I am still unclear of the role of HCl. Was it used to simply neutralize the solution? If I recall correctly, no aromatic smell occurred until acid hydrolysis (terminology?).

End
----------------------

If there or any other questions I can answer or pictures of anything I may add to give some insight, please let me know. I hope I have done well in explaining my procedure.

Attachment: An Insight of the Reactions of Amines with Trichloroisocyanuric Acid.pdf (160kB)
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[*] posted on 11-8-2014 at 17:53


You could try using THF as a solvent instead of Ether.
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[*] posted on 11-8-2014 at 18:07


I have run this reaction several times following the literature procedure. I have not achieved the yields of phenylacetonitrile claimed, in fact far less. I do get a pleasant smelling liquid, just not much of it. Hypochlorite gives at least comparable results without the hassle of TCCA and its by-products.

AvB
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[*] posted on 12-8-2014 at 09:53


Quote: Originally posted by TheChemiKid  
You could try using THF as a solvent instead of Ether.


I will have to purchase some of this and give it a try. Thank you for the suggestion. I will likely also purchase the ether.

Quote: Originally posted by AvBaeyer  

I have run this reaction several times following the literature procedure. I have not achieved the yields of phenylacetonitrile claimed, in fact far less. I do get a pleasant smelling liquid, just not much of it. Hypochlorite gives at least comparable results without the hassle of TCCA and its by-products.


The yield is extremely low, no? The paper states 0.87grams, at 0.786 g/mL, this should only be about 1.1 mL. Not very much, but if I obtain even a few drops it could be chalked up as a success and maybe even scaled up. I have a good amount of Phe left, and buckets of TCCA, I may try to scale it to maybe 50g of Phe. If literature yields are correct, that's a good 62mL of BzCN, yes?

May I ask why you suggest hypochlorite? Is it because bleach is relatively cheap? Additions of TCCA wasn't too much of a hassle, very manageable gasses evolved.
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[*] posted on 12-8-2014 at 11:02


Quote: Originally posted by Thecriscoking  
Experimental from reference
...
After 10 min, when TLC analysis showed the complete absence of the L -phenylalanine, the reaction mixture was treated with HCl (15 mL), followed by an aq solution of 3 N HCl (2.5 mL).

That is an obvious error in the article. It should state that they diluted with water (15 mL) and treated with 3M HCl (2.5 mL).
Quote:
The mixture was removed from the ice bath and 4mL of conc. HCl was added to the solution and the entire contents of the vial was transferred to a 125mL flask (as it was all I have to work with). The remaining 11mL of conc. HCl (to total 15mL as suggested in the reference) was added to the 125mL flask, with some used to rinse the 10mL vial.

Why did you add concentrated hydrochloric acid? It makes no sense and can be detrimental given that the product is hydrolysable in acidic media. There is no mention of using conc. HCl in the article.
Quote:
Since no Et2O was available, toluene (2x30mL, much higher than the references suggests) was used in place to extract from the mixture. The toluene was then dried over Na2SO4, decanted off into another 125mL flask.

Toluene is a terrible choice. How are you going to separate it from the product?
You should use dichloromethane, MTBE, or ethyl acetate utmost. Anything higher boiling is impossible to rotavap away (unless you purge the residuals with a lower boiling solvent - in the case of toluene methanol can be used).

Quote:
-Upon adding TCCA, I was unsure if much of it dissolved into solution. If I am not mistaken, there should be deposits of cyanuric acid when it has reacted? Would someone please clarify this for me.

The NaOH is not in excess, so there should indeed be cyanuric acid precipitating and the reaction mixture should have become slightly acidic. Carbon dioxide should be forming. Since the media should slowly become acidic, good stirring should be used, or else you risk to have unreacted TCCA present (especially since this is usually granulated, rather than pulverized).
Quote:
-After total addition of the acid and the evolution of gas ceased, the smell took on a very familiar aromatic smell. Hard to explain, but it reminded me slightly of benzaldehyde.

The smell of phenylacetonitrile is a bit similar to benzaldehyde, at least as far as I remember.
Quote:
-Since Et2O was unavailable, would toluene be a suitable alternative? I have read that nitriles will dissolve well in nonpolars, but I was not certain.

Phenylacetonitrile is a liquid at room temperature and is soluble in practically all organic solvents.
Quote:
-I now, presumably, have a solution of BzCN in toluene. My next plan is to simply boil off the toluene, as it's B.P. is at least 100C less. Does this seem like a liable route?

Firstly, BzCN is not phenylacetonitrile, it stands for benzoyl cyanide instead. The correct shorthand formula is BnCN or PhCH2CN.
Secondly, toluene cannot just be boiled off from a liquid. You either have to rotavap, add portions of methanol and rotavap again a few times, or fractionally distill. There is no other simple way.
Quote:
-I understand that the NaOH was used to react the TCCA with the amine, but I am still unclear of the role of HCl. Was it used to simply neutralize the solution? If I recall correctly, no aromatic smell occurred until acid hydrolysis (terminology?).

You do not want to do any hydrolysis, if your goal is BnCN. The addition of HCl is more or less obsolete. In principle, the synthetic chemist would want to make sure to destroy any remaining N-chloroamine, as well as assure a low pH in order to fix any basic side products in the aqueous phase (amines such as the starting material). Dilute HCl will serve both purposes. However, the reaction mixture should already be acidic, because one equivalent of HCl forms during the reaction.
Quote: Originally posted by TheChemiKid  
You could try using THF as a solvent instead of Ether.

THF is miscible with water!




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[*] posted on 12-8-2014 at 14:19


Quote: Originally posted by Nicodem  

THF is miscible with water!

Yes. But even small amount of soluble salt (NaCl,Na2SO4,KNO3....) forces THF to salt out almost completely.

It is easy to remove toluene from benzyl cyanide by distilling it with water. Azeotrope water-toluene comes first at 85 C or so. Benzyl cyanide distills also with water but very slowly (~1 drop per ~10 cm3 of water). So at 95-98 C distillation can be stopped because almost all toluene is then removed.





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[*] posted on 17-8-2014 at 08:12


Nicodem, Thank you for clearing many things up. The error in adding HCl then dilute HCl had me confused for quite some time and I did not feel comfortable veering from the paper. The addition of the conc. HCl derived from my confusion in the paper asking for HCl then dilute HCl, where I assumed the initial HCl (15mL) was concentrated. Toluene was the only solvent readily at hand without having to wait days for shipping and such. DCM and Et2O will both be ordered very shortly.

A quick question: Why can toluene not be simply boiled off? I feel I am misunderstanding a key concept, as I thought due to the large difference in b.p., BnCN would simply be left as a liquid behind (with trace amounts of toluene).

kmno4, simply adding water (assuming equimolar amounts to the toluene) will allow the water-toluene azeotrope to distill over in full (read: relatively close to full)? I always assumed that only a small percentage formed the azeotrope. Any more information will be greatly appreciated.

I plan to scale the reaction up as soon as I get all the necessary solvents.
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[*] posted on 17-8-2014 at 10:30


In small amounts, Diethyl Ether is easily acquired. Just buy yourself a can of automotive Quick-Start fluid. I'm sure somewhere in the archives, there will be a procedure for isolating the Ether therein.
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[*] posted on 19-8-2014 at 09:04


Quote: Originally posted by Thecriscoking  
A quick question: Why can toluene not be simply boiled off? I feel I am misunderstanding a key concept, as I thought due to the large difference in b.p., BnCN would simply be left as a liquid behind (with trace amounts of toluene).

Because as you evaporate the toluene, its molar fraction reduces, which causes its partial pressure above the liquid to drop. For this reason, it is not possible to efficiently remove such high boiling solvents from liquid or amorphous products using a rotavapor or other evaporation devices with limited heating and vacuum control. See Rault's law for details.
For removal of solvents like toluene from liquid products, or particularly from the annoyingly nasty resinous products, methanol can be used to purge the residual toluene with its vapors. In practice, any lower boiling solvent can be used for purging a higher boiling solvent away, but synthetic chemists prefer using azeotrope forming solvents expecting a better efficiency (methanol for toluene, water for pyridine, etc.).




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[*] posted on 25-8-2014 at 22:29


Quote: Originally posted by Thecriscoking  

kmno4, simply adding water (assuming equimolar amounts to the toluene) will allow the water-toluene azeotrope to distill over in full (read: relatively close to full)? I always assumed that only a small percentage formed the azeotrope. Any more information will be greatly appreciated.

No - water should be in large (molar) excess, then all toluene is removed, leaving your nitrile (or anything high boiling) + water in flask. It is good method for removing small amounts of solvent from heat-sensitive or/and high-boiling compounds(s), because temperatures during dist. are never higher than 100 C.


In this way I removed traces of benzaldehyde/nitromethane from raw beta-nitrosyrene. By the way, I 'discovered' that beta-nitrostyrene also can be distilled with water(steam), but rather in not very efficient manner: about 2-3g per 100g of distilled water.
But such product is very pure, completely stable in air, not changing its colour and getting sticky or giving off benzaldehyde.




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[*] posted on 27-8-2014 at 10:33


Very interesting, I've never heard about this method before.

Might it also work on Tryptophane instead or would the TCCA also oxidize the indole ring?

PS: Could be also a novel (maybe even one-pot) route to NN-Dialkyl substitutet trypamine derivates from subsituted trypamines, by simply reacting the NN-dichloride intermediate with the corresponding alkoxide, right? (At least if the TCCA doesn't destroy the indole ring). Would be a quite funky and easy way of NN-dialkylation.
Any thoughts about this?

[Edited on 27-8-2014 by Reregister]
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[*] posted on 27-8-2014 at 13:48


I would guess that the indole would get oxidized, probably at the 3-position. But maybe a way could be worked around it. I believe that there is a report on Rhodium on forming the Strecker degradation product (indol-3-yl acetaldehyde) by reacting with very dilute hypochlorite. So maybe this oxidative decarboxylation could work if similar precautions are taken. Experiment will tell.

I think alkoxide would just act as a base and form the elimination product (nitrile). I'm pretty sure that the alkylation you speak of wouldn't (couldn't) happen. At most, the alkoxide would substitute at oxygen rather than carbon.

[Edited on 27-8-2014 by Crowfjord]
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[*] posted on 18-3-2015 at 07:35


I almost have my bench built, so I figured I would have some down time.

I have Na-DCCA, and had some phenylalanine pills on hand, and wanted to attempt the oxidative decarboxylation of an alpha-amino acid. I decided to use Na-DCCA, as opposed to TCCA, and skip using a base and see if the phenylalanine would still go into solution. It did, and did so very well! I used about 5g of phenylalanine, and upon each addition to the Na-DCCA in water there was a lot of off-gassing and heat. The mixture started turning very yellow, almost orangish. Even upon the first addition, an extremely nauseating smell of rose, or some other floral scent, brutally emanated from the flask (you are seriously warned--I was also stupid for not attempting this is a closed system).

I wasn't planning on actually doing anything with the product, so I used toluene to attempt to just see if I could separate the colored oil from the mixture, and wow, did it. The toluene took on a very deep yellow-orangish color. I wasn't in an analytical mood as it was late at night, and hadn't weighed out anything, so the Na-DCCA could have been very much in excess. I also didn't weight the starting toluene to be able to compare it to the final solution to determine how much had been solvated. After this, I really don't care, and don't plan on attempting it again!

The problem: As I was disposing of the experiment this morning, I became very aware of lachrymatory effects that I hadn't seen mentioned before. Suddenly, my eyes and the skin around my nose were burning! Is it likely that an excess of Na-DCCA proceeded all the way to the chloride, or possibly even a chloride with the same length carbon chain? Or are these effects known?

I still feel like I am covered in rose vomit! I think I might go throw up now. :o

[Edited on 18-3-2015 by Loptr]

[Edited on 18-3-2015 by Loptr]
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[*] posted on 19-3-2015 at 06:05


I would guess that you made some benzyl chloride as a by-product. It is a potent lachrymator, and some people can be sensitized to it and similar compounds (Bz chloroformate is particularly bad) which make them even more potent. When you have certain benzyl groups and a chloride source, there is a chance to make some benzyl chloride. I would guess than the cyanide can act as a good enough leaving group to be displaced by chloride, which is also present.
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[*] posted on 19-3-2015 at 06:50


I've worked with phenylacetonitrile before, and remember it has a very penetrating odour sort of in-between that of benzaldehyde and phenylacetic acid. I tried to minimise contact with it due to the fact it is an R26 (T+) compound, and whilst I don't recall any lachrymatory effects, it was handled appropriately in a fumehood. However, the Aldrich MSDS suggests a "burning sensation" as a symptom of exposure.
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[*] posted on 20-3-2015 at 02:14


its funny that TCCA would oxidise phenylalanine to phenacetonitrile while bleach will oxidise it to the aldehyde,I thought TCCA was much more powerful that bleach:o
Quote: Originally posted by Reregister  

Might it also work on Tryptophane instead or would the TCCA also oxidize the indole ring?

Quote: Originally posted by Crowfjord  
I would guess that the indole would get oxidized, probably at the 3-position. But maybe a way could be worked around it. I believe that there is a report on Rhodium on forming the Strecker degradation product (indol-3-yl acetaldehyde) by reacting with very dilute hypochlorite. So maybe this oxidative decarboxylation could work if similar precautions are taken. Experiment will tell.

here is that report
http://www.sciencemadness.org/talk/viewthread.php?tid=39224
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[*] posted on 27-4-2015 at 14:05


I thought this might be helpful if added to this content.

The Oxidation of Amino-Acids to Cyanides
H. D. Dakin. Biochem. J. 10, 319 (1916)

This paper establishes the cyanides are produced by the decomposition of previously formed dichloroamino-acids, and are as follows.

R-CH(NH2)-COOH --> R-CH(NCl2)-COOH --> R-CN + 2HCl + CO2

So it seems that an excess of hypochlorite is is required to form the dichloroamino acids, otherwise it seems aldehydes are the products.

Attachment: The Oxidation of Amino-Acids to Cyanides_Dakin.pdf (462kB)
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[Edited on 28-4-2015 by Loptr]
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[*] posted on 28-4-2015 at 03:11


Quote: Originally posted by Loptr  
I thought this might be helpful if added to this content.

The Oxidation of Amino-Acids to Cyanides
H. D. Dakin. Biochem. J. 10, 319 (1916)

This paper establishes the cyanides are produced by the decomposition of previously formed dichloroamino-acids, and are as follows.

R-CH(NH2)-COOH --> R-CH(NCl2)-COOH --> R-CN + 2HCl + CO2

So it seems that an excess of hypochlorite is is required to form the dichloroamino acids, otherwise it seems aldehydes are the products.


Holy crap, I love that it is nearly 100 yrs old.
Good info.
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[*] posted on 28-4-2015 at 06:54


Quote: Originally posted by morganbw  
Quote: Originally posted by Loptr  
I thought this might be helpful if added to this content.

The Oxidation of Amino-Acids to Cyanides
H. D. Dakin. Biochem. J. 10, 319 (1916)

This paper establishes the cyanides are produced by the decomposition of previously formed dichloroamino-acids, and are as follows.

R-CH(NH2)-COOH --> R-CH(NCl2)-COOH --> R-CN + 2HCl + CO2

So it seems that an excess of hypochlorite is is required to form the dichloroamino acids, otherwise it seems aldehydes are the products.


Holy crap, I love that it is nearly 100 yrs old.
Good info.


morganbw
Yep, next year. The author refers to previous work on the subject, which would have to be even older.

Langheld [Langheld, 1909] only went as far as the monochloroamino acids, which yielded the corresponding aldehydes after hydrolysis. So if using stoichiometric amounts of HOCL yield aldehydes by way of the monochoroamino acid, then two equivalents should result in the nitrile.

I am not sure of its reliability, but I have read in Advances in Taste-and-Odor Treatment and Control that the highest level of phenylacetaldehyde was produced in water treatment plants when the chlorine-to-amino acid ratio was 1.5, under neutral conditions, and a reaction time of 2 hours.

Page 85, taken from Hrudey et al. (1989)
https://books.google.com/books?id=mBnKIRVt4JIC&lpg=PA81&...

[Edited on 28-4-2015 by Loptr]
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[*] posted on 12-2-2017 at 15:10


I have been reading up on this reaction for the preparation of malonic acid from aspartic acid, but I think I have found a problem with the experimental as stated.

The procedure for phenylalanine uses two equivalents TCCA, three equivalents of NaOH, and three equivalents of amino acid. However, unless I am mistaken, the reaction proceeds by dehydrohalogenation of a dichloroamino acid intermediate. This will end up producing six equivalents of HCl! Wouldn't this lead to problems with the reaction going to completion, or am I missing something?
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[*] posted on 12-2-2017 at 17:36


Quote: Originally posted by Cryolite.  
I have been reading up on this reaction for the preparation of malonic acid from aspartic acid, but I think I have found a problem with the experimental as stated.

The procedure for phenylalanine uses two equivalents TCCA, three equivalents of NaOH, and three equivalents of amino acid. However, unless I am mistaken, the reaction proceeds by dehydrohalogenation of a dichloroamino acid intermediate. This will end up producing six equivalents of HCl! Wouldn't this lead to problems with the reaction going to completion, or am I missing something?

Cyanoacetate hydrolysis to get malonic acid...nice.

Where did you get those numbers? Into the article they say into the amino acid halogenation "2/3 TCCA"...that is 3 times less than what you wrote.

The production of acid medium with TCCA is forbidden for safety reason...explosive NCl3 formation...so always with a slight exces base.




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[*] posted on 12-2-2017 at 19:44


It's two equivalents of TCCA for every three of the amino acid. That is equivalent to 2/3 mol eq of TCCA, but its easier to write it with whole numbers.
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[*] posted on 12-2-2017 at 20:00


Quote: Originally posted by AvBaeyer  
I have run this reaction several times following the literature procedure. I have not achieved the yields of phenylacetonitrile claimed, in fact far less. I do get a pleasant smelling liquid, just not much of it. Hypochlorite gives at least comparable results without the hassle of TCCA and its by-products.

AvB


That's interesting. I have 20 grams of phenylalanine, but I was kind of planning on using it to try to make phenylacetaldehyde by hypochlorite oxidation and was unaware that any benzyl cyanide might be produced... do you have a literature reference for this?




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[*] posted on 12-2-2017 at 20:12


Quote: Originally posted by Cryolite.  
It's two equivalents of TCCA for every three of the amino acid. That is equivalent to 2/3 mol eq of TCCA, but its easier to write it with whole numbers.

Quoted from last page of first document:
L-Phenylalanine (1.20 g, 7.6 mmol) was dissolved in an aq solution of 2 N NaOH (3.8 mL) and treated with TCCA (1.17 g, 5.1 mmol) at 25 °C
--> amino acid 7,6 mmol
--> NaOH 7,6 mmol (2 mole/l = 2 N = 2000 mmol/l = 2 mmol/ml so 3,8 ml = 7,6 mmol)
--> TCCA 5,1 mmol (= 2/3 equivalent = 5,1 mmol /7,6 mmol)

The formed dichloride will thus be 7,6 mmol and it will set 15,2 mmol of HCl free to form the nitrile.
To neutralise this you have 7,6 mmol of NaOH what is insufficient as you stated.

Maybe that one of the product of reaction is also helping neutralization?
(-NCl-CO-)3 + H2N-CH(CO2H)-CH2-Ar --> (-NH-CO-)3 + Cl2N-CH(CO2H)-CH2-Ar
Cl2N-CH(CO2H)-CH2-Ar -2 NaOH-> 2 NaCl + N#C-CH2-Ar + CO2(g)
(-NH-CO-)3 + H2O + HCl --> NH4Cl + CO2



[Edited on 13-2-2017 by PHILOU Zrealone]




PH Z (PHILOU Zrealone)

"Physic is all what never works; Chemistry is all what stinks and explodes!"-"Life that deadly disease, sexually transmitted."(W.Allen)
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[*] posted on 13-2-2017 at 10:14


Quote: Originally posted by JJay  


That's interesting. I have 20 grams of phenylalanine, but I was kind of planning on using it to try to make phenylacetaldehyde by hypochlorite oxidation and was unaware that any benzyl cyanide might be produced... do you have a literature reference for this?


JJay, I tried the same thing hoping to get phenylacetaldehyde; I just treated a solution of phenylalanine in water with a large excess of concentrated bleach with periodic cooling, and based on the resulting product and its odor, assumed it was the aldehyde. Until I shot in on the GC-MS at work and discovered the following chromatogram:

Benzyl cyanide from phenylalanine_Amos.PNG - 25kB
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