Sciencemadness Discussion Board - Oxidative decarboxylation with TCCA

Oxidative decarboxylation with TCCA

Thecriscoking - 11-8-2014 at 17:34

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)
This file has been downloaded 877 times

TheChemiKid - 11-8-2014 at 17:53

You could try using THF as a solvent instead of Ether.

AvBaeyer - 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

Thecriscoking - 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.

Nicodem - 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!

kmno4 - 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.

Thecriscoking - 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.

zed - 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.

Nicodem - 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.).

kmno4 - 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.

Reregister - 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]

Crowfjord - 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]

Loptr - 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.

[Edited on 18-3-2015 by Loptr]

[Edited on 18-3-2015 by Loptr]

Dr.Bob - 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.

DJF90 - 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.

CuReUS - 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

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

Loptr - 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)
This file has been downloaded 2124 times

[Edited on 28-4-2015 by Loptr]

morganbw - 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.

Loptr - 28-4-2015 at 06:54

Quote: Originally posted by morganbw

Quote: Originally posted by Loptr

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]

Cryolite. - 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?

PHILOU Zrealone - 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.

Cryolite. - 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.

JJay - 12-2-2017 at 20:00

Quote: Originally posted by AvBaeyer

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?

PHILOU Zrealone - 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]

Amos - 13-2-2017 at 10:14

Quote: Originally posted by JJay

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

Cryolite. - 13-2-2017 at 14:32

I have a feeling all halogen-based oxidizers will produce the nitrile and not the aldehyde. The nucleophillic nitrogen will attack the active halogen, forming a haloamine. This will then dehydrohalogenate to a haloimine, which is stabilized against hydrolysis by the electron withdrawing halogen on the nitrogen. Finally, this eliminates carbon dioxide and another hydrogen halide unit to form the nitrile. Note that an aldehyde can only be formed if the haloimine intermediate hydrolyzes to the alpha keto acid, which decarboxylates as expected. This is unlikely for the reason stated above. The usual Strecker degradation uses alloxan as the oxidizer-- this will instead form a standard imine intermediate, which will hydrolyze as we want. Unless a large excess of the amino acid is used, I don't see how hypochlorite or TCCA could reasonably produce a good yield of aldehyde.

JJay - 13-2-2017 at 15:37

Quote: Originally posted by Cryolite.

I have a feeling all halogen-based oxidizers will produce the nitrile and not the aldehyde. The nucleophillic nitrogen will attack the active halogen, forming a haloamine. This will then dehydrohalogenate to a haloimine, which is stabilized against hydrolysis by the electron withdrawing halogen on the nitrogen. Finally, this eliminates carbon dioxide and another hydrogen halide unit to form the nitrile. Note that an aldehyde can only be formed if the haloimine intermediate hydrolyzes to the alpha keto acid, which decarboxylates as expected. This is unlikely for the reason stated above. The usual Strecker degradation uses alloxan as the oxidizer-- this will instead form a standard imine intermediate, which will hydrolyze as we want. Unless a large excess of the amino acid is used, I don't see how hypochlorite or TCCA could reasonably produce a good yield of aldehyde.

That very well may be correct, but there are references on this page which state otherwise: http://www.sciencemadness.org/talk/viewthread.php?tid=66331

I have tried this before, and while I never managed to obtain a yield that I could measure, the rose smell was powerful and unmistakable.

JJay - 13-2-2017 at 15:39

Quote: Originally posted by Amos

Quote: Originally posted by JJay

Wow, that's pretty amazing. That would explain why I never managed to isolate any product....

Boffis - 13-2-2017 at 21:52

@Amos, that spectra is really interesting, it shows that you are getting aromatic halogenation to a limited extent (c 10%). Maybe using a slight excess of phenylalanine and keeping the solution cool would help to reduce this side reaction. Its certainly a problem to bear in mind. When I use hypochlorite solutions I usually standardize it against iodide/thiosulphate so that I know what I am dealing with.

@Cryolite, I haven't read the aldehyde papers but I would have thought that you could simply use hald the amount of hypochlorite /TCCA and then hydrolyse the imine as a sequential process, I doubt that you would even have to isolate the imine.

Cryolite. - 14-2-2017 at 17:17

@Boffis: I'm pretty sure that using stoichiometric amounts of TCCA would at best lead to a mixture of starting material, aldehyde, and nitrile. You may actually do worse than this, as imines are less basic than amines and so are likely to be more able to get halogenated, especially without excess base. Then again, I haven't done the reaction and I'm just theorizing things, so I might be wrong.

Darkstar - 16-2-2017 at 03:22

@Cryolite: As JJay pointed out, there are numerous examples in the literature of hypochlorite being used to convert amino acids into aldehydes, so it would seem that it is indeed possible. For example, the authors of one of the references in the thread JJay linked to claimed to have obtained phenylacetaldehyde from phenylalanine in 60% yield using one equivalent of sodium hypochlorite in aqueous solution. It should be noted, however, that both of their amino acid and sodium hypochlorite solutions were extremely diluted, and a phosphate buffer was used to maintain a pH of around 7. It's also worth mentioning that the hypochlorite solution was added very slowly over the course of ten minutes with constant stirring.

I think the reason Amos failed to produce any phenylacetaldehyde was because he used a large excess of concentrated bleach. I believe the key to getting the aldehyde is keeping the concentration of the hypochlorite as low as possible, while also keeping the pH as close to neutral as possible. The idea here is to chlorinate the nitrogen once and then quickly eliminate the chloro group via decarboxylation. We want to avoid forming an imine through normal E2 elimination prior to the decarboxylation step. By keeping the hypochlorite concentration low, we avoid over-chlorinating the nitrogen; by keeping the pH neutral, we avoid eliminating the chloro group via deprotonation of the adjacent carbon. Also, by keeping the pH closer to neutral, most of the hypochlorite will be in the form of hypochlorous acid, which is most likely the real oxidizing species in these reactions anyway. In Amos's case, the large stoichiometric excess of hypochlorite most likely led to over-chlorination and too high of a pH, favoring the nitrile over the aldehyde.

The reaction we want is this:

The reaction we don't want is this:

The problem with forming the imine before the decarboxylation step is that even if the imine hydrolyzes immediately afterwards, the carboxyl group can't just suddenly leave as CO₂ now that it's an alpha-keto acid. Just like in Strecker degradations, something must first act as an electron sink before the carboxyl group can leave, otherwise you inevitably end up with an extremely unfavorable acyl anion intermediate, which are highly unstable and rarely ever observed in practice (if at all).

While I suppose it's possible that an alpha-keto acid intermediate may actually help to facilitate the decarboxylation of unreacted amino acid molecules by condensing with them and acting as an electron sink, the problem is that the reaction mixture is not only aqueous, but extremely dilute as well. So how beneficial this would turn out to be, I don't know. My guess is that something like this would have to happen in order for decarboxylation to occur:

PHILOU Zrealone - 16-2-2017 at 03:41

If the pH is too high like it is usually in commercial bleach for safety reasons (avoid to set toxic gaseous Cl2 free), you will get nitrile and subsequent hydrolysis products (phenylethanoic acid, phenylethanoic amide and NH3), but also aldehyd crotonisation/condensation of phenylethanal from the very activated benzyl position (trapped between the aromatic EWG and the aldehyd EWG...both helping also terminal decarboxylation.

You will end up with a polymer (-CH(Ar)-CHOH-)n that will crotonise to (-CH(Ar)=CH-)n + n H2O thus poly-phenylacetylen and eventually the cyclic trimer 1,3,5-triphenyl-benzene.

[Edited on 16-2-2017 by PHILOU Zrealone]

Amos - 16-2-2017 at 09:39

Quote: Originally posted by JJay

Quote: Originally posted by Amos

Wow, that's pretty amazing. That would explain why I never managed to isolate any product....

I thought for sure I had the correct product too, as a general trend is that these large aromatic nitrile molecules tend to smell very similar to their corresponding aldehydes; so much so that scented consumer products meant for more robust environments (such as detergents and cleaners) often substitute a nitrile for more reactive aldehyde aroma compounds (cinnamaldehyde, citral, etc.)

Amos - 16-2-2017 at 09:40

Quote: Originally posted by Boffis

@Amos, that spectra is really interesting, it shows that you are getting aromatic halogenation to a limited extent (c 10%). Maybe using a slight excess of phenylalanine and keeping the solution cool would help to reduce this side reaction. Its certainly a problem to bear in mind. When I use hypochlorite solutions I usually standardize it against iodide/thiosulphate so that I know what I am dealing with.

Oh, I know I definitely went overboard; I also left the product sitting underneath the bleach for far too long. This is something I intend to carry out in a more controlled manner at a later date and provide a write-up for on the forum.

JJay - 16-2-2017 at 13:28

Quote: Originally posted by Amos

Quote: Originally posted by JJay

Quote: Originally posted by Amos

Wow, that's pretty amazing. That would explain why I never managed to isolate any product....

I probably won't be trying it again. The last thing I need is to accidentally manufacture a listed chemical....

Mush - 22-9-2019 at 11:07

Odorous Products of the Chlorination of Phenylalanine in Water: Formation, Evolution, and Quantification

Ingrid FreuzeStéphan BrosillonDorine HermanAlain LaplancheChristian DémocrateJacques Cavard

Environ. Sci. Technol.2004; 38, 15, 4134-4139
Publication Date:June 22, 2004
https://doi.org/10.1021/es035021i

Abstract

To explain some of the possible origins of an odor episode which took place in a drinking water supply in the region of Paris (France), the chlorination reaction in water of phenylalanine was studied. This amino acid was chosen for first experiments because of its physical and chemical particular properties. Changes in the different byproducts formed were followed by high-performance liquid chromatography (HPLC) over a period of time. N-chlorophenylalanine (mono-N-chlorinated amino acid) and then phenylacetaldehyde were the major products formed for the lower chlorine to nitrogen molar ratios. For Cl/N molar ratios of 1 and beyond, phenylacetonitrile and N-chlorophenylacetaldimine appeared and increased with the chlorination level. N-chlorophenylacetaldimine was quantified by using its difference of stability in various organic solvents. Our attention was first directed to the monochlorinated derivative but further examination indicated that it could not be responsible for odor troubles: it dissociated before reaching the consumer's tap and it was produced at consistently low yields under conditions relevant to drinking water treatment. On the contrary, chloroaldimine appeared to be a very odorous and water-stable product: it strongly smells of swimming pool with a floral background. The odor detection threshold is about 3 μg·L-1 and it can persist for more than one week at 18 °C. It is now suspected of being a source of off-flavor concerns among consumers.

http://sci-hub.tw/10.1021/es035021i