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AvBaeyer
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Phenylacetonitrile from Phenylalanine
Preparation of Phenylacetonitrile from Phenylalanine
Introduction
Recently I needed a small quantity of phenylacetonitrile (PAN) for use as an intermediate for the synthesis of some stilbene derivatives. Well
documented procedures exist for the synthesis of PAN from benzyl halides and cyanide salts [1]. This route was not acceptable due to safety concerns.
However, it is well established that that treatment of amino acids with hypochlorous acid / hypochlorite will lead to aldehydes and nitriles [2]. In
fact this reaction has been widely studied in depth primarily due to its importance in water treatment [3-5]. Synthetic utilization of the reaction of
amino acids with hypochlorous acid / hypochlorite to provide either aldehydes or nitriles is quite rare since both types of compounds have many good
synthesis routes. Nonetheless, interest in this reaction specifically with phenylalanine has been documented on the Sciencemadness site [6, 7].
Oxidation of phenylalanine with common sodium hypochlorite bleach gives a complex mixture of products probably due to the high alkalinity of the
solution. This is clearly shown in the post by Amos [6]. The reaction of bleach with phenylalanine does afford primarily PAN in a buffered medium [5]
though chlorination of the phenyl ring is still found. Unfortunately, the buffered reaction is quite dilute and is not readily scaleable. Dakin
reported the use of Chloramine-T as a suitable reagent in place of sodium hypochlorite for the conversion of amino acids to nitriles though he did not
report the reaction with phenylalanine [2, 8]. Two reports have appeared using trichlorisocyanuric acid (TCCA) to convert phenylalanine to PAN in high
yields [9, 10]. One of these [9] was the stimulus for the Sciencemadness discussion [6].
In my investigations the use of TCCA under a variety of experimental conditions to form PAN leads to complex, highly colored mixtures showing a
multitude of spots by TLC. This I believe is due to the fact that it is generally insoluble in most solvents and that when added to a reaction as a
solid creates “hot” spots of uncontrollable reactivity. In short, the reagent is relatively useless for any work at a reasonable scale. Loptr [6]
reported trying to use sodium dichloroisocyanurate (NaDCCA) but without any follow up information regarding further experiments. I decided to follow
up this initial report and investigate the potential for synthesis of PAN using NaDCCA.
NaDCCA is a widely used compound for which there is much available on-line information which will not be referenced hjere. It is easily available OTC
as the dihydrate in highly pure form. It is readily water soluble giving a near neutral solution unlike commercial bleach. Although its dissolution
results in a complex set of equilibria, the ultimate reactive species appears to be hypochlorite. Information regarding its use as a chemical
synthesis reagent appears to be scant [11, 12] though I have not done an exhaustive search.
Results and Discussion
The initial reaction was carried out following the procedure in [9] after taking into account the errors in the published experimental [6]. NaDCCA was
added as a solid in small portions. NaDCCA was equimolar to the phenylalanine. The room temperature reaction was extremely exothermic and darkened
considerably. After work up and extraction with dichloromethane, TLC indicated at least six products connected by heavy streaking. Cooling the
phenylalanine sodium salt solution made little difference in the outcome.
A second series of experiments involved adding the NaDCCA dissolved in water to the phenylalanine solution. Without cooling (ambient temperature) the
reaction was strongly exothermic and darkened considerably giving a complex product mixture though PAN appeared to be a major component by TLC.
Finally, it was found that slow addition of the NaDCCA solution to a cold phenylalanine sodium salt solution gave a very pale yellow reaction mixture
along with a white precipitate. The reaction was stirred at ambient until carbon dioxide gas evolution was no longer visible. Heating of the reaction
even to a modest 35 C to speed up decarboxylation resulted in a dark reaction mixture and several side products. Under these conditions the work up
was somewhat complicated as the PAN was strongly occluded in the isocyanuric acid precipitate. However, thorough washing of the precipitate with
dichloromethane provided a crude product which by TLC was nearly pure PAN and another less polar material. It is presumed, though not proven, that the
less polar material may be the 2-chloro and 4-chloro derivatives of PAN. This reaction has been scaled up to ca. 0.1 mole and consistently afforded
yields of 75%-80% of pure distilled PAN.
Experimental
Materials. L-Phenylalanine and NaDCCA dihydrate (99% purity) were obtained from ordinary OTC sources. Dilute sodium hydroxide solution was prepared by
dilution of carbonate-free 50% w/w sodium hydroxide solution and titration against standard potassium acid phthalate and phenolphthalein. TLC was run
using silica gel plates in 9 hexane: 1 ethyl acetate and visualizing with uv and iodine.
Preparation of Phenylacetonitrile
Phenylalanine (15.62 g, 94.5 mmol) was dissolved in 50 ml 1.89 M sodium hydroxide and 50 ml water in a 400 ml beaker equipped with a thermometer
reaching into the solution and set up for magnetic stirring. The clear solution was chilled to ca 5 C in an ice bath. Sodium dichloroisocyanurate
dihydrate (24.23 g, 94.5 mmol) was dissolved in150-160 ml water at room temperature. The NaDCCA solution was transferred to an addition funnel and
added dropwise with strong stirring to the phenylalanine solution at a rate which maintained the temperature below 10 C. After the first ca 20 ml of
NaDCCA were added isocyanuric acid began to precipitate. After ca 50 ml of the NaDCCA were added gas evolution was noticeable and continued throughout
the addition. Small amounts of water were added dropwise if the stirring became too difficult. The addition required about 45 min to complete. The
reaction was then kept in the ice bath with stirring for ca 45 min then removed from the bath and stirred for about 5 hr. At this point gas evolution
appeared to have ceased. The pH of the reaction was 6-7 and there was a faint positive test with starch-iodide paper. A 10% solution of sodium
bisulfite was added dropwise until the starch-iodide test was negative. This required about 2-3 ml.
The reaction was filtered and the cake sucked as dry as possible. A small amount of yellow oil was evident. The cake was washed with dichloromethane
(2x50 ml) giving a yellow organic solution. The aqueous filtrate was extracted with dichloromethane (2x25 ml). The organic solutions were combined and
washed with 5% sodium bisulfite (1x50 ml), 5% potassium carbonate (1x50 ml) and half-saturated brine (1x50 ml). The organic solution was dried
overnight over sodium sulfate during which time dissolved isocyanuric acid also precipitated. The mixture was filtered and the solvent removed by
distillation giving a dark yellow oil (ca 12 g). TLC indicated 2 components: PAN Rf = 0.63 (compared to authentic sample) and a minor faster running
spot near the solvent front. There was also a small amount of origin material. The crude product was distilled and boiled sharply at 78-79 C at 2.5 mm
affording 8.88 g (Y=80%) of PAN as single spot on TLC. A small amount of tarry material remained which consisted of a multitude of products by TLC.
Conclusion
A procedure has been developed for the synthesis of useful amounts of phenylacetonitrile in high yield from OTC starting materials. The procedure is
somewhat lengthy but if done carefully is worth the effort. If further scale up is desired, mechanical stirring will be useful. The scale described
here is taxing on a strong magnetic stirrer as the precipitate is somewhat gummy due to occluded product.
The reaction conditions described here can probably be applied to most amino acids. Exceptions are tyrosine which easily ring chlorinates, tryptophan
which will suffer oxidation of the indole ring, and aspartic acid which will not give cyanoacetic acid but instead further chlorination and oxidation
products. These comments are based on known chemistry with hypochlorite and Chloramine-T.
References
1. Organic Syntheses, Col. Vol I, p107.
2. HD Dakin, Biochemical J. 1916, 10, 319-323 and references cited therein.
3. ZT How et al., J. Environ. Sci., 2017, in press (doi.org/10.1016/j.jes.2017.05.025)
4. ZT How et al., Environ. Sci. Tech. 2017, 51, 4870-4876.
5. X Ma et al., Water Res. 2016, 102, 202-210.
6 http://www.sciencemadness.org/talk/viewthread.php?tid=32534
7 http://www.sciencemadness.org/talk/viewthread.php?tid=66331
8 HD Dakin, Biochemical J. 1917, 11, 79-95.
9 L DeLuca et al., Synlett 2004, 2180-2184.
10 GA Hiegel et al., Synth. Commun. 2004, 34, 3449-3453.
11 M Pallavicini et al. Tet. Lett. 2010, 51, 5540-5542 and references cited therein.
12 JVP Katura et al., Org. Process Res. Dev. 2016, 20, 1828-1832.
AvB
[Edited on 15-8-2017 by AvBaeyer]
[Edited on 15-8-2017 by AvBaeyer]
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JJay
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Very cool. Bravo.
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Loptr
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Very nice, AvBaeyer!
I am so glad to see that this was picked back up!
"Question everything generally thought to be obvious." - Dieter Rams
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wg48
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AvBaeyer:
Nice write up.
Can you give some more details on your TLC procedure?
Was the UV lamp a lower pressure mercury lamp (UVB/C) as opposed to a black light (UVA) ?
I assume the plates where not already dyed with a florescent material and the iodine produces florescent compounds with the products and hence
visualise the spots with UV. Is this a common procedure for this type of reaction or do you have to try various procedures to find a working one ?
If you did not already have a sample of target product I assume it would make for difficulty interpreting the spots and selecting solvent/s for it.
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Amos
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Excellent work, and thanks for the mention. Do you have access to any instruments to determine the side products of the reaction and/or the proportion
of phenylacetonitrile in your crude product?
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AvBaeyer
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JJay and Loptr: Thank you.
wg48: Thank you. I use commercial microscope slide size TLC plates from various sources (Whatman and others) which are active at 254 nm. This is a
relatively expensive way to go but saves so much time. I have had plenty of experience making "homemade" TLC plates - no more.
For visualization I use a Mineral Light UV lamp with a 254 nm tube (from Dr. Bob) and an iodine jar as a secondary method. Sometimes I will also use a
spray reagent to identify specific compounds or functional groups.
Selecting solvents for most non-charged compounds is usually based on mixtures of hexane and ethyl acetate. There are other more exotic mixtures for
polar and charged compounds. It is an art form that is honed with experience. If you are really interested in TLC and chromatography in general, I
strongly recommend the "bible:"
E.Stahl, Thin-Layer Chromatography, A Laboratory Handbook, Springer-Verlag 1969.
Used copies come available from time to time. It is worth every cent.
Amos: Thank you. I have no analytical instrumentation. My lab bench is an 18 in x 36 in space in my garage. As I mentioned, when the reaction is run
in the cold and kept at ambient for completion, there only appears to be the 2 spots I see on TLC plus a bit of origin material in the extract. As you
can (now post edit) see, the isolated yield of distilled pure product is 80% not counting hold up in the distillation system. Obviously the tarry pot
residue says there are multiple minor products (decomposition perhaps?) present at the end of the distillation as well as some residual PAN. I
triturated the tar with hexane which gave an orange extract. TLC of this solution showed primarily PAN and the original faster running spot. There
were also a couple of other faint spots not previously seen just ahead and behind the PAN spot. It appears that the actual yield of PAN is somewhat
higher than that isolated.
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fastbre4k
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Very cool, i like to do this reaction but i live in germany and we just have access only to TCCA as pool chlorine tabs.
can anyone tell me a brand name for Sodium dichloroisocyanurate? so properly i can buy it online..
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wg48
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Quote: Originally posted by fastbre4k  | Very cool, i like to do this reaction but i live in germany and we just have access only to TCCA as pool chlorine tabs.
can anyone tell me a brand name for Sodium dichloroisocyanurate? so properly i can buy it online.. |
"Suds Online" sell on Ebay UK something called "Stabilised Chlorine Granules" Its the dihydrate of Sodium dichloroisocyanurate. 2kg for £12.50
I think think this link points to it http://www.ebay.co.uk/itm/2kg-Stabilised-Chlorine-Granules-f...
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zed
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Thank you AvBaeyer!
I knew the reaction had been reported (from France). But to my knowledge, no-one here, has ever reported using it successfully.....to produce usable
amounts of PAN.
Been reports, but they were more-or-less...... reports of failure.
Nice! Congratulations !
[Edited on 21-8-2017 by zed]
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AvBaeyer
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Zed,
Thanks for the compliment. Do you have the French reference you mention? I did a SciFinder search and did not come up with anything though that may be
due to my limitations. Was the French reference using hypochlorite or NaDCCA?
AvB
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UC235
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Im fairly sure trichloroisocyanuric acid in bicarbonate buffer can accomplish the same transformation. I failed to isolate product from a very small
scale test on another amino acid, but addition of the TCCA caused aggressive offgassing of CO2.
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Corrosive Joeseph
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| Quote: Originally posted by AvBaeyer |
I strongly recommend the "bible:"
E.Stahl, Thin-Layer Chromatography, A Laboratory Handbook, Springer-Verlag 1969.
Used copies come available from time to time. It is worth every cent.
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Apologies for being totally off-topic............. Free bibles
http://gen.lib.rus.ec/book/index.php?md5=60565D398EA7F079434...
/CJ
Being well adjusted to a sick society is no measure of one's mental health
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zed
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AVBaeyer,
Perhaps I mis-remembered. Actually, this Italian paper looks very familiar.
www.sciencemadness.org/talk/files.php?pid=69963&aid=1539
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wg48
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I am not able to access that site. Perhaps someone who got a copy of one of those free bibles can help me please. U2u me.
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AvBaeyer
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UC235,
TCCA will in fact "do the reaction." Unfortunately, TCCA is extremely difficult to use on any useful scale. As I pointed out, it must be added as a
solid because it is not water soluble. It then forms hot spots in the reaction. This in turn leads to a nearly uncontrollable exotherm, severe
darkening of the reaction mixture and many side products. I have spent a lot of time examining the amino acid to nitrile reaction. I believe that the
procedure I have posted is the easiest and cleanest of any that I have tried and definitely scalable with proper equipment.
Zed: Your cited paper is reference 9 in my write up.
AvB
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morganbw
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This was a nice post. It was pleasant to read a post of a synthesis that actually went beyond the color or the odor of the chemical.
This is a chemical for which I have zero need of but I am, truly, tempted to create it out of sport. Thank you.
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Metacelsus
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| Quote: Originally posted by wg48 |
I am not able to access that site. Perhaps someone who got a copy of one of those free bibles can help me please. U2u me. |
Try changing your DNS settings (for example, to 80.82.77.83).
Or you can try: http://libgen.io/ads.php?md5=60565D398EA7F079434E24E3142F4B5...
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Chemi Pharma
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Here's the papers pointed as references 9 and 10, cited by @AVBayer at his original post, dealing with TCCA oxidation of aminoacids to a nitrile with
one less carbon and a plus archive dealing with decarboxilation of aminoacids by N-Bromosuccinimide (NBS) to nitriles and further reduction to amines.
Very instructive!
Attachment: Amino Acids into Nitriles with Trichloroisocyanuric Acid.pdf (1.1MB)
This file has been downloaded 945 times
Attachment: aminoacids and amines to nitriles and chloroamines with TCCA.pdf (160kB)
This file has been downloaded 854 times
Attachment: aminoacids decarboxylation to nitriles and further reduction to amines with n-bromosuccnimide and nickel boride.PDF (66kB)
This file has been downloaded 811 times
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AvBaeyer
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As an addendum, I have recently tried using 1,3-dibromo-5,5-dimethylhydanoin (DBDMH) as the oxidizing agent with only poor results. It appears based
on literature reports that DBDMH has reaction profiles which need to be tailored to the reaction being studied. I have not had the time to more
carefully refine the reaction of DBDMH with phenylalanine except to say that phenylacetontrile is produced in modest amounts along with several other
products not seen in the NaDCCA reaction I reported above. The potential advantage of DBDMH is that the by-product 5,5-dimethylhydantoin is water
soluble and would ease the work-up.
AvB
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Loptr
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| Quote: Originally posted by AvBaeyer | As an addendum, I have recently tried using 1,3-dibromo-5,5-dimethylhydanoin (DBDMH) as the oxidizing agent with only poor results. It appears based
on literature reports that DBDMH has reaction profiles which need to be tailored to the reaction being studied. I have not had the time to more
carefully refine the reaction of DBDMH with phenylalanine except to say that phenylacetontrile is produced in modest amounts along with several other
products not seen in the NaDCCA reaction I reported above. The potential advantage of DBDMH is that the by-product 5,5-dimethylhydantoin is water
soluble and would ease the work-up.
AvB |
Is the difference between hypochlorous and hypobromous acid? Maybe we can find DCDMH on the shelves somewhere. That way you would still have the
benefits of the insoluble hydantoin by-product.
[Edited on 12-4-2018 by Loptr]
"Question everything generally thought to be obvious." - Dieter Rams
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AvBaeyer
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I think the problem is the formation of "hot spots" around the insoluble particles of DBDMH just like with TCCA. Even with cooling the reaction
mixture, both DBDMH and TCCA lead to rapidly accelerating exotherms and dark reaction mixtures with multiple products.
Also, I do not think the Br vs Cl is a problem as NBS works in these types of reactions.
Thanks for the thoughts.
AvB
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Loptr
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DBDMH is soluble in acetone and ethanol, so what about an aqueous solvent system with one of those? What about a two phase system using PTC
conditions? Generate the hypobromous acid in the aqueous phase, and transfer it into a NP phase.
"Question everything generally thought to be obvious." - Dieter Rams
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AvBaeyer
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I think that using mixed and possible reactive solvents or PTC only complicates a rather simple situation. In principle, the cyanuric acid by-product
from NaDCCA is soluble in base and can be removed that way. Phenylacetonitrile poses the problem of also being soluble in aqueous base to some extent.
I do not think the problem is intractable, just difficult. Just needs some real experiments to be done.
AvB
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El.Sorbos
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Ok, first of all thank you AV for your great work!
I have tried to reproduce this, two times my yield's are half less of them you got.
In my first experiment i proceed a 3x molar ratio from your quantity's, without separation of the cyanuric acid a water steam distillation the nitrile
was isolated, then purified in vacuum distillation. My first yield was about 14g.
In an second experiment a 2x molar ratio with a better stirring and cooling was applied, the solid acid after reaction was filtered of and an
extraction from the solid with 3x DCM was proceed with out sucking funnel. the liquid solution of PAN was also extracted with DCM, the organic layer's
combined. The product was also vacuum distillate over a vigreux column, a nice smelling and clear product was collected. Yield about 10g.
The reaction conditions are the same as in your experiment.
I wondering why i get so low yield's, is it possible that i have to suck the acid cake try and use ether instead of DCM. Can it be that the DCM react
whit the cyanuric acid, because the filtrate is black wich it is impossible to clean up in a simple vacuum distillation, the distillate is also black
and a fraction column is essential.
Have someone can reproduce the yield in this reaction?
kind regards
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AvBaeyer
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It sounds as if your temperature control was not like it should be. It is extremely important to maintain the INTERNAL reaction temperature below 10*C
during the addition of the NaDCCA solution. The reaction darkens considerably and forms many side products if the temperature is not controlled. The
reaction is quite exothermic and very efficient cooling is required to effectively scale this process.
Hope this helps,
AvB
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