Sciencemadness Discussion Board

Phenylacetonitrile from Phenylalanine

AvBaeyer - 14-8-2017 at 19:23

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]

JJay - 14-8-2017 at 22:11

Very cool. Bravo.

Loptr - 15-8-2017 at 06:43

Very nice, AvBaeyer!

I am so glad to see that this was picked back up!

wg48 - 15-8-2017 at 07:30

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.

Amos - 15-8-2017 at 09:30

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?

AvBaeyer - 15-8-2017 at 13:29

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.

fastbre4k - 19-8-2017 at 05:55

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..

wg48 - 19-8-2017 at 06:40

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...

zed - 21-8-2017 at 12:56

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]

AvBaeyer - 22-8-2017 at 08:24

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

UC235 - 22-8-2017 at 17:09

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.

Corrosive Joeseph - 22-8-2017 at 17:30

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.



Apologies for being totally off-topic............. Free bibles
http://gen.lib.rus.ec/book/index.php?md5=60565D398EA7F079434...


/CJ

zed - 22-8-2017 at 18:08

AVBaeyer,

Perhaps I mis-remembered. Actually, this Italian paper looks very familiar.

www.sciencemadness.org/talk/files.php?pid=69963&aid=1539

wg48 - 22-8-2017 at 22:08

Quote: Originally posted by Corrosive Joeseph  

Apologies for being totally off-topic............. Free bibles
http://gen.lib.rus.ec/book/index.php?md5=60565D398EA7F079434...


/CJ


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.

AvBaeyer - 23-8-2017 at 18:40

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

morganbw - 11-4-2018 at 02:46

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.

Metacelsus - 11-4-2018 at 04:39

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...

Chemi Pharma - 11-4-2018 at 05:23

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 944 times

Attachment: aminoacids and amines to nitriles and chloroamines with TCCA.pdf (160kB)
This file has been downloaded 851 times

Attachment: aminoacids decarboxylation to nitriles and further reduction to amines with n-bromosuccnimide and nickel boride.PDF (66kB)
This file has been downloaded 810 times

AvBaeyer - 11-4-2018 at 11:11

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

Loptr - 12-4-2018 at 09:46

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]

AvBaeyer - 12-4-2018 at 18:13

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

Loptr - 12-4-2018 at 19:29

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.

AvBaeyer - 13-4-2018 at 17:51

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

El.Sorbos - 12-7-2018 at 14:49

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

AvBaeyer - 12-7-2018 at 18:06

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

El.Sorbos - 19-7-2018 at 15:56

In my second experiment strong cooling with water salt/ice solution was applied, so temperatures didn't rose over 10 degree. Also stirring was strong enough, so no hot spots are noticeable. (mechanical stirring)

Your filter cake extract was also black, so i come to the thesis the solvent are react with the dichlorocynuricacid?

I think one of my errors was my extraction technique, because i worked sloppy. In my next try i will perform additional a slower addition of my NaDCCA, maybe i underestimated the reaction kinetic and you a right with the temperature argument. :)


JJay - 19-7-2018 at 16:39

When I was sorting through some old research recently, I ran across a paper saying that monochlorinated amino acids degrade irreversibly in the presence of base to form aldehydes, while dichlorinated amino acids degrade to form nitriles.

If aldehydes are forming, that can hurt yields in at least a couple of ways - by using up the amino acid to produce side products - and by unwanted chlorination of the product by unconsumed chlorine. I'm not sure how fast the degradation into an aldehyde is, but I'm pretty sure that water can serve as the base, especially if the temperature is high enough. I guess that is why amino acid to aldehyde syntheses with TCCA or hypochlorite tend to use such dilute conditions. I'll see if I can find the paper....


[Edited on 20-7-2018 by JJay]

AvBaeyer - 21-7-2018 at 18:12

JJay,

What you have mentioned is actually quite important for the success of the procedure I posted. The reaction I described uses the sodium salt of phenylalanine and an aqueous solution of NaDCC. As a result, the pH of the reaction is always near neutrality which inhibits the formation of the aldehyde product. Thus, N-dichlorination becomes the predominant pathway with subsequent formation of the nitrile as a slow step. As I have also pointed out, careful temperature control is extremely important to inhibit the formation of dark colored by-products. I believe the good points you have raised are covered in some of the references I cited.

AvB

JJay - 21-7-2018 at 22:20

Yep, quite likely. You really did some amazing work on this, BTW.

Loptr - 7-8-2018 at 06:26

I found another paper regarding the bromodecarboxylation of alpha-amino acids that I haven't seen before. It discusses some of the reactions that take place when using NBS that can lead to the expected nitrile, a nitrile of one less carbon, or an aldehyde.

Attachment: J. Biol. Chem.-1961-Stevenson-715-7.pdf (382kB)
This file has been downloaded 652 times

John paul III - 4-7-2019 at 08:49

What the puropse of washing the organic solution with K2CO3 and brine?

thioacetone - 21-12-2022 at 16:01

Hi just wondering a few things - if anyone can please help:

- Can I use diethyl ether instead of DCM?
- I don't have access to iodine/iodides for the starch test - is there any way to avoid it?
- Can I use sodium metabisulfite instead of bisulfite?
- Can I dry with anhydrous magnesium sulfate instead of sodium sulfate?

Thanks