P2P-derivate related

[politoxicomania]

P2P from Phenylacetic Acid is known and described at rhodium.

What about a Claisen kondesation of
betaphenyl-alphacarbonacidmethylester
with aceticacidmethylester followed by hydrolyse and decarboxylation to yield the keton.
Look here:


Anyone tried this before ?

Seems to be workable and easy procedure.

[Nicodem]

The alpha-hydrogen in the phenylactic acid ester is much more acidic than the alpha-H in the acetic acid ester!
As a result you would get the Ph-CH^--COOMe nucleophyle attacking the carbonyl group of the acetic acid ester or of the other molecule of Ph-CH₂-COOMe since they don't differ enough in reactivity.
However a similar reaction where a Ph-CH₂-COCl and a sodium salt of diethylmalonate is used to produce Ph-CH₂-CO-CH(COOEt)₂ is well known. This can be hydrolised and decarboxylated to P2P.
But please don't ask for references as you can find a lot about this rxn in the library. It is a well known rxn for producing methylketones from acids.

[politoxicomania]

its irrelevant if the aceticacidester attacs the carbonyl funtion of the phenylaceticacidester or the other way
both will yield the same keton after hydrolyseis and decarboxylation
aceticacidmethylester in an great molar excess is needed to prevent coupling of two phenylaceticacidesters together .

[Nicodem]

Oh shit, I forgot to draw the reaction on paper. You are right. But are you sure the yields would be higher than the usual ketonisation reactions between phenylacetic and acetic acid? These mixed acyloyl condensations are not wery used often unles the pKa's of the alpa-H differ enough. That's why in the analogous condensation phenylacetonitrile is used instead of phenylacetic ester. The -CN group makes the alpha-H even more acidic than the -COOR does.

[politoxicomania]

Thats why i asked if someone tried this before.
The Claisen kondensation should be in the 30-80% range
And Aceticacidmethylester is cheap my god.
I should calculate the molar costs of the keton.

[politoxicomania]

Thanks to nicodem.

P2P from Phenylaceticacidmethylester


Reaktion:

Chemicals:
Phenylaceticacidmethylester :
19,5€ /250ml
M= 150,174 g/mol

Aceticacidmethylester :
11,6€ /1000ml
M= 74,079 g/mol

Piperidin :
14,20€/100ml
M= 85,15 g/mol

Procedure:

A 500ml rbf equipped with a magnetic stirrer, a reflux kondenser and heater is filled with 250ml dried aceticacidmethylester. 15 g (~0,1 mol) phenylaceticacidmethylester and a katalytical amount of piperidin (~5ml) is added and the solution refluxed for about 4 hours.
After this most Aceticacidmethylester is distilled off and aqueous NaOH solution is added (100ml 2M) and again refluxed for about 4 hours.
After this the solution is acidified by aq. HCl to pH=3-4 till CO2 evolution is observed. Reflux again for about 2 hours. Distill off the solvents and extract the aqueous phase with ether (3 times with 50ml).
Collect the organic phases, drie them over sodiumsulfat, distill off the ether and fraktionate distill the residue in water-jet vakuum to yield the keton in about 30-80% yield.


Comments:
Piperidin as a base is my kanonical choice.
Also possible is NEt3 or other waterfree bases.

[politoxicomania]

Ph-CH2-COCl + LiCH3 = great fun

but definitly not available for swim

[Nicodem]

Are you sure that people here like to read posts like this? It nice and cool if you make proposals for a new synthetic pathway but you could at least keep them as proposals backed up with examples, theory, links and literature. Don’t you think it is a little bit impertinent sending write ups of reactions that were not made in a real world?
Besides you seem too misunderstood my reply. If you would do enough reading of the Rhodium’s site you would at least find what I was referring too:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenylacetone.html#benzylcyanide

Don’t you think there must be a reason a nitrile is used instead of an ester? The pKa (in water) of Ph-CH2-CN is 20.8 while the Ph-CH2-COOR has a magnitude lower acidity (10 or more times less). As you probably know this is crucial for the formation of the nucleophyle. I’m not saying using phenylacetic ester would not yield P2P but if it would it would quite certainly give lower yields. And there are also some reasons your “write up” is inadequate (not in tune with theory).

[politoxicomania]

Yes thank u that u remind me of very easier and better hypothetical reactions.

I want a constructive critic of the mentioned method.

If swim can easiely obtain the mentioned chemicals it would be better for him to try this method instead of handling a cyanid. Not because of the danger to impure possible products, but to avoid releasing noxious material to the environment.
No problem to handle cyanides like these in a professional laboratory, but think about all the swims out there.......
Better keep it easy and unnoxious,untoxic and undangerous as possible.
Isnt it ?

[moo]

Piperidine? Amines react with esters forming amides and alcohols, so a metal alkoxide might be a better choice.

[politoxicomania]

NaOEt ?

Other ideas ?

[Nicodem]

...I was a little pissed by the way you presented that procedure not even explicitly stating that it was only hypothetical. Sorry again, I was not in the best mood yesterday. If you realy want a constructive critique then I'll give you some.

Moo already told you about the piperidine. The use of an alkoxyde is a requirement, preferably the same as on the ester. Sodium ethoxyde would do and ethanol would a be better solvent than excess ethylacetate (methylacetate has a lower b.p. so it is less good for reflux conditions). Using too much excess ethylacetate might led to excessive side reactions that would consume the ethoxyde (the formation of a much less basic sodium ethylacetoacetate: 2AcOEt + EtO^- => Me-CO^-=CH-COOEt + EtOH).

Your "description" of the hydrolisys/decarboxylation as well as of the isolation also leaves many options for a constructive comment but that is not so important untill a TLC shows any progress of the reaction.

You also forgot the main question? Is the the proposed reaction mechanisticaly OK. The thing about the acidity of the alpha-hydrogens was already covered and seams to be OK. But what about the difference in the electrophylicity of the two different carbonyl groups? If the carbonyl of the phenylacetic ester is more electrophylic than the one from the AcOEt you can expect an extensive side reaction - the self condensation of two phenylacetic ester molecules). So before buying the chemicals you first have to find out wich one of the carbonyls is more electrophylic. What you want is a more electrophylic C=O on the ethylacetate. Going to a library and finding some data on the inductive efect of a benzene ring would help. But you can think practicaly and deduce it from the acidity data you already have as it is connected also with the electrophylicity of the carbonyl. (Could this be another reason why phenylacetonitrile is used? The addition of a carboanion on the nitrile is less favored than on the -COOR, isn't it?)

Please, don't take anything personaly. You can still prove me that I'm wrong.  

P.S. If a compound is called "benzylcianide" it doesn't mean it dissociate into a toxic cianide anion. Its other name phenylacetonitrile does't sound scary, doesn't it? If you would check the MSDS of it you would see that is not nearly so toxic like metal cianides. It is a barely volatile liquid that in time hydrolises to amonia and phenylacetic acid when spilled in nature, so there is no need to call for an ecological dissaster unless you work with industrial amounts. Of course it is toxic, but many other stuff you meet in a lab are much worse. Even some houshold chemicals can do you much more harm if improperly handled!

[politoxicomania]

Thanks to nicodem for his constructive critic.

Its like i said:
The mentioned chemicals are easiely obtainable in germany.
2 days ago a friend asked me to give him an easy procedure to yield P2P. (i know that he have to learn much in preparative chemistry so i decided to keep it easy and untoxic) I remembered a kondensation like this from my first semester in organic chemistry where piperidin was used as a katalysator.
But now i´m confused. I´ve read lots of posts and hypothetical methods which yields are much lower as 50%.
Even at rhodium methods can be found which are
1. hypothetical
2. low yielding
3. complicated

btw organic chemistry is not my building site. i´m specialized in anorganic chemistry and drug syntheses is only a little hobby for me.

Selfcritic:
This method is hypothetical and not proofed, but possible.
Other solvents like alkohol are possible but contraproduktive in this reaktion because an alkohol creates and must be deleted from the reaktion mixture.
Alkohols possibly form s a aceotrop with aceticacidmethylester and could be destilled off. (possible!! not proofed)
As katalyst we need a strong base, which isnt nucleophile.
Piperidin or NEt3 could be used. (possible! not proofed)
Every student learns to take NaOEt, Na or sodiumamides as katalyst in claisen kondensations.  But is this a must ?
This method can be improoved if u are able to obtain LDA (Lithium di isoproyl amin). Ill bet yields could be very high.

P.S. If a compound calls a nitril or cyanide it definetly contains a CN functional group. Compounds like these havn´t to be toxic or noxious but can evolve HCN if they are treated with strong acids. It is my job to handle compounds like these every day. I dont wanna make P2P (can buy it from every ordenary chemical supplier).
But now imagine a bee and think about murphys law.
Cant make anything idiot-proof.
The idiots are too imaginative.

In relation to improoved Claisen kondensations:
Why do u want to use CN-compound,which makes the a more acidic, if u can take a NO2-compound, where the a is much more acidic ?

[politoxicomania]

All critic and selfcritic brought me to this idea :



Thats very hypothetical i know.
But again :
What do u think about it ?
I think that the first reaction must be quantitative. The  problem is the hydrolysis and decaroxylation.


I should post some procedures from BuCl to LDA, if someone is interested.

[politoxicomania]

The reaktion above is really nothing new. The experimental part of this reaktion is not the kondensation, but the hydrolysis and decarboxylation. Decarboxylation of a beta-keto-carbonacid should work fine.

After a morning of work i found a few minutes to look it up and found the preparation of Methyl-3-oxo-2-phenylbutyrate from methylacetate and methyl-phenylacetate. Conditions are THF, -78°C and KOBu^t as base. Yields are moderate (39%) after distillation.

Here is the paper :

J. Chem. Soc., Perkin Trans. 1, 1997, 767ff

http://www.politoxicomania.de/perkin1.rar

Can someone help me to bring it to .pdf format ?

[Nicodem]

Glad to see you actualy doing some literature search. It took you long but please continue.

You can use almost any desktop publishing software to make a PDF (Page Maker, InDesign) or just use Adobe Distiller. I'm sure you will find better directions if you UTFSE. It would be nice if you transform whatever it is in that RAR into a PDF or DejaVue format otherwise nobody is gonna read it.

If a compound calls a nitril or cyanide it definetly contains a CN functional group. Compounds like these havn´t to be toxic or noxious but can evolve HCN if they are treated with strong acids.

Stop thinking anorganicaly. That is not true. Only some cianohydrines and acylcianides can be hydrolised to hydrogen cianide in certain conditions. Please check the MSDS for phenylacetonitrile before proclaiming it dangerous. Does acetonitrile (methylcianide), a common solvent, produce hydrogen cianide in contact with acids? No, it does not. It gets hydrolised to acetic acid!

[Captain_America]

You can use almost any desktop publishing software to make a PDF (Page Maker, InDesign) or just use Adobe Distiller.

I think that he wants someone to UNrar (unpack) the packed file for him to a *.pdf...

[politoxicomania]

The above mentioned reaktion is no longer hypothetical.
The conditions are not as easy as i thought but it is possible. Unfortunately the idea was 8 years old.

On the way to P2P....

The idea was to generate P2P from easiely available chemicals. Phenylaceticacidmethylester and aceticacidmethylester are easiely available in germany and rel. cheap.
The theoretical easy Claisen kondensation of the two esters must be improoved to the following:



This reaktion was made in 1996 in the netherland during a study of germination stimulants for seed of ..... who knows.
The paper was published in 1997 (ive already post the ref.)

Now here ive got the .pdf file for u.

J. Chem. Soc., Perkin Trans. 1, 1997, 767-774.

(http://www.politoxicomania.de/perkin1.pdf)

Experimental :
The beta-keto ester was prepared by condensation of methylphenylacetate and methylacetate following a modified literature procedure (Chem.Abstr.,1968, 68, 105193x.) using KOBu^t as the base in THF. It was essential to keep the reaction mixture at -78°C to avoid complete self-condensation (nicodem was right) of methylphenylacetate. It was obtained in a moderate yield (39%) after distillation.

Now we need to hydrolyse the ester and decarboxylise the betaketo-carbonacid.



This should be easy.


But now i have to say  that i´m disappointed. I thought that this forum seems to be the right place to post a hypothetical method to psychoactive species and precursors. Am i so wrong?
All u need is a paper to believe in something ?
What is about all the chemists working out there on new species while u sit there and read papers about possible reaktions ? Where is your patriotism ? Make your own thoughts! Nothing whould be made if chemists whould alwas say: Do some lterature search.......!

[Nicodem]

Nothing whould be made if chemists whould alwas say: Do some lterature search.......!

There is a saying:
5 hours in the library saves 5 days in the laboratory.
(in many cases it can take even up to 5 weeks or months and think also of the expenses for all the wasted chemicals )
Consider all the pressure to get you in the library as a kind of education

But I still don't understand why you don't like phenylacetonitrile. You surely can't say it is more expensive. Your phenylacetic ester is prepared from it and usually the precursors are cheaper (for some unknown reason this is not always true). Now, what do you want? A reaction that requires extreme conditions and give low yields or one that give higher yield with much less effort?

[politoxicomania]

The idea was to generate P2P from easiely available chemicals.
Now i ll compare Phenylacetonitril with Phenylaceticacidmethylester:

Phenylacetonitil:
T , R 23/24/25 , S 23,45
Merck Index, Beil.9,441
16,6€/500ml

Phenylaceticacidmethylester:
Xn , R 21
Beil.9,434
19,5€/250ml

Ok the Phenylacetonitril is much cheaper for chemists, but definitly not available for bees in germany, because of the Merck index.
And it is Toxic while the ester is only Xn.