Sciencemadness Discussion Board

Improvement in the yield of racemic PPA*HCl via Akabori reaction (35 % molar)

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Quantum_Dom - 17-8-2010 at 21:24

This thread is dedicated to those who do desktop research and solely base theyre argument on theory. It is also dedicated to my good friend and colleague Xtaldoc.

This subject is a favorite of mine. It’s a very nice (and hard) problem to tackle. Such an elegant and OTC mean of obtaining racemic phenylpropanolamine (PPA) and yet so many obstacles and problems regarding proper work-up, understanding of the overall mechanism or the nature of the byproduct formation. Not to mention a less than respectable reported molar yield of 15 % in average! I spent a lot of time studying and trying to tweak the reaction protocol and finally I am very happy to report a 35 % molar yield of racemic PPA*HCl (based on alanine). I apologize to the moderators for opening a new thread in advance but I figured the previous one was rather old and convoluted. Feel free to merge it with the old one if its not worthy of a new thread.

This has been discussed over and over at many different sites and I am sure you are well aware of it. This is why I will solely base my post on the Cycloknight's thread [1] as I believe it is the most complete and up to date on the subject. Furthermore, my improved work-up and yield is directly inspired and based on CycloKnight’s write-up, the Yokoyama et al. article [2] and some comments that Nicodem made in the Cycloknight's thread [3]. Before I get to the actual protocol I need to make a few remarks which will make (I hope) the various steps in my procedure more transparent and justifiable.

1-Lots of people are arguing that the only compound obtained in this procedure is 1,2-diphenylethanolamine (DPEA) quoting this study and affirming that no PPA is obtained at all. DPEA is indeed the major product but it is easily removed in the work-up. The reason the authors are not isolating any PPA is mainly due to 1) the very little scale theyre working on (amount of PPA is almost insignificant at this scale), 2) they are omitting to concentrate the aqueous phase extracts in the work-up (the latter contains PPA*HCl). This will be re-explained later and will prove by the same occasion that referring to that article, to conclude that PPA is not in fact produced, is incorrect.

2-The Yokoyama article mentions that the stoechiometry of the reaction involves two moles of benzaldehyde; one for the formation of PPA and one that condense with the latter to form an oxazolidine. The latter can further be hydrolyzed in the work-up, to regenerate PPA and benzaldehyde, by refluxing the whole mixture, after the condensation/decarboxylation is over. A large excess of benzaldehyde (6 equivalents) is also needed to maximize yields.

3-An important point was made by Nicodem in the CycloKnight’s thread regarding the possibility of an acid-base reaction between alanine and PPA. PPA being a base (primary amine) and alanine having a carboxylic acid moiety, it is not impossible for the two to combine and form a salt that will surely precipitate in benzaldehyde. This topic was discussed and illustrated by me and Naf1 at The Vespiary [4]. Knowing that in CycloKnights work-up all solids after the decarboxylation are assumed to be unreacted alalnine, and therefore discarded, it is normal to wonder if theyre is not actual PPA*alaninate thrown away at the same time.


It is basically on those last two points that I believe my work-up of the reaction is superior, cleaner and brings a better yield of clean racemic PPA*HCl. Heres the protocol:

In a 1 L RBF, 358 g of benzaldehyde (3.36 moles) and 50 g of finely crushed DL-alanine (0.56 moles) were mixed together with magnetic stirring. It was attached to a simple distillation setup and heated on an oil bath at 140 celsius for 3 hours [5] (Figure-1). No more CO2 was evolved from the flask at this point and the color of the mixture was a deep burgundy (almost black). The flask was removed from the oil bath and let cool on its own for 20 minutes. Afterwards, 100 mL of 20 % AcOH in Toluene were added to the flask and the latter was stirred, at RT, for 20 minutes [6]. When this induction period was over, 400 mL of 15 % HCl (aq) was added to the flask and the whole mixture was refluxed gently on the oil bath for 3 hours. Afterwards, the pH of the mixture was verified to be strongly acidic. If not, small portions of concentrated HCl (aq) were added until it was and the mixture was refluxed for another 30 minutes. The flask was then removed from the oil bath, the mixture left to cool for a bit and then rapidly separated with a separation funnel while still warm [7] (Figure-2). An orange/red aqueous phase and a dark black organic phase were obtained [8] (Figure-3).

The aqueous phase was washed 3 times with 150 mL of DCM [9] (Figure-4). Then the volume of the aqueous phase was reduced, with gentle heating and stirring, until half of the volume was vaporized [10] (Figure-5). The remaining aqueous phase was washed 3 other times with 75 mL DCM. The aqueous phase was then treated with small portions of NaHCO3 [11] until fizzing becomes less violent (Figure-6), then small portions of NaOH were added until pH was strongly alkaline. A light brown-yellow oily layer with a strong and biting amine smell separated from the aqueous phase (Figure-7). The latter was separated and the aqueous phase was extracted 4 times with 200 mL DCM [12]. All the NP fractions were pooled together, washed 2 times with 100 mL BRINE and the DCM was stripped off to afford a viscous brown oil that partially turns to a solid once cooled [13].

The oil was dissolved in 5 times its volume of dry acetone. Small portions of an 1:3 HCl (muriatic)-isopropanol solution were added until pH 4 was reached [14]. Large amounts of crystalline material precipitated during the addition (Figure-8 and 9). The flask was put in the freezer overnight, the crystalline material was vacuum filtered and washed with small portions of cold and dry acetone. 33.2 g of racemic PPA*HCl were obtained (Figure-10). Evaporation of the acetone liquor afforded another 3 g after appropriate washing and drying. Melting point, after 1 week in the dessicator, was 131-136 0C [15]. The product gave a positive test to Chen’s reagent and to the nitrous acid test [16]. It has a very distinctive smell reminding of crude benzoic acid [17].

[1] http://www.sciencemadness.org/talk/viewthread.php?tid=5979
[2] https://www.thevespiary.org/talk/index.php?action=dlattach;t...
[3] http://www.sciencemadness.org/talk/viewthread.php?tid=5979&a...
[4] https://www.thevespiary.org/talk/index.php/topic,714.0.html
[5] No changes were made to CycloKnights protocol except longer time for decarboxylation and higher amount of benzaldehyde used.
[6] Glacial acetic acid being soluble in toluene, this step was performed in order to protonate the oxazolidine dissolved in the excess benzaldehyde and make it more prone to hydrolysis latter on. I have no evidence if this step is necessary but I was inspired by the Yokohama et al. article were it is used.
[7] The two phases separate very cleanly while still warm ( 50-55 0C). If the phases are left to cool at RT, the whole mixture turns into a nasty emulsion that wont separate and heating needs to be reapply to separate the phases.
[8] The aqueous phase contains PPA salts, DPEA salts and other water soluble impurities. The NP layer contains a large amount of tar and lots of unreacted benzaldehyde which can be vacuum-distilled later on by firstly washing a few times with diluted aqueous sodium carbonate the NP layer.
[9] This steps is really important as it removes most of the DPEA salts, chloroform is also equally good.
[10] This step is crucial as PPA freebase is soluble in water and will therefore allow one to maximize extraction efficiency once the freebase will be released. An Erlenmeyer or a large flask with a neck is recommended here to minimize aerosol lost. Do not bring the solution to a boil either. The temperature was 80-85 0C and it took roughly 5 hours for evaporation. Evaporation under vacuum would be of course ideal.
[11] The resulting aqueous solution being strongly acidic, the use of sodium bicarbonate allows for smoother neutralization of the excess acid (less heat is generated). Also, a greater amount of salt will be present in the solution and will force the PPA freebase to separate more efficiently.
[12] Do not dry the DCM fraction with magnesium sulfate as a gelatinous addition complex is obtained.
[13] This is mostly due to the fact that the oil is a mixture of 4 different isomers with different melting points.
http://www.thevespiary.org/rhodium/Rhodium/chemistry/nor-pse...
[14] Gassing is not recommended here to claim the hydrochloride.
http://www.thevespiary.org/rhodium/Rhodium/chemistry/nor-pse...
[15] Reported melting point: 134-137°C (butanol-ether (50:50 v/v))
http://www.thevespiary.org/rhodium/Rhodium/chemistry/nor-pse...
[16] Chen’s reagent is specific for alpha-hydroxy amines such as (pseudo)ephedrine and PPA’s. Nitrous acid test indicates a primary amine.
[17] PHENYLPROPANOLAMINE HYDROCHLORIDE, ANALYTICAL PROFILES OF DRUG SUBSTANCES VOLUME 12, Isadore Kanfer, John M. Haigh, and Roslind Dowse




Please post any comments, critique and/or interrogations. I would love to discuss it with anyone interested in optimizing yields furthermore or reproducing my results.- QD


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[Edited on 18-8-2010 by Quantum_Dom]

Methyl.Magic - 18-8-2010 at 08:16

Very nice work thanks :D

The report is complete and very instructive. The methods, especially the workup seems better than Cycloknight version.

i'll try this next week with pictures !

bye

Quantum_Dom - 18-8-2010 at 09:58

Quote: Originally posted by Methyl.Magic  
Very nice work thanks :D

The report is complete and very instructive. The methods, especially the workup seems better than Cycloknight version.

i'll try this next week with pictures !

bye


Thank you Methyl !:) Cant wait to hear your results. Please if unsure about something, feel free to PM or ask in this thread at any time ;).

DDTea - 18-8-2010 at 10:10

I have an idea for how you could improve this; well, not so much as improving the yield, but in experimental design. I'm new to this topic, so I haven't had a chance to read through all of your references yet:

One of your suggestions is that a portion of your product reacts with benzoic acid in solution to form a Phenyl Propanolamine-Benzoate salt.

What would be more interesting is if you could compare the physical properties of the products of two reactions: one with an unmodified protocol with the low yields, and the second where you save ONLY the product from extracting the precipated solids. A direct comparison of the two would either support or disprove the claim that these two portions are the same compound and that this new protocol actually improves the yield of the reaction.

Quantum_Dom - 18-8-2010 at 10:19

Quote: Originally posted by DDTea  


One of your suggestions is that a portion of your product reacts with benzoic acid in solution to form a Phenyl Propanolamine-Benzoate salt.


Actually no, if what Nicodem's proposed is occuring, the PPA molecule would react with the carboxylic moiety on alanine to generate an Alaninate salt. No benzoic acid is involved at all.
http://img517.imageshack.us/img517/4269/ppaalaninate2.gif

Quote: Originally posted by DDTea  


What would be more interesting is if you could compare the physical properties of the products of two reactions: one with an unmodified protocol with the low yields, and the second where you save ONLY the product from extracting the precipated solids. A direct comparison of the two would either support or disprove the claim that these two portions are the same compound and that this new protocol actually improves the yield of the reaction.


Well I did ran the reaction previously according to the classical write-up and can assure you that yields are greatly improved. But, it might also be due to the excess benzaldehyde and the hydrolysis work-up as well.

[Edited on 18-8-2010 by Quantum_Dom]

DDTea - 18-8-2010 at 10:31

Sorry I goofed; I meant the alaninate salt.

What I'm asking is that how do you *know* it is, in fact, an alaninate salt and not unreacted alanine that is left over after the reaction? It would be interesting to see you do the nitrous acid test, Chen's test, and melting point on only the proposed PPA liberated from the alaninate salt. Then a comparison to a PPA reference, i.e. that product of an unmodified protocol, would support the claim that there actually is PPA bound to unreacted alanine that would otherwise be discarded without your modified protocol.

Also you state, "PPA being a base (primary amine) and alanine having a carboxylic acid moiety, it is not impossible for the two to combine and form a salt that will surely precipitate in benzaldehyde." Now an interesting question is, "How soluble is PPA*Alaninate in benzaldehyde?"

Quantum_Dom - 18-8-2010 at 10:39

Quote: Originally posted by DDTea  
Sorry I goofed; I meant the alaninate salt.

What I'm asking is that how do you *know* it is, in fact, an alaninate salt and not unreacted alanine that is left over after the reaction?

Ah ok I see your point now.:) Well I dont know if the alaninate salt formation its occuring BUT if it is occuring people previously were tossing it out as garbage! My work-up does not discriminates on this, if its only alanine it goes in aqueous extracts and stays there. If there is PPA*Alaninate, it goes as well in the aqueous extracts but the freebase is eventually liberated and isolated.

Quote: Originally posted by DDTea  

Now an interesting question is, "How soluble is PPA*Alaninate in benzaldehyde?"

Not a clue ! But being a strongly ionic specie, common sense would lead one to believe that benzaldehyde couldnt solvate it and if it does slightly, the salt will preferentially go into the water extracts anyways.



[Edited on 18-8-2010 by Quantum_Dom]

DDTea - 18-8-2010 at 10:45

Quote: Originally posted by Quantum_Dom  

Ah ok I see your point now.:) Well I dont know if the alaninate salt formation its occuring BUT if it is occuring people previously were tossing it out as garbage! My work-up does not discriminates on this, if its only alanine it goes in aqueous extracts and stays there. If there is PPA*Alaninate, it goes as well in the aqueous extracts but the freebase is eventually liberated and isolated.

Quote: Originally posted by DDTea  

Now an interesting question is, "How soluble is PPA*Alaninate in benzaldehyde?"

Not a clue ! But being a strongly ionic specie, common sense would lead one to believe that benzaldehyde couldnt solvate it.

[Edited on 18-8-2010 by Quantum_Dom]


So, the burden of proof is still on you to show this information experimentally! :)

We need to see numbers and confirmation. Assumption isn't enough. Don't forget, that C=O bond in Benzaldehyde has a strong dipole moment, so common sense isn't enough.

Quantum_Dom - 18-8-2010 at 10:52

Quote: Originally posted by DDTea  


So, the burden of proof is still on you to show this information experimentally! :)

We need to see numbers and confirmation. Assumption isn't enough. Don't forget, that C=O bond in Benzaldehyde has a strong dipole moment, so common sense isn't enough.


Well I hardly see where you coming from with all this as I never actually stated that I proved the PPA*alaninate was actually forming. I think you misunderstood here. All Im saying is that if it is forming, Im taking the means to recover it thats all.

Making assumptions and hypothesis is part of the scientific method too you know. Also, Im affraid you cant atribute the solvent efficiency of a compound by simply looking at one of its functional group. The elementary rule "likes dissolve likes" might bee good for elementary college chemistry but its far from being an absolute.

[Edited on 18-8-2010 by Quantum_Dom]

DDTea - 18-8-2010 at 11:01

Quote: Originally posted by Quantum_Dom  
Quote: Originally posted by DDTea  


So, the burden of proof is still on you to show this information experimentally! :)

We need to see numbers and confirmation. Assumption isn't enough. Don't forget, that C=O bond in Benzaldehyde has a strong dipole moment, so common sense isn't enough.


Well I hardly see where you coming from with all this as I never actually stated that I proved the PPA*alaninate was actually forming. I think you misunderstood here. All Im saying is that if it is forming, Im taking the means to recover it thats all.

Making assumptions and hypothesis is part of the scientific method too you know. Also, Im affraid you cant atribute the solvent efficiency of a compound by simply looking at one of its functional group. The elementary rule "likes dissolve likes" might bee good for elementary college chemistry but its far from being an absolute.

[Edited on 18-8-2010 by Quantum_Dom]


If you're not sure that PPA*alaninate is being formed, then how can you say that recovering the mystery precipitate is improving the yield and not just contaminating your product?

Yes, assumptions and hypothesis are part of the scientific method, but so is questioning results and eliminating sources of confoundment.

No, "like dissolves like" is not an absolute, which is why I'd like to see a measurement. If you can say, "Only a negligible amount of PPA*Alaninate dissolves in benzaldehyde at X *C (whatever the temperature of the benzaldehyde is in this reaction) (reference to data showing solubility)," then that carries more weight than simply saying, "[it] will surely precipitate in benzaldehyde."

Your work is good and interesting, but I still see unanswered questions that need to be addressed.

Quantum_Dom - 18-8-2010 at 11:13

Quote: Originally posted by DDTea  

If you're not sure that PPA*alaninate is being formed, then how can you say that recovering the mystery precipitate is improving the yield and not just contaminating your product?

Did you actually read my post ? I suggest you restart again. Theyres other variables that I have changed from the original write-up. You wont find a single sentence where Im affirming that better yields are obtained because of the extraction of a POSSIBLE PPA*Alaninate. None.

My product was carachterized to a certain extent with physical properties that agreed with the litterature. No I do not have access to NMR or GC/MS.

I dont mind defending my work to youre criticism but as a form of respect you should at least read the post entirely. You admited not so long ago that you didnt even do that. Not very rational. Seems to me that even If I would break down the process quantum mechanically you would still argue. So I guess youll have to take what I give you or otherwise refute my work if you are such an authority.:)


DDTea - 18-8-2010 at 12:07

Quote: Originally posted by Quantum_Dom  
Quote: Originally posted by DDTea  

If you're not sure that PPA*alaninate is being formed, then how can you say that recovering the mystery precipitate is improving the yield and not just contaminating your product?

Did you actually read my post ? I suggest you restart again. Theyres other variables that I have changed from the original write-up. You wont find a single sentence where Im affirming that better yields are obtained because of the extraction of a POSSIBLE PPA*Alaninate. None.

My product was carachterized to a certain extent with physical properties that agreed with the litterature. No I do not have access to NMR or GC/MS.

I dont mind defending my work to youre criticism but as a form of respect you should at least read the post entirely. You admited not so long ago that you didnt even do that. Not very rational. Seems to me that even If I would break down the process quantum mechanically you would still argue. So I guess youll have to take what I give you or otherwise refute my work if you are such an authority.:)



You're really touchy. I'm not attacking you personally, just chill out and address the points at hand. You asked for criticism, so I'm pointing out things that you're not adequately addressing--things that would make this whole write-up a lot stronger than it currently is.

You don't need NMR or GC/MS to determine the structure and quantum mechanics isn't so important here. What you DO need is good experimental design.

You DID say this:
Quote:

It is basically on those last two points that I believe my work-up of the reaction is superior, cleaner and brings a better yield of clean racemic PPA*HCl. Heres the protocol


One of those last two points was the issue of recovering PPA from supposed PPA*Alaninate. If you can't clearly show that what you are recovering is, in fact, PPA, then you cannot show that your reaction is "cleaner"--because you may well have a contaminated product.

It's not enough to simply believe your work-up is superior, cleaner, and brings a better yield of clean racemic PPA*HCl. You have to prove it, which you did not.

Another suggestion: why would you change so many variables in a single run? Why not show how each one, independently, affects the yield so that every change can be quantified?

Maybe if you drew a tree diagram of the steps of your work-up that shows what you expect is in the portions you save and the portions you discard, this would be even clearer. Something quick in MS Paint would suffice.

[Edited on 8-18-10 by DDTea]

Quantum_Dom - 18-8-2010 at 12:59

Quote:

You're really touchy. I'm not attacking you personally, just chill out and address the points at hand.You asked for criticism, so I'm pointing out things that you're not adequately addressing


Oh Im pefectly calm good sir. I just dont argue for the sake of arguing, its a waste of time thats all. You were rather deforming and misquoting what I was stating while bluntly admitting along the way you were unfamiliar with the topic and havent read the entire thread. Its a little disrespectful, thats all. I took the time to organize a proper timeline and joined many references so that the least one who wants to criticize has to do is fully analyze whats at stake first.


Quote:

You don't need NMR or GC/MS to determine the structure

what do you need then to caractherize a structure ? Other options are brute-force physical carachteristics. Surely you were not implying assumption and deduction, that would be incomplete and unscientific as you stated earlier.

Quote:

What you DO need is good experimental design.

Theyres always room for improvement I agree and looking forward to.

Quote:

You DID say this:

It is basically on those last two points that I believe my work-up of the reaction is superior, cleaner and brings a better yield of clean racemic PPA*HCl. Heres the protocol[/rquote]

One of those last two points was the issue of recovering PPA from supposed PPA*Alaninate. If you can't clearly show that what you are recovering is, in fact, PPA, then you cannot show that your reaction is "cleaner"--because you may well have a contaminated product.

Im fairly sure I provided enough evidence based on previous studies and reports that my product is clean and well carachterize. Is it ACS reagent grade ? I doubt it. You seem to stick to the notion that the point of this experiment was to prove that a PPA*alaninate was actually generated and recuperating it is the whole reason why yields are greater. If it were, I would actually have tried to isolate the damn thing instead of going through all that trouble dont you think ?

I used the terms "basically" and "possibility" meaning that I had no proof whatsoever to affirm that it was one of the variable or all the variables that increased the yield and yes...give a cleaner product (maybe you should have a look at the previous thread I was quoting and then youll understand the purpose of the adjective cleaner in this context).


Quote:

It's not enough to simply believe your work-up is superior, cleaner, and brings a better yield of clean racemic PPA*HCl. You have to prove it, which you did not.

Of course I did not...according to you. You are actually incapable of giving a single argument on why I failed to do so.

Quote:

Another suggestion: why would you change so many variables in a single run? Why not show how each one, independently, affects the yield so that every change can be quantified?

Because the purpose of this experiment was to increase the yield of PPA*HCl period. It was never meant to be a kinetic study of alaninate salts formation in Benzaldehyde or the partition coefficient determination of aminoalcohols. All succeptible modifications were considered at the same time to maximize the probability of PPA isolation.

Quote:

Maybe if you drew a tree diagram of the steps of your work-up that shows what you expect is in the portions you save and the portions you discard, this would be even clearer. Something quick in MS Paint would suffice.

Again I hardly see where you getting at. I admit product isolation can sometimes be synonymous with art but the substrate at stake here does not even come close to require such a scheme IMO. Thanks for the suggestion though.


[Edited on 18-8-2010 by Quantum_Dom]

Globey - 18-8-2010 at 15:53

Totally awesome job!!!

12332123 - 20-8-2010 at 04:38

This is really great, but could you please quickly clarify something for me? When you say you used a 1:3 HCl soln in isopropyl alcohol do you refer to an anhydrous soln of the gas or a simple mixture of concentrated acid and alcohol?

Quantum_Dom - 20-8-2010 at 05:00

Quote: Originally posted by 12332123  
This is really great, but could you please quickly clarify something for me? When you say you used a 1:3 HCl soln in isopropyl alcohol do you refer to an anhydrous soln of the gas or a simple mixture of concentrated acid and alcohol?


No, I used 1 part muriatic acid to 3 parts IPA.

Ephoton - 20-8-2010 at 05:01

hmmm goodbye darzen :(

Quantum_Dom - 20-8-2010 at 05:07

Quote: Originally posted by Ephoton  
hmmm goodbye darzen :(


LOL why ? Yield-wise I doubt the procedure with deactivated benzaldehydes will ever be viable, even with N-methylated amino acids. Its just fun to tackle as a challenge and so should be working with the Darzen ;).

[Edited on 20-8-2010 by Quantum_Dom]

Melgar - 24-8-2010 at 06:26

Awesome! I can see QD's annoyance at arguing on the same topic over and over based on what is a fairly trivial part of the reaction. I had to do that recently with a professor who kept insisting that because I didn't know the exact reaction mechanism at one point of a reaction, then clearly I had no clue what I was doing. Never mind all my proof that the synthesis worked.

I'm curious as to whether anyone here has worked with ion-exchange resin. It can be very effective at separating ions from everything else, and could potentially pull all the amines out of an aqueous solution with very good yields. Since three or four different amines are produced with this reaction, it may not be that valuable, but could be helpful for cleanup at the end.

Quantum_Dom - 24-8-2010 at 08:30

Quote: Originally posted by Melgar  
Awesome! I can see QD's annoyance at arguing on the same topic over and over based on what is a fairly trivial part of the reaction. I had to do that recently with a professor who kept insisting that because I didn't know the exact reaction mechanism at one point of a reaction, then clearly I had no clue what I was doing. Never mind all my proof that the synthesis worked.


Haha, yes I know that feeling all too well. I must admit I was a little tired and impatient on the day I exchanged with DDTea and later apologized via U2U for being harsh. ;)



Quote: Originally posted by Melgar  

I'm curious as to whether anyone here has worked with ion-exchange resin. It can be very effective at separating ions from everything else, and could potentially pull all the amines out of an aqueous solution with very good yields. Since three or four different amines are produced with this reaction, it may not be that valuable, but could be helpful for cleanup at the end.


Good point. I would love to have a more detailed report on what exactly constitutes the mixture after the condensation/decarboxylation step. One thing I noticed and didnt talked about in my original post is that the benzylamine formation seemed to be fairly reduced as the distillate recovered was essentially colorless and transparent and didnt had that yellow-red tone than previous runs where lower equivalents of benzaldehyde was used. It could still have been trapped and failed to carry over so of course its purely speculative.





[Edited on 24-8-2010 by Quantum_Dom]

alternative solvent to DCM or possible modification to workup?

percholator - 24-8-2010 at 11:25

Sorry, a bit of a novice here. (And sorry if a bit off topic)

For curiosity's sake, I was wondering if there might be a suitable alternative to DCM as a solvent for removing the DPEA in the workup (preferably non-halogenated). Also, might it be possible to modify the workup to include centrifugation instead? Thanks in advance.

Quantum_Dom - 24-8-2010 at 12:25

Quote: Originally posted by percholator  
Sorry, a bit of a novice here. (And sorry if a bit off topic)

For curiosity's sake, I was wondering if there might be a suitable alternative to DCM as a solvent for removing the DPEA in the workup (preferably non-halogenated). Also, might it be possible to modify the workup to include centrifugation instead? Thanks in advance.


Well you could still use toluene to remove the benzaldehyde and other impurities in the acidic extract but an halogenated solvent is an absolute must to remove DPEA*HCl (I dont know about Tetrachloroethylene). If you cant do that, youll need to freebase the amines and fractionally distill the PPA. Perhaps an isolation exploiting respective solubilities could work too. I never tried. Why not try it and report back ? :).

Youll need to explain in which part of the procedure youre considering centrifugation as I am not following you.

percholator - 24-8-2010 at 12:52

Correct me if I'm wrong (I cannot easily find credible info on the BP of all amines formed), but it looks like PPA would be the first fraction to come over and with decent margin of separation over the other fractions. Would there be any worries about thermal degradation of product? If so, to what extent might this be a problem and how might the distillate be cleaned? Would multiple distillations be required for decent purity?

Please excuse my lack of knowledge, I am still very new to the hobby, and am just trying to familiarize myself with some concepts through specific examples. I will try and find out the answers to these questions while I wait on a reply here. Thanks again :)

percholator - 24-8-2010 at 12:58

Sorry, forgot to include this, but in regards to the distillation of the freebase amines, I am more interested in conditions where it is carried out under atmospheric pressures.

Quantum_Dom - 24-8-2010 at 12:59

Quote: Originally posted by percholator  
Correct me if I'm wrong (I cannot easily find credible info on the BP of all amines formed), but it looks like PPA would be the first fraction to come over and with decent margin of separation over the other fractions. Would there be any worries about thermal degradation of product? If so, to what extent might this be a problem and how might the distillate be cleaned? Would multiple distillations be required for decent purity?

Yes youll need to have a reliable vacuum source to perform such a distillation and the racemic PPA fraction is the first one expected.


Quote: Originally posted by percholator  

Please excuse my lack of knowledge, I am still very new to the hobby, and am just trying to familiarize myself with some concepts through specific examples. I will try and find out the answers to these questions while I wait on a reply here. Thanks again :)

I see, no worries. We all have been there. But I would suggest you first educate yourself through general litterature and then consider specific concepts.

QD

percholator - 24-8-2010 at 13:10

Thanks! I will definitely familiarize myself with the basic concepts first. Would you personally have any recommendations? Maybe some online resources?

When I do get to a point where I am knowledgeable enough and have the resources, I'll give this reaction a shot with distillation as part of the workup and report back :)

Quantum_Dom - 24-8-2010 at 13:19

Quote: Originally posted by percholator  
Thanks! I will definitely familiarize myself with the basic concepts first. Would you personally have any recommendations? Maybe some online resources?

When I do get to a point where I am knowledgeable enough and have the resources, I'll give this reaction a shot with distillation as part of the workup and report back :)


Vogel's Textbook of Practical Organic Chemistry- A. I. Vogel

The Organic Chem Lab Survival Manual: A Student's Guide to Techniques- James W. Zubrick

Good luck and have fun ! :)

QD

Methyl.Magic - 25-8-2010 at 10:45

Today I started your method today, I used 5.3 eq of benzaldehyde instead of 6 and I refluxed for 8h ! The solution is amber and honey-like. I'll post pictures and workup tomorrow or later... It looks promising though.

Quantum_Dom - 25-8-2010 at 10:47

Quote: Originally posted by Methyl.Magic  
Today I started your method today, I used 5.3 eq of benzaldehyde instead of 6 and I refluxed for 8h ! The solution is amber and honey-like. I'll post pictures and workup tomorrow or later... It looks promising though.


Awesome, it will be nice to know how much, if any, extra benzaldehyde is overkill.

Thanks again Methyl (and remember KEEP ALL PHASES untill the end :P !)

Oh...and does it look like this ?

pic_amber.gif - 148kB

[Edited on 25-8-2010 by Quantum_Dom]

Methyl.Magic - 25-8-2010 at 11:03

The color of my solution is darker (amber-like) and has a honey consistency. I havent treated it with AcOH in toluene (why ???) nor with HCl 15percent yet...

Quantum_Dom - 25-8-2010 at 11:05

Quote: Originally posted by Methyl.Magic  
The color of my solution is darker (amber-like) and has a honey consistency. I havent treated it with AcOH in toluene (why ???) nor with HCl 15percent yet...


Ohhhh nevermind then, this picture is when the aqueous layer is clean from the DCM washes and is ready to be freebased. Forget it ;),

Glacial acetic acid being soluble in toluene, this step was performed in order to protonate the oxazolidine dissolved in the excess benzaldehyde and make it more prone to hydrolysis latter on. I have no evidence if this step is necessary but I was inspired by the Yokohama et al. article were it is used. Dont do it if you feel like its useless, its your procedure ;).

[Edited on 25-8-2010 by Quantum_Dom]

Methyl.Magic - 25-8-2010 at 11:15

ok thansk for the info, I understood you used AcOH in toluene because of its higher solubility than aqueous HCl. I'll try to add only AcOH. I'm going to the lab to take some photos. I'll post these here in about one hour.

Quantum_Dom - 25-8-2010 at 11:20

Quote: Originally posted by Methyl.Magic  
ok thansk for the info, I understood you used AcOH in toluene because of its higher solubility than aqueous HCl. I'll try to add only AcOH. I'm going to the lab to take some photos. I'll post these here in about one hour.


Hmmm I think you should still add some np solvent like toluene or xylene in there tough, otherwise you might have a hard time separating the two phases after hydrolysis. The role of the toluene is also to dissolve all the tar and water insolubles.I dont know, you might have a hard time if you dont do it,

And I did used AcOH because of its superior solubility in non polar solvents, thats the whole point.



[Edited on 25-8-2010 by Quantum_Dom]

Methyl.Magic - 25-8-2010 at 12:52

Here is the benzaldehyde I used. It was quite old. You can't see well on the picture but there is a 2-3cm layer of benzoic acid crystals. Therefore BnO was washed with 1N NaOH and brine to remove the possible benzoic acid present in the BnO. The benzaldehyde was not dried after the washing.


339 g (3.20 mol, 5.3eq based on l-alanine) of Benzaldehyde are poured in a 500ml RBF.




54.3 g (0.6 mol) of l-alanine are weighed out and finely crushed with a pistil before being added to the benzaldehyde.






A reflux condenser fitted with a recovering tap is added to the RBF and the mixture is stirred for 30 min (l-alanine is not totally soluble in BnO) and refluxed overnight for 8h. Only about 30ml of water/benzaldehyde are recovered. I thought I could recover more benzaldehyde, so I placed vacuum to get a few ml of BnO/water again. I understood it was not possible to recover more BnO, therefore I turned off the pump. There are some benzoic acid crystals in the appartus (see arrow on the picture)




The solution is dark amber and honey-like (high viscosity). As you can see, I tilted the flask at 90 degree and I could take the picture on time (the liquid was not horizontal yet).



I added 30ml AcOH, swirled the flask because my stirbar is too little to be effective. I diluted it with 150 ml of toluene and magnetically stirred it for the night. I'll continue tomorrow morning.


[Edited on 25-8-2010 by Methyl.Magic]

Quantum_Dom - 25-8-2010 at 12:57

Looks good :). Im suprised how clean you post-reaction is though :o. It seems clearer than mine but perhaps its just an optical effect as I definitely see the viscous nature when I zoom in on the pic.

At what temperature was the system ? You mentionned reflux so I assume it was higher than 160 0C ???

Thank you and looking forward for more :).

QD



[Edited on 25-8-2010 by Quantum_Dom]

roamingnome - 25-8-2010 at 17:40

@ Quantum_Dom

you said you used you used DL alanine
it is said that this doesn't play a role in this reaction mechanism anyway. But im rusty on those particulars now.

but M.M is clearly using L it might be interesting to see yield variances or product racemization as this reaction gets going.
That may be to difficult without special equipment though.

cheers though!

:cool:

Quantum_Dom - 25-8-2010 at 17:51

Quote: Originally posted by roamingnome  
@ Quantum_Dom

you said you used you used DL alanine
it is said that this doesn't play a role in this reaction mechanism anyway. But im rusty on those particulars now.

but M.M is clearly using L it might be interesting to see yield variances or product racemization as this reaction gets going.
That may be to difficult without special equipment though.

cheers though!

:cool:


Thanks ! :)

You know, previously when asked if theyre could be any product stereoselectively depending on the amino acid chirality, I always responded the usual answer: absolutely not. But Yokoyama reports a counterintuitive diastereomeric ratio for some substrates when N-methylalanine is used. Note that all the activated benzaldehydes present a diastereomeric excess. I have no clue why though as its...well... all japanese to me. So the issue you brought-up is definitely not trivial. Have a look. :)

QD

Attachment: Yuusaku Yokoyama.pdf (117kB)
This file has been downloaded 912 times











[Edited on 26-8-2010 by Quantum_Dom]

Nicodem - 26-8-2010 at 01:20

Quote: Originally posted by Quantum_Dom  
You know, previously when asked if theyre could be any product stereoselectively depending on the amino acid chirality, I always responded the usual answer: absolutely not. But Yokoyama reports a counterintuitive diastereomeric ratio for some substrates when N-methylalanine is used. Note that all the activated benzaldehydes present a diastereomeric excess. I have no clue why though as its...well... all japanese to me. So the issue you brought-up is definitely not trivial. Have a look. :)

Do not confuse diastereoselectivity with enantioselectivity! Diastereoselectivity is a phenomenon observable even in symmetric reactions and it depends solely on the mechanism and substrate: the typical example thought in the school is the electrophilic addition of Br2 on an alkene double bond where the diastereoselectivity is extremely high (anti addition). In this specific reaction between benzaldehyde and alanine, some degree of diastereoselectivity is bound to be observed as it can be deduced already by the most likely mechanism approach. The transition states leading to each diastereoisomer are at different energy levels, so some selectivity is expected. The diastereomeric ratio is however totally independent of the starting alanine configuration.

Enantioselectivity is something different and could depend on the configuration of the alanine used. However, it is hard to imagine a mechanism for this reaction where racemization does not occur. Still, whenever starting with an asymmetric reaction environment it is always possible that some degree of retention or inversion is observed in the product even when the chiral atom is required to change orbital hybridization in an sp3>sp2>sp3 manner in the expected mechanism. Obviously, chiral induction can never be excluded in an asymmetric media, regardless of the mechanism, but in such case where racemization is part of the mechanism, the enantiomeric excesses are usually low to negligible as they commonly depend on much weaker induction phenomenons (like intermolecular interactions between the transition states and the surrounding chiral molecules). Exceptions are always possible though. However, when starting with a totally symmetric reaction media (DL-alanine) no enantioselectivity can ever be expected, yet there can be expected the diastereoselectivity will be exactly the same regardless of whether you start with L-, D- or DL-alanine.

Also, it is unreasonable to discuss about "activated benzaldehydes" when you do not even define which effects activate them and which don't. The term "activated" in regard to aromatic systems is most commonly used as synonymous to "nucleophilic aromatic Pi-system" and thus activated in regard to electrophilic aromatic substitution (EAS), which is something completely different to what we have here. The electronic effects probably have some major effect to the rate of this reaction, but as seen in table 1 of the paper you attached, an electron poor benzaldehyde (considered "deactivated" for EAS) gave the same yield as the electron moderately rich ones ("activated" for EAS). The two most electron rich ones gave better yields, but since this is not a trend observed in other substrates, you can't say that activation in this reaction corresponds to the "activation" in the same manner as considered in EAS reactions.

Quantum_Dom - 26-8-2010 at 01:50

Nicodem, first of all thank you for taking the time to write such a lengthy critique. I do understand that sometimes people can abuse terminology which can annoy the purists as I am also found of rigor.

I do understand, even better now with this thorough precision, the difference between the two different path at stake and realize the chemical environment on the substrate is essentially determining diastereoselectivity and the latter is absolutely not dictate by the chirality of the amino acid. Again thank you.

Quote: Originally posted by Nicodem  


Also, it is unreasonable to discuss about "activated benzaldehydes" when you do not even define which effects activate them and which don't. The term "activated" in regard to aromatic systems is most commonly used as synonymous to "nucleophilic aromatic Pi-system" and thus activated in regard to electrophilic aromatic substitution (EAS), which is something completely different to what we have here. The electronic effects probably have some major effect to the rate of this reaction, but as seen in table 1 of the paper you attached, an electron poor benzaldehyde (considered "deactivated" for EAS) gave the same yield as the electron moderately rich ones ("activated" for EAS). The two most electron rich ones gave better yields, but since this is not a trend observed in other substrates, you can't say that activation in this reaction corresponds to the "activation" in the same manner as considered in EAS reactions.


Please dont be offended, but arent you a little severe with me here ? ;) First of all I found your explanation for the yield variation of substituted amino-alcohols a little evasive and incomplete. It IS the very electrophilic aromatic substitution that dictates the yield of this reaction and this is what I was referring to all along. If you look at the mechanism of the Akabori reaction that you drew yourself in 2006 youll see that you omitted a crucial side-reaction (probably for clarity's sake but still the mechanism is incomplete). Indeed when the intermediate carbanion is formed, theyre is also the possibility for delocalization of the charge to the benzylic carbon i.e Ph-CH(-)-N=CH-R where Ph is the aromatic ring of the starting aldehyde. Now this step is far from being trivial as it is the main path of many substrates to...did you guess ? Thats right...the corresponding 1,2-diphenylethanolamine derivative.

Im sure you are aware of the fact that some Akabori reaction yield in major proportion the desired amino-alcohol where others yield mainly the corresponding diphenylethanolamine. The main reason for this is the ability for the ring to stabilize the carbanion. The more resonance structures of intermediate carbanions, the more stable it is. The stabler it is, the more likely it will react with one equivalent of the starting aldehyde to yield :

Ph-CH(-)-N=C-R + PhCHO ------- PhCH(CH2(OH)Ph)-N=C-R

which yields after hydrolysis of the imine: PhCH2(OH)CH(NH2)Ph (1,2-diphenylethanolamine)

So as you see, considering the ACTIVATION or DEACTIVATION of substituted benzaldehydes here is far from being unreasonable as you said. Allow me to show you why:

Aldehyde

H : 48 % deactivating for EAS: Stable carbanion. 1,2-diphenylethanolamine favored. Almost parity with amino-alcohol since deactivation is LESS strong.

4-Br : 43 % deactivation for EAS: strongly deactivating group in para position. Stable carbanion. 1,2-diphenylethanolamine favored.

4-OMe: 83 % moderatly activating for EAS: Unstable carbanion amino-alcohol favored.

3,4-OCH2O : 87 % moderatly activating for EAS: Unstable carbanion amino-alcohol favored.

4-NO2 : 45 % deactivating for EAS: strongly deactivating group in para position. Stable carbanion 1,2-diphenylethanolamine favored.

4-Me : 55 % weakly activating for EAS: Unstable carbanion amino-alcohol favored. Almost parity with 1,2-diphenylethanolamine since activation is LESS strong.


So my advice to you for the future will not involve chemistry but rather moderator's etiquette. It would be nice from now on if you could take a few minutes before charging into someone like that, especially if this person is rather new here. Not all of these new members around here are aspiring drug cooks or kewls to whom youre throwing your weight around. So please be careful.


Again, thank you for your time.
QD

[Edited on 26-8-2010 by Quantum_Dom]

roamingnome - 26-8-2010 at 17:44

I thought of one more relevant question!

Did you evaporate that DCM?
If so was there anything in it, and how much?

The 1,2-diphenylethanolamine bi-product is as equally important in reaction discovery and mass balance as the PPA.

Thanks again

how bout alanine recovery too



oh and people are quite moody in science land here, but i wouldn't gripe on nicoderm as he'll rip you a new text book up the arse. some people have just been around long enough


[Edited on 27-8-2010 by roamingnome]

[Edited on 27-8-2010 by roamingnome]

[Edited on 27-8-2010 by roamingnome]

Nicodem - 27-8-2010 at 00:21

Quote: Originally posted by Quantum_Dom  
Nicodem, first of all thank you for taking the time to write such a lengthy critique. I do understand that sometimes people can abuse terminology which can annoy the purists as I am also found of rigor.

Actually, it wasn't a critique, because there was nothing to criticize. A critique necessarily pertains to something someone did. Since this is about concepts and arguments, it is supposed to be a discussion by definition. I do understand that understanding the difference in diastereoselectivity and enantioselectivity is something that takes years to fully comprehend. It is not about terminology, but strictly about concepts. For example, a warning to Methyl.Magic about his misuse of the "Bn" shorthand for benzylidene, instead of using it for benzyl as it generally accepted, would be being a purist about terminology, but the issues about stereoselectivity that I tried to explain are about the (misunderstood) concepts. And if you think it is about terminology, well, then I obviously failed in explaining what it is about.

Quote:
Please dont be offended, but arent you a little severe with me here ? ;) First of all I found your explanation for the yield variation of substituted amino-alcohols a little evasive and incomplete. It IS the very electrophilic aromatic substitution that dictates the yield of this reaction and this is what I was referring to all along.

If you check the table you will see that the nucleophilicity of the aromatic system is not directly connected with the yield in the sense of this being a trend. Also, yields are not directly connected with reaction rates, but in absence of such data, let's stick to yields as relevant. For example, like I already tried to tell you previously, the yields for p-nitro- and p-methylbenzaldehyde are more or less identical even though the first aromatic system is a very poor nucleophile (deactivated for EAS) and the second one is a very much more nucleophilic substrate for EAS. If you try to compare this with the concept of activated/deactivated for EAS, then you need to do this strictly and see if it fits. For example, taking nitration as the typical schoolbook example of EAS, ask yourself if the yield of nitration of p-nitrobenzaldehyde would be the same as for p-methylbenzaldehyde at the conditions where this reacts efficiently. Well, I can tell you that p-nitrobenzaldehyde does not get nitrated at all at such conditions. Now, compare also the yield of p-bromo- and p-nitrobenzaldehyde. Why are they about identical if, as you believe, the yields correlate with activation/deactivation for EAS? Yet, in the Akabori reaction they are apparently similarly reactive (or at least their yield do not differ dramatically). Do you now see the difference between an apparent exception (piperonal, anisaldehyde) and a trend (not observed in the whole series of table 1)?
The reason I said it was unreasonable to discuss in terms of activated/deactivated without defining these, is in that using that you imply you know what activates and what deactivates the substrate for the Akabori reaction. Do you know? Or do you just compare the reaction with EAS, because you are trying to cling on a more familiar reaction? If it is the first then you are expected to give a hypothesis, if it is the second then you are comparing apples and oranges.
If you really want to understand how the substitution pattern on benzaldehydes influences the reactions of benzaldehydes on the carbonyl, then you need to read about the Hammett correlation. This will explain you some things that apparently interest you and for a bonus you will be able to, not only gain new knowledge, but also give up on comparing apples and oranges. Like I already said in my previous reply, if two phenomenons are connected with related electronic effects, it does not mean they are also the one and the same phenomenon: apples and oranges are not the same, even if both are both round.

Quote:
Indeed when the intermediate carbanion is formed, theyre is also the possibility for delocalization of the charge to the benzylic carbon i.e Ph-CH(-)-N=CH-R where Ph is the aromatic ring of the starting aldehyde. Now this step is far from being trivial as it is the main path of many substrates to...did you guess ? Thats right...the corresponding 1,2-diphenylethanolamine derivative.

.......

So as you see, considering the ACTIVATION or DEACTIVATION of substituted benzaldehydes here is far from being unreasonable as you said. Allow me to show you why:

Aldehyde

H : 48 % deactivating for EAS: Stable carbanion. 1,2-diphenylethanolamine favored. Almost parity with amino-alcohol since deactivation is LESS strong.

4-Br : 43 % deactivation for EAS: strongly deactivating group in para position. Stable carbanion. 1,2-diphenylethanolamine favored.

4-OMe: 83 % moderatly activating for EAS: Unstable carbanion amino-alcohol favored.

3,4-OCH2O : 87 % moderatly activating for EAS: Unstable carbanion amino-alcohol favored.

4-NO2 : 45 % deactivating for EAS: strongly deactivating group in para position. Stable carbanion 1,2-diphenylethanolamine favored.

4-Me : 55 % weakly activating for EAS: Unstable carbanion amino-alcohol favored. Almost parity with 1,2-diphenylethanolamine since activation is LESS strong.

This is a more reasonable thinking, but again you failed to notice the same thing. When you will read upon Hammett you will notice that there is a substrate that strikes out of the trend. The substituent that stabilizes the benzylic carboanion the most (actually it is magnitudes more stable than on any other benzaldehyde above) gives the same moderate yield as most other benzaldehydes.
I can't read Japonese. Can you please explain where does it say that the yields are affected by the consumption of alanine in the side reaction forming 1,2-diphenylethanolamine? Where is the table of the ratio between the three products? The paper you attached shows only the ratio between two diastereoisomers of 1-aryl-2-amino-1-propanol. Is there anything more on this topic in the discussion part of the article? Now, if there is an article describing the ratio of all (side) products in relation to the substitution pattern, then that info could give enough information to present a plausible hypothesis on how these substituents (de)activate the substrate toward the Akabori reaction. But in the absence of such information I propose not to propose anything even remotely unreasonable at all. There is no reason for being unreasonable.

Quote:
So my advice to you for the future will not involve chemistry but rather moderator's etiquette. It would be nice from now on if you could take a few minutes before charging into someone like that, especially if this person is rather new here. Not all of these new members around here are aspiring drug cooks or kewls to whom youre throwing your weight around. So please be careful.

If for whatever reason you find it important to to keep an appearance of not being a drug cook, then I can tell you that your habit, of going into a paranoid mode whenever someone wants to start a discussion in this thread, is certainly not helping. Perhaps your over-sensitivity might not be that obvious or annoying to yourself, but it sure is surprising and annoying to me. So, my humble suggestion is to stick to discussing chemistry and stay away from forum moderation policy. If I would consider you a kewl or drug cook, do you seriously believe I would have wasted time trying to direct you to more knowledge and understanding? But perhaps I was wrong like I often am.

Quantum_Dom - 27-8-2010 at 11:05

Quote: Originally posted by roamingnome  
I thought of one more relevant question!

Did you evaporate that DCM?
If so was there anything in it, and how much?

The 1,2-diphenylethanolamine bi-product is as equally important in reaction discovery and mass balance as the PPA.

Thanks again

how bout alanine recovery too



oh and people are quite moody in science land here, but i wouldn't gripe on nicoderm as he'll rip you a new text book up the arse. some people have just been around long enough

[Edited on 27-8-2010 by roamingnome]


Thanks for the advice roamingnome. I have nothing to gain or lose here and I surely not am intimidated by anyone regardless of theyre reputation. That being said, I am not here to get into argumentative wars either and will therefore debate when valid debatable issues are involved

I did recover most of the DCM used to wash the acidic extracts but what remained was mostly viscous sludge with a strong benzaldehyde smell. No attempt to analyze it was done. I certainly am taking notes on your proposal. The remaining alanine, if any, is extracted in the aqueous phase so I think it would be quite cumbersome in trying to recover it.

Quote: Originally posted by Nicodem  
Actually, it wasn't a critique, because there was nothing to criticize. A critique necessarily pertains to something someone did. Since this is about concepts and arguments, it is supposed to be a discussion by definition. I do understand that understanding the difference in diastereoselectivity and enantioselectivity is something that takes years to fully comprehend. It is not about terminology, but strictly about concepts. For example, a warning to Methyl.Magic about his misuse of the "Bn" shorthand for benzylidene, instead of using it for benzyl as it generally accepted, would be being a purist about terminology, but the issues about stereoselectivity that I tried to explain are about the (misunderstood) concepts. And if you think it is about terminology, well, then I obviously failed in explaining what it is about.


No you didn’t failed at all, again my poor vocabulary comes into the balance and disrupts the equilibrium. I know it is no excuse but I do not speak english as a first language as I am sure you already realized. So sometimes I get lost in translation and uses words that I think are synonyms. Critique which is opinion-related and correction which is fact-related are surely not, same thing goes for terminology and concepts, so again my bad.
Quote: Originally posted by Nicodem  

If you check the table you will see that the nucleophilicity of the aromatic system is not directly connected with the yield in the sense of this being a trend. Also, yields are not directly connected with reaction rates, but in absence of such data, let's stick to yields as relevant.

Well I agree that their is surely no linear correlation between the two and yields are depending on many, microscopic and macroscopic, variables. But still, I do see a relevant trend. If one could run a few quantum-mechanical calculations, and numerically assign a value to the activation potential of a given functionality, Im fairly sure one could appreciate much more the relation between the two. Using solely yield here is imprudent but not irrelevant.
Quote: Originally posted by Nicodem  

For example, like I already tried to tell you previously, the yields for p-nitro- and p-methylbenzaldehyde are more or less identical even though the first aromatic system is a very poor nucleophile (deactivated for EAS) and the second one is a very much more nucleophilic substrate for EAS.


Im sorry, I thought you were referring to benzaldehyde and p-methylbenzaldehyde in your original reply. Perhaps actually mentioning them in your post could have avoided such confusion and enabled you to not have to repeat yourself ?

Quote: Originally posted by Nicodem  

If you try to compare this with the concept of activated/deactivated for EAS, then you need to do this strictly and see if it fits. For example, taking nitration as the typical schoolbook example of EAS, ask yourself if the yield of nitration of p-nitrobenzaldehyde would be the same as for p-methylbenzaldehyde at the conditions where this reacts efficiently. Well, I can tell you that p-nitrobenzaldehyde does not get nitrated at all at such conditions. Now, compare also the yield of p-bromo- and p-nitrobenzaldehyde. Why are they about identical if, as you believe, the yields correlate with activation/deactivation for EAS? Yet, in the Akabori reaction they are apparently similarly reactive (or at least their yield do not differ dramatically).

I couldn’t agree more with the nitration example but I fail to see where did at any point mentioned that the Akabori reaction involved an actual substitution on the aromatic ring ? Besides, no carbocation is ever involved so I don’t understand why you would bring the nitration reaction to the table. Also, the efficiency of the substitution reactions you are referring to is dependant on the nature of the electrophile involved. Sure, the yield between p-nitrobenzaldehyde and p-methylbenzaldehyde are marginally different but the trend is still respected regardless on how small the difference is. Correct me if Im wrong but both halides and nitro functionalities are deactivating groups and therefore fail to see where one should refute my statement by observing theyre similar yield as an anomaly. As I said previously, yields are affected by a great deal of variables and using them as a reaction rate substitute is imprudent but not
irrelevant.

Quote: Originally posted by Nicodem  

Do you now see the difference between an apparent exception (piperonal, anisaldehyde) and a trend (not observed in the whole series of table 1)?

I always did, way before we engaged in this discussion actually. But so far, even with your valid but unconvincing arguments, I do not consider qualifying this observation as unreasonable. And no, I am not saying that to be argumentative.

Quote: Originally posted by Nicodem  

The reason I said it was unreasonable to discuss in terms of activated/deactivated without defining these, is in that using that you imply you know what activates and what deactivates the substrate for the Akabori reaction. Do you know? Or do you just compare the reaction with EAS, because you are trying to cling on a more familiar reaction? If it is the first then you are expected to give a hypothesis, if it is the second then you are comparing apples and oranges.

Well as, I said previously, I fail to see where did at any point mentioned that the Akabori reaction involved an actual substitution on the aromatic ring. Stating that a substrate is expected to be activated/deactivated because of the nature of its substituents and therefore predicting how the said substrate will stabilize an intermediate carbanion is valid as far as Im concerned. It does not constitute an abuse of language nor confusion of multiple unrelated phenomenas.

Quote: Originally posted by Nicodem  

If you really want to understand how the substitution pattern on benzaldehydes influences the reactions of benzaldehydes on the carbonyl, then you need to read about the Hammett correlation.

Thanks for the reference, I was aware of Hammett's equation and this is the whole reason I mentionned previously that theyre was no linear correlation between the two observables. Though Im fairly sure my understanding is sound so far weather you seem to judge it impaired or not.

Quote: Originally posted by Nicodem  

if two phenomenons are connected with related electronic effects, it does not mean they are also the one and the same phenomenon: apples and oranges are not the same, even if both are both round.

Well you sure right about that. But I don’t see how this is relevant to this case as you haven’t shown in any ways so far that I have made such a ludicrous misconception.

Quote: Originally posted by Nicodem  

This is a more reasonable thinking

Coming from you Ill take that as a compliment.

Quote: Originally posted by Nicodem  

but again you failed to notice the same thing. When you will read upon Hammett you will notice that there is a substrate that strikes out of the trend. The substituent that stabilizes the benzylic carboanion the most (actually it is magnitudes more stable than on any other benzaldehyde above) gives the same moderate yield as most other benzaldehydes.
I can't read Japonese. Can you please explain where does it say that the yields are affected by the consumption of alanine in the side reaction forming 1,2-diphenylethanolamine? Where is the table of the ratio between the three products? The paper you attached shows only the ratio between two diastereoisomers of 1-aryl-2-amino-1-propanol. Is there anything more on this topic in the discussion part of the article?

Actually this is not even an article but a simple abstract from a conference proceeding. The actual information that I have on the influence of the substituents versus nature of the product has been published in several study regarding the decarboxylation of amino acids in aromatic aldehydes.. Would you like me to dig them up and post them here ?

Quote: Originally posted by Nicodem  

Now, if there is an article describing the ratio of all (side) products in relation to the substitution pattern, then that info could give enough information to present a plausible hypothesis on how these substituents (de)activate the substrate toward the Akabori reaction. But in the absence of such information I propose not to propose anything even remotely unreasonable at all. There is no reason for being unreasonable.

I agree, I should have been more rigorous and post actual published data before making a statement.

Quote: Originally posted by Nicodem  

If for whatever reason you find it important to to keep an appearance of not being a drug cook, then I can tell you that your habit, of going into a paranoid mode whenever someone wants to start a discussion in this thread, is certainly not helping. Perhaps your over-sensitivity might not be that obvious or annoying to yourself, but it sure is surprising and annoying to me. So, my humble suggestion is to stick to discussing chemistry and stay away from forum moderation policy. If I would consider you a kewl or drug cook, do you seriously believe I would have wasted time trying to direct you to more knowledge and understanding? But perhaps I was wrong like I often am.


I am sorry if my challenging comment was interpreted as rude. It was not my intention. But I have to admit that the term unreasonable in my language is pretty strong and synonymous with foolishness. Now I don’t know if it was the actual intent you were giving it to it in this particular situation but I felt it was a little exaggerated of you and so I responded with emotion. I am sorry. I do appreciate a lot that you even take the time to respond to me (this applies to anyone who contributes to this thread as well) and will surely be more careful in the future if you can forgive my lack of judgment.

Best Regards,
QD

EDIT: In parallel to all this I completely forgot that I was looking forward to upload the entire japanese collection of Akabori-related studies. I dont think it was ever uploaded here so please give a heads-up if it where. This is as thorough as I could found on this particular reaction and yes it is in japanese with random parts in english. And no, babel fish does not yield a clean translation nor does google translate :( So if any kind soul, who happens to be fluent in japanese, can help out with translating the main interesting parts, it would be greatly appreciated.

Attachment: Akabori.Momotani- Ephedrine and adrenaline system.pdf (318kB)
This file has been downloaded 1197 times

Attachment: Akabori.Momotani-About a new mode of formation of ephedrine and related compounds.pdf (357kB)
This file has been downloaded 1264 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. I.pdf (1022kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. II.pdf (848kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. III.pdf (752kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. IV.pdf (920kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. V.pdf (539kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. VI.pdf (746kB)
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Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. VII.pdf (564kB)
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[Edited on 28-8-2010 by Quantum_Dom]

Nicodem - 28-8-2010 at 03:20

Quote: Originally posted by Quantum_Dom  

Well I agree that their is surely no linear correlation between the two and yields are depending on many, microscopic and macroscopic, variables. But still, I do see a relevant trend. If one could run a few quantum-mechanical calculations, and numerically assign a value to the activation potential of a given functionality, Im fairly sure one could appreciate much more the relation between the two. Using solely yield here is imprudent but not irrelevant.

You can do quantum-mechanical calculations as a way to evaluate electronic effects on a reaction rate or equilibrium, only if you know at least two important things: the identity of the rate limiting step and its transition state. Also, this can not give anything but relative values and even these poorly take into account the solvent and other interactions. And nothing about side reactions. I did not review the literature on the Akabori reaction, but from what I read there is nearly not enough information to conclude anything about these things.

Quote:
I couldn’t agree more with the nitration example but I fail to see where did at any point mentioned that the Akabori reaction involved an actual substitution on the aromatic ring ? Besides, no carbocation is ever involved so I don’t understand why you would bring the nitration reaction to the table.

Exactly my point that I'm desperately trying to put forward since my first reply here. I was trying to warn you that using phrases as activated and deactivated is misleading to those who read your posts, because most people use those as synonymous to aromatic ring nucleophilicity in regard to their interaction with electrophiles (that is EAS). You should have defined what you mean by (de)activated in the context of the Akabori reaction, but then you did the exact opposite and compared the substrate reactivity to be that of EAS reactions. And that is why I gave you the example above, so that you could have a chance to see how such comparison makes no sense in regard to the given yields.

Quote:
Correct me if Im wrong but both halides and nitro functionalities are deactivating groups and therefore fail to see where one should refute my statement by observing theyre similar yield as an anomaly.

Actually, halogens are activating by resonance and deactivating by induction, while nitro is deactivating by both, resonance and induction. Thus halogens are ortho/para directing and deactivating, while nitro is meta directing and strongly deactivating. The methyl substituent is activating by hyperconjugation and nearly neutral by induction, thus ortho/para directing. But all this is only in regard to the EAS reaction. Their electronic effects in other reactions can be activating or deactivating and how this occurs has no direct relation to the electrophilic aromatic substitution. For example, in the reaction of HCN with substituted benzaldehydes (another reaction that has nothing to do with EAS) the p-nitro substituent gives an equilibrium constant of 1420 while the p-methoxy substituent gives only 32. In another example, in the nucleophilic substitution on benzyl halides, the p-nitro substituent is deactivating while the p-methoxy is activating. As you see, even though the new bond formation takes place in the same benzylic position influence of the same para-substituents can be the opposite - that's because they are different reactions, with different transition states and different rate limiting steps. The electronic effects can have opposite effects and what I was afraid you was doing, and it later on turned to be the case, was that you was trying to generalize reactivity in the Akabori reaction with that of EAS, which would be the "unreasonable" part. Here the word "unreasonable" was used in the strict dictionary meaning of "not guided by reason or sound judgement" or "not in accordance with practical realities", though now that I actually checked the dictionary it also says it can have the meaning of "not having the faculty of reason", which is obviously the one that upsets you (English is not my native language either!).

Quote:
Quote: Originally posted by Nicodem  

if two phenomenons are connected with related electronic effects, it does not mean they are also the one and the same phenomenon: apples and oranges are not the same, even if both are both round.

Well you sure right about that. But I don’t see how this is relevant to this case as you haven’t shown in any ways so far that I have made such a ludicrous misconception.

For one thing there is no trend in yields, just two exceptions in a small series. Nothing really can be concluded from that in regard to substrate reactivity, except that those two were found to give better yields. That is without considering the fact that reactivity does not necessarily reflects in yields.
What appears as an misconception is that you believe you know what substitution pattern acts as activating or deactivating for the Akabori reaction. My goal was to show you that such belief is impairing your judgement (like every belief does by definition), not specifically in regard to this reaction, but chemical reactivity in general. It is simply misleading to use prejudices in evaluating reactivity (thinking in terms of de/activating effects in EAS when the reaction is not EAS) rather than evaluate the origins of reactivity (electronic and steric effects, which are common to Akabori, EAS and all the other reactions). Once you will go beyond that way of simplistic thinking many things will become clearer to you (and many new questions will arise).

Quote:
Actually this is not even an article but a simple abstract from a conference proceeding. The actual information that I have on the influence of the substituents versus nature of the product has been published in several study regarding the decarboxylation of amino acids in aromatic aldehydes.. Would you like me to dig them up and post them here?

If there is such information that can shed light on the reaction mechanism, then it is certainly a good idea to make a review and post it here. For one, I would be interested in reading more about it, but perhaps I'm not the only one.
Quote:
But I have to admit that the term unreasonable in my language is pretty strong and synonymous with foolishness. Now I don’t know if it was the actual intent you were giving it to it in this particular situation but I felt it was a little exaggerated of you and so I responded with emotion.

It it was not my intent to say that you are being foolish or in any way offend you. You should have a better opinion of yourself and be more self confident about your abilities, after all you demonstrated you are skilled in experimental work and that you have a understanding of what you are doing. Now demonstrate you are skilled also in your learning abilities and try to go further. I can guarantee you, that whatever new you will learn will reflect in further improvements in designing experiments.

Quantum_Dom - 28-8-2010 at 03:32

Please see my previous post for recently uploaded articles

Other batch of the japanese collection of Akabori-related studies:


Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part I.pdf (455kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part II.pdf (570kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part III.pdf (385kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part IV.pdf (500kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part V.pdf (476kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part VI.pdf (213kB)
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Attachment: Chemical Reactions of Amino Acids with Aldehydes. Part VII.pdf (312kB)
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--------------------------------------------------------------------------------
Quote: Originally posted by Nicodem  

You can do quantum-mechanical calculations as a way to evaluate electronic effects on a reaction rate or equilibrium, only if you know at least two important things: the identity of the rate limiting step and its transition state. Also, this can not give anything but relative values and even these poorly take into account the solvent and other interactions. And nothing about side reactions. I did not review the literature on the Akabori reaction, but from what I read there is nearly not enough information to conclude anything about these things.

Youre right. These quantities, for what they would be worth, would not bring anything signifcant to the problem at stake here since it is a poorly understood dynamical system after all and no information regarding the environment would be considered either. My bad.

Quote: Originally posted by Nicodem  

Exactly my point that I'm desperately trying to put forward since my first reply here. I was trying to warn you that using phrases as activated and deactivated is misleading to those who read your posts, because most people use those as synonymous to aromatic ring nucleophilicity in regard to their interaction with electrophiles (that is EAS). You should have defined what you mean by (de)activated in the context of the Akabori reaction, but then you did the exact opposite and compared the substrate reactivity to be that of EAS reactions. And that is why I gave you the example above, so that you could have a chance to see how such comparison makes no sense in regard to the given yields.


Well Nicodem believe it or not but I finally understand where you were coming from all along and I cant believe I didnt realized it sooner since you were so obviously dangling the answer in front of me (I know I am slow). Of course I was wrong and I was indeed mixing apples and oranges (mind you I knew the expression and didnt need an explicit definition :P). The simplest analogy I can come up with, as I write these lines, is that a carboxylic acid moiety might have a carbonyl functionality, like a ketone for example, and yet the two behave completely different chemically. So it would be wrong, and downright unreasonable, to assume that a ketone would react with ammonia by solely referring to acid-base reactivity.

Just like electronic effects, such as inductive or resonance, are involved in substituted aromatic systems, and therefore surely in electrophilic aromatic substitution mechanisms too, using them to describe a certain effect on a system does NOT implicate that one will deal with an electrophilic aromatic substitution problem per se! Basically I was using the concepts (activation/deactivation) of EAS to describe the influence of electro-withdrawing(donating) functionalities on an aromatic sytem even though no electrophilic substitution phenomena where ever involved in the first place. I sure see how that could mislead a reader to conclude otherwise as it is a widely known and studied topic. Hehe…but of course you knew that all along. I appreciate youre heads-up and patience for repeating yourself so often. So thank you.

If I can manage to find it, I still will post the study I was referring to regarding the substituent pattern on the ring versus the yield of reaction (notice that I didn’t used any unreasonable terminology here ;)) It might be something worthwhile in the long run, who knows. But that’s a whole different story.

Regards,
QD

[Edited on 28-8-2010 by Quantum_Dom]

Methyl.Magic - 30-8-2010 at 10:57

Hello,

Today I bring up news of my work up:

The honey-like liquid is poured into a 1000ml erlenmeyer, and is treated with 400ml 15% HCl. The RBF was washed with 2x 50 ml toluene. The three-phase mixture is strongly stirred at RT for 5 days. I have to point out the QD extraction was much better because he used DCM instead of toluene and DCM will probably mix with tar and decrease its viscosity, making the PPA more able to be dissolved in the water phase. That's why I let stirred for 5 days : to be sure all the PPA is in the water phase. You can also heat but I got the time because I was working on other projects ;).

5 days later, the toluene and most of the HCl is manually separated and poured in a separating funnel. Aqueous layer is separated out to give what you see in the picture below


100ml of water is added to the tar, the erlenmeyer is vigorously shaked and the water layer is poured (along with a little amount of tar) to the sep funnel (picture).

By drmethyl at 2010-08-30

Tar is thrown away, aqueous phase is mixed with the first one and washed with 2x100 ml, 2x50ml toluene.

(second wash )


(third wash)


(last wash, I stopped washing here because toluene is almost clear)


(washed aqueous phase - PPA HCl)


(erlenmeyer with tar)


Next, I treated the acidic solution with 25% NaOH ( I had to put the solution in the sep funnel because my beaker was too little... ) and it immediatly became milky, with a thin layer at the top of the milk. I didnt notice a smell of amine but I assume its PPA freebase.



I added toluene 100ml toluene and shaked it but the milky color still remains.


[Edited on 30-8-2010 by Methyl.Magic]

Quantum_Dom - 30-8-2010 at 11:17

Hi Methyl.Magic, good to see youre back. :)

A quick comment as I do not have much time right now is that you ommited to reduce the volume of the aqueous extracts and, even more importantly, washed them with a chlorinated solvent. That white scum-gel substance is 1,2-diphenylethanolamine freebase.

Will be back shortly,
QD

Methyl.Magic - 30-8-2010 at 12:04

Hey, I really hesitated to wash with DCM but I finally skip it because toluene was nicely effective and I bet the main by-product is phenylethanolamine HCl and DCM would probably not dissolve it.


That white scum-gel substance is 1,2-diphenylethanolamine freebase.
--> thanks for this nice clue QD !!! How do you know its this product ? did you analyse it ? why is it less soluble than PPA in toluene ? I would bet the opposite if I were you because of the polarity.

Another strange thing :

When I separated out the first acidic fraction from the toluene/tar I noticed I strange amazing effect in the beaker. It's probably the HCl evaporating but im not sure. There is only acidic water (HCl) with a little toluene/tar at the top. Check out the attached video.

http://www.youtube.com/watch?v=dSqlNKXb2PA

This is old notes I found in my lab ;)



Quantum_Dom - 30-8-2010 at 12:28

Ok back....:) Just watched that video you linked, interesting to say the least. Thanks :).

Quote: Originally posted by Methyl.Magic  
Hey, I really hesitated to wash with DCM but I finally skip it because toluene was nicely effective and I bet the main by-product is phenylethanolamine HCl and DCM would probably not dissolve it.


Actually racemic 1,2-diphenylethanolamine (DPEA) IS the main product of this reaction and racemic PPA the byproduct. The main purpose of using a chlorinated solvent such as DCM or chloroform for the washes is because of their ability to solvate DPEA hydrochloride salts.

Quote: Originally posted by Methyl.Magic  

thanks for this nice clue QD !!! How do you know its this product ? did you analyse it ? why is it less soluble than PPA in toluene ? I would bet the opposite if I were you because of the polarity.

Unfortunately no I never did any quantitative analysis on it, my statement only rely on the work-up observations of benzaldehyde/alanine in different published studies and published physical properties. I dont know when you took these pics, but if you let the whole mixture settle for a while, it will become more manageable for filtration. You ask a good question about its failure to go into toluene once you attempted to wash it out, to this I have no idea.

Quote: Originally posted by Methyl.Magic  

When I separated out the first acidic fraction from the toluene/tar I noticed I strange amazing effect in the beaker. It's probably the HCl evaporating but im not sure. There is only acidic water (HCl) with a little toluene/tar at the top. Check out the attached video.

Sure is a funky effect :cool: . Seems to me like the water insoluble junk trapped at the bottom of the beaker, and slowly migrating back on top, is making the np thin layer at the top vibrate as soon as it hits it.

QD


hector2000 - 31-8-2010 at 03:52

Final Product contain Racemic PPA and Unknown componet that has sour taste
I washed it several times with diffrent solvent but no success.
Also you can use N-methyl-alanine(Produced by Pyruvic acid+Methylamine) and get ephedrine(but i dont know which type of n-methyl-alanine produce.! N-Methyl-l-alanine or N-methyl-R-alanine?)

Quantum_Dom - 31-8-2010 at 04:06

Quote: Originally posted by hector2000  
Final Product contain Racemic PPA and Unknown componet that has sour taste
I washed it several times with diffrent solvent but no success.
Also you can use N-methyl-alanine(Produced by Pyruvic acid+Methylamine) and get ephedrine(but i dont know which type of n-methyl-alanine produce.! N-Methyl-l-alanine or N-methyl-R-alanine?)

Please try to work on the quality of your post and avoid posting half-ass information and gibberish. This thread is not about any diastereomers of ephedrine either.

Tasting an isolated compound in hoping to characterize it is absolutely irresponsible and dangerous :mad:. If you are proning such methods, I have no desire to discuss this procedure with you.

[Edited on 31-8-2010 by Quantum_Dom]

turd - 31-8-2010 at 14:42

Sorry for off-topic, but please help a complete OC-idiot:
Quote: Originally posted by Ephoton  
hmmm goodbye darzen :(

How do you make phenylpropanolamines via Darzens? I figure benzaldehydes, halopropionic acid alkyl esters and base give epoxides. But then - ring opening with ammonia or via PAC (phenylacetylcarbinol)? Or are you talking about a different Darzens? I don't get it. :(

PS: Thanks for the experimental details!

Quantum_Dom - 31-8-2010 at 14:53

Quote: Originally posted by turd  
Sorry for off-topic, but please help a complete OC-idiot:
Quote: Originally posted by Ephoton  
hmmm goodbye darzen :(

How do you make phenylpropanolamines via Darzens? I figure benzaldehydes, halopropionic acid alkyl esters and base give epoxides. But then - ring opening with ammonia or via PAC (phenylacetylcarbinol)? Or are you talking about a different Darzens? I don't get it. :(

PS: Thanks for the experimental details!


Hey turd thanks for dropping by :cool:

Im far from being an authority in this whole area but Im fairly sure those interested in the Darzens condensation, as an alternative to the work presented here, are looking forward to obtain the product of the catalytic dehydrative deamination of PPA;). No amino-alcohol will ever be involved in their scheme.

My bet is benzaldehyde condensed with a given 2-halopropionate alkyl ester followed by hydrolysis of the glycidic ester and decarboxylation/rearrangement of the epoxide .

QD
[Edited on 1-9-2010 by Quantum_Dom]Typo

[Edited on 1-9-2010 by Quantum_Dom]

turd - 1-9-2010 at 10:41

Oh, I see. Thanks for clearing that up.

Melgar - 1-9-2010 at 21:56

A bit off-topic, but are there any good ways of getting benzaldehyde from benzyl alcohol? I found one that uses DMSO and HBr, but it recommends like 5 times as much DMSO as benzyl alcohol, and DMSO and benzaldehyde have similar boiling points so it seems they'd be hard to separate.

Quantum_Dom - 1-9-2010 at 22:32

Quote: Originally posted by Melgar  
A bit off-topic, but are there any good ways of getting benzaldehyde from benzyl alcohol? I found one that uses DMSO and HBr, but it recommends like 5 times as much DMSO as benzyl alcohol, and DMSO and benzaldehyde have similar boiling points so it seems they'd be hard to separate.


Thats actually a very good question and usually people who havent spent a great time tackling it will claim facile and high yielding conversion with gentle oxidizers and conditions or two-steps procedures via hydrolysis of benzal chloride or oxidation of benzyl chloride to name a few.Well all I can tell you is that I guess it depends if youre looking for a preparative scale procedure, in order to obtain a decent amount for various future experiments, or is it simply on a pure interest of synthesizing a little benzaldehyde.

The latter procedures involve cumbersome work-ups, a great amount of work for a less than modest payoff IMHO. Especially for the direct oxidation of benzyl alcohol as it is rather a pain to separate it from benzaldehyde. And people that will recommend you to use the bisulfite adduct procedure, when youre working almost on a molar scale, just dont know any better ;). This is why I wouldnt recommend benzyl alcohol as a facile and worrieless substrate for benzaldehyde. IIRC Klute predicted high yields using catalytic amount of 4-oxo-TEMPO (from triacetonamine) with an oxidizer such as an hypochlorite salt or TCCA but cant figure out where I saw him say that :(. Ill look and let you know if you want.


Im curious about your proposal, dont think I ever heard of it. Do you have any references or a link to a thread here ? It sure is a lot of DMSO if you want to work on a preparative scale though.:o

QD

[Edited on 3-9-2010 by Quantum_Dom]

hector2000 - 2-9-2010 at 01:29

Quote: Originally posted by Quantum_Dom  

Please try to work on the quality of your post and avoid posting half-ass information and gibberish. This thread is not about any diastereomers of ephedrine either.

Tasting an isolated compound in hoping to characterize it is absolutely irresponsible and dangerous :mad:. If you are proning such methods, I have no desire to discuss this procedure with you.

[Edited on 31-8-2010 by Quantum_Dom]

Please calm down and dont Disrespect
I dıd this reaction several time according to another threat on this site(i forget link)i know chemistry of drug and i know tasting small amount of ppa is not dangerous also i know PPA has bitter taste but my PPA(by akabori reaction) is sour.
İ think impurity is amino acid.i dont want to make ephedrine and as you wrote before I just referred to maknig N-methyl-alanine from Pyruvic acid

Quantum_Dom - 2-9-2010 at 16:33

Quote: Originally posted by hector2000  

i know chemistry of drug and i know tasting small amount of ppa is not dangerous also i know PPA has bitter taste but my PPA(by akabori reaction) is sour.

No, tasting (regardless of the quantity involved) a product you do not know the nature or idendity makes you a cook, not a chemist.

Quote: Originally posted by hector2000  

İ think impurity is amino acid.i dont want to make ephedrine and as you

No, again you do not know as you havent characterized the said impurity with valid chemical analysis techniques.

Melgar - 2-9-2010 at 19:41

I attached the paper where they oxidize benzyl alcohol to benzaldehyde with DMSO. Seems the end products are dimethyl sulfide (which has a low boiling point) and water. But maybe the huge excess of DMSO can be avoided?

Attachment: dmso_oxidation.pdf (25kB)
This file has been downloaded 3153 times


percholator - 2-9-2010 at 19:43

Quick question... On the previous page methyl_magic posted a picture of his reaction mixture after several toluene washes and addition of NaOH... please correct me if I am wrong (I am having difficulty finding information on DPEA freebase), but it looks as though the DPEA is prone to forming some sort of emulsion with the aqueous phase, or at least it is not as quick as the PPA freebase to separate from the aqueous phase.. or it has a greater specific gravity than water... If any of these is the case, could a number of repeated washes with water and shaking be used en lieu of a chlorinated solvent or distillation?

jon - 3-9-2010 at 12:00

QD you're a lifesaver as i have a bitch who suffers badly from incontinence.
i will give one recommendation but this is some fine chemistry
that Aq phase holds some ppa mayb e 5g/100ml
i would suggest you salt it while it's warmed until it can hold no more salts and add ipa and separate the ipa after 30 seconds of stirring or so.

Methyl.Magic - 5-9-2010 at 13:27

Hi !

I am a bit late sorry but Im just back from france. So here is the last part of my workup. I have not the final yield yet.

After let the solution for 1 night, the white scum dissapeared. The solution is extracted with 3x100ml 1x50 ml of toluene. The solvent is rotavapored off and the resulting brown oil is dissolved in 3 times its volume of acetone, then titrated with 37% HCl. White crystals immediatly formed. The flask is put in the freezer for a few days.

The brown PPA freebase


Crystallisation with conc. HCl


The aqueous solution is extracted with 3x50ml DCM. This latter is dried over MgSO4 and boiled off. The resulting yellow/orange oil is dissolved in 3x its volume of acetone and is titrated with conc HCl to give tiny amount of white crystals.

After removed DCM


second crystallisation (in acetone/DCM)


The first crop is filtrated through a buchner and the cake is washed with 2x30ml acetone. The crystals are still drying in an oven at 80°C.



The second crop is filtrated, washed and dried separately. The expected yield is poor. Im waiting for the results before posting comments.


Quantum_Dom - 5-9-2010 at 16:53

Hi Methyl.Magic :)

Thanks for reporting back, I must say Im very suprised the white suspension you obtained went back into solution, but again I never did a work-up without reducing the water extracts by at least half the initial volume. I hope you kept you aqueous layer, if you did I would recommend to reacidify the latter untill pH 2-3 and evaporate slowly the water to a maximum and repeat the acid/base extraction. You should be able to extract the remainings but they will be contaminated. It would interesting IMO to establish a separation method of PPA*HCl and DPEA*HCl.

Thanks again for the lovely images :cool: (nice rotavapor, im jealous :P)
QD

[Edited on 6-9-2010 by Quantum_Dom]

Methyl.Magic - 6-9-2010 at 05:28

Hey !

I was also surprised the scum went back into the solution... There was another strange thing, too : When I shaked the solution with toluene for the first time, the toluene layer was slightly yellow. I let the solution in the funnel overnight. The next day, the scum dissapeared. The yellow toluene was separated out and the aqueous solution was extracted again with toluene. Now the toluene is brown...

The main reason why I didnt concentrated the water solution is I thought PPA freebase is much more soluble in toluene than water and the aqueous layer contains plenty of NaCl formed when I neutralised with 25% NaOH.

I have no idea about separating DPEA from PPA. But when I washed the cake with acetone, some crystals went away with acetone. I have no idea about the solubility of PPA HCl in acetone but I think it can be like ephedrine (poor solubility).

I think the main mistake I did was while the extraction of tar with HCl. You used DCM which dissolved the tar and makes it more "extractable". My tar was extremely sticky and it was difficult for the acidic water to go through. The PPA could clutch at the tar and couldnt be protonated and solubilised in acidic water even with the several days stirring I've done.

Another mistake is I didnt check the reflux temperature during the first step.

The main problem with this method, beside poor yield, is benzaldehyde must be used in large excess (6 eq.). BA (not BnO ! ) is the most expensive reagent here and despite of its large excess it's difficult to recover it (did you try ??) because of the tar. Distillation is not possible, maybe you should form the bisulfite adduct if not many tar.

Next time I'll try again, like you can see in the picture of my report, the condensation of nitroethane with BA then reduction with H2SO4/Zn HCOOH/Zn or HCl/In.

Quantum_Dom - 6-9-2010 at 06:16

Quote: Originally posted by Methyl.Magic  

The main reason why I didnt concentrated the water solution is I thought PPA freebase is much more soluble in toluene than water and the aqueous layer contains plenty of NaCl formed when I neutralised with 25% NaOH.


Its understandable as I too was not too keen in vaporizing all that water at first. But I assure you that a great deal of material was left in that aqueous phase when you treated it with NaOH.

Quote: Originally posted by Methyl.Magic  

I have no idea about separating DPEA from PPA. But when I washed the cake with acetone, some crystals went away with acetone. I have no idea about the solubility of PPA HCl in acetone but I think it can be like ephedrine (poor solubility).


Very interesting, I dont have data regarding solubility in acetone of either compound. Was the acetone thoroughly dry and cold ? Was it evaporated to isolate the material that it solvate ?

Quote: Originally posted by Methyl.Magic  

I think the main mistake I did was while the extraction of tar with HCl. You used DCM which dissolved the tar and makes it more "extractable". My tar was extremely sticky and it was difficult for the acidic water to go through. The PPA could clutch at the tar and couldnt be protonated and solubilised in acidic water even with the several days stirring I've done.


Im not sure I understand what step you are referring to, Im confuse. Im having a hard time understanding if you are talking about the DCM wash of the HCl extracts or the hydrolysis step right after the decarboxylation.

Quote: Originally posted by Methyl.Magic  

Another mistake is I didnt check the reflux temperature during the first step.


Yes I think this was a bit too much, the decarboxylation does not need to reach reflux. Leaving it at that temperature for so long also (8 hrs) is too long IMO and might have contributed in the great amount of tar you obtained.


Quote: Originally posted by Methyl.Magic  

The main problem with this method, beside poor yield, is benzaldehyde must be used in large excess (6 eq.). BA (not BnO ! ) is the most expensive reagent here and despite of its large excess it's difficult to recover it (did you try ??) because of the tar. Distillation is not possible, maybe you should form the bisulfite adduct if not many tar.


Indeed, it is wasteful in benzaldehyde, especially if the latter is hard to obtain for an experimenter. Even if its readily available and cheap, the yield of PPA*HCl will always be low. So in terms of efficiency, there is no doubt in my mind that the reaction will never be viable. If my reactional parameters are use, the np layer after hydrolysis needs to be washed with diluted aqueous sodium carbonate 3-4 times. Then one can vacuum distill a fair amount of benzaldehyde back. Again, I guess the main reason you couldnt claim any back was the rather high temperature you used and reaction time too. An awful lot must have polymerized. I also remember that it was contaminated with benzoic acid, maybe it could be a factor too.


Quote: Originally posted by Methyl.Magic  

Next time I'll try again, like you can see in the picture of my report, the condensation of nitroethane with BA then reduction with H2SO4/Zn HCOOH/Zn or HCl/In.


Ah now I understand ;). Did you took a melting point of your produt ? TLC ? Any attempt to characterize ? It will be nice to compare with a sample obtained via condensation/reduction of benzaldehyde and nitroethane.

Thank you very much for sharing data Methyl.Magic:)

QD

Melgar - 6-9-2010 at 10:46

Just some ideas here: would this reaction be inhibited by either benzoic acid or benzyl alcohol? If so, which one would inhibit it more? Also, what would be a better ratio to use if trying to maximize yield with respect to alanine?

I've made benzaldehyde before by ozonolysis of styrene, and also by oxidation of benzyl alcohol. It's kind of tricky to purify though.

Quantum_Dom - 6-9-2010 at 11:42

Quote: Originally posted by Melgar  
Just some ideas here: would this reaction be inhibited by either benzoic acid or benzyl alcohol? If so, which one would inhibit it more? Also, what would be a better ratio to use if trying to maximize yield with respect to alanine?


Good question, of course I will only speculate but if the media is fairly acidic, this could influence the reaction greatly as an intermediate carbanion is formed in the mechanism and would be quenched by an acidic media. Theyre is also the influence on the reactivity of alanine as the amino group will be protonated in sufficiently acidic media. The list goes on and I cant really speculate much without actual data. The only way of figuring out the optimal benzaldehyde ratio, without overkilling it, would be to establish an experimental design where yields of PPA are calculated with respect to the variation of initial benzaldehyde equivalents used. Thats the only way.

Quote: Originally posted by Melgar  

also by oxidation of benzyl alcohol. It's kind of tricky to purify though.


You did ? Which procedure did you used ? I thought you never tried it before as you said earlier you were looking for a procedure to do it ? Sorry, I surely misunderstood you ;) Thanks for the DMSO paper by the way :) (I dont think it is a viable way but its just a hunch).

Melgar - 6-9-2010 at 19:10

Actually, I was more interested in optimizing yield based on benzaldehyde, since alanine is really easy to get here but not so for benzaldehyde. Right now I'm trying to oxidize benzyl alcohol by stirring it with chlorine bleach. It definitely has the benzaldehyde smell, but we'll see if the Cannizzaro reaction plays a major role with those reagents. I'm interested in knowing if adding alanine slowly to the benzaldehyde could improve yields, since there would be a high aldehyde/amino acid ratio at the beginning, theoretically improving yields. But maybe it doesn't matter at all? Once I get the benzaldehyde I'll have to give it a shot.

Methyl.Magic - 7-9-2010 at 13:16

Hi,

I've just done the melting point test... It starts melting at 255°C and totally melted at 280°C ...

Litterature : PPA = 190-200°C

I think we got the wrong product... Did you analyse yours ?

Methyl.Magic - 7-9-2010 at 13:17

oh I forgot the yield...

total amount is 3.6g ... A big Deception :(

Quantum_Dom - 7-9-2010 at 14:30

Quote: Originally posted by Methyl.Magic  
Hi,

I've just done the melting point test... It starts melting at 255°C and totally melted at 280°C ...

Litterature : PPA = 190-200°C

I think we got the wrong product... Did you analyse yours ?


Methyl.Magic, have a look at the third paragraph in my original post for product characterization.

Your product is too contaminated to make an assumption, but it seems like its mostly benzylamine *HCl

Identification
Name Benzylamine hydrochloride
Synonyms Benzylammonium chloride
Melting point 262-263 ºC
Water solubility SOLUBLE

Nicodem - 7-9-2010 at 14:46

The erythro isomer: hydrochloride mp = 172-194 °C, free base mp = 100-105 °C
The threo isomer: hydrochloride mp = 171-173 °C, free base mp = 71-105 °C
These are actually just some averages from several sources, because there are very different data, particularly for the free bases (some as low as 50 °C). In essence, for both diastereoisomers, the melting points are similar, except maybe a bit higher for the erythro isomer.

The hydrochloride of the 1,2-diphenylethanolamine erythro isomer has a mp = 215-216.5 °C.

I see that some people still did not bother to learn the theory of liquid-liquid extraction. The solubility is not directly correlated to the partition coefficient - contrary to what some here believe. I'm not going to repeat myself, so I will just point to another thread: http://www.sciencemadness.org/talk/viewthread.php?tid=12017

Quantum_Dom - 7-9-2010 at 16:32

Quote: Originally posted by Melgar  
I'm interested in knowing if adding alanine slowly to the benzaldehyde could improve yields, since there would be a high aldehyde/amino acid ratio at the beginning, theoretically improving yields. But maybe it doesn't matter at all? Once I get the benzaldehyde I'll have to give it a shot.


Sorry I missed out your post earlier on. I also was considering, in my previous work prior to the one posted here, introducing slowly the amino acid within the reaction flask in order to keep the ratio of benzaldehyde/alanine high in all times. But the side reactions do not involve a too high concentration of alanine. The main points that are favoring side-reactions are rather related to the stability of the different intermediates involved in the mechanism. The main reason for large excess of benzaldehyde is to make sure that the intermediate carbanion reacts with another equivalent of aldehyde rather than with water (see illustrated mechanism).


Edit: I would also like to bring your attention to this study. It reports that when an equimolar amount of a (un)substituted benzaldehyde is dripped in a slurry of amino acid refluxing in DMF, large amounts of the corresponding benzylamine can be isolated. On the other hand, when 4 equivalents are used the corresponding alkamines (amino-alcohols) are rather obtained.

QD

[Edited on 8-9-2010 by Quantum_Dom]

Attachment: A Novel Synthesis of Benzylamines.pdf (619kB)
This file has been downloaded 860 times


Francis Crick - 10-9-2010 at 14:35

Reaction was prepared á la original Quantum Dot with some modifications as listed below.

1. LG 500 mL Benzaldehyde and and LG 50g D,L Alanine were stirred for 20 min before being heated on a 150 C bath for 3 hours.

[CO2 was observed evolving after 20 min of heating. After 3 hours, solution was not black but more a dark golden yellow. Assumed less by-products were present.No distillate was collected. ]

2. Solution cooled before 150 mL of 5% AcOH in Toluene was added. Stirred 20 min. 500 mL of 15% HCl added.

3. Gently refulxed for 3 hours.

[Mixture appears identical to figure 2 of the QD write up]

4. Left to cool slightly before being separated warm.

[On separating, aqueous phase is a lot less orange in color than in figure 3 of QD but tar layer is similar colour]

5. Washed aqueous with 3x 100 mL of DCM.

[NP solution dark brown, aqueous slightly yellowish]

6. Reduced aqueous solution through vaporising by 1/5

[No fume hood available and the vapor was yuk so stopped earlier than would have liked]

7. Washed with 3x 100 mL DCM

[NP solution very light dark brown, aqueous still slightly yellow, almost clear]

8. Treated aqueous with saturated NaHCO solution, followed by aqueous NaOH until strongly basic

[Strong aqueous basic solutions were added. NaHCO resulted in lots of fizzing. Took a lot of base to make basic ~ 500 sat. NaHCO and 500 mL very strong NaOH. Upon approaching basic, a white cloudy fraction appeared in the bottom of the beaker and spread through out on additional base additions. No oily fraction was observed as in figure 7.]

9. Extracted aqueous phase with 4 x 200 mL of DCM.

[no brown colour was observed in DCM fraction]

10. Removed DCM via evaporation overnight.

[Approximately 5 g of white solid with distinctive green tinge remained after all DCM had been removed]

All solutions have been kept. Any suggestions on where the PPA is (if there is any) and how to get it out would be much appreciated.

Lots of love,

Francis

Quantum_Dom - 10-9-2010 at 17:24

Quote: Originally posted by Francis Crick  
Reaction was prepared á la original Quantum Dot with some modifications as listed below.


My user is Quantum_Dom

Quote: Originally posted by Francis Crick  

1. LG 500 mL Benzaldehyde and and LG 50g D,L Alanine were stirred for 20 min before being heated on a 150 C bath for 3 hours.

[CO2 was observed evolving after 20 min of heating. After 3 hours, solution was not black but more a dark golden yellow. Assumed less by-products were present.No distillate was collected. ]


Dont know if I understand right but did you keep stirring while the decarboxylation was performed ? It is critical.


Quote:

6. Reduced aqueous solution through vaporising by 1/5


Only a 1/5 of the initial volume? It is not enough. I reduced the volume by half and it was the bare minimum IMO.

Quote:

Treated aqueous with saturated NaHCO solution, followed by aqueous NaOH until strongly basic

[Strong aqueous basic solutions were added. NaHCO resulted in lots of fizzing. Took a lot of base to make basic ~ 500 sat. NaHCO and 500 mL very strong NaOH. Upon approaching basic, a white cloudy fraction appeared in the bottom of the beaker and spread through out on additional base additions. No oily fraction was observed as in figure 7.]


So if I understand correctly, you reduced the volume of the aqueous acidic extracts to only rediluted them later by adding aqueous solution of base ??? Is that correct ? If it is, it does not make much sense as the sole purpose of reducing the volume of water is to force any material to separate from the latter in the first place.


Well all I can suggest is that youre material is still in the aqueous phase since you omitted to reduce the latter properly and rediluted it by adding aqueous alkaline afterwards. The alkaline material (NaHCO3 and NaOH) needs to be add as is, not in solution regardless of the concentration.

Hope it helps,

QD





[Edited on 11-9-2010 by Quantum_Dom]

Francis Crick - 10-9-2010 at 19:35

Sorry about the naming issue QD, brain must have been skim reading your name for a while :o your work is very much admired from these parts

Yes, the aqueous was reduced then aqueous base added to it as it was thought a LOT less base would be needed than was required.

If there is indeed still PPA present in the aqueous, would one expect to see the freebase rise to sit on top as the volume reduces? Or would it be better to acidify with HCl, reduce volume then basify again to get at the freebase?

And is the freebase actually brown or that just a result of byproducts present in the sample prior to the crystallization?

Quantum_Dom - 10-9-2010 at 21:40

Quote: Originally posted by Francis Crick  
Sorry about the naming issue QD, brain must have been skim reading your name for a while :o your work is very much admired from these parts

Yes, the aqueous was reduced then aqueous base added to it as it was thought a LOT less base would be needed than was required.

If there is indeed still PPA present in the aqueous, would one expect to see the freebase rise to sit on top as the volume reduces? Or would it be better to acidify with HCl, reduce volume then basify again to get at the freebase?

And is the freebase actually brown or that just a result of byproducts present in the sample prior to the crystallization?


I am still confused as you didnt really answered what I was asking for. I know you reduced the volume (by only 1/5 th of the inital volume). What I am telling you is that:

1. You did not reduce sufficiently the acidic extract volume.
2. Not only you did not reduce the acidic extract enough, you returned to square one by flooding the system with almost 1 L of aqueous base. I mentionned on many occasions, that the freebase of PPA has affinity with water. Too large a volume of water, smaller the yield of extraction with a non-polar solvent.

Please have another look at the write-up in my original post as everything is explained there.

QD

Melgar - 11-9-2010 at 17:34

Would there be any harm from heating this reaction for too long? If not, it would seem that if there's both unreacted alanine and unreacted benzaldehyde, letting it react a bit longer, or adding the alanine in portions, might be helpful. If heating too long is harmful though, then those would be bad ideas.

Francis Crick - 12-9-2010 at 17:23

Understood QD, but if the reaction could be done again from scratch it would. I should have made it more clear as I was asking what would be the best approach to take after this most unfortunate of errors.

Either:

1. acidfy the now 1.8 L basic solution, reduce the volume by heating then re-basify to extract with DCM

or

2. reduce the volume of the 1.8L basic solution by heating then extract with DCM

Due to concerns with excess NaCl with all the HCl and NaOH additions, the decision was made to take option 2 and just reduce the solution.

Upon reducing the volume to 600 mL, an obvious orange color has been developing in the aqueous solution so its looking promising. clear solid 'salt like' matter has also been forming in the bottom of the beaker so it may help to filter these prior to DCM extraction. It is planned to continue to reduce the volume to 200mL, vacuum filter the solids out warm, extract with 5 x 200 mL DCM and continue as per the original QD method.

One further question, is removing the DPEA from the aqeuous as sensitive to its concerntration as the PPA? I notice that 3 x 150 mL DCM extactions preceed the reduction in aqeuous volume whilst 3 x 75 mL DCM follow it. Any particular reason for this?

Suggestions are more than welcome. Will post yields soon.

Quantum_Dom - 13-9-2010 at 10:33

Quote: Originally posted by Francis Crick  
Understood QD, but if the reaction could be done again from scratch it would. I should have made it more clear as I was asking what would be the best approach to take after this most unfortunate of errors.

Either:

1. acidfy the now 1.8 L basic solution, reduce the volume by heating then re-basify to extract with DCM

or

2. reduce the volume of the 1.8L basic solution by heating then extract with DCM

Due to concerns with excess NaCl with all the HCl and NaOH additions, the decision was made to take option 2 and just reduce the solution.

Upon reducing the volume to 600 mL, an obvious orange color has been developing in the aqueous solution so its looking promising. clear solid 'salt like' matter has also been forming in the bottom of the beaker so it may help to filter these prior to DCM extraction. It is planned to continue to reduce the volume to 200mL, vacuum filter the solids out warm, extract with 5 x 200 mL DCM and continue as per the original QD method.

One further question, is removing the DPEA from the aqeuous as sensitive to its concerntration as the PPA? I notice that 3 x 150 mL DCM extactions preceed the reduction in aqeuous volume whilst 3 x 75 mL DCM follow it. Any particular reason for this?

Suggestions are more than welcome. Will post yields soon.


IMO I would avoid evaporating the water without reacidifying the whole as PPA will steam distill. To what extent, I dont know.

I do not understand the second part.

QD

Melgar - 20-9-2010 at 10:30

Quick question... is most of the DPEA left in the nonpolar layer? Also, is the reddish-brown product DPEA? I'm guessing the reason for evaporating most of the solvents and then basing the aqueous layer is to saturate it with salt so less of the PPA base can dissolve in it.

Nicodem - 17-4-2011 at 06:43

A notice to those few members who brought this otherwise nice thread down to the level of kewls:
All your posts from the recent revival of the thread were split and moved elsewhere where they fit better.

Stop posting junk replies into this thread! If you have something off-topic to discuss on such a kewlish level, at least have the decency to do so in a separate thread in the Beginnings section. Only post here when you have something to add on topic and on the same level of discourse.

Melgar - 17-4-2011 at 07:19

There are other ways to work this reaction up. For example, I evaporated away all the liquid, leaving me with PPA HCl and some other junk, then rinsed the other junk away with acetone.

Obviously I'm a student of the "Good Enough" school of philosophy. :P

The more steps I have to take, the more likely I am to screw up something, so this may not be a bad way to go.

[Edited on 4/17/11 by Melgar]

jon - 17-4-2011 at 22:56

yeah it is a bad way to go about it.
what happens with these kind of amino alcohols is they are volitile with steam
even thier hydrochlorides.
did you take a m.p. afterwards?
and diphenylethanolamine i can't tell you exactly the solubility data i have looked for it in chem abs.
other than to say the scientists at sigma aldrich said it dissolves .6 g/100 ml in ethanol under sonication.
so likely you can easily remove it by simply salting out the aqueous phase at ph 12 and saturating with isopropanol.

also wanted to add that you can suppress the steam volatility of these type of compounds by acidifying it to ph3 or less

that keeps water tied up as the hydronium ion so it does'nt tie up with your substrate.

[Edited on 18-4-2011 by jon]

Melgar - 18-4-2011 at 15:37

Well there's an excess of HCl already in the solution; as it gets down to the last little bit, the HCl fumes are quite intense. Did not take a melting point, but I did do a few DCM washes like the OP did, so there shouldn't be too much diphenylethanolamine. With such an excess of benzaldehyde, I don't think there's going to be much alanine left, and most of the rest of the products would evaporate away.

crystalXclear - 18-4-2011 at 21:01

I must agree with the tasting of any known/unknown rxn soultion, as being one of the crazyist things to do, to say the least.
BUT, And I hope this will not only prevent it being repeated, but posibly help identify the substance, or it's main constituant at least.

After reading a post on a body building site, beta alanine/l-alanine, was said to be VERRY SOUR tasting & had to be sweetened with OJ before being used as a pre workout suppliment drink.

apollogies if this is of little or no usefull info, I just thaught it worth mentioning. Xtal

jon - 18-4-2011 at 23:35

this is standard extraction protocol for ppa.
i found this in a book at the pharmacy library so i would stick with convention it always works for me.

azo - 20-4-2011 at 02:54

just a thought on the akabori reaction ! I no there is much speculation on the steriochemistry of ppa ,but could someone correct me if i am wrong. but i think that you will get dextro and levro forms of both norephedrine and norpsuedoephedrine is this correct . sorry if im wrong


regards azo

questions - 14-6-2011 at 00:49

I can make benzaldehyde from cinnamon bark oil but the product I always end up with has still got some cinnamon oil in it.
It is about 80% benzaldehyde and 20% cinnaomon oil.
I'm thinking of just mixing and reacting this solution with the N-methylalanine to make the pseudoephedrine

Do you think the cinnamic aldehyde will react with the n-methylalanine and or even stuff up the reaction some how?

jon - 25-6-2011 at 23:32

yes i think it would it has the same functional group so it would tie up your alanine i would carefully fractionate it.
or remove it chemically by means of oxidation with acidic potassium permanganate.
you could test for it's presence by adding bromine for a double bond test.

AZO you would get erythro/threo isomers of course.
there are two stereocenters i don't see this reaction being selective chirally.

[Edited on 26-6-2011 by jon]

questions - 31-8-2011 at 01:02

How would I separate the cinnamon aldehyde from the benzaldehyde by the method you mentioned using acidic potassium permanganate?

weldit - 31-8-2011 at 09:54

The best way to seperate them is by distillation

Benzaldehyde 178
Cinnamaldehyde 248

fanglongcan - 20-9-2011 at 02:24

I would like to ask
After alkalization ,Is the extraction of water phase?or Oily extract?

overload - 1-10-2011 at 18:15

So has anyone written up an example they would like to share? Since this thread is about improving efficiency I think an efficient example or method should be provided that explains what is actually going on. For example.

"150 ml of DMSO is added to extract impurities such as *insert impurities here* and then the dmso is separated and set aside for recycling."

overload - 1-10-2011 at 19:03


Quote: Originally posted by Melgar  
There are other ways to work this reaction up. For example, I evaporated away all the liquid, leaving me with PPA HCl and some other junk, then rinsed the other junk away with acetone.

Obviously I'm a student of the "Good Enough" school of philosophy. :P

The more steps I have to take, the more likely I am to screw up something, so this may not be a bad way to go.

[Edited on 4/17/11 by Melgar]



Could youexplain what you did in a little more detail so that we can better understand what your talking about?


Quote: Originally posted by jon  
yeah it is a bad way to go about it.
what happens with these kind of amino alcohols is they are volitile with steam
even thier hydrochlorides.
did you take a m.p. afterwards?
and diphenylethanolamine i can't tell you exactly the solubility data i have looked for it in chem abs.
other than to say the scientists at sigma aldrich said it dissolves .6 g/100 ml in ethanol under sonication.
so likely you can easily remove it by simply salting out the aqueous phase at ph 12 and saturating with isopropanol.

also wanted to add that you can suppress the steam volatility of these type of compounds by acidifying it to ph3 or less

that keeps water tied up as the hydronium ion so it does'nt tie up with your substrate.

[Edited on 18-4-2011 by jon]



[Edited on 2-10-2011 by overload]

fanglongcan - 16-10-2011 at 19:41

The aqueous phase was then treated with small portions of NaHCO3 [11] until fizzing becomes less violent (Figure-6), then small portions of NaOH were added until pH was strongly alkaline. A light brown-yellow oily layer with a strong and biting amine smell separated from the aqueous phase .

I tried to do so,But when it alkalinization after ,In oil layer unknown things have contact .Who can tell me how to clear these things






cipi - 23-12-2011 at 15:37

Quote: Originally posted by Quantum_Dom  
Quote: Originally posted by hector2000  

i know chemistry of drug and i know tasting small amount of ppa is not dangerous also i know PPA has bitter taste but my PPA(by akabori reaction) is sour.

No, tasting (regardless of the quantity involved) a product you do not know the nature or idendity makes you a cook, not a chemist.


If resisting to taste the chemical you just produced without knowing what it is makes you a chemist then even monkeys can be chemists. Simply put a monkey infront of a beaker filled with sulfuric acid and a beaker filled with ethanol get him to pour one into the other and then have him run away. Monkey chemist.

[Edited on 23-12-2011 by cipi]

cipi - 28-12-2011 at 08:55

To expand the possibilities of the akabori different benzaldehydes such as 4-fluorobenzaldehyde or clorobenzaldehyde might be used in place of regular benzaldehyde. "Substituted" benzaldehydes being used in akabori have been discussed before but no results have been posted -so?-

Waffles SS - 14-9-2012 at 21:34

Yield may increase if we Use certain solvents(like DMSO)?

Yuusaku Yokoyama(2007) used DMSO and got 79% yield

Attachment: Yuusaku Yokoyama.pdf (117kB)
This file has been downloaded 954 times


jon - 15-9-2012 at 09:35

i had a hunch about that solvent years ago i fucking knew it.
of course they are using methyl alanine so the yeilds will be higher naturally.
but still it's a rung up.
now we need to optimize solvent ratios i don't understand japanesse.

[Edited on 16-9-2012 by jon]

Hilski - 20-9-2012 at 10:44

Holy shit!
This would lead one to believe that yields in the range of 60%-70% are possible, given the right conditions. But seeing as how I'm an uncultured ass, and can't read Japanese (or any other non-English language) I'm not 100% sure I saw what I think I saw. I think.

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