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

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


Figure-1

Figure-2

Figure-3

Figure-4

Figure-5

Figure-6

Figure-7

Figure-8

Figure-9

Figure-10













[Edited on 18-8-2010 by Quantum_Dom]

Very nice work thanks

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

Quote: Originally posted by Methyl.Magic

Very nice work thanks 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 .

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.

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.

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?"

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.

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.

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]

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.

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.

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?

hmmm goodbye darzen

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]

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.

alternative solvent to DCM or possible modification to workup?

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.

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

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?

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

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

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

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 !)

Oh...and does it look like this ?



[Edited on 25-8-2010 by Quantum_Dom]

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]

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.

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]

Looks good . Im suprised how clean you post-reaction is though . 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]

@ 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!

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!

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 1138 times











[Edited on 26-8-2010 by Quantum_Dom]

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.

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]

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.

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.

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]

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.

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.

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.

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).

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)?

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.

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.

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.

Quote: Originally posted by Nicodem

This is a more reasonable thinking

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?

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.

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 1433 times

Attachment: Akabori.Momotani-About a new mode of formation of ephedrine and related compounds.pdf (357kB)
This file has been downloaded 1533 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. I.pdf (1022kB)
This file has been downloaded 1200 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. II.pdf (848kB)
This file has been downloaded 977 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. III.pdf (752kB)
This file has been downloaded 1025 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. IV.pdf (920kB)
This file has been downloaded 1102 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. V.pdf (539kB)
This file has been downloaded 1505 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. VI.pdf (746kB)
This file has been downloaded 1037 times

Attachment: Studies on Reactions between Aromatic Aldehydes and α-Amino Acids. VII.pdf (564kB)
This file has been downloaded 966 times

[Edited on 28-8-2010 by Quantum_Dom]

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.

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.

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.

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 ). 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]

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]

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

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

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.

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.

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 . 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

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 . If you are proning such methods, I have no desire to discuss this procedure with you.

[Edited on 31-8-2010 by Quantum_Dom]

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!

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

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]

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.

QD

[Edited on 3-9-2010 by Quantum_Dom]

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 . If you are proning such methods, I have no desire to discuss this procedure with you. [Edited on 31-8-2010 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.

Quote: Originally posted by hector2000

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

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.

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 (nice rotavapor, im jealous )
QD

[Edited on 6-9-2010 by Quantum_Dom]

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.

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).

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.

Quote: Originally posted by Methyl.Magic

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

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.

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

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?

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).

oh I forgot the yield...

total amount is 3.6g ... A big Deception

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 ?

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.

Quote: Originally posted by Francis Crick

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

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. ]

Sorry about the naming issue QD, brain must have been skim reading your name for a while 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?

Quote: Originally posted by Francis Crick

Sorry about the naming issue QD, brain must have been skim reading your name for a while 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?

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.

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.

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]

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. 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]

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]

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.