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Author: Subject: Improvement in the yield of racemic PPA*HCl via Akabori reaction (35 % molar)
percholator
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[*] posted on 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 :)
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Quantum_Dom
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[*] posted on 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




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[*] posted on 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.
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[*] posted on 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]




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[*] posted on 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...
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[*] posted on 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]




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[*] posted on 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.
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[*] posted on 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]




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[*] posted on 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]
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[*] posted on 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]




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[*] posted on 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:
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[*] posted on 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)
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[Edited on 26-8-2010 by Quantum_Dom]




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[*] posted on 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.




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[*] posted on 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]




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[*] posted on 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]
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[*] posted on 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.




…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)

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Quantum_Dom
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[*] posted on 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 1196 times

Attachment: Akabori.Momotani-About a new mode of formation of ephedrine and related compounds.pdf (357kB)
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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]




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[*] posted on 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.
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[*] posted on 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]




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[*] posted on 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]
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[*] posted on 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




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[*] posted on 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 ;)


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[*] posted on 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





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[*] posted on 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?)




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[*] posted on 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]




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