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Ebao-lu
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Nicodem, i understand, i mean that in organic chemistry they seldomly perform experiments with _set_ of reaction vesels in one experiment. I think
that for amateur chemists, set of test tubes in a water bath is better then one mini- round-bottomed flask + one mini-reflux (sometimes more expensive
then large ones). Besides, less paranoy with smells and parents, because most experiments are conducted in a kitchen/bathroom
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chemrox
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Nicodem please read the damned paper. As to experimental scale I agree; 10mmol is an average experiment with us except for scaleup trials and those
go to 10 g yields at times.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Nicodem
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I did not read it, I just skimmed trough it, but I could find nothing relevant about ketals being formed during their synthesis which uses the Michael
addition of ethyl acrylate, the intramolecular Claisen condensation (Dieckmann condensation), C-alkylation, and finally the
hydrolysis/decarboxylation of the beta-ketoester. Nothing unusual here. The only mention of ketals in the paper is in that they observed that some of
their 4-piperidones formed the hydrochlorides of the coresponding ketals (instead of the original ketones) in their attempts to make the
hydrochlorides using ethanolic HCl (which is how ketals are made anyway). However, this was not part of their synthetic route and I don't know how
this observation could be relevant. If you, by a thorough reading, noticed any ketals as synthetic intermediates, please let us know.
…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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chemrox
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I'm glad you noticed the reaction was intramolecular. When you chastised me earlier you had somehwo missed that calling it a Claisen. I missed the
whole thing the first time around calling it a reduction so I don't claim superior virtue. What I object to is this trigger happy urge to attack
people for what you perceive to be as their chemical shortcomings. As you said, you decide to get offended and act on that basis. I had a guy like
you working for me a few years ago and he resisted all my efforts to develop him into a competent manager. I had to fire him or lose other employees
I had a lot of time invested in. Learn the art of correcting people in a way that makes them appreciative rather than defensive. After all this is
all voluntary. Back to the ketals, they're in the intermediates under experimental in the middle of the article. If you're saying they're not
important that's an opinion I guess, the authors found them, reported them and so did I by paraphrasing the experimental rundown.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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chemrox
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On another subject in this thread, I worked with piperidones for about a year and one thing that came up whenever I combined a 4-piperidone with
another compound was red impurities. I'm wondering if anyone has a guess as to what might be involved. I don't have a GC-MS and the stuff doesn't
give a consistent IR picture that I can detect. At first I thought a halide might be the culprit because I was using an organo bromide but the same
color showed up with other transformations not involving halides. It's not a major issue but I'm curious.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Nicodem
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| Quote: | Originally posted by chemrox
I'm glad you noticed the reaction was intramolecular. When you chastised me earlier you had somehwo missed that calling it a Claisen.
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It is a Claisen condensation. Read the replies again. You have been told this several times. "Intramolecular" is not the name of a reaction, it only
means the reaction occurs inside the same molecule.
| Quote: | | What I object to is this trigger happy urge to attack people for what you perceive to be as their chemical shortcomings. |
This has nothing to do with "chemical shortcomings". It is a personality thing (not just my personality though).
| Quote: | | Back to the ketals, they're in the intermediates under experimental in the middle of the article. If you're saying they're not important that's an
opinion I guess, the authors found them, reported them and so did I by paraphrasing the experimental rundown. |
Where? I can't find anything about them being synthesis intermediates. They report the very classical synthetic route to 4-piperidones with the scheme
depicted. There are no ketals besides the only obtained from the 4-piperidones with ethanolic HCl. Please post a graphic with a route where ketals are
intermediates, or at least your interpretation of the reaction scheme. Maybe this will clear the issue as pictures say much more than words.
| Quote: | | On another subject in this thread, I worked with piperidones for about a year and one thing that came up whenever I combined a 4-piperidone with
another compound was red impurities. |
When a ketone turns red it usually means the red products is some crap (technically called "tarry materials"). They generally give consistent IR
spectra.
…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)
Read the The ScienceMadness Guidelines!
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chemrox
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"S-2‘-phenylethyl-4-piperidone e t hylketal [in italics] (35 g) as a pale yellow oil
which could not be distilled. Found: equiv., 279; calcd. for
*‘ Melting points are uncorrected. t Analyses are by Mr. G. S. Crouch, School of Pharmacy, University of London;
equivalent weights of bases and salts mere determinod by titration in non-aqueous
media.
(p. 50)
C17H27O2N equiv., 277). It gave a hydrochloride. needles from
ethanol, m.p. 178-179" dec."
(p. 51)
look harder next time, bottom of page 50 to top of page 51 in the article btw it didn't copy and paste very well
[Edited on 12-2-2009 by chemrox]
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Nicodem
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Is this some weird way of saying "I was wrong"? Because what you did was copy-pasting from the experimental section where they describe the
preparation of the ketal from the ketone, that is from N-2'-phenylethyl-4-piperidone. So, how can the ketal be an intermediate step in the
synthesis of the N-2'-phenylethyl-4-piperidone when it is prepared from N-2'-phenylethyl-4-piperidone? Probably I'm just stupid, but
to me this appears against all logic.
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kmno4
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All stupidity lies on chemrox's side (and not for the first and not for the last time).
Chemrox is/are not partner for discussions.
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chemrox
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Look again:
(KMNO4- shoo!)
"A mixture of N-2'-phenylethyl-
4-piperidone ethylketal (20 g) and dilute aqueous hydrochloric
acid (150 ml) was refluxed for 2 h. cooled aid washed with ether.
The free base was liberated with aqueous ammonia and extracted
with ether. After drying (Na2,SO4), the ether was evaporated
and the residue (13.0 g) crystallized from light petroleum (b.p.
80-100) to give N-2'-phenylethyl-4-piperidone"
I don't know what you're reading. Right there the last step is to refulx the ketal with acid and work it up with ammonia to give the to give the NPP.
Now please apologize and let's move on.
[Edited on 12-2-2009 by chemrox]
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Nicodem
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Oh my god! You just cited the experimental where they recover N-phenylethyl-4-piperidone from its ketal which was made from
N-phenylethyl-4-piperidone in the first place. That is not part of the synthetic route. You confused a characterization/derivatization
chemical acrobatics with being part of the preparation itself. What are you thinking about, if about anything at all, when reading papers?
Edit: OK, I think I know what got you confused. You probably missed or did not understood the explanation on page 38 where they explained that during
their attempt at forming the hydrochloride from N-phenylethyl-4-piperidone in ethanol (experimental on lower half of page 50), an incidental
ketalization occurred with the solvent. They explain this probably happened to previous researchers as well since their EA were not in good agreement
with the expected hydrochloride. That's why they characterized the hydrochloride of the ketal, the ketal itself, as well as recover the ketone by the
hydrolysis procedure you posted above. This acrobatics was only to prove a concept and correct the results of older researchers.
When reading scientific papers it is best to first read the discussion and then the experimental, by reading just the experimental like you seem to
have done you only get more confused.
[Edited on 12/2/2009 by Nicodem]
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chemrox
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If that's the case I wholeheartedly apologize for all my remarks. Let's be sure. I shall re-read the whole thing-it's a long sucker and I'm into
triazines now. (Too much crossover with med chem related issues in the piperidones.) I will shout "Oops" and push a peanut with my nose around my
building three times if you're right about this not being part of the experimental procedure.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Globey
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based solely on the formally low price for multi Kg quantities of NPP, one might guess the synthesis was indeed simple (2-pea, dmk, CH3O), one pot,
etc. the higher current price is probably more a reflection of additional administrative requirements now attached to the chemical.
______________________________________________________________________________________________________________________
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added to their posts, in an attempt to demonstrate to everyone just how sophisticated they think they are), usually abuse their power of moderation to
troll the most. Having blanket license to troll (as moderator) makes one’s intellect dull, as instead of defending one’s wit with the mighty pen
(or keyboard), a dictator can just execute all threats, and cleanse/falsify the record.
Time to stop crying “trolling, troll!” every time a nobody (in your book), has out witted you."
[Edited on 12-2-2009 by Globey]
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chemrox
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ketals article
@Nicodem:- I feel we both bear responsibility. You for not reading the experimental section thoroughly before jumping all over me and me for not
reading the text before reporting the experimental content. You hadn't either I saw. As an interesting footnote the patent document also mentioned
the ketal as an intermediate product. The intermediate ketal formation was the cause of a lot of consternation over melting points while this
chemistry was being developed and a paper was published addressing the issue. I have attached it. If anybody want to compare the patent with the
paper it is British patent (GB?) 832491. After reviewing all three papers I am not pushing a peanut around my building. Although the intermediate
ketal was not intended and when the authors wanted to characterize it further they made it from the piperidone, nevertheless it was reported in the
sequence I stated; in both the paper and the patent.
[Edited on 12-2-2009 by chemrox]
Attachment: Ready Formation of Ketals by 4-Piperidones.pdf (316kB)
This file has been downloaded 1144 times
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Nicodem
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That is a more thorough explanation on the issue of the unusual ease of 4-piperidones reacting with alcohols in acidic. Yes, I admit I only read the
page 38 the first time you mentioned ketals and I told you about them not being reaction intermediates already in my first reply to your objection,
but you did not bother checking. I did not read the experimental before yesterday when you still insisted about them being intermediates on the route
N-phenylethyl-4-piperidone. I have limited free time, you know.
As an interesting note, this reactivity of the carbonyl group in protonated 4-piperidones is otherwise general. For example, even plain 4-piperidone
hydrochloride forms a stable hydrate with water, probably due to the electron withdrawing effect of the ammonium group. Essentially they behave as
electron poor ketones, of which chloral is one such textbook example.
…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)
Read the The ScienceMadness Guidelines!
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chemrox
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That's fine as far as it goes but this started out with you telling everyone I didn'y know what a Claisen condensation is, when it was in fact a
Dieckmann, that I didn't know what a ketal was and all before you'd read any of the source material. I suggest if you have limited time you might
limit your attacks too. Indeed, way do you attack? It's not at all helpful and just makes the forum a less pleasant place to be. Let us both go
forward and try to do a little better in future.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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BobHawson
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Does anyone have access to these?
(1) Scott, Robbins and Chen, Science, 104,587 (1946).
(2) Jensen, Lindquist. Rekling and Wolffbrandt, Dansk ~Tidsskr.
Farm., 17, 173 (1943): C. A.. 39, 2506 (1945); Lee and co-workers.
J. Org. Chem., 12, 894, 904, 911 (1947).
(3) Blicke, “The Mannich Reaction,” “Organic Reactions,” 1,
303 (1942).
(4) Kuhn, Badstabner and Grundmann, Ber., 69, 98 (1936).
Taken from: http://www.sciencemadness.org/talk/viewthread.php?action=att...
They haven't been mentioned yet and I think they're quite relevant:
"
A number of piperidones have been prepared by
the Mannich reaction[3]. It should be possible to
extend the use of this reaction for the synthesis of
a large variety of 4-piperidones with different substituents
in the 1,2,3,5 and 6 positions.
"
I think this has the implication that the Mannich reaction worked with making unsubstituted piperidones like npp.
I'd know for sure if someone could find the articles, particularly number 3.
BobHawson
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Polverone
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Organic Reactions Volume 1 was scanned by S.C. Wack and has been in the library for a while now.
Edit: I should add that almost all of the information published about synthetic analgesics based on substituted piperidones and the Mannich reaction
post-dates the review in Organic Reactions.
[Edited on 2-26-2009 by Polverone]
PGP Key and corresponding e-mail address
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chemrox
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Thanks SC Wack, Polverone and the text gods for a non-volatile upload. It is too bloody frustrating to go to a journal that is on an expired
&-shared site or is a multi-volume set where each volume takes 5 minuted to start the dl and you're limited to two a day for 34 volume set. Oh
and it's compressed too. @ Polverone- ahem, I have seen articles from McElvain, Rice and some others since 1942.. quite a few into the early 50's.
They're not Mannich condensations though. Seems like Mansfield and Schmidle did some Mannich condensations and double Mannichs to make piperidines.
[Edited on 27-2-2009 by chemrox]
Attachment: Derivs XVIII-Mcelvain & Rorig.pdf (769kB)
This file has been downloaded 1580 times
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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BobHawson
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N-Phenethyl2-6biphenylpiperidone > NPP
How would one convert N-Phenethyl2-6biphenylpiperidone into NPP?
N-Phenethyl2-6biphenylpiperidone synthesis is here: http://www.sciencemadness.org/talk/viewthread.php?action=att...
BobHawson
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not_important
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I would not do the conversion for two reasons
1. SFAIK it is not easy to remove an aromatic substitute from the piperidone ring, the ring is very likely to be destroyed.
2. NNP is Official Disapproved of in a number of countries, having possession is reason for various and vigorous treatments by LEAs.
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BobHawson
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Is a reaction possible with n,n-dimethylphenethylamine and acetone to give NPP?
BobHawson
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chemchemical
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I thought this article sounds interesting as a possible starting point to making NPP from PEA, unfortunately the online articles for 1998 do not
include the first two volumes.
"Fentanyl of a potent anilidopiperidine analgesic has been synthesized from a simple phenylethylamine by four step sequence. The key part of this
synthesis involves an efficient construction of phenylethylpiperidone skeleton via aminomethano desilyltion-cyclization followed by Swern oxidation.
Arch Pharm Res. 1998 Feb;21(1):70-2."
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BobHawson
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Also, would a reaction between N,N,-diethylphenethylamine and formaldehyde produce NPP?
I don't know what such a reaction would be called, if there is one.
BobHawson
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BobHawson
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4-Piperidone Synthesis
Anyone know of routes to piperidone not starting with piperidine?
I have utse and know of no posts on this chem btw.
BobHawson
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