romanceliu
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Willgerodt Reaction
m-aminophenylacetic acid
the mixture of m-aminoacetophenone 0.5mol ,sulfur 1.25mol and morpholine 1.00mol was refluxed for two hours .The cooled reaction mixture was taken
up in
chloroform and the solutiou was washed twice with water.
The chloroform was removed under vacuum and the resi-
due was refluxed for four hours with 500 cc. of concentrated
hydrochloric acid. Precipitated sulfur was removed by
filtration and the filtrate was taken to dryness under
vacuum. An excess of 35% c'austic soda was added and
the solution was again taken to dryness in order to remove
retained morpholine. An excess of concentrated hydro-
chloric acid was added and the mixture was taken to dry-
ness a third time, then the residue was leached with boiling
absolute alcohol (300 cc.). The solvent was removed
from this alcoholic extract and the residue was refluxed
one-half hour with 500 cc. of concentrated hydrochloric
acid (see following paragraph). The hydrochloric acid
was removed under vacuum and the residue was dried
by azeotropic distillation with toluene. The dry residae
of m-aminophenylacetic acid hydrochloride weighed 88.5
g. (94.5% yield). A small portion of the material was
recrystallized from absolute alcohol;
the question is that the reaction need a lot of concentrated
hydrochloric acid.
can you gei me some advice that is reduce the hydrochloric
and gei me some document about the new method of hydrolysis.thanks
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Ebao-lu
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I suppose, the use of so huge excesses of HCl is in order in have a little better yields. The third HCl manipulation seems to be done in order to
hydrolize unhydrolized thiomorpholide and morfolide (they used to eliminate morpholine with alkali drying, but "forgot" to remove (thio)morfolide). If
the yield is not very critical for you, i am sure you can reduce the HCl amount practically at all steps, and in "excess" cases, use just a little
molar excess. Probably, unreacted (thio)morpholide could be removed by extracting it with some organic solvent after drying the alkali solution. Try
to hydrolize your RM after wilderodt reaction in small scale experiments untill you get fine yields.
[Edited on 11-1-2009 by Ebao-lu]
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Sauron
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There are plenty of other ways to make phenylacetic acids, why don't you investigate those if this reaction's usage of conc HCl strikes you as
onerous?
At least half a dozen routes ought to be obvious to anyone worthy of calling himself an organic chemist. I will not catalog them as most people
interested in phenylacetic acids only have one thing on their minds.
Sic gorgeamus a los subjectatus nunc.
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Ebao-lu
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I quess, thats because romanceliu needs m-amino phenylacetic acid.. so amphetamine was not his aim i beleive. HCl is probably used (instead of H2SO4)
because while drying acidic aniline sulphates may give sulfanilic acids, that will mud the product.
If you realy need unsubstituted phenylacetic acid, there are many methods to do it, and after willgerodt reaction you can feel free to use H2SO4 (if
it is required, i will provide a procedure for that(or you can find it in google)).
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romanceliu
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thanks , if i reduce the HCL, the yeid is low ,
can you gei me some document about H2SO4 instead , i do not find in google ,
i find the m-aminophenylacetic acid though R-CN. but i do not find route,
can you gei me some anther routes ,
thanks
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jon
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what about the grignard intermediate react with co2 and quench thought about that?
example:
m-aminobenzylmagnesium chloride +CO2 then quench.
chlorinating the toluidine might be problematic seeing how you would wind up with chloramides as well, hmmm?
[Edited on 13-1-2009 by jon]
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Ebao-lu
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NH2 group protons are acidic, and gringard will surely deproronate it, becoming a m-aminotoluene. Maybe other metals instead of Mg will not give such
reactive organometallics, but RMgX is surely intolerant to NH2. m-toluidine is a problem itself, it is much less avaliable then o- and p-, and it
would be mostly ring chlorinated There is some slight possibility that protonized amino group is a meta- orientant, maybe aniline is m-alkylated it
some conditions, for example could amidometylation(H2SO4, HOCH2NHCOR), or chloromethylation give the desired m-product?
As for H2SO4, it is used in case of unsubstituted phenylacetic acid, the evaporated chloroform extract (equal to 1 mole of acetophenone/styrene taken)
is refluxed with 1200ml 50 weight % H2SO4 for 10 hours, then extracted with ether 3 times, combined extracts are washed with 100 ml 12% NaOH, then
alkaline layer is acidified with HCl and extracted with ether, combined extracts are evaporated, yield=84%)
[Edited on 13-1-2009 by Ebao-lu]
[Edited on 13-1-2009 by Ebao-lu]
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Sauron
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m-aminophenylacetonitrile is ibvious. Get there from the m-aminobenzyl chloride or bromide and there from side chain halogenation of m-aminotoluene
(m-toluidine.) m-Toluidine from reduction of m-nitrotoluene.
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jon
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theres also the sodium dichromate oxidation of m-amino-1-ethylbenzene as a possibility.
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Sauron
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I believe that will chew the ethyl group back to methyl or carboxyl but not -CH2COOH. Too brute force.
Now, you could easily oxidize an Ar-CH2-CH2-OH to an arylacetic acid, but, you've got to make that first.
And what will happen to that amino group while this vigorous oxidation is going on?
[Edited on 14-1-2009 by Sauron]
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Ebao-lu
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Probably, starting with m-nitrobenzaldehyde(BA nitration), it is possible to make m-nitromandelic acid(KCN, then hydrolysis) and then reducing it
directly to m-aminophenylacetic acid(OH group in a-position is known to be removable by H2/catalyst, NO2 is reduced in same conditions). But this
route would require gaseous hydrogen, catalyst and KCN(feasible to use acetonecyanhydrine instead). There should be the conditions to remove OH, but
not hydrogenate COOH, i hope it is possible to find them.
Ipso-substitution with CN- also should be avoided if it could take place.
edited: maybe, gaseous H2 is not required. Just found a mеntion that "p-nitromandelic acid is reduced to p-aminophenylacetic acid by SnCl2/conc
HCl "
The same will hopefully be possible with m-nitromandelic acid, but the stability of a-carbocathion should be more problematic in case of meta-amino,
unlike p-.
[Edited on 13-1-2009 by Ebao-lu]
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Sauron
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That's rather a long way round a relatively simple problem.
Acetone cyanohydrin has just about vanished from even the big name chem suppliers, I know because I tried to buy some. Aldrich still sells it but
wants massive hazmat fees.
You can make it but that requires KCN or NaCN and you are back to square one.
How about preparing or obtaining m-chloroaniline, and reacting it with the sodio derivative of diethyl malonate then working up (saponification,
decarboxylation) to to m-aminoPA?
Monochlorination of nitrobenzene will orient meta and then Zn/HCl will reduce the nitro group.
A lot more straightforward than nitrating benzaldehyde (which requires protecting the aldehyde as the diacetate, using acetic anhydride).
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romanceliu
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start with m-nitrobenzaldehyde. chlorination ,cyanidation.hydrolysis and reduction. this route is too long , it is very dangerous to use the KCN or
NaCN , difficulty to buy .it is not fit the procuct in large scale ,
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Sauron
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Why large scale?
Are you a hobbyist or what?
You certainly are not an industrial chemist.
So why large scale? Why do you want a LOT of m-aminophenylacetic acid?
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Ebao-lu
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Chorination is not there (it was said concerning chlorination of nitrobenzene)
Hypotetic route with cyanide is just the contrary for large scale quantities, possible to use it in industry, not in lab. If i understood correctly,
you are interested in good yields(thats probably because m-aminoacetophenone isn't cheap). Then imagine, how the large scale synth(what do you mean be
that?) will hit your/your lab's pocket. Maybe it is better to find another route, not from m-aminoacetophenone? Sauron suggested quite a nice one,
besides m-chloroaniline is avaliable and comperatively inexpensive.
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