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clearly_not_atara
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| Quote: | | if there were no references on the alkylation with acetonitrile,how did you know it would work ? was it your own idea ? then you should have mentioned
that . |
I saw it in a paper while I was doing research on the question a few days ago, but I didn't save the reference because I didn't think that
p-bromochlorobenzene was a reasonable intermediate anyway. p-dichlorobenzene was unreactive but p-bromochlorobenzene had an (iirc) 40% yield. I don't
remember the conditions either, for what it's worth. I've just spent quite a while looking for it and I can't find it again, sorry. (aaaaaargh!!)
[Edited on 26-2-2016 by clearly_not_atara]
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CuReUS
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I was thinking about this synthesis and it dawned upon me that the reason we got stuck was because all of us kept p-choro phenylacetonitrile as our
target compound from the get-go instead of thinking about other routes.
I think there might be an easier approach which bypasses the phenylacetonitrile
we could monoarylate malononitrile using p-chlorobromobenzene and then react the p-chloro-2-phenylpropane dinitrile with 1 mole of ethylMgBr,which
would be slowly dripped into the flask containing dinitrile under vigorous stirring.
ref for the monoarylation- SYNGENTA PARTICIPATIONS AG Patent: WO2004/50607 A1, 2004
(they use bromobenzene,but I think p-chlorobromobenzene would also work)
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Assured Fish
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| Quote: |
I was thinking about this synthesis and it dawned upon me that the reason we got stuck was because all of us kept p-choro phenylacetonitrile as our
target compound from the get-go instead of thinking about other routes. I think there might be an easier approach which bypasses the
phenylacetonitrile we could monoarylate malononitrile using p-chlorobromobenzene and then react the p-chloro-2-phenylpropane dinitrile with 1 mole of
ethylMgBr,which would be slowly dripped into the flask containing dinitrile under vigorous stirring. ref for the monoarylation- SYNGENTA
PARTICIPATIONS AG Patent: WO2004/50607 A1, 2004 (they use bromobenzene,but I think p-chlorobromobenzene would also work)
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But the malonitrile would also attack the chloride leaving us with side reactions such as 2-(4-phenyldipropane) dinitrile and 4-bromo-2-phenylpropane
dinitrile. 
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CuReUS
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first of all,thank you so much for reviving the thread,I thought it died
Quote: Originally posted by Assured Fish  |
But the malonitrile would also attack the chloride leaving us with side reactions such as 2-(4-phenyldipropane) dinitrile and 4-bromo-2-phenylpropane
dinitrile. |
that is a possibility,but keep in mind that the bromine is a better leaving group and if the concentration of dinitrile was kept at a minimum,this
side reaction could be avoided.After all,there are many reactions where Br in the ring reacts more preferentially compared to Cl.Infact,atara's first
idea(condensation between acetonitrile and p-chlorobromobenzene) used this very logic
anyways,after some thinking,I realised that this too is not a good route because the dinitrile is not easy to obtain.Until now,atara's tyrosine idea
is the only one that is good enough IMHO
If only triphenylphosphine could be made from OTC chemicals
[Edited on 29-5-2016 by CuReUS]
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sparkgap
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A high school synthesis of Daraprim
It apparently hasn't been posted on this thread, but recently some Australian students tried a relatively safer (than the patented synthesis) method
for synthesizing pyrimethamine. Their notes can be found here.
sparky (~_~)
"What's UTFSE? I keep hearing about it, but I can't be arsed to search for the answer..."
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Assured Fish
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@sparkgap somebody should probably give this to NurdRage, It appears the kids added a third methylation step as well as using potassium tert-butoxide
instead of sodium methoxide in the second step to form 2-(4-chlorophenyl)-3-oxopentanenitrile.
I remember hearing about this and brushing it off as if the kids just went out and bought the benzylnitrile and followed the patent.
The old always underestimate the young.
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Dr.Bob
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The kids were directed by a trained chemist, they did not just randomly do this. But it is a great learning experience, and shows both that the
compound is not only practical to make, and the process can be improved, most likely, to be better, but it also teaches some of the non-science
aspects of the problem.
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zed
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Well, it has been a while, but I did stumble across a paper related to this topic today.
A decent yield of P-chloro-aniline, from Acetanilide. It utilizes TCCA.
Recent reports of Aniline being readily produced by the decarboxylation of PABA, with this report of easy Para Chlorination of Acetanilide add up to
an easier synthesis of this material.
Now coupling the Diazonium salt of that Chloro Aniline, to produce the Amino-Acid isn't a certainty, but it is helpful if you can easily and cheaply
make the precursors..
https://www.scielo.br/pdf/qn/v31n1/a30v31n1.pdf
Translation:
To a suspension of acetanilide (0.68 g, 5 mmol) in H2SO4 conc. (6.0 mL) in a 25 mL Beaker, kept under magnetic stirring in an ice bath, between 0 and
4 ° C, trichloroisocyanuric acid (0.52 g, 25 mmol). After 15 min, the reaction solution was poured into a Beaker containing approximately 50 mL of
ice (Scheme 1). The formed precipitate was vacuum filtered in a Büchner funnel and recrystallized in a water / ethanol mixture (70:30).
Para-chloroacetanilide was obtained, after recrystallization, in 56% yield and characterized by melting point: 178 ° C (literature 178-179 ° C) and
spectroscopic data from IR, 1H NMR and 13C NMR.
Hydrolysis of para-chloroacetanilide
In a round-bottom flask connected to a reflux condenser, 1.76 g of para-chloroacetanilide and 10 mL of 70% (w / w) solution of H2SO4 were added. The
mixture was refluxed for 40 min and poured, still hot, into 50 ml of cold distilled water, followed by the addition of 40 ml of 20% NaOH aqueous
solution (or enough to precipitate precipitate). White). The white precipitate formed was vacuum filtered in a Büchner funnel and washed with ice
water (Scheme 1). Para-chloroaniline was obtained in 56% yield and characterized by the melting point 72 ° C (literature 72.5 ° C) and the data of
IR, 1H NMR and 13C NMR.
RESULTS AND DISCUSSION
Electrophilic halogenation of aromatic compounds is a widely studied reaction in organic chemistry. It occurs through an electrophilic substitution,
with the attack on the electrophile by the electrons of the pi connection of the aromatic ring. The slow reaction step is the formation of the Wheland
cationic intermediate, which then loses a proton, to restore aromaticity. The entry of the electrophile is governed by the nature of the substituent
that is attached to the aromatic ring.
In the case of chlorination of acetanilide, the substitution can occur in the ortho and para positions, due to the increase in the electronic density
of the ring conferred by the NHAc activator group. It was observed by gas chromatography that only the monochlorinated product in the position for the
aromatic ring was obtained from the precipitate formed, after the reaction was poured over ice. However, after neutralizing the acid solution with
aqueous NaOH solution and proceeding with the extraction of the aqueous phase with ethyl acetate, the presence of the monochlorinated product in the
ortho- (dashes) position was verified by GC-MS and dichlorinated product, in addition to para-chloroacetanilide.
When the acidic aqueous phase obtained after washing with water is concentrated by heating, fine crystals in the form of reddish needles form on the
bottom of the beaker. The infrared spectrum showed that these are crystals of isocyanuric acid 6.
It is possible to increase the yield of para-chloroacetanilide if the acid solution of the chlorination reaction is neutralized with sodium hydroxide
and then extracted with ethyl acetate. It is necessary to
However, it is necessary to recrystallize the solid formed twice with a water / ethanol mixture (70:30), to remove ortho-chloroacetanilide and
2,4-dichloroacetanilide. This procedure results in a total yield of 62% of pure para-chloroacetanilide.
CONCLUSION
This work shows a new possibility of using trichloroisocyanuric acid, a cheap and easy-to-handle reagent. This can be used, successfully, for the
chlorination of aromatic systems activated in experimental classes of Chemistry and Pharmacy courses.
Because it is a very fast reaction, it allows the student to synthesize, recrystallize and hydrolyze para-chloroacetanilide to para-chloroaniline in
the same class.
Chlorination of acetanilide with ATCI or the commercial product Genclor has numerous advantages over N-chlorosuccinimide and N-chlorosaccharin. In
addition to being a very low price reagent (R $ 6.00 - 200 g), it is more selective for obtaining the chlorinated product in the para position and,
after neutralization, the saline solution can be discarded without major concerns.
[Edited on 25-4-2021 by zed]
[Edited on 25-4-2021 by zed]
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