UnintentionalChaos
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Frustrating Chemical
I have been looking at several syntheses for a flavonol and all of them seem to require one chemical that seems infuriatingly hard or impossible to
prepare without access to acetyl chloride or acetic anhydride. The compound I am interested in in 2,4,6-trihydroxyacetylbenzene. Any brillantly clever
OTC preparation ideas would be much appreciated. Thank you for your assistance.
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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stoichiometric_steve
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2,4,6-trihydroxyacetophenone - seems pretty available to me.
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Sauron
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Why not just make your own acetyl chloride from TCT and acetic acid?
Sounds like you want to do a Friedel Crafts acylation of 2,4,6 trihydroxybenzene. AlCl3 in CS2?
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UnintentionalChaos
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If I had TCT, I would have used it already. I am actually looking at the Hunsdiecker reaction for production of acetyl chloride right now which uses
silver salts semi-catalytically. I can regenerate the Ag2O from the halide salt waste in any case, so it shouldn't be a huge problem. The only
sticking point is that it is carried out in carbon tet and that is not remotely easily available. Has anyone been able to produce it on a lab scale?
I'm more interested in the reactions here than I am in the product, since the final compound is nothing particularly useful in further reactions nor
very difficult to acquire. It is possible to make CCl4 from CS2, but CS2 is pricey from what I can find.
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'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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Nicodem
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Why don't you use the usual method for preparing 2,4,6-trihydroxyacetophenone, the reaction of flouroglucinol with acetonitrile saturated with HCl?
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Sauron
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Phloroglucinol if what you mean I think (sym trihydroxybenzene.)
Anyway yes CCl4 can be made from CS2 if you don't mind generating a lot of chlorine, these are slowly percolated through a column bed of granular
activated carbon at a controlled temperature, this produced a mixture of SCl2 and CCl3SCl, both of which are nasty. You can however seperate them by
fractionation ( FUME HOOD! ) and then just reduce the CCl3SCl with iron filings and purify the CCl4 that results. And you have a batch of SCl2 left
over. I have posted about this before and I have a lot of details.
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not_important
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Would this route work -
nitrate ethylbenzene to the 2,4,6 trinitro compound
oxidise both of the benzylic hydrogens, directly to the ketone, indirectly via the alcohol, or indirectly by di-halogenation and hydrolysis.
reduce the nitro groups to aminos
hydrolyse the triamino compound to the trihydroxy by treatment with hot base.
The trinitro => triamino => trihydroxy steps are one of the manufacturing routes to phloroglucinol.
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UnintentionalChaos
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My main problem there is getting the ethylbenzene. I can't even find toluene anywhere....xylene i can get 4L for $15 US though (not helpful here)....I
guess toluene is just frowned upon as a precursor. That would have been my initial method of attack, save for the lack of reagents....I do like the
sound of that procedure, Nicodem...This may just be me being ignorant, but what is the mechanism for the reaction/Can you give me a reference or
synthesis please.
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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UnintentionalChaos
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I found the synthesis on Orgsyn, Nicodem. Do you think this synthesis could also work using phloroglucinol instead of resorcinol? (EDIT: Link refuses
to work, just search orgsyn for resacetophenone...it is the first hit)
So, the product I am trying to make is Phloracetophenone. I also found a very simple production method for the phloroglucinol http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0455
Now for some TNT and Chromic Acid....
Another thought....trinitration of m-xylene would most likely proceed to a product suitable for making into phloroglucinol, and commercial xylene is
generally 45-60% m-xylene to start with. The isomers have drastically different freezing points, -48C, -24C, and 12C for the meta, ortho, and para
isomers, respectively. If I could chill down xylene to @-35C and stabilize it there, I could obtain a very meta-xylene enriched mixture. Also, I
imagine that nitration of xylene proceeds more easily than that of toluene since the ring is further activated by the extra methyl group (which also
happens to be in a reinforcing position with regards to the first one)
[Edited on 4-6-07 by UnintentionalChaos]
EDIT #2: The following procedure is for gallacetophenone and requires acetic anhydride...If the same is required for phloroglucinol, I have just hit a
nice stopping block in my until now, highly OTC preparation
[Edited on 4-6-07 by UnintentionalChaos]
Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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Nicodem
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The reaction is called the Houben-Hoesch Reaction* and the acetylation of phloroglucinol with acetonitrile is its classical representation in most schoolbooks. The reaction
mechanism is identical to the general mechanism of Friedel-Crafts acylation (with the electrophile formed from the HCl addition on the triple bond of
the nitrile).
Some experimentals for preparing 2,4,6-trihydroxyacetophenone monohydrate this way:
Bioorganic & Medicinal Chemistry Letters, 15 (2005) 5027-5029.
Bioorganic & Medicinal Chemistry Letters, 14 (2004) 3949-3952.
Organic Letters, 6 (2004) 4647-4650.
Indian Drugs, 37 (2000) 500-505.
Journal of the Chemical Society, Perkin Transactions 1, (1980) 2894-900. (uses TfOH instead of HCl)
* original papers:
K. Hoesch, Ber., 48 (1915) 1122.
J. Houben, Ber., 59 (1926) 2878.
PS: This is by far the most common method of preparing this compound. At least 2/3 of all references uses this reaction. Please, next time check the
literature first, before calling it a "frustrating chemical". I expected some extremely scary structure by seeing that misleading thread title. 
Edit: I missed your new post before. Preparing phluoroglucinol is pretty much a nonsense unless you are in a masochistic mode. It is not particularly
expensive while preparing it is only rational industrially. No, you can not use o- and p-xylenes which are the main constituents of commercial xylene
(Where have you heard m-xylene is the major constituent? And, no, xylenes can not be separated by freezing.).
Edit2: The Friedel-Crafts acetylation of phlouroglucinol with acid anhydrides and acid chlorides gives a mixture of mono- and diacetylphlouroglucinol.
Depending on conditions there can be up to 30% of diacetyl product. I'm sure the same problem appears also when acids are used though I have not seen
literature examples. This means you would have to recrystallize the crude product a couple of time and thus lower the yield dramatically. This is why
the mild Houben-Hoesch reaction is so much preferred in literature examples (it only gives one product). Therefore I would rather avoid the method as
used in the Org. Syth. preparation of resacetophenone, but it should work on phluoroglucinol as well. But I would not waste phluoroglucinol by trying
a new method when there is already a simple and full proof one available.
[Edited on by Nicodem]
…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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UnintentionalChaos
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Thanks for all the help....I thought m-xylene was the major constituent since p-xylene turns into PETE bottles and o-xylene turns into phthalic acid
for a whole lot of things, but I remember this being brought up a LONG time ago and it was probably covered in much greater detail then. Maybe I am in
masochist mode. 
I couldn't find much on the compound because Iwasn't using the term phloroacetopenone (and didn't find that name until later on)...i was searching for
2,4,6-trihydroxyacetylbenzene, which turns up very little. I had even asked my chem professor about synthesizing it and didn't get an "Oh, thats not
too difficult a compound to make" or "thats a very basic synthesis," but not everyone can be a walking dictionary of reactions.
The whole freezing xylene thing probably only got thought up because I am quite tired and wasn't thinking when writing that.
Well, my perspective on making this has made some massive loops through this thread and I've definetly learned something.
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'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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Nicodem
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Just for the record, the Houben-Hoesch reaction for preparing 2,4,6-trihydroxyacetophenone is featured also in this Org. Syn. article: http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv2...
| Quote: | Originally posted by UnintentionalChaos
I had even asked my chem professor about synthesizing it and didn't get an "Oh, thats not too difficult a compound to make" or "thats a very basic
synthesis," but not everyone can be a walking dictionary of reactions. |
The decay of the educational system in USA is so pathetically sad. It is not particularly sad that someone does not know the Houben-Hoesch reaction
even though it is described in nearly all basic organic chemistry schoolbooks (I have to admit that I had to check a book to get its exact name and
spelling). What is truly sad is that now chemistry teachers are as worthless as to not being able to imagine a hypothetical retrosynthesis for a
compound as simple as this! But the most terrible things of all is that (s)he was unable to suggest you how to find the literature references. No one
is a walking dictionary, which is why we have libraries!
[Edited on by Nicodem]
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