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JohnWW
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Acetophenones (acetophenone itself is methyl phenyl ketone) from benzaldehydes sounds similar to the well-known benzoin condensation, in which
benzoin, C6H5CH(OH)C(=O)C6H5 is produced from the condensation of two molecules of benzaldehyde with formation of a new C-C bond, catalysed by the CN-
anion. It was discovered in 1903. Other catalysts for it have been found, e.g. thiamine and some other aliphatic and aromatic amines. It is to be
noted that benzoin has a chiral (optically active) C atom; the racemic mixture would probably be produced.
However, any such reaction of something else, e.g. another aldehyde, with benzaldehyde (or its substituted derivatives) itself, with a suitable
catalyst such as CN-, would be liable to produce a mixture containing benzoin (or its derivatives).
See:
http://en.wikipedia.org/wiki/Benzoin_condensation
http://www.organic-chemistry.org/namedreactions/benzoin-cond...
http://individual.utoronto.ca/ekwan/benzoin.pdf
http://www.cerlabs.com/experiments/10875407374.pdf
http://www.imm.ac.cn/journal/ccl/1603/160312-321-04-0122-p4....
http://www.chempensoftware.com/reactions/RXN115.htm
http://www.ingentaconnect.com/content/els/00404039/1998/0000...
http://cat.inist.fr/?aModele=afficheN&cpsidt=18443067
http://www.womensmedia.com/new/?p=pharmacy2-Thiamine-catalyz...
http://www.nationmaster.com/encyclopedia/Benzoin-condensatio...
http://www.ias.ac.in/resonance/April2008/p355-368.pdf
http://www.experiencefestival.com/benzoin_condensation
http://courses.chem.psu.edu/chem35/Syn%20Sp06/35Exp12.pdf
[Edited on 15-8-08 by JohnWW]
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Klute
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Hum, great idea actually, I might try making benzoin derivatives and see hwo they smell, if they smell.. IIRC, the condensation requires cyanide
caatlysis, though? I'll have a look again. Thansk for the idea!
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Klute
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I stumbled on an article on a-alkylcinnamic acids, were they prepare various derivatives. This gave me an idea for preparing acetophenones from
benzaldehdyes, through the benzalacetones:
-Aldol condensation of the aldehydes with acetone (which I have already done with a series of aldehydes, very simple and high yielding reaction):
Ar-CHO + Me2CO --NaOH--> Ar-CH=CH-COCH3
-Haloform reaction to the cinnamic acids:
Ar-CH=CH-COCH3 --NaOCl--> Ar-CH=CH-COOH
>80% yields, very easy reaction.
The cinnamic acids could also be prepared by the Perkin reaction.
-Bromination of the double bond to the dibromides:
Ar-CH=CH-COOH --Br2--> Ar-CHBr-CHBr-COOH
They perform the reaction in CCl4, I'm sure DCM will substitute very well. 75-90% yields.
-Double halogeno-elimination decarboxylation to the phenylacetylenes:
Ar-CHBr-CHBr-COOH ---KOH/EtOH--> Ar-CCH
70% yield.
The phenylacetylenes can then be hydrated to the acetophenones:
Ar-CCH ---H2O--> Ar-CO-CH3
I found a few mentionnings of this hydration, it cna be done using formic acid apparently. Ideally, mercuric salts should be used, but I ratehr use
something else. I'll keep on looking around, perhaps a simple dilute H2SO4 reflux would do the trick.
That's a farily long reaction scheme, but if it avaoid diazomethane... The yields are mostly on the high side, and the bromination and
decarboxyaltion/elimiantion can be done one-pot, perhasp even the hydration aswell (neutralize the KOH with H2SO4, reflux and distill).
I don't think there will be any demethyaltion of the alkoxy aldehdyes.
The phenolic aldehdyes might be a little more tricky, they could oxidize during the haloform, and the arene might be sufficently activated to cause
some ring-bromiantion when forming the dibromides... An eventual protection could be possible.
I could also form the respective bromostyrenes from the dibromides, and see how they smell. Straight b-bromostyrene is a classical academic
preparation..
Forming the acetylide anion and alkylating it with alkyl halide sounds like an interesting approach to, I think NaH would be enough to form the anion.
Could also prepare b-ketoalcohols by adding the anion to a ketone, and hydrating the alkyne. If the conditions are rought enough the b-alcohol could
dehydrate to form a aromatic a,b-unsaturated ketone? i could always do this in a seperate step in any case...
Any thoughts, ideas, suggestions?
EDIT: ref:
Some alpha-Alkylcinnamic Acids And Their Derivatives
Marston Taylor Bogert and David Davidson
J. Am. Chem. Soc.; 54(1), 334 - 338 (1932)
DOI: 10.1021/ja01340a050
[Edited on 14-9-2008 by Klute]
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kmno4
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It is a long way and total yield <20%.
"Similar" way could be:
benzaldehyde--oxidation-->benzoic acid
benzoic acid+acetic acid--catal.decarboxyl.-->acetophenone
or via calcium salts.
Your "multistep idea" reminds me making benzophenone from benzaldehyde (without Grignard).
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smuv
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You can oxidize to the benzoic acid and then treat with 2eq of methyl lithium. After acidic workup the acetophenone is directly obtained. Of course
I have no idea if you are equipped for this.
You can make the nitrile and hit it with methyl magnesium bromide. Acetophenone after hydrolysis.
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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chemoleo
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Although it is not based on benzaldehyde as a starting compound, but benzoic acid, acetophenone could be made by ketonisation decarboxylation from an
equimolar mix of dry Na-benzoate and NaAc, similar to the production of acetone from CaAc2, or benzophenone from Na-benzoate on its own.
This approach was also discussed here with unrelated compounds https://sciencemadness.org/talk/viewthread.php?tid=9717 , and also in some other threads which I can't find.
Attached also a paper on ketonisation decarboxylation of various carboxy acids - I think I got from one of those threads I couldn't find.
Attachment: Ketonization of Carboxylic Acids by Decarboxylation.pdf (154kB)
This file has been downloaded 984 times
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Tolerance is good. But not with the intolerant! (Wilhelm Busch)
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Klute
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Thanks for the suggestions.
I'm not too found of pyrolysis reactions to be honest. I might give it a try on the cheapest aldehdyes though, but I'd prefer other routes.
I am equipped for organometallic reactions, although I don't have any lithium or alkyl lithium at hand. BuLi isn't something I would like to keep in
the fridge next to my food. The grignard on the benzonitrile is pretty interesting though. A direct grignard on the aldheyde is said to be pretty low
yielding..
This could be a good way of using any over-oxidized aldehydes. I could also give it a try on vanillin and a few of it's derivatives.
I think there is a way of obtaining directly the esters from the aldehdyes by oxidating them in presence of the alcohols, i could then form the amide
and dehydrate to the benzonitrile with sulfamic acid.
Or , the benzoic acids could be directly converted into the nitriles via urea/sulfamic acid.
Then a grignard as usual, followed by hydrolysis of the iminium salt. Simple 
Somehow it hurts me to oxidize those poor aldehdyes, I think I will get a few substitued alkoxybenzoic acids, and dealkylate/realkylate them a bit..
There is also the possibility of forming the acetophenones by FC alkylation with the acids and PPA with a Dean Stark. I've been wanting to try this
alkylation out for a while, but I am somewhat limited on the subtitued arenes. I suppose I could try it out on phenol, guiacol, etc
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Flip
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Now here is an idea worth exploring...
Why don't you form the epoxide by trimethylsulfoxide and then obtain the ketone by hydrolysis?
DMS + CH3I --> TMS(+)
1. benzaldehyde + TMS(+) --> styrene epoxide
2. styrene epoxide + h2so4 --> acetophenone
I believe you might actually get a mixture of products tho.. the ketone as well as the aldehyde.. still.
[Edited on 9/15/08 by Flip]
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smuv
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I beleive you can make nitriles from aldehydes via NH3 and I2 (if you dont want to go through the low yielding sulphamic acid/urea route).
If you want to directly acylate; the hosch and nencki reactions could be useful for highly activated aromatics (phenols) in leu of the friedel-crafts.
EDIT: Got another idea (probably more academic than practical). Form a thioacetal (if that's the proper name) with propane-1,3-dithiol; deprotonate
it; alkylate with MeBr; hydrolyze. This might work with ethylene glycol or other diols but classically its done with the di-thiol as a way to make
alkanes (reductive elimination via CTH).
[Edited on 9-15-2008 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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chemoleo
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| Quote: | | [qutoe]I'm not too found of pyrolysis reactions to be honest. I might give it a try on the cheapest aldehdyes though, but I'd prefer other routes.
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Not sure if you are aware of it, but the production of benzene worked quite well that way from Na-benzoate and NaOH (https://sciencemadness.org/talk/viewthread.php?tid=8027 check the first post by Axt). I don't see why it shouldn't work with i.e. acetophenone.
Admittedly you'd have to separate undesired products (such as di-phenyl, benylphenone etc) but distillation should be appropriate for that.
Most importantly, benzoic acid is readily available, and so is acetic acid, and both are cheap... not much to lose, don't you think?
Never Stop to Begin, and Never Begin to Stop...
Tolerance is good. But not with the intolerant! (Wilhelm Busch)
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Klute
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Well, acetophenone itself I don't really care, I'm aiming at the subtitued ones. So I could use p-hydroxybenzoic acid, p-methoxy and the other few
pretty cheaply, but the others I would have to use the aldhedyes I have, which bothers me a bit.. But I agree it's worth a try. I guess phenolic
compounds might be prone to excessive side reactions?
I will have a look in the trimethylsulfoxide route,as it seems intersting, and maybe the acetal alkylation route: propanedithiol is pretty expensive:
60E 25mL.... Remember these are my personal fundings!
Smuv, have you any further info on the NH3/I2 nitrile preparation?
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S.C. Wack
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I can save smuv the search because I have this at my fingertips, I was just looking at a different benzaldehyde->benzonitrile conversion last
Saturday [JCS 1564 (1965), IIWC], and have these all together in my mind at least. BTW the JCS paper gave high yields of nitrile from benzaldehydes,
but it may be a little less economical, using hydroxylamine HCl, sodium formate, and 98-100% HCOOH, though yes these aren't exactly expensive things
and iodine is not cheap.
Anyways - Hive post 421248 in living color, Vitus' post of Tet. Lett. 42, 1103 (2001). (BTW in a later article [JOC 68, 1158 (2003)] with one of same
authors, the nitriles were unisolated intermediates to amides in high yield, by addition of 35% H2O2 after the mixture became colorless.)
Attachment: 421248.zip (37kB)
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Klute
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Thank you very much S.C Wack, very helpfull!
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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S.C. Wack
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| Quote: | Originally posted by kmno4
| Quote: | Originally posted by S.C. Wack
There is high yielding preparation of acetophenone from benzaldehyde and diazomethane in the literature (...) |
Yes, namely ? |
According to volume 8 of Organic Reactions, which is advisable reading on the subject,
Ber. 40, 479 (1907) (97%)
Ann. 433, 64 (1923) (quantitative).
BTW according to Coyne, Clear-Seal joints are shaped on a mandrel while hot, and not ground.
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Klute
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I have located an article mentionning the preparation of substitued acetophenones after double-decarboxylation (like not_important mentionne don the
first page) of an acylated diethyl malonate (well, decarboxylation of the benzoylacetic acid). The reaction is referenced from a J. Prakt. Chema
rticle availble at Gallica.
Attachment: benzoylacetate.pdf (2.5MB)
This file has been downloaded 534 times
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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S.C. Wack
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Might as well throw out there another preparation of benzonitriles via hydroxylamine since I found another [Chem. Ind. 1873 (1961)] in my notes
similar to the one that I already mentioned. This one uses acetate and GAA instead of formic and formate but the yields are lower, 50% from piperonal,
67% from anisaldehyde, 80% from vanillin. The point is that I have a feeling that even cheaper methods using hydroxylamine HCl and perhaps mineral
acids in cheap solvent might be in the literature. It is in the literature for a small number of aliphatic aldehydes for sure.
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Klute
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Ok, i appears the acylation of diethyl malonate anion looks like the most attracting method.. according to J. Am. Chem. Soc., 1946, 68 (7), pp
1386–1388, high yields of the methyl ketones are obtained after decarboxylation using sulfuric and acetic acids.. I have seen another ref where
propionic acid is used.
The acetoacetic esters can be used in place of diethyl malonate.
The acyl chlorides are availbale from the benzaldehydes by oxidation with H2O2, KMnO4, etc, followed by reaction with SOCl2, or by direct chlorination
of the benzaldehydes, although I afraid this will lead to nuclear chlorination with activated aldehydes (vanillin, etc)
This is on my to-do's list, as soon as I get the lab running back again!
Targeted acetophenones: 2-methoxy, 2-hydroxy, 4-methoxy, 4-hydroxy, 3-methoxy-4-hydroxy, 3,4-dimethoxy, and possibly ethoxy derivatives!
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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zed
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Flip.
The treatment of styrene epoxides, with acid, might be likely to produce phenylacetadehydes, rather than acetophenones.
Such reactions usually proceed through cleavage of the epoxide ring, via addition of H20, followed by dehydration of the resulting 1,2-diol.
Since, the benzylic ion is most stable, it is from there, that the OH group is most likely to be removed. The resulting unstable intermediate should
then rearrange to form the Phenylacetaldehyde, not the acetophenone.
This is analogous to the formation of Phenyl-2-propanones, via the treatment of epoxides, produced by by the action of Peroxide/Formic Acid, on
propenyl benzenes.
.......................................................................................................................................
Klute,
The pathway to ketones via pyrolysis/distillation of salts of carboxylic acids(Fe, Ca, or Pb), has been well discussed. And, while somewhat less than
elegant, it is straightforward.
I have read accounts that suggest performing the pyrolysis under vacuum is helpful for improving yields, as it aids in removing the formed ketones
quickly from the reaction mix.
Some suggest that yields as high as 70% may be obtained.
[Edited on 14-9-2009 by zed]
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Klute
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Just realized there is a Org SYn preparation for o-nitroacetophenone using the benzoyl chloride/diethyl malonate route!
http://orgsyn.org/orgsyn/default.asp?dbname=orgsyn&dataa...
The yields look very good! Can't wait to try this out.. I still have to figure out the best way of oxidizing the benzaldehydes to the acids without
permangante or chromate salts.. H202 I'm scared might do a Dakin or Bayer villiger reaction forming the phenol.. NaOCl might chlorinate the
activated aromatique.. I will surely be starting with vanillin.. ANy suggestions?
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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Klute
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Ok, shortened the reaction path a little. I remebered reading about reacting benzaldehyde with TCCA to form benzoyl chloride. Indeed, Nicodem poste
dsome info on this in the acetic anhydride thread (p.20). Well, that french patent only claims 48% yield with benzaldehyde, and there musn't be any amino or hydroxy
substituants.. I'm afraid an activated aromatic like 3,4-dimethoxybenzaldehdye or p,o-methoxybenzaldehydes will get chlorinated on the arene..
So I was thinking of oxidizing the benzaldehydes to the acids using NaOCl and cat. Ni (II) salt (ref posted somewhere on the board, can't bother to
find it, it nearly 6 am and I still haven't slept yet), then forming the acyl chlorides with SOCl2.
Well, it seems SOCl2 can directly convert the benzaldehydes to benzoyl chlorides, Nicodem posted a article. Unfortunaly it's a terahedron, and science
direct is down for the moment.. So I will request it later.. Hopefully the yields are good, and activated aldehdyes can be used! Bam, two steps to
the acetophenones! Exactly what I needed..
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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not_important
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Quote: Originally posted by Klute  | ...
So I was thinking of oxidizing the benzaldehydes to the acids using NaOCl and cat. Ni (II) salt (ref posted somewhere on the board, can't bother to
find it, it nearly 6 am and I still haven't slept yet), then forming the acyl chlorides with SOCl2.
... |
While you then mention a possible more direct route, the NaOCl-Ni(II) oxidation was recently dredged up here http://www.sciencemadness.org/talk/viewthread.php?tid=12832
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zed
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The Cannizzaro reaction comes to mind. Easy. Very little waste. Treat your benzaldehyde with base. Yields approximately 50% Benzoic acid....50%
Benzyl Alcohol.
Reoxidize your Benzyl Alcohol.
Wiki has an interesting reference.
I'm inclined to think that air should oxidize benzaldehydes directly to benzoic acids, under mild conditions. But, I don't have a ready reference.
Mostly, I've spent time searching, for an easy methods to achieve the opposite......Reducing Carboxylic acids to Aldehydes.
[Edited on 22-9-2009 by zed]
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Ephoton
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I always liked the idea of making diazomethane from hydrazine, chloroform and caustic.
very easy for the home chemist too make.
whats an explosive but a few hundred yards away with an extension cord to
turn the heat off .
e3500 console login: root
bash-2.05#
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