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Klute
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Acetophenones from benzaldehydes?
Does anyone know of a practical way of forming acetophenones from benzaldehydes? Substitued acetophenones are said to often posses appreciable smells
as their corresponding 2-butanones.
What came to mind is the addition of a methyl grignard reagent on the aldehyde, followed by the oxidation of the resulting phenyl-1-ethanol to the
acetophenone.. Org syn says these reactions aren't always straight forward, and in some casesa re low yielding or prone to formation of by-products.
Apparently organo-titanium and dialkyl zinc reagents can be used too, but I would prefer sticking with a grignard if possible.
I would like to know if anyone has an ideas involving less strict reaction conditions than grignards?
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PainKilla
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How about formation of the cyanohydrin followed by reduction/oxidation?
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Klute
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Nice, i hadn't thought of that. But I don't have any cyanides, and don't really feel confortable using any...
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not_important
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Then how about reacting it with acetic anhydride in a Perkin reaction, decarboxylation to the styrene, and add water?
If that sounds interesting you might wish to look at
doi:10.1016/j.tet.2007.08.034
Tetrahedron
Volume 63, Issue 45, 5 November 2007, Pages 11070-11077
Arun K. Sinha, Vinod Kumara, Abhishek Sharma, Anuj Sharma and Rakesh Kumar
An unusual, mild and convenient one-pot two-step access to (E)-stilbenes from hydroxy-substituted benzaldehydes and phenylacetic acids under microwave
activation: a new facet of the classical Perkin reaction
While they use phenylacetic acids it might work satisfactory with acetic acid.
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Nicodem
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One way of benzaldehyde to acetophenone homologation is by carbene insertion using diazomethane:
Ar-CHO + CH2N2 => Ar-CO-CH3 +N2
There are a few old papers describing the reaction. However, preparing and working with diazomethane is not considered particularly "practical".
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
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Klute
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Thank you all for your comments. It seems the grignard is finally the best option then, I do not posses enough Ac2O to try out all the derivatives I
want, but do have enough magnesium. I was thinking of generating the reagent using Painkilla's excellent MeBR generation, to avoid that costy MeI.
I kind of felt diazomethane would work, I must haev read about it in a book or such, but I was searching under "diazomethane methylation benzaldehyde"
and obviously didn't find anything.
EDIT: Well, another idea appeared from a review on the preparation of p-nitroacetophenone requested by Quino, the acylation of diethyl malonate with
p-nitrobenzoyl chloride, followed by hydrolysis and decarboxylation. thenyields can be brought up to 99% under the adequate solvent conditions!
The respective benzoyl chlorides can be produced by chlorination of the benzaldehydes, and then reacted with the mono-anion of diethylmalonate (they
use the ethylmagnesium anion), I could just aswell try the sodium anion.
[Edited on 23-7-2008 by Klute]
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Ritter
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| Quote: | Originally posted by Nicodem
One way of benzaldehyde to acetophenone homologation is by carbene insertion using diazomethane:
Ar-CHO + CH2N2 => Ar-CO-CH3 +N2
There are a few old papers describing the reaction. However, preparing and working with diazomethane is not considered particularly "practical".
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Working with diazomethane (if not a trained chemist in a well-equipped lab setting), especially in quantities in excess of a few grams, is not the
easiest or least expensive way of killing yourself but it is on the list of such options.
Health & safety data for it: http://www.osha.gov/SLTC/healthguidelines/diazomethane/recog...
To give you some idea of the hazards associated with this reagent, Aeroject in CA practices diazomethane chemistry at scale in remote-controlled
bunkers. See http://www.thomasarchibald.com/adobe/diazomethane.pdf.
My opinion of this material is that it should be discussed only in the Energetic Materials forum.
Ritter
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Karl Marx
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not_important
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see | Quote: | | Gutsche, C.D. “The Reaction of Diazomethane and Its Derivatives with Aldehydes and Ketones” ; Org. React. (N.Y.) 1954, Vol. 8, P. 364.
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Also note that Perkin reaction can be done with the acid under certain conditions. Also the related Knoevenagel condensation can use diesters of
malonic acid, which would require a double decarboxylation.
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S.C. Wack
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If the corresponding benzoic acids are stable to considerable heat, perhaps oxidation and reflux with equal amounts of iron and acetic acid would be
interesting though not the highest-yielding. Diazomethane might give an unbeatable yield if done properly.
EDIT:
| Quote: | Originally posted by Ritter
My opinion of this material is that it should be discussed only in the Energetic Materials forum. |
Maybe you should start a new thread on it.
[Edited on 23-7-2008 by S.C. Wack]
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Klute
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I haev realized that the chlorination of benzaldehyes to the benzoyl chlorides might not be applicable to the substrates I plan on using, mainly
phenolic and alkoxy-benzaldehydes, which would surely be ring chlorinated to a large extent during that reaction...
I could use thionyl chloride after oxidation of th ealdehydes for small scale reactions, if the sub benzoyl chlorides can be easily distilled under
25torr, but it just seems a pity to oxidize the aldehydes 
I do not have the adequate glassware to handle diazomethane unfortuanly, I'm sure this would be the most direct option if done cautiously..
BTW, I meant sodium and ethylmagnesium anion, not salt. Sorry for the confusion. I will correct this in the above post.
S.C.Wack, the reduction of the benzoic acids with iron and AcOH, to produce the aldehydes? Actually I have the corresponding aldehydes at hand
already, but not the acids.
[Edited on 23-7-2008 by Klute]
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S.C. Wack
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| Quote: | Originally posted by Klute
S.C.Wack, the reduction of the benzoic acids with iron and AcOH, to produce the aldehydes? |
??? Of course not. You seemed interested in acetophenones, so there you go. Known for ketones from both aliphatic and aromatic acids. Not a great
method because it needs a lot of heat and other groups on the ring interfere, and higher acids give better yields. Friedel made acetophenone in 1857
from dry distillation of Ca acetate and benzoate, and this is probably not a huge improvement.
[Edited on 23-7-2008 by S.C. Wack]
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Klute
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Ah, ok. I thought that was a simple reduction and didn't really undersatnd the point. Thank you for pointing this out.
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Ritter
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| Quote: | Originally posted by S.C. Wack
Maybe you should start a new thread on it.
[Edited on 23-7-2008 by S.C. Wack] |
Too unstable & toxic.
Ritter
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Ephoton
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from what I have read diazomethane is only unstable to friction if in pure state. when in
ether it is no were near as unstable.
the ether having a low evap temp makes as a great buffer for the diazomethane as
when the diazomethane evaporates so does the ether making for a dilution to the
emitions given off of any operations useing the solution.
Maby oneday I will have the chance to make and use this wonderfull reagent
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Klute
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Well, this reagent is very commonly used in research labs, especially with fatty acids caracterisations and peptides, but requires special equipment
and care. I really don't think it's the kind of chemical that only has it's place in energetics sections, considering it's great use and applications.
The problem with ether solution and groud glass joints is that any little amount of solution diffusing throught he joint by capilarrity will quickly
evaporate, leaving a conc. diazomethane on a high surface material, which can be enough to cause detonation, or the slightest twist on the joint.
Don't get me wrong: it certainly isn't the kind of chemical to use on amateur setting if one isn't already familiar and trained for the use of this
compound.
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kmno4
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| Quote: | Originally posted by Nicodem
One way of benzaldehyde to acetophenone homologation is by carbene insertion using diazomethane:
Ar-CHO + CH2N2 => Ar-CO-CH3 +N2
There are a few old papers describing the reaction. However, preparing and working with diazomethane is not considered particularly "practical".
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Acetophenone reacts with diazomethane giving another homolog:
Ar-CH2-CO-CH3 and - propably- cyclic ether (disubstituted, at the same carbon with Ar and CH3, ethylene oxide). CH2N2 reacts very unselectively and
many products should be expected.
[Edited on 26-7-2008 by kmno4]
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Nicodem
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True, but the reaction is not so fast and the acetophenones can be made the main product - at least according to the papers I saw (should check the
review Not_important refers to, since I don't know where I have the original papers). For example, Chemische Berichte, 97 (1964) 1470-1481
claims quantitative conversion of o-methylthiobenzaldehyde to o-methylthioacetophenone with diazomethane (I have not read it yet).
Also this a bit newer paper (where a safer reagent than diazomethane is used) might contain some newer references about the reaction (but I don't have
the time to go to the library now):
New methods and reagents in organic synthesis. 11. Reaction of trimethylsilyldiazomethane with aromatic aldehydes
Hashimoto, Norio; Aoyama, Toyohiko; Shioiri, Takayuki.
Heterocycles, 15 (1981) 975-979.
Abstract: Me3SiCHN2 reacts with RCHO (R = Ph, substituted phenyl) in the presence of Et3N in MeOH to give I and II, as well as RCOMe, RCH2COMe, and
III. The products depend on the solvent and the substituent on the arom. ring.
…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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Ephoton
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I never liked the idea of useing nitroso compounds to make diazomethane.
purely because you have to purchase them or something from some were that is not a normal shopping habit for some one not doing something way more
interesting than the average person.
the only way around this to synthesis alkali nitrites via some kind of high temp nastiness.
I always like the idea of chloroform, hydrazine sulfate and caustic as a way to make
diazomethane.
setup in full reflux setup with gas head on top.
make sure you have a second neck to drip in the diazomethane (I think long time since I read it.)
I can dig up reffs if any one is interested I have them on my server some were .
so many things can be done with diazomethane for organic chemistry its not funny.
ideas or questions on both for me would be
what happens when I add diazomethane to a tri hydroxy benzaldehyde
(ie 3 ,4 ,5 hydroxy benzaldehyde).
does the hydroxyl groups methylate compleatly first or does the aldehyde
get formed into a ketone.
if so how many hydroxyls get converted to methoxy groups before it touches the
carbonyl group.
I think in my books diazomethane comes to mind in the same class as ketene.
a short cut through the old school foundry lab idea.
as most people who have made one or the other would know they all
come with there price.
but I dont think a person who has learned about this subtance properly has
a reason to fear it any more than ketene.
in the patent I have I remeber it stating that the method they used to make diazomethane
was perfectly safe with ground glass joints.
there method did not use any kind of dilutent either the diazo that came off of the the reaction
was pure and all through a ground glass setup.
what happens when you add it to an alkali metal
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DJF90
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IIRC Diazomethane is made using ground glass apparatus, but the joints are FLAME POLISHED.
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S.C. Wack
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http://www.sigmaaldrich.com/catalog/search/TablePage/1718574...
I have a couple pieces (a three way and a Liebig) of flawless Wheaton Clear-Seal, they're pretty neat but I wish I had a complete set. I don't think
that they are polished, they are made in a different way altogether.
There is high yielding preparation of acetophenone from benzaldehyde and diazomethane in the literature, and other related preparation of further
methylated products. All in the conditions I guess. The fine print.
[Edited on 30-7-2008 by S.C. Wack]
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kmno4
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| Quote: | Originally posted by S.C. Wack
There is high yielding preparation of acetophenone from benzaldehyde and diazomethane in the literature (...) |
Yes, namely ?
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ziqquratu
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Diazomethane is dangerous, but like anything can be handled properly if you take care. In our lab, we make it from Diazald, using a Buchner flask as
the generator and a pasteur pipette as the bubbler (we have two sets of the extremely expensive Aldrich polished-joint glassware, but for whatever
reason we don't bother with it).
Basically (and from memory) - Sep funnel in rubber stopper in Buchner, add KOH(aq) to Diazald (aq or EtOH, can't remember offhand). Sidearm connected
via vinyl tubing to pasteur pipette which is immersed in reaction mixture,
The MOST important things to take note of are:
- Glassware should be scrupulously clean
- Sharp edges MUST be avoided. The pipette is OK so long as it ALWAYS stays immersed. The reason, I'm told, is that the edges can induce small
crystals to form (of what, exactly, I'm not sure, but I'm going on what I've been told, and I've seen an explosion for no reason other than a small
fracture in the sidearm), which are liable to explode
- Control the addition very carefully, so as not to get an exotherm, and if you get layers forming, block your ears and run away!
- ALWAYS USE AN EXPLOSION SHIELD!
I can check with some people who do it slightly more often, if anyone's interested.
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Klute
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Thank you for the details ziqquratu, it would be great to have the the opinion of people regularily using it, especially if the polished-joint
glassware isn't mandatory!
\"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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benzylchloride1
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I have found a good way of producing acetophenone derivatives with fairly common chemicals. Oxidation of ethylbenzene and substituted ethylbenzenes by
ammonium persulfate with a catalytic amount of silver nitrate produces acetophenone derivatives. A microscale and a scaled up procedure can be found
on page 394-398 of Microscale Organic Laboratory by Mayo, Pike and Butcher, 2nd edition. Ethylbenzene can be made by the catalytic hydrogenation of
styrene which can be easily prepared by the pyrolysis of polystyrene (Styrofoam) in a pyrex glass distillation set. I have not run this experiment yet
with ethylbenzene, but I have tested the reagents on styrene which oxidizes it to benzaldehyde and probably benzoic acid. 
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Klute
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Thank you for sharing. I remeber trying this syteme for oxidation of toluene and benzyl alcohols to their aldehydes, also the Fe2+/Cu2+ one with mixed
results. What kind of yields did you get with styrene? did you isolate your aldehyde?
Unfortunaly, this can't be of much use for producing substitued acetophenones from their corresponding benzaldehydes.
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