Fery
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phenoxyacetone
kmno4 pointed me out, that he would like to prepare phenoxyacetone and that it has good scent. He also sent me an old paper with the preparation.
Attachment: ph_ac_berichte.pdf (35kB)
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The paper was written in German language. I tried OCR and online translation.
What I understood - they did it this way:
phenol (about 4-fold excess as it solves also as a solvent) + Na -> dry sodium phenolate dissolved in excess of phenol
sodium phenolate dissolved in phenol + chloroacetone -> phenoxyacetone + NaCl
add excess water solution of NaOH so the phenol as a solvent is converted also into sodium phenolate
steam distill out the phenoxyaceton
this is the OCR and online translation:
| Quote: | B. Stoermer: rather the effect of chloroacetone
on sodium phenolates and a synthesis of coumarone derivatives.
[Preliminary communication from the chemical institute of the University of Rostock.]
(Received on May 17th.)
C. Pomeranz recently published a treatise
on the phenyl ether of glycolaldehyde, phenoxylacetaldehyde,
and on phenoxylacetal, from which coumarone could not be obtained by condensation. I have been working on a similar
work on phenoxylacetone for some time, and although it is not yet finished, I would like to report very briefly on the results to date, which give
hope for the synthesis of the homologous methylcoumarone, in order to ensure that I can continue working without interruption. Phenoxylactone,
C6H5O.CH2.CO.CH3, or the phenyl ether of acetone alcohol is very easily obtained by the action of pure monochloroacetone on completely dry sodium
phenolate. The latter is best prepared by adding the amount of sodium calculated for one molecule of chloroacetone to dry phenol and choosing 3 to 4
times the amount of phenol itself as the diluent, since chloroacetone does not react with free phenol. Every trace of water must be excluded, since
the sodium hydroxide formed smears the chloroacetone. Once all the sodium has dissolved, the chloroacetone is slowly added and finally heated until
the smell of the latter has disappeared. The mass turns brown, becomes thin and contains the sodium chloride in finely divided suspension. The mixture
is then made strongly alkaline and the phenoxylacetone (phenacetol) formed is expelled in a stream of steam, which separates out as a water-colored
oil and is extracted with ether. It is obtained completely pure from the bisulfite compound, which crystallizes beautifully, using dilute sodium
hydroxide solution. It then boils completely at 229-230° (uncorrected) and forms a colorless, pleasant-smelling oil.
Analysis: Calculated for C9H10O7.
Percent: C 72.00, H 6.60.
Fl. » » 71.50, 71.88, » 6.91, 6.71.
The hydrazone, C6H5.0.CH2C(N.NH.C6H5)CH3, is easily obtained by bringing together identical molecules of the components as a viscous yellow mass,
which soon becomes solid and crystalline. It is obtained from methyl alcohol, the only crystallizing agent, by repeated recrystallization in dazzling
white, bluish fluorescent flakes, which very quickly turn yellow and brown in air and then dissolve into a red smear.
Analysis: Calculated for CjsHieNjO.
Percent: N 11.55.
Fl. » » ll.üti.
'J Monatsh. f. Chem. 15, 73y and ff.
So far I have only been able to obtain the oxime as an oil.
If you add phenacetol in small portions to 3-4 cc of well cooled (by cold mixing) concentrated sulphuric acid, after a few minutes the intensely red
thick solution is diluted with water, neutralised with sodium hydroxide solution and distilled in a steam distiller, a yellowish oil is obtained which
shows all the properties of the methylcoumarone already described by Hantzsch1). It smells as strong as naphthalene, but more pleasant, no longer
reacts with phenylbutyrazine, thus no longer contains any ketone oxygen, is transformed into an amorphous mass by sulphuric acid, adds bromine
smoothly and boils at 190-191°, a difference (actually 188-189°) that can be explained by the small amount that was available to me at the time. The
condensation will probably take place even more easily if the paraforming to the hydroxyl group is occupied. Chloroacetone naturally shows the same
reaction with other sodium phenolates, only the results are different. Mr. Hermes, a student, prepared p-cresoxylacetone as a liquid that boils at
about 240° and Mr. Hermes, a student, prepared p-cresoxylacetone as a liquid that boils at about 240°. S c h r e c k e n b e r g er
presented the solid 2-naphtoxylacetone melting at 85°, of which the latter was a relatively stable hydraion melting at 154°.
The work is continued.
Rostock, May 16, 1895. |
sodium is not easy to obtain so I tried the reaction in water with presumptions of lower yield due to chloroacetone hydrolysis (which could be at
least partially reduced by NOT using excess of NaOH)
I did the reaction this way:
Into phenol add solution of NaOH (slightly less than theoretical amount)
add chloroacetone and let it to react
workup - add excess of solution of NaOH to convert phenol back to Na phenolate (some chloroacetone hydrolyses into HCl which converts Na phenolate
into free phenol, during workup it is necessary to convert phenol into Na phenolate)
steam distill (product is steam volatile, Na phenolate is not)
Density 1.097 g.cm-3 at 25 °C which causes some challenges observed during practical experiment
What I did, serves only as a starting point and could be improved:
Distilled water was boiled for 5 minutes to expell dissolved O2 and CO2, cooled down to room temperature.
26,0 g NaOH (0,650 mol) was dissolved in 40 cm3 of the water in 100 cm3 beaker and cooled down to room temperature.
61,4 g of phenol (M = 94,11 g.mol-1, n = 0,652 mol) was added into 1 liter 2 neck round bottomed flask (half a liter flask seems to be large enough
and could be used), 10 cm3 of water, stir bar and was magnetically stirred for short time, part of the phenol dissolved.
The solution of NaOH was added slowly dropwise into the phenol in RBF, note there is necessity to add slightly less NaOH than stoichiometric amount so
the final mixture is not strongly alkaline due to excess of NaOH but only weak akaline due to sodium phenolate. The reaction was slightly exothermic
and the content heated to about 40 C (determined by touching by a hand).
Tip of glass rod was used to touch the solution and pH checked with universal pH paper, it should be only weakly alkaline (Na phenoxide), not strongly
alkaline (degraded phenol with low purity and thus excess of NaOH, degraded discolored wet phenol could be easily purified by vacuum distillation
using water aspirator level vacuum where the phenol boils at around 100 C, use cooling water with temperature around 50 C to prevent phenol from
solidifying in the condenser and especially in the narrow glass tube of the vacuum adapter).
Reflux condenser was attached and a dropping funnel with chloroacetone was mounted (70% of the amount prepared at 1 mol scale which is impure and contains acetone and another impurities, pls read the
link), so 80,3 g of from the whole 114,7 g was taken, note again this is not pure chloroacetone but contains a lot of impurities.
While magnetically stirring the content in the RBF, the chloroacetone was added dropwise during 1 hour (40-50 drops per 1 minute). The reaction was
slightly exothermic and the walls of the flask were warm when touched by hand, but there was no reflux, everything condensed on the walls of the flask
at such a slow addition rate of chloroacetone.
At some time a sound of "smooth stirring" (flat PTFE stir bar sliding easily on flat glass walls) changed to "dry phenomenon" when the stir bar
started to scrape crystals of NaCl adhered on the glass walls of the flask (invisible in dark reaction mixture), maybe using little more water would
prevent crystallization of NaCl and would keep it dissolved.
After 1 hour when dropping finished, heating was turned on and the reaction refluxed for 1 hour (maybe unnecessary, no lachrymatory chloroacetone
present anymore even before reflux, maybe the reflux is only harmfull and could cause some undesired aldol condensations).
Using 250 cm3 sep. funnel (half a liter would be better), upper organic phase was kept and low water phase containing NaCl was discarded. Water phase
had nice smell, but I'm unable to describe/characterize it.
Water phase was alkaline on universal pH paper = not enough chloroacetone, but good that all was consumed and there was not excess of HCl which would
cause aldol condensation side reactions.
Washed twice with 100 cm3 of 5% NaOH saturated with NaCl (10 g NaOH into 150 cm3 of water, later add 50 g of NaCl).
Organic layer was always top and much darker, almost black, much more viscous, water phase dark red colored and so dark that it was hard / almost
impossible to distinguish between the 2 phases.
Washed with 100 cm3 saturated NaCl, here finally the 2 layers and the border visible, water layer still alkaline on universal pH paper (very likely
washing out Na phenoxide from the organic layer, using less NaCl would increase washing out Na phenoxide but would cause difficulties in phases
separation).
Washed again with 100 cm3 saturated solution of NaCl, water phase still alkaline.
Washed finally with 100 cm3 of water, now the organic phase was the bottom !!!
Weight of the crude product 46,3 g
10g NaOH was dissolved in 400 ml water in 1 liter RBF and the crude product added (if some phenol still present, the NaOH would convert in into Na
phenolate which is not steam volatile and would stay in the flask during the following steam distillation). Maybe less of NaOH would be sufficient.
A distillation using Dean-Stark trap apparatus was attempted but it was not good enough. The density of phenoxyacetone is about 1,1 higher than water
but a lot of the product stayed on the top and flew back into the distillation flask though the arm of the apparatus.
Distillation was continued using Clevenger distillation apparatus and STRONG MAGNETIC STIRRING (prevent bumping, the density of organic layer > the
density of water so it tended to collect on the bottom, magnetic stirring was essential, even during stirring there were like 2-3 second intervals
when the boil interrupted temporarily and then resumed with higher intensity).
When the blobs of the product on the surface became big enough, their broke surface tension and adhesive forces to glass walls and sunk to the bottom.
Luckily also Clevenger apparatus had some small nonzero volume reservoir on the bottom where the product collected and was periodically drained out.
Phenoxyacetone has a nice scent and is also an inhibitor of acetylcholinesterase.
https://pubmed.ncbi.nlm.nih.gov/7073703/
DOI: 10.1016/0006-291x(82)90679-9
[Edited on 6-2-2025 by Fery]
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Fery
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phenol in reaction flask
phenol reacted with solution of NaOH into solution of Na phenolate
reaction apparatus, chloroacetone (very impure) in addition funnel
first few drops of chloroacetone change the color of the reaction mixture into red
after the 1 hour lasting dropwise addition of chloroacetone the reaction was heated and refluxed (I'm not sure whether this is necessary and whether
the chloroacetone did not react completely already during the dropwise addition)
crystals of NaCl on the bottom after the reaction was finished
mixture in separatory funnel, border of the 2 layers invisible but will be visible later
during slow draining out when the upper organic layer reaches the stopcock the border becomes visible
  
washing with NaOH saturated with NaCl to get rid of possible free phenol (I'm not sure whether this is necessary and whether the mixture couldn't be
processed further even without this step?)
steam distillation using Clevenger apparatus
the density of the product is 1,1 but a lot of it stays floating on the surface in the Clevenger apparatus and only later when the blob becomes bigger
it breaks surface tension and overcomes adhesive forces on the glass walls and sinks down, luckily the Clevenger apparatus has also some small
reservoir on the bottom
         
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kmno4
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In my opinion, using impure starting materials and obtaining end product of unknown purity makes no sense.
However, doing nothing also gives nothing, yield 0 % 
Besides, all procedures I know give merely 20%-50% yields of pure phenoxyacetone and I am not going to try them.
Funny thing : today I have found preparation with simple modification, giving output > 90% of distilled product. This is worth trying, but maybe in
a few days.
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Illegal Parkinson
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What is it to be used for? My database gives the following list of applications:
1. Isoxsuprine
2. Phenoxypropazine
3. Phenoxybenzamine
4. Racefemine
5. Solpecainol
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Fery
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kmno4: the yield was only 7,5 grams which is slightly less than 10%. It was made only for checking its scent. The procedure I tried should be
improved. It should also be further purified by bisulfate adduct method, recrystallization and decomposing back into the product. Impurities were only
in chloroacetone as I did not distill out acetone. No chance to separate mono and dichloroacetone by simple distillation. The acetone presence did not
worry me as it is trivial to get rid of (washing the product with water). I vacuum distilled the phenol prior the reaction using water aspirator pump.
Let us know about your new method.
Illegal Parkinson - it was made to scent it. Good that you found a lot of medicinal applications. It inhibits acetycholinesterase but I don't know how
strong and whether reversible or irreversible. Reversible inhibitors (donepezil, rivastigmine, galantamine) are used in treatment of Dementia of
Alzheimer Type (DAT). Side effects are gastrointestinal (nauzea, diarrhea, increased bowels movement), cardiovascular (atrioventricular block = a
block of electrical signal conduction in heart), respiratory (bronchoconstriction). Irreversible inhibitors are even stronger and are used as
antidotes for organophosphates poisoning.
[Edited on 7-2-2025 by Fery]
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kmno4
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| Quote: | What is it to be used for? My database gives the following list of applications:
1. Isoxsuprine
2. Proparoksytoniczne
3. Phenoxybenzamine
4. Racefemine
5. Solpecainol |
It is up to you.
Fery: 10% of something sounds like by-product.
It is mentioned elsewhere, that under your conditions only "black tarry material is produced". 10% of something is close to this .
B.p. at 760 mmHg for this compound is about 230 C without reported decomposition and I can perform this without problems.
I am currently performing some supporting experiment, but it looks like failure 
But the rest is almost ready. Acetonylation will be performed in acetone with K2CO3. Everyone uses K2CO3.... Na2CO3 is not good ? Why ? Thermal
instability of NaHCO3 (->water formation) or what ?
Using only chlorocetone gives yields ~20 %, but with rather simple "trick" it jumps to more than 90%. At least they say so, in several independet old
and new articles.
[Edited on 10-2-2025 by kmno4]
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bnull
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Quote: Originally posted by kmno4  | | Acetonylation will be performed in acetone with K2CO3. Everyone uses K2CO3.... Na2CO3 is not good ? Why ? Thermal instability of NaHCO3 (->water
formation) or what ? |
Probably solubility of the carbonate in acetone. The same thing happens when making polysulfides and thiosulfate from sulfur and sodium or potassium
carbonate with ethanol as solvent: sodium sucks, potassium is pretty good.
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Fery
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kmno4 - that looks promising
maybe the reflux part was not necessary and caused only side reactions, after the dropwise addition of chloroacetone there were enough crystals of
NaCl which was heard by a "dry" noise as stir bar was scraping crystals formed on glass walls of the reaction flask
it was only a preliminary experiment to obtain the scent, whether ever it is worth to synthesize this compound, mission accomplished and I do not
expect to repeat the synthesis again
K salts should be better soluble and less hygroscopic than Na salts
C6H5OH + K2CO3 -> C6H5OK + KHCO3
C6H5OK will be very likely soluble in acetone at least a little while KHCO3 very likely insoluble or very poorly soluble
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Fery
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Here a method with 90-95% yield:
https://sci-hub.se/10.1021/ja01205a012
Attachment: hurd1946.pdf (406kB)
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kmno4
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Finally I performed this acetonylation.
The product is not yet prepared in pure state, but it really has rather original scent, phenolic but with some "grassy" note, slightly similar to
phenylacetone.
It was prepared from iodoacetone (generated separately in situ, without its extraction, from chloroacetone and KI in acetone), phenol, K2CO3 in
acetone at almost room temperature.
It was used slight excess of phenol and when reaction is finished, the post-reaction mixture is no more lachrymatory.
Parallelly, it was performed (still lasting) similar experiment with benzyl alcohol. Unforunately, it seems that consumption of iodoacetone is very
slow, or just there is no reaction at all
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Fery
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kmno4 - great achievement! The scent is unique and pleasant.
Did you add only small (catalytic) amount of KI or equimolar? If equimolar and performing larger scale synthesis I wonder whether cheaper KBr would
help significantly.
So you would like to react benzyl alcohol instead of phenol?
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kmno4
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Hah, thanks.
I used chloroacetone/KI ~1/1,1 molar, but I have impression it is overkill. See for example this paper by DOI : 10.5012/bkcs.2013.34.3.875
They do this in very great dilution, I used proportions 5 g of chloroacetone + KI + c.a. 3 cm3 acetone. The mixture soon becomes reddish-brown, I left
it for ~24 h with shaking from time to time. At the end of this period, the mixture looks "badly" - reddish-brown suspension of solids. It is then
transferred (it is more or less problematic, some additional acetone was used for rinsing) to the phenol/carbonate/acetone mixture. There is no need
to do this drop-by-drop.
Total volume of everything added was ~30 cm3 and put on stirrer.
Iodoacetone is described as "viscous brown syrup", what is rather amazing. It also penetrates and stains plastic (PP, PE) as iodine does. One thing
still amazes me: preparation of iodoacetone from chloroacetone by this method works, though C-I bond is much less weaker than C-Cl bond. Possibly, in
gas phase, such reaction would go in opposite way.
REMARK : iodoacetone and chloroacetone can be completely removed/destroyed with aid of Na2SO3. Reaction is fast (seconds), possibly some sulfonic
derivatives are formed, water soluble. Excellent way to clean the glass setup.
I tried benzyl alcohol for fun, just to see what happens.
In literature it is mentioned that this reaction (also in different variants) will not work. Benzyloxyacetone is prepared by multistep reactions, not
involving halogenoacetone.
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kmno4
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Experiment with benzyl alcohol came to an end.
After several days, some TBACl (~0,1 g) was added. This caused(?) that lachrymatory odour dissapeared (after additional time, not at once). After
acetone evaporation and water treatment, the crude product (brown liquid) separates. It has no benzyl alcohol smell. The odour is sweety, candy-like,
but with nauseating note, similar to ethyl benzoate.
I am going to do another experiment with phenol, but without previous iodoacetone preparation and with "catalytic" amount of KI + chloroacetone amount
as given earlier.
My old chloroacetone slowly, very slowly becomes yellow, I have to do "something" with it
ps. all produsts will be purified later, currently my distillation setup is configured for another experiment
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kmno4
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Another few experiments were performed.
Instead of molar amount of KI, fixed amount (~1 g) was used.
It means: everything was put into flask, without dropping etc. and put on mag. stirrer. I noticed that the reaction is mildly exotermic after short
time, but there is no need to do anything with it. The flask is all the time closed with a stopper.
In no more than ~12 h the mixture is no more lachrymatory, it looks and smell as the mixtures prepared earlier.
Instead of K2CO3, Na2CO3 was tested. After ~24 h of stirring, the color remains almost the same, a drop taken was strongly lachrymatory, leaving only
phenol odour.
Apparently the reaction does not go, or is veeery slow. Tiny amount of TBACl was added (<50 mg) and soon after this the color of the mixture
reddens, odour of phenoxyacetone becomes perceptible (this experiment is not finished yet)
Instead of phenol, hydroquinone was used with double molar amount of chloroacetone. After ~24 h, the post reaction mixture is no more lachrymatory.
The residue is sticky mass, not washable with water, with weak pleasant scent, very similar to.... diethyl malonate.
ps. all post-reaction mixtures are blackish, or brownish or at least deeply red. That is why I hate working with phenols 
[Edited on 13-3-2025 by kmno4]
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Illegal Parkinson
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I said 2. Phenoxypropazine not 2. Proparoksytoniczne
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bnull
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What do you mean?
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DraconicAcid
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When KMnO4 quoted Illegal Parkinson, his words got changed into something resembling Polish. Weird.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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bnull
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Yeah, I found where. Some sort of Polish joke, I suppose. Thanks.
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