Sciencemadness Discussion Board

Willgerodt-Kindler featuring acetophenone

Benignium - 2-12-2020 at 21:06

I came across a rather novel use for acetophenone where a phenylacetothiomorpholide intermediate is formed and then hydrolyzed to yield phenylacetic acid. It seemed like a fun and reasonable way to synthesize this forbidden fruit of a chemical so I gave it a go.

First, 7.40 grams of morpholinium chloride was weighed and to this was added 2.63 grams of sodium hydroxide as a 50% solution in water. Sufficient water was added to dissolve everything. A small amount of anhydrous potassium carbonate was added and the mixture was filtered. The filtrate was substituted for pure morpholine. According to pH paper, the pH of the filtrate was about 10.5. Its mass was roughly twice that of the morpholinium salt used.

The morpholine solution was added to a 25 mL flat bottomed boiling flask along with 1.28 grams of sulfur, 2.40 grams of acetophenone and 1.2 grams of crumbly but ever so slightly wet p-toluenesulfonic acid. The mixture was held at a reflux with strong stirring for 12 hours.

Shortly after beginning of reflux:

After those first 12 hours, the mixture was cooled and about 8 grams of 40% aqueous NaOH was added. Finally 300 milligrams of crude (about 80%) didecyldimethylammonium chloride, made by evaporating down a disinfectant containing 5% DDAC and 1% alcohol hydroxylate, was added where the procedure being followed called for triethylbenzylammonium chloride.

After 12 hours:

The mixture was refluxed for a further 12 hours and, once cooled, it was acidified using 30% HCl to a pH of 6 and filtered. The weakly acetophenone scented solids were washed thoroughly with a small amount of DI water and discarded. The filtrate was further acidified and a red oil separated from the solution as an unmistakably honey-like aroma filled the room. The oil was retained and dissolved in saturated sodium bicarbonate solution which was then washed with 4x25 mL portions of ethyl acetate. The aqueous phase was once more acidified using HCl. Beautiful lustrous crystals of phenylacetate instantly started precipitating. The solids were collected by filtration and the filtrate was concentrated by boiling, then cooled down to yield more crystals. There was also some orange oil that had to be removed using a pipette. The concentration was repeated once more before a point of diminishing returns due to the orange impurity was reached to obtain a final yield of 610 milligrams (22.43%).

Beginning of second reflux:

At pH 6:

At pH 6 (filtered):

610 mg of phenylacetic acid crystals:

The yield is far from great and far from the reported 80% but, frankly, this was to be expected. As there was only ever a very weak odor of acetophenone left after the reaction, and no detectable morpholine stench, I suspect that the fault is with the hydrolysis step. Particularly the use of DDAC instead of TEBA. There is more to be done to determine the efficacy of DDAC and it is entirely possible that there is no benefit at all from using it. I will revisit this experiment sometime in the near future and I will update this thread with any findings.

[Edited on 3-12-2020 by Benignium]

zed - 2-12-2020 at 22:04

Interesting. I am familiar with the reaction, but I haven't performed it.

Some variations utilize Sulfur and Ammonia, or Ammonium Polysulfide.

I was always kind of concerned about H2S. Nasty stuff. Where does it go?

Opylation - 3-12-2020 at 00:29

I'm sure you could just feed it into a NaOH wash solution, no? Isn't that the preferred route to make Na2S anyway? Whenever I see a reaction that deals with H2S that's the first thing that comes to my mind.

Beautiful reaction pictures! I love the ending picture of your product too. I recently stumbled upon an interesting preparation of methyl benzyl ketone. I can't remember what I was looking for, I think it was for a preparation of some OLED organic but Google thought that the page was apparently the same thing. Anyways it used rather extreme conditions, with thorium oxide and acetic acid to form the phenylacetone. The page actually took me down the rabbit hole looking at the mechanics of the process, apparently it's called the Ruzicka large-ring synthesis, just an alternate form. Thorium is a radioactive element too which was why it was so bizarre to find it being used as a catalyst.

Edit: I remember what I was looking for. It was a dehydration procedure for 1-hydroxy-1-phenyl-tetraphenylcyclopentadiene. Kind of odd that it sent me in that direction but interesting procedure nonetheless

[Edited on 3-12-2020 by Opylation]

zed - 3-12-2020 at 15:06

Extreme? Well, yes and no. Utilizes a tube furnace, packed with a catalyst, impregnated on pumice.

You could build the device in a day or two. And, the Thorium utilized, would not be the radioactive sort. ( I stand corrected. Thorium is mildly radioactive.)

The way I remember it, the construction of the device, and the procedure itself, can be found in Vogel.

Vogel, may be perused in our own library, just a click away.

You will recall, that in "Breaking Bad", Walter White utilizes this reaction sequence, to make his P2P.

Just drip reactants into one end of the tube furnace, and product drips out of the other end.

Anyway, kind of surprised to see the Willgerodt run in water. I didn't know you could do that.

Procedures I have read, usually utilize higher temperature.

Some, run the reaction "neat". Morpholine, Substrate, and Sulfur. Mix 'em up, and Microwave them.

About 150 C, for just a few minutes.......

Morpholine, by the way, is reputed to be "nasty". And, by nasty, I mean it appears to be a blistering agent. Undiluted and Unneutralized, it will damage your skin, and maybe more.

Just read a paper on it. They go on and on about it, yet never deliver, simple to understand cautions. Like "Don't get this stuff on your Dick!" "I'll burn you bad!" Anyway, here is the paper.

[Oh, Thorium? Back in the day, we thought the Thorium Breeder Reactor, was a sure thing. Coming any day. Never happened.

[Edited on 4-12-2020 by zed]

Boffis - 4-12-2020 at 09:57

@ Benignium, nice work and write up. I notice in Vogel that he used dry morpholine and sulphur to convert beta-naphthyl methyl ketone to beta-naphthylacetic acid and in the aqueous medium he indicates that yellow ammonium sulphide and either dioxane or pyridine to improve the miscibility of the organic phase. Since morpholine is a sort of halfway house between pyridine and dioxane it will probably work but you may need an excess of it. Maybe also try preparing a polysulphide solution first instead of adding the sulphur directly to the reaction mixture.

Johnny Windchimes - 4-12-2020 at 14:17

Nice job! It works with cinnamic acid and styrene if I recall as well, although I've only ever done it with Acetophenone. Davis1947 uses cinnamic acid, attached below.

As mentioned, I've done this before but there are a few easier ways that omit using PTC(s) and Morpholine. You'll need a "sealed pipe 'bomb'" however.....

Detar1946 is what you want.

It works, it stinks, and the MILLISECOND you crack open the cooled sealed vessel you will forever smell cat urine and sickly sweet honey, concentration dependent; the sealed pipe bomb part makes the phenylacetamide, BUT ALSO very small amounts of Phenylacetic acid as well.

The nightmarish liquid volume boil down and final steps to PAA will haunt my basement forever.

I recently had occasion to use a heat gun to quickly dry something or other, and on the bench must have been a molecule of PAA because the SECOND the heat gun hit it, the entire lab reeked of honey.

One final note, H2S and its problems were largely mitigated by the pipe bomb sealed reactor detar1946 method if I recall; I'm super tired and just skimmed the thread and the papers I have saved.

Post Script : I threw in an old Hive post about that breaking bad Thorium / Glacial tube furnace dealio mentioned above; they use different catalysts because Thorium's not exactly growing on trees. It works, lots of pictures, etc....


Attachment: jain1974 - Copy.pdf (317kB)
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Attachment: mujahidalam2003 - Copy.pdf (144kB)
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Attachment: davis1947 - Copy.pdf (232kB)
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Attachment: detar1946 - Acetophenone to Phenylacetic Acid - Copy.pdf (603kB)
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[Edited on 4-12-2020 by Johnny Windchimes]

Attachment: Festers old PAA to P2P Tube Furnace Setup - Copy.pdf (114kB)
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kmno4 - 4-12-2020 at 16:03

Long time ago I performed this reaction* few times, just to see how it works at all. The work-up is reatively simple, but I was never able to obtain more than ~40% yield of final acid, even if acetophenone was not detected in post-reaction mixture.
It still remains to me as some kind of mystery : where the damned ketone disappeared... :mad:

* acetophenone+morpholine+sulfur+heating

zed - 5-12-2020 at 01:37

The construction of a convenient tube furnace is outlined by Vogel. Page 338...With a schematic.

The tube furnace has other uses. I have been informed that Indole, which is not directly available by the Fischer Synthesis, from acetaldehyde-phenylhydrazone.... may be produced by passing the Phenylhydrazone thru a. tube furnace. I don't like the idea, perhaps because I'm overly cautious. But, the process is reputed to work.

As for the above papers referencing the Wilgerodt reaction.....There are more possibilities than I imagined.

Under some reaction conditions, the product is an Amide.

Under other conditions, a Thioamide or a Thioamide of Morpholine.

Some reaction conditions utilize H2S, and some don't.

Moreover, some authors suggest, that when the reaction is run utilizing Alkenes (like Styrene) lots of Hydrogen Sulfide is evolved.

I don't like surprises involving the unexpected evolution of lots of Hydrogen Sulfide.

It appears under some conditions the reaction is pretty safe, and under other conditions it is pretty dangerous.

So, improvising should be done with caution.

Thorium is available, too expensive, but available.

[Edited on 5-12-2020 by zed]

[Edited on 5-12-2020 by zed]