Maui3
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Decarboxylation of Phenylalanine to Phenylethylamine with Acetophenone
For my synthesis of MAO-inhibitors, which are old-school antidepressants that rarely are used anymore, I needed 2-phenylethylamine. There are a dozen
ways to synthesize 2-phenylethylamine, such as from nitrostyrenes, phenylacetic acids, phenylacetonitriles, and so on. These methods are all
documented very well... so I naturally chose the method that is the least documented - for some reason that I really don't know.
I chose to do a decarboxylation of phenylalanine with acetophenone.
Procedure:
I mixed 20 g phenylalanine with 100 g acetophenone in a 250 mL round-bottom flask. I placed the round-bottom flask in a 250 mL heating mantle and
equipped the flask with a condenser cooled with room-temperature water. I started heating the mixture to around 150–170 °C. The mixture went
opaque → opaque and yellow → transparent and yellow → transparent and orange. I also observed a "hissing" sound coming through the condenser...
I assume this is the CO2? I also placed a balloon on top of the condenser to see when the mixture stopped releasing CO2. Over 3 hours, I slowly kept
increasing the heat until it was around 180–200 °C, which probably was not necessary. In all, it took about 3 hours before the CO2 generation
considerably slowed down... or that was just my brain imagining things. Either way, I stopped the heating there.
After cooling the mixture, I poured it into a beaker and added a lot of water and enough HCl for the mixture to be strongly acidic. I stirred the
mixture vigorously, and two layers separated. The acetophenone was the upper layer for me, and I separated the two layers.
I distilled off all the HCl-water solution from the aqueous layer until only a thick liquid was left behind. I cooled this liquid, and
phenylethylamine HCl soon started to precipitate as a yellow-beige solid.
I am very bad at recrystallizations... but I tried to recrystallize from denatured ethanol (93% ethanol, the rest being butanone, denatonium benzoate,
and probably also water). It did grow nice crystals... until it all decided to precipitate out as a big porridge, now being beige in color. Oh well -
at least I didn't destroy all the product from the recrystallization - that has happened before.
I unfortunately did not measure the yield, but... it's not bad. Convert that to whatever percentage you think is fitting.
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Niklas
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Triturating with some acetone should get rid of most the remaining colored impurities I would guess.
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Fery
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Nice experiment. I wonder whether the reaction completed or whether some unreacted phenylalanine could stay (workup with NaOH could get rid of it). As
you wrote - MAO inhibitors were used as antidepressants, I remember e.g. selegiline, it was beneficiary especially when the depression was as a
symptom of Parkinson disease.
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bnull
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Looks pretty good. Do you have a reference? Also, could you please add some pictures? I'd like to see the final result, porridge or not.
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Ormarion
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Nice procedure, close to what is used in general for tryptophan decarboxylations. If you wanna push a bit more i recommend you try tetraline with a
pinch of 3 pentanone or MEK as catalyst, cleanest decarboxylation reaction i did personally
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Lionel Spanner
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Funnily enough I've been doing some experiments with amino acid decarboxylation - a poorly documented procedure with a lot of half-truths and
borderline superstition floating around - and can share a helpful hint.
You can get more pure final product, and a better yield, by extracting the acetophenone imine from solution with 10% acetic acid, then freebasing it,
extracting it with a suitable solvent (I used ether) and hydrolysing the extract with hydrochloric acid.
From my experiences using benzoic acid in acetone, imine hydrolysis is not an instantaneous reaction; it's likely it'll need some mixing and/or
heating. This may not be the case with hydrochloric acid.
[Edited on 7-6-2025 by Lionel Spanner]
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Maui3
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Thank you for the tips, I'll try those, when I get to doing it again.
I don't have a reference, I adapted another synthesis for phenylalanine.
I'll send a picture of the product once its dry 
I can try to remove the impurities with acetone and NaOH. I used most of it for another synthesis now, but when I get to making it again, I'll try
that, thanks.
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