Benzedrine - Old Book Synthesis

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Author	Topic: Benzedrine - Old Book Synthesis
Rhenium Member	posted 01-25-99 06:45 AM Hi all Bee's, Whilst I was looking wistfully through the index of another old chem book which I had collected, when mine eyes drifted accross this reference for the synthesis of Benzedrine. Pheylacetic acid + Acetone in the presence of Sodium Acetate and with heat give Phenylacetone. Then react phenylacetone with NH2OH to give the the oxime, then reduction with H2 and Pt to give the final product. This is interesting for two reason I guess. First they say that this is a commercial synthesis, and secondly because although I've seen sodium acetate used before (the Russian reference in CA) I've never seen it used in conjunction with acetone. Suggestions anyone? The book is pg 219-220 A Modern Introduction to Organic Chemistry, William B Smith Charles E Merrill Books Inc, Columbus Ohio 1961 -- Congress number 61-10942 They also give a nice synth for novocaine. Rhenium
Beagle Member	posted 01-25-99 11:26 AM You never can tell what kind of useful info may turn up in an old textbook, but I suspect that this is a typo here, acetone should read acetic anhydride.
ChemHack Member	posted 01-25-99 12:21 PM Perhaps the Sodium Acetate plays the role of the Acetic Anhydride?
ChemHack Member	posted 01-25-99 12:28 PM Hmmmmm...... dunno about that but here is another idea: Sodium Acetate is used to prepare Acetic Anhydride, with acetyl chloride I think.... ?
Piglet Member	posted 01-26-99 09:33 AM I cannot comment on the P2P production, other than to say it sounds real interesting. The bit I'm into is the use of NH2OH as the source of the NH2 species. Oximes can be reduced in a number of cool ways. Acidic (in formic) or basic (in NaOH) Zn reductions, hydride reductions, and of course the hydrogenation using Pt. The only small fly in the ointment seems to be the oxime formation. Water soluable ketones are easy (just dH2O with NH2OH.HCl and something to buffer pH). Water insoluable ketones require slightly more messing. Shulgin amongst others uses an alcoholic solution with pyridine (no fun) or maybe NH4/Na/K acetate (CA 61,6953 [1964]). Could you outline the oxime formation for me, thanks Piglet
Rhenium Member	posted 01-27-99 07:56 AM Hi everyone, I can't really give much more detail, because there wasn't much more than that in the book. They definitely used acetone (dimethyl ketone, 2-propanone - call it what you will) as they had the structure presented there. Unfortunately that was about all. The oxime formation was not particularly clear, just an arrow over the page and voila there's the oxime. The details are so sketchy I can't even say what the solvent was used for that step. I will have another look, but details are scanty. Rhenium
psychokitty Member	posted 01-27-99 10:20 AM Any references in there? If there are, look them up as I'm sure they'll indicate details to the reaction mechanism, even if the syntheis of phenylacetone is not given as one of their examples. --Psychokitty
Labrat Member	posted 01-27-99 10:39 AM Rhenium, surely you must smell something fishy about this synth: phenylacetate + acetone -> phenylacetone. I just can't believe that the whole acetate moiety can be replaced with acetone. It would be possible to condense phenylacetic acid with acetone like with acetic anhydride. In that case the alpha-carbon of phenylacetic acid is deprotonated and the anion condenses with acetone, forming an intermediate which decarboxylates and ... about here the intermediate should lose a methylgroup if we want P2P to form. Does anyone have better suggestions? Or better yet, Rhenium, can you provide us with a ref? Thanks. Lr/
Beagle Member	posted 01-27-99 11:45 AM I could see how acetone and phenylacetic acid could condense with a very strong base, but sodium acetate? Maybe under pressure/heat, but no way with simple reflux.
Labrat Member	posted 01-28-99 09:52 AM How do you explain then that phenylacetic acid and acetic anhydride condense with sodium acetate as added base (at high temperatures)? The phenylacetic acid is easily deprotonated at the alpha-carbon because this carbon atom is both attached to a phenyl group and a carboxyl group. When the alpha-carbon is deprotonated, the charge is delocalised over the carboxyl and maybe the phenylgroup. Fact is, that sodium acetate or pyridine are strong enough bases to do the job. But this was all pretty clear to me. What I don't understand is why phenylacetone is formed in the condensation of phenylacetic acid and acetone. Do you have a clue Beagle? Lr/
psychokitty Member	posted 01-28-99 12:24 PM I'll just say this much so that I can take a different stance than everybody: I believe you Rhenney. I really do. --Psychokitty
Beagle Member	posted 01-28-99 12:54 PM Labrat: Nope, I'm pretty clueless generally. But I see the mechanism of the acetic anhydride/PAA condensation as not involving a deprotonation directly. Maybe I'm off base here, but seems like PAA would form a mixed anhydride with the Ac2O. Now the alpha hydrogens become much more acidic, and deprotonation, or much more likely, polarization can occur on the alpha carbon that allows the condensation to take place. In the case of PAA/acetone, where a mixed anhydride cannot form, the carboxyl proton will be MUCH more acidic. Thus, it will have to dissociate first. This very much decreases the acidity of the alpha proton. You need something on the order of butyllithium to get the dianion of PAA. And I take back what I said about seeing how PAA and acetone could condense, even with strong base. Too many carbons in acetone, you'd have to lose one somewhere. Until someone comes up with a decent mechanism or ref on this, I have to stand by my statement that this is a typo. Maybe if there was acetic ACID present, and enough heat, there could be in situ generation of an equilibrium of acetic anhydride from the sodium acetate. I have been known to postulate why known reactions aren't possible before, but I think that I'm right on this one.
Beagle Member	posted 01-28-99 01:06 PM Boy I hate eating my words so soon after they come out of my mouth. OK, maybe I see how it could work, but the acetone plays no role here except as solvent: PAA and Na acetate form a mixed anhydride first. Next this condenses with another molecule of the mixed anhydride or acetic anhydride formed from the acetate. The acetylated PAA can now be decarboxylated to give P2P, as in the PAA/Ac2O synthesis. The only problem I see with this is that sodium acetate and PAA are not going to want to form the anhydride. Maybe with mucho heat, under pressure.
Osmium Member	posted 01-28-99 01:40 PM One of the first P2P syntheses was done by pyrolysis of an intimate mixture of PAA and Ba(OAc)2. Strange that the same reaction should take place in acetone. Another example: Ca(OAC)2 ---heat---> acetone
Beagle Member	posted 01-28-99 02:05 PM Do you have any idea what is going on in the reaction Ca(OAC)2 ---heat---> acetone ?
Osmium Member	posted 01-28-99 02:47 PM No.
Rhodium Administrator	posted 01-28-99 03:26 PM In the Ca(OAc)2 => acetone thing, it is pretty clear to me that the acetate pyrolyzes (into Ac- and CaOAc+), and then the cation sucks an electron from the anion, precipitating the stable CaO, and creates two free radical Ac* which immediately combines to give acetone. Or perhaps it's free radicals all the way ( CaOAc => CaO + 2 Ac* ), what do I know? Regarding the P2P synth, there is a reaction called the Fries rearrangement, in which phenylacetate is reacted with AlC3 to form 2-hydroxy-phenylacetone, but NaOAc isn't exactly AlCl3... There is also this ref, found in MV Smith's "Psychedelic Chemistry": Amphetamines from Phenylacetates CA 35, 5868 (1941) Add 0.44 moles ring substituted phenylacetate, 100 g acetic anhydride and 30 g sodium acetate and heat at 145-150°C for 18 hours to get ca. 0.4 moles of the methyl-phenylacetate (I). Add (I) and formamide (or N-methyl-formamide for the N-methyl cpd.), heat 4-5 hours at 180-195°C, cool and extract with CHCl3. Evaporate in vacuum, dissolve residue in 40% sulfuric acid and heat at 90-125°C for 5-6 hours. Neutralize and add solid NaOH to precipitate about 50% amphetamine. Treat with 10% sulfuric acid to get the sulfate.
Osmium Member	posted 01-29-99 03:27 AM THIS IS THE RUSSIAN REF I WAS SEARCHING SO BAD! Of course they do not use "phenlyacetate", they use PAA; and they do not produce "methyl-phenylacetate", they make P2P. This procedure works as stated, I did it with 80% yield. The workup is a bit tricky, as it is not given in the ref. Someone I know hydrolysed the still refluxing reaction by adding water through the condensor. He had to repaint the ceiling and the walls.
Labrat Member	posted 01-29-99 10:07 AM Beagle: you're right, if there's phenylacetate and acetic anhydride, you'll get formation of the mixed anhydride, then deprotonation. The free carboxylic acid will indeed be much less basic. But I do think that acetone is playing a part here. If it only served as a solvent, it would be pretty worthless. The bp of acetone is 57 C and the rxn will prolly occur at much higher temperature (like the phenylacetate/acetic anhydride condensation), so the acetone would be evaporated before the rxn started. I may be wrong on this if the rxn temperature is <60 C, so correct me here if you can. But I still don't see the mechanism of the condensation here. Would it be like Beagle suggested, that a mixed anhydride is formed in acetone, which decarboxylates? That would make the rxn temperature <60 C and this would be a VERY good synth! Or would a sealed vessel and high temperatures be necessary? I wish we could finally get a ref on this, so we could clear things up a bit. Lr/
Rhenium Member	posted 01-29-99 11:03 AM Hi everyone, I have started a bit of a discussion here. It's very late at night, and all I can say is that the book seems to indicate that acetone might be one of the reactants. They have PAA + Acetone --> phenylacetone. Now when I see a plus sign, I think reactant, not solvent. Can someone else find this book to prove that I'm not hallucinating? I'm going to be away at a conference for two weeks and won't be able to provide anymore details. Rhenium
Beagle Member	posted 01-29-99 12:29 PM Rhenium: Have a good time! Rhodium & Osmium: I noticed that method in Psych. Chem. too, but never realized that it refered to PAA and P2P. I guess that if you kind of look at it funny, then you could call P2P methyl-phenylacetate! But I always thought it was talking about the ester, and wondered what the hell was going on. And regarding adding water to hot acetic anhydride, I know what you mean! Labrat: I don't think that there is any way that acetic or mixed anydride forms here at <60 deg. And the decarboxylation is DEFINATELY not occuring under these conditions. If the reaction is indeed progressing as I suggested, then pressure would be a must in order to get the heat up. Sounds like Rhen's book is just giving the basic outline, maybe they left out the seperate decarboxylation step. Or decarboxylation cold occur after removal of the solvent, under heat/vacuum.
niteflier Member	posted 01-29-99 10:25 PM hmmmm...I never did figure out the mechanics of the synth from PAA, NaA, and AA, but the synth outlined in the M.V.Smith book works well....also can say for sure that AA ( acetic anhydride ) is not needed if you use lead acetate instead of Na. Wouldnt recommend using PAA and lead acetate though, (although yeilds are good), as you need really vicious vacuum to distill as high temps will destroy your glassware with a residual lead/crud cake. I guess if you have strong enough vacuum it would be OK.....hope I give someone sharper than me a clue as to the exact mechanics of this rxn....
niteflier Member	posted 01-30-99 03:45 PM On rhodium's homepage, posted by drone 342, is a discussion and description of P2P via the enolate of acetone......?
Labrat Member	posted 01-31-99 04:21 PM Rhenium: I already checked my library for that book. It wasn't in there. Beagle: maybe this was an industrial process for preparing P2P? There's an indication of what is reacted with what, but I need rxn conditions like temperature, pH, stirring, etc! We could continue the discussion on the mechanism of this rxn for quite some time, but I think it's best to wait until somebody finds that book in their library and get a ref on this. It's prolly all explained in there. Lr/
hummmm Member	posted 12-20-1999 02:06 AM I aint never head of half that shit tlake dabout iin such an idoot version are you fucking rushian or speak pig latin>>>>>>>>................. FUCK WHORES>>>>>>>>>>>>>................
Xaja Member	posted 12-20-1999 02:27 AM Wow FMAN has dragged up something interesting here. Maybe he is useful after all. But using Pb acetate in place of AA is not the go - bad yields. Anyway, it's PAA that's hard to come by these days. But it would be cool to know whether PAA + acetone + Na acetate runs or not. Anyone?
CHEMMAN Member	posted 12-20-1999 04:11 AM Thought Id throw this one in.I was in a uni library researching benzedrine synths in old books.Little details were given,but two ingredients were analine and acetone .!!!!!! I dont remember all but these two stick in my mind.

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