Sciencemadness Discussion Board - Synthesis of L-Phenylacetylcarbinol(L-PAC)

Synthesis of L-Phenylacetylcarbinol(L-PAC)

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hector2000 - 2-5-2009 at 01:23

Thanks Sauron.
I dont access to refrence part because admin dont allow to me(yet)
You say right.ishould read more about Grignard reagents and i am donig it.
I am lucky because i found Methylmagnesiumchloride(20% solution in tetrahydrofuran) but this is very expensive.
You say true and i was wrong because PhMgCl will not produce PAC(excuse me).
Now i think everything is ready for reaction but maybe i cant provide N2 and just i will react methylmagnesiumchloride with tributyltin chloride.

Sauron - 2-5-2009 at 02:09

The forum library is not ib References and is not password protected.

Http://www.sciencemadness.org/library

You will want PRACTICAL ORGANIC CHEMISTRY by Arthur Vogel

Anything by Ludwig Gattermann

Amything by David Shirley

Anything by J.Cohen

Commercial Grignards are expensive, make your own, read the Brauer except I posted carefully

Here is a better descripttion of the prep of ethylmagnesiumbromide and from it, tetraethyltin. This from Organic Syntheses.

It states that same yields cab be had for tetra-n-propyltin and tetra-n-butyltin. Just use molar equivalents of n-butyl bromide in the Grignard step.

Ethyl bromide is C2H5Br
n-Butyl bromide is C4H9Br
Adjust accordingly

[Edited on 2-5-2009 by Sauron]

Attachment: CV4P0881.pdf (131kB)
This file has been downloaded 876 times

hector2000 - 2-5-2009 at 09:00

Thanks Sauron,
I download this books and i am reading that.
also i buy Methylmagnesiumchloride(20% solution in tetrahydrofuran) and Tributyltin chloride and did reaction today.
I mix one mole Methylmagnesiumchloride and one mole Tributyltin chloride together(in dry ET2O)slowly.
i didnt use N2 gas(because i dont have it)
Now i should distil it?
Also i did reaction between oxalyl chloride and benzene in FC and i made Ph-(CO)-(CO)-Cl (GC-Ms Show yield 36%)
Now iam ready for reaction between MeSnBu3 and Ph-(CO)-(CO)-Cl (if really MeSnBu3 made successfully)

[Edited on 2-5-2009 by hector2000]

Sauron - 2-5-2009 at 15:44

I posted reaction of tributyltin chloride and a Grignsrd reagent upthread, from Org Syn.

Follow workup instrucyions in that.

MeMgCl like all Grignards is air and moisture sensitive, and should be transferred by syringe or a transfer kine, If you just opened the bottle and poured it in you very likely lost some in the process.

I tols you study now, bench work later but you are in a hurry to throw chemicals together.

Well, good luck.

I hope you at least used a fume hood. Oxalyl chloride is very irritating, and releases carbon monoxide when it reacts. nBu3Sn Cl STINKS. Amd is toxic like most metal alkyls. Protect yourself.

36% seems low for that Friedel Crafts, you can do better.

[Edited on 2-5-2009 by Sauron]

DJF90 - 2-5-2009 at 16:33

Hector: Did you make sure you used ANHYDROUS AlCl3 for the FC reaction? Also, if you cant use an inert atmosphere for the grignard at least use dried glassware and drying tubes to prevent ingress of moisture.

Sauron - 2-5-2009 at 20:25

On page 4 of this thread I posted a file CV90707

That is Org.Syn/ Collective Volume 9 page 707 and after.

It describes reaction of nBu3SnCl with an allyl Grignard reagent and the method of working up.

By working up we mean decomposing the complex of the two reactants to release the desired product and the byproduct (magnesium salts)

This is usually done with water first (distilled water) and then with a dile soln of HCl usually 5-10%

Two laters will form, an ether layer containing the product and an aqueous layer containing the salts

Separate the layers in a sep.funnel, dry the ether layer, strip the ether, and distill under vacuum.

For details see CV90707

USE FUME HOOD

DJF90 - 2-5-2009 at 20:47

Another idea for chemical synthesis comes from along the same lines as one of Sauron's sugestions.

> React propionyl chloride with benzene in the F-C reaction (anhydrous AlCl3 as catalyst).
> The resulting compound should be oxidised to a 1,2 dicarbonyl using SeO2 (I dont think the aryl substituent on the first carbonyl alters this reaction but I may be wrong)
>Reduce the phenyl ketone to hydroxyl with NaBH4. This ketone should be reduced in preference due to the electron withdrawing effect of the phenyl group hence increasing the electrophilicity of this carbonyl.

Sauron - 2-5-2009 at 23:19

Product of F-C is

Ph-CO-CH2-Me

That's propiophenone, he can buy it cheap!

Target is

Ph-CHOH-CO-Me

Little or no advantage to starting with 2-chloropropionyl chloride, as far as I can see

And less advantageous that oxalyl chloride in FC followed by MeSnnBu3, or pyruvoyl chloride in the FC, or stepwise reaction of oxalyl chloride with PhSnnBu3 and MeSnnBu3.

All of which give

Ph-CO-CO-Me

which needs only reduction at the benzylic (C1) carbonyl.

[Edited on 3-5-2009 by Sauron]

hector2000 - 3-5-2009 at 01:05

I used dry glassware and dry AlCl3.
I think some Memgcl decompose in air(i used electronic Pipet but i didnt use N2)
Yes i used fume hood and mask.
But i think fc reaction has low yield
I search and didnt find Seo2.
MeMgBr will decompose i air like MeMgCl?
I used below ratio and same reaction for making Ph-(Co)-(Co)-Cl
http://www.erowid.org/archive/rhodium/chemistry/phenylaceton...
But i used more oxalyl chloride
unfortunately GC-Ms dont show MeSnBu3 and i should myself analyze result.

DJF90 - 3-5-2009 at 01:45

FC acylation is fairly HIGH yielding. There is a difference between DRY and ANHYDROUS AlCl3 hector... The amount of MeMgBr to decompose through atmospheric reaction should be fairly small unless the air has a high percentage of water vapour. Is your benzene anhydrous? I suspect that there was some source of water somewhere that killed off your acyl chloride.

hector2000 - 3-5-2009 at 04:51

Yes.all of my chemical is lab grade and without water(all of them are old merck product)
I did again FC reaction(yield was ~40).
Yield is not important problem.
seprate Ph-(Co)-(Co)-Cl from solution is problem because solution color is black and dirty and when i distil by vacum i have gummy tar in my flask.
May be water in air(moisture) make problem

DJF90 - 3-5-2009 at 05:23

Sounds like you might have had some polymerisation...

For workup of FC of oxalyl chloride and benzene, first add enough 2M NaOH to hydrolyse the acid chloride and form the sodium carboxylate. Transfer the liquid portion of the flask into a sep. funnel and you should have two layers. I assume you used benzene as the solvent in the reaction and this will be the dark coloured layer (polymerisation products) ABOVE the aqueous layer that contains your carboxylate salt. The aqueous layer is run out of the funnel into a beaker or conical flask where it can be acidified with 2M HCl and your product will either precipitate out, then you can filter, dry and recrystallise

OR

You will need to add an organic solvent like ether to dissolve it from the aqueous layer, use the sep. funnel, this time keeping the TOP (ethereal) layer, and then evapotate off the ether on a waterbath or a rotovap to leave phenylglyoxylic acid, PhC(O)COOH.

panziandi - 3-5-2009 at 05:33

Lab grade reagents are rarely anhydrous. You should always dry any reagent grades, especially older solvents in partially filled bottles.

Did you use a moisture trap? You should always use a guard tube filled with CaCl2 or NaOH pellets when doing a Grignard reaction etc if you are not using a N2 or Ar atmosphere.

There shouldn't be any alkylations (that would be a low yielding side reaction) and multiple acylations are extremely unlikely since acylations typically give monoacylated products. Trouble with oxalyl chloride is that the product is a acyl chloride so that could acylate another benzene.

Sauron - 3-5-2009 at 06:46

Hector, what solvent did you use in the FC acylation of benzene with (COCl)2? The solvent of choice is CS2

An excess of oxalyl chloride is required to prevent formation of Ph-CO-CO-Ph

Oxalyl chloride is a diacid chloride

Venzene can react at both ends. The excess should be 1.5-3X which makes for added cost

CS2 is a fire hazard, be careful.

hector2000 - 3-5-2009 at 07:11

I didnt use solvent.
I used 85 cc Oxalyl chloride(1 mole) and 89cc Benzene(1 mol)
I did reaction like below reaction:
http://www.erowid.org/archive/rhodium/chemistry/phenylaceton...

Sauron - 3-5-2009 at 07:29

Hector, I told you to use CS2 zolvent,

That Rhodium page is about making P2P for methamphetamine cooking.

The reaction is an alkylation.

Your reaction is a acylation.

If you cannot follow instructions I cannoy help you.

Do the reaction again, use 2 mol (COCl)2 to 1 mol benzene and run this in a liter of CS2,

And you want to know why your yield was low?

No solvent
No excess oxalyl chloride

hector2000 - 3-5-2009 at 07:41

Quote: Originally posted by Sauron

Hector, I told you to use CS2 zolvent,

That Rhodium page is about making P2P for methamphetamine cooking.

The reaction is an alkylation.

Your reaction is a acylation.

If you cannot follow instructions I cannoy help you.

Do the reaction again, use 2 mol (COCl)2 to 1 mol benzene and run this in a liter of CS2,

And you want to know why your yield was low?

No solvent
No excess oxalyl chloride

You say true that reaction is alkylation.
Tonight i will try again reaction with Cs2
This time i will use more oxalyl chloride
unfortunately MeMgCl is expensive here and i should use lot of MeMgcl(because that is 20% in THF) for 100gram PAC

Sauron - 3-5-2009 at 07:53

Make your own MeMgCl (or Br or I)

hector2000 - 3-5-2009 at 10:59

I did acylation again.
I used 170 cc Oxalyl chloride(2 mole) and 89cc Benzene(1 mol) and 50cc CS2 and anhydrous AlCl3
Yield was ~69%
Remaing little red tar(not black)
Also i did final reaction (MeSnnBu3 (1 mole)+Ph-(Co)-(Co)-Cl (1 mole) in dry Et2O)
some heat produced.
Gc-Ms show Ph-(Co)-(Co)-Me Yield %10

Sauron - 3-5-2009 at 19:23

Better! You doubled your yield from the F-C acylation. Tarring is almost eliminated, and you got the organotin reaction to work.

If we can find the literature prep of phenylgkyoxalyl chloride (1-phenyl-2-oxo-acetyl chloride) it will help you optimize reaction time (or you can follow reaction to maximum with GC).

Next you have to isolate the PhCOCOMe and reduce the stuff to DL-PAC and finally strategize the resolution to D-PAC and L-PAC.

Good work last night!.

hector2000 - 4-5-2009 at 02:41

I did PhCOCOMe reaction many time(because Yield is low) and maybe tonight do final reaction.
After lot of search i found SEO2 here.
Also i want to try 2-chloropropionyl chloride method because i think that method is cheaper and maybe has better Yield.
Reaction between Ph-(CO)-CH(OH)-Me and Seo2 for making Ph(CO)-(CO)-Me has special point?(like use N2 gas,...)
I think after this reaction i can recycle Seo2(Convert SE to Seo2) by Patent number #2,616,791 then there is no need for buy seo2 again.
But i have no information and difficulty of reaction between Ph-(CO)-CH(OH)-Me and Seo2.May guide me?

[Edited on 4-5-2009 by hector2000]

Sauron - 4-5-2009 at 03:31

69% is not low yield and is not even optimized yet.

You are worried about cost of MeMg-halide? I told you - make your own!

hector2000 - 4-5-2009 at 05:52

No. FC reaction for make Ph-(Co)-(Co)-Cl has good yield but reaction between MeSnnBu3 and Ph-(Co)-(Co)-Cl has bad yield(i did this reaction 5 time).
also i will do this route for making PAC but i am interesting to know about 2-chloropropionyl chloride method.
I have problem just in the Seo2 step and i dont know instruction of this reaction
i accept that i can build MeMg-hallide but i have question:
We can produce MeSnnBu3 from MeMgI and Bu3SnCl?or we should use Bu3SnI?

DJF90 - 4-5-2009 at 06:39

I assume the use of methyl tributyltin is to methylate the acid chloride selectively over the ketone? Instead, might you use the methylmagnesium iodide/bromide/chloride in the presence of cataytic Cu (I)? Or perhaps prepare the organocopper first by reaction of methylmagnesium halide with copper (I) halide in ether, then transfer the ethereal solution to the reaction flask (or use it as is).

An alternative (with slightly more steps but still viable) is to hydolyse the acid chloride, then under acid catalysis form the ketal (and the ester) then you can just use the methylmagnesium halide, to form 3-oxo(protected)-3-phenylpropan-2-ol. Deprotect with aqueous acid and oxidise the alcohol to the ketone with something like acidified dichromate. The phenyl ketone can then be reduced using NaBH4.

[Edited on 4-5-2009 by DJF90]

Sauron - 4-5-2009 at 07:23

I know you can buy nBu3SnCl but it is easy to make nBu3SnI

Start with nBu-halide (which one does not matter) amd prepare nBuMg-halide in dry ether. Treat 4 mols with one mol Anhydrous SnCl4 added drop by drop. Work up according to instructions in Org Syn paper I gace you for tetraethyltin.

Treat the tetrabutyltin with one mol I2 (again in ether), you get nBu3SnI and nBuI.

Easy.

Now you can react with MeMgI to obtain nBu3SnMe,

You can also make your own MeI for making the Grignard, It takes MeOH, I2 and a catalytic amount of red P. MUCH cheaper than buying it.

hector2000 - 4-5-2009 at 07:49

Thanks Sauron(khorb koon)
I know i can build tetrabutyltin but now i should use lab grade tetrabutyltin because i sholud gve L-Pac sample.
I found Tetra-nButyltin here(not expensive)
If this is possible please guide me for Seo2 reaction
I have suggestion:
FC reaction between 1,1 dichloroacetone and benzene will not help our?

[Edited on 4-5-2009 by hector2000]

Sauron - 4-5-2009 at 16:59

F-C alkylation of benene with 1,1-dichloroacetone ought to work. Can you buy it?

I thought of this also a few days ago but did not have time to check the literature.

Chloroacetones are nasty.

I will look in Pacquette's book for typical SeO2 oxidation.

[Edited on 5-5-2009 by Sauron]

Eureka!

Sauron - 4-5-2009 at 21:12

Here is a short cheap prep of PhCOCOMe aka "acetylbenzoyl" that was jiding in Org.Syn. I told you to search there!

1. Buy or make propiophenone Ph-CO-CH2-Me

You make it by FC acylation of benzene with propionyl chloride

2. Treat with methyl nitrite (you generate yourself, easy - MeOH, NaNO3, H2O, cold dil H2SO4) to get

Ph-CO-C(=NOH)-Me

Isonotrosopropiophenone

3. Hydrolyze with dil H2SO4(details included)

No SeO2 needed.

PDF attached

Attachment: PhCOCOMe.pdf (177kB)
This file has been downloaded 2399 times

[Edited on 5-5-2009 by Sauron]

Nicodem - 5-5-2009 at 00:17

I seriously do not know if this thread is supposed to be for making fun out of Hector's ignorance and laziness or is this supposed to be a serious discussion...

Anyway, I don't get the point. It is not possible to use pyruvic acid chloride in Friedel-Crafts acylations. That would yield acetophenone and not PhCOCOMe. Also, I have serious doubts about Hector being able to do what none has yet been able to do, that is to acylate benzene with oxalyl chloride to give PhCOCOCl. I have not seen any experimental data nor the output of his famous GC-MS. Where are the chromatograms and mass spectra?

One of the published methods for preparing racemic PAC is to nitrosate propiophenone, reduce with NaBH4 and hydrolyse the alpha-hydroxyoxime. So Sauron, do I have to assume that you are fooling with Hector by exploiting his laziness and reluctance to search the literature? If so, maybe I should just close this thread. This forum is for amateurs to share knowledge and not for making fun out of wannabe professional chemists who are too lazy to go to the library and rather want to exploit amateurs to do this.

Also, Hector, are you planning to fraud a pharmaceutical company by selling them racemic PAC? You really must be naive to believe that they will trust your own declaration of optical purity rather than checking in their own lab. Please, do not sell us bullshit about how you are going to resolve the enantiomers because no resolution method ever can be cheaper and more efficient than the L-PAC production through biofermentation.

hector2000 - 5-5-2009 at 00:50

Quote: Originally posted by Nicodem

I seriously do not know if this thread is supposed to be for making fun out of Hector's ignorance and laziness or is this supposed to be a serious discussion...

Anyway, I don't get the point. It is not possible to use pyruvic acid chloride in Friedel-Crafts acylations. That would yield acetophenone and not PhCOCOMe. Also, I have serious doubts about Hector being able to do what none has yet been able to do, that is to acylate benzene with oxalyl chloride to give PhCOCOCl. I have not seen any experimental data nor the output of his famous GC-MS. Where are the chromatograms and mass spectra?

One of the published methods for preparing racemic PAC is to nitrosate propiophenone, reduce with NaBH4 and hydrolyse the alpha-hydroxyoxime. So Sauron, do I have to assume that you are fooling with Hector by exploiting his laziness and reluctance to search the literature? If so, maybe I should just close this thread. This forum is for amateurs to share knowledge and not for making fun out of wannabe professional chemists who are too lazy to go to the library and rather want to exploit amateurs to do this.

Also, Hector, are you planning to fraud a pharmaceutical company by selling them racemic PAC? You really must be naive to believe that they will trust your own declaration of optical purity rather than checking in their own lab. Please, do not sell us bullshit about how you are going to resolve the enantiomers because no resolution method ever can be cheaper and more efficient than the L-PAC production through biofermentation.

Really i am tired of accuse.when you stop it?
Probably i am crazy and did this analyze in my dream with GC-MS?(hmmm sweet dream)
This lazy people did 20 time raction so far(from 4 day ago).
This lazy people setup GC-Ms(difficult work because you should provide vaccum and this take 24hour)for every test.
This lazy spend lot of money for this reaction.
Important to know that all of these work did by a person that dont have one hand,one eye,and two finger from right hand therefore i am very lazy.
Excuse this lazy person and this person will leave this forum
If Sauron want to see analyze page(GC-MS) i will send it by PM
Bye

Sauron - 5-5-2009 at 01:02

Nicodem, let me assure you that I am studying this for my own amuse,emt and not playing cat and mouse with hectotr,

So if you close this thread you will be doing an injustice to everyone participating in it.

DJK90, panziamdi amd I are sharing information with each other, hector is an ancillary bystander.

I do not follow your remark that pyruvoyl chloride would give acetophenone (like acetyl chloride) under FC acylation conditions. Is that supported in the lit.?

The route from propio[hemone was suggested earlier by DJK but he made an error about the product. I revived this a post up from yours, based om Org.Sy. procedures

I looked for FC acylation of benzene with (COCl)2 but Org.Reactions 3 covers alkylations only. I assume this would have been done in the 19th century amd thus best recourse in lack of a focused review is Beilstein. You seem to think it has never been done, why not?

Oxalyl chloride acylates napthalene readily.

See Aldrich tech bulletin and refs, attached.

Attachment: al_techbull_al110.pdf (253kB)
This file has been downloaded 1625 times

Sauron - 5-5-2009 at 01:21

I stated far upthread that the racemic PAC will have to be resolved to an ee at least as good as what the biotech processes give c.ee 90%.

Hector has three choice

Traditional - fract cryst. of a derivative made with a chiral compounm e,g, tartaric acid

Chiral chromatography on a prep scale

Enzymatic resolution if such a method exists for this substrate.

The second method is probably unapproachable.

The first is laborious.

The third may be best if it exists.

Nicodem - 5-5-2009 at 02:16

Quote: Originally posted by hector2000

Excuse this lazy person and this person will leave this forum
If Sauron want to see analyze page(GC-MS) i will send it by PM
Bye

Seems like you finally understood that "The art and science of amateur experimentalism" has nothing to do with profit seeking. It is always nice to see someone finally starts respecting our ethics, even though only out of resentment.

Quote: Originally posted by Sauron

Nicodem, let me assure you that I am studying this for my own amuse,emt and not playing cat and mouse with hectotr,

So if you close this thread you will be doing an injustice to everyone participating in it.

DJK90, panziamdi amd I are sharing information with each other, hector is an ancillary bystander.

That was the only reason why I did not closed the thread when I was supposed to. But the more I followed the more it appeared to me that you were just fooling around with Hector. Sorry if I had the wrong impression. Things are not always like they appear to be and I will respect the sincere interest on the topic as long as it will remain sincere.

Quote:

I do not follow your remark that pyruvoyl chloride would give acetophenone (like acetyl chloride) under FC acylation conditions. Is that supported in the lit.?

There is not a single report of a Friedel-Crafts acylation with pyruvic acid chloride in the literature. There can be two reasons: a.) nobody ever tried because expecting decarbonylation in the presence of AlCl3 (keep in mind that decarbonylation is a problem already during the formation of pyruvic chloride and only mild reagents like Cl2CHOMe give good yields); or b.) nobody was able to get it to work and never considered to report what was already considered obvious by that time. The option a. seems unlikely, because there are conditions which are known to inhibit decarbonylations to a minimum where this is possible (like using MeNO2 or CS2 as solvent and milder acids as catalysts) and so I think someone must have checked them on this acid chloride. I believe the reason b. to be more likely.

Quote:

The route from propio[hemone was suggested earlier by DJK but he made an error about the product. I revived this a post up from yours, based om Org.Sy. procedures

That is what lead me to believe that you were playing cat and mouse, because one of the simplest syntheses of PAC is to start from propiophenone nitrosation, but not the way you presented it (for a moment, I thought that was some kind of a funny diversion - I mean SeO2 for an industrial process and such!).

Quote:

I looked for FC acylation of benzene with (COCl)2 but Org.Reactions 3 covers alkylations only. I assume this would have been done in the 19th century amd thus best recourse in lack of a focused review is Beilstein. You seem to think it has never been done, why not?

Oxalyl chloride acylates napthalene readily.

This was already discussed in an earlier thread. Essentially, it is possible to do a Friedel-Crafts with oxalyl chloride but like the examples in that Aldrich review show, this can be done in a way where decarbonylation of the intermediate arylglyoxalyl chloride is prevented by its further reaction (like in the case of naftalene or in the examples where a double acylation to ArCOCOAr products is given). Of course, if you use AlCl3 in solvents like CH2Cl2 or do not keep the temperature low enough, the oxalyl chloride decomposes even before reacting with the substrate. Otherwise, Friedel-Crafts with oxalyl chloride gives benzoic acids, benzoyl chlorides, ArCOCOAr and/or ArCOAr (depending on the conditions and work-up: there is an old paper describing these experiments of acylating benzene with ClCOCOCl, but at the moment I can't find it - I will post it when I figure out where I saved it). The exceptions are the substrates nuclephilic enough so that a Lewis acid catalyst is not required and therefore no decabonylation can happen (like indole, for example).
This is due to the same property of oxalyl chloride that makes it so suitable for the formation of acid chlorides (that it gives off only gaseous products like CO, CO2 and HCl), but in this case it leads to undesirable reactions. I actually believe that it might be possible to use some of these Lewis acid sensitive acid chlorides like alpha-oxo-acid chlorides and alkyl chloroformates in Friedel-Crafts acylations, it is just seems that nobody have developed a general method.

[Edited on 5/5/2009 by Nicodem]

Sauron - 5-5-2009 at 02:53

I'm sitting here at the scanner 12 hrs a day digitizing Mellor (see New Book Thread-Inorganic for evidence) and have no time for gamesmanship.

When DJK posted about benzene and oxalyl chloride in FC, he mistakenly thought the product would be "acetylbenzoyl" but of course it would not be, that was when I stated that ti get the diketone by that reaction, the acid chloride would have to be pyruvoyll.

The absence of literature was not encouraging but, I did not have time for a proper search.

Then we went off on a tangent because I stumbled across that recent organostannane paper.

That was interesting to me.

Then a day or two ago while looking for SeO2 methodology I ran into the nitrosation of propiophenone followed by acid hydrolysis to get to acetylbenzoyl. So I posted that. Closely akin to the racemic PAC method you mention, just a swap of order of steps.

Peripatetic meanderings, no doubt, but not too bad for being done during breaks from scanning.

Same diketone acetylbenzoyl is used in classical prep of racemic ephedrine an reductive amination with MeNH

Proper name

1-Phenyl-propane-1,2-dione

Can also be obtained by SeO2 oxidation of phenylacetone.

[Edited on 5-5-2009 by Sauron]

DJF90 - 5-5-2009 at 04:01

Couple of points from me:

I have no interest in l-PAC itself, just the organic chemistry involved in the synthesis. It was quite intriguing to find out that pyruvic acid does not form an acyl chloride by "conventional means"... I still propose that the ketal protected acid be tried to see if this works instead.

When I suggested the use of oxalyl chloride I did not expect the prouct to be "acetylbenzoyl", but merely 1-oxo-1-phenyl-propionic acid, which is what I seemed to remember l-PAC being from a quick glimpse of its structure. I should have double checked the structure before I posted, and I am sorry for not doing so.

Interestingly I've just found an orgsyn article using oxalyl chloride in friedel-crafts alkylation. I had read that the reaction forms an acyl chloride (I assumed -C(O)COCl to be the group added), but I didnt realise that the oxalyl chloride fragments first to form phosgene. The second article is a similar reaction but is less explicit about what happens:

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv7...
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=CV5...

Oxidation with SeO2 was first mentioned by Sauron earlier in this thread (not sure of his suggested substrate). The I was flicking though a book on bifunctional compounds ("Bifunctional Compounds" by Ward, Oxford Chemistry Primer #17) and randomly came across a-oxidation of ketones with SeO2, forming the 1,2-diketone. I remembered this thread and posted accordingly.

As a side note: The oxford chemistry primers are really good compact sources of specific knowlege. It is useful to have a selection as when you get stuck on a designing a synthesis and can't remember an FGI or stereo/chemoselectivity then you just have to reach for the appropriate primer. I thoroughly recommend them and over the summer when I have alot more time than now (I have preliminary exams in 5 weeks) I shall borrow a couple of useful ones from the library here (organic chemistry of course!) and scan them in (so long as they aren't already on giga.

Sauron: I've noticed that lately your typing isnt as good at it used to be. You havent damaged your extremities have you?

[Edited on 5-5-2009 by DJF90]

Sauron - 5-5-2009 at 04:19

It's the eyes not the fingers. Or I should say "eye" since one is long gone,

Assumin that the propiophenone route is setlled upon, SeO2 is no longer required.

Propiophenone + MeONO
Ph-CO-C(=NOH)-Me + H2SO4 -> Ph-CO-CO-Me

Reduction NaBH4 -> DL-PAC

Piece of cake

Comes the resolution, bubble bubble toil and trouble...

Sauron - 5-5-2009 at 04:44

DJK, in the first example from Org.syn. (COCl)2 is reacted with AlCl3 in DCM in absence of any aryl substrate, this is not FC acylation.

Will AlCl3 + phosgene in solution acylate an arene in absence of oxalyl chloride? Well, phosgene is an acid chloride,

In the second example, the initially formed acid chloride is deliverately hydrolyzed with aqueous HCl bringing about decarboxylation. This begs the question of whether the Ar-CO-COCl is isolable under any consitions.

DJF90 - 5-5-2009 at 05:06

Well I suppose it should be isolatable so long as it is kept as the chloride, seeing as decarboxylation only occurs when the carboxylic acid is formed?

From the acyl chloride on react with MeCu (not sure if this is quite the correct formula?) Would normally use a corey house reagent (LiCuR2) but figured for ease and simplicity (no methyllithium needed) methylcopper could be used(formed from MeMgX and CuX?)?

Sauron - 5-5-2009 at 08:33

What do you think about F-C alkylation of benzene w/ 1,1-dichloroacetone?

Product Ph-CHCl-CO-Me

1-Phenyl-1-chloroacetone.

Hydrolyze w/ sod.carbonate to DL-PAC.

hector's initiative.

The reagent is cheap. I expect reagent and product to be lachrymatory.

[Edited on 5-5-2009 by Sauron]

Nicodem - 5-5-2009 at 08:44

Nice finds DJF. I was not aware examples this reactions were at Org. Synth. as well.

The decarbonylation (not to be confused with decarboxylation of alpha-oxoacids which yields aldehydes!) happens due to Lewis acid induced carbocation fragmentation of oxalyl chloride (like in the first Org. Synth. example) or by the same mechanism at the stage of the unstable ArCOCOCl. In any case acylium cations and carbocations in general tend to fragmentate or rearrange unless first consumed by a competing reaction (like acylation in case of Friedel-Crafts), but some are so unstable that under some conditions fragmentate even earlier. For example, the discussed alpha-oxoacylium carbocations are highly unstable and decarbonylate, but also (as reported already by Friedel and Crafts in their seminal papers) carbocations derived from alkyl chloroformates (decarboxylation) and primary alkyl halides (rearrangement).

Sauron, the Friedel-Crafts reaction using phosgene is known for a long time already and it gives benzoic acids and benzophenones in a conditions depending ratio (see The journal of industrial and engineering chemistry, 14 (1922) 406-408 for the first study).

Attached is a paper dealing with the Friedel-Crafts acylation with oxalyl chloride. For those interested in finding more on this, it also has some references to earlier use of this reaction for the synthesis of benzoic acids:

Friedel-Crafts Reaction of Oxalyl Chloride with Pentamethylbenzene
N. E. Alexandrou
J. Chem. Soc. (C), 1969, 536-537.

Attachment: phpaMwsOD (254kB)
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Edit: Seems like the attachment function is malfunctioning again. My file was renamed to some nonsense code. However, I downloaded it and renamed it to .pdf and it opens in Acrobat.

[Edited on 5/5/2009 by Nicodem]

DJF90 - 5-5-2009 at 09:10

Sauron: I can't see a problem with 1,1-dichloroacetone in a FC reaction. It doesnt look as though the carbocation can rearrange either.

Sauron - 5-5-2009 at 19:52

Thanks Nicodem.

It was actually hector who wanted to do the FC w/oxalyl chloride rather than the stepwise reaction of oxalyl chloride with PhSnnBu3 and MeSnnBu3, a reaction reported in last month's JOC. I liked the organotin route's novelty as cost and pharmaceutical acceptibility are not my worry.

That does give "acetylbenzoyl" but clearly will never be economically competitive with propiopheone/MeONO et seq. much less biotech.

And thanks DJK, I will see if 1m1-dichloroacetone is in the Org.React. V3 FC review.

[Edited on 6-5-2009 by Sauron]

Sauron - 6-5-2009 at 05:35

I only just obtained a translation of a Ber. paper on pyruvoyl vhloride from TMS-pyrucate and (COCl)2.

This makes it abundantly clear how fragile pyruvoyl chloride is, something no apparent from the Org.Syn. prep.

[Edited on 6-5-2009 by Sauron]

Attachment: Haeusler and Schmidt Pyruvic Acid Chloride.pdf (43kB)
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Sandmeyer - 8-5-2009 at 21:01

Quote: Originally posted by Sauron

Thanks Nicodem.

It was actually hector who wanted to do the FC w/oxalyl chloride rather than the stepwise reaction of oxalyl chloride with PhSnnBu3 and MeSnnBu3, a reaction reported in last month's JOC. I liked the organotin route's novelty as cost and pharmaceutical acceptibility are not my worry.

Haha, no, no - organotin reactants are last resort chemistry...

What JOC paper are you talking about btw...? How is the oxalyl chloride to be used to make phenylacetylcarbinol? Even if it worked (which it will not with AlCl3 - see DJF90's post containing orgsyn refs.) you would add a 2 carbon chain, this chain is already present in readily available mandelic acid. A scifinder search should be done but I can't do it now, however google search on mandelic acid in this context gave following reference: J. Am. Chem. Soc., 1932, 54 (1), pp 234–236 DOI: 10.1021/ja01340a033 but, why speed, why push?

Sauron - 8-5-2009 at 21:34

It might help if you bothered to read the thread.

hector2000 wants to make L-PAC and is looking at non-biotech routes.

I could care less about L-PAC but was kicking some idead around.

Organotin alkyls of the tpe nBu3SnR where R is alkyl or aryl, react with oxalyl chloride to produce diketones. The sequential reaction of nBu3SnPh, and nBu3SnMe, with oxalyl chloride gives PhCOCOMe.

The same diketone is produced by nitrosating propiophenone with MeONO and hydrolyzing w/H2SO4. This is described in Org Syn and the diketone employed in synthesis of racemic ephedrine..

Hector has a lot to learn abour optical resolution.

But that's not my headache,

[Edited on 5-11-2009 by Polverone]

turd - 9-5-2009 at 04:02

Quote: Originally posted by Sandmeyer

A scifinder search should be done but I can't do it now, however google search on mandelic acid in this context gave following reference: J. Am. Chem. Soc., 1932, 54 (1), pp 234–236

That sounds much more OTC and amateur friendly. I wonder if one would need less of an MeMgI excess if one reacted the mandelamide beforehand with Na to obtain the Na-salt? And whether one could use other amides - mandelamide is expensive!

Sauron - 9-5-2009 at 04:25

Interesting although I fail to see what is OTC about it.

Attachment: ja01340a033.pdf (58kB)
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hector2000 - 9-5-2009 at 06:25

I did Reaction between 1,1 dichloroacetone and benzene in FC and then hydrolyze it and got DL-PAC
but yield is bad.
Mandelamide method is not easy as 1,1dichloroacetone method but is interesting.
Mandelamide is very expensive and i didnt find method for making it.

Sauron - 9-5-2009 at 07:08

Hecttor, you mudt nunderstand that this mandelamide methos makes L-PAC and not DL-PAC and therefore, solves the problem of resolving the optical isomers.

You make mandelamide from mandelic acid and ammonia.

Give me a little tome to study thw paper.

[Edited on 9-5-2009 by Sauron]

turd - 9-5-2009 at 07:34

Quote: Originally posted by hector2000

Mandelamide is very expensive and i didnt find method for making it.

You must be kidding - the carboxylic acid to amide transformation is a classic. I can only conclude that you didn't find it because you didn't search.

Anyway, if you're going to buy it instead of making it, you could just as well buy mandelonitrile which is quite cheap (the racemate) and probably needs less MeI.

Damn, my intent was to not participate in this thread anymore and now I did it again.

hector2000 - 9-5-2009 at 07:40

I now mandelamide make L-pac and this is very interesting also has easy route to produce L-pac But you should accept that 1,1 dichloroacetone method is easier.
Unfortunately just 1,1dichloroacetone methos has low yield and long way for purification
I got red DL-PAC and it need to distil 2 or 3 time for change color
But my yield was ~30%-~40% and this reaction is lachrymatory(before you said it)
after adding 1,1dichloroacetone to benzene lot of heat involve and after reflux color of solution turn to black(i dont know why black!?!)
I did this reaction 2 time but really is simple but problem is purification.
Also maybe i test mandelamide method but i should make mandelamide first
Do you have instruction of reaction between mandelic acid and ammonia for making mandelamide?because i just find below method for making mandelamide
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...

[Edited on 9-5-2009 by hector2000]

Sandmeyer - 9-5-2009 at 08:39

Quote: Originally posted by Sauron

It might help if you bothered to read the thread.

hector2000 wants to make L-PAC and is looking at non-biotech routes.

I could care less about L-PAC but was kicking some idead around.

Organotin alkyls of the tpe nBu3SnR where R is alkyl or aryl, react with oxalyl chloride to produce diketones. The sequential reaction of nBu3SnPh, and nBu3SnMe, with oxalyl chloride gives PhCOCOMe.

The same diketone is produced by nitrosating propiophenone with MeONO and hydrolyzing w/H2SO4. This is described in Org Syn and the diketone employed in synthesis of racemic ephedrine..

Hector has a lot to learn abour optical resolution.

But that's not my headache,

I wanted to compare your oxalyl chloride/organotin proposal to the possibility of starting from mandelic acid since both would depend on a intermediate having a 2 carbon atoms long alkyl chain. I haven't done any literature searches - it is possible that DL-PAC can be made more efficiently using entirely different approach from completely OTC chemicals, but that was not my point.

Quote: Originally posted by Sauron

Interesting although I fail to see what is OTC about it.

Well, at least it is more OTC than using organotin reagents coupled with oxalyl chloride.

Quote: Originally posted by turd

Ok, I'm away from the litterature, but there are other leaving groups, for instance you can use a secondary amine to make a tertiary amide and treat that with MeI grignard...

[Edited on 5-11-2009 by Polverone]

Sandmeyer - 9-5-2009 at 09:42

PS. Boric acid (OTC) catalysis can be used to make the amide (tertiary in this case) http://www.orgsyn.org/orgsyn/prep.asp?prep=v81p0262

[Edited on 5-11-2009 by Polverone]

Nicodem - 9-5-2009 at 12:16

You both forget that wherever there is prohibition there is also a black market for the precursors. For example, the moment most of the European countries banned MDMA, there was immediately established a black market for 3,4-methylenedioxyphenylacetone produced semilegally in some industrial environments specifically for costumers from Europe. I remember the criminals were able to buy it in Netherlands for an equivalent of a few thousands dollars which was pretty cheap (IRC, the price I heard of was 10000 DM in the nineties). The main obstacle for the local criminals was to get a chemist without any ethical concerns to synthesize the target drug.
Now, consider that in the USA the ephedrine containing pills were banned and all those poor meth cooks, who never bothered to learn chemistry, because too busy stripping match boxes, now desperately look for more (pseudo)ephedrine. For them it does not matter that much if the precursor is racemic. Still better than studying chemistry in order to use simpler syntheses.
Of course no chemical synthesis of L-PAC can ever be comparable to the economy of the biophermentation where the main cost is the starting materials and the energy consumed for distillation, while most of the solvent gets recycled. I'm inclined to believe that not even racemic PAC can be made as cheaply as L-PAC. But mind that L-PAC is immediately consumed to produce the ephedrines and it is also not available trough the chemical sellers, so I would not be surprised that some criminal organizations desperately look for someone willing to do the custom synthesis of this stuff.

hector2000 - 9-5-2009 at 12:40

Quote: Originally posted by turd

Yes, that would be crazy, and that's why my first guess was 4-methylaminorex. But now I'm not convinced any more and maybe hector2000 *is* crazy after all. Seeing how he can get all kind of non-OTC chemicals, I wonder why he doesn't simply use mandelonitrile + MeMgBr or mandelic acid + MeLi or just buys the stupid PAC. I mean really, this whole thread makes no sense.

[Edited on 9-5-2009 by turd]

Do you know price of Meli?(very expensive)and sensitive to air.also about MeMgBr
You think this is cheap to make lpac from this method?
Who said i want to build meth?if i want to build meth i will buy ephedrine and make from that!
Please read this topic carefuly

Sandmeyer - 9-5-2009 at 16:42

Quote: Originally posted by hector2000

If you use MeLi you don't even have to make the amide, it reacts directly with carboxylic acids to give ketones[1], hence it might potentially be a one-step process, you can make your own MeLi from MeCl[2] (tedious, requires a real lab, but doable and cheap), or from MeI[3] (convenient) lithium gives good atom economy ~7g/mol. Methyliodide is relatively expensive commercially, but you can recycle the expensive iodine and make your own MeI from cheap methanol, I've done this in bathroom so it's easy. If you want to make PAC indu$trially then you should stick to the fermentation, of course. If you're unable to do that and can't accept that a synthesis would be more costly, then find other ways to fill your pockets with money.

[1]: http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0775
[2]: http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0346
[3]: http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0859 see note 4

[Edited on 10-5-2009 by Sandmeyer]

Sauron - 9-5-2009 at 17:53

First of all, I am only interested in the chemistry and not at all in making PAC, ephedrine or anything else in that family.

Hector2000 can and has explain his interest in making L-PAC commercially as a supplier to a pharm company in his country.

Unsubstantiated and pointless accusations serve no one.

Thanks, sandmeyer, for the ref to the Grigmard rxn with d-mandelamide. Whether hector understands it or not, or elects to do it, is beyond your control or mine. He seems to still be focused on a low yield FC prep of racemic PAC which will do him no good at all, his client wants L-PAC.

I do not believe the scale required to produce wty he wants by S.cervisea method is viable for him, and in any case he would need some microbio;ogists.

As usual hector is kvetching about costs.

Hector:

1. I told you upthread MAKE YOUR OWN MeI from methanol, I2 and little red P catalyst per Org Syn. This is easy and cheap.

Then use that to make your own MeMgI.

2. You need d-mandelic acid. That is dextrorotatory. If you can find it it will be costly. You have an alternative.

dl-Mandelic acid is CHEAP. Buy it and resolve it into its isomers yourself using the d- and l-isomers of ephedrine. I attach na paper describing this, also from JACS. Same author and volume as Sandmeyer's reference.

Three crystallizations and you will have the pure d-mandelic acid.

It is easy to turn that into d-,amdelamide

And thus obtain the L-PAC you need. NOT DL-PAC.

Do you have a polarimeter? I can assure you your client does. How will you check the optical rotation of your L-PAC and thus calculate its ee?

A good Chinese polarimeter is $300, maybe double that with DHL from Shanghai. I have one. The same instrument is sold by several European companies for $2000, but they just buy them from same factory I do. Different label same scope.

The DL-PAC route is ONLY to be condered if you have NO method for L-PAC.

Now you have such a method, so forget DL-PAC.

You did say there is lots of ephedrine in Iran so you should be able to obtain the required d-ephedrine as well as l-ephedrine.

So d-,amdelamide will be easy and cheap for you.

Folloe instructions in this paper.

[Edited on 10-5-2009 by Sauron]

Attachment: ja01381a042.pdf (76kB)
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Sauron - 9-5-2009 at 19:00

I see. Well as far as I recall hector has only asked about acetic anhydride, which many of us want, and L-PAC which has been been posted about profusely by others, notably solo, without any objections from you.

Personally I have ebjoyed participating in this thread, and turned up a number of reactions I find interesting, even if most of them did not turn out to be productive for hector.

So I reject your criticism, sorry.

Hector, is ephedrine's stereoisomers are unavailable or too dear you can use (+)-phenylethyllamine and (-)-phenylethylamine.

L. Smith, J. Prakt. Chem., 84, 743 (1911); A. W. Ingersoll, S. H. Babcock, and F. B. Burns, J. Am. Chem. Soc., 55, 411 (1933).

For the prep of mandelamide, see attached Org.Syn. paper and also the refs and notes below:

"Mandelamide has been prepared by treating the ethyl ester with concentrated aqueous ammonia,1,2 and a saturated ethanolic solution of ammonia has been used to effect ammonolysis of the methyl ester.3 Esters of mandelic acid were treated with liquid ammonia at its boiling point;4 this procedure was improved by use of ammonia at superatmospheric pressures and higher temperatures.5 The procedure described in this synthesis was first used by Ôeda.6"

--------------------------------------------------------------------------------

References and Notes
1.
Beyer, J, prakt. Chem., (2) 31, 390 (1885).
2.
Einhorn and Feibelmann, Ann., 361, 145 (1908).
3.
McKenzie and Wren, J. Chem. Soc., 93, 311 (1908).
4.
Glattfeld and MacMillan, J. Am. Chem. Soc., 58, 898 (1936).
5.
Kleinberg and Audrieth, J. Org. Chem., 3, 312 (1938).
6.
Ôeda, Bull. Chem. Soc. Japan, 11, 385 (1936).

--------------------------------------------------------------------------------

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[Edited on 10-5-2009 by Sauron]

Sauron - 9-5-2009 at 19:17

L-PAC is not a controlled substance, and anyway the forum policy is to be unconcerned with law is it not?

I will admit hector is not an especially gratifying student to practice one's pdagogical skills on, but if beins a dim and sluggish student were a crime then the univerity classrooms would be a lot emptier.

I am satisfied hector is no cook, amd so AFAUK are the mods, at least nicodem. So as long as my patience holds, and it behooves me to advise him I will do so. I do not see how this possibly concerns you. You need not read this thread, and no one is calling upon you for assistance. You are not the guardian of polverone's bandwidth, polverone is.

Hector

Here is the resolution of dl-mandelic acid with the two stereoisomers of a-phenylethylamine.

In Kg quantities the (R)-(+) and (S)-(-)-1-phenulethylamines are about 40 US cents a gram (BASF products sold by Acros, 99%).

DL-mandelic acid is VERY CHEAP.

So now you know how to resolve racemic mandelic acid and how to prepare (R)-(+)-mandelamide from that acid and ammonia.

All you need to do is react that with MeMgI which you can make yourself from methanol, iodine, a smmall amount of red phosphorus catalyst; mafnesium turnings and diethyl ether.

And there is your L-PAC.

Attachment: ja01328a061.pdf (120kB)
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[Edited on 10-5-2009 by Sauron]

[Edited on 5-11-2009 by Polverone]

turd - 10-5-2009 at 02:27

If MeI is the price determining factor then I'm not convinced this reaction is ideal. I guess quite a lot of it is lost on the alcohol group and on the acidic amide group. Mandelic acid + 2Li + MeLi seems to be more favourable. Or mandelonitrile + Na + MeMgX, but mandelonitrile is proably harder to make a diastereomeric derivate of.
If Nicodem is right and the "L-PAC" will sooner or later end up in American pill crusher's flask anyway, the "pharm company" might not care about enantiomeric purity and the propiophenone process looks like a real winner.

[Edited on 5-11-2009 by Polverone]

Sauron - 10-5-2009 at 05:39

Recommending ;ithiarion to someone who ubtil a week or 10 days ago had never done a Grignard strikes me as odd. Lithiation is a technique intensive procedure and rather unforgiving of tyros. Do I detect a whiff of disingenuosness in the suggestion?

[Edited on 5-11-2009 by Polverone]

turd - 10-5-2009 at 06:34

Feel free to detect anything you want in my suggestions, but if someone can cook Grignards, he should be able to do simple Li-organyls (we're not talking about super reactive -78°C stuff here). Indeed, my first metal-organic reaction was with Li (admittedly with the very unreactive PhLi). Personally I'd prefer to work with MeLi solutions over working with chloro-acetones or oxalylchloride. YMMV.

[Edited on 5-11-2009 by Polverone]

hector2000 - 10-5-2009 at 09:06

I want to try mandelamide method but i have question
For making mandelamide we should use (R)-(-)-Mandelic acid(Cas#611-71-2) or (S)-(+)-Mandelic acid(Cas#17199-29-0)?Which one is d-mandelic acid?
Also i found Phenylethylamine but which one is need for my work?R-(+)-1-Phenylethylamine or S-(-)-1-Phenylethylamine?
Unfortunately i have problem with temp -10c for making mandelamide but i will try it with ice and NaCl and NH4No3
Also i can buy pseudoephedrine here(this is very cheaper than Phenylethylamine)
Pseudoephedrine is suitable for resolution mandelic acid?

[Edited on 10-5-2009 by hector2000]

[Edited on 10-5-2009 by hector2000]

Sauron - 10-5-2009 at 09:39

Hector

To make L-PAC you must use d-mandelic acid to make d-mandelamide.

This is by definition (+)-mandelic acid.

You want for resolution of dl-mandelic acid both isomers of 1-phenylethylamine.

That is (S)-(-) and (R)-(+)

Do you completely understand what all that means?

NO psuedoephedrine is NOT suitable replacement.

[Edited on 10-5-2009 by Sauron]

turd - 10-5-2009 at 12:54

Quote:

You want for resolution of dl-mandelic acid both isomers of 1-phenylethylamine.

Why is that? From my limited understanding you need one enantiomer of the amine to turn your racemic acid into two diastereomeric salts, which you then separate using conventional methods (crystallization, chromatography). Or did you mean you need either isomer?

Quote:

I want to try mandelamide method

If the MeMgI is your limiting reagent you probably should try to make the salt of the alcohol and maybe try a tertiary amide? Otherwise you'll lose at least an molar equivalent of your MeMgI. (I'm starting to sound like a broken record...)

[Edited on 5-11-2009 by Polverone]

hector2000 - 10-5-2009 at 14:29

Quote: Originally posted by turd

I don't want to start a discussion on principles, but for me hector is the archetypical cook. Maybe he isn't cooking psychoactives, just precursors, but AFAICT he's not interested in chemistry, only profits.

You sure that my love is just Chemistry and learning it.
For the chemistry i lose one of the my hand and my eye(when i was youngger in lab i save life of two student and i lose my hand and eye)
Unfortunately here and in university we dont have good teacher and good equipment and really we dont learn enough about chemistry.
I wish i go to usa or germany for learn chemistry in university but this is very big wish and this is impossible
Ok back to chemistry
Sauron i underestand what you said and i want to try mandelamide method but i have problem with temp -10c.
I think for the reaction between MeMgI and mandelamide we should use N2 gas for better yield.

DJF90 - 10-5-2009 at 14:35

Hector: -10C is a simple temperature to achieve. Supposedly NaCl/crushed ice in a ratio of 1:3 (w/w I believe) will get you to -20C, but this is slightly unrealistic. However -10C should be well in its ability.

Polverone - 10-5-2009 at 19:29

I went away for the weekend and this is the mess that greets me when I return! If you think forum rules have been breached, report the specific posts and reasons via to a mod or admin via U2U (some have already done this for posts in this thread). If you just want to speculate about someone's motivations and character, don't do it in public here. It doesn't belong in this thread. Don't contribute to a thread if you don't like the participants, but don't drag it off topic either.

turd - 10-5-2009 at 21:04

I wonder why you refuse to address my (IMHO valid) points: In the article Sandmeyer posted, they use a fourfold excess of MeI. Seems quite wasteful for someone who complains about the price of MeI and there surely are better published methods around.

And why the need for *both* enantiomers of phenetylamine in optical resolution - can someone explain that?

[Edited on 5-11-2009 by Polverone]

turd - 10-5-2009 at 21:30

It would be nice if you'd someday explain that resolution thingy and if/why it wouldn't be a good idea to use tertiary amides and first make a salt of the alcohol with cheap Na. Stirring might prove problematic, but you will end up with a Mg salt anyway.

[Edited on 5-11-2009 by Polverone]

turd - 10-5-2009 at 23:54

Well looks like MeLi on mandelic acid gives low yields.
But you may be interested in regio- and stereo(kindof)selective reduction of PhCOCOMe.

Tetrahedron Letters, 28(50), 6313-16; 1987
Journal of Catalysis, 204(2), 281-291; 2001
Tetrahedron Letters, 29(35), 4485-8; 1988
Journal of Organic Chemistry, 73(17), 6559-6569; 2008
Journal of Molecular Catalysis A: Chemical, 236(1-2), 227-238; 2005
Tetrahedron, 61(8), 2217-2231; 2005

Sorry, if these have been posted before, I can't be bothered to read this "thread".

Sauron - 11-5-2009 at 00:14

Hector

The cost of MeI is of no concern if you simply make your own.

Two methods are detailed in Org.Syn.

Methyl alcohol, Iodine and a little red P catalyst

or

KI and Me2SO4 that is (MeO)2SO2, dimethyl sulfate

Both are easy and cheap

I advise against MeLi and now the one proposing it admits it is low yield.

The proposal of regio- and stereiselective reduction of acetylbenzoyl may have merit, but the devil is in the details. See what catalysts, conditions and yields are like.

We already know a regioselective reducing agent.

But not also stereoselective.

DJF90 - 11-5-2009 at 02:26

Hector: MeI should not be a challenge for you to make so long as you have the starting materials; Sauron has listed two methods. The corresponding grignard reagent (MeMgI) can also be made fairly easy, and as such should represent no problems. Sauron suggested making your own MeMgI wayyyyyy back in this thread, but I guess you failed to take note. It is FAR cheaper than buying the commercial stuff!

Sauron - 11-5-2009 at 05:32

Here is the Org.Syn. prep of MeI by two methods.

Others give you citations, I give you PDFs.

Attachment: CV2P0399.pdf (185kB)
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Polverone - 11-5-2009 at 08:49

I believe I have removed most of the bickering. Please, nobody add more for me to remove.

turd - 11-5-2009 at 09:21

Quote: Originally posted by Sauron

I advise against MeLi and now the one proposing it admits it is low yield.

What a strange choice of words, given that I never promised great yields or anything. But let's do the math:
The reference I posted gives 45% for mandelic-acid + MeLi --> PAC. Yes, a lousy yield.

Now via the mandelamide.
Orgsyn gives: mandelic-acid + NH3 (liquid!) --> mandelamide 62%, I'd say OK, but you'll probably find better.
The 1932 article: mandelamide + MeI + Mg --> PAC 70% (nice, but maybe a little bit optimistic - they took a fraction from 110°-140°C)
Gives 62% x 70% = 43%

So unless my calculations are off, you have 45% in one reaction vs. 43% in two reactions (meaning more solvent, more work, and so on). I guess common sense has a clear answer to that one. A part from that I still don't see why MeLi from MeI would be more demanding than doing classic Grignards. Or how someone who can handle liquid NH3 would have problems with MeLi.

PS: I really don't care what route hector2000 choses, I'm not here to win some strange popularity contest. How silly would that be?
PPS: I'm not an organiker so take everything with a grain of salt.

turd - 11-5-2009 at 09:32

Quote: Originally posted by DJF90

Hector: -10C is a simple temperature to achieve. Supposedly NaCl/crushed ice in a ratio of 1:3 (w/w I believe) will get you to -20C, but this is slightly unrealistic. However -10C should be well in its ability.

This is so strange... The guy can buy get oxalylchloride and whatnot, but no dry ice? Also I think he missed the part about the liquid ammonia, how is he going to condense that? Maybe the suggestion of a secondary/tertiary amide isn't so dumb after all? But first and foremost I think the guy should start thinking for himself.

DJF90 - 11-5-2009 at 11:58

Hector may have access to dry ice, but if the reaction only needs to be cooled to -10C then I dont think there is a dry ice bath he could use for that. Theoretically he could use a CaCl2.6H2O/ice bath to ~-40C, and this should be sufficient for condensing ammonia although it will not work as well as a dry ice bath.

[Edited on 11-5-2009 by DJF90]

turd - 11-5-2009 at 12:31

Quote: Originally posted by DJF90

Hector may have access to dry ice, but if the reaction only needs to be cooled to -10C then I dont think there is a dry ice bath he could use for that.

Why? It's just a matter of how deep you insert your flask in the cooling bath.

Quote:

Theoretically he could use a CaCl2.6H2O/ice bath to ~-40C, and this should be sufficient for condensing ammonia although it will not work as well as a dry ice bath.

Well sure, good luck with that.

But seriously, he should simply use a non-volatile amine together with a water scavenger like toluene, which will give higher yields and will need much less work. Maybe even use an enantiomeric amine, then he could do the enantiomeric resolution at this step.

The best advice still is: just buy the silly thing.

DJF90 - 11-5-2009 at 14:53

Just buying it isnt exactly going with the flow of amateur chemistry now is it...

I know that the CaCl2/ice bath isnt efficient, but its better than nothing and should do the job (I did imply it wouldn't be great...)

Toluene is NOT a "water scavenger"... It merely forms an azeotrope which is distilled off, removing the water from the reaction mixture. Hydrolysing an amide takes pretty harsh conditions, and so if theres no conc. acid or conc. base around then I doubt very much that yields will suffer due to the presence of just water.

Sauron - 11-5-2009 at 19:01

Bandying words with turd is not a productive pasttime. He's out to wreck this thread, not to enlighten anyone about anything.

Give his a wide berth and no replies t all. Send him to Coventry.

turd - 11-5-2009 at 22:09

Quote: Originally posted by DJF90

Just buying it isnt exactly going with the flow of amateur chemistry now is it...

Of course not. But hector has made it quite clear that he needs 100g L-PAC to sell it to a "pharm-company". My opinion is that his best option would be to act as a reseller, lest he hurts himself more. So I think this is the best advice we can give him. Still we can discuss the chemistry, although IMHO it's quite boring to discuss chemistry that no one will perform.

Quote:

I know that the CaCl2/ice bath isnt efficient, but its better than nothing and should do the job (I did imply it wouldn't be great...)

An honest question: would *you* do that? Can you imagine a situation where someone can acquire large amounts of anhydrous NH3 but no dry ice?

Quote:

Toluene is NOT a "water scavenger"... It merely forms an azeotrope which is distilled off, removing the water from the reaction mixture.

Yeah, you know what I meant. Toluene + Dean Stark trap removes water, I don't know what the correct term is.

Quote:

Hydrolysing an amide takes pretty harsh conditions, and so if theres no conc. acid or conc. base around then I doubt very much that yields will suffer due to the presence of just water.

Well, they use a Dean Stark trap in the OrgSyn procedure Sandmeyer posted (http://www.orgsyn.org/orgsyn/prep.asp?prep=v81p0262). Maybe it is superfluous, but that makes my point even stronger: why make mandelamide with liquid NH3, when you can make a secondary/tertiary amide with much less work and probably higher yields?

@Sauron: you're cute. But I think the members on this board are old enough to decide who they talk to.

[Edited on 12-5-2009 by turd]

turd - 11-5-2009 at 23:36

BTW, you are right, there is no need for a Dean Stark trap. Here are some examples (though I cannot assess if they are too sterically hindered).
Jpn. Kokai Tokkyo Koho, 05294911, 09 Nov 1993, Heisei (Patent written in Japanese

)
Journal of Organic Chemistry, 52(22), 4978-84; 1987 (83% for the benzylamide)
Tetrahedron Letters, 26(7), 811-14; 1985
Journal of Molecular Catalysis A: Chemical, 276(1-2), 235-243; 2007 (DCC, 95%)
Tetrahedron: Asymmetry, 16(11), 1953-1958; 2005 (DCC, 94%)
Heterocycles, 22(4), 773-8; 1984 (39-79%)

hector2000 - 12-5-2009 at 00:33

Turd,
Maybe reaction between MeLi and mandelic acid has better Yield but you should accept the price of MeLi is very expensive and sure this price isnt important for 100gram LPac but if pharm company accept my sample then we should provide l-pac for pharma company continuesly and in this point the price of final product will be important.
do you think reaction between Mei and Li make good yield MeLi?
2 Li + MeI → LiMe + LiI
Sauron(Thanks),
I did mandelamide reaction difficuly but i got mandelamide.
Now for reaction between mandelamide and MeMgI i should use mandelamide.Hcl ?

[Edited on 12-5-2009 by hector2000]

Sauron - 12-5-2009 at 01:27

Hector

Follow thw protocol in JACS

If it says mandelamine hcl, use that

Otherwise use free mandelamide

Did you resolve dl-mandelic acid, or did you buy d-mandelic acid (R)-(+)-mandelic acid?

MeLi gives crap yields with mandelic acid

MeMgI iodide gives good yields with mandelamide but protocol requires 4X excess.

This is not a problem if you make your own MeI and MeMgI.

hector2000 - 12-5-2009 at 07:03

I buy (R)-(+)-mandelic acid for both reaction (MeLi reaction and Mandelamide reaction)
For purification of mandelamide i react it with HCL and dissolve it in water and separate water then react it (water+mandelamide.hcl) with Naoh solution and separate it with DCM and evaporate solvent but when i add Naoh solution lot of gas produced(i think that was ammonia because i test this gas with wet Ph paper and paper show Ph 14)this is normal?mandelamide didnt destroy?
I test result of reaction between 1,1dichloroacetone and benzene in FC by GC-MS and got interesting result.
GC-Ms show diffrent componet but really dont show this componet and we guess that is:
(PH)2-CH-C(=O)-CH3(~10-12%)(GS-Ms dont realize it and we guess it)
PH-CH(OH)-C(=O)-CH3(~30-36%)(GC-MS realize it)
Maybe i miskate but when i show result to my friend(chemist)he accept that probably this componet produced

[Edited on 12-5-2009 by hector2000]

turd - 12-5-2009 at 09:42

Quote:

Now for reaction between mandelamide and MeMgI i should use mandelamide.Hcl ?

Quote:

If it says mandelamine hcl, use that Otherwise use free mandelamide

Quote:

For purification of mandelamide i react it with HCL and dissolve it in water and separate water then react it (water+mandelamide.hcl)

AmiDe guys, not amiNe.

hector: If you really made mandelamide, please post details of reaction, workup and analysis. I think this is quite interesting, since I have D/L-mandelic acid and no use for it!

Yes, making MeLi is easy if you can work under intert gas, see the note Sandmeyer posted:

Quote:

4. The methyllithium must be prepared from methyl iodide because the presence of the iodide anion is essential. The submitters prepared methyl lithium in the following manner. Methyliodide (425.7 g., 3.00 moles) was added with stirring to 48 g. (7.0 g. atoms) of lithium in 2.5 l. of ether under nitrogen at a rate adequate to maintain gentle reflux of the ether. After 24 hours the solution of methyllithium was decanted into a storage vessel filled with nitrogen. The concentration was estimated in the usual way by hydrolysis of an aliquot and titration with 0.1N hydrochloric acid.

Of course you can not just react mandelic acid with MeLi. You will have to fetch literature references for good ideas. (First two aliquots of LiH? The organic experts will be able to help you out.)

But really, you will never be able to compete against the pros in eastern asia, so buy the stuff, sell it for a profit and enjoy your free time!

hector2000 - 12-5-2009 at 10:48

Quote: Originally posted by turd

I didnt analyse it but when i add Naoh solution ammonia gas produce.maybe mandelamide.hcl will not produce and my method for purification is wrong.
Before i think HCL will made salt of mandelamide like amin because it has NH2 but i mistake sorry.

[Edited on 12-5-2009 by hector2000]

DJF90 - 12-5-2009 at 11:44

Reacting the mandelic acid with two equivalents of MeLi will do the trick. Alternatively to save an equivalent you could use another base to deprotonate the acid.

turd - 12-5-2009 at 13:05

I think you forgot the benzylic OH - that one has to be deprotonated too if you don't want to lose another equivalent of MeLi. I wonder if it will be the cause of cyclisation - once I tried to make an amide of ethylenediamine and all I got was a silly imidazole.

hector2000 - 13-5-2009 at 01:45

I find out When reaction time between 1,1dichloroacetone and benzene in FC increase then yield of (PH)2-CH-C(=O)-CH3
Working with MeLi is not simple and that is very expensive and isnt easy to make
I see before that L-PAC is unstable componet and sensitive to high temp.this is true?
What temp?

Cyrex - 13-5-2009 at 08:17

I wonder how Amination of L-pac make L-ephedtine not D-ephedrine?!

KINDLY STAY ON TOPIC!

Sauron - 13-5-2009 at 11:57

Learn some stereochemistry and the answer will pop out.

Your question is a good one. HOWEVER, this thread is not about ephedrine, nor is it a proper venue for a discourse on stereochemical notation, nor mechanism of reductive amination. Those are what it takes to answer your question fully, and if you want to start a thread about those with L-PAC -> ephedrine as an example in point, I'm sure it will be an instructive one,

But not here!

[Edited on 14-5-2009 by Sauron]

[Edited on 14-5-2009 by Sauron]

hector2000 - 16-5-2009 at 12:48

Quote: Originally posted by Sauron

I stated far upthread that the racemic PAC will have to be resolved to an ee at least as good as what the biotech processes give c.ee 90%.

Hector has three choice

Traditional - fract cryst. of a derivative made with a chiral compounm e,g, tartaric acid

Chiral chromatography on a prep scale

Enzymatic resolution if such a method exists for this substrate.

The second method is probably unapproachable.

The first is laborious.

The third may be best if it exists.

which type of tartaric acid?L(+)tartaric acid?D(-)tartaric acid?
d-tartaric acid?what is d-tartaric acid?(L(+)tartaric acid?)

Sauron - 16-5-2009 at 22:04

Hector, tartaric acid is simply an example.

It may or may not be effective for the resolution of racemic (dl-) PAC.

Why are you messing with such resolution when you have means of producing L-PAC now?

hector2000 - 17-5-2009 at 01:37

I made little L-pac from mandelamide method but after calculate the price i find out that this methos isnt economic for our.
We decide to produce L-pac from 1,1 dichloro acetone because is very chepaer than mandelamide method and just in one step.
Now i am working on resolution of racemic PAC
Maybe you say we shoud separate DL-mandelic acid but i should say phenylethyllamine is very expensive here.
1,1 dichloro acetone has cheaper price

[Edited on 17-5-2009 by hector2000]

Sauron - 17-5-2009 at 03:34

OK hector, do what you want.

You will find the resolution of PAC tedious and expensive I think. Anyway search in the literature for best resolving agent and method for PAC.

Good luck. I think you will need it.

hector2000 - 17-5-2009 at 04:54

Thanks Sauron
anybody has idea for resolution racemic DL-PAC?

[Edited on 17-5-2009 by hector2000]

turd - 17-5-2009 at 13:22

Yeah, oxidize it to PhCOCOCH3 and stereoselectively reduce it. And I'm only half joking. Suddenly propiophenone becomes interesting again, eh?

But totally seriously: If you enter PhCHOHCOCH3 as product molecule in SciFinder or Beilstein/Crossfire you will find quite a lot of papers on racemic resolution of PAC. You will also find tons of different syntheses for your target molecule and this could have spared us the whole thread.

PS: When do we get the experimental details for mandelamide and its physical characteristics (mp), since you suggest that you made L-PAC via the mandelamide?

Cyrex - 17-5-2009 at 13:46

interesting method

[Edited on 17-5-2009 by Cyrex]

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