dormouse
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04-19-00 11:45
No 122752
      what happened to my enolate review?! -drone 342
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Author Topic:†† what happened to my enolate review?!
drone 342
Member posted 09-14-98 06:44 PM †††  † ††
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I went through the time and trouble to do a literature review on te synthesis of phenylacetones from arylhalides and acetones, and it disappeared? Did anybody get a chance to see it, and where is it now? I really don't want to do all that work again.

-drone #342


Rhodium
Administrator posted 09-14-98 07:08 PM †††  † ††
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I captured it before it vanished:

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JOC, 1976, 41, 3677-3682

Describes the use of different solvents for Srn1 rxn's (e.g. halobenzenes reacting with the enolate of acetone in solvents like NH3, t-BuOH, DMSO, DMF, CH3CN, etc.)

JOC, 1977, 42, 1449-1460

Back-to-back rockin' chemical fun! Describes the kinetics of arylhalides reacting with various ketones in various solvents (including, I believe, bromobenzene reacting with the acetone enolate in DMSO!!!) Also describes the use of catalysts, temperature variations, etc...

JOC, 1983, 48, 3109-3112

Photostimulation of the same reaction

JOC, 1984, 49, 3041-3042

Describes the use of iron, copper, and tin species as catalysts in making phenylacetones from PhI, PhBr, and o-chloroaniline - yields were pretty good.

JOC, 1984, 49, 4881-4883

Further dispells the myth of the necessity of NH3 as a solvent, describes the use of various enolates.

Have fun, and don't spill any alkoxide bases on yerself!

Before I forget, for those of you not familiar with the premise of this post, a strong base (pKa>23; e.g. various alkoxides or alkali amides) is mixed in with acetone in an aprotic solvent (NH3, DMSO, CH3CN, etc.), and the enolate is formed. A halobenzene is added, and reacts to form phenylacetone.

-drone #342


drone 342
Member posted 09-14-98 08:18 PM †††  † ††
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PHhheww! I was a little worried there! Glad to see you were on top of that. Thanks.

As you can see, the reaction is pretty straight-forward, and the yields listed on most of the experiments are pretty high (80 to 90%, if memory serves.)

enjoy,

-drone #342


ICEKAT
Member posted 09-16-98 10:11 PM †††  † ††
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Drone #342-

I wish I had more to offer on this topic but I did take the time to scan those articles and get them to OP so if anyone wants to look at them so this string can fly E-mail Optimus Prime. Hope this helps those intrested in adding there insights to this topic. Serving you my fellow worker bees.

ICEKAT


drone 342
Member posted 09-17-98 08:50 PM †††  † ††
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Icekat,

Yes, thank you, commrad. When the glorius revolution happens, and the chemically-altered peseants rise up against the tyrrany their narrow-minded sober opressors, your contribution to the struggle will reward you greatly.

Down with moderation!

-drone #342


ICEKAT
Member posted 09-20-98 04:10 PM †††  † ††
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I am not against moderation infact I am FOR moderation just against the Bully tactics and twisted truths backed by unjust laws enforced by the Sheep armed to the teeth. We all know these as the DEA... empowered by the holy mission to rid the world of drugs while they sit back and pop their asprin and antacid tablets and give there kids sudafed at night to help with there colds. Moderation yes but DEA no! I would rather see a people earn there sobriety by choice than forced by law and opression. Laws must exist for orders sake but.......


drone 342
Member posted 09-20-98 04:51 PM †††  † ††
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By my very nature, I am fundamentally anarachistic, with a deep distaste for ANY authority, especially morally corrupt and intellectually bankrupt groups like the DEA. But this discussion is not chemistry, let's get back to topic.

As you can clearly see, this is an excellent way to make p2p. With the variations described, an industrial-scale synthesis using acetone and bromo- or (better yet) chlorobenzene would make p2p production ridiculously cheap -- perhaps around 0.02USD/gram or less!

Think about it: perhaps the most expensive reagent would be thte alkali metal, and that's still cheap if you go through the right sources, or make your own.

The next step is of course to apply it to aromatically sustituted amphetamines. Which ampetamines would this method lend itself most to? From a purely economic standpoint, this method looks rather udesirable, but maybe I'm missing something. Any ideas?

Finally, in my pervasive efforts to "push the envelope", what about the use of other metals? Could Mg be used instead? Imagine: magnesium and IPA react to form Mg(OiPr)2, which when added to acetone, would readily react to form the desired enolate. With the desired enolate in hand, could one then react this with the halobenze to form p2p in yet an eaven cheaper and easier manner?

This is a little wierd, since we got essentially a magnesium salt reacting with a halobenzene -- if you're noggin is screwed on half-correctly, the first thing to come to mind should be the Grignard reaction. But is it rational to concern yourself with the possibility of some sort of Grignard side-reaction?

Looking at redox potentials, it looks like Mg should be readily oxidized from its metalic state by alcohols, but is anybody familiar with magnesium alkoxide formation? Perhaps just adding Mg to dry IPA, adding a little I2 will do the trick. By using this metal, we have several advantages:

1) Easier to work with. Mg turnings can more reasonably exposed to air than any alkali metal.

2) Cheaper. Old computer hardware, as well as automotive parts, are made of pure Mg -- this scrap material could readily be condorated, or used as is, for a fraction of what it costs to purchase.

3) More easily aquired. By havign one less reagent to purchase, you can worry that much less about your anonymity.

4) There was a fourth reason, but my brain isn't working, and I can't remember what it was.

-drone #342


drone 342
Member posted 09-20-98 05:17 PM †††  † ††
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In case anybody was wondering "just how would one go about making Magnesium alkoxides, anyways?", here you go. The first seven are articels regarding the synthesis of Magnesium ethoxide, while the subsequent articles detail the synthesis of Mg(OMe)2. Looking at the scant details provided, it looks like my hypothesized reaction involving I2 as a catalyst was right on the money.

Reaction Details 1 of 7

Reaction Classification Preparation
Reagent iodine
HgCl2
magnesium
Ref. 1 1386163; Journal; Villani; Nord; JACSAT; J.Amer.Chem.Soc.; 69; 1947; 2605;
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Reaction Details 2 of 7

Reaction Classification Preparation
Reagent iodine
xylene
magnesium
Ref. 1 1386183; Journal; Smith; Wiley; JACSAT; J.Amer.Chem.Soc.; 68; 1946; 889;
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Reaction Details 3 of 7

Reaction Classification Preparation
Temperature 100 ÝC
Other conditions Leiten ueber mit Jod aktiviertes Magnesiumpulver
Ref. 1 1386181; Journal; Terentjew; ZAACAB; Z.Anorg.Allg.Chem.; 162; 349; ZRKOAC; Zh.Russ.Fiz.-Khim.O-va; 60; 86;
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Reaction Details 4 of 7

Reaction Classification Preparation
Reagent magnesium amalgam
Ref. 1 1386179; Journal; Tissier; Grignard; COREAF; C.R.Hebd.Seances Acad.Sci.; 132; 836;
Ref. 2 1386176; Journal; Meunier; COREAF; C.R.Hebd.Seances Acad.Sci.; 134; 472;
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Reaction Details 5 of 7

Reaction Classification Preparation
Temperature 280 - 290 ÝC
Other conditions Leiten ueber Magnesiumpulver
Ref. 1 1386182; Journal; Terentjew; BSCFAS; Bull.Soc.Chim.Fr.; <4> 35; 1150;
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Reaction Details 6 of 7

Reaction Classification Preparation
Reagent xylene
mercury chloride
iodine
magnesium turnings
Ref. 1 1386180; Journal; Meerwein; Schmidt; JLACBF; Justus Liebigs Ann. Chem.; 444; 236;
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Reaction Details 7 of 7

Reaction Classification Preparation
Reagent iodine
Temperature 60 ÝC
Ref. 1 6044665; Journal; Lin, Ji-Mao; Li, Hui-Hui; Zhou, Ai-Min; TELEAY; Tetrahedron Lett.; EN; 37; 29; 1996; 5159-5160;

Reaction

Reaction ID 1603236
Reactant BRN 1098229 methanol
Product BRN 3552337 2CH3O*Mg
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Reaction Details 1 of 3

Reaction Classification Preparation
Reagent Mg
Catalyst I
Time 5 hour(s)
Temperature 64 ÝC
Ref. 1 5607748; Journal; Yamaguchi, Osamu; Kawabe, Katsuji; Shimizu, Kiyoshi; JCDTBI; J.Chem.Soc.Dalton Trans.; EN; 1983; 2139-2142;
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Reaction Details 2 of 3

Reaction Classification Preparation
Reagent Mg, I2
Other conditions Heating
Ref. 1 5751596; Journal; Staretz, Marianne E.; Hastie, Susan Bane; JMCMAR; J.Med.Chem.; EN; 36; 6; 1993; 758-764;
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Reaction Details 3 of 3

Reaction Classification Preparation
Reagent iodine
Temperature 60 ÝC
Ref. 1 6044665; Journal; Lin, Ji-Mao; Li, Hui-Hui; Zhou, Ai-Min; TELEAY; Tetrahedron Lett.; EN; 37; 29; 1996; 5159-5160;

Finally, I wanted to discuss the use of yet another, even cheaper metal: aluminum. Aluminum isopropoxide is a strong base, and is also easily produced (incidentally, it is a reducing reagent (org. react. 2, 178 (1944))) However, what sort of problems might one run into with this reagent? Anything particularily unusual regarding its chemical nature? Here's a ref on its synthesis:

Reaction

Reaction ID 742385
Reactant BRN 635639 propan-2-ol
Product BRN 3910275 propan-2-ol; aluminium-triisopropylate
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Reaction Details

Reaction Classification Chemical behaviour
Reagent aluminum
Catalyst AlCl3
Temperature 81.5 ÝC
Other conditions influence of acetone and other additives
Subject studied Kinetics
Ref. 1 5587650; Journal; Srebrodol'skii, Yu. I.; Knyazeva, E. N.; Pomytkin, A. P.; Boldog, I. I.; JAPUAW; J.Appl.Chem.USSR (Engl.Transl.); EN; 63; 11; 1990; 2310-2313; ZPKHAB; Zh.Prikl.Khim.(Leningrad); RU; 63; 11; 1990; 2497-2501;

-drone #342


drone 342
Member posted 09-20-98 05:55 PM †††  † ††
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Some further thoughts: most aluminum alkoxides won't work, since the resulting mess would undergo the Meerwin-Ponndorf-Verley reduction, yielding IPA, and acetone. Scratch this idea, and let's investigate further the possible uses of everybody's other favorite light-weight metal: magnesium. Any other ideas?

My "Bob"! This is too much to think about! Aside from the halobenzene, look at the possible "ingredients" to this "recipe": IPA, a mag wheel from a sportscar or fancy-shmancy bicycle, acetone, and a little DMSO as a solvent. Have I gone completely insane, or does this make sense to anybody? If this is as good as it sounds, I'm going to soil myself!

Think about it: true, Mg is a little leavier than Na, but having a valence of 2+ rather than just 1+ means even less has to be used. Since the pKa os the corresonding metal alkoxide is unaffected, gram-for-gram less is needed. After looking long and deep (about 30 sec.) into the possibility of a Grignard side reaction, I realize how impossible that would be. Tell me I'm dreamng!

-drone #342


drone 342
Member posted 10-07-98 02:50 PM †††  † ††
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Enolate phenylacetone synthesis FAQ, test version 1.0

by drone #342

So as to ensure that nobody thinks Iíve been shirking in my work here , I thought Iíd post some gleanings from the enolate literature I scanned in a couple weeks ago. I dedicate this FAQ to the lovely and delightfully lecivious Fraeulein, ms honey.

Phenylacetone is a nifty chemical; much sought after, but oh-so-elusive due to silly little societal restrictions. But enough political diatribing; letís get to the matters at hand -- how to make it out of acetone, and common chemicals.

There are a myriad of ingenious methods of making phenylacetone Ė some starting with phenylacetic acid, some with benzyl chloride, and dozens of others. This FAQ will concern itself with producing this lovely stuff from halobenzenes (i.e. chlorobenzene, bromobenzene, and iodobenzene), and acetone enolates Ė made by reacting acetone with a strong base.

I wonít go into the mechanisms and enolate chemistry too far, other than a general overview. Enolate chemistry is a fascinating field Ė much of it very cutting edge (though this ainít.) Generally, what we have here is a strong base (i.e. a base with a pKa higher than acetone, which is 23), reacting with acetone to form an enolate:


Me-(C=O)-Me + Base -> Me-(C-O-)=CH2 Na+
(acetone ) (sodium enolate of acetone)

This is a great nucleophile, and the actual reaction that makes the good stuff is a simple nucleophilic Sn1 Reaction, where the halide dissociates from the halobenzene, leaving it open for an attack by the enolate, which produces phenylacetone and a salt.

But hereís the other thing to take into consideration. The way that the halobenzene reacts is that the halogen has to come off first. This means that the better the halogen is at leaving, the faster everything goes. In DMSO, iodobenzene is about 6 times faster than bromobenzene(1), and no real study has been for chlorobenzene that Iíve found, though there have been studies using it in this type of reaction. Weíll just leave fluorobenzene alone.

Anyway, any college chemistry book will describe these things in much better detail and with a lot more clarity than I can right now (Iím in a hurry.) Now, letís get to business.

Phenylacetone from acetone enolate is a reaction thatís been very well covered, since its such a classic, simple Sn1 reaction to study. The reagents are cheap, and its all pretty straight forward. Because of this, a ton of variations have been investigated, and a lot have progress has been made. The kinetics are all well-studied, catalysts have been investigated, solvents, different halides, etc. This leaves us with a lot of good stuff to work with. Rather than re-invent the wheel, I decided Iíll do a review of the best articles, and include the relevant experimental sections. Enjoy; may you never sleep.

(1) JOC, 42, 8, 1977, 1449-1457

This is the one that started it all, essentially. The title was "Dark Reactions of Halobenzenes with Pinacolone Enolate Ion. Evidence for a thermally induced Aromatic Snr1 Reaction". In this reaction, they used various catalysts in different quantities to get this going a little faster. Typical procedures included 0.024 M PhI, 0.1 M enolate, and a catalyst like bubbling O2 or 0.0025 M Fe(NO3)3. Reactions were essentially done after an hour.

There are a few things of course to keep in mind here. Of course, acetone should be substituted in equimolar amounts wherever they use pinacolone. Everything should be anhydrous, and thatís mainly it.

"Dark Reaction of Halobenzene and Pinacolone Enolate in Me2SO. Typical Procedure. A. Potassium tert-butoxide (freshly sublimed) was placed into a 100-ml one-neck flask with a gas inlet side arm and short condenser. The flask and fittings were completely wrapped with opaque tape and all reactions were carried out in a nitrogen atmosphere. Dimethyl sulfoxide (50 ml) was added with a syringe through the condenser and after several minutes of stirring the apparatus was placed in a 25 *C thermostat bath. After equilibration the appropriate amounts (Table 1) of aryl halide and pinacolone were added and the flask was well swirled to mix the contents. At the desired time (Table 1), the solution was acidified with dilute nitric acid, 150 ml of water was added, and the mixture was extracted with three portions of ether. The combined ether fractions were washed with water and dried. In preparative runs, the ether was removed and the resulting product was purified by preparative GLC and distillation. In analysis runs, an internal standard was added and the ether solution was analyzed by GLC. The aqueous extracts were usually titrated for halide ion."

JOC 1983, 48, 3109-3112

The procedure they refer to by Bunnett, Scamehorn, and Traber is the procedure in JOC, 42, 8, 1977, 1449-1457 (see earlier in this FAQ.) Using the modifications they list for bromobenzene gives by far the most attractive conditions.


"Reaction of Acetone Enolate (1) and Iodobenzene (2). The procedure followed was similar to that described by Bunnett Scamehorn, and Traber.7 The deep-brown solution obtained by mixing acetone enolate (10 mmol) with iodobenzene (2.4 mmol) was irradiated for 1 h (3.8 h when filtered) with a focused high pressure mercury lamp. The reaction was quenched with 60 ml of water and extracted three times with ether. The organic layer was analyzed by GLC (5% SE30 on Chromosorb P. 130-230 įC at 4į/min, biphenyl internal standard). The major product isolated was phenylacetone (88%), although a number of unidentified minor products could be detected in trace quantity.

"Reaction of Acetone Enolate (1) and Bromobenzene (2). In a procedure similar to that described above, the enolate derived from 0.73 ml (10.0 mmol) of acetone was allowed to react with 0.25 ml (2.4 mmol) of bromobenzene. After irradiation of the bright yellow charge transfer complex with a high-pressure mercury lamp for 1.25 h (6 h filtered), the solution became orange. After workup as described above, phenylacetone was obtained in 94% yield."

JOC, 1984, 49, 4881-4883

ÖJust another example of the same reaction involving iodobenzene and acetone enolate in DMSO. Substitute acetone for pinacolone accordingly. Yields of the acetone are around 50% from iodobenzene.

"Reaction of Iodobenzene and Ketone Enolate in Me2SO. General Procedure. Me2SO (25 ml) was transferred by syringe into a N2-purged 100-mL 3-neck flask fitted with two stoppers and a closed-end 12-mm tube with a 60į bend. The flask and tube were wrapped with black opaque tape. Freshly sublimed potassium tert-butoxide (1.22 g, 0.010 mol) was added, and the tube was charged with 1.00 g (0.010 mol) of pinacolone and 0.51 g (0.0025 mol) of iodobenzene. Stirring was employed to dissolve the base, and the tube containing the ketone and PhI was cooled with a dry ice acetone bath The system was evacuated and filled with nitrogen. This procedure was repeated 3-8 times. After the freeze pump-thaw cycles were complete, the reactants were added to the flask by rotation of the bent tube. The solution was stirred and the flask placed in a 25 įC temperature bath. After 1 h, 6 N sulfuric acid (1.85 ml) was added. The solution was diluted with 50 ml of water and extracted 3x with ether. The combined ether extract was washed with water (3x) and dried (MgSO4), and an internal standard (phenylacetone) added for GLC analysis. The aqueous layers were combined and an aliquot was used for iodide analysis. For each ketone studied, the product from at least one reaction was isolated by preparative GLC or by column chromatography on silica gel, and the IR and NMR spectra were compared with those of authentic compounds. Four identical experiments carried out as above with iodobenzene and pinacolone gave yields (r) of 67.2%, 60.0%, 66.5%, and 68.1%."

JOC, 1984, 49, 3041-3042

Now this one is interesting for several reasons. First, the main point of research was finding catalysts to activate the halobenzene for nucleophilic attack. As it turns out, FeSO4 worked pretty well for reactions involving iodobenzene, and even involving chloroaniline (yield was 51%, though it undergoes an intramolecular reaction to form 2-methylindole, which was the chemical measured to determine yield), though mixed results were obtained with bromobenzene. Its important to note that results were best when ANHYDROUS FeSO4 was used.

The other interesting things was that they used ammonia as their solvent. Why? I guess they wanted to go with a classic, though DMSO is a lot nicer to deal with. Maybe they didnít want DMSO already seemingly catalytic effect interfering. Who knows? Anyway, here it is.

"Typical experimental procedure: Ammonia (60 ml) was distilled from sodium into a three-necked flask flushed with N2 and equipped with a cold-finger type condenser (with 2propanol and solid CO2 in the coolant well) and a serum cap. The glassware had been flamed in a stream of nitrogen. Under magnetic stirring,4.5 g of freshly sublimed t-BuOK and 300 mg of dried FeSO4 were added through paper funnels. The color of the solution became green-gray. Pinacolone (3.8 g) was added from a syringe and after few minutes also PhI (2.6 g) was added from a syringe This marked the beginning of the reaction. The flask was kept under magnetic stirring in a dark hood for 20 min. and then NH4NOS was added to quench the reaction. A rusty color developed; after evaporation of ammonia, water was added and the mixture was extracted with ether, washed with water and dried over Na2SO4. Removal of the solvent left a yellow liquid which was distilled (bp 98 įC at 2 mm Hg) to give 1.9 5 of colorless liquid 2 (85% yield)."

Well, thatís about it for now. Look for future FAQís, with more user-friendly directions than this one, as well as directions for producing your own home-made bromobenzene and iodobenzene from OTC materials. This ought to give you enough to gnaw on for a long while.

-drone #342