dormouse (Member) 04-19-00 11:45 No 122752 |
what happened to my enolate review?! -drone 342 (Rated as: excellent) |
Bookmark | ||||||
Author Topic: what happened to my enolate review?! drone 342 Member posted 09-14-98 06:44 PM ---------------------------------------- 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 --------- 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 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 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 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 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 Reaction Details 1 of 7 Reaction Classification Preparation Reaction Details 2 of 7 Reaction Classification Preparation Reaction Details 3 of 7 Reaction Classification Preparation Reaction Details 4 of 7 Reaction Classification Preparation Reaction Details 5 of 7 Reaction Classification Preparation Reaction Details 6 of 7 Reaction Classification Preparation Reaction Details 7 of 7 Reaction Classification Preparation Reaction Reaction ID 1603236 Reaction Details 1 of 3 Reaction Classification Preparation Reaction Details 2 of 3 Reaction Classification Preparation Reaction Details 3 of 3 Reaction Classification Preparation 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 Reaction Details Reaction Classification Chemical behaviour -drone #342 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 by drone #342 So as to ensure that nobody thinks I’ve been shirking in my work here , I thought I’d 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; let’s 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 – 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 – made by reacting acetone with a strong base. I won’t go into the mechanisms and enolate chemistry too far, other than a general overview. Enolate chemistry is a fascinating field – much of it very cutting edge (though this ain’t.) 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: 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 here’s 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 I’ve found, though there have been studies using it in this type of reaction. We’ll 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 (I’m in a hurry.) Now, let’s get to business. Phenylacetone from acetone enolate is a reaction that’s 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 I’ll 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 that’s 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 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 …Just 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 60° 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 °C 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 didn’t 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 °C at 2 mm Hg) to give 1.9 5 of colorless liquid 2 (85% yield)." Well, that’s about it for now. Look for future FAQ’s, 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 |
||||||||