(Hive Bee)
12-22-03 11:04
No 478384
(Rated as: excellent)
High Bees!
SWIM had his first experience with P2P-synthesis out of aniline... The yield is something that has to be improved, but if we work together on this one it could develop to a very useful method!
Lego posted this procedure once before: Post 448826 (Lego: "P2Ps via Meerwein arylation Actually Lego was...", Methods Discourse)
Patent US5811586
Exampe 4: 1-(3-trifluoromethyl)phenyl-propan-2-one
220 ml of water and 180 g of 37% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10°C with an ice bath and then at 5°C, an aqueous solution containing 42.2 (0.612 moles) of sodium nitrite in 50 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added in 30 minutes to a mixture warmed at 40°C made by 800 ml of water, 280 ml of methanol, 1.50 g (0.015 moles) of cupric chloride, 49.2 g (1.200 moles) of anhydrous sodium acetate and 75.2 (0.751 moles) of isopropenyl acetate.
The reaction temperature goes up till a maximum value of 60°C, the reaction mixture is kept under stirring for further 30 minutes at this temperature and then is cooled to 20°C. 350 ml of heptane are added and the two layers are separated. The aqeuous layer is discarded while the organic layer is washed with water and concentrated under vacuum to remove the solvent. The obtained oil is distilled under vacuum at 10 mm Hg collecting the fraction that distills at 98°-102°C. 72 grams of pure ketone are obtained with a yield to 59.1% calculated on the starting m-trifluormethylaniline.
The reaction was performed on a 50% scale (based on the amounts of the above example).
Flask 1:
To a 500 ml One-Neck-Flask 100 ml tap water, 90 g (76 mol) conc. HCl and 28 ml aniline (brown coloured) were added.
- exothermic reaction, smoke formation
The mixture was cooled in an ice-water-bath, the smoke disappeared.
When the internal temperature has reached 4°C a cooled solution of 22.1 g NaNO2 in 40 ml tap water was added slowly via a pressured equalized addition funnel. During the addtion the mixture was stirred vigorously. The temperature was controlled carefully to hold in under 4-5°C.
Flask2:
2000 ml three-necked flask
400 ml tap water
140 ml MeOH
24.6 g anhydrous sodium acetate
41 ml isopropenyl acetate (forms two layers)
1.5 g Cu(I)-Cl (pretty old, greenish colour), 200%
Everything was mixed in the flask, and stirred. The mixture was heated to 40°C, and the aniline mixture (Flask 1) was added over 45 minutes (1-2 drops per second)
formation of red coloured reaction products. After finished addition the mixture was much clearer then during the addition of the diazonium salt solution.
After finished addition the flask was held at 60°C for further 30 min.
after cooling to RT the mixture was extracted with 3x75 ml of petroleum ether (b.p. 50-90°C), the pooled organic extracts were washed with 100 ml of water and evaporated under vacuo.
The first extract was analyzed by TLC (ethyl acetate:methanol, 4:1, Post 476488 (Rhodium: "Pd/C & NH4OAc Reductive Amination of P2P's", Methods Discourse)) and showed two spots. One sticking on the starting line and another one close to the front which had the same Rf-value as P2P from an authentic sample (473189)
The residue was distilled under aspirator vacuum (12mm Hg) to yield a fraction between 90°C-100°C, which was yellow in colour. - The weight of the fraction was 11g which is a ~25% yield calculated on the amount of aniline used.
Flask 1 - filled with smoke
Addition of the Sodium Nitrite solution
During the addition the solution became more orangish
Flask 1 after finished addition. Flask 2 is meanwhile heated to 40°C.
Addition of the diazonium salt solution to flask 2 caused a red reaction product to appear.
After finished addition - back to room temperature
Extraction with petrol ether.
Product in the receiver (boiling @ 95°C-100°C/12mm Hg)
Closeup. The top seems to be much more orange (like a 2 phase system), but the phases were miscible without problems.
The P2P seems to bee much darker than it usually is (compared to the sample that was prepared via PAA/AAA), but the TLC seems to be clean - 1 single spot with the same Rf-Value than the authentic sample. Refractive index of the product will be checked within the next 2 weeks.
Discussion & further changes:
- Substitute the MeOH with Acetone (cheaper, better available and non-toxic)
- usage of fresh CuCl
- decreasing the amounts of solvent for bigger batches.
- What does the darker colour of the P2P mean? Maybe only minimal impurities.
- there could be better methods for reaction workup. Steam distillation, followed by extraction or just extracting the ketone as the bisulfite addukt.
Conclusion:
This method for P2P-synthesis out of cheap & non watched chemicals seems to be working, and can be done within one afternoon. The yield wasnt to good at the 1st try (25%), but i´m sure that we can modify this synthesis to improve the yield. Would be nice if any other bees would like to work together on this topic.
Have fun & bee safe!
Xicori 
(Hive Bee)
12-22-03 18:57
No 478474
Just a suggestion- You may want to play with your TLC elution mixture, specifically decreasing the polarity of it to try to get your P2P spot more around an Rf of 0.5. I say this because with the current solvent polarity pushing the spots so high up (0.8-0.9 Rf) there could be impurities you aren't seeing because they are also being pushed up to such a high Rf. I'd suggest using a mixture of ethyl acetate and hexane, it allows you to control the polarity much more effectively then ethyl acetate and methanol.
But otherwise, hey! That's pretty cool!
-SpicyBrown
(Stranger)
12-22-03 20:07
No 478482
Interrresting,
I see now:
This reaction most likely can be applied to 2,5-Dimethoxyaniline too.
Which can be made by:
1. Mononitration of p-Dimethoxbenzene
Post 473658 (Lego: "Mononitration of 1,4-dimethoxybenzene", Chemistry Discourse)
2. Reduction of the nitrobenzene to the aniline w/ eg. SnCl2 (easiest)
Post 353135 (foxy2: "Aromatic nitro red. w. stannous chloride (SnCl2)", Novel Discourse)
Post 326270 (Cyrax: "Reduction of nitrobenzene", Chemistry Discourse)
or w/ any of the other methods
Yields are acceptable or moderate, but the procedures are simple, using easily available chemicals.
And the yield of the above reaction can surely be increased
!The writeup is really
, as usual, Xicori!
" Unorthodox cooking, illicit cooking. A bit of real science, in fact. "
(Hive Bee)
12-23-03 18:47
No 478691
(Rated as: excellent)
Great work, Xicori!
Your suggestions on further experiments sound good.
Just a few ideas:
1. The diazotation has to be carried out in a polar solvent, in our case water, but the isopropenyl acetate is not soluble in water. Therefore an organic solvent (MeOH or acetone) together with water is used as solvent for isopropenyl acetate. Isopropenyl acetate will not dissolve completely in this mixture but a PTC might work wonderful here.
2. Russian Journal of Organic Chemistry, 2000, 70(10), 1600-1602 (http://angelfire.lycos.com/scifi2/lego/
The pH of the reaction solution is very important. The best yields of the products were obtained in a weakly acidic medium (pH 3-4). To maintain the pH at a required level, solutions of the diazo compounds were partially neutralized before addtion. The mineral acid remaining in the solution and the acid released during the process were neutralized by periodically adding powdered calium carbonate. Raising the aciditiy to pH 2 sharply decreases the yields of products I and II and favors by-product formation (ArCl, tars, etc.).
Although they use phenylvinyl ether this might lead to a new modification. One could add any base to the diazotized solution to raise the pH to 3-4 and use a buffer system (e.g. sodium citrate and HCl) in the solution containing the isopropenyl acetate.
3. Use an organic solvent other than petrolether, e.g. toluene (might form an azeotrope with isopropenyl acetate) or ether for the extraction of P2P from the reaction mixture to avoid co-extraction of all this brown stuff.
Can CuCl2 be used in place of CuCl?
Yes, the Russian article uses CuCl2 (cupric chloride).
Patent US5811586 claims:
Process for manufacturing 1-(3-trifluoromethyl)phenyl-propan-2-one
intermediate in the synthesis of the anorexic drug fenfluramine. The process comprises reacting the diazonium salt of the 3-trifluoromethylaniline with isopropenyl acetate in a polar solvent in presence of catalytic amounts of a cuprous or cupric salt or of a mixture thereof and, optionally, of a base and purifying the raw product through bisulfite complex or distillation under vacuum.
The tendency is to push it as far as you can
(Stranger)
12-25-03 15:03
No 478974
Seems like getting CuCl is a problem for some guys.
It can be made by shaking a CuCl2 solution with copper powder.
Now copper powder can be made very simply by dissolving aluminium foil in an acidic solution of a copper salt, for instance CuSO4 plus HCl (the Cu(I)-salt may precipitate as an intermediate in this reaction) .
(Hive Bee)
12-25-03 16:05
No 478979
(Rated as: good read)
Copper(I) chloride is also produced hydrometallurgically by the reduction of copper(II) in the presence of chloride ions [71]
2 CuCl2 + Na2SO3 + H2O ---> 2 CuCl + Na2SO4 + 2 HCl :
Other reducing agents can be used, such as metallic copper, sulfurous acid, hydroxylamine, hydrazine, or phosphorous acid. The copper(I) chloride solution is produced, for example, by mixing a copper(II) chloride solution with metallic copper in the presence of hydrochloric acid or sodium chloride. The colorless to brown solution is stable only in the absence of air. Continuous preparations of copper(I) chloride solutions have been developed [72] , [73]. When they are diluted with water, a white crystalline material precipitates which can be vacuum dried or washed with sulfurous acid, then with alcohol and ether, and carefully dried. Zinc has also been used as a reducing agent in a more recent process [74].
Production of copper(I) chloride by treatment of ores with iron(III) chloride solutions [75] , [76] and recovery of the product through chlorination in pit furnaces above 800 °C [77] have also been attempted.
[71] R. Keller, H. Wycoff, Inorg. Synth. 2 (1946) 1 – 4.
[72] Schering, DE 1 080 088, 1958 (H. Niemann, K. Herrmann).
[73] Harshaw, US 2 367 153, 1945 (C. Swinehart).
[74] Goldschmidt, DE 3 305 545, 1983 (E. Mack, L. Witzke).
[75] Cyprus Metallurg., DE 2 607 299, 1976 (D. Goens, P. Kruesi).
[76] Cyprus Metallurg., US 3 972 711, 1976 (D. Goens, P. Kruesi).
[77] Metallgesellschaft, DE 1 174 996, 1963 (K. Meyer, H. Ransch, H. Pietsch); DE 1 180 946, 1963; DE 1 160 622, 1963.
roger2003
(Chief Bee)
12-27-03 15:21
No 479289
This reaction most likely can be applied to 2,5-Dimethoxyaniline too.
I must unfortunately disagree here. The Meerwein Arylation is unfortunately only really useful for electron-deficient aromatic substrates, with electron-donating groups the yield goes down. For further reference about yield trends see the article linked in Post 392827 (Rhodium: "Aniline to Allylbenzene by Diazotization (Diazall)", Methods Discourse)
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
12-28-03 16:52
No 479477
Your writeup with pics is a great contribution. I am guessing the big hurdle for some bees is going to be that isopropenyl acetate. I have checked the two megasuppliers that I know whom sell to non-businesses and they do not even have that chem listed in their inventory. I am sure it can be ordered, but unless someone has a !cheap! prep..(patents, journals maybe??) or a more common name/technical source it might be hard to pull this one off...
CW
<========>
(Ãóðó)
12-28-03 17:42
No 479481
(Rated as: excellent)
Prepn of phenyldiazonium tetrafluoroborates (Khimicheskie reaktivy i praparaty, Trydi IREA, issue 28, p. 199 (russian)) :
...6.9 g of o-nitroaniline (0.05 mol) was dissolved in 20 ml of ethylacetate. This solution was placed in beaker, cooled with ice bath, and then added 23 ml of 30% tetrafluoroboric acid. Keeping temperature near 3-7 C during 1 hour was added (in small portions) 3.6 g. of sodium nitrite, the end of reaction determined by presence of free nitrous acid (KJ-starh test). Then RM cooled to 2 C, precipitated diazonium salt filtered off, washed with ethylacetate and air-dried. Yield 11.4 g., 96%
Addition of phenyldiazonium teterafluoroborates to acrylates:
SYNLETT, May 1995, p. 441, First Heck Reactions of Aryldiazonium Salts using Heterogeneous Catalysts
General procedure for the synthesis of cinnamic acid esters: 30 mmol of the corresponding diazonium salt and 60 mmol of acrylic acid ester are suspended in 40 ml of the solvent. Subsequently, 0.6 mmol of palladium on activated charcoal (5% by weight) is added at 0°C. Then the reaction mixture is heated to 60°C in the course of 1 hour and stirred for 12 hours at this temperature. After cooling to room temperature, the catalyst is filtered off and washed with the solvent. The solvent is then evaporated in vacuo and the crude product is further purified by crystallisation or chromatography on SiO2.
Under catalyzed 5% Pd/C reaction of p-methoxyphenyldiazonium tetrafluoroborate with ethylacrylate in ethanol media - yield of ethyl p-methoxycinnamate is 98%.
(Chief Bee)
12-28-03 18:26
No 479496
Can you use isopropenyl acetate in heck arylations?
The Hive - Clandestine Chemists Without Borders
(Ãóðó)
12-28-03 21:37
No 479521
Can you use isopropenyl acetate in heck arylations?
Heck arylation is a relatively novel, flexible and high yelding route of Pd catalyzed addition fo phenyl radical to activated double bonds, oxirans and so on. What about isopropenyl acetate - such reactions currently not described, but possibly it may works, try it.
(Chief Bee)
12-28-03 22:34
No 479525
But if you didn't infer the use of isopropenyl acetate here, why did you bring up the topic of heck arylations in conjunction with P2P syntheses?
The Hive - Clandestine Chemists Without Borders
(Ãóðó)
12-29-03 18:35
No 479652
Rhodium,
But if you didn't infer the use of isopropenyl acetate here, why did you bring up the topic of heck arylations in conjunction with P2P syntheses?
try looking at this as reply to your phrase from this thread:
I must unfortunately disagree here. The Meerwein Arylation is unfortunately only really useful for electron-deficient aromatic substrates, with electron-donating groups the yield goes down.
It's very sad, that you can not understand my previous post. Well, I try to formulate one-sentence abstract: there is a simple and efficient alternative of Meerwein arylation, that works for electron-reach aromatic substrates with yields up to 98% .
Hope this helps.
(Chief Bee)
12-31-03 05:05
No 479892
Hmm... I see from your writings that you say that heck arylations has been performed with oxiranes - I have tried to make a literature search for "heck oxirane*" and "heck epoxide*" at the university, but to no avail. Would you say that one could perform a Heck arylation of an arenediazonium salt with propylene oxide (or maybe epichlorohydrin to give the ketone)? Do you have any general references for pd-catalyzed epoxide arylations?
Has 2-nitroethene or 2-nitro-2-propene been used as the alkene in any heck arylations?
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
01-06-04 16:15
No 480749
High Bees!
Swim ran again a TLC on the reaction product, together with the P2P from Post 473189 (Xicori: "P2P-Success! (Phenylacetic acid/AA/NaAc)", Stimulants), and the suspected oxime from Post 480140 (Xicori: "P2P Oxime Questions", Newbee Forum), but the results are a bit strange and swim isnt sure anymore that he got (pure) P2P in the Meerwein arylation
1a and 3a seem to be the same substances (something very polar?!). But WTF could this be? Anilin.HCl is nearly impossible because the organic extracts were successively washed with water. - Any Ideas?
1b/2a seems to be the P2P (?), but 2b an 2c makes swim wonder - the ketone was carefully distilled with a vigreux column, so what could these impurities be?
3b i suspect to be the P2P-Oxime - and the impurities in the P2P avoiding the stuff to crystallise...
SWIM is more or less a newbee on the topic of TLC so any help would be greatly appreceated!
The plates were developed with iodine vapour. Swim was to lazy to dilute the substances proper so they were applied pure (but only very tiny spots). - I know this isnt the best praxis, i´ll dilute them next time
Can the size of the spot be compared with the amount of the substance present in the sample?
Many thanks, and best wishes to all the bees out there
xicori
(Chief Bee)
01-06-04 23:03
No 480803
1b/2a seems to be the P2P (?), but 2b an 2c makes swim wonder - the ketone was carefully distilled with a vigreux column, so what could these impurities be?
A very well-known impurity in P2P made from PAA/AA is Dibenzyl Ketone (../rhodium /p2p.di
And as that substance is less polar than P2P itself (bigger molecule, but the same number of polar carbonyls), it fits very well with the fact that you have your 'mystery spot' at a higher Rf.
Can the size of the spot be compared with the amount of the substance present in the sample?
Not very exact with the naked eye, but with a little technology it goes pretty well:
[green]Quantitative and Qualitative TLC Analysis of 5-MeO-DMT
By Clear Light and Desert Sun
We are reporting here our method for qualitative and quantitative analysis of the titled compounds using prior hive posts in addition to a unique photometric method for quantitative analysis of UV and visualized chromophores.
Full Report: ../rhodium/pdf /5-meo-dmt.qua
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
01-07-04 02:31
No 480830
Thanks for the response, Rhodium!
Dibenzylketone was my first thought too, but Dibenzylketone boils at ~320°C, while P2P boils about 100°C lower..
So is it possible that so much Dibenzylketone was carried over at the distillation (a 30cm vigreux column was used) to give such a big spot on the TLC plate? Maybe there is some azeotrope formation between P2P/Dibenzylketone?
Swim will try the Meerwein reaction once more the next days, using Acetone instead of Methanole and purification via the bisulfite adduct. - hopefully this will give one single spot on the TLC plate then
What do you think about the spots 1a and 3a? What polar impurities could be present in the product? - any ideas?
so long,
xicori
(Newbee)
01-07-04 11:34
No 480892
Swim will try the Meerwein reaction once more the next days, using Acetone instead of Methanole
I would avoid using acetone as a solvent in the presence of diazonium salts as they are somewhat electrophilic and tend to substitute the acidic protons alpha to the carbonyls producing alpha-carbonyl-arylhidrazone compounds.
(This reaction can actually be performed very efficiently with betta-dicarbonyl compounds as they have a more acidic methylene group and is called the Japp-Klingemann reaction – as an example, it can be useful for the: Synthesis of 5-substituted indole derivatives, part II. Synthesis of sumatriptan through the Japp-Klingemann reaction. Heterocycles, 53 (2000), 665-673.)
Maybe you can just try with isopropanol or ethanol if you suspect methanol to be inappropriate.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
01-07-04 19:05
No 480937
(Rated as: good read)
Patent US4604243
Abstract: An olefin, especially an activated olefin, is arylated by reaction with an arylamine, such as an aniline, in an inert polar organic solvent and in the presence of an alkyl nitrite, a hydrogen halide, and a catalytic amount of a copper catalyst having the copper in an oxidation state below +2.
[...]
Exemplary of the arylamines that can be used are aniline, 4-methoxyaniline, 3,4-dimethoxyaniline, 3,4,5-trimethoxyaniline, 4-(2-methyl-2-phenylpropyloxy)aniline, 4-nitroaniline, 4-acetylaniline, 4-chloroaniline, 2,4-dichloroaniline, 4-methylaniline, p-phenyldiamine, benzidine, p-aminobiphenyl, 3-aminoquinoline, 5-nitro-2-aminothiazole, aminonaphthalene, etc.
[...]
Olefins utilizable in the process are also generally descriable as those already known to be capable of being used in Meerwein-type arylation reactions. Such olefins incluce simple alkenes, such as ethylene, but are preferably activated olefins, i.e., olefins wherein the ethylenic bond is activated by being attached to an electro-withdrawing group, such as carbonyl, cyano, halo, aryl, vinyl, etc.
Here we go!
Although they use a huge excess of olefine (13-19 times more olefine than aniline!) they proved the synthetic possibility of this reaction for the synthesis of amphetamine precursors.
The tendency is to push it as far as you can
(Official Hive Translator)
01-08-04 03:52
No 481040
Patent US2622078 states that adding acetone during diazotization helps greatly in reducing the number of byproducts etc etc.
They use ~1:1 - 2:1 water:acetone system on subst. aminosulfonic acids, but they say that much higher concentrations can bee used, although it may present difficulties since their starting materials are not very NP-soluble.
In the end of their procedures they add more acetone to crush out the product diazonium salt.
Antoncho
(Official Hive Translator)
01-08-04 04:00
No 481043
Patent US4604243
Abstract: An olefin, especially an activated olefin, is arylated by reaction with an arylamine, such as an aniline, in an inert polar organic solvent and in the presence of an alkyl nitrite, a hydrogen halide, and a catalytic amount of a copper catalyst having the copper in an oxidation state below +2.
Alas, if you look into the examples, you'll find out that only for the electron-poor nuclei did they get decent yields
In case of 3,4-diMeO- the yield was in ~30% range.
If a patent says that something is a 'suitable' substrate, it usually means nothing to bee sure of.
Antoncho
(Hive Bee)
01-12-04 23:15
No 482074
(Rated as: excellent)
Organic Reactions, 1976, 24, 225-259 (http://lego.chemistry.tripod.com/Journa
The Meerwein arylation reaction
Introduction
The arylation of unsaturated compounds by diazonium salts with copper salt catalysis was first disclosed by Hans Meerwein1,2. Meerwein arylation proceeds best when the double bond is activated by an electron attracting group Z, such as carbonyl, cyano, aryl, vinyl, ethynyl, or chloro. The net result is the union of the aryl group with the carbon atom beta to the activating group, either by substitution of a beta-hydrogen atom or by addition of Ar and Cl to the double bond.
ArN2Cl + RCH=CRZ --Copper salt---> ArCR=CRZ and/or ArCHRC(R)ClZ
The generally accepted mechanism of the reaction involves the aryl radical Ar• from the diazonium salt, though the manner of its formation and its subsequent reaction is still controversial.
[...]
Mechanism
The Meerwein arylation is one example of the very general group of redox-modulated radical addtions to olefins5. A cationic mechanism advocated at one time is no longer accepted3. A simplified mechanism accounts for the main features of the reaction.
(1) 2CuCl2 + CH3COCH3 (solvent) --> 2CuCl + HCl + ClCH2COCH3
(2) ArN2Cl + CuCl --> ArN2• --> Ar• + N2 + CuCl2
(3) Ar• + CH2CHZ --> ArCH2CH(Z)•†
(4) ArCH2CH(Z)• + CuCl2 --> ArCH2CH(Z)Cl + CuCl
--> ArCH=CHZ + CuCl + HCl
(5) Ar• + CuCl2 --> ArCl + CuCl (Sandmeyer)
(6) Ar• + CH3COCH3 --> ArH + • CH2COCH3 + products containing the acetonyl group, including ArCH2COCH3‡
† The radical ArCH2CHZ• has been detected by electron spin resonance (esr) spectroscopy in mixtures of ArN2BF4 and CH2=CHZ after reduction by a one-electron reducing agent.6
‡ The reported ArCH2COCH3 may arise through addition to a low equilibrium concentration of acetone enol7,8.
As noted by the underlining above, chloroacetone, ArCl, and ArH are by-products always encountered in Meerwein arylations. Indeed, the chief challenge in improving yields is minimization of the competitive side reactions leading to these products.
Meerwein's classical conditions involve aqueous acetone solvent and cupric chloride catalyst. Reduction of cupric chlorid to cuprous chloride by acetone is well established. Most authors therefore ascribe the initiating step to a one-electron reduction of the diazonium salt by cuprous chloride. This may be correct in many cases, but it cannot be so in useful solvents that do not reduce cupric chloride, such as water, acetonitrile, N-methylpyrrolidone, or sulfolane3. Moreover, numerous papers mention that cupric chloride is effective and cuprous chloride is not, for certain systems.
[...]
The influence of pH on yield was frequently been noted but never explained; for example, in some work, most diazonium salts give best results at pH 3-4, whereas bisdiazonium salts (e.g. from benzidine) and p-nitrobenzenediazonium salts give best results near pH 1.
It seems likely that the Meerwein arylation is really a group of reactions governed by several related mechanisms, not just one.
Scope and Limitations
The Unsaturated Component
Enol esters and enol ethers react normally; their arylation affords an indirect method of arylating aldehydes and ketones on the alpha-carbon atom.
RCOCH3 --> R'OCR=CH2 --ArN2X--> R'OCRXCH2Ar --> ArCOCH2Ar
R' = alkyl, acyl
Unsaturated sulfonic acids, sulfones, and phosphonate esters give the expected products. The CH=N bond in aldoximes3 or aldehyde phenylhydrazones19,20 is arylated without copper by replacement of the aldehyde hydrogen. However, enamines undergo azo coupling at the alpha-position21. Heterocyclic N-oxides are ring-arylated22,23. Unsaturated phosphorous compounds, R3P=CR2, have not been evaluated and would make an interesting study.
[...]
Side reactions
A recent study with p-chlorobenzenediazonium chloride and five diverse oleinfe14,24 showed that the best yield of Meerwein product was obtained with low cupric ion concentrations. The major side prodcut under these conditions was ArH, while at higher cupric ion concentrations the Sandmeyer product ArCl became more prominent. These conclusions may not apply with other diazonium salts, however. ArH formation is usually described to hydrogen abstraction from a reactive C-H bond (as in acetone)46, but it has also been ascribed to reduction of diazonium ion by cuprous ion25. To phrase it differently, diazonium ion is an oxidizing agent and so ensures that the concentration of cuprous ion does not exceed a certain low steady state.
"Diazo resins" frequently accompany the Meerwein product, especially at more alkaline pH. It has been shown repeatedly that most diazonium salts function best (give higher yields) at pH 3-5, whereas nitro-substituted and bisdiazonium salts function best at pH 1-247-49. This effect may be related to foreign anions. It should be noted that the neutralisation of the strongly acidic diazotization solution with sodium bicarbonate or calcium oxide usually affords higher yields. This result is in contrast with the sodium acetate of the classical Meerwein conditions.
[...]
Under standard Meerwein conditions, with diazonium salt and olefin present in equimolar quantities, telomerization seems to be insignificant.
ArN2Cl + CH2=CHZ (excess) --> ArCH2CHZCl + Ar(CH2CHZ)nCl
Copper-promoted diazonium salts may initiate acrylonitrile polymerization, especially in the absence of chloride ion50.
[...]
Synthetic applications of the Meerwein arylation
The adducts of vinyl chloride (ArCH2CHCl2) yield arylacetaldehydes on hydrolysis65-66, the vinyl acetate adducts ArCH2CHClOAc are more readily hydrolyzed to the same aldehydes67. Similarly, the adducts from vinylidene chloride (ArCH2Cl3) yield arylacetic acids68.
The adducts from acryl acids derivatives (ArCH2CHClZ) have been aminated to an extensive series of ring-substituted phenylalanines ArCH2CH(NH2)CO2H after transformation of group Z to a carboxyl group69-77.
Experimental conditions
No extensive research has been directed toward greater convenience and yields. Perhaps the most rapid progress will come from an understanding of the effect of pH and of buffer constituents on the reaction. Acetate ion, commonly used in the earlier studies3, may function as a ligand to copper and thus modify its properties.
The concentration of chloride and other anion is another parameter, Meerwein products have been obtained from diazonium acetates, fluroborates, sulfates, and nitrates, in the absence of halides, though the yields are lower than for the corresponding reactions in the presence of halide3,18,67 On the other hand, addition of extra chloride ion may improve the yield; p-CH3C6H4CH2CHClCN was prepared in 56% yield by the standard Meerwein conditions, but in 89% yield on addition of an extra mole of chloride ion78.
Low yields are usually attributable to copper-catalyzed side reactions that consume aryl radicals. Reduced copper concentrations tend to favor Meerwein arylation over the Sandmeyer reaction and hydrogen abstraction14,21. Since ArH is probably formed by the reaction of Ar• with a readily abstracted hydrogen atom, solvents like ethers and alcohols with the grouping H-C-O are unsuitable for Meerwein arylation. Despite the ease of hydrogen abstraction from acetone, most workers persist in using it because of availability, convenience, cost, and tradition. To the list of alternative solvents such as acetonitrile, N-methylpyrrolidone,71, dimethyl sulfoxide, and sulfolane3, one might add formamide, whose use hat not been yet reported. gamme-Butyrolactone was suggested previously3 but proved not to be useful71. Acetic acid improves yields, according to one report79.
Substantially all research on the Meerwein arylation has been employed deliberately homogenous solutions. A proposed two-phase system has not been tried3. A new field of study is suggested by the recent understanding of reactions in micelles and reactions with phase-transfer catalysts80. Readers are reminded that emulsion polymerization is an extremly important (and successful) reaction in which radicals generated in an aqueous phase react in high yields in a micelle. Polymerization during a Meerwein arylation is controllable by the chain-transfer abilities of copper derivatives.
No alternative to copper salts has been demonstrated to be widely applicable, though ferrous iron is sometimes effective3,67. Yet important side reactions are also associated with copper ions. Perhaps the desirable properties of copper could be seperated from the undesirable by addtion of a suitable ligand (compare Ref. 37), but those which complex too tightly to copper destroy the catalytic activity3,10,25. Recent work with organocopper ligands and the influence of copper on other organic reactions15,46. may suggest appropriate candidates. Alternative to copper many be nonmetallic reagents which reduce diazonium salts; tetraphenylethylene and hydroquinone are two possibilities already mentioned.
CAVEAT: It is highly probable that the various experimental condtions are not truly independent, but rather are linked. Thus a change in pH will probably change the ionic/covalent proportion of the diazonium salt. Adjustment of pH is frequently accomplished with foreign anions, e.g. acetate, which may function as ligands for copper. A change in solvent will change the dielectric constant and solvating power of the medium and the activities of ions. Thus arylation does not proceed in dry acetone, but in commences when water is added25. The experimenter will therefore save time by applying the principles of statistical design of experiments*. The approach in which all variables, but one are held constant almost certainly will not lead to optimization of a procedure.
Tabular survey of the Meerwein arylation reaction
| Unsaturated compound | Product(s) and Yield(s) (%) | Refs. |
| CH2=CHOAc | AcOCHClCH2C6H4X-p X = H (51) X = Cl (53) X = NO2 (41) X = OCH3 (30) X = CH3 (44) |
67 |
References
1. J. Prakt. Chem. [2] 152, 239 (1939)
2. Angew. Chem., Int. Ed. Engl., 5, 333 (1966)
3. Org. Reactions, 11, 189 (1960)
[...]
5. Accts. Chem. Res., 8, 165, (1975); Adv. Heterocyl. Chem., 16, 123 (1974)
6. J. Chem. Soc., Perkin II, 1973, 2134
7. Bull. Soc. Chim. France, 1972, 1921
8. Bull. Soc. Chim. France, 1972, 1926 (http://angelfire.lycos.com/scifi2/lego/
[...]
14. J. Org. Chem., 34, 710 (1969)
15. J. Amer. Chem. Soc., 96, 7753 (1974)
[...]
18. J. Org. Chem. USSR, 9, 2157 (1973) [C.A., 80, 36809m (1974)]
19. Angew. Chem., 67, 705 (1955)
20. Ann., 611, 108 (1958)
21. Enamines, Dekker, New York, 1969, pp. 158-160; 414-415. See also J. Org. Chem. USSR, 1, 882 (1965) [C.A., 63, 2928g, 6893h (1965)]
22. Itsuu Kenkyosho Nempo, 1971, 25 [C.A., 77, 61765g (1972)]
23. Atti Accad. Naz. Lincci, Rend., Cl. Sci. Fis., Max. Nat., 26, 39 (1959) [C.A., 53, 21929e (1959)].
24. J. Org. Chem., 34, 714 (1969)
25. J. Gen. Chem. USSR, 31, 1191 (1951) [C.A., 55, 23387d (1961)]. See also Ref. 27.
[...]
27. Ukr. Khim. Zh., 24, 217 (1958) [C.A., 52, 18271e (1958)]
[...]
45. J. Gen. Chem. USSR, 34, 3393 (1964) [C.A., 62, 3958f (1965)]
46. Tetrahedron Lett., 1975, 143; J. Org. Chem., 38, 1126 (1973); Adv. Organomet. Chem., 12, 215 (1974)
47. J. Gen. Chem. USSR, 31, 1774 (1961) [C.A., 55, 24675e (1961)]
48. J. Gen. Chem. USSR, 32, 592 (1962) [C.A., 58, 1383e (1963)]
49. J. Org. Chem. USSR, 1, 2034 (1965) [C.A., 64, 9617a (1966)]
50. Ko Fen Tsu T'ung Hsun, 7, 79 (1965) [C.A., 64, 3691e (1966)]
[...]
65. J. Gen. Chem. USSR, 31, 3391 (1964) [C.A. 62, 3958e (1965)]
66. J. Org. Chem. USSR, 1, 1395 (1965) [C.A., 64, 721a (1966)]
67. J. Org. Chem. USSR, 8, 2216 (1972) [C.A., 78, 42962f (1973)]
68. J. Gen. Chem. USSR, 32, 1256 (1962) [C.A., 58, 1383g (1963)]
69. J. Gen. Chem., USSR, 28, 226 (1958) [C.A., 52, 1279l (1958)]
70. Chem. Ind. (London), 1960, 468
71. Proc. Chem. Soc., 1962, 117
72. J. Org. Chem., 26, 2707 (1961)
73. J. Org. Chem., 27, 4460 (1962)
74. Nature, 205, 1165 (1965)
75. Can. J. Chem., 45, 329 (1967)
76. J. Org. Chem., 26, 3362 (1961)
77. J. Org. Chem., 34, 744 (1969)
78. Jap. Kokai, 73, 67, 236 [C.A., 80, 3280d (1974)]
79. Ger. Offen, 2,016, 809 (Oct. 29, 1970) [C.A., 74, 42117d (1971)]; Belg. Pat. 741,640 [C.A., 74, 76154b (1971)]
80. Angew. Chem., Int. Ed. Engl., 13, 170 (1974); Accts. Chem. Res., 2, 329 (1969)
The candle that burns twice as bright burns half as long
(Official Hive Translator)
01-13-04 05:49
No 482117
A very good article, Lego! Thank you!
Don't you find it strange that there's no mention of electrophyllicity of the aryl diazonium counterpart as the important parameter?
Another thing i'd like to notice (and, more specifically, ask Xicori if he ever smelled this
):As noted by the underlining above, chloroacetone,... are by-products always encountered in Meerwein arylations.
Does this side-rxn happen to a great extent?
Also, form this article can bee unquestionably inferred that acetone should bee the prefered solvent:
Since ArH is probably formed by the reaction of Ar• with a readily abstracted hydrogen atom, solvents like ethers and alcohols with the grouping H-C-O are unsuitable for Meerwein arylation. Despite the ease of hydrogen abstraction from acetone, most workers persist in using it because of availability, convenience, cost, and tradition.
(Hive Bee)
01-15-04 01:37
No 482454
@Antoncho:
Thanks for the support!
Chloroacetone is only formed under classical Meerwein conditions, i.e. with acetone/H2O as solvent, therefore it is very unlikely that chloroacetone was a byproduct in Xicori's reaction.
Don't you find it strange that there's no mention of electrophyllicity of the aryl diazonium counterpart as the important parameter?
Yes, but unfortunately the article is too old to send the author an email and ask him
@Nicodem:
You are absolutely right (concerning the side-reaction of acetone) in theory, as the author is right to state that alcohols are not suitable solvents, but in practice both solvents seem to work.
@Xicori:
Repeating this reaction is an excellent idea. But Lego would like to suggest one or two things:
For your second run change nothing than the solvent (acetone instead of methanol). In the first reaction twice the amount (compared to the patent) of CuCl was used and the pH was not adjusted. The review claims that low concentrations of copper reduce side-reactions (Sandmeyer, etc.) but if two reaction parameters are changed it is not possible to say what reaction parameter influenced the yield. The next time the reaction is performed
one could either buffer the solution or use CuCl2 and so on, as long as the Hive's community has found the ideal reaction parameters.Your old CuCl was much better for the reaction than new one
.Chloroacetone is formed as a by-product if acetone is used as solvent but as a mixture with water. Chloroacetone is miscible with water and its boiling point is 119°C, so nobee has to bee afraid of evaporating chloroacetone but one should bee carefull nonetheless.
Phase transfer catalysis: Hm, Lego's idea was not that new, the author suggested it 30 years ago
. But there is one thing to mention: in this reaction there is water soluble cation (phenyldiazonium) which should react with a non-polar molecule (isopropenyl acetate). If one of the standard PTCs (any quaternary ammonium compound like a tetrabutylammonium salt or benzenetriooctyl ammonium chloride) not the phenyldiazonium cation but the counter anion (chloride) is soluble in the organic phase. Therefore an anionic phase transfer catalyst has to bee used. Sodium dodecylbenzenesulfonate is used as PTC for preparation of azo dyes in the reaction of phenyldiazonium tetrafluoroborates. As this PTC is well established in diazonium chemistry it might bee a good point to start from. Another interesting PTC are poly(ethylenglycol)s, especially PEG 400, which is non-ionic.The Meerwein arylation might bee interesting not only for plain P2P but also for substituted ones. One could start from 2,5-dibromoaniline (25 g ~ 100$) to get 2,5-dibromo-P2P or 2,5-dibromo-phenylacetaldehyde, then methoxylate and reduce to get 2,5-DMA or 2C-H. Another possiblity is to use 4-chloroaniline (100 g ~ 10$) to get 4-chloro-P2P which is reacted sodium methanethiolate to get 4-methylthio-P2P which is an excellent precursor for the interesting compound MTA. You want mescaline or TMA? Meerwein arylation with 4-methoxyaniline aka p-anisidine (250 g ~ 45$), dibrominate and get 3,5-dibromo-4-methoxy-P2P, then a methoxylation and a reductive amination to get your desired compound.
The candle that burns twice as bright burns half as long
(Chief Bee)
01-15-04 03:36
No 482467
You cannot methoxylate halo-substituted P2P's, as the basic conditions would be too harsh on the ketone function. It would have to be protected: Post 482354 (Rhodium: "Ketone ketal protection", Newbee Forum)
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
01-20-04 22:57
No 483611
(Rated as: excellent)
Russian Journal of Organic Chemistry, Vol. 38, No. 1, 2002, pp. 38-46 (http://lego.chemistry.tripod.com/Journa
Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 1, 2002, pp. 47-55.
Modified Versions of the Meerwein and Sandmeyer Reactions
N. D. Obushak, M. B. Lyakhovich, and E. E. Bilaya
Ivan Franko Lviv National University, ul. Universitetskaya 1, Lviv, 79000 Ukraine
Abstract: Chloroarylation of unsaturated compounds with arenediazonium chlorides in the presence of CuCl2 as catalyst involves intermediate formation of arenediazonium tetrachlorocuprates(II) [ArN2+]2 CuCl4 2-.
A procedure for preparative isolation of these intermediates was developed, and they were shown to be efficient arylating agents. Reactions of [ArN2+]2 CuCl4 2- with unsaturated compounds gave the corresponding Meerwein products; a mechanism was proposed for these reactions. In polar solvents arenediazonium tetrachlorocuprates(II) are converted into chloroarenes, presumably through a cyclic transition state.
[...]
I-III, V, Ar = Ph (a), 3-MeC6H4 (b), 4-MeC6H4 (c), 2-MeOC6H4 (d), 4-MeOC6H4 (e), 3-BrC6H4 (f), 4-BrC6H4 (g), 2,4-Cl2C6H3 (h), 2,5-Cl2C6H3 (i); IV, Ar = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c).
Table 1. Yields, decomposition points, and v(N=N) frequencies of arenediazonium tetrahalocuprates(II) IIIa-IIIi and IVa-IVc
| Compound no. | Yield (%) | Decomposition point, °C | v(N=N), cm-1 |
| IIIa | 83 | 86-87 | 2268 |
| IIIb | 88 | 92-93 | 2251 |
| IIIc | 93 | 100-101 | 2244 |
| IIId | 91 | 121-122a | 2244 |
| IIIe | 97 | 126-127 | 2236 |
| IIIf | 84 | 121-122 | 2253 |
| IIIg | 94 | 117-118 | 2246 |
| IIIh | 79 | 109-110 | 2242 |
| IIIi | 81 | 103-104 | 2254 |
| IVa | 26 | 70-71 | 2262 |
| IVb | 58 | 75-76 | 2240 |
| IVc | 50 | 82-83 | 2235 |
Table 3. Yields of alkyl 3-aryl-2-chloropropionates VIIa-VIIi and 3-aryl-2-chloropropionitriles VIIj-VIIn
| Comp. no | Ar | R | R' | Yield (%) |
| VIIa | 3-MeC6H4 | H | CO2Me | 41 |
| VIIb | 4-MeC6H4 | H | CO2Me | 56 |
| VIIc | 2-MeOC6H4 | H | CO2Me | 42 |
| VIId | 4-MeOC6H4 | H | CO2Me | 70 |
| VIIe | 2,5-Cl2C6H3 | H | CO2Me | 69 |
| VIIf | 2-MeOC6H4 | H | CO2Me | 44 |
| VIIg | 3-MeC6H4 | H | CO2Me | 42 |
| VIIh | 4-MeC6H4 | Me | CO2Me | 59 |
| VIIi | 4-MeOC6H4 | Me | CO2Me | 60 |
| VIIj | 3-MeC6H4 | H | CN | 42 |
| VIIk | 4-MeC6H4 | H | CN | 72 |
| VIIl | 2-MeOC6H4 | H | CN | 40 |
| VIIm | 2,5-Cl2C6H3 | H | CN | 66 |
| VIIn | 4-BrC6H4 | H | CN | 61 |
[...]
Experimental
Arenediazonium tetrachlorocuprates IIIa-IIIi.
Arenediazonium chlorides I-Ii were obtained by diazotization of 0.1 mol of the corresponing amines, following a standard procedure (HCl, NaNO2). A solution of 81.1 g of FeCl3 · 6H2O in a minimal amount of water was added to a solution of diazonium salt Ia-Ii in water at 35°C.
a. Concentrated hydrochloric acid was added dropwise with stirring at 0-5°C to a solution of IIa-IIi (see above). Salts III-IIIi quantitatively precipitated from the solution.
b. A solution of 5.6 g of CuCl2 · 2H2O in 75 ml of ethanol and 5 ml of concentrated hydrochloric acid was added at 0°C to a solution of 65 mmol of salt IIa-IIi in 100 ml of acetone. The precipitate of salt IIIa-IIIi was filtered off, washed with diethyl ether, and dried in air. An additional amount of IIIa-IIIi was precipitated from the filtrate by adding 150 ml of diethyl ether.
[...]
Reactions of arenediazonium tetrachlorocuprates(II) IIIa-IIIi with unsaturated compounds.
Salt IIIa-IIIi, 40 mmol, was added in portions over a period of 1 h to a mixture of 0.1 mol of unsaturated compound, 40 ml of acetone, and 40 ml of water, while stirring at 20-25°C. The mixture was kept until nitrogen no longer evolved (~2.5 h), diluted with 100 ml of water, and extracted with diethyl ether. The extract was dried over MgSO4 and evaporated, and the residue was distilled under reduced pressure to isolate compounds VIIa-VIIn.
The tendency is to push it as far as you can
(Hive Bee)
02-06-04 16:59
No 486901
High Bees!
The reaction was tried out once more, but this time acetone instead of methanole was used.
During the addition of the diazonium salt the solution turned a deep black, and also a very bad smell was noticed. The intense black colour made it nearly impossible to seperate the layers using DCM, bacause both layers had the same colour.
A lot of (acidic) gasses envolved during the reaction, so a gas trap filled with NaOH-Solution was used to protect the chemist
After workup a lot of unreacted isopropenyl acetate & a lot of black tar was recovered
This seems to make methanole the one and only choice for this reaction, because with methanole the reaction ran very clear.
The distilled product from the reaction must(!) be further purified via the bisulfite adduct, because there seems to be a lot of phenole contaminating the final product (phenole´s boiling point is close to the boiling point of p2p).
best wishes,
xicori