08-24-03 10:01
No 455373
In my dreams, when I had a sep-funnel, I'd make phenyl-magnesium bromide or another Grignard reagent by slowly dripping p-bromoanisole, bromobenzene, etc. into THF/Mg. What about adding all of the bromobenzene to the THF, then slowly add the Mg? Maybe I could add a little ethyl iodide and iodine catalysts to the THF and bromobenzene(or p-bromoanisole)?
Love my country, fear my government.
(Hive Bee)
08-24-03 12:31
No 455391
..because:
- an excess of Mg must be maintained, otherwise you will get a lot of biphenyl from Wurtz-like coupling
- each and every portion of your Mg turnings have to be pre-activated to keep the reaction running, I think the addition of iodine to your bromobenzene/THF mixure won't help that much
- it is very unlikely that you can keep your Mg turnings dry and clean (no oxidised surface) during the addition without working under inert atmosphere in a closed apparatus, equipped with some kind of dispenser especially designed for the addition of solids
- addition of a solid to a reaction mixture is a lot more of hassle than the addition of a liquid
If you have no dropping or sep funnel, use a syringe instead, of course in combination with a septum (replaces stopper). Septum can be replaced with multiple layers of parafilm or a simple balloon (deflated). For very small batches, even a pipet, fixed with a stopper to one neck of your reaction flask might work...
Quidquid agis, prudenter agas et respice finem!
(PVC-Analog Taste-Tester)
08-25-03 00:23
No 455462
Cool, thanks for the heads-up! I'll just put together a large pipet. Moisture in the air doesn't scare me as far as 1-1.5 mole batches go, just as long as ethyl iodide and iodine is used. Also, rolling a few marbles around in the reaction flask works wonders with preping the magnesium turnings. Thanks, again. Peace!
Love my country, fear my government.
(Hive Bee)
08-25-03 19:11
No 455585
(Rated as: excellent)
If you want to activate your Mg thoroughly, i have another suggestion for you:
1-Phenylethylmagnesium chloride in Et O solution (4.2)
Magnesium turnings (16 g, 660 mmol) were transferred to a 250mL roundbottomed three necked flask, equipped with a 250mL pressure-equalized dropping funnel. Glass splinters, 1 cm in size approximately (1-2 Pasteur pipettes, carefully granulated by gloved hand), and a Teflon stirring egg (40mm) were added. The system was purged by N2. The stirring speed was adjusted in such a manner that excessive vortex formation was avoided, which could have led to less interaction between the Teflon stirring egg and the mixture of glass splinters and magnesium turnings. This mechanical activation was carried out overnight. After this time, the magnesium particle size was reduced and a charcoal-grey powder covered the Mg-particles, glass splinters and the wall of the flask. A small amount of Et O was added, sufficient to moisten the magnesium.
The mixture was cooled to 0°C and a solution of 1-phenyl-ethyl chloride (13.2g, 100mmol) in 150 mL Et O was added slowly (~1 drop s ). It should be emphasized that no additional activation or initiation is performed.
After addition, the solution was stirred for another 3 hours. The Grignard reagent solution was titrated against 0.1 M 2-butanol solution in xylene, with 2,2'-bipyridine as indicator. The solution can be stored under N2 at room temperature for several weeks without decomposition.
I've copied this from a dissertation (at least I think it was a dissertation) I've found somewhere on the net. However, I forgot to copy the URL this excerpt is from, so I have to supply it to you "as is"....
But I assume you (like me) have no inert gas to work with, so you could do the same what I have done for phenylmagnesium bromide. I did practically the same like in the forementioned excerpt, but I worked the Mg under ether (no inert gas, just a blanket of ether fumes) over night and I had pre-activated my Mg-turnings by carefully heating them with a few crystals of iodine in a test tube. When I added the ethereal bromobenzene solution by the drop to the mechanically activated Mg under ether (ether heated up just below boiling), there was only a induction period of maybe 2-3 minutes before the grignard started working, no further activation was required...
Quidquid agis, prudenter agas et respice finem!
(PVC-Analog Taste-Tester)
08-26-03 07:13
No 455711
Thanks for the glass splinter idea! I've used chunks of broken glass rolled around with marbles, but smaller pieces of glass would be more helpful. I've never done it dry; always with solvent covering it. I've never used a stirbar to make a Grignard. If I had the opportunity, I would, but with the way I do it, it isn't needed. As far as Grignards go, I haven't had much "luck" with ether. I love using tetrahydrofuran. Your mention of 1-phenyl-ethyl chloride gets me thinking about its use in the synthesis of PCP-analogues. Since that's probably a watched chem, maybe 1-thienyl-ethyl bromide could be used?
Love my country, fear my government.
(Hive Bee)
08-26-03 20:34
No 455815
If your goal is TCP
, there is no way with 1-thienyl-ethyl bromide...ummm..in fact, I've never heard such an animal exists. You must use 2-bromothiophene for the Grignard, which, according to the literature, will work in the synthesis.But back to "How to set up a Grignard reaction differently", I do not suggest to prepare the activated magnesium dry, there is a slight misunderstanding - my fault, I didn't explain it good enough.
Just preactivate Mg by careful heating with iodine, dump the preactivated Mg with some glass splinters and your marbles in the reaction flask and add enough THF to cover all ingredients to block oxygen from air. Use the means you normally use to "disintegrate" (I really love this word
) the Mg to fine and very reactive particles by agitating it over night in the stoppered flask.Worked for me, should work for you..
Quidquid agis, prudenter agas et respice finem!
(PVC-Analog Taste-Tester)
08-27-03 05:35
No 455902
Yes, I know that 2-bromothiophene is needed to make TCP. I have a collection of just about every dissociative patent and journal. I was just saying that maybe an active product could be obtained from 1-thienyl-ethyl bromide. Imagine all the PCP-analogues that can be made.
Love my country, fear my government.
(Hive Bee)
08-27-03 20:52
No 456041
...with 2-(1-bromoethyl)-thiophene, if my understanding of 1-thienyl-ethylbromide is correct?
Hmm, I simply don't know if such an exchange will lead to an active compound. But I think it won't work or at last it won't work well, since in compounds like PCP, TCP and PCE the aromatic ring is directly bonded to the carbon at which the nitrogen is seated. But that's just my opinion, I don't want to discourage you in your quest for analogues.
Hopefully, a bee with a better background in SAR can help you
Quidquid agis, prudenter agas et respice finem!
(Chief Bee)
11-02-04 20:46
No 539365
(Rated as: good read)
I believe this is the full text to the method described in Post 455585 (hermanroempp: "Marbles - grignard activation with glass splinters", Chemistry Discourse)
Hendrik van der Worp
Enantioselective cross-coupling reactions: A new route to enantiomerically pure α-arylpropionic acids
Thesis, Univ. Groningen, NL (1997) (http://www.ub.rug.nl/eldoc/dis/science/
Methods to prepare magnesium surfaces
There are many ways to activate Mg, and the chemist who tries - without much success - to initiate Grignard reagent formation can reckon on well-intentioned colleagues suggesting a myriad of techniques, from the sublime to the strange; from adding a crystal elementary iodine, to the use of slightly wet solvent or the addition of some saliva.
To prepare magnesium surfaces reproducibly is notoriously difficult. Surface oxides, adsorbed insulating layers and crystal lattice orientation can affect the heterogeneous reaction rates. As a result, not only the initiation but also the reproduction of the Grignard reaction is difficult. The following survey of magnesium surface pretreatments is indicative, and does not claim to be complete; they can be divided in two types: mechanical and chemical.
Generally, magnesium turnings are sufficiently prepared for reactive halides after removal of surface oxides and contaminations by hand with pestle and mortar. It is suggested that bending magnesium strips would cause crystal lattice dislocations, making them appropriate for Grignard reactions. Magnesium turnings can be activated by [3,4i] sonication; this method appears to be critically dependent on the water content of the ethereal solution. It is suggested that the function of the ultrasound is to disperse surfacebound water from the magnesium.[16] Sometimes, sonication is the preferred technique for effecting the Barbier variation of the Grignard reaction, where magnesium, organohalide and carbonyl compound are introduced concomitantly and the Grignard reagent is intercepted as fast as it is formed.[17]
Instead of mechanical activation, chemical activation with a crystal of elementary iodine is satisfactory in a fair number of the reactions. Among the numerous other chemical activators are bromine, iron trichloride, or a readily reactive alkyl halide (e.g. methyl iodide). A small portion of a preformed Grignard reagent (preferentially a left-over of a former experiment), is often successful.
A well known activation procedure is Rieke's method, where magnesium halides are reduced in situ by metallic potassium, yielding a finely divided black powder of metallic magnesium.[18] An alternative method for the synthesis of finely divided magnesium requires the evaporative sublimation of high purity metal in vacuo with condensation into a solvent slurry at –19°C.[19]
Magnesium amalgam can be formed by dissolving magnesium powder in mercury, which appears to react slowly, but uniformly over the entire surface. Reduction of mercuric halides by magnesium furnishes an amalgam as well,[20] though contaminated with halides, a disadvantage, as we will see. In the next section, we discuss the influence of the composition of Grignard solutions on ee in asymmetric couplings.
Experimental
Magnesium turnings were purchased from Fluka and from Janssen (now Acros Chimica). The magnesium turnings obtained from Janssen were nearly flat pieces [probably offcuts of a magnesium ribbon instead of turnings], and were activated more readily than the more wrinkled magnesium turnings that were purchased from Fluka.
Magnesium turnings (16 g, 660 mmol) were transferred to a 250-mL roundbottomed three necked B24 flask, equipped with a 250 mL pressure-equalized dropping funnel. Glass splinters, 1 cm in size approximately (1-2 Pasteur pipettes, carefully granulated by gloved hand), and a Teflon stirring egg (40 mm) were added. The system was purged by N2. The stirring speed was adjusted in such a manner that excessive vortex formation was avoided, which could have led to less interaction between the Teflon stirring egg and the mixture of glass splinters and magnesium turnings. This mechanical activation was carried out overnight. After this time, the magnesium particle size was reduced and a charcoal-grey powder covered the Mg-particles, glass splinters and the wall of the flask. A small amount of Et2O was added, sufficient to moisten the magnesium. The mixture was cooled to 0°C and a solution of alkyl halide (100 mmol) in 150 mL Et2O was added slowly (~1 drop/sec). It should be emphasized that no additional activation or initiation is performed. After addition, the solution was stirred for another 3 hours.
References
3. Kharasch, M.S.; Reinmuth, O. "Grignard reactions of nonmetallic substances", Prentice-Hill Inc. New York; 1954.
4i. Hill, C.L.; Vander Sande, J.B.; Whitesides, G.M. J. Org. Chem. 1980, 45, 1020.
16. Sprich, J.D.; Levandos, G.S. Inorg. Chim. Acta 1982, 76, 1241.
17. Ishiwaka, N.; Koh, M.G.; Kitazume, T.; Choi, S.K. Fluorine Chem. 1984, 24, 419.
18a. Rieke, R.D.; Hudnall, P.M. J. Am. Chem. Soc. 1972, 94, 7178.
18b. Rieke, R.D.; Bales, S.E. J. Chem. Soc., Chem. Commun. 1973, 879.
18c. Rieke, R.D.; Bales, S.E. J. Am. Chem. Soc. 1974, 96, 1775.
18d. Rieke, R.D.; Li, P.T.-Z.; Burns, T.P.; Uhm, S.T. J. Org. Chem. 1981, 46, 4323.
19. Kündig, E.P.; Perret, C. Helv. Chim. Acta 1981, 64, 2606.
20a. Teerlinck, C.E.; Bowyer, W.J. J. Org. Chem. 1996, 61, 1059.
20b. Koon, S.E.; Oyler, C.E.; Hill, J.H.M.; Bowyer, W.J. J. Org. Chem. 1993, 58, 3225.
20c. Wang, J. Stripping Analysis: Principles, Instrumentation, and Applications VCH Publishers: Deerfield Beach, FL, 1985
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