Sciencemadness Discussion Board

Grignard Reagent 4-chlorophenylmagnesium bromide

yogi - 30-1-2005 at 09:43

Hi.
Was wondering if anyone knows how one can synth the grignard reagent 4-chlorophenylmagnesium bromide ?
I was thinking about going from 4-chlorophenol, then replacing OH with Br and then adding Mg on it.
Anyone got any tips or ideas?


Edit by chemoleo: title changed.

[Edited on 30-1-2005 by chemoleo]

Synopsis - 30-1-2005 at 10:21

Replacing a phenolic alcohol to a bromide is not a trivial experiment. Furthermore, adding Mg to 4-bromochlorobenzene will result in a mixture of 4-bromophenylmagnesiumchloride and 4-chlorophenylmagnesiumbromide which, I guess, isn't what you're looking for.

I think paradichlorobenzene is a way better precursor here, as it's cheap and dosen't have the complications of the chlorobromo analog. However, I have no clue how paradichlorobenzene behaves when treated with magnesium. It should make the desired reagent though, in theory...

trilobite - 1-2-2005 at 02:31

It is very hard to get aromatic chlorines to react with magnesium. It is possible, but doesn't happen easily with standard Grignard reagent preparation method. To my knowledge the particular Grignard reagent is prepared from 4-chlorophenyl bromide.

[Edited on 1-2-2005 by trilobite]

trilobite - 1-2-2005 at 17:18

One possible route to 4-chlorophenyl bromide is to brominate acetanilide (from aniline + AcOH), hydrolyse it to 4-bromoaniline, diazotise the aniline and treat it with CuCl/HCl (Sandmeyer) to get the desired product. Vogel's 3rd edition should be more than you need to tell you how.

Synopsis - 1-2-2005 at 17:38

It is indeed rather hard to *initiate* the reaction between an organic chloride and magnesium. Having made phenylmagnesiumchloride many time, I can tell you that to keep the reaction going is as simple as for a bromide or iodide.

Also, halogen-metal exchanges are readily occuring between organic halides and Grignard reagents, favoring the more electronegative halide as counter anion (fluoride>chloride>bromide>iodide). Thus, I have serious doubt about such a reaction.

Quote:
To my knowledge the particular Grignard reagent is prepared from 4-chlorophenyl bromide.

Do you have a reference about this reagent? I would be really like to find out if polyhalogenated benzenes really can be regioselectively metallated.

Grignards from aromatic chlorides

trilobite - 2-2-2005 at 12:45

Well, surprisingly to me my textbook told that aromatic chlorides do react with magnesium but it takes THF as a solvent, diethyl ether will not work. Thanks for pointing it out, I was stuck in the early 20th century. ;) It is discussed in Journal of Organic Chemistry 22, 1202-1206 (1957), the attachment, and please notice how they also prepare 4-chlorophenylmagnesium chloride from p-dichlorobenzene which is highly interesting, making it possible to prepare chlorobenzene from p-dichlorobenzene too.The following patents might be of interest regarding preparation of PhMgCl.

US2795628, US2795627, US2816937, AT195443, US2838508, GB824175, FR1171022

I didn't have time to dig up the original preparation of 4-chlorophenylmagnesium bromide, but here is an abstract which should convince you.

Preparation of Grignard reagents in hydrocarbons containing tetrahydrofuran.
Leigh, T.
Chemistry & Industry (10), 426-7 (1965)

Grignard reagents can be prepd. in hydrocarbons contg. 1 mole tetrahydrofuran (THF) per mole Mg. Thus, in the presence of 1.0, 0.55, and 0.25 mole THF in PhMe the yields of BuMgCl were 92, 78, and 63%, resp. Grignard reagents of the following compds. were prepd. (% yield): MeCl (97), MeI (94), AmBr (86), n-C16H33Br (80), PhBr (90), p-ClC6H4Me (85), 1-bromonaphthalene (94), p-ClC6H4OMe (80), p-BrC6H4Cl (87), PhCH2Cl (80).

This invention is patented in GB870415. It is also possible to prepare 4-bromophenylmagnesium bromide from p-dibromobenzene in a bit lowered yield (70% if I understand correctly) in ether, this is discussed in Bull. Soc. Chim. Fr. [4] 41, 933-936 (1927) (available on request), Compt. Rend. 136, 1138 (1903) (available from http://gallica.bnf.fr/periodiques.htm , the full name of the journal being Comptes rendus hebdomadaires des séances de l'Académie des sciences).

Attachment: JOC_22_1202-6_1957_PhMgCl.pdf (646kB)
This file has been downloaded 1483 times

S.C. Wack - 2-2-2005 at 13:54

Quote:

my textbook told that aromatic chlorides do react with magnesium but it takes THF as a solvent, diethyl ether will not work


Take a look at that US2816937 that you mentioned. Vitus posted that at the Hive last year, I remembered.

trilobite - 2-2-2005 at 14:58

That's true, it was a good find.

Synopsis - 2-2-2005 at 17:40

Yeah, the older litterature is sometimes (often ;)) misleading. Note that even in THF it's still a pain to initiate the reaction between an organic chloride and magnesium without help. Preheating the magnesium (under nitrogen or argon flow) roughly 5 minutes with a bunsen burner (hot enough to break the oxide layer) greatly helps. Also, adding iodide crystals or ethylene bromide (which produces ethylene as side product) greatly reduces the initiating period.

Well, this abstract hasn't convinced me. I have no doubt that the Grignard reagent of 4-ClPhBr can be made. I simply fear this reagent isn't 4-ClPhMgBr, rather a mixture of 4-ClPhMgBr, 4-BrPhMgCl, 4-BrPhMgBr, 4-ClPhMgCl as well as the diorganomagnesium species via the Schlenk equilibrium. I might well be wrong, though. Diethylether as solvent might gives regioselectivity to the process. A definitive proof would be, for example, the exclusive isolation of PhCl (no PhBr formed) from the reaction between the reagent and water. NMR studies of the reagent in solution would also be convincing, but well, the dinosaurs of the older litterature can't offer that ;).

[Edited on 3-2-2005 by Synopsis]

yogi - 3-2-2005 at 03:17

thats a great one trilobite.
And even thogh synopsis got a point, I htnk this is going to the right direction.
This reagent i mentioned is nesscery to make the areocline coke anlaogs found on rhodium.
if an easy way could be found, we can finely have cheap coke for the masses !
:cool:

Ill be looking into it and keep you guys posted.

[Edited on 3-2-2005 by yogi]

Monsieur Grignard

Sandmeyer - 8-2-2005 at 04:25

There is an example in the litterature* of the preparation of Grignard reagent from p-dibromobenzene, where only one bromine is affected. Since it is harder to form Grignard reagent from Ar-Cl, my guess would be that you can start from 1-bromo-4-chloro-benzene to make the desired cmpnd.

*: Procedure types out upon request...

wow

gringobonk - 8-2-2005 at 21:02

i'm so happy to have stumbled upon this site. i am pretty much a novice with chemistry. i did well in high school but that's the extent of my knowledge. i have been tinkering with morphine extractions from poppy pods (ugh i can't wait for summer to just grow some!) lately which has increased my interest in chemistry again. the arecoline extract caught my attention about a month ago. my worry is that the 4-chlorophenylmagnesium bromide is not easily purchased and this thread seems to confirm that.

can 4-chlorophenylmagnesium bromide be purchased by just any one? i'm assuming not since people are discussing how to make it (unless the process is for shits and giggles).

if not, then are most if not all of the precursors purchasible by any one?

thanks for any advice on the matter.

Synopsis - 8-2-2005 at 22:46

Well, to my surprise I found a paper about cocaine analogs on a rhodium mirror that make use of the reagent in a michael addition (J. Med. Chem. 1998, 41, 1962-1969). It's nice to know that aryl bromides may be selectively reacted with magnesium in presence of chlorine substituent! Thanks for getting me out of my "everything is unstable or subject to lots of side-reactions" attitude :) They have the reagent in ethyl ether solution, which I would favor as solvent for the reaction (as opposed to GB870415 which uses THF to make the reagent).

trilobite - 9-2-2005 at 14:34

You're welcome! There are hundreds of mentions of that reagent in literature, but very little information of the dimagnesium Grignard. It seems it can be prepared though, but the reaction is not fast even with the most active magnesium (prepared by reducing MgCl2 with potassium) and proceeds stepwise even then.

Synopsis - 9-2-2005 at 16:10

In this paper : Nielsen, D. R.; McEwen, W. E. J. Am. Chem. Soc. 1957, 79, 3081-3084 it seems rather easy to make the dimagnesium reagent.

The best yield of I [benzene 1,4-diboronic acid] was obtained by use of the Grignard reaction. A mixture of p-dibromobenzene and two equivalents of magnesium in tetrahydrofuran was refluxed for a period of seven hours, then methyl borate was added to the reaction mixture...

If you're looking for something faster, treating p-dibromobenzene with lithium or a reactive alkyllithium will generate the dilithio reagent quite fast. Adding MgBr2 to the latter should result in quantitative formation of benzene 1,4-dimagnesiumbromide.

[Edited on 10-2-2005 by Synopsis]

trilobite - 9-2-2005 at 16:40

Oh, by dimagnesium compound I meant the one derived from p-chlorobromobenzene, not p-dibromobenzene. I think the paper describing the activated magnesium, written by a guy called Rieke (don't have the ref handy, are you interested?), studied also the p-dibromo and found out that there was a great difference.

Sandmeyer - 10-2-2005 at 00:59

If it works with p-dibromobenzene, why wouldn't it work with p-chlorobromobanzene?

p-chloroiodobanzene might even prove more advantageous as there is even bigger contrast in reactivity between chlorine and iodine substituent.

A relatively cheap route (iodine can be recycled) to p-chloroiodobenzene is from chlorobenzene: Lulinski, Piotr; Skulski, Lech; Bull. Chem. Soc. Jpn.; 73; 4; 2000; 951 - 956. For this they use iodine and H2SO4 in AcOH with various oxidizing agents (MnO2, NaIO4, CrO3 and so on)... The yileds are from 70 - 98 %...

A Russian group used KMnO4: Chaikovskii, V.K.; Novikov, A.N.; J.Appl.Chem.USSR; 57; 1; 1984; 121-123; Zh.Prikl.Khim.(Leningrad); RU; 57; 1; 1982; 134-137.


I would prefer this route over the diazotization in this case, it is cheaper, less work, more OTC, higher yielding, but of course often you need Sandmeyer. ;)

[Edited on 10-2-2005 by Sandmeyer]