Antoncho
(Official Hive Translator)
03-27-02 09:22
No 288566
      Diazomethane. Methylations with diazomethane.
(Rated as: excellent)
    

This is another of the procedures presented to HyperLab by Zealot, a highly remarkable individual, who has just recently joined our small community.

There are more to the procedures he submitted, but i'll omit some of the theory, if any questions should arise - ask.





Alkylations of phenols with diazomethane is a carbene reaction - where the reacting species is :CR2 - another well-known of this kind is Reimer-Tiemann formylation, where the active particle is :CCl2.

The unique property of diazomethane methylations is that, in case of polyhydric phenols, methylation occurs at only one -OH of the ring, until virtually all of the starting reagent is monomethylated; only then the second hydroxyl starts being methylated, and, in case of three hydroxies, this rxn also selectively proceeds until full dimethylation occurs, etc.

Thus, taking a calculated qtty of reagents, it is possible to stop the rxn at any of the stages, obtaining a good yield of, say, p-MeO-phenol or diMeO-phloroglucinol, which can bee then subjected to Reimer-Tiemann or Duff formylation.

Decomposition of diazomethane, required to form :CH2 radical, is catalyzed by Cu species - copper powder, Cu2+ or Cu+ unhydrous salts (sulfate, stearate, halides, complexes w/phosphoric acid), where Cu powder is the least reactive, Cu+ the most and CuSO4 is of intermediate activity.

Contrary to the accepted opinion, diazomethane is not so much poisonous and dangerous. The main thing to keep in mind is that one shouldn't heat concentrated solutions of DM by adding large qtties of it to the rxn , and not to add too much of decomposition catalyst (copper salt).

Tranferring diazomethane solutions is still better to carry out in a gas mask or in a gloveboxsmile

The following is a practically confirmed - and optimized - writeup (Zealot also stated the original printed procedure, but there's really no need to quote it)




Preparation of diazomethane

1. Nitrosylurea.

100 g (1,5 mole) methylamine*HCl and 300 g (5mole) tech grade urea is dissolved in 400ml tap water and the mixtr is heated w/a reflux condenser for 3 hrs at steady boiling. Then into the hotmixtr is added 110 g NaNO2 - the soln turns slightly yellow and a weak ammoniac smell appears. It's then cooled to 0 C and with good stirring there is added a thoroughly chilled mixtr of 110 g conc. H2SO4 and 600 g ice or snow. Nitrosylurea floats as a white foamy crystalline precipitate.
Yield 110-122 g (66-72%)

It is used immediately (it can bee washed, filtered and dried - but that's highly undesirable, since it's unstable and decomposes slowly at temps above zero - at 20 C it decomposes instantly, but w/out an explosion - however, emitting poisonous and stinky methylisocyanate)

2. Diazomethane.

Into a FBF there is poured 100ml hexane (or any other water-immiscible unreactive liquid - benzene, ether), 40 ml 40% KOH or NaOH, all is chlilled to 5 C, then w/constant cooling and shaking, 10 g nitrosylurea is added 9(Zealot: "...i always worked w/amounts 2-3 times more than") over the course of 1-2 mins (longer addition time doesn't affect the yield). Dark-yellow hexane layer is easily decanted, it contains 2,8 g diazomethane, some impurities and water. water can bee removed by drying it w/KOH (don't use KOH as sharp sticks - sharp edges facilitate DM's decomposition), however, for methylations water needs not bee removed.







Examples.

1. Preparation of p-MeO-phenol.

To asoln of 14,7g hydroquinone in 100 ml benzene there's added 0,05 g unhydrous CuSO4 and w/intensive stirring and RT there's added gradually 7 g DM in 150 ml benzene over 1 hour. When all dM is added, the rxn is stirred for 30 mins at RT and 30 mins at ~50 C.
Then the rxn is washed w/50% NaOH aq., until the washes remain completely colorless. Benzene is distilled off, giving an insignificant qtty of p-DMB. The aq. washes are neutralized HCl untill wekly acidic, xtract w/ether or C6H6 and evaporate to obtain ~15 g p-MeO-phenol as slightly brownish crystals.

2. Preparation of p-diMeO-benzene.

To a soln of 9 g HQ in 100 ml benzene there's added 0,05 g unhydrous CuSO4 and over an hour, w/intensive stirring and RT, there's gradually poured in 8 g DM in 150 ml benzene. When all is added, the rxn is stirred for 30 min at RT and 30 min at ~50C.
Then into the rxn, without cooling it, there's added in drops a small qtty of HCOOH, until doesn't lead to emission of gas (N2). The mixtr is washed w/2*30 ml water to remove residual CuSO4 and HCOOH,dried w/MgSO4 and the solvt removed on waterbath. Yield almost quantitive - ~11 g.






Antoncho

P.S. I am certain that this is not the only way to use diazomethane (although the only another i can remember at the moment is chloroacetone synthlaughcrazylaughcrazy). If anybee has any ideas about this most interesting chemical, please, post them here!
 
 
 
 
    hest
(Hive Bee)
03-27-02 10:52
No 288595
      Diazomethane is the last way to put in a ...     

Diazomethane is the last way to put in a methylengroup. It a shity material, damm explosive and toxic, so i think trhis synth has only teoretical interes.

there are two thing I don't work with, the first one is HMPA, the sec. is diazomethane.
 
 
 
 
    terbium
(Old P2P Cook)
03-27-02 11:22
No 288612
      Diazomethane     

Contrary to the accepted opinion, diazomethane is not so much poisonous and dangerous.

Tranferring diazomethane solutions is still better to carry out in a gas mask or in a glovebox

These two statements seem contradictory. First you say it is not so toxic then you say that it should be used in a glove box.

Actually, while I consider it to be "quite toxic", I always just used a good, professional fume hood when working with it. Using a glove box seems to be too much and also quite cumbersome; preparing a quatity of diazomethane while working in a glove box would be difficult.

As for the nitrosylurea, what is its potential as a carcinogen? Aldrich sells a diazomethane precursor they call Diazald which they claim is much less carcinogenic than many other diazomethane precursors.
 
 
 
 
    terbium
(Old P2P Cook)
03-27-02 11:28
No 288616
      A good fume hood is all you need.     

Diazomethane is the last way to put in a methylengroup. It a shity material, damm explosive and toxic
Sub-molar quatities are really not a problem at all if you use Diazald and the Aldrich suggested preparation procedure. A good fume hood obviates the toxicity and always co-distilling it with and using it in ether makes it non-explosive. For a long time I used to prepare it weekly.
 
 
 
 
    uemura
(Hive Photographer)
03-27-02 11:48
No 288625
      Highly carcinogen     

Antoncho,

Nitrosylurea has another problem beside explosiveness and immediate toxidity. Any dimethylamine present in the methylamine gives highly carcinogen dimethylnitrosamine!

Uemura would not use this stuff for methylation! Believe it or not, he had in the past produced some CH2N2 via the nitrosylurea but for much more profoud purpose than methylation. You can use it to make an alkyl-acide one carbon longer when you apply it to the alkyl-acide-chloride (Arndt-Eisner rxn).

BTW: There are more stable and less toxic compounds from which you can also prepare CH2N2. There are however not OTC producable (eg. the nitrosomethyltoluenesulfamide).

Carpe Diem
 
 
 
 
    slappy
(Hive Bee)
03-27-02 18:36
No 288789
      Yuck     

There are two things that I plan on going my entire carreer without using, HMPA and Dimethyl Mercury. But not Diazomethane. We all know that Mercury compounds are bad, and I try to avoid them all together. But HMPA is especially insidious because is persistant, with a low vapour pressure and a high bp, and it is readily absorbed through the skin. There really isn't any reason to use HMPA anymore, because DMPU (Dimethylpropyleneurea) works as a substitute for it under almost all conditions. I get really nervous whenever I use anything carcinogenic, Iodomethane, Hydrazine, Methyl Triflate, alkyl electrophiles, anything.

Diazomethane is really easy to work with in moderation. Terbium is exactly right, if you use the special generator, and aren't making mole's of it in your garage, you have nothing to worry about. Diazomethane is more than just a methylating agent, it is a stabilized carbene. You can do all kinds of cool reactions with it, like cyclopropanation of alkenes. A whole slew of C-C bond insertion reactions. Like Benzene -> Cycloheptatriene. C-C bond insertion into polarized bonds, like the ring expantion of cyclic ketones and esters (lactones). You can also expand an aliphatic ester by one carbon e.g. R-CH2-COOR -> R-CH2-CH2-COOR.
 
 
 
 
    PrimoPyro
(Hive Prodigy)
03-27-02 19:01
No 288799
      Dichlorocarbene Formylation     

After reading that little bit on the Reimer-Tiemann formylation, and the active formylating agent being :CCl2, I wonder if dichlorocarbene produced from a different source could formylate (after reaction with hydroxide) an aromatic ring by itself?

The two problems I see right off are that dichlorocarbene must be prepared in situ, as it cannot be isolated and transferred, and that polyformylations would be likely to occur if the reaction pace were not kept very slow.

But if these parameters could be met, say by using chloroform as solvent for a substance such as 2,5-DMBA, and slow addition of sodium ethoxide to produce the dichlorocarbene by NaOEt + CHCl3 --> NaCl + EtOH + :CCl2 then perhaps the dichlorocarbene could chloromethylenate the aromatic ring, then the benzal chloride could be reacted with potassium hydroxide to form the benzaldehyde.

                                                    PrimoPyro

Vivent Longtemps La Ruche!
 
 
 
 
    Antoncho
(Official Hive Translator)
03-27-02 19:51
No 288827
      Thank you everyone!     

It was very delighting to read this thread after the night's sleep. Very informative, thank you all a lot!

SWIAntoncho has no plans for diazomethane - he just translated the proc. exactly the way Zealot submitted it. Thought that might bee of interest. Living up to my titlesmilesmile

Then - PrimoPyro! Your idea anout ethanolic/EtOH Reimer-Tiemann is hilarious, IMHO! The only thing i worry about is the possibility of benzalchloride's reacting w/EtOH to form diethylacetal (which, however, can bee easily decomposed backto aldehyde - and, quite possibly, protect the product from tarring, thus increasing yield).

The point here is that formation of dichlorocarbene is the rate-limiting step in the rxn - and the stronger the base, the faster the rxn.

Anyone ever heard of this? Should bee proally described in literature, if it works...

Antoncho
 
 
 
 
    PrimoPyro
(Hive Prodigy)
03-27-02 19:59
No 288829
      Dictionary     

I first learned of this long ago, in my dictionary of chemistry.

I cant seem to find it right now, Im obviously not looking up the right things. I will look around for a little more info.

Antoncho, what makes the proposal so funny?

                                                    PrimoPyro

Vivent Longtemps La Ruche!
 
 
 
 
    PrimoPyro
(Hive Prodigy)
03-27-02 20:40
No 288841
      Carbenes
(Rated as: excellent)
    

The Generation and Fate of Carbenes

Carbenes are chiefly formed in two ways, though other pathways are also known.

1.In alpha elimination, a carbon loses a group without its electron pair, usually a proton, and then a groups with its pair, usually a halide ion:

CHR2Cl - H+ - Cl- --> CR2:

The most common example is formation of dichlorocarbene by treatment of chloroform with a base, and geminal alkyl dihalides with Me3Sn-, but many other examples are known, such as

CCl3COO- ==°C==> :CCl2 + CO2 + Cl-

2.Disintegration of compounds containing certain types of double bonds:

The two most important ways of forming :CH2 are the following examples:

Photolysis of ketene: CH2=C=O ==hv==> :CH2 + CO

and the isoelectronic decomposition of diazomethane:

CH2=N=N ==hv==> :CH2 + N2

Diaziranes (isomeric with diazoalkanes) also give carbenes.

Dichlorocarbene is water sensitive, as it is hydrolyzed to formic acid or carbon monoxide.

For more detailed information:

Jones Jr., M. Acc. Chem. Res., 1974, 7, 415; Kirmse, W. in Bamford; Tipper Comprehensive Chemical Kinetics, vol. 9; Elsevier: NY, 1973, p.373; Ref. 267.
Petrosyan, V.E.; Niyazymbetov, M.E. Russ. Chem. Rev., 1989, 58, 644.
Kirmse, W. Angew. Chem. Int. Ed. Engl., 1965, 4, 1/

There's a lot more information, too of course. I'll keep reading.

                                                    PrimoPyro

Vivent Longtemps La Ruche!
 
 
 
 
    Vitus_Verdegast
(Hive Addict)
01-24-04 18:54
No 484470
      Preparation of diazomethane solutions
(Rated as: good read)
    

This is from Berichte (D. Chem. Gesell.) 45 (1912) p. 505 :

As pointed out earlier in this thread, great care should be taken when working with diazomethane. It should only be handled by a well-trained professional chemist.

Experimental part

In a bromination flask fitted with an Allihn condensor is added a solution of 50 gr (4 Mol.) potassium hydroxide in 150 ccm absolute alcohol and a solution of 10 gr (1 Mol.) hydrazin in 50 ccm absolute alcohol. To this hot solution is added dropwise with an addition funnel a solution of 30 gr chloroform (1.25 Mol.) in 50 ccm absolute alcohol, at a rate which caused a controllable (not too vigorous) reaction to occur. The end of the addition funnel must be kept appropriately under the surface of the solution all the time, as to minimize the evaporation of the chloroform. During the reaction a constant steam of nitrogen gas was passed through the apparatus. The alcohol fumes are condensed by the condensor, while the diazomethane is carried through by the stream of nitrogen into a well cooled solution of ether. The yield of diazomethane is ca. 25%. The solutions thus prepared can be used in methylation reactions as is.


The reaction proceeds through this equation:

NH2NH2 + CHCl3 + 3KOH  __>  :CNNH2 + 3KCl + 3H2O

:CNNH2 __>  CH2N2



If an excess of chloroform and KOH is used, isonitrile is formed:

NH2NH2 + 2CHCl3 + 6KOH  __>  :CN2C: + 6KCl + 6H2O



Acetophenone to phenylacetone: PhCOCH3 + CH2N2 --AlCl3--> P2P (50%)

Katalysierte Homologisierung Cycloaliphatischer und Aliphatischer Ketone mit Diazoalkanen
Eugen Müller, Martin Bauer
Ann. Chem. 654, 92-111 (1962) ../rhodium/pdf /diazomethane.ketone.homologation.pdf

(edited, forgot to mention the condensorcrazy)

I like to watch (http://www.churchofeuthanasia.org/iltow_100k.wmv)
 
 
 
 
    Rhodium
(Chief Bee)
01-25-04 14:46
No 484552
      Diazald Diazomethane     

A rapid, safe and convenient procedure for the preparation and use of diazomethane
P. Lombardi
Chemistry & Industry 708 (1990) (../rhodium/chemistry /diazald.html)

The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Nicodem
(Hive Bee)
01-26-04 01:07
No 484633
      In situ diazomethane generation?     

PrimoPyro: ...NaOEt + CHCl3 --> NaCl + EtOH + :CCl2 then perhaps the dichlorocarbene could chloromethylenate the aromatic ring...

I'm afraid dichlorocarbene reacts with ethanol as it is much more nucleophilic than DMB. Besides the dichlorocarbene is not electrophilic enough to react with phenolethers in the first place, only with phenols (Reimer-Tiemann, you know) and this only in the organic phase where the conc. of water is minimum.
I read in an review about gem-dichlorocyclopropanation (R-CH=CH2 + :CCl2) that the addition of ethanol is deleterious for the reaction, I think the same goes for the Reimer-Tiemann. However the reaction of NaOEt and CHCl3 can be useful for producing triethylorthoformate.

Question:
Does anybody know any reasons why the procedure posted by Vitus (N2H4+CHCl3) would not work for in situ generation of diazomethane in methylation of phenoles?

For example, if one was to add hydroquinone just after CHCl3 (maybe with some cat. amount of CuSO4) would not this result in giving DMB?

“The real drug-problem is that we need more and better drugs.” – J. Ott