Sciencemadness Discussion Board

Preparation of bis(2-chloroethyl) ether

Lambda-Eyde - 3-10-2011 at 15:18

(Disclaimer: Google turns up just garbage, the threads on the forum are old and useless. A SciFinder search didn't give anything of relevance, either. Sorry.)





I am interested in preparing bis(2-chloroethyl) ether, or 2,2'-dichlorodiethyl ether (CAS# 111-44-4). Purchasing it is expensive and would most likely put me on a CWC watchlist, due to its similarity with the infamous sulfur mustard.

Anyways, the reason I need it is that I'd like some to synthesize dibenzo-18-crown-6, according to the organic syntheses procedure:


(Note how they warn the user against the dangers of benzene, but fail to mention anything about the toxic haloether)

Now, the obvious place to start is from diethylene glycol, HO-C<sub>2</sub>H<sub>4</sub>-O-C<sub>2</sub>H<sub>4</sub>-OH. DEG is cheap, available and doesn't raise anyone's eyebrows. It also finds use as a solvent in various reactions, such as the Wolff-Kishner reduction.

The question is, what reagent would be needed for this transformation (OH -> Cl)? Would HCl/ZnCl<sub>2</sub> suffice, or do I need to pull out the big guns? (SOCl<sub>2</sub>, P chlorides) I lack the latter, and the Polish suppliers who used to provide red phosphorus for a reasonable price are in legal trouble after the 22/7 terror attacks in Norway. Ordering from them would earn me a visit from a certain three-letter agency anyways. Anyone who knows of a reliable, not-so-pricey, European supplier of red phosphorus are welcome to send me a U2U.

Oh, but I digress. If the transformation cannot be achieved by HCl/ZnCl<sub>2</sub>, then it must be possible to prepare the bromine analogue, bis(2-bromoethyl) ether by treating the glycol with HBr. HI would certainly cleave the ether. I expect the bromine analogue to behave similarly (and let go of its halogens more easily). The higher molecular weight and therefore higher boiling point could prove to be an obstacle during distillation.


And a word on safety: I am aware that this compound is extremely nasty. In addition to being very similar to sulfur mustard, it is also a proven carcinogen. One of the hazard statements in the MSDS is "Fatal on skin contact". When preparing or using this chemical, what precautionary measures should I take, other than working in a fume hood? "Airless" technique?


Thanks in advance for the answers.

matei - 4-10-2011 at 04:59

I think it would be easier and safer to replace bis(2-chloroethyl)ether with diethyleneglycol ditosylate. Tosylate derivatives of oligoethyleneglycols can be prepared easily as in Acta Chem. Scand. 1972, 26, 1471 or Bull. Chem. Soc. Jpn., 1990, 63, 1260. If I recall diethyleneglycol ditosylate is also toxic but not carcinogenic as bis(2-chloroethyl)ether is (it should also be less volatile so easier to work with). You can also check Synthesis, 1976, 515 and Synthesis, 1976, 516.

Nicodem - 4-10-2011 at 10:28

Any acid catalysed nucleophilic chlorination is likely to cleave the ether link at the conditions required for a primary alcohol chlorination.

You can use the Appel reaction which leaves ethers untouched. You can use trichloroisocyanuric acid or N-chlorosuccinimide instead of the less easily obtainable CCl4, but beware of the exothermic initial reaction. Triphenylphosphine is quite common in any lab, so you should not have troubles obtaining it, though other phosphines can be used as well.

Otherwise, I agree with Matei that the ditosylate is much simpler to make and use. Also, tosyl chloride is a common and cheap chemical. You can use NaOH as a base. There is a thread with references for the preparation of alkyl tosylates at the forum (UTFSE).

Lambda-Eyde - 4-10-2011 at 12:11

Quote: Originally posted by matei  
I think it would be easier and safer to replace bis(2-chloroethyl)ether with diethyleneglycol ditosylate.


Thanks for the excellent idea! I didn't consider any other leaving groups besides halogens. And thanks for the references. I did a literature search myself and found a few helpful articles (I think some of your references were among them).
Quote: Originally posted by Nicodem  
Any acid catalysed nucleophilic chlorination is likely to cleave the ether link at the conditions required for a primary alcohol chlorination.

Of course. I didn't consider the elevated reaction temperatures needed for chlorination of primary alcohols when considering the resistance of the R-O-R' link to HCl. (Thanks for telling me without using your usual tone. ;))
Quote: Originally posted by Nicodem  
You can use the Appel reaction which leaves ethers untouched. You can use trichloroisocyanuric acid or N-chlorosuccinimide instead of the less easily obtainable CCl4, but beware of the exothermic initial reaction. Triphenylphosphine is quite common in any lab, so you should not have troubles obtaining it, though other phosphines can be used as well.

In my lab it's actually the other way around - I have 500 mL of CCl<sub>4</sub> sitting peacefully in a locker, but no triphenylphosphine. The price of PPh<sub>3</sub> is quite prohibiting - and when you consider the molecular weight of the compound, the price per mole is even more unappealing. I'd like to use the Appel reaction some time though, but substituting the bis(2-chloroethyl) ether with the ditosylate sounds like a better idea in this case.
Quote: Originally posted by Nicodem  
Otherwise, I agree with Matei that the ditosylate is much simpler to make and use. Also, tosyl chloride is a common and cheap chemical. You can use NaOH as a base. There is a thread with references for the preparation of alkyl tosylates at the forum (UTFSE).

Yes, tosyl chloride is cheap and available to me. Although I can't avoid feeling that I'm "cheating" by purchasing it. Synthesizing it from p-TsOH would require SOCl<sub>2</sub> or phosphorus chlorides, thus bringing me back to square one. I'll consider purchasing it.

I hope to write a detailed write-up in the prepublications section if I can pull off this whole project. I've recently moved 120 km away from my lab to attend university, but I hope to frequently go and spend time in the lab (where I can do something interesting, as opposed to the gen.chem. labs we're doing :P)


The attached reference claims 89 % yield of DEG-ditosylate on a 100 mmol scale by simply grinding DEG, p-TsCl and potassium carbonate together in a mortar for a few minutes. It doesn't get any easier!

Attachment: Chemoselective and scalable preparation of alkyl tosylates under solvent-free conditions.pdf (656kB)
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