Sciencemadness Discussion Board - Ozonelabs- Synthesis of 1,4-Bis(3-chloropropoxy)benzene

Ozonelabs- Synthesis of 1,4-Bis(3-chloropropoxy)benzene

Ozonelabs - 23-1-2010 at 14:25

Hi everyone,

We have been studying various etherifications for a long time now and after much experimentation seem to have optimised the technique.

After sucess using Bromoethane (90% yield) and Iodomethane (94% yield) we have detailed the preparation of 1,4-Bis(3-chloropropoxy)benzene as a building block for future reactions.

We hope that this is of use to the community, as always any feedback is much appreciated.

Sincere regards,

The Ozonelabs Team

Attachment: 1,4-Bis(3-chloropropoxy)benzene.pdf (252kB)
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mr.crow - 23-1-2010 at 15:00

Excellent work

When you get the yield you can see if any of the chlorine reacted forming byproducts.

Happyer - 23-1-2010 at 15:07

That TLC looks like a fairly good yield was obtained, based on the hydroquinone marker.

entropy51 - 23-1-2010 at 15:20

Interesting synthesis. Nice writeup, as always!

I do these O-alkylations using acetone and K2CO3 instead of MeOH and NaOH. When finished by TLC, rotovap off the acetone and take up the product in a suitable solvent (typically DCM). Then wash with dilute NaOH to remove any residual phenolic starting material, dry and rotovap off the DCM. I haven't tried it on these starting materials, however.

Jor - 23-1-2010 at 16:36

So what do you want to make with this compound?

Not sure, but aren't compounds like these (halogenated ethers) very carcinogenic? This looks like a good molecule for linking DNA, although it is somewhat bulky.

mr.crow - 23-1-2010 at 16:50

Quote: Originally posted by Jor

So what do you want to make with this compound?

Not sure, but aren't compounds like these (halogenated ethers) very carcinogenic? This looks like a good molecule for linking DNA, although it is somewhat bulky.

Sort of like nitrogen and sulfur mustard gas. The Cl attacks the N or S and forms a cyclic sulfonium or ammonium compound that reacts with DNA. I doubt oxygen ethers can do this.

bis-chloromethyl ether also comes to mind. The ether could just be activating the chlorine as an alkylating agent.

Ozonelabs - 23-1-2010 at 16:59

We will try to get an NMR and GC/MS done at some point.

Entropy- the acetone/ carbonate is the main method emloyed, but often gives really lousy yields, it seems as though this technique cuts out much hastle- it makes use if the greater solubility of the sodium hydroxide and gives much shorter reaction times.

The yield does look promising, certainly given the short reaction time.

Jor- the end product will hopefully be prepared by next week.
Regarding the carcinogenicity, perhaps you are refering to compounds such as dichloromethyl methyl ether? Despite the extraordinarily sparse info in literature, we came across no similar compounds that had carcinogenic effects whatsoever. Also, as you mention the benzene ring coupled with both chloropropoxy groups would probably be a little bulky.

All comments appreciated.

The Ozonelabs Team

entropy51 - 23-1-2010 at 17:19

Quote: Originally posted by Ozonelabs

Entropy- the acetone/ carbonate is the main method emloyed, but often gives really lousy yields, it seems as though this technique cuts out much hastle- it makes use if the greater solubility of the sodium hydroxide and gives much shorter reaction times.

The reason I mentioned this method is that my yields are usually quantitative. I haven't tried with your starting materials, but my notebooks have many examples.

[Edited on 24-1-2010 by entropy51]

Peroxid - 24-1-2010 at 00:29

"Sort of like nitrogen and sulfur mustard gas. The Cl attacks the N or S and forms a cyclic sulfonium or ammonium compound that reacts with DNA. I doubt oxygen ethers can do this."

No, oxygen can't do this, so there is no vesicant effect! I read this in Mario Sartori's book at page 92.

"Dichloroethyl ether, though very similar in its chemical
properties to the sulphur derivative, has very different physiopathological
properties, being destitute of vesicant power.
According to Hofmann this lack of vesicant power must be
attributed to the fact that dichloroethyl ether, unlike dichloroethyl
sulphide, cannot penetrate the epidermis."

[Edited on 24-1-2010 by Peroxid]

DJF90 - 24-1-2010 at 00:43

""Sort of like nitrogen and sulfur mustard gas. The Cl attacks the N or S and forms a cyclic sulfonium or ammonium compound that reacts with DNA. I doubt oxygen ethers can do this."

Wrong way round. Chlorine won't attack anything, its the sulfur and nitrogen that are the nucleophiles.

And I think you'll find that chloromethyl ethers CAN do this, as oxygen has a habit of forming oxocarbenium ions, allowing formation of a potent electrophile after departure of chloride. This is why bis(chloromethyl)ether is so nasty. Dichloromethyl methyl ether however is not so bad, and I suspect the presence of the extra chlorine atom prevents such behaviour (i.e. makes it less favourable) by imparting a negative inductive effect as all halogens do.

Check out the anchimeric effect if you want more info. An interesting corollary is that bis(chloromethyl) sulfide is nothing like sulfur mustard!

Peroxid - 24-1-2010 at 01:43

"An interesting corollary is that bis(chloromethyl) sulfide is nothing like sulfur mustard!"

As i know sulfur mustard (HD) is bis-(2-Chloroethyl)sulfide, not chloromethyl!

DJF90 - 24-1-2010 at 07:55

Quote: Originally posted by Peroxid

"An interesting corollary is that bis(chloromethyl) sulfide is nothing like sulfur mustard!"

As i know sulfur mustard (HD) is bis-(2-Chloroethyl)sulfide, not chloromethyl!

That is the point :|

smuv - 24-1-2010 at 08:02

@Ozone*, Some Constructive criticism:

You should really wash the product 2-3x with aqueous alkali, then water. I think you will find that the product will look significantly better afterwords.

I think you are spotting too much onto your tlc plate, your solutions are too concentrated, or you are using too wide of a capillary tube.

Nonetheless, this is good work. It is nice to see some people posting there experimental results.

[Edited on 1-24-2010 by smuv]

Ozonelabs - 24-1-2010 at 08:36

smuv- absolutly, we literally had just enough time to get the product into the filter before we needed to leave the lab. Tomorrow the product will be dissolved in DCM (or Et2O) and washed with NaOH soln and worked up (still recrystallised).

Also, as time was tight we didn't have time to draw out the TLC spotter, hence the spots were larger than ideal.

Many thanks.

Arrhenius - 24-1-2010 at 09:02

Is there a reason you didn't follow a standard phenol alkylation prep? Most often this reaction is done with K2CO3 in refluxing acetone and gives a very clean product.

smuv - 24-1-2010 at 09:08

While I don't have experience with this specific product, with other phenols I have alkylated, good results can be attained simply by rigorously washing with alkali in the filter funnel. I only point this out, because if you are like me and have to distill your Et2O and DCM, this makes the preparation more convenient. If you follow this route, and you don't want to wait for the product to fully dry/don't want it to melt in the drying oven, dry it 'during' the recrystallization. So for example, you have a wet product you would like to recrystallize from hexanes/2-butanone. Dissolve the product into the butanone and boil it in the hood for a while, to remove the water/butanone azeotrope, then add hexanes as necessary to lower the solubility of the product, take it off the hotplate and recrystallize.

[Edited on 1-24-2010 by smuv]

smuv - 24-1-2010 at 09:15

@Arrhenius, as many people who have experience with the acetone/K2CO3 system can attest, the reactions can be sluggish with rxn rate highly dependent on stirring speed, sensitive to K2CO3 particle size, work poorly with 'wet' K2CO3 and are bad for large scale because the K2CO3 sluge causes the stirbar to decouple form the magnet at the necessary stir speeds to ensure a reasonable reaction rate.

Ozonelabs - 24-1-2010 at 09:15

Arrhenius- The only similar reaction to this one in literature called for a 24 hour reflux and gave 30% yields. Having already played with this reaction with NaOH/MeOH in the past (curiosity and all that), we thought we might end up with a better yield. EDIT: basically echoing what smuv just said! Potassium carbonate/acetone reactions just don't seem as effective, for all of the reasons given.

smuv- you have a good point, washing with NaOH in the filter may well clean things up quickly. The rotovap/ dry ice condenser does a good enough job of distilling whichever solvent we choose to use with minimal losses- though your suggestion would be well suited for any without those facilities.

[Edited on 24-1-2010 by Ozonelabs]

Arrhenius - 24-1-2010 at 09:25

Huh. Ok. I was just curious. I've done several alkylations of phenols, and all of them were as I described, with anhydrous K2CO3 (easy to dry), acetone and catalytic KI (in situ finkelstein). For instance, alkylation of salicylaldehyde derivatives was quantitative in a couple of hours, and one spot(UV) by TLC.

smuv - 24-1-2010 at 09:37

Remember Arrhenius, the K2CO3 does not dissolve, so if you have a mole of K2CO3 in your reaction flask that is 140g of solid that your stirbar must overcome. Also, anhydrous K2CO3 that has picked up a little water, or solvents that are not completely anhydrous cause the K2CO3 to clump making the solution even harder to stir. Due to the low solubility of K2CO3, the reaction rates are also sensitive to the particle size of the K2CO3 granules. This is a reaction that works pretty well on smaller scales but when you get out of mmol scale, the yields/convenience dwindle.

Nicodem - 24-1-2010 at 12:35

First, thanks Ozonelabs for sharing your experience.

To those concerned with carcinogenity and vesicant activity: 3-Phenoxypropyl halides do not apply here. For a mustard-like activity the alkylating reagent firstly needs to have a strongly nucleophilic beta-neighbouring group, but secondly, at the same time the formed three membered ring must still be a good or better electrophile. While the R2N- and RS- groups do fit both criteria, the alkoxy (RO-) and even less so the phenoxy (PhO-) groups, do not fulfil the first criteria (the O-nucleophilicity in these ethers is extremely poor when compared to their N- and S- analogues). The three membered ring (an oxonium salt) then would form via the neighbouring group assistance is an even stronger and much harder electrophile than the N- and S- analogues, but it simply does not have the opportunity to form due to the above explained reason. Besides, in gama-haloethers like the discussed compound, the intramolecular cyclisation would have to form a four membered ring which is very, very unfavourable when compared to a three membered ring formation which is extremely facile.
The chloromethyl alkyl ethers are a different beast. Here the assisting group is on the alpha position and therefore stabilizes the carbocation making these compounds very reactive via SN1 substitutions. But here the formation of the oxonium intermediate does not require an intramolecular cyclisation, but a mere O-C bond formation with the (reversible) expulsion of the leaving group (chloride). One bond is formed and one is broken, which means the thermodynamics don't suffer much except for the difference of these bonds strengths (and here the solvent effect with the energy of ions solvation comes at rescue).

Quote: Originally posted by smuv

@Arrhenius, as many people who have experience with the acetone/K2CO3 system can attest, the reactions can be sluggish with rxn rate highly dependent on stirring speed, sensitive to K2CO3 particle size, work poorly with 'wet' K2CO3 and are bad for large scale because the K2CO3 sluge causes the stirbar to decouple form the magnet at the necessary stir speeds to ensure a reasonable reaction rate.

I can attest that some alkylations with K2CO3/acetone work beautifully while some just don't no matter how long you run the reaction, and that all you said is true. From my limited experience I had the impression that K2CO3/acetone works relatively well with reactive alkyl halides (primary alkyl bromides/iodides/tosylates) and unhindered phenols that are fairly acidic and do not form poorly soluble potassium phenoxides. But still I do not feel comfortable enough in predicting which combination might work and which would not. In my experience K2CO3/acetonitrile works way better, probably only because of the higher reflux temperature. With this K2CO3/acetonitrile method, the only alkylation of a (monohydric) phenol with 1-bromo-3-chloropropane that I ever did, gave me a near quantitative yield without any 3-phenoxypropyl bromide side product being detectable with NMR. On the other side, using K2CO3/DMF gave a mixture of the chloro and bromo products, probably because KBr is more soluble/reactive in DMF and causes the Cl/Br nucleophilic exchange. This is probably not such a problem in MeOH as solvent, regardless the relatively good KBr solubility, because protic solvents solvate bromide anions rendering them less nucleophilic (but we will see what Ozonelabs has to say about it if he manages to do a GC and/or NMR measurement). Otherwise, using KOH/ethanol (or other hydroxides in other alcohols) was the method of choice for alkyl phenol ethers synthesis in the first half of the previous century. I don't know why it got so forgotten.