Leo Szilard
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Reactions of alcohols to form alkyl bromides and tosylates
Every student it taught about the reaction between alcohols and PBr3 to form alkyl bromides. Is this reaction commonly used or has it largely been
replaced by milder reactions such as the Appel reaction?
My next question relates to the reactions of alcohols (let's just assume 1o alcohols) with tsCl. I have often been curious why this
reaction doesn't generally yield alkyl chlorides. Treatment of alcohols with thionyl chloride does yield alkyl chlorides. The thionyl
chloride reaction and tsCl reaction proceed through similar mechanisms, so why can't chloride displace -OTs to yield an alkyl chloride? Is chloride
not a strong enough nuclophile? My thought is that chloride probably can displace -OTs, but it's an equilibrium process. So unless you modify the
reaction conditions (e.g. somehow precipitate out sulfonate, or maybe adding a quat chloride ptc), the equilibrium favors the tosylate product. When
chloride displaces the chlorosulfite ester in the thionyl chloride reaction, the leaving group breaks down into SO2 and Cl- which is clearly an
irreversible process. Is that the secret to the thionyl chloride/alcohol reaction? Any thoughts about my hypothesis?
I have seen at least one paper that discusses the formation of alkyl chloride from alcohols upon treatment with tsCl; however, (most of) the
substrates were substituted benzyl alcohols and the yields were mediocre at best.
http://www.mdpi.com/1420-3049/16/7/5665/pdf
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smaerd
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Leo - Tosylation does not always afford a tosylate substitution and as your intuition suggests can create alkyl chlorides. I was actually going to
recommend that you read "Treatment of Alcohols with Tosyl Chloride Does Not always Lead to the Formation of Tosylates", (Chuanmin Qi, Et Al.
Molecules 2011, 16, 5665-5673; doi:10.3390/molecules16075665) until I saw the link.
This paper does mention that the chloride nucleophile although weak can and likely does displace tosylate functionalities. This is especially
pronounced on conjugated systems which have electron withdrawing groups (nitro, halogens, etc) where the alcohol is alpha or in the benzylic position
to the pi system. Although it can also occur with electron donating groups as well.
I'm not sure if PBr3 has been replaced, it's effective. It really depends on the substrate I guess. There are many ways to generate alkyl halides
though. My personal favorite is to create a tosylate and then do a finkelstein (cool reaction if you like this kind of chemistry) to the iodide. I
just prefer working with tosylchloride because it is a solid. Displacements of leaving groups with other leaving groups is definitely known to happen
and is thought to occur via an equilibrium process through an SN2 like reaction. IE: finkelstiens often use excess iodide to drive the reaction to
completion.
You could always do an experiment related to that. It sounds pretty easy to me. However, analysis at home might be tricky. Monitoring pH might be a
way to approach it if the tosylate is leaving.
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Leo Szilard
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I think this would be fun to experiment with...not very earth-shattering, but it would be useful in building my chops in the lab. I have a lot of
tosyl chloride. It's pretty old, but it's been stored properly. Despite proper storage, it's a little bit clumpy, but I suspect it will be fine after
recrystallization.
I also think it would be neat to compare the relative rates of elimination and substitution between tosylates and alkyl halides. I can't cite any
sources, but I've been taught that alkyl halides readily eliminate when treated with a strongly basic nucleophile such as alkoxide; whereas tosylates
give more of the substitution product. It would be very instructive to compare these relative rates as a function of temperature, solvent, and
substrate (comparing benzylic, allylic, presence or absence of electron withdrawing groups or donating groups, etc.)
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byko3y
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I think tosylates and chloride (bromide, iodide) are in equilibrium, but when the HBr is somehow separated (by distillation or 2-phase extraction),
then the equilibrium is shifted. As you know, hydrogen halides dissolve in water, but when you use alcohol as a solvent, then the hydrogen halides are
driven away quickly.
I want to remind you of a nice old way of making alkyl halides, which is a reaction of alcohol with hydrogen halide. Either you drive away the alkyl
halide as fast as it is formed (they are more volatile than alcohols), or use some catalyst, such as ZnCl2, or HMPT as a solvent. Tertiary alcohols
react faster, secondary slower, and primary react really slow (Lucas' reagent).
In fact, very few people actually know the reason of the difference between POCl3 and PCl3, while they can tell about about some well known reactions
of those reagents. Practically, if you don't remove hydrogen chloride from the reaction, you will get an alkyl chloride with any reagent.
You can obtain phosphonate esters using PCl3 by performing the reaction with alcohol at lower temperature and carefully removing the formed HCl http://cssp.chemspider.com/Article.aspx?id=488 However, when using PCl3 you always see some alkyl chloride as a byproduct, so something like
pyridine is needed to avoid them.
POCl3 elimination gives better elimination yields with tertiary alcohols, while PCl3 gives better yield of alkyl chloride from primary and secondary
alcohols.
And in the case of electrophilic reagents, such as amides, you will get an iminium chloride using POCl3, though I think the elimination takes place
there first.
Still, I'm not really sure about the difference, I would be glad to know some more information.
And back to the sulfonates. Most likely the POCl3 scenario works for sulfonates, such as tosyl chloride or mesyl chloride - they are in equilibrium
with alkyl chlorides, but the hydrogen chloride flyes away really fast, because it has low solubility in alcohols and esters, so the alkyl sulfonate
ester is left in the mixture.
Chlorosulfite is easily broken into SO2 and HCl, which are not capable of forming esters with alcohols - this is why chemists love thionyl chloride.
Elimination is always possible if the medium is acidic, but, as I've already said, the medium quickly becomes non-acidic. Heating the reagents with
some toluenesolfonic acid will make the elimination happen in good yield.
Leo Szilard, there's a nice article explaining some eliminations and substitutions of alkyl halides http://www.masterorganicchemistry.com/2014/01/10/synthesis-3...
[Edited on 14-5-2015 by byko3y]
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Leo Szilard
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byko3y, thanks for your thoughts. Let me digest this a bit and I'll reply with my thoughts or questions. Good stuff.
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