[Allendo]

Hi Team
I have learned that if I have a primary alcohol (of course the -OH is a bad leaving group) and I want to change it to a good leaving group. I can add, for example, PBr3. This will transform my alcohol as follow
R-OH + PBr3 ---> R-O-PBr2 ---> R-Br. And We say now we have a good leaving group as -Br

However, if I use TosCl, then
R-OH + TosCl ---> R-OTos. And We say now we have a good leaving group as -OTos.

My question is why we treat them differently? I think -O-PBr2 must be a decent leaving group as well. Why can't it keep R-O-PBr2 form. Or why R-OTos stops here instead of keep transforming to R-Cl?

Thanks
Allen

[hollytara]

It is a good question. 

In theory, you could use R-OPBr2.  But when you make it, you also generate HBr which gives you Br-, which then can displace the OPBr2- group.  (pKa of H3PO3 is 1.1 - this is about as close as you can get to HOPBr2)

The same with thionyl chloride, the ROH becomes RO-SOCl and HCl, which then generates Cl- to displace the SO2Cl-  (pKa of H2SO3 is 1.  The SO2Cl- then dissociates to SO2 and Cl-.

For the tosyl chloride, the pKa of tosic acid is -2.1 (so one expects the tosylate to be a better leaving group than either OPBr2- or SO2Cl-).  Yet the sulfonate is not displaced by the chloride!

[rolnor]

I think R-OTos will react with Cl- if given enough time.

[Allendo]

If tosylate to be a better leaving group than either OPBr2- or SO2Cl-, and Cl- is a decent Nucleophile, won't there be a substitution?

[Babcock_Hall]

This is a bit speculative.  However, IIRC the solvent in some tosylations is pyridine, and a by-product is pyridinium chloride, a.k.a. pyridine•HCl, which is a solid.  Possibly the concentration of the free chloride ion is too low to displace the tosylate group.

[Allendo]

Thanks for your reply.

I agree pyridine is the common solvent and pyridine*HCl will precipitate. But isn't the same logic apply to SOCl2 or PBr3/PCl3 reaction?
In other words, pyridinium chloride should decrease the free Cl- in solution to prevent the last step of SN2 in primary alcohol PCl3 reaction (R-O-PCl2 ---> R-Cl)

[hollytara]

I think PBr3 conditions usually do not include pyridine.

For the thionyl chloride/pyridine reaction it is usually done with no solvent so the thionyl chloride / pyridine mixture is pretty polar (and aprotic!) and will dissolve the pyridinium chloride well.

The tosyl chloride rxn is usually done in a solvent like dichloromethane and the pyridinium chloride will be less soluble.

So solvent probably makes a difference

[wildfyr]

I believe this JChemEd paper clears things up

https://pubs.acs.org/doi/pdf/10.1021/ed051p348

So essentially, chloride isn't nucleophilic enough to displace tosylate under typical room temperature conditions, but if you're heating your tosylation you may observe some alkyl chloride form. hollytara mentions the most salient point, which is that a smart chemist will run these reactions in a solvent like DCM/chloroform/toluene where the halide salt byproducts have poor solubility.


Also R-OPBr₂ isn't very stable, the other two bromines can be displaced and create a mess of bis and tris substituted phosphorous cores. Or even worse, they can react with adventitious water to give phosphonic acids. Suddenly, we are discussing 6 different molecules in this reaction. To get mono R-O-PBr₂ you'd have to carefully add low concentrations of alcohol to a solution of PBr₃ and make sure its all done very dry. With tosyl chloride, just dump it all together at RT in DCM, it would work even open to air.

Tosyl chloride only reacts once. And any that is accidentally hydrolyzed is easily removed via a water wash. Its common to use a bit excess tosyl chloride.

One last persnickity detail for any practicing organic chemists, this detail of even tosyl chloride possibly giving you the alkyl chloride could be seen as an argument to use p-toluene sulfonic, mesyl, or triflic anhydride instead if you require strong heating (especially above toluene temps) to get the alcohol to react. Something I never considered before today. I've tosylated in hot DMF before, probably had contamination. I think I was tosylating PEG and just needed a decent leaving group so if some chloro formed it didn't matter in retrospect. But for a small molecule, at the very least your NMR, LC, or mass spec would be confusing if you had 10% chloro substitution.

[rolnor]

If you make triflate its impossible to use triflic chloride, you get RCl so in this case the anhydride is good. Also you need a hindered base like 2,6-lutidine, otherwise you get quaternary salt of the base. I think its standard to use pyridine as solvent when you make tosylate but this is just old habit, its better with a solvent like DCM, I agree.