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Tosylates And Mesylates

Today we’re going to talk about a different way of making alcohols into good leaving groups – by turning them into tosylates and mesylates (“organosulfonates”). Here’s a brief summary of what we’ll cover here:

Making Alcohols Into Good Leaving Groups, Part 2

We’ve seen that alcohols are poor substrates for substitution reactions. The main problem is that the hydroxyl group is a strong base, and thus a poor leaving group.

In the last post we saw that we can convert alcohols into alkyl halides by adding strong  hydrohalic acids (HCl, HBr, HI):  the strong acid protonates R-OH to give R-OH2+ (with the better leaving group, H2O) and then substitution by the halide ion can occur.

In contrast to alcohols, alkyl halides are GREAT substrates for nucleophilic substitution reactions.

Unfortunately this doesn’t always work well. There are two main problems. First of all, on certain secondary alcohols the reaction proceeds through an SN1 pathway, which can lead to rearrangements. Secondly, in so doing, we can end up scrambling any stereocenters that are present. For instance if we start with one enantiomer in the reaction below, we end up with some racemization of the final product.

So is there some other way to convert alcohols into good leaving groups that doesn’t have these problems?

Sure thing!

One Good Idea (Which Doesn’t Actually Work That Well)

We all know that hydroxide (HO- ) is a strong base. But have we seen any examples of weak bases with a negative charge on the oxygen?

Yes! Sulfuric acid (H2SO4) is a very strong acid (pKa of about -3) and its conjugate acid, -OSO3H , is therefore a weak base. This is due to two key factors – first of all, delocalization of charge on the other oxygens through resonance, and secondly, the inductive effect of those oxygens helping to redistribute the charge.

So in a perfect world, if we had some way of easily turning an alcohol (R-OH) into an alkyl hydrogen sulfate (R-OSO3H) then we’d have a nice way of making an alcohol into a good leaving group.

So how might this work in practice? Actually it doesn’t work very well!

It’s not that OSO3H is a poor leaving group (it’s a great leaving group). The problem is that many nucleophiles are quite basic (remember – the conjugate base is a better nucleophile) and the OSO3H still has a very acidic proton (that OH group has a pKa of about 2, making it a stronger acid than acetic acid).

The bottom line is that if we add a basic nucleophile, an acid base reaction will occur instead of our desired substitution reaction. The nucleophile will be protonated into its conjugate acid (less nucleophilic) and any substitution reactions will be considerably slower. Not ideal!

Introducing “Tosylates” and “Mesylates”

Is there some way around this? Sure! It’s just a matter of replacing that OH group on the sulfur by some kind of relatively inert organic group (R group) that doesn’t have an acidic proton.

If we swap in a methyl group (CH3) our leaving group would be OSO2CH3, or “methanesulfonate” (commonly called, “mesylateand abbreviated OMs. This has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles.

Another popular option is using the conjugate base of p-toluenesulfonic acid, (“p-toluenesulfonate”) commonly called “tosylate” and abbreviated OTs.

These groups have essentially identical leaving group ability and for our purposes are interchangeable. Some textbooks tend to use Ts more, others use Ms. It doesn’t really matter for us at this stage: they both work.

[A third option, less commonly seen in introductory courses, is the “triflate” (Tf) group, which replaces the three hydrogens on methanesulfonate with three fluorines. The conjugate acid, trifluoromethanesulfonic acid, is among the more acidic species known (pKa of -13!) and for this reason, triflate is a really “hot” leaving group when attached to alkyl groups: it likes to leave of its own accord! It’s more commonly used on aromatic alcohols and other species that don’t form carbocations as easily]

How Do We Make Mesylates And Tosylates From Alcohols? 

So how can we apply this? If we have an alcohol, how do we turn that hydroxyl into a tosyl or mesyl group?

It’s relatively straightforward actually. We use “mesyl chloride” (MsCl) or “tosyl chloride” (TsCl), and the neutral alcohol performs a substitution reaction on sulfur, leading to formation of O-S and breakage of S-Cl. Then, deprotonation of the charged alcohol leads to the neutral mesylate or tosylate.

Note that the stereochemistry is completely unchanged here (unlike if we had used H-Cl, for example). Watch out for this – stereochemistry is often tested on exams!

[By the way – sometimes you might see that an organic base such as pyridine is also added, which helps the process along by removing HCl as it is formed. ]

Specific Examples

Let’s finish up by seeing some specific examples of Ts and Ms in action. As they contain a good leaving group, alkyl tosylates or mesylates can perform all of the substitution and elimination reactions of alkyl halides. A few examples are shown below.  Get familiar with MsCl and TsCl in both their abbreviated and expanded (i.e. “drawn-out”) forms.

Next time…

In the last two posts we’ve seen how useful it is to be able to convert alcohols to good leaving groups. In our next post we’ll cover one last method to do this that involves some new reagents, PBr3 (including other phosphorus halides) and SOCl2.

Next Post – PBrAnd SOCl2


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