Alcohols, Epoxides and Ethers
Tosylates And Mesylates
Last updated: February 24th, 2020 |
All About 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:
Table of Contents
- Making Alcohols Into Good Leaving Groups (Part 2)
- A Good Idea That Doesn’t Actually Work Well: Sulfate Leaving Groups
- Introducing “Tosylates” and “Mesylates”
- How Tosylates And Mesylates Are Made From Alcohols
- Four Specific Examples of Tosylates and Mesylates In Action
- Summary: Tosylates and Mesylates
- (Advanced) References and Further Reading
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?
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!
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, “mesylate” and 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]
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. ]
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.
6. Summary: Tosylates And Mesylates
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 – PBr3 And SOCl2
- ON ESTERS OF p-TOLUENESULFONIC ACID
The Journal of Organic Chemistry, 1944, 09 (3), 235-241
Early reference on tosylation by Stuart Tipson, who was at the Mellon Institute of Industrial Research (now Carnegie-Mellon University).
- The tosylation of alcohols
George W. Kabalka, Manju Varma, Rajender S. Varma, Prem C. Srivastava, and Furn F. Knapp Jr.
The Journal of Organic Chemistry, 1986, 51 (12), 2386-2388
This paper describes an improved procedure for tosylation of alcohols.Besides the p-toluenesulfonyl group, other sulfonate esters can be prepared as leaving groups from alcohols (e.g. mesylate, brosylate, triflate, trifluoroacetate, nonaflate, etc.). Two papers describing mesylate ester synthesis are described below:
- Kinetic and spectroscopic characterisation of highly reactive methanesulfonates. Leaving group effects for solvolyses and comments on geminal electronic effects influencing SN1 reactivity
William Bentley, Manfred Christl, Ralf Kemmer, Gareth Llewellyn and John E. Oakley
J. Chem. Soc., Perkin Trans. 2, 1994, 2531-2538
- Palladium-catalyzed Buchwald-Hartwig Amination and Suzuki-Miyaura Cross-coupling Reaction of Aryl Mesylates
Shun Man Wong, Pui Ying Choy, On Ying Yuen, Chau Ming So, and Fuk Yee Kwong
Synth.2015, 92, 195-212
The first step in this procedure is the mesylation of p-t-butylphenol.
- Synthesis of some novel trifluoromethanesulfonates and their reactions with alcohol
Charles D. Beard, Kurt Baum, and Vytautas Grakauskas
The Journal of Organic Chemistry, 1973, 38 (21), 3673-3677
Triflate (-SO2CF3) esters are much more reactive than tosylates or mesylates, since the triflate anion is a superb leaving group. This paper describes the synthesis of various triflate esters but gives no mention for safety considerations – these are potent alkylating agents and are highly carcinogenic.