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Alcohols, Epoxides and Ethers

By James Ashenhurst

Tosylates And Mesylates

Last updated: September 13th, 2019 |

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:

00-summary

Table of Contents

  1. Making Alcohols Into Good Leaving Groups (Part 2)
  2. A Good Idea That Doesn’t Actually Work Well: Sulfate Leaving Groups
  3. Introducing “Tosylates” and “Mesylates”
  4. How Tosylates And Mesylates Are Made From Alcohols
  5. Four Specific Examples of Tosylates and Mesylates In Action
  6. Summary: Tosylates and Mesylates

1. 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.

0-alcohols bad

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.

1-alcohols-dont-work

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.

2-conv alc to tos mes

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

Sure thing!

2. 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.

3-sulfuric acid

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!

4-hydrogen sulfate

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!

3. 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]

5-other lgs

4. 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!

6-how tos mes works

[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. ]

5. Four Specific Examples Of Tosylates and Mesylates In Action

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.

7-specifices

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 – PBrAnd SOCl2

 

Comments

Comment section

46 thoughts on “Tosylates And Mesylates

    1. Thanks Brandon!
      I didn’t want to go into the nitpicky details, but my understanding is that NEt3 and stronger bases will generate the sulfene, while pyridine and other similar bases (like DMAP) will add to the sulfur and create an activated, charged intermediate (like DMAP+acyl halide) which is then attacked by the alcohol. [that’s why I left pyridine out of the mechanism : – ) ]

      1. My understanding is that pyridine/DMAP acts as both base and nucleophile. The base character generate the sulfene, which is then attacked by a second molecule of pyridine/DMAP to form the charged intermediate you’re referring to (this step also deprotonates the first unit of pyridine/DMAP).

        The nature of the reaction could change depending on the type of sulfonyl chloride. For example, t-burylsulfonyl chloride can’t form the sulfene, and must react via either SN1 or SN2. It’s also an incredibly poor electrophile, to the point where it does not react with amines under standard conditions, necessitating a weird oxidation from the sulfinamide to make t-butylsulfonamide.

        1. That’s interesting (and weird), because TsCl or benzenesulfonyl chloride don’t have any problem reacting with amines AFAIK.

          My friend Jeff who did some research proposals on sulfenes is of the opinion that DMAP might be a strong enough base to form the sulfene, whereas pyridine is not.
          “I think that DMAP probably would go via the sulfene. It’s basicity is closer to NEt3 than it is to pyridine and in organic solvents it may even be more basic: accordingly to Wikipedia, pKb of DMAP in MeCN is 17.95 (Couldn’t easily find the DMSO value). TEA in DMSO is 9, while pyridine is 3.4 in DMSO.”

    1. On paper, no, nothing bad should happen. In practice, aldehydes are susceptible to air oxidation (among other side reactions) and are often kept in protected form until needed.

  1. Truly great post! One small thing, though: in the text there appears “trifluoromethylsulfonic acid”, which I thing should read “trifluoromethanesulfonic acid”, as it actually does in the picture below the paragraph.

  2. Well ,the last two examples that you gave in your arcticle……is there any chance that they’ll not follow the mentioned mechanism…..like in the 3rd example instead of E2, can it be Sn2..??

  3. Dear Sir,

    I have one problem, my compound is open sugar molecule, I have to tosylate selectively the primary alcohol. I have try the pyridine as a base, but I am not able to get the product. Please give your suggestion.

    Thanks

    1. I would selectively tritylate the primary alcohol with trityl chloride, protect the other alcohols with acetic anhydride or TBS, remove the trityl group with trichloroacetic acid, then convert the primary alcohol into a tosylate with TsCl.

  4. Hi, thank you for nice explanations! Got a question… Is it will be a problem for mesilation of free OH, if i have another hydroxyl in the compound already protected with trityl group? I just need farther convert mesyl into azide, since it well leaving group. And need to keep other primary OH protected during this pricedure. Any advise please! Thank you!

  5. If pyridine or triethylamine are used can the Chloride anion be a nucleophile and attack the R group attached to the Oxygen? Will there be a proportion of alkyl halides?

    1. Great question, actually. Generally not a problem with alkyl tosylates, ALTHOUGH it can be a problem with allylic tosylates (and mesylates!!) As one famous organic chemist (BMT) likes to say, “Chloride ion is a bad actor!!!” If you’re really paranoid about this, you use Ms2O (methanesulfonic anhydride).

  6. Hi, James

    Just a question. If there are amine or thiol groups on your alcohol compound, do MsCl and TsCl attack them instead of alcohol?

    Thank you for your work.

    1. Thiols and amines (but particularly amines) can react with MsCl and TsCl. For that reason, when one is trying to synthesize a given molecule it is important to only have one reactive functional group present and have the others deactivated through protection. Trying to selectively tosylate or mesylate a molecule that has multiple unprotected functional groups is a recipe for a lot of wasted time.

      1. Dear James,

        What if you make the reaction in absence of a base and the amine groups are already hydrochloric salts?

        Thank you.

      2. Hi James,
        Reaction of TsCl with alcohols and amines. Would you expect to get same degree of tosylation and leaving group? Which one is easy to work with alcohols or amines?

        1. I’m not completely sure about the question being asked.
          If the question is: “if you have an alcohol and an amine on a molecule, which one will react with TsCl first?”
          The answer to that is, the amine, by a large margin because amines are many orders of magnitude more nucleophilic.
          It is relatively difficult to remove a Ts group from nitrogen, therefore it is not recommended as a protecting group.
          If you could clarify your question then I could try to answer it differently.

  7. Dear Sir,

    I would like to do selective mesylation to primary alcohol, but in my two alcohol functional groups are there primary and tertiary.

    some time i can able to obtained only selective mesylated product. but most of the time i got both alcohols mesylation.

    could you please give your suggestion

  8. Hi, James
    if indole and secondary alcohol are part of molecule then any chance of selectively dehydrating alcohol, (alcohol is secondary aryl alcohol from benzene ring part of indole)

      1. Hi James, Thanks for reply.
        Structures are as follows

        Starting Ar-CH(OH)-CH2-CH2(-Indole)
        Product Ar-CH=CH-CH2(-Indole)
        or
        Starting Ar-CH(OH)-CH2-CH(-Ar and -Indole)
        Product Ar-CH=CH-CH(-Ar and -Indole)
        Ar is Aromatic ring

  9. Hi Sir,
    I was going through the above comments and i have one query here that why trityl chloride is used for selective protection of primary hydroxyl group in glucosides?

  10. Great article regarding alcohol protective groups! I read it with high interest because I’m performing protection of alcohols followed by a substitution reaction. The molecule I’m working on consists of a secondary acohol and a secondary amide. The idea is to protect the alcohol as OMs or OTs to make it a better leaving group which would then react with the amide group and close the structure (cyclization) to form a 2,5-substituted pyrrolidine.
    Am I thinking correctly? Following your guide the NH of the amide should be nucleophilic enough for the cyclisation and OTs or OMs would easy leave. I’m using pyridine to speed up the reaction too.

    Structure: CH3-CH(OH)-CH2-CH2-C(O)-NH-R
    Where R is usually a Ph group or substituted aromatic ring.

    Thanks for your help!

  11. Hi James,

    Great article!

    One small issue I found: The article introduces Tosylates and Mesylates not only as a way to make alcohols into good leaving groups, but also as a way to convert OH into a better leaving group **that allows us to avoid the problems of rearrangements and racemization**… How exactly does this happen?

    From my understanding, convertion of OH to OMs/OTs doesn’t allow us to avoid this problems under a possible SN1 mechanism.

    For instance:
    Wouldn’t it be correct to asume that the reaction of the alcohol with HBr via SN1 shown at the start of the page would also lead to rearrangement and racemization if one was to replace the OH group with OTs/OMs?

    The way I’ve seen it presented before (Clayden) is as a way to turn OH into a good leaving group, given a nucleophile that is incompatible with a strong acid. (Example: Consider the lithium derivative of an alkyne, prepared by deprotanating said alkyne with BuLi; this could react with an alcohol that has been previously treate with TsCl/pyridine, to give the SN2 product; this would NOT happen in a strong acidic environment due to the alkyne being re-protonated). Tried to upload an image of the reaction I’m referencing (also from Clayden) but couldn’t find a way to do so.

    I think this might be a better way to present it; instead of mentioning avoiding re-arrangements and racemization, which I think is not avoided by tosylates or mesylates.

    Would love to hear your opinion on this!

    -Aldo

    1. Hi Aldo. Perhaps I wasn’t clear enough. What I meant to say is that going from OH to OTs allows OH to be converted to a good leaving group WITHOUT the intermediate formation of OH2+ (and possible ionization –> rearrangement) in the process, as is the case with HBr/HCl.
      I did not mean to imply that alkyl tosylates cannot undergo rearrangements. They can.
      I just meant to say it is a milder way of converting alcohols to good leaving groups.
      Hope that explains it! James

  12. Sir i also worked in carbohydrate chemistry, but i have suffered one problem, the problem is when i want to try tosylation of prymary alcohol in open sugar in presence Py & TsCl, the reaction not perform.
    But, in cyclic sugar, 6 th prymary alcohol Tosylation in presence Py & TsCl, also Perform, Please sir help me about your kind guidance, How to do this prymary alcohol tosylation in presence secondary alcohol, where secondary alcohol remain same. But prymary alcohol only react & convert with tosylated product.
    i shall be highly obliged with you.

  13. Hi James, this was a great post! Just a question: doesn’t mesylate still contain acidic hydrogen because of the the methyl group?
    I know carbon is not electronegative but is it not so that in it’s conjugate acid, the electron pair of the carbanion is in resonance with SO3 making the conjugate acid stable, and the hydrogen reactive … Sort of like an active hydrogen (I think?)

  14. Question. Thank you very much for your post and your endless effort to make organic chemistry readily assessable for people to learn. I have a question. If Its which is a good leaving group is in an acidic environment. Does it need to then be protonated first? Cause I did not see you talk about that in this post. Thank you so much.

    1. I hate to say, “it depends” , but it depends. Good leaving groups are weak bases. If the proposed leaving group is already a weak base before deprotonation (e.g. TsO- ) then protonation won’t be necessary. However if the proposed leaving group is not a weak base (e.g HO-) then protonation will make it a much better leaving group.

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