Mesylates and Tosylates
An alcohol’s -OH is a terrible leaving group (hydroxide has pKa 15.7, so OH⁻ is a strong base that refuses to leave). To get any substitution or elimination chemistry from an alcohol, you usually have to convert the -OH into something that leaves easily. The two most common lab-scale options are mesylates (-OMs) and tosylates (-OTs), both sulfonate esters derived from strong sulfonic acids.
After mesylation or tosylation, the carbon that was once a terrible SN2 substrate becomes an excellent one. The -OMs and -OTs groups rank among the best leaving groups available to an organic chemist, alongside halides and triflates.
The Conversion
A primary, secondary, or tertiary alcohol can be converted to a tosylate by reacting with tosyl chloride (TsCl) in the presence of a weak base like pyridine or triethylamine:
R-OH + TsCl + base → R-OTs + base-H⁺Cl⁻
The mechanism is straightforward: the alcohol’s oxygen attacks the electrophilic sulfur of tosyl chloride; chloride leaves; the base removes the proton that was on the alcohol’s oxygen. The net result is that the C-O bond of the alcohol is preserved and the H of the OH is replaced by a Ts group.
Mesylation works the same way with mesyl chloride (MsCl) and pyridine. Both reactions are fast, clean, and do not affect stereochemistry at the carbon bearing the OH because the C-O bond is never broken during the installation.
Why Sulfonates Are So Good as Leaving Groups
Sulfonate esters have three oxygens sharing the negative charge after departure, giving extensive resonance stabilization:
- Mesylate anion (CH₃SO₃⁻): three equivalent resonance forms, charge spread over three oxygens. pKa of methanesulfonic acid is −2.
- Tosylate anion (CH₃C₆H₄SO₃⁻): same resonance stabilization plus inductive effect from the aryl group. pKa of p-toluenesulfonic acid is −3.
- Triflate anion (CF₃SO₃⁻): same resonance plus strong inductive effect from three fluorines. That makes triflic acid a superacid, stronger than water can measure, so no pKa is quoted for it next to −2 and −3. It is far and away the strongest of the three.
Excellent leaving-group ranking: triflate > tosylate ≈ mesylate > iodide > bromide > chloride.
Stereochemistry Preservation
A critical feature: the C-O bond on the original alcohol’s carbon is NEVER broken during mesylation or tosylation. Only the O-H bond reacts. This means the stereochemistry at the carbon is preserved. If you started with (R)-2-butanol, you get (R)-2-butyl tosylate.
This stereochemical fidelity is why mesylates and tosylates are so useful in synthesis: you can set up a defined stereocenter with an alcohol, convert to the sulfonate, and then carry out a stereospecific SN2 with inversion to get the other configuration. Two steps, one defined stereochemical flip.
The Downstream Reactions
Once you have a mesylate or tosylate, it behaves exactly like an alkyl halide for all SN1/SN2/E1/E2 purposes. The choice of reaction depends on the substrate (1° vs. 2° vs. 3°), the nucleophile/base, and conditions. Two common sequences:
SN2 sequence:
- R-OH + TsCl/pyridine → R-OTs.
- R-OTs + Nu⁻ (strong nucleophile, polar aprotic solvent) → R-Nu + OTs⁻.
- Net result: OH has been replaced by Nu with inversion of configuration.
E2 sequence:
- R-OH + TsCl/pyridine → R-OTs.
- R-OTs + bulky strong base (tBuO⁻) → alkene + OTs⁻ + H-base.
- Net result: dehydration of the alcohol via clean E2 mechanism.
Mesylate vs. Tosylate: When to Use Which
Both are excellent leaving groups. Practical differences:
- Tosylates are cheaper to make (TsCl is inexpensive) and give crystalline intermediates, which makes them easy to purify.
- Mesylates are smaller and less bulky, which can matter if you are working with a sterically congested substrate.
- Tosylates are more stable (can be stored for weeks); mesylates are somewhat more reactive.
On the MCAT, either abbreviation (OMs or OTs) signals “excellent leaving group” - you rarely need to distinguish them beyond that.
Alternatives: PBr₃, SOCl₂, HX
Sometimes you want to convert the alcohol all the way to a halide rather than a sulfonate. Three common reagents:
- PBr₃: R-OH → R-Br via a cyclic mechanism. Good for 1° and 2° alcohols.
- SOCl₂: R-OH → R-Cl. Byproducts are HCl and SO₂ gas, which leave easily.
- HX (HCl, HBr, HI): R-OH + HX → R-X + H₂O. Good for 3° alcohols (goes through SN1). 1° and 2° can give mixtures or be too slow.
All of these convert the -OH into a halide leaving group, which then behaves like an alkyl halide in subsequent reactions. The sulfonate route is preferred when preserving stereochemistry; the halide route is preferred when cost or accessibility matters.