Organic Reagents
Reagent Friday: TsCl (p-toluenesulfonyl chloride) and MsCl (methanesulfonyl chloride)
Last updated: January 29th, 2020 |
TsCl (p-toluenesulfonyl chloride) And MsCl (methanesulfonylchloride) As Reagents In Organic Chemistry
In a blatant plug for the Reagent Guide, each Friday I profile a different reagent that is commonly encountered in Org 1/ Org 2.
A friend of mine works in human resources at a company that runs huge warehouses, and they have a lot of staff turnover. He told me about one forklift driver whose favorite habit was to speed by groups of guys in the warehouse, give them the double finger salute, and yell, “F*** you, bitches!!!” as he sped by, laughing. My friend and his co-workers in upper management were like, “what can we do to get rid of this guy?”.
TsCl and MsCl: Two Reagents That Convert Hydroxyl Groups (OH) Into Good Leaving Groups
Alcohols: there are times you need to get rid of them too. Except there’s one problem. They’re terrible leaving groups. Remember that good leaving groups are weak bases? Hydroxide ions are strong bases, and therefore very poor leaving groups.
However there’s a way to turn the OH group into a good leaving group – if you can convert it into a weaker base.
One practical way this is done is with the sulfonates p-toluenesulfonylchloride (TsCl) and methanesulfonylchloride (MsCl).
Treatment of an alcohol with TsCl or MsCl, usually in the presence of a weak base such as pyridine, results in the sulfonate esters. (The purpose of pyridine is to mop up any HCl that is formed during the course of the reaction.)
Conversion to the sulfonate esters does one thing: the conjugate bases – toluenesulfonate and methanesulfonate are now extremely weak bases, since they’re heavily stabilized by resonance.
Weak bases, you say? That makes them great leaving groups. And you are right. The sulfonate esters participate easily in reactions such as substitution and elimination reactions.
And there you go.
For more, see this post: Three Ways To Make OH Into A Better Leaving Group
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So in the end it turned out that the crazy forklift driver insulted the wrong guy. He called one of co-workers a “dick”, and he then complained to management. (“Bitch” was OK, but “dick” was insulting, apparently). The management wanted to “terminate”, as they say, but my friend told them they didn’t have legal grounds to do so yet: instead, they gave the employee a written warning. He explained it to them this way. “Think of it like putting him on the tee, so that the next time he screws up, we send him down the fairway of life”.
That’s what TsCl and MsCl do. They take an alcohol and put it on the tee, so that the next reaction can send it down the fairway of life.
P.S. You can read about the chemistry of TsCl and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF.
(Advanced) References and Further Reading
- ON ESTERS OF p-TOLUENESULFONIC ACID
STUART TIPSON
The Journal of Organic Chemistry, 1944, 09 (3), 235-241
DOI: 10.1021/jo01185a005
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
DOI: 1021/jo00362a044
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
DOI: 10.1039/P29940002531 - 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
DOI: 10.15227/orgsyn.092.0195
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
DOI: 1021/jo00961a003
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.
Mestyl chloride and the tosyl chloride can be used for the protection of amino acid and in which condition?
You probably don’t want to use them as protecting groups unless you are comfortable with using a reagent like sodium amalgam to remove them, which can be strongly basic. There are much better protecting groups for amines, like carbamates.
Its just awesome!!! Never thought in this way for the reagents being used. Thanks for giving new direction to me…
I can’t find the answer to this question anywhere and I am desperate. I have asked my teachers, googled it endlessly, and asked in youtube comments. Please give me a good answer that a 5th grader would understand. When do you choose to use tosylate to make OH a good leaving group INSTEAD of using an acid to protonate the alcohol??? Like, if you were given a substrate and asked to choose reagents and solvents to achieve the desired SN2 transformation, why would you want TsCl in certain instances instead of acid? Thanks =)
Because strong acid creates R-OH2+ , which is itself a strong acid. What if you wanted to use as your nucleophile the acetylide ion RCC (-) ? That’s a useful way of making a new carbon-carbon bond, right? Well, the acetylide ion is very basic. If acid is present, then the acetylide ion will just be protonated to give the alkyne, ,RCCH. No reaction.
So, in short, one good reason is that a leaving group like OTs or OMs is more compatible with strongly basic nucleophiles. I discuss this more in this post: https://www.masterorganicchemistry.com/2015/03/10/tosylates-and-mesylates/
can this happen in tertiary alcohol as well ?
Tertiary alcohols may be converted to tosylates and mesylates, yes.
Hey quick question about using TsCl to convert the alcohol into a better leaving group. If your keeping track of absolute stereochem on a problem and the alcohol is wedged, will converting it to OT’s switch it to dashed. I am working on a synthesis problem along these lines.
Thank You.
-Matthew
No it absolutely will not. An alcohol treated with TsCl will retain its stereochemistry.
Can’t the chloride ion formed undergo an sn2 with the tosylate formed.
No, chloride ion is a far better nucleophile. Good question though. Alkyl chlorides will undergo substitution with bromide ion and iodide ion.
What is we don’t use pyridine? Will it still replace OH to OTs?
HCl will form. In some cases, particularly with benzylic or tertiary alcohols, the O will then be protonated, resulting in an even better leaving group. Through either ionization (SN1 pathway) or direct displacement, substitution of OTs for Cl can then occur. The result is that alkyl chlorides are obtained, sometimes with scrambling of stereochemistry due to the SN1 pathway. To prevent this, 1 equivalent of base is used.
Related to this: https://pubs.acs.org/doi/abs/10.1021/jo00829a084
If you have a diol with secondary and primary alcohol on the same molecule, which you react with 1 equivalent of tosyl chloride, which alcohol will be converted to the tosylate?
In practice, you will obtain a mixture that will require separation, and thus attempting to do so is impractical.
It is possible to selectively protect a primary alcohol through use of the extremely bulky triphenylmethyl (“trityl”) group.
So I’m preparing for one of the toughest entrance exams in the world and this site is legit making me dream of scoring full in Chemistry. Thanks a ton, Mr. James