# Why is pyridine used when making tosyl esters from alcohols?

Tosyl chloride is used to make a hydroxyl group into a better leaving group. However, when the reaction of tosyl chloride and an alcohol occurs, a weak base such as pyridine should be used. Why?

The function of pyridine is actually not so simple and not so easy to notice at first glance. There is a fundamental reason why pyridine is used to promote the acylation reaction, which is that it can act as a catalyst.

Despite its basicity and the subsequent formation of its chlorhydrate salt after the tosylation reaction, pyridine is also an excellent nucleophile. Pyridine is, in fact, more nucleophilic than the alcohol, and it attacks the acyl chloride rapidly, forming a highly electrophilic (because of the positive charge) intermediate: N-tosylpyridinium chloride. It is indeed this intermediate the actual tosylating agent which reacts with the alcohol to give the ester. Because pyridine is acting as a nucleophile to speed up the reaction, yet is unchanged by the reaction, it is a "nucleophilic" catalyst.

The byproduct of the reaction is hydrochloric acid, and with pyridine forms the water soluble pyridinium chloride, which is readily removed in work-up. Other preparations might use triethylamine instead of pyridine.

A base is needed to remove $\ce{HCl}$ produced in the reaction. A weak base is needed because strong bases are usually strong nucleophiles as well and would react with tosil chloride themselves. A tertiary amine and not primary/secondary is used, because amines are in general stronger nucleophiles than alcohols, but tertiary amines would give quite electrophilic products themselves. Pyridine is used, because nitrogen in it is in $\mathrm{sp^2}$ state, resulting in significantly lowered nucleophilicity.

• This answer is difficult to accept in the context of the pyridinium tosylate intermediate. – Lighthart Jan 30 '15 at 19:04
• @Lighthart Elaborate, please. – permeakra Jan 30 '15 at 23:42
• Pyridine reacts as a nucleophile with Tosyl Chloride and it is a stronger nucleophile than the alcohols in this reaction. You, yourself, pointed that out with tertiary amines. A base is needed for charge balance/acid neutralization, and said base must not irreversibly form an adduct with the tosyl chloride. Pyridine satisfies this requirement, so any mention of pyridine's lowered nucleophilicity is potentially misleading – Lighthart Jan 30 '15 at 23:55
• @Lighthart Primary and secondary amines reacting with $\ce{TsCl}$ produce cation, that can throw away a proton, so the overall reaction would be $\ce{2R2NH2 + ClTs = {R2NH2}^{+} Cl^- + R2NTs}$, while in case of tertiary amines and pyridine the product would be $R_3NTs^+$ cation that cannot stabilise by throwing away a proton and is an electrophile itself, donating tosil fragment just as tosil chloride. So, unlike secondary and primary amines, tertiary amines can be used in this reaction. – permeakra Jan 31 '15 at 8:48
• I'm not disputing your statements. What I'm saying is that comments about the nucleophilicity of pyridine make the issue somewhat more complex, and are not, strictly speaking, necessary for explaining the role of pyridine in the reaction (from the material balance perspective). The implied formation of a pyridindium tosylate may be interesting from the mechanistic perspective, but it is not clear that such a perspective is relevant to the OP. Also mixing the comments that tertiary amines are stringer nucleophiles than alcohols with 'pyridine [has lower nucleophilicity' may be confusing. – Lighthart Jan 31 '15 at 17:13

In my experience with acylations and esterificatio, (both O-acyl and O-propionylations) , a very small catalytic amnt of DMAP (100 mg per mole of product) along with reduced qty of pyridine has allowed the room temp acylation of some normally sterically hindered organics in less than 30 mins. In fact, while working with temp sensitive piperidine based compounds, the acylation was performed at - 10 deg C and had 98% conversion in 35 mins. The undesirable temp sensitive side products were at less than 1% and with some optimization managed to get undesired side products down to less than 0.05%. Of course DMAP is considered more toxic than regular pyridine, but it just with pyridine it can be separated from products by similar methods. We were dealing with esp lipophilic compounds acylated in DCM, and removal of pyridines simply involved a wash with acidic water. Even though the products formed HCL salts. Their products are lipophilic nature kept them in the DCM layer. We never experienced more than 5% product loss during acid wash workup and optimization reduced the workup loss to 2%. Overall, DMAP is impressive and stuff. Even with non temp sens acylations, you can still achieve rapid nearly full acylations in 20 mins at room temp and also the use of a small cat qty of DMAP seems to reduce the pyridine requirements, in our case we reduced pyridine qty by a factor of 5 without detriment to our yield or efficiency In my experience with acylations, using acyl and propionylations, a very small catalytic amnt of DMAP (100 mg per mole of product) along with pyridine has allowed the room temp acylation of some normally sterically hindered organics in less than 30 mins. In fact, while working with temp sensitive piperidine based compounds, the acylation was performed at - 10 deg C and had 98% conversion in 35 mins. The undesirable temp sensitive side products were at less than 1% and with some optimization managed to get undesired side products down to less than 0.05%. Of course DMAP is considered more toxic than regular pyridine, but it just with pyridine it can be separated from products by similar methods. We were dealing with esp lipophilic compounds acylated in DCM, and removal of pyridines simply involved a wash with acidic water. Even though the products formed HCL salts. Their products are lipophilic nature kept them in the DCM layer. We never experienced more than 5% product loss during acid wash workup and optimization reduced the workup loss to 2%. Overall, DMAP is impressive and stuff. Even with non temp sens acylations, you can still achieve rapid nearly full acylations in 20 mins at room temp and also the use of a small cat qty of DMAP seems to reduce the pyridine requirements, in our case we reduced pyridine qty by a factor of 5 without detriment to our yield or efficiency.

The temp sensitive reaction was primary alcohol phenylpipedidine to ester acylation. It is temp and acidic sensitivity was needed to avoid problematic olefination of alcohol forming a undesirable phenylpyridine which at the time was suspected to have possible neurotoxicity mediated thru MAO mediated biotransformation that have been known to have highly specific dopaminergic neuron toxicity and have henceforth been utilized to induce Parkinsonism in animals for the testing of anti Parkinson agents, selegline and others have resulted from this line of research. A related study showing phenylpyridinium toxicity to be highly dependent on N-substitution on the piperidine, any group larger than N-propyl showed no reactivity to MAO B or MAO A enzymes, thereby not undergoing the enzymatic transformation to neurotoxicm. Our piperidine was substituted both on the carbon ring and N-phenylpropyl on piperidine nitrogen so there was no surprise when later testing found the olefin byproducts to have no MAO reactivity. Even taking into acct the lack of toxicity of our undesirable byproducts, the DMAP was an impressive catalyst for acylation and ESTERIFICATION that I still would have chosen to work with it out of the convenience of performing rapid room temp acylations with minimal pyridine and easy workup. DMAP is also highly effective in N-acylations with similar benefits in efficiency and yield. I've read of some studies that also show rapid conversion of N-acylations at room temp with tiny catalytic qty of DMAP.

• Welcome to chemistry.se! Please use proper spelling and punctuation. I don't see how this text answers the question posed. – Martin - マーチン Oct 4 '19 at 11:50