p-Toluenesulfonic Acid

[104-15-4]  · C7H8O3S  · p-Toluenesulfonic Acid  · (MW 172.22) (monohydrate)

[6192-52-5]  · C7H10O4S  · p-Toluenesulfonic Acid  · (MW 190.24) (Na salt)

[657-84-1]  · C7H7NaO3S  · Sodium p-Toluenesulfonate  · (MW 194.20)

(acid catalyst frequently used in nonpolar media; effective in carbonyl protection-deprotection; selectively cleaves N-Boc, other amine protecting groups; superior for enol ether, acetate preparation; used in esterifications, dehydrations, isomerizations, rearrangements)

Alternate Name: tosic acid.

Physical Data: the anhydrous acid exists as monoclinic leaflets or prisms, mp 106-107 °C; pKa -6.62 (H2SO4).1 There is also a metastable form, mp 38 °C. The monohydrate is a white crystalline powder, mp 103-106 °C.

Solubility: sol water (67 g/100 mL), ethanol, ethyl ether. The sodium salt is very sol water.

Form Supplied in: widely available as the monohydrate, which is commonly used. Various metal salts are also commercially available.

Analysis of Reagent Purity: by acid-base titrimetry.46

Purification: precipitated or crystallized from HCl soln, aq EtOH; the free acid has been crystallized from several organic solvents.47

Handling, Storage, and Precautions: highly toxic, oxidizing agent. Extremely irritating to the skin and mucous membranes. Use of gloves and protective clothing is recommended.2 Use in a fume hood.

Acid Catalyst.

Tosic acid is one of the most widely used organic acid catalysts, particularly in nonpolar solvents. It is utilized frequently in many of the common acid-catalyzed reactions and transformations in organic chemistry, including esterification, formation of acetals, dehydration processes, preparation of enol ethers and acetates, and rearrangement and isomerization processes. A comprehensive literature review of even its recent uses is beyond the scope of this publication; representative examples of each of the above-mentioned classes are presented.

Formation and Cleavage of Acetals.

Tosic acid is perhaps the most common acid catalyst for the protection of ketones as acetals. The reaction is conventionally carried out in refluxing toluene or benzene with removal of water by a Dean-Stark trap (eq 1).3 Although Boron Trifluoride Etherate is the customary catalyst for the condensation of ketones with alkyldithiols, tosic acid is a milder reagent and has been used for this purpose (eq 2).4 p-Toluenesulfonic acid may also be used in lieu of BF3.Et2O in the tetrahydropyranylation and methoxytetrahydropyranylation of alcohols (3 examples).5

Treatment of acetals (eqs 3 and 4)6,7 with aqueous tosic acid effects cleavage to the carbonyl compounds.

In a recently described synthesis of (+)-phyllanthocin,8 spiroacetalization of (1) to form key intermediate (2) was studied (eq 5). Acid-catalyzed cyclization by tosic acid was found to be superior to 10-Camphorsulfonic Acid- or base-catalyzed cyclization using 1,8-Diazabicyclo[5.4.0]undec-7-ene.

Esterification and Lactone Formation.

Tosic acid has been used in lieu of mineral acid in Fischer esterifications of carboxylic acids (eq 6).9 Hydroxy acids (eq 7)10,11 and aldehyde carboxylic acids (eq 8)10 may be cyclized to lactones and enol lactones, respectively, by treatment with tosic acid in organic solvent.

Tosic acid has also been used to catalyze internal translactonization processes (eq 9).12

Dehydration Processes.

Dehydration of ketols to a,b-unsaturated compounds is effectively catalyzed by tosic acid;13 addition of calcium chloride to the reaction mixture has been noted to give superior results in some instances.14,15 Other acid-catalyzed processes can occur concomitantly, such as cleavage of silyl ethers.16 Tosic acid adsorbed on silica gel was found to be an effective catalyst for the dehydration of secondary and tertiary alcohols (16 examples),17 including a number of steroid alcohols which are resistant to most methods of catalyzed dehydration (eq 10).

p-Toluenesulfonic acid has been used to catalyze the formation of enamines; water is removed via azeotropic distillation.18 The dehydration of primary nitro compounds by tosic acid provides access to nitrile oxides, which can subsequently engage in 1,3-dipolar cycloaddition reactions.19 Oximes may be dehydrated to nitriles by heating with tosic acid in DMF.20 Reaction of cyclohexanone oximes with ketene in the presence of tosic acid results in aromatization to aryl amines.21 This constitutes a milder method for Semmler-Wolff aromatization than those previously reported.

Cationic Rearrangements and Isomerizations.

In a study of Wagner-Meerwein rearrangements of tricyclo[]undecanones catalyzed by tosic acid,22 (3) was converted to (4) in refluxing benzene in 82% yield (eq 11). A similar rearrangement has been utilized in the synthesis of cyclopentanoid sesquiterpenes (eq 12).23 Similar processes in which the migrating atom is sulfur have been reported;24 sulfur-containing bicyclo[10.5.0]alkenes and related compounds have been obtained via tosic acid-catalyzed ring expansions of sulfoxides (eq 13).25

Treatment of tertiary vinyl alcohols with tosic acid in a mixture of Acetic Acid and Acetic Anhydride effects their conversion to allylic acetates (eq 14).26 Treatment of b-hydroxyalkyl phenyl sulfides with tosic acid in refluxing benzene results in migration of the phenylthio group to generate allylic sulfides.27

Synthesis of Enol Ethers and Acetates.

Tosic acid is, in general, superior to other common catalysts (Sulfuric Acid, Phosphoric Acid, potassium acetate) for enolization in the conversion of ketones to their enol acetates using acetic anhydride.28,29 This methodology has been used extensively in steroid synthesis.30-33 Isopropenyl acetate may also be used with removal of acetone by slow distillation (eq 15).34 Enol ethers may similarly be obtained by treatment with tosic acid and alcohol in refluxing benzene or toluene followed by azeotropic removal of water.35

Synthesis of Steroid Acetates.

Tosic acid has been used to good effect in the acetylation of steroid substrates, replacing the commonly used Pyridine catalyst. Treatment of cholestane-3b,5a,6b-triol with pyridine and acetic anhydride afforded the 3,6-diacetate; heating the triol with tosic acid in acetic anhydride provided the desired triacetate.36 Acetylation of the 17a-hydroxyl group of progesterone has been accomplished by this method.37,38

Addition of Alcohols to Nitriles (Ritter Reaction).

Esters may be prepared by the acid-catalyzed addition of alcohols to nitriles. Tosic acid is the preferred catalyst for this reaction.39

Cleavage of Amine Protecting Groups.

t-Butyloxycarbonyl (Boc) groups may be cleaved from protected amines in the presence of t-butyl- and p-methoxybenzyl esters by the action of tosic acid in a mixture of ethanol and ether (eq 16) (seven examples).40 p-Methoxybenzyloxycarbonyl groups may be removed with tosic acid in acetonitrile.41

Synthesis of Substituted Methylbenzenes.

Tosic acid is lithiated at the 2-position with 2 equiv of n-Butyllithium; the resulting anion may be reacted with various electrophiles. Desulfonylation of the substituted product constitutes a synthesis of meta-substituted toluenes.42

Synthesis of Sulfones.

Alkyl p-tolyl sulfones may be prepared by reaction of the p-Toluenesulfonyl Chloride with Grignard reagents. p-Tolyl aryl sulfones can be synthesized by the condensation of tosic acid with aromatic compounds in Polyphosphoric Acid;43 alternatively, the sulfonyl chloride may be reacted with aromatic substrates under Friedel-Crafts conditions.43 Milder conditions using Phosphorus(V) Oxide-Methanesulfonic Acid have been reported.44

Amine Salts.

Amines are frequently converted to their tosylate salts for characterization.45

Related Reagents.

Hydrochloric Acid; Methanesulfonic Acid; Sulfuric Acid; Trifluoroacetic Acid; Trifluoromethanesulfonic Anhydride.

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Gregory S. Hamilton

Scios Nova, Baltimore, MD, USA

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