p-TOLUENESULFONIC ACID

1

p-Toluenesulfonic Acid

SO

3

H

[104-15-4]

C

7

H

8

O

3

S

(MW 172.22)

InChI = 1/C7H8O3S/c1-6-2-4-7(5-3-6)11(8,9)10/h2-5H,1H3,(H,

8,9,10)/f/h8H

InChIKey = JOXIMZWYDAKGHI-FZOZFQFYCL
(monohydrate)
[6192-52-5]

C

7

H

10

O

4

S

(MW 190.24)

InChI = 1/C7H8O3S.H2O/c1-6-2-4-7(5-3-6)11(8,9)10;/h2-5H,

1H3,(H,8,9,10);1H2/f/h8H;

InChIKey = KJIFKLIQANRMOU-LUXJPWOACG
(Na salt)
[657-84-1]

C

7

H

7

NaO

3

S

(MW 194.20)

InChI = 1/C7H8O3S.Na/c1-6-2-4-7(5-3-6)11(8,9)10;/h2-5H,

1H3,(H,8,9,10);/q;+1/p-1/fC7H7O3S.Na/q-1;m

InChIKey = KVCGISUBCHHTDD-YENMBZFSCC

(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; pK

a

−6.62 (H

2

SO

4

).

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.

Original Commentary

Gregory S. Hamilton
Scios Nova, Baltimore, MD, USA

Acid Catalyst. Tosic acid is one of the most widely used or-

ganic acid catalysts, particularly in nonpolar solvents. It is uti-
lized 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 pro-
cesses. 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 BF

3

·Et

2

O in

the tetrahydropyranylation and methoxytetrahydropyranylation of
alcohols (3 examples).

5

O

Br

HO

OH

Br

O

O

(1)

p

-TsOH, benzene

reflux

95%

HS

SH

(2)

O

O

O

O

S

S

O

H

p

-TsOH, toluene

reflux

98%

Treatment of acetals (eqs 3 and 4)

6,7

with aqueous tosic acid

effects cleavage to the carbonyl compounds.

O

HO

O

O

OH

O

O

OH

OH

(3)

p

-TsOH

H

2

O, CH

2

Cl

2

(4)

p

-TsOH

EtOH, H

2

O

97%

O

O

O

C

9

H

19

OTHP

O

C

9

H

19

OH

In a recently described synthesis of (+)-phyllanthocin,

8

spiro-

acetalization 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.

O

BnO

O

OH

O

(5)

O

O

OBn

O

O

(1)

(2)

p

-TsOH

benzene

72%

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, re-

spectively, by treatment with tosic acid in organic solvent.

p

-TsOH

EtOH

O

O

O

CO

2

Et

CO

2

Et

(6)

Avoid Skin Contact with All Reagents

2

p-TOLUENESULFONIC ACID

(7)

p

-TsOH

CH

2

Cl

2

62%

CO

2

H

OH

O

O

H

(8)

p

-TsOH

cyclohexane

52%

CO

2

H

CHO

O

O

H

Tosic acid has also been used to catalyze internal translactoniza-

tion processes (eq 9).

12

(9)

O

O

O

p

-TsOH

93%

O

OH

OH

Dehydration Processes. Dehydration of ketols to α,β-unsatu-

rated 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 pro-

cesses 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

-TsOH, silica gel

45 °C, 1 h

87%

HO

H

H

(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 cyclohex-

anone 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[4.3.2.0]undeca-
nones catalyzed by tosic acid,

22

(3) was converted to (4) in reflux-

ing 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

(3)

(4)

O

O

(11)

p

-TsOH

benzene, reflux

82%

(12)

p

-TsOH

benzene, reflux

98%

(13)

S

S

O

p

-TsOH

benzene, reflux

75%

S

S

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 β-hydroxyalkyl phenyl

sulfides with tosic acid in refluxing benzene results in migration
of the phenylthio group to generate allylic sulfides.

27

Ph

OH

(14)

OAc

Ph

p

-TsOH

Ac

2

O, AcOH

91%

Synthesis of Enol Ethers and Acetates. Tosic acid is, in gen-

eral, superior to other common catalysts (Sulfuric Acid, Phos-
phoric 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

OAc

CO

2

Me

O

CO

2

Me

OAc

(15)

p

-TsOH

89%

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-
3β,5α,6β-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 17α-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 pres-
ence 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

(16)

p

-TsOH, EtOH

3 h, Et

2

O

93%

Boc-

D

-Ala–

D

-Ala–OBu

D

-Ala–

D

-Ala–OBu

A list of General Abbreviations appears on the front Endpapers

p-TOLUENESULFONIC ACID

3

Synthesis of Substituted Methylbenzenes. Tosic acid is lithi-

ated at the 2-position with 2 equiv of Butyllithium; the resulting
anion may be reacted with various electrophiles. Desulfonyla-
tion 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 Poly-
phosphoric Acid;

43

alternatively, the sulfonyl chloride may be

reacted with aromatic substrates under Friedel–Crafts condi-
tions.

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

First Update

Julia Haas & Yvan Le Huérou
Array BioPharma, Boulder, CO, USA

Tosylation of Alcohols. The tosylation of alcohols is used

extensively in organic synthesis.

48

The most common tosylation

methods rely on the use of tosyl chloride or anhydride in the pres-
ence of a base,

49

but significant amounts of the corresponding

chlorides can be formed during these reactions. The use of
p

-toluenesulfonic acid in accord with alkyl orthoformates, alkyl

ethers, esters, or 2-alkoxybenzothiazolium salts to produce
tosylates can avoid alkyl chloride formation and other potential
side reactions.

50

Solid-phase bound dehydrating agents can also

be used.

51

Recently, methods involving p-toluenesulfonic acid

in the presence of catalytic Fe(III)-montmorillonite,

52

cobalt(II)

chloride,

53

or silica chloride

54

have been reported (eq 17). Typ-

ically, these reactions are run in refluxing dichloromethane or
dichloroethane, with 1 equiv of p-toluenesulfonic acid. Water
is the only by-product. The reactions are generally high yield-
ing with primary and secondary alcohols, less efficient with phe-
nols, and inefficient with tertiary alcohols. An interesting feature
of this method is its regioselectivity: the difference in reaction
rates between primary and secondary alcohols allows for selective
tosylations (eq 18). This is of particular interest for the monotosy-
lation of terminal diols (eq 19), which usually require an activa-
tion step (formation of tin acetals for example) to achieve selective
monotosylation.

55

ROH

ROTs + H

2

O

catalysis

1 equiv p-TsOH

ClCH

2

CH

2

Cl/CH

2

Cl

2

reflux

R = primary/secondary alkyl,

aryl, benzyl

(17)

Formation of α

α

α-Tosyloxy Ketones. α-Tosyloxy ketones are

useful precursors for the construction of heterocyclic compounds

such as thiazoles, selenazoles, oxazoles, imidazoles, pyrazoles,
benzofurans, or lactones. The α-sulfonyloxylation of ketones is
a well-known synthetic transformation and a number of methods
have been reported for this purpose.

56

However, direct, regiospe-

cific α-sulfonyloxylations of unsymmetrical ketones are difficult
to achieve.

57

The first method to overcome this problem was

reported in 1998 and consists in treating 2-alkanones with corres-
ponding copper(II) organosulfonates (prepared from copper(II)
oxide and the respective organosulfonic acids in situ) (eq 20).

58

OH

OH

OH

OTs

OTs

OTs

p

-TsOH

silica chloride

DCM, reflux

86%

8%

(18)

+

R

OH

OH

R

OTs

OH

Fe

3+

-mont, p-TsOH

ClCH

2

CH

2

Cl

reflux

R = alkyl, OH

(19)

O

Alk

OTs

O

Alk

CH

3

CN, reflux, 14 h

(20)

CuO, p-TsOH

Other methods have since extended the scope of the reaction by

using hypervalent iodine reagents

59

such as [hydroxyl(tosyloxy)

iodo]benzene (Koser’s reagent) allowing the formation of aryl,
heteroaryl, or cycloalkyl α-tosyloxy ketones (eq 21).

60,61

Koser’s

reagent is usually formed by reacting (diacetoxy)iodobenzene and
p

-toluenesulfonic acid monohydrate either in solution

60

or by

grinding in a mortar.

61

R

O

R

′

R

O

R

′

OTs

A: ArI(OAc)

2

(1.2 equiv), p-TsOH·H

2

O (2.4 equiv), CH

3

CN, reflux

B: ArI(OAc)

2

, p-TsOH·H

2

O

R = aryl, alkyl, heteroaryl, cycloalkyl
R

′ = H, Me, Ac, cycloalkyl

Conditions:

(21)

A polymer-supported version of these methods has also been

developed. It allows for the formation of a wide variety of func-
tionalized molecules by release of the polymer-bond α-tosyloxy
ketones (eq 22).

62

The polymer-supported α-tosyloxy ketones

react with nucleophiles (carboxylic acids, phenols, thiols, amines),
bis-nucleophiles (to form heterocycles), or alkynyl Grignard
reagents.

Avoid Skin Contact with All Reagents

4

p-TOLUENESULFONIC ACID

R

O

R

′

SO

3

H·H

2

O

SO

3

I

Ph

OH

PhI(Ac)

2

R

O

O

R

′

O

2

S

S

NH

2

PPTS

R

R

′

S

N

R

O

Nu

R

′

Nu = carboxylic acid, phenols,
thiols, amines, nitrile

NuH

(22)

R = alkyl, cycloalkyl, Bz
R

′ = alkyl, cycloalkyl, Ac, CO

2

Me, aryl

The supported p-toluenesulfonic acid monohydrate is also of

interest for the formation of α-tosyloxy ketones from olefins or
epoxides (eq 23).

R

′

R

R

O

O

R

′

O

2

S

SO

3

H·H

2

O

R = alkyl, cycloalkyl
R

′ = cycloalkyl, H

1. DMDO

2.

3. DMP

(23)

α

-Tosyloxy ketones and α-tosyloxy aldehydes can be prepared

from alcohols by treatment with iodosylbenzene and p-toluenesul-
fonic acid monohydrate (eq 24).

63

Secondary alcohols give

α

-tosyloxy ketones in high yields, while primary alcohols give

α

-tosyloxy aldehydes in moderate yields. The formation of

heteroaromatic rings such as thiazoles, imidazoles, or imidazo
[1,2-a]pyridines can be accomplished when the crude α-tosyloxy
ketones are treated with thioamide, benzamidine, or 2-aminopyri-
dine, respectively.

R

OH

R

′

R

O

R

′

OTs

heterocycles

PhIO (3 equiv)

p

-TsOH·H

2

O (2.5 equiv)

CH

3

CN, heat, 1.5 h

R = aryl, alkyl, H
R

′ = H, alkyl

(24)

Selective N-Debenzylation of Amides. N-Benzylamides can

be debenzylated efficiently with p-toluenesulfonic acid in re-
fluxing toluene (eq 25).

64

This reaction is attractive because

other debenzylation methods such as catalytic hydrogenation and
refluxing in trifluoroacetic acid often fail to provide good yields of

the desired products. Unsubstituted (X = H) as well as methoxy-
substituted benzyl groups can be removed cleanly, and various
functional groups are tolerated in this reaction. For 2,4-dimethoxy-
benzylamides, selective N-debenzylation can be accomplished in
the presence of Fmoc, BOC, or trityl-protecting groups. Optically
pure amino acid amides can be debenzylated without epimeri-
zation.

p-

TsOH (4 equiv)

toluene, reflux

R

O

N
H

X

R

O

NH

2

(25)

65–100%

Selective Cleavage of Acetyl Groups.

Deacetylations of

alcohols occur in good yields using p-toluenesulfonic acid mono-
hydrate in CH

2

Cl

2

/MeOH.

65

Under these conditions, O-acetyl

groups can be cleaved chemoselectively in the presence of
O

-benzoyl groups (eq 26).

p-

TsOH (2 equiv)

40

°C

O

OCH

3

OBz

BzO

AcO

OAc

O

OCH

3

OBz

BzO

HO

OH

(26)

91%

Synthesis of Thioesters from Thioacetylenes. Thioesters can

be prepared by reacting thioacetylenes with p-toluenesulfonic acid
in dichloromethane in the presence of silica gel (eq 27).

66

The

yields are generally good and both alkyl- and aryl substituents are
tolerated at R

1

and R

2

.

p-

TsOH

silica gel, 40

°C

R

1

SR

2

R

1

O

S

R

2

(27)

51–87%

Bromination of Acetophenones.

Acetophenones can be

brominated using N-bromosuccinimide and p-toluenesulfonic
acid in methanol.

67

Depending on the reaction conditions and the

substrate, both α-bromination and ring bromination products can
be obtained (eq 28). Ultrasound accelerates the α-bromination
reaction, allowing for lower temperatures and shorter reaction
times. 4-Substituted acetophenones exclusively give the corres-
ponding α-bromination products, even under thermal conditions.
A full equivalent of p-toluenesulfonic acid is needed for complete
conversion, and the reactions do not take place in the absence of
p

-toluenesulfonic acid thermally or sonically.

NBS, p-TsOH

MeOH

O

O

Br

A

O

Br

B

(28)

35

°C, ultrasound

conditions

71%

65

°C

29%

0%

100%

+

Synthesis of α

α

α-Aryl-β

β

β-amino Esters Through 1,2-Aryl

Migration.

p

-Toluenesulfonic acid catalyzes the decomposi-

tion of α-diazo esters and subsequent 1,2-aryl migration.

68

A list of General Abbreviations appears on the front Endpapers

p-TOLUENESULFONIC ACID

5

p

-Toluenesulfonic acid is superior to transition metal catalysts

such as Rh

2

(OAc)

4

and Cu(acac)

4

in this reaction in that it more

selectively promotes aryl migration over hydride migration. The
diazo esters can be prepared from aldehyde-derived tosyl imines
by DBU-catalyzed addition of ethyl diazoacetate. This sequence
was applied to the synthesis of α-aryl-β-amino esters (eq 29).

69

p-

TsOH (1 mol%)

CH

2

Cl

2

, 0

°C

N

2

CHCO

2

Et, DBU

CH

2

Cl

2

, rt

85–96%

O

OEt

N
H

Ts

Ar

O

OEt

N
H

Ts

Ar

Ar

H

N

Ts

Ts

N

2

O

OEt

Ar

HN

(29)

63–84%

79–95%

Pd/C, MeOH, rt

Use of p-Toluenesulfonic Acid in Borane-mediated Reduc-

tions. p-Toluenesulfonic acid can be added to borane-mediated
reductions to increase their selectivity. For example, addition of
p

-toluenesulfonic acid has been reported to increase the enantio-

selectivity in a CBS-catalyzed reduction of a ketone,

70

and to

increase the chemoselectivity in the reduction of α,β-unsaturated
hydrazones to form allyl hydrazines.

71

Miscellaneous Reactions. p-Toluenesulfonic acid has been

used for the formation and cleavage of diphenylmethyl ether pro-
tecting groups,

72

and for the synthesis of furans and pyrans via

the rearrangement of phenylthio-substituted 1,n-diols.

73

Polymer-

supported p-toluenesulfonic acid reagents are widely used as
scavenger agents for amines in solid supported and parallel
syntheses.

74

Related

Reagents. Hydrochloric Acid; Methanesulfonic

Acid; Sulfuric Acid; Trifluoroacetic Acid; Trifluoromethanesul-
fonic Anhydride.

1.

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Ed.; Merck: Rahway, NJ, 1989; p 1501.

2.

The Sigma-Aldrich Library of Chemical Safety Data

, 2nd ed.; Lenga,

R. E., Ed.; Sigma-Aldrich: Milwaukee, 1988; Vol. 2, p 3366.

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, 305.

5.

van Boom, J. H.; Herschied, J. D. M., Synthesis 1973, 169.

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Oikawa, Y.; Nishi, T.; Yonemitsu, O., J. Chem. Soc., Perkin Trans. 1
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7.

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30

, 7325.

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Suemune, H.; Oda, K.; Saeki, S.; Sakai, K., Chem. Pharm. Bull. 1988,
36

, 172.

11.

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Corey, E. J.; Brunelle, D. J.; Nicolaou, K. C., J. Am. Chem. Soc. 1977,
99

, 7359.

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14.

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15.

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30

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Zhang, W.-Y.; Jakiela, D. J.; Maul, A.; Knors, C.; Lauher, J. W.; Helquist,
P.; Enders, D., J. Am. Chem. Soc. 1988, 110, 4652.

17.

D’Onofrio, F.; Scettri, A., Synthesis 1985, 1159.

18.

Hünig, S.; Lücke, E.; Brenninger, W., Org. Synth. 1961, 41, 65; Org.
Synth., Coll. Vol. 1973

, 5, 808.

19.

Shimizu, T.; Hayashi, Y.; Teramura, K., Bull. Chem. Soc. Jpn. 1984, 57,
2531.

20.

Antonowa, A.; Hauptmann, S., Z. Chem. 1976, 16, 17.

21.

Tamura, Y.; Yoshimoto, Y.; Sakai, K.; Kita, Y., Synthesis 1980, 483.

22.

Peet, N. P.; Cargill, R. L.; Bushey, D. F., J. Org. Chem. 1973, 38, 1218.

23.

Pirrung, M. C., J. Am. Chem. Soc. 1979, 101, 7130.

24.

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A list of General Abbreviations appears on the front Endpapers