HYDROGEN CHLORIDE

1

Hydrogen Chloride

1

CIH

[7647-01-0]

ClH

(MW 36.46)

InChI = 1/ClH/h1H
InChIKey = VEXZGXHMUGYJMC-UHFFFAOYAT

(reagent for hydrochlorination of alkenes and alkynes;

4

cleaves

epoxides

1b

and ethers;

21a

converts alcohols to chlorides

12b

and

diols to cyclic ethers;

17

chloroalkylates arenes;

22

converts

aldehydes to α-chloro ethers

23b

)

Alternate Name: Hydrochloric Acid

.

Solubility:

sol most organic solvents.

2

Form Supplied in:

widely available; compressed gas; 1 M solu-

tion in AcOH, Et

2

O, or Me

2

S; 4 M solution in dioxane; 37%

aqueous solution.

Preparative Methods:

addition of H

2

SO

4

to NaCl or 37% aque-

ous HCl.

3

Handling, Storage, and Precautions:

highly toxic and corrosive;

handle only in a fume hood.

Hydrochlorination of Alkenes and Alkynes.

HCl under-

goes solution-phase addition readily to C=C double bonds that
are strained or from which the resulting carbocation is benzylic
or tertiary.

1a

However, other alkenes do not undergo addition at

preparatively useful rates.

4

Although addition can be facilitated

by Lewis acid catalysis,

5

mono- and 1,2-disubstituted alkenes un-

dergo polymerization under these conditions.

5a

The rate of ad-

dition is inversely proportional to the electron donor strength of
the solvent, following the order heptane ≈ CHCl

3

>

xylene >

nitrobenzene >> MeOH > dioxane > Et

2

O.

6,7

In the strongly

donating solvent Et

2

O, even highly reactive alkenes undergo slow

addition unless one of the reactants is present in high concentra-
tion. Additions conducted in solutions saturated with HCl exhibit
an inverse temperature coefficient because of the increased solu-
bility of HCl at lower temperatures.

3b

Alkynes undergo addition more slowly than alkenes, requir-

ing extended reaction times, elevated temperatures, and, usually,
Lewis acid catalysis.

1a

However, dialkylalkynes afford the (Z)-

vinyl chloride on treatment with refluxing aqueous HCl (eq 1).

8

Pr

Pr

Pr

Cl

Pr

(1)

37% HCl

80 °C, 18 h

81%

Addition to alkenes and alkynes is greatly facilitated by the

presence of appropriately prepared silica gel or alumina.

4

Alkenes

and alkynes that exhibit little or no reaction with HCl in solution
readily undergo addition under these conditions. The reaction is
rendered even more convenient by the use of various inorganic and
organic acid chlorides that afford HCl in situ in the presence of
silica gel or alumina. Surface-mediated hydrochlorination of 1,2-
dimethylcyclohexene in CH

2

Cl

2

gives initially the syn adduct,

which undergoes equilibration with the thermodynamically more
stable trans isomer under the reaction conditions (eq 2).

4

Thus

either isomer can be obtained in high yield through the proper

choice of reaction conditions. Similarly, phenylalkynes initially
afford syn adducts, which undergo subsequent equilibration with
the thermodynamically more stable (Z) isomers (eq 3).

4

Again,

either isomer can be obtained in high yield.

Cl

H

Cl

H

(2)

SiO

2

or

Al

2

O

3

HCl

HCl

Ph

R

Ph

Cl

R

Ph

Cl

R

(3)

R = Me or Ph

SiO

2

or Al

2

O

3

SOCl

2

Cleavage of Epoxides to Chlorohydrins.

The addition of

HCl to epoxides to form chlorohydrins proceeds readily with
either 37% aqueous HCl or solutions of anhydrous HCl in a variety
of organic solvents.

1b,9

For simple alkyl-substituted oxiranes, ad-

dition typically occurs through backside attack of chloride ion
on the protonated epoxide, resulting in net inversion of the car-
bon center (eq 4).

1b,9

For aryl- or vinyl-substituted epoxides (in

which more carbocationic character is involved in the transition
state during ring opening), the stereochemical outcome may range
from complete retention to predominant inversion and is highly
solvent dependent.

10

Anhydrous conditions and solvents of low

dielectric strength favor syn cleavage, while anti cleavage is fa-
vored in the presence of water or in hydroxylic solvents.

10

(4)

O

Cl

OH

37% HCl

2 h

77%

Cleavage of simple alkyl-substituted epoxides under anhydrous

conditions typically favors formation of the chlorohydrin in which
chlorine is at the less highly substituted position (eqs 5 and 6).

11

More highly substituted epoxides, particularly aryl-substituted,
give increasing amounts of the opposite regioisomer. Regioselec-
tivity is also very sensitive to the solvent system employed for the
reaction (eqs 5 and 6).

O

Cl

OH

OH

Cl

(5)

+

THF

THF/H

2

O

84%
40%

16%
60%

HCl

O

Cl

OH

OH

Cl

(6)

+

THF

THF/H

2

O

62%
25%

38%
75%

HCl

Avoid Skin Contact with All Reagents

2

HYDROGEN CHLORIDE

Reaction with Alcohols. The reaction of HCl with alcohols

to form alkyl chlorides is a general reaction, giving good to high
yields of products. Primary and secondary aliphatic alcohols are
most easily converted to the corresponding chlorides with ei-
ther 37% aqueous HCl or anhydrous HCl at elevated tempera-
tures in the presence of Zinc Chloride.

12

Phase-transfer cataly-

sis has also been employed in the synthesis of primary chlorides
from alcohols.

13

The need for a catalyst can be avoided by us-

ing the highly polar solvent HMPA.

14

Tertiary,

7,15a

benzylic,

15b

and allylic

15c

alcohols are readily converted to chlorides at 25

◦

C,

or lower, without the need for catalysts. Glycerol can be selec-
tively mono- or dichlorinated by controlled addition to HCl to
AcOH solutions.

16

Bis(benzylic) diols have been converted in

good yields to substituted cyclic ethers with HCl, whereas reaction
with HBr or HI followed a completely different course (eq 7).

17

(7)

O

OH

OH

37% HCl

∆, 6 h

80%

Reductions with HCl. HCl has been used to reduce a series

of 1,4-cyclohexanediones to the corresponding phenols in good
yield (eq 8).

18

(8)

37% HCl

∆, 15 h

O

O

OH

70%

α

-Diazo ketones are reduced to α-chloromethyl ketones by

either anhydrous HCl in organic solvents or 37% aqueous HCl in
Et

2

O.

19

Generally, good to high yields are obtained. Chloroace-

tone was synthesized in this manner without the complicating
formation of dichlorides (eq 9).

19c

N

2

O

HCl

Et

2

O

Cl

O

(9)

68%

Although aryl sulfoxides are reduced to sulfides by HCl,

accompanying ring chlorination limits the usefulness of the re-
action.

20

Cleavage of Ethers. Allyl, t-butyl, trityl, benzhydryl, and ben-

zyl ethers are cleaved by HCl in AcOH (eq 10).

21a

In some cases,

aryl methyl ethers have been successfully cleaved (eq 11).

21b

OCH

2

Ph

OMe

R

O

MeO

OH

O

OH

OMe

R

(10)

37% HCl

AcOH

80 °C, 1.5 h

R =

89%

NH

MeO

MeO

OMe

NH

MeO

HO

OH

(11)

20% HCl

∆, 13 h

57%

Reaction with Aldehydes. Arenes react readily with mixtures

of HCl and formaldehyde in the presence of a Lewis acid, usually
ZnCl

2

, to give the chloromethylated derivative.

22

Yields are good

and the reaction conditions can be controlled to afford predomi-
nantly mono- or disubstituted products. Chloroalkylations can be
effected with other aldehydes such as propanal and butanal. In the
presence of alcohols, HCl and aldehydes give high conversions to

α

-chloro ethers (eq 12).

23

Ph

OH

H

H

O

Ph

O

Cl

(12)

+

83%

HCl

Related Reagents. Formaldehyde–Hydrogen Chloride; Hy-

drochloric Acid.

1.

(a) Larock, R. C.; Leong, W. W., Comprehensive Organic Synthesis 1991,
4

, 269. (b) Parker, R. E.; Isaacs, N. S., Chem. Rev. 1959, 59, 737.

2.

Fogg, P. G. T.; Gerrard, W.; Clever, H. L. In Solubility Data Series;
Lorimer, J. W.; Ed.; Pergamon: Oxford, 1990; Vol. 42.

3.

(a) Maxson, R. N., Inorg. Synth. 1939, 1, 147. (b) Brown, H. C.; Rei,
M.-H.; J. Org. Chem. 1966, 31, 1090.

4.

(a) Kropp, P. J.; Daus, K. A.; Crawford, S. D.; Tubergen, M. W.; Kepler,
K. D.; Craig, S. L.; Wilson, V. P., J. Am. Chem. Soc. 1990, 112, 7433.
(b) Kropp, P. J.; Daus, K. A.; Tubergen, M. W.; Kepler, K. D.; Wilson,
V. P.; Craig, S. L.; Baillargeon, M. M.; Breton, G. W., J. Am. Chem. Soc.
1993, 115, 3071. (c) Kropp, P. J.; Crawford, S. D., J. Org. Chem. 1994,
59

, 3102.

5.

(a) Shields, T. C., Can. J. Chem. 1971, 49, 1142. (b) Hassner, A.; Fibiger,
R. F., Synthesis 1984, 960.

6.

(a) O’Connor, S. F.; Baldinger, L. H.; Vogt, R. R.; Hennion, G. F., J.
Am. Chem. Soc. 1939

, 61, 1454. (b) Hennion, G. F.; Irwin, C. F., J. Am.

Chem. Soc. 1941

, 63, 860.

7.

For a different order, see: Brown, H. C.; Liu, K.-T.; J. Am. Chem. Soc.
1975, 97, 600.

8.

Hudrlik, P. F.; Kulkarni, A. K.; Jain, S.; Hudrlik, A. M., Tetrahedron
1983, 39, 877.

9.

(a) Lucas, H. J.; Gould, C. W., Jr., J. Am. Chem. Soc. 1941, 63, 2541. (b)
Buchanan, J. G.; Sable, H. Z. In Selective Organic Transformations;
Thyagarajan, B. S., Ed.; Wiley: New York, 1972; Vol. 2, p 1.
(c) Armarego, W. L. F. In Stereochemistry of Heterocyclic Compounds;
Taylor, E. C.; Weissberger, A., Eds.; Wiley: New York, 1977; p 23. (d)
Bartok, M.; Lang, K. L. In The Chemistry of Ethers, Crown Ethers,
Hydroxyl Groups and Their Sulfur Analogues

; Patai, S., Ed.; Wiley:

New York, 1980; Part 2, p 655.

10.

Berti, G.; Macchia, B.; Macchia, F., Tetrahedron 1972, 28, 1299.

11.

Lamaty, G.; Maloq, R.; Selve, C.; Sivade, A.; Wylde, J., J. Chem. Soc.,
Perkin Trans. 2 1975

, 1119.

12.

(a) Copenhaver, J. E.; Whaley, A. M., Org. Synth., Coll. Vol. 1941, 1,
142. (b) Vogel, A. I., J. Chem. Soc 1943, 636. (c) Atwood, M. T., J. Am.
Oil Chem. Soc. 1963

, 40, 64.

13.

Landini, D.; Montanari, F.; Rolla, F., Synthesis 1974, 37.

14.

Fuchs, R.; Cole, L. L., Can. J. Chem. 1975, 53, 3620.

15.

(a) Norris, J. F.; Olmsted, A. W., Org. Synth., Coll. Vol. 1941, 1, 144.
(b) Pourahmady, N.; Vickery, E. H.; Eisenbraun, E. J., J. Org. Chem.
1982, 47, 2590. (c) Melendez, E.; Pardo, M. C., Bull. Soc. Chem. Fr.
1974, 632.

16.

Conant, J. B.; Quayle, O. R., Org. Synth., Coll. Vol. 1941, 1, 292, 294.

A list of General Abbreviations appears on the front Endpapers

HYDROGEN CHLORIDE

3

17.

Parham, W. E.; Sayed, Y. A., Synthesis 1976, 116.

18.

Rao, C. G.; Rengaraju, S.; Bhatt, M. V., J. Chem. Soc., Chem. Commun.
1974, 584.

19.

(a) McPhee, W. D.; Klingsberg, E., Org. Synth., Coll. Vol. 1955, 3, 119.
(b) Dauben, W. G.; Hiskey, C. F.; Muhs, M. A., J. Am. Chem. Soc. 1952,
74

, 2082. (c) Van Atta, R. E.; Zook, H. D.; Elving, P. J., J. Am. Chem.

Soc. 1954

, 76, 1185.

20.

Madesclaire, M., Tetrahedron 1988, 44, 6537.

21.

(a) Bhatt, M. V.; Kulkarni, S. U., Synthesis 1983, 249. (b) Brossi, A.;
Blount, J. F.; O’Brien, J.; Teitel, S., J. Am. Chem. Soc. 1971, 93, 6248.

22.

Olah, G. A.; Tolgyesi, W. S. In Friedel–Crafts and Related Reactions;
Olah, G. A., Ed.; Interscience: New York, 1964; Vol. 2, Part 2,
p 1.

23.

(a) Marvel, C. S.; Porter, P. K., Org. Synth., Coll. Vol. 1932, 1, 377.
(b) Grummitt, O.; Budewitz, E. P.; Chudd, C. C., Org. Synth., Coll. Vol.
1963, 4, 748. (c) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman,
R. K.; Medwid, J. B., Org. Synth., Coll. Vol. 1988, 6, 101.

Gary W. Breton & Paul J. Kropp

University of North Carolina, Chapel Hill, NC, USA

Avoid Skin Contact with All Reagents