HYDROGEN CHLORIDE 1
choice of reaction conditions. Similarly, phenylalkynes initially
Hydrogen Chloride1
afford syn adducts, which undergo subsequent equilibration with
the thermodynamically more stable (Z) isomers (eq 3).4 Again,
CIH
either isomer can be obtained in high yield.
Cl
[7647-01-0] ClH (MW 36.46)
H
InChI = 1/ClH/h1H
HCl
InChIKey = VEXZGXHMUGYJMC-UHFFFAOYAT
SiO2
or
(2)
(reagent for hydrochlorination of alkenes and alkynes;4 cleaves
Al2O3
Cl
epoxides1b and ethers;21a converts alcohols to chlorides12b and
HCl
H
diols to cyclic ethers;17 chloroalkylates arenes;22 converts
aldehydes to Ä…-chloro ethers23b)
Alternate Name: Hydrochloric Acid.
Cl Cl
SOCl2
Solubility: sol most organic solvents.2
(3)
Ph R Ph Ph
SiO2 or Al2O3
Form Supplied in: widely available; compressed gas; 1 M solu-
R
tion in AcOH, Et2O, or Me2S; 4 M solution in dioxane; 37% R
aqueous solution.
R = Me or Ph
Preparative Methods: addition of H2SO4 to NaCl or 37% aque-
ous HCl.3
Handling, Storage, and Precautions: highly toxic and corrosive;
Cleavage of Epoxides to Chlorohydrins. The addition of
handle only in a fume hood.
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-
Hydrochlorination of Alkenes and Alkynes. HCl under-
dition typically occurs through backside attack of chloride ion
goes solution-phase addition readily to C=C double bonds that
on the protonated epoxide, resulting in net inversion of the car-
are strained or from which the resulting carbocation is benzylic
bon center (eq 4).1b,9 For aryl- or vinyl-substituted epoxides (in
or tertiary.1a However, other alkenes do not undergo addition at
which more carbocationic character is involved in the transition
preparatively useful rates.4 Although addition can be facilitated
state during ring opening), the stereochemical outcome may range
by Lewis acid catalysis,5 mono- and 1,2-disubstituted alkenes un-
from complete retention to predominant inversion and is highly
dergo polymerization under these conditions.5a The rate of ad-
solvent dependent.10 Anhydrous conditions and solvents of low
dition is inversely proportional to the electron donor strength of
dielectric strength favor syn cleavage, while anti cleavage is fa-
the solvent, following the order heptane H" CHCl3 > xylene >
vored in the presence of water or in hydroxylic solvents.10
nitrobenzene >> MeOH > dioxane > Et2O.6,7 In the strongly
37% HCl
donating solvent Et2O, even highly reactive alkenes undergo slow OH
2 h
addition unless one of the reactants is present in high concentra- O (4)
77%
tion. Additions conducted in solutions saturated with HCl exhibit Cl
an inverse temperature coefficient because of the increased solu-
bility of HCl at lower temperatures.3b
Cleavage of simple alkyl-substituted epoxides under anhydrous
Alkynes undergo addition more slowly than alkenes, requir-
conditions typically favors formation of the chlorohydrin in which
ing extended reaction times, elevated temperatures, and, usually,
chlorine is at the less highly substituted position (eqs 5 and 6).11
Lewis acid catalysis.1a However, dialkylalkynes afford the (Z)-
More highly substituted epoxides, particularly aryl-substituted,
vinyl chloride on treatment with refluxing aqueous HCl (eq 1).8
give increasing amounts of the opposite regioisomer. Regioselec-
tivity is also very sensitive to the solvent system employed for the
37% HCl
Cl reaction (eqs 5 and 6).
80 °C, 18 h
Pr Pr Pr (1)
81%
Pr
OH Cl
HCl
O + (5)
Addition to alkenes and alkynes is greatly facilitated by the
Cl OH
presence of appropriately prepared silica gel or alumina.4 Alkenes
THF 84% 16%
and alkynes that exhibit little or no reaction with HCl in solution
THF/H2O 40% 60%
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
OH Cl
silica gel or alumina. Surface-mediated hydrochlorination of 1,2-
HCl
O + (6)
dimethylcyclohexene in CH2Cl2 gives initially the syn adduct,
Cl OH
which undergoes equilibration with the thermodynamically more
THF 62% 38%
stable trans isomer under the reaction conditions (eq 2).4 Thus
THF/H2O 25% 75%
either isomer can be obtained in high yield through the proper
Avoid Skin Contact with All Reagents
2 HYDROGEN CHLORIDE
MeO MeO
20% HCl
Reaction with Alcohols. The reaction of HCl with alcohols
", 13 h
to form alkyl chlorides is a general reaction, giving good to high
NH NH (11)
MeO 57% HO
yields of products. Primary and secondary aliphatic alcohols are
OMe OH
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-
Reaction with Aldehydes. Arenes react readily with mixtures
sis has also been employed in the synthesis of primary chlorides
of HCl and formaldehyde in the presence of a Lewis acid, usually
from alcohols.13 The need for a catalyst can be avoided by us-
ZnCl2, to give the chloromethylated derivative.22 Yields are good
ing the highly polar solvent HMPA.14 Tertiary,7,15a benzylic,15b
and the reaction conditions can be controlled to afford predomi-
ć%
and allylic15c alcohols are readily converted to chlorides at 25 C,
nantly mono- or disubstituted products. Chloroalkylations can be
or lower, without the need for catalysts. Glycerol can be selec-
effected with other aldehydes such as propanal and butanal. In the
tively mono- or dichlorinated by controlled addition to HCl to
presence of alcohols, HCl and aldehydes give high conversions to
AcOH solutions.16 Bis(benzylic) diols have been converted in
Ä…-chloro ethers (eq 12).23
good yields to substituted cyclic ethers with HCl, whereas reaction
O
with HBr or HI followed a completely different course (eq 7).17
HCl
+ (12)
Ph OH Ph O Cl
83%
H H
37% HCl
Related Reagents. Formaldehyde Hydrogen Chloride; Hy-
", 6 h
OH
drochloric Acid.
O (7)
OH 80%
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.
Reductions with HCl. HCl has been used to reduce a series
2. Fogg, P. G. T.; Gerrard, W.; Clever, H. L. In Solubility Data Series;
of 1,4-cyclohexanediones to the corresponding phenols in good
Lorimer, J. W.; Ed.; Pergamon: Oxford, 1990; Vol. 42.
yield (eq 8).18
3. (a) Maxson, R. N., Inorg. Synth. 1939, 1, 147. (b) Brown, H. C.; Rei,
M.-H.; J. Org. Chem. 1966, 31, 1090.
O OH
4. (a) Kropp, P. J.; Daus, K. A.; Crawford, S. D.; Tubergen, M. W.; Kepler,
37% HCl
K. D.; Craig, S. L.; Wilson, V. P., J. Am. Chem. Soc. 1990, 112, 7433.
", 15 h
(b) Kropp, P. J.; Daus, K. A.; Tubergen, M. W.; Kepler, K. D.; Wilson,
(8)
70%
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,
O
59, 3102.
5. (a) Shields, T. C., Can. J. Chem. 1971, 49, 1142. (b) Hassner, A.; Fibiger,
Ä…-Diazo ketones are reduced to Ä…-chloromethyl ketones by
R. F., Synthesis 1984, 960.
either anhydrous HCl in organic solvents or 37% aqueous HCl in
6. (a) O Connor, S. F.; Baldinger, L. H.; Vogt, R. R.; Hennion, G. F., J.
Et2O.19 Generally, good to high yields are obtained. Chloroace- Am. Chem. Soc. 1939, 61, 1454. (b) Hennion, G. F.; Irwin, C. F., J. Am.
Chem. Soc. 1941, 63, 860.
tone was synthesized in this manner without the complicating
7. For a different order, see: Brown, H. C.; Liu, K.-T.; J. Am. Chem. Soc.
formation of dichlorides (eq 9).19c
1975, 97, 600.
8. Hudrlik, P. F.; Kulkarni, A. K.; Jain, S.; Hudrlik, A. M., Tetrahedron
HCl
O O
Et2O
1983, 39, 877.
N2
Cl (9)
9. (a) Lucas, H. J.; Gould, C. W., Jr., J. Am. Chem. Soc. 1941, 63, 2541. (b)
68%
Buchanan, J. G.; Sable, H. Z. In Selective Organic Transformations;
Thyagarajan, B. S., Ed.; Wiley: New York, 1972; Vol. 2, p 1.
Although aryl sulfoxides are reduced to sulfides by HCl,
(c) Armarego, W. L. F. In Stereochemistry of Heterocyclic Compounds;
accompanying ring chlorination limits the usefulness of the re-
Taylor, E. C.; Weissberger, A., Eds.; Wiley: New York, 1977; p 23. (d)
action.20 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.
Cleavage of Ethers. Allyl, t-butyl, trityl, benzhydryl, and ben-
10. Berti, G.; Macchia, B.; Macchia, F., Tetrahedron 1972, 28, 1299.
zyl ethers are cleaved by HCl in AcOH (eq 10).21a In some cases,
aryl methyl ethers have been successfully cleaved (eq 11).21b 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,
37% HCl
OCH2Ph OH 142. (b) Vogel, A. I., J. Chem. Soc 1943, 636. (c) Atwood, M. T., J. Am.
AcOH
Oil Chem. Soc. 1963, 40, 64.
OMe OMe
80 °C, 1.5 h
13. Landini, D.; Montanari, F.; Rolla, F., Synthesis 1974, 37.
(10)
89%
14. Fuchs, R.; Cole, L. L., Can. J. Chem. 1975, 53, 3620.
R R
15. (a) Norris, J. F.; Olmsted, A. W., Org. Synth., Coll. Vol. 1941, 1, 144.
MeO O
(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.
R =
1974, 632.
OH O
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. 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,
18. Rao, C. G.; Rengaraju, S.; Bhatt, M. V., J. Chem. Soc., Chem. Commun.
p1.
1974, 584.
23. (a) Marvel, C. S.; Porter, P. K., Org. Synth., Coll. Vol. 1932, 1, 377.
19. (a) McPhee, W. D.; Klingsberg, E., Org. Synth., Coll. Vol. 1955, 3, 119.
(b) Grummitt, O.; Budewitz, E. P.; Chudd, C. C., Org. Synth., Coll. Vol.
(b) Dauben, W. G.; Hiskey, C. F.; Muhs, M. A., J. Am. Chem. Soc. 1952,
1963, 4, 748. (c) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman,
74, 2082. (c) Van Atta, R. E.; Zook, H. D.; Elving, P. J., J. Am. Chem.
R. K.; Medwid, J. B., Org. Synth., Coll. Vol. 1988, 6, 101.
Soc. 1954, 76, 1185.
20. Madesclaire, M., Tetrahedron 1988, 44, 6537.
Gary W. Breton & Paul J. Kropp
21. (a) Bhatt, M. V.; Kulkarni, S. U., Synthesis 1983, 249. (b) Brossi, A.;
University of North Carolina, Chapel Hill, NC, USA
Blount, J. F.; O Brien, J.; Teitel, S., J. Am. Chem. Soc. 1971, 93, 6248.
Avoid Skin Contact with All Reagents