Hydrogen Chloride1

ClH

[7647-01-0]  · ClH  · Hydrogen Chloride  · (MW 36.46)

(reagent for hydrochlorination of alkenes and alkynes;4 cleaves epoxides1b and ethers;21a converts alcohols to chlorides12b and diols to cyclic ethers;17 chloroalkylates arenes;22 converts aldehydes to a-chloro ethers23b)

Alternate Name: Hydrochloric Acid

Solubility: sol most organic solvents.2

Form Supplied in: widely available; compressed gas; 1 M solution in AcOH, Et2O, or Me2S; 4 M solution in dioxane; 37% aqueous solution.

Preparative Methods: addition of H2SO4 to NaCl or 37% aqueous HCl.3

Handling, Storage, and Precautions: highly toxic and corrosive; handle only in a fume hood.

Hydrochlorination of Alkenes and Alkynes.

HCl undergoes 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 undergo polymerization under these conditions.5a The rate of addition is inversely proportional to the electron donor strength of the solvent, following the order heptane &AApprox; CHCl3 > xylene > nitrobenzene >> MeOH > dioxane > Et2O.6,7 In the strongly donating solvent Et2O, even highly reactive alkenes undergo slow addition unless one of the reactants is present in high concentration. Additions conducted in solutions saturated with HCl exhibit an inverse temperature coefficient because of the increased solubility of HCl at lower temperatures.3b

Alkynes undergo addition more slowly than alkenes, requiring 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

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 CH2Cl2 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.

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, addition typically occurs through backside attack of chloride ion on the protonated epoxide, resulting in net inversion of the carbon 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 favored in the presence of water or in hydroxylic solvents.10

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. Regioselectivity is also very sensitive to the solvent system employed for the reaction (eqs 5 and 6).

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 either 37% aqueous HCl or anhydrous HCl at elevated temperatures in the presence of Zinc Chloride.12 Phase-transfer catalysis has also been employed in the synthesis of primary chlorides from alcohols.13 The need for a catalyst can be avoided by using the highly polar solvent HMPA.14 Tertiary,7,15a benzylic,15b and allylic15c alcohols are readily converted to chlorides at 25 °C, or lower, without the need for catalysts. Glycerol can be selectively 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

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

a-Diazo ketones are reduced to a-chloromethyl ketones by either anhydrous HCl in organic solvents or 37% aqueous HCl in Et2O.19 Generally, good to high yields are obtained. Chloroacetone was synthesized in this manner without the complicating formation of dichlorides (eq 9).19c

Although aryl sulfoxides are reduced to sulfides by HCl, accompanying ring chlorination limits the usefulness of the reaction.20

Cleavage of Ethers.

Allyl, t-butyl, trityl, benzhydryl, and benzyl ethers are cleaved by HCl in AcOH (eq 10).21a In some cases, aryl methyl ethers have been successfully cleaved (eq 11).21b

Reaction with Aldehydes.

Arenes react readily with mixtures of HCl and formaldehyde in the presence of a Lewis acid, usually ZnCl2, to give the chloromethylated derivative.22 Yields are good and the reaction conditions can be controlled to afford predominantly 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 a-chloro ethers (eq 12).23

Related Reagents.

Formaldehyde-Hydrogen Chloride; Hydrochloric Acid.


1. (a) Larock, R. C.; Leong, W. W. COS 1991, 4, 269. (b) Parker, R. E.; Isaacs, N. S. CRV 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. JOC 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. JACS 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. JACS 1993, 115, 3071. (c) Kropp, P. J.; Crawford, S. D. JOC 1994, 59, 3102.
5. (a) Shields, T. C. CJC 1971, 49, 1142. (b) Hassner, A.; Fibiger, R. F. S 1984, 960.
6. (a) O'Connor, S. F.; Baldinger, L. H.; Vogt, R. R.; Hennion, G. F. JACS 1939, 61, 1454. (b) Hennion, G. F.; Irwin, C. F. JACS 1941, 63, 860.
7. For a different order, see: Brown, H. C.; Liu, K.-T. JACS 1975, 97, 600.
8. Hudrlik, P. F.; Kulkarni, A. K.; Jain, S.; Hudrlik, A. M. T 1983, 39, 877.
9. (a) Lucas, H. J.; Gould, C. W., Jr. JACS 1941, 63, 2541. (b) Buchanan, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley: New York, 1972; Vol. 2, pp 1-92. (c) Armarego, W. L. F. In Stereochemistry of Heterocyclic Compounds; Taylor, E. C.; Weissberger, A., Eds.; Wiley: New York, 1977; pp 23-25. (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, pp 655-657.
10. Berti, G.; Macchia, B.; Macchia, F. T 1972, 28, 1299.
11. Lamaty, G.; Maloq, R.; Selve, C.; Sivade, A.; Wylde, J. JCS(P2) 1975, 1119.
12. (a) Copenhaver, J. E.; Whaley, A. M. OSC 1941, 1, 142. (b) Vogel, A. I. JCS 1943, 636. (c) Atwood, M. T. J. Am. Oil Chem. Soc. 1963, 40, 64.
13. Landini, D.; Montanari, F.; Rolla, F. S 1974, 37.
14. Fuchs, R.; Cole, L. L. CJC 1975, 53, 3620.
15. (a) Norris, J. F.; Olmsted, A. W. OSC 1941, 1, 144. (b) Pourahmady, N.; Vickery, E. H.; Eisenbraun, E. J. JOC 1982, 47, 2590. (c) Melendez, E.; Pardo, M. C. BSF 1974, 632.
16. Conant, J. B.; Quayle, O. R. OSC 1941, 1, 292, 294.
17. Parham, W. E.; Sayed, Y. A. S 1976, 116.
18. Rao, C. G.; Rengaraju, S.; Bhatt, M. V. CC 1974, 584.
19. (a) McPhee, W. D.; Klingsberg, E. OSC 1955, 3, 119. (b) Dauben, W. G.; Hiskey, C. F.; Muhs, M. A. JACS 1952, 74, 2082. (c) Van Atta, R. E.; Zook, H. D.; Elving, P. J. JACS 1954, 76, 1185.
20. Madesclaire, M. T 1988, 44, 6537.
21. (a) Bhatt, M. V.; Kulkarni, S. U. S 1983, 249. (b) Brossi, A.; Blount, J. F.; O'Brien, J.; Teitel, S. JACS 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, pp 1-92.
23. (a) Marvel, C. S.; Porter, P. K. OSC 1932, 1, 377. (b) Grummitt, O.; Budewitz, E. P.; Chudd, C. C. OSC 1963, 4, 748. (c) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman, R. K.; Medwid, J. B. OSC 1988, 6, 101.

Gary W. Breton & Paul J. Kropp

University of North Carolina, Chapel Hill, NC, USA



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