THIONYL CHLORIDE 1
alcohol in the chloride. Alternatively, use of amine bases, most
Thionyl Chloride1
commonly Pyridine,18 results in a shift in the mechanism to SN2
(eq 4) and consequently overall inversion. Excess pyridine may
SOCl2
cause dehydrochlorination or alkylation of the base. If inversion
of the substrate is desired or the stereochemical outcome need not
be controlled, the use of pyridine or other amine base is recom-
[7719-09-7] Cl2OS (MW 118.97)
mended since the resulting high chloride concentrations minimize
InChI = 1/Cl2OS/c1-4(2)3
rearrangements and eliminations.19,17a Alternatively, catalysis of
InChIKey = FYSNRJHAOHDILO-UHFFFAOYAN
the chlorination by Hexamethylphosphoric Triamide results in
(chlorination of alcohols,2 carboxylic acids,3 and sulfonic acids;4 inversion.20 With allylic substrates, rearranged products generally
predominate, especially in nonpolar solvents.21 Use of Tributy-
dehydration of amides;5 formation of imidoyl chlorides,6 sulfur-
lamine as the base can result in unrearranged allylic products.22
containing heterocycles,7 and the Vilsmeier reagent)
8 ć%
Physical Data: bp 76 C; d 1.631 g cm-3.
R1 Cl
Solubility: sol ethers, hydrocarbons, halogenated hydrocarbons;
O R1
+ SO2 (4)
reacts with water, protic solvents, DMF, DMSO. R2 S O Cl
R2
N +
Form Supplied in: colorless to yellow liquid.
Purification: impurities cause formation of yellow or red colors.
Iron contamination can cause a black color. Fractional distilla-
tion, either directly9 or from triphenyl phosphite10 or quinoline
Representative procedures are available for the chlorination of
and linseed oil,11 has been recommended.
tetrahydrofurfuryl alcohol,23 benzoin,24 and ethyl mandelate.25
Handling, Storage, and Precautions: very corrosive and reactive;
The use of thionyl chloride for this transformation usually gives
the vapor and liquid are irritating to the eyes, mucous mem-
less rearrangement and elimination than conc HCl, PCl3, or PCl5.
branes, and skin. Protective gloves should be worn when han-
For compounds which are acid-sensitive, Triphenylphosphine
dling to avoid skin contact. Thionyl chloride should be stored
Carbon Tetrachloride may be used.
in glass containers at ambient temperature and protected from
moisture. It reacts with water to liberate the toxic gases HCl
Carboxylic Acid Chlorides from Acids. Thionyl chloride
and SO2. Since most reactions using SOCl2 evolve these gases,
has been the most widely used reagent for the preparation of acid
they should be performed only in well-ventilated hoods. Above
chlorides. Carboxylic anhydrides also react with SOCl2, giving
ć%
140 C, SOCl2 decomposes to Cl2, SO2, and S2Cl2. Iron and/or
2 equiv of the acid chloride.26 The procedure normally involves
zinc contamination may cause catastrophic decomposition.12
heating the carboxylic acid with a slight to large excess of SOCl2
in an inert solvent or with SOCl2 itself as the solvent. Operation at
the boiling point of the solvent speeds removal of the byproducts,
Chlorides from Alcohols. Thionyl chloride reacts with pri-
HCl and SO2. The ease of removal of the byproducts is the chief
mary, secondary, and tertiary alcohols to form chlorosulfite esters
advantage of SOCl2 over PCl5 and PCl3. This simple procedure
(eq 1) which can be isolated.13 The fate of these esters depends
gives good yields of the acid chlorides of butyric,27 cinnamic,28
on the reaction conditions, especially the stoichiometry, solvent,
and adipic acid.29 The reactions are first order in each reactant and
and base. If 2 equiv of alcohol and pyridine are used relative to
electron-withdrawing groups on the acid decrease the rate.30 Sev-
thionyl chloride, dialkyl sulfites may be isolated (eq 2).14
eral agents have been developed for the catalysis of this reaction.
Pyridine was historically the most common; its presumed mode of
ROH + SOCl2 ROSOCl + HCl (1)
action is to ensure the presence of soluble chloride (as Pyridinium
py
Chloride) which reacts with the intermediate as shown in eq 5
2 BuOH + SOCl2 BuOSO2Bu (2)
77 84% Catalytic pyridine ensures that the chlorination of certain diacids
such as succinic acid proceeds completely to the diacid chloride
When thionyl chloride is in excess, or when alkyl chlorosulfites
rather than stopping at the anhydride.31 The preparation of aro-
are treated with thionyl chloride,15 alkyl chlorides are produced
matic acid chlorides also commonly uses pyridine as a catalyst
and the byproducts are HCl and SO2. The mechanism of this
(eq 6).32 Trichloroacetic acid, which is unreactive toward thionyl
reaction may be SN1, SN2, SNi, or SN2 (with allylic or propargylic
chloride alone, is chlorinated by the use of pyridine catalyst.33
alcohols). In the absence of base the SNi mechanism operates;
O O
retention of configuration is observed in the alkyl chloride (eq 3).16
S RCOCl + SO2 + Cl (5)
Considerable ionic character may be involved in this process and
R O Cl
small amounts of elimination or rearrangement are common as
Cl
side reactions.17
HO2C CO2H ClOC COCl
excess SOCl2
R1 R1
cat. pyridine
40 180 °C
+ SO2 (3) (6)
O Cl
reflux, 20 h
R2 S O R2
97%
CO2H COCl
Cl
Thus, simple heating of the alcohol with thionyl chloride alone N,N-Dimethylformamide is a particularly effective catalyst for
is often the preferred method for retaining the configuration of the the formation of acid chlorides with SOCl2 and is now commonly
Avoid Skin Contact with All Reagents
2 THIONYL CHLORIDE
the catalyst of choice.34 The chloromethyleneiminium chloride Reactions with Aldehydes and Ketones. Aromatic or Ä…,²-
intermediate is the active chlorinating species (see Dimethylchlo- unsaturated aldehydes or their bisulfite addition compounds are
romethyleneammonium Chloride). converted to gem-dichlorides by treatment with SOCl2, either neat
Esters of amino acids may be produced directly from the amino or in an inert solvent such as nitromethane (eq 11).47 This process
acid, alcohol, and thionyl chloride. One procedure involves the is readily catalyzed by HMPA.48 Thionyl chloride may be pre-
sequential addition of thionyl chloride and then the acid to chilled ferred over the more commonly used PCl5 if removal of byprod-
methanol.35 Alternatively, benzyl esters have been prepared by ucts is problematic with the latter reagent.
the slow addition of SOCl2 to a suspension of the amino acid in
cat. DMF
ć%
benzyl alcohol at 5 C.36
 10 °C
PhCHO SOCl2 PhCHCl2 (11)
+
For the formation of acid chlorides, the competing reactions
89%
of concern are Ä…-oxidation and acid-catalyzed degradation. The
use of solid Sodium Carbonate in the reaction mixture can mini-
Carbonyl compounds or nitriles49 with Ä…-hydrogens may be
mize the latter for some compounds.37 As shown in eq 7, even sim-
oxidized at this position by thionyl chloride. This reaction appears
ple carboxylic acids with enolizable hydrogens Ä… to the carboxylic
more often as a troublesome side reaction than a useful synthetic
functionality are subject to oxidation under standard chlorinating
procedure. Nitriles with one Ä…-hydrogen produce Ä…-cyanosulfinyl
conditions.38 Since the unoxidized acid chloride is the precursor
chlorides (eq 12) while those with two Ä…-hydrogens give moderate
to the sulfenyl chloride, careful attention to stoichiometry and
yields of Ä…-chloro-Ä…-cyanosulfinyl chlorides.50
reaction time can effectively minimize this problem.
HCl, ether
reflux, 14 h Me2CHCN + SOCl2 (12)
Ph
NC SOCl
+ excess SOCl2 + 0.08 equiv pyridine
0 °C, 7 d
CO2H
61%
50%
Ph Cl
(7)
COCl
Oxidation of Activated C H Bonds. As shown in eq 13,
SCl
extensive oxidation adjacent to carbonyl groups is possible with
SOCl2 under relatively mild conditions.51 The process often stops
after formation of the Ä…-chlorosulfenyl chloride. Remarkably,
Sulfonyl and Sulfinyl Chlorides from Sulfonic and Sulfinic
these may be easily hydrolyzed back to the carbonyl compounds
Acids. Alkyl or arylsulfonyl chlorides are prepared by heating
from which they were derived.52 Alternatively, they may be treated
the acid with thionyl chloride; DMF catalyzes this reaction. (+)-
with a secondary amine such as morpholine followed by hydroly-
Camphorsulfonyl chloride is produced in 99% yield without a
sis to yield the Ä…-dicarbonyl compound. Similar oxidation of acid
catalyst.39 Use of the salts of sulfinic acids minimizes their oxida-
derivatives during acid chloride formation is possible (see above).
tion; p-toluenesulfinyl chloride is produced in about 70% yield
O O (13)
from sodium p-toluenesulfinate dihydrate with excess thionyl
cat pyridine
SCl S
chloride.40 Phosphorus(V) Chloride is more commonly used for PhCOMe + excess SOCl2 +
Ph Ph
20 °C, 2.5 h
this transformation.
95% Cl Cl
Nitriles and Isocyanides via Amide Dehydration. Thionyl
Methyl groups attached to benzenoid rings may be oxidized
chloride dehydrates primary amides to form nitriles (eq 8); for
by SOCl2 without added catalysts. The range of reactivity is
example, 2-ethylhexanonitrile is produced in about 90% yield by
large and not well understood; the products may be monochlo-
heating with SOCl2 in benzene.41 Substituted benzonitriles are
rinated or further oxidation to the trichloromethyl aromatic sys-
readily produced from benzamides.42 These reactions may also
tem is possible.53 2-Methylpyrroles are similarly oxidized.54 In
be catalyzed by DMF.43 N-Alkylformamides may be dehydrated
systems with vicinal methyl and carboxylic acid groups, both ox-
to isocyanides.44
idation of the methyl group and cyclization to a Å‚-thiolactone
can occur.55 In conjunction with radical initiators, SOCl2 can
RCONH2 + SOCl2 RCN + SO2 + 2 HCl (8)
chlorinate alkanes.56 Aryl methyl ethers can be oxidized on the
aromatic ring to give arylsulfenyl chlorides which may undergo
further reactions.57 This latter process, which presumably occurs
Reactions with Secondary Amides. Treatment of N-alkyl or
via electrophilic aromatic substitution, is another potential serious
N-aryl secondary amides with thionyl chloride in an inert solvent
side reaction for active substrates.
such as methylene chloride results in the formation of imidoyl
chlorides (eq 9).45 Upon heating, the imidoyl chlorides from N-
Rearrangement Reactions. Thionyl chloride can act as the
alkylamides undergo scission to generate nitriles and alkyl chlo-
dehydrating agent in the Beckman58 and Lossen rearrangements59
rides via the von Braun degradation (eq 10).46
and promotes the Pummerer rearrangement.60
Ph
Ph
Synthesis of Heterocyclic Compounds. Thionyl chloride and
RCONHPh SOCl2 (9)
+ N
100%
pyridine at elevated temperatures convert diarylalkenes, styrenes,
Cl
and cinnamic acids to benzo[b]thiophenes61 and adipic acid to 2,5-
SOCl2
bis(chlorocarbonyl)thiophene.62 Additional heterocycles which
PhCONHBu PhCN + BuCl + SO2 + HCl (10)
69 75%
have been prepared include thiazolo[3,2-a]indol-3(2H)-ones,63
A list of General Abbreviations appears on the front Endpapers
THIONYL CHLORIDE 3
oxazolo[5,4-d]pyrimidines,64 and 1,2,3-thiadiazoles.65 Treatment 17. (a) Hudson, H. R.; de Spinoza, G. R., J. Chem. Soc., Perkin Trans. 1
1976, 104. (b) Lee, C. C.; Finlayson, A. J., Can. J. Chem. 1961, 39, 260.
of 1,2-diamino aromatic compounds with thionyl chloride gives
18. Ward, A. M., Org. Synth., Coll. Vol. 1943, 2, 159.
good yields of fused 1,2,5-thiadiazoles.66
19. Stille, J. K.; Sonnenberg, F. M., J. Am. Chem. Soc. 1966, 88, 4915.
Other Applications. Thionyl chloride has been used to con- 20. Normant, J. F.; Deshayes, H., Bull. Soc. Chem. Fr. 1972, 2854.
vert epoxides to vicinal dichlorides67 and for the preparation of di-
21. Caserio, F. F.; Dennis, G. E.; DeWolfe, R. H.; Young, W. G., J. Am.
alkyl sulfides from Grignard reagents.68 Phenols react with SOCl2 Chem. Soc. 1955, 77, 4182.
to produce aryl chlorosulfites and diaryl sulfites69 or nuclear sub- 22. Young, W. G.; Caserio, F. F., Jr.; Brandon, D. D., Jr.; J. Am. Chem. Soc.
stitution products. As shown in eq 14, Aluminum Chloride catal- 1960, 82, 6163.
ysis yields symmetric sulfoxides, while in the absence of Lewis 23. Brooks, L. A.; Snyder, H. R., Org. Synth., Coll. Vol. 1955, 3, 698.
acids, aromatic thiosulfonates are the principal products.70 Pri- 24. Ward, A. M., Org. Synth., Coll. Vol. 1943, 2, 159.
mary amines, especially aromatic ones, react with SOCl2 to pro-
25. Eliel, E. L.; Fisk, M. T.; Prosser, T., Org. Synth., Coll. Vol. 1963, 4, 169.
duce N-sulfinylamines, which are potent enophiles and useful pre-
26. Kyrides, L. P., J. Am. Chem. Soc. 1937, 59, 206.
cursors to some heterocyclic compounds.71
27. Helferich, B.; Schaefer, W., Org. Synth., Coll. Vol. 1932, 1, 147.
28. Womack, E. B.; McWhirter, J., Org. Synth., Coll. Vol. 1955, 3, 714.
O
29. Fuson, R. C.; Walker, J. T., Org. Synth., Coll. Vol. 1943, 2, 169.
O
excess SOCl2
HO S
30. Beg, M. A.; Singh, H. N., Z. Phys. Chem. 1968, 237, 128; 1964, 227,
HO
S OH
0 80 °C
272.
56%
31. Cason, J.; Reist, E. J., J. Org. Chem. 1958, 23, 1492.
32. Sandler, S. R.; Karo, W. Organic Functional Group Preparations, 2nd
SOCl2, AlCl3 53%
(14)
O
CCl4, 0 25 °C ed.; Academic: Orlando, 1983; Vol. 1, p 157.
HO S
33. Gerrard, W.; Thrush, A. M., J. Chem. Soc 1953, 2117.
34. Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H., Helv. Chim. Acta
1959, 42, 1653.
OH
35. Uhle, F. C.; Harris, L. S., J. Am. Chem. Soc. 1956, 78, 381.
36. Patel, R. P.; Price, S., J. Org. Chem. 1965, 30, 3575.
37. Coleman, G. H.; Nichols, G.; McCloskey, C. M.; Anspon, H. D., Org.
Related Reagents. Dimethylchloromethyleneammonium
Synth., Coll. Vol. 1955, 3, 712.
Chloride; Hexamethylphosphoric Triamide Thionyl Chloride;
38. Krubsack, A. J.; Higa, T., Tetrahedron Lett. 1968, 5149.
Hydrogen Chloride; Oxalyl Chloride; Phosgene; Phosphorus(III)
39. Sutherland, H.; Shriner, R. L., J. Am. Chem. Soc. 1936, 58, 62.
Chloride; Phosphorus(V) Chloride; Phosphorus Oxychloride;
40. Kurzer, F., Org. Synth., Coll. Vol. 1963, 4, 937.
Phosphorus(V) Oxide; Triphenylphosphine Carbon Tetrachlo-
41. Krynitsky, J. A.; Carhart, H. W., Org. Synth., Coll. Vol. 1963, 4, 436.
ride; Triphenylphosphine Dichloride.
42. Goldstein, H.; Voegeli, R., Helv. Chim. Acta 1943, 26, 1125.
43. Thurman, J. C., Chem. Ind. (London) 1964, 752.
44. (a) Tennant, G. In Comprehensive Organic Chemistry; Barton, D. H. R.;
Ollis, W. D., Eds.; Pergamon: Oxford, 1979; 2, p 569. (b) Niznik, G. E.;
1. (a) Pizey, J. S. Synthetic Reagents; Wiley: 1974; Vol. 1, p 321. (b) Davis,
Morrison, W. H., III; Walborsky, H. M., Org. Synth. 1971, 51, 31.
M.; Skuta, H.; Krubsack, A. J., Mech. React. Sulfur Compd. 1970, 5, 1.
45. von Braun, J.; Pinkernelle, W., Chem. Ber. 1934, 67, 1218.
2. Brown, G. W. In The Chemistry of the Hydroxyl Group; Patai, S., Ed.;
Interscience; London, 1971; Part 1, p 593. 46. (a) Challis, B. C.; Challis, J. A. The Chemistry of Amides; Zabicky, J.,
Ed.; Interscience; New York, 1970; p 809. (b) Vaughn, W. R.; Carlson,
3. Ansell, M. F. In The Chemistry of Acyl Halides; Patai, S., Ed.;
R. D., J. Am. Chem. Soc. 1962, 84, 769.
Interscience: London, 1972; p 35.
47. Newman, M. S.; Sujeeth, P. K., J. Org. Chem. 1978, 43, 4367.
4. Hoyle, J. In The Chemistry of Sulfonic Acids, Esters, and Their
Derivatives; Patai, S.; Rappoport, H., Eds.; Wiley: New York, 1991; 48. Khurana, J. M.; Mehta, S., Indian J. Chem., Sect. B 1988, 27, 1128.
p 379.
49. Martinetz, D., Z. Chem. 1980, 20, 332.
5. Mowry, D. T., Chem. Rev. 1948, 42, 257.
50. Ohoka, M.; Kojitani, T.; Yanagida, S.; Okahara, M.; Komori, S., J. Org.
6. Ulrich, H. Chemistry of Imidoyl Halides; Plenum: New York, 1968; p Chem. 1975, 40, 3540.
13.
51. (a) Oka, K.; Hara, S., Tetrahedron Lett. 1976, 2783. (b) Oka, K., Synthesis
7. Davis, M., Adv. Heterocycl. Chem. 1982, 30, 62. 1981, 661.
8. Weil, E. D. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd 52. Oka, K.; Hara, S., Tetrahedron Lett. 1977, 695.
Ed.; Wiley: New York, 1978; Vol. 22, p 127.
53. Davis, M.; Scanlon, D. B., Aust. J. Chem. 1977, 30, 433.
9. Bell, K. H., Aust. J. Chem. 1985, 38, 1209.
54. Brown, D.; Griffiths, D., Synth. Commun. 1983, 13, 913.
10. Fieser, L. F.; Fieser, M., Fieser & Fieser 1967, 1, 1158.
55. Walser, A.; Flynn, T., J. Heterocycl. Chem. 1978, 15, 687.
11. Martin, E. L.; Fieser, L. F., Org. Synth., Coll. Vol. 1943, 2, 569.
56. Krasniewski, J. M., Jr.; Mosher, M. W., J. Org. Chem. 1974, 39, 1303.
12. Spitulnik, M. J., Chem. Eng. News 1977, (Aug 1), 31.
57. Bell, K. H.; McCaffery, L. F., Aust. J. Chem. 1992, 45, 1213.
13. Gerrard, W., J. Chem. Soc 1940, 218.
58. Donaruma, L. G.; Heldt, W. Z., Org. React. 1960, 11, 1.
14. Suter, C. M.; Gerhart, H. L., Org. Synth., Coll. Vol. 1943, 2, 112.
59. Yale, H. L., Chem. Rev. 1943, 33, 242.
15. Frazer, M. J.; Gerrard, W.; Machell, G.; Shepherd, B. D., Chem. Ind.
60. (a) Russell, G. A.; Mikol, G. J. In Mechanisms of Molecular Migrations;
(London) 1954, 931.
Thyagarajan, B. S., Ed.; Interscience: New York, 1968; 1, p 157. (b)
16. Lewis, E. S.; Boozer, C. E., J. Am. Chem. Soc. 1952, 74, 308. Durst, T., Adv. Org. Chem. 1969, 6, 356.
Avoid Skin Contact with All Reagents
4 THIONYL CHLORIDE
61. (a) Blatt, H.; Brophy, J. J.; Colman, L. J.; Tairych, W. J., Aust. J. 67. Campbell, J. R.; Jones, J. K. N.; Wolfe, S., Can. J. Chem. 1966, 44, 2339.
Chem. 1976, 29, 883. (b) Campaigne, E. In Comprehensive Heterocyclic
68. Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. In The Chemistry of
Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Sulphones and Sulphoxides; Patai, S.; Rappoport, Z.; Stirling, C. J. M.,
4, p 870, 889.
Eds.; Wiley: New York, 1988; Chapter 8, p 257.
62. Nakagawa, S.; Okumura, J.; Sakai, F.; Hoshi, H.; Naito, T., Tetrahedron
69. Gerrard, W., J. Chem. Soc 1940, 218.
Lett. 1970, 3719.
70. (a) Takimoto, H. H.; Denault, G. C., J. Org. Chem. 1964, 29, 759. (b)
63. Showalter, H. D. H.; Shipchandler, M. T.; Mitscher, L. A.; Hagaman, E.
Oae, S.; Zalut, C., J. Am. Chem. Soc. 1960, 82, 5359.
W., J. Org. Chem. 1979, 44, 3994.
71. Kresze, G.; Wucherpfennig, W., Angew. Chem., Int. Ed. Engl. 1967, 6,
64. Senga, K.; Sato, J.; Nishigaki, S., Heterocycles 1977, 6, 689.
149.
65. Meier, H.; Trickes, G.; Laping, E.; Merkle, U., Chem. Ber. 1980, 113,
183.
David D. Wirth
66. (a) Komin, A. P.; Carmack, M., J. Heterocycl. Chem. 1975, 12, 829. (b)
Eli Lilly and Company, Lafayette, IN, USA
Hartman, G. D.; Biffar, S. E.; Weinstock, L. M.; Tull, R., J. Org. Chem.
1978, 43, 960.
A list of General Abbreviations appears on the front Endpapers