[67-66-3]  · CHCl3  · Chloroform  · (MW 119.38)

(commonly a solvent in organic synthesis; also used in the preparation of dichlorocarbenes and a-trichloromethyl carbinols; and as a trichlorolithiocarbenoid precursor)

Physical Data: mp -63.5 °C; bp 61.7 °C; d 1.483 g cm-3.

Solubility: very slightly sol water; sol ether, acetone, benzene, and ligroins.

Form Supplied in: colorless liquid with a sweet pleasant odor; available in high purity (99-99.9%).

Handling, Storage, and Precautions: oxidized by air and sunlight to phosgene. The addition of a small amount of alcohol or pentylenes prevents this. The solution should be handled with the usual precautions related to highly toxic substances; cancer suspect agent.

Formation of Dichlorocarbenes.

Chloroform reacts more rapidly with aqueous base than does dichloromethane or carbon tetrachloride (eq 1). The reaction proceeds by an SN1cB mechanism1 that involves the loss of a proton, followed by loss of Cl-.2 The dichlorocarbene is then hydrolyzed to formic acid or carbon monoxide.3 Most reactions involving chloroform are based on its ability to form a dichlorocarbene in alkali media. The dichlorocarbenes are obtained by reacting CHCl3 and OH-, often under phase-transfer catalysis conditions,4 and the dichlorocarbenes react with alkenes and nonalkene substrates.5

Addition to Alkenes via Dihalocarbenes.

Dichlorocarbenes add to double bonds to give 1,1-dichlorocyclopropanes6 that are versatile substrates for subsequent ring opening.7 Dihalocyclopropanes are very useful compounds8 that can be reduced to cyclopropanes, treated with Magnesium to give allenes, or converted to many other products. As an example, dichlorocarbene can be used as a high yield two-step alternative to the Simmons-Smith reaction (eq 2).9 It is also useful for the preparation of 2-chloronaphthalene derivatives (eq 3).10

When more than one isolated double bond is present in a substrate, products of both mono and multiple cyclopropanation are isolated, unless a selective phase-transfer catalysis method is used. Dichlorocyclopropanation can be followed by rearrangement if the dichlorocarbene adduct is either strained or otherwise unstable (eq 4).11 Another useful rearrangement involves the expansion of pyrroles and indoles to pyridines and quinolines derivatives, respectively (eq 5).12

A similar rearrangement has been reported for the addition to furans, thiophenes, and polycyclic aromatics which, by loss of a proton, form expanded trienes with an exocyclic double bond (eq 6).13 A second equivalent of dichlorocarbene can add to the exocyclic double bond, but in poor yield (eq 7).

The formation of 1,1-dichlorocyclopropanes from allylic alcohols is of particular synthetic value because the initial adducts can undergo rearrangement under acidic conditions to give good yields of cyclopentenones (eq 8).14 If an electron-withdrawing group is present on the double bond, a Michael addition with trichloromethyl anion might occur (eq 9).15

The most studied reaction of chloroform involving the formation of a dichlorocarbene is the Reimer-Tiemann reaction.16 This reaction is commonly divided into normal and abnormal transformations, depending on the reaction products. A normal Reimer-Tiemann reaction is one in which a phenol (or electron-rich aromatic such as pyrrole) yields one or more aldehydes on treatment with chloroform and alkali (eq 10).17

The abnormal Reimer-Tiemann reaction product can be subdivided further into cyclohexadienones and ring-expansion products. When ortho- or para-substituted phenols are subjected to the reaction, 2,2- or 4,4-disubstituted cyclohexadienones may be obtained, in addition to the normal product (eq 11).18 With certain five-membered ring substrates, a ring expansion can also occur (eq 12).19

Several other methods for the direct introduction of an aldehyde group into an aromatic ring exist under acidic and/or anhydrous conditions.20 The Reimer-Tiemann reaction is mainly useful for phenols21 and certain heterocyclic compounds, such as pyrroles and indoles. Attempts to improve the procedure have focused on the nature of the base, the effect of the solvent, the use of phase-transfer catalysts,22 the use of ultrasound,23 cyclodextrins, and alternative precursors to dichlorocarbene.24 No modification has led to a significant improvement in yield. However, alterations in ortho/para ratios and increased yields of abnormal products have been accomplished.25

Addition to Nonalkenic Substrates via Dihalocarbenes.

Halocarbenes insert much less readily than carbenes to C-H single bonds, though a number of instances have been reported (eq 13).26

The reaction of dichlorocarbene with substrates other than hydrocarbons appears to be initiated by coordination of the electrophilic carbene with a Lewis basic site. Subsequent reactions that are attributable to differences in the basic functions or involvement with other reactive sites lead to differences in the chemistry of each substrate. The reactions of phase-transfer-generated dichlorocarbene with organic molecules possessing such heteroatoms as oxygen, nitrogen, and sulfur and no other more reactive functionality have led to a number of useful transformations. Alcohols react to give chlorides (eq 14).27 Allylic alcohols that contain particularly reactive double bonds react preferentially at the alkenic sites.28 In the absence of such complications, alcohols larger than about seven carbons react to yield chlorides, whereas small water-soluble alcohols generally yield the corresponding orthoformate in poor yield (eq 15).29

The facile addition of dichlorocarbenes under phase-transfer conditions has also been observed with imines30 and can be a convenient pathway for the synthesis of some nitrogen-containing ring systems.31 The hydrolysis of the C,N-diarylaziridines to the corresponding a-chloroacetanilides was also reported (eq 16).32

The reaction of chloroform under basic conditions is a common test for both primary aliphatic and aromatic amines (eq 17). The so-called Hofmann carbylamine reaction can also be used synthetically for the preparation of isocyanides, though yields are generally not high.33 However, some improved procedures have been reported.34 When secondary amines are involved, the adduct cannot lose two molecules of HCl; instead it is hydrolyzed to an N,N-disubstituted formamide (eq 18).35 The reaction also yields imidazopyridines when a-(aminomethyl)pyridines are reacted with chloroform under phase-transfer catalysis conditions (eq 19).36

Dichlorocarbene can also be used as a dehydrating agent with primary amides, amidines, thioamides, and aldoximes, giving the corresponding nitriles (eq 20).37

Friedel-Crafts Reaction.

Chloroform reacts with aromatics rings38 to form di- and triarylmethanes (eq 21).39 The coupling of the two phenyl rings to the methyl group can be followed by a Scholl condensation (eq 22).40 The reaction can also be used for the high-yield synthesis of highly chlorinated mono-, di-, and triarylmethanes.41

Addition to Aldehydes.

Chloroform can condense with aromatic aldehydes under basic conditions (or by cathodic reduction)42 to produce aryl trihalomethyl-substituted methanols (eq 23).43

In the case of aliphatic aldehydes the reaction is not efficient due to the aldol condensation. However, a convenient general synthesis of a-trichloromethyl carbinols can now be used.44 Condensation of chloroform with aliphatic ketones to form dialkyl(trichloromethyl) carbinols45 can also be accomplished in lower yields, except in the case of cyclohexanone where the product was obtained in 92% yield.46

Trichloromethyl carbinols can be oxidized to ketones,47 hydrolyzed to hydroxy acids,48 condensed to diaryltrichloroethanes and related products,49 or can be used for the preparation of ordinary derivatives of the hydroxy group, such as the chloride50 or the acetate.51 They can also be reduced to give (Z)-vinyl chlorides.52 Secondary trichloromethyl carbinols are reduced by chromium(II) to form (Z)-monochlorovinyl compounds in one step; in the presence of a carboxy function in the a-position, an (E) double bond is formed. Tertiary carbinols favor the formation of dichlorovinyl compounds and rearranged carbonyl products (eq 24).

A variety of a-chloromethyl, a,a-dichloromethyl, and a,a,a-trichloromethyl ketones can also be synthesized from trichloromethyl carbinols utilizing cathodic reduction (eq 25).53

Another use of the reaction of the aryl trihalomethyl-substituted methanols involves their reaction with nucleophiles54 under basic conditions, by forming first a dichloro epoxide, which in turn reacts with the nucleophile to form an acid chloride that gives rise to the final product (eq 26). This reaction is used for the preparation of a-substituted arylacetic acids, where the a-substituent is methoxy55 (or alkoxy56 in general), hydroxy,57 amino,58 and even chloro.59 A method for the preparation of a-methoxy aliphatic acids has also been reported.60

Reactions via Trichlorolithiocarbenoids.

Chloroform can be lithiated to form Cl3CLi, a species that has proven to be a versatile synthon,61 although other polyhalomethanes are sometimes preferred. Of particular interest is the reaction of Cl3CLi with carbonyl functions (eq 27).62

Polyhalomethyllithium carbonyl adducts may be easily converted to a variety of important structural classes, such as a-chloro ketones,63 a,b-unsaturated aldehydes,64 a-chloroaldehydes,65 a-hydroxyaldehydes,66 and dichloroalkenes.67 Chloroform can readily give (trichloromethyl)alkenes by deprotonation with butyllithium and alkylation by iodoalkenes. The chloroalkenes generated can then undergo interesting transition metal catalyzed intramolecular cyclizations,68 affording five- or six-membered rings (eq 28). Trichlorolithiomethane can also generate gem-dichloroalkenes by reacting with a-sulfonyl carbanions,69 although their bromo analogs give better results (eq 29).

Chloroform in the presence of lithium triethylmethoxide can be used to convert organoboranes to the corresponding trialkyl carbinols (eq 30).70 The reaction proceeds in good yield for tri-n-butylborane, but gives poor results when extended to tri-s-butylborane and other secondary, hindered organoboranes. Dichloromethyl Methyl Ether is a much more effective participant in this reaction.71

Related Reagents.

Bromoform; Phenyl(tribromomethyl)mercury; Phenyl(trichloromethyl)mercury.

1. (a) Hine, J. JACS 1950, 72, 2438. (b) Le Noble, W. J. JACS 1965, 87, 2434.
2. For a discussion of the SN1cB mechanism see: Pearson, R. G.; Edgington, D. N. JACS 1962, 84, 4607.
3. For a review on carbenes see: Kirmse, W. Carbene Chemistry, 2nd ed.; Academic: New York, 1971; pp 129-141.
4. For reviews of the use of phase-transfer catalysis in the addition of dihalocarbenes see: (a) Starks, C. M.; Liotta, C. Phase Transfer Catalysis; Academic: New York, 1978; pp 224-268. (b) Weber, W. P.; Gokel, G. W. Phase Transfer Catalysis in Organic Synthesis; Springer: New York, 1978; pp 18-71.
5. For a review of the addition of halocarbenes see: Parham, W. E.; Schweizer, E. E. OR 1963, 13, 55.
6. (a) Starks, C. M. JACS 1971, 93, 195. (b) Makosza, M.; Wawrzyniewicz, M. TL 1969, 4659.
7. Kulinkovich, O. G. RCR 1989, 58, 711.
8. For a review of dihalocyclopropanes, see: Banwell, M. G.; Reum, M. E. Adv. Strain. Org. Chem. 1991, 1, 19.
9. Kraus, W.; Klein, G.; Sadlo, H.; Rothenwörker, W. S 1972, 485.
10. Makosza, M.; Gajos, I. Rocz. Chem. 1974, 48, 1883.
11. For a review of the addition of dihalocarbenes to bridged bicyclic alkenes see: Jefford, C. W. C 1970, 24, 357.
12. Kwon, S.; Nishimura, Y.; Ikeda, M.; Tamura, Y. S 1976, 249.
13. Weyerstahl, P.; Blume, G. T 1972, 28, 5281.
14. Hiyama, T.; Tsunaka, M.; Nozaki, H. JACS 1974, 96, 3713.
15. Makosza, M.; Gajos, I. Bull. Acad. Polon. Sci. 1972, 20, 33.
16. For a review see: Wynberg, H.; Meijer, E. W. OR 1982, 28, 1.
17. Robinson, E. A. JCS 1961, 1663.
18. Auwers, K.; Keil, G. CB 1902, 35, 4207.
19. Ciamician, G. L. CB 1904, 37, 4200.
20. (a) Gatterman reaction: Truce, W. E. OR 1957, 9, 37. (b) Gatterman-Koch reaction: Crounse, N. N. OR 1949, 5, 290. (c) Vilsmeier reaction: Fieser, L. F.; Hartwell, J. L.; Jones, J. E.; Wood, J. H.; Bost R. W. OSC 1955, 3, 98. (b) Duff reaction: Ferguson, L. N. CR 1946, 38, 229.
21. Wagner, R. B.; Zook, H. D. Synthetic Organic Chemistry; Wiley: London, 1953; p 307.
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24. see Ref. 16, p 15.
25. Increased para selectivity has been achieved by the use of polyethylene glycol: Neumann, R.; Sasson, Y. S 1986, 569.
26. Boev, V. I. JOU 1981, 17, 1190.
27. Tabushi, I.; Yoshida, Z.; Takahashi, N. JACS 1971, 93, 1820.
28. Hiyama, T.; Tsukanaka, M.; Nozaki, H. JACS 1974, 96, 3713.
29. De Wolfe, R. H. S 1974, 153
30. Graefe, J. ZC 1974, 14, 469.
31. (a) Takahashi, M.; Takada, T.; Sakagami, T. JHC 1987, 24, 797. (b) Petrov, O. S.; Oginayov, V. I.; Mollov, N. M. S 1987, 637.
32. Makosza, M.; Kacprowicz, A. Rocz. Chem. 1974, 48, 2129.
33. For a review of isocyanides, see Periasamy, M.; Walborsky, H. M. Org. Prep. Proc. Int. 1979, 11, 293.
34. (a) Weber, W. P.; Gokel, G. W. TL 1972, 1637. (b) Weber, W. P.; Gokel, G. W.; Ugi, I. K. AG(E) 1972, 11, 530.
35. (a) Saunders, M.; Murray, R. W. TL 1959, (6), 88. (b) Frankel, M. B.; Feuer, H.; Bank, J. TL 1959, (7), 5.
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37. Schroth, W.; Kluge, H.; Frach, R.; Hodek, W.; Schädler, H. D. JPR 1983, 325, 787.
38. For a review of alkyl halides in the Friedel-Crafts reaction, see: Olah, G. A. In Friedel-Crafts and Related Reactions; Drahowzal, F. A., Ed.; Wiley: New York, 1963-1965; Volume 2, pp 449-475.
39. Dolgov, B. N.; Sorokina, N. T.; Cherkasov, A. S. JGU 1951, 21, 509 (Chem. Zentr. 1952, 1631) (CA 1951, 45, 8464e).
40. Wang, H.; Kispert, L. D.; Sang, H. JCS(P2) 1989, 1463.
41. Ballester, M.; Riera, J.; Costaner, J.; Rovira, C.; Armet, O. S 1986, 64.
42. Shono, T.; Kise, N.; Masuda, M.; Suzumoto, T. JOC 1985, 50, 2527.
43. For a review on the preparation and on some of their chemical reactions, see: (a) Ledrut, J.; Combes, G. Ind. Chem. Belg. 1954, 19, 120. (b) Ledrut, J.; Combes, G. Ind. Chem. Belg. 1962, 19, 635.
44. Wyvratt, J. M.; Hazen, G. G.; Weinstock, L. M. JOC 1987, 52, 944.
45. Weizmann, C.; Bergmann, E.; Sulzbacher, M. JACS 1948, 70, 1189.
46. Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010.
47. Dinesman, A. CR 1905, 141, 201.
48. see Ref. 43(a).
49. Hofmann, J. E.; Schriesheim, A. In Ref. 38, Vol. 2, part 1, p 618.
50. Manedov, S.; Leiner, G. Y.; Khydrov, D. N. ZOB 1964, 34, 53.
51. Chen, T. C.; Sumerford, W. T. JACS 1950, 72, 5124.
52. Wolf, R.; Steckhan, E. JCS(P1) 1986, 733.
53. Shono, T.; Kise, N.; Yamazaki, A.; Ohmizu, H. TL 1982, 23, 1609.
54. For a review of the reactions of aryl trichloromethyl carbinols, see Reeve, W. S 1971, 3, 131.
55. Reeve, W.; Compere, E. L., Jr. JACS 1961, 83, 2755.
56. (a) Hebert, P. BSF(4) 1920, 27, 50. (b) Weizmann, C.; Sulzbacher, M.; Bergmann, E. JACS 1948, 70, 1153. (c) Bergmann, E. D.; Ginsburg, D.; Lavie, D. JACS 1950, 72, 5012.
57. Compere, E. L., Jr. JOC 1968, 33, 2565.
58. Reeve, W.; Fine, L. W. JOC 1964, 29, 1148.
59. see Ref. 54, p. 135.
60. Compere, E. L., Jr.; Shockravi, A. JOC 1978, 43, 2702.
61. Kobrich, G. AG(E) 1972, 11, 473.
62. Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010.
63. Kobrich, G.; Grosser, J. CB 1973, 106, 2626.
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65. Kobrich, G.; Werner, W. TL 1969, 2181.
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Morris Srebnik & Eric Laloë

University of Toledo, OH, USA

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