CHLOROFORM

1

Chloroform

CHCl

3

[67-66-3]

CHCl

3

(MW 119.38)

InChI = 1/CHCl3/c2-1(3)4/h1H
InChIKey = HEDRZPFGACZZDS-UHFFFAOYAG

(commonly a solvent in organic synthesis; also used in the prepa-
ration of dichlorocarbenes and α-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 sun-

light 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 car-
bon tetrachloride (eq 1). The reaction proceeds by an S

N

1cB

mechanism

1

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 CHCl

3

and OH

−

, often

under phase-transfer catalysis conditions,

4

and the dichlorocar-

benes react with alkenes and nonalkene substrates.

5

OH

–

CCl

3

–

– Cl

–

(1)

HCCl

3

:CCl

2

Addition to Alkenes via Dihalocarbenes. Dichlorocarbenes

add to double bonds to give 1,1-dichlorocyclopropanes

6

that are

versatile substrates for subsequent ring opening.

7

Dihalocyclo-

propanes are very useful compounds

8

that can be reduced to cy-

clopropanes, 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-chlorona-

phthalene derivatives (eq 3).

10

(2)

Cl

Cl

Na, NH

3

:CCl

2

:CCl

2

Cl

Cl

EtOH

KOH

Cl

(3)

When more than one isolated double bond is present in a sub-

strate, 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 unsta-
ble (eq 4).

11

Another useful rearrangement involves the expansion

of pyrroles and indoles to pyridines and quinolines derivatives, re-
spectively (eq 5).

12

(4)

Cl

Cl

Cl

Cl

:CCl

2

N
H

R

1

R

2

N
H

Cl

Cl

R

1

R

2

N

R

1

Cl

R

2

(5)

:CCl

2

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).

+

Cl

Cl

Cl

Cl

(6)

:CCl

2

Cl

:CCl

2

Cl

Cl

Cl

(7)

The formation of 1,1-dichlorocyclopropanes from allylic alco-

hols 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

OH

OH

Cl

Cl

O

(8)

:CCl

2

H

+

CN

CN

Cl

Cl

Cl

3

C

CN

CCl

3

–

(9)

–

Michael pathway

The most studied reaction of chloroform involving the for-

mation 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

Avoid Skin Contact with All Reagents

2

CHLOROFORM

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

NaOH (aq), CHCl

3

OH

OH

CHO

OH

+

CHO

(10)

The abnormal Reimer–Tiemann reaction product can be sub-

divided further into cyclohexadienones and ring-expansion prod-
ucts. 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

OH

OH

CHO

O

CHCl

2

NaOH (aq), CHCl

3

+

(11)

N

K

N
H

CHO

N

Cl

NaOH (aq), CHCl

3

+

(12)

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

phenols

21

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

(13)

R

R

Cl

Cl

:CCl

2

+

The reaction of dichlorocarbene with substrates other than

hydrocarbons appears to be initiated by coordination of the elec-
trophilic carbene with a Lewis basic site. Subsequent reactions
that are attributable to differences in the basic functions or in-
volvement with other reactive sites lead to differences in the chem-
istry of each substrate. The reactions of phase-transfer-generated
dichlorocarbene with organic molecules possessing such heter-
oatoms as oxygen, nitrogen, and sulfur and no other more reac-
tive 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

(14)

ROH

+

:CCl

2

RCl

+

CO

(15)

HCCl

3

+

3 RO

–

HC(OR)

3

+

3 Cl

–

The facile addition of dichlorocarbenes under phase-transfer

conditions has also been observed with imines

30

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 α-chloroacetanilides was also reported (eq 16).

32

N

R

2

R

1

:CCl

2

N

R

2

R

1

Cl

Cl

H

2

O

R

1

H
N

R

2

Cl

O

(16)

The reaction of chloroform under basic conditions is a com-

mon 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 α-(aminomethyl)pyridines are re-
acted with chloroform under phase-transfer catalysis conditions
(eq 19).

36

N

H

H

R

Cl

Cl

(17)

C N R

+

–

– 2 HCl

+

–

RNH

2

:CCl

2

N

H

H

R

Cl

Cl

N

R

R

Cl

Cl

+

–

(18)

NR

2

O

H

H

2

O

N

NH

2

N

NH

2

Cl

2

C

N

CN

+

N

(19)

N

–

Dichlorocarbene can also be used as a dehydrating agent with

primary amides, amidines, thioamides, and aldoximes, giving the
corresponding nitriles (eq 20).

37

NR

2

O

H

R

N

–

O

Cl

Cl

+

:CCl

2

(20)

+

Friedel–crafts Reaction. Chloroform reacts with aromatics

rings

38

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

(21)

Al, CuCl

Ph

2

CH

2

+

Ph

3

CH

C

6

H

6

+

CHCl

3

A list of General Abbreviations appears on the front Endpapers

CHLOROFORM

3

2 C

6

H

6

+

CHCl

3

AlCl

3

Cl

Ph

Ph

Ph

Ph

(22)

+

2 HCl

Scholl

AlCl

3

Addition to Aldehydes. Chloroform can condense with aro-

matic aldehydes under basic conditions (or by cathodic re-
duction)

42

to produce aryl trihalomethyl-substituted methanols

(eq 23).

43

KOH

OH

Ph

CCl

3

PhCHO

+

CHCl

3

(23)

In the case of aliphatic aldehydes the reaction is not efficient

due to the aldol condensation. However, a convenient general
synthesis of α-trichloromethyl carbinols can now be used.

44

Con-

densation of chloroform with aliphatic ketones to form dialkyl(tri-
chloromethyl) carbinols

45

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

hy-

drolyzed to hydroxy acids,

48

condensed to diaryltrichloroethanes

and related products,

49

or can be used for the preparation of ordi-

nary derivatives of the hydroxy group, such as the chloride

50

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 pres-
ence of a carboxy function in the α-position, an (E) double bond
is formed. Tertiary carbinols favor the formation of dichlorovinyl
compounds and rearranged carbonyl products (eq 24).

OH

R

CCl

3

Cr

2+

Cl

R

Cl

R

Cl

(24)

+

A variety of α-chloromethyl, α,α-dichloromethyl, and α,α,α-

trichloromethyl ketones can also be synthesized from trichloro-
methyl carbinols utilizing cathodic reduction (eq 25).

53

R

CCl

3

OH

R

CCl

3

OMe

R

CCl

3

O

R

CHCl

2

O

(25)

R

O

Cl

NaH, MeI

Another use of the reaction of the aryl trihalomethyl-substituted

methanols involves their reaction with nucleophiles

54

under ba-

sic 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 prepara-
tion of α-substituted arylacetic acids, where the α-substituent is
methoxy

55

(or alkoxy

56

in general), hydroxy,

57

amino,

58

and even

chloro.

59

A method for the preparation of α-methoxy aliphatic

acids has also been reported.

60

OH

Ar

CCl

3

KOH

O

Cl

Cl

Ar

O

Cl

Nu

Ar

(26)

Nu

–

Reactions via Trichlorolithiocarbenoids. Chloroform can be

lithiated to form Cl

3

CLi, a species that has proven to be a versa-

tile synthon,

61

although other polyhalomethanes are sometimes

preferred. Of particular interest is the reaction of Cl

3

CLi with

carbonyl functions (eq 27).

62

O

CHCl

3

OH

(27)

lithiated base

CHCl

3

Polyhalomethyllithium carbonyl adducts may be easily con-

verted to a variety of important structural classes, such as α-chloro
ketones,

63

α

,β-unsaturated aldehydes,

64

α

-chloroaldehydes,

65

α

-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 cat-
alyzed intramolecular cyclizations,

68

affording five- or six-

membered rings (eq 28). Trichlorolithiomethane can also generate
gem

-dichloroalkenes by reacting with α-sulfonyl carbanions,

69

although their bromo analogs give better results (eq 29).

I

CCl

3

RuCl

2

(PPh

3

)

3

Cl

H

H Cl Cl

CHCl

3

+

BuLi

+

(28)

R

Li

SO

2

Ph

Cl

Cl

R

+

CCl

3

Li

(29)

+

PhSO

2

Li

+

LiCl

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-butyl-
borane and other secondary, hindered organoboranes. Dichloro-
methyl Methyl Ether is a much more effective participant in this
reaction.

71

(30)

Bu

3

B

+

CHCl

3

LiOCEt

3

[O]

Bu

3

COH

Related

Reagents. Bromoform;

Phenyl(tribromomethyl)-

mercury; Phenyl(trichloromethyl)mercury.

1.

(a) Hine, J., J. Am. Chem. Soc. 1950, 72, 2438. (b) Le Noble, W. J. J.
Am. Chem. Soc. 1965

, 87, 2434.

2.

For a discussion of the S

N

1cB mechanism see: Pearson, R. G.;

Edgington, D. N., J. Am. Chem. Soc. 1962, 84, 4607.

3.

For a review on carbenes see: Kirmse, W. Carbene Chemistry, 2nd ed.;
Academic: New York, 1971; p 129.

Avoid Skin Contact with All Reagents

4

CHLOROFORM

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; p 224. (b) Weber, W. P.; Gokel,

G. W. Phase Transfer Catalysis in Organic Synthesis; Springer: New
York, 1978; p 18.

5.

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6.

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, 1, 19.

9.

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Makosza, M.; Gajos, I., Rocz. Chem. 1974, 48, 1883.

11.

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12.

Kwon, S.; Nishimura, Y.; Ikeda, M.; Tamura, Y., Synthesis 1976, 249.

13.

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14.

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15.

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16.

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17.

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Auwers, K.; Keil, G., Chem. Ber. 1902, 35, 4207.

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Morris Srebnik & Eric Laloë

University of Toledo, Toledo, OH, USA

A list of General Abbreviations appears on the front Endpapers