Reactivity of chlorinating agents/PPh3 for the chlorination of alcohols and carboxylic acids: a comparative study

Article abstract of DOI:10.1016/j.tetlet.2006.11.060

The reactivity of chlorinating agents was examined with the aid of ¹H NMR using competitive reactions between selected chlorinating agents and CBr₄ towards alcohols and carboxylic acids. The reactivity was greatly dependent on the type of substituent on the chlorinating agents. COCCl₃ and CN substituted trichloromethyl groups enhanced the reactivity of the chlorinating agent with PPh₃ for the chlorination of alcohols and carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2006.11.060

Tetrahedron Letters 48 (2007) 223–226
Reactivity of chlorinating agents/PPh3 for the chlorination
of alcohols and carboxylic acids: a comparative study
Wanchai Pluempanupat,a Oraphin Chantarasriwong,a Piyada Taboonpong,a
Doo Ok Jangb,* and Warinthorn Chavasiria,*
aNatural Products Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
bDepartment of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
Received 30 September 2006; revised 28 October 2006; accepted 9 November 2006
Abstract—The reactivity of chlorinating agents was examined with the aid of 1H NMR using competitive reactions between selected
chlorinating agents and CBr4 towards alcohols and carboxylic acids. The reactivity was greatly dependent on the type of substituent
on the chlorinating agents. COCCl3 and CN substituted trichloromethyl groups enhanced the reactivity of the chlorinating agent
with PPh3 for the chlorination of alcohols and carboxylic acids.
Ó 2006 Elsevier Ltd. All rights reserved.
Alkyl chlorides and acid chlorides are generally utilized
+
Cl3CR
+
Cl2CR
RCl
Cl PPh3
PPh3
as both synthetically useful intermediates and valuable
end products in chemical industries and pharmaceutical
science.1,2 These compounds are prepared by the
reaction of alcohols and carboxylic acids with common
reagents such as SOCl2 and (COCl)2.3 However, such
protocols cannot be applied to acid-sensitive com-
pounds due to the vigorous conditions and the forma-
tion of strong acid (HCl) during the process. One
applicable method involves the use of PPh3 and a
chlorinating agent (Cl3CR, R = Cl, CCl3, COCCl3, CN
or CONH2).4–6 These coupling reagents are important
since the chlorination of alcohols and carboxylic acids
could be performed efficiently under mild and acid-free
conditions to afford the desired alkyl and acid chlorides
in high to excellent yields.
A
ROH
+ O PPh3
Cl
RO PPh3
B
A
O
O
O
RCOH
+
RCCl
O PPh3
+
Cl
RCO PPh3
C
Scheme 1. General mechanism.
We have recently explored the effect of various chlori-
nating agents on the chlorination of alcohols and carb-
oxylic acids and have also introduced Cl3CCONH2 as
another versatile chlorinating agent.6 The difference in
reactivity of these reagents under optimized conditions
could be observed. For example, the chlorination of a
carboxylic acid using Cl3CCN/PPh3 smoothly pro-
ceeded at room temperature while Cl3CCONH2/PPh3
required reflux in CH2Cl2. In addition, Cl3CCN was a
more efficient reagent for the conversion of sulfonic
acids to sulfonyl chlorides under the same conditions.8
Presumably, the type of electron-withdrawing group
on the chlorinating agents could affect the reactivity.
The conversion of alcohols and carboxylic acids into the
corresponding chlorides with various coupling reagents
proceeded via a similar mechanism (Scheme 1).6,7 PPh3
reacts with Cl3CR to give an intermediate A which sub-
sequently reacts with alcohols or carboxylic acids yield-
ing an alkoxyphosphonium salt (B or C) which then
transforms to the corresponding chlorides by SN2
displacement.
Keywords: Chlorinating agent; PPh3; Alcohol; Carboxylic acid.
*
The reactivity of these reagents has nevertheless not yet
been thoroughly examined. We report herein a relative
Corresponding authors. Tel.: +66 2 2187625; fax: +66 2 2187598
(W.C.); e-mail: warintho@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.060

224
W. Pluempanupat et al. / Tetrahedron Letters 48 (2007) 223–226
reactivity study of various chlorinating agents towards
the chlorination of alcohols and carboxylic acids.
spectrum displayed two triplet signals for the halide
substituted methylene protons at dH 3.62 and 3.47,
respectively.
The reactivity of various chlorinating agents was inves-
tigated using a competitive reaction between a reference
compound (CBr4) and various chlorinating agents
towards 2-phenylethanol (Table 1). The reactivity of
selected chlorinating agents was rationalized by the ratio
of the yield obtained of 2-phenylethyl chloride (1) and
2-phenylethyl bromide (2).
In the absence of chlorinating agent, 2 was obtained as
the sole product in high yield (entry 1). No reactivity
was observed when using chlorinating agents containing
an alkyl group or another Cl atom (CCl4) on the Cl3C–
group under the specified conditions (entries 2–4). The
reactivity of Cl3CCONH2 was comparatively similar
to those of Cl3CCCl3, Cl3CCO2Et, Cl3CCO2 Pr and
Cl3CCONHPh (entries 5–9). On the other hand, both
Cl3CCOCCl3 and Cl3CCN, bearing a strong electron-
i
The ratio of 1 and 2 was calculated by 1H NMR,
utilizing toluene as an internal standard (Fig. 1). The
Table 1. Reactivity comparison of chlorinating agents on the chlorination of 2-phenylethanol
PPh3 (1.5 equiv)
CBr4 (0.75 equiv)
Chlorinating agent (0.75 equiv)
Ph
Ph
Ph
+
OH
Cl
Br
CH2Cl2, RT, 15 min
Yielda (%)
1
2
Entry
Chlorinating agent
Ratio of 1/2
Reactivityb
1
2
1
2
3
4
5
6
7
8
9
None
CCl4
Cl3CCH2OH
CH3CO2CH2CCl3
Cl3CCCl3
Cl3CCO2Et
0
0
0
0
23
26
27
21
14
70
65
69
70
57
62
76
73
73
76
70
24
32
—
—
—
—
0.30
0.36
0.37
0.28
0.20
2.92
2.03
—
—
—
—
1.07
1.29
1.32
1
0.71
10.43
7.25
i
Cl3CCO2 Pr
Cl3CCONH2
Cl3CCONHPh
Cl3CCOCCl3
Cl3CCN
10
11
a The yield was determined based on 1H NMR integration.
b Based on Cl3CCONH2.
Figure 1. 1H NMR spectrum of 1 and 2 in the crude mixture from the competitive reaction between Cl3CCN and CBr4.

W. Pluempanupat et al. / Tetrahedron Letters 48 (2007) 223–226
225
withdrawing group, showed significantly higher reactiv-
ity, 10.43- and 7.25-fold, over Cl3CCONH2 (entries 10
and 11).
Cl3CCOCCl3 and Cl3CCN still exhibited the highest
levels of reactivity (entries 5 and 6).
It should be pointed out here that Cl3CCN displayed
higher reactivity than Cl3CCOCCl3 in the case of di-
phenylacetic acid. On the other hand, in the case of
2-phenylethanol, Cl3CCOCCl3 showed higher reactivity
than Cl3CCN.
The prominent reactivity of Cl3CCOCCl3 and Cl3CCN
was confirmed using another experiment (Table 2).
Selected chlorinating agents coupled with PPh3 were
allowed to react with 2-phenylethanol to produce 1
within 5 min. The mixture was then treated with CBr4
to transform the remaining alcohol into 2. If the chlori-
nating agent selected was reactive, it would afford 1 in
high yields before addition of CBr4 to yield 2. Interest-
ingly, Cl3CCOCCl3 and Cl3CCN could still produce 1
in high yields compared with Cl3CCONH2 (entries
2–4). This clearly indicated that these reagents possessed
high reactivity which was in good agreement with prior
observations.
Considering the reactivity of the chlorinating agents on
the formation of alkyl chlorides and acid chlorides, chlo-
rinating agents possessing strong electron-withdrawing
groups such as COCCl3 and CN showed the highest
reactivity. This postulation can be used as a fundamen-
tal concept for the development of new efficient chlori-
nating agents or as a guideline to optimize suitable
conditions.
Furthermore, the reagents bearing electron-withdrawing
groups were also investigated in a competitive reaction
with diphenylacetic acid under the same conditions
(Table 3). Similar levels of reactivity were observed in
the cases of Cl3CCONH2, Cl3CCCl3 and Cl3CCO2Et
being 1, 0.73 and 0.69, respectively (entries 2–4).
A typical experimental procedure is as follows: To a stir-
red solution of 2-phenylethanol or diphenylacetic acid
(0.25 mmol) and a mixture of chlorinating agent
(0.188 mmol) and CBr4 (0.188 mmol) in dry CH2Cl2
(0.5 mL) was added PPh3 (0.375 mmol) at rt under
an N2 atmosphere. After 15 min, the amount of the
Table 2. Reactivity comparison of chlorinating agents on the chlorination of 2-phenylethanol
PPh3 (1.5 equiv)
Chlorinating agent
(0.75 equiv)
CBr4 (0.75 equiv)
RT, 10 min
Ph
Ph
Ph
+
OH
Cl
Br
CH2Cl2, RT, 5 min
1
2
Entry
Chlorinating agent
Yielda (%)
Ratio of 1/2
Reactivityb
1
2
1
2
3
4
None
0
75
67
0
—
0.31
—
—
1
—
11.13
Cl3CCONH2
Cl3CCOCCl3
Cl3CCN
21
97
76
22
3.45
a The yield was determined based on 1H NMR integration.
b Based on Cl3CCONH2.
Table 3. Reactivity comparison of chlorinating agents on the chlorination of diphenylacetic acid
PPh3 (1.5 equiv)
CBr4 (0.75 equiv)
Ph
Ph
O
Chlorinating agent (0.75 equiv)
Ph
Ph
O
Ph
Ph
O
+
CDCl3, RT, 15 min
OH
Cl
Br
3
4
Entry
Chlorinating agent
Yielda (%)
Ratio of 3/4
Reactivityb
3
4
1
2
3
4
5
6
None
0
50
49
49
80
Quant
82
49
51
35
14
0
—
—
Cl3CCCl3
Cl3CCO2Et
Cl3CCONH2
Cl3CCOCCl3
Cl3CCN
1.02
0.96
1.40
5.71
—
0.73
0.69
1
4.08
—
a The yield was determined based on 1H NMR integration.
b Based on Cl3CCONH2.

226
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Acknowledgements
This work was financially supported by a joint research
project under the NRCT-KOSEF international cooper-
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grateful for the support from CBMH.
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