Mild electrophilic halogenation of chloropyridines using CCl4 or C2Cl6 under basic phase transfer conditions

Article abstract of DOI:10.1016/j.tetlet.2004.04.177

Effective chlorination of 2,3,5,6-tetrachloropyridine to pentachloropyridine was realized under mild phase transfer conditions with carbon tetrachloride and 50% NaOH or solid K₃PO₄. Mechanistic study of this reaction indicated the possibility of an aromatic carbanionic intermediate. Hexachloroethane was established as a more selective electrophilic chlorination agent.

Full text of DOI:10.1016/j.tetlet.2004.04.177

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5061–5063
Mild electrophilic halogenation of chloropyridines using CCl4 or
C2Cl6 under basic phase transfer conditions
Ashutosh V. Joshi, Mubeen Baidossi, Nida Qafisheh, Elsa Chachashvili and Yoel Sasson*
Casali Institute of Applied Chemistry, Hebrew University of Jerusalem, 91904 Jerusalem, Israel
Received 23March 2004; revised 19 April 2004; accepted 30 April 2004
Abstract—Effective chlorination of 2,3,5,6-tetrachloropyridine to pentachloropyridine was realized under mild phase transfer
conditions with carbon tetrachloride and 50% NaOH or solid K3PO4. Mechanistic study of this reaction indicated the possibility of
an aromatic carbanionic intermediate. Hexachloroethane was established as a more selective electrophilic chlorination agent.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In this work we describe an aromatic chlorination pro-
cess using carbon tetrachloride as a reagent and a sol-
vent under PTC/OH conditions. The reaction is
demonstrated using an electron poor 2,3,5,6-tetrachlo-
ropyridine as substrate, which is converted to penta-
chloropyridine. We assert a new aromatic chlorination
mechanism where a chloronium cation attacks an aro-
matic carbanion to form a new C–Cl bond.
A major contribution of phase transfer catalysis to the
organic chemist’s toolbox has been the replacement of
anhydrous strong bases such as alkali metal alkoxides,
amides or hydrides with the aqueous sodium hydroxide/
quaternary ammonium catalyst combination (PTC/
OH),1 mainly in alkylation and related reactions. This
was achieved by combining an acid–base equilibrium
step with a biphasic anion exchange extraction step,
which consequently allowed the deprotonation of
exceedingly weak (mainly carbon) acids.2 Thus, sub-
strates with pKa’s as high as 23could be smoothly
alkylated with alkyl halides or sulfates.3 Weaker acids
could not be alkylated under PTC/OH conditions but
there are reports on the oxidation of diphenylmethane4
(pKa ¼ 31–32), isomerization of allyl benzene5
(pKa ¼ 34) and H/D exchange of thiophene6
(pKa ¼ 38.4). The latter is an example of a unique
transformation most likely involving an aromatic carb-
anionic intermediate.
Formation of C–halogen bonds from C–H bonds is a
fundamental reaction in organic synthesis.7;8 Haloge-
nation of C–H bonds has also been extensively studied
in the presence of phase transfer catalysts.3 Polyhalo-
methanes as a source of halogen have been utilized for
halogenation, for example, for iodination of alkanes,9
halogenation of terminal acetylenes10 and of acidic
hydrocarbons in the presence of tetrabutylammonium
fluoride.11 A recent review presents an account of reac-
tions of practical significance of CCl4 and CBr4 with
carbanions.12 In this context, the synthesis of polychlo-
rinated pyridines such as 2,3,6-trichloro-, 2,3,5-tri-
chloro-, 3,4,5-trichloro-, 2,3,4,5-tetrachloro-, 2,3,5,6-
tetrachloro- and 2,3,4,5,6-pentachloro pyridines, which
are useful as intermediates for herbicides and insecti-
cides13 are of considerable interest. They are usually
prepared by chlorination of pyridines13 or picolines14 at
high temperatures, generally leading to a variety of
products such as dichloro, trichloro, tetrachloro and
pentachloropyridines. 2,3,5,6-Tetrachloropyridine has
been selectively synthesized by the reaction of trichloro-
acetyl chloride and acrylonitrile15 and also by selective
reduction of pentachloropyridine with Zn dust in a basic
medium.16 A Dow patent claims high yields of penta-
chloropyridine by reaction of vapors of n-valeronitrile
No other reaction, beside H/D exchange, was hitherto
demonstrated to proceed via a putative aromatic carb-
anion intermediate generated under mild, aqueous PTC/
OH conditions.
Keywords: Halogenation; Phase transfer; Polyhalomethane; Potassium
phosphate; Aromatic carbanion.
* Corresponding author. Tel.: +972-2-6584530; e-mail: ysasson@
huji.ac.il
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.177

5062
A.V.Joshi et al./ Tetrahedron Letters 45 (2004) 5061–5063
and chlorine at a temperature of about 600 °C.17 Thus
with this background in mind, where there are reports
on the direct preparation of pentachloropyridine and
2,3,5,6-tetrachloropyridine, we thought it worthwhile to
complete this reaction cycle by exploring the possibility
of the chlorination of 2,3,5,6-tetrachloropyridine to
pentachloropyridine with polyhalomethane under basic
phase transfer conditions.
In order to attain a better selectivity for II in the chlo-
rination of I, it is thus essential to avoid the formation of
CHCl3, which in turn will avert the generation of the
side products. For this aim we applied hexachloroethane
as a chlorinating agent18c in chlorination of I. Analysis
of the product mixture indicated 80% conversion after 4
hours with 96% selectivity for II (Eq. 4). Tetrachloro-
ethylene was also found as a reaction product. The latter
has additional advantages since it can be recycled to
hexachloroethane.
2. Results and discussion
Cl
Cl
C
Cl
Cl
Cl
Cl
Cl
0
+ NaCl + H O
TBAB, 50
EDC
2
+ C Cl
2
6
ð4Þ
In a typical reaction, a mixture of 0.5 mmol of 2,3,5,6-
tetrachloropyridine, I (108 mg), 10 mL carbon tetra-
chloride (CCl4, solvent and chlorinating agent),
6.0 mmol sodium hydroxide (240 mg, 50% w/w solution),
10 mol % tetra-n-butylammonium bromide (TBAB,
16 mg), was stirred at 50 °C in a round bottom flask
equipped with an efficient condenser for 4 h. GC analysis
of the reaction mixture after this time revealed 98%
conversion. Pentachloropyridine, II was obtained with
80% selectivity (Eq. 1).
+ Cl C=CCl
2
2
+ NaOH
Cl
N
II
Cl
N
I
Surprisingly, only 30% conversion was achieved after
24 h when bromotrichloromethane was utilized as a
halogen source under identical conditions. The product
obtained was 4-bromo-2,3,5,6-tetrachloropyridine. This
could probably be a result of the lower electrophilicity of
the bromonium cation compared to the chloronium
cation intermediate.
2,3,5-Trichloropyridine was also subjected to the chlo-
rination reaction under identical conditions. Tetrachlo-
ropyridine was obtained (88% selectivity) with 33%
conversion after 4 h. Formation of the 2,3,4,5-tetra-
chloropyridine isomer was confirmed by the facile for-
mation of its corresponding sulfate salt.20
Cl
Cl
Cl
Cl
Cl
Cl
Cl
+ CHCl
NaOH (50%), 4h
0
ð1Þ
+ CCl
Cl
3
4
TBAB, 50
C
N
I
N
II
Cl
Two side products were also identified: 4-trichloro-
methyl-2,3,5,6-tetrachloropyridine (5%) IV and 4-di-
chloromethyl-2,3,5,6-tetrachloropyridine (13%), III,18
the structures of which were confirmed by GC–MS
The presence of a phase transfer catalyst was proved to
be critical. The reaction barely occurred when it was
excluded. Tetra-n-butylammonium chloride was slightly
inferior to TBAB.
analysis. Formation of the latter could be attributed to
18a
the reaction of chloroform with II
turn could be converted in equilibrium to IV (Eq. 3) in
(Eq. 2), which in
There was an effect of the NaOH amount on the rate of
reaction. By performing the reaction with 4 equiv
instead of 12 equiv under identical conditions only 80%
conversion was observed after 5.5 h. Evidently the excess
of base was needed for kinetic reasons and could be
recovered after the reaction was complete.
the presence of excess CCl4.18b
Cl
CHCl
2
Cl
Cl
Cl
Cl
Cl
Cl
+ 2CHCl + NaOH
+ CCl + NaCl + H O
ð2Þ
ð3Þ
3
4
2
N
II
Cl
N
Cl
III
Shreiner has suggested that the pathway for the occur-
rence of halogenation reactions using polyhaloalkanes
in basic conditions, for instance in the case of iodination
of alkanes was via the formation of a tetrahalomethane
anion radical formed by interaction of a hydroxide ion
with carbon tetrahalide.21 Proof for this mechanism was
obtained from observations of the effect of addition of a
radical anion scavenger such as p-dinitrobenzene.22
When we added 15 mol % of p-dinitrobenzene under the
reaction conditions, formation of pentachloropyridine
was found to be greatly affected with only 50% con-
version achieved after 4 h. This indicates the possibility
of the reaction occurring via a similar radical anion
mechanism proposed earlier. However, there are reports
on H/D exchange of aromatic hydrogens even in the
case of substrates such as thiophene, which has a very
low pKa of 38.4, in the presence of 60% NaOH/D2O6
suggesting that carbanion formation may also occur in
the case of p-DNB. The latter can be compared in
acidity to pentafluorobenzene, which has a pKa of ca
25.8.23
CCl
CHCl
2
Cl
3
Cl
Cl
Cl
Cl
Cl
NaOH (50%)
+ CHCl3
+ CCl4
Cl
N
III
Cl
N
IV
This type of equilibrium processes has been previously
discussed by Orvik.18a;b
Indeed, when the reaction was continued further for a
longer period (20 h) it was observed that formation of
the side products increased with only 56% of II
remaining and the rest being mainly III and IV. More-
over conducting the reaction of II with 8 equiv of CHCl3
in dichloroethane and 50% NaOH confirmed the for-
mation of III and even the formation of bis(dichlo-
romethyl)-trichloropyridine. This is a unique instance
where, in the presence of a base, chloroform forms a
dichloromethyl anion and a chloronium cation rather
than the obvious trichloromethyl anion.19

A.V.Joshi et al./ Tetrahedron Letters 45 (2004) 5061–5063
5063
Hence we decided to explore the other possibility, the
reaction occurring via the formation of the tetrachlo-
ropyridine carbanion. Facile H/D exchange occurred
when I was exposed to either D2O or CDCl3 in the
presence of NaOH and 90% of deuterium exchange was
determined by NMR analysis after 3h at ambient
temperature. The GC–MS analysis of the sample con-
firmed the formation of 4-deuterated I suggesting the
formation of a carbanion intermediate. This was also
substantiated by an earlier report where the complex
base BuLi–LiDMAE reacted with pyridine to give a
metallated species.24
analysis and interpretation of several products in this
study.
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Acknowledgements
We thank Dr. Sudhakar Bhusare and Mr. Khalil for
NMR Analysis. We thank Mrs. Marcela Haimberg and
Mr. Michael Mogilnitsky from the MS laboratory at
Makhteshim Chemical Works, Beer Sheva, for GCMS