Increased intensity of tert-butoxyl radical emission in 4-chloro-2- methylphenoxyacetic acid (MCPA) synthesis

Article abstract of DOI:10.1002/(SICI)1096-9063(199912)55:12<1229::AID-PS67>3.0.CO;2-D

The important herbicide, 2-methyl-4-chlorophenoxyacetic acid (MCPA) was synthesized by the chlorination of 2-methylphenoxyacetic acid with tert-butyl hypochlorite in the presence of methyl N,N-dimethylglycinate as a catalyst, giving a high yield and regioselectivity. The reaction was investigated using the spin-trapping technique in electron paramagnetic resonance measurement conditions, with nitrosodurene as a spin trap. Increased intensity emission of the tert-butoxyl radical (2.9 times in relation to the starting level) was observed after the catalyst had been introduced into the reaction mixture, indicating a free radical mechanism for the reaction.

Full text of DOI:10.1002/(SICI)1096-9063(199912)55:12<1229::AID-PS67>3.0.CO;2-D

Pesticide Science
Pestic Sci 55:1229±1232 (1999)
Communication to the Editor
Increased intensity of tert-butoxyl radical
emission in 4-chloro-2-methylphenoxyacetic
acid (MCPA) synthesis
1
2
2
´
Adam Jezierski, Jerzy Zakrzewski * and Wiesław Moszczynski
1Institute of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland
2Institute of Industrial Organic Chemistry, 6 Annopol, 03-236 Warsaw, Poland
Abstract: The important herbicide, 2-methyl-4-chlorophenoxyacetic acid (MCPA) was synthesized by
the chlorination of 2-methylphenoxyacetic acid with tert-butyl hypochlorite in the presence of methyl
N,N-dimethylglycinate as a catalyst, giving a high yield and regioselectivity. The reaction was investi-
gated using the spin-trapping technique in electron paramagnetic resonance measurement conditions,
with nitrosodurene as a spin trap. Increased intensity emission of the tert-butoxyl radical (2.9 times in
relation to the starting level) was observed after the catalyst had been introduced into the reaction
mixture, indicating a free radical mechanism for the reaction.
# 1999 Society of Chemical Industry
Keywords: 4-chloro-2-methylphenoxyacetic acid; 2-methylphenoxyacetic acid; tert-butyl hypochlorite; methyl
N,N-dimethylglycinate; tert-butoxyl radical; nitrosodurene; spin trapping
1
INTRODUCTION
As a free-radical mechanism of chlorination may give
rise to high regioselectivity,7 the investigation of MPA
chlorination using a spin trapping technique is also
reported. The latter technique involves the reaction of
unstable, short-lived free radicals with a spin trap (a
nitroso compound or a nitrone) resulting in more
stable nitroxyl radicals which are detected by electron
paramagnetic resonance (EPR)8±10 (Fig 2).
In recent years considerable attention has been given
to regioselectivity in the halogenation of the aromatic
nucleus. High regioselectivity in the halogenation of
phenols and phenol ethers has been recently re-
(and references cited therein)
ported.1,2
herbicide.
The commercial
acid
4-chloro-2-methylphenoxyacetic
(MCPA) is manufactured by the chlorination of 2-
methylphenoxyacetic acid (MPA) (Fig 1).
The chlorination of MPA may be realized in many
ways: eg with gaseous chlorine in organic solvents,3,4
in an alkaline-aqueous medium,5 or with hypochlor-
ous acid in aqueous medium.6o-Chlorination to give 6-
chloro-2-methylphenoxyacetic acid and/or cleavage of
the phenoxyacetic acid molecule to give the respective
chlorophenols may occur as undesired side reactions.
In this paper, we report high regioselectivity in
MCPA synthesis by chlorination of MPA with tert-
butyl hypochlorite (tert-BuOCl) in the presence of
methyl N,N-dimethylglycinate (DMGM) as a catalyst.
2
EXPERIMENTAL
2.1 EPR Spectroscopy
EPR spectra were determined with Bruker ESP 300 E
and Radiopan SE spectrometers (9 GHz - X band) and
adjusted with a computer program `Simfonia'. Radical
concentration data were obtained by double integra-
tion of the EPR signal. Before the EPR measurement,
all samples were deoxygenated by passing a nitrogen
stream through the solution.
Figure 1. Synthesis of 4-chloro-2-methylphenoxyacetic acid (MCPA), by
the chlorination of 2-methylphenoxyacetic acid (MPA).
Figure 2. The principle of the spin-trapping technique.
* Correspondence to: Jerzy Zakrzewski, Institute of Industrial Organic Chemistry, 6 Annopol, 03-236 Warsaw, Poland
E-mail: inorg@atos.warman.com.pl
Contract/grant sponsor: Polish State Committee for Scientific Research; contract/grant number: 7108 92C/0589.
(Received 10 May 1999; accepted 27 July 1999)
# 1999 Society of Chemical Industry. Pestic Sci 0031±613X/99/$17.50
1229

A Jezierski, J Zakrzewski, W MoszczynÂski
Solvent
Presence of catalyst
Yield of MCPA (%)
Selectivity a
Water
‡
‡
‡
97
141
98
Chloroform
Toluene
Water
96
96.5
84
141
8.5
13
Toluene
a
De®ned as a ratio of MCPA to 6-chloro-2-methylphenoxyacetic acid (4-Cl/6-Cl ratio).
87
Table 1. MPA chlorination; laboratory scale;
influence of the catalyst (DMGM)
2.2 Chemicals
solvent (Table 1; 60ml). If water was used as a solvent,
the pH was adjusted with sodium hydroxide to 8.5±9.
tert-BuOCl (2.5g, 0.023mol) was added dropwise for
15±20min at 10±25°C. The organic solvent was
evaporated to dryness in vacuo. If water was used as
a solvent, the product was extracted into the organic
layer using methylene chloride (50ml). MCPA
(m.p 118±119°C) was obtained in the yields given in
Table 1.
MPA was purchased from Aldrich. tert-BuOCl was
obtained by chlorination of tert-butyl alcohol.11
Methyl N,N-dimethylglycinate (DMGM) was ob-
tained by reaction of dimethylamine with methyl
chloroacetate.12 For microscale chlorination in an
EPR tube, a DMGM stock solution (0.08547mmol
ml 1) was prepared as follows: 0.1000g DMGM was
weighed into a 10ml capacity volumetric ¯ask, and
toluene was added to 10ml. The following spin traps:
2-methyl-2-nitrosopropane,
a-nitroso-b-naphthol,
2.3.2 Small scale (Table 2)
benzylidene-tert-butylnitrone, (4-nitrobenzylidene)-
tert-butylnitrone, 3,3,5,5-tetramethyl-1-pyrroline N-
oxide were purchased from Aldrich and applied
without further puri®cation. Nitrosodurene was
synthesized using known methods.13,14 2-Methyl-2-
nitrosopropane and benzylidene-tert-butylnitrone
were also obtained in several steps (yields in parenth-
eses): benzylidene-tert-butylnitrone from tert-butyl-
To a suspension of MPA (0.13g, 0.78mmol) in
toluene or chloroform (1ml) in a 5mm ID tube was
added DMGM stock solution (Table 2) and tert-
BuOCl (0.1ml), followed by solvent to a total volume
of 1.8ml. The course of the reaction was monitored
visually. The poorly soluble MPA disappeared after
the times given in Table 2.
hydroxylamine
and
benzaldehyde
(63%),15
2.3.3 EPR measurement conditions (Table 3, Fig 3)
Toluene (1ml) was placed in the EPR tube. Nitro-
sodurene (0.127g, 0.78mmol), tert-BuOCl (0.096g,
0.885mmol, 0.1ml) and MPA (0.13g, 0.78mmol)
were added and the reaction mixture was diluted ten-
fold. DMGM stock solution (0.5ml, 0.0427mmol,
5.5mol%) was then added, the tube placed in the
spectrometer and the spectrum recorded.
tert-butylhydroxylamine from 2-methyl-2-nitropro-
pane (82%);16 2-methyl-2-nitrosopropane and 2-
methyl-2-nitropropane from tert-butylamine (15%
and 39% respectively),17 tert-butylamine from tert-
butylurea (83%);18 tert-butylurea from urea and
tert-butyl alcohol (30%).19
2.3 Preparation of MCPA by chlorination of MPA
with tert-BuOCI in the presence of DMGM
2.3.1 Preparative scale (Table 1)
3
RESULTS AND DISCUSSION
MPA (3.3g, 0.02mol) and DMGM (0.02g,
0.17mmol, 0.85mol%) were added to an appropriate
3.1 MPA chlorination on a preparative scale
MPA was chlorinated with tert-BuOCl in the presence
Time of disappearance of MPA
precipitate
DMGM stock solution a (ml) Mol DMGM/mol MPA (%) In chloroform (min) In toluene (h)
0.02
0.1
0.2
0.4
a
0.22
1.1
90
20±40
20
24
10
2.2
Table 2. MPA chlorination in EPR tube:
rate of the reaction measured as the time of
disappearance of MPA precipitate
4.4
5±6
Concentration of DMGM in the solution ± see Section 2.2.
Table 3. MPA chlorination; influence of DMGM addition on increasing tert-butoxyl radical emission measured as a tert-BDNO concentration
Plot in Fig 3
Reaction mixture
Relative increase of nitroxyl radical (EPR spectrum intensity)
a
b
c
Toluene/nitrosodurene/tert-BuOCl
1 [def.]
1.3
Toluene/nitrosodurene/tert-BuOCl ‡ MPA
Toluene/nitrosodurene/tert-BuOCl/MPA ‡ DMGM
2.9
1230
Pestic Sci 55:1229±1232 (1999)

Increased tert-butoxyl radical emission in MCPA synthesis
conditions of the EPR tube reaction of MPA chlorina-
tion were optimized. The following factors were
investigated:
. the choice of a spin trap and a solvent,
. the evaluation of the level of tert-butoxyl radical
emission,
. the conditions of the experiment (the concentration
of reagents in the EPR tube and the sequence of
their addition).
3.2.2.2 The choice of spin trap and solvent
The following spin traps were examined: nitroso
compounds: nitrosodurene, 2-methyl-2-nitrosopro-
pane, a-nitroso-b-naphthol; nitrones: benzylidene-
tert-butylnitrone,
(4-nitrobenzylidene)-tert-butyl-
Figure 3. EPR spectra of tert-BDNO: (a) starting level – mixture of toluene,
nitrosodurene, tert-BuOCl; (b) as (a) ‡ MPA; (c) as (a) ‡ MPA ‡ DMGM.
nitrone, 3,3,5,5-tetramethyl-1-pyrroline N-oxide.
The most stable spin adduct tert-BDNO was detected
in the case of nitrosodurene as a spin trap (Fig 4).
With chloroform as solvent, the EPR spectrum of
the radical was observed immediately after placing the
EPR tube in the spectrometer, but the concentration
of the spin adduct tert-BDNO decreased rapidly. In
toluene the adduct was more stable. This observation
is in accordance with results presented in Table 2, and
thus toluene was chosen for the further investigations.
The hyper®ne splitting aN of tert-BDNO in toluene
is 27.6G (25.00±25.80G)21±25. The observed higher
value of aN in the reaction mixture indicates an inter-
action of the spin adduct tert-BDNO with MPA and/or
its chlorination product. At lower concentrations of
MPA, the value will be about 26G. The in¯uence of
the polarity of the various components present in a
mixture containing radicals on the aN value has been
reported.26,27 The typical value of the hyper®ne
splitting constant aN for aryl alkoxy nitroxides is in
the range 13±15G [Reference 9, pp 67±68]. The value
of almost twice this ®gure observed for tert-BDNO is
explained by Sueishi et al 21 as being due to the steric
hindrance of the 2,6-dimethyl groups in the nitro-
of methyl N,N-dimethylglycinate (DMGM) as a
catalyst.20 The crucial importance of the catalyst on
the yield and especially the selectivity of the process is
shown in Table 1.
3.2 MPA chlorination in EPR conditions
3.2.1 Conversion to small-scale conditions
In order to transfer the reaction to EPR measurement
conditions, it was performed on a small scale. The
rates of reaction in EPR tubes were measured in
chloroform and in toluene by the disappearance of the
MPA precipitate. The results are presented in Table 2.
3.2.2 EPR measurements
3.2.2.1 General
The reaction was performed in an organic solvent
(toluene) using an equimolar amount of a spin trap
(nitrosodurene) with the EPR tube placed in the
measuring cavity of the EPR spectrometer at ambient
temperature. The EPR spectrum was recorded during
the reaction for the investigated steady-state system.
Two general observations were made:
sodurene fragment, the perpendicular position of this
fragment towards the N-O group and there being no
.
interaction between unpaired electron and the
benzene nucleus.
(i) no adduct of the chlorine radical was detected with
any spin trap;
3.2.2.3 Evaluation of the level of tert-butoxyl radical
emission
When the nitosodurene and tert-BuOCl were dissolved
in toluene in the EPR tube, a constant level of the
spectrum of tert-BDNO (Fig 3) was observed; this was
(ii) an EPR spectrum of a nitroxyl radical generated
from the tert-butoxyl radical was detected in the
majority of experiments.
In order to record the best EPR spectrum, the
Figure 4. tert-Butoxy-2,3,5,6-tetramethylphenyl
nitroxide (tert-BDNO) – a spin adduct of
nitrosodurene and tert-butoxyl radical.
Pestic Sci 55:1229±1232 (1999)
1231

A Jezierski, J Zakrzewski, W MoszczynÂski
Ï
Ï
5 Rapos P, Kovac J and Batora V, 2-Methyl-4-chlorophenoxy)
acetic acid, Czech Patent 91160 (1959); Chem Abstr 55:7358 d
(1961).
caused by the homolytic cleavage of tert-BuOCl,
probably due to the in¯uence of light and temperature.
6 Oxboel A, Holm-Jensen B (KVK Agro A/S), A method for
preparing (4-chloro-2-methylphenoxy)alkanoic acids. PCT
Int. Appl. WO 92/01663 (1992), Chem Abstr 116:235250 j
(1992).
3.2.2.4 Conditions of the experiment
The best quality EPR spectra were obtained when the
starting reagents were diluted and mixed in the
sequence: toluene, nitrosodurene, tert-BuOCl, MPA,
DMGM.
7 Dermer OC and Edmison MT, Radical substitution in aromatic
nuclei. Chem Rev 57:77±122 (1957).
8 Janzen EG, Spin trapping. Accounts Chem. Res 4:31±40 (1971).
9 Aurich HG and Weiss W, Formation and reactions of aminyl-
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11 Vogel AI, tert-Butyl hypochlorite, in Textbook of Practical Organic
Chemistry, WNT, Warsaw. p 343 (1984).
3.2.2.5 Increasing tert-butoxyl radical level
The above results served as a basis for the ®nal
evaluation of the level of free radicals in full reaction
conditions. As mentioned, the mixture of tolue-
ne ‡ nitrosodurene ‡ tert-BuOCl yields a low but
constant level of tert-BDNO. Addition of MPA
resulted in an increase of the radical level of about
30%. Introduction of DMGM resulted in a 2.9 times
(standard deviation: 0.3) increase of the radical level in
relation to the starting level. This is shown in Table 3
and on Fig 3.
12 Willstaetter R, Ueber betaine. Berichte 35:584±620 (1902).
13 Smith LI and Taylor FL, Studies on the polymethylbenzenes.
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18 Pearson DE, Baxter JF and Carter KN, Hydrolysis of tert-
butylurea. Org Synth, Coll. Vol III, 154±156.
4
CONCLUSION
The observed increase of tert-butoxyl radical concen-
tration after addition of the catalyst, DMGM, shows
the in¯uence of the catalyst on the intensity of
homolytic cleavage of tert-BuOCl and supports the
likely free radical mechanism for the reaction investi-
gated. This may be considered as a reason for the
observed high regioselectivity.
19 Smith LI and Emerson OH, tert-Butylurea. Org Synth Coll. Vol
III, 151±152
Â
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alkanecarboxylic acids. Polish Patent Application ZP-321 980
(1997).
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N, Spin trapping as applied to radicals produced by the
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ACKNOWLEDGEMENTS
This work was supported by the Polish State Com-
mittee for Scienti®c Research (7108 92C/0589). A
computer program `Simfonia' was kindly provided by
Bruker.
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