# Highly Selective Synthesis of Chlorophenols under Microwave Irradiation

Authors: Yawen Xiong; Hongdong Duan; Xia Meng; Zhaoyun Ding; Weichun Feng
Journal: Journal of Chemistry
 (2016)

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## Abstract

Oxychlorination of various phenols is finished in 60 minutes with high efficiency and perfect selectivity under microwave irradiation. These reactions adopt copper(II) chloride (CuCl2) as the catalyst and hydrochloric acid as chlorine source instead of expensive and toxic ones. Oxychlorination of phenols substituted with electron donating groups (methyl, methoxyl, isopropyl, etc.) atortho- andmeta-positions is accomplished with higher conversion rates, lower reaction time, and excellent selectivity. A proposed reaction mechanism is deduced; one electron transfers from CuCl2 to phenol followed by the formation of tautomeric radical that can be rapidly captured by chlorine atom and converts intopara-substituted product.


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## Body

## 1. Introduction

Chlorophenols are essential chemical intermediates in industry for the preparation of drugs, dyes, insecticides, herbicides, functional polymers, and so forth [1–3]. They are traditionally synthesized through electrophilic aromatic halogenations reactions [4], which are usually accompanied with the formation of byproducts including acetone and methylstyrene as well as high energy consumption [2]. Thus, it is necessary to develop green and effective method to produce these important materials.As an alternative method, direct oxidative chlorination catalyzed by CuCl2 has been applied industrially to the conversion of ethylene into 1,2-dichloroethane [5], but there is very little literature reporting the oxychlorination of aromatics [6–8]. These reactions are usually carried out with poor selectivity and produce complex mixtures including mono- and poly-chloride substituted aromatic compounds [7, 8], which need further purification to get the desired products. Moreover, utilization of high value peroxo compounds such as m-chloroperbenzoic acid and potassium peroxomonosulfate is also an annoying problem [7, 8]. After the cheapest dioxygen was found as the oxidant, researches on oxychlorination of aromatics become interesting and attractive. Menini and Gusevskaya reported the synthesis of chlorophenols catalyzed by CuCl2; dioxygen was used as oxidant and lithium chloride was the chlorinating agent [9, 10], by which the oxychlorination reaction could be conducted under mild conditions, but some of the compounds were obtained with low selectivity and long reaction time [9, 10].Microwave-promoted organic synthesis has been rapidly developed as it can dramatically shorten the reaction time and save the energy in a variety of synthetic transformations [11]. This paper describes an economically and easy to handle way to synthesize chlorophenols catalyzed by CuCl2 under microwave irradiation. In this reaction, dioxygen is used as oxidant and hydrochloric acid as the chlorinating agent instead of expensive and toxic ones (Scheme 1).Scheme 1
Microwave-promoted oxychlorination of phenols.


## 2. Experimental

Chemical reagents were obtained from commercial sources and used without further purification.1H NMR spectra were recorded with a 400 MHz Bruker AV III spectrometer. HRMS spectra (negative) were finished on a Thermo Electron LTQ-Orbitrap XL spectrometer. All the reactions were performed on a MCR-3 microreactor (Beijing Xianghu Science and Technology Development Co., Ltd., Beijing, China) and measured by a gas chromatography (GC) using a Shimadzu GC-2014C instrument.


### 2.1. General Methods

Phenols (78 mmol) and a catalytic amount of CuCl2 (7.8 mmol) were dissolved in 100 mL of aqueous hydrochloric acid solution (6 mol/L), and the mixture was bubbled with dioxygen (22 mL/min). The reaction was performed on a microreactor at 50°C and measured by gas chromatography (GC). After GC showed the disappearance of the starting material, the reaction was extracted with dichloromethane (100 mL × 2), and the organic layer was washed with water (50 mL × 2) and fractionated to give the desired product.1H NMR and HRMS spectra can be seen in the Supplementary Materials available online at http://dx.doi.org/10.1155/2016/2960414.Compound1b: 1H NMR (400 MHz, CDCl3) δ 7.24–7.17 (m, 2H, Ph), 6.77–6.74 (m, 2H, Ph), 5.27 (s, 1H, OH); HRMS (ESI-TOF)m/z: calcd for C6H4ClO  M-H- 127.0029, found 126.9956.Compound2b: 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H, OH), 6.95 (d, J=2.0 Hz, 1H, Ph), 6.79–6.75 (m, 2H, Ph), 3.78 (s, 3H, OCH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO2  M-H- 157.0135, found 157.0056.Compound3b: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H, OH), 6.94–6.90 (m, 2H, Ph), 6.76 (dd, J=3.2, 8.8 Hz, 1H, Ph), 3.69 (s, 3H, OCH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO2  M-H- 157.0135, found 157.0059.Compound4b: 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, OH), 7.16 (d, J=8.8 Hz, 1H, Ph), 6.74 (d, J=2.4 Hz, 1H, Ph), 6.62 (dd, J=2.8, 8.8 Hz, 1H, Ph), 2.24 (s, 3H, CH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO  M-H- 141.0185, found 141.0116.Compound5b: 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.23 (s, 1H), 7.60 (d, J=2.8 Hz, 1H, Ph), 7.54 (dd, J=2.8, 8.8 Hz, 1H, Ph), 7.05 (d, J=8.8 Hz, 1H, Ph); HRMS (ESI-TOF)m/z: calcd for C7H4ClO2  M-H- 154.9978, found 154.9898.Compound6b: 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H, OH), 7.04 (s, 1H, Ph), 6.72 (s, 1H, Ph), 3.15–3.12 (m, 1H, CH(CH3)2), 2.19 (s, 3H, CH3), 1.12 (d, J=6.8 Hz, 6H, CH(CH3)2); HRMS (ESI-TOF)m/z: calcd for C10H13ClO  M-H- 183.0655, found 183.0579.Compound7b: 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, OH), 7.10 (d, J=2.4 Hz, 1H, Ph), 7.01 (dd, J=2.8, 8.4 Hz, 1H, Ph), 6.78 (d, J=8.8 Hz, 1H, Ph), 2.11 (s, 3H, CH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO  M-H- 141.0185, found 141.0107.


## 2.1. General Methods

Phenols (78 mmol) and a catalytic amount of CuCl2 (7.8 mmol) were dissolved in 100 mL of aqueous hydrochloric acid solution (6 mol/L), and the mixture was bubbled with dioxygen (22 mL/min). The reaction was performed on a microreactor at 50°C and measured by gas chromatography (GC). After GC showed the disappearance of the starting material, the reaction was extracted with dichloromethane (100 mL × 2), and the organic layer was washed with water (50 mL × 2) and fractionated to give the desired product.1H NMR and HRMS spectra can be seen in the Supplementary Materials available online at http://dx.doi.org/10.1155/2016/2960414.Compound1b: 1H NMR (400 MHz, CDCl3) δ 7.24–7.17 (m, 2H, Ph), 6.77–6.74 (m, 2H, Ph), 5.27 (s, 1H, OH); HRMS (ESI-TOF)m/z: calcd for C6H4ClO  M-H- 127.0029, found 126.9956.Compound2b: 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H, OH), 6.95 (d, J=2.0 Hz, 1H, Ph), 6.79–6.75 (m, 2H, Ph), 3.78 (s, 3H, OCH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO2  M-H- 157.0135, found 157.0056.Compound3b: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H, OH), 6.94–6.90 (m, 2H, Ph), 6.76 (dd, J=3.2, 8.8 Hz, 1H, Ph), 3.69 (s, 3H, OCH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO2  M-H- 157.0135, found 157.0059.Compound4b: 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, OH), 7.16 (d, J=8.8 Hz, 1H, Ph), 6.74 (d, J=2.4 Hz, 1H, Ph), 6.62 (dd, J=2.8, 8.8 Hz, 1H, Ph), 2.24 (s, 3H, CH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO  M-H- 141.0185, found 141.0116.Compound5b: 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.23 (s, 1H), 7.60 (d, J=2.8 Hz, 1H, Ph), 7.54 (dd, J=2.8, 8.8 Hz, 1H, Ph), 7.05 (d, J=8.8 Hz, 1H, Ph); HRMS (ESI-TOF)m/z: calcd for C7H4ClO2  M-H- 154.9978, found 154.9898.Compound6b: 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H, OH), 7.04 (s, 1H, Ph), 6.72 (s, 1H, Ph), 3.15–3.12 (m, 1H, CH(CH3)2), 2.19 (s, 3H, CH3), 1.12 (d, J=6.8 Hz, 6H, CH(CH3)2); HRMS (ESI-TOF)m/z: calcd for C10H13ClO  M-H- 183.0655, found 183.0579.Compound7b: 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, OH), 7.10 (d, J=2.4 Hz, 1H, Ph), 7.01 (dd, J=2.8, 8.4 Hz, 1H, Ph), 6.78 (d, J=8.8 Hz, 1H, Ph), 2.11 (s, 3H, CH3); HRMS (ESI-TOF)m/z: calcd for C7H6ClO  M-H- 141.0185, found 141.0107.


## 3. Results and Discussion

### 3.1. Oxychlorination of Phenols

Oxychlorination of various phenols was performed to investigate the reactivities (Table1). Under microwave irradiation, 4-chlorophenol was prepared with high efficiency (93.4%) and perfect selectivity (96.6%), and the reaction was finished only in 60 minutes at 50°C (Entry 1) with minor amounts ofortho-substituted products being detected. Oxychlorination of phenols substituted by electron donating groups (methyl, methoxyl, isopropyl, etc.) atortho- andmeta-positions was accomplished with higher conversion rates, lower reaction time, and excellent selectivity. In particular, compound6a, simultaneously substituted by methyl and isopropyl groups atortho- andmeta-positions, completed the conversion with 100% efficiency and 99.8% selectivity (Entry 6). Furthermore, oxychlorination ofortho-substituted phenol with aldehyde group was still finished with high efficiency and excellent selectivity (Entry 5) but in 50 minutes. Substituting phenol with methoxyl group (3a) atpara-position, the oxychlorination reaction occurred atortho-position with lower conversion rate and poor selectivity due to the dual-orienting effect (Entry 3).Table 1
Oxychlorination of phenols under microwave irradiation.
Entry
Substrate (0.78 M)
Product
Time (min)
Conversion (%)
Selectivity (%)
1
60
93.4
96.6
2
20
97.2
98.8
3
20
90.1
79.3
4
20
93.5
99.4
5
50
94.7
93.5
6
10
100
99.8
7
20
96.5
91.7
Conditions: microwave irradiation; solvent, aqueous hydrochloric acid solution (6 mol/L); reaction temperature (50°C). Conversion and selectivity were determined by GC.


### 3.2. Proposed Reaction Mechanism

Different conditions were researched to investigate the proposed reaction mechanism in oxychlorination of phenol. As it is shown in Table2, without addition of hydrochloric acid, there was no chlorination product detected in this reaction, and the chlorination efficiency was only 10.3% when hydrochloric acid was replaced with sulfuric acid, which indicated that hydrochloric acid was performed as chlorine source. As the catalyst, CuCl2 played an essential role in chlorination reaction. In the absence of CuCl2, no product was formed and no other reactions were occurred, and replacement of CuCl2 by lithium chloride still could not promote the reaction. Furthermore, the conversion rate was relatively low when the procedure was not bubbled with dioxygen, which proved its participation in oxidation.Table 2
Oxychlorination of phenol.
Entry
Acid
Catalyst
Dioxygen flow rate (mL/min)
Conversion (%)
Selectivity (%)
1
—
CuCl2 (0.1 eq.)
O2 (22 mL/min)
—
—
2
—
CuCl2 (2 eq.)
O2 (22 mL/min)
—
—
3
HCl (6 mol/L)
CuCl2 (0.1 eq.)
—
30.2
96.3
4
HCl (6 mol/L)
—
O2 (22 mL/min)
—
—
5
HCl (6 mol/L)
CuCl2 (0.1 eq.)
O2 (22 mL/min)
93.4
96.6
6
HCl (6 mol/L)
CuCl2 (2 eq.)
O2 (22 mL/min)
94.1
96.9
7
HCl (2 mol/L)
CuCl2 (0.1 eq.)
O2 (22 mL/min)
77.7
95.7
8
HCl (6 mol/L)
LiCl (2 eq.)
O2 (22 mL/min)
3.1
93.1
9
H2SO4 (6 mol/L)
CuCl2 (2 eq.)
O2 (22 mL/min)
10.3
96.0
Conditions: microwave irradiation; solvent, H2O for 1-2, aqueous hydrochloric acid solution for 3–8, aqueous sulfuric acid solution for 9; reaction time (60min); reaction temperature (50°C). Conversion and selectivity were determined by GC.A proposed reaction mechanism is depicted in Scheme2. As conventional mechanism of phenol chlorination [9], one electron transfers from Cu(II) to phenoxy radicalB via the complexA and simultaneously generates copper(I) chloride (CuCl). Then, radicalB converts to the tautomeric structureC, followed by chlorination with CuCl2 to form intermediate productD and CuCl. Tautomerization ofD affords the desired product 4-chlorophenol, and CuCl generated in this reaction converts to CuCl2 in the presence of hydrochloric acid and dioxygen. Our previous experiments revealed that insufficient concentration of [H+] caused the transformation of radicalC to benzoquinone. Furthermore, major byproduct monitored in this reaction was 2-chlorophenol which was generated from tautomerization of radicalC intoE, and further conversions as the similar procedure to form 4-chlorophenol gave theortho-substituted product. It seems that the key step of the reaction is the formation of radicalsC, and they are easily and rapidly captured by chlorine atoms compared with radicalsE. Due to the high efficiency and perfect selectivity of this reaction, we deduce that microwave irradiation promoted the generation of radicalsC, and their chlorination occurs faster than the traditional methods. And microwave irradiation seems to prevent the tautomerization of radicalsC intoE, which may be caused by the lower reaction temperature.Scheme 2
Proposed reaction mechanism of oxychlorination of phenol.


## 3.1. Oxychlorination of Phenols

Oxychlorination of various phenols was performed to investigate the reactivities (Table1). Under microwave irradiation, 4-chlorophenol was prepared with high efficiency (93.4%) and perfect selectivity (96.6%), and the reaction was finished only in 60 minutes at 50°C (Entry 1) with minor amounts ofortho-substituted products being detected. Oxychlorination of phenols substituted by electron donating groups (methyl, methoxyl, isopropyl, etc.) atortho- andmeta-positions was accomplished with higher conversion rates, lower reaction time, and excellent selectivity. In particular, compound6a, simultaneously substituted by methyl and isopropyl groups atortho- andmeta-positions, completed the conversion with 100% efficiency and 99.8% selectivity (Entry 6). Furthermore, oxychlorination ofortho-substituted phenol with aldehyde group was still finished with high efficiency and excellent selectivity (Entry 5) but in 50 minutes. Substituting phenol with methoxyl group (3a) atpara-position, the oxychlorination reaction occurred atortho-position with lower conversion rate and poor selectivity due to the dual-orienting effect (Entry 3).Table 1
Oxychlorination of phenols under microwave irradiation.
Entry
Substrate (0.78 M)
Product
Time (min)
Conversion (%)
Selectivity (%)
1
60
93.4
96.6
2
20
97.2
98.8
3
20
90.1
79.3
4
20
93.5
99.4
5
50
94.7
93.5
6
10
100
99.8
7
20
96.5
91.7
Conditions: microwave irradiation; solvent, aqueous hydrochloric acid solution (6 mol/L); reaction temperature (50°C). Conversion and selectivity were determined by GC.


## 3.2. Proposed Reaction Mechanism

Different conditions were researched to investigate the proposed reaction mechanism in oxychlorination of phenol. As it is shown in Table2, without addition of hydrochloric acid, there was no chlorination product detected in this reaction, and the chlorination efficiency was only 10.3% when hydrochloric acid was replaced with sulfuric acid, which indicated that hydrochloric acid was performed as chlorine source. As the catalyst, CuCl2 played an essential role in chlorination reaction. In the absence of CuCl2, no product was formed and no other reactions were occurred, and replacement of CuCl2 by lithium chloride still could not promote the reaction. Furthermore, the conversion rate was relatively low when the procedure was not bubbled with dioxygen, which proved its participation in oxidation.Table 2
Oxychlorination of phenol.
Entry
Acid
Catalyst
Dioxygen flow rate (mL/min)
Conversion (%)
Selectivity (%)
1
—
CuCl2 (0.1 eq.)
O2 (22 mL/min)
—
—
2
—
CuCl2 (2 eq.)
O2 (22 mL/min)
—
—
3
HCl (6 mol/L)
CuCl2 (0.1 eq.)
—
30.2
96.3
4
HCl (6 mol/L)
—
O2 (22 mL/min)
—
—
5
HCl (6 mol/L)
CuCl2 (0.1 eq.)
O2 (22 mL/min)
93.4
96.6
6
HCl (6 mol/L)
CuCl2 (2 eq.)
O2 (22 mL/min)
94.1
96.9
7
HCl (2 mol/L)
CuCl2 (0.1 eq.)
O2 (22 mL/min)
77.7
95.7
8
HCl (6 mol/L)
LiCl (2 eq.)
O2 (22 mL/min)
3.1
93.1
9
H2SO4 (6 mol/L)
CuCl2 (2 eq.)
O2 (22 mL/min)
10.3
96.0
Conditions: microwave irradiation; solvent, H2O for 1-2, aqueous hydrochloric acid solution for 3–8, aqueous sulfuric acid solution for 9; reaction time (60min); reaction temperature (50°C). Conversion and selectivity were determined by GC.A proposed reaction mechanism is depicted in Scheme2. As conventional mechanism of phenol chlorination [9], one electron transfers from Cu(II) to phenoxy radicalB via the complexA and simultaneously generates copper(I) chloride (CuCl). Then, radicalB converts to the tautomeric structureC, followed by chlorination with CuCl2 to form intermediate productD and CuCl. Tautomerization ofD affords the desired product 4-chlorophenol, and CuCl generated in this reaction converts to CuCl2 in the presence of hydrochloric acid and dioxygen. Our previous experiments revealed that insufficient concentration of [H+] caused the transformation of radicalC to benzoquinone. Furthermore, major byproduct monitored in this reaction was 2-chlorophenol which was generated from tautomerization of radicalC intoE, and further conversions as the similar procedure to form 4-chlorophenol gave theortho-substituted product. It seems that the key step of the reaction is the formation of radicalsC, and they are easily and rapidly captured by chlorine atoms compared with radicalsE. Due to the high efficiency and perfect selectivity of this reaction, we deduce that microwave irradiation promoted the generation of radicalsC, and their chlorination occurs faster than the traditional methods. And microwave irradiation seems to prevent the tautomerization of radicalsC intoE, which may be caused by the lower reaction temperature.Scheme 2
Proposed reaction mechanism of oxychlorination of phenol.


## 4. Conclusions

This paper describes the preparation of various chlorophenols promoted by microwave irradiation. Copper(II) chloride is used as the catalyst and hydrochloric acid as chlorine source instead of expensive and toxic ones. Using phenols substituted with electron donating groups atortho- andmeta-positions as substrates generates chlorophenols with higher conversion rates, lower reaction time, and excellent selectivity, and no polychlorination products are detected. From a proposed reaction mechanism, we deduce that the reaction is inclined to form tautomeric radicalsC that can be rapidly captured by chlorine atoms and convert intopara-substituted products.



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*Source: 2960414-2016-04-26.xml*