Chloromethylation of Aromatic Compounds Catalyzedby Surfactant Micelles in Oil–Water Biphasic System

Qifa Liu Æ Wei Wei Æ Ming Lu Æ Feng Sun ÆJiang Li Æ Yuchao Zhang

Received: 8 December 2008 / Accepted: 27 February 2009 / Published online: 17 March 2009

� Springer Science+Business Media, LLC 2009

Abstract In this work, the chloromethylation reaction of

aromatic compounds was performed successfully by micel-

lar catalysis in oil/water biphasic system at high reactant

loadings that exceeded the solubilization capacity of micel-

lar solutions. The effects of cationic, nonionic and anionic

surfactants on the reaction were compared. The mechanism

of chloromethylation reaction and the mechanism of micel-

lar catalysis were investigated. The results show that the

micellar catalysis is an effective way to realize the chlo-

romethylation. The chloromethylation reaction consists of

electrophilic substitution reaction and nucleophilic substi-

tution reaction. Cationic surfactants, especially those

containing longer hydrophobic carbon chain, are more

effective. Selectivity for mono-chloromethylation was

remarkably improved and regioselectivity was found to be

dependent on the nature of the surfactant. Under the optimal

reaction conditions, chloromethylation of isopropylbenzene

could obtain 97.5% selectivity in mono-chloromethylation

and 8.28 para/ortho selectivity ratio at 89.8% conversion.

Keywords Chloromethylation � Aromatic compound �Micellar catalysis � Surfactant � Selectivity

1 Introduction

Chloromethyl-substituted aromatic compounds are very

important intermediates which have widespread application

in fine-chemicals, pharmaceuticals, polymers, etc. [1–5].

The most commonly employed procedures for chlorome-

thylating aromatic compounds have been the use of

chloromethyl methyl ether and/or bis-chloromethyl ether

(or reagent combinations which can result in the formation

of these ethers) and Lewis acid as the catalysts [6–8].

Selectivity and yield of the mono-chloromethyl derivatives

are determined by the consecutive formation of the poly-

chloromethylation byproducts and the formation of diaryl-

methane derivatives and other byproducts, because of the

Friedel–Crafts alkylation catalyzed by the same Lewis acid,

and are often not so high [9]. Moreover, the hazards asso-

ciated with these chloromethylethers are apparently so

severe that classical procedures for the direct or indirect

chloromethylation under Friedel–Crafts conditions are

essentially no longer used. Other procedures [10–14] which

do not utilize extremely hazardous materials have all been

developed with different degrees of success. The chlorom-

ethylation of aromatic compounds with hydrochloric acid,

paraformaldehyde as well as catalysts such as phase-trans-

fer catalysts [9, 15] and rare-earth metal triflates [16] in

aqueous system are very promising methods. The catalytic

effect of surfactant micelles on a great number of reactions

is well known [17–24]. The dramatic increase in reaction

rate results from localized concentration of both lipophilic

and hydrophilic reactants near them by micellar solubili-

zation and electrostatic interaction, and from the fact that

micelles can provide an environment more conducive to the

desired reaction, without the addition of an organic solvent

[25]. In our previous paper, we once applied micellar

catalysis in a single-phase system to realize the

Q. Liu � W. Wei � M. Lu (&) � J. Li

Chemical Engineering College, Nanjing University of Science

and Technology, Nanjing 210094, People’s Republic of China

e-mail: luming302@126.com

F. Sun � Y. Zhang

Nanjing Cosmos Chemical Co., Ltd, Nanjing 211162,

People’s Republic of China

123

Catal Lett (2009) 131:485–493

DOI 10.1007/s10562-009-9926-x

chloromethylation of 2-bromoethylbenzene successfully

[26]. While investigations of single-phase systems are

invaluable to understand how different factors affect these

reactions, industrial production commonly employs reac-

tant loading of 10–50%, which exceeds the maximum

solubilization capacity of micellar solutions [18]. Organic

reactions conducted in these aqueous micellar systems thus

must work with two-phase emulsions where a portion of

reactant substrates are solubilized in the micelles and the

remaining portion form emulsified droplets dispersed in the

bulk aqueous phase. Under the diffusion action, the reactant

substrates within the emulsified droplets can be transferred

unceasingly into the micelles; at the same time, the products

formed within micelles can also be transferred into the

emulsified droplets continuously. Therefore, the emulsified

droplets act as not only a source of reactant materials but

also an acceptor of reaction products [18, 27]. In this paper,

the chloromethylation of aromatic compounds would be

realized with high conversion and high selectivity for

mono-chloromethylation by application of micellar cataly-

sis in oil/water biphasic system where the formation of

carcinogenic chloromethylether and/or bis-chloromethyl

ether can be avoided because of large quantities of water in

this system [28]. For the initial experiments, we selected

isopropylbenzene (IPB) as a model substrate (Scheme 1),

and then the optimal conditions were applied to a range of

aromatic compounds.

2 Experimental

2.1 Materials

Cetyltrimethylammonium bromide (CTAB), dodecyltri-

methylammonium bromide (DTAB), sodium dodecyl

sulfonates (SDS) and nonylphenol polyoxyethylene ether

(NP-10) purchased from Aldrich Chemical Co., Inc. were of

analytical grade and used without further purification. All

other reagents employed were commercial chemicals with

analytical pure grades or chemical grades and were used

without further treatment. Distilled water was used for all the

reactions.

2.2 Analysis

All the chloromethylated products were determined in

some cases by comparison of their GC (retention time)

with those of authentic samples and in others (for new

compounds) by GC (Trace Ultra)-MS (Trace DSQ), IR, 1H

NMR and elemental analysis. Conversions and selectivities

were based on GC analyses with area normalization.

2.3 Experimental Procedure

Typical procedures for the chloromethylation are shown by

using isopropylbenzene (IPB) as a model substrate. The

reaction was carried out in a 1,000 mL four-necked flask

immersed in an oil bath kept at a given temperature and

equipped with a dynamoelectric stirrer, a reflux condenser,

an anhydrous HCl gas inlet and a thermometer. The reactor

was charged with IPB (120.2 g, 1.0 mol) and concentrated

aqueous hydrochloric acid solution (300 mL) of surfactant

with the desired concentration. The mixture was stirred for

2 h in order to solubilize fully IPB in the surfactant micelle

solution (the remaining portion of IPB formed emulsified

droplets dispersed in the aqueous phase) and then para-

formaldehyde (36.0 g, 1.2 mol) was added as a solid after

the reaction temperature reached to 80 �C. At the same

time, anhydrous HCl gas was bubbled through the reaction

mixture with a rate of about 450 mL/min. After the reac-

tion run for a period of time at constant temperature, the

reaction was over. After cooling and demulsifying, the

organic products were separated and the aqueous solution

was extracted with chloroform (3 9 50 mL). The com-

bined organic extracts were neutralized with aqueous

saturated sodium bicarbonate solution, washed with water

until neutralization and dried over anhydrous sodium sul-

fate. The analyses by Agilent6890 gas chromatography

equipped with a HP-5MS capillary column (30 m 9

0.32 mm 9 0.25 mm ID) and a hydrogen flame detector

were carried out subsequent to filtering of the resulting

organic products. The GC conditions were as follows:

injection port temperature was set at 280 �C and detector

temperature at 300 �C. Inlet pressures of nitrogen gas and

hydrogen gas were 65 and 80 KPa, respectively, and the

amount of test specimen was 0.1 lL. The temperature

program started at 80 �C and maintained this temperature

for 2 min, then ramped to 165 �C at 7 �C/min, again up to

250 �C at 25 �C/min followed by 15 min at 250 �C.

Finally, the solvent was removed and the residue was

distilled under vacuum to give pure chloromethylisopro-

pylbenzene identified by 1H NM or its authentic sample.

In order to examine the effects of different factors such

as surfactant concentration, nature of surfactant and

structure of surfactant on the chloromethylation of IPB, the

experiments under varying conditions were carried out

according to the aforementioned procedure. In some cases,

in order to confirm the reaction mechanism, the bromom-

ethylation was also performed using the same reaction

conditions as the above chloromethylation except replacing

HCl with HBr.

(H3C)2CMicellar catalysis

CH2Cl

(H3C)2C(CH2O)n/Hydrochloric acid

Scheme 1

486 Q. Liu et al.

123

3 Results and Discussion

3.1 Chloromethylation

The chloromethylation of isopropylbenzene (IPB) was

carried out in oil–water biphasic system in the presence and

absence of CTAB. Figure 1 shows the experimental results.

As shown in Fig. 1, in the absence of surfactant (CTAB),

the chloromethylation reaction proceeded very slowly, and

only 40.1% conversion was obtained within 6 h. Reaction

performed with CTAB (its critical micelle concentration,

CMC, in pure water at 25 �C is 9.20 9 10-4 mol L-1

[29]) at a concentration of 1.29 9 10-2 mol L-1, i.e.,

14CMC, proceeded very rapidly and the conversion of IPB

reached 89.8% in a shorter time (4 h), which demonstrated

the high efficiency of micellar catalysis, as expected.

When no surfactant (CTAB) was used, under the stirring

conditions, the reaction system was a suspension with two

phases and the interface area between oil phase and aqueous

phase was very small; so the reaction rate of chloromethy-

lation occurred mainly at the interface was quite low and the

conversion of IPB was not so high. However, when CTAB

was used, there were numerous micelles in the reaction

system and IPB was solubilized into these micelles, resulting

in a larger oil–water interfacial area and a higher reaction

rate compared to the system without CTAB. Because the

used amount of IPB in our research system was very high,

except one portion was solubilized into the micelles, the

other portion formed O/W emulsion. Under the diffusion

action, the reactant materials (IPB) within the emulsified

droplets could be transferred unceasingly into the micelles;

simultaneously, the chloromethylated products formed

within micelles could also be transferred into the emulsified

droplets continuously. Therefore, the emulsified droplets

acted both as a continuous source of reactant materials and a

sink into which the resulting products entered, so that the

chloromethylation reaction of IPB could keep continuous

progress and higher conversions thus could be attained. This

process was probably analogous to the emulsion polymeri-

zation one [18, 27].

3.2 Effect of Concentration of Surfactant

The influence of CTAB concentration on the conversion of

IPB is shown in Fig. 2. When CTAB concentration was

below CMC, conversion of IPB was quite low, and did not

change with surfactant concentration nearly. However, the

conversion of IPB increased with an increase in CTAB

concentration after CMC sharply, and did not obviously

change after CTAB concentration reaching to 14CMC.

These results fully reveal that the rapid increase of the rate

of chloromethylation is correlated with the formation of

CTAB micelles and the increase of its micelle concentra-

tions. When the concentration of CTAB was smaller than

CMC, CTAB was dissolved by the molecular state in the

water phase, and the micellar concentration together with

the resulting IPB solubilizing capacity seemed too low to

induce a significant micellar catalysis process. Once the

concentration of CTAB was higher than CMC, micelles was

formed in the aqueous phase, IPB was solubilized into these

micelles. Thus, the concentration of IPB in the aqueous

phase increased and, in addition, the interface area between

the oil phase and the aqueous phase was magnified sud-

denly, the rate of the chloromethylation reaction occurred

on the surfaces of micelles or at the interface of oil phase/

0 1 2 3 4 5 60

20

40

60

80

100

Con

vers

ion

of IP

B (

%)

Time (h)

CTAB No catalyst

Fig. 1 Relationship between conversion and reaction time in the

presence and absence of CTAB. Reaction conditions: IPB, 120.2 g

(1.0 mol); paraformaldehyde, 36.0 g (1.2 mol); conc. HCl, 300 mL;

anhydrous HCl gas, 450 mL/min; reaction temperature: 80 �C;

concentration of CTAB: 1.29 9 10-2 mol L-1 (ca. 14-fold CMC)

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5

30

40

50

60

70

80

90

100

Con

vers

ion

of IB

P (

%)

log [c/(mol/L)]

CTAB

CMC 14CMC

Fig. 2 Relationship between conversion and concentrations of

CTAB. Reaction conditions: IPB, 120.2 g (1.0 mol); paraformalde-

hyde, 36.0 g (1.2 mol); conc. HCl, 300 mL; anhydrous HCl gas,

450 mL/min; reaction temperature: 80 �C; reaction time: 4 h

Chloromethylation of Aromatic Compounds 487

123

water phase was accelerated abruptly, so the conversion of

IPB showed a break point at CMC. After CMC, the number

of micelles increased with increasing CTAB concentration

resulting in the continuous increases of the solubilization

capacity of IPB and the interfacial area, so the rate of the

reaction speeded up and the conversion was enhanced. The

further increase of CTAB concentration could induce

micelles to expand, which could cause slow increase of oil/

water interfacial area. Therefore, at high CTAB concen-

tration, the rate increase became gradually slow and the

conversion of IPB did not change significantly. As seen

from Fig. 2, the optimum CTAB concentration in present

system is 14CMC, namely, 1.29 9 10-2 mol L-1.

3.3 Effect of the Nature of Surfactant

Three types of cationic (CTAB), nonionic (NP-10) and

anionic (SDS) surfactants were used alone to catalyze the

chloromethylation of IPB in oil/water two-phase system.

Figure 3 shows the conversion varied with the change of

the reaction time at the same temperature (80 �C) and with

a concentration condition of 14CMC. It was observed in

Fig. 3 that the conversion of IPB was dependent on the

cationic, nonionic and anionic surfactant micelles. The

conversion was highest for the cationic surfactant (CTAB)

system, lower for the nonionic surfactant (NP-10) and

much lower for the anionic surfactant (SDS). The different

catalytic abilities of these surfactants were presumably

caused by two reasons: (1) the different micellization

behavior (critical micelle concentration CMC and micellar

aggregation number Nagg and so on) and (2) the mechanism

of chloromethylation. On the one hand, CTAB, NP-10 and

SDS belong to different types of surfactants and have

different CMC. The lower CMC leads to more micelles to

form at the same concentration causing more IPB to be

solubilized into micelles and greater collision probability

[29] between IPB and hydrophilic reactive species. On the

other hand, the different catalytic abilities of surfactants

suggest the chloromethylation reaction among IPB,

hydrochloric acid, formaldehyde and surfactant has a

unique mechanism, and it possibly consists of two steps:

electrophilic substitution reaction and nucleophilic substi-

tution reaction, which can be expressed as follows:

Scheme 2 shows a plausible mechanism for the chlo-

romethylation of IPB. Firstly, depolymerization of

paraformaldehyde by acid catalysis of hydrochloric acid

yields formaldehyde which reacts with proton (H?) to yield

hydroxymethyl cation (?CH2OH) and the electrophilic

substitution reaction mainly occurs within the micelle sur-

face by subsequent attack of the ?CH2OH on benzene ring

of IPB solubilized in the surfactant micelles to give iso-

propylbenzyl alcohol; then the resulting alcohol under the

action of acid gives a benzyl carbonium ion and water very

rapidly; finally, the benzyl carbonium ion reacts with anions

Cl- to yield the desired products. The surfactant micelles

play a very important role in the chloromethylation process

to locally concentrate the reacting species near them by

micellar solubilization and electrostatic interaction [30].

This leads to a large increase in the effective reactant

concentration and oil–water interfacial area and the

observed rate of chloromethylation increases accordingly.

As far as the mechanism of chloromethylation by

treatment with formaldehyde and HCl, ?CH2OH and chlo-

romethyl cation (?CH2Cl) are the species frequently

suggested [31]. It is highly impossible that the ?CH2Cl

exists in any chloromethylation systems [32], particularly in

aqueous solutions under mild conditions. The present

proposed chloromethylation mechanism consists of elec-

trophilic substitution reaction and nucleophilic substitution

reaction and the attacking species of electrophilic substitu-

tion reaction is the ?CH2OH. This conclusion was

confirmed, particularly on the basis of the finding that the

chloromethylation and bromomethylation of toluene, eth-

ylbenzene and IPB gave an identical ratio of para/ortho-

isomer (Table 1). The analogous results were obtained by I.

N. Nazarov and A. V. Semenovsky [33]. These results

showed that in the chloromethylation and bromomethylation

the same attacking species was active, consisting of the

protonated form of formaldehyde, namely, ?CH2OH. Pro-

vided the reaction involved the halogenomethyl cation, then

bromomethylation should have afforded a greater amount of

the para-isomer than chloromethylation, since the bulk of

the bromomethyl group is significantly greater than that of

chloromethyl group [6]. Furthermore, it has shown

that, under the present chloromethylation conditions, the

0 1 2 3 40

20

40

60

80

100

Con

vers

ion

of IP

B (

%)

Time (h)

SDSCTAB NP-10

Fig. 3 Relationship between conversion and reaction time for three

types of surfactants. Reaction conditions: IPB, 120.2 g (1.0 mol);

paraformaldehyde, 36.0 g (1.2 mol); conc. HCl, 300 mL; anhydrous

HCl gas, 450 mL/min; reaction temperature: 80 �C; concentrations of

surfactants: 14CMC

488 Q. Liu et al.

123

hydroxy-group in the benzyl alcohol was fully substituted by

chlorine [6].

In Fig. 3, it can be found that the conversion of IPB

catalyzed by CTAB micelles was much higher than that

catalyzed by SDS micelles, on the reasonable assumption

that a common mechanism is at work in the chlorome-

thylation of 2-bromoethylbenzene and IPB in micellar

catalysis systems, the rationale for this behavior should the

same, already discussed in the former case [26].

Two kinds of cationic surfactants, CTAB and DTAB,

were used to research the effects of different cationic sur-

factants with different structures on micellar catalysis. The

experimental results are shown in Fig. 4. CTAB and DTAB

both exhibit higher catalytic activity for the chloromethy-

lation reaction of IPB because of their strong solubilization

power and electrostatic interaction with anions Cl-.

However, the micellar catalysis effect of CTAB was much

stronger than that of DTAB. The main reason causing the

difference should be attributed to their different molecular

structures. CTAB and DTAB belong to identical series of

cationic surfactants, and the hydrophobic chain of CTAB

contains a total number of 16 carbon atoms while DTAB

has a hydrophobic chain of 12 carbon atoms. The longer

the hydrophobic carbon chain is, the lower the CMC is and

the greater the aggregate number (Nagg) is. So CTAB has a

lower CMC (9.2 9 10-4 mol L-1) and a greater Nagg

(61) than DTAB (CMC: 1.5 9 10-2 mol L-1 and Nagg: 50

[29]). Thereby, at the same concentration there was more

IPB solubilized in CTAB micellar system which resulted in

a higher rate of chloromethylation reaction and a greater

conversion in a given reaction time. Therefore, cationic

surfactant with longer hydrophobic carbon chain is more

suitable for the chloromethylation of IPB in the micellar

catalysis system.

Electrophilic substitution reaction:

CH2 O + H+ CH2 OH

+ ( )1

CH(CH3)2

+ CH2 OH+ + H

+( )2

CH(CH3)2

CH2OH

Nucleophilic substitution reaction:

CH(CH3)2

CH2OH

+ H+

+ H2O ( )3

CH(CH3)2

CH2+

CH(CH3)2

CH2OH2+

CH(CH3)2

CH2

+ Cl- ( )4

CH(CH3)2

CH2Cl+

Scheme 2 Plausible

mechanism of

chloromethylation of IPB

Chloromethylation of Aromatic Compounds 489

123

3.4 Selectivity

Micelles have been regarded as microreactors that provide

hydrophobic reaction sites for the acceleration of organic

reactions. In some cases the selectivity of the correspond-

ing reaction was altered due to the preorganizational

function of micelles [30, 34]. In our micellar catalytic

system, surfactant micelles can provide a high interfacial

area between oil phase and aqueous phase and also afford

oriented effect, which might improve selectivity and regi-

oselectivity for mono-chloromethylation. Table 2 shows

the experimental results. When surfactants were not used,

the selectivity was very low and decreased from 76.3 to

64.7%; however, the selectivity was distinctly improved in

the presence of surfactants. The highest selectivity for

mono-chloromethylation at 43.2% conversion after 1 h was

98.9% when the CTAB concentration was 1.29 9

10-2 mol L-1 which decreased to 97.5% at 89.8% con-

version after 4 h. This decrease in the selectivity with an

increase in conversion is likely to be due to subsequent

chloromethylation of mono-chloromethyl products to

polychloromethylation byproducts. Chloromethylation in

solution of other surfactants such as NP-10 and SDS gave

similar decrease in selectivity with an increase in conver-

sion as shown in Table 2.

The regioselectivity was found to be dependent on the

nature of the surfactant employed. CTAB and NP-10 were

seen to increase the para/ortho (p/o) selectivity ratio

compared with the system containing no surfactant. In the

case of anionic surfactant, SDS was seen to decrease the

p/o selectivity ratio (Table 2). When IPB was solubilized in

micelles, its isopropyl group would penetrated in the

hydrophobic core and a relative para-position of benzene

ring projecting out of the micelles towards the aqueous

phase, which would change the regioselectivity of chlo-

romethylation reaction. In addition, electrostatic interaction

between the charge on the micelle surface and the?CH2OH in the electrophilic substitution reaction (step 2 in

Scheme 2) would be another reason to bring about the

different p/o selectivity. For CTAB, electrostatic repulsion

disfavored the attack of the ?CH2OH at ortho-position of

IPB but favored at para-position. Thus, the chloromethy-

lation of IPB solubilized in CTAB micelles shows higher

para-position selectivity. However, for SDS, electrostatic

attraction increased the probability of the attack of the?CH2OH at ortho-position of IPB and the para-position

selectivity for chloromethylation of IPB solubilized in SDS

micelles was shown to be lower than the blank experiment

Table 1 Para–ortho isomer ratio in the chloromethylation and bromomethylation of aromatic hydrocarbons

Substrate Chloromethylation Bromomethylation

Conversion (%) Para/ortho Conversion (%) Para/ortho

Toluene 98.2 2.79 98.7 2.80

Ethylbenzene 93.5 3.60 94.2 3.41

Isopropylbenzene 89.8 8.28 88.5 7.85

Reaction conditions: substrate, 1.0 mol; paraformaldehyde, 1.2 mol; conc. HCl (or 48 wt% hydrobromic acid), 300 mL; anhydrous HCl (or

anhydrous HBr), 450 mL/min; concentration of CTAB: 1.29 9 10-2 mol L-1 (ca. 14-fold CMC). Conversions and selectivities are based on the

GC with area normalization

0 1 2 3 40

20

40

60

80

100

Con

vers

ion

of IP

B (

%)

Time (h)

DTAB CTAB

Fig. 4 Relationship between conversion and reaction time for two

kinds of cation surfactants. Reaction conditions: IPB, 120.2 g

(1.0 mol); paraformaldehyde, 36.0 g (1.2 mol); conc. HCl, 300 mL;

anhydrous HCl gas, 450 mL/min; reaction temperature: 80 �C;

concentrations of surfactants: 14CMC

Table 2 Selectivity for mono-chloromethylation of IPB in the pres-

ence of surfactants

Surfactant 1 h

Selectivity % (p/o)

4 h

Selectivity % (p/o)

CTAB 98.9 (8.45) 97.5 (8.28)

NP-10 93.4 (7.79) 88.3 (7.46)

SDS 85.2 (6.57) 73.1 (6.02)

No surfactant 76.3 (7.68) 64.7 (7.17)

Reaction conditions: IPB, 120.2 g (1.0 mol); paraformaldehyde,

36.0 g (1.2 mol); conc. HCl, 300 mL; anhydrous HCl gas, 450 mL/

min; reaction temperature: 80 �C; concentrations of surfactants:

14-fold CMC; reaction time: 4 h; selectivities (p/o) were based GC

with area normalization

490 Q. Liu et al.

123

Table 3 Chloromethylation of aromatic compounds

Entry Substrate Con. (%) Sel. (%) p/o Temp./t Products and yield (%)

1 69 95.7 80°C /4h

CH2Cl

64.8

2

CH3

98.2 93.5, 2.79 80°C /4h

CH3

CH2Cl

85.6

3

CH2CH3

93.5 96.3, 3.60 80°C /4h

CH2CH3

CH2Cl

89.7

4

CH2CH2Cl

40.0 82.8, 3.30 80°C /8h

CH2CH2Cl

CH2Cl

31.3

5

C(CH3)3

86.0 98.1, 28.20b 80°C /4h

C(CH3)3

CH2Cl

77.2

6c

n-C12H25

58.3 99.5 80°C /4h

n-C12H25

CH2Cl

56.5

7

CH3

CH396.8 98.8 80°C /4h

CH3

CH3

CH2Cl

67.7

CH3

CH3

CH2Cl19.4

CH3

CH3

CH2Cl

ClH2C 1.5

8

CH3

CH3

92.5 91.5 80°C /4h

CH3

H3C

CH2Cl

83.7

CH3

CH2Cl

CH2Cl

H3C

5.6

9

CH3

CH3

90.1 85.9 80°C /4h

CH3

CH3

CH2Cl

75.5

CH3

CH3

CH2Cl

ClH 2C

12.1

10

CH3CH3

CH3

93.0 97.6 80°C /4h

CH3CH3

CH3

CH2Cl

88.7 CH3CH3

CH3

CH2Cl

CH2Cl

1.9

11

CH3CH3

C(CH 3)3

95.8 86.2d 80°C /4h

CH3CH3

C(CH 3)3

CH2Cl

68.8

Chloromethylation of Aromatic Compounds 491

123

in which no surfactant was used. For NP-10, the attack of

the ?CH2OH on IPB solubilized in NP-10 micelles at

ortho-position was prevented by non-polar micellar core,

while the polar aqueous phase provided a more favorable

locale for the attack of the ?CH2OH at the para-position.

Thus, the observed p/o selectivity ratio of mono-chlorom-

ethylation is CTAB [ NP-10 [ no Surf. [ SDS.

3.5 Chloromethylation of Aromatic Compounds

Table 3 summarizes the application of CTAB to the

chloromethylation of aromatic compounds under the

concentration condition of 14CMC. All aromatic compounds

were efficiently converted to the corresponding chloromethyl-

substituted aromatic compounds in good to excellent isolated

yield under mild reaction conditions. Benzene, toluene, eth-

ylbenzene, tert-butylbenzene and n-dodecylbenzene gave

monochloromethylated products in high yield, which was

attributed to the deactivating effect of a –CH2Cl group. For

example, we found that benzene could be chloromethylated

only once, even after prolonged reaction time because the

deactivating action of one –CH2Cl group was already suffi-

cient to inhibit the introduction of a second group. Compared

to alkylbenzene, 2-chloroethylbenzene showed relatively low

Table 3 continued

Entry Substrate Con. (%) Sel. (%) p/o Temp./t Products and yield (%)

12

OCH 3

100 92.1, 3.17 10°C /4.5h

OCH 3

CH 2 Cl

89.4

OCH 3

CH 2 Cl

CH 2 Cl

5.3

13 O CH 3

100 100 40°C /0.5h O CH 3

ClH 2 C 97.3

14 S

100 75.0 e 5°C /0.5h S CH 2 Cl

64.8 S CH 2 Cl ClH 2 C

18.1

15 O

O 99.4 99.6 80°C /8h

O

O

CH 2 Cl

98.0

16 97.9 96.6 80°C /5h

CH 2 Cl

91.0

17

CH 2

100 78.1 f 80°C /4h

CHCH 2 Cl

75.3

18

Cl

0 - 80°C /24 -

aReaction conditions: substrate, 1.0 mol; paraformaldehyde, 1.2 mol; conc. HCl, 300 mL; anhydrous HCl, 450 mL/min; concentration of CTAB:

1.29 9 10-2 mol L-1 (ca. 14-fold CMC). Conversions and selectivities are based on the GC with area normalization. All yields are for pure,

isolated productsb Here indicated the para/meta isomer selectivity ratio and almost no ortho isomer was observedc 1-(Chloromethyl)-4-dodecylbenzene (6): Mp: 35–36 �C, bp: 152–154 �C/2 mm. IR (KBr): 675 (C–Cl) cm-1. 1H NMR (CDCl3, 300 MHz): d0.85 (3H, t, CH3), 1.21–1.57 (20H, o, CH2), 2.59 (2H, t, CH2), 7.10 (2H, d, ArH), 7.32 (2H, d, ArH), 4.61 (2H, s, CH2Cl). GC/MS: m/z = 294

(M?), 259, 139, 105, 91, 77. Elemental analysis: C, 77.40%; H, 10.61%; Cl, 11.95% calculated from C19H31Cl. Found: C, 77.38%; H, 10.60%;

Cl, 12.02%d Accompanied by the formation of di-(2,6-dimethyl-4-t-butylphenyl) methanee Insoluble floccule formedf A consecutive addition of hydrogen chloride occurred

492 Q. Liu et al.

123

activities in the chloromethylation. The substitution occurred

mainly in the ortho- and para-position and the p/o selectivity

ratio was higher than that as reported [6, 35], which indicated

that the aromatic compounds attained a preferred molecular

orientation in CTAB micelles. The active aromatic com-

pounds such as xylene, mesitylene, anisole, thiophene and so

on gave monochloromethylated products in high yield and

selectivity, and also gave disubstituted ones in low yield.

While in the case of 2-methylfuran only 5-chloromethylation

taken place, as expected for anisole a mixture of para/ortho

position isomers was formed with a little amount of disub-

stituted products. Because styrene displays the largest electron

densities in the b-position (at the terminal =CH2 group)

preferably attacked by the electrophile ?CH2OH, chlorome-

thylation of styrene gave not chloromethylstyrene but

cinnamyl chloride along with 1-phenyl-1,3-dichloropropane

as major byproduct owing to a consecutive addition of

hydrogen chloride. Chloromethylation of chlorobenzene also

gave no corresponding chloromethylated product.

4 Conclusions

In this research, micellar-catalyzed chloromethylation

reaction of aromatic compounds in an oil–water biphasic

system was carried out successfully. When no surfactants

were used, the interface area between oil phase and water

phase was very small, so the rate of chloromethylation

reaction occurring at the oil–water interface was quite low;

however, when surfactant micelles were formed, aromatic

compounds was solubilized into numerous micelles, the

interface area of oil phase/water phase was magnified

suddenly and the rate of chloromethylation reaction was

accelerated abruptly. Cationic surfactants are more suitable

for the chloromethylation reaction. Furthermore, the

structure of cationic surfactant can influence the micelli-

zation behavior of surfactant and the micellar catalysis

effect as well. The selectivity for mono-chloromethylation

was remarkably improved in the micellar solutions. Further

aspects of the micellar catalysis and the application to

organic synthesis and practical chemical processes are

under investigation.

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