J. Chil. Chem. Soc., 55, Nº 1 (2010)
The excellent catalytic abilities of the catalytic system suggest the
chloromethylation reaction among aromatic hydrocarbons, formaldehyde, zinc
chloride, acetic acid, sulfuric acid and PEG-800 has a particular mechanism.
Scheme 2 shows a plausible mechanistic pathway for the chloromethylation of
aromatic hydrocarbons. Before the chloromethylation, there exists an obvious
oil-water biphasic system, and the under layer (water phase) consists of zinc
chloride, acetic acid, sulfuric acid and formaldehyde, the upper layer (oil phase)
is the substrate (aromatic hydrocarbon), and PEG-800 exists between the two
phases. During the process of chloromethylation, the oil-water biphasic system
disappeares and a homogeneous reaction medium is formed by phase transfer
catalysis. It is considered that the activation of formaldehyde is a first step
for the enhancement of the chloromethylation18,21. 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 by subsequent attack of the
+CH OH on benzene ring of aromatic hydrocarbons to give aromatic carbinol;
then2the 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. Afer the completion of the reaction, a complete
phase-separation is formed again after being cooled to room temperature, the
upper layer of the product, was removed by extraction with methylene chloride
and the catalytic system, containing zinc chloride, acetic acid, sulfuric acid and
PEG-800, was concentrated to remove water produced in the reaction through
water knockout drum and then recycle.
catalysis, the application to organic synthesis, and practical chemical processes
are under investigation.
EXPERIMENTAL
Apparatus and reagents
All chemicals were obtained commercially and used without further
purification. The target products were characterized by Elemental analysis,
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1H NMR, or compared with their authentic samples. H NMR spectra were
recorded on a Bruker 400 MHz spectrometer using CDCl as the solvent
with tetramethylsilane (TMS) as an internal standard. Hi3gh performance
liquid chromatography (HPLC) experiments were performed on a liquid
chromatograph (Dionex Softron GmbH, America), consisting of a pump (P680)
and ultraviolet-visible light detector (UVD) system (170U). The experiments
were performed on Diacovery C18 column, ø 4.6×150 mm. Elemental analysis
were performed on a Vario EL III instrument (Elmentar Anlalysensy Teme
GmbH, Germany).
Typical procedure of chloromethylation using toluene as an example
A 250 mL three-necked flask was loaded with toluene (9.2 g, 0.1 mol),
paraformaldehyde (3.15 g, 0.105 mol), ZnCl2 (13.6 g, 0.1 mol), 50%H SO (60
mL), AcOH (30 mL) and PEG-800 (4 g, 5 mmol). Hydrogen chloride2gas4was
bubbled into the flask at the flow rate of 10 mL/min. The reaction mixture was
stirred at 50°C for 8 h, the reaction progress was monitored by HPLC. After the
reaction, the reaction mixture was cooled to room temperature and extracted
with methylene chloride (3×10 mL). The organic phases were combined and
rinsed with 50% NaHCO solution (3×10 mL ) and water (2×10 mL), then
dried with sodium sulfate,3filtered, and evaporated to dryness in vacuo, and the
organic residue was resolved in methylene chloride and analyzed by HPLC.
Each product was separated by silica-gel column chromatography, then the
solvent was removed under vacuum to give the desired product. The next run
was performed under identical reaction conditions.
4-(chloromethyl)-1,2-dimethylbenzene (4a): 1H NMR (CDCl3): δ 7.04-
7.16 (d, 3H, ArH), 4.56 (s, 2H, CH2Cl), 2.33 (s, 6H, CH3). Anal. Calc. for
C9H11Cl: C, 69.90; H, 7.17; Cl, 22.93%. Found: C, 69.86; H, 7.16; Cl, 22.92%.
1-(chloromethyl)-2,3-dimethylbenzene (4b): 1H NMR (CDCl3): δ 7.07-
7.24 (m, 3H, ArH), 4.57 (s, 2H, CH2Cl), 2.35 (s, 3H, CH ), 2.21 (s, 3H, CH3).
Anal. Calc. for C H11Cl: C, 69.90; H, 7.17; Cl, 22.93%.3Found: C, 69.89; H,
7.17; Cl, 22.91%.9
2-(chloromethyl)-1,4-dimethylbenzene (5a): 1H NMR (CDCl3): δ 7.08-
7.19 (d, 3H, ArH), 4.59 (s, 2H, CH Cl), 2.37 (s, 3H, CH ), 2.32 (s, 3H, CH3).
Anal. Calc. for C H11Cl: C, 69.90; 2H, 7.17; Cl, 22.93%.3Found: C, 69.88; H,
7.18; Cl, 22.89%.9
1-(chloromethyl)-2,4-dimethylbenzene (6a): 1H NMR (CDCl3): δ 7.03-
7.18 (m, 3H, ArH), 4.55 (s, 2H, CH2Cl), 2.36 (s, 3H, CH ), 2.31 (s, 3H, CH3).
Anal. Calc. for C H11Cl: C, 69.90; H, 7.17; Cl, 22.93%.3Found: C, 69.87; H,
7.19; Cl, 22.91%.9
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1-(chloromethyl)-4-isopropylbenzene(7a): H NMR (CDCl ): δ 7.34 (m,
2H, ArH), 7.18 (m, 2H, ArH), 4.48 (s, 2H, CH2Cl), 2.84 (m, H,3CH), 1.54 (d,
6H, CH3). Anal. Calc. for C H13Cl: C, 71.21; H, 7.77; Cl, 21.02%. Found: C,
71.17; H, 7.76; Cl, 21.01%. 10
Scheme 2. Plausible mechanism of chloromethylation of aromatic
hydrocarbons
1-(chloromethyl)-2-isopropylbenzene (7b): 1H NMR (CDCl3): δ 7.14-7.29
(m, 4H, ArH), 4.51 (s, 2H, CH2Cl), 2.83 (m, H, CH), 1.56 (d, 6H, CH3). Anal.
Calc. for C10H13Cl: C, 71.21; H, 7.77; Cl, 21.02%. Found: C, 71.19; H, 7.78;
Cl, 21.00%.
CONCLUSIONS
In summary, the catalytic system (ZnCl2/AcOH/H2SO /PEG-800)
has been proven to be an effective promoter for the chloromet4hylation of
aromatic hydrocarbons. The chloromethyl acid complex consisting of a certain
concentration of sulphuric acid and acetic acid in a peculiar volume ratio for
the chloromethylation is the first glittery point in our paper, which can be use
efficiently for the chloromethylation of various aromatic hydrocarbons by
changing the concentration of sulfuric acid and the volume ratio of sulfuric
acid and acetic acid. This procedure not only enhanced the yield, but also the
selectivity for para-chloromethylated product could almost be improved by
5~15% contrast to other procedures catalyzed by lewis acids, ionic liquids,
rare-earth metal triflates, etc4-21, whose selectivity for para-isomer were usually
70~82%. Another glittery point was that we have developed an inexpensive,
old but new, efficient, and convenient chloromethylation procedure catalyzed
by ZnCl2/AcOH/H SO4/PEG-800 in aqueous media under PTC conditions,
the present metho2d has many obvious advantages compared to previous
methods, such as easy product isolation, simple methodology, the excellent
yield, generality, and the excellent recyclability of the catalytic system, etc,
though it is not satisfied for the chloromethylation of desactivating aromatic
hydrocarbons such as benzoic acid and chlorobenzene.
2-(chloromethyl)-4-methylphenol (9a): 1H NMR (CDCl3): δ 6.98-7.17 (m,
3H, ArH), 5.39 (s, 1H, OH), 4.57 (s, 2H, CH Cl), 2.84 (m, H, CH). Anal. Calc.
for C H ClO: C, 61.35; H, 5.79; Cl, 22.64;2O, 10.22%. Found: C, 61.31; H,
5.79; 8Cl9, 22.63; O, 10.19%.
6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene (10a): 1H NMR (CDCl3):
δ 7.03-7.11 (m, 3H, ArH), 4.56 (s, 2H, CH2Cl), 2.81 (s, 2H, CH2), 1.53 (s, 2H,
CH2). Anal. Calc. for C11H13Cl: C, 73.12; H, 7.25; Cl, 19.62%. Found: C, 73.08;
H, 7.26; Cl, 19.59%.
5-(chloromethyl)-1,2,3,4-tetrahydronaphthalene (10b): 1H NMR (CDCl3):
δ 7.00-7.09 (m, 3H, ArH), 4.54 (s, 2H, CH2Cl), 2.83 (s, 2H, CH2), 1.55 (s, 2H,
CH2). Anal. Calc. for C11H13Cl: C, 73.12; H, 7.25; Cl, 19.62%. Found: C, 73.07;
H, 7.24; Cl, 19.61%.
4-(chloromethyl)biphenyl (11a): 1H NMR (CDCl3): δ 7.39-7.57 (m, 9H,
ArH), 4.63 (s, 2H, CH2Cl). Anal. Calc. for C13H11Cl: C, 77.04; H, 5.47; Cl,
17.49%. Found: C, 77.01; H, 5.46; Cl, 17.47%.
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4,4’-bis(chloromethyl)biphenyl (11b): H NMR (CDCl3): δ 7.46 (m, 4H,
ArH), 7.58 (m, 4H, ArH), 4.64 (s, 2H, CH2Cl). Anal. Calc. for C H12Cl2: C,
66.95; H, 4.82; Cl, 28.23%. Found: C, 66.89; H, 4.83; Cl, 28.24%.14
1-chloro-4-(chloromethyl)benzene (13a): 1H NMR (CDCl3): δ 7.41 (m,
Judging from the conditions employed, this chloromethylation method
showed has great prospects in industrial applications. Further aspects of the
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