Synthetic and mechanistic investigation of piperonyl butoxide from dihydrosafrole

Article abstract of DOI:10.1007/s11164-011-0333-8

Piperonyl butoxide (PBO) 1 was prepared via the successive chloromethylation and etherification of dihydrosafrole 3. In this work, during the chloromethylation of 3, several by-products such as 5 (the isomer of chloromethyldihydrosafrole 4), 6-propylpiperonyl alcohol 6, bis(chloromethyl)- dihydrosafrole 7 and 8, bis(2-propyl-4,5-methylenedioxyphenyl)methane 9 and di(2-propyl-4,5-methy lene-dioxybenzyl)ether 10 were found. However, it was found that 5, 6, 7, and 8 could undergo a further reaction to the final product (PBO), rather than its derivatives, though the by-products 9 and 10 still existed. Based on these results, the plausible mechanism of the chloromethylation and etherification of 3 was proposed. Furthermore, the reliability of the plausible mechanism was verified by quantum chemical calculations using DFT. In addition, the final product (PBO) was produced with a high selectivity and yield by reducing the by-products 9 and 10. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0333-8

Res Chem Intermed (2012) 38:147–160
DOI 10.1007/s11164-011-0333-8
Synthetic and mechanistic investigation of piperonyl
butoxide from dihydrosafrole
•
Shuai Wang Jinqiang Liu Chao Qian Xinzhi Chen
•
•
Received: 14 February 2011 / Accepted: 24 May 2011 / Published online: 9 June 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Piperonyl butoxide (PBO) 1 was prepared via the successive chlo-
romethylation and etherification of dihydrosafrole 3. In this work, during
the chloromethylation of 3, several by-products such as 5 (the isomer of
chloromethyldihydrosafrole 4), 6-propylpiperonyl alcohol 6, bis(chloromethyl)-
dihydrosafrole 7 and 8, bis(2-propyl-4,5-methylenedioxyphenyl)methane 9 and
di(2-propyl-4,5-methy lene-dioxybenzyl)ether 10 were found. However, it was
found that 5, 6, 7, and 8 could undergo a further reaction to the final product (PBO),
rather than its derivatives, though the by-products 9 and 10 still existed. Based on
these results, the plausible mechanism of the chloromethylation and etherification of
3 was proposed. Furthermore, the reliability of the plausible mechanism was verified
by quantum chemical calculations using DFT. In addition, the final product (PBO)
was produced with a high selectivity and yield by reducing the by-products 9 and 10.
Keywords Piperonyl butoxide Á Chloromethylation Á Etherification Á
Dihydrosafrole Á Density functional
Introduction
Piperonyl butoxide (PBO) 1, a methylenedioxyphenyl compound, is the first major
insecticide synergist and now used in a wide variety of pesticides, such as
pyrethrins, pyrethroids, carbamates and so on [1, 2]. It was first synthesized in 1946
S. Wang Á J. Liu Á C. Qian Á X. Chen (&)
Department of Chemical and Biological Engineering, Zhejiang University,
Hangzhou 310027, China
e-mail: xzchen@zju.edu.cn; chemtec@163.com
J. Liu
College of Chemistry and Chemical Engineering, Luoyang Normal University,
Luoyang 471022, China
123

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S. Wang et al.
O
O
O
O
O
O
hydrogenization
etherification
chloromethylation
Cl
2
3
4
O
O
O
O
O
1
Scheme 1 Synthesis of PBO from Safrole 2
by Wachs [3]. Since then, more interest centered around its preparation. It is
generally prepared via the successive chloromethylation and etherification of
dihydrosafrole 3 starting from naturally occurring safrole 2 (Scheme 1). The yield
of PBO from 3 is relatively low, though the method of hydrogenation is mature.
Previous research has mainly focused on the conditions of chloromethylation
(reagent of chloromethylation, catalyst, reaction temperature or promoter) and
etherification (solvent, reaction temperature, or base types) [4–10]. However, little
information has been mentioned as to why the yield of the two steps is low, and the
mechanism about the two steps has rarely been investigated. For these reasons, we
have undertaken lots of experiments on the chloromethylation and etherification
process with 3 as the starting material in order to understand the mechanism that
might help to improve the total yield of PBO.
In this paper, we report the method to improve the yield of PBO and our
observations on the mechanism of the chloromethylation and etherification of 3. The
plausible mechanism was also tested by quantum chemical calculations using
density functional theory (DFT) with the program package DMol3 in Materials
Studio of Accelrys Inc [11–13].
Results and discussion
Synthesis of chloromethyldihydrosafrole 4
The chloromethylation of aromatic hydrocarbons has been widely studied in the
literature, and the most common procedures have been the use of hydrochloric acid
and trioxane or paraformaldehyde as a formaldehyde precursor with Lewis acid as
the catalyst [14, 15]. In our initial experiment, the chloromethylation of 3 was
carried out in the presence of hydrochloric acid and paraformaldehyde according to
the previous study [16, 17]. The analysis of the products was by GC–MS. To our
disappointment, our attempts to reproduce the reported produce led to poor
selectivity; multiple by-products were produced. Except for bis(2-propyl-4,5-
methylenedioxyphenyl)methane 9, other by-products, which were seldom reported
like 4-chloromethyldihydrosafrole 5, 6-propylpiperonyl alcohol 6, 4,5-bis(chloro-
methyl)-6-propyl-1,3-benzodioxole 7, 4,6-bis(chloromethyl)-5-propyl-1,3-benzodi-
oxole 8, and di(2-propyl-4,5-methy lene-dioxybenzyl)ether 10 were detected. Due
123

Synthetic and mechanistic investigation of piperonyl butoxide
149
to the high activity of 3 (the methylenedioxy and n-propyl groups are both electron-
donating), it is favorable for electrophilic substitution. In recent studies, the
chloromethylation of aromatic compounds with hydrochloric acid, paraformalde-
hyde as well as catalysts such as phase-transfer catalysts [18–20], rare-earth metal
triflates [21], and micellar catalysis in an oil/water biphasic system [22] are proved
to be very promising methods. To enhance the selectivity and yield, lots of
experiments on different reaction conditions were done on the base of the previous
work and the results were shown in Table 1 (Fig. 1).
When no catalyst was used, the reaction rate of chloromethylation was relatively
low (Table 1, entry 1–3), and with increase in temperature, yield of 7, 8, and 9 were
also increased, while yield of 5 decreased (Table 1, entry 1–7). Perhaps at low
temperature the effect of steric hindrance on the reaction is rather low, and
activation energy of the reaction is the dominant factor. When Lewis acid was
added, the reaction rate was increased, and furthermore, the by-products increased
at the same time (Table 1, entry 5–7) because of the Friedel–Crafts alkylation
catalyzed by the same Lewis acid. In the presence of a phase-transfer catalyst or
rare-earth metal triflates, there was no obvious change in selectivity though the
reaction rate could also be improved. Compared with Lewis acid, these catalysts are
active at very low concentrations while a stoichiometric amount of Lewis acid
catalyst to substrate is required, making the work-up procedure tedious. In an oil/
water biphasic system with the addition of surfactant (CTAB), as the results shown
in entry 10, the chloromethylation of 3 was also resulted in high conversion and
high percent of by-products 7, 8, 9, and 10. Perhaps 3 was solubilized into micelles,
resulting in a larger oil–water interfacial area, a higher reaction rate compared to the
system without micelles and the decrease in selectivity, which was likely due to
the subsequent chloromethylation of mono-chloromethyl products with the above
by-products.
In summary, the results in Table 1 show that 3 could be reacted with high
conversion and rapid reaction rate, but the selectivity is rather low even under
various conditions. So the desired chloromethyldihydrosafrole 4 must be separated
and purified by vacuum distillation before it can be reacted further to produce PBO
1, but if such a method is used, the final yield of 1 would be no more than 75%.
Plausible mechanism of the chloromethylation and etherification of 3
Without considering the purification of 4, we used the crude chloromethyldihy-
drosafrole as the starting material for etherification. To our surprise, the possible
by-products 11, 12, 13 (Fig. 2) were not detected by GC–MS. The by-products of
the chloromethylation step, 9 and 10 were still detected. The disappearance of 11
might be attributed to its isomerization to 1, and the reason why 12 or 13 were not
detected could be explained by Scheme 2. Based on this discovery, purification
of chloromethyldihydrosafrole is no longer necessary. To increase the selectivity
and yield of 1, only 9 and 10 need to be decreased, which were produced during
the chloromethylation of 3.
During the chloromethylation of 3, we found the intermediate 6, so the plausible
mechanism of chloromethylation can be presented as shown in Scheme 3. It mainly
123

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S. Wang et al.
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Synthetic and mechanistic investigation of piperonyl butoxide
151
O
O
O
O
Cl
O
OH
O
Cl
Cl
5
6
7
O
O
Cl
O
O
O
O
O
O
O
Cl
O
O
8
9
10
Fig. 1 By-products of the chloromethylation of dihydrosafrole 3
3
3
3
O
O
O
O
O
O
O
O
O
3
O
O
3
11
12
13
Fig. 2 The possible by-products of the etherification
O
O
O
OH-
+
Cl
HO
O
O
O
O
O
O
Cl
OH
O
-HCHO
O
O
O
O
Scheme 2 Plausible mechanism of the etherification
consists of two steps: electrophilic substitution and nucleophilic substitution, which
can be expressed as follows:
Firstly, depolymerization of paraformaldehyde by acid catalysis of hydrochloric
acid yields formaldehyde, which reacts with a proton (H?) to give hydroxymethyl
cation (?CH2OH) and the electrophilic substitution mainly occurs by subsequent
attack of the ?CH2OH on benzene ring of 3 to give 4; 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 afford the desired
product. Meanwhile, the benzyl carbonium ion can also react with benzene ring to
give by-product 9, or with 4 to give 10. In addition, the production of by-products 5,
7, and 8 leads to the same product 4.
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S. Wang et al.
O
C
OH
C
O
O
O
O
+
H
+
H
+
OH
H
H
H
H
O
O
O
O
H2O
+
OH2
Cl-
CH2
O
O
+
Cl
main reaction
O
O
+
O
O
O
O
+
H
CH2
said reaction
O
O
O
O
+
OH
O
O
+
H
O
said reaction
O
O
Scheme 3 Plausible mechanism of the chloromethylation
As shown in Scheme 3, it is important to enhance the concentration of Cl- and
H?, for more H? is advantageous to generate hydroxymethyl cation and benzyl
carbonium ion, and more Cl- is beneficial to produce the desired product and lessen
the probability between benzyl carbonium ion and 3, 4, or 6. So it is favorable to
increase the concentration of hydrochloric acid, however, the concentration of
hydrochloric acid decreased obviously with the consumption of hydrogen chloride
and escape from the mixture at high temperature. In order to keep the hydrochloric
acid concentration at a high level, we use a polymer of formaldehyde in the reaction
system containing concentrated hydrochloric acid, instead of aqueous formalde-
hyde, or to bubble the gaseous hydrogen chloride at the end of the reaction. In this
paper, the method of adding phosphorus trichloride dropwise was used. It not only
produces hydrogen chloride but also consumes water. Also, the solvent must be
considered, because it can reduce by-products by dispersing the starting material
and products, decreasing their collision probability. The reaction temperature is also
an important factor. At lower temperature, not only the reaction is slower but also
the yield is poor. While at higher temperatures, the hydrogen chloride escapes and
the by-products increase. Table 2 shows the effect of the above factors.
Without further purification, the products of the chloromethylation can directly
react with the sodium salt of diethylene glycol monobutyl ether. This sort of ether
preparation is known as the classical Williamson synthesis [23]. Generally, the
influencing factors are the temperature and the catalyst type. In this paper, the
reaction results at different reflux temperatures (cyclohexane, toluene, p-xylene,
and mesitylene) and catalyzed by different bases (sodium hydroxide, potassium
123

Synthetic and mechanistic investigation of piperonyl butoxide
153
Table 2 Effect of different factors for the chloromethylation of 3
Entry Reaction Reaction
time(h)
Catalyst Solvent
Conversion (%) Selectivity %
temperature (°C)
(9)
(10)
1
2
3
4
5
6
6
6
6
6
70
70
70
50
90
None
PCl3
PCl3
PCl3
PCl3
None
None
98.1
98.5
3.7
2.1
1.8
1.8
2.8
1.5
0.9
0.7
0.7
1.2
Cyclohexane 98.3
Cyclohexane 96.3
None
98.8
Reaction conditions: 3, 25.0 g (0.15 mol); paraformaldehyde, 9.0 g (0.3 mol); conc. HCl, 30 mL;
cyclohexane, 40 mL; PCl3, 8 mL, added dropwise after 4 h. Conversions and selectivities are based on
the GC with area normalization. Selectivities of other products are not considerate because they can all be
etherealizated to the final product (PBO)
hydroxide, and sodium carbonate) have indicated that the two factors have little
effect. Since the chloromethylation was carried out using cyclohexane as solvent,
the same solvent was used for the etherification.
Quantum chemical calculations on the synthesis of PBO
Computational method
In order to test the reliability of the plausible mechanism, DFT is used in this work
to perform thermodynamic calculation for the proposed pathways. DFT has been
very popular for calculations in chemistry since the 1970s, and it is now a widely
used method for electronic calculations. Perdew and Wang’s 1991 function (PW91)
was used [24, 25]. A double-numeric polarized basis set (DNP) and truncate real-
˚
space cut-off of 4.0 A were employed. These basis functions are numerically exact
atomic orbitals, so that this quality of basis set gives rise to very little superposition
effects [11].
The geometries of all the reactants, intermediates and products were optimized.
The transition state (TS) search was performed with the linear and quadratic
synchronous transit (LST/QST) complete search [26]. TS structures were verified
using the TS confirmation tool. The solvent effect was estimated using the
conductor-like screening model (COSMO) [27, 28], in which the solute molecules
form a cavity within the dielectric continuum of permittivity e. Compared to other
continuum models, COSMO does not require complicated boundary conditions for a
dielectric in order to obtain screening charges. It uses a simple boundary condition
for a conductor.
Computational results and discussion
All the reactants, intermediates, and TS structures in the proposed reaction pathways
are optimized firstly. Reaction Gibbs energy and barrier of every elementary
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S. Wang et al.
reaction are then calculated. The results are shown in Table 3. According to the
reaction Gibbs energy of every elementary reaction in Table 3, Gibbs energy of the
possible reactions was calculated as shown in Table 4.
Table 3 Gibbs energies and barriers of every elementary reaction
Reaction
Reaction
Gibbs
Entry
Reaction
Barrier
energy
(kJ/mol)
(kJ/mol)
1
2
2.47
1.05
13.46
-13.01
3
4
5
8.45
18.42
3.79
7.14
-1.54
2.51
6
7
8
17.86
8.00
-7.72
-6.61
-1.34
15.45
9
10.24
6.28
-4.02
5.02
10
11
12
7.05
5.97
5.33
4.22
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Synthetic and mechanistic investigation of piperonyl butoxide
155
Table 3 continued
13
14
15
16
17
10.56
9.86
2.53
3.71
1.02
0.56
-2.55
18.69
17.65
8.12
18
19
7.95
7.34
-4.21
4.52
20
21
22
23
24
7.86
1.72
1.75
1.26
12.39
6.54
-5.33
-4.22
-5.02
2.54
123

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S. Wang et al.
Table 3 continued
25
26
9.52
1.03
0.37
-1.05
5.88
2.56
27
28
2.74
18.75
20.38
-2.23
8.43
29
30
10.88
As shown in Table 4, the Gibbs energy of reaction 2 is the highest (Table 4, entry
1–5), and thus, it is hard to produce 14, and indeed in the experiment two kinds of the
mono-substituted chloromethyl substances were found, not three. Table 4 also
contains the Gibbs energy of the etherification (entry 6–8). Obviously the Gibbs
energy of reaction 6 is lowest, and the others are relatively higher, especially
reactions 9 and 10. So it is possible that the by-products 11, 12, and 13 have not been
found and they are likely to be converted to the desired product (PBO).
Conclusions
In summary, many by-products were found during the chloromethylation of
dihydrosafrole, such as the isomer of chloromethyldihydrosafrole, 6-propyl piper-
onylic alcohol 6, bis(chloromethyl)-dihydrosafrole 7 and 8, the diphenylmethane
derivative 9 and so on. In the experiment, 5, 6, 7, and 8 could further react to give the
final product (PBO), not the derivatives of PBO, though the by-products 9 and 10 still
existed. So the main influencing factor of the selectivity and yield of PBO is how to
reduce the by-products 9 and 10. According to this result, the plausible mechanism of
the chloromethylation and etherification of dihydrosafrole was put forward. Further-
more, the reliability of the plausible mechanism was tested by quantum chemical
calculations using DFT. In addition, the method of adding dropwise phosphorus
trichloride was used, and in this way the hydrochloric acid concentration was kept at a
high level. The yield and selectivity of the final product (PBO) was rather high.
123

Synthetic and mechanistic investigation of piperonyl butoxide
157
Table 4 Reaction energy of some possible reactions
Reaction
Gibbs
Entry
Reaction
energy
(kJ/mol)
1
2
-13.55
9.59
3
4
-5.01
-8.03
5
6
7
-6.95
-4.65
-2.79
8
9
-3.19
7.38
8.65
10
Experimental
Chemicals and instruments
1
Commercial reagents were used as received. H NMR spectrum was recorded on a
400-MHz spectrometer with CDCl3 as solvent and Me4Si as an internal standard.
The proton broadband decoupled 13C NMR spectrum was recorded at 101 MHz.
123

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S. Wang et al.
CDCl3 (Me4Si as an internal standard) served as solvent. The following
abbreviations were used to designate chemical shift multiplicities: s = singlet,
d = doublet, t = triplet, m = multiple. All first-order splitting patterns were
assigned on the basis of the appearance of the multiplet. Splitting patterns that
could not easily be interpreted are designated as multiplet (m) or broad (br). IR
spectra were recorded on an FTIR spectrometer. GC–MS analysis was carried out
using an Agilent 6890 N gas chromatograph interfaced to a 5973 N mass selective
detector. The column used was a HP-5 MS (5% phenylmethyl-polysiloxane)
30 m 9 0.25 mm i.d. column, df = 0.25 lm. 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 260 °C at 20°C/
min followed by 25 min at 260 °C. The MSD parameters were electron impact in
full scan mode.
General procedure for producing chloromethyldihydrosafrole 4
A visually clean, 250-mL three-neck round-bottom flask was charged with
paraformaldehyde (9.00 g, 0.30 mol) and concentrated hydrochloric acid
(38 wt%, 30 mL) and then heated to 40 °C with stirring until paraformaldehyde
was completely dissolved to get a clear solution. The solvent cyclohexane (50 mL)
and the starting material 3 (25.00 g, 0.15 mol) were then added, keeping the internal
temperature at 70 °C. After 4 h, phosphorus trichloride (10 mL, 0.12 mol) was
added dropwise over 3 h. The phases were allowed to separate when the mixture
was cooled to room temperature. The organic layer was removed and the aqueous
layer was back-extracted with cyclohexane (20 mL). The organic phases were
combined and washed with half-brine (30 mL). Without further purification, the
organic phase could be used directly in the next reaction. The mixture was analyzed
by GC–MS. The conversion of 3 was 98.3%, and the selectivities of 9 and 10 were
1.8% and 0.7%. The main product 4 could be obtained at about 155 °C, at 10 mm of
mercury when the above mixture was further distilled in vacuo. It is a colorless oil
that is heavier than water. Chloromethyldihydrosafrole 4: 1H NMR (CDCl3,
400 MHz) d 6.80 (s, 1H), 6.67 (s, 1H), 5.91 (s, 2H), 4.55 (s, 2H), 2.61 (t,
J = 6.8 Hz, 2H), 1.62 (m, J = 7.6 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 101 MHz) d 147.9, 145.7, 135.7, 128.0, 110.1, 109.6, 101.1, 44.5, 34.2,
24.5, 13.9; IR (film) mmax/cm-1 2,962, 2,930, 2,875, 2,770, 1,620, 1,485, 1,379,
1,260, 1,170, 1,130, 1,040, 938, 866, 700, 645; MS (EI, 70 eV), m/z (relative
abundance) 212 (M?, 44), 183 (58), 177 (100), 149 (32), 119 (24), 89 (21), 77 (11),
63 (9), 51 (8), 39 (7).
Respective values for the by-products. 6-Propylpiperonyl alcohol 6: MS (EI,
70 eV), m/z (rel abundance) 194 (M?, 77), 176 (57), 165 (60), 149 (22), 135 (17),
1
107 (100), 91 (14), 77 (44); H NMR (CDCl3, 400 MHz) d 7.02 (s, 1H), 6.91 (s,
1H), 6.04 (s, 2H), 4.61 (s, 2H), 2.67 (t, 2H), 1.68 (m, 2H), 1.54 (s, 1H), 0.97 (t, 3H);
13C NMR (CDCl3, 100 MHz) d 147.8, 147.5, 137.1, 133.6, 108.8, 108.2, 101.4,
62.9, 37.5, 25.6, 14.1. 4,5-Bis(chloromethyl)-6-propyl-1,3-benzodioxole 7: MS (EI,
123

Synthetic and mechanistic investigation of piperonyl butoxide
159
70 eV), m/z (rel abundance) 260 (M?, 28), 225 (100), 197 (24), 161 (23), 115 (11),
77 (16); 1H NMR (CDCl3, 400 MHz) d 6.89 (s, 1H), 6.02 (s, 2H), 4.89 (s, 4H), 2.61
(t, 2H), 1.61 (m, 2H), 0.99 (t, 3H); 13C NMR (CDCl3, 100 MHz) d 147.9, 146.5,
134.2, 130.8, 125.3, 108.6, 102.6, 62.9, 43.5, 38.7, 33.8, 25.2, 14.4. 4,6-
Bis(chloromethyl)-5-propyl-1,3-benzodioxole 8: MS (EI, 70 eV), m/z (rel abun-
dance) 260 (M?, 64), 231 (100), 225 (74), 189 (41), 159 (72), 131 (40), 115 (22), 91
(18), 77 (30); 1H NMR (CDCl3, 400 MHz) d 6.98 (s, 1H), 6.08 (s, 2H), 4.89 (s, 2H),
4.84 (s, 2H), 2.65 (t, 2H), 1.64 (m, 2H), 0.97 (t, 3H); 13C NMR (CDCl3, 100 MHz) d
146.2, 145.9, 133.1, 131.7, 127.0, 108.5, 102.3, 44.9, 39.8, 33.9, 24.7, 13.8. Bis(2-
propyl-4,5-methylenedioxyphenyl)methane 9: MS (EI, 70 eV), m/z (rel abundance)
1
340 (M?, 57), 297 (5), 267 (13), 238 (9), 211 (11), 176 (100), 152 (9), 115 (6); H
NMR (CDCl3, 400 MHz) d 7.01 (s, 2H), 6.97 (s, 2H), 6.09 (s, 4H), 4.04 (s, 2H),
2.63 (t, 4H), 1.68 (m, 4H), 0.99 (t, 6H); 13C NMR (CDCl3, 100 MHz) d 146.8,
146.6, 134.7, 133.0, 111.0, 107.7, 102.0, 39.2, 33.7, 24.6, 13.9. di(2-propyl-4,5-
methylene-dioxybenzyl)ether 10: MS (EI, 70 eV), m/z (rel abundance) 370 (M?,
51), 176 (91), 150 (76), 135 (100), 119 (50), 91 (33); 1H NMR (CDCl3, 400 MHz) d
6.99 (s, 2H), 6.87 (s, 2H), 6.07 (s, 4H), 4.82 (s, 4H), 2.68 (t, 4H), 1.67 (m, 4H), 1.01
(t, 6H); 13C NMR (CDCl3, 100 MHz) d 147.5, 146.9, 135.7 134.6, 110.7, 108.5,
101.2, 71.6, 33.9, 24.8, 14.2.
General procedure for producing PBO 1
A visually clean, 250-mL three-neck round-bottom flask was charged with sodium
hydroxide (15.00 g, 0.38 mol), water (10 mL) and diethylene glycol monobutyl
ether (30.00 g, 0.19 mol) and then the mixture was refluxed using a water trap until
no more water was collected (about 1 h). The solution was cooled to room
temperature and the mixture of chloromethyl compounds (the organic phase
obtained in the chloromethylation of 3) was added. The mixture was then refluxed
for 5 h. After cooling to room temperature, water (70 mL) was added until the salt
dissolved. The layers were allowed to separate and the cyclohexane was distilled
off. The remaining oil was distilled in vacuo. Some of the excess diethylene glycol
monobutyl ether distilled over, and then PBO (48.65 g, 94.3%) of high purity
(98.2%) was obtained, distilling at 230 °C at 10 mm of mercury. It is a colorless oil,
1
soluble in benzene, cyclohexane, and most organic solvents. H NMR (CDCl3,
400 MHz) d 6.85 (s, 1H), 6.66 (s, 1H), 5.90 (s, 2H), 4.48 (s, 2H), 3.69–3.57 (m, 8H),
3.46 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 8.0 Hz, 2H), 1.61–1.52 (m, 4H), 1.41–1.31
(m, 2H), 0.95 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
101 MHz) d 146.9, 145.4, 135.0, 128.9, 109.4, 109.3, 100.7, 71.2, 70.8, 70.7, 70.6,
70.1, 69.3, 34.3, 31.7, 24.5, 19.2, 14.0, 13.9; IR (film) mmax/cm-1 2,960, 2,930,
2,870, 1,620, 1,485, 1,375, 1,259, 1,228, 1,105, 1,039, 935, 865; MS (EI, 70 eV), m/
z (rel abundance) 338 (M?, 10), 193 (15), 176 (100), 149 (42), 119 (22), 91 (13), 74
(8), 57 (25), 41 (13), 29 (8).
Similarly, experiments of chloromethylation and etherification under different
conditions were carried out, and the results are shown in Tables 1 and 2.
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Acknowledgments The authors gratefully acknowledge the funding support by a grant from the
National Natural Science Foundation of China and the Natural Science Foundation of the Zhejiang
Province (Y4090045 and R4090358).
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