Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine from phenol, aniline and formaldehyde

Article abstract of DOI:10.1016/j.cclet.2014.12.005

To study the synthesis of 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine (benzoxazine), the reaction paths of phenol, aniline and formaldehyde were investigated by analyzing the synthesis crude products. With the aid of high-performance liquid chromatography (HP

Full text of DOI:10.1016/j.cclet.2014.12.005

G Model
CCLET 3174 1–5
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
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Original article
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Study on products and reaction paths for synthesis of 3,
4-dihydro-2H-3-phenyl-1,3-benzoxazine from phenol, aniline
and formaldehyde
* *
Q1 Cheng-Xi Zhang, Yu-Yuan Deng, Yi-Yang Zhang, Po Yang , Yi Gu
6
7
State Key Laboratory of Polymer Materials Engineering, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
A R T I C L E I N F O
A B S T R A C T
Article history:
To study the synthesis of 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine (benzoxazine), the reaction paths
of phenol, aniline and formaldehyde were investigated by analyzing the synthesis crude products. With
the aid of high-performance liquid chromatography (HPLC), chromatographic column and preparative
HPLC, seven compounds originated from the crude products were obtained and their chemical structures
were elucidated. Possible reaction paths are proposed based on these compounds. Results show that N-
hydroxymethyl aniline (HMA) derived from the reaction of formaldehyde and aniline is probably the key
intermediate during the reaction. HMA can react with itself or other reactants to form other
intermediates, such as 1,3,5-triphenyl-1,3,5-triazinane and 2-((phenylamino)methyl)phenol, and
further form benzoxazine and byproducts.
Received 29 September 2014
Received in revised form 12 November 2014
Accepted 19 November 2014
Available online xxx
Keywords:
Benzoxazine
Synthesis reaction path
Synthetic product
Competing reaction
Intermediate
ß 2014 Po Yang and Yi Gu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
8
9
1. Introduction
Many studies have focused on synthesizing novel benzoxazine 28
monomers [26–28]. However, a number of factors, including the 29
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27
Q2
Polybenzoxazines, obtained via thermal polymerization of
corresponding benzoxazine monomers, have received widespread
research interest because of their excellent performance [1–7]. The
synthesis of benzoxazine monomer was first reported by Holly and
Cope [8], in which it can be obtained by a variety of synthetic
routes [9–12]. The most universal route is using phenols, primary
amines, and formaldehyde as starting materials [3,13–18]. For this
route, Burke proposed the possible reaction path: N,N-dihydrox-
ymethyl amine (I) is initially generated (Scheme 1, step 1) and then
converted into 2-(N-hydroxymethyl-N-substituted amino)methyl-
phenol (N-hydroxymethyl Mannich base) (II) (Scheme 1, step 2).
Benzoxazine (III) is then formed via the dehydration reaction of N-
methylol and phenol hydroxyl group (Scheme 1, step 3)
[1,2,13]. Moreover, many studies about the effects of different
reactant structures [13,16,19–22], reactant ratios [23,24], reaction
temperatures [15], solvent effect [25], and reaction duration [22]
have also been reported; results showed that these conditions can
influence benzoxazine yield and generate various byproducts.
formation of byproducts, remain unresolved, leading to the low 30
yield and poor purity of benzoxazine monomers, which may 31
complicate the purification process or influence the properties of 32
polybenzoxazines. These problems will further limit the develop- 33
ment of benzoxazine. Nonetheless, to the best of our knowledge, 34
the compositions and chemical structures of the synthetic 35
products have not been discussed in detail. The chemical 36
composition of the synthetic product is only a general description 37
of the product, dimer, and oligomer, and these indistinct 38
conclusions are insufficient to control the synthesis reaction from 39
the perspective of the reaction mechanism. Moreover, character- 40
izing the composition and chemical structure in a reaction mixture 41
is difficult with the use of spectroscopic techniques. Further 42
studies on the products of benzoxazine synthesis are needed.
43
This work aims to study the products from the reactions among 44
phenol, aniline, and formaldehyde. Elucidation of the compositions 45
and chemical structures of the crude products can provide 46
information in understanding the reaction paths in benzoxazine 47
synthesis. Thus, we focus on separating the compounds from the 48
crude products by using high-performance liquid chromatography 49
(HPLC), column chromatography (CC), and preparative HPLC. The 50
separated compounds are characterized by nuclear magnetic 51
resonance (NMR) and mass spectrometry (MS). Reaction paths of 52
*
Corresponding authors.
E-mail addresses: hawkyangpo@gmail.com (P. Yang), guyi@scu.edu.cn (Y. Gu).
http://dx.doi.org/10.1016/j.cclet.2014.12.005
1001-8417/ß 2014 Po Yang and Yi Gu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: C.-X. Zhang, et al., Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-
benzoxazine from phenol, aniline and formaldehyde, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.12.005

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CCLET 3174 1–5
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C.-X. Zhang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
R1
OH
O
N
CH2OH
Step 2
Step 1
Step 3
CH2OH
NH2R1
2
CH2O
R1
N
+
N
OH
R2
R2
CH2OH
R1
I
II
R2
III
Scheme 1. Reported reactions in benzoxazine synthesis from phenol, primary amine, and formaldehyde [1].
53
54
55
56
57
58
the synthesis from phenol, aniline, and formaldehyde are proposed
based on the results. N-hydroxymethyl aniline (HMA) derived from
the reaction between formaldehyde and aniline is probably the key
intermediate during the reaction. The results are beneficial for
further fundamental and systematic studies on the mechanism of
the benzoxazine synthesis.
2.3. Synthesis of 3,4-dihydro-2H-3-phenyl-1,3-benzoxazine
103
Stoichiometric amounts of aniline (0.2 mol, 18.6 g), phenol
(0.2 mol, 18.8 g) and aqueous formaldehyde solution (0.4 mol,
32.5 g) were dissolved in dioxane (50 mL) in a 150 mL three-
necked flask. The mixture was stirred and refluxed at 80 8C for 5 h.
The crude products were dried with anhydrous sodium sulfate, and
then the solvent was removed by rotary evaporation.
The crude products were separated firstly using gradient
solution column chromatography. Then the separative products
were further separated and purified by preparative HPLC. The
analytical data of the compounds separated from the crude
products were as follow:
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112
113
114
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2. Experiment
2.1. Materials and measurements
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Phenol and aniline (ꢀ99%, ACS) were obtained from Aladdin
chemistry Co., Ltd. Paraformaldehyde (ꢀ98%) was acquired from
Ercros Industrial S.A. Spain. Dioxane (ꢀ99%), toluene (ꢀ99%),
ethanol (ꢀ99%), and sodium sulfite (ꢀ97%) were purchased from
the Chengdu Kelong Chemical Reagents Corp. (China). All of the
reagents were used as received. Silica gel (200–300 mesh) for
column chromatography (CC) was purchased from Qingdao
Haiyang Chemical Co., Ltd. (China).
1H NMR, 13C NMR and 2D NMR spectra were performed on a
Bruker AV II-600 NMR, in which deuterated dimethyl sulfoxide
(DMSO-d6) was used as solvent and tetramethylsilane as internal
standard.
ꢂ
ꢂ
ꢂ
4-((Phenylamino)methyl)phenol (2): 1H NMR (600 MHz, DMSO-
d6): 9.23 (s, 1H), 7.14 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz),
6.69 (t, 2H, J = 4.3 Hz), 6.56 (d, 2H, J = 7.9 Hz), 6.48 (d, 1H,
J = 7.1 Hz), 6.01 (s, 1H), 4.11 (d, 2H, J = 5.9 Hz). 13C NMR
11167
d
118
119
120
121
122
123
(151 MHz, DMSO-d6):
d 156.56, 149.24, 130.63, 129.20,
128.91, 116.02, 115.47, 112.71, 46.55. HRMS (ESI) m/z
200.1073 [(MH)+; calcd. for C13H14NO: 200.1075].
2-((Phenylamino)methyl)phenol (3): 1H NMR (600 MHz, DMSO-
12245
d6):
d
9.49 (s, 1H), 7.17 (d, 1H, J = 7.4 Hz), 7.03 (t, 3H, J = 7.8 Hz),
126
127
128
129
130
131
6.81 (d, 1H, J = 8.0 Hz), 6.72 (t, 1H, J = 7.4 Hz), 6.56 (d, 2H,
J = 8.0 Hz), 6.49 (t, 1H, J = 7.2 Hz), 5.97 (t, 1H, J = 5.9 Hz), 4.18 (d,
Analytical HPLC was performed on a Waters 2695 Separations
Module equipped with a Waters 2996 phodediode array detector
and Empower workstation software (Waters, Milford, MA, USA).
2H, J = 5.9 Hz). 13C NMR (151 MHz, DMSO-d6):
d 155.47, 149.34,
129.23, 128.69, 127.88, 126.27, 119.22, 116.07, 115.36, 112.67,
41.88.
2,20-((Phenylimino)bis(methylene))bisphenol (4): 1H NMR
The CC was a SunFire C18 (150 mm ꢁ 4.6 mm, I.D. 5
mm) (Waters,
Milford, MA, USA). The gradient program was as follows: step 1,
45–95% acetonitrile over 25 min; step 2, 95% acetonitrile over
5 min; step 3, 45% acetonitrile over 5 min. The mobile phase was a
mixture of acetonitrile and water.
13323
(600 MHz, DMSO-d6):
d
9.57 (s, 1H), 7.06 (q, 2H, J = 8.0 Hz),
134
135
136
137
138
139
140
6.99 (d, 1H, J = 7.4 Hz), 6.84 (d, 1H, J = 7.9 Hz), 6.72 (t, 1H,
J = 7.4 Hz), 6.57 (d, 1H, J = 8.5 Hz), 6.54 (d, 1H, J = 7.2 Hz), 4.54 (s,
2H). 13C NMR (151 MHz, DMSO-d6):
d 155.51, 148.99, 129.38,
127.92, 127.39, 124.65, 119.30, 115.97, 115.42, 112.07,
49.80. HRMS (ESI) m/z 306.1497 [(MH)+; calcd. for C20H20NO2:
306.1494].
Preparative HPLC separations were performed on a PACK-N-
SEPTM dynamic axial chromatographic column: LC50.340.VE100
PS TH (I.D. 50 mm, length 340 mm, NovaSep, Pompey, France).
Packing material was ODS (S-10
mm, YMC Co., Ltd., Japan). The
column yielded a bed volume of 625 mL and void volume of
212 mL. The preparative HPLC system was equipped with HPG500
Pump (Sunyear Scientific Inc., Shanghai, China) and was monitored
by a Smartline UV 2500 detector (Knauer, Berlin, Germany).
Calesep workstation version 2.22 was used as the workstation
(Sunyear Scientific Inc., Shanghai, China).
All of the mass spectra were acquired using a Micromass Q-TOF
micro mass spectrometer (Waters Corp., Milford, MA, USA)
equipped with electrospray ionization source. All of the operations,
as well as data acquisition and analyses, were controlled using
Masslynx V4.1 software (Waters Corp., Milford, MA, USA).
ꢂ
ꢂ
3,4-Dihydro-2H-3-phenyl-1,3-benzoxazine
(6): 1H
NMR
14412
(600 MHz, DMSO-d6): 7.23 (t, 2H, J = 7.9 Hz), 7.13 (d, 2H,
d
143
144
145
146
147
J = 8.3 Hz), 7.10 (s, 1H), 7.08 (t, 1H, J = 7.8 Hz), 6.85 (t, 2H,
J = 7.5 Hz), 6.72 (d, 1H, J = 8.1 Hz), 5.44 (s, 2H), 4.65 (s, 2H). 13C
NMR (151 MHz, DMSO-d6):
d 154.43, 148.27, 129.56, 128.10,
127.64, 121.78, 120.93, 120.89, 117.80, 116.68, 79.11, 49.36.
2-((3-Phenyl-3,4-dihydroquinazolin-1(2H)-yl)methyl)phenol
14489
(7): 1H NMR (600 MHz, DMSO-d6)
d
9.59 (s, 1H), 7.19 (t, 2H,
150
151
152
153
154
155
156
157
158
J = 7.9 Hz), 7.07–6.99 (m, 4H), 6.97 (d, 1H, J = 7.2 Hz), 6.91 (t, 1H,
J = 7.4 Hz), 6.84 (d, 1H, J = 7.9 Hz), 6.78 (t, 1H, J = 7.2 Hz), 6.64 (t,
1H, J = 7.4 Hz), 6.56 (t, 1H, J = 7.3 Hz), 6.42 (d, 1H, J = 8.2 Hz), 4.85
(s, 2H), 4.58 (s, 2H), 4.39 (s, 2H,). 13C NMR (151 MHz, DMSO-d6):
155.40, 149.27, 145.20, 129.41, 128.23, 128.05, 127.75, 127.04,
124.70, 120.58, 119.67, 119.20, 116.94, 116.87, 115.41, 112.04,
66.88, 50.99, 48.46. HRMS (ESI) m/z 317.1650 [(MH)+; calcd. for
d
96
2.2. Preparation of aqueous formaldehyde solution
97
98
99
100
101
102
The aqueous formaldehyde solution was prepared as follows:
Approximately 70 g of water was adjusted to pH 8 using 4% NaOH
solution. Paraformaldehyde (30 g) was added, and the mixture was
stirred at 70 8C for 1 h to form a transparent solution with pH 5–6.
The concentration of formaldehyde was confirmed by titration
with sodium sulfite.
C
21H21N2O: 317.1654].
ꢂ
1,3,5-Triphenyl-1,3,5-triazinane (9): 1H NMR (600 MHz, DMSO-
15690
d6):
d
7.23–7.15 (m, 1H), 7.06 (d, 1H, J = 7.9 Hz), 6.78 (t, 1H,
161
162
163
J = 7.2 Hz), 4.90 (s, 1H). 13C NMR (151 MHz, DMSO-d6):
d 148.25,
128.90, 119.86, 116.80, 66.95.
Please cite this article in press as: C.-X. Zhang, et al., Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-
benzoxazine from phenol, aniline and formaldehyde, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.12.005

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C.-X. Zhang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
16
6
4
5
ꢂ
2,6-Bis((phenylamino) methyl) phenol (10): 1H NMR (600 MHz,
DMSO-d6): 8.84 (s, 1H), 7.10 (d, 2H, J = 7.5 Hz), 7.05 (t, 4H,
J = 7.8 Hz), 6.74 (t, 1H, J = 7.5 Hz), 6.60 (d, 4H, J = 7.9 Hz), 6.53 (t,
2H, J = 7.2 Hz), 6.01 (t, 2H, J = 5.2 Hz), 4.27 (d, 4H, J = 5.1 Hz). 13
NMR (151 MHz, DMSO-d6): 153.16, 149.22, 129.28, 127.09,
3.2. Reaction path inferred from the composition of synthetic products 213
166
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170
171
d
As mentioned above, this work aims to investigate the 214
reaction path of benzoxazine synthesis by analyzing the 215
composition of the final products. Previous studies claimed that 216
the benzoxazine synthesis is initiated by the reaction between 217
primary amine and formaldehyde to form the highly reactive 218
intermediate N,N-dihydroxymethylamine, which subsequently 219
reacted with other reactants or intermediates (Scheme 1, step 1) 220
[13], resulting in tertiary amine compounds. According to this 221
hypothesis, no secondary amine compounds should be formed 222
during this reaction. However, three secondary amine com- 223
pounds 2, 3 and 10 were found in the final products. Among all 224
C
d
126.95, 119.71, 116.49, 113.00, 65.39, 42.82. HRMS (ESI) m/z
305.1652 [(MH)+; calcd. for C20H21N2O: 305.1654].
172
173
3. Results and discussion
3.1. Composition analysis of the crude products
these compounds, the generation of compound
3 can be 225
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The reaction involving phenol, aniline, and formaldehyde at a
molar ratio of 1:1:2 occurred in the presence of dioxane. After this
reaction, the crude products were characterized by HPLC and the
results are presented in Fig. 1. Nine peaks (peaks 1–9) are found,
which probably suggest that the crude products contain nine
components. In order to study these components, CC and
preparative HPLC were applied to separate and purify the crude
products. Seven compounds were obtained, and their retention
times (RT) and UV absorption were assessed by HPLC. These
compounds corresponding to the peaks of 1, 2, 3, 4, 6, 7 and 9
(Fig. 1) were obtained. The chemical structures of these
compounds were elucidated by NMR and MS (see Supporting
information) and summarized in Table 1.
As shown in Table 1, almost no aniline was detected, whereas a
small amount of phenol (1) remained after reaction, and the most
abundant compound in these crude products was benzoxazine (6).
Three phenylaminomethyl moiety-containing compounds (com-
pounds 2, 3 and 10) were obtained. The difference between the
isomers (2 and 3) is the substituted positions of phenylamino-
methyl on phenolic rings. For compound 10, two ortho positions of
the hydroxyl group were substituted by phenylaminomethyl. In
addition, the tertiary amine moieties were observed in compound
4, 7, and 9. In the separation results, the compounds corresponding
to peaks 5 and 8 in Fig. 1 were not obtained. Preparative HPLC was
applied to separate the two compounds, which were separated
from the crude products and monitored by UV-detector. However,
when we used HPLC to confirm the collected solution, the
compounds corresponding to peaks 5 and 8 were observed, and
several new compounds were also detected. The phenomena
showed these two compounds corresponding to peaks 5 and
8 were unstable in the eluent, and can partially convert into some
new compounds easily. Therefore, resulting in no pure compounds
corresponding to peaks 5 and 8 were gained. Moreover, a
compound with RT of 13.486 min was separated from the crude
products, but almost no corresponding peak was observed in
Fig. 1. This is probably because the compound accumulated during
the repeated separation processes to a level that met the minimum
requirement of separation experiment, even though this com-
pound was only a small fraction of the crude products.
explained by the hydrolysis reaction of benzoxazine monomer. 226
Other compounds such as compounds 2 and 10 are very difficult 227
to obtain if the first step of the reaction is indeed between 228
formaldehyde and primary amine to generate N,N-dihydrox- 229
ymethlyamine. Therefore, N,N-dihydroxymethlyamine is not 230
likely the intermediate during benzoxazine synthesis. A more 231
reasonable intermediate probably is N-hydroxymethyl aniline 232
(HMA), which could be further transformed to compounds 2, 3 233
and 10, although no existence of HMA could be confirmed yet 234
[29,30]. In addition, in a previous report about benzoxazine 235
synthesis [10], the active intermediate of compound 9 could 236
also be generated from the self-reaction of HMA, which further 237
imply that HMA is possibly the key intermediate. The probable 238
path of the reaction may be as following: formaldehyde initially 239
reacts with primary amine to generate HMA, which subsequently 240
reacts with other reactants and intermediates to give the final 241
products.
242
To illustrate the reaction path during benzoxazine synthesis, 243
the reactions generated benzoxazine are denoted as the main 244
reaction, whereas the others are considered side reactions. Based 245
on the compositions and chemical structures of the synthetic 246
products, in the case of the main reaction, the favored path of 247
benzoxazine that was synthesized from phenol, aniline, and 248
formaldehyde is proposed (Scheme 2). The first step of reaction is 249
the formation of active intermediate HMA, which is derived from 250
the reaction between formaldehyde and primary amine. One HMA 251
molecule then reacts with the other HMA molecule to generate 252
compound 9, which can be converted into benzoxazine by reacting 253
with paraformaldehyde and phenol [10] (Scheme 2, path a). 254
However, if HMA attacks at the ortho position of phenol, then it will 255
form compound 3, which can also immediately transform into 256
benzoxazine via reaction with formaldehyde (Scheme 2, path b) 257
[31].
258
For the side reactions, when one HMA attack at the para 259
position of phenol, compound 2 is formed. Compound 10 can be 260
generated if HMA attacks at the ortho position of phenol ring of 261
compound 3. However, if compound 3 reacts with HMA and 262
formaldehyde, compound 7, which has a –N–CH2–N– structure, is 263
generated. Given that no N-hydroxymethyl Mannich base was 264
found in final products, compound 4 probably stems from the 265
reaction between benzoxazine and phenol as previously reported 266
[13].
267
Results of the reaction path indicate that HMA derived 268
from the reaction of aniline and formaldehyde is the key 269
intermediate during the synthesis of benzoxazine. Although 270
HMA was not observed in final products because of its high 271
activity, it is nonetheless acceptable given that the path can 272
illustrate the experiment very well. The reaction path of 273
benzoxazine synthesis is controlled by competing reactions of 274
HMA with different reactants and intermediates, and these 275
competing reactions determine the type and amount of the final 276
Fig. 1. The HPLC result of the crude products from the reaction among phenol,
aniline and formaldehyde.
products.
277
Please cite this article in press as: C.-X. Zhang, et al., Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-
benzoxazine from phenol, aniline and formaldehyde, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.12.005

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C.-X. Zhang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Table 1
Identification of compounds in the crude product from the reaction among aniline, phenol and formaldehyde.
Peak no.
1
RT (min)
lmax (nm)
Structure
Crude products
3.138
Separated
3.156
270.6
OH
1
2
6.091
5.807
246.9
OH
NH
2
3
7.343
7.339
244.5
OH
NH
3
4
9.526
9.478
252.8
OH
OH
N
4
5
6
10.307
11.406
Not obtained
11.558
241.0
275.3
O
N
6
7
14.032
13.931
250.5
OH
N
N
7
8
9
15.161
17.521
Not obtained
17.542
248.1
N
N
N
9
Not observed
13.486
241.0
287.9
OH
HN
10
NH
Please cite this article in press as: C.-X. Zhang, et al., Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-
benzoxazine from phenol, aniline and formaldehyde, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.12.005

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4. Conclusion
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In this work, the synthetic products of the reaction among
phenol, aniline, and formaldehyde were studied in detail. Seven
compounds were obtained and characterized. A possible reaction
path of benzoxazine synthesis from phenol, aniline and formalde-
hydewasproposedbasedontheresults. HMA, generatedfirstlyfrom
the reaction of formaldehyde and primary amine, is the key
intermediate. HMA can attack at the ortho position of phenol to
generate compound 3, which can immediately react with formal-
dehyde to form benzoxazine. HMAcan also react withformaldehyde
and aniline to form compound 9, which can transform into
benzoxazine through its reaction with phenol and formaldehyde.
However, when HMA reacts with other intermediates and reactants,
side reactions occur to form byproducts such as compound 2. The
results of this study will help researchers to understand the
synthesis of benzoxazine, as well as the design and development of
novel benzoxazines.
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Acknowledgment
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
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Please cite this article in press as: C.-X. Zhang, et al., Study on products and reaction paths for synthesis of 3,4-dihydro-2H-3-phenyl-1,3-
benzoxazine from phenol, aniline and formaldehyde, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.12.005