Synthesis of α-hydroxyphosphonate cyclotriphosphazene under solvent-free conditions with a basic catalyst

Article abstract of DOI:10.1080/10426507.2016.1166503

An α-hydroxyphosphonate cyclotriphosphazene compound, hexa-(4-diethylphosphate-hydroxymethyl-phenoxy)-cyclotriphosphazene) (HDHPCP), was synthesized in two steps. First, the intermediate hexa-(4-aldehyde-phenoxy)-cyclotriphosphazene (HAPCP) was synthesize

Full text of DOI:10.1080/10426507.2016.1166503

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of α-hydroxyphosphonate
cyclotriphosphazene under solvent-free conditions
with a basic catalyst
Lisheng Zhou, Guangcheng Zhang, Jianwei Li & Yunjie Feng
To cite this article: Lisheng Zhou, Guangcheng Zhang, Jianwei Li & Yunjie Feng (2016):
Synthesis of α-hydroxyphosphonate cyclotriphosphazene under solvent-free conditions
with a basic catalyst, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2016.1166503
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1166503
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Synthesis of α-hydroxyphosphonate cyclotriphosphazene under solvent-free conditions with
a basic catalyst
Lisheng Zhou, Guangcheng Zhang, Jianwei Li, Yunjie Feng
MOE Key Lab of Applied Physics and Chemistry in Space, Department of Applied Chemistry,
College of Science, Northwestern Polytechnical University, Xi’an, 710072, China
Corresponding Author E-mail: zhangguc@nwpu.edu.cn
Abstract
An α-hydroxyphosphonate cyclotriphosphazene compound, hexa-(4- diethylphosphate-
hydroxymethyl- phenoxy)-cyclotriphosphazene) (HDHPCP), was synthesized in two steps.
Firstly, the intermediate hexa-(4-aldehyde-phenoxy)-cyclotriphosphazene (HAPCP) was
synthesized by the elimination reaction of hexachlorocyctriphosphazene (HCCP) with
4-hydroxybenzaldehyde. Then, HDHPCP was obtained by Pudovik reaction under solvent free
condition. In this step, the effects of the type and amount of catalyst on reaction time and yield
were investigated, and it was found that triethylamine (TEA) has better activity than KF and
K2CO3. When the molar ratio of HAPCP to TEA was 1:5, the reaction gave an excellent yield of
95.4% in 70 min. Under these conditions, the reaction was easy to work-up, time-saving,
environmentally benign and with high yield. FTIR, NMR and elemental analysis results confirmed
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that HDHPCP was synthesized successfully, and the TGA measurement indicated that it presents
good thermal stability and high char residual.
Keywords
cyclotriphosphazene, α-hydroxyphosphonate, Pudovik reaction, solvent-free condition
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Introduction
Organophosphorus compounds have drawn much attention in recent years, because these
compounds have a wide range of applications in the areas of medicinal, agricultural and industrial
chemistry according to their biological and physical properties[1-6]
.
Hexachlorocyclotriphosphazene (HCCP), with a six-membered ring backbone of alternating
phosphorus and nitrogen atoms, is the most important intermediate in the field of
polyphosphazenes. In HCCP, the P-Cl bonds with high activity are easy to react with nucleophilic
reagents, such as sodium alkoxides or aryloxides, primary or secondary amines, or organometallic
compounds. Therefore, cyclophosphazene derivatives with diverse physical and chemical
properties have been prepared by reaction with different nucleophiles[7]. The special structures of
cyclophosphazenes provide these materials with good fire resistant behaviors due to their high
phosphorus content [8-12]. Besides, the functional materials based on cyclophosphazenes, which
with properties of optical[13-15], photoresponsive liquid-crystalline[16], or biological activities[17, 18]
,
have also been reported.
Meanwhile, among known organophosphorus compounds, phosphonates have received
considerable attention due to their biological activities[19, 20], flame retardant properties[21-24], metal
chelating properties[25, 26] and biodegradabilities[27]. α-Hydroxyphosphonates are compounds of
significant biological activities, such as renin inhibitors[28, 29], HIV proteases[30], antibacterial
agents[31, 32], and enzyme inhibitors[33]. α-Hydroxyphosphonates are most frequently synthesized
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using the so-called Pudovik reaction, which is the addition of dialkyl or diaryl H-phosphonates to
carbonyl compounds[34, 35]. This atom-economic and straightforward protocol can be successfully
performed under environmentally friendly conditions. Fully esterified phosphites such as the
addition of triethyl or trimethyl phosphite to carbonyl compounds are synthesized by the so-called
Abramov reaction (seen in Scheme 1)[1]. In the structure, R1 represents organic group, R2 and R3
represent organic groups or H atoms, respectively. In recent years, solvent-free reactions in the
field of organic synthesis have drawn much attention. Solvent free conditions have advantages
compared with tradition organic reactions in a solvent medium, such as being environmentally
benign, economically beneficial, usually time saving, and with high yields[36, 37]
.
By considering all of the above aspects, we synthesized an α-hydroxyphosphonate
cyclotriphosphazene, hexa-(4- diethylphosphate- hydroxymethyl- phenoxy)-cyclotriphosphazene)
(HDHPCP), in two steps. In the first step, the intermediate HAPCP was synthesized according to
the literature[10, 38]. In the second step, the target molecule HDHPCP was obtained by Pudovik
reaction under solvent-free condition with base catalyst. As reported by Kamalakar[39] that in the
Pudovik reaction, acid catalysts had less activities than base catalysts, so we chose three bases, KF,
K2CO3 and TEA, as catalysts. The chemical structure of HDHPCP was characterized by FT-IR，
1H NMR, 13C NMR, 31P NMR, elemental analysis, and its thermal stability was evaluated by TGA.
Results and discussion
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Synthesis of HDHPCP
HDHPCP was prepared in two steps from HCCP (Scheme 2). In the first step, HAPCP was
obtained by the elimination reaction of HCCP with 4-hydroxybenzaldehyde. In the second step,
HDHPCP was synthesized by a Pudovik reaction between HAPCP and diethyl phosphate in the
presence of a base as catalyst under solvent free condition. In this step, three different bases (KF,
K2CO3 and TEA) were chose as catalysts to optimize of the experimental conditions.
Table 1 shows the results of HAPCP reacting with diethyl phosphate at different type and
amount of catalysts. When KF and K2CO3 are selected as catalysts, the investigated molar ratios of
HAPCP to catalyst are 1:6, 1:12, 1:18 and 1:24, respectively. With an increasing amount of
catalyst, the reaction time decreased, but the yields show different situations. Because the reaction
proceeds under solvent free condition, the reaction mixture usually became solidified when it is
completed, this can also act as a criterion for the end of the reaction. As the reaction progressed,
the viscosity of the mixture increased gradually until it can’t be stirred, which proved to be the
ending of the reaction. The preferable molar ratios for HAPCP to KF and K2CO3 were found to be
1:24 and 1:12. When TEA is selected as the catalyst of this reaction, there are some differences of
experimental conditions and reaction phenomena from those observed when KF and K2CO3 acting
as catalyst.
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The molar ratios of HAPCP to TEA are investigated at the range from 1:1 to 1:6. When the
molar ratio is 1:1, no desirable product is detected after the reaction was stirred at room
temperature for 24 h. It can also be found that when the molar ratio is 1:5 an excellent yield 95.4%
was obtained in 70 min. Not only acting as a catalyst, we speculate that TEA still acts as solvent in
some extent. Because unlike being solidified when KF and K2CO3 act as catalyst, the reaction
mixture can be stirred continually, which is also benefit for the reaction to continue and produce a
high yield. By contrasting these three catalysts, TEA shows better catalytic effect in yields and
reaction times.
Characterization of HDHPCP
The chemical structures of HAPCP and HDHPCP were characterized by 1H, 13C, 31P NMR
and FTIR spectroscopy. The NMR and FTIR data obtained for HAPCP are in agreement with
previous studies[8, 10, 38]. The 1H NMR spectrum of HDHPCP is shown in Figure S 1 (available
online in Supplemental Materials). The signal peaks at 7.27 ppm and 6.96-6.72 ppm are
contributed to benzene ring protons, the peak at 5.00 ppm is assigned to hydroxyl protons. The
ethyl protons are detected at 3.99 ppm and 1.39-1.03 ppm. In the 13C NMR spectrum of HDHPCP
(Figure S 2), C-6 is found with different chemical shifts (63.1 and 63.5 ppm), this may attribute to
the P atom being attached to a chiral carbon (C-5), and thus the substituents on the P atom are
nonequivalent. Furthermore, being affected by the adjacent P atom, the C-5 is detected as split
peaks at 68.9 and 70.5 ppm. Other chemical shifts (ppm) are assigned to the aromatic carbon
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resonances: 149.9 (C1), 134.1 (C3), 128.5 (C4), 120.5 (C2). In the corresponding 31P NMR
spectrum (Figure S 3), two peaks at chemical shifts at 21.8 and 9.3 ppm are assigned to the
phosphorus atoms in phosphonate and cyclotriphosphazene structure of HDHPCP, respectively.
The FTIR spectrum of HDHPCP (Figure S4) exhibits absorption peaks at 1210 cm1 and 1180
cm1 corresponding to the P = N stretching vibration of cyclophosphazene ring. The strong
absorption peaks at 1160 cm1 and 955 cm1 reveal the presence of a phosphazene structure
(P-O-Ph). The spectrum of HAPCP shows the absorption peaks at 2825, 2733 and 1707 cm1
illustrating the presence of the aldehyde group (-CHO), whereas in the spectrum of HDHPCP,
these peaks disappear, and strong absorption peak at 3278 cm1 takes place corresponding to the
hydroxyl stretching (-OH). Furthermore, the absorption peaks at 2980 and 2906 cm1 are attributed
to the stretching vibration -CH2CH3.
The characterization results of FTIR, NMR and elemental analysis confirm the chemical
structure of HDHPCP, indicating that HDHPCP was successfully synthesized. Although the
compound has been reported, the synthesis method presented in this paper is different compared
with the reported method[40, 41]. And the results indicate that the solvent free condition is
convenient to operate, time saving and high yield compared with tradition method.
Thermal analysis of HDHPCP
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The thermal stability of HDHPCP was investigated using themogravimetric analysis (TGA)
and derivative thermogravimetry (DTG) in the temperature range from room temperature to 850°C
in air, and the corresponding TGA/DTG curve is shown in Figure 1. The slight weight loss occur
below 150°C may attributed to the evaporation of the residual solvent and loss of adsorbed water.
The initial decomposition temperature (T5) of HDHPCP is 196°C. According to the DGT curve,
the thermal degradation occurs mainly in four steps. The first weight loss interval at 169-255°C
(weight loss = 18.4 wt%), with the maximum degradation rate at 220°C, is probably due to the
cleavage of P-OEt bonds. The second weight loss interval is in range of 255-330°C and the
maximum degradation rate peak appears at 282°C. During this stage, 6.8 wt% weight loss of
original sample occurs, which may be attributed to the intramolecular or intermolecular
dehydration of the hydroxyl groups. The third decomposition stage in the temperature range of
355-435°C may be related to the release of phosphoric acid or metaphosphoric acid, with a minor
weight loss (2.8 wt%). The last stage loss occurs at higher temperature range from 570 to 810°C
probably due to the cleavage of aryloxy groups. Above 700°C, the TGA curve becomes more flat.
The char yields of HDHPCP at temperature of 600°C and 800°C are 53.7% and 18.0%,
respectively, meaning that this compound has good thermal stability.
Experimental Section
Materials
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Hexachlorocyclotriphosphazene (HCCP) was purchased from Shandong Lanyin Chemical
Co. Ltd., China. Diethyl phosphate and p-hydroxybenzaldehyde were purchased from Sinopharm
Chemical Reagent Co. Ltd. Anhydrous KF was obtained from Aladdin Industrial Inc. K2CO3 and
triethylamine were purchased from Tianjin Kemiou Chemical Reagent Co. Ltd., China. All
solvents were purchased from commercial sources and purified by standard methods.
Characterization
1H, 13C and 31P NMR spectra were recorded on a Bruker Advance 400-MHz spectrometer
operated at 400, 101 and 162 MHz, respectively. The spectra were recorded with TMS as internal
standard or with 85% phosphoric acid aqueous as external reference. Fourier transform infrared
(FTIR) spectra were characterized on potassium bromide discs and Perkin Elmer 400 spectrometer
(USA). TGA measurements were carried out on a TA thermogravimetric analyzer Q50.
Specimens of about 20 mg were heated from room temperature to 850°C at a rate of 20°C/min in
air. Elemental analyse was determined on a Perkin Elmer 2400 CHNS/O Analyzer.
Synthesis of HAPCP and HDHPCP
Synthesis of hexa-(4-aldehyde-phenoxy)-cyclotriphosphazene (HAPCP)
In a three-neck round-bottom flask equipped with a reflux condenser and a constant drip
funnel, HCCP (5.0 g, 14.4 mmol) and K2CO3 (25.8 g, 187.0 mmol) were stirred in THF (100 mL)
in an ice bath under nitrogen atmosphere. Simultaneously, p-hydroxybenzaldehyde (12.3 g, 10.1
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mmol) in THF (50 mL) was added into the above mixture dropwise. Then, the reaction mixture
was heated to reflux and then allowed to stir vigorously for 24 h. After that, the mixture was
filtered and the filtration was concentrated on a rotary evaporator. The obtained crude product was
recrystallized from chloroform/petroleum ether and then washed by ethanol and dried in vacuum.
Finally, HAPCP was obtained as white solid powder.
Yield: 89%. 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.5
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 190.5 (-CHO), 154.5, 133.8, 131.5, 121.3(-C6H4). 31P
NMR (162 MHz, CDCl3) δ 7.3.
Synthesis of hexa-(4- diethylphosphate- hydroxymethyl- phenoxy)-cyclotriphosphazene)
(HDHPCP)
HAPCP (1 eq.) and diethyl phosphate (7 eq.) were placed in a round-bottom flask, and stirred
at room temperature for 30 min. A certain amount of catalyst (KF, K2CO3 or TEA) was added to
the above mixture and stirred until it completed. The crude product was dissolved in DCM,
extracted and the obtained solvent was concentrated to yield HDHPCP as a white solid
(hygroscopic). Further purification of HDHPCP was by recrystallization from DCM/ petroleum
ether.
1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 16.3 Hz, 12H), 6.96-6.72 (m, 12H), 5.00 (dd, J = 25.0,
13.2 Hz, 6H), 3.99 (dd, J = 35.7, 7.0 Hz, 24H), 1.39 -1.03 (m, 36H). 13C NMR (101 MHz, CDCl3)
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δ 149.9, 134.1, 128.5, 120.5 (-C6H4), 69.3 (-C-OH), 63.4 (-CH2CH3), 16.4 (-CH2CH3). 31P NMR
(162 MHz, CDCl3) δ 21.8, 9.3. Anal. Calcd for C66H96N3O30P9 : C, 46.90; H, 5.73; N, 2.49. Found:
C, 46.84; H, 5.76; N, 2.47.
Conclusion
α-Hydroxyphosphonate cyclotriphosphazene, HDHPCP, was successfully synthesized in two
steps from hexachlorocyclotriphosphazene. In the synthesis of HDHPCP from HAPCP, solvent
free condition was used and three base catalysts were selected and explored the effects of different
catalyst and amount to the reaction times and yields. The results indicated that TEA had better
catalytic effect compared to KF and K2CO3. When the molar ratio of HAPCP to TEA is 1:5 gives
an excellent yield of 95.4% in 70 min, which is much faster and higher yield than tradition method
in organic solvent. It is speculated that this may because TEA not only act as catalyst during the
reaction, but also play the role of solvent to be convenient for the molecular motion, thus
promoting the reaction. The chemical structure of HDHPCP was characterized by FT-IR，1H
NMR, 13C NMR, 31P NMR, elemental analysis, and the thermal stability was measured by TGA.
According to the obtained results, HDHPCP may has potential flame retardant property, and the
performance of related research will be done in our later works. In conclusion, we have develpoed
a highly efficient, environmentally friendly synthesis of α-hydroxyphosphonate
cyclotriphosphazene under solvent free condition with base catalyst. This method provides method
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for the preparation of α-hydroxyphosphonates and will be increasingly necessary for phosphazene
commercialization.
Acknowledgements
This study was supported by the National Science Foundation of Shaanxi Province
(2015JM5231), and the Overall Scientific and Technological Innovation Program of Shaanxi
Province (2013SZS17-Z01), foundation for the Fundamental Research Funds for Central
Universities (20151099201).
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Table 1. Synthesis of HDHPCP with different amounts of catalystsa
Entry
1
Catalyst
KF
Molar ratiob
1:6
Time
4.5 h
2 h
Yieldc %
66.3
KF
1:12
1:18
1:24
1:6
82.7
2
KF
1.5 h
40 min
10 h
6 h
76.5
3
KF
83.2
4
K2CO3
K2CO3
K2CO3
K2CO3
TEA
TEA
TEA
TEA
TEA
TEA
89.8
5
1:12
1:18
1:24
1:1
90.3
6
5 h
80.1
7
2 h
77.0
8
24 h
6 h
No Reaction
77.6
9
1:2
10
11
12
13
14
1:3
4 h
79.6
1:4
1.5 h
70 min
40 min
92.9
1:5
95.4
1:6
93.9
aReaction condition: 1 mmol HAPCP, 7 mmol diethyl phosphate, catalyst, r.t.
bMolar ratio of HAPCP with catalyst
cIsolated purified product.
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Figure 1. TGA/DTG curve of HDHPCP
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Scheme 1. Synthesis protocols of α-hydroxyphosphonates
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Scheme 2. Synthetic route for HDHPCP
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