Design of experiments on the transesterification of tris(p-nitrophenyl) phosphate with sodium methoxide

Article abstract of DOI:10.1080/104265090509171

A design of experiments was conducted to study the transesterification of tris(p-nitrophenyl) phosphate with sodium methoxide. The factorial design was performed to check the experimental conditions that favored ths yield of bis(p-nitrophenyl) methyl phosphate in a semi-batch process. The experiments were performed using a Mettler RC1 calorimeter. The reaction temperature, the addition order of reagents and the time spent in those additions were analyzed at two different levels. The results showed the addition order of reagents as the most important factor to guarantee the improvement of the reaction yielding bis(p-nitrophenyl) methyl phosphate. It was demonstrated that the temperature has a small effect on the reaction yield between 5 and 30°C. An important effect was observed with regard to the addition time of reagents and yield: when the tris(p-nitrophenyl)phosphate is added to the methoxide solution (58% on average) while no effect was observed when the methoxide solution was added to the phosphate (87% on average). Theses results indicated that the addition could be made in times shorter than five minutes under the latter condition. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090509171

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Design of Experiments on the
Transesterification of tris(p-
nitrophenyl) Phosphate with
Sodium Methoxide
a
a
Rafael C. Seiceira , Hatumi T. Nakayama , Claudio
a
a
Costa Neto , João F. Cajaiba da Silva & Marcelo S.
b
Pedrosa
a
Uníversidade Federal do Rio de Janeiro, Instituto
de Quimica, Departamento de Química Orgânica,
Pólo de Xistoquímica , Rio de Janeiro, Brazil
b
Unigranrio, Instituto de Ciências Exatas e da
Natureza, Duque de Caxias and Cefet Química,
Nilópolis , Rio de Janeiro, Brazil
Published online: 21 Dec 2010.
To cite this article: Rafael C. Seiceira , Hatumi T. Nakayama , Claudio Costa Neto ,
João F. Cajaiba da Silva & Marcelo S. Pedrosa (2005) Design of Experiments on
the Transesterification of tris(p-nitrophenyl) Phosphate with Sodium Methoxide,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:2, 389-395, DOI:
10.1080/104265090509171
To link to this article: http://dx.doi.org/10.1080/104265090509171
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Phosphorus, Sulfur, and Silicon, 180:389–395, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090509171
Design of Experiments on the Transesterification of
tris(p-nitrophenyl) Phosphate with Sodium Methoxide
Rafael C. Seiceira
Hatumi T. Nakayama
Claudio Costa Neto
Jo a˜ o F. Cajaiba da Silva
Un `ı versidade Federal do Rio de Janeiro, Instituto de Quimica,
Departamento de Qu ´ı mica Org aˆ nica, P o´ lo de Xistoqu ´ı mica, Rio de
Janeiro, Brazil
Marcelo S. Pedrosa
Unigranrio, Instituto de Ci eˆ ncias Exatas e da Natureza, Duque de
Caxias and Cefet Qu ´ı mica, Nil o´ polis, Rio de Janeiro, Brazil
A design of experiments was conducted to study the transesterification of tris(p-
nitrophenyl) phosphate with sodium methoxide. The factorial design was performed
to check the experimental conditions that favored ths yield of bis(p-nitrophenyl)
methyl phosphate in a semi-batch process. The experiments were performed using a
Mettler RC1 calorimeter. The reaction temperature, the addition order of reagents
and the time spent in those additions were analyzed at two different levels. The
results showed the addition order of reagents as the most important factor to guar-
antee the improvement of the reaction yielding bis(p-nitrophenyl) methyl phosphate.
It was demonstrated that the temperature has a small effect on the reaction yield be-
◦
tween 5 and 30 C. An important effect was observed with regard to the addition time
of reagents and yield: when the tris(p-nitrophenyl)phosphate is added to the methox-
ide solution (58% on average) while no effect was observed when the methoxide solu-
tion was added to the phosphate (87% on average). Theses results indicated that the
addition could be made in times shorter than five minutes under the latter condition.
Keywords Design of experiments; transesterification; triaryl phosphates
INTRODUCTION
The procedures available to synthesize esters of phosphoric acid
containing alkyl and aryl groups, employ phosphorus oxychloride,
Received April 20, 2004; in final form June 30, 2004.
Acknowledgement: We thank FINEP and CAPES for the financial support.
Address correspondence to Jo a˜ o F. Cajaiba da Silva, Rua Pojuca, 208 Casa 4-Rio de
Janeiro, Rio de Janeiro 21930-180, Brazil. E-mail: cajaiba@iq.ufrj.br
389

3
90
R. C. Seiceira et al.
phosphorodichloridates, pyrophosphates and the transesterification of
aromatic phosphates.1
A procedure, described in the literature, to prepare bis(p-
nitrophenyl)methyl phosphates from tris(p-nitrophenyl)phosphate
with sodium alkoxides, stated that it is necessary to keep the reac-
tion media at low temperatures and the alkoxide addition should be as
2
slow as possible. Nevertheless, smilar products were obtained in high
3
yields using shorter addition times. This paper intends to clarify the
effect of the temperature, addition time and order of reagent addition
on the yield of bis(p-nitrophenyl)methyl phosphate.
RESULTS AND DISCUSSION
Bis(p-nitrophenyl)methyl phosphate 2 was prepared by equimolar reac-
tion of tris(p-nitrophenyl)phosphate 1 and a sodium methoxide solution,
as shown in Scheme 1.
SCHEME 1
The effects of the temperature, order of reagent addition, and time
spent in the additions on the product yields were evaluated through
a full three factor-two level design of experiments (DOE) as shown in
Table I.
Temperature and the addition time showed negative effects on yield
and the order of reagent addition presented a positive result. A syner-
gism between addition order ard addition time factors was observed as
mathematically expressed by the Eq. (1)
%2 = +68.48 − 3.02.A − 1.89.B + 17.23.C + 2.03.B.C
(1)
where: A = temperature, B = addition time and C = addition order.
Higher yields were always obtained when methoxyde was added to
the tris(p-nitrophenyl) phosphate (86.5% on average) instead of the in-
verse order (57.7%), that favors products of multiple exchanges.

Transesterification of tris-(p-nitrophenyl)phosphate
391
TABLE I Reaction Conditions and Yield of 2
Factor B
addition time
(min)
2
Experiment
Experiment
Factor A
Factor C
addition order
yield
(%)
◦
a
(
standard order) (run order) temperature ( C)
5
6
4
8
9
1
4
1
6
7
3
2
5
3
0
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
−15
−15
−15
30
30
30
30
30
5
5
5
5
30
30
30
5
30
5
Phos in mtx
Phos in mtx
mtx in phos
Phos in mtx
mtx in phos
mtx in phos
Phos in mtx
Phos in mtx
mtx in phos
Phos in mtx
mtx in phos
mtx in phos
mtx in phos
Phos in mtx
mtx in phos
Phos in mtx
51.2
51.0
88.7
43.9
87.3
84.0
52.2
58.0
82.2
43.1
89.4
83.2
83.2
51.9
87.9
58.6
1
1
1
−15
30
30
−15
30
30
1
1
1
−15
30
30
30
1
−15
5
5
−15
aPhos in mtx means: addition of 1 to sodium methoxide solution. mtx in phos means:
addition of sodium methoxide to 1.
It can be also observed that the temperature effects are indepen-
dent of the addition order. It was not possible to verify any signifi-
cant synergic effect between temperature and addition order. Thus, a
◦
◦
temperature rise from −15 C to 30 C led to a reduction of the bis(p-
nitrophenylmethyl)phosphate yield of about 4–7%, regardless of the
addition order. These yield differences do not justify the more expen-
sive conditions of keeping lower temperatures.
The synergic effect between the time and addition order observed in
Figure 1 shows that the yields were not significantly affected by the
addition time when methoxide was added to the phosphate solution,
but if this order was inverted the yields could be increased with shorter
addition times. However, the best yield was always obtained by the first
addition procedure.
The negligible effect of the addition time on the yield of the reaction
when methoxide was added to the aryl phosphate shows that this reac-
tion could be carried out in less time. It suggests that the reaction that
led to the first exchange product 2 is faster than the two subsequent
exchange reactions. This observation is in accord with a nucleophilic
substitution mechanism where the positive charge on the phosphorus
decreases when an aryl group is displaced by an alkyl group.3

3
92
R. C. Seiceira et al.
FIGURE 1 The synergic effect between addition time and the addition order
factors.
To check if the above observations could be applied to the transes-
terification of other aromatic phosphates with sodium alkoxides, the
products showed in Scheme 2 were prepared by simultaneous addi-
tion of the aromatic phosphate and the alkoxide in methylene chloride
TABLE II Spectrometric data of the diaryl alkyl phosphates
presented in Scheme 2
MS
NMR
FTIR
P O C
Base
peak
(m/z) (m/z)
1H
31P
(δ ppm)
+−
M
P O
(cm 1)
−
−1
(cm )
NO
(δ ppm)
2
3
4
5
6
7
8
9
4.1, 7.5, 8.3
1.5, 4.5, 7.5, 8.3
4.0, 7.2, 7.3
1.4, 4.3, 7.2, 7.3
0.95, 1.7, 4.2, 7.2, 7.3
4.1, 7.2, 7.3, 7.4
1.4, 4.4, 7.3, 7.4
0, 97, 1.8, 4.3, 7.4
−14.8
−15.8
−13.4
14.3
1299
1291
1299
1300
1297
1199, 1053, 951
1201, 1030, 949
1196, 1051, 958
1196, 1042, 962
1196, 1015, 954
—
—
—
—
127 332
128 346
128 360
−14.2
−14.2 1305, 1257 1223, 1102, 1065, 940 133 402
−15.2 1312, 1260 1226, 1102, 1065, 940 363 416
−15.1 1300, 1256 1223, 1101, 1056, 1024 351 430
1
1
1
0
1
2
0.91, 1.4, 1.7, 4.4, 7.3, 7.4 −15.1 1305, 1256 101, 105, 1036, 952
351 444
0.93, 1.7, 4.4, 7.2, 7.4
−15.1 1305, 1257 1225, 1101, 1058, 1018 243 458
15.1 1305, 1258 1224, 1101, 1056, 1021 162 472
0.91, 1.3, 1.7, 4.4, 7.3, 7.4

Transesterification of tris-(p-nitrophenyl)phosphate
393
SCHEME 2
solvent. The diaryl alkyl phosphates were obtained in yields ranging
from 79–85%. All compounds were purified by flash chromatograpy us-
ing hexane/ethyl acetate (30%) as an eluent. The characterization of
1
31
the products was achieved using FTIR, CG-MS, and H, and P NMR
as shown in Table II.
CONCLUSION
It was verified that it is not necessary to use low temperatures and long
addition times to obtain high yields of diaryl alkyl phosphates through

3
94
R. C. Seiceira et al.
the trasesterification of triaryl phosphates, contrary to what has been
mentioned in the literature.
EXPERIMENTAL SECTION
The design of experiments were analysed using the Design Ease pro-
gram from State Ease Inc. in Minneapolis, USA.
Infrared spectra were recorded on a Nicolet 740 FTIR spectropho-
1
31
tometer. H NMR (200 MHz) and P NMR (81 MHz) spectra were
recorded on a Bruker HC200, CDCl3 was used as solvent and chemical
shifts were expressed in δ (ppm) units using TMS as internal reference
1
31
for H spectra and H3PO4 (85%) as external reference for P. Electron
impact mass spectra were recorded on a Hewlett-Packard 5790 at 70 eV.
The symmetrical phosphates used us starting compounds for
the preparation of the diaryl alkyl phosphates 2–12, (tris(p-
nitrophenyl) phosphate, tris(p-chlorophenyl) phosphate, and tris(2:4-
dichlorophenyl) phosphate) were prepared by a one-pot methodology.
Bis(p-nitrophenyl) phosphate
The experiments were performed using a Mettler Toledo RC1 calorime-
5
ter. A complete description of this reactor can be found in the literature.
The RC1 vessel was charged with 1.150 L of dichloromethane and
23 g of tris(p-nitrophenyl) phosphate were manually transferred to
the vessel. The speed of the anchor agitator was kept constant at 150
rpm. The reaction was initiated when a methanolic solultion of sodium
methoxyde (1.15 g of sodium per 75 mL methanol) was added to the
tri(p-nitrophenyl)phosphate solution (5 or 30 minutes). The same con-
centration of reagents (0.05 mol/L) were used in the reactions in which
tris(p-nitrophenyl) phosphate was added to methoxide. After the ad-
dition, the mixture was transfered to an 1.5 L Erlenmeyer flask and
the percipitated sodium p-nitrophenoxide was filtered off. The filtrate
was repeatedly washed with cold water until the washings were color-
less. The methylene chloride was removed by distillation. The resulting
solid bis(p-nitrophenyl)methyl phosphate was recrystallized from ethyl
acetate.
Diaryl Alkyl Phosphates
Compounds 3–12
A methanolic solution of sodium methoxide (1.15 g of sodium per
100 mL of methanol) was added in a few seconds to a stirred solu-
tion of 0.005 mol of the appropriate triaryl phosphate in 100 mL of

Transesterification of tris-(p-nitrophenyl)phosphate
395
methylene chloride at room temperature. The reaction was stirred for
0 minutes and the precipitated sodium phenoxide was filtered off. The
1
filtrate was washed repeatedly with cold water. The methylene chloride
was removed by distillation. The yields for the products were between
79–85%.
REFERENCES
[
1] G. M. Kosolapoff and L. Maier, Organic Phosphorus Compounds. Vol. 6. (New York,
J. Wiley, 1972).
[
[
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Sulfur, 131, 97 (1997).
[
4] J. F. Cajaiba da Silva, H. T. Nakayama, and C. Costa Neto, Phosph. Sulfur, 131, 71
(
1997).
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[
3