Synthesis and proton dissociation properties of arylphosphonates: A microwave-assisted catalytic arbuzov reaction with aryl bromides

Article abstract of DOI:10.1002/hc.21053

A series of substituted diethyl arylphosphonates was synthesized by the microwave-assisted Arbuzov reaction of triethyl phosphite and aryl bromides in the presence of NiCl₂ as the catalyst under solvent-free conditions in good yields. The resulting phosphonates were hydrolyzed to the corresponding arylphosphonic acids whose acidity was evaluated by physicochemical methods.

Full text of DOI:10.1002/hc.21053

Heteroatom Chemistry
Volume 23, Number 6, 2012
Synthesis and Proton Dissociation Properties
of Arylphosphonates: A Microwave-Assisted
Catalytic Arbuzov Reaction with Aryl Bromides
Gyo¨rgy Keglevich,1 Alajos Gru¨n,1,2 Adrienn Bo¨lcskei,1
La´szlo´ Drahos,3 Ma´rta Kraszni,4 and Gyo¨rgy T. Balogh5
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2Research Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
3Hungarian Academy of Sciences, Chemical Research Center, 1525 Budapest, Hungary
4Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary
5Gedeon Richter Plc., 10, P.O. Box 27, 1475 Budapest, Hungary
Received 30 May 2012; revised 27 August 2012
by the reaction of dialkyl chlorophosphates with
ABSTRACT: A series of substituted diethyl arylphos-
metal organic reagents, such as aryl lithium or aryl-
phonates was synthesized by the microwave-assisted
magnesium bromide [2]. The catalytic phosphony-
Arbuzov reaction of triethyl phosphite and aryl bro-
lation of arenes with dialkyl phosphites was also de-
mides in the presence of NiCl2 as the catalyst
scribed using a Mn(II)/Co(II)/O2 redox couple [3].
under solvent-free conditions in good yields. The re-
Perhaps the best method for the synthesis of a spe-
sulting phosphonates were hydrolyzed to the corre-
cial group of phosphonates, arylphosphonates, com-
sponding arylphosphonic acids whose acidity was
prises the coupling of aryl halides with dialkyl phos-
ꢀC
evaluated by physicochemical methods.
2012 Wi-
phites in the presence of catalysts that are most often
Pd(PPh3)4, CuI, or Pd(OAc)2 (with an additive) also
requiring the presence of a base [4–9]. In a typical
procedure, the components are stirred in toluene at
70–90◦C for 4–24 h to afford the arylphosphonates
in good yields.
ley Periodicals, Inc. Heteroatom Chem 23:574–
582, 2012; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.21053
The synthesis of arylphosphonates by the Ar-
buzov reaction is prevented by the decreased reac-
tivity of aryl halides. However, under photochem-
ical conditions, the reaction of aryl iodides with
trialkyl phosphites afforded dialkyl arylphospho-
nates [10–12]. Catalysts like nickel-chloride also pro-
moted the reactions under discussion. Thus, reacting
aryl bromides and triethyl phosphite at 150–160◦C,
the arylphosphonates were obtained in 60–90%
yields [13]. Later on, the Arbuzov reaction was also
accomplished under solventless microwave (MW)
INTRODUCTION
Phosphonates are versatile intermediates in syn-
thetic organic chemistry [1]. They can be prepared
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu
Contract grant sponsor: Hungarian Scientific and Research
Fund (OTKA)
Contract grant number: K83118.
2012 Wiley Periodicals, Inc.
ꢀC
574

Synthesis and Proton Dissociation Properties of Arylphosphonates 575
TABLE 1 Optimization of the MW-Assisted Solvent-Free Reaction of Bromobenzene and Triethyl Phosphite in the Presence
of NiCl2 Catalyst
TEP/PhBr
Molar Ratio
NiCl2
(mol%)
Conversion to
Entry
T (◦C)
t (h)
Phenylphosphonate (%)a
1
2
3
4
5
6
1
1
1
1
1
1.2
5
5
5
5
10
10
120
140
140
160
160
160
2
1
2
2
2
2
56
61
67
78
86
99
aOn the basis of GC.
conditions. Although the arylphosphonates were
prepared in 62–98% yields, the procedure is not re-
producible as a domestic MW oven was applied and
the temperatures were not detected and given [14].
Others [15] and we [16–24] found that MW may be
an invaluable tool in organophosphorus chemistry.
MW irradiation may make possible reactions that
are otherwise impossible under conventional condi-
tions of heating. Such a reaction is the direct esteri-
fication of phosphinic acids [16, 17]. In other cases,
MW simply causes a significant rate enhancement,
such as in the case of inverse Wittig type reactions
[18, 19] or in Diels–Alder reactions [20]. It is also
possible that a catalyst is substituted by the MW ir-
radiation. It was proved that there is no need for any
“exotic” catalyst in the Kabachnik–Fields reaction if
it is accomplished under MW and solventless condi-
tions [21]. We also found that the solid–liquid phase
alkylation of a few CH acidic phosphonates did not
require the presence of a phase transfer catalyst if
the reaction was carried out using MW [22–24].
We wished to study the MW-assisted Arbuzov
reaction of aryl bromides and triethyl phosphite in
detail, providing a general and reproducible proce-
dure. Hydrolysis of the resulting diethyl arylphos-
phonates may give arylphosphonic acids as valuable
target compounds.
ment (ionic strength, temperature) described in the
publications mentioned, the ionization constants of
arylphosphonic acids investigated are highly vari-
able. Moreover, the experimental technique used to
determine pKa before the 1990s, namely direct pon-
tentiometric titration, has a less accuracy to give the
Hammett equation of arylphosphonic acids. There-
fore, further motivation of our project was to re-
vise the accuracy of ionization constants (pKa1 and
pKa2) and also to refine the effect of substituents on
the proton dissociation of the related arylphospho-
nic acids.
RESULTS AND DISCUSSION
Synthesis of Diethyl Arylphosphonates and
Arylphosphonic Acids
First the basic model, the Arbuzov reaction of tri-
ethyl phosphite (TEP) and bromobenzene was sub-
jected to a detailed study using an equimolar quan-
tity of the reactants under solvent-free conditions.
From the data of Table 1, one can see that the opti-
mum temperature of the catalytic MW-assisted Ar-
buzov reaction is 160◦C. It is advantageous to use the
TEP in a quantity of 1.2 equiv and the NiCl2 catalyst
in a 10% molar quantity. After a reaction time of 2
h, the conversion to diethyl phenylphosphonate (2a)
was quantitative and the preparative yield was 90%
(Table 1/entry 6).
Similarly to substituted benzoic acid derivatives,
the proton dissociation of arylphosphonic acids also
depends on the electronic character of the sub-
stituent in the aromatic ring. For these compounds,
a linear correlation was found between the pKaX val-
ues and the Hammett parameters (σ) of the sub-
stituent X of the aryl group in aqueous solution
(Eq. (1)) [25].
The optimum set of conditions was applied
to the synthesis of other arylphosphonates 2b–l
(Scheme 1).
In the case of ortho-substituted model com-
pounds, a longer reaction time of 3 h had to be used
to overcome the decreased reactivity deriving from
the steric hindrance. Diethyl arylphosphonates 2b–
l were obtained in yields of 67–86% after column
chromatography. From among the 12 products, 2a–
c, 2f–h, and 2j,k have been described earlier [30–32]
whereas compounds 2d, 2e, 2i, and 2l are new. 31P
NMR and mass spectral data of the known phos-
phonates were compared with those reported in the
pKaX = ρꢀσ + b
(1)
There are a number of reports in the literature on this
linear correlation for arylphosphonic acid deriva-
tives, most notably those of Jaffe et al. [26], Nualla´in
[27], Hoefnagel et al. [28], and Nagarajan et al. [29].
However, with respect to the experimental environ-
Heteroatom Chemistry DOI 10.1002/hc

576 Keglevich et al.
OEt
OEt
R1
OH
OH
R1
OEt
OEt
R1
O
O
O
Br
R1
+
P
P
12 h, Δ
6 equiv. cc.HCl
MW
160°C, 2 h
P
(EtO)3P
NiCl2
R4
R4
R2
R4
R2
R2
R4
R2
R3
R3
R3
R3
2
3
1
2
R1
H
CH3
H
H
H
H
H
H
F
H
H
F
R2
H
H
H
H
H
H
H
H
H
F
R3
H
H
CH3
R4
Yield (%)
90
3
R1
H
CH3
H
H
H
H
H
H
F
H
H
F
R2
H
H
H
H
H
H
H
H
H
F
R4
H
H
H
H
H
H
H
H
H
H
H
F
Yield (%)
90
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
H
H
H
F
a
b
c
d
e
f
g
h
i
H
H
CH3
73
85
77
88
79
93
79
81
86
71
8 6
74
72
69
73
67
Cyclohexyl
OCF3
CF3
OCH3
C(O)CH3
H
C y c l o h e x y l
OCF3
CF3
OCH3
C(O)CH3
H
H
F
j
k
l
H
F
H
71
91
74
j
k
l
82
73
78
H
H
H
H
H
SCHEME 2
SCHEME 1
tic samples. The identity of the species synthesized
was confirmed. At the same time, the new arylphos-
phonic acids were characterized by 31P, 13C, and 1H
NMR, as well as HRMS data.
All together, eight new arylphosphonic acids
were made available by us.
literature. The 31P NMR chemical shifts measured
matched the values described. The new species were
fully characterized by 31P, 13C, and 1H NMR, as well
as HR mass spectral data. It is noteworthy that di-
ethyl arylphosphonates 2a–c, 2f–h, and 2j,k were
prepared earlier by the catalytic coupling reaction
of aryl bromides and diethyl phosphite [30–32].
It can be seen that our MW-assisted and solvent-
free procedure makes possible the efficient synthesis
of diethyl arylphosphonates at 160◦C in the presence
of NiCl2 catalyst. The yields seem to be somewhat
better (67–90%) as compared to those (60–90%) of
the literature method [13]. The reaction times un-
der MW conditions are presumably shorter (in most
cases 2 h) than that applied under traditional ther-
mal conditions, but, unfortunately, no such data
were provided [13]. Obviously, the method described
by us is of more general value and is also suitable for
the synthesis of other dialkyl phosphonates.
Study on the Proton Dissociation of
Arylphosphonic Acids
To evaluate substituent effects on the proton disso-
ciation equilibria of arylphosphonic acid derivatives
(Scheme 3), first the ionization constants (pKa1 and
pKa2) of the molecules shown in Scheme 1 were mea-
sured with a high accuracy.
In earlier studies, where direct potentiometry
had been applied, the pKa2 values of arylphosphonic
acids could be reproduced typically, with a standard
deviation of 0.03 whereas for pKa1 values below 2.0
the deviation was 0.08 [29]. We had to choose an
analytical technique making it possible to measure
the ionization constants of the related arylphospho-
nic acids (3) with a high accuracy. In the past two
decades, the direct potentiometric method had been
substituted by the difference pH-metric titration and
the NMR-pH titration techniques [40, 41]. Although
both methods provide more accurate pKa values, the
difference pH-metric titration can only be used in
In the second step, the diethyl arylphosphonates
2a–l were hydrolyzed by 6 equiv of 37% hydrochlo-
ric acid at around 110–115◦C (at reflux) for 12 h
(Scheme 2).
The arylphosphonic acids (3) precipitated
partially during the hydrolysis. After complete hy-
drolysis, the mixture was concentrated in vacuum to
afford the products (3a–l) in yields of 71–93% in a
purity of at least 98%. From among the arylphospho-
nic acids, 3a, 3c, 3f, 3g, and 3k have been described
and partially characterized [31, 33–35], 3b and 3h–j
were described and characterized only by a melt-
ing point [36–39], whereas the remaining products
3d, 3e, and 3l are new. Spectral parameters of the
known species were compared with those of authen-
O
O
O
P
pKa1
pKa2
Ar
P
OH
Ar
P
O
Ar
O
−
−
H
H
OH
OH
O
+ H
+ H
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Proton Dissociation Properties of Arylphosphonates 577
the pH range of 2.0–12.0. Under pH 2.0 and above
pH 12.0, typically the NMR-pH titration technique
is applied [42, 43]. Accordingly, pKa1 values were
measured by NMR-pH titrations whereas the pKa2
values were determined by the difference pH-metric
method. First, we compared the in house experimen-
tal ionization constants of arylphosphonic acids with
the measured values of Nagarajan et al. [29] and also
with those predicted by two validated in silico pKa
predictors [44], namely ACD [45] and Marvin [46]
plugins.
ic
SD
Huose)
Hm-etr
p
in
(
rcne
a2
aiton
e
i
irt
pK
D
a
a
SD
As can be seen in Table 2, the mean of abso-
lute error (MAE) of the first proton dissociation con-
stants (pKa1) between the two experimental results
was significantly lower (MAEpKa1 = 0.14 0.03) than
that for the second proton dissociation constants
(pKa2, MAEpKa1 = 0.57 0.08). In accord with this
observation, correlations between the in silico and
both sets of experimental data were considerably
better for the pKa1 values than for the pKa2 values
(Table 3).
Ttir
osue)
H
(ni
a1
pK
NRM-pH
a2
pK
2]9
jna
[
a.l
Moreover, correlation between the in house and
the Marvin based in silico data were significantly
lower for the full set of compounds than for the over-
lapping set with Nagarajan et al. [29].
et
Nagr
a1
a
K
pK
The results indicate that the effect of sub-
stituents is more critical in the second proton dis-
sociation step of arylphosphonic acids, and the pre-
diction of the pKa2 values for the newly synthesized
compounds is more difficult. Next, we evaluated the
Hammett equations of the related arylphosphonic
acids (3) on their first and second proton dissoci-
ation constants (Table 4). Based on Scheme 3, the
Hammett-type linear free energy relationships were
determined both on our and Nagarajan et al.’s data
sets.
a2
cKp
CD
A
v0.1
a1
cKp
a2
cKp
Our experimental data showed that the pKa1 and
pKa2 values correlated very well with the σ values
of the meta and para substituents, and the correla-
tion coefficients were moderately higher than those
from the Nagarajan’s study. Comparing the Ham-
mett equations published [29] and for our set of
compounds (3), we found a similar relationship for
the pKa2 values and there was a considerable dif-
ference for the pKa1 values with respect to the ρ
constants. Contrary to this, regarding the intercepts
(Scheme 3), there was a considerable difference in
the Hammett relationships for the pKa2 values.
In summary, a series of diethyl arylphospho-
nates and arylphosphonic acids were made avail-
able. The arylphosphonates were synthesized by
the catalytic MW-assisted Arbuzov reaction of aryl
bromides and triethyl phosphite under solvent-free
conditions. Accurate proton dissociation constants
were determined for 12 arylphosphonic acids using
vni
v95.4
Mra
a1
cKp
a
K
4]7
[
)
(
Hmaet
Cpmounds
a
Heteroatom Chemistry DOI 10.1002/hc

578 Keglevich et al.
TABLE 3 Correlation Coefficients between Experimental
Microwave Technology Ltd., Buckingham, UK) us-
ing 50 W. After completion of the reaction, the crude
mixture was purified by column chromatography
(silica gel, 3% methanol in chloroform as the elu-
ent) to afford products 2a–l as oils listed below.
The following compounds were thus prepared:
Diethyl Phenylphosphonate (2a). Yield: 90%; 31P
NMR (CDCl3) δ: 18.9; δ [30] (CDCl3): 18.8; LC-MS
215.1 (M + H); (M + H)+found = 215.0838 C10H16O3P
requires 215.0837.
and Predicted pKa Values for Different Set of Compounds
Nagarajan
et al.
In
In
Predictors
Housea
Houseb
Marvin v5.9.4
pKa1
pKa2
pKa1
pKa2
0.8400
0.7797
0.7744
0.5344
0.8111
0.6854
0.8052
0.7461
0.6885
0.5554
0.8889
0.8156
ACD v11.01
aFor the overlapping set of compounds with Nagarajan et al. [29].
bFor the whole test set (12 compounds).
Diethyl
(2-Methylphenyl)Phosphonate
(2b).
Yield: 86%; 31P NMR (CDCl3) δ: 19.5; δ [30]: 19.4;
13C NMR (CDCl3) δ: 16.3 (d, J = 6.5, CH2CH3), 21.2
(d, J = 3.6, CH3), 61.9 (d, J = 5.6, CH2CH3), 125.4
(d, J = 14.6, C5*), 126.8 (d, J = 183.1, C1), 131.2 (d. J
TABLE 4 Hammett-Type Linear Free Energy Relationships
for Arylphosphonic Acids
Nagarajan et al. [29]:
pKa1 = 0.856σ + 1.84 (R2 = 0.9872)
*
= 14.9, C3 ), 132.5 (d, J = 2.9, C4), 133.8 (d, J = 10.2,
pKa2 = 0.980σ + 7.48 (R2 = 0.9778)
C6), 141.8 (d, J = 10.2, C2), *may be reversed; (M +
In house:
H)+
= 229.0998, C11H18O3P requires 229.0994.
pKa1 = 0.784σ + 1.68 (R2 = 0.9844)
found
pKa2 = 1.003σ + 6.98 (R2 = 0.9884)
Diethyl (4-Methylphenyl)Phosphonate (2c). Yield:
71%; 31P NMR (CDCl3) δ: 20.6; δ [30]: 19.5; (M +
H)+
= 229.0994, C11H18O3P requires 229.0994.
found
TABLE 5 Quantities of the Starting Aryl Bromides
Diethyl (4-Cyclohexylphenyl)Phosphonate (2d).
Yield: 86%; 31P NMR (CDCl3) δ: 20.5; 13C NMR
(CDCl3) δ: 16.4 (d, J = 6.5, CH3), 26.0 (s, 2×CH2),
26.8 (s, 2×CH2), 34.1 (s, CH2), 44.7 (s, CH), 62.0 (d,
J = 5.3, OCH2), 125.3 (d, J = 188.9, C1), 127.1 (d, J =
15.2, C3), 131.5 (d, J = 10.3, C2), 152.8 (d, J = 3.1, C4);
1H NMR (CDCl3) δ: 1.25–1.43 (m, 12H, CH2, CH3),
1.74–1.85 (m, 4H, CH2), 2.54 (t, 1H, J = 6.4, CH),
4.05–4.14 (m, 4H, CH2CH3), 7.27–7.30 (m, 2H, ArH),
Quantities of Starting
Material
Compound
g
mL
1a
1b
1c
1d
1e
1f
1g
1h
1i
0.47
0.51
0.51
0.72
0.72
0.68
0.56
0.60
0.53
0.53
0.53
0.58
0.32
0.36
0.37
0.56
0.45
0.42
0.38
0.36
0.33
0.33
0.33
0.34
7.69–7.74 (m, 2H, ArH); (M + H)+
= 297.1622,
found
C11H18O3P requires 297.1620.
Diethyl [4-(Trifluoromethoxy)Phenyl]Phosphonate
(2e). Yield: 74%; 31P NMR (CDCl3) δ: 17.1. 13C NMR
(CDCl3) δ: 16.5 (d, J = 6.4, CH3), 62.5 (d, J = 5.5,
CH2CH3), 120.5 (q, J = 258.7, CF3), 120.6 (d, J =
15.8, C3), 127.4 (d, J = 191.5, C1), 134.0 (d, J = 11.0,
1j
1k
1l
1
C2), 152.4 (m, C4); H NMR (CDCl3) δ: 1.34 (t, 6H,
J = 7.1, CH3), 4.03–4.24 (m, 4H, CH2CH3), 7.30–7.33
up-to-data NMR-pH and difference pH-metric titra-
tions. Some specific differences were found, as com-
pared to earlier published results regarding pKa val-
ues and Hammett-type linear free energy relation-
ships.
(m, 2H, ArH), 7.84–7.91 (m, 2H, ArH); (M + H)+
found
= 299.0659 C11H15O4PF3 requires 299.0660.
Diethyl [4-(Trifluoromethyl)Phenyl]Phosphonate
(2f). Yield: 72%; 31P NMR (CDCl3) δ: 17.1; δ [31]:
16.3, δ [30]: 16.2; LC-MS: 282. (M + H).
Diethyl (4-Methoxyphenyl)Phosphonate (2g).
Yield: 69%; 31P NMR (CDCl3) δ: 20.8; δ [30]: 19.7;
LC-MS: 244 (M + H).
EXPERIMENTAL
General Procedure for the Preparation of Aryl
Phosphonates (2a–l)
Diethyl (4-Acetylphenyl)Phosphonate (2h). Yield:
73%; 31P NMR (CDCl3) δ: 16.9; δ [30]: 19.7; LC-MS:
256 (M + H).
3.0 mmol aryl bromide 1 (see Table 5), 0.63 mL (3.60
mmol) of triethyl phosphite, and 0.039 g (0.30 mmol)
of nickel chloride catalyst were measured in a stan-
dard MW reaction vessel that was supplied with a
pressure controller and irradiated at 160◦C for 2–3 h
with stirring in a CEM Discover MW reactor (CEM
Diethyl (2-Fluorophenyl)Phosphonate (2i). Yield:
67%; 31P NMR (CDCl3) δ: 13.8. 13C NMR (CDCl3) δ:
16.3 (d, J = 6.5, CH3), 62.5 (d, J = 5.6, CH2CH3), 116.1
(dd, J1 = 8.0, J2 = 22.6, C3), 116.4 (dd, J1 = 188.1, J2 =
18.3, C1), 124.1 (dd, J1 = 13.8 J2 = 3.6, C5), 134.8 (dd,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Proton Dissociation Properties of Arylphosphonates 579
J1 = 6.3, J2 = 2.2, C4*), 135.0 (dd, J1 = 6.0, J2 = 3.7,
C6*), 163.4 (d, J2 = 252.9, C2), *may be reversed; 1H
NMR (CDCl3) δ: 1.30 (t, 6H, J = 7.0, CH3), 4.02–4.20
(m, 4H, CH2CH3), 7.04–7.22 (m, 2H, ArH), 7.47–7.54
Phenylphosphonic Acid (3a). Yield: 90%; mp:
150–152◦C (dec.), mp [48]: 168◦C; 31P NMR (D2O)
δ: 16.9; δ [33] (DMSO): 14.6; 13C NMR (DMSO) δ:
108.2 (d, J = 14.7, C3); 109.9 (d, J = 10.4, C2), 110.1
(m, 1H, ArH), 7.77–7.87 (m, 1H, ArH); (M + H)+
(d, J = 181.8, C1), 111.8 (d, J = 3.0, C4); (M + H)+
found
found
= 233.0744 C10H15O3PF requires 233.0743.
= 159.0214; C6H7O3P requires 159.0211.
Diethyl (3-Fluorophenyl)Phosphonate (2j). Yield:
82%; 31P NMR (CDCl3) δ: 16.7 (d, J = 8.7); δ [32]:
17.4 (d, J = 8.6); 13C NMR (CDCl3) δ: 16.4 (d, J =
6.4, CH3), 62.5 (d, J = 5.5, CH2CH3), 118.7 (dd, J1 =
10.4, J2 = 22.2, C2), 119.7 (dd, J1 = 3.1, J2 = 24.1,
C4), 127.6 (dd, J1 = 9.2, J2 = 2.1, C6), 130.6 (dd, J1 =
17.5, J2 = 7.4, C5), 131.1 (dd, J1 = 187.8, J2 = 6.1, C1),
162.5 (dd, J1 = 21.5, J2 = 247.8, C3); δ [32] (CDCl3):
16.1 (d, J = 6.1), 62.2 (d, J = 6.1), 118.3 (dd, J1 =
22.4, J2 = 10.2), 119.3 (dd, J1 = 21.4, J2 = 3.1), 127.3
(dd, J1 = 3.1, J2 = 9.2), 130.4 (dd, J1 = 17.3, J2 = 8.1),
131.2 (dd, J1 = 188.2, J2 = 6.1), 162.3 (dd, J1 = 21.2,
J2 = 249.2); 1H NMR (CDCl3) δ: 1.34 (t, 6H, J = 7.2,
CH3), 4.03–4.24 (m, 4H, CH2CH3), 7.22–7.28 (m, 1H,
ArH), 7.42–7.64 (m, 3H, ArH); LC-MS: 232 (M + H).
Diethyl (4-Fluorophenyl)Phosphonate (2k). Yield:
73%; 31P NMR (CDCl3) δ 17.9; δ [30]: 17.7; 13C NMR
(CDCl3) δ: 16.2 (d, J = 6.4, CH3), 62.0 (d, J = 5.5,
CH2CH3), 115.7 (dd, J1 = 16.3, J2 = 21.4, C3), 124.4
(dd, J1 = 192.8, J2 = 3.4, C1), 134.2 (dd, J1 = 11.3,
J2 = 8.9, C2), 165.2 (dd, J1 = 3.9, J2 = 253.4, C4); 1H
NMR (CDCl3) δ: 1.33 (t, 6H, J = 7.1, CH3), 4.02–4.22
(m, 4H, CH2CH3), 7.12–7.19 (m, 2H, ArH), 7.78–7.87
(m, 2H, ArH); LC-MS: 232 (M + H).
(2-Methylphenyl)Phosphonic Acid (3b). Yield:
73%; mp: 137–138◦C, mp [36]: 138–141◦C; 31P NMR
(DMSO) δ: 13.3; 13C NMR (DMSO) δ: 21.1 (d, J = 3.9,
CH3) 125.2 (d, J = 13.5, C5)*, 130.8 (d, J = 14.3, C3)*,
131.2 (d, J = 3.0, C4), 132.1 (d, J = 9.8, C6), 132.2 (d, J
= 178.5, C1), 140.5 (d, J = 9.9, C2), *may be reversed;
1H NMR (DMSO) δ: 2.78 (s, 3H, CH3), 7.49–7.53 (m,
2H, ArH), 7.63–7.67 (m, 1H, ArH), 7.97–8.04 (m, 1H,
ArH); (M + H)+
= 173.0365, C7H10O3P requires
found
173.0368.
(4-Methylphenyl)Phosphonic Acid (3c). Yield:
85%; mp: 172–174◦C (dec), mp [39]: 185–187◦C; 31
P
NMR (DMSO) δ: 14.0; δ [33] (D2O): 19.5; 13C NMR
(DMSO) δ: 20.9 (s, CH3) 128.5 (d, J = 12.9, C3)*, 130.5
(d, J = 6.7, C2)*, 133.1 (d, J = 174.3, C1), 140.5 (C4),
1
*may be reversed; H NMR (DMSO) δ: 2.4 (s, 3H,
CH3); 7.2 (d, 2H, J = 1.8, ArH), 7.6 (d, 2H, J = 2.3,
ArH); (M + H)+
= 173.0367, C7H10O3P requires
found
173.0368.
(4-Cyclohexylphenyl)Phosphonic
Acid
(3d).
Yield: 77%; mp: 154–156◦C; 31P NMR (DMSO) δ:
13.3; 13C NMR (DMSO) δ: 25.7 (CH2), 26.4 (2×CH2),
33.9 (2×CH2), 44.0 (CH), 126.6 (d, J = 14.5, C3)*,
130.7 (d, J = 10.3, C2)*, 131.1 (d, J = 184.3, C1),
1
Diethyl (2,5-Difluorophenyl)Phosphonate (2l).
Yield: 78%; 31P NMR (CDCl3) δ: 11.6 (dd, J1 = 6.0,
J2 = 2.5); 13C NMR (CDCl3) δ: 16.2 (d, J = 6.4, CH3),
62.8 (d, J = 5.7, CH2CH3), 117.7 (ddd, J1 = 7.9 C6, J2
= 9.8, J3 = 25.7, C6), 118.2 (ddd, J1 = 188.1, J2 = 21.6,
J3 = 6.5 C1), 120.9 (ddd, J1 = 4.6, J2 = 25.3, J3 = 6.5,
150.9 (d, J = 2.9, C4), *may be reversed; H NMR
(DMSO) δ: 1.13–1.44 (m, 6H, CH2), 1.65–1.77 (m,
4H, CH2), 2.50 (bs, 1H, CH), 7.25–7.34 (m, 2H, ArH),
7.56–7.63 (m, 2H, ArH); (M+H)+
= 241.0993;
found
C12H17O3P requires 241.0994.
[4-(Trifluoromethoxy)Phenyl]Phosphonic
Acid
*
C3*), 121.3 (ddd, J1 = 2.6, J2 = 8.9, J3 = 24.2, C4 ),
(3e). Yield: 88%; mp: 122–124◦C; 31P NMR (DMSO)
δ: 15.8; 13C NMR (DMSO) δ: 119.9 (q, J = 255.4,
CF3), 120.5 (d, J = 14.6, C3)*, 132.9 (d, J = 10.8,
C2)*, 133.7 (d, J = 181.1, C1), 150.1 (d, J = 1.8, C4),
*may be reversed; 1H NMR (DMSO) 7.43 (d, 2H,
158.2 (ddd, J1 = 19.4, J2 = 2.6, J3 = 245.4, C5), 159.2
1
(dd, J2 = 249.0, J3 = 2.3 C2) *may be reversed; H
NMR (CDCl3) δ: 1.29 (t, 6H, J = 7.1, CH3), 4.03–4.23
(m, 4H, CH2CH3), 6.99–7.09 (m, 1H, ArH), 7.13–7.21
(m, 1H, ArH), 7.42–7.53 (m, 1H, ArH); (M + H)+
J = 7.5, ArH), 7.67–7.82 (m, 2H, ArH); (M + H)+
found
found
= 251.0649 C10H14O3P F2 requires 251.0649.
= 243.0031, C7H6F3O4P requires 243.0034.
[4-(Trifluoromethyl)Phenyl]Phosphonic
Acid
(3f). Yield: 79%; mp: 174–175◦C, mp [39]: 177–
178◦C; 31P NMR (DMSO) δ: 10.5; δ [31] (C6D6): 14.1;
13C NMR (DMSO) δ: 124.4 (d, J = 272.7, CF3), 125.5
(dd, J1 = 14.3, J2 = 3.8, C3), 131.6 (dd, J1 = 3.1, J2 =
32.5, C4), 131.8 (d, J = 10.2, C2), 139.4 (d, J = 179.4,
C1);1H NMR (DMSO) δ: 7.69–7.99 (m, ArH); LC-MS:
General Procedure for the Preparation of Aryl
Phosphonic Acids (3a–l)
To 3.0 mmol of the arylphosphonates (2a–l) pre-
pared above, 4.2 mL of 37% hydrochloric acid was
added and the mixture was refluxed on stirring for
12 h. Then the contents of the flask were concen-
trated in vacuum to give products 3a–l as solid pow-
ders, after digestion in ethyl acetate, in a purity of
>98%.
227 (M + H); (M + H)+
= 227.0082 C7H7O3PF3
found
requires 227.0085.
(4-Methoxyphenyl)Phosphonic Acid (3g). Yield:
93%; mp: 177–178◦C, (mp [35]: 179◦C); 31P NMR
Heteroatom Chemistry DOI 10.1002/hc

580 Keglevich et al.
(DMSO) δ: 12.5; δ [35]: 15.1; 13C NMR (DMSO) δ:
55.7 (s, CH3), 114.1 (d, J = 15.0, C3), 125.3 (d, J =
181.4, C1), 132.9 (d, J = 11.1, C2), 161.8 (d, J = 2.0,
C4), δ [35]: 55.9 (s), 114.2 (d, J = 15), 126.2 (d, J =
C2) *may be reversed; 1H NMR (DMSO) δ: 7.28–7.55
(m, 3H, ArH); (M+H)+
= 195.0020, C6H6F2O3P
found
requires 195.0023.
1
188), 133.1 (d, J = 11), 161.9 (d, J = 3); H NMR
Difference pH-Metric Method for the
Measurement of pKa2 Values of Arylphosphonic
Acids (3)
(DMSO) δ: 3.75 (s, 3H, CH3), 6.97 (d, J = 7.8, 2H,
ArH), 7.59 (dd, J = 11.5, J = 8.5, 2H, ArH), δ: 7.58
(dd, J = 12, J = 8, 2H), 6.98 (dd, J = 8, J = 2, 2H),
6.23 (bs, 2H), 3.8 (s, 3H); (M + H)+
= 189.0315,
found
The ionization constants of arylphosphonic acids (3)
were measured by the standard GLpKa approach
using difference pH-metric titration. A GLpKa-
automated pKa analyzer (Sirius Analytical Instru-
ment Ltd., Forest Row, UK) fitted with a combined
Ag/AgCl pH electrode was used for the determina-
tion of the dissociation constants. The pKa values
were calculated by RefinementProTM software (Sir-
ius Analytical Instrument Ltd., Forest Row, UK). The
methodologies used by the software have been de-
scribed in earlier publications [49]. In each experi-
ment, 10.00 mL of a 1 mM aqueous solution of sam-
ple was prealkalined to pH 12.0 with 0.5 M KOH, and
then titrated with 0.5 M HCl to an appropriately high
pH 2.0. The titrations were carried out at a constant
ionic strength (I = 0.15 M KCl) and temperature
(t = 25.0 0.5◦C) and under nitrogen atmosphere. A
minimum of three parallel measurements were car-
ried out in each case, and the pKa values of samples
were calculated by the RefinementProTM software.
C7H9O4P requires 189.0317.
(4-Acetylphenyl)Phosphonic Acid (3h). Yield:
79%; mp: 157–159◦C, mp [37]: 163–167◦C; 31P NMR
(DMSO) δ: 16.9; 13C NMR (DMSO) δ: 26.9 (s, CH3),
127.9 (d, J = 14.0 C3)*, 130.9 (d, J = 9.9, C2)*, 138.5
(d, J = 2.9, C4), 138.9 (d, J = 178.1, C1), 197.9 (s,
1
C O), *may be reversed; H NMR (DMSO) δ: 2.59
(s, 3H, CH3), 7.77–7.84 (m, 2H, ArH), 7.98–8.02 (m,
2H, ArH); (M + H)+
= 201.0314, C8H10O4P re-
found
quires 201.0317.
(2-Fluorophenyl)Phosphonic Acid (3i). Yield:
81%; mp: 144–146◦C, mp [38]: 146–149◦C; 31P NMR
(DMSO) δ: 7.4; 13C NMR (DMSO) δ: 115.6 (dd, J1 =
7.1, J2 = 22.4, C3), 121.2 (dd, J1 = 178.7, J2 = 19.1,
C1), 123.8 (dd, J1 = 12.8, J2 = 3.3, C5), 133.2 (dd, J1
= 5.3, J2 = 5.0, C4), 133.5 (dd, J1 = 8.3, J2 = 1.5, C6),
1
162.4 (d, J = 247.4, C2); H NMR (DMSO) δ: 7.18–
7.28 (m, 2H, ArH) 7.52–7.59 (m, 1H, ArH), 7.65–7.75
(m, 1H, ArH); (M + H)+
= 177.0123, C6H7FO3P
found
requires 177.0117.
(3-Fluorophenyl)Phosphonic Acid (3j). Yield:
71%; mp: 94–95◦C, mp [39]: 95–98◦C; 31P NMR
(DMSO) δ: 10.8 (d, J = 8.1); 13C NMR (DMSO) δ:
116.9 (dd, J1 = 10.0, J2 = 21.5, C2), 117.9 (dd, J1 = 2.4,
J2 = 20.8, C4), 126.7 (dd, J1 = 8.9, J2 = 3.2, C6), 130.8
(dd, J1 = 16.2, J2 = 7.3, C5), 137.0 (dd, J1 = 179.5, J2
NMR-pH Titrations for the Measurement of
pKa1 Values of Arylphosphonic Acids (3)
For the NMR-pH titration solutions of 12 aromatic
phosphonic acid derivatives, each of 20–22 differ-
ent pH values within the pH range of 0.9–4.0 were
prepared. Each solution contained 1–2 mM of a
phosphonic acid derivative (3), 1 mM dichloroacetic
acid as an NMR-pH indicator, 0.1 M 2,2-dimethyl-
2-silapentane-5-sulfonate as a chemical shift refer-
ence, and 5% D2O. Using such a small amount of
D2O, the shift of pH scale was within the deviation
limit (0.02 pH unit) [50, 51]. The ionic strength of
the solutions was set to 0.15 M with KCl. The NMR
measurements were carried out on a Varian VNMRS
1
= 5.1, C1), 161.8 (dd, J1 = 20.1, J2 = 244.3, C3); H
NMR (DMSO) δ: 7.31–8.19 (m, Ar); (M+H)+
=
found
177.0114, C6H7FO3P requires 177.0117.
(4-Fluorophenyl)Phosphonic Acid (3k). Yield:
91%; mp: 120–121◦C, mp [39]: 120–122◦C; 31P NMR
(DMSO) δ: 12.2; δ [31] (D2O): 15.1; 13C NMR (DMSO)
δ: 115.4 (dd, J1 = 15.3, J2 = 21.0, C3), 130.5 (dd, J1
= 183.9, J2 = 3.2, C1), 133.4 (dd, J1 = 11.2, J2
=
8.6, C2), 163.9 (dd, J1 = 3.3, J2 = 246.6, C4); 1H NMR
(DMSO) δ: 7.24–7.31 (m, 2H, ArH), 7.68–7.77 (m, 2H,
ArH); (M + H)+found = 177.0119, C6H7FO3P requires
177.0117.
1
spectrometer (599.9 MHz for H) equipped with a
dual 5-mm inverse-detection gradient probehead at
1
25
0,5◦C. H NMR spectra of the solutions were
(2,5-Difluorophenyl)Phosphonic Acid (3l). Yield:
74%; mp: 158–159◦C; 31P NMR (DMSO) δ: 4.8; 13C
NMR (DMSO) 118.1 (ddd, J1 = 8.2, J2 = 8.2, J3 =
25.7 C6), 119.4 (ddd, J1 = 5.7, J2 = 24.8, J3 = 5.7,
recorded with a double pulse field gradient spin echo
pulse sequence to suppress the solvent signal [52],
and the spectra were processed by a VNMRJ 2.2C
software.
The pKa1 values of phosphonic acids were de-
termined by the Perrin–Fabian method without
*
C3*), 120.9 (dd, J2 = 8.7, J3 = 24.0, C4 ), 123.6 (dd,
J1 = 175.1, J2 ∼ 23, J3 ∼ 5, C1) 157.8 (ddd, J1 = 18.1,
J2 = 1.5, J3 = 241.7, C5), 159.2 (dd, J2 = 245.5, J3 = 1.7
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Proton Dissociation Properties of Arylphosphonates 581
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δLobs = δL
(δHL − δL)(δIobs − δI)
+
(1 − 10ꢁpK )(δIobs − δI) + 10ꢁpK (δHI − δI)
(2)
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