Hydroxy-bisphosphinic acids: Synthesis and complexation properties with transition metals and lanthanide ions in aqueous solution

Article abstract of DOI:10.1007/s13738-015-0787-5

Treatment of acyl chlorides with a mixture of ammonium hypophosphite and hexamethyl disilazene gave 1-hydroxy-1,1-bisphosphinic acids. Acid dissociation constants (pKa) of 1-hydroxy-1,1-bisphosphinic acids were determined by the pH-potentiometric techniqu

Full text of DOI:10.1007/s13738-015-0787-5

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0787-5
ORIGINAL PAPER
Hydroxy‑bisphosphinic acids: synthesis and complexation
properties with transition metals and lanthanide ions in aqueous
solution
Babak Kaboudin1 · Ali Ezzati1 · Mohammad Reza Faghihi1 · Ali Barati1 ·
Foad Kazemi1 · Hamid Abdollahi1 · Tsutomu Yokomatsu2
Received: 7 July 2015 / Accepted: 20 November 2015
© Iranian Chemical Society 2015
Abstract Treatment of acyl chlorides with a mixture of
ammonium hypophosphite and hexamethyl disilazene gave
1-hydroxy-1,1-bisphosphinic acids. Acid dissociation con-
stants (pKa) of 1-hydroxy-1,1-bisphosphinic acids were
determined by the pH-potentiometric technique. Compl-
exation properties of 1-hydroxy-1-phenylmethyl-1,1-bis(H-
phosphinic acid) (HBPA 1) with Ca2+ as well as transition
Keywords Hydroxyphosphinic acids · Dissociation
constant · Coordination ability · Transition metals ·
Lanthanide ions
Introduction
metals Fe2+, Ni2+, Cu2+, Cr3+ and lanthanide ions La3+
,
Organophosphinic acids, organic derivatives of phosphinic
acid, have found a wide range of application in the areas
of industrial, agricultural, and medical chemistry owing to
their biological and physical properties as well as their util-
ity as synthetic intermediates [1–3]. Among organophos-
phinic acids, 1-hydroxyphosphinic acids are an important
class of compounds that exhibit a variety of interesting and
useful properties [4]. For example, though complexation
properties of 1-hydoxyphosphinic acids are similar to those
natural 2-hydroxy acids in many respects, the stability
constants of metal–phosphinic acids complexes are lower
than those of carboxylic acids due to less basic properties
of a phosphinate group than carboxylate group [5–9]. It is
known that multidentate ligands containing two or three
phosphinic acid groups strongly form complexes with tran-
sition metals and lanthanide ions to exhibit biological activ-
ity [10–15]. The Gd3+ complexes of multidentate phos-
phinic acid ligands have been used as contrast enhancing
agents in magnetic resonance imaging [16, 17].
Gd3+ were studied in aqueous solution. The stabilizing
ability of complexes of HBPA 1 with these ions in aqueous
solutions was determined to show a significant difference
in the complex stability due to the transition metals.
Graphical abstract The coordination of 1-hydroxy-
1,1-bis(H-phosphinic acid) to metals.
O
H P OH
M+
R
OH
+
H P OH
O
Ca2+, Ni2+, Cu2+, Fe3+, Cr3+, La3+, Gd3+
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-015-0787-5) contains supplementary
material, which is available to authorized users.
1-Hydroxy-1,1-bisphosphonic acids are also broadly
used in medicinal chemistry as important regulators of cal-
cium metabolism in living organisms by affecting the func-
tioning of bone cells, such as osteoclasts and osteocytes
[18]. These cells are responsible for bone formation and
desorption and 1-hydroxy-1,1-bisphosphonic acids, such
as alendronate and pamidronate (Fig. 1) can be used in the
treatment of osteoporosis and Paget disease [19]. In con-
trast to the widely studied 1-hydroxy-1,1-bisphosphonic
* Babak Kaboudin
kaboudin@iasbs.ac.ir
1
Department of Chemistry, Institute for Advanced Studies
in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731,
Iran
2
School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
1 3

J IRAN CHEM SOC
acid derivatives in medicinal chemistry [20–24], relatively
few papers have reported on the chemistry of 1-hydroxy-
1,1-bisphosphinic acids, although there is evidence that
bisphosphinic acids are pharmaceutically active [12, 20,
25–27].
Recently, our laboratories reported novel and conveni-
ent methods for the synthesis of a variety of phosphinic
acid derivatives [28–35]. We also reported the synthesis
and complexation properties of N,N-bis(phosphinomethyl)
amines, as a novel aminophosphinic acids, containing C2-
axis of symmetry with two phosphinic moieties [36, 37].
As part of our efforts to introduce novel structures of phos-
phinic acids, we have now synthesized and characterized
a series of 1-hydroxy-1,1-bisphosphinic acids (Scheme 1).
The complexation properties and stability constants for
complexes of 1-hydroxy-1,1-bisphosphinic acids with
some metal ions are studied by the UV–Vis spectroscopy.
were used for the analytical TLC. All solution studies were
carried out with a pH meter that calibrates by buffer solu-
tion 2 and 9 before using. In all potentiometric titrations,
titrant additions were performed with the use of a digital
burette (Metrohm Dosimat automatic burette). Spectropho-
tometric titrations were carried out on a Pharmacia Biotech
Ultrospec 4000 instrument.
General procedure for the preparation
of 1‑hydroxy‑1,1‑bisphosphinic acids
Bis[(trimethylsilyl)oxy]phosphine (Me3SiO)2PH was pre-
pared under an argon atmosphere using the literature pro-
cedure [38]. Ammonium hypophosphite (0.83 g, 10 mmol)
was suspended in (Me3Si)2NH (2 mL, 10 mmol) and
the mixture was heated overnight at 110 °C (bath tem-
perature) under a flow of argon. The mixture containing
(Me3SiO)2PH was cooled to 0 °C. To this mixture, the
solution of acyl chloride (5 mmol) in dry toluene (5 mL)
was added dropwise, and the resulting mixture was stirred
overnight at RT. Methanol (5 mL) was added to the reac-
tion mixture and the mixture was stirred for 30 min. Dur-
ing removal of volatiles under reduced pressure, a white
precipitate was formed. The precipitate was collected and
was washed with acetone (50 mL) and methanol (50 mL)
to give 1-hydroxy-1,1-bis(H-phosphinic acid) as a fine,
white powder after being dried in air at room temperature
(Yields: 47–61 %).
Experimental
Instrumentation
The chemicals were obtained from commercial sources
and purified by distillation or recrystallization before use.
1H–NMR, 13C–NMR and 31P–NMR spectra were recorded
on a 400 Bruker Avance instrument. Chemical shifts are
reported in δ unit and expressed in ppm. High-resolution
mass spectra (HRMS) were recorded on a Waters LCT ESI-
TOF mass spectrometer using electrospray ionization (ESI)
techniques. Merck Silica-gel 60 F254 plates (No. 5744)
1‑Hydroxy‑1‑phenylmethyl‑1,1‑bis(H‑phosphinic acid)
(HPBA 1)
1
White solid; mp: 210–212 °C; H NMR(D2O, 400 MHz):
1
3
6.97 (2H, dt, JHP = 537.6 Hz, JHP = 12 Hz,), 7.27
(1H, d, J = 7.2 Hz), 7.36 (2H, t, J = 7.6 Hz), 7.47 (2H,
d, J = 7.2 Hz); 13C NMR (D2O-100.6 MHz): 77.2 (t,
1JCP = 91.5 Hz), 125.2, 127.1, 128.3, 136.0; 31P NMR
(D2O/H3PO4,162.0 MHz): 30.44 ppm; HRMS calcd for
C7H11O5P2 (MH+): 237.0082; Found: 237.0083.
PO3H2
H2N
PO3H2
PO3H2
H2N
PO3H2
HO
HO
Pamidronate
Aledronate
Fig. 1 Structures of the pamidronate and aledronate
1‑Hydroxy‑1‑(2‑fluorophenyl)methyl‑1,1‑bis(H‑phosphinic
acid) (HPBA 2)
O
(2 eq)
Cl
R
O
P
1
1
White solid; mp: 199–201 °C; H NMR(D2O, 400 MHz):
O
P
H
R
H
OH
OH
OH
OSiMe3
OSiMe3
Toluene (5 mL)
HMDS
110oC, Ar
1
H
H
7.08 (2H, ddt, JHP = 540.0 Hz, JHF = 5.6 Hz,
H
P
15 h, Ar
3JHP = 18.4 Hz), 7.02–7.07 (1H, m), 7.15 (1H, t,
J = 7.2 Hz), 7.22–7.27 (1H, m), 7.45–7.50 (1H, m);
O
NH4
P
O
0 oC to rt, Ar
HPBA-1-6
13C NMR (D2O-100.6 MHz): 77.3 (dt, JCP = 86.5 Hz,
1
JCF = 6.0 Hz), 115.6, 123.6, 124.3, 128.0, 131.8, 159.1
(d, JCF = 244.5); 31P NMR (D2O/H3PO4,162.0 MHz):
22.55 ppm; HRMS calcd for C7H10FO5P2 (MH+):
254.9988; Found: 254.9992.
R: C6H5-(HPBA 1), 2-FC6H4-(HPBA 2), 2-ClC6H4-(HPBA 3),
C6H5CH2-(HPBA 4), CH3CH2CH2-(HPBA 5), t-Bu-(HPBA 6)
Scheme 1 Synthesis route of HPBAs 1–6
1 3

J IRAN CHEM SOC
1‑Hydroxy‑1‑(2‑chlorophenyl)methyl‑1,1‑bis(H‑phosphinic
acid) (HPBA 3)
prepared in three times distilled water. The titration experi-
ments were performed under Argon atmosphere at room
temperature. The dissociation and protonation constants are
determined by pH-metric titration of 50 ml aqueous solu-
tions containing 2 × 10−3 M of ligand and a require volume
of HCl at a fixed ionic strength of 0.05 M NaNO3 over the
pH range of 1.86–12.50 with standardized NaOH (0.2 M).
A nonlinear least-square curve-fitting program such as the
Newton–Gauss–Levenberg/Marquardt (NGL/M) method
with the Newton–Raphson algorithm is used to compute
the equilibrium concentrations of all species for the calcu-
lation of equilibrium constants and total component con-
centration [39].
1
White solid; mp: 230–232 °C; H NMR(D2O, 400 MHz):
7.30 (2H, dt, 1JHP = 555.6 Hz, 3JHP = 14.4 Hz,), 7.20–7.36
(3H, m), 7.62 (1H, d, J = 6.8 Hz); 13C NMR (D2O-100.6
1
MHz78.9 (t, JCP = 84.5 Hz), 127.0, 128.2, 128.5, 130.6,
135.7; 31P NMR (D2O/H3PO4,162.0 MHz): 21.56 ppm;
HRMS calcd for C7H10ClO5P2 (MH+): 270.9692; Found:
270.9689.
1‑Hydroxy‑2‑phenylethyl‑1,1‑bis(H‑phosphinic acid)
(HPBA 4)
1
White solid; mp: 203–205 °C; H NMR(D2O, 400 MHz):
Spectrophotometric titrations
3.08 (2H, t, JHP = 12.4 Hz), 6.75 (2H, dt, 1JHP = 532.0 Hz,
3JHP = 10.4 Hz), 7.19–7.36 (5H, m); 13C NMR (D2O-
Metallic ion solutions (0.001 M) were prepared in deion-
ized water and adjusted in pH = 7 using phosphate buffer.
The ionic strength was fixed with NaNO3 (0.05 M). The
UV–Vis titrations were performed with two different pro-
cedures, considering either metal ions or ligand as titrant
by adding specific volumes of metallic ions solutions (or
HBPA 1 ligand solution) to a 3 mL of aqueous solution of
1–5 × 10−5 M HBPA 1 ligand (or metal ions). Before the
data are acquired, the solution is stirred, and enough time
is allowed for complete equilibration before the data are
acquired. The absorbance intensities are measured at 25 °C.
The stability constants of the complexes were calculated
by fitting the experimental data to the desire complexation
model using the NGL/M method.
1
100.6 MHz): 48.9, 73.7 (t, JCP = 94.6 Hz), 126.7,
128.0, 131.3, 135.4; 31P NMR (D2O/H3PO4,162.0 MHz):
23.82 ppm; HRMS calcd for C7H12O5P2Na: 273.0085;
Found: 273.0053.
1‑Hydroxy‑1‑butyl‑1,1‑bis(H‑phosphinic acid) (HPBA 5)
1
White solid; mp: 194–196 °C; H NMR(D2O, 400 MHz):
0.78 (3H, t, J = 7.2 Hz), 1.38–1.43 (2H, m), 1.59–1.70
1
3
(2H, m), 6.80 (2H, dt, JHP = 525.2 Hz, JHP = 17.2 Hz);
13C NMR (D2O-100.6 MHz): 14.2, 16.2, 32.8, 74.1 (t,
1JCP = 94.6 Hz); 31P NMR (D2O/H3PO4,162.0 MHz):
25.00 ppm; HRMS calcd for C4H13O5P2(MH+): 203.0238;
Found: 203.0238.
1‑Hydroxy‑2,2‑dimethylpropyl‑1,1‑bis(H‑phosphinic acid)
(HPBA 6)
Results and discussion
Synthesis of ligands HPBA1‑6
White solid; mp: 210–212 °C; 1H NMR(D2O,
1
400 MHz): 1.09 (9H, s), 6.95 (2H, dt, JHP = 530.4 Hz,
Six derivatives of 1-hydroxy-1,1-bis(H-phosphinic acids)
(HPBAs 1–6) were synthesized via a two-step reaction
sequence which is described in Scheme 1. According to
Scheme 1, in the first step, bis(trimethylsilyl)hypophos-
phite was generated in situ from ammonium hypophosphite
and hexamethyldisilazane. Then, in the second step, it was
treated with an acid chloride (1a–f) to yield the correspond-
ing 1-hydroxy-1,1-bis(H-phosphinic acid) (HPBAs 1–6) in
good yields. All HPBAs 1–6 were isolated as white stable
3JHP
=
17.2 Hz); 13C NMR (D2O-100.6 MHz):
1
26.4, 36.7, 78.8 (t, JCP = 89.5 Hz); 31P NMR (D2O/
H3PO4,162.0 MHz): 25.65 ppm; HRMS calcd for
C5H15O5P2(MH+): 217.0395; found: 217.0386.
Potentiometric measurements
The titrations can be done manually by a burette under
computer controls and the pH meter which provides infor-
mation about the total concentrations of protons, [H+], at
any time during a titration. Before the data are acquired,
the solution is stirred and enough time is allowed for com-
plete equilibration after each addition. Sodium hydrox-
ide solution (0.2 M) was standardized against potassium
hydrogen phthalate (0.1 M) and HCl solution concentration
was determined with NaOH. All the aqueous solutions are
solids and the structures were confirmed by H NMR, 31P
1
NMR, 13C NMR and HRMS. In the H NMR spectra of
1
HPBAs 1–6, the chemically equivalent protons connected
to phosphorus atoms should display a doublets, which is
due to coupling of protons with the phosphorus atom. How-
ever, these chemically equivalent protons were found not to
be magnetically equivalent and H NMR spectrum is quite
different from a simple doublet expected for the protons
1
1 3

J IRAN CHEM SOC
connected to phosphorus atoms. For example, in the case of
compound HPBA 3, the H-NMR spectrum exhibited one
predicted for the ligands of HPBAs 1–6 since they have
two phosphinic acid groups.
1
doublet with unexpected side peaks in each peak at δ 6.60
and 7.99 ppm indicative of H–P coupling (1JHP = 556 Hz
Stability constants for the complexes of ligand HPBA 1
3
and JHP = 40 Hz) that shows two chemically equivalent
protons are not magnetically equivalent because Ha and
Hb do not couple to Pa with the same coupling constant
(Fig. 2). The 13C-NMR spectrum exhibited one triplet peak
at δ 78.8 ppm indicative of P–C–P coupling (1JCP = 84 Hz).
The 2D H–H COSY showed a strong coupling between H
and P with cross peaks at 6.60 and 7.99 ppm. The 2D het-
ero nuclear H–C HSQC shows correlations between pro-
tons directly attached to heteronuclei carbon (see support-
ing information).
HPBAs 1–6 are composed of one hydroxyl group and two
symmetrical phosphinate units that might combine with
transition metals and lanthanide ions in 1:1 or 2:1 of the
ligand to metal ratio. In this study, HPBA 1 was chosen as
a model compound to demonstrate the complexing proper-
ties of 1-hydroxy-1,1-bisphosphinic acids with metal ions.
The formation of equilibria between the ligand (HPBA 1)
and metal ions Ca2+, Ni2+, Cu2+, Fe3+, Cr3+ as well as
lanthanide ions La3+, Gd3+ were studied by UV–Vis spec-
troscopy. The stability constants of interaction of ligand
HPBA 1 with metal ions in aqueous solution of pH = 7
were studied at an ambient temperature. The titrations
were performed with two different procedures, consider-
ing either metal ions or ligand as titrant. For the calcula-
tion of the stability constants of the complexes, formation
of ML2 complex for all systems was expected based on the
quality and number of donor atoms in the ligand and the
properties of metal ions. However, the stoichiometry of the
resulting complexes was determined from the absorbance
mole-ratio plots as well as continuous variation method at
the wavelength of corresponding complexes. According to
the results, the formation of the complex ML2 was consid-
ered for all studied systems (see supporting information).
As a sample of the experimental spectra, Fig. 3a shows
UV–Vis titration spectra curves of Fe3+ on stepwise addi-
tion of aqueous solutions of HPBA 1. This plot revealed
two isosbestic points formed at 284 and 354 nm, respec-
tively. The presence of isosbestic point during a chemical
change (complex formation of the ligand with Fe3+) is
good evidence that only two principal species are present,
and that they have a constant total concentration [40].
As mentioned, the stoichiometry of the complexes
metal–ligand HPBA 1 was studied by spectrophotometric
titrations using absorbance mole-ratio plots and continuous
variation method. As a typical example, Fig. 3b shows the
absorption intensity changes as a function of the [HPBA 1]/
[Fe3+] molar ratio. The molar ratios of the ligand HPBA 1
varied from 0 to 4 and absorbance values were plotted at
the wavelength of 450 nm. These changes could be pointed
to the ratio of ligand HPBA 1 and Fe3+ ion. The formation
curve of the [HPBA 1]/[Fe3+] complex would extrapolate
to a coordination number of 2, and strongly supports the
formation of ML2-type complex, in which one metal ion
is coordinated by two ligands of HPBA 1. In addition,
continuous variation method was used to show a distinct
maximum point in the corresponding plots at mole frac-
tion of about 0.33, which strongly emphasized the forma-
tion of 1:2 complex between Fe3+ and HPBA 1 ligand. This
Dissociation constants of HPBAs 1–6
The dissociation constants of the six ligands were obtained
using a potentiometric method. All ligands possess two dis-
sociation constants. The dissociation constants, defined as
Kai = [H(n-i)L][H+]/[H(n-i+1)L] where n is the number of
protons, were determined in the pH range of about 1.86–
12.5 in the presence of 0.05 M NaNO3 at 25.0 0.1 °C.
The pKa values and log β values (protonation constants,
defined as βi = [HiL]/[H+]i[L]) are calculated and sum-
marized in Table 1. The standard deviation of constants,
obtained from fitting the algorithm are also shown in
Table 1. Theoretically, two dissociation constants are
O
Cl
Ha Pa OH
OH
Hb Pb OH
O
Fig. 2 Two chemically equivalent protons Ha and Hb are not mag-
netically equivalent
Table 1 Dissociation and protonation constants of 1-hydroxy-
1,1-bis(H-phosphinic acids) (HPBAs 1–6) at 25 °C
HPBA pKa1
pKa2
Logβ1
Logβ2
1
2
3
4
5
6
8.6 0.6
8.3 0.1
8.65 0.07 9.71 0.05 9.71 0.05 18.36 0.05
11.9 0.4
11.9 0.4
20.6 0.4
9.65 0.08 9.65 0.08 17.96 0.07
8.1 0.7
8.3 0.1
9.86 0.07 9.86 0.07
17.9 0.7
9.33 0.07 9.33 0.07 17.63 0.08
8.63 0.07 9.33 0.05 9.33 0.05 17.96 0.05
1 3

J IRAN CHEM SOC
Fig. 3 a UV–Vis spectra for
titration of Fe3+ (4.2 × 10−5
M) with stepwise addition of
HPBA 1 (0.001 M), b molar
ratio plot ([HPBA 1]/[Fe3+]) for
the investigated complexation
at 450 nm, c respective molar
absorptivity spectra and d
calculated concentration profiles
of the components
well as lanthanide ions La3+, Gd3+ are shown in Table 2.
The data given in Table 2 revealed that the stability of the
complexes of the ligand HPBA 1 with different metal ions
decreases in the order La3+ > Gd3+ > Ni2+ > Ca2+ > Fe3+
> Cu2+ ≫ Cr3+. The comparison of the stability constants
indicates that Gd3+, La3+, Ni2+ have the highest tendency
to make coordination with the ligand HPBA 1. Since alco-
hols are known to be poor donors for the lanthanides, the
results suggest us that the phosphinate groups contribute
to increase the overall stability of the complexes [42]. The
presence of two phosphinic acids in the ligand has an extra
HO
O
O
P
O
O
P
OH
P
H
P
O
HO
O
H
P
O
O
H
H
O
O
O
H
O
OH2
H
O
P
M
H2O
M
M
O
O
H
O
O
OH
H
O
HO
P
O
O
P
P
H
O
O
P
H
C
P
H
HO
H
P
O
O
(b)
(a)
(c)
Fig. 4 Hypothetical structures for ML2 complexes of Mn+
Table 2 Stability constants for the ligand HPBA‑1 and metal ions
Ca2+, Ni2+, Cu2+, Fe3+, Cr3+ and lanthanide ions La3+, Gd3+ at room
temperature, in concentration of 0.05 M NaNO3
coordination number was a common characteristic of all
mole-ratio plots related to the other metal ions complexa-
tion with ligand HPBA 1. It is more likely that the forma-
tion of two six-membered (ML2) chelating rings around
metal ions leads to a more stable square-planar arrange-
ment (Fig. 4) [41]. Stability constants of the resulting ML2
complexes were determined by fitting the experimental data
using a NGL/M method. Figure 3c, d shows concentration
profiles and molar absorptivities of the present chemical
components of titration of Fe3+ with HPBA 1 obtained by
fitting the spectroscopic data.
Metal
logβML2
Ca (II)
Ni (II)
10.8 0.1
10.80 0.09
9.88 0.09
10.55 0.06
–
Cu (II)
Fe (III)
Cr (III)a
La (III)
Gd (III)a
12.6 1.4
11.6 0.2
a
The complexation constant between the ligand (HPBA‑1) and Cr3+
The stability constants of ML2 complexes of the ligand
HPBA 1 and metal ions Ca2+, Ni2+, Cu2+, Fe3+, Cr3+ as
could not be calculated, due to no interaction of Cr3+ with the ligand
1 3

J IRAN CHEM SOC
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