Aminoalkylbis(phosphonates): Their complexation properties in solution and in the solid state

Article abstract of DOI:10.1002/ejic.200600615

Five geminal bis(phosphonates) containing an amino group in the α, γ or δ position of the carbon chain have been synthesised and their acid-base and complexation properties with Cu²⁺, Zn²⁺, Ca²⁺, Mg²⁺ and Na⁺ ions studied by potentiometry. Determination of the stability constants of the complexes with divalent metal ions is complicated by the formation of precipitates. The results of these studies show a negligible effect of the hydroxo group in the α position on the acid-base and complexation properties of the ligands. The presence of an amino group in the α position, however, decreases the basicity, which results in a lower complexation ability of the bis(phosphonates). The crystal structures of the three ligands with different degrees of protonation have also been determined. The structure of the triammonium salt of aminomethylbis(phosphonic acid) shows that the proton is bound to the nitrogen atom in monoprotonated species. The structure of the Cu²⁺ complex of pamidronate [(Cu₂(H₂pam) ₂}·H₂O]_n shows the presence of dimeric units with a relatively short distance (2.99 A) between the metal centres. These units form a coordination polymeric chain. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejic.200600615

FULL PAPER
DOI: 10.1002/ejic.200600615
Aminoalkylbis(phosphonates): Their Complexation Properties in Solution and
in the Solid State
[a]
[a]
[a]
ˇ
ˇ
ˇ[a]
Vojtech Kubícek,* Jan Kotek, Petr Hermann, and Ivan Lukes
Keywords: Phosphonates / Complexation / Stability constants / Potentiometry
Five geminal bis(phosphonates) containing an amino group
bis(phosphonates). The crystal structures of the three ligands
in the α, γ or δ position of the carbon chain have been synthe- with different degrees of protonation have also been deter-
sised and their acid–base and complexation properties with
Cu2+, Zn2+, Ca2+, Mg2+ and Na+ ions studied by potentiome-
try. Determination of the stability constants of the complexes
with divalent metal ions is complicated by the formation of
precipitates. The results of these studies show a negligible
effect of the hydroxo group in the α position on the acid–base
and complexation properties of the ligands. The presence of
an amino group in the α position, however, decreases the ba-
sicity, which results in a lower complexation ability of the
mined. The structure of the triammonium salt of aminometh-
ylbis(phosphonic acid) shows that the proton is bound to the
nitrogen atom in monoprotonated species. The structure of
the Cu2+ complex of pamidronate [{Cu2(H2pam)2}·H2O]n
shows the presence of dimeric units with a relatively short
distance (2.99 Å) between the metal centres. These units
form a coordination polymeric chain.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Recently, attention has been paid to tissue-specific im-
aging and therapy. Attachment of a biologically active
molecule to a molecule of contrast agent results in the bind-
ing of such species to specific tissue and increases their local
concentration. This provides a better contrast and leads to
the use of lower doses of the contrast agents and thera-
peutic agents. In these applications, bis(phosphonates) can
play the role of a targeting group as their conjugate with
the medically active molecule can be swiftly and strongly
adsorbed on the surface of bones and other calcified tis-
sues.[2,3] Recently, we have contributed to this field by study-
ing the bis(phosphonate)-modified macrocyclic ligand
H4dota (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraace-
tic acid), which is useful for targeted visualisation of
calcified tissues by magnetic resonance imaging (MRI) or
other radiodiagnostic/therapeutic treatment.[4]
Most of the clinically used bis(phosphonates) contain an
amino group in the carbon chain. These aminoalkylbis-
(phosphonates) strongly complex transition metal ions. De-
spite this fact, only a few studies have concentrated on their
acid–base and complexation properties,[5–13] and generally
only protonation constants have been determined. In the
case of some ligands, their complexing behaviour with Cu2+
ions has also been studied.[5,6,11,13] Unfortunately, the re-
ported results are not always consistent. Some of the disso-
ciation/protonation constants are beyond the lower or
higher limits of the applied methods and, therefore, they
were not determined. Furthermore, most of the studies were
performed in presence of Na+/K+ ions.[5,6,9–13] As these ions
are complexed by the bis(phosphonates),[14,15] all reported
values of dissociation/protonation and complex stability
Introduction
Pyrophosphate is an important regulator of calcium me-
tabolism in living organisms. Replacement of the bridging
oxygen atom of pyrophosphate with methylene or a substi-
tuted methylene group results in the formation of geminal
bis(phosphonic acids), hereafter referred to simply as bis-
(phosphonates). This group of compounds has been inten-
sively studied over the last fifty years. As the central carbon
atom can be substituted with many different organic
groups, a huge number of bis(phosphonates) have been syn-
thesised. Their low toxicity, high biological stability (they
are not metabolized) and high affinity for calcium and
calcified tissues have made them suitable for many biomedi-
cal applications.[1] After adsorption on the bone surface, bis-
(phosphonates) can affect the functioning of bone cells such
as osteoclasts and osteocysts, which are responsible for
bone formation and desorption. Because of this, bis(phos-
phonates) can be used in the treatment of osteoporosis,
Paget disease and other diseases of calcified tissues. The
large variability of bis(phosphonates) provides a wide scope
of therapeutic effects, and some of the bis(phosphonates)
used therapeutically nowadays are shown in Table 1. Bis-
(phosphonates) form complexes with divalent and trivalent
transition metal ions, and these complexes have been ap-
plied in bone radiotherapy and for palliation of pain associ-
ated with metastatic bone cancer.[1]
[a] Department of Inorganic Chemistry, Charles University,
Hlavova 8, 12840 Prague 2, The Czech Republic
E-mail: vvvojta@volny.cz
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
Eur. J. Inorg. Chem. 2007, 333–344
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
333

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
FULL PAPER
Table 1. Bis(phosphonates) [R1R2C(PO3H2)2] used in medical practice.
Figure 1. Structures of the ligands discussed.
constants are disturbed by the formation of such affects the other protonation constants. The highest dissoci-
complexes. ation constants were determined by NMR titration follow-
In light of this we decided to use the non-complexing ing the procedure described recently in the literature.[17]
tetramethylammonium cation in the supporting electrolyte
to avoid alkali metal complex formation. In this work, we
report on the results of a solution study of four bis(phos-
phonates) containing an amino group in the side chain.
Furthermore, as the bis(phosphonate) moiety is often con-
nected by a peptidic bond in the bifunctional ligands, we
chose a new amide derivative H4aca as a model compound
for comparison (Figure 1). The protonation constants and
stability constants with Cu2+, Zn2+, Ca2+, Mg2+ and Na+
ions are presented. The crystal structures of three ligands
and one Cu2+ complex have also been determined by single-
crystal X-ray diffraction analysis.
The ligands H4pam, H4ale, H4meth and H4prop exhibit
similar acid–base behaviour, with five protonation con-
stants spread over the whole pH range (Table 2). The first
two pKa’s lie in the strongly acidic region and correspond
to the first deprotonation of each phosphonic acid group.
The next constant is found close to the neutral region and
represents release of the third proton from the bis(phos-
phonic acid) group, and the last two constants lie in the
strongly alkaline region. The lower one is usually ascribed
to the last deprotonation of the bis(phosphonic acid) moi-
ety, and the last deprotonation occurs from the amino
group.[18] The last proton is bound to the nitrogen atom
in almost all poly(aminophosphonates).[19] This assignment
can be supported by the crystal structure of the tris(am-
monium) salt of H4meth (see below), whose structure con-
tains a fully deprotonated bis(phosphonic acid) group,
whereas the amino group remains protonated. The pKa val-
ues of H4meth are somewhat distinct from those of the
Results and Discussion
Acid–Base Properties
Phosphonic acids undergo their first deprotonation in other ligands, with the most significant difference being ob-
the strongly acidic (pK1 Յ 2) and the second one in the served for the pKa(HL3–) and pKa(H2L2–) values, which are
weakly acidic region (pK2 = 5–6).[16] A different situation between one and two units lower than those found for the
occurs in the case of bis(phosphonates), where a strong elec- other ligands. Such behaviour can be explained by steric
trostatic interaction between the two geminal phosphonic and/or electronic effects. The protonated amino group on
acid groups results in a large enhancement of the basicity the same carbon atoms can efficiently interact intramolecu-
of the moiety. Furthermore, the presence of an amino group larly (electrostatically and/or through hydrogen bonds[20]
brings another protonation site into the molecule, which with only one negatively charged phosphonate group. The
)
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Eur. J. Inorg. Chem. 2007, 333–344

Aminoalkylbis(phosphonates)
FULL PAPER
Table 2. Values of protonation/dissociation constants of the ligands.
Species
H4pam
logβ
H4ale
H4meth
logβ
H4aca
H4prop
pKa
logβ
pKa
pKa
logβ
pKa
logβ
pKa
HL3–
H2L2–
H3L–
H4L
13.06(3)[a]
23.36(5)
29.21(7)
31.01(9)
–
13.06
10.30
5.85
1.80
Ͻ1.2
12.68(2)[a]
23.75(1)
30.11(1)
32.30(2)
–
12.68
11.07
6.36
2.19
Ͻ1.2
11.43(2)
19.72(3)
25.07(3)
26.25(6)
–
11.43
8.29
5.35
1.18
Ͻ1.2
10.73(4)
18.22(6)
23.98(7)
25.34(8)
–
10.73
7.49
5.76
1.36
–
12.76(2)[a]
23.42(2)
29.57(3)
31.68(4)
–
12.76
10.66
6.15
2.11
Ͻ1.2
H5L+
[a] Determined by NMR titration. No control of the ionic strength.
other ligands with a more flexible carbon chain can be pres- plex with an [H2L2M] stoichiometry is referred to as [221]
ent in conformations where such convenient interaction(s) and the value of its overall stability constant as logβ221. The
with both phosphonate groups are maximized. The strong- charges of the complexes are omitted, and throughout the
est interaction should then be expected for H4pam, which following text pH means –log[H+].
contains the shortest ethylene chain, and, indeed, it exhibits
the most basic last deprotonation. Alternatively, the pres- Divalent Metal Ions
ence of electron withdrawing (protonated) amino and phos-
Speciation of the complexes with biogenic metal ions
phonic acid moieties on the same carbon atom (α to each
(Cu2+, Zn2+, Ca2+ and Mg2+) in aqueous solution was
other) can decrease the values of all dissociation constants.
studied by potentiometry (Figure 2). Following the pro-
A comparison of ligands H4pam and H4prop shows a small
cedure described in the Experimental Section, three sets of
effect of the α-hydroxo group on the acid–base properties
data with ligand-to-metal ratios 1:1, 2:1 and 1:2 were re-
of ligands.
corded for each ion. All these measurements were compli-
The ligand H4aca contains an amide nitrogen atom in-
cated by precipitate formation. In general, the precipitation
stead of an amino group, which means that only four de-
started with increasing abundance of the uncharged [211]
protonation steps can occur. The first one lies in the
complex at a pH between 2.5 and 6.0. The precipitate was
strongly acidic region, with two more in the neutral and the
usually fully dissolved under basic conditions (pH 9–11, de-
last one in the rather alkaline region. When compared with
pending on the ligand and metal combination and ratio; see
other bis(phosphonates) [e.g. methanediphosphonic acid:
Table S1). Additionally, in some cases data could not be
pK(HL3–) = 10.6, pK(H2L2–) = 7.05, pK(H3L–) = 2.77,
recorded due to extended precipitate formation over a wide
pK(H4L) = 1.6],[21] H4aca shows higher overall basicity due
pH range, especially for systems containing H4meth or for
to the higher value of pK(H3L–).
mixtures with an excess of metal ion. Obviously, the sta-
We carried out all measurements in the presence of non-
bility constants of the species abundant mostly in the pH
complexing tetramethylammonium cations to avoid alkali
range where the precipitates were present were not access-
metal ion complex formation, therefore our results differ
ible, which means that a chemical model for many systems
from those reported in the literature (determined in the
does not involve non-protonated species and direct com-
presence of Na+ or K+ ions).[5,6,9–13] The differences are
parison of the complexation properties of different ligands
particularly pronounced in the value of the last dissociation
is somewhat difficult. The results are compiled in Table 3,
constant. In the presence of Na+/K+ ions, the values re-
and all distribution diagrams are provided as Supporting
ported in the literature are lower by one or even two orders
Information (Figures S2–S7).
of magnitude due to alkali metal ion assisted deprotonation
The chemical models for speciation of H4pam, H4ale,
(see Table S2 in the Supporting Information). Although the
H4meth and H4prop complexes are similar. Complexation
stabilities of the K+ complexes of bis(phosphonates) are
starts below pH 2 with formation of the [311] complex. At
much lower than those with Na+, this interaction cannot
higher pH, less protonated species are present. The high
be negligible[14,15] and the values of the dissociation/proton-
negative charge of the fully deprotonated bis(phosphonate)
ation constants should be changed.
group of the ligands disfavours formation of the [021] com-
plexes and only the [121] and [221] species can be found in
mixtures with an excess of the ligands. From a comparison
Complexation Properties
of the constants corresponding to coordination of the first
In order to simplify the following text we will use a three- and second ligand molecules in their monoprotonated form
digit code to describe the composition of the complexes. (i.e. formation of the [111] and [221] complexes; Table 4), it
The first digit represents the number (stoichiometric coeffi- is clear that the second consecutive stability constants are
cient) of protons, the second one is the number of ligand only slightly lower than the first ones. This fact indicates
molecules and the third is the number of metal ions. A negligible steric crowding due to coordination of the first
negative value of the first digit represents a hydroxo com- protonated ligand molecule.
plex or untypical release of a proton(s) from, under com-
In equimolar solutions and at metal excess, 1:2 L:M com-
mon conditions, a fully deprotonated ligand molecule, for plexes are formed under neutral and alkaline conditions. As
example alkoxide anion formation. As an example, a com- one ligand molecule binds two metal ions, all the protons
Eur. J. Inorg. Chem. 2007, 333–344
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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335

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
FULL PAPER
Figure 2. Species distribution plot for aqueous solutions of Cu2+ and H4ale with metal/ligand ratios of 1:1 (A), 1:2 (B) and 2:1 (C); Mg2+
and H4ale 1:1 (D) and 1:2 (E); Na+ and H4ale 10:1 (F). The grey areas were not studied during the experiment due to formation of a
precipitate.
are released and these complexes do not exist in a proton- plex was found in all systems containing H4aca. The sta-
ated form. All systems containing Cu2+ and Zn2+ exhibit a bility constants of H4aca complexes are between the values
high abundance of the [–111], [–112] and [–212] species in found for H4meth and those found for the other ligands. In
the alkaline region. In these complexes, deprotonation of conclusion, the stabilities of the complexes follow the gene-
the coordinated water molecule and/or deprotonation of the ral order H4pam ≈ H4ale ≈ H4prop Ͼ H4aca Ͼ H4meth.
hydroxy group of ligands H4pam and H4ale has to occur,
The solid-state structures of bis(phosphonate) complexes
although these two possibilities could not be distinguished typically show oligomeric or polymeric coordination chains
by potentiometry due to a proton ambiguity. As expected, with the bis(phosphonic acid) group acting as a bridging
the stability of the complexes follows the order Cu2+
Ͼ
moiety.[22] Therefore, the presence of these complicated
Zn2+ Ͼ Mg2+ Ͼ Ca2+. The stabilities of the complexes with structures in solution is expected as well.[18] Unfortunately,
H4pam, H4ale and H4prop are similar, whereas the presence the complexity of the studied systems did not allow us to
of an amino group in the α position decreases the basicity take these multinuclear/polymeric complexes into account
of H4meth and leads to a lower stability of its complexes.
As H4aca contains an amide group instead of an amino
group it prefers to form less protonated complexes and the
complexation process starts at higher pH. The same effect
during the refinement of the potentiometric data.
Sodium
As expected, the complexes with Na+ ion exhibit the low-
was observed for 2:1 L:M complexes, where the [021] com- est stability constants of all the metal ions studied (Table 3),
336
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Eur. J. Inorg. Chem. 2007, 333–344

Aminoalkylbis(phosphonates)
FULL PAPER
Table 3. Stability constants of metal–ligand complexes.
Cation
Cu2+
h
l
m
logβhlm
H4meth
H4pam
H4ale
H4aca
H4prop
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
3
2
1
0
–1
2
1
0
0
–1
–2
1
1
1
1
1
2
2
2
1
1
1
1
1
1
1
1
1
1
1
2
2
2
32.66(8)
29.53(6)
33.82(3)
30.20(3)
24.65(4)
15.09(6)
3.78(5)
41.69(8)
30.90(7)
–
–
32.90(3)
29.30(3)
–
23.95(1)
19.40(3)
13.71(6)
2.98(6)
–
29.02(8)
18.6(1)
–
–
–
–
5.30(9)
42.4(1)
3.14(6)
41.44(8)
30.60(8)
–
24.63(4)
14.76(8)
4.13(6)
–
–
–
18.6(2)
–
23.4(1)
15.31(8)
4.76(8)
–
2.60(7)
Zn2+
3
2
1
0
–1
2
1
0
–1
–2
1
1
1
1
1
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
31.48(4)
28.24(3)
–
11.57(6)
1.12(8)
39.10(8)
–
32.52(2)
28.85(3)
22.68(7)
12.5(1)
1.23(8)
40.43(8)
29.30(9)
–
–
26.74(9)
23.72(6)
–
9.8(1)
–0.79(8)
–
31.75(2)
–
23.54(7)
–
–
24.36(6)
14.78(7)
3.91(7)
44.9(1)
33.9(1)
22.7(1)
–
–1.34(1)
32.17(3)
22.46(7)
–
5.83(4)
–
–
–
13.44(8)
–
–2.64(6)
9.0(2)
–
–
–0.77(8)
–
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
Ca2+
2
1
1
0
1
1
2
1
1
1
1
2
26.70(8)
17.25(8)
20.8(1)
9.1(1)
25.82(2)
15.72(8)
20.00(6)
–
Mg2+
3
2
1
0
2
1
0
0
–1
1
1
1
1
2
2
2
1
1
1
1
1
1
1
1
1
2
2
30.6(2)
26.68(3)
20.08(7)
–
37.3(2)
25.8(1)
–
31.56(6)
26.89(2)
19.78(5)
–
36.19(9)
24.24(8)
–
–
–
–
30.78(9)
26.29(2)
18.80(4)
–
18.2(4)
7.7(4)
32.6(4)
21.6(4)
–
19.79(3)
9.32(5)
–
–
–
–
–
12.54(9)
–
14.86(2)
–
15.2(2)
–
13.9(1)
2.3(1)
–
–
–
–
Na+
3
2
1
0
–1
–2
1
1
1
1
1
1
1
1
1
1
2
2
29.5(1)
24.23(6)
14.82(3)
3.25(2)
–
30.73(6)
24.98(3)
14.43(3)
3.04(2)
–
25.8(1)
20.6(1)
12.83(5)
1.74(4)
–9.51(6)
–
–
30.31(8)
24.46(7)
14.53(4)
–
–7.20(2)
–
19.54(8)
12.36(7)
2.04(5)
–8.52(4)
–
–19.22(2)
–19.26(2)
[a] These systems were not studied due to extensive precipitate formation.
Table 4. Formation constants of the [111] and [221] complexes.
Cu2+:H4ale
Zn2+:H4ale
Zn2+:H4prop
Mg2+:H4pam
Mg2+:H4ale
19.8
16.4
Mg2+:H4meth
M + HL h MHL
MHL + HL h M(HL)2
24.7
17.0
22.7
17.8
24.4
20.5
20.1
17.2
18.2
14.4
therefore a 1:10 L:M ratio was used to obtain a reasonable dance. Formation of the [–112] and [–212] species can be
abundance of the complexes in solution. No precipitation explained by deprotonation of the water molecules coordi-
was observed in these systems. For H4pam, H4ale, H4meth nated to the Na+ ion and/or deprotonation of α-hydroxo
and H4prop, interaction starts below pH 2 with formation group. Although formation of the Na+ hydroxo complexes
of the [311] complex. H4aca exhibits similar differences to is unusual, their inclusion in the calculations significantly
those described above (complexation starts at higher pH (3– improves the fit of the experimental data (Figure S1). The
4) with formation of the [211] complex). Despite a tenfold presence of a hydroxide anion in the solid-state structure of
excess of Na+ ions, less than 60% of the ligand is present trisodium phosphate is well known.[23,24] The stability order
in the form of complexes below pH 10, where only 1:1 L:M of the complexes is the same as that found for the divalent
complexes are present. Under strongly alkaline conditions, metal ions (H4pam ≈ H4ale ≈ H4prop Ͼ H4aca Ͼ H4meth).
the 1:2 L:M hydroxo species are present in significant abun-
Eur. J. Inorg. Chem. 2007, 333–344
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337

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
FULL PAPER
Simulation of Speciation under Physiological Conditions
(phosphonate) ligands. The effect of bioligands on the
abundance of complexes with alkali and alkaline earth
metal ions is probably negligible due to the low stability of
the complexes with these bioligands.
At physiological pH, all studied aminoalkylbis(phos-
phonates) are present mostly in their doubly protonated
form (H2L)2–. As the third dissociation constant of the
amide derivative H4aca is 7.49, both (Haca)2– and (H2aca)–
are present in almost equimolar concentrations at a pH of
around 7. As strongly acidic conditions are necessary for
protonation of bis(phosphonates) to form H4L species,
these compounds remain in the ionised form in living or-
ganisms, thus disfavouring their absorption in the gastroin-
testinal tract upon oral administration.[1]
Crystal Structures
The crystal structures of H4meth, H4aca and H4prop
with various degrees of protonation and the Cu2+ complex
of H4pam were determined.
The phosphonate groups in the structure of H4aca·thf
are fully protonated (Figure 4). A lower hydrophilicity of
the amide-containing ligand results in the formation of a
solvate with one molecule of thf and two layers in the crys-
tal. One layer consists of the ligand molecules, which are
connected to each other by hydrogen bonds, and the second
one is formed by thf molecules (Figure 5, Table S3). The
To demonstrate the speciation of aminoalkylbis(phos-
phonates) in body liquids, we chose the commercially ap-
plied ligand Aledronate (H4ale). With the concentrations of
metal ions commonly found in human blood plasma (Cu2+
:
0.15 µ; Zn2+: 0.2 µ; Ca2+: 3 m; Mg2+: 1 m; Na+:
0.138 )[25] and at physiological pH (7.4), we obtained the
abundances shown in Figure 3. It is evident that the ma-
jority of the ligand (approx. 90%) is bound in the form of
Ca2+, Mg2+ and Na+ complexes. The complexes are un-
charged or singly negatively charged. As the form (free acid/
complex, charge, polarity etc.) could dramatically change
the pharmacological behaviour of the studied compound,
formation of the above-mentioned complexes should be
carefully taken into account during all medical and bio-
logical studies dealing with bis(phosphonates). Whereas al-
kali and alkaline earth metal complexes are preferentially
formed due to high concentration of these metal ions at
higher Aledronate concentrations, at lower Aledronate con-
centrations (Ͻ10–5 ) the high stabilities of the transition
metal complexes become important and increasing abun-
dances of Cu2+ and Zn2+ complexes are obtained. The high
stability of these complexes could decrease the bioavail-
ability of the bis(phosphonate). In real living systems, we
should expect a slightly lower abundance of these com-
plexes due to the presence of many natural ligands (acetate,
Figure 4. The molecular structure of H4aca in the crystal structure
citrate, amino acids, phosphates etc.) that compete with bis- of H4aca·thf.
Figure 3. Simulation of the distribution of Aledronate (H4ale)-containing species in human blood plasma.
338
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2007, 333–344

Aminoalkylbis(phosphonates)
FULL PAPER
position of the thf molecules is stabilized by hydrogen
bonds between the ether oxygen atom and the phosphonate
hydroxo groups of the ligand. The geometry around the
phosphorus atoms is roughly tetrahedral, with slightly
longer P–O distances to the protonated oxygen atoms than
to the phosphoryl oxygen atom (Table 5).
Figure 6. The molecular structure of H3prop– in the crystal struc-
ture of (NH4)(H3prop)·H2O.
The bis(phosphonic acid) group in the single crystals of
(NH4)3(Hmeth)·H2O is fully deprotonated (Figure 7). The
negative charge of the bis(phosphonic) unit is compensated
by three ammonium cations and the protonated amino
group of the ligand molecule. All phosphonate oxygen
atoms are equivalent due to charge delocalisation (Table 5).
An extended hydrogen-bond framework is also found in
this structure. The ammonia cations are bound to phos-
phonate oxygen atoms by strong hydrogen bonds (O–N dis-
tances in the range 2.68–3.01 Å, Table S5). In addition, the
co-crystallised water molecule forms hydrogen bonds with
the phosphonate oxygen atoms (Ow–O distances of 2.77
and 2.90 Å, Table S5). This is the first reported structure to
directly confirm the expected protonation scheme of amino-
alkylbis(phosphonates). As the last proton is localised on
the amino group, this supports the assumption that the fi-
nal dissociation constant corresponds to a release of the
proton from this group.
Figure 5. Crystal packing in the structure of H4aca·thf.
Table 5. Geometry around the phosphorus atoms in the crystal
structures of the free ligands.
H4aca·thf
(NH4)(H3prop)·H2O (NH4)3(Hmeth)·H2O
P1–O11
P1–O12
P1–O13
P1–C1
P2–O21
P2–O22
P2–O23
P2–C1
C1–P1–O11
C1–P1–O12
C1–P1–O13
O11–P1–O12
O11–P1–O13
O12–P1–O13
C1–P2–O21
C1–P2–O22
C1–P2–O23
O21–P2–O22
O21–P2–O23
O22–P2–O23
1.528(1)
1.551(1)
1.495(1)
1.825(2)
1.537(2)
1.542(2)
1.484(1)
1.826(2)
108.6(1)
106.3(1)
107.5(1)
113.2(1)
115.9(1)
104.9(1)
105.8(1)
104.6(1)
112.7(1)
108.7(1)
111.7(1)
112.8(1)
1.572(1)
1.510(1)
1.514(1)
1.812(2)
1.580(1)
1.500(1)
1.514(1)
1.827(2)
106.6(1)
109.4(1)
107.0(1)
108.0(1)
109.6(1)
115.9(1)
104.4(1)
108.1(1)
111.0(1)
109.6(1)
109.4(1)
113.9(1)
1.519(1)
1.529(1)
1.522(1)
1.842(1)
1.520(1)
1.524(1)
1.517(1)
1.839(1)
107.0(1)
103.5(1)
109.0(1)
112.2(1)
112.0(1)
112.5(1)
105.8(1)
107.4(1)
103.8(1)
113.3(1)
113.1(1)
112.6(1)
A
lower degree of protonation was found in
(NH4)(H3prop)·H2O (Figure 6). Each phosphonic acid
group and the amino group binds one proton. The P–O
bonds are noticeably longer to the protonated oxygen
atoms, and the geometry around the phosphorus atoms is
tetrahedral (Table 5). The crystal structure is stabilized by
an extensive three-dimensional framework of hydrogen
bonds between the phosphonate oxygen atoms, the ligand
amino group, the ammonia cations and co-crystallised
water molecule (Table S4).
Figure 7. Molecular structure of (Hmeth)3– in the crystal structure
of (NH4)3(Hmeth)·H2O.
Eur. J. Inorg. Chem. 2007, 333–344
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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339

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
FULL PAPER
Figure 8. Chain design of [Cu2(H2pam)2]n from the crystal structure of the [{Cu2(H2pam)2}·H2O]n. Symmetry operations: a: –x + 2, –y
+ 1, –z + 1; b: x – 1, y, z; c: –x + 1, –y + 1, –z + 1.
The crystal structure of [{Cu2(H2pam)2}·H2O]n shows an to form a four-membered metallacycle with a Cu1–Cu1c
infinite linear polymeric chain. The coordination sphere of separation of 3.21 Å. Each tetragonal pyramid is linked by
the Cu2+ ion is square-pyramidal (Figure 8, Table 6). The a bridging ligand to a neighbouring molecule lying below
basal plane of the pyramid is formed by one oxygen atom the basal plane, with a Cu1–Cu1a separation of 2.99 Å. The
of each phosphonic acid group of two different ligand geometrical parameter τ has a value of 0.005, which corre-
molecules (O11, O21, O13a and O23a), and one of the oxy- sponds to an almost ideal square pyramid (theoretical value
gen atoms of the basal plane of the neighbouring unit is of τ = 0, compared to an ideal trigonal bipyramid with τ
coordinated to the Cu2+ ion in the apical position (O23b) = 1).[26] One uncoordinated phosphonate oxygen atom is
protonated as well as an amino group, and the coordination
polymeric chains are connected by hydrogen bonds
(Table S6).
Table 6. Bond lengths and angles found in the structure of
[{Cu2(H2pam)2}·H2O]n.[a]
The Cu1–Cu1a distance of 2.99 Å in the Cu2(pam)2 moi-
P1–O11
P1–O12
P1–O13
P1–C1
P2–O21
P2–O22
P2–O23
P2–C1
C1–P1–O11
C1–P1–O12
C1–P1–O13
O11–P1–O12
O11–P1–O13
O12–P1–O13
C1–P2–O21
C1–P2–O22
C1–P2–O23
O21–P2–O22
O21–P2–O23
O22–P2–O23
1.530(1)
1.539(2)
1.522(2)
1.838(2)
1.532(1)
1.520(1)
1.534(1)
1.852(2)
107.1(1)
104.1(1)
108.4(1)
111.2(1)
113.6(1)
111.9(1)
106.2(1)
109.0(1)
104.6(1)
113.4(1)
112.8(1)
110.4(1)
Cu1–O13a
Cu1–O11
Cu1–O21
Cu1–O23a
Cu1–O23b
1.953(1)
1.966(1)
1.986(1)
2.011(1)
2.191(1)
ety is too long for metal–metal bond formation. A similar
design was previously found for Cu2+ complexes of 1-
hydroxyethyl-1,1-bis(phosphonic acid),[27] with protonated
diaminoalkanes as counter cations. These compounds show
a moderately strong antiferromagnetic interaction.[27,28]
O13a–Cu1–O11
O13a–Cu1–O21
O13a–Cu1–O23a
O13a–Cu1–O23b
O11–Cu1–O21
O11–Cu1–O23a
O11–Cu1–O23b
O21–Cu1–O23a
O21–Cu1–O23b
O23a–Cu1–O23b
167.0(1)
90.1(1)
89.0(1)
100.7(1)
90.5(1)
87.7(1)
91.1(1)
167.4(1)
112.2(1)
80.4(1)
Conclusions
We have reported the acid–base and complexation behav-
iour of five bis(phosphonate) ligands containing an amino
group in the side chain. The protonation constants and sta-
bility constants of their complexes with Cu2+, Zn2+, Ca2+
,
Mg2+ and Na+ ions have been determined by means of
potentiometric titrations. The bis(phosphonic acid) group
exhibits four dissociation constants — two in the strongly
acidic region, the third in the neutral region and the last
one in the alkaline region. The amino groups undergo de-
protonation under strongly alkaline conditions. Determi-
[a] Symmetry operations: a: –x + 2, –y + 1, –z + 1; b: x – 1, y, z;
c: –x + 1, –y + 1, –z + 1.
340
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Aminoalkylbis(phosphonates)
FULL PAPER
acetonitrile (50 mL) was added dropwise to a solution of acetyl
chloride (3.0 g, 38.2 mmol) and Na2CO3 (5.2 g, 49 mmol) in dry
acetonitrile (50 mL) at –40 °C. After the addition was finished, the
mixture was warmed slowly to room temperature and stirred over-
night. After treatment with charcoal and filtration, the unreacted
acetyl chloride was removed by repeated vacuum evaporation with
toluene. The product was obtained as a colourless oil in a yield of
4.4 g (97%). C7H17NO8P2: calcd. C 29.28, H 5.27, N 4.88; found
C 29.42, H 5.41, N 4.25. 1H NMR (CDCl3): δ = 1.34 (m, 12 H,
nation of the stability constants was complicated by the pre-
cipitation of insoluble complexes. The stability constants of
the complexes follow the order H4pam ≈ H4ale ≈ H4prop Ͼ
H4aca Ͼ H4meth. Complicated chemical models containing
complexes with 1:1, 2:1 and 1:2 L:M ratios and various de-
grees of protonation were found for all systems with di-
valent metals. In Na+-containing systems, 1:1 complexes co-
ver the whole pH scale except strongly alkaline conditions,
where 2:1 complexes are present. A comparison of the
CH2CH3), 2.08 (s, 3 H, CH3CO), 4.19 (m, 8 H, OCH2), 5.06 (td,
3
properties of the studied ligands has shown a negligible ef- 2JP,H = 21.4, JH,H = 10.4 Hz, 1 H, PCHP), 6.75 (br. s, 1 H, NH)
2
ppm. 31P NMR (CDCl3): δ = 17.0 ppm (d, JH,P = 21.4 Hz). ESI/
fect of the α-hydroxy group on the acid–base and coordina-
tion properties of the bis(phosphonates), whereas the pres-
MS: calculated 368.3; found 368.3 [M + Na+].
ence of the amino group in the α position significantly de-
creases the overall basicity of the ligand and the stability of amidomethylbis(phosphonate) (3.0 g, 8.7 mmol) was dissolved in
Acetamidomethylbis(phosphonic acid) (H4aca): Tetraethyl acet-
30% HBr/AcOH (50 mL) in a 100-mL flask and stirred for 24 h
at room temperature. After removal of the volatiles on a rotary
evaporator, the resulting oil was dissolved in EtOH (30 mL). Pre-
cipitation of the crude product from solution occurred on standing.
After 3 h, the precipitate was filtered off and extracted with boiling
EtOH (100 mL). After filtration with charcoal, volatiles were re-
moved in vacuo. The crude product was recrystallised from water
by addition of thf. The product was filtered, washed with thf and
dried at room temperature over P2O5. Yield: 1.7 g (63%) as adduct
6·thf. C7H17NO8P2: calcd. C 27.55, H 5.61, N 4.59; found C 27.62,
its complexes. Simulation of Aledronate (H4ale) speciation
in human blood plasma shows a high abundance of Ca2+
,
Mg2+ and Na+ complexes. At lower overall concentrations
of bis(phosphonate), increasing abundances of Cu2+ and
Zn2+ complexes are expected. The crystal structures of the
ligands show a different degree of protonation. The struc-
ture of the triammonium salt of aminomethylbis(phos-
phonic acid), which contains a monoprotonated ligand
molecule, nicely documents the protonation scheme of the
studied compounds — the last proton is released from the H 5.60, N 4.35. 1H NMR (D2O/NaOD): δ = 1.63 (m, 4 H,
amino group. The crystal structure of the Cu2+ complex of
CH2CH2CH2 thf), δ = 1.94 (s, 3 H, CH3CO), δ = 3.49 (m, 4 H,
2
CH2CH2O thf), 4.46 (t, JP,H = 21.3 Hz, 1 H, PCHP) ppm. 31P
H4pam shows a polymeric coordination chain. The square-
2
pyramidal coordination sphere of Cu2+ contains five oxy-
NMR (D2O/NaOD): δ = 17.0 ppm (d, JH,P = 21.3 Hz). ESI/MS:
calculated 256.0; found 255.8 [M + Na+].
gen atoms from five different phosphonic acid groups. In
Crystal-Structure Determination: Single crystals of H4aca·thf were
selected from the recrystallised matter before the filtration. Single
crystals of (NH4)(H3prop)·H2O were prepared by the following
method: H4prop was dissolved in concentrated ammonia, the solu-
tion was evaporated, and the oily residue was dissolved in water
and crystallised by slow vapour diffusion of iPrOH into the solu-
tion. Single crystals of (NH4)3(Hmeth)·H2O were prepared by slow
vapour diffusion of EtOH into a solution of H4meth in 5% ammo-
nia. Single crystals of [{Cu2(H2pam)2}·H2O]n were prepared by hy-
drothermal synthesis. Thus, H4pam (352.5 mg, 1.50 mmol) and
CuCO3 (185.1 mg, 1.50 mmol) were suspended in water (30 mL)
and the mixture was heated at 70 °C in a closed flask. After three
weeks, shiny greenish-blue needles of [{Cu2(H2pam)2}·H2O]n had
formed. They were decanted off and dried in air. Yield: 446.3 mg
(95%). C6H20Cu2N2O15P4: calcd. C 20.79, H 3.30, N 4.58; found
C 21.05, H 3.48, N 4.39.
The selected crystals were mounted on glass fibres in a random
orientation in silicone grease or epoxide glue. Diffraction data were
collected using graphite-monochromated Mo-Kα radiation with an
Enraf–Nonius KappaCCD diffractometer at 150(1) K [Cryostream
Cooler (Oxford Cryosystem)] or 294(1) K and analysed using the
HKL DENZO program package.[32] The structures were solved by
direct methods, and refined by full-matrix least-squares techniques
(SIR92,[33] SHELXL97[34]). The scattering factors used for neutral
atoms were included in the SHELXL97 program. In the case of
[{Cu2(H2pam)2}·H2O]n a Gaussian absorption correction was ap-
plied.[35] Further details are given in Table 7.
the polymeric chain, two tetragonal pyramids are oriented
towards each other and their basal planes are linked to-
gether with a Cu–Cu distance of 2.99 Å.
Experimental Section
Materials and Methods: Commercially available chemicals were of
synthetic purity and were used as received. Acetonitrile was dried
by distillation from P2O5. Elemental analyses were performed at
the Institute of Macromolecular Chemistry (Academy of Science
of the Czech Republic, Prague). 1H (400 MHz) and 31P
(161.9 MHz) NMR spectra were recorded with a Varian UNITY
PLUS-400 spectrometer in 5-mm sample tubes. NMR experiments
were performed at 298 K. For the measurements in D2O, tert-butyl
alcohol was used as an internal standard with the methyl signal
referenced to δ = 1.20 ppm (1H). For the measurements in CDCl3,
tetramethylsilane was used as an internal standard with the methyl
signal referenced to δ = 0.00 ppm (1H). The 31P chemical shifts
were measured with respect to 1% H3PO4 in D2O as an external
standard (substitution method). Mass spectra were recorded with
a Bruker Esquire 3000 spectrometer equipped with an electrospray
ion source and an ion trap detector. All measurements were carried
out in the positive-ion mode.
Synthesis: Ligands H4pam,[29] H4ale,[29] H4meth[30] and H4prop[31]
were prepared by modification of reported procedures. The ligands
were chemically pure (NMR, MS) and composition of the samples
was checked by elemental analysis; see the Supporting Information
for full experimental and analytical details, and discussion of the
synthesis.
All non-hydrogen atoms were refined anisotropically. In the struc-
ture of H4aca·thf, the molecule of tetrahydrofuran solvate was
found to be very disordered. This disorder was refined by splitting
the carbon chain into two positions with occupancies of 61:39. The
hydrogen atoms of the ligand molecule were localised in the elec-
tronic density difference map, however, they were fixed in theoreti-
Tetraethyl Acetamidomethylbis(phosphonate): A solution of tetra-
ethyl aminomethylbis(phosphonate)[30] (4.0 g, 13.2 mmol) in dry
Eur. J. Inorg. Chem. 2007, 333–344
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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341

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
FULL PAPER
Table 7. Experimental data of reported crystal structures.
H4aca·thf
(NH4)(H3prop)·H2O
(NH4)3(Hmeth)·H2O
{[Cu2(H2pam)2]·H2O}n
Formula
Molecular wt.
Colour
C7H17NO8P2
305.16
colourless
rod
C3H16N2O7P2
254.12
colourless
plate
CH18N4O7P2
260.13
colourless
prism
C3H11CuNO8P2
314.61
greenish blue
rod
Shape
Dimensions [mm]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
0.10ϫ0.25ϫ0.50
triclinic
P1 (no. 2)
0.03ϫ0.20ϫ0.28
monoclinic
C2/c (no. 15)
13.0593(3)
7.2487(2)
21.3368(5)
90
100.0962(15)
90
1988.53(9)
8
0.33ϫ0.40ϫ0.50
orthorhombic
Pna21 (no. 62)
17.9266(1)
9.6087(2)
6.2007(4)
90
0.13ϫ0.15ϫ0.40
monoclinic
P21/c (no. 14)
5.4824(1)
14.3335(4)
11.6411(3)
90
103.1868(15)
90
890.66(4)
4
¯
5.2717(2)
9.5220(3)
13.1921(5)
89.261(2)
85.688(2)
76.917(3)
643.19(4)
2
α [°]
β [°]
90
90
γ [°]
V [Å3]
1068.08(7)
4
1.618
Z
Dc [gcm–3]
T [K]
1.576
294(1)
1.698
150(1)
2.346
150(1)
150(1)
θ range [°]
Index ranges
3.10–27.50
–6 Յ h Յ 6
–11 Յ k Յ 12
–17 Յ l Յ 17
0.370
1.94–27.48
–16 Յ h Յ 16
–9 Յ k Յ 9
–27 Յ l Յ 27
0.455
2.40–27.49
–23 Յ h Յ 23
–12 Յ k Յ 12
–8 Յ l Յ 8
0.430
3.36–27.48
–7 Յ h Յ 6
–18 Յ k Յ 18
–15 Յ l Յ 15
2.839
µ [mm–1]
F(000)
Independent data
320
2920
1072
2280
552
2325
636
2026
Observed data [Io Ͼ 2σ(Io)] 2530
1950
128
1.067
2285
200
1.080
1940
137
1.110
Parameters
191
1.051
Gof on F2
R, RЈ (all data)
wR, wRЈ (all data)
0.0389, 0.0462
0.0993, 0.1056
0.0309, 0.0398
0.0763, 0.0806
0.0183, 0.0190
0.0470, 0.0477
0.0221, 0.0232
0.0587, 0.0592
cal (H–C) or original (H–O,N) positions with thermal parameters
Ueq(H) = 1.2Ueq(C) or 1.3Ueq(N,O) as the free refinement led to
unrealistic bond lengths and angles. Hydrogen atoms belonging to
solvate thf molecule were fixed in theoretical positions using a ri-
ding model. In the structure of (NH4)3(Hmeth)·H2O, all hydrogen
atoms were refined isotropically. In the structures of
(NH4)(H3prop)·H2O and [{Cu2(H2pam)2}·H2O]n, the hydrogen
atoms were localised in the electronic density difference map, but
they were fixed in theoretical (H–C) or original (H–O,N) positions
using a riding model with Ueq(H) = 1.2Ueq(C) or 1.3Ueq(N,O) as
the free refinement led to unrealistic bond lengths and angles. The
independent unit of (NH4)(H3prop)·H2O consists of a ligand mole-
cule, two ammonium cations occupying special positions (with
half-occupancy) and one water molecule. In the other structures,
no special positions are occupied. The non-centrosymmetric struc-
ture of (NH4)3(Hmeth)·H2O was refined with a contribution of ra-
cemic twinning with a ratio between both antipodes 62:38.
hydroxide solution was standardised against potassium hydrogen
phthalate and the HCl solution against the approx. 0.2  NMe4OH
solution. Stock solutions of the individual metal cations were pre-
pared by dissolving hydrates of M(NO3)2 or dried NaCl. The di-
valent metal ion contents in the stock solutions were determined
by titration with standard Na2H2edta solution. The analytical con-
centration of ligand stock solution was determined together with
refinement of protonation constants with the OPIUM[37] software
package (see below).
Potentiometric Titrations: Titrations were carried out in a vessel
thermostatted at 25.0Ϯ0.1 °C, at an ionic strength I = 0.1 
(NMe4Cl) and in the presence of extra HCl in the pH range 1.7–
11.9 (protonation constants and complex with Na+) using a PHM
240 pH-meter, a 2-mL ABU 900 automatic piston burette and a
GK 2401B combined electrode (all from Radiometer, Denmark).
For systems with divalent metal ions, a precipitate was usually pres-
ent at pH’s between about 4 and 9, so data for this region were not
collected. The initial volume was 5 mL and the concentration of
the ligand was about 0.004 . L:M molar ratios of 1:10 (Na+ sys-
tem), 1:1, 2:1 and 1:2 (other systems) were used. Five parallel ti-
trations were carried out for each ratio, with each titration con-
sisting of 40–50 points. An inert atmosphere was ensured by con-
stant passage of argon saturated with the vapour of the solvent
used in the measurements.
CCDC-612685 (H4aca·thf), -612687 [(NH4)(H3prop)·H2O], -612686
[(NH4)3Hmeth·H2O] and -612688 [{Cu2(H2pam)2}·H2O]n contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Determination of Dissociation and Stability Constants
Chemicals and Stock Solutions for Potentiometric Titrations: Water
was purified with a Milli-Q (Millipore) purification system. The
stock solution of hydrochloric acid (ca. 0.03 ) was prepared from
a 35% aqueous solution (puriss., Fluka). Commercial NMe4Cl
(99%, Fluka) was recrystallised from boiling iPrOH and the solid
salt was dried with P2O5 in vacuo to constant weight (this dried
salt is extremely hygroscopic).[36] Carbonate-free NMe4OH solution
(ca. 0.2 ) was prepared from this NMe4Cl by ion exchange on
Dowex 1 (OH– form, under argon, with carbonate-free water). The
The constants (with their standard deviations) were calculated with
the program OPIUM.[37] This program minimizes the criterion of
the generalized least-squares method using the calibration function
E = E0 + Slog[H+] + j1 [H+] + j2 Kw/[H+]
where the additive term E0 contains the standard potentials of the
electrodes used and the contributions of inert ions to the liquid-
junction potential, S corresponds to the Nernstian slope, the value
342
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2007, 333–344

Aminoalkylbis(phosphonates)
FULL PAPER
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all systems studied are shown in Figures S2–S7. The hydrogen-
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Acknowledgments
Support from the Grant Agency of the Czech Republic (no. 203/06/
0467) and the Grant Agency of Academy of Science of the Czech
Republic (no. KAN201110651; program “Nanotechnology for So-
ciety”) is acknowledged. This work was carried out in the frame-
work of COST D38 and the NoE projects supported by the Euro-
pean Union, EMIL (no. LSHC-2004-503569) and DiMI (no.
LSHB-2005-512146). We thank Ms. M. Malíková for her help with
the titration experiments.
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343

V. Ku b ícˇek, J. Kotek, P. Hermann, I. Lukesˇ
[37] M. Kývala, I. Lukesˇ, International Conference on Chemometrics [38] C. F. Baes Jr., R. E. Mesmer, The Hydrolysis of Cations, Wiley,
FULL PAPER
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OPIUM is available (free of charge) from http://www.natur.cu-
ni.cz/~kyvala/opium.html.
New York, 1976.
Received: June 29, 2006
Published Online: November 3, 2006
344
www.eurjic.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2007, 333–344