Aminoalkyl-1,1-bis(phosphinic acids): Stability, acid-base, and coordination properties

Article abstract of DOI:10.1002/ejic.201402420

Four geminal bis(phosphinic acids), namely, aminomethylbis(H-phosphinic acid) (H₂L¹) and 4-aminobutyl-1-hydroxy-1,1-bis(R-phosphinic acid) with R = H (H₂L²), Me (H₂L³) and CH₂CH₂COOH (H₄L⁴), were studied. Their acid-base properties and coordination ability towards Cu²⁺, Ni²⁺ and Zn²⁺ ions were studied by potentiometry, UV/Vis spectroscopy and NMR spectroscopy. The amine group in H₂L¹ has a lower protonation constant (log K_a = 6.79) than those found for other studied bisphosphinates (log K_a = 10.75-11.05) with distant amine groups. The structure of [Ca(H₂L²-O,O')(HL²-O,O')]Cl revealed an octahedral arrangement of the metal coordination sphere and a linear polymeric structure, which forms through eight-membered Ca(-O-P-O-)₂Ca rings. The structure of [Cu(HL³-O,O')₂(H₂O)]·5H₂O shows two chelating bisphosphinate groups in an equatorial O₄ environment. The structure of [Cu(H_0.5L³-O,O')(NO₃)_0.5]·2.25H₂O shows two different coordination environments, one is an elongated tetragonal pyramid, and the other is a trigonal bipyramid with a bidentate nitrate ion. Four geminal bisphosphinates were synthesized, and their acid-base properties and coordination behaviour with Cu²⁺, Zn²⁺ and Ni²⁺ ions were studied. The compounds show lower amine basicity and complex stability constants than those of analogous bisphosphonates. In the solid-state structures of the Ca²⁺ and Cu²⁺ complexes, the bisphosphinates are coordinated in O,O'-chelating mode.

Full text of DOI:10.1002/ejic.201402420

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DOI:10.1002/ejic.201402420
Aminoalkyl-1,1-bis(phosphinic acids):
Stability, Acid–Base, and Coordination Properties
[a]
[a]
[a]
ˇ
ˇ
Tomás David, Sona Procházková, Jan Kotek,
[a]
[a]
ˇ
ˇ
ˇ[a]
Vojtech Kubícek,* Petr Hermann, and Ivan Lukes
Keywords: Ligand design / O ligands / Phosphinic acids / Hydrolytic stability / Stability constants / Acidity
Four geminal bis(phosphinic acids), namely, aminomethyl-
bis(H-phosphinic acid) (H2L1) and 4-aminobutyl-1-
hydroxy-1,1-bis(R-phosphinic acid) with R = H (H2L2), Me
(H2L3) and CH2CH2COOH (H4L4), were studied. Their acid–
base properties and coordination ability towards Cu2+, Ni2+
and Zn2+ ions were studied by potentiometry, UV/Vis spec-
troscopy and NMR spectroscopy. The amine group in H2L1
has a lower protonation constant (logKa = 6.79) than those
found for other studied bisphosphinates (logKa = 10.75–
11.05) with distant amine groups. The structure of [Ca(H2L2-
O,OЈ)(HL2-O,OЈ)]Cl revealed an octahedral arrangement of
the metal coordination sphere and a linear polymeric struc-
ture, which forms through eight-membered Ca(–O–P–O–)2Ca
rings. The structure of [Cu(HL3-O,OЈ)2(H2O)]·5H2O shows
two chelating bisphosphinate groups in an equatorial O4 en-
vironment. The structure of [Cu(H0.5L3-O,OЈ)(NO3)0.5]·
2.25H2O shows two different coordination environments, one
is an elongated tetragonal pyramid, and the other is a trigo-
nal bipyramid with a bidentate nitrate ion.
or tyrosine phosphatase;[16] however, their high hydroxyapa-
tite affinity excludes any biomedical application that is not
related to bone tissue.
Introduction
Geminal bisphosphonates (BPs) are an important group
of organophosphorus compounds. The proximity of two
phosphonate groups leads to strong chelating ability[1] and
strong interactions with the surfaces of various inorganic
materials.[2,3] Their high affinity to hydroxyapatite, which
is the main inorganic component of bone tissue, provides
extensive medical applications in the treatment of osteopo-
rosis and other diseases of calcified tissues.[4] The anchoring
of BPs on the surface of titanium dioxide,[5–7] iron ox-
ides[8–11] and many other inorganic materials has been em-
ployed in a broad range of academic and industrial applica-
tions.[2,3,12,13] An important class of BPs are those that bear
an amine group in the side chain. They show specific phar-
maceutical properties and, in addition, the amine group can
be utilized as a reactive moiety for the attachment of vari-
ous functionalities such as different drugs, fluorescent lab-
els, complexes of metal radioisotopes or peptides to deliver
their cargo to bone or calcified tissues.[12–15] Bisphosphon-
ates may also act as inhibitors in biochemical pathways as
they interact with the metal ions that are typically present
in the active centres of enzymes such as adenosinetriphos-
phatases (ATPases), farnesyl transferase, squalene synthase
The coordination properties of the geminal bisphos-
phonate group have been found to be very advantageous.
Thus, polydentate ligands bearing this group have been de-
signed and synthesized, and their coordination to metal
ions in aqueous solutions as well as in the solid state has
been investigated.[1] The geminal bisphosphonate group in-
teracts strongly with hard metal ions and often bridges two
or more metal ions to form polymeric structures. Owing to
its excellent coordination ability, the bisphosphonate group
might be considered as an excellent building block in the
design of polydentate ligands. These ligands are mainly in-
vestigated as metal carriers for biomedical applications such
as magnetic resonance imaging (MRI), radiodiagnosis
[positron emission tomography (PET) and single-photon
emission computed tomography (SPECT)] or radiotherapy.
However, the strong adsorption to bone mineral and the
strong affinity to inorganic materials disable some applica-
tions of the bisphosphonate conjugates in biomedical fields.
This disadvantage of bisphosphonates could be over-
come through the use of geminal bisphosphinates
(Scheme 1), which have a similar metal-ion binding motif
to that of BPs but show negligible adsorption on inorganic
surfaces.[17,18] Unlike BPs, much less attention has been de-
voted to geminal bisphosphinates,[19–21] and only a few
complexation studies have been published.[22] Whereas re-
search on BPs is mostly focused on bone or calcium-related
issues, bisphosphinates might be studied as inhibitors of
[a] Department of Inorganic Chemistry, Faculty of Science,
Charles University in Prague,
Hlavova 2030, 128 40 Prague 2, Czech Republic
E-mail: kubicek@natur.cuni.cz
www: http://web.natur.cuni.cz/anorchem/19/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201402420.
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various enzymes or as chelating groups in biomedical appli-
Results and Discussion
cations for which strong bone affinity is undesirable.
Furthermore, bisphosphinates offer new structural motifs
(Scheme 1) as each phosphinate group can be attached to
two carbon atoms. This allows the synthesis of polydentate
ligands bearing bisphosphinate groups in the middle of a
polyamine chain, for example, and fine tuning of the coor-
dination properties of such ligands. Owing to their chain-
forming ability, the bisphosphinate ligands might be inter-
esting building blocks for metal–organic framework (MOF)
materials.
Synthesis and Stability of the Ligands
The synthetic pathways used for preparation of H2L1,
H2L2, H2L3 and H4L4 are depicted in Schemes 3 and 4.
Compound H2L1 was synthesized by modification of the
previously reported method that utilizes the reaction of
ethyl formimidate (I) with bis(trimethylsilyl)hypophosphite
(IIa).[24] Our approach employs the in situ formation of the
pyrophoric phosphine IIa and an easy purification without
the need to distil the silylated intermediate. Compounds
H2L2, H2L3 and H4L4 were synthesized by the reaction of
the N-protected 4-aminobutanoyl chloride IV with 2 equiv.
of phosphine IIa or the appropriate bis(trimethylsilyl)phos-
phonite IIb or IIc. The reaction is analogous to those pre-
viously reported for geminal bis(H-phosphinates)[18,25] and
for cyclic aminobisphosphinates.[20] The protected interme-
diates Va–Vc were treated with aqueous HCl or with
hydrazine to remove the phthalimide protecting group; the
tert-butyl ester groups of Vc were also removed during the
reaction with hydrazine. The reaction mixture obtained af-
ter the deprotection of Vc contained a side-product
(ca. 30%), which was identified as the monohydrazide of
H4L4 (Figure S1).
Scheme 1. General structure of bisphosphinates and their possible
utilization as chain-forming groups.
Recently, we have reported on 1-hydroxyalkyl-bis(H-
phosphinic acids)[18] and symmetrical methylene-bis-
[(aminomethyl)phosphinic acids] (Scheme 2, H2L5–H2L7)
with amine groups at the opposite ends of the molecules.[23]
As a continuation of this study, we present here four gemi-
nal bisphosphinates, H2L1, H2L2, H2L3 and H4L4, with an
aminoalkyl group attached to the central carbon atom
(Scheme 2). They are analogues of aminomethyl-bis(phos-
phonic acid) (H4meth) and 4-aminobutyl-1-hydroxy-1,1-bis-
(phosphonic acid) (alendronate, H4ale). The acid–base
properties and coordination ability of these new bisphos-
phinates were studied to get more information on this class
of chelating agents and to define structural motifs suitable
for molecules/conjugates for which low bone affinity and a
rather weak complexing power are necessary requirements.
The data will be used in the design of polydentate ligands
for biomedical applications.
Scheme 3. Synthesis of H2L1. Reagents and conditions: (a) HMDS,
100 °C; (b) 1. CH2Cl2, r.t.; 2. EtOH, r.t.; (c) 1 m aq. HCl, 80 °C.
The bis(phosphinic acids) H2L1 and H2L2 show limited
stability in aqueous solutions owing to the presence of gem-
inal H-phosphinic acid groups. The decomposition is very
slow in alkaline solutions (1 m aq. NaOH), and only traces
(Ͻ10%) of decomposition products were found after 20 d
at 80 °C. On the contrary, both compounds show complete
decomposition in acidic media (1 m aq. HCl). The half-lives
of H2L1 and H2L2 were 3.2 and 194 h at 80 °C, respectively
(Figure S2). In the latter case, the value is in the same range
as the half-lives previously reported for other geminal
bis(H-phosphinic acids),[18] and the decomposition (for-
mally, hydrolysis) yields the appropriate α-hydroxyalkyl(H-
phosphinic acid) VI and phosphorous acid. On the con-
trary, the decomposition of H2L1 in acidic solution is signif-
icantly faster, which indicates the low stability of the amino-
methyl-bis(H-phosphinic acid) fragment. The decomposi-
tion quantitatively yields aminomethyl-(H-phosphinic acid)
(III, Scheme 3)[26] and 4-amino-1-hydroxybutylphosphinic
acid (VI, Scheme 4);[27] it could be considered as a new syn-
Scheme 2. Structures of studied aminoalkyl-1,1-bisphosphinates
and related compounds.
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phinate groups in comparison with that of fully ionized
phosphonates; the fully deprotonated phosphonate group
is strongly electron-donating and increases the basicity of
adjacent amine groups.[29] The other protonation constants
of H2L3 are ascribed to the protonation of the bisphosphin-
ate groups and they are similar to those previously pub-
lished for H2pcpPh (Scheme 2, Table 1).[30] For H4L4, the
next two protonations are for the carboxylate groups, and
the last determined protonation constant belongs to a phos-
phinate group. The values are in the expected range for
–
–
the –PO2 –CH2CH2CO2 fragment.[31,32] The protonation
constant of the second phosphinate group was not access-
ible as it is too low to be determined by potentiometry. The
hydroxy group cannot undergo deprotonation in aqueous
solution unless metal ions are present (see below).
The coordination properties of the bisphosphinates were
studied in the systems with Cu2+, Zn2+ and Ni2+ ions for
1:1, 1:2 and 2:1 (2:1 only for ligand H4L4) metal/ligand ra-
tios. The results are summarized in Tables 2 and S1, and
the distribution diagrams are shown in Figures 1 and S5–
S10. The dominant complexes formed are those with 1:1
M/L ratios. Complexation starts at pHϽ 2 with the forma-
tion of protonated complexes. The protons are very
probably localized on the amine and/or carboxylate groups
(for H4L4). The stability constants (logKML) are higher for
H4L4, in agreement with the higher basicity of its amine
group and with the higher denticity of the ligand owing
to presence of the additional carboxylate group. The lower
overall basicities of H2L3 and H4L4 lead to lower stability
constants for their complexes than the logKML values for
the complexes of their bisphosphonate analogues H4meth
and H4ale (Table 2).[28] Surprisingly, the Zn2+ complexes
show higher stability than the Ni2+ complexes, which points
to a rather hard character for the studied bisphosphinate
ligands.
Scheme 4. Synthesis of the studied bisphosphinates. Reagents and
conditions: (a) TMSCl/DIPEA, CH2Cl2, r.t.; (b) 1. CH2Cl2, r.t.;
2. EtOH, r.t.; (c) N2H4·H2O in EtOH, r.t.; or conc. aq. HCl, reflux;
(d) 1 m aq. HCl, 80 °C. Pht = phthaloyl.
thetic route for the preparation of H-phosphinic acids. On
the other hand, H2L3 and H4L4 are fully stable in aqueous
solution at any pH.
Acid–Base and Coordination Properties
The solution behaviour of the hydrolytically stable gemi-
nal bisphosphinates H2L3 and H4L4 and their complexes
was studied by potentiometry. In parallel, the protonation
constant of the amine group, which is the crucial factor for
the coordination properties of the ligands, was determined
by NMR titration of H2L1 and H2L2 (Figures S3 and S4).
The protonation constants of the [LM] or [HLM] species
The values of the protonation constants are summarized in indicate that the protons are bound to distant amine and/
Table 1. The highest constant was assigned to the proton- or carboxylate groups, and the ligands are probably coordi-
ation of the amine group (for the protonation schemes see nated only through the phosphinate groups, as was similarly
Schemes S1 and S2). The basicity of the amine group in found for the complexes in the solid state (see below). In
H2L1 was found to be significantly lower than those of most of the studied systems, the stabilities of the complexes
H2L2, H2L3 and H2L4 owing to the presence of two prox- are not high enough to prevent the precipitation of the
imate strongly electron-withdrawing H-phosphinate groups. metal hydroxides and, thus, the titrations had to be termin-
In addition, the basicities of the studied compounds are ated in the neutral region. That was not the case for the
significantly lower than those published for the analogous Cu2+/H2L3, Cu2+/H4L4 and Ni2+/H2L3 systems, for which
BPs H4meth and H4ale (Scheme 2, Table 1).[28] This could [H–1LM] and [H–2LM] species were identified; here, the
be explained by the lower charge of the deprotonated phos- negative index values represent the formation of hydroxido
Table 1. Overall (logβ) and stepwise (pKa) protonation constants of the studied geminal bisphosphinates and related ligands.
H2L1[a]
pKa
H2L2[a]
pKa
H2L3[b]
pKa
H4L4[b]
pKa
H4meth[c]
pKa
H4ale[c]
pKa
H2pcpPh[d]
pKa
Species
logβ
logβ
HL
6.79(2)
10.78(3)
10.75(1)
14.38(2)
16.33(2)
–
10.75
3.63
1.95
–
11.05(1)
16.43(1)
20.74(1)
23.35(1)
11.05
5.38
4.31
2.61
11.43
8.29
5.35
1.18
12.68
11.07
6.36
3.33
1.35
–
[e]
[e]
H2L
H3L
H4L
[e]
[e]
–
–
2.19
–
[a] This work, determined by 1H and 31P NMR spectroscopy (25 °C, without ionic strength control). [b] This work, determined by
potentiometry (25 °C, I = 0.1 m KNO3). [c] Determined by potentiometry [25 °C, I = 0.1 m (NMe4)Cl].[28] [d] Determined by potentiometry
[25 °C, I = 0.5 m (NMe4)Cl].[30] [e] Not determined owing to the low stability of the compounds under acidic conditions.
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Table 2. Equilibrium constants (25 °C, I = 0.1 m KNO3) of the pH. In addition, the metal-induced deprotonation is driven
complexes in the systems containing the title ligands and selected
by the formation of two five-membered chelate rings. Anal-
divalent metal ions. The negative hydrogen stoichiometry repre-
ogous behaviour has been reported recently for the P-
sents the formation/coordination of alcoholate anion or formation
methylhydroxy group of the hydroxymethylene-bis[(amino-
of hydroxido complexes.
methyl)phosphinates] H2L5 and H2L6 (Scheme 2)[22] and
Metal ion
Cu2+
Equilibrium
H2L3
H2L4
macrocyclic complexes bearing N-methylene(hydroxy-
Cu2+ + (L)2– h [Cu(L)]
8.12
4.58
7.21
–
6.69
11.97
2.66
–
4.00
2.77
2.74
3.05
–
9.25
5.67
7.47
4.68
7.67
11.50
–
4.67
4.01
4.65
–
methyl)phosphinate pendant arms.[32,33]
Cu2+ + (HL)– h [Cu(HL)]+
[Cu(L)] + H+ h [Cu(HL)]+
[Cu(HL)]+ + H+ h [Cu(H2L)]2+
[CuH–1(L)]– + H+ h [Cu(L)]
[CuH–2(L)]2– + H+ h [CuH–1(L)]
[Cu(HL)]+ + (HL)– h [Cu(HL)2]
[Cu(L)]2– + Cu2+ h [Cu2(L)]
Zn2+ + (HL)– h [Zn(HL)]+
[Zn(HL)]+ + H+ h [Zn(H2L)]2+
[Zn(HL)]+ + (HL)– h [Zn(HL)2]
Ni2+ + (HL)– h [Ni(HL)]+
For both H2L3 and H4L4, species with different stoichio-
metries were also identified. The high denticity of H4L4 al-
lows the formation of dinuclear [LM2] complexes. On the
contrary, owing to its lower denticity, H2L3 forms [H2L2M]
species, in which the coordination of two ligand molecules
protonated on the distant amine group is supposed (see be-
low). The coordination of the second ligand molecule or
the second metal ion is not thermodynamically favoured
and, thus, both types of complexes are present in solution
as minor species (Figure 1).
Zn2+
Ni2+
3.36
4.66
–
[Ni(HL)]+ + H+ h [Ni(H2L)]2+
[NiH–1(L)]– + 2H+ h [Ni(HL)]+
[NiH–2(L)]2– + H+ h [NiH–1(L)]–
2ϫ8.53
10.65
To obtain more information about the coordination
modes in the species suggested by the potentiometric mod-
els, the UV/Vis spectra of the Cu2+–H2L3 and Cu2+–H4L4
systems were recorded under conditions under which one
species is dominant in solution according to the distribution
diagrams (Figures 1, S5 and S8). At slightly acidic pH, light
blue protonated species are present in solution. Their elec-
tronic spectra (Figure 2) show d–d transitions with maxima
at 792 (ε = 30 m–1 cm–1) and 776 nm (ε = 35 m–1 cm–1) and
ligand-to-metal charge transfer (CT) bands with maxima at
212 (ε = 2500 m–1 cm–1) and 218 nm (ε = 3030 m–1 cm–1) for
–
Figure 1. Distribution diagrams of (A) Cu2+–H2L3 (cL = 4 mm, cCu
= 2 mm) and (B) Cu2+–H4L4 (cL = cCu = 4 mm) systems.
complexes or metal-induced deprotonation of the hydroxy
group attached to the bridging carbon atom. For both H2L3
and H4L4, the high abundance and broad dominance range
of the [H–1ML] species as well as their electronic spectra
(see below) point to deprotonation of the central hydroxy
group. The close proximity of two strongly electron-with-
drawing phosphinate groups increases the acidity of the
hydroxy group and, thus, the metal ions induce its depro-
Figure 2. UV/Vis spectra of Cu2+ complexes with H2L3 and H2L4
(25 °C, water). (A) cM = 0.5 mm, cL = 1.0 mm; (B) cM = 5 mm, cL
tonation and simultaneous coordination even at neutral = 10 mm.
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the complexes of H2L3 and H4L4, respectively. The spectra bidentate mode, that is, one oxygen atom originates from
are similar to those of [Cu(H2O)6]2+, which suggests that each phosphinate group. This motif is typical for geminal
they have a coordination sphere formed by the oxygen bisphosphonate and bisphosphinate complexes.[1,34] The
atoms of the phosphinate groups and water molecules as other motif is formed by one phosphinate group of each
observed in the solid state (see below). At slightly alkaline ligand that is simultaneously coordinated to the axial posi-
pH, at which the [H–1LCu] species are exclusively present, tion of a neighbouring metal centre to form a M–O–P–O–
the solution changed to a more intensive green in accord- M bridge. Two neighbouring metal centres are connected
ance with the shift of the d–d transition maxima {673 nm, through two of these bridges to form an eight-membered
ε
=
57 m–1 cm–1 for [Cu(H–1L3)]– and 694 nm,
ε
=
ring, which is typical for solid-state structures of phosphi-
55 m–1 cm–1 for [Cu(H–1L4)]3–}. In addition to the high-en- nate complexes.[35] Both coordination motifs are similar to
ergy CT bands, additional UV bands with maxima at 272 those found for aminobisphosphonate Ca2+ complexes. 4-
(ε = 2280 m–1 cm–1) and 268 nm (ε = 2300 m–1 cm–1) for the Amino-1-hydroxybutyl-1,1-bis(phosphonic acid) (alendron-
complexes of H2L3 and H4L4, respectively, appeared and ate, H4ale) and 3-amino-1-hydroxypropyl-1,1-bis(phos-
probably correspond to ligand-to-metal CT transitions phonic acid) (pamidronate) form polymeric complexes con-
originating from the alcoholate oxygen atom on the central taining both O,OЈ-bidentate (one oxygen from each phos-
carbon atom. Thus, these data point to the presence of a phonate) and M–O–P–O–M bridge motifs.[36] However, the
different chromophore in the [H–1LM] species, which prob- presence of three oxygen atoms on each phosphonate leads
ably contains two phosphinate groups and the alcoholate to a different overall arrangement of the metal centres and
oxygen atoms. The data are similar to those observed for ligand molecules. In addition, 1-hydroxy-1,1-bis(phosphon-
the analogous Cu2+ complexes of H2L5 and H2L6, for ates) also exhibit tridentate coordination to Ca2+ ions
which the coordination of the central alcoholate group was through two phosphonates and hydroxy oxygen atoms as
confirmed by solid-state X-ray diffraction.[23]
has been recently reported for another Ca2+–alendronate
complex.[37] Similarly to our structure, all of the mentioned
bisphosphonate complexes also contain a protonated amine
group that is not involved in metal-ion coordination.
X-ray Diffraction Study
During our attempts to crystallize H2L2, single crystals
were obtained. Surprisingly, X-ray structure analysis re-
vealed the presence of a polymeric Ca2+ complex. The pres-
ence of Ca2+ ions was confirmed by atomic absorption
spectroscopy (AAS) and was explained by the slow leaching
of Ca2+ ions from the glass vial used during the slow
crystallization. The slow complex formation is essential for
the growth of single crystals. Any attempts to synthesize the
complex directly from Ca2+ salts and the ligand led to the
precipitation of colloidal solids.
The metal ion was octahedrally coordinated only by the
phosphinate oxygen atoms, and the amine group of the li-
gand was distant and protonated. One of phosphinate
groups was disordered with P–O distances of ca. 1.50 Å in
the first arrangement and 1.51 and 1.55 Å in the second
one (Table S2); this points to the probable protonation of
one of the oxygen atoms in the latter case. Indeed, an elec-
tronic maximum was present close to the oxygen atom
bound to the phosphorus atom with the longest P–O bond,
which was attributable to a hydrogen atom. Therefore, the
phosphinate group was modelled as disordered in two posi-
tions with equal occupancy, one deprotonated, and the
other protonated; therefore, H2L2 and (HL2)– species are
equally abundant. Such a half protonation of the ligand
Figure 3. Part of coordination polymer found in the crystal struc-
ture of [Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl. Of the variants caused by
the disorder of the phosphinate function, the one representing the
leads to equal abundance of [(Ca2+
and [(Ca2+
)
0.5(Cl–)0.5{(H2L2)}]0.5+
0.5(Cl–)0.5{(HL2)–}]0.5– species and, thus, to the
protonated phosphinate [(Ca2+ 0.5(Cl–)0.5{(H2L2)}]0.5+ is shown.
)
)
overall formula [Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl. The coordi-
nation geometry of the Ca2+ centre is given in Table S3,
and the structure is depicted in Figures 3, S11 and S12. The
Carbon-bound hydrogen atoms are omitted for clarity.
Attempts to crystallize the transition metal complexes
bisphosphinate groups exhibit two different coordination studied by potentiometry were mostly unsuccessful owing
motifs. The equatorial plane of the octahedron is defined to the formation of oily or microcrystalline products. We
by six-membered chelates formed by two ligands in O,OЈ- successfully grew single crystals from the Cu2+–H2L3 sys-
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tem, for which two different solid phases were obtained (de- stabilized by a rich network of strong to medium-strong
pending on the experimental conditions). In the first case hydrogen bonds between phosphinates, protonated amines,
[the diffusion of dibenzylamine/iPrOH solution into an ligand hydroxy groups and water molecules.
aqueous Cu(NO3)2–H2L3 solution to form pale blue crys-
Table 3. Geometry of the Cu2+ coordination sphere of [Cu(HL3-
tals], the X-ray diffraction analysis revealed the formula
O,OЈ)2(H2O)]·5H2O.
[Cu(HL3-O,OЈ)2(H2O)]·5H2O. The Cu2+ ion is coordinated
Bond lengths [Å]
Bond angles [°]
in an almost regular square-pyramidal coordination sphere
(τ = 0.05)[38] formed by four in-plane oxygen atoms of two
different chelating bisphosphinate groups (each oxygen
atom originates from a different phosphinate group) and
an apically coordinated water molecule (Figures 4 and S13,
Table 3). The nitrogen atoms of the ligand molecules are
protonated and are away from the coordination sphere. The
tetragonal base is slightly distorted with coordination bond
lengths dCu–O = 1.93–1.98 Å (Table 3), and the mean differ-
ence of the atoms from the average O4 plane is Ϯ0.022(1) Å.
The Cu–O1c distance to the axial water molecule is ca.
2.25 Å. The in-plane O–Cu–O angles defined by the oxygen
atoms from one ligand molecule are slightly larger (90 and
92°, respectively) than the angles defined by the oxygen
atoms from different ligand molecules (ca. 88°). The Cu2+
ion is located very close to the tetragonal base; it is only
slightly above the O4 plane by 0.160(1) Å. The in-plane lo-
cation of the Cu2+ ion mostly predestines the coordination
of the sixth donor atom below the basal plane to complete
the octahedral sphere. However, surprisingly, there is no
such interaction as a result of the geometry of the crystal
packing (Figures 5 and S14). The neighbouring complex
units are closely packed in the direction of the Cu–O1c coor-
dination bond and do not allow enough space for coordina-
tion in the octahedral mode, as there is a short distance
(3.40 Å) between the Cu2+ ion and the coordinated water
Cu1–O1C
Cu1–O11A 1.9789(11)
Cu1–O21A 1.9447(11)
Cu1–O11B
Cu1–O21B
2.2457(13)
O1C–Cu1–O11A
O1C–Cu1–O21A
O1C–Cu1–O11B
O1C–Cu1–O21B
O11A-Cu1–O21A
O11A-Cu1–O11B
O11A–Cu1–O21B
O21A–Cu–O11B
O21A–Cu–O21B
O11B–Cu–O21B
92.62(5)
99.81(5)
95.39(5)
90.93(5)
90.33(5)
171.98(5)
87.91(5)
88.03(5)
169.18(5)
92.24(5)
1.9784(11)
1.9343(12)
Figure 5. Crystal packing in the solid-state structure of [Cu(HL3-
O,OЈ)2(H2O)]·5H2O; view along the y axis. Solvate water molecules
and carbon-bound hydrogen atoms are omitted for clarity.
Similarly to the Ca2+ complex, the bisphosphinate coor-
molecule from the neighbouring unit (x, 1/2 – y, 1/2 + z), dination mode and geometry in the Cu2+ complex resemble
which blocks the sixth position. Water solvate molecules fill those that have been reported for complexes of aminoalk-
the space between the complex units and are located close ylbisphosphonates. However, the lower number of oxygen
to the coordinated water molecule. The whole structure is atoms results in monomeric bisphosphinate complex, con-
trary to the bisphosphonates, which mostly form dinuclear
complexes or coordination polymers.[1] The monomeric
structure is rather unusual for complexes of simple amino-
alkylphosphinates, for which, if the amine group is proton-
ated, the phosphinate group often bridges metal ions to
form dimeric or polymeric structural motifs.[35] On the
other hand, the bisphosphinate H2pcpPh often forms
square-pyramidal Cu2+ complexes,[30,34] which possess both
monomeric and polymeric structures, and the Cu–O coordi-
nation bonds (1.9–2.0 Å) are of the same length as those
found in the structure of [Cu(HL3-O,OЈ)2(H2O)]·5H2O. De-
spite their significantly lower basicity, bisphosphinates show
Cu–O bond lengths similar to those found in Cu2+ com-
plexes of bisphosphonates. This points to the ionic nature
of the coordination bonds in complexes of both kinds of
ligands.
When a solution of Cu2+–H2L3 in a water/iPrOH mix-
ture was crystallized in the presence of nitrate anions at pH
≈ 4.5, light blue-green crystals of a coordination polymer
with the formula [Cu(H0.5L3-O,OЈ)(NO3)0.5]·2.25H2O were
Figure 4. Structure of the [Cu(HL3-O,OЈ)2(H2O)] complex unit in
the crystal structure of [Cu(HL3-O,OЈ)2(H2O)]·5H2O. Carbon-
bound hydrogen atoms are omitted for clarity.
isolated. The structure is polymeric, and, similarly to the
previous case, the ligand molecules are coordinated only
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Table 4. Geometry of the coordination spheres of both independent Cu2+ ions in the structure of [Cu(H0.5L3-O,OЈ)(NO3)0.5]·2.25H2O.
Bond lengths [Å]
Bond angles [°]
Bond angles [°]
Cu1–O11
Cu1–O21
Cu1–O1N
1.952(2)
1.945(2)
2.428(2)
O11–Cu1–O21
93.26(7)
86.04(6)
180
86.74(7)
93.96(6)
90.06(8)
180
O12–Cu2–O22
94.74(8)
82.91(7)
146.1(1)
87.14(8)
130.95(7)
88.95(7)
173.5(1)
85.14(7)
130.95(7)
48.04(8)
O11–Cu1–O1N
O12–Cu2–O1N
O11–Cu1–O11#[a]
O11–Cu1–O21#[a]
O11–Cu1–O1N#[a]
O21–Cu1–O1N
O12–Cu2–O12#[b]
O12–Cu2–O22#[b]
O12–Cu2–O1N#[b]
O22–Cu2–O1N
Cu2–O12
Cu2–O22
Cu2–O1N
1.981(2)
1.946(2)
2.627(2)
O21–Cu1–O21#[a]
O21–Cu1–O1N#[a]
O1N–Cu1–O1N#[a]
O22–Cu2–O22#[b]
O22–Cu2–O1N#[b]
O1N–Cu2–O12#[b]
O1N–Cu2–O1N#[b]
89.94(8)
180
[a] Symmetry-related atom through centre of symmetry (2 – x, –y, 2 – z). [b] Symmetry-related atom through twofold axis (2 – x, y, 2.5 –
z).
through the phosphinate oxygen atoms. A part of the coor- through one oxygen atom from each phosphinate group.
dination polymer is shown in Figures 6 and S15. In this Each bisphosphinate group is coordinated to two metal
structure, two different coordination environments of the centres in such a chelating mode.
copper(II) ions are present. The Cu1 ion is coordinated in
a centrosymmetric tetragonal bipyramid elongated by the
Jahn–Teller effect with Cu–O axial distances (2.42 Å) signif-
Conclusions
icantly longer than the equatorial ones (ca. 1.95 Å). The
Four geminal bis(phosphinic acids) were synthesized as
equatorial sites are occupied by phosphinate oxygen atoms
a new class of chelating ligand. The acids with H–P bonds
from two ligand molecules, whereas the oxygen atoms of
show limited stability in acidic solutions. The hydrogen
the nitrate anions are bound at the axial sites (Figure 6).
atom, which has a somewhat hydride character, behaves as
The coordination sphere of Cu2 is very irregular, although
an electron-withdrawing substituent and decreases the sta-
the Cu centre possesses twofold symmetry. The coordina-
bility of the C–P bond in a formally hydrolytic reaction. On
the other hand, the presence of other P–C bonds leads to
fully stable compounds. The presence of two electron-with-
tion sphere can be viewed as a trigonal bipyramid with one
equatorial position occupied by a bidentate κ-O,OЈ-nitrate
ligand with a very long coordination interaction (dCu–O
=
drawing phosphinate groups leads to a low electron density
on the adjacent amine group in H2L1 and, thus, to the low
value of its protonation constant. The same effect leads also
to easy metal-assisted deprotonation of the central hydroxy
groups in H2L3 and H4L4, and the alcoholate coordination
stabilizes their complexes at neutral and slightly alkaline
pH. In connection with our recent results, this phenomenon
seems to be general for the coordination properties of li-
gands with the P-hydroxymethyl moiety. The studied bis-
phosphinates show lower basicity of their amine groups
and, thus, less stable complexes with divalent metal ions in
comparison with their bisphosphonate analogues. The bis-
phosphinate moiety forms six-membered chelate rings,
which are preferred over the coordination of the weakly ba-
sic amine groups. Owing to presence of very acidic phos-
phinic acid groups, the complexation of the studied metal
ions proceeds even at solutions with low pH; this is a highly
desirable property in the design of new polydentate ligands
for biomedical applications.
2.63 Å). The other equatorial bonds and the axial bonds
are much shorter (1.98 and 1.95 Å, respectively). Selected
relevant structural parameters are listed in Table 4. Simi-
larly to the previous structures, the bisphosphinate group is
coordinated to each metal centre in O,OЈ-bidentate mode
Experimental Section
Materials and Methods: Commercially available chemicals had syn-
thetic purity and were used as received. Organic solvents had syn-
thetic purity and were also used as received. Dry CH2Cl2 was
freshly distilled with P2O5. Deionized water was used for synthesis
and measurements. [2-(tert-Butyloxycarbonyl)ethyl]phosphinic acid
Figure 6. Part of the structure of the complex polymer [Cu(H0.5L3-
O,OЈ)(NO3)0.5
]
in the crystal structure of [Cu(H0.5L3-O,OЈ)-
(NO3)0.5]·2.25H2O. Water solvate molecules and carbon-bound
hydrogen atoms are omitted for clarity. Of the two disordered posi-
tions of the aminopropyl side chain, the one with tentative proton-
ation of the RNH3 group is shown.
was prepared according to the published procedure.[39] The 1H, 13
C
+
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and 2D NMR [H-H COSY, H-C HSQC and H-C HMBC] spectra
were recorded at 25 °C with a Bruker Avance III 600 MHz spec-
trometer equipped with a triple-resonance cold probe. The 31P
NMR spectra were recorded at 25 °C with a Varian NMR system
operating at 300 MHz proton frequency with an ASW probe. The
suspended in HMDS (50 mL), and the mixture was heated at
110 °C under a gentle flow of argon overnight. The mixture con-
taining pure HP(OTMS)2 was cooled to r.t., and dry CH2Cl2
(25 mL) was added. Then, a freshly prepared solution of IV ob-
tained from 4-(phthalimido)butanoic acid (3.79 g, 15.1 mmol) was
added, and the mixture was stirred at r.t. overnight. Then, the re-
sulting solution was added dropwise into EtOH (200 mL) to hy-
drolyze the silyl ester groups. The precipitate was collected on a
glass frit and washed with EtOH (50 mL). Another fraction of the
solid was collected from the filtrate after it had stood overnight.
Both fractions were combined and dried with P2O5 in a vacuum
desiccator. The crude 4-(phthalamido)butyl-1,1-bis(H-phosphinic
acid) (Va) was obtained as a white powder (5.85 g) and was not
further purified. The crude Va was dissolved in a mixture of 75%
aq. N2H4 (60 mL) and EtOH (60 mL), and the solution was stirred
at r.t. overnight. An excess of EtOH (300 mL) was then added, and
the flask was refrigerated for 3 d. The upper phase was decanted;
the resulting oil was dissolved in water (40 mL), and EtOH
(300 mL) was added. The next day, the upper phase was decanted,
and the remaining oil was dissolved in conc. aq. ammonia
(100 mL), evaporated to dryness and further coevaporated three
times with water. The residue was dissolved in water (100 mL), and
the resulting solution was adjusted to pH 8 with 2 m aq. NaOH.
The solution was evaporated to dryness, the residue was dissolved
in water (100 mL), and the solution was again adjusted to pH 8
with 2 m aq. NaOH. This procedure was repeated until the redis-
solved aq. solution reached pH 8. Then, the solution was concen-
trated to 10 mL and slowly added dropwise into a vigorously stirred
mixture of anhydrous EtOH/tetrahydrofuran (EtOH/THF, 1:1,
400 mL). The precipitate was collected on a glass frit and washed
with MeOH (200 mL). The resulting solid was dissolved in water
(100 mL), and some charcoal was added. The mixture was filtered,
and the filtrate was evaporated to dryness and further coevaporated
several times with water (100 mL). The resulting solid was dried
with P2O5 in a vacuum desiccator. The product was obtained as a
white crystalline powder as a mixed ammonium–sodium salt
NMR spectra were referenced to tBuOH (internal standard, δH
=
1.25 ppm, δC = 30.3 ppm) and 85% H3PO4 (external standard, δP
= 0 ppm). Chemical shifts are given in ppm, and the coupling con-
stants are given in Hz. ESI-MS spectra were recorded with a Bruker
Esquire 3000 spectrometer with ESI ionization and ion-trap detec-
tion. TLC was performed with silica on aluminium sheets (Merck
1.0554 F254); the spots were detected by UV fluorescence (λ =
254 nm) or visualized with iodine vapour. Mobile phases for TLC
were freshly prepared prior to use.
Aminomethyl-bis(H-phosphinic acid) (H2L1): Under an argon atmo-
sphere, dry (NH4)H2PO2 (10.0 g, 120 mmol) was suspended in
hexamethyldisilazane (HMDS, 100 mL), and the mixture was
heated at 110 °C under a gentle flow of argon overnight. The mix-
ture containing pure HP(OTMS)2 (TMS = tetramethylsilane) was
cooled to r.t., and dry CH2Cl2 (100 mL) was added. A suspension
of ethyl formimidate hydrochloride (3.31 g, 30.2 mmol) in dry
CH2Cl2 (150 mL) was added dropwise, and the mixture was stirred
at r.t. overnight. Then, the resulting solution was added dropwise
into EtOH (500 mL) to hydrolyze the silyl ester groups. The precipi-
tate was collected on a glass frit, and this crude product was puri-
fied on a strong cation exchange resin (Dowex 50; H+ form; elution
with water followed by 50% aq. EtOH). The fractions containing
the product were combined and evaporated under reduced pressure.
The resulting oil was further dried under reduced pressure for sev-
eral days at r.t. The product was obtained as a colourless oil, which
1
solidified on standing (1.95 g, 37% yield). H NMR (NaOD/D2O,
pD 7): δ = 2.94 (t, 2JH,P = 15 Hz, 1 H, CH), 7.08 (d, 1JH,P = 541 Hz,
1
2 H, PH) ppm. 13C{1H} NMR: δ = 54.4 (t, JC,P = 80 Hz, CH)
1
ppm. 31P NMR: δ = 17.0 (dm, JP,H = 541 Hz) ppm. MS (–): m/z
= 158.6 [M – H]–. MS (+): m/z = 160.7 [M + H]+. TLC (MeCN/
MeOH/conc. aq. NH3 3:1:2): Rf = 0.2. CH7NO4P2 (159.0): calcd.
C 7.6, H 4.4, N 8.8; found C 7.8, H 4.5, N 8.7.
1
(2.29 g, 54%). H NMR (D2O, pD 7): δ = 1.90 (m, 2 H, CH2CP),
3
1.99 (m, 2 H, CH2CH2N), 3.05 (t, JH,H = 7 Hz, 2 H, CH2N), 6.96
Aminomethyl-(H-phosphinic acid) (III): In a glass vial, H2L1
(40.1 mg; 252 μmol) was dissolved in 1 m aq. HCl (0.5 mL), and
the mixture was heated at 80 °C for 2 d. After cooling to r.t., the
mixture was evaporated to dryness. The residue was dissolved in
water (0.5 mL), and iPrOH (3.0 mL) was then added to produce a
cloudy mixture. The mixture was refrigerated overnight, and the
upper phase was discarded; the resulting oil was purified on a
strong cation exchange resin (Dowex 50; H+ form; elution with
water followed by 10% aq. pyridine). The pyridine fraction was
evaporated to dryness and coevaporated with water several times.
The resulting oily product (31P NMR purityϾ 95%) was charac-
terized without further purification or isolation. 1H NMR (D2O,
(dt, 1JH,P = 527 Hz, 3JH,P = 17 Hz, 2 H, PH) ppm. 13C{1H} NMR:
2
δ = 23.6 (t, JC,P = 6 Hz, CH2CP), 29.5 (s, CH2CN), 42.2 (s,
1
CH2N), 75.8 (t, JC,P = 93 Hz, CP) ppm. 31P NMR: δ = 24.5 (dm,
1JP,H = 527 Hz) ppm. 31P{1H} NMR: δ = 24.5 (s) ppm. MS (–):
m/z = 215.4 [M – H]–. TLC (EtOH/conc. aq. NH3 1:1): Rf = 0.3.
Na1.6(NH4)0.4C4H11NO5P2·0.5H2O (282.2): calcd. C 17.0, H 4.7, N
6.9; found C 17.2, H 4.8, N 6.7.
4-Amino-1-hydroxybutyl-1-(H-phosphinic acid) (VI): In a glass vial,
H2L2 (300 mg, 1.06 mmol) was dissolved in 1 m aq. HCl (5 mL),
and the mixture was heated at 80 °C for 30 d. After cooling to
r.t., the mixture was evaporated to dryness. The crude product was
purified on a strong cation exchange resin (Dowex 50; H+ form;
elution with water followed by 10% aq. pyridine). The pyridine
fraction was evaporated to dryness and coevaporated with water
several times. The resulting oily product (94% purity as determined
by 31P NMR spectroscopy) was analyzed without further purifica-
tion.
2
1
pD 4): δ = 3.04 (d, JH,P = 11 Hz, 2 H, CH2,), 7.08 (d, JH,P
=
541 Hz, 1 H, PH) ppm. 13C{1H} NMR: δ = 39.3 (d, 1JC,P = 89 Hz,
CH2) ppm. 31P NMR: δ = 14.5 (dt, JP,H = 541 Hz, JP,H = 11 Hz)
ppm. MS (–): m/z = 94.2 [M – H]–. TLC (MeCN/MeOH/conc. aq.
NH3 3:1:2): Rf = 0.6.
1
2
4-(Phthalimido)butanoyl Chloride (IV): In a 50 mL flask, 4-(phthal-
imido)butanoic acid (3.79 g, 15.1 mmol) was dissolved in CH2Cl2
(25 mL), and (COCl)2 (3.20 mL, 37.5 mmol) was added. The re-
sulting mixture was stirred at r.t. for 3 h and then evaporated to
dryness. The residue was coevaporated three times with dry CH2Cl2
and then dissolved in dry CH2Cl2 (10 mL). The solution was used
immediately as obtained in the next reactions.
1H NMR (D2O, pD 4): δ = 1.64 (m, 1 H, CH2CP), 1.79 (m, 1 H,
CH2CP), 1.79 (m, 1 H, CH2CH2N), 1.93 (m, 1 H, CH2CH2N), 3.06
1
(m, 2 H, CH2N), 3.58 (m, 1 H, CHP), 6.79 (dm, JH,P = 509 Hz, 1
3
H, PH) ppm. 13C{1H} NMR: δ = 24.1 (d, JC,P = 12 Hz,
1
CH2CH2N), 26.7 (s, CH2CP), 39.9 (s, CH2N), 70.3 (d, JC,P
=
4-Amino-1-hydroxybutyl-1,1-bis(H-phosphinic acid) (H2L2): Under 109 Hz, CP) ppm. 31P NMR: δ = 29.1 (d, JP,H = 509 Hz) ppm.
1
an argon atmosphere, dry (NH4)H2PO2 (5.00 g, 60.2 mmol) was
4364
31P{1H} NMR: δ = 29.15 (s) ppm. MS (–): m/z =152.0 [M – H]–.
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FULL PAPER
MS (+): m/z = 154.2 [M + H]+. TLC (EtOH/conc. aq. NH3 1:1):
Rf = 0.5.
4-Amino-1-hydroxybutyl-1,1-bis[(methyl)phosphinic acid] (H2L3): In
product-containing fractions (eluted with 50% aq. AcOH) were
combined, evaporated to dryness and further coevaporated with
water. The resulting solid was dried with P2O5 in a vacuum desicca-
tor. The product was obtained as a white hygroscopic powder
(486 mg, 49%). 1H NMR (D2O, pD 2): δ = 2.03 (m, 4 H,
CH2CH2N and CH2COH), 2.16 (m, 4 H, CH2P), 2.67 (m, 4 H,
a
100 mL flask, N-ethyl-diisopropylamine (DIPEA, 12.0 mL,
68.8 mmol) was added to a solution of methylphosphinic acid
(2.21 g, 27.6 mmol) in dry CH2Cl2 (25 mL). Subsequently, chloro-
trimethylsilane (TMSCl, 8.80 mL, 69.0 mmol) was slowly added,
and the resulting mixture was stirred at r.t. for 3 h. Then, a freshly
prepared solution of IV obtained from 4-(phthalimido)butanoic
acid (2.78 g, 11.1 mmol) was added, and the mixture was stirred at
r.t. overnight. Ethanol (50 mL) was then slowly added to the reac-
tion mixture to hydrolyze the silyl ester groups. The resulting solu-
tion was evaporated to dryness and then coevaporated with
CH2Cl2. The residue was dissolved in 2 m aq. NaOH (50 mL) and
extracted with CH2Cl2 (4ϫ 50 mL). The aqueous phase was evapo-
rated to dryness, and the residue was purified on a strong cation
exchange resin (Dowex 50, H+ form, elution with water), and the
eluate was evaporated to dryness. The resulting mixture was dis-
solved in 6 m aq. HCl (100 mL) and heated to reflux for 3 d. Then,
the reaction mixture was cooled to r.t. After 3 h, the precipitated
phthalic acid was removed by filtration, and the filtrate was evapo-
rated to dryness. The residue was dissolved in a mixture of THF/
MeOH/water (2:1:2, 5 mL) and purified by column chromatog-
raphy [SiO2; elution with THF/MeOH/conc. aq. NH3 2:1:2 fol-
lowed by 1:1:2; Rf (product) = 0.1Ǟ0.4]. The fractions containing
the pure product were combined, and the solvents were evaporated
to dryness. The ammonia was removed from the crude product on
a strong cation exchange resin (Dowex 50, H+ form, elution with
water followed by 10% aq. pyridine). The pyridine fraction was
evaporated to dryness and coevaporated several times with water.
The residual pyridine was removed on a weak cation exchange resin
(Amberlite CG50, H+ form, water elution). The fractions contain-
ing the product were combined, and the solvents were evaporated
to dryness. The resulting solid was dried with P2O5 in a vacuum
desiccator. The product was obtained as a white powder (1.81 g,
3
CH2CO2H), 3.05 (t, JH,H = 7 Hz, 2 H, CH2N) ppm. 13C{1H}
NMR: δ = 24.4 (s, CH2COH), 23.3 (m, CH2P), 27.4 (s, CH2C2H),
1
30.1 (s, CH2CH2N), 40.5 (s, CH2N), 76.0 (t, JC,P = 92 Hz, CP),
3
178.2 (d, JC,P = 15 Hz, CO) ppm. 31P{1H} NMR: δ = 44.4 (s)
ppm. MS (–): m/z = 359.1 [M – H]–. MS (+): m/z = 361.2 [M + H]
+, 383.4 [M + Na]+, 399.2 [M + K]+. TLC (THF/MeOH/conc. aq.
NH3 2:1:2): Rf = 0.2. C10H21NO9P2·1.5H2O (388.2): calcd. C 30.9,
H 6.2, N 3.6; found C 30.7, H 5.8, N 3.9.
The fractions eluted from the strong anion exchange resin with
20% aq. AcOH contained a side-product (ca. 30% yield), which
was identified as the hydrazide of H4L4 (for the structure, see Fig-
ure S1). 1H NMR (D2O, pD 2): δ = 1.90–2.23 (m, 8 H, CH2CH2N,
CH2COH, CH2P), 2.56–2.73 (m, 4 H, CH2COOH), 3.05 (m, 2 H,
CH2N) ppm. 13C{1H} NMR: δ = 22.5 (CH2COH, s), 23.1–24.3 (m,
CH2P), 26.8 (s, CH2CO), 27.6 (s, CH2CO), 30.2 (m, CH2CH2N),
40.6 (s, CH2N), 76.3 (t, 1JC,P = 93 Hz, CP), 174.5 (d, 3JC,P = 13 Hz,
3
CONH), 178.6 (d, JC,P = 14 Hz, COOH) ppm. 31P{1H} NMR: δ
2
2
= 41.2 (d, JP,P = 28 Hz, 1 P), 42.9 (d, JP,P = 28 Hz, 1 P) ppm.
MS (–): m/z = 374.3 [M – H]–. MS (+): m/z = 375.9 [M + H]+.
TLC (THF/MeOH/conc. aq. NH3 2:1:2): Rf = 0.3.
Kinetics of Hydrolysis: The hydrolyses of H2L1 and H2L2 at concen-
trations of 10 mm were followed by 31P NMR spectroscopy. The
experiments were performed at constant temperature (80 °C) main-
tained by a thermostatted bath or by the NMR spectrometer. The
experiments were performed in 1 m aq. HCl (pH 0) or 1 m aq.
NaOH (pH 14).
Potentiometric Titrations: The methodology of the potentiometric
titrations and processing of the experimental data were analogous
to those previously reported.[40] The titrations were performed in a
vessel thermostatted at (25Ϯ0.1) °C with solutions of ionic
strength I = 0.1 m KNO3. The ligand-to-metal ratios were 1:1 and
2:1 (as well as 1:2 for H4L4) with cL = 0.004 m; the pH range was
1.7–12 (or until metal hydroxide precipitated). The titrations were
performed at least three times, and each consisted of ca. 40 points.
The water ion product (pKw = 13.78) and the stability constants
of the M2+–OH– systems were taken from ref.[41] The calculated
protonation constants βn are concentration constants and are de-
fined by βn = [HnL]/([H]n[L]); logK1 = logβ1 and logKn = logβn –
1
60%). H NMR (D2O, pD 6): δ = 1.38 (m, 6 H, CH3), 2.01 (m, 4
3
H, CH2CH2N and CH2CO), 3.04 (t, JH,H = 7 Hz, 2 H, CH2N)
ppm. 13C{1H} NMR: δ = 16.9 (m, CH3), 24.4 (s, CH2CO), 31.9 (s,
1
CH2CH2N), 42.5 (s, CH2N), 77.8 (t, JC,P = 93 Hz, CP) ppm.
31P{1H} NMR: δ = 39.9 (s) ppm. MS (–): m/z = 243.7 [M – H]–,
488.8 [2M – H]–. TLC (THF/MeOH/conc. aq. NH3 1:1:2): Rf = 0.4.
C6H17NO5P2·1.5H2O (272.2): calcd. C 26.5, H 7.4, N 5.2; found C
26.7, H 7.0, N 5.5.
4-Amino-1-hydroxybutyl-1,1-bis[(2-carboxyethyl)phosphinic
acid]
(H4L4): In a 50 mL flask, DIPEA (7.21 mL, 41.4 mmol) was added
to a solution of [2-(tert-butyloxycarbonyl)ethyl]phosphinic acid
(1.34 g, 6.90 mmol) in dry CH2Cl2 (10 mL). Subsequently, TMSCl
(5.25 mL, 41.4 mmol) was slowly added, and the resulting mixture
was stirred at r.t. for 3 h. Then, a freshly prepared solution of IV
obtained from 4-(phthalimido)butanoic acid (600 mg, 2.57 mmol)
was added, and the mixture was stirred at r.t. overnight. Ethanol
(20 mL) was then slowly added to the reaction mixture to hydrolyze
the silyl ester groups. The resulting solution was evaporated to dry-
ness and then coevaporated with CH2Cl2. The residue was dis-
solved in 3% aq. HCl (30 mL) and extracted with CH2Cl2 (5ϫ
15 mL). The organic layers were combined, and the solvents were
evaporated to dryness. The crude compound Vc was dissolved in a
mixture of N2H4 (75% aq. solution, 20 mL) and EtOH (20 mL),
and the mixture was stirred at r.t. for 3 d. An excess of EtOH
(100 mL) was then added, and the mixture was refrigerated over-
night. The upper phase was decanted, and the resulting oil was
purified on a strong anion exchange resin (Dowex 1, OH– form,
logβn–1. The overall stability constant are defined by βhlm
=
[MmHhLl]/([M]m[H]h[L]l). The constants (with standard deviations)
were calculated with the program OPIUM.[42] Throughout the pa-
per, pH means –log[H+].
1
NMR Titrations: The 31P{1H} and H NMR titration experiments
to determine the nitrogen protonation constants of H2L1 and H2L2
(pH 4–13, ca. 15 points) were performed without control of ionic
strength at 25.0 °C and ligand concentration cL = 0.004 m. A coax-
ial capillary tube with D2O and H3PO4 was used for the lock signal
and referencing. The pH values of the samples were adjusted with
0.1 m aq. HCl or 0.1 m aq. NaOH. The protonation constants were
obtained with the software OPIUM[40] by simultaneous treatment
of 1H and 31P NMR spectroscopic data. The overlap of both 1H
NMR signals in the P–C–CH2–CH2 fragment of H2L2 disabled the
precise analysis and, thus, only the signal of the methylene group
attached to the amine group was used for evaluation of the data.
UV/Vis Measurements: UV/Vis spectra were measured with a Schi-
elution with water followed by 20% and 50% aq. AcOH). The madzu UV-2401PC spectrometer at 25 °C in the wavelength range
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200–900 nm. Solutions of ligand and metal ions were mixed, and
the pH was adjusted to the desired value by the addition of 0.1 m
aq. HCl or 0.1 m aq. NaOH. Then, the samples were diluted with
water to reach a final metal concentration cM = 5 mm for measure-
ments in the visible region or cM = 0.5 mm for measurements in
the UV region.
thermal parameters Ueq(H) = 1.2Ueq(X), as their free refinement
led to several unrealistic bond lengths. For the crystal structure of
[Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl, the independent unit is formed by
Ca, Cl and one ligand molecule, and the Ca and Cl atoms are in
special positions with half occupancy. The amine group of the li-
gand is protonated. One of phosphinate functions was found to be
disordered and was modelled in two positions with equal occu-
pancy (Figure S11). In one possibility, the phosphinate function is
protonated, whereas in the second possibility it is not, as documen-
ted also by the P–O bond lengths (Table S2). Such half protonation
is a result of a need to compensate the overall charge of the Ca2+
X-ray Diffraction: A few single crystals of [Ca(H2L2-O,OЈ)(HL2-
O,OЈ)]Cl were obtained by long time (1 month) standing of a closed
vial containing a mixture of H2L2 (18.5 mg, mixed sodium ammo-
nium salt), 3% aq. HCl (160 μL), iPrOH (400 μL) and water
(200 μL). The source of calcium is probably the glass of the vial;
its presence in the mother solution was confirmed by AAS analysis.
and Cl– ions and results in the formal formula (Ca2+ 0.5(Cl–)0.5
) -
{(H1.5L2)0.5–}, that is, [Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl. For
[Cu(HL3-O,OЈ)2(H2O)]·5H2O, no special treatment was needed.
For [Cu(H0.5L3-O,OЈ)(NO3)0.5]·2.25H2O, the independent unit is
formed by one ligand molecule, two half-occupied copper(II) ions,
a half-occupied nitrate anion and some solvate water molecules.
The ligand oxygen atoms are deprotonated and coordinated to
Cu2+ ions, and the ligand hydroxy group was clearly found to be
protonated. Therefore, the ligand molecule must be partially pro-
tonated by 0.5H on the side amine group to ensure electroneutrality
of the overall formula. This is probably a reason for the observed
disorder of the aliphatic part of the molecule; therefore, this disor-
der was modelled by splitting the side chain over two positions with
half occupancy. However, although some maxima in the electron
difference map could be attributed to hydrogen atoms, not all
hydrogen atoms could be located (as the disorder is probably more
complicated) and, therefore, the hydrogen atoms were placed in
theoretical or original positions by using a riding model. The amine
group in one of the two positions was tentatively declared as pro-
tonated, and the AFIX 137 instruction was used; the protons of
the second half of the amine group were located in the electronic
map. In the cavities of the polymeric complex framework, some
maxima of electron density were found in the free space between
the polymeric chains and attributed to solvate water molecules.
However, their mutual geometry and low intensities point to a com-
plicated disorder, which was modelled by their attribution to water
molecules with 0.25–0.5 occupancy. This resulted in more than two
H2O molecules per formula unit, but a number of small maxima
Single crystals of [Cu(HL3-O,OЈ)2(H2O)]·5H2O were obtained by
slow diffusion of a 4% dibenzylamine solution in iPrOH (1 mL)
into a solution of H2L3 (19.5 mg, 71.6 μmol) and Cu(NO3)2·6H2O
(9.6 mg, 32.6 μmol) in water (0.5 mL).
Single crystals of [Cu(H0.5L3-O,OЈ)(NO3)0.5]·2.25H2O were pre-
pared by mixing H2L3 (19.6 mg, 72.0 μmol), Cu(NO3)2·6H2O
(19.3 mg, 65.5 μmol) and picric acid (16.5 mg, 72.0 μmol) in water
(0.5 mL). Guanidinium carbonate was added until all solid dis-
solved (pH ≈ 4.5), and the mixture was briefly heated at 80 °C. A
blue powder formed over a few weeks and was collected by fil-
tration, dissolved in water (0.5 mL) and crystallized by the addition
iPrOH (0.5 mL). The complex also formed in the absence of picric
acid and guanidinium carbonate; however, the single crystals were
of low quality.
The diffraction data were collected at 150 K (Cryostream Cooler,
Oxford Cryosystem) by using a Nonius Kappa CCD diffractometer
and Mo-Kα radiation (λ = 0.71073 Å). The frames were integrated
with the Bruker SAINT software package by using a narrow-frame
algorithm.[43] The data were corrected for absorption effects by
using the multiscan method (SADABS).[44] The structures were
solved by direct methods (SHELXS97)[45] and refined by full-ma-
trix least-squares techniques (SHELXL97).[46] All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were lo-
cated in the electron density difference map; however, they were
placed in theoretical (C–H, N–H) or original (O–H) positions with
Table 5. Experimental data of reported crystal structures.
[Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl
[Cu(HL3-O,OЈ)2(H2O)]·5H2O
[Cu(H0.5L3-O,OЈ)(NO3)0.5]·2.25H2O
Formula
Mw
C8H25CaClN2O10P4
508.71
C12H44CuN2O16P4
659.91
C6H20CuN1.5O8.75P2
378.71
Colour
Shape
colourless
prism
light blue
prism
light blue-green
prism
Dimensions [mm]
Crystal system
Space group
0.105ϫ0.203ϫ0.261
monoclinic
C2/c
0.287ϫ0.405ϫ0.421
monoclinic
P21/c
0.265ϫ0.276ϫ0.379
monoclinic
C2/c
a [Å]
b [Å]
c [Å]
23.6965(11)
5.2028(2)
18.4274(8)
119.639(2)
1974.62(15)
4
15.5110(2)
16.1990(2)
11.2788(2)
103.428(1)
2756.47(7)
4
14.8708(3)
17.7541(4)
12.8882(4)
124.8959(8)
2790.87(12)
8
β [°]
V [Å3]
Z
Dcalcd. [gcm–3]
1.711
0.826
1.590
1.093
1.803
1.833
μ [mm–1]
F(000)
1056
2266, 2017
130
1388
6338, 5660
328
1564
3202, 2841
190
Diffractions, observed [I0Ͼ2σ(I0)]
Parameters
GoF on F2
1.078
1.053
1.110
R, RЈ (all data)
wR, wRЈ (all data)
Difference max., min. (eÅ–3)
0.0297, 0.0346
0.0790, 0.0823
0.534, –0.385
0.0266, 0.0306
0.0763, 0.0792
0.963, –0.493
0.0342, 0.0379
0.0968, 0.0995
0.854, –0.594
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FULL PAPER
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CCDC-983603 {for [Ca(H2L2-O,OЈ)(HL2-O,OЈ)]Cl}, -983601 {for
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Support from the Grant Agency of the Czech Republic (grant
number P207/10/P153), the Grant Agency of the Charles Univer-
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Czech Republic (Long-Term Research Plan, grant number
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