Coordination properties of cyclam (1,4,8,11-tetraazacyclotetradecane) endowed with two methylphosphonic acid pendant arms in the 1,4-positions

Article abstract of DOI:10.1039/b803235a

The title ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-diyl- bis(methylphosphonic acid) (H₄te2p^1,4, H₄L), was prepared by an optimized synthetic approach and its complexing properties towards selected metal ions were stud

Full text of DOI:10.1039/b803235a

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Coordination properties of cyclam (1,4,8,11-tetraazacyclotetradecane)
endowed with two methylphosphonic acid pendant arms in the 1,4-positions†
Jana Havl´ıcˇkova´, Hana Medova´, Toma´sˇ Vitha, Jan Kotek,* Ivana C´ısarˇova´ and Petr Hermann
Received 25th February 2008, Accepted 30th June 2008
First published as an Advance Article on the web 26th August 2008
DOI: 10.1039/b803235a
The title ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-diyl-bis(methylphosphonic acid) (H4te2p1,4,
H4L), was prepared by an optimized synthetic approach and its complexing properties towards selected
metal ions were studied by means of potentiometry. The ligand forms a very stable complex with
copper(II) (log b(CuL) = 27.21), with a high selectivity over binding of other metal ions (e.g.
log b(ZnL) = 20.16, log b(NiL) = 21.92). The crystal structures of two intermediates in the ligand
synthesis and two forms of the nickel(II) complex (obtained by crystallization at different pH) were
determined. From acid solution, the crystals of trans-O,O-[Ni(H3L)]Cl·H2O were isolated. In such
complex species, one phosphonate pendant arm is double- and the second arm is monoprotonated. The
isolation of such species demonstrates a high kinetic inertness of the complex. The central metal ion is
surrounded by four in-plane nitrogen atoms (in the ring configuration III) and two oxygen atoms of
pendant moieties in the apical positions of octahedral coordination sphere. From neutral solution, the
crystals of {trans-O,O-[Ni(H2L)]}3·5H2O were isolated. The molecular structures of the complex units
found in this structure are analogous to that found in trans-O,O-[Ni(H3L)]Cl·H2O.
Introduction
Most of the studies on macrocyclic ligands have been focused
on derivatives bearing additional coordinating pendant groups
which influence both thermodynamic stability and kinetics of the
complexation/decomplexation. Among the macrocycles, 1,4,8,11-
tetraazacyclotetradecane (cyclam, Chart 1) is one of the most
studied azacycles.1,2 Cyclams (fourteen-membered tetraamine
macrocycles) show the ability to complex first-row transition metal
cations, especially copper(II), and the complexes are often highly
thermodynamically stable and kinetically inert.3
The investigations into the cyclam-derived ligands and their
complexes is often motivated by their use in medicine.3,4 It
was found that cyclam-based anti-HIV agents are even more
active in vivo in the form of complexes with several metal
Chart 1 Structures of ligands mentioned in the text.
ions.3,5 The macrocyclic ligands are used as chelators of the
offer an excellent binding environment for Cu(II) ion as the
metal radioisotopes in targeted radiopharmaceuticals.3,6 For the
ion fits ideally in the macrocyclic cavity.3,8 Chelators utilized for
utilizations in nuclear medicine, macrocyclic ligands are generally
complexation of copper radionuclides are often based on 1,4,8,11-
preferred to open-chain ligands due to higher stability and usually
tetraazacyclotetradecane-1,4,8,11-tetraacetic
acid
(H4teta,
higher inertness of their complexes. Among metal radioisotopes,
the copper radionuclides (especially 64Cu and 67Cu) seem to be
very promising. They undergo various decays, exhibit suitable
properties for application in both scintigraphic imaging (single-
photon imaging and positron emission tomography) as well as in
targeted radiotherapy.7 The ligands based on the cyclam skeleton
Chart 1). However, such ligands have more donor atoms (8) than
is required by copper(II) (5–6) and, therefore, several pendant
arms remain non-coordinated in the copper(II) complexes.9 It
was shown, that such copper(II) complexes are not optimal for
biomedical applications as they lose the metal ion in vivo.10
The investigations of macrocycles derivatized with four
methylphosphonic acid (–CH2–PO3H2)11 or methylphosphinic
acid (–CH2–P(R)O2H)12 pendant arms (Chart 1) started sev-
eral years ago. However, similarly to the H4teta derivatives,
the ligands have more coordinating atoms and the ligands
should rather be considered as derivatives of N,N¢,N¢¢,N¢¢¢-
tetramethylcyclam which forms generally kinetically less inert
complexes than cyclam itself.13 Therefore, copper(II) complexes of
cyclam derivatives having a smaller number of pendant arms have
Department of Inorganic Chemistry, Universita Karlova (Charles Univer-
sity), Hlavova 2030, Prague 2, 128 40, Czech Republic. E-mail: modrej@
natur.cuni.cz; Fax: +420-2-2195-1253; Tel: +420-2-2195-1261
† Electronic supplementary information (ESI) available: scheme of the
ligand synthesis; molecular structures of the [Ni(H2L)] complex units;
NMR spectra of H4L at different pH; distribution diagrams of the free
ligand and the M(II)–H4te2p1,4 systems (M = Ca, Pb, Ni, Zn, Cd). CCDC
reference numbers 679184–679187. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b803235a
5378 | Dalton Trans., 2008, 5378–5386
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been studied. The studies involved ligands with one carboxylic
acid14 or pyridine15 pendant arm, or two acetate,16,17 amine,17
acetamide17,18 or pyridine19,20 coordinating pendant arms.
We have already prepared cyclam substituted with only
one pendant arm21 or with two methylphosphonic acid pen-
dant arms in “trans” (1,8) positions (H2te1p and H4te2p1,8,
Chart 1).22 Both ligands form extremely stable copper(II)
complexes,21,23 and the complexation reaction was found to be
very selective for copper(II) over zinc(II).24 We prepared the ti-
tle ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-diyl-bis(methyl-
phosphonic acid) (H4te2p1,4, H4L, Chart 1),25 but a scaling up of
the synthesis based on the original procedure was complicated by
extensive chromatographic separations. So, we decided to develop
another synthesis, based on previously reported oxalylbis(amide)
protection.26 Here, we report on the optimized ligand synthesis and
the investigations into complexing properties of H4te2p1,4 towards
selected divalent metal ions.
salt as follows. The reaction mixture from the original synthesis26
(5 mmol scale, 1.00 g of cyclam) was evaporated to dryness, and
re-dissolved in 15 ml of ethanol. Concentrated aq. HCl (1 ml)
was added dropwise and the white precipitate was collected by
filtration and dried in a desiccator (1.36 g, 83%). Found: C, 43.9;
H, 7.2; Cl, 22.0; N, 17.0%. Calc. for 1·2HCl, C12H24Cl2N4O2, M =
327.3: C, 44.0; H, 7.4; Cl, 21.7; N, 17.1%. Colourless needles of
1·2HCl suitable for X-ray diffraction were prepared by vapour
diffusion of ethanol into aq. solution of 1·2HCl, acidified by a
drop of a diluted aq. HCl.
Isolation of 1,4-dibenzyl-1,4,8,11-tetraazacyclotetradecane, 3.
After hydrolysis of 2 in aq. NaOH and extraction of 3 into
chloroform and evaporation,26 the compound was isolated by
crystallization from concentrated aq. HBr (75%, based on 1·2HCl)
as an off-white solid. Found: C, 37.7; H, 6.0; Br, 41.6; N, 7.2%.
Calc. for 3·4HBr·4H2O, C24H48Br4N4O4, M = 776.3: C, 37.1; H,
6.2; Br, 41.2; N, 7.2%. Colourless plates of 3·4HBr·2H2O were
formed by slow cooling of a hot solution of 3 in diluted (1 : 1) aq.
HBr.
Experimental
Chemicals
Synthesis of 8,11-dibenzyl-1,4-bis(diethoxyphosphorylmethyl)-
1,4,8,11-tetraazacyclotetradecane, 4. Compound 3·4HBr·4H2O
(5.45 g, 7.0 mmol) was dissolved in water (100 ml) and NaOH (5 g)
was added. Free base 3 was extracted by CHCl3 (3 ¥ 50 ml) and
the extracts were combined and dried over Na2SO4. The mixture
was filtered and the solvent was evaporated. The macrocycle
was dissolved in triethyl phosphite (11.6 g, 74 mmol, 10 equiv.).
Paraformaldehyde (1.10 g, 37 mmol, 5 equiv.) was added and the
mixture was stirred at 75 ◦C for 4 d in a closed flask. The reaction
mixture was poured onto a column of strong cation exchanger
(Dowex 50, 100 ml, H+ form). The non-cyclic compounds were
eluted by EtOH : water (3 : 1, 500 ml) mixture. The product 4
was collected by EtOH : conc. aq. NH3 (5 : 1, 250 ml) mixture.
After evaporation, the product was isolated as a brownish oil.
TLC (ninhydrin) brown spot, Rf = 0.9; dH(CDCl3) 1.31 (12 H,
m, CH3), 1.62 (4 H, p, 3JHH 6.8, CH2CH2CH2), 2.59 (4 H, t, 3JHH
6.8, NCH2CH2CH2N), 2.62 (4 H, s, NCH2CH2N), 2.70 (4 H,
Cyclam27 and compounds 1–326 were synthesised by published
methods. Paraformaldehyde was filtered from aged aqueous
solutions of formaldehyde (Lachema) and was dried in a desiccator
over conc. H2SO4. All other chemicals were used as received from
commercial sources. Metal ion stock solutions were prepared by
dissolution of recrystallized M(NO3)2·xH2O in deionized water;
the metal content was determined by titration with Na2H2edta
solution. A standard nitric acid solution was prepared by passing
an aq. potassium nitrate solution through a Dowex 50W-8 (H+
form) column. A carbonate-free KOH (~0.2 M) solution was
standardized against potassium hydrogen phthalate and the HNO3
(~0.03 M) solution against the KOH solution.
Instrumental methods
NMR spectra were recorded on a Varian VNMRS300 spectrome-
ter operating at 299.9 (1H), 75.4 (13C) and 121.4 (31P) MHz. NMR
spectra references: tetramethylsilane for CDCl3 solutions (dH, dC =
0 ppm) and t-BuOH for D2O solutions (dH = 1.25 ppm, dC = 32.0
ppm) as internal references and 85% D3PO4 in D2O (dP = 0.0
ppm) as an external reference. Chemical shifts d are given in ppm
and coupling constants J are reported in Hz. Abbreviations of
signal multiplicities: s (singlet), d (doublet), t (triplet), q (quartet),
p (pentet), m (multiplet) and br (broad). The ESI-MS spectra
were acquired on a Bruker ESQUIRE 3000 spectrometer with
ion-trap detection in both positive and negative modes. Thin layer
chromatography (TLC) was performed on aluminium sheets Silica
gel 60 F254 (Merck KGaA, Germany) using 2-propanol : conc. aq.
NH3 : water 7 : 3 : 3 mixture as mobile phase with ninhydrin spray
or dipping of the sheets in 5% aq. solution of CuSO4 detection.
Elemental analyses were done in the Institute of Macromolecular
Chemistry (Academy of Sciences of the Czech Republic, Prague).
3
t, JHH 6.8, NCH2CH2CH2N), 2.79 (4 H, s, NCH2CH2N), 2.95
2
(4 H, d, JPH 10.0, CH2P), 3.48 (4 H, s, CH2Ph), 4.12 (8 H, m,
OCH2) and 7.2–7.6 (10 H, m, arom.); dC(CDCl3) 17.0 (4 C, CH3),
1
25.0 (2 C, CH2CH2CH2), 51.0 (2 C, d, JPC 628, CH2P), 51.2 (2
3
C, PhCH2NCH2), 52.4 (2 C, PhCH2NCH2), 53.2 (2 C, d, JPC
3
35.2, PCH2NCH2), 54.1 (2 C, d, JPC 35.2, PCH2NCH2), 60.3 (2
2
C, PhCH2), 63.3 (4 C, d, JPC 148, OCH2), 128.3 (2 C, arom.),
129.3 (4 C, arom.), 130.5 (4 C, arom.), 140.0 (2 C, arom. CCH2);
dP(CDCl3) 31.1 (br s).
Synthesis of 8,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-
1,4-diyl-bis(methylphosphonic acid), 5. The compound 4 ob-
tained above was dissolved in diluted aq. HCl (1 : 1, 70 ml) and
the mixture was heated under reflux for 24 h. The volatiles were
evaporated and the residue was dissolved in a small amount of
water and poured onto a column of strong cation exchanger
(Dowex 50, 100 ml, H+ form). The column was washed by water
till neutrality of the eluate and the product 5 was collected with
5% aq. HCl. Fractions containing the product were evaporated,
re-dissolved in water and chromatographed on a column of weak
cation exchanger (Amberlite CG50, 50 ml, H+ form) with 3% aq.
HCl as a mobile phase. Fractions containing pure product (TLC
Synthesis
Isolation of 1,5,8,12-tetraazabicyclo[10.2.2]hexadecane-13,14-
dione, 1. Due to problematic isolation of 1 as a free base
according to ref. 26, we isolated the compound as dihydrochloride
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check) were combined, and the product was crystallized from hot
water with a few drops of conc. aq. HCl. The white hydrochloride
salt was collected by filtration and dried in air (1.66 g, 33%, based
on 3·4HBr·4H2O). Found: C, 43.3; H, 7.0; Cl, 15.2; N, 7.7; P, 8.6%.
Calc. for 5·3HCl·2H2O, C26H49Cl3N4O8P2, M = 714.0: C, 43.7; H,
6.9; Cl, 14.9; N, 7.8; P, 8.7%; TLC (ninhydrin) purple spot, Rf =
0.6; dH(D2O/NaOD, pD = 13.8) 1.68 (4 H, br, CH2CH2CH2), 2.53
(8 H, br + s, CH2CH2CH2 + NCH2CH2N), 2.64 (4 H, d, 2JPH 10.7,
CH2P), 2.75 (4 H, br, CH2CH2CH2), 2.86 (4 H, s, NCH2CH2N),
3.49 (4 H, s, CH2Ph), 7.16 (4 H, m, arom.) and 7.32 (6 H, m, arom.);
dC(D2O/NaOD, pD = 13.8) 21.2 (2 C, CCC), 45.4 (2 C, CCC),
49.8 (2 C, CCC), 52.7 (2 C, NCCN), 53.2 (2 C, NCCN), 57.0 (2 C,
d, 1JCP 142, CP), 61.4 (2 C, CPh), 129.9 (2 C, arom.), 130.8 (4 C,
arom.), 132.1 (4 C, arom.), 139.4 (2 C, arom.); dP(D2O/NaOD,
The complex formation was evident from colour change (green to
+
violet) and MS (m/z (ESI) +445.2 ([M + H]+, C12H29N4NiO6P2
requires 445.1), -443.0 ([M - H]-, C12H27N4NiO6P2 requires
-
443.1)). The solution was concentrated to ~0.5 ml. Violet plates
of trans-O,O-[Ni(H3L)]Cl·H2O were formed by a slow vapour
diffusion of acetone and analyzed by X-ray crystallography.
Preparation of {trans-O,O-[Ni(H2L)]}3·5H2O
Ligand (50 mg of H4te2p1,4·4H2O, 0.11 mmol) was dissolved in
water (2 ml) and mixed with excess of freshly prepared Ni(OH)2
(prepared from 52 mg of NiCl2·6H2O by addition of diluted aq.
NaOH and centrifugation). The solution was stirred overnight at
room temperature and unreacted Ni(OH)2 was filtered off. The
complex formation was evident from the colour of the solution
2
pD = 13.8) 16.7 (t, JPH 11.8); m/z (ESI) +569.4 ([M + H]+,
C26H43N4O6P2 requires 569.3), -567.3 ([M - H]-, C26H41N4O6P2
(violet) and MS (m/z (ESI) +445.2 ([M + H]+, C12H29N4NiO6P2
+
-
+
requires 445.1), -443.0 ([M - H]-, C12H27N4NiO6P2 requires
-
requires 567.3).
443.1)). The single crystals—violet-blue plates—of {trans-O,O-
[Ni(H2L)]}3·5H2O were formed by a slow vapour diffusion of
acetone.
Attempt of synthesis of 1,4-bis(diethoxyphosphorylmethyl)-1,4,
8,11-tetraazacyclotetradecane, 6. Compound 4 (0.32 g) was
dissolved in EtOH (10 ml) in double-necked flask (50 ml) under
argon. To the solution, a 10% Pd/C catalyst (0.20 g) was added.
The flask was flushed with hydrogen, and the mixture was stirred
under hydrogen atmosphere for 12 h. A new portion of catalyst
(0.20 g) was added and the mixture was stirred for further 24 h.
After that time, a sample of the mixture was filtered, evaporated to
dryness and analyzed by NMR. According to 1H NMR, complete
Crystallography
Selected crystals were mounted on a glass fibre in random orien-
tation and cooled to 150(1) K. The diffraction data were collected
employing a Nonius Kappa CCD diffractometer (Enraf-Nonius)
˚
using Mo-Ka (l = 0.71073 A) at 150(1) K (Cryostream Cooler,
debenzylation occurred, but three major peaks appeared in the 31
P
Oxford Cryosystem) and analyzed using the HKL DENZO
program package.28 The structures were solved by direct methods
and refined by full-matrix least-squares techniques (SIR92 (ref. 29)
and SHELXL97 (ref. 30)). The used scattering factors for neutral
atoms were included in the SHELXL97 program.
NMR spectrum at 29.5 (15%), 31.3 (65%) and 31.8 (20%) ppm.
Trial of de-esterification of the product mixture in dry HBr–AcOH
solution (30% w/w) led to a more complicated mixture (5 peaks
in 31P NMR spectrum at 11.1 (15%), 11.6 (15%), 11.9 (40%), 12.9
(20%) and 14.0 (10%) ppm).
In the structure of 1·2HCl, all non-hydrogen atoms were refined
anisotropically. The hydrogen atoms attached to carbon and
nitrogen atoms were located in the electron density difference map;
however, the hydrogen atoms attached to carbon atoms were fixed
in theoretical positions using Ueq(H) = 1.2Ueq(C).
Synthesis of 1,4,8,11-tetraazacyclotetradecane-1,4-diyl-
bis(methylphosphonic acid), H4te2p1,4 (H4L)
Compound 5·3HCl·2H2O (1.40 g, 2.1 mmol) was dissolved in a
mixture of water (15 ml) and AcOH (10 ml) in a double-necked
flask (50 ml) under argon. To the solution, a 10% Pd/C catalyst
(0.15 g) was added. The flask was flushed with hydrogen and the
mixture was stirred under a hydrogen atmosphere for 24 h. The
catalyst was filtered off and the solution was evaporated to dryness.
The residue was dissolved in a small amount of water and poured
onto a column of strong cation exchanger (Dowex 50, 100 ml, H+
form). The column was washed by water till neutrality of the eluate
and the product H4te2p1,4 was collected by 5% aq. NH3. Fractions
containing the product were evaporated to dryness. The residue
was re-dissolved in water and chromatographed on a column of
weak cation exchanger (Amberlite CG50, 50 ml, H+ form) with
water. The product was crystallized from conc. aq. solution by slow
addition of acetone. The white solid H4te2p1,4·4H2O was collected
by filtration and dried in air (0.52 g, 54%). The characteristics were
identical to those reported.25
In the structure of 3·4HBr·2H2O, an independent unit is formed
by one half of the amine molecule (the molecule lies on the
crystallographic double-fold axis), two bromide anions and one
solvate water molecule. The bromide anions occupy three positions
(one with full and two with half crystallographic occupancies).
Most of hydrogen atoms were located in the electron density
difference map; however, due to the presence of a heavy atom,
all hydrogen atoms were fixed in theoretical (C–H, N–H) or
original (O–H) positions using Ueq(H) = 1.2Ueq(X). Due to
a high absorption coefficient, absorption correction (Gaussian
integration31) with scaling factors Tmin = 0.2902 and Tmax = 0.7003
was applied.
In the structure of trans-O,O-[Ni(H3L)]Cl·H2O, all non-
hydrogen atoms were refined anisotropically. The hydrogen atoms
were located in the electron density difference map; however, due
to the presence of a heavy atom, all hydrogen atoms were fixed
in theoretical (C–H, N–H) or original (O–H) positions using
Ueq(H) = 1.2Ueq(X).
Preparation of trans-O,O-[Ni(H3L)]Cl·H2O
Ligand (50 mg of H4te2p1,4·4H2O, 0.11 mmol) was dissolved with
an equimolar amount of NiCl2·6H2O (26 mg) in water (2 ml)
and the solution was heated in a closed vial at 100 ◦C overnight.
In the structure of {trans-O,O-[Ni(H2L)]}3·5H2O, three complex
molecules and five water solvate molecules form the structurally
independent unit. All non-hydrogen atoms were refined anisotrop-
ically (except of those belonging to the disordered phosphonate)
5380 | Dalton Trans., 2008, 5378–5386
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and the hydrogen atoms attached to carbon and nitrogen atoms
were fixed in theoretical positions using Ueq(H) = 1.2Ueq(X). One
phosphonate pendant group was best refined as disordered in
two positions (with the common carbon and nickel-coordinated
oxygen atoms). A low-quality of crystal data and a high number of
refined parameters led to high uncertainties; therefore, some atoms
have relatively high thermal parameters and, so the hydrogen
atoms of water solvate molecules could not be located in the
electron density map.
The water ion product was taken from literature (pKw = 13.78).32
The constants with their standard deviations were calculated
with the OPIUM program package.33 The program minimises
the criterion of the generalised least-squares method using the
calibration function
E = E0 + S ¥ log [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. The term S corresponds to the Nernstian slope
and the j1 ¥ [H+] and j2 ¥ [OH-] terms are contributions of the
H+ and OH- ions to the liquid-junction potential. They cause a
deviation from a linear dependence between E and -log [H+] only
in strongly acidic or strongly alkaline solutions. The calibration
parameters were determined from titration of the standard HNO3
with the standard KOH solutions before and after every titration of
the ligand (ligand/metal ion system) to give calibration–titration
pairs used for calculations of the constants. The protonation con-
stants bh are defined as concentration constants bh = [HhL]/([H]h ¥
[L]). The concentration stability constants bhlm are defined by the
equation bhlm = [HhLlMm]/([H]h ¥ [L]l ¥ [M]m). In the definitions,
the charges of the species are omitted for clarity.
Crystal data. 1·2HCl, C12H24Cl2N4O2, M = 327.25, mono-
˚
˚
˚
clinic, a = 9.6533(3) A, b = 15.5059(4) A, c = 10.3121(2) A, b =
◦
3
˚
93.5297(16) , U = 1540.62(7) A , space group P21/c (no. 14), Z =
4, 3533 reflections measured, 2869 unique, the final wR2 = 0.0798
(all data). CCDC 679187.
3·4HBr·2H2O, C24H44Br4N4O2, M = 740.27, monoclinic, a =
˚
˚
˚
7.27000(10) A, b = 20.5765(4) A, c = 20.0208(4) A, b =
◦
3
˚
99.6839(13) , U = 2952.26(9) A , space group C2/c (no. 15), Z =
4, 3408 reflections measured, 2854 unique, the final wR2 = 0.0659
(all data). CCDC 679184.
trans-O,O-[Ni(H3L)]Cl·H2O, C12H31ClN4NiO7P2, M = 499.51,
˚
˚
orthorhombic, a = 7.9420(2) A, b = 9.4016(3) A, c = 27.8565(8)
3
˚
˚
A, U = 2079.98(10) A , space group P212121 (no. 19), Z = 4,
4739 reflections measured, 4236 unique, the final wR2 = 0.0872
(all data). CCDC 679186.
NMR titrations
{trans-O,O-[Ni(H2L)]}3·5H2O, C36H94N12Ni3O23P6,
M
=
The 31P NMR titration experiments for determination of the
highest protonation constants of the ligand (-log [H+] 11.6–
13.5) were carried out by the recommended method34 under
the conditions of potentiometric titrations (H2O, 0.1 M KNO3,
25.0 ◦C, 0.004 M ligand); however, with no control of ionic strength
at the last points above -log [H+] 13. A coaxial capillary with D2O
was used for a lock. The protonation constant was calculated with
OPIUM from the dependence of dP on -log [H+].
˚
˚
1425.18, hexagonal, a = 15.2662(1) A, c = 43.2280(4) A, U =
3
˚
8724.84(11) A , space group P61 (no. 169), Z = 6, 13 307
reflections measured, 9407 unique, the final wR2 = 0.1673 (all
data). CCDC 679185.
Potentiometric titrations
Equilibria in systems of the ligand in free form (protonation study)
and with Ca(II), Cu(II), Zn(II), Cd(II) and Pb(II) were established
fast and, thus, they could be studied by conventional titrations.
Titrations were carried out in a thermostatted vessel at 25.0
0.1 ◦C, at constant ionic strength I(KNO3) = 0.1 M, using a PHM
240 pH-meter, a 2 ml ABU 900 automatic piston burette and a GK
2401B combined electrode (all Radiometer). The concentration of
the ligand was approximately 0.004 M. The ligand-to-metal ratio
was 1 : 1 in all cases and the initial volume was about 5 ml. The
measurements were taken with an addition of excess of HNO3 to
the mixture. The starting value of -log [H+] was typically 1.65
(the Cu(II) system) or 1.8 (other systems). The mixtures were
titrated with the solution of KOH till -log [H+] of about 12.5.
Titrations of each system were carried out at least four times.
Each titration consisted of about 40 points (with approximately
the same number of data points in both acid and alkaline regions).
An inert atmosphere was ensured by a constant passage of argon
saturated with water vapour.
The complexation reaction was too slow to be followed by
standard titrations in the Ni(II) system. Thus, this system was
studied by the “out-of-cell” method. Three titrations were done,
each consisting of 30 points (i.e. from 30 solutions mixed separately
in test tubes). Initial volume of the samples was about 1 ml. The
tubes were left firmly closed for 1 h, then an appropriate amount of
the KOH solution was added and the tubes were tightly closed. The
potential was then determined with a freshly calibrated electrode
after 3 weeks.
Results and discussion
Syntheses
Originally, H4te2p1,4 was prepared via thiophosphonylbis(amide)
protection of 1,4-positions of the cyclam ring,25 but scaling up
the synthesis was complicated due to extensive chromatographic
purifications. Thus, we proposed a new synthetic pathway, employ-
ing known oxalylbis(amide)- and bis(benzyl)-protected cyclams
1, 2 and 3 (Scheme S1†).26 However, in the original article,
the authors isolated the oxalylcyclam 1 by simple crystallization
which did not work in our hands. Therefore, we decided to
isolate the compound 1 in the form of dihydrochloride which
precipitated easily from ethanol solution of 1 on addition of conc.
aq. HCl. The dibenzylcyclam 3 was isolated after crystallization
from conc. aq. HBr acid as 3·4HBr·4H2O. Originally, we tried
the crystallization from conc. aq. HCl, but the hydrochloride
precipitated in an extremely fine form and, thus, was hardly
filterable. The dibenzylcyclam 3 reacted with triethyl phosphite
and paraformaldehyde forming protected intermediate 4 in a
quantitative yield (according to 31P NMR). After removal of excess
formaldehyde and phosphite, the protecting benzyl groups as well
as phosphonate ethyl ester groups were cleaved. First, we tried
reductive debenzylation of the ester 4 in presence of Pd/C. This
procedure led to a complicated mixture of products instead of pure
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compound 6. Further hydrolysis of ester moieties (HBr–AcOH)
resulted in inseparable mixture of products. Therefore, the ester
groups were hydrolyzed first to obtain acid 5 and benzyl groups
were removed in the last step to obtain H4te2p1,4 in an overall
moderate yield.
Crystal structures
Crystal structure of 1·2HCl. Compound 1·2HCl crystallized
in the form of colourless needles. The independent unit of the
crystal structure is formed by one macrocyclic molecule and two
chloride counter-ions. The six-membered cycle (Fig. 1) formed by
oxalyl group bonded to macrocycle nitrogen atoms N1 and N4 is
perpendicular to the plane of the rest of the macrocycle. The crystal
structure is stabilized by intermolecular hydrogen bond network
between protonated amino groups, chloride anions (dN ◊ ◊ ◊ Cl ~ 3.0–
Fig. 2 Molecular structure of the H434+ tetracation found in the crystal
structure of 3·4HBr·2H2O. Hydrogen atoms on carbon atoms are omitted
for the sake of clarity. Thermal ellipsoids show 50% probability level.
˚
˚
3.1 A) and oxygen atoms belonging to the neighbouring molecule
between protonated amino groups, bromide anions (dN ◊ ◊ ◊ Br ~ 3.2 A)
˚
˚
#
(dN ◊ ◊ ◊ O ~ 2.8–2.9 A).
and oxygen atoms of solvate water molecule (dN ◊ ◊ ◊ O ~ 2.7 A). There
are also contacts between solvate water hydrogen atoms and the
˚
bromides (dO ◊ ◊ ◊ Br ~ 3.3–3.4 A).
Crystal structure of trans-O,O-[Ni(H3L)]Cl·H2O. The inde-
pendent unit is formed by a complex molecule, a chloride anion
and a solvate water molecule. Coordination sphere of Ni(II)
ion is octahedral, with four macrocycle nitrogen atoms in the
equatorial plane and two apically coordinated oxygen atoms of the
phosphonate pendant arms (Fig. 3). Coordination bond lengths
have common values for these types, with slightly longer bonds
˚
(by ~0.06 A) between the central ion and the tertiary amino
groups compared to the secondary ones (Table 1). The macrocycle
is in the most stable configuration III,35 which is the most
common configuration found for Ni(II) complexes with cyclam-
like ligands.36 The geometries around the phosphorus atoms are
roughly tetrahedral. One phosphonate is monoprotonated, and
the other is double-protonated on the non-coordinated oxygen
atoms. The isolation of such a species points to a high inertness
of the complex, as the second protonation step of the coordinated
phosphonate group proceeds typically with pKa ~ 1.23,37,38 Similar
over-protonated species were isolated also in the case of Ni(II)
complexes of H4te2p1,8 (ref. 37). The orientation of phosphonate
pendant arms above and below the macrocyclic plane is fixed
by intramolecular hydrogen bonds between hydrogen atom of
secondary amino group (hydrogen atoms attached to N8 and
Fig. 1 Molecular structure of the H212+ dication found in the crystal
structure of 1·2HCl. Hydrogen atoms on carbon atoms are omitted for the
sake of clarity. Thermal ellipsoids show 50% probability level.
Crystal structure of 3·4HBr·2H2O. In the structure of
3·4HBr·2H2O, all amino groups are protonated. The macrocycle is
in the most common rectangular conformation (3,4,3,4)-A with all
amino groups lying in the corners of the rectangle (Fig. 2).2 The
whole structure is stabilized by intermolecular hydrogen bonds
Fig. 3 Molecular structure of the complex units found in the crystal structure of trans-O,O-[Ni(H3L)]Cl·H2O, showing the hydrogen bond system
(dashed). Hydrogen atoms attached to carbon atoms are omitted for the sake of clarity. Thermal ellipsoids show 50% probability level.
5382 | Dalton Trans., 2008, 5378–5386
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Table 1 Selected geometric parameters of the nickel(II) coordination
spheres in the crystal structures of trans-O,O-[Ni(H3L)]Cl·H2O and {trans-
O,O-[Ni(H2L)]}3·5H2O
with four macrocycle nitrogen atoms in equatorial positions (with
configuration III) and two phosphonate oxygen atoms in axial
positions (Fig. S1†). Coordination bond lengths have common
˚
values for these types, with slightly longer bonds (by ~0.06 A)
{trans-O,O-[Ni(H2L)]}3·5H2O
between the central ion and the tertiary amino groups compared
to the secondary ones (Table 1). In summary, the low quality of
the diffraction data led to high uncertainties of atom positions and
high anisotropic displacement parameters. However, the complex
stereochemistry was unambiguously determined.
trans-O,O-
[Ni(H3L)]Cl·H2O Molecule A Molecule B Molecule C
˚
Distances/A
Ni1–N1
Ni1–N4
Ni1–N8
Ni1–N11
Ni1–O11
Ni1–O21
2.130(3)
2.136(3)
2.076(3)
2.076(3)
2.106(2)
2.119(2)
2.14(1)
2.09(1)
2.06(1)
2.08(1)
2.14(1)
2.09(1)
2.13(1)
2.10(1)
2.06(1)
2.07(1)
2.14(1)
2.09(1)
2.16(1)
2.13(1)
2.07(1)
2.08(1)
2.09(1)
2.10(1)
Ligand protonation
The first two dissociation constants of azacycle amino groups
having phosphonic acid pendant arms are usually very high (pKa
~13),39 i.e. the values lie out of the region of potentiometric
titrations and, thus, they cannot be determined by this method.
Therefore, 31P NMR titration was employed to obtain the values
of log b11 and log b21. However, only the value of log b21 constant
could be fitted. This fact can be attributed to lower precision
of data due to non-constant ionic strength at -log [H+] > 12.5
and/or a relatively low number of data points (comparing to
potentiometry). In addition, such behaviour can point to a
“reverse order” of protonation (dissociation) constants due to the
presence of an intramolecular hydrogen bond (for more discussion
see Fig. S2†).22 The presence of strong hydrogen bonds in the
Angles/◦
N1–Ni1–N4
N1–Ni1–N8 175.4(1)
N1–Ni1–N11 94.1(1)
N1–Ni1–O11
N1–Ni1–O21
N4–Ni1–N8
N4–Ni1–N11 175.5(1)
N4–Ni1–O11
N4–Ni1–O21
N8–Ni1–N11 85.3(1)
N8–Ni1–O11
N8–Ni1–O21
86.5(1)
86.6(4)
176.7(5)
95.7(4)
86.7(5)
91.3(5)
91.9(5)
172.9(6)
95.1(6)
84.7(6)
86.1(3)
90.5(5)
91.4(4)
91.7(4)
88.5(5)
178.1(5)
88.5(3)
173.1(5)
93.8(5)
85.3(5)
93.1(5)
91.6(5)
174.9(5)
93.3(5)
86.2(5)
86.8(3)
87.9(4)
93.8(3)
91.5(4)
89.0(5)
178.3(4)
86.1(5)
174.7(4)
94.6(5)
94.6(5)
93.1(4)
93.3(5)
176.8(5)
90.1(4)
86.3(4)
86.3(5)
86.3(5)
92.2(4)
93.2(4)
90.5(5)
176.3(4)
86.1(1)
91.8(1)
94.5(1)
94.1(1)
85.7(1)
89.3(1)
92.7(1)
N11–Ni1–O11 93.3(1)
N11–Ni1–O21 89.9(1)
O11–Ni1–O21 176.3(1)
1
system is evidenced from the appearance of H NMR spectra at
different solution pH. The signals are broad in pH region 3–13
(where the macrocyclic amine groups bind just two protons, Fig.
S3†). The corresponding overall protonation constant log b21 is
higher than that observed for cyclam40 and tetraacetate derivative
H4teta,41 as it is typical for aminomethylphosphonic acids.39,42,43
The third and fourth protons are attached to oxygen atoms of
the phosphonate moieties, with the values of the dissociation
constants (pKa 6.56 and 5.19) typical for such dissociations.39,42,43
The final values of protonation (dissociation) constants were
obtained from simultaneous fitting of both 31P NMR and poten-
tiometry data and are compiled in Table 2. The corresponding
distribution diagram is given in Fig. S4.†
N11) and uncoordinated oxygen atoms of the phosphonates
(O23 and O12, respectively) with intermediate lengths (dN ◊ ◊ ◊ O
~
˚
2.9 A). The complex molecules are connected in infinite chains
via a very short intermolecular hydrogen bond between one –
OH group of the double-protonated phosphonate (O12) and the
non-protonated oxygen atom of the second pendant phosphonate
of a neighbouring molecule (O23#) with O12 ◊ ◊ ◊ O23# separation
˚
of 2.41 A. Similar short hydrogen bonds connecting the neigh-
bouring units were observed also in the structures of trans-O,O-
[Co(Hte2p1,8)]·6H2O (ref. 38) and trans-O,O-[Cu(H2te2p1,8)]·2H2O
(ref. 23) complexes. A further hydrogen bond network is formed
between protonated phosphonates, the water solvate and the
chloride anions.
Stability of complex species
Crystal structure of {trans-O,O-[Ni(H2L)]}3·5H2O. The in-
dependent unit is formed by three complex molecules and five
solvate water molecules. Coordination spheres of all nickel(II)
ions are very similar to each other and to the previous complex,
In all systems studied, the ligand forms 1 : 1 complex species which
can be additionally mono- and double-protonated. In the systems
with Pb(II), a triple-protonated species was also detected in a low
abundance at -log [H+] 4–7. The results are compiled in Table 3.
Table 2 Protonationa constants of H4te2p1,4 and dissociationb constants of H4te2p1,4 and related ligands (Chart 1; 25.0 ◦C, I(KNO3) = 0.1 M)
a
b
log bh
pKa
22
h
H4te2p1,4
Equilibriumc
H4te2p1,4
Cyclam 40
H2te1p 21
H1te1a 14a
H4te2p1,8
H8tetp 44
H4teta 41
1
2
3
4
5
6
—
HL ꢀ H+ + L
—
11.29
10.19
1.61
1.91
—
12.49
11.76
6.05
2.42
—
12.18
10.87
3.01
< 2
< 2
—
—
—
10.58
10.17
4.09
3.35
—
25.72(3)d
32.28(1)
37.47(1)
39.77(1)
—
H2L ꢀ H+ + HL
H3L ꢀ H+ + H2L
H4L ꢀ H+ + H3L
H5L ꢀ H+ + H4L
H6L ꢀ H+ + H5L
25.72d
6.56
5.19
2.30
—
26.41d
6.78
5.36
1.15
—
25.28d
8.85
7.68
6.23
5.33
—
2.16d
—
a
bh = [HhL]/([H]h ¥ [L]). b Ka = ([H] ¥ [Hn-1L])/[HnL]. c Charges of species are omitted for clarity. d Values in italics correspond to protonation/dissociation
over two steps.
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Table 3 Stability constants of complexes of H4te2p1,4 with selected metal
ions (25.0 ◦C, I(KNO3) = 0.1 M)
In the systems with transition metal ions (Ni(II), Cu(II), Zn(II)
and Cd(II)), the high values of the log b011 and the values of the
pKa clearly show that all four nitrogen atoms are coordinated in all
complex species, and the coordination sphere is probably closed
by at least one phosphonate pendant arm. The protonation of
these complexes takes place on the non-coordinated phosphonate
oxygen atoms (see also above for the crystal structure of Ni(II)
complex). The first protonation occurs with pKas slightly higher
(6.81 for Cu(II), 6.88 for Zn(II) and 7.80 for Cd(II)) or slightly
lower (6.14 for Ni(II)) than the corresponding pKa value of the
free ligand (6.56). The second protonations occur with lower pKas
compared to that of the free ligand. The similar drop of pKa values
of the phosphonate pendant arm upon coordination was observed
also for analogous complexes of H4te2p1,8 (ref. 23, 45) and H2te1p
(ref. 21).
The highest stability was found for the Cu(II) complex, as it
commonly reflects the Irving–Williams trend and, in addition, the
optimal size of the cyclam ring for this cation. The complexation
of Cu(II) starts in the acidic region and the metal ion is fully
encapsulated in the complex below pH ~3 (Fig. 4). The selectivity
of the ligand for Cu(II) is very high as the difference between
corresponding stability constants is about seven and five orders
of magnitude for the Cu/Zn and Cu/Ni pairs, respectively.
These facts are very promising for a potential analytical or
radiopharmaceutical use. The calculated distribution diagrams of
other studied systems are given in the ESI (Fig. S7–S9).†
a
b
Cation
Ni(II)
h
l
m
log bhlm
pKa
0
1
2
0
1
2
0
1
2
0
1
2
0
1
2
3
0
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
21.92(6)
28.06(6)
33.18(3)
27.21(3)
34.02(3)
38.93(2)
20.16(3)
27.04(1)
31.47(4)
17.03(2)
24.83(1)
29.75(3)
12.85(4)
23.05(3)
29.44(3)
34.73(9)
3.42(5)
—
6.14
5.12
Cu(II)
Zn(II)
Cd(II)
Pb(II)
—
6.81
4.91
—
6.88
4.43
—
7.80
4.92
—
10.20
6.39
5.29
—
11.92
12.12
Ca(II)
15.34(9)
27.46(5)
a
bhlm = [HhLl Mm]/([H]h ¥[L]l ¥ [M]m). b Ka = ([H] ¥ [M(Hh–1L)])/[M(HhL)].
In the case of calcium(II), the value of log b011 is low, pointing to a
very low abundance of the complex species in solution (Fig. S5†).
The initially formed diprotonated complex [Ca(H2L)] probably
loses protons from nitrogen atoms of the macrocycle, as can be seen
from the pKas of 12.12 and 11.92. Thus, the metal ion is probably
coordinated only by the oxygen atoms of the phosphonate pendant
moiety in double-protonated complex, and the macrocyclic part
starts to coordinate only after the full deprotonation in very
alkaline solutions. Similar coordination behaviour was found also
for H4te2p1,8 (ref. 45) and H2te1p (ref. 21).
In the case of lead(II) complexation, the value of log b011 is
much higher than that found for Ca(II), and the abundances of
complex species are also higher. Free lead(II) ion is not present in
the equimolar mixture above pH ~8 (Fig. S6†). The complexation
starts with formation of triprotonated complex [Pb(H3L)]+, which
has maximal abundance at pH ~5. According to its pKa (5.29), it
loses a proton probably from the phosphonate pendant arm. The
second pKa (6.39) is also comparable to the values corresponding
to phosphonate moieties, but the last one is much higher (10.20).
It suggests two possible explanations. In the first case, two oxygen
atoms (one of each pendant arm) are protonated as well as
one nitrogen atom of the macrocycle in the triple-protonated
complexes. In such case, at least other nitrogen atoms of the
macrocycle should be involved in metal coordination in the
[Pb(H2L)] species; but such a species exists even at pH below 5,
and such coordination of the macrocycle nitrogen atom would be
very unusual. The second possibility suggests that the metal ion
is bound only by pendant arms in the triple-protonated complex
and two macrocycle nitrogen atoms are still protonated. In this
case, due to a higher affinity of Pb(II) for nitrogen coordination
(compared to the Ca(II) complex), the pKa values corresponding
to the [Pb(H2L)] species would be lowered by several orders of
magnitude compared to those of the free ligand. Furthermore, as
the X-ray diffraction study of the solid phase formed from Pb(II)–
H4te2p1,8 system at pH ~6 revealed Pb(II) coordination by only
phosphonate groups and protonation of two nitrogen atoms.45 So,
the second alternative of proton locations seems to be correct.
Fig. 4 Distribution diagram for the Cu(II)–H4te2p1,4 system (cL = cCu
=
0.004 M).
From the comparison of stability constants determined for
the title ligand and the related compounds (Table 4), it is clear
that the cyclam skeleton substituted by several pendant arms
based on phosphorus acid is a good choice as the ligands have
a high selectivity of copper(II) complexation. In the H4te2p1,4
case, the complexation of copper(II) is more selective compared
to its 1,8-isomer23 and the monophosphonate derivative H2te1p.21
Furthermore, the complexation reaction is relatively fast (similarly
to the 1,8-isomer) in slightly acid solutions, and much faster
than that of the monophosphonate ligand, H2te1p,21 and cyclam46
itself; it points to an acceleration effect of more phosphonate
pendant arms. The concentration of free Cu(II) ion in the Cu(II)–
H4te2p1,4 system (expressed as pCu = -log [Cu(II)] calculated for an
equimolar ligand–Cu(II) mixture) is about one order of magnitude
lower than that for the 1,8-isomer and closer to values for other
ligands with coordinating pendant arms (Table 4). However,
5384 | Dalton Trans., 2008, 5378–5386
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Table 4 Comparison of stability constants (log b011) of the [M(L)] com-
7 (a) R. B. Wilder, G. L. DeNardo and S. J. DeNardo, J. Clin.
Oncol., 1996, 14, 1383–1400; (b) I. Novak-Hofer and P. A. Schubiger,
Eur. J. Nucl. Med. Mol. Imaging, 2002, 29, 821–830; (c) S. V. Smith,
J. Inorg. Biochem., 2004, 98, 1874–1901; (d) X. Sun and C. J. Anderson,
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G. R. Weisman and C. J. Anderson, Curr. Pharm. Des., 2007, 13, 3–16.
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Anal. Biochem., 1985, 148, 249–253.
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C: Cryst. Struct. Commun., 1988, 44, 1740–1742; (b) E. Espinosa, M.
Meyer, D. Berard and R. Guilard, Acta Crystallogr., Sect. C: Cryst.
Struct. Commun., 2002, 58, m119-m121; (c) J. D. Silversides, C. C.
Allan and S. J. Archibald, Dalton Trans., 2007, 971–978.
plex species formed with H4te2p1,4 and related ligands
Ligand
Ni(II)
Zn(II) Cd(II) Pb(II)
Ca(II) Cu(II)
pCua
H4te2p1,4
H4te2p1,8
H2te1pc
Cyclamd
H4tetad
H8tetp
21.92
21.99
—
22.2
19.91
—
20.16
20.35
21.03
15.2
17.03
17.89
15.91
11.3
12.85
14.96
—
10.9
14.3
15.5e
3.45
5.26
3.07
—
8.42
—
27.21
25.40
27.34
28.1
9.4
8.1
10.1
11.9
9.1
b
16.62
18.25
21.74
17.6e
16.7e
25.99f
8.4
a Calculated for -log [H+] = 7.4 and cL = cM = 0.004 M. b Ref. 23, 45.
c Ref. 21. d Ref. 47. e Ref. 48. f Ref. 41b.
10 L. A. Bass, M. Wang, M. J. Welch and C. J. Anderson, Bioconjugate
Chem., 2000, 11, 527–532.
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2003, 8, 217–225.
the lower pCu values for the phosphorus-containing ligands are
mainly given by the very high overall basicity of the ligands. The
kinetics of complex formation and dissociation is under study.
12 (a) I. La´za´r, A. D. Sherry, R. Ramasamy, E. Bru¨cher and R. Kiraly,
Inorg. Chem., 1991, 30, 5016–5019; (b) K. Bazakas and I. Lukesˇ,
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(b) D. Tschudin, A. Basal and T. A. Kaden, Helv. Chim. Acta, 1988, 71,
100–106.
Conclusions
The title ligand, H4te2p1,4, forms extremely stable complex with
Cu(II) (log b(CuL) = 27.21) with a high selectivity of complexation
over other metal ions (e.g. log b(ZnL) = 20.16, log b(NiL) = 21.92).
The complexation of copper(II) proceeds relatively fast as it could
be determined by conventional potentiometric titration. It makes
the ligand promising as the parent chelator for possible radiophar-
maceutical applications. The ligand forms octahedral trans-O,O
Ni(II) complexes with the most stable macrocycle configuration III.
From acid solution, the crystals of trans-O,O-[Ni(H3L)]Cl·H2O
were isolated with mono- and double-protonated phosphonate
pendant arms. The isolation of such species points to a high
inertness of the complex. From neutral solutions, the crystals of
{trans-O,O-[Ni(H2L)]}3·5H2O were isolated where each pendant
arm is monoprotonated.
15 D. Tschudin, A. Riesen and T. A. Kaden, Helv. Chim. Acta, 1989, 72,
313–319.
16 (a) I. M. Helps, D. Parker, J. Chapman and G. Ferguson, J. Chem. Soc.,
Chem. Commun., 1988, 1094–1095; (b) J. Chapman, G. Ferguson, J. F.
Gallagher, M. C. Jennings and D. Parker, J. Chem. Soc., Dalton Trans.,
1992, 345–353.
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1772; (b) L. Siegfried, A. Comparone, M. Neuburger and T. A. Kaden,
Dalton Trans., 2005, 30–36.
18 C. Bucher, E. Duval, J.-M. Barbe, J.-N. Verpeaux, C. Amatore and R.
Guilard, C. R. Acad. Sci., Ser. IIc: Chim., 2000, 3, 211–222.
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Acknowledgements
This work was supported by the Grant Agency of the Czech
Republic (203/06/0467), the Ministry of Education and Youth
of Czech Republic (MSM0021620857) and COST D38.
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