Synthesis of N-methyl alkylaminomethane-1,1-diphosphonic acids and evaluation of their complex-formation abilities towards copper(II)

Article abstract of DOI:10.1016/j.poly.2014.09.031

A series of N-methyl alkylaminomethane-1,1-diphosphonic acids (3a-g) with a common tertiary nitrogen atom (CH₃-N-R) bearing linear or branched alkyl, cycloheptyl or phenylalkyl R substituents was synthesized in the reaction of diethylphosphonat

Full text of DOI:10.1016/j.poly.2014.09.031

Polyhedron 85 (2015) 675–684
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Polyhedron
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Synthesis of N-methyl alkylaminomethane-1,1-diphosphonic acids and
evaluation of their complex-formation abilities towards copper(II)
b
a
b
c
Barbara Kurzak a, , Waldemar Goldeman , Magdalena Szpak , Ewa Matczak-Jon , Anna Kamecka
⇑
a Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland
b
_
Department of Chemistry, Wrocław University of Technology, Wybrzeze Wyspian´skiego 27, 50-370 Wrocław, Poland
c Institute of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-methyl alkylaminomethane-1,1-diphosphonic acids (3a–g) with a common tertiary nitrogen
atom (CH3–N–R) bearing linear or branched alkyl, cycloheptyl or phenylalkyl R substituents was synthe-
sized in the reaction of diethylphosphonate with triethyl orthoformate and secondary amine followed by
hydrolysis, and by the Eschweiler–Clarke methylation of the alkylaminomethane-1,1-diphosphonic acids
with formic acid and formaldehyde. Complex-formation abilities of 3a–g towards copper(II) in solution
were studied by means of pH-potentiometry, ESI-MS spectrometry, UV–Vis and EPR methods.
Evaluation of stability constants for the Cu(II) complexes of 3a–g has revealed their dependence on a
combination of steric and electronic effects imposed by R substituents. It has been demonstrated that
compounds with linear or branched alkyl on the N atom (3a, 3d, 3e) form the most stable complexes with
Cu(II), the least stable are complexes of 3f, which can be attributed to the steric effect imposed by cyclo-
heptyl ring attached directly to the N atom. In addition to the main [Cu(HL)2] complexes, with well-
known {O, O} chelating binding mode, [Cu(HL)L] and [CuL2] species with the {O, N} donor set, protonated
dinuclear [Cu2HxL3] (x = 4, 5, 6) species have been detected in all studied systems. The nitrogen coordina-
tion in the [Cu(HL)L] and [CuL2] complex has been confirmed by Vis and EPR spectra.
Received 14 June 2014
Accepted 28 September 2014
Available online 8 October 2014
Keywords:
Bisphosphonates
Copper(II) complexes
pH potentiometry
EPR
Vis spectroscopy
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
enzyme of the mevalonate pathway, farnesyl pyrophosphate syn-
thase (FPPS) [7–9].
Bisphosphonates, a class of compounds sharing a common
P–C–P backbone, are known to play a crucial role in various med-
ical applications. At now, they are considered the most effective
drugs for prevention and treatment of bone disorders such as oste-
oporosis, Paget’s disease and osteolytic bone metastases [1–4]. The
medical use of bisphosphonates stems from their specific proper-
ties such as strong affinity of phosphonic/phosphonate groups for
various metal ions as well as their high potential to form hydrogen
bonds [5,6]. It is widely accepted that antiresorptive properties of
bisphosphonates rely on two mechanisms: (a) high affinity for cal-
cium ions enables their targeting to mineral component of bone
(hydroxyapatite) that prevents both its growth and dissolution/
breakdown (b) after absorption on bone surface they target selec-
tively bone resorbing cells (osteoclasts) and inhibit their activity. It
is well documented that the major target of the most potent bis-
phosphonates characterized by the presence of one of more nitro-
gen atoms in their side chains (NBPs) is magnesium-dependent
A high affinity of bisphosphonates for hydroxyapatite has also
been utilized to deliver diagnostic and therapeutic pharmaceuti-
cals to bone surface [10–12]. Moreover, some bisphosphonate-
functionalized compounds have been developed as potential
chelating agents in metal intoxication therapy [13], and some oth-
ers have proven to be useful reagents for detecting biologically
important metal ions [14]. On the other hand, complexation of
metal ions, followed by spectrophotometric detection of M(II)
complexes (M = Cu, Fe) has been shown to be useful approach for
quantification of bisphosphonates in biological fluids and pharma-
ceutical formulations [15–17]. Considering a broad spectrum of
biological utilities of bisphosphonates as well as their strong
affinity for metal ions, detailed structure-correlated studies of
individual properties of ligands and in-depth understanding com-
plex-formation driving factors, thermodynamic stability of metal
complexes and their speciation in solution are desired. This might
help to establish structure-activity relationships and shed light on
the in vivo mode of action of bisphosphonate-based compounds.
Bisphosphonates display unique coordination properties
accounted for by a short distance between two phosphonate
⇑
Corresponding author.
E-mail address: bkurzak@gmail.com (B. Kurzak).
http://dx.doi.org/10.1016/j.poly.2014.09.031
0277-5387/Ó 2014 Elsevier Ltd. All rights reserved.

676
B. Kurzak et al. / Polyhedron 85 (2015) 675–684
functions, which facilitates their synergic ability of acting as one
[CP2O6] unit, which affords involvement up to six phosphonate
O-donors in metal ions coordination. This results in a variety of
coordination modes, depending on a size and chemical nature
of side chains attached to the carbon atom, protonation degree of
phosphonic/phosphonate groups, specificity and coordination
geometry requirements of a given metal ion as well as presence/
absence of additional functional groups in their structures [5]. The
studies on the Zn(II), Mg(II) and Ca(II) complexation by structurally
diverse derivatives of aminomethane-1,1-diphosphonic acid char-
and 300.13 MHz, respectively, at 300 K, and are given in relation
to 85% H3PO4 (31P NMR) and SiMe4, (1H, 13C). All experiments were
performed with locking spectrometer on deuterium from a solvent.
All reagents were of commercial quality, purchased from
Sigma–Aldrich and were used without further purification. The
identity of synthesized compounds was confirmed by NMR, their
purity, the concentrations of the ligand stock solutions used for
potentiometric measurements and the HCl concentration were
determined by pH-potentiometric titrations using the Gran’s
method [40]. The CuCl2 and HCl stock solutions were prepared
from Titrisol concentrates (Merck) for the preparation of standard
solutions. The exact concentration of copper ions stock solution
was determined via complexometric ethylenediaminetetraacetate
(EDTA) titration. Carbonate-free potassium hydroxide solution
(the titrant) was prepared from cc. KOH and standardized against
a standard potassium hydrogen phthalate solution. All solutions
were prepared with bi-distilled water.
acterized by the presence of C –Namino bond (Scheme 1, left) have
a
revealed several key feature that seem to be universal when consid-
ering their complex-formation abilities in solution [18–21]. Despite
the incorporation of the amino functionality, compounds of this
class demonstrate preference towards chelation via the phospho-
nate functions and formation of O-bonded complexes over a broad
range of pH. This is because of strong basicity of the nitrogen proton
that permits the formation of nitrogen-bonded complexes only in
alkaline solutions. Indeed, tendency towards formation of soluble,
protonated oligonuclear complexes has been observed, which is
especially notable at 1:1 metal to ligand ratio, in the intermediate
pH range and at higher concentrations. Some aminomethane-1,1-
diphosphonic acid derivatives have also been suggested to form oli-
gonuclear complexes with Cu(II) [22,23].
Herein we describe the synthesis of N-methyl alkylaminome-
thane-1,1-diphosphonic acids (Scheme 1, right) with common ter-
tiary nitrogen atom (CH3)–N–R, where R is linear or branched alkyl,
cycloheptyl or phenylalkyl as well as their complex-formation abil-
ities towards copper(II) in solution studied by means of pH-poten-
tiometry, ESI-MS, EPR and NIR–Vis–UV methods. Compounds 3a–g
were designed with an intention to obtain aminobisphosphonates
with improved solubility in water as compared to previously stud-
ied mono N-substituted compounds (Scheme 1, left).
2.2. Syntheses
N-Methyl-n-pentylamine was prepared from n-pentylamine
according to literature procedure with 53% yield (bp760 = 114–
118 °C) [41]. 3-Phenylpropyl isocyanide was prepared from
3-phenylpropylamine by standard procedure [42], and the crude
product was purified by bulb to bulb distillation with 44% yield
(bp20 = 140–150 °C). The NMR spectra of obtained 3-phenylpropyl
isocyanide are consistent with given in the literature [43].
2.2.1. Synthesis of N-methyl alkylaminomethane-1,1-diphosphonic
acid 3a and 3b
A
mixture of N-methylbenzylamine (12.1 g, 0.10 mol) or
N-methyl-n-pentylamine (10.1 g, 0.10 mol), diethyl phosphonate
(27.6 g, 0.20 mol) and triethyl orthoformate (16.3 g, 0.11 mol) was
stirred and heated at about 150–155 °C (oil bath temperature) with
continuous distillation of the ethanol produced. When the evolution
of ethanol has cased (about 4 h), the reaction mixture was cooled to
room temperature, the volatiles were removed by rotary evapora-
tion (boiling water bath, 20 mmHg) and the residue was treated
with 6 M hydrochloric acid (300 ml). Obtained solution was heated
under reflux for 8 h, the hydrolysate was cooled to room tempera-
ture and washed with dichloromethane (1 ꢀ 50 ml, 3 ꢀ 20 ml).
Water phase was evaporated to dryness (boiling water bath,
20 mmHg) and repeatedly co-distilled with water (5 ꢀ 100 ml).
Obtained crude product was treated with acetone (50 ml), filtered
off, washed with acetone (4 ꢀ 25 ml) and dried in air, yielding 3a
(10.6 g, 36% yield, based on N-methylbenzylamine) and 3b (14.3 g,
52% yield, based on N-methyl-n-pentylamine) as white solids. Crude
solids were purified by recrystallization from water solutions.
N-Methylpentylaminomethane-1,1-diphosphonic acid (3a):
31P{1H}(121 MHz, D2O+NaOD) d: 9.63 (s); 1H NMR (300 MHz,
D2O+NaOD) d: 0.73 (t, 3H, J = 6.8 Hz, CH3), 1.10–1.30 (m, 4H,
CH3(CH2)2), 1.52 (quintet, 2H, J = 7.7 Hz, NCH2CH2), 2.87 (s, 3H,
CH3N), 3.02 (t, 1H, J = 19.1 Hz, CHP2), 3.23 (t, 2H, J = 7.7 Hz,
NCH2); 13C{1H}NMR (75 Hz, D2O+NaOD) d: 13.10 (CH3), 21.57
(CH2), 24.79 (CH2), 27.66 (CH2), 40.24 (NCH3), 57.01 (NCH2),
63.12 (t, J = 114.4 Hz, CHP2).
Searching data bases we found only few examples of N-methyl
alkylaminomethane-1,1-diphosphonic acids, like N-octyl and
N-hexyl [24], N-(2-carboxylethyl) [25], N-cycloheptyl (N-methyl
Incadronate) [26], N-benzyl derivative [27,28], and the simplest
one, namely N,N-dimethylaminomethane-1,1-diphosphonic acid,
the only one which has been extensively studied. Some biological
[29,30] and NMR [31,32], studies of N,N-dimethylaminomethane-
1,1-diphosphonic acid have been performed, and solid state studies
have revealed diversified coordination capabilities of such ligand
affording the formation of metal complexes with a whole spectrum
of structures, from 0D isolated coordination units up to 3D coordi-
nation frameworks [33–37]. Moreover, complexation abilities of
N,N-dimethylaminomethane-1,1-diphosphonic acid have been
examined in solution [38,39], indicating the formation of highly
stable mononuclear complexes with trivalent metal ions such as
Ga3+, In3+, and Fe3+
.
2. Experimental
2.1. General information
The 31P{1H}, 13C{1H} and 1H NMR spectra were recorded on a
Bruker DRX spectrometer operating at 121.50 MHz, 75.46 MHz
O
P
O
P
3a R = n-pentyl
3b R = Ph-CH2
3e R = 1-methylhexyl
3f R = cycloheptyl
3g R = Ph-(CH2)3
HO
OH
O-
HO
OH
O-
O
R NH
H
P
R NH
P
O
3c R = Ph-(CH2)2
3d R =sec-butyl
OH
CH3 OH
3a-g
Scheme 1. Mono N-substituted (left) and N-methyl alkylaminomethane-1,1-diphosphonic acids 3a–g (right).

B. Kurzak et al. / Polyhedron 85 (2015) 675–684
677
N-Methylbenzylaminomethane-1,1-diphosphonic acid (3b):
2.2.4. Synthesis of N-methyl alkylaminomethane-1,1-diphosphonic
acids 3c-g
31P{1H}(121 MHz, D2O+NaOD) d: 8.35 (s); 1H NMR (300 MHz,
D2O+NaOD) d: 2.84 (s, 3H, CH3N), 3.18 (t, 1H, J = 18.6 Hz, CHP2),
4.54 (s, 2H, CH2), 7.37–7.40 (m, 3H, ArH), 7.42–7.47 (m, 2H,
ArH); 13C NMR (75 Hz, DMSO-d6) d: 41.56 (NCH3), 57.68 (t,
J = 118.6 Hz, CHP2), 59.67 (NCH2), 129.39, 130.01, 131.40, 131.52.
To suspension of alkylaminomethane-1,1-diphosphonic acids
3c0–g0 (0.010 mol) in water (10 ml), formic acid (50 ml) and 36%
solution of formaldehyde in water (4.2 g, 0.05 mol) were added
and the reaction mixture was heated at reflux for 24 h. The reac-
tion mixture was cooled to room temperature and evaporated to
dryness (boiling water bath, 20 mmHg) and repeatedly co-distilled
with water (5 ꢀ 50 ml). Obtained residue was treated with acetone
(20 ml), filtered off, washed with acetone (4 ꢀ 10 ml) and dried in
air, yielding the crude products: 2.5 g of 3c (80%), 2.3 g of 3d (90%),
2.4 g of 3e (81%), 2.5 g of 3c (83%) and 3.1 g of 3g (97%) as white
solids. The crude products were crystallized from water–96% etha-
nol mixture (1:1, v/v) in a case of 3c and 3f, and from water solu-
tions in case of 3d, 3e and 3g.
N-Methyl-2-phenylethylaminomethane-1,1-diphosphonic acid
(3c): 31P {1H}(121 MHz, D2O+NaOD) d: 16.28 (s); 1H NMR
(300 MHz, D2O+NaOD) d: 2.42 (s, 3H, CH3), 2.56 (m, 2H, CH2, AA0BB0
system), 2.74 (t, 1H, J = 21.8 Hz, CHP2), 2.88 (m, 2H, NCH2, AA0BB0
system), 7.00 (m, 1H, J = 4.3 Hz (virtual coupling), p-ArH), 7.08 (d,
4H, J = 4.3 Hz (virtual coupling), m- and o-ArH); 13C{1H}NMR
(75 Hz, D2O+NaOD) d: 33.33 (CH2), 40.05 (CH3), 58.20 (CH2),
64.69 (t, J = 120.6 Hz, CHP2), 126.29, 128.63, 128.88, 139.71.
( )-N-Methyl-1-methylpropylaminomethane-1,1-diphosphonic
acid (3d): 31P{1H}(121 MHz, D2O+NaOD) d: 8.83 (s, I = 100%), 8.95
(s, I = 100%); 1H NMR (300 MHz, D2O+NaOD) d: 0.77 (t, 3H,
J = 7.4 Hz, CH3CH2), 1.16 (d, 3H, J = 6.5 Hz, CH3CH), 1.48 (m, 1H,
CHaHb), 1.67 (m, 1H, CHaHb), 2.90 (s, 3H, CH3N), 3.24 (t, 1H,
J = 19.1 Hz, CHP2), 3.68 (m, 1H, NCHCH3); 13C{1H}NMR (75 Hz,
D2O+NaOD) d: 8.85 (CH3), 14.11 (CH3), 24.43 (CH2), 36.47 (NCH3),
59.40 (t, J = 108.0 Hz, CHP2), 64.64 (NCH).
( )-N-Methyl-1-methylhexylaminomethane-1,1-diphosphonic
acid (3e): 31P{1H}(121 MHz, D2O+NaOD) d: 31P{1H}(121 MHz,
D2O+NaOD) d: 9.53 (s, I = 100%), 9.91 (s, I = 100%); 1H NMR
(300 MHz, D2O+NaOD) d: 0.64 (t, 3H, J = 6.7 Hz, CH3CH2), 1.05–
1.25 (m, 9H, 3 ꢀ CH2 + CH3CH), 1.32 (m, 1H, CHaHb), 1.60 (m, 1H,
CHaHb), 2.81 (s, 3H, CH3N), 3.18 (t, 1H, J = 19.3 Hz, CHP2), 3.59
(m, 1H, NCHCH3); 13C{1H}NMR (75 Hz, D2O+NaOD) d: 13.24
(CH3), 15.48 (CH3), 21.72 (CH2), 23.66 (CH2), 30.89 (CH2), 31.60
(CH2), 36.74 (NCH3), 61.88 (t, J = 114.0 Hz, CHP2), 62.19 (t,
J = 2.3 Hz, NCH).
N-Methylcycloheptylaminomethane-1,1-diphosphonic acid (3f,
N-methyl Incadronate): 31P {1H} (121 MHz, D2O+NaOD) d: 8.80
(s); 1H NMR (300 MHz, D2O+NaOD) d: 1.45–1.65 (m, 8H,
4 ꢀ CH2), 1.77 (m, 2H, 2 ꢀ CHaHb), 2.07 (m, 2H, 2 ꢀ CHaHb), 3.03
(s, 3H, CH3), 3.37 (t, 1H, J = 19.0 Hz, CHP2), 3.89 (m, 1H, NCH,);
13C {1H}NMR (75 Hz, D2O+NaOD) d: 23.39 (CH2), 27.05 (CH2),
29.17 (bs, CH2), 36.61 (CH3), 60.48 (t, J = 108.8 Hz, CHP2), 67.68
(s, CHN).
2.2.2. Synthesis of alkylaminomethane-1,1-diphosphonic acid 3c0-f0
Compounds 3c0–f0 were obtained according to the same proce-
dure as 3a and 3b except that instead of N-methylbenzylamine
and N-methyl-n-pentylamine,
a
phenethylamine (12.1 g,
0.10 mol), ( )-sec-butylamine (7.3 g, 0.10 mol), ( )-2-heptylamine
(11.5 g, 0.10 mol) and cycloheptylamine (11.3 g, 0.10 mol) were
used. The crude products were crystallized from: water–acetone
mixture (1:2, v/v) in a case of 3c0, yields 13.3 g (45%, based on
phenethylamine), water–96% ethanol mixture (1:2, v/v) in a case
of 3d0, yields 6.2 g (25%, based on ( )-sec-butylamine), water in a
case of 3e0, yields 12.1 g (42%, based on ( )-2-heptylamine) and
water–acetone mixture (1:1, v/v) in a case of 3f0, yields 16.6 g
(58%, based on cycloheptylamine).
2-Phenylethylaminomethane-1,1-diphosphonic acid (3c0): 31P
NMR {1H} (121 MHz, D2O+NaOD): d 18.02; 1HNMR (300 MHz,
D2O+NaOD): d 2.32 (t, J = 17.2 Hz, 1H, CHP2) 2.53 (t, J = 7.6 Hz,
2H, CH2), 2.79 (t, J = 7.6 Hz, 2H, CH2), 7.00 (m, 1H, p-ArH), 7.07–
7.14 (m, 4H, m- and o-ArH); 13CNMR (300 MHz, D2O+NaOD): d
35.63 (CH2), 52.03 (bs, CH2), 59.070 (t, J = 128.9 Hz, NCH), 126.00,
128.48, 128.63, 140.48.
( )-1-Methylpropylaminomethane-1,1-diphosphonic acid (3d0):
31P{1H}(121 MHz, D2O+NaOD) d: 8.78 (s, I = 100%), 8.90 (s,
I = 100%); 1H NMR (300 MHz, D2O+NaOD) d: 0.81 (t, 3H, J = 7.5 Hz,
CH3CH2), 1.09 (d, 3H, J = 6.4 Hz, CH3CH), 1.37 (m, 1H, CHaHb), 1.61
(m, 1H, CHaHb), 2.90 (t, 1H, J = 16.5 Hz, CHP2), 3.34 (m, 1H,
NCHCH3); 13C{1H}NMR (75 Hz, D2O+NaOD) d: 9.10 (CH3), 16.95
(CH3), 27.27 (CH2), 54.51 (bs, NCH), 55.30 (t, J = 123.4 Hz, CHP2).
( )-1-Methylhexylaminomethane-1,1-diphosphonic acid (3e0):
31P{1H}(121 MHz, D2O+NaOD) d: 31P{1H}(121 MHz, D2O+NaOD) d:
18.00 (d, J = 4.5 Hz, I = 100%), 17.88 (d, J = 4.5 Hz, I = 100%); 1H
NMR (300 MHz, D2O+NaOD) d: 0.62 (t, 3H, J = 6.5 Hz, CH3CH2),
0.79 (d, 3H, J = 6.2 Hz, CH3CH), 0.91–1.24 (m, 7H, 3 ꢀ CH2 +
CHaHb),1.36 (m, 1H, CHaHb), 2.60 (t, 1H, J = 17.5 Hz, CHP2), 2.87
(m, 1H, NCHCH3); 13C{1H}NMR (75 Hz, D2O+NaOD) d: 13.26
(CH3), 15.76 (CH3), 21.71 (CH2), 24.08 (CH2), 30.73 (CH2), 32.81
(CH2), 53.61 (t, J = 112.6 Hz, CHP2), 56.52 (bs, NCH).
Cycloheptylaminomethane-1,1-diphosphonic acid (3f0, Incadro-
nate): 31P{1H}(121 MHz, D2O+NaOD) d: 8.50 (s); 1H NMR
(300 MHz, D2O+NaOD) d: 1.35–1.43 (m, 6H, 2 ꢀ CH2 + 2 ꢀ CHaHb),
1.53–1.67 (m, 4H, 2 ꢀ CHaHb + 2 ꢀ CHcHd), 2.03 (m, 2H, 2 ꢀ CHcHd),
3.41 (t, 1H, J = 18.0 Hz, CHP2), 3.58 (m, 1H, NCH,); 13C{1H}NMR
(75 Hz, D2O+NaOD) d: 23.80 (CH2), 27.86 (CH2), 33.15 (CH2),
55.32 (t, J = 127.6 Hz, CHP2), 67.68 (t, J = 4.8 Hz, CHN). The 1H
NMR spectrum is consistent with literature data [26].
N-Methyl-3-phenylpropylaminomethane-1,1-diphosphonic
acid (3g): 31P {1H} (121 MHz, D2O+NaOD) d: 13.27 (s); 1H NMR
(300 MHz, D2O+NaOD) d: 1.62–1.72 (m, 2H, CH2CH2N), 2.43 (bt,
2H, J = 7.7 Hz, CH2), 2.57 (s, 3H, CH3), 2.84 (t, 1H, J = 20.5 Hz,
CHP2), 2.93 (m, 2H, NCH2, AA0BB0 system), 7.04 (m, 1H, p-ArH),
7.09–7.16 (m, 4H, m- and o-ArH); 13C {1H}NMR (75 Hz, D2O+NaOD)
d: 28.41 (CH2), 32.40 (CH2), 40.05 (CH3), 56.34 (CH2), 64.28 (t,
J = 111.5 Hz, CHP2), 125.98, 128.44, 128.55, 142.15.
2.2.3. Synthesis of 3-phenylpropylaminomethane-1,1-diphosphonic
acid 3g0
Bisphosphonic acid 3g0 was prepared according to the method-
ology developed previously in our laboratory [44], starting from
3-phenylpropylisocyanide (7.3 g, 0.05 mol) and yields 13.1 g of
3-phenylpropylaminomethane-1,1-diphosphonic 3g0 (85%, based
on starting isocyanide, see Scheme 2).
2.3. Potentiometric measurements
3-Phenylpropylaminomethane-1,1-diphosphonic acid (3g0): 31P
{1H} (121 MHz, D2O+NaOD) d: 18.33 (s); 1H NMR (300 MHz,
D2O+NaOD) d: 1.40 (quintet, 2H, J = 7.4 Hz, CH2), 2.20 (t, 1H,
J = 17.1 Hz, CHP2), 2.30 (t, 2H, J = 7.4 Hz, CH2), 2.45 (t, 2H,
J = 7.4 Hz, CH2), 6.87–7.03 (m, 5H, Ph); 13C NMR (75 Hz,
D2O+NaOD) d: 31.49 (CH2), 32.90 (CH2), 50.73 (t, J = 5.6 Hz,
CH2N), 59.44 (t, J = 129.5 Hz, CHP2), 125.77, 128.41, 128.49,142.93.
The potentiometric titrations were performed in 3 cm3 samples
with the ligand concentration of 1.5 ꢀ 10ꢁ3 mol dmꢁ3. Potentio-
metric measurements of the free ligands were carried out in the
range pH 2–11.5. The copper(II)-to-ligand molar ratios ranged from
1:1.5 to 1:3, three or four different ratios were applied for each sys-
tem studied. These samples were titrated in the pH range 2.5–11.5.

678
B. Kurzak et al. / Polyhedron 85 (2015) 675–684
Me
N
O
Me
N
O
P
OEt
OH
OH
OEt
OEt
Me
N
O
P
OEt
HC OEt
OEt
P
OH
OEt
OEt
150-160oC
-EtOH
6M HClaq
8h reflux
R
R
2
H
+
H
+
R
P
P
OH
R=PhCH2-, CH3(CH2)4-
OEt
O
O
1a,b
2a,b
3a,b
Scheme 2. Direct synthesis of N-methyl alkylaminomethane-1,1-diphosphonic acids 3a and 3b.
Precipitation was observed at pH values above 4 when metal:
ligand molar ratio was <1:1.5 and in the systems with metal
excess.
microwave energy by water very narrow sample tubes were used
for liquid solution measurements. The samples for EPR measure-
ments were prepared in water/ethylene glycol (4:1 v/v) solution
to ensure good glass formation with a copper(II) concentration of
4 ꢀ 10ꢁ3 mol dmꢁ3 in all samples. The copper(II) ion to ligands
molar ratios were the same as those used in the UV–Vis measure-
ments. The solutions were usually measured at the same pH range
as in the potentiometric studies. The pH of solutions was measured
using Elmetron, CPC401 pH-meter with a combined pH electrode.
The potentiometric titrations were performed using an auto-
matic titrator system Titrando 809 (Metrohm) with a Metrohm
6.0234.100 type combined glass electrode filled with 3 M KCl in
water. The measurements were carried out in an argon atmosphere
at 298 K at constant ionic strength (0.2 mol dmꢁ3 KCl). The elec-
trode system was calibrated daily in hydrogen ion concentration
using HCl solution (0.02 mol dmꢁ3 in KCl) against standard KOH
solution (0.15 mol dmꢁ3). The resulting titration data were used
to calculate the standard electrode potentials, E°, and the dissocia-
tion constant for water (pKw = 13.74 0.02). The calibration of the
electrode was as pH = –log[H+].
The protonation constants of the ligand and the concentration
stability constants (logbpqr) of metal complexes were calculated
by means of a general computational program, HYPERQUAD 2006
[45]. The uncertainties (3SD values) of the stability constants are
given in parentheses in Table 1. The stability constants of M2+–OH
systems were included in the calculations and were taken from
the literature [46]. The charges of the complexes have been omitted
in the text, Table and Figures. It is to note that due to high basicity of
the (CH3)–NH+–R group, the pKðNHþÞ values cannot be determined
by pH-metric titrations and therefore are ignored in the calculation
process. Thus, HL3ꢁ is assumed in calculations as the fully deproto-
nated form of the ligands. The equilibrium models and the corre-
sponding stability constants giving the best fits of the pH-metric
titration curves are presented in Table 1.
2.6. NMR measurements
Samples for 1H and 31P{1H} NMR titration studies were pre-
pared in D2O with a ligand concentration of 1 ꢀ 10ꢁ2 M. Titrations
were performed over a pH range ca. 2–13. The pH was measured
using a Radiometer pH M83 instrument equipped with a Mettler
Toledo INLAB 422 combined electrode and is given as meter read-
ings without correction for pD.
2.7. UV–Vis measurements
Jasco V-570 spectrophotometer was used to record the elec-
tronic absorption spectra in the range of 300–900 nm at room tem-
perature. The path length was 3 cm. The measurements were
carried out in aqueous solution, at different pH values (0.5 pH unit
step) between 2.0 and 12, at all metal to ligand molar ratios stud-
ied, and at 4 ꢀ 10ꢁ3 mol dmꢁ3 copper(II) concentration. All the
solutions were freshly prepared using bi-distilled water. The metal
ion to ligand ratios for the copper(II):ligand system were 1:2 and
1:3.
2.4. ESI-MS measurements
ESI-MS experiments for the Cu(II)–ligand systems were per-
formed on a Bruker MicrOTOF-Q spectrometer (Bruker Daltonics,
Bremen, Germany) equipped with an Apollo II electrospray ioniza-
tion source with an ion funnel. The spectra were acquired in both
positive and negative ion mode. The experiments were performed
for the solutions with 1:1.5 and 1:2 metal-to-ligand molar ratios.
The pH of starting aqueous solutions was at ca. 6.5 and 10 by an
addition of the desired amount of KOH. Routinely the 50:50 (v/v)
MeOH/H2O samples were measured. However, the variations of
the analyte composition down to 5% of MeOH did not change the
species composition. Samples were infused into the ESI source at
3. Results and discussion
3.1. Synthesis of compounds 3a–g
Target N-methyl alkylaminomethane-1,1-diphosphonic acids
3a–g were prepared in two different ways. The first, one-pot, two
step procedure is based on the reaction of secondary amines with
dialkylphosphonates and trialkylorthoformates at elevated tem-
perature [26,47]. Thus, the corresponding N-methyl alkylamines
1a and 1b were heated at 150–160 °C with diethylphosphonate
and triethyl orthoformate until the evolution of the ethanol
stopped. The crude tetraethyl esters 2a and 2b were used in the
next step without further purification. Thus, the crude reaction
mixture obtained at first step was hydrolyzed by refluxing with
6 M hydrochloric acid to give desired 3a and 3b with 36% and
52% yield, respectively (Scheme 2). Compound 3a is new, and 3b
has been described in the literature. Maier synthesized 3b by the
reaction of N-benzyl-N-methylformamide with triethylphosphite
in the presence of phosgene and subsequent acid hydrolysis [27].
Compound 3b was also described by Ling et al., but without any
experimental details and spectroscopic data [28].
a flow rate of 3 ll/min. Before each run, the instrument was cali-
brated externally with the Tunemix TM mixture (BrukerDaltonik,
Germany) in quadratic regression mode. The instrumental param-
eters were as follows: the scan range m/z 200–2000, end plate
offset ꢁ500 V, dry gas nitrogen (4 L/min), temperature 473 K, cap-
illary voltage 4500 V, ion energy 5 eV. Data analysis was carried
out with the use of Bruker Daltonics Data Analysis software v. 3.4.
2.5. EPR measurements
The EPR spectra were measured using a Bruker Elexsys E500
spectrometer equipped with an NMR teslameter (ER 036TM) and
frequency counter (E 41 FC) at X-band frequency at 77 K and at
room temperature. The simulations of experimental spectra were
performed to reach the EPR parameters using computer program
WINEPR SIMFONIA, version 1.26. Due to the strong absorption of
Compounds 3c–g were synthesized by the reductive methyla-
tion of mono N-substituted alkylaminomethane-1,1-diphosphonic
acids 3c0–g0 via the Eschweiler–Clarke reaction [48–50]. Thus,
refluxing of 3c0–g0 with formaldehyde and an excess of formic acid
by 24 h yielded the final N-methyl alkylaminomethane-1,

B. Kurzak et al. / Polyhedron 85 (2015) 675–684
679
Table 1
Protonation constants (logbnH), cumulative formation constants (logbpqr values) for the complexes formed with Cu(II)–L system, at T = 298 K, I = 0.2 mol dmꢁ3 (KCl).
Compound
Species
3d
3a
3e
3f
3b
3c
3g
ap q r
R = sec-butyl
R = n-pentyl
R = 1-methylhexyl
R = cycloheptyl
R = Ph–CH2
R = Ph–(CH2)2
R = Ph–(CH2)3
H(HL)
H2 (HL)
H3(HL)
0 1 1
0 1 2
0 1 3
8.68(1)
13.39(1)
8.57(1)
13.47(1)
15.25
8.57
4.90
1.78
8.72(2)
13.51(2)
15.32(10)
8.72
4.79
1.81
8.72(1)
13.48(1)
15.55(12)
8.72
4.76
2.07
8.51(1)
13.35(2)
8.48(1)
13.33(1)
8.53(1)
13.41(1)
ðPO3
ðPO3
H
ꢁ Þ
pK
pK
pK
8.68
4.71
8.51
4.84
8.48
4.85
8.53
4.88
H
ꢁ Þ
ðPO3 H2
Þ
[Cu(H2L)]
[Cu2(H2L)3]
[Cu2(H2L)2(HL)]
[Cu2(H2L)(HL)2]
[Cu(HL)]
1 1 1
2 3 3
2 3 2
2 3 1
13.10(3)
41.98(8)
37.92(4)
33.22(6)
8.41(6)
13.02(2)
41.74(5)
37.38(5)
32.49(5)
8.52(4)
13.28(2)
42.04(7)
37.97(5)
33.06(7)
8.85(3)
12.88(3)
41.78(5)
37.54(3)
32.62(5)
8.15(5)
13.01(4)
41.37(15)
37.46(5)
32.47(8)
8.28(8)
12.93(2)
41.32(5)
37.28(2)
32.42(3)
8.32(3)
12.94(2)
41.71(5)
37.46(3)
32.62(4)
8.33(4)
1 1 0
[Cu(HL)2]
[CuL]
[Cu(HL)L]
[CuL2]
1 2 0
13.82(5)
ꢁ0.68(8)
3.83(7)
ꢁ6.95(7)
13.41(3)
ꢁ0.49(5)
3.58(5)
ꢁ7.22(5)
13.82(4)
ꢁ0.48(8)
3.66(5)
ꢁ6.78(5)
13.55(4)
ꢁ1.06(7)
3.43(5)
13.38(7)
ꢁ0.75(10)
3.75(10)
ꢁ6.05(9)
13.41(3)
ꢁ0.51(4)
3.66(4)
ꢁ6.80(4)
13.42(4)
ꢁ0.60(6)
3.48(5)
ꢁ7.40(5)
1 1 ꢁ1
1 2 ꢁ1
1 2 ꢁ2
5.41
4.89
4.97
5.40
8.12
4.73
10.12
5.10
5.09
5.09
8.06
4.61
9.94
10.88
logK
logK
½CuðHLÞ
½CuH2Lꢃ
ꢃ
2ꢁ pKPO
3Hꢁ
8.39
4.69
9.99
10.78
3.00
8.12
4.50
9.83
10.80
3.63
8.49
4.43
10.16
10.44
3.88
8.17
4.73
9.63
9.80
3.18
8.08
4.61
9.75
10.46
3.23
pK
pK
½CuðH2LÞꢃ
½CuðHLÞ2
ꢃ
pK[Cu(HL)L]
logðK
2.75
=K
ꢃÞ
½CuðHLÞ2
½CuðHLÞꢃ
v2
r
8.72
7.86
2.19
4.72
8.74
4.93
6.03
7.39
26.74
8.39
4.74
4.03
11.78
5.82
a
The constants are calculated for the equilibrium: pM + qHL + rH = MpLqHr+q
.
1-diphosphonic acids 3c–g in 80–97% (Scheme 3). Among com-
pounds 3c–g, only 3c (N-methyl Incadronate) is known in the liter-
ature, prepared by Takeuchi et al. [26] by Eschweiler–Clarke
methylation of tetraethyl ester of Incadronate and subsequent
hydrolysis of obtained N-methylated tetraethyl ester. Our results
have shown that direct Eschweiler–Clarke methylation of Incadro-
nate gave better results.
Starting mono N-substituted alkylaminomethane-1,1-diphos-
phonic acids 3c0–f0 were prepared from appropriate primary
amines using similar procedure as for 3a and 3b. 3-Phenylpropy-
laminomethane-1,1-diphosphonic acid (3g0) was obtained in the
reaction of 3-phenylpropylisocyanide with two equivalents of tri-
ethylphosphite in the presence of stoichiometric amount of hydro-
chloride, followed by hydrolysis with 6 M hydrochloric acid [44]
with 85% yield (Scheme 4).
1-diphosphonic acids [20]. The last proton dissociates from the
nitrogen atom of (CH3)–NH+–R group in strongly alkaline pH
þÞ
(pKðNH > 13), therefore the deprotonation constant for this pro-
cess cannot be determined by pH-potentiometric titrations under
experimental conditions [51]. The basicity of this group is higher
as compared to NRH+2 group of previously studied compounds
(Scheme 1a) and may be attributed to the inductive effect of elec-
tron attracting methyl substituent placed on the amino nitrogen
atom. A clear evidence for very high basicity of (CH3)–NH+–R group
is provided by 31P and 1H NMR titration curves of representative 3a
and 3f, which in contrast to previously studied N-n-pentylami-
nomethane-1,1-diphosphonic acid [20] do not show any changes
in chemical shifts versus pH in alkaline conditions (Fig. 1).
3.3. Cu(II) complexes of 3a–g in solution
ESI-MS experiments have been performed with the aim to
establish stoichiometries of the complexes formed in Cu(II) solu-
tions with ligands 3a–g. This technique is not able to define the
number of ionizable protons in the species, however, the determi-
nation of their molecular weight, charge, and isotopic distribution
patterns offers a powerful tool for the elucidation of stoichiome-
tries of metal complexes pre-formed in solution. Indeed, series of
adducts with same M(II):ligand molar ratio and variable number
of alkali cations seem to be a good indication of reliability of stoi-
chiometric recognition [52,53]. The ESI-MS spectra of all studied
systems exhibit peaks corresponding mostly to single positive
and single negative molecular ions, which can easily be attributed
to the 1:1, 1:2 and 2:3 M(II):L complexes. All peak assignments are
3.2. Acid–base properties of 3a–g
The compounds of interest (Schemes 1–4) contain five dissocia-
ble protons in the fully protonated form, [H5L]+. The first deprotona-
tion step in the phosphonic (PO3H2) groups takes place in very
acidic pH (ca. ꢂ1.5–2) and therefore usually lies out of measurable
pH range (2–11.5). In our case, the pK
values are determined
Þ
ðPO3H2
only for 3a, 3e and 3f. The subsequent deprotonation steps corre-
spond to release of protons from phosphonate (PO3Hꢁ) groups
(see Table 1). The values of deprotonation constants for these pro-
cesses lie in the range of 4.71–4.90, 8.48–8.72log units and corre-
spond well with previously reported for other aminomethane-1,
Me
N
O
H
N
O
OH
OH
OH
OH
O
P
OH
O
H2O
P
OH
R
R
+
+
24h reflux
H
H
P
H
OH
P
1) 3HCl in dioxane
H
N
O
P
OH
OH
N+
OEt
+ 2 P OEt
OEt
CH2Cl2, -15oC
OH
OH
O
O
C
OH
OH
2) 6M HClaq
8h reflux
3c`-g`
3c-g
P
O
3g`
Scheme 3. Synthesis of the N-methyl alkylaminomethane-1,1-diphosphonic acids
3c–g via Eschweiler–Clarke methylation.
Scheme 4. Synthesis of 3-phenylpropylaminomethane-1,1-diphosphonic acid 3g0.

680
B. Kurzak et al. / Polyhedron 85 (2015) 675–684
confirmed by comparison of calculated and experimental isotope
distribution patterns, as presented in Fig. 2 for the representative
Cu(II)–3a (Fig. 2a–c) and Cu(II)–3f (Fig. 2d) systems.
10.5. The species distribution curves derived from the potentio-
metric calculations carried out in the pH range 2–10.5 do not differ
considerably. Therefore, the Cu(II)–3a metal-to-ligand 1:2 molar
ratio system was chosen to be representative for species distribu-
tion and variations of visible absorption maximum wavelengths as
a function of pH (Fig. 3).
In view of the above consideration, the stability constants of the
complexes in the studied systems have been calculated based on
the assumption that stoichiometries of the most chemically signif-
icant complexes are consistent with stoichiometries detected by
ESI-MS method. The pH-potentiometric calculations have been
performed with the use of approach, which neglects proton-
dissociation from the highly basic (CH3)–NH+–R group and consid-
ers HL3ꢁ ligand form as L3ꢁ in the formation equilibrium pM +
The speciation calculated for the Cu(II)–3a 1:2 molar ratio sys-
tem indicates that the process of complexation begins below pH 2
where [Cu(H2L)] and [Cu2(H2L)3] complexes start to form. These
complexes are the only species present in equilibrium up to pH
ꢂ3 (Fig. 3). Spectral parameters calculated from the EPR spectra
performed at pH ꢂ2–3.3 (g = 2.418–2.425, A = 132ꢁ134 ꢀ 10ꢁ4
þÞ
qHL + rH = MpLqHr+q. This is acceptable when reliable pKðNH
k
k
values cannot be determined [54] and was previously used by us
for evaluation of the stability constants of Zn(II), Mg(II) and Ca(II)
complexes formed by bisphosphonates containing piperidyl-, mor-
pholinyl- and thiomorpholinyl- side chains [21,51].
In general, titrations of respective ligand in the presence of var-
ious equivalents of Cu(II) have been analyzed in batch calculations,
in which all titration curves are fitted at the same time with one
model. The equilibrium models and corresponding stability
constants giving the best fits of experimental and calculated
pH-metric titration curves are collected in Table 1.
cmꢁ1 and g\=2.081–2.083) differ only slightly from those calcu-
lated for Cu(II) aqua ion (g = 2.415, A = 135 ꢀ 10ꢁ4 cmꢁ1 and
k
k
g\ = 2.084 [22]. This indicates only minor changes in the donor
set around copper(II) ion. It was reported that the displacement
of water molecules around copper(II) ions by PO3Hꢁ or PO32ꢁ
donors does not greatly affect the EPR parameters [55]. Similarly,
the energy of d–d transition at pH ꢂ3 and kmax ꢂ805–798 nm with
e
ꢂ22–25 is typical for copper(II) complexes with pure oxygen sur-
rounding. The pK
values for ligands 3a–g (Table 1, row 5
½CuðH2LÞꢃ
from bottom), characteristic for the deprotonation step for the
[Cu(H2L)] complexes, are close to the corresponding deprotonation
constants of ‘free’ ligands (Table 1). Thus, they can be assigned to
deprotonation of phosphonate PO3Hꢁ group. In [Cu(HL)] the ligand
coordinates copper(II) with simple {O, O}-type bidentate manner
using one oxygen atom of each suitably positioned phosphonate
(PO23ꢁ) groups to form the six-membered chelate ring (Scheme 5).
Additionally, taking into account the difference in acidity of the
coordinating phosphonate groups, the equilibrium constant
The pH-metric titrations indicate that the extent of complex
formation in the copper(II) systems with ligands 3a–g is quite sim-
ilar. Each sample could be titrated without precipitation up to pH
(a) 12
11
10
9
-N-R
logK
LÞꢃ ꢁ pKPO , is roughly of the same order of magnitude
½CuðH2
3Hꢁ
as stability constants, logK[Cu(HL)] (Table 1). This fact suggests the
same {O, O} bidentate binding mode of the ligands in [Cu(HL)]
and [Cu(H2L)] species (Scheme 5). The preference for such coordi-
nation is well documented in the literature [22,55,56,57].
R = n-pentyl
R = cycloheptyl (3f)
R = n-pentyl (3a)
A common feature of the Cu(II) systems with 3a–g is the forma-
tion of oligonuclear species (most likely dinuclear complexes)
besides the mononuclear ones (Table 1, Figs. 2 and 3). So, besides
the [Cu(H2L)] complex, dinuclear [Cu2(H2L)3] species occur above
pH 2.5 (maximum above 60% at pH ꢂ3.5). The [Cu2(H2L)2(HL)]
and [Cu2(H2L)(HL)2] species occur above pH 4.5 (Scheme 6); the
latter one existing with a major contribution in the range of pH
4.5.0–7.5 (maximum above 80% at pH 6) and exists in an equilib-
rium with a another major contribution of [Cu(HL)2] (maximum
above 85%, pH ꢂ9) in the range of pH 6.5–7.5.
8
7
6
0
2
4
6
8
10
12
14
pH
3,8
3,6
3,4
3,2
3,0
2,8
(b)
The EPR experiments clearly support the above indication. A
pronounced formation of oligonuclear species demonstrated on
the speciation diagrams (Fig. 3 as an example) is always accompa-
nied by broadening of EPR signals in the acidic solution until pH 6.7
(Fig. 4, pH = 4.1 and 5.4). In addition, the obtained energy of d–d
R = cycloheptyl (3f)
R = n-pentyl (3a)
transition at pH range 4–6.5 (760–750 nm with
e
ꢂ38–42 molꢁ1
cmꢁ1 dm3, Fig. 3) agrees well with the energy reported for oligonu-
clear species formed by aminomethane-1,1-diphosphonic acids
that contain oxygen donor atoms in coordination sphere of Cu(II)
[57,22]. The ability of gem-phosphonate groups to coordinate
metal ions in solutions through more than one oxygen atom each
is well documented [19] and is also commonly observed in the
solid state [58].
-N-R
R = n-pentyl
In all the studied systems the [Cu(HL)2] species are formed in
basic solution despite their very high electric charge and consider-
able steric hindrance caused by two coordinated ligands. Interest-
ingly, a distinct change of EPR spectral features is noticed as the pH
of solution increases above pH 7 where mononuclear complexes
are predicted (Fig. 4). The EPR spectra performed at pH about
0
2
4
6
8
10
12
14
pH
Fig. 1. (a) 31P NMR and (b) 1H NMR (CH proton) titration curves vs. pH for the
compounds 3a, 3f and previously studied N-n-pentylaminomethane-1,1-diphos-
phonic acid [20]. Please note chemical non-equivalence of PO3H2/PO3Hꢁ groups of
3a and 3f reflected in their 31P NMR spectra performed in acidic conditions.
6.5–9.5 reveal distinctly lower values of g parameter (g ꢂ2.371–
k
2.386 and g\ ꢂ2.065–2.071) and higher values of A parameter
k

B. Kurzak et al. / Polyhedron 85 (2015) 675–684
681
Fig. 2. Experimental and simulated isotope distribution patterns demonstrating the most significant Cu(II)–ligand stoichiometries detected in the ESI-MS spectra of
representative Cu(II)–3a (a–c) and Cu(II)–3f (d) systems.
(144ꢁ151 ꢀ 10ꢁ4 cmꢁ1) as compared to those for [Cu(H2L)] species
(see above). Furthermore, the energy of d–d transition for the
[Cu(HL)2] species equal to 744 nm with
e
ꢂ37 molꢁ1 cmꢁ1 dm3 is
100
80
60
40
20
0
640
660
680
700
720
740
760
780
800
higher in relation to the d–d absorption band of [Cu(H2L)]
(Fig. 2). These spectroscopic results strongly support the involve-
ment of second ligand in the Cu(II) coordination sphere. For this
species the simple bidentate {O, O}-coordination through phospho-
nate PO23ꢁ groups of both ligand molecules, resulting in the forma-
tion of two six-membered chelate rings, is the most probable
(Scheme 5). Such type of binding mode with four phosphonate
groups in the equatorial positions around metal center was
reported for bis-complexes formed by various bisphosphonates
[59].
10
7
5
1
3
9
4
2
A
logðK
lot of data for stepwise stability constant ratios,
=K
ꢃÞ, can be found in the literature [60]. Using
½CuðHLÞꢃ
½CuðHLÞ2
8
6
the above expression for 3a–g, we obtained the values given in
Table 1 (row 3 from bottom). Their comparison shows that binding
of second ligand is not so strongly hindered as for mono
N-substituted aminomethane-1,1-diphosphonic acids (Scheme 1,
left) [20]. For the systems with 3a, 3d and 3e the values of
2
4
6
8
10
12
pH
Fig. 3. Species distribution curves as a function of pH for conditions used in EPR and
UV–Vis spectroscopy (solid line) and variations of visible absorption maximum
wavelength (square) for the copper(II)–3a system at 1:2 molar ratio, cCu(II) = 4 ꢀ
10ꢁ3 mol dmꢁ3. 1 – Cu2+; 2 – [Cu(H2L)]; 3 – [Cu2(H2L)3]; 4 – [Cu2(H2L)2(HL)];
logðK
=K
ꢃÞ are evidently higher than for the systems
½CuðHLÞꢃ
½CuðHLÞ2
with 3b, 3c and 3g, which is likely due to the presence of phenyl
ring in their side chains. The smallest value is obtained for the sys-
tem with 3f bearing bulky cycloheptyl ring (Table 1).
5
–
[Cu2(H2L)(HL)2];
6 – [Cu(HL)]; 7 – [Cu(HL)2]; 8 – [CuL]; 9 – [Cu(HL)L];
10 – [CuL2]. The range simulated for conditions used in UV–Vis studies (dot line).

682
B. Kurzak et al. / Polyhedron 85 (2015) 675–684
HO
O
O
As shown on the species distribution diagram of the representa-
tive Cu(II)–3a system (Fig. 3), the [Cu(HL)L] complex starts to form
above pH 8. Its formation is accompanied by detectable changes in
electronic absorption spectra. The pH dependence of kmax in the
OH2
Cu
OH2
Cu
O
O
O
O
O
O
Me
N+H
Me
N+H
Me
H+N
H2O
O
P
O
O
P
P
O
O
O
P
P
H2O
P
R
R
R
OH2
OH2
visible spectra collected for the Cu(II)–3a system shows
a
O
O
O
ꢂ20 nm blue shift (the value of kmax decreases from ꢂ744 at pH
ca. 8.0 to ꢂ725–729 at pH ca. 10–10.5), which parallels the forma-
tion of the [Cu(HL)L] from [Cu(HL)2] species.
Above pH 9.5 consecutive species starts to form. This is
completely deprotonated complex species [CuL2]. Its formation is
followed by the explicit changes in the EPR and electronic
absorption spectra (Fig. 4). The EPR spectrum recorded at pH ꢂ12
[Cu(H2L)], pH = 2.7, ~ 30%
[Cu(HL)2], pH = 8.5, ~ 84%
O
O
OH2
O
O
Me
O
Me
N+H
H2O
H2O
O
P
P
O
O
Me
H+N
P
O
O
Cu
N
Cu
O
P
R
R
O
P
OH2
P
O
R
O
O
corresponding to [CuL2] complex with g = 2.239,
A
ꢂ201–
OH2
O
k
k
O
203 ꢀ 10ꢁ4 cmꢁ1 and g\ ꢂ2.052–2.053 parameters is apparently
different from those recorded for the solutions where [Cu(HL)2]
has been found to be predominant (Fig. 4). Moreover, the electronic
absorption spectra collected for these systems in basic solutions
show a spectacular blue shift (the value of kmax decreases from
ꢂ725 at pH ca. 10.0 to ꢂ670–650 above pH ca. 12–13), which par-
allels the formation of the [CuL2] species. Both EPR and visible spec-
tral parameters are consistent with those reported for phosphonic
species with the nitrogen donor(s) complexed to Cu(II) [61–64].
This allows anticipation that the coordination in these complexes
is realized by both oxygen and nitrogen donor atoms as a result
of Cu(II)-promoted nitrogen deprotonation (Scheme 5).
O
[Cu(HL)], pH ~ 5 – 7.5, ~ 8%
[Cu(HL)L], pH = 10.3, ~ 54%
O
O
P
O
O
O
O
Me
P
O
P
O
Me
O
O
H2O
H2O
R
N
N
N
R
Cu
Cu
R
Me
O
O
P
P
O
O
P
OH2
O
O
O
O
[CuL], pH = 10 – 10.5, ~ 10%
[CuL2], pH = 12, ~ 90%
Scheme 5. Schematic representations showing the possible structures of the
mononuclear complex species formed in the water solution of Cu(II)–L systems and
pH range of their major concentration.
A
comparison of relative stability constants log K½CuðHLÞꢃꢁ
ðPO3Hꢁ
ðPO3Hꢁ
ðpK
Þ þ pK
ÞÞ for 3a, 3d and 3e (ꢁ4.95, ꢁ4.98, ꢁ4.66,
respectively), 3b, 3c and 3g (ꢁ5.07, ꢁ5.01, ꢁ5.08, respectively)
R
R
Me
O
Me
O
N+H
N+H
O
O
P
P
P
P
O
O
HO
H2O
O
O
O
O
O
OH2
OH2
H2O
Cu
Cu
Me
Me
O
O
O
O
Me
N+H
O
Me
N+H
O
P
O
O
H+N
R
H+N
R
P
OH
P
OH
P
P
2O
2O
O
O
R
R
Cu
P
Cu
P
O
P
O
O
O
O
O
O
O
OH
OH
OH
OH
OH2
OH2
[Cu2(H2L)3], pH ~ 3.5 – 3.9, ~ 60%
[Cu2(H2L)2(HL)], pH ~ 4.4 – 5.0, ~ 40%
R
Me
N+H
O
O
P
P
O
O
O
O
OH2
H2O
Cu
Me
O
O
Me
N+H
O
P
O
H+N
P
OH
P
2O
O
R
R
Cu
OH2
[Cu2(H2L)(HL)2], pH ~ 5.7 – 6.6, ~ 80%
P
O
O
O
O
OH
O
Scheme 6. Schematic representations showing the possible structures of the dinuclear complex species formed in the in the water solution of Cu(II)–L systems and pH range
of their maximum concentration.

B. Kurzak et al. / Polyhedron 85 (2015) 675–684
683
confirmed by ESI-MS and EPR experiments, is the formation of
dinuclear [Cu2HxL3] (x = 4, 5, 6) species besides of mononuclear
[CuHxL] and [CuHxL2] ones (x = 0, 1, 2). A comparison of stabilities
of [Cu(HL)] complexes clearly indicates their strong dependence on
electronic and steric effects imposed by R substituents attached to
the nitrogen atom. Compounds with linear or branched alkyl on
the nitrogen atom form the most stable complexes with Cu(II),
the least stable are complexes of 3f containing cycloheptyl ring
attached directly to the nitrogen atom.
pH
2.0
3.1
4.1
5.4
Acknowledgments
Financial support by a statutory activity subsidy from the Polish
Ministry of Science and Higher Education for the Department of
Chemistry of Wrocław University of Technology (W.G. and E.M.J.)
and Faculty of Chemistry, University of Opole (B.K. and M.Sz.) is
gratefully acknowledged.
6.7
8.0
9.5
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