Non-symmetrical bis(aminoalkyl)phosphinates: New ligands with enhanced binding of Cu(ii) ions

Article abstract of DOI:10.1039/c8nj01094c

Three novel, non-symmetrical bis(aminoalkyl)phosphinic acids, L¹-L³, have been synthesized and characterized. Solution studies on the coordination abilities of the ligands have shown that these compounds form various protonated mono-

Full text of DOI:10.1039/c8nj01094c

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Non-symmetrical bis(aminoalkyl)phosphinates: new ligands with the enhanced binding
of Cu(II) ions
Karolina Piasta,a Anna Dziełak,b Artur Mucha,b and Elżbieta Gumienna-Konteckaa*
a Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
b
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and
Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Abstract
Three novel, non-symmetrical bis(aminoalkyl)phosphinic acids, L1-L3, have been synthesized and
characterized. Solution studies on the coordination abilities of the ligands have shown that these
compounds form variously protonated mono- and bis-complexes, where copper (II) coordination is
realized through the nitrogen atom(s) of the amino group(s), supported by oxygen(s) from the
phosphinate unit(s). Potentiometric titrations and a full spectroscopic analysis clarified the species
distribution profiles and detailed coordination modes. The results show that L1-L3 ligands are efficient
chelating agents for Cu(II) ions; their metal binding abilities were compared to structurally related
compounds described earlier in the literature.
Keywords: Ligand design, aminophosphinic acids, Cu(II) complexes, stability constants
1. Introduction
Aminophosphinic acids, phosphorus analogues of natural amino acids and short peptides comprising
C-P(O)(OH)-C structural motif, have attracted significant consideration because of their notable
biological activity. Accordingly, aminophosphinic acids have been studied as potent antimicrobial,
antiviral, antitumor, and neuromodulatory agents.1 These activities basically originate from inhibition
of enzymes of different class, in particular, proteases and ligases.2, 3 The most recognized, recent
achievements in enzyme inhibition involved phosphinic peptide analogs and metallo-containing
proteases of biomedical importance, e.g. representatives of matrix metalloproteinase family, and
mammalian, bacterial and protozoal aminopeptidases.4, 5
The presence of an additional α-amino group in the fundamental aminophosphinic motif results with
an enhanced potential of structural diversification of biologically active compounds.
Bis(aminomethyl)phosphinic acids that can be symmetrically or non-symmetrically substituted at the
α-carbon and/or nitrogen atom(s) offer an opportunity to refine steric complementarity of
competitive ligands with the active site of enzymatic targets, and binding affinity to catalytic metal
ions of metallo-dependent proteins. Following this concept, non-symmetrical and C2-symmetrical
phosphinic peptides were synthesized and found very potent inhibitors of HIV1 protease.6-8 The N-C-
P-C-N backbone is also present in the structures of high-affinity ligands of the M1 alanyl
aminopeptidase (Scheme 1), a zinc-dependent exopeptidase involved in angiogenesis and tumor
10
invasion.9,
Recently, we described N-alkyl-bis(aminomethyl)phosphinic inhibitors of urease
(Scheme 1), a hydrolase responsible for global nitrogen circulation by urea cleavage, which among
others is a virulence factor of digestive and urinary tract pathogens.11, 12

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Scheme 1. Exemplified structures of competitive inhibitors which comprise bis(aminoalkyl)phosphinic acid
motif and are targeted towards metal-containing hydrolases: alanyl aminopeptidase and bacterial ureases.
Apart from biological activity, structurally diverse aminophosphinic acids have been considered as
ligands for metal ion complexation.13-15 In the particular case of the N-C-P-C-N scaffold, the most
systematic studies involved cyclic and acyclic bis(aminometyl)phosphinates lacking substituents of
the α-carbon atoms.16-18 These polydentate ligands, especially symmetrical phosphinate-containing
heterocycles functionalized additionally with carboxylate groups, the derivatives of glycine or
iminodiacetic acid, were studied with a range of trivalent lanthanide and biologically relevant
19
divalent metal ions.18, The non-symmetrical and α-substituted N-C-P-C-N derivatives have been
21
characterized to much less extent.20, As an extension to those previous complexation studies
performed in our laboratories, we present here the coordination ability of three novel
bis(aminoalkyl)phosphinic acid derivatives containing a tertiary amino group (N,N-dialkyl ligand L1
and azacyclic compounds L2 and L3, Scheme 2) towards Cu(II) ions.

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Scheme 2. Structures of ligands studied and discussed.
2. Experimental
2.1.Materials
All chemicals were of analytical grade and were used without further purification. Depending on the
solubility of studied ligands, the solution studies were performed in water (L1 and L3) or in a
MeOH/H2O (80:20 w/w) mixture (L2). Measurements requiring ionic strength were performed in 0.1
M NaClO4. The solution of copper (II) ions were prepared by dissolving Cu(ClO4)2∙6H2O in water and
standardized by ICP-AES. HClO4 solution was titrated by standardized NaOH in MeOH/H2O solution.
Carbonate-free NaOH solution was standardized by titration with potassium hydrogen phthalate.
Caution! Perchlorate salts combined with organic ligands are potentially explosive and should be
handled in small quantity and with the necessary precautions.
2.2.Ligand synthesis
2.2.1.
General
synthetic
procedure.10
α-(N-Benzyloxycarbonylamino)benzyl-H-
phosphonous acid, 0.92 g, 3.0 mmol)22 and a secondary amine or amino acid (4.5 mmol, 1.5 eq.; for
piperazine: 1.5 mmol, 0.5 eq., 0.13 g) were dissolved in a hot water/acetic acid/HClconcd mixture
(10/10/0.5 mL). Formaldehyde (36-38% aqueous solution, 6.0 mmol, 2.0 eq., 0.55 mL) was added to
the clear solution. Following addition the mixture was stirred for 1 h and refluxed for 3 h, then cooled
to room temperature and left for crystallization overnight at 4°C. The precipitated white solid was
filtered, wash with water and dried in the air. The Cbz protection was removed by the action of HBr
(33% solution in AcOH, 10 mL per 1 g) for 2 h at room temperature. The volatile acids were removed
under reduced pressure. The residue was triturated with diethyl ether, the white solid was filtered,
washed with ether and dried in the air.
The 1H and 13C NMR spectroscopic experiments were performed on a Jeol JNM-ECZ 400S Research FT
NMR Spectrometer (JEOL Ltd., Tokyo, Japan) operating at 399.78 MHz (1H) MHz and 100.52 MHz
(13C). The 31P experiments were performed on a Bruker Ultrashield Spectrometer (Bruker,
Rheinstetten, Germany) operating at 121.5 MHz (31P{1H}). Measurements were made in D2O
solutions supplied by ARMAR AG (Dottingen, Switzerland). Chemical shifts are reported in ppm
relative to TMS and 85% H3PO4, used as external standards. Mass spectra were recorded using a
Waters LCT Premier XE mass spectrometer (method of ionization ESI).
2.2.2.
L1: N-{[α-Aminobenzyl(hydroxy)phosphoryl]methyl}-N-benzylaminoacetic acid. Yield
1
48%. H NMR (ppm, D2O, 399.78 MHz) δ: 7.26-7.39 (m, 10H, 2 × C6H5), 4.38 (d, J = 11.6 Hz, 1H, CH),
4.27 (s, 2H, CH2), 3.71 (s, 2H, CH2), 3.18 (d, J = 8.4 Hz, 2H, CH2). 13C NMR (ppm, D2O, 100.52 MHz) δ:
169.17, 131.35, 131.03 (d, J = 4.0 Hz), 130.52, 129.52, 129.50, 129.42, 128.37, 127.80 (d, J = 5.0 Hz),
60.64 (d, J = 3.0 Hz), 55.80 (d, J = 4.0 Hz), 54.88 (d, J = 97.5 Hz), 50.18 (d, J = 92.5 Hz). 31P NMR (ppm,
D2O, 121.5 MHz) δ: 19.33. HRMS (ESI) m/z calcd for C17H22N2O4P [M+H]+: 349.1312, found: 349.1346.
2.2.3.
L2: α-Aminobenzyl[(tetrahydroisoquinoline-1-yl)methyl]phosphinic acid. Yield 70%. 1H
NMR (ppm, D2O, 399.78 MHz) δ: 7.37 (m, 5H, C6H5), 7.13-7.18 (m, 3H, 3 × CHar), 6.97 (m, 1H, CHar),
4.48 (d, J = 11.2 Hz, 1H, CH), 4.24 (AB system, J = 14.0 Hz, 2H, CH2), 3.61 (m, 1H, CH), 3.28 (m, 3H, CH
+ CH2), 3.05 (m, 1H, CH), 2.91 (m, 1H, CH). 13C NMR (ppm, D2O, 100.52 MHz) δ: 131.11 (d, J = 4.0 Hz),
130.27, 129.61, 129.58, 128.74, 128.48, 127.96 (d, J = 5.0 Hz), 127.13, 126.78, 126.77, 55.39 (d, J =
24.1 Hz), 54.92 (d, J = 78.5 Hz), 52.32, 52.28, 24.52. 31P NMR (ppm, D2O, 121.5 MHz) δ: 19.07. HRMS
(ESI) m/z calcd for C17H22N2O2P [M+H]+: 317.1413, found: 317.1403.

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2.2.4.
L3: (Piperazine-1,4-diyl)bis[α-aminobenzyl(methyl)phosphinic acid]. Yield 71%. 1H
NMR (ppm, D2O + NaOD, 399.78 MHz) δ: 7.28 (m, 8H, 8 × CHar), 7.21 (m, 2H, 2 × CHar), 4.60 (d, J =
12.0 Hz, 2H, 2 × CH), 2.23-2.78 (m, 12H, 6 × CH2). 13C NMR (ppm, D2O+ NaOD, 100.52 MHz) δ: 138.51,
128.39 (d, J = 2.0 Hz), 127.50 (d, J = 4.0 Hz), 127.06 (d, J = 2.0 Hz), 56.70 (d, J = 93.5 Hz), 55.38 (d, J =
105.6 Hz), 54.19. 31P NMR (ppm, D2O+ NaOD, 121.5 MHz) δ: 35.13. HRMS (ESI) m/z calcd for
C20H31N4O4P [M+H]+: 453.1815, found: 453.1711.
2.3.Physical measurements
2.3.1.
Potentiometric titrations of ligands and their complexes were performed using an
automatic titrator system Titrando 905 (Metrohm) with a combined glass electrode (Mettler Toledo
InLab Semi-Micro) calibrated daily in hydrogen ion concentration using HClO4. The electrode of the
organic solvent system was filled with 0.1 M NaCl in MeOH/H2O (80:20 w/w) and conditioned two
weeks before the first measurements were made. Between measurements electrode was stored in
the same electrolyte solution. The pKw in the MeOH/H2O 80:20 w/w system was -14.42.23 The
experiments were carried out under argon atmosphere at 25±0.2˚C. All potentiometric titrations
were performed on 3 ml samples with the ligand concentration of 2∙10-3 M and 1:1 and 1:2 Cu(II) to
ligand molar ratios in pH range 2-11. For L3 also the 2:1 Cu(II) to ligand ratio was performed. For L1 no
precipitation occurred in the entire pH range. For L2 in 1:1 and for L3 in 2:1 Cu(II) to ligand molar ratio
a bluish precipitate occurred above pH 7 and pH 6, respectively, and these pH ranges were not
included in the data processing. The exact concentration of the ligand was determined using the
method of Gran.24 The potentiometric data were refined with Superquad program.25 The overall
protonation constants βn are concentration constants and are defined by βn= [HnL] / ([H]n× [L])
(stepwise protonation constants are defined as logK1= logβ1; logKn= logβn– logβn–1). The overall
stability constant are defined by βhlm= [MmHhLl] / ([M]m×[H]h× [L]l). In the calculations of complex
stability constants the protonation constants of free ligands (Table 2), and the hydrolysis constants
-
related to Cu(OH)+ (logβ11 = −8.1), Cu(OH)2 (logβ12 = −16.1), Cu(OH)3 (logβ13 = −26.7) and
Cu(OH)42- (log
β
14 = −39.6) species were taken into account.26
2.3.2.
UV-Vis spectroscopy. All absorption spectra were recorded on Varian CARY 300 UV-
Vis spectrophotometer at 25.0±0.2˚C. pH-dependent UV-Vis titrations were performed in the pH
range 2-11. The combined glass electrode (Mettler Toledo InLab Semi-Micro) was prepared as in the
case of potentiometric titration calibrated with buffers prepared in MeOH/H2O (80:20 w/w) mixture
before every measurement.27, 28 The concentration of the ligand was around 2∙10-3M. The starting pH
was adjusted to around 2 with HClO4 and the titration was carried out in a cell with 1 cm optical path
length. For Cu(II) complexes, titrations were performed in a 1 cm cell with 3.2 ml as total volume of
the solution containing 1:1 and 1:2 molar ratios of Cu(II):ligand for L1 and L2, and additionally 2:1 for
L3.
2.3.3.
EPR spectroscopy. EPR spectra were recorded on a Bruker ELEXSYS E500 CW-EPR
spectrometer supplied with frequency counter (E 41 FC) at X-band frequency and an NMR teslameter
(ER 036TM), at 77K. The solutions for EPR were prepared by using MeOH/H20 mixture (80/20 w/w)
for L2 ligand and H2O/ethylene glycol mixture (3:1 v/v) for L1 and L3. pH-dependent EPR titrations
were performed in the pH range 2-11, for 1:1 and 1:2 molar ratios of Cu(II):ligand for L1 and L2, and
additionally 2:1 for L3. The parameters of experimental spectra were calculated through spectra
simulation in Doubletnew (EPR OF S=1/2) program by Dr. Andrew Ozarowski, National High Field
Magnetic Laboratory, University of Florida.

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2.3.4.
Mass spectrometry. Electrospray ionization mass spectrometry (ESI-MS) data were
collected using a BrukerMicrO-TOF-Q spectrometer and a Bruker apex ultra FT-ICR mass
spectrometer (BrukerDaltonik, Germany), equipped with an Apollo II electrospray ionization source
with an ion funnel. Stock solutions were prepared by using MeOH/H2O mixture (80/20 w/w) as a
solvent. The Cu(II) to ligand molar ratio was 1:2 and the pH of the solutions was 8. The instrument
parameters were: dry gas–nitrogen, temperature 200°C, ion source voltage 4500 V, collision energy
10 eV. The calibration of the instrument was performed using the Tunemix mixture (BrukerDaltonik,
Germany) in the quadratic regression mode. The spectra were recorded both in the positive and
negative ion mode in the range 100 to 1500 m/z and analyzed with Bruker Compass DataAnalysis 4.0
software. The overall charge of the analyzed ion was calculated on the base of the distance between
the isotopic peaks.
3. Results and discussion
3.1.Design and synthesis
To obtain non-symmetrically substituted bis(aminoalkyl)phosphinic acid ligands, a three-component
Mannich-type condensation29 (the Kabachnik-Fields reaction30) was employed with N-protected
benzylphosphonous acid as the key substrate. The structure of the added aminomethyl portion was
determined by a secondary amine/amino acid used. The reaction of these starting materials with
formaldehyde was performed in acidic conditions and gave solid products in a moderate to good
yield (48-71%, Scheme 3). Deprotection of the N-termini (Cbz removal) proceeded quantitatively
under the action of hydrobromic acid.
Scheme 3. Phosphinomethylation of a secondary amino grup with H-phosphinic acid and formaldehyde,
followed by the N-termini deprotection.
3.2.Speciation studies
The acid-base properties of studied ligands were determined in order to evaluate their coordination
properties toward copper (II) ions.
3.2.1.
Ligands’ protonation constants. Protonation macroconstants of studied ligands were
determined by potentiometric titrations in pH range of 2-11, and obtained values are presented in
Table 1. The deprotonated form of the ligand L1, [L]2-, may attach four protons, to two amine groups,
and the carboxylate and phosphinate residues. However, in the measured pH range, three
protonations steps were observed, with logK1 = 11.11, logK2 = 9.06 and logK3 = 5.02. The protonation
constant of the phosphinic PO(OH) group is too low (< 2) to be determined by potentiometric

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measurements. As the protonation processes of the two amine groups overlap, unequivocal
assignment of the protonation macroconstants to either of the groups is impossible without
determination of microconstants by NMR titrations. However, the value of logK1 = 11.11 is similar to
that reported to TEA (10.78)31 and GlyDP ligand (11.3),15 suggesting that this logK corresponds to
tertiary amine group. The values logK2 = 9.06 and logK3 = 5.02 may be assigned to primary amine and
carboxylate groups, respectively, comparing to apl ligand with logK values 8.82 and 1.98 (Table 1,
Table S1).20 The less acidic character of carboxylate residue in L1, can be explained by a smaller
withdrawing effect of the tertiary amine group, in comparison to the one caused by secondary amine
in apl.
The deprotonated form of L2, [L]-, may also attach three protons in the measured pH range (Table 1).
The logK1 = 8.38 and logK3 = 2.12 are related to proton dissociation from the primary amine and
phosphinate group, respectively. The calculated values are higher than those reported to other
aromatic aminophosphinates.13 The increase of protonation constants for amine and phosphinic
group results from the use of the MeOH/H2O (80/20 w/w) mixed solvent.32 The change of solvent
was necessary due to solubility problems of L2 Cu(II) complexes (vide infra). The second protonation
constant (logK2 = 5.46) corresponds to tetrahydroisoquinoline N atom and is similar to that reported
to THQ and 2,N,N-TMA (Table 1, Table S1).33, 34
Table 1. Protonation constants (logKH) of L1 – L3 ligands,a and selected analogous compounds.
Species
L1
Logβ
logKH Protonation site Reference
This work
LH-
11.11(1)
NTertiary amine
LH2
20.17(1) 9.06 NPrimary amine
25.19(1) 5.02 OCarboxylate
+
LH3
L2
This work
This work
LH
8.38(1)
NPrimary amine
+
LH2
13.84(6) 5.46 NIsoquinoline
15.96(2) 2.12 OPhosphinate
2+
LH3
L3
LH-
8.75(1)
NPrimary amine
LH2
16.50(1) 7.75 NPrimary amine
22.36(2) 5.86 NPiperazine
25.29(2) 2.93 NPiperazine
+
LH3
2+
LH4
20
Apl
LH
8.82
NPrimary amine
6.55 NSecondary amine
1.98 OCarboxylate
LH2
15.37
17.35
LH3
20
35
Appg
LH
8.19
NPrimary amine
LH2
10.98
2.79 OCarboxylate
MBAPA
LH
9.49
NPrimary amine
8.80 NPrimary amine
2.09 OPhosphinate
LH2
18.29
20.38
LH3
13
AMPA

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LH
8.29
NPrimary amine
OPhosphinate
LH2
9.29
1.0
16
AM2P
LH
8.509
15.580
16.35
NPrimary amine
7.071 NPrimary amine
0.77 OPhosphinate
LH2
LH3
36
37
EDBPA
LH
7.58
NSecondary amine
LH2
11.90
4.32 NSecondary amine
PDMBPA
LH
6.719
9.341
NPiperazine
LH2
2.622 NPiperazine
37
PMPA
LH
8.41
11.3
10.78
5.86
5.03
NPiperidine
15
GlyDP
LH
NTertiary amine
NTertiary amine
NTertiary amine
NSecondary amine
31
TEA
LH
33, 34
33
2,N,N-TMA
LH
THQ
LH
a
I = 0.1 M (NaClO4), T = (25.0 ± 0.2) oC, solvent: H2O for L1 and L3, and MeOH/H2O 80:20 w/w for L2.
The L3 ligand behaves in measured pH range like a four-protonic acid, with protonation constants
logK1 = 8.75 and logK2 = 7.75 most probably corresponding to primary amine groups, and logK3 = 5.86
and logK4 = 2.93 related to deprotonation of piperazine N atoms (Table 1, Table S1). The obtained
values are in a good agreement with pK values reported earlier for PDMBPA,37 MBAPA,35 and
aromatic aminophosphinates.13 The protonations of both phosphinic PO(OH) groups occur much
below pH 2 and constants corresponding to these processes were not determined under our
experimental conditions.
3.2.2.
Stoichiometry of Cu(II) complexes. Formation of complexes in solution upon mixing
L1, L2 and L3 ligands with Cu(II) ions was in the first place monitored using ESI-MS spectrometry.
Although ESI-MS is not able to distinguish the ionizable protons in the species, this method can be
successfully applied to determine the metal-to-ligand stoichiometry directly from the m/z values, and
has been employed by us for this purpose on previous occasions.38-41 Analysis of the ESI-MS spectra
of the reaction mixture of Cu(II):L1 showed the formation of monomeric species, successfully
- -
attributed to {[CuL1] + ClO4 } (m/z 507.9815). Similar behaviour has been observed for Cu(II):L3
system, where appearing species was interpreted as {[CuL3H]+}+ (m/z 514.0933). The presence of
CuL2 species was not observed. The ESI-MS spectra of the reaction mixture of Cu(II):L2 indicated the
formation of the following complexes: {[CuL2 ] + Na+}+ (m/z 716.1787), {[CuL2 ] + K+}+ (m/z 732.1533),
2
2
{[Cu2L2 ] + H+}+ (m/z 1389.3961) and {[Cu2L2 ] + Na+}+ (m/z 1411.3896).
4
4

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3.2.3.
Stability constants of Cu(II) complexes. To determine the complex formation
properties of L1, L2 and L3 towards Cu(II) ions, an informative combination of potentiometry, UV-
Visible and Electron Paramagnetic Resonance spectroscopies was used. Potentiometric titrations
gave insight into the thermodynamic parameters of the studied complexes, allowing us to compare
their stability and pH-dependent distribution to other, relevant phoshinic ligands. UV-Vis and EPR
were helpful to precisely identify the binding sites, the donor atoms and the coordination geometry
of complex species formed in solution. The EPR spectra recorded in magnetic field range 0 - 5000 G
for Cu(II) complexes with L1-L3 ligands did not give any indication for the formation of dimeric forms
(the characteristic hyperfine splitting should be seen for the two different resonance transitions: the
“forbidden” at ~1500 G and the “allowed” ~2400 G, due to the interaction of the unpaired electron
with two Cu(II) nuclei (ΣI = 2 × 3/2) that leads to seven hyperfine splitting lines with A|| about half of
A|| value for S = 1/2 Cu(II) species).42
The potentiometric titrations performed for Cu(II):L1 system suggest the formation of four
monomeric [CuL1Hn] (n = 1, 0, -1, -2) species (Table 2, Figure 1). The formation of the first complex,
[CuHL1]+, starts already at pH around 2 (Figure 1). The UV–Vis absorption d–d band centered at 750
nm with ε = 35 M-1cm-1 (Figure S1, Table 2) indicates an involvement of one nitrogen atom besides
oxygen donor(s) in copper ion binding. Potentiometry based stoichiometry suggests that one oxygen
atom may come from the carboxylate unit while the other from phosphinate (if taking part in the
coordination). EPR spectra with AII = 160.7 and gII = 2.30 further confirm the participation of one
nitrogen in the binding (at pH below 2.5, before the coordination starts to take place, the EPR
parameters: AII = 119.0 G and gII = 2.41, Figure S1, are in agreement with the Peisach-Blumberg plot
for four oxygen donors43). Analogous EPR parameters were shown for the CuL complex in Cu(II):apl
system.20 In the case of no participation of the amino group in copper coordination, and binding only
by oxygen donor(s), smaller AII and larger gII should be obtained, as observed for the Cu(II):appg CuL
complex.20 The deprotonation of [CuHL1]+ to [CuL1] is accompanied by a blue-shift of the d–d bands,
with the Vis absorption maxima reaching 665 nm (Figure S1), indicating structural rearrangement and
involvement of another nitrogen donor in copper coordination. Also, the change of EPR parameters,
i.e. an increase of AII to 175.3, and a decrease of gII to 2.27 (Figure S2, Table 2) confirms the same set
of donors. With further increase of pH, the next species, [CuL1H-1]-, starts to dominate in solution,
followed
by
the
formation
of
[CuL1H-2]2-. The minor changes in spectroscopic parameter, i.e. the d-d band centered at 645 nm
(ε = 90 M-1cm-1) and EPR parameters (AII = 175.3 and gII = 2.27) correspond to two nitrogen atoms
maintained in copper (II) coordination sphere. The negative number of protons in the notation of
complexes means deprotonation of coordinated water molecules and the two species should be
noted as [CuL1(OH)]-, and [CuL1(OH)2]2-, respectively. Therefore, the tri- or quadri-dentate equatorial
coordination of the L1 ligand in the [CuL1] hampers the formation of CuL2 species in the studied
system.
Table 2. Potentiometric and spectroscopic data of Cu(II) complexes of studied ligands.a
Potentiometry
UV-Vis
EPR
gII
Reference
This work
Species
Cu(II) : L1
[CuHL1]+
[CuL1]
logβ
logK
λmax [nm] εmax
AII
23.24(5)
19.37(4)
10.05(5)
750
665
650
35
90
90
160.7
175.3
175.3
2.30
2.27
2.27
3.87
9.32
[CuL1H-1]-

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[CuL1H-2]2-
Cu(II) : L2
[CuHL2]2+
[CuL2]+
-1.56(7)
11.61
650
90
Nd
Nd
This work
11.87(3)
7.25(4)
730
700
665
Nd
50
Nd
Nd
4.62
75
Nd
Nd
[CuL2 ]
12.44(6)
-7.93(4)
125
nd
165.4
165.4
2.28
2.28
2
[CuL2 H-2]2-
20.28
2
Cu(II) : L3
[CuL3]
This work
11.55(7)
605
190
174.9
2.21
20
Cu(II) : apl
[CuHL]+
15.79
12.08
2.60
720
667
650
50
61
74
166
181
181
2.273
2.248
2.244
[CuL]
3.71
9.48
[CuLH-1]-
[CuL2]2-
14.91
20
Cu(II) : appg
[CuHL]+
10.55
5.66
750
720
683
25
30
39
134
134
136
2.348
2.330
2.295
[CuL]
4.89
7.12
[CuLH-1]-
[CuL2]2-
-1.46
9.55
35
13
16
Cu(II) : MBAPA
[CuL]
[CuLH-1]-
[CuLH-1]2-
Cu(II) : AMPA
[CuL]+
9.87
1.05
-9.48
8.82
10.53
5.45
9.99
1.20
702
670
678
42
61
48
140
135
166
2.341
2.293
2.266
[CuL2]
[CuL2H-1]-
Cu(II) : AM2P
[CuHL]2+
[CuL]+
8.79
5.07
12.71
7.64
[CuHL2]+
19.79
13.05
3.07
[CuL2]
6.74
9.98
11.73
616
[CuL2H-1]-
[CuL2H-2]2-
Cu(II) : EDBPA
CuL
-8.66
36
37
10.10
Cu(II) : PDMBPA
CuL
3.18
CuH2L2
17.79
37
Cu(II) : PMPA
CuL
4.91
a
I = 0.1 M (NaClO4), T = (25.0 ± 0.2) oC, solvent: H2O for L1 and L3, and MeOH/H2O 80:20 w/w for L2.
UV–Vis experimental errors:
λmax = ±2 nm,
ε
= ±5%.

New Journal of Chemistry
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DOI: 10.1039/C8NJ01094C
Because of the structural analogy, the Cu(II) complexes of L1 were compared to apl and appg ligands,
both possessing the aminocarboxylate function able to support Cu(II) coordination to
aminophosphinate donor groups.20 Both ligands formed protonated [CuHL]+ complexes by
+
coordinating the metal ion via the amino acid moiety, while the terminal NH3 group was
protonated. In the case of apl, this coordination resulted in the formation of a five-membered
chelate ring with a N,O bonding mode, while in the case of appg only monodentate coordination of
the carboxylate was possible at the pyroglutamate moiety; the tertiary amine was not able to bind
the metal ion. The deprotonation of [CuHL]+ was definitely accompanied by a structural
rearrangement; in the [CuL] species, appg bound to Cu(II) at the aminophosphinate moiety, forming
a five-membered N,O chelate ring, while apl coordinated in a tridentate manner via the phosphinate
and the two amino groups, forming a (5,5)-membered joined chelate system. Quadridentate
coordination of the apl ligand including the simultaneous binding of the carboxylate was also
assumed. In contrast to Cu(II)-L1 system, above pH 6, apl and appg formed [CuL2]2- complexes.20 The
differences in the coordination ability of all three ligands are reflected in logKCuL values (Table S2),
indicating the advantageous arrangement of donors in L1, with over 5 orders of magnitude gain in
stability with respect to apl, and 13 to appg. In order to understand the impact of amine-
phosphinate-Cu(II) binding in more detail, we compare the stability of Cu(II)- L1 complexes with the
apl and appg analogues on so-called competition plots, i.e. in a hypothetical situation in which
equimolar concentrations of the three reagents (Cu(II), L1 and apl, or appg, respectively) are mixed.
Calculations are based on binding constants collected in Table 2, both for the new L1 ligand and
literature analogues.20 From the competition plots presented in Figure 2, it is clear that the L1 ligand
is much more competitive towards Cu(II) binding than both, apl and appg ligands along entire pH
range studied. The higher stability of L1 complexes most probably stem from higher basicity of the
carboxylate and tertiary amino groups, and their simultaneous involvement, together with
aminophosphinate donors, in equatorial metal coordination in [CuL1], with the formation of three
five-membered chelate rings.
100
[CuL1]
free Cu(II)
[CuL1H-1]-
[CuHL1]+
80
60
40
[CuLH-2]2-
20
0
2
3
4
5
6
7
8
9
10
11
pH

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[CuL22H-2]2-
100
80
60
40
20
0
[CuL22]
free Cu(II)
[CuL2]+
[CuHL2]2+
2
3
4
5
6
7
8
9
10
11
pH
100
[CuL3]
free Cu(II)
80
60
40
20
0
2
3
4
5
6
7
8
9
10
11
pH
Figure 1. Species distribution profiles for Cu(II) complexes of L1-L3 in molar ratio Cu(II):L 1:2.
Data obtained for the second studied system, Cu(II):L2, suggest that L2 ligand might bind the metal
ion in a tridentate manner, via primary amine, isoquinoline and phosphinate donor groups. The
complexation starts with monomeric [CuHL2]2+ and [CuL2]+ species, which are present in solution in
pH range of 3 - 8.5 (with the maximum at pH 4.7 and 5.6, respectively, Figure 1). The precipitation of
bluish precipitate above pH around 7 at Cu(II) to L2 ratio of 1:1 prevented the detection of [CuL2H-1]
species. The monomeric complexes are followed by [CuL2 ] species, prevailing in pH range of 7-10.
2
Besides these three species, the formation of a hydroxo [CuL2 H-2]2- (or more precisely [CuL2 (OH)2]2-
2
2
was calculated as a further base-consuming process took place over pH 10. The species corresponds
to simultaneous deprotonation of two water molecules in the copper (II) coordination sphere. The

New Journal of Chemistry
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DOI: 10.1039/C8NJ01094C
complex formation scheme corresponds to Cu(II) binding process described previously for
aminophosphinates.13, 16
The UV-Vis and EPR spectral parameters are consistent with the speciation model based on the
potentiometric data and proposed binding modes. In the UV-Vis spectra collected over pH 4 - 5.5, the
maximum of d-d band shifts from 740 nm (ε = 50 M-1cm-1) towards 700 nm (ε = 75 M-1cm-1),
respectively. Although d-d band with maximum at 700 nm is rather indicative for 1N coordination, it
is sensitive mainly to the equatorial coordination and the observed wavelength does not exclude
coordination of the second nitrogen in the axial position in [CuL2]+ complex. The logK between the
two monomeric [CuHL2]2+ and [CuL2]+ species is 0.84 logK units lower than the constant of NIsoquinoline
in free ligand (4.62 versus 5.46, Table 1), what may suggest its involvement in Cu(II) binding in [CuL2]+
(together with other two donor atoms). The formation of [CuL2 ] is reflected by the shift of the UV-
2
Vis bands towards 665 nm (ε = 125 M-1cm-1) (Table 2, Figure S1), and this spectral behaviour is
characteristic for the presence of two nitrogen donors in complex coordination sphere, here from
two aminophosphinate moieties. The lack of any further significant changes in visible spectra
confirms that the coordination behaviour of [CuL2 H-2]2- complex does not change. EPR parameters,
2
AII=165.4 and gII=2.28 are typical for 2N species with square-bypiramidal geometry13 (Figure S2, Table
2), indicating aminophosphinate mode of binding.
Because of possible coordination patterns of L2 ligand, i.e. tridentate via primary amine, isoquinoline
and phosphinate donor groups in [CuL2]+ species, and bidentate through aminophosphinate moieties
in [CuL2 ] and [CuL2 H-2]2- complexes, we compare its binding ability with the AM2P16 and AMPA13
2
2
chelators. Although an increase of L2 logKCuL and logKCuL (Table S2) may indicate that it forms
2
stronger copper complexes than the AMPA analogue,13 yet they are weaker than the species formed
by AM2P.16 However, it has to be underlined, that current thermodynamic data have been obtained
in a methanol/water mixture (80:20 w/w), and previously a high amount of methanol in solvent
composition was shown to increase the stability constants of Cu(II):aminohydroxamate complexes by
44, 45
several orders of magnitude.38,
Therefore, it can be concluded that the stabilization of the
Cu(II):L2 complexes may come from the intrinsic property of the ligand and complexes structures,
supported by subtle effects of organic solvent, like specific solvation effects, or electric permeability.
[CuL1]
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
[CuL1]
[CuL1H-1]-
[CuL1H-1]-
free Cu(II)
[CuHL1]+
free Cu(II)
[CuHL1]
[CuH(apl)]+
[Cu(apl)]
[CuL1H-2]2-
[CuH(appg)]+
[CuL1H-2]2-
2
3
4
5
6
7
8
9
10
11
2
3
4
5
6
7
8
9
10
11
pH
pH

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100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
[CuL3]
free Cu(II)
[Cu(EDBPA)]
[CuL3]
[Cu(MBAPA)H-2]2-
40
30
20
10
0
free Cu(II)
[Cu(MBAPA)H-1]-
[Cu(MBAPA)]
2
3
4
5
6
7
8
9
10
11
2
3
4
5
6
7
8
9
10
11
pH
pH
Figure 2. Competition plots between studied ligands, their corresponding analogues and Cu(II), describes
complex formation at different pH values in a hypothetical situation in which equimolar amounts of the three
reagents are mixed. Calculations are based on binding constants from Table 2. Conditions: [Cu(II)] = [L1-3] =
[L] = 3 mM.
The potentiometric data for Cu(II):L3 system indicate the formation of only one, monomeric, species
[CuL3], present in solution above pH 4.5 (Table 2, Figure 1). The protonated and hydroxo species
introduced into calculated model were rejected. The absorption spectra show d-d transitions
maximum centered at 605 nm (ε = 190 M-1cm-1) (Figure S1, Table 2), even when pH-dependent
titrations were carried out for Cu(II):L3 molar ratio 1:2. The EPR parameters also indicate the
formation of only one complex with parameters AII = 174.9 and gII = 2.21. These spectroscopic
parameters are about the usual characteristics of 3N species,38, 43 and therefore may suggest the
involvement of three nitrogen atoms (two from primary amines and one from piperazine ring), and
one or two phosphinate oxygens in Cu(II) coordination environment. The lack of protonated species
further supports this coordination environment. For 2:1 Cu(II):L3 molar ratio, despite excess of the
Cu(II) used, no species of M2L stoichiometry could be identified , and a blueish precipitate occurred
above pH 6 (this pH range was not included in the data processing). Earlier studies carried out for
PDMBPA showed the formation of CuL and Cu(HL)2 complexes, with only one side of the ligand
involved in metal binding via the piperidine nitrogen and phosphinic oxygen.37 For this ligand the
possibility of the inversion of the piperazine ring to gauche conformation and simultaneous
coordination of both piperazine N atoms to Cu(II) could not be assumed due to a rigidity of the
piperazine ring. Moreover, the complexes formed were less stable than those for the PMPA (Scheme
1).37 However, the comparison of the coordination ability of L3 to these two ligands should be
restricted to pH 7, as above a formation of insoluble polymeric species was assumed, for which
stability constants could not be determined. An efficient combination of amino and phosphinic
groups has been proposed in MBAPA,35 and EDBPA,36 which revealed strong, tetradentate
complexation of Cu(II) ions via both phosphinate oxygen atoms and both amine groups (logKCuL of
9.4935 and 10.10,36 respectively). The chelating efficiency of discussed L3 ligand, reflected as logKCuL
=
11.55, exceeds the ones corresponding to the above bis(amino-phosphinic) ligands by 1.5-2 orders of
magnitude, what suggests an involvement of an additional factor influencing the stability. Therefore,
the proposed arrangement of donors, i.e. location of the amino group close to the phosphinate and
piperazine atoms, enhances the binding power of the ligand, making it an efficient chelator. The
competition results shown in Figure 2 clearly indicate that L3 ligand forms much more stable

New Journal of Chemistry
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complexes than the MBAPA along entire pH range. However, the competition between L3 and EDBPA
chelator,36 shows that for the latter system, [CuL] complex predominates the solution already from
pH 2.5, while [CuL3] is formed only above pH 4.5, and become significantly more competitive above
pH 7. We can hypothesize that this additional stability of L3 at alkaline pH might be explained by the
participation of all donor groups in metal coordination and the formation of five five-membered
chelate rings with completion of Cu(II) coordination sphere by one ligand. It’s difficult to assume if
there is an inversion of the piperazine ring in L3, but such a rearrangement would be necessary for
the formation of 3N or 4N Cu(II) complex.
4. Conclusions
The three new non-symmetrical bis(aminoalkyl)phosphinate ligands, namely L1–L3, were synthesized
and evaluated for coordination of Cu(II) ions. The protonation schemes of the ligands followed
classical scheme, with logK constants of amine, piperazine, carboxylate and phosphinate groups
being in a good agreement with corresponding values reported earlier for analogous compounds.
For all ligands the metal-to-ligand stoichiometry of Cu(II) complexes was determined by ESI-MS, and
further confirmed by potentiometric studies. Potentiometric titrations together with a full
spectroscopic analysis clarified the species distribution profiles and detailed coordination modes.
The results show that all ligands are good chelating agents for Cu(II) ions, with L1 and L3 being
especially efficient. The arrangement of donors in L1 ligand allows its wrapping around Cu(II) ions in
[CuL1] complex, making the complexation very competitive. Although it’s difficult to assume if there
is an inversion of the piperazine ring in L3 facilitating formation of 3N or 4N [CuL3] complex, it is clear
that the addition of amino groups to piperazine-1,4-diylbis(methylene)bis(phosphinic acid),
enhanced the binding power of the ligand, making it an efficient chelator.
Acknowledgments
The financial support from the National Science Centre Poland, UMO-2015/19/B/ST5/00413, is
gratefully acknowledged.
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Novel, non-symmetrical bis(aminoalkyl)phosphinic acids exhibit enhanced efficiency in Cu(II) ions
binding.