Homo- and heteropolynuclear Ni2+ and Cu2+ complexes of polytopic ligands, consisting of a tren unit substituted with three 12-membered tetraazamacrocycles

Article abstract of DOI:10.1039/b709422a

Two new polytopic ligands L¹ and L² have been synthesized. They consist of a central tren unit to which three 1,4,7,10-tetraazacyclododecane rings are attached via an ethylene and a trimethylene bridge, respectively. The complexation

Full text of DOI:10.1039/b709422a

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Homo- and heteropolynuclear Ni2+ and Cu2+ complexes of polytopic ligands,
consisting of a tren unit substituted with three 12-membered
tetraazamacrocycles†
Liselotte Siegfried,a C. Niamh McMahon,a Jan Baumeister,a Markus Neuburger,a Thomas A. Kaden,*a
Sreekanth Anandaramb and Cornelia G. Palivanc
Received 20th June 2007, Accepted 13th August 2007
First published as an Advance Article on the web 30th August 2007
DOI: 10.1039/b709422a
Two new polytopic ligands L1 and L2 have been synthesized. They consist of a central tren unit to which
three 1,4,7,10-tetraazacyclododecane rings are attached via an ethylene and a trimethylene bridge,
respectively. The complexation properties of L1 and L2 towards Cu2+ and Ni2+ were studied by
potentiometric pH titration, UV-Vis, EPR spectroscopy and kinetic techniques. As a comparison, the
Cu2+ and Ni2+ complexes with L3 (1-(N-methyl-2-aminoethyl-1,4,7,10-tetraazacyclododecane)) were
also investigated. The crystal structures of [CuL3H(H2O)](ClO4)3 and [NiL3Cl](ClO4) were solved and
show that the side chain in its protonated form is not involved in coordination, whereas deprotonated it
binds to the metal ion. The thermodynamically stable 3 : 1 complexes of L1 or L2 have a metal ion in the
three macrocyclic units. However, when three equivalents of Cu2+ are added to L1 or L2 the metal ion
first binds to the tren unit and only then to the macrocycles. The kinetics of the different steps of
complexation have been studied and a mechanism is proposed.
Examples of polytopic ligands containing macrocyclic units can
Introduction
be found in the literature.7,8 In several cases rigid structural units,
Polyazamacrocyclic ligands and open chain polyamines differ
which can fix the geometry of the molecule, have been selected as
significantly in their complexation properties towards transition
the central part of such polytopic ligands. Accordingly, phloroglu-
cinol (a 1,3,5-substituted benzene ring) has been used to synthesize
thermodynamic stability than open chain ligands (macrocyclic
a large series of linked macrocycles, which can form polynuclear
metal ions.1 Polyazamacrocycles often give complexes of higher
effect),2 and in many cases species which are kinetically inert to
acid dissociation. So, for example, the Ni2+ complex of 1,4,8,11-
tetraazacyclotetradecane (cyclam) is stable in 10 M HClO4,
conditions under which electrochemistry has been performed,3
whereas the Ni2+ complex of trien dissociates at stopped flow rates
in 0.1 M HClO4.4 In addition, the coordination geometry of the
complexes is generally induced by the somewhat rigid macrocycles,
whereas open chain ligands, being more flexible, adapt themselves
to the geometric requirements of the metal ion.5
complexes with Zn2+ and Cu2+.9 In a similar way, 2,4,6-triamino-
1,3,5-triazine has been chosen as the central part of a chelator to
which three macrocycles are coupled, so that three Cu2+ ions can be
coordinated to it.10 In other cases the flexible aliphatic polyamine
tren has also been used as a central part of such ligands.11,12 As a
consequence of its tripodal structure it can generate a bowl-shaped
cavity with C3v symmetry and the presence of three primary amino
groups means it can be acylated or alkylated to give substituted
tris-derivatives. So Bazzicalupi et al.11 have prepared a compound
Because of these different properties it is interesting to built new
chelators in which both structural elements are included.6 This
would allow the same metal ion to be introduced in two different
environments, so that different chemical properties result, or on the
other hand, it would allow heteronuclear species to be synthesized
by sequential addition of two different metal ions. However, the
synthetic effort to prepare heterodi- or heteropolytopic ligands
and the desired heteronuclear complexes is, in general, still rather
demanding and thus, before applications can be developed it is
necessary to investigate routes which can lead to new compounds.
which in its protonated form as polyammonium ion is able to bind
−
ClO4
.
In a previous paper,12 we reported two new compounds L4 and
L5, in which three 1,4,8,11-tetraazacyclotetradecanes (cyclam) are
connected to a central tren unit through ethylene or trimethylene
bridges to give chelators which are able to form tri- and tetranu-
clear complexes with Ni2+ and Cu2+. It has been shown that by
sequential addition of metal ions the first three are incorporated
into the macrocyclic rings, which give the thermodynamically more
stable complexes, whereas the fourth in bound by the tren unit.
In this way, heteronuclear complexes with three Cu2+ in the
macrocycles and one Ni2+ in the tren unit, or vice versa, were
prepared in a relatively simple way.
aDepartment of Chemistry, Spitalstr. 51, 4056 Basel, Switzerland. E-mail:
th.kaden@unibas.ch
bDepartment of Physical Chemistry, ETH-Zurich, CH-8093, Zurich,
Switzerland
We have now prepared similar compounds L1 and L2 with
the smaller 1,4,7,10-tetraazacyclododecane ring (cyclen), which
in contrast to cyclam is not able to encompass the metal ions
and thus gives complexes with different geometries than those
of the previous derivatives with cyclam. In addition the simpler
cDepartment of Chemistry, Klingelbergstr. 80, 4056 Basel, Switzerland.
E-mail: cornelia.palivan@unibas.ch
† CCDC reference numbers 654220 and 654221. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b709422a
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compound L3 was also prepared to model a part of the more
complicated ligands.
product was isolated in 78% yield as a white solid (32 g, 0.08 mol).
1H-NMR (CDCl3): dH 2.28 (s, CH3, 3 H), 2.44 (s, CH3, 3 H), 2.57
(s, CH3, 6 H), 3.17 (dd, J = 5.1 Hz, CH2, 2 H), 4.01 (dd, J =
5.1 Hz, CH2, 2 H), 5.1 (s, NH, 1 H), 7.32 (d, J = 8.3 Hz, CH,
2 H), 7.72 (d, J = 8.3 Hz, CH, 2 H); 13C-NMR (CDCl3): dC 21.3
(CH3), 22.1 (CH3), 23.2 (CH3), 42.0 (CH2), 69.1 (CH2), 128.3,
130.4, 132.5, 132.8, 133.8, 139.4, 142.9, 145.7 (aromC).
N-Mesitylenesulfonyl aziridine (5). The synthesis was per-
formed analogously to the preparation of N-tosyl aziridine.16
The product was isolated as a bright yellow powder in almost
1
quantitative yield. H-NMR (CDCl3): dH = 2.30 (s, CH3, 3 H),
2.33 (br, CH2, 4 H), 2.69 (s, CH3, 6 H), 6.97 (s, CH, 2H); 13C-
NMR (CDCl3): dC 21.4 (CH2), 23.4 (CH3), 27.0 (CH3), 132.2,
133.0, 140.5, 143.5 (aromatic C). Found C, 58.55; H, 6.82; N,
6.05%. C11H15NO2S requires C, 58.64; H, 6.71; N, 6.22%. M =
225.31.
1-(2-Mesitylenesulfonylaminoethyl)-4,7,10-tris(tert-butyloxy-
carbonyl)-1,4,7,10-tetra-azacyclododecane (6). N-Mesitylenesul-
fonyl aziridine 5 (1.9 g, 8.5 mmol) and 2 (4 g, 8.47 mmol)
were dissolved in dry acetonitrile (30 ml) and the solution was
placed in a Young–Schlenk tube. The solution was subjected to
four freeze–pump–thaw cycles. Under low pressure, the degassed
solution was heated to 105 ◦C overnight in the sealed Young–
Schlenk tube. After cooling the solution was evaporated and the
product isolated in nearly quantitative yield as a white solid (5.91 g,
8.4 mmol). Purification for analytical purposes was accomplished
by column chromatography over silica gel with ethyl acetate–
dichloromethane (1 : 6). 1H-NMR (CDCl3): dH 1.44 (s, tBu, 18 H),
Experimental
Materials and methods
All reagents and solvents obtained from commercial sources
were used without further purification. Infrared spectra as KBr
pellets (1–3%) were measured on an ATI Matteson Genesis Series
1
FTIRTM. H- and 13C-NMR spectra were recorded on a Bruker
AC250, Bruker AC400 or Bruker AC500 spectrometer. Reported
chemical shifts are relative either to TMS (CDCl3) or sodium
3-(trimethylsilyl)propyl-sulfonate (D2O). Elemental analyses were
performed by the analytical laboratory of the Institute for Organic
Chemistry of the University of Basel. Electrospray-MS was run
on a Finnigan MAT, FAB–MS on a VG-70–35.
3-(1,4,7,10-tetraazacyclododec-1-yl)propionic acid (1)13 and
1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane
(2)14 were prepared according to the literature.
t
1.46 (s, Bu, 9 H), 2.28 (s, CH3, 3 H), 2.63 (s + br, CH3, 6 H;
NCH2, 6 H), 2.95 (dd, J = 6.1 Hz, CH2, 2 H), 3.31 (br, CH2, 4 H),
3.42 (br, CH2, 4 H), 3.54 (br, CH2, 4 H), 5.37 (s, NH, 1 H), 6.93
(s, CH, 2 H); 13C-NMR (CDCl3): dC 21.27, 23.36 (arom-CH3),
28.93, 29.08 (C(CH3)3), 49.00 (b, N–CH2), 132.28, 134.12, 139.50,
142.28 (aromC). Found C, 58.35; H, 8.34; N, 9.78; O, 18.32%.
C34H59N5O8S requires C, 58.51; H, 8.52; N, 10.03; O, 18.34%.
M = 697.93.
N-Mesitylenesulfonyl ethanolamine (3). N-Protection was
achieved following the route used by Bergeron et al.15 Mesitylene-
sulfonyl chloride (50 g, 0.229 mol), dissolved in dichloromethane
(100 ml), was added under cooling (0 ◦C) to ethanolamine
(13.27 g, 0.217 mol) in a mixture of dichloromethane (200 ml)
and 2 M NaOH (200 ml) under rapid stirring. The mixture
was allowed to warm up overnight. The layers were separated
and the aqueous phase extracted twice with dichloromethane.
The combined organic phases were washed with water and
concentrated in vacuo to yield N-mesitylenesulfonyl ethanolamine
Tris[3-aza-3-mesitylenesulfonyl-5-{4,7,10-tris(tert-butyloxy-
carbonyl)-4,7,10-tetraaza-cyclododec-1-yl}pentyl]amine
(7).
CAUTION! Tris(2-chloroethyl)amine is a strong vesicant. Wear
protective garment! 1-(2-Mesitylenesulfonylaminoethyl)-4,7,10-
tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane
6
(4.0 g, 5.7 mmol) was dissolved in dry DMF (50 ml), to which a
suspension of 60% sodium hydride in oil (230 mg, 5.7 mmol) was
added. The mixture was slowly heated to 70 ◦C under stirring and
kept at this temperature for 2 h. After the solid had completely
dissolved and gas evolution stopped, tris(2-chloroethyl)amine
(390 mg, 1.9 mmol) in dry DMF (3 ml) was added and the mixture
heated overnight at 70 ◦C. A white precipitate of sodium chloride
was filtered off and the solution evaporated to dryness. The solid
was dissolved in diethyl ether and filtered to remove traces of
salt. After evaporation the product was isolated in 94% yield as
a white powder (3.95 g, 18 mmol). Purification for analytical
purposes was accomplished by column chromatography over
1
as a white solid (25 g, 0.103 mol). H-NMR (CDCl3): dH 2.29 (s,
CH3, 3 H), 2.62 (s, CH3, 6 H), 3.01 (dd, J = 5.1 Hz, CH2, 2 H),
3.65 (dd, J = 5.1 Hz, CH2, 2 H), 5.4 (s, NH, 1 H), 6.94 (s, CH,
2 H); 13C-NMR (CDCl3): dC 21.3 (CH3), 23.2 (CH3), 45.0 (CH2),
61.5 (CH2), 132.4, 133.8, 139.5, 142.7 (aromC).
N-Mesitylenesulfonyl-o-tosyl ethanolamine (4). To a solution
of 3 (25 g, 0.103 mol) and triethylamine (101 g) in dichloromethane
(200 ml), a solution of toluenesulfonyl chloride (20.62 g, 0.108 mol)
in dichloromethane (70 ml) was added dropwise at 5 ◦C. The
mixture was stirred overnight at r.t. and treated with sat. NaCl
and 10% citric acid. The organic phase was dried with Na2SO4
and evaporated to dryness. The white solid was extracted with
diethyl ether and filtered. After evaporation of the solvent, the
1
silica gel with ethyl acetate–dichloromethane (1 : 6). H-NMR
t
t
(CDCl3): dH 1.38 (s, Bu, 18 H), 1.41 (s, Bu, 9 H), 2.25 (s, CH3,
3 H), 2.46 (br, NCH2, 6 H), 2.54 (s, CH3, 6 H), 2.97–3.39 (br,
NCH2, 16 H), 6.91 (s, CH, 2 H); 13C-NMR (CDCl3): dC 21.3, 23.3
4798 | Dalton Trans., 2007, 4797–4810
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(arom-CH3), 28.8, 29.1 (C(CH3)3), 41.8, 45.7, 48.0, 50.2, 52.7,
54.2, 55.3 (N–CH2–), 67.0, 79.6, 79.8 ((CH3)3CO), 132.5, 133.8,
140.5, 143.0, 155.6 (aromC). Found C, 59.04; H, 8.42; N, 9.84;
O, 17.45%. C34H59N5O8S requires C, 59.26; H, 8.57; N, 10.24; O,
17.54%. M = 2188.92.
4.70 mmol) were added. To the mixture, which was stirred for
3 h, then degassed and backfilled with N2, a pre-cooled solution
of tris(2-aminoethyl)amine (0.19 g, 1.30 mmol) and triethylamine
(0.84 g, 8.30 mmol) in CH2Cl2 (10 ml) was added via syringe.
The reaction solution was stirred for a further 3 h at 0 ◦C and
then at r.t. overnight. The solid product was filtered off and the
volatiles were removed in vacuo to leave a foamy off-white solid.
Acetonitrile (10 ml) was added and the flask was cooled for 2 h
at −18 ◦C. The subsequent precipitate was filtered off and the
solution returned to the freezer for a further 16 h. Any further
precipitate was then filtered off and the solvent removed from
the product in vacuo. The product was further purified using
a short silica gel 60 column eluting with CH2Cl2–MeOH (80 :
20). The product was a pale white solid. Yield: 1.23 g (55%).
Tris[3-aza-5-(1,4,7,10-tetraazacyclododec-1-yl)pentyl]amine (L1).
Compound 7 (1.5 g, 0.68 mmol) was dissolved in a mixture of
CH2Cl2 (15 ml), TFA (4 ml) and phenol (1.3 g) and stirred for 14 h
at r.t. to cleave the boc groups. The triflate salt was precipitated
with diethyl ether and the resulting solid dissolved in a mixture
of CF3COOH–trifluoromethane sulfonic acid (9 : 1, 40 ml) and
stirred for 48 h. The triflate salt was precipitated from the dark
red solution by adding an excess of diethyl ether (200 ml). It
was washed and centrifuged repeatedly with diethyl ether until
the washing solution was colourless. The remaining solid was
dried in vacuo and dissolved in a minimum amount of water. The
free base was obtained from ion exchange chromatography with
Dowex 2 charged with OH ions after evaporation of the solvent.
It was isolated as a light brown semi-solid. Yield: 440 mg (87%).
1H-NMR (CDCl3): dH 2.50–2.66 (m, 36 H, N–CH2 + 12 NH);
13C-NMR (CDCl3): dC 44.0, 44.9, 45.6, 46.1, 46.7, 51.4, 53.7, 53.7
(N–CH2).
1
ESI-MS: m/z 1726 (M, 100). H-NMR (CDCl3): dH 1.46, 1.49
(2 s, 81 H, (CH3)3C), 2.37 (m, 6 H, CH2C(O)N), 2.55–2.75 (2
m, 18 H, NCH2), 3.02 (m, 6 H, NCH2CH2NC(O)), 3.25–3.55 (3
broad m, 42 H, NCH2 of cyclen and NCH2CH2NC(O)); 13C-NMR
(CDCl3): dC 28.9, 29.1 ((CH3)3CO), 38.00 (C(O)NCH2), 48–52 (all
NCH2), 79.8 [(CH3)3CO], 157.2, 155.8 (NC(O)O of BOC), 173.0
(CH2C(O)NCH2). TLC: CH2Cl2–MeOH (80 : 20) Rf = 0.56.
Tris-[3-aza-6-(1,4,7,10-tetraazacyclododec-1-yl)hexyl]amine (L2).
Compound 9 (1 g, 0.58 mmol) was dissolved in dry thf (10 ml)
under an argon atmosphere. A 1 M solution of BH3·thf (12 ml,
12 mmol) was added using a syringe and the solution refluxed for
The free base was converted to the hydrochloride salt by
dissolving it (0.12 g, 0.16 mmol) in MeOH (15 ml) and adding
HCl (36%, 1.5 ml). After cooling at −18 ◦C for 18 h the colourless
product was filtered off, washed with cold MeOH and diethyl ether
◦
48 h under argon. To the solution, which was cooled to 0 C, a
1
mixture of methanol and water was slowly added. The solution
was evaporated to dryness and conc. HCl–H2O (1 : 1, 15 ml) was
added. The flask was heated to 110 ◦C for 1 h with the solid
dissolving after a short period of time. The acid was evaporated
yielding a white solid. The solid was dissolved in water and put
through a Dowex 2 ion-exchange column in the OH− form. When
the water was evaporated, a pale yellow oil resulted which still
contained thf. Some of this thf can be removed by gel filtration
with Sephadex-15 and water as an eluent. The product was dried
in vacuo. Yield: 390 mg (86%) (with some thf). ES MS: m/z 784
and dried in vacuo. Yield: 190 mg (89.4%). H-NMR (D2O): dH
3.10–2.80 (3 m, 18 H, R2N–CH2–H), 3.30–3.10 (3 m, 18 H, H+N–
CH2–H); 13C-NMR (CDCl3): dC 41.30. 42.27, 43.02, 43.64, 47.75,
47.47, 48.98 (N–CH2–), 48.82 (MeOH). Found C, 32.77; H, 7.81;
N, 16.68%. C36H100N16Cl16. 1 MeOH requires C, 32.72; H, 7.73; N,
16.52%. M = 1356.50.
3-[4,7,10-Tris(t-butyloxycarbonyl)-1,4,7,10-tetraazacyclododec-
1-yl]propionic acid (8). To a solution of 3-(1,4,7,10-tetra-
azacyclododec-1-yl)propionic acid as the lithium salt (2.5 g,
10.0 mmol), dissolved in DMF (350 ml), a solution of di-t-
butylcarbonate (6.5 g, 29.8 mmol) in DMF (100 ml) was added
slowly over 60 min. The solution was then stirred for 2 h. The
solvent was evaporated. The crude product mixture was purified
by flash chromatography on a Silicagel 60 column using CH2Cl2–
MeOH (80 : 20) as an eluent. The product was a pale yellow oil
which foams when dried under vacuum. Yield 3.4 g (62.5%). FAB-
MS: m/z 545 (M + 1, 30), 307 (15), 245 (M − 3BOC, 45), 154 (tBu2,
100), 136 (70), 57 (tBu, 75). 1H-NMR (CDCl3): dH 1.48, 1.49 (2 s,
ratio 2 : 1, 27 H, (CH3)3C), 2.52 (t, 2 H, 3J = 6.8 Hz, CH2CO2H),
2.78–2.72 (m, 4 H, NCH2), 2.97 (m, 2 H, a-CH2), 3.44–3.33 (m,
8 H, NCH2 of cyclen), 3.49–3.56 (m, 4 H, NCH2 of cyclen); 13C-
NMR (CDCl3): dC 28.9 ((CH3)3CO), 29.1, 48.2, 50.1, 53.8, (all
NCH2 of cyclen and NCH2CH2CO2H), 79.9, 80.3 ((CH3)3CO),
155.9, 156.5 (NC(O)O), 175.5 (CO2H). TLC (80 : 20 = CH2Cl2–
MeOH) Rf = 0.6.
1
(M, 100), 629 (M·H2O − cyclen, 25), 612 (M − cyclen, 60). H-
NMR (D2O): dH 1.57 (m, 6 H, NCH2CH2CH2N of amine), 2.38–
2.75 (br m, 72 H, all NCH2 of cyclen and amine); 13C-NMR
(D2O, DMSO): dC 27.6 (CH2CH2CH2), 45.3 (CH2 of C6, C7), 45.8
(CH2 of C5, C8), 47.1 (CH2 of C2, C9), 47.6 (N(H)CH2CH2CH2),
48.9 (N(H)CH2CH2N), 52.0 (CH2 of C1, C10), 53.6 (NCH2 a to
cyclen), 54.8 (CH2CH2 a to 3N). IR KBr disk (free base) m/cm−1:
3390, 2934, 2833, 1567, 1463, 1407, 1351, 1296, 1111, 1065, 814.
1-[(2-(Mesitylenesulfonyl-2-methylaminoethyl)]-1,4,7,10-tetra-
azacyclododecane (10). To compound 6 (2.5 g, 3.58 mmol)
dissolved in CH2Cl2 (25 ml) a NaH suspension (65%, 143 mg,
3.87 mmol) and CH3I (0.3 ml, 4.8 mmol) were added. The mixture
was refluxed for 6 h. After cooling to r.t. the suspension was
washed with H2O (10 ml), the organic phase dried over Na2SO4,
filtered and evaporated to dryness to yield 1-(2-mesitylenesulfonyl-
2-methylaminoethyl)-4,7,10-tris(tert-butyloxycarbonyl)-1,4,7,10-
tetraazacyclododecane, which was dissolved in a mixture of
CH2Cl2 (50 ml), TFA (4 ml) and phenol (1.3 g) and stirred
for 14 h at r.t. To complete the reaction the triflate salt was
dissolved in a mixture of CF3COOH–trifluoromethanesulfonic
acid (40 ml, 9 : 1) and stirred for 48 h. Thereafter, the triflate salt
was precipitated from the dark red solution by adding an excess of
Tris-[3-aza-4-oxo-6-{4,7,10-tris(t-butyloxycarbonyl)-1,4,7,10-
tetraazacyclododec-1-yl}hexyl]amine (9). 1-(4,7,10-Tris(tert-bu-
tyloxycarbonyl)-1,4,7,10-tetraazacyclododec-1-yl)-propionic acid
8 (2.14 g, 3.96 mmol) was dissolved in CH2Cl2 (10 ml) and cooled
to 0 ◦C. To this solution, N-hydroxysuccinimide (NHS, 1.0 g,
8.69 mmol) and N,Nꢀ-dicyclohexyl carbodiimide (DCC, 0.97 g,
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diethyl ether. The precipitate was washed repeatedly with diethyl
ether and centrifuged until the washing solution was colourless.
The remaining solid was dried in vacuo. A small amount was
portions, whereby the solution turned light blue and a precipitate
formed. The solution was filtered and diluted to exactly 10 ml. For
the potentiometric titrations, a stock solution of [Ni3(L1)] (3 ml),
H2O (5 ml) and KNO3 (0.404 g) were mixed.
1
converted to the free base. H-NMR (CDCl3): dH 2.3 (s, 3 H, 1
aryl-CH3), 2.52 (s, 6 H, 2 aryl-CH3), 3.30 (t, CH2–N-mesityl),
2.65–2.88 (m + s, 9 N–CH2– +1 N–CH3), 6.94 (s, 2 H, arom).
[Ni3Cu(L1)] system. To 3 ml of the stock solution of [Ni3(L1)],
a CuSO4 solution (0.5 ml 0.0204 M) was added at pH 8. After
20 min the solution was filtered to remove any excess of Cu(OH)2.
1-(2-Methylaminoethyl)-1,4,7,10-tetraazacyclododecane L3.
The triflate salt of 10 (1.04 g, 1.06 mmol) was dissolved in a
mixture of CF3COOH and trifluoromethyl sulfonic acid (40 ml,
1 : 1) and stirred at 45 ◦C for 24 h under a N2-atmosphere.
Thereafter, the dark solution was cooled to r.t. and diethyl ether
(200 ml) was added. The mixture was cooled to −14 ◦C. The
black oily residue was filtered off and the solution evaporated
to dryness. Yield: 800 mg (94.3%). To further purify the product
it was converted into the hydrochloride via treatment with a
Cl loaded ion exchanger in a batch procedure. The resulting
product was recrystallized from EtOH (10 ml), HCl (0.3 ml 36%)
and H2O. The first precipitate was filtered off and the filtrate
[Cu3(L2)] system. To the free base L2 (21.51 mg), dissolved in
water (10 ml), a solution of Cu(ClO4)2·6H2O (33.38 mg, 5 ml) was
added. The solution immediately turned deep blue and the pH
changed to 5.1. The solution was stirred for 20 min. The pH was
brought to 1 and H2S was bubbled through the solution to remove
any excess copper. The brown precipitate was filtered off and the
solution was run through a Dowex 2 column in its OH− form,
filtered and brought to 50 ml with water. KNO3 was added so that
I = 0.5 M and the pH was adjusted with 1 M HNO3 to ca. 2.8 to
obtain the solution for the titrations.
A fourth equivalent of copper or nickel was added to solutions
of the [Cu3(L2)] system and titrations were carried out, but both
Cu(OH)2 as well as Ni(OH)2 precipitated during the titrations
indicating that the [Cu4(L2)] or [Cu3Ni(L2)] species did not form.
1
evaporated to dryness. Yield: 360 mg (82.5%). H-NMR (D2O):
dH 2.69 (s, N–CH3), 2.85–2.97 (t, 5 N–CH2–), 3.1–3.25 (t, 5 N–
CH2–); 13C-NMR (D2O): dC 33.6 (N–CH3), 41.9, 42.6, 44.8, 47.9
(N–CH2–ring), 44.5 (CH2–N–CH3), 48.5 (N–CH2–CH2–N–CH3).
[Ni4(L2)] system. To a solution of L2 (56.6 mg) in water
(10 ml), Ni(ClO4)2·6H2O (63.66 mg) dissolved in water (5 ml)
was added. The solution slowly turned yellow and was stirred for
3 d and made up to 50 ml. 10 ml of this solution were used for
spectrophotometric titration after addition of buffers as below.
10 mg of Ni(ClO4)2·6H2O was added to 25 ml of the solution at
pH = 7.5 and stirred for a further 24 h. The pH was then changed
to 11 and the solution filtered to remove excess Ni(OH)2. KNO3
and 1 M HNO3 were added, the solution brought back to 25 ml
and used immediately for potentiometric titrations.
[CuL3H(H2O)](ClO4)3. To the free base of L3 (80 mg,
0.348 mmol), dissolved in MeOH (5 ml), Cu(ClO4)2·6H2O
(155.4 mg, 0.42 mmol) was added. The solution turned blue
immediately and a dark blue precipitate formed. Everything
dissolved following addition of further MeOH (10 ml) and heating.
After filtration and evaporation of the solvent to 5 ml, blue crystals
formed, which were recrystallized from MeOH. Yield: 150 mg
(68.9%). From the filtrate RSA-suitable crystals were obtained
upon slow evaporation of the solvent. ESI-MS (1 mg per 25 mg
MeOH; 10 ll min−1) m/z 391.3 (M+ − ClO4), 291.2 (M+ − 2ClO4).
[Ni3Cu(L2)] system. The [Ni4(L2)] solution (25 ml) was used
to form [Ni3Cu(L2)] by addition of excess Cu(ClO4)2·6H2O in a
two step process. Initially Cu(ClO4)2·6H2O (3.85 mg) was added
at pH 3.4 and the solution stirred for 15 min. The pH was then
changed to 11 and the solution filtered to remove Ni(OH)2 from the
exchange reaction. The pH was then brought to 3.0 and further
Cu(ClO4)2·6H2O (6.85 mg) added. The pale blue solution was
again brought to pH 11, then filtered to remove any excess of
Cu2+. The solution was reacidified, rediluted to 25 ml with water, so
that it was ready for potentiometric titrations. After completion,
buffers were added to 10 ml of the solution as below and the
spectrophotometric titrations measured.
For the spectrophotometric titrations in general, 5 or 10 ml of
the potentiometric solution were taken and placed in a volumetric
flask, the buffers were added (see below) and the pH adjusted to
ca. 2.8 with 1 M HNO3. An accurately weighted aliquot of this
solution was then placed in the cuvette for titrations.
[NiL3Cl]ClO4. To the hydrochloride of L3 (120 mg, 0.52 mmol)
dissolved in MeOH (5 ml), a solution of Ni(ClO4)2·6H2O (13 ml,
0.045 M) was added. After formation of a yellow precipitate, the
solution was filtered and evaporated to 3 ml, whereupon violet
crystals were obtained which were filtered off and dried in vacuo.
To the filtrate LiOH was added, the solution was filtered again and
the solvent slowly evaporated at r.t. to give crystals which showed
that the amino group of the side chain was coordinated to the
metal ion. ESI (1 mg per 10 ml MeOH + 0.5 ml H2O): m/z 388.3
(M+ − ClO4), 386.2 (M+ − ClO4 − 2H+), 875 (dimer, M2 − ClO4).
Potentiometric and spectrophotometric solutions
[Cu3(L1)] system. To the hydrochloride of L1 (100 mg,
0.074 mmol), dissolved in water (5 ml), CuSO4·5H2O (55 mg,
0.22 mmol) was added. The solution turned blue immediately. A
pH of 11 was set using a KOH solution (4 ml 0.4 N), after which
no further colour change was observed. The pH was brought back
to 8, the solution evaporated to 3 ml, filtered and separated over a
G15 Pharmacia column (2 cm, 51 cm). The band of the pure 3 : 1
complex was then diluted with water in a flask to an exact volume
(25 ml), to obtain a stock solution.
pH Titrations
pH Titrations were run under N2 at 25
0.1 ◦C and I =
0.5 M (KNO3) on the automatic titrator previously described,17
consisting of a Metrohm 605 pH-meter, a Metrohm 665 burette, a
thermostatted titration vessel and a 286-AT PC controlling the
set up. Typical concentrations were: [L] = 0.6–1.3 × 10−3 M.
[NaOH] = 0.4 M and was added in 0.003 to 0.008 ml steps. The
[Ni3(L1)] system. L1 (51.41 mg, 0.038 mmol) was dissolved
in H2O (3 ml) and NiSO4·6H2O (42.99 mg, 0.163 mmol) was
added. To this a NaOH-solution (1.3 ml, 0.4 N) was given in small
4800 | Dalton Trans., 2007, 4797–4810
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aliquots were chosen to yield ca. 98 data points for each titration.
Calibration of the electrode and determination of aH and pKw was
performed as described.17 The evaluation of the protonation and
stability constants was carried out using the program TITFIT,18
in which the stability constants are defined by eqn (1)
The 63Cu/65Cu isotopes in their natural abundance were con-
sidered for each spectrum. The simulations simultaneously taking
into account two or more paramagnetic species were performed
until further changes in the EPR parameters did not improve the
quality of the fit.
[MmLlHh]
[M]m [L]l ahH
bmlh
=
(1)
Pulse-EPR measurements
The HYSCORE and pulse ENDOR spectra were measured at X-
band on a Bruker E580 spectrometer (mw frequency 9.73 MHz)
equipped with a CF935 cryostat from Oxford Inc. Measurements
in frozen solutions at a temperature of 20 K and a repetition time
of 1 ms. The field-swept EPR spectrum was measured by recording
the FID following a 700 ns long mw pulse at 20 K. HYSCORE
spectra were measured at X-band with a repetition time of 1 ms
using the sequence p/2–s–p/2–t1–p–t2–p/2–s-echo. The mw pulse
lengths were tp = tp/2 = 16 ns, with starting times t0 = 96 ns and a
time increment of Dt = 12 ns (data matrix 300 × 300). An eight-step
phase cycle was applied to suppress the unwanted echo crossings.
The spectra were recorded with s value = 114 ns. Davies ENDOR
experiments were carried out at X-band at a temperature of 20 K,
by using the pulse sequence p–T–p/2–s–p–s-echo, with mw pulse
lengths of tp/2 = 32 ns and a selective radio frequency p pulse of
length 10000 ls with variable frequency applied during the time
interval T. HYSCORE and ENDOR spectra were simulated with
the program EasySpin.22b
where aH is the proton activity.
Spectrophotometric titrations
Spectrophotometric titrations were carried out on an ATI Uni-
cam UV4 instrument, with the program SPECTRATE,19 using
1 cm quartz cuvettes and working at 25 ◦C and I = 0.5 M
(KNO3). Buffer concentrations were 0.015 M for each of the
four buffers: piperazine-N,Nꢀ-bis(3-propane sulfonic acid), 2-
(cyclohexylamino)ethane sulfonic acid, 2-morpholinoethane sul-
fonic acid, N-methylmorpholine. [NaOH] = 0.4 M, added in
aliquots of 0.01 ml, waiting time after addition varied from 60
to 120 s. Typical concentrations: [M3L] = 0.6–1.3 × 10−3 M. The
calculations were carried out using the program SPECFIT.20
Kinetics
Complex formation kinetics were carried out at 25.0
0.1 ◦C
using a KinTec Minimixer stopped-flow instrument with a 2 cm
cell, connected to J&M Tidas MMS16 VIS500/1 photodiode array
using a range 300–1000 nm. The spectra were recorded with the
program Kinspec235.21 Typical concentrations were: [L1] = 7.5 ×
10−4 M, [Cu2+] = 7.5 × 10−4 –2.25 × 10−3 M, Cbuffer = 0.04 M
(2,6-lutidine-3-sulfonic adic), I = 0.5 M (KNO3), pH 4.95. The
rate constants of the single experiments were calculated with the
program SPECFIT.20 The k-values reported are the means of at
least three experiments. The slow step of the complexation was
followed on an ATI Unicam UV4 instrument, with the program
Vision, using a scan method, taking spectra every 10–15 min, with
1 cm quartz cuvettes and working at 25 ◦C and I = 0.5 M (KNO3).
The spectral range was 450–850 nm. The rate constants of the
single experiments were calculated with the program SPECFIT.20
X-Ray structures†
Crystal data for [CuL3H(H2O)](ClO4)3 and [NiL3Cl]ClO4 are given
in Table 1. The COLLECT suite23 has been used for data collection
and integration. The structures were solved by direct methods
using the program SIR92.24 Least-squares refinement against F
was carried out on all non-hydrogen atoms using the program
CRYSTALS.25 Plots were produced using ORTEP3 for Windows.26
Results and discussion
Synthesis
For the synthesis of L1 and L3 we have used a new method,
based on the reaction of the triply boc-protected 1,4,7,10-
tetraazacyclododecane (2) with N-mesitylenesulfonyl aziridine (5),
to give the monosubstituted macrocycle (6) (Scheme 1). The
sodium salt of 6, obtained by treatment with NaH, was then
alkylated either with tris(2-chloroethyl)amine or methyliodide to
give the compounds 7 and 10, respectively. Finally the protecting
groups of 7 and 10 were cleaved off using a mixture of trifluo-
roacetic acid and trifluoromethanesulfonic acid to produce L1 and
L3, respectively. Both products were purified by crystallizing their
hydrochloride salts.
Ligand L2 was prepared using the method previously described12
for the analogous compounds with a 14-membered ring. The triply
protected macrocycle carrying a propionic acid side chain (8) is
activated withN-hydroxysuccinimide (NHS)anddicyclohexyl car-
bodiimide (DCC) and coupled with tren using the stoichoimetric
ratio 3 : 1 to give the triamide 9 (Scheme 2). The reduction and
deprotection of 9 was carried out in a one-pot reaction by reacting
it first with BH3·thf and then with HCl to hydrolyze the boramine
and cleave off the boc-groups. A comparison of the two synthetic
CW-EPR measurements
Solutions (1 × 10−3 M) of the metal complexes with L1, L2, and
L3 were prepared in H2O–MeOH = 10 : 1 as nitrate salts at
selected pH values (6.6, 11.0 for [Cu3L1], 3.7, 6.6 for [Cu3L2],
3.1, 10.3 [CuL3], 5.0, 8.0 for [Ni3CuL1], and 5.0 for [Ni3CuL2]).
EPR spectra of the complexes in solution were recorded either at
ambient temperature (295 K) or at 123 K with an EPR Bruker
ESP300E X-band spectrometer. All spectra were recorded using
100 kHz modulation frequency and microwave power of 0.5–
1 mW. Optimisation of the spectral resolution was achieved by
making multiple acquisition (20 scans) and using fast Fourier
transformation with a Gaussian profile for subsequent noise
reduction. DPPH was used as a field marker (g = 2.0036).
Symfonia software from Bruker22a was used to simulate all the
spectra, based on a third order perturbation theory treatment and
with the assumption that gyromagnetic and hyperfine tensors are
aligned. Linewidth tensors were based on Lorentzian (295 K) and
Gaussian (77 K) shape.
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Table 1 Crystal data and structural refinement for [CuL3H(H2O)](ClO4)3 and [NiL3 Cl]ClO4
Formula
C11H30Cl3CuN5O13
C11H27Cl2N5NiO4
MW/g Mol−1
Temperature/K
Crystal system
Space group
610.29
173
422.98
173
Monoclinic
P21/n
13.5959(10)
12.1317(10)
14.2676(10)
90
104.341(9)
90
2280.0(3)
1.853◦/28.505◦
4
Monoclinic
P21
8.9858(1)
7.9727(1)
12.3989(2)
90
96.8678(8
90
881.90(2)
1.654◦/30.010◦
2
˚
a/A
˚
b/A
˚
c/A
a/◦
b/◦
c /◦
Volume/A
hmin/hmax
Z
3
˚
Density calc./mg m−3
Abs. coefficient/mm−1
Min/max transmission
F(000)
1.778
1.382
0.76/0.87
1260
1.593
1.428
0.87/0.90
444
Crystal size/mm
Radiation
Weighting scheme
Reflections collected
Independent reflections
R(int)
Observed reflections
Number of var.
R
wR2
Goodness of fit
0.1 × 0.2 × 0.25
0.07 × 0.10 × 0.35
˚
˚
Mo-Ka (k = 0.71073 A)
Mo-Ka (k = 0.71073 A)
Chebychev polynomial
Chebychev polynomial
47 840
5774
0.099
4375
298
0.0332
0.0575
1.0995
−0.48/0.65
n/a
9615
5112
0.021
4567
209
0.0291
0.0361
1.0409
−0.56/0.87
0.042(9)
−3
˚
Residual electron density/e A
Flack parameter
routes shows that they are more or less equivalent, except for
the highly toxic tris(2-chloroethyl)amine, which has to be handled
with care. Therefore, depending on the availability of the starting
material and on the nature of the final product one has now two
ways to prepare such compounds.
Cu–N angles are between 86.2◦ and 87.1◦, and the N–Cu–O
angles are in the range of 100.2–109.8◦. The macrocycle, being
to small to encompass the Cu2+ ion, is folded so the four nitrogen
donors can bind to the metal ion. The geometry around the Cu2+
resembles very closely that observed for the Cu2+ complex with
the unsubstitued macrocycle.27 This is not surprising since the
amino group of the side chain, being protonated, is not involved
in coordination as established by analysing the HYSCORE spectra
(see below).
Interestingly, the three perchlorates are all on the hydrophilic
side of the cation, upon which we also find the coordinated water
molecule and the NH groups, whereas the hydrophobic back side
has no charged species in its surroundings (Fig. 2). There are
several H-bridges in particular two starting from the ammonium
group of the side chain to the oxygens of the perchlorate ions.
With this arrangement hydrogen bonds can be made between the
perchlorates and the water molecule or the NH of the amino
groups.
Structural studies
The structure of the complex [CuL3H(H2O)](ClO4)3, in which the
side chain amino group is protonated, shows that the metal ion
has a square pyramidal geometry (Fig. 1). The four nitrogens of
the macrocycle form the base of the pyramid and a water molecule
occupies the apical position.
Fig. 1 ORTEP plot of◦the structure of [CuL3H(H2O)]3+. Selected bond
˚
lengths (A) and angles ( ): Cu–N(1) 2.052(2), Cu–N(2) 2.002(3), Cu–N(3)
2.006(3), Cu–N(4) 2.001(2), Cu–O(1) 2.173(2); N(1)–Cu–N(2) 86.19(10),
N(2)–Cu–N(3) 86.40(11), N(1)–Cu–N(4) 87.10(10), N(3)–Cu–N(4)
86.56(10), N(1)–Cu–O(1) 104.36(9), N(2)–Cu–O(1) 100.21(10), N(3)–Cu–
O(1) 102.32(9), N(4)–Cu–O(1) 109.76(10). Ellipsoid probability 50%.
−
Fig. 2 Hydrophilic interactions between [CuL3H(H2O)]3+ and the ClO4
ions.
˚
The Cu–N bond lengths are in the normal range (2.001–2.05 A),
˚
whereas the Cu–O bond is somewhat longer (2.173 A). The N–
4802 | Dalton Trans., 2007, 4797–4810
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Fig. 3 ORTEP plot of the structure of [NiL3Cl]+. Selected bond lengths
◦
˚
(A) and angles ( ): Ni–N(1) 2.1420(16), Ni–N(2) 2.0951(17), Ni–N(3)
2.1456(18), Ni–N(4) 2.1241(16), Ni–N(5) 2.1076(17), Ni–Cl(1) 2.4566(5);
N(1)–Ni–N(2) 81.05(7), N(2)–Ni–N(3) 81.81(8), N(3)–Ni–N(4) 82.93(7),
N(4)–Ni–N(5) 83.46(7), Cl(1)–Ni–N(1) 100.85(5), Cl(1)–Ni–N(2) 85.27(5),
Cl(1)–Ni–N(3) 95.85(5), Cl(1)–Ni–N(5) 86.97(5). Ellipsoid probability
50%.
between cis-ligands are between 81.05 and 104.56◦ because of the
different nature of the donors.
Potentiometric results
Potentiometric pH titrations were used to study the complexation
behaviour of the three ligands in aqueous solution. If one
equivalent of M2+ (Cu2+ or Ni2+) is added to the model compound
L3, the metal ion is bound by the macrocycle in such a strong
manner that even at pH 2.5 the metal ion remains attached to the
macrocycle. At this low pH the amino group of the side chain is
protonated so that the species [ML3H]3+ results. By adding base to
such a solution one can deprotonate [ML3H]3+ to [ML3]2+ (eqn (2)).
Scheme 1 Synthesis of L1 and L3.
[ML3H]3+ ꢀ [ML3]2 + H+; KH,1
(2)
The low values of log KH,1 4.55(3) and 3.62(3) for Cu2+ and
Ni2+, respectively, indicate that together with deprotonation the
resulting amino group also coordinates to the metal ion. In the
case of Cu2+, both [ML3H]3+ and [ML3]2+ have a pentacoordinate
metal ion. In [ML3H]3+ the coordination sphere is N4(H2O) (see
structure), whereas in [ML3]2+ we have a N5 environment. For Ni2+
we start in [NiL3H]3+ with a N4(H2O)2 coordination sphere and
we obtain for [NiL3]2+ a N5(H2O) coordinated pseudo octahedral
species.
Beside the protonation/deprotonation of the side chain we
also observe hydrolysis reactions. For Ni2+ we obtain a dimeric
species [(NiL3)2OH]3+ (eqn (3)), whereas for Cu2+ the monomeric
[CuL3OH]+ is found only at high pH.
2[NiL3H]2+ + H2O ꢀ [(NiL3)2OH]3+ + H+; KH,2
(3)
Although the Ni2+ and Cu2+ complexes of L3 behave in a
similar way at low pH, they differ at higher pH. At low pH the
coordination of the side chain is observed in both cases, giving a
pentacoordinate Cu2+ and a hexacoordinate Ni2+. In the case of
Cu2+ there is no water molecule left in the coordination sphere of
[CuL3]2+ so we expect hydrolysis only at quite high pH. Indeed the
pH titration shows that hydrolysis takes place at pH > 10. In the
complex [NiL3]2+ there is one coordinated water molecule which
can hydrolyze. The pH titration shows that this takes place with
log KH,2 = 8.22(3) and that 0.5 equivalent H+ are released so that
a dimeric species [(NiL3)2OH]3+ must be postulated.
Scheme 2 Synthesis of L2.
The structure of the Ni2+ complex of L3 shows that the amino
group of the side chain can bind to the metal ion. The Ni2+,
hexacoordinate in a pseudo-octahedral environment, is bound by
the five nitrogens of the macrocycle and a chloride ion (Fig. 3). The
Ni–N bonds are in their normal range for high spin hexacoordinate
Ni2+ (2.0951–2.145 A). The Ni–Cl bond is 2.4566 A. The angles
˚
˚
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Table 2 Log Ki values (with standard deviation) for the protonation of
the trinuclear Cu2+ and Ni2+ complexes with L1 and L2 and Cu2+ binding
to [Ni3L1]6+ and to [Ni3L2]6+ at 25 ◦C and I = 0.5 M (KNO3)
ion. The complexation equilibrium is described by eqn (8) and (9)
and the constants are also given in Table 2.
[CuNi3LH]9+ ꢀ [CuNi3L]8+ + H+; K5
(8)
Cu2+
Ni2+
L1
L2
L1
L2
[Ni3LH2]8+ + Cu2+ ꢀ [CuNi3L]8+ + 2H+; K6
(9)
Species
i
log Ki
log Ki
log Ki
log Ki
a
a
a
a
As in the case of the Cu2+ complexes of tren and of the mono-
cyclam derivative of tren,7 protonation (K5) of the tetranuclear
species takes place in the pH range of 4, thus indicating that one
side chain of the tren can be displaced from the coordination
sphere of Cu2+. The tendency to bind a fourth metal ion in the
tren unit of L1 and L2 is lower than that of L4 or L5 which both
have a 14-membered macrocyclic ring. This is due to the fact that
the 14-membered ring can encompass a metal ion like Cu2+ or
Ni2+ with a strong ligand field so that only a weak binding in the
axial position occurs. In contrast, metal ions bound by L1 and L2
have a much higher tendency to bind additional ligands since the
12-membered macrocycles do not give a ligand field as strong as
the 14-membered ones. Since the binding of the fourth metal ion
can only take place when the secondary amino groups of tren are
released from the metal ions in the macrocycles, the weaker they
are coordinated by the three metal ions in the macrocycles, the
better is the binding of the fourth metal ion. This is probably also
the reason that the [Cu3L]6+ species does not bind an additional
Cu2+.
[M3LH4]10+
[M3LH3]9+
[M3LH2]8+
[M3LH]7+
[M3L]6+
1
2
3
4
5
6
2.86(2)
3.74(1)
4.04(1)
5.06(1)
4.41(8)
>3.0
4.78(3)
4.80(5)
8.44(4)
4.17(3)
<3.0
3.56(9)
4.03(2)
5.61(5)
—
<3.0
5.82(3)
6.98(3)
8.20(4)
—
[MNi3LH]9+
[MNi3L]8+
−5.29(1)
−6.21(1)
—
—
a Fully formed at the beginning of the titration.
The pH titrations with a 3 : 1 metal to ligand stoichiometry of
ligands L1 and L2 with Cu2+ and Ni2+ could be fitted with a series of
protonated species [M3LHn] (n = 4 to 0). The log Ki values, defined
in eqns 4–7, obtained with the program TITFIT18 are collected in
Table 2.
[M3LH4]10+ ꢀ [M3LH3]9+ + H+; K1
[M3LH3]9+ ꢀ [M3LH2]8+ + H+; K2
[M3LH2]8+ ꢀ [M3LH]7+ + H+; K3
[M3LH]7+ ꢀ [M3L]6+ + H+; K4
(4)
(5)
(6)
(7)
Spectrophotometric titrations
The spectral properties of the Cu2+ and Ni2+ complexes of L3
are indicative of penta- and hexacoordination, respectively.29 The
band at 600 nm for [CuL3H]3+ and at 608 nm for [CuL3]2+ clearly
show (Table 3) that as well as the four nitrogens of the macrocycle,
a water molecule ([CuL3H]3+) or the amino group of the side chain
([CuL3]2+) are also bound. Thus, for [CuL3H]3+ we observe in
aqueous solution the same coordination geometry as in the solid
state. For [NiL3H]3+ and [NiL3]2+ we have bands (Table 3), which
are typical for hexacoordinate high spin Ni2+. So in [NiL3H]3+ we
have a N4O2 chromophore and in [NiL3]2+ a N5O chromophore.
In contrast to the ligands L4 and L5 containing 14-membered
macrocycles which are able to encompass the metal ions and thus
give square planar complexes when the side chain is protonated,
and species with penta- or hexacoordinate geometry when the
side chain is bound, the coordination geometry of the complexes
with L3 (and L1, L2) is constant. As a consequence the spectral
At higher pH values additional equilibria leading to hydroxo
species exist, but the slow equilibration prevents an accurate
evaluation of the constants. K1 is the protonation of the tertiary
nitrogen of the tren unit and the value can be compared to that of
trenH4 which has log K = 2.60.28
4+
The other deprotonation steps are probably due to the coordi-
nation of the secondary amino groups of tren to the metal ions
bound by the macrocycles as observed for the model compound
L3. An indication for this is given by the observation that the
values of K2–K4 are lower for L1, the compound with the shorter
C2 chain, than for L2 with a C3-bridge. The trinuclear Cu2+ and
Ni2+ complexes of L1 and L2 were also tested to see whether or not
they can bind an additional metal ion in the tren unit. Whereas the
species [Cu3L]6+ did not show any tendency to bind an additional
Cu2+ or Ni2+, the [Ni3L]6+ complexes were able to coordinate a Cu2+
Table 3 Spectral properties of the Ni2+ and Cu2+ complexes with L1, L2 and L3 at 25 ◦C and I = 0.5 M (KNO3), calculated from spectrophotometric
titrations
Ni2+
Cu2+
Species
kmax/nm (e/M−1 cm−1
)
Species
kmax/nm (e/M−1 cm−1
)
[NiL3H]3+
[NiL3]2+
880 (18), 575 (11), 400 (sh)
880 (18), 575 (11), 400 (sh)
880 (61), 560 (37), 400 (sh)
880 (45), 550 (32), 400 (sh)
882 (54), 570 (18), 350 (sh)
882 (43), 570 (31), 330 (sh)
870 (210), 650 (130), 590 (112), 400 (sh)
858 (221), 654 (131), 570 (98), 380 (sh)
[CuL3H]3+
[CuL3]2+
600 (269)
608 (251)
599 (1019)
604 (969)
595 (658)
602 (716)
[Ni3L1H3]9+
[Ni3L1]6+
[Cu3L1H3]9+
[Cu3L1]6+
[Ni3L2H3]9+
[Ni3L2]6+
[Cu3L2H3]9+
[Cu3L2]6+
[Ni3CuL1]8+
[Ni3CuL2]8+
4804 | Dalton Trans., 2007, 4797–4810
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changes for these complexes are small. This is the reason that
spectrophotometric titrations could not be used for the evaluation
of stability constants. However, with the known stability constant
from potentiometric titrations the spectra of the single species
could be calculated (Table 3). The spectra of the Cu2+ and Ni2+
complexes of L1 and L2 closely resemble those of the simpler
systems with L3. So we propose similar structures, with no side
chain coordination at low pH, or with coordination of the amino
group of the side chain at high pH.
In contrast to these small spectral changes, the binding of Cu2+
to [Ni3L1]6+ or [Ni3L2]6+ can be followed spectrophotometrically,
since, aside from the relatively weak band of the hexacoordinate
high spin Ni2+, the typical bands of the [Cutren]2+ chromophore
can be observed (Fig. 4).
EPR measurements
The EPR spectrum of the Cu2+ complex with L3, used as model to
understand the more complicated systems with different coordina-
tion sites for the metals, exhibits an axial structure at pH = 3.7 with
the perpendicular region overlapping with the parallel region in the
intermediate magnetic field (Fig. 5). The presence of weak peaks
in the low field part of the parallel region (marked by *) indicates
that there is a second paramagnetic species B present as a minor
component, the spectrum of which is partially superimposed on
that of the major species, A. Computer simulation procedures
allowed us to find the best parameters to fit the CW-EPR of both
paramagnetic species (Table 4). When the pH is increased to 10.3,
the EPR parameters of the species A do not change, indicating
that there is no geometry modification in the pH domain from
3.7 to 10.3. In contrast, the second paramagnetic species B is no
longer present at high pH values. The fluid solution spectra are
well resolved, the four hyperfine transition patterns are affected
by a significant mI dependence, as is typical for Cu2+ (Fig. 6).
The spectrum does not change upon increasing the pH, thus the
coordination geometry around copper is preserved. Futhermore,
the isotropic EPR parameters obtained from the simulation of
fluid solution spectra correspond to the isotropic values calculated
from parameters for species A of the frozen solution. Therefore this
species is stable and maintains its geometry under very different
experimental conditions, as previously shown for other similar
derivatives.30 As the EPR parameters of A are close to those of
the Cu2+ complex with 1,4,7,10-tetraazacyclododecane, we assume
that the geometry of the first coordination sphere around Cu2+ is
also square pyramidal but with a slight distortion, as is indicated
by the Aꢁ and gꢁ values.31 In the case of the minor species B, the
small Aꢁ values, around 120 G, are close to the ones obtained for
dimeric species where the hyperfine coupling constant is half that
of monomeric species.30
Fig. 4 Spectrophotometric pH titration of [Ni3L1]6+ (c = 1.14 × 10−3 M)
and Cu2+ (c = 1.14 × 10−3 M). Inset: Fit of the curve at k = 870 nm, ꢀ
experimental points, — calculated curve.
From such spectrophotometric titrations the spectra (Table 3)
of the heteronuclear species were determined.
The Cu2+ complex of L1 has at pH 6.6 a similar frozen solution
EPR spectrum (Fig. 7). EPR parameters obtained from the best
Fig. 5 EPR spectra of the Cu2+ complex with L3 at 123 K and pH = 3.7 (a), and pH = 10.3 (c), together with their simulations (b and d, respectively).
* indicates additional peaks of the minor species, B. (e) Zoom of the low field region of the EPR spectrum of Cu2+ complex with L3.
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Table 4 EPR parameters for Cu2+ complexes of L1, L2, and L3 in frozen (123 K) and fluid (295 K) solutions
g
A/MHz
Ligand/species
T/K
pH
3.1
3.1
10.3
10.3
6.6
11.0
11.0
3.7
3.7
6.6
6.6
5.0
5.0
8.0
5.0
gxx
gyy
gzz
giso
Axx
Ayy
Azz
Aiso/MHz
L3/A [CuL3]2+
L3/B [CuL3H]3+
L3/A [CuL3]2+
L3/A [CuL3]2+
L1/A [Cu3L1]6+
L1/A [Cu3L1]6+
L1/A [Cu3L1]6+
L2/A [Cu3L2]6+
L2/A [Cu3L2]6+
L2/A [Cu3L2]6+
L2/A [Cu3L2]6+
L1/A [Ni3CuL1]2+
L1/B [Ni3CuL1]8+
L1/[Ni3CuL1]8+
L2/[Ni3CuL2]8+
123
123
123
295
123
123
295
123
295
123
295
123
123
123
123
2.046
2.067
2.046
—
2.035
2.035
—
2.046
—
2.046
—
2.078
2.067
2.068
—
2.067
2.067
—
2.062
—
2.062
—
2.209
2.256
2.207
—
2.205
2.205
—
2.205
—
2.208
—
2.111
2.130
2.107a
2.107
2.102a
2.102a
2.100
2.104a
2.104
2.106a
2.105
2.098a
2.188a
2.098a
2.107a
34.4
28.9
34.3
—
19.9
19.9
—
43.0
—
43.0
—
40.7
28.9
34.7
—
34.7
34.7
—
51.9
—
51.9
—
550.3
372.6
546.7
—
549.3
549.3
—
552.4
—
543.9
—
208.5
143.5
205.2a
200.5
201.3 a
201.3 a
191.0
215.8a
209.1
212.9a
206.2
2.033
2.063
2.033
2.036
2.072
2.081
2.072
2.082
2.205
2.420
2.205
2.204
17.1
2.9
2.9
17.4
2.9
2.9
549.3
372.6
549.3
573.7
194.6a
126.1 a
185.0 a
223.0 a
42.7
52.5
a Calculated value.
Fig. 6 EPR spectra at 295 K of the Cu2+ complex with L3 at pH = 3.7 (a)
and pH = 10.3 (b), together with their simulation (c).
Fig. 7 EPR spectra of Cu2+ complex with L1 at 123 K and pH = 6.6 (a),
and pH = 11.0 (b), together with their simulation (c).
fit simulation (Table 4) establish that there is one mononuclear
species at pH above 6 which does not change its coordination
sphere around the copper ion. The forbidden transitions (DMS =
2) appearing at pH = 6.6 in the half-field region, are poorly defined
due to the very low intensity. It is thus not possible to estimate the
Cu–Cu distance from the ratio of the intensity of the forbidden
transition to the intensity of the allowed transition.32 However,
this observation is a qualitative indication that there are small
spin–spin interactions generated by the presence of the Cu2+ in
macrocyclic rings not spaced widely enough by the C2 chains.
Fluid solution EPR spectra do not show all four Cu2+ transi-
tions, due to a bigger dependence of the line width on mI and
rotational conditions of the complexes, but still allow accurate
isotropic EPR parameters to be obtained (Table 4). As these
spectra are identical to those calculated from the frozen solution
simulations, we consider that the paramagnetic species is very
stable and does not change its geometry either as function of
pH or temperature. In the case of L1 the geometry of the first
coordination sphere is close to that of the A species from L3.
There are smaller gyromagnetic factors, which reveal a different
spin–orbit coupling which may be due to the presence of the other
Cu2+ in the vicinity.
The frozen solution EPR spectra for the Cu2+ complex of L2 with
a C3 chain are shown in Fig. 8. As in the case of L3 there are two
paramagnetic species: one major, A, and a second one, B, present
in traces which were not taken into account in the simulation. The
EPR parameters of A at pH = 3.7 are slightly different from those
at pH = 6.6. They do not indicate another coordination geometry
around the metal ion but rather a more distorted geometry at high
pH (Table 4).
Fluid solution EPR spectra show a well resolved four line
pattern as in the case of L3, and they can be simulated with
isotropic parameters identical to those calculated from the frozen
solution spectra. This reveals that in the case of a C3-chain
too, the paramagnetic species is stable and does not depend on
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Fig. 8 EPR spectra of the Cu2+ complex with L2 at 123 K and pH = 3.7
(a), and pH = 6.0 (b), together with their simulation (c).
the temperature conditions. The absence of half-field forbidden
transitions supports the assumption that a longer spacer prevents
spin–spin interactions between the copper centres.
Because the CW-EPR spectra did not show any super-hyperfine
pattern from directly coordinated 14N nuclei, pulse-EPR measure-
ments (as Davies ENDOR and HYSCORE experiments) were
carried out for [Cu3L1], [Cu3L2] and [CuL3]. These are used to
complete the picture of the metal environment by indicating
whether the nitrogen from the amino group of the side chain is
participating as axial ligand for the copper ion.
Davies ENDOR spectra of all the samples, measured along
different field positions yielded broad features, attributed to
a hyperfine coupling with Amax = 15 MHz, arising from the
interaction with different 1H nuclei in the system. There were no
observable peaks above 21 MHz in the Davies-ENDOR spectra,
therefore we expect that the 14N contribution from the axial
nitrogen is small, if at all present is hidden under the ENDOR
lines corresponding to the 1H nuclei.
Fig. 9 HYSCORE spectra of the Cu2+ complex with L1 (A), and L2 (B),
at 20 K and pH = 6.0. The observer positions are near to gꢁ (2880 G). The
cross-peaks corresponding to 14N and 13C are labelled. The 14N cross-peaks
in the (+,+) quadrant are double quantum transitions.
measured near to the g⊥ region, and this is evidence that the
hyperfine coupling contribution along this direction is negligibly
small.
In the case of [CuL3] at low pH a similar Davies-ENDOR
spectrum was obtained. The aspect of the HYSCORE spectrum
(Fig. 10) was, for this complex, also close to those previously
observed for [Cu3L1] and [Cu3L2] complexes. But there were no
observable cross peaks arising from the 14N nuclei, indicating
therefore the absence of the interaction between the unpaired
electron and an axially situated 14N nuclei. This is in accordance
In the case of HYSCORE spectra of all complexes, we observed
1
cross peaks arising mainly from H nuclei situated in the vicin-
ity of the unpaired electron. Cross peaks arising from several
13C nuclei in the natural abundance are also observed in the
(+,+) quadrant of the HYSCORE spectra, but will not be
discussed here. In the case of [Cu3L1] and [Cu3L2], the peaks
corresponding to a weakly coupled nitrogen were observed in the
(+,+) quadrant of the HYSCORE spectra recorded near to the gꢁ
region (Fig. 9).
The single quantum peaks are not resolved for both complexes
and have the aspect of a matrix line, which indicates that one
of the hyperfine coupling values may be negative. The peaks
corresponding to the double quantum transitions were observed
as cross peaks and we used them to estimate the values of the
hyperfine coupling constants. They have been estimated from the
frequency simulation of the HYSCORE spectra (see Fig. 9). The
calculated values for both complexes are similar, |A(14N)| = [0.1,
2.6, 0.9] MHz, and indicate that they arise from the same axially
coordinated 14N nucleus. These peaks were not observed when
Fig. 10 HYSCORE spectrum for [CuL3] measured at low pH at 20 K at
observer positions near to gꢁ (3100 G). The cross-peaks corresponding to
13C nuclei are labelled. The anti diagonal line labelled 14N is drawn along
the double quantum and single quantum frequency of the 14N Larmor
frequency. Nitrogen cross peaks are absent. Features in (−,+) quadrant
arise due to imperfect p pulse.
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with the equilibrium measurements which indicate that the side
chain is protonated at low pH.
Kinetics
The kinetics of the complex formation of L1 with Cu2+ at pH 5 are
a complicated process. In a first and rapid step Cu2+ reacts with
the tren part of the molecule giving a first intermediate [CuTL]2+
(Scheme 3) with a typically broad absorption band at 850 nm. This
first step is clearly an equilibrium at pH ∼5, since the intensity of
the absorption band of [CuTL]2+ depends on the excess of Cu2+
used to study the kinetics.
In order to study the second coordination environment of the
ligands L1 and L2, based on the tren moiety, excess of Ni2+ was
used to block the macrocyclic rings and prevent Cu2+ migrating
from tren into the macrocycles. In the case of the complex with
L1, the frozen solution EPR spectrum at pH 5.0 is of very low
intensity, compared to that where only Cu2+ was used as metal
ion for coordination, and indicates the presence of three different
paramagnetic species. By analysing the parallel region of the
spectrum, one of the species, Aꢀ, is similar to the species A found
for [Cu3L1]6+, while a second one, Bꢀ, has a higher gyromagnetic
factor gꢁ than all the other species (see Fig 11c and 11d). In
the high field region (see Fig. 11a), there are peaks which are
presumed to correspond to the inverse spectrum, characteristic of
the paramagnetic species [Cutren]2+,33 but in low amounts, which
prevent us simulatating it with enough accuracy. This seems to
indicate that even when Ni2+ is present in excess, the macrocyclic
rings are still stronger complexing groups for Cu2+ rather than the
tren moiety. Therefore Cu2+ is migrates to this region of the ligands
and displaces Ni2+. By increasing the pH to 8.0, the intensity of
the EPR signal is lowered dramatically and therefore only the
paramagnetic species with Cu2+ in the macrocyclic rings can be
observed. We do not exclude the possibility of Cu2+ coordination
in the tren region at this pH, but the low intensity of the EPR
spectrum prevents us from proving it. At room temperature, the
species found at 123 K were in such low concentration that we
could not obtain any EPR signal, even after multiple acquisitions.
In this case the forbidden transitions in the half-field region
are also very low in intensity, indicating only weak spin–spin
interactions (as above for Cu3L1).
Scheme 3 Mechanism of the complexation of Cu2+ with L1. CuT and
CuC indicate that Cu2+ is bound by the tren and the macrocyclic units,
respectively.
For the equilibrium constant we have used a value K = k1/k2 =
2.5 × 105 which optimizes the fitting of the curves and is close to
the thermodynamic value KCuTren = 3.105.34 [CuTL]2+ now has two
possibilities of further reaction: either it can pick up an additional
Cu2+ in one of the macrocyclic rings to give [CuTCuCL]4+ with a
bimolecular rate constant k3, or it can translocate the Cu2+ from the
tren unit to a macrocyclic ring [CuCL]2+ (k7). Under the conditions
used (pH 5, threefold excess of Cu2+) the translocation is slower
than the bimolecular reaction to give [CuTCuCL]4+ (Fig. 12). This
can be checked by using 1 equivalent Cu2+ per ligand, so that k3
can be neglected and the translocation process k7 can be measured
directly.
Fig. 11 EPR spectrum of the complex [Ni3CuL1]8+ at 123 K and pH =
5.0 (a), together with its simulation (b), taking into account two species (c
and d, respectively).
Fig. 12 Kinetics of the complexation of Cu2+ with L1 at pH = 5.0, [L1] =
7.5 × 10−4 M, [Cu2+] = 2.25 × 10−3 M. Inset: Fit of the curve at k = 848 nm
(a) and at k = 620 nm (b).
In the case of [Ni3CuL2]8+ the frozen solution spectrum indicates
the presence of one major species, similar to species A from
[Cu3L2]6+ and only very low intensity peaks in the high-field region,
where the inverse spectrum of Cu2+ coordinating to the tren moiety
should appear.
[CuTCuCL]4+ contains one Cu2+ in the macrocyclic ring and one
Cu2+ bond to the tren unit according to its absorption spectrum
(Fig. 13) with a band at ∼600 nm and one at ∼850 nm. This 2 : 1
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then intermediate reacts with the third Cu2+ to give [CuT(CuC)2L]6+,
which now has to translocate the Cu2+ from the tren unit to
the macrocyclic ring to give [(CuC)3Lꢀ]6+. Finally the complex
[(CuC)3Lꢀ]6+ rearranges itself to the thermodynamically most stable
form [(CuC)3L]6+. If we compare the values of k1, k3, and k4 which
all describe the bimolecular reaction of Cu2+ with the ligand which
contains 0, 1, or 2 Cu2+ per ligand, a decrease from 490 M−1 s−1 to
20 M−1 s−1 to 6 M−1 s−1 is observed. The large difference between k1
and k3 or k4 is due to the fact that in the first step Cu2+ is reacting
with the tren moiety, whereas in the second and third step it
reacts with the macrocycles. The translocation reactions k5 (0.25 ×
10−3 s−1) and k7 (3.0 × 10−3 s−1) differ by a factor of 12 indicating
that when no Cu2+ is present in the macrocycles the translocation
is faster than when two of the macrocycles are already blocked
as in [CuT(CuC)2L]6+. When we compare the translocation in the
case of L1 (3.0 × 10−3 s−1) with that of the analogous compound
containing 14-membered macrocycles L4, for which 6.2 × 10−2 s−1
was obtained33 for the translocation of the first Cu2+, we see that
the process for L1 is distinctly slower than that for L4. This could
be due to the fact that in L1 only has ethylene bridges, so that a
somewhat stressed situation results when the nitrogen donors of
the tren are replaced by those of the macrocycles; whereas in L4
both ethylene and propylene bridges are present which can give a
less stressed situation via chelate ring formation, especially where
there exists a sequence in which five chelate rings alternate with
six rings.
difficult to bind a fourth metal ion, as indicated by the HYSCORE
spectra. UV-Vis spectra and EPR measurements indicate that the
metal ions have structures with equatorial coordination similar to
that observed in the model compound L3.
Acknowledgements
This work was supported by the Swiss National Science Founda-
tion (Project No. 2000–66826.01) and this is gratefully acknowl-
edged. CP and SA are thanking Prof. A. Schweiger for providing
CW and pulse EPR facilities at ETH Zurich.
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