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Cite this: Dalton Trans., 2011, 40, 9145

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C-Branched chiral (racemic) macrocyclic amino acids: structure of their
Ni(II), Zn(II) and Cu(II) complexes†
Daniel Pellico,a Mar Gómez-Gallego,*a Rosa Escudero,a Pedro Ramı́rez-López,b Montserrat Olivánc and
Miguel A. Sierra*a

Received 30th March 2011, Accepted 9th June 2011
DOI: 10.1039/c1dt10539f

A new procedure for the synthesis of macrocyclic embedded bis-a-amino acids and their use as
cation-ligands is described. These compounds are able to form stable Cu(II), Zn(II) and Ni(II) complexes
as long as they have a flexible tether between the two nitrogen atoms. For a given macrocycle, the X-ray
diffraction studies revealed diastereomerically pure complexes having different geometries depending
on the metal ion.

Introduction

Polyazamacrocycles and macrocycles containing mixed donor
atoms (i.e. N, O) 1 are well known for their ability to bind
metal ions.1,2 To broaden their chelating abilities and thence the
scope of their applications, these structures frequently incorporate
functionalized pendant arms linked to the nitrogen atoms (Fig. 1),
generally carboxylic acids or their derivatives3 (2–4), amines,4 and
more rarely phosphonic5 and sulfonyl groups.6 These structural
modifications modulate the selectivity of a given chelating cavity
from first-row transition divalent metal ions to the lanthanides.7

The versatility of these structures as metal binding agents has
been exploited in different fields ranging from antitumor agents,8

biomedical applications (among others, contrast agents and shift
reagents in magnetic resonance imaging (MRI) based techniques)9

to luminescent sensors in optical methods.7h–l,10

By contrast, the analogous C-branched polyazamacrocyclic
cavities have been hardly studied. The few structures reported
are generally azacyclophanes such as 5–7,11 analogous to con-
formationally constrained a-amino acids and of great interest
as synthetic receptors to probe the binding mode of bioactive
molecules (Fig. 2).12 However, the use of these chiral cavities to
complex metal ions has not been reported.

The search for new small molecule chelating agents is an
interesting area of research, as they constitute one of the future

aDepartamento de Quı́mica Orgánica, Facultad de Quı́mica, Universi-
dad Complutense, 28040, Madrid, Spain. E-mail: margg@quim.ucm.es,
sierraor@quim.ucm.es
bInstituto de Quı́mica Orgánica, Consejo Superior de Investigaciones
Cientı́ficas (CSIC), Juan de la Cierva 3, 28006, Madrid, Spain
cDepartamento de Quı́mica Inorgánica, Instituto de Sı́ntesis Quı́mica y
Catálisis Homogénea, Universidad de Zaragoza-CSIC, 50009, Zaragoza,
Spain
† Electronic supplementary information (ESI) available: 1H and 13C-NMR
spectra of new compounds 11–16. Crystallographic Information Files
(CIF) for compounds 8a-Ni(II), 8a-Zn(II), and 8a-Cu(II). CCDC reference
numbers 819737–819739. For ESI and crystallographic data in CIF or
other electronic format, see DOI: 10.1039/c1dt10539f

Fig. 1

promising strategies for treating diseases associated with localized
metal accumulation.13 Metals such as iron, copper, and zinc
play complicated roles in human health and disease. While all
three metals are essential nutrients utilized as various protein
cofactors, their misappropriation within cells and tissues can
lead to significant damage that has been linked to Parkinson’s,
Alzheimer’s, and other neurodegenerative diseases.13,14

Our ongoing work devoted to preparing different macro-
cyclic structures having specific properties15 by peripheral
functionalization16 of preformed macrocyclic di- and polyimines,
led us to devise the synthesis of a series of novel chiral macrocycles
8 (Fig. 2) which are constrained bis-a-aminoacids17 having the
structural features to bind metal ions (that is, a framework with
mixed N,O donor atoms) and C-linked carboxylate groups as
branched arms.18 In this work we also study their ability to form

This journal is © The Royal Society of Chemistry 2011 Dalton Trans., 2011, 40, 9145–9153 | 9145

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Fig. 2

complexes with Ni(II), Zn(II) and Cu(II), and discuss their X-ray
structures.

Results and discussion

The synthesis of the bis-a-aminoacids 8 was carried out starting
from the corresponding macrocyclic diimines 9–12 as shown in
Scheme 1. Thus, diimines 9–12 were transformed into the corre-
sponding bis-aminonitriles 13–16 by a double Strecker reaction,19

at room temperature using trimethylsilyl cyanide (TMSCN) as the
cyanide source. Compounds 13–16 were obtained in quantitative
yields directly from the reaction crude, and as diastereomeric
mixtures. In all cases their IR spectra showed weak CN stretch-
ing bands in the range 2227–2230 cm-1, characteristic of a-
aminonitriles.20 Compounds 13–16 are slightly unstable and were

used in the next step without further purification (see experimental
section for details).21 The assignment of the stereochemistry of
the meso and racemic isomers in each case, was carried out
by the study of the CH signals in the 1H-NMR spectra in the
presence of Eu(III) tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate] Eu(hfc)3. After the addition of this chiral shift
reagent, the splitting of the CH singlets at 4.84, 4.83, 5.20 and
4.91 ppm (compounds 13–16, respectively) was clearly observed,
in concordance with the expected behavior for RR/SS (racemic)
isomers. However, in all cases, the CH signals at 5.02, 5.01, 5.33 and
4.98 ppm (compounds 13–16, respectively), remained unaltered
as expected for the RS/SR (meso) form. The addition of the
lanthanide hardly affects the rest of the signals in the NMR
spectra, which points to the coordination of the Eu(III) with the
carboxylate groups outside the macrocycle.7b

Bis-aminonitriles 13–16 were hydrolyzed by refluxing in HCl
to the corresponding bis-a-aminoacids 8a–d which were ob-
tained as diastereomeric mixtures of hydrochlorides, with yields
ranging from 61–73% (Scheme 1). The stereochemistry of the
meso/racemic isomers of compounds 8a–d was again established
by means of 1H-NMR experiments in the presence of Eu(hfc)3.
In all cases, the meso/racemic isomeric ratios were identical to
those of the previous aminonitriles, indicating that there was no
epimerization of the stereogenic centers during the acid treatment.
As an example, Fig. 3 shows the Eu(hfc)3

1H-NMR experiment
with bis-a-aminoacid 8a. The addition of the chiral shift reagent
provoked the shielding of both CH signals but only the splitting
of the more deshielded CH singlet (racemic isomer).

The ability of the macrocyclic bis-a-aminoacids 8a–d to form
complexes with divalent metal cations was next addressed.
The complexes were formed by treating solutions of equimolar
amounts of the corresponding bis-aminoacid with Ni(II), Zn(II)
and Cu(II) salts, at pH 8 at room temperature. Bis-a-aminoacids
8a and 8b having flexible tethers between the amino groups,
were able to form stable complexes with all the divalent metals

Scheme 1

9146 | Dalton Trans., 2011, 40, 9145–9153 This journal is © The Royal Society of Chemistry 2011

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Fig. 3 (A) 1H-NMR (D2O, 295 K) spectrum (CH signals) of 8a. (B)
1H-NMR (D2O, 295 K) spectrum (CH signals) of 8a after the addition of
Eu(hfc)3.

tested, whereas bis-a-aminoacids 8c and 8d bearing rigid tethers,
failed. The characterization of the metal complexes was made by
ESI-MS spectra (positive mode) which showed in all cases the
corresponding [M+Na]+ and [M+H]+ peaks with the expected
isotopic distribution (see for example Fig. 4).

Further information about the structure of the metal complexes
formed was gained by X-ray diffraction analysis. Suitable crystals
were obtained by slow crystallization at room temperature from
solutions of complexes 8a-Ni(II) (MeOH/CH3CN/H2O), 8a-
Zn(II) (MeOH/H2O) and 8a-Cu(II) (MeOH/H2O). In each case
only crystals of a pure diastereomeric complex were obtained
and the analysis of their structures revealed different coordination
modes, depending on the nature of the metal. Thus, for 8a-Ni(II)
the crystals correspond to the racemic complex and the metal
complex is a distorted octahedron involving the nitrogen atoms
of the macrocyclic ring, the oxygen atoms of the carboxylates and
the oxygen atoms of the ether groups (Fig. 5). Bond distances
fall in the range 2.02–2.13 Å, typical for Ni(II) in an octahedral
environment.

An extended view of the structure of 8a-Ni(II) (Fig. 6) shows
that the molecules of this complex are associated by means
of intermolecular hydrogen bonds between the hydrogen atoms
of the NH groups and the nickel-bonded oxygen atoms of the

Fig. 5 Molecular diagram of complex 8a-Ni(II). Selected bond lengths (Å)
and angles (deg): Ni–O(1) = 2.0311(17), Ni–O(3) = 2.0376(17), Ni–O(5) =
2.1339(18), Ni–O(6) = 2.1356(18), Ni–N(1) = 2.036(2), Ni–N(2) = 2.022(2);
O(1)–Ni–O(3) = 177.19(7), N(1)–Ni–O(6) = 167.52(8), N(2)–Ni–O(5) =
165.36(8). Ellipsoids 50% probability level.

carboxylates (O(1) and O(3)) to generate infinite chains. Each of
the non-bonded oxygen atoms of the carboxylates (O(2) and O(4))
are associated by means of hydrogen bonds to two crystallization
water molecules.

In the case of 8a-Zn(II) the crystals of the meso-complex reveal
a distorted trigonal bipyramid geometry around the metal center,
with N(1) and O(3) occupying the apical positions (N(1)–Zn–
O(3) 171.96(15)), and N(2), O(1) and the water molecule (O(7))
in the equatorial plane (Fig. 7). In this case the ether oxygen
atoms of the ligand do not coordinate to the metal and the zinc
atom is placed outside the cavity formed by the macrocyclic ligand.
There are intramolecular O ◊ ◊ ◊ H bonds between both ether oxygen
atoms (O(6) and O(5)) and the hydrogen atom of one of the
NH groups (H(22)). An extended view of the structure (Fig. 8)
indicates also intermolecular interactions between the other NH-
hydrogen atom of the molecule (H(21)) and the oxygen atom O(1)
of the neighboring molecule, and between an OH-hydrogen atom
of the coordinated water molecule O(7) and the oxygen O(2) of
the neighboring molecule to generate infinite chains.

The X-ray structure of 8a-Cu(II) (Fig. 9) consists of two
Cu(II) centres bridged by two oxygen atoms of the carboxylate
groups. The dimer exhibits a (m2-oxo) Cu(1)O2Cu(1A) ring with

Fig. 4 (A) Experimental (left) and theoretical (right) isotopic distribution of [M+Na]+ of 8b-Zn(II) complex. (B) Experimental (left) and theoretical
(right) isotopic distribution of [M+Na]+ of 8b-Ni(II) complex.

This journal is © The Royal Society of Chemistry 2011 Dalton Trans., 2011, 40, 9145–9153 | 9147

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Fig. 6 Crystal packing of 8a-Ni(II) showing the H bonding pattern (blue
atoms, N; red, O; green, Ni). Hydrogen atoms not involved in hydrogen
bonding as well as water crystallization molecules not involved in hydrogen
bonding with the complex have been omitted for clarity.

Fig. 7 Molecular diagram of complex 8a-Zn(II). Selected bond lengths
(Å) and angles (deg): Zn–O(1) = 2.003(3), Zn–O(3) = 2.018(3), Zn–O(7) =
2.018(3), Zn–N(1) = 2.100(4), Zn–N(2) = 2.072(4); N(1)–Zn–O(3) =
171.96(15), O(1)–Zn–N(2) = 129.61(15), N(2)–Zn–O(7) = 116.00(16),
O(1)–Zn–O(7) = 114.39(14), N(1)–Zn–O(1) = 80.41(15), N(1)–Zn–O(7) =
96.09(15), N(1)–Zn–N(2) = 95.00(15), O(3)–Zn–O(1) = 95.55(14),
O(3)–Zn–O(7) = 91.91(15), O(3)–Zn–N(2) = 82.17(14) .Ellipsoids 50%
probability level.

a Cu ◊ ◊ ◊ Cu separation of 3.4959(18) Å and bridging angles of
81.4(2)◦ (O(3)–Cu–O(3A)) and 98.6(2)◦ (Cu(1)–O(3)–Cu(1A)).
The geometry around each copper center can be described as a
distorted octahedron. The equatorial positions are occupied by the
nitrogen atoms N(1) and N(2) (Cu(1)–N(1) 1.998(6), Cu(1)–N(2)
1.974(6) Å) and by the carboxylate oxygen atoms O(3) and O(4)
(Cu(1)–O(3) 1.947(5), Cu(1)–O(4) 1.919(6) Å). The axial positions
are occupied by the ether atom O(1) and a bridging carboxylate
oxygen of the neighbouring ligand bonded to Cu(1A) (Cu(1)–

Fig. 8 Crystal packing of 8a-Zn(II) showing the H bonding pattern (blue
atoms, N; red, O; purple, Zn). Hydrogen atoms not involved in hydrogen
bonding as well as solvent crystallization molecules have been omitted for
clarity.

Fig. 9 Molecular diagram of complex 8a-Cu(II). Selected bond lengths
(Å) and angles (deg): Cu(1)–O(3) = 1.947(5), Cu(1)–O(4) = 1.919(6),
Cu(1)–N(1) = 1.998(6), Cu(1)–N(2) = 1.974(6), Cu(1)–O(3A) = 2.627(5),
Cu(1)–O(1) = 2.744(7), Cu(1) ◊ ◊ ◊ Cu(1A) = 3.4959(18); O(3)–Cu(1)–N(1) =
172.3(2), O(4)–Cu(1)–N(2) = 176.6(2), O(4)–Cu(1)–N(1) = 85.1(2),
N(1)–Cu(1)–N(2) = 98.1(2), O(1)–Cu(1)–O(3A) = 153.3(2). Ellipsoids 50%
probability level.

O(1) = 2.744(7), Cu(1)–O(3A) = 2.627(5) Å). The neighbouring
ligands are connected by means of hydrogen bonding between
the hydrogen atom of N(1) and the non-coordinating carboxylate

9148 | Dalton Trans., 2011, 40, 9145–9153 This journal is © The Royal Society of Chemistry 2011

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oxygen atom O(5) and between the hydrogen atom of N(2) and the
carboxylate oxygen atom O(4). An extended view of the structure
(Fig. 10) also indicates intermolecular interactions between the
hydrogen atom of N(1) and the non-coordinating carboxylate
oxygen atom O(5) of the neighbouring dimer, generating infinite
chains.22

Fig. 10 Crystal packing of 8a-Cu(II) showing the H bonding pattern (blue
atoms, N; red, O; orange, Cu). Hydrogen atoms not involved in hydrogen
bonding as well as solvent crystallization molecules have been omitted for
clarity.

The structures of the metal complexes 8a-Ni(II), 8a-Zn(II) and
8a-Cu(II) are a good example of how a chiral macrocycle can
modulate its binding properties depending not just on the size of
the cavity, or the number and type of the donor atoms, but also
on the geometry imposed by their stereogenic centers. Thus, in the
octahedral racemic-8a-Ni(II) all N,O donor atoms are involved in
a hexacoordinate complex, placing the metal inside the cavity. By
contrast, the meso-complexes 8a-Zn(II) and 8a-Cu(II), having the
same cavity size and donor atoms, show arrangements that place
the metal outside the macrocycle. Examples of both, coordination
and non-coordination of the ether oxygen atoms with the metal,
have been reported for Ni(II) complexes derived from N-branched
(N-CH2CH2OH and N-CH2CONH2) macrocycles23 having size
cavities and N,O mixed donor atoms as in 8a.24 The formation
of different diastereomeric complexes depending on the metal ion
could constitute an a la carte method for the separation of the
isomeric cavities 8. To test this point, crystals of the 8a-Cu(II)
complex were treated with KOH (20% w/w in water) and after
acidulation and filtration of the salts formed, pure macrocycle
meso-8a could be obtained (the 1H-NMR spectrum showed the
characteristic singlet at 5.42 ppm for this isomer).

Conclusions

An efficient approach for the synthesis of C-branched macro-
cycles with (N,O) mixed donor atoms is described. Starting
from macrocyclic diimines and by means of a Strecker reaction
and subsequent hydrolysis, macrocyclic bis-a-aminoacids 8 were
prepared in good yields. These new compounds are small chiral
(racemic) molecules analogous to constrained a-aminoacids and
have shown their ability to form complexes with Cu(II), Zn(II) and
Ni(II). The structures of the metal complexes racemic-8a-Ni(II),

meso-8a-Zn(II) and meso-8a-Cu(II) are a good example of how
a chiral macrocycle can modulate its metal binding properties
depending not just on the size of the cavity, or the number and
type of the donor atoms, but also on the geometry imposed by
their stereogenic centers, leading to different diastereomerically
pure complexes. As far as we are aware, these are the first metal
complexes derived from C-branched polyazamacrocyclic cavities
reported in the literature.

Experimental

General procedures

Diimines 9 and 10 were prepared following the previously reported
procedures.25 1H NMR and 13C NMR spectra were recorded at
22 ◦C on Bruker Avance 300 (300.1 and 75.4 MHz) or Bruker 200-
AC (200.1 and 50 MHz) spectrometers. Chemical shifts are given
in ppm relative to CDCl3 (1H, 7.27 ppm) and CDCl3 (13C, 77.0
ppm); D2O (1H, 4.60 ppm), and D2O/Na2CO3 (13C, 165.0 ppm).
IR spectra were taken on a Bruker Tensor 27 (MIR 8000–400 cm-1)
spectrometer. Mass spectra were recorded on a QSTAR pulsar I,
(hybrid analyzed QTOF, applied biosystems) (ESI), or a MAT 95
XP ThermoFinnigan (FAB) apparatus. CH2Cl2was distilled from
calcium hydride and THF from sodium-benzophenone. Flame-
dried glassware and standard Schlenk techniques were used for
moisture sensitive reactions. All commercially available organic
reagents were used without further purification.

Caution: HCN is produced by reaction of trimethylsilyl cyanide
(TMSCN) with acid, water or protic solvents. All reactions using
this reagent should be carried out using the adequate precautions in
well ventilated hoods.

Diimine 11. Was obtained as yellow oil (1.05 g, 90%) by reflux-
ing 1,3-bis(2-formylphenyl)-1,3-dioxapropane (1.0 g, 3.7 mmol)25

and (0.3 g, 3.7 mmol) 1,4-diamine-2-butyne in 500 cm3 MeOH for
24 h. 1H NMR (300 MHz, CDCl3) d 9.22 (s, 2H, CH N), 7.92
(dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 2H, ArH), 7.42–7.36 (m, 2H, ArH),
7.07–6.96 (m, 4H, ArH), 4.69 (s, 4H, CH2–N), 4.24 (t, J = 5.9 Hz,
4H, CH2O), 2.36 (q, J = 5.9 Hz, 2H, CH2). 13C-NMR (50 MHz,
CDCl3) d 158.2 (C N), 158.0, 131.9, 127.5, 125.8, 121.7, 114.0
(ArC), 82.8 (C), 67.3 (CH2O), 47.3 (CH2N), 28.5 (CH2). IR (Film)
nmax 3070, 2891, 2217, 1640, 1597, 1293, 1240, 1108, 1058, 754
cm-1. ESI-MS: 333.1 [M+H]+.

Diimine 12. Was obtained as pale yellow oil (1.27 g,
93%) by refluxing 1,2-bis(2¢-formylphenyl)-1,3-dioxaethane (1.0 g,
3.56 mmol)25 and a,a¢-diamine-m-xylene (0.48 g, 3.56 mmol) in
500 cm3 MeOH for 24 h. 1H NMR (300 MHz, CDCl3) d 8.76
(s, 2H, CH N), 7.84 (d, J = 7.6 Hz, 2H, ArH), 7.36–7.28 (m,
2H, ArH), 7.20 (m, 4H, ArH) 7.06–6.95 (m, 4H, ArH), 4.67 (s,
4H, CH2O), 4.34 (s, 4H, CH2–N). 13C NMR (50 MHz, CDCl3)
d 158.8 (C N), 157.5, 138.1, 131.6, 128.5, 128.1, 127.9, 127.6,
125.2, 121.1, 110.9 (ArC), 65.8 (CH2O), 64.3 (CH2N). IR (Film)
nmax 3018, 2935, 1634, 1598, 1485, 1450, 1290, 1242, 1111, 1062,
751 cm-1.

General procedure for the synthesis of bis-aminonitriles 13–16

To a solution of the corresponding diimine in anhydrous THF,
under an argon atmosphere and at 0 ◦C, TMSCN was added in
a 1 : 3 molar ratio. The reaction mixture was stirred at 0 ◦C for

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30 min, then at room temperature for 20 h, quenched at 0 ◦C
with NH4Cl (10 cm3, sat. soln.) and extracted with CH2Cl2 (2 ¥
100 cm3). The combined organic extracts were washed with water,
brine and dried over MgSO4. The solution was filtered and the
solvent was removed under vacuum. Bis-aminonitriles 13–16 were
obtained in nearly quantitative yields as unstable oils and were
used in the following step without further purification.

Bis-aminonitrile 13. From 0.64 g (2.1 mmol) of diimine 9 and
0.8 cm3 (6.3 mmol) TMSCN, bis-aminonitrile 13 was obtained
in quantitative yield (0.75 g) as pale yellow oil and as a 1 : 2
(meso/racemic) diastereomeric mixture. 1H NMR (200 MHz,
CDCl3) d 7.53–7.34 (m, 4H, ArH), 7.06–6.85 (m, 4H, ArH), 5.02 (s,
0.7H, CH, meso), 4.84 (s, 1.3H, CH, racemic), 4.44 (s, 4H, CH2O),
3.01–2.90 (m, 2H, CH2N), 2.76–2.65 (m, 2H, CH2N), 1.89–1.79
(m, 2H, CH2).13C NMR (75 MHz, CDCl3) d 155.9, 155.4, 130.7,
130.5, 129.5, 129.1, 122.9, 122.8, 121.9 (ArC), 118.6, 118.7 (CN),
111.1, 110.0 (ArC), 65.9, 65.5 (CH2O), 51.9, 51.1 (CH2N), 47.5,
46.1 (CH), 25.5, 25.0 (CH2). IR (KBr) nmax 3309, 3018, 2929, 2229
(w), 1597, 1494, 1453, 1249, 1113, 1060, 753 cm-1.

Bis-aminonitrile 14. From 1.0 g (3.1 mmol) of diimine 10 and
1.25 cm3 (9.3 mmol) TMSCN, bis-aminonitrile 14 was obtained
in quantitative yield (1.16 g) as pale yellow oil and as a 1 : 1
(meso/racemic) diastereomeric mixture. 1H NMR (200 MHz,
CDCl3) d 7.48–7.26 (m, 4H, ArH), 7.06–6.86 (m, 4H, ArH), 5.01
(s, 1H, CH meso), 4.83 (s, 1H, CH racemic), 4.42–4.28 (m, 4H,
CH2O), 2.94–2.67 (m, 4H, CH2N), 2.35–2.28 (m, 2H, CH2), 1.76–
1.65 (m, 2H, CH2). 13C NMR (50 MHz, CDCl3) d 156.3, 156.2,
130.7, 130.6, 129.4, 128.9, 124.8, 124.2, 121.7, 121.4, 121.1 (ArC),
119.1, 118.9 (CN), 114.5, 114.1 (ArC), 66.7, 65.9 (CH2O), 51.2,
49.9 (CH), 46.2, 46.1 (CH2N), 29.8, 29.6, 28.3 (CH2). IR (KBr)
nmax 3310, 3018, 2930, 2230 (w), 1597, 1495, 1453, 1371, 1249,
1110, 1060, 938, 754 cm-1.

Bis-aminonitrile 15. From 1.2 g (3.1 mmol) of diimine 11 and
1.25 cm3 (9.3 mmol) TMSCN, bis-aminonitrile 15 was obtained
in quantitative yield (1.19 g) as pale yellow oil and as a 1 : 1
(meso/racemic) diastereomeric mixture. 1H NMR (300 MHz,
CDCl3) d 7.58–7.46 (m, 1H, ArH), 7.40–7.33 (m, 3H, ArH),
7.08–6.95 (m, 4H, ArH), 5.33 (s, 1H, CH meso), 5.20 (s, 1H, CH
racemic), 4.34–4.26 (m, 4H, CH2O), 3.64 (s, 2H, CH2–N), 3.59 (s,
2H, CH2N), 2.43–2.31 (m, 2H, CH2).13C NMR (75 MHz, CDCl3) d
155.7, 155.6, 130.8, 130.7, 130.5, 129.1, 128.8, 124.8, 123.6, 121.7,
121.6 (ArC), 118.6, 118.5 (CN), 113.1, 113.0 (ArC), 80.8, 80.7 (C),
65.1, 65.0 (CH2O), 48.5, 47.9 (CH), 36.7, 36.6 (CH2N), 29.1, 29.0
(CH2). IR (KBr) nmax 3329, 3017, 2931, 2226 (w), 1599, 1492, 1451,
1245, 1114, 1061, 751 cm-1.

Bis-aminonitrile 16. From 0.8 g (2.5 mmol) of diimine 12 and
0.92 cm3 (7.5 mmol) TMSCN, bis-aminonitrile 16 was obtained
in quantitative yield (1.05 g) as pale yellow oil and as a 1 : 1
(meso/racemic) diastereomeric mixture. 1H NMR (300 MHz,
CDCl3) d 7.54–7.47 (m, 2H, ArH), 7.40–7.21 (m, 6H, ArH), 7.08–
7.00 (m, 2H, ArH), 6.95–6.89 (m, 2H, ArH), 4.98 (s, 1H, CH meso),
4.91 (s, 1H, CH racemic), 4.43–4.35 (m, 4H, CH2–O), 4.07–3.85
(m, 4H, CH2–N). 13C NMR (75 MHz, CDCl3) d 155.5, 155.3,
138.3, 138.2, 130.4, 130.3, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1,
127.2, 123.2, 123.0, 121.4 (ArC), 118.9, 118.8 (CN), 67.8, 67.7
(CH2O), 51.0, 51.8 (CH2N), 47.8, 47.5 (CH). IR (KBr) nmax 3315,

3020, 2936, 2229 (w), 2217, 1598, 1495, 1450, 1243, 1110, 1058,
751 cm-1.

General procedure for the synthesis of bis-aminoacids 8a–d

Concentrated aqueous HCl (12 M) (15–20 cm3) was added over
the freshly prepared bis-aminonitrile. The mixture was heated at
50–60 ◦C for 2 h and then water (20 cm3) was added and the
resultant mixture was refluxed for 4 h. The solution was filtered and
the solvent removed under reduced pressure. The solid obtained
was washed with acetone and dried. Bis-aminoacids 8a–d were
obtained as hydrochlorides, and as a mixture of meso/racemic
isomers.

Bis-a-aminoacid 8a. Following the general procedure, 635 mg
(65% from imine 9) bis-a-aminoacid 8a was obtained as a pale
pink solid and as a 1 : 2 (meso/racemic) diastereomeric mixture.
1H NMR (200 MHz, D2O) d 7.57–7.50 (m, 2H, ArH), 7.38–
7.33 (m, 2H, ArH), 7.23–7.08 (m, 4H, ArH), 5.48 (s, 1.3H, CH,
racemic), 5.42 (s, 0.7H, CH, meso), 4.65–4.50 (m, 4H, CH2O),
3.16–2.87 (m, 4H, CH2N), 2.61–2.43 (m, 1H, CH2), 2.20–1.98 (m,
1H, CH2). 13C NMR (75 MHz, D2O/Na2CO3) d 180.4, 180.3
(C O), 161.4, 161.0, 135.9, 135.8, 135.4, 135.2, 128.0, 127.9,
126.4, 126.3, 117.1, 117,0 (ArC), 71.8, 71.4 (CH2O), 66.2, 66.0
(CH), 50.0, 49.9 (CH2N), 29.3, 29.2 (CH2). IR (KBr) nmax 3410,
3126, 2936, 1734, 1632, 1495, 1452, 1403, 1330, 1252, 1117, 766
cm-1. ESI-MS: 401.3 [M+H]+; HRMS (ESI): calc for C21H24N2O6:
400.1634; found 400.1631.

Bis-a-aminoacid 8b. Following the general procedure, 1.1 g
(73% from imine 10) bis-a-aminoacid 8b was obtained as a pale
pink solid and as a 1 : 1 (meso/racemic) diastereomeric mixture.
1H NMR (200 MHz, D2O) d 7.52–7.05 (m, 8H, ArH), 5.32 (s, 1H,
CH, racemic), 5.29 (s, 1H, CH, meso), 4.40–4.05 (m, 4H, CH2O),
3.07–2.50 (m, 4H, CH2N), 2.20–1.60 (m, 4H, CH2). 13C NMR
(75 MHz, D2O/Na2CO3) d 179.4, 179.2 (C O), 161.8, 161.5,
136.2, 136.0, 135.7, 135.3, 128.8, 127.8, 127.1, 126.4, 119.0, 118,3
(ArC), 72.2, 69.8 (CH2O), 65.8, 65.6 (CH), 51.6, 48.9 (CH2N),
33.8, 32.6, 29.3, 29.2 (CH2). IR (KBr) nmax 3265, 2883, 1753, 1635,
1598, 1560, 1485, 1240, 1110, 1031 cm-1. ESI-MS: 415.2 [M+H]+;
HRMS (ESI): calc for C22H26N2O6: 414.1791; found 414.1784.

Bis-a-aminoacid 8c. Following the general procedure, 1.18 g
(66% from imine 11) bis-a-aminoacid 8c was obtained as a pale
pink solid and as a 1 : 1 (meso/racemic) diastereomeric mixture.
1H NMR (300 MHz, D2O) d 7.39–6.88 (m, 8H, ArH), 5.37 (s, 1H,
CH, racemic), 5.27 (s, 1H, CH, meso), 4.29–4.08 (m, 4H, CH2O),
3.75 (s, 2H, CH2N), 3.74 (s, 2H, CH2N), 2.19–2.08 (m, 2H, CH2).
13C NMR (125 MHz, D2O/Acetone d6) d 170.4, 170.2 (C O),
157.1, 133.1, 132.9, 130.1, 129.4, 123.0, 122.9, 119.1, 114.8, 113,9
(ArC), 79.0, 78.8 (C), 67.5, 65.7 (CH2O), 57.8, 57.3 (CH), 35.5,
35.4 (CH2N), 29.4, 28.5 (CH2). IR (KBr) nmax 3387, 2944, 2803,
1746, 1652, 1598, 1559, 1494, 1248, 1100, 1049 cm-1. ESI-MS:
425.1 [M+H]+; HRMS (ESI): calc for C23H25ClN2O6:460.1401;
found 460.1414.

Bis-a-aminoacid 8d. Following the general procedure, 700 mg
(61% from imine 12) bis-a-aminoacid 8d was obtained as a pale
yellow solid and as a 1 : 1 (meso/racemic) diastereomeric mixture.
1H NMR (300 MHz, D2O) d 784 (s, 1H, ArH), 7.56–7.37 (m, 6H,
ArH), 7.23–7.10 (m, 5H, ArH), 5.43 (s, 1H, CH, racemic), 5.31

9150 | Dalton Trans., 2011, 40, 9145–9153 This journal is © The Royal Society of Chemistry 2011

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(s, 1H, CH, meso), 4.44–4.14 (m, 8H, CH2O + CH2N). 13C NMR
(75 MHz, D2O/Na2CO3) d 179.5 (C O), 159.5, 159.3, 139.0,
138.8, 133.3, 132.8, 132.7, 132.4, 132.1, 128.9, 128.3, 125.2, 124.8,
117.1, 116.0 (ArC), 71.2, 70.9 (CH2O), 63.2, 63.1 (CH), 52.9, 52.7
(CH2N). IR (KBr) nmax 3392, 2929, 2813, 1743, 1652, 1558, 1494,
1251, 1112, 1049 cm-1. ESI-MS: 463.1 [M+H]+. HRMS (ESI): calc
for C26H26N2O6 ([M+H]+): 462.1791; found 462.1790.

General procedure for the synthesis of metal complexes

A solution of the corresponding bis-aminoacid hydrochloride 8a–d
in water was adjusted to pH 8.5 with 10% NaOH. Then, a solution
of the corresponding metallic salt in 2–3 cm3 of water was added,
slowly, dropwise, maintaining the pH 8.5 by successive additions
of 5% NaOH and 5% HCl. The molar ratio aminoacid/metal salt
was 1 : 1. After the addition, the solution was adjusted to pH 7 and
the mixture was kept in the refrigerator overnight. The solution
was filtered (0.45 mm membrane) and the solvent was removed
under vacuum, to yield the metal complexes, which were analyzed
by ESI-MS or FABMS.

Cu(II)-8a. Following the general procedure, from bis-a-
aminoacid 8a (0.41 mmol, 200 mg) and CuCl2·2H2O (0.41 mmol,
68 mg). The Cu(II) complex was obtained as a dark blue solid
(145 mg, 75%). ESI-MS: 484.0 [M+Na]+, 461.9 [M+H].+ IR
(KBr) nmax 3405, 3215, 2951, 1617, 1601, 1492, 1384, 1245, 1110,
834 cm-1. HRMS (ESI): calc for C21H22N2O6Cu: 461.0774; found
461.0785.

Cu(II)-8b. Following the general procedure, from bis-a-
aminoacid 8b (0.42 mmol, 200 mg) and CuCl2·2H2O (0.42 mmol,
70 mg). The Cu(II) complex was obtained as a dark blue solid
(140 mg, 72%). ESI-MS: 498.0 [M+Na]+, 476.0 [M+H]+. IR (KBr)
nmax 3415, 3210, 2921, 1618, 1603, 1494, 1384, 1244, 1111, 833 cm-1.
HRMS (ESI): calc for C22H24N2O6Cu: 475.0930; found 475.0942.

Zn(II)-8a. Following the general procedure, from bis-a-
aminoacid 8a (0.41 mmol, 200 mg) and Zn(NO3)2·6H2O
(0.41 mmol, 120 mg). The Zn(II) complex was obtained as a pale
yellow solid (123 mg, 65%). 1H NMR (700 MHz, D2O/MeOD)
d 7.59-7-38 (m, 4H, ArH), 7.30-7.07 (m, 4H, ArH), 4.70-4.44 (m,
4H, CH2O), 3.24-3.03 (m, 2H, CH2N), 3.02-2.90 (m, 2H, CH2N),
2.73-2.64 (m, 2 H, CH2). 13C NMR (176 MHz, D2O/MeOD)
d 181.3, 179.6 (C=O), 158.6, 156.3, 136.6, 133.4, 132.3, 131.2,
128.6, 125.5, 123.3, 122.7, 114.5, 114.0 (ArC), 70.0, 68.9 (CH2O),
66.0, 63.5 (CH), 48.6, 45.8 (CH2N), 28.2 (CH2). FABMS: 482.5
[M+H2O+H]+. IR (KBr) nmax 3446, 3133, 2935, 1643, 1609, 1495,
1384, 1248, 1118, 835 cm-1. HRMS (ESI): calc for C21H22N2O6Zn:
462.0769; found 462.0761.

Zn(II)-8b. Following the general procedure, from bis-a-
aminoacid 8b (0.42 mmol, 200 mg) and Zn(NO3)2·6H2O
(0.42 mmol, 124 mg). The Zn(II) complex was obtained as a pale
yellow solid (140 mg, 70%). 1H NMR (700 MHz, D2O/MeOD) d
7.53-6.98 (m, 8H, ArH), 4.54-4.45 (m, 1H, CH2O), 4.44-4.31 (m,
2H, CH2O), 4.28-4.19 (m, 1H, CH2O) 3.13-2.64 (m, 4H, CH2N),
2.54-2.36 (m, 2H, CH2), 2.14-2.02 (m, 2 H, CH2). 13C NMR
(176 MHz, D2O/MeOD) d 179.7, 178.4 (C=O), 158.2, 155.3, 134.9,
131.8, 130.8, 129.7, 126.0, 122.9, 120.5, 119.1, 112.9, 111.6 (ArC),
74.1, 67.9 (CH2O), 64.7, 61.6 (CH), 48.3, 44.8 (CH2N), 28.8, 26.3
(CH2). ESI-MS: 499.1 [M+Na]+, 477.1 [M+H]+. IR (KBr) nmax

3441, 3140, 2925, 2853, 1632, 1601, 1493, 1384, 1250, 1111, 835,
760 cm-1. HRMS (ESI): calc for C22H24N2O6Zn: 476.0926; found
476.0927.

Ni(II)-8a. Following the general procedure, from bis-a-
aminoacid 8a (0.41 mmol, 200 mg) and Ni(NO3)2·6H2O
(0.41 mmol, 118 mg). The Ni(II) complex was obtained as a green
solid (120 mg, 63%). ESI-MS: 479.2 [M+Na]+, 457.3 [M+H]+. IR
(KBr) nmax 3390, 3175, 2935, 1631, 1602, 1494, 1384, 1249, 1111,
834, 757 cm-1. HRMS (ESI): calc for C21H22N2O6Ni: 456.0831;
found 456.0858.

Ni(II)-8b. Following the general procedure, from bis-a-
aminoacid 8b (0.42 mmol, 200 mg) and Ni(NO3)2·6H2O
(0.42 mmol, 121 mg). The Ni(II) complex was obtained as a green
solid (115mg, 60%). ESI-MS: 493.1 [M+Na]+, 471.1 [M+H]+. IR
(KBr) nmax 3386, 3187, 1633, 1601, 1492, 1384, 1246, 1111, 1052,
834, 757 cm-1. C22H24N2O6Ni: 470.0988; found 470.1013

X-Ray data collection and structure refinement of complexes
8a-Ni(II), 8a-Zn(II) and 8a-Cu(II)

Crystals suitable for the X-ray diffraction were obtained by crys-
tallization in MeOH/CH3CN/H2O (8a-Ni(II)) and MeOH/H2O
(8a-Zn(II) and 8a-Cu(II)). X-Ray data were collected on a Bruker
Smart APEX CCD diffractometer equipped with a normal focus,
2.4 kW sealed tube source (Mo radiation, l = 0.71073 Å) operating
at 50 kV and 30 mA. Data were collected over the complete sphere
by a combination of four sets. Each frame exposure time was
10 s (8a-Ni(II), 8a-Cu(II)) or 30 s (8a-Zn(II)) covering 0.3◦ in w.
Data were corrected for absorption by using a multiscan method
applied with the SADABS program.26 The structures were solved
by the Patterson method. Refinement, by full-matrix least squares
on F 2 with SHELXL97,27 was similar for all complexes, including
isotropic and subsequently anisotropic displacement parameters.
The hydrogen atoms were observed or calculated and refined freely
or using a restricted riding model. A methylene group (C10) of 8a-
Ni(II) was found to be disordered and was refined with an isotropic
model in two positions (0.5/0.5). For 8a-Ni(II) seven molecules
of water were observed in the asymmetric unit as crystallization
solvent. For 8a-Zn(II), 2.5 (water) and 0.5 (ethanol) molecules were
observed in the asymmetric unit as crystallization solvents. For 8a-
Cu(II) three molecules of water were observed in the asymmetric
unit as crystallization solvent. All the highest electronic residuals
were observed in the close proximity of the metal centers and make
no chemical sense.

Crystal data for 8a-Ni(II): C21H22N2NiO6·7(H2O), MW 583.23,
blue, prism (0.12 ¥ 0.10 ¥ 0.08), monoclinic, space group P21/n,
a: 10.5486(10) Å, b: 16.1100(15) Å, c: 15.8867(15) Å, a: 90.00◦, b:
108.0310(10)◦, g : 90.00◦, V = 2567.2(4) Å3, Z = 4, Dcalc: 1.509 g
cm-3, F(000): 1232, T = 173(2) K, m = 0.825 mm-1. 27 115 measured
reflections (2q: 3–57◦, w scans 0.3◦), 6253 unique (Rint = 0.0933);
min./max. transm. factors 0.766/0.940. Final agreement factors
were R1 = 0.0429 (3550 observed reflections, I > 2s(I)) and wR2 =
0.0958; data/restraints/parameters 6253/7/376; GoF = 0.892.
Largest peak and hole 0.494 and -0.412 e Å-3.

Crystal data for 8a-Zn(II): C21H24N2O7Zn·0.5(C2H6O)·
2.5(H2O), MW 549.87, colorless, needle(0.20 ¥ 0.06 ¥ 0.05),
monoclinic, space group P21, a: 11.7777(11) Å, b: 7.4694(7)
Å, c: 14.6265(13) Å, a: 90.00◦, b: 107.0520(10)◦, g : 90.00◦,

This journal is © The Royal Society of Chemistry 2011 Dalton Trans., 2011, 40, 9145–9153 | 9151

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V = 1230.2(2) Å3, Z = 2, Dcalc: 1.484 g cm-3, F(000): 576, T =
173(2) K, m = 1.056 mm-1. 11 233 measured reflections (2q:
3–58◦, w scans 0.3◦), 5872 unique (Rint = 0.0747); min./max.
transm. factors 0.857/0.925. Final agreement factors were R1 =
0.0508 (4290 observed reflections, I > 2s(I)) and wR2 = 0.1263;
data/restraints/parameters 5872/9/328; GoF = 0.963. Largest
peak and hole 1.165 and -0.522 e Å-3.

Crystal data for 8a-Cu(II): C42H44Cu2N4O12·3H2O, MW 977.94,
blue, prism (0.25 ¥ 0.12 ¥ 0.12), monoclinic, space group C2/c,
a: 13.4667(13) Å, b: 21.127(2) Å, c: 16.2489(17) Å, a: 90.00◦,
b: 92.054(2)◦, g : 90.00◦, V = 4620.1(8) Å3, Z = 4, Dcalc: 1.466
g cm-3, F(000): 2032, T = 296(2) K, m = 0.990 mm-1. 18 880
measured reflections (2q: 3–52◦, w scans 0.3◦), 4511 unique (Rint =
0.1579); min./max. transm. factors 0.850/1.0. Final agreement
factors were R1 = 0.0739 (2130 observed reflections, I > 2s(I)) and
wR2 = 0.2682; data/restraints/parameters 4511/0/285; GoF =
1.034. Largest peak and hole 1.567 and -0.382 e Å-3.

Acknowledgements

Support for this work under grants CTQ-2010-20714-C02-
01/BQU to MAS, CTQ2008-00810 to MO and Consolider
Ingenio 2010 CSD2007-00006 from the MICINN (Spain) and
P2009/PPQ1634-AVANCAT from the Comunidad de Madrid
(CAM) is gratefully acknowledged. PRL thanks the CSIC for a
JAE post-doctoral grant. We would also like to thank Prof. Ángel
Gutiérrez Alonso for fruitful discussions.

Notes and references
1 Reviews: (a) P. A. Vigato, S. Tamburini and L. Bertolo, Coord. Chem.

Rev., 2007, 251, 1311; (b) J. P. Danks, N. R. Champness and M.
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P. Paoletti and P. Paoli, Coord. Chem. Rev., 1992, 120, 51; (d) R.
Hancock and A. E. Martell, Chem. Rev., 1989, 89, 1875. Some recent
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Biagini, A. J. Blake, C. Caltagirone, F. Demartin, G. De Filippo, F. A.
Devillanova, A. Garau, K. Gloe, F. Isaia, V. Lippolis, B. Valtancoli
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D. Lampeka, P. Lightfoot and H. Pritzkow, Dalton Trans., 2007,
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C. Giorgi, P. Paoletti, R. Pardini, M. R. Tinè and B. Valtancoli, Dalton
Trans., 2004, 463; (h) J. D. Lewis and J. N. Moore, Dalton Trans., 2004,
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A. Garau, F. Isaia, V. Lippolis, P. Mariani, U. Papke, L. Tei and G.
Verani, Dalton Trans., 2003, 901; (j) A. Bencini, E. Berni, A Bianchi, C.
Giorgi, B. Valtancoli, D. K. Chand and H. J. Schneider, Dalton Trans.,
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Chem.–Eur. J., 2003, 9, 800.

2 For the use of these structures in building supramolecular networks
see: (a) M. P. Suh, Y. E. Cheon and Y. E. Lee, Coord. Chem. Rev.,
2008, 252, 1007; (b) S. P. Gavrish, Y. D. Lampeka, H. Pritzkow and P.
Lightfoot, Dalton Trans., 2010, 39, 7706. For a recent example of the
use of these structures as enzyme mimics see: (c) W. C. Ellis, C. T. Tran,
M. A. Denardo, A. Fischer, A. D. Ryabov and T. J. Collins, J. Am.
Chem. Soc., 2009, 131, 18052 and references therein.

3 (a) J. Costamagna, G. Ferraudi, B. Matsuhiro, M. Campos-Vallette, J.
Canales, M. Villagrán, J. Vargas and M. J. Aguirre, Coord. Chem. Rev.,
2000, 196, 125; (b) M. Meyer, V. Dahaoui-Gindrey, C. Lecomte and
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A. J. Leong, L. F. Lindoy, P. Hendry, S. V. Smith and D. Yellowlees, J.
Coord. Chem., 1988, 19, 189.

4 See for example: (a) A. Rastogi and R. Nayan, J. Coord. Chem., 2009,
62, 3366; (b) C. Anda, A. Bencini, E. Berni, S. Ciattini, F. Chuburu, A.
Danesi, C. Giorgi, H. Handel, M. Le Baccon, P. Paoletti, R. Tripier,
V. Turcry and B. Valtancoli, Eur. J. Inorg. Chem., 2005, (11), 2044;
(c) M. C. Aragoni, M. Arca, A. Bencini, A. J. Blake, C. Caltagirone,
A. Decortes, F. Demartin, F. A. Devillanova, E. Faggi, L. S. Dolci, A.
Garau, F. Isaia, V. Lippolis, L. Prodi, C. Wilson, B. Valtancoli and N.
Zaccheroni, Dalton Trans., 2005, 2994; (d) M. P. Clares, J. Aguilar, R.
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J. Blake, J. P. Danks, W-S. Li, V. Lippolis and M. Schröder, J. Chem.
Soc., Dalton Trans., 2000, 3034; (g) L. Tei, A. J. Blake, A. Bencini, B.
Valtancoli, C. Wilson and M. Schröder, J. Chem. Soc., Dalton Trans.,
2000, 4122; (h) J. C. Tao, Y. J. Wu and J. Y. Song, Polyhedron, 1999, 18,
1015.

5 (a) R. Fenton, L. F. Lindoy, R. C. Luckay, F. R. Turville and G.
Wei, Aust. J. Chem., 2001, 54, 59; (b) W. Clegg, P. B. Iveson and J.
C. Lockhart, J. Chem. Soc., Dalton Trans., 1992, 3291.

6 A. Castries, A. Escande, H. Fensterbank, E. Magnier, J. Marrot and C.
Larpent, Tetrahedron, 2007, 63, 10330.

7 Some references of metal complexes derived from N-carboxylic acid
branched azamacrocycles: (a) J. Brunner, H. Pritzkow and R. Krämer,
Dalton Trans., 2005, 338; (b) T. Gunnlaugsson, J. P. Leonard, S.
Mulreadya and M. Nieuwenhuyzen, Tetrahedron, 2004, 60, 105; (c) E.
Terreno, M. Botta, F. Fedeli, B. Mondino, L. Milone and S. Aime, Inorg.
Chem., 2003, 42, 4891; (d) M. B. Inoue, H. Santacruz, M. Inoue and Q.
Fernando, Inorg. Chem., 1999, 38, 1596; (e) S. L. Wu, K. A. Johnson
and W. D. Horrocks, Inorg. Chem., 1997, 36, 1884; (f) J. Huskens, D. A.
Torres, Z. Kovacs, J. P. Andre, C. F. G. C. Geraldes and A. D. Sherry,
Inorg. Chem., 1997, 36, 1495; (g) J. Costa, R. Delgado, M. C. Figueira,
R. T. Henriques and M. Teixeira, J. Chem. Soc., Dalton Trans., 1996, 65.
Selected recent references for lanthanide complexes: (h) L. S. Natrajan,
N. M. Khoabane, B. L. Dadds, C. A. Muryn, R. G. Pritchard, S. L.
Heath, A. M. Kenwright, I. Kuprov and S. Faulkner, Inorg. Chem.,
2010, 49, 7700; (i) L. S. Natrajan, A. J. L. Villaraza, A. M. Kenwright
and S. Faulkner, Chem. Commun., 2009, 6020; (j) M. P. Placidi, A J. L.
Villaraza, L. S. Natrajan, D. Sykes, A. M. Kenwright and S. Faulkner,
J. Am. Chem. Soc., 2009, 131, 9916; (k) S. J. A. Pope, B. P. Burton-Pye,
R. Berridge, T. Khan, P. J. Skabara and S. Faulkner, Dalton Trans.,
2006, 2907; (l) K. Sénéchal-David, S. J. A. Pope, S. Quinn, S. Faulkner
and T. Gunnlaugsson, Inorg. Chem., 2006, 45, 10040.

8 The iron complexes of macrocyclic polyaminocarboxylates have been
tested as antitumor agents, see: (a) H.-S. Chong, H. A. Song, X. Ma, S.
Lim, X. Sun and S. B. Mhaske, Chem. Commun., 2009, 3011; (b) H.-S.
Chong, X. Ma, H. Lee, P. Bui, H. A. Song and N. Birch, J. Med. Chem.,
2008, 51, 2208 and references therein.

9 Selected reviews: (a) S. Lee, J. Xie and X. Chen, Chem. Rev., 2010, 110,
3087; (b) T. J. Wadas, E. H. Wong, G. R. Weisman and C. J. Anderson,
Chem. Rev., 2010, 110, 2858; (c) J. L. Major and T. J. Meade, Acc.
Chem. Res., 2009, 42, 893; (d) S. Liu, Chem. Soc. Rev., 2004, 33, 445;
(e) W. A. Volkert and T. J. Hoffman, Chem. Rev., 1999, 99, 2269; (f) P.
Caravan, J. J. Ellison, T. J. McMurry and R. B. Lauffer, Chem. Rev.,
1999, 99, 2293; (g) C. J. Anderson and M. J. Welch, Chem. Rev., 1999,
99, 2219; (h) J. A. Balschi, K. Clarke, L. C. Stewart, M. Bernard and
J. S. Ingwall, in Methods in Biomedical Magnetic Resonance Imaging
and Spectroscopy, ed. I. R. Young, Chichester, UK, 2000, vol. 2, pp.
871–879.

10 (a) J-C. G. Bünzli, Chem. Rev., 2010, 110, 2729; (b) C. P. Montgomery,
B. S. Murray, E. J. New, R. Pal and D. Parker, Acc. Chem. Res.,
2009, 42, 925; (c) D. Parker, Coord. Chem. Rev., 2000, 205, 109;
(d) W. D. Horrocks and D. R. Sudnick, Acc. Chem. Res., 1981, 14,
384.

11 (a) R. Quevedo, I. Ortiz and A. Reyes, Tetrahedron Lett., 2010, 51, 1216;
(b) S. E. Gibson, J. O. Jones, S. B. Kalindjian, J. D. Knight, N. Mainolfi,
M. Rudd, J. W. Steed, M. J. Tozerb and P. T. Wright, Tetrahedron, 2004,
60, 6945; (c) J. W. Janetka and D. H. Rich, J. Am. Chem. Soc., 1997,
119, 6488.

12 S. Kotha, Acc. Chem. Res., 2003, 36, 342.
13 L. R. Pérez and K. J. Franz, Dalton Trans., 2010, 39, 2177.
14 (a) E. Gaggelli, H. Kozlowski, D. Valensin and G. Valensin, Chem.

Rev., 2006, 106, 1995; (b) R. R. Crichton, D. T. Dexter and R. J. Ward,
Coord. Chem. Rev., 2008, 252, 1189; (c) P. Faller and C. Hureau, Dalton
Trans., 2009, 1080.

9152 | Dalton Trans., 2011, 40, 9145–9153 This journal is © The Royal Society of Chemistry 2011

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15 See: (a) D. Pellico, M. Gómez-Gallego, P. Ramı́rez-López, M. J.
Mancheño, M. A. Sierra and M. R. Torres, Chem.–Eur. J., 2010,
16, 1592; (b) D. Pellico, M. Gómez-Gallego, P. Ramı́rez-López, M.
J. Mancheño, M. A. Sierra and M. R. Torres, Chem.–Eur. J., 2009, 15,
6940; (c) M. A. Sierra, D. Pellico, M. Gómez-Gallego, M. J. Mancheño
and M. R. Torres, J. Org. Chem., 2006, 71, 8787.

16 The concept of peripheral functionalization was initially introduced by
Still and Schreiber: (a) W. C. Still and A. G. Romero, J. Am. Chem.
Soc., 1986, 108, 2105; (b) S. L. Schreiber, T. Sammakia, B. Hulin and
G. Schulte, J. Am. Chem. Soc., 1986, 108, 2106.

17 (a) F. Yunta, S. Garcı́a-Marco, J. J. Lucena, M. Gómez-Gallego, R.
Alcázar and M. A. Sierra, Inorg. Chem., 2003, 42, 5412; (b) M. A.
Sierra, M. Gómez-Gallego, R. Alcázar, J. J. Lucena, F. Yunta and S.
Garcı́a-Marco, Dalton Trans., 2004, 3741; (c) M. Gómez-Gallego, M.
A. Sierra, R. Alcázar, P. Ramı́rez, C. Piñar, M. J. Mancheño, S. Garcı́a-
Marco, F. Yunta and J. J. Lucena, J. Agric. Food Chem., 2002, 50, 6395.

18 Compounds 8 are closely related to the macrocyclic bis b-aminoacids
prepared by us by periphery functionalization of macrocyclic diimines
(see ref. 17c) and also share structural features with the known chelating
agent o,o-EDDHA and with the lipophilic prodrug DP-109 (1,2-
bis(2-aminophenyloxy)ethane-N,N,N¢,N¢-tetraacetic acid) that shows
a great chelating efficacy for Zn(II) and Cu(II) ions and is under trial as
a viable candidate for Alzheimer’s disease therapy. See: L. E. Scott and
C. Orvig, Chem. Rev., 2009, 109, 4885.

19 (a) M. S. Sigman, P. Vachal and E. N. Jacobsen, Angew. Chem., Int.
Ed., 2000, 39, 1279; (b) H. Groger, Chem. Rev., 2003, 103, 2795; (c) M.
S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed., 2006, 45, 1520.

20 See for example: (a) J. Blacker, L. A. Clutterbuck, M. R. Crampton,
C. Grosjean and M. North, Tetrahedron: Asymmetry, 2006, 17, 1449;
(b) N. S. Josephson, K. W. Kuntz, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 2001, 123, 11594.

21 a-Aminonitriles easily decompose by means of the undesirable retro-
Strecker reaction. See: P. Vachal and E. N. Jacobsen, Org. Lett., 2000,
2, 867.

22 Dimeric structures of Cu(II) complexes. From macrocyclic ligands:
(a) X-H. Bu, M. Du, L. Zhang, Z-L. Shang, R-H Zhang and M.
Shionoya, J. Chem. Soc., Dalton Trans., 2001, 729; (b) D. Kong, J.
Mao, A. E. Martell and A. Clearfield, Inorg. Chim. Acta, 2003, 342,
260. Acyclic ligands: ; (c) C.-T. Yang, M. Vetrichelvan, X. Yang, B.

Moubaraki, K. S. Murray and J. J. Vittal, Dalton Trans., 2004, 113; (d) S.
Reinoso, P. Vitoria, L. San Felices, A. Montero, L. Lezama and J. M.
Gutiérrez-Zorrilla, Inorg. Chem., 2007, 46, 1237; (e) A. Erxleben, Inorg.
Chim. Acta, 2009, 362, 839; (f) T. Gunnlaugsson, M. Nieuwenhuyzen
and C. Nolan, Polyhedron, 2003, 22, 3231; (g) A. S. de Sousa and M.
A. Fernandes, Polyhedron, 2002, 21, 1883; (h) P. Gómez-Saiz, R. Gil-
Garcı́a, M. A. Maestro, J. L. Pizarro, M. I. Arriortua, L. Lezama, T.
Rojo, M. González-Álvarez, J. Borrás and J. Garcı́a-Tojal, J. Inorg.
Biochem., 2008, 102, 1910.

23 For N,O coordinated N-branched (N-CH2CH2OH and N-
CH2CONH2) Ni(II) macrocyclic complexes, see: (a) K. R. Adam, C.
Clarkson, A. J. Leong, L. F. Lindoy, M. McPartlin, H. R. Powell and S.
V. Smith, J. Chem. Soc., Dalton Trans., 1994, 2791. For the analogous
N,O coordinated non-branched macrocycles, see: (b) K. Henrick, L. F.
Lindoy, M. McPartlin, P. A. Tasker and M. P. Wood, J. Am. Chem.
Soc., 1984, 106, 1641; (c) L. A. Drummond, K. Henrick, M. J. L
Kanagasundaram, L. F. Lindoy, M. McPartlin and P. A. Tasker, Inorg.
Chem., 1982, 21, 3923. For non-coordination of the ether oxygen donor
atoms in macrocyclic Ni(II) complexes, see for example: (d) N. A. Bailey,
D. E. Fenton, S. J. Kitchen, T. H. Lilley, M. G. Williams, P. A. Tasker,
A. J. Leong and L. F. Lindoy, J. Chem. Soc., Dalton Trans., 1991,
7627; (e) H. Adams, N. A. Bailey, D. E. Fenton, S. J. Kitchen and P. A.
Tasker, J. Chem. Soc., Dalton Trans., 1990, 1111.

24 For N,O coordination in non-branched macrocyclic Cu(II) complexes,
see for example: (a) K. R. Adam, G. Anderegg, L. F. Lindoy, H. C. Lip,
M. McPartlin, J. H. Rea, R. J. Smith and P. A. Tasker, Inorg. Chem.,
1980, 19, 2956. For non-coordination of the ether oxygen donor atoms
in Cu(II) complexes, see for example: (b) K. R. Adam, L. F. Lindoy, H.
C. Lip, J. H. Rea, B. W. Skehon and A. H. White, J. Chem. Soc., Dalton
Trans., 1981, 74.

25 (a) A. Simion, C. Simion, T. Kanda, S. Nagashima, Y. Mitoma, T.
Yamada, K. Mimuro and M. Tashiro, J. Chem. Soc., Perkin Trans.
1, 2001, 2071; (b) C. Simion, A. Simion, Y. Mitoma, S. Nagashima,
T. Kawaji, I. Hashimoto and M. Tashiro, Heterocycles, 2000, 53,
2459.

26 SADABS: Area-detector absorption correction, Bruker-AXS, Madison,
WI, 1996.

27 (a) SHELXTL Package v. 6.10, Bruker-AXS, Madison, WI, 2000; (b) G.
Sheldrick, Acta Crystallogr., 2008, A64, 112.

This journal is © The Royal Society of Chemistry 2011 Dalton Trans., 2011, 40, 9145–9153 | 9153

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