Unsymmetrically substituted side-bridged cyclam derivatives and their Cu(II) and Zn(II) complexes

Article abstract of DOI:10.1039/b709747f

A series of new compounds built up on the skeleton of 1,5,8,12- tetraazabicyclo[10.2.2]hexadecane (1,4-ethylene-bridged cyclam, 1,4-en-cyclam) were synthesized and characterized by means of NMR and MS spectroscopy and a single-crystal X-ray structure determination. The attempts to substitute the secondary amino group of the p-nitrobenzyl-1,4-en-cyclam 3, using acetic acid derivatives as the alkylating agents, led to unexpected substitution of one of the piperazine ring nitrogen atoms, yielding the monoquaternary derivatives 4^Br and 5^Br, respectively. In order to explain this reaction behaviour, the solution structure of the starting compound 3 was established using 2D-NMR techniques. The acid-base behaviour of the ligands and thermodynamic stability constants of their copper(ii) and zinc(ii) complexes were determined using potentiometric titrations. Stability constants of the investigated metal complexes are significantly lower than those of the cyclam complexes and comparable to those of the Me₄cyclam complexes. A copper(ii) complex of amine 3 was prepared and characterized. In the solid state, this complex has the central copper atom surrounded by five donor atoms forming a coordination sphere with geometry between trigonal bipyramid and square pyramid. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/b709747f

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Unsymmetrically substituted side-bridged cyclam derivatives and their
Cu(II) and Zn(II) complexesw
ˇ ˇ
Jan Plutnar, Jana Havlıckova, Jan Kotek,* Petr Hermann and Ivan Lukes
´
´
Received (in Durham, UK) 28th June 2007, Accepted 13th November 2007
First published as an Advance Article on the web 29th November 2007
DOI: 10.1039/b709747f
A series of new compounds built up on the skeleton of 1,5,8,12-tetraazabicyclo[10.2.2]hexadecane
(1,4-ethylene-bridged cyclam, 1,4-en-cyclam) were synthesized and characterized by means of
NMR and MS spectroscopy and a single-crystal X-ray structure determination. The attempts to
substitute the secondary amino group of the p-nitrobenzyl-1,4-en-cyclam 3, using acetic acid
derivatives as the alkylating agents, led to unexpected substitution of one of the piperazine ring
nitrogen atoms, yielding the monoquaternary derivatives 4Br and 5Br, respectively. In order to
explain this reaction behaviour, the solution structure of the starting compound 3 was established
using 2D-NMR techniques. The acid–base behaviour of the ligands and thermodynamic stability
constants of their copper(II) and zinc(II) complexes were determined using potentiometric
titrations. Stability constants of the investigated metal complexes are significantly lower than
those of the cyclam complexes and comparable to those of the Me4cyclam complexes. A
copper(II) complex of amine 3 was prepared and characterized. In the solid state, this complex has
the central copper atom surrounded by five donor atoms forming a coordination sphere with
geometry between trigonal bipyramid and square pyramid.
copper(II) complex inertness towards any type of decomposi-
Introduction
tion and rapid complex formation under mild conditions. The
ligands used today satisfy at most two of these requirements
simultaneously. The cross-bridged cyclam-based ligands
(Fig. 1) are usually easily prepared11 and their copper(II)
complexes exhibit enormous kinetic inertness towards decom-
plexation,4–7 but formation of the complexes themselves re-
quires either intensive heating (480 1C for several hours) or a
mild heating (B50 1C) for a prolonged time-period,12 thus
making these ligands unsuitable either for copper complexa-
tion after conjugation to a biomolecule (in the case of bifunc-
tional chelators – BFCs) or for short-lived copper isotopes
complexation. On the other hand, the known side-bridged
cyclam-based ligands form copper(II) complexes much more
easily but their kinetic inertness is significantly lower com-
pared to the cross-bridged analogues (half-life in acid solutions
in order of days, vs. years for the cross-bridged ligands).5,6,9
The ethylene-side-bridged cyclam 1 (Fig. 1) was prepared
for the first time in the early 1980s13 and the pathway leading
Cyclic amines derived from cyclam (1,4,8,11-tetraazacyclote-
tradecane) have been widely investigated as ligands suitable
for copper(II) complexation. Introduction of one to four acidic
pendant arms (acetates, methylphosphonates etc.) to the
nitrogen atoms leads to macrocyclic chelators (e.g. TETA,1
1,8-H4te2p)2 forming good stability copper(II) complexes.
Further improvements to the complex stability can be
achieved by structural modifications of the cyclam skeleton,
especially by limiting freedom of the macrocyles by introduc-
tion of a (carbon) bridge connecting two nitrogen atoms of the
ring. The bridged azamacrocycles thus formed may be divided
into two principal groups—the cross-bridged (with two distal
nitrogen atoms connected) and the side-bridged (with two
adjacent nitrogen atoms connected) ligands.3 Whereas the
compounds of the former group are known to form copper(II)
complexes of a high kinetic inertness towards decomplexa-
tion,4–7 data concerning the copper(II) complexes of the
ligands of the latter groups are relatively scarce.8,9
In the search for an ideal copper(II)-encapsulating ligand
suitable for in vivo applications10 of radiolabelled complexes
(60Cu, 61Cu, 62Cu, 64Cu and 67Cu, with half lives between 0.16
and 62 h) several aspects have to be regarded, including
straightforward and uncomplicated ligand synthesis, good
Department of Inorganic Chemistry, Faculty of Science, Charles
University in Prague, Hlavova 2030, Prague 2, 12843, Czech
Republic. E-mail: modrej@natur.cuni.cz; Fax: +420221951253;
Tel: +420221951261
w Electronic supplementary information (ESI) available: Complete
crystal, data collection and refinement details, 2D-NMR spectra
together with signal assignment and complete set of distribution
diagrams. See DOI: 10.1039/b709747f
Fig. 1 Structure and numbering scheme of 1,5,8,12-tetraazabicy-
clo[10.2.2]hexadecane 1 (side-bridged cyclam) and structure of the
cross-bridged cyclam.
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the bisaminal yields were reported to be good to excellent
(480%),11 in our hands the yield did not exceed 50%. One of
the reasons of this result may be the composition of the
commercially available 40% w/w (6 M) aqueous glyoxal
solution which is known to contain concentration- and tem-
perature-dependent amounts of the reactive monomeric
species, this amount being substantially lowered with the
increasing total concentration and the age of the material
(oxidation on exposition to air).17,18
A suitable alternative source of glyoxal is its trimeric form.
Dissolution of the trimer in hot distilled water (B70–80 1C)
produces a solution in which the hydrated glyoxal monomer
1
(ethane-1,1,2,2-tetraol) predominates (according to H NMR
measurements). This monomer reacts, after dilution by metha-
nol, with cyclam to give the bisaminal in high and reproducible
yields (B75–85%).
Alkylation of the bisaminal intermediate in a suitable
solvent produces the monoquaternary ammonium salt in form
of a precipitate (toluene or acetonitrile for R = benzyl,11,19
acetonitrile for R = p-nitrobenzyl,9 2Br). Reduction of a
suspension of the ammonium salt in ethanol by a 20-fold
excess of NaBH4 in 5 days produces the desired 1,4-en-cyclam
derivative.11 The amount of time needed to complete the
reaction can be reduced under reflux conditions.16b It is
possible to reduce the amount of the reducing agent used in
the reaction either by conducting the reaction in methanol
(10-fold excess of NaBH4 is needed)20 or in ethanol containing
approx. 10% of water (2-fold excess of the reductant, see
Experimental section). Use of the latter solvent also signifi-
cantly reduces the time needed to complete the reaction (from
5 days to 8 h).
Fig. 2 An overview of compounds prepared in this work.
to mono-substituted derivatives of 1 was discovered in mid-
1990s.14 The kinetic inertness studies of copper(II) complex of
the amine 1 revealed,9 that the inertness of this complex
towards acid-assisted decomplexation is comparable to that
of the cyclam-copper(II) complex and, in addition, the thermo-
dynamic stability of this complex, together with the protona-
tion constants of the free ligand,15 are also close to the values
found for cyclam and its copper(II) complex, respectively.
Quite recently four papers dealing with mono-functiona-
lized derivatives of the side-bridged cyclam were released by
Archibald’s group, concerning their use as copper(II) and
zinc(II) chelators for medicinal use.16
Substitution of the secondary amino nitrogen of the mono-
substituted 1,4-en-cyclam derivative 3 has been attempted
either by an alkylation reaction or by a Mannich-type reac-
tion. Although the alkylation of similar derivatives in the
presence of an additional base has been described,20 alkylation
of the p-nitrobenzyl-substituted compound by either ethyl
bromoacetate or tert-butyl bromoacetate in a polar solvent
(acetonitrile) in the presence of a base (Na2CO3, K2CO3, Et3N
The aim of our work was to prepare BFCs based on the
side-bridged cyclam functionalized by p-nitrobenzyl group (as
a spacer precursor) and by an acidic group to improve the
complexation parameters of the side-bridged macrocycle
(Fig. 2).
i
or Pr2NEt) led to formation of monoquaternized dialkylated
derivative 5Br (after acidic hydrolysis, Fig. 2, Scheme 2).
Analysis of the reaction mixtures had shown that yield of
the diacetate 5Br was quantitative, relative to the amount of
alkylating agent used in the reaction and only a trace amount
of monoalkylated derivative (most probably 4Br, see below)
and half of the unreacted starting material 3 were present.
Results of the potentiometric titrations (see below) revealed
that the starting amine 3 behaves as a very strong base. Thus,
we decided to carry out the reaction without any additional
base and with half an equivalent of bromoacetic acid (as the
alkylating agent) in dry, non-polar solvent (diethyl ether).
Results and discussion
Synthesis
The general synthetic pathway leading to the monosubstituted
1,4-en-cyclam derivatives is shown in Scheme 1.11,14 The first
synthetic step, the glyoxal-cyclam bisaminal preparation, con-
sists in an addition of aqueous solution of glyoxal (1,2-
ethanedione) to a cyclam suspension in acetonitrile. Although
Scheme 1
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containing phosphinic acid results in the appearance of an
inconsiderable amount of side-products, the most abundant
among them being the hydroxymethylphosphinic acid (HO-
CH2(OH)(O)PCH2N–) derivative.
Scheme 2
NMR measurements
In the aromatic region of the proton NMR spectra, all the
compounds shown in Fig. 2 exhibit a pair of doublets (an
unresolved AA0BB0 pattern) at dH approx. 8 ppm, character-
istic for the p-nitrophenyl group. With the exception of the
structurally rigid ammonium salt 2Br (Fig. 2) the aliphatic
regions of the 1H NMR spectra of the compounds measured in
water contain sets of hardly distinguishable multiple signals.
In addition to these signals, in the spectra of compound 6 a
wide doublet assigned to the phosphorus-attached proton
(1JHP = 522 Hz) appears at B6.9 ppm. In the 31P NMR
spectra of ligand 6 a corresponding doublet at d 26.2 ppm is
present. The value of the H–P coupling constant is in range of
values typical for alkylphosphinic acids (R–PH(O)OH).21
To determine the structure of the ligand 3 in solution,
several two-dimensional correlation NMR spectra have been
measured (1H–13C gHSQC, gHMBC and 1H–1H COSY,
NOESY). Results of the HSQC and HMBC experiments were
used to assign the H–C and C–C connectivities. In contrast to
our expectations, results of the NOESY measurements did not
help to unambiguously establish the conformation of the
piperazine subunit as the exchange signals are assignable to
both possible conformations (i.e. chair and twisted boat).
The gHSQC and gHMBC experiments were also conducted
in order to determine the H–C and C–C connectivities in the
diacetate derivative 5Br. The second acetate group was loca-
lized at the nitrogen atom closer to nitrobenzyl-bearing nitro-
gen atom (‘cis’ to the nitrobenzyl group, ‘trans’ to the second
acetate group). This structural motif was later confirmed by
the solid-state structure determination.
Under such conditions amine 3 (the strongest base in the
system) hydrobromide precipitation was expected, with the
desired product 4a left in solution. To our surprise, analysis of
the precipitate had shown that monoquaternized monoalky-
lated compound 4Br was prepared (Scheme 3).
The reasonable explanation of this behaviour could be
found in the basicity of the secondary nitrogen atom of the
starting compound 3. This compound might have been iso-
lated in its monoprotonated form as an ionic pair with
hydroxide anion (see Experimental section). The relatively
high basicity of the ligand 3 may facilitate existence of this
ionic pair in benzene. According to the molecular mechanics
(MM+) modelling results, the additional proton attached to
the secondary nitrogen atom N8 would participate in the
hydrogen bond system involving N12 and N5 nitrogen atoms,
thus deactivating these atoms for further reaction with elec-
trophiles. The only nitrogen atom in such systems available for
further substitution is the N1 atom, which is too distant from
the hydrogen bond system to participate in it (in the case of the
twisted-boat piperazine ring conformation) or its lone electron
pair is oriented outwards the macrocyclic ring (in the case of
the piperazine ring chair conformation). The expected hydro-
gen-bond system is very similar to that found in the solid-state
structure of 4Br (see below). The alkylating agent attacks this
nitrogen atom forming the ‘tetraalkylammonium’ quaternary
centre. If the reaction proceeds in a non-polar solvent (diethyl
ether) the product precipitates out of the reaction mixture in
form of a yellow powder having the structure and composition
shown in Scheme 3. In reaction media with higher polarity
(acetonitrile), where the monoquaternized derivative remains
in solution, and in the presence of an additional base, this
molecule preferably reacts on the N8 atom with further
equivalent of the alkylating agent, forming the compound
5Br. The reactivity of the secondary amine atom N8 of
compound 4Br must be significantly higher than the reactivity
of the N1 nitrogen atom of the piperazine subunit in com-
pound 3 as the final reaction mixture contains only a trace
amount of the monoalkylated product 4Br (detectable by the
MS spectrometry) and a majority of the dialkylated com-
pound 5Br (together with half-amount of the unreacted com-
pound 3). This change of the N8-atom’s reaction behaviour is
related to a change of its basicity, which is lower in compound
4Br due to the presence of an additional positive charge in the
molecule.
X-Ray structural studies
In order to determine the structure of the prepared compounds
in the solid state, several attempts to prepare single crystals of
the ligands or their metal complexes have been done. Crystals
suitable for the single-crystal X-ray structure determination
have been obtained from solutions of compound 4Br and the
copper(II) complex of ligand 3—[Cu(3)Br][PF6]. For the com-
plete crystal, data collection and refinement details see
the ESI.w
The methylphosphinate and methylphosphonate derivatives
have been synthesized via Mannich-type reactions of the
secondary amine, paraformaldehyde and an appropriate phos-
phorus precursor (H3PO2, ambient temperature, to produce
the methylphosphinate 6; or P(OEt)3 at elevated temperature,
to produce (after acid hydrolysis) the methylphosphonate 7 in
a low yield). Raising the temperature of the reaction mixture
Scheme 3
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Crystal structure of 4Brꢁ2.5H2O
Table 1 Estimated distances (A) and angles (1) in the H-bond system
of 4+ ion
The quaternary ammonium salt 4Br crystallizes with deproto-
nated carboxylate group and protonated N8 nitrogen atom
(Fig. 3). The piperazine ring has the ‘chair’ conformation (the
most stable for the six-membered cyclohexane-like rings) with
the lone pair of the tertiary N12 atom heading towards the
inner space of the macrocyclic ring and participating in the
hydrogen bonds system among the N5, N8 and N12 nitrogen
atoms (N8ꢁ ꢁ ꢁN12 2.80 A, N8ꢁ ꢁ ꢁN5 2.91 A, see Table 1. The
carboxylate group O211 oxygen atom participates in a rela-
tively strong intermolecular hydrogen bond including N8 and
H82 atoms of the neighbouring molecule (O211#ꢁ ꢁ ꢁN8 2.71
A). One of the central propylene carbon atoms (C3) is
disordered over two positions with relative population 62:38.
The Brꢂ anion compensates the positive charge of the whole
molecule. Furthermore, the crystal unit contains two solvate
water molecules with full occupancy and one which was best
fitted with 50% occupancy.
H81ꢁ ꢁ ꢁN5
2.47
2.06
1.83
N8ꢁ ꢁ ꢁN5
N8ꢁ ꢁ ꢁO211a
N8–H82ꢁ ꢁ ꢁO211a
2.91
2.80
2.71
H81ꢁ ꢁ ꢁN12
H82ꢁ ꢁ ꢁO211a
N8ꢁ ꢁ ꢁN12
N8–H81ꢁ ꢁ ꢁN5
110
139
167
N8–H81ꢁ ꢁ ꢁN12
a
x, ꢂy, z + 0.5.
meter describing five-coordinated geometries along the Berry
rearrangement between a trigonal bipyramid and a square
pyramid (t = (b ꢂ a)/60, with t = 1 for trigonal bipyramidal
and t = 0 for square pyramidal geometry),22 is 0.51 (b =
N1–Cu1–N8, a = N5–Cu1–N12). The structural motif of this
complex is essentially identical to that of a recently reported17b
complex [Cu(L)Cl][CuCl2] (where L = 5-benzyl-1,5,8,12-tet-
raazabicyclo[10.2.2]hexadecane), with the t-parameter equal
to 0.54.
Potentiometric titrations
Copper(II) complex of ligand 3
In order to determine the acid–base properties of the newly
prepared ligands and the thermodynamic stability constants of
their complexes with copper(II) and zinc(II), the pH-metric
titration experiments were conducted. The resulting values of
the protonation and dissociation constants of the ligands in
aqueous solution are presented in Table 3, whereas the stabi-
lity constants of their CuII and ZnII complexes are listed in
Table 4.
The crystal structure of the [Cu(3)Br][PF6] complex exhibits a
five-coordinated copper(II) metal centre (Fig. 4). In the struc-
ture, a weak coordination interaction between copper and
bromine atoms (Cu1–Br1A 2.7 A, see Table 2) appears. The
bromine atom has been found disordered in two almost
equally populated positions (relative abundance 56 : 44), the
less populated position being more distant from the copper
centre (3.3 A) than the position of the weakly coordinated
bromine atom. The positions of the bromine atom are prob-
ably influenced by the proximity of the N8-bound hydrogen
atom (N8ꢁ ꢁ ꢁBr1A 3.122 A, N8ꢁ ꢁ ꢁBr1B 3.254 A, but the
hydrogen atom could not be located in the difference Fourier
map).
There could be four species with different degree of proto-
nation found in the aqueous solutions of the monosubstituted
compound 3, depending on the pH value. The fully deproto-
nated species becomes predominant at pH value close to 12.
The most basic nitrogen atom should be the secondary amine
N8 (pKa B11). The second proton is probably caught by the
piperazine-ring nitrogen atom in ‘trans’ position to N8 (N1;
pKa B8). The last two protons seem to be attached simulta-
neously to the ligand skeleton at the N5 and N12 atoms
(pKa(H3L) + pKa(H4L) B3).
The heavy atom (bromine) disorder and low diffraction data
quality unfortunately shift the structure’s uncertainty towards
relatively high values (R0 B0.17, wR0 B0.49), however the
other structural parameters (thermal parameters, bond dis-
tances deviations etc.) were satisfactory (Fig. 4).
As expected,23 the overall basicity of the ligand 6, bearing an
additional methylphosphinate group, is lower than the basicity
of the parent amine 3. The phosphinate compound is fully
deprotonated at pH value above 11. The first proton
The coordination sphere of the central copper atom
(Table 2) could be described as an intermediate structure
between square pyramid and trigonal bipyramid. The t-para-
Fig. 3 The ORTEP view of 4+ ion with 30% probability thermal
ellipsoids (carbon-bound hydrogen atoms, and the ring-disorder are
omitted for clarity).
Fig. 4 The ORTEP view of the [Cu(3)Br] + ion with 30% probability
thermal ellipsoids (hydrogen atoms and the bromine disorder are
omitted for clarity).
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Table 2 Selected bond distances (A) and bond angles (1) in the
[Cu(3)Br]+ ion
Table 3 Protonation and dissociation constants of the investigated
compounds determined in 0.1 M aq. KNO3 at 25 1C
1a
cyclamb
Me4cyclambc
Cu1–N1
Cu1–N8
Cu1–Br1A
2.076(10)
1.850(13)
2.718(8)
Cu1–N5
2.009(10)
1.996(9)
3.286(13)
3
6
Cu1–N12
Cu1–Br1B
log b1
log b2
log b3
log b4
pKa(HL)
pKa(H2L)
pKa(H3L)
pKa(H4L)
a
11.35(8)
9.21(1)
—
—
—
—
—
—
—
—
—
—
—
—
9.36
9.02
2.54
2.25
19.61(1) 16.54(2)
18.13(4)
22.44(3) 18.9(1)
—
N1–Cu1–N5
N1–Cu1–N12
N5–Cu1–N8
N5–Cu1–Br1A
N8–Cu1–Br1A
93.2(5)
76.1(4)
93.5(5)
100.0(3)
83.9(4)
N1–Cu1–N8
173.2(4)
96.0(4)
N1–Cu1–Br1A
N5–Cu1–N12
N8–Cu1–N12
N12–Cu1–Br1A
11.36
8.25
—
9.21
7.33
1.59
0.8
12.54 11.4
9.42 10.28
0.73
142.7(4)
97.8(4)
1.6
2.1
2.83d
—
116.4(3)
b
Data for 1 taken from ref. 15. Data for cyclam and Me4cyclam
c
were taken from ref. 25. Me4cyclam = 1,4,8,11-tetramethyl-1,4,8,11-
d
tetraazacyclotetradecane. pKa(H3L) + pKa(H4L).
(pKa B9.2) is probably attached either to the N5 atom
(bearing the p-nitrobenzyl group) or N8 atom (bearing the
methylphosphinate). In the next step (pKa B7.3) one of the
piperazine ring nitrogen atoms is protonated. The lowest (the
most acidic, pKa B0.8) dissociation constant detected corre-
sponds to protonation of the remaining nitrogen atom and/or
the methylphosphinate moiety (the value is similar to the
constants obtained for aminomethylphosphinic acids).24 The
fifth expected dissociation constant was not detected due to
the potentiometric method limitations (the constant is ex-
pected to be very low).
B2.5) but prevailing in Zn2+–6 system (up to B90% at
ꢂlog[H+] B4.5). On the basis of comparison of the pKa
values of the uncoordinated ligands and the complexes it
seems reasonable that the first complexation step involves
coordination of the phosphinate oxygen atom and at least
one nitrogen atom of the macrocyclic ring (most probably the
N8 atom bearing the methylphosphinate group) with the
additional proton being attached to the piperazine ring N1
atom. This species transforms at higher ꢂlog[H+] values to
the [M(L)]+ species, this being the major complex in the
alkaline ꢂlog[H+] region. For a complete set of distribution
diagrams of the described systems see the ESI.w
The acid–base behaviour of the investigated compounds can
be well described as a combination of the cyclam and Me4
cyclam properties. The basicity of the secondary amino group
in 3 is the same as in cyclam. The basicity of the remaining
tertiary amino groups is much closer to Me4cyclam than to
cyclam. As expected, the acid–base behaviour of the com-
pound 6 is similar to that of Me4cyclam.
When comparing to the copper(II) and zinc(II) complexes of
cyclam and Me4cyclam, respectively, the ligands 3 and 6 form
complexes with a lower thermodynamic stability. The stability
of complexes of the investigated compounds is significantly
lower than the stability of the corresponding cyclam com-
plexes (e.g. B12 orders of magnitude for Cu(II) and B7 orders
of magnitude for the Zn(II) complex of 3). On the other hand,
comparison of CuII complex 3 stability constant (15.5) with
the stability constant of [Cu(1)] (26.1)15 shows the same trends
in the values as in the case of CuII complexes of cyclam (28.1)
and Me4cyclam (18.3), respectively (a difference of approx. 10
orders of magnitude). The difference could be ascribed prob-
ably to lower basicity of 3 compared to 1 as an effect of
presence of an additional substituent (p-nitrobenzyl group).
Unfortunately, no data for a similar ZnII complex are
available.
The complexation of ZnII and CuII proceeded relatively
slowly in the pH range used for the potentiometric experi-
ments, thus the titrations involving the metal–ligand systems
have been conducted using the ‘out-of-cell’ method (i.e. the
solutions were prepared in the desired ligand–metal ratio,
known amount of the base was added and the mixtures were
left to equilibrate at 25 1C for 4 days).
The complexation of copper(II) and zinc(II) with ligand 3
shows usual behaviour (cf. Fig. 5). The ligands start to
coordinate in acidic (CuII, ꢂlog[H+] B2) or slightly acidic
region (ZnII, ꢂlog[H+] B5.5), respectively, forming the ex-
pected [M(L)]2+ species prevailing up to the strongly alkaline
region (in the case of CuII). The ZnII-complex decomposed at
ꢂlog[H+] 49 and some insoluble product precipitated out of
the solution (probably Zn(OH)2).
In the system M2+–6, the complexation starts in strongly
acidic region by formation of the [M(HL)]2+ species, being
low-abundant in the case of copper(II) (up to 20% at ꢂlog[H+]
The lower stability constant ratio (log bCu ꢂ log bZn) ob-
served for the complexes of 6 (B3.2) over the similar com-
plexes of Me4cyclam (B7.9) could be ascribed to the
Table 4 Stability constants of copper(II) and zinc(II) complexesa
3
6
Cyclamd
Cu2+
Me4cyclamd
1c
Equilibriumb
log bhlm
Cu2+
Cu2+
Zn2+
Cu2+
Zn2+
Zn2+
Cu2+
Zn2+
M + L " ML
H + L + M " HML
HML " ML + H
a
log b011
log b111
pKa
26.1
—
—
15.50(5)
—
—
8.5(1)
—
—
14.71(3)
16.81(9)
2.10
11.53(9)
16.94(5)
5.41
28.1
—
—
15.2
—
—
18.3
—
—
10.4
—
—
b
c
d
Determined in 0.1 M KNO3 at 25 1C. Charges of the species are omitted for clarity. Data for 1 were taken from ref. 15. Data for cyclam and
Me4cyclam were taken from ref. 25.
ꢀc
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to-metal ratio was 1 : 1 in all cases. The initial volume was ca. 5
ml (in the protonation constants determination experiments)
or ca. 1 ml (in the out-of-cell experiments involving metal
complexes, see below). The measurements were taken with a
HNO3 excess added to the mixture to ensure a low starting pH
value. The mixtures were titrated with the stock KOH solution
(B0.2 M) in the region of ꢂlog[H+] = 1.6–12.0. Titrations for
each system were carried out at least four times. Each titration
consisted of ca. 40 points (protonation constants) or 25 points
(metal complexation). Inert atmosphere was provided by
constant passage of argon saturated with water vapour. The
metal complexation reactions were too slow to be followed by
standard titrations, thus the systems were studied by the ‘out-
of-cell’ method. Each solution was mixed separately in the test
tube and an appropriate amount of the KOH solution was
added to each of the test tubes to simulate the common
titration. The tubes were tightly closed and left to equilibrate
for four days at ambient temperature (the amount of added
KOH solution and equilibration times were determined in
separate preliminary experiments). The amount of HX (X =
Cl, Br) present in the ligand stock solutions was determined
gravimetrically in form of AgX.
Fig. 5 Projection of species distributions in the Cu2+–3 and Zn2+–3
systems (0.1 M KNO3, 25 1C, cM = cL = 0.004 M).
stabilizing effect of the hard phosphinate group present in
ligand 6 for the zinc(II) complex formation.
The constants with their standard deviations were calcu-
lated using the OPIUM program package.28 The program
minimises the criterion of the generalized least-squares method
using the calibration function given in eqn (1).
Experimental
General
The analytical grade chemicals were purchased from Lachema
(Czech Republic), Fluka, Sigma-Aldrich or Merck and were
used as received. All the reactions were carried out under
ambient atmosphere. Cyclam was prepared by a slightly
modified literature procedure,26 using glyoxal hydrate trimer
and Raney-Nickel. Sulfonate cation exchange resin (Dowex
50, Fluka) and an anion exchange resin (Dowex 1, Fluka) were
used for column chromatography.
E = E0 + S log[H+] + j1[H+] + j2Kw/[H+]
(1)
The term E0 contains the standard potentials of the electrodes
used and the contributions of inert ions to the liquid-junction
potential. The term S corresponds to the Nernstian slope and
the terms j1[H+] and j2Kw/[H+] = j2[OHꢂ] are contributions
of the H+ and OHꢂ ions to the liquid-junction potential. The
calibration parameters were determined from titration of the
standard HNO3 with the standard KOH solution before and
after each titration of the ligand/metal ion system to give
calibration–titration pairs used for calculations of the stability
Elemental analyses were conducted at the Institute of
Macromolecular Chemistry of Academy of Sciences of the
Czech Republic (Prague). Melting points were determined
using a Kofler hot-stage apparatus (Boetius) and are uncor-
rected. NMR spectra were recorded on a Varian Unity Inova
400 spectrometer at 400.0 MHz for 1H, 161.9 MHz for 31P and
100.6 MHz for 13C nuclei with internal references TMS for
CDCl3 solutions and t-BuOH for D2O solutions, and external
reference 85% H3PO4. The temperature (25 1C) was controlled
by a VT-regulator, containing a thermocouple calibrated using
MeOH and ethylene glycol according to a reported proce-
dure.27 Multiplicity of the signals is indicated as follows: s ꢂ
singlet, d – doublet, t – triplet, q – quintet, m – multiplet, br –
broad. The values of coupling constants (J) are given in Hz,
chemical shifts (d) are given in ppm. MS spectra were recorded
on a Bruker Esquire 3000 spectrometer equipped with electro-
spray ion source and ion-trap detection in positive-ion mode.
constants. The concentration stability constants are bhlm
=
[HhLlMm]/([H]h[L]l[M]m). The water ion product pKw taken
for calculations was 13.78. Stability constants of metal hydro-
xo complexes included in the calculations were taken from
literature.25
Crystallography
The diffraction data were collected using a Nonius Kappa
CCD diffractometer (Enraf-Nonius) at 150(1) K using Mo-Ka
radiation (l = 0.71073 A) and analysed using the HKL
program package.29 The structures were solved using direct
methods and refined by full-matrix least-squares techniques
(SIR9230 and SHELXL97).31 Scattering factors for neutral
atoms were included in the SHELXL97 program. All non-
hydrogen atoms were refined anisotropically. The hydrogen
atoms were located in the electron density difference map;
however they were fixed in theoretical or their original posi-
tions with thermal parameters Ueq(H) = 1.2Ueq(C) or 1.3-
Ueq(N), as the free refinement led to several unreal bond
lengths and to extreme increase of number of refined para-
meters. In the structure of 4Brꢁ2.5H2O, solvate water molecules
Potentiometric measurements
The potentiometric titrations were carried out in a thermo-
stated vessel at 25.0 ꢃ 0.1 1C, at constant ionic strength
I(KNO3) = 0.1 mol dmꢂ3, using a PHM 240 pH-meter, a
2 ml ABU 900 automatic piston burette and a GK 2401B
combined glass electrode (Radiometer). The ligand concentra-
tion in the titration vessel was ca. 0.004 mol dmꢂ3. The ligand-
ꢀc
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New J. Chem., 2008, 32, 496–504 | 501

View Article Online
were best refined in three positions, two of them fully and the
last one half-occupied. Thermal ellipsoids of some oxygen
atoms were very prolate, however, trials to refine these atoms
in several positions did not improve the final fit. The hydrogen
atoms attached to the solvate molecules could not be localized
on the difference Fourier map. Crystal data quality of
[Cu(3)Br][PF6] was very low due to high mosaicity of the
crystal. Trials for data correction for absorption lead to
worsening of the R-factor, therefore, the refinement was done
with uncorrected data.
12.2 and, 1H), 2.9–3.15 (m, 7H), 3.23 (td, J = 13.6 and 2.8,
1H), 3.31 (br d, J = 11.6, 1H), 3.45 (td, J = 13.6 and 4, 1H),
3.57 (td, J = 13.6 and 3.6, 1H), 3.70 (br s, 1H, CH), 4.19 (td, J
= 14 and 4, 1 H), 4.32 (d, 1H, J = 1.6, CH), 4.81 and 5.23
(AB, J = 13.2, 2H, CH2Ar), 7.75 (d, J = 8.8, 2H, ArH), 8.27
(d, J = 8.8, 2H, ArH); 13C{1H} NMR (D2O): d 18.0, 18.4,
41.9, 46.6, 48.6, 51.3, 51.9, 53.3, 53.9, 60.3, 61.1, 69.5, 82.6,
124.2, 132.8, 134.6, 149.0; ESI-MS: m/z 358.3 (M+).
5-(4-Nitrobenzyl)-1,5,8,12-tetraazabicyclo[10.2.2]hexadecane
(3). Perhydro-3a-(4-nitrobenzyl)-3a,5a,8a,10a-tetraazapyre-
nium bromide (2Br) (1 g, 2.3 mmol) was dissolved in an
EtOH/H2O mixture (30 ml EtOH + 5 ml H2O) at ambient
temperature. To the stirred solution sodium borohydride (0.3
g, 8 mmol) was added and the mixture was stirred at ambient
temperature overnight. The reaction was quenched by careful
addition of 10% aq. HCl (5 ml) and the solvents were
evaporated. The remaining solid was dissolved in distilled
water (30 ml) and the pH of the solution adjusted to B13
by KOH. The mixture was extracted by benzene (3 ꢄ 25 ml),
the organic phases were collected and dried over Na2SO4 and
evaporated to yield an yellow oil, which was used in next
reaction step without further purification (0.79 g, 96%). 1H
NMR (CDCl3): d 1.69 (q, J = 4.8, 2H, –CH2CH2CH2–), 1.76
(q, J = 4.8, 2H, –CH2CH2CH2–), 2.26 (ddd, 2H), 2.53 (t, 2H),
2.55–2.70 (m, 10H), 2.90 (t, J = 4, 2H, –CH2CH2CH2–), 3.02
(ddd, 2H), 3.18 (ddd, 2H), 3.71 (s, 2H, –CH2Ar), 7.47–7.50
and 8.16–8.20 (AA0BB0, 2H each, ArH); 13C{1H} NMR
(CDCl3): d 23.63, 26.10, 48.09, 48.33, 50.10, 51.22, 54.65,
54.79, 55.70, 56.95, 57.58, 123.29, 129.70, 146.89, 147.02 (for
the complete signal assignment see ESIw); ESI-MS: m/z 362.4
(M + H+).
Crystal data for 4Brꢁ2.5H2O. C21H39N5O6.5Br, Mr = 545.28;
colourless prism, monoclinic, space group C2/c,
a
=
=
19.4788(4),
b = 19.7272(4), c = 13.7214(3), b
97.7160(11)1, V = 5224.88(19) A3, Z = 8, Dc = 1.387 g
cmꢂ3, ymax = 27.501, m(Mo-Ka) = 1.619 mmꢂ1, T = 150 K.
Crystal data for [Cu(3)Br][PF6]. C19H31CuN5O2BrF6P, Mr
ꢀ
= 649.91; blue plate, triclinic, space group P1, a = 6.9960(4),
b = 10.2570(8), c = 17.8780(15) A, a = 73.592(3), b =
84.539(5), g = 80.636(4)1, V = 1212.60(16) A3, Z = 2, Dc =
1.780 g cmꢂ3, ymax = 27.471, m(Mo-Ka) = 2.688 mmꢂ1
T = 150 K.
,
CCDC reference numbers 652360 and 652361. For crystal-
lographic data in CIF or other electronic format see DOI:
10.1039/b709747f
Syntheses
Perhydro-3a,5a,8a,10a-tetraazapyrene. This compound was
prepared using the reported procedure,9 modified in the
following manner: in a 50 ml flask, glyoxal trimer dihydrate
(1.8 g, 8.6 mmol) was mixed with distilled water (20 ml) and
heated to approximately 80 1C (until all solids dissolved). The
solution was cooled to B60 1C and diluted by methanol (20
ml). In a separate 500 ml flask, cyclam (5 g, 25 mmol) was
dissolved in methanol (200 ml) and cooled using an ice-bath to
B3 1C. To this solution was added the above-prepared solu-
tion of glyoxal in a dropwise manner in B30 min. The cooling
bath was removed after complete addition and the resulting
mixture was further stirred at ambient temperature for 2 h.
The solvents were evaporated and 50 ml of acetonitrile were
added to the mixture to precipitate the unreacted cyclam. The
precipitate was filtered off and the solvent evaporated do give
a slightly yellow oil, which was used without any further
purification. Yield 4.9 g (87%, based on cyclam).
The yellow oil was dissolved in 49% aq. HBr (5 ml). The
solution was left in a glass desiccator filled with acetone. On
vapour diffusion over several days, light yellow needles of the
hydrate of hydrobromide salt of 3 precipitated out of the
solution. The product was filtered off, washed with acetone
and air-dried to yield yellowish needles of the product (1.20 g,
76%). mp = 182–184 1C. Found: C 27.20, H 5.30, N 8.31.
Calc. for C19H31N5O2ꢁ5HBrꢁ4H2O: C 27.23, H 5.29, N 8.36%.
1H NMR (D2O): d 1.9–2.2 (br m, 4H), 2.7–3.1 (br m, 8H),
3.2–3.7 (br m, 12H), 4.1 (br, 2H), 7.48 (d, J = 8.8, 2H, ArH),
2.20 (d, J = 8.8, 2H, ArH); 13C{1H} NMR (D2O): d 23.24,
25.78, 47.69, 48.02, 49.67, 50.92, 54.20, 54.36, 55.33, 56.57,
57.16, 122.87, 129.3, 146.53. 146.60; ESI-MS m/z 362.4
(M + H+).
ESI-MS: m/z 223.2 (M + H+), 245.2 (M + Na+).
Perhydro-3a-(4-nitrobenzyl)-3a,5a,8a,10a-tetraazapyrenium
bromide (2Br). The oil prepared in the previous step was
dissolved in anhydrous acetonitrile (25 ml) and 4-nitrobenzyl
bromide (6 g, 27.8 mmol) was added to the solution. The
mixture became cloudy after approximately 60 min of stirring
and was further stirred for 48 h. The resulting light yellow
precipitate was filtered off, washed with 10 ml of acetonitrile
and 10 ml of methylene dichloride and dried in vacuo to give
the product in form of a yellowish powder (9.1 g, quant. 84%
Attempted syntheses of 4a resulting in preparation of 5Br. To
the yellow oil prepared from 2 g of 2Br as described above
dissolved in acetonitrile (50 ml), 1 equiv. of a base (0.5 g of
Et3N, 0.6 g of DIPEA or 0.7 g of K2CO3) was added. To the
mixture 1 equiv. of the alkylating agent (0.8 g of ethyl
bromoacetate or 0.9 g of tert-butyl bromoacetate, respectively)
was slowly added and the mixture was stirred overnight at
ambient temperature. The resulting solution was evaporated
(in the case of K2CO3 after filtration of the solids) and the
resulting ester was hydrolysed (stirring the ethyl ester under
reflux in 6 M aq. HCl or the tert-butyl ester at ambient
temperature with trifluoroacetic acid–methylene dichloride
1
based on cyclam); mp 189–190 1C; H NMR (D2O): d 1.4 (br
d, J = 13.99, 1H), 1.75 (br d, J = 14.33, 1H), 2.15 (qt, 2H),
2.29 (td, J = 13.6 and 4, 2 H), 2.4–2.5 (m, 2H), 2.61 (td, J =
ꢀc
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(1 : 1) overnight). The mixture was evaporated yielding an
yellow oil, which was dissolved in B5 ml of 49% aq. HBr. On
addition of several drops of distilled water the product began
to crystallise within 1 min and the mixture was left for
crystallisation for further 5 min. The resulting crystalline
material was filtered off, washed with cold ethanol (10 ml)
and acetone (10 ml) and air-dried to yield off-white micro-
crystalline product 5Br (4.2 g, quantitative, based on the
amount of added alkylating agent).
[5-(4-Nitrobenzyl)-1,5,8,12-tetraazabicyclo[10.2.2]hexadec-8-
yl]methylphosphinic acid (6). 5-(4-Nitrobenzyl)-1,5,8,12-tetra-
azabicyclo[10.2.2]hexadecane (3), prepared from 2 g of 2Br as
described above, was dissolved in 5 M aq. HCl (10 ml). To the
stirred mixture paraformaldehyde (0.35 g, 12 mmol) and solid
phosphinic acid (1.5 g, 23 mmol) were added and the suspen-
sion was stirred and heated to B35 1C for 72 h. The resulting
solution was evaporated in vacuo (with the water-bath tem-
perature not exceeding 40 1C), dissolved in distilled water
(5 ml) and chromatographed using cation-exchanging resin
(Dowex 50 in H+ form, elution H2O, followed by 5% aq.
ammonia). The ammonia eluate was evaporated, the residue
dissolved in water and re-chromatographed using an anion-
exchanging resin (Dowex 1 in OHꢂ form, elution H2O fol-
lowed by 10% acetic acid). The acidic eluate was evaporated,
the residue dissolved in mixture of ethanol (5 ml) and conc. aq.
HCl (1 ml). Acetone (100 ml) was added to the solution to
precipitate the product in form of a hydrochloride salt, which
was filtered after overnight standing at ambient temperature
(transformation of the amorphous precipitate to a microcrys-
talline powder) and dried under vacuum to yield 0.86 g of an
off-white powder (27% based on 2Br).
Mp = 171–172 1C. Found: C 32.33, H 5.28, N 7.89, Br
35.87. Calc. for C23H36N5O6Brꢁ3HBrꢁ3H2O: C 32.30, H 5.30,
1
N 8.19, Br 37.37%. H NMR (D2O): d 2.26 (m, 2H, –CH2C-
H2CH2–), 2.4 (m, 2H, –CH2CH2CH2–), 3.2–3.41 (m, 8H), 3.63
(t, J = 5.2, 2H), 3.76–3.96 (m, 6H), 4.15 (t, J = 6.8, 2H),
4.20–4.32 (m, 4H), 4.44 (s, 1H), 4.46 (s, 1H), 7.73 (d, J = 8.8,
2H, ArH), 8.33 (d, J = 8.8, 2H, ArH); 13C{1H} NMR (D2O):
d 20.04, 22.02, 45.88, 52.26, 52.74, 54.22, 55.12, 56.14, 56.32,
57.20, 58.86, 63.17, 126.61, 134.93, 139.1, 151.2, 168.2, 176.8;
ESI-MS m/z 477.8 (M + H+), 500 (M ꢂ H + Na+).
1-Carboxymethyl-5-(4-nitrobenzyl)-5,8,12-triaza-1-azoniabi-
cyclo[10.2.2]hexadecane bromide (4Br). 5-(4-Nitrobenzyl)-
1,5,8,12-tetraazabicyclo[10.2.2]hexadecane prepared from 2 g
of 2Br as described above, was dissolved in diethyl ether (50
ml). Bromoacetic acid (0.3 g, 2.1 mmol, B0.45 eq) solution in
diethyl ether (10 ml) was then added in a dropwise manner to
the macrocycle solution at ambient temperature with vigorous
stirring. Immediately on mixing of the reagents a slightly
yellow precipitate appears in the reaction mixture. After the
complete addition of the alkylating agent the mixture was
stirred for further 60 min, the liquid phase was decanted and
the remaining solid was air-dried. The crude product was
dissolved in an EtOH–H2O mixture (5 ml, 1 : 1) and the
solution carefully covered with a large amount of acetone.
After 48 h of standing a drop of deep yellow oil separated on
the bottom of the flask and some yellow crystals precipitated
on the walls of the flask. The crystals were carefully separated,
washed with acetone and air-dried, yielding 0.43 g of the
product (19%, B95% purity according to NMR measure-
ments). 100 mg of the product were dissolved in hot distilled
water in a NMR tube. On slow cooling to room temperature
yellow crystals suitable for the single-crystal X-ray analysis
appeared on the walls of the tube.
Found: C 39.73, H 6.53, N 11.32, Cl 22.09. Calc. for
C20H34N4O5Pꢁ4HClꢁH2O: C 39.81, H 6.68, N 11.61, Cl
25.63%. 1H NMR (D2O): d 2.05 (br, 2H, –CH2CH2CH2–),
2.20 (br, 2H, –CH2CH2CH2–), 2.60–3.85 (br m, 18H), 4.40 (s,
2H, –CH2Ar), 6.92 (d, J = 522, 1H, P–H), 7.70 (d, J = 8.8,
2H, ArH), 8.20 (d, J = 8.8, 2H, ArH); 31P NMR (D2O): d 26.2
(d, J = 522, P–H); ESI-MS m/z 439.9 (M + H+).
[5-(4-Nitrobenzyl)-1,5,8,12-tetraazabicyclo[10.2.2]hexadec-8-
yl]methylphosphonic acid (7). 5-(4-Nitrobenzyl)-1,5,8,12-tetra-
azabicyclo[10.2.2]hexadecane (3), prepared from 2 g of 2Br as
described above, was dissolved in triethyl phosphite (10 ml)
and paraformaldehyde (0.3 g, 10 mmol) was added. The
heterogeneous mixture was warmed to 50 1C and stirred at
this temperature for 72 h. The solution was cooled to ambient
temperature and chromatographed using cation-exchanging
resin (Dowex 50 in H+-form, elution H2O–ethanol 1 : 1, H2O
followed by conc. aq. NH3–ethanol 1 : 1). The ammonia eluate
was evaporated in vacuo to produce a diethyl ester of 7 as a
yellow oil (ESI-MS m/z 512.3 (M + H+). The crude ester was
dissolved in 5 M aq. HCl (30 ml) and refluxed for 24 h. The
solvent was evaporated, the residue dissolved in 49% aq. HBr
(2 ml) and precipitated by addition of acetone (100 ml). On
standing for 48 h the amorphous solid became more compact
and was filtered off, washed with acetone (20 ml) and dried
under vacuum to yield the product (0.31 g, 12% of expected
amount based on 2) in form of hydrobromide hydrate as a
light yellow powder.
The oily substance remaining after isolation of the first
batch of the product was dissolved in 4 M ethanolic HBr
solution (10 ml). The solvents were evaporated under vacuum
yielding the product in form of hydrobromide hydrate as a
light yellow powder (1.06 g, overall yield B50%) with purity
similar to the first batch of crystals.
Mp = 186–190 1C. Found: C 31.22, H 5.40, N 8.44, Br
37.24. Calc. for C21H33N5O4Brꢁ3HBrꢁ3.5H2O: C 31.29 , H
5.50, N 8.64, Br 39.65%. 1H NMR (D2O): d 1.98 (q, 2H,
–CH2CH2CH2–), 2.05 (q, 2H, –CH2CH2CH2–), 2.70–2.98 (m,
8H), 3.20–3.28 (m, 4H), 3.34 (t, J = 5.2, 2H), 3.39 (t, J = 5.3,
2H), 3.80–3.88 (br m, 4H), 3.90 (s, 2H), 4.15 (s, 2H), 7.53 (d, J
= 8.8, 2H, ArH), 8.26 (d, J = 8.8, 2H, ArH); 13C{1H} NMR
(D2O): d 20.69, 21.67, 45.51, 49.36, 50.79, 52.07, 54.82, 55.39,
55.52, 61.96, 63.74, 123.79, 131.17, 143.59, 147.18, 168.72;
ESI-MS m/z 420.0 (M + H+), 442.0 (M + Na+).
Mp = 179–180 1C. Found: C 30.23, H 5.19; N 8.45, Br
39.74. Calc. for C20H33N5O4Pꢁ4HBrꢁ2H2O: C 30.10, H 5.18, N
8.77, Br 42.66%; 1H NMR (D2O): d 2.1–2.45 (m, 4H, –CH2C-
H2CH2–), 2.75–4.15 (br m, 18H), 4.52 (s, 2H, –CH2Ar), 7.83
(d, J = 8.8, 2H, ArH), 8.36 (d, J = 8.8, 2H, ArH); 31P NMR
(D2O): d 22.62 (s, pD B1), 18.69 (s, pD B13, NaOD);
13C{1H} NMR (D2O, pD B13): d 21.7, 21.9, 44.0, 44.4,
47.5, 47.9, 50.1, 50.4, 51.1, 51.9, 53.8, 58.0, 123.5, 130.9,
145.4, 146.9; ESI-MS m/z = 455.8 (M + H+).
ꢀc
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Preparation of [Cu(3)Br][PF6]. 5-(4-Nitrobenzyl)-1,5,8,12-
tetraazabicyclo[10.2.2]hexadecane (100 mg, 0.1 mmol) in the
form of the HBr adduct prepared as described above, was
dissolved in distilled water (1 ml). CuCl2ꢁ2H2O (21 mg, 0.1
mmol) was dissolved in another 1 ml of distilled water and this
solution was added to the solution of ligand 3. The violet-blue
solution was refluxed for 10 min and an ethanolic solution of
NH4PF6 (20 mg in 1 ml of EtOH) was added. The final
solution was concentrated under reduced pressure to precipi-
tate the complex, which was filtered off, washed with H2O
(1 ml) and ethanol (1 ml) and air-dried to yield a deep violet
powder of the complex (54 mg, 70%). This product was
recrystallized from acetonitrile (1 ml) to form blue–violet
single crystals suitable for X-ray structure determination.
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16 (a) G. C. Valks, G. McRobbie, E. A. Lewis, T. J. Hubin, T. M.
Hunter, P. J. Sadler, C. Pannecouque, E. De Clerq and S. J.
Archibald, J. Med. Chem., 2006, 49, 6162; (b) A. Khan, J. D.
Silversides, L. Madden, J. Greenman and S. J. Archibald, Chem.
Commun., 2007, 416; (c) J. D. Silversides, C. C. Allan and S. J.
Archibald, Dalton Trans., 2007, 971; (d) G. McRobbie, G. C.
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Conclusions
Synthesis of a series of new compounds built on the 1,4-en-
cyclam skeleton is reported. During the synthetic procedure an
unexpected alkylation pathway of the mono-p-nitrobenzyl-
substituted derivative was observed. The protonation con-
stants of the ligands together with the thermodynamic stability
constants of their copper(II) and zinc(II) complexes are surpris-
ingly lower than expected for the constrained azamacrocycles.
Formation of the metal complexes is relatively slow at room
temperature, thus the pH-metric experiment cannot be fol-
lowed by common procedure but only by using the out-of-cell
method; however, these complexes should be of use for com-
plexation of copper radioisotopes with life-times of the order
of hours (64Cu and 67Cu). The thermodynamic stability con-
stant of the CuII complex of 3 is approx. 10 orders of
magnitude lower than the constants of the similar complex
of ligand 1 (15.5 vs. 26.1). The difference is in good agreement
with the constants observed for copper(II) complexes of cyclam
and Me4cyclam (28.1 vs. 18.3).
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´
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The solid-state structure of the [Cu(3)Br][PF6] complex was
also determined; the copper central atom is surrounded by the
macrocycle and the bromine atom forming a coordination
sphere which is intermediate between trigonal bipyramidal and
square pyramidal.
Acknowledgements
23 I. Lukes, J. Kotek, P. Vojtı
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Chem. Soc., Dalton Trans., 1996, 2685.
´
sek and P. Hermann, Coord. Chem.
We thank Dr I. Cısarova for X-ray data acquisition. This
´ ´
´
sek, I. Cısarova and P. Hermann, J.
´ ´
work was supported by the Grant Agency of the Czech
Republic (GACR 203/06/0467), Academy of Sciences of
Czech Republic (AVCR KAN 2011106510), Ministry of Edu-
cation and Youth of Czech Republic (Long term research plan
of the Ministry of Education of the Czech Republic
No. MSM0021620857) and EU COST D38 programme.
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package is available (free of charge) on http://www.nature.cuni.cz/
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504 | New J. Chem., 2008, 32, 496–504