Equilibrium and kinetic properties of CuII cyclophane complexes: The effect of changes in the macrocyclic cavity caused by changes in the substitution at the aromatic ring

Article abstract of DOI:10.1002/ejic.200701109

The o-B232, m-B232 and p-B232 cyclophanes result from attaching the terminal amine groups of 1,4,8,11-tetraazaundecane (232) to the benzylic carbons of the corresponding o-, m- or p-xylanes. The cavity size of these cyclophanes changes moderately as a con

Full text of DOI:10.1002/ejic.200701109

FULL PAPER
DOI: 10.1002/ejic.200701109
Equilibrium and Kinetic Properties of CuII Cyclophane Complexes: The Effect
of Changes in the Macrocyclic Cavity Caused by Changes in the Substitution
at the Aromatic Ring
Begoña Verdejo,[a] Manuel García Basallote,*[b] Armando Ferrer,[b] María Angeles Mañez,[b]
[b]
[c]
[c]
[d]
ˇ
Juan Carlos Hernández, Martin Chadim, Jana Hodacová,* José Miguel Llinares,
Conxa Soriano,[d] and Enrique García-España*[a]
Dedicated to Professor Ramón Mestre on the occasion of his retirement
Keywords: Cyclophanes / Copper(II) complexes / Protonation constants / Kinetics / Macrocyclic ligands
The o-B232, m-B232 and p-B232 cyclophanes result from at-
taching the terminal amine groups of 1,4,8,11-tetraaza-
undecane (232) to the benzylic carbons of the corresponding
o-, m- or p-xylanes. The cavity size of these cyclophanes
changes moderately as a consequence of the substitution at
the aromatic ring. The effects caused by these changes on
the equilibrium constants for protonation and CuII complex
formation of the cyclophanes are analyzed and compared
with those of the noncyclic 232 polyamine. All three cy-
clophanes form mononuclear complexes, but only o-B232 is
able to coordinate to CuII through the four amine groups
simultaneously, whereas m-B232 and p-B232 can only use
three nitrogen donors. The larger cavity and higher flexibility
of the latter two cyclophanes allow them to form stable dinu-
clear CuII complexes. The kinetics of the acid-promoted
dissociation of CuII from its mono- and dinuclear complexes
has also been studied and the results indicate the existence
of large differences in the kinetic properties for the com-
plexes with these three closely related ligands. Whereas the
mononuclear m-B232 and p-B232 complexes decompose
with very similar kinetic behaviour to that of the Cu(232)2+
complex, the lability of the Cu–N bonds is largely reduced in
the Cu(o-B232)2+ complex, and this leads to slower decompo-
sition and even to a different rate law for this complex. The
dinuclear complexes are not formed with o-B232, and very
different decomposition kinetics is observed for the com-
plexes formed by m-B232 and p-B232. In the case of m-B232,
the two metal ions are situated very close to each other,
which causes a rapid release of one of them upon reaction
with acid. In contrast, the larger size of p-B232 allows it to
accommodate two metal ions without important electrostatic
or steric interactions so that they are released with statistic-
ally controlled kinetics.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
ionic species as a function of the protonation state of the
amine groups.[2] These receptors form very stable complexes
with 3d metal ions, their stability usually increasing with
the number of donor groups because of the chelate
effect.[3] For the case of CuII, open-chain tetraamine ligands
such as 1,4,7,10-tetraazadecane (222) and 1,4,8,11-tetraaza-
undecane (232) form very stable complexes in which the
four amine donor groups are arranged in a square-planar
disposition around the metal ion.[4] The 232 complexes are
more stable than the 222 complexes because of both the
higher basicity of the ligand and its capability to form one
six-membered chelate ring that reduces the steric con-
straints associated with tetradentate coordination at the
corners of a square.[5,6] In fact, the crystal structure of [Cu-
(232)](ClO4)2 shows a square-planar coordination mode for
the tetraamine,[7] whereas for the related 222 complex the
exclusive formation of five-membered chelate rings forces
the metal ion to be situated out of the plane defined by
Polyamine ligands constitute one of the most commonly
used families of receptors in coordination chemistry[1] be-
cause of their capability to coordinate metal ions and an-
[a] Departament de Química Inorgànica, Institut de Ciència Mo-
lecular (ICMOL),Universitat de València, Edificio de Institutos
de Paterna,
Apartado de Correos 22085, 46071 Valencia, Spain
Fax: +34-96-3543274
E-mail: enrique.garcia-es@uv.es
[b] Departamento de Ciencia de los Materiales e Ingenieria Metal-
úrigica, Facultad de Ciencia, Universidad de Cádiz,
Apdo. 40, Puerto Real, 11510 Cádiz, Spain
E-mail: manuel.basallote@uca.es
[c] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic,
Flemingovo nam. 2, 16610 Prague 6, Czech Republic
[d] Departament de Química Orgànica, Institut de Ciència Molec-
ular (ICMOL), Universitat de València, Edificio de Institutos
de Paterna,
Apartado de Correos 22085, 46071 Valencia, Spain
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
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FULL PAPER
the four nitrogen donors.[8] These differences between very plex, whose crystal structure reveals the ligand’s bidendate
closely related ligands can be useful for medical applica- character with respect to each one of the metal centres.[17]
tions such as the investigation of chelating alternatives for Although there is a large amount of information regarding
-penicilamine in the treatment of Wilson’s disease, in dinuclear complexes formed with cyclophanes and related
which large amounts of CuII are accumulated in the organ- ligands with a large macrocyclic cavity, the information
ism.[9,10] In this way, it has been shown that the 232 polya- available regarding the relative stability and, especially, the
mine leads to higher copper excretion rates than the 222 kinetic properties of the mono- and dinuclear complexes
polyamine or -penicilamine.[11] Another potential impor- formed with cyclophanes derived from open-chain tetra-
tant medical application of this kind of ligand is the devel- amines such as 232 is relatively scarce.[18] In this sense, the
opment of compounds useful for radiopharmaceutical ap- study of the family of cyclophanes shown in Scheme 1 pro-
plications with copper-64, as it has been suggested that cy- vides an excellent opportunity to analyze in detail the way
clic polyamines with a cyclam backbone are optimal for in which subtle modifications, such as those caused by a
these purposes.[12]
change in the substitution at the aromatic spacer, affect
The formation of macrocyclic ligands composed of these these properties. The synthesis of the m-B232 and p-B232
polyamines and an aromatic spacer (cyclophanes) results in ligands is described for the first time in this paper, and these
increases in the rigidity and preorganization of the organic have been used to conduct a comparative equilibrium and
molecule, and this has been exploited in recent decades to kinetic study on their copper complexes (Figure 1).
develop a rich and interesting chemistry[13] that includes the
formation of tertiary species suitable for recognition or
catalytic purposes.[14] From the point of view of the present
work, it is interesting to note that these kinds of complexes
can undergo reorganization movements associated with the
protonation of the uncoordinated nitrogen atoms, which
can be observed by studying the kinetics of the acid-
promoted decomposition of the different species of com-
plexes.[15] These reorganization processes resemble some
molecular movements occurring in nature that are powered
by gradients in the proton concentration such as the rota-
tion of the γ protein in the F0/F1 ATP-synthase and the
flagellar rotation in bacteria.[16]
Another interesting case is that in which the aromatic
spacer causes the donor groups in the polyamine chain to
behave as two separate subunits that simultaneously coordi-
nate two metal centres, as occurs in the case of the dinuclear
2,5,8,11-tetraaza[12]paracyclophane (p-B222) CuII com-
Figure 1. Synthetic pathway for the synthesis of the m-B232 and p-
B232 cyclophanes.
Scheme 1.
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Equilibrium and Kinetic Properties of CuII Cyclophane Complexes
stants from a regular trend have been previously observed
for cyclam and other ligands.[17–20] The formation of intra-
molecular hydrogen bonds is strongly favoured by the pres-
ence of the o-xylyl spacer, but they do not appear to be
relevant in the protonation of the related macrocycles con-
taining m- and p-xylyl spacers.[17]
Results and Discussion
Synthesis and Protonation of the Cyclophanes
The o-B232 polyamine has been prepared as described
previously.[18] The preparation of the new m-B232 and p-
B232 cyclophanes has been carried out using a procedure
similar to that previously described for related cyclophane
ligands.[15,17] This procedure is depicted in Figure 1 and it
consists of three sequential steps involving tosylation of the
polyamine, cyclization by reaction with the corresponding
dibromoxylene and detosylation to obtain the final prod-
ucts, which were isolated as the tetrahydrobromide adducts.
Full details are given in the Experimental section.
The protonation equilibrium constants for the whole
series of ligands in Scheme 1 were obtained from the analy-
sis of potentiometric titrations, and their values are in-
cluded in Table 1. The open-chain 232 ligand shows a sig-
nificantly higher overall basicity than its cyclic analogues,
which can be related to its higher flexibility and higher
capability to separate the positive charges created upon pro-
tonation. For the case of the cyclophanes, the cyclic nature
of the ligands introduces severe constraints on the relative
positions of the different amine groups, which results in a
decreased basicity. In addition, although the presence of an
aromatic spacer forces the separation of the two nitrogen
atoms closer to the spacer (Figure 2), it also leads to a lower
flexibility. As a consequence, the four successive proton-
ation constants for m-B232 and p-B232 are smaller than the
corresponding constants for 232, the difference increasing
with the degree of protonation. However, the behaviour of
o-B232 is slightly different: the first two protonation pro-
cesses occur with constants significantly larger than those
found for the acyclic 232 ligand. This increased basicity in
the early protonation stages can be explained by the forma-
tion of intramolecular hydrogen bonds between couples of
protonated and unprotonated nitrogen atoms, as revealed
by NMR studies at different pH values[21] and by the crystal
structure of the [H2(o-B232)](picrate)2·1/2(C3H6O) mole-
cule.[18] As the third and fourth protonation steps involve
the breaking of the hydrogen bond network, the values of
the corresponding equilibrium constants are smaller than
for the other ligands, the fourth one being so small that it
cannot be determined from the potentiometric data (logK
Ͻ 2). These deviations in the values of the protonation con-
Figure 2. Estimated size of the macrocyclic cavity in the o-B232,
m-B232 and p-B232 cyclophanes as calculated with molecular mod-
eling.
The Stability of CuII Complexes
Table 2 includes the stability constants of the CuII com-
plexes with the 232, o-B232, m-B232 and p-B232 ligands.
These values were derived from the analysis of the potentio-
metric titrations of solutions containing the metal and the
ligand in 1:1 and 2:1 molar ratios at 298.1 K in the presence
of 0.15 moldm–3 NaClO4 (for solubility reasons, NaCl was
used in the case of p-B232).
The data for the 232 and o-B232 ligands had been pub-
lished previously,[5,6,18] and so they will be discussed only
briefly for comparative purposes. The equilibrium model
for the CuII complexes of these two ligands is very simple
and includes only the formation of CuL2+ and HCuL3+ spe-
cies, without any evidence of the formation of dinuclear
species. Despite the fact that the crystal structures of the
complexes with both ligands are similar with the four amine
groups coordinated to the metal centre in the equatorial
plane,[7,18] the stability of the CuL2+ complex with o-B232
is about five orders of magnitude lower than that formed
with the acyclic 232 ligand. In contrast, the formation of
HCuL3+ from CuL2+ is more favoured for the cyclic ligand.
These observations can be explained by considering the
lower basicity of o-B232 and the formation of a seven-mem-
bered chelate ring in the Cu(o-B232)2+ species.
Table 1. Logarithms of the stepwise protonation constants for 232,
o-B232, m-B232 and p-B232 measured in 0.15 moldm–3 NaClO4 at
298.0Ϯ0.1 K.
The equilibrium model required for a satisfactory fit of
the data for the m-B232 and p-B232 cyclophanes is more
complex, with the formation of additional mononuclear
Reaction
232
10.10(5)[b] 11.01(3)
o-B232[d]
m-B232
p-B232
[H2CuL4+
,
H3CuL5+ and CuL(OH)+] and dinuclear
H + L = HL[a]
H + HL = H2L
H + H2L = H3L
H + H3L = H4L
log β[c]
9.83(8)
8.60(8)
5.92(1)
3.88(1)
28.23
9.55(3)
8.59(3)
5.81(5)
4.50(5)
28.45
[Cu2L4+, Cu2L(OH)3+ and Cu2L(OH)22+] species. It is im-
portant to note that because of the close proximity of the
metal centres in the dinuclear complexes, conversion to hy-
droxo-bridged species is favoured for both cyclophanes as
a way to reduce electrostatic repulsion. As expected from
the size of the macrocyclic cavity, the stability of the dinu-
clear species is higher in the case of p-B232. The same
9.42(3)
7.17(2)
5.76(2)
32.45
9.88(3)
2.20(7)
Ͻ2
23.09
[a] Charges not included. [b] The numbers in parentheses show the
standard deviation in the last significant figure. [c] Cumulative ba-
sicity constant for the ligand. [d] Data from ref.[18]
.
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Table 2. Logarithms of the stability constants for the formation of CuII complexes with the 232, o-B232, m-B232 and p-B232 ligands
measured in 0.15 moldm–3 NaClO4 at 298.0Ϯ0.1 K.
Reaction[a]
232[b]
o-B232[c]
m-B232
p-B232[d]
M + L p ML
23.30(1)
26.38(3)
17.73(3)
21.62(5)
13.29(1)
20.48(4)
24.11(1)
–
12.71(1)
18.80(9)
23.69(1)
27.83(1)
–
M + H + L p MHL
M + 2 H + L p MH2L
M + 3 H + L p MH3L
M + L + H2O p ML(OH) + H
–
–
–
–
–
–
4.15(2)
2 M + L p M2L
2 ML + L + H2O p M2L(OH) + H
2 ML + L + H2O p M2L(OH)2 + H
–
–
–
–
–
–
–
16.81(2)
–
5.96(1)
9.31(9)
3.28(1)
[a] Charges not included. [b] The numbers in parentheses show the standard deviation in the last significant figure. [c] Data from ref.[18]
[d] Measured in 0.15 moldm–3 NaCl: logKHL/H·L = 9.82(5), logKH2L/H·HL = 8.57(5), logKH3L/H·H2L = 5.77(8), logKH4L/H·H3L = 4.41(8).
model was previously used for the related p-B222 ligand, clophanes derived from the related 222 polyamine: logK for
although in that case the shorter length of the polyamine the formation of Cu(m-B222)2+ is 13.52 whereas this value
leads to a smaller cavity size and to less stable dinuclear for the related o-B222 species (19.58) is several orders of
2+
species [logβ = 3.44 for the Cu2(p-B222)(OH)2 species vs. magnitude higher.[18]
5.96 for the corresponding p-B232 species]. The symmetri-
cal nature of the m-B232 and p-B232 ligands makes it rea-
sonable to think that the structure of the dinuclear com-
plexes is similar to that previously reported for [Cu2(p-
B222)Cl4],[17] in which each metal centre is coordinated to
two of the amine groups in the cyclophane.
The stability of the mononuclear CuL2+ species with the
m-B232 and p-B232 ligands is very similar to and about
four orders of magnitude lower than that of the related o-
B232 complex, which suggests that changing the substitu-
tion at the aromatic ring from ortho to meta or para causes
a change in the coordination mode of the cyclophanes.
Figure 3. Schematic representation of copper coordination with m-
However, as the p-B232 data were obtained in the presence
of Cl– and the crystal structure of the Cu(o-B232)2+ com-
plex also reveals the presence of a coordinated chloride, it
can be argued that these differences in the equilibrium con-
stants are caused, at least in part, by the change in the na-
B232, o-B232 and p-B232.
Additional information about the dentate character of
ture of the supporting electrolyte. Nevertheless, although the cyclophanes in the CuL2+ species can be obtained by
precipitation hinders the determination of the complete set comparing the values of its protonation constants with
of equilibrium constants for the CuII–p-B232 system in those of the free ligand species with the same charge. Al-
0.15 moldm–3 NaClO4, the analysis of potentiometric data though deriving coordination numbers just from free energy
in this medium allows for the determination of the stability terms can often be misleading, a careful consideration of
of the mononuclear species and the results indicate that the protonation constants of the complexes as well as com-
logK for the formation of Cu(p-B232)2+ is 12.05. This value parison with related systems may be useful in some in-
is quite close to that in Table 2 and shows that changing stances. In this way, it is found that the conversion of CuL2+
the nature of the anion in the supporting electrolyte from to HCuL3+ (CuL2+ + H+ p CuHL3+; logK = 7.19 and 6.09
chloride to perchlorate does not lead to large changes in for m-B232 and p-B232, respectively) occurs with constants
the stability of the metal complexes; therefore the stability higher than those corresponding to the protonation of
differences found for the three cyclophanes must be mainly H2L2+ to give H3L3+ (logK = 5.92 and 5.81 for m-B232 and
associated with changes in the nature of the ligand. p-B232, respectively), which clearly indicates that the first
Whereas for o-B232 all four nitrogen donors are able to protonation of the metal complex occurs at a noncoordi-
coordinate simultaneously to the metal centre, in the case nated amine group. Moreover, as the logK values for the
of m-B232 and p-B232 the substitution at the aromatic ring formation of the Cu(m-B232)2+ and Cu(p-B232)2+ species
hinders the simultaneous coordination of the two benzylic are close to those found for related polyamines acting as
nitrogen atoms and the ligand can only use a maximum of tridentate ligands,[17,23] it is reasonable to conclude that m-
three donor groups in the formation of mononuclear com- B232 and p-B232 coordinate to the metal centre in CuL2+
plexes (see Figure 3).[22] In agreement with this conclusion, using the two central and one of the benzylic amine groups,
a similar behaviour is observed for the complexes with cy- the other benzylic nitrogen remaining uncoordinated.
1500
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Equilibrium and Kinetic Properties of CuII Cyclophane Complexes
sulting from the protonation or hydroxylation of the CuL2+
complexes.[15,23] For this reason, it is necessary to control
the pH of the starting complex solution in these kinetic
studies by selecting pH values at which the distribution
curves indicate the existence of a single major species. The
application of this criterion to the ligands studied in the
present work indicates that the only species whose decom-
position kinetics can be measured without interference from
significant amounts of other species in equilibrium are
Kinetics of the Acid-Promoted Decomposition of
the CuII Complexes
As an example, the species distribution curves corre-
sponding to the formation of CuII complexes in solutions
containing CuII and m-B232 in 1:1 and 2:1 molar ratios
are included in Figure 4, which shows that solutions with
equimolar amounts of metal and cyclophane contain mo-
nonuclear species with a protonation degree that changes
with pH and that the formation of dinuclear complexes is
negligible. In contrast, the dinuclear complexes dominate
the distribution curves in neutral and basic solutions con-
taining a 2:1 molar ratio (Cu/L). The distribution curves for
the formation of metal complexes with the other ligands are
included in the Supporting Information.
Cu(232)2+, Cu(o-B232)2+, HCu(m-B232)3+, Cu(m-B232)2+
,
2+
Cu(m-B232)OH+, Cu2(m-B232)(OH)2 and Cu2(p-B232)-
(OH)22+. A kinetic study on the decomposition of these spe-
cies according to Equation (1) was carried out to analyze
the effects caused by changes in the size of the macrocyclic
cavity and its results are summarized in Table 3.
HyCuxL2x+ + H+ Ǟ x Cu2+ + HnLn+
(1)
exc
Table 3. Summary of the kinetic data for the decomposition of the
CuII complexes with the 232, o-B232, m-B232 and p-B232 ligands
measured in 0.15 moldm–3 NaClO4 at 298.0Ϯ0.1 K.
Species
Rate law[a]
Kinetic parameters[b]
Cu(232)2+ [c]
bc[H+]/(1 + c[H+]) b = 0.35(2) s–1
c = 50(6) mol–1dm3
Cu(o-B232)2+ [d]
d[H+]2 + e
d = 1.9(2)ϫ10–4
mol–2 dm6s–1
e = 1.1(3)ϫ10–5 s–1
a = 0.5(2) s–1
HCu(m-B232)3+
a + bc[H+][e]
bc = 118(5) mol–1dm3s–1
bc = 2.55(7) mol–1 dm3s–1
bc[H+][f]
Cu(m-B232)2+
[g]
Cu(m-B232)(OH)+
Cu2(m-B232)(OH)2
[g]
[h]
2+
2+ [i]
Cu2(p-B232)(OH)2
a + bc[H+]
a = 0.59(7) s–1
bc = 8.6(4) mol–1dm3s–1
[a] See explanation in the text. [b] The numbers in parentheses show
the standard deviation in the last significant figure. [c] Similar re-
sults are obtained when the supporting electrolyte is changed from
NaClO4 to NaCl or KNO3. [d] Data obtained in 1.0 moldm–3 Na-
ClO4. [e] First resolved kinetic step. [f] Second resolved kinetic step.
[g] The decomposition of these species occurs with the same kinet-
ics as for HCu(m-B232)3+. [h] The decomposition of this species
starts with a very fast step (Ͻ1.7 ms) that leads to a mononuclear
species, which decomposes more slowly with the same kinetics as
for HCu(m-B232)3+. [i] Data obtained in 0.15 moldm–3 NaCl.
Figure 4. Species distribution curves for the formation of CuII com-
plexes with the m-B232 cyclophane. The curves were obtained using
[L] = 1.0ϫ10–3 moldm–3 and CuII in 1:1 (top) or 2:1 (bottom)
molar ratios.
Inspection of the species distribution curves for the dif-
Ligands 232 and o-B232 only form mononuclear CuII
ferent CuII–L systems indicates that the degree of complex- complexes, the CuL2+ species showing in both cases a single
ation is negligible in strongly acidic solutions; therefore, the absorbance band with maxima centred at similar wave-
addition of an excess of acid to a solution of the complexes lengths [530 nm for Cu(232)2+ and 540 nm for Cu(o-
will result in complex decomposition with formation of B232)2+]; this suggests that the coordination environment
Cu2+
and the corresponding protonated form of the li- around the metal centre is the same, surely with all four
(aq)
gand [Equation (1)]. For other CuII polyamine systems, the nitrogen donors of the ligand coordinated, as revealed by
kinetics of this process has been found to occur over time the crystal structure of the complexes.[7,18] Despite the simi-
scales that span from sub-millisecond to days (or more) in larity of the structure and absorption band in both com-
duration, with this being dependent on the lability of the plexes, the decomposition kinetics of Cu(232)2+ and Cu(o-
metal–ligand bonds. Although most of the literature kinetic B232)2+ is very different. For the complex with the noncy-
studies on complex decomposition have been carried out by clic 232 polyamine, the reaction occurs in the stopped-flow
adding the acid excess to a solution prepared from a solid time scale and leads to complete decomposition of the com-
sample of the complex, we have previously demonstrated plex, as revealed by the complete disappearance of the ab-
that the kinetics of complex decomposition can be signifi- sorption band typical of the complex (Figure 5). The pro-
cantly different for closely related species such as those re- cess occurs in a single kinetic step with observed rate con-
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M. García Basallote, J. Hodacˇová, E. García-España et al.
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stants that show saturation behaviour with respect to the by Margerum and other workers,[15,24,25] which assumes
acid concentration [Figure 6 and Equation (2)]. The rate that dissociation of the Cu–N bond in the rate-determining
constants were found to be independent of the nature of the step occurs with the formation of an activated intermediate,
salt used as supporting electrolyte and, actually, the data in (CuL2+)*, with an increased Cu–N distance under steady-
Figure 6 were obtained by averaging the results obtained in state conditions [Equation (3)]. However, in this intermedi-
the presence of NaClO4, NaCl or KNO3 (0.15 moldm–3). ate there is no complete breaking of the bond; this is only
The values obtained from the fit of the experimental data completed upon acid (kH) or solvent (kH O) attack [Equa-
to Equation (2) are b = (0.35Ϯ0.02) s–1 and c = tions (4) and (5)]. As this intermediate 2is formed under
(50Ϯ6) mol–1 dm3, a being negligible. These results are in steady-state conditions, its concentration remains too low
good agreement with literature data,[24] although there are during the whole decomposition process and so it is not
small differences that can be related to the different concen- detectable in the kinetic traces, which simply show ab-
trations of supporting electrolyte used, as ionic strength ef- sorbance changes with time according to a single ex-
fects are expected to be important in this kind of reaction ponential. When the rate of decomposition through solvent
between charged species.
attack is much slower than that corresponding to acid at-
tack, the rate law has the same form as Equation (2), with
the a term being negligible, and b = k1 and c = kH/k–1,
where the constants k1 and k–1 represent the rate constants
for the reversible formation of the activated (CuL2+)* inter-
mediate from the starting complex. According to this
mechanism, the value of k1 = (0.35Ϯ0.02) s–1 provides in-
formation about the lability of the Cu–N bond.
a + bc[H+]
kobs
=
(2)
1 + c[H+]
CuL2+ p (CuL2+)*; k1, k–1
(3)
(4)
(5)
(CuL2+)* + H+ Ǟ Cu2+
+ HxLx+; kH
(aq)
(CuL2+)* + H2O Ǟ Cu2+
+ HxLx+; kH O
(aq)
2
Although decomposition of the Cu(o-B232)2+ complex
also occurs in a single measurable kinetic step, the process
is several orders of magnitude slower and it could only be
made to occur to a significant extent by increasing the acid
concentration by an order of magnitude, which also re-
quired an increase in the concentration of the supporting
electrolyte up to 1.0 moldm–3 NaClO4. Even under those
conditions, complete decomposition of the complex was not
achieved in all cases and the process occurs under equilib-
rium conditions at [H+] as high as 0.1–0.2 moldm–3. The
dependence of the observed rate constant on the acid con-
centration is also different, the plot of kobs vs. [H+] showing
the existence of a nonzero intercept and a second-order de-
pendence on the acid concentration (Figure 7). These data
could be reasonably well fit to Equation (6), with values of
e = (1.1Ϯ0.3)ϫ10–5 s–1 and d = (1.9Ϯ0.2)ϫ 10–4 mol–2
dm6 s–1. Although a second-order dependence with respect
to the acid concentration has been previously reported for
the decomposition of other complexes,[26] to the best of our
knowledge there is only a single recent report in which this
dependence coexists with a nonzero intercept in the rate law
for the decomposition of CuII polyamine complexes.[27]
Interpreting the rate law in Equation (6) in terms of the
Margerum’s mechanism requires that the rate-determining
step be associated with the breaking of the second Cu–N
bond rather than the dissociation of the first one. Given
that the process occurs under reversible equilibrium condi-
tions, the experimental data can be interpreted with the
Figure 5. Typical spectral changes observed during the acid-pro-
moted decomposition of the Cu(232)2+ complex. Plotted spectra
were recorded at 0.825 s intervals and show the complete disap-
pearance of the Cu(232)2+ absorbance centred at ca. 530 nm.
Figure 6. Plot of the acid concentration dependence of the observed
rate constant for the acid-promoted decomposition of the CuII
complexes with the 232 ligand.
With regard to the intimate mechanism of decomposition mechanism shown in Equations (7), (8) and (9), which indi-
of Cu(232)2+, the experimental rate law in Equation (2) can cates that acid attack on the activated intermediate to break
be interpreted in terms of the classical mechanism proposed the first bond does not result in complex decomposition but
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Equilibrium and Kinetic Properties of CuII Cyclophane Complexes
match the size of the CuII ion,[18] the more flexible noncy-
clic 232 ligand is also able to arrange itself in a similar way
around the metal ion without introducing important steric
constraints[7] and, actually, Cu(232)2+ decomposes more
slowly than complexes with other tetraamines that form
more distorted complexes.[24] To understand the very dif-
ferent decomposition kinetics of the CuII complexes with
232 and o-B232, it must be remembered that the reaction
kinetics is not only determined by the starting reagents, but
also depend on the chemical transformations occurring
along the reaction coordinate. As the decomposition pro-
cess starts with the elongation of the Cu–N bond (k1 step),
complexation with a ligand such as o-B232, which not only
readily accommodates a metal ion, but also introduces seri-
ous constraints on the lengthening of the metal–ligand
bonds, will lead to a significant decrease in the rate of de-
composition with respect to similar complexes with ligands
that are more flexible and able to reorganize more easily
upon an increase in the Cu–N distance. The present results
would thus indicate that the Cu(o-B232)2+ structure hinders
elongation of the Cu–N bond and makes the distortion
achieved in the k1 step too small to lead to complete com-
plex decomposition upon attack by a single H+, so that a
second proton attack is required. In contrast, the flexibility
of the noncyclic 232 ligand allows for the formation of an
activated intermediate, (CuL2+)*, with a larger increase of
the metal–ligand distance, which results in faster decompo-
sition upon proton attack.
Figure 7. Plot of the acid concentration dependence of the observed
rate constant for the acid-promoted decomposition of the CuII
complexes with the o-B232 ligand.
leads to the formation of a new I* intermediate that re-
quires attack by a second proton. If the processes in Equa-
tions (7) and (8) occur under conditions of reversible equi-
libria largely displaced to the left-hand side, the rate law for
this mechanism has the same form as in Equation (6) with
the equivalencies d = K1KH1k2 and e = k–2. As the nonzero
intercept can be related to the contribution of the reverse
process to the rate of reaction, there is no need to include
a kH O term for solvent attack, as was the case for the other
As a consequence of their higher cavity size, the m-B232
and p-B232 cyclophane ligands are able to simultaneously
coordinate two metal ions to thus yield binuclear species.
2
complex with the same kinetics of decomposition.[27] Re-
gardless, some contribution to the e term from parallel
water attack cannot be ruled out in the case of Cu(o-
B232)2+ on the basis of the current experimental data.
2+
For the case of m-B232, Cu2(m-B232)(OH)2 is the major
species in basic solutions containing CuII and m-B232 in a
2:1 molar ratio. The corresponding Cu2L(OH)3+ complex
only exists as a minor species, and Cu2L4+ cannot be de-
tected in the potentiometric studies This suggests that al-
though the size of this cyclophane allows for the simulta-
neous coordination of two metal ions, these are forced to
be too close to each other and a significant stability is only
achieved when two OH– bridges reduce the electrostatic re-
pulsion between the dipositive centres. In agreement with
kobs = e + d[H+]2
(6)
(7)
(8)
(9)
CuL2+ p (CuL2+)*; k1, k–1, K1
(CuL2+)* + H+ p I*; kH1, k–H1, KH1
I* + H+ p Cu2+ + HxLx+; k2, k–2; K2
The acquisition of very different results for the decompo- these considerations, the kinetic studies on the decomposi-
sition of the closely related Cu(232)2+ and Cu(o-B232)2+ tion of Cu2(m-B232)(OH)22+ indicate that upon addition of
complexes deserves some additional commentary. Although an excess of acid there is a rapid release of one of the metal
it can be intuitively thought that the kinetics of complex ions within the mixing time of the stopped-flow instrument
decomposition must be correlated with the stability of the (ca. 1.7 ms), and that this process is followed by the slower
decomposing complex, the present data clearly illustrate decomposition of the resulting mononuclear complex
that complex stability is not the major factor in determining [Equations (10) and (11)]. The latter process occurs with the
the rate of complex decomposition. Actually, Cu(o- same kinetics that is observed when the decomposition is
B232)2+ decomposes with rate constants four to five orders studied using starting solutions containing the mononu-
of magnitude slower than Cu(232)2+, despite the higher sta- clear HCu(m-B232)3+, Cu(m-B232)2+ or Cu(m-B232)(OH)+
bility of the latter species by more than five orders of mag- complexes, which indicates that the protonation processes
nitude. It has been proposed that the rate of demetallation associated with the interconversion of these species are very
of metal polyamine complexes can be correlated with the fast and that the decomposition of the more protonated
deviations of the coordination environment around the HCu(m-B232)3+ species is the kinetic process being moni-
metal centre with respect to ideal geometries, the more dis- tored in all cases. This observation is also in agreement with
torted complexes decomposing faster.[26,28] However, al- the stability results, which showed that not all of the amino
though the size of the cavity in o-B232 appears to exactly groups in m-B232 coordinate simultaneously to a single
Eur. J. Inorg. Chem. 2008, 1497–1507
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M. García Basallote, J. Hodacˇová, E. García-España et al.
For the case of p-B232, the distribution curves for solu-
FULL PAPER
metal ion, so that one of them remains uncoordinated and
behaves as a free amine, which results in very rapid proton- tions with 1:1 molar ratios show that there are no pH values
ation. The disappearance of the absorption band at 580 nm at which any of the mononuclear species exist without sig-
associated with the release of the metal ion from HCu(m- nificant amounts of other species in equilibrium; therefore,
B232)3+ occurs with biphasic kinetics, the rate constants for a separate kinetic study of the decomposition of the dif-
both resolved steps showing a linear dependence with re- ferent species is not possible. In any case, experiments were
spect to the acid concentration (Figure 8). These results can carried out that monitored the kinetics of decomposition of
be fit to Equation (12) with a = (0.5Ϯ0.2) s–1 and bc = solutions containing a mixture of mononuclear species,
(118Ϯ5) mol–1 dm3 s–1 for the first step, and with a negligi- which allowed the observation of the disappearance of a
ble value for a and bc = (2.55Ϯ0.07) mol–1 dm3 s–1 for the band at 580 nm in a single kinetic step. The values of kobs
second step. This rate law can also be interpreted on the for this process show a dependence with respect to the acid
basis of the classical mechanism of decomposition dis- concentration that can also be fit to Equation (12) with bc
cussed above, although the existence of a nonzero intercept = 48Ϯ2 mol–1 dm3 s–1 and a negligible value of a. These
for the first step indicates that in this case there is a signifi- values indicate that the decomposition kinetics of the mo-
cant contribution of the solvent attack (kH O) to the rate of nonuclear p-B232 complexes does not appear to be very
2
complex decomposition. The quotient bc/a corresponds to different from those observed for the 232 complex, which is
the kH/k
ratio and provides information about the rela- in agreement with an increase in the flexibility of the cy-
H2O
tive rates of decomposition through the parallel attacks by clophane complexes as the cavity size increases.
H+ and H2O.[23] Unfortunately, the absence of curvature in
For p-B232, the cyclophane with the largest cavity size
the plots in Figure 6 precludes the estimation of the lability of those studied in the present work, the equilibrium behav-
2+
of the Cu–N bonds through the resolution of values for b. iour also shows the formation of a stable Cu2L(OH)2
In any case, the values of the product bc for both steps is complex as the major species in basic solutions containing
less than an order of magnitude different from the value CuII and L in a 2:1 molar ratio. This species shows an elec-
for the complex with the noncyclic 232 ligand tronic absorption spectrum with an absorption band
(17.5 mol–1 dm3 s–1), which suggests that coordination of centred at 660 nm that disappears slowly upon addition of
only three of the four amine groups in the m-B232 complex excess acid. The process occurs in a single kinetic step with
leads to a kinetic behaviour that resembles that of the acy- rate constants whose dependence on the acid concentration
clic ligands, a situation very different from that found for can also be fit to Equation (12) with a = 0.59Ϯ0.07 s–1 and
o-B232.
bc = 8.6Ϯ0.4 mol–1 dm3 s–1. It is important to note that the
initial spectrum recorded in the stopped-flow experiments
2+
for the decomposition of Cu2(p-B232)(OH)2 coincides
2+
Cu2(m-B232)(OH)2 + H+ Ǟ Cu2+ + HCu(m-B232)3+
(10)
(11)
(12)
exc
with that recorded for the dinuclear complex (band at
660 nm), so that the process whose kinetics is being moni-
tored is that represented by Equation (13). In contrast, for
the related dinuclear m-B232 complex, the initial spectrum
in the kinetic experiments shows the band of the mononu-
clear species, which thus shows the rapid release of one
metal ion from the dinuclear species [Equations (10) and
(11)].
HCu(m-B232)3+ + H+ Ǟ Cu2+ + H4(m-B232)4+
exc
kobs = a + bc[H+]
Cu2(p-B232)(OH)2 + H+ Ǟ 2Cu2+ + H4(p-B232)4+
(13)
2+
exc
The observation of a single kinetic step for the release of
two metal ions from a binuclear complex has been pre-
viously observed for other systems and has been interpreted
in terms of the statistically controlled dissociation kinetics
of both metal ions.[29] This indicates that the size of the p-
B232 cyclophane allows for the simultaneous coordination
of two metal ions without significant electronic or steric
interaction between them, so that they behave as indepen-
dent reacting centres and dissociate with rate constants dif-
fering only in the statistical 2:1 ratio, in the same way as
dinuclear complexes with macrocycles of larger size.
Conclusions
Figure 8. Plot of the acid concentration dependence of the observed
rate constants for the acid-promoted decomposition of the mono-
nuclear CuII complexes with the m-B232 ligand. The circles and
the triangles correspond to the k1obs and k2obs, respectively.
As a whole, the stability and kinetic data in this paper
indicate that subtle changes in the size of the macrocyclic
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Eur. J. Inorg. Chem. 2008, 1497–1507

Equilibrium and Kinetic Properties of CuII Cyclophane Complexes
N,NЈ,NЈЈ,NЈЈЈ-Tetratosyl-2,5,9,12-tetraaza[13]paracyclophane
(p-
cavity of cyclophanes derived from the 232 open-chain tet-
raamine lead to gradual but relevant changes in the proper-
ties of their CuII complexes. For the smaller member of the
series (o-B232), a single metal ion is tightly coordinated to
the four amine groups to yield a very stable complex that
decomposes very slowly upon acid attack. When the substi-
tution at the aromatic ring changes to meta or para, one of
the benzylic amine groups cannot coordinate to the metal
ion and the stability of the mononuclear complexes de-
B232·4Ts): This compound was obtained by following the same
procedure as that for the synthesis of m-B232·4Ts but with 1,4-
bis(bromomethyl)benzene as a spacer; yield 3.7 g, 87%; m.p. 176–
1
178 °C. H NMR (CDCl3, 300 MHz): δ = 7.72 (d, J = 8 Hz, 4 H),
7.61 (d, J = 8 Hz, 4 H), 7.31 (d, J = 8 Hz, 4 H), 7.26 (d, J = 8 Hz,
4 H), 4.07 (s, 4 H), 3.01–2.95 (m, 4 H), 2.80–2.75 (m, 4 H), 2.70 (t,
J = 6 Hz, 4 H), 2.40 (s, 6 H), 2.37 (s, 6 H), 2.40–2.30 (m, 2 H)
ppm. 13C NMR (CDCl3, 75.43 MHz), δ = 144.3, 144.0, 136.6,
135.0, 134.5, 130.3, 130.2, 130.1, 128.0, 127.9, 54.9, 48.5, 48.3, 47.8,
creases by several orders of magnitude. In contrast, triden- 26.9, 22.0, 21.9 ppm. MS (FAB): m/z 879 [M + H]+.
tate coordination allows for higher flexibility and the com-
plexes decompose faster, with kinetic behaviour quite close
2,5,9,12-Tetraaza[13]metacyclophane (m-B232·4HBr): m-B232·4Ts
(2.5 g, 2.8 mmol) and phenol (13 g, 144 mmol) were suspended in
to that of the open-chain 232 ligand. The higher members
of the series (m-B232 and p-B232) are also able to form
dinuclear species whose stabilities increase with the size of
the macrocyclic cavity. Whereas the size of the p-B232 com-
plex is large enough to allow for the metal centres to behave
independently with respect to dissociation and thus decom-
pose with statistically controlled kinetics, for the case of m-
B232 the metal ions are situated closer to each other and
one of them dissociates very rapidly upon reaction with
acid. These results demonstrate that the kinetics of demetal-
lation of macrocyclic CuII complexes can be finely tuned
by introducing minor modifications in the ligand structure,
which can be exploited, for example, when designing cop-
per-64 radiopharmaceuticals.
HBr/OHAc (33%, 140 mL). The mixture was stirred at 90 °C for
24 h. Then the heating was stopped and after several hours a solid
appeared which was filtered and extensively washed with EtOH/
1
CH2Cl2 (1:1); yield 1.3 g, 73%; m.p. 238–240 °C. H NMR (D2O,
300 MHz): δ = 7.79 (s, H), 7.70 (s, 3 H), 4.48 (s, 4 H), 3.51–3.43
(m, 4 H), 3.40–3.32 (m, 4 H), 3.15 (t, J = 8 Hz, 4 H), 2.00–1.89
(m, 2 H) ppm. 13C NMR (D2O, 75.43 MHz): δ = 135.2, 134.8,
134.2, 52.6, 45.8, 43.7, 42.4, 24.3 ppm. C15H30N4Br4 (586.07):
calcd. C 30.7, H 5.2, N 9.6; found C 30.7, H 5.5, N, 9.4.
2,5,9,12-Tetraaza[13]paracyclophane (p-B232·4HBr·H2O): This
compound was obtained by the same procedure detailed for m-
B232·4HBr; yield 1.5 g, 91%; m.p. 226–228 °C. 1H NMR (D2O,
300 MHz): δ = 7.69 (s, 4 H), 4.44 (s, 4 H), 3.32–3.37 (m, 4 H),
3.01–3.06 (m, 4 H), 2.96 (t, J = 8 Hz, 4 H), 1.49–1.55 (m, 2 H)
ppm. 13C NMR (D2O, 75.43 MHz): δ = 132.1, 132.0, 50.6, 43.4,
41.3, 40.7, 20.5 ppm. C15H32N4OBr4 (604.09): calcd. C 29.8, H 5.3,
N, 9.3; found C 29.6, H 5.3, N 9.2.
Experimental Section
NMR Measurements: The 1H and 13C NMR spectra were recorded
N,NЈ,NЈЈ,NЈЈЈ-Tetratosylbis(2-aminoethyl)propylenediamine (232·4Ts):
Bis(2-aminoethyl)propylenediamine (1.5 g, 9.4 mmol) dissolved in
THF (400 mL) was mixed with K2CO3 (5.3 g, 38.1 mmol) dissolved
in water (100 mL). Tosyl chloride (7.4 g, 38.8 mmol) dissolved in
THF (100 mL) was then added dropwise to the mixture and this
was stirred for a further 24 h. Then the organic phase was separated
and vacuum evaporated to dryness. The residue was heated at re-
flux in EtOH, and the resulting solid was filtered and extensively
washed with EtOH; yield 5.5 g, 75%; m.p. 60–62 °C. 1H NMR
(CDCl3, 300 MHz): δ = 7.75 (d, J = 8 Hz, 4 H), 7.63 (d, J = 8 Hz,
4 H), 7.29 (t, J = 7 Hz, 8 H), 5.75 (t, J = 6 Hz, 2 H), 3.17 (s, 6 H),
3.11 (t, J = 7 Hz, 6 H), 2.42 (s, 6 H), 2.40 (s, 6 H), 2.00–1.93 (m,
2 H) ppm. 13C NMR (CDCl3, 75.43 MHz), δ = 143.8, 143.4, 136.8,
134.7, 129.9, 129.7, 127.3, 127.0, 50.3, 48.4, 43.4, 28.5, 21.5 ppm.
MS (FAB): m/z = 777 [M + H]+.
with
a Bruker Advance AC-300 spectrometer operating at
299.95 MHz for H and at 75.43 MHz for 13C. For the 13C NMR
spectra, dioxane was used as a reference standard (δ = 67.4 ppm)
and for the 1H spectra, the solvent signal was used. Adjustments
to the desired pH were made using drops of DCl or NaOD solu-
tions. The pD was calculated from the measured pH values by
using the correlation pH = pD – 0.4.[30]
1
Potentiometric Measurements: The potentiometric titrations were
carried out at 298.1Ϯ0.1 K using NaClO4 (0.15 ) as the support-
ing electrolyte. The experimental procedure (burette, potentiometer,
cell, stirrer, microcomputer, etc.) has been fully described else-
where.[31] The acquisition of the emf data was performed with the
PASAT computer program.[32] The reference electrode was a Ag/
AgCl electrode in a saturated KCl solution. The glass electrode was
calibrated as a hydrogen ion concentration probe by the titration
of previously standardized amounts of HCl with CO2-free NaOH
solutions, and the equivalence point was determined by Gran’s
method,[33] which gives the standard potential, E°Ј, and the ionic
product of water [pKw = 13.73(1)].
N,NЈ,NЈЈ,NЈЈЈ-Tetratosyl-2,5,9,12-tetraaza[13]metacyclophane (m-
B232·4Ts): 232·4Ts (3.7 g, 4.8 mmol) and K2CO3 (6.7 g,
48.2 mmol) in dry CH3CN (50 mL) was placed in a round-bot-
tomed flask. A solution of 1,3-bis(bromomethyl)benzene (1.3 g,
4.8 mmol) in dry CH3CN (30 mL) was then slowly added to this,
and the mixture was heated at reflux under a nitrogen atmosphere
for 24 h and then filtered. The solution was vacuum evaporated to
dryness, and the oily product was taken up into EtOH and heated
The HYPERQUAD computer program was used to calculate the
protonation and stability constants.[34] The 2.5–11.0 pH range was
investigated and the concentration of the metal ions and of the
at reflux to obtain a white solid (3.2 g, 76%). M.p. 119–121 °C. 1H ligands ranged from 1ϫ10–3 to 5ϫ10–3 moldm–3 with M/L molar
NMR (CDCl3, 300 MHz): δ = 7.75 (d, J = 8 Hz, 4 H), 7.64 (d, J ratios varying from 2:1 to 1:2. The different titration curves for
= 8 Hz, 4 H), 7.32 (d, J = 8 Hz, 4 H), 7.27 (d, J = 8 Hz, 4 H), 4.06 each system (at least two) were treated either as a single set or as
(s, 4 H), 2.96–2.93 (m, 4 H), 2.83–2.71 (m, 8 H), 2.40 (s, 6 H), 2.36 separated curves without significant variations in the values of the
(s, 6 H), 2.40–2.30 (m, 2 H) ppm. 13C NMR (CDCl3, 75.43 MHz):
δ = 144.4, 144.2, 137.2, 134.2, 133.9, 130.4, 130.3, 129.6, 129.5,
128.2, 127.2, 55.1, 50.0, 49.3, 49.2, 22.0, 21.9 ppm. MS (FAB): m/z
= 879 [M + H]+.
stability constants. Finally, the data sets were merged together and
treated simultaneously to give the final stability constants. The re-
ported estimation of the errors corresponds in all cases to the stan-
dard deviation in the fit of the whole data set for a given system.
Eur. J. Inorg. Chem. 2008, 1497–1507
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1505

M. García Basallote, J. Hodacˇová, E. García-España et al.
FULL PAPER
Kinetic Measurements: The decomposition kinetics of the CuII
complexes with the m-B232, p-B232 and 232 ligands were studied
at 298.1 K using an Applied Photophysics SX17MV stopped-flow
spectrophotometer with a PDA.1 diode-array detector. Solutions
of the metal complexes for the kinetic studies were prepared with
a ligand concentration of 1.0ϫ10–3 moldm–3, and the CuII/L ratio
(1:1 or 2:1) and the pH of the starting solutions were selected from
the species distribution curves so that the concentration of one of
the complex species was at a maximum while that of the other ones
was maintained at a minimum. For this reason, in general only
those species which represent at least 80% of the total complex
under some conditions were studied. The solutions of the starting
complexes were mixed in the stopped-flow instrument with solu-
tions containing an excess of acid under pseudo first-order condi-
tions, which required in some cases dilution of the stock complex
solution. The same procedure was used to study the kinetics of
decomposition of the Cu(o-B232)2+ complex, although this reac-
tion occurs more slowly and was studied using a conventional Cary
50-Bio UV/Vis spectrophotometer. The kinetic experiments were
carried out with the ionic strength adjusted to 0.15 moldm–3 with
NaClO4 (o-B232 and m-B232) or NaCl (p-B232). For the case of
the linear 232 ligand, the kinetic experiments were repeated using
different supporting electrolytes (NaClO4, NaCl and KNO3) with-
out significant differences between them.
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Supporting Information (see also the footnote on the first page of
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Acknowledgments
Financial support from the Spanish Dirección General de In-
vestigación Científica y Técnica (DGICYT), research projects
CTQ2006-15672-CO5-01 and CTQ2006-14909-CO2-01), Genera-
litat Valenciana (GV06/258) and Junta de Andalucía (FQM-137)
is gratefully acknowledged. A. F. acknowledges a grant from the
Programa de Doctorado Conjunto entre la Universidad de Cádiz
y las Universidades Cubanas (Spain). J. M. Ll. thanks the Spanish
Ministerio de Ciencia y Tecnología (MCYT) for a Ramón y Cajal
contract.
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Received: October 13, 2007
Published Online: January 29, 2008
Eur. J. Inorg. Chem. 2008, 1497–1507
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
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