Recognition of oxalate by a copper(II) polyaza macrobicyclic complex

Article abstract of DOI:10.1002/chem.201100428

A new polyamine macrobicyclic compound was synthesised through a [1+1] "tripod-tripod coupling" strategy and using a Schiff base condensation reaction, followed by sodium borohydride reduction. The resulting compound is a heteroditopic cage (btpN₇) in which one of the head units is appropriate for the coordination of copper(II), whereas the other head is available for additional hydrogen-bonding and electrostatic interactions with substrates. The acid-base behaviour of the new compound, the stability constants of its complex with the Cu²⁺ ion and the association constants of the copper(II) cryptate with oxalate (oxa^2-), malonate (mal ^2-), succinate (suc^2-), maleate (male^2-) and fumarate (fum^2-) were determined by potentiometry at 298.2K in aqueous solution and at an ionic strength of 0.10mol dm^-3 in KNO ₃. These studies revealed a clear preference of the receptor [CuH_hbtpN₇H₂O]^(2+h)+ for oxa ^2- over the other dicarboxylate substrates. This arises from co-operativity between metal-anion coordination and electrostatic and hydrogen-bonding interactions, in accordance with the ideal size of this dicarboxylate, which allow it to take full advantage of the potential binding sites of the receptor. A qualitative indicator-displacement study, in agreement with the potentiometric studies, demonstrated that the copper cryptate receptor can be used as a selective visual sensor for oxalate.Copyright

Full text of DOI:10.1002/chem.201100428

DOI: 10.1002/chem.201100428
Recognition of Oxalate by a Copper(II) Polyaza Macrobicyclic Complex
Pedro Mateus,[a] Rita Delgado,*[a, b] Paula Brand¼o,[c] and Vꢀtor Fꢁlix[d]
Abstract: A new polyamine macrobicy-
clic compound was synthesised through
a [1+1] “tripod–tripod coupling” strat-
egy and using a Schiff base condensa-
tion reaction, followed by sodium boro-
hydride reduction. The resulting com-
pound is a heteroditopic cage (btpN7)
in which one of the head units is appro-
priate for the coordination of copper-
the association constants of the cop-
per(II) cryptate with oxalate (oxa2ꢀ),
malonate (mal2ꢀ), succinate (suc2ꢀ),
maleate (male2ꢀ) and fumarate (fum2ꢀ)
were determined by potentiometry at
298.2 K in aqueous solution and at an
ionic strength of 0.10 moldmꢀ3 in
KNO3. These studies revealed a clear
the other dicarboxylate substrates. This
arises from co-operativity between
metal–anion coordination and electro-
static and hydrogen-bonding interac-
tions, in accordance with the ideal size
of this dicarboxylate, which allow it to
take full advantage of the potential
binding sites of the receptor. A qualita-
tive indicator-displacement study, in
agreement with the potentiometric
studies, demonstrated that the copper
cryptate receptor can be used as a se-
lective visual sensor for oxalate.
preference
of
the
receptor
A
[CuHhbtpN7H2O](2+h)+ for oxa2ꢀ over
able for additional hydrogen-bonding
and electrostatic interactions with sub-
strates. The acid–base behaviour of the
new compound, the stability constants
of its complex with the Cu2+ ion and
Keywords: anionic substrates · cage
compounds · cryptands · molecular
recognition · sensors
Introduction
molecular chemistry of anions much work has been devoted
to the design of new synthetic receptors for carboxylates,
which has resulted in a plethora of compounds that take ad-
vantage of binding sites such as ammonium, guanidinium,
urea, amide groups and metal ions.[5]
Carboxylate functionality is part of a wide range of biologi-
cally active entities, and in many cases is responsible for
their biochemical properties.[1] The recognition and trans-
port of carboxylate-containing substrates is of great biologi-
cal and medicinal relevance. For instance, the specific recog-
nition and transport of dicarboxylates across biological
membranes is crucial in the metabolism of cells,[2] the sens-
ing and signalling of amino acids play important roles in reg-
ulating cell functions[3] and the mechanism of action of the
vancomycin antibiotics is highly dependant on carboxylate
binding.[4] Not surprisingly, since the early days of the supra-
Two common approaches have been used in the design of
synthetic receptors for carboxylate binding in aqueous solu-
tion: the incorporation of polyammonium groups and of
Lewis acid centres.[6] Thus polyamine groups have been in-
cluded in macrocyclic and macrobicyclic architectures to be
used in the protonated form for the direct interaction of
anions,[7] or in the neutral form for the coordination to
metal ions.[8] A few examples exist in the literature that
combine both ammonium groups (or other positively
charged groups) and metal centres in macrocyclic or tripodal
architectures, in which the two sites cooperatively bind the
carboxylates.[9,8a,c,d] However, to the best of our knowledge,
this approach has never been explored using macrobicyclic
compounds.
[a] P. Mateus, Prof. R. Delgado
Instituto de Tecnologia Quꢀmica e Biolꢁgica
UNL, Av. da Repfflblica—EAN
2780-157 Oeiras (Portugal)
Fax : (+351)21-441-12-77
Herein we present a new heteroditopic macrobicyclic
compound (btpN7), which combines two different head
units, a tren-derived and a 2,4,6-triethylbenzene-derived
one, separated by relatively long and rigid p-xylyl spacers.
The present compound is the third member of a family of
heteroditopic heptaamine cryptands, the first one described
by Heyer and Lehn (btN7O3)[10] and the second by Steed
et al. (btN7);[11] however, the framework of our compound
forms the larger cavity of the series (see Scheme 1).
E-mail: delgado@itqb.unl.pt
[b] Prof. R. Delgado
Instituto Superior TØcnico, DEQB, Av. Rovisco Pais
1049-001 Lisboa (Portugal)
[c] Dr. P. Brand¼o
Departamento de Quꢀmica, CICECO
Universidade de Aveiro, 3810-193 Aveiro (Portugal)
[d] Prof. V. FØlix
Departamento de Quꢀmica
CICECO and Secżo Autꢁnoma de CiÞncias da Safflde
Universidade de Aveiro, 3810-193 Aveiro (Portugal)
In the design of btpN7, the tren-derived head unit was
chosen due to its tendency to coordinate copper(II) in a
trigonal-bipyramidal geometry, thereby leaving a vacant
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100428.
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Chem. Eur. J. 2011, 17, 7020 – 7031

FULL PAPER
Results and Discussion
Synthesis of the cryptand: The
synthesis of heteroditopic mac-
robicyclic compounds requires
two critical steps: formation of
a
tripodal intermediate and
macrobicyclisation through
[1+1] “tripod–tripod coupling”
strategy.[13] The new polyamine
macrobicyclic compound was
a
Scheme 3. Tripodal compound
used for comparison purposes.
Scheme 1. The new compound btpN7 and the two heteroditopic hepta-
amine cryptands already reported.[10,11]
prepared
as
outlined
in
ACHTUNGTRENNUNG
Scheme 4. A key element in this synthesis was the 4-(dieth-
oxymethyl)benzaldehyde, in which one of the aldehyde
apical position for further coor-
dination to a substrate, whereas
the
2,4,6-triethylbenzene-de-
rived head unit provides a rigid
organic scaffold that contains
three ammonium sites in the
right position for hydrogen-
bonding and electrostatic inter-
actions with the substrate. In a
somewhat similar approach,
heteroditopic
macrobicycles
that contain a crown ether sub-
unit and amide functionalities
have been developed to bind
alkali metal–halide ion pairs in
organic solvents.[12]
We expected that the crypt-
ate formed by coordination of
Scheme 4. Synthetic procedure of btpN7.
copper(II) with btpN7 would be
suitable for interaction with di-
carboxylates, thus in the present work we seek the selective
uptake of the substrate with appropriate size to take full ad-
vantage of co-operativity between the copper site and the
ammonium binding sites (Scheme 2).
A tren-derived tripodal compound (tbN4, Scheme 3) was
also studied as a model of the copper(II)-binding part of the
btpN7 cryptand.
groups is protected in the form of diethylacetal and the
other is available to react with tren. After in situ sodium
borohydride reduction followed by acid hydrolysis of the
acetal groups, a tripodal trialdehyde intermediate was ob-
tained in good yield. This intermediate was then treated
with 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene (again
through Schiff base condensation and without high dilution
conditions) to afford a triimine compound, which, after
sodium borohydride reduction, resulted in the desired poly-
amine macrobicycle in overall very good yield.
Acid–base behaviour of the synthesised compounds: The
protonation constants of btpN7 and tbN4 were determined
by potentiometry in aqueous solution at 298.2 K and ionic
strength 0.10 moldmꢀ3 in KNO3. The results are collected in
Table 1 and the corresponding species distribution diagrams
are represented in Figure 1 and Figure 2.
Six protonation constants were found for btpN7 in the
working pH region (2.9–9.0), which correspond to the suc-
cessive protonations of the secondary amines. The stepwise
values decrease with increasing protonation state of the re-
ceptor due to both increasing electrostatic repulsion be-
tween positive charges and to statistical factors. In the stud-
Scheme 2. Copper(II) cryptate of btpN7 and its cascade species formed
with the studied dicarboxylates.
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R. Delgado et al.
Table 1. Overall (bHi ) and stepwise protonation (KHi ) constants of btpN7 and tbN4 in H2O.[a]
Crystal structure: The single-
crystal X-ray diffraction of the
protonated btpN7 receptor re-
vealed that the asymmetric unit
is composed of one [H7btpN7]7+
receptor cation, eight chloride
anions, four methanol and five
water molecules. The molecular
diagram presented in Figure 3
shows that one water molecule
together with a methanol mole-
cule and two halide anions are
Equilibrium reaction
logbHi [b]
Equilibrium reaction
logKHi
btpN7
tbN4
9.27(1)
17.66(1)
24.68(1)
–
–
–
btpN7
tbN4
L+H+ÐHL+
9.05(1)
17.57(1)
25.22(1)
32.08(1)
38.75(1)
44.68(1)
L+H+ÐHL+
9.05
8.52
7.65
6.86
6.67
5.93
9.27
8.39
7.02
–
–
–
L+2H+ÐH2L2+
L+3H+ÐH3L3+
L+4H+ÐH4L4+
L+5H+ÐH5L5+
L+6H+ÐH6L6+
HL+ +H+ÐH2L2+
H2L2+ +H+ÐH3L3+
H3L3+ +H+ÐH4L4+
H4L4+ +H+ÐH5L5+
H5L5+ +H+ÐH6L6+
[a] T=(298.2ꢁ0.1) K; I=(0.10ꢁ0.01) moldmꢀ3 in KNO3. [b] Values in parenthesis are standard deviations in
the last significant figures.
located inside of the cryptand cage. Furthermore, the charge
balance requires that one water molecule is protonated, thus
leading to the molecular formula [H7btpN
7ACHTUNGTRENNUNG(H2O)-
A
N
ACHTUNGTRENNUNG
Figure 1. Species distribution diagram of the protonation of btpN7.
CbtpN =1.0”10ꢀ3 moldmꢀ3
.
7
Figure 2. Species distribution diagram of the protonation of tbN4. CtbN
=
4
1.0”10ꢀ3 moldmꢀ3
.
ied pH region, the protonation constant of the tertiary
amine of the tren-derived head unit was not obtained, which
should be very acidic due to the nearby presence of three
positive charges. The same was found for tbN4, for which
only three protonation constants were determined that cor-
respond to the successive protonations of the secondary
amines.
Figure 3. X-ray crystal structure of [H7btpN7ACHTNUGTRNENGU(H2O)AHCUTNGTREN(NUGN MeOH)Cl2]Cl6·
ACHUTNRGEN(NUG H3O)·3ACHTUNGTERN(NUGN H2O)·3MeOH in two different views: the upper view shows the
[H7btpN7]7+ cation interacting with chloride anions and solvent water
molecules through hydrogen bonds and, in the lower view, the encapsula-
tion of the {(H2O)ACTHNUTRGNEUNG
(MeOH)Cl2}2ꢀ assembly together with the approxi-
mately C3 cryptand symmetry are emphasised. The figure is presented in
colour in the Supporting Information.
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Oxalate Recognition
FULL PAPER
Table 2. Overall (bH L A ) and stepwise (KH L A ) association constants for the indicated equilibria in H2O.[a]
expected if one takes into ac-
count that the crystals suitable
for X-ray determination were
h
l
a
h
l
a
[c]
Equilibrium reaction[b]
logbH
hLlAa
suc2ꢀ
oxa2ꢀ
mal2ꢀ
fum2ꢀ
male2ꢀ
grown only from a very acidic 7H+ +btpN7 +A2ꢀÐH7btpN7A5+
51.12(5)
47.34(2)
40.60(6)
–
–
50.74(5)
47.10(2)
40.57(5)
–
6H+ +btpN7 +A2ꢀÐH6btpN7A4+
46.81(3)
–
46.69(2)
–
logKHhLlAa
–
2.01
–
46.86(4)
–
hydrochloride water/methanol
solution.
One external chloride coun-
ter ion and the hydroxyl group
of the encapsulated methanol
were found to be disordered
(see the Experimental Section).
In addition, only the hydrogen
atoms of the encapsulated
5H+ +btpN7 +A2ꢀÐH5btpN7A3+
H6btpN76+ +HAꢀÐH7btpN7A5+
2.61
2.66
1.85
–
2.13
–
1.96
2.42
1.82
–
2.18
–
H6btpN76+ +A2ꢀÐH6btpN7A4+
H5btpN75+ +A2ꢀÐH5btpN7A3+
[a] T=(298.2ꢁ0.1) K; I=(0.10ꢁ0.01) moldmꢀ3 in KNO3. [b] A2ꢀ indicates in general the dicarboxylate anion.
[c] Values in parenthesis are standard deviations in the last significant figures.
water molecule were located. In these circumstances, the de-
tailed analysis of the hydrogen-bonding interactions is some-
what limited and will be discussed as follows. The {(H2O)-
The association constant values are low for all the studied
dicarboxylates, with the highest values corresponding to the
association of H6btpN7 with the fully ionised dicarboxy-
6+
A
lates. Oxalate (oxa2ꢀ) and fumarate (fum2ꢀ) display slightly
higher association constants than the rest of the substrates.
It is unlikely that oxa2ꢀ, due to its small size, can take ad-
vantage of the ditopic nature of the cryptand, thus its higher
association constant should arise from binding of both car-
boxylate groups to one of the head units and to its higher
charge density, whereas in the case of fum2ꢀ the higher asso-
ciation constant should be due to the better fit into the
cavity and its rigidity.
multiple hydrogen bonds as shown in Figure 3. The corre-
sponding hydrogen-bond dimensions are listed in Table S1
in the Supporting Information. The water molecule is con-
ꢀ
comitantly hydrogen-bonded to the N H tertiary amine
ꢀ
(N···O distance of 2.726(5) Š and N H···O angle of 170(4)8)
and two chloride anions (Cl···O distances of 3.206(4) and
ꢀ
3.189(3) Š and O H···Cl angles of 157(4) and 163(3)8, re-
spectively), which establish two independent hydrogen
ꢀ
bonds, each with adjacent N H binding groups from the
The generally low association constants of the protonated
receptor with the dicarboxylate anions derive from the
degree of flexibility of the receptor and its lack of pre-or-
ganisation. Indeed the crystal structure of [H7btpN7]7+
(Figure 3) shows the secondary ammonium groups of the
tren head unit turned to the outside of the cavity due to
mutual electrostatic repulsions, which suggests that a rear-
rangement of the receptor conformation is needed for the
binding of dicarboxylate anions (Scheme 5), with conse-
three secondary amines linked to the 2,4,6-triethylbenzene
cap. The corresponding N···Cl distances range from 3.189(3)
to 3.294(3) Š. The methanol molecule forms two hydrogen
ꢀ
bonds with the remaining two N H binding sites of this
structural unit with N···O distances of 2.978(4) and
2.970(6) Š and corresponding N H···O angles of 159(4) and
165(4)8, respectively. Five chloride counter anions surround
ꢀ
the receptor to form with the NH2 binding sites of the tren
ꢀ
moiety a total of six N H···Cl hydrogen bonds with N···Cl
distances that range from 2.988(4) to 3.113(4) Š. Further-
more, all chloride anions (including the disordered one) and
the surrounded solvent molecules (methanol and water) in-
teract at short Cl···O and O···O distances, which are consis-
tent with the existence of a 3D network of hydrogen bonds.
The receptor adopts approximately a C3 symmetry with
pseudo-three-fold axis perpendicular to the benzene ring
ꢀ
and bisecting the N H tertiary amine (see lower view,
Figure 3). It is interesting to note that the secondary amines
of the tren subunit are apart from each other and turn to
the outside of the cavity due to the electrostatic repulsions.
Scheme 5. Representation of possible conformational rearrangement of
H6btpN7 needed for dicarboxylate binding.
6+
Binding affinity of the protonated forms of btpN7 towards
dicarboxylates: The association constants of the protonated
forms of btpN7 with several dicarboxylates that differ in
chain length were determined by potentiometry in aqueous
solution at 298.2 K and 0.10 moldmꢀ3 KNO3. The values are
collected in Table 2. The protonation constants of the dicar-
boxylates were also determined under the same experimen-
tal conditions and used in the calculations (Table S1 in the
Supporting Information).
quent energy penalty and loss of selectivity. It is also likely
that nitrate present in the supporting electrolyte may com-
pete with the dicarboxylates, thereby contributing to the low
association constants observed.
Copper(II) coordination studies: The stability constants of
the copper(II) complexes of btpN7 and tbN4 were deter-
mined by potentiometry in aqueous solution at 298.2 K and
0.10 moldmꢀ3 KNO3. The results are collected in Table 3
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R. Delgado et al.
Table 3. Overall (bM H L ) and stepwise (KM H L ) stability constants of the copper(II) complexes of btpN7 and
actions with anionic substrates.
Unlike tbN4, for which proton-
ated copper complexes were
not found, btpN7 forms three
protonated complexes that cor-
respond to the protonation of
the three secondary amines of
the 2,4,6-triethylbenzene head
unit (see Table 3).
m
h
l
m
h l
tbN4 in aqueous solution.[a]
[b]
Equilibrium
(logbM
)
Equilibrium
(logKM
)
mHhLl
mHhLl
btpN7
tbN4
btpN7
tbN4
Cu2+ +3H+ +LÐ
Cu2+ +2H+ +LÐ
N
31.39(1)
26.36(1)
20.01(1)
12.35(1)
2.78(1)
–
–
–
–
G
G
5.03
6.35
7.66
12.35
9.57
–
–
–
–
G
Cu2+ +H+ +LÐ
G
G
Cu2+ +LÐ
Cu2+ +LÐ
Cu2+ +LÐ
G
15.20(1)
6.92(1)
ꢀ4.61(3)
N
15.20
8.28
11.53
[a] T=(298.2ꢁ0.1) K; I=(0.10ꢁ0.01) moldmꢀ3 in KNO3. [b] Values in parenthesis are standard deviations in
The stability constant that
corresponds to the formation of
[CubtpN7]2+ is almost three log
the last significant figure.
units lower than that of [CutbN4]2+. This is due, at least in
part, to constraints in the conformation of btpN7 that in-
crease the energetic cost of rearrangement of the secondary
amine groups of the tren head unit for the coordination of
the metal ion compared to what happens with tbN4, which
has higher freedom of motion. Thus, the coordination to
copper(II), besides affording a favourable enthalpic contri-
bution to the binding of dicarboxylates, also pre-organise
the receptor for the encapsulation of anionic substrates.
Also interesting to note is that the water molecule bound
to the copper cryptate deprotonates at a higher pH (9.57)
than that of the tripodal copper complex (8.28), which indi-
cates that the coordinated water molecule is less susceptible
to deprotonation when encapsulated into the framework of
the cryptand, possibly due to the network of hydrogen
bonds formed in the cavity (see Figures 4 and 5).
Figure 4. Species distribution diagram calculated for the complexes of
Cu2+ with btpN7. CCu =CbtpN =1.0”10ꢀ3 moldmꢀ3. Charges were omitted
7
for simplicity.
Cascade species formed by the copper(II) complexes of
btpN7 and tbN4 with dicarboxylate substrates: The associa-
tion constants of copper(II) complexes of btpN7 and tbN4
with the dicarboxylate substrates were determined in aque-
ous solution at 298.2 K and 0.10 moldmꢀ3 KNO3. The results
are collected in Table 4. The stability constants of the cop-
per(II) complexes of the studied dicarboxylates were also
determined under the same experimental conditions and
used in the calculations (Table S3 in the Supporting Infor-
mation).
and the corresponding species distribution diagrams are rep-
resented in Figure 4 and Figure 5.
Only mononuclear species were found for btpN7, even
when two equivalents of copper were added. This fact indi-
cates that the 2,4,6-triethylbenzene unit is not able to coor-
dinate copper(II), and instead acts as a rigid organic scaffold
to hold the three additional ammonium sites that are capa-
ble of establishing hydrogen-bonding and electrostatic inter-
The association constants of the copper(II) complexes of
btpN7 with the dicarboxylate anions are much higher than
when only the cryptand is the receptor (Table 2 and
Table 4). In all cases the association constants are larger at
the triprotonated state of the cryptate and decrease with de-
creasing protonation of the cryptate, which provides evi-
dence of the existence of electrostatic and possibly hydro-
gen-bonding interactions. Oxa2ꢀ is clearly the preferred di-
carboxylate. It presents the highest association constants,
followed by malonate (mal2ꢀ). The species distribution dia-
gram for the system [CuHhbtpN
Supporting Information) shows that the [CuH3btpN CHTUNGTRENNUNG
(oxa)]h+ (Figure S1 in the
7A
(oxa)]3+
is the predominant species and reaches a maximum at
pH 6.2. However, in the absence of oxa2ꢀ, the relative per-
centage of [CuH3btpN7]5+ species is low (Figure 4) due to
the buildup of positive charge in the interior of the cavity.
This indicates that the binding of oxa2ꢀ helps to relieve the
electrostatic repulsions that stabilise the supercryptate,
Figure 5. Species distribution diagram calculated for the complexes of
Cu2+ with tbN4. CCu =CtbN =1.0”10ꢀ3 moldmꢀ3. Charges were omitted
4
for simplicity.
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Oxalate Recognition
FULL PAPER
Table 4. Overall (bH L A ) and stepwise (KH L A ) association constants for the indicated equilibria in H2O.[a]
h
l
a
h
l
a
[c]
Equilibrium reaction[b]
logbH
hLlAa
oxa2ꢀ
mal2ꢀ
suc2ꢀ
fum2ꢀ
btpN7
male2ꢀ
btpN7
btpN7
tbN4
btpN7
tbN4
btpN7
tbN4
Cu2+ +4H+ +L+A2ꢀÐCuH4LA4+
Cu2+ +3H+ +L+A2ꢀÐCuH3LA3+
Cu2+ +2H+ +L+A2ꢀÐCuH2LA2+
Cu2+ +H+ +L+A2ꢀÐCuHLA+
Cu2+ +L+A2ꢀÐCuLA
42.88(3)
37.54(1)
30.58(3)
22.5(1)
–
–
41.81(3)
35.84(1)
29.59(3)
22.48(4)
–
–
–
–
–
–
–
–
–
–
33.67(3)
29.11(3)
24.14(3)
17.75(5)
34.94(2)
29.26(2)
22.58(2)
–
34.79(2)
29.53(1)
22.56(4)
–
35.30(3)
29.58(2)
22.67(6)
–
22.80(5)
17.69(3)
22.88(2)
17.71(3)
logKH L A
h
l
a
CuH3L5+ +A2+ÐCuH3LA3+
CuH2L4+ +A2+ÐCuH2LA2+
CuHL3+ +A2+ÐCuHLA+
CuL2+ +A2+ÐCuLA
6.15
4.22
2.49
–
–
–
–
2.55
4.45
3.23
2.47
–
–
–
–
2.49
3.55
–
–
–
2.51
3.40
3.17
2.55
–
3.91
3.22
2.66
–
2.90
2.57
–
[a] T=(298.2ꢁ0.1) K; I=(0.10ꢁ0.01) moldmꢀ3 in KNO3. [b] A2ꢀ denote in general the dicarboxylate anion and L the cryptand or the tripodal com-
pounds. [c] Values in parenthesis are standard deviations in the last significant figures.
[CuH3btpN
(oxa)]3+. With all the other studied dicarboxy-
previous studies demonstrated that oxa2ꢀ is the anion most
strongly bound to the protonated species of the copper(II)
cryptate, followed by mal2ꢀ. However, the values listed in
Table 4 do not give a simple snapshot of what happens when
all the studied anions are mixed with the copper(II) cryptate
over the pH range in aqueous solution. To evaluate the
competition of the various anions for the receptor, a binding
diagram was plotted that represents the overall percentages
of the associated species as a function of the pH for equimo-
lar amounts of the studied dicarboxylates and of copper
cryptate[14] (see Figure 6). At pH 6.2 the copper-cryptate re-
ceptor clearly prefers oxa2ꢀ in the presence of equimolar
amounts of all the other studied dicarboxylates, with the
lates, the [CuH3btpN7(A)]3+ species is not so dominant,
which suggests that in those cases the fit of the anions is not
as good as for oxa2ꢀ. It is also noteworthy that the decrease
of binding constants with decreasing protonation state of
the cryptate is much more marked for oxa2ꢀ and mal2ꢀ,
whereas for succinate (suc2ꢀ), fum2ꢀ and maleate (male2ꢀ)
the decrease is relatively small. This indicates that oxa2ꢀ and
mal2ꢀ fit better than the other studied anions into the crypt-
ate cavity and took advantage of both the coordination to
copper(II) and the electrostatic and hydrogen-bonding inter-
actions with the ammonium groups of the 2,4,6-triethylben-
zene head unit. In all cases the association constants that
correspond to the formation of neutral and deprotonated
cascade species, [CubtpN7(A)], is too low to be determined
and the hydroxide ion is able to displace the dicarboxylates
from the cavity at pH higher than 9.0. This clearly indicates
that the electrostatic and possibly also the hydrogen-bond-
ing formation with the ammonium groups of the 2,4,6-tri-
S[CuHhbtpN7ACTHNUTRGNEUNG
(oxa)]h+ supercryptate that represents 88% of
the total S[CuHhbtpN7(A)]h+ species.
ACHTUNGTRENNUNGethylbenzene head unit contribute to the stabilisation of the
anions in the cryptate cavity.
On the other hand, the association constants of the cop-
per(II) complexes of the noncyclic receptor, tbN4, with
oxa2ꢀ, mal2ꢀ and suc2ꢀ, determined also for reasons of com-
parison, revealed that the values are of about 2.5log units
for all the dicarboxylate anions studied. These low and simi-
lar values of binding constants mean that all dicarboxylates
bind to the copper(II) complex of tbN4 by the same mode,
and in the absence of any other binding sites the receptor
cannot distinguish the substrates. These data support our
conclusion that the discrimination of the dicarboxylate
anions by the protonated forms of the copper(II) cryptate is
a consequence of the inclusion of oxa2ꢀ and mal2ꢀ in the
cryptate cavity and is derived from the additional stabilisa-
tion of the carboxylate moiety not coordinated to the cop-
per(II), by electrostatic and possible hydrogen-bonding for-
mation with the ammonium groups of the 2,4,6-triethylben-
zene head unit.
Figure 6. Distribution diagram of the overall amounts of supramolecular
species formed between [CuHhbtpN7](2+h)+ and each dicarboxylate.
CbtpN =CCu =CA/3=1.0”10ꢀ3 moldmꢀ3
.
7
Spectroscopic studies: To gain further insight into the bind-
ing event and the characteristics of the copper-binding site,
the absorption and EPR spectra of [CuHhbtpN7](2+h)+
Study of selective uptake of oxa2ꢀ anion from protonated
forms of the cryptate over other dicarboxylate anions: The
(Figure 7) and [CuHhbtpN7ACHTGNUTERNNUG
(oxa)]h+ (Figure 8) were record-
Chem. Eur. J. 2011, 17, 7020 – 7031
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7025

R. Delgado et al.
Figure 8. Absorption and X-band EPR spectra of [CuHhbtpN7ACHTUNGTRENNUNG
(oxa)]h+ at
Figure 7. Absorption and X-band EPR spectra of [CuHhbtpN7](2+h)+ at
several pH values (1=pH 6.3, 2=pH 7.0, 3=pH 8.8, 4=pH 11.4). The
complexes were prepared at 1.0”10ꢀ3 moldmꢀ3 in water for the spectro-
photometric and at 5.0”10ꢀ4 moldmꢀ3 in water/ethylene glycol solutions
(1:1 vol) for the EPR measurements. The EPR spectra were recorded at
a microwave power of 2.0 mW, frequency (n) 9.67 GHz, T=89 K.
several pH values (2=pH 6.3, 3=pH 7.0, 4=pH 8.8, 5=pH 11.4). The
complexes were prepared at 1.0”10ꢀ3 moldmꢀ3 in water for the spectro-
photometric and at 5.0”10ꢀ4 moldmꢀ3 in water/ethylene glycol solutions
(1:1 vol) for the EPR measurements. The EPR spectra were recorded at
a microwave power of 2.0 mW, frequency (n) 9.67 GHz, T=89 K (1=
[CuACHTNUTGRNEUNG
(oxa)2]2ꢀ; pH 6.3; 6=[CuHhbtpN7](2+h)+, pH 11.4).
ed in the pH 6.3–11.4 region. The results are summarised in
Table 5.
geometry is distorted from trigonal-bipyramidal to a square-
pyramidal structure due to the formation of [Cubtp-
N7(OH)]+.[15] Simulation of the EPR spectra (Table 5, Fig-
ure S2 in the Supporting Information) recorded in the 6.3–
8.8 pH range indicated three different principal values of g,
with (g1 +g2)/2>g3 and the lowest value smaller than 2.04,
which are indicative of five-coordinate copper complexes
with a geometry intermediate between trigonal bipyramidal
and square pyramidal geometries.[17] For complexes of this
type, a parameter R can be indicative of the predominance
The absorption spectra of [CuHhbtpN7](2h)+ at pH values
ranging from 6.3 to 8.8 (Figure 7a) show a maximum at
850 nm and a shoulder at 705 nm that are indicative of trigo-
nal bipyramidal geometry,[15] which can be assigned to the
dxy,dx2ꢀy2 !dz2 and dxz,dyz!dz2 transitions, respectively, and
agree well with those of copper complexes of tren and other
tren-derived compounds found in the literature.[16,17] On in-
creasing the pH, the higher-energy band becomes more in-
tense than the lower energy one, thereby indicating that the
Table 5. X-band EPR[a] and absorption spectra[b] data for the Cu2+ complexes of btpN7 and respective associations with oxalate.
Complex
pH
Species
g1
g2
g3
A1
A2
A3
R
l [nm] (e [cmꢀ1 molꢀ1dm3])
”104 cmꢀ1
1
2
1
2
2.217
2.248
2.219
2.253
2.254
2.153
2.094
2.153
2.072
2.087
2.002
2.010
1.995
2.013
2.032
124
156
127
154
160
87
12
85
12
37
60
8
61
1
2.4
0.5
2.4
0.3
0.3
6.3–8.8
705 (130); 850 (226)
[CuHhbtpN7](2+h)+
[CuHhbtpN7oxa]h+
11.4
6.3
678 (184); 820 (175)
674 (103)
17
[a] All the complexes were prepared at 5.0”10ꢀ4 moldmꢀ3 in H2O/ethylene glycol (1:1) and the spectra were recorded at a microwave power of 2.0 mW,
frequency (n) 9.67 GHz, T=89 K. [b] All the complexes were prepared at 1.0”10ꢀ3 moldmꢀ3 in H2O.
7026
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Chem. Eur. J. 2011, 17, 7020 – 7031

Oxalate Recognition
FULL PAPER
of the dz2 or dx2ꢀy2 orbital in the ground state, R=
The results of the spectroscopic studies suggest that the
binding of oxa2ꢀ to the [CuHhbtpN7](2+h)+ receptor is accom-
panied by a rearrangement of the conformation of the
copper cryptate such that a change from trigonal bipyrami-
dal to square pyramidal geometry of the copper site occurs.
This should happen by increasing the angle N1-Cu-N2 until
N1, N2, N4, and O are almost coplanar (see Scheme 6).
(g2ꢀg3)/(g1ꢀg2) with g1 >g2 >g3. If R>1, the greater contri-
G
bution to the ground state arises from the dz2 orbital and the
geometry is closer to a trigonal bipyramidal geometry; if
R<1, the greater contribution to the ground state arises
from the dx2ꢀy2 orbital and the geometry approaches a more
square pyramidal geometry.[18] In the case of the spectra re-
corded between pH 6.3–8.8, the parameter R has a value of
2.4, which is in agreement with a trigonal bipyramidal geom-
etry. The hyperfine splitting values are also in the range ex-
pected for trigonal bipyramidal complexes.[17] Also noticea-
ble was the presence of a small amount of a second species
with g1 >(g2 +g3)/2, R=0.5, which should correspond to a
distorted square pyramidal geometry. Upon increasing the
pH, this second species becomes predominant, which is in
agreement with what was observed in the absorption spec-
trum upon formation of the [CubtpN7(OH)]+ species (Fig-
ure 7b and Figure S3).
Scheme 6. Proposed change of geometry of the copper site upon oxa2ꢀ
binding.
The absorption spectra of [CuHhbtpN7ACHTNUGRTNEUNG
(oxa)]h+ at pH 6.3
and 8.8 (Figure 8a) show a maximum at 674 nm, which tails
into the low-energy region of the spectrum. This band
occurs in the same wavelength as the maximum of the
[CubtpN7(OH)]+ species, thereby suggesting that both spe-
cies should have approximately the same distorted square
pyramidal geometry. Also, it is clear that as the pH increases
from 6.3 to 11.4 the spectra resemble more those of the
[CuHhbtpN7](2+h)+, in agreement with what was observed by
potentiometry that the association constants are larger at
the triprotonated state of the cryptate and decrease with de-
creasing protonation of the cryptate. Simulation of the EPR
Indicator-displacement assay: An indicator-displacement
assay was carried out to further reveal the selectivity of the
[CuHhbtpN7](2+h)+ receptor for the studied dicarboxylate
anions in a qualitative and more visual manner. This
method, first introduced in the supramolecular field by
Inouye et al.[19] and later popularised by Anslyn et al.,[20]
consists of the use of an indicator bound to a receptor by
means of non-covalent interactions, which is then displaced
from the receptor by a substrate with a high enough binding
constant. This displacement induces a drastic change in the
optical properties of the released indicator. The adaptation
of this methodology to our system is illustrated in Scheme 7.
In the current assay, pyrocatechol violet (PV) was used as
the indicator. First the spectrum in the visible region of PV
was recorded in the presence of btpN7 at pH 6.2 (Figure 9a),
thereby showing that the indicator is not affected by the
presence btpN7 in the absence of copper(II) and retains its
yellow colour. In the concentration used and in the absence
of indicator, the absortion the copper(II) cryptate in the
350–800 nm region is negligible. Upon addition of copper to
a mixture of PV and btpN7 (Figure 9b) at the same pH, a
drastic change in colour takes place and the solution turns
spectrum of [CuHhbtpN7ACHTNUTRGENUNG
(oxa)]h+ recorded at pH 6.3
(Table 5, Figure S4 in the Supporting Information) indicated
three different principal values of g, with g1 >(g2 +g3)/2 and
R=0.3, which correspond to a geometry closer to a square
pyramid. The hyperfine splitting values are also in the range
expected for square pyramidal complexes.[16] As in the case
of the electronic spectra, it is also clear that as the pH in-
creases the spectra resemble more those of the
[CuHhbtpN7](2+h)+ system (Figure 8b) , thus agreeing well
with the potentiometric studies.
Scheme 7. Indicator-displacement assay.
Chem. Eur. J. 2011, 17, 7020 – 7031
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7027

R. Delgado et al.
crease with as protonation of the receptor decreases, which
provides evidence of complementary electrostatic and possi-
bly hydrogen-bonding interactions. These cooperative ef-
fects between coordination to the copper(II) centre, electro-
static and hydrogen-bonding interactions are particularly
evident when oxa2ꢀ is the anionic substrate.
At pH 6.2 the copper cryptate receptor clearly prefers
oxa2ꢀ in the presence of equimolar amounts of all the other
studied dicarboxylates, thereby suggesting that this dicarb-
AHCTUNGTREGoNNNU xylate has the ideal size to take full advantage of the po-
tential binding sites of the receptor. The qualitative study
provided by the indicator-displacement assay, which used
pyrocatechol violet as the indicator, is in excellent agree-
ment with the potentiometric studies and demonstrated that
the copper cryptate receptor can be used as a selective
visual sensor for oxalate. It should be noted that the devel-
opment of optical oxalate detectors is of great interest in
the analysis of food, natural waters and urine due to its det-
rimental effects on the human body and its importance in
the diagnosis of a number of diseases.[21]
Figure 9. UV/Vis absorbance spectra of aqueous solutions of PV under
the following conditions: a) CPV =CbtpN /2=5.0”10ꢀ5 moldmꢀ3, b) CPV
=
7
CbtpN /2=CCu =5.0”10ꢀ5 moldmꢀ3
,
c) CPV =CbtpN /2=CCu =Coxa/3=5.0”
7
7
10ꢀ5 moldmꢀ3
,
d) CPV =CbtpN /2=CCu =Cmal/3=5.0”10ꢀ5 moldmꢀ3
,
7
e) CPV =CbtpN /2=CCu =Csuc/3=5.0”10ꢀ5 moldmꢀ3. All spectra recorded
7
at T=(298.2ꢁ0.1) K and pH 6.2.
blue due to the formation of [CuHhbtpN7](2+h)+–PV com-
plex. Figure 9 clearly shows that only oxalate can displace
the indicator from the receptor to yield a change of colour
to green (not yellow because under the conditions used the
indicator is not fully displaced), which is in perfect agree-
ment with the potentiometric studies. For a competitive
binding diagram calculated with the concentrations used in
the indicator-displacement assay and a colour picture of the
solutions used, see Figures S5 and S6 in the Supporting In-
formation.
Experimental Section
General: All solvents and chemicals were commercially purchased re-
agent-grade quality and used as supplied without further purification,
except 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene and tbN4, which
were prepared according to literature methods.[22,23] NMR spectra used
for characterisation of products and binding experiments were recorded
using a Bruker Avance 400 instrument. TMS was used as reference for
the 1H NMR spectroscopic measurements in CDCl3. Peak assignments
are based on peak integration and multiplicity for 1D 1H spectra and on
COSY, NOESY and HMQC experiments. Microanalyses were carried
out by the ITQB Microanalytical Service. The electronic spectra were re-
corded using a UNICAM UV/Vis spectrophotometer model UV-4. EPR
spectroscopy measurements were recorded using a Bruker ESP 380 spec-
trometer equipped with continuous-flow cryostat for liquid nitrogen and
operating at X band.
Conclusion
Synthesis of tripodal trialdehyde: A solution of 4-(diethoxymethyl)ben-
A new heteroditopic macrobicyclic heptamine compound
was prepared in good yield through a new [1+1] “tripod-
tripod coupling” strategy using the Schiff base condensation
reaction.
zaldehyde (2.320 g, 11.14 mmol) in EtOH (10 cm3) was added dropwise
over 15 min to
a magnetically stirred solution of tren (536 mg,
3.66 mmol) in EtOH (10 cm3) at around 58C. The mixture was left under
stirring at RT overnight. Solid NaBH4 (832 mg, 22.1 mmol) was added in
small portions to avoid excessive foaming. After the addition was com-
pleted, the mixture was left under stirring at RT until the bubbling
ceased, and under reflux for 3 h. The solution was filtered and evaporat-
ed under vacuum almost to dryness, then water was added (20 cm3) and
the rest of the ethanol was evaporated. The solution was made strongly
basic with 6 moldmꢀ3 KOH (20 cm3) and extracted with CHCl3 (3”
50 cm3). The organic portions were collected and extracted with
6 moldmꢀ3 HCl (20 cm3). The aqueous phase was separated, washed with
CHCl3 (3”50 cm3) and left stirring overnight. The solution was then put
in an ice bath and 6 moldmꢀ3 KOH (30 cm3) was slowly added. The solu-
tion was extracted with diethyl ether (3”50 cm3), the organic portions
were collected in an Erlenmeyer flask, dried over anhydrous sodium sul-
fate, filtered and evaporated to dryness to give the crude tripodal trialde-
hyde (1.666 g, 90%) as a pale yellow viscous oil. The product was further
purified by column chromatography using CH2Cl2/MeOH/NH3 (aq,
90:9:1) as eluent. 1H NMR (400 MHz, CDCl3, 298 K; Me4Si): d=9.90 (s,
Aqueous-solution studies revealed that the values of the
association constants of the protonated cryptand, HnbtpN7n+
,
N
U
N
R
T
N
T
C
A
with all the studied dicarboxylate anions are very low. These
low constants and lack of selectivity of the various anions
for the receptor was attributed to the flexibility and lack of
pre-organisation of the receptor. The copper(II) complex of
the tripodal compound, [CutbN4ACHTUNRTGNEUNG(H2O)], which is related to
the part of the cryptand coordinated to the copper(II)
centre, also exhibited small binding constants and no selec-
tivity for the series of studied anions. These features empha-
sise that polyammonium and metal-binding sites working in-
dependently are unable to provide either strong interaction
or selectivity.
When the copper(II) complex of btpN7 is the receptor for
the same series of dicarboxylate anions, much higher associ-
ation constants are found. In addition, the constants are
higher for the tri-protonated state of the cryptate and de-
3H; HC=O), 7.70 (d, 3J
J=8.0 Hz, 6H; H2/H6 of p-xylyl), 3.76 (s, 6H; CH2p-xylyl), 2.63 (t, 3J-
ACHTUNGTRENUN(NG H,H)=8.0 Hz, 6H; H3/H5 of p-xylyl), 7.36 (d,
ACHUTNGREUNNG ACHTUNGTERN(NUGN H,H)=8.0 Hz, 6H;
(H,H)=8.0 Hz, 6H; NCH2CH2NH), 2.55 (t, 3J
NCH2CH2NH), 2.04 ppm (brs, 3H; N H); 13C NMR (100 MHz, CDCl3,
298 K; Me4Si) d=191.86 (C=O), 147.31 (C1 of p-xylyl), 135.42 (C4 of p-
ꢀ
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Chem. Eur. J. 2011, 17, 7020 – 7031

Oxalate Recognition
FULL PAPER
xylyl), 129.90 (C3/C5 of p-xylyl), 128.44 (C2/C6 of p-xylyl), 54.02
(NCH2CH2NH), 53.63 (CH2p-xylyl), 47.14 ppm (NCH2CH2NH).
Equipment and working conditions: The equipment used was described
before.[26] The ionic strength of the experimental solutions was kept at
(0.10ꢁ0.01) moldmꢀ3 with KNO3, the temperature was maintained at
(298.2ꢁ0.1) K. Atmospheric CO2 was excluded from the titration cell
during experiments by passing purified nitrogen across the top of the ex-
perimental solution.
Synthesis of Schiffꢂs base of btpN7: A solution of 1,3,5-tris(aminomethyl)-
2,4,6-triethylbenzene (350 mg, 1.4 mmol) in MeCN (65 cm3) was added
dropwise over 15 min to a magnetically stirred solution of the tripodal tri-
aldehyde (700 mg, 1.4 mmol) in MeCN (185 cm3). The mixture was left
under stirring overnight and a white precipitate formed, which was sepa-
rated by filtration and washed with MeCN (about 100 cm3) to remove
any unreacted starting materials. The precipitate was suspended in
CHCl3 (100 cm3), ultrasonicated for 1 h and filtered off. Evaporation of
the solvent yielded the desired triimine (860 mg, 88%), which was dried
under vacuum. 1H NMR (400 MHz, CDCl3, 298 K; Me4Si): d=7.22 (s,
Measurements: The [H+] of the solutions was determined by the mea-
surement of the electromotive force of the cell, E=E’8+Qlog[H+]+Ej.
The term pH is defined as ꢀlog[H+]. Values for E’8, Q, Ej and K’w were
determined by titration of a solution of known hydrogen-ion concentra-
tion at the same ionic strength and using the acid pH range of the titra-
tion. The liquid-junction potential, Ej, was found to be negligible under
the experimental conditions used. The value of K’w (the ionic product of
water) was determined from data obtained in the alkaline range of the ti-
tration, considering E’8 (the formal potential) and Q (2.303RT/F (59.16
mV at 298.2 K)) valid for the entire pH range and found to be equal to
10ꢀ13.76 under our experimental conditions. Before and after each set of ti-
trations, the glass electrode was calibrated as an [H+] probe by titration
of 1.000”10ꢀ3 moldmꢀ3 standard HNO3 solution with standard KOH.
Every measurement was carried out with 0.050 mmol of ligand in a total
volume of 40 cm3. The exact amount of ligand was obtained by determi-
nation of the excess amount of acid present in a mixture of the ligand
and standard 1.4”10ꢀ2 moldmꢀ3 HNO3 by titration with standard KOH
solution. Copper complexation experiments were performed in the pres-
3H; HC=N), 6.91 (d, 3J
3J
(H,H)=8.0 Hz, 6H; H2/H6 of p-xylyl), 4.99 (s, 6H; CH2bz), 3.76 (s,
6H; CH2p-xylyl), 1.19 (t, 3J(H,H)=8.0 Hz, 9H; bzCH2CH3), 2.84 (t, 3J-
(H,H)=8.0 Hz, 6H; NCH2CH2NH), 2.60 (t, 3J
(H,H)=8.0 Hz, 6H;
NCH2CH2NH), 2.43 (q, 3J
(H,H)=8.0 Hz, 6H; bzCH2CH3), 1.19 ppm (t,
3J(H,H)=8.0 Hz, 9H; bzCH2CH3); 13C NMR (100 MHz, CDCl3, 298 K;
ACHTUNGTRENNUNG(H,H)=8.0 Hz, 6H; H3/H5 of p-xylyl), 6.85 (d,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Me4Si) d=161.5 (C=N), 143.9 (C1/C3/C5 of bz), 143.3 (C1 of p-xylyl),
134.4 (C4 of p-xylyl), 132.7 (C2/C4/C6 of bz), 128.6 (C3/C5 of p-xylyl),
127.1 (C2/C6 of p-xylyl), 53.9 (NCH2CH2NH), 53.8 (CH2p-xylyl), 51.3
(CH2bz), 46.4 (NCH2CH2NH), 24.0 (bzCH2CH3), 16.5 ppm (bzCH2CH3).
Synthesis of btpN7: Solid NaBH4 (1.200 g, 31.7 mmol) was added in small
portions to a magnetically stirred suspension of the triimine (432 mg,
0.54 mmol) in methanol (100 cm3). After the addition was completed, the
mixture was left under stirring at RT for 2 h, and under reflux overnight.
The solution was evaporated under vacuum almost to dryness, then water
(20 cm3) was added and the entire methanol was evaporated. The solu-
tion was made strongly basic with 6 moldmꢀ3 KOH and extracted with
CHCl3 (3”50 cm3). The organic portions were collected in an Erlenmey-
er flask, dried over anhydrous sodium sulfate, filtered off and evaporated
to dryness to give btpN7 (750 mg, 90%) as a white solid. M.p. 1928C
(decomp.); 1H NMR (400 MHz, CDCl3, 298 K; Me4Si): d=6.81 (d, 3J-
ence CuACTHNUTRGEN(UNG NO3)2 in 0.5, 1.0 and 2.0 CCu/CL ratios. Studies of the association
of the protonated forms of btpN7 with the dicarboxylate anions were car-
ried out in the presence of the dicarboxylates in 1.0 and 3.0 CA/CbtpN
7
ratios. The ternary systems measurements were carried out in the simul-
taneous presence of copper(II), ligand and dicarboxylate anions for 1:1:1
and 1:1:3 CCu/CL/CA ratios. Each titration curve typically consisted of one
hundred points in the 3.0–10.0 pH range, with a minimum of two repli-
cates undertaken. All the anions were independently titrated alone and
in the presence of copper(II) ion at 1:1 and 2:1 CCu/CA ratios. Back-titra-
tions with standard HNO3 solution were performed to confirm the values
of the final E’8 readings.
A
ACHTUNGTREN(NGNU H,H)=8.0 Hz, 6H;
Calculation of equilibrium constants: Overall protonation constants, bHi ,
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
of the free ligands and of the studied dicarboxylates, the overall stability
bzCH2CH3), 1.69 (brs, 3H; N H), 1.23 (brs, 3H; N H), 1.12 ppm (t, 3J-
ꢀ
ꢀ
constants of complexes, bM
(M=Cu2+ and L=btpN7 or tbN4 or the
mHhLl
(H,H)=8.0 Hz, 9H; bzCH2CH3); 13C NMR (100 MHz, CDCl3, 298 K;
studied dicarboxylate anions), and the overall association constants of
Me4Si) d=142.8 (C1/C3/C5 of bz), 139.7 (C1 of p-xylyl), 138.9 (C4 of p-
xylyl), 133.7 (C2/C4/C6 of bz), 128.8 (C3/C5 of p-xylyl), 128.4 (C2/C6 of
p-xylyl), 54.8 (NCH2CH2NH), 54.5 (CH2p-xylyl), 51.6 (p-xylylCH2), 47.9
(NCH2CH2NH), 45.9 (CH2bz), 22.8 (bzCH2CH3), 17.0 ppm (bzCH2CH3);
ESI-MS (MeOH): m/z: 702.5 [M+H]+; elemental analysis calcd (%) for
C45H63N7: C 77.0, H 9.04, N 13.97; found: C 76.7, H 8.9, N 13.9.
the complexes of btpN7 or tbN4 with the dicarboxylates, bH L A , were cal-
h
l
a
culated by fitting the potentiometric data obtained for all the performed
titrations in the same experimental conditions with the HYPERQUAD
program.[27] The initial computations were obtained in the form of overall
stability constants, bM
=[MmHhLlAa]/[M]m[H]h[L]l[A]a. The errors
mHhLlAa
quoted are the standard deviations of the overall stability constants given
directly by the program for the input data, which include all the experi-
mental points of all titration curves. The HYSS program[28] was used to
calculate the concentration of equilibrium species from the calculated
constants from which distribution diagrams were plotted. The species
considered in a particular model were those that could be justified by the
principles of coordination and supramolecular chemistry.
Crystals of [H7btpN7ACHTUNGTRENNUNG(H2O)CAHTUGTNREN(NUG MeOH)Cl2]Cl6·AHCTUNGERTG(NNUN H3O)·3ACHTNGUTRENUN(GN H2O)·3MeOH: The
cryptand btpN7 (4.0 mg, 5.7 mmol) was dissolved in MeOH (200 mL) and
37% HCl (29 mL) was added. Immediately a white precipitate formed.
Water (10 mL) was added and the solution heated until it was clear, then
the mixture was allowed to slowly cool to RT. Single colourless crystals
suitable for X-ray crystallographic determination were obtained over-
night.
Absorption and X-band EPR spectra: Solutions of [CuHhbtpN7](2+h)+
and [CuHhbtpN7ACTHNUTRGNEUNG
(oxa)]h+ were prepared in 1.0”10ꢀ3 moldmꢀ3 concentra-
Potentiometric measurements
tion and the pH was adjusted to 6.3, 7.0, 8.8 and 11.4 with small additions
of either standard KOH or HNO3 solutions. All absorption spectra were
recorded from 350 to 900 nm at T=(298.2ꢁ0.1) K. Ethylene glycol was
added to these solutions in a 1:1 proportion and the EPR spectra record-
ed at a microwave power of 2.0 mW, frequency (n) 9.67 GHz, T=89 K.
EPR spectra were simulated using SpinCount software.[29]
Reagents and solutions: All the solutions were prepared by using demin-
eralised water (obtained by a Millipore/Milli-Q system). A stock solution
of the receptor was prepared at around 2.0”10ꢀ3 moldmꢀ3. Stock solu-
tions of the dicarboxylic acids (analytical grade) were prepared at about
5.0”10ꢀ2 moldmꢀ3 and the concentrations were checked by titration with
standard 0.100 moldmꢀ3 KOH solutions.
Indicator-displacement assay: Stock solutions of pyrocatechol violet
A stock solution of CuACHTUNGTRENNUNG(NO3)2 (analytical grade) was prepared at about
(1.50”10ꢀ3 moldmꢀ3), btpN7 (2.00”10ꢀ3 moldmꢀ3) and Cu
ACTHNUGTRNEUGN(NO3)2 (4.00”
5.0”10ꢀ2 moldmꢀ3 and the exact concentration checked by titration with
K2H2edta (edta=ethylenediaminetetraacetic acid) following standard
methods.[24] Carbonate-free solutions of the KOH titrant were prepared
from a Merck ampoule diluted with 1000 cmꢀ3 of water (freshly boiled
for about 2 h and allowed to cool under nitrogen). These solutions were
discarded every time carbonate concentration was about 0.5% of the
total amount of base. The titrant solutions were standardised (tested by
Granꢃs method).[25]
10ꢀ2 moldmꢀ3) were prepared in aqueous solution. From the stock solu-
tions, five other solutions were prepared with the following concentra-
tions: 1) CPV =CbtpN /2=5.0”10ꢀ5 moldmꢀ3, 2) CPV =CbtpN /2=CCu =5.0”
7
7
10ꢀ5 moldmꢀ3
,
3) CPV =CbtpN /2=CCu =Coxa/3=5.0”10ꢀ5 moldmꢀ3
,
7
4) CPV =CbtpN /2=CCu =Cmal/3=5.0”10ꢀ5 moldmꢀ3 and 5) CPV =CbtpN /2=
7
7
C
Cu =Csuc/3=5.0”10ꢀ5 moldmꢀ3. The pH of the above solutions was ad-
justed to 6.2 with small additions of either standard KOH or HNO3 solu-
Chem. Eur. J. 2011, 17, 7020 – 7031
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7029

R. Delgado et al.
tions. All spectra were recorded from 350 to 850 nm at T=(298.2ꢁ
da, Coord. Chem. Rev. 2006, 250, 3219–3244; d) P. A. Gale, S. E.
Garcꢀa-Garrido, J. Garric, Chem. Soc. Rev. 2008, 37, 151–190; e) C.
Caltagirone, P. A. Gale, Chem. Soc. Rev. 2009, 38, 520–563; f) P. A.
Gale, Chem. Soc. Rev. 2010, 39, 3746–3771.
0.1) K.
Crystal data: C49H97Cl8N7O8; Mr =1212.0; monoclinic; space group P21/c;
Z=4; a=23.3117(11), b=31.4728(15), c=23.0916(11) Š; b=117.740(2)8;
V=6337.7(5) Š3; 1calcd =1.251 Mgmꢀ3
.
[6] a) E. Garcꢀa-EspaÇa, P. Dꢀaz, J. M. Llinares, A. Bianchi, Coord.
Chem. Rev. 2006, 250, 2952–2986; b) S. Kubik, C. Reyheller, S.
Stüwe, J. Inclusion Phenom. Macrocyclic Chem. 2005, 52, 137–187.
[7] a) B. Dietrich, M. W. Hosseini, J.-M. Lehn, R. B. Sessions, J. Am.
Chem. Soc. 1981, 103, 1282–1283; b) E. Kimura, A. Sakonaka, T.
Yatsunami, M. Kodama, J. Am. Chem. Soc. 1981, 103, 3041–3045;
c) M. W. Hosseini, J.-M. Lehn, J. Am. Chem. Soc. 1982, 104, 3525–
3527; d) B. Dietrich, J. Guilhem, J.-M. Lehn, C. Pascard, E. Son-
veaux, Helv. Chim. Acta 1984, 67, 91–104; e) M. W. Hosseini, J.-M.
Lehn, Helv. Chim. Acta 1986, 69, 587–603; f) J.-M. Lehn, R. Meric,
J.-P. Vigneron, B. Waksman, C. Pascard, J. Chem. Soc. Chem.
Commun. 1991, 62–64; g) A. Bencini, A. Bianchi, M. I. Burguete,
E. Garcꢀa-EspaÇa, S. V. Luis, J. A. Ramirez, J. Am. Chem. Soc. 1992,
114, 1919–1920; h) A. Bencini, A. Bianchi, M. I. Burguete, P. Dap-
porto, A. DormØnech, E. Garcꢀa-EspaÇa, S. V. Luis, P. Paoli, J. A.
Ramirez, J. Chem. Soc. Perkin Trans. 2 1994, 2, 569–577; i) Q. Lu,
R. J. Motekaitis, J. J. Reibenspies, A. E. Martell, Inorg. Chem. 1995,
34, 4958–4964; j) M.-P. Teulade-Fichou, J.-P. Vigneron, J.-M. Lehn,
J. Chem. Soc. Perkin Trans. 2 1996, 2, 2169–2175; k) T. Paris, J.-P.
Vigneron, J.-M. Lehn, J. Inclusion Phenom. Macrocyclic Chem.
1999, 33, 191–202; l) I. Alfonso, B. Dietrich, F. Rebolledo, V. Gotor,
J.-M. Lehn, Helv. Chim. Acta 2001, 84, 280–295; m) C. Miranda, F.
Escartꢀ, L. Lamarque, M. J. R. Yunta, P. Navarro, E. Garcꢀa-EspaÇa,
M. L. Jimeno, J. Am. Chem. Soc. 2004, 126, 823–833; n) C. Anda,
A. Llobet, A. E. Martell, J. Reibenspies, E. Berni, X. Solans, Inorg.
Chem. 2004, 43, 2793–2802; o) J. Nelson, M. Nieuwenhuyzen, I. Pµl,
R. M. Town, Dalton Trans. 2004, 229–235; p) C. Bazzicalupi, A.
Bencini, A. Bianchi, L. Borsari, C. Giorgi, B. Valtancoli, J. Org.
Chem. 2005, 70, 4257–4266; q) S. Carvalho, R. Delgado, N. Fonseca,
V. FØlix, New J. Chem. 2006, 30, 247–257; r) A. Arbuse, C. Anda,
M. A. Martꢀnez, J. PØrez-Mirꢁn, C. Jaime, T. Parella, A. Llobet,
Inorg. Chem. 2007, 46, 10632–10638; s) C. Cruz, R. Delgado,
M. G. B. Drew, V. FØlix, J. Org. Chem. 2007, 72, 4023–4034; t) C.
Bazzicalupi, A. Bencini, A. Bianchi, C. Borri, A. Danesi, E. Garcꢀa-
EspaÇa, C. Giorgi, B. Valtancoli, J. Org. Chem. 2008, 73, 8286–8295;
u) A. Gonzµlez-lvarez, I. Alfonso, P. Dꢀaz, E. Garcꢀa-EspaÇa, V.
Gotor-Fernµndez, V. Gotor, J. Org. Chem. 2008, 73, 374–382; v) S.
Carvalho, R. Delgado, M. G. B. Drew, V. Calisto, V. FØlix, Tetrahe-
dron 2008, 64, 5392–5403; w) C. Cruz, V. Calisto, R. Delgado, V.
FØlix, Chem. Eur. J. 2009, 15, 3277–3289; x) S. Carvalho, R. Delga-
do, V. FØlix, Tetrahedron 2010, 66, 8714–8721.
The X-ray data were collected using a CCD Bruker APEX II at 150(2) K
with graphite-monochromatised MoKa radiation (l=0.71073 Š) with the
crystal positioned at 35 mm from the CCD and the spots were measured
using a counting time of 60 s. Data reduction and multi-scan absorption
correction effects were carried out using the SAINT-NT software from
Bruker AXS. The structure was solved by direct methods and by subse-
quent difference Fourier syntheses and refined by full-matrix least-
squares on F2 using the SHELX-97 system programs.[30] One chloride
counter ion and the encapsulated methanol molecule (see above) were
found disordered over two alternative positions. The methanol atomic
positions were included in the structure refinement with refined occupan-
cies of 1ꢀx and x, with x being equal to 0.31(2). Occupancy factors of
two chloride alternative positions were set to 0.88 and 0.12, respectively.
Anisotropic thermal parameters were used for all non-hydrogen atoms.
ꢀ
ꢀ
The C H and O H (methanol solvent molecules) hydrogen atoms were
inserted in the structure refinement in calculated positions with isotropic
parameters equivalent to 1.2 times those of the atom to which they are
attached. The hydrogen atoms of the water-encapsulated molecule as
ꢀ
well as the N H hydrogen atoms were obtained from the last Fourier
map and they were inserted in the structure refinement with the same
thermal constraints used for the other hydrogen atoms. The hydrogen
ꢀ
atoms of the remaining water mother liquor molecules as well the O H
of the disordered methanol molecule were not discernible from the last
difference Fourier maps and consequently were not taken into account.
A total of 44831 reflections were collected and subsequently merged
with 11116 unique reflections with an Rint of 0.0336. The final refinement
of 717 parameters converged to final R indices R1 =0.0662 and wR2 =
0.1887 for 8832 reflections with I>2s(I) and R1 =0.0836 and wR2 =
0.2101 for all hkl data. Molecular diagrams presented are drawn with
PyMOL.[31]
CCDC-809812 ([H7btpN7ACHTUNGNRET(NUNG H2O)ACHUTNTGRNEUG(N MeOH)Cl2]Cl6·ACHTUNGTREGUN(NN H3O)·3ACHTUNGTREN(UNNG H2O)·3MeOH)
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
[8] a) A. E. Martell, R. J. Motekaitis, J. Am. Chem. Soc. 1988, 110,
8059–8064; b) R. J. Motekaitis, A. E. Martell, Inorg. Chem. 1991,
30, 694–700; c) Q. Lu, J. J. Reibenspies, A. E. Martell, R. J. Mote-
kaitis, Inorg. Chem. 1996, 35, 2630–2636; d) C. Bazzicalupi, A. Ben-
cini, A. Bianchi, V. Fusi, E. Garcꢀa-EspaÇa, C. Giorgi, J. M. Llinares,
J. A. Ramirez, B. Valtancoli, Inorg. Chem. 1999, 38, 620–621; e) L.
Fabbrizzi, A. Leone, A. Taglietti, Angew. Chem. 2001, 113, 3156–
3159; Angew. Chem. Int. Ed. 2001, 40, 3066–3069; f) N. Marcotte,
A. Taglietti, Supramol. Chem. 2003, 15, 617–625; g) S. Carvalho, C.
Cruz, R. Delgado, M. G. B. Drew, V. FØlix, Dalton Trans. 2003,
4261–4270; h) M. Boiocchi, M. Bonizzoni, L. Fabbrizzi, G. Piovani,
A. Taglietti, Angew. Chem. 2004, 116, 3935–3940; Angew. Chem.
Int. Ed. 2004, 43, 3847–3852; i) M. Bonizzoni, L. Fabbrizzi, G. Pio-
vani, A. Taglietti, Tetrahedron 2004, 60, 11159–11162; j) F. Li, R.
Delgado, V. FØlix, Eur. J. Inorg. Chem. 2005, 4550–4561; k) B. Ver-
dejo, J. Aguilar, A. DomØnech, C. Miranda, P. Navarro, H. R. JimØ-
nez, C. Soriano, E. Garcꢀa-EspaÇa, Chem. Commun. 2005, 3086–
3088; l) L. Fabbrizzi, F. Foti, A. Taglietti, Org. Lett. 2005, 7, 2603–
2606; m) M. Boiocchi, M. Bonizzoni, A. Moletti, D. Pasini, A. Ta-
glietti, New J. Chem. 2007, 31, 352–356; n) S. Carvalho, R. Delgado,
M. G. B. Drew, V. FØlix, M. Figueira, R. T. Henriques, Polyhedron
2008, 27, 679–687.
The authors acknowledge the Fundażo para a CiÞncia e a Tecnologia
(FCT) and Programa Operacional CiÞncia e Inovażo (POCTI), with co-
participation of the European Community funds FEDER, for financial
support under project PTDC/QUI/68582/2006. The NMR spectrometers
are part of the National NMR Network (REDE/1517/RMN/2005) sup-
ported by POCTI 2010 and the FCT. We also acknowledge M. C. Almei-
da for providing elemental analysis and ESI-MS data from the Elemental
Analysis and Mass Spectrometry Service at the ITQB and Dr. Filipe de
Oliveira for help with the EPR spectra simulations. Pedro Mateus thanks
FCT for the grant (SFRH/BD/36159/2007).
[1] J. M. Berg, J. L. Tymoczko, L. Stryer, Biochemistry, 5th ed., W. H.
Freeman, New York, 2002, pp. 465–484.
[2] a) S. N. Yurgel, M. L. Kahn, FEMS Microbiol. Rev. 2004, 28, 489–
501; b) I. G. Janausch, E. Zientz, Q. H. Tran, A. Krçger, G. Unden,
Biochim. Biophys. Acta Bioenerg. 2002, 1553, 39–56.
[3] R. Hyde, P. M. Taylor, H. S. Hundal, Biochem. J. 2003, 373, 1–18.
[4] D. H. Williams, B. Bardsley, Angew. Chem. 1999, 111, 1264–1286;
Angew. Chem. Int. Ed. 1999, 38, 1172–1193.
[5] a) The Supramolecular Chemistry of Anions (Eds.: A. Bianchi, K.
Bowman-James, E. Garcia-EspaÇa), Wiley-Blackwell, New York,
1997; b) R. J. Fitzmaurice, G. M. Kyne, D. Douheret, J. D. Kilburn, J.
Chem. Soc. Perkin Trans. 1 2002, 841–864; c) P. A. Gale, R. Quesa-
[9] a) H. Aït-Haddou, S. L. Wiskur, V. M. Lynch, E. V. Anslyn, J. Am.
Chem. Soc. 2001, 123, 11296–11297; b) L. A. Cabell, M. D. Best,
7030
www.chemeurj.org
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7020 – 7031

Oxalate Recognition
FULL PAPER
J. J. Lavigne, S. E. Schneider, D. M. Perreault, M.-K. Monahan, E. V.
Anslyn, J. Chem. Soc. Perkin Trans. 2 2001, 315–323; c) Z. Zhong,
E. V. Anslyn, Angew. Chem. 2003, 115, 3113–3116; Angew. Chem.
Int. Ed. 2003, 42, 3005–3008; d) M. D. Best, E. V. Anslyn, Chem.
Eur. J. 2003, 9, 51–57; e) S. L. Tobey, E. V. Anslyn, J. Am. Chem.
Soc. 2003, 125, 10963–10970; f) A. D. Hughes, E. V. Anslyn, Proc.
Natl. Acad. Sci. USA 2007, 104, 6538–6543.
[18] B. J. Hathaway, J. Chem. Soc. Dalton Trans. 1972, 1196–1199.
[19] M. Inouye, K. Hashimoto, K. J. Isagawa, J. Am. Chem. Soc. 1994,
116, 5517–5518.
[20] S. L. Wiskur, H. Ait-Haddou, J. J. Lavigne, E. V. Anslyn, Acc. Chem.
Res. 2001, 34, 963–972.
[21] a) F. Wu, Z. He, Q. Luo, Y. Zeng, Food Chem. 1999, 65, 543–546;
b) F. Hong, N.-O. Nilvebrant, L. J. Jçnsson, Biosens. Bioelectron.
2003, 18, 1173–1181; c) A. Kazemzadeh, F. Moztarzadeh, Sens. Ac-
[10] D. Heyer, J.-M. Lehn, Tetrahedron Lett. 1986, 27, 5869–5872.
[11] C. A. Ilioudis, D. A. Tocher, J. W. Steed, J. Am. Chem. Soc. 2004,
126, 12395–12402.
´
´
tuators B 2005, 106, 832–836; d) S. Milardovic, I. Kerekovic, M.
Nodilo, Talanta 2008, 77, 222–228.
[12] a) S. S. Flack, J.-L. Chaumette, J. D. Kilburn, G. J. Langley and M.
Webster, J. Chem. Soc. Chem. Commun. 1993, 399–401; M. J. Deetz,
M. Shang, B. D. Smith, J. Am. Chem. Soc. 2000, 122, 6201–6207;
b) J. M. Mahoney, A. M. Beatty, B. D. Smith, J. Am. Chem. Soc.
2001, 123, 5847–5848; J. M. Mahoney, R. A. Marshall, A. M. Beatty,
B. D. Smith, S. Camiolo, P. A. Gale, J. Supramol. Chem. 2001, 1,
289–292; C. Suksai, P. Leeladee, D. Jainuknan, T. Tuntulani, N.
Muangsin, O. Chailapakul, P. Kongsaeree, C. Pakavatchai, Tetrahe-
dron Lett. 2005, 46, 2765–2769.
[13] B. Dietrich, M. W. Hosseini, J.-M. Lehn, R. B. Sessions, Helv. Chim.
Acta 1985, 68, 289–299.
[14] a) A. Bianchi, E. Garcꢀa-EspaÇa, J. Chem. Educ. 1999, 76, 1727–
1732; b) P. Mateus, N. Bernier, R. Delgado, Coord. Chem. Rev. 2010,
254, 1726–1747.
[22] K. J. Wallace, R. Hanes, E. V. Anslyn, J. Morey, K. V. Kilway, J.
Siegel, Synthesis 2005, 2080–2083.
[23] J. P. Collman, L. Fu, P. C. Herrmann, Z. Wang, M. Rapta, M. Brçr-
ing, R. Schwenninger, B. Boitrel, Angew. Chem. 1998, 110, 3592–
3595; Angew. Chem. Int. Ed. 1998, 37, 3397–3400.
[24] G. Schwarzenbach, W. Flaschka, Complexometric Titrations, Me-
thuen, London, 1969, pages 252–258.
[25] F. J. Rossotti, H. J. Rossotti, J. Chem. Educ. 1965, 42, 375–378.
[26] P. Mateus, R. Delgado, P. Brand¼o, S. Carvalho, V. FØlix, Org.
Biomol. Chem. 2009, 7, 4661–4673.
[27] P. Gans, A. Sabatini, A. Vacca, Talanta 1996, 43, 1739–1753.
[28] L. Alderighi, P. Gans, A. Ienco, D. Peters, A. Sabatini, A. Vacca,
Coord. Chem. Rev. 1999, 184, 311–318.
[29] SpinCount software, created by Professor M. P. Hendrich at Carne-
gie Mellon University. SpinCount is available at http://www.chem.
cmu.edu/groups/hendrich/.
[15] M. Duggan, N. Ray, B. Hathaway, G. Tomlinson, P. Brint, K. Pelin,
J. Chem. Soc. Dalton Trans. 1980, 1342–1399.
[16] F. Thaler, C. D. Hubbard, F. W. Heinemann, R. van Eldik, S. Schin-
dler, I. Fµbiµn, A. M. Dittler-Klingemann, F. E. Hahn, C. Orvig,
Inorg. Chem. 1998, 37, 4022–4029.
[30] G. M. Sheldrick, Acta Crystallogr. A 2008, 64, 112–122.
[31] W. L. DeLano, The PyMOL Molecular Graphics System, 2002;
http://www.pymol.org.
[17] A. Bencini, I. Bertini, D. Gatteschi, A. Scozzafava, Inorg. Chem.
1978, 17, 3194–3197.
Received: February 8, 2011
Published online: May 6, 2011
Chem. Eur. J. 2011, 17, 7020 – 7031
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7031