Templated synthesis of copper(II) azacyclam complexes using urea as a locking fragment and their metal-enhanced binding tendencies towards anions

Article abstract of DOI:10.1002/chem.200901364

Copper(II) azacyclam complexes 3²⁺ and 4²⁺ were obtained through a metal-templated procedure involving the pertinent open-chain tetramine, formaldehyde and a phenylurea derivative as a locking fragment. Both metal complexes can estab

Full text of DOI:10.1002/chem.200901364

DOI: 10.1002/chem.200901364
Templated Synthesis of Copper(II) Azacyclam Complexes Using Urea as a
Locking Fragment and Their Metal-Enhanced Binding Tendencies towards
Anions
Massimo Boiocchi,[b] Luigi Fabbrizzi,*[a] Mauro Garolfi,[a] Maurizio Licchelli,*[a]
Lorenzo Mosca,[a] and Cristina Zanini[a]
In memory of Professor Alan M. Sargeson
Abstract: Copper(II) azacyclam com-
plexes 32+ and 42+ were obtained
through a metal-templated procedure
involving the pertinent open-chain tet-
ramine, formaldehyde and a phenylur-
ea derivative as a locking fragment.
Both metal complexes can establish in-
teractions with anions through the
metal centre and the amide NH group.
Equilibrium studies in DMSO by a
spectrophotometric titration technique
were carried out to assess the affinity
of 32+ and 42+ towards anions. While
the NH group of an amide model com-
pound and the metal centre of the
plain CuII(azacyclam)2+ complex do
not interact at all with anions, 32+ and
42+ establish strong interactions with
nounced cooperative effect. In particu-
lar, 1) they form stable 1:1 and 1:2
complexes with H2PO4 ions in a step-
ꢀ
wise mode with both hydrogen-bonding
and metal–ligand interactions, and 2) in
the presence of CH3COOꢀ, they under-
go deprotonation of the amido NH
group and thus profit from axial coor-
dination of the partially negatively
charged carbonyl oxygen atom in a
scorpionate binding mode.
oxo anions, profiting from
a pro-
Keywords: copper · macrocyclic li-
gands · receptors · scorpionates ·
template synthesis
Introduction
Metal-template syntheses lie at the heart of the chemistry of
macrocycles[1,2] and provide effective tools for the develop-
ment of supramolecular chemistry.[3] The prototype of tet-
raaza macrocycles, cyclam (2), could be obtained in high
yield through Schiff base condensation of glyoxal with the
open chain tetramine 3.2.3-tet (1), which is preoriented for
cyclization by the NiII template.[4] The “reversible” C=N
bond was hydrogenated, and made “irreversible”, by
NaBH4. Cyclam can then be isolated by demetallation with
cyanide in boiling basic solution and liquid–liquid extraction
(see Scheme 1).[5]
[a] Prof. L. Fabbrizzi, Dr. M. Garolfi, Prof. M. Licchelli, Dr. L. Mosca,
Dr. C. Zanini
Scheme 1. Nickel(II)-templated synthesis of cyclam.[5]
Dipartimento di Chimica Generale
Universitꢀ di Pavia
via Taramelli 12, 27100 Pavia (Italy)
Fax : (+39)0382-528544
E-mail: luigi.fabbrizzi@unipv.it
Later, further convenient template syntheses of cyclam-
like macrocycles and macrocyclic complexes were intro-
duced, inspired by the classical Sargeson template syntheses
of CoIII sepulchrate and sarcophagine (sar) complexes.[6,7] In
the one-pot syntheses of these cage complexes, first six mol-
[b] Dr. M. Boiocchi
Centro Grandi Strumenti, Universitꢀ di Pavia
via Bassi, 27100 Pavia (Italy)
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FULL PAPER
ecules of formaldehyde undergo Schiff base condensation
with the primary amino groups of [CoIII(en)3]3+ (en: 1,2-dia-
minoethane), and then two equivalents of a triprotic acid
has been used to cyclize linear tetramines of varying length
to give CuII complexes with tetraaza macrocycles of ring size
ranging from 13 to 16 members.[11] Also, primary anilines
have been extensively used as locking fragments to give 14-
membered azacyclam complexes. An interesting example is
the reaction of melamine, which contains three aniline NH2
fragments in the 1,3,5-positions of a phenyl ring, with three
[CuII(tetramine)]2+ complexes, in the presence of formalde-
hyde and base to give a trimetallic species of C3v symme-
[6]
(NH3 or CH3NO2),[7] in the presence of base, are deproton-
ated stepwise, and corresponding anions consecutively
ACTHNUTRGNEUNG
attack the imine bonds (synthesis of [CoIII(diNOsar)]3+ is il-
lustrated in Scheme 2). Astonishingly, 12 particles, organised
by the cobalt centre, sequentially go to the right place in
order to react and ultimately give the highly symmetric and
aesthetically pleasing CoIII cage complex.[8]
.[12,13]
try
We observed more recently that the NH2 group of amides,
both carboxyamides, RC(O)NH2 and sulfonamides,
RS(O2)NH2, works well as a locking fragment in the synthe-
sis of CuII[14] and NiII azacyclam complexes (Scheme 4).[15]
ACTHNUTRGNEUNG
Scheme 2. Synthesis of [CoIII(diNOsar)]3+ (diNOsar=dinitrosarcopha-
gine).[7] CH3NO2 can be replaced by the other triprotic acid NH3 to give
the [CoIII(sepulchrate)]3+ complex.[6]
The same strategy was then applied to the synthesis of
cyclam-like macrocycles and macrocyclic complexes: in this
case, a diprotic acid AH2 is required to accomplish cycliza-
tion. For example, Sargeson et al. reported the reaction of
two equivalents of nitroethane (CH3CH2NO2) with
[CuII(ethylenediamine)2]2+ in the presence of formaldehyde
and base to give a dinitrocyclam complex (see Scheme 3,
route a).[9]
Scheme 4. Metal-templated synthesis of azacyclam complexes from com-
plexes of CuII and NiII with a linear tetramine in the presence of formal-
dehyde and base by using a carboxyamide or a sulfonamide as locking
fragment.
The good reactivity seems to be related to the relatively
high acidity of amides. As carboxyamide or sulfonamide de-
rivatives are in general easily attainable, this approach
allows one to append to an azacyclam complex almost any
desired functionality. Examples include a redox-active subu-
nit (e.g., ferrocene)[16] and a fluorogenic fragment (e.g.,
naphthalene)[17] to give multifunctional molecular devi-
ces.[18,19]
We report here the synthesis of two novel CuII azacyclam
complexes obtained through the reaction illustrated in
Scheme 3, in which a phenylurea moiety was employed as a
locking fragment (Scheme 5).
Metal azacyclam complexes 32+ and 42+ have an amide
NH group which is polarised by the directly bound electron-
withdrawing nitro- or cyanophenyl group. Secondary amido
groups activated by electron-withdrawing substituents have
been extensively used as hydrogen-bonding donors in the
design of a variety of anion receptors.[20] We report here an
investigation on how the proximate metal centre (which can
Scheme 3. Synthesis of cyclam-like macrocyclic complexes from bis-ethyl-
enediamine complexes of CuII and NiII in the presence of formaldehyde
and base by using a diprotic acid AH2 as locking fragment.
Then, Suh and Kangly described the reaction of primary
amines (CH3NH2, C2H5NH2) with [NiII(en)2]2+ and
[CuII(en)2]2+ (en=ethylenediamine) to give diazacyclam
complexes
(see
Scheme 3,
route b).[10] CuII or NiII ions
could be used as a template in
view of their propensity to
form thermodynamically stable
square-planar complexes with
two en molecules. The nitro-
ethane/formaldehyde approach
Scheme 5. Synthesis of copper(II) azacyclam complexes by using a phenylurea derivative as locking fragment.
Chem. Eur. J. 2009, 15, 11288 – 11297
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11289

L. Fabbrizzi, M. Licchelli et al.
Table 1. Selected bond lengths [ꢂ] and bond angles [8] around the metal
centre in [3]ACTHNUGTRENN(UNG NO3)2 and [4]ACTHUNGTRENNNUG
interact with anions itself) modifies anion-recognition prop-
erties of the secondary amido group, and vice versa.
A
[4]ACHTUNGTRENNUNG(NO3)2
Equilibrium studies in polar DMSO medium have shown
that the CuII azacylam subunit strongly increases the acidity
of the amide NH group, inducing deprotonation in the pres-
ꢀ
Cu(1) N(2)
2.021(5)
2.003(5)
1.990(5)
2.009(5)
86.3(2)
178.3(2)
93.6(2)
94.0(2)
177.8(2)
86.2(2)
2.024(5)
2.001(5)
2.006(5)
2.009(5)
85.7(2)
175.1(5)
94.6(2)
93.2(2)
173.3(2)
85.9(2)
ꢀ
Cu(1) N(3)
ꢀ
Cu(1) N(4)
ꢀ
ence of CH3COOꢀ and favouring binding of the H2PO4 ion
ꢀ
Cu(1) N(5)
through simultaneous establishment of hydrogen-bonding
and metal–ligand interactions. On the other hand, no inter-
action was observed with reference amides 5 and 6. This in-
dicates the special role played by the proximate metal aza-
cyclam complex.
N(2)-Cu(1)-N(3)
N(2)-Cu(1)-N(4)
N(2)-Cu(1)-N(5)
N(3)-Cu(1)-N(4)
N(3)-Cu(1)-N(5)
N(4)-Cu(1)-N(5)
2+
ꢀ
ꢀ
with Cu(1) O(4) 2.41(1), Cu(1) O(7) 2.55(1) ꢂ for 3 and
Cu(1) O(2) 2.41(1), Cu(1) O(5) 2.64(1) ꢂ for 42+. Such
long interatomic distances suggest that the NO3 counter-
ꢀ
ꢀ
ꢀ
A carboxyamide group was appended to the nitrogen
atom of cyclen (1,4,7,10-tetraazacyclododecane) through re-
action with aliphatic and aromatic isocyanates, and the inter-
action of the corresponding CuII and ZnII complexes with
DNA was investigated.[21]
ions may be involved in only very weak coordinative inter-
actions.
ꢀ
The mean Cu N distance is 2.01(1) ꢂ for both azacyclam
complexes 32+ and 42+. This value is only a bit shorter than
ꢀ
the strain-free Cu N distance of 2.03 ꢂ reported for 14-
membered tetraaza macrocycles.[22] The tertiary nitrogen
atom of each azacyclam ring is not involved in coordination
and plays a mere architectural role; it shows a nearly trigo-
nal-planar geometry, sp2 hybridization and pronounced in-
volvement of the lone pair in the amide bond.
Results and Discussion
Structure of azacyclam complexes: Figure 1 shows the mo-
lecular structures, determined by single crystal X-ray studies,
of copper(II) azacyclam complexes 32+ and 42+, which were
obtained as nitrate salts. Selected geometrical features
around the CuII centres are reported in Table 1.
In both complexes, the cyclam-like ring is present as the
R,S,S,R diastereoisomer (also denoted trans-III form),[23] the
most stable and most frequently observed configurational
isomer of metal complexes with the unsubstituted cyclam
ligand.[24] Similar bond lengths, bond angles and configura-
tion have been observed in previously investigated carbox-
yamide-functionalised CuII azacyclam complexes.[25] The
phenylamide group points outward from the metal centre,
leaving open room for coordination of further ligands to
CuII.
Both complexes exhibit an almost regular square-planar
coordination geometry of the metal centre and the copper
atoms deviate from the best plane of the four secondary
amino groups by only 0.03(1) ꢂ in 32+ and 0.10(1) ꢂ in 42+
.
The two oxygen atoms of the nitrate counterions are located
in the two axial positions of a rather elongated octahedron
Figure 1. ORTEPs of copper(II) azacyclam complex salts [3]ACHTNUTRGENNUG(NO3)2 (a), and [4]ACHTUNGTERN(NUGN NO3)2 (b). Thermal ellipsoids are drawn at 30% probability; only H
atoms bonded to Namine atoms are shown.
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Template Synthesis of Copper(II) Azacyclam Complexes
FULL PAPER
Anion binding: equilibrium studies with model amides:
Anion interactions with neutral receptors like amides are
typically investigated in aprotic media (CHCl3, MeCN,
DMSO) to avoid competition of the solvent in donating H-
bonds to the anion. Moreover, the stability of the receptor–
anion association complexes decreases along the series
CHCl3 >MeCN>DMSO, which reflects increasing solvent
polarity and higher energy
Interaction of CuII azacyclam complexes 32+ and 42+ with
CH3COOꢀ: metal-assisted amide deprotonation: Figure 2a
shows spectra taken over the course of titration of a 5ꢃ
10ꢀ5 m solution of CuII azacyclam complex 32+, [CuII(LH)]2+
,
in DMSO with [Bu4N]CH3COO. The receptor shows a
rather intense band centred at 330 nm, responsible for the
pale yellow colour.
spent in desolvating the
anion.[26] The present study
was carried out in DMSO, due
to the very poor solubility of
ionic complexes 32+ and 42+ in
less polar solvents.
Binding tendencies of the
amide NH group towards
anions were investigated by
carrying out spectrophotomet-
ric titration experiments. In a
typical experiment, a 5ꢃ10ꢀ5
m
Figure 2. a) Spectra taken over the course of the titration of a 5ꢃ10ꢀ5 m solution of CuII azacyclam complex
32+, [CuII(LH)]2+, in DMSO with a 4.5ꢃ10ꢀ3 m DMSO solution of [Bu4N]CH3COO. b) Dashed lines: concen-
tration of the undeprotonated [CuII(LH)]2+ and deprotonated [CuII(L)]+ species (off right vertical axis); sym-
bols: absorbance of the bands centred at 350 nm for [CuII(LH)]2+ (right vertical axis) and 450 nm for
[CuII(L)]+ (left vertical axis).
solution of the receptor was ti-
trated with a 5ꢃ10ꢀ3 m solution
of the tetrabutylammonium
salt of the envisaged anion. On
light absorption, metal-con-
taining phenylurea derivatives
32+ and 42+, as well as reference metal-free amides 5 and 6,
give rise to a charge-transfer transition, basically from the
nitrogen atom of the NH group to the electron-withdrawing
substituent (NO2 or CN), along the phenyl ring, which re-
sults in a rather intense absorption band in the UV region.
The optical transition generates a partial negative charge on
the substituent and a partial positive charge on the amide
nitrogen atom. Thus, interaction of a negatively charged ion
at the NH group is expected to stabilise the excited state
and thus reduce the energy of the transition. As a conse-
quence, on interaction with the anion, a red shift of the ab-
sorption band should be observed. The stronger the anion–re-
ceptor interaction, the more pronounced the red shift.
On addition of acetate, the solution progressively takes
on a bright yellow colour, while the intensity of the band at
330 nm decreases and a new band forms and develops at
450 nm. Such large red shifts of charge-transfer bands of
amide (and urea) receptors (100 nm in the present case) and
drastic colour changes are typically associated with deproto-
nation of the NH group.[28–31] Thus, the occurrence of an
acid–base neutralisation equilibrium is suggested [Eq. (1)]
½CuIIðLHÞꢁ2þ þ CH3COOꢀ Ð ½CuIIðLÞꢁþ þ CH3COOH
ð1Þ
Best fitting of spectrophotometric titration data with a
non-linear least-squares procedure[32] over the interval 250–
550 nm was obtained by assuming a 1:1 equilibrium with
logK=4.807ꢂ0.03. Figure 2b shows the percentage concen-
trations of undeprotonated [CuII(LH)]2+ and deprotonated
[CuII(L)]+, calculated on the basis of the logK value. Occur-
rence of equilibrium (1) is confirmed by the fact that 1) the
absorbance of the 32+ receptor (e.g., taken at 350 nm) super-
imposes well on the concentration profile of [CuII(LH)]2+
and 2) the absorbance of the band at 450 nm superimposes
well on the concentration profile of [CuII(L)]+. Acetate-in-
duced deprotonation of an NH group in DMSO was previ-
ously observed for thiourea derivatives bearing strongly
electron withdrawing substituents.[33] Thiourea is a distinctly
stronger acid than urea in DMSO (pKa values: 21.1 and
26.95, respectively).[34] Moreover, in the mentioned case,[33]
two stepwise equilibria occurred: first, the formation of a
genuine thiourea/acetate H-bonded complex, then deproto-
nation of the NH group with simultaneous formation of the
[CH3COOH···CH3COO]ꢀ H-bonded self-complex. Quite
To assess the hydrogen-bonding donor tendencies of the
amide group in the absence of any cooperative effect of the
proximate metal centre, preliminary titration experiments
were carried out for reference amides 5 and 6 in DMSO so-
lution. However, even on addition of a large excess of the
ꢀ
more basic anions (CH3COOꢀ and H2PO4 ) no significant
spectral modification were observed. In particular, no shift
of the charge-transfer transition bands centred at 350 (5, e=
13400) and at 280 nm (6, e=24400 cmꢀ1 mꢀ1) was detected.
To verify binding tendencies towards anions of amides 5 and
6, the same titration experiments were carried out also in
the less polar solvent MeCN. However, also in this case, no
spectral changes were observed. This indicates that recep-
tor–anion association constants are smaller than 100 and
demonstrates the poor donating tendencies of a single NH
group towards anions. Indeed, the numerous investigated
amide-based anion receptors contain several NH groups,
strategically placed inside a cavity.[27]
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L. Fabbrizzi, M. Licchelli et al.
surprisingly, in the present case, acetate-induced deprotona-
tion of the NH group 1) takes place with the less acidic urea
subunit, and 2) does not involve formation of the
[CH3COOH···CH3COO]ꢀ complex, but occurs directly on
addition of only 1 equiv of acetate. This evidence points to-
wards a significant cooperative effect exerted by the CuII–
azacyclam subunit and, in particular, by the CuII centre.
However, no information on the state of the CuII centre
over the course of the titration can be inferred from absorp-
tion spectra, because the intense charge-transfer band of the
deprotonated species covers the wavelength interval in
which d–d bands of CuII(azacyclam)2+ complexes are typi-
cally observed.
ops at 330 nm. Again, this strongly red-shifted band is ascri-
bed to the deprotonated species [CuII(L)]2+, which forms ac-
cording to an acid–base equilibrium of type (1). The logK
value for proton transfer from the amide NH group to
CH3COOꢀ is 4.35ꢂ0.03, that is, 0.5 units lower than for 32+
,
a difference which may reflect the stronger polarizing effect
exerted by the nitro group. Conveniently, the band of the
deprotonated form of 42+, [CuII(L)]+, appears at relatively
high energy and leaves the visible region, where d–d transi-
tions take place uncovered.
Figure 4a shows d–d spectra taken during the titration of
a
1.02ꢃ10ꢀ3
m
solution of 42+ in DMSO with
[Bu4N]CH3COO. The band centred at 510 nm (short dashes
The situation may be more
convenient in the case of the
CuII derivative 42+, in which a
cyanophenyl substituent is
present. In fact, the charge-
transfer transition of the cya-
nophenylamide unit takes
place below 300 nm, and the
band pertinent to the depro-
tonated form, if any, should
not interfere with d–d transi-
tions. Figure 3 shows the
Figure 4. a) Spectra taken over the course of the titration of a 1.02ꢃ10ꢀ3 m solution of the CuII azacyclam com-
plex 42+, [CuII(LH)]2+, in DMSO with a 0.102m DMSO solution of [Bu4N]CH3COO. b) Dashed lines: concen-
tration of undeprotonated [CuII(LH)]2+ and deprotonated [CuII(L)]+ species (right vertical axis); symbols: ab-
family of spectra obtained
during the titration of a 5ꢃ
10ꢀ5 m solution of CuII azacy-
+
sorbance of the band centred at 550 nm for [CuII(L)] (left vertical axis).
clam
complex
42+
,
[CuII(LH)]2+, in DMSO with
[Bu4N]CH3COO.
The spectrophotometric response is analogous to that ob-
served for 32+. In the present case, the functionalised CuII
azacyclam complex, before acetate addition, shows an in-
tense absorption band, centred at 270 nm, which originates
from the optical transition from the N,N’-dialkylurea subunit
to the cyano group. This band is centred at a higher energy
than in the nitro derivative, due to the lower intensity of the
transition dipole. Acetate addition makes the band at
270 nm decrease, while a new intense band forms and devel-
in Figure 4a) is that typically observed for
a
CuII(azacyclam)2+ complex with square-planar coordination
geometry (as shown, for instance, by the crystal and molecu-
lar structure in Figure 1a). On CH3COOꢀ addition, the
band is shifted to higher wavelength and increases in inten-
sity. Such behaviour is indicative of a change from fourfold
coordination with square-planar geometry to fivefold coor-
dination, probably with square-pyramidal geometry. In par-
ticular, the broad band at 510 nm must be considered as an
envelope of three bands result-
ing from xz,yz!x2ꢀy2, z2!
x2ꢀy2 and xy!x2ꢀy2 transi-
tions the square-planar com-
plex.[35] Approach of a fifth
donor atom along the z axis
raises the energy of the levels
with a z component, and this
results in a decrease in the
energy of pertinent transitions
of and ultimately causes a shift
of the envelope to higher
wavelengths. Moreover, on in-
Figure 3. a) Spectra taken over the course of the titration of a 5ꢃ10ꢀ5 m solution of the CuII azacyclam complex
42+, [CuII(LH)]2+ in DMSO with a 4.5ꢃ10ꢀ3 m DMSO solution of [Bu4N]CH3COO. b) Dashed lines: concen-
tration of the undeprotonated [CuII(LH)]2+ and deprotonated [CuII(L)]+ species (off right vertical axis);
b) symbols: absorbance of the bands centred at 280 nm for [CuII(LH)]2+ (right vertical axis) and at 330 nm for
teraction of a fifth donor atom,
the azacyclam complex loses
its centre of symmetry, a cir-
cumstance which renders d–d
+
[CuII(L)] (left vertical axis).
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Template Synthesis of Copper(II) Azacyclam Complexes
FULL PAPER
transitions “less” forbidden and increases the absorbance.[36]
On this basis, we suggest that the fifth donor atom is the car-
bonyl oxygen atom of the urea subunit, which, on deproto-
nation of the NH group, takes on a partial negative charge.
The process is tentatively illustrated in Scheme 6.
negative charge and the system is reset to state a (as indicat-
ed by the full restoration of the charge-transfer bands at 330
(32+) and at 270 nm (42+). Coordination of the C=O group
in a scorpionate mode prior to acetate addition can be ruled
out for two main reasons: 1) the structures of the complex
salts [3]ACHTUNRTGENNUG(NO3)2 and [4]ACHTUNGTRENNUNG(NO3)2
shown in Figure 1 indicate that
the phenylamide pendant arm
points outwards from the
metal centre; 2) the d–d band
of 42+ appears at the same
wavelength as those of CuII
complexes with cyclam and
azacyclam derivatives not bear-
ing
a
carboxyamide group,
while axial perturbation would
cause a definite red shift.
Interaction of the CuII-azacy-
clam complexes 3 and 4 with
H2PO4ꢀ: metal-assisted forma-
tion of H-bonded complexes:
Scheme 6. Metal-induced deprotonation of the secondary amide group. The deprotonation process is made
feasible by coordination of the partially negatively charged carbonyl oxygen atom to the CuII centre.
ꢀ
Macrocycles with a movable pendant arm whose coordi-
nating tendencies can be switched on/off by an external
input (e.g., a change of pH) are called scorpionands.[37] One
of the first examples was the the NiII complex of N-aminoe-
thylcyclam.[38] At pH<3, the amine group is protonated and
the pendant arm stays far away from the metal centre
(Scheme 7a); at pH>3, the amino group is no longer pro-
tonated and binds to the metal centre from the top, like the
tail of a scorpion (Scheme 7b).
The H2PO4 ion is distinctly less basic than CH3COOꢀ (pKA
values in water: 1.97[39] and 4.76,[40] respectively) and does
not induce deprotonation of the amide NH group of CuII
azacyclam complexes 32+ and 42+; in fact, it gives genuine
association complexes, held together by H-bonds and metal–
ligand interactions, as shown by unambiguous spectrophoto-
metric evidence.
Figure 5a shows spectra taken over the course of the titra-
tion of a dilute solution (5ꢃ10ꢀ5 m) of 42+, [CuII(LH)]2+
,
with [Bu4N]H2PO4. Addition of the anion induces a moder-
ate red shift of the charge-transfer band centred at 270 nm,
the maximum of which, after addition of an excess of phos-
phate, is red-shifted by about 10 nm. Such behaviour is typi-
cally observed in phenylurea derivatives following H-bond-
ing interaction of anions at the NH group.[28–31] Best fitting
of titration data was obtained by assuming the presence of
two complex species at equilibrium, one containing one
phosphate anion, and the other two phosphate anions,
formed according to two stepwise processes [Eqs. (2) and
(3)].
Scheme 7. Metal scorpionate equilibrium. Deprotonation of the ethylam-
monium side chain induces axial binding of the primary amine group,
with a change of the coordination geometry from square-planar (a) to oc-
tahedral (b).[37]
½CuIIðLHÞꢁ2þ þ H2PO4 Ð ½CuIIðLHÞðH2PO4Þꢁþ
ꢀ
ð2Þ
ð3Þ
½CuIIðLHÞðH2PO4Þꢁþ þ H2PO4 Ð ½CuIIðLHÞðH2PO4Þ2ꢁ
ꢀ
Systems 32+ and 42+ are new examples of scorpionate
complexes, the uncoordinated (a in Scheme 6) or coordinat-
ed (c) state of which is changed through an auxiliary acid–
base reaction (CH3COOꢀ + H+QCH3COOH). Thus, the
acidic behaviour of the amide NH group, which is not ob-
served at all in the model compounds 5 and 6, seems to be
solely determined by coordination to the proximate metal
centre of the carbonyl oxygen atom, which, on NH deproto-
nation, takes on a partial negative charge. On addition of
acid (e.g., CF3SO3H), the deprotonated amide group takes
on one proton, the carbonyl oxygen atom loses the partial
The equilibrium constants for the two stepwise equilibria
are logK1 =4.27ꢂ0.01 and logK2 =3.66ꢂ0.04 for Equa-
tions (2) and (3), respectively. Figure 5b shows how the con-
centration of the three species at equilibrium, [CuII(LH)]2+
,
[CuII(LH)(H2PO4)]+ and [CuII(LH)
ACHTUNGTRNNEUG ACHUTNGTREN(NNGU H2PO4)2], vary over the
course of titration with phosphate. The decreasing absorb-
ance of the band centred at 270 nm superimposes well on
the decreasing profile of the concentration of the uncom-
plexed receptor [CuII(LH)]2+. On the other hand, the ab-
sorbance of the red-shifted band, centred at 280 nm, maxi-
Chem. Eur. J. 2009, 15, 11288 – 11297
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11293

L. Fabbrizzi, M. Licchelli et al.
ꢀ
dinative CuII/H2PO4 interac-
tions. The titration profile in
Figure 6b
(absorbance
at
550 nm vs. equiv of phosphate)
reaches saturation on addition
of 2 equiv of the anion. This
unambiguously indicates that
both the first and the second
ꢀ
H2PO4 anion interact with the
CuII centre of the 42+ receptor.
This may be surprising, if one
considers the behaviour of ref-
erence azacyclam complex 7.
On addition of an excess of
Figure 5. a) Spectra taken over the course of the titration of a 5ꢃ10ꢀ5 m solution of the CuII azacyclam complex
42+ [CuII(LH)]2+
in DMSO with [Bu4N]H2PO4. b) Long-dashed line: concentration of the receptor
[CuII(LH)]2+; short-dashed line: concentration of 1:1 complex [CuII(L)(H2PO4)]+; dash-dotted line: concentra-
tion of 1:2 complex [CuII(LH)
(H2PO4)2] (off right vertical axis); symbols:~, absorbance at 320 nm, monitoring
the decreasing concentration of the receptor [CuII(LH)]2+ (right vertical axis); !: absorbance at 370 nm, mon-
itoring the increasing concentration of both [CuII(LH)(H2PO4)]+ and [CuII(LH)
(H2PO4)2] (left vertical axis).
,
,
H2PO4 to a 10ꢀ3 m of 7 in
ꢀ
AHCTUNGTRENNUNG
DMSO, no modifications were
observed in the d–d band. This
indicates that the phosphate
ion has a poor affinity towards
AHCTUNGTRENNUNG
N
ACHTUNGTRENNUNG
mum intensity of which is achieved after addition of about
ꢀ
20 equiv of H2PO4 , seems to be associated with formation
of both 1:1 and 1:2 receptor:anion complexes, as it develops
ACTHNUTRGNEUNG
on initial anion addition, when [CuII(LH)(H2PO4)]+ forms,
and keeps increasing as the concentration of [CuII(LH)-
(H2PO4)]+ decreases and the concentration of [CuII(LH)-
(H2PO4)2] rises. However, prior to putting forward any hy-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
pothesis on the nature and geometry of the 1:1 and 1:2 asso-
ciation complexes, it is useful to assess whether the metal
centre is involved in the interaction with the anion. Thus,
the same titration experiment was carried out on a more
concentrated solution (1.40ꢃ10ꢀ3 m), in order to detect
changes in the d–d spectrum of the CuII–azacyclam subunit
the CuII centre of the azacyclam complex in a DMSO solu-
tion and, in any case, it is not able to displace solvent mole-
cules, which are present in an overwhelming amount, from
the apical positions of the elongated coordination octahe-
dron. This suggests that, in complex 42+, phosphate binding
to the metal centre must be driven by an additional interac-
tion: hydrogen bonding, as tentatively illustrated in
Scheme 8.
of 42+
.
Figure 6a shows spectra recorded during the titration with
phosphate. It is observed that on anion addition the d–d
band pertinent to the [CuII(LH)]2+ receptor undergoes a
definite red shift and a significant increase in intensity. Such
spectral modifications point towards establishment of coor-
We hypothesise that in the first step one of the two
ꢀ
oxygen atoms of the H2PO4 ion bearing a partial negative
charge binds to the CuII centre, while the other partially
negatively charged oxygen
atom receives an H-bond from
the amide NH group. In the
ꢀ
second step, an H2PO4 ion
binds to the CuII ion through
the oxygen atom that formally
bears a full negative charge,
while one of its OH groups do-
nates an H-bond to the carbon-
yl oxygen atom of the pendant
phenylurea subunit. According
to Scheme 8, the first step
profits firstly from coordinative
interaction of the CuII ion with
Figure 6. a) Spectra taken over the course of the titration of a 1.40ꢃ10ꢀ3 m solution of CuII azacyclam complex
42+, [CuII(LH)]2+, in DMSO with a 0.101m DMSO solution of [Bu4N]H2PO4. b) Dashed lines: concentration
an oxygen atom with a formal
1
charge of ꢀ = and secondly
of the [CuII(LH)]2+ receptor and of the anion association complexes [CuII(L)(H2PO4)]+ and [CuII(L)
ACTHNUGTRENNUG AHCTUNGTREN(NNGU H2PO4)2]
2
(right vertical axis); symbols: absorbance of the d–d band centred at 550 nm for [CuII(LH)]2+ (right vertical
from an H-bonding interaction
involving a nitrogen atom and
+
axis) and at 550 nm for [CuII(L)] (left vertical axis).
11294
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Chem. Eur. J. 2009, 15, 11288 – 11297

Template Synthesis of Copper(II) Azacyclam Complexes
FULL PAPER
tral features cannot help to dis-
criminate
(H2PO4)]+ and [{CuII(LH)-
(H2PO4)}2]2+ complexes, as the
the
[CuII(LH)-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CuII centre in both complexes
would experience interactions
with the same set of donor
atoms. However, formation of
a stable dimeric species, fully
saturated and not inclined to
react with a further phosphate
ion, would imply that spectral
modifications stop after the ad-
dition of one equivalent of
H2PO42ꢀ. The fact that the ti-
tration profile (see triangles in
ꢀ
Scheme 8. Hypothesised two-step binding of H2PO4 to a CuII(azacyclam)2+ complex acting as a ditopic anion
receptor (R=NO2, 32+; CN, 42+).
1
an oxygen atom with a formal charge of ꢀ = . Then, the
2
second step profits 1) from the metal–ligand interaction of
CuII with an oxygen atom with a formally integer negative
charge (more exothermic effect) and 2) from H-bonding in-
volving neutral oxygen atoms (less exothermic). The two
Figure 7. The H-bonded dimeric complex [H2PO4···H2PO4]2ꢀ (8), which
may form in polar non-aqueous media, for example, DMSO; on the right
side, the structure of the dimer, as observed in the crystal structure of the
complex with 1,1-(4-nitrophenyl)-3-{2-[3-(4- nitrophenyl)ureido]cyclohex-
yl}urea is shown.[41] Dashed lines indicate H-bonding interactions
(OꢀH···O). Structure redrawn from data deposited at the Cambridge
Crystallographic Data Centre: CCDC-268368.
overall energy contributions should be of comparable mag-
nitude and, therefore, the sequence of steps illustrated in
Scheme 7 could be reasonably inverted.
In the case of the nitro derivative 32+, logK1 (3.90ꢂ0.04)
and logK2 (4.01ꢂ0.06) are coincident (within standard devi-
ations). This may be surprising, because, other terms being
the same, logK1 should be 0.6 units larger than logK2, due
to the statistical effect (=log4). However, other factors can
contribute, such as the different degrees of freedom of the
receptor before and after interaction with the first phos-
phate ion: in particular, the rigidified [CuII(LH)]2+ complex
will experience a lower entropy loss when binding the
second phosphate anion. Moreover, slightly different confor-
mational arrangement of receptors 32+ and 42+, as evi-
denced by X-ray structure determination, can account for
the different patterns of logK1 and logK2 values. In any
case, logb2 values (=logK1 +logK2) are the same for both
32+ and 42+ receptors (7.9 log units), which indicates a sub-
stantial balance of energy contributions in the interaction of
each amide-functionalised azacyclam complex with two
phosphate anions.
Figure 6b) reaches a plateau only on addition of two equiva-
lents of anion strongly supports the occurrence of two step-
wise equilibria, as described by Equations (2) and (3), ac-
cording to the mechanism illustrated in Scheme 8.
In conclusion, the phosphate ion, in DMSO solution, does
not show any affinity towards the NH groups of model
amide derivatives 5 and 6 or towards the CuII centre in the
amide-NH-free azacyclam complex 7. However, it forms
stable 1:1 and 2:1 association complexes with receptors 32+
and 42+, thanks to establishing two-point interactions of H-
bonding and metal–ligand nature with the receptor and a
significant cooperative effect.
ꢀ
Interestingly, only CH3COOꢀ and H2PO4 are able to in-
teract with receptors 32+ and 42+. Less basic oxoanions, for
ꢀ
ꢀ
ꢀ
In polar non-aqueous solvents, the H2PO4 ion may form
example, HSO4 and NO3 , even if added in a large excess,
do not modify the UV and visible absorption spectra of both
amide functionalised azacyclam complexes. No effect was
observed also on addition of Clꢀ, Brꢀ and Iꢀ, a behaviour
which reflects their inability to act as a bridging ligand in re-
H-bonded dimers, as illustrated by formula 8 in Figure 7,
which also shows the structure of the dimer observed in the
crystal structure of the isolated receptor/anion complex, in
which the receptor is a bis-urea derivative.[41] Thus, one
cannot exclude that the [CuII(LH)
(H2PO4)]+ complex un-
ceptors 32+ and 42+
.
dergoes a dimerisation process [Eq. (4)].
2þ
2 ½CuIIðLHÞðH2PO4Þꢁþ Ð ½fCuIIðLHÞðH2PO4Þg2ꢁ
ð4Þ
Conclusions
In the dimeric complex [{CuII(LH)
(H2PO4)}2]2+, the di-
This work has demonstrated the versatility of metallo-azacy-
clam-based systems as anion receptors. In particular, the
proximate metal centre dramatically enhances the intrinsi-
cally poor H-bond donor tendencies of a single secondary
amide group through two distinctive cooperative effects:
Chem. Eur. J. 2009, 15, 11288 – 11297
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11295

L. Fabbrizzi, M. Licchelli et al.
N’,N’-Dimethyl-N-(4-cyanophenyl)urea (6): 4-Cyanophenylisocyanate
(0.29 g, 2.01 mmol); N’,N’-dimethyl-N-(4-cyanophenyl)urea (0.25 g,
1.32 mmol, 65.7%). ESI-MS (ꢀ): m/z: 302.3 [M+CF3COO]ꢀ (89), 413.1
[2M+Cl]ꢀ (100), 439.9 [2M+NO3]ꢀ (63), 490.6 [2M+CF3COO]ꢀ (96); IR
(Nujol): n˜ =3297 (NH stretch), 1653 (CO stretch); 2218 cmꢀ1 (CN
stretch).
1) in the presence of an ion that is not too basic, such as
ꢀ
H2PO4 , the CuII–azacyclam receptor provides multiple
binding sites for formation of 1:1 and 1:2 association com-
plexes, whose high stability in solution seems to be related
to a favourable geometrical complementarity between re-
ceptor and anion(s); 2) in the case of the more basic
CH3COOꢀ ion, the receptor offers an intramolecular bind-
ing mechanism for coordination of the carbonyl oxygen
atom, which favours deprotonation of the amide group, a
process never observed in the presence of acetate. More-
over, coordination of the tetramine macrocycle provides two
unique and functional features: 1) open space for coordina-
tion of further ligands, including anions, in the apical posi-
tions of an elongated octahedron; 2) high kinetic resistance
to demetallation, even in the presence of a large excess of
anions.
Copper(II) azacyclam complex [3]ACHTNUTRGENN(UG NO3)2: CuACHTUGNTERN(NUGN NO3)2·3H2O (0.63 g,
2.6 mmol) dissolved in ethanol (10 mL), 1,3-bis(2’-aminoethylamino)pro-
pane (0.40 g, 2.5 mmol) in EtOH (15 mL) and 4-nitrophenylurea (8,
0.45 g, 2.5 mmol) in EtOH (30 mL) were placed in a screw-capped glass
vial. To this solution triethylamine (0.75 mL, 5.4 mmol) and aqueous
formaldehyde (36.5%, 2 mL, 26.5 mmol) were subsequently added . The
reaction container was kept for three days in a oven adjusted to 758C. A
deep violet solid formed at the bottom of the container, and the solvent
was decanted. The solid was washed with small portions of ethanol and
collected by filtration under vacuum to yield 0.36 g of the crystalline
complex salt (0.65 mmol, 27.4%). ESI-MS (+): m/z (%): 490.1
[M+NO3]+ (100); IR (Nujol): n˜ =3228 (NH stretch), 1696 (CO stretch),
1540, 1329 (NO2 sym. and asym. stretch).
Copper(II) azacyclam complex [4]
ACHTUGNTERN(NUNG NO3)2: The same procedure was fol-
lowed as for [4]CAHTNUGTRNE(NUG NO3)2 complex but using 4-cyanophenylurea (9). Yield
36%. ESI-MS (+): m/z: 453.2 [M+HCOO]+ (100); IR (Nujol): n˜ =3196
(NH stretch), 1673 (CO stretch), 2220 (CN stretching), 1327 cmꢀ1 (ni-
trate).
Experimental Section
X-ray crystallographic studies: Diffraction data for crystals of [3]
ACHTUNGTRENNUNG(NO3)2
and [4](NO3)2 were collected at ambient temperature on a conventional
AHCTUNGTRENNUNG
General procedures and materials: All reagents for syntheses were pur-
chased from Aldrich/Fluka and used without further purification. 1,3-
Bis(2-aminoethylamino)propane was synthesised according to a reported
procedure.[42] All reactions were performed under a dinitrogen atmos-
phere. UV/Vis spectra were recorded on a Varian CARY 50 or CARY
100 spectrophotometer with quartz cuvettes of the appropriate path
length (0.1 or 1 cm). The concentration of the chromophore and the opti-
cal path were adjusted to obtain spectra with AUꢃ1. In titrations with
anions, spectra of samples were recorded after addition of aliquots of the
tetraalkylammonium salt of the envisaged anion under an inert atmos-
phere. IR spectra were recorded on a Perkin-Elmer Spectrum BX FTIR
instrument; samples were finely ground and dispersed in Nujol, NaCl
windows were used. Mass spectra were acquired on a Thermo-Finnigan
ion-trap LCQ Advantage Max instrument equipped with an ESI source.
Enraf-Nonius CAD4 four-circle diffractometer working with graphite-
monochromatised MoKa radiation (l=0.71073 ꢂ). Crystal data for the
two complexes are listed in Table 2.
Data reductions (including intensity integration, background, Lorentz
and polarisation corrections) were performed with the WinGX pack-
age;[43] absorption effects were evaluated with the psi-scan method,[44]
and absorption correction was applied to the data (min./max. transmis-
sion factors were 0.714/0.844 and 0.834/0.902 for [3]ACTHUNRTGENNUG(NO3)2 and [4]ACHTUNGTRENNUNG(NO3)2,
respectively). Both crystal structures were solved by direct methods (SIR
97)[45] and refined by full-matrix least-square procedures on F2 using all
reflections (SHELXL 97).[46] Anisotropic displacement parameters were
refined for all non-hydrogen atoms. For both molecular complexes, hy-
Synthesis of phenylureas 8 and 9: The appropriate 4-substituted phenyli-
socyanate was dissolved in diethyl ether (30 mL) with vigorous stirring.
Gaseous ammonia was bubbled through the ethereal solution until com-
plete precipitation occurred. Vacuum filtration, followed by washing with
portions of cold diethyl ether, afforded the desired product in a high
yield.
Table 2. Crystal data for investigated crystals.
[3]
N
[4]ACHTGNURETNNU(G NO3)2
formula
M
C16H27Cu N9O9
553.02
C17H27CuN9O7
533.03
0.36ꢃ0.29ꢃ0.10
violet
monoclinic
P21/c (no. 14)
7.8787 (17)
14.0459(11)
21.5091(41)
108.294(16)
2260.0(7)
4
1.567
1.026
w scans
2–25
4304
3993
0.0318
2383
crystal dimension [mm]
0.64ꢃ0.45ꢃ0.17
pale red
monoclinic
P21 (no. 4)
7.7883(23)
10.6983(13)
14.0517(23)
91.687(15)
1170.3(4)
2
4-Nitrophenylurea (8): 4-Nitrophenylisocyanate (0.57 g, 3.47 mmol); 4-ni-
trophenylurea (0.56 g, 3.09 mmol, 89%); pale yellow powder. ESI-MS:
(ꢀ): m/z (%): 180.2 [MꢀH]ꢀ (54), 226.1 [M+HCOO]ꢀ (100); IR:
(Nujol): n˜ =3500, 3317, 3279, 3154, 3093 (NH stretch); 1690 (CO stretch);
1560, 1322 cmꢀ1 (NO2 sym. and asym. stretch).
crystal colour
crystal system
space group
a [ꢂ]
b [ꢂ]
c [ꢂ]
4-Cyanophenylurea (9): 4-Cyanophenylisocyanate (1 g, 6.94 mmol); 4-cy-
anophenylurea (1.08 g, 6.70 mmol, 96.5%); white powder; ESI-MS (ꢀ):
m/z : 383.6 [2M+NO3]ꢀ (100). IR: (Nujol): n˜ =3483, 3378 (NH stretch),
1676 (CO stretch); 2219 cmꢀ1 (CN stretch).
b [8]
V [ꢂ3]
Z
1calcd [gcmꢀ3
]
1.569
1.000
Synthesis of N’,N’-dimethyl-N-phenylureas 5 and 6: The corresponding 4-
substituted phenyl isocyanate was dissolved in diethyl ether (30 mL) with
vigorous stirring. Gaseous dimethylamine (generated by warming 5 mL
of 40% aqueous dimethylamine) was bubbled through the organic phase
until complete precipitation occurred. The precipitate was collected by
vacuum filtration and washed with portions of cold diethyl ether, to
afford the desired product in a high yield.
m
A
]
scan type
w scans
q range [8]
2–30
measured reflns
unique reflns
4415
4003
Rint
0.0134
strong data [IO >2s(IO)]
refined parameters
R1, wR2 (strong data)
R1, wR2 (all data)
GOF
2925
320
0.0488, 0.0776
0.1114, 0.1262
1.029
0.88/ꢀ0.43
N’,N’-Dimethyl-N-(4-nitrophenyl)urea
(5):
4-Nitrophenylisocyanate
310
(0.31 g, 1.89 mmol); N’,N’-dimethyl-N-(4-nitrophenyl)urea (0.35 g,
1.69 mmol, 89.4%). ESI-MS (ꢀ): m/z (%): 208.4 [MꢀH]ꢀ (25), 244.2
[M+Cl]ꢀ (44), 254.0 [M+HCOO]ꢀ (100), 452.8 [2M+Cl]ꢀ (75), 462.7-
0.0605, 0.1223
0.1381, 0.1667
1.020
1.15/ꢀ0.75
ACHTUNGTRENNUNG
[2M+HCOO]ꢀ (33); IR (Nujol): n˜ =3340 (NH stretch), 1652 (CO
max./min. residuals [eꢂꢀ3
]
stretch), 1538, 1325 cmꢀ1 (NO2 sym. and asym. stretch).
11296
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Chem. Eur. J. 2009, 15, 11288 – 11297

Template Synthesis of Copper(II) Azacyclam Complexes
FULL PAPER
drogen atoms bonded to atoms forming the penta-aza macrocyclic ring
were placed at calculated positions with the appropriate AFIX instruc-
tions and refined using a riding model; the hydrogen atom bonded to the
amide group of the pendant arm was located in the final DF maps and re-
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ꢀ
fined while restraining the N H distance to be 0.90ꢂ0.01 ꢂ. The Flack
parameter,[47] calculated for the non-centrosymmetric crystal of the [3]-
A
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Received: May 21, 2009
Published online: September 11, 2009
Chem. Eur. J. 2009, 15, 11288 – 11297
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