New polyaminocarboxylate macrocycles containing phenolate binding units: synthesis, luminescent and relaxometric properties of their lanthanide complexes

Article abstract of DOI:10.1039/c7dt00291b

The synthesis of two new polyaminocarboxylate macrocycles incorporating one or two intracyclic phenol units (H₄L¹ and H₈L², respectively) is described. The 12-membered H₄L¹ macrocycle leads to soluble and stable mononuclear Ln^III complexes of [(L¹)Ln(H₂O)₂]^- composition (Ln = Eu, Tb and Gd) in aqueous solutions. In Tris buffer (pH 7.4), the [(L¹)Tb(H₂O)₂]^- complex displays a suitable efficiency for sensitized emission (η_sens = 48%) and a high luminescence quantum yield (Φ = 22%), which is worthy of note for a bis-hydrated terbium complex. Besides, luminescence experiments show that bidentate endogenous anions (citrate, carbonate, and phosphate) do not displace the two inner-sphere water molecules of this complex. In contrast, the possible presence of LMCT states causes the europium complex to be weakly luminescent. The [(L¹)Gd(H₂O)₂]^- complex is characterized by high relaxivity (r298 K1 = 7.2 s^-1 mM^-1 at 20 MHz) and a very short water residence time of the coordinated water molecules (τ298 KM = 9 ns), promising values for the realisation of macromolecular systems with high relaxivities. Thus, the Tb and Gd complexes of the H₄L¹ macrocycle exhibit several improvements in terms of luminescent (lower excitation energy, higher brightness) and relaxometric (shorter τ_M) properties compared to the corresponding LnPCTA complexes, where a phenol moiety substitutes a pyridine ring. On the other hand, the 24-membered H₈L² macrocycle including two phenol units in its structure leads to dinuclear complexes of [(L²)Ln₂]^2- composition. Its terbium complex shows a long luminescence lifetime (2 ms) and a high quantum yield (43%) in aqueous solutions, making this compound a new promising candidate for time-resolved applications.

Full text of DOI:10.1039/c7dt00291b

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January 2016 Pages 1–398
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New polyaminocarboxylate macrocycles containing phenolate binding units: synthesis,
luminescent and relaxometric properties of their lanthanide complexes†
a,b
a,b
a,b
c,d
Morgane Enel, Nadine Leygue, Stéphane Balayssac, Sophie Laurent, Chantal
a,b
c,d
a,b
Galaup,* Luce Vander Elst* and Claude Picard*
a
CNRS; Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique,
SPCMIB, UMR-5068; 118 Route de Narbonne, F-31062 Toulouse cedex 9, France.
E-mail: picard@chimie.ups-tlse.fr (CP), galaup@chimie.ups-tlse.fr (CG)
b
Université de Toulouse; UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules
d’Intérêt Biologique, SPCMIB; 118 route de Narbonne, F-31062 Toulouse cedex 9, France.
c
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical
Chemistry, University of Mons, 23 Place du Parc, B-7000 Mons, Belgium.
E-mail: luce.vanderelst@umons.ac.be
d
Center for Microscopy and Molecular Imaging (CMMI), Rue Adrienne Bolland, 8, B-6041
Gosselies, Belgium
†
1
Electronic supplementary information (ESI) available: DOSY experiments, H NMR and MS
1
2
4 8
spectra of compounds 3, 4, H L and H L . HILIC-UPLC chromatograms and HMRS spectra
1
1
2
of TbL , GdL and Tb L complexes. Spectroscopic characterization of Tb and Eu complexes.
2
1
Influence of concentrations on the relaxation rate of GdL complex.
1

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Abstract
The synthesis of two new polyaminocarboxylate macrocycles incorporating one or two
1
2
1
intracyclic phenol units (H
4 8 4
L and H L , respectively) is described. The 12-membered H L
III
1
-
macrocycle leads to soluble and stable mononuclear Ln complexes of [(L )Ln(H
2 2
O) ]
composition (Ln = Eu, Tb and Gd) in aqueous solutions. In Tris Buffer (pH 7.4),
1
-
[
(L )Tb(H
2
O)
2
] complex displays a suitable efficiency for the sensitized emission (ηsens
=
48%) and a high luminescence quantum yield (Φ = 22%) which is worthy of note for a bis-
hydrated terbium complex. Besides, luminescence experiments show that bidentate
endogenous anions (citrate, carbonate, and phosphate) do not displace the two inner-sphere
water molecules of this complex. In contrast, the possible presence of LMCT states causes the
1
-
europium complex to be weakly luminescent. [(L )Gd(H O) ] complex is characterized by a
2
2
298K
-1
-1
high relaxivity (r
1
= 7.2 s mM at 20 MHz) and a very short water residence time of the
2
98K
coordinated water molecules (τM
= 9 ns), a promising value for the conception of
1
4
macromolecular systems with high relaxivities. Thus, Tb and Gd complexes of the H L
macrocycle exhibit several improvements in terms of luminescent (lower excitation energy,
higher brightness) and relaxometric (shorter τ ) properties compared to the corresponding
M
LnPCTA complexes, where a phenol moiety substitutes pyridine ring. On the other hand, the
2
24-membered H
8
L macrocycle including two phenol units in its structure leads to dinuclear
2
2-
complexes of [(L )Ln ] composition. Its terbium complex shows a long luminescence
2
lifetime (2 ms) and a high quantum yield (43%) in aqueous solutions, rendering this
compound a new promising candidate for time-resolved applications.
2

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Introduction
To date various macrocyclic azaligands containing one or more phenolic groups have been
designed to coordinate metal ions into their macrocyclic cavity. This is due to the higher
thermodynamic and kinetic stabilities of macrocyclic chelates vs. acyclic chelates and the key
role played by the phenolic moiety. This aromatic unit has several characteristics such as: (i)
remarkable coordinating properties towards a large variety of ions, (ii) charge as a function of
pH (0 at low pH and -1 at high pH values), (iii) interesting photoactive properties for the
access of optical sensors, (iv) capability for binding two metal centres in a bridge position,
allowing stabilization of dinuclear species, (v) a benzene ring allowing a great synthetic
flexibility. Macrocyclic ligands containing phenolic unit(s) have been largely used in
1
transition-metal complexes but have received less attention as lanthanide chelators. Moreover,
III
the physicochemical properties of Ln complexes formed by this type of ligands are
2
essentially reported in the solid state or in organic solutions. For example, Nakai et al.
III
demonstrated recently that terbium complexes derived from tacn (1,4,7-triazacyclononane)
and cyclen (1,4,7,10-tetraazacyclododecane) platforms bearing three and four phenol pendant
arms, respectively, are highly oxygen sensitive luminescent probes, but operating only in THF
2a,b
solutions. The literature regarding the incorporation of phenolic function into macrocyclic
III
ligands able to complex Ln ions in aqueous solutions is very limited. Sherry used a
gadolinium complex based on a DO3A core (DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-
3
triacetic acid) with a p-nitrophenolic pendant arm as a pH-responsive MRI contrast agent.
The luminescence properties of a dinuclear europium complex derived from two DO3A units
4
separated by a p-nitrophenolic group were highlighted very recently by Faulkner. We can
also note that Bünzli and co-workers briefly reported the photophysical and relaxometric
5
properties of mono-aqua lanthanide iminophenolate cryptates.
III
In the course of our research on the design of Ln complexes acting as luminophores and
6
paramagnetic contrastophores by simple permutation of the lanthanide ion, we were
interested in the development of a new macrocyclic chelator derived from the DOTA
backbone (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) where a
1
phenolic unit is substituted for a dimethylene aminoacetate moiety (ligand H L , Fig. 1). In
4
this structure, the diethylenetriaminetriacetic acid core is an efficient chelating system for
III
III
Ln ions in aqueous solutions. Since Ln ions exist as a hydrated aqua ion with ~8-9 inner-
sphere water molecules below pH ~ 6 in aqueous solutions, the heptadenticity of this ligand
3

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III
allows the coordination of one or two water molecules in the inner-sphere of Ln complexes.
On the one hand, this structural parameter fulfils the requirement of Gd-based relaxation
1
agents, where the metal centre catalytically shortens the longitudinal (T ) relaxation times of
III
nearby water protons. In these systems, it is well known that di-aqua Gd complexes possess
an intrinsically higher relaxivity than those complexes of similar size with a hydration state of
7
1
. On the other hand, the presence of a metal hydration state in luminescent lanthanide
complexes implies non radiative deactivation pathways associated with energy transfer
III
8
between Ln excited states and OH oscillators. Nevertheless, in some cases di- or tri-aqua
9
terbium complexes can display interesting photophysical properties. Moreover, the phenolic
unit is able to promote the so-called "antenna effect" where light absorbed by the organic
ligand is transferred via singlet and triplet states to the excited resonant levels of the
10
lanthanide ions. Prior to this work, Natrajan et al. reported the structure and spectroscopy
III
11
behaviour of Tb complex with a closely related acyclic ligand, H
In aqueous solutions, this complex exists as unusual discrete dimeric pairs (M
Tb, L = 5-Me-HXTA) and no water molecule are coordinated to the two metal ions. It
5
(5-Me-HXTA) (Fig. 1).
2 2
L
species; M
=
displays a luminescence quantum yield of around 50% which is among the highest reported in
III
aqueous solutions for Tb complexes.
1
In this contribution, we report the synthesis of the 12-membered macrocycle H
4
L and its
2
corresponding dimeric 24-membered macrocycle H
8
L . A detailed photophysical study in
1
2
III
III
aqueous solutions of the mononuclear LnL and dinuclear Ln
2
L complexes (Ln = Eu , Tb )
was undertaken to help us better understand the role played by the various factors that
1
determine their luminescence properties. Since we showed that the LnL complexes are able
to coordinate two water molecules, we have also investigated the relaxation properties of the
1
1
17
GdL complex in aqueous solution by H relaxometry and O NMR. Attention was also paid
1
to the kinetic stability of bis-hydrated LnL complexes towards bidentate anions interactions
2
+
III
and transmetallation process with Zn ions. Finally, comparison to the parent Ln PCTA
12
III
complexes containing a pyridinic intracyclic unit and Gd DOTA allowed us to evaluate the
influence of a phenol moiety on the luminescent and relaxometric properties of 12-membered
III
macrocyclic Ln complexes.
Results and discussion
Synthesis
4

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1
Our synthetic strategy for the preparation of H
4
L was based on the use of unprotected phenol
derivative and a linear triamine bearing tert-butyl acetate pendant groups (Scheme 1). This
triamine 1 may be prepared in three steps from commercially available diethylenetriamine
13
following our previously reported procedure (overall yield: 74%). Using these synthons
avoids harsh conditions generally required for deprotection of phenolic ethers and the need of
14
a N-carboxyalkylation step on polyamine macrocycles. As reported in the literature, the use
of a 2-fold aminomethylation reaction implying iminodiacetate derivatives/paraformaldehyde
with substituted phenols is the route of choice to have access to corresponding acyclic
1
1,15
ligands.
In this context, we initially attempted the synthesis of macrocycle 3 via mannich
reaction between p-cresol and triamine 1. However this synthetic route proved unsuccessful
and only the formation of acyclic intermediate products was observed from numerous
attempts. Our efforts were then turned towards a classical direct alkylation of bis(halomethyl)
phenol on triamine 1. Condensation of 2,6-bis(bromomethyl)-4-methyl-phenol with triamine 1
was carried out in acetonitrile at reflux and in the presence of sodium carbonate as a base and
-3
1
without using high-dilution technique (reactants concentration 2 × 10 M). H NMR DOSY
analysis of the crude mixture showed the presence of only two species which display
2
-1
translational diffusion coefficients (D) relative to CDCl
3
of 710 and 560 ꢀm s (Fig. 2). The
positive electrospray mass spectrum established the formation of both the 12-membered
1
+
4
monomer structure 3 ([H L +H] at m/z = 578.4, 100%) and the corresponding 24-membered
2
+
8
dimer structure 4 ([H L +H] at m/z = 1155.7, 100%). After purification by column
chromatography on alumina, macrocycles 3 and 4 were isolated in 31 and 55% yields,
respectively. Although no polymeric species was detected in this macrocyclization process,
the 1:1 cyclization reaction is not promoted with respect to the 2:2 process by a sodium
"
template″ effect. Besides, changing the nature of the alkaline carbonate has noticeable effects
on the monomer-dimer distribution in this macrocyclization reaction. Under similar reaction
conditions, the ratio of monomer/dimer selectivity (R) is increased by a factor of 4.8 by
replacing sodium carbonate (R = 0.56) by lithium carbonate (R = 2.7). Other alkaline
2 3 2 3
carbonate (K CO and Cs CO ) favour the production of the dimeric species but is
accompanied by a higher formation of by-products. The more favourable formation of the
monomer [1 + 1] macrocycle in the presence of the lithium cation may be attributed to a
better fit of this ion with the macrocyclic cavity. It is worth noting that these 12-membered
1
and 24-membered macrocycles 3 and 4 can be readily distinguished by H NMR spectroscopy
†
1
(
Fig. 2 and ESI Fig S1 and S2 ). Their H NMR spectra display significant difference,
5

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reflecting some rigidity of the monomeric species and a more fluxional system for dimeric
species. Compound 3 displays AX and AB spin patterns for pseudo benzylic protons (J =12.9
Hz) and methylenic protons of the two lateral ester arms (J =16.8 Hz), respectively, a singlet
for the central arm and three signals for the remaining macrocyclic protons in the 2.03 – 2.92
1
ppm range. The H NMR spectrum of 4 shows only four sets of signals for the methylenic
protons. Subsequent acid hydrolysis (HCl, rt) of the tert-butyl ester functionalities afforded
1
2
†
4 8
the ligands H L and H L as hydrochloride salts in good yields (See ESI, Fig. S3 and S4 ).
III
1
2
The stoichiometry of the Tb complexes formed with H
4
L and H
8
L were determined by a
III
III
mol ratio method. By monitoring the Tb luminescence as the function of Tb added to an
aqueous solution of ligands (Tris buffer, pH 7.4), binding curves were obtained (Fig. 3). The
total integrated intensity of the emission increased upon Tb addition up to one equivalent
1
2
(
H L ) and two equivalents (H L ), after which a plateau in the emission intensity was
4
8
reached. These data are consistent with the formation of a single complex species with a 1:1
1
2
-
ligand-to-lanthanide stoichiometry for ligand H
4 8
L and a 1:2 stoichiometry for H L . The ESI
1
2
3+
-
MS spectra obtained with aqueous solutions containing H L or H L and Tb in a ratio 1:1
4
8
or 1:2, respectively, are in agreement with the results of luminescence titrations. These spectra
are characterized by the presence of base peaks corresponding to one or two negatively
1
-
2 2-
2
charged species ([TbL ] or [Tb L ] , supporting the formation of mono- or di-nuclear
III
complexes. Consequently, the Ln (Ln = Eu, Tb, Gd) chelates derived from these ligands
were prepared at room temperature in aqueous solutions with an appropriate slight molar
3 2
excess (ca. 10%) of the lanthanide salts (LnCl .6H O) to avoid the presence of free ligands.
After purification (Waters sep-pack® cartridge C18), no peaks ascribable to the free ligand
were found in the ESI mass spectra and HILIC-UPLC analyses of the complexes (See ESI,
†
III
III
III
Fig. S5-S7 ). Yields were quantitative. Interestingly, the Eu , Gd and Tb complexes
1
2
showed identical UPLC retention times within their respective series (L and L ), suggesting
III
that Ln ions share the same coordination sphere for each complexes series.
1
2
2
Photophysical properties of TbL and Tb L complexes
III
The main electronic and photophysical properties of the two Tb complexes are given in
III
Table 1, together with analogous data of other relevant Tb complexes for comparison. Their
UV-Vis spectra are similar, displaying two absorption bands at 242 and 296 nm in air
equilibrated Tris buffer (50 mM, pH 7.4). When compared to TbPCTA, the sensitizer
6

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phenolate induces a shift of the lowest-energy absorption band towards lower energy (red
shift of 27 nm).
1
2
2
At room temperature, the emission spectra of TbL and Tb L show typical narrow-band
lanthanide luminescence in the visible region after excitation into the lowest-energy
absorption band of the two ligands (λexc = 296 nm) (Fig. 3). These emission bands at 490, 545,
5
7
5
86 and 622 nm, with weaker signals in the 640-700 nm were assigned to the D → F (J = 0-
4
J
III
16
5
7
6
) transitions of Tb ion. In both cases, the sensitive D → F transition at 545 nm is the
4
5
most prominent and accounts for ~ 55% of the total integrated emission intensity. As expected,
the absorption and excitation spectra overlap well, which confirms the sensitized character of
†
the observed emissions (See ESI, Fig. S8 ).
3
+
More insight in the nature of the coordination sphere of the Tb centre may be obtained from
the emission lifetimes. For the two complexes, luminescence decays are monoexponential
functions, suggesting the presence of a single emissive solution species in each complex and
2
the presence of two metal sites with very similar environment in Tb
2
L . At room temperature,
5
1
the emission lifetime of the D level are 1.16 and 2.02 ms with TbL having the shortest
4
value. From the lifetime data in the deuterated and non-deuterated water, calculation of the
number of metal-bound water molecules (q) was possible, owing to the well-established
17
18
isotope effect and by using the empirical relationship developed by Beeby et al. This
analysis indicated that two water molecules are present in the first coordination sphere of the
1
2
2
metal in TbL , whereas no water molecules are present in the case of Tb L (Table 1). If the
determination of the hydration sphere of the metal assesses the extent of the radiationless
deactivation of Tb(III) excited states by OH oscillators, this value is also suggestive of the
3
+
number of remaining atoms in the first coordination sphere as Tb prefers a coordination
19
1
4
number of 8-9 in aqueous solutions. Assuming that the ligand H L is heptadentate, these
1
results are fitting in well with a nine-coordinated TbL complex. The absence of coordinated
2
2
water molecules in Tb
2
L leads us to suppose that the two metal ions are bridged by each ꢀ -
PhO phenolate moiety, leading to an overall coordination number of 8 for each terbium ion
(Fig. 4). Such behaviour has been observed in the solid state and in solution for the 2:2
11
dimeric complex [Tb(5-Me-HXTA)]
2
.
On the other hand, no concentration effects were
1
-
observed for TbL . The measurement of the luminescence lifetime over a concentration of 10
6
-3
to 10 M led to monoexponential fitting of the decay curves and to τ values constant within
error (1.16 ms), in agreement with the presence of a single emissive species with two inner-
sphere water molecules and the preservation of a mono-nuclear structure. From the data
7

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2
reported in Table 1, we can notice that lifetimes in D O solutions at 298 and 77 K are similar
for both complexes. This result shows that temperature-dependant non-radiative decay
processes, such as a back-energy transfer from the metal-centred level to the ligand-centred
triplet level which is observed particularly for Tb complexes, do not occur.
As well established, the energy levels of the ligand excited states play a leading role in the
20
intramolecular energy transfer process (L* → Ln*). Hence, we investigated as usual the
III
behaviour of these ligand-centred (LC) levels in the corresponding Gd complexes (Fig. 5).
1
In Tris buffer and at room temperature, the emission spectrum of GdL is dominated by a
broad emission band with a peak maximum at 338 nm after excitation at 296 nm. The
-1
relatively small Stokes shift (ca. 4200 cm ) and the fact that the intensity of the observed
emission band vanishes when a short delay (10 ꢀs) is enforced led us to assign this band to
1
ππ*transitions. A similar fluorescence emission band (λem = 345 nm, λexc = 290 nm) was
2
1
reported for the anionic phenol in aqueous solution. At low temperature (77 K) in a 4:1 Tris
buffer-glycerol glass, a second emission band is observed with a maximum around 405 nm
and a single-exponential time decay with a lifetime of 1.48 ms. On the bases of its energy
3
level and long-living excited states, this emission is attributed to ππ*transitions. From these
1
experiments, the energy of the 0-0 transition of the first excited singlet state of GdL was
-1
estimated to be 32500 cm (intercept of the absorption and fluorescence spectra) and the
-1
value of the 0-0 energy for the ligand triplet state was estimated to be 26000 cm (shoulder at
1
3
85 nm in the phosphorescence spectrum). The calculated energy for T
1
in GdL is consistent
-1
with previous reports of the phenol T
1
energy level by Latva et al. (26600 cm ) in 5-Me-
-1
MeMe
2a,22
HXTA and Nakai et al. (26460 cm ) in [Gd(
ArO)
3
tacn].
1
Similar energies for S and
-1
2
T
1
excited states (32700 and 26500 cm , respectively) were observed for Gd
2
L . For the two
1
3
3
5
investigated complexes, the energy gaps ꢁE ( ππ* − ππ*) and ꢁE ( ππ* − D
4
) amount to
-1
6
200/6500 and 5500/6000 cm , respectively. These data are in accordance with the empirical
1
3
-1
rules for effective intersystem crossing, ISC, (ꢁE ( ππ* − ππ*) < 7000 cm ) and irreversible
III 5
3
5
energy transfer between the antenna triplet state and the Tb
D
4
state (ꢁE ( ππ* − D ) >
4
-
1 23,24
2
000 cm ).
1
2
Overall quantum yields (
Φ
ov) of TbL and Tb
2
L , defined as the ratio between the number of
III
photons emitted by the Ln ion and the number of photons absorbed by the ligand, were
determined experimentally by excitation of the ligand (λexc = 296 nm) in aerated Tris buffer
(pH 7.4) and at room temperature. Despite the presence of two coordinated water molecules
1
the luminescence quantum yield of TbL remains very interesting in H
2
O solution with a 22%
8

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value and is significantly larger than that of bis-hydrated complex TbPCTA (8.3%). Besides,
2
Tb
2
L displays a quantum yield (43%) higher or close to the ones reported for terbium-based
TM 25
commercial luminescent probes (32% for Tb(DTPA-Cs124) and 50% for Tb(Lumi4 )). It
is also interesting to note that this quantum yield is close to that reported for the
2 2
corresponding dinuclear complex [Tb(5-Me-HXTA)] . In D O solution the quantum yields of
1
2
TbL and Tb L are similar and consistent with the dependence of the luminescence quantum
2
III
yields of Tb complexes as a function of the lowest triplet state energy of the ligand,
2
4
proposed by Latva et al. To our knowledge, this is only the second report of luminescence
III
properties in aqueous solutions of a dinuclear Tb complex derived from a macrocyclic
2
6
1
2
ligand. In a second step, the
Φ
ov values for TbL and Tb
2
L complexes have been analyzed
8
in terms of eqn (1) which takes into account the multistep pathway of an antenna effect.
Φ
ov
=
η
sens
×
Φ
Tb
eqn (1)
In this equation,
ηsens corresponds to the sensitization efficiency which is mainly reflecting
ISC and energy transfer from the ligand-centred triplet state to the lanthanide (ηsens = ΦISC
ET) and Tb the intrinsic quantum yield, i.e. the quantum yield by direct excitation of the
lanthanide ion. Assuming that the decay process at 77 K in a deuterated solvent is purely
×
η
Φ
10, 27
radiative,
Φ
Tb can be estimated through eqn (2).
298K
77K
Φ
Tb = τobs
(H
2
O) / τobs
(D
2
O)
eqn (2)
As can be seen in table 1, the sensitization efficiency, that is independent of the presence of
inner-sphere water molecule, is comparable for the two complexes (~ 50%), indicating a
1
2
rather efficient sensitization process. TbL and Tb L have close-lying energies of both the
2
ligand singlet and triplet states, this suggests equivalent ΦISC and that the energy transfer
3
efficiency ηET does not depend on the ππ* → Ln* energy gap. As the efficiency of Förster
6
energy transfer from the antenna to the lanthanide follows an r dependence, it is likely that
similar chromophore – metal distance occurs in these two different structures. On the other
hand, the ligand-to-metal energy transfer process is sensitive to the replacement of a pyridine
1
moiety with phenol moiety, increasing ηsens by a factor of 2.4 from TbPCTA to TbL . Since
Φ
Tb is similar for these two complexes, the difference in their
Φov values is due to the
difference in sensitization efficiency.
III
The emission properties of these Tb complexes in aerated solutions at room temperature
remained unchanged for several days in Tris buffer (pH 7.4), which highlights their stabilities
2
1
in aqueous media. On the other hand, Tb
2
L is more resistant than TbL to transchelation in
III
the presence of DTPA, a competing ligand which binds strongly to Tb (K(TbDTPA) = 5.1
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2
2 28
1
0 ). In the presence of one equivalent of DTPA and based on luminescence experiments,
2
1
8.5% of Tb
2
L and 77% of TbL were dissociated after 24h in Tris buffer (pH 7.4). The
1
weaker kinetic inertness of TbL could be related to the presence of two water molecules in its
first coordination sphere. Nevertheless, in the same experimental conditions, the bis-hydrated
TbPCTA complex was only 6% dissociated. Further potentiometric studies would have to be
performed in order to gain a quantitative understanding of the stability of these complexes.
The partial or complete displacement of the inner-sphere water molecules by bidentate
endogenous anions (phosphate, carbonate, L-lactate) has often been observed for bis-hydrated
29
1
lanthanide complexes. In this direction, we investigated this behaviour for the TbL complex
by luminescence spectroscopy. If one or both water molecules are indeed replaced by these
1
oxoanions, the luminescence intensity and lifetime will increase. TbL complex (50 ꢀM) was
challenged in Tris buffer by a great excess of these anions in relation to their physiological
concentrations in human plasma (phosphate, 1.1 mM; carbonate, 26 mM and L-lactate, 2.3
3
0
mM). Addition of phosphate caused no changes in the observed emission intensity, while
addition of citrate or carbonate caused a small variation (~ 10%) in intensity. In all three cases,
the slight increase of emission lifetimes (1.17 < τ < 1.25 ms) is consistent with the retention of
1
the two coordinated water molecules and therefore the absence of interaction between TbL
and these dianions, in a mono- or bidentate manner. In the same experimental conditions, a
†
similar behaviour was observed with TbPCTA (See ESI, Fig. S9 ). In these two complexes,
the relative position of the two first-shell water molecules is certainly not adapted for
bidentate interactions. In DO3A-type complexes, the water molecules are adjacent in the
coordination polyhedron allowing a bidentate binding of these anions. We have also studied
-
1
the displacement of inner-sphere water molecules by small-hard charged F anions in TbL
and TbPCTA complexes. This effect has been successfully exploited in sensitized
III
31
luminescent Ln systems, reducing the H O quenching. In the presence of a saturating
2
-
anion concentration (0.1 M, F ), the luminescence lifetime is increased by a factor of 1.08
1
(
TbL ) and 1.57 (TbPCTA). The displacement of water from the coordination sphere of the
1
metal is thus more marked for TbPCTA. The presence of an overall negative charge of TbL ,
III
-
limiting electrostatic interactions between Tb and F ions, could explain this result.
1
2
2
Photophysical properties of EuL and Eu L complexes
1
2
2
At room temperature, excitation into the ligand levels of EuL and Eu L complexes results in
III
characteristic emission of Eu ion in the visible region (500 – 800 nm) with the strongest
10

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5
7
†
emission based on the D
0
→ F
2
transition occurring at 616 nm (See ESI, Fig. S10 ). The
-1
triplet energies of the two investigated ligands (26000/26500 cm ) are suitable to give rise to
III
-1
5
energy transfer to the accepting levels of the Eu ions (17500 cm ≤ E D (J = 0-3) ≤ 24500
J
-1
III
cm ), but only weak lanthanide-based luminescence was observed from these Eu complexes
1
2
1
2
in contrast to the results for TbL and Tb L . EuL and Eu L complexes are characterized by
2
2
very low quantum yields, 0.03% and 0.55% respectively, in comparison with that of EuPCTA
4.3%). These very weak metal-based emissions may be rationalized by the presence of
(
nonradiative LMCT (ligand-to-metal charge-transfer) states, as might be expected with the
III
low reduction potential of the Eu ion and an electron donating phenolate antenna
1
1,32,33
group.
These LMCT transitions are tentatively assigned in the UV-vis absorption
3
-1
spectra as a tail of the lowest-energy absorption band (at 360 nm, ε = 80 and 260 dm mol
-1
1
2
†
11
cm for EuL and Eu L , respectively (See ESI, Fig. S11 )). At room temperature, the
2
1
luminescence lifetime of EuL is 0.31 ms, similar to EuPCTA (τ = 0.37 ms) and typical of
III
2
bishydrated Eu complexes. Besides, the τ value of Eu
2
L is 0.55 ms and lies in the lower
III
range of those usually observed for Eu complexes with no inner-sphere water molecules. A
similar lifetime value was reported recently for an europium complex derived from a
34
1
2
2
nonadentate picolinate ligand. Finally, luminescence lifetimes of EuL and Eu L measured
in deuterated aqueous solutions (τ = 0.87 and 0.70 ms, respectively) confirm the hydration
D
III
number observed for the corresponding Tb complexes.
1
Relaxometric studies of GdL complex.
1
The relaxometric properties of GdL were first assessed by measuring its overall relaxivity r
1
which represents the increase in the longitudinal nuclear magnetic relaxation rate of water
protons promoted by the paramagnetic complex. For comparison purpose, this parameter is
III
commonly measured for a millimolar solution of the Gd complex in water at pH 7, at 20
1
-1
-1
MHz and 298 or 310 K. In these conditions, the relaxivity of GdL is 7.2 and 5.7 s mM at
III
298 and 310 K, respectively. These values are clearly higher than those of mono-aqua Gd
310
-1
-1
35
complexes, currently clinically used MRI CAs (r1 = 3.5 - 3.8 s mM at 20 MHz). On the
III
other hand, they are in the range of those reported for other di-aqua Gd complexes of small
-1
-1
36
size with relaxivities ranging from 5.7 to 10.2 s mM at 20 MHz and 298 K. Besides, we
-1
-1
can note that the value of 5.7 s mM is slightly higher than that of the parent GdPCTA
310
-1
-1 37
complex where a pyridine ring is substituted for a phenol moiety (r
1
= 5.4 s mM ). The
11

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1
presence of two water molecules in the first coordination sphere of the GdL complex was
1
confirmed by the measurement of the O-17 chemical shift of GdL as compared to that of Gd-
DOTA for which q=1. A value of 1.75 was obtained in good agreement with the value
obtained by photophysical measurements of the corresponding Tb and Eu complexes.
In addition to the hydration state, the residence time (τM) or the corresponding exchange rate
(kex =1/τM) of water molecules in the inner-coordination sphere of a gadolinium ion and the
III
38
tumbling motion of the complex (τR) contribute to the overall relaxivity of a Gd chelate.
There are several well established physico-chemical methods to determine these two
39
parameters. The quantitative evaluation of
M
τ can be carried out through the analysis of the
17
17
R
temperature dependence of the reduced transverse O relaxation rate of water ( O−1/T
2
) at
1
1
high field. The analysis of the H nuclear magnetic relaxation dispersion ( H NMRD), that is
given by the proton relaxivity measurements at different magnetic fields, can provide access
to rotational correlation time (
τ
R
).
profile as a function of the temperature of a 14.5 mM GdL solution was
recorded at 11.7 T and pH 7. The result is plotted in Figure 6 with the corresponding
17
R
1
The O−1/T
2
17
calculated curves for GdPCTA and GdDOTA at 7.05 T. The reduced O transverse relaxation
1
rates of GdL show a continuous increase with decreasing temperature, indicating a maximum
at temperature lower than 280 K and characteristic of a complex in the fast exchange regime.
By comparison, the data obtained for GdPCTA show that its exchange rate in the investigated
temperature range is in the fast to intermediate regime with a maximum around 290 K. These
profiles markedly differ from that of GdDOTA which exhibits a classical bell shaped curve
with a maximum around 308 K. A qualitative analysis of these data indicates that water
1
exchange rate increases in the order GdDOTA < GdPCTA < GdL . Athough the number of
data points is small, a theoretical treatment of the experimental data was attempted as
40
previously described. In the fit, the following parameters have been adjusted: the enthalpy
≠
≠
and entropy of activation of the water-exchange process (ꢁH and ꢁS ), and the parameters
2
describing electron spin relaxation (B = 2.4
ꢁ
and
V
τ ). The number of inner-sphere water
molecule was fixed to q = 2, while the scalar coupling constant (A/h) and the activation
6
-1
-1
energy related to
τ
v v
(E ) were set to - 3.0 × 10 rad s and 1 KJ mol , respectively. The
parameters resulting from the best fit are presented in Table 2. The large activation enthalpy
≠
≠
1
(
ꢁH ) and the positive activation entropy (ꢁS ) indicate that GdL likely undergoes a
dissociatively activated water exchange involving an eight-coordinate complex in the
41
transition state. This was also supported by the nine-coordinate ground state structure of this
12

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298
complex. The water residence time was calculated at 298 and 310K, providing
τ
M
= 9.0 ±
310
0.6 ns and
τ
M
M
= 3.1 ± 0.2 ns values. The τ value of 9.0 ns is around 8 and 18 times shorter
than those reported at 298 K for electrically neutral complexes GdPCTA (70 ns) and
4
2
GdDO3A (160 ns). These data show again that the introduction of an aromatic unit which
rigidifies a ligand framework does not have a detrimental effect on the flexibility of the inner-
sphere to limit water exchange and that complexes with negative overall charge have faster
1
water exchange than neutral complexes. The faster water-exchange rate of GdL relative to
GdPCTA is also possibly due to the steric constraints at the site of water-coordination caused
by the six-membered chelate ring formed after coordination of the phenolate to the metal ion
1
in GdL relative to the corresponding five-membered chelate ring in GdPCTA. The impact of
M
expanding the chelate ring size in this way on τ is well documented. For example, a
structural analogue of GdDOTA bearing an extra methylene carbon on the macrocyclic
43
backbone (GdTRITA) displays a 66-fold shorter residence time compared to GdDOTA. A
shortening of was also observed by replacing a pyridyl donor by a pyridine N-oxide or a
phenolate donor in one pendant arm of DO3A derivatives. Interestingly, this
ns is also shorter than the values measured for other di-aqua complexes that lie in the range
τ
M
44
M
τ value of 9
3
6
from 19 (Gd(TAM-TRI)) to 303 ns (Gd(PTDITA)). The occurrence that τ
the relaxation rate is also inferred from the qualitative analysis of the temperature dependence
of r at pH 7 and 20 MHz (Fig. 7). The complex exhibits an exponential increase in r when
M
does not limit
1
1
the temperature is lowered from 318 to 278 K. This behaviour is quite typical for Gd chelates
whose relaxivity is not limited by the coordinated water residence time but is largely
dominated by rotational dynamics.
1
1
The H NMRD profile of GdL was determined at 310 K in the proton Larmor frequency
range 15 kHz and 60 MHZ and was reported in Figure 8. This profile displays the typical s-
III
shape of small size Gd chelates. It is characterized by two regions of constant r
1
with higher
and lower relaxivity at low and high magnetic fields, respectively, and a single dispersion
1
between 3 and 60 MHz. The possibility of self-aggregation was excluded by recording the H
NMRD profile for two different concentrations (0.90 and 1.81 mM), revealing an identical
†
1
1
profile (See ESI, Fig. S13 ). As we can see in Figure 8, the H NMRD profiles of GdL and its
parent complex GdPCTA are quite similar, with only relaxivities at low field slightly higher
for GdPCTA. This demonstrates again that a variation of the
τ
M
value has no effect on the
relaxivity observed at 310 K for small-sized complexes if τ
M
is smaller than 500 ns. The
1
NMRD profile of GdL was analyzed by a fitting procedure according to the established
13

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theory for paramagnetic relaxation using the contributions from the inner-sphere and outer-
sphere water molecules to the proton relaxivity (Solomon-Bloembergen-Morgan and Freed
45
theories, respectively). In this analysis, we have not taken into account the contribution of
water molecules in the second coordination sphere, that is when these molecules are bound to
the ligand. For the majority of polyaminocarboxylate complexes, the water molecules are not
hydrogen bonded to the carboxylate oxygen atoms, in contrast with ligands bearing
46
phosphorous acid functions. In the fitting procedure, some parameters were fixed in
agreement with previous studies: the metal-water proton distances in the first coordination
sphere (r) and in the outer sphere (d) were fixed at 0.31 and 0.36 nm, respectively; the relative
2
-1
17
diffusion constant (D) was set at 3300 ꢀm s ;
M
τ was fixed at the value determined by O
4
7
1
relaxometry. A good fit for the H NMRD profile has been obtained with these fixed
parameters (Fig. 8) and the most relevant parameters obtained are given in Table 3, together
III
with analogous data of other relevant Gd complexes for comparison. The fitted value of
τ
R
(53 ps) is close to the values of structurally similar complexes reported in table 3, confirming
that the complex does not self-assemble in the investigated concentration range.
1
An informative comparison is GdL versus the commercially available mono-aqua GdDOTA
with regard to the factors influencing the relaxometric properties. These two complexes share
structural parameters, such as a 12-membered macrocyclic backbone and several bidentate
aminoacetate chelating moieties and an overall negative charge. Besides, they differ from one
1
another in the ligand denticity (heptadentate for H
4
L versus octadentate for H
4
DOTA) and
1
the presence of an aromatic unit concerning GdL . At 310 K and 20 or 60 MHz, the relaxivity
1
1
of GdL is 1.6 times higher than that of GdDOTA. The H NMR profiles of the two
complexes (Fig. 8) display the typical s-shape of low-molecular weight and rapidly tumbling
1
chelates. Compared to GdDOTA, the profile of GdL shows increased r
1
values over the
entire investigated magnetic range. The difference in relaxivity is attenuated in the low
magnetic field region, as a consequence of the higher value of the electronic relaxation time at
zero field (τ ) for GdDOTA. This may be related to a higher symmetry of this complex with
SO
1
respect to GdL . As the two complexes have identical τ values (53 ps at 310 K) in agreement
R
-1
1
4
with the similar molecular weight of the ligands (MW = 409.4 and 404.4 g mol for H L and
H DOTA, respectively), one concludes that the difference in the relaxivity is due to the
4
hydration number differing by one unit. Besides, we notice a significant acceleration of the
1
1
-
2 2
water exchange on the GdL complex; at 298 K the [GdL (H O) ] species exchanges 27
-
times faster than [GdDOTA(H O)] (39 times faster at 310 K). It is generally accepted that a
2
14

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decrease of the residence time of the coordinated water molecule can be caused by several
main factors: (i) a change in the mechanism of water exchange from a dissociatively activated
process to an associatively activated process, (ii) a change in the overall charge of the
complexes with more negative charge leading to faster exchange, (iii) an increased hindrance
4
8
of the water coordination site. The calculated values of the activation enthalpy and entropy
1
35a
≠
-1
≠
-1
-1
of GdL and GdDOTA (ꢁH = 65.5 and 50.1 kJ mol , ꢁS = 129 and 48.7 J mol K ,
respectively) point to a dissociative activation mode of the water exchange mechanism in both
complexes. The two complexes also display each a single negative overall charge and a
III
similar charge density near the Gd ion. The introduction of a rigid aromatic unit and two six-
membered chelate rings producing steric strains at the water binding sites may be identified as
the two factors contributing to the acceleration of the water exchange. As a matter of fact, the
leaving of the coordinated water molecule, which is the rate-determining step for a
dissociatively activated water exchange, is largely facilitated by an increased steric crowding
48
around the water molecule.
1
III
Finally, GdL satisfies the accepted empirical assay for kinetic stability (inertness) of Gd
4
9,50
chelates, developed by Muller and coll. and applied by other research groups.
In this fast
III
initial screening carried out close to physiological pH, Gd chelate was challenged in a
2+
phosphate-buffered solution with an equivalent concentration of Zn ions (the most abundant
endogenous metal ions with a concentration of ~ 32 ꢀM in human plasma) and the occurrence
of transmetallation was monitored by relaxometry. The procedure is based on the very low
III
-
solubility of free Gd ions in phosphate solution (formation of GdPO
4
species with Ksp = 10
2
2.2
p
1
)
and on the subsequent decrease of the relaxation rate R
of the solution. In Figure 9, the
p
1
p
1
p
p
evolution with time of the ratio of relaxation rates R
(t)/ R
(t
0
1 1 0
), where R (t) and R (t ) are
1
the relaxation rates at time t and zero, respectively, is shown for GdL (2.5 mM) in phosphate
2
+
buffer (67 mM, pH 7) in the absence or in the presence of Zn ions (2.5 mM). No significant
changes in relaxivity over a long period were observed for sample containing this Gd chelate
after addition of 27 equiv of phosphate. This excludes a dissociation process or the formation
of ternary complex with this anion, strengthening the results obtained by luminescence
1
experiments with TbL . We can note that significant (~ 25 to 75%) effects of phosphate on the
III
relaxivity of acyclic Gd complexes with two inner-sphere water molecules have been
5
1
2+
p
1
observed. In the presence of Zn , the relaxation rate R drops very slightly (7%) in the
beginning of the experiment and then remains constant at least over a seven-day period. It can
1
be concluded that the macrocyclic structure of GdL is more kinetically inert than the acyclic
35a,37, 50d
structure GdDTPA and is as inert as macrocyclic complexes GdDO3A and GdPCTA.
15

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Conclusions
This report describes new members of the class of polyaminocarboxylate macrocycles
III
III
targeted for Ln complexation in aqueous solutions and whose Ln complexes may act as
1
luminophores or paramagnetic contrastophores. The 12-membered (H L ) and 24-membered
4
2
1
(H
8
2 2
L ) macrocyclic ligands form hydrolytically stable mononuclear ([(L )Ln(H O) ]Na) and
2
dinuclear ([(L )Ln
2
)]Na
2
) complexes with the investigated lanthanide ions (Ln = Eu, Tb, Gd).
III
The Tb complexes display efficient phenol-sensitized emission in the visible region (ηsens
~50%) with long emission lifetimes at room temperature (in the ms range) and high quantum
1
-
2 2 2
yields (~ 50% in D O). The solution structure of [(L )Tb(H O) ] , coupled with the occurrence
of a residual negative charge, does not allow the replacement of the inner-sphere water
molecules with bidentate anions such as carbonate, citrate or phosphate, as commonly
observed for DO3A-based heptadentate complexes. At 20 MHz, the proton longitudinal
1
-
-1
-1
relaxivities, r
1
, of ([(L )Gd(H
2
O)
2
] ) complex are 7.2 and 5.7 s mM (20 MHz, 298 and 310
, is 53 ps (310 K). These r and τ
K, respectively) and the rotational correlation time, τ
R
1
R
values are comparable to those of Gd complexes with two water molecules in their first
coordination sphere and similar molecular weight. Besides, the very short residence time of
298K
M
the coordinated water molecules (τ
= 9 ns) is in the range of the optimal values required
for the attainment of very high relaxivity once the chelate would have been bound to a slowly
rotating macromolecular structure. Moreover this complex is as stable in respect to
2
+
transmetallation by Zn ions as those with other macrocyclic ligands like DOTA or PCTA.
The introduction of a phenolic ring instead of a pyridine ring in the 12-membered macrocyclic
polyaminocarboxylate skeleton gives rise to; i) an excitation at lower energy (ꢁλ ~ 30 nm)
and a twofold increase of the luminescence brightness at λmax due to a better sensitization
efficiency (Tb complex) and ii) a higher water exchange rate of one order of magnitude
between inner-sphere water molecules and bulk water due to the presence of a six-membered
chelate ring in the coordination polyhedron (Gd complex). Finally, judicious substitution of
III
the phenol unit should enable improved properties for luminescence and relaxometry of Ln
complexes derived from this new family of polyaminocarboxylate macrocycles.
Experimental
16

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General
1
13
H and C spectra were recorded using a Bruker Avance 300 spectrometer operating at 300
1
13
MHz for H and 75 MHz for C or on a Bruker Avance 500 spectrometer operating at 500
1
13
MHz for H and 125 MHz for C. Chemical shifts are reported in ppm, with residual
1
protonated solvents as the internal references. 2D DOSY H NMR spectrum was recorded
with a bipolar pulse pairs-stimulated echo pulse sequence with longitudinal eddy current
52
delay on the Bruker Avance 500 spectrometer equipped with a 5 mm cryoprobe at 298K
†
(
refer to ESI ). IR spectra were recorded on a Perkin-Elmer FT-IR 1725x spectrometer.
Electrospray (ES) mass spectra were obtained on a Q TRAP Applied Biosystems
spectrometer and High-Resolution Mass Spectra (HRMS) on a Xevo G2 QTof Waters
spectrometer. Elemental analyses were recorded on a Perkin Elmer 2400 series II
Simultaneous CHN elemental analyser at the “Service d’Analyse”, Laboratoire de Chimie de
Coordination (Toulouse). The analytical HILIC-UPLC analyses were performed on a Waters
UPLC Acquity apparatus with PDA (photodiode array) and SQ (simple quadripole) detectors,
and using an Acquity BEH HILIC column (1.7 ꢀm, 100 × 2.1 mm) with a flow rate of 0.4 mL
-1
min . Analyses were performed using a linear gradient system solvent A/solvent B 5/95 to
0/50 in 7 min, then an isocratic elution (50/50) for 10 min. For system 1, solvents were H
0.1% HCOOH (solvent A) and CH CN + 0.1% HCOOH (solvent B) and for system 2,
solvents were ammonium formate buffer 10 mM pH8 (solvent A) and ammonium formate
buffer 100 mM pH8/CH CN 10/90 (solvent B).
5
2
O
+
3
3
Photophysical experiments
Absorption measurements were done with a Hewlett Packard 8453 temperature-controlled
spectrometer in 10 mm quartz cuvette. Emission, excitation spectra and luminescence decays
at room temperature of lanthanide complexes were measured using a Cary Eclipse
spectrofluorimeter equipped with a Xenon flash lamp source and a Hamamatsu R928
photomultiplier. At liquid-nitrogen temperature, a LS-50B Perkin-Elmer spectrofluorimeter
equipped with a Xenon flash lamp source, a Hamamatsu R928 photomultiplier and the low-
o
temperature accessory n L2250136 was used. Excitation spectra were corrected for the
excitation light intensity, while emission spectra were corrected for the instrument response.
Lifetimes τ (uncertainty ≤ 5%) are made by monitoring the decay at a wavelength
corresponding to the maximum intensity of the emission spectrum, following pulsed
excitation. They are the average values from at least five separate measurements covering two
17

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or more lifetimes. The luminescence decay curves were fitted by an equation of the form I(t)
I(0) exp(ꢀt/ ) by using a curve-fitting program. The inner-sphere water coordination number
=
τ
18
(q) was calculated using equation: q = A (k
H
– k
D
– kcorr
)
where A is an empirically
Eu
Tb
determined proportionality factor (A = 1.2 ms and A = 5.0 ms), k and k are the decay
H
D
2 2
rate constants (k = 1/τobs, τobs in ms) in H O and D O solutions respectively, and kcorr is a
-1
-1
factor to correct for closely diffusing second-sphere water molecules (0.25 ms and 0.06 ms
3
+
3+
for Eu and Tb , respectively).
Quantum yields were determined by a comparative method with a standard reference;
estimated experimental errors for quantum yield determination are ± 10%. Quinine sulfate in
53
54
1
N sulfuric acid (Φ = 0.546) and Cs
3
[Tb(pic)
3
] (Φ = 22 % in TRIS buffer pH 7.4) were
55
3 2
used as standards for Tb complexes and [Ru(bpy) ]Cl (Φ = 4% in water) for Eu complexes.
Relaxometric experiments
III
In these experiments, the exact Gd concentration of solutions was determined by proton
3
relaxivity measurements at 0.47 T and 37°C after mineralization in concentrated HNO .
17
The O transverse relaxation times were measured using the standard Carr-Purcell-Meiboom-
Gill spin-echo pulse sequence on 0.4 mL samples contained in 5 mm o.d. tubes on a Bruker
Avance 500 spectrometer. The temperature was regulated by air or nitrogen flow controlled
by a Bruker BVT 3200 unit. The value of q was obtained by comparing the O-17 chemical
shifts measured at 330 K and 11.7 T (Bruker Avance-500 spectrometer) on solutions of Gd-
1
DOTA (8.75 mM) and GdL complex (9.5 mM) dissolved in 0.35 mL of water added 0.05 mL
of D O for the lock.
2
Proton nuclear magnetic relaxation dispersion (NMRD) profiles were recorded over a
magnetic field range from 0.015 to 40 MHz on a Stelar Spinmaster FFC fast field cycling
NMR relaxometer. Measurements were performed at 310 K on 0.6 mL of solutions contained
in 10 mm o.d. Pyrex tubes. Additional relaxation rates at 20 and 60 MHz were obtained on a
Bruker Minispec mq20 and a Bruker Minispec mq60, respectively.
II
Transmetallation by Zn ions was evaluated from the decrease in the water proton
longitudinal relaxation at 310 K and 20 MHz (Minispec mq20) of buffered solutions (pH 7,
III
phosphate buffer: [KH
2
PO
4
] = 26 mM, [Na
2
HPO
4
] = 41 mM) containing the Gd complex
(
2.5 mM) and ZnCl (2.5 mM).
2
18

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N,N',N"-[(tert-Butoxycarbonyl)methyl]diethylenetriamine (1): This compound was
1
3
synthesized following our procedure.
2,6-bis(bromomethyl)-4-methylphenol (2): This compound was synthesized following a
56
modified literature procedure. At room temperature, a solution of 33% HBr in acetic acid (4
mL) was added to 2,6-bis(hydroxymethyl)-4-phenol (841 mg, 5 mmol). Upon stirring for 0.25 h,
a sticky mass was formed and H
.5 h, and then filtered. The light yellow solid was sublimated under vacuum to give the product
as a white solid (1.05 g, 71%). Mp: 116-118 °C. R (silicagel, CH Cl /petroleum ether 40:60):
2
O was added (10 mL). The mixture was stirred for an additional
0
f
2
2
-
1
1
0
2
2
2
.48. IR (KBr disc)
ν
/cm 3519, 2915, 2839, 1603, 1486, 1210. H NMR (300 MHz; CDCl
3
):
δ
13
.26 (s, 3H), 4.54 (s, 4H), 5.44 (s, 1H), 7.08 (s, 2H). C NMR (75 MHz; CDCl
3
):
δ
20.3 (CH
3
),
+
9.5 (CH
2
), 125.0 (Cq), 130.7 (Cq), 131.9 (CH), 151.0 (Cq). DCI-NH
3
/MS: m/z 296.9, 294.9,
+
+
92.9 ([M+H] ), 215.0, 213.0 ([C
9
H10BrO] ).
Fully protected ligands 3 and 4
To a solution of triamine 1 (390 mg, 0.875 mmol) in dry acetonitrile (440 mL), was added in
one portion sodium carbonate (0.93 g, 8.77 mmol) and then dibromo compound 2 (258 mg,
0
.877 mmol). The suspension was heated at reflux for 16 h and was cooled to room
temperature. The salts were filtered off and the filtrate was concentrated in vacuo. The oily
residue was purified by chromatography on alumina eluting first with CH Cl , then with
CH Cl /methanol (98:02) to give the expected macrocycles 3 (155 mg, 31%) and 4 (280 mg,
5%) as yellow oils.
By using similar reaction conditions but with Li
2
2
2
2
5
2
CO
3
instead of Na
2
CO
3
as base, macrocycles
3
and 4 were isolated in 63 and 23 yields, respectively.
-
1
1
Compound 3: R
f
(alumina, CH
):
.49 (m, 2H), 2.68-2.92 (m, 4H), 3.05 (s, 2H), 3.28 (d, J = 16.8 Hz, A part of an AB system,
H), 3.35 (d, J = 16.8 Hz, B part of an AB system, 2H), 3.47 (d, J = 12.9 Hz, A part of an AX
2
Cl
2
): 0.35. IR
ν
/cm 2977, 2932, 2841, 1734, 1367, 1155. H
NMR (300 MHz; CDCl
3
δ 1.41 (s, 9H), 1.50 (s, 18H), 2.03-2.14 (m, 2H), 2.23 (s, 3H), 2.35-
2
2
system, 2H), 4.32 (d, J = 12.9 Hz, X part of an AX system, 2H), 6.81 (s, 2H), 9.81 (s br, 1H).
1
3
C NMR (75 MHz; CDCl
5.7 (CH ), 56.5 (CH ), 80.6 (Cq), 81.2 (Cq), 125.8 (Cq), 128.2 (Cq ), 130.4 (CH), 154.1
Cq ), 170.2 (CO), 170.3 (CO). ES /MS: m/z 578.4 ([M+H] , 100%).
3 3 3 2 2 2
): δ 20.5 (CH ), 28.1 (CH ), 49.7 (CH ), 51.0 (CH ), 51.1 (CH ),
5
2
2
+
+
(
19

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DOI: 10.1039/C7DT00291B
-1
Compound 4: R
f
(alumina, CH
2
Cl
2
): 0.07. IR
ν/cm 2977, 2933, 2858, 1732, 1481, 1367,
1
1
1
2
156. H NMR (300 MHz; CDCl
3
):
δ 1.42 (s, 18H), 1.45 (s, 36H), 2.18 (s, 6H), 2.73-2.78 (m,
13
6H), 3.23 (s, 8H), 3.30 (s, 4H), 3.71 (s, 8H), 6.82 (s, 4H). C NMR (75 MHz; CDCl
3
): δ
0.4 (CH ), 28.1 (CH ), 51.3 (CH ), 51.4 (CH ), 53.8 (CH ), 55.3 (CH ), 55.4 (CH ), 80.6
3
3
2
2
2
2
2
(Cq), 80.8 (Cq), 123.2 (Cq), 127.0 (Cq), 129.8 (CH), 153.7 (Cq), 170.5 (CO), 170.8 (CO).
+
+
2+
ES /MS: m/z 1157.7 ([M+H] , 100%), 578.4 ([M+2H] , 47%).
1
Ligand H
4
L : The triester 3 (100 mg, 0.173 mM) was stirred in a mixture of CH
2
Cl
2
(5 mL)
and HCl 20% in water (5 mL) at room temperature for 1 day. The aqueous layer was
1
evaporated under reduced pressure to give H
4
L in the form of its hydrochloride salt as a
1
beige powder (85 mg, 92%). UPLC analysis (system 1); t
O):
.23 (d, J = 13.4 Hz, 2H), 4.98 (d, J = 13.4 Hz, 2H), 7.28 (s, 2H). C NMR (125 MHz; D O):
R
= 1.87 min. H NMR (500 MHz;
D
2
δ 1.62-1.98 (m, 2H), 2.24 (s, 3H), 2.37-2.69 ( m, 2H), 3.11-3.47 (m, 6H), 4.14 (s, 4H),
13
4
2
δ
19.4 (CH
3
), 52.4 (CH
2
), 53.7 (CH
2
), 54.7 (CH
2
), 57.4 (CH
2
), 58.5 (CH
2
), 122.7 (Cq), 133.6
+
+
(
Cq), 134.7 (CH), 150.7 (Cq), 168.8 (CO), 175.0 (CO). ES /MS: m/z 410.1 ([M+H] , 100%).
+
+
ES /HRMS Calcd for C19
Found: C, 42.30; H, 5.69; N, 7.45. Calcd for C19
.83. UV/Vis λmax (50 mM Tris buffer, pH 7.4)/nm: 229 sh (ε/dm mol cm 5990), 288
2490).
H
28
N
3
O
7
[M+H] : m/z = 410.1927, found: m/z = 410.1915. Anal.
H
27
N
3
O
7
+3HCl+1H O: C, 42.51; H, 6.01; N,
2
3
-1
-1
7
(
2
Ligand H
8
L :
The hexaester 4 (100 mg, 0.087 mM) was stirred in a mixture of CH Cl (5 mL) and HCl 20%
2
2
in water (5 mL) at room temperature for 1 day. The aqueous layer was evaporated under
2
reduced pressure to give H
8
L in the form of its hydrochloride salt as a beige powder (81 mg,
1
8
5%). UPLC analysis (system 2); t
R
= 4.47 min. H NMR (300 MHz; CDCl
3
):
δ
2.18 (s, 6H),
2.92-3.11 (m, 8H), 3.21 (s, 4H), 3.26-3.44 (m, 8H), 3.76 (s, 8H), 4.33 (s, 8H), 7.21 (s, 4H).
1
3
C NMR (75 MHz; D
2
O):
3 2 2 2 2
δ 19.3 (CH ), 49.0 (CH ), 52.1 (CH ), 53.9 (CH ), 55.3 (CH ),
5
5.6 (CH ), 118.4 (Cq), 131.6 (Cq), 135.7 (CH), 152.9 (Cq), 170.2 (CO), 174.2 (CO).
2
+
+
+
+
ES /MS: m/z 841.3 ([M+Na] , 100%), 819.3 ([M+H] , 35%). ES /HRMS Calcd for
+
C H N O Na [M+Na] : m/z = 841.3596, found: m/z = 841.3657; calcd for C H N O
38
54
6
14
38 55
6
14
+
[
M+H] : m/z = 819.3776, found: m/z = 819.3807. Anal. Found: C, 42.13; H, 6.13; N, 7.53.
Calcd for C38
H
54
N
6
2
O14+6HCl+3H O: C, 41.81; H, 6.09; N, 7.70. UV/Vis λmax (50 mM Tris
3
-1
-1
buffer, pH 7.4)/nm: 224 sh (ε/dm mol cm 15120), 288 (6510).
20

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1
2
[
LnL ]Na and [Ln
2
L ]Na
2 2
complexes. General procedure: To a solution of ligand in H O
was added LnCl ,6H
3
2
O (1.1 equiv.). After stirring at room temperature for 1h, pH was
adjusted to 5-6 with NaOH 0.1 M and the mixture was then stirred overnight at room
temperature. The pH was then adjusted to 7 with NaOH 0.1 M, the solvent was evaporated to
a minimum and the solution was loaded on a Waters Sep-Pak® cartridge (C , 10 g).
18
2 2
Cartridge was rinsed with H O to remove salts and the product was eluted with a H O/MeOH
1:1 mixture. The solvents were removed in vacuo to give the expected complexes with
III
quantitative yields. The absence of free Ln ions in these complexes was verified using a
classic test with an arsenazo indicator solution.
1
-
[
TbL ]Na: UPLC analysis (system 1); t
R
= 3.43 min. ES /HRMS Calcd for C19
23 3 7
H N O Tb
1
-
[
TbL ] : m/z = 564.0789, found: m/z = 564.0800. UV/Vis λ (50 mM Tris buffer, pH
max
3
-1
-1
7
.4)/nm: 245 (ε/dm mol cm 6480), 296 (2980). Luminescence λem (50 mM Tris buffer, pH
.4; 298 K; λexc = 296 nm)/nm: 490 (relative intensity, corrected spectrum 35), 545 (100), 586
7
(26), 623 (15), 638-700 (6).
1
-
[
EuL ]Na: UPLC analysis (system 1); t
R
= 3.46 min. ES /HRMS Calcd for C19
H
23
N
3
O
7
Eu
1
-
153
151
[
EuL ] : m/z = 558.0748 ( Eu) and 556.0734 ( Eu), found: m/z = 558.0756 and m/z =
3
-1
-1
5
7
5
56.0742, respectively. UV/Vis λmax (50 mM Tris buffer, pH 7.4)/nm: 245 (ε/dm mol cm
680), 296 (3650). Luminescence λem (50 mM Tris buffer, pH 7.4; 298 K; λexc = 296 nm)/nm:
92 (relative intensity, corrected spectrum 32), 616 (100), 652 (4), 698 (65).
1
-
[
GdL ]Na:UPLC analysis (system 1); t
R
= 3.47 min. ES /HRMS Calcd for C19
23 3 7
H N O Gd
1
-
158
[
GdL ] : m/z = 563.0782 ( Gd), found: m/z = 563.0778. UV/Vis λmax (50 mM Tris buffer, pH
3
-1
-1
7
.4)/nm: 245 (ε/dm mol cm 5960), 296 (2810). Fluorescence λem (50 mM Tris buffer, pH
.4; 298 K; λexc = 296 nm)/nm: 338. Phosphorescence λem (50 mM Tris buffer/glycerol 4:1; 77
7
K; λexc = 296 nm)/nm: 405; lifetime 1.48 ms.
2
]
-
[
Tb L Na : UPLC analysis (system 2); t = 3.88 min. ES /HRMS Calcd for C H N O Tb
2
2
R
38 47
6
14
2
2
-
2 2-
[
Tb
2
L +H] : m/z = 1129.1658, found: m/z = 1129.1636; calcd for C38
46
H N
6
O
14Tb
2
2
[Tb L ] :
m/z = 564.0789, found: m/z = 564.0796. UV/Vis λmax (50 mM Tris buffer, pH 7.4)/nm: 242
3
-1
-1
(
ε/dm mol cm 16850), 296 (6920). Luminescence λ (50 mM Tris buffer, pH 7.4; 298 K;
em
λ
exc = 296 nm)/nm: 490 (relative intensity, corrected spectrum 37), 545 (100), 585 (27), 622
(
[
(
15), 638-700 (7).
2
]
-
Eu L Na : UPLC analysis (system 2); t = 4.09 min. ES /MS: m/z 1137.2
2
2
R
151,153
2
-
151,153
2
-
[
Eu
2
L +Na] , 100%), 1115.3 ([
2
Eu L +H] , 27%), UV/Vis λmax (50 mM Tris buffer,
3
-1
-1
pH 7.4)/nm: 242 (ε/dm mol cm 15250), 295 (6390). Luminescence λem (50 mM Tris buffer,
21

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DOI: 10.1039/C7DT00291B
pH 7.4; 298 K; λexc = 296 nm)/nm: 593 (relative intensity, corrected spectrum 35), 617 (100),
52 (7), 697 (72).
6
2
]
-
[Gd
2
L Na
2
: UPLC analysis (system 2); t
R
= 4.05 min. ES /HRMS Calcd for
2
-
158
C
C
38
38
H
46
47
N
N
6
6
O
14Gd
2
2
2
Na [Gd L +Na] : m/z = 1149.1470 ( Gd), found: m/z = 1149.1451; calcd for
2
-
158
H
O14Gd
2
[Gd L +H] : m/z = 1127.1650 ( Gd), found: m/z = 1127.1626; calcd for
2
2-
158
C H N O Gd [Gd L ] : m/z = 563.0786 ( Gd), found: m/z = 563.0791. UV/Vis λ (50
38
46
6
14
2
2
max
3
-1
-1
mM Tris buffer, pH 7.4)/nm: 242 (ε/dm mol cm 15790), 296 (6740). Fluorescence λem (50
mM Tris buffer, pH 7.4; 298K; λexc = 296 nm)/nm: 329. Phosphorescence λem (50 mM Tris
buffer/glycerol 4:1; 77 K; λexc = 296 nm)/nm: 416
Acknowledgements
We thank Isabelle Fabing for technical assistance on UPLC equipment provided by the
Integrated Screening Platform of Toulouse (PICT, IBiSA). This work was supported by the
French Ministère de la Recherche (Ph.D. grant for M.E.) and the CNRS. S.L. and L.V.E.
thank the FNRS (Fonds National de la recherche scientifique), and ARC Programs (AUWB-
2010-10/15-UMONS-5) of the French Community of Belgium, the UIAP VII program of
Belgium and the Center for Microscopy and Molecular Imaging (CMMI, supported by the
European Regional Development Fund and the Walloon Region).
References
1
(a) S. Goswami, S. Maity, A. C. Maity, A. Kumar Das, K. Khanra, T. Kanti Mandal and N.
Bhattacharyya, Tetrahedron Lett., 2014, 55, 5993-5997; (b) K. Zhang, C. Jin, H.-Q. Chen, G.
Yin and W. Huang, Chem. Asian J., 2014, 9, 2534-2541; (c) Y.-Y. Liu, W.-J. Gong, J.-C. Ma
and J.-F. Ma, J. Coord. Chem., 2013, 66, 4032–4051; (d) Y. Fu, Z. Xing, C. Zhu, H. Yang, W.
He, C. Zhu and Y. Cheng, Tetrahedron Lett., 2012, 53, 804-807;(e) G. Ambrosi, M. Formica,
V. Fusi, L. Giorgi, E. Macedi, M. Micheloni and R. Pontellini, Inorg. Chim. Acta, 2009, 362,
3709-3714; (f) G. Ambrosi, M. Formica, V. Fusi, L. Giorgi and M. Micheloni, Coord. Chem.
Rev., 2008, 252, 1121-1152; (g) H. Okawa, H. Furutachi and D. E. Fenton, Coord. Chem.
Rev., 1998, 174, 51-75.
22

Page 23 of 36
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00291B
2
(a) H. Nakai, T. Goto, K. Kitagawa, K. Nonaka, T. Matsumoto and S. Ogo, Chem.
Commun., 2014, 50, 15737-15739; (b) H. Nakai, K. Nonaka, T. Goto, J. Seo, T. Matsumoto
and S. Ogo, Dalton Trans., 2015, 44, 10923-10927; (c) B. Makhinson, A. K. Duncan, A. R.
Elam, A. de Bettencourt-Dias, C. D. Medley, J. E. Smith and E. J. Werner, Inorg. Chem.,
2013, 52, 6311-6318; (d) P. Gawryszewska and J. Lisowski, Inorg. Chim. Acta, 2012, 383,
220-229.
3
M. Woods, G. E. Kiefer, S. Bott, A. Castillo-Muzquiz, C. Eshelbrenner, L. Michaudet, K.
McMillan, S. D. K. Mudigunda, D. Ogrin, G. Tircso, S. Zhang, P. Zhao and A. D. Sherry, J.
Am. Chem. Soc., 2004, 126, 9248-9256
4
O. A. Blackburn, M. Tropiano, L. S. Natrajan, A. M. Kenwright and S. Faulkner, Chem.
Commun., 2016, 52, 6111-6114.
5
C. Platas, F. Avecilla, A. de Blas, T. Rodríguez-Blas, C. F. G. C. Geraldes, E. Toth, A. E.
Merbach and J.-C. G. Bünzli, J. Chem. Soc., Dalton Trans., 2000, 611-618.
6
(a) N. Leygue, A. Boulay, C. Galaup, E. Benoist, S. Laurent, L. Vander Elst, B. Mestre-
Voegtle and C. Picard, Dalton Trans., 2016, 45, 8379-8393; (b) S. Laurent, L. Vander Elst, C.
Galaup, N. Leygue, S. Boutry, C. Picard and R. N. Muller, Contrast Media Mol. Imaging,
2014, 9, 300-312; (c) C. Picard, N. Geum, I. Nasso, B. Mestre, P. Tisnes, S. Laurent, R. N.
Muller and L. Vander Elst, Bioorg. Med. Chem. Lett., 2006, 16, 5309-5312; (d) I. Nasso, C.
Galaup, F. Havas, P. Tisnès, C. Picard, S. Laurent, L. Vander Elst and R. N. Muller, Inorg.
Chem., 2005, 44, 8293-8305.
7
8
9
K. W.-Y. Chan and W.-T. Wong, Coord. Chem. Rev., 2007, 251, 2428-2451.
A. de Bettencourt-Dias, Curr. Org. Chem., 2007, 11, 1460-1480.
See for examples: (a) L. J. Charbonniere, S. Mameri, D. Flot, F. Waltz, C. Zandanel and R.
F. Ziessel, Dalton Trans., 2007, 2245-2253; (b) A. Nonat, P. H. Fries, J. Pécaut and M.
Mazzanti, Chem. Eur. J., 2007, 13, 8489-8506.
10 N. Sabbatini, M. Guardigli and J.-M. Lehn, Coord. Chem. Rev., 1993, 123, 201-228.
23

Dalton Transactions
Page 24 of 36
View Article Online
DOI: 10.1039/C7DT00291B
11 L. S. Natrajan, P. L. Timmins, M. Lunn and S. L. Heath, Inorg. Chem., 2007, 46, 10877-
10886.
12 (a) W. D. Kim, G. E. Kiefer, F. Maton, K. McMillan, R. N. Muller and A. D. Sherry, Inorg.
Chem., 1995, 34, 2233-2243 ; (b) S. Aime, M. Botta, S. Geninatti Crich, G. B. Giovenzana, G.
Jommi, R. Pagliarin and M. Sisti, Inorg. Chem., 1997, 36, 2992-3000 ; (c) J.-M. Siaugue, F.
Segat-Dioury, A. Favre-Reguillon, V. Wintgens, C. Madic, J. Foos and A. Guy, J. Photochem.
Photobiol. A, 2003, 156, 23-29; (d) G. Tircso, Z. Kovacs and A. D. Sherry, Inorg. Chem.,
2006, 45, 9269-9280.
13 C. Galaup, J.-M. Couchet, S. Bedel, P. Tisnès and C. Picard, J. Org. Chem., 2005, 70,
2274-2284.
14 (a) G. Ambrosi, M. Formica, V. Fusi, L. Giorgi, E. Macedi, M. Micheloni, P. Paoli and P.
Rossi, Inorg. Chem., 2009, 48, 10424-10434; (b) H.-H. Chen, J. Yang, Y.-Y. Liu and J.-F. Ma,
CrystEngComm, 2013, 15, 5168-5178.
15 (a) L. Ma, L. Lu, M. Zhu, Q. Wang, F. Gao, C. Yuan, Y. Wu, S. Xing, X. Fu, Y. Mei and
X. Gao, J. Inorg. Biochem., 2011, 105, 1138-1147; (b) J. Kankare, A. Karppi and H. Takalo,
Anal. Chim. Acta, 1994, 295, 27-35; (c) J. Kankare, K. Haapakka, S. Kulmala, V. Nanto, J.
Eskola and H. Takalo, Anal. Chim. Acta, 1992, 266, 205-212.
16 F. S. Richardson, Chem. Rev., 1982, 82, 541-552.
17 (a) W. D. W. Horrocks Jr. and D. R. Sudnick, Acc. Chem. Res., 1981, 14, 384-392; (b) W.
D. W. Horrocks Jr. and D. R. Sudnick, J. Am. Chem. Soc., 1979, 101, 334-340.
18 A. Beeby, I. M. Clarkson, R. S. Dickins, S. Faulkner, D. Parker, L. Royle, A. S. de Sousa,
J. A. G. Williams and M. Woods, J. Chem. Soc., Perkin Trans. 2, 1999, 493-503.
19 S. A. Cotton, Comptes Rendus Chimie, 2005, 8, 129-145.
20 S. V. Eliseeva and J.-C. G. Bünzli, Chem. Soc. Rev., 2010, 39, 189-227.
24

Page 25 of 36
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00291B
21 O. N. Tchaikovskaya, I. V. Sokolova, R. T. Kuznetsova, V. A. Swetlitchnyi, T. N.
Kopylova and G. V. Mayer, J. Fluoresc, 2000, 10, 403-408.
22 T. Ala-Kleme, K. Haapakka and M. Latva, Anal. Chim. Acta, 1999, 395, 205-211.
23 C. P. Montgomery, B. S. Murray, E. J. New, R. Pal and D. Parker, Acc. Chem. Res., 2009,
42, 925-937.
24 M. Latva, H. Takalo, V.-M. Mukkala, C. Matachescu, J.-C. Rodriguez-Ubis and J.
Kankare, J. Lumin., 1997, 75, 149-169.
25 (a) M. Xiao and P. R. Selvin, J. Am. Chem. Soc., 2001, 123, 7067-7073; (b) J. Xu, T. M.
Corneillie, E. G. Moore, G.-L. Law, N. G. Butlin and K. N. Raymond, J. Am. Chem. Soc.,
2
2
2
011, 133, 19900-19910.
6 E. Brunet, O. Juanes, R. Sedano and J.-C. Rodríguez-Ubis, Org. Lett., 2002, 4, 213-216.
7 See for examples: (a) A. P. Bassett, S. W. Magennis, P. B. Glover, D. J. Lewis, N. Spencer,
S. Parsons, R. M. Williams, L. De Cola and Z. Pikramenou, J. Am. Chem. Soc., 2004, 126,
413-9424; (b) P. Gawryszewska, J. Sokolnicki, A. Dossing, J. P. Riehl, G. Muller and J.
9
Legendziewicz, J. Phys. Chem. A, 2005, 109, 3858-3863; (c) I. Nasso, S. Bedel, C. Galaup
and C. Picard, Eur. J. Inorg. Chem., 2008, 2064-2074; (d) A. R. Ramya, M. L. P. Reddy, A. H.
Cowley and K. V. Vasudevan, Inorg. Chem., 2010, 49, 2407-2415.
28 A. E. Martell, R. M. Smith, Critical Stability Constants, Plenum Press, New York, 1974,
vol.1, p 282.
29 See for examples: (a) J. I. Bruce, R. S. Dickins, L. J. Govenlock, T. Gunnlaugsson, S.
Lopinski, M. P. Lowe, D. Parker, R. D. Peacock, J. J. B. Perry, S. Aime and M. Botta, J. Am.
Chem. Soc., 2000, 122, 9674-9684; (b) V. C. Pierre, M. Botta, S. Aime and K. N. Raymond,
Inorg. Chem., 2006, 45, 8355-8364; (c) D. Imperio, G. B. Giovenzana, G.-I. Law, D. Parker
and J. W. Walton, Dalton Trans., 2010, 39, 9897-9903.
25

Dalton Transactions
Page 26 of 36
View Article Online
DOI: 10.1039/C7DT00291B
30 L. S. Nikolaeva, V. V. Chirkov, N. A. Dobrynina, L. A. Lyapina and V. E. Pastorova,
Pharm. Chem. J., 2005, 39, 57-63.
3
1 G. Mathis, Clin. Chem., 1993, 39, 1953-1959.
2 L. R. Morss, Chem. Rev., 1976, 76, 827-841.
3
33 S. J. A. Pope, A. M. Kenwright, S. L. Heath and S. Faulkner, Chem. Commun., 2003,
1550-1551.
34 C. Guanci, G. Giovenzana, L. Lattuada, C. Platas-Iglesias and L. J. Charbonniere, Dalton
Trans., 2015, 44, 7654-7661.
35 (a) S. Laurent, L. Vander Elst and R. N. Muller, Contrast Media Mol. Imaging, 2006, 1,
128–137; (b) D. H. Powell, O. M. Ni Dhubhghaill, D. Pubanz, L. Helm, Y. S. Lebedev, W.
Schlaepfer and A. E. Merbach, J. Am. Chem. Soc., 1996, 118, 9333-9346.
36 (a) A. Vagner, E. Gianolio, S. Aime, A. Maiocchi, I. Toth, Z. Baranyai and L. Tei, Chem.
Commun., 2016, 52, 11235-11238; (b) C. S. Bonnet, S. Laine, F. Buron, G. Tircso, A. Pallier,
L. Helm, F. Suzenet and E. Toth, Inorg. Chem., 2015, 54, 5991-6003; (c) Z. Baranyai, L. Tei,
G. B. Giovenzana, F. K. Kalman and M. Botta, Inorg. Chem., 2012, 51, 2597-2607; (d) C. S.
Bonnet, F. Buron, F. Caillé, C. M. Shade, B. Drahos, L. Pellegatti, J. Zhang, S. Villette, L.
Helm, C. Pichon, F. Suzenet, S. Petoud and E. Toth, Chem. Eur. J., 2012, 18, 1419-1431; (e)
G. Tallec, D. Imbert, P. H. Fries and M. Mazzanti, Dalton Trans., 2010, 39, 9490-9492; (f) S.
Aime, L. Calabi, C. Cavallotti, E. Gianolio, G. B. Giovenzana, P. Losi, A. Maiocchi, G.
Palmisano and M. Sisti, Inorg. Chem., 2004, 43, 7588-7590; (g) M. K. Thompson, M. Botta,
G. Nicolle, L. Helm, S. Aime, A. E. Merbach and K. N. Raymond, J. Am. Chem. Soc., 2003,
125, 14274-14275.
37 M. Port, I. Raynal, L. Vander Elst, R. N. Muller, F. Dioury, C. Ferroud and A. Guy,
Contrast Media Mol. Imaging, 2006, 1, 121-127.
38 P. Hermann, J. Kotek, V. Kubicek and I. Lukes, Dalton Trans., 2008, 3027-3047.
26

Page 27 of 36
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00291B
39 P. Caravan, Chem. Soc. Rev., 2006, 35, 512-523.
40 (a) L. Vander Elst, F. Maton, S. Laurent, F. Seghi, F. Chapelle and R. N. Muller, Magn.
Reson. Med., 1997, 38, 604-614; (b) R. N. Muller, B. Radüchel, S. Laurent, J. Platzek, C.
Piérart, P. Mareski and L. Vander Elst, Eur. J. Inorg. Chem., 1999, 1949-1955; (c) S. Laurent,
L. Vander Elst, S. Houzé, N. Guérit and R. N. Muller, Helv. Chim. Acta, 2000, 83, 394-406.
41 K. Micskei, L. Helm, E. Brucher and A. E. Merbach, Inorg. Chem., 1993, 32, 3844-3850.
42 S. Aime, M. Botta, S. Geninatti Crich, G. Giovenzana, R. Pagliarin, M. Sisti and E.
Terreno, Magn. Reson. Chem., 1998, 36, S200-S208.
43 S. Laus, R. Ruloff, E. Toth and A. E. Merbach, Chem. Eur. J., 2003, 9, 3555-3566.
44 (a) M. Polasek, M. Sedinova, J. Kotek, L. Vander Elst, R. N. Muller, P. Hermann and I.
Lukes, Inorg. Chem., 2009, 48, 455-465; (b) S. Dumas, V. Jacques, W.-C. Sun, J. S.
Troughton, J. T. Welch, J. M. Chasse, H. Schmitt-Willich and P. Caravan, Invest. Radiol.,
2010, 45, 600-612.
45 S. Laurent, C. Henoumont, L. Vander Elst and R. N. Muller, Eur. J. Inorg. Chem., 2012,
1889-1915.
46 (a) S. Aime, E. Gianolio, D. Corpillo, C. Cavallotti, G. Palmisano, M. Sisti, G. B.
Giovenzana and R. Pagliarin, Helv. Chim. Acta, 2003, 86, 615-632 ; (b) S. Aime, M. Botta, L.
Frullano, S. Geninatti Crich, G. Giovenzana, R. Pagliarin, G. Palmisano, F. Riccardi Sirtori
and M. Sisti, J. Med. Chem., 2000, 43, 4017-4024.
47 L. Vander Elst, A. Sessoye, S. Laurent and R. N. Muller, Helv. Chim. Acta, 2005, 88, 574-
587.
48 a) A. S. Merbach, L. Helm and E. Toth, in The Chemistry of Contrast Agents in Medical
nd
Magnetic Resonance Imaging, 2 edition, ed. A. S. Merbach, L. Helm and E. Toth, John
Wiley & Sons, Chischester, 2013, chapter 2, 25-81; b) B. N. Siriwardena-Mahanama and M. J.
Allen, Molecules, 2013, 18, 9352-9381.
27

Dalton Transactions
Page 28 of 36
View Article Online
DOI: 10.1039/C7DT00291B
4
9 (a) S. Laurent, L. Vander Elst, F. Copoix and R. N. Muller, Invest. Radiol., 2001, 36, 115-
22; (b) S. Laurent, L. Vander Elst, C. Henoumont and R. N. Muller, Contrast Media Mol.
1
Imaging, 2010, 5, 305-308.
50 (a) J. Yu, A. F. Martins, C. Preihs, V. Clavijo Jordan, S. Chirayil, P. Zhao, Y. Wu, K. Nasr,
G. E. Kiefer and A. D. Sherry, J. Am. Chem. Soc., 2015, 137, 14173-14179; (b) M. Moula
Karimdjy, G. Tallec, P. H. Fries, D. Imbert and M. Mazzanti, Chem. Commun., 2015, 51,
6836-6838; (c) A. C. Mendonça, A. F. Martins, A. Melchior, S. M. Marques, S. Chaves, S.
Villette, S. Petoud, P. L. Zanonato, M. Tolazzi, C. S. Bonnet, E. Toth, P. Di Bernardo, C. F. G.
C. Geraldes and M. A. Santos, Dalton Trans., 2013, 42, 6046-6057; (d) M. Polasek and P.
Caravan, Inorg. Chem., 2013, 52, 4084-4096; (e) K.-H. Jung, H.-K. Kim, G. H. Lee, D.-S.
Kang, J.-A. Park, K. M. Kim, Y. Chang and T.-J. Kim, J. Med. Chem., 2011, 54, 5385-5394;
(f) L. Moriggi, C. Cannizzo, C. Prestinari, F. Berrière and L. Helm, Inorg. Chem., 2008, 47,
8357-8366.
51 (a) S. Silverio, S. Torres, A. F. Martins, J. A. Martins, J. P. André, L. Helm, M. I. M. Prata,
A. C. Santos and C. F. G. C. Geraldes, Dalton Trans., 2009, 4656-4670; J. B. Livramento, A.
Sour, A. Borel, A. E. Merbach and E. Toth, Chem. Eur. J., 2006, 12, 989-1003.
5
2 C. S. Johnson Jr, Prog Nucl Magn Reson Spectrosc., 1999, 34, 203-256.
3 S. R. Meech and D. Phillips, J. Photochem., 1983, 23, 193-217.
5
54 (a) A.-S. Chauvin, F. Gumy, D. Imbert and J.-C. G. Bünzli, Spectrosc. Lett., 2004, 37,
517-532; (b) A.-S. Chauvin, F. Gumy, D. Imbert and J.-C. G. Bünzli, Spectrosc. Lett., 2007,
40, 193.
55 H. Ishida, S. Tobita, Y. Hasegawa, R. Katoh and K. Nozaki, Coord. Chem. Rev., 2010, 254,
2449-2458.
56 B. M. Trost, V. S. C. Yeh, H. Ito and N. Bremeyer, Org. Lett., 2002, 4, 2621-2623.
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Captions
1
2
Fig. 1 Chemical structures of H L , H L and other ligands discussed in this work.
4
8
1
3
Fig. 2 H DOSY NMR spectrum (500 MHz, CDCl ) of the crude mixture resulting from
1
reaction between triamine 1 and dibromo compound 2. H NMR resonances of macrocycles 3
closed circles) and 4 (open circles).
(
1
2
Fig. 3 Corrected emission spectra of TbL and Tb L complexes recorded at room
2
temperature in Tris buffer (pH 7.4). The emission spectra resulted from a UV-light excitation
1
2
at 296 nm. The insets show the total emission intensity of solutions of H L or H L as the
4
8
3
function of TbCl added in Tris buffer (pH 7.4).
1
Fig. 4 Schematic representation of mononuclear LnL , LnPCTA complexes and dinuclear
2
Ln L complexes.
2
_
__
.
. ..
Fig. 5 Normalized (a) absorption (- - -), (b) fluorescence (
)
) and (c) phosphorescence (- - -
1
2
2
spectra of GdL and Gd L complexes. The absorption and fluorescence spectra were
measured at 298 K in Tris buffer (pH 7.4) and the phosphorescence spectra at 77 K in Tris
buffer-glycerol (4:1 v/v) glassy matrix.
17
R
2
1
Fig. 6 Reduced transverse O relaxation rate of water (1/T
) for aqueous solutions of GdL
(
T.
closed circles) at 11.75 T, GdPCTA (open circles) and GdDOTA (closed triangles) at 7.05
3
5a
Fig. 7 Temperature (278 – 318 K) dependence of the proton longitudinal relaxivity, r
GdL complex in water at 20 MHz.
1
, of
1
1
Fig. 8 Proton NMRD data obtained at 310 K on a 0.90 mM GdL (closed circles), a 0.54 mM
GdPCTA solution (open circles) and a 1.5 mM GdDOTA (closed triangles) solution in water.
The lines correspond to the theoretical fittings.
p
p
Fig. 9 Evolution of the ratio R
1
(t)/R
1 0 0
(t ) (T = 310 K, B = 0.47 T, 20 MHz) vs. time for
1
1
solutions of GdL in phosphate buffer (67 mM, pH 7.0) (open circles), GdL (closed circles)
and GdDTPA (dashed line) in phosphate buffer containing an equimolar amount of Zn ions.
2
+
29