Mn2+Complexes Containing Sulfonamide Groups with pH-Responsive Relaxivity

Article abstract of DOI:10.1021/acs.inorgchem.0c02098

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6′-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2′-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide a pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonations of the sulfonamide groups of the ligands are characterized by protonation constants of log KiH<= 10.36 and 10.59 for DPASAm3- and HNO2ASAm2-, respectively. These values decrease dramatically to log KiH = 6.43 and 5.42 in the presence of Mn2+, because of the coordination of the negatively charged sulfonamide groups to the metal ion. The higher log KiH value in [Mn(DPASAm)]- is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)]- is six-coordinated. The X-ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N atom, the N atom of the sulfonamide group, and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)]- complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (<7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)]- falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p = 3.8 mM-1 s-1 at pH 9.0 to r1p = 8.9 mM-1 s-1 at pH 4.0 (10 MHz, 25 °C).

Full text of DOI:10.1021/acs.inorgchem.0c02098

pubs.acs.org/IC
Article
Mn2+ Complexes Containing Sulfonamide Groups with pH-
Responsive Relaxivity
Rocío Uzal-Varela, Aurora Rodríguez-Rodríguez, Miguel Martínez-Calvo, Fabio Carniato, Daniela Lalli,
́
́
David Esteban-Gomez, Isabel Brandariz, Paulo Perez-Lourido, Mauro Botta,* and Carlos Platas-Iglesias*
Cite This: https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We present two ligands containing a N-ethyl-4-(trifluoromethyl)-
benzenesulfonamide group attached to either a 6,6′-(azanediylbis(methylene))-
dipicolinic acid unit (H3DPASAm) or a 2,2′-(1,4,7-triazonane-1,4-diyl)diacetic
acid macrocyclic platform (H3NO2ASAm). These ligands were designed to
provide a pH-dependent relaxivity response upon complexation with Mn2+ in
aqueous solution. The protonation constants of the ligands and the stability
constants of the Mn2+ complexes were determined using potentiometric titrations
complemented by spectrophotometric experiments. The deprotonations of the
sulfonamide groups of the ligands are characterized by protonation constants of log
KHi = 10.36 and 10.59 for DPASAm3− and HNO2ASAm2−, respectively. These
values decrease dramatically to log KHi = 6.43 and 5.42 in the presence of Mn2+,
because of the coordination of the negatively charged sulfonamide groups to the
metal ion. The higher log KHi value in [Mn(DPASAm)]− is related to the formation
of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)]− is six-coordinated. The X-ray crystal structure of
Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is
fulfilled by the donor atoms of the two picolinate groups, the amine N atom, the N atom of the sulfonamide group, and a
coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)]− complex and the lower protonation constant
of the sulfonamide group results in complex dissociation at relatively high pH (<7.0). However, protonation of the sulfonamide
group in [Mn(DPASAm)]− falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p
3.8 mM−1 s−1 at pH 9.0 to r1p = 8.9 mM−1 s−1 at pH 4.0 (10 MHz, 25 °C).
=
impairment, which accumulate the metal ion in the body and,
in some cases, develop a potentially fatal disease called
nephrogenic systemic fibrosis.10,11 This prompted the different
medicine agencies to revise some of the protocols and
prescribe information warnings, which prevented the detection
of new cases. More recently, reports of Gd3+ deposition in the
brain and other organs opened the debate on the long-term
safety of some Gd3+ contrast agents,12 which eventually led to
the suspension of the authorizations in Europe of some of the
agents based on nonmacrocyclic structures.13
The past decade witnessed a renewed interest in developing
transition-based MRI probes as alternatives to the classical
Gd3+ agents.14,15 In particular, both Mn2+ and Fe3+ complexes
were proposed as Gd3+ alternatives as T1-shortening contrast
agents, since they can reach relaxivities comparable to those of
INTRODUCTION
■
Contrast agents for application in magnetic resonance imaging
(MRI) are a class of paramagnetic compounds that are injected
in the body to enhance image contrast, thereby aiding a more
precise and accurate diagnosis of different pathologies.1,2
Paramagnetic ions containing Mn2+ and Fe3+ were considered
as MRI agents in the early times of MRI, back in the 1970s and
early 1980s.3−6 Soon afterward, it was discovered that some
Gd3+ complexes are very efficient relaxation agents,7 which
were subsequently introduced in clinical practice and applied
to aid diagnosis in millions of MRI scans every year.1 Contrast
agents based on Gd3+ are complexes with polyaminopolycar-
boxylate ligands that ensure a very high stability to avoid the
release of the toxic metal ion in vivo.8 These complexes
contain a water molecule coordinated to the metal ion that
exchanges with the water of the surrounding tissues, providing
an efficient mechanism to shorten the relaxation times of water
proton nuclei, thereby increasing the signal intensity.9
Received: July 15, 2020
The contrast agents available in the market are considered
very safe pharmaceuticals, although some problems of toxicity
have been reported. These toxicity issues have been associated
with the administration of Gd3+ agents to patients having renal
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
© XXXX American Chemical Society
Inorg. Chem. XXXX, XXX, XXX−XXX
A

Inorganic Chemistry
pubs.acs.org/IC
Article
27
commercially available Gd3+ agents.16,17 These two metal ions
present S ground-energy terms for the free ion, that often
modulation of H relaxivity. Thus, we hypothesized that the
incorporation of an N-ethylbenzenesulfonamide group to these
platforms should provide rather stable Mn2+ complexes with
pH-responsiveness, since the deprotonated sulfonamide group
is expected to remain coordinated to the metal ion.
Sulfonamide protonation should trigger the coordination of a
water molecule replacing the sulfonamide N atom, resulting in
an increase of proton relaxivity and, thus, MRI contrast.
Herein, we present the synthesis and characterization of the
ligands containing N-ethyl-4-(trifluoromethyl)-
benzenesulfonamide groups H3DPASAm and H3NO2ASAm
(see Chart 1). The presence of the electron-withdrawing CF3
group was envisaged to push the pKa of the sulfonamide group
to the biologically relevant window, in view of the lower charge
of Mn2+, compared to Gd3+. We report the synthesis of the
ligands, a detailed assessment of the thermodynamic stability of
the corresponding Mn2+ complexes, and their relaxometric
behavior. We also present the X-ray structure of the
[Mn(H3DPASAm)]− complex.
1
6
originate ground-energy electronic states characterized by slow
relaxation times of the electron spin in high-spin complexes,
making them powerful relaxation agents. As in the case of Gd3+
agents,18−20 responsive contrast agents may be designed by
programming a change in the number of coordinated water
molecules triggered by an alteration of a physiologically
relevant parameter (i.e., pH, concentration of biogenic anions
́
or cations). This was demonstrated recently by Tircso et al.
with the [Mn(PC2A-EA)] complex (Chart 1). The aminoethyl
Chart 1. Ligands Discussed in the Present Work
RESULTS AND DISCUSSION
■
Synthesis. The H3DPASAm ligand was synthesized by
alkylation of N-(2-aminoethyl)-4-(trifluoromethyl)-
benzenesulfonamide (1) with ethyl 6-(chloromethyl)picolinate
and subsequent acid hydrolysis of the ester groups (see
Scheme 1). Compound 1 was obtained in 92% by reaction of
4-(trifluoromethyl)benzenesulfonyl chloride and ethylendi-
amine in CH2Cl2 at 0 °C. The ligand was isolated with an
overall yield of 36% over the three steps. Ligand H3NO2ASAm
was prepared by alkylation of the NO2A(OtBu)2 precursor
w i t h N - ( 2 - b r o m o e t h y l ) - 4 - ( t r i fl u o r o m e t h y l ) -
benzenesulfonamide (3) in acetonitrile in the presence of
K2CO3 as a base (Scheme 1). The latter was isolated in 81%
yield by reaction of 2-bromoethan-1-amine hydrobromide and
4-(trifluoromethyl)benzenesulfonyl chloride, using Et3N as a
base. Acid hydrolysis of the tert-butyl ester groups of the ester
intermediate 4 with 3 M HCl at room temperature afforded
the desired ligand in 71% yield over the three steps.
X-ray Structure. Single crystals with a formula of
Na[Mn(DPASAm)(H2O)]·2H2O were obtained by slow
evaporation of an aqueous solution of the complex at pH
9.9. Crystals contain two [Mn(DPASAm)(H2O)]− complexes
joined by two Na+ cations, generating a centrosymmetric
{Na2(H2O)2[Mn(DPASAm)(H2O)]2} entity (Figure 1).
Table 1 presents the bond distances of the metal coordination
environments. Each Mn2+ ion is coordinated to the tertiary N
atom of the ligand N2 and the donor atoms of the picolinate
groups N1, N3, O1, and O3, which define a pentagonal plane
of the pentagonal bipyramidal coordination polyhedron
(deviation from planarity = 0.19 Å). Heptacoordination is
relatively rare in first-row transition-metal complexes, being
however more common for Mn than for any other element of
the series.28 The N atom of the sulfonamide group N4 and the
oxygen atom of a coordinated water molecule O7 occupy the
apical positions of the pentagonal bipyramid. The N4−Mn1−
O7 angle (174.76(8)°) deviates by ∼5° from the linear value
expected for a pentagonal bipyramid. The angles defined by
adjacent donor atoms of the equatorial plane and the metal ion
fall within the range of 68.8°−79.3°, and thus present relatively
small deviations from the ideal value (72°).
group of the ligand is protonated in the biologically relevant
pH window (log KHMnL = 6.88), so that a water molecule
replaces the amine donor atom, causing a remarkable relaxivity
increase.21
A few years ago, we initiated a research program aimed at
developing potential candidates as Mn2+-based MRI contrast
agents. We developed a series of ligands based on both
macrocyclic and acyclic frameworks, functionalized with
picolinate or acetate pendant arms. Some representative
members of the picolinate family are H3DPAAA, H2DPAMeA,
and their derivatives (see Chart 1).22,23 Among the macro-
cyclic ligands, we explored derivatives of 1,4,7-tetraazacyclon-
onate,24 containing two acetate groups (H2NO2A) incorporat-
ing different functions on the third N atom of the macrocyclic
unit,25 or cyclen-based ligands such as H2DO2A and related
systems.26 The Mn2+ complexes of DPAAA3− and NO2A2−
were shown to contain a water molecule coordinated to the
metal ion; DPAMeA yields a Mn2+ complex with two inner-
sphere water molecules.
The sulfonamide N atom N4 gives the strongest interaction
with the Mn2+ ion, while the tertiary amine N atom N2 appears
to provide a rather weak bond, as usually observed in
The N-ethylbenzenesulfonamide group was found to be
well-suited to provide Gd3+-based agents with pH-dependent
B
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
Scheme 1. Synthesis of the H3DPASAm and H3NO2ASAm
Ligands
Figure 1. X-ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O
with atom numbering. The ORTEP plot is at the 50% probability
level.
Table 1. Bond Distances of the Metal Coordination
Environments in Na[Mn(DPASAm)(H2O)]·2H2O
bond
bond distance (Å)
bond
bond distance (Å)
Mn1−N4
Mn1−O3
Mn1−O1
Mn1−N1
Mn1−N3
Mn1−O7
Mn1−N2
2.197(2)
Na1−O1
Na1−O3
Na1−O4
Na1−O6
Na1−O9
Na1−O10
2.5295(18)
2.3951(17)
2.4741(18)
2.3484(18)
2.381(2)
2.2188(15)
2.2600(15)
2.2609(19)
2.2716(18)
2.3457(16)
2.514(2)
complexes with tripodal ligands.29 The bond distances
involving the donor atoms of the picolinate groups are similar
to those reported for related seven-coordinate Mn2+ com-
plexes.24,29 The sulfonamide group is a relatively common
motif in Mn2+ coordination chemistry that is generally
coordinated through the N atom.30
2.5160(18)
The Na+ cations are coordinated to an oxygen atom of the
sulfonamide group (O6) and three oxygen atoms of the
carboxylate groups (O1, O3, and O4). The carboxylate group
containing O1 and O4 is involved in μ3-η1:η2 coordination
through O1 and O4, while the carboxylate group containing
O3 provides a μ2-η2 coordination.31 Six-coordination is
completed by the O atoms of two water molecules, resulting
in a distorted octahedral environment around the Na+ cations.
The Mn−O distance involving the μ2-η2 carboxylate (Mn−O3
= 2.2188(15) Å) is ca. 0.05 Å shorter than the Mn−O1 bond
(2.2600(15) Å), which implies a μ3-η1:η2 carboxylate.
Ligand Protonation Constants and Stability Con-
stants of the Mn2+ Complexes. The protonation constants
of the NO2ASAm3− ligand were determined by potentiometric
titrations at 25 °C in 0.15 M NaCl. However, potentiometry
did not allow an accurate determination of the values of log K1H
and log KH2 , likely because of partial (nonvisible) precipitation
of the ligand. Thus, both potentiometric and spectrophoto-
metric titrations were used for independent protonation
constant determination. Representative potentiometric titra-
tions curves are presented in Figures S1 and S2 in the
Supporting Information. The protonation constants of
DPASAm3− were determined using spectrophotometric
titrations, because precipitation was observed at the concen-
tration required for potentiometric experiments (>1 mM).
Table 2 compares the determined log KHi values with those
reported for the analogous ligands containing an acetate group
replacing the sulfonamide pendant (DPAAA3− and
NOTA3−).22,32,33 The data reported in the literature for
NOTA3− was measured using 0.1 M ionic strengths, and thus
we used potentiometry to determine the protonation constants
of this ligand, using a 0.15 M NaCl background electrolyte.
The absorption spectrum of DPASAm3− recorded at pH
0.82 is dominated by a band with a maximum at 269 nm,
characteristic of the picolinic acid chromophore (see Figure
2).34 Increasing the pH causes an increase in the intensity of
the absorption maximum, which experiences a slight shift to
longer wavelengths. The absorption spectra recorded in the pH
range of 0.82−12.45 were fitted to obtain the ligand
C
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
Table 2. Protonation Constants of the Ligands and Stability Constants of Their Mn2+ Complexes Determined by
Potentiometric and Spectrophotometric Titrations at 25 °C in 0.15 M NaCl
a
b
DPASAm3−
DPAAA3−
NO2ASAm3−
NOTA3− (I = 0.15 M)
NOTA3− (I = 0.1 M)
a
c
d
log KH1
10.36(1)
6.13(1)
3.68(1)
2.43(1)
13.53(1)
6.44(2)
−
7.26
3.90
3.29
1.77
13.19
2.90
11.26(7)
10.59(8)
12.05(6)
5.77(6)
3.30(6)
2.20(7)
15.6(1)
13.17 /11.41
a
c
d
d
d
e
log KH2
5.74 /5.74
a
a
c
log KH3
log KH4
4.57(5)/4.57(5)
2.65(5)/2.69(5)
15.29(5)
3.22 /3.16
c
1.96 /1.71
c
log KMnL
log KMnLH
log KMnLOH
16.30 /14.9
5.52(5)
11.97
8.98
f
pMn
7.82
6.63
7.97
a
b
Values obtained with spectrophotometric titrations at 25 °C in 0.15 M NaCl. Equilibrium constants in 0.15 M NaCl and 25 °C taken from ref 22.
c
d
Equilibrium constants in 0.1 M Me4NCl ionic strength and 25 °C taken from ref 32. Equilibrium constants in 0.1 M ionic strength and 25 °C
e
f
taken from ref 33. Stability constant in 0.1 M Me4NCl ionic strength and 25 °C taken from ref 39. Defined as −log[Mn2+]free at pH 7.4 for
[Mn2+]tot = [L]tot = 10−5 M.
The absorption band experiences drastic changes above pH
∼9, associated with a protonation constant of log K2H
=
10.59(8). However, the protonation event associated with a
protonation constant of log KH1 = 11.26(7) is characterized by
slight changes of the absorption spectrum. Thus, the first
protonation constant of NO2ASAm3− can be attributed to the
macrocyclic ring, while the second is assigned to the
sulfonamide group. Therefore, the sulfonamide groups in
DPASAm3− and NO2ASAm3− are characterized by very similar
protonation constants. Spectrophotometric titrations of
NO2ASAm3− in the pH range of 1.6−6.2 were also performed
(see Figure S5 in the Supporting Information). Although
spectral variations were not as pronounced as at basic pH, the
protonation constants LogKH3 and log K4H obtained by this
method show an excellent agreement with the potentiometric
data (see Table 2).
A comparison of the protonation constants associated with
the amine N atom of DPAAA3− (log K1H = 7.26) and
DPASAm3− (log KH2 = 6.13) shows that the substitution of the
acetate group by an N-ethylsulfonamide pendant causes a
decrease in the basicity of the amine N atom. A similar effect is
evident by comparing the log KH1 values determined for
NO2ASAm3− and NOTA3−.
Figure 2. Absorption spectra of a 6.55 × 10−5 M solution of
DPASAm3− recorded at different pH values (blue trace, pH 12.45; red
trace, pH 0.82). Inset shows changes in absorbance at 249 nm
(circles), fitted values (black line), and the species distribution
diagram.
protonation constants listed in Table 2. The absorption spectra
calculated for the different species present in solution are
shown in Figure S3 in the Supporting Information.
The first protonation constant determined for NOTA3− in
0.15 M NaCl is ca. 1 log K unit lower than that measured in
0.1 M Me4NCl,32 which likely reflects the formation of a
relatively stable Na+ complex. The remaining protonation
constants determined using these two ionic strength back-
grounds are in excellent agreement. Speciation diagrams
calculated for DPASAm3−, NO2ASAm3− and NOTA3− are
presented in Figures S6−S8 in the Supporting Information.
The stability constants of the Mn2+ complexes were
determined using spectrophotometric (DPASAm3−) or
potentiometric (NO2ASAm3− and NOTA3−) titrations. The
absorption spectra of the Mn2+:DPASAm3− system experience
important changes with pH (see Figure 3). The intensity of the
absorption maximum at 269 nm decreases in the pH range of
1.3−3.4 as the protonated complex [Mn(HDPASAm)] is
formed. The deprotonation and coordination of the
sulfonamide pendant induces a second decrease of the
absorbance at 269 nm above pH ∼4.5 until reaching pH ∼7.8.
The stability of the NOTA3− complex was also investigated
using potentiometry, for comparative purposes. The stability
constant of the Mn2+ complexes with NOTA3− determined in
0.15 M NaCl (log KMnL = 15.6) is slightly lower than that
reported in 0.1 M Me4NCl (log KMnL = 16.3). These values, in
The first protonation constant of the DPASAm3− ligand
H
(logK1 = 10.36) can be assigned to the protonation of the
sulfonamide N atom by comparison with the protonation
constants of DPAAA3−. This protonation constant is similar to
that reported for DO3A ligands containing sulfonamide (log
KH = 11.02)35 or dansyl (log KH = 10.8)36 groups. The second
protonation event involves the amine N atom of the ligand,
while log KH3 and log KH4 are associated with the protonation of
the carboxylate functions of the picolinate groups.37
The NO2ASAm3− ligand presents two protonation con-
stants with log KHi values of 11.26 and 10.59, which are related
to the protonation of the sulfonamide group and a N atom of
the macrocyclic fragment. However, an unambiguous attribu-
tion of each protonation event is not possible, based on
potentiometric data. Therefore, we performed spectrophoto-
metric titrations in the pH range of ca. 9−13. The absorption
spectrum of the ligand recorded at pH ∼9 presents a well-
defined maximum at 268 nm, with two additional components
at 262 and 276 nm (see Figure S4 in the Supporting
Information), typical of the sulfonamide chromophore.38 The
increase in the pH of the solution provokes an increase of the
intensity of the band, which becomes broader and ill-defined.
D
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
Figure 3. Absorption spectra of a 6.55 × 10−5 M solution of
DPASAm3− and 1 equiv of Mn2+ recorded at different pH values (blue
trace, pH 8.54; red trace, pH 0.82). Inset shows changes in
absorbance at 250 nm (circles) and species distribution diagram.
turn, are slightly higher than those reported initially by Sherry
et al. in 0.1 M Me4NCl (log KMnL = 14.9).39
The stability constants determined for the Mn2+ complexes
of DPASAm3− and NO2ASAm3− are comparable to those of
the parent carboxylate analogues DPAAA3− and NOTA3−.
However, the high basicity of the sulfonamide group provokes
a significant decrease of the conditional stability at
physiologically relevant pH values. This is reflected in the
calculated pMn values, which define the stability of the
complexes under specific conditions.40 The pMn value
determined for the NO2ASAm3− complex is one unit lower
than that of DPAAA3−, with an even more pronounced effect
observed by comparing the pMn values of the NO2ASAm3−
and NOTA3− complexes. The lower basicity of DPAAA3− is
also responsible for the high pMn value, compared to
NOTA3−, despite the fact that the log KMnL value is more
than 2 orders of magnitude higher for the latter.
Figure 4. Speciation diagrams calculated for the Mn2+:DPASAm3−
(top) and Mn2+:NO2ASAm3− (bottom) systems. [Mn2+] = [L] =
10−3 M. Circles represent the relaxivities of [Mn(DPASAm)]− (top)
and [Mn(NO2ASAm)]− (bottom) recorded at different pH values
(298 K, 10 MHz).
sociates below pH ∼5 (see Figure S9 in the Supporting
Information).
Both the [Mn(DPASAm)]− and [Mn(NO2ASAm)]−
complexes protonate at relatively high pH values, with log
Relaxometric Study. The potential response of [Mn-
(DPASAm)]− and [Mn(NO2ASAm)]− to changes in pH was
analyzed by measuring proton relaxivities (r1p) of aqueous
solutions of the complexes at 10 MHz and 25 °C. The
[Mn(NO2ASAm)]− complex presents a low and constant
relaxivity of 1.6 mM−1 s−1 in the pH range of 7−10 (see Figure
4). This relaxivity is characteristic of Mn2+ complexes that lack
coordinated water molecules (q = 0), the observed relaxivity
being the result of the outer-sphere contribution.41 The outer-
sphere contribution is the result of the dipolar coupling
between the electron spin of the paramagnetic center and the
nuclear spins of water molecules diffusing in the proximity of
the paramagnetic complex. Lowering the pH below pH 7
results in a sharp increase of r1p, which reaches a value of 11.5
mM−1 s−1 at pH 2.5. This agrees with the species distribution
diagram reported in Figure 4, which shows that protonation of
the complex occurs below pH ∼8 and complex dissociation
below pH ∼7. Thus, the increase in relaxivity observed below
pH ∼7 is likely related to both complex protonation and
dissociation. To confirm this, we recorded 1H nuclear magnetic
relaxation dispersion (NMRD) profiles at pH 4.0. The NMRD
profile shows the dispersion in the range of 3−20 MHz, typical
of small Mn2+ complexes, together with a second dispersion
below 1 MHz that is characteristic of the scalar contribution to
K
MnHL values of 6.43 and 5.52, respectively. These protonation
events can be ascribed to the protonation of the sulfonamide
group. The decrease of 4−5 orders of magnitude in the
protonation constants of the sulfonamides in the presence of
Mn2+ confirms the coordination of the sulfonamide N atom to
the metal ion, as observed in the solid state (see above). The
coordinated sulfonamide group is more basic in [Mn-
(DPASAm)]− than in [Mn(NO2ASAm)]−. This likely reflects
a stronger coordination of the sulfonamide N atom in the six-
coordinate [Mn(NO2ASAm)]− complex, compared to the
seven-coordinate [Mn(DPASAm)]− analogue.
The speciation diagrams calculated for the Mn2+:DPASAm3−
and Mn2+:NO2ASAm3− systems, using the equilibrium
constants given in Table 2, clearly confirm the higher stability
of the [Mn(DPASAm)]− complex, which protonates below pH
∼9 and exists largely as the protonated form in the pH range of
5−4 (see Figure 4). Below pH ∼4, complex dissociation
occurs. Conversely, [Mn(NO2ASAm)]− protonates at a lower
pH (less than ∼8.0), already dissociating below pH 7.0. As a
result, the maximum concentration of the protonated species is
observed at pH 5.1 (55%), with 18% and 27% of the total
manganese being present as the anionic complex and the free
metal ion, respectively. The [Mn(NOTA)]− complex dis-
E
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
relaxivity in the aquated [Mn(H2O)6]2+ complex (see Figure 5,
as well as Figure S10 in the Supporting Information).42,43 This
sum of the self-diffusion coefficients of water molecules and the
paramagnetic species, and water diffuses much faster than the
complex. Thus, these parameters support the reliability of the
analysis, indicating that the value assumed for aMnH is
reasonable.
The relaxivity of the DPASAm3− complex at pH 9 (10 MHz,
25 °C, 3.8 mM−1 s−1) is compatible with the presence of a
water molecule in the first coordination sphere of the metal
ion. Decreasing the pH of the solution causes an important
increase in relaxivity, which reaches a value of 8.9 mM−1 s−1 in
the pH range of 5.5−4.0 (Figure 4). This behavior can be
attributed to the protonation and decoordination of the
sulfonamide group, which allows a second water molecule to
enter the Mn2+ coordination environment, yielding a bis-
hydrated complex at low pH. The analysis of the r1p vs pH
dependence yields a pKa of 6.90
0.02. This value differs
slightly from that obtained with potentiometric measurements
(pKa = 6.43; recall Table 2), likely as a result of the different
ionic strengths used in the two experiments.
Figure 5. Comparison between the 1H NMRD profile of [Mn-
(NO2ASAm)]− recorded at pH 8.0 (blue circles), pH 4.0 (red
1
diamonds), and the H NMRD profile of [Mn(H2O)6]2+ reported in
1
The H NMRD profiles of the DPASAm3− complex were
ref 42. All data were acquired at 298 K.
recorded at three temperatures and pH values of 9.1 and 4.7
(see Figure 7), so that the nonprotonated [Mn(DPASAm)]−
and the protonated [Mn(HDPASAm)] species are largely
dominant (recall Figure 4). The relaxivities observed at low pH
are higher than those determined at basic pH over the entire
range of proton Larmor frequencies, which is consistent with
an increased hydration number upon complex protonation.
The inner-sphere contribution to relaxivity (r1p,is) in Mn2+
complexes is dependent on the relaxation rate of inner sphere
protons (TH1m), the mean residence time of a water molecule in
the inner coordination sphere of the metal ion (τm = 1/kex),
and the number of inner-sphere water molecules (q):47
indicates that, at pH 4, the complex is largely dissociated,
which is consistent with the speciation diagram shown in
Figure 4.
The relaxivity of the [Mn(NO2ASAm)]− complex was
1
further analyzed by recording H NMRD profiles at pH 8.0
and three different temperatures (283, 298, and 310 K) in the
q
1
1000
1
r
=
×
×
1p,is
T1Hm + τm
55.55
(1)
The relaxation rate of inner sphere protons in Mn2+
complexes other than the aqua ion is generally dominated by
the dipole−dipole (DD) mechanism:48
DD
2
2 γ 2g2μB
rMnH
i
j
y
z
i
j
y
z
μ
3τ
1 + ωI τ
7τ
1
T1m
2 i
y
0
I
d1
d2
j
j
j
j
z
z
z
z
j
j
j
z
z
z
j
j
j
j
z
z
z
z
=
S(S + 1)
+
2
1 + 4ω2τ
H
2
2
6
15 4π
k
{
d1
s d2
k
{
k
{
(2)
In eq 2, g is the electron g-factor, rMnH the distance between
the electron and nuclear spins, μB the Bohr magneton, γI the
1H gyromagnetic ratio, S the total spin (5/2 for a high-spin
Mn2+ complex), ωI the proton resonance frequency, and ωS
the Larmor frequency of the Mn2+ electron spin. The
correlation time τdi is given by eq 3, where τR is the rotational
correlation time, and Tie are the longitudinal (i = 1) and
transverse (i = 2) relaxation times of the electron spin.
Figure 6. 1H NMRD profiles of [Mn(NO2ASAm)]− recorded at pH
8.0. The solid lines correspond to the fit of the data as described in
the text.
proton Larmor frequency range of 0.01−120 MHz (Figure 6).
1H relaxivity decreases as the temperature increases, as
expected, because of the increase of the relative translational
44
1
1
τR
1
τm
1
diffusion coefficient DMnH
.
The relaxivities observed for
=
+
+
with i = 1, 2
[Mn(NO2ASAm)]− were analyzed using Freed’s outer-sphere
model.45 The fits of the NMRD data were performed by
assuming a value of 3.6 Å for aMnH, which is the distance of
closest approach of the proton nuclei of outer sphere water
molecules to the paramagnetic ion. All other parameters were
determined from the least-squares fit of the data (see Table 3).
The values of the relative diffusion coefficient (D2M9n8H) and its
activation energy (EDMnH) are very similar to those determined
for the self-diffusion of water in water (23 × 10−10 m2 s−1 and
17.6 kJ mol−1, respectively).46 This is expected, as D2M9n8H is the
τ
T
(3)
di
ie
The τR values characteristic of small Mn2+ complexes are
typically <100 ps, while τm is generally in the nanosecond time
scale. Furthermore, most often, TH1m is longer than τm, so that
water exchange has little effect in eq 1. As a result, 1H NMRD
profiles are quite often insensitive to water exchange.
Unfortunately, the low solubility of the DPASAm3− complex
prevented us from recording 17O NMR measurements, which
provide direct access to water exchange dynamics.49
F
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
1
Table 3. Parameters Obtained from the Fits of H NMRD Data
Value
b
c
parameter
(× 107 s−1
[Mn(HDPASAm)]
[Mn(DPASAm)]−
[Mn(NO2ASAm)]−
[Mn(DPAMeA)]
[Mn(DPAAA)]−
a
298
k
)
30.6
−
−
−
−
−
−
30.6
28.1
47.8
25.3
39.2
22.4
17.3
0.238
2.74
3.6
12.6
42.7
47.6
22.8
19.4
22.4
17.3
0.55
ex
a
ΔH⧧ (kJ mol−1
)
28.1
τ2R98 (ps)
72.0 0.8
23.9 0.5
99.4 4.4
21.6 1.8
14.3 0.06
Er (kJ mol−1
)
τ2v98 (ps)
56
2
15.6 0.9
22.3 0.2
a
a
298
D
(× 10−10 m2 s−1
EDMnH (kJ mol−1
)
22.3
22.3
23
MnH
a
a
)
23
23
5
Δ2 (× 1020 s−2
rMnH (Å)
aMnH (Å)
q298
)
0.130 0.010
0.76 0.05
1.7 0.1
a
a
a
2.741
2.741
−
2.756
a
a
a
a
3.6
3.6
3.6
3.6
a
a
a
a
2
1
0
2
1
a
b
c
Parameters fixed during the fitting procedure. Data from ref 23. Data from ref 22.
Figure 7. 1H NMRD profiles of the Mn2+ complex of DPASAm3− recorded at pH 9.1 (left) and 4.7 (right). The solid lines correspond to the fit of
the data, as described in the text.
1
The H NMRD profiles recorded at basic pH, where the
[Mn(DPASAm)]− species largely dominates the speciation in
solution, could be fitted very well by assuming that τm provides
a negligible contribution to eqs 1 and 3 (recall Table 3 and
Figure 7). Furthermore, we also fitted the temperature
dependence of r1p recorded at 32 MHz in the temperature
range of 283−323 K (see Figure S11 in the Supporting
Information). The fit of the data was performed by fixing some
of the parameters to reasonable values: the diffusion coefficient
and its activation energy were fixed to the values obtained for
[Mn(NO2ASAm)]−, aMnH was set to 3.6 Å, the number of
coordinated water molecules was assumed to be q = 1, and
rMnH was fixed to the average Mn···Hwater distance observed in
the X-ray structure of the complex described above. The fit of
the data provided a τ2R98 value that is very reasonable (99 ps),
considering the size of the complex.23 The parameters
characterizing the relaxation of the electron spin, the mean
square transient ZFS energy (Δ2), and its correlation time (τv)
take values that are in the normal range observed for Mn2+
complexes.
because of solubility limitations, we hypothesized that the
[Mn(HDPASAm)] complex must present a water exchange
rate very similar to [Mn(DPAMeA)], as the two species are
expected to present very similar coordination environments: a
pentagonal bipyramidal coordination, where the equatorial
plane is defined by the amine N atom and the donor atoms of
the two picolinate units, with two water molecules occupying
the axial positions.23
A very good fit of the experimental data was obtained by
298
fixing k
and ΔH⧧ to the values determined for [Mn-
ex
(DPAMeA)] from 17O NMR measurements (recall Table 3).23
This analysis yielded a τ2R98 value (72 ps) that is somewhat
shorter than at basic pH, likely because of increased flexibility
of the complex upon decoordination of the sulfonamide
pendant.
The value of Δ2 varies significantly, depending on the nature
of the axial donor, being lower for the complex at low pH,
where two water molecules occupy the axial positions. The
ZFS energy is very sensitive to the symmetry of the
coordination environment, increasing as the symmetry is
lowered.50 Thus, it is reasonable that the presence of two
different donor atoms in axial positions (water and
sulfonamide N atom) results in a higher ZFS energy. A similar
trend can be observed by comparing the Δ2 values reported for
[Mn(DPAMeA)] and [Mn(DPAAA)]− (recall Table 3). In the
latter case, a carboxylate oxygen atom occupies one of the axial
positions in the pentagonal bipyramidal coordination environ-
ment.22
1
The H NMRD profiles recorded at pH 4.7, where the
protonated [Mn(HDPASAm)] complex is the dominant
species, together with the temperature dependence of r1p at
32 MHz, were also analyzed quantitatively. Attempts to fit the
data using the same approach applied for the data at high pH
did not reproduce the experimental data well, particularly at
low temperatures. This suggests that the contribution of τm to
eq 3 is not negligible. In the absence of 17O NMR data,
G
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
synthesis reported in the literature.52 A solution of 4-
(trifluoromethyl)benzenesulfonyl chloride (0.500 g, 2.044 mmol) in
CH2Cl2 (20 mL) was added to a solution of ethylendiamine (1.228 g,
20.43 mmol) in CH2Cl2 (200 mL) at 0 °C. The mixture was stirred at
room temperature for 16 h and then extracted with 1 M HCl (3 × 100
mL). The combined aqueous phases were basified to pH 10 with
NaOH and extracted with CH2Cl2 (3 × 100 mL). The organic
extracts were dried with Na2SO4 and concentrated, affording 1 as a
CONCLUSIONS
■
In this work, we have presented two ligands containing a
sulfonamide pendant and their Mn2+ complexes, which were
conceived as potential pH-responsive MRI agents. In the case
of [Mn(DPASAm)]−, protonation of the sulfonamide group
was observed close to the physiologically relevant pH range.
Complex protonation provokes a 2.3-fold increase in 1H
relaxivity from r1p = 3.8 mM−1 s−1 at pH 9.0 to r1p = 8.9 mM−1
s−1 at pH 4.0 (20 MHz, 25 °C). Relaxometric and
potentiometric studies are in good mutual agreement, showing
that the complex is perfectly stable in the pH range of 4−10.
The X-ray structure of the [Mn(DPASAm)]− complex
evidences coordination of the deprotonated sulphonamide N
atom, as well as the presence of a coordinated water molecule.
The relaxometric characterization showed that the relaxivity
increase observed upon complex protonation is related to the
coordination of a second water molecule.
1
white solid (0.502 g, 1.871 mmol, 92% yield). H NMR (300 MHz,
CDCl3) δ 8.01 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 3.00 (t, J
= 5.6 Hz, 2H), 2.93−2.71 (m, 2H). 19F NMR (282 MHz, CDCl3) δ
−63.1. MS (ESI+): m/z calcd for C9H12F3N2O2S [M + H]+: 269.06.
Found: 269.06.
Diethyl 6,6′-(((2-((4-(trifluoromethyl)phenyl)sulfonamido)-
ethyl)azanediyl)bis(methylene))dipicolinate (2). A solution of
ethyl 6-(chloromethyl)picolinate (0.2981 g, 1.493 mmol) in dry
CH3CN (3 mL) was added dropwise to a solution of compound 1
(0.2001 g, 0.7459 mmol) containing K2CO3 (0.2577 g, 1.864 mmol)
in dry CH3CN (35 mL). A catalytic amount of KI was added and the
mixture was purged with an argon flow while stirred at room
temperature for 6 days. The reaction mixture was filtered and the
filtrate was evaporated to dryness in vacuo. The product was purified
by MPLC on neutral alumina (CH2Cl2:MeOH 90:10 (v:v)) and
isolated as a yellow oil (0.2752 g, 0.4628 mmol, 62% yield). 1H NMR
(300 MHz, CDCl3) δ 8.04 (m, 2H), 7.97 (m, 2H), 7.45−7.80 (m,
The [Mn(NO2ASAm)]− complex is also protonated,
although the sulfonamide group was found to be considerably
less basic than in [Mn(DPASAm)]− (pKa = 5.5 and 6.4,
respectively). This can be attributed to a stronger Mn−
Nsulfonamide interaction in [Mn(NO2ASAm)]−, because of the
lower coordination number of the metal ion. Besides the lower
pKa, [Mn(NO2ASAm)]− is characterized by a lower condi-
tional stability than [Mn(DPASAm)]−, associated with a high
basicity of the macrocyclic structure. As a result, the
[Mn(NO2ASAm)]− complex dissociates at a relatively high
pH. These results highlight that ligand basicity plays a key role
in the stability of potential Mn2+ MRI contrast agents, so that
this issue should be carefully considered for ligand design.
Overall, the results reported in this paper provide a proof-of-
concept on the design of pH-responsive Mn2+ MRI probes
based on reversible binding of sulfonamide groups, although
further probe optimization to improve kinetic inertness is
required for practical applications, as the [Mn(DPASAm)]−
complex dissociates very quickly when challenged with an
excess of Zn2+ (see Figure S35 in the Supporting Information).
Another aspect that must be considered is the biodistribution
of the probe, because the intensity of the MRI signal will be
dependent both on the protonation state of the complex and
the local concentration of the agent.
3
6H), 7.11 (b, 1H), 4.51 (q, J = 7.1 Hz, 4H), 3.89 (s, 4H), 3.14 (b,
3
2H), 2.84 (m, 2H), 1.46 (t, J = 7.1 Hz, 6H). 19F NMR (282 MHz,
CDCl3) δ −63.0. 13C NMR (75.5 MHz, CDCl3) δ 165.0, 159.4,
147.6, 144.4, 137.4, 133.5 (1JC−F = 32.2 Hz), 127.5, 126.3, 125.9,
123.5, 61.8, 59.5, 53.8, 41.3, 14.2. MS(ESI+): m/z calcd for
C27H29F3N4NaO6S [M + Na]+: 617.17. Found: 617.17.
H3DPASAm. Compound 2 (0.2501 g, 0.4206 mmol) was dissolved
in 6 M HCl (20 mL) and the mixture was heated at 55 °C for 16 h.
The acid was evaporated, water (3 mL) was added and evaporated
again twice to remove most of the HCl. The ligand was isolated by
1
filtration as a white solid (0.1435 g, 0.2528 mmol, 60% yield). H
NMR (500 MHz, D2O, pH 14) δ 7.50−7.65 (m, 8H), 7.18 (m, 2H),
3.60 (s, 4H), 2.63 (m, 2H), 2.33 (m, 2H). 19F NMR (376 MHz, D2O,
pH 14) δ −62.5. 13C NMR (126 MHz, D2O, pH 14) δ 172.7, 168.4,
157.6, 152.5, 146.5, 138.1, 126.5, 125.7, 125.3, 122.2, 60.0, 55.6, 42.2.
HRMS (ESI−): m/z calcd for C23H20F3N4O6S [M−H]−: 537.1061.
Found: 537.1064. Elemental analysis: calculated for C23H21F3N4O6S·
0.8HCl: C: 48.84; H: 3.69; N: 9.54. Found: C: 48.66; H: 3.87; N:
9.87. IR (ATR, ν[cm−1]): 1738 ν(CO), 1575 ν(CN), 1356,
1322, 1164 ν(SO).
N-(2-Bromoethyl)-4-(trifluoromethyl)benzenesulfonamide
(3). The synthesis followed the procedure reported for closely related
compounds.53 2-Bromoethan-1-amine hydrobromide (0.4702 g, 2.295
mmol, 1 equiv) and triethylamine (0.640 mL, 4.5918 mmol, 2 equiv)
were dissolved in CH2Cl2 (15 mL). 4-(Trifluoromethyl)-
benzenesulfonyl chloride (0.5614 g, 2.295 mmol, 1 equiv) dissolved
in CH2Cl2 (2 mL) was added dropwise to the solution while stirring
at room temperature. The yellowish solution was stirred for 24 h. The
solution was washed with 1 M HCl (3 × 15 mL) followed by brine
(10 mL). The organic layer was dried using Na2SO4, filtered and the
solvent was evaporated. The white solid was washed with acidified
water (pH 5; 2 × 10 mL) and dried (0.6154 g, 1.853 mmol, 81%
yield). 1H NMR (300 MHz, CDCl3): δ 8.02 (d, 3J = 8.5 Hz, 2H), 7.81
EXPERIMENTAL SECTION
■
Materials and Methods. Ethyl 6-(chloromethyl)picolinate51 was
prepared following the literature methods. Di-tert-butyl 2,2′-(1,4,7-
triazonane-1,4-diyl)diacetate (NO2AtBu) was purchased from
CheMatech (Dijon, France). All other reagents were purchased
from Aldrich Chemical Co.
High-resolution electrospray-ionization time-of-flight ESI-TOF
mass spectra were recorded using a LC-Q-q-TOF Applied Biosystems
QSTAR Elite spectrometer in positive and negative mode. Mass
spectra recorded using electron impact ionization were recorded with
a Thermo MAT95XP instrument. Elemental analyses were accom-
plished on a ThermoQuest Flash EA 1112 elemental analyzer.
Medium performance liquid chromatography (MPLC) was per-
formed using a Puriflash XS 420 instrument equipped with a reverse-
phase Puriflash 15C18HP column (60 Å, spherical 15 μm, 20 g) and
UV-DAD detection at 210 and 254 nm, and operating at a flow rate of
10 mL/min. Aqueous solutions were lyophilized using a Telstar
3
(d, J = 8.5 Hz, 2H), 5.24 (b, 1H), 3.43 (m, 4H). 19F NMR (282
MHz, CDCl3): −63.1. 13C NMR (75.5 MHz, CDCl3): δ 143.5, 127.5,
126.5 (2JC−F = 3.8 Hz), 44.6, 31.5. MS (EI, 70 eV): m/z calcd for
C9H9BrF3NO2S [M+]: 330.9. Found: 330.9. Elemental analysis:
Calculated for C9H9BrF3NO2S: C: 32.55; H: 2.73; N: 4.22; S: 9.65.
Found: C: 33.07; H: 2.62; N: 3.93; S: 9.54.
1
Cryodos-80 apparatus. H, 13C, and 19F NMR spectra of the ligands
2,2′-(7-(2-((4-(Trifluoromethyl)phenyl) sulfonamido)ethyl)-
1,4,7-triazonane-1,4-diyl)diacetate (4). Di-tert-Butyl 2,2′-(1,4,7-
triazacyclononane-1,4-diyl)diacetate (0.1999 g, 0.5592 mmol, 1
equiv) was dissolved in dry CH3CN (10 mL) and K2CO3 (0.1932
g, 1.398 mmol) was added under argon. The mixture was stirred at
room temperature and compound 3 (0.1857 g, 0.5591 mmol, 1 equiv)
and their precursors were recorded at 298 K, using Bruker AVANCE
III 300 or Bruker Avance 500 spectrometers. 19F chemical shifts were
referenced by using sodium triflate on a D2O solvent (δ 75.6 ppm).
N-(2-Aminoethyl)-4-(trifluoromethyl)benzenesulfonamide
(1). This compound was prepared using a slight modification of the
H
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
dissolved in CH3CN (5 mL) was added. The mixture was heated and
stirred at 60 °C 24 h and then the carbonate was removed by
filtration. The evaporation of the solvent yielded a yellowish oil that
was purified on neutral alumina using MPLC (CH2Cl2/MeOH
(10%)). The fractions containing the product were concentrated
The HypSpec2014 program was used to determine the equilibrium
constants and the spectra of the absorbing species.54
Relaxometric Measurements. 1/T1 1H nuclear magnetic
relaxation dispersion (NMRD) profiles were measured with a fast-
field cycling (FFC) Stelar SmarTracer relaxometer over a continuum
of magnetic field strengths from proton Larmor frequencies of 0.01−
10 MHz, with an uncertainty in 1/T1 of ca. 1%. Data in the 20−120
MHz range were collected with a high-field relaxometer (Stelar) that
was equipped with the HTS-110 3T metrology cryogen-free
superconducting magnet. The analyses were performed by using the
standard inversion recovery sequence with a typical 90° pulse width of
3.5 μs and the reproducibility of the data was within 0.5%. The
temperature was controlled with a Stelar VTC-91 heater airflow
equipped with a copper-constantan thermocouple (uncertainty of
0.1 K).
1
affording a yellow oil (0.3297 g, 0.5416 mmol, 97% yield). H NMR
(300 MHz, CDCl3) δ 8.00 (d, 3J = 8.3 Hz, 2H), 7.75 (d, 3J = 8.3 Hz,
3
2H), 3.31 (s, 4H), 3.02 (t, J = 5.4 Hz, 2H), 2.87−2.59 (m, 14H),
1.44 (s, 18H). 19F NMR (282 MHz, CDCl3): δ −63.0. 13C NMR
(126 MHz, CDCl3): 171.3, 144.4, 133.8 (1J = 32.9 Hz), 127.5, 126.0
(2J = 3.6 Hz), 80.9, 58.9, 56.0, 55.3, 55.0, 54.7, 28.2. HRMS (ESI+):
m/z Calcd for C27H44F3N4O6S [M + H]+: 609.2928. Found:
609.2916. IR (ATR, ν[cm−1]): 1733 ν(CO), 1323, 1159, 1129
ν(SO).
H3NO2ASAm. Compound 4 (0.1240 g, 0.2037 mmol) was
dissolved in 3 M HCl (20 mL) and the mixture was stirred 24 h at
room temperature. The acid was evaporated, water (3 mL) was added
and evaporated again twice to remove most of the HCl. The product
was lyophilized to afford a white solid (0.1096 g, 0.1838 mmol, 90%
yield). 1H NMR (500 MHz, D2O, pH 1.5): 8.07 (d, 3J = 8.3 Hz, 2H),
7.99 (d, 3J = 8.3 Hz, 2H), 3.83 (s, 4H), 3.53−3.30 (m, 12H), 3.18 (s,
4H). 19F NMR (282 MHz, D2O, pH 1.5): δ −63.1. 13C NMR (126
MHz, D2O, pH 1.5): 173.9, 140.8, 134.5 (1JC−F = 32.7 Hz), 127.6,
126.9 (2JC−F = 3.7 Hz), 56.4, 55.4, 51.1, 49.9, 48.5, 38.3. HRMS
(ESI+): m/z calcd for C19H28F3N4O6S [M + H]+: 497.1676. Found:
497.1668. Elemental analysis: Calculated for C19H27F3N4O6S·2HCl·
1.5H2O: C: 38.26; H: 5.41; N: 9.39; S: 5.38. Found: C: 38.38; H:
5.14; N: 9.03; S: 5.03. IR (ATR, ν[cm−1]): 1732 ν(CO), 1321,
1163 ν(SO).
The Mn2+ complexes were prepared by mixing solutions of MnCl2
and the corresponding ligand, using a ∼5% molar excess of the latter
to avoid the presence of free Mn2+ in solution. The pH was adjusted
to ∼7.0 with HCl or NaOH. The concentration of Mn2+ chelates was
assessed by 1H NMR measurements (Bruker Advance III
Spectrometer equipped with a wide-bore 11.7 T magnet), using the
well-established Evans’ method.58
Table 4. Crystal Data and Structure Refinement Details
parameter
value
formula
molecular weight, MW
C23H26F3MnN4NaO10S
685.47
crystal system
triclinic
Potentiometric and Spectrophotometric Measurements.
Ligand protonation constants and stability and protonation constants
of the Mn2+ complexes were determined by potentiometric or
spectrophotometric titrations, using the HYPERQUAD2013 pro-
gram.54 All measurements were performed at 298 K with an ionic
strength adjusted to 0.15 M using NaCl. Stability constants of the
metal complexes were obtained from titrations at a metal-to-ligand
concentration ratio of 1:1. The MnCl2 solution was standardized by
titration with EDTA at pH 10 (NH3/NH4Cl buffer) in the presence
of triethanolamine to avoid manganese precipitation. Eriochrome
Black T was employed as an indicator.55 The concentration of the
solution was double-checked by titrating chloride with AgNO3, using
potassium chromate as an indicator.55
Potentiometric titrations were performed with a dual-wall cell
thermostated at 298 K using circulating water. All measurements were
performed with magnetic stirring to homogenize the solutions
(starting volume of 10 mL), while bubbling nitrogen on the surface
of the solution to avoid CO2 absorption. The concentration of the
ligand in the titration cell was 2−3 mM, while titrations covered the
pH range of ca. 2.0 to 12.0. The solution of the ligand, in the absence
and presence of the metal ion, was titrated with standard solutions of
hydrochloric acid or sodium hydroxide. The titrant was delivered with
a Crison microBu 2030 automatic buret, using 2.5 or 1.0 mL syringes.
A Crison micropH 2000 pH meter, connected to a glass electrode
(Radiometer pHG211) and a reference electrode (Radiometer
REF201), was used to measure the electromotive force (emf) values.
The procedures used for electrode calibration were described in detail
elsewhere.56 The formation of the Mn2+ complexes of DPASAm3−
and NO2ASAm3− was fast. In the case of the NOTA3− complex, the
equilibrium was attained more slowly, taking 5−10 min, depending on
the pH. Back titrations were performed to confirm that the
equilibrium was attained.
space group
P1
̅
a
b
c
α
8.9108(6) Å
9.2961(7) Å
17.0716(12) Å
97.133(2)°,
95.201(3)°
97.178(2)°
1384.08(17) Å3
702
β
γ
V
F(000)
Z
Dcalc
μ
2
1.645 g cm−3
5.494 mm−1
4.84°−71.28°
0.0485
θ range
Rint
measured reflections
goodness of fit, GOF on F2
R1
a
22598
1.045
0.0401
wR2 (all data)
largest differences
0.1036
0.504 e Å−3 (peak), −0.509 eÅ−3 (hole)
a
Of which 5243 were independent and 5047 were unique, with I >
2σ(I).
X-ray Diffraction Measurements. A single crystal of Na[Mn-
(DPASAm)(H2O)]·2H2O was analyzed via XRD. Crystallographic
data were collected at room temperature using a Bruker Smart 6000
CCD detector and Cu Kα radiation (λ = 1.54178 Å) generated by an
Incoatec microfocus source equipped with Incoatec Quazar MX
optics. The software APEX259 was used for collecting frames of data,
indexing reflections, and the determination of lattice parameters,
SAINT60 for integration of the intensity of reflections, and SADABS61
for scaling and empirical absorption correction. The structure was
solved by dual-space methods using the program SHELXT.62 All non-
hydrogen atoms were refined with anisotropic thermal parameters by
full-matrix least-squares calculations on F2 with the SHELXL-2018/3
program.63 Hydrogen atoms were inserted at calculated positions and
constrained with isotropic thermal parameters, except for the H atom
of the water molecules, which were located from a Fourier-difference
The UV−vis absorption spectra were recorded with a Uvikon-XS
(Bio-Tek Instruments) double-beam spectrophotometer, using cells
with a path length of 1 cm. The spectra were recorded in the range
230−310 nm (80 wavelengths) for every solution. The pH of the
solutions below 2.8 or above 11.9 was adjusted directly with standard
solutions of hydrochloric acid or sodium hydroxide. Otherwise,
different buffers were used to facilitate pH adjustment: borax, 0.0125
M (pH range 8−10.8); phosphate (pH ranges of 5.8−8.0, 0.05 M;
and 10.9−12.0, 0.025 M) or acetate (pH range of 3.5−5.3, 0.02 M).57
I
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
map and refined isotropically. Crystal data and structure refinement
details are given in Table 4.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c02098.
■
sı
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors C.P.-I. and D.E.-G. thank Ministerio de Economia y
Competitividad (No. CTQ2016-76756-P) and Xunta de
Galicia (Nos. ED431B 2017/59 and ED431D 2017/01) for
generous financial support. R.U.-V. thanks Xunta de Galicia
(No. ED481A-2018/314) for funding her Ph.D. contract.
M.B., F.C., and D.L. are grateful to Universita del Piemonte
Orientale per financial support (No. FARC 2019). M.M.-C.
thanks Ministerio de Ciencia e Innovacion and Ministerio de
Universidades for the Distinguished Research Contract
Potentiometric titration curves, speciation diagrams,
spectrophotometric titrations, relaxometric data, NMR
and MS of ligands and their precursors (PDF)
■
́
Accession Codes
CCDC 2015848 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
̀
́
“Beatriz Galindo” (No. BEAGAL18/00144).
AUTHOR INFORMATION
Corresponding Authors
REFERENCES
■
■
(1) Wahsner, J.; Gale, E. M.; Rodríguez-Rodríguez, A.; Caravan, P.
Chemistry of MRI Contrast Agents: Current Challenges and New
Frontiers. Chem. Rev. 2019, 119, 957−1057.
́
́
Carlos Platas-Iglesias − Centro de Investigacions Cientıficas
́
Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Coruna,
̃
̃
(2) The Chemistry of Contrast Agents in Medical Magnetic Resonance
́
́
Imaging, 2nd Edition; Merbach, A., Helm, L., Toth, E., Eds.; Wiley,
2013.
(3) Lauterbur, P. C.; Mendoça-Dias, M. H.; Rudin, A. A.
Augmentation of Tissue Water Proton Spin-Lattice Relaxation Rates
by In Vivo Addition of Paramagnetic Ions, in Frontiers of Biological
Energetics; Dutton, P. O., Leigh, J., Scarpa, A., Eds.; Academic Press:
New York, 1978; pp 752−759.
Spain; orcid.org/0000-0002-6989-9654;
Email: carlos.platas.iglesias@udc.es
Mauro Botta − Dipartimento di Scienze e Innovazione
̀
Tecnologica, Universita del Piemonte Orientale “A. Avogadro”,
15121 Alessandria, Italy; orcid.org/0000-0003-4192-
355X; Email: mauro.botta@uniupo.it
(4) Brady, T. J.; Gebhardt, M. C.; Pykett, I. L.; Buonanno, F. S.;
Newhouse, J. H.; Burt, C. T.; Smith, R. J.; Mankin, H. J.; Kistler, J. P.;
Goldman, M. R.; Hinshaw, W. S.; Pohost, G. M. NMR Imaging of
Forearms in Healthy Volunteers and Patients with Giant-Cell Tumor
of Bone. Radiology 1982, 144, 549−552.
(5) Goldman, M. R.; Brady, T. J.; Pykett, I. L.; Burt, C. T.;
Buonanno, F. S.; Kistler, J. P.; Newhouse, J. H.; Hinshaw, W. S.;
Pohost, G. M. Quantification of Experimental Myocardial Infarction
Using Nuclear Magnetic Resonance Imaging and Paramagnetic Ion
Contrast Enhancement in Excised Canine Hearts. Circulation 1982,
66, 1012−1016.
Authors
Rocío Uzal-Varela − Centro de Investigacions Cientıficas
́
́
́
Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Corun
Spain
Aurora Rodríguez-Rodríguez − Centro de Investigacions
̃
̃
a,
́
́
́
Cientıficas Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Coruna,
Spain; orcid.org/0000-0002-4951-4470
Miguel Martínez-Calvo − Centro de Investigacions Cientıficas
̃
̃
́
́
(6) Young, I. R.; Clarke, G. J.; Baffles, D. R.; Pennock, J. M.; Doyle,
F. H.; Bydder, G. M. Enhancement of Relaxation Rate with
Paramagnetic Contrast Agents in NMR Imaging. Clin. Imag. 1981,
5, 543−547.
́
Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Corun
Spain; orcid.org/0000-0001-7059-0956
̃
̃
a,
Fabio Carniato − Dipartimento di Scienze e Innovazione
(7) Carr, D. H.; Brown, J.; Bydder, G. M.; Weinmann, H. J.; Speck,
U.; Thomas, D. J.; Young, I. R. Intravenous Chelated Gadolinium as a
Contrast Agent in NMR Imaging of Cerebral Tumours. Lancet 1984,
323, 484−486.
̀
Tecnologica, Universita del Piemonte Orientale “A. Avogadro”,
15121 Alessandria, Italy; orcid.org/0000-0002-6268-1687
Daniela Lalli − Dipartimento di Scienze e Innovazione
(8) Sarka, L.; Burai, L.; Brucher, E. The Rates of the Exchange
̈
̀
Tecnologica, Universita del Piemonte Orientale “A. Avogadro”,
Reactions between [Gd(DTPA)]2‑ and the Endogenous Ions Cu2+
and Zn2+: A Kinetic Model for the Prediction of the In Vivo Stability
of [Gd(DTPA)]2‑, Used as a Contrast Agent in Magnetic Resonance
Imaging. Chem. - Eur. J. 2000, 6, 719−724.
15121 Alessandria, Italy
́
́
́
David Esteban-Gomez − Centro de Investigacions Cientıficas
́
Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Corun
Spain; orcid.org/0000-0001-6270-1660
̃
̃
a,
(9) Sherry, A. D.; Wu, Y. The Importance of Water Exchange Rates
in the Design of Responsive Agents for MRI. Curr. Opin. Chem. Biol.
2013, 17, 167−174.
(10) Grobner, T. Gadolinium - A Specific Trigger for the
Development of Nephrogenic Fibrosing Dermopathy and Nephro-
genic Systemic Fibrosis? Nephrol., Dial., Transplant. 2006, 21, 1104−
1108.
(11) Marckmann, P.; Skov, L.; Rossen, K.; Dupont, A.; Damholt, M.
B.; Heaf, J. G.; Thomsen, H. S. Nephrogenic Systemic Fibrosis:
Suspected Causative Role of Gadodiamide Used for Contrast-
Enhanced Magnetic Resonance Imaging. J. Am. Soc. Nephrol. 2006,
17, 2359−2362.
́
́
Isabel Brandariz − Centro de Investigacions Cientıficas
́
Avanzadas (CICA) and Departamento de Quimica
Fundamental, Universidade da Coruna, 15008 A Corun
Spain
̃
̃
a,
́
́
́
Paulo Perez-Lourido − Departamento de Quımica Inorganica,
Facultad de Ciencias, Universidade de Vigo, 36310 Pontevedra,
Spain; orcid.org/0000-0003-2281-3064
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c02098
J
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
(12) (a) Kanal, E.; Tweedle, M. F. Residual or Retained
Gadolinium: Practical Implications for Radiologists and Our Patients.
Radiology 2015, 275, 630−634. (b) Fraum, T. J.; Ludwig, D. R.;
Bashir, M. R.; Fowler, K. J. Gadolinium-Based Contrast Agents: A
Comprehensive Risk Assessment. J. Magn. Reson. Imaging 2017, 46,
338−353.
Picolinate-Containing Macrocyclic Mn2+ Complexes as Potential MRI
Contrast Agents. Inorg. Chem. 2014, 53, 5136−5149.
(25) (a) Pujales-Paradela, R.; Carniato, F.; Esteban-Gomez, D.;
Botta, M.; Platas-Iglesias, C. Controlling water exchange rates in
potential Mn2+-based MRI agents derived from NO2A2−. Dalton
Trans. 2019, 48, 3962−3972. (b) Patinec, V.; Rolla, G. A.; Botta, M.;
Tripier, R.; Esteban-Gomez, D.; Platas-Iglesias, C. Hyperfine
Coupling Constants on Inner-Sphere Water Molecules of a
Triazacyclononane-based Mn(II) Complex and Related Systems
Relevant as MRI Contrast Agents. Inorg. Chem. 2013, 52, 11173−
11184.
(13) Le Fur, M.; Caravan, P. The Biological Fate of Gadolinium-
Based MRI Contrast Agents: A Call to Action for Bioinorganic
Chemists. Metallomics 2019, 11, 240−254.
(14) Viswanathan, S.; Kovacs, Z.; Green, K. N.; Ratnakar, S. J.;
Sherry, A. D. Alternatives to Gadolinium-Based Metal Chelates for
Magnetic Resonance Imaging. Chem. Rev. 2010, 110, 2960−3018.
(15) (a) Gupta, A.; Caravan, P.; Price, W. S.; Platas-Iglesias, C.;
Gale, E. M. Applications for Transition-Metal Chemistry in Contrast-
Enhanced Magnetic Resonance Imaging. Inorg. Chem. 2020, 59,
6648−6678. (b) Drahos, B.; Lukes, I.; Toth, E. Manganese(II)
Complexes as Potential Contrast Agents for MRI. Eur. J. Inorg. Chem.
2012, 2012, 1975−1986. (c) Pan, D.; Schmieder, A. H.; Wickline, S.
A.; Lanza, G. M. Manganese-Based MRI Contrast Agents: Past,
Present, and Future. Tetrahedron 2011, 67, 8431−8444.
́
́
(26) Forgacs, A.; Tei, L.; Baranyai, Z.; Esteban-Gomez, D.; Platas-
Iglesias, C.; Botta, M. Optimising the relaxivities of Mn2+ complexes
by targeting human serum albumin (HSA). Dalton Trans. 2017, 46,
8494−8504.
(27) (a) Lowe, M. P.; Parker, D.; Reany, O.; Aime, S.; Botta, M.;
Castellano, G.; Gianolio, E.; Pagliarin, R. pH-Dependent Modulation
of Relaxivity and Luminescence in Macrocyclic Gadolinium and
Europium Complexes Based on Reversible Intramolecular Sulfona-
mide Ligation. J. Am. Chem. Soc. 2001, 123, 7601−7609. (b) Lowe,
M. P.; Parker, D. Controllable pH Modulation of Lanthanide
Luminescence by Intramolecular Switching of the Hydration State.
(16) (a) Gale, E. M.; Atanasova, I. P.; Blasi, F.; Ay, I.; Caravan, P. A
Manganese Alternative to Gadolinium for MRI Contrast. J. Am. Chem.
Soc. 2015, 137, 15548−15557. (b) Rolla, G. A.; Platas-Iglesias, C.;
́
1
Chem. Commun. 2000, 707−708. (c) Takacs, A.; Napolitano, R.;
Botta, M.; Tei, L.; Helm, L. H and 17O NMR Relaxometric and
́
́
́
́
Purgel, M.; Benyei, A. C.; Zekany, L.; Brucher, E.; Toth, I.; Baranyai,
̈
Computational Study on Macrocyclic Mn(II) Complexes. Inorg.
Chem. 2013, 52, 3268−3279. (c) Su, H.; Wu, C.; Zhu, J.; Miao, T.;
Wang, D.; Xia, C.; Zhao, X.; Gong, Q.; Song, B.; Ai, H. Rigid Mn(II)
Chelate as Efficient MRI Contrast Agent for Vascular Imaging. Dalton
Trans. 2012, 41, 14480−14483. (d) Phukan, B.; Mukherjee, C.;
Goswami, U.; Sarmah, A.; Mukherjee, S.; Sahoo, S. K.; Moi, S. C. A
New Bis(aquated) High Relaxivity Mn(II) Complex as an Alternative
to Gd(III)-Based MRI Contrast Agent. Inorg. Chem. 2018, 57, 2631−
Z.; Aime, S. Solution Structures, Stabilities, Kinetics, and Dynamics of
DO3A and DO3A−Sulphonamide Complexes. Inorg. Chem. 2014, 53,
2858−2872. (d) Moriggi, L.; Yaseen, M. A.; Helm, L.; Caravan, P.
Serum Albumin Targeted, pH-Dependent Magnetic Resonance
Relaxation Agents. Chem. - Eur. J. 2012, 18, 3675−3686.
(28) (a) Casanova, D.; Alemany, P.; Bofill, J. M.; Alvarez, S. Shape
and Symmetry of Heptacoordinate Transition-Metal Complexes:
Structural Trends. Chem. - Eur. J. 2003, 9, 1281−1295. (b) Regueiro-
̂
2638. (e) Ndiaye, D.; Sy, M.; Pallier, A.; Meme, S.; de Silva, I.;
́
́
Figueroa, M.; Lima, L. M. P.; Blanco, V.; Esteban-Gomez, D.; de Blas,
̀
́
Lacerda, S.; Nonat, A. M.; Charbonniere, L. J.; Toth, E.
Unprecedented Kinetic Inertness for a Mn2+-Bispidine Chelate: A
Novel Structural Entry for Mn2+-Based Imaging Agents. Angew. Chem.,
Int. Ed. 2020, 59, 11958−11963.
A.; Rodríguez-Blas, T.; Delgado, R.; Platas-Iglesias, C. Reasons
Behind the Relative Abundances of Heptacoordinate Complexes
along the Late First-Row Transition Metal Series. Inorg. Chem. 2014,
53, 12859−12869.
́
(17) (a) Rodríguez, E.; Roig, A.; Molins, E.; Arus, C.; Quintero, M.
́
̃
R.; Cabanas, M. E.; Cerdan, S.; Lopez-Larrubia, P.; Sanfeliu, C. In
(29) (a) Huang, Q.; Zhai, B. Crystal Structure, Thermal and
Magnetic Studies of a Dinuclear Mn(II) Complex with Decadentate
Picolinate Based Ligand. J. Coord. Chem. 2007, 60, 2257−2263.
̈
(b) Khannam, M.; Weyhermuller, T.; Goswami, U.; Mukherjee, C. A
Highly Stable L-Alanine-Based Mono(aquated) Mn(II) Complex as a
vitro Characterization of an Fe8 Cluster as Potential MRI Contrast
Agent. NMR Biomed. 2005, 18, 300−307. (b) Wang, H.; Jordan, V.
C.; Ramsay, I. A.; Sojoodi, M.; Fuchs, B. C.; Tanabe, K. K.; Caravan,
P.; Gale, E. M. Molecular Magnetic Resonance Imaging Using a
Redox-Active Iron Complex. J. Am. Chem. Soc. 2019, 141, 5916−
5925.
(18) Lux, J.; Sherry, A. D. Advances in Gadolinium-Based MRI
Contrast Agent Designs for Monitoring Biological Processes in vivo.
Curr. Opin. Chem. Biol. 2018, 45, 121−130.
T1-Weighted MRI Contrast Agent. Dalton Trans. 2017, 46, 10426−
́
́
10432. (c) Gerey, B.; Gennari, M.; Goure, E.; Pecaut, J.; Blackman,
A.; Pantazis, D.; Neese, F.; Molton, F.; Fortage, J.; Duboc, C.;
Collomb, M.-N. Calcium and Heterometallic Manganese−Calcium
Complexes Supported by Tripodal Pyridinecarboxylate Ligands:
Structural, EPR and Theoretical Investigations. Dalton Trans. 2015,
44, 12757−12770. (d) Martin-Diaconescu, V.; Gennari, M.; Gerey,
B.; Tsui, E.; Kanady, J.; Tran, R.; Pecaut, J.; Maganas, D.; Krewald, V.;
Goure, E.; Duboc, C.; Yano, J.; Agapie, T.; Collomb, M.-N.; DeBeer,
S. Ca K-Edge XAS as a Probe of Calcium Centers in Complex
Systems. Inorg. Chem. 2015, 54, 1283−1292.
(19) Angelovski, G. What We Can Really Do with Bioresponsive
MRI Contrast Agents. Angew. Chem., Int. Ed. 2016, 55, 7038−7046.
(20) Heffern, M. C.; Matosziuk, L. M.; Meade, T. J. Lanthanide
Probes for Bioresponsive Imaging. Chem. Rev. 2014, 114, 4496−4539.
́
́
́
́
́
(21) Botar, R.; Molnar, E.; Trencsenyi, G.; Kiss, J.; Kalman, F. K.;
́
Tircso, G. Stable and Inert Mn(II)-Based and pH-Responsive
Contrast Agents. J. Am. Chem. Soc. 2020, 142, 1662−1666.
(22) Forgacs, A.; Pujales-Paradela, R.; Regueiro-Figueroa, M.;
Valencia, L.; Esteban-Gomez, D.; Botta, M.; Platas-Iglesias, C.
Developing the Family of Picolinate Ligands for Mn2+ Complexation.
Dalton Trans. 2017, 46, 1546−1558.
́
(30) (a) Macías, B.; Villa, M. V.; Lapresa, R.; Alzuet, G.; Hernandez-
Gil, J.; Sanz, F. Mn(II) Complexes with Sulfonamides as Ligands.
DNA Interaction Studies and Nuclease Activity. J. Inorg. Biochem.
2012, 115, 64−71. (b) Seidler-Egdal, R. K.; Johansson, F. B.; Veltze,
S.; Skou, E. M.; Bond, A. D.; McKenzie, C. J. Tunability of the
́
(23) (a) Regueiro-Figueroa, M.; Rolla, G. A.; Esteban-Gomez, D.; de
MIIMIII/MII2 and MIII2/MIIMIII (M = Mn, Co) Couples in bis-μ-O,O-
́
Blas, A.; Rodriguez-Blas, T.; Botta, M.; Platas-Iglesias, C. High
Relaxivity Mn2+-Based MRI Contrast Agents. Chem. - Eur. J. 2014, 20,
17300−17305. (b) Forgacs, A.; Regueiro-Figueroa, M.; Barriada, J. L.;
Esteban-Gomez, D.; de Blas, A.; Rodriguez-Blas, T.; Botta, M.; Platas-
Iglesias, C. Mono-, Bi-, and Trinuclear Bis-Hydrated Mn2+ Complexes
as Potential MRI Contrast Agents. Inorg. Chem. 2015, 54, 9576−
9587.
Carboxylato-μ-OR Bridged Complexes. Dalton Trans. 2011, 40,
3336−3345. (c) Veltze, S.; Egdal, R. K.; Johansson, F. B.; Bond, A. D.;
McKenzie, C. J. Coordinative Fexibility in an Acyclic Bis-
(sulfonamide) Ligand. Dalton Trans. 2009, 10495−10504.
(31) Gao, J.; Ye, K.; He, M.; Xiong, W.-W.; Cao, W.; Lee, Z. Y.;
Wang, Y.; Wu, T.; Huo, F.; Liu, X.; Zhang, Q. Tuning Metal−
Carboxylate Coordination in Crystalline Metal−Organic Frameworks
Through Surfactant Media. J. Solid State Chem. 2013, 206, 27−31.
(24) Molnar, E.; Camus, N.; Patinec, V.; Rolla, G. A.; Botta, M.;
Tircso, G.; Kalman, F. K.; Fodor, T.; Tripier, R.; Platas-Iglesias, C.
K
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
pubs.acs.org/IC
Article
(32) Drahos, B.; Kubicek, V.; Bonnet, C. S.; Hermann, P.; Lukes, I.;
Toth, E. Dissociation Kinetics of Mn2+ Complexes of NOTA and
DOTA. Dalton Trans. 2011, 40, 1945−1951.
through 17O NMR Line Widths. J. Am. Chem. Soc. 2013, 135, 18600−
18608.
(50) (a) Borel, A.; Kang, H.; Gateau, C.; Mazzanti, M.; Clarkson, R.
B.; Belford, R. L. Variable Temperature and EPR Frequency Study of
Two Aqueous Gd(III) Complexes with Unprecedented Sharp Lines.
J. Phys. Chem. A 2006, 110, 12434−12438. (b) Borel, A.; Laus, S.;
Ozarowski, A.; Gateau, C.; Nonat, A.; Mazzanti, M.; Helm, L.
Multiple-Frequency EPR Spectra of Two Aqueous Gd3+ Polyamino
Polypyridine Carboxylate Complexes: A Study of High Field Effects. J.
Phys. Chem. A 2007, 111, 5399−5407. (c) Khan, S.; Kubica-Misztal,
A.; Kruk, D.; Kowalewski, J.; Odelius, M. Systematic Theoretical
Investigation of the Zero-Field Splitting in Gd(III) Complexes: Wave
Function and Density Functional Approaches. J. Chem. Phys. 2015,
142, No. 034304.
(51) Fornasier, R.; Milani, D.; Scrimin, P.; Tonellato, U. Functional
Micellar Catalysis. Part 8. Catalysis of the Hydrolysis of p-Nitrophenyl
Picolinate by Metal-Chelating Micelles Containing Copper(II) or
Zinc(II). J. Chem. Soc., Perkin Trans. 2 1986, 2, 233−237.
(52) Tan, J.; Tang, W.; Sun, Y.; Jiang, Z.; Chen, F.; Xu, L.; Fan, Q.;
Xiao, J. pH-Regulated Transfer Hydrogenation of Quinoxalines with a
Cp*Ir-diamine Catalyst in Aqueous Media. Tetrahedron 2011, 67,
6206−6213.
(53) Moss, T. A.; Barber, D. M.; Kyle, A. F.; Dixon, D. J. Catalytic
Asymmetric Alkylation Reactions for the Construction of Protected
Ethylene-Amino and Propylene-Amino Motifs Attached to Quater-
nary Sterocenters. Chem. - Eur. J. 2013, 19, 3071−3081.
(54) Gans, P.; Sabatini, A.; Vacca, A. Investigation of Equilibria in
Solution. Determination of Equilibrium Constants with the HYPER-
QUAD Suite of Programs. Talanta 1996, 43, 1739−1753.
(55) Vogel, A. I. Vogel’s Textbook of Quantitative Chemical Analysis;
Longman Scientific & Technical, Wiley: Harlow, Essex, New York,
1989.
(33) Van der Merwe, M. J.; Boeyens, J. C. A.; Hancock, R. D.
Crystallographic and Thermodynamic Study of Metal Ion Size
Selectivity in the Ligand 1,4,7-Triazacyclononane-N,N’,N”-triacetate.
Inorg. Chem. 1985, 24, 1208−1213.
(34) Pujales-Paradela, R.; Carniato, F.; Uzal-Varela, R.; Brandariz, I.;
́
Iglesias, E.; Platas-Iglesias, C.; Botta, M.; Esteban-Gomez, D. A
Pentadentate Member of the Picolinate Family for Mn(II) Complex-
ation and an Amphiphilic Derivative. Dalton Trans. 2019, 48, 696−
710.
(35) Takacs, A.; Napolitano, R.; Purgel, M.; Benyei, A. C.; Zekany,
L.; Brucher, E.; Toth, I.; Baranyai, Z.; Aime, S. Solution Structures,
Stabilities, Kinetics, and Dynamics of DO3A and DO3A−
Sulphonamide Complexes. Inorg. Chem. 2014, 53, 2858−2872.
(36) Lowe, M. P.; Parker, D. pH Switched Sensitisation of
Europium(III) by a Dansyl group. Inorg. Chim. Acta 2001, 317,
163−173.
́
(37) Rodríguez-Rodríguez, A.; Garda, Z.; Ruscsak, E.; Esteban-
́
Gomez, D.; de Blas, A.; Rodríguez-Blas, T.; Lima, L. M. P.; Beyler,
2+
2+
́
M.; Tripier, R.; Tircso, G.; Platas-Iglesias, C. Stable Mn , Cu and
Ln3+ Complexes with Cyclen-Based Ligands Functionalized with
Picolinate Pendant Arms. Dalton Trans. 2015, 44, 5017−5031.
(38) Amendola, V.; Fabbrizzi, L.; Mosca, L.; Schmidtchen, F.-P.
Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors: A
Thermodynamic Study. Chem. - Eur. J. 2011, 17, 5972−5981.
(39) Cortes, S.; Brucher, E.; Geraldes, C. F. G. C.; Sherry, A. D.
Potentiometry and NMR Studies of l,5,9-Triazacyclododecane-
N,N’,N”-triacetic Acid and Its Metal Ion Complexes. Inorg. Chem.
1990, 29, 5−9.
(40) Drahos, B.; Kotek, J.; Hermann, P.; Lukes, I.; Toth, E. Mn2+
Complexes with Pyridine-Containing 15-Membered Macrocycles:
Thermodynamic, Kinetic, Crystallographic, and 1H/17O Relaxation
Studies. Inorg. Chem. 2010, 49, 3224−3238.
(41) Botta, M.; Carniato, F.; Esteban-Gomez, D.; Platas-Iglesias, C.;
Tei, L. Mn(II) Compounds as an Alternative to Gd-Based MRI
́
́
(56) Caneda-Martínez, L.; Valencia, L.; Fernandez-Perez, I.;
Regueiro-Figueroa, M.; Angelovski, G.; Brandariz, I.; Esteban-
́
Gomez, D.; Platas-Iglesias, C. Toward Inert Paramagnetic Ni(II)-
Based Chemical Exchange Saturation Transfer MRI Agents. Dalton
Trans. 2017, 46, 15095−15106.
́
(57) Bates, R. G.: Determination of pH, Theory and Practice. 2nd
Edition; John Wiley & Sons: New York, London, Sydney, Toronto,
1973.
Probes. Future Med. Chem. 2019, 11, 1461−1483.
́
(42) Esteban-Gomez, D.; Cassino, C.; Botta, M.; Platas-Iglesias, C.
1
17O and H Relaxometric and DFT Study of Hyperfine Coupling
(58) (a) Evans, D. F. The Determination of the Paramagnetic
Susceptibility of Substances in Solution by Nuclear Magnetic
Resonance. J. Chem. Soc. 1959, 2003−2005. (b) Evans, D. F.;
Fazakerley, G. V.; Phillips, R. F. Organometallic Compounds of
Bivalent Europium, Ytterbium, and Samarium. J. Chem. Soc. A 1971,
1931−1934.
(59) APEX2, SMART, SAINT; Bruker AXS, Inc.: Madison, WI, USA,
2007.
(60) SAINT, Version 8.37A; Bruker AXS, Inc.: Madison, WI, USA,
2015.
Constants in [Mn(H2O)6]2+. RSC Adv. 2014, 4, 7094−7103.
(43) Balogh, E.; He, Z.; Hsieh, W.; Liu, S.; Toth, E. Dinuclear
Complexes Formed with the Triazacyclononane Derivative
ENOTA4‑: High-Pressure 17O NMR Evidence of an Associative
Water Exchange on [MnII (ENOTA)(H2O)2]. Inorg. Chem. 2007, 46,
2
238−250.
́
(44) Aime, S.; Botta, M.; Esteban-Gomez, D.; Platas-Iglesias, C.
Characterisation of Magnetic Resonance Imaging (MRI) Contrast
Agents Using NMR Relaxometry. Mol. Phys. 2019, 117, 898−909.
(45) Freed, J. H. Dynamic Effects of Pair Correlation Functions on
Spin Relaxation by Translational Diffusion in Liquids. II. Finite Jumps
and Independent T1 Processes. J. Chem. Phys. 1978, 68, 4034−4037.
(46) Mills, R. Self-Diffusion in Normal and Heavy Water in the
Range 1−45°. J. Phys. Chem. 1973, 77, 685−688.
(47) Luz, Z.; Meiboom, S. Proton Relaxation in Dilute Solutions of
Cobalt(II) and Nickel(II) Ions in Methanol and the Rate of Methanol
Exchange of the Solvation Sphere. J. Chem. Phys. 1964, 40, 2686−
2693.
(61) Sheldrick, G. M. SADABS, Version 2014/5; Bruker AXS, Inc.:
Madison, WI, USA.
(62) (a) SHELXT, Version 2014/5. (b) Sheldrick, G. M. SHELXT -
Integrated Space-Group and Crystal-Structure Determination. Acta
Crystallogr., Sect. A: Found. Adv. 2015, A71, 3−8.
(63) (a) SHELXL, Version 2018/3. (b) Sheldrick, G. M. A Short
History of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008,
A64, 112−122.
(48) (a) Solomon, I. Relaxation Processes in a System of Two Spins.
Phys. Rev. 1955, 99, 559−565. (b) Solomon, I.; Bloembergen, N.
Nuclear Magnetic Interactions in the HF Molecule. J. Chem. Phys.
1956, 25, 261−266. (c) Bloembergen, N. Proton Relaxation Times in
Paramagnetic Solutions. J. Chem. Phys. 1957, 27, 572−573.
(d) Bloembergen, N.; Morgan, L. O. Proton Relaxation Times in
Paramagnetic Solutions. Effects of Electron Spin Relaxation. J. Chem.
Phys. 1961, 34, 842−850.
(49) Gale, E. M.; Zhu, J.; Caravan, P. Direct Measurement of the
Mn(II) Hydration State in Metal Complexes and Metalloproteins
L
https://dx.doi.org/10.1021/acs.inorgchem.0c02098
Inorg. Chem. XXXX, XXX, XXX−XXX