Controlling water exchange rates in potential Mn2+-based MRI agents derived from NO2A2-

Article abstract of DOI:10.1039/c9dt00211a

We report a series of pentadentate ligands based on a 1,4,7-triazacyclononane-1,4-diacetic acid (H₂NO2A) containing different substituents attached to the third nitrogen atom of the macrocyclic unit. Detailed ¹H Nuclear Magnetic Rela

Full text of DOI:10.1039/c9dt00211a

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Paradela, F. Carniato, D. Esteban-Gómez, M. Botta and C. Platas-Iglesias, Dalton Trans., 2019, DOI:
10.1039/C9DT00211A.
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ISSN 1477-9226
PAPER
Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
framework
a Zr-metal–organic
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Controlling water exchange rates in potential Mn2+-based MRI
agents derived from NO2A2-
Received 00th January 20xx,
Accepted 00th January 20xx
a
Rosa Pujales-Paradela,*a Fabio Carniato,b David Esteban-Gómez, Mauro Botta,b and Carlos
Platas-Iglesias*a
DOI: 10.1039/x0xx00000x
We report a series of pentadentate ligands based on a 1,4,7,-triazacyclononane-1,4-diacetic acid (H2NO2A) containing
different substituents attached to the third nitrogen atom of the macrocyclic unit. A detailed 1H Nuclear Magnetic
Relaxation Dispersion (NMRD) characterisation of the corresponding Mn2+ complexes suggest the formation of six-
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coordinate species in solution containing an inner-sphere water molecule. This was confirmed by recording transverse 17
O
relaxation time and chemical shift measurements. The water exchange rate of the coordinated water molecule was found
298
to be strongly influenced by the nature of the substituent R at position 7 of the triazacyclononane unit (R = Me, kex
=
62.6107 s-1; R = Bz, kex298 = 4.4107 s-1; R = 1-phenylethyl, kex298 = 2.6107 s-1). The decreasing exchange rates are explained
by the increasing bulkiness of the substituent, which hinders the approach of the entering water molecule in an
associatively activated water exchange mechanism. This is supported by DFT calculations (M062X/TZVP), which confirm
the associative nature of the water exchange reaction. A potentially decadentate ligand containing two NO2A units linked
by a xylenyl spacer in the meta position was also synthesised. The corresponding binuclear Mn2+ complex contains two
1
metal ions with different hydration numbers, as evidenced by H NMRD and 17O NMR measurements. DFT calculations
show that this is related to the presence of a bridging bidentate -1-carboxylate group connecting the two metal centers.
The results reported in this work provide a straightforward strategy to control the exchange rate of the coordinated water
molecule in this family of MRI contrast agent candidates.
already used Gd3+ chelates, because of the raising concerns
about some health risks associated with their use.3 Although
none of the studies reported so far demonstrated a clinically
Introduction
Magnetic Resonance Imaging (MRI) has emerged during the
last few decades as one of the most successful and widely used
diagnostic imaging modalities, which nevertheless is under
continuous development and improvement. Contrast agents
(CA) are broadly used during the MRI scans in order to improve
the contrast in the recorded images of organs and tissues,
increasing the sensitivity and decreasing the acquisition
times.1 These agents are usually paramagnetic metal
complexes with good water solubility that increase the
relaxation rates of water proton nuclei in their vicinity.1,2 One
of the most common and widespread CAs used in clinical
practice is DOTAREM®, a Gd3+ macrocyclic complex that
presents high stability and relaxivity.1 In the last few years, a
renewed interest has emerged to find alternatives to the
relevant toxic effect directly attributed to gadolinium
deposition in brain and other tissues,4 gadolinium contrast
agents are related to the onset of nephrogenic systemic
fibrosis (NSF) in patients with abnormal and even normal renal
function, or that have experienced liver transplantation.3
Several suspensions of marketing authorizations and
restrictions in the use of linear gadolinium based-contrast
agents have been executed recently by some international
regulatory health authorities,5 and these restrictions are likely
to be expanded in the nearly future.
In this renewed interest on alternatives to gadolinium
contrast agents, high-spin manganese(II) complexes are
playing a strong leading position,6-9 due to a number of
optimal features: high effective magnetic moment associated
with the presence of five unpaired d electrons, long electronic
relaxation time and fast water exchange kinetics.6 In recent
papers, we have reported several manganese systems that
present relatively high relaxivities, comparable to those of
small monohydrated Gd3+ complexes.10 These chelates should
guarantee a high thermodynamic and kinetic stability to avoid
the release of the Mn2+ ion in vivo,11 and they should present
one free coordination site to the metal ion for at least one
water molecule. Besides, the ligands should provide a good
a. Universidade da Coruña,Centro de Investigacións Científicas Avanzadas (CICA)
and Departamento de Química, Facultade de Ciencias, 15071, A Coruña,
Galicia, Spain. Email: carlos.platas.iglesias@udc.es
b. Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte
Orientale “A. Avogadro”, Viale T. Michel 11, 15121 Alessandria, Italy. E-mail:
mauro.botta@uniupo.it
† Electronic supplementary information (ESI) available: 1H, 13C NMR and mass
spectra of the ligands and their precursors and complexes, equations used for
the analysis of 1H and 17O NMR data and optimized Cartesian coordinates
obtained with DFT calculations. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2016
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redox stability to avoid the oxidation of Mn2+ to Mn3+, which containing different pendant arms attached toVitehweArttichleirOdnlinNe
298
commonly furnishes lower relaxivities.12 Noteworthy, it has atom of the macrocyclic unit presented kex
DOI: 10.10v3a9/luCe9DsTi0n02t1h1Ae
been proven that contrast agents based on macrocyclic metal range 1.3-2.7107 s-1.17
complexes are generally kinetically more inert than linear
analogues.13
The motivation of this study was to analyse the effect that
steric hindrance provokes in the water exchange rate of
[Mn(NO2A)] derivatives. We hypothesised that the presence of
bulky groups on the vicinity of the water binding site may
hinder the approach of a water molecule from the bulk,
following an associatively activated mechanism. To this aim,
we prepared the H2BzNO2A and H2MeBzNO2A ligands
(Scheme 1) and performed a full relaxometric characterisation
of the corresponding Mn2+ complexes using Nuclear Magnetic
Relaxation Dispersion (NMRD)18 and 17O NMR studies. The
different bulkiness of the groups attached to the secondary
amine of NO2A and the comparison with [Mn(MeNO2A)]
allows to rationalise the water exchange dynamics in this
family of complexes. Furthermore, we also report here the
binuclear complex [mBz(MnNO2A)2)], in an attempt to
increase the observed relaxivity by slowing down the
molecular tumbling of the complex in solution.
N
N
N
N
N
N
N
N
N
COOH
COOH
COOH
COOH
COOH
H2BzNO2A
COOH
H2MeBzNO2A
H2MeNO2A
COOH
HOOC
HOOC
N
N
HOOC
N
N
N
N
N
N
N
N
COOH
N
N
COOH
COOH
mBz(H2NO2A)2
HOOC
H4ENOTA
Scheme 1. Chemical structure of the ligands studied in this work.
Among the different parameters that affect the efficiency
(relaxivity) of Mn2+-based contrast agents, the exchange rate
of the coordinated water molecule(s) plays an important key
role. Some time ago, É. Tóth and co. reported a detailed
characterisation of the NO2A derivative [Mn2(ENOTA)]
Results and discussion
Synthesis. The triazacyclononane-based ligands H2BzNO2A,
H2MeBzNO2A and mBz(H2NO2A)2 were prepared by alkylation
of the bis-protected triazacyclononane derivative di-tert-butyl
(Scheme 1), which was found to possess a rather slow water
298
exchange rate of the coordinated water molecule (kex
=
5.5107 s-1),14 comparable to that of the aquated [Mn(H2O)6]2+
2,2′-(1,4,7-triazacyclononane-1,4-diyl)diacetate
(NO2AtBu)
298
ion (kex
= 2.8107 s-1).15 In a subsequent study, we
with alkyl bromide derivatives 1a, 1b or 1c (Scheme 2). The
protected ligands were isolated in quantitative yields, and then
treated with TFA to remove the tert-butyl protecting groups.
The final ligands were isolated in nearly quantitative amounts.
investigated the [Mn(MeNO2A)] complex, which was found to
present a water exchange rate one order of magnitude higher
298
(kex
=
62.6107 s-1).16 Other [Mn(NO2A)] derivatives
X
Br
X
X
1a: X = H
1b: X = CH3
N
N
N
N
N
N
COOH
i)
O
ii)
O
O
O
COOH
2a: X = H
2b: X = CH3
H2BzNO2A: X = H
H2MeBzNO2A: X = CH3
NH
N
N
O
O
O
O
O
O
O
O
HOOC
COOH
COOH
O
HOOC
Br
Br
N
N
N
N
O
N
N
1c
i)
N
N
N
N
O
N
N
ii)
O
mBz(H2NO2A)2
2c
Scheme 2. Synthesis of the ligands discussed in this work. Conditions: i) K2CO3 in CH3CN, 48 h, 100%; ii) TFA:CH2Cl2, RT, 48h, 88-100%.
2 | Dalton Trans., 2016, 00, 1-14
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DOI: 10.1039/C9DT00211A
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The preparation of the Mn2+ complexes was carried out by coordination environment of at least one of the Mn2+ ions
a solvothermal approach using n-butanol as solvent and DIPEA differs with respect to those of the mononuclear analogues.
as base. The complexes were purified by reverse-phase
The relaxivities of the three complexes (25 ⁰C, 20 MHz) were
medium pressure liquid chromatography (MPLC). The high- measured over a broad pH range, from 3 to 12, to assess their
resolution mass spectra (ESI+, Figures S13-S15, ESI†) confirm the stability around physiological pH (Fig 1). The observed
formation of the complexes.
relaxivities are constant in the pH range 6.0-9.0. Below that
range relaxivity increases due to the stepwise dissociation of
the complex and formation of [Mn(H2O)6]2+, which presents a
relaxivity of 8.6 mM-1s-1 under these conditions.15b Above pH
9 r1p experiences a significant increase, which might be
related to an acceleration of the water exchange process by a
base-catalysed mechanism. A relaxivity increase at high pH
values was observed previously for lanthanide complexes
presenting slow water exchange thanks to the prototropic
base-catalysed mechanism.21,22 Since water exchange in these
[Mn(NO2A)] derivatives is rather fast and does not limit
relaxivity at 298 K (see below), the relaxivity increase at basic
pH must be related to a different effect. It has been shown
that [Mn(NO2A)] complexes form hydroxo species at basic
pH.17 Thus, the formation of hydroxo species is most likely
responsible for the observed behaviour, either by affecting the
number of proton nuclei in the vicinity of the metal ion, the
Mn···H distance or the rotational dynamics of the complex.
1H NMRD measurements. Proton Nuclear Magnetic Relaxation
Dispersion (1H NMRD) profiles were recorded at 10, 25 and 37
⁰C in the proton Larmor Frequency range from 0.01 to 70 MHz.
The analysis of the 1H NMRD profiles provides additional
information on the different mechanisms and physicochemical
parameters that affect the observed relaxivity (Figure 2). The
Figure 1. Plot of the 1H relaxivities at 20 MHz and 298 K as a function of pH.
1
pH dependence of H relaxivity (r1p). The assessment of the
efficiency of a paramagnetic complex as a contrast agent in
vitro is determined by its relaxivity, r1p, defined as the
relaxation enhancement of water protons induced by the
paramagnetic agent at 1 mM concentration (based on the
paramagnetic metal ion).
NMRD
profiles
recorded
for
[Mn(BzNO2A)]
and
The relaxivity determined for [Mn(BzNO2A)] at pH 6.47 (25
⁰C, 20 MHz) is 3.43 mM-1 s-1, a value that is close to that
reported for monohydrated complexes of similar size, such as
[Mn(EDTA)]2- (3.3 mM-1 s-1 at pH 7.4, 25 ⁰C and 20 MHz).19 The
r1p value measured for [Mn(MeBzNO2A)] under the same
conditions (3.54 mM-1 s-1) is very similar, indicating a low
impact of the added methyl group on the observed relaxivity.
These relaxivity values suggest the presence of a water
molecule coordinated to the metal ion in both [Mn(BzNO2A)]
and [Mn(MeBzNO2A)], indicating that the presence of the
methyl group does not affect the hydration state of the
complex. Meanwhile, the relaxivity measured for the dinuclear
chelate [mBz(MnNO2A)2)] (2.58 mM-1 s-1) is decidedly lower
than those of the related mononuclear complexes. However,
this relaxivity is still higher than the one observed for non-
hydrated Mn2+ complexes such as [Mn(DO3A)]-,19 but close to
the r1p values reported for complexes with 0 < q < 1 (q is the
number of coordinated water molecules).20 Thus, the relaxivity
measured for [mBz(MnNO2A)2)] suggests that the
[Mn(MeBzNO2A)] are nearly identical in the whole range of 1H
Larmor frequencies, which suggests that the two complexes
present very similar structures and dynamics. The relaxivities
of the dinuclear complex [mBz(MnNO2A)2)] are clearly lower,
again suggesting a lower hydration number. The NMRD
profiles recorded for the three complexes present a single
dispersion in the range  2 – 20 MHz and two plateaus at low
(< 2 MHz) and high (> 20 MHz) fields. The relaxivity at high
field decreases with increasing temperature in all cases, a
situation typical of small Mn2+ chelates presenting fast rotation
(short rotational correlation times, R).18 It is also worth
mentioning that the NMRD profiles do not show a second
dispersion at low field (0.3-0.02 MHz), which is characteristic
of complexes that present a sizeable scalar contribution to
relaxivity. This second dispersion was so far only observed for
the aquated ion [Mn(H2O)6]2+ and [Mn2(ENOTA)].14,15
Recently, Peters and Geraldes have proposed a method to
1
determine the hydration number of Mn2+ complexes from H
NMRD measurements.23 These authors proposed a correlation
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1
= 푟2푝[Mn2 +
]
of the hydration number q with the relaxivity observed at 0.01
MHz (and 25 ⁰C) and the molecular weight (FW) of the
complex:
(7)
푇2푝
View Article Online
DOI: 10.1039/C9DT00211A
The temperature dependence of r2p measured for the three
complexes shows that [Mn(BzNO2A)] and [Mn(MeBzNO2A)]
present very similar transverse relaxivities at the maximum of
the temperature dependence (r2p300 mM-1 s-1, Figure 3),
푟1푝
푞 =
(1)
―3
9.16 1 ― 푒( ―2.97 × 퐹푊 × 10
)
{
}
The relaxivities at 0.01 MHz and 25 ⁰C were determined to be while the relaxivity measured for [mBz(MnNO2A)2)] is about
4.97, 6.63, 6.88 and 4.38 mM-1 s-1 for [Mn(MeNO2A)], one half of those observed for the mononuclear complexes
[Mn(BzNO2A)], [Mn(MeBzNO2A)] and [mBz(MnNO2A)2)], (r2p150 mM-1 s-1). Thus, these results indicate that the
which correspond to q values of 0.9, 0.9, 1.1 and 0.5. The binuclear [mBz(MnNO2A)2)] complex presents
a lower
estimated uncertainty of the method was determined to be hydration number than the mononuclear analogues. By
+0.4 units. These results point to the formation of assuming a A/ value of -33106 rad s-1, Caravan proposed that
monohydrated species for all mononuclear complexes of this each coordinated water molecule should provide
series, while the dinuclear complex [mBz(MnNO2A)2)] likely contribution of 510 mM-1 s-1 to r2p. This results in hydration
presents a lower effective hydration number. numbers of q = 0.6 for the mononuclear complexes and q = 0.3
a
17O NMR measurements. Transverse 17O NMR relaxation rate for [mBz(MnNO2A)2)]. Since the proton relaxivities point to the
measurements were recorded at 11.75 T to obtain information presence of a coordinated water molecule in [Mn(BzNO2A)]
regarding the hydration number and water exchange rate of and [Mn(MeBzNO2A)], we conclude that our 17O r2p
the coordinated water molecule (kex = 1/m). The paramagnetic measurements underestimate the hydration number of these
17O transverse relaxation rates 1/T2p can be approximated by:
complexes. We attribute this to the fact that the
approximations described above are not completely fulfilled.
Indeed, neglecting the chemical shift difference between
bound and bulk water (m) in Eq (2) affect the transverse
relaxation rates significantly (Fig S16, ESI+). Furthermore, the
―1
푇2―푚2 + 휏푚―1
푞[Mn2 + ] 1
푇
+ ∆휔2푚
1
1
1
2푚
=
―
=
(2)
2
푚 (휏푚―1 + 푇2푚) + ∆휔2푚
―1
푇2푝
푇2,표푏푠
푇2,푟푒푓
[H2O]
휏
Where 1/T2,obs and 1/T2,ref are the observed relaxation rates assumption that T1e >> m may also not be completely valid. For
for the solution of the paramagnetic complex and of the instance, the water exchange rate obtained for [Mn(BzNO2A)]
diamagnetic reference, respectively, while 1/T2m is the at the maximum observed in Fig 3 (9107 s-1) is in the same
relaxation rate of the bound water molecule. By neglecting the order of magnitude than the value of T1e obtained from
chemical shift difference between bound and bulk water simulations of the transient zero field splitting in
(m), the 1/T2p values can be approximated as:
[Mn(MeNO2A)] (1107 s-1).25 Thus, taken together the 17O
and 1H data are compatible with q = 1 mononuclear complexes
and a q = 0.5 dinuclear [mBz(MnNO2A)2)] complex. Our DFT
calculations presented below provide support to this
1
푞[Mn2 +
]
1
=
(3)
푇2푝
[H2O] 휏푚 + 푇2푚
The 17O transverse relaxation rate of the coordinated water hypothesis.
molecule is dominated by the scalar mechanism according to: With the hydration numbers in hand, we obtained the
2
푆(푆 + 1) 퐴
1
1
reduced transverse relaxation rates (1/T2r), which are
normalised for the molar fraction of bound water Pm:
≅
=
휏
푠1
(ℏ)
(4)
푇2푚 푇2,푠푐
3
1
1
1
1
1
Here, A/ is the scalar hyperfine coupling constant and S is
the electron spin (S = 5/2 for a high-spin Mn2+ complex). 1/s1
is the sum of the exchange rate constant and the electron spin
relaxation rate:
=
―
≈
(8)
[
]
푇2푟
푃푚 푇2,표푏푠
푇2,푟푒푓
휏푚 + 푇2푚
The temperature dependence of T2m and m are generally
opposite, so that the residence time of the coordinated water
molecule is shortened on increasing temperature (i. e. kex
increases), while T2m becomes longer. Thus, the plots of 1/T2r
versus reciprocal temperature present different slopes
1
1
1
=
+
(5)
휏푠1
휏푚
푇1푒
Caravan et al.24 noticed that at high magnetic fields T1e >> depending on the term that dominates the denominator of Eq
m, so that m is the correlation time that dominates in Eq (4). (2). A positive slope is then expected in the plots of 1/T2r
As a result, at the maximum of the temperature dependence versus 1/T for systems in the fast exchange regime, while the
of 1/T2p, where T2m = m, one can obtain Eq (6) by combining opposite behaviour should be observed for complexes within
Eqs (3) and (4):
the slow exchange regime. In the case of the complexes
investigated here, the 1/T2r data present a maximum that
point to a changeover from the low water exchange regime at
2
푞 = 푟2푝,푚푎푥[H2O]
(6)
low temperatures to a fast water exchange at high
퐴
(
)
푆(푆 + 1)
표
3
ℏ
temperatures (Figure 2). This temperature dependence of
1/T2r is in clear contrast with that observed for
[Mn(MeNO2A)], which was characterised by a very fast water
In Eq (6) r2p stands for the transverse 17O relaxivity, defined
as:
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exchange.16 We also notice that the maximum of the 1/T2r is and [Mn(MeBzNO2A)] with respect to [Mn(BzNO2A)], which
View Article Online
DOI: 10.1039/C9DT00211A
shifted towards higher temperatures for [mBz(MnNO2A)2)] anticipates a slightly faster water exchange in the latter.
(B)
1
Figure 2. Left panel: H NMRD profiles recorded at different temperatures for [Mn(BzNO2A)], [Mn(MeBzNO2A)] and [mBz(MnNO2A)2)]. Right panel:
Reduced transverse 17O NMR relaxation rates and chemical shifts versus reciprocal temperature. The red lines represent the fits of the data as explained in
the text.
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Table 1. Parameters obtained from the simultaneous analysis of 17O NMR and 1H NMRD data.a
View Article Online
c
[Mn(BzNO2A)]
5.0/3.4/2.8
4.4 + 0.1
32.17 + 1.5
-27 + 8
[Mn(MeBzNO2A)]
5.3/3.5/2.7
2.6 + 0.1
25.4 + 0.9
-10 + 6
[mBz(MnNO2A)2]
3.8/2.6/2.2
2.4 + 0.1
[Mn(MeNO2A)] b
3.3/2.8
62.6 + 2.3
DOI: 10.1039/C9DT00211A
[Mn2(ENOTA)]
r1p at 10/25/37 ⁰C / mM-1 s-1 b
298
7
-1
푘
5.5
20.5
-28
85
푒푥 / 10 s
H‡ / kJ mol-1
S‡ / J mol-1 K-1
31.1 + 1.6
11 + 1.0
-23 + 7
78.7 + 0.7
20.8 + 0.6
휏2푅98
Er / kJ mol-1
휏2푉98
Ev / kJ mol-1
298
36 + 3
/ ps
52.8 + 0.1
26.7 + 0.8
67.2 + 0.6
24.6 + 0.5
22.8 + 0.7
21.4 + 3.8
1.0a
18
7.7
/ ps
25 + 2
1.0a
51 + 4
52 + 4
1.0a
1.0a
24.8
23.0a
20.0a
20.0a
26.9 + 4.0
MnH / 10-10 m2 s-1
퐷
20.0a
EDMnH / kJ mol-1
2 / 1019 s-2
AO/ħ/ 106 rad s-1 d
AO/ħ/ 106 rad s-1 e
rMnH/Å
20
20
20
17.3 + 2.4
7.2 + 1.5
-46.0 + 0.2
-52.3
18
0.47
-32.7
6.9 + 0.4
-44.1 + 2.7
1.69 + 0.08
-49.6 + 2.3
-51.3
2.26 + 0.11
-32.6 + 0.9
-52.0
2.85a
3.6a
0.5a
2.77a
2.75
3.2
1
2.85a
2.865a
aMnH/Å
q298
3.6a
3.6a
1a
3.6a
1a
1a
Parameters fixed during the fitting procedure. b Data from Ref 16. Data from ref 14. Experimental values obtained from 17O NMR measurements.
a
c
d
e
Obtained with DFT calculations.
The 17O hyperfine coupling constants (AO/ħ) are in the upper
part of the range typically observed for small Mn2+ complexes
(25 106 to 47  106 rad s-1).28 Furthermore, they are in very
good agreement with the values estimated by DFT calculations
(see below), which confirms that the hydration numbers used
in the analysis are correct.
휏298
) obtained for
푅
The rotational correlation times
(
[Mn(BzNO2A)] and [Mn(MeBzNO2A)] are very similar, but
somewhat longer than the value reported previously for
[Mn(MeNO2A)], as would be expected on the basis of their
휏2푅98
molecular weights. The
value obtained for
[mBz(MnNO2A)2)] is about 50% longer than that of
[Mn(MeNO2A)], matching rather well that of [Mn2(ENOTA)]
(Table 1).
The parameters related to the relaxation of the electron spin
of the Mn2+ ion (the mean square zero-field-splitting energy
(2) and its associated correlation time (V) are similar to the
Figure 3. Plot of the transverse 17O relaxivity as a function of temperature
recorded
at
11.75
T.
Fittings of the 17O NMR and 1H NMRD data. The quantitative values reported for other Mn2+ complexes. The mononuclear
analysis of the 17O and H NMRD data was carried out using complexes [Mn(BzNO2A)] and [Mn(MeBzNO2A)] present very
1
the Solomon-Bloembergen-Morgan theory to describe the similar parameters, which suggests very similar coordination
inner-sphere contribution26 and Freed’s model27 to account for environment of the metal ion in the two complexes. The value
the outer-sphere contribution to relaxivity. The complete set of 2 obtained for [mBz(MnNO2A)2)] is somewhat higher, but
of equations used, together with those describing the 17O NMR very similar to that of [Mn(MeNO2A)].
data, are given in the Electronic Supplementary Information
The water exchange rates determined for this family of complexes
(ESI†). These equations depend upon a large number of match the qualitative analysis presented in the previous section.
298
parameters, hence to achieve a reliable analysis some of them The water exchange rate determined for [Mn(BzNO2A)] (kex
=
had to be fixed to standard values during the fitting procedure: 4.4107 s-1) is one order of magnitude lower than the one obtained
298
298
The distances between the proton nuclei of inner-sphere for [Mn(MeNO2A)] (kex = 63107 s-1). This very different kex
water molecules and the metal ion (rMnH) were fixed to the values highlight the impact that an increasing steric hindrance has
average values obtained from DFT calculations (Table 1), while on the water exchange rate. Increasing further the steric hindrance
the distance of closest approach of outer-sphere water by introducing a methyl group at the benzylic carbon reduces
298
molecules aMnH was set at 3.6 Å. Finally, the diffusion further the water exchange rate (kex
= 2.6107 s-1 for
퐷298
coefficient MnH and its activation energy EDMnH were fixed to [Mn(MeBzNO2A)]).
Finally,
the
binuclear
complex
established values.19 Table 1 shows the parameters obtained [mBz(MnNO2A)2)] displays a water exchange rate similar to that of
from the fittings, which are compared with those reported [Mn(MeBzNO2A)]. The activation entropies obtained from the fit of
previously for [Mn(MeNO2A)] and [Mn2(ENOTA)].14,16
the 17O NMR data are negative and very close to that reported for
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6 | Dalton Trans., 2016, 00, 1-14
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[Mn2(ENOTA)], in line with an associatively activated water
exchange reaction.14
Additional DFT calculations were performed to gain insight into
the mechanism responsible for the water exchange reaction in this
Theoretical calculations. DFT calculations (M062X/TZVP) were family of complexes.30 For this purpose, we used a model of the
View Article Online
DOI: 10.1039/C9DT00211A
carried out to gain information on the structures of the complexes [Mn(MeNO2A)] complex including six explicit water molecules.
described in this work and their water exchange kinetics. The We
then
optimised
the
geometries
of
the
[Mn(MeNO2A)] complex was studied with DFT calculations in a [Mn(MeNO2A)(H2O)]·5H2O and [Mn(MeNO2A)(H2O)2]·4H2O
previous work including a coordinated water molecule and a systems (Fig 5), which turned out to correspond to local energy
variable number of explicit second-sphere water molecules.16 These minima of the potential energy surface. Our calculations
studies showed that the inclusion of two second-sphere water predict that the monohydrated complex is more stable than
molecules was critical for an adequate description of the Mn-Owater the q = 2 complex, with a Gibbs free energy difference of 7.2 kJ
distances and scalar hyperfine coupling constants AO/ħ. We mol-1. Thus, our calculations with the M062X functional predict
therefore included two explicit second-sphere water molecules in the correct hydration number for the [Mn(MeNO2A)] complex,
our models. In the case of the complex of mBz(MnNO2A)2 the in line with recent findings.31 Next we located the transition
experimental 1H NMRD and 17O NMR data suggest the presence of a state connecting the two energy minima, which provided an
water molecule coordinated to one of the Mn2+ ions, while the activation free energy of G#298 = 7.6 kJ mol-1. The distance
second one does not contain a coordinated water molecule. We between the metal ion and the entering water molecule
hypothesised that a carboxylate group of one of the NO2A units of decreases from 6.01 to 3.22 Å to reach the transition state,
the ligand could coordinate simultaneously to the two Mn2+ ions, as while the Mn-O distance involving the coordinated water
bridging carboxylate groups were observed previously in the solid molecule experiences only a slight increase from 2.17 to 2.19
state structures of Mn2+ complexes with polyaminopolycarboxylate Å, in line with an associatively activated mechanism. The
ligands.29
The
optimised
geometry
of
the calculated activation entropy is negative (S# = -47.3 J mol-1 K-1),
[mBz(MnNO2A)(MnNO2A)(H2O)]·2H2O system (Figure 4) supports as would be expected for an associative mechanism,32 representing
the different hydration numbers of the two Mn2+ ions, as a result of the main contribution to the free energy barrier at 298 K.
the presence of a bridging bidentate -1-carboxylate group.
The
Mn-Owater
distances
calculated
for
[Mn(MeNO2A)(H2O)]·2H2O, [Mn(BzNO2A)(H2O)]·2H2O and
[Mn(MeBzNO2A)(H2O)]·2H2O are virtually identical (2.183-
2.185 Å), while for the [mBz(MnNO2A)(MnNO2A)(H2O)]·2H2O
system this distance is slightly shorter (2.141 Å). The scalar
hyperfine coupling constants AO/ħ obtained with DFT for
[Mn(MeNO2A)(H2O)]·2H2O, [Mn(BzNO2A)(H2O)]·2H2O and
[Mn(MeBzNO2A)(H2O)]·2H2O are also very similar (-50106
rad s-1), and show
a satisfactory agreement with the
experimental values, though the deviation is more important
in [Mn(MeBzNO2A)(H2O)]·2H2O. These results confirm that the
1
hydration numbers assumed for the analysis of the H NMRD
and 17O NMR data are correct, and that the bulkiness of the
substituents attached to position 7 of the triazacyclononane
unit does not significantly influence the strength of the
Mn-Owater bonds.
Figure 5. Structures of the energy minimum (a) and transition state (b)
characterising the associative water exchange mechanism in
[Mn(MeNO2A)(H2O)]·5H2O (M062X/TZVP). Bond distances are provided in
Å.
Figure 4. Structure of the [mBz(MnNO2A)(MnNO2A)(H2O)]·2H2O system
obtained with DFT calculations (M062X/TZVP). Bond distances are provided
in
Å.
Conclusions
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In this work, we have presented a family of Mn2+ complexes with without further purification. The protected lVigieawnAdrtsiclewOnelirnee
ligands containing a NO2A2- chelating unit functionalised with hydrolysed using a 1:1 TFA:CH2Cl2 mixture (8 mL), stirring at
DOI: 10.1039/C9DT00211A
different substituents at the third nitrogen atom of the room temperature for 48 h. Once the deprotection was
triazacyclononane moiety. A detailed relaxometric study showed completed, the solution was concentrated in vacuo and
demonstrated that the water exchange process becomes slower washed several times with water (5x10 mL). The product was
upon increasing the steric hindrance around the water binding site. redissolved in water and lyophilised to obtain the final ligands.
This can be accounted for by the associative mechanism followed Synthesis of di-tert-butyl 2,2'-(7-benzyl-1,4,7-triazonane-1,4-
by the water exchange process. The increased bulkiness of the diyl)diacetate (H2BzNO2AtBu, 2a). This compound was
substituent hinders the approach of the entering water molecule, obtained by using NO2AtBu (0.2059 g, 0.5759 mmol), benzyl
causing a destabilisation of the seven-coordinated transition state. bromide (1a, 68.5 µL, 1 eq) and K2CO3 (0.138 g, 1.73 eq).
DFT calculations provided support for the associative water Yellowish oil (0.260 g, quantitative). 1H NMR (300 MHz, CDCl3):
exchange mechanism.
δH (ppm): 7.31-7.25 (5H, m, CHPh), 3.67 (2H, m, CH2), 3.30-3.24
The results reported here give insight at the molecular level on (4H, m, CH2), 2.93-2.80 (2H, m, CH2), 1.45-1.38 (18H, m, CH2);
important parameters that control the efficiency of Mn2+ complexes 13C NMR (75 MHz, CDCl3): δC (ppm) 171.46 (COOtBu), 139.94
as MRI contrast agents. In the case of Gd3+ MRI contrast agents the (CPh), 129.01 (CPh), 128.11 (CPh), 126.76 (CPh), 80.58 (-OC(CH3)3),
studies reported during the last two decades provide a plethora of 62.54 (CH2), 59.85 (CH2), 55.35 (CH2), 55.15 (CH2), 28.19 (CH3).
data that enable a rational control of some key physicochemical Mass spectrometry (ESI+) m/z (%BPI): 448.32 (100)
parameters. For instance, steric compression around the water ([C24H42N3O4]+).
coordination site was found to accelerate the water exchange Synthesis of 2,2'-(7-benzyl-1,4,7-triazonane-1,4-diyl)diacetic
1
process, by facilitating the dissociative water exchange reaction.33 acid (H2BzNO2Ac). Yellowish solid (0.3363 g, quantitative). H
In the case of Mn2+ complexes the amount of data accumulated is NMR (300 MHz, D2O): δH (ppm) 8.28 (3H, s, CHPh), 7.60 (1H, s,
far lower, so that the design of potential MRI contrast agent on a CHPh), 7.58 (2H, s, CHPh), 4.53 (4H, s, CH2), 3.64-3.58 (8H, d,
rational basis is more difficult. We have shown here that increasing CH2), 3.22 (6H, s, CH2); 13C NMR (75 MHz, D2O): δC (ppm)
the steric compression around the water coordination site may 174.73 (COOH), 166.01 (CPh), 131.02 (CPh), 130.30 (CPh), 129.46
have opposite effects on the water exchange rates of Gd3+ and Mn2+ (CPh), 60.54 (CH2), 57.55 (CH2), 50.69 (CH2), 50.45 (CH2), 49.22
complexes.
(CH2). Mass spectrometry (ESI+) m/z (%BPI): 336.19 (100)
([C17H26N3O4]+), 358.17 (10) ([C17H25N3NaO4]+), 374.15 (7)
([C17H25KN3NaO4]+). HR-MS (ESI+) m/z: [M+Na]+, calculated:
336.1917, found: 336.1931.
Experimental Section
Synthesis of di-tert-butyl 2,2'-(7-(1-phenylethyl)-1,4,7-
triazonane-1,4-diyl)-diacetate (H2MeBzNO2AtBu, 2b). This
compound was obtained using NO2AtBu (0.2066 g, 0.578
mmol), α-methylbenzyl bromide (1b, 81.3 µL, 1 eq) and K2CO3
Materials and methods
NO2AtBu was purchased from CheMatech (Dijon, France). All
other reagents and solvents were commercial and used
without further purification. 1H and 13C NMR spectra were
recorded at 25⁰C on Bruker Avance 300 MHz and Bruker
Avance 500 MHz spectrometers. High resolution electrospray-
ionization time-of-flight (ESI-TOF) mass spectra were obtained
in the positive mode using a LC-Q-q-TOF Applied Biosystems
QSTAR Elite spectrometer. Elemental analyses were carried
out on a ThermoQuest Flash EA 1112 elemental analyser.
Medium performance liquid chromatography (MPLC) was
carried out 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
lyophilised using a Telstar Cryodos-80 apparatus.
1
(0.121 g, 1.5 eq). Yellowish oil (0.267 g, quantitative). H NMR
(300 MHz, CDCl3): δH (ppm) 7.34-7.32 (2H, d, CHPh), 7.27-7.22
(2H, t, CHPh), 7.18-7.13 (1H, t, CHPh), 3.79 (1H, s, CH), 3.24 (4H,
s, CH2), 2.90-2.69 (12H, m, CH2), 1.40 (18H, s, CH3), 1.32-1.31
(4H, d, CH3). 13C NMR (75 MHz, CDCl3): δC (ppm) 171.48
(COOtBu), 144.60 (CPh), 127.97 (CPh), 127.83 (CPh), 126.52 (CPh),
80.50 (-OC(CH3)3), 63.17 (CH), 59.58 (CH2), 55.93 (CH2), 55.20
(CH2), 52.71 (CH2), 28.18 (-OC(CH3)3). Mass spectrometry (ESI+)
m/z (%BPI): 462.33 (100) ([C26H44N3O4]+), 406.27 (12)
([C22H36N3O4]+).
Synthesis of 2,2'-(7-(1-phenylethyl)-1,4,7-triazonane-1,4-
diyl)diacetic acid (H2MeBzNO2A). Yellowish solid (0.200 g,
1
quantitative). H NMR (300 MHz, D2O) ): δH (ppm) 7.57-7.53
Synthetic procedures.
(5H, m, CHPh), 3.65 (16H, m, CH2), 3.18 (1H, s, CH), 1.79-1.77
(3H, d, CH2). 13C NMR (75 MHz, D2O): δC (ppm) 174.77 (COOH),
135.36 (CPh), 132.13 (CPh), 131.16 (CPh), 130.56 (CPh), 67.96
(CH), 57.75 (CH2), 51.72 (CH2), 50.86 (CH2), 15.66 (CH3). Mass
spectrometry (ESI+) m/z (%BPI): 350.21 (100) ([C18H28N3O4]+),
372.19 (17) ([C18H27N3NaO4]+), 388.15 (12) ([C18H27KN3O4]+).
HR-MS (ESI+) m/z: [M+Na]+, calculated: 350.2074, found:
350.2071.
General procedure for synthesis of the ligands
Triazacyclononane derivative NO2AtBu was dissolved in CH3CN
(20 mL) in the presence of K2CO3. A solution of the
corresponding bromide precursor in CH3CN (20 mL) was added
dropwise to the suspension and the mixture was stirred during
48 h at room temperature. Once the alkylation was completed,
the reaction mixture was filtered and the filtrate concentrated
in vacuum at low temperature (30⁰C) to afford yellowish oils
that were characterised by 1H and 13C NMR and mass
spectrometry (see details below), and used in the next step
Synthesis
of
tetra-tert-butyl
2,2',2'',2'''-((1,3-
phenylenebis(methylene))bis(1,4,7-triazonane-7,1,4-
triyl))tetraacetate (mBz(NO2AtBu)2, 2c). This compound was
8 | Dalton Trans., 2016, 00, 1-14
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obtained using NO2AtBu (0.3022 g, 0.8453 mmol), α,α′- 1H NMRD and 17O NMR measurements. The proton 1/T1 NMRD
View Article Online
dibromo-m-xylene (1c, 0.1151 g, 0.5 eq) and K2CO3 (0.294, 5 profiles were measured on
eq). Yellow oil (0.345 g, quantitative). 1H NMR (300 MHz, SmartTracer relaxometer (Mede, Pv, Italy) over a continuum of
CDCl3): δH (ppm) 7.42 (1H, t, CHPh), 7.28-7.26 (2H, d, CHPh), magnetic field strengths from 0.00024 to 0.25
a
fastDOfIi:e1l0d.-1c0y3c9l/iCn9gDT0S0t2e1l1aAr
T
7.06-7.04 (1H, d, CHPh), 3.97 (2H, s, CH2), 3.01-2.52 (30H, m, (corresponding to 0.01-10 MHz proton Larmor frequencies).
CH2), 1.72-1.69 (4H, s, CH2), 1.13-1.11 (36H, d, CH3). 13C NMR The relaxometer operates under computer control with an
(75 MHz, CDCl3): δC (ppm) 170.53 (COOtBu), 131.54 (CPh), absolute uncertainty in 1/T1 of ± 1%. The temperature control
129.95 (CPh), 129.00 (CPh), 116.45 (CPh), 81.00 (-OC(CH3)3), was carried out using a Stelar VTC-91 airflow heater equipped
59.86 (CH2), 57.72 (CH2), 52.48 (CH2), 27.86 (-OC(CH3)3). Mass with
a
calibrated copper–constantan thermocouple
spectrometry (ESI+) m/z (%BPI): 817.58 (15) ([C44H77N6O8]+), (uncertainty of ±0.1 K). Additional data points in the range 20-
409.29 (100) ([C44H78N6O8]2+).
Synthesis of
60 MHz were obtained on a Stelar Relaxometer equipped with
2,2',2'',2'''-((1,3- a Bruker WP80 NMR electromagnet adapted to variable-field
phenylenebis(methylene))bis(1,4,7-triazonane-7,1,4-
measurements (15-80 MHz proton Larmor frequency). The
triyl))tetraacetic acid (mBz(H2NO2A)2). Reddish solid (0.250 g, exact complex concentration was determined by the BMS shift
1
quantitative). H NMR (300 MHz, D2O): δH (ppm) 7.66 (4H, m, method at 11.7 T.34 17O NMR measurements were recorded on
CHPh), 3.67-3.13 (32H, m, CH2), 1.21 (4H, s, CH2); 13C NMR (75 a Bruker Avance III spectrometer (11.7 T) equipped with a 5
MHz, D2O): δC (ppm) 165.37-165.02 (COOH), 135.25 (CPh), mm probe and standard temperature control unit. Aqueous
134.48 (CPh), 132.15 (CPh), 61.95 (CH2), 52.33 (CH2), 51.95 solution of the complexes (ca. 6-10 mM) containing 2.0% of
(CH2), 50.81 (CH2). Mass spectrometry (ESI+) m/z (%BPI): the 17O isotope (Cambridge Isotope) were used. The observed
631.27 (100) ([C28H44KN6O8]+), 593.33 (20) ([C28H45N6O8]+), transverse relaxation rates were calculated from the signal
669.22 (33) ([C28H43K2N6O8]+). HR-MS (ESI+) m/z: [M+Na]+, width at half-height.
calculated: 593.3293, found: 593.3268.
pH stability range. Solutions of [Mn(BzNO2A)], [Mn(MeBzNO2A)]
General procedure for synthesis of the complexes
and [mBz(MnNO2A)2] (1 mM) were prepared in the pH range 1.72–
10.5. The longitudinal relaxation rates were measured at 20 MHz
and 298 K. The measurements were carried out in a BrukerMinispec
MQ 20.
The corresponding triazacyclononane ligand derivative was
dissolved in n-BuOH (10 mL) in the presence of DIPEA (5 eq.)
with the assistance of an ultrasound bath. The solution was
purged with an argon flow and afterwards the solid
manganese salt, MnCl2·4H2O, was added. The reaction was
maintained at 112 ⁰C for 6 h. The reaction was stopped and
allowed to cool down to room temperature. The reaction
mixture was concentrated in vacuum and redissolved in
dichloromethane. The product was extracted with water (4x5
mL) and the aqueous phase was evaporated to furnish a
yellowish solid. The solid was purified by MPLC using a reverse-
phase C18 column. An aqueous solution of the compound in
the eluting conditions (CH3CN:H2O, v:v, containing 0.1%
triethylamine) was prepared and filtered through a cellulose
filter (0.20 µm pore size) before injection. The purification
method was carried out in gradient of solvent B (CH3CN, 5 to
10%) in solvent A (H2O). The fractions containing the complex
were combined and the solvent was removed in vacuum. The
final product was redissolved in water and lyophilised to
furnish the final complexes.
Synthesis of [Mn(BzNO2A)]. Yellowish solid (0.066 g, 34%).
Mass spectrometry (ESI+) m/z (%BPI): 411.1 (100)
([C17H23N3O4NaMn]+). HR-MS (ESI+) m/z: [M+Na]+, calculated:
411.0961, found: 411.0954.
Synthesis of [Mn(MeBzNO2A)]. Yellowish solid (0.086 g, 37%).
Mass spectrometry (ESI+) m/z (%BPI): 425.11 (100)
([C18H25N3O4NaMn]+), 403.13 (17) ([C18H26N3O4Mn]+). HR-MS
(ESI+) m/z: [M+Na]+, calculated: 425.1117, found: 425.1113.
Synthesis of [mBz(MnNO2A)2]. Yellowish solid (0.090 g, 39%).
Mass spectrometry (ESI+) m/z (%BPI): 721.16 (100)
([C28H40N6O8NaMn2]+), 699.18 (8) ([C28H41N6O8Mn2]+). HR-MS
(ESI+) m/z: [M+Na]+, calculated: 721.1560, found: 721.1551.
Computational details. Full geometry optimisations of the
[Mn(MeNO2A)(H2O)]·xH2O (x = 2, 5), [Mn(BzNO2A)(H2O)]·2H2O,
[Mn(MeBzNO2A)(H2O)]·2H2O and [mBz(MnNO2A)2]·3H2O systems
were performed employing DFT calculations at the
M06-2X/TZVP35,36 level employing the Gaussian 09 package
(Revision E.01).37 Solvent effects (water) were introduced by using
the integral equation formalism variant of the polarizable
continuum model (IEFPCM).38 No symmetry constraints have been
imposed during the optimisations. All stationary points found as a
result of geometry optimisation were confirmed to represent
energy minima on the potential energy surfaces via frequency
analysis. 17O hyperfine coupling constants were calculated using the
M06-2X functional in combination with aug-cc-pVTZ-J basis set for
Mn39 and the EPR-III40 basis set for the ligand atoms.
The potential energy surface of the [Mn(MeNO2A)(H2O)]·5H2O
system was investigated by performing relaxed potential energy
surface scans, which were generated by either: i) increasing the
distance between Mn and the oxygen atom of the coordinated
water molecule in steps of 0.1 Å, and ii) Shortening the distance
between a second-sphere water molecule and the Mn atom in
steps of 0.1 Å. The geometries generated from these calculations
were subsequently used to calculate the transition state
characterising the associative water exchange mechanisms with the
aid of the synchronous transit-guided quasi-Newton approach.41
Saddle points were characterised using frequency calculations,
which also provided zero-point energies (ZPEs), enthalpies (H) and
free energies (G) at 298.15 K and 1 atm.
Acknowledgements
This journal is © The Royal Society of Chemistry 2016
Dalton Trans., 2016, 00, 1-14 | 9
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Dalton Transactions
I. Brandariz, E. Iglesias, C. Platas-Iglesias, M. Botta and D.
Authors R. P.-P., I. B., E. I., C. P.-I. and D. E.-G. thank Ministerio de
Economía y Competitividad (CTQ2016-76756-P) and Xunta de
Galicia (ED431B 2017/59 and ED431D 2017/01) for generous
financial support and Centro de Supercomputación of Galicia
(CESGA) for providing the computer facilities. R. P.-P. thanks
Ministerio de Economía y Competitividad for a PhD FPI grant (BES-
2014-068399) and a fellowship for a short term stay in Alessandria
(EEBB-I-18-13075). M.B. and F.C. are grateful to Università del
Piemonte Orientale for financial support (Ricerca locale 2016). This
work was carried out within the framework of the COST CA15209
Action “European Network on NMR Relaxometry”.
View Article Online
Esteban-Gomez, Dalton Trans., 2019, 4D8O, 6I:9106..1039/C9DT00211A
11 G. F. Kwakye, M. M.B. Paoliello, S. Mukhopadhyay, A. B.
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Baranyai, E. Brucher, F. Uggeri, A. Maiocchi, I. Toth, M.
Andrasi, A. Gaspar, L. Zekany and S. Aime, Chem. Eur. J.,
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14 E. Balogh, Z. He, W. Hsieh, S. Liu and É. Tóth, Inorg. Chem.,
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Table of Contents Entry
Steric hindrance around the Mn2+ ion affects dramatically the water exchange rate of the
coordinated water molecule.