Accelerating water exchange in GdIII-DO3A-derivatives by favouring the dissociative mechanism through hydrogen bonding

Article abstract of DOI:10.1039/c8cc08556k

The Gd^III-complexes of DO3A-acetophenone and ortho- or para- hydroxyacetophenone ligands have been investigated to assess the effect of the presence of a phenol group on the relaxivity and on the water exchange rate of these potential MRI contr

Full text of DOI:10.1039/c8cc08556k

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Accelerating water exchange in GdIII–DO3A-
derivatives by favouring the dissociative
mechanism through hydrogen bonding†
Cite this: Chem. Commun., 2019,
55, 513
Received 25th October 2018,
Accepted 10th December 2018
a
b
b
Loredana Leone,
Marco Milanesio
David Esteban-Gomez,
Carlos Platas-Iglesias,
´
a
a
and Lorenzo Tei
*
DOI: 10.1039/c8cc08556k
rsc.li/chemcomm
The GdIII-complexes of DO3A-acetophenone and ortho- or para- structure was also proved to be a successful strategy to accel-
hydroxyacetophenone ligands have been investigated to assess the erate water exchange. This was achieved by enlarging the size of
effect of the presence of a phenol group on the relaxivity and on the macrocycle in DOTA from a 12- to a 13-membered ring,5 or
the water exchange rate of these potential MRI contrast agents. by replacing an acetate arm by bulkier propionate or phospho-
H-Bonding between the ortho-phenol(ate) groups and the water nate arms in both macrocyclic6 and non-macrocyclic ligands.7
molecules involved in the dissociative exchange mechanism is Water exchange in GdIII complexes often proceeds through a
shown to speed up the water exchange rate by stabilizing the dissociative mechanism and all strategies to increase kex rely on
eight-coordinate transition state.
the destabilization of the reactant, typically a nine-coordinate
q = 1 complex, with respect to the eight-coordinate transition
Positive Magnetic Resonance Imaging (MRI) contrast agents state. Intramolecular hydrogen bonds between an H-bond
(CAs) are paramagnetic metal complexes able to reduce the acceptor present on a pendant arm and the coordinated water
longitudinal relaxation time (T1) of protons in their vicinity. molecule (or the coordinated hydroxyl group) have been
Their efficiency (relaxivity, r1) depends on several structural recently shown to increase the relaxivity of small molecular
features of the complex, typically GdIII or MnII derivatives, weight GdIII complexes by restricting the rotation about the
affecting the mode of interaction and magnetic coupling Gd–Ow bond or by accelerating proton exchange, respectively.8,9
between the paramagnetic ion and the surrounding water However, in these examples the H-bond formation did not
molecules. Among them, the exchange rate (kex) of the water involve modulation of kex.
molecule coordinated to the metal center is a parameter of
In this work we present acetophenone, 20- and 40-hydroxy-
paramount importance.1 Different strategies have been developed phenacyl derivatives of DO3A (DO3A-AP, DO3A-oHAP and
to control kex by modifying the structural and electronic features DO3A-pHAP, DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic
of GdIII complexes.2 For instance, it is well known that the acid, Scheme 1) and a detailed study of the water exchange rates
GdDOTA complex and related systems may exist in solution as of the inner-sphere water molecules present in their GdIII
two diastereoisomers with either capped square antiprismatic complexes. DO3A-AP and p-methoxy and p-dimethylamino
(SAP) or capped twisted-square antiprismatic (TSAP) coordination substituted derivatives have already been described in the
polyhedra.3 TSAP isomers present higher kex values than SAP literature,10 with the ketone-sensitised luminescence study on
isomers, due to a more pronounced steric hindrance around the corresponding EuIII complexes. Herein, we will show that
the coordinated water molecule.4 Steric compression around the presence of hydrogen-bond acceptors in the periphery of
the coordinated water molecule by modification of the ligand
a Dipartimento di Scienze e Innovazione Tecnologica (DiSIT),
`
Universita degli Studi del Piemonte Orientale ‘‘Amedeo Avogadro’’,
Viale T. Michel 11, I-15121 Alessandria, Italy. E-mail: lorenzo.tei@uniupo.it
b
´
´
Centro de Investigacions Cientıficas Avanzadas (CICA) and Departamento de
´
˜
˜
Quımica, Facultade de Ciencias, Universidade da Coruna, 15071 A Coruna,
Galicia, Spain
† Electronic supplementary information (ESI) available: Experimental details,
crystallographic data, spectroscopic data and geometries obtained with DFT.
CCDC 1875349. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8cc08556k
Scheme 1 Chemical structures of DO3A-AP and DO3A-HAP ligands.
Chem. Commun., 2019, 55, 513--516 | 513
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the coordinated water molecule accelerates dramatically the molecules is formed because the phenol group stand out of the
water exchange rate.
Gd-DO3A pseudo-spherical moiety (Fig. S6, ESI†).
1
The synthesis of DO3A-HAP chelators started from the reaction
A high-resolution H NMR investigation on the EuDO3A-AP
of DO3A(tBu)3 with o- or p-methoxy-2-bromoacetophenone and EuDO3A-HAP complexes (pH 7 and 283, 298 and 310 K)
followed by simultaneous deprotection of the methyl ether allowed to determine the ratio between SAP and TSAP isomers
and the tert-butyl esters by using MeOH : HBr (aq) (1 : 1/v : v) in solution (Fig. S7–S10, ESI†).12 In the case of EuDO3A-oHAP,
into a microwave oven (60 1C, 70 W, 18 psi, 15 min) (Scheme S1 the 1H NMR spectra were recorded at two different pH, 3.5 and
in ESI†). Complexation was accomplished by using the LnCl3 9.5, in order to obtain the spectra of both protonated and
salts (LnIII = Gd, Eu) in water at pH 7. Free lanthanide ion deprotonated species. In all cases, a higher amount (72–78%) of
excess was eliminated by precipitation and filtration of the SAP isomer was found.
hydroxide at basic pH. The pH dependence of the relaxivity (r1) of
A complete 1H and 17O NMR relaxometric study was carried
GdDO3A-HAP complexes was measured to assess the possible out to obtain detailed information of the physicochemical
change in r1 with deprotonation of the phenol group. The graph properties of the complexes. The r1 values for GdDO3A-AP and
of r1 vs. pH (Fig. S11, ESI†) shows no evident change in r1 in the GdDO3A-HAP (both ortho and para derivatives) at 20 MHz, 298
range of pH 2–12, whereas variable pH UV-vis measurements on and 310 K and pH 7.0 are listed in Table 1 (for GdDO3A-oHAP r1
DO3A-HAP ligands and on the corresponding GdIII-complexes values are reported at pH 4 and 9). The r1 values are consistent
(Fig. S1–S3, ESI†) show a red shift of the absorption upon with the presence of one water molecule in the inner coordina-
deprotonation of the phenol group. Similarly to other GdIII tion sphere of the metal ion (q = 1), although they are slightly
complexes having a pH sensitive ligating group,11 the differences higher than the values measured in analogous conditions for
in pKa between ligands and GdIII complexes (9.87 ꢀ 0.09 for other q = 1 Gd-complexes of comparable molecular weight.
DO3A-oHAP; 8.67 ꢀ 0.01 for DO3A-pHAP; 7.69 ꢀ 0.04 for For GdDO3A-oHAP, the relaxometric properties were studied
GdDO3A-oHAP; 7.01 ꢀ 0.03 GdDO3A-pHAP) can be attributed independently at acid and basic pH (pH 4 and 9) in order to
to the delocalization of the anionic charge driven by the check a possible pH dependence of the relaxometric parameters.
metal ion and formation of an enolate anion. Interestingly, for Notably, the variable-temperature 17O R2 profiles of GdDO3A-
DO3A-oHAP and GdDO3A-oHAP the pKa are higher due to the oHAP at both pH (Fig. 1A and Fig. S13, ESI†) are clearly different
six-membered H-bonded ring between the carbonyl oxygen and from those of the other Gd-chelates, showing an R2 decrease
the phenolic OH that reduces the electron withdrawing effect of with increasing T.
the acyl group on pKa (Fig. S2, ESI†).
For all complexes, the presence of two species with very
The single crystal X-ray diffraction analysis (see ESI† for details) different water exchange dynamics can be envisaged by the
of GdDO3A-oHAP was carried out on a thin lamina and the crystal shapes of the curves that are distant from the simple pseudo-
structure showed a P21/c space group (CCDC 1875349†). The exponential decay expected for systems containing one coordi-
complex presents a SAP coordination around the GdIII metal centre nated water molecule in exchange with bulk solvent. Thus, we
with a cis/trans disordered 2-hydroxyacetophenone moiety considered the presence in solution of the SAP and TSAP
1
with a 20/80 ratio (Fig. S4, ESI†), suggesting the presence isomers observed in the H NMR spectra of the corresponding
of the two conformations in solution. The phenolic OH forms Eu-complexes. Similar observations were recently reported for
an intermolecular H-bond in trans conformation while an GdHPDO3A,13 a hydroxyphenyl derivative of GdHPDO3A,14 and
intramolecular water assisted H-bond is observed in the cis previously for two GdDOTA–bisamide complexes15 showing
conformation (Fig. S5, ESI†). Notably, the Gd–Owater distance that the TSAP isomer, present in lower concentration, has
(2.37(1) Å) is rather short compared to similar structures in a tM (tM = 1/kex) significantly shorter than that observed for
CCDC. Moreover, a peculiar porous network, filled by water the SAP isomer. The variable-temperature 17O R2 profiles were
Table 1 Best-fit parameters obtained from the analysis of the 1/T1 1H NMRD profiles (298 K) and 17O NMR data for GdHPDO3A,a GdDO3A-AP, GdDO3A-
oHAP (at pH 4 and 9) and GdDO3A-pHAPb
Parameter
r2198 (mMꢁ1 sꢁ1 c
Isom.
GdHPDO3A
GdDO3A-AP
GdDO3A-oHAP (pH 4)
GdDO3A-oHAP (pH 9)
GdDO3A-pHAP
)
4.6
3.6
65
640
8.9
9.9
1.5
8
5.1 ꢀ 0.1
4.6 ꢀ 0.1
100 ꢀ 2
1200 ꢀ 20
25 ꢀ 2
6.4 ꢀ 0.2
5.4 ꢀ 0.3
105 ꢀ 3
210 ꢀ 5
2.2 ꢀ 0.1
8.5 ꢀ 0.5
3.0 ꢀ 0.4
5.7 ꢀ 0.2
24.8 ꢀ 0.3
34 ꢀ 2
6.4 ꢀ 0.2
4.9 ꢀ 0.3
105 ꢀ 3
256 ꢀ 12
4.7 ꢀ 5
5.8 ꢀ 0.1
4.9 ꢀ 0.2
95 ꢀ 5
r3110 (mMꢁ1 sꢁ1 c
)
t2R98 (ps)
t2M98 (ns)
SAP
TSAP
SAP
TSAP
SAP
TSAP
SAP
950 ꢀ 10
7.1 ꢀ 0.7
7.0 ꢀ 0.3
3.3 ꢀ 0.2
5.8 ꢀ 0.1
3.4 ꢀ 0.2
54 ꢀ 3
D2 (1019 sꢁ2
t2V98 (ps)
)
9.8 ꢀ 0.3
5.0 ꢀ 0.2
5.1 ꢀ 0.1
14.8 ꢀ 0.3
50 ꢀ 2
4.7 ꢀ 0.5
3.2 ꢀ 0.3
6.5 ꢀ 0.3
30.0 ꢀ 0.5
37 ꢀ 2
30
53
15
EM (kJ molꢁ1
)
TSAP
27 ꢀ 1
40 ꢀ 1
39 ꢀ 1
32 ꢀ 2
a
b
298
From ref. 13. The parameters fixed in the fitting procedure are: q = 1, rGdO = 2.5 Å, rGdH = 3.0 Å, aGdH = 4.0 Å,
D
= 2.25 ꢂ 10ꢁ5 cm2 sꢁ1
,
GdH
ER = 1.6 kJ molꢁ1, Ev = 1 kJ molꢁ1, A/ꢀh = ꢁ3.6 ꢂ 106 rad sꢁ1
. 20 MHz.
c
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Fig. 1 Transverse 17O relaxation rates measured at 11.74 T for (A) GdDO3A-oHAP at pH 9, 13.1 mM and (B) for GdDO3A-pHAP at pH 7, 19.2 mM. The red
and blue lines represent the calculated contributions of the isomeric species SAP and TSAP, respectively. (C) 1H NMRD profiles recorded at 298 for
GdDO3A-oHAP at pH 9 (empty circles) and GdDO3A-pHAP at pH 7 (black triangles).
fitted according to the well-established set of Swift–Connick are crucial for a proper description of the Gd–Owater distances
equations16 using a model that considers the presence in and spin-density distributions.22 Bulk solvent effects were
solution of two isomeric species whose relative population is considered by using a polarizable continuum model. The
extrapolated from the 1H NMR spectra of the Eu-complexes (the optimized geometry of the GdDO3A-oHAP system presents a
TSAP/SAP ratio is considered constant over the range of tem- slightly longer Gd–Owater distance (2.503 Å) than GdDO3A-AP
peratures under examination, Fig. S7–S10, ESI†). Moreover, the (2.469 Å). The exchange of the coordinated water molecule with
Nuclear Magnetic Resonance Dispersion (NMRD, Fig. S12, ESI†) bulk water in this type of complexes follows a dissociative
data were analysed using the standard Solomon Bloembergen mechanism, and thus a longer Gd–Owater distance anticipates
Morgan model for the inner-sphere relaxation mechanism17 and a faster water exchange.23 The coordinated water molecule in
Freed’s model for the outer-sphere components18 considering a GdDO3A-oHAP is involved in hydrogen-bonding interaction
weighted average of the values obtained for the two isomers by with the oxygen atom of the phenolate group. The water
fitting the 17O NMR data (Table 1). The rotational correlation exchange reaction in these complexes was further investigated
time tR, considering that two isomers have similar rotational by locating the transition states (TS) connecting the nine-
dynamics, was determined for all complexes by fitting the NMRD coordinate complexes and the eight-coordinate intermediate
profiles. Values in the range 90–105 ps were found, in line with generated in a dissociative pathway (Fig. 2). The Gdꢃ ꢃ ꢃOwater
tR values obtained for Gd-complexes of analogous molecular distances in these TSs are much more different than in case of
volume.1 The fitting data were compared in Table 1 to the the fundamental state, being 3.606 and 3.436 Å for GdDO3A-AP
parameters reported for GdHPDO3A in which the model for and GdDO3A-oHAP, respectively. In GdDO3A-oHAP the water
the two isomeric species was also considered. The results show a molecule leaving the GdIII coordination environment is hydrogen-
fast kex for all TSAP isomers (tM ranges from 2.2 to 25 ns) but a bonded to the phenolate group, which stabilizes the eight-
marked difference in the tM of the SAP isomer of GdDO3A-oHAP coordinate transition state. The activation free energies (DG #298
)
(E200 ns) with respect to the other Gd-complexes (E1 ms). obtained with DFT (36.3 and 21.8 kJ molꢁ1 for GdDO3A-AP and
Notably, this fast kex for the SAP isomer GdDO3A-oHAP does
not change with pH and thus passing from a neutral to an
anionic complex. The fast kex for GdDO3A-oHAP clearly suggests
that, in solution, the 2-hydroxyacetophenone moiety must be
cis conformation and the o-phenolic OH involved in the kex
acceleration. This is maybe due to solvent assisted H-bonding
to the coordinated water molecule, as shown by the cis con-
formation of the crystal structure (Fig. S5, ESI†). Notably,
in case of GdDO3A-pHAP, when the OH points outside the
coordination cage, the kex of the SAP isomer is slow as in case
of the simple acetophenone system, or LnIII–DOTA-derivatives
having ketone donor pendant arms.19
A Density Functional Theory (DFT) study was performed to
gain further insight into the fast water exchange observed for
the SAP isomer of GdDO3A-oHAP. Thus, the structures of the
SAP isomers of GdDO3A-AP and deprotonated GdDO3A-oHAP
Fig. 2 Structures of the local energy minima (left) and transition states
(right) characterizing the dissociative water exchange mechanism in
were optimized at the M062X/LCRECP/6-311G(d,p)20,21 level
(see computational details in ESI†). The model systems inves-
tigated included a few second-sphere water molecules, which
GdDO3A-AP and GdDO3A-oHAP. The numbers represent the calculated
activation free energies in kJ molꢁ1
.
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GdDO3A-oHAP, respectively) further confirm the TS stabilization. Conflicts of interest
Thus, intramolecular hydrogen-bonding interactions with the
peripheral phenolate group favour the exchange of the coordi-
There are no conflicts to declare.
nated water molecule, thereby accelerating kex. The analysis
Notes and references
of the activation enthalpies (DH#) and entropies (DS#)
provides additional insight into the reasons behind the fast
water exchange rate in GdDO3A-oHAP. For GdDO3A-AP our
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DFT calculations provide DH# = 42.0 kJ molꢁ1 and DS#
=
+19.2 J molꢁ1
K
ꢁ1. Positive DS# values are expected for a
dissociatively activated mechanism. In the case of GdDO3A-oHAP
we obtained DH # = 17.4 kJ molꢁ1 and DS# = ꢁ14.8 J molꢁ1 Kꢁ1
.
The lower DH# value obtained for GdDO3A-oHAP is likely the
result of (i) a weaker (longer) Gd–Owater bond, and (ii) the
strengthening of the hydrogen-bonding interaction involving
the departing water molecule and the phenolate oxygen atom
on moving from the ground to the transition state. The low DH#
in GdDO3A-oHAP is compensated in part by an unfavourable
entropy contribution, which we ascribe to the formation of
an ordered hydrogen bonding network in the TS of GdDO3A-
oHAP (involving the departing water molecule, the phenolate
oxygen atom and second-sphere water molecules). The DFT
calculations have known limitations, in particular regarding
the accuracy of the entropy contributions, given the limited
number of explicit water molecules included in the model.
Nevertheless, they strongly support the stabilization of the TS
through H-bond, with consequent lowering of the energy
barrier and acceleration of the water exchange reaction in
GdDO3A-oHAP. This effect is rather common in biochemistry
and catalysis, as for instance in the amide bond-formation
process.24
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Interestingly, the reduction of the ketone to hydroxyl group
in GdHPDO3A-phenol chelate reported recently9,14 did not
result in an increase of the kex.14 However, intramolecular
H-bonding between the coordinated hydroxyl group and the
phenolate group generated a relaxivity increase due to proton
exchange.9 Therefore, we can highlight that the acceleration of
kex requires not only H-bond between the coordinated water
molecule and the phenolate oxygen, but also a conjugated sp2
ortho-hydroxyacetophenone system.
In conclusion, we have shown that hydrogen bonds involving
the coordinated water molecule and heteroatoms in the periph-
ery of the water binding site can accelerate water exchange rate
by an order of magnitude. As a result, both the SAP and TSAP
298
ex
isomers of GdDO3A-oHAP present very high k
values. These
16 T. J. Swift and R. E. Connick, J. Chem. Phys., 1962, 37, 307.
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GdIII-based contrast agents, as fast water exchange rates
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C. Platas-Iglesias, ChemPhysChem, 2012, 13, 3640.
23 M. Regueiro-Figueroa and C. Platas-Iglesias, J. Phys. Chem. A, 2015,
CA15209 ‘‘European Network on NMR Relaxometry’’. The
´
authors thank Centro de Supercomputacion de Galicia (CESGA)
119, 6436.
for providing the computer facilities.
24 A. Rimola, M. Sodupe and P. Ugliengo, J. Phys. Chem. C, 2016, 120, 24817.
516 | Chem. Commun., 2019, 55, 513--516
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