Ab Initio Design Of Chelating Ligands Relevant To Alzheimer'S Disease: Influence Of Metalloaromaticity - Physical Chemisrty Page 4
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8The Journal of Physical Chemistry A
ARTICLE
Table 2. Computed Reaction Free Energies at T = 298 K,
Table 1. B3LYP Main Structural Parameters of the Chelating
a
ΔG
Ligands and of Their Cu(II) Complexes
(in kilocalories per mole), and Stability Constants,
sol
log β
, of the Formation of the Complexes According to the
2
2+
+
ligand
complex
Reaction [Cu(H
O)
]
+ 2HL f [Cu(L)
] + 4H
O + 2H
system
2
4
2
2
ÀOHn and NÀOH4 Ligands) in Water (ε = 78.4)
(HL = N
ÀOHn
N
X
R(CuÀN) j(NCuO/OCuN)
X
H-bond
R(CuÀO)
ΔG
log β
complex
ÀOH1
sol
2
N
1.721
1.920
1.999
33.5
NH
ÀOH2
À20.5
1.735
1.933
1.983
0.0
15.1
N
[Cu(N
-O1)
]
NH
NH
2
ÀOH3
À26.0
N
1.781
1.964
1.979
0.0
[Cu(N
-O2)
]
19.1
NH
NH
2
ÀOH1
À32.9
N
1.796
1.917
2.004
33.4
[Cu(N
-O3)
]
24.1
O
NH
2
ÀOH2
À20.6
1.801
1.934
1.978
0.0
15.1
N
[Cu(N
-O1)
]
O
O
2
ÀOH3
À25.7
N
1.827
1.964
1.971
0.0
[Cu(N
-O2)
]
18.8
O
O
2
ÀOH1
À33.7
N
1.739
1.904
2.024
39.8
[Cu(N
-O3)
]
24.7
S
O
2
ÀOH2
À15.0
N
1.739
1.913
2.024
0.0
[Cu(N
-O1)
]
11.0
S
S
2
ÀOH3
À22.0
N
1.781
1.945
2.015
0.0
[Cu(N
-O2)
]
16.1
S
S
2
À31.1
NÀOH4
1.644
1.982
1.933
0.0
[Cu(N
-O3)
]
22.8
S
2
a
À42.1
H-bond refers to hydrogen bond distance in the neutral ligand, R to
[Cu(NÀO4)
]
30.8
2
bond lengths in the complex, and j to the dihedral angle between
log β
metalated ring planes. Distances are in angstroms and angles are in
are summarized in Table 2. First of all, the good agreement
2
degrees.
observed between the computed log β
stability constants of
2
ÀOH1 and N
ÀOH1 (15.1
[Cu(L)
] complexes with L = N
2
O
S
ÀOHn, X = O, S, NH, n = 1, 2, 3, 4 in Scheme 1) are
work (N
and 11.0, respectively) with the values determined experimen-
X
38
38
based on previously characterized ones
by simplifying their
tally by UVÀvis pH titrations (14.4 and 12.0) is remarkable,
aromatic moieties. Their coordination to Cu(II) leads to metal/
which provides confidence of the strategy employed in the
ligand 1:2 stoichiometric systems, in which the binding OH group
present study. For all X groups considered (NH, O, and S),
deprotonates, thereby forming neutral [Cu(L)
] complexes, with
results indicate that the chelating ability of the different ligands
2
ÀOH3 > N
ÀOH2 >
two metalated rings that may manifest aromatic properties. This
follows the order: NÀOH4 > N
X
X
ÀOH1; that is, the lesser aromatic the moieties in the ligand
set of metal ion chelators will allow us to analyze how much the
N
X
π electronic properties of the ligand influence the metalloaro-
the more favorable the complex formation. The less chelating
ÀOH1, which can also be
maticity and the stability of the complex formed upon coordina-
ability is clearly observed for N
X
tion to Cu(II). It is worth mentioning that NÀOH4 is not in its
attributed to the fact that it leads to the most distorted complex
most stable form, which corresponds to the tautomer including
(j around 33À39°). For the same aromatic backbone, the
complex stability as a function of X follows the trend: O ≈
NH
and CdO functionalities. However, because NÀOH4
2
NH > S. This is likely due to the presence of S in the five-
arises from the complete removal of the aromatic moieties, the
data derived from this ligand can be considered as a limiting case.
membered ring, which decreases the electronic density of the
The optimized [Cu(L)
] complexes and the main structural
coordinating N as compared with ligands with X = O or NH, in
2
features computed at the B3LYP level are shown in Figure 1 and
agreement with the trend observed for the CuÀN distance in the
Table 1, respectively. Similarly to that observed for HCQ
different complexes.
77
coordinating to Cu(II)
and in agreement with the EPR experi-
Energy Decomposition Analysis.
With the purpose of
ÀOH1 and N
ÀOH1),
38
ments of [Cu(L)
] (L = N
the [Cu(L)
]
acquiring a better understanding on the bonding between Cu(II)
2
O
S
2
ÀOHn (n = 2, 3, and 4) ligands
complexes formed with the N
and the ligands and the corresponding reaction energies, pre-
X
adopt a square-planar geometry. Values of the dihedral angle
vious to the analysis of the metalloaromaticity, we have per-
defined by the two metalated ring planes (j) have also been
formed an EDA at the B3LYP/TZ2P level of theory using the
incorporated as a way to gauge the planarity of the complexes.
B3LYP/10s7p4d1f]-optimized geometries. For these calcula-
Not unexpectedly considering that the coordinating oxygen atom
tions, we have considered three fragments for each complex:
always has a larger negative charge than the coordinating nitrogen
the Cu(II) metal ion and the two equivalent anionic ligands. The
one, the R(CuÀO) bond distance is shorter than the R(CuÀN)
values obtained for the [Cu(N
-On)
] (n = 1À3) family
NH
2
one in all cases. Interestingly, a correlation between the R(CuÀN)
complex and for [Cu(NÀO4)
] are shown in Table 3. As it can
2
and R(CuÀO) bond distances for each [Cu(N
-On)
] complex
be seen, the preparation energies (ΔE
) are relatively small and
X
2
prep
is observed: the shorter the R(CuÀN) the longer the R(CuÀO).
very similar for the different compounds. The interaction energies
The relative rigidity of the ligand explains why the reduction of
(ΔE
) follow the above-mentioned trend of the reaction ener-
int
the R(CuÀO) bond length implies an increase in the R(CuÀN)
gies (ΔE), with the [Cu(NÀO4)
] and [Cu(N
-O1)
] com-
2
NH
2
distance. Changes in these two distances are related to the influ-
plexes being the most and least stable ones (À709.84 and
À1
ence that the π-electron delocalization has on the σ-electron
À672.66 kcal mol
, respectively). This trend is mostly caused
density at the basic sites (see below).
by the electrostatic interaction term (ΔV
) because it goes
elstat
À1
from À605.15 ([Cu(N
]) to À685.26 kcal mol
The stability constants of the Cu(II) complexes have been evalu-
-O1)
NH
2
2+
ated by computing the reaction free energy of [Cu(H
O)
]
+
([Cu(NÀO4)
]). This is not surprising because the interaction
2
4
2
+
in aqueous solution (log β
2HL f [Cu(L)
] + 4H
O + 2H
=
is given between two anionic ligands and a central dication. The
2
2
2
À(1)/(2.303RT)ΔG
fact that ΔV
* ), the solvent effects being accounted for
is larger (in absolute values) in [Cu(NÀO4)
]
sol
elstat
2
48
with the polarizable continuum model.
The reaction free energies
than in [Cu(N
-O1)
] is reasonable because in the former
NH
2
(ΔG
) at T = 298 K along with the estimated stability constants
complex the negative charge of the ligand is more concentrated,
sol
12662
|J. Phys. Chem. A 2011, 115, 12659–12666
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