Ab Initio Design Of Chelating Ligands Relevant To Alzheimer'S Disease: Influence Of Metalloaromaticity

The Journal of Physical Chemistry A

ARTICLE

Table 3. Energy Decomposition Analysis for the [Cu(N

-On)

]

Family Complex (n = 1À3) and [Cu(NÀO4)

]

[Cu(N

[Cu(NÀ

O1)

]

O2)

]

O3)

]

O4)

]

ΔV

À605.15

À629.89

À664.77

À685.26

elstat

ΔE

215.84

219.82

216.21

231.34

Pauli

ΔE

À134.43

À137.75

À139.81

(σ)

ΔE

À112.63

À92.97

À87.12

(π)

ΔE

À293.43

À288.57

À270.02

À267.52

Figure 2. Lowest-lying π-orbital of the [Cu(NÀO4)

] species.

ΔE

À682.75

À698.64

À718.58

À721.45

int

Isosurfaces are of 0.3 and À0.3 au.

ΔE

10.08

9.27

14.19

11.60

prep

ΔE

À672.66

À689.38

À704.39

À709.84

of HOMA and I

(vide infra) descriptors confirm that [Cu(NÀO4)

]

In ADF, for EDA with hybrid B3LYP, ΔE

= ΔE

(σ) + ΔE

(π) +

and related species have Mobius metalloaromaticity.

ΔE

(HF exchange).

Values in kilocalories per mole.

As mentioned in the Introduction, metalloaromaticity may

inﬂuence the stability of certain complexes, and this could be the

whereas in the latter one the charge is delocalized along the

case for the present ones. To have a deeper insight into this problem,

aromatic backbone. As expected, the ΔE

term increases with

we have performed a detailed analysis on the aromaticity occurr-

Pauli

the reduction of the sum of the R(CuÀO) and R(CuÀN) bond

ing in the metalated rings of the Cu(II)-complexes and their

distances. ΔV

enlarges (in absolute value) for shorter R(CuÀN)

possible correlation with the computed stability constants. At

elstat

bond distances.

ﬁrst instance, the electronic-based I

and the geometric-based

Lets now consider the ΔE

term and its σ and π compo-

HOMA indices at the metalated ring have been calculated for

nents.

An analysis of the electron charge transfer between the

] complex families (X= NH, O, S; n = 1 À 3) as

the [Cu(N

-On)

anionic ligands and Cu(II) indicates that there is a σ-donation of

well as for [Cu(NÀO4)

]. Figure 3 depicts the correlation

∼0.20 e from the anionic ligand lone pairs to Cu(II) and a

and HOMA with the computed log β

between both I

. (The

π-backdonation of <0.05 e from the occupied Cu(II) orbitals of

corresponding values are available in the Supporting Information.)

proper symmetry to the π* LUMO orbital of the ligands. There is

It can be seen that for [Cu(N

], and

-O2)

], [Cu(N

-O3)

also some π-donation, but it is almost negligible. Thus, σ-donation is

[Cu(NÀO4)

] the degree of metalloaromaticity increases (the

clearly more important than π-back-donation, which manifests

and HOMA values increase) and the stability constants are

energetically in a larger ΔE

(σ) contribution as compared with

larger. This trend, however, is not followed by [Cu(N

-O1)

]

ΔE

(π). The ΔE

(σ) term depends on the σ-donor character of

and [Cu(N

-O1)

], which exhibit a slightly larger degree of

the ligand. For instance, phenols are more acidic than aliphatic

metalloaromaticity, but smaller log β

values than [Cu(N

ÀOH2 ligand has a

alcohols; therefore, the deprotonated N

O2)

] and [Cu(N

-O2)

], respectively. This can be explained

ÀOH3 and NÀOH4. Ob-

lower basicity than deprotonated N

by the already aforementioned ligandÀligand repulsion occur-

served ΔE

(σ) variations follow the same trend (in absolute values)

ring in [Cu(N

-O1)

] and [Cu(N

-O1)

], which destabilizes

as the reaction energies and stability constants: [Cu(NÀO4)

] >

the complex; that is, for these particular cases, the complex

[Cu(N

-O3)

] > [Cu(N

-O2)

]. [Cu(N

-O1)

] would

stability is inﬂuenced by steric eﬀects. The fact that the aroma-

likely have a lower ΔE

(σ); however, for this complex, it is

ticity of the metallacycle decreases with the presence of more

not possible to compute it because of its nonplanar geometry,

aromatic moieties in the ligand is reminiscent of what happens

which prevents decomposing ΔE

into its σ- and π-components.

with acenes. The aromaticity of the most external ring of acenes

Overall, these results reﬂect that those anionic ligands that have

was found to decrease when adding six-membered rings to the

the negative charge more delocalized along the ligand are those

series, that is, when going from the smallest member of the series

with less σ-donor character and also those having the lowest

83,84

(benzene) to, for instance, nonacene.

Accordingly, an en-

ΔV

component. Consequently, they lead to complexes with

hancement of the degree of aromaticity in the metalated ring

elstat

larger R(CuÀN) bond distances and thus form less stable

drives to more favorable ΔG

and log β

values, and thus one

sol

complexes. The π-back-donation reﬂected in the ΔE

(π) com-

can conclude that the most stable complexes are those that

ponent follows the opposite trend. This is also understandable

present higher degrees of metalloaromaticity. This situation is

because those anions that have a more delocalized charge are less

similar, although not analogous, to the increase in aromaticity

reluctant to accept π-electron donation from the metal.

observed in certain resonance assisted hydrogen bonds when the

Metalloaromaticity Analysis.

Figure S1 in the Supporting

85À87

proton is substituted by a Li

cation.

Information depicts the eight occupied molecular orbitals with

π-symmetry for the [Cu(NÀO4)

] species (similar orbitals but

’ CONCLUSIONS

more extended are found for the rest of the complexes), whereas

the most stable π-orbital of this system (À10.971 eV) is also

In the present work, DFT calculations have been used to analyze

drawn in Figure 2. Each atom in the double ring contributes one

the coordinative properties of a set of chelating ligands toward

π-electron except the oxygen and the Cu atoms that contribute

Cu(II). These chelators are based on multifunctional ligands

two and four electrons to the π-system, respectively. As a whole,

previously identiﬁed and characterized by some of us

to exhibit

the complex is a 16 π-electron planar metallacycle with some orbitals

the proper pharmacokinetic properties to be used as potential metal-

showing phase inversions as the one in Figure 2. These phase

chelators in AD. Particular emphasis is paid on the aromaticity

79,80

inversions are typical of species with Mobius aromaticity

present in the metalated rings of the complexes and its inﬂuence on

like twisted 4N annulenes.

The analysis of MOs and the calculation

the chelating ability of the complex. ll considered ligands enclose

12663

|J. Phys. Chem. A 2011, 115, 12659–12666

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