Dramatically enhanced carbon acidity of the nitrobenzyl fragment in a nickel(II) scorpionate complex

Article abstract of DOI:10.1021/ol050981q

(Chemical Equation Presented) The -CH₂- group of the 2-nitrobenzyl pendant arm of the scorpionate complex I deprotonates in basic aqueous solution (pK_a = 10.6), due to the coordination of the nitronate group to the nickel(II) center.

Full text of DOI:10.1021/ol050981q

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3417-3420
Dramatically Enhanced Carbon Acidity
of the Nitrobenzyl Fragment in a
Nickel(II) Scorpionate Complex
Massimo Boiocchi,† Luigi Fabbrizzi,*,‡ Francesco Foti,§ Enrico Monzani,‡ and
Antonio Poggi‡
Centro Grandi Strumenti, Dipartimento di Chimica Generale, and INSTM, Sezione di
PaVia, UniVersita` di PaVia, 27100 PaVia, Italy
luigi.fabbrizzi@unipV.it
Received April 30, 2005
ABSTRACT
The
−CH2− group of the 2-nitrobenzyl pendant arm of the scorpionate complex I deprotonates in basic aqueous solution (pKa ) 10.6), due to
the coordination of the nitronate group to the nickel(II) center. Metal coordination enhances 2-nitrobenzene acidity by 10 orders of magnitude.
The 2-nitrobenzyl chromophore, which presents an intense
absorption band centered at ∼330 nm, is widely utilized as
a signaling unit in host-guest recognition processes,1 as a
photosensitive protecting group,2 and for the photorelease
of biologically relevant compounds (e.g., caged ATP).3
Nitrobenzyl photochemical activity is related to the nitro-
to-aci-nitro tautomerization process. In the case of 2-nitro-
toluene (1), a pKT ) 17.0 ( 0.2 for the tautomerization
equilibrium was calculated from the thermodynamic cycle
illustrated in Scheme 1.4
Brønsted acidity of the -CH3 group (pKa(1) ) 20.6),4 a
feature probably related to the loss of aromaticity associated
with the formation of the nitronate ion (mesomeric form b
in Scheme 1).
We considered the opportunity of enhancing the acidity
of the 2-nitrobenzyl fragment by stabilizing the nitronate ion
Scheme 1
It appears that the scarse tendency of 2-nitrotoluene to
convert to the aci-nitro tautomer is related to the very low
† Centro Grandi Strumenti.
‡ Dipartimento di Chimica Generale.
§ INSTM.
(1) Boiocchi, M.; Del Boca, L.; Esteban-Go´mez, D.; Fabbrizzi, L.;
Licchelli, M.; Monzani, E. J. Am. Chem. Soc. 2004, 126, 16507-16514.
(2) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(3) Il’ichev, Y. V.; Schwo¨rer, M. A.; Wirz, J. J. Am. Chem. Soc. 2004,
126, 4581-4595.
10.1021/ol050981q CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/08/2005

through coordination to a metal center. In this connection,
we prepared molecule 3, in which a 2-nitrobenzyl pendant
arm has been covalently linked to the nitrogen atom of a
cyclam ring. The 2-susbstituted positional isomer was chosen
in order to favor the coordination of the nitro-nitronate group
to the metal, immobilized within the cyclam ring.
amine), are those expected for a low-spin ion.7 Most
importantly, the nitro group is completely excluded from the
coordination sphere, being far away from the metal center,
at a quite long distance: 4.83 Å, from NiII to the nearest
oxygen atom (O2). Probably because of steric reasons, the
nitro group is not coplanar with the aromatic ring, but the
two planes form an angle of 45.6°.
Cyclam and its derivatives firmly encircle divalent transi-
tion metal ions to give complexes, which are especially stable
with respect to demetalation.5 For instance, the square planar
[NiII(cyclam)]2+ complex lasts in 1 M HClO4 with a lifetime
τ ) 30 years.6 On reaction of NiII(CF3SO3)2 with 3 (LH),
the yellow diamagnetic [NiII(LH)](CF3SO3)2 complex salt
was obtained in a crystalline form, whose molecular structure
When dissolved in water, the metal complex shows an
intense absorption band at 330 nm, due to the nitrobenzyl
group, with a shoulder at 450 nm, which is ascribed to the
d-d transition of the low-spin square-planar NiII center, thus
confirming the noncoordination of the nitrobenzyl pendant
arm in solution. When the pH is increased through addition
of standard NaOH, no modification of the spectrum is
observed until pH 10, when the shoulder at 450 nm begins
to decrease and a new, weaker band develops at 550 nm.
Such a spectral pattern is typically noted in the presence of
a low-spin to high-spin conversion, which accompanies a
change of the coordination geometry from square-planar to
octahedral.7 It is suggested that, in basic solution, the -CH2-
group linking the cyclam ring to the 2-nitrobenzene fragment
undergoes deprotonation, which induces the following
events: (i) movement of the pendant arm toward the
metallocyclam subunit; (ii) electronic rearrangement to give
the anion of the nitronic acid; and (iii) formation of a
-
coordinative bond between one oxygen atom of the -NO2
group and the NiII center. At the same time, a water molecule
occupies the remaining site of the coordination octahedron.
The overall process is pictorially illustrated in Scheme 2.
Figure 1. ORTEP diagram of the [NiII(3)](CF3SO3)2‚CH3OH
complex. Thermal ellipsoids are drawn at the 30% probability level.
Hydrogen atoms, triflate anions, and a methanol solvent molecule
have been omitted for clarity. Selected bond lengths (Å) and angles
(deg): Ni1-N1 1.985(4), Ni1-N2 1.945(4), Ni1-N3 1.933(5),
Ni1-N4 1.930(4); N1-Ni1-N2 93.68(18), N1-Ni1-N3 178.52-
(19), N1-Ni1-N4 88.03(17), N2-Ni1-N3 86.10(21), N2-Ni1-
N4 174.66(19), N3-Ni1-N4 92.32(20).
Scheme 2
was determined through X-ray diffraction studies. Figure 1
shows an ORTEP view of the metal complex.
The plot of absorbance at 450 nm vs pH (see inset, Figure
2) exhibits a sigmoidal profile, which has been fitted through
a nonlinear least-squares procedure,8 to give a pKA value of
10.71 ( 0.01 for the acid dissociation equilibrium: [NiII-
(LH)]2+ / [NiII(L-)]+ + H+. Solid and dashed lines in the
inset indicate the % concentration of the two species present
at the equilibrium, I and II (as illustrated in Scheme 2),
respectively, over the investigated pH range. On addition of
standard acid, the band at 450 nm is fully restored,
demonstrating the reversibility of the process.
The metal shows a regular square-planar coordination
geometry, the mean deviation for nitrogens from the N1-
N2-N3-N4 best plane being 0.055(5) Å, while the deviation
of Ni1 from such a plane is 0.032(1) Å. The NiII-N bond
distances, ranging from 1.936(5) Å (average of the three
NiII-secondary amine bonds) to 1.985(4) Å (NiII-tertiary
This indicates the intramolecular nature of the process and
confirms the hypothesis that deprotonation is facilitated by
coordination of the nitronate anion to the nickel(II) center.
(4) Schwo¨rer, M.; Wirz, J. HelV. Chim. Acta 2001, 84, 1441-1458.
(5) Busch, D. H. Acc. Chem. Res. 1978, 11, 392-400.
(6) Billo, E. J. Inorg. Chem. 1984, 23, 236-238.
(7) Boiocchi, M.; Fabbrizzi, L.; Foti, F.; Va´zquez, M. Dalton Trans. 2004,
2616-2620.
(8) Gans, P.; Sabatini, A.; Vacca, A. Talanta 1996, 43, 1739.
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Org. Lett., Vol. 7, No. 16, 2005

Figure 2. Visible spectra recorded over the course of the titration
of an aqueous solution of [NiII(3)](CF3SO3)2 with standard base.
Inset: change of the absorbance at 450 nm with pH.
Occurrence of the process sketched in Scheme 2 was
substantiated by 1H NMR titration experiments. In particular,
a 7.5 × 10-3 M solution of [NiII(LH)](CF3SO3)2 in CD3OD
was titrated with a standard solution of potassium tert-
1
butoxide in the same solvent. Figure 3 shows the H NMR
spectra obtained over the course of titration and illustrates
well the spin conversion of the diamagnetic [NiII(LH)]2+
complex to the paramagnetic [NiII(L-)]+.
Figure 3. 1H NMR spectra recorded over the course of the titration
of a 7.5 × 10-3 M solution of [NiII(1)](CF3SO3)2 in CD3OD with
potassium tert-butoxide, up to 1 equiv of base.
First of all, it should be observed that the spectrum of
[NiII(LH)]2+ displays somewhat broad signals, which indicate
a small, yet detectable, paramagnetic contribution. This may
be due to the fact that paramagnetic excited states, close in
energy to the diamagnetic ground state, are being populated
at room temperature. Such a fraction of paramagnetic
complex could not be detected by the less sensitive spec-
trophotometric technique. Even if the presence of broad
signals does not allow the complete assignment of the
resonances, the peaks of the protons of the aromatic residues
and those in positions 3 and 8 of cyclam can be easily
assigned by observing their relative intensity and position
in the spectrum. In the following discussion, the other
resonances in the molecule are tentatively assigned by
considering their chemical shifts, integrals, and isotropic shift
changes during titration. On addition of base, all protons of
the -CH2- groups directly linked to the nitrogen atoms of
the cyclam ring undergo a downfield shift. This is ascribed
to a direct contact effect associated with the presence of σ
interactions between the unpaired electrons in dx2-y2 and dz2
orbitals of the high-spin NiII center and cyclam nitrogen
atoms. Signals pertaining to protons in positions 3 and 8,
which are farther away from metal-bound nitrogen atoms,
undergo an upfield shift, which indicates that, besides the
direct contact contribution, an important contribution of
pseudocontact polarization is present. Most significantly,
signals of protons in 1, belonging to the -CH2- group
linking the cyclam ring to the 2-nitrobenzene moiety,
undergo, on base addition, an upfield shift and, after addition
of 1 equiv of base, disappear. This unequivocally indicates
the deprotonation of the benzylic -CH2- group. Moreover,
the addition of base causes a marked broadening of the
aromatic protons of the 2-nitrobenzyl moiety to below the
signal-to-noise ratio. The large increase in the relaxation rate
for these protons cannot be ascribed to dipolar contribution
to the relaxation, in view of their distance from the metal
center, or to a direct contact effect, as such an effect should
vanish along the π skeleton. It is suggested that broadening
of the aromatic protons is due to a significant contribution
1
of spin polarization through π orbitals to the H NMR
relaxation rates. In particular, following -CH2- deproto-
nation and -NO2- coordination to NiII, a significant fraction
of unpaired electrons of the paramagnetic metal center can
be delocalized onto the π system of the 2-nitrobenzyl moiety.
Comparison of pKa values of 2-nitrotoluene and of the
[NiII(LH)]2+ complex (20.6 and 10.6, respectively) highlights
the role that metal ions can have in enhancing the acidity of
carbon acids. A previous example refers to the ZnII complex
of a cyclen ligand, equipped with a 4-bromophenacyl-pendant
arm.9 Coordination to the ZnII center of the negatively
charged oxygen atom of the enolate form induced a reduction
of pKa of the -CH2- group by ∼10 log units (from 18.3 of
Org. Lett., Vol. 7, No. 16, 2005
3419

acetophenone to 8.4 of the ZnII cyclen complex), providing
an example of metal-driven cheto/enol tautomerization
and modeling the activity of the zinc-containing enzyme
aldolase. Moreover, it has been shown that the pKa of 1,3-
diketones in MeCN solution can be reduced by as much as
12 log units, due to the interaction of the enolate form with
coordinatively unsaturated CuII ion(s), inside a concave
receptor.10 In the present case, the high endergonicity of the
deprotonation of nitrobenzyl -CH2- fragment is balanced
by the favorable contribution associated with the formation
of a coordinative bond between NiII and an oxygen atom of
the nitronate fragment (an enthalpy term). The pH-controlled
coordination of a side-chain covalently linked to a metallo-
cyclam subunit and bearing a deprotonatable donor group
(ammonium,11 carboxyamide,12 sulfonamide)13 has been
observed in a variety of metal complexes with cyclam
derivatives. These ligands were named scorpionands,14
considering the fact that an aggressive tail can sting from
the top a chelated and immobilized individual (the metal).
It appears that scorpionate arrangement and facilitated
coordination of the covalently linked pendant arm (a favor-
able entropy term) are essential for the occurrence of metal-
induced -CH2- deprotonation. The use of the cyclam ring
provides, as a further advantage, the occurrence of a square-
to-octahedral geometry change, which brings in the additional
energy contribution of the axial binding of a water molecule.
In conclusion, it has been demonstrated that a proximate
metal center can effect a drastic reduction of pKa of carbon
acids and assist otherwise unfavorable tautomeric conver-
sions.
Acknowledgment. Financial support of the Italian Min-
istry of University and Research (PRIN-Dispositivi Su-
pramolecolari; FIRB-Project RBNE019H9K) is gratefully
acknowledged. We are indebted to Professor Angelo Albini
for helpful discussion.
Supporting Information Available: Details of syntheses
of 3 and [NiII(3)](CF3SO3)2 and X-ray crystallographic data
in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
(9) Kimura, E.; Gotoh, T.; Koike, T.; Shiro, M. J. Am. Chem. Soc. 1999,
121, 1267-1274.
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E. V. Chem. Eur. J. 2005, 11, 2385-2394.
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OL050981Q
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Zema, M. Chem.sEur. J. 2002, 8, 4965-4972.
(14) Fabbrizzi, L.; Licchelli, M.; Pallavicini, P.; Parodi, L. Angew. Chem.,
Int. Ed. 1998, 37, 800-802.
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