Synthesis, Characterization, and Stereoselective Oxidations of the Dinuclear Copper(II) Complex Derived from a Chiral Diamino-m-xylenetetra(benzimidazole) Ligand

Article abstract of DOI:10.1002/ejic.201500046

Recent advances in dinuclear copper complexes as mimics of the catalytic centers of tyrosinase and catechol oxidase allowed the reproduction of the structural and mechanistic aspects of the enzymes. However, a challenging objective is the development of chiral complexes for bioinspired enantioselective oxidation reactions. Here, we report the synthesis and characterization of a dinuclear copper(II) complex with a new chiral diamino-m-xylenetetra(benzimidazole) ligand (L55Bu4), which has chiral centers at the four 2-methylbutyl substituents of the benzimidazole rings. The spectral characteristics, ligand binding properties, and reactivity of [Cu^II₂L55Bu4]⁴⁺ in the catalytic oxidations of several biogenic catechols (L-/D-dopa, L-/D-DopaOMe, and L-/D-norepinephrine) and thioanisole are reported. The best discriminating properties are displayed towards the DopaOMe derivatives, for which the oxidation rate of the L enantiomer is approximately one order of magnitude larger than that of the opposite D isomer. A dinuclear copper(II) complex derived from a chiral hexadentate nitrogen ligand is reported as a new catalyst for asymmetric oxidations. For biogenic catechols as model substrates, the best enantioselectivity is obtained in the oxidation of the methyl esters of L-/D-Dopa, for which 70%ee is obtained in favor of the L enantiomer.

Full text of DOI:10.1002/ejic.201500046

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DOI:10.1002/ejic.201500046
Synthesis, Characterization, and Stereoselective
Oxidations of the Dinuclear Copper(II) Complex Derived
from a Chiral Diamino-m-xylenetetra(benzimidazole)
Ligand
[
a]
[a]
[a]
Maria Lucia Perrone, Eliana Lo Presti, Simone Dell’Acqua,
[a]
[b]
[a]
Enrico Monzani, Laura Santagostini, and Luigi Casella*
Keywords: Bioinorganic chemistry / Asymmetric catalysis / Oxidation / Copper / Ligand design
Recent advances in dinuclear copper complexes as mimics of
the catalytic centers of tyrosinase and catechol oxidase al-
lowed the reproduction of the structural and mechanistic as-
pects of the enzymes. However, a challenging objective is
the development of chiral complexes for bioinspired enantio-
selective oxidation reactions. Here, we report the synthesis
and characterization of a dinuclear copper(II) complex with
a new chiral diamino-m-xylenetetra(benzimidazole) ligand
substituents of the benzimidazole rings. The spectral charac-
teristics, ligand binding properties, and reactivity of
II
L55Bu4]4+ in the catalytic oxidations of several biogenic
[Cu
2
catechols
(
L-/
D-dopa,
L-/
D-DopaOMe, and
L-/D-norepi-
nephrine) and thioanisole are reported. The best discriminat-
ing properties are displayed towards the DopaOMe deriva-
tives, for which the oxidation rate of the
approximately one order of magnitude larger than that of the
opposite isomer.
L enantiomer is
(
L55Bu4), which has chiral centers at the four 2-methylbutyl
D
with and discriminate between chiral substrates.[2b] For this
reason, the trinuclear complexes systematically exhibited
Introduction
The topic of dioxygen activation by copper enzymes con- superior discriminating capacities than those of their dinu-
taining dinuclear active sites continues to attract consider- clear counterparts. However, the synthetic procedures to
able interest from synthetic bioinorganic chemists, in view obtain the various types of chiral N ligands are always
8
of the intrinsic potential of the Cu O intermediate species, challenging, and the need to protect the chiral residues from
2
2
2
2
in either the μ-η :η -peroxodicopper(II), bis(μ-oxo)di- epimerization reactions must be taken into account. There-
1
1
copper(III), or trans-μ-η :η -peroxodicopper(II) isomeric fore, we were interested in the development of structurally
forms, to promote oxidation reactions.[
1–3]
The recent ad- simpler dinuclear complexes with chiral hexadentate nitro-
[4,5]
vances in catalytic phenol hydroxylation
and sulfoxid- gen ligands of the type that we previously studied as tyrosi-
[
6]
[6,9,10]
ation by biomimetic dicopper complexes show promising nase biomimetic models.
These ligands are basically
perspectives and the possibility of new applications in syn- built by connecting two tridentate copper binding residues
thetic chemistry. For several years, we have been interested with a meta-xylyl bridging unit. Among the resulting dicop-
in the development of chiral analogues of these biomimetic per complexes, the one that performed as the best catalyst
complexes and actively pursued practical methods to assay for oxidation reactions is that derived from the ligand lab-
their chiral discriminating properties.[
2b,7,8]
Our approach eled as L55.
[6,10a]
The structures of both the dicopper(I)–
was essentially based on the synthesis of chiral octadentate L55 and dicopper(II)–L55 complexes, the latter as a di-
nitrogen ligands that could host two or three copper(II) methoxido-bridged species, have been characterized pre-
[
9b]
centers, two of which function as the site of oxygen binding viously by X-ray analysis.
and activation, and the third serves as an anchor to interact
In this paper, we describe the synthesis of a new chiral
ligand of the L55 type, L55Bu4, in which chirality is intro-
duced through the replacement of the N-methyl groups
originally present on the four benzimidazole rings of L55
by 2-methylbutane residues (Scheme 1). We also report the
characterization of the dinuclear copper(II) complex of
[
[
a] Department of Chemistry, University of Pavia,
Via Taramelli 12, 27100 Pavia, Italy
E-mail: Luigi.Casella@unipv.it
http://chimica.unipv.eu/site/home.html
b] Department C.I.M.A. Lamberto Malatesta, University of L55Bu4 and its stereoselective catalytic oxidation of several
Milano,
representative catechol substrates. The enantioselective oxy-
genation of thioanisole has also been studied as an example
of a monooxygenation reaction.
Via Venezian 21, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201500046.
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Scheme 1. Structure of L55Bu4 and the corresponding dicopper(II) complex.
transfer (LMCT) transitions (see Figure S1),[9a] whereas the
maximum of the broad ligand field (LF) envelope shifts
from λ = 690 to ca. 600 nm. The CD spectrum of
Results and Discussion
Synthesis
II
4+
[
3
Cu 2L55Bu4]
exhibits a negative CD band at λ ≈
The synthetic route to L55Bu4, outlined in Scheme 2, in-
volves the reaction of the tridentate binding arm bis[(2-
benzimidazolyl)methyl]amine with m-bromoxylene to af-
ford the diaminotetrabenzimidazole intermediate (L55H).
This product is then reacted with excess (S)-(+)-2-methyl-
iodobutane to afford N-substituted chiral benzimidazoles.
The alkylation reaction produces many byproducts, con-
sisting of the tri-, di-, and monoalkylated L55H, even if a
large excess of alkylating agent is used. The dicopper(II)
II
80 nm, which we associate with π(benzimidazole)ǞCu
LMCT, and a couple of optically active d–d bands at λ =
80 (positive) and 700 nm (negative, see Figure S2). In gene-
5
ral, the optical activity of these CD bands is very weak
because the chiral centers of the ligand L55Bu4 are located
outside the chelate rings of the copper(II) chromophores,
II
in contrast to the common situation in Cu –amino acid
complexes, for example.
II
As for the parent [Cu 2L55(OH)2] complex,[9a] NMR
2+
4
+
complex [Cu L55Bu4] was readily obtained by reacting
2
spectroscopy experiments confirmed the bis(μ-hydroxido)-
the free ligand with copper(II) salts.
II
2+
bridged coordination mode in [Cu 2L55Bu (OH) ] . The
4
2
1
broad and featureless paramagnetic H NMR spectrum of
Cu 2L55Bu4] in deuterated methanol undergoes marked
II
4+
[
Spectroscopic Characterization of the Dicopper(II)
Complex
changes upon the addition of hydroxide ions. The spectrum
of the bis(hydroxido) complex displays narrow signals typi-
II
4+
The electronic spectrum of [Cu L55Bu ] resembles cal for diamagnetic species, because the strong antiferro-
2
4
that of the parent [Cu 2L55] complex[9a] and shows sim- magnetic coupling between the two Cu centers mediated
ilar pH-dependent features owing to the dissociation of by the double μ-hydroxido bridge leads to an S = 0 ground
water molecules bound to the copper(II) centers. In particu- state (Figure 1). All of the proton resonances of the ligand
II
4+
II
II
lar, the formation of the bis-μ(hydroxido)dicopper(II) spe- are slightly downfield shifted in the spectrum of [Cu 2L55-
2+
cies in methanol solution is accompanied by the develop- Bu (OH) ] owing to the positively charged metal ions,
4
2
ment of two prominent near-UV absorption bands at λ = and it is also possible to observe a slightly broadened peak
–
1
–1
3
08 and 354 nm (ε = 5430 and 5700 m cm , respectively), at δ = 9.7 ppm, attributable to the protons of the μ-
II
owing to coupled hydroxidoǞCu ligand-to-metal charge- hydroxido ligands.
Scheme 2. Synthetic pathway to the ligand L55Bu4.
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1
II
L55Bu4]4+ in CD
Figure 1. H NMR spectra of (a) the ligand L55Bu4 and (b) complex [Cu
2
3
OD as well as the same solution of the
–
2
complex after the addition of (c) 1 and (d) 2 equiv. of OH ions from a 2 m solution of NaOH in D O.
II
Binding experiments were also performed with the azido μ-azidoǞCu LMCT band for the monoazido adduct of
II
4+
ligand. As we expected, the binding behavior of this ligand [Cu 2L55Bu4] are clearly resolved in the CD spectrum,
II
4+
II
4+ [9a]
to [Cu 2L55Bu4] was similar to that to [Cu L55] ,
in which there are a negative peak at λ = 318 nm and a
2
and the aim of these experiments was to observe the CD positive peak at λ = 410 nm for the high-energy and low-
features of a chiral chromophore containing an intramo- energy components, respectively (Figure 2, A). However, it
lecular azido bridge between two copper(II) centers. To the is worth noting that the corresponding bis-μ(azido)-dicop-
best of our knowledge, such information is currently avail- per(II) adduct also exhibits peculiar CD features. The spec-
able only for met-azido hemocyanin.[
11]
The near-UV trum is difficult to interpret, as the high-energy component
LMCT features of a μ-azido dicopper(II) chromophore appears to be reversed in sign and a new prominent negative
consist of a broad, multicomponent absorption owing to peak occurs at λ = 387 nm (Figure 2, B). The slight redshift
[12]
the coupling of the LMCT transition moments. This fea- for the low-energy component of positive sign for the
ture was indeed observed for the azide adduct of LMCT band at λ = 410 nm is only due to partial cancelling
II
4+ [9a]
[
Cu L55] ,
but unlike μ-azido met-hemocyanin, for out by the peak at λ = 387 nm. The complex CD pattern
2
[11]
which the bridge is assumed to be μ-1,3, the evidence was of the bis-μ(azido)dicopper(II) chromophore possibly arises
for a μ-1,1 bridging mode in the model complex (Scheme 3). from exciton coupling of the LMCT transitions, which is
expected to increase the number of components of the elec-
tronic bands.
Significant changes also occur in the LF spectrum of
II
4+
[
Cu 2L55Bu4] on azide binding. The absorption maxi-
mum of the d–d envelope shifts to λ = 650 nm, and this is
accompanied by changes in the CD spectrum, in which the
prominent band occurs at λ = 610 nm and is now of positive
sign. Notably, no significant CD changes in the d–d spec-
trum can be observed for the monoazido and bisazido ad-
Scheme 3. Mono- and bis-μ-1,1-azido-bridged dicopper(II) com-
plexes of L55Bu4.
II
4+
ducts of [Cu L55Bu4] (Figure 2); therefore, no struc-
2
tural rearrangements occur in the dicopper(II) core and
both azido ligands are coordinated with the same binding
mode (Scheme 3).
Thus, the addition of azide ions to [CuII2L55Bu4]4+
yielded near-UV LMCT features almost superimposable
II
4+ [9a]
with those observed for [Cu L55] ;
an asymmetric
2
band with a poorly defined shoulder on the low-energy tail
developed at λ ≈ 370 nm and progressively moved to λ ≈
Stereoselective Catalytic Oxidation of Catechols
3
90 nm as more azide ions were added up to a azide/Cu
Biogenic catechols[13] (Scheme 4) represent a useful fam-
2
[9a]
ratio of 2:1 (see Figure 2).
The two components of the ily of chiral substrates for investigations of the discriminat-
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Figure 2. UV/Vis and CD spectra of (A) [CuII )]3+ and (B) [CuII ]2+ in methanol solution.
L55Bu4(N L55Bu4(N )
2 3 2 3 2
Scheme 4. Enantiomeric pairs of catecholic substrates studied in the catalytic oxidations.
4+
ing ability of [CuII L55Bu4] , and we used them previously complexes.[8] The oxidations of ortho-catechols with an
2
for investigations with other chiral dinuclear and trinuclear amino group in the alkyl chain initially produce the corre-
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Scheme 5. Initial steps of the oxidative metabolism of biogenic catecholamines.[14]
sponding quinones, but these rapidly evolve to amino- strictly true only at neutral pH); CatH is the substrate, Qui
2
II
2+
chromes (Scheme 5), which are the only observable interme- is the corresponding quinone, and [Cu 2O /Cat] is the
2
diates in the oxidative oligomerization pathway of these necessary ternary intermediate complex between the Cu O2
2
[
14]
compounds.
species and the catechol. With the electron-rich 3,5-di-tert-
In our previous studies, we routinely studied the catalytic butylcatechol, the first step of the reaction catalyzed by
II
4+
oxidations in slightly alkaline medium and trapped the [Cu 2L55] was faster than the second step by almost one
[
10a]
quinones initially formed in the reaction with the reagent order of magnitude;
3
therefore, it was possible to sepa-
-methyl-2-benzothiazolinone hydrazone.[ However, as we rate the two reaction steps. This analysis is straightforward
have recently found that this reagent is not redox-inno- when a biphasic behavior of the reaction is evident from
8]
[
15]
cent, we preferred to directly follow the formation of the the absorbance versus time profile of the experiment.
intermediate aminochrome in the present investigation in As for the oxidation of the biogenic catechols by
II
4+
the absence of any added reagents. To slow down the oxi- [Cu 2L55Bu4] , the plots of absorbance change versus
dative polymerization of this species as much as possible, time exhibited monophasic behavior, and it was impossible
we performed the catalytic experiments at the slightly acidic to separate the two steps of the reaction. However, as the
pH of 5.1, at which the optical signature of the amino- dependence of the initial reaction rates as a function of sub-
chrome develops steadily over a sufficient time interval. strate concentration exhibited hyperbolic behavior, we
Thus, by following the initial accumulation of aminochrome could determine the kinetic parameters with a simplified
through its characteristic absorption band at λ ≈ 475 nm, Michaelis–Menten scheme involving the pre-equilibrium
we could perform a complete kinetic study and deduce the binding of the substrate followed by its conversion to the
key parameters that illustrate the stereochemical prefer- product. The results, in terms of kcat and K , are collected
m
II
4+
ences of [Cu L55Bu4] .
in Table 1.
2
The mechanism for the oxidation of catechols was
To assess the chiral discriminating properties of
II
4+ [10a]
given the [CuII L55Bu4] , we used the twoparameters R(kcat) and
4+
studied previously in detail for [Cu L55] ;
2
2
identity of the copper coordination sphere, we assume that R(kcat/K ), expressed as percentages. They are defined by
m
II
4+
the same mechanism is also valid for [Cu L55Bu4] . the following relationships:
2
Briefly, the reaction proceeds in two steps, in which a mo-
lecule of catechol is initially oxidized by the dicopper(II)
complex, the resulting dicopper(I) complex subsequently re-
acts with dioxygen, and a second molecule of catechol is
then oxidized by the intermediate dicopper-–dioxygen spe-
cies, as summarized in the following reaction scheme.
Then, RϾ0 indicates preference for the l enantiomeric
substrate, and RϽ0 indicates preference for the d enantio-
meric substrate. Basically, R(kcat/K ) expresses the chiral
m
discriminating capacity of the catalyst at low substrate con-
centration, and R(kcat) expresses that under substrate-satu-
rating conditions. In the former case, the substrate affinity
The starting dicopper(II) complex is assumed to contain for the active form of the dinuclear copper catalyst plays an
a hydroxido bridge, which facilitates the formation of a important role, as only a fraction of the catalyst is bound
II
II 2+
bridged catecholate adduct [Cu –Cat–Cu ] (this may be to the catechol, whereas the rate of the reaction under fully
Table 1. Kinetic parameters for the catalytic oxidation of catecholic substrates in methanol/50 mm aqueous acetate buffer, pH 5.1, 10:1
(v/v), 25 °C.
–
1
[m–1 s–1]
Substrate
K
m
[mM]
k
cat [s ]
k
cat/K
m
R(kcat) [%]
m
R(kcat/K ) [%]
–3
–4
–2
–3
–4
–4
l-Dopa
d-Dopa
l-DopaOMe
d-DopaOMe
l-Norepinephrine
d-Norepinephrine
0.12Ϯ0.02
0.07Ϯ0.015
0.25Ϯ0.03
0.020Ϯ0.007
0.11Ϯ0.01
0.11Ϯ0.01
(1.1Ϯ0.1)ϫ10
(9.7Ϯ0.5)ϫ10
(1.3Ϯ0.1)ϫ10
(2.3Ϯ0.1)ϫ10
(7.5Ϯ0.2)ϫ10
(7.9Ϯ0.1)ϫ10
9.0
+4
–21
13.9
53.7
114.0
6.9
+70
–3
–36
–3
7.3
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saturated conditions depends only on the electron transfer ester derivatives. The strong preference for binding the d
from the bound catechol to the dicopper active species and, enantiomer to the dicopper–L55Bu4 active species, which
hence, its relative spatial orientation is important.
contains four (S)-2-methylbutyl side chains, determines the
The first observation from the data in Table 1 is that chi- negative R(kcat/K ) values obtained for the catalytic oxid-
m
rality at the carbon atom directly bonded to the catechol ation of both pairs of l-/d-Dopa and l-/d-DopaOMe sub-
ring is clearly not recognized by the complex and, hence, strates. However, stronger binding does not correspond to
no significant discrimination occurs between the enantio- a faster reaction rate, and the reactivity order is reversed
mers of norepinephrine. This result is not new and was ob- for both pairs of catecholic substrates. For l-/d-DopaOMe,
tained previously for structurally different dinuclear com- the oxidation rate of the l enantiomer is approximately one
[
8b,8c]
plexes.
On the other hand, some significant enantio- order of magnitude larger than that of the opposite d iso-
selectivity is observed with the l-/d-Dopa substrates, par- mer. This difference is remarkable and appears to be essen-
ticularly for the methyl ester derivatives (Figure 3). This can tially due to a more favorable disposition for electron trans-
be explained by assuming that an efficient two-electron fer of the bound catechol in the transition state, although
transfer from the catechol to the dicopper centers requires the rate of release of the quinone product may make some
the substrate to bind to the metal ions as a bridging ligand contribution.
in a deprotonated form, as indicated in the reaction scheme
We speculate that the orientation of the aromatic ring
outlined above. Considering the strong propensity of com- of the copper-bound catechol may be determined by ring
plexes of the L55 type to form monoatomic bridges with stacking interactions with the benzimidazole rings of
[
9,10a]
exogenous ligands,
we believe that the catechol will L55Bu4 in the complex and that, in turn, this arrangement
2
1
bind in an η :η fashion, as was proposed for related ami- is influenced by steric interactions between the chiral sub-
nopolybenzimidazole complexes on the basis of IR and Ra- stituents on both the substrate and the ligand. Then, these
[10d]
man spectroscopy studies (Scheme 6).
interactions must be more favorable for the Dopa substrates
with l configuration to allow a disposition of the copper-
bound catechol group that facilitates the electron transfer
to the dicopper active species.
Catalytic Sulfoxidation
Tyrosinase has been reported to catalyze the asymmetric
oxidation of sulfides to sulfoxides in the presence of a sacri-
ficial cosubstrate that acts as a reducing agent and, thereby,
[
16]
performs like an external monooxygenase.
Sulfide oxid-
ation is of great interest in organic synthesis, because or-
ganic sulfoxides are useful intermediates for the preparation
[
17]
of bioactive molecules.
The majority of metal-catalyzed
sulfoxidations employ hydrogen peroxide or alkyl peroxides
[
18]
Figure 3. Plots of the rates of the catalytic oxidation of l-dopaOMe as oxidizing agents,
but we recently reported that
II
4+
II
4+
(
2
circles) and d-dopaOMe (triangles) promoted by [Cu L55Bu4] .
[
Cu 2L55] promotes catalytic sulfoxidation with O and
a sacrificial cosubstrate, similarly to tyrosinase. Thus, we
performed a preliminary study with the parent chiral
2
[
6]
II
4+
[
Cu 2L55Bu4] analogue to investigate whether the oxid-
ation of the standard substrate thioanisole could occur
enantioselectively. Hydroxylamine was used as a reducing
cosubstrate under the same conditions as those for the reac-
II
4+
tions studied with [Cu 2L55] . The results were not too
exciting, as (S)-methyl phenyl sulfoxide was obtained with
a modest 12%ee. However, this is not surprising because
thioanisole must interact inside the cavity provided by the
dicopper complex through noncovalent π–π stacking inter-
Scheme 6. Binding of catechol as a bridging dianionic ligand to the
dicopper(II) center of L55Bu4.
This arrangement allows the chiral amino acid/ester por- actions with the benzimidazole rings of the ligand; in this
tion of the substrate to approach the benzimidazole alkyl arrangement, the small methyl substituent of the substrate
chains with the chiral centers, which are oriented outside cannot significantly interact with the chiral chains of the
the cavity of the dicopper site and, therefore, recognition is ligand, which point outwards. Therefore, the enantioselec-
possible. A strong argument for this interpretation is the tive sulfoxidation should be probed with substrates with
remarkable difference in Km between the l and d enantio- larger substituents at the sulfur atom, and different auxil-
mers of the two Dopa substrates, particularly for the methyl iary reducing agents should perhaps also be checked.
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ture of ethyl acetate/methanol (8:2) and 1.5% aqueous ammonia
Conclusions
1
(
3
30%) as the eluent, yield 41%. H NMR (CD OD): δ = 7.48 (dd,
The dinuclear copper(II) complex [CuII2L55Bu4] , de- J = 6.0, 3.0 Hz, 8 H), 7.16 (dd, J = 6.0, 3.0 Hz, 12 H), 3.95 (s, 8
4+
+
rived from a chiral diamino-m-xylenetetra(benzimidazole) H), 3.58 (s, 4 H) ppm. MS: m/z = 657 [M + H] .
ligand structurally related to the previously studied L55,
catalyzes the oxidation of l-/d-catechols with variable de-
grees of stereoselectivity. The best performance (70%ee)
(
S)-N,NЈ-[1,3-Phenylenebis(methylene)]bis(1-{1-[(S)-2-methyl-
butyl]-1H-benzimidazol-2-yl}-N-[(1-{(S)-2-methylbutyl}-1H-benz-
imidazol-2-yl)methyl]methanamine) (L55Bu4): L55H (0.205 g,
was obtained in the oxidation of the enantiomeric pair l-/ 0.3 mmol) was dissolved in dimethyl sulfoxide (DMSO, 4 mL), and
d-DopaOMe with a strong preference for the l enantiomer, KOH (0.175 g, 3.0 mmol) was subsequently added with stirring,
which is oxidized at a rate approximately one order of mag- which was continued at room temp. for 1 h. The solution turned
from orange to brown. Then, (S)-2-methyliodobutane (0.162 mL,
nitude larger than that of the opposite d isomer. The limita-
1.25 mmol) was added, and the reaction proceeded at room temp.
tions in the discriminating properties toward the other sub-
strates appear to be caused by the location of the chiral
centers of the L55Bu4 ligand outside the metal chelate
rings, too far away to significantly interact with the substit-
uents present on the substrates when these bind to the metal
centers within the cavity of the complex. In any case, the
overnight with the flask covered with aluminum foil to prevent
photodegradation of the chiral iodide, which is photosensitive. Fur-
ther additions of small amounts of the chiral iodide were made (up
to a total of 5 mmol) until the starting material disappeared, as
followed by mass spectrometry. The solution was diluted with water
(
20 mL) to afford a white suspension, which was extracted 10 times
II
4+
performance of [Cu 2L55Bu4] will be scrutinized in the with dichloromethane. The organic phases were collected and
more challenging monooxygenase reactions of both organic washed twice with water, dried with Na SO , and filtered, and the
2
4
sulfides (in a more systematic way) and phenolic com- solvent was removed by rotary evaporation to give the crude prod-
uct. The product mixture was separated by semipreparative HPLC
pounds.
with a C18 reversed-phase column and a gradient of acetonitrile/
water from 45:55 to 100:0 containing 0.1% trifluoroacetic acid over
2
3 min (the retention time of the product was 15 min). The com-
Experimental Section
bined fractions containing L55Bu4 were dried by rotary evapora-
tion, treated with concentrated ammonia, and extracted with
dichloromethane to isolate the free amine, yield ca. 11%. H NMR
Materials and Physical Methods: All reagents and solvents from
commercial sources were of the highest purity available and were
used as received. Elemental analyses were obtained at the Micro-
analysis service of the Milano CIMA department. CD spectra were
obtained with a Jasco J500 spectropolarimeter; the spectra were
recorded at 0.2 nm resolution in the range λ = 300–700 nm at
1
(
CDCl
3
): δ = 7.74 (dd, J = 6.0, 3.0 Hz, 4 H), 7.28–7.17 (m, 14 H),
7
8
7
.15 (d, J = 7.4 Hz, 2 H), 6.97 (s, 1 H), 3.92 (dd, J = 35.1, 13.5 Hz,
H), 3.71 (dd, J = 35.0, 13.0 Hz, 4 H), 3.47 (ddd, J = 22.9, 14.4,
.7 Hz, 8 H), 1.65–1.44 (m, 4 H), 0.85–0.68 (m, 4 H), 0.55 (t, J =
0 nmmin–1 with three scans acquired for each spectrum. The
7.2 Hz, 12 H), 0.48–0.31 (m, 4 H), 0.25 (d, J = 6.6 Hz, 12 H) ppm.
5
1
3
C NMR (CDCl
Q), 131.49 (CH), 129.61 (CH), 129.07 (CH), 123.03 (CH), 122.39
(CH), 120.14 (CH), 110.48 (CH), 59.54 (CH ), 51.13 (CH ), 49.83
CH ), 35.18 (CH), 26.90 (CH ), 16.54 (CH ), 11.59 (CH ) ppm.
MS: m/z = 937.6 [M + H] , 469.8 [M + 2H] . UV (MeOH): λmax
3
): δ = 151.65 (Q), 142.77 (Q), 139.12 (Q), 135.89
NMR spectra were recorded with a Bruker AVANCE 400 spec-
trometer operating at 9.37 T with frequencies of 400.13 and
(
1
13
2
2
1
00.6 MHz for H and C, respectively. The data acquisition and
(
2
2
3
+
3
processing were performed with a standard Bruker software pack-
age (Topspin 1.3). The UV/Vis spectra were recorded with an Ag-
ilent 8453 spectrophotometer. The HPLC analyses were performed
with a Jasco HPLC instrument equipped with two PU-1580 pumps
and a MD-1510 diode array detector (working range: 195–659 nm).
The mass spectra were recorded with a Thermo-Finnigan LCQ
ADV MAX spectrometer.
+
–
1
–1
(
(
ε, m cm ) = 280 (2700), 330 (350, sh), 380 (150) nm. CD
MeOH): λmax (Δε, m cm ) = 280 (–0.3), 320 (+0.02) nm.
–
1
–1
[Cu
2
L55Bu4][ClO : The complex was prepared by dissolving
4 4
]
L55Bu4 (10 mg, 11 μmol) in methanol (0.5 mL) and then adding a
solution of Cu(ClO ·6H (7.9 mg, 22 μmol) in methanol
4
)
2
2
O
Bis[(1H-benzimidazol-2-yl)methyl]amine (BB5H): The synthesis of (0.5 mL). The solution, which turned from yellow to dark green,
BB5H was performed as previously reported with some modifica-
was stirred for 15 min at room temp., and then diethyl ether was
added until a green precipitate appeared. The green solid was col-
lected by filtration, washed three times with diethyl ether, and then
[
19]
tions. 1,2-Diaminobenzene (4.05 g, 0.037 mol) and iminodiacetic
acid (2.5 g, 0.019 mol) were intimately crushed and then suspended
in ethyleneglycol. The suspension was stirred overnight at 190 °C
in a preheated oil bath. The mixture was poured into cold water to
precipitate the crude product. The pale violet solid was collected
by filtration and then recrystallized three times from 1:1 water/
dried under vacuum. C60
4 2 10 2
H76Cl Cu N O16·4H O: calcd. C 46.97,
H 5.52, N 9.13; found C 46.82, H 5.50, N 8.87. UV (MeOH): λmax
–
1
–1
(ε, m cm ) = 315 (1700, sh), 355 (840), 688 (200) nm. CD
–
1
–1
(MeOH): λmax (Δε, m cm ) = 380 (–0.05), 560 (+0.01), 690 (–0.04,
methanol to give a pale brown solid (yield: 50%). MS: m/z = 278 br) nm.
+
1
[
M + H] . H NMR (CD
3
OD): δ = 7.54 (dd, J = 6.0, 3.0 Hz, 4 H),
Catalytic Oxidation of o-Catechols: The kinetics for the oxidation
of the chiral ortho-catechols l-Dopa, d-Dopa, l-DopaOMe,
d-DopaOMe, l-norepinephrine, and d-norepinephrine were
studied by UV/Vis spectroscopy with a magnetically stirred and
thermostatted (at 20.0Ϯ0.1 °C) optical cell of 1 cm path length. A
mixture of acetate buffer (50 mm, pH 5.1) and methanol (1:10 v/v)
was used as the solvent for the catalytic oxidations. The experi-
ments were performed over the substrate concentration range
7.22 (dd, J = 6.0, 3.0 Hz, 4 H), 4.11 (s, 4 H) ppm.
N,NЈ-[1,3-Phenylenebis(methylene)]bis{N-[(1H-benzimidazol-2-yl)-
methyl]-1-(1H-benzimidazol-2-yl)methanamine} (L55H): To a solu-
tion of BB5H (0.50 g, 1.8 mmol) in dry N,N-dimethylformamide
(DMF, 70 mL) were sequentially added m-bromoxylene (0.238 g,
0
.9 mmol) and solid Na CO (0.191 g, 1.8 mmol), and the mixture
2
3
was heated at 80 °C for 48 h. The solvent was removed by rotary
evaporation to yield the crude product, which was purified by
chromatography with silica gel as the stationary phase and a mix-
–
5
–3
–6
5ϫ10 to 1ϫ10 m, and a constant concentration of 5ϫ10
m
of the copper complex was used. The experiments were initiated by
Eur. J. Inorg. Chem. 0000, 0–0
7 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Job/Unit: I50046
/KAP1
Date: 06-03-15 14:25:01
Pages: 9
www.eurjic.org
FULL PAPER
the addition of a few microliters of a methanolic solution of the
complex to a solution of the substrate in the mixed aqueous/meth-
anol buffer (final volume 2.5 mL). The formation of the corre-
sponding aminochrome was followed through the development of
the band at λ = 475 nm for l-/d-Dopa and l-/d-norepinephrine
and at λ = 468 nm for l-/d-DopaOMe. In all of the experiments,
the noise was reduced by reading the absorbance difference be-
tween the εmax of the aminochrome and that at λ = 820 nm, and
the initial rates of the oxidation were obtained by fitting the ab-
sorbance versus time curves in the first few seconds of the reactions.
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To convert the rate data from Δabsorbance/time to ms , the ab-
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sorbance changes were divided by the molar extinction coefficient
of the aminochrome (3600 m–1 cm–1)[20] and the molar catalyst con-
centration. The dependence of the reaction rates of the catalytic
reactions as a function of the substrate concentration exhibited hy-
perbolic behavior; therefore, the kinetic parameters (kcat, K ) were
m
estimated by fitting the data to a Michaelis–Menten equation, im-
plemented in the Sigma-plot software. The enantioselectivity of the
catalytic reaction was evaluated through the two parameters R(kcat
and R(kcat/K ) defined above.
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Inorg. Chem. 1993, 32, 2056–2067; b) G. Battaini, L. Casella,
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Catalytic Oxidation of Thioanisole: To a 10 μm solution of
Cu L55Bu ][ClO (1.9 mL) in methanol/acetate buffer (pH 5.1;
:1 v/v), thioanisole (2.8 μl, 2ϫ10 mol) was added, and the reac-
[
3
2
4
4 4
]
–5
tion was started by the addition of 0.2 m hydroxylamine hydro-
chloride (100 μL). The reaction mixture was stirred for 24 h at
room temperature and then quenched by the addition of 1 m aque-
ous perchloric acid (1 mL). The solution was concentrated under
vacuum to remove the volatile methanolic component, and the re-
sidual aqueous phase was extracted six times with small volumes
of dichloromethane. The combined organic phase was dried with
2
406–2409; Angew. Chem. 2010, 122, 2456; d) T. Plenge, R.
Dillinger, L. Santagostini, L. Casella, F. Tuczek, Z. Anorg. Allg.
Chem. 2003, 629, 2258–2265.
Na
2
SO
4
and filtered, and the solvent war removed by careful rotary
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evaporation at room temp. (thioanisole is volatile, and is partially
lost in the work-up). The crude product was dissolved in hexane
and analyzed by HPLC with a chiral Lux 50 Amylose-2 column
(250ϫ4.6 mm) with a 7:3 hexane/ethanol mixture as eluent to de-
termine the enantiomeric enrichment of methyl phenyl sulfoxide.
The retention times are 39 and 41 min for the (S) and (R) sulfox-
ides, respectively.
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Acknowledgments
Res. 2007, 40, 300–308; d) A. Napolitano, P. Manini, M. d’Is-
This work was supported by the Italian Ministero dell’Università
e della Ricerca (MIUR), through the PRIN (Programmi di Ricerca
di Rilevante Interesse Nazionale) project 2010M2JARJ_004. The
COST CM1003 Action and CIRCMSB are also gratefully
acknowledged.
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Received: January 15, 2015
Published Online: ᭿
Eur. J. Inorg. Chem. 0000, 0–0
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Job/Unit: I50046
/KAP1
Date: 06-03-15 14:25:01
Pages: 9
www.eurjic.org
FULL PAPER
Chiral Complexes for Oxidations
M. L. Perrone, E. Lo Presti,
S. Dell’Acqua, E. Monzani,
L. Santagostini, L. Casella* .............. 1–9
A dinuclear copper(II) complex derived
from a chiral hexadentate nitrogen ligand
is reported as a new catalyst for asymmetric
oxidations. For biogenic catechols as model
substrates, the best enantioselectivity is ob-
tained in the oxidation of the methyl esters
of l-/d-Dopa, for which 70%ee is obtained
in favor of the l enantiomer.
Synthesis, Characterization, and Stereose-
lective Oxidations of the Dinuclear Cop-
per(II) Complex Derived from a Chiral Di-
amino-m-xylenetetra(benzimidazole)
Li-
gand
Keywords: Bioinorganic chemistry / Asym-
metric catalysis / Oxidation / Copper /
Ligand design
Eur. J. Inorg. Chem. 0000, 0–0
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim