Selective Aromatic Hydroxylation with Dioxygen and Simple Copper Imine Complexes

Article abstract of DOI:10.1002/chem.201501003

The formation of a bis(μ-oxido)dicopper complex with the ligand 2-(diethylaminoethyl)-6-phenylpyridine (PPN) and its subsequent hydroxylation of the pendant phenyl group (studied earlier by Holland et al., Angew. Chem. Int. Ed. 1999, 38, 1139-1142) has been reinvestigated to gain a better understanding of such systems in view of the development of new synthetic applications. To this end, we prepared a simple copper imine complex system that also affords selective o-hydroxylation of aromatic aldehydes by using dioxygen as the oxidant: Applying the ligand N′-benzylidene-N,N-diethylethylenediamine (BDED), salicylaldehyde was prepared in good yields and we show that this reaction also occurs through an intermediate bis-μ-oxido copper complex. The underlying reaction mechanism for the PPN-supported complex was studied at the BLYP-D/TZVP level of density functional theory and the results for representative stationary points along reaction paths of the BDED-supported complex reveal a closely related mechanistic scenario. The results demonstrate a new facile synthetic way to introduce OH groups into aromatic aldehydes.

Full text of DOI:10.1002/chem.201501003

DOI: 10.1002/chem.201501003
Full Paper
&
Hydroxylation |Hot Paper|
Selective Aromatic Hydroxylation with Dioxygen and Simple
Copper Imine Complexes
Jonathan Becker,[a] Puneet Gupta,[b, e] Friedrich Angersbach,[c] Felix Tuczek,*[d]
Christian Näther,[d] Max C. Holthausen,*[b] and Siegfried Schindler*[a]
Dedicated to Professor Manfred Scheer on the occasion of his 60th birthday
Abstract: The formation of a bis(m-oxido)dicopper complex
with the ligand 2-(diethylaminoethyl)-6-phenylpyridine (PPN)
and its subsequent hydroxylation of the pendant phenyl
group (studied earlier by Holland et al., Angew. Chem. Int. Ed.
1999, 38, 1139–1142) has been reinvestigated to gain
a better understanding of such systems in view of the devel-
opment of new synthetic applications. To this end, we pre-
pared a simple copper imine complex system that also af-
fords selective o-hydroxylation of aromatic aldehydes by
using dioxygen as the oxidant: Applying the ligand N’-ben-
zylidene-N,N-diethylethylenediamine (BDED), salicylaldehyde
was prepared in good yields and we show that this reaction
also occurs through an intermediate bis-m-oxido copper
complex. The underlying reaction mechanism for the PPN-
supported complex was studied at the BLYP-D/TZVP level of
density functional theory and the results for representative
stationary points along reaction paths of the BDED-support-
ed complex reveal a closely related mechanistic scenario.
The results demonstrate a new facile synthetic way to intro-
duce OH groups into aromatic aldehydes.
Introduction
model systems (for selected references see refs. [1f], [2]). So
far, however, only a few copper complexes have been identi-
fied that are actually able to hydroxylate organic substrates in
a catalytic fashion, similar to the enzyme.[3] In mechanistic con-
siderations, a bimetallic, side-on peroxido dicopper complex
has been accepted as the catalytically active species for a long
time, until later findings in a bioinorganic model system pro-
vided evidence for a rapid peroxido/bis-m-oxido equilibrium in
solution, with a subtle influence of the particular supporting
ligand environment, the solvent, and counterions on the rela-
tive thermodynamic stabilities of the individual isomers.[4] With
this equilibrium representing a low-barrier initial OÀO bond-
breaking step along the hydroxylation pathway, Tolman and
co-workers suggested the involvement of a bis(m-oxido) inter-
mediate as the effective hydroxylating species in the course of
aromatic CÀH bond-activation processes taking place in en-
zymes or synthetic models. To investigate this question further,
Holland et al. devised a bioinorganic model based on the
ligand 2-(diethylaminoethyl)-6-phenylpyridine (PPN, Figure 1).[5]
Treating the PPN copper(I) complex with O2 at low tempera-
tures they observed initial formation of a bis(m-oxido)dicopper
complex followed by the subsequent hydroxylation of the
pendant phenyl group even at low temperatures.
Tyrosinase, a copper enzyme, is an important monooxygenase
responsible for the o-hydroxylation of the amino acid tyro-
sine.[1] Aiming at the transfer of its function to synthetic appli-
cations, enormous research efforts over the past decades have
led to the development of a vast number of bioinorganic
[a] J. Becker, Prof. Dr. S. Schindler
Institut für Anorganische und Analytische Chemie
Justus-Liebig-Universität Gießen
Heinrich-Buff-Ring 58, 35392 Gießen (Germany)
E-mail: siegfried.schindler@anorg.chemie.uni-giessen.de
[b] P. Gupta, Prof. Dr. M. C. Holthausen
Institut für Anorganische und Analytische Chemie
Johann Wolfgang Goethe-Universität Frankfurt
Max-von-Laue-Strasse 7
60438 Frankfurt am Main (Germany)
E-mail: max.holthausen@chemie.uni-frankfurt.de
[c] Dr. F. Angersbach
Universität Hamburg, Fachbereich Chemie
Martin-Luther-King-Platz 6
20146 Hamburg (Germany)
[d] Prof. Dr. F. Tuczek, Prof. Dr. C. Näther
Institut für Anorganische Chemie
Christian-Albrechts-Universität zu Kiel
Max-Eyth-Strasse 2, 24118 Kiel (Germany)
[e] P. Gupta
Current address:
Max-Planck-Institute für Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mülheim an der Ruhr (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501003.
Figure 1. The ligands PPN ((a) R=Et, X=H) and BDED ((b) R=Et, X=Y=H).
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We reinvestigated this system by means of fast stopped-
flow techniques at low temperatures to establish a clearer pic-
ture of the formation of the bis(m-oxido)dicopper intermediate
and its reactivity. Although this system is interesting in terms
of mechanistic insight, the prospects of its use for synthetic
applications appear very limited. To further investigate the
transferability of the structure–reactivity relationship, we de-
vised a related system based on the supporting ligand N’-ben-
zylidene-N,N-diethylethylenediamine (BDED, Figure 1), which
exhibits the same basic structural features but is synthetically
more readily accessible. The reactivity of the copper complex
formed with this ligand against dioxygen is studied and possi-
ble synthetic application in stoichiometric selective oxidations
is reported herein. Furthermore, we unveiled the underlying
mechanistic scenario for both systems by quantum chemical
means.
Figure 2. Time-resolved UV/Vis spectra of the reaction of [Cu(PPN)]CF3SO3
(2.5”10À4 m) with dioxygen (5.1”10À3 m) in acetone at À918C over 900 s.
The inset shows the increase of absorbance at 400 nm over time (first order
rate constant kobs =2.6”10À3 sÀ1; fit after the initial lag time).
Results and Discussion
Because 2-(chloromethyl)-6-phenylpyridine, the starting materi-
al used by Holland et al. for the synthesis of the PPN ligand,
was no longer commercially available we developed a slightly
different synthetic route to this ligand according to literature
procedures (Scheme 1).[5,6]
mediates such as, for example, superoxido or peroxido com-
plexes were observed.
Clouding of the solutions over time precluded further de-
tailed kinetic analysis. Due to the quite fast consecutive hy-
droxylation reaction, even at low temperatures, it was not pos-
sible to isolate and structurally characterize the bis(m-oxido) di-
copper intermediate complex. The first-order “decomposition”
reaction (formation of the phenolate-bridged complex,
Scheme 2) had been investigated by Holland et al.,[5] who re-
ported a rate constant of k=6”10À4 sÀ1 in acetone at À708C.
1H NMR spectroscopy and GC/MS revealed partial hydroxyl-
ation of the ligand after decomposition of the product com-
plex. The postulated mechanism is presented in Scheme 2.[5]
We studied the underlying reaction mechanism at the BLYP-
D/TZVP(COSMO) level of density functional theory (DFT; see
Scheme 1. Synthesis of PPN.
The structure of the complex [Cu(PPN)CH3CN]SbF6 was previ-
ously characterized by Holland et al. and exhibits an unusual T-
shaped coordination geometry about
a three-coordinate
copper ion in the solid state.[5] For reasons detailed below, we
prepared this complex in situ in acetone by mixing a solution
of [Cu(CH3CN)4]CF3SO3 under argon with a PPN solution satu-
rated with dioxygen. Figure 2 displays the evolving time-re-
solved UV/Vis spectra recorded in a stopped-flow measure-
ment at À918C, which indicates that the CuI complex reacts
quite slowly, over a period of 900 seconds, to a bis(m-oxido) di-
copper complex. Except for an initial lagging period associated
with complex formation, the spectral changes are identical to
those reported previously by Holland et al.[5] After about
30 seconds, the features of complex formation visible at the
beginning of the reaction disappear and an exponential in-
crease in absorbance sets in. No indications for other inter-
Scheme 2. Oxidation of [Cu(PPN)CH3CN]SbF6 with dioxygen (Scheme re-
drawn from ref. [5]).
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the Computational Details section below), employing a slightly
truncated PPN model ligand L1 (Figure 1a: R=Me, X=H). All
energies reported below refer to Gibbs energies in kcalmolÀ1
relative to the bis(m-oxido)dicopper(III) complex (2 in
Scheme 3) at À708C. Akin to earlier mechanistic studies on ar-
omatic hydroxylation reactions,[2c,4a,7] we assume initial forma-
tion of the (m-h2:h2-peroxido)dicopper(II) complex and we
chose 1 as starting point for the exploration of reaction path-
ways (Scheme 3). We find that 1 is less stable than the bis(m-
oxido) isomer 2 by 10 kcalmolÀ1 and the core-isomerization
process through TS12 is connected with a minute activation
barrier of merely 1 kcalmolÀ1. Thus, fully in line with the experi-
mental observation, we conclude that isomer 2 represents the
dominant species in the initial phase of the reaction. One of
the m-O atoms in the dicopper core of 2 is already located in
close proximity (2.86 Š) to one of the ortho-carbon atoms of
the phenyl group, which predetermines the position of the
subsequent regioselective ligand hydroxylation commencing
with the CÀO bond formation via TS23 (DG° =13 kcalmolÀ1).
The resulting s-complex 3 is thermodynamically unstable and
two pathways branch off at this point. Along path 1, complex
3 directly transforms into complex 4 through proton transfer
onto the second m-O atom. This highly exergonic step results
in the formation of a (m-OH)(m-O)-dicopper complex, which
represents the final product of the reaction sequence studied
here (in our experiments, liberation of the hydroxylated ligand
is accomplished by warming the reaction mixture to RT and
aqueous workup, in line with the reported procedure of Hol-
land et al.[5]). However, with TS34 giving rise to an effective ac-
tivation barrier of DG° =22 kcalmolÀ1 for the process leading
from 2 to 4, path 1 cannot kinetically compete with path 2:
The latter involves exergonic decay of 3 to the intermediate di-
enone 5 and subsequent proton abstraction via TS56 followed
by a conformational transition leads to 4. With an effective ac-
tivation barrier of DG° =14 kcalmolÀ1 associated with TS35,
the sequence 2!5!4 represents the preferred route to prod-
uct formation and the emergence of a dienone inter-
mediate is coherent with the mechanistic picture
suggested in earlier work.[2c] However, the low barrier
of merely 6 kcalmolÀ1 computed for the strongly ex-
ergonic decay of the dienone intermediate to form
6, and subsequently 4, implies that this species will
most likely escape any attempts for an experimental
characterization.
For further comparison with the experimental re-
sults of Holland et al., we also investigated the influ-
ence of activating and deactivating substituents X in-
troduced para to the activation position in the
phenyl ring.[5] The activation barriers resulting for the
substituted systems compiled in Table 1 were com-
puted as the Gibbs energy difference at À708C be-
tween 2-X and TS35-X assuming that the nature of
the overall rate-limiting step in the course of the hy-
droxylation reaction (i.e., the 1,2-H shift for the dien-
one formation) remains unaltered upon substitution.
The resulting differences in computed barrier heights
clearly follow the expected trend for substituent ef-
fects in electrophilic aromatic substitution reactions,
which validates the view that the bis(m-oxido)dicop-
per core acts as an electrophile.[5] The high activation
barrier obtained for the complex with the strongly
deactivating NO2 substituent (20 kcalmolÀ1) is in line
with the fact that Holland et al. did not observe for-
mation of the hydroxylated PPN(NO2) product in
their low-temperature experiments.[5]
Our efforts to isolate the supposed primary prod-
uct of this reaction, the (m-phenoxido)(m-OH)dicopper
complex (see Scheme 2) remained unsuccessful. Yet,
during workup of one reaction batch we were able
to isolate the copper(II) complex with PPN, in which
the two copper(II) ions are bridged by two hydroxide
groups. According to the reaction mechanism de-
tailed above (Scheme 2) only one of the two ligands
constituting the dinuclear complex is hydroxylated,
that is, the maximum product yield is 50%. The re-
Scheme 3. Computed reaction pathways for the intramolecular aromatic hydroxylation
reaction of the PPN ligand starting from 1. Gibbs energies relative to 2 in kcalmolÀ1
(BLYP-D/TZVP(COSMO) results, À708C, solvent acetone) are given in parentheses togeth-
er with the characteristic imaginary wavenumbers of transition states. For all stationary
points reported, closed-shell singlet wave functions resulted in the computations, except
TS34, for which a broken-symmetry wave function was obtained. Irrelevant H atoms not
shown.
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lar structure as derived by using X-ray crystallography is shown
in Figure 4. Crystallographic data for this and the correspond-
Table 1. Substituent effects on the overall rate-limiting step of the hy-
droxylation reaction.
À
ing complex with the SbF6 anion are provided as Supporting
Information.
X
DG° [kcalmolÀ1
]
Effect of X
OCH3
OH
CH3
CH=CH2
H
9.8
11.2
12.7
13.6
14.4
15.5
18.7
20.0
20.5
Strongly activating
Weakly activating
Reference
Weakly deactivating
F
CHO
NO2
CF3
Strongly deactivating
Figure 4. ORTEP plot of the molecular structure of [Cu(BDED)2]+. Anion and
hydrogen atoms are omitted for clarity; ellipsoids are drawn at 50% proba-
bility.
maining unreacted ligand equivalents form the bis(m-hydroxi-
do) complex [Cu2(PPN)2(OH)2](CF3SO3)2, which crystallized when
the solution was left on the bench after oxidation. A similar
observation and crystal structure for a steroid system had
been described by Schçnecker et al. previously and by Herres
et al. for a related bisguanidine copper complex system.[2m,8]
The molecular structure of the cation of this binuclear complex
is shown in Figure 3. Crystallographic data are provided in the
Supporting Information.
It is interesting to note that the PPN-supported copper(I)
complex forms with a 1:1 ligand to CuI ratio (together with
a coordinated acetonitrile molecule)[5] whereas we find a 2:1
stoichiometry in the crystal structure reported above. To avoid
potential problems in our kinetic studies with the formation of
this complex, we decided to devise an in situ formation of the
CuI/BDED complex in a 1:1 stoichiometry by mixing the ace-
tone solution of the copper(I) salt under argon and the O2-sa-
turated acetone solution of the ligand within the stopped-flow
unit. The same procedure was used in our mechanistic study
on the CuI/PPN system described above and thus equivalent
reaction conditions were established in both experiments.
Figure 5 shows time-resolved UV/Vis spectra obtained from
a stopped-flow measurement at À90.08C. The optical feature
evolving at lmax =400 nm is consistent with the formation of
a bis(m-oxido) complex for the CuI/BDED system as well. As
before facile kinetic fitting was not possible, however, the CuI/
BDED complex clearly reacted faster than the CuI/PPN com-
plex.
We performed the same reaction also in a bench-top experi-
ment. After workup of the product solution according to
Scheme 4 we identified the product salicylaldehyde by NMR
spectroscopy and GC/MS. It is formed in high yields (approach-
ing the optimum yield of 50%), which clearly demonstrates
that selective aromatic hydroxylation can be achieved efficient-
ly also by application of simple imine ligands (Scheme 4). This
opens encouraging perspectives for synthetic applications of
related ligands. The importance of ortho-hydroxylation of
arenes has been discussed previously.[10] For copper chemistry
on biomimetic hydroxylation reactions, early work by RØglier
and co-workers should be pointed out.[11] More recently, Schç-
Figure 3. Molecular structure of the cation of [Cu2(PPN)2(OH)2](CF3SO3)2.
In contrast to the preparatively rather demanding synthesis
of PPN, efficient synthetic access to the BDED ligand is readily
achieved in a simple Schiff-base reaction from benzaldehyde
and N,N-diethylethylenediamine according to the literature.[9]
To the best of our knowledge, BDED has not been used as
a supporting ligand for metal ions thus far. We were able to
crystallize the CuI complex [Cu(BDED)2]CF3SO3 and its molecu-
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Scheme 5. Selected reaction steps computed for the intramolecular aromatic
hydroxylation reaction for the BDED ligand starting from 1’. Gibbs energies
relative to 2’ in kcalmolÀ1 (BLYP-D/TZVP(COSMO) results, À708C, solvent
acetone) are given in parentheses together with the characteristic imaginary
wave numbers of transition states. For all stationary points reported, closed-
shell singlet wave functions resulted in the computations, except TS34’, for
which a broken-symmetry wave function was obtained. Irrelevant H atoms
not shown.
Figure 5. Time-resolved UV/Vis spectra of the reaction of [Cu(BDED)]CF3SO3
(5.0”10À4 m) with dioxygen (5.1”10À3 m) in acetone at À898C over 200 sec-
onds. The inset shows increase of absorbance at 400 nm over time (first
order rate constant kobs =5.65”10À2 sÀ1).
To assess substituent effects, we synthesized a series of
BDED derivatives (Figure 1b: R=Et with Y (X=H)=Me, OMe,
Cl, NO2 and X (Y=H)=Me, NO2). We prepared the correspond-
ing copper(I) complexes and treated them with dioxygen in
the same way as described before for the parent BDED system.
Only negligible effects were observed for ligands with
a methyl or a methoxy group. The hydroxylated product still
forms in high yields and for the methyl-substituted BDED
ligand (Figure 1b, R=Et, Y=H, X=Me) hydroxylation occurs in
ortho and para position of the methyl group, as expected. In
contrast, hydroxylation yields were low for the chloro-substi-
tuted ligand (Y=Cl) and hydroxylation did not occur for nitro-
substituted ligands. The latter finding is in accord with the
report of Holland et al. for the nitro analogue of PPN[5] and
with the results of our model calculations on substituent ef-
fects on the effective barrier heights presented above. We also
tested a BDED derivative, in which we replaced the ethyl
groups at the amine donor by methyl groups (Figure 1b: R=
Me, X=Y=H) and we observed only insignificant differences
in terms of reactivity, but a slightly smaller yield of the hy-
droxylated product was obtained.
Scheme 4. Oxidation of the CuIBDED complex with dioxygen.
necker et al. in particular have demonstrated the potential of
such reactions in steroid synthesis.[2m,12]
To evaluate the influence of the supporting ligand environ-
ment on the energetics of the hydroxylation reaction, we per-
formed additional DFT calculations for the BDED-supported
complexes. As before, we employed a slightly truncated molec-
ular model in these calculations, in which we replaced the
ethyl groups at the amine donor by methyl groups. We opti-
mized a number of minima as well as two transition structures
(Scheme 5) that characterize the hydroxylation pathways iden-
tified for the PPN-based system. Comparison of the results for
both systems reveals largely identical structural features and
we found no indication of variations as to the reaction path-
ways and the nature of the rate-limiting steps. Based on these
results we estimate a slightly lower overall activation barrier
for the hydroxylation (via TS34’: 13.6 kcalmolÀ1 vs. TS34:
14.4 kcalmolÀ1), which is perfectly in line with the observation
that hydroxylation in the BDED system occurs at higher rates
in the experiments.
Furthermore, although obviously less attractive in terms of
potential synthetic applications, we tested whether the re-
duced form of the BDED ligand would also support ligand hy-
droxylation reaction. The corresponding H2BDED ligand was
obtained by the treatment of BDED with sodium borohydride
(Figure 6).
However, because of problems with
disproportionation reactions it was im-
possible to obtain and characterize the
copper(I) complex of this ligand in the
solid state. Oxidation experiments con-
ducted in the same way as described for
Figure 6. The ligand
H2BDED.
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the imine complex did not lead to ligand hydroxylation. Even
so, a copper(II) complex with this ligand was obtained by treat-
ing CuCl2 with H2BDED. The molecular structure of
[Cu(H2BDEDCl2] and crystallographic data are presented in the
Supporting Information.
one species, from which the product species is formed in sub-
sequent steps. The bis(m-oxido)complex and the 1,2-H shift
transition state represent the rate-determining states[14] of the
reaction sequence studied here, which is characterized by the
effective largest barrier of 14 kcalmolÀ1. Substituent effects on
this barrier height are consistent with the characterization of
the bis(m-oxido) complex as an electrophile in this reaction.
We have further demonstrated experimentally, as well as
theoretically, that the same facile selective hydroxylation of ar-
omatic aldehydes can also be achieved by using the related
supporting imine ligand BDED, which is synthetically much
easier to access than the PPN ligand. It is interesting to note at
this point that intermediacy of a peroxido complex can be ex-
cluded here, which is in contrast to a related binuclear copper
complex that some of us investigated previously.[2c] Although
an intramolecular o-hydroxylation was also observed, the
active complex was characterized as a peroxido complex and
no bis(m-oxido) complex could be detected. Complexes of this
type have already been used in synthesis,[15] although synthetic
applications are limited for this kind of system.
Finally, it is important to note that the BDED system can be
quite sensitive with respect to particular conditions employed
in the synthetic procedures. For example, when a solution of
[Cu(CH3CN)4]CF3SO3 with BDED in dichloromethane was treated
at À808C with dioxygen, and kept at this temperature for
more than half an hour, no hydroxylation was observed. In-
stead, after evaporation of the solvent, crystals of a dinuclear
bis-hydroxido bridged copper(II) complex with a N,N-diethyle-
thylendiamine ligand was obtained. The molecular structure of
this complex (Figure 7; see the Supporting Information for the
crystallographic data) reveals that the imine bond in the BDED
ligand was cleaved: One could even smell the free benzalde-
hyde from the solution (a crystal structure of this complex with
a different anion has been reported previously).[13]
We could clearly demonstrate that the possibility of prepar-
ing complexes of this type in situ and using dioxygen as an ox-
idant makes the whole setup promising for a number of prep-
arative applications in the future. Herein we have provided
a new synthetic approach in regard to the importance of
ortho-hydroxylation of arenes[10] discussed above.
Experimental Section
Materials and methods
Solvents and reagents used were of commercially available reagent
quality. [Cu(CH3CN)4]CF3SO3 and [Cu(CH3CN)4]SbF6 were synthesized
according to literature procedures.[16] 1H NMR and 13C NMR spectra
were measured on a Bruker AV 400 and Bruker AV 200 spectrome-
ter. GC/MS spectra were recorded on a HP GL 6890 chromatograph
with a HP 5973 mass detector.
Figure 7. Molecular structure of the cation of [Cu2(Et2en)(OH)2](CF3SO3)2.
Conclusion
In the present contribution we have reinvestigated the aromat-
ic hydroxylation effected by a dinuclear Cu2O2 complex sup-
ported by PPN ligands, which was studied earlier by Holland
et al.[5] Stopped-flow measurements at low temperatures re-
vealed the relatively fast formation of a bis(m-oxido)dicopper
complex; however, no further intermediates such as a superoxi-
do complex could be detected. We have elucidated the under-
lying reaction mechanism by DFT calculations. Fully in line with
the interpretation of experimentally observed UV/Vis signa-
tures, the quantum chemical results reveal the bis(m-oxido) di-
nuclear complex as the dominant intermediate present in the
initial phase of the reaction; the corresponding side-on peroxi-
do complex is less stable by 10 kcalmolÀ1. The hydroxylation
sequence commences with an attack of one of the m-O atoms
of the bis(m-oxido) complex on the phenyl group of the PPN
ligand, which results in the formation of a thermodynamically
and kinetically unstable s-complex. Along the favored reaction
path, this complex decays through a 1,2-H shift to form a dien-
Low-temperature stopped-flow measurements
Low-temperature stopped-flow experiments were performed by
using a commercial HI-TECH SF-61SX2 instrument (TgK Scientific,
Bratford-on-Avon, UK). Solvents used for stopped-flow measure-
ments and experiments under inert conditions were obtained as al-
ready pure chemicals and distilled under argon atmosphere prior
to transferring them into a glovebox (MBraun, Garching, Germany).
For the reaction of [Cu(PPN)]+ with dioxygen, a 5”10À4 m solution
of PPN and a 5”10À4 m solution of [Cu(CH3CN)4]CF3SO3 in acetone
were prepared under inert conditions within the glovebox. For the
corresponding reaction of [Cu(BDED)]+ with dioxygen, a 1”10À3
m
solution of BDED and a 1”10À3 m solution of [Cu(CH3CN)4]CF3SO3
in acetone were prepared under the same conditions. The solu-
tions were transferred separately with gastight syringes to the
stopped-flow instrument. The ligand solution was saturated with
dioxygen (5.0) by bubbling a gas stream through the liquid for
10 min (10.2”10À3 m).[17]
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sition states TS34 and TS34’, broken-symmetry wave functions
were obtained with lower energies than the RKS singlet wave func-
tions; the former were used for geometry optimizations and har-
monic frequency calculations on these two species. All stationary
points have been characterized as minima or first order saddle
points by eigenvalue analysis of the diagonalized Hessians. The
connection of transition states and related minima was established
by employing small geometry displacements along both directions
of the imaginary vibrational mode resulting from the vibrational
frequency calculations on the transition structures, followed by un-
constrained geometry optimizations. XYZ coordinates of optimized
minima and transition states are provided in the Supporting Infor-
mation.
Single-crystal X-ray structure determinations
The X-ray crystallographic data for [Cu2(N,N-(Et)2en)2OH2](CF3SO3)2
were collected using a BRUKER/NONIUS KappaCCD detector with
a BRUKER/NONIUS FR591 rotating anode radiation source and an
OXFORD CRYOSYSTEMS 600 low temperature system. MoKa radia-
tion with wavelength 0.71073 Š and a graphite monochromator
were used. The PLATON MULABS semi-empirical absorption correc-
tion using multiple scanned reflection was applied on the data and
the structure was solved by intrinsic phasing using SHELXT2014[18]
and refined with SHELXL2014/6.[19] All non-hydrogen atoms were
refined anisotropically, CÀH and NÀH hydrogen atoms were posi-
tioned geometrically and OÀH hydrogen atoms were located in dif-
ference map and refined isotropically.
Based on these optimized geometries, subsequent single-point
energy calculations were performed at the BLYP-D3[21,25]/def2-
TZVP(SDD) level including the COSMO continuum solvation
model[26] implemented in the ORCA 2.9 program (solvent ace-
tone).[27] The resolution-of-identity (RI)[28] approximation for the
BLYP functional was used employing the auxiliary def2-TZVP/J
basis set.[29] For TS34 and TS34’, broken-symmetry singlet energies
(EBS) were obtained by applying the formalism of Yamaguchi[30] as
implemented in the ORCA program. All energies obtained were
corrected to obtain Gibbs energies at 203 K by adding the corre-
sponding thermal and entropic increments derived from the Hessi-
an calculations with the Gaussian program (the “freqchk” utility
program of Gaussian 09 was used for this purpose). Total electronic
energies and Gibbs energies at 203 K for all stationary points re-
ported are provided in the Supporting Information. Figure of the
molecular structures were produced by means of the CYLview pro-
gram.[31]
For [Cu(BDED)2]CF3SO3 data collection, a BRUKER D8 Venture
system equipped with dual ImS microfocus sources, a PHOTON100
detector and an OXFORD CRYOSYSTEMS 700 low-temperature
system was used. Data collection was performed using MoKa radia-
tion with wavelength 0.71073 Š and a collimating Quazar multilay-
er mirror. Semi-empirical absorption correction from equivalents
was applied using SADABS-2014/4 and the structure was solved by
intrinsic phasing using SHELXT2014.[18] Refinement was performed
against F2 using SHELXL-2014/7.[19] All non-hydrogen atoms were
refined anisotropically and hydrogen atoms were positioned geo-
metrically.
For [Cu2(PPN)2(OH)2](CF3SO3)2, data collection was performed by
using a STOE Imaging Plate Diffraction System (IPDS-1) with MoKa
radiation. The structure was solved with direct methods using
SHELXS-97 and refinement was performed against F2 using
SHELXL-97.[19] All non-hydrogen atoms were refined anisotropic.
The CÀH H atoms were positioned with idealized geometry and re-
fined isotropic with Uiso(H)=1.2 Ueq(C) using a riding model. The
OÀH H atom was located in difference map, its bond lengths set
to ideal values and finally it was refined isotropic using a riding
model.
Syntheses
2-(Diethylaminomethyl)-6-phenylpyridine (PPN): The ligand was
synthesized following slightly modified literature procedures[6] and
only the last step was performed according to the publication by
Holland et al.[5] because the starting material was no longer com-
mercially available.
CCDC-1047585 ([Cu2(N,N-(Et)2en)OH2](CF3SO3)2)), CCDC-1047583
([Cu(BDED)2]CF3SO3),
and
CCDC-1032911
([Cu2(PPN)2(OH)2]-
(CF3SO3)2)) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2-Bromo-6-formylpyridine: Following the literature procedure,[6a]
2,6-dibromopyridine (11.8 g, 50.0 mmol) was dissolved in dry dieth-
yl ether (150 mL) under argon atmosphere and cooled to À808C.
With vigorous stirring a solution of BuLi in hexane (2.50 m,
20.0 mL, 50.0 mmol) was added slowly. After 30 min dimethylfor-
mamide (4.5 mL, 60.0 mmol) was added dropwise and the temper-
ature was held for another 20 min. Then the solution was slowly
heated to 08C. Hydrochloric acid (1 m) was added until an acid pH
was reached and the mixture was neutralized with an aqueous so-
lution of NaHCO3. After workup with ethyl acetate and water the
combined organic layers were dried over Na2SO4 and kept in a re-
frigerator overnight. White-yellow crystals precipitated and were
washed with pentane (3.72 g, 20.0 mmol, 40.0% yield). 1H NMR
(400 MHz, CDCl3): d=10.01 (s, 1H), 7.93 (d, 1H, J=6.6 Hz),
7.75 ppm (m, 2H, J=7.8 Hz); 13C NMR (100 MHz, CDCl3): d=191.7,
153.5, 142.6, 139.4, 132.7, 120.4 ppm.
Computational details
Geometry optimizations and harmonic frequency calculations were
performed with the Gaussian 09 program[20] employing the disper-
sion corrected[21] BLYP-D2 density functional in combination with
a triple-z basis-set/effective core potential (ECP) one-particle de-
scription (the def2-TZVP[22] basis set was used for C, H, N, and O
atoms, and the quasi-relativistic SDD-type[23] ECP together with the
corresponding triple-z basis set[23] was used for Cu; this combina-
tion is denoted def2-TZVP(SDD)). For improved computational effi-
ciency the density-fitting approximation was used and the corre-
sponding density-fitting basis set was generated automatically by
routines implemented in the Gaussian09 program (“auto” key-
word).[24] Default integration grids and convergence criteria have
been used throughout. All structure optimizations were initially
performed employing restricted Kohn–Sham (RKS) singlet wave
functions. Subsequently we searched for energetically low lying
unrestricted Kohn–Sham (UKS) wave functions with broken spin
and spatial symmetry (“broken-symmetry” wave functions) using
the “guess=mix” keyword. In all cases but two, the UKS wave
functions collapsed during the self-consistent field optimization
and closed-shell singlet wave functions resulted. For the two tran-
6-Phenyl-2-pyridinecarboxaldehyde: This reaction was performed
according to the procedure described by Lin Chuang et al.[6b]
Under inert conditions, [Pd(PPh3)4] (0.37 g, 0.30 mmol) was dis-
persed in dry toluene and then added to a solution of 2-bromo-6-
formylpyridine (2.0 g, 11 mmol) in toluene. A solution of Na2CO3
(2 m) was degassed with argon for two hours and 11 mL were
added to the reaction mixture. The solution was heated for 16 h to
908C. After cooling to room temperature CH2Cl2 (80 mL) and an
aqueous solution of Na2SO4 (2m, 40 mL) was added. The organic
Chem. Eur. J. 2015, 21, 11735 – 11744
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11741
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Full Paper
layer was washed with brine and dried over Na2SO4. It was concen-
trated under reduced pressure and kept in the refrigerator. Grey
crystals precipitated and were washed with pentane (1.4 g,
[CuI(BDED)2]CF3SO3:
BDED
(82 mg,
0.4 mmol)
and
[Cu(CH3CN)4]CF3SO3 (38 mg, 0.1 mmol) were dissolved in dry ace-
tone (2 mL) in a glovebox under argon atmosphere. Orange crys-
tals were obtained by slow ether diffusion over four weeks at
À408C.
1
7.6 mmol, 69.9%). H NMR (400 MHz, CDCl3): d=10.03 (s, 1H), 7.95
(d, 2H, J=8.0 Hz), 7.75 (m, 3H, J=2.9 Hz), 7.36 ppm (m, 3H, J=
7.5 Hz); 13C NMR (100 MHz, CDCl3): d=194.0, 157.9, 152.8, 137.78,
129.7, 129.1, 129.0, 128.3, 127.1, 125.4, 124.5 ppm.
[CuI(BDED)2]SbF6: BDED (41 mg, 0.20 mmol) and [Cu(CH3CN)4]SbF6
(93 mg, 0.20 mmol) were dissolved in dry THF (1 mL) under inert
conditions. Orange crystals were obtained with ether diffusion at
À408C over one week.
N’-Benzyl-N,N-diethyl-ethane-1,2-diamine (H2BDED): A solution of
sodium borohydride (0.80 g, 21.1 mmol) in about methanol
(50 mL) was added slowly to
27.0 mmol) in methanol (50 mL). After stirring for 30 min, the reac-
tion mixture was heated under reflux for another 2 h. The mixture
was washed three times with diethyl ether after aqueous workup.
It was dried over Na2SO4 and the solvent was removed under
vacuum. A yellow oil was obtained (4.88 g, 23.7 mmol, 87.6%).
1H NMR (400 MHz, CDCl3): d=7.30 (m, 2H), 7.22 (m, 3H), 3.78 (s,
2H), 2.67 (t, 2H, J=5.6 Hz), 2.56 (t, 2H, J=5.6 Hz), 2.49 (q, 4H, J=
7.1 Hz), 1.94 (s, 1H), 0.99 ppm (t, 6H, J=7.1 Hz); 13C NMR (100 MHz,
CDCl3): d=140.6, 128.3, 128.1, 126.8, 54.1, 52.7, 47.0, 46.9,
11.8 ppm.
6-Phenyl-2-pyridinemethanol:
A solution of NaBH4 (0.380 g,
10.0 mmol) in water (10 mL) was added to a solution of 6-phenyl-
2-pyridinecarboxaldehyde (1.38 g, 7.57 mmol) in methanol (30 mL).
After stirring at room temperature for 30 min, the mixture was
heated to boiling point and was then heated at reflux for 50 min.
When the mixture was cooled to room temperature, the methanol
was removed under reduced pressure and to the remaining solu-
tion hydrochloric acid (1 m) was added to reach an acid pH. Then
the pH was raised to 12 with sodium hydroxide (1 m). The solution
was washed three times with CH2Cl2 and the combined organic
layers were dried over Na2SO4. The solvent was removed under re-
duced pressure. A yellow, partly crystallized oil was obtained (1.0 g,
a solution of BDED (5.55 g,
1
4.16 mmol, 72.3%). H NMR (400 MHz, CDCl3): d=7.98 (d, 2H, J=
7.1 Hz), 7.67 (t, 1H, J=7.4 Hz) 7.57 (d, 1H, J=7.4 Hz), 7.41 (m, 3H,
J=7.8 Hz), 7.13 (d, 1H, J=8.0 Hz), 4.78 (s, 2H), 4.34 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=137.5, 129.2, 128.8, 127.0, 127.0,
119.0, 118.8, 64.0 ppm.
[CuII(H2BDED)Cl2]: Copper(II) chloride (0.83 g, 4.88 mmol) was dried
with heating under vacuum and dissolved in a few mL of acetone.
H2BDED (1.00 g, 4.85 mmol) was added dropwise and the complex
solution was divided in several samples and crystallized at À308C.
Green crystals were obtained.
2-(Chloromethyl)-6-phenylpyridine hydrochloride: Following the
literature procedure of Makowska-Grzyska et al.[6c] thionyl chloride
(6 mL) was added dropwise to 6-phenyl-2-pyridinemethanol
(1.00 g, 5.40 mmol) under inert conditions while being cooled with
an ice bath. At the end of the reaction, the mixture was heated
under reflux for two hours. The remaining thionyl chloride was re-
moved under reduced pressure and the residue was washed sever-
Synthetic hydroxylation reactions: A solution of [Cu(CH3CN)4]-
CF3SO3 (9.4 g, 25 mmol) in acetone (70 mL) was prepared under
inert condition and a solution of BDED (5.1 g, 25 mmol) in acetone
(20 mL) was added at room temperature. Dioxygen was passed
through the mixture for 45 min. After one hour, 1 m HCl (40 mL)
was added. The mixture was stirred for one hour and then heated
to its boiling point. Most of the acetone was then removed under
reduced pressure, CuCl2 (2 g, 12 mmol) was added, and the mix-
ture was washed with CH2Cl2. The combined organic phases were
stirred over Na2SO4 and the solvent was removed under reduced
pressure. The remaining oil was purified with flash chromatogra-
phy over aluminium oxide with CH2Cl2. Pure salicylic aldehyde was
obtained (0.24 g, 2.0 mmol, 8%).
al times with CH2Cl2.
A white solid was obtained (1.06 g,
5.16 mmol, 95.6%). 1H NMR (400 MHz, CDCl3): d=8.31 (t, 2H, J=
8.2 Hz), 8.18 (d, 1H, J=7.3 Hz) 7.92 (dd, 2H, 4.3 Hz), 7.61 (m, 2H,
J=3.9 Hz), 7.27 (s, 1H), 5.49 ppm (s, 2H); 13C NMR (100 MHz,
CDCl3): d=155.0, 154.3, 144.1, 132.3, 129.5, 129.1, 124.0, 41.3 ppm.
2-(Diethylaminomethyl)-6-phenylpyridine: The ligand was syn-
thesized according to the literature.[5] A mixture of 2-(chlorometh-
yl)-6-phenylpyridine hydrochloride (0.60 g, 3.0 mmol) and diethyla-
mine (4.5 mL, 43 mmol) in dry THF (40 mL) with powdered KOH
(1.5 g, 27 mmol) was heated to reflux under inert conditions for
22 h. The solvent was removed under reduced pressure and water
(5 mL) and brine (5 mL) were added to the residue. The mixture
was washed with diethyl ether several times and the combined or-
ganic layers were dried over Na2SO4. After removing the solvent
under reduced pressure the remaining oil was purified using a Ku-
gelrohr distillation. A yellow oil was obtained (0.44 g, 1.8 mmol,
Variation of the BDED ligand: 2-(Diethylamino)ethyl(4-methoxy-
phenyl)methylideneamine (X=H, Y=OMe): 4-Methoxybenzalde-
hyde (1.36 g, 10.0 mmol) was dissolved in methanol (300 mL).
While stirring over Na2SO4, N,N-diethylethylendiamine (1.16 g,
10.0 mmol) was added. After heating at reflux for 24 h the solvent
was removed under reduced pressure and a slightly yellow oil was
obtained (2.14 g, 9.5 mmol, 95%). 1H NMR (400 MHz, CDCl3): d=
8.23 (s, 1H), 7.66 (d, 2H, J=8.7 Hz), 6.91 (d, 2H, J=8.7 Hz), 3.83 (s,
3H), 3.69 (t, 2H, J=7.5 Hz), 2.77 (t, 2H, J=7.5 Hz), 2.61 (q, 4H, J=
7.2 Hz), 1.06 ppm (t, 6H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): d=
161.5, 161.1, 129.6, 129.3, 113.9, 59.8, 55.3, 53.6, 47.6, 11.9 ppm.
1
61.4%). H NMR (400 MHz, CDCl3): d=7.92 (d, 2H, J=7.1 Hz), 7.62
(t, 1H, J=7.6 Hz), 7.49 (d, 1H, J=8.0 Hz), 7.36 (m, 4H, J=3.9 Hz),
3.76 (s, 2H), 2.55 (q, 4H, J=7.0 Hz), 1.02 ppm (t, 6H, J=7.3 Hz);
13C NMR (100 MHz, CDCl3): d=139.7, 136.9, 128.7, 127.0, 121.1,
118.4, 59.5, 47.4, 12.1 ppm.
N’-Benzylidene-N,N-diethyl-ethylendiamine (BDED): A solution of
benzaldehyde (7.96 g, 75.0 mmol) in diethyl ether (200 mL) was
stirred for one hour over MgSO4 at room temperature. Then the
mixture was heated for another hour under reflux. The solvent was
removed under reduced pressure after filtration. A yellow oil was
2-(Diethylamino)ethyl(4-nitrophenyl)methylideneamine (X=H,
Y=NO2): N,N-Diethylethylendiamine (1.16 g, 10.0 mmol) was
added to a solution of p-nitrobenzaldehyde (1.51 g, 10.0 mmol) in
methanol (300 mL) stirred over Na2SO4. After 24 h the solvent was
removed under reduced pressure and a viscous, red oil was ob-
1
1
obtained (13.2 g, 64.9 mmol, 86.5%). H NMR (400 MHz, CDCl3): d=
tained (2.07 g, 8.3 mmol, 83%). H NMR (400 MHz, CDCl3): d=8.39
8.21 (s, 1H), 7.64 (m, 2H, J=2.4 Hz), 7.31 (t, 2H, J=2.8 Hz), 3.64 (t,
2H, J=7.1 Hz), 2.70 (t, 2H, J=7.5 Hz), 2.53 (q, 4H, J=7.3 Hz),
0.97 ppm (t, 6H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): d=161.7,
136.3, 130.5, 128.6, 128.0, 60.0, 53.5, 47.6, 12.0 ppm.
(s, 1H), 8.26 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz), 3.79 (t, 2H,
J=6.9 Hz), 2.81 (t, 2H, J=6.9 Hz), 2.61 (q, 4H, J=7.1 Hz) 1.05 ppm
(t, 6H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3): d=159.4, 148.9,
141.8, 128.7, 123.8, 60.1, 53.2, 47.6, 11.9 ppm.
Chem. Eur. J. 2015, 21, 11735 – 11744
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11742
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2-(Diethylamino)ethyl(4-methyl-phenyl)methylideneamine (X=
H, Y=Me): 4-Methylbenzaldehyde (0.60 g, 5.0 mmol) and N,N-di-
ethylethylendiamine (0.58 g, 5.0 mmol) were dissolved in about
50 mL diethyl ether and stirred for one hour over Na2SO4 and then
heated under reflux for another hour. After filtration the solvent
and remaining starting material were removed under reduced
pressure and a yellow oil was obtained (0.79 g, 3.7 mmol, 73%).
1H NMR (400 MHz, CDCl3): d=8.26 (s, 1H), 7.60 (m, 2H), 7.22 (m,
2H), 3.71 (t, 2H, J=7.2 Hz), 2.78 (t, 2H, J=7.2 Hz), 2.61 (q, 4H, J=
7.2 Hz), 2.38 (s, 3H), 1.06 ppm (t, 6H, J=7.2 Hz); 13C NMR (100 MHz,
CDCl3): d=161.7, 140.8, 133.7, 129.3, 128.0, 59.9, 53.5, 47.6, 21.5,
12.0 ppm.
was added and dioxygen was passed through the solution for
30 min. For the other derivatives, 2-(diethylamino)ethyl(4-methyl-
phenyl)methylideneamine, 2-(diethylamino)ethyl(4-chloro-phenyl)-
methylideneamine, and 2-(diethylamino)ethyl(3-methyl-phenyl)me-
thylideneamine, 1 mmol was dissolved in dry acetone (10 mL) and
a solution of [Cu(CH3CN)4]CF3SO3 (377 mg, 1 mmol) in dry acetone
(10 mL) was added. Dioxygen was also passed through these com-
plex solutions. For N’-Benzylidene-N,N-dimethyl-ethylendiamine
(1.76 g, 10 mmol) ligand and [Cu(CH3CN)4]CF3SO3 (3.76 g, 10 mmol)
in dry acetone (40 mL) were used in similar way. The mixture was
left overnight in the refrigerator. Hydrochloric acid (20 mL 1 m) was
added and the solution was heated up to 708C for 30 min. Most of
the acetone was removed under reduced pressure and the remain-
ing solution was washed with CH2Cl2 several times. The combined
organic phases were dried over Na2SO4, the solvent was removed
and a “pre”-purification was performed over silica. The remaining
oil was analyzed by using GC/MS.
2-(Diethylamino)ethyl(4-chloro-phenyl)methylideneamine (X=H,
Y=Cl): N,N-Diethylethylendiamine (1.16 g, 10.0 mmol) was added
to a solution of 4-chlorobenzaldehyde (1.41 g, 10.0 mmol) in dieth-
yl ether (60 mL). The solution was stirred over Na2SO4 for one hour
and heated under reflux for one hour. The solvent and remaining
starting material were removed under reduced pressure after filtra-
tion and a slightly yellow oil was obtained (2.04 g, 8.6 mmol, 86%).
1H NMR (200 MHz, CDCl3): d=8.25 (s, 1H), 7.63 (m, 2H), 7.39 (m,
2H), 3.71 (t, 2H, J=7.2 Hz), 2.78 (t, 2H, J=7.2 Hz), 2.59 (q, 4H, J=
7.2 Hz) 1.05 ppm (t, 6H, J=7.2 Hz); 13C NMR (50 MHz, CDCl3): d=
160.3, 136.4, 134.7, 129.2, 128.8, 59.9, 53.4, 47.6, 11.9 ppm.
Acknowledgements
Pascal Specht is acknowledged for his assistance with some of
the experiments performed during his Bachelor research proj-
ect (JLU, Gießen). P.G. gratefully acknowledges a Ph.D. grant
provided by the Beilstein-Institut, Frankfurt am Main (Germany)
within the research collaboration NanoBiC. Quantum chemical
calculations have been performed at the Center for Scientific
Computing (CSC) Frankfurt on the Fuchs and LOEWE-CSC high-
performance computer clusters.
2-(Diethylamino)ethyl(3-nitrophenyl)methylideneamine
(X=
NO2, Y=H): m-Nitrobenzaldehyde (7.56 g, 50.0 mmol) was solved
in diethyl ether (150 mL) and N,N-diethylethylendiamine (5.81 g,
50.0 mmol) was added. It was stirred over Na2SO4 and heated
under reflux for 16 h. The mixture was filtrated and the solvent
was removed under reduced pressure; a yellow oil was obtained
(12.02 g, 48.0 mmol, 96%). 1H NMR (400 MHz, CDCl3): d=8.56 (s,
1H), 8.37 (s, 1H), 8.24 (d, 1H, J=7.9 Hz), 8.07 (d, 1H, J=7.9 Hz),
7.59 (t, 1H, J=7.9 Hz), 3.77 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=
7.0 Hz), 2.62 (q, 4H, J=7.1 Hz), 1.05 ppm (t, 6H, J=7.1 Hz);
13C NMR (100 MHz, CDCl3): d=159.0, 148.5, 138.0, 133.5, 129.5,
124.8, 122.5, 59.8, 53.3, 47.6, 12.0 ppm.
Keywords: aldehydes
·
copper
·
density functional
calculations · hydroxylation · transition states
[1] a) E. I. Solomon, U. M. Sundaram, T. E. Machonkin, Chem. Rev. 1996, 96,
2563–2605; b) H. Decker, R. Dillinger, F. Tuczek, Angew. Chem. Int. Ed.
2000, 39, 1591–1595; Angew. Chem. 2000, 112, 1656–1660; c) .
Sµnchez-Ferrer, J. N. Rodríguez-López, F. García-Cµnovas, F. García-Car-
mona, Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1995, 1247,
1–11; d) Y. Matoba, T. Kumagai, A. Yamamot, H. Yoshitsu, M. Sugiyama,
J. Biol. Chem. 2006, 281, 8981–8990; e) H. Decker, T. Schweikhardt, F.
Tuczek, Angew. Chem. Int. Ed. 2006, 45, 4546–4550; Angew. Chem.
2006, 118, 4658–4663; f) L. Que, Jr., W. B. Tolman, Nature 2008, 455,
333–340.
[2] a) A. L. Lewis, W. B. Tolman, Chem. Rev. 2004, 104, 1047–1076; b) L. M.
Mirica, X. Ottenwaelder, T. D. P. Stack, Chem. Rev. 2004, 104, 1013–1045;
c) O. Sander, A. Henß, C. Näther, C. Würtele, M. C. Holthausen, S. Schin-
dler, F. Tuczek, Chem. Eur. J. 2008, 14, 9714–9729; d) L. Q. Hatcher, K. D.
Karlin, J. Biol. Inorg. Chem. 2004, 9, 669–683; e) M. Becker, S. Schindler,
K. D. Karlin, T. A. Kaden, S. Kaderli, T. PalanchØ, A. D. Zuberbühler, Inorg.
Chem. 1999, 38, 1989–1995; f) K. D. Karlin, S. Kaderli, A. D. Zuberbühler,
Acc. Chem. Res. 1997, 30, 139–147; g) K. D. Karlin, J. C. Hayes, Y. Gult-
neh, R. W. Cruse, J. W. Mckown, J. P. Hutchinson, J. Zubieta, J. Am. Chem.
Soc. 1984, 106, 2121–2128; h) S. Itoh, H. Kumei, M. Taki, S. Nagatomo, T.
Kitagawa, S. Fukuzumi, J. Am. Chem. Soc. 2001, 123, 6708–6709; i) M.
RØglier, C. Jorand, B. Waegell, J. Chem. Soc. Chem. Commun. 1990,
1752–1755; j) A. Company, S. Palavicini, I. Garcia-Bosch, R. Mas-BallestØ,
L. Que Jr. , E. V. Rybak-Akimova, L. Casella, X. Ribas, M. Costas, Chem.
Eur. J. 2008, 14, 3535–3538; k) T. Osako, K. Ohkubo, M. Taki, Y. Tachi, S.
Fukuzumi, S. Itoh, J. Am. Chem. Soc. 2003, 125, 11027–11033; l) S. Itoh,
S. Fukuzumi, Acc. Chem. Res. 2007, 40, 592–600; m) B. Schçnecker, T.
Zheldakova, Y. Liu, M. Kçtteritzsch, W. Günther, H. Gçrls, Angew. Chem.
Int. Ed. 2003, 42, 3240–3244; Angew. Chem. 2003, 115, 3361–3365; n) S.
Palavicini, A. Granata, E. Monzani, L. Casella, J. Am. Chem. Soc. 2005,
127, 18031–18036; o) K. D. Karlin, C. X. Zhang, A. L. Rheingold, B. Gallik-
er, S. Kaderli, A. D. Zuberbühler, Inorg. Chim. Acta 2012, 389, 138–150;
2-(Diethylamino)ethyl(3-methyl-phenyl)methylideneamine (X=
Me, Y=H): N,N-Diethylethylendiamine (0.59 g, 5.0 mmol) was
added to a solution of 3-methylbenzaldehyde (0.60 g, 5.0 mmol) in
diethyl ether (50 mL). The solution was stirred for one hour over
Na2SO4 and heated under reflux for another hour. After filtration
and removing the solvent under reduced pressure, a slightly
1
yellow oil was obtained (1.00 g, 4.6 mmol, 92%). H NMR (400 MHz,
CDCl3): d=8.28 (s, 1H), 7.46 (m, 2H), 7.23 (m, 2H), 3.72 (t, 2H, J=
7.2 Hz), 2.78 (t, 2H, J=7.2 Hz), 2.61 (q, 4H, J=7.2 Hz), 2.38 (s, 3H),
1.06 ppm (t, 6H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): d=162.0,
138.3, 136.3, 131.4, 128.9, 128.5, 125.6, 59.9, 53.6, 47.6, 21.3,
12.0 ppm.
N’-Benzylidene-N,N-dimethyl-ethylendiamine (R=Me): Benzalde-
hyde (5.31 g, 50.0 mmol) and N,N-dimethylethylendiamine (4.41 g,
50.0 mmol) were dissolved in diethyl ether (200 mL). The reaction
mixture was stirred over Na2SO4 for one hour and heated under
reflux for one hour. It was filtrated, the solvent was removed under
reduced pressure and a slightly yellow oil was obtained (7.87 g,
44.5 mmol, 89%). 1H NMR (400 MHz, CDCl3): d=8.31 (s, 1H), 7.73
(m, 2H), 7.40 (m, 3H), 3.75 (t, 2H, J=7.1 Hz), 2.66 (t, 2H, J=7.1 Hz),
2.32 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=161.8, 136.2, 130.6,
128.5, 128.1, 60.1, 59.9, 45.9 ppm.
Aromatic hydroxylation with BDED variations: For each of the
modified BDED-ligands 2-(diethylamino)ethyl(4-methoxy-phenyl)-
methylideneamine, 2-(diethylamino)ethyl(4-nitrophenyl)methyl-ide-
neamine, and 2-(diethylamino)ethyl(3-nitrophenyl)methylidenea-
mine, 5 mmol were dissolved in acetone (10 mL) under inert condi-
tions. A 0.6 m solution of [Cu(CH3CN)4]CF3SO3 in acetone (8.3 mL)
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p) M. S. Nasir, B. I. Cohen, K. D. Karlin, J. Am. Chem. Soc. 1992, 114,
2482–2494; q) K. D. Karlin, M. S. Nasir, B. I. Cohen, R. W. Cruse, S. Kaderli,
A. D. Zuberbühler, J. Am. Chem. Soc. 1994, 116, 1324–1336.
[13] P. Naumov, S. W. Ng, J. Coord. Chem. 2006, 59, 1307–1309.
[14] S. Kozuch, J. M. L. Martin, ChemPhysChem 2011, 12, 1413–1418.
[15] C. Zondervan, E. K. van den Beuken, H. Kooijman, A. L. Spek, B. L. Ferin-
ga, Tetrahedron Lett. 1997, 38, 3111–3114.
[16] G. J. Kubas in Inorganic Syntheses (Ed.: D. F. Shriver), Vol. 19, John Wiley
& Sons, New York, 1979, p. 1990.
[17] P. Luehring, A. Schumpe, J. Chem. Eng. Data 1989, 34, 250–252.
[18] G. M. Sheldrick, Acta Crystallogr. A 2015, 71, 3–8.
[19] G. M. Sheldrick, Acta Crystallogr. A 2008, 64, 112–122.
[20] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Strat-
mann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dan-
nenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,
J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford, CT, 2009.
[3] a) L. Casella, M. Gullotti, R. Radaelli, P. Di Gennaro, J. Chem. Soc. Chem.
Commun. 1991, 1611–1612; b) M. Rolff, J. Schottenheim, G. Peters, F.
Tuczek, Angew. Chem. Int. Ed. 2010, 49, 6438–6442; Angew. Chem.
2010, 122, 6583–6587; c) A. Hoffmann, C. Citek, S. Binder, A. Goos, M.
´
´
Rübhausen, O. Troeppner, I. Ivanovic-Burmazovic, E. C. Wasinger, D. P.
Stack, S. Herres-Pawlis, Angew. Chem. Int. Ed. 2013, 52, 5398–5401;
Angew. Chem. 2013, 125, 5508–5512; d) J. Schottenheim, N. Fateeva, W.
Thimm, J. Krahmer, F. Tuczek, Z. Anorg. Allg. Chem. 2013, 639, 1491–
1497; e) M. Rolff, J. Schottenheim, H. Decker, F. Tuczek, Chem. Soc. Rev.
2011, 40, 4077–4098; f) L. Santagostini, M. Gullotti, E. Monzani, L. Case-
lla, R. Dillinger, F. Tuczek, Chem. Eur. J. 2000, 6, 519–522; g) B. T. Op’
t Holt, M. A. Vance, L. M. Mirica, D. E. Heppner, T. D. P. Stack, E. I. Solo-
mon, J. Am. Chem. Soc. 2009, 131, 6421–6438.
[4] a) L. M. Mirica, M. A. Vance, D. J. Rudd, B. Hedman, K. O. Hodgson, E. I.
Solomon, T. D. P. Stack, Science 2005, 308, 1890–1892; b) S. Herres-
Pawlis, P. Verma, R. Haase, P. Kang, C. T. Lyons, E. C. Wasinger, U. Flçrke,
G. Henkel, T. D. P. Stack, J. Am. Chem. Soc. 2009, 131, 1154–1169; c) J. A.
Halfen, S. Mahapatra, E. C. Wilkinson, S. Kaderli, V. G. Young, Jr., L.
Que Jr. , A. D. Zuberbühler, W. B. Tolman, Science 1996, 271, 1397–
1400; d) L. Que, Jr., W. B. Tolman, Angew. Chem. Int. Ed. 2002, 41, 1114–
1137; Angew. Chem. 2002, 114, 1160–1185; e) K. V. N. Esguerra, Y. Fall, J.-
P. Lumb, Angew. Chem. Int. Ed. 2014, 53, 5877–5981; Angew. Chem.
2014, 126, 5987–5991; f) K. V. N. Esguerra, Y. Fall, L. Peitjean, J.-P. Lumb,
J. Am. Chem. Soc. 2014, 136, 7662–7668.
[21] a) A. D. Becke, Phys. Rev. A 1988, 38, 3098–3100; b) C. Lee, W. Yang,
R. G. Parr, Phys. Rev. B 1988, 37, 785–789; c) B. Miehlich, A. Savin, H.
Stoll, H. Preuss, Chem. Phys. Lett. 1989, 157, 200–206; d) S. Grimme, J.
Comput. Chem. 2006, 27, 1787–1799.
[5] P. L. Holland, K. R. Rodgers, W. B. Tolman, Angew. Chem. Int. Ed. 1999, 38,
1139–1142; Angew. Chem. 1999, 111, 1210–1213.
[22] a) A. Schäfer, H. Horn, R. Ahlrichs, J. Chem. Phys. 1992, 97, 2571–2577;
b) F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297–3305.
[23] M. Dolg, U. Wedig, H. Stoll, H. Preuss, J. Chem. Phys. 1987, 86, 866–872.
[24] a) B. I. Dunlap, J. Chem. Phys. 1983, 78, 3140–3142; b) B. I. Dunlap, J.
Mol. Struct. 2000, 529, 37–40.
[6] a) A. Orita, H. Taniguchi, J. Otera, Chem. Asian J. 2006, 1, 430–437;
b) C. L. Chuang, K. Lim, Q. Chen, J. Zubieta, J. W. Canary, Inorg. Chem.
1995, 34, 2562–2568; c) M. M. Makowska-Grzyska, E. Szajna, C. Shipley,
A. M. Arif, M. H. Mitchell, J. A. Halfen, L. M. Berreau, Inorg. Chem. 2003,
42, 7472–7488.
[25] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132,
154104–154119.
[7] a) Y. F. Liu, J. G. Yu, P. E. M. Siegbahn, M. R. A. Blomberg, Chem. Eur. J.
2013, 19, 1942–1954; b) M. Güell, J. M. Luis, P. E. M. Siegbahn, M. Solà,
J. Biol. Inorg. Chem. 2009, 14, 273–285; c) A. Poater, M. Solà, Beilstein J.
Org. Chem. 2013, 9, 585–593; d) A. Poater, X. Ribas, A. Llobet, L. Cavallo,
M. Solà, J. Am. Chem. Soc. 2008, 130, 17710–17717.
[8] S. Herres, A. J. Heuwing, U. Flçrke, J. Schneider, G. Henkel, Inorg. Chim.
Acta 2005, 358, 1089–1095.
[9] A. R. Surrey, J. Am. Chem. Soc. 1949, 71, 2941–2942.
[10] a) X. Li, Y.-H. Liu, W.-J. Gu, B. Li, F.-J. Chen, B.-F. Shi, Org. Lett. 2014, 16,
3904–3907; b) F. Mo, L. J. Trzepkowski, G. Dong, Angew. Chem. Int. Ed.
2012, 51, 13075–13079; Angew. Chem. 2012, 124, 13252–13256.
[11] a) E. AmadØi, E. H. Alilou, F. Eydoux, M. Pierrot, M. RØglier, B. Waegell, J.
Chem. Soc. Chem. Commun. 1992, 1782–1784; b) I. Blain, P. Bruno, M.
Giorgi, E. Lojou, D. Lexa, M. RØglier, Eur. J. Inorg. Chem. 1998, 1297–
1304; c) I. Blain, M. Giorgi, I. De Riggi, M. RØglier, Eur. J. Inorg. Chem.
2000, 393–398.
[12] a) B. Schçnecker, C. Lange, J. Organomet. Chem. 2006, 691, 2107–2124;
b) B. Schçnecker, C. Lange, T. Zheldakova, W. Günther, H. Gçrls, G.
Vaughan, Tetrahedron 2005, 61, 103–114; c) B. Schçnecker, T. Zheldako-
va, C. Lange, W. Günther, H. Gçrls, M. Bohl, Chem. Eur. J. 2004, 10,
6029–6042.
[26] A. Klamt, G. Schüürmann, J. Chem. Soc. Perkin Trans. 2 1993, 799–805.
[27] F. Neese, U. Becker, D. Bykov, D. Ganyushin, A. Hansen, R. Izsak, D. G.
Liakos, C. Kollmar, S. Kossmann, D. A. Pantazis, T. Petrenko, C. Reimann,
C. Riplinger, M. Roemelt, B. Sandhçfer, I. Schapiro, K. Sivalingam, B. We-
zisla, ORCA - An ab initio, DFT and semiempirical SCF-MO package, Ver-
sion 2.9, MPI for Chemical Energy Conversion, Mülheim, Germany, 2012.
[28] a) R. A. Kendall, A. Früchtl, Theor. Chem. Acc. 1997, 97, 158–163; b) K.
Eichkorn, O. Treutler, H. Öhm, M. Häser, R. Ahlrichs, Chem. Phys. Lett.
1995, 240, 283–290; c) K. Eichkorn, F. Weigand, O. Treutler, R. Ahlrichs,
Theor. Chem. Acc. 1997, 97, 119–124.
[29] F. Weigend, Phys. Chem. Chem. Phys. 2006, 8, 1057–1065.
[30] a) K. Yamaguchi, Y. Takahara, T. Fueno in Applied Quantum Chemistry
(Ed.: V. H. Smith), Reidel, Dordrecht, 1986, p. 155; b) T. Soda, Y. Kitaga-
wa, T. Onishi, Y. Takano, Y. Shigeta, H. Nagao, Y. Yoshioka, K. Yamaguchi,
Chem. Phys. Lett. 2000, 319, 223–230.
[31] C. Y. Legault, CYLview, version 1.0b ed., UniversitØ de Sherbrooke, Sher-
brooke, QC, 2009, http://www.cylview.org.
Received: March 13, 2015
Published online on June 18, 2015
Chem. Eur. J. 2015, 21, 11735 – 11744
www.chemeurj.org
11744
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim