Influence of induced steric on the switchover reactivity of mononuclear Cu(II)-alkylperoxo complexes

Article abstract of DOI:10.1016/j.ica.2018.09.087

Coordination and steric environment around a metal center plays an indispensable role in its reactivity. In this report we have synthesized two bispidine based Cu(II)-OOR (R = ^tBu) complexes [Cu(L1)(OO^tBu)]⁺ and [Cu(L2)(OO^tBu)]⁺ having different steric environment around the metal center and characterized by various spectroscopic techniques. These Cu(II)-OOR species show reactivity towards oxygen atom transfer and aldehyde deformylation reactions. In contrast to the previously reported nucleophilic oxidation, aldehyde deformylation reaction by these complexes proceed via an initial H-atom abstraction with KIE of 12 and 8 respectively. It has been observed that more steric bulk at N3 and N7 position of bispidine ligand prefers the oxygen atom transfer reaction while it hinders the H-atom abstraction for Cu(II)-alkylperoxo complexes.

Full text of DOI:10.1016/j.ica.2018.09.087

Accepted Manuscript
Research paper
Influence of induced steric on the switchover reactivity of mononuclear Cu(II)-
alkylperoxo complexes
Sayanta Sekhar Nag, Gourab Mukherjee, Prasenjit Barman, Chivukula V. Sastri
PII:
S0020-1693(18)31300-8
https://doi.org/10.1016/j.ica.2018.09.087
ICA 18545
DOI:
Reference:
To appear in:
Inorganica Chimica Acta
Received Date:
Revised Date:
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29 September 2018
29 September 2018
Please cite this article as: S.S. Nag, G. Mukherjee, P. Barman, C.V. Sastri, Influence of induced steric on the
switchover reactivity of mononuclear Cu(II)-alkylperoxo complexes, Inorganica Chimica Acta (2018), doi: https://
doi.org/10.1016/j.ica.2018.09.087
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Influence of induced steric on the switchover reactivity of
mononuclear Cu(II)-alkylperoxo complexes
Sayanta Sekhar Nag, Gourab Mukherjee, Prasenjit Barman, Chivukula V. Sastri*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam – 781039, India
Email id: sastricv@iitg.ac.in; Tel.: +91-361-258-2323
Abstract
Coordination and steric environment around a metal center plays an indispensable role in its reactivity. In this
t
t
+
report we have synthesized two bispidine based Cu(II)-OOR (R = Bu) complexes [Cu(L1)(OO Bu)] and
[
t
+
Cu(L2)(OO Bu)] having different steric environment around the metal center and characterized by various
spectroscopic techniques. These Cu(II)-OOR species show reactivity towards oxygen atom transfer and
aldehyde deformylation reactions. In contrast to the previously reported nucleophilic oxidation, aldehyde
deformylation reaction by these complexes proceed via an initial H-atom abstraction with KIE of 12 and 8
respectively. It has been observed that more steric bulk at N3 and N7 position of bispidine ligand prefers the
oxygen atom transfer reaction while it hinders the H-atom abstraction for Cu(II)-alkylperoxo complexes.
Keywords: Cu(II)-alkylperoxo, Electrophilic deformylation, Steric effect, Kinetics, Biomimetic chemistry
1
. Introduction
into normal condition (e.g. methanol from methane).
The protein environment around the metal center
plays a decisive factor for this kind of unusual
reactions. In synthetic model chemistry, several
examples have been reported in past few years, which
shows how ligand architecture plays a vital role in the
reactivity of the metal-oxygen intermediates [10-18].
Herein, we have demonstrated how changing steric
bulk in the ligand architecture changes the reactivity
of bispidine based Cu intermediates. Mononuclear
transition metal alkylperoxo complexes are imperative
in assorted biological and catalytic oxidation reaction
The aerobic life on earth is highly dependent on the
activation of O-O bond of O by various metabolic
2
and biosynthetic pathways. Fe, Mn and Cu containing
metalloenzymes are mainly responsible for majority
of these biological reactions. Although the activation
of molecular oxygen is a crucial process but it is
thermodynamically favoured, it is spin forbidden and
hence kinetically not feasible unless accelerated by
some transition metal ions.
The vital steps involved in activation of dioxygen is
the formation/cleavage of O-O and O-H bonds, which
leads to the formation of high valent metal-oxygen
[19-20]. In biology the direct formation of Fe(III)–
alkylperoxo intermediate was observed in
Homoprotocatechuate 2,3-dioxygenase and purple
lipoxygenase like enzymes [21-22]. In past few years
various Cu(II)–oxygen intermediates have been
characterized and served as models of lipid
peroxidation [23-25].
intermediates.
High
valent
metal-oxygen
intermediates are frequently involved in the catalytic
cycles involved in the metabolically important
oxidative transformations [1-9]. Metalloenzymes
catalyzed oxidative reactions of organic molecules are
often substrate specific, sometimes regioselectivity
and stereoselectivity are also observed. The biological
reactions are an enigma for synthetic chemists to fit

Figure 1: Molecular structure of the ligands and Cu(II)-alkylperoxo complexes (DFT optimised structures) studied in this work.
Mononuclear Cu(II)-OOR intermediates have been were prepared under argon atmosphere in a glovebox.
t
+
used as a model system to understand the reactivity of Alkylperoxo complexes [Cu(L1)(OO Bu)]
and
non-coupled binuclear copper enzymes, Dopamine β- [Cu(L2)(OO Bu)] were generated in situ. α-[D1]-2-
mono-oxygenase (DβM) and Peptidyglycine α- phenylpropionaldehyde (α-[D1]-PPA, ∼90%,
t
+
D
hydroxylating monooxygenase (PHM) [26-28]. Since enriched) was purchased from RVL Scientific &
the first report of crystal structure of a mononuclear Engineering Pvt. Ltd. (Lucknow, India). L1 was
Cu(II)-alkylperoxo intermediate by Kitajima et al., a prepared according to previously reported procedure
lot of advances have been made [29-30]. Exhaustive and L2 was prepared with slight modification [13, 47-
studies on the synthesis, spectroscopic nature and 48].
reactivity of the Cu(II)–alkylperoxo complexes have
2
2
.2 Synthesis of the ligands and complexes
been reported in past decades. Most of the Cu(II)–
alkylperoxo species demonstrate electrophilic
reactivity towards organic substrates [31-37]. Very
few examples of the nucleophilic oxidation activity of
a Cu(II)-alkylperoxo complex were reported [38].
.2.1. Synthesis of L2:
Dimethyl acetonedicarboxylate (7.2 mL, 50 mM) was
taken in 20 mL of CH OH and was cooled to 0 °C. A
3
solution of pyridine-2-carboxyaldehyde (9.53 mL, 100
mM) and benzyl amine (5.46 mL, 50 mM) were added
to it dropwise. After completion of addition, the
solution was allowed to stir at 0 ºC overnight. The
white precipitate thus obtained was filtered and
washed with cold ethanol and dried in vacuum. The
product obtained was of high purity (>97%) and used
as such for the next step.
Bispidine ligands have been highly used in
biomimetic chemistry to understand the reactivity of
various metal-oxygen intermediates [39-44]. These
ligands, due to their very rigid adamantane type
backbone enforce the metal center to adapt a square-
pyramidal geometry [45]. The substituent at N3 and
N7 position of bispidine ligands are known to play an
important role in the reactivity of the intermediates for
Fe and Mn based systems [12-15]. Herein we report
the effect of ligand architecture on the reactivity of
mononuclear bispidine based Cu(II)–alkylperoxo
species as well as its reactivity towards aldehyde
deformylation and oxygen atom transfer to
triphenylphosphine.
To a suspension of the above obtained white solid
(16.7 g, 36.6 mM) in 200 mL ethanol, aqueous
formaldehyde (37%, 7.05 mL, 87 mM) and benzyl
amine (4.75 mL, 43.5 mM) were added dropwise. The
reaction was allowed to reflux for 4 hours. The brown
solution obtained after the end of the reaction was
0
concentrated and kept at -15 C. White solid was
2
. Experimental
obtained after several days. The white solid was
recrystallized from acetonitrile. Yield: 36%.
2
.1 Reagents and materials
1
H NMR (600 MHz, CDCl ): δ (ppm) 8.54 (s, 2H),
3
All reagents were of the highest grade commercially
available and were used without further purification,
unless stated otherwise. Solvents were dried according
to previously reported procedure and distilled under
argon prior to use [46]. Cu(II) precursor complexes
8
7
2
2
.02 (d, J = 7.8 Hz, 2H), 7.48 – 7.43 (m, 7H), 7.25 –
.21 (m, 3H), 7.18 – 7.15 (m, 2H), 6.89 (d, J = 7.0 Hz,
H), 5.15 (s, 2H), 3.77 (s, 6H), 3.52 (s, 2H), 3.41 (s,
H), 3.12 (d, J = 12.2 Hz, 2H), 2.54 (d, J = 12.2 Hz,

1
3
2
1
1
1
H); C NMR (150 MHz, CDCl ) δ (ppm) 203.8 (s), voltage was set at
2
kV. X-band electron
3
68.8 (s), 158.3 (s), 149.4 (s), 137.1 (s), 136.1 (s), paramagnetic resonance (EPR) was measured on a
33.3 (s), 130.8 (d, J = 18.5 Hz), 128.7 (s), 128.3 (s), JES-FA200 ESR spectrometer at 77K in acetonitrile
27.9 (s), 127.6 (s), 124.7 (s), 123.1 (s), 69.2 (s), 62.8 solution. Experimental conditions [frequency, 9.44
(
s), 62.3 (s), 59.7 (s), 55.0 (s), 52.78 (s); ESI-MS GHz; power, 0.995 mW; field center, 336.00 mT,
+
(m/z): Calculated for C H N O : 591.26, found: width, ±150.00 mT; sweep time, 30.0 s; modulation
3
5
35
4
5
5
91.32. Elemental Analysis: Calculated for frequency, 100.00 kHz, width, 0.1 mT; amplitude,
C H N O C 71.17, H 5.80, N 9.49, Measured C 100, and time constant, 0.03 s] were kept the same for
3
5
34
4
5
7
0.72, H 5.36, N 9.72.
all the samples. Structure optimization of the
intermediates were performed using Gaussian 09
software using UB3LYP/BS1 method using solvent
correction for acetonitrile [49].
2
.2.2 General procedure for Synthesis of Cu(II)
complexes
An acetonitrile
trifluoromethane-sulfonate (0.5 mM) was added
solution
of
copper(II)
2
.4 Kinetics studies
dropwise to the ligand (0.5 mM) and allowed to stir at All reactions were performed in a 1.0 cm path length
room temperature inside a glovebox. After stirring UV cuvette by monitoring UV-Vis spectral changes of
overnight, reaction mixture was filtered and diethyl a 1.0 mM acetonitrile solution of complex upon
o
ether was added slowly and kept at -40 C. Vapour addition of excess amount of substrate. The second-
diffusion of ether gives microcrystalline product.
order rate constants were determined by plotting the
observed pseudo first-order rate constants against
different substrate concentrations. The rate constants
were averaged by the three determinations, and
standard deviation is less than 10% of the given
values.
[
Cu(L1)(CH CN)](OTf) : Yield = 64%; Light Blue,
3
2
Elemental
Analysis:
Calculated
for
C H N S O F Cu C 38.55, H 3.47, N 8.33,
2
7
29
5
2
11 6
Measured C 38.15, H 3.01, N 8.53; ESI-MS (m/z):
+
Calculated for C H N SO F Cu 650.07, found:
6
2
4
26
4
8 3
2
+
50.09; Calculated for C H N O Cu : 250.56, 2.5 Product Analysis
23 26 4 5
2
+
found: 250.54; Calculated for C H N O Cu :
2
5
29
5
5
Product analysis was performed on WATERS
ACQUITY UPLC equipped with variable
wavelength UV-200 detector. Products were separated
2
71.06, found: 271.06 ; EPR: g = 2.082, g = 2.360;
⊥ ||
a
A = 207 G.
||
[
Cu(L2)(CH CN)](OTf) : Yield = 69%; Dark Blue, on Waters Symmetry C18 reverse phase column (4.6
3
2
Elemental
Analysis:
Calculated
for × 250 mm), and detection was made at 215 and 254
C H N S O F Cu C 47.15, H 3.75, N 7.05, nm and product yields were determined by
3
9
37
5
2
11 6
Measured C 46.65, H 3.35, N 7.30; ESI-MS (m/z): comparison with standard curves of known authentic
+
Calculated for C H N SO F Cu : 820.14, found: samples.
3
6
36
4
9 3
2
+
8
20.24; Calculated for C H N O Cu : 335.60,
35 36 4 6
found 335.61; EPR: g = 2.073, g = 2.385; A = 190
3
. Result and Discussion
⊥
||
||
G.
.3 Instrumentation
UV-Vis absorption spectra and kinetic data were
3
.1. Generation and Characterization of Cu(II)-
t
OO Bu complexes
2
Cu(II) precursor complexes [Cu(L1)(CH CN)](OTf)
and [Cu(L2)(CH CN)](OTf) were prepared inside
3
2
3
2
recorded on Hewlett-Packard 8453
a
glovebox and were characterized by UV-Vis
absorption spectroscopy, electrospray ionization mass
spectrometry (ESI-MS) and electron paramagnetic
resonance
complexes
spectrophotometer equipped with either a constant
temperature circulating water bath or a liquid nitrogen
1
cryostat (Unisoku) with a temperature controller. H
(EPR)
spectroscopy.
Alkylperoxo
(1) and
1
3
and C NMR spectra were recorded at room
temperature with Bruker 600/150 MHz
t
+
[Cu(L1)(OO Bu)]
+
a
t
[Cu(L2)(OO Bu)] (2) were generated from their
spectrometer. ESI-MS spectra were recorded on a
Waters (Micromass MS Technologies) Q-TOF
Premier mass spectrometer by infusing sample
directly into the source at 10 µL/min using a syringe
pump at 80 ºC capillary temperature, the source
Cu(II) precursors, using 10 equiv. of tert-Butyl
hydroperoxide ( BuOOH) and 2.5 equiv. of
triethylamine (TEA) in CH CN at 25 ºC.
Intermediates 1 and 2 were characterized by various
t
3
spectroscopic techniques. Both the intermediates

persisted ten days at ambient temperature. Complex 1 However, no such shift was observed in the charge
transfer band. These results demonstrate that the
introduction of the steric bulk results in the
perturbation around the metal center. The electrospray
ionisation mass spectra (ESI-MS) of 1 and 2 exhibit
t
+
prominent peaks for [Cu(L1)(OO Bu)]
and
Cu(L2)(OO Bu)] at m/z = 590.16 (calcd. 590.18) and
42.28 (calcd. 742.24) respectively (Fig. 2b and Fig.
t
+
[
7
S4, Supporting Information). The X-band EPR
spectrum of a frozen CH CN solution of 1 and 2
3
measured at 77 K shows an axial signal with g =
⊥
2
.065 and g = 2.360 (A = 199 G) and g = 2.055 and
∥ || ⊥
g = 2.351 (A = 196 G) (Fig. 2c and Fig. S4,
∥
||
Supporting Information) respectively. These values
are in accordance with previously reported results
suggesting a square pyramidal geometry for the Cu(II)
ion [34].
3
.2. Reactivity with PPh3
The reactivity of the Cu(II)–alkylperoxo complexes
were investigated in two electron atom transfer
reactions with triphenylphosphine (PPh3) and
aldehyde
deformylation
reaction
with
2-
Phenylpropionaldehyde (see scheme 1). Upon the
addition of 80 equiv. PPh to the acetonitrile solution
3
of 1 and 2 species at 25 ºC, the intermediates decayed
and gave triphenylphosphine oxide as major product
(Fig. 3 and Fig. S5, Supporting Information).
Figure 2: (a) UV-Vis spectrum of 1 mM of 1 (Blue) and 2 (Red) in
CH CN at 25 ºC (b) ESI-MS spectrum of 1 [inset black and red
line shows experimental and simulated isotope distribution pattern
respectively] (c) EPR spectrum for 1 at 77 K in CH CN
3
3
Figure 3: UV-Vis spectrum for decay of 1 (1 mM) at 25 ºC upon
addition of PPh (80 mM) in CH CN [inset shows the time trace
for the peak at 423 nm].
3
3
exhibits absorption spectra with an intense charge
-1
-1
transfer band (LMCT) at 423 nm (ε ≈ 860 M cm ),
-1
-1
and a weak band at 610 nm (ε ≈ 150 M cm ) for d-d The pseudo first-order rate constants (k ) were
obs
transition. Similarly, complex 2 has electronic monitored with the decay of the LMCT at 423 nm for
-1
-1
transitions at 423 nm (ε ≈ 810 M cm ) and 595 nm 1 and 2. The kobs values increased linearly with
-
1
-1
(
ε ≈ 155 M cm , Fig. 2a). The UV-Vis features increasing PPh concentration, giving second-order
3
-2
-1 -1
observed for 1 and 2 are similar to previously reported rate constants (k ) of the reactions, 2.1 x 10 M s
Cu(II)-alkylperoxo complexes [34]. A blue shift of 15 and 6.1 x 10-2
2
-1 -1
M
s
with 1 and 2 as oxidants,
nm was observed in d-d transitions on replacing respectively (Fig. 4a). Therefore, it appears that 2
methyl with benzyl group at the N3 and N7 positions. reacts with PPh about three times faster than 1.
3

Table 1: Spectroscopic and kinetic data for 1 and 2.
k2 with
α-[D1]-PPA (M s )
λmax (nm)
EPR
k2 with
3
k2 with
-1 -1
Intermediates
-1
-1
-1 -1
-1 -1
(
ε M cm ) parameters PPh (M s ) 2-PPA (M s )
(KIE)
g⊥ = 2.065
t
+
+
[
Cu(L1)(OO Bu)]
423 (860)
610 (158)
2.1 x 10-2
6.1 x 10-2
2.7 x 10-2
2.2 x 10 (12)
-3
g∥ = 2.360
A = 199 G
(1)
||
g⊥ = 2.055
t
[
Cu(L2)(OO Bu)]
2)
423 (810)
595 (155)
9.3 x 10-3
1.2 x 10 (8)
-3
g∥ = 2.351
(
A = 196 G
||
-2
-1 -1
-3
-1 -1
3
.3. Reactivity with 2-Phenylpropionaldehyde
of 2.7 x 10 M s and 9.3 x 10 M s , respectively
(
Fig. 4b). The product analysis of the reaction solution
2
-Phenylpropionaldehyde (2-PPA) has been used
revealed acetophenone as the major product.
Therefore, it appears that 1 reacts with 2-PPA about
three times faster than 2.
widely as a substrate for deformylation reaction. Upon
addition of 10 equiv. of 2-PPA to an acetonitrile
solution of 1 and 2, the characteristic absorption band
for intermediate changes in which a first-order decay
profile was observed (Fig. S6, Supporting
Information).
Scheme 1: Reactions discussed in the work.
The deformylation of aldehydes by Cu(II)-
alkylperoxo complexes were previously reported to
proceed via nucleophilic pathway by the attack at the
carbonyl center [38]. However, recently an alternative
mechanism has been evolved. It has been
demonstrated that the deformylation reaction can
proceed via an initial α-hydrogen atom abstraction
followed by a keto-enol tautomerism in case of
Mn(III)-peroxo intermediates [15,44].
Thus in order to investigate the plausible pathway for
the deformylation of 2-PPA to acetophenone, we have
employed α-[D1]-2-phenylpropionaldehyde (α-[D1]-
PPA) as a mechanistic probe. Thus, upon addition of
α-[D1]-PPA to 1 and 2 in CH CN at 25 ºC we have
3
-3
–
observed a second-order rate constant of 2.2 x 10 M
1
–1
-3
–1 –1
s and 1.2 x 10 M s respectively (Fig. 5 and Fig.
S7, Supporting Information).
Figure 4: Plot of kobs against different concentration of (a) PPh
b) 2-PPA and the second-order rate constant for the reaction of
PPh and 2-PPA with 1 () and 2 ().
3
,
(
3
The pseudo first-order rate constants increased
proportionally with an increase of the 2-PPA
concentration, allowing us to measure second-order
rate constant of the reaction with 1 and 2 as oxidants

We would like to thank CIF, IIT Guwahati for
instrumental support and Mr. Dibyajyoti Borah from
IIT Guwahati for technical support. We acknowledge
financial support from Department of Science and
Technology (DST-SERB), India (EMR/2014/000279)
and the British Council for UK-India Education
Research Initiative (UKIERI) award (DST/INT/UK/P-
1
51/2017).
Supporting Information
Supporting Information contains characterization data
for ligand and metal complexes and kinetic data.
Figure 5: Plot of kobs against the concentration of 2-PPA () and
α-[D1]-PPA () with 1 in CH CN at 25 ºC.
Reference
3
As such, the deformylation reaction slows down [1]. R. A. Sheldon, J. K. Kochi, Metal-Catalyzed Oxidation
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complex 1 and 2 also react with 2-PPA via an initial
hydrogen atom abstraction reaction from the α-
position with a kinetic isotope effect (KIE) of 12 and
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