Copper-hydroperoxo-mediated N-debenzylation chemistry mimicking aspects of copper monooxygenases

Article abstract of DOI:10.1021/ic800617m

A substantial oxidative N-debenzylation reaction along with PhCH=O formation occurs from a hydroperoxo-copper(II) complex that has a dibenzylamino substrate (-N(CH₂Ph)₂ appended as a substituent on one pyridyl group of its tripodal tetradentate TMPA (also TPA, (2-pyridylmethyl) amine)) ligand framework. During the course of the (L^N(CH2Ph)2)CuII(- QOH) reactivity, the formation of a substrate and a ^-OOH-derived (an oxygen atom) alkoxo Cu^II(^-OR) complex occurs. The observation that the same Cu^II(^-OR) species occurs from Cu^I/PhlO chemistry suggests the possibility that a copper-oxo (cupryl) reactive intermediate forms during the alkoxo species formation; new ESI-MS data provide further support for this high-valent intermediate. A net H atom abstraction chemistry is proposed on the basis of the kinetic isotope effect studies provided here and the previously published study for a closely related Cu^II(^-OOH) species incorporating dimethylamine (-N(CH₃)₂) as the internal substrate;²⁷ the Cu^I/PhlO reactivity with similar isotope effect results provides further support. The reactivity of these chemical systems closely resembles the proposed oxidative N-dealkylation mechanisms that are effected by the copper monooxygenases, dopamine β-monooxygenase (DβM) and peptidylglycine-α-hydroxylating monooxygenase (PHM).

Full text of DOI:10.1021/ic800617m

Inorg. Chem. 2008, 47, 8736-8747
Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry Mimicking
Aspects of Copper Monooxygenases
Debabrata Maiti, Amy A. Narducci Sarjeant, and Kenneth D. Karlin*
Department of Chemistry, The Johns Hopkins UniVersity, Baltimore, Maryland 21218
Received April 5, 2008
A substantial oxidative N-debenzylation reaction along with PhCHdO formation occurs from a hydroperoxo-copper(II)
complex that has a dibenzylamino substrate (sN(CH2Ph)2 appended as a substituent on one pyridyl group of its
tripodal tetradentate TMPA (also TPA, (2-pyridylmethyl)amine)) ligand framework. During the course of the
II -
-
II -
(LN(CH Ph) )Cu ( OOH) reactivity, the formation of a substrate and a OOH-derived (an oxygen atom) alkoxo Cu ( OR)
complex occurs. The observation that the same CuII(-OR) species occurs from CuΙ/PhIO chemistry suggests the
possibility that a copper-oxo (cupryl) reactive intermediate forms during the alkoxo species formation; new
ESI-MS data provide further support for this high-valent intermediate. A net H atom abstraction chemistry is proposed on
the basis of the kinetic isotope effect studies provided here and the previously published study for a closely related
CuII(-OOH) species incorporating dimethylamine (sN(CH3)2) as the internal substrate;27 the CuΙ/PhIO reactivity
with similar isotope effect results provides further support. The reactivity of these chemical systems closely resembles
the proposed oxidative N-dealkylation mechanisms that are effected by the copper monooxygenases, dopamine
ꢀ-monooxygenase (DꢀM) and peptidylglycine-R-hydroxylating monooxygenase (PHM).
2
2
Introduction
The study of copper(I)-dioxygen adducts and their (re-
duced) derivatives is of considerable current interest.1–8 In
large part, these efforts comprise the desire to elucidate
fundamental aspects such as the structural type along with
associated spectroscopy, electronic structure, and, of course,
reactivity patterns. Inspirations for such investigations also
come from aspects of bioinorganic chemistry; we wish to
provide fundamental information that may be relevant to
copper metalloenzyme active sites, where the processing of
molecular oxygen occurs. Included in the latter are the copper
monooxygenases, peptidylglycine-R-hydroxylating monoox-
ygenase (PHM) and dopamine ꢀ-monooxygenase (DꢀM),
which are mammalian proteins that serve in the biosynthesis
Figure 1. Homologus copper protein DꢀM (bottom), which transforms
dopamine to norepinephrine, and homologous copper protein PHM (top),
which hydroxylates the C-terminus of the peptide backbone, a process that
is followed by N-dealkylation by PAL.
of various neuropeptides or hormones.9–12 Figure 1 outlines
the specific reactions that are carried out. Each involves an
* To whom correspondence should be addressed. E-mail: karlin@jhu.edu.
(1) Itoh, S.; Fukuzumi, S. Acc. Chem. Res. 2007, 40, 592–600.
(2) Cramer, C.; Tolman, W. Acc. Chem. Res. 2007, 40, 601–608.
(3) Suzuki, M. Acc. Chem. Res. 2007, 40, 609–617.
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(5) Quant Hatcher, L.; Karlin, K. D. J. Biol. Inorg. Chem. 2004, 9, 669–
683.
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Blackburn, N. J. J. Biol. Chem. 2006, 281, 4190–4198.
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13105–13110.
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8736 Inorganic Chemistry, Vol. 47, No. 19, 2008
10.1021/ic800617m CCC: $40.75  2008 American Chemical Society
Published on Web 09/11/2008

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
Scheme 1
insertion of one oxygen atom (from O2) into the substrate.
For DꢀM, net benzylic hydroxylation occurs, whereas for
PHM, hydroxylation is followed by N-dealkylation. The active
sites of each enzyme are known to be very similar, and each
contains two copper ions. Previous biophysical studies have
shown these to be relatively far apart, and more recent X-ray
crystallographic structures of PHM show them to be ∼11 Å
apart.12 Thus, the mechanism of action focuses on the copper
chemistry taking place at one of the two copper ions CuM (t
CuB), whereas the other copper ion CuH (t CuA) serves to
transfer electrons.
Because of the history of biochemical/biophysical studies
on these enzymes and in the context of considering various
copper-dioxygen-derived species that are either known
orunknownininorganicchemistry,ahydroperoxo-copper(II)
(CuII(-OOH)) complex and a superoxo-copper(II) (CuII-
(O2•-)) complex derived from the initial CuΙ-O2 chemistry
or the high-valent cupryl [CuII-O•] have been discussed
as species that might be responsible for an initial hydrogen
atom abstraction reaction.2,4,8,9,11–18 For some time, a
hydroperoxo complex was suggested, but more recently,
both experimental and computational (bio)chemistry sug-
gest that the CuII(O2•-) moiety is relevant.4,9–11,13 Fur-
thermore, one crystal structure of PHM reveals what is
best described as a CuMII(O2•-) moiety that is perfectly
juxtaposed to the relevant substrate C-H bond. Other
theoretical treatments prefer a prior (rather than subse-
quent) O-O cleavage from CuII(-OOH), which leads to
a high-valent [Cu-O]2+ or [Cu-O]+ (equivalent to
CuIII-O•) moiety (cupryl) that affects H atom transfer.14,15
To obtain answers or to provide insight, synthetic bioinorganic
chemists have been actively pursuing the chemistry of mono-
nuclear copper-dioxygen-derived complexes, especially in the
reactivity toward substrates.2,19–27 Scheme 1 presents the several
species that may affect H atom abstractions, which are followed
by the net transfer of an oxygen atom to the substrate (i.e.,
monooxygenase activity).
In biomimetic studies that are approached via coodination
chemistry efforts, two types of hydroperoxide-copper spe-
cies have been produced to date: µ-1,1-hydroperoxo-dicop-
per(II) complexes and mononuclear complexes. We have
recently demonstrated substrate C-H activation chemistry
starting from well-characterized dinuclear µ-(-OOH)-dicop-
per(II) complexes, oxidative N-dealkylation, or RCH2CtN
oxidative cleavage (to the RCHdO aldehyde and cya-
nide).28,29 Suzuki has also observed a hydrocarbon attack
from a CuII (-OH)2 and H2O2 reaction, which gives a
2
CuII-OORligand-substrate product.30 A number of well-charac-
terized mononuclear CuII(-OOH) complexes have been
described;31–37 however, substrate oxidations have been
limited to organic sulfides37 or olefins (but in low yields).32
In our own laboratories, we have in the last year been able
to demonstrate C-H activation and thus oxygenation from
CuII(-OOH) complexes, as further discussed. There have
been notable advances in the generation of a mononuclear
CuII(O2•-) or CuIII(O22-) species,2,24,25,38 but a chemistry in
which such entities attack substrate C-H bonds has yet to
be described. There are no discrete examples or direct
evidence of mononuclear high-valent copper-oxo species;
however, see the further discussion below.
Within the context of the introduction given above, we
describe the chemistry of the new ligand LN(CH Ph) (Chart 1,
below) and its copper-complex-promoted oxidative chem-
istry. Whereas the main focus is on a mononuclear
2
2
CuII(-OOH) species, [(LN(CH Ph) )Cu ( OOH)] (2), we comple-
ment it with (ligand)CuΙ-O2 reactivity and a separate attempt
to interrogate the possible involvement of cupryl chemistry.
II -
+
2
2
(13) Chen, P.; Solomon, E. I. J. Am. Chem. Soc. 2004, 126, 4991–5000.
(14) Yoshizawa, K.; Kihara, N.; Kamachi, T.; Shiota, Y. Inorg. Chem. 2006,
45, 3034–3041.
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J. Am. Chem. Soc. 2006, 128, 12817–12828.
(16) Evans, J. P.; Ahn, K.; Klinman, J. P. J. Biol. Chem. 2003, 278, 49691–
49698.
(17) Decker, A.; Solomon, E. I. Curr. Opin. Chem. Biol. 2005, 9, 152–
163.
(18) Schro¨der, D.; Holthausen, M. C.; Schwarz, H. J. Phys. Chem. B 2004,
108, 14407–14416.
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45, 7160–7172.
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Rheingold, A. L.; Solomon, E. I.; Karlin, K. D. J. Am. Chem. Soc.
2005, 127, 15360–15361.
(30) Itoh, K.; Hayashi, H.; Furutachi, H.; Matsumoto, T.; Nagatomo, S.;
Tosha, T.; Terada, S.; Fujinami, S.; Suzuki, M.; Kitagawa, T. J. Am.
Chem. Soc. 2005, 127, 5212–5223.
(19) Fujii, T.; Yamaguchi, S.; Hirota, S.; Masuda, H. Dalton Trans. 2008,
164–170.
(20) Kunishita, A.; Ishimaru, H.; Nakashima, S.; Ogura, T.; Itoh, S. J. Am.
Chem. Soc. 2008, 130, 4244–4245.
(31) Kodera, M.; Kita, T.; Miura, I.; Nakayama, N.; Kawata, T.; Kano,
K.; Hirota, S. J. Am. Chem. Soc. 2001, 123, 7715–7716.
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Kitagawa, T. Inorg. Chem. 2000, 39, 4358–4369.
(21) Kunishita, A.; Teraoka, J.; Scanlon, J. D.; Matsumoto, T.; Suzuki,
M.; Cramer, C. J.; Itoh, S. J. Am. Chem. Soc. 2007, 129, 7248–7249.
(22) Hong, S.; Huber, S. M.; Gagliardi, L.; Cramer, C. C.; Tolman, W. B.
J. Am. Chem. Soc. 2007, 129, 14190–14192.
(23) Fujii, T.; Yamaguchi, S.; Funahashi, Y.; Ozawa, T.; Tosha, T.;
Kitagawa, T.; Masuda, H. Chem. Commun. 2006, 4428–4430.
(24) Maiti, D.; Lee, D.-H.; Gaoutchenova, K.; Wu¨rtele, C.; Holthausen,
M. C.; Sarjeant, A. A. N.; Sundermeyer, J.; Schindler, S.; Karlin, K. D.
Angew. Chem., Int. Ed. 2008, 47, 82–85.
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Mukai, M.; Kitagawa, T.; Einaga, H. Angew. Chem., Int. Ed. 1998,
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K.; Masuda, H. Chem. Lett. 2004, 33, 1556–1557.
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Karlin, K. D. J. Am. Chem. Soc. 2007, 129, 264–265.
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Inorganic Chemistry, Vol. 47, No. 19, 2008 8737

Maiti et al.
stirred for 25 min at room temperature. The complex was precipitated
as a greenish-blue solid upon the addition of Et2O (140 mL). The
supernatant was decanted, and the resulting crystalline solid was
washed two times with Et2O and was dried under vacuum to afford
This work follows our recent work in which we employed a
close analog [(LN(CH ) )Cu ( OOH)] (3), where both ligands
are the derivatives of TMPA (also TPA, tris(2-pyridylmethy-
l)amine)) (Chart 1, below); this shows that the hydroperoxo
group that is coordinated to copper(II) can affect oxidative
N-dealkylation chemistry on the juxtaposed dimethylamino
II -
+
3 2
[(LN(CH Ph) )Cu (H2O)(ClO4)]ClO4(acetone) (1) (0.305 g, 72% yield).
Single crystals were obtained by the vapor diffusion of Et2O into a
solution of the complex in acetone. Anal. Calcd for
II
2
2
substrate.27 In this Article, the chemistry of the LN(CH Ph) analog
is fully described.
2
2
II
[(LN(CH Ph) )Cu (H2O)(ClO4)]ClO4(acetone), C35H39Cl2CuN5O10: C,
51.01; H, 4.77; N, 8.50. Found: C, 50.88; H, 4.88; N, 8.37. X-band
EPR in acetone at 77 K: g| ) 2.252, g⊥ ) 2.047, A| ) 170 G, A⊥ )
29.5 G.
2
2
Experimental Section
II -
+
Generation of [(LN(CH Ph) )Cu ( OOH)] (2) and Reactivity
Study. In 20 mL of acetone solution, complex 1 (0.337 g, 0.409
mmol) was dissolved and was cooled to -80 °C by the use of an
acetone/dry ice bath. The addition of Et3N (0.412 g, 4.08 mmol)
2
2
Materials and Methods. Unless otherwise stated, all solvents
and chemicals used were commercially available analytical grade.
Acetone, diethyl ether, pentane, propionitrile, methanol, and tet-
rahydrofuran (THF) were used after being passed through a 60-
cm-long column of activated alumina (Innovative Technologies)
under argon. The deoxygenation of solvents was affected either by
repeated freeze/pump/thaw cycles or by bubbling with argon for
30-45 min. Dioxygen was dried by being passed through a short
column of supported P4O10 (Aquasorb, Mallinckrodt). The prepara-
tion and handling of air-sensitive compounds were performed under
an argon atmosphere and by the use of standard Schlenk techniques
or in an MBraun Labmaster 130 inert-atmosphere (<1 ppm O2,
<1 ppm H2O) drybox filled with nitrogen. Elemental analyses were
and 50 wt % H2O2 (252 µL, 4.09 mmol) (Aldrich) led to the
II -
formation of the green complex [(LN(CH Ph) )Cu ( OOH)]ClO4 (2)
(λ ) 380 nm, ε ) 1400 M-1cm-1). When an aliquot of this -80
°C green solution was injected into the mass spectrometer, a parent
peak cluster at m/z ) 581.03 that corresponded to the positive ion
2
2
[(LN(CH Ph) )Cu (OOH)] was observed. When H218O2 was used for
II
+
2
2
the formation of complex 2, the positive ion peak clusters shifted
II
+
to m/z ) 585.09. The alkoxide product [(LN(CH Ph) )Cu (OOH)]
2
2
(2) was detected with a parent peak cluster at m/z ) 563.05 that
1
performed by Desert Analytics (Tucson, AZ). H NMR and 13C
-
corresponded to the positive ion [(LN(CH Ph)(PhCHO ))CuII]+ (4). An
2
NMR spectra were measured on a Bruker 400 MHz spectrometer.
Chemical shifts were reported as δ values relative to an internal
standard(Me4Si)andtheresidual-solventprotonpeak.Ultraviolet-visible
spectra were recorded on a Hewlett-Packard model 8453A diode-
array spectrophotometer equipped with a two-window quartz H. S.
Martin Dewar filled with cold MeOH (25 to -85 °C) maintained
and controlled by a Neslab ULT-95 low-temperature circulator. The
spectrophotometer cells that were used were made by Quark Glass,
and each had a column, a pressure/vacuum side stopcock, and a
EPR spectrum of the reaction mixture containing complex 4 reveals
typical Cu(II) axial species supporting its mononuclear formulation.
When the formation of complex 2 was carried out with H218O2,
the positive ion peak clusters of complex 4 shifted to m/z ) 565.20.
X-band EPR of complex 2 in acetone at 77 K: g| ) 2.240, g⊥ )
2.041, A| ) 180 G, A⊥ ) 27 G. The hydroperoxo species [(LN(CH Ph) )-
CuII(-OOH)]ClO4 (2) was kept at -80 °C and was stirred for 15
min. Upon warming, the solution was carefully concentrated to 4
mL under vacuum, and the ESI-MS of the reaction solution was
recorded. The resulting copper solution was washed three times
with Et2O (200 mL) whereupon the Et2O solutions were combined
and dried over Na2SO4. The Et2O solution was analyzed by GC
and GC-MS (see below for conditions), which confirmed the
formation of PhCHO (authentic commercial PhCHO was also used
for the comparison) (43% yield). When the formation of complex
2 was carried out with H218O2 and similar follow-up procedures
were performed, ∼65% 18O-atom incorporation in PhCHO occurred.
Isolation of Organic Products. After a washing with Et2O, the
residual material was treated with 250 mL of saturated Na2EDTA/
H2O solution, and the organic part was extracted by using 80 mL
of CH2Cl2. The CH2Cl2/Na2EDTA/H2O extraction was repeated
three times to ensure complete demetalation. The organic CH2Cl2
solution was dried over anhydrous Na2SO4, was filtered, and was
concentrated by rotory evaporation. The ESI-MS of the organic
extract was recorded. The isolation and purification by column
chromatography (with Al2O3, 2% MeOH + CH2Cl2) revealed
2
2
-
path length of 2 mm. The copper complexes are ClO4 and
B(C6F5)4- salt complexes unless otherwise stated. Caution! Whereas
we haVe experienced no problems in working with perchlorate
compounds, they are potentially explosiVe, and care must be taken
to refrain from working with large quantities. Electrospray ioniza-
tion mass spectra were acquired by the use of a Finnigan LCQ
Deca ion-trap mass spectrometer equipped with an electrospray
ionization source (Thermo Finnigan, San Jose, CA). For metastable
species (as described below), samples were introduced from low-
temperature solutions with a liquid-N2 precooled plastic syringe
and were quickly injected into the instrument sample port that feeds
the instrument syringe pump, which operates at 10 µL/min via a
silica capillary line. The heated capillary temperature was 250 °C,
and the spray voltage was 5 kV. X-ray diffraction was performed
at the X-ray diffraction facility at The Johns Hopkins University.
The X-ray intensity data were measured on an Oxford Diffraction
Xcalibur 3 system equipped with a graphite monochromator, an
Enhance (Mo) X-ray source (λ ) 0.71073Å) that was operated at
2 kW (50 kV, 40 mA), and a CCD detector. The frames were
integrated with the Oxford Diffraction CrysAlisRED software
package. X-band electron paramagnetic resonance (EPR) spectra
were recorded on a Bruker EMX CW EPR spectrometer that was
controlled with a Bruker ER 041 XG microwave bridge operating
at the X band (∼9 GHz). The low-temperature experiments were
carried out via a N2(l) finger Dewar.
unreacted LN(CH Ph) (0.032 g, ∼16%) and the N-debenzylated
2
2
product LNH(CH Ph) (0.077 g, ∼48%). The products were character-
2
1
ized by ESI-MS, H NMR, 13C NMR, and thin-layer chromatog-
raphy (TLC). The formation of LN(CH Ph)(COPh) and LN(COPh) (0.014
g, ∼7%; ESI-MS: 522.53 (M + Na) and 536.31 (M + Na),
respectively) and LNH(COPh) (0.004 g, ∼3%; ESI-MS: 410.65 (M +
H) and 432.51 (M + Na)) was also observed. Several attempts to
isolate these organic products in an absolute pure form were
unsuccessful because of their comparable Rf values; however, their
formulation can be confirmed from both pre- and postdemetalation.
2
2
II
+
Synthesis of [(LN(CH Ph) )Cu (H2O)(ClO4)] (1). The synthesis
2
2
and characterization of LN(CH Ph) was recently reported.39 Ligand
LN(CH Ph) (0.250 g, 0.515 mmol) was treated with CuII(ClO4)2 ·
2
2
2
2
We did not find any evidence of LNH formation.
2
6H2O (0.191 g, 0.516 mmol) (Aldrich) in acetone (10 mL) and was
8738 Inorganic Chemistry, Vol. 47, No. 19, 2008

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
Experiment Adding Only One Equivalent Peroxide. Triethy-
lamine (Et3N, 0.041 g, 0.408 mmol) and 50 wt % H2O2 (25 µL,
0.408 mmol) were added to the 20 mL of acetone solution (-80
°C) of complex 1 (0.337 g, 0.409 mmol). Our following procedures
mmol) was taken with 4.0 mL of CH3CN under argon and was
stirred for 30 min and cooled to -40 °C. Via a syringe, 1 mL of
this CH3CN solution was introduced anaerobically into the -40
°C solution of complex 6. The ESI-MS of this low-temperature
copper solution was recorded and showed the initial strong peak at
similar to those described above produced unreacted LN(CH Ph) (0.130
2
2
III
+
g, ∼65%), LNH(CH Ph) (0.026 g, ∼16%), and LN(CH Ph)-(COPh) plus
m/z ) 564.25 because of high-valent [(LN(CH Ph) )Cu dO] species
2
2
2
2
LN(COPh) (0.002 g, ∼1%). A similar reaction in methanol as the
formation. The decomposition of this 564 species was followed with
2
–
solvent lead to the formation of ∼14% LNH(CH Ph)
,
<1%
respect to time, which leads to the alkoxo species [(LN(CH Ph)(PhCHO )
)
2
2
LN(CH Ph)(COPh), and LN(CH Ph) in ∼68% yield. The starting ligand
CuII]+ (4) (m/z ) 563.18). When the formation of complex 4 was carried
2
2
2
LN(CH Ph) was obtained in ∼64% yield along with ∼14% L
out with PhIO plus H218O, the positive ion peak clusters of complex 4
NH(CH2Ph)
2
2
and <1% LN(CH Ph)(COPh) in propionitrile as the solvent for an
shifted to m/z ) 565.34.
2
analogous [(LN(CH Ph) )Cu (H2O)(ClO4)] (1)/H2O2/Et3N reaction.
Reaction of [(LN(CH ) )Cu ]B(C6F5)4 (7)39 with PhIO.
II
+
Ι
2
2
3 2
LNH(CH Ph). H NMR (CDCl3, δ): 3.70 (s, 2H, CH2Py), 3.89 (s,
[(LN(CH ) )Cu ]B(C6F5)4 (7) (0.015 g, 0.014 mmol) was dissolved
in 15 mL of CH3CN inside the drybox and was taken in a 25 mL
Schlenk flask. In a separate Schlenk flask, PhIO (0.031 g, 0.140
mmol) was taken with 5.0 mL of CH3CN under argon and was
stirred for 30 min. Via a syringe, 1 mL of this CH3CN solution
(-40 °C) was introduced anaerobically into the -40 °C solution
of complex 7. The ESI-MS of the low-temperature copper solu-
1
Ι
2
3 2
4H, 2CH2Py), 4.48 (d, 2H, CH2Ph), 5.13 (s, 1H, NH), 6.22 (d, 1H),
6.83 (d, 1H), 7.09 (t, 2H), 7.11-7.44 (m, 5H), 7.45-7.68 (m, 5H),
8.49 (d, 2H). 13C NMR (CDCl3, δ): 46.51, 60.21, 77.39, 104.74,
112.04, 121.86, 122.83, 126.79, 127.41, 128.55, 136.38, 137.89,
139.43, 143.28, 148.99, 157.76, 158.29, 159.84. ESI-MS: 396.68
(M + H), 418.33 (M + Na). Rf ) 0.23, alumina, 2% MeOH +
tion was recorded, and it showed the strong peak at m/z ) 411.18.
CH2Cl2.
Ι +
When a similar reaction was carried out with [(LN(CH )(CD ))Cu ] and
PhIO, the positive ion peak clusters contained dominant peaks
at m/z ) 413.24 and 414.14 because of the generation of
Ι +
Reaction of [(LN(CH Ph) )Cu ] (6) with O2. The synthesis and
3
3
2
2
characterization of the copper(I) complex [(LN(CH Ph) )Cu ]B(C6F5)4
Ι
2
2
(6) was previously reported.39 The formation of the bis(µ-
-
-
[(LN(CH )(CD O ))CuΙ]+ and [(LN(CD )(CH O ))CuΙ]+, respectively.
oxo)dicopper(III) complex [((LN(CH Ph) )Cu )2(O2-)2](B(C6F5)4)2 (9)
from the O2 reactivity of complex 6 was confirmed by low-
temperature UV-vis and resonance Raman (rR) spectroscopy. For
III
3
2
3
2
2
2
Chemistry of [(LN(CH ) )Cu ( OOH)] (3) and its Reac-
II -
+
3
2
tivity Study. The synthesis, characterization, and reactivity studies
of the copper(II)-hydroperoxo complex [(LN(CH ) )Cu -
(-OOH)]ClO4 (3) were previously reported.27 Via a further
examination in the present study, we were able to isolate a small
II
3
2
the determination of ligand oxidation chemistry, a solution of
[(LN(CH Ph) )Cu ] (6) (0.125 g, 0.101 mmol) in a 25 mL Schlenk
flask with 6 mL of Et2O was prepared in the glovebox. The removal
to the benchtop and the cooling to -80 °C, followed by the bubbling
of O2 via a long syringe needle (20 s), was carried out, and this
was followed by the removal of excess dioxygen via evacuation
and purging with argon. After 30 min, the solution was warmed to
room temperature, and demetalation procedures with Na2EDTA/
H2O/CH2Cl2 were performed; this resulted in the production of
Ι +
2
2
II
amount of one decomposition product, [(LN(CH ) )Cu -
3
2
(HCOO-)(ClO4)CuII-(LNH(CH ))](ClO4)2 (11), with dicopper(II)
3
centers bridged by the (HCOO-) group from the reactivity of
complex 3 in acetone. Compound 11 was characterized crystallo-
graphically, and its EPR and ESI-MS characterization studies were
performed. (See Supporting Information.) We also previously
27
II -
+
described the chemistry of [(LN(CH )(CD ))Cu ( OOH)] (3-CD3)
for which we now find that the extracted unreacted ligand has its
isotope label scrambled. (See the discussion below.)
dipicolylamine (0.001 g, ∼4%), LNH(CH Ph) (0.002 g, ∼5%), and
3
3
2
unreacted LN(CH Ph) (0.037 g, ∼75%).
2
2
Synthesis of [LNH(CH Ph))CuII(Cl)]+ (10). We followed the
2
synthetic procedures that were previously employed in generating
crystalline copper(II)-chloride complexes via ligand-Cu(I)-
Results and Discussion
CHCl3 chemistry.27,40 Isolated LNH(CH Ph) (0.050 g, 0.126 mmol)
2
and [CuΙ(CH3CN)4]ClO4 (0.042 g, 0.128 mmol) were placed in a
25 mL Schlenk flask under argon. Dioxygen-free CH3CN (2 mL)
was added under argon to form a yellow solution, and this was
stirred for 10 min. Deoxygenated CHCl3 (0.3 mL) was then added
under argon whereupon the solution ceased to look transparent and
turned green. After 2 h, 20 mL of Et2O was added to precipitate
the copper complex. X-ray-quality crystals of this compound,
Ligand Design and Hydroperoxo-Copper(II) Com-
plexes. We have previously carried out and published
extensive studies concerning the dioxygen reactivity of the
parent-ligand copper(I) complex [(TMPA)CuΙ(CH3CN)]+
along with a variety of analogs.41–43 Masuda and cowork-
ers44,45 elaborated on the TMPA framework by inputting
potential hydrogen-bonding moieties and placing them in
6-pyridyl positions. In a series of studies, they showed that
ligand-copper(I) compounds react with O2 to form binuclear
copper-dioxygen adducts (formally µ-1,2-peroxodicopper(II)
complexes) that do show altered UV-vis and rR spectro-
[(LNH(CH Ph))CuII(Cl)]+ (10), were obtained from the reaction solution
2
after the precipitation that was prompted by Et2O. The green
precipitate was recrystallized two times from CH3CN/Et2O. Anal.
Calcd for C25H29Cl2CuN5O6: C, 47.66; H, 4.64; N, 11.12. Found:
C, 47.71; H, 4.34; N, 11.08. After the vacuum drying, the green
crystals weighed 0.054 g (68%).
Ι
Reaction of [(LN(CH Ph) )Cu ]B(C6F5)4 (6) with PhIO.
(41) Hatcher, L. Q.; Karlin, K. D. AdV. Inorg. Chem. 2006, 58, 131–184.
(42) Karlin, K. D.; Zuberbu¨hler, A. D. Formation, Structure, and Reactivity
of Copper Dioxygen Complexes In Bioinorganic Catalysis, 2nd ed.;
Reedijk, J., Bouwman, E., Eds.; Marcel Dekker: New York, 1999; pp
469-534.
2
2
[(LN(CH Ph) )Cu ]B(C6F5)4 (6)39 (0.018 g, 0.015 mmol) was dissolved
in 18 mL of CH3CN inside the drybox and was taken in a 25 mL
Schlenk flask. In a separate Schlenk flask, PhIO (0.033 g, 0.150
Ι
2
2
(43) Karlin, K. D.; Kaderli, S.; Zuberbu¨hler, A. D. Acc. Chem. Res. 1997,
30, 139–147.
(39) Maiti, D.; Woertink, J. S.; Narducci Sarjeant, A. A.; Solomon, E. I.;
Karlin, K. D. Inorg. Chem. 2008, 47, 3787–3800.
(40) Lucchese, B.; Humphreys, K. J.; Lee, D.-H.; Incarvito, C. D.; Sommer,
R. D.; Rheingold, A. L.; Karlin, K. D. Inorg. Chem. 2004, 43, 5987–
5998.
(44) Yamaguchi, S.; Wada, A.; Funahashi, Y.; Nagatomo, S.; Kitagawa,
T.; Jitsukawa, K.; Masuda, H. Eur. J. Inorg. Chem. 2003, 437, 8–
4386.
(45) Wada, A.; Honda, Y.; Yamaguchi, S.; Nagatomo, S.; Kitagawa, T.;
Jitsukawa, K.; Masuda, H. Inorg. Chem. 2004, 43, 5725–5735.
Inorganic Chemistry, Vol. 47, No. 19, 2008 8739

Maiti et al.
Chart 1
II
Figure 2. ORTEP diagram of [(LN(CH Ph) )Cu (H2O)(ClO4)](ClO4) (1).
Thermal ellipsoids are drawn by ORTEP and represent 50% probability
surfaces. Cu(1)-O(1) ) 1.9723(11), Cu(1)-N(1) ) 1.9885(12), Cu(1)-N(3)
) 1.9965(12), Cu(1)-N(1) ) 2.0104(12), and Cu(1)-N(4) ) 2.935 Å;
∠O(1)-Cu(1)-N(1) ) 94.34(5), ∠O(1)-Cu(1)-N(3) ) 99.06(5), and
∠N(1)-Cu(1)-N(3) ) 166.31(5)°.
2
2
compounds, we reported two examples in the last year in
which we mounted a potentially oxidizable substrate within
Chart 2
the ligand framework, N(CH3)2, that is, LN(CH ) (Chart 1)27
3 2
or a hydrocarbon aryl group,26 thus fixed by covalent bonding
to be potentially juxtaposed to a CuII(-OOH) moiety or a
species derived from it via O-O cleavage. As mentioned in
the Introduction, we detail the overall oxidative copper ion
chemistry with LN(CH Ph)
.
2
2
II
Copper(II) Complex [(LN(CH Ph) )Cu (H2O)(ClO4)]-
ClO4 (1). For the purpose of generating a hydroperoxo
complex by starting with Cu(II) and adding H2O2, we
straightforwardly synthesized complex 1. (See Experimental
Section.) X-ray-quality crystals were obtained, and the
structure is described here (Figure 2).
2
2
The copper(II) ion is five-coordinate. The oxygen atom
O(1) from a water molecule along with the alkylamino
nitrogen N(2) and pyridyl groups that are not substituted in
the 6 position (N(1) and N(3)) comprise the basal plane of
the structure found in pyramidal geometry around a copper
center. One of the two perchlorate anions coordinates as the
fifth axial ligand, Cu(1)-O(2)perchlorate ) 2.3515(11) Å. A
simple geometric analysis indicates that the overall coordina-
tion geometry is a slightly distorted square pyramid (τ )
0.156, where τ ) 0.00 for a perfect square pyramid and τ )
1.00 for a trigonal bipyramid).46 The copper ion (Cu(1)) lies
in the best least-squares basal plane. The pyridyl substituents
arm (with N(4)) is moved and twisted away from the copper
ion (Cu · · · N(4) ) 2.9345(13) Å), most likely because of
steric issues with the 6-dibenzylamino substituent.40,47 The
structure is likely maintained in the solution because a typical
axial EPR is observed (Figure 3a).
scopic properties due to H bonding.44,45 Furthermore, Ma-
suda generated a variety of hydroperoxo-copper(II) com-
plexes via (ligand-CuII + H2O2 + base) reactions, including
those shown in Chart 2.33–36 As indicated, one of these could
be characterized by X-ray crystallography.33
However, the oxidative reactivity of these mononuclear
CuII(-OOH) species (with tetradentate chelates) toward
exogenous substrates was not observed. One reason for such
inactivity could be that potential substrates could not achieve
an appropriate proximity (either spatially or temporarily) to
the CuII(-OOH) moiety. Another explanation could be that
the stabilization of the CuII(-OOH) unit with H bonding
comesatthecostofreactivity.Concerninghydroperoxo-Cu(II)
II
Hydrogen Peroxide Reactivity of [(LN(CH Ph) )Cu -
2
2
II
(H2O)(ClO4)]ClO4 (1). Generation of [(LN(CH Ph) )Cu -
(-OOH)]+ (2). The green product solution that forms
following the addition of 2 to 3 equiv of H2O2/Et3N using
2
2
(46) Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor, G. C.
J. Chem. Soc., Dalton Trans. 1984, 1349–1356.
(47) Maiti, D.; Woertink, J. S.; Vance, M. A.; Milligan, A. E.; Narducci
Sarjeant, A. A.; Solomon, E. I.; Karlin, K. D. J. Am. Chem. Soc. 2007,
129, 8882–8892.
8740 Inorganic Chemistry, Vol. 47, No. 19, 2008

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
LN(CH Ph)(COPh) (m/z ) 500.32 (M + H), 522.35 (M + Na)),
2
the overoxidized/oxygenated amide derived from benzoic
acid LNH(COPh) (m/z ) 410.47 (M + H), 432.41 (M + Na)),
and the doubly oxygenated (bis-amide) parent ligand LN(COPh)
2
(m/z ) 514.22 (M + H), 536.27 (M+Na)) are present.
Unreacted ligand LN(CH Ph) (m/z ) 486.36 (M + H), 418.49
(M + Na)) is also present. The absolute yields (average of
three runs) are summarized in Scheme 2.
2
2
We also observed overoxidized products, that is, more than
the single two-electron substrate oxidation (peroxide as an
oxidizing/oxygenating agent) in our previously published
results with LN(CH ) and [(LN(CH ) )Cu ( OOH)] (3).27
II -
+
3 2
3 2
However, here no corresponding LNH product derived from
2
complex 2 was observed. In the present chemistry, chro-
matographic separation/isolation reveals that only ∼16%
Figure 3. EPR (X band, 77 K, acetone) spectra of (a)
yield of the original LN(CH Ph) ligand remains after reactions.
2
2
II
[(LN(CH Ph) )Cu (H2O)(ClO4)](ClO4) (1) (g| ) 2.252, g⊥ ) 2.047, A| ) 170
2
2
The major (∼48%) new organic product formed is the
II -
G, A⊥ ) 29.5 G) and (b) [(LN(CH Ph) )Cu ( OOH)](ClO4) (2) generated from
the reaction of complex 1 with H2O2 (g| ) 2.240, g⊥ ) 2.041, A| ) 180 G,
A⊥ ) 27 G).
2
2
oxidatively singly N-debenzylated compound LNH(CH Ph)
2
(Scheme 2). As would be expected in an N-dealkylation
reaction, a corresponding aldehyde should form, and
indeed we observe ∼43% yield of benzaldehyde as
determined by GC and GC-MS spectroscopy. When
50% H2O2(aq) to a greenish-blue acetone solution of complex
1 at -80 °C is formulated as the hydroperoxide species
II -
+
[(LN(CH Ph) )Cu ( OOH)] (2). The band at λmax ) 380 nm
(ε ) 1400 M-1cm-1) is assignable to a -OOHs > CuII
LMCT absorption on the basis of the correspondence with
a number of literature examples.27,33–37 An axial CuII EPR
spectrum is also observed for complex 2, which is consistent
with a single mononuclear species formulation but is
distinguishable from complex 1 (Figure 3b).
2
2
labeled hydrogen peroxide is used in the reaction that gives
II
[(LN(CH Ph) )Cu (-18O18OH)]+ (2-18O), 18O-labeled PhC-
(18O)H is formed, and ∼65% of the theoretically expected
18O is incorporated. Benzaldehyde, with its fairly exchange-
able (with water) carbonyl group, is well documented in not
always retaining a high degree of 18O incorporation.48,49 As
mentioned and from the yields obtained (Scheme 2), small
but significant amounts of formally four- or eight-electron
2
2
II -
+
Direct evidence of [(LN(CH Ph) )Cu ( OOH)] (2) comes
from ESI-MS. The injection of a -80 °C acetone solution
of complex 2 produces a highest-molecular-weight parent-
peak cluster with m/z ) 581.03 and an expected 63,65Cu
pattern, corresponding to the monocation as formulated. As
indicated (Figure 4a), the most prominent ESI-MS peak at
2
2
overoxidized products form, including ketones LN(CH Ph)(COPh)
2
plus LN(COPh) (7%) and LNH(COPh) (3%) (Scheme 2). These
2
are likely derived from the reaction of the initial two-electron
oxidation products with an excess of hydrogen peroxide.
(Also, see below.)
m/z ) 548.59 matches a complex that has lost (H)OOH,
II +
[(LN(CH Ph) )Cu ] . When the formation of complex 2 was
2
2
When only 1 equiv of H2O2/Et3N is used to generate
carried out using H218O2 instead, the positive ion peak shifted
II -
+
[(LN(CH Ph) )Cu ( OOH)] (2), a warming and a workup lead
2
2
to 585.09 because of the formation of [(LN(CH Ph) )-
CuII(-18O18OH)]+ (2-18O); the fitting of the parent peak
pattern around m/z ) 585 indicates >99% 18O incorporation.
Hydrogen peroxide or -OOH is known to attack the
carbonyl group of acetone, and Itoh and coworkers21 recently
observed a thus-formed alkylperoxo adduct bound to cop-
per(II) in related but tridentate ligand-copper complex
chemistry. However, by ESI-MS, we see no evidence of such
a hydroperoxo-acetone-copper(II) complex. Also, see the
further discussion below.
2
2
to considerably more (∼65%) unreacted LN(CH Ph) , and the
2
2
yield of primary mono-N-debenzylated ligand-substrate
LNH(CH Ph) drops to 16%; only 1% (total) of LN(CH Ph)(COPh)
2
2
plus LN(COPh) is obtained. No LNH(COPh) or LNH is observed.
Thus, the major reaction product is again the two-electron
2
2
(from one H2O2) oxidatively N-dealkylated LNH(CH Ph), which
2
is formed in a dose-dependent manner. Furthermore, fol-
lowing our comments above, we wanted to rule out the
possible involvement of a solvent in activating the hydrop-
eroxo species. Thus, we carried out the formation of
II -
+
[(LN(CH Ph) )Cu ( OOH)] (2) in both propionitrile and
methanol solvents, separately. In both cases, product distri-
butions were found to be similar to those found for acetone.
We conclude that the CuII(-OOH)+ moiety truly affects the
oxidations observed.
II
Ligand Oxidative Reactivity for [(LN(CH Ph) )Cu -
(-OOH)]+ (2). Hydroperoxo-copper(II) species 2 is stable
in solution at -80 °C, but a warming results in a change to
a darker-green color. Thin-layer chromatography and
ESI-MS data obtained from the product solution that has been
stripped of copper ion (by the addition of Na2EDTA(aq) and
an extraction into CH2Cl2; see Experimental Section) shows
that the formation of several new organic products has
occurred. Thus, the singly N-dealkylated (i.e., N-debenzy-
2
2
2
2
Some further insights into the overall chemistry occurring
in this system come from the direct ESI-MS reaction solution
following the warming to room temperature but prior to the
extraction of the copper ion with EDTA (vide supra). The ESI-
MS data (in Supporting Information) reveal the presence of
lation) compound LNH(CH Ph) (m/z ) 396.48 (M + H), 418.49
2
2
(M + Na)), the singly oxygenated organic compound
several copper complexes, [(LNH(CH Ph))Cu]+ (m/z ) 457.48) and
Inorganic Chemistry, Vol. 47, No. 19, 2008 8741

Maiti et al.
II
-
N(CH2Ph)2
Figure 4. ESI-MS spectra of (a) [(LN(CH Ph) )Cu ( OOH)](ClO4) (2) from the reaction of complex 1 with H2O2 and (b) [(L
)CuII(-18O18OH)](ClO4)
2
2
(2-18O) generated by complex 1/H218O2.
Scheme 2
[(LNH(CH Ph))Cu(acetone)]+ (m/z
)
517.27) (unreacted
relevant to the biomimetic nature of the reaction chemistry and
also provides some insight into mechanistic considerations.
2
[(LN(CH Ph) )Cu] (m/z ) 548.53)). In addition, a prominent
+
2
2
(intense) ESI-MS cluster is found at m/z ) 563.05, which
X-ray Crystal Structure of [(LNH(CH Ph))CuII(Cl)]ClO4
2
-
corresponds to alkoxide species [(LN(CH Ph)(PhCHO ))CuII]+ (4);
2
(10). We wish to verify further our major organic product
assignment, and thus for LNH(CH Ph) that was isolated and
see Scheme 2. In a corresponding experiment with
2
[(LN(CH Ph) )CuII(-18O18OH)]+ (2-18O), 18O does appear in this
2
2
purified via column chromatography, we formed a copper-
-
alkoxide product, [(LN(CH Ph)(PhCH(18)O ))Cu]+ (m/z ) 565.19; 94%
2
complex product. Under Ar, the reaction of LNH(CH Ph) and
2
18O incorporation). As will be described below, this finding is
CuΙ(MeCN)4(ClO4) in acetonitrile followed by the addition
(48) Lee, D.; Lippard, S. J. Inorg. Chem. 2002, 41, 827–837.
8742 Inorganic Chemistry, Vol. 47, No. 19, 2008
of CHCl3 leads to the chloro-copper(II) complex

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
[(LNH(CH Ph))CuII(Cl)]+ (10). (See Experimental Section.) An
O-O cleavage chemistry and give a high-valent copper-oxo
species, something that is sought after but unknown. (See
further discussion below.) There is a very broad and more
established FeIII-OOR (R ) H, alkyl, or acyl; either heme
or nonheme iron) homolytic or heterolytic O-O cleavage
(bio)chemistry.52–57 In this context, iodosylbenzene or analog
donors have been widely utilized with reduced metal
complexes to generate higher-valent metal-oxo complexes
(i.e., PhIO + ligand-Mn+; (M ) heme or nonheme Fe, Mn,
etc.) f ligand-Mn+2 ) (O2-) + PhI).58–61 As referred to in
the Introduction, a copper-oxo moiety is seen either to be
responsible for the H atom abstraction in PHM or DꢀM or
to form later in the reaction sequence/mechanism.
2
X-ray structure of the pentacoordinate complex was obtained
(see the diagram), and it confirms the presence and the
identity of LNH(CH Ph). The full X-ray structure is presented
2
in the Supporting Information.
In fact, we were previously successful in affecting the C-H
activation and the ligand methyl group hydroxylation, leading
to an alkoxo product [(TMG3trenO-)CuII]+; see the diagram
(TMG3tren is tris(2-(N-tetramethylguanidyl)ethyl)amine).24
Corresponding CuΙ/O2 Chemistry with LN(CH Ph)
.
2
2
Whereas the results that were presented so far implicate the
CuII(-OOH) moiety as being responsible for the observed
reactivity (Scheme 2), as before,27 we have examined the
Ι
products of the O2 reaction with [(LN(CH Ph) )Cu ]B(C6F5)4 (6)
to determine if copper(I)-dioxygen might be responsible.
This does not seem to be the case (vide infra).
2
2
In the context of other work, the complex 6/O2 reactions
result in the formation of the metastable bis(µ-oxo)dicop-
per(III) complex, [((LN(CH Ph) )Cu )2(O )2](B(C6F5)4)2 (9),
which could be characterized by low-temperature UV-vis
and rR spectroscopy.39 By warming such solutions to room
temperature and following Na2EDTA/H2O/CH2Cl2 demeta-
lation procedures, we found the organic products and yields
of these (which are low) to be quite different from the
III
2-
2
2
Most interestingly, for the present system, the reaction of
Ι +
PhIO with the cuprous complex [(LN(CH Ph) )Cu ] (6) did
2
2
–
produce [(LN(CH Ph)(PhCHO ))CuII]+ (4) (Scheme 2), as de-
2
tected by ESI-MS (m/z ) 563.18) and as corroborated
II
+
[(LN(CH Ph) )Cu (H2O)(ClO4)] (1)/H2O2/Et3N chemistry
when employing PhI18O (m/z ) 565.34) because of
2
2
–
[(LN(CH Ph)(PhCH(18)O ))CuII]+ (4-18O) in complementary experi-
2
(Scheme 2). Some of the oxidative N-dealkylation product
LNH(CH Ph) is observed but in only ∼5% total yield. A small
ments. (See Supporting Information.) One thus could suggest
2
II
+
that the cupryl species [(LN(CH Ph) )Cu -O•] (8) formed
during the reaction and affected the hydroxylation. However,
caution is required because it is possible that an iodo-
2
2
amount of new product dipicolylamine (∼4% yield) is also
observed; this must be derived from the CuIII2(O2-)2 attack
on the benzylic position of the substituted (i.e., with
N(CH2Ph)2) pyridyl moiety, which is analogous to that
previously seen by Suzuki and coworkers.50,51 Most of the
recovered organic (∼75%) is unreacted starting ligand
sylbenzene-bound copper complex (e.g., [(LN(CH Ph) )-
CuΙ-OIPh]+) is the true oxygenating agent and that prior
O-O cleavage did not occur.
2
2
LN(CH Ph) (Scheme 2). The CuΙ/O2 reaction would normally
Potentially exciting observations occurred when we fol-
2
2
progress through a copper-superoxo [CuII(O2 )] initial
lowed the [(LN(CH Ph) )Cu ] (6)/PhIO chemistry using
ESI-MS as a function of time; the reaction was carried out at
-40 °C, and aliquot samples were injected into the mass
spectrometer while initially at this temperature. Most inter-
-
Ι +
2
2
species,6,7 thus the observed oxidative chemistry of
II
+
[(LN(CH Ph) )Cu (H2O)(ClO4)] (1)/H2O2/Et3N does not proceed
2
2
via a superoxo species. The lack of an effective N-debenzylation
reaction of LN(CH Ph) by [CuIII2(O2-)2]2+ is most likely due to
the axial positioning of the N,N-dibenzyl arm that prevents the
oxo-atom attack. Suzuki and coworkers demonstrated such an
axial ligand elongation for 6-substituted 2-pyridyl ligand
arms in [((6-Me2TPA)CuIII)2(O2-)2]2+ (X-ray, Me2TPA is
(2-pyridylmethyl)bis(6-methyl-2-pyridylmethyl)amine).50
estingly, early on in the reaction, ∼1 min after the addition
2
2
Ι +
of PhIO to [(LN(CH Ph) )Cu ] (6) (CH3CN solvent, -40 °C),
the predominant detected higher-molecular-weight ESI-MS
species occurs with the strongest peak at m/z ) 564.25
2
2
(51) Mizuno, M.; Honda, K.; Cho, J.; Furutachi, H.; Tosha, T.; Matsumoto,
T.; Fujinami, S.; Kitagawa, T.; Suzuki, M. Angew. Chem., Int. Ed.
2006, 45, 6911–6914.
(52) Shan, X.; Que, L., Jr J. Inorg. Biochem. 2006, 100, 421–433.
(53) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L., Jr Chem. ReV. 2004,
104, 939–986.
Reaction of [(L)CuΙ]+ with PhIO. One might anticipate
II -
+
that [(LN(CH Ph) )Cu ( OOH)] (2) could potentially undergo
2
2
(49) Greenzaid, P.; Luz, Z.; Samuel, D. Trans. Faraday Soc. 1968, 64,
(54) Soper, J. D.; Kryatov, S. V.; Rybak-Akimova, E. V.; Nocera, D. G.
J. Am. Chem. Soc. 2007, 129, 5069–5075.
2780–2786.
(50) Hayashi, H.; Fujinami, S.; Nagatomo, S.; Ogo, S.; Suzuki, M.; Uehara,
A.; Watanabe, Y.; Kitagawa, T. J. Am. Chem. Soc. 2000, 122, 2124–
2125.
(55) Nam, W.; Han, H. J.; Oh, S. Y.; Lee, Y. J.; Choi, M. H.; Han, S. Y.;
Kim, C.; Woo, S. K.; Shin, W. J. Am. Chem. Soc. 2000, 122, 8677–
8684.
Inorganic Chemistry, Vol. 47, No. 19, 2008 8743

Maiti et al.
Figure 5. ESI-MS spectra from the reaction of [(LN(CH Ph) )Cu ] (6) with PhIO, suggesting the transient formation of the cupryl complexes
Ι
+
2
2
-
II
+
[(LN(CH Ph) )Cu -O•] (8) at m/z ) 564.25 (∼70% formation) and [(LN(CH Ph)(PhCHO ))CuII]+ (4) at m/z ) 563.18 (∼30% formation). Insets showing the
expected pattern for (a) 100% formation of complex 8 and (b) 100% formation of complex 4 and (c) the best fit to the data with 70% formation of complex
8 plus 30% formation of complex 4. See the text for further discussion.
2
2
2
-
) 414.14) and [(LN(CH )(CD O ))CuII]+ (m/z ) 413.24) (Figure
6). This may be compared to the finding that kH/kD ≈ 2.2
3
2
(Figure 5), which in fact corresponds to a cupryl species,
III
+
III
II
[(LN(CH Ph) )Cu dO] (complex 8, Cu dO t Cu -O•). This
2
2
for the [(LN(CH )(CD ))Cu ( OOH)] (3) reaction.27 Considering
that 1.9 and 2.2 are nearly within the experimental error we
suggest that both the [(L)CuII(-OOH)]+ and [CuΙ]+/PhIO
chemistries proceed through a common reactive intermediate,
the cupryl species [(L)CuII-O•]+. (See the diagram.) The
data are suggestive but are probably not yet good enough to
firmly establish cupryl chemistry.
II -
+
3
3
peak is observed only early on as the product alkoxo complex
-
[(LN(CH Ph)(PhCHO ))CuII]+ (4) (m/z ) 563.18) comes in and
2
dominates. Notice that the theoretical fitting of this early-
time mass spectrum best corresponds to a mixture of 70%
cupryl (complex 8) and 30% alkoxo product 4 (Figure 5).
In the Supporting Information, we show a succession of mass
spectra (as a function of time) that demonstrates how the
putative cupryl is there initially but disappears after ∼5 to 6
min; it is almost absent after ∼3 min. The yields of the
organics from the reaction of [(LN(CH Ph) )Cu(I)]B(C6F5)4 (6)
with PhIO could not be determined because of insufficient
separation and tailing observed in column and thin-layer
chromatography.
2
2
Similarly, we carried out a PhIO reaction with the
previously studied ligand complex with dimethylamino
To summarize this section of the discussion, we employed
PhIO reactions with reduced complexes [(L)CuΙ]+ to probe
the possibility that high-valent cupryl species are involved
in the reactions of [(L)CuII(-OOH)]+ (i.e., following hemolyt-
ic O-O bond cleavage). For both the ligand complexes with
substituents/substrate, [(LN(CH ) )Cu ] (7).27,39 Electrospray
Ι +
3 2
ionization mass spectrometry data indicate that the corre-
-
sponding alokoxide product forms (i.e., [(LN(CH )(CH O ))-
3
2
CuII]+ (5) (m/z ) 411.18)). (See Supporting Information.)
LN(CH Ph) and LN(CH ) , PhIO reactions do produce the
expected alkoxo products (Scheme 2), and the mass spec-
trometric data (Figure 5) appear to give direct evidence of
the presence or the formation of the cupryl complex for one
2
2
3 2
This also forms from [(LN(CH ) )Cu ( OOH)] (3) chemistry,
II -
+
3 2
as reported.27 Interestingly, when the partially deuteriated
ligand complex [(LN(CH )(CD ))Cu ] (7-CD3) was reacted with
Ι +
3
3
II
+
case, [(LN(CH Ph) )Cu O•] (8). We do not wish to state overly
strongly that we have detected the first copper cupryl. The
overall reaction yields are not exceptional for the PhIO
2
2
PhIO, the ESI-MS analysis lead to the conclusion that for
this reaction the kinetic isotope effect (kH/kD) is 1.9 on the
-
basis of the relative formation of [(LN(CD )(CH O ))CuII]+ (m/z
3
2
8744 Inorganic Chemistry, Vol. 47, No. 19, 2008

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
-
2
Ι
Figure 6. ESI-MS spectra obtained from the reaction of [(LN(CH )(CD ))Cu ]+ (7) with PhIO. The ratio of formation of [(LN(CD )(CH O ))CuII]+ (m/z ) 414.14)
3
3
3
-
versus that of [(LN(CH )(CD O ))CuII]+ (m/z ) 413.24) suggests that kH/kD ≈ 1.9. The inset shows the expected (calculated) ESI-MS spectral pattern for a
reaction that would lead to kH/kD ≈ 1.9.
3
2
Scheme 3
Scheme 4
reaction chemistry, although this is probably not the ideal
oxo transfer agent. Also, whereas we detected the cupryl
species in the ESI-MS experiments by using PhIO, for some
reason, it was not observed when employing PhI18O;
however, that final product alkoxide did contain 18O. In
addition to the chemistry described here (and the initial
Article),27 CuII-O-OR homolytic cleavage has been sug-
gested to lead to a CuII-O• transient reactive species that
may affect substrate oxidation/oxygenation chemis-
try.20,22,24,62–64 Scheme 4 depicts some of the recent synthetic
examples.20,22,27
Mechanistic Discussion. Oxidative N-dealkylation is a
relatively common reaction in the biotransformation of
alkylamines; it is also catalyzed by cytochrome P450
monooxygenases. Considerable experimental effort has gone
into differentiating between conventional hydrogen atom
transfer (HAT) and a sequential reaction in which single-
electron-transfer (SET) oxidation is followed by deprotona-
tion.57,65–67 Oxidative N-dealkylation of the ligand bound
to copper in CuIII2(O2-)2 compounds has been observed
where mechanistic studies favored initial HAT.7We also
Inorganic Chemistry, Vol. 47, No. 19, 2008 8745

Maiti et al.
Scheme 5
have reported on cases where a CuIII2(O2-)2 (or side-on-
bound peroxo-dicopper(II) species in equilibrium with
this) oxidatively N-dealkylates substituted dimethylanilines
but where a shift in mechanism from ET to HAT was
observed, depending on the ease of substrate one-electron
oxidation.68
Figure 7. ORTEP diagram of the cationic component of
II
-
[(LN(CH ) )Cu (HCOO )(ClO4)CuII(LNH(CH3))](ClO4)2 (11). Thermal ellipsoids
are drawn by ORTEP and represent 50% probability surfaces. Cu(1)-O(2)
) 1.42(2), Cu(1)-N(3) ) 2.020(3), Cu(1)-N(2) ) 2.022(3), and Cu(1)-N(1)
) 2.023(3) Å; ∠O(2)-Cu(1)-N(3) ) 96.00(11), ∠O(2)-Cu(1)-N(2) )
175.51(13), ∠N(3)-Cu(1)-N(2) ) 82.15(12), and ∠O(2)-Cu(1)-N(1)
) 99.39(11)°.
3
2
As discussed above for the complexes’ N,N-dimethyl groups
at the 6-position of one arm of the TMPA-derived ligand,
In Scheme 5, we also show (Path B) how an overoxidized
product amide would most likely form in the model synthetic
system via a facile nucleophilic attack of a second equivalent
of the hydroperoxide anion. In connection with other
II -
+
observed KIE values are ∼2.2 for [(LN(CH )(CD ))Cu ( OOH)]
3
3
(3-CD3)27 chemistry and ∼1.9 for [(LN(CH )(CD ))Cu ] (7-
CD3)/PhIO chemistry. These results suggest that a net H atom
abstraction occurs. Organic products isolated (i.e., recovered
Ι +
3
3
overoxidation product chemistry, we recently isolated a small
II
amount of
a
decomposition product, [(LN(CH ) )Cu -
II -
+
dialkyl ligand) from [(LN(CH )(CD ))Cu ( OOH)] chemistry
3
2
3
3
(HCOO-)(ClO4)CuII-(LNH(CH ))](ClO4)2 (11), for which we
were able to obtain an X-ray structure (Figure 7). (See
Supporting Information.) This originates from the previously
3
included those due to the scrambling of isotopes via radical
intermediates, and LN(CH )(CD ), LN(CH )(CD H), LN(CH )(CDH ), and
3
3
3
2
3
2
LN(CH ) were all observed. However, more studies would be
3 2
described chemistry of [(LN(CH ) )Cu ( OOH)] (3). This odd
II -
+
3 2
required to differentiate between HAT and a SET step.
On the basis of the results described here, we outline our
dicopper(II) complex possesses a bridging formate (HCOO-)
group wherein one of the copper ligands is LN(CH ) (i.e., the
3 2
proposed mechanism of the reaction for [(LN(CH R′) )-
CuII(-OOH)]+ chemistry (Scheme 5). The initial net HAT
(occuring either directly from the hydroperoxide or following
O-O cleavage) substrate H atom abstraction would lead to
a high-valent CuII-O• (also CuIII dO) and substrate iminium
radical cation species; rebound produces the alkoxide (Path
A). Most often in the synthetic system and always in the
enzyme, protonation (from active-site solvent) releases the
organic products observed, the amine and the corresponding
aldehyde.
2
2
unreacted starting ligand), and the other copper ion is
supported by the singly N-demethylated product LNH(CH ). An
3
EPR spectrum of the isolated crystals that were dissolved in
acetone indicates the presence of two independent Cu(II) ions
with overlapping axial spectra. (See Supporting Information.)
Furthermore, an ESI-MS of the material contains two strong
peaks: the one at m/z
) 427.04 corresponds to
II
-
+
[(LNH(CH ))Cu (HCOO )] , and the other at m/z ) 441.04
3
corresponds to [(LN(CH ) )Cu (HCOO )] . The generation of
formate (HCOO-) can be envisaged because formaldehyde
was previously detected as a product derived from complex
3. Similarly, we are able to detect a small ESI-MS peak at
m/z ) 579.17 from the decomposition product mixture of
II
-
+
3 2
(56) Traylor, T. G.; Traylor, P. S. Reactions of Dioxygen and Its Reduced
Forms with Heme Proteins and Model Porphyrin Complexes In ActiVe
Oxygen in Biochemistry; Valentine, J. S., Foote, C. S. , Greenberg,
A., and Liebman, J. F., Eds.; Chapman & Hall: New York, 1995; pp
84-187.
II -
+
[(LN(CH Ph) )Cu ( OOH)] (2), which corresponds to a
2
2
(57) Meunier, B.; de Visser, S. P.; Shaik, S. Chem. ReV. 2004, 104, 3947–
3980.
copper-complex species containing benzoate, [(LNH(CH Ph))-
2
CuII(PhCOO-)]+ (i.e. a further oxidation product of benzal-
dehyde, which was a primary product derived from complex
2). All of these overoxidized products are obtained in very
low yields. Nevertheless, they are indicative of the extensive
chemistry occurring in the manner proposed.
(58) Que, L., Jr Acc. Chem. Res. 2007, 40, 493–500.
(59) McLain, J. L.; Lee, J.; Groves, J. T. Biomimetic Oxygenations Related
to Cytochrome P450: Metal-Oxo and Metal-Peroxo Intermediates In
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Meunier, B., Ed.; Imperial College Press: London, 2000; pp 91-169.
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M.-J.; Tosha, T.; Kitagawa, T.; Solomon, E. I.; Nam, W. J. Am. Chem.
Soc. 2007, 129, 1268–1277.
(61) Qin, K.; Incarvito, C. D.; Rheingold, A. L.; Theopold, K. H. J. Am.
Chem. Soc. 2002, 124, 14008–14009.
(62) Chen, P.; Fujisawa, K.; Solomon, E. I. J. Am. Chem. Soc. 2000, 122,
10177–10193.
PAM Chemistry Mimic. We have shown here that the
II -
+
hydroperoxo group reaction in [(LN(CH Ph) )Cu ( OOH)]
2
2
(2) leads to the formation of oxidatively N-dealkylated
LNH(CH Ph) plus PhCHdO. The -N(CH2Ph)2 substrate
2
(63) Comba, P.; Knoppe, S.; Martin, B.; Rajaraman, G.; Rolli, C.; Shapiro,
B.; Stork, T. Chem.sEur. J. 2008, 14, 344–357.
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(ligand substituent) resides in close proximity to the
CuII(-OOH) moiety (Scheme 3, R′ ) Ph), and essentially
8746 Inorganic Chemistry, Vol. 47, No. 19, 2008

Copper-Hydroperoxo-Mediated N-Debenzylation Chemistry
identical chemistry occurs for R′ ) H.27 As described
above, a copper(II)-alkoxide complex forms prior to
organic product release (Scheme 3).
of the tripodal-tetradentate TMPA-ligand framework. In the
previous Communication and from the present full Article,
we can argue that CuII(-OOH) or a species generated from
it (i.e., a high-valent copper-oxo species) can initiate useful
substrate hydroxylation reactions that are occurring in the
enzyme PAM (PHM + PAL) (Figure 1). Net substrate
H-atom abstraction occurs starting with the CuII(-OOH)
moiety, and the likely structure of an intermediate substrate
organic radical species is proposed, which accounts for the
observed products. The formation of a substrate and an
-OOH-derived alkoxo CuII(-OR) complex has been proven;
the latter has also been proposed in PHM mechanisms. The
fact that the alkoxo complex forms from either CuII(-OOH)
or CuΙ/PhIO chemistry suggests the possibility that a high-
valent copper-oxo reactive intermediate forms and ESI-
MS data provide some further support. Clearly, however,
further studies on this or other systems need to be carried
out to substantiate truly the existence of a cupryl species
and to elucidate the full chemistry of the already-existing
CuII(-OOH) and CuII(O2-•) complexes.
Thus, the present model systems (R′ ) H, Ph) very closely
resemble much of the proposed oxidative N-dealkylation
reaction mechanism affected by PAM (Figure 1). There, an
active-site reactive species forms at CuM with His2Met
coordination, which is ideally juxtaposed to the prohormone
peptide substrate C-H group of the terminal glycine.
Furthermore, our cupric-alkoxide complex, which is formed
II -
+
N(CH2Ph)2
from [(LN(CH Ph) )Cu ( OOH)] (2) or [(L
)CuΙ]+ (6)/
2
2
PhIO reactivity mimics the product substrate CuII-alkoxide
complex discussed for both PHM and DꢀM. (See the
diagram.9) However, as stated in the Introduction, the current
thought is that a copper-superoxo complex may be the active
species or it could be a cupryl species derived from
CuII(-OOH) O-O bond cleavage. Our results, with a
reactivity pattern so close to that of PHM/PAM, rather favor
the view that the reactive species is a hydroperoxo or cupryl
group.
Acknowledgment. This work was supported by grants
from the National Institutes of Health (K.D.K., GM28962).
Supporting Information Available: X-ray structures with
selected bond lengths and angles; ESI-MS and other spectroscopic
details. This material is available free of charge via the Internet at
http://pubs.acs.org.
Summary
This Article summarizes our advances in oxidative N-
dealkylation chemistry with hydroperoxo-copper(II) com-
plexes that have a dialkylamino substrate (-N(CH2Ph)2 or
-N(CH3)2) appended as a substituent on one pyridyl group
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K. D. J. Am. Chem. Soc. 2005, 127, 5469–5483.
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Inorganic Chemistry, Vol. 47, No. 19, 2008 8747