Copper(II)-hydroperoxo complex induced oxidative N-dealkylation chemistry

Article abstract of DOI:10.1021/ja0719024

A significant oxidative N-demethylation reaction occurs from a hydroperoxo-copper(II) species when formed within a tripodal tetradentate ligand framework possessing a pendant dimethylamine substrate. This mimics the monoxygenase activity occurring in the copper enzyme PHM. Observation of a product-based alkoxide-Cu intermediate and determination of a reaction kinetic isotope effect (k_H/k_D(intra) ～ 2.3) by studying the ligand-N(CH₃)(CD₃) substrate provide further insights. The mononuclear Cu^II(-OOH) entity or species derived from this can promote biomimetic reactivity and thus requires further attention in biological or synthetic mechanistic studies. Copyright

Full text of DOI:10.1021/ja0719024

Published on Web 05/03/2007
Copper(II)-Hydroperoxo Complex Induced Oxidative N-Dealkylation
Chemistry
Debabrata Maiti, Amy A. Narducci Sarjeant, and Kenneth D. Karlin*
Department of Chemistry, The Johns Hopkins UniVersity, Baltimore, Maryland 21218
Received March 18, 2007; E-mail: karlin@jhu.edu
In this report, we describe the generation of a new hydroperoxo-
copper(II) mononuclear complex which effects oxidative N-
dealkylation chemistry on a substrate which is juxtaposed to the
II -
reacting Cu ( OOH) moiety. The interest in such an investigation
derives from copper bioinorganic chemistry: (a) There remain
fundamental questions concerning the inherent coordination struc-
tures and reactivity of single-copper complexes bound to dioxygen
-
and its reduced derivatives, such as superoxide (O
2
), peroxide
2-
-
1-4
(O
2
), or hydroperoxide ( OOH).
(b) Structurally similar
peptidylglycine-R-hydroxylating monooxygenase (PHM) and dopam-
5
ine â-monooxygenase (DâM) effect related substrate hydroxylation
II -
reactions at a mononuclear copper center. A Cu ( OOH) moiety
was previously implicated as the active species formed prior to
5
DâM or PHM substrate H-atom abstraction. More recent experi-
mental and computational chemistries have, however, brought
I
II
-
attention to a Cu /O
2
-derived superoxo Cu (O
2
) moiety as the likely
Figure 1. Formation and reactivity of a hydroperoxo-copper(II) complex
effecting oxidative N-dealkylation of a ligand-substrate -N(CH3)2 group.
H-atom abstracting agent.5 Still other theoretical treatments prefer
-7
8
II -
a prior (rather then subsequent) O-O cleavage from Cu ( OOH)
leading to a high-valent [Cu-O]2 or [Cu-O] moiety which
effects H-atom transfer. As applied to PHM, the methylene H-atom
abstraction from and subsequent rebound to the (peptide)C(O)-
+
+ 9
Et
3 2
N using 50% H O2(aq) to a greenish blue acetone solution of 1
at -80 °C gives a green product solution with complex formulated
N(CH )
II -
+
as the hydroperoxide [(L
3 2)Cu ( OOH)] (2); a charge-transfer
NHCH
2
COOH substrate would give hydroxylated (peptide)C(O)-
absorption maximum often seen for such species in the 350-400
NHCH(OH)-COOH; this subsequently transforms to amine (here
carboxamide) (peptide)C(O)NH
products.8 Our results presented here suggest that a Cu ( OOH)
species or a product derived from this merits further serious attention
in discussions of enzyme mechanism or applications to practical
chemistry.
11
14
nm region is not clearly present, but direct evidence for 2 comes
from electrospray ionization mass spectrometry (ESI-MS). Injection
of -80 °C acetone solutions of 2 gives a dominant parent peak
cluster with m/z ) 429.02 and an expected 6 Cu pattern. When
2
and aldehyde HC(O)COOH
c
II -
3,65
1
8
formation of 2 was instead carried out using H
ion peak shifts to 433.15, that is, [(L
2
O
2
, the positive
N(CH )
II -18 18
3 2)Cu ( O OH)] ; fitting
of the parent peak pattern around m/z ) 433 indicates >99%
+
Here, we employ the TMPA {≡ TPA ≡ tris(2-pyridylmethyl)-
1
8
O
amine)} ligand framework; these derivatives or analogues have been
incorporation. The EPR spectrum of 2 is also axial, consistent with
1
-4
extensively used to generate a variety of O
including binuclear Cu
2
-derived complexes
1
2
a single species that is different from 1.
II
2-
III
2-
2
(µ-1,2-O
2
2 2
) and Cu (µ-O ) and mono-
N(CH )
II -
+
[
(L
warming results in a change to a darker green color. Analysis of
the reaction mixture obtained by addition of Na EDTA(aq), extraction
3
2
)Cu ( OOH)] (2) is stable in solution at -80 °C, but
II
- 10
II -
1,11
nuclear Cu (O
2
)
or Cu ( OOH)
species. Masuda and co-
workers11 have generated the latter wherein they placed H-bonding
2
groups off of the pyridyl 6-position TMPA “arms”, stabilizing the
II -
into CH
2
Cl
2
to remove the Cu ion, and chromatographic separation/
Cu ( OOH) moiety. Here, we instead place there a potentially
N(CH )
isolation reveals that only ∼14% yield of the original L
3 2 ligand
oxidizable substrate and find that such a single pyridyl 6-dimethyl-
amino group is indeed subjected to oxidation from copper-
hydroperoxide-derived chemistry.
remains.12 The major (40-45%) new organic product is the
NH(CH )
oxidatively N-dealkylated compound L
3
; complementing this
The copper(II) mononuclear complex [(LN(CH3)2)CuII(H
O)]2+ (1)
is the formation of formaldehyde (∼40%) as determined from the
2
12
II
Nash test (Figure 1). Confirmation comes from X-ray analysis
(as bis-perchlorate salt) was synthesized from Cu (ClO
4
)
2 2
•6H O
II
NH(CH )
3
N(CH )
of a Cu -chloride derivative formed from isolated L
[(L
,
plus ligand L
3
2
added together in acetone, precipitated with
NH(CH )
II
+
12
NH(CH )
3
12
3
)Cu (Cl)] (3). The chemistry leading to L
plus
Et
2 2
O, and recrystallized from acetone/Et O. An X-ray structure
2
CH dO thus mimics the monooxygenase activity occurring in PHM
(Figure 1) reveals a square-based pyramidal structure, with dipi-
(
vide supra), where 2 or a product derived from it reacts with
colylamine (N1, N2, N3) and a water molecule in the basal plane;
the pyridyl arm with a 6-dimethylamino group binds axially, Cu1-
N4 ) 2.3596 (17) Å. The structure is likely maintained in solution,
as a typical axial EPR spectrum (X-band, 77 K) for a mononuclear
3 2
the -N(CH ) substrate placed in close proximity to the
Cu ( OOH) moiety. We also observe an intermediate suggested
12
II -
in PHM mechanistic discussions, a product-based alkoxide, here
N(CH )(CH O-
II +
[(L
3
2
)Cu ] (4; diagram below). This complex with m/z
Cu(II) complex is observed, g
|
) 2.253, g
⊥
) 2.052, A
|
) 174 G,
A
⊥
) 31.5 G. Following the method typically employed to generate
) 411.12 is detected upon mass spectrometric analysis of reaction
II
13
18
hydroperoxo-Cu complexes, addition of 2-3 equiv of H
2
O
2
/
mixtures prior to removal of the Cu ion (vide supra); use of H
2
O
2
6720
9
J. AM. CHEM. SOC. 2007, 129, 6720-6721
10.1021/ja0719024 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
II -
Scheme 1
Cu ( OOH) moiety or a subsequently formed high-valent Cu-oxo
species is the actual initial oxidant in our system; further studies
including attention to O-O cleavage and proton inventories are in
progress.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (K.D.K., GM28962).
Supporting Information Available: Synthetic and reactivity
details, product analyses/characterization, and CIF files. This material
is available free of charge via the Internet at http://pubs.acs.org.
in the reaction confirms the formulation (m/z 413.20).12 The release
NH(CH )
References
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and CH dO.
3
2
(
(
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(
(
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4
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N(CH )(CHO)
NH
2
electron oxidation products) aldehyde L
3
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(
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(
11) (a) Fujii, T.; Yamaguchi, S.; Funahashi, Y.; Ozawa, T.; Tosha, T.;
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N(CH )
II -
+
H
2 2
O
/Et
3
N is used to generate [(L
3 2)Cu ( OOH)] (2), warming
N(CH )
and workup leads to considerably more (∼60%) unreacted L
3
2
,
NH(CH3)
the yield of primary mono-N-demethylated ligand substrate L
N(CH )(CHO)
is obtained and no LNH
drops to 15-20%, only 3-4% L
3
2
is observed.12 Thus, the major reaction product, the biomimetic
(12) See Supporting Information.
(
13) Fujii, T.; Naito, A.; Yamaguchi, S.; Wada, A.; Funahashi, Y.; Jitsukawa,
K.; Nagatomo, S.; Kitagawa, T.; Masuda, H. Chem. Commun. 2003,
2700-2701.
NH(CH )
oxidatively N-dealkylated ligand, L
dependent manner.
3
, is formed in a “dose”-
N(CH )(CD )
II -
+
(14) Increased absorption does occur in this region; at λ ) 380 nm, an
Further insights come from using [(L
3
3
)Cu ( OOH)]
absorptivity of 1200 M- cm is observed.
1 -1
(
2-CD
versus -N(CD
product yields after warming -80 °C solutions and workup, an
3
), setting up an intramolecular substrate competition, N(CH
3
)
1
(
15) The k
(Scheme 1); ESI-MS data give k
calculations do not include any consideration of L
H D
/k of 2.4 is based on H NMR spectroscopy of product solutions
3
) oxidation (Scheme 1). On the basis of the relative
H
/k ) 2.2, thus the average ) 2.3. These
D
N(CD3)(CHO)
formation,
product; if this occurred,
NH(CD )
3
which could transform to additional L
1
5
apparent deuterium isotope effect of ∼2.3 is deduced (Scheme 1).
k
H
/k
comparisons of our k
since we cannot yet ascribe a specific temperature to our k
D
would even be larger, as pointed out by reviewers. Note that
5
H
/k
D
with literature values are difficult to interpret
/k
The k
(
/k
H D
observed in PHM is ∼11, while k
H D
/k values vary greatly
H
D
.
1-25) for a variety of chemical systems studied, primarily bis-
(16) (a) Nehru, K.; Seo, M. S.; Kim, J.; Nam, W. Inorg. Chem. 2007, 46,
293-298. (b) Bhakta, M.; Hollenberg, P. F.; Wimalasena, K. Chem.
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P450 Monooxgenase, 3rd ed.; Kluwer Academic/Plenum Publishers: New
York, 2005. (d) Meunier, B.; de Visser, S. P.; Shaik, S. Chem. ReV. 2004,
3
µ-oxo-dicopper(III) complexes. Our low value is similar to that
observed for oxidative N-dealkylations mediated by cytochrome
16
P450 monooxygenase, heme synthetic analogues, as well as non-
104, 3947-3980.
IV
16a
heme Fe dO. Thus, in our system, a reactive copper-based
(
17) (a) Shearer, J.; Zhang, C. X.; Zakharov, L. N.; Rheingold, A. L.; Karlin,
K. D. J. Am. Chem. Soc. 2005, 127, 5469-5483. (b) Itoh, K.; Hayashi,
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5212-5223. (c) Li, L.; Sarjeant, A. A. N.; Karlin, K. D. Inorg. Chem.
intermediate (vide infra) may initiate the oxidative process by
N(CH ) methyl group H-atom abstraction; such a N-CR H-atom
3 2
abstraction or another route involving initial rate-limiting electron-
transfer oxidation to give an amine radical cation and follow-up
are the two mechanisms extensively discussed for enzyme/chemical
2006, 45, 7160-7172.
II III
-
(µ-O2-)
(
18) Cu (O
present system. A -80 °C O
(5) leads to a species with CuIII (µ-O2-)2 spectroscopic
2
) or Cu
2
2
complexes are unlikely to be involved in the
2
reaction of a copper(I) complex of LN(CH3)2,
iron or copper oxidative N-dealkylations.1 We note that 2-CD
6,17
[(LN(CH3)2)Cu
I +
]
2
2
3
1
signatures; warming to rt and workup affords only 7% N-dealkylated
N(CD )(CHO)
chemistry also leads to some aldehyde L
3
(Scheme 1),
NH(CH )
3
N(CH )(CHO)
product L
3
and 3% L
. Dipicolylamine is also detected,
N(CH )(CDO)
but only reaction on the CH
is detected. Formation of L
3
group occurs as no L
3
product
indicating a completely different position of attack and oxidative chemistry
III
2-
2
by the Cu
2
(µ-O
)
core. A copper(I) reaction with O
2
would necessarily
NH
2
is also not observed.
II
-
proceed through a Cu (O
2
) initial species, suggesting this is not important
While we and others have observed and studied oxidative
N-dealkylation chemistry using well characterized dicopper com-
in the oxidative chemistry observed.
(
19) There are literature examples where oxidative C-N cleavage occurs from
2 2 2
reactions with O , H O , or other oxidants, where copper complex
III
2-
plexes possessing bis-µ-oxo-dicopper(III) Cu
peroxo Cu (µ- OOH) cores,
2
2
(µ-O
)
2
or hydro-
20a-c
characterization is unavailable.
Also, amine oxidation can occur by
II
-
3,17b,c
initial electron transfer from high redox potential Cu complexes.20d,e
this is the first detailed report
(
20) (a) Karlin, K. D.; Gultneh, Y. Prog. Inorg. Chem. 1987, 35, 219-327.
with mechanistic insights on a discrete mononuclear copper(II)-
hydroperoxide complex 2 which mediates an effective oxidative
(
b) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1991, 32, 3831-3834.
(c) Nishino, S.; Kunita, M.; Kani, Y.; Ohba, S.; Matsushima, H.; Tokii,
T.; Nishida, Y. Inorg. Chem. Commun. 2000, 3, 145-148. (d) Reddy, K.
V.; Jin, S.-J.; Arora, P. K.; Sfeir, D. S.; Maloney, S. C. F.; Urbach, F. L.;
Sayre, L. M. J. Am. Chem. Soc. 1990, 112, 2332-2340. (e) Wang, F.;
Sayre, L. M. Inorg. Chem. 1989, 28, 169-170.
1
8-20
N-dealkylation reaction similar to that occurring in PHM.
While
II
a superoxo-Cu moiety may be effective as a H-atom abstracting
agent,10,11a
II -
the further consideration of a Cu ( OOH) entity in PHM
or DâM mechanism is warranted. We cannot say whether the
JA0719024
J. AM. CHEM. SOC.
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VOL. 129, NO. 21, 2007 6721