Nitric oxide release via oxygen atom transfer from nitrite at copper(ii)

Article abstract of DOI:10.1039/C6CC08745K

Nitric oxide is a vital signaling molecule that controls blood flow and oxygenation and nitrite serves as an important reservoir for nitric oxide in biology. While copper containing enzymes are known to reduce nitrite to nitric oxide, herein we report a new pathway to release nitric oxide via oxygen atom transfer from nitrite at a copper(ii) site.

Full text of DOI:10.1039/C6CC08745K

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DOI: 10.1039/C6CC08745K
Journal Name
COMMUNICATION
Nitric Oxide Release via Oxygen Atom Transfer from Nitrite at
Copper(II)
Received 00th January 20xx,
Accepted 00th January 20xx
Zeinab Sakhaei, Subrata Kundu, Jane Donnelly, Jeffery A. Bertke, William Kim, and Timothy H.
Warren*
DOI: 10.1039/x0xx00000x
www.rsc.org/
18, 19
Nitric oxide is a vital signaling molecule that controls blood flow oxophilic substrates such as phosphines PR ,
dialkyl
3
20
21
and oxygenation and nitrite serves as an important reservoir for sulfides R S, and thiols RSH reduce iron- and cobalt-nitrite
2
nitric oxide in biology. While copper containing enzymes are complexes [M](NO ) to corresponding metal-nitrosyl species
2
known to reduce nitrite to nitric oxide, herein we report a new [M](NO) with formation of the corresponding oxygenated
pathway to release nitric oxide via oxygen atom transfer from products phosphine oxide O=PR3, sulfoxide O=SR , and
2
nitrite at a copper(II) site.
sulfenic acid RS(O)H, respectively (Scheme 1).
Despite the importance of copper enzymes such as
-
2
Nitrite (NO ), a ubiquitous molecule in biology, serves as a
reservoir for nitric oxide (NO) activity in many tissues capable
1
-4
of widespread transport via circulation in the blood.
-
Conversion of NO2 to nitric oxide is especially crucial under
hypoxic conditions since NO enhances blood oxygenation and
5, 6
flow. In mammals, nitrite reduction to NO is catalysed by a
variety of iron-dependent nitrite reductases such as
7
haemoglobin and cytochrome c oxidase (CcO) . In the case
-9
10
-
of CcO, copper assists the NO2 / NO interconversion in the
11-14
binuclear iron/copper active site.
Moreover, nitrite
reduction to nitric oxide is an integral part of the
biogeochemical denitrification pathway that involves copper-
containing nitrite reductase enzymes (CuNIR), present in many
denitrifier organisms such as Alcaligenes xylosoxidans and
1
5-17
Alcaligenes faecalis.
Another nitrite reaction of potential biological significance is
oxygen atom transfer (OAT) from nitrite bound metal
complexes to electron rich substrates which is present in
1
0
Scheme 2 Synthesis of copper(I) and copper(II) nitrite complexes 2 and 3.
several metalloenzymes, such as cytochrome c and has
inspired synthetic metal-nitrite complexes. For instance,
Scheme 1 O-atom transfer reactions of metal-bound nitrite.
PR3
+ O PR3
+ O SR2
+ RS(O)H
O
O
III
[
M ]
N
+
R S
[M](NO)
2
RSH
porphyrin / macrocyclicdonors
M = Fe / Co
2
3
a.
Department of Chemistry, Georgetown University, Washington, DC, USA. *Email:
thw@georgetown.edu
Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Fig. 1 X-ray structures of copper(I) and copper(II) nitrite complexes 2 and 3.
†
Electronic
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Supplementary
Information
(ESI)
available:
See
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Journal Name
5, 17, 22
ceruloplasmin in nitrite homeostasis,
we are not aware
View Article Online
DOI: 10.1039/C6CC08745K
-
benzene
I
2
of examples in which copper nitrite complexes engage in OAT
reactions. Herein we describe a new nitrite to nitric oxide
reduction pathway that proceeds via OAT enabled by nitrite
coordination at Cu(II) but not Cu(I).
2
[Cu ](η -benzene)
O
[CuII]
[CuI]
1
N
O
CuII]
I
2
O
[
N
+ [Cu ](η -benzene)
xs NO
- N
4
O
3
O
2
We prepared the electron-deficient
β
-diketiminato
) by addition of
β-diketiminate Li[ Pr NN ] to a suspension of CuCl
i
2
copper(I) complex [ Pr NN ]Cu(
η
-benzene) (
1
Scheme 3 Synthesis of mixed valence dicopper nitrite complex 4.
2
F6
i
the lithium
2
F6
in benzene, isolated in 75% yield (Scheme S1; Fig. S19). This
copper model complex supports both copper(I) and copper(II)
nitrite complexes. Addition of [Bu N]NO to
4
1
in THF results in
2
nitrite coordination giving an anionic copper center in
i
1
[
NBu ]{[ Pr NN ]Cu(
κ
-NO )} (
2
) which may be prepared in
5% yield (Scheme 2). X-ray analysis (Fig. 1) reveals two
in the asymmetric unit that
feature trigonal planar Cu centers (sum of angles about Cu =
4
2
F6
2
7
independent molecules of
2
I
1
3
60.58(8) and 359.37(8)°) with κ -N bonding of the nitrite
anion (Cu-N = 1.923(2) and 1.920(2) Å). In each molecule of
the nitrite N-O distances are asymmetric, with a shorter N-O
1.208(3) and 1.191(3) Å) and longer N-O (1.251(2) and
.264(3) Å) bond distances. These nitrite N-O distances and
their asymmetry has been observed in other copper(I) nitrite
2
,
(
1
Fig. 3 X-ray structure of mixed valence dicopper nitrite complex 4.
2
3
structures with tridentate ligands. This asymmetry in N-O frequencies somewhat obscured by the strong C-F stretches in
bond lengths could be due to the presence of the IR spectrum of
tetrabutylammonium cation in close proximity. The IR
Cyclic voltammetry (CV) of both
spectrum of contains NO stretching bands for the anion at (Figs. 2, S16, S17) at RT reveal a quasi-reversible reduction
213 and 1294 cm , which shift to lower frequencies at 1190 wave centered at E1/2 = -0.42 V vs Fc /Fc. This is markedly
3
.
2
and 3 in tetrahydrofuran
2
2
-1
+
1
-
1
15
+
I
and 1280 cm respectively, when prepared from [Bu N] NO .
4
lower than the values of -0.20 to -0.36 V (vs. Fc /Fc) in LCu NO
2
2
The
corresponding
copper(II)
) may be prepared by reaction of
equiv. AgNO in fluorobenzene to give dark green in 80% favourable in the
yield (Scheme 2). X-ray crystallography (Fig. 1) reveals nearly complexes with tridentate supporting ligands due to the
nitrite
complex complexes supported by neutral tridentate ligands (L =
i
2
25
II
I
[
Pr NN ]Cu(
2
κ
-O N) (
3
1
with substituted Tpm, TACN). Thus, Cu to Cu reduction is less
-diketiminato copper(II) nitrite than these
F6
2
1
3
β
3
2
2
symmetric
κ
-O,O coordination of nitrite to a square planar anionic nature of reduced
2
. In contrast to the clean 1-electron
and , one electron oxidation of
copper center with Cu-O1 and Cu-O2 bond distances of interconversion between
.0286(19) Å and 2. 0126(19) Å, respectively. The nitrite ligand the electron-rich
has nearly identical N3-O1 and N3-O2 bond distances of irreversible.
2
I
3
Me2
-
+/0
2
TpCu NO (Eox = -0.38 V vs Fc ) is
2
23
1
.259(3) and 1.263(3) Å, respectively. The higher oxidation
state of relative to anionic is also reflected in shorter Cu- disproportionation of NO at copper(I) complexes
Nβ-dik distances of 1.901(2) and 1.900(2) Å in as compared to the reaction of TpCu(NO) to give TpCu(NO ) and N O,
the Cu-Nβ-dik distances that range from 1.942(2) to 1.975(2) Å also examined the addition of NO to
in two independent molecules of . Moreover, the copper(II) to the
-diketiminato copper(II) nitrite
center gives rise to a well-resolved four-line pattern in the RT
to excess (2-4 equiv) NO(g) at RT in fluorobenzene results in
EPR spectrum of in pentane with giso = 2.098, ACu = 205 MHz, formation of the mixed valence Cu(II)/Cu(I) dinuclear nitrite
and A2N = 36 MHz (Fig. S12). The IR spectrum of complex
Since copper(II) nitrite complexes have been prepared via
26-28
3
2
such as in
26,27
3
we
as a potential pathway
3. Instead, exposure of
2
2
1
2
β
1
3
i
2
1
3
-1
complex {[ Pr NN ]Cu} (
µ-
κ
:
κ
-O N)
2
(4
)
in 80% yield.
2
15
F6
2
24
exhibits a diagnostic ν
-1
vibrational frequency at 887 cm
Furthermore,
NO : 881 cm ) with the higher energy N-O stretching formation of N O by N NMR spectroscopy in the addition of
N NMR spectroscopy confirms the co-
15
2
O-N-O
1
(
5
15
2
15
NO to
1
(Figure S3). Dinuclear
4
was prepared independently
2
i
via the reaction of [ Pr NN ]Cu(
η
-benzene)
(1
)
with
2
F6
i
2
[
i
Pr
2
NNF6]Cu(κ
2
-O
2
N)(3)
[ Pr NN ]Cu(κ -O N) (3
) (Scheme 3). X-ray studies reveal both
a square planar (Cu1) and trigonal copper centers (Cu1’) that
are each similar to the copper coordination environments in
and , respectively. The equivalent Cu1-O distances of 2.029(9)
Å and the Cu1’-N distance of 1.880(2) Å are similar to that
found in and , respectively. The two copper centers in are
related by the c-glide plane [-x+1, y, -z+3/2].
EPR studies also confirm the presence of one copper(II)
center in the structure of . The frozen glass EPR spectrum of
II
II
+
II
)[CuI]
2 F6 2
{
[Cu ](NO
2
)[Cu ]} / [Cu ](NO
2
3
2
II
I
I
I
-
[
Cu ](NO
2
)[Cu ] / {[Cu ](NO
2
)[Cu ]}
3
2
4
-
0.9
-0.6
-0.3
0
-0.9
-0.6
-0.3
0
0.3
0.6
Potential vs Fc/Fc+ (V)
Potential vs Fc/Fc+ (V)
Fig. 2 Cyclic voltammograms of
3
(left) and 4 (right) in THF.
4
4
2
| J. Name., 2012, 00, 1-3
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Importantly, the copper(II) oxidation state isVrieewqAurtiirceledOnflioner
2
PPh3
I
[
Cu ]-PPh3 + O=PPh3 + NO
NO loss in the reaction of these copper nitrite complexes with
i
DOI: 10.1039/C6CC08745K
CuII] O
1
(
a)
b)
[
N
benzene-d6
5
PPh and CNAr. Reaction of [Bu N]{[ Pr NN ]Cu(κ -NO )} (2)
2
3
4
2
F6
O
2 CNAr
I
3
[Cu ]-CNAr + NO
with 1 equiv. PPh or ArNC in THF simply results in substitution
3
I
of the nitrite anion at [Cu ] to give adducts
6
5
or
6, respectively
15
15
(
Scheme 4b). As followed by N NMR in THF, use of
1 15
N
PPh3
[Cu ]-PPh3 + NO2-
I
O
O
i
substituted [Bu N]{[ Pr NN ]Cu(
15
- NO )} (2- N) (
κ
δ
132 ppm)
4
2
F6
2
(
[CuI]
N
THF-d8
5
results in observation of the free nitrite anion (
S9).
δ 237 ppm) (Fig.
CNAr
I
-
2
[Cu ]-CNAr + NO2
6
In summary, the fluorinated
I
β-diketiminate ligand
Pr NN ] supports anionic Cu and neutral Cu nitrite
i
II
[
2
F6
Scheme 4. Reactivity of (a) copper(II) and (b) copper(I) nitrite complexes
and with PPh and CNAr.
2
II
as well as a neutral, mixed valence Cu / Cu
I
3
3
complexes
2
and
3
II
. The Cu center in
nitrite species
4
3
activates nitrite towards
in pentane (Fig. S15) displays a well-resolved four-line
reduction to NO by PPh and CNAr while the corresponding
3
1
hyperfine splitting with g = 2.050, g = 2.200, A ( N) = 48
4
⊥
‖
⊥
63/65
anionic copper(I) complex
2 simply loses the nitrite anion upon
1
4
63/65
MHz, A ( N) = 49 MHz, A (
⊥
Cu) = 35 MHz, A‖(
Cu) = 530
‖
interaction with these Lewis bases. OAT reactivity at copper(II)
results from the ability of the copper(II) center to also accept
an electron as nitrite undergoes reduction by one electron to
give NO, enabling the two-electron OAT reaction. Thus, these
studies reveal that NO may be also generated at copper(II),
adding to the NO formation pathway involving protonation of
MHz at 293K with superhyperfines from the β-diketiminate
nitrogen donors. Cyclic voltammetry of complex in THF
exhibits two quasi-reversible one-electron waves at E = -0.41
4
1
/2
+
and +0.38 V vs. Fc /Fc. These are assigned to the
II
I
I
I
-
II
Cu ](NO )[Cu ] / {[Cu ](NO )[Cu ]} and {[Cu ](NO )[Cu ]}
II
+
[
[
/
2
2
2
II
Cu ](NO )[Cu ] redox couples, respectively.
I
2
23,26
nitrite at copper(I).
i
We find that the copper(II) nitrite [ Pr NN ]Cu(
2
κ
-O N) (
2
3
)
2
F6
THW is grateful to the US National Science Foundation (NSF
CHE-1459090 and CHE-1337975 (X-ray)) as well as the
Georgetown Environment Initiative for financial support.
undergoes ready reduction at RT with PPh3 (Scheme 4a).
Addition of 2 equiv. PPh to in benzene results in a bleaching
over ca. 30 min with concomitant gas
3
3
of the green color of
3
31
evolution. Monitoring the reaction by P NMR spectroscopy Notes and references
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(
δ
= 25.5 ppm) and
= 3.8 ppm). The phosphine adduct
may be independently prepared by addition of PPh to
1
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(1). To identify and quantify the
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This journal is © The Royal Society of Chemistry 20xx
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