Phenol Reduces Nitrite to NO at Copper(II): Role of a Proton-Responsive Outer Coordination Sphere in Phenol Oxidation

Article abstract of DOI:10.1021/jacs.9b11597

In the view of physiological significance, the transition-metal-mediated routes for nitrite (NO₂^-) to nitric oxide (NO) conversion and phenol oxidation are of prime importance. Probing the reactivity of substituted phenols toward the nitritocopper(II) cryptate complex [mC]Cu(κ²-O₂N)(ClO₄) (1a), this report illustrates NO release from nitrite at copper(II) following a proton-coupled electron transfer (PCET) pathway. Moreover, a different protonated state of 1a with a proton hosted in the outer coordination sphere, [mCH]Cu(κ²-O₂N)(ClO₄)₂ (3), also reacts with substituted phenols via primary electron transfer from the phenol. Intriguingly, the alternative mechanism operative because of the presence of a proton at the remote site in 3 facilitates an unusual anaerobic pathway for phenol nitration.

Full text of DOI:10.1021/jacs.9b11597

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Communication
Phenol Reduces Nitrite to NO at Copper(II): Role of a Proton-
Responsive Outer Coordination Sphere on Phenol Oxidation
Aditesh Mondal, Kiran P. Reddy, Jeffery A. Bertke, and Subrata Kundu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2020
Downloaded from pubs.acs.org on January 8, 2020
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Phenol Reduces Nitrite to NO at Copper(II): Role of a Proton-
Responsive Outer Coordination Sphere on Phenol Oxidation
Aditesh Mondal,† Kiran P. Reddy,† Jeffery A. Bertke,‡ and Subrata Kundu*†
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†School of Chemistry, Indian Institute of Science Education and Research (IISER), Thiruvananthapuram 695551, India
‡Department of Chemistry, Georgetown University, Box 571227-1227, Washington, D. C. 20057, United States
Supporting Information Placeholder
ABSTRACT: In the view of physiological significance,
the transition metal-mediated routes for nitrite (NO2 ) to
Scheme 1
-
nitric oxide (NO) conversion and phenol oxidation are of
prime importance. Probing the reactivity of substituted
phenols towards nitrito copper(II) cryptate [mC]Cu(2-
O2N)(ClO4) (1a), this report illustrates NO release from
nitrite at copper(II) following a proton-coupled-electron-
transfer (PCET) pathway. Moreover,
a different
protonated state of 1a with a proton hosted at an outer
coordination sphere [mCH]Cu(2-O2N)(ClO4)2 (3) also
reacts with substituted phenols via a primary electron-
transfer from the phenol. Intriguingly, the alternative
mechanism operative due to the presence of a proton at
the remote site in 3 facilitates an unusual anaerobic
pathway for phenol nitration.
Since the recognition of nitric oxide (NO) as a
signaling
molecule
in
vasodilation
and
neurotransmission, the chemical routes leading to NO
generation are of paramount interest.1 NO generated
from nitrite offers an O2-independent route and aids in
hypoxia rehabilitation by enhancing blood-oxygenation
and -flow.2 While heme-Fe dependent cofactors such as
deoxyhemoglobin, cytochrome c oxidase (CcO) mediate
-
-
the one-electron reduction of NO2 to NO (NO2 + 2H+ +
e-  NO + H2O) in mammals,3 prokaryotic organisms
employ copper nitrite reductase (CuNiR) for reducing
the electron transfer (ET) from T1 to T2 during nitrite
reduction is promoted by an initial proton transfer (PT)
(Scheme 1).7,8 Furthermore, a recent study employing
serial femtosecond crystallography (SFX) and
synchrotron radiation crystallography (SRX) data
corroborates that nitrite binding and protonation assist
the electron transfer (ET) during the CuNiR activity.9
-
NO2 to NO as a critical step in the denitrification route
of the biogeochemical nitrogen cycle.4
CuNiR enzyme consists two mononuclear copper
sites: a type 1 (T1) Cu site with (His)2(Met)Cu(Cys)
entity for electron transfer (ET) and a type 2 (T2) Cu site
with (His)3Cu-OH2 coordination motif for substrate
binding and reduction.5 It is noteworthy that the proton-
responsive amino acid residues such as Asp98 and
His255 are suitably located near the T2 site and facilitate
proton transfer (PT).5,6 A combination of steady-state
kinetics and pulse radiolysis experiments suggest that
While both the reduced and oxidized forms of the T2
site of CuNiR bind nitrite in 2-O,O’ fashion,5 CuNiR
model complexes typically exhibit 1-N (in the reduced
state) and 2-O,O’ (in the oxidized state) binding
modes.4,10,11,12 Notably, most of the previous reports
illustrate the release of NO from copper(I) nitrite
complexes in presence of exogenous proton source such
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as acetic acid.10,12 Interestingly, a transient copper(I) 1-
O nitrite adduct species supported by a proton-
responsive tripodal ligand is depicted to participate in
nitrite reduction through a ligand assisted proton and
electron transfers.13 Surprisingly, only a handful
examples of NO release from copper(II) nitrito
complexes are documented (Scheme 1).11,14 For
instance, -diketiminato [CuII](2-O2N) complex
transfers oxygen-atom to triphenyl phosphine and
releases NO.11 Another recent report illustrates that a
nucleophilic attack of thiol on the nitrito moiety in an
spectrum of 1a in acetonitrile exhibits a broad and low-
intensity absorption centered at λmax/nm (ε/M−1cm−1) =
670 (190), which presumably arises from the low energy
d-d transitions of an S = ½ d9 CuII centre (Figure S2).
Moreover, the X-band electron paramagnetic resonance
(EPR) spectrum of 1a in acetonitrile at 77 K shows a
spectral pattern typical of an S = ½ d9 CuII centre in a
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electron deficient
-diketiminato [CuII](2-O2N)
complex affords S-nitrosothiol, which rapidly
decomposes to disulphide and NO.14 Electrocatalytic
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reduction of NO2 to NO at CuII sites has been illustrated
very recently.15 We herein disclose reduction of nitrite to
NO at a mononuclear CuII cryptate featuring a remote
proton-responsive functional group. Along with the
illustration of phenol-mediated reduction of nitrite to
NO through proton-coupled-electron-transfer (PCET)
pathway, this report outlines new bio-relevant routes for
O2-independent oxidative modifications of phenol
distorted octahedral geometry (Figure S3).16
Figure 1. X-ray crystal structures of {[mC]Cu(2-O2N)}+
(in 1a) and {[mCH]Cu(2-O2N)}2+ (in 3) cores. H-atoms
(except N5-H5 for 3) have been omitted for clarity.
Scheme 2. Syntheses of 1a, 1b, 2, and 3.
Intrigued by the availability of a well-define free
cavity in 1a consisting of an apical tertiary amine site
N5 (Cu···N5 7.175 Å) with three ethereal oxygen sites
as H-bond acceptors, we anticipate that the N5 site may
serve as a proton-responsive moiety. Hence, we strive to
isolate the protonated form of the {[mC]Cu(2-O2N)}+
core. A controlled protonation of mC employing
NH2OH•HCl in methanol followed by metalation with
Cu(ClO4)2•6H2O affords [mCH]CuCl(ClO4)2 (2) in 72%
yield (Figures S7-S10). Subsequently, a treatment of an
acetonitrile solution of 2 with an equimolar amount of
AgNO2 yields [mCH]Cu(2-O2N)(ClO4)2 (3) in 94%
yield. X-ray crystallographic analysis reveals that the
copper site in 3 possess a distorted octahedral geometry
with an unsymmetrically bound nitrite anion in 2-O,O’
fashion (Figures 1B and S11). While the Cu1–N/O4
distances and the binding mode of nitrite anion in 3 are
comparable to those in 1a (Table S1), the Cu1···O5
interatomic distance in 3 is slightly longer (Cu1···O5
2.754 Å). Interestingly, refinement of the N-H moieties
in 3 obtained from the difference map renders the
protonated amine N5–H5 engaged in the H–bonding
interactions with two ethereal oxygen sites (O1···H5
2.277 Å and O2···H5 2.228 Å). Notably, the interatomic
distance between O4···H5 (3.829 Å) is significantly
longer relative to the sum of their van der Waals radii
2.72 Å, thereby indicating noninteraction between the
nitrite anion and the protonated outer coordination
sphere. The UV-vis spectrum of 3 in acetonitrile
displays a low-intensity, broad band centered at λmax/nm
(ε/M−1cm−1) = 660 (180) (Figure S12). Furthermore, the
oxidation state of Cu in 3 has been verified by EPR
spectroscopy (Figure S13).16
including nitration.
Metalation of the tripodal heteroditopic cryptand
(mC) with Cu(ClO4)2•6H2O followed by nitration with
NaNO2 in methanol results in an air-stable bluish-green
complex [mC]Cu(2-O2N)(ClO4) (1a) in 84% yield
(Scheme 2). The molecular structure of 1a obtained
from single crystal X-ray diffraction depicts that the
copper site (Cu1–N1 2.0302(14) Å, Cu1–N2 2.0767(15)
Å, Cu1–N3 2.2358(15) Å, Cu1–N4 2.0566(15) Å, Cu1–
O4 1.9570(12) Å, and Cu1···O5 2.626 Å) is best
described as a distorted octahedral geometry (Figures
1A and S1) with an unsymmetrical 2-O,O’ binding of
nitrite anion (O4–N6 1.280(2) Å, O5–N6 1.230(2) Å,
and O4–N6–O5 114.01(14)). The UV-vis absorption
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Influenced by the previously reported NO releasing
Mechanistically, two distinct pathways may be
envisaged for such a bimolecular interaction between 1a
and ArOH (Scheme 3). Prompted by the previous report
on nitrite-mediated nitrosation of nucleophiles at a
copper(II) site,14 we considered a possible nucleophilic
attack by ArOH on the activated nitrite anion of
reactivity of nitrite at copper(I) upon protonation,10,12 we
envision that nitrite bound to a copper(II) site
conceivably lead to the generation of NO in presence of
a H-atom (H+, e-) source. Illustrating the reaction of
nitrite at a copper(II) site with a H-atom (H+, e-) source,
an equimolar reaction of 1a with 2,4-di-tert-butylphenol
(2,4-DTBP) at 65 C under anaerobic condition leads to
a color change (Figure 2). Mass spectroscopic and
elemental analyses on the inorganic byproduct suggest
the formation of [mC]Cu(OH)(ClO4) (4) (Figures S15-
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{[CuII](2-O2N)}+ core in 1a followed by
a
decomposition of the resultant O-nitrosated product
(ArO-NO) yielding NO. To probe this hypothesis, we
carried out a reaction between [mC]Zn(2-O2N)(ClO4)
(1b) and excess 2,4-DTBP at 65 C for several days, but
1b does not react with 2,4-DTBP (Figure 2A, Figures
S25).18 Thus, this observation disfavors the
consideration of nucleophilic attack by phenol on the
nitrite anion in a {[MII](2-O2N)}+ core (Scheme 3A).
Alternatively, phenol may reduce nitrite to NO through a
concerted or stepwise transfer(s) of H+ and e-. Assessing
the mechanism further, a kinetic isotope effect (KIE) on
the second-order rate constant k2(OH)/k2(OD) is found
to be 2.01 and 2.06 for 2,4-DTBP-OH/OD and 4-MeO-
C6H4-OH/OD, respectively (Figures S27, S29). The
definite influence of the deuteration of the phenolic OH
on k2 clearly suggests the engagement of a proton-
transfer (PT) in the rate-determining-step.19,20 In
addition, the plot of log k2 versus one-electron oxidation
potentials of substituted phenols (Eox) exhibits a
negative slope, thereby suggesting the contribution of an
electron-transfer (ET) in the rate-determining-step
(Figure S30). Hence, these results corroborate that the
ET from phenol to 1a is coupled with a concomitant PT,
thereby suggesting the proton-coupled-electron-transfer
(PCET) mechanism for phenol-mediated nitrite to NO
transformation at CuII (Scheme 3B).21 Notably, similar
kinetic investigations with comparable KIE values
(1.21.56) and log k2 versus Eox correlations have been
demonstrated for the oxidation of substituted phenols by
copper-oxygen species following PCET route.20,21
Subsequent to the PCET from ArOH to 1a, transient
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S19). H NMR and GC-MS analyses of the resultant
reaction mixture indicate the formation of oxidatively
coupled phenol 3,3’,5,5’-tetra-tert-butyl-(1,1’-biphenyl)-
2,2’-diol (5) in 43% yield with concomitant generation
of NO as trapped by (dtc)2Fe (dtc = N,N-diethyldithio
carbamate) (Figures S20-S24).17 In presence of an
excess equivalent of substituted phenol (2,4-DTBP) at
65 C, the absorption feature of 1a at 670 nm changes to
a distinguishable lower intensity d-d band obeying first-
order kinetics and the resulting pseudo-first-order rate
constant (kobs) is found to be proportional to the
concentration of 2,4-DTBP (Figures 2B, S26, S37).
Thus, the kinetic experiments illustrate that the reaction
between 1a and substituted phenol (ArOH) follows a
simple bimolecular reaction with the rate law of
intermediates
such
as
{[CuI](NO2H)}+
and
{[CuII](OH)(NO)}+ may be involved prior to NO
release.22
Scheme 3. Mechanistic pathways considered for the
reaction of phenol with [CuII](2-O2N).
Figure 2. (A) Reactions of 2,4-di-tert-butylphenol (2,4-
DTBP) with {[mC]MII(2-O2N)}+ cores in 1a and 1b. (B)
Changes in the UV-vis absorption features of 1a upon
addition of 200 equiv 2,4-DTBP-OH at 65 C. Inset: The
time traces for the changes in 670 nm band in presence of
200 equiv of 2,4-DTBP-OH (blue trace) and 2,4-DTBP-OD
(red trace) at 65 C.
k2[1a][ArOH].
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To conclude, this study illustrates phenol-mediated
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Scheme 4
reduction of nitrite to NO, which is reminiscent of the
increase of NO flux from the interactions of dietary
polyphenols and nitrite in stomach.29,30 The mechanistic
investigations utilizing a structurally characterized
nitrito copper(II)-cryptate [mC]Cu(2-O2N)(ClO4) (1a)
imply the involvement of proton-coupled-electron-
transfer (PCET) in nitrite reduction. In addition, this
report outlines that the controlled protonation of the
outer coordination sphere of 1a causes the mechanistic
switchover, thereby turning on an unprecedented
anaerobic pathway for the nitration of phenol, even
though the proton-responsive moiety is remote from the
[Cu](2-O2N) site. Hence, the current study not only
reveals a new route for the reduction of nitrite to NO,
but also offers a lens to view an unusual anaerobic
pathway for oxidative phenol nitration. A detailed
mechanism of anaerobic phenol nitration is the subject
of our future study.
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Strikingly,
[mCH]Cu(2-O2N)(ClO4)2
a
stoichiometric reaction between
(3) and 2,4-di-tert-
butylphenol (2,4-DTBP) at 65 C under anaerobic
condition evolves NO and yields oxidative products of
phenol consisting of 5 (31%) and 2,4-di-tert-butyl-6-
nitrophenol (6) (8%) (Scheme 4, Figures S22-S24).
While phenols are known to react with free NO2,23
phenol nitration in the biological milieu is proposed to
occur via an electrophilic aromatic substitution
+
employing NO2 /NO2 electrophiles in situ generated
ASSOCIATED CONTENT
Supporting Information
from a metastable peroxynitrite intermediate.24 Notably,
the peroxynitrite species forms through an O2-dependent
pathway involving the interaction between a formal
superoxide species and free NO.25 In the present case,
however, phenol nitration proceeds through an O2-
independent route. Interestingly, monitoring of the
reaction of excess 2,4-DTBP with 3 in acetonitrile at 65
C by UV-vis analysis reveals that the overall reaction is
slower as compared to that with 1a and does not follow
The Supporting Information is available free of charge on
the ACS Publications website. UV-vis, EPR, NMR, X-ray
crystallographic, and experimental details (PDF).
AUTHOR INFORMATION
Corresponding Author
a
pseudo-first-order decay profile (Figure S31).
*S.K. skundu@iisertvm.ac.in, skundu.chem@gmail.com
Moreover, the employment of 2,4-DTBP-OD does not
alter the time-trace of the reaction (Figure S32)
significantly, thereby indicating the non-involvement of
the proton-transfer (PT) in the rate-determining step.
Notably, interactions of triflic acid with high-valent Mn-
oxo species has been illustrated to accelerate ET rate and
leads to a switchover of the H+/e- transfer mechanism.26
We, therefore, postulate that the presence of a proton in
the outer coordination sphere of [mCH]Cu(2-
O2N)(ClO4)2 (3) reduces the rate of PT from the phenol.
Unlike the reaction between 1a and 2,4-DTBP
proceeding with comparable rates of proton and electron
transfers, the reaction of 3 presumably proceeds via a
primary electron-transfer (ET) from ArOH to generate a
transient [ArOH]•+ species, a portion of which reacts
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
S.K. gratefully acknowledges Early Career Research
Award (ECR/2017/003200) from SERB and start-up fund
from IISER Thiruvananthapuram. A.M. is also thankful to
IISER Thiruvananthapuram for a fellowship. SAIF – IIT
Bombay is acknowledged for the EPR measurements.
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Atom Abstraction by
a
High-Valent Manganese(V)-Oxo
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a
(28)Control experiments (Table S3) demonstrate the role of complex
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(17)While the released NO was trapped qualitatively, the quantitation
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ambient conditions.
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protonation of the remote site
N
N
1
2
3
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H
O
O
O
O
O
N
O
N
OH
tBu
N
N
O
tBu
O
O
O
PCET
H
N
H
N
CuII
N
N
CuII
N
N
H
H
H
H
NO
NO
OH
tBu
Switchover of the Mechanism
OH
tBu
NO2
tBu
+ o,o’-biphenol
tBu
8
9
OH
tBu
tBu
PCET in NO2- to NO Transformation
Anaerobic Phenol Nitration
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