Copper/TEMPO Redox Redux: Analysis of PCET Oxidation of TEMPOH by Copper(II) and the Reaction of TEMPO with Copper(I)

Article abstract of DOI:10.1021/acs.inorgchem.9b01326

Copper salts and organic aminoxyls, such as TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), are versatile catalysts for aerobic alcohol oxidation. Previous reports in the literature contain conflicting proposals concerning the redox interactions that take place between copper(I) and copper(II) salts with the aminoxyl and hydroxylamine species, TEMPO and TEMPOH, respectively. Here, we reinvestigate these reactions in an effort to resolve the conflicting claims in the literature. Under anaerobic conditions, Cu^IIX₂ salts [X = acetate (OAc), trifluoroacetate (TFA), and triflate (OTf)] are shown to promote the rapid proton-coupled oxidation of TEMPOH to TEMPO: Cu^IIX₂ + TEMPOH → Cu^IX + TEMPO + HX. In the reaction with acetate, however, slow reoxidation of Cu^IOAc occurs. This process requires both TEMPO and HOAc and coincides with the reduction of TEMPO to 2,2,6,6-tetramethylpiperidine. Analogous reactivity is not observed with trifluoroacetate and triflate species. Overall, the facility of the proton-coupled oxidation of TEMPOH by Cu^II salts suggests that this process could contribute to catalyst regeneration under aerobic oxidation conditions.

Full text of DOI:10.1021/acs.inorgchem.9b01326

Article
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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Copper/TEMPO Redox Redux: Analysis of PCET Oxidation of
TEMPOH by Copper(II) and the Reaction of TEMPO with Copper(I)
Michael C. Ryan,‡ Lauren D. Whitmire,‡ Scott D. McCann, and Shannon S. Stahl*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: Copper salts and organic aminoxyls, such as TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl), are versatile catalysts for
aerobic alcohol oxidation. Previous reports in the literature contain
conflicting proposals concerning the redox interactions that take
place between copper(I) and copper(II) salts with the aminoxyl and
hydroxylamine species, TEMPO and TEMPOH, respectively. Here,
we reinvestigate these reactions in an effort to resolve the conflicting
claims in the literature. Under anaerobic conditions, CuIIX2 salts [X
= acetate (OAc), trifluoroacetate (TFA), and triflate (OTf)] are
shown to promote the rapid proton-coupled oxidation of TEMPOH
to TEMPO: CuIIX2 + TEMPOH → CuIX + TEMPO + HX. In the reaction with acetate, however, slow reoxidation of CuIOAc
occurs. This process requires both TEMPO and HOAc and coincides with the reduction of TEMPO to 2,2,6,6-
tetramethylpiperidine. Analogous reactivity is not observed with trifluoroacetate and triflate species. Overall, the facility of the
proton-coupled oxidation of TEMPOH by CuII salts suggests that this process could contribute to catalyst regeneration under
aerobic oxidation conditions.
Scheme 1. Simplified Mechanism for Cu/TEMPO-
Catalyzed Alcohol Oxidation
INTRODUCTION
■
Combinations of a copper salt and organic aminoxyl, such as
TEMPO (2,2,6,6-tetramethylpiperidine N-oxyl), represent
some of the most effective catalyst systems for the aerobic
oxidation of alcohols.1−11 The most widely used catalysts
feature 2,2′-bipyridine (bpy) as the ancillary ligand. The
alcohol oxidation reactions often proceed at room temperature
with ambient air as the oxidant, undergo the chemoselective
oxidation of primary alcohols in the presence of secondary
alcohols,7,8 tolerate diverse functional groups including sulfides
and amines,7−11 and have been applied to process scale
applications in the pharmaceutical industry.12−14 Mechanistic
studies have shown that CuII and aminoxyl engage in a
cooperative mechanism in which the two one-electron oxidants
promote the efficient two-electron oxidation of the sub-
strate.15−22 Following alcohol oxidation, the reduced catalyst
system is regenerated by O2, completing the overall catalytic
cycle depicted in Scheme 1.
Many details of the catalyst oxidation half-reaction are not
well understood. Reactions between O2 and nitrogen-ligated
copper complexes have been the subject of extensive
fundamental study.23−27 Reactive Cu/O2 species, including
superoxo, peroxo, and oxo species, are often invoked in
hydrogen-atom transfer (HAT) reactions, and HAT from weak
O−H bonds, such as those in TEMPOH and phenols, has
been demonstrated in several fundamental studies of reactive
Cu/O2 species.28−31 These precedents prompted us to propose
that analogous reactivity could be involved in the catalyst
reoxidation half-reaction of Cu/aminoxyl-catalyzed aerobic
alcohol oxidations.8 In a complementary effort, we demon-
strated electrochemical alcohol oxidation with a (bpy)Cu/
TEMPO catalyst system,21 and the data from this study
implicated a mechanism in which CuII mediates the oxidation
of TEMPOH to TEMPO under anaerobic conditions. In both
the aerobic and anaerobic mechanisms, oxidation of the
hydroxylamine to an N-oxyl radical is proposed to proceed
with the reduction of CuII to CuI (Figure 1A).
Sheldon and co-workers have separately reported that
TEMPO reacts with CuIOAc in acetonitrile to generate a
CuII-TEMPO complex (i.e., with a TEMPO− ligand), as
evident from the appearance of a 670 nm band in the UV−
visible spectrum of the reaction mixture (Figure 1B).15 The
oxidation of CuI by TEMPO has been invoked as a mechanism
Received: May 6, 2019
© XXXX American Chemical Society
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Figure 1. Previously proposed reactions between Cu and
TEMPO(H), including (A) the oxidation of TEMPOH by Cu/O2
or CuIIX2 and (B) the reduction of TEMPO by CuI.
for catalyst reoxidation in several studies of catalytic aerobic
alcohol oxidation.6,15,32 Although several well-defined CuII-
aminoxyl complexes have been reported in the literature, all of
these precedents formally correspond to CuII complexes
bearing an aminoxyl rather than an aminoxide (e.g., TEMPO−)
ligand.33−35 Nonetheless, the reaction in Figure 1B provides an
alternative mechanism for CuI oxidation in the catalytic
reactions.
The reactions presented in Figure 1A,B are not directly the
microscopic reverse of each other, but they nevertheless appear
to be contradictory. Here, we report a study of reactions
between copper(I/II) salts and TEMPO(H) in an effort to
resolve this apparent contradiction. We show that a series of
CuIIX2 salts (X = OAc, TFA, OTf) mediate the efficient
proton-coupled oxidation of TEMPOH to afford CuIX,
TEMPO, and HX. We also observe the oxidation of CuI in
the presence of TEMPO; however, this reactivity is observed
with CuIOAc but not with CuITFA or CuIOTf sources. In
addition, this reaction requires the presence of AcOH, it
exhibits slow rates, and it occurs with cleavage of the N−O
bond in TEMPO, generating 2,2,6,6-tetramethylpiperidine as a
byproduct. Electrochemical and spectroscopic studies of
different Cu salts and TEMPO/TEMPOH under similar
reaction conditions provide a foundation for understanding
these results, all of which suggest that the simple one-electron
oxidation of CuI by TEMPO is not a favorable reaction and
does not contribute to catalytic alcohol oxidation reactions.
Figure 2. UV−visible analysis of reactions between copper(I/II) salts
and TEMPO(H) species. (A) Oxidation of TEMPOH by (bpy)-
CuII(OTf)2 under anaerobic conditions, replicating conditions
reported by Badalyan et al.21 Conditions: 2 mM TEMPOH, 2 mM
CuIIOTf2, 2 mM 2,2′-bipyridine, 100 mM 2,6-lutidine, MeCN, 273 K,
and 50 min. (B) Oxidation of CuIOAc by TEMPO, replicating
conditions reported by Dijksman et al.15 Conditions: 2 mM TEMPO,
2 mM CuIOAc, MeCN, 273 K, 4 h. The CuII concentration was
obtained by constructing a UV−visible calibration curve of CuIIOAc2
in MeCN at 670 nm.
RESULTS AND DISCUSSION
■
Reproduction of Previous Results That Appear To Be
Contradictory. We began our study by revisiting the
reactions between copper(I/II) salts and TEMPO(H) species
that were reported previously by us21 and by Sheldon and co-
workers15 (Figure 2). The reaction conditions and reagents are
somewhat different in the two studies; however, the original
conditions were retained in order to enable direct assessment
of the results. The first experiment probed the stoichiometric
reaction of (bpy)CuII(OTf)2 with TEMPOH and 2,6-lutidine
in MeCN under N2 by UV−visible spectroscopy (Figure 2A).
The addition of TEMPOH led to the rapid reduction of CuII
to CuI, as evident from the disappearance of the CuII
absorption band at 720 nm and the appearance of a strong
absorption feature at 440 nm, attributed to bpy-ligated
CuIOTf. The second experiment probed the reaction of
TEMPO with CuIOAc in MeCN (Figure 2B; no bpy ligand
was included in this reaction in order to match the originally
reported conditions15). A new absorption feature at 670 nm
emerged slowly over the course of 4 h, consistent with the
formation of CuII under these reaction conditions. The λmax
observed in this spectrum matches that of CuIIOAc2 in MeCN,
suggesting that the CuII product may not correspond to the
original proposed [CuII−ONR2] adduct (further discussion
below).36 These observations validate the previously reported
observations.
Assessment of Reactions between Copper(I/II) Salts
and TEMPO(H) Species under Uniform Conditions. The
different reagents in the two reactions, including the presence/
B
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absence of bpy as a neutral ligand, the presence/absence of
base, and the use of OAc/OTf as an anionic ligand, could
influence the reaction outcome. We therefore tested the
reaction of TEMPOH with three different CuIIX2 sources (X =
OAc, TFA, and OTf) in the absence of bpy and base (Figure
3). The reactions proceed rapidly in all cases and lead to a
reduction of CuII, as evident by the disappearance of the
absorption band between 670 and 760 nm. No further reaction
is apparent following the oxidation of TEMPOH by CuIITFA2
and CuIIOTf2; however, the reduction of CuIIOAc2 to CuIOAc
by TEMPOH is followed by a slow reappearance of CuII, as
evident by the reappearance of the broad absorption feature at
670 nm. The latter result notwithstanding, these data show
that TEMPOH undergoes rapid oxidation by CuIIX2 salts, even
in the absence of the 2,2′-bipyridine and 2,6-lutidine additives
present in Figure 3A.
The slow regeneration of CuII in the reaction of TEMPOH
with CuIIOAc2 in Figure 3A resembles the appearance of CuII
in the reaction of CuIOAc and TEMPO in Figure 2B. This
similarity prompted us to investigate reactions of different
CuIX salts (X = OAc, TFA, OTf) with TEMPO (Figure 3B).
TEMPO was added to a solution of the CuIX species in
MeCN, and the reaction was monitored by UV−visible
spectroscopy at the λmax wavelength corresponding to the d−
d transition of the CuII species (670−760 nm). Only in the
case of CuIOAc was formation of CuII observed from the
reaction (Figure 3B; cf. red trace for OAc versus the blue and
black traces for TFA and OTf).
Several experiments were carried out to further probe the
(re)generation of CuII observed from reactions conducted in
the presence of acetate. The reduction of CuIIOAc2 by
TEMPOH was monitored over a longer time period (Figure 4,
Figure 4. Single wavelength (λ = 670 nm) UV−visible time courses
monitoring [CuII] from reactions between copper(I/II) acetate and
TEMPO(•/H). Conditions: 2 mM CuIIOAc2 or CuIOAc, 2 mM
TEMPO or TEMPOH, 2 mM HOAc, 4 mL of MeCN, N2 or 15
mTorr static vacuum, 273 K, 8 h. CuII concentrations were obtained
by constructing a UV−visible calibration curve of CuIIOAc2 in MeCN
at 670 nm. Lines reflect smooth fits of the data simply to guide the
eye.
black trace) under the original experimental conditions, and a
91% yield of CuII was obtained after 8 h. Recognizing that
adventitious O2 could contribute to the background oxidation
of CuI, efforts were made to ensure the rigorous exclusion of
oxygen from the reaction mixture (see sections VI−VIII in the
Supporting Information for details). Even under these
conditions, the slow formation of CuII was observed over 8 h
but in much smaller amounts (Figure 4, red trace). An
analogous experiment was conducted starting from CuIOAc
and TEMPO and 1 equiv of HOAc, mimicking the product
mixture expected from the reaction of CuIIOAc2 and
TEMPOH. The resulting time course (Figure 4, blue trace)
is very similar and corresponds to a 15% yield of CuIIOAc2.
Repetition of the latter experiment, but in the absence of
HOAc, resulted in a negligible formation of CuII (Figure 4,
green trace).
Figure 3. Analysis of reactions between copper(I/II) salts and
TEMPO(H) species with different anions (X = OAc, TFA, OTf). (A)
Reduction of CuIIX2 species observed upon addition of TEMPOH.
Single-wavelength data obtained at 670 nm (OAc, red), 715 (TFA,
blue), and 760 (OTf, black). Conditions: 2 mM TEMPOH, 2 mM
CuIIX2, MeCN, 273 K, 0.5 h. For second-order fits to the kinetic data
and estimated rate constants, see Figure S5 in the Supporting
Information. (B) Optical changes observed at 670, 715, and 760 nm
upon addition of TEMPO to solutions of CuIOAc, CuITFA, and
CuIOTf, respectively, in MeCN. Oxidation to CuII is observed only
with CuIOAc. Conditions: 2 mM TEMPO, 2 mM CuIX, MeCN, 273
K, 4 h. CuII concentrations in panels A and B were obtained by
constructing UV−visible calibration curves of the corresponding
CuIIX2 salts in MeCN at their respective λmax. Lines reflect smooth fits
of the data simply to guide the eye.
Efforts were undertaken to identify the oxidant that accounts
for the slow oxidation of CuIOAc. A small amount of 2,2,6,6-
C
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Figure 5. (A) Cyclic voltammograms of TEMPO in the presence and absence of HOAc/nBu4NOAc buffer and of CuIIX2 salts. CV conditions
(TEMPO): 2 mM TEMPO, 20 mM HOAc, 20 mM nBu4NOAc, 0.1 M Bu4NPF6, MeCN, 200 mV/s scan rate. CV conditions (CuIIX2): 2 mM
CuX2, 10 mM TFAH, 0.1 M Bu4NPF6, MeCN, 100 mV/s scan rate, glassy carbon working electrode, Pt wire counter electrode. (B) EPR spectra
of CuII salts. 10 mM CuIIX2, 50 mM TFAH, MeCN, 150 K. (C) Proposed equilibrium between the EPR-silent [CuIITFA2]2 paddlewheel dimer
and EPR-active monomeric CuIITFA2, promoted by TFAH.
tetramethylpiperidine (TMPH, 6%) was identified by GC−MS
from the anaerobic reactions between CuIIOAc2/TEMPOH
and CuIOAc/TEMPO/HOAc. Recognizing that the con-
version of TEMPO to TMPH/H2O is a 3e−/3H+ redox
process (see further discussion below), this reaction accounts
for the oxidation equivalents needed for the formation of the
observed 15% yield of CuIIOAc2 observed in Figure 4 (blue
trace).
solution as the EPR-silent [Cu(OAc)2]2 paddlewheel
dimer.41,42 CuIIOTf2 exhibits an axial EPR signal consistent
with a monomer CuII species solvated by MeCN.43 CuIITFA2
exhibits an EPR signal with only 67% of the signal intensity of
CuIIOTf2; however, the intensity increases to 96% when 5
equiv of TFAH is present.
The above CV and EPR data suggest that two different
CuIITFA2-derived species are present in solution, consistent
with an equilibrium mixture of the EPR-silent [Cu(TFA)2]2
dimer and the EPR-active monomer (Figure 5C). This
observation is consistent with the presence of a single
electroactive species present in the CV obtained from this
mixture (Figure 5B). Consistent with this interpretation, X-ray
crystal structures of both monomeric CuIITFA2(H2O)4 and
paddlewheel dimeric [CuIITFA2]2·2MeCN have previously
been obtained by the recrystallization of CuIITFA2 from H2O
and MeCN, respectively.44 We postulate that TFAH favors
monomeric CuII via hydrogen bonding to the Cu-bound
trifluoroacetate ligands.
Analysis of CuIIX2 Species in Solution. The influence of
the anion (OAc, TFA, or OTf) and the role of HOAc on the
(slow) regeneration of CuII (cf. Figures 3 and 4) prompted us
to obtain cyclic voltammograms (CVs) of the different Cu salts
and TEMPO under conditions relevant to the reactions
(Figure 5A). The TEMPO/TEMPO− and TEMPO/TEM-
POH redox couples are electrochemically irreversible,
consistent with previous reports in the literature;37−39
however, approximate midpoint potentials (Emp) of −1.5 and
−0.84 V vs Fc+/Fc were estimated from CVs obtained in the
absence40 and presence of a buffered mixture of HOAc/
Bu4NOAc (Figure 5A, red and blue traces). The different
CuIIX2 salts exhibit quasi-reversible CV features, with values
that differ by >1 V, depending on the identity of the anionic
ligand: Emp(CuII/I) = −0.61 V (OAc) and 0.64 V (OTf) vs
Fc+/Fc. The CV of CuIITFA2 exhibits two ill-defined quasi-
reversible redox features at 0.010 and 0.48 V. The addition of 5
equiv of trifluoroacetic acid (TFAH) to this solution, however,
leads to the appearance of a single quasi-reversible wave at 0.48
V.
Mechanistic Analysis and Discussion. CuIIX2 sources
with all three anionic ligands, X = OAc, TFA, OTf, promote
the rapid oxidation of TEMPOH to TEMPO, as shown in
Figure 3A. The data presented also show, however, that
CuIOAc undergoes oxidation to CuIIOAc2 in the presence of
TEMPO (Figure 4), resembling the observations reported
previously.15 The reaction is complicated by the facile
oxidation of CuI by O2, even in trace quantities, (Figure 4),
but the oxidation of CuIOAc by TEMPO via cleavage of the
N−O bond to form TMPH can also account for the slow
generation of CuII under these conditions.
The three CuIIX2 salts were also analyzed by electron
paramagnetic resonance (EPR) spectroscopy. (See Figure 5B
for spectra of frozen MeCN solutions.) CuIIOAc2 exhibits
negligible EPR activity, consistent with it being present in
The effect of bpy on the CuII/I redox potential was analyzed
in a previous mechanistic study of Cu/TEMPO-catalyzed
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alcohol oxidation,18 but the contribution of the anionic ligand
in the CuII/I redox potential in bpy-free catalyst systems has
not been characterized.5,15,45 The strong influence of the
anionic ligands on the CuII/I redox potentials exceeds what
might be expected on the basis of the anion basicity alone. This
deviation is attributed to the ability of acetate (and, to a lesser
extent, trifluoroacetate) to stabilize CuII via the formation of
the carboxylate-bridged dicopper paddlewheel complex. In the
case of acetate, the CuII/I redox potential approaches that of
the TEMPO/TEMPOH redox potential (Figure 5A). The two
different CuII/I redox potentials observed with TFA, which are
assigned to dimeric and monomeric structures and which differ
by nearly 400 mV, highlight the stabilizing effect of dimer
formation.
CONCLUSIONS
■
The results described here demonstrate that a series of
different CuIIX2 sources (X = OAc, TFA, and OTf) mediate
the efficient proton-coupled oxidation of TEMPOH to afford
the aminoxyl radical. The reported oxidation of CuIOAc by
TEMPO has been reproduced; however, this reactivity is
attributed to the presence of trace O2 in the reaction mixture
or a slower oxidation process that involves the cleavage of the
N−O bond of TEMPO. CuIIX2-mediated PCET oxidation of
TEMPOH provides the basis for the regeneration of the
TEMPO cocatalyst during anaerobic (electrochemical) alcohol
oxidation, and the facility of this process suggests that it could
also contribute under aerobic oxidation conditions, without
requiring the involvement of reactive Cu/O2 species.52 The
identity of the anionic (X) ligand has a significant influence on
the CuII/I redox potential, but the rapid oxidation of TEMPOH
is observed in all cases, even with the low-potential CuIIOAc2
species. These results are rationalized by the involvement of
proton transfer in the oxidation process, whereby the beneficial
effect of more basic anionic ligands offsets the lower CuII/I
redox potentials.
The anionic ligand effects on the CuII/I redox potentials
rationalize why CuIOAc is the only CuIX species that
undergoes oxidation by TEMPO under anaerobic conditions
(cf. Figures 3 and 4). Single-electron transfer from CuI to
TEMPO is thermodynamically unfavorable, and the lack of
reactivity observed in the absence of HOAc is consistent with
this conclusion (cf. Figure 4, green trace). The proton-coupled
reduction of TEMPO to TEMPOH by CuIOAc (cf. Figure
6A) is also unfavorable, but this reaction is only slightly uphill
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01326.
■
S
Experimental procedures and compound characteriza-
tion data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: stahl@chem.wisc.edu.
■
ORCID
Scott D. McCann: 0000-0001-6899-9816
Shannon S. Stahl: 0000-0002-9000-7665
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
Figure 6. Elementary steps proposed to explain the oxidation of
CuIOAc by TEMPO in the presence of HOAc. (A) Redox
equilibrium between CuIOAc/HOAc/TEMPO and CuIIOAc2/
TEMPOH. (B) TEMPOH disproportionation to TMPH and
TEMPO+. (C) TEMPO+-mediated oxidation of CuIOAc.
ACKNOWLEDGMENTS
■
We thank the DOE (DE-FG02-05ER15690) for funding.
Spectroscopic instrumentation was partially supported by the
NIH (1S10 OD020022) and the NSF (CHE-1048642 and
CHE-0741901).
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The net reaction arising from these steps, shown in Figure 6A−
C, shows that 3 equiv of CuIOAc is oxidized for each equiv of
TEMPO converted to TMPH.
■
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F
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