Selective oxidation of exogenous substrates by a bis-Cu(III) bis-oxide complex: Mechanism and scope

Article abstract of DOI:10.1016/j.ica.2018.11.027

Cu(III)₂(μ-O)₂ bis-oxides (O) form spontaneously by direct oxygenation of nitrogen-chelated Cu(I) species and constitute a diverse class of versatile 2e^?/2H⁺ oxidants, but while these species have attracted attention as biomimetic models for dinuclear Cu enzymes, reactivity is typically limited to intramolecular ligand oxidation, and systems exhibiting synthetically useful reactivity with exogenous substrates are limited. O_TMPD (TMPD = N¹, N¹, N³, N³-tetramethylpropane-1,3-diamine) presents an exception, readily oxidizing a diverse array of exogenous substrates, including primary alcohols and amines selectively over their secondary counterparts in good yields. Mechanistic and DFT analyses suggest substrate oxidation proceeds through initial axial coordination, followed by rate-limiting rotation to position the substrate in the Cu(III) equatorial plane, whereupon rapid deprotonation and oxidation by net hydride transfer occurs. Together, the results suggest the selectivity and broad substrate scope unique to O_TMPD are best attributed to the combination of ligand flexibility, limited steric demands, and ligand oxidative stability. In keeping with the absence of rate-limiting C–H scission, O_TMPD exhibits a marked insensitivity to the strength of the substrate C^α–H bond, readily oxidizing benzyl alcohol and 1-octanol at near identical rates.

Full text of DOI:10.1016/j.ica.2018.11.027

Accepted Manuscript
Research paper
Selective Oxidation of Exogenous Substrates by a Bis-Cu(III) Bis-Oxide Com-
plex: Mechanism and Scope
Tao A.G. Large, Viswanath Mahadevan, William Keown, T. Daniel P. Stack
PII:
S0020-1693(18)31316-1
https://doi.org/10.1016/j.ica.2018.11.027
ICA 18642
DOI:
Reference:
Inorganica Chimica Acta
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Accepted Date:
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20 November 2018
20 November 2018
Please cite this article as: T.A.G. Large, V. Mahadevan, W. Keown, T.D.P. Stack, Selective Oxidation of Exogenous
Substrates by a Bis-Cu(III) Bis-Oxide Complex: Mechanism and Scope, Inorganica Chimica Acta (2018), doi:
https://doi.org/10.1016/j.ica.2018.11.027
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1
Selective Oxidation of Exogenous Substrates by a Bis-Cu(III) Bis-Oxide
Complex: Mechanism and Scope
Tao A. G. Large, Viswanath Mahadevan, William Keown, T. Daniel P. Stack*
Department of Chemistry, Stanford University, Stanford, CA 94305, USA
*Corresponding author, stack@stanford.edu
Abstract: Cu(III)2(μ-O)2 bis-oxides (O) form spontaneously by direct oxygenation of nitrogen-chelated Cu(I)
species and constitute a diverse class of versatile 2e-/2H+ oxidants, but while these species have attracted attention as
biomimetic models for dinuclear Cu enzymes, reactivity is typically limited to intramolecular ligand oxidation, and
systems exhibiting synthetically useful reactivity with exogenous substrates are limited. OTMPD (TMPD = N1, N1, N3,
N3-tetramethylpropane-1,3-diamine) presents an exception, readily oxidizing a diverse array of exogenous substrates,
including primary alcohols and amines selectively over their secondary counterparts in good yields. Mechanistic and
DFT analyses suggest substrate oxidation proceeds through initial axial coordination, followed by rate-limiting
rotation to position the substrate in the Cu(III) equatorial plane, whereupon rapid deprotonation and oxidation by net
hydride transfer occurs. Together, the results suggest the selectivity and broad substrate scope unique to OTMPD are
best attributed to the combination of ligand flexibility, limited steric demands, and ligand oxidative stability. In
keeping with the absence of rate-limiting C–H scission, OTMPD exhibits a marked insensitivity to the strength of the
substrate Cα–H bond, readily oxidizing benzyl alcohol and 1-octanol at near identical rates.
Keywords: Copper-dioxygen; Selective oxidation; Alcohol oxidation; Amine oxidation; Aerobic oxidation; C–H
bond activation
1. Introduction
Cu(III)2(μ-O)2 bis-oxide (O) species formed through the direct oxygenation of nitrogen-ligated Cu(I) complexes
have attracted attention over the past several decades as systems biomimetic of binuclear copper enzymes. This class
of Cu/O2 intermediates is the most prevalent in synthetic systems, stabilized by bi-, tri- and tetra-dentate amine
ligands [1, 2]. Though established as powerful and versatile 2e-/2H+ oxidants, the reactivity of characterized O
species is limited largely to thermal decomposition via intramolecular oxidation of the supporting ligands. Systems
reported to effect reactivity directed towards exogenous substrates are limited and focus on net O-atom transfer and
oxidation of non-coordinating substrates or anions [2, 3]. Whereas mechanisms have been proposed for
oxygenations [4-6] and oxidations of hydrocarbons [7] and phenols (1e-/1H+ C–C coupling) [8], detailed
mechanistic studies are absent for substrates such as alcohols and amines. While mechanistic understanding lags
substrate scope, promising developments raise the prospect of extension to catalytic oxidations as well. Itoh has
reported catalytic hydrocarbon oxidation by an O species using H2O2 [9], and Lumb has reported catalytic reactivity
with phenols using a μ-η2,η2-(O2)dicopper(II) (SP) species, which is known to exist in equilibrium with its Cu(III) O
-
isomer when weakly coordinating anions are used (e.g., SbF6 ) [10]. Learning how intermolecular oxidation of more
coordinating substrates by O species occurs will allow further exploitation of their oxidizing potential in synthetic
transformations.
Abbreviations: OTMPD = [(LTMPD)2Cu(III)2(μ-O)2]2+, LTMPD = N1, N1, N3, N3-tetramethylpropane-1,3-diamine,
OTMED = [(LTMED)2Cu(III)2(μ-O)2]2+, LTMED = N1, N1, N3, N3-tetramethylethane-1,2-diamine, OTMCHD
[(LTMCHD)2Cu(III)2(μ-O)2]2+, LTMCHD = N1,N1,N2,N2-tetramethyl-1R,2R-diaminocyclohexane, OHMPD
=
=
[(LHMPD)2Cu(III)2(μ-O)2]2+, LHMPD = N1, N1, N3, N3, 2, 2-hexamethylpropane-1,3-diamine, OPD = [(LPD)2Cu(III)2(μ-
O)2]2+, LPD = propane-1,3-diamine, KIE = kinetic isotope effect, PDS = product determining step, RLS = rate-
limiting step, DFT = density functional theory, MeCN = acetonitrile, PhCN = benzonitrile, LUMO = lowest
occupied molecular orbital, LMCT = ligand-to-metal charge transfer, HAT = hydrogen atom transfer, EXAFS =
extended X-ray absorption fine structure

2
We report herein a more detailed study of the reactivity of OTMPD with exogenous substrates, including a proposed
mechanism of selective alcohol and amine oxidation [11]. OTMPD exhibits not only relatively high stoichiometric
conversions of alcohol and alkoxide substrates to the corresponding ketone and aldehyde products (Fig. 1), but also
high selectivity for primary alcohols over secondary alcohols in the presence of NEt3. While the rate of alcohol
oxidation by OTMPD exhibits a marked insensitivity to the strength of the Cα–H bond, no appreciable over-oxidation
beyond the ketone or aldehyde products is observed. Similar selectivity is observed with primary amines, which
react 100 times faster than secondary amines at 193 K.
Fig. 1. Reaction of OTMPDPhCN-(ClO4)2 ([(LTMPD)2Cu2O2](ClO4)2, 1 equiv, 10 mM) with alcohols (2 equiv) at 233 K
in CH2Cl2. Yields based on oxidant.
The broad scope of reactivity and high selectivity exhibited by OTMPD remain unprecedented among the limited
number of O species reported to exhibit exogenous substrate reactivity to date, and inform on the use of the
Cu(III)2O2 core in effecting the versatile and highly selective stoichiometric oxidation of a wide variety of
exogenous substrates using O2 as the terminal oxidant.
2. Experimental
2.1 Chemicals
Solvent purification was performed using a Pure-Solv 400 system (Innovative Technology) or as reported previously
-
-
-
-
-
[11]. All solvents were stored under a N2 atmosphere. [CuI(MeCN)4](X) (X= CF3SO3 , ClO4 , SbF6 , PF6 , BF4 ) and
[CuI(PhCN)4](X) (X= CF3SO3 , ClO4 ) were synthesized by a variation of literature methods [12]. Preparation and
manipulation of Cu(I) complexes was performed in a N2 dry box with [O2] < 1.0 ppm (Braun). Low-temperature
UV/Vis spectra were collected using a Varian Cary 50 Scan spectrophotometer fitted with fiber-optic leads and
custom-designed quartz probes (1 cm and 0.1 cm pathlengths, Hellma) in custom-designed sample cells
(ChemGlass). Variable low temperature studies used an FTS cooling bath (Kinetics Thermal Systems, MC480A1).
Solution 1H NMR measurements were performed using a Varian XL 400 MHz spectrometer using TMS as an
internal reference. GC-MS analysis was performed using an HP 5970 instrument equipped with an AT-5
(ALLTECH) column and mass-selective detector. The purity of ligands and quantification of reaction products were
assessed by GC using an HP 5890 instrument equipped with an HP-DB1 column and FID detector. Benzonitrile was
used as an internal standard for alcohols, and acetophenone for amines.
-
-
N1, N1, N3, N3-tetramethylpropane-1,3-diamine (LTMPD):
LTMPD (Sigma-Aldrich, 99%) was stirred overnight over sodium hydride and distilled under vacuum (0.1 mm Hg).
The ligand purity was >99.5% by GC/GC-MS. GC-MS: [60 °C (1 min) to 180 °C (2 min) at 30 °C • min-1]; tr = 4.5
min (130, M+).
N1, N1, N3, N3, 2, 2-hexamethylpropane-1,3-diamine (LHMPD):

3
2,2-dimethylpropane-1,3-diamine (5.0 g, Aldrich) was added to a solution of HCOOH (10 equiv) and HCHO (37%
aqueous solution, 10 equiv), and was heated at reflux overnight, whereupon the solution was made basic by addition
of NaOH (2 M, aqueous) and extracted into diethyl ether (4 × 25 mL). The ether solution was dried over K2CO3, and
the solvent removed by rotary evaporation. The resulting oil was distilled in vacuo from CaH2 to afford the product
as a colorless oil (75%). 1H NMR (CDCl3, 400 MHz): δ 0.9 (m, 6 H); 2.0 (m, 4 H); 2.2 (m, 12 H). GC-MS: [60 °C
(1 min) to 180 °C (2 min) at 30 °C • min-1]; tr = 5.2 min (158, M+).
-
-
-
-
-
-
-
[(LTMPD)CuI(MeCN)](X) (X = CF3SO3 , ClO4 , SbF6 , PF6 , BF4 ); [(LTMPD)CuI(PhCN)](X) (X = CF3SO3 , ClO4 ):
Equimolar amounts of either [CuI(MeCN)4](X) or [CuI(PhCN)4](X) and LTMPD were combined as CH2Cl2 solutions
in a N2 dry box immediately before use. [(LTMPD)CuI(MeCN)](CF3SO3): 1H NMR (CDCl3, 400 MHz), δ 1.7 (m, 4 H);
2.1 (s, 9 H); 2.5 (s, 14 H); 2.65 (m, 3 H).
O Species, [L2Cu(III)2(O)2]2+:
-
-
-
-
OTMPDMeCN-(X)2, LTMPD, MeCN, X = (CF3SO3 , ClO4 , SbF6 , PF6 , BF4-)
OTMPDPhCN-(X)2, LTMPD, PhCN, X = (CF3SO3 , ClO4 , SbF6 )
-
-
-
OHMPDMeCN-(X)2, LHMPD, MeCN, X = (CF3SO3 )
-
A 1.0 or 0.1 mM solution of pre-mixed 1:1 [CuI(MeCN)4](X) or [CuI(PhCN)4](X) and diamine ligand in CH2Cl2 was
oxygenated by bubbling O2 through a needle at 193 K, generating the O species as intense yellow solutions with
characteristic optical features at ca. 300 nm and ca. 400 nm (Table 1). O species can be obtained in higher yields
when pre-mixed 1:1 Cu(I)-ligand solutions are injected into pre-oxygenated solvent, though this methodology is not
always practical for many of the experiments reported herein.
PhCH2OD, PhCD2OH, PhCH(D)OH, and PhCH(D)O-:
PhCH2OD: NaH (1.1 equiv) was added to PhCH2OH (neat) and stirred until H2 evolution ceased. The resulting
solution was quenched using excess D2O (99.9%). The alcohol was extracted into dry ether, the ether extract was
dried over K2CO3, and the solvent was removed to afford PhCH2OD (>98% D by 1H NMR). PhCD2OH,
PhCH(D)OH, and PhCH(D)O- salts were prepared by literature methods [11, 13].
2.2 Oxidation of Exogenous Substrates
Solutions of OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 (10 mM, 5 mL in CH2Cl2) were prepared from the pre-mixed 1:1
Cu(I)-ligand precursors by addition of excess O2 (1 atm) at 193 K. Two equiv of substrate per oxidant were used
unless otherwise noted. For anaerobic substrate oxidations, excess O2 was removed and the solution was flushed
with N2 prior to substrate addition. Similar product distributions were obtained for alcohol oxidation reactions
performed under O2 and N2 at 233 K. Alcohol oxidations without NEt3 were carried out at 233 K, and all other
reactions were carried out under N2 at 193 K unless otherwise noted. The resulting reaction mixtures were quenched
by dropwise addition of aqueous ammonia (30%) until the CH2Cl2 layer turned colorless, and passed through a
column of neutral activated alumina (Brockmann I, ~150 mesh, 58 Å) followed by MeOH (2 mL). The copper
product is retained, and the organic products elute. The reaction mixture was analyzed by GC/GC-MS. Mass
recovery of the products was greater than 90% based on addition of an internal calibrant (benzonitrile for alcohols,
acetophenone for amines).
Substrate chase experiments were performed at 293 K in the presence of NEt3 (2 equiv), or at 233 K in the absence
of NEt3. In each experiment, a second alcohol substrate was injected 2 min after addition of the first. The relative
amounts of the corresponding substituted benzaldehyde products were analyzed by GC-MS.
2.3 Kinetic Isotope Effects
The intramolecular kinetic isotope effect (KIE) for benzyl alcohol oxidation by OTMPDMeCN-(CF3SO3)2 was
determined from the product ratio of PhCDO and PhCHO using PhC(H)(D)OH (2 equiv, >98% D as determined by
GC-MS) as the substrate. The product ratio was determined by a least-squares component analysis of the product
aldehyde, using the 105-108 peak intensities and component spectra of authentic samples. The intramolecular KIE
for the sodium salt of PhC(H)(D)O- was determined using the same method. The intermolecular KIE was obtained

4
by addition of a 1:1 mixture of PhCH2OH:PhCD2OH to OTMPDMeCN-(CF3SO3)2 at varied temperatures (193 – 253 K).
The mixture of PhCDO and PhCHO products was analyzed as above for three independent reaction mixtures. The
decay of the ca. 400 nm optical band of OTMPD (0.1 mM) was used to determine the relative rates of oxidation for
PhCH2OH (kH = 3.9 × 10-4 s-1) relative to PhCD2OH (kD = 3.6 × 10-4 s-1) (KIE = 1.1 at 253 K, CH2Cl2, 40 equiv
substrate), and PhCH2OH (kH = 3.5 × 10-4 s-1) relative to PhCH2OD (kD = 3.7 × 10-4 s-1) (KIE = 1 ± 0.1 at 233 K, 40
equiv substrate). Each rate constant is reported as the average of two independent reactions. The same methodology
was used to determine the rates of oxidation of PhCH2OH (kH = 4.7 × 10-4 s-1) and PhCH2OD (kD= 1.3 × 10-4 s-1) in
the presence of 2 equiv NEt3 (KIE = 3.6 at 213 K, 20 equiv substrate), the rates of oxidation of PhCH2OH and
PhCD2OH in the presence of 2 equiv NEt3 (KIE = 1 at 193 K, 2 equiv substrate), and the rates of oxidation of
PhCH2ONa (3.7 × 10-1 s-1) and PhCD2ONa (9.0 × 10-2 s-1) at 193 K (KIE = 4.1, 2 equiv substrate).
2.4 OTMPD Thermal Decomposition
The decomposition kinetics of OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 in the absence of added substrate were
measured by monitoring the decay of their characteristic 400 nm optical features (0.1 mM or 1.0 mM) in CH2Cl2.
OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 were generated by oxygenation at 193 K, and then transferred to a second
cooling bath at a predetermined temperature. Thermal equilibration from 193 K to 253 K required ca. 2 min as
assessed by an OMEGA temperature probe inserted directly into the solution. Data for kinetic analysis were
collected only after thermal equilibration was complete. The rate constants for thermal decomposition were obtained
using SPECFIT [14] through a multi-wavelength (300–500 nm) component analysis. Among all data sets, the
number of significant eigenvectors calculated was generally two. For all data sets, good first-order (A → B) fits were
obtained. Thermal decomposition products were isolated by the method described previously (Section 2.2). The
ligand products were analyzed by GC/GC-MS. In all cases, ligand mass recovery was >90% relative to internal
standards added to the solutions. Only a small amount of ligand dealkylation was observed (<5%). LTMPD: [60 °C (1
min) to 180 °C (2 min) at 30 °C • min-1]; tr = 4.5 min (130, M+). Lmonodemethylated TMPD: [50 °C (1 min) at 20 °C • min-1
to 120 °C (1 min)]; tr = 2.4 min (116, M+).
2.5 Computational Methods
DFT calculations were performed using Gaussian 09, Revision D.01 [15]. Optimizations were performed using the
ωB97-xD functional [16] and def2TZVP basis set [17] with SMD implicit solvation in CH2Cl2 [18], and minima
verified by frequency calculations by the same method. Single point energy calculations were performed using
analogous methodology with the inclusion of Douglas-Kroll-Hess second-order (DKH2) scalar relativistic
corrections [19-23]. Natural Bonding Orbitals were calculated using NBO version 3.1 [24], and orbital visualization
was performed in GaussView 5 and LUMO [25]. Preliminary transition-state searches were performed using the
ωB97-xD functional and def2SVP basis set with SMD implicit solvation in CH2Cl2. Transition states were verified
by IRC calculations using the same methodology.

5
3. Results
3.1 Characterization
-
-
-
-
-
Reaction of Cu(I) precursors [(LTMPD)CuI(MeCN)](X) (X = CF3SO3 , ClO4 , SbF6 , PF6 , BF4 ) and
[(LTMPD)CuI(PhCN)](X) (X = CF3SO3 , ClO4 ) with O2 at 193 K in aprotic solvents yielded yellow-brown solutions
typical of [L2Cu(III)2O2]2+ (O) complexes, featuring intense LMCT features at ca. 300 nm (16,000 M-1 cm-1) and ca.
400 nm (24,000 M-1 cm-1) characteristic of OTMPD (Table 1).
-
-
Counteranion Absorption Maxima (nm)
SbF6-
248
249
249
249
248
248
299
299
301
301
299
299
397
397
400
400
400
400
CF3SO3-
PF6-
BF4-
ClO4- (MeCN)
ClO4- (PhCN)
Table 1. Absorption maxima of OTMPD varying counteranions and nitrile ligands (1 mM Cu, CH2Cl2, 193 K).
3.2 OTMPD and OHMPD Thermal Decomposition
Thermal decomposition of alkylamine-ligated O species generally occurs at temperatures greater than 233 K,
proceeding typically through oxidative N-dealkylation of the ligand. The mechanism of this reaction is generally
ascribed to rate-limiting HAT from an NCα–H bond to a bridging oxide ligand of the Cu2O2 core [26-28].
Thermal decomposition of OTMPDMeCN-(CF3SO3)2 (193 K – 253 K) yielded Eyring activation parameters ∆H‡ = 13.1
-
kcal • mol-1 and ∆S‡ = -22 cal • mol-1 ([Cu] = 0.1 mM, CF3SO3 , CH2Cl2). Analysis of the ligand decomposition
products, however, revealed only 5% ligand dealkylation, as compared with the 50% yield anticipated for a 2e-/2H+
oxidant. Apart from the monodemethylated ligand, no other ligand oxidation product was detected by GC. The
thermal decay rates were found to be independent of the weakly coordinating counteranions examined, as well as the
nitrile ligands used in the Cu(I) precursors (MeCN, PhCN; Fig. 2). The analogous OHMPD species formed with
LHMPD was found to decompose nearly 5 times faster than OTMPDMeCN-(CF3SO3)2 or OTMPDPhCN-(CF3SO3)2 under
similar conditions.
Fig 2. Optically measured thermal decomposition rate constants of O species at 263 K (1.0 mM Cu, CH2Cl2)
3.3 Reactivity with PPh3, Phenols, Catechols, and Hydrocarbons
MeCN
Complexes OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 act as mild oxidants toward a variety of bonds. OTMPD
-
(CF3SO3)2 reacts efficiently with PPh3 under N2 to form PPh3O, with 2,4-di-tert-butylphenol to generate the C–C
coupled bis-phenol, with 2,4-di-tert-butylcatechol to generate 3,5-di-tert-butylbenzoquinone, and with 4-
methylthiocresol to generate 1,2-di-p-tolyldisulfane (Fig. 3) [11]. Though the reactions observed with thiols and
phenols are consistent with a HAT mechanism, OTMPDMeCN-(CF3SO3)2 exhibits no apparent reactivity over hrs with
even weak C–H bonds [29] such as N-methyl-9,10-dihydroacridine (C–H BDE = 80 kcal•mol-1), dihydroanthracene
(C–H BDE = 78 kcal•mol-1), and 1,4-cyclohexadiene (C–H BDE = 76 kcal•mol-1).

6
Fig. 3. Reactivity of OTMPD observed with exogenous substrates (substrate:oxidant 2:1). Yields based on oxidant.
3.4 Alcohol Oxidation
OTMPDMeCN-(CF3SO3)2 reacts with a variety of alcohols to selectively generate aldehyde and ketone products, with
60-70% product yields after ca. 5 h at 233 K (2:1 substrate:oxidant ratio, CH2Cl2, yields based on oxidant) (Fig. 4
and Fig. 5).

7
Fig. 4. Alcohol oxidation by OTMPDMeCN-(CF3SO3)2 at 233 K in CH2Cl2 after ca. 5 h (substrate:oxidant 2:1). Yields
based on oxidant.
Fig. 5. Dependence of yield on counteranion and Cu(I) precursor in benzyl alcohol oxidation in CH2Cl2
(substrate:oxidant 2:1). Yields based on oxidant.
While independent of counteranion, these yields exhibit a surprising dependence on the choice of Cu(I) precursor
(Fig. 5); whereas the reaction of benzyl alcohol with OTMPDMeCN-(CF3SO3)2 ([(LTMPD)2Cu2O2](CF3SO3)2), prepared
from [(LTMPD)CuI(MeCN)](CF3SO3), proceeds with 60% substrate conversion, these yields increase to 90% with
OTMPDPhCN-(CF3SO3)2 ([(LTMPD)2Cu2O2](CF3SO3)2), prepared from [(LTMPD)CuI(PhCN)](CF3SO3). These yields do
not change appreciably using deuterated PhCN-d5 or MeCN-d3 in the oxidant preparation.
As OTMPD does not react appreciably with either aldehydes or ketones, synthetically useful yields (>90%) are
accessible using an excess of oxidant per substrate; 1-octanol, for instance, yielded >95% octaldehyde using 2.5
equiv of OTMPDMeCN-(CF3SO3)2 relative to 1-octanol. Under the excess oxidant conditions, at most 5% over-
oxidized products were detected by GC.
OTMPDMeCN-(CF3SO3)2 also exhibits a ca. 2:1 selectivity for primary over secondary alcohols assessed by
intermolecular competitions (1-octanol versus 2-octanol, Fig. 6). Addition of 2 equiv of NEt3 increases this
selectivity to 18:1, and accelerates the reaction substantially such that reaction proceeds with high yields within 3 h
at 193 K rather than 3–5 h at 233 K. 2 equiv of 2,6-lutidine also increases the selectivity in favor of primary
alcohols, but to a more staid 7:1 ratio.

8
Fig. 6. Intermolecular and intramolecular competitive alcohol oxidation by OTMPDMeCN-(CF3SO3)2 under excess
substrate conditions in the absence (233 K for ca. 5 h) or presence (193 K, ca. 3 h) of base (NEt3 or 2,6-lutidine, 2
equiv) in CH2Cl2.
Whereas OTMPDMeCN-(CF3SO3)2 exhibits uniform selectivity for primary over secondary alcohols, a remarkable
absence of discrimination is observed among primary alcohols. While 1-octanol is generally regarded as less
MeCN
oxidizable than benzyl alcohol due to its substantially stronger Cα–H BDE [29], the reaction of OTMPD
-
(CF3SO3)2 with a 1:1 alcohol mixture affords a 1:1 mixture of 1-octaldehyde and benzaldehyde at an overall
conversion of 60%, comparable to that observed for the oxidation of benzyl alcohol alone (Fig. 6).
Intramolecular competition experiments among primary alcohols and between primary and secondary alcohols
afforded similar results (Fig. 6). Oxidation of 1,4-benzyldimethanol in the absence of NEt3 yielded a statistical 2:1
mixture of the mono-aldehyde and di-aldehyde; addition of excess oxidant (4 equiv per substrate) affords exclusive
MeCN
di-aldehyde product in a 60% overall yield based on substrate. Likewise, oxidation of 1,5-hexanediol by OTMPD
-
(CF3SO3)2 with 2 equiv of NEt3 per diol affords 5-hydroxyhexanal and 5-hydroxy-2-hexanone in a 20:1 ratio, along
with some lactone product generated by a secondary oxidation of the cyclized 5-hydroxyhexanal (Fig. 6). This
indicates > 25:1 primary:secondary selectivity in oxidizing 1,5-hexanediol under these conditions. By contrast, the
selectivity using a Swern oxidation, a standard organic transformation of alcohols to aldehydes, is in our hands only

9
2:1. Near-complete conversion of 1,5-hexanediol to the lactone is possible using excess OTMPDMeCN-(CF3SO3)2 (4
equiv per diol).
3.5 Reactivity with Amines
In addition to alcohols, OTMPDMeCN-(CF3SO3)2 reacts selectively with primary and secondary amines to generate
both 4e-/4H+ and 2e-/2H+ oxidation products, respectively. Primary amines, such as benzylamine and
benzylethylamine, react in a 1:1 substrate:oxidant ratio to yield their nitrile products, benzonitrile and benzylcyanide,
respectively, consistent with the intermediacy of an imine product (Fig. 7). As observed among alcohols, secondary
benzylamines react 100 times more slowly than a primary benzylamine. No appreciable tertiary amine oxidation is
observed.
Fig. 7. Oxidation of amines (1 equiv, 20 mM) by OTMPDMeCN-(CF3SO3)2 (1 equiv, 20 mM) at 193 K in CH2Cl2.
Yields after aqueous workup (NR = no reaction). k1/k2 = 100 by optical spectroscopy. [a] Number of independent
experiments. Yields based on oxidant.
3.6 Mechanistic Studies of Alcohol Oxidation
3.6.1 Kinetic Model and Biphasic Reaction Kinetics
The reaction rate of OTMPDMeCN-(CF3SO3)2 with benzyl alcohol under pseudo-first order conditions of substrate (20
equiv) at 233 K increased linearly with the concentration of both OTMPDMeCN-(CF3SO3)2 and benzyl alcohol (Fig. 8),
MeCN
consistent with a first-order rate dependence of each species. The optical traces of the decay of OTMPD
-
(CF3SO3)2 over time fit best an A → B → C kinetic model involving an initial slower step preceding a rate-limiting
step, yielding pseudo first-order rate constants kobs = 1.5 × 10-3 s-1 for the initial A → B step, and kobs = 5.3 × 10-4 s-1
for the second step (B → C).

10
Fig. 8. Dependence of initial rates on initial concentrations of OTMPDMeCN-(CF3SO3)2 (left) and benzyl alcohol
(right). Linear fits to the data give log(kobs) = 0.99 • log([Cu]) – 1.82 (R2 = 0.98) and log(kobs) = 0.74 • log([benzyl
alcohol]) – 5.2 (R2 = 0.99).
3.6.2. Chase Experiments
The biphasic kinetics observed suggest an initial, fast substrate coordination step. A series of substrate chase
experiments probed the reversibility of this postulated substrate binding step in the presence and absence of added
NEt3. In each set of experiments, OTMPDMeCN-(CF3SO3)2 was allowed to react with a twofold excess of total alcohol
to assure incomplete substrate conversion. The alcohols were added sequentially, 2 min apart, with the product ratio
determined by GC (Table 2).
Substrate 1
p-H + p-CF3
p-H
Substrate 2
--
p-CF3
0.9
1
:
:
:
:
:
:
p-H
1.1
1.6
1
(A)
(B)
p-CF3
p-H
p-CF3
1.5
1
p-H
p-CF3
p-H
1.4
1
p-CF3
2.0
Table 2. Relative amounts of benzaldehyde products, p-CF3 and p-H, obtained in chase experiments (2 equiv total
alcohol) with OTMPDMeCN-(CF3SO3)2 (1 equiv) in the absence (A, 233 K) or presence (B, 293 K) of NEt3 (2 equiv).
Substrate 2 was added 2 minutes after substrate 1.
Whereas the reaction of 1 with a 1:1 mixture of p-CF3 benzyl alcohol: p-H benzyl alcohol yields a nearly equimolar
mixture of the respective oxidation products (0.9:1.1), chasing p-H benzyl alcohol with its p-CF3 analog afforded a
1.6:1 excess of the p-H product, and chasing p-CF3 benzyl alcohol with p-H benzyl alcohol afforded a similar 1.5:1
excess of the p-CF3 product. Similar selectivity was observed upon addition of NEt3: chasing p-H benzyl alcohol
with p-CF3 benzyl alcohol afforded a 1.4:1 excess of the p-H product, as compared to a slightly higher 2:1 excess of
the p-CF3 product for the reverse experiment.
3.6.3. Kinetic Isotope Effects and Hammett Analysis
Under the hypothesis that C–H cleavage might prove rate-limiting, the intermolecular competition of PhCH2OH
with PhCD2OH was examined over a temperature range of 193–253 K. Independent optical monitoring of the
pseudo first-order decay of OTMPDMeCN-(CF3SO3)2 (1 equiv) in the presence of excess PhCH2OH or PhCD2OH (40
equiv) gave nearly identical rates with a KIE (kH/kD) of 1.1 at 253 K. Comparable KIEs were obtained for an
intermolecular competitive experiment using a 1:1 mixture of PhCH2OH with PhCD2OH over a temperature range
of 193–253 K. A primary intramolecular KIE occurs in the oxidation of PhC(H)(D)OH over a similar temperature
range (kH/kD = 4.8 at 233 K), and an identical primary intramolecular KIE was observed using the sodium salt of

11
PhC(H)(D)O- (Fig. 9). In light of the rate acceleration observed in the presence of base, the involvement of rate-
limiting O–H bond cleavage was interrogated as well; competition of PhCH2OH with PhCH2OD in independent
absolute rate experiments yielded a KIE (kH/kD) of 1 ± 0.1 at 233 K (0.05 mM OTMPDMeCN-(CF3SO3)2, 40 equiv
alcohol per complex).
Substrate(s)
KIE (kH/kD)
T (K)
PhCH2OH / PhCD2OH
(Intermolecular)
1.1
233
PhC(H)(D)OH
4.8
233
233
193
233
213
213
(Intramolecular)
PhC(H)(D)O-
4.8
(Intramolecular)
PhCH2O- / PhCD2O-
(Absolute Rates)
PhCH2OH / PhCH2OD
(Absolute Rates)
PhCH2OH / PhCH2OD
(Absolute Rates, NEt3)
PhCH2OH / PhCD2OH
(Absolute Rates, NEt3)
4
1 ± 0.1
3.6
1.1
MeCN
Fig. 9. (Left) Kinetic isotope effects measured for oxidation of benzyl alcohol and derivatives by OTMPD
-
(CF3SO3)2, and (right) Hammett linear free energy relationship for the oxidation of para-substituted benzyl alcohol
derivatives by OTMPDMeCN-(CF3SO3)2. For the Hammett plot [30], a linear fit gives log(k/k0) = 0.215•σ – 0.00366 (R2
= 0.99, ρ = –0.2).
A Hammett analysis further probed the nature of the rate-limiting transition state in the oxidation. A series of para-
substituted benzyl alcohols (p-F, p-Cl, p-H, p-Me, p-OMe) [30] yielded a small negative ρ value of –0.2 (Fig. 9).
3.6.4. Radical Clocks
Radical clocks provide an opportunity to probe the involvement of a substrate radical following a putative product-
determining C–H scission. With the intermediacy of a long-lived radical intermediate, ring-opened products are
anticipated [31-33]. Cyclobutanol and cyclopropyl(phenyl)methanol (2 equiv) are oxidized efficiently by
OTMPDMeCN-(CF3SO3)2 (1 equiv) at 233 K to their carbonyl products (Fig. 4). In both cases, no radical
rearrangement products could be detected by GC.
3.6.5 Reactivity Summary
OTMPD formed by the direct oxygenation of Cu(I) in the presence of LTMPD reacts selectively with primary alcohols
and amines to yield their respective 2e-/2H+ and 4e-/4H+ oxidation products (aldehydes and nitriles) in 60–90%
yields (Section 3.4 and Section 3.5). With alcohols, higher yields are possible using either OTMPDPhCN-(CF3SO3)2,
in which the Cu(I) precursor is ligated by benzonitrile rather than acetonitrile, or an excess of OTMPDMeCN-(CF3SO3)2.
While the reaction is highly selective for primary substrates over their secondary congeners, a striking lack of
discrimination is observed between 1-octanol and benzyl alcohol, despite the dramatically different Cα–H bond
strengths. Oxidation of tertiary amines, tertiary alcohols, and hydrocarbons is not observed. The oxidation reaction
is dramatically accelerated and its selectivity enhanced by the addition of NEt3, with reactions complete in 3 h at 193
K. Indeed, 1,5-hexanediol can be oxidized to its lactone product in high yields (4e-/4H+ oxidation) with a primary-
to-secondary selectivity of >25:1 using a twofold excess of oxidant and 2 equiv of NEt3
.
Kinetic studies by optical spectroscopy suggest an initial binding event prior to the rate-limiting step, and
mechanistic studies with deuterated benzyl alcohols indicate that the rate-limiting step (RLS) in the absence of NEt3
does not involve O–H or C–H bond cleavage. Intramolecular KIEs indicate that the product-determining step (PDS)

12
does involve C–H bond cleavage, through either a net hydride transfer or short-lived radical intermediate (Section
3.6).
4. Discussion
4.1. Exogenous Reactivity
While several earlier studies probed the reactivity of equilibrium mixtures of O and isomeric side-on peroxide μ-
η2,η2-(O2)dicopper(II) (sP) species [2, 34], the first detailed reactivity study of a characterized “spectroscopically
pure” Cu(III)2(μ-O)2 species with exogenous substrates used the bidentate diamine ligand LTMPD of this study [11].
While the ability of an O species to effect intramolecular ligand oxidation is well established [2], the LTMPD
species (OTMPD) efficiently projects its oxidizing ability to exogenous substrates, evidenced by limited
intramolecular ligand demethylation upon thermal decomposition (Section 3.2) [27].
O
More recent reports extend the oxidative substrate scope of O species: ortho hydroxylation of phenolic substrates to
catechols and quinones, the oxidative reactivity effected by the binuclear copper enzyme tyrosinase [6, 8]; oxidation
of weak O–H and C–H bonds [7, 35-38]; catalytic oxidation of cyclohexane to cyclohexanol and cyclohexanone
using H2O2 as the oxidant [9] and stoichiometric oxidation of THF to THF-OH and γ-butyrolactone [39], as well as
oxidation of toluene to benzyl alcohol [40]. Regioselective and enantioselective oxidative dearomatization reactions
(net O-atom transfer) are also possible, including the first asymmetric synthesis of the azaphilone natural products
(+)-sclerotiorin and (+)-8-O-methylsclerotiorinamine and the preparation of several unnatural azaphilones, with
asymmetric induction achieved using sparteine ligands [41-43]. The reactions of characterized O species are joined
by numerous catalytic oxidations involving Cu(I) salts and O2 in which the active oxidant species remain unclear
[44]. Yet despite ongoing discovery of new reactivity, a dearth of detailed mechanistic studies of exogenous
substrate oxidation by O species persists [2].
Most O species formed with peralkylated amines have a limited stability at 233 K, the temperature investigated for
the initial alcohol oxidations in this study. Yet, OTMPD in CH2Cl2 is remarkably stable at 233 K relative to other O
species, which correlates with its stronger methyl NCα–H bonds as compared to other alkyl substituents. Indeed, O
species with ligands possessing weaker NCα–H bonds thermally decay faster, consistent with rate-limiting
intramolecular HAT to the oxide ligand of the Cu2O2 core. To our knowledge, the only more thermally stable
dicationic O species is OTMCHD [45].
An Eyring analysis of the first-order thermal decay rates of OTMPDMeCN-(CF3SO3)2 (193–253 K, [Cu] = 0.1 mM,
CH2Cl2) provides activation parameters of ∆H‡ = 13.1 kcal mol-1 and ∆S‡ = -22 cal•mol-1. While the enthalpic term
is lower than other systems, the large negative entropic term contributes substantially to the barrier of ligand C-H
activation [45, 46]. Ligand product analysis following thermal decay reveals only 5% ligand demethylation, rather
than 50% assuming the Cu2O2 core serves as a 2e-/2H+ oxidant. At parity of N-alkyl substituents, three major
factors may influence the decay mechanism: exogenous nitrile ligands (MeCN/PhCN) from the Cu(I) starting
material, weakly coordinating counteranions, and the structure of the ligating diamine. The decay rates of
OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 are effectively identical across all anions investigated (Fig. 2), excluding the
first two possibilities. A reduction in ligand flexibility at parity of donor moieties is possible by introduction of two
methyl groups in the propylene backbone; OHMPDMeCN-(CF3SO3)2 decomposes nearly 5 times faster than
OTMPDMeCN-(CF3SO3)2 under similar reaction conditions (Fig. 2). An increase in ligand conformational flexibility
offers one explanation for the increase in thermal stability with LTMPD, presumably through attenuation of ligand
self-oxidation, allowing oxidizing capacity to be directed instead towards exogenous substrates. Indeed, alcohol
oxidation yields with OHMPDMeCN-(CF3SO3)2. are at best one third those with OTMPDMeCN-(CF3SO3)2.
4.2. Mechanistic Analysis with Exogenous Substrates
The ability of OTMPD to effect such a broad range of selective and efficient oxidations, including oxidation of
alcohols, stands in contrast with other known alkylamine-ligated O species [45]. The reactivity of OTMPD is
foremost consistent with increased ligand flexibility (vide supra) and axial substrate accessibility to the OTMPD core.

13
This postulate is structurally supported by a fifth Cu–N/O scattering interaction needed in the EXAFS model at each
Cu(III), consistent with association of a counteranion (2.32 Å, Fig. 10) [11]. A similar coordinated counteranion is
observed by single crystal X-ray diffraction at the LTMPD-ligated Cu(III) in a mixed-ligand β-diketiminate/TMPD
-
Cu(III)2(μ-O)2 structure (CF3SO3 , Cu ⋯ O = 2.61 Å) [47]. Such axial coordination is not observed in more
sterically congested diamine-ligated O species, and is consistent with a more sterically accessible axial approach for
coordinating substrates in OTMPD
.
Fig. 10. Close counteranion association observed by EXAFS for OTMPDMeCN-(CF3SO3)2 and by single crystal X-ray
diffraction for the LTMPD-ligated Cu(III) site in a mixed-ligand O system [11, 47].
The disposition of the N-methyl groups of OTMPD, however, does preclude direct access to the electrophilic O–Oσ*
LUMO, colinear with the O–O vector, thereby attenuating reactivity with non-coordinating substrates such as
hydrocarbons (Fig. 11) [2, 24, 35]. OTMPD reacts selectively with coordinating substrates such as alcohols and
amines but exhibits no apparent reactivity with weak hydrocarbon C–H bonds. By contrast, OPD, with much
reduced steric demands (Fig. 11), reacts with weak C–H bonds of exogenous substrates through a rate-limiting C–H
scission at 150 K [36]. In this case, DFT calculations support direct access of the C-H bond to the electrophilic O–
Oσ* LUMO.
OTMPD
OTMED
OPD
Fig. 11: Natural Bonding Orbitals for the electrophilic O–Oσ* LUMOs and space-filling representations of OTMPD
OTMED, and OPD.
,
The axial accessibility of OTMPD is consistent with the biphasic kinetics observed for OTMPDMeCN-(CF3SO3)2 with
benzyl alcohol if the fast, initial optical changes are interpreted as a substrate binding event. The small negative
Hammett ρ value for p-substituted benzyl alcohol oxidations indicates faster reactivity with more donating alcohols,
consistent with a stronger binding event as the benzyl alcohols become more electron-rich. The significant rate-
enhancement observed with added alkoxides or added NEt3 strongly suggests that the mechanism of neutral alcohol

14
oxidation involves initial coordination of the neutral substrate. The product mixtures observed in substrate chase
experiments, in which a second alcohol is injected 2 minutes after the first, support the reversibility of this binding
event.
The LMCT energies of O species in the 250-400 nm range are most sensitive to equatorial ligation. Addition of an
alcohol to OTMPD solutions slightly attenuates the intensity of the LMCT features, but without an appreciable energy
shift (Fig. 12). Such optical behavior is consistent with initial alcohol coordination in an axial position. Itoh and
Fukuzumi proposed a similar axially coordinated intermediate to an O species in the oxidation of sulfides to
sulfoxides [4]. In this species as well, the initial intermediate exhibits a notable diminution in its LMCT intensities
without a significant shift in energy.
Fig. 12. Optical spectra of OTMPDMeCN-(CF3SO3)2 (black trace) and putative substrate-coordinated intermediate (red
trace) upon injection of benzyl alcohol (100 equiv) at 193 K in CH2Cl2.
The proclivity of OTMPD to coordinate exogenous ligands in the axial position finds strong precedent in not only the
-
close anion coordination of CF3SO3 , but also the more recent discovery of facile ligand exchange upon addition of
exogenous nitrogenous ligands to OTMPD at 150 K [48]. Despite the ability of OTMPD to oxidize primary amines at
193 K, addition of 2 equiv of LPD to OTMPD at 150 K results in rapid ligand exchange to form OPD (Fig. 13). The
lack of primary amine oxidation is rationalized by the disposition of the electrophilic O LUMO orthogonal to an
axial position. A substantial structural reorganization would be required prior to substrate oxidation (Fig. 13). For
LPD, this reorganizational barrier is evidently sufficiently high to preclude oxidation before de-complexation of the
initial ligand and chelation of the Cu(III).
Fig. 13. Reactivity of OTMPD with monodentate amines (substrate oxidation) and concerted core capture by chelating
propylenediamine at 150 K.
An axially coordinated alcohol requires a similar rotation from its initial orientation into the equatorial Cu2O2 plane
such that the alcohol Cα–H group is positioned appropriately for oxidation (Fig. 14). As primary C–H/D and O–
H/D KIEs are not observed using suitably deuterated benzyl alcohols, neither C–H nor O–H cleavage appears rate-
limiting. This stands in contrast to the reaction of OTMED (Fig. 11), in which C–H bond cleavage is rate-limiting
[46]. The rate-limiting step for OTMPD alcohol oxidation is proposed to be an axial-to-equatorial rotation of the
ligated alcohol concurrent with the equatorial-to-axial positioning of one amine group of LTMPD. As this axial amine
will be associated weakly on the d8 Cu(III) center, it provides an incipient base to deprotonate an equatorially ligated
alcohol, acidified relative to a free alcohol. The geometric acrobatics required in this rotation and ultimate alcohol

15
deprotonation by one amine group of the ligand highlight an importance of flexibility in the ligand backbone.
(A)
(B)
Fig. 14. Electrophilic OTMPD LUMOs calculated with methanol (A) and methoxide (B) model substrates coordinated
axially (top) versus equatorially (bottom).
This rate-limiting rotation is proposed to be followed by rapid O–H and C–H scission (Fig. 15). The identical
primary intramolecular KIEs for PhCHDOH and PhCHDO- Li+ (kH/kD = 4.8 at 233 K) are consistent with a shared
PDS, which requires alcohol O–H deprotonation prior to C–H cleavage. The C–H bond cleavage could proceed
through HAT with a triplet transition state, or remain on a single surface from the starting materials to proceed
through a net hydride transfer to the Cu2O2 core. As cyclobutanol is oxidized cleanly to its ketone without detection
of radical rearrangement products, net hydride transfer on a singlet surface is the simplest mechanistic interpretation.
Preliminary DFT calculations at the ωB97-xD/def2SVP level using ethanol as a model substrate are consistent with
the mechanism proposed above, implicating an initial, reversible coordination of the neutral alcohol in the axial
position, followed by a rate-limiting rotation of the neutral alcohol into the equatorial plane and release of one amine
moiety of LTMPD. This rate-limiting rotation is followed by a lower barrier deprotonation of the coordinated alcohol
to form the equatorially coordinated alkoxide, hydrogen bonded to the protonated LTMPD amine. A facile net
hydride transfer from the coordinated alkoxide to the Cu2O2 core in a 5-membered transition state provides the
carbonyl product and a [(LTMPD)2Cu(II)2(O)(OH)]2+ species on a singlet surface. Rapid proton transfer from the
protonated amine of LTMPD then affords the presumed [(LTMPD)2Cu(II)2(OH)2]2+ product. While analogous
reactivity by HAT is possible, preliminary calculations place the barrier to a triplet pathway higher by 5 kcal•mol-1.
Fig. 15. Proposed mechanism of neutral alcohol oxidation by OTMPD involving net hydride transfer (2e-/1H+) on a
singlet surface to the Cu2O2 core.
The role of exogenous NEt3 and 2,6-lutidine in increasing the rate and selectivity of alcohol oxidation is currently
less clear, but one postulate is that these bases deprotonate the axially ligated alcohol, accelerating the previously
rate-limiting rotation, and thereby enhancing the rate. Whereas the absence of a primary O–H/D KIE indicates that
O–H/D cleavage is not rate-limiting for neutral alcohols in the absence of NEt3, addition of 2 equiv NEt3 leads not

16
only to an accelerated rate, but also to a primary O–H/D KIE (Fig. 9). This result is consistent with deprotonation
becoming the rate-limiting step. The reaction is further accelerated when the alcohol is fully deprotonated to yield
the alkoxide, with a lower barrier to rotation suggested by the exceedingly fast reaction of alkoxides with OTMPD at
233 K; the reaction occurs upon mixing. In the reaction of alkoxides, the emergence of a primary C–H/D KIE
(observed for neutral alcohols in neither the absence nor presence of NEt3) indicates that full deprotonation is
required in order to accelerate the reaction to the point at which C–H/D cleavage becomes rate-limiting. A
significant reduction of the rotational barrier upon deprotonation is recapitulated in DFT calculations as well. The
dramatic increase in selectivity for primary versus secondary alcohols from 2:1 to 18:1 using NEt3 (Fig. 6) would
follow naturally from repulsion between the substrate, coordinated axially in a sterically congested environment, and
the sterically demanding NEt3 base. A reduction in steric demands, as with 2,6-lutidine, attenuates this selectivity to
7:1 (Fig. 6).
5. Conclusions
The bis-Cu(III) bis-(μ-O) complex OTMPD effects the selective oxidation of exogenous primary alcohols to
aldehydes and primary amines to nitriles in synthetically useful yields (up to >90%) using a twofold excess of this
oxidant. In contrast with related O species, alcohol oxidation by OTMPD exhibits not only high selectivity, but also a
remarkable insensitivity to the strength of the Cα–H bond, oxidizing benzyl alcohol and 1-octanol at identical rates.
Spectroscopic and kinetic analyses converge to a mechanism in which initial axial coordination of neutral alcohols is
followed by rate-limiting rotation into the equatorial plane, whereupon rapid deprotonation and subsequent C–H
scission by the bis-oxide O–Oσ* LUMO can occur. Radical clock experiments suggest that this reactivity takes place
in the absence of long-lived radical intermediates, consistent with a net hydride transfer on a singlet surface, a
mechanistic postulate supported by DFT. The importance of ligand flexibility in enabling this reactivity is
highlighted by comparison with related O species, which display an increasing competence in alcohol oxidation as
the ligand backbone becomes more flexible and steric demands decrease. While this mechanistic analysis begins to
illuminate the mechanism of neutral alcohol oxidation by OTMPD, investigation into the origins of dramatic rate
acceleration and enhanced selectivity in the presence of added NEt3, as well as substantially increased yields with
oxidants prepared from PhCN versus MeCN precursors, remain ongoing.
Acknowledgements
This work was supported by the National Institutes of Health [GM120187]. The contents of this publication are
solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.
Declarations of interest
none
Highlights




Bis-Cu(III) bis-oxides (O) form spontaneously from simple Cu(I) diamine complexes under O2
While powerful 2e-/2H+ oxidants, their reactivity with exogenous substrates is limited
OTMPD effects selective oxidation of alcohols and amines in >90% yields with excess oxidant
Mechanistic analyses suggest alcohol oxidation occurs through net hydride transfer
References
[1] L.M. Mirica, X. Ottenwaelder, T.D.P. Stack, Structure and Spectroscopy of Copper−Dioxygen Complexes,
Chemical Reviews, 104 (2004) 1013-1046.
[2] C.E. Elwell, N.L. Gagnon, B.D. Neisen, D. Dhar, A.D. Spaeth, G.M. Yee, W.B. Tolman, Copper–Oxygen
Complexes Revisited: Structures, Spectroscopy, and Reactivity, Chemical Reviews, 117 (2017) 2059-2107.
[3] E.A. Lewis, W.B. Tolman, Reactivity of Dioxygen−Copper Systems, Chemical Reviews, 104 (2004) 1047-1076.
[4] M. Taki, S. Itoh, S. Fukuzumi, Oxo-Transfer Reaction from a Bis(μ-oxo)dicopper(III) Complex to Sulfides,
Journal of the American Chemical Society, 124 (2002) 998-1002.

17
[5] S.V. Pavlova, K.H. Chen, S.I. Chan, Spectroscopic characterization of the oxo-transfer reaction from a bis(mu-
oxo)dicopper(III) complex to triphenylphosphine, Dalton Trans, DOI 10.1039/B406692H(2004) 3261-3272.
[6] A. Company, S. Palavicini, I. Garcia-Bosch, R. Mas-Balleste, L. Que, Jr., E.V. Rybak-Akimova, L. Casella, X.
Ribas, M. Costas, Tyrosinase-like reactivity in a Cu(III)2(mu-O)2 species, Chemistry, 14 (2008) 3535-3538.
[7] M. Taki, S. Itoh, S. Fukuzumi, C−H Bond Activation of External Substrates with a Bis(μ-oxo)dicopper(III)
Complex, Journal of the American Chemical Society, 123 (2001) 6203-6204.
[8] T. Osako, K. Ohkubo, M. Taki, Y. Tachi, S. Fukuzumi, S. Itoh, Oxidation Mechanism of Phenols by
Dicopper−Dioxygen (Cu2/O2) Complexes, Journal of the American Chemical Society, 125 (2003) 11027-11033.
[9] C. Shimokawa, J. Teraoka, Y. Tachi, S. Itoh, A functional model for pMMO (particulate methane
monooxygenase): Hydroxylation of alkanes with H2O2 catalyzed by beta-diketiminatocopper(II) complexes, J Inorg
Biochem, 100 (2006) 1118-1127.
[10] M.S. Askari, K.V.N. Esguerra, J.-P. Lumb, X. Ottenwaelder, A Biomimetic Mechanism for the Copper-
Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol, Inorganic Chemistry, 54 (2015) 8665-8672.
[11] V. Mahadevan, J.L. DuBois, B. Hedman, K.O. Hodgson, T.D.P. Stack, Exogenous Substrate Reactivity with a
[Cu(III)2O2]2+ Core:ꢀ Structural Implications, Journal of the American Chemical Society, 121 (1999) 5583-5584.
[12] G.J. Kubias, A.L. Monzyk, A.L. Crumbliss, Tetrakis(Acetonitrile)Copper(I) Hexafluorophosphate, in: D.F.
Shriver (Ed.) Inorganic Synthesis2007, pp. 90-92.
[13] I.M. Goldman, Large isotope effect in the manganese dioxide oxidation of benzyl alcohol, The Journal of
Organic Chemistry, 34 (1969) 3289-3295.
[14] SPECFIT\32, Spectrum Software Associates, Marlborough, MA, 2004.
[15] G.W.T. M. J. Frisch, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G.
A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H.
P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J.
Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T.
Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K.
Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT,
2016.
[16] J.-D. Chai, M. Head-Gordon, Long-range corrected hybrid density functionals with damped atom–atom
dispersion corrections, Physical Chemistry Chemical Physics, 10 (2008) 6615-6620.
[17] F. Weigend, R. Ahlrichs, Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence
quality for H to Rn: Design and assessment of accuracy, Physical Chemistry Chemical Physics, 7 (2005) 3297-3305.
[18] A.V. Marenich, C.J. Cramer, D.G. Truhlar, Universal Solvation Model Based on Solute Electron Density and
on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions, The
Journal of Physical Chemistry B, 113 (2009) 6378-6396.
[19] M. Douglas, N.M. Kroll, Quantum electrodynamical corrections to the fine structure of helium, Annals of
Physics, 82 (1974) 89-155.
[20] B.A. Hess, Applicability of the no-pair equation with free-particle projection operators to atomic and molecular
structure calculations, Physical Review A, 32 (1985) 756-763.
[21] B.A. Hess, Relativistic electronic-structure calculations employing a two-component no-pair formalism with
external-field projection operators, Physical Review A, 33 (1986) 3742-3748.
[22] G. Jansen, B.A. Hess, Revision of the Douglas-Kroll transformation, Physical Review A, 39 (1989) 6016-6017.
[23] L. Visscher, K.G. Dyall, Dirac–Foch Atomic Electronic Structure Calculations Using Different Nuclear Charge
Distributions, Atomic Data and Nuclear Data Tables, 67 (1997) 207-224.
[24] A.E.R. E. D. Glendening, J. E. Carpenter, and F. Weinhold, NBO Version 3.1, DOI.
[25] M.T. Keiber-Emmons, LUMO, version 1.0.1, Ephrata, PA, 2012.
[26] S. Mahapatra, J.A. Halfen, W.B. Tolman, Mechanistic Study of the Oxidative N-Dealkylation Reactions of
Bis(μ-oxo)dicopper Complexes, Journal of the American Chemical Society, 118 (1996) 11575-11586.
[27] V. Mahadevan, Z. Hou, A.P. Cole, D.E. Root, T.K. Lal, E.I. Solomon, T.D.P. Stack, Irreversible Reduction of
Dioxygen by Simple Peralkylated Diamine−Copper(I) Complexes:ꢀ Characterization and Thermal Stability of a
[Cu2(μ-O)2]2+ Core, Journal of the American Chemical Society, 119 (1997) 11996-11997.
[28] C.J. Cramer, C.R. Kinsinger, Y. Pak, Mechanism of intramolecular C–H bond activation in [(LCu)2(μ-O)2]2+
(L=1,4,7-trialkyl-1,4,7-triazacyclononane): quantum mechanical/molecular mechanical modeling, Journal of
Molecular Structure: THEOCHEM, 632 (2003) 111-120.

18
[29] Y.R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, 2007.
[30] C.D. Ritchie, W.F. Sager, An Examination of Structure‐Reactivity Relationships, in: S.G. Cohen, A.
Streitwieser, R.W. Taft (Eds.) Progress in Physical Organic Chemistry1964, pp. 323-400.
[31] O. Pestovsky, A. Bakac, Reactivity of Aqueous Fe(IV) in Hydride and Hydrogen Atom Transfer Reactions,
Journal of the American Chemical Society, 126 (2004) 13757-13764.
[32] J. Rocek, A.E. Radkowsky, One-electron vs. two-electron oxidations. Vanadium(V) and manganese(III)
oxidations of cyclobutanol, The Journal of Organic Chemistry, 38 (1973) 89-95.
[33] N.Y. Oh, Y. Suh, M.J. Park, M.S. Seo, J. Kim, W. Nam, Mechanistic insight into alcohol oxidation by high-
valent iron-oxo complexes of heme and nonheme ligands, Angew Chem Int Ed Engl, 44 (2005) 4235-4239.
[34] J. Shearer, C.X. Zhang, L.N. Zakharov, A.L. Rheingold, K.D. Karlin, Substrate Oxidation by
Copper−Dioxygen Adducts:ꢀ Mechanistic Considerations, Journal of the American Chemical Society, 127 (2005)
5469-5483.
[35] C. Citek, J.B. Gary, E.C. Wasinger, T.D.P. Stack, Chemical Plausibility of Cu(III) with Biological Ligation in
pMMO, Journal of the American Chemical Society, 137 (2015) 6991-6994.
[36] C. Citek, B.-L. Lin, T.E. Phelps, E.C. Wasinger, T.D.P. Stack, Primary Amine Stabilization of a Dicopper(III)
Bis(μ-oxo) Species: Modeling the Ligation in pMMO, Journal of the American Chemical Society, 136 (2014)
14405-14408.
[37] I. Garcia-Bosch, R.E. Cowley, D.E. Díaz, R.L. Peterson, E.I. Solomon, K.D. Karlin, Substrate and Lewis Acid
Coordination Promote O–O Bond Cleavage of an Unreactive L2CuII2(O22–) Species to Form L2CuIII2(O)2 Cores
with Enhanced Oxidative Reactivity, Journal of the American Chemical Society, 139 (2017) 3186-3195.
[38] T.-D.J. Stumpf, M. Steinbach, C. Würtele, J. Becker, S. Becker, R. Fröhlich, R. Göttlich, S. Schindler,
Reactivity of Copper Complexes with Bis(piperidinyl)methane and Bis(quinolinyl)methane Ligands, European
Journal of Inorganic Chemistry, 2017 (2017) 4246-4258.
[39] Y. Kajita, H. Arii, T. Saito, Y. Saito, S. Nagatomo, T. Kitagawa, Y. Funahashi, T. Ozawa, H. Masuda,
Syntheses, Characterization, and Dioxygen Reactivities of Cu(I) Complexes with cis,cis-1,3,5-Triaminocyclohexane
Derivatives:ꢀ A Cu(III)2O2 Intermediate Exhibiting Higher C−H Activation, Inorganic Chemistry, 46 (2007) 3322-
3335.
[40] C.-C. Liu, T.-S. Lin, S.I. Chan, C.-Y. Mou, A room temperature catalyst for toluene aliphatic C–H bond
oxidation: Tripodal tridentate copper complex immobilized in mesoporous silica, Journal of Catalysis, 322 (2015)
139-151.
[41] A.R. Germain, D.M. Bruggemeyer, J. Zhu, C. Genet, P. O'Brien, J.A. Porco, Synthesis of the azaphilones (+)-
sclerotiorin and (+)-8-O-methylsclerotiorinamine utilizing (+)-sparteine surrogates in copper-mediated oxidative
dearomatization, J Org Chem, 76 (2011) 2577-2584.
[42] J. Zhu, N.P. Grigoriadis, J.P. Lee, J.A. Porco, Synthesis of the Azaphilones Using Copper-Mediated
Enantioselective Oxidative Dearomatization, Journal of the American Chemical Society, 127 (2005) 9342-9343.
[43] S. Dong, E. Hamel, R. Bai, D.G. Covell, J.A. Beutler, J.A. Porco, Enantioselective Synthesis of (+)-
Chamaecypanone C: A Novel Microtubule Inhibitor, Angewandte Chemie International Edition, 48 (2009) 1494-
1497.
[44] S.E. Allen, R.R. Walvoord, R. Padilla-Salinas, M.C. Kozlowski, Aerobic Copper-Catalyzed Organic Reactions,
Chemical Reviews, 113 (2013) 6234-6458.
[45] A.P. Cole, V. Mahadevan, L.M. Mirica, X. Ottenwaelder, T.D.P. Stack, Bis(μ-oxo)dicopper(III) Complexes of
a Homologous Series of Simple Peralkylated 1,2-Diamines:ꢀ Steric Modulation of Structure, Stability, and
Reactivity, Inorganic Chemistry, 44 (2005) 7345-7364.
[46] P. Kang, E. Bobyr, J. Dustman, K.O. Hodgson, B. Hedman, E.I. Solomon, T.D.P. Stack, Bis(μ-oxo)
Dicopper(III) Species of the Simplest Peralkylated Diamine: Enhanced Reactivity toward Exogenous Substrates,
Inorganic Chemistry, 49 (2010) 11030-11038.
[47] N.W. Aboelella, E.A. Lewis, A.M. Reynolds, W.W. Brennessel, C.J. Cramer, W.B. Tolman, Snapshots of
Dioxygen Activation by Copper:ꢀ The Structure of a 1:1 Cu/O2 Adduct and Its Use in Syntheses of Asymmetric
Bis(μ-oxo) Complexes, Journal of the American Chemical Society, 124 (2002) 10660-10661.
[48] C. Citek, S. Herres-Pawlis, T.D.P. Stack, Low Temperature Syntheses and Reactivity of Cu2O2 Active-Site
Models, Accounts of Chemical Research, 48 (2015) 2424-2433.
Highlights

Bis-Cu(III) bis-oxides (O) form spontaneously from simple Cu(I) diamine complexes under O2

19



While powerful 2e-/2H+ oxidants, their reactivity with exogenous substrates is limited
OTMPD effects selective oxidation of alcohols and amines in >90% yields with excess oxidant
Mechanistic analyses suggest alcohol oxidation occurs through net hydride transfer

LCuI + O2
O
N
R
R
R
H
N
N
N
N
O
CuIII
CuIII
O
OH
R
NH2