A biomimetic pathway for vanadium-catalyzed aerobic oxidation of alcohols: Evidence for a base-assisted dehydrogenation mechanism

Article abstract of DOI:10.1002/chem.201202499

The first step in the catalytic oxidation of alcohols by molecular O ₂, mediated by homogeneous vanadium(V) complexes [LV ^V(O)(OR)], is ligand exchange. The unusual mechanism of the subsequent intramolecular oxidation of benzyl alcoholate ligands in the 8-hydroxyquinolinato (HQ) complexes [(HQ)₂V^V(O)(OCH ₂C₆H₄-p-X)] involves intermolecular deprotonation. In the presence of triethylamine, complex 3 (X=H) reacts within an hour at room temperature to generate, quantitatively, [(HQ)₂V ^IV(O)], benzaldehyde (0.5 equivalents), and benzyl alcohol (0.5 equivalents). The base plays a key role in the reaction: in its absence, less than 12 % conversion was observed after 72 hours. The reaction is first order in both 3 and NEt₃, with activation parameters δH ⁺=(28±4) kJ mol^-1 and δS⁺=(- 169±4) J K^-1 mol^-1. A large kinetic isotope effect, 10.2±0.6, was observed when the benzylic hydrogen atoms were replaced by deuterium atoms. The effect of the para substituent of the benzyl alcoholate ligand on the reaction rate was investigated using a Hammett plot, which was constructed using σ_p. From the slope of the Hammett plot, ρ=+(1.34±0.18), a significant buildup of negative charge on the benzylic carbon atom in the transition state is inferred. These experimental findings, in combination with computational studies, support an unusual bimolecular pathway for the intramolecular redox reaction, in which the rate-limiting step is deprotonation at the benzylic position. This mechanism, that is, base-assisted dehydrogenation (BAD), represents a biomimetic pathway for transition-metal-mediated alcohol oxidations, differing from the previously identified hydride-transfer and radical pathways. It suggests a new way to enhance the activity and selectivity of vanadium catalysts in a wide range of redox reactions, through control of the outer coordination sphere.

Full text of DOI:10.1002/chem.201202499

FULL PAPER
DOI: 10.1002/chem.201202499
A Biomimetic Pathway for Vanadium-Catalyzed Aerobic Oxidation of
Alcohols: Evidence for a Base-Assisted Dehydrogenation Mechanism
Bethany N. Wigington,[a] Michael L. Drummond,[b] Thomas R. Cundari,*[b]
David L. Thorn,[c] Susan K. Hanson,*[c] and Susannah L. Scott*[a, d]
Abstract: The first step in the catalytic
oxidation of alcohols by molecular O2,
mediated by homogeneous vana-
dium(V) complexes [LVV(O)(OR)], is
ligand exchange. The unusual mecha-
nism of the subsequent intramolecular
oxidation of benzyl alcoholate ligands
in the 8-hydroxyquinolinato (HQ)
complexes [(HQ)2VV(O)(OCH2C6H4-p-
X)] involves intermolecular deprotona-
tion. In the presence of triethylamine,
complex 3 (X=H) reacts within an
hour at room temperature to generate,
quantitatively, [(HQ)2VIV(O)], benzal-
dehyde (0.5 equivalents), and benzyl al-
cohol (0.5 equivalents). The base plays
a key role in the reaction: in its ab-
sence, less than 12% conversion was
observed after 72 hours. The reaction is
first order in both 3 and NEt3, with ac-
negative charge on the benzylic carbon
atom in the transition state is inferred.
These experimental findings, in combi-
nation with computational studies, sup-
port an unusual bimolecular pathway
for the intramolecular redox reaction,
in which the rate-limiting step is depro-
tonation at the benzylic position. This
mechanism, that is, base-assisted dehy-
drogenation (BAD), represents a bio-
mimetic pathway for transition-metal-
mediated alcohol oxidations, differing
from the previously identified hydride-
transfer and radical pathways. It sug-
gests a new way to enhance the activity
and selectivity of vanadium catalysts in
tivation
parameters
and
DH° =(28ꢁ
4) kJmolꢀ1
DS° =(ꢀ169ꢁ
4) JKꢀ1 molꢀ1. A large kinetic isotope
effect, 10.2ꢁ0.6, was observed when
the benzylic hydrogen atoms were re-
placed by deuterium atoms. The effect
of the para substituent of the benzyl al-
coholate ligand on the reaction rate
was investigated using a Hammett plot,
which was constructed using sp. From
the slope of the Hammett plot, 1= +
(1.34ꢁ0.18), a significant buildup of
Keywords: aerobic
oxidation
·
base-assisted catalysis · biomimetic
synthesis · Hammett correlation ·
vanadium
a
wide range of redox reactions,
through control of the outer coordina-
tion sphere.
Introduction
toxicity, and an environmentally benign reaction byproduct
(H2O). Complexes of several noble transition metals, includ-
ing Pd,[2] Rh,[3] and Ru,[4] have proven to be versatile cata-
lysts in a wide range of aerobic oxidation reactions. There is
also strong interest in the design of oxidation catalysts based
on Earth-abundant metals, such as V[5] and Cu.[6] However,
these catalysts typically operate by redox mechanisms that
are very different from those of the noble metals, the
former showing greater propensity to engage in one-electron
(radical) processes.[7] Hence, an important factor in “reverse
engineering” noble-metal catalysts using base metals as
their replacements is the potential selectivity issues arising
from radical chemistry.[8] In this context, it is interesting that
The development of selective aerobic oxidation catalysts is
desirable for the production of many important fine chemi-
cal products.[1] Dioxygen has significant advantages over sto-
ichiometric metal-based oxidants and even organic oxidants;
these advantages include low cost, ready availability, low
[a] B. N. Wigington, Prof. Dr. S. L. Scott
Department of Chemistry and Biochemistry
University of California, Santa Barbara, CA 93106-9510 (USA)
[b] Dr. M. L. Drummond, Prof. Dr. T. R. Cundari
Department of Chemistry
Center for Advanced Scientific Computing and Modeling (CASCaM)
University of North Texas, Denton, TX 76201 (USA)
E-mail: thomas.cundari@unt.edu
Nature uses 3d metals, such as Fe and Cu, to oxidize even
[9]
ꢀ
the most inert C H bonds selectively. Metalloenzymes are
[c] Dr. D. L. Thorn, Dr. S. K. Hanson
Chemistry Division
adept at using both inner and outer coordination sphere in-
teractions for controlling activity and selectivity. Neverthe-
less, most biomimetic approaches, with some notable recent
exceptions,[10] have emphasized inner coordination sphere
chemistry.[11] Methods of inducing two-electron reactivity,
long a hallmark of the 4d and 5d metals, through the partici-
pation of noncoordinated sites may be the key to a greater
exploitation of 3d metals in catalysis.[12]
Los Alamos National Laboratory
Los Alamos, New Mexico 87545 (USA)
E-mail: skhanson@lanl.gov
[d] Prof. Dr. S. L. Scott
Department of Chemical Engineering
University of California, Santa Barbara 93106-5080 (USA)
Fax : (+1)805-893-4731
E-mail: sscott@engineering.ucsb.edu
In view of these criteria, the rational design of environ-
mentally benign oxidation catalysts requires a detailed un-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202499.
Chem. Eur. J. 2012, 18, 14981 – 14988
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14981

derstanding of the mechanisms of transition-metal-mediated
oxidations. This is illustrated in the recent development of
Pd-based systems for aerobic alcohol oxidation, for which
mechanistic insight into the role of ligand modulation and
base promoters led to the design of robust, active, and selec-
tive catalysts.[2a,d,e]
Aerobic oxidation using vanadium catalysts may have an
even wider substrate scope and application. Mild and selec-
tive vanadium-catalyzed oxidation reactions of benzylic, al-
lylic, and propargylic alcohols has been demonstrated.[13] Va-
nadium/Schiff base complexes are highly enantioselective
catalysts for the aerobic oxidative kinetic resolution of a-hy-
droxy-esters, -amides, and -phosphonates at ambient temper-
ature.[14] Vanadium complexes induce oxidative decarboxyla-
tion in certain hydroxy carboxylic acids[15] and a-amino
acids,[16] desilylation of benzylic silanes,[17] as well as oxida-
tion of lignin model compounds.[18] However, the mecha-
nisms of vanadium-mediated oxidation reactions are compa-
ratively less well understood.
The facile interconversion of vanadium oxidation states
(for example, VV, VIV, and VIII) can make it difficult to iden-
tify redox pathways. In alcohol oxidations, both hydrogen
atom abstraction[5e,19] and hydride abstraction[5c,d,f,14b,c,18] by
the vanadyl oxo ligand have been postulated. Littler and
Waters proposed the former, based on indirect evidence of
Scheme 1. Catalytic oxidation of benzylic, allylic, and propargylic alco-
hols by [(HQ)2VV(O)OiPr] (1).
Herein, we present the combined results of our experi-
mental (kinetics) and computational (density functional
theory) studies on the key redox step in the catalytic oxida-
tion of alcohols. For benzyl alcoholate complexes, we find
that the external base initiates the reaction by abstracting a
proton at the benzylic position. The result is an unusual
base-assisted dehydrogenation, which is reminiscent of met-
alloenzyme pathways. The results may have important rami-
fications for future catalyst development because they sug-
gest new ways to tune the activity and selectivity of vanadi-
um catalysts for the oxidation of alcohols and other sub-
strates.
Results
ꢀ
radical intermediates and the appearance of C C bond-fis-
sion products.[20] Similarly, Rocek and Aylward reported that
ˇ
A rapid reaction takes place between [(HQ)2VV(O)OiPr]
(1) and various para-substituted benzyl alcohols in either
THF or CH2Cl2 at room temperature [Eq. (1)]. Ligand ex-
change generates [(HQ)2VV(O)(OCH2C6H4-p-X)], where X
is OCH3 (2), H (3), CH3 (4), F (5), CF3 (6), or CN (7). Com-
plexes 3–7 were characterized by 51 V, 1H, and 13C NMR
spectroscopy, IR spectroscopy, and mass spectrometry; com-
plex 2 was reported previously.[13]
+
VO2 reacts with 2-ethyl-cyclobutanol by a radical pathway
to give the ring-opened product, 4-hydroxyhexanal.[19] In
other cases, the absence of ring-scission products has been
used to support hydride-transfer pathways. For example,
Toste and co-workers found that oxidation of (ꢁ)-methyl 2-
hydroxy-2-(2-phenyl-cyclopropyl)acetate gave the corre-
sponding ketone, thus ruling out a mechanism involving a
carbinol radical.[5f]
A few previous reports have suggested that bases can pro-
mote vanadium-mediated alcohol oxidations. Ragauskas and
Jiang studied the aerobic oxidation of activated benzylic and
allylic alcohols with [VIV(O)
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(DABCO).[5a,b] Recently, some of us reported kinetic evi-
dence for pyridine promotion of stoichiometric oxidation of
aliphatic alcohols by [(dipic)VV(O)OiPr] (H2dipic=dipico-
linic acid).[5a,b,21] However, the dependence of the rate on
the concentration of pyridine was complex, because the base
also coordinates to the catalyst. We also reported that the 8-
hydroxyquinolinato complex, [(HQ)2VV(O)OiPr] (1), cata-
lyzes the aerobic oxidation of lignin model compounds, in-
cluding benzylic, allylic, and propargylic alcohols
(Scheme 1).[13] The catalytic activity of 1 in the presence of
triethylamine was higher than that of several other vanadi-
um-based catalysts.[13] Although no rate dependence on the
base concentration was reported, there is no evidence that
triethylamine binds to 1, and there is no open coordination
site for such binding. Therefore, we chose 1 to elucidate the
precise role of the base in these vanadium-catalyzed aerobic
oxidations of alcohols.
1
Complexes 2–7 show characteristic signals in the H NMR
spectrum in the range 6.57–6.80 ppm, corresponding to the
benzylic protons. These signals appear downfield from those
of the free benzyl alcohols (4.57–4.77 ppm). Each complex
gives one signal in the 51V NMR spectrum. Differences in
the 51V NMR chemical shifts are slight (ranging from
ꢀ473 ppm for 2, to ꢀ477 ppm for 6), but nevertheless corre-
late approximately with the electronic nature of the para
substituent. The IR spectrum of each complex contains a
peak in the narrow range 959–961 cmꢀ1, which was assigned
to the V=O stretching mode.
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Biomimetic Aerobic Oxidation
FULL PAPER
Table 1. Dependence of kobs for the redox reaction of 3 on the concentra-
tion of NEt3 in 1,2-dichloroethane.
Rate law for the intramolecular redox reaction: In the ab-
sence of added base, complex 3 is relatively stable in CD2Cl2
at room temperature. For example, the H NMR spectrum
showed less than 12% conversion over the course of
72 hours at 303 K. However, when NEt3 (2 equivalents) was
added to a solution of 3 in [D4]-1,2-dichloroethane in an
NMR tube at room temperature under Ar, the reaction pro-
ceeded readily and conversion was complete within 2 hours,
affording benzaldehyde (0.5 equivalents, 100% yield), and
benzyl alcohol (0.5 equivalents, 100% yield) [Eq. (2)].
[a]
[b]
103 kobs [sꢀ1
]
102 k [mꢀ1 sꢀ1
10.9ꢁ0.42
]
1
T [K]
G
303
303
303
303
303
293
313
323
333
1.57ꢁ0.13
2.62ꢁ0.10
4.20ꢁ0.60
5.46ꢁ1.05
8.40ꢁ0.80
1.74ꢁ0.31
4.35ꢁ0.68
5.65ꢁ0.77
7.98ꢁ0.81
7.2ꢁ1.3
18.1ꢁ2.8
23.6ꢁ3.2
33.2ꢁ3.4
[a] Each value is the average of three independent experiments. The un-
certainty is the standard deviation of the average. [b] Each value is the
ratio of the averaged value of kobs and the concentration of NEt3. The un-
certainty is the standard deviation of kobs, divided by 0.024m.
The accompanying VIV product, [(HQ)2VIV(O)] (8), was
isolated and identified previously.[13]
Kinetic data was obtained by monitoring, using UV/Vis
spectroscopy, the intramolecular redox reaction of 3 in the
presence of 24 mm NEt3 in 1,2-dichloroethane at 303 K. The
data from a typical experiment are shown in Figure 1. In the
UV/Vis spectrum, there are two clean isosbestic points, at
382 and 426 nm, which persist throughout the course of the
reaction, thus indicating quantitative conversion of 3 into 8
without accumulation of intermediates. The reaction is first
order in 3, with kobs =(2.62ꢁ0.10)ꢁ10ꢀ3 sꢀ1, Figure 1 (inset).
The linear dependence of kobs on the concentration of NEt3
is shown in Table 1 and Figure 2. The rate law is therefore
also first order in NEt3, [Eq. (3)]
Figure 2. Dependence of the pseudo-first-order rate constants for the
redox reaction of 3 on the concentration of NEt3 in 1,2-dichloroethane at
303 K. Error bars are based on uncertainties given in Table 1.
Activation parameters: Kinetic data were collected for the
redox reaction of 3 at several different temperatures,
Table 1. The resulting Eyring plot, shown in Figure 3, gave
DH° =(28ꢁ4) kJmolꢀ1 and DS° =(ꢀ169ꢁ4) JKꢀ1 molꢀ.[22]
The large, negative value for DS° is consistent with a bimo-
lecular reaction.
-d½3ꢂ=dt ¼ k½NEt3ꢂ½3ꢂ ¼ kobs½3ꢂ
ð3Þ
Figure 1. Time-resolved UV/Vis spectra showing the redox reaction of 3
(0.34 mm) in the presence of NEt3 (24 mm) in 1,2-dichloroethane at 303 K
under Ar. Spectra were recorded at 20 s intervals over a period of 1 h.
The inset shows the evolution of the absorbance at 500 nm as a function
of time, as well as the curve fit obtained using the first-order rate equa-
tion.
Figure 3. Eyring plot for the redox reaction of 3 in the presence of NEt3
in 1,2-dichloroethane.
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14983

T. R. Cundari, S. K. Hanson, S. L. Scott et al.
Kinetic isotope effect: The selectively deuterated complex
[(HQ)2VV(O)
(CD2C5H5)] ([D2]-3) was prepared by the reac-
amine. The use of the more basic amine, HNEt2 (pKb =3.07
in toluene), leads to a faster reaction (k=(21.2ꢁ1.00)ꢁ
10ꢀ2 mꢀ1 sꢀ1) than that mediated by NEt3 (pKb =3.33; k=
(10.9ꢁ0.42)ꢁ10ꢀ2 mꢀ1 sꢀ1). Interestingly, it is also more effec-
tive than the more basic, yet bulkier amine, HNiPr2 (pKb =
2.80 in toluene; k=(10.5ꢁ2.46)ꢁ10ꢀ2 mꢀ1 sꢀ1).[24] When the
even bulkier amine, HNiBu2 (pKb =3.18), was used, the re-
action was even slower (k=(4.38ꢁ1.04)ꢁ10ꢀ2 mꢀ1 sꢀ1) than
that using NEt3. These differences in rate constants suggest
that steric hindrance also plays a role in the base-assisted re-
action, thus providing another means to tune the catalyst
system.
ACHTUNGTRENNUNG
tion of 1 with [a,a-D2]benzyl alcohol in THF. At 303 K in
1,2-dichloroethane, the redox reaction of [D2]-3 (k=(1.07ꢁ
0.04)ꢁ10ꢀ2 mꢀ1 sꢀ1) is an order of magnitude slower than that
of unlabeled 3 (k=(10.9ꢁ0.42)ꢁ10ꢀ2 mꢀ1 sꢀ1). The kinetic
isotope effect, kH/kD, is therefore 10.2ꢁ0.6. Its magnitude
confirms that it is a primary kinetic isotope effect, suggest-
ꢀ
ing that cleavage of a benzylic C H bond occurs during the
rate-determining step.
para-Substituent effects: To probe electronic effects on the
rate of the redox reaction, the kinetics were evaluated for
each member of the series [(HQ)2VV(O)(OCH2C6H4-p-X)],
where X=OMe, CH3, H, F, CF3, and CN. The rate constants
are given in Table 2, and the resulting Hammett plot, con-
structed using sp values,[23] is shown in Figure 4. The rate
constants are sensitive to the identity of the para substitu-
ent, with electron-withdrawing substituents enhancing the
reaction rate. The large positive 1 value, +(1.34ꢁ0.18), im-
plies that negative charge develops on the benzylic carbon
atom in the transition state.
Computational modeling of the reaction mechanism: DFT
calculations on the singlet potential energy surface using the
parent complex
3 gave a high free-energy barrier,
132 kJmolꢀ1 at 298 K, for direct intramolecular hydride
ꢀ
transfer from the benzylic C H bond of the alcoholate
ligand to the vanadyl oxo ligand. In contrast, the calculated
free-energy barrier for the intermolecular pathway is more
favorable, at only 94 kJmolꢀ1. In this mechanism, that is,
base-assisted dehydrogenation (BAD), NEt3 abstracts a
proton from the benzylic position, giving coordinated ben-
zaldehyde and, formally, a VIII complex. A spin crossover
from singlet to the triplet state also occurs at this stage, with
the latter being more stable than the former by 71 kJmolꢀ1.
The protonated base, HNEt3+, subsequently approaches the
vanadyl oxo ligand and transfers a proton. This reaction is
downhill, with no calculated barrier. The resulting aldehyde
Table 2. Dependence of the rate constant for the intramolecular redox
reaction of [(HQ)2VV(O)OCH2C6H4-p-X], on the nature of the para sub-
stituent, X.[a]
[b]
[c]
Complex
X
sp
102 k [mꢀ1 sꢀ1
]
2
4
3
5
6
7
OCH3
CH3
H
F
CF3
CN
ꢀ0.27
ꢀ0.17
0.00
0.06
0.54
5.46ꢁ1.01
6.46ꢁ0.16
10.9ꢁ0.42
7.82ꢁ0.46
43.3ꢁ1.67
107ꢁ1.68
complex, [(HQ)VIII(OH)
ACHTUNGTNER(NUNG O=CHPh)], presumably then
comproportionates with 3 to generate the VIV product 8
[Eq. (3)], as previously proposed for
a closely-related
0.66
system.[21] Calculated transition-state geometries correspond-
ing to intramolecular hydride transfer and the BAD mecha-
nism are shown in Figure 5.
[a] In 1,2-dichloroethane at 303 K. [b] Values from ref. [22]. [c] Each
value is the average of three independent experiments. The uncertainty is
the standard deviation of the average.
Computational modeling with HNEt2 instead of NEt3 re-
vealed identical behavior, except that the free-energy barri-
er for transfer of the benzylic proton to HNEt2 was reduced
to 79 kJmolꢀ1. This is presumably because HNEt2 also forms
a hydrogen bond with the oxygen atom of a hydroxyquinoli-
nato ligand, resulting in a much closer approach (V–N) to
the active site than for NEt3, Figure 5c. Computational at-
tempts to locate a concerted mechanism, in which a proton
is transferred to the oxo ligand while the benzylic carbon
atom is being deprotonated, were unsuccessful; these at-
tempts led mostly to collapse to stepwise transition states,
although one such attempt indicated a highly unfavorable
process with a barrier greater than 188 kJmolꢀ1.
A computational Hammett study was also performed to
investigate para-substituent effects for both intra- and inter-
molecular reaction mechanisms. Complexes 2–6 were inves-
tigated, as was the complex with NO2 as the para substitu-
ent. For intramolecular hydride transfer, the correlation be-
tween sp and the calculated rate constants is weak (R2 =
0.22), although the correlation is consistent with slightly
faster reactions for ligands with more electron-withdrawing
para substituents, 1= +(0.26ꢁ0.22) (see the Supporting In-
Figure 4. Hammett plot for the intramolecular redox reaction of
[(HQ)2VV(O)OCH2C6H4-p-X], in 1,2-dichloroethane at 303 K.
Secondary amines: We also examined the redox reaction of
3 in the presence of various amines, HNR2 (24 mm, 303 K).
In all cases, the rate law is first order in the secondary
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Biomimetic Aerobic Oxidation
FULL PAPER
Figure 5. Calculated transition states in the redox reaction of 3: a) intramolecular hydride transfer to the vanadyl oxo ligand, and b) and c) base-assisted
dehydrogenation by NEt3 and HNEt2, respectively. For b), the distances Et3N H and Cbenzyl…H are 1.17 and 1.59 ꢂ, respectively. Most hydrogen atoms
ꢀ
have been omitted for clarity. Color scheme: V=magenta, N=blue, C=gray, O=red, H=orange.
formation). For the mechanism based on an intermolecular
BAD, the correlation between sp and the calculated rate
constant is very good (R2 =0.98) and the effect is much
stronger: 1= ++(2.86ꢁ0.19). Thus computations and experi-
ment follow the same trend, with much greater rate acceler-
ation occurring for electron-poor benzyl alcoholate ligands.
Discussion
Most metal-mediated alcohol oxidations that involve
Brønsted bases as co-catalysts operate through a fundamen-
tally different mechanism than the one described in this
study. Bases have proven to be important in both Cu-[6b] and
Pd-mediated[25] alcohol oxidations, where they serve to de-
protonate coordinated alcohols at the OH group, thereby
generating alkoxide complexes as intermediates prior to the
redox step. Detailed mechanistic studies by Sigman et al.
showed the dual role of bases in Pd-catalyzed aerobic oxida-
tion of secondary alcohols, both in coordinating themselves
to the metal and in deprotonating the coordinated alco-
hol.[26]
For our vanadium catalyst, the base plays an unusually
direct role in the redox step, that is, abstracting a proton
from the a position of the alcoholate ligand (Scheme 2a).
Calculations predict a free-energy barrier for NEt3-assisted
deprotonation of 3 that is 38 kJmolꢀ1 lower than for direct
hydride transfer to the oxo ligand. Extracting the enthalpic
and entropic components of the free-energy barriers reveals
a higher enthalpic cost for intramolecular hydride transfer:
DH° is lower by 49 kJmolꢀ1 for intermolecular base-assisted
dehydrogenation (BAD). However, the bimolecular nature
of BAD also makes DS° more negative, by 37 JKꢀ1 molꢀ1.
Overall, the calculated activation free energy for the latter
reaction is in reasonable agreement with the experimental
value.
Based on these findings, we now propose an explanation
for the complex rate-dependence of alcohol oxidation by
[(dipic)VV(O)(OR)] on pyridine concentration,[21] Sche-
me 2b. One pyridine molecule occupies the open coordina-
tion site, while a second molecule abstracts a proton from
the a-position of the vanadium-bound alcoholate ligand.
The rate of alcohol oxidation is significantly enhanced by
Scheme 2. Comparison of key steps in base-assisted dehydrogenation for
two different [LV(O)OR] complexes, a) without, and b) with an open co-
ordination site.
more basic substituted pyridines (1=ꢀ2.5), consistent with
their role in this deprotonation step.
The proposed BAD mechanism for [(HQ)2V(O)(OR)] is
also supported by the agreement between the large positive
experimental and calculated Hammett parameters for para-
substituted benzyl alcohols. In contrast, most prior Hammett
studies of benzylic alcohol oxidations involving metal-based
oxidants report negative 1 values.[27] For example, in the oxi-
dation of benzylic alcohols by either [RuCl
2ACHTUNGTRENNUNG(PPh3)3]/
TEMPO[28] or [(neocuproine)Pd(OAc)2],[29] the 1 value was
ACHTUNGTRENNUNG
determined to be ꢀ0.58 in each case, signifying a buildup of
positive charge on the benzylic carbon atom in the transition
state owing to rate-limiting b-hydride elimination. When a
high-valent iron–oxo complex was used to oxidize para-sub-
stituted benzyl alcohols, the reaction rate was not greatly in-
fluenced by the nature of the para substituent.[30] Poor corre-
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T. R. Cundari, S. K. Hanson, S. L. Scott et al.
lations with conventional Hammett s and s+ values are usu-
ally attributed to radical character at the benzylic position
in the transition state.[30b] For the vanadium-mediated alco-
hol oxidation reaction studied herein, plotting the rate as a
function of s values revealed no correlation, which is incon-
sistent with the potential involvement of benzyl radicals.[31]
Few reported alcohol oxidation reactions mediated by
transition-metal complexes exhibit positive 1 values, and
none are strongly positive. Sigman and Jensen reported a
complexes such as 3 and an external base. The redox process
involves deprotonation of the benzylic position by NEt3 in
the rate-determining step, followed by the transfer of the
+
proton from HNEt3 to the vanadyl oxo ligand. Thus the
overall intramolecular redox reaction is in fact intermolecu-
lar, and is mediated by a redox-inactive co-catalyst. Com-
pared to most transition-metal-catalyzed alcohol oxidations,
this mechanism is highly unusual. It results in a nonradical,
two-electron pathway resembling those proposed for certain
metalloenzyme-catalyzed oxidations.[34–35] These mechanistic
insights indicate that highly active and selective catalytic ox-
idation processes may be designed using first-row transition-
metal catalysts in conjunction with either external bases as
co-catalysts, or ligands with appropriately positioned pend-
ant bases to serve as proton shuttles.
negligible 1 value (+0.03) in the PdACTHNUTRGNENUG(OAc)2-catalyzed aero-
bic oxidation of benzyl alcohols.[32] Recently, Guzei and co-
workers observed the oxidation of primary and secondary
benzylic alcohols by a tetrametallic ruthenium-oxo-hydroxo-
hydride complex.[27] Whereas the Hammett correlation for
the oxidation of secondary alcohols suggested negative
charge buildup on the benzylic carbon atom (1= +0.22),
primary alcohols displayed the opposite trend (1=ꢀ0.45).[27]
The base-assisted dehydrogenation pathway reported here
resembles that of certain enzymatic oxidations, for which
crystallographic and biochemical analyses suggest that the
rate is highly dependent on the ability of specific catalytic
residues near the active site to act as proton acceptors.[33]
For example, the mechanism proposed for benzylamine oxi-
dation by bovine serum amine oxidase involves proton ab-
straction by an active-site base (aspartate),[34] affording a
carbanion intermediate with partial delocalization of the
negative charge into the aromatic ring of the substrate. A
similar mechanism involving aspartate was proposed for the
oxidation of benzyl alcohols and amines by methylamine de-
hydrogenase, which showed an increase in rate with elec-
tron-withdrawing para substituents.[34–35] The reported 1
value, +1.47, is very similar to the value measured here.
Finally, DuBois and Bullock and co-workers recently
demonstrated the ability of pendant bases in the second co-
ordination sphere of nickel complexes to facilitate proton
transfer,[36] reminiscent of the proton conduction channels in
the active sites of hydrogenase enzymes. Pendant amines
promote H2 activation by acting as proton relays, lowering
the energy barrier of the transfer of protons to and from the
catalytically active metal site.[36a] DuBois, Kubiak and co-
workers have shown that these complexes can be used as
catalysts for the electrochemical oxidation of formate.[37]
Electrochemical and spectroscopic studies suggested rate-
determining proton transfer to a pendant amine ligand of
the Ni–formate complex, thus avoiding direct hydride trans-
fer to the metal center. This b-deprotonation is a multi-site
proton-coupled electron transfer (MS-PCET) process. Simi-
lar to the base-assisted dehydrogenation pathway postulated
herein, it involves the initial movement of a proton and two
electrons to two separate sites.[38]
Experimental Section
General considerations: Unless specified otherwise, all manipulations
were carried out under a dry argon atmosphere using standard glove-box
and Schlenk techniques. Deuterated solvents were purchased from Cam-
bridge Isotope Laboratories and dried over CaH2. Anhydrous acetoni-
trile, CH2Cl2, THF, and diethyl ether were obtained from Fisher Scientific
and were used as received. 1,2-Dichloroethane and NEt3 were dried over
CaH2. In addition, dichloroethane was stored over 4 ꢂ molecular sieves.
1H, 13C, and 51V NMR spectra were recorded at room temperature on
Bruker AV400 and AV500 spectrometers as well as
a Varian
VNMRS 600 spectrometer. Chemical shifts (d) were referenced either in-
ternally to the residual solvent signal or externally to VOCl3 (0 ppm). IR
spectra were recorded on a Varian 1000 FT-IR Scimitar Series instru-
ment. Complexes 1 and 2 were prepared as previously reported.[13] HR-
MS spectra were recorded on a Micromass QTOF2 Quadrupole/Time-of-
Flight Tandem mass spectrometer in the UCSB Mass Spectrometry Fa-
cility.
Synthesis of [(HQ)2VV(O)
ACHTUGNTERN(NUNG OCH2C6H5)] (3): Benzyl alcohol (466 mg,
4.31 mmol) and [(HQ)2VO(OiPr)] (163 mg, 0.394 mmol) were dissolved
AHCTUNGTRENNUNG
in THF (2 mL). The reaction mixture was allowed to stand at room tem-
perature for 20 min, then the solvent was removed under vacuum. The
dark red residue was dissolved in THF (1 mL), and diethyl ether (10 mL)
and pentane (3 mL) were added. Cooling the mixture to ꢀ208C over-
night resulted in the formation of a dark red precipitate. After decanting
the supernatant, the solid was washed with diethyl ether (2ꢁ2 mL) and
1
dried under vacuum. Yield: 158 mg (87%); H NMR (400 MHz, CD2Cl2):
d=8.59 (d, 1H, J
HQ), 8.14 (d, 1H, J
HQ), 7.60–7.53 (m, 2H; HQ), 7.37–7.13 (m, 11H; HQ), 6.80 (d, 1H,
(H,H)=13.6 Hz; V-OCHH), 6.65 ppm (d, 1H, J(H,H)=13.6 Hz; V-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
J
N
ACHTUNGTRENNUNG
OCHH); 13C{1H} NMR (100 MHz, CD2Cl2): d=164.8, 163.5, 146.7, 146.3,
144.5, 142.9, 141.8, 141.7, 139.9, 139.0, 137.9, 130.5, 130.4, 129.8, 129.3,
128.7, 127.9, 127.6, 122.7, 122.6, 118.4, 115.4, 111.9, 110.6, 90.1 ppm;
51V NMR (105 MHz, CD2Cl2): d=ꢀ473 ppm (s); IR: n=961 cmꢀ1 (V=
O); HRMS (ESI/TOF): m/z calcd for C25H19N2O4V+Na+: 485.0682
[M+Na]+; found: 485.0661.
Complexes 4–7 were prepared following similar procedures to that de-
scribed above for 3.
[(HQ)2VV(O)(OCH2C6H4-p-CH3)] (4): Yield: 59.7 mg (92%); 1H NMR
(400 MHz, CD2Cl2): d=8.58 (brs, 1H; HQ), 8.42 (brs, 1H; HQ), 8.15 (d,
1H, J
ACHUTNGTRENNUG(H,H)=8.0 Hz; HQ), 8.05 (d, 1H, JCAHTUNGTRENNUNG
Conclusion
(m, 2H; HQ), 7.28–7.07 (m, 10H; HQ), 6.75 (d, 1H, JAHCTUNGTRENNUNG
V-OCHH), 6.59 (d, 1H, JACHTUGNTRENNNUG
Experimental and computational studies concur that the
mechanism of alcohol oxidation catalyzed by 1 likely in-
volves a bimolecular reaction between vanadium alcoholate
CH3); 13C{1H} NMR (100 MHz, CD2Cl2): d=164.7, 163.4, 146.5, 146.1,
139.8, 138.8, 138.5, 137.7, 137.6, 130.4, 130.3, 129.6, 129.5, 129.3, 129.1,
127.7, 127.4, 122.5, 122.4, 118.1, 115.2, 111.7, 110.4, 105.4, 90.2, 21.3 ppm;
14986
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14981 – 14988

Biomimetic Aerobic Oxidation
FULL PAPER
51V NMR (105 MHz, CD2Cl2): d=ꢀ474 ppm (s); IR (thin film): n=
960 cmꢀ1 (V=O); HRMS (ESI/TOF): m/z calcd for C26H21N2O4V+Na+:
499.0839 [M+Na]+; found: 499.0812.
completion of the reaction, A0 is the initial absorbance, At is the absorb-
ance measured at time t, and kobs is the pseudo-first-order rate constant.
[(HQ)2VV(O)(OCH2C6H4-p-F)] (5): Yield: 46 mg (82%); 1H NMR
(400 MHz, CD2Cl2): d=8.58 (d, 1H, JACTHUNGTRENNNUG
At ¼ A1 þ ðA0ꢀA1Þ expðꢀkobstÞ
ð4Þ
J
J
ACHTUNGTRENNUNG(H,H)=4.0 Hz; HQ), 8.15 (d, 1H, JCAHTUNGTRENNUNG
ACHTUNGTRENNUNG
Computational methods: Mechanisms were investigated at the M06/6–
311+ +(d,p) level of theory. Density functional theory (DFT) simula-
tions employed the Gaussian 09 package.[40] The M06 functional[41] was
6.96 (t, 2H; aryl), 6.72 (d, 1H, J
(d, 1H, J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
used in conjunction with the extended Pople basis set, 6–311+ +GACHTUNGTRENNUNG(d,p)
G
ACHTUNGTRENNUNG
and an ultrafine integration grid.[42]
146.5, 146.1, 141.6, 139.7, 138.9, 137.8, 137.5, 130.4, 130.3, 129.6, 129.4,
129.3, 129.1, 122.5, 122.4, 118.3, 115.4, 115.3, 115.2, 111.7, 110.3,
88.9 ppm; 51V NMR (105 MHz, CD2Cl2): d=ꢀ474 ppm (s); IR (thin
film): n=960 cmꢀ1 (V=O); HRMS (ESI/TOF): m/z calcd for
C25H18FN2O4V+Na+: 503.0588 [M+Na]+; found: 503.0562.
[(HQ)2VO(OCH2C6H4-p-CF3)] (6): Yield: 45 mg (61%); 1H NMR
(400 MHz, CD2Cl2): d=8.58 (d, 1H, JACTHUNGTRENNNUG
All quoted energies are free energies calculated at 298.15 K and 1 atm,
using unscaled vibrational frequencies. Stationary points were character-
ized as minima or transition states via calculation of the energy Hessian
and observation of the correct number of imaginary frequencies (zero or
one, respectively). All geometry optimizations were performed without
symmetry restraints. A restricted or unrestricted Kohn–Sham formalism
was used for closed- and open-shell species, respectively. Both singlet and
triplet energy surfaces were explored. The singlets were consistently
lower in energy than the triplets by at least 84 kJmolꢀ1; consequently,
only singlet energies are reported here unless otherwise indicated.
J
J
ACHTUNGTRENNUNG(H,H)=4.0 Hz; HQ), 8.15 (d, 1H, JCAHTUNGTRENNUNG
ACHTUNGTRENNUNG
6.96 (t, 2H; aryl), 6.72 (d, 1H, J
(d, 1H, J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENUN(NG C,F)=272 Hz), 122.1, 122.0, 118.1, 114.9,
111.3, 109.9, 87.5 ppm; 51V NMR (105 MHz, CD2Cl2): d=ꢀ477 ppm (s);
IR (thin film): n=960 cmꢀ1 (V=O); HRMS (ESI/TOF): m/z calcd for
C26H18F3N2O4V+Na+: 553.0556 [M+Na]+; found: 553.0530.
Acknowledgements
This work was supported by the NSF through the Center for Enabling
New Technologies through Catalysis (CENTC). In addition, B.N.W ac-
knowledges support from the ConvEne IGERT Program (NSF-
DGE 0801627). S.K.H. thanks the LANL Institute for Multiscale Materi-
als Studies for support. Portions of this work were performed using the
Central Facilities of the Materials Research Laboratory at UC Santa Bar-
bara, supported by the MRSEC Program of the NSF under Award No.
DMR 1121053 and a member of the NSF-funded Materials Research Fa-
cilities Network (www.mrfn.org).
(HQ)2VV(O)(OCH2C6H4-p-CN) (7): Yield: 64.8 mg (95%); 1H NMR
(400 MHz, CD2Cl2): d=8.58 (d, 1H, JACTHUNGTRENNNUG
J
J
ACHTUNGTRENNUNG(H,H)=4.5 Hz; HQ), 8.15 (d, 1H, JCAHTUNGTRENNUNG
ACHTUNGTRENNUNG
7.11 (m, 2H; HQ), 6.73 (d, 1H, J
(d, 1H, J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
d=164.6, 163.3, 147.4, 146.7, 146.2, 141.7, 139.7, 139.0, 137.9, 132.7, 132.4,
130.5, 130.4, 129.6, 129.2, 127.5, 127.4, 122.6, 122.5, 119.4, 118.7, 115.5,
111.8, 111.2, 110.3, 87.6 ppm; 51V NMR (105 MHz, CD2Cl2): d=
ꢀ476 ppm (s); IR (thin film): n=959 cmꢀ1 (V=O); HRMS (ESI/TOF):
m/z calcd for C26H18N3O4V+Na+: 510.0635 [M+Na]+; found: 510.0610.
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alcohol was carried out according to a reported literature procedure.[39]
Yield: 88.6 mg (38%); 1H NMR (400 MHz, CDCl3): d=7.37 (m, 4H),
7.33–7.28 ppm (m, 1H).
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Synthesis of [(HQ)2VV(O)
similar to that used for the synthesis of unlabeled 3. Yield: 98 mg (97%);
1H NMR (500 MHz, CD2Cl2): d=8.59 (d, 1H, J
(H,H)=4.5 Hz; HQ),
(H,H)=4.5 Hz; HQ), 8.15 (d, 1H, J(H,H)=8.0 Hz; HQ),
(H,H)=8.5 Hz; HQ), 7.59–7.53 (m, 2H; HQ), 7.36–
ACTHUNGTREN(NUNG OCD2C6H5)] ([D2]-3): The procedure was
AHCTUNGTRENNUNG
8.43 (d, 1H, J
N
ACHTUNGTRENNUNG
8.05 (d, 1H,
JACHTUNGTRENNUNG
7.13 ppm (m, 12H; HQ); 13C{1H} NMR (100 MHz, CD2Cl2): d=164.7,
163.4, 146.5, 146.1, 141.6, 141.5, 139.8, 138.9, 137.8, 130.4, 130.3, 129.6,
129.1, 128.9, 128.6, 127.8, 127.6, 127.3, 122.5, 122.4, 118.2, 115.2, 111.7,
110.4, 89.2 ppm; 51V NMR (105 MHz, CD2Cl2): d=ꢀ479.4 ppm (s); IR
(thin film): n = 960 cmꢀ1 (V=O); HRMS (ESI/TOF): m/z calcd for
C25H17D2N2O4V+Na+: 488.0886 [M+Na]+; found: 487.0791.
Kinetics experiments: All experiments were carried out under Ar in 1,2-
dichloroethane, using square quartz cuvettes (path length, 1 cm) sealed
with Teflon septum caps. In a typical experiment, NEt3 was added by sy-
ringe to a thermally equilibrated cuvette containing 3 mL of a solution of
the vanadium complex (0.3–0.4 mm). The concentration of NEt3 was
varied in the range 12–72 mm to evaluate its reaction order, then held
constant at 24 mm for all other measurements. Reactions were initiated
by the addition of NEt3. The absorbance at 500 nm was recorded as a
function of time, using an Agilent 8453 UV/Vis spectrophotometer equip-
ped with a Peltier thermostatted cell holder for complexes 2–5. For com-
plexes 6 and 7, experiments were performed on a Shimadzu UV-2401PC
spectrometer equipped with a TCC-240 A thermoelectrically tempera-
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non-linear least-squares fitting (with uniform data weighting) of the inte-
grated first-order rate equation [Eq (4)]; A1 is the final absorbance at
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Received: July 13, 2012
Published online: October 18, 2012
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