Mechanistic Study of Ruthenium-Catalyzed C-H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest

Article abstract of DOI:10.1021/jacs.8b10950

We have recently disclosed [(dtbpy)₂RuCl₂] as an effective precatalyst for chemoselective C-H hydroxylation of C(sp³)-H bonds and have noted a marked disparity in reaction performance between 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy)- and 2,2′-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure-activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4′-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis-N-oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy)₂(dtbpy N-oxide)]²⁺ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-generation catalyst systems for C-H hydroxylation.

Full text of DOI:10.1021/jacs.8b10950

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Mechanistic Study of Ruthenium-Catalyzed C−H Hydroxylation
Reveals an Unexpected Pathway for Catalyst Arrest
James B. C. Mack,‡ Katherine L. Walker,‡ Sophia G. Robinson,§ Richard N. Zare,*,‡
Matthew S. Sigman,*,§ Robert M. Waymouth,*,‡ and J. Du Bois*,‡
‡Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, California 94305, United States
§Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S
* Supporting Information
ABSTRACT: We have recently disclosed [(dtbpy)2RuCl2] as an effective precatalyst for chemoselective C−H hydroxylation of
C(sp3)−H bonds and have noted a marked disparity in reaction performance between 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy)-
and 2,2′-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this
catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been
unveiled through evaluation of ligand structure−activity relationships, electrochemical and kinetic studies, and pressurized
sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification
of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as
measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is
dependent on the identity of bipyridyl 4,4′-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis-N-
oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a
catalytically inactive tris-ligated [Ru(dtbpy)2(dtbpy N-oxide)]2+ complex. Insights gained through this work highlight the power
of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-
generation catalyst systems for C−H hydroxylation.
efficient precatalyst for oxidation of 3° and benzylic C−H
bonds in aqueous acid medium.7 Efforts to improve the scope
and performance of this chemistry have motivated mechanistic
studies to understand off-pathway reactions that limit catalyst
turnover numbers. These investigations have revealed an
unexpected pathway for catalyst arrest that illuminates the link
between ligand substitution and catalyst performance.
INTRODUCTION
■
The evolution of catalytic methods for selective C−H bond
oxidation has transformed the practice of complex molecule
synthesis.1 These technologies provide single-step access to
value-added products, including modified natural products,
active pharmaceutical ingredients, and drug metabolites.2 The
prevalence of reports describing new catalysts and protocols
for C−H oxidation notwithstanding, efficient chemo- and site-
selective functionalization of substrates bearing polar func-
tional groups, and in particular nitrogen-based substituents,
remains a formidable challenge for methods development.3,4
Recent disclosures from our lab and others capitalize on
seminal work by Adam and co-workers to address the intrinsic
problems with oxidative cross-reactivity of amines and
azaheterocycles.5,6 To this end, we have demonstrated that a
mononuclear Ru-catalyst derived from 4,4′-di-tert-butyl-2,2′-
bipyridine (dtbpy), cis-[Ru(dtbpy)2X2], functions as an
BACKGROUND
■
Prior work from our laboratories has shown that both
[Ru(Me3tacn)Cl3] (Me3tacn = N,N′,N″-trimethyl(1,4,7-triaza-
cyclononane)) and cis-[Ru(dtbpy)2Cl2] function as effective
precatalysts for C−H oxidation using terminal oxidants such as
ceric ammonium nitrate (CAN), NaIO4, and H5IO6.4a,8,9
A
Received: October 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
salient feature of these catalyst systems is kinetic stability in
aqueous acid. By comparison, first-row catalysts are generally
unstable under oxidizing conditions in aqueous solution.10 The
use of aqueous acid as a solvent medium solubilizes polar
substrates and retards amine reactivity through protonation.
Although [Ru(Me3tacn)Cl3] affords turnover numbers
(TONs; TON = mol product/mol Ru) of 5−80 with select
substrates, catalyst modification to improve scope and
efficiency is severely restricted by an inflexible ligand design.
In contrast, substituted 2,2′-bipyridines can be used to
generate an array of sterically and electronically disparate cis-
(bpy)2Ru(II)X2 complexes that serve as precatalysts for C−H
oxidation (Figure 1). For the purpose of exploring catalyst
structure−function, this system is considerably advantaged
over Ru-tacn.
method A).13 With select ligands, however, isolation of pure
product remained difficult. The addition of carbonate offered a
convenient solution to the separations problem, allowing for
isolation of a single Ru species as the carbonate adduct
(Scheme 1, method B). The chelating nature of the carbonate
ligand presumably biases formation of the cis-configured
[bis(bipyridine)Ru(CO3)] complex. This protocol may prove
effective for generating other cis-configured Ru derivatives.
A series of Ru-precatalysts derived from chelating dipyridyl
ligands was evaluated under a standard protocol in an
oxidation reaction of 3-methylpentyl benzoate 5 (5 mol %
catalyst, H5IO6 or (NH4)2Ce(NO3)6, AcOH/H2O, 4 h, Table
1). Notably, dichloro- and carbonato-derived complexes
Table 1. Examination of Ru Precatalysts for C−H
a
Hydroxylation
Figure 1. Mechanistic study of Ru-catalyzed C−H hydroxylation
reaction to understand differences in precatalyst performance.
Turnover numbers (TONs) determined from reactions performed
with 0.5 mol % catalyst loading.
We have employed a suite of electrochemical, spectroscopic,
and modern spectrometric analysis methods to interrogate the
mechanism of Ru-catalyzed C−H oxidation. These studies
have been guided by three overarching questions: (1) what is
the influence of bipyridine structure on catalyst TONs; (2)
what is the nature of the active Ru-oxidant(s); (3) what is
(are) the pathway(s) for inhibition of reaction turnover and/or
catalyst arrest. Our work has culminated in the surprising
discovery of a mechanism for catalyst arrest involving ligand
dissociation and oxidation to form a catalyst poison. Insights
afforded from these findings will guide the design of high-
performance, next-generation C−H oxidation catalysts.
a
Reactions were conducted on 0.10 mmol scale. Conditions: 5 mol %
cis-[(ligand)2RuCl2] or cis-[(ligand)2Ru(CO3)] (3.125 mM), 2.0−6.0
equiv of oxidant (125−375 mM), AcOH/H2O, 4 h. Product
1
conversions estimated by H NMR integration of unpurified reaction
b
c
mixtures against an internal standard. R2 = H. Oxidation of 5 is not
productive with H5IO6; CAN = (NH4)2Ce(NO3)6.
RESULTS AND DISCUSSION
■
Precatalyst SAR and Reaction TON. To better under-
stand the effects of catalyst structure on TON, we examined
[bis(bipyridyl)RuX2] catalysts bearing differentially substituted
bipyridine ligands.11 Attempted preparation of these complexes
using a reported literature route (2 equiv of ligand, RuCl3,
refluxing dimethylformamide (DMF)) generally yielded
mixtures of mono-, bis-, and tris-ligated Ru(II) and Ru(III)
complexes.12 Changing solvent and Ru salt afforded signifi-
cantly improved product yields and a reliable method for
preparing new [bis(bipyridyl)RuCl2] precatalysts (Scheme 1,
performed equivalently in all cases examined (entries 1 and
2, 4 and 5). In general, precatalysts derived from electron-rich
bipyridine ligands (e.g., alkyl-, MeO-) displayed the highest
TONs (entries 1−3, 6, and 7).14 Among the precatalysts
tested, cis-[Ru(dtbpy)2(CO3)] (1), was distinguished as the
top performer (entry 1), matched only by cis-[Ru(4,4′-
(MeO)2-bpy)2(CO3)] (4) in combination with a large excess
of (NH4)2Ce(NO3)6 (entry 7).
To gain additional insight into the link between ligand
structure and catalyst TON, reaction progress was monitored
by 1H NMR (Figure 2). For this analysis, oxidation of
substrate 5 was analyzed using precatalysts cis-[Ru-
(dtbpy)2(CO3)] (1), cis-[Ru(dmbpy)2(CO3)] (2) (dmbpy =
4,4′-dimethyl-2,2′-bipyridine), and cis-[Ru(bpy)2(CO3)] (3).
The efficiencies of these three complexes for C−H
hydroxylation are varied despite modest differences in
structure (see Figure 1).15 All three precatalysts show an
Scheme 1. Synthesis of Dichloro- and η3-Carbonato-Ru(II)
Precatalysts
B
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
that cis-[(bpy)2Ru(CO3)] (3) in aqueous HClO4 cycles
reversibly between five oxidation states, Ru(II) to Ru(VI).17
Related studies characterized [(6,6′-Cl2bpy)2Ru(O)2]2+, a cis-
configured Ru(VI)-dioxo adduct, and demonstrated that this
complex can promote stoichiometric C−H hydroxylation of
simple alkanes.18 Substrate oxidation by a Ru(V)-oxo or -dioxo
intermediate also appears to be possible based on the available
electrochemical data.
Cycling of 1 from 0.4 to 1.5 V at a 10 mV/s scan rate
afforded a fully reversible redox wave (black trace) that reflects
multiple Ru oxidation states and is analogous to data recorded
by Meyer with 3.19 Redox waves at 0.6, 1.2, and 1.35 V (vs
SCE) were thus assigned as Ru(II)/Ru(III), Ru(IV)/Ru(V),
and Ru(V)/Ru(VI) couples, respectively. To determine which
form(s) of 1 might participate in C−H hydroxylation, cyclic
voltammograms were obtained with added substrate (0.5 mM,
Figure 3, red trace).20 In these experiments, a small current
increase was noted at 1.20 V with a second, more substantial
rise in current as the potential was scanned past 1.30 V. The
increase in current at a given potential is indicative of
electrocatalytic oxidation.20 Conversely, the absence of a
change in current below ∼1.18 V implies that Ru oxidation
states of 1 below this applied potential are unreactive with
substrate. This conclusion is supported by a series of constant
potential bulk electrolysis reactions in which no substrate
oxidation was detected at potentials below 1.15 V (Table S3).
Data obtained from CV and bulk electrolysis experiments
with precatalyst 1 in the presence of substrate are consistent
with an electrocatalytic process mediated by a Ru(VI) oxidant.
The structure of this intermediate is presumed to be cis-
[(dtbpy)2Ru(O)2]2+ by inference to prior work.17 The small
increase in current at 1.2 V (red trace, Figure 3) suggests, but
does not conclusively establish, that a Ru(V) species may also
function as a competent oxidant. The closeness of the onset
potentials for Ru(V) and Ru(VI) further obscures this analysis.
Analogous experiments with precatalysts 2−4 led to the same
conclusions, as peak potentials for Ru(IV)/Ru(V) and Ru(V)/
Ru(VI) couples are within error for all four complexes
examined (Figure S1).
Figure 2. Reaction progress kinetic profiles of precatalysts 1, 2, and 3
in the oxidation of 5. Conditions: 5 mol % cis-[(ligand)2Ru(CO3)]
(3.125 mM), 2.0 equiv of H5IO6 (125.0 mM), AcOH/H2O. Product
conversions estimated by H NMR integration of unpurified reaction
mixtures against an internal standard.
1
initial phase of rapid product formation during the first 5 min
of reaction (Figure 2). Complexes 1 and 2 feature a second
phase of product formation before plateauing at 10 and 20
min, respectively. By contrast, the reaction with 3 reaches
completion within ∼4 min. From these data, it appears that
reaction performance is correlated with catalyst lifetime and
not intrinsic differences in catalyst activity. Accordingly,
subsequent experiments were devised to challenge this
conclusion.
Electrochemical Studies of Precatalysts 1−4. Electro-
chemical measurements were conducted with precatalysts 1−4
to compare the redox potentials of the different Ru species and
to determine if more than one Ru oxidant was capable of
hydroxylating substrate. Cyclic vol (CVs) tammograms of each
precatalyst were recorded in aqueous HClO4 and in AcOH/
aqueous HClO4 mixtures in the absence and presence of
substrate (Figures 3, S2 and S3).16 Meyer previously reported
CV recordings show no evident link between catalyst
structure, thermodynamic redox potential, and reaction
performance. In addition, these experiments fail to provide
definitive evidence for Ru(V) as an active oxidant, although the
reactivity of Ru(VI) with substrate is clear.21 Accordingly, with
the goal of understanding performance differences between
precatalysts 1−3 (see Figure 1), experiments using alternative
analytical methods, including NMR and mass spectrometry,
were pursued.
19F NMR Spectroscopy and Mass Spectrometric
Investigations of Catalyst Speciation. 19F NMR spectros-
copy provides a useful analytical method for tracking catalyst
speciation as a function of reaction progress.22 In order to
measure catalyst lifetime and to gain insight into the
distribution of Ru products formed throughout the course of
the hydroxylation reaction, a Ru(II) precatalyst derived from
5,5′-difluoro-4,4′-dimethyl-2,2′-bipyridine (7) was prepared
(Figure 4). Analysis of the spent oxidation reaction of 5 with
precatalyst 7 performed under standard conditions revealed
the primary 19F-signal to be that of free ligand. This result is
consistent with early work of Meyer and gives the first clue that
ligand dissociation may be a primary degradation event
limiting catalyst TONs.17
Figure 3. Cyclic voltammograms of 1 mM cis-[(dtbpy)2Ru(CO3)] 1
in 1:1 AcOH/0.75 M aqueous HClO4; (pH 0.5) in the absence and
presence of substrate. Cyclic voltammetry performed with a 10 mV/s
scan rate using a glassy carbon working electrode, platinum mesh
counter electrode, and SCE reference electrode. The substrate for
these experiments is 2-amino-6-methylheptane; see Supporting
Information for details.
C
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. 19F NMR spectroscopy reveals loss of ligand in the
oxidation of 5 by fluorine-substituted catalyst 7; see Supporting
Information for experimental details.
Subsequent experiments aimed at tracking reaction progress
through 19F NMR spectroscopy were attempted, but were
unable to provide useful information regarding catalyst
speciation. These studies were confounded by the poor
signal-to-noise of the 19F spectra, in part due to the
paramagnetism of some of the Ru intermediates. Reaction
monitoring by real-time mass spectrometry thus became the
method of choice for analyzing catalyst speciation and
decomposition pathways.
Mass spectrometry is ideally suited for studying catalyst
speciation in our C−H oxidation reaction given the unique
isotopic fingerprint of Ru. In practice, in situ monitoring of the
Ru-catalyzed reaction is possible using pressurized sample
infusion mass spectrometry (PSI-MS).23 This method enables
continuous infusion of a sample from a reaction that is
performed in a conventional round-bottom flask setup under
standard conditions. Temporal resolution of ion counts
permits correlation of different analytes with kinetic events
relevant to reaction catalysis.24 Accordingly, we anticipated
that data obtained from PSI-MS could provide key insights
into the reaction mechanism and catalyst degradation path-
ways.
For the PSI-MS study that follows, speciation of precatalyst
1 was examined for reactions with H5IO6 in the absence and
presence of substrate 5 (Figures 5 and S5−S11). The
carbonato form of 1 was selected for this analysis, as the
dichloro derivative produced more complex (due to splitting
from multiple chloride isotopes) and often overlapping signals
in the mass chromatogram, thus complicating analysis.25
Additional Ru-containing ions that are not highlighted in the
following discussion are, in large part, related analytes with
additional MeCN ligands or different counterions or charges
(details can be found in the Supporting Information). Putative
structures of individual ions are inferred using tandem MS/MS
methods and, when possible, by direct comparison of MS data
with authentic samples.
Figure 5. (A) Mass chromatogram from m/z 400 to 900 taken at 0.5
min of a reaction containing 5 mol % 1, 1.0 equiv of 5, and 2.0 equiv
of H5IO6. Inset: Spectrum from m/z 420 to 440. (B) Extracted ion
chromatographs of select Ru species. Each trace is normalized to the
total ion count, and the highest intensity is set to 1.0. Dead time offset
of −0.5 min has been applied.
Initial PSI-MS control experiments were performed in the
absence of substrate with precatalyst 1 (3.125 mM) and H5IO6
(125.0 mM) (Figure S11). Upon addition of H5IO6, two
prominent ions centered at m/z 713.3004 and 845.1694 are
immediately detected. Within 3 min of initiating the reaction,
both of these species are no longer present (Figure S11).26
These signals correspond to a Ru(IV)-oxo and a Ru(VI)-dioxo
species, respectively, with assignments supported by collision-
induced dissociation (CID) MS/MS data (structures appear in
Figure 5B). Prior work by Meyer has indicated that the
Ru(VI)-dioxo form of precatalyst 3, [(bpy)2Ru(O)2]2+, is quite
labile and degrades within seconds following generation.17
Therefore, it is notable that PSI-MS enables detection of the
analogous complex generated from 1.
Performing the equivalent PSI-MS experiments in the
presence of substrate 5 (62.5 mM) shows the same ions at
713.3004 and 845.1694, along with a third prominent ion at
m/z 888.1866 (Figure 5). We have assigned this latter species
as a Ru(V)-oxo complex. All three high-valent intermediates
appear rapidly upon addition of H5IO6; however, with
substrate present, the ion counts corresponding to these
analytes do not deplete until 15−20 min (Figure 5B, black,
teal, green traces). As the cyclic voltammetry and bulk
electrolysis data indicate that Ru species formed at potentials
below ∼1.18 V are unreactive toward substrate (vide supra), we
surmise that the Ru(IV) ion at m/z 713.3004 is a resting state
of the catalyst, not responsible for direct turnover of product.
D
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Among the different Ru analytes formed in reactions with
substrate 5, including the aforementioned high-valent Ru-oxo
and -dioxo ions, two species at m/z 438.2056 and 429.7034 are
particularly telling of the reaction mechanism (Figure 5B).
These intermediates have been assigned as substrate-bound
ruthenium complexes (i.e., Ru-alkoxides). The identification of
[(dtbpy)2Ru(OH)(OR)]2+ at m/z 438.2506 provides strong
evidence for the role of a Ru(VI)-dioxo oxidant as an active
hydroxylating agent under the reaction conditions. Formation
of this product could occur through either a canonical C−H
abstraction/radical rebound mechanism or a concerted [3 + 2]
cycloaddition, both of which have been proposed for cis-dioxo-
Ru C−H hydroxylation reactions.27,28 Similarly, the ion at m/z
429.7034 corresponding to the Ru(III)-alkoxide could
plausibly derive from substrate reacting with a Ru(V)-oxo
species.
Having obtained support from complementary electro-
chemical and MS experiments for the generation of, at
minimum, two active oxidants, we next attempted to determine
the reaction mechanisms and structures of catalyst products
responsible for inhibiting turnover. Among the different
pathways that may result in catalyst degradation or arrest, we
initially considered two: dimerization (pathway 1, Figure 6)
Figure 7. Proposed structures of stable Ru dimers.
mechanisms involving ligand dissociation were subsequently
interrogated.
PSI-MS and HPLC Evaluation of Ligand Dissociation.
In accordance with data from 19F NMR studies (vide supra),
PSI-MS confirms that ligand dissociation occurs for all three
precatalysts examined (Figure S46−S49). Mono- and bis-N-
oxidized ligand products are detected in addition to free ligand.
These data give qualitative evidence for marked differences in
the rate of ligand dissociation between the three precatalysts.
Signals correlating with monobipyridyl-Ru adducts appear at
early reaction time points for precatalysts 2 and 3, but not for 1
(Figures S35, S39).32 Additionally, for complexes 2 and 3,
detection of free ligand and product formation appear to reach
a maximum at the same time point; this is not the case for
precatalyst 1. These findings strongly implicate ligand
dissociation as a deleterious process that limits reaction
turnover. The heightened performance of 1 appears to derive
from the kinetic stability of the oxidized form(s) of the
(dtbpy)2Ru complex with respect to ligand exchange.
In support of the results from our PSI-MS study, we have
quantified by HPLC ligand dissociation as a function of
reaction progress (Figure 8). A standard oxidation reaction was
performed and sampled at different time points to measure free
ligand concentration in addition to mono- and bis-N-oxide
products, which were also detected. Consistent with our MS
data, the total amount of dissociated ligand is lowest (∼20%)
in experiments with precatalyst 1. By comparison, complex 3
Figure 6. Postulated degradation mechanisms of [bis(bipyridyl)-
RuX2] precatalysts under oxidative conditions. R = H, Me, or Bu.
t
and ligand dissociation (pathway 2).29 In the latter case, the
resulting monoligated (bpy)Ru complex is unlikely to support
catalysis.30 Our analysis of these processes capitalized on the
availability of three structurally related precatalysts, 1−3, and
the evident differences in reaction performance between these
complexes (see Figure 1).
PSI-MS Study of Catalyst Dimerization. Catalyst
dimerization (pathway 1, Figure 6) is commonly invoked
with reactive metal-oxo species and was assumed a likely
pathway for catalyst inactivation.31 When precatalyst 1 is
mixed with H5IO6 and substrate 5, PSI-MS reveals an ion at
m/z 779.7384 that corresponds to a dimeric Ru(IV/V) species.
This signal appears within 1 min and then dissipates over the
course of 20 min (see Figures 5, S8). The transient nature of
this ion suggests that this particular species is kinetically labile
under the reaction conditions. Interestingly and in spite of the
excess of H5IO6 used in this process, lower valent dimeric
complexes (e.g., Ru(III/IV), Ru(IV/IV)) are detected within
∼10 min of initiating the reaction (Figure 7); signals ascribed
to these species increase until the reaction no longer proceeds.
The ion count for these two complexes is quite low, and, thus,
we posit that dimer formation is only partly responsible for
catalyst arrest. Dimeric adducts of precatalysts 2 and 3 are not
detected at all when monitored by PSI-MS. Collectively, these
results are rather surprising given the predilection for reactive
metal-oxo species to aggregate.31 In our prior studies with
[Ru(Me3tacn)Cl3], dimerization was identified as the primary
mode of catalyst inactivation.31d As dimer formation is unable
to fully account for differences in catalyst performance,
Figure 8. Quantitative HPLC evaluation of ligand loss versus time for
catalysts 1−3 in the oxidation of substrate 5. Percentage of total
ligand dissociation assumes 1 equiv per catalyst; see Supporting
Information for details.
E
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
rapidly loses a bpy group, reaching a maximum (>70%) within
minutes after the reaction commences. Peak ligand loss is
coincident with cessation of catalyst turnover. Thus, the major
pathway that limits TONs with precatalyst 3 is ascribed to
ligand dissociation (pathway 2, Figure 6). Conversely, the
absence of such a correlation with precatalyst 1 intimates that
more than one pathway leading to catalyst decomposition/
inactivation is operative.
To test if dtbpy N-oxide functions as a catalyst poison,
varying quantities of this material were added to a
hydroxylation reaction of 5 performed under standard
conditions (Table 2). Remarkably, even small amounts of
a
Table 2. Catalyst Poisoning by dtbpy N-Oxide
Identification of a Catalyst Arrest Mechanism. PSI-MS
data for reactions with 1 were further examined to understand
the differential performance of this precatalyst. From this
analysis, a prominent signal at m/z 461.2406 was identified as a
tris(bipyridyl)Ru(II) complex (8) (Figure 9). The structure of
a
Conditions: 5 mol % cis-[(dtbpy)2RuCl2] (3.125 mM), dtbpy N-
oxide, 2.0 equiv of H5IO6 (125 mM), AcOH/H2O, 1 h. Product
1
conversions estimated by H NMR integration of unpurified reaction
mixtures against an internal standard.
the N-oxide (0.1 mol %) reduced product conversion by ∼2-
fold (entry 2). With 5 mol % of this additive, the reaction was
completely shut down (entry 5). Subsequent experiments
showed that the addition of free ligand, dtbpy, was similarly
deleterious to catalyst performance.37 In addition, only trace
alcohol product 6 was obtained when the bpy-derived tris-
complex was tested as a precatalyst (see Supporting
Information for details). Together, these findings provide
compelling evidence that formation of 8 is a principal pathway
for catalyst deactivation in reactions with 1 (Figure 10). The
two other bipyridyl complexes, 2 and 3, are more susceptible
to ligand dissociation, and thus this alternative channel for
catalyst arrest may play a less prevalent role in affecting TONs.
At present, the mechanism of formation of the tris-
(bipyridyl)Ru(II) complex 8 remains outstanding. Our finding
that catalyst turnover is retarded by the addition of small
quantities of free ligand (dtbpy) would seem to favor the
pathway outlined above. It is possible, however, that N-oxide
formation occurs through a unimolecular event in which the
bound bipyridyl ligand is directly oxidized.38
Figure 9. (A) Mass spectrum from m/z 400 to 900 obtained from a
reaction with precatalyst 1 at 23 min. (B) Extracted ion chromato-
graph of tris-bipyridyl Ru complex 8 recorded over the reaction time
course. The trace is normalized to the total ion count, and the highest
intensity is set to 1. A dead time offset of −0.5 min has been applied.
adduct 8 was suggested from MS and MS/MS analysis to
comprise two dtbpy ligands and one dtbpy N-oxide.33
Interestingly, maximum ion counts for 8 coincide with the
time the reaction catalyzed by 1 takes to reach completion
(∼20 min).34,35
CONCLUSIONS
■
Continuing efforts to develop Ru catalysts for chemoselective
C(sp3)−H oxidation have motivated the studies described
herein. As with many redox processes, mechanistic analysis is
challenged by the fleeting lifetime of intermediates, the
presence of more than one chemically competent active
species, and the multifarious pathways for catalyst decom-
position and/or arrest. As an analytical method, the ability to
monitor reaction progress using high mass-accuracy mass
spectrometry is differential. For our purposes, by pairing PSI-
MS with electrochemical and kinetic measurements, we have
gained a comprehensive understanding of the chemistry of
bis(bipyridyl)Ru complexes as oxidation catalysts. These
insights include (1) support for Ru(VI) and Ru(V)-oxo
complexes as active hydroxylating agents; (2) direct evidence
of ligand dissociation; (3) affirmation that the rate of bipyridyl
Detection of the tris-complex 8 is quite surprising in
considering plausible mechanisms through which this adduct
may form. In light of our other observations, one obvious
pathway involves oxidation of the dissociated ligand and
binding of the resulting bipyridyl N-oxide to a Ru center. The
fact that 8 is a Ru(II) complex (as indicated by MS) is,
however, hard to rationalize given the excess amount of H5IO6
that is present under the reaction conditions. In addition, the
low pH of the reaction medium would be expected to
protonate dtbpy and therefore disfavor ligand N-oxidation.36
Accordingly, further experiments were designed to query the
mechanism of formation of 8 and the likelihood that this
adduct is an arrested state of the catalyst.
F
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 10. Proposed mechanisms of degradation of bis(bipyridyl)Ru catalysts under oxidative conditions.
(d) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C−H Bond
Functionalization: Emerging Synthetic Tools for Natural Products
and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960−9009.
(e) Tao, P.; Jia, Y. C−H Bond Activation in the Total Syntheses of
Natural Products. Sci. China: Chem. 2016, 59, 1109−1125.
(f) Domingo, V.; Quilez del Moral, J. F.; Barrero, A. F. Recent
Accomplishments in the Total Synthesis of Natural Products Through
C−H Functionalization Strategies. Stud. Nat. Prod. Chem. 2016, 48,
1−28. (g) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.;
Krska, S. W. The Medicinal Chemist’s Toolbox for Late Stage
Functionalization of Drug-like Molecules. Chem. Soc. Rev. 2016, 45,
546−576. (h) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S. Transition
Metal-Catalyzed Site- and Regio-Divergent C−H Bond Functional-
ization. Chem. Soc. Rev. 2017, 46, 4299−4328. (i) Saint-Denis, T. G.;
Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)−H
Bond Activation by Chiral Transition Metal Catalysts. Science 2018,
359, No. eaao4798. (j) Karimov, R. R.; Hartwig, J. F. Transition-
Metal-Catalyzed Selective Functionalization of C(sp3)−H Bonds in
Natural Products. Angew. Chem., Int. Ed. 2018, 57, 4234−4241.
(2) (a) Chorghade, M. S.; Hill, D. R.; Lee, E. C.; Pariza, R. J.;
Dolphin, D. H.; Hino, F.; Zhang, L.-Y. Metalloporphyrins as Chemical
Mimics of Cytochrome P-450 Systems. Pure Appl. Chem. 1996, 68,
753−756. (b) Sawayama, A. M.; Chen, M. M. Y.; Kulanthaivel, P.;
Kuo, M.-S.; Hemmerle, H.; Arnold, F. H. A Panel of Cytochrome
P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead
Compounds. Chem. - Eur. J. 2009, 15, 11723−11729. (c) Cusack, K.
P.; Koolman, H. F.; Lange, U. E. W.; Peltier, H. M.; Piel, I.;
Vasudevan, A. Emerging Technologies for Metabolite Generation and
Structural Diversification. Bioorg. Med. Chem. Lett. 2013, 23, 5471−
exchange is influenced by 4,4′-substitution; and (4) character-
ization of three different pathways that limit catalyst TONs:
dimerization, ligand loss, and catalyst poisoning by bipyridyl
N-oxide formation. These findings are testament to the
transformative power of PSI-MS for methods research and
development, and have provided an unexpected level of clarity
to the mechanistic complexities of our Ru-catalyzed C−H
hydroxylation reaction.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b10950.
■
S
Experimental details, characterization data, and PSI-MS
analysis (PDF)
AUTHOR INFORMATION
Corresponding Authors
*rnz@stanford.edu
■
*sigman@chem.utah.edu
*waymouth@stanford.edu
*jdubois@stanford.edu
ORCID
James B. C. Mack: 0000-0001-7033-1014
Katherine L. Walker: 0000-0002-7924-8185
Richard N. Zare: 0000-0001-5266-4253
Matthew S. Sigman: 0000-0002-5746-8830
Robert M. Waymouth: 0000-0001-9862-9509
J. Du Bois: 0000-0001-7847-1548
́
5483. (d) Genovino, J.; Sames, D.; Hamann, L. G.; Toure, B. B.
Accessing Drug Metabolites via Transition-Metal Catalyzed C−H
Oxidation: The Liver as Synthetic Inspiration. Angew. Chem., Int. Ed.
2016, 55, 14218−14238. (e) Blakemore, D. C.; Castro, L.; Churcher,
I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic
Synthesis Provides Opportunities to Transform Drug Discovery. Nat.
Chem. 2018, 10, 383−394.
Notes
The authors declare no competing financial interest.
́
(3) (a) Genovino, J.; Lutz, S.; Sames, D.; Toure, B. B.
̈
ACKNOWLEDGMENTS
Complementation of Biotransformations with Chemical C−H
Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in
Complex Pharmaceuticals. J. Am. Chem. Soc. 2013, 135, 12346−
12352. (b) Rasik, C. M.; Brown, M. K. Total Synthesis of
Gracilioether F: Development and Application of Lewis Acid
Promoted Ketene-Alkene [2 + 2] Cycloadditions and Late-Stage
C−H Oxidation. Angew. Chem., Int. Ed. 2014, 53, 14522−14526.
Hung, K.; Condakes, M. L.; Morikawa, T.; Maimone, T. J. Oxidative
Entry into the Illicium Sesquiterpenes: Enantiospecific Synthesis of
(+)-Pseudoanisatin. J. Am. Chem. Soc. 2016, 138, 16616−16619.
(c) Griffiths, R. J.; Burley, G. A.; Talbot, E. P. A. Transition-Metal-
Free Amine Oxidation: A Chemoselective Strategy for the Late-Stage
Formation of Lactams. Org. Lett. 2017, 19, 870−873. (d) Gan, P.;
Pitzen, J.; Qu, P.; Snyder, S. A. Total Synthesis of the Caged Indole
Alkaloid Arboridinine Enabled by Aza-Prins and Metal-Mediated
Cyclizations. J. Am. Chem. Soc. 2018, 140, 919−925.
■
We thank the National Science Foundation under the Center
for Chemical Innovation in Selective C−H Functionalization
(CHE-1700982), the Air Force Office of Scientific Research
Initiative (AFOSR FA9550-16-1-0113), and Novartis Pharma-
ceuticals for financial support of this work. J.B.C.M. and
K.L.W. are grateful to the Center for Molecular Analysis and
Design (CMAD, Stanford University) for research fellowships.
K.L.W. and S.G.R. would like to thank the NSF for graduate
research fellowships.
REFERENCES
■
(1) For recent reviews, see: (a) Godula, K.; Sames, D. C−H Bond
Functionalization in Complex Organic Synthesis. Science 2006, 312,
67−72. (b) Newhouse, T.; Baran, P. S. If C−H Bonds Could Talk:
Selective C−H Bond Oxidation. Angew. Chem., Int. Ed. 2011, 50,
3362−3374. (c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent
Developments in Natural Product Synthesis Using Metal-Catalysed
C−H Bond Functionalisation. Chem. Soc. Rev. 2011, 40, 1885−1898.
(4) For representative examples of C−H oxidation of natural
products and active pharmaceutical ingredients, see: (a) McNeill, E.;
Du Bois, J. Catalytic C−H Oxidation by a Triazamacrocyclic
Ruthenium Complex. Chem. Sci. 2012, 3, 1810−1813. (b) Gormisky,
G
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
P. E.; White, M. C. Catalyst-Controlled Aliphatic C−H Oxidations
with a Predictive Model for Site-Selectivity. J. Am. Chem. Soc. 2013,
135, 14052−14055. (c) Adams, A. M.; Du Bois, J. Organocatalytic
C−H Hydroxylation with Oxone® Enabled by an Aqueous
Fluoroalcohol Solvent System. Chem. Sci. 2014, 5, 656−659.
(d) See, Y. Y.; Herrmann, A. T.; Aihara, Y.; Baran, P. S. Scalable
C−H Oxidation with Copper: Synthesis of Polyoxypregnanes. J. Am.
Chem. Soc. 2015, 137, 13776−13779.
(11) In situ preparation of Ru complexes affords multiple products,
as determined by H NMR.
(12) Sullivan, B. P.; Salmon, D. J.; Meyer, T. J. Mixed Phosphine
2,2’-Bipyridine Complexes of Ruthenium. Inorg. Chem. 1978, 17,
3334−3341.
(13) Ashford, D. L.; Brennaman, M. K.; Brown, R. J.; Keinan, S.;
Concepcion, J. J.; Papanikolas, J. M.; Templeton, J. L.; Meyer, T. J.
Varying the Electronic Structure of Surface-Bound Ruthenium(II)
Polypyridyl Complexes. Inorg. Chem. 2015, 54, 460−469.
(14) A Ru(II) precatalyst derived from 4,4′-bis(dimethylamino)-
2,2′-bipyridine fails to catalyze C−H hydroxylation.
(15) Turnover differential between precatalysts is more pronounced
at lower catalyst loadings.
(16) Cyclic voltammogram recordings were performed exclusively
with Ru-carbonato complexes, as the corresponding dichloro adducts
yielded featureless CVs.
1
́
́
̃
ez, M. E.; Bernardini, C. B.; Mello,
(5) Asensio, G.; Gonzalez-Nun
R.; Adam, W. Regioselective Oxyfunctionalization of Unactivated
Tertiary and Secondary C-H Bonds of Alkylamines by Methyl-
(Trifluoromethyl)Dioxirane in Acid Medium. J. Am. Chem. Soc. 1993,
115, 7250−7253.
(6) (a) Dangel, B. D.; Johnson, J. A.; Sames, D. Selective
Functionalization of Amino Acids in Water: A Synthetic Method
via Catalytic C−H Bond Activation. J. Am. Chem. Soc. 2001, 123,
8149−8150. (b) Malik, H. A.; Taylor, B. L. H.; Kerrigan, J. R.; Grob,
J. E.; Houk, K. N.; Du Bois, J.; Hamann, L. G.; Patterson, A. W. Non-
Directed Allylic C−H Acetoxylation in the Presence of Lewis Basic
Heterocycles. Chem. Sci. 2014, 5, 2352−2361. (c) Lee, M.; Sanford,
M. S. Platinum-Catalyzed, Terminal-Selective C(sp3)−H Oxidation of
Aliphatic Amines. J. Am. Chem. Soc. 2015, 137, 12796−12799.
(d) Howell, J. M.; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White, M.
C. Remote Oxidation of Aliphatic C−H Bonds in Nitrogen-
Containing Molecules. J. Am. Chem. Soc. 2015, 137, 14590−14593.
(e) Adams, A. M.; Du Bois, J.; Malik, H. A. Comparative Study of the
Limitations and Challenges in Atom-Transfer C−H Oxidations. Org.
Lett. 2015, 17, 6066−6069. (f) Mbofana, C. T.; Chong, E.;
Lawniczak, J.; Sanford, M. S. Iron-Catalyzed Oxyfunctionalization of
Aliphatic Amines at Remote Benzylic C−H Sites. Org. Lett. 2016, 18,
4258−4261. (g) Lee, M.; Sanford, M. S. Remote C(sp3)−H
Oxygenation of Protonated Aliphatic Amines with Potassium
Persulfate. Org. Lett. 2017, 19, 572−575. (h) Schultz, D. M.;
(17) Dobson, J. C.; Meyer, T. J. Redox Properties and Ligand Loss
Chemistry in Aqua/Hydroxo/Oxo Complexes Derived from cis- and
trans-[(bpy)2RuII(OH2)2]2+. Inorg. Chem. 1988, 27, 3283−3291.
(18) (a) Che, C.-M.; Leung, W.-H. A cis-Dioxoruthenium(VI)
Complex as Active Oxidant of Chloride and Organic Substrates;
Preparation, Characterization, and Reactivity of cis-[RuVI(6,6′-
Cl2bpy)2O2]2+. J. Chem. Soc., Chem. Commun. 1987, 18, 1376−
1377. (b) Che, C. M.; Leung, W. H.; Li, C. K.; Poon, C. K. Synthesis,
Reactivities and Electrochemistry of Trans-Dioxoruthenium(VI)
Complexes of π-Aromatic Diimines. J. Chem. Soc., Dalton Trans.
1991, 3, 379−384. (c) Che, C.-M.; Cheng, K.-W.; Chan, M. C. W.;
Lau, T.-C.; Mak, C.-K. Stoichiometric and Catalytic Oxidations of
Alkanes and Alcohols Mediated by Highly Oxidizing Ruthenium−
Oxo Complexes Bearing 6,6‘-Dichloro-2,2‘-Bipyridine. J. Org. Chem.
2000, 65, 7996−8000.
(19) Cyclic voltammograms of precatalyst 1 measured in either
aqueous HClO4 or a 1:1 mixture of HClO4/AcOH showed similar
redox behavior; see Figure S2 for comparison.
́
Levesque, F.; DiRocco, D. A.; Reibarkh, M.; Ji, Y.; Joyce, L. A.;
(20) (a) Che, C.-M.; Leung, W.-H.; Poon, C.-K. Oxidation of
Organic Substrates Catalysed by Trans-[RuIII(phen)2(OH)(OH2)]-
[ClO4]2 and Trans-[RuIII(bpy)2(OH)(OH2)][ClO4]2. J. Chem. Soc.,
Chem. Commun. 1987, 3, 173−175. (b) Lau, T. C.; Che, C. M.; Lee,
W. O.; Poon, C. K. Ruthenium Catalysed Oxidation of Alkanes with
Alkylhydroperoxides. J. Chem. Soc., Chem. Commun. 1988, 21, 1406−
1407.
(21) We assume based on earlier work by Meyer (see ref 17) that Ru
oxidants generated under chemical and electrochemical conditions are
equivalent.
Dropinski, J. F.; Sheng, H.; Sherry, B. D.; Davies, I. W. Oxy-
functionalization of the Remote C−H Bonds of Aliphatic Amines by
Decatungstate Photocatalysis. Angew. Chem., Int. Ed. 2017, 56,
15274−15278. (i) Olivo, G.; Farinelli, G.; Barbieri, A.; Lanzalunga,
O.; Di Stefano, S.; Costas, M. Supramolecular Recognition Allows
Remote, Site-Selective C−H Oxidation of Methylenic Sites in Linear
Amines. Angew. Chem., Int. Ed. 2017, 56, 16347−16351. (j) Dantig-
́
nana, V.; Milan, M.; Cusso, O.; Company, A.; Bietti, M.; Costas, M.
Chemoselective Aliphatic C−H Bond Oxidation Enabled by Polarity
Reversal. ACS Cent. Sci. 2017, 3, 1350−1358. (k) Nanjo, T.; De
Lucca, E. C.; White, M. C. Remote, Late-Stage Oxidation of Aliphatic
C−H Bonds in Amide-Containing Molecules. J. Am. Chem. Soc. 2017,
139, 14586−14591. (l) Jana, S.; Ghosh, M.; Ambule, M.; Sen Gupta,
S. Iron Complex Catalyzed Selective C−H Bond Oxidation with
Broad Substrate Scope. Org. Lett. 2017, 19, 746−749. (m) Kawamata,
Y.; Yan, M.; Liu, Z.; Bao, D. H.; Chen, J.; Starr, J. T.; Baran, P. S.
Scalable, Electrochemical Oxidation of Unactivated C−H Bonds. J.
Am. Chem. Soc. 2017, 139, 7448−7451. (n) Cooper, J. C.; Luo, C.;
Kameyama, R.; Van Humbeck, J. F. Combined Iron/Hydroxytriazole
Dual Catalytic System for Site Selective Oxidation Adjacent to
Azaheterocycles. J. Am. Chem. Soc. 2018, 140, 1243−1246.
(7) Mack, J. B. C.; Gipson, J. D.; Du Bois, J.; Sigman, M. S.
Ruthenium-Catalyzed C−H Hydroxylation in Aqueous Acid Enables
Selective Functionalization of Amine Derivatives. J. Am. Chem. Soc.
2017, 139, 9503−9506.
(22) Chiappini, N. D.; Mack, J. B. C.; Du Bois, J. Intermolecular
C(sp3)−H Amination of Complex Molecules. Angew. Chem., Int. Ed.
2018, 57, 4956−4959.
(23) (a) Vikse, K. L.; Ahmadi, Z.; Luo, J.; van der Wal, N.; Daze, K.;
Taylor, N.; McIndoe, J. S. Pressurized sample infusion: An easily
calibrated, low volume pumping system for ESI-MS analysis of
reactions. Int. J. Mass Spectrom. 2012, 323−324, 8−13. (b) Yunker, L.
P. E.; Stoddard, R. L.; McIndoe, J. S. Practical approaches to the ESI-
MS analysis of catalytic reactions. J. Mass Spectrom. 2014, 49, 1−8.
(c) Hesketh, A. V.; Nowicki, S.; Baxter, K.; Stoddard, R. L.; McIndoe,
J. S. Simplified Real-Time Mass Spectrometric Analysis of Reactions.
Organometallics 2015, 34, 3816−3819. (d) Theron, R.; Wu, Y.;
Yunker, L. P. E.; Hesketh, A. V.; Pernik, I.; Weller, A. S.; McIndoe, J.
S. Simultaneous Orthogonal Methods for the Real-Time Analysis of
Catalytic Reactions. ACS Catal. 2016, 6, 6911−6917.
(8) Chan, S. L. F.; Kan, Y. H.; Yip, K. L.; Huang, J. S.; Che, C.-M.
Ruthenium Complexes of 1,4,7-Trimethyl-1,4,7-Triazacyclononane
for Atom and Group Transfer Reactions. Coord. Chem. Rev. 2011,
255, 899−919.
(24) Chromatographs of observed species are normalized by first
dividing the maximum intensity Ru(102) peak in the isotope
distribution by the total ion count at that time point. A second
normalization factor is applied to set the maximum normalized
intensity of each species in the ion chromatograph to “1”.
(25) As noted previously, the carbonato and dichloro complexes
perform identically for all substrates examined.
(26) Analogous trends were observed for precatalysts 2 and 3, with
signals corresponding to high-valent Ru compounds growing in
sharply during the burst phase and decreasing rapidly as the reaction
(9) Lee, S.; Fuchs, P. L. Chemospecific Chromium[VI] Catalyzed
Oxidation of C−H Bonds at −40 °C. J. Am. Chem. Soc. 2002, 124,
13978−13979.
(10) Bipyridine complexes of Mn and Fe fail to catalyze
hydroxylation when reactions are performed in aqueous acetic acid;
see Supporting Information for details.
H
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
ceases. Mass chromatograms and assignments of relevant ions for
reactions with precatalysts 2 and 3 are available in the Supporting
Information.
(36) The dtbpy N-oxide complex 8 forms even if CF3SO2OH is
added to the reaction mixture; see the Supporting Information for
details.
(37) The effect of dtbpy N-oxide as a catalyst poison is less
pronounced for reactions employing the dichloro adduct of 1. An
explanation for this result is not evident at this time.
(38) (a) Tatsumi, K.; Hoffmann, R. Metalloporphyrins with Unusual
Geometries. 2. Slipped and Skewed Bimetallic Structures, Carbene
and Oxo Complexes, and Insertions into Metal-Porphyrin Bonds.
Inorg. Chem. 1981, 20, 3771−3784. (b) Mahy, J. P.; Battioni, P.;
Mansuy, D. Formation of an Iron(III) Porphyrin Complex with a
Nitrene Moiety Inserted into a Fe−N Bond during Alkene
Aziridination by [(Tosylimido)Iodo]Benzene Catalyzed by Iron(III)
Porphyrins. J. Am. Chem. Soc. 1986, 108, 1079−1080.
(27) For publications discussing a [3 + 2] mechanism of
hydroxylation, see: (a) Bakke, J. M.; Lundquist, M.; Pedersen, U.;
Rasmussen, P. B.; Lawesson, S.-O. The RuO4 Oxidation of Cyclic
Saturated Hydrocarbons. Formation of Alcohols. Acta Chem. Scand.
1986, 40b, 430−433. (b) Bakke, J. M.; Brænden, J. E.; Dahlin, B.-M.;
Dahlman, O.; Enzell, C. R.; Pettersson, T. Derivatisation of Saturated
Hydrocarbons. The Mechanism of RuO4 Oxidations. Acta Chem.
Scand. 1991, 45, 418−423. (c) Bakke, J. M.; Bethell, D.; Harrit, N.;
Holm, A.; Spielbuchler, P.; Pedersen, J. B.; Krogsgaard-Larsen, P. The
̈
Mechanism of RuO4-Mediated Oxidations of Saturated Hydro-
carbons. Reactivity, Kinetic Isotope Effect and Activation Parameters.
Acta Chem. Scand. 1992, 46, 644−649. (d) Bakke, J. M.; Frøhaug, A.
E.; Kjekshus, A.; Springborg, J.; Wang, D.-N.; Paulsen, G. B.; Nielsen,
R. I.; Olsen, C. E.; Pedersen, C.; Stidsen, C. E. The Mechanism of
RuO4-Mediated Oxidations of Saturated Hydrocarbons. Solvent
Effects and Substituent Effects. Acta Chem. Scand. 1994, 48, 160−
164. (e) Bakke, J. M.; Frøhaug, A. E. Ruthenium Tetraoxide Mediated
Reactions: The Mechanisms of Oxidations of Hydrocarbons and
Ethers. J. Phys. Org. Chem. 1996, 9, 310−318. (f) Bakke, J. M.;
Frøhaug, A. E. Mechanism of RuO4-Mediated Oxidations of Saturated
Hydrocarbons, Isotope Effects, Solvent Effects and Substituent
Effects. J. Phys. Org. Chem. 1996, 9, 507−513. (g) Drees, M.;
Strassner, T. Ruthenium Tetraoxide Oxidations of Alkanes: DFT
Calculations of Barrier Heights and Kinetic Isotope Effects. J. Org.
Chem. 2006, 71, 1755−1760.
(28) For representative publications discussing stepwise C−H
oxidation by oxo-metal species, see: (a) Groves, J. T.; McClusky, G.
A. Aliphatic Hydroxylation via Oxygen Rebound. Oxygen Transfer
Catalyzed by Iron. J. Am. Chem. Soc. 1976, 98, 859−861. (b) Filatov,
M.; Harris, N.; Shaik, S. On the ‘rebound’ Mechanism of Alkane
Hydroxylation by Cytochrome P450: Electronic Structure of the
Intermediate and the Electron Transfer Character in the Rebound
Step. Angew. Chem., Int. Ed. 1999, 38, 3510−3512.
(29) Ligand oxidation may represent a third pathway by which
turnover is adversely effected. Such a process would yield a modified
ligand that is presumably unable to support a high-valent Ru oxidant.
(30) Experiments with a mono(dtbpy)Ru precatalyst yielded only a
single turnover, providing support to this claim; see Scheme S3 for
details.
(31) (a) Collin, J. P.; Sauvage, J. P. Synthesis and Study of
Mononuclear Ruthenium(II) Complexes of Sterically Hindering
Diimine Chelates. Implications for the Catalytic Oxidation of Water
to Molecular Oxygen. Inorg. Chem. 1986, 25, 135−141. (b) Cozzi, P.
G. Metal-Salen Schiff Base Complexes in Catalysis: Practical Aspects.
Chem. Soc. Rev. 2004, 33, 410−421. (c) Ingram, A. J.; Solis-Ibarra, D.;
Zare, R. N.; Waymouth, R. M. Trinuclear Pd3O2 Intermediate in
Aerobic Oxidation Catalysis. Angew. Chem., Int. Ed. 2014, 53, 5648−
5652. (d) Flender, C.; Adams, A. M.; Roizen, J. L.; McNeill, E.; Du
Bois, J.; Zare, R. N. Speciation and Decomposition Pathways of
Ruthenium Catalysts Used for Selective C−H Hydroxylation. Chem.
Sci. 2014, 5, 3309−3314.
(32) The lifetime of the mono(bpy)Ru complex is fleeting based on
PSI-MS analysis, and thus it is unlikely that this intermediate
functions as a competent oxidant.
(33) A mono-oxidized, tris-bipyridyl Ru complex has been
characterized; see: Ghosh, P. K.; Brunschwig, B. S.; Chou, M.;
Creutz, C.; Sutin, N. Thermal and Light-Induced Reduction of
Ru(bpy)33+ in Aqueous Solution. J. Am. Chem. Soc. 1984, 106, 4772−
4783.
(34) Assignment of this structure is based on MS/MS analysis and
comparison of chromatograms to those obtained from an authentic
sample; see the Supporting Information for details.
(35) Analogous tris-Ru complexes were also detected in reactions
with precatalysts 2 and 3; see the Supporting Information for details.
I
DOI: 10.1021/jacs.8b10950
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX