Activation and Oxidation of Mesitylene C-H Bonds by (Phebox)Iridium(III) Complexes

Article abstract of DOI:10.1021/acs.organomet.5b00200

A pincer iridium(III) complex, (Phebox)Ir(OAc)₂OH₂ (1) (Phebox = 3,5-dimethylphenyl-2,6-bis(oxazolinyl)), selectively cleaves the benzylic C-H bond of mesitylene to form an isolable iridium mesityl complex, (Phebox)Ir(mesityl)(OAc) (3), in >90% yield. The trifluoroacetate analogue, (Phebox)Ir(OCOCF₃)₂OH₂ (2), was synthesized to compare with complex 1 for C-H activation, and (Phebox)Ir(mesityl)(OCOCF₃) (4) was synthesized by ligand exchange of complex 3. Both complexes 1 and 2 catalyze H/D exchange between mesitylene and D₂O at 180 °C, exclusively at the benzylic position; 2 gave a higher turnover number (11 TO) than 1 (6 TO) in 12 h. Using d₄-acetic acid as the source of deuterium, up to 92 turnovers of benzylic H/D exchange of mesitylene were obtained with complex 1. (Phebox)Ir(OCOCF₃)₂OH₂ catalyzed the benzylic C-H oxidation of mesitylene using Ag₂O as a terminal oxidant at 130 C, to form 3,5-dimethylbenzaldehyde and 3,5-dimethylbenzoic acid in 35% ± 4% yield (5.1 ± 0.6 TO). DFT calculations were used to investigate two possible pathways for the catalytic oxidation of mesitylene: (1) C-H activation followed by oxy-functionalization and (2) Ir-oxo formation followed by outer-sphere C-H hydroxylation. Results of calculations of the C-H activation pathway appear to be the more consistent with the experimental observations. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.organomet.5b00200

Article
pubs.acs.org/Organometallics
Activation and Oxidation of Mesitylene C−H Bonds by
(Phebox)Iridium(III) Complexes
Meng Zhou,† Samantha I. Johnson,‡ Yang Gao,† Thomas J. Emge,† Robert J. Nielsen,*,§
William A. Goddard, III,§ and Alan S. Goldman*,†
†Department of Chemistry and Chemical Biology, Rutgers New Brunswick, Busch Campus, 610 Taylor Road, Piscataway, New Jersey
08854, United States
‡Department of Applied Physics and Materials Science and §Department of Chemistry, California Institute of Technology, Pasadena,
California 91125, United States
S
* Supporting Information
ABSTRACT: A pincer iridium(III) complex, (Phebox)Ir-
(OAc)2OH2 (1) (Phebox = 3,5-dimethylphenyl-2,6-bis-
(oxazolinyl)), selectively cleaves the benzylic C−H bond of
mesitylene to form an isolable iridium mesityl complex,
(Phebox)Ir(mesityl)(OAc) (3), in >90% yield. The trifluor-
oacetate analogue, (Phebox)Ir(OCOCF3)2OH2 (2), was
synthesized to compare with complex 1 for C−H activation,
and (Phebox)Ir(mesityl)(OCOCF3) (4) was synthesized by
ligand exchange of complex 3. Both complexes 1 and 2 catalyze
H/D exchange between mesitylene and D2O at 180 °C,
exclusively at the benzylic position; 2 gave a higher turnover
number (11 TO) than 1 (6 TO) in 12 h. Using d4-acetic acid as
the source of deuterium, up to 92 turnovers of benzylic H/D exchange of mesitylene were obtained with complex 1.
(Phebox)Ir(OCOCF3)2OH2 catalyzed the benzylic C−H oxidation of mesitylene using Ag2O as a terminal oxidant at 130 °C, to
form 3,5-dimethylbenzaldehyde and 3,5-dimethylbenzoic acid in 35% 4% yield (5.1 0.6 TO). DFT calculations were used to
investigate two possible pathways for the catalytic oxidation of mesitylene: (1) C−H activation followed by oxy-functionalization
and (2) Ir-oxo formation followed by outer-sphere C−H hydroxylation. Results of calculations of the C−H activation pathway
appear to be the more consistent with the experimental observations.
high-valent metal oxo complex cleaves the C−H bond and
forms a C−O bond. Such reactivity of iron, manganese, and
ruthenium complexes is often considered as proceeding via a
biomimetic pathway.1,41,76,77 Alternatively, in the inner-sphere
pathway,59 a metal−alkyl complex is formed via C−H
activation,78,79 and its oxidation can then lead to C−O bond
formation. This reactivity, known for platinum and palladium
complexes, is typically referred to as C−H activation followed
by oxy-functionalization.6,80
In contrast to the well-established systems based on Fe, Mn,
Ru, Pt, and Pd complexes, selective catalytic C−H oxidation
based on complexes of iridium is an emerging area of
research.57,81,82 In the early 1980s, Maitlis and co-workers
reported83,84 the synthesis of Cp*IrV(Me)4 (Cp* = C5Me5),
which proceeded via an aerobic oxidation. Later, Bergman and
co-workers examined and expanded this chemistry.85 In a
different line of research, Wilkinson and co-workers reported
the synthesis and X-ray structure of a trimesityliridium(V) oxo
complex in 1993.86 Brown and co-workers later found87 that
trimesityliridium(III) can catalyze aerobic oxidation of
INTRODUCTION
■
The development of catalysts for the selective oxidation of C−
H bonds is one of the most challenging1 goals of modern
chemistry, intensely pursued2 for applications ranging from the
synthesis of fine chemicals3,4 to the production of liquid fuel
from methane.5−25 Direct methanol formation from methane
could lead to a more energy-efficient process than the syngas
route currently practiced in industry.7,9,26,27 The direct and
regioselective oxidation of alkyl groups could drastically
improve step economy28 for the synthesis of oxygenates.5,29−38
Metalloenzymes can effect C−H bond oxidations with
extraordinary efficiency; approaches to this problem are
therefore often biomimetic or bioinspired.39−43
Iron,29−31,44−52 manganese,53−55 ruthenium,56,57 plati-
num,15,19 and palladium58−66 complexes are well-developed
for selective catalytic C−H oxidation. In contrast to early work
such as Fenton chemistry,67 these systems do not rely on a free
hydroxyl radical intermediate to cleave the C−H bond.1 The
metal complexes are responsible for the C−H cleavage, which is
considered more likely to afford high selectivity.31,38,53,58,68−75
Mechanistic studies on selective C−H oxidation have offered
support for both outer-sphere and inner-sphere reaction
pathways.59 In the outer-sphere pathway, a terminal or bridging
Received: March 13, 2015
© XXXX American Chemical Society
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Scheme 1. Mesitylene Benzylic C−H Activation by 1 and X-ray Crystal Structure of Product 3
Scheme 2. Apparent Equilibrium Resulting from Addition of Acetic Acid to 3 and C−H Activation of Mesitylene
triphenylphosphine, where trimesityliridium(V) oxo was
generated in situ by dioxygen. In recent years Crabtree and
others37,81,82,88,89 have shown that organometallic
[Cp*IrIII(chelate)X] (X = monodentate anionic ligand)
complexes are precatalysts for stereoretentive alkane oxidation
by NaIO4. In this system, the Cp* ligand may be lost under
catalytic oxidation conditions, to generate a di-μ-oxo iridium
dimer bearing chelate ligands.90 Recently, Ison and co-
workers91,92 reported that [Cp*Ir(NHC)(pyridine)(Me)]+
(NHC = N-heterocyclic carbene) can be aerobically oxidized
in the presence of HCl to generate methanol and [Cp*Ir-
also studied the C−H activation carried out by (Phebox)Ir and
relevant complexes computationally.103
EXPERIMENTAL RESULTS
■
C−H Activation of Mesitylene by (Phebox)Ir-
(OAc)2OH2 and (Phebox)Ir(OCOCF3)2OH2. (Phebox)Ir-
(OAc)2OH2 (1) effected the C−H activation of mesitylene at
130 °C in the presence of K2CO3 to form (Phebox)Ir(mesityl)-
(OAc) (3) in >90% yield (Scheme 1). C−H activation
occurred selectively at the benzylic position, and no significant
(<5%) product from aryl C−H activation could be detected. A
base, K2CO3, was used to drive the reaction to completion. An
intramolecular benzylic C−H activation of a mesityl ligand
moiety in TpMSIr (TpMS = hydrotris(3-mesitylpyrazol-1-yl)-
borate) was reported by Carmona.125
+
(NHC)(pyridine)Cl] .
BACKGROUND
■
Phosphorus-ligated pincer iridium complexes are considered
privileged catalysts for alkane dehydrogenation93 and related
reactions.94 However, such complexes may not be compatible
with the strong oxidants13,19,34,37,58 often used for C−H
oxidation, due to the thermodynamically very favorable
oxidation of phosphorus.87 Nitrogen-ligated pincer iridium
complexes,23,95,96 which are presumably more oxidation-
resistant, have been reported but were rarely explored for
direct C−H oxidation except in one study by Periana, Goddard,
and co-workers.23
Without K2CO3, but under otherwise identical conditions, 3
was formed in 74% yield after 12 h along with 12% unreacted
starting material 1. With a different sample, after a reaction time
of 20 h, complex 3 was obtained in 66% yield along with 13%
unreacted starting material (i.e., there was no difference within
the limits of experimental error), consistent with the reaction
having reached equilibrium within 12 h in the absence of
K2CO3. A reaction time of 1 h in the absence of K2CO3 resulted
in a 31% yield of complex 3.
We report in this article on nitrogen-ligated (Phebox)Ir (III)
(Phebox = 3,5-dimethylphenyl-2,6-bis(oxazolinyl)) complexes
for the catalytic C−H oxidation of mesitylene. C2-Symmetric
“Phebox” ligands have been widely applied by Nishiyama and
others in various metal-catalyzed asymmetric C−C bond-
forming reactions.97,98 Nishiyama and co-workers99 reported
that (Phebox)IrIII(OAc)2OH2 (1) can undergo C−H activation
of benzene or n-octane (via concerted metalation−deprotona-
tion100) to form isolable (Phebox)Ir(Ph)(OAc) or (Phebox)-
Ir(n-octyl)(OAc), respectively. Later, Goldberg and co-workers
discovered101,102 that (Phebox)Ir(OAc)(H), formed by elimi-
nation of 1-octene from (Phebox)Ir(n-octyl)(OAc), can be
aerobically oxidized to form H2O and 1; these reactions suggest
that the (Phebox)Ir system could effect a catalytic aerobic
oxidation of n-octane. Goldberg, Cundari, and co-workers have
To test the proposal that equilibrium had been reached in the
experiments described above, complex 3 (10.6 mM) in
mesitylene was treated with one equivalent of acetic acid
under otherwise identical conditions (130 °C, 12 h). Complex
1 formed in 10% yield (1.1 mM), and 74% of complex 3 (7.8
mM) was recovered. This product distribution is in close
agreement with that obtained from reaction 1 with mesitylene
(complex 1 in 12% yield and complex 3 in 74% yield), in
support of the conclusion that equilibrium had been reached.
We are unable to quantify the amount of water in solution at
equilibrium and, therefore, to obtain a rigorous value for the
equilibrium constant for the reaction in Scheme 2. However,
the DFT-calculated value of ΔG = −12.5 kcal/mol for this
reaction (see Computational section) corresponds to an
equilibrium constant of 6 × 106 M−1 at 130 °C. On the basis
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of the apparent equilibrium concentrations of 3 (7.8 mM), 1
(1.1 mM), and HOAc (10.6−1.1 mM = 9.5 mM) noted above,
this corresponds to an H2O concentration of 18 mM; this value
seems to be a reasonable order of magnitude, in support of the
validity of the DFT calculations.
4) using trifluoroacetic acid and crystallographically charac-
terized. Goldberg and co-workers have applied a similar method
to vary the anionic monodentate ligand of (Phebox)IrH(X) (X
= derivatives of acetate).101
Mesitylene H/D Exchange Catalyzed by (Phebox)Ir-
(OAc)2(OH2) and by (Phebox)Ir(OCOCF3)2(OH2). Catalytic
H/D exchange between mesitylene and deuterated acids was
investigated (Scheme 5). We chose d4-acetic acid as the
deuterium source when using complex 1 and d1-trifluoroacetic
acid when using complex 2. The reactions were conducted in
mesitylene solvent (7.2 M).
Complex 1 has been reported to react with toluene to
undergo activation of the aryl C−H bonds at the meta and para
positions.99 The absence of significant aryl C−H activation
(<5% yield) with mesitylene in favor of benzylic C−H
activation is thus presumably due to steric hindrance of the
aryl C−H bonds.60,104
2
The reaction mixtures were monitored by 13C-decoupled D
A new complex, (Phebox)Ir(OCOCF3)2OH2 (2) (Figure 1),
the trifluoroacetate analogue of 1, was synthesized, but under
NMR spectroscopy after three periods at different temperature
(Table 1). In the first stage we analyzed the reaction mixture
prior to heating (entries 1 and 4 in Table 1). The solution was
then heated for 12 h at 130 °C in the second stage (entries 2
and 5). In the final stage the reaction was heated for an
additional 48 h at 180 °C (entries 3 and 6).
Neither benzylic nor aryl H/D exchange was detectible (<10
mM) after 12 h at 130 °C (entries 1 and 2 in Table 1). Upon
increasing the temperature to 180 °C, benzylic H/D exchange
was catalyzed by 1, giving 92 turnovers after 48 h (entry 3 in
Table 1 and eq 1 in Scheme 5). 1-(Deuteriomethyl)-3,5-
dimethylbenzene (eq 1 in Scheme 5) formed (975 mM), while
no significant (<10 mM) 1,3,5-trimethyl-2-deuteriobenzene
was detected. Control experiments without complex 1 but
under otherwise identical conditions (see Supporting Informa-
tion for details) showed that no significant amount (<10 mM)
of 1-(deuteriomethyl)-3,5-dimethylbenzene or 1,3,5-trimethyl-
2-deuteriobenzene was formed under these conditions.
The catalytic H/D exchange may result from reversible C−H
activation, as depicted in Scheme 6. As illustrated in Scheme 1,
complex 1 can effect C−H activation and acetic acid
elimination; the reverse reaction with d4-acetic acid would
yield 1-(deuteriomethyl)-3,5-dimethylbenzene (Scheme 6).
Notably, exclusive benzylic rather than aryl H/D exchange
was detected by 2D NMR analysis, consistent with the
selectivity observed in stoichiometric C−H activation (Scheme
1).
Figure 1. Complex 2 and its X-ray crystal structure.
identical conditions (in the presence of K2CO3, at 130 °C) it
only effected C−H activation of mesitylene to give 4 in 18%
yield (Scheme 3). At the end of the reaction 47% of unreacted
Scheme 3. C−H Activation of Mesitylene by Complex 2
When complex 2 was used with d1-trifluoroacetic acid as a
source of deuterium, 1.03 M 1,3,5-trimethyl-2-deuteriobenzene
was detected after 12 h at 130 °C. Thus, 97% of the deuterium
from d1-trifluoroacetic acid had been incorporated into
mesitylene (entry 5 in Table 1) at the aryl position. No
significant (<10 mM) 1-(deuteriomethyl)-3,5-dimethylbenzene
was detected. Control experiments without complex 2 but
under otherwise identical conditions revealed that d1-trifluoro-
acetic acid underwent H/D exchange at the aryl position, but
not at the benzylic position (Scheme 7; see Supporting
Information for details of background aryl H/D exchange
carried out with d1-trifluoroacetic acid under various con-
starting material complex 2 was recovered. In the absence of
K2CO3, but under otherwise identical reaction conditions,
complex 2 gave no indication of activation of mesitylene C−H
bonds; 70% of unreacted starting material complex 2 was
recovered, and no significant formation of complex 4 was
detected (<1%).
The low yield to form 4 from 2 by C−H activation of
mesitylene is indicated by DFT calculations to be due to
unfavorable reaction thermodynamics (see Computational
Results and Discussion). Nevertheless complex 4 was
synthesized in >90% yield from 3 by ligand exchange (Scheme
Scheme 4. Synthesis of 4 from 3 Using Trifluoroacetic Acid and X-ray Crystal Structure of 4
C
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2
Scheme 5. H/D Exchange between Mesitylene and Deuterated Acids Catalyzed by Complex 1 or 2, Analyzed by D NMR
Spectroscopy
Table 1. H/D Exchange (Mesitylene with CD3CO2D or CF3CO2D) by 1 and 2
a
b
entry complex
time
15 min
temperature (°C) benzylic H/D exchange turnovers and concentration 1,3,5-trimethyl-2-deuteriobenzene concentration
1
2
3
4
5
6
1
1
1
2
2
2
23
130
180
23
<10 mM
<10 mM
<10 mM
<10 mM
<10 mM
1028 mM
827 mM
additional 12 h
additional 48 h
15 min
<10 mM
92 TO, 975 mM
<10 mM
additional 12 h
additional 48 h
130
180
<10 mM
19 TO, 201 mM
a
Reaction conditions: 10.6 mM (1 equiv) complex 1 or 2, d4-acetic acid 1.06 M (100 equiv) for entries 1 to 3 and d1-trifluoroacetic acid 1.06 M (100
equiv) for entries 4 to 6, mesitylene 7.19 M, 300 μL; in a J-Young NMR tube under 1 atm argon with <0.5 ppm of H2O or O2; see Supporting
b
Information for more details on reaction setup. Turnovers were measured by 2D NMR analysis using CD3CN as internal standard added at the end
of reaction (see Supporting Information for more details); turnovers = concentration of 1-(deuteriomethyl)-3,5-dimethylbenzene or 1,3,5-trimethyl-
2-deuteriobenzene divided by concentration of Ir complex, 10.6 mM; 1-(deuteriomethyl)-3,5-dimethylbenzene and 1,3,5-trimethyl-2-
deuteriobenzene deuterium chemical shift confirmed by spiking with purchased d12-mesitylene.
conversion to 1,3,5-trimethyl-2-deuteriobenzene with no
significant formation (<10 mM) of 1-(deuteriomethyl)-3,5-
dimethylbenzene detected (see Supporting Information).
The background aryl H/D exchange with d1-trifluoroacetic
acid (Scheme 7) complicated the analysis. In catalytic H/D
exchange using complex 2 (entry 6 in Table 1), background
aryl H/D exchange presumably depleted d1-trifluoroacetic acid
at an early stage of the reaction at 180 °C, leaving only a low
concentration of d1-trifluoroacetic for 2-catalyzed benzylic H/D
exchange (Scheme 8).
Scheme 6. Catalytic H/D Exchange Possibly Due to
Reversible C−H Activation by Complex 1
To compare complexes 1 and 2 for catalytic H/D exchange
of mesitylene, we attempted to use deuterated acids in large
excess to avoid depletion of d1-trifluoroacetic acid due to
background aryl H/D exchange. However, we found that a very
high concentration of d1-trifluoroacetic (10.8 M) at 180 °C
resulted in high background benzylic H/D exchange without
catalyst (see Supporting Information for details), precluding the
value of this experiment.
ditions); thus the aryl H/D exchange observed in entry 4 is
attributable to this d1-trifluoroacetic acid background reaction.
Gunnoe and co-workers have recently studied in detail aryl H/
D exchange by acids.105
Upon raising the temperature to 180 °C, after 48 h 1-
(deuteriomethyl)-3,5-dimethylbenzene (201 mM; 19 turnovers
benzylic H/D exchange) was observed, presumably catalyzed
by 2. A control experiment without 2 gave only complete
a
Scheme 7. Control Experiments without Ir Catalyst: Aryl H/D Exchange with d1-Trifluoroacetic Acid
a
See Supporting Information for details of reaction conditions.
D
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Scheme 8. Depletion of d1-Trifluoroacetic Acid at the Early Stage of H/D Exchange Catalyzed by Complex 2, Due to
Background H/D Exchange with d1-Trifluoroacetic Acid (Entry 6, Table 1)
We next investigated D2O as a source of deuterium for
catalytic H/D exchange of mesitylene (Scheme 9). In the
Complex 1 was somewhat less active than 2 for catalyzing H/D
exchange of mesitylene with D2O, giving 6 turnovers of 1-
(deuteriomethyl)-3,5-dimethylbenzene (64 mM). No signifi-
cant (<10 mM) aryl H/D exchange was detected when using
D2O as the deuterium source.
Scheme 9. Catalytic H/D Exchange Using D2O as Source of
2
Deuterium, Analyzed by D NMR Spectroscopy
The activity of H/D exchange of complex 2 significantly
increased under basic conditions (entry 5 in Table 2), giving 41
turnovers in the presence of 4 equiv of K2CO3 under otherwise
identical conditions (12 h).
The higher catalytic activity of complex 2 vs 1 for H/D
exchange of mesitylene was consistent with results of DFT
calculations (see Computational section). TS1-OCOCF3, the
transition state for C−H activation by complex 2, was
calculated to be 4.5 kcal/mol lower in energy than TS1-OAc,
the transition state for C−H activation by complex 1.
Oxidation of Mesitylene Catalyzed by (Phebox)Ir-
(OAc)2(OH2) and (Phebox)Ir(OCOCF3)2(OH2) Using Ag2O
as Terminal Oxidant. We find that the (Phebox)Ir complexes
catalyze the oxidation of mesitylene using Ag2O as the terminal
oxidant (Scheme 10).106 With complex 2, 20 equiv of Ag2O,
absence of Ir, no significant (<10 mM) background H/D
exchange with D2O was detected at either the benzylic or aryl
position (entry 1 in Table 2), even at 180 °C. With complex 2,
no significant (<10 mM) H/D exchange was observed after 12
h at 130 °C (entry 2 in Table 2). However, after 12 h at 180
°C, 11 turnovers of exclusively benzylic H/D exchange were
obtained (115 mM) (eq 2 in Scheme 9 and entry 3 in Table 2).
Scheme 10. Oxidation of Mesitylene Catalyzed by Complex
1 or 2 Using Ag2O as Terminal Oxidant
Table 2. Comparing Complexes 1 and 2 for Catalytic
Mesitylene H/D Exchange with D2O
b
benzylic H/D
1,3,5-trimethyl-2-
deuteriobenzene
concentration
and mesitylene as solvent in excess, 3,5-dimethylbenzaldehyde
(DBAL) and 3,5-dimethylbenzoic acid (DBAC) were produced
(2.9 turnovers total; entry 1 in Table 3). Silver mirror deposited
on the glass wall of the reaction vessel, consistent with
reduction of Ag2O to Ag(0). The result was reproducible (entry
2).
temperature
exchange turnovers
and concentration
a
entry complex
(°C)
1
2
3
4
5
none
180
130
180
180
180
<10 mM
<10 mM
<10 mM
<10 mM
<10 mM
<10 mM
2
2
1
2
<10 mM
11 TO, 115 mM
6 TO, 64 mM
41 TO, 435 mM
Formation of both DBAL and DBAC was determined by 1H
NMR analysis and confirmed by spiking the reaction mixtures
with authentic samples. Each equivalent of DBAL formed
should consume 2 equiv of Ag2O, and each equivalent of
DBAC formed should consume 3 equiv of Ag2O. The reaction
yield, based on Ag2O, the limiting reagent, was therefore 42%
(see footnote e in Table 3 for method of calculation).
At the end of the 2-catalyzed oxidation reaction, we
recovered complex 2 in 21% yield in the case of entry 1
(18% recovery yield in the repeated run in entry 2). Thus, the
complex appears to be at least stable enough to resist total
decomposition under harsh oxidation conditions. We could not
identify any other (Phebox)Ir complex, if present.
c
a
Reaction conditions: 10.6 mM (1 equiv) complex 1 or 2, D2O (3.68
M, 20 μL, 1.11 mmol), mesitylene (7.19 M, 300 μL); in a J-Young
NMR tube under 120 psi argon; see Supporting Information for more
b
2
details on reaction setup. Turnovers measured by D NMR analysis
using C6D6 as internal standard added at the end of reaction (see
Supporting Information for more details); turnovers = concentration
of 1-(deuteriomethyl)-3,5-dimethylbenzene or 1,3,5-trimethyl-2-deu-
teriobenzene divided by concentration of Ir complex, 10.6 mM; 1-
(deuteriomethyl)-3,5-dimethylbenzene and 1,3,5-trimethyl-2-deuterio-
benzene deuterium chemical shift confirmed by spiking with
c
purchased d12-mesitylene. K2CO3 (42.4 mM, 13 μmol) was added
to the reaction mixture.
E
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Table 3. Catalytic Oxidation of Mesitylene by Ag2O (130 °C, 12 h)
b
d
e
Ag2O “concentration” and
DBAL concentration and
DBAC concentration and
total
yield (based on
Ag2O)
a
c
c
entry
complex
equiv
turnovers
turnovers
turnovers
fi
1 ,
2
2
2
2
1
2
5
212 mM, 20 equiv
212 mM, 20 equiv
424 mM 40 equiv
424 mM 40 equiv
424 mM, 40 equiv
424 mM 40 equiv
424 mM 40 equiv
424 mM 40 equiv
212 mM, 20 equiv
424 mM 40 equiv
3.2 mM, 0.3 TO
5.3 mM, 0.5 TO
13 4 mM, 1.2 0.4 TO
0.7 TO
28 mM, 2.6 TO
25 mM, 2.4 TO
41 3 mM, 3.9 0.3 TO
3.6 TO
2.9
42%
41%
35% 4%
31%
7%
gi
,
2
2.9
ij
3 ,
5.1 0.6
4.4
4
i
5
7.4 mM, 0.7 TO
6.4 mM 0.6 TO
0.4 mM 0.04 TO
3.2 mM 0.3 TO
none
4.2 mM, 0.4 TO
44 mM 4.1 TO
none
1.1
k
6
4.7
34%
0.2%
2%
i
7
l
0.04
0.3
8
[Cp*IrCl2]2
none
none
h
9
none
none
none
0%
10
none
none
none
0%
a
Reaction conditions: 10.6 mM (1 equiv) complex 1 or 2, Ag2O: 99% purity unless noted otherwise, mesitylene: 7.19 M, 300 μL, in a J-Young NMR
b
tube under 1 atm argon with <0.5 ppm of H2O or O2, at 130 °C and for 12 h. Ag2O did not dissolve in solution, and the “concentration” (mol per
c
liter) is given only for the purpose of calculation; Turnovers were measured by 1H NMR analysis using CH3CN as an internal standard added at the
d
e
end of reaction (see Supporting Information for more details). Total turnovers = turnovers based on DBAL + turnovers based on DBAC. Yield
was based on Ag2O, the limiting reagent; yield = (2[DBAL] + 3[DABC])/[Ag2O]. 21% (2.2 mM) of complex 2 recovered. 18% (1.9 mM) of
f
g
h
i
j
complex 2 recovered. The same reaction was performed twice and gave identical results. Ag2O in 99.99% purity. Average results of three runs.
k
l
Water (10 μL, 1.9 M, 0.56 mmol) was added. 5.3 mM of the dimer was used.
Figure 2. Calculated free energies (kcal/mol) for the (1) C−H activation pathway and (2) Ir-oxo pathway in catalytic mesitylene oxidation using
complex 1a or 2a; X = OAc or OCOCF3; “Phebox” ligand is not shown but is implied, except in complexes 1a, 2a, 3a, and 4a; no calculations
performed for 6-OAc and 6-OCOCF3.
Using 40 equiv of Ag2O and complex 2, 5.1 0.6 turnovers
were obtained for the formation of DBAL and DBAC in total,
corresponding to 35% 4% yield based on Ag2O (99.99% pure
Ag2O, entry 3; see Supporting Information for a commercial
source of this Ag2O sample). Three identical reactions were
carried out to obtain the average yield and turnover number.
We tested the same reaction, but using a different sample of
Ag2O (99% pure; see Supporting Information for a commercial
source of this Ag2O sample). No significant changes caused by
a different Ag2O sample were observed (entry 4). Without Ir,
but under conditions otherwise identical to the reaction in
entry 3, no oxidation of mesitylene occurred (entries 9 and 10).
The reaction in entry 9 was performed twice to ensure
reproducibility.
no significant (0.2% yield) amount of product from oxidation
of mesitylene was obtained (entry 7). A 41% recovery yield of
complex 5 was obtained at the end of reaction.
Goldberg and co-workers reported that addition of water
promoted octane C−H activation.102 We therefore tested water
as an additive in 1.9 M for oxidation of mesitylene catalyzed by
complex 2 (entry 6). No effect on turnover or yield of oxidation
product was observed. Thus, the result at least suggested that
the reaction catalyzed by complex 2 can significantly tolerate
the presence of water.
Crabtree and Voutchkova reported107 that oxidation of
mesitylene can be catalyzed by [Cp*IrCl2]2, possibly as a
precursor to heterogeneous material. Under our conditions
[Cp*IrCl2]2 was a poor catalyst (2% yield; entry 8).
Overall, our results indicate that the new complex, 2, was
significantly more active for the oxidation of mesitylene using
Ag2O as terminal oxidant than any other Ir complex tested.
In contrast to complex 2, using complex 1 and under
otherwise identical conditions, only close to one turnover was
obtained for product formation (entry 5). Using (Phebox)-
IrCl2(OH2) (5), which could not carry out C−H activation,99
F
DOI: 10.1021/acs.organomet.5b00200
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Article
Scheme 11. Oxidation of (Phebox)Ir Mesityl Complexes 3 and 4 by One Equivalent of Ag2O
Oxidation of (Phebox)Ir Complexes 1, 2, 3, and 4 by
One Equivalent of Ag2O. We considered the question of
whether the catalytic oxidation of mesitylene proceeded via C−
H activation followed by oxy-functionalization59,79 or via Ir-oxo
formation followed by C−H hydroxylation.52,59 DFT calcu-
lations suggested that both pathways (Figure 2) could be
energetically accessible.
For the C−H activation followed by oxy-functionalization
(pathway 1 in Figure 2), we had demonstrated that complexes
1 and 2 were capable of C−H activation of mesitylene
(Schemes 1 and 8). We next investigated the oxy-functionaliza-
tion of (Phebox)Ir mesityl complexes 3 and 4.
complex 4 in the presence of one equivalent of NaOCOCF3
gave DBAC in 106% yield and DBAL in 62% yield (entry 5 in
Table 4). No significant amount of complex 4 (<1%) was
recovered at the end of the reaction. The 168% combined yield
of DBAC and DBAL suggested that complex 4 effected catalytic
turnover. Use of 20 equiv of Ag2O with complex 3 in the
presence of one equivalent of NaOAc gave DBAC in 44% yield
and DBAL in 7% yield (entry 6 in Table 4).
The above results indicated that complex 4 was capable of
oxy-functionalization only in the presence of an additional
1
trifluoroacetate ligand. Several new H NMR peaks appeared
that could potentially be assigned to Ir complexes associated
with oxy-functionalization. However, we were unable to isolate
and characterize these new species.
To test the pathway of Ir-oxo formation followed by C−H
hydroxylation (pathway 2 in Figure 2), we attempted to
synthesize (Phebox)Ir oxo complexes that were suggested by
DFT calculations as shown in 5-OAc and 5-OCOCF3 of Figure
2. Complexes 1 and 2 were treated with one equivalent of Ag2O
in both mesitylene and C6F6 solvent.
(Phebox)Ir mesityl complexes 3 and 4 were treated with one
equivalent of Ag2O at 130 °C for 12 h (Scheme 11 and Table
4). Complex 3 was resistant to oxidation, and more than 90% of
Table 4. Oxidation of (Phebox)Ir Mesityl Complexes 3 and 4
by One Equivalent of Ag2O
DBAL
b
DBAC
b
recovered Ir
a
entry complex
additive
none
yield
yield
mesityl complex
Under oxidation conditions similar to those in the oxy-
functionalization of complexes 3 and 4, 12 h at 130 °C (see
Supporting Information for details), reaction of complexes 1
and 2 with Ag2O in C6F6 solvent gave mostly (80%) recovered
1 and 2. Formation of complex 3 in 65% yield was observed in
the reaction of complex 1 in mesitylene solvent (see Supporting
1
2
3
4
5
6
3
3
4
4
4
3
none
none
none
1%
none
<1%
none
4%
quantitative
>90%
49%
NaOAc
none
NaOCOCF3
NaOCOCF3
NaOAc
31%
c
c
62%
7%
106%
44%
<1%
<10%
1
Information for details). New H NMR peaks appeared, which
a
Reaction conditions: 21.2 mM, 6.4 μmol (1 equiv) of complex 1 or 2,
could potentially be assigned to new Ir complexes, but we were
unable to isolate or characterize these species.
Ag2O 99.99% purity in one equivalent (21.2 mM) unless stated
otherwise, mesitylene (7.19 M, 300 μL), NaOAc or NaOCOCF3 (21.2
mM, 6.4 μmol); in a J-Young NMR tube under 1 atm argon with <0.5
ppm of H2O or O2; at 130 °C and for 12 h; Ag2O did not dissolve in
solution, and its concentration was used only for the purpose of
COMPUTATIONAL RESULTS AND DISCUSSION
■
Methods. All optimizations and frequency and solvation
calculations were completed using B3LYP108,109 with the Los Alamos
small-core potential110 and the 2-ζ basis set on iridium and the 6-
31G** basis set on organics.111,112 Single-point, large basis set
calculations were completed with M06113 with LACV3P**++
augmented with f-functions and diffuse functions on iridium.114
Organic molecules were treated with 6-311G**++.115,116 Solvation in
mesitylene was applied using the Poisson−Boltzmann polarizable
continuum model, with a dielectric constant of 2.284 and solvent
radius of 2.60 Å. Free energies of acetic acid, HOCOCF3, and
mesitylene were obtained by calculating the 1 atm free energy and
subtracting the empirical free energy of vaporization (2.4 for 1 M acid
in mesitylene and 3.4117 kcal/mol for liquid mesitylene). The molar
value for acid was extrapolated from VLE data for dilute acetic acid in
benzene.118 Analytical frequency calculations were used to validate all
transition states.
b
calculations. Yield = concentration of DBAL or DBAC divided by
concentration of Ir complex, 10.6 mM; DBAL and DBAC
1
concentrations were measured by H NMR analysis using CH3CN
as an internal standard added at the end of the reaction (see
c
Supporting Information for more details). 20 equiv of Ag2O used.
complex 3 was recovered at the end of the reaction (entries 1
and 2 in Table 4). No significant (<1% yield) product of oxy-
functionalization, DBAL or DBAC, was detected with or
without one equivalent of NaOAc. The additional equivalent of
NaOAc added (entry 2) was intended to match the conditions
in catalytic oxidation of mesitylene using complex 1 (entry 5 in
Table 3), which contained two acetate ligands.
With complex 4 no significant product (<1% yield) from
oxy-functionalization was detected in the absence of
NaOCOCF3 (entry 3 in Table 4). Only 49% of complex 4
was recovered at the end of the reaction. However, in the
presence of one equivalent of NaOCOCF3, DBAC in 3% yield
and DBAL in 1% yield were generated from oxidation of
complex 4 (entry 4 in Table 4). At the end of the reaction 31%
of complex 4 was recovered. Use of 20 equiv of Ag2O with
Free energies were calculated with the following equation:
G = EM06 + Gsolv + EZPE + Hvib + HTR − T(Svib + Selec
)
where Gsolv is the solvation energy, EZPE is the zero point energy, HTR
(12/2 kBT) is the translational and rotational enthalpy, and Svib and Selec
are the vibrational and electronic enthalpic terms, respectively. In
order to calculate reaction energies involving Ag2O, DFT calculations
were performed using O2 (1 atm) as oxidant, then corrected using the
G
DOI: 10.1021/acs.organomet.5b00200
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Article
difference between the standard potentials for the reduction of O2 to
water (1.23 V vs NHE) and Ag2O(s) to Ag(s) and water (1.17 V vs
NHE);119 1.4 kcal/mol per electron was added to the values obtained
using O2 as the oxidant. All calculations were completed in Jaguar.120
These methods have been previously applied in other organometallic
systems, leading to good agreement with experiment.121,122 In these
calculations, p-CH3 complexes were substituted for the m-bis-CH3
complexes used in experiment. Justification can be seen in the
Supporting Information.
Two proposed pathways for mesitylene C−H bond activation by
complexes 1a and 2a are shown in Figure 2. The experimentally
prepared aquo complexes were taken as the ground states for all
calculations. Two different ground states were calculated for the two
coordinating ligands. In complex 1a, the ground state for the acetate
complex, the coordinated aqua ligand prefers to occupy the equatorial
position, whereas in complex 2a, the ground state for the
trifluoroacetate complex, the aqua ligand prefers the axial position.
In pathway (1), C−H activation of mesitylene proceeds via TS1 with
binding of the benzylic carbon to iridium occurring concertedly with
hydrogen transfer to the oxygen of the anionic ligand (a concerted
metalation-deprotonation mechanism13,100).
hydroxide complex, shown in 6. The formation of 5-OAc is uphill
from 1a by 12.4 kcal/mol, while the formation of 5-OCOCF3 is only
uphill from 2a by 4.9 kcal/mol.
The transition state for the hydrogen abstraction by the oxo group
is shown by TS2. At 38.1 kcal/mol, the calculated barrier for hydrogen
abstraction by Ir-oxo complex 5-OAc, via transition state TS2-OAc, is
lower than TS2-OCOCF3 (46.7 kcal/mol), by 8.6 kcal/mol. Given
that the trifluoroacetate complex 2 is the more effective catalyst for
oxidation, and given that a calculated comparison of two such closely
analogous transition states should be quite reliable, this argues strongly
against the oxo pathway (at least for catalysis by complex 2). In
marked contrast, for the C−H activation pathway, TS1-OCOCF3 is
significantly lower than TS1-OAc, in accord with the observation that
trifluoroacetate complex 2 catalyzes both oxidation and H/D exchange
faster than complex 1.
Thus, the calculations predict that the trifluoroacetate ligand favors
the kinetics of C−H activation (in accord with the faster H/D
exchange) as compared with the acetate ligand, while it disfavors the
oxo pathway. This may suggest that trifluoroacetate in this type of
system is more promising than acetate for C−H functionalization,
since the oxo pathway (if operative) is less likely to afford the
intriguing selectivity that is offered by transition-metal-catalyzed C−H
activation.
In C−H activation by complex 1a, the transition state TS1-OAc has
an activation barrier of 42.6 kcal/mol. The trifluoroacetate analogue,
TS1-OCOCF3 (Figure 3), is lower in free energy, 38.1 kcal/mol.
CONCLUSION
■
We report that (Phebox)Ir complex 2 catalyzes oxidation of
mesitylene using Ag2O as terminal oxidant. C−H activation by
2 and 1 are both observed in nonoxidative stoichiometric
conditions, although the trifluoroacetate Ir mesityl complex 4
could be synthesized in high yield only by the ligand exchange
reaction of 3. The observation of H/D exchange catalyzed by 1
and 2 further illustrates the ability of these complexes to effect
C−H activation. The isolated mesityl complexes serve as
catalysts or catalyst precursors for oxidation reaction and thus
seem to be competent as potential intermediates in the catalytic
cycle. An alternative oxidation pathway, involving formation of
an Ir oxo complex followed by C−H hydroxylation, was
investigated using DFT. The DFT calculations suggest,
however, that the Ir oxo pathway would be significantly more
favorable for TS2-OAc than for TS2-OCOCF3, which is in
disagreement with the more rapid oxidation by trifluoroacetate
complex 2.
Figure 3. (a) Calculated structures of TS1-OCOCF3 and TS1-
OCOCH3 (peripheral atoms omitted for clarity). (b) Selected
interatomic distances indicated (Å).
EXPERIMENTAL SECTION
■
Supporting Information includes experimental procedures for
syntheses and characterizations of complexes 1, 2, 3, and 4. It also
includes experimental details of C−H activation, H/D exchange, and
oxidation reactions. Supporting Information includes details of DFT
calculations and data analysis for X-ray structure determinations of
new complexes 2, 3, and 4.
Proceeding along the reaction coordinate from TS1, the acetic acid or
trifluoroacetic acid (HX) molecule is eliminated to give complex 3a or
4a. Notably, although TS1-OAc has a higher energy than TS1-
OCOCF3, formation of the reaction product, 3a (from TS1-OAc), is
significantly less endergonic than formation of complex 4a (from TS1-
OCOCF3) (by 4.9 kcal/mol). Thus, the calculations are consistent
with both the faster kinetics of H/D exchange catalyzed by 2 vs 1 and
the observations indicating that C−H activation by 2 to give the
mesityl complex 4 is thermodynamically less favorable than the
reaction of 1 to give 3. It should be noted however that the calculated
differences in both the reaction kinetics and thermodynamics are much
greater than is indicated by the experimental results.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00200.
Once formed, complexes 3a and 4a may undergo a variety of
possible routes discussed in the literature to form a C−O bond;7,23 the
complexity of such reactions, particularly with Ag2O as oxidant, is
beyond the scope of this work. An alternative oxidation pathway
begins with the direct oxidation to give Ir-oxo complexes 5. Iron,
manganese, and ruthenium oxo complexes typically can undergo a fast
hydrogen abstraction reaction with alkanes, often leading to
overoxidation.123,124 This reaction yields a carboradical and IrIV
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: smith@wag.caltech.edu (R. J. Nielsen).
*E-mail: alan.goldman@rutgers.edu (A. S. Goldman).
Notes
The authors declare no competing financial interest.
H
DOI: 10.1021/acs.organomet.5b00200
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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ACKNOWLEDGMENTS
■
We thank Chevron Corporation and NSF, through the CCI
Center for Enabling New Technologies through Catalysis
(CENTC), CHE-1205189, for funding. We thank Oleg
Mironov and Robert J. Saxton for helpful discussions. S.I.J. is
supported by the National Science Foundation Graduate
Research Fellowship under Grant No. DGE-1144469.
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DOI: 10.1021/acs.organomet.5b00200
Organometallics XXXX, XXX, XXX−XXX