Non-directed, carbonate-mediated C-H activation and aerobic C-H oxygenation with Cp?Ir catalysts

Article abstract of DOI:10.1039/c6dt00234j

The effect of oxidatively stable L- and X-type additives on the activity of Cp?Ir catalyst precursors in the C-H activation of arenes has been studied. Turnover numbers for C-H activation of up to 65 can thus be achieved, as determined by H/D exchange in MeOH-D₄. In particular, carbonate additives are found to enhance the C-H activation reactivity of Cp?Ir(H₂O)₃(OTf)₂ (1) more significantly than L-type ligands investigated in this study. Based on these studies, Cp?Ir/carbonate systems are developed that catalyze the aerobic C_sp³-H oxygenation of alkyl arenes, employing air as oxidant.

Full text of DOI:10.1039/c6dt00234j

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DOI: 10.1039/C6DT00234J
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Non-Directed, Carbonate-Mediated C-H Activation and Aerobic
C-H Oxygenation with Cp*Ir Catalysts
M. E. Kerr,a,b I. Ahmed,a A. Gunay,a N. J. Venditto,a F. Zhu,a E. I. Ison,c and M. H. Emmert*a
Received 00th January 20xx,
Accepted 00th January 20xx
The effect of oxidatively stable L- and X-type additives on the activity of Cp*Ir catalyst precursors in the C-H activation of
arenes has been studied. Turnover numbers for C-H activation of up to 65 can thus be achieved, as determined by H/D
exchange in MeOH-D4. In particular, carbonate additives are found to enhance the C-H activation reactivity of
Cp*Ir(H2O)3(OTf)2 (1) more significantly than L-type ligands investigated in this study. Based on these studies, Cp*Ir
/carbonate systems are developed that catalyze the aerobic Csp3-H oxygenation of alkyl arenes, employing air as oxidant.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Cp*Ir complexes have been widely used as catalyst precursors ammonium nitrate (CAN) whose presence has been shown to
in oxidative chemistry during the last 20 years. Some examples result in degradation of the Cp* ligand24 makes it unlikely that
are water oxidation,1 H2 activation,2 dehydrogenation,3 the catalyst structure remains unchanged under these reaction
transfer (de)hydrogenation,3,4 and aerobic alcohol oxidation.5-8 conditions.22,§ The second example oxidizes alkyl arenes
Furthermore, Cp*Ir complexes have been widely explored as selectively to the highest oxidized product, i.e. methyl arenes
catalysts for C-H activation and catalysts with a [Cp*Ir(PMe3)] are transformed into benzoic acids and methylene groups in
core are among the most active catalysts known in benzylic positions are transformed into the corresponding
stoichiometric and catalytic scenarios.9-12 However, translating ketones.23
this remarkable activity in C-H bond cleavage into reactivity for In summary, the search for Cp*Ir based C-H functionalization
C-H bond functionalization has proven to be challenging, likely catalysts has mainly focused on varying L-type ligands. The
due to the oxidative sensitivity of the activating ligand PMe3.
new approach described in this manuscript evaluates the
Thus, subsequent efforts have focused on synthesizing influence of oxidatively stable L- and X-type additives on the
catalysts bearing similarly electron-donating, but oxidatively C-H activation performance of Cp*Ir catalyst precursors. The
stable ligands. Several such examples have incorporated results of these investigations suggest that X-type additives –
carbene and pyridine ligands and several such catalyst carbonates in particular – can render the Cp*Ir center highly
structures enable C-H activation as demonstrated by H/D activated towards C-H bond cleavage. Subsequently,
exchange reactivity.13-15 Interestingly, employing CO as ligand combining this catalyst system with suitable carboxylic acids
to replace PMe3 results in a tendency to form bimetallic and air as oxidant establishes active catalysts for Csp3-H
complexes, which are unreactive towards C-H bond cleavage.16 oxygenations of alkyl arenes with selectivity for C-O bond
Furthermore, several Cp*Ir complexes have been used as formation in the benzylic position.
catalyst precursors for directed C-H functionalization, in which
the directing group on the substrate likely acts as L-type ligand
on the Ir center of the catalyst.17-21 However, only two
examples of non-directed (non-chelate assisted) C-H
functionalizations with Cp*Ir catalysts have been reported.22,23
In the first example, the use of the very strong oxidant ceric
Results and discussion
H/D Exchange of Cp*Ir complexes
Our interest initially focused on establishing the effects of
L-type and X-type additives, which had not been studied in
detail in the literature, on C-H activation reactivity with Cp*Ir
catalyst precursors. To this end, H/D exchange reactions were
performed in MeOH-D4 at 150 °C, generating data comparable
to activity data already published.13,14 In our hands, the
a.Department of Chemistry & Biochemistry, Worcester Polytechnic Institute, 100
Institute Road, Worcester, MA 01609, United States.
b.Chemistry Department, Worcester State University, 486 Chandler Street,
Worcester, MA 01602, United States.
c. Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive,
Raleigh, NC 27695-8204, United States.
catalyst precursor Cp*Ir(H2O)3(OTf)2
(1) showed 11  1
turnover numbers (TON) at a catalyst loading of 2 mol % (Table
1, entry 1);‡ [Cp*IrCl2]2, a common catalyst precursor for
Electronic Supplementary Information (ESI) available: Experimental procedures,
tabulated results of catalytic experiments including standard deviations. See
DOI: 10.1039/x0xx00000x
oxidative chemistry6,7,21 showed lower activity (3
 1 TON).
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Interestingly, the simple addition of 4 mol % AgOTf, AgBF4, or up to 20, while electron-poor pyridines (e.g.
Journal Name
9
) did not improve
View Article Online
DOI: 10.1039/C6DT00234J
AgPF6 to [Cp*IrCl2]2 did not result in high activity (1 to 5 TON). C-H activation activity as compared to the reaction in the
This suggests that – unlike in H/D exchange experiments with absence of ligands. Overall, even though the activities
Pt and Pd catalysts25,26 – the presence of AgCl is detrimental to obtained in these studies are not rivalling the reactivities
C-H activation reactivity. Due to these results,
catalyst precursor in all further studies.
1
was used as obtained with analogous Cp*Ir(PMe3) complexes,10 they
suggest that the identity of the L-type ligand is indeed
important for promoting C-H activation in these catalyst
structures.
Table 1. Results of H/D exchange with L- and X-type additives. Conditions:
Cp*Ir(H2O)3(OTf)2 (6.5 mg, 9.5 μmol, 2.0 mol %), additive (2.0 to 16 mol %), benzene (42
μL, 37 mg, 0.475 mmol, 1.00 equiv), MeOH-D4 (0.48 mL, 0.43 g, 12 mmol, 25 equiv),
150 °C, 24 h.
X-type Additives. In a next step, we evaluated how X-type
additives would affect the C-H activation reactivity of
Cp*Ir(H2O)3(OTf)2 (1), as prior work with complexes of the
formular Cp*Ir(carbene)X2 (X = SO4, NO3, O2CCF3, Cl, OTf) has
shown such effects to be associated with the identity of the
ligands X.13 Interestingly, the presence of carbonate salts such
as Na2CO3 or Cs2CO3 (Table 1, entries 14 and 15) resulted in
significantly higher catalytic activity (32 and 33 TONs,
respectively) than observed with any of the L-type ligands
evaluated previously. Higher loadings of Li2CO3, Na2CO3, or
Cs2CO3 enhanced this effect even further (entries 19 to 23),
leading to up to 65 TON in H/D exchange. These TONs are
comparable to TONs achieved previously with Cp*Ir(carbene)
complexes in MeOH-D4, which are the only known Cp*Ir
complexes with oxidatively stable ligands that also show high
reactivity in for non-directed C-H activation.13,14,15 In contrast
to the significant reactivity enhancement by carbonates, other
X-type additives such as NaOAc, NaO2CtBu, or KF (entries 16 to
18; 10 TON each) did not show analogous activating effects,
while Na2SO4 (entry 24) promoted the H/D exchange activity
similar to the carbonate additives (23 TON). These data
suggest that carbonate additives are unique with regard to
their ability to promote non-directed C-H activation at the
Cp*Ir core; to the best of our knowledge, our observations are
the first documentation of this effect. Involvement of
carbonate ligands in C-H activation has previously been
proposed for Pd catalysts;27,28 these examples invoke the
ability of carbonate ligands to act as internal bases, enabling
C-H activation through a concerted metalation-deprotonation
(CMD) pathway.29,30
Entry
1
2
3
4
5
6
7
8
Additive
TON
11(1)
21(10)
17(4)
19(2)
27(12)
13(2)
20(1)
12(1)
9(1)
Entry
13
14
15
16
17
18
19
20
21
22
23
24
Additive
TON
18(5)
32(3)
33(8)
10(2)
10(4)
10(2)
53(1)
46(6)
28(6)
49(9)
65(1)
23(4)
-
2
3
4
5
6
7
8
9
2 mol % Li2CO3
2 mol % Na2CO3
2 mol % Cs2CO3
2 mol % NaOAc
2 mol % NaO2CtBu
2 mol % KF
4 mol % Li2CO3
4 mol % Na2CO3
4 mol % Cs2CO3
8 mol % Li2CO3
16 mol % Li2CO3
2 mol % Na2SO4
9
10
11
12
10
11
12
14(1)
18(1)
<7(3)
L-type Additives. Next, we evaluated the influence of different
L-type ligands on the H/D exchange activity of . We reasoned,
that air-stable, electron-rich ligands such as phosphines (
and ; Figure 1) or phosphine oxides ( ) might mimic the
1
2, 3,
6
4, 5
influence of PMe3 on the Ir center and promote C-H activation,
while providing an oxidatively stable catalyst structure, which
could then be further employed in oxidative C-H
functionalization.
C-H Oxygenation of Alkyl Arenes
Since carbonate additives showed reactivity enhancing effects
on the C-H activation of benzene in MeOH-D4, we reasoned
that this reactivity might be transferable to establish oxidative
C-H functionalizations of arenes. We focused on aerobic
reactivity in the presence of air, as oxygen has previously been
used in oxidations catalyzed by Cp*Ir complexes;6,7 moreover,
such conditions do not seem to suffer from the decomposition
of Cp*Ir complexes observed with stronger, homogeneous
oxidants.24 We further reasoned that the used of p-xylene as
substrate would provide valuable insight into the possibility of
selective oxidation of Csp2-H or Csp3-H bonds.31 Our initial
experiments (Scheme 1, eq. 1) quantified the extent of
background oxidation, which is expected at the benzylic
position in the presence of O2 at high temperatures.32 Under
FIgure 1. L-type used in H/D exchange studies.
Indeed, all tested phosphines and phosphine oxides (entries 2-
6, Table 1) provided higher reactivity (TONs up to 27) than the
catalyst precursor
electron-rich pyridines (
1
by itself (11 TON; entry 1). Interestingly,
10 11) also provided higher TONs
7
,
,
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dependence on the amount of added Na2CO3 atVlioewwArltoicaledOinnlignes
DOI: 10.1039/C6DT00234J
(<10 equiv.) for both catalysts (1 and [Cp*IrCl2]2), suggesting
the used conditions, this reaction provided a mixture of
products, with the benzylic ester as the minor product and
benzylic alcohol and aldehyde as major products. Excitingly
adding either catalyst or [Cp*IrCl2]2 to the reaction mixture
resulted in a significant higher yield of ester (Scheme 1, eq.s
2/3), while formation of and remained almost unaffected.
Ester could generally be formed through two plausible, Ir
catalyzed pathways: (i) By esterification reaction between
alcohol and PhCO2H or (ii) by C-H activation of p-xylene,
2
3
4
that the carbonate additive plays a role in activating the
catalytic reaction. A similar trend can be observed for PhCO2H
at low loadings (Scheme 3; <150 equiv.), while a larger excess
of either Na2CO3 or PhCO2H leads to a decrease in turnover.
Different amounts of p-xylene, which is used both as substrate
and as solvent in these reactions, do not show a clear influence
on the TONs (see SI, Table 10).
1
2
3
4
2
3
followed by reductive elimination forming a new C-O bond. In
order to distinguish between these two pathways, we reacted
3
(45 μmol; the amount typically formed in the non-catalyzed
background reaction) with PhCO2H in the presence and
absence of Ir catalyst; these reactions were performed in PhCl
as solvent in order to avoid formation of
3 or 2 from p-xylene,
which would complicate the analysis of the resulting products.
Interestingly, neither reaction in PhCl formed any ester
product
2 (Scheme 1, eq.s 4/5), suggesting that formation of 2
as shown in eq.s 2/3 is unlikely to proceed through simple
esterification. This allows us to determine TONs for these
reactions, resulting in 1 TON/[Ir] for [Cp*IrCl2]2 as catalyst and
2 TON/[Ir] for 1.
Scheme 2. Effect of Na2CO3 Loading on TON. All values for TON/[Ir] are
corrected for background reactivity. Equiv. Na2CO3 are based on 6 μmol [Ir] = 1
equiv. Conditions: Ir catalyst (6 μmol [Ir]), Na2CO3 (0 to 100 mg, 0 to 0.94 mmol,
0 to 160 equiv.), p-xylene (1.5 mL, 1.3 g, 12.2 mmol, 2033 equiv.), benzoic acid
(60 mg, 0.49 mmol, 83 equiv.), 125 °C, 18 h.
In contrast, experiments evaluating the dependence of the
catalytic activity (as characterized by TON) on the catalyst
concentration show a clear dependence on the catalyst
loading (Scheme 4) with higher TONs observed at lower
catalyst loadings. This suggests that the catalytic activity
observed here might suffer from catalyst decomposition to a
bimetallic, catalytically inactive species as observed in the
aerobic oxidation of alcohols.6 Based on these observations,
low catalyst loadings (1.5 μmol
1) were used in the following
experiments in order to favor high TONs.
Scheme 1. Aerobic C-H Oxygenation of Csp3-H Bonds by Cp*Ir/Carbonate: Initial
Reactivity of Catalyst System and Background Reactions. Conditions: Ir catalyst
(6 μmol [Ir], 1 equiv.), Na2CO3 (0 or 8 equiv.), p-xylene (1.5 mL, 2033 equiv.),
benzoic acid (0 or 83 equiv.), 125 °C, 18 h. All values for TON/[Ir] are corrected
for background reactivity. Conditions for esterification background:
Cp*Ir(H2O)3(OTf)2 (0 or 6 μmol [Ir]), Na2CO3 (47 μmol, 8 equiv.), benzoic acid
(0.49 mmol, 82 equiv.), 125 °C, 18 h.
Optimizations of C-H Oxygenation. Having established that
formation of
2 is dependent on the Cp*Ir catalysts employed,
we investigated the effects of the different components of the
reaction system on the catalytic activity (Schemes 2 to 4 and
SI, Tables 7 to 13). Initial studies (Scheme 2) show a distinct
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Scheme 3. Effect of Benzoic Acid Loading on TON. All values for TON/[Ir] are
corrected for background reactivity. Equiv. PhCO2H are based on 6 μmol [Ir] = 1
equiv. Conditions: Ir catalyst (6 μmol [Ir]), Na2CO3 (5.0 mg, 0.047 mmol, 8.0
equiv.), p-xylene (1.5 mL, 1.3 g, 12 mmol, 2033 equiv.), benzoic acid (5 to 210
mg, 0.041 to 1.8 mmol, 7 to 344 equiv.), 125 °C, 18 h.
benzylic C-H bonds provided higher TONs. In contrast, the
DOI: 10.1039/C6DT00234J
tertiary benzylic C-H bond in cumene as substrate did not
result in Ir catalyzed turnover, but produced a significant
amount of oxygenated product in a non-catalyzed background
reaction (151(8) μmol; see SI, Table 17).
View Article Online
C-H Oxygenation: Carboxylic Acid Scope. Next, the generality of
the catalytic system was explored, employing
1 as the superior
Preliminary Mechanistic Study: H/D Exchange with p-Xylene
catalyst in combination with a variety of carboxylic acids
(Scheme 5). Depending on the carboxylic acid loading, TONs up
to 11 were observed in these reactions; in particular, the
carboxylic acids AcOH and EtCO2H resulted in high TONs. The
Despite the many possible questions about the catalytic
system, we considered the selectivity for the functionalization
of benzylic Csp3-H bonds to be particularly intriguing, as
previous catalytic H/D exchange studies with Cp*Ir(PMe3)Cl2
show selectivity for aromatic Csp2-H and non-benzylic Csp3-H
bonds in alkyl arenes.10 Furthermore, stoichiometric C-H
activation with Cp*Ir(PMe3)(CH3)(OTf) also shows a preference
for the cleavage of aromatic Csp2-H bonds in alkyl arenes such
as o-xylene and tetrahydronapththalene.33
i
more sterically bulky acid PrCO2H formed lower yields of the
corresponding ester. Within the series of aromatic carboxylic
acids tested, the electron-withdrawing substituent CF3 favored
ester formation, while the electron-donating substituent CH3
resulted in lower yields and only 3 TON.
Scheme 6. Aerobic Oxidation Products with Various Alkyl Arenes. All values for TON
are corrected for background reactivity (see SI, Table 17). Conditions: 1 (1.5 μmol),
Na2CO3 (47.2 μmol, 31 equiv.), alkyl arene (12.2 mmol, 8133 equiv.), AcOH (2.62 mmol,
1747 equiv.), 125 °C, 18 h.
In order to better understand if benzylic Csp3-H activation can
indeed occur under the developed reaction conditions, we
performed H/D exchange of p-xylene in MeOH-D4 in the
presence of Li2CO3, in analogy to the best H/D exchange
conditions established above for benzene as substrate. In
agreement with the previously documents H/D exchange
preference of Cp*Ir(PMe3)Cl2,10 a clear preference for aromatic
Csp2-H activation was observed (17% D incorporation; Scheme
7).
Scheme 4. Effect of Catalyst Loading on TON. All values for TON/[Ir] are
corrected for background reactivity. Conditions: Ir catalyst (1.5 μmol to 15 μmol
[Ir]), Na2CO3 (5 mg, 0.047 mmol), p-xylene (1.5 mL, 1.3 g, 12.2 mmol), benzoic
acid (1.5 mL, 1.3 g, 12.2 mmol), 125 °C, 18 h.
Scheme 5. Carboxylic Acid Scope. All values for TON are corrected for background
reactivity (see SI, Table 15). Standard Conditions: 1 (1.0 mg, 1.5 μmol [Ir]), Na2CO3 (5.0
mg, 47 μmol, 31 equiv.), p-xylene (1.5 mL, 1.3 g, 12.2 mmol, 8133 equiv.), carboxylic
acid (0.819 mmol, 546 equiv.), 125 °C, 18 h. aHigh Loading of Carboxylic Acid
Conditions: as above, but 2.62 mmol carboxylic acid (1747 equiv.).
Scheme 7. H/D Exchange of p-Xylene. Conditions: 1 (9.5 μmol, 2.0 mol %), Li2CO3 (76
μmol, 16 mol %), MeOH-D4 (0.48 mL, 0.43 g, 12 mmol, 25 equiv.), p-xylene (59 μL, 51
mg, 0.48 mmol, 1.0 equiv.), 150 °C, 24 h.
This suggests the possibility that initial C-H activation of
p-xylene proceeds through Csp2-H activation and that Csp3-H
activation is less favourable, but accessible under the reaction
conditions. In this scenario, formation of the benzylic ester
product could occur selectively, if the organometallic Ir-aryl
C-H Oxygenation: Alkyl Arene Scope. As AcOH provided high
TONs in the previous study, AcOH was further employed in a
short substrate scope study to gain insight into which types of
C-H bonds can be oxygenated under the developed conditions
(Scheme 6). Interestingly, both alkyl arenes with secondary
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and Ir-benzyl intermediates are in equilibrium; in this case,
Curtin-Hammett control can be expected to favour the
formation of benzyl ester, if it proceeds through a lower
energy transition state than aryl ester formation. Further
support for this mechanistic scenario comes from the
observation that small amounts of aryl ester product are
formed (TON <0.3) under the C-H oxygenation conditions
developed above, indicating that principally both isomeric
ester products can be accessed. However, in the absence of
further mechanistic studies it is possible that the C-H
activation and functionalization mechanism both act in unison,
but are unrelated to each other.
Notes and references
‡ The obtained TON of 11(1) is in agreement with the previously
determined TON of 16(2) for H/D exchange catalyzed by
ref. 14), considering that the spreadsheet used for calculating
TONs based on incorporation of deuterium has a statistical error
of ±5 TON.25
§ Even though the mild conditions applied here likely keep the
Cp*Ir unit intact, it is possible that the benzylic C-H bonds in the
Cp* ligand are attacked, which would lead to decomposition.34
View Article Online
DOI: 10.1039/C6DT00234J
1 (see
1
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In conclusion, this manuscript describes the discovery that
carbonate additives can significantly influence the C-H
activation reactivity of Cp*Ir-based catalyst precursors, as
studied in detail by H/D exchange in MeOH-D4. Remarkably,
the resulting catalyst systems enable the aerobic Csp3-H
functionalization of alkyl arenes in benzylic position without
the need for a catalyst directing group, forming ester products
with up to 25 TONs. H/D exchange with p-xylene as substrate
suggests that Csp2-H activation is more favourable with the
catalytic system than Csp3-H activation, but further mechanistic
studies need to be performed in order to better understand
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catalyst ([Cp*IrCl2]2 or Cp*Ir(H2O)3(OTf)2; 1.5 to 15 μmol [Ir]),
carbonate additive (0 to 0.94 mmol, 0 to 160 equiv.), p-xylene
(0.1 to 5.0 mL), and carboxylic acid (0.041 to 1.75 mmol, 7.0 to
344 equiv.) were mixed in a 20 mL scintillation vial. The vial
was tightly sealed with a Teflon®-lined vial cap and heated to
125 °C for 18 h on a preheated vial plate. After the reaction
time was complete, the mixture was allowed to cool to room
temperature and PhBr (10 μL, 95 μmol) was added as GC
standard. The mixture was extracted with H2O (5 mL), the
organic phase was filtered through celite, and the resulting
filtrate was analyzed by GC-FID and/or GC-MS. Yields were
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Carbonate additives enhance the activity of [Cp*Ir(H2O)3](OTf)2 for non-directed C-H activations and the
aerobic C-H oxygenation of alkyl arenes.

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