Pd-Catalyzed Aerobic Oxidation Reactions: Strategies to Increase Catalyst Lifetimes

Article abstract of DOI:10.1021/jacs.7b11372

The palladium complex [(neocuproine)Pd(μ-OAc)]₂[OTf]₂ (1, neocuproine = 2,9-dimethyl-1,10-phenanthroline) is an effective catalyst precursor for the selective oxidation of primary and secondary alcohols, vicinal diols, polyols, and carbohydrates. Both air and benzoquinone can be used as terminal oxidants, but aerobic oxidations are accompanied by oxidative degradation of the neocuproine ligand, thus necessitating high Pd loadings. Several strategies to improve aerobic catalyst lifetimes were devised, guided by mechanistic studies of catalyst deactivation. These studies implicate a radical autoxidation mechanism initiated by H atom abstraction from the neocuproine ligand. Ligand modifications designed to retard H atom abstractions as well as the addition of sacrificial H atom donors increase catalyst lifetimes and lead to higher turnover numbers (TON) under aerobic conditions. Additional investigations revealed that the addition of benzylic hydroperoxides or styrene leads to significant increases in TON as well. Mechanistic studies suggest that benzylic hydroperoxides function as H atom donors and that styrene is effective at intercepting Pd hydrides. These strategies enabled the selective aerobic oxidation of polyols on preparative scales using as little as 0.25 mol % of Pd, a major improvement over previous work.

Full text of DOI:10.1021/jacs.7b11372

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Article
Pd-Catalyzed Aerobic Oxidation Reactions:
Strategies to Increase Catalyst Lifetimes
Wilson Ho, Kevin Chung, Andrew J. Ingram, and Robert M. Waymouth
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11372 • Publication Date (Web): 15 Dec 2017
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Pd-Catalyzed Aerobic Oxidation Reactions: Strategies to Increase
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Wilson C. Ho,a Kevin Chung,a,b Andrew J. Ingram,a,c and Robert M. Waymouth*a
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aDepartment of Chemistry, Stanford University, Stanford, California 94306, United States
bFormosa Plastics Corporation, 201 Formosa Drive, Point Comfort, Texas 77978, United States
cJames R. Randall Research Center, Archer Daniels Midland Company, Decatur, Illinois 62521,
United States
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Abstract
The palladium complex [(neocuproine)Pd(μ-OAc)]2[OTf]2 (1, neocuproine = 2,9-
dimethyl-1,10-phenanthroline) is an effective catalyst precursor for the selective oxidation of
primary and secondary alcohols, vicinal diols, polyols, and carbohydrates. Both air and
benzoquinone can be used as terminal oxidants, but aerobic oxidations are accompanied by
oxidative degradation of the neocuproine ligand, thus necessitating high Pd loadings. Several
strategies to improve aerobic catalyst lifetimes were devised, guided by mechanistic studies of
catalyst deactivation. These studies implicate a radical autoxidation mechanism initiated by H-
atom abstraction from the neocuproine ligand. Ligand modifications designed to retard H-atom
abstractions as well as the addition of sacrificial H-atom donors increase catalyst lifetimes and
lead to higher turnover numbers (TON) under aerobic conditions. Additional investigations
revealed that the addition of benzylic hydroperoxides or styrene lead to significant increases in
TON as well. Mechanistic studies suggest that benzylic hydroperoxides function as H-atom
donors and that styrene is effective at intercepting Pd hydrides. These strategies enabled the
selective aerobic oxidation of polyols on preparative scales using as little as 0.25 mol% Pd, a
major improvement over previous work.
Introduction
Selective oxidations are among the most important reactions for the synthesis of fine and
commodity chemicals.1-3 Air is a convenient terminal oxidant due to its abundance and high
oxidation potential.4-6 Aerobic oxidations catalyzed by Pd have been known for decades, but
interest in them was reinvigorated by studies demonstrating that in appropriate ligation
environments, Pd(0) can be readily re-oxidized by O2.3, 7-11 This has enabled new strategies for
the selective catalytic aerobic oxidation of alcohols.12-13
The dimeric complex [(neocuproine)Pd(μ-OAc)]2[OTf]2 (1) has proven to be a highly
chemoselective aerobic alcohol oxidation catalyst precursor that operates at room temperature.14-
16 Catalytic oxidation of α,ω-diols to lactones17 with 1 provides an expedient synthesis of
monomers for ring-opening polymerization.18-19 This catalyst exhibits high selectivity for the
oxidation of secondary alcohols in vicinal diols15-16, 20 and carbohydrates10, 21-23 to generate α-
hydroxyketones. α-Hydroxyketones appear in numerous synthetic targets and can serve as
versatile intermediates for further modification.24-29 The selective oxidation of alcohols in
unprotected polyhydroxylated substrates and carbohydrates provides an alternative to multi-step
protection and deprotection strategies.23, 30
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While air or O2 is a convenient and readily available oxidant, there are significant
challenges associated with using O2 in a selective manner due to its redox stoichiometry. As O2
is a 4-electron oxidant, the generation of highly reactive partially reduced oxygen species can
lead to competitive non-selective autoxidation pathways.4-5 In the case of 1, catalysis under
aerobic conditions causes oxidative degradation of the methyl groups on the neocuproine ligand,
eventually leading to the inactive complex 4 (Scheme 1). For this reason 1,4-benzoquinone (BQ)
is occasionally employed as the terminal oxidant instead of dioxygen, but removal of the reduced
hydroquinone complicates product isolation. Modified phenanthroline-based ligands designed to
be more resistant to oxidation were previously synthesized and tested, but their use only
improved the TON slightly.31-32 Another major catalyst deactivation pathway is the formation of
Pd(0) aggregates, i.e., “Pd black.” Guided by mechanistic knowledge of these deactivation
pathways, herein we describe several strategies to improve catalyst lifetimes and turnover
numbers (TON = moles product/mole Pd) from ~35 to >300 at room temperature.
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Scheme 1. Mechanism of alcohol oxidation by Pd complex 1 and its proposed deactivation pathways.
YOO• represents a reactive partially reduced oxygen species. Only one pathway for Pd reoxidation is
shown; others may be operative.
Herein we present evidence implicating that H-atom abstraction (HAA) of a benzylic
hydrogen from the neocuproine ligand initiates a radical autoxidation process that degrades the
ligand (Scheme 1), and we accordingly designed strategies to suppress this pathway and increase
TON. Traditional H-atom donors such as phenols are effective additives for this purpose, as are
benzylic hydroperoxides. The oxidative degradation of ligands under aerobic conditions has
historically been a challenge for Pd catalysis, and so this work is of broad relevance to the field.7
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The other approach to improve TON focused on preventing Pd black formation. Styrene
was found to be highly effective for this purpose, and its mechanism of action is more complex
than simply binding to Pd(0) species as an olefin. We present evidence that styrene provides
another pathway for Pd hydride B to be converted back into active catalyst without going
through Pd(0). Styrene is converted to a benzylic hydroperoxide in the process, which in turn can
also act as an H-atom donor to further improve TON. The synthetic utility of these TON
enhancing strategies was demonstrated in the preparative scale aerobic oxidations of several
polyol substrates. In each case the high chemoselectivity of catalyst 1 was retained.
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Results and Discussion
Pathways for Oxidative Ligand Degradation. Prior mechanistic investigations
combined with in situ Electrospray Ionization Mass Spectrometry (ESI-MS)33-34 revealed several
oxidized Pd intermediates that form during the catalytic aerobic oxidation of alcohols or
disproportionation of hydrogen peroxide.33 Ions corresponding to the Pd alkylperoxo complex 3
were identified as a key intermediate in the formation of the Pd carboxylate 4 (Scheme 1) which
had been previously isolated14 and shown to be inactive for catalytic alcohol oxidation. These
observations spawned the hypothesis that oxidative degradation of the ligand was initiated by
hydrogen atom abstraction of a benzylic C-H bond mediated by reactive peroxide species;
subsequent trapping of the resultant benzylic radical by O2 could explain the formation of 3. This
hypothesis was supported by isotope labeling experiments which revealed that both oxygens in 3
were derived from O2.33 Related pathways have been proposed from metal hydroperoxo
compounds for both Ni and Pd complexes.35-40
Addition of Phenolic Additives to Mitigate Oxidative Degradation. Guided by the
hypothesis that hydrogen atom abstraction is a key step in the oxidative degradation of 1, we
investigated whether the addition of sacrificial hydrogen atom donors would inhibit this pathway
and lead to higher turnover numbers. Phenols are used as H-atom donors or antioxidants in a
wide variety of reactions,41-43 so several phenols were tested as additives in alcohol oxidations
with catalyst 1.22 The phenols were screened at a concentration of 50 mM in the oxidation of 1,2-
propanediol ([1,2-PD]0 = 0.25 M) with Pd complex 1 ([Pd]0 = 2×[1]0 = 1.0 mM) in acetonitrile
under 1.2 atm O2 (Table 1). After 16 h the yield of hydroxyacetone (HA) was assessed by GC-
FID with an internal standard to assess the number of catalytic turnovers (TON = mmol HA /
mmol Pd). Low Pd loadings and long reaction times were employed to ensure that the maximal
TON of the catalyst had been reached. For small scale reactions throughout this work, the
standard deviation for yields between repeated experiments is ±3%.
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Table 1. Influence of phenolic additives on the catalytic oxidation of 1,2-propanediol
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Yield
Entry
Additive
TONb
(GC)a
12%
27%
14%
21%
23%
21%
11%
1
2
3
4
5
6
7
None
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67
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2,6-iPr2-phenol (5)
2,6-tBu2-phenol
2,4,6-tBu3-phenol (25 mM)
2,4,6-tBu3-phenol (50 mM)
2,4,6-tBu3-phenol (100 mM)
2,6-iPr2-aniline
Conditions: 0.25 M 1,2-propanediol, 1.0 mM Pd (0.4 mol%), 50 mM additive, 2 mL MeCN, rt, 16 h.
Reactions done in duplicate. The reactions were carried out in a sealed metal reactor with a shared
headspace of 1.2 atm O2. aYield of HA, as measured by GC-FID with either biphenyl or naphthalene
internal standards. bTON = (mmol HA)/(mmol Pd).
The addition of phenols led to an improvement in the yield of hydroxyacetone generated,
corresponding to an increase in turnover number from 31 to as high as TON = 67 in the case of
2,6-diisopropylphenol (5, Table 1, entry 2). For 2,4,6-tri-tert-butylphenol, varying the additive
concentration from 25 mM to 100 mM had little effect on TON. Addition of 2,6-
diispropylaniline44 did not result in an increase in yield relative to that observed in the absence of
additive (Table 1, entry 1 vs. 7).
During the aerobic oxidation of the sugar octyl β-D-glucopyranoside21 with 2,6-di-tert-
butylphenol at 50 °C, the biphenol 6 was observed by 1H-NMR and was subsequently isolated
and characterized (4.5% yield relative to initial phenol loading). The formation of biphenol 6 is
consistent with the intermediacy of phenoxy radicals during the reaction (Scheme 2),45 thus
supporting that the phenols act as sacrificial H-atom donors. Control experiments in the presence
of alcohol substrate but no Pd catalyst verified that none of the biphenol is formed after 21 h at
50 °C.
Scheme 2. Coupling of phenoxy radicals to produce an isolable biphenol
Analysis of the reaction stoichiometry reveals that the increase in the moles of alcohols
oxidized exceeds the moles of phenol consumed. For example, in the oxidation of 1,2-
propanediol (0.1 mmol) at room temperature, 4 μmol of the phenol 5 was consumed while the
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conversion of 1,2-propanediol increased by 30 μmol over the control reaction with no additives.
This suggests that phenol is able to enhance Pd catalyst lifetimes without being consumed on
every turnover.
Kinetic experiments (see Supporting Information) showed that the addition of phenols
had a negligible effect on the rate of the aerobic oxidation of 1,2-propanediol. Phenols also had
no effect on the yield of hydroxyacetone when benzoquinone was used as the terminal oxidant in
the absence of O2. These results suggest that phenols likely do not serve other roles in improving
aerobic TON.
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Ligand Modifications. Previous investigations revealed that the methyl substituents at
the 2,9-positions of phenanthroline are critical for the room temperature activity of these phen-
based Pd complexes,31 but are also a liability. The cationic Pd phenanthroline complexes lacking
2,9-substituents are inactive at room temperature (Table 2, entry 1), which we have attributed to
the stability of the -hydroxo complexes analogous to 1OH (Scheme 1).31 Previous attempts to
generate more oxidatively-resistant ligands by the introduction of CF3 groups led to only modest
improvements in the turnover numbers.31 The 2,9-diethyl-1,10-phenanthroline ligand was also
ineffective (Table 2, entry 8), revealing that the catalytic activity is quite sensitive to steric
effects.
In an effort to generate Pd complexes that might be more resistant to hydrogen atom
abstraction, several modified neocuproine ligands were investigated, including d6-neocuproine
(which bears perdeuterated methyl groups),32-33 2,9-dimethyl-5-nitro-1,10-phenanthroline (7),
and 2,9-dimethyl-1,10-phenanthroline-5,6-dione (8). If hydrogen atom abstraction were the key
step in oxidative catalyst degradation, then complexes bearing the deuterated ligand should
exhibit longer lifetimes due to the deuterium isotope effect.46 Similarly, ligands 7 and 8 were
investigated because toluenes bearing electron-withdrawing substituents are known to undergo
slower rates of hydrogen atom abstraction.47
Chart 1. Modified neocuproine ligands
These new ligands were tested in the aerobic oxidation of 1,2-propanediol in MeCN
utilizing the isolated complexes [(L)Pd(OAc)]2[OTf]2 and/or the complexes prepared in situ.31
Oxidation of 1,2-propanediol with the Pd complex d12-1, derived from the d6-neocuproine ligand,
led to higher yields of hydroxyacetone, corresponding to a 60% increase in the turnover number
from TON = 35 to TON = 56 (Table 2, entries 2-5). Similar results were recently reported by de
Vries and Minnaard.32 The NO2-substituted neocuproine ligand 7 afforded a similar increase in
TON, whereas the diketone ligand 8 was inactive for the aerobic oxidation of 1,2-propanediol.
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Table 2. Influence of ligands on the catalytic oxidation of 1,2-propanediol
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Catalyst
Prep.
Yield
(GC)
Entry
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TON
1
2c
3c
4
phen
neoc
isolated
isolated
in situa
isolated
in situa
in situb
in situb
in situb
<1%
18%
17%
29%
27%
29%
<1%
<1%
<2
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34
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54
59
<2
<2
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neoc
d6-neoc
d6-neoc
7
5
6c
7
8
8
2,9-Et2-phen
Conditions: 0.25 M 1,2-propanediol, 1.25 mM Pd (0.5 mol%), 1 mL MeCN, rt, air, 24 h. The vials were
open-capped for the initial 6 h. aCatalyst prepared in situ by reacting a 2:1:1 mixture of ligand / Pd(OAc)2 /
[Pd(MeCN)4][BF4]2 for 1 h prior to reaction. bComponents complexed for 24 hours prior to reaction.
cReaction done in duplicate.
Cosolvents with Benzylic C-H Bonds. We also investigated whether solvents containing
weak C-H bonds might serve as sacrificial hydrogen atom donors to increase catalyst lifetimes.
The influence of aromatic cosolvents, including those bearing benzylic C-H bonds, was
investigated on the aerobic oxidation of 1,2-propanediol with Pd complex 1 (Table 3). These
experiments were carried out at a lower concentration of 1,2-propanediol (0.1 M) than those
reported in Table 1; under these conditions, the yield and turnover number of the control reaction
were slightly lower (TON = 21, Table 3, entry 1) than those observed at the higher concentration
(TON = 31, Table 1, entry 1).
Table 3. Influence of cosolvents on the catalytic oxidation of 1,2-propanediol
Entry
Cosolventa
[9]b
(mM) (NMR)c
Yield
TON
1
2
MeCN
EtPhd
PhMe
PhH
0
0
11%
23%
22%
20%
19%
47%
46%
45%
25%
23%
21
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44
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38
93
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89
50
47
3
0
4
0
5
tBuPh
EtPhe
EtPhf
EtPhg
MeCN
MeCNh
0
6
45
47
16
46
0
7
8
9
10
Conditions: 0.1 M 1,2-propanediol, 0.5 mM Pd (0.5 mol%), 1 mL 1:1 (v/v) MeCN/cosolvent, 28 °C, 1 atm
O2, 26 h. Reactions done in duplicate. aUnless otherwise specified, the cosolvents were used from
commercial sources without further purification. The PhMe contained negligible amounts of toluene
hydroperoxide. bConcentrations based on the total reaction volume. cYield of HA, as measured by 1H-
NMR with dimethyl sulfone as the internal standard. dEtPh distilled from Na/benzophenone. eReagent
grade EtPh containing 90 mM 9. fDistilled EtPh combined with pure sample of 9. gDistilled EtPh allowed to
autoxidize on the benchtop for 6 weeks. h50 mM dihydroanthracene added to total reaction volume.
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These experiments revealed a modest influence of aromatic cosolvents on the yields of
hydroxyacetone generated (Table 3, entries 1-5). Catalytic oxidation of 1,2-propanediol with Pd
complex 1 (0.5 mol% Pd) in a 50/50 (v/v) mixture of acetonitrile and ethylbenzene (distilled over
Na/benzophenone) afforded a 23% yield of hydroxyacetone (TON = 46), approximately twice
that observed in pure acetonitrile. Similar increases were observed for benzene, toluene, and tert-
butylbenzene, indicating that aromatic cosolvents have a modest but reproducible effect on
catalyst lifetimes. The use of purified ethylbenzene (EtPh) led to a modest increase in the
reaction rate relative to that observed in MeCN (see Supporting Information).
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A larger effect on TON was observed when reagent grade ethylbenzene was employed as
a cosolvent. Under these conditions (Table 3, entry 6) the yield of hydroxyacetone increased to
47%, corresponding to TON = 93. This dramatic effect was traced to the presence of 1-
phenylethyl hydroperoxide 9 present in the unpurified ethylbenzene (approx. 90 mM in 100
vol% EtPh). Appreciable amounts of 9 form in EtPh during storage under air. The role of 9 as a
beneficial additive was established by the addition of an independently prepared sample of the
hydroperoxide 9 to distilled EtPh; when this mixture was used as a cosolvent, the yields and
TON matched that observed when reagent grade EtPh was used as a cosolvent (Table 3, entry 7).
Moreover, when the aerobic oxidation of 1,2-propanediol was carried out in acetonitrile with 46
mM of the hydroperoxide 9 but without another cosolvent, the yield of hydroxyacetone
increased, affording TON = 50 (Table 3, entry 9). This increase was similar to that observed
when 50 mM 9,10-dihydroanthracene, a benzylic H-atom donor, was added to the reaction
carried out in MeCN (Table 3, entry 10).
When reagent grade EtPh containing hydroperoxide 9 was used as a cosolvent for the
aerobic oxidation of 1,2-propanediol, 1H-NMR and GC-FID analyses of the reaction mixtures
revealed the presence of acetophenone, 1-phenylethanol, and 9 (approx. 15-40 mM each, and
always totaling more than [9]0 = 45 mM). These products are characteristic of the well-
established mechanism for the radical autoxidation of ethylbenzene (Scheme 3)48 and the
reactivity of alkylperoxides.49-50 In contrast, if distilled EtPh was used as the cosolvent in the
oxidation of 1,2-propanediol, much lower concentrations of acetophenone, 1-phenylethanol, and
9 were detected during the reaction (approx. 2 mM total).
Scheme 3. Mechanism of EtPh autoxidation
18O-labeling experiments were carried out to confirm that the oxygen atoms in the
acetophenone and 1-phenylethanol byproducts come from O2. When the oxidation of 1,2-
propanediol was carried out under an 18O2 atmosphere in 1:1 (v/v) distilled EtPh/MeCN, analysis
of the reaction mixture by GC-MS revealed that 100% of the 1-phenylethanol and 82% of the
acetophenone was labeled with 18O. In contrast, for the analogous reaction carried out with air
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(16O2) in the presence of 0.5 M H2 O, no 18O was detected in the 1-phenylethanol and only 5%
18O incorporation was detected in the acetophenone.
These experiments indicate that the dramatic increase in the turnover numbers observed
in the aerobic oxidation of 1,2-propanediol in the presence of reagent grade ethylbenzene (Table
3, entry 6) is due to: (i) the beneficial effect of aromatic cosolvents, and (ii) the presence of the
hydroperoxide 9. As Hermans et al. had previously highlighted the key role of 9 as an H-atom
donor in the EtPh autoxidation mechanism,48 these results lead to the rather surprising suggestion
that the hydroperoxide 9 extends the lifetime of the Pd catalyst 1 by functioning as an efficient
sacrificial hydrogen atom donor. Anaerobic experiments indicated that although 9 can function
as a terminal oxidant for this reaction, it performs substantially worse than O2.
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Proposed Ligand Degradation Mechanism. The nature of the partially reduced oxygen
species responsible for ligand degradation cannot be unambiguously established. Prior
mechanistic studies33 revealed a complicated reaction network involving multiple pathways for
both alcohol oxidation and hydrogen peroxide disproportionation catalyzed by Pd complex 1.
One plausible reactive oxygen species is the binuclear Pd peroxo complex C (Scheme 4) that
was previously identified by ESI-MS33 and is generated from the neutral Pd peroxo 2 and the
dication [LPd(MeCN)2]2+. DFT calculations of this species indicate that the -peroxo and
diradical structures are both feasible. This complex is expected to be highly reactive toward
hydrogen atom abstraction from the benzylic C-H bond of the neocuproine ligand based on
analogy to similar -peroxo Cu,51-54 Pd/Cu55 and Ni complexes.39-40
Scheme 4. Possible mechanism for oxidative degradation of Pd catalyst 1
Hydrogen atom abstraction from a ligand methyl group would generate a benzylic
radical, which would be expected to react rapidly with dioxygen to generate the peroxyl
intermediate D (Scheme 4). In the presence of another suitable hydrogen atom donor – which
could even be another molecule of catalyst – the peroxyl D would react to form the Pd
benzylperoxo 3, which we have implicated as a key intermediate on the path to the catalytically
inactive carboxylate 4. We propose that the beneficial effect of sacrificial hydrogen atom donors
is due, in part, to their ability to quench partially reduced reactive oxygen species, such as in the
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conversion of reactive intermediate C to the -hydroxo complex 1OH, which we have previously
shown to be a chemically and kinetically competent catalytic species.14, 33
Several experiments indicate that the mononuclear Pd peroxo 2 is not likely to be
responsible for ligand degradation. This complex can be isolated33-34, 56 and is stable in solution
for days. In addition, when the related (bathocuproine)Pd(O2) (bathocuproine = 2,9-dimethyl-
4,7-diphenyl-1,10-phenanthroline) complex 2a was mixed with 9,10-dihydroanthracene in 1:1
(v/v) CD3CN/CD2Cl2 under moisture- and O2-free conditions, no anthracene or anthraquinone
was produced even after 6.5 h at room temperature (Scheme 5).57-58 This latter result suggests
that the peroxo 2 is incapable of abstracting C-H bonds even as weak as 76 kcal/mol (cf. 87
kcal/mol for the benzylic C-H in 2-methylpyridine).59
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The trinuclear species [(neoc)3Pd3O2]2+ is another intermediate that has been implicated
in the catalytic cycle, and our studies have shown that it can be converted to [(neoc)Pd(OAc)]+ in
high yield.33-34 The fact that this trinuclear species is isolable and stable in CD3CN for days
suggests that it is unlikely to be responsible for ligand degradation.
Scheme 5. (bathocuproine)Pd(O2) is unreactive toward dihydroanthracene.
Preventing Pd Black – Olefinic Additives. For 1 and many other Pd complexes, the
competitive precipitation of Pd black is another significant means of catalyst degradation. Pd
black formation is typically observed in aerobic alcohol oxidations with catalyst 1 when the diol
concentration (>0.3 M), Pd loading (>5 mM), or temperature (>40 °C) is sufficiently high. To
identify additives that might bind to and stabilize Pd(0) intermediates, we screened several
olefins in aerobic alcohol oxidations at elevated temperature (see Supporting Information). Initial
results revealed that styrene was particularly effective at increasing turnover numbers (Table 4).
Catalytic aerobic oxidation of 1,2-propanediol ([1,2-PD]0 = 0.1 M) with complex 1 (0.5
mol% Pd) at 25°C in acetonitrile affords a 10% yield of hydroxyacetone, corresponding to TON
= 21. However, in the presence of 0.5 M styrene, the yield of hydroxyacetone increases to 22%,
corresponding to TON = 44 (Table 4, entry 2). The positive effect of styrene was more
pronounced at higher substrate concentrations ([1,2-PD]0 = 0.2 M in entries 3-4, TON increases
from 32 to 111) and temperatures (60 °C in entries 9-10, TON increases from 22 to 227). At 60
°C, signficant amounts of Pd black are formed in the absence of styrene, but almost none forms
in its presence.
Performing the oxidation in the presence of both styrene (0.5 M) and 50 vol% reagent
grade ethylbenzene at room temperature for 72 h under 1.2 atm O2 achieved an impressive
average TON of 354. At room temperature, these turnover numbers are among the highest
reported for a Pd aerobic alcohol oxidation catalyst.60-61 Similar enhancements in TON were
observed for other substrates (see “Preparative Scale Oxidations” below). Some styrenic
additives with substituents on the phenyl ring also provided TON improvements. In contrast,
styrenic additives with substituents on the olefin such as α-methylstyrene, β-methylstyrene, or
trans-stilbene had negligible effect on the catalytic reaction or TON.
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Table 4. Influence of styrene on the catalytic oxidation of 1,2-propanediol
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9
[1,2-PD]0
(M)
Yield
(GC)
Entry
mol% Pd
0.5
Additives
none
TON
21
1
2
0.1
0.1
0.2
0.2
0.1
0.1
0.5
0.5
0.1
0.1
10%
22%
24%
83%
25%
51%
14%
89%
11%
57%
10
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21
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59
60
0.5
0.5 M styrene
none
43
3
0.75
0.75
0.5
32
4
0.5 M styrene
46 mM 9
111
50
5
0.5 M styrene
6
0.5
101
57
45 mM 9
7
0.25
0.25
0.5
none
0.5 M styrene
50 vol% EtPhb
8a
9c
10c
354
22
none
0.25
0.5 M styrene
227
Conditions: 1 mL MeCN, 28 °C, 1 atm O2, 26 h. Reactions done in duplicate. a72 hours, 2 mL total
solvent. bReagent grade, which contained 90 mM 9 in 100 vol% EtPh. c60° C.
Control experiments confirmed that the presence of 4-tert-butylcatechol, a stabilizer in
commercial styrene present at approx. 50 ppm concentration, was not responsible for the
increased yields at these concentrations. GC-FID and 1H-NMR analyses of the reactions carried
out with styrene by gas chromatography revealed the formation of the hydroperoxide 9,
acetophenone, 1-phenylethanol, benzaldehyde, and various oligomers as the byproducts of
styrene. According to gel permeation chromatography, the oligostyrenes were of low molecular
weight (Mn < 1000).
Styrene Additives: Mechanistic Investigations. Isotopic labeling experiments were
carried out to assess the fate of styrene additives in the catalytic oxidation of 1,2-propanediol and
isopropanol (Scheme 6). Analyses of styrene-derived coproducts generated from 1,2-propanediol
oxidations conducted in MeCN with isotopically labeled 18O2 by GC-MS revealed that the
acetophenone, 1-phenylethanol, and benzaldehyde each contained >90% 18O incorporation,
indicating that the oxygen atoms in these monomeric styrene byproducts all come from
dioxygen. In contrast, when the reaction was carried out in the presence of air (16O2) and 0.5 M
H2 O, these byproducts exhibited minimal 18O incorporation.
Oxidation of d8-isopropanol under analogous conditions in the presence of styrene
revealed that a significant amount of deuterium was incorporated onto the non-aromatic carbons
18
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of hydroperoxide 9, acetophenone, and the remaining styrene, and that this amount of deuterium
corresponds closely to the amount of d6-acetone generated. Control reactions with D2O and
proteo-isopropanol led to minimal deuterium incorporation on those carbons, demonstrating that
the deuterium comes from the methine C-D of d8-isopropanol. These results strongly imply that
the deuteration of styrene and its byproducts is mediated by palladium hydride species.
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Scheme 6. Isotopic labeling experiments with styrene. For the deuterium labeling experiments, the
percentages indicate what fraction of the compound present at the end contains at least one deuterium in
the positions marked with arrows.
These results suggest that styrene plays multiple roles in enhancing the lifetime of Pd
complex 1. We propose that styrene is converted primarily to hydroperoxide 9 via a Pd-mediated
mechanism. Control experiments with styrene glycol and styrene oxide ruled them out as
potential intermediates (see Supporting Information). 1H-NMR monitoring of the reaction over
time indicated that styrene is consumed at the same rate as that of the alcohol substrate (Figure
1), which implies that styrene reacts quantitatively with a catalytic intermediate, most likely the
Pd hydride. These timepoint data suggest that acetophenone and 1-phenylethanol arise from the
decomposition of 9 because their concentrations do not become significant until very late into the
reaction. For instance, at t = 17 h the ratio [9] : [acetophenone] : [1-phenylethanol] = 90 : 7 : 3,
while at 51 h the ratio was 74 : 11 : 14.62
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1,2-PD conversion
styrene conversion
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hydroperoxide
acetophenone
9
1-phenylethanol
benzaldehyde
0
0
20
40
60
t (h)
Figure 1. Reaction monitoring of a large scale aerobic oxidation of 1,2-propanediol with styrene.
Conditions: 0.5 M 1,2-propanediol, 0.25 mol% Pd, 0.5 M styrene, 50 mL 1:1 (v/v) MeCN/EtPh (reagent
grade, [9]0 < 5 mM in the total reaction mixture), rt, air, 51 h. Molar quantities determined by 1H-NMR with
dimethyl sulfone as the internal standard. Very similar data are also observed when a different substrate
(glycerol) is used in 100 vol% MeCN (see Supporting Information).
The observation of significant incorporation of deuterium into the styrene byproducts
from the oxidation of d8-isopropanol indicates that styrene is also effective at intercepting
palladium hydrides, which provides a potential alternative pathway for the aerobic regeneration
of the catalyst that avoids Pd(0) intermediates. A plausible mechanism is provided in Scheme 7,
wherein reversible insertion of styrene into the Pd-H (or Pd-D in the case of d8-isopropanol
oxidation) bond would generate the secondary benzylic Pd alkyl E.63 Insertion of dioxygen could
then give rise to the Pd alkylperoxo F,64-67 which upon exchange with a proton source would
regenerate the catalyst while producing hydroperoxide 9. The insertion of O2 into Pd-alkyl bonds
is rare, but has been observed in other contexts.64-67 The primary hydroperoxide PhCH2CH2OOH
and its decomposition products are not observed, suggesting that either dioxygen inserts
preferentially into the benzylic Pd-alkyl or that the olefin insertion/de-insertion equilibrium
strongly favors the benzylic isomer.68-69 The reversibility of olefin insertion for both Pd alkyl
isomers is evidenced by the observed deuteration of styrene at both the α and β positions
(Scheme 6). The benzylic isomer may be stabilized by a π-benzyl interaction with the metal.
That α- and β-methylstyrene and trans-stilbene are unreactive under similar conditions might
indicate that these additives are less reactive toward Pd hydrides.
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Scheme 7. Proposed mechanisms for TON enhancement by styrene
In support of this mechanism, electrospray ionization mass spectrometry (ESI-MS) of
reaction aliquots revealed ions consistent with Pd alkyl E (m/z 419.0734) and Pd alkylperoxo F
(m/z 451.0632). One implication of this mechanism is that hydroperoxide 9 is produced instead
of water, at least until 9 itself decomposes over time to acetophenone and water. Consistent with
this prediction, in the aerobic oxidation of 1,2-propanediol monitored by 1H-NMR, the ratio of
water produced to hydroxyacetone was found to be 0.94, while in the presence of styrene this
ratio decreased to 0.29. Furthermore, in the latter case the ratio of water produced to
acetophenone was 0.93.
Preparative Scale Oxidations. The synthetic utility of these strategies for mitigating
catalyst deactivation was assessed in several preparative scale reactions (Scheme 8). Catalytic
oxidation of methyl α-D-xylopyranoside (328 mg, 2 mmol, Scheme 8a),22 carried out in the
presence of 1 atm of O2 with 1 mol% Pd and 0.5 eq phenol 5 in MeCN at 60 °C for 6 h, occurred
selectively at the C3-position to afford a 73% isolated yield of the 3-ketose 10 following silica
gel chromatography. In contrast, oxidation of analogous pyranosides with benzoquinone as the
terminal oxidant21 or with the deuterated catalyst d12-1 required 6 mol% Pd under aerobic
conditions.32 A key advantage of these phenolic additives is that they can be used in
substoichiometric amounts and are converted into a small number of well-defined byproducts.
Catalytic oxidation of 3-phenyl-1,2-propanediol (5 mmol, 0.75 g, Scheme 8b) with 0.4
mol% Pd and 1.5 eq styrene in 1:1 (v/v) MeCN/EtPh (reagent grade, [9]0 < 5 mM in the total
reaction mixture) at room temperature for 37 h to give the α-hydroxyketone 11 in 72% isolated
yield following chromatography and recrystallization. Notably this reaction was conducted in an
uncovered Erlenmeyer flask and was very simple to set up. With the same substrate, increasing
the temperature to 50 °C enabled significant reductions in both reaction time (15 h) and Pd
loading (0.25 mol%) with only a minor decrease in isolated yield (68%).
Aerobic oxidation of 1,2-propanediol (7.61 g, 100 mmol, Scheme 8d) at 50 °C with
catalyst 1 (0.25 mol% Pd) and 1.25 eq styrene in 1:1 (v/v) MeCN/EtPh (reagent grade, [9]0 = 45
mM in the total reaction mixture) afforded a 76% NMR yield (TON = 303) of hydroxyacetone
by analysis of the crude reaction mixture. Hydroxyacetone is polar enough to be separated from
the styrene oligomers by silica gel chromatography alone. However, due to its volatility,
concentration in vacuo of the relevant fractions gave only 32% isolated yield.
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The aerobic oxidative lactonization of diethylene glycol15 (1.06 g, 12.5 mmol, Scheme
8e) was carried out with 1.5 mol% Pd and 3.5 eq styrene in MeCN at 50 °C to afford p-
dioxanone in 59% isolated yield following chromatography and vacuum sublimation at room
temperature. This is a significant improvement over our previously reported procedure,15 which
required Pd loadings of 11 mol% to achieve a similar isolated yield (65%). The oxidative
lactonization of N-Boc diethanolamine15, 18 in the presence of 1.25 mol% Pd and 3.5 eq styrene
afforded a 54% isolated yield of the morpholinone 12 after chromatography and recrystallization
(Scheme 8f). While this yield is lower than that reported previously (76%), the much lower Pd
loading (1.25% vs. 20%) facilitated product work-up.
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Scheme 8. Preparative scale aerobic oxidations. Isolated yields after purification are given. aScaled
relative to the portion of the crude subjected to purification.
Conclusion
The major deactivation pathways for Pd catalyst 1 under aerobic conditions, namely
oxidative degradation of the ligand and Pd black formation, were mitigated with several
complementary approaches, achieving >10 fold improvements in turnover number. A radical-
based mechanism for ligand degradation was proposed that is initiated by H-atom abstraction
from a ligand methyl group by a reactive oxygen species on Pd. This insight informed the choice
of alternate ligands or phenol or styrene additives to increase the catalyst lifetimes. Styrene was
identified as a potent additive for the prevention of Pd black, and its novel mechanism of action
was elucidated.
Employing these techniques in preparative scale reactions allowed the catalyst loadings
to be reduced to <1 mol% Pd, a considerable advance over prior studies which required 5-10%
Pd loadings to reach high conversion. The high chemoselectivities of catalyst 1 were retained,
and the desired products could be isolated from the reaction mixtures using standard methods.
These studies reveal that the addition of sacrificial H-atom donors such as phenols are effective
in catalytic aerobic oxidation reactions. An unexpected discovery was that benzylic
hydroperoxides like 9 are also effective at increasing catalyst lifetimes.
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The use of styrenes as additives revealed a novel process for mitigating the formation of
Pd black, which we propose is a consequence of intercepting reactive Pd hydrides. The addition
of styrene is useful in those cases where product separation from the oligomers is
straightforward, but the use of a stoichiometric additive is not an ideal solution, and moreover
the styrene byproducts cannot be separated from non-polar compounds by chromatography
alone. Nevertheless, these studies reveal that strategies to intercept reactive cationic Pd hydrides,
which are readily deprotonated to Pd(0), might be profitably investigated as a means to mitigate
the formation of Pd black in many Pd-catalyzed reactions.
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Associated Content
Experimental procedures, characterization data, and turnover number data are available in the
Supporting Information via the Internet.
Author Information
Corresponding Author
waymouth@stanford.edu
Notes
The authors declare no competing financial interest.
Acknowledgements
We acknowledge support from the Department of Energy (Office of Basic Energy Science,
Catalysis Science Program, Award DE-SC0018168). We thank Katherine L. Walker and Prof.
Richard N. Zare for the ESI-MS experiments with styrene. W.C.H. is grateful for a Benchmark
Stanford Graduate Fellowship. K.C. is grateful for a Stanford Graduate Fellowship. A.J.I is
grateful for a Robert N. and Anne T. Bass Stanford Graduate Fellowship, an NSF Graduate
Research Fellowship, and a Stanford Center for Molecular Analysis and Design Fellowship.
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1,2-PD conversion
styrene conversion
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acetophenone
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benzaldehyde
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