A Continuous-Flow Process for Palladium-Catalyzed Olefin Cleavage by using Oxygen within the Explosive Regime

Article abstract of DOI:10.1002/cctc.201700671

A continuous-flow protocol for Pd-catalyzed olefin cleavage by using molecular oxygen as the sole oxidant to give carbonyl compounds was explored. The developed flow protocol allowed the use of a low catalyst loading (0.1 mol %), and decomposition of the active catalyst was prevented through stabilization by poly(ethylene glycol)-400 (PEG-400), which was present as a cosolvent. Radical scavengers inhibited the reaction, which indicated the involvement of a free-radical path in the reaction mechanism. The applicability of the continuous-flow protocol was demonstrated on several olefin substrates. The continuous-flow process enabled safe and scalable olefin cleavage.

Full text of DOI:10.1002/cctc.201700671

Accepted Article
Title: Development of a Continuous-Flow Process for a Pd-Catalyzed
Olefin Cleavage using Oxygen within the Explosive Regime
Authors: Christopher Hone, Anne O'Kearney-McMullan, Rachel
Munday, and C. Oliver Kappe
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10.1002/cctc.201700671
ChemCatChem
COMMUNICATION
Development of a Continuous-Flow Process for a Pd-Catalyzed
Olefin Cleavage using Oxygen within the Explosive Regime
Christopher A. Hone,[a,b] Anne O’Kearney-McMullan,[c] Rachel Munday[c] and C. Oliver Kappe*[a,b]
The development of a continuous-flow protocol for a Pd-catalyzed
olefin cleavage using molecular oxygen as the sole oxidant to give
carbonyl compounds is described. The flow protocol uses a low
catalyst loading (0.1 mol%) and decomposition of the active catalyst
is prevented through stabilization by poly(ethylene)glycol-400 (PEG-
400), which is present as a co-solvent. Radical scavengers inhibit
the reaction indicating the involvement of a free radical path in the
reaction mechanism. The applicability of the continuous-flow
protocol is demonstrated on several olefin substrates. The
continuous-flow process enables safe and scalable olefin cleavage
using pure O2.
Significant progress has been made in the development of
olefin cleavage reactions that utilize molecular oxygen as a
suitable green alternative to existing oxidizing agents.[9] O2 has
the advantage that it is a cheap, highly abundant and odorless
non-toxic gas, which can easily be removed after reaction.[10]
However, O2 generally displays low reactivity and poor
selectivity. Therefore, despite the advances made, many of the
protocols suffer from limitations such as high catalyst loadings,
specialized ligand systems, very high operating pressures or
environmentally unfriendly solvents.[9] Pd-catalyzed aerobic
oxidation reactions have shown great versatility and promise in
organic synthesis.[11] In particular, the Tsuji−Wacker oxidation of
terminal olefins to methyl ketones, which uses a Pd catalyst and
Cu cocatalyst under an oxygen atmosphere, is a very important
reaction to the chemical industry.[12] We were intrigued by the
work of Wang and Jiang which reported a highly efficient Pd-
catalyzed olefin cleavage using molecular oxygen as the sole
oxidant.[13,14] This discovery opens a new route for the direct
oxidation of olefins with molecular oxygen. The reactions were
performed in a batch pressure autoclave, with Pd(OAc)2 as
catalyst, PTSA (p-toluenesulfonic acid monohydrate) as additive,
pure O2 as oxidant and H2O as reaction solvent giving the best
result (Scheme 1).[13]
The utility of aldehydes and ketones as valuable intermediates in
modern organic synthesis has made the oxidative cleavage of
the
C=C
double
bond
a
fundamentally
important
transformation.[1] The classical protocol for olefin cleavage is by
ozonolysis using ozone (O3) gas. Ozonolysis is generally a high
yielding, highly selective and green process.[2,3] However,
ozonolysis with olefins is highly exothermic and involves the
formation of a hazardous ozonide intermediate. O3 is also a
highly flammable and extremely poisonous gas with
a
characteristic pungent odor. Therefore, ozonolysis is often
avoided in synthesis due to safety concerns, particularly at
industrial scales.[3,4] Alternative strategies for olefin cleavage to
form aldehydes and ketones using more benign oxidants have
proved successful.[5-8] Selective olefin cleavage with high-valent
oxometal catalysts, such as OsO4 or RuO4, in the presence of a
secondary stoichiometric oxidant, normally either NaIO4 or
NaClO, was achieved in the early 2000s.[5,6] Even more recently
aryl-λ3-iodane-based protocols have been reported, which utilize
environmentally friendly iodine reagents.[7,8] In this procedure
PhIO/HBF4 (1.1 equiv. each) induces alkene scission into
Pd(OAc)2 (2 mol%)
R3 R4
O
O
PTSA
(20 mol%)
R1 R2
°
8 bar O2 100
,
C
R3 R4
R2
R1
0.33 M in H2O
batch
24 h
autoclave,
Scheme 1. Batch conditions for a Pd-catalyzed direct oxidation of olefins to
carbonyl compounds (see ref 13 for more details).
aldehydes selectively.[7] Subsequently,
a procedure using
catalytic iodomesitylene with mCPBA as stoichiometric oxidant
was developed.[8] These methods generally suffer from the
limitation that they are inherently atom inefficient due to the
requirement of a stoichiometric oxidant, which also needs to be
removed after the reaction.
O2 has the disadvantage that it is a highly energetic gas and
oxidizer, which in the presence of an organic solvent as a fuel
and an ignition source results in a potentially flammable mixture.
The safety issues surrounding O2 make it one of the least
frequently used oxidants.[10] A diluted form of O2 gas, consisting
of less than 10% O2 in N2, is normally used to prevent the risk of
combustions in the presence of flammable organic solvents.[15]
Many of the safety and process challenges associated with O2
are better addressed through the application of continuous-flow
reactors.[16-18] In a recent concept article we have demonstrated
that safe operation can be ensured employing properly designed
continuous-flow reactors even when using pure O2 in the
presence of flammable organic solvents at elevated
temperatures and pressure.[18]
[a]
Dr. Christopher A. Hone and Prof. Dr. C. Oliver Kappe
Institute of Chemistry, University of Graz, NAWI Graz,
Heinrichstrasse 28, A-8010 Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
Homepage: http://goflow.at
[b]
[c]
Dr. Christopher A. Hone and Prof. Dr. C. Oliver Kappe
Research Center Pharmaceutical Engineering (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Anne O’Kearney-McMullan and Dr. Rachel Munday
AstraZeneca
Herein, we present preliminary results for a scalable Pd-
catalyzed olefin cleavage protocol using molecular oxygen under
process intensified conditions in continuous-flow mode. To our
Silk Road Business Park, Macclesfield, SK10 2NA (United Kingdom)
Supporting information for this article is given via a link at the end of
the document
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10.1002/cctc.201700671
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COMMUNICATION
knowledge, this is the first reported continuous-flow olefin
cleavage procedure using molecular oxygen as the sole oxidant.
A flow reactor system (Figure 1) was assembled consisting
of a high-pressure pump (Uniqsis, P), a sample loop (SL,
volume = 2 mL), a reactor coil (o.d. 1/16”, i.d. 1/8”, 60 mL
internal volume) made from 316 stainless steel, which was
heated within a GC oven (RTU), and a backpressure regulator
(BPR, Vapourtec, max. 10 bar).[19] A mass flow controller
(ThalesNano, MFC) was used for the introduction of oxygen in a
controller manner. The mixing of the gas and liquid stream was
achieved using a T-piece (T) to provide a gas-liquid segmented
flow regime.
1, entry 2). Significant levels of catalyst and substrate
decomposition were observed at 140 °C (Table 1, entry 3).
The use of DMA and DMSO, both with water as a co-
solvent, gave high conversion but favored the formation of
acetophenone (Table 1, entries 4 and 5). Interestingly, the use of
poly(ethylene glycol)-400 (PEG-400) as solvent resulted in good
substrate conversion and gave benzaldehyde in a moderate
57% yield (Table 1, entry 6). PEG is known to stabilize active Pd
catalysts.[20] In addition, PEG has received significant interest as
an inexpensive, non-volatile, and an environmentally benign
solvent.[21] PEG-400 is endowed with a viscosity value of 90 cP
at 25 °C, which drops to 7.3 cP at 100 °C. A co-solvent is
typically used to reduce the viscosity of the solution for more
amenable flow processing.[22] Pleasingly, PEG400/PhMe (1:1)
provided good solubility of the reaction components and
benzaldehyde in 61% yield (Table 1, entry 7). In addition,
increasing the concentration from 0.35 M to 1.0 M gave a slight
increase in benzaldehyde yield (Table 1, entry 8). However, Pd
black precipitation was observed in these screening experiments
which indicated catalyst decomposition.
RTU
MFC
BPR
SL
T
N2
O2
P
Importantly, higher benzaldehyde yields were obtained
when the catalyst loading was decreased (Figure 2). With a
catalyst loading of only 0.1 mol% of Pd(OAc)2 a benzaldehyde
yield of 72% was obtained (Table 1, entry 9). Appreciable Pd
black precipitation was not observed at this catalyst loading.
Pd(0) species aggregate to generate Pd clusters, which
ultimately irreversibly precipitate in the form of Pd black. [23] The
reduction of catalyst loading to 0.1 mol% gave significantly
Carrier solvent
Figure 1. Continuous-flow setup for Pd-catalyzed olefin cleavage using
molecular oxygen (for further details, see the Supporting Information).
We commenced our studies using styrene 1 as a model
compound to provide benzaldehyde 2 and formaldehyde 3 as
the cleaved products (Table 1). Styrene and its derivatives are a
notoriously difficult substrate class due to facile polymerization.
Formaldehyde is also known to polymerize or can undergo
further oxidation to form CO2 as side product. We initially
undertook an additive, catalyst, ligand screening and solvent
campaign (see the Supporting Information for a summary). We
assessed the reactions against two main criteria: (i) to provide a
homogeneous liquid feed; and (ii) to achieve moderate to good
conversion in residence times appropriate for a tubular flow
reactor setup (<30 min). The previously reported batch
conditions were unsuitable for direct transfer to continuous
processing due to the insolubility of the reaction components in
H2O and long reaction time (24 h) (Scheme 1).[13]
Apart from H2O, tert-butanol was the best performing
solvent in the study by Wang and Jiang. A solvent mix of t-
BuOH/PhMe (5:1) was used to prevent t-BuOH from freezing in
the flow tubes and pumps at room temperature. This solvent mix
was used for the additive, catalyst and ligand screening (Table
S1). Similar benzaldehyde yields were obtained when different
Pd catalysts were trialed. The presence of nitrogen ligands
appeared to reduce conversion. The addition of an acid additive
increased the benzaldehyde yield. The absence of water from
the reaction appeared to decrease conversion. However, the
addition of too much water favored the formation of
acetophenone, the Tsuji−Wacker product.[12] Most experiments
performed poorly with <40% benzaldehyde yield in virtually all
cases (see Supporting Information). Insufficient conversion was
observed at 100 °C (Table 1, entry 1). A reaction temperature of
120 °C gave the best conversion and benzaldehyde yield (Table
higher activity (TON=720) compared to
2 mol% loading
(TON=45).[24] Doubling the residence time resulted in no
improvement in benzaldehyde yield.
Table 1. Solvent and temperature optimization of styrene oxidation.a
O
O
Pd cat
acid additive
O
H
O2
solvent
H
H
1
2
3
4
Conv. 1
Yield 2
Yield 4
Entry
Solvent
T [°C]
[%][b]
[%]b
[%]b
1c
2c
3c
4
t-BuOH/PhMe (5:1)
t-BuOH/PhMe (5:1)
t-BuOH/PhMe (5:1)
DMA/H2O (5:1)
100
120
140
120
120
120
120
120
120
30
48
40
75
85
90
78
79
81
15
38
17
16
14
57
61
63
72
7
8
7
52
63
7
5
DMSO/H2O (5:1)
PEG400
6c
7c
8c,d
9c,e
PEG400/PhMe (1:1)
PEG400/PhMe (1:1)
PEG400/PhMe (1:1)
15
13
3
[a] Conditions: substrate (0.700 mmol), Pd(OAc)2 (2 mol%), PTSA.H2O (20
mol%), diphenylether (internal standard (IS), 25 mol%) in solvent 2 mL,
organic flow rate 0.5 mL min−1, O2 gas flow rate = 11 mLn min−1, 10 bar, tres
=
~25 min. [b] Conversion and yields based on absolute quantities measured
using an internal standard by HPLC (at 254 nm). [c] H2O (1.1 equiv). [d]
substrate (2.00 mmol). [e] substrate (2.00 mmol), Pd(OAc)2 (0.1 mol%).
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The intensified continuous-flow process therefore
enables a significantly shorter reaction time to be used, from
24 h in batch to 25 min in flow. In addition, the catalyst loading
has been reduced from 2 mol% in batch to 0.1 mol% in flow.
The PEG400/PhMe solvent mix provides good solubility of all
the reaction components and PEG400 stabilizes the active Pd
catalyst. The substrate concentration was also successfully
increased from 0.33 M in batch to 1.0 M in flow.
Table 2. Scope of the Pd-catalyzed oxidative olefin cleavage under
continuous-flow conditions.a
Conv
[%][b]
Yield
Entry
Substrate
Product
[%][b,c]
O
81
72
94
1
2
O
100
Cl
Cl
O
45
95
42
3
4
N
N
O2
O2
O
45(40)f
MeO
MeO
O
87
73
5
O
94d
87d
6e
O
7e
74
56
Figure 2. Influence of catalyst loading on conversion and product yields. For
reaction conditions and analytics, see Table 2 entry 1.
O
8e
9
74
52
O
O
85d
14d
To shed light on the possible mechanism of the transformation,
radical scavengers were added to the reaction. Styrene
conversion and benzaldehyde yield dropped dramatically by
the addition of 10 mol% radical inhibitor such as 4-tert-
butylcatechol (TBC) or 2,6-dibutyl-4-methylphenol (BHT)
(Figure S2). A radical scavenger acts as a terminating agent
which suppresses autoxidation by converting peroxy radicals
to hydroperoxides. These results indicate that the olefin
cleavage goes through a radical auto-oxidation mechanism.[25]
4-Tert-butylcatechol (TBC) at 10 to 15 ppm is added to
commercially-available styrene and many of its derivatives as
N
52
74
46
70
N
10
11
N
N
O
N
N
S
S
[a] Conditions: substrate (2.00 mmol), Pd(OAc)2 (0.1 mol%), PTSA.H2O (20
mol%), diphenylether (IS, 25 mol%) and H2O (1.1 equiv) in PhMe/PEG400 1:1 (2
mL), organic flow rate 0.5 mL min−1, O2 gas flow rate = 11 mLn min−1, 120 °C, 10
bar, tres = 25 min. [b] Conversion and yield based on absolute quantities
measured using an internal standard by HPLC (at 254 nm). [c] Molecular weights
confirmed by GC-MS. [d] Conversion and yield based on absolute quantities
measured using an internal standard by GC-FID. [e] substrate (1.00 mmol) due
to solubility. [f] Eliminated aldol product.
a
stabilizer to prevent decomposition from radical
polymerization during storage and reaction.
The applicability of this continuous-flow protocol to olefin
stilbene was less reactive than 1,1-disubstituted alkenes (Table
2, entry 8). However, the oxidative cleavage of aliphatic
camphene proved the most challenging with only 16%
conversion (Table 2, entry 9). These results indicate that steric
hindrance plays a significant role in affecting the efficiency of
oxidation. Interestingly, heterocyclic terminal olefins, not tested
by Wang and Jiang, could also be transformed into the
corresponding aldehydes using the continuous-flow protocol
(Table 2, entries 10, 11).
The continuous-flow process for the olefin cleavage of
styrene could be operated consistently over a period of 20 min
to give 81% conversion of styrene and 72% benzaldehyde yield
(HPLC assay yields, averages of 11 samples collected
throughout operation, see Figure 3).
substrates is shown in Table 2.[26] Aromatic terminal alkenes with
electron-rich and electron-poor substituents in the para position
were reacted to give the corresponding aldehydes (Table 2,
entries 2–4). 4-Chlorostyrene showed high reactivity giving full
conversion and 94% product yield (Table 2, entry 2). The
presence of an electron withdrawing nitro group within the
substrate resulted in the cleavage working less effectively (Table
2, entry 3). Unfortunately, 4-vinylanisole proved susceptible to
forming the eliminated aldol product (Table 2, entry 4). The
oxidation of α-methylstyrene occurred efficiently to give the
corresponding ketone in 73% yield (Table 2, entry 5). The
cleavage reaction was also highly selective for an aromatic gem-
disubstituted alkene to give the desired ketone in 87% yield
(Table 2, entry 6). We next turned to substrates not included in
the original scope (Table 2, entries 3,7–11).[13] The olefin
cleavage of (4-methylpent-1-ene-2,4-diyl)dibenzene proved
more difficult with only 56% yield and multiple side product
formation (Table 2, entry 7). In line with expectations, trans-
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entry 1. No samples were taken until the carrier solvent (colorless) had passed
through (indicated by the double headed arrow) and color (reaction mixture)
was observed at the BPR.
[15] a) Also known as the “limiting oxygen concentration”, see: a) P. M.
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Res. Dev. 2013, 17, 282–293;
In conclusion, we have demonstrated a Pd-catalyzed direct
oxidation of olefins into carbonyl compounds using a continuous-
flow reactor. Low catalyst loadings (0.1 mol%) provided
moderate to excellent product yields in a short 25 min residence
time. The presence of a radical scavenger was shown to have a
negative effect on the olefin cleavage and indicates the reaction
takes place via a free radical mechanism. A major advantage of
the flow protocol is the ability to handle pure O2 under process
intensified conditions in a safe and scalable manner.
[16] For reviews on flow chemistry, see: a) B. Gutmann, D. Cantillo, C. O.
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117; and e) B. Pieber, C. O. Kappe, Top. Organomet. Chem. 2015, 57,
97−136.
Keywords: continuous flow • oxidation • olefin cleavage •
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2016,1, 595–612.
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benzaldehyde) / (moles of Pd).
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[26] The yields given are HPLC or GC assay yields based on absolute
quantities measured against an internal standard. The compounds
were fully isolated and characterized by Wang and Jiang, see ref 13.
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Title
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Christopher A. Hone,[a,b] Anne
O’Kearney-McMullan,[c] Rachel
Munday[c] and C. Oliver Kappe*[a,b]
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Development of a Continuous-Flow
Process for a Pd-Catalyzed Olefin
Cleavage using Oxygen within the
Explosive Regime
The development of a continuous-flow protocol for a Pd-catalyzed olefin cleavage
using molecular oxygen as the sole oxidant to give carbonyl compounds is
described. The applicability of the continuous-flow protocol is demonstrated on
several olefin substrates. The continuous-flow process enables safe and scalable
olefin cleavage using pure O2.
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