Environmentally responsible, safe, and chemoselective catalytic hydrogenation of olefins: ppm level Pd catalysis in recyclable water at room temperature

Article abstract of DOI:10.1039/d0gc02087g

Textbook catalytic hydrogenations are typically presented as reactions done in organic solvents and oftentimes under varying pressures of hydrogen using specialized equipment. Catalysts new and old are all used under similar conditions that no longer reflect the times. By definition, such reactions are both environmentally irresponsible and dangerous, especially at industrial scales. We now report on a general method for chemoselective and safe hydrogenation of olefins in water using ppm loadings of palladium from commercially available, inexpensive, and recyclable Pd/C, together with hydrogen gas utilized at 1 atmosphere. A variety of alkenes is amenable to reduction, including terminal, highly substituted internal, and variously conjugated arrays. In most cases, only 500 ppm of heterogeneous Pd/C is sufficient, enabled by micellar catalysis used in recyclable water at room temperature. Comparison with several newly introduced catalysts featuring base metals illustrates the superiority of chemistry in water.

Full text of DOI:10.1039/d0gc02087g

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Environmentally responsible, safe, and
chemoselective catalytic hydrogenation of
olefins: ppm level Pd catalysis in recyclable
water at room temperature†
Cite this: DOI: 10.1039/d0gc02087g
c
Balaram S. Takale, *a Ruchita R. Thakore,a Eugene S. Gao,a,b Fabrice Gallou
a
and Bruce H. Lipshutz
*
Textbook catalytic hydrogenations are typically presented as reactions done in organic solvents and
oftentimes under varying pressures of hydrogen using specialized equipment. Catalysts new and old are
all used under similar conditions that no longer reflect the times. By definition, such reactions are both
environmentally irresponsible and dangerous, especially at industrial scales. We now report on a general
method for chemoselective and safe hydrogenation of olefins in water using ppm loadings of palladium
from commercially available, inexpensive, and recyclable Pd/C, together with hydrogen gas utilized at 1
atmosphere. A variety of alkenes is amenable to reduction, including terminal, highly substituted internal,
and variously conjugated arrays. In most cases, only 500 ppm of heterogeneous Pd/C is sufficient,
enabled by micellar catalysis used in recyclable water at room temperature. Comparison with several
newly introduced catalysts featuring base metals illustrates the superiority of chemistry in water.
Received 18th June 2020,
Accepted 25th August 2020
DOI: 10.1039/d0gc02087g
rsc.li/greenchem
In response to these concerns, many processes showcasing
homo- or heterogeneous base metal-catalyzed hydrogena-
1. Introduction
Catalytic hydrogenation of olefins is among the most powerful tion10,11 of olefins have been reported of late. For example, a
of reactions used by many chemical industries, being applied complex iron catalyst under hydrogen pressure has been used
to the preparation of pharmaceuticals,1 commodity chemicals, successfully by von Wangelin et al.12 The Chirik group13,14 has
agrochemicals, and many other valued products.2 In most described an earth-abundant Co catalyst to achieve hydro-
cases, hydrogenations are catalyzed by transition metals such genation, also relying on hydrogen pressure (Fig. 1).15 Very
as Pd, Rh, Pt, and Ru3 due to their high activity, availability, recently, Beller et al. identified a bio-mass-derived chitosan-
and ease of handling. Unfortunately, these catalysts are typi- supported Co-catalyst requiring both high temperatures and
cally required in relatively large amounts, especially under very high hydrogen pressures (Fig. 1).16 Hence, in moving away
homogeneous conditions4,5 where direct catalyst recycling can from highly active precious metal-based hydrogenations, harsh
be especially challenging.6 By contrast, olefin hydrogenation reaction conditions may be needed which raises safety con-
based on heterogeneous catalysis allows for facile catalyst re- cerns, especially as olefin-containing substrate complexity
cycling, which can be a more attractive option.7 However, the increases. Independent of metal, loadings, and conditions, all
catalyst itself oftentimes contains a transition metal that is current processes are utilized in organic solvents, further
unequivocally endangered.8 Moreover, such catalysis requires depleting the world’s petroleum reserves, which is undeniably
use of organic solvents in pressurized containers, and at cata- unsustainable.
lyst loadings that can lead to products containing excessive
amounts of residual metal beyond FDA limits.9
Alternatively, commercially available 2–10 mol% Pd/C17 in
methanol is widely used for hydrogenation of olefins.
However, such a general reagent oftentimes lacks chemo-
selectivity towards olefins in the presence of other reducible
functional groups.18 Typically, a catalyst poison may be
required to achieve the desired selectivity.19
aDepartment of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, USA. E-mail: lipshutz@chem.ucsb.edu, balaram_takale@ucsb.edu
bDepartment of Chemistry, Harvey Mudd College, Claremont, California 91711, USA
cNovartis Pharma AG, CH-4057 Basel, Switzerland
Our research programs focus on developing technologies20
that include recognition of the need, on occasion, to address
time-honored, fundamental processes such as olefin hydrogen-
ation that today, lack an environmentally responsible yet
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc02087g
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Fig. 1 Representative previously used catalysts vs. Pd/C in micellar
media (water) applied to the hydrogenation of olefins.
Fig. 2 Screening of reaction medium for hydrogenation using alkene 1.
reaction performed “on water” was very sluggish, as was use of
a traditional organic solvent (MeOH) under these very mild
conditions; only a balloon of hydrogen is needed for these
reductions.18
general protocol. In an effort to minimize usage of precious
metals, and in particular, palladium, while offering especially
valuable options for realizing chemoselectivity, we have endea-
vored to convert traditional catalytic hydrogenation into a reac-
tion that relies not only on ppm levels of an otherwise in-
expensive and readily available catalyst, Pd/C, but also a reac-
tion that can be run in recyclable water at ambient tempera-
tures using micellar catalysis conditions.21 The “nano-to-
nano” effect,22 only operable in water, was anticipated to
deliver the nanomicelle-housed substrate olefin directly to the
heterogeneous nanoparticles as catalyst, thereby avoiding
the typical need for heating of heterogeneous reactions.16
Moreover, the far greater solubility of hydrogen in hydrocarbon
media relative to water, leading to very high concentrations
within micellar cores, works further to the advantage of chem-
istry in water and was anticipated to add to the mildness of
conditions needed.23 In this report we describe an unpre-
cedented, environmentally attractive process, documenting
that a wide variety of alkenes can now be hydrogenated safely
using hydrogen gas in the absence of special equipment, and
in water at room temperature using only 500 ppm of Pd
derived from inexpensive and commercially available Pd/C.
Further evaluation of this ppm Pd/C-catalyzed hetero-
geneous hydrogenation was conducted on several styrene
derivatives under an atmosphere of hydrogen (Table 1;
Conditions A). Conversion to the corresponding product of
reduction occurred quickly (ca. 1–2 h, products 3–6) at room
temperature. In general, alkenes conjugated either directly
to an aromatic or heteroaromatic ring (products 7 and 8) gave
excellent yields of the desired products. Both nitrile (products 9
and 10) and ester groups (products 12–15, 17 and 18) were
stable under these conditions. Phenylcyclohexene (leading to
product 16) and ethyl acrylate (giving product 14), which led to
poor yields using high pressures of H2 as previously
described,12 reacted smoothly in water under atmospheric
hydrogen gas. Amide, carbamate, and lactam functionalities
were all tolerated (products 19–22). A conjugated phosphine
oxide could also be reduced efficiently without compromising
the PvO bond (product 24). Allylic and vinyl sulfones behaved
similarly (products 25 and 26, respectively), while various alke-
nylboron derivatives were hydrogenated without noticeable
deborylation (products 27–30). Further extension to the syn-
thesis of intermediates en route to pharmaceutical targets (e.g.,
Pfizer’s SSRI sertraline; 32, and the anti-inflammatory agent
2. Results and discussion
Screening of the reaction medium was performed using sub- nabumetone, 33)27 is suggestive of broad utility of this
strate olefin 1 (Fig. 2), with TPGS-750-M24 being the most process.
This protocol has also been applied to several olefin-con-
nor cremophore EL (kolliphore EL)26 was as effective, while the taining natural products (Table 2). Noteworthy is the case of
effective. Neither the recently introduced surfactant Coolade,25
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Table 1 Functional group tolerance for hydrogenation of olefins
Reaction conditions: 0.25 mmol substrate, 500 ppm of 1 wt% Pd/C stirred at rt in TPGS-750-M/H2O [0.5 M] under Conditions A or B; Conditions
A = H2 balloon (1 atm); Conditions B = 1.2–1.5 equiv. Et3SiH. a Reaction temperature was 45 °C. b Pd/C loading was 1000 ppm. c Pd/C loading was
2000 ppm. d NMR yield. e Intermediate en route to sertraline.
α-damascone, where the enone was reduced to product 34 Hence, as illustrated, several types of olefin-containing natural
chemoselectively, leaving the isolated alkene intact. Other products can be efficiently hydrogenated without impacting
examples include reductions of carvone (product 35), linalool other functionality in these molecules, attesting to the very
oxide (product 36), and rose oxide (product 37), among others mild conditions involved.
or as their allylated derivatives (products 38–41 and 46), all
In some cases, e.g., camphene (Table 2, product 43), hydro-
undergoing reduction efficiently at room temperature under genation was especially challenging due to the volatility of the
atmospheric hydrogen, and using only 500 ppm of the Pd cata- starting alkene. Hence, an alternative to hydrogen gas was
lyst. Bridged bicyclic systems containing olefins were also developed based on readily available and inexpensive triethyl-
hydrogenated under identical conditions (products 42–44). silane and H2O in the presence of Pd/C, likewise leading to the
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Table 2 Hydrogenation of olefins found in various natural products
Reaction conditions: 0.25 mmol of substrate, 500 ppm of 1 wt% Pd/C was stirred at rt in TPGS-750-M/H2O (0.5 M) under Conditions A or B;
Conditions A = H2 balloon (1 atm); Conditions B = 1.2–1.5 equiv. Et3SiH per double bond. a Reaction temperature was 45 °C. b Pd/C loading was
1000 ppm. c Pd/C loading was 2000 ppm.
desired products in high yields. Several additional examples
using this source of hydrogen can also be found in Tables 1
and 2 (Conditions B).
A particularly meaningful study further highlighting the
“greenness” of this process (in addition to the ppm levels of
Pd involved) comes in the form of its potential for recycling of
both the catalyst and aqueous reaction medium (Scheme 1),
properties which are uncharacteristic of alternative processes.
Here, four successive 1-pot reactions, each at the multi-gram
scale, were performed on different substrates involving an
initial investment of only 500 ppm Pd/C, using a balloon as
the source of hydrogen. An additional 100 ppm Pd/C was
added to the final recycling so as to account for the loss of
catalyst during handling. Nonetheless, this brought the total
use of palladium to 600 ppm, or 150 ppm Pd/reduction. Since
Scheme 1 E Factor, recycling of solvent and catalyst. Reaction con-
ditions: 50 mmol of substrate, 500 ppm of 1 wt% Pd/C was stirred at rt
each of these products could be obtained by simple distillation
from the reaction mixture, no organic solvent was needed at
in TPGS-750-M/H2O [0.5 M] under Conditions A (hydrogen balloon)
any point (e.g., for extraction), leading to an overall E Factor,28
until the second recycle. Then, 100 ppm Pd/C and 1.5 equiv. Et3SiH
were added for the 3rd recycle.
as a measure of waste created, of zero. Even taking into
account the water associated with use of aqueous TPGS-750-M
(a total of 98 mL were used), the E Factor over four reactions is
still only 4.2 (i.e., weight of waste water/weight of product =
98 g/23.2 g). Recycling experiments on the same substrate gave an isolated yield of 85%. The last recycling afforded a
leading to product 6 were also performed for five runs. The 75% yield, suggesting that additional catalyst or extended reac-
first three led to isolated yields of 90–93%, while the fourth tion times might be needed (see SI).
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Metal-catalyzed hydrogenations, especially those that rely ducts 56 and 57) as well as alkyl bromides gave the expected
on relatively harsh conditions required to achieve full conver- results (58 and 59).
sions to the desired product, oftentimes present selectivity
Comparison studies illustrate additional merits of this new,
issues. We have examined model substrates bearing additional green technology in water relative to other very recent, albeit
easily reducible functionality, such as adducts containing a traditional processes that feature base metal catalysts
ketone, aldehyde, or nitro group (Table 3). Presumably due to (Scheme 2). Under similar conditions, the desired saturated
the mildness of these conditions, excellent selectivities were ester 14 was prepared quantitatively using 500 ppm of Pd/C
observed. For example, in the case where a substrate contains under a balloon of hydrogen at room temperature. On the
a conjugated ketone, the corresponding products (50 and 51) other hand, only a 55% yield was obtained, as reported, upon
were obtained in high yields. Compounds with an aldehyde treatment with an iron catalyst under pressure after heating at
present, however, afforded somewhat lower yields of products 80 °C. Hydrogenation of olefins using a heterogeneous cobalt
(52 and 53) reflecting competitive carbonyl reduction. catalyst16 offers reaction conditions that call for specialized
Regioselective reduction of a terminal alkene in the presence equipment to accommodate ten atmospheres of hydrogen
of an internal olefin could also be achieved (product 54). pressure, along with a temperature of 60 °C.
Selective reduction of the alkene in m-nitrostyrene to 3-ethylni-
Alternatively, both targets 21 and 56 could be prepared
trobenzene 55 is also noteworthy.29 Additional applications to using the same low loadings of heterogeneous Pd/C (500 ppm)
more challenging substrates, including aryl (poly)halides (pro- at rt, in water. Notably, in the case of the N-olefinic lactam, the
reaction time was dramatically reduced from eighteen to two
Table 3 Chemo- or regio-selective hydrogenation and halide stability
studies
Conditions: 0.25 mmol substrate, 500 ppm of 1 wt% Pd/C stirred at rt
in TPGS-750-M/H2O [0.5 M] under Conditions A or Conditions B;
Conditions A = H2 balloon (1 atm); Conditions B = 1.2–1.5 equiv.
Et3SiH per double bond. a Reaction temperature was 45 °C. b Pd/C
loading was 1000 ppm.
Scheme 2 Comparison of ppm Pd/C vs. literature processes.
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allows for hydrogenations to be run on many types of olefins
without recourse to alternative catalysts, whether derived from
base or precious metals, that must first be made and then
used under more vigorous and far less environmentally
responsible conditions. Switching to olefin hydrogenations in
water, following Nature’s lead, is long overdue.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support provided by the NSF (CHE 18-56406),
Novartis, and PHT International (postdoctoral fellowship to
B. S. T.) is warmly acknowledged.
Scheme 3 ICP-MS analysis of residual Pd in products 2, 19, 45, and 46.
Conditions A = H2 balloon (1 atm); Conditions B = 1.2–1.5 equiv. Et3SiH.
hours to give 21. Hydrogenation of α-methyl p-chlorostyrene
proceeded smoothly under nano-to-nano conditions without
dehalogenation to give the desired product 57 in 99% yield. By
contrast, to achieve similar results, 100 times higher loading
of an iron catalyst was used in organic solvent in a system
designed to handle hydrogen under high pressure.12 Lastly, a
triglyceride underwent triple hydrogenation to arrive at stearin
60 (90% isolated yield), also run on a gram scale using
1000 ppm Pd/C, or only 333 ppm Pd (0.0333 mol%) per alkene.
The same cobalt catalyst (2.9% loading) required 150 °C at 40
bar of hydrogen pressure to obtain 93% conversion.16
Heterogeneous catalysis oftentimes offers the advantage of
low levels of catalyst leaching into a reaction mixture, leading
to limited product contamination by residual metal(s). Given
the low loadings of Pd involved in these hydrogenations, and
as expected from prior studies,20–22 ICP-MS analyses of pro-
ducts 2, 19, 45, and 46 (Scheme 3) led, in all cases, to residual
levels below 1 ppm Pd;30 the FDA limit for residual Pd per
dose is ≤10 ppm.9
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