A palladium nanoparticle-nanomicelle combination for the stereo-selective semihydrogenation of alkynes in water at room temperature

Article abstract of DOI:10.1002/anie.201407723

The addition of NaBH₄ to Pd(OAc) ₂ in water containing nanomicelles leads to the generation of H2 and Pd nanoparticles. Subsequent reduction of disubstituted alkynes affords Z-alkenes in high yields. These reactions are general, take place in water at ambient temperatures, and offer recycling of the aqueous reaction mixture along with low overall E Factors.

Full text of DOI:10.1002/anie.201407723

Angewandte
Chemie
DOI: 10.1002/anie.201407723
Semihydrogenation
A Palladium Nanoparticle–Nanomicelle Combination for the Stereo-
selective Semihydrogenation of Alkynes in Water at Room
Temperature**
Eric D. Slack, Christopher M. Gabriel, and Bruce H. Lipshutz*
Abstract: The addition of NaBH4 to Pd(OAc)2 in water
containing nanomicelles leads to the generation of H2 and Pd
nanoparticles. Subsequent reduction of disubstituted alkynes
affords Z-alkenes in high yields. These reactions are general,
take place in water at ambient temperatures, and offer recycling
of the aqueous reaction mixture along with low overall
E Factors.
ular approach,[2] net semihydrogenation can be effected with
several other metal catalysts, including those containing Cu,[3]
Au,[4] Ru,[5] Rh,[6] Pt,[7] Ni,[8] Cr,[9] V,[10] and Fe.[11] While each of
these processes has its virtues, the sheer number of reports
suggests that no single methodology appears to be sufficiently
general. Moreover, the question remains as to what extent
a Lindlar reduction, or these alternatives, is environmentally
benign. In other words, how “green” are they? In fact,
virtually all of them fail to adhere to most of the 12 Principles
of Green Chemistry;[12] each relies on one or more organic
solvents in which the reduction is conducted, many need
energy in the form of heat, and recycling of the reaction
medium is rare[2d,13] (Scheme 1).
Here we disclose a very simple, safe, general, and
environmentally responsible protocol for alkyne semihydro-
genation that applies to most alkyne substitution patterns of
interest. The newly developed methodology takes advantage
of 1) the far greater dissolution properties of gases, including
H2, in hydrocarbons as opposed to water;[14] thus, under
micellar conditions, higher concentrations of H2 should be
present inside a micelle compared to the surrounding aqueous
medium, and 2) the attractive interactions between metal
nanoparticles and poly(ethylene glycol) (PEG).[15] To avoid
excessive amounts of hydrogen gas and the need for reactions
to be run under pressure in sealed vessels, generation of H2
was accomplished by adding substoichiometric amounts of
NaBH4 to the reaction mixture (Scheme 2). The release of
hydrogen gas is effected upon addition of a catalytic amount
of inexpensive Pd(OAc)2 (1 mol%) admixed with NaBH4
(initially 0.05 equiv, then 0.35 equiv; see below) to water, in
which is dissolved the designer surfactant TPGS-750-M
(2 wt%), which contains MPEG-750.[16]
T
he Lindlar reduction of alkynes has stood the test of time,
routinely appearing in textbooks as a fundamental approach
to Z alkenes. Dating back to the original report in 1952,[1] this
semihydrogenation process traditionally relies on a heteroge-
neous catalytic source of palladium (e.g., Pd/CaCO3) deacti-
vated with lead, and the stereoselectivity of the reaction is
further enhanced by the presence of a “poison” such as
quinoline (Scheme 1). While the expected outcome is often
Scheme 1. Textbook Lindlar reduction conditions.
achieved, especially in simpler cases of dialkyl-substituted
acetylenes, more highly functionalized substrates have proven
to be challenging. Moreover, losses as a result of the
generation of the undesired E isomer, as well as complica-
tions associated with solid supports containing a high surface
area are not uncommon. These limitations have led to
a plethora of alternative procedures reported within the
past decade alone. While palladium catalysis remains a pop-
[*] E. D. Slack,[+] C. M. Gabriel,[+] Prof. Dr. B. H. Lipshutz
Department of Chemistry and Biochemistry
University of California, Santa Barbara
CA 93106 (USA)
E-mail: lipshutz@chem.ucsb.edu
[+] These authors contributed equally to this work.
[**] Financial support of our program in green chemistry provided by
the NIH (GM 86485) is warmly acknowledged. Early work on this
project by Anish Bhattacharjya is appreciated. Cryo-TEM images
from Dr. Stephan Kraemer are also appreciated. We are indepted to
Johnson-Matthey (Dr. T. Colacot) for providing the Pd used in this
work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407723.
Scheme 2. Approach to alkyne semihydrogenation in aqueous nano-
micelles.
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Table 1: Surfactant screening.
Pd
Conv.[b]
[%]
Ratio
E
Entry
Solvent
source[a]
Z
Alkane
1
2
3
4
5
6
7
8
water
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdI2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
100
100
100
100
100
100
100
100
100
58
25
25
0
25
25
0
25
14
28
5
5
5
7
4
50
50
100
25
72
58
<1
<1
5
cremophore[c]
Brij 30[c]
Triton X-100[c]
SDS[c]
50
14
14
95
95
90
50
96
89
SPGS[c]
TPGS[c]
TPGS[c]
TPGS[d]
DME
Figure 1. Cryo-TEM image showing palladium nanoparticles (dark;
arrows) aggregated around spherical nanomicelles in water.
9
10
11
12
1
<1
3
MeCN
THF
8
9
With stirring at room temperature, the mixture turns to
a black, seemingly homogeneous aqueous solution in which
spherical micelles aggregate around palladium nanoparticles
generated by the NaBH4 (Figure 1). The newly formed H2
seeks preferential dissolution within the lipophilic micellar
cores, although adsorption onto the surface of the metal is
also likely. Introduction of an alkyne leads to its dissolution
within surfactant nanoreactors that interact with palladium.
Reduction to Z-olefinic products then occurs at room
temperature in about one hour in excellent yields. Stock
solutions of this reagent can be stored and used over time.[17]
Curiously, while several other salts or complexes of
Group 10 metals (e.g., NiCl2, Ni(OAc)2, [Pd2(dba)3]) were
either inactive or led to mixtures of E and Z alkenes and
alkanes,[18] PdCl2 resulted in the quantitative reduction to the
corresponding alkane (Scheme 3). Alternatively, the same
over-reduction is observed using a balloon of hydrogen gas in
place of prior reduction of Pd(OAc)2 with NaBH4.
8
All reactions were run at a substrate concentration of 0.5m; ratios were
determined by GC-MS and confirmed by H NMR spectroscopy.
[a] 1 mol% Pd. [b] Determined by GC-MS. [c] 2 wt% solution. [d] 5 wt%
solution.
1
6). To assess overall scope, an expanded study was undertaken
examining several types of alkynes, including unsymmetri-
cally disubstituted, terminal, and conjugated cases (Table 2).
Additional examples of propargylic and homopropargylic
alcohols and their ester derivatives were very amenable to
semireduction (Table 2, entries 1–5), as was the correspond-
ing acetal (entry 6). A conjugated aryl alkyl alkyne (Table 2,
entry 7) afforded the corresponding styrenyl array in a Z to E
ratio of 95:5. Characteristic of this chemistry in water, free
hydroxy and amino groups (Table 2, entries 1, 4, 5, 7, and 15)
presented no obvious limitations. Other conjugated acety-
lenes bearing ester moieties led to more than 95% of the
desired Z-configured a,b-unsaturated esters, including those
containing ketone (Table 2, entry 10) and epoxide (entry 11)
residues. Terminal alkynes (entries 12–15) reacted to afford
the targeted monosubstituted alkenes. While stereodefined
centers present in a-amino acids such as proline and alanine
derivatives (Table 2, entries 13 and 14) remained fully intact,
as did their N-Cbz groups, some reduction of the olefin in an
acrylate was observed, leading to a drop in the yield
(entry 12). Interestingly, a representative silylalkyne was
fully inert to these semihydrogenation conditions (Table 2,
entry 16), which could be used to synthetic advantage.
Another major characteristic of this process is the
opportunity to recycle the contents of the entire reaction
mixture. Once the reduction is complete, in-flask extraction
with a single organic solvent allows the isolation and eventual
purification of the desired product. Both a typical reaction
mixture and the in-flask extraction with an ethereal solvent
(Et2O or MTBE) or hydrocarbon (e.g., hexanes) are shown in
Figure 2. Remaining in the water are the surfactant, LiCl, and
the palladium catalyst. Addition of fresh NaBH4 (0.35 equiv)
leads to an active catalyst ready for re-introduction of the
starting material. As illustrated in Scheme 4, this process
could be repeated five times without a change in yield or
Scheme 3. Full reduction of alkyne using PdCl2.
When functionalized alkynes, for example, propargylic
alcohols, were exposed to our standard conditions, far lower
Z selectivities were observed. Fortunately, we discovered that
under otherwise identical conditions but in the presence of
LiCl (2 equiv), both the yields and extent of Z-alkene
formation are very high. Neither other salts of lithium
(LiBr, Li2CO3, LiOH), nor sodium (NaCl), were nearly as
effective as this additive.[19]
The choice of TPGS-750-M as surfactant was also shown
to be critical in its key role as reaction solvent (Table 1). Thus,
while the corresponding hydrogenation “on water”[20] (i.e., in
the absence of the surfactant) afforded mostly the over-
reduced, saturated product (Table 1, entry 1), none of the
alternative commercially available surfactants led to the
desired Z alkene in synthetically useful amounts (entries 2–
2
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Table 2: Scope of the semihydrogenation in water at room temperature.
Conv.
[%]
Ratio of
Yield
[%]
Entry Alkyne
Z
E
alkane
1
2
100
100
96
4
–
–
90
99
99 <1
99 <1
3
100
–
96
Scheme 4. Recycling and E Factor for alkyne semihydrogenation.
4
5
6
100
96
99 <1
99 <1
99 <1
–
–
98
91
98
chemicals area, and over five times lower than typical values
of 25–100 typical of pharmaceutical companies.[21,22] The
flexibility of this sequence is further manifested upon alter-
ation of the nature of the alkyne participating in each recycle
(Scheme 5).
100
<1
7
93
95
5
–
90
8
95
100
100
100
100
99 <1
95 <1
99 <1
99 <1
–
5
85
90
95
90
82
9[d]
10[c]
11
12
–
–
–
–
–
–
<1
13
14
100
100
<1
<1
98
97
–
–
15
16
93
0
–
0
–
–
<1
90
0
–
All reactions were run at a substrate concentration of 0.5m, with 2 equiv
LiCl, 0.5 equiv NaBH4, and 1 mol% Pd(OAc)2 with standard generation
of the catalyst unless stated otherwise. [a] Run with 1 equiv LiCl. [b] No
deprotection of protected alcohols or amines was detected. [c] Reduction
of ketone was observed if no palladium was present. [d] No LiCl.
Scheme 5. Recycling of the aqueous reaction mixture using different
starting materials (MTBE extraction).
In an effort to determine the source of both hydrogen
atoms in the product alkenes, semireduction of a conjugated
alkyne was carried out under our standard conditions replac-
ing water with D2O. Interestingly, two enoates were isolated
in a 1:1 ratio, with each containing one H and one D atom
(Scheme 6). This suggests, contrary to the traditional cis mode
À
of addition, that Pd H is adding in a random fashion to the
Figure 2. Appearance of a reaction mixture during the semihydrogena-
tion process (left) and upon extraction with ether (right).
stereochemical outcome. The use of very limited amounts of
organic solvent for these extractions resulted in an especially
low E Factor of 3.4, based solely on organic solvent usage,
which is on the low end of those characteristic of the fine
Scheme 6. Semihydrogenation of a conjugated alkyne in D2O.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Received: July 29, 2014
Published online: && &&, &&&&
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[17] Stock solutions have been used for weeks at a time. See SI for
preparation of the catalyst suspension.
Keywords: green chemistry · Lindlar reductions · micelles ·
nanoparticles · semihydrogenation
.
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4
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Semihydrogenation
Nano, meet nano! The addition of NaBH4
to Pd(OAc)2 in water containing nano-
micelles leads to generation of H2 and Pd
nanoparticles. This combination leads to
clean and highly selective conversion of
alkynes to Z-alkenes at room temper-
ature. The aqueous mixture is smoothly
recycled without loss of reagent activity,
stereochemical outcome, or yield. Fur-
thermore, many functional groups are
tolerated under these green conditions.
E. D. Slack, C. M. Gabriel,
B. H. Lipshutz*
&&&& — &&&&
A Palladium Nanoparticle–Nanomicelle
Combination for the Stereoselective
Semihydrogenation of Alkynes in Water at
Room Temperature
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