A Supramolecular Strategy for Selective Catalytic Hydrogenation Independent of Remote Chain Length

Article abstract of DOI:10.1021/jacs.9b05604

Performing selective transformations on complex substrates remains a challenge in synthetic chemistry. These difficulties often arise due to cross-reactivity, particularly in the presence of similar functional groups at multiple sites. Therefore, there is a premium on the ability to perform selective activation of these functional groups. We report here a supramolecular strategy where encapsulation of a hydrogenation catalyst enables selective olefin hydrogenation, even in the presence of multiple sites of unsaturation. While the reaction requires at least one sterically nondemanding alkene substituent, the rate of hydrogenation is not sensitive to the distance between the alkene and the functional group, including a carboxylate, on the other substituent. This observation indicates that only the double bond has to be encapsulated to effect hydrogenation. Going further, we demonstrate that this supramolecular strategy can overcome the inherent allylic alcohol selectivity of the free catalyst, achieving supramolecular catalyst-directed regioselectivity as opposed to directing-group selectivity.

Full text of DOI:10.1021/jacs.9b05604

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
A Supramolecular Strategy for Selective Catalytic Hydrogenation
Independent of Remote Chain Length
Trandon A. Bender, Robert G. Bergman,* Kenneth N. Raymond,* and F. Dean Toste*
Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, Berkeley, California 94720-1460, United States
S
* Supporting Information
ABSTRACT: Performing selective transformations on
complex substrates remains a challenge in synthetic
chemistry. These difficulties often arise due to cross-
reactivity, particularly in the presence of similar functional
groups at multiple sites. Therefore, there is a premium on
the ability to perform selective activation of these
functional groups. We report here a supramolecular
strategy where encapsulation of a hydrogenation catalyst
enables selective olefin hydrogenation, even in the
presence of multiple sites of unsaturation. While the
reaction requires at least one sterically nondemanding
alkene substituent, the rate of hydrogenation is not
sensitive to the distance between the alkene and the
functional group, including a carboxylate, on the other
substituent. This observation indicates that only the
double bond has to be encapsulated to effect hydro-
genation. Going further, we demonstrate that this
supramolecular strategy can overcome the inherent allylic
alcohol selectivity of the free catalyst, achieving supra-
molecular catalyst-directed regioselectivity as opposed to
Figure 1. Selected applications of organometallic catalyzed reactions
directing-group selectivity.
supported by supramolecular hosts. (a) Selective hydroformylation by
a supramolecular supported rhodium catalysts selects for a single
major regioisomer. (b) Selective metal (Ir or Rh) catalyzed allylic
alcohol isomerization achieved by host induced size-selectivity. (c)
Proposal for the selective hydrogenation based on size-selectivity
where a single point of unsaturation could be selectivity activated over
others in the same substrate.
upramolecular catalysis offers a unique means of achieving
Sregioselectivity via three-dimensional control over steric
and noncovalent interactions between substrate and the host
cavity.1−6 This has been demonstrated in a number of
instances ranging from organic to organometallic trans-
formations.7−16 In one important example, supramolecular
support of a metal-mediated hydroformylation reaction leads
to a change in the selectivity of the transformation through the
steric and secondary interactions achieved by a supramolecular
scaffold (Figure 1a).17−21 Our group has also demonstrated the
ability of a host-encapsulated rhodium (1) and ruthenium
catalyst to perform isomerization of allylic alcohols to
aldehydes (Figure 1b).22,23 Using rhodium, it was shown
that the encapsulated organometallic complex exhibits
divergent reactivity from that of the free species.
reactions. Specifically, that size-selectivity could be harnessed
to achieve exquisite catalyst-directed selectivity in a complex
substrate, in contrast to size-discrimination between sub-
strates.25−27 Herein we report the ability to hydrogenate a
single point of unsaturation of a polyene in the absence of any
substrate-driven selectivity to demonstrate a new approach for
performing site- and size-selective hydrogenation (Figure 1c).
We also provide evidence that complete encapsulation in the
host cavity is not required to achieve selective alkene
hydrogenation.
Initial experiments showed that supramolecular catalyst 1,
which is prepared in situ by mixing rhodium complex 2 and the
Raymond tetrahedron in a 1:1 ratio (Figure 1), hydrogenated a
simple terminal olefin substrate (Table 1, entry 1). Free
catalyst 2 also efficiently hydrogenated the same terminal
These examples clearly demonstrate that the encapsulation
of transition metal-catalysts in supramolecular assemblies can
be leveraged to achieve unique selectivity; however, application
of this strategy to more complex substrates, bearing multiple
sites of reactivity, remains rare especially in catalytic
processes.24 We hypothesized that the supramolecular
strategies that enable selective transformations of subtly varied
substrates might provide new avenues for site-selective
Received: May 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b05604
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Journal of the American Chemical Society
Communication
supported and free catalyst offered promise for realizing
selective olefin hydrogenation.
Table 1. Screening of General Hydrogenation Reactivity for
Simple Olefinic Substrates by Catalyst 1
A competition experiment was then performed to determine
if 1 could discriminate between methyl- and ethyl-substituted
olefins (3 and 5, respectively). Good conversion of methyl-
olefin (3) was observed while ethyl-olefin starting material (5)
was recovered in high yield (Figure 2a). In the analogous
a
b
12h reaction time. Reactions performed at 50 °C.
olefin, but significantly faster (1 h versus 12 h) than
supramolecular catalyst 1. To verify that this reactivity
difference was due to host encapsulation of 2, a standard
control reaction was performed: to in situ formed 1 was added
strongly binding guest Et4N+ (as salt [Et4N][Cl]), resulting in
ejection of 2 and Et4N-blocked host.28 With the cavity of the
host blocked, complex 2 maintained the same levels of
reactivity (>99% conversion, 1 h) since it was no longer
encapsulated demonstrating that encapsulation does modify
reactivity.
Further experiments showed that catalyst 2 efficiently
hydrogenated the compounds shown in entries 1−7 in Table
1 within 1 h. In contrast, 1 hydrogenates a methyl-substituted
substrate (Table 1, entry 2), but ethyl-substituted substrates
show only minor conversions with cis- giving slightly higher
conversions than trans- (Table 1, entries 3 and 4). Performing
the same reaction with Et4N-blocked host yields full
conversion of these substrates, further demonstrating that the
lack of reactivity is a result of the host prohibiting reactivity at
the encapsulated organometallic catalyst.
This trend continued upon moving the double bond another
carbon unit away from the terminal position, leading to no
detectable conversion of the allylic alcohol (Table 1, entry 5).
To demonstrate that alcohols were not the only substrates
tolerated under these conditions, additional functional groups
were tested (Table 1, entries 6−8). Each showed good
conversion. Notably, carboxylic acid (Table 1, entry 8) remains
reactive even under pH 8.0 buffered conditions. Encapsulation
of a carboxylate anion with the anionic cage would be
unfavorable, suggesting substrate encapsulation is not a
requirement for hydrogenation.29 Moreover, catalyst 2 gave
incomplete conversion in the presence of the carboxylic acid.
This stark difference in reactivity between supramolecular
Figure 2. Competition experiments to demonstrate divergent
selectivity of free catalyst 2 compared to the supramolecular
supported catalyst 1. (a) Supramolecular supported size-selective
hydrogenation of methyl- vs ethyl-olefin. (b) Catalyst 2 shows no
selectivity between methyl- vs ethyl-olefin. (c) Allylic alcohol-directed
hydrogenation results in selective hydrogenation of substrate 6 over 3
at early reaction times. (d) Supramolecular supported catalysis
overrides native allylic alcohol directing effect and selectively
hydrogenates 3.
control reaction without supramolecular host, full conversion
of both substrates occurred rapidly to yield hexanol 4 (Figure
2b). Based on this selectivity, along with the lack of reactivity
of allylic alcohol (Table 1, entry 5) it was proposed that
catalyst control with 1 should be able to override inherent
allylic alcohol directed rhodium hydrogenation. A competition
between allylic alcohol 6 and methyl-olefin 3 with free catalyst
2 showed good selectivity for hydrogenation of 6 over 3 at an
early time point (Figure 2c). In contrast, good conversion of 3
and recovery of 6 was observed in the presence of catalyst 1,
demonstrating the ability of the supramolecular scaffold to
overcome native catalyst selectivity (Figure 2d).
To expand this strategy of selective hydrogenation, alkyne
substrates were investigated. As with alkene hydrogenation,
methyl substituted alkyne 7 was readily converted by catalyst 1.
Under room temperature conditions, cis-alkene 8 was
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DOI: 10.1021/jacs.9b05604
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Journal of the American Chemical Society
Communication
observed, and high conversion was realized upon warming the
reaction mixture (Figure 3a, 9). In agreement with the results
Figure 4. (a) Supramolecular host supported hydrogenation of
trans,trans-2,4-hexadiene-1-ol (12) to cis-3-hexen-1-ol (13). (b)
Under dideuterium conditions, selective 1,4-addition was observed
to yield a single major isomer 14.
the walls, leading to host-selected product 13. To further
support the 1,4-addition mechanism, the analogous reaction
was performed with deuterium gas. From this reaction, the
doubly deuterated cis-product (14) was exclusively observed.
Interestingly, the product of this transformation was a single
isomer indicating good regioselective and diastereoselective
deuterium addition within the host (Figure 4b).33
Figure 3. Supramolecular supported catalyst selectively hydrogenates
alkynes based on size-exclusion. (a) Hydrogenation of methyl-alkyne
7 provided cis-alkene 8 at room temperature and heating afforded fully
hydrogenated 9. (b) Competition between methyl- and ethyl-alkyne
(7 and 10, respectively) provided size-selective hydrogenation of 7
and full recovery of 10. (c) Methyl-alkene 11 was selectively
hydrogenated with full recovery of ethyl-alkyne 10.
To further demonstrate that site-selective hydrogenation
could be realized through catalyst control, polyenol 15, where
the olefins are not in conjugation as above, was investigated
(derived from lineolenic acid). Selective hydrogenation of any
point of unsaturation on 15 would be challenging due to a lack
of directing groups and similar reactivity. This proved to be the
case upon subjecting 15 to hydrogenation with catalyst 2.
Hydrogenation gives multiple intermediate products at early
time points that rapidly converged to the fully hydrogenated
alcohol. However, subjecting 15 to host-supported hydro-
genation conditions gave minor conversion even with heating
and extended reaction times (Figure 5). This lack of reactivity
is in agreement with previous experiments indicating no
reactivity at ethyl-substituted olefins.
To overcome this lack of reactivity, the larger pyrene-walled
supramolecular host 16 was investigated.34 In analogy to our
observations with the naphthalene host, 2 is a good guest
within 16. Performing hydrogenation of 15 with this larger
supramolecular host provided good conversion of the starting
material to yield the monohydrogenated product 17. This
product was verified by direct analogy to authentic material
(see Supporting Information for details). Increasing the
catalyst loading gave complete conversion to provide the
singly hydrogenated product 17 in 74% yield (Figure 5a).
Interpreting the larger size of host 16 to be the reason for
increased reactivity is reasonable. However, the increased size
does not mean that 16 fully encapsulates the substrate during
the reaction, whereas the smaller host cannot. Instead, it is
proposed that 16 is able to allow enough of the guest to enter
and undergo hydrogenation at the metal center while some
portion of the substrate remains outside of the host. This is in
observed above, ethyl alkyne 10 was unreactive. A direct
competition experiment between methyl- and ethyl-alkyne (7
and 10, respectively) showed selectivity for conversion of the
methyl-alkyne (Figure 3b). Hydrogenation with 2 displays
minimal selectivity and rapidly hydrogenates both 7 and 10.
From these competition experiments, it was proposed that
the supramolecular supported catalyst should be able to
selectively hydrogenate a sterically accessible alkene in the
presence of an inherently more reactive alkyne. This would
provide support for the ability of this catalyst to perform site
selective hydrogenation when cross reactivity is a concern.
When subjecting a mixture of 10 and 11 to catalyst 2, alkyne
hydrogenation was more rapid than that of the alkene.
However, supramolecular catalyst 1 provides good conversion
of alkene 11 and recovery of 10 (Figure 3c), providing another
example of catalyst control that is different from reactivity of
the free catalyst.
With the goal of performing site-selective hydrogenation on
a substrate containing multiple sites of unsaturation, dieneol 12
was explored. Upon subjecting 12 to supramolecular hydro-
genation conditions, the major product was cis-3-hexen-1-ol
13, which is challenging to produce under standard rhodium
hydrogenation conditions.30−32 In contrast, free catalyst 2
provided a mixture of products that eventually converged to
fully hydrogenated hexanol.
The selective formation of 13 was proposed to occur via a
1,4-hydride addition mechanism (Figure 4a). In this reaction
sequence, the steric confinement provided by the host cavity is
proposed to force the intermediate rhodium bound mono-
alkene (I) into a cis-orientation to minimize steric clash with
C
DOI: 10.1021/jacs.9b05604
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Journal of the American Chemical Society
Communication
ORCID
Kenneth N. Raymond: 0000-0001-6968-9801
F. Dean Toste: 0000-0001-8018-2198
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Director, Office of Science,
Office of Basic Energy Sciences, and the Division of Chemical
Sciences, Geosciences, and Bioscience of the U.S. Department
of Energy at Lawrence Berkeley National Laboratory (Grant
No. DE-AC02-05CH11231) and a NIH Postdoctoral Fellow-
ship to T.A.B. (Grant No. 1F32GM129933-01).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b05604.
■
S
Experimental details, characterization data, and methods
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*rbergman@berkeley.edu
*raymond@socrates.berkeley.edu
*fdtoste@berkeley.edu
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