Supramolecular Host-Selective Activation of Iodoarenes by Encapsulated Organometallics

Article abstract of DOI:10.1021/jacs.8b11842

Supramolecular hosts offer defined microenvironments that facilitate selective host-guest interactions, enabling reactivity that would otherwise be challenging in bulk solution. While impressive rate enhancements and selectivities have been reported, similar reactivity can often be accessed through modifications of reaction conditions even in the absence of the host. We report here an oxidative addition of aryl halides across the metal centers in Cu(I) and Pd(II) organometallics that is assisted by the presence of a supramolecular host, realized via electrostatic stabilization and increased local substrate concentrations. When reaction conditions were screened to assess background reactivity, alternative reactivity (typically decomposition) resulted, indicating that encapsulation led to host-selective reaction trajectories.

Full text of DOI:10.1021/jacs.8b11842

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Supramolecular Host-Selective Activation of Iodoarenes by
Encapsulated Organometallics
Trandon A. Bender,‡ Mariko Morimoto,‡ 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, California 94720, United States
S
* Supporting Information
ABSTRACT: Supramolecular hosts offer defined micro-
environments that facilitate selective host−guest interactions,
enabling reactivity that would otherwise be challenging in bulk
solution. While impressive rate enhancements and selectivities
have been reported, similar reactivity can often be accessed
through modifications of reaction conditions even in the
absence of the host. We report here an oxidative addition of
aryl halides across the metal centers in Cu(I) and Pd(II)
organometallics that is assisted by the presence of a
supramolecular host, realized via electrostatic stabilization and increased local substrate concentrations. When reaction
conditions were screened to assess background reactivity, alternative reactivity (typically decomposition) resulted, indicating
that encapsulation led to host-selective reaction trajectories.
INTRODUCTION
■
Advances made at the interface of organometallic chemistry
and microenvironment catalysis have broadened the scope and
relevance of supramolecular strategies in synthetic chemis-
try.1−11 Notable examples include allylic alcohol isomer-
izations,12,13 hydroformylations,14,15 and alkyne hydrations.16
However, examples of transformations that are supramolecular
host-selective are rare in a growing field, where applications
typically involve accelerating reaction rates and/or improving
selectivities from those conducted in bulk solution. For
example, we have previously shown that the M4L6 Raymond
tetrahedron (1) accelerates the reductive elimination of ethane
from a Au(III) complex by more than a million-fold (Figure
Figure 1. (a) Previously reported cage-accelerated reductive
1).9
elimination. (b) This work: cage-mediated oxidative addition of
Despite the impressive rate acceleration achieved with 1,
iodoarenes under mild conditions.
reductive eliminations from high-valent gold complexes have
been shown to proceed at a comparable rate even in the
conditions. Moreover, modifying reaction conditions (elevated
absence of the host. Thus, overcoming background reactivity is
temperature, additives, etc.) to assess divergent reactivity
one of the most challenging aspects in organometallic
would further demonstrate that the selected reaction is a cage-
transformations promoted by supramolecular hosts. Similar
specific transformation. Although not obvious a priori, we
reactivity in the absence of supramolecular influence indicates
discovered that the Cu(I)/(III)18 and Pd(II)/(IV)19 oxidative
that the host remains selective for a lowest energy reaction
addition/reductive elimination cycles with iodoarenes are
pathway. Therefore, demonstrating a transformation in which
excellent candidates to perform such an investigation.
the host not only accelerates but alters the lowest energy
reaction pathway from that in bulk solution would be an
RESULTS AND DISCUSSION
We first investigated the ability of a simple 1,2-bis-
(dimethylposphino)ethane (DMPE)−copper complex
■
intriguing step forward for the field, as very few examples are
known.17
The dearth of examples where a supramolecular host “turns
on” distinct reactivity for an organometallic transformation
presents an opportunity to identify a reaction that is typically
not facile under traditional organic and host (aqueous)
Received: November 2, 2018
© XXXX American Chemical Society
A
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Article
((DMPE)CuBr, 2; Scheme 1) to undergo iodoarene carbon−
iodine oxidative addition. Although this copper−phosphine
the resulting cationic species.10 Combining a small excess of 2
with 1 resulted in a heterogeneous mixture. Removal of
remaining solid by filtration after 30 min yielded a 1:1
host:guest complex, as indicated by diagnostic upfield shifted
resonances for encapsulated 3 (Figure 2a).
Scheme 1. Proposed M4L6-Mediated Mechanism for
Formation of Asymmetric Aryl Phosphonium 4
Addition of iodobenzene to 3 resulted in new upfield shifts
in the 1H NMR spectrum corresponding to simultaneous
encapsulation of the copper complex and iodobenzene (I,
Figure 2b).20−22 Over the course of 12 h at room temperature,
full conversion of the starting material to a new product was
observed with concomitant loss of symmetry in both
encapsulated 3 and the host (Figure 2c). A 2D NOESY
experiment of the product indicated correlation between the
aromatic peaks and one set of DMPE methyl peaks. This
observation provided initial support for copper phosphonium
4, where an aryl-dimethylphosphonium ion had formed at one
phosphine, while the other remained coordinated to the
copper center (by analogy to the {1H}31P shift of the starting
material).23 Further evidence of an aryl phosphonium
copper(I) species was obtained by independently preparing
ethyldimethyl (phenyl)phosphonium 5 (see Supporting
Information, p S6) and subjecting it to the M4L6 assembly.
The {1H}31P NMR shift of the encapsulated phosphonium 5
was identical to that of one of the phosphine signals of the
asymmetric DMPE backbone of aryl phosphonium copper
species 4. Lastly, electrospray ionization mass spectrometry
(ESI-MS) confirmed encapsulated 4, predominantly detected
in the −3 and −4 charge states (see Supporting Information, p
S22), verifying that the species is monocationic, with the
iodide (from iodobenzene) still ligated to copper.
complex is an atypical catalyst for traditional Ullmann-type
coupling reactions, it proved to be an ideal species for this
investigation due to its high stability under aqueous conditions,
which arises from its low solubility in water. In contrast, the
amine-ligated analogues rapidly disproportionated in aqueous
media, rendering direct comparison between the host-
mediated system and the potential background organometallic
reaction spectroscopically challenging. Due to the low
solubility of 2, no reactivity was observed upon combination
with iodobenzene in water, even after long reaction times and
heating. More interesting still is the lack of reactivity in
conventional organic solvents (such as methylene chloride and
acetonitrile), where both 2 and iodobenzene are fully soluble.
Given these negative controls in both aqueous and organic
media, we sought to determine if reactivity was possible under
the influence of supramolecular host 1. It has been
demonstrated previously that 1 functions as a halide abstractor
toward neutral organometallics, promoting encapsulation of
While the resulting Cu(I)−I phosphonium product (4) was
unexpected, it implies room-temperature carbon−iodine
oxidative addition with encapsulated 3 followed by rapid
aryl−phosphine reductive elimination via a putative Cu(III)
intermediate (II, Scheme 1). Lack of reactivity in control
studies indicated that reaction progress is specific to cage 1 and
raises the question as to the exact role of the host in this
transformation and whether the same reactivity could be
Figure 2. (a) Encapsulation of copper(I) complex 3 in a 1:1 host:guest ratio determined by 1H NMR (500 MHz, 25 °C). (b) Coencapsulation of
aryl iodide and 3.20 (c) Encapsulated product 4 after oxidative addition and rapid reductive elimination of iodobenzene.
B
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observed with an exogenous halide abstractor. To this end,
sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (Na-
BArF) was investigated as a model halide abstractor for this
transformation (Table 1).
however, upon investigating iodotoluene substrates (Table 2,
entries 4−6). Combining para-iodotoluene with encapsulated
3 did not result in coencapsulation or new reactivity, as
evidenced by 1H NMR spectroscopy. Coencapsulation of
meta-iodotoluene was also not observed; however, starting
material was slowly consumed and resulted in the formation of
the analogous phosphonium product with heating (50 °C, 12
h), suggesting that this substrate undergoes rapid ingress/
egress.24 ortho-Iodotoluene showed coencapsulation as ob-
served with iodobenzene, but no subsequent reactivity at room
temperature. As with meta-iodotoluene, warming the reaction
mixture resulted in full conversion to the analogous
phosphonium salt.
From this it is found that in the case of para-substituted
iodotoluenes (Table 2, entries 3 and 4) no Michaelis complex
is observed along with no detectable conversion due either to
poor guest encapsulation or to steric encumbrance of the
elongated substrate. Furthermore, meta-iodotoluene (Table 2,
entry 4) reacts sluggishly (12 h at 50 °C) without the
observation of a Michaelis complex, indicating more favorable
exchange or steric profile. However, when a defined Michaelis
complex is observed, reactivity under mild conditions (12 h at
RT) proceeds as in the case of iodotoluene. An exception is
when substrate steric hindrance occurs, as is the case with
ortho-iodotoluene, requiring more forcing conditions (12 h at
50 °C).
This reactivity is congruent with previous reports demon-
strating that two substrate molecules of iodobenzene and
ortho-iodotoluene encapsulate within 1, whereas only a single
molecule of meta- and para-iodotoluene can be accommo-
dated, consistent with the hypothesis that reactivity is specific
to strongly bound guests.25 Furthermore, it is worth noting
that although para-iodotoluenes are more reactive toward
oxidative addition than ortho-iodotoluenes under traditional
organic conditions, this trend is reversed under host-mediated
conditions. Confinement within the host thus not only enables
iodoarene activation under unusually mild conditions but also
gives rise to atypical selectivities due to differential guest
binding.
In light of these results, we sought to demonstrate that host
stabilization of a cationic organometallic species in the
presence of a good organic guest could facilitate another
transformation contingent upon the presence of 1. The
Pd(II)/Pd(IV) oxidative addition/reductive elimination cycle
with iodoarenes was selected as a challenging but interesting
manifold to investigate. Initial studies were conducted with
(DMPE)Pd(II)MeCl, which, analogously to Cu complex 2,
was quantitatively encapsulated within the host as the
monocationic species (see Supporting Information, p 7).
Upon addition of iodobenzene to the host-encapsulated
DMPE Pd(II)Me cation, rapid conversion of the encapsulated
species was observed by 1H NMR spectroscopy. Analysis of the
extracted reaction mixture revealed trace amounts of toluene, a
product expected from oxidative addition/reductive elimina-
tion of the methyl and aryl ligands. The control reaction in the
absence of host, however, demonstrated significant background
reactivity, presumably due to solubility and stability of
(DMPE)Pd(II)MeCl in water. Attributing this stability to
the strongly coordinating bidentate phosphine ligands,
monodentate PEt3 Pd dimer 6 was investigated.
Table 1. Reaction Conditions and Results for Control
Experiments
entry
halide abstractor
NaBArF
solvent
product 4
trace
no conversion
complex mixture
no conversion
no conversion
no conversion
1
2
3
4
5
6
D2O
D2O
DCM
DCM
MeCN
MeCN
NaBArF
NaBArF
Copper complex 2, iodobenzene, and 2 equiv of NaBArF
were combined in water. The solubility of the starting complex
improved slightly, and monitoring over extended times
resulted in trace 4 by {1H}31P NMR, while no reactivity was
observed with addition of NaBArF to 2 in acetonitrile. A
mixture of products was observed when the reaction was
conducted in dichloromethane; however, after removal of
solvent from this reaction and addition of 1 in D2O, no
encapsulated phosphonium species were observed, suggesting
that 4 was not present in the crude reaction mixture.
Furthermore, addition of 2 equiv of iodobenzene to DMPE
in refluxing benzene resulted in no reactivity over extended
reaction times, verifying the participation of copper in
phosphonium formation. Taken together, these data demon-
strate that host 1 is uniquely selective for this transformation
and different approaches result in either trace to no conversion
or nonproductive (decomposition) reactivity.
To further explore the generality of the above reactivity,
additional substrates were screened for oxidative addition/
reductive elimination with encapsulated 3. This screening
indicated that stabilization of Cu(I) cation 3 within 1 was not
the only factor responsible for the observed reactivity. For
instance, oxidative addition with aryl halide substrates bearing
para-electron-donating and -withdrawing substituents gave no
conversion (Table 2, entries 2, 3). Insight was gleaned,
Table 2. Investigating Oxidative Addition Protocol with
Alternative Substrates
entry
X
R1
R2
R3
Michaelis complex/oxidative addition
1
2
3
4
5
6
Br
I
I
I
I
H
H
H
H
H
Me
H
H
H
Me
H
H
F
OMe
H
Me
H
observed, no conversion
not observed, no conversion
not observed, no conversion
not observed, full conversion
not observed, no conversion
a
a
The lack of solubility of 6 in water resulted in no reactivity
with iodobenzene in a background control reaction. Utilization
of a halide abstractor (NaBArF) resulted in rapid decom-
I
H
observed, full conversion
a
Reaction performed at 50 °C.
C
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position to palladium black with no iodobenzene activation.
Despite significantly improved solubility in dichloromethane,
no reaction was observed between iodobenzene and 6, and
heating (100 °C) eventually resulted in decomposition.
Addition of a halide abstractor to the reaction mixture in
dichloromethane resulted in rapid decomposition, which again
precluded reactivity with iodobenzene (Table 3).
oxidative addition and subsequent Csp3−P or Csp2−P
reductive elimination to give 8 and 9, respectively. In addition
to phosphonium products, toluene was detected by H NMR
1
spectroscopy and GC/MS analysis upon workup, thus
supporting the intermediacy of a putative Pd(IV) complex
that can also undergo Csp2−Csp3 reductive elimination.
As the Pd(0)/Pd(II) redox cycle may also be a possible
mechanism for the production of the species observed above,
additional control experiments were performed to determine if
this cycle was operative. Generation of encapsulated 8 and
palladium black occurs without the addition of iodobenzene
over extended times. Since reductive elimination provides a
source of Pd(0) that, although very insoluble, could result in
Pd(0) reactivity and subsequent product formation, additional
control experiments were performed. A sample of 7 was
allowed to stand for 24 h, yielding full conversion of the
starting material to Pd(0) and encapsulated 8. Introduction of
iodobenzene to this mixture resulted in no formation of 9, and
Table 3. Reaction Conditions and Results for Control
Experiments
entry
halide abstractor
NaBArF
solvent
result
1
2
3
4
D2O
D2O
DCM
DCM
Pd(0), trace 8
no conversion
Pd(0), trace 8
no conversion
NaBArF
1
only residual iodobenzene was detected by H-NMR or GC/
MS analysis, suggesting that oxidative addition/reductive
elimination is occurring within host 1 from a Pd(II) species.
In conclusion, the ability of supramolecular host 1 to
stabilize a reactive cationic organometallic in the presence of a
well-encapsulated iodoarene guest has demonstrated reactivity
that occurs selectively within the host cavity. The observation
that oxidative addition with simple Cu(I) and Pd(II) salts
occurs under mild conditions in water illustrates that
supramolecular cages can provide access to host-selective
reaction trajectories.
Combining palladium dimer 6 with the host provided
quantitative encapsulation of a unique monomeric cationic Pd
species 7 (Figure 3a). In analogy to our observations using Cu
complex 2, it is proposed that dimer cleavage and palladium
uptake by the host occurs with concomitant loss of chloride to
yield a stabilized palladium cation, which is presumably
solvated within the host. Upon addition of iodobenzene (5
equiv), encapsulated 7 was consumed, and two distinct species
formed. The identity of the products, 8 and 9, was verified by
direct analogy to authentically prepared phosphonium salts.
The generation of these products is indicative of iodoarene
Figure 3. (a) 1H NMR analysis (500 MHz, 25 °C) of palladium(II) monomer 7 encapsulated in host 1. (b) Coencapsulation of aryl iodide and 7.
1
(c) H NMR analysis after addition of iodobenzene, indicating encapsulation of phosphonium products 8 and 9.
D
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(10) Wang, Z. J.; Brown, C. J.; Bergman, R. G.; Raymond, K. N.;
Toste, F. D. Hydroalkoxylation Catalyzed by a Gold(I) Complex
Encapsulated in a Supramolecular Host. J. Am. Chem. Soc. 2011, 133,
7358−7360.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b11842.
■
S
(11) Otte, M. Size-Selective Molecular Flasks. ACS Catal. 2016, 6,
6491−6510.
General synthetic procedures, ESI-MS data, and
characterization of new compounds (PDF)
(12) Leung, D. H.; Bergman, R. G.; Raymond, K. N. Highly
Selective Supramolecular Catalyzed Allylic Alcohol Isomerization. J.
Am. Chem. Soc. 2007, 129, 2746−2747.
AUTHOR INFORMATION
■
(13) Brown, C. J.; Miller, G. M.; Johnson, M. W.; Bergman, R. G.;
Raymond, K. N. High-Turnover Supramolecular Catalysis by a
Protected Ruthenium(II) Complex in Aqueous Solution. J. Am. Chem.
Soc. 2011, 133, 11964−11966.
Corresponding Authors
*rbergman@berkeley.edu
*raymond@socrates.berkeley.edu
*fdtoste@berkeley.edu
́
(14) García-Simon, C.; Gramage-Doria, R.; Raoufmoghaddam, S.;
Parella, T.; Costas, M.; Ribas, X.; Reek, J. N. H. Enantioselective
Hydroformylation by a Rh-Catalyst Entrapped in a Supramolecular
Metallocage. J. Am. Chem. Soc. 2015, 137, 2680−2687.
ORCID
F. Dean Toste: 0000-0001-8018-2198
Author Contributions
(15) Dydio, P.; Detz, R. J.; de Bruin, B.; Reek, J. N. H. Beyond
Classical Reactivity Patterns: Hydroformylation of Vinyl and Allyl
Arenes to Valuable β- and γ-Aldehyde Intermediates Using Supra-
molecular Catalysis. J. Am. Chem. Soc. 2014, 136, 8418−8429.
(16) Cavarzan, A.; Scarso, A.; Sgarbossa, P.; Strukul, G.; Reek, J. N.
H. Supramolecular Control on Chemo- and Regioselectivity via
Encapsulation of (NHC)-Au Catalyst Within a Hexameric Self-
Assembled Host. J. Am. Chem. Soc. 2011, 133, 2848−2851.
‡T. A. Bender and M. Morimoto contributed equally.
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). The
Advanced Light Source is supported by the Director, Office
of Science, Office of Basic Energy Sciences, of the U.S.
Department of Energy under Contract No. DE-AC02-
05CH11231. We gratefully thank Dr. Rita V. Nichiporuk for
her expertise and guidance in electrospray mass spectrometry
of metal−ligand complexes and Dr. Michael W. Mara for XAS
measurements.
(17) For a selection of organic reactions with dependence on a
supramolecular host, see: (a) Dalton, D. M.; Ellis, S. R.; Nichols, E.
M.; Mathies, R. A.; Toste, F. D.; Bergman, R. G.; Raymond, K. N.
12−
Supramolecular Ga4L6 Cage Photosensitizes 1,3-Rearrangement of
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Soc. 2015, 137, 10128−10131. (b) Wu, N. W.; Rebek, J. Cavitands as
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Water. J. Am. Chem. Soc. 2016, 138, 7512−7515. (c) Shi, Q.;
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(20) Detection of coencapsulated iodobenzene and copper species 3
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However, direct NOE correlation of an analogous substrate, ortho-
iodotoluene, and copper species 3 was observed. See Supporting
Information for experimental details.
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