Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones: Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles

Article abstract of DOI:10.1021/jacs.8b11840

Catalytic carbonyl-olefin metathesis reactions have recently been developed as a powerful tool for carbon-carbon bond formation. However, currently available synthetic protocols rely exclusively on aryl ketone substrates while the corresponding aliphatic analogs remain elusive. We herein report the development of Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis reactions for aliphatic ketones. Mechanistic investigations are consistent with a distinct mode of activation relying on the in situ formation of a homobimetallic singly bridged iron(III)-dimer as the postulated active catalytic species. These "superelectrophiles" function as more powerful Lewis acid catalysts that form upon association of individual iron(III)-monomers. While this mode of Lewis acid activation has previously been postulated to exist, it has not yet been applied in a catalytic setting. The insights presented are expected to enable further advancement in Lewis acid catalysis by building upon the activation principle of "superelectrophiles" and to broaden the current scope of catalytic carbonyl-olefin metathesis reactions.

Full text of DOI:10.1021/jacs.8b11840

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Article
Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones:
Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles
Haley Albright, Paul S. Riehl, Christopher C. McAtee, Jolene P Reid, Jacob Ryan Ludwig,
Lindsey Karp, Paul M. Zimmerman, Matthew S Sigman, and Corinna S. Schindler
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 31 Dec 2018
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Catalytic Carbonyl‐Olefin Metathesis of Aliphatic Ketones: Iron(III)
Homo‐Dimers as Lewis Acidic Superelectrophiles
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Haley Albright,† Paul S. Riehl,† Christopher C. McAtee,† Jolene P. Reid,§ Jacob R. Ludwig,† Lindsey A.
Karp,† Paul M. Zimmerman,† Matthew S. Sigman§ and Corinna S. Schindler.*,†
†Willard Henry Dow Laboratory, Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Ar-
bor, Michigan 48109, United States
§University of Utah, Department of Chemistry, 315 South 1400 East, Salt Lake City, Utah 84112, United States
Supporting Information Placeholder
ABSTRACT: Catalytic carbonyl-olefin metathesis reactions have recently been developed as a powerful tool for carbon-carbon bond
formation. However, currently available synthetic protocols rely exclusively on aryl ketone substrates while the corresponding ali-
phatic analogs remain elusive. We herein report the development of Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis
reactions for aliphatic ketones. Mechanistic investigations are consistent with a distinct mode of activation relying on the in situ
formation of a homobimetallic singly-bridged iron(III)-dimer as the postulated active catalytic species. These “superelectrophiles”
function as more powerful Lewis acid catalysts that form upon association of individual iron(III)-monomers. While this mode of
Lewis acid activation has previously been postulated to exist, it has not yet been applied in a catalytic setting. The insights presented
are expected to enable further advancement in Lewis acid catalysis by building upon the activation principle of “superelectrophiles”
and to broaden the current scope of catalytic carbonyl-olefin metathesis reactions.
Introduction
[2+2]-cycloaddition resulting in the desired metathesis product.
While successful protocols for intramolecular and intermolecu-
Carbonyl-olefin metathesis reactions are at the forefront of cur-
lar Lewis acid-catalyzed carbonyl-olefin metathesis have been
rent research as a result of their potential for direct carbon-car-
reported following this reaction design principle,7,8 all current
bon bond formation between carbonyl and olefin functionali-
procedures rely exclusively on aryl carbonyls as substrates
ties. Distinct approaches for carbonyl-olefin metathesis have
while the reaction of aliphatic ketones remain elusive.4-8 We re-
been advanced relying on stepwise oxetane formation and sub-
port herein the development of a catalytic carbonyl-olefin ring-
sequent fragmentation,1 the use of molybdenum alkylidenes as
closing metathesis of aliphatic ketones that proceeds in yields
reagents,2 or bicyclic hydrazine catalysts which enable the first
up to 94% and tolerates a variety of functional groups. Mecha-
catalytic protocol to effect this transformation.3 Additionally,
nistic investigations reveal a distinct mode of activation for ali-
Lewis acid-catalyzed protocols have recently been developed as
phatic ketones relative to their aromatic analogs in which the
a viable reaction design for carbonyl-olefin metathesis.4-6 Upon
formation of a homobimetallic singly-bridged iron(III)-dimer as
binding to a Lewis acid catalyst, such as FeCl3, the carbonyl
the active catalytic species enables the formation of a signifi-
functionality is activated to perform a [2+2]-cycloaddition
cantly enhanced electrophilic moiety.
forming an intermediate oxetane, which subsequently under-
goes a retro-
In our initial efforts to develop an FeCl3-catalyzed carbonyl-
olefin metathesis reaction, we had investigated both aryl ketone
1 and aliphatic ketone 4 in their ability to undergo the desired
transformation and observed profound differences in reactiv-
ity.5a While phenyl ketone 1 leads to carbonyl-olefin metathesis
product 2 in 99% yield relying on 5 mol % FeCl3 as the Lewis
acid catalyst (Fig. 1), the corresponding methyl ketone 4 failed
to undergo the desired transformation under otherwise identical
reaction conditions. As part of our mechanistic investigations
towards FeCl3-catalyzed carbonyl-olefin metathesis reactions,5c
we identified three main challenges associated with aliphatic
ketones as substrates. 1) In the carbonyl-olefin metathesis reac-
tions of aryl ketones, catalyst turnover is enabled due to the fa-
vored binding of the substrate 8 to FeCl3 by 2.4 kcal/mol in
Figure 1. Comparison of aryl ketones and aliphatic ketones in
comparison to acetone 6 (Fig. 2A). However, aliphatic ketones
FeCl3-catalyzed carbonyl-olefin metathesis.
(7) bind less strongly to the FeCl3 catalyst by ~1 kcal/mol as
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3) Recent investigations of Brønsted acid-catalyzed oxygen
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8
atom transfer reactions have shown that alternate oxetane frag-
mentation pathways exist competing with carbonyl-olefin me-
tathesis reactions.9 Specifically, acidic protons in the α-position
to the carbonyl functionality can engage in distinct oxetane
fragmentation pathways under acid-catalyzed conditions form-
ing the corresponding unsaturated alcohols 10 via elimination
(Fig. 2C).10 On the basis of the identified challenges, we ex-
pected aliphatic ketones to require activation by a Lewis acid
far exceeding the strength of FeCl3. Additionally, we switched
from β-ketoester 4 bearing an acidic α-proton to methyl ketone
11 incorporating an α-quaternary carbon as a substrate for the
evaluation of distinct Lewis acids to avoid competing oxetane
fragmentation pathways (Table 1).
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Results and Discussion
Our initial efforts focused on the evaluation of more powerful
Lewis acids compared to FeCl3 upon conversion with aliphatic
ketone 11. However, using substoichiometric amounts of the
strong Lewis acid, AlCl3, no formation of the desired metathesis
product 12 was observed (entry 1, Table 1). Nevertheless, the
use of stoichiometric amounts of the strong Lewis acid ethyl
aluminum sesquichloride (EASC) resulted in the formation of
12 in 30% yield and with complete consumption of substrate 11
(entry 6, Table 1). Control reactions with weaker Lewis acids,
including SnCl4 and GaCl3 also resulted in the formation of the
desired cyclopentene 12, albeit in low yields of 30% and 21%,
respectively, and increased decomposition of starting material
(entries 3 and 5, Table 1). Similarly, BF3ꞏEt2O formed the de-
sired product in 24% while TiCl4 failed to provide cyclopentene
12 under otherwise identical reaction conditions. Based on this
range of reactivities observed with Lewis acids varying in
strength, we investigated varying amounts of FeCl3 upon con-
version with methyl ketone 11. Surprisingly, formation of me-
tathesis product 12 was observed in yields of up to 44% with an
abbreviated reaction time of 15 minutes, in comparison to 16 to
24 hours with other Lewis acids (entry 7, Table 1). Increasing
catalyst loading to 10 mol % FeCl3 proved beneficial and re-
sulted in improved yields of 68% within 15 minutes (entry 8,
Table 1). Further efforts identified conducting the reaction for
3 hours as optimal, resulting in 74% yield of metathesis product
12 and 78% conversion of starting material 11 (entry 9, Table
1). In ensuing attempts to further optimize this transformation,
we observed a decreased yield of 37% when the reaction was
conducted in dichloromethane as solvent under otherwise iden-
tical reaction conditions (entry 10, Table 1). Furthermore, no
formation of the desired metathesis product 12 was detected us-
ing toluene as the reaction solvent. Both of these results are in
stark contrast to carbonyl-olefin metathesis reactions of aryl ke-
tones which tolerate chlorinated hydrocarbon solvents as well
as aromatic solvents.5a,c Less than stoichiometric amounts of
Brønsted acids including HCl, TfOH, and H2SO4 did not result
in the formation of the desired carbonyl-olefin metathesis prod-
uct 12 (entries 12-14, Table 1). Interestingly, the results ob-
tained relying on FeCl3 as optimal Lewis acid catalyst did not
corroborate our preceding theoretical investigations focused on
enthalpies for Lewis acid activation that predict the need for a
more potent Lewis acid to effectively activate aliphatic ketones
(Fig. 2).
Figure 2. Challenges associated with aliphatic ketones in cata-
lytic carbonyl-olefin metathesis reactions.
compared to their aromatic analogs (8) thereby requiring
stronger Lewis acids to efficiently activate these less reactive
substrates for carbonyl-olefin metathesis (Fig. 2A). Addition-
ally, competitive binding of the Lewis acid with the acetone by-
product 3 is more prominent for aliphatic ketones and catalyst
inhibition becomes a concern. 2) Our mechanistic investiga-
tions identified the aromatic moiety of aryl ketones as a required
structural component that plays a crucial role in transition state
stabilization5c by redistributing electron density (8, Fig. 2B).
Table 1. Lewis acid evaluation in the carbonyl-olefin metathe-
sis of aliphatic ketone 11.
We next explored the effect of varying alkene substitution in
the iron (III)-catalyzed carbonyl-olefin metathesis reaction of
aliphatic ketones. While ketone 11a bearing a prenyl fragment
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tified as the most promising additive enabling catalytic car-
Table 2. Evaluation of olefin substitution in the carbonyl-olefin
1
2
metathesis of aliphatic ketones 11a-f.
bonyl-olefin metathesis of electronically differentiated styrene
derivatives in up to 78% yield (Table 2).
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9
The optimized reaction conditions developed for the catalytic
carbonyl-olefin metathesis of aliphatic ketones proved efficient
for a variety of substrates incorporating distinct substituents and
functional groups (Tables 3 and 4). Substrates including elec-
tron-deficient aryl residues in the β-position resulted in good to
excellent yields of 63-93% of the desired metathesis products
(13-17, Table 3). Electron-rich aryl-moieties bearing methyl,
isopropyl, tert-butyl or methoxy substituents provided up to
94% yield of the desired products (18-21, Table 3). Addition-
ally, substrates with methyl or chloro substituents in the ortho-
position led to diminished yields of 63% and 50%, respectively
(25 and 26), while meta-substituted substrates provided good
yields ranging from 64-76% (22-24, Table 3). Interestingly, a
thiophene-containing substrate was well tolerated under the re-
action conditions resulting in 54% yield of the desired product
27. In addition to methyl ketones, distinct aliphatic substituents
including ethyl and isobutyl carbonyls were tolerated under the
optimized reactions conditions (30, 31 and 32, Table 4) alt-
hough in slightly lower yields of 34-62%, presumably due to
the increased steric bulk near the reactive carbonyl. Substrates
bearing additional alkene functionalities, such as cinnamyl and
geranyl substituents, proved compatible and resulted in the cor-
responding products 37 and 38 in 60% and 31% yield, respec-
tively. Various substituents in the α-position to the carbonyl
were tolerated under the reaction conditions. Cyclopentene 36
bearing two aliphatic moieties was obtained in 56% yield while
cyclopropyl derivative 35 was formed in 58% isolated yield.
Substrates bearing the β-ketoester moiety (44, 45, and 46, Table
4) yielded lower amounts of the metathesis products or did not
undergo metathesis at all. Cyclohexyl carbonyl derivatives were
efficient under the optimized reaction conditions leading to the
formation of the corresponding bicyclic scaffolds in up to 78%
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resulted in the formation of metathesis product 12 in 74% yield,
the corresponding styrenyl analogs 11b-11f initially showed lit-
tle or no reactivity under identical reaction conditions. Subse-
quent studies revealed that the lack of reactivity can be at-
tributed to competing product inhibition of the aryl aldehyde
byproduct formed (see Supporting Information for details).
Therefore, we focused on the evaluation of reagents capable of
sequestering the corresponding aldehyde byproducts to avoid
catalyst inhibition.5f Ultimately, allyltrimethylsilane was iden-
Table 3. Substrate scope of aryl variation.
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Table 4. Substrate scope of distinct functional group incorporation.
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yield (39-43). Interestingly, a cycloheptyl-derived substrate did
not result in the formation of the desired metathesis product, but
led to the isolation of oxetane 4711 in 52% yield, providing ad-
ditional support for the reaction mechanism.
sulting in optimal yields of 74% (entry 6, Table 5). No product
was observed relying on toluene as solvent and diminished
yields of 37% under otherwise identical conditions were ob-
tained in dichloromethane (entries 4 and 5, Table 5). In compar-
ison, product formation in high yields ranging from 65% to 99%
is observed when the corresponding aryl ketone 48 is reacted
with 5 mol % of FeCl3 in these solvents. 2) Higher catalyst load-
ings of 10 mol % FeCl3 were shown to result in higher yields of
the desired carbonyl-olefin metathesis product 12 while the
analogous transformation of aryl ketones 48 proceeds in high
yields with as little as 1 mol % FeCl3. 3) Additionally, subse-
quent gas-phase simulations of the reaction path for FeCl3-cat-
alyzed carbonyl-olefin metathesis of aliphatic ketone 11 re-
vealed activation barriers of >25 kcal/mol which are too high
for the reaction to proceed. Comparatively, the corresponding
activation barrier for aryl ketones was found to be 14.5 kcal/mol
(Table 5).
Mechanistic Investigations
Over the course of our studies towards optimizing catalytic car-
bonyl-olefin metathesis reactions of aliphatic ketones, we note
three key differences in reactivity compared to aryl ketone sub-
strates. 1) FeCl3-catalyzed carbonyl-olefin metathesis of ali-
phatic ketones proceeded best in dichloroethane as solvent re-
Table 5. Evaluation of solvent and catalyst loading for aryl (48)
vs. aliphatic (11) ketone substrates.
Intrigued by the high reactivity of FeCl3 and unique solvent de-
pendence observed in the carbonyl-olefin metathesis of ali-
phatic ketone 11, we initiated kinetic studies to obtain further
insight into the controlling features of this transformation (Fig.
3). Mechanistic investigations of the catalytic carbonyl-olefin
metathesis reaction of aryl ketone 1 had previously revealed a
zero order dependence on substrate concentration and first order
dependence in FeCl3.5c This indicated that the catalyst resting
state has monomeric FeCl3 bound to the substrate in Lewis acid-
base complex 50 and undergoes a classic activation mode with
a single Lewis acid monomer (Fig. 3). Similarly, carbonyl-ole-
fin metathesis of aryl ketone 48 bearing an α-quaternary center
was also found to have first order dependence on FeCl3 concen-
tration and zero order in substrate. Importantly, kinetic evalua-
tion of the analogous aliphatic ketone 11 also displayed zero
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Figure 3. Kinetic investigations of the catalytic carbonyl-ole-
fin metathesis reaction with two independent methods relying
on “initial rates” based on the decay of substrate and the “Nor-
malized time scale method”. A. Rate order results for aryl ke-
tones. B. Rate order results for aliphatic ketones. C. Catalytic
resting states following kinetic investigation.
Figure 4. A. Lewis acid activation modes (M = metal) and pos-
tulated activation mode: “superelectrophiles”. B. Homobime-
tallic association of Lewis acids in Friedel-Crafts alkylation and
Diels-Alder reactions.
under Olah’s definition of superelectrophiles15 by exhibiting re-
activity that substantially exceeds that of their corresponding
monomer 55. While the synthetic realization and application of
heterobimetallic superelectrophiles that result from the associa-
tion of Lewis acids comprised of two different metals has led to
important developments in organometallic chemistry,16 the re-
lated homobimetallic case is still considered uncommon.17 Con-
sequently, the principle of homobimetallic association of Lewis
acids has remained unexplored in catalysis. Isolated reports of
order with respect to substrate, which is consistent with a cata-
lyst resting state of monomeric FeCl3 bound to substrate (52,
Fig. 3). However, ketone 11 was shown to proceed with second
order kinetics in FeCl3,12,13 implying that a different mode of
Lewis acid activation is operative for aliphatic ketones (Fig. 3).
Specifically, these kinetic results are consistent with a hypoth-
esis that two equivalents of FeCl3 are involved in the rate-deter-
mining step of carbonyl-olefin metathesis of aliphatic ketones
while only one equivalent of FeCl3 is involved in the analogous
reaction of aryl ketones.
It has previously been postulated that individual Lewis acid
monomers 55 could associate to form singly-bridged dimers 54
that retain an open coordination site rendering them as stronger
Lewis acids than their corresponding monomers (Fig. 4A). This
strategy was described as a “highly desirable”14 reaction design
principle in Lewis acid catalysis as early as the 1960s as an ap-
proach to generate stronger Lewis acids by taking advantage of
their inherent tendency to associate into “superelectrophiles”.
Polarization of singly-bridged dimers 54 could induce subse-
quent ionization into doubly electron-deficient ion pairs 53. Im-
portantly, both singly-bridged dimers 54 and ion pairs 53 fall
Figure 5. Proposed superelectrophiles for aliphatic ketones in
catalytic carbonyl-olefin metathesis reactions.
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coworkers to suggest an activation mode based on Lewis acid
A. IR Spectroscopic Measurements Support Iron-Dimer
1
2
3
4
5
6
7
8
superelectrophiles (59, Fig. 4B) but dimers 54 or ion pairs 53
could not be differentiated. Later, Evans suggested carbonyl ac-
tivation by homobimetallic ion pairs 60 in stoichiometric
Et2AlCl-mediated Diels-Alder reactions to account for unique
reactivity observed with Al-based Lewis acids (Fig. 4B).19,20,21
97
91
85
1700 cm-1
Based on this literature precedent and our results obtained in the
kinetic investigations, we considered two distinct activation
modes for aliphatic ketones in catalytic carbonyl-olefin metath-
esis reactions relying on singly-bridged FeCl3 dimer (61) or ion
pair (62) (Fig. 5). In the neutral pathway, the first equivalent of
FeCl3 binds aliphatic ketone 11 to form the catalyst resting state
52. Coordination of a second equivalent of FeCl3 generates sin-
gly-bridged homobimetallic dimer 61 (Fig. 5) as a Lewis acid
superelectrophile. The resulting increase in substrate polariza-
tion leads to efficient activation of the substrate for carbonyl-
olefin metathesis. Alternatively, homobimetallic dimer 61 can
undergo solvent-assisted polarization to result in ion pair 62,
which similarly represents a Lewis acid superelectrophile capa-
ble of activating the substrate for carbonyl-olefin metathesis.
O
1642
Me
Ph
1615
Me
Me
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Me
63
substrate 63
substrate 63 + 1 equiv FeCl3
substrate 63 + 2 equiv FeCl3
1700
1710
1760
1660
1610
1560
1510
wavenumbers (cm-1
)
B. Calculations Support IR Results
Cl
Cl
Cl
Cl
In order to gain initial support for the formation of Lewis acid
superelectrophiles and differentiate between neutral singly-
bridged dimers or ion pairs as active catalytic species, we con-
ducted infrared spectroscopic measurements that relate Lewis
acid-carbonyl activation to Lewis acid strength based on the
change in absorption frequency observed.22,23 A new signal with
an absorption frequency of 1642 cm-1 is observed when ketone
63 is treated with equimolar amounts of FeCl3, consistent with
1642 cm-1
1615 cm-1
Fe
Fe
Cl
Fe
Cl
Cl
Cl
O
O
Cl
Me
Me
Ph
Me
Ph
Me
Me
Me
more Lewis
acidic
Me
Me
64
65
(measured) = 27 cm-1 vs. (calculated) = 20.02 cm-1
C. Raman Spectroscopic Measurements Support Iron-Dimer
4
DCE
Et4NFeCl4
63 + 1 equiv FeCl3
63 + 2 equiv FeCl3
Et4NCl
3
FeCl3
2
FeCl4
330
FeCl3
1
360
0
-1
-2
170
236
302
368
434
500
Raman Shift (cm-1
)
Cl
Cl
Cl
Cl
Fe
Fe
Fe
Cl
Cl
Cl
Cl
O
O
Me
Me
FeCl4
Me
Ph
Me
Ph
Me
Me
Me
Me
65
66
Figure 6. A. Infrared spectroscopic measurements of 63. B.
Calculations for IR data. C. Raman spectroscopic data of 63.
homobimetallic association of Lewis acids have been postu-
lated to be operative but exclusively in stoichiometric reaction
settings. The observation of second order rate dependence in
GaCl3-mediated Friedel-Crafts alkylations18 led Brown and
Figure 7. Electron paramagnetic resonance spectroscopic
measurements of 63.
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single carbonyl activation upon coordination of FeCl3 to form
complex 64 (Fig. 6A). Addition of a second equivalent of FeCl3
1
2
3
4
5
6
7
8
9
resulted in a third signal with a lower absorption frequency at
1615 cm-1, suggesting increased carbonyl activation of 63 by a
stronger Lewis acid. Both the singly-bridged FeCl3 dimer (61)
and the corresponding ion pair (62) are expected to lower car-
bonyl absorption frequencies upon coordination and are con-
sistent with calculations of the expected differences in shifts of
absorption frequencies that match the experimentally observed
shifts (ΔC=Omeasured vs. ΔC=Ocalc.: 27 vs. 20.0 cm-1) (Fig. 6B).
10
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Experiments relying on Raman spectroscopy show no for-
-
mation of FeCl4 (330 cm-1)25,26 upon addition of FeCl3 to ali-
phatic ketone 63 in dichloroethane (Fig. 6C) indicating that the
ion pair 66 is not present. Electron paramagnetic resonance
(EPR) experiments were performed to gain further support for
the catalyst resting state in this transformation and distinguish
between singly-bridged dimers or ion pairs as active catalytic
species. Increasing amounts of aliphatic ketone 63 were added
to a solution of FeCl3 in dichloroethane while the concentration
of FeCl3 remained the same (Fig. 7). High spin EPR spectra
with g = 4.29 were obtained for all ratios of 63 bound to FeCl3
as expected for iron (III) species. The addition of excess ali-
phatic ketone 63 leads to an increase in signal strength, con-
sistent with an iron(III)-bound complex 64 as the major species
in solution and supports the catalyst resting state of monomeric
FeCl3 bound to substrate. In comparison, the singly-bridged
Figure 8. A. Proposed homobimetallic superelectrophile utilizing
different Lewis acids. B. Generation of stronger superelectrophiles
with MCl3 and MBr3 to increase reactivity.
homo-dimer 65 is expected to be favored with an excess of
FeCl3 relative to ketone 63. While the homo-dimer 65 is EPR
silent, the corresponding monomeric complex 64 is EPR active
Figure 9. Quantum chemical investigations. A. Enthalpic profile and B. reaction pathway of the computationally proposed
reaction mechanism for carbonyl-olefin metathesis of aliphatic ketones using FeCl3.
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in accordance with the observed signal. Importantly, no signal
-
is observed for the FeCl4 anion, which is EPR-active,24 provid-
1
2
ing additional support for a neutral reaction pathway.
3
4
5
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7
8
9
These combined mechanistic investigations and substrate eval-
uation in the carbonyl-olefin metathesis reaction of aliphatic ke-
tones support a carbonyl-activation mode based on iron(III)
homo-dimers as superelectrophiles. To reinforce this hypothe-
sis, we examined the possibility of generating even more reac-
tive dimers functioning as Lewis acidic superelectrophiles
which could lead to increased yields of the desired metathesis
products. The composition of GaCl3 and GaBr3 mixtures in non-
polar solvents has previously been studied by Černý and
coworkers.27 Specifically, halogen exchange between both
Lewis acids was shown to occur and the predominant species at
equimolar composition are Ga2Cl3Br3 and Ga2Cl4Br2. We pos-
tulated that two distinct iron-derived Lewis acids bearing sub-
stituents differing in electronegativity, specifically FeCl3 and
FeBr3, would also undergo halogen exchange in solution to
form a stronger Lewis acidic superelectrophile in situ which
could result in increased yields of the desired metathesis prod-
uct (Fig. 8). When 10 mol % of a 1:1 ratio of FeCl3 and FeBr3
was used with ketone 11, the desired carbonyl-olefin metathesis
product was obtained in a slightly higher yield when compared
to the FeCl3 homo-dimer (82% yield vs. 74% yield). This result
is consistent with the hypothesis that stronger superelectro-
philes can be generated from dissimilar iron-based Lewis acids
and result in increased substrate activation (see Supporting In-
formation for additional experimental and spectroscopic details
on this experiment).
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As a next step, quantum chemical simulations were performed
to probe the mechanism of catalytic carbonyl-olefin metathesis
reaction of aliphatic ketones.28,29 These simulations were per-
formed using density functional theory at the B97-D level in-
cluding implicit solvation, see Supporting Information for more
details. Figure 9 shows the most favorable reaction pathway
found for the monomeric FeCl3-substrate complex (shown in
grey) and the corresponding singly-bridged homo-dimer
(shown in blue). Both pathways consist of concerted, asynchro-
nous ring-closing (B) and ring-opening (D) steps involving an
oxetane intermediate C, which were operative in the carbonyl-
olefin metathesis of aryl ketones. The overall barriers, however,
show that the initial step of the reaction is enthalpically pre-
ferred by 3.5 kcal/mol when two equivalents of FeCl3 are bound
to the substrate in a homo-dimeric manner. The most favored
computed metathesis pathway is the Lewis acid activation of a
Lewis acid, which ultimately leads to a superelectrophile func-
tioning as a stronger catalyst consistent with contraction of the
Fe-O bond by 0.05Å in A compared to the monomeric FeCl3-
complex (see Supporting Information for details). Likewise, the
Fe-Cl distance of the Fe-Cl-Fe bridge is elongated by 0.12Å,
resulting in charge transfer from the first iron to the second iron
as this bond is activated. In total, a single FeCl3 molecule is able
to withdraw 0.33 electrons from the substrate, but two mole-
cules of FeCl3 extract 0.45 units of charge. This increased
charge withdrawal through this singly-bridged dimer is needed
for aliphatic substrates, but seemingly not for the corresponding
aryl analogs due to the ability of aryl ketones to delocalize
charge through conjugation. These simulations are therefore
consistent with spectroscopic results, which display increased
Figure 10. Evaluation of aromatic α-substituent features dictating
rate in the reaction of aliphatic ketones. A. MLR model using ben-
zoic acids as simple probes prioritizes NBOC=O and sterimol L as
key contributing factors in the benzylic series. B. Univariate cor-
relation between NBOC=O and measured ΔΔG‡. Red points rep-
resent outliers with large substituents at the 3-position that perform
worse than expected based on electron density effects alone.
carbonyl activation when multiple units of Lewis acid are avail-
able and are also in accordance with the observed second order
rate dependence of FeCl3.
While we have demonstrated the use of the carbonyl olefin me-
tathesis reaction on a wide range of aliphatic substrates, the sig-
nificant changes in structure coupled with the competitive bind-
ing scenarios to the Lewis acid make it difficult to separate the
individual features of the substrate that impact the reaction out-
come. To avoid the complexity of connecting the substrate
structure to more than one fundamental process, we hypothe-
sized that analysis of a modular model substrate class could of-
fer more informative insight into the substrate sensitives to a
singular reaction event. The diversity of the benzylic-derived
substrates (Table 3) offers the requisite changes to both the re-
mote electronic and steric environments (Fig. 10) for a training
set but also incorporates sufficient overlapping features for
analysis. The relative rate values were measured for 12 sub-
strates under uniform reaction conditions and, as expected, do
not mirror the trend in the associated isolated yields, suggesting
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A. Mechanism for Carbonyl-Olefin Metathesis of Aliphatic Ketones
B. Activation of Aryl ketones
1
2
3
4
5
6
7
8
O
Cl
Me
not activated enough
Fe
O
Ph
Ph
Cl
Cl
for carbonyl-olefin metathesis
Me
O
Me
Me
zero order
Ph
Me
Ph
Me
in substrate
Me
Me
Me
48
Me
11
zero order
52 Me
first order
in FeCl3
FeCl3
in substrate
catalyst resting
state
Cl
9
Cl
Cl
Fe
Cl
"super-electrophile"
stronger Lewis
acid
Fe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cl
Cl
Fe
O
Cl
Cl
Cl
Me
O
Me
FeCl3
FeCl3
Ph
Ph
Ph
Me
Me
activated for carbo-
nyl-olefin metathesis
Me
Me
61
Me
51
second order
in FeCl3
catalyst resting
state
Cl
Cl
Cl
Fe
Fe
Cl
Cl
Cl
Me
Me
Me
O
Me
O
Me
Ph
+
H
Ph
Me
Me
O
Me
Me
70
Ph
+
3
12
Me
Me
Ph
49
3
supported by DFT calculations, IR, EPR, and Raman spectroscopy
Figure 11. A. Mechanistic hypothesis presenting reactive activation mode for aliphatic ketones requiring second coordination of
FeCl3 to undergo metathesis. B. Substrate activation of aryl ketone substrates by monomeric FeCl3.5c
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32,33
other events contribute to this outcome. Considering the sub-
stituents under evaluation, we employed the corresponding ben-
zoic acids on the basis of the Sigman group’s recent effort to
develop enhanced parameter sets using these simple surro-
gates.30 Computation optimizations were performed at the M06-
FeCl3
is bound to substrate, is sufficiently activated to un-
dergo carbonyl-olefin metathesis. This is consistent with the ob-
served first order kinetics in FeCl3 and our computational inves-
tigations which identified the aryl moiety as an essential struc-
tural component for transition state stabilization by delocalizing
electron density to facilitate formation of the oxetane interme-
diate.5c In comparison, aliphatic ketones are devoid of this sta-
bilization and thus the catalyst remains in its resting state 52
until a second equivalent of FeCl3 binds to form singly-bridged
homo-dimer 61. This homobimetallic association of a second
equivalent of FeCl3 generates a stronger Lewis acid which func-
tions as a superelectrophile that is capable of lowering the en-
ergy of the transition state to provide sufficient activation for
carbonyl-olefin metathesis (Fig. 11). The resulting increase in
substrate polarization leads to formation of intermediate ox-
etane 70, which upon subsequent fragmentation results in the
desired metathesis product 12 and acetone byproduct 3.
2X/def2-TZVP level of theory wherein NBO charges, IR vi-
brations and Sterimol values were collected to probe structural
effects.31 These parameters were correlated to ΔΔG‡, calculated
using the equation ΔΔG‡ = −RTꢀln(krel), by using linear regres-
sion fitting to quantitatively analyze the substituent effects on
reaction rate. A two parameter model was sufficient to describe
the structural effects of this subset of substrates affecting the
rate of reaction (Fig. 10A). Note that a reasonable linear corre-
lation can only be obtained after the removal of the 4-Br sub-
strate (R2 = 0.46, if included). Electron density measured
through the NBOC=O charge, was found to be the most signifi-
cant reactivity discriminant, in which increasing the electron
donating ability of the substituent on the aromatic ring increased
the rate of reaction. Steric effects were of little consequence to
rate and were only pronounced when substituents larger than
fluorine were introduced at the 3-position, which slow the rate
of reaction substantially. Reasonable steric bulk at the 3-posi-
tion is not taken into account by NBOC=O therefore displaying
two outliers (Fig. 10B). This data is in agreement with the hy-
pothesis that a stronger Lewis acid initially accelerates the re-
action rate to allow for the less reactive aliphatic substrates to
undergo metathesis.
Studies by Wong and Brown33a have shown that Lewis acids,
such as GaCl3, are stabilized in hydrocarbon solvents. Specifi-
cally, GaCl3-Cl-R adducts are formed and the stability of these
decreases with increased branching of the hydrocarbon sol-
vents. Consequently, FeCl3-DCE adducts are expected to be
less stable than FeCl3-DCM adducts which is consistent with
DCE being the superior solvent in carbonyl-olefin metathesis
reactions of aliphatic ketones. Additionally, DCE has a higher
capability to stabilize charge due to its increased dielectric con-
stant compared to DCM, which also aids the transition state sta-
bilization of carbonyl-olefin metathesis reactions of aliphatic
ketones (see Supporting Information for details).
Based on these combined results, we propose separate activa-
tion modes for Lewis acid-catalyzed carbonyl-olefin metathesis
reactions of aryl and aliphatic ketones. When considering aryl
ketones, the catalyst resting state 51, in which monomeric
Conclusion
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(3) For organocatalytic approaches, see: (a) Griffith, A.K.; Vanos,
Lewis acid activation through bimetallic association was postu-
lated sixty years ago as a viable avenue to generate stronger
Lewis acid catalysts. While this concept has been advanced in
the context of heterobimetallic association, the corresponding
homobimetallic association was considered to be “of little or no
synthetic consequence”.17 The results presented herein show
that the concept of Lewis acid activation by association can be
expanded to include homobimetallic interactions as a desirable
reactivity mode. We demonstrate the synthetic realization and
importance that homobimetallic association has in Lewis acid
catalysis by accessing superelectrophiles in situ to give rise to
more potent catalytic species. These proposed superelectro-
philic singly-bridged iron(III) homo-dimers lead to more reac-
tive Lewis acid-complexes that are capable of activating previ-
ously unreactive substrates for the catalytic carbonyl-olefin me-
tathesis reactions of aliphatic ketones.
C.M.; Lambert, T.H. J. Am. Chem. Soc. 2012, 134, 18581-18584. (b)
Hong, X.; Liang, Y.; Griffith, A.K.; Lambert, T.H.; Houk, K.N. Chem.
Sci. 2014, 5, 471-475.
(4) For Brønsted and Lewis acid mediated carbonyl-olefin metathesis
reactions, see: (a) Schopov, I.; Jossifov, C. Chem., Rapid Commun.
1983, 4, 659-662. (b) Soicke, A.; Slavov, N.; Neudörfl, J.-M.; Schmalz,
H.-G. Synlett 2011, 17, 2487-2490; (c) van Schaik, H.-P.; Vijn, R.-J.;
Bickelhaupt, F. Angew. Chem. Int. Ed. 1994, 33, 1611-1612. (d)
Jossifov, C.; Kalinova, R.; Demonceau, A. Chim. Oggi 2008, 26, 85-
87.
(5) (a) Ludwig, J.R.; Zimmerman, P.M.; Gianino, J.B.; Schindler, C.S.
Nature 2016, 533, 374-379. (b) McAtee, C.M.; Riehl, P.S.; Schindler,
C.S. J. Am. Chem. Soc. 2017, 139, 2960-2963. (c) Ludwig, J.R.; Phan,
S.; McAtee, C.M.; Zimmerman, P.M.; Devery III, J.J.; Schindler, C.S.
J. Am. Chem. Soc. 2017, 139, 10832-10842. (d) Groso, E.J.; Golonka,
A.N.; Harding, R.A.; Alexander, B.W.; Sodano, T.M.; Schindler, C.S.
ACS Catalysis 2018, 8, 2006-2011. (e) Albright, H., Vonesh, H.L.,
Becker, M.R., Alexander, B.W., Ludwig, J.R., Wiscons, R.A.,
Schindler, C.S. Org. Lett. 2018, 20, 4954-4958. (f) Ma, L.; Li, W.; Xi,
H.; Bai, X.; Ma, E.; Yan, X.; Li, Z. Angew. Chem. Int. Ed. 2016, 55,
10410-10413. (g) For example, a single literature report of an alumi-
num-mediated fragmentation of aliphatic oxetanes exists resulting in
30% yield of the corresponding olefin product: Jackson, A.C., Gold-
man, B.E., Snider, B.B. Intramolecular and intermolecular Lewis acid
catalyzed ene reactions using ketones as enophiles. J. Org. Chem.
1984, 49, 3988-3994. In comparison, boron trifluoride and Brønsted
acid-mediated fragmentation of oxetanes bearing aromatic moieties are
more prominent. For an example, see: Carless, H.A.J., Trivedi, H.S. J.
Chem. Soc. Chem. Comm. 1979, 8, 382-383.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
General methods; detailed experimental studies; compu-
tational experiments; 1H and 13C NMR spectra
AUTHOR INFORMATION
Corresponding Author
* corinnas@umich.edu
(6) For a review on Lewis acid-catalyzed carbonyl-olefin metathesis
reactions, see: Ludwig, J.R.; Schindler, C.S. Synlett 2017, 28, 1501-
1509.
(7) For approaches relying on carbocation-based Lewis acids as cata-
lysts in carbonyl-olefin metathesis, see: (a) Bah, J.; Franzén, J.; Eur. J.
Org. Chem. 2015, 8, 1834-1839; (b) Tran, U.P.N.; Oss, G.; Pace, D.P.;
Ho, J.; Nguyen, T.V. Chem. Sci. 2018, 9, 5145-5151.
(8) For an approach relying on Brønsted acid-catalyzed carbonyl-olefin
metathesis reactions inside a supramolecular host, see: (a) Catti, L.;
Tiefenbacher, K. Angew. Chem. Int. Ed. 2018, 57, 14589-14592. For
an iodine-catalyzed approach, see: (b) Nguyen, T.V., Tran, U.P.N.,
Oss, G., Breugst, M., Detmar, E., Liyanto, K. ChemRxiv.
doi:10.26434/chemrxiv.7057913.
(9) Ludwig, J.R., Watson, R.B., Nasrallah, D.J., Gianino, J.B., Zim-
merman, P.M., Wiscons, R., Schindler, C.S. Science, 2018, 361, 1363-
1369.
(10) Unpublished results.
(11) Demole, E., Enggist, P., Borer, M.C. Helv. Chim. Acta. 1971, 54,
1845-1864.
(12) Baxter, R.D., Sale, D., Engle, K.M., Yu, J., Blackmond, D.G. J.
Am. Chem. Soc. 2012, 134, 4600-4606.
(13) Burés, J. Angew. Chem. Int. Ed. 2016, 55, 2028-2031.
(14) Negishi, E. Chem. Eur. J. 1999, 5, 411-420.
(15) (a) Olah, G.A. Angew. Chem. Int. Ed. 1993, 32, 767-788. (b) Olah,
G.A., Klumpp, D.A. Superelectrophiles and Their Chemistry. Wiley-
VCH Verlag GmbH & Co. KGaA 2007.
(5) Shambayati, S., Crowe, W.E., Schreiber, S.L. Angew. Chem. Int.
Ed. 1990, 29, 256-272.
(16) In comparison, the corresponding heterobimetallic association of
two different metal-derived Lewis acids have been widely investigated
to induce distinct reactivity, such as ate complexation and transmetal-
lation. For examples, see: (a) Sugasawa, T., Toyoda, T., Adachi, M.,
Sasakura, K. J. Am. Chem. Soc. 1978, 100, 4842-4852. (b) Douglas,
A.W., Abramson, N.L., Houpis, I.N., Karady, S., Molina, A., Xavier,
L.C., Yasuda, N. Tetrahedron Lett. 1994, 35, 6807-6810.
(17) Negishi, E. Pure & Appl. Chem. 1981, 53, 2333-2356.
(18) DeHaan, F.P., Brown, H.C. J. Am. Chem. Soc. 1969, 91, 4844-
4850.
ACKNOWLEDGMENT
This work was supported by the NIH/National Institute of General
Medical Sciences (R01-GM118644 to C.S.S. and R35GM128830
to P.M.Z.), the National Science Foundation (CHE-1763436 to
M.S.S), the Alfred P. Sloan Foundation and the David and Lucile
Packard Foundation (fellowships to C.S.S.). H.A., C.C.M. and
J.R.L. thank the National Science Foundation for predoctoral fel-
lowships (DGE 1256260). Computational resources were provided
by the Center for High Performance Computing at the University
of Utah and the Extreme Science and Engineering Discovery Envi-
ronment (XSEDE), which is supported by the NSF (ACI-1548562).
We are very grateful to Prof. Nathaniel Szymczak, Prof. Adam
Matzger, Prof. Nicolai Lehnert, Andrew Hunt and Corey White
(University of Michigan) for help conducting IR, Raman and EPR
spectroscopic measurements as described in this manuscript and
accompanying supporting information. Prof. James Devery (Loy-
ola University Chicago) is gratefully acknowledged for helpful
suggestions regarding the kinetic measurements described in this
manuscript.
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