Origins of initiation rate differences in ruthenium olefin metathesis catalysts containing chelating benzylidenes

Article abstract of DOI:10.1021/jacs.5b01144

A series of second-generation ruthenium olefin metathesis catalysts was investigated using a combination of reaction kinetics, X-ray crystallography, NMR spectroscopy, and DFT calculations in order to determine the relationship between the structure of the chelating o-alkoxybenzylidene and the observed initiation rate. Included in this series were previously reported catalysts containing a variety of benzylidene modifications as well as four new catalysts containing cyclopropoxy, neopentyloxy, 1-adamantyloxy, and 2-adamantyloxy groups. The initiation rates of this series of catalysts were determined using a UV/vis assay. All four new catalysts were observed to be faster-initiating than the corresponding isopropoxy control, and the 2-adamantyloxy catalyst was found to be among the fastest-initiating Hoveyda-type catalysts reported to date. Analysis of the X-ray crystal structures and computed energy-minimized structures of these catalysts revealed no correlation between the Ru-O bond length and Ru-O bond strength. On the other hand, the initiation rate was found to correlate strongly with the computed Ru-O bond strength. This latter finding enables both the rationalization and prediction of catalyst initiation through the calculation of a single thermodynamic parameter in which no assumptions about the mechanism of the initiation step are made.

Full text of DOI:10.1021/jacs.5b01144

Article
pubs.acs.org/JACS
Origins of Initiation Rate Differences in Ruthenium Olefin Metathesis
Catalysts Containing Chelating Benzylidenes
Keary M. Engle,† Gang Lu,‡ Shao-Xiong Luo,† Lawrence M. Henling,† Michael K. Takase,† Peng Liu,*,‡,§
K. N. Houk,*,§ and Robert H. Grubbs*,†
†Arnold and Mabel Beckman Laboratories of Chemical Synthesis, California Institute of Technology, Pasadena, California 91125,
United States
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
§Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: A series of second-generation ruthenium olefin metathesis
catalysts was investigated using a combination of reaction kinetics, X-ray
crystallography, NMR spectroscopy, and DFT calculations in order to
determine the relationship between the structure of the chelating o-
alkoxybenzylidene and the observed initiation rate. Included in this series
were previously reported catalysts containing a variety of benzylidene
modifications as well as four new catalysts containing cyclopropoxy,
neopentyloxy, 1-adamantyloxy, and 2-adamantyloxy groups. The initiation
rates of this series of catalysts were determined using a UV/vis assay. All four
new catalysts were observed to be faster-initiating than the corresponding
isopropoxy control, and the 2-adamantyloxy catalyst was found to be among
the fastest-initiating Hoveyda-type catalysts reported to date. Analysis of the
X-ray crystal structures and computed energy-minimized structures of these
catalysts revealed no correlation between the Ru−O bond length and Ru−O
bond strength. On the other hand, the initiation rate was found to correlate
strongly with the computed Ru−O bond strength. This latter finding enables
both the rationalization and prediction of catalyst initiation through the calculation of a single thermodynamic parameter in
which no assumptions about the mechanism of the initiation step are made.
Chart 1. Commonly Used Ruthenium-Based Olefin
Metathesis Catalysts (1−4)
1. INTRODUCTION
a
Olefin metathesis is a powerful method for the synthesis of
substituted alkenes.1 Among the late transition metals that
catalyze olefin metathesis, ruthenium has proven to be
particularly useful in practical applications because of its
tolerance for air, moisture, and heteroatom-containing func-
tional groups.
During the past three decades, the field of ruthenium-
catalyzed olefin metathesis has advanced rapidly, largely driven
by the discovery and development of new catalysts with
improved reactivity and selectivity (Chart 1).1 In the early
1990s, our group developed a series of well-defined ruthenium-
based olefin metathesis catalysts containing a stable ruthe-
nium−alkylidene.2 Since that time, the influence of various
neutral (L-type) and anionic (X-type) ligands and alkylidene/
benzylidene moieties has been extensively studied, leading to
catalysts that are efficient in a range of transformations (e.g., 1
and 2).3,4 In 1999, Hoveyda and co-workers made an important
discovery that the presence of an o-isopropoxybenzylidene led
to chelated catalyst 3 in which the alkoxy group is coordinated
at the axial site typically occupied by a phosphine ligand.5
Shortly thereafter, the Hoveyda6a and Blechert6b groups
a
Cy = cyclohexyl; SIMes = 1,3-bis(mesityl)-2-imidazolidinylidene.
extended this approach to the 1,3-bis(mesityl)-2-imidazolidi-
nylidene (SIMes)-containing second-generation catalyst 4. The
chelating benzylidene was found to impart exceptional stability
to this family of catalysts, especially with respect to air and
moisture. Moreover, the absence of phosphine ligands in 4
prevents certain phosphine-mediated catalyst decomposition
Received: February 5, 2015
© XXXX American Chemical Society
A
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pathways.1g Together, these properties have made 3, 4, and
ruthenium center more electrophilic. Methoxy-substituted
catalyst 7 was found by our group23b and by Plenio19 to be
faster-initiating than its isopropoxy congener, presumably as a
result of attenuated steric hindrance around the ruthenium
center and a less Lewis basic oxygen. Similarly, Plenio and co-
workers recently found that catalyst 8 containing a phenoxy
group is exceptionally fast-initiating.20
related catalysts useful tools in organic synthesis.1
The rate of catalyst initiation is central to metathesis
reactivity,7,8 and different initiation rates are optimal for
different applications.1,9,10 Hence, the ability to rationally select
a catalyst to achieve a desired initiation rate is practically
important. However, with many systems, including Hoveyda-
type catalysts, the initiation rate trends are not well understood,
which hampers strategic selection of catalysts by end users.
Hoveyda-type catalysts initiate through an olefin metathesis
reaction between the chelated ruthenium benzylidene and an
olefin substrate. This reaction liberates one equivalent of an o-
alkoxystyrene derivative and one equivalent of the propagating
ruthenium alkylidene.8 Catalysts containing the classical
chelating o-isopropoxybenzylidene are known to initiate slowly,
which can be disadvantageous in some settings.1,9,10
There are several challenges in rationalizing and predicting
initiation rates across this series. First, many of these catalysts
have not been compared in standardized head-to-head assays to
quantify initiation. Second, because the benzylidene structural
modifications vary so widely among 4−8, there are no obvious
unifying physical organic parameters that would explain and
predict initiation across this series. Third, the mechanism of
initiation of Hoveyda-type catalysts is complex and is the topic
of ongoing investigation in the literature (Scheme 1).25
A
A large number of catalysts containing alternative chelating
alkylidenes/benzylidenes have previously been reported,9−24
and it has been found empirically that catalyst initiation rates
vary widely across this series. Several modifications have led to
faster-initiating catalysts (e.g., 5−7; Chart 2).12,14,20 Wakamatsu
recent mechanistic study by Plenio19 suggested that Hoveyda-
type catalysts initiate by competing dissociative and interchange
mechanisms, with the relative activation energies being a
function of catalyst structure, olefin identity, and reaction
conditions. In the absence of a clear mechanistic model,
elucidating structure−activity relationships is difficult. The goal
of the present investigation was to overcome these issues and
develop a conceptual framework for rationalizing initiation rates
of ruthenium olefin metathesis catalysts with chelated
benzylidenes. In particular, we aimed to identify a parameter
that would be effective for this purpose and could be
determined in silico without making assumptions about the
mechanism of catalyst initiation.
Chart 2. Representative Known Fast-Initiating Catalysts with
Hoveyda-Type Chelating Benzylidenes (5−8)
2. RESULTS
This problem was approached using a combination of
organometallic synthesis, reaction kinetics, NMR spectroscopy,
X-ray crystallography, and density functional theory (DFT)
calculations. A structurally diverse collection of known and new
catalysts were included in this study with the aim of obtaining
insights that are generally applicable across the entire series of
ruthenium olefin metathesis catalysts with chelating o-
alkoxybenzylidenes. In particular, catalysts with sterically and
electronically modified chelating benzylidene aryl groups (5
and 6) and alkoxy groups (7−12) were investigated. The
and Blechert discovered that the presence of an aryl group
ortho to the isopropoxy group led to improved initiation (5),
presumably through a buttressing effect in which the isopropyl
group is pushed toward the equatorial chloride ligands,
inducing unfavorable steric interactions.12 Grela and co-workers
found that an electron-withdrawing nitro group on the
benzylidene also led to faster initiation (6).14 It is believed
that the electron-withdrawing nature of the nitro group
weakens the RuC and Ru−O bonds and renders the
Scheme 1. Possible Initiation Mechanisms of Hoveyda-Type Catalysts, Including Transition State Structures for Proposed Rate-
Limiting Steps
B
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a
initiation rates across this series were found to vary over 2
orders of magnitude, representing a relatively wide range of
reactivity profiles. X-ray crystal structures for all of the catalysts
in this investigation were previously reported or were solved
during the course of this study.
Scheme 3. Wittig Olefination To Prepare Styrenes 19−22
2.1. Synthesis and Reactivity of Catalysts with
Modified Chelating Alkoxy Groups. Certain structural
features of the chelating alkylidene/benzylidene moiety,
especially the identity of the chelating functional group9,22
and the electronic properties of the benzylidene aryl ring,14−19
have been investigated in detail. Other structure−activity
relationships, however, are less well understood. In particular,
little is known about how variation of the chelating alkoxy
group in Hoveyda-type catalysts (3 and 4) affects the initiation
efficiency.23,24 The precedent of Blechert’s catalyst 512,13 and
other reports23,24 suggested that variation of the steric and
electronic properties of the alkoxy group would be an effective
means of modulating initiation rate. Thus, to bridge this gap in
knowledge, the first step in this investigation was to synthesize
alkoxy-modified catalysts.
a
For detailed procedures, see the Supporting Information.
a
Table 1. Complexation To Prepare 9−12
As an isopropyl group is of intermediate size, catalysts at the
extremes of the steric spectrum were targeted (Chart 3). Thus,
yield (%)
entry styrene
R
product method A method B method C
1
2
3
4
19
20
21
22
c-Pr
9
10
11
12
80
51
15
38
35
75
79
74
79
Chart 3. New Hoveyda-Type Catalysts Containing Alkoxy-
Modified Chelating Benzylidenes (9−12)
CH2t-Bu
2-Ada
43
10−34
57−64
1-Ada
a
Method A: 2 (0.2 mmol), styrene (0.2 mmol), and CuCl (0.2 mmol).
Method B: 2 (0.2 mmol), styrene (0.4 mmol), and Amberlyst-15 (0.8
mmol). Method C: 23 (0.2 mmol), styrene (0.2 mmol), and
Amberlyst-15 (0.8 mmol).
E2 elimination, Simmons−Smith cyclopropanation, and various
protecting group manipulations was undertaken to prepare
benzaldehyde 14 (Scheme 2a; also see the Supporting
Information).27 o-Alkoxybenzaldehydes 16−18 were prepared
from 2-fluorobenzaldehyde in a more straightforward manner
by the aforementioned SNAr chemistry (Scheme 2b).26 o-
Alkoxybenzaldehydes 14 and 16−18 were then converted to
styrenyl ethers 19−22 by Wittig olefination (Scheme 3).
Three methods were compared in the final complexation
step (Table 1). In method A, second-generation SIMes/PCy3-
containing catalyst 2 was allowed to react with 1 equiv of 19−
22 in the presence of CuCl as the phosphine scavenger.
Precipitation to remove CuCl·PCy3, filtration, and separation
by silica gel column chromatography provided 9−12.6a More
strongly chelating benzylidenes, as in 9 (c-Pr) and 12 (1-Ada)
(vide infra), were higher-yielding. Catalyst 11 (2-Ada) was
problematic to prepare using method A and gave variable yields
because of decomposition in solution outside of the glovebox.
In method B, CuCl was replaced with Amberlyst-15 resin
(immobilized H+)28 and the loading of 19−22 was increased
from 1 to 2 equiv. This procedure was operationally simpler, as
purification consisted of filtration to remove the resin,
sonication in pentane, filtration to collect the precipitated
catalyst, and repeated washing with MeOH and pentane to
remove impurities. The yields of 9−12 were generally lower
than with method A, except in the case of 11 (2-Ada). Lastly, in
method C, indenylidene monopyridine catalyst 2329 was used
in combination with 1 equiv of 19−22 and Amberlyst-15
resin.19,28 Following purification as in method B, catalysts 9−12
were obtained in high yield. Notably, the yields of 10 and 11
were markedly improved with method C compared with
to complement catalysts 7 and 8, which contain sterically small
alkoxy/aryloxy groups that are weak Lewis bases, cyclopropyl
catalyst 9 was prepared. At the other end of the spectrum,
catalysts 10−12 with sterically bulky neopentyl, 2-adamantyl,
and 1-adamantyl groups were also synthesized.
The investigation commenced with the synthesis of the
desired catalysts according to the route shown in Schemes 2
and 3 and Table 1. To access catalysts of this type, a modular
synthetic route using SNAr chemistry was developed.26
Cyclopropyl catalyst 9, however, could not be prepared in
this way because of the instability of cyclopropoxide anion.
Thus, a more circuitous sequence that relies on haloalkylation,
Scheme 2. Synthesis of Aldehyde Intermediates 14 and 16−
a
18
a
For detailed procedures, see the Supporting Information.
C
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methods A and B. This is likely due to the fact that the
chelation strength in these catalysts is weak, which opens the
possibility for secondary metathesis with the equivalent of
alkene that is liberated from the progenitor catalyst (2 or 23).
With 2 this alkene is styrene, while with 23 it is 1-methylene-3-
phenyl-1H-indene. Because the latter is more substituted and
thus more sterically hindered, secondary metathesis is slower.
Overall, method C was optimal in terms of overall yield and
operational convenience, particularly in the case of catalysts
with weak chelation (10 and 11).30,31 Nevertheless, methods A
and B could be useful in some contexts, given the widespread
availability of starting catalyst 2.
°C under pseudo-first-order conditions.7 The reaction progress
was monitored by following the decay of the λmax peak by UV/
vis spectroscopy at regular intervals. The value of kinit for each
catalyst was measured in triplicate, and the relative rate with
respect to catalyst 4 (krel) was also calculated (Table 2).
The initiation rates of 9−12 compared favorably with those
of the known fast-initiating catalysts 5−8. The order of the
measured kinit values was consistent with the catalytic 1H NMR
data (Scheme 4). Among the catalysts tested, Blechert’s catalyst
5 was found to be the fastest-initiating. Overall, these data
demonstrate that the steric and electronic properties of the
benzylidene play a major role in determining the initiation
efficiency. Moreover, alkoxy group modification alone is
capable of tuning the initiation rate over 2 orders of magnitude.
The fact that isomeric catalysts 11 and 12 in particular display
such different initiation rates, despite the fact that they both
have a sterically bulky alkoxy substituent and differ only by the
substitution position at the adamantyl group, was unexpected
and merited further investigation (see section 3.2).
The catalytic reactivities of the four new catalysts were next
determined by studying their performance in a representative
ring-closing metathesis (RCM) reaction of N-tosyldiallylamine
(24) using catalyst 4 as a benchmark (Scheme 4). The
Scheme 4. RCM Kinetics with Substrate 24 Using Various
a
1
Catalysts, As Monitored by H NMR Spectroscopy
2.3. X-ray Crystal Structures and DFT-Optimized
Structures. Structural, spectroscopic, and computational
studies were next undertaken to understand the origins of the
initiation rate trends in this series of catalysts and to test
whether key metrics from these techniques correlated with the
empirical initiation rates.
To this end, single crystals of Blechert’s catalyst 512 (the
structure of which had not been previously reported; Chart 4)
and the new catalysts 9−12 (Charts 5−8) suitable for X-ray
diffraction were grown and analyzed.34 These data confirmed
the expected connectivity of the five catalysts. Catalysts 5 and
10 both crystallized in the P21/c space group. Catalyst 9
crystallized in the Pna21 space group with two crystallo-
graphically inequivalent conformers in the unit cell. Catalysts
11 and 12 were found to be isostructural, both crystallizing in
the Pca21 space group with two inequivalent conformers in the
unit cell. X-ray structures for 4 and 6−8 have been previously
reported.20,23a,35
To complement the X-ray structures, the optimized geo-
metries of 4−12 were located using several DFT methods that
have been commonly employed in recent computational studies
of ruthenium olefin metathesis catalysts.36 We first considered
two classical density functionals: B3LYP37 with a mixed basis
set of LANL2DZ for ruthenium and 6-31G(d) for other
atomsthe level of theory that we have consistently used for
geometry optimization in transition-metal−catalyzed reactions,
including olefin metathesis with ruthenium catalystsand
BP8638 with the SVP basis set, as recommended by Cavallo in a
recent benchmark study on ruthenium complexes in olefin
metathesis.39 In addition, we tested three modern density
functionals: M06,40 M06-L,41 and ωB97x-D,42 which have been
shown to give smaller errors for Ru−O and Ru−C bond
lengths in previous benchmark studies by Truhlar and Jensen.43
In the M06, M06-L, and ωB97x-D calculations, the SDD basis
set for Ru and the 6-31G(d) basis set for other atoms were
used.44 The computed Ru−O and RuC(benzylidene) bond
lengths are compiled and compared with the bond distances in
the X-ray structures in Table 3.
a
Each data point represents the average of three independent
experiments.
reactions were carried out in triplicate with 0.1 mol % catalyst
at 25 °C, and the reaction progress was monitored by 1H NMR
spectroscopy.32,33 With all five catalysts, RCM proceeded to
>98% conversion within 90 min. Consistent with our
hypothesis at the outset, the kinetic reactivity was found to
be strongly dependent on the nature of the alkoxy group. The
order of reactivity was found to be 11 (2-Ada) > 10 (CH2t-Bu)
> 12 (1-Ada) > 9 (c-Pr) > 4 (i-Pr). Catalytic metathesis
reactions with the other catalysts in this study (5−8) have
previously been demonstrated.12,14,20,23b
2.2. Catalyst Initiation Rates. To quantify the catalyst
initiation rates (kinit), the four new catalysts 9−12 were
measured along with representative previously reported
catalysts 4−8. As discussed above, this particular set of catalysts
was selected because it represents a wide variety of benzylidene
modifications, including steric and electronic modification of
the aryl ring and the alkoxy group. Initiation rates were
determined by reacting a stoichiometric quantity of the catalyst
with a large excess of butyl vinyl ether (BVE) (30 equiv) at 10
In general, the Ru−O and RuC bond lengths remain fairly
constant across this series. One striking exception is the long
Ru−O bond in 11, which is evident in both the experimental
structures and optimized geometries at different theoretical
levels. Elongation of the Ru−O bond occurs to relieve an
energetically unfavorable steric clash between a methylene unit
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a b
,
Table 2. Initiation Rates of Catalysts 4−12, Displayed in Increasing Order
entry
cat.
R1
i-Pr
R2
R3
λmax (nm)
kinit (10−4 s−1
)
krel
1
2
3
4
5
6
7
8
9
4
9
H
H
H
H
H
H
H
H
Ph
H
378
376
372
376
382
380
370
380
374
0.401 0.037
0.721 0.004
0.757 0.054
1.53 0.09
3.46 0.61
10.8 0.8
1.0
1.8
1.9
3.8
8.6
c-Pr
H
6
i-Pr
NO2
H
7
Me
12
10
8
1-Ada
CH2t-Bu
Ph
H
H
26
H
49.1 5.5
120
140
250
11
5
2-Ada
i-Pr
H
54.4 5.6
H
98.5 32.0
a
b
The kinit values are reported as averages (with 95% confidence intervals) determined from three independent trials. The relative rate (krel) was
calculated by dividing the kinit value of the catalyst of interest by the kinit value for catalyst 4.
a
a
Chart 4. X-ray Crystal Structure of 5
Chart 5. X-ray Crystal Structure of 9
a
50% probability ellipsoids. Hydrogen atoms have been omitted for
clarity. Two crystallographically inequivalent molecules (A and B) are
present in the unit cell; for clarity, only one is shown. Selected bond
lengths (Å) for 9: molecule A: Ru1−Cl1 2.3377(14), Ru1−Cl2
2.3327(14), Ru1−O1 2.223(4), Ru1−C1 1.968(5), Ru1−C31
1.836(5); molecule B: Ru1−Cl1 2.3275(14), Ru1−Cl2 2.3312(13),
Ru1−O1 2.249(4), Ru1−C1 1.985(5), Ru1−C31 1.830(5). CCDC
1044211.34
a
50% probability ellipsoids. Hydrogen atoms have been omitted for
clarity. Selected bond lengths (Å) for 5: Ru1−Cl1 2.34983(15), Ru1−
Cl2 2.34349(15), Ru1−O1 2.2443(4), Ru1−C1 1.9808(5), Ru1−C22
1.8337(5). CCDC 1017843.34
on the 2-Ada group (C35) and the SIMes−dichlororuthenium
fragment.45 The Ru−O bonds of catalysts 5, 9, 10, and 12 are
of typical length, and no such obvious steric clash is observed.
This unfavorable steric interaction contributes to 11’s faster
initiation compared with 12 (see section 3.2 for more detailed
discussion).
Of the five computational methods, B3LYP and BP86
systematically overestimated the Ru−O bond lengths by about
0.1 Å, in line with the previous computational benchmark
studies.43 M06, M06-L, and ωB97x-D also led to longer Ru−O
distances than the X-ray structures, while the mean absolute
errors (MAEs) are smaller. However, since the Ru−O distances
are very similar in most of the catalysts (except 11), all five
methods tested yielded only moderate correlations between the
computed and X-ray distances (see Charts S22−S26 in the
Supporting Information).
(5−12). These catalysts also show comparatively short ipso-C···
Ru distances. These two observations are consistent with
donation of the p orbital of the ipso-C to the metal center as a
stabilizing interaction in cases where the Ru−O bond is
comparatively weak.46 For example, in the crystal structure of
Hoveyda catalyst 4, the ipso-C···Ru distance is 3.307 Å,23a
compared with 3.151 Å in Blechert’s catalyst 5.
1
2.4. NMR Spectroscopy. Diagnostic peaks from the H
and 13C NMR spectra in CD2Cl2 were next compiled (Table
4).12,14,47 The resulting data reveal a positive correlation
1
between the initiation rate and the benzylidene H NMR shift,
a weak negative correlation between the initation rate and the
NHC 13C NMR shift, and no correlation between the
benzylidene 13C NMR shift and the initiation rate. The
relationship between initiation rates, Ru−O bond strengths,
and NMR shifts is further discussed in section 3.3.
2.5. Computed Ru−O Bond Energies. To understand the
relationship between the structural data and the observed
Another point of interest in this collection of X-ray and DFT
structures is that the N-Mes aryl rings on the alkoxy side are
substantially puckered in many of the fast-initiating catalysts
E
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a
a
Chart 6. X-ray Crystal Structure of 10
Chart 8. X-ray Crystal Structure of 12
a
50% probability ellipsoids. Hydrogen atoms and DCM solvent have
been omitted for clarity. Selected bond lengths (Å) for 10: Ru1−Cl1
2.3314(3), Ru1−Cl2 2.3270(3), Ru1−O1 2.2860(8), Ru1−C1
1.9848(10), Ru1−C31 1.8275(10). CCDC 1044212.34
a
50% probability ellipsoids. Hydrogen atoms have been omitted for
clarity. Two crystallographically inequivalent molecules (A and B) are
present in the unit cell; for clarity, only one is shown. Selected bond
lengths (Å) for 12: molecule A: Ru1−Cl1 2.3190(6), Ru1−Cl2
2.3633(5), Ru1−O1 2.2540(14), Ru1−C1 1.9890(19), Ru1−C22
1.828(2); molecule B: Ru1−Cl1 2.3197(6), Ru1−Cl2 2.3645(6),
Ru1−O1 2.2602(16), Ru1−C1 1.985(2), Ru1−C22 1.828(2). CCDC
1017841.34
a
Chart 7. X-ray Crystal Structure of 11
calculations using geometries optimized with M06, M06-L, or
ωB97x-D (see the Supporting Information for details). In the
following sections, all of the calculations were performed using
B3LYP/LANL2DZ−6-31G(d) for geometry optimization and
M06/SDD−6-311+G(d,p)/SMD(toluene) for single-point en-
ergies, which is consistent with our previous computational
studies of ruthenium-catalyzed olefin metathesis.
The Ru−O bond strengths computed by the two methods
correlated well with one another (Chart 9). The calculations
indicated that the fast-initiating catalysts 8 (Ph), 11 (2-Ada),
and Blechert’s catalyst 5 all have a weaker Ru−O bond than
catalysts 4, 6, and 9.
a
50% probability ellipsoids. Hydrogen atoms have been omitted for
clarity. Two crystallographically inequivalent molecules (A and B) are
present in the unit cell; for clarity, only one is shown. Selected bond
lengths (Å) for 11: molecule A: Ru1−Cl1 2.3242(12), Ru1−Cl2
2.3570(11), Ru1−O1 2.338(3), Ru1−C1 1.984(4), Ru1−C22
1.827(4); molecule B: Ru1−Cl1 2.3220(11), Ru1−Cl2 2.3550(11),
Ru1−O1 2.355(3), Ru1−C1 1.986(4), Ru1−C22 1.821(4). CCDC
1017842.34
3. DISCUSSION
The data from the approaches and techniques above were
analyzed in detail to investigate the origins of the initiation rate
trends and to correlate various metrics across this series.
3.1. Distortion Energies and Strain Release in the
Initiation Step. An initial question concerned the relative
importance of different factors to the Ru−O bond strengths in
catalysts 4−12. Two plausible contributions are (1) electronic
effects that alter the charges on Ru and/or O and (2) the
release of strain energy in the chelated catalyst. Thus, to test
whether catalysts with weak Ru−O bonds and high initiation
rates have high strain energies, we calculated the strain energies
in the catalysts using distortion energy analysis.49
The total strain energy of the chelated catalyst is dissected
into the distortion energies of the SIMes−dichlororuthenium
methylidene fragment and the alkoxyphenyl fragment. The
distortion energy of each fragment is calculated from the energy
difference between the geometry of the fragment in the
chelated catalyst and the fully optimized geometry in the
absence of the other fragment (see the Supporting Information
for overlays of the distorted and fully optimized fragments).
kinetic reactivity, the strengths of Ru−O bonding48 in catalysts
4−12 were evaluated in two ways (Table 5): (1) by calculating
the energy difference between the ground-state chelated
conformation A and the nonchelated 14-electron complex B
formed by dechelation of the Ru−O bond and rotation of the o-
alkoxyphenyl group (ΔGr(A → B)) and (2) by calculating the
reaction energy of initiation with BVE to form a common 14-
electron Fischer carbene complex C (ΔGr(A → C)). These
energies were calculated using M06 single-point calculations
with a mixed basis set of SDD for ruthenium and 6-311+G(d,p)
for other atoms and the SMD solvation model in toluene. The
geometries were optimized with B3LYP/LANL2DZ−6-
31G(d). Although B3LYP gave relatively large errors in the
Ru−O distances, we found that employing B3LYP or BP86 in
geometry optimization yielded better correlation between the
computed Ru−O bond strengths and ln(kinit) than the
F
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Journal of the American Chemical Society
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Table 3. Summary of Experimental and Computed Ru−O and RuC Bond Distances for Representative Catalysts, Displayed
in Order of Increasing kinit
bond distances (Å)
exptl
computed
M06
a
X-ray
RuC
1.829
B3YLP
BP86
M06-L
ωB97x-D
entry cat.
R1
i-Pr
R2
R3
Ru−O
Ru−O RuC Ru−O RuC Ru−O RuC Ru−O RuC Ru−O RuC
b
1
2
3
4
5
6
7
8
9
4
9
H
H
H
H
H
H
H
H
Ph
H
2.256
2.236
2.273
2.265
2.257
2.286
2.286
2.347
2.244
2.36
2.34
2.39
2.33
2.39
2.39
2.35
2.48
2.39
0.108
1.85
1.85
1.84
1.85
1.84
1.84
1.85
1.84
1.84
0.019
2.35
2.33
2.37
2.33
2.36
2.36
2.34
2.44
2.37
0.089
1.85
1.85
1.85
1.85
1.85
1.85
1.85
1.85
1.85
0.026
2.31
2.28
2.33
2.31
2.32
2.33
2.30
2.42
2.34
0.054
1.82
1.83
1.82
1.83
1.82
1.82
1.83
1.82
1.82
0.011
2.33
2.31
2.34
2.34
2.33
2.37
2.34
2.44
2.36
0.079
1.84
1.85
1.84
1.84
1.84
1.84
1.84
1.84
1.84
0.017
2.29
2.26
2.31
2.29
2.30
2.31
2.28
2.38
2.30
0.031
1.82
1.82
1.81
1.82
1.81
1.81
1.82
1.81
1.81
0.016
c
c-Pr
H
1.833
1.827
1.798
1.828
1.828
1.815
1.824
cd
,
6
i-Pr
NO2
H
e
c
f
7
Me
12
10
8
1-Ada
CH2t-Bu
Ph
H
H
cg
,
H
c
11
5
2-Ada
i-Pr
H
H
1.834
h
MAE:
a
For clarity, experimental values are shown to three decimal places without estimated standard deviations. The estimated standard errors are typically
b
c
in the range of 0.001−0.005 Å. See the Supporting Information for additional details. Experimental: DCM solvate; CCDC 620588 (ref 23a). The
experimental values are averages for the two crystallographically inequivalent molecules found in the unit cell. Experimental: H2O solvate; CCDC
d
e
f
g
698596 (ref 35). Experimental: hexane solvate; CCDC 620589 (ref 23a). Experimental: DCM solvate. Experimental: CCDC 908389 (ref 20).
h
The mean absolute error (MAE) is the average absolute error among the nine computed structures with respect to the crystallographic value.
Table 4. Diagnostic NMR Peaks of Catalysts 4−12,
Table 5. Computed Ru−O Bond Strengths, Displayed in
Order of Increasing kinit
a
Displayed in Order of Increasing kinit
RuCHAr
NHC
13C
entry cat.
R1
i-Pr
R2
R3
1H
13C
b
1
2
3
4
5
6
7
8
9
4
9
H
H
H
H
H
H
H
H
Ph
H
16.52
16.50
16.42
16.48
16.48
16.58
16.64
16.69
16.62
295.8
293.0
290.4
290.4
300.0
295.9
290.7
298.9
298.2
211.1
211.5
208.4
210.5
211.7
210.4
209.3
209.2
210.6
c-Pr
H
b
c
c
c
6
i-Pr
NO2
H
c
c
7
Me
12
10
8
1-Ada
CH2t-Bu
Ph
H
H
c
c
H
11
5
2-Ada
H
b
i-Pr
H
a
b
Spectra in CD2Cl2 These values were independently measured and
corresponded closely with previously published values in the literature:
c
entry 1, ref 47; entry 3, ref 14; entry 9, ref 12. Average of two or more
peaks corresponding to the benzylidene NMR peak.
Ru−O bond strength
(kcal/mol)
The computed distortion energies of catalysts 4−12 are
summarized in Chart 10.
entry
cat.
R1
i-Pr
R2
R3
ΔGr(A→B) ΔGr(A→C)
In general, the sum of the distortion energies of the two
fragments parallels the initiation rate. In particular, fast-
initiating catalysts 11 and 5 show substantial distortion in the
chelated structures, indicating that strain release is a key factor
that controls the rate of initiation with these catalysts. The
distortion in the alkoxybenzylidene moiety in Blechert’s catalyst
5 is noticeably greater than that in the other catalysts. This
indicates that the main driving force for this fast-initiating
catalyst is the release of strain between the R1 (i-Pr) and R2
(Ph) groups in the catalyst, where Ru−O chelation forces the
R1 group to point toward R2. Because of the steric repulsion
between the 2-adamantyloxy group and the chloride ligands
and/or N-Mes aryl group (see section 3.2 for more details),
both the alkoxybenzylidene and SIMes−dichlororuthenium
methylidene fragments in 11 are more distorted than those in
4. Similar, albeit weaker, steric repulsions with the alkoxy
groups in 10 and 12 also lead to slightly greater distortion
energies than in catalyst 4.
1
2
3
4
5
6
7
8
9
4
9
H
H
H
H
H
H
H
H
Ph
H
12.8
10.8
14.1
8.6
6.3
4.6
5.8
3.6
4.6
3.0
3.0
3.2
2.0
c-Pr
H
6
i-Pr
NO2
H
7
Me
12
10
8
1-Ada
CH2t-Bu
Ph
H
11.5
10.8
9.8
H
H
11
5
2-Ada
i-Pr
H
9.6
H
7.6
With certain catalysts, the distortion energies were lower
than those for others in the series with similar initiation rates,
including 6 (R1 = i-Pr; R3 = NO2), 7 (R1 = Me), and 8 (R1 =
Ph). For example, 8 has a similar initiation rate and Ru−O
bond strength to 11 but has 1.2 kcal/mol lower distortion
energy. This indicates that strain release effects do not promote
initiation in these complexes. Thus, this analysis revealed that
strain release is the major factor for the observed enhanced
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and yellow), it is evident that the majority of its steric bulk is
directed toward the face of the N-Mes group and the chloride
ligands. In contrast, the 1-Ada group orients its steric bulk away
from the face of the N-Mes group and the chloride ligands.
Rotation about the alkoxy C−O bond in 11 and 12 is restricted
by developing A1,3 strain with the ortho C−H bond.
Additionally, the fact that the chelating alkoxy group in 11
contains a secondary carbon rather than a tertiary carbon as in
12 is also likely a contributing factor, since the former would be
expected to be a weaker Lewis base.
Chart 9. Ru−O Bond Strengths ΔGr(A → B) (Method 1)
versus ΔGr(A → C) (Method 2)
3.3. Analysis of Collective Data. The metrics generated
above were tested for possible correlation against the initiation
rate in order to identify parameters that would be useful in both
explanatory and predictive senses. First, structural metrics were
compared with the ln(kinit) values and Ru−O bond strengths.
Generally in coordination chemistry, ligand−metal bond
distances correlate with bond strengths. It was thus surprising
that there was no correlation between the computed or
experimental Ru−O bond lengths and the Ru−O bond
strengths or ln(kinit) values in this series (see Charts S28−
S30 in the Supporting Information). More specifically, within
the “normal” range for a Ru−O bond (approximately 2.24−
2.29 Å), there is no relationship between the Ru−O bond
strength and the Ru−O bond length. The only case in which an
usually long Ru−O bond was observed was in the 2-Ada
catalyst 11, and it may be generally true that elongation of this
bond can only be achieved in systems in which the alkoxy
group is sterically hindered and conformationally constrained.
Thus, the observation of a long Ru−O bond (>2.30 Å) in a
SIMes-based Hoveyda-type catalyst likely indicates a weak Ru−
O bond. However, the converse is not necessarily true; weak
Ru−O bonds can and often do have “normal” Ru−O bond
lengths (2.23−2.29 Å), as exemplified by catalyst 5. The lack of
correlation in this respect is attributed to the intramolecular
tethering of the ether ligand and the overall rigidity of the
system. Because the structural data did not track with the
initiation rates, other metrics were next considered.
Chart 10. Computed Distortion Energies of the SIMes−
Dichlororuthenium Methylidene Fragment (Shown in Blue)
and the Alkoxyphenyl Fragment (Shown in Red) in Catalysts
4−12, Displayed from Left to Right in Order of Increasing
a
kinit
a
The distortion energy of the fragment is defined as the difference
between the energies of the distorted geometry of the fragment in the
chelated catalyst and the fully optimized geometry in the absence of
the other fragment.
As mentioned in section 2.4, NMR spectroscopy proved to
be a useful tool in this respect. Ru−O bond strengths and
ln(kinit) values were found to correlate with the chemical shifts
of key resonances in the 1H and 13C NMR spectra (Table 4). In
the case of the benzylidene 1H NMR shift, there was a positive
correlation with ln(kinit) (Chart 12). This is consistent with a
weaker Ru−O bond making the ruthenium center more
electron-deficient, causing the C−H bond of the benzylidene
to be deshielded. On the other hand, there was a weak negative
correlation between ln(kinit) and the NHC 13C NMR shift. This
initiation rates with 5, 11, 10, and 12, while the rates with
catalysts 6, 7, and 8 are likely to be dominated by electronic
effects.
3.2. Comparison of Catalysts 11 (2-Ada) and 12 (1-
Ada). A structural basis for the observed reactivities of catalysts
11 and 12 is shown in Chart 11. As mentioned previously, an
unfavorable methylene−N-Mes steric clash weakens the Ru−O
bond in catalyst 11. This clash is ultimately the result of the
unique geometry of the 2-Ada group and the conformationally
restricted rotation about the alkoxy C−O bond. When the 2-
Ada group is viewed as a substituted cyclohexane ring (green
1
Chart 12. ln(kinit) versus Benzylidene H NMR Shift
Chart 11. Structural Basis for the Difference between the
Initiation Rates of Catalysts 11 and 12
H
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trend is consistent with a weaker Ru−O bond increasing the
degree of π back-bonding from the metal to the NHC and
exhibiting an attenuated trans influence. Grela’s catalyst 6 was
found to be an outlier, likely because of the strongly electron-
withdrawing character of the NO2 group. When 6 was excluded
from the analysis, the R2 value improved from 0.08 to 0.49. No
relationship quantitatively and constructed a model that echoes
previous qualitative observations in the literature.12−25,35
The Ru−O bond energies from the two methods presented
above thus constitute powerful thermodynamic metrics for
explaining and predicting the initiation kinetics in the absence
of any assumptions about the mechanism of the initiation step.
The fact that this thermodynamic metric is well-correlated to
ln(kinit) across a broad range of benzylidene structures with
different steric and electronic properties speaks to its generality
and utility. Moreover, an attractive aspect of using computed
Ru−O bond energies for this purpose is that predictions about
a catalyst can be made without the need to first synthesize it.
An important caveat to this analysis is that there is almost
certainly a lower limit beyond which weak Ru−O bonds no
longer form stable chelates. Catalysts 5 and 11 appear to be
close to this limit, as both show increased susceptibility to
decomposition when dissolved in solution in air.
correlation was found between ln(kinit) and the benzylidene 13
C
NMR shift (see Charts S31−S33 in the Supporting
Information).
Of the quantitative measurements in this study, the
computed Ru−O bond strengths in section 2.5 were the
most informative (Charts 13 and 14). The initiation rate,
Chart 13. ln(kinit) versus Ru−O Bond Strength ΔGr(A → B)
(Method 1)
4. CONCLUSIONS
A systematic investigation was undertaken to understand
factors that influence the initiation rates in a series of
ruthenium olefin metathesis catalysts containing chelating
benzylidenes. This study combined insights from organo-
metallic synthesis, reaction kinetics, X-ray crystallography,
NMR spectroscopy, and DFT calculations.
Four new second-generation catalysts, 9−12, were synthe-
sized, and all four exhibited improved initiation compared with
the isopropoxy congener 4. Catalyst 11 was found to be
especially fast-initiating. The enhanced initiation rate is caused
by a steric clash between a methylene group and the SIMes−
dichlororuthenium fragment that is induced by the geometry of
the 2-Ada group. This study demonstrates that alkoxy group
modification alone is an effective strategy for tuning the
initiation rate of Hoveyda-type catalysts over several orders of
magnitude. It also illustrates the 2-Ada group as a unique alkyl
substituent in coordination chemistry and catalysis.
Chart 14. ln(kinit) versus Ru−O Bond Strength ΔGr(A → C)
(Method 2)
Structural, spectroscopic, and computational insights on
these new catalysts and several previously reported catalysts
from the literature revealed the critical role of the Ru−O bond
strength in the catalyst initiation rate. While the Ru−O bond
strengths correlated with shifts of key resonances in the NMR
spectra, no correlation was observed with the experimental or
computed Ru−O bond distances. It is anticipated that this
study will provide a conceptual framework for continuing
efforts in catalyst development and will guide practitioners’
selection of a specific catalyst for a given application. Moreover,
in the long term, investigations of this nature will help enable
prediction of new catalyst properties through computation.
ln(kinit), correlated most strongly with ΔGr(A → C) (method
2), while ΔGr(A → B) (method 1) gave a weaker correlation.
In both plots, the methyl-substituted catalyst 7 was found to be
an outlier. Removal of this catalyst from the series improved the
R2 values from 0.48 to 0.73 and from 0.79 to 0.89 for methods
1 and 2, respectively (see Charts S34 and S35 in the Supporting
Information). Using BP86 in place of B3LYP for the geometry
optimizations improved the R2 value with method 1 from 0.48
to 0.80 and led to similar R2 values with method 2.
Interestingly, using the M06, M06-L, and ωB97x-D methods
in the geometry optimizations all led to worse R2 values (see
Tables S17−S20 in the Supporting Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, NMR spectra of new compounds, CIFs of
catalysts 5 and 9−12, optimized Cartesian coordinates and
energies, and details of computational methods. This material is
available free of charge via the Internet at http://pubs.acs.org.
While the exact mechanism of initiation of Hoveyda-type
catalysts remains the topic of ongoing investigation in the
literature,19,25,50 the correlation between the Ru−O bond
energy and ln(kinit) demonstrates that destabilizing the
benzylidene moiety by weakening the Ru−O bond leads to
higher observed initiation rates. Herein we have delineated this
AUTHOR INFORMATION
■
Corresponding Authors
*pengliu@pitt.edu
*houk@chem.ucla.edu
*rhg@caltech.edu
I
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Journal of the American Chemical Society
Article
Lett. 2008, 10, 1303−1306. (b) Farina, V.; Shu, C.; Zeng, X.; Wei, X.;
Han, Z.; Yee, N. K.; Senanayake, C. H. Org. Process Res. Dev. 2009, 13,
250−254.
Notes
The authors declare no competing financial interest.
(11) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
794−796.
ACKNOWLEDGMENTS
■
(12) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
2403−2405.
Dr. Bruce S. Brunschwig is acknowledged for assistance with
the UV/vis kinetics experiments, which were carried out at the
Molecular Materials Research Center of the Beckman Institute
at Caltech. Prof. Jeffrey S. Cannon (Occidental College) and
Zachary K. Wickens (Grubbs group, Caltech) are thanked for
helpful discussions. The research described herein was
supported financially by the ONR (Award N00014-12-1-
0596) and the NIH NIGMS (Award F32GM108145;
postdoctoral fellowship to K.M.E.). The Bruker KAPPA
APEXII X-ray diffractometer was purchased via an NSF
CRIF:MU award to the California Institute of Technology
(CHE-0639094). Materia, Inc. is thanked for the generous
donation of catalysts 2, 4, S16, and S17 and (E/Z)-1-
isopropoxy-4-nitro-2-(prop-1-en-1-yl)benzene (S20). Calcula-
tions were performed on supercomputers from the DoD
HPCMP Open Research Systems and the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by the NSF.
(13) The Blechert chelate (as in 5) has been successfully used to
improve initiation in ruthenium catalysts with a wide variety of L- and
X-type ligands. For examples, see: (a) Van Veldhuizen, J. J.;
Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J.
Am. Chem. Soc. 2003, 125, 12502−12508. (b) Berlin, J. M.; Campbell,
K.; Ritter, T.; Funk, T. W.; Chlenov, A.; Grubbs, R. H. Org. Lett. 2007,
9, 1339−1342. (c) Gatti, M.; Vieille-Petit, L.; Luan, X.; Mariz, R.;
Drinkel, E.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2009, 131, 9498−
9499.
(14) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int.
Ed. 2002, 41, 4038−4040.
(15) Zaja, M.; Connon, S. J.; Dunne, A. M.; Rivard, M.; Buschmann,
N.; Jiricek, J.; Blechert, S. Tetrahedron 2003, 59, 6545−6558.
(16) Zhan, Z.-Y. J. Recyclable Ruthenium Catalysts for Metathesis
Reactions. U.S. Patent US20070043180 A1, Feb 22, 2007.
(17) Vinokurov, N.; Garabatos-Perera, J. R.; Zhao-Karger, Z.;
Wiebcke, M.; Butenschon, H. Organometallics 2008, 27, 1878−1886.
̈
(18) Rix, D.; Caijo, F.; Laurent, I.; Boeda, F.; Clavier, H.; Nolan, S.
P.; Mauduit, M. J. Org. Chem. 2008, 73, 4225−4228.
(19) Thiel, V.; Hendann, M.; Wannowius, K.-J.; Plenio, H. J. Am.
Chem. Soc. 2012, 134, 1104−1114.
REFERENCES
■
(1) For reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18−29. (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
(20) Kos, P.; Savka, R.; Plenio, H. Adv. Synth. Catal. 2013, 355, 439−
447.
(21) Nelson, D. J.; Queval, P.; Rouen, M.; Magrez, M.; Toupet, L.;
̈
3012−3043. (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592−4633. (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4490−4527. (e) Schrock, R. R. Chem.
Rev. 2009, 109, 3211−3226. (f) Samojłowicz, C.; Bieniek, M.; Grela,
K. Chem. Rev. 2009, 109, 3708−3742. (g) Vougioukalakis, G. C.;
Grubbs, R. H. Chem. Rev. 2010, 110, 1746−1787. (h) Hoveyda, A. H.
J. Org. Chem. 2014, 79, 4763−4792. (i) Nelson, D. J.; Manzini, S.;
Urbina-Blanco, C. A.; Nolan, S. P. Chem. Commun. 2014, 50, 10355−
10375.
(2) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1992, 114, 3974−3975. (b) Nguyen, S. T.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858−9859.
(3) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039−2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100−110.
(4) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953−956.
(5) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791−799. For a review,
see: (b) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.;
Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org.
Biomol. Chem. 2004, 2, 8−23.
(6) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168−8179. (b) Gessler, S.; Randl, S.;
Blechert, S. Tetrahedron Lett. 2000, 41, 9973−9976.
(7) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543−6554.
(8) After initiation, the benzylidene moiety is no longer attached to
the catalyst, meaning that the propagating species for catalysts 4−12
and other second-generation catalysts will be identical. For this reason,
the initiation rate, the rate of o-alkoxystyrene rechelation, and the rates
of various catalyst decomposition events are the most crucial variables
to consider when comparing a series of catalysts in which the
benzylidene moiety is varied.
(9) For a review of ruthenium olefin metathesis catalysts containing
chelating benzylidenes, see: Vidavsky, Y.; Anaby, A.; Lemcoff, N. G.
Dalton Trans. 2012, 41, 32−43.
(10) For an illustrative application of catalyst 6 in macrocyclic RCM
on a process scale, see: (a) Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.;
Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, V.; Senanayake, C. H. Org.
́ ́ ́
Caijo, F.; Borre, E.; Laurent, I.; Crevisy, C.; Basle, O.; Mauduit, M.;
Percy, J. M. ACS Catal. 2013, 3, 259−264.
(22) For representative reports describing alternative chelating
functional groups, see: (a) van der Schaaf, P. A.; Kolly, R.; Kirner,
H.-J.; Rime, F.; Muhlebach, A.; Hafner, A. J. Organomet. Chem. 2000,
̈
606, 65−74. (b) Furstner, A.; Thiel, O. R.; Lehmann, C. W.
̈
Organometallics 2002, 21, 331−335. (c) Slugovc, C.; Perner, B.;
Stelzer, F.; Mereiter, K. Organometallics 2004, 23, 3622−3626.
(d) Barbasiewicz, M.; Szadkowska, A.; Bujok, R.; Grela, K. Organo-
metallics 2006, 25, 3599−3604. (e) Hejl, A.; Day, M. W.; Grubbs, R.
H. Organometallics 2006, 25, 6149−6154. (f) Ben-Asuly, A.; Tzur, E.;
Diesendruck, C. E.; Sigalov, M.; Goldberg, I.; Lemcoff, N. G.
Organometallics 2008, 27, 811−813. (g) Kost, T.; Sigalov, M.;
Goldberg, I.; Ben-Asuly, A.; Lemcoff, N. G. J. Organomet. Chem.
2008, 693, 2200−2203. (h) Tzur, E.; Szadkowska, A.; Ben-Asuly, A.;
Makal, A.; Goldberg, I.; Wozniak, K.; Grela, K.; Lemcoff, N. G.
́
̇
Chem.Eur. J. 2010, 16, 8726−8737. (i) Szadkowska, A.; Zukowska,
K.; Pazio, A. E.; Wozniak, K.; Kadyrov, R.; Grela, K. Organometallics
́
2011, 30, 1130−1138. (j) Ginzburg, Y.; Anaby, A.; Vidavsky, Y.;
Diesendruck, C. E.; Ben-Asuly, A.; Goldberg, I.; Lemcoff, N. G.
Organometallics 2011, 30, 3430−3437. (k) Lexer, C.; Burtscher, D.;
Perner, B.; Tzur, E.; Lemcoff, N. G.; Slugovc, C. J. Organomet. Chem.
2011, 696, 2466−2470. (l) Peeck, L. H.; Savka, R. D.; Plenio, H.
Chem.Eur. J. 2012, 18, 12845−12853. (m) Barbasiewicz, M.;
Michalak, M.; Grela, K. Chem.Eur. J. 2012, 18, 14237−14241.
(23) For relevant reports, see refs 5, 18, and 19 and the following:
(a) Barbasiewicz, M.; Bieniek, M.; Michrowska, A.; Szadkowska, A.;
Makal, A.; Wozniak, K.; Grela, K. Adv. Synth. Catal. 2007, 349, 193−
́
203. (b) Hejl, A. Ph.D. Thesis, California Institute of Technology,
Pasadena, CA, 2007. (c) Bornand, M.; Torker, S.; Chen, P.
Organometallics 2007, 26, 3585−3596.
(24) For multidentate chelating alkoxy-derived benzylidenes, see:
(a) Bieniek, M.; Bujok, R.; Cabaj, M.; Lugan, N.; Lavigne, G.; Arlt, D.;
Grela, K. J. Am. Chem. Soc. 2006, 128, 13652−13653. (b) Bieniek, M.;
́
Samojłowicz, C.; Sashuk, V.; Bujok, R.; Sledz, P.; Lugan, N.; Lavigne,
́
G.; Arlt, D.; Grela, K. Organometallics 2011, 30, 4144−4158.
(25) For reports concerning the initiation mechanism of Hoveyda-
type catalysts, see refs 19 and 23b and the following: (a) Vougiouka-
J
DOI: 10.1021/jacs.5b01144
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
lakis, G. C.; Grubbs, R. H. Chem.Eur. J. 2008, 14, 7545−7556.
(b) Solans-Monfort, X.; Pleixats, R.; Sodupe, M. Chem.Eur. J. 2010,
16, 7331−7343. (c) Vorfalt, T.; Wannowius, K.-J.; Plenio, H. Angew.
Chem., Int. Ed. 2010, 49, 5533−5536. (d) Ashworth, I. W.; Hillier, I.
H.; Nelson, D. J.; Percy, J. M.; Vincent, M. A. Chem. Commun. 2011,
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J.
J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
47, 5428−5430. (e) Nunez-Zarur, F.; Solans-Monfort, X.; Rodríguez-
̃
Santiago, L.; Sodupe, M. Organometallics 2012, 31, 4203−4215.
(f) Ashworth, I. W.; Hillier, I. H.; Nelson, D. J.; Percy, J. M.; Vincent,
M. A. ACS Catal. 2013, 3, 1929−1939.
̈
D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.
(37) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785−
789. (b) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
J. Phys. Chem. 1994, 98, 11623−11627.
(38) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098−3100. (b) Perdew,
J. P. Phys. Rev. B 1986, 33, 8822−8824.
(39) (a) Poater, A.; Pump, E.; Vummaleti, S. V. C.; Cavallo, L. J.
Chem. Theory Comput. 2014, 10, 4442−4448. For earlier examples
using BP86 to study ruthenium-catalyzed olefin metathesis reactions,
see: (b) Adlhart, C.; Chen, P. Angew. Chem., Int. Ed. 2002, 41, 4484−
4487. (c) Diesendruck, C. E.; Tzur, E.; Ben-Asuly, A.; Goldberg, I.;
Straub, B. F.; Lemcoff, N. G. Inorg. Chem. 2009, 48, 10819−10825.
(40) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.
(41) Zhao, Y.; Truhlar, D. G. J. Chem. Phys. 2006, 125, 194101.
(42) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10,
6615−6620.
(43) (a) Kulkarni, A. D.; Truhlar, D. G. J. Chem. Theory Comput.
2011, 7, 2325−2332. (b) Minenkov, Y.; Singstad, Å.; Occhipinti, G.;
Jensen, V. R. Dalton Trans. 2012, 41, 5526−5541.
(44) Here we used computationally less-demanding double-ζ basis
sets in the geometry optimizations since the previous benchmark
studies revealed relatively small differences between double- and triple-
ζ basis sets in geometry optimizations of ruthenium complexes. See
refs 39a and 43a.
(45) The 2-Ada group in catalyst 11 is oriented closer to one of the
N-Mes aryl rings and to the chloride ligands than the i-Pr and 1-Ada
groups in catalysts 4 and 12, respectively. See the Supporting
Information.
(26) Engle, K. M.; Luo, S.-X.; Grubbs, R. H. J. Org. Chem. 2015, 80,
4213−4220.
(27) (a) Cote, B.; Ducharme, Y.; Frenette, R.; Friesen, R.; Martins, E.
(Merck & Co.). Tri-aryl-substituted-ethane PDE4 Inhibitors. U.S.
Patent US20020156105 A1, Oct 24, 2002. (b) Cherian, J.; Choi, I.;
Nayyar, A.; Manjunatha, U. H.; Mukherjee, T.; Lee, Y. S.; Boshoff, H.
I.; Singh, R.; Ha, Y. H.; Goodwin, M.; Lakshminarayana, S. B.;
Niyomrattanakit, P.; Jiricek, J.; Ravindran, S.; Dick, T.; Keller, T. H.;
Dartois, V.; Barry, C. E., III J. Med. Chem. 2011, 54, 5639−5659.
(28) Monsaert, S. F.; Verpoort F. W. C. (Umicore AG & Co. KG and
Ghent University). Process for Preparation of Ruthenium-Based
Carbene Catalysts with Chelating Alkylidene Ligands. World Patent
WO2011091980 A1, Aug 4, 2011.
(29) (a) Monsaert, S.; Drozdzak, R.; Dragutan, V.; Dragutan, I.;
Verpoort, F. Eur. J. Inorg. Chem. 2008, 432−440. (b) Urbina-Blanco,
C. A.; Manzini, S.; Gomes, J. P.; Doppiu, A.; Nolan, S. P. Chem.
Commun. 2011, 47, 5022−5024. For a relevant review, see: (c) Boeda,
F.; Clavier, H.; Nolan, S. P. Chem. Commun. 2008, 2726−2740.
(30) Catalysts 9−12 are air-stable, free-flowing green solids that can
be conveniently stored and manipulated as solids outside of the
glovebox. In solution, however, catalyst 11 is susceptible to
decomposition when dissolved in organic solvents that have not
been rigorously dried and degassed. It is recommended that standard
Schlenk techniques be employed when 11 is used outside of the
glovebox. Catalysts 9, 10, and 12 are more robust toward air and
moisture in solution and can be handled in organic solvents that have
not been rigorously dried or degassed. Across the series of catalysts
that were examined in this study (4−12), it was found that faster-
initiating catalysts tended to be more susceptible to decomposition in
solvents that were not rigorously dried and degassed. It is likely that
decomposition is mediated by trace quantities of dissolved O2. For
relevant discussion, see ref 21.
(31) The procedures using Amberlyst-15 resin are advantageous in
terms of operational simplicity, as they do not require purification by
silica gel column chromatography. Instead, the workup involves
precipitation, filtration, and repeated washing with MeOH and
pentane. With 11, precipitating the catalyst immediately and purifying
it through a series of washes is important because the catalyst
decomposes when dissolved in organic solvents that have not been
rigorously dried and degassed.
(32) RCM kinetics experiments were performed according to a
previously published procedure. See: Ritter, T.; Hejl, A.; Wenzel, A.
G.; Funk, T. W.; Grubbs, R. H. Organometallics 2006, 25, 5740−5745.
(33) For consistent results in RCM kinetics, the purity of the solvent
and the diene were found to be critical. See the Supporting
Information.
(34) CCDC 1017843 (5), 1044211 (9), 1044212 (10), 1017842
(11), and 1017841 (12) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
(46) (a) Sußner, M.; Plenio, H. Chem. Commun. 2005, 5417−5419.
̈
(b) Leuthaußer, S.; Schmidts, V.; Thiele, C. M.; Plenio, H. Chem.
̈
Eur. J. 2008, 14, 5465−5481. (c) Credendino, R.; Falivene, L.; Cavallo,
L. J. Am. Chem. Soc. 2012, 134, 8127−8135.
(47) (a) Vehlow, K.; Maechling, S.; Blechert, S. Organometallics 2006,
25, 25−28. (b) Vehlow, K.; Maechling, S.; Kohler, K.; Blechert, S. J.
̈
Organomet. Chem. 2006, 691, 5267−5277.
(48) These thermodynamic values are a means of measuring the
strengths of Ru−O bonding interactions. Though they are not bond
dissociation energies in a classical sense, throughout the text we refer
to these values as “bond strengths” in the interest of brevity.
(49) For applications of distortion/interaction analysis in organo-
metallic chemistry, see: (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J.
Am. Chem. Soc. 2008, 130, 10848−10849. (b) Green, A. G.; Liu, P.;
Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 4575−4583.
For computational studies of strain energies using the fragmentation
approach, see: (c) Fernan
́
dez, I.; Bickelhaupt, F. M.; Cossío, F. P.
dez, I.;
Chem.Eur. J. 2012, 18, 12395−12403. (d) Fernan
́
Bickelhaupt, F. M.; Cossío, F. P. Chem.Eur. J. 2014, 20, 10791−
10801.
(50) One model is that Hoveyda-type catalysts initiate by competing
dissociative and interchange mechanisms. For a detailed discussion, see
ref 19 and references therein. In both mechanisms, a weaker Ru−O
bond would decrease the activation barrier for initiation. For example,
because of the weaker Ru−O bond, the computed barrier for the
dissociative initiation pathway of 11 is 1.7 kcal/mol lower than that of
4. See the Supporting Information for details.
(35) Barbasiewicz, M.; Szadkowska, A.; Makal, A.; Jarzembska, K.;
Wozniak, K.; Grela, K. Chem.Eur. J. 2008, 14, 9330−9337.
́
(36) All of the computations were performed in the gas phase with
Gaussian 09: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J.
L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
K
DOI: 10.1021/jacs.5b01144
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX