From Resting State to the Steady State: Mechanistic Studies of Ene-Yne Metathesis Promoted by the Hoveyda Complex

Article abstract of DOI:10.1021/jacs.6b01887

The kinetics of intermolecular ene-yne metathesis (EYM) with the Hoveyda precatalyst (Ru1) has been studied. For 1-hexene metathesis with 2-benzoyloxy-3-butyne, the experimental rate law was determined to be first-order in 1-hexene (0.3-4 M), first-order in initial catalyst concentration, and zero-order for the terminal alkyne. At low catalyst concentrations (0.1 mM), the rate of precatalyst initiation was observed by UV-vis and the alkyne disappearance was observed by in situ FT-IR. Comparison of the rate of precatalyst initiation and the rate of EYM shows that a low, steady-state concentration of active catalyst is rapidly produced. Application of steady-state conditions to the carbene intermediates provided a rate treatment that fit the experimental rate law. Starting from a ruthenium alkylidene complex, competition between 2-isopropoxystyrene and 1-hexene gave a mixture of 2-isopropoxyarylidene and pentylidene species, which were trappable by the Buchner reaction. By varying the relative concentration of these alkenes, 2-isopropoxystyrene was found to be 80 times more effective than 1-hexene in production of their respective Ru complexes. Buchner-trapping of the initiation of Ru1 with excess 1-hexene after 50% loss of Ru1 gave 99% of the Buchner-trapping product derived from precatalyst Ru1. For the initiation process, this shows that there is an alkene-dependent loss of precatalyst Ru1, but this does not directly produce the active catalyst. A faster initiating precatalyst for alkene metathesis gave similar rates of EYM. Buchner-trapping of ene-yne metathesis failed to deliver any products derived from Buchner insertion, consistent with rapid decomposition of carbene intermediates under ene-yne conditions. An internal alkyne, 1,4-diacetoxy-2-butyne, was found to obey a different rate law. Finally, the second-order rate constant for ene-yne metathesis was compared to that previously determined by the Grubbs second-generation carbene complex: Ru1 was found to promote ene-yne metathesis 62 times faster at the same initial precatalyst concentration.

Full text of DOI:10.1021/jacs.6b01887

Article
pubs.acs.org/JACS
From Resting State to the Steady State: Mechanistic Studies of Ene−
Yne Metathesis Promoted by the Hoveyda Complex
Justin R. Griffiths, Jerome B. Keister,* and Steven T. Diver*
Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, New York 14260-3000, United States
S
* Supporting Information
ABSTRACT: The kinetics of intermolecular ene−yne metathesis
(EYM) with the Hoveyda precatalyst (Ru1) has been studied. For
1-hexene metathesis with 2-benzoyloxy-3-butyne, the experimental
rate law was determined to be first-order in 1-hexene (0.3−4 M),
first-order in initial catalyst concentration, and zero-order for the
terminal alkyne. At low catalyst concentrations (0.1 mM), the rate
of precatalyst initiation was observed by UV−vis and the alkyne
disappearance was observed by in situ FT-IR. Comparison of the rate of precatalyst initiation and the rate of EYM shows that a
low, steady-state concentration of active catalyst is rapidly produced. Application of steady-state conditions to the carbene
intermediates provided a rate treatment that fit the experimental rate law. Starting from a ruthenium alkylidene complex,
competition between 2-isopropoxystyrene and 1-hexene gave a mixture of 2-isopropoxyarylidene and pentylidene species, which
were trappable by the Buchner reaction. By varying the relative concentration of these alkenes, 2-isopropoxystyrene was found to
be 80 times more effective than 1-hexene in production of their respective Ru complexes. Buchner-trapping of the initiation of
Ru1 with excess 1-hexene after 50% loss of Ru1 gave 99% of the Buchner-trapping product derived from precatalyst Ru1. For the
initiation process, this shows that there is an alkene-dependent loss of precatalyst Ru1, but this does not directly produce the
active catalyst. A faster initiating precatalyst for alkene metathesis gave similar rates of EYM. Buchner-trapping of ene−yne
metathesis failed to deliver any products derived from Buchner insertion, consistent with rapid decomposition of carbene
intermediates under ene−yne conditions. An internal alkyne, 1,4-diacetoxy-2-butyne, was found to obey a different rate law.
Finally, the second-order rate constant for ene−yne metathesis was compared to that previously determined by the Grubbs
second-generation carbene complex: Ru1 was found to promote ene−yne metathesis 62 times faster at the same initial
precatalyst concentration.
precatalyst (Scheme 1). This investigation provides insight on
the alkene initiation process as it relates to catalysis.
INTRODUCTION
■
Metathesis of unsaturated carbon−carbon bonds has become
an indispensible method for the catalytic formation of new
carbon−carbon bonds. Alkene and ene−yne metathesis are
widely used in a variety of applications and have been successful
in bringing about bond formation in complex molecules bearing
high densities of functional groups, for example, in the total
synthesis of natural products and for the synthesis of
medicinally relevant compounds.1 The metathesis catalysts
used in these settings are diverse.2 Particular emphasis in
catalyst development has focused on the chelating ether motif
discovered by Hoveyda and co-workers.3 Many of the most
challenging current applications in total synthesis employ the
Hoveyda catalyst (Ru1)3b,c or variants.1c,f,j,n,o,r,s,v,x,y,ab−ad
Recently, mechanistic work by Plenio and co-workers has
shed light on the initiation of alkene metathesis by the Hoveyda
catalyst and its electronically tuned variants.4 However, it was
unclear how the rapid initiation profile is linked to formation of
an active intermediate, catalysis, and decomposition. For ene−
yne metathesis, the phosphine-free nature of precatalyst Ru1
should increase the ene−yne metathesis rate by limiting
unproductive resting states. In this paper, we describe a
mechanistic and kinetic study of ene−yne metathesis promoted
by the Hoveyda (a.k.a. Hoveyda−Grubbs) ruthenium carbene
The Hoveyda precatalyst is widely used and is a uniquely
active metathesis precatalyst. The Grubbs catalyst Ru3 initiates
by a dissociative pathway that is independent of alkene
concentration (0.173−1.02 M).5 In contrast, Hoveyda-type
catalysts initiate with alkenes differently. During a ring-closing
Scheme 1. Kinetic Study of Ene−Yne Metathesis Promoted
by Phosphine-Free Initiators (inset)
Received: February 19, 2016
© XXXX American Chemical Society
A
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metathesis (RCM) study, Dorta and co-workers found that
rates of RCM showed diene concentration dependence,
unexpectedly proceeding at faster rates for more concentrated
diene solutions.6 This indicated that the initiation step
depended on alkene concentration. The Hoveyda catalyst
Ru1 initiates with vinyl ethers with a negative entropy of
activation (ΔS⧧).4b,7 Detailed kinetic studies have been
reported by Plenio and co-workers.4b Plenio observed the
disappearance of the precatalyst Ru1 by UV−vis monitoring.5a,8
The initiation step was found to be a composite of interchange
and dissociative mechanisms that depends on the structure of
the alkene, its concentration, and the Hoveyda-type precatalyst
used. For precatalyst Ru1 and 1-hexene, the mechanism is
predominantly associative, proceeding by an interchange
process, and the rate law is roughly first-order in alkene.4
Though kinetic models of initiation are sound, the Ru1
initiation process is not well understood. The overall activation
process forms a catalytic intermediate that is common to both
alkene and ene−yne metathesis. Recently, Grubbs and co-
workers studied initiation by Hoveyda-type precatalysts and
noted that “the mechanism of initiation by the Hoveyda-type
initiators is complex and the subject of ongoing investigation”.2a
Initiation has been studied from the front end: the rate of
disappearance of the precatalyst Ru1 can be directly observed
with different alkenes.4 This is due to the loss of a metal-to-
ligand charge transfer (MLCT) band associated with Ru1
(UV−vis). It is thought that intermediates are formed that lead
to the active catalyst.4a,9 Experimentally, this has been difficult
to study because as Ru1 decreases there are no observable
intermediates (Scheme 2). What does the precatalyst give as it
initiation. This can indirectly probe the production of an active
catalyst through its participation in a catalytic process.
Phosphine-bound intermediates are thought to play an
important role in ene−yne metathesis using the second-
generation Grubbs complex Ru3. A proposed mechanism of
ene−yne metathesis (EYM) was suggested for the Ru3 carbene
precatalyst (Scheme 3).10 The mechanism involves initiation of
the alkene to make an intermediate [Ru]CHR (A). Alkyne
insertion into the ruthenium carbene gives vinyl carbene B. The
rate-determining step occurs from B, which exists in an
unproductive equilibrium with its phosphine-bound resting
state C. Intermediate C was hypothesized to slow catalysis, as it
requires a phosphine dissociation step. The equilibrium
between C and B regulates active carbene intermediates
passing through the slow step, which involves alkene binding.
The vinyl carbene has been calculated to be a stable carbene
intermediate (as compared to [Ru]CHR), and the alkyne
insertion step is an irreversible elementary step.11 The rates of
internal alkynes or EYM promoted by phosphine-free initiators
(e.g., Ru1, Ru2) have not been studied.12
Ene−yne and alkene metathesis share some reactive
intermediates. In EYM, reactive intermediates include both
ruthenium carbenes and ruthenacyclobutanes (rcb or rcbs).
The active catalysts in alkene metathesis are the ruthenium
carbenes [Ru]CHR and [Ru]CH2. These 14-electron,
coordinatively unsaturated species are highly reactive and have
not been directly observed. Romero and Piers13 and Wenzel
and Grubbs14 independently found rcb intermediates in alkene
metathesis. On the basis of the rates of exchange between α-
and β-carbons of the rcb, the corresponding η2-alkene complex
is about 12 kcal/mol higher in energy above the rcb. Loss of the
coordinated alkene gives the highly active 14-electron
ruthenium carbene intermediate (A in Scheme 3).
Scheme 2. Disappearance of Precatalyst Ru1 and the Net
Initiation Process
Ene−yne metathesis features a unique ruthenium carbene,
the vinyl-substituted carbene. In ene−yne metathesis, vinyl
carbenes B are formed after the alkyne insertion step; their
existence was inferred from a kinetic study of the catalytic
reaction.10,15 Like ruthenium alkylidenes (A), vinyl carbenes B
are unstable and highly reactive 14-electron intermediates. DFT
studies have gauged their relative energy levels.9,16 With the
first-generation Grubbs catalyst, vinyl carbenes have been
observed spectroscopically.17 If a chelating group is present, the
vinyl carbene may be stabilized enough to be isolable.18 The
reaction rate of vinyl carbene−phosphine complex reacting with
p-substituted styrenes was studied as a model step of the vinyl
carbene turnover step.19 On the basis of our earlier kinetic
initiates? Is it possible that the active catalyst concentration may
change over time? If the precatalyst does not directly form the
active catalyst, what rate process regulates the formation of the
active catalyst? One way to approach this problem is to track
̀
the rate of a catalytic process vis-a-vis the precatalyst rate of
Scheme 3. Previously Proposed Mechanism of Ene−Yne Metathesis (with Grubbs catalyst Ru3)10
B
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Scheme 4. Two Distinct Decomposition Pathways for Ruthenium Vinyl Carbenes26,27
study,10 the phosphine-bound resting state C was viewed as a
barrier to catalysis by regulating active vinyl carbene B.
Simplistically, we reasoned that if there were no phosphine-
bound resting state C, the EYM would proceed at a faster
reaction rate.
structural effects in the alkyne reactant? Can any reactive
intermediates be trapped or observed spectroscopically? Is a
faster initiator for alkene metathesis better for ene−yne
metathesis also? Herein we present a detailed kinetic study of
ene−yne metathesis promoted by the Hoveyda precatalyst Ru1.
We employ a rapid trapping technique using added isocyanides
to trigger a Buchner reaction that potentially allows
identification of carbene intermediates. The simultaneous
observation of the Ru1 initiation reaction and that of catalytic
ene−yne metathesis allowed a unique and direct comparison
that relates initiation of precatalyst to the rate of ene−yne
metathesis. These studies revealed that steady-state concen-
tration of reactive intermediates was rapidly attained and
maintained over the duration of the catalytic reaction.
Carbene intermediates and ruthenacyclobutanes are highly
reactive intermediates and are known to decompose by several
different pathways. The activation free energy (ΔG‡) for
initiation of Ru1 with butyl vinyl ether is +19.6 kcal/mol
(toluene at 303 K).9b The resulting carbene intermediate is
almost 20 kcal/mol higher in energy than the chelated
precatalyst and is susceptible to decomposition. Metathesis of
1-alkenes proceeds through a [Ru]CH2 species. Grubbs and
co-workers found that the ruthenium methylidene undergoes
decomposition to form a dinuclear ruthenium hydride.20 In the
presence of coordinating ligands, the ruthenium methylidene
may extrude a phosphorus ylide, eliminating metathesis
activity.21 Ruthenium carbenes undergo dimerization, thereby
destroying the carbene and abolishing metathesis activity.22
Some Hoveyda-type complexes undergo intramolecular CH
activation.23 In the presence of alcohols, such as allylic or
primary alcohols, ruthenium carbenes are converted into
ruthenium hydrides,24 which abolish metathesis reactivity and
may lead to unwanted side reactions such as alkene
isomerization. Ruthenacyclobutanes have also been found to
thermally decompose through a β-hydride elimination/
reductive elimination pathway.25
RESULTS
■
To study the rate of ene−yne metathesis we enlisted IR
spectroscopy for the in situ monitoring of terminal alkyne
concentration. Alkyne loss was monitored by integration of the
CH stretching IR absorption in a thermostated reaction vessel
under an argon atmosphere. Typical conditions used 0.08 M
alkyne 1A, 1-hexene (0.5−4.0 M), and 0.1 mM Ru1 in toluene
at 25 °C (eq 1, Scheme 1). The IR method provides a large
number of data points, and the experiments are easily repeated
so that multiple trials of each set of conditions could be done to
maximize data accuracy. At high 1-hexene concentrations or
higher catalyst loadings, the alkyne disappeared linearly over
time (Figure 1), indicating zero-order dependence on alkyne
For decomposition related to ene−yne metathesis, there are
distinct pathways that depend on the presence of the alkyne.
First, a vinyl carbene derived from Ru1 may insert a second
alkyne, giving F (eq 2, Scheme 4). This species may undergo
reductive elimination, thereby destroying the carbene and
eliminating metathesis activity.26 Second, Grubbs and co-
workers observed that Ru3 reacted with phenyl-containing
alkynes to give complexes that appeared to be derived from
vinyl carbene intermediates but were found to be metathesis-
inactive (eq 3, Scheme 4).27 Other related alkyne side reactions
such as cyclotrimerization28 are also known; however, these do
not destroy the ruthenium carbene. Of course, analogous
pathways may operate for ruthenium vinyl carbenes as for
ruthenium alkylidenes. Vinyl carbene dimerization was
observed by Fogg and co-workers, where the organic
dimerization byproduct was identified.29
Figure 1. Plot of alkyne conversion versus time. Alkyne concentration
was determined by integration of the alkyne CH stretching frequency
at 3310 cm−1 at 5 s intervals. Reaction conditions: 0.08 M alkyne 1A, 3
M 1-hexene, 0.1 mM Ru1 in toluene at 25 °C. In this run, kobs was
found to be (1.26 0.02) × 10−3 M/s.
On the basis of these considerations, we initiated a
mechanistic study of the EYM promoted by the phosphine-
free precatalyst Ru1. Several questions guided the design of our
study. If phosphine regulates vinyl carbene intermediates with
phosphine-containing Grubbs catalysts such as Ru3, what
happens when no phosphine is present? Is the rate law the
same, and in what way does the reaction show sensitivity to
concentration, as we observed in the previous study with Ru3.
The linear plot directly provides the rate of alkyne
disappearance, which is reported as kobs. Because of the zero-
order alkyne dependence and the pseudo-order conditions, rate
= kobs, and kobs has units of M/s. A solvent effect was
observed,2b,5a,30 with reaction rates found to be at least 6 times
faster in toluene as compared to 1,2-dichloroethane (DCE). As
C
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a result, the kinetic runs were performed in toluene.
Importantly, the initial precatalyst concentration ([Ru1]0)
could be reduced to 0.1 mM, or 0.125 mol %, based on the
alkyne, and most reactions (>1 M 1-hexene) went to
completion.31
Orders in Reactants and Lack of Saturation Kinetics.
Variation of the alkene concentration from 0.5 to 4.0 M
revealed a first-order dependency and lack of saturation kinetics
(Figure 2). The initial alkyne concentration was 0.08 M
Figure 3. Overlay of precatalyst initiation rate and rate of ene−yne
metathesis. The alkyne 1A disappearance (diamonds) matches the left
y-axis, measured by diminution of the alkyne absorbance at 3310 cm−1,
measured by in situ FT-IR. The initiation rate of Ru1 (squares)
matches the concentrations on the right y-axis, measured by
disappearance of the absorption at 377 nm, determined by UV−vis.
Each kinetic run was performed under identical conditions but
obtained separately. Conditions: 0.1 mM Ru1, 80 mM alkyne 1A, 3 M
1-hexene, toluene, 25 °C.
Figure 2. Plot of kobs vs [1-hexene]. From 0.5 to 4 M 1-hexene,
saturation of the reaction rate was not observed. Reaction conditions:
0.08 M alkyne 1A, 0.5−4.0 M 1-hexene, 0.1 mM Ru1 in toluene at 25
°C. At higher 1-hexene concentrations, the significantly faster reaction
rates provided fewer data points, increasing the error.
of alkyne 1A (e.g., reflecting the EYM rate) is ∼30 s, and the
half-life of Ru1 is ∼19 s. Ene−yne metathesis continues as long
as precatalyst Ru1 remains.
Lower alkene concentration results in incomplete conversion
due to catalyst decomposition. In similar measurements made
at 1 M 1-hexene (data not shown), the EYM stalled at 50%
conversion after 100 s.32 By that time, 97% of Ru1 had
initiated. At these lower alkene concentrations, the EYM rate is
slower and incomplete conversion of alkyne is found. This
suggests that the EYM cannot stay ahead of decomposition.
An active catalyst persists longer under alkene metathesis
conditions than under ene−yne metathesis conditions (Figure
4). The rate of ene−yne metathesis and the rate of alkene
throughout this study. By taking the ln(kobs) and plotting
against ln[1-hexene], the order in 1-hexene was found to be
1.03
0.05 (data not shown),32 similar to a previous study
using the Grubbs complex Ru3.10 At this stage, a vinyl carbene
intermediate B (Scheme 3, above) was hypothesized whose rate
of catalytic turnover would be dependent on alkene
concentration. With a small amount of catalytic intermediate,
we expected that it would be possible to saturate the reaction
rate by employing successively higher alkene concentrations.
However, Figure 2 shows that the reaction rate could not be
saturated, even at 4 M 1-hexene.32
The order in the catalyst was similarly determined and gave
an overall rate law for the ene−yne metathesis. The
concentration of the active form of the catalyst cannot be
directly measured, but it is proportional to the initial
concentration of precatalyst [Ru1]0. Obtaining kobs at
increasing Ru1 concentrations (0.1−1 mM Ru1, 80 mM 1A,
0.5 M 1-hexene in toluene at 25 °C) showed an increasing
rate.33 A plot of ln(kobs) vs ln[Ru1]0 was linear with a slope of
0.97, indicating a first-order rate dependence on [Ru1]0.32
Overall, the experimental rate law was thus determined to be
rate = kEYM[Ru1]0 [alkene]1[alkyne]0 (under conditions that
1
lead to complete consumption of alkyne).
Figure 4. Comparison of alkene and ene−yne metathesis. Alkene
metathesis followed the formation of 5-decene (GC). For ene−yne
metathesis, the concentration of 1,3-diene 2A was calculated by
following alkyne disappearance (in situ IR) according to [2A] = [1A]0
− [1A]t. Conditions: 0.1 mM Ru1, 0 or 80 mM alkyne 1A, 1 M 1-
hexene, toluene, 25 °C.
Dual Tracking of Alkyne Disappearance and Precata-
lyst Initiation. A direct rate comparison between alkyne
consumption and precatalyst Ru1 consumption (the first step
of catalyst initiation) was possible. The low precatalyst
concentration permitted the use of two spectroscopic methods:
IR to track alkyne concentration and UV−vis to track the
precatalyst Ru1 concentration over time. These two methods
allowed for the determination of ene−yne metathesis rate and
the rate of catalyst initiation (Ru1 decay) under the same
conditions but as separate experiments (Figure 3).
Full precatalyst initiation occurs on roughly the same time
scale as complete conversion of the alkyne. The plot is scaled
with respect to total change in species (A) concentration from
[A]0 to [A]t→∞ showing that each species reaches ∼90%
conversion at about 50 s. By inspection of Figure 3, the half-life
metathesis was followed under identical conditions (0.1 mM
Ru1, 0 or 80 mM alkyne 1A, 1 M 1-hexene, toluene, 25 °C).
For instance, in Figure 4, the EYM proceeded to about 50%
conversion to 1,3-diene 2A after 200 s and then stalled. At this
point, precatalyst Ru1 had fully initiated. In contrast, alkene
metathesis conversion to 5-decene, in the absence of alkyne,
continues for much longer periods. In alkene metathesis, active
catalyst is still present at least 10 times longer than under
comparable conditions of ene−yne metathesis. This is due to
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greater catalyst decomposition occurring under ene−yne
metathesis conditions.
Trapping Studies Using the Isocyanide-Promoted
Buchner Reaction. Earlier, we reported rapid Buchner
quenching reactions promoted by isocyanides.34 We thought
that this reaction might allow us to trap the active carbene
intermediates that form upon precatalyst disappearance. To
detect reactive intermediates, the rate of isocyanide-promoted
Buchner reaction has to be faster than the expected lifetime of
the intermediate. From the kinetic runs above, 0.1 mM Ru1
gives complete conversion of 80 mM alkyne, thereby giving a
turnover number of 800 (or higher). The reaction in Figure 3 is
complete in 60 s, meaning that the lifetime of catalytic
intermediate(s) is ≤75 ms. Before quenching-rate studies could
be performed, it had to be determined that [Ru]CHR could
be rapidly trapped by an added isocyanide.
To evaluate the feasibility of trapping alkylidenes [Ru]
CHR, a suitable 14-electron alkylidene surrogate was needed.
The Grubbs pyridine solvate 335 offers a means to isolate and
handle a surrogate for the 14-electron ruthenium carbene
intermediate under question. Following Sponsler’s protocol,36
we prepared the new alkylidene 4 (eq 4). When 4 was exposed
carbene back to the chelated precatalyst Ru1. In the reverse
direction, eq 6 depicts initiation of Ru1 with 1-hexene. In a
typical catalytic metathesis application, the concentration of
alkene is much higher relative to Ru1 and any released 11
(which will only be as high as the precatalyst loading).
A simple experiment showed that the isocyanide quench was
capable of trapping metal carbenes faster than ruthenium
carbene exchange. Starting with carbene complex 4, an
equimolar amount of 11 was added at the same time as an
excess of isocyanide 5 (eq 7, Table 1, entry 1). If no carbene
Table 1. Relative Rate of Buchner-Trapping vs Carbene
Exchange
to p-chlorophenyl isocyanide (5), Buchner insertion produced a
new complex (6) in 69% isolated yield. Presumably one or both
pyridines are dissociated, providing a similar intermediate as
encountered in the alkene self-metathesis of 1-hexene and ene−
yne metathesis between 1-hexene and an alkyne.
Additionally, the ruthenium methylidene [Ru]CH2 proved
trappable by isocyanide-promoted Buchner insertion. The
ruthenium methylidene is the chain carrier in alkene metathesis
and may form late in ene−yne metathesis due to alkene self-
metathesis. Earlier work showed that the corresponding Cy3P
complex (H2IMes) (Cy3P)Cl2RuCH2 was trapped by CO
and isocyanides.34c Exposure of Piers’s catalyst 713 to ethylene
produced an intermediate that at low temperature can be
observed as the ruthenacyclobutane 8. Addition of an excess of
p-chlorophenyl isocyanide (5) gave the new complex 10 (eq 5).
However, the rate of the Buchner reaction in relation to
catalytic ene−yne metathesis was not established. Could the
Buchner reaction be used to trap intermediates under catalytic
conditions?
The exchange of one carbene fragment for another one is
termed transalkylidenation, and it is one of the fastest processes
in alkene metathesis (eq 6).37 Transalkylidenation proceeds
through a ruthenacyclobutane intermediate 12.13,14 Starting
with the active carbene species 4, capture by 2-isopropoxystyr-
ene (11) forms 12, which can break down to form the Hoveyda
complex Ru1 and 1-hexene. As written from left to right, eq 4
depicts the “boomerang effect”,3a,b,38 where 11 returns active
a
b
entry
added alkene
none
time interval (min) relative ratio 6:13 (%)
1
2
3
4
0
1
1
1
100
24
not detected
none
76
48
40
1-hexene (0.8 M)
1-hexene (1.6 M)
52
60
a
b
Complex 4 and 11 were each 10 mM, in CD2Cl2, at 25 °C. Relative
ratio determined by 1H NMR spectroscopy with mesitylene as an
internal standard.
exchange occurred, species 4 would trap as 6. If carbene
exchange were faster than the isocyanide-promoted Buchner
reaction, then a mixture of products would result. In the event,
a single Buchner insertion product 6 was obtained, giving
resonances at δ 5.82, 5.53, and 3.32 ppm for the cyclo-
heptatriene vinylic and methine protons. The previously
characterized complex 13 was not present. At this stoichiom-
etry, it can be concluded that the isocyanide coordination/
Buchner insertion is faster than carbene exchange using styrene
11 (transalkylidenation process).39
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If a waiting time interval is added, a significant amount of
metal carbene exchange (transalkylidenation) is found. If
addition of 11 precedes the addition of isocyanide by 1 min,
then 76% exchange had occurred, giving predominantly 13
(Table 1, entry 2).34c In the presence of an 80-fold excess of
alkene (Table 1, entry 3), significant return to Ru1 is evidenced
by the nearly 1:1 mixture of 6 and 13, despite the 80-fold excess
of 1-hexene. On the basis of this result, the effective molarity40
of the chelating alkene 11 is 80 compared to 1-hexene. This
suggests that a recapture by ejected styrene 11 can occur
competitively with a large excess of a terminal alkene.41
because no 6 was found. Lack of 6 is most likely due to a very
low concentration of the active carbene.
That Ru1 had disappeared cannot be taken as an initiation to
form an active catalyst. If it were a direct process, as Ru1
disappeared, the active carbene would concomitantly appear
and rise in concentration. On the basis of the diminished UV
absorption, the precatalyst Ru1 had significantly initiated to a
new species. It is presumed that Ru1 enters the equilibrium of
eq 9 (Scheme 5), leading to G, H, or I. The isocyanide-
triggered Buchner insertion traps what appears to be Ru1,
which implies that a rapid equilibrium exists between these
intermediates. We already showed that isocyanides can induce a
Buchner reaction from ruthenacyclobutanes (vide supra). Each
of these reactive intermediates still contains the 2-isopropox-
ystyrene ligand and could therefore produce 13. This may be a
Curtin−Hammett situation, where the reactive intermediates of
eq 9 (Scheme 5) have lower energies of interconversion than
the barrier of isocyanide-promoted insertion.
Inhibition Studies.42 Addition of 2-isopropoxystyrene
(11) had a small inhibitory effect on the ene−yne metathesis
reaction rate (Table 2). The ene−yne metathesis of 1A and 1-
a
Table 2. Inhibition of EYM by 2-Isopropoxystyrene (11)
entry
Ru1 (mM)
11 (mM)
kobs (M s−1
)
krel
1
2
3
1
1
1
0
1
3
(2.80 0.02) × 10−4
(2.35 0.01) × 10−4
(2.20 0.01) × 10−4
1.00
0.84
0.79
Trapping under EYM delivered very little Buchner-trapping
products and similarly did not identify any ruthenium carbene
intermediates. The EYM was run to varying conversions and
quenched by addition of isocyanide (eq 10). In the first case,
a
Conditions: 0.08 M alkyne 1A, 1 M 1-hexene, 1 mM Ru1, 0−3 mM
11, 1,2-DCE, 25 °C (temperature control), with the change in alkyne
absorbance at 3310 cm−1 monitored by in situ FT-IR.
hexene was examined. Without added styrene, the krel was set as
1.00 (entry 1). With an equimolar amount of 11 present, the
rate was slower, giving krel = 0.84 (entry 2). In this case, the
molar ratio of 1-hexene/11 is 1000:1. When the concentration
of 11 was tripled, a further, albeit smaller, diminution of rate
was observed (krel = 0.79, entry 3). On the basis of the
isocyanide trapping experiments, the apparent equilibrium
constant for exchange of 2-isopropoxystyrene (11) for 1-hexene
is ca. 80, so the expected change in concentration of the active
catalyst in the presence of added 3 mM 11 at 1 M hexene is ca.
80% of that which would be present in the absence of added 11.
This equilibrium estimate is consistent with the observed 21%
reduction in rate (entry 3 vs 1, Table 2).
Trapping Studies under Metathesis Conditions. With a
sufficiently fast Buchner reaction, we attempted to trap
intermediates present in precatalyst initiation (alkene meta-
thesis) and those present during ene−yne metathesis.
After the precatalyst had initiated, Buchner-trapping gave
exclusively the 2-isopropoxyarylidene insertion product (13).
After 4 min, >50% of Ru1 had initiated, on the basis of UV−vis
studies.4b,43 At this point, isocyanide was added, giving 13 in
99% yield (eq 8, Scheme 5). Whatever species had formed
upon loss of Ru1, it still retained the 2-isopropoxystyrene
moiety, which became trapped as the Buchner product 13. The
intermediate formed was not the active carbene [Ru]CHR,
after 40% conversion of alkyne, isocyanide quench resulted in
<5% 13 and 90% 11. After a longer time interval, 85%
conversion of alkyne had occurred, with a similar ratio of
Buchner product 13 and styrene 11 observed. At these
incomplete alkyne conversions, most of the precatalyst had
initiated. Unlike the alkene metathesis example above, Buchner
quenching of an EYM did not show trapping as precatalyst
Ru1, since complex 13 was not obtained above trace levels.
This is due to greater decomposition triggered by the presence
of the terminal alkyne.
Alkyne Steric Effects. An additional alkyne substrate
showed that the ene−yne metathesis rate is sensitive to steric
effects in terminal alkynes. A propargylic phenyl group was
compared to a methyl group (1B vs 1A; see structures in
Scheme 1 above). With a methyl substituent, the EYM rate was
2.75 times faster than with a phenyl substituent.32 The rate of
EYM of terminal alkynes is sensitive to the degree of
propargylic substitution.
Unbranched Terminal Alkynes. Propargyl benzoate did
not react cleanly to give the 1,3-diene product under any of the
Scheme 5. Buchner-Trapping under Alkene Metathesis Conditions
F
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reaction conditions used in this study. At 2 M 1-hexene, the
reaction stalled at 30% conversion to 2C (eq 11). Propargyl
Rate with Grela Catalyst. A faster initiating precatalyst
gives similar kobs for the ene−yne metathesis of 1A and 1-
hexene. In ring-closing metathesis (RCM) applications, the
overall rate is initiation-limited:2a,c,4 faster initiators give faster
rates of RCM. For instance, the Grela precatalyst45 Ru2
initiates with the alkene diethyl diallylmalonate (DEDAM) 3.2
times faster than the precatalyst Ru1, resulting in a faster RCM
(Table 4).4a,46 In contrast, the EYM rate does not correlate
Table 4. EYM Rate Constant and Initiation Rate Constant of
Two Different Catalysts
benzoate 1C is known to engage in a unique decomposition
pathway26 which destroys the RuC bond and produces a
metathesis-inactive Ru product. At higher 1-hexene concen-
tration, complete conversion could be obtained, but an
inseparable byproduct 14 was also formed (eq 11). Normally,
ene−yne metathesis of terminal alkynes and 1-alkenes is faster
than alkene self-metathesis. However, such high alkene
concentrations lead to competitive alkene metathesis, which
results in a [Ru]CH2 species. In the presence of an alkyne,
[Ru]CH2 leads to the unwanted byproduct. For alkynes
prone to decomposition, higher alkene concentration and
higher loading of Ru1 helps outpace decomposition. For
synthetic applications employing ene−yne metathesis of
unbranched terminal alkynes, alternative reaction conditions1q
or use of a different Grubbs precatalyst (such as Ru3) would be
advisible.
a
b
precatalyst kEYM (M−1 s−1
)
kinit (M−1 s−1
)
krel (initiation, DEDAM)
Ru1
Ru2
4.3 1.1
5.0 1.0
0.0238 0.0032
0.0764 0.0020
1.00
3.21
a
This work. Conditions: 0.08 M alkyne 1A, 1 M 1-hexene, 0.1 mM
Ru1, toluene, 25 °C (temperature control), with the change in alkyne
absorbance at 3310 cm−1 monitored by in situ FT-IR. The
experimental kobs values were divided by [1-hexene] and [Ru1] to
b
obtain the second-order rate constant, kEYM
.
Reaction with diethyl
diallylmalonate (DEDAM), in toluene, at 40 °C. From ref 4a.
with initiation rate differences for the Hoveyda and Grela
precatalysts (Table 4); if it did, the EYM by Ru2 would be ∼3
times faster than that promoted by Ru1.
DISCUSSION
Internal Alkynes. Internal alkynes react via a different rate
law. Unlike terminal alkynes, the rate of disappearance of
internal alkyne 15 shows exponential decay, indicating non-
zero-order dependence (eq 12). Logarithmic plots gave straight
■
The kinetic and mechanistic studies presented above provide a
better picture of metatheses promoted by the phosphine-free
precatalyst Ru1. The initiation process of Ru1 and the
intermediacy of RuCHR are relevant to both alkene and
ene−yne metathesis. Control studies established that the rate of
Buchner insertion was fast enough to trap ruthenium carbene
intermediates. The comparison between catalyst longevity
under alkene vs ene−yne metathesis shows that catalyst is
longer lived in alkene metathesis and that catalyst decom-
position is more pronounced in the presence of a 1-alkyne. At
the very low precatalyst loadings used, no carbene inter-
mediates could be trapped even when most of the precatalyst
had initiated.
lines (ln[15] vs t), indicating first-order alkyne dependence
(Table 3). Similar to the studies with terminal alkynes, no
a
Table 3. EYM Reaction Rate for Internal Alkyne 15
entry
1-hexene (M)
kobs (s−1
)
The active form of the catalyst is present in a low, steady-
state concentration. The dual rate plot in Figure 3 shows that
the rate of EYM does not increase as more precatalyst initiated.
As the precatalyst Ru1 continues to disappear, the rate of the
ene−yne metathesis remains the same. This indicates that the
active catalyst does not increase in concentration; the catalyst is
present in a steady-state concentration until no Ru1 remains.47
The low concentration of active catalyst is maintained due to an
uncharacterized decomposition pathway that is not present (or
much less important) in alkene metathesis. At low alkene
concentration, decomposition can be seen in the dual rate plots
tracking the precatalyst initiation step with the rate of alkyne
disappearance.32 A steady-state kinetic model has been applied
to RCM by Plenio and co-workers, where an undefined
decomposition step was assumed.48
In the initiation process, the disappearance of Ru1 does not
directly result in an active carbene. The initiation of Ru1 is
measured by the decay in the UV−vis of the MLCT band at
377 nm, which does not directly measure or quantitate the
active carbene. The isocyanide trapping experiments above
show that when Ru1 has initiated, only Buchner insertion due
to a 2-isopropoxyarylidene is seen. This suggests that rapid
disappearance of precatalyst Ru1 gives intermediates shown in
1
2
3
1
2
3
(7.17 0.51) × 10−3
(1.35 0.05) × 10−2
(1.85 0.25) × 10−2
a
Conditions: 0.08 M 15, 1−3 M 1-hexene, 0.1 mM Ru1, toluene, 25
°C (temperature control), with the change in the carbonyl absorbance
at 1755 cm−1 monitored by in situ FT-IR.
saturation kinetics were observed up to 3 M 1-hexene
concentration. The ln(kobs) obtained from the slopes of the
lines were plotted against ln[1-hexene] to give a kinetic order of
0.84.32 Further dependencies in catalyst and alkene remain to
be determined in the future, and are the subject of ongoing
studies.
Though they obey a different rate law, internal alkynes react
at similar overall rates as compared to terminal alkynes. For
comparison, terminal alkyne 1A had a t1/2 = 52 s (apparent
zero-order kobs, 0.08 M alkyne, 2 M 1-hexene, 0.1 mM Ru1).
The internal alkyne 15 showed a t1/2 = 72 s (apparent first-
order kobs, 0.08 M alkyne, 2 M 1-hexene, 0.1 mM Ru1). This
data provides an interesting comparison considering that the
different alkynes have different overall reaction orders and
different rate-determining steps.12,44
G
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the box of Scheme 5, which become trapped as Buchner
product 13 upon isocyanide addition. At least one additional
step is needed to produce the active carbene.
similar for these two precatalysts. We think it is most likely to
be ruthenacyclobutane H or the η2-styrene complex I.
Calculations are also consistent with this hypothesis: Solans-
Monfort and co-workers calculated the free energy of the
styrene decoordination step (for both the interchange and
dissociative pathways) and found a small energy difference
between Ru1 and Ru2.9a
The alkyne structure affects the reaction rate and rate-
determining step. Of the two terminal alkynes compared,
greater propargylic bulk results in a slower EYM. This is
different than what we found in our earlier kinetic study of
EYM using Ru3 when a phosphine was present. In a
phosphine-free system, the increased bulk of the alkyne
substituent slows the intrinsic reaction rate (fewer catalytic
turnovers) of the slow step of catalysis. Second, rates of EYM
were found to be comparable for terminal alkynes as compared
to internal alkynes, although they obey different rate laws.
Internal alkynes show first-order alkyne dependence, whereas
terminal alkynes show zero-order alkyne dependence.
Capture of active ruthenium carbene by 2-isopropoxystyrene
is highly effective. Trapping by 2-isopropoxystyrene occurs
(starting from complex 4) even with a large excess of 1-alkene
present. With 0.8 M 1-hexene and 0.01 M 11, roughly equal
amounts of Buchner complexes were obtained. This provides
an effective molarity (EM)40,49 of 11 as 80 (compared to 1-
hexene). This could provide a useful way to benchmark alkene
reactivity vs 11. The carbene exchange pathway (trans-
alkylidenation) can be arrested by the addition of an isocyanide.
The isocyanide-triggered Buchner reaction provides a con-
venient means to identify ruthenium carbenes as their stable,
metathesis-inactive coordination complexes. Trapping studies
using the Buchner insertion were used to validate that
ruthenium carbene intermediates could be trapped if present.
The proposed mechanism in Scheme 7 is consistent with the
experimental rate law and mechanistic studies. Carbene
Previous work is suggestive of reactive intermediates that are
immediately formed upon precatalyst Ru1 disappearance.
Plenio suggested that the formation of G might account for
the loss of a MLCT band at 377 nm. On the basis of a DFT
calculation, Solans-Monfort and co-workers9a proposed that the
dissociation of styrene from I is the rate-determining step. For
the initiation process shown in eq 9 (Scheme 5), this is the last
step that leads to an active carbene. Related calculations by
Ashworth et al. indicate that species G has a UV spectrum
similar to that of Ru1, whereas I lacks a UV absorption around
377 nm.9b These workers concluded that when the UV
absorption (due to the MLCT band) is gone, the precatalyst
and intermediates G and H have progressed to I (Scheme 5).
The similar rates of EYM by Ru1 and Ru2 suggest a two-step
initiation process. The similar rate of EYM by Ru2 suggests that
there is a bottleneck in the initiation process that regulates the
formation of the active carbene. Further, this step must be
relatively insensitive to the electronic nature of the styrene
ligand. Despite different rates of alkene initiation, precatalysts
Ru1 and Ru2 lead to a similar steady-state concentration of
active catalyst for the EYM. The similar rates of EYM by the
two different precatalysts are inconsistent with a scenario where
the precatalyst immediately produced an active carbene. We
postulate that the two precatalysts initiate to form an
intermediate, which in turn delivers a low concentration of
the active carbene by a second, similar rate. The disappearance of
the precatalyst in the first initiation step is alkene-dependent
and can be seen by a loss of the MLCT band. Rather than
producing an active catalyst, this first step produces an
intermediate (Scheme 6).
Scheme 6. Two-Step Initiation Scenario (rates for ethyl vinyl
ether taken from the work of Plenio and co-workers)4a
Scheme 7. Proposed Mechanism
This two-step initiation process is sensitive to electronic
effects at the first step but not in the rate-controlling formation
of the active catalyst. The two-step initiation hypothesis is
consistent with an interesting observation made by Plenio and
co-workers during their seminal study.4a The rates of the first
step of initiation (e.g., the disappearance rate of precatalyst) are
different for Ru1 and Ru2. The rate constants shown in
Scheme 6 are taken from Plenio’s work with ethyl vinyl ether.
Plenio identified an intermediate that absorbed at 500 nm,
which underwent a slower rate of decay as compared to the rate
of Ru1 precatalyst disappearance.4a The decay of this
intermediate led to the active catalyst. Importantly, Plenio
found that the rate of this second initiation step was identical
for Ru1 and Ru2 and alkene-independent. Therefore, we
suggest that the intermediates G−I are rapidly formed in an
alkene-dependent manner, but the formation of the active
catalyst for EYM is slower, is not alkene-dependent, and is
intermediate A is the active 14-electron intermediate formed
by a two-step initiation process of Ru1 with alkene. Because
initiation is rate-controlled by a slow, alkene-independent step,
catalysts Ru1 and Ru2 promote EYM at similar rates. Alkyne
insertion into carbene A by step k1 produces the carbene
intermediate B. Vinyl carbenes B are calculated to be more
stable than ruthenium carbenes that lack conjugation.11 Step k2
consumes alkene and forms the 1,3-diene product. The lack of
phosphine-bound resting states result in high kinetic activity of
A and B toward unsaturated reactants, allowing hundreds of
turns of the catalytic cycle before decomposition occurs. The
decomposition pathway, unique to terminal alkyne-derived
vinyl carbenes B, is faster than the decomposition pathway
identified by Plenio and co-workers48 for RCM and much faster
H
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than the decomposition of [Ru]CHR under alkene cross-
metathesis conditions.
initiation, kEYM/ki2, gives the ratio of k2/kdec = 750.54 This
value is similar to the expected value of 800.55
A lower propagation/decomposition ratio (k2/kdec) is
calculated for a substituted terminal alkyne. For phenyl-
substituted alkyne 1B, kobs was 2.77 × 10−4 M/s. By dividing
Kinetic Treatment. The lack of trapping of carbenes and
observed decomposition at low alkene concentration led us to
hypothesize steady-state concentrations for both ruthenium
carbene intermediates A and B. The rate data comparisons for
precatalyst initiation (UV−vis) and rate of EYM (in situ IR)
show that the rate of EYM does not increase as more
precatalyst initiates. Kinetic treatment must explain the
experimental rate law determined to be rate =
kobs by the initial concentrations of 1-hexene and Ru1, kEYM
=
1.39 M−1 s−1, where kEYM = (k2kinit/kdec). If kEYM is divided by
the temperature-corrected ki2 obtained from Plenio’s data,4a
one obtains the ratio of propagation (catalysis) over the rate of
decomposition, k2/kdec = 270. This is 2.8 times less than that
observed with alkyne 1A. Most likely this is attributable to a
smaller k2 rather than a larger kdec, since competition studies
corroborated the individual kinetic runs for individual alkynes.
Additional steric bulk can either impede the approach of alkene
on intermediate B or destabilize the ruthenacyclobutane E. A
higher energy E will have a higher energy transition state, which
would reduce the value of the rate constant k2. In this scenario,
the propagation rate of 1B is about 3 times less than that of 1A.
The ene−yne metathesis of alkyne 1A and 1-hexene
promoted by the Hoveyda precatalyst Ru1 is significantly
faster than that promoted by the Grubbs catalyst (Ru3). In this
study, we determined the rate constant of EYM with Ru1 to be
kEYM = 3.9 0.6 M−1 s−1 (toluene, 298 K). In contrast, the
same alkyne displayed an experimental second-order rate
constant of 0.063 M−1 s−1 (toluene, 298 K) with Ru3.10 This
indicates that precatalyst Ru1 promotes EYM ∼ 62 times faster
than Ru3. Mechanistically, the phosphine-free catalyst systems
studied here are not regulated at the vinyl carbene stage. In
EYM promoted by Ru3, the vinyl carbene exists in an
unproductive equilibrium with its phosphine complex. In
phosphine-free systems, there is no such unproductive resting
state, which contributes to a faster catalytic process.
50
1
k[Ru1]0 [alkene]1[alkyne]0 for terminal alkynes. A key issue
is whether there is alkene dependency in the precatalyst
initiation step; if there is, an alkene dependency (i.e., kinetic
order) > 1 would be expected.51 Previous work shows that
there are two discrete kinetic steps in precatalyst initiation: one
alkene-dependent and one not alkene-dependent. This is
important because it helps explain the similar rates for
precatalysts Ru1 and Ru2 and pinpoints the alkene dependency
to the catalytic cycle, not to the initiation process. In their study
of RCM by Hoveyda-type precatalysts, Plenio and co-workers
did not ascribe alkene dependence to the initiation step; alkene
dependence was only due to the catalytic process,48 similar to
our kinetic treatment.
Using the steady-state assumption for both reactive
ruthenium carbene intermediates yields eq 13, which conforms
with the experimentally determined rate law. This rate
treatment eliminates alkyne concentration from the rate
equation and predicts a first-order dependence of the alkene
and precatalyst. The derivation is provided in the Supporting
Information.
d[alkyne]
kinitk
kdec
2 [Ru1][alkene]
Decomposition of vinyl carbene intermediates derived from
terminal alkynes is predicted in this study. The decomposition
appears to be first-order in Ru because the overall order of Ru is
first-order in the experimental rate law; a different order would
be expected if decomposition was, for example, second-order.
Plenio and co-workers48 identified two distinct decomposition
pathways in RCM catalyzed by Ru1: a first-order and second-
order pathway.56 Decomposition is faster under ene−terminal
alkyne metathesis as compared to alkene metathesis. We ascribe
this decomposition due to the vinyl carbene intermediate B.
Decomposition via A, an intermediate common to both alkene
and ene−yne metathesis, is also possible, but it alone does not
explain the lower catalyst lifetime seen in ene−yne metathesis
(due to the presence of a terminal alkyne). One possible
deactivation pathway is alkene coordination by the vinyl moiety
of the vinyl carbene, an intramolecular reaction. Grubbs et al.
have observed this type of coordination, which resulted in a
metathesis-inactive complex.27 Additionally, vinyl carbenes can
react with alkyne to give oligomer or undergo decomposition
by a known pathway.26 Carbenic reactions such as cyclo-
propanation and CH bond insertion are additional possibilities.
Further studies are needed to elucidate the decomposition
pathway.
rate = −
=
dt
(13)
Comparison of Rates. Comparison of the EYM apparent
second-order rate constant with the Ru1 disappearance rate
shows that EYM is significantly faster. The kobs values for EYM
can be divided by the concentrations of alkene and [Ru1]0 to
provide an experimental second-order rate constant kEYM
the basis of 29 trials, a value of kEYM = 3.9
.
52 On
0.6 M−1 s−1
(toluene, 298 K) is obtained (at 0.1−3 mM Ru1, 1−4 M 1-
hexene, and 80 mM alkyne 1A). We observed the
disappearance of Ru1 in the absence of alkyne, obtaining kinit
= 0.011 0.001 M−1 s−1 (0.1 mM Ru1, 1 M 1-hexene, toluene,
298 K). This value is very similar to the rate constant reported
in the literature4b after adjusting for temperature differences. At
the same alkene concentration, the EYM rate is at least 390
times faster than the alkene-dependent Ru1 initiation rate.53
The experimentally determined kEYM can be used to extract
the ratio of catalyst propagation to catalyst decomposition (k2/
kdec). At the low catalyst loadings used, a net catalyst turnover
number of ∼800 is anticipated. From the rate treatment of eq
13 (and derived in the Supporting Information), the
experimental kEYM equals (k2kinit/kdec). If kEYM is divided by
the limiting ki2 rate constant, one obtains the ratio of
propagation (catalysis) over the rate of decomposition, k2/
kdec. Above, a value of kEYM = 3.9(0.6) M−1 s−1 (toluene, 298 K)
was found. For Ru1 initiation, we use Plenio’s rate of the second
step of initiation, ki2 = 0.0288 s−1 (alkene-independent, toluene,
CONCLUSION
■
In summary, a detailed kinetic study of ene−yne metathesis
catalyzed by the Hoveyda complex (Ru1) was performed. This
study examined the relationship of the precatalyst initiation
process with the rate and structural sensitivities of catalytic
EYM with different alkynes. The first step of precatalyst
initiation was tracked simultaneous with alkyne disappearance,
40 °C).4a We corrected this rate to 25 °C (Eyring equation), to
298
obtain ki2
= 0.0052 s−1. Dividing the second-order rate
constant by the alkene-independent step of precatalyst
I
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which led to a steady-state hypothesis of active ruthenium
carbene. By observing catalysis, the reaction rate did not change
and there was not a buildup of an active carbene concomitant
with Ru1 disappearance. The precatalyst initiation process is
relevant to the Hoveyda-type catalysts and is significant for
both alkene and ene−yne metathesis. After precatalyst Ru1 had
initiated, isocyanide-triggered Buchner reaction trapped a 2-
isopropoxybenzylidene exclusively, suggesting that the precata-
lyst initiated to an intermediate that retained the styrene. In
ene−yne metathesis, Buchner insertion did not yield any
trapping products, which suggests that there is irreversible entry
into catalysis and a small, steady-state concentration of active
ruthenium carbene catalyst. The irreversibility implies high
turnover and decomposition from intermediates in the catalytic
cycle. An active catalyst persists longer under alkene metathesis
conditions versus ene−yne metathesis conditions with terminal
alkyne. Kinetic treatment is consistent with decomposition
through the vinyl carbene intermediate. These studies clearly
demonstrate that there is a bottleneck in the initiation process
that ultimately produces a steady-state concentration of the
active carbene species. Similar rates of EYM using precatalysts
that have different alkene initiation rates may be explained by a
two-step initiation process where the formation of the active
catalyst is not alkene-dependent and not sensitive to the styrene
ligand. Last, it should be noted that these kinetic studies were
performed at very high alkene concentrations and low
precatalyst loading using three terminal alkynes and one
internal alkyne.
(2) Hindered, α-branched terminal alkynes react more slowly
than less-hindered α-branched terminal alkynes. (3) Internal
alkynes follow a different rate law, which shows alkyne
dependence.
Catalysts. (1) The rate of ene−yne metathesis by Ru1 is 62
times faster than the rate of ene−yne metathesis promoted by
the Grubbs catalyst Ru3 (1-hexene and 1A). (2) Compared to
Ru1, a faster-initiating Hoveyda-type precatalyst Ru2 (Grela
catalyst) gives a similar rate of ene−yne metathesis between 1-
hexene and 1A. This was interpreted in terms of a two-step
initiation process where the second step results in rate-limiting
production of active ruthenium carbene. The second step is not
alkene-dependent and not as sensitive to the electronic nature
of the styrene.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b01887.
■
S
Additional graphs, experimental procedures, and charac-
terization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*keister@buffalo.edu
*diver@buffalo.edu
Notes
The authors declare no competing financial interest.
There are several conclusions that can be summarized on the
basis of their relevance to ene−yne metathesis, initiation, alkyne
structural effects, and the nature of the catalyst.
ACKNOWLEDGMENTS
■
Ene−Yne Metathesis. (1) For the terminal alkyne 1A, the
The authors thank the NSF (CHE-1012839 to S.T.D. and
J.B.K. and CHE-1300702 to S.T.D.) for financial support of this
work. We thank Dr. Jennifer Marshall for preliminary kinetic
studies performed in dichloroethane solvent and the UB
Chemistry Department for the Speyer Graduate Fellowship
awarded to J.R.G. We are also grateful to Dr. Dick Pederson
(Materia) for the generous gift of the Grubbs−Hoveyda
complexes used in this study. We dedicate this work to the
memory of Wes Walker (Mettler Toledo).
e x p e r i m e n t a l r a t e l a w w a s f o u n d t o b e
k[Ru1]0 [alkene]1[alkyne]0. (2) On the basis of dual tracking
1
of both the precatalyst initiation and the rate of ene−yne
metathesis, a steady-state concentration of active catalyst was
inferred. The rate of EYM did not increase as more precatalyst
initiation occurred. (3) Active catalyst persists longer under
alkene metathesis conditions as compared to ene−yne
metathesis with terminal alkynes. This is attributed to
decomposition via the vinyl carbene intermediate. Kinetic
treatment modeling decomposition through this intermediate
yielded a rate law that matched the experimental rate law. (4)
The rate of ene−yne metathesis is at least 390 times faster than
the disappearance of the UV absorbance of Ru1 (its alkene-
dependent rate of initiation).
Precatalyst Initiation. (1) Buchner-trapping of ruthenium
carbene intermediates in alkene and ene−yne metathesis
supports a two-step initiation process where an intermediate
is first formed in a rapid, alkene-dependent step. This
intermediate is likely a ruthenacyclobutane or a Ru carbene
bearing the 2-isopropoxystyrene ligand. It undergoes a slower,
alkene-independent conversion to the active ruthenium carbene
intermediate. (2) The active ruthenium carbene intermediate
was not trapped by isocyanide-promoted Buchner reaction.
Control experiments verified that a [Ru]CHR species would
give a Buchner product. The lack of trapping is understandable
in terms of the low, steady-state concentration of reactive
intermediates and the low precatalyst concentration used.
Alkynes. (1) A linear terminal alkyne yielded the 1,3-diene
only at the highest alkene concentrations, and a byproduct was
noted. These alkynes decompose Ru1, and higher alkene
concentrations are needed to outpace catalyst decomposition.
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(41) Longer time intervals resulted in slight changes: after 3 min,
42% 6 and 55% 13 were found.
(42) The 1,3-diene product did not inhibit the rate of ene−yne
metathesis. Addition of 0.08 M diene 2A to the ene−yne metathesis of
1A and 1-hexene gave an observed rate of kobs = (2.74 0.04) × 10−4
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diene product, kobs = (2.67 0.03) × 10−4 M/s.
(43) At the same concentrations, Plenio and co-workers reported t1/2
∼ 2.4 min.
(44) In ethylene−alkyne metathesis, terminal alkyne 1A was found to
react slightly faster than internal alkyne 15, and the unbranched alkyne
1C did not react at all. See ref 12.
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(46) Each of the precatalysts Ru1 and Ru2 have alkene-dependent
initiation rate laws and, upon initiation, lead to the same active catalyst.
(47) If the active catalyst A was accumulating by [Ru1]0 − [Ru1]t =
[A]t, then [A] would increase over time. If [A] was increasing, then a
changing slope for the alkyne conversion rate would be expected. This
is evidently not the case, since the alkyne conversion rate data in
Figures 1 and 3 show a constant slope.
(48) Thiel, V.; Wannowius, K.-J.; Wolff, C.; Thiele, C. M.; Plenio, H.
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(50) The rate behavior of internal alkynes will not be treated here
due to a different rate law.
(51) Second-order because alkene dependence would occur in both
the initiation of the precatalyst and in the catalytic cycle where alkyne
is consumed.
(52) Obtained at 80 mM 1A, over the alkene concentration range of
0.5−4.0 M and at 0.1 mM Ru1 in toluene at 25 °C. Under these
pseudo-order conditions, rate = kobs[alkyne]0 and kobs = k[Ru1][1-
hexene].
(53) Comparison is made to the first initiation rate observed by
Plenio because there is data for 1-hexene. This initiation rate is second-
order and is dependent on the alkene concentration.
(54) The expression k2/kdec is a ratio of second-order to first-order
rate constants with units of M−1.
(55) Interestingly, if the kI ratethe rate of Ru1 UV disappear-
anceis used as the initiation rate, a much lower turnover number of
390 is calculated. The turnover based on catalyst loading should be
800.
(56) In the RCM, bimolecular decomposition is most likely a result
of [Ru]CH2 reacting with the Hoveyda-type precatalysts. The
methylidene [Ru]CH2 occurs in alkene metathesis but is not
formed to a significant extent during ene−yne metathesis.
L
DOI: 10.1021/jacs.6b01887
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