A General Decomposition Pathway for Phosphine-Stabilized Metathesis Catalysts: Lewis Donors Accelerate Methylidene Abstraction

Article abstract of DOI:10.1021/jacs.6b08372

Sterically accessible Lewis donors are shown to accelerate decomposition during catalysis, for a broad range of Grubbs-class metathesis catalysts. These include benzylidene derivatives RuCl₂(NHC)(PCy₃)(=CHPh) (Ru-2: NHC = H₂IMes, a; IMes, b; H₂IPr, c; IPr, d; H₂ITol, e) and indenylidene complexes RuCl₂(NHC)(PCy₃)(=C₁₅H₁₀) (NHC = H₂IMes, Ru-2f; IMes, Ru-2g). All of these precatalysts form methylidene complex RuCl₂(NHC)(=CH₂) Ru-3 as the active species in metathesis of terminal olefins, and generate RuCl₂(NHC)(PCy₃)(=CH₂) Ru-4 as the catalyst resting state. On treatment with a 10-fold excess of pyridine, Ru-4a and Ru-4b decomposed within minutes in solution at RT, eliminating [MePCy₃]Cl A by net loss of three ligands (PCy₃, methylidene, and one chloride), and a mesityl proton. In comparison, loss of A from Ru-4a in the absence of a donor requires up to 3 days at 55 °C. The σ-alkyl intermediate RuCl₂(¹³CH₂PCy₃)(NHC) (py)₂ resulting from nucleophilic attack of free PCy₃ on the methylidene ligand was undetectable for the H₂IMes system, but was spectroscopically observable for the IMes system. The relevance of this pathway to decomposition of catalysts Ru-2a-g was demonstrated by assessing the impact of pyridine on the in situ-generated methylidene species. Slow initiation (as observed for the indenylidene catalysts) did not protect against methylidene abstraction. Importantly, studies with Ru-4a and Ru-4b indicated that weaker donors (THF, MeCN, DMSO, MeOH, and even H₂O) likewise promote this pathway, at rates that increase with donor concentration, and severely degrade catalyst productivity in RCM, even for a readily cyclized substrate. In all cases, A was the sole or major ³¹P-containing decomposition product. For DMSO, a first-order dependence of decomposition rates on DMSO concentration was established. This behavior sends a warning about the use of phosphine-stabilized metathesis catalysts in donor solvents, or with substrates bearing readily accessible donor sites. Addition of pyridine to RuCl₂(H₂IMes)(PCy₃)(=CHMe) did not result in ethylidene abstraction, indicating that this decomposition pathway can be inhibited by use of substrates in which the olefin bears a β-methyl group.

Full text of DOI:10.1021/jacs.6b08372

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Article
A General Decomposition Pathway for Phosphine-Stabilized Metathesis
Catalysts: Lewis Donors Accelerate Methylidene Abstraction
William Lorne McClennan, Stephanie Alyssa Rufh, Justin
Alexander MacDonald Lummiss, and Deryn Elizabeth Fogg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08372 • Publication Date (Web): 13 Oct 2016
Downloaded from http://pubs.acs.org on October 13, 2016
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Journal of the American Chemical Society
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A General Decomposition Pathway for Phosphine-Stabilized Metath-
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William L. McClennan, Stephanie A. Rufh, Justin A. M. Lummiss, and Deryn E. Fogg*
Department of Chemistry and Centre for Catalysis Research & Innovation, University of Ottawa, Ottawa, Ontario,
Canada K1N 6N5
<
Supporting information placeholder>
ABSTRACT: Sterically accessible Lewis donors are shown to accelerate decomposition during catalysis, for a broad range
of Grubbs-class metathesis catalysts. These include benzylidene derivatives RuCl (NHC)(PCy )(=CHPh) (Ru-2: NHC =
2
3
H IMes, a; IMes, b; H IPr, c; IPr, d; H ITol, e) and indenylidene complexes RuCl (NHC)(PCy )(=C H ) (NHC = H IMes,
2
2
2
2
3
15 10
2
Ru-2f; IMes, Ru-2g). All of these precatalysts form methylidene complex RuCl (NHC)(=CH ) Ru-3 as the active species in
2
2
metathesis of terminal olefins, and generate RuCl (NHC)(PCy )(=CH ) Ru-4 as the catalyst resting state. On treatment
2
3
2
with a tenfold excess of pyridine, Ru-4a and Ru-4b decomposed within minutes in solution at RT, eliminating
MePCy ]Cl A by net loss of three ligands (PCy , methylidene, and one chloride), and a mesityl proton. In comparison, loss
[
3
3
of A from Ru-4a in the absence of a donor requires up to 3 days at 55 °C. The σ-alkyl intermediate
1
3
RuCl ( CH PCy )(NHC)(py) resulting from nucleophilic attack of free PCy on the methylidene ligand was undetectable
2
2
3
2
3
for the H IMes system, but was spectroscopically observable for the IMes system. The relevance of this pathway to de-
2
composition of catalysts Ru-2a–g was demonstrated by assessing the impact of pyridine on the in situ-generated methyli-
dene species. Slow initiation (as observed for the indenylidene catalysts) did not protect against methylidene abstraction.
Importantly, studies with Ru-4a and Ru-4b indicated that weaker donors (THF, MeCN, DMSO, MeOH, and even H O)
2
likewise promote this pathway, at rates that increase with donor concentration, and severely degrade catalyst productivity
3
1
in RCM, even for a readily-cyclized substrate. In all cases, A was the sole or major P-containing decomposition product.
For DMSO, a first-order dependence of decomposition rates on DMSO concentration was established. This behaviour
sends a warning about the use of phosphine-stabilized metathesis catalysts in donor solvents, or with substrates bearing
readily accessible donor sites. Addition of pyridine to RuCl (H IMes)(PCy )(=CHMe) did not result in ethylidene abstrac-
2
2
3
tion, indicating that this decomposition pathway can be inhibited by use of substrates in which the olefin bears a β-
methyl group.
Introduction
Molecular metathesis catalysts have transformed organic
1
,2
synthesis in academia.
With pharmaceutical and
speciality-chemicals manufacturing processes now
3
-6
emerging, the demand for improved understanding of
7,8
catalyst decomposition is increasing. Catalyst lifetimes
control metathesis productivity, and are also critical to
product selectivity, because decomposed catalyst species
9,10
can catalyze side-reactions such as C=C isomerization.
A central question is therefore the nature of the
decomposition pathways operative during catalysis.
a
For the structures of the NHC ligands, see Figure S1.
7,8
Examined here is the decomposition of phosphine-
stabilized catalysts (Chart 1) by Lewis donors. Such
donors may be present as unprotected functional groups
on substrates or solvents, or as contaminants introduced
In the hundreds of ruthenium metathesis catalysts
developed to date, a recurring structural feature is a
stabilizing phosphine ligand that is lost during initiation.
1,11
Reaction the
RuCl (NHC)(=CH ) Ru-3, a key catalytic intermediate
2
of
liberated
phosphine
with
9
with the solvent, a reagent, or prior synthetic steps.
2
a
formed in metathesis of terminal olefins, generates the
Chart 1. Metathesis Catalysts Examined
catalyst resting state Ru-4 (Scheme 1, top). The latter
1
2
species is slow to re-enter the active cycle, owing to the
1
3
inverse trans effect exerted by the NHC ligand, and the
limited steric pressure exerted by the methylidene
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moiety, relative to the benzylidene group in the
precatalyst.
Scheme 2. Intercepted σ-Alkylphosphonium Species
1
4,15
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Scheme 1. Reactions of Ru-3 with Free PCy : Phos-
3
phine Re-uptake vs. Methylidene Abstraction
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Under the same conditions, the labelled H
Ru-4a decomposed within minutes (87% *A, 13% free
PCy ), without observable intermediates. We
IMes complex
2
An alternative, more deleterious reaction pathway
13,16
(
Scheme 1, bottom) has been established
for the
3
H IMes derivative Ru-3a. Here nucleophilic attack by free
hypothesized that a σ-alkyl intermediate is formed, but
that it is very short-lived, because facile C–H activation of
the mesityl o-methyl groups promotes the elimination
2
17
PCy on the methylidene carbon culminates in release of
3
[
MePCy ]Cl A: that is, in loss of three ligands
3
(
methylidene, phosphine, and one chloride ligand, as well
step. Such C–H activation is a common feature for the
22
as a proton). This catalyst decomposition pathway,
H IMes and IMes ligands. For H IMes complexes, this
2 2
16,18
originally described as requiring 3 days at 55 °C,
was
susceptibility may be enhanced by the significant double-
bond character present in the Ru–H IMes bond, a
found to occur much more rapidly on coordination of
2
19-21
amines.
In the present work, we demonstrate that
consequence of π-back-donation from Ru onto the
23
“
donor-accelerated decomposition” is general for
saturated Arduengo carbene. Backbonding has been
phosphine-stabilized catalysts of the Grubbs class,
including indenylidene catalysts, and that it is promoted
by a range of weaker donors, including MeCN, DMSO,
shown to retard rotation about the Ru–H IMes bond in
2
13
Ru-4a. The corresponding σ-alkyl intermediate Ru-8a
may thus be locked into a conformation that favours the
H O, THF, and methanol. We show that the mechanism
incipient interaction between the σ-alkyl carbon and the
2
24,25
is associative in donor, and that the rate of
decomposition therefore increases with increasing
concentration. Finally, we demonstrate that the
ethylidene complex RuCl (H IMes)(PCy )(=CHMe) does
mesityl group,
upon swivelling about the N–C bond
Mes
26,27
(Chart 2a and inset).
Chart 2. Ru–NHC Rotation in Second-Generation σ-
Alkyl Species, and Impact on C–H Activation (inset)
2
2
3
not undergo alkylidene abstraction by PCy . Collectively,
3
these findings have important implications for use of the
large class of ruthenium metathesis catalysts based on
the archetypal, phosphine-stabilized Grubbs catalyst Ru-
(a)
(b)
PCy3
PCy3
2a.
H
PCy3
Cl
Cl
N
N
N
N
Results and Discussion
Cl
Ru
py
py
Cl
Ru
py
py
Cl
N
N
Observation of the σ-Alkyl Intermediate in the
Ru
L
Second-Generation
System.
In
a
prior
Cl
20
L
communication, we described the near-quantitative
formation and crystallographic characterization of a σ-
alkyl intermediate (Ru-7, Scheme 2) generated by
reaction of the first-generation Grubbs methylidene
Mes
Ru-8b
Ru-8a
In seeking evidence for such a σ-alkyl intermediate in the
second-generation systems, we turned to the “unlocked”
complex Ru-8b (Chart 2b), in which we anticipated that
free rotation of the IMes ligand should retard C–H
complex Ru-6 with pyridine. In this system, both PCy3
ligands were displaced by pyridine. In consequence,
elimination of the alkyl ligand took place only over days
1
3
in solution at RT, or 18 h at 60 °C. C-Labelling studies
31
activation. A P NMR signal was indeed observed at ca. 61
1
3
1
enabled location of the diagnostic C{ H} NMR doublet
ppm immediately after adding 10 equiv pyridine to a C D
6
6
1
3
for the Ru– CH PCy moiety, which appears unusually far
2
3
solution of Ru-4b, but elimination of phosphonium salt
MePCy ]Cl A was complete within 15 min. Injection of a
1
upfield (δ –12.3 ppm; J = 9.8 Hz) owing to shielding of
C
PC
[
3
the carbon nucleus by the formally anionic Ru center.
smaller excess of pyridine (3 equiv) resulted in slower
decomposition of Ru-4b: we will return to the
mechanistic implications of this observation below.
Under these conditions, Ru-8b decomposed at a rate
3
1
The P nucleus is correspondingly deshielded by its
3
1
1
positive charge, and the P{ H} NMR doublet for *Ru-7 is
shifted ca. 20 ppm downfield relative to the value for Ru-
6, to 55.7 ppm.
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NHC ligand (confirmed by d-labelling studies, see below),
slightly slower than the rate at which it formed (Figure 1).
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Thus, a singlet was observed at 61.3 ppm (maximum 13%),
but was rapidly exceeded in intensity by the singlet due
to A at 34.2 ppm. After 75 min, neither Ru-4b nor Ru-8b
as well as a chloride ligand. For sterically unencumbered
amines of sufficiently high nucleophilicity, direct
methylidene abstraction by amine has been shown to
3
1
n
2
remained: the dominant P-containing species was A (ca.
0%). A small proportion of free PCy was also observed,
offer
a
competing pathway: NH Bu, for example,
n
19
9
abstracts the methylidene ligand as neutral NHMe Bu.
3
indicating a minor contribution from an additional,
unidentified pathway. Given the transience and low
No evidence of the corresponding methylpyridinium
chloride was observed in the present work, however.
1
3
concentration of putative Ru-8b, we turned to
C
1JPC = 10 Hz
1JPC = 12 Hz
labelling studies for unequivocal confirmation of its
identity.
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δC δP 61.3
27.4
δP 55.7
δC –12.3
–
PCy3
PCy3
*
*
Cl
Cl
N
N
N
Ru
N
N
Ru
N
N
Cl
Cl
100
A
*Ru-7
*Ru-8b
80
60
40
20
0
Ru-4b
Ru-8b
Figure 2. Key NMR shifts for first- and second-generation σ-
alkyl complexes.
PCy3
Scope with Respect to Catalyst. The broader relevance
of this pathway was examined for an array of
commercially-available catalysts (2a–2g; Chart 1), upon
metathesis with ethylene at 50 °C. This treatment
generates the methylidene species Ru-3/ Ru-4 in situ,
enabling us to assess the impact of added pyridine on the
0
15
30
45
60
75
Time (min)
Figure 1. Direct observation of the short-lived σ-alkyl inter-
mediate formed by IMes complex Ru-4b (20 mM [Ru], RT =
22 °C).
proportion of [MePCy ]Cl A present at 2 h. In all cases,
3
13
Accordingly, C-labelled *Ru-4b was prepared by the
pyridine treatment accelerated catalyst decomposition,
with the extent of of methylidene abstraction (as judged
from % A) ranging from 80–100%: see Figure 3.
method previously developed for its H IMes analogue
2
21
*
Ru-4a, and treated with a threefold excess of pyridine
at ambient temperature in C D . NMR analysis was
6
6
For the benchmark H IMes catalyst Ru-2a, the dominant
2
initiated immediately after injecting pyridine. Diagnostic
species present after 2 h at 50 °C in the absence of py was
13
1
31
1
C{ H} and P{ H} NMR doublets for *Ru-8b were
the resting-state methylidene complex Ru-4a (62% of
1
31
1
observed (δ –27.4 ppm, δ 61.3 ppm; J = 12 Hz). This
total P{ H} NMR integration), the balance of material
being due to A. In the presence of 10 py, formation of A
was quantitative. Similar behaviour was observed for the
C
P
PC
multiplicity, and the magnitude of the JCP coupling
constant, offer strong evidence for the proposed
assignment, comparing well with values for *Ru-7 (Figure
H IPr complex Ru-2c and IPr catalyst Ru-2d.
2
2). The location of the Ru–C signal in *Ru-8b, ca. 15 ppm
In the donor-free control experiments, the IPr and IMes
systems (Ru-2d and Ru-2b, respectively) show a higher
proportion of the methylidene species relative to their
further upfield than that for *Ru-7, is consistent with
shielding by the more strongly-donating IMes ligand,
relative to the pyridine ligands in *Ru-7. A six-
coordinate, bis(pyridine) structure is shown, by analogy
31
saturated analogues, as expected given the stronger
binding of phosphine ligands trans to an unsaturated
to that established crystallographically for Ru-7 and for
13
NHC. Importantly, however, the increased strength of
28
the H IMes derivative of the benzylidene precatalyst.
2
the Ru–PCy bond does not confer protection against
3
However, all of these complexes are likely to exist in
dynamic equilibrium with the five-coordinate mono-
donor-accelerated methylidene abstraction: like Ru-2c,
the IPr complex Ru-2d undergoes complete
decomposition to A within 2 h when ethylene and
pyridine are simultaneously present, while the IMes
29
pyridine species.
We conclude that the mechanism established for Ru-6 is
3
0
32
indeed also operative in the second-generation systems.
That is: (1) the incoming donor displaces the PCy
derivative Ru-2b eliminates 74% A. For the latter
3
system,
a minor contribution from an additional,
1
7d
ligand and stabilizes the resulting methylidene species;
2) nucleophilic attack of the free phosphine on the
unidentified pathway is implied by the observation of free
(
PCy : 9% in the control experiment, and 26% in the
3
1
methylidene carbon ensues, forming the σ-alkyl
intermediate, and (3) the alkyl moiety is liberated as the
phosphonium salt A by abstraction of a proton from the
presence of pyridine. As noted above, H NMR analysis
shows no evidence of the pyridinium salt [MeNC H ]Cl,
3
3
5
5
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ruling out the possibility that pyridine competes for abstraction. To examine this point, we treated Ru-4a and
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attack on the methylidene site.
its less labile IMes analogue Ru-4b with a range of less
potent donors at 50 °C. Shown in Table 1 is the
proportion of A formed, vs. Ru-4 remaining, after 2 h.
These figures should be compared to a baseline value of
1
0% or 3% for Ru-4a or Ru-4b, respectively, in the base-
free control experiments (entry 1). Values for pyridine are
shown as the final table entry, for comparison. In all
cases, the trend seen with the IMes complex Ru-4b
parallels that with Ru-4a. While stronger Ru–PCy3
binding lessens the impact on decomposition rates, it
also limits entry into the active cycle for metathesis.
0
1
2
3
4
5
6
7
8
9
0
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2
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Table 1. Loss of Ru-4 and Yield of [MePCy ]Cl (A) on
3
a
Treatment with L-Donors (n Equiv) for 2 h at 50 °C
entry L-donor
n
% Ru-4 lost (% A formed)
a: H IMes
b: IMes
3 (N.D.)
3 (N.D.)
3 (N.D.)
3 (N.D.)
3 (N.D.)
–
8 (8)
–
10 (10)
–
18 (16)
–
2
1
None
NEt3
O=P(NMe2)3 10
O=C(NMe2)2 10
0
10
10 (10)
11 (11)
13 (13)
16 (16)
11 (11)
2
3
4
Figure 3. Accelerating effect of pyridine on decomposition
of phosphine-stabilized catalysts under ethylene. Complexes
grouped by behaviour; for codes, see Chart 1.
5
a
MeCN
10
neat
10
100
10
5b
100 (100)
20 (20)
30 (30)
25 (25)
49 (49)
35 (35)
93 (93)
49 (49)
6
6
7
a
b
a
THF
The indenylidene catalysts Ru-2f and Ru-2g (bearing
H IMes and IMes ligands, respectively) are far less active
2
H O
2
than the other systems examined. In the absence of
pyridine, catalyst initiation was incomplete in both cases,
with 19% Ru-2f, and 86% Ru-2g, remaining unreacted
even after 2 h at 50 °C under ethylene. (As expected, the
balance was chiefly the resting-state methylidene
complexes Ru-4a or Ru-4b). Again, however, poor
turnon efficiency does not protect against donor-
accelerated methylidene abstraction. Both Ru-2f and Ru-
7
b
100
10
100
10
8a
8b
9
DMSO
MeOH
pyridine
29 (29)
100 (90)
b
c
10
a
10
100 (100)
C D solvent, [Ru] = 20 mM. % Loss of Ru-4 determined by
6
6
1
H NMR analysis, by integration of the methylidene signal vs.
31
1
internal standard (TMB); % A by P{ H} NMR analysis, as a
percentage of total integration. N.D. = not determined; peak
intensity insufficient for reliable P NMR integration. Ru-4
completes the mass balance, except where noted. Complete
in <10 min at RT. For L = py, free PCy accounts for the dis-
crepancy between %Ru-4b lost and %A formed.
2g show >80% decomposition to A in the presence of
pyridine (91% for Ru-2f; 82% for Ru-2g). We infer that
pyridine binding accelerates initiation for these species,
but that methylidene abstraction is competitive with
metathesis. As with Ru-2b, a small proportion of free
31
b
c
3
PCy was also observed.
3
The NEt , phosphoramide, and urea additives shown in
3
The H ITol derivative Ru-2e likewise exhibited >80%
2
entries 2-4 were chosen for the detrimental impact of
these and related structures in other contexts, including
elimination of A following treatment with ethylene and
pyridine. Also present was ca. 10% of an as-yet
unidentified species, observed as a P{ H} NMR singlet at
3,9,36-
3
1
1
in metathesis promoted by non-phosphine catalysts.
39
1
The absence of any significant impact for any of these
4
8.1 ppm. No alkylidene signal was evident by H NMR
indicates that the Lewis basicity of the donor is
irrelevant, if steric congestion precludes access to the
analysis, ruling out the possibility that this is simply a
pyridine adduct of Ru-2e or its methylidene resting state.
Complicating analysis is the presence of ca. 15%
impurities in the commercial precatalyst (see Figure
40
metal center. This is consistent with the prior finding
that added DBU did not trigger decomposition of Ru-2a
19
3
4
into A during catalysis.
S15).
Identification of the unknown species was
Of note, even relatively weak donors such as MeCN, THF,
therefore not pursued.
and H O accelerate decomposition (entries 5–7).
2
In all cases, the [MePCy ]Cl marker A was the dominant
3
3
1
Addition of MeCN had minimal impact in small amounts
P-containing species present after 2 h exposure to
(
10 equiv), but decomposition was quantitative at 2 h in
ethylene at 50 °C. We conclude that abstraction of the
methylidene ligand by phosphine is the major pathway
operative, and that such abstraction is significantly
accelerated by the Lewis donor pyridine.
neat MeCN (entries 5a, 5b; see also Figure 4a). Similarly,
while 10 equiv THF and H O proved innocuous, a tenfold
2
increase led to ca. 30% or 50% decomposition,
respectively, notwithstanding the weak oxophilicity of
these ruthenium complexes. The heightened effect of
water and methanol, relative to THF (entries 7a and 9, vs.
Scope with Respect to Donor. Of keen interest is the
extent to which Lewis bases other than pyridine and
primary or secondary amines
1
9,21,35
accelerate methylidene
6
a), may be due to attractive hydrogen-bonding
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Journal of the American Chemical Society
respectively). This is consistent with the reported
1
3
interactions with the chloride ligands. While additional
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
decomposition pathways could be envisaged for these H-
bond donors, A was the sole or dominant phosphorus
product in all cases, indicating that methylidene
abstraction is the principal vector for decomposition.
operation of the inverse trans effect in the NHC complex
Ru-4a, which enhances the Ru–PCy3 bond strength.
Secondly, the rate of formation of
A no longer
corresponds to the rate of loss of Ru-6. This is consistent
with displacement of both PCy ligands from Ru-6, upon
Accelerated methylidene abstraction by MeCN, THF,
3
which the C-H activation step becomes rate-determining,
DMSO, H O, and MeOH helps to account for the sub-
2
20
as with the pyridine system shown in Scheme 2.
optimal metathesis performance of phosphine-
41-45
functionalized catalysts in these solvents.
More
While isolation of the σ-alkyl intermediate for the
H IMes complex was precluded by facile C–H activation,
2
generally, it provides the first clear explanation for low
metathesis productivities in polar media, despite the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
as indicated above, the σ-alkyl complex RuCl (σ-
2
correlation between solvent polarity and faster initiation
CH PCy )(DMSO) Ru-9 decomposed slowly. Indeed, this
2
3
3
46
(
phosphine loss) established for Ru-2a. This behaviour
complex could be isolated in ca. 60% yield following
treatment of Ru-6 with a 100-fold excess of DMSO
(Scheme 3). Its molecular identity is supported by NMR
and combustion analysis. The fac,S-coordination mode is
is of particular note given interest in metathesis in water
43,44,47-49
and “green” solvents, often bearing ether donors.
The impact of water holds arguably even greater
significance, given its ubiquity as a contaminant in
synthetic and process chemistry.
proposed on the basis of the predominance of this
50-52
binding mode in other Ru complexes.
IR evidence is
consistent with S-binding (two strong ν(S=O) bands at
-1
-1
(a)
(b)
1
072 and 1017 cm , vs. an expected value of ca. 950 cm for
A
Ru-4a
100
0.018
the O-bound linkage isomer). The chemical shifts and
multiplicities for the Ru-CH PCy moiety agree well with
2
3
75
Ru-6
those for pyridine analogue Ru-7 (see Scheme 3 and
0.012
20
Figure 2, left). The stability of these species reflects the
%
50
absence of a readily-activated C-H bond, a consequence
0.006
0
2
5
of the displacement of both PCy ligands (see discussion
3
Ru-4a
above).
0
Scheme 3. σ-Alkyl Intermediates Accessible by Inhib-
iting C–H Activation of Ancillary Ligands
0
50
Equiv DMSO
100
MeCN Water THF
Figure 4. (a) Impact of donor stoichiometry on decomposi-
tion of RuCl (H IMes)(PCy )(=CH ) Ru-4a (C D , 50 °C, 2 h;
2
2
3
2
6
6
data from Table 1). (b) First-order dependence of decomposi-
tion rates on [DMSO] for Ru-4a and Ru-6 at 25 °C. See Ta-
bles S3 and S4.
Associative Mechanism and Implications. Rates of
metathesis by Ru-2a and its analogues are independent
of olefin concentration, because loss of PCy3 is rate-
46
Rate-Determining Step. Within the H IMes system, the
2
limiting. In the absence of donors, loss of PCy likewise
3
rapidity of the C-H activation step (k , Scheme 4) means
4
controls the rate of decomposition of the resting-state
13,31
that only the starting methylidene complex Ru-4a and
species Ru-4a and Ru-4b.
The rapidity with which
decomposition product [MePCy ]Cl A are observed. Rate-
3
these complexes decompose in the presence of donor
ligands (see above) strongly suggests an associative
pathway for the decomposition reaction, as does the
impact of donor bulk and stoichiometry. For sterically
accessible donors, coordination to the Ru center prior to
PCy3 loss would plausibly create a degree of steric
pressure that promotes expulsion of the phosphine
ligand.
determining L-binding is unsurprising, given steric
constraints on approach of L to five-coordinate Ru-4a
imposed by the cumulative bulk of the H IMes and PCy3
2
ligands. Of note, however, the rate-determining step for
the IMes system Ru-4b switches to C-H activation, as
inferred from the fact that the σ-alkyl intermediate is
observable. The energetic barriers to donor binding and
to C-H activation are evidently very similar.
To probe this point, Ru-4a was treated with varying
concentrations of DMSO, with which decomposition is
sufficiently slow to monitor at RT, and the rates of loss of
Ru-4a (Figure 4b) and formation of A were measured.
Both rates exhibit a first-order dependence on [DMSO].
Decomposition of the first-generation complex Ru-6 was
likewise first-order in [DMSO], but two notable
differences emerged. First, the reaction was five-fold
Corroboration of this point comes from deuterium-
D
labelling studies using the d -H IMes complex Ru-4a ,
22
2
containing perdeuterated mesityl groups. On treating
this labelled complex with pyridine, the σ-alkyl species
D
Ru-8a could be observed at short reaction times (29% at
5
min, with essentially quantitative liberation of the
phosphonium salts at 10 min). That is, deuteration is
sufficient to change the rate-determining step from
-
1
faster (kobs = 0.0003 and 0.0015 min for Ru-4a and Ru-6,
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Journal of the American Chemical Society
Page 6 of 13
pyridine binding to C–H activation. A similar effect was favouring an intramolecular pathway. For the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
evident with DMSO, with which decomposition was
slower, and rate constants could be measured. The
kinetic isotope effect (as judged from the k /k ratio),
methylidene complexes, intermolecular attack of
phosphine at the more accessible methylidene carbon
([Ru]=CH ) is validated by our decomposition studies in
H
D
2
5
3
was 1.5, at the low end for a primary kinetic isotope
the presence of added phosphine.
5
4
effect, perhaps indicating that C–H activation is only
partially rate-determining. An additional factor, however,
may be competing H/D scrambling between the
methylidene and the o-CD3 groups (analogous to
methylidene–phosphine exchange processes reported in
Impact on Metathesis. The drastically inhibiting impact
of amines in metathesis reactions catalyzed by Ru-2a has
19,21
been described elsewhere.
The rapidity of
19
decomposition, and the co-formation of A, testify to the
capacity of such donors to accelerate methylidene
abstraction. To assess the impact of weaker donors, we
examined the metathesis productivities attainable for the
readily-cyclized diene diethyl diallylmalonate (1) in the
presence of added water or methanol, or in neat THF,
MeCN, or DMSO. The results are collected in Table 2. In
the control experiment in anhydrous toluene, RCM was
quantitative at 2 h at a catalyst loading of 0.05 mol%. This
corresponds to a turnover number (TON) of 2,000. In
neat THF at 50 °C, RCM activity dropped by more than
5
5
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the first-generation catalysts). Thus, while H NMR and
MALDI-MS analysis of the products formed on
D
decomposition of Ru-4a confirmed incorporation of a
mesityl o-CD3 deuteron as [CH DPCy ]Cl, essentially
2
3
equal amounts of non-deuterated A were also evident,
accompanied by lesser proportions of the d -A and d -A
2
3
5
6
isotopologues (22% and 8%, respectively; Figure S10).
Scheme 4. Shifting Rate-Limiting Step in Donor-
Accelerated Methylidene Abstraction
3
0%, to a TON of 1,440. The presence of 5% degassed
H O in toluene caused a 65% drop in TON. With 5%
2
MeOH, MeCN, and DMSO, the impact was even more
detrimental: for the DMSO reaction, metathesis was
essentially quenched. The ease with which 1 normally
undergoes RCM underscores the severity of this
degradation in metathesis performance.
Of note, reaction at 30 °C does not inhibit methylidene
abstraction. Indeed, the impact of donors on total
metathesis productivity is in general even more
deleterious, in keeping with prior findings of faster
increases in rates of metathesis as a function of
9,57
temperature, relative to rates of decomposition.
Table 2. Donor-Accelerated Decomposition: Impact
a
of Weak Donors on Metathesis Productivity
Consistent with intermolecular attack of PCy3 on the
methylidene ligand, as shown in Schemes 1 and 4,
decomposition of the IMes complex Ru-4b exhibits a rate
3
0
dependence on [PCy3]. Thus, reaction with a threefold
excess of pyridine under the conditions of Figure 1
resulted in complete decomposition within 50 min in the
a
entry solvent medium
% conv. (TON)
5
8
presence of 10 PCy , but required 75 min in the absence of
50 °C
30 °C
3
b
c
added PCy (Figure S14; Tables S2, S3).
1
toluene
THF
20:1 toluene-H O
20:1 toluene-MeOH
20:1 toluene-MeCN
20:1 toluene-DMSO
100 (2,000)
72 (1,440)
35 (700)
18 (360)
13 (260)
1 (20)
100 (2,000)
13 (260)
24 (480)
5 (100)
17 (340)
1 (20)
3
2
3
4
5
6
a
In an important study of the first-generation benzylidene
catalyst Ru-1, Diver, Keister and co-workers described
related but distinct behaviour on treatment with
2
1
7d
isocyanides. Liberation of the ylide PhCH=PCy B was
3
observed, rather than the phosphonium salt
b
[(PhCH )PCy ]Cl A' corresponding to A. Intramolecular
Calibrated GC-FID analysis; ±2% in replicate runs. Quan-
titative within 10 min. Quantitative within 60 min.
2
3
c
1,2-migration of the PCy ligand onto the benzylidene
3
carbon was proposed on the basis of a competition
experiment involving addition of a threefold excess of
Of particular interest is the impact of the weak donor
H O, which represents a ubiquitous contaminant in
n
n
2
P Bu , in which the observed ratio of B to PhCH=P Bu
3
3
organic synthesis. To explicitly tie the presence of water
to formation of A during catalysis, a related experiment
was carried out with pro-lactone 3 (Scheme 5). Use of this
substrate has the dual advantage of verifying the impact
of water in an RCM reaction of broad interest, i.e.
macrocyclization, while ensuring complete catalyst
(B’) was ca. 2:1, rather than the 1:3 ratio expected for the
intermolecular pathway. The discrepancy may reflect
steric differences between the benzylidene and
methylidene complexes. Substitution at the Ru=CHR site
may inhibit intermolecular approach of PR , instead
3
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Journal of the American Chemical Society
to the problem of catalyst decomposition. More
conscription at ruthenium loadings high enough to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
permit interrogation by NMR methods. Analysis after 2 h
fundamentally, they demonstrate that the ethylidene
moiety indeed resists donor-accelerated decomposition,
offering the first clear insight into the superior metathesis
performance attainable with β-methyl olefins, vs. α-
olefins.
at 50 °C in 20:1 C D –H O indicates that A accounts for
6
6
1
2
3
1
ca. 38% of the total P{ H} NMR integration, with ca. 50%
being due to the resting-state methylidene complex Ru-
4
a. Also observed is a small amount of free PCy (7%),
3
and two minor, unidentified species (see SI, Figure S20).
A control experiment confirmed that the proportion of A
formed in the absence of water is substantially lower (7%
A).
Scheme 6. Resistance of Ethylidene Ligand to Nucle-
ophilic Abstraction by PCy3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Evidence for Water-Accelerated Methyli-
dene Abstraction During RCM Macrocyclization
The Cazin group recently described the negative impact
of water on RCM yields in the challenging cyclization of a
derivative of diethyl diallylmalonate bearing geminally-
Conclusions
The foregoing demonstrates that the resting-state
methylidene complexes formed by phosphine-stabilized
5
9
disubstituted olefins. The present study is only the
second report of the severely deleterious impact of water
on Ru-catalyzed olefin metathesis: it is the first to
demonstrate that even facile metathesis reactions are
affected, and to advance a mechanistic basis for this
behaviour. While the present study does not rule out
other, additional avenues for catalyst degradation, it
clearly demonstrates that water significantly accelerates
the methylidene-abstraction pathway.
metathesis catalysts are subject to
a
common
decomposition pathway: specifically, abstraction of the
methylidene ligand as [MePCy ]Cl A. Sterically accessible
3
Lewis donors are shown to accelerate this process, at
rates that depend on donor concentration. Because of the
associative nature of this pathway, even rather feeble
donors such as THF, H O, and MeOH are able to
2
promote decomposition when present in significant
amounts, with drastic consequences even for metathesis
of readily-cyclized substrates such as diethyl
diallylmalonate. These results highlight the limited
compatibility of phosphine-functionalized metathesis
catalysts with substrates bearing a terminal olefin.
Wherever sterically accessible donor functionalities are
present (whether in the solvent, within the substrate
structure, or in contaminants), they can trigger
irreversible loss of the critical methylidene moiety from
the active species. Installation of a β-methyl substituent
is shown to circumvent this catalyst decomposition
pathway.
Blocking Methylidene Abstraction. A final set of
experiments examined the possibility that this
decomposition pathway could be blocked by introducing
a methyl substituent on the methylidene ligand. This
question was inspired by reports of higher turnover
numbers in metathesis when α-olefins were replaced by
6,60-62
β-methyl olefins,
and by the trend in half-lives at 55
°
C reported in the RuCl (PCy ) (=CHR) series: R = Ph, 8
2
3 2
5
5
days; R = Me, 8 h, R = H, 40 min.
To test the resistance of the ethylidene moiety to
abstraction by PCy , Ru-10 was generated in situ in the
3
presence of pyridine (Scheme 6). Complete conversion of
15
Ru-2a into known Ru-10 and bis-pyridine adduct Ru-11
Experimental
(
70:30) was evident after 1 h at 50 °C. Decomposition
General Procedures. Reactions were carried out in an
occurred over ca. 48 h, as compared to the timescale of
N -filled glovebox at room temperature (25 ±2 °C), unless
2
minutes at RT for the methylidene complex Ru-4a.
otherwise indicated. Solvents were purified as described
31
Unexpectedly, NMR analysis revealed that the major P-
below, then stored under N in the glovebox over 4 Å
2
containing product was [MePCy ]Cl A (34.2 ppm; 56% of
3
molecular sieves (except MeOH: stored over 3 Å sieves)
for at least 16 h prior to use. HPLC-grade C H , C H and
total integration) – despite the evidence for complete
formation of the ethylidene complex – accompanied by
6
6
7
8
THF (Fisher) were dried and degassed using a Glass
Contour solvent purification system (water content prior
to sieve treatment, as measured by Karl-Fischer titration:
C H , 4 ppm; C H , 4 ppm; THF, 10 ppm). MeOH was
PCy (10.5 ppm, 34%) and an unidentified product (47.2
3
ppm, 10%). The identity of A was confirmed by MALDI-
TOF mass spectrometry; no signal was observed for
6
6
7
8
[
EtPCy ]Cl. We attribute liberation of A to isomerization
3
2
distilled from magnesium turnings, pentane from P O5
1
of 2-butene into 1-butene (observed by H NMR analysis),
metathesis of which enables partial formation and
decomposition of Ru-4a. These results indicate that use
of 2-butene in cross-metathesis is an incomplete solution
after pre-drying over MgSO , DMSO (>99%, BDH),
4
MeCN (>99%, Fisher), pyridine (>99%, Fisher) and NEt3
(
99%, Alfa Aesar) from CaH . Deionized H O was
2 2
degassed by five consecutive freeze/pump/thaw cycles, as
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was C D6 (Cambridge Isotopes). CD Cl (Cambridge
Page 8 of 13
D
Synthesis of RuCl (d -H IMes)(PCy )(=CH ) Ru-4a .
6
2
2
2
22
2
3
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Isotopes) was purchased in sealed ampoules and used as
received. Hexamethylphosphoramide, tetramethylurea
The deuterium-labelled compound was prepared
according to the method established for non-labelled Ru-
66
(
both 99%, Sigma-Aldrich) and diethyl diallylmalonate (1;
8%, Sigma-Aldrich) were freeze-thaw degassed as above.
Ruthenium catalysts Ru-2c, Ru-2e (Sigma-Aldrich), Ru-
f and Ru-2g (Strem) were used as received, as were
dodecane (>99%, Sigma-Aldrich), potassium hydrotris(1-
pyrazolyl)borate KTp (>99%, Sigma-Aldrich),
trimethoxybenzene (TMB, Sigma-Aldrich), ethylene
4a, but using free d -H IMes. The free carbene was
22 2
68
66
9
generated and installed by the reported methods.
NMR chemical shifts agree with with the values reported
for the non-labelled species.
2
Decomposition of Grubbs Methylidene Complexes
by Pyridine. In a representative procedure, a screw-cap
NMR tube was charged with Ru-4b (230 μL of a 43 mM
stock solution in C D ; 0.012 mmol), TMB (ca. 1 mg), and
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
BOC Ultra-High Purity Grade 3.0, 99.9%; Linde), C-
6
6
1
3
labelled ethylene (99% C-enriched; Sigma-Aldrich), and
cis-2-butene (>99%, GFS Chemicals). 1-Methylpyridinium
chloride [MeNC H ]Cl (>98%, TCI Chemicals) was dried
C D (350 μL), to obtain a final Ru concentration of 20
6
6
1
mM. A H NMR spectrum was recorded to establish the
initial integration ratio of Ru-4b vs. TMB. Pyridine (24 μL
of a 1.3 M stock solution in C D ; 3 equiv) was injected at
the NMR instrument. An immediate colour change from
yellow-brown to deep red resulted, with turbidity
developing within minutes. The septum was covered with
5
5
under vacuum at 30 °C for 24 h prior to NMR analysis.
Literature procedures were used to prepare the following:
6
6
6
3
64
64
65
66
66
IMes, Ru-2a, Ru-2b, Ru-2d, Ru-6, Ru-4a, *Ru-
21
66
21
4a, Ru-4b (the reported improved workup was used
for Ru-4a and Ru-4b), d -H IMes•HCl and pro-lactone
3. NMR spectra were recorded at 23 ±2 °C, and
22d
31
22
2
Parafilm, the tube shaken well, and P NMR acquisition
67
was immediately initiated. Spectra were collected at 5-
min intervals for the first 50 min, then at 75 min (see SI).
A transient signal assigned to Ru-8b (see next) was
observed over the period 3–45 min. Complete loss of
starting Ru-4b was evident at 75 min. P{ H} NMR values
are reported as a percentage of total integration P{ H}
referenced against the residual proton signals of the
1
31
deuterated solvents ( H) or 85% H PO ( P). Elemental
3
4
analysis was carried out by MHW Laboratories (Phoenix,
AZ). GC quantification was performed on samples diluted
with CH Cl (ACS reagent grade) on an Agilent 7890A
31
1
31
1
2
2
Series autosampler and an Agilent HP-5 polysiloxane
column (30 m length, 320 ꢀm diameter), using an inlet
split ratio of 10:1, an inlet temperature of 250 °C, and
helium (UHP grade) as the carrier gas to maintain
column pressure at 11.512 psi. The FID response was
maintained between 50-2000 ρA, using analyte
concentrations of ca. 5 mM. Calibration curves (peak
areas vs. concentration) were constructed in the relevant
concentration regime for substrates 1 and 3, and their
RCM products 2 and 4. Conversions and yields in
catalytic runs were determined from the integrated peak
areas, relative to dodecane as internal standard, and
compared to the initial integration ratio of substrate to
(
121 MHz, C D ): δ 34.2 (s, [MePCy ]Cl A, 89%), 10.4 (s,
6
6
3
PCy , 11%). See Figure 1, Figure S7 and Table S2. With 10
equiv py, at 10 min, full decomposition is seen: P{ H} (121
3
31
1
MHz, C D ): δ 34.2 (s, A, 81%), 10.4 (s, PCy , 19%).
6
6
3
Impact of [PCy ] on Rate of Decomposition of Ru-4b
by Pyridine. As above but with 10 equiv PCy added.
3
3
Complete loss of starting Ru-4b was evident at 50 min.
3
1
1
P{ H} (121 MHz, C D ): δ 34.2 (s, [MePCy ]Cl A, 91%), 10.4
6
6
3
(
s, PCy , 9%). See Figure S14b and Table S3.
3
Decomposition of IMes Derivative *Ru-4b by
Pyridine: Direct Observation of σ-Alkyl Intermediate
13
RuCl
indicated for Ru-4b and pyridine. C{ H} (75 MHz, C
collected over 2–16 min, 512 scans, key signals only): δ –
(σ- CH PCy )(IMes)(py), *Ru-8b. Procedure as
2
2 3
1
3
1
dodecane. IR data were collected on
a
ATR-IR
D ;
6 6
spectrometer. Mass spectra were recorded on a Bruker
Daltonics UltraFleXtreme MALDI time-of-flight mass
spectrometer interfaced to a glovebox.
1
1
27.4 (d, JPC = 11.6 Hz, Ru-CH
PCy
2
2
), 1.2 (d, JPC = 47.8 Hz,
]Cl) *A, 295.4 (d, JCP = 9.5 Hz, Ru=CH , *Ru-
4b). P{ H} (121 MHz, C D ; collected over 16–22 min, 200
3
1
3
[ CH
PCy
3
3
2
3
1
1
13
6
6
Synthesis of RuCl (IMes)(PCy )(= CH ), *Ru-4b.
2
3
2
1
2
21
scans): δ 61.3 (d, J = 11.6 Hz, *Ru-8b, 6%), 40.9 (d, J
=
PC
PC
Prepared as described for *Ru-4a, using IMes in place of
H IMes. Yield of *Ru-4b: 102 mg (50%; 99.5% C-
1
1
3
9.5 Hz, *Ru-4b, 32%), 34.2 (d, JPC
=
47.8 Hz,
2
1
3
[ CH PCy ]Cl *A, 54%), 10.5 (s, free PCy , 8%). See Figure
3
3
3
enriched). Isolated yields are adversely affected by partial
3
1
1
1
S8. At 75 min: P{ H} (121 MHz, C D ): δ 34.2 (d, J = 47.8
Hz, [ CH PCy ]Cl *A, 90%), 10.4 (s, PCy , 10%); no Ru-
6
6
PC
solubility in the solvents used to extract PCy and *A.
3
1
3
3
3
3
Chemical shifts are in excellent agreement with the
values reported for the non-labeled isotopologue, with
phosphine species apparent.
Decomposition of RuCl (H
a by Pyridine. As for Ru-4b above, using 10 equiv
pyridine. No signal for Ru-4a was apparent after 5 min.
13
31
1
2
13
added C coupling. P{ H} (121 MHz, C D ): δ 40.9 (d, J
2
IMes)(PCy )(= CH ) *Ru-
2 3 2
6
6
PC
1
1
4
=
9.5 Hz). H NMR (300 MHz, C D ): δ 18.76 (d, J
=
6
6
HC
1
57.8 Hz, 2H, Ru=CH ), 6.90 (s, 2H, Mes m-CH), 6.72 (s,
2
3
1
1
1
2H, Mes m-CH), 6.23 (br s, 1H, NCH=), 6.13 (br s, 1H,
P{ H} (121 MHz, C
6
D
6
): δ 34.2 (d,
]Cl *A, 87%), 10.4 (s, PCy , 13%).
Decomposition of RuCl (d -H IMes)(PCy )(=CH ) Ru-
JPC = 47.8 Hz,
1
3
NCH=), 2.60 (s, 6H, o-CH ), 2.47-2.27 (overlapping, 9H,
CH
3
PCy
3
3
3
o-CH and Cy), 2.19 (s, 3H, p-CH ), 2.11 (s, 3H, p-CH ),
3
3
3
2
22
2
3
2
13
1
D
1
.78-1.47 (m, 15H, Cy), 1.29-1.01 (m, 15H, Cy). C{ H} (75
4
a by Pyridine. As for *Ru-4a above. Analysis at 5 min:
2
3
1
1
D
MHz, C D )(methylidene signal only): δ 295.4 (d, J
=
6
6
CP
P{ H} (121 MHz, C D ): δ 60.1 (s, Ru-8a , 29%), 34.09-
6
6
9
.5 Hz, Ru=CH ). For spectra, see Figure S2.
2
34.17 (m, d -A, 57%), 10.4 (s, PCy , 14%). At 10 min (full
n
3
31
1
decomposition): P{ H} (121 MHz, C D ): δ 34.2 (m, d -A,
6
6
n
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-
1
8
7%), 10.5 (s, PCy , 13%). MALDI-TOF MS (pyrene
COSY, no correlation. ATR-IR: ν(S=O) 1072, 1017 cm (s,
S-bonded DMSO). Anal. Calc'd. for C H Cl O PRuS : C,
3
69
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
matrix; m/z): 295.256 (C H P, A; calcd 295.255), 296.261
1
9
36
25 53
2
3
3
(
C H DP, d -A, calcd 296.262), 297.267 (C H D P, d -A;
42.85; H, 7.62. Found: C, 43.05; H, 7.75. For spectra, see
Figures S3-S6.
1
9
35
1
19 34
2
2
calcd 297.268); 298.277 (C H D P, d -A; calcd 298.274).
See Figures S9, S10.
1
9
33
3
3
Impact of Donors on RCM. A Schlenk tube was loaded
with diethyldiallyl malonate 1 (48 mg, 0.2 mmol),
Decomposition of in situ-Generated Methylidene
Complexes by Pyridine. In a representive procedure, a
2
loaded with Ru-2b (10 mg, 0.01 mmol) and 2 mL C H .
The solution was freeze-pump-thaw degassed three
times, and allowed to thaw under ethylene. Pyridine (8
dodecane (34 mg, 0.2 mmol; internal standard), H O (90
2
5 mL Schlenk tube equipped with a Kontes tap was
ꢀL, 0.01 mmol) and toluene (1.8 mL). An aliquot was
6
6
removed for GC-FID analysis to establish the starting
ratio of DDM to dodecane. To the flask was added
catalyst Ru-2a from a stock solution in toluene (33 ꢀL of a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ
L, 0.1 mmol, 10 equiv) was added via syringe against a
3
.0 mM solution containing 12.8 mg Ru-2a in 5.0 mL
positive pressure of ethylene. The flask was sealed,
returned to the glovebox, and heated at 50 °C. A color
change from pink to orange-red occurred within minutes.
After 2 h, a C D spike was added, and the P{ H} NMR
spectrum was measured. P{ H} (121 MHz, C D ): δ 34.2
toluene; 0.001 mmol, 0.05 mol%). The reaction was
heated for 2 h at 50 ±1 °C in a thermostatted oil bath in
the glovebox. A sample was then removed, quenched
with KTp (10 mg/mL in THF; 10 equiv vs. Ru-2a), and
analyzed by GC-FID; see Figure S17.
31
1
6
6
31
1
6
6
(
(
s, [MePCy ]Cl A, 74%), 10.5 (s, PCy , 26%. See Figure S11b
3 3
Evidence
for
Water-Accelerated
Methylidene
for the control experiment with Ru-2b under ethylene in
Abstraction During RCM Macrocyclization. In the
glovebox, a J. Young NMR tube was charged with Ru-2a
the absence of pyridine, see Figure S11a). Table S1
summarizes the data for all catalysts studied.
(
11.6 mg, 0.0137 mmol), prolactone 3 (33.7 mg, 0.137 mmol,
Representative Procedure for Reaction of Ru-4a or
Ru-4b with Lewis Donors. Experiments carried out as
above, with the following modifications. The donor was
added in the glovebox following measurement of the
initial ratio of Ru-4a to TMB; the sample was shaken well
and transferred to an oil bath set at 50 °C for 2 h. For
DMSO (10 equiv): P{ H} NMR (121 MHz, C D ): δ 38.2 (s,
Ru-4a, 65%), 34.2 (s, [MePCy ]Cl A, 35%). H NMR (300
MHz, C D ): δ 18.42 (s, Ru-4a, 65%). For control
1
0 equiv), 0.67 mL C D , and degassed H O (35 μL, 20:1
6
6
2
v/v vs. C D solvent). The sample was heated at 50 °C as
6
6
for DDM. A colour change from pink to orange occurred
within the first 20 min. Phosphorus speciation at 2 h:
3
1
1
P{ H} NMR (121 MHz, C D ; as % of total integration): δ
6
6
3
8.2 (s, Ru-4a, 50%), 33.9 (s, [MePCy ]Cl A, 38%), 31.1
3
3
1
1
6
1
6
(3%, unassigned), 29.1 (3%, unassigned), free PCy (10.4
3
3
ppm, 6%). See Figure S20. No Ru-2a (30.1 ppm)
remained. The signal for A is broadened (ω1/2 33 Hz) and
its chemical shift ca. 0.3 ppm upfield relative to the values
above, perhaps indicating H-bonding with water.
6
6
experiment without donor, see Figure S12; for
representative spectra for the DMSO experiment above,
see Figure S13.
Reaction of RuCl (H IMes)(PCy )(=CHMe) Ru-10
2
2
3
Variants: For H O and THF, corresponding experiments
were carried out with 100 equiv R O; for MeCN, with neat
MeCN; see Figure 4a in main text. Kinetics studies carried
out with 10, 33, 55, 78, and 100 equiv DMSO at RT and
monitored for 27 h: see Figure 4b, Table S4 (data) and
Table S5 (half-lives and rate constants).
2
(Generated in situ) with Pyridine. A solution of Ru-2a
2
(10 mg, 0.012 mmol), 600 μL C D , and TMB (ca. 1 mg;
6
6
1
internal standard) was prepared and analyzed ( H NMR)
to establish the initial integration ratio of Ru-2a vs. TMB.
Pyridine (10 μL, 0.12 mmol, 10 equiv) was added, and the
solution was freeze-pump-thaw degassed (3x) and
allowed to thaw under an atmosphere of cis-2-butene.
The NMR tube was then sealed and heated at 50 °C in a
thermostatted oil-bath in the glovebox. Decomposition
rates were established by NMR analysis. Key signals at 1 h
Synthesis of RuCl (σ-CH PCy )(DMSO) , Ru-9. To a
stirred solution of Ru-6 (131 mg, 0.175 mmol) in C H (8
2
2
3
3
6
6
mL) in a 25 mL Schlenk flask was added DMSO (1.24 mL
1.37 g, 17.5 mmol, 100 equiv). A colour change from pink
to yellow occurred over 2 h, but reaction was incomplete.
After 4 h, no further Ru-6 was present by P NMR
analysis. Pentane (20 mL) was added to precipitate pale
yellow Ru-9, which was filtered off and washed with cold
pentane (5 x 2 mL). Yield 74 mg (60%, 0.11 mmol). P{ H}
NMR (121.5 MHz, C D ): δ 51.9 (s). H NMR (300 MHz,
C D ): δ 3.34 (overlapping s, 12H, ((CH ) SO) , 3.19 (s, 6H,
((CH ) SO)), 3.06-2.95 (m, 3H, Cy), 2.25-2.15 (m, 6H, Cy),
1.71-1.55 (m, 10H, Cy), 1.42-1.27 (m, 12H, Cy), 1.13-1.04 (m,
2H, Cy), 0.96 (d, 2H, J = 15.2 Hz, Ru-CH PCy ). C{ H}
(75 MHz, C D ; selected): δ –8.8 (d, J = 22.2 Hz, Ru-
CH PCy ). Experiments supporting assignment of the σ-
CH PCy doublet at 0.96 ppm: H- C HMQC correlation
with C{ H} NMR doublet at –8.8 ppm; H- P HMQC
correlation with P{ H} NMR singlet at 51.9 ppm; H- H
1
3
(see Figure S18): H NMR (300 MHz, C
D ) δ 19.67 (q, JHH
6
6
3
1
= 6.4 Hz, RuCl (H IMes)(py) (=CHMe) Ru-11, 30%), 18.99
2
2
2
3
2
31
1
(q of d, J = 5.5 Hz, J = 0.7 Hz, Ru-10, 70%). P{ H}
HH
HP
NMR (121.5 MHz, C
D ): δ 28.99 (s, Ru-10, 70%), 10.5 (s,
6
6
3
1
1
31
1
free PCy
, 30%). At 48 h (Figure S19): P{ H} NMR (121.5
3
1
MHz, C D ) δ 47.2 (s, unidentified, 11%), 34.2 (s,
6
6
6
6
[MePCy
MS (m/z): 295.26, [MePCy
]Cl A, 56%), 10.5 (s, free PCy
]Cl
36P] : 295.26). No signal observed for [EtPCy
3
, 34%). MALDI-TOF
(Calcd m/z for
]Cl
6
6
3
2
2
3
3
A
3
2
3
+
[C19
H
2
13
1
+
(Calc’d m/z for [C20H38P] : 309.27).
HP
2
3
1
6
6
PC
Control Experiment: Decomposition of in situ-
Generated RuCl (H IMes)(PCy )(CHMe) Ru-10 in the
2
3
2
2
3
1
13
2
3
Absence of Pyridine. Complete decomposition was
1
3
1
1
31
1
evident after 15 days. Key signals at 1 h: H NMR (300
3
1
1
1
1
3
2
MHz, C D ) δ 18.99 (q of d, J = 5.5 Hz, J = 0.7 Hz,
6
6
HH
HP
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1
1
Ru-10, 100%). P{ H} NMR (121.5 MHz, C D ): δ 28.99 (s,
involvement of Ru nanoparticles formed following loss of
[MePCy ]Cl from Ru-2a, see: (b) Higman, C. S.; Lanterna, A. E.;
Marin, M. L.; Scaiano, J. C.; Fogg, D. E. ChemCatChem 2016, 8,
446–2449.
11)
008−1015.
12)
6
6
3
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Ru-10, 100%). After 15 days: P{ H} NMR (121.5 MHz,
C D ) δ 71.8 (s, unidentified, 5%), 71.2 (s, unidentified,
%), 47.2 (s, unidentified, 12%), 34.2 (s, [MePCy ]Cl A,
6
6
2
7
3
(
Hughes, D. L. Org. Process Res. Dev. 2016, 20,
75%).
1
(
Styrenyl ether-stabilized catalysts of the Hoveyda
AUTHOR INFORMATION
Corresponding Author
class, in contrast, readily enter the active cycle for metathesis, as
13
indicated by experiments with a C-labelled styrenyl ether. See:
Bates, J. M.; Lummiss, J. A. M.; Bailey, G. A.; Fogg, D. E. ACS
Catal. 2014, 4, 2387−2394.
*
Email dfogg@uottawa.ca.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
Funding Sources
(13)
McDonald, R.; Fogg, D. E. Chem. Sci. 2015, 6, 6739–6746.
14) Lummiss, J. A. M.; Perras, F. A.; Bryce, D. L.; Fogg, D.
E. Organometallics 2016, 35, 691–698.
15) Sponsler and co-workers pointed out the
corresponding labilizing effect of alkylidene substituents on
metathesis reactivity. See: Williams, J. E.; Harner, M. J.;
Sponsler, M. B. Organometallics 2005, 24, 2013–2015.
Lummiss, J. A. M.; Higman, C. S.; Fyson, D. L.;
This work was funded by NSERC of Canada.
Notes
The authors declare no competing financial interest.
(
(
ASSOCIATED CONTENT
Supporting Information
(16)
W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961–7968.
(17) For precedents for attack of phosphine on a [Ru]=CHR
Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M.
NHC structures; additional NMR spectra for new complexes,
impure H ITol complex Ru-2e and decomposition experi-
2
2
ments; tabulated data for kinetics studies; H NMR and
carbon in complexes related to Ru-2a, see: (a) Burrell, A. K.;
Clark, G. R.; Rickard, C. E. F.; Roper, W. R.; Wright, A. H. J.
Chem. Soc., Dalton Trans. 1991, 609-614. (b) Werner, H.; Stuer,
W.; Weberndorfer, B.; Wolf, J. Eur. J. Inorg. Chem. 1999, 1707–
1713. (c) Hansen, S. M.; Rominger, F.; Metz, M.; Hofmann, P.
Chem. Eur. J. 1999, 5, 557–566. (d) Galan, B. R.; Pitak, M.;
Keister, J. B.; Diver, S. T. Organometallics 2008, 27, 3630–3632.
See below for evidence supporting the intermolecular pathway
depicted in Scheme 1.
MALDI-TOF MS evidence for the deuterated phosphonium
salts, and a representative GC trace from catalysis . This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
NSERC is thanked for financial support, and Dr. Emma Davy
(
Fogg group) for Karl-Fischer measurements of water con-
(18)
Methylidene abstraction was reportedly slow for Ru-
tent in organic solvents. Valuable discussions with Dr. Car-
olyn Higman, Prof. Jeffrey Keillor and Prof. Steve Diver are
gratefully acknowledged.
4a at 55 °C, requiring 3 days for complete decomposition. See:
ref 16. In separate experiments, we measured a decomposition
half-life of ca. 160 min at 60 °C (specifically, 53% loss of
alkylidene signals, 45% A (ref 14), a figure in good agreement
with the value of 144 min measured in ref 19.
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(1)
Wiley: Hoboken, NJ, 2014.
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(20) Lummiss, J. A. M.; McClennan, W. L.; McDonald, R.;
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(
2
(
(21)
Lummiss, J. A. M.; Botti, A. G. G.; Fogg, D. E. Catal.
Sci. Technol. 2014, 4, 4210–4218.
(22) For selected examples of the C–H activation of mesityl
o-methyl groups in ruthenium complexes of H IMes and IMes,
2
(
Large-Scale Synthesis of Pharmaceuticals. In Handbook of
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Weinheim, 2015; Vol. 2, pp 633–658.
see ref 16 and: (a) Jazzar, R. F. R.; Macgregor, S. A.; Mahon, M.
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(23) For leading references, see ref 13 and: (a) Comas-Vives,
A.; Harvey, J. N. Eur. J. Inorg. Chem. 2011, 5025-5035. (b)
Vummaleti, S. V. C.; Nelson, D. J.; Poater, A.; Gomez-Suarez, A.;
Cordes, D. B.; Slawin, A. M. Z.; Nolan, S. P.; Cavallo, L. Chem.
Sci. 2015, 8, 1895–1904.
(24) Fernandez, I.; Lugan, N. l.; Lavigne, G.
Organometallics 2012, 31, 1155−1160.
(25) Credendino, R.; Falivene, L.; Cavallo, L. J. Am. Chem.
Soc. 2012, 134, 8127–8135.
(26) Gallagher, M. M.; Rooney, A. D.; Rooney, J. J. J.
Organomet. Chem. 2008, 693, 1252–1260.
(27) Kotyk, M. W.; Gorelsky, S. I.; Conrad, J. C.; Carra, C.;
Fogg, D. E. Organometallics 2009, 28, 5424–5431.
(5)
Fandrick, K. R.; Savoie, J.; Jinhua, N. Y.; Song, J. J.;
Senanayake, C. H., Challenges and Opportunities for Scaling the
Ring-Closing Metathesis Reaction in the Pharmaceutical
Industry. In Olefin Metathesis – Theory and Practice, Grela, K.,
Ed. Wiley: Hoboken, 2014; pp 349-366.
(6)
Pederson, R. L.; Nickel, A., Commercial Potential of
Olefin Metathesis of Renewable Feedstocks. In Olefin
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(7)
Chadwick, J. C.; Duchateau, R.; Freixa, Z.; van
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Stability – Deactivation. Wiley-VCH: Weinheim, 2011.
(
8)
016, 358, 3–25.
9) van Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E., Ring-
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2
(
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Grela, K., Ed. Wiley: Hoboken, NJ, 2014; pp 85–152.
(10)
For the poor kinetic competence of molecular hydride
species often cited as potential culprits, see: (a) Higman, C. S.;
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Journal of the American Chemical Society
(28) Sanford, M. S.; Love, J. A.; Grubbs, R. H.
2 2 6 6
°C in THF was 1.1 h, vs. 2.5 h in CH Cl , and 6.6 h in C H . See:
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Organometallics 2001, 20, 5314–5318.
(29) Conrad, J. C.; Yap, G. P. A.; Fogg, D. E.
Organometallics 2003, 22, 1986–1988.
ref 21.
(43) Tomasek, J.; Schatz, J. Green Chem. 2013, 15, 2317–2338.
(44) Grela, K.; Gulajski, L.; Skowerski, K., Alkene
Metathesis in Water. In Metal-Catalyzed Reactions in Water,
Dixneuf, P. H.; Cadierno, V., Eds. Wiley-VCH: Weinheim, 2013;
pp 291–336.
(30) Independent decomposition experiments with first-
generation complex Ru-6 likewise support an
intermolecular pathway, even in the absence of added
donors. Thus, a half-life of 67 ±3 h was measured for Ru-6 at
(
45) Stark, A.; Ajam, M.; Green, M.; Raubenheimer, H. G.;
Ranwell, A.; Ondruschka, B. Adv. Synth. Catal. 2006, 348, 1934–
941.
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53) Measured rate constants (kobs ) for decomposition on
reaction with 10 DMSO at 25 °C: for disappearance of Ru-4a:
2
2 °C in C D , but this figure dropped to 13.5 ±0.2 h when 10
6 6
1
equiv PCy was present. The stability of this complex exhibits
3
a non-linear dependence on temperature
31) The background reaction, i.e. methylidene abstraction
in the absence of an added donor, was shown to be dissociative
in PCy in experiments carried out on the Ru-4a system. See:
.
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(
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(
refs 13 and 16. For a detailed kinetics derivation, see Supporting
Information for ref 13.
(
3
(32) A slight increase in the proportion of PCy is observed
under ethylene, relative to the experiments with the isolated
methylidene complexes Ru-4b. This is consistent with the
operation of additional elimination pathways in the presence of
ethylene. See: van Rensburg, W. J.; Steynberg, P. J.; Meyer, W.
H.; Kirk, M. M.; Forman, G. S. J. Am. Chem. Soc. 2004, 126,
14332–14333.
(
(
(
(33) The poor solubility of the pyridinium salt in non-
polar solvents (confirmed with an authentic sample of
[MeNC H ]Cl) could mask its presence in this experiment.
–1
D
–1
0
1
.003 min ; for disappearance of Ru-4a : 0.002 min (k
.5).
54) Gomez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111,
H D
/k =
6
5
The benzene solvent was therefore evaporated, and the
(
1
residue redissolved in CDCl . The H NMR spectrum showed
3
4
857–4963.
no evidence of the diagnostic methyl singlet seen for
(55) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202–
7207.
authentic samples at 4.79 ppm in CDCl (see Figure S16)
.
3
(34) These impurities may also contribute to elimination of
(56) Formation of non-labelled A,
d
2
-A and
-A, may reflect scrambling between
functionality, and the
3
d -A, in
2
A from the H ITol catalyst Ru-2e. However, the commercial
addition to the expected d
the mesityl o-CD
cyclohexyl rings. Minor scrambling into the cyclohexyl rings is
consistent with Figure S10a, while an early report described
exchange between the methylidene and cyclohexyl sites in the d-
labelled first-generation system RuCl (PCy )(=CD ). See: ref 55.
2 3 2
An alternative, intriguing possibility raised by a referee is
reversible C–H activation.
1
availability of this catalyst has been discontinued owing to
problems with decomposition on long-term storage. It has been
replaced by its phosphine-free styrenyl ether analogue. Personal
Communication, John Phillips, Catalyst R&D, Materia, Inc.
3
group, the Ru=CH
2
(35) Half-lives
RuCl (H IMes)(PCy
mM Ru, C ). At RT: with H
7 min; with morpholine, 14 h; with DBU, >24 h, as compared to
for
decomposition
of
2
2
3 2
)(=CH ) Ru-4a on addition of 1 equiv L (20
n
6
D
6
2
N Bu, < 3 min; with pyrrolidine,
8
>
(
57) Monfette, S.; Eyholzer, M.; Roberge, D. M.; Fogg, D. E.
Chem. Eur. J. 2010, 16, 11720–11725.
58) In comparison, use of the second-generation Hoveyda
n
2
24 h in the absence of added L. At 60 °C: with H N Bu, < 3 min;
with pyrrolidine, 8 min; with morpholine, 35 min; with DBU, 127
min (ref 19). For values in the absence of added L, see: refs 18, 19.
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Clark, W. M. Org. Process Res. Dev. 2008, 12, 226–234.
(
catalyst resulted in 100% conversion in neat toluene or 20:1
toluene-MeCN under the conditions of Table 2, but 31% in 20:1
toluene-H O, consistent with Cazin’s finding (ref 59) of a more
2
generally deleterious role for water than has hitherto been
acknowledged.
(
38) Ireland, B. J.; Dobigny, B. T.; Fogg, D. E. ACS Catal.
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39) Nagarkar, A. A.; Crochet, A.; Fromm, K. M.; Kilbinger,
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3
40) While binding of tertiary amines such as NEt to Ru
(
59) Guidone, S.; Songis, O.; Nahra, F.; Cazin, C. S. J. ACS
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61) Nickel, A.; Ung, T.; Mkrtumyan, G.; Uy, J.; Lee, C. W.;
2
(
(
(
(
centers has been established, the complexes involved are
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a discussion of such complexes and their degradation products,
see: (a) Fogg, D. E.; James, B. R. Inorg. Chem. 1995, 34, 2557–61.
For examples of Ru complexes containing macrocyclic,
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Che, C.-M.; Cheng, Y. F.; Phillips, D. L.; Zhu, N. Inorg. Chem.
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(
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Fogg, D. E. ChemCatChem 2012, 4, 2020–2025.
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(
(
2008, 47, 10308–10316, and references therein.
(41) Zhao, Z.-X.; Wang, H.-Y.; Guo, Y.-L. Rapid Commun.
(
Mass Spectrom. 2011, 25, 3401-3410.
Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur.
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(42) Donor-accelerated methylidene abstraction accounts
for the observation of shorter lifetimes for Ru-4 and related
methylidene complexes in THF. See: refs 13, 21. For the
methylidene derivative of Ru-1, for example, the half-life at 35
(
66) Lummiss, J. A. M.; Beach, N. J.; Smith, J. C.; Fogg, D. E.
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(
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68) Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H.
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4971.
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