Origin of the Breakthrough Productivity of Ruthenium-Cyclic Alkyl Amino Carbene Catalysts in Olefin Metathesis

Article abstract of DOI:10.1021/jacs.9b10750

Examined herein is the basis for the outstanding metathesis productivity of leading cyclic alkyl amino carbene (CAAC) catalysts relative to their important N-heterocyclic carbene (NHC) predecessors, as recently demonstrated in the topical contexts of metathesis macrocyclization and the ethenolysis of renewable oils. The difference is traced to the stability to decomposition of the metallacyclobutane (MCB) intermediate. The CAAC catalysts are shown to undergo little to no β-H elimination of the MCB ring, a pathway to which the H₂IMes catalysts are highly susceptible. Unexpectedly, however, the CAAC catalysts are found to be more susceptible to bimolecular coupling of the key intermediate RuCl₂(CAAC)(a? CH₂), a reaction that culminates in elimination of the methylidene ligand as ethylene. Thus, an NMR study of transiently stabilized RuCl₂(L)(py)(a? CH₂) complexes (L = CAAC or H₂IMes) revealed bimolecular decomposition of the CAAC derivative within 5 min at RT, as compared to a time scale of hours for the H₂IMes analogue. The remarkable productivity of the CAAC catalysts is thus due to their resistance to β-elimination, which enables their use at part per million loadings, and to the retarding effect of these low catalyst concentrations on bimolecular decomposition.

Full text of DOI:10.1021/jacs.9b10750

Subscriber access provided by BOSTON UNIV
Communication
Origin of the Breakthrough Productivity of Ruthenium-CAAC
Catalysts in Olefin Metathesis (CAAC = Cyclic Alkyl Amino Carbene)
Daniel L. Nascimento, and Deryn E. Fogg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10750 • Publication Date (Web): 26 Nov 2019
Downloaded from pubs.acs.org on November 30, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Origin of the Breakthrough Productivity of Ruthenium-CAAC
Catalysts in Olefin Metathesis (CAAC = Cyclic Alkyl Amino
Carbene)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Daniel L. Nascimento and Deryn E. Fogg*
Center for Catalysis Research & Innovation, and Department of Chemistry and Biomolecular Sciences, University
of Ottawa, Ottawa, Canada K1N 6N5
Supporting Information Placeholder
ABSTRACT: Examined herein is the basis for the outstanding metathesis productivity of leading CAAC catalysts relative
to their important N-heterocyclic carbene (NHC) predecessors, as recently demonstrated in the topical contexts of
metathesis macrocyclization and the ethenolysis of renewable oils. The difference is traced to the stability to
decomposition of the metallacyclobutane (MCB) intermediate. The CAAC catalysts are shown to undergo little to no β–
H elimination of the MCB ring, a pathway to which the H2IMes catalyst are highly susceptible. Unexpectedly, however,
the CAAC catalysts are found to be more susceptible to bimolecular coupling of the key intermediate
RuCl2(CAAC)(=CH2), a reaction that culminates in elimination of the methylidene ligand as ethylene. Thus, an NMR study
of transiently-stabilized RuCl2(L)(py)(=CH2) complexes (L = CAAC or H2IMes) revealed bimolecular decomposition of the
CAAC derivative within 5 min at RT, as compared to a timescale of hours for the H2IMes analogue. The remarkable
productivity of the CAAC catalysts is thus due to their resistance to -elimination, which enables their use at ppm
loadings, and to the retarding effect of these low catalyst concentrations on bimolecular decomposition.
Ruthenium-catalyzed olefin metathesis, widely embraced
as a core methodology in organic synthesis,1,2 is now
Scheme 1. Intrinsic Decomposition Pathways
Established for Phosphine-Free Ru-H2IMes
Metathesis Catalysts.
beginning
to
see
uptake
in
pharmaceutical
manufacturing.3 The demands of process chemistry are
bringing new recognition to long-standing challenges of
catalyst productivity.4 While steps can be taken to
circumvent decomposition induced by extraneous
contaminants,3,5 intrinsic decomposition is
a more
fundamental problem.
Two such pathways have been established for the
dominant N-heterocyclic carbene (NHC) catalysts:
bimolecular coupling of methylidene A (Scheme 1a),6,7
and -elimination of the ruthenacyclobutane (Scheme
1b).8 Particularly vulnerable to -elimination is the
unsubstituted ruthenacyclobutane B (R = H)9 formed on
reaction of A with the ethylene co-product generated in
metathesis of terminal olefins. Ethylene has been shown
to limit metathesis yields in multiple contexts,10 most
prominently process chemistry11,12 and continuous-flow
metathesis.13
Striking, therefore, is the extraordinary productivity
demonstrated for metathesis catalysts bearing a cyclic
alkyl amino carbene (CAAC; Chart 1) in place of an NHC
ligand.14-18 Even in ethenolysis – that is, generation of -
olefins from unsaturated internal olefins of plant or algal
origin,3a,19-22 under an atmosphere of ethylene – turnover
numbers (TONs) as high as 340,000 could be achieved
using a CAAC catalyst.15 This represents a level of
efficiency 2 orders of magnitude higher than that
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
attained with leading H2IMes catalysts14 under standard
conditions of metathesis.
phosphonium alkylidene catalysts (see Ru-3(C1)), which
irreversibly eliminate the phosphonium ylid 1 on reaction
with ethylene.25 This effects quantitative formation of the
metallacyclobutane (MCB), which in turn permits access
to the target methylidene species. The recently
1
2
3
4
5
6
7
8
Chart 1. Metathesis Catalysts Discussed.
reported18 indenylidene dimer Ru-1(C1) offers
a
convenient alternative to the benzylidene complexes
typically used to synthesize the carbide precursors to the
Piers catalysts.9,26-28 Treatment of Ru-1(C1) with Feist's
ester and PiPr3 gave the CAAC carbide Ru-2(C1), which
upon protonation with triflic acid generated the CAAC-
Piers catalyst Ru-3(C1).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Synthesis of Methylidene Complex C(C1).
CO2Me
The origin of this remarkable performance has received
little study to date. Grubbs and Bertrand proposed that
A(C1), the CAAC analogue of intermediate A, may be
more stable to insertion of the N-aryl substituent into
the Ru=CH2 bond (for ligand structures, see Chart 1).15
Lemcoff and co-workers23 pointed out that the CAAC
catalysts cause significantly less C=C migration: as the
latter side-reaction is promoted by decomposed
catalyst,24 this is indirect evidence for the greater stability
of the CAAC catalysts. We speculated that the resistance
to C=C isomerization, as well as the remarkable
ethenolysis productivity noted above, reports on the
capacity of the propagating species to resist the
decomposition pathways of Scheme 1. In a study of
state-of-the-art CAAC catalysts, we demonstrate that -
elimination is indeed dramatically suppressed, although
bimolecular coupling remains operative.
Ph
C
Cl
Cl
CO2Me
PiPr3
Ru PiPr3
Cl
C1
C1 Ru
Cl
Ru-2(C1)
2
Ru-1(C1)
HX (X = OTf)
Cl
X–
PiPr3
+
Cl
C1
Cl
C2H4
py
C1 Ru
Ru
py
Cl
C1 Ru
Cl
Ru-3(C1)
B(C1)
C(C1)
1
Cl
[H2C=CHPiPr3]X
With Ru-3(C1) in hand, we generated the 14-electron
MCB B(C1) in situ, via the methodology developed by
Piers for H2IMes analogue B.27 To guard against
premature decomposition of the MCB, we introduced
ethylene at –78 °C, rather than at –50 °C as in the original
report. Nevertheless, formation of B(C1) was complete
within 10 min. Addition of cold py triggered immediate
retro-addition, and trapped the methylidene species
A(C1) as the py adduct C(C1). The phosphonium salt 1
was then precipitated with cold pentane and filtered off
under vacuum, enabling isolation of C(C1) free of both 1
and ethylene.
We began by evaluating the susceptibility of nG(C1) to
bimolecular coupling. This catalyst was chosen for study
given its record-setting productivity in macrocyclic ring-
closing metathesis (mRCM),16-18 and its striking tolerance
for the contaminants present in technical-grade ethylene
in ethenolysis,18 relative to methyl-substituted C215
(Chart 1). Steric protection by the phenyl group at the
quaternary CAAC carbon in the C1 ligand appears to
improve its stability to contaminants,18 and we queried
whether this might also inhibit bimolecular coupling.
Controlled decomposition of the H2IMes and CAAC
methylidene complexes C and C(C1) (Figure 1) was
carried out in parallel, to probe their relative
susceptibility to bimolecular coupling under directly
comparable conditions. NMR tubes were filled to 80%
capacity with the catalyst solutions, to limit volatilization
of C2H4.29 After measuring an initial 1H NMR spectrum at
–20 °C (a temperature at which both complexes are
stable), the samples were immediately warmed to 23 °C.
Much faster decomposition was observed for CAAC
derivative C(C1), with complete disappearance of the
alkylidene signal within <5 min (Figure 1a).
Decomposition of the H2IMes analogue C, in comparison,
was only 95% complete after 3 h. Ethylene, the marker
for bimolecular coupling, was observed in 81% or 75%
We thus set out to assess the susceptibility to
bimolecular coupling of methylidene intermediate
RuCl2(C1)(=CH2) (A(C1)), relative to its H2IMes analogue
A. The hallmark for this coupling reaction is release of
ethylene. We recently developed
a
protocol for
quantitation of the ethylene product, via synthesis and
cryogenic isolation of transiently-stabilized pyridine
adducts of A (e.g. RuCl2(H2IMes)(py)(=CH2), C), and
controlled decomposition of the adducts in the presence
of an internal standard.6
Accordingly, we undertook synthesis of the CAAC-
methylidene complex C(C1): see Scheme 2. Key
precursors to these complexes are the Piers-class
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
yield, respectively (Figure 1b).30 These yields represent
mesityl p-methyl group, could potentially retard
1
2
3
4
5
6
7
8
lower limits, owing to diffusion of ethylene into the
headspace.29 It should be noted that the high Ru
concentrations required for rapid NMR analysis (20 mM)
accelerate bimolecular reaction, exaggerating absolute
rates of decomposition. However, the increased
susceptibility of the CAAC catalyst to bimolecular
decomposition is maintained under catalytic conditions,
at micromolar Ru concentrations and lower: see later.31
warm
bimolecular coupling.
Of note, early studies of CAAC catalysts revealed
incomplete RCM of standard substrates at catalyst
loadings of 1-5 mol%.36 This limited performance may
reflect the propensity of the CAAC catalysts for
bimolecular coupling at high Ru concentrations.
Consistent with this inference, two subsequent literature
reports reveal increased productivity as CAAC loadings
are reduced.15,18 To probe this point, and to complement
the NMR study above, the productivities of the H2IMes
and CAAC catalysts were compared under conditions of
catalysis, in the self-metathesis of styrene at 50 °C. We
find a slight increase in TON for nG when the catalyst
loading is increased from 1 ppm to 50 ppm (from 19,300
to 19,600). In contrast, TONs for nG(C1) decline 4-fold
(from 27,800 at 1 ppm to 6,500 at 50 ppm). Clearly, both
systems participate in bimolecular decomposition, but
the CAAC catalyst is significantly more sensitive.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
Cl
–20 °C
to 23 °C
0.5
py
Cl
L
Ru
C
L
Ru
A
A(C1)
+ py
CDCl3
Cl
+ Ru products
C(C1)
(20 mM; + IS)
The data so far indicate that the standout performance
of the CAAC catalysts does not arise from resistance to
bimolecular decomposition. We therefore sought to
examine their susceptibility to the second major
decomposition pathway discussed above: unimolecular
decomposition via -elimination of the MCB ring
(Scheme 1b). In this case, the behaviour of the CAAC and
NHC derivatives was compared by examining two top-
performing CAAC catalysts, nG(C1) and nG(C2), in
parallel with the Grela catalyst nG. The latter has long
been valued for its outstanding performance in ring-
closing and cross-metathesis.1-3 The enhanced lability,
and hence enhanced initiation efficiency, conferred by
the nitro group para to the ether donor (see Chart 1) is a
critical asset in the Ru-CAAC catalyst platform, given the
much slower initiation noted above.18,32
Figure 1. Assessing the Susceptibility to Bimolecular
Coupling of the CAAC and H2IMes Methylidene
Complexes, C(C1) and C, Respectively. IS = Internal
Standard.
The data of Figure 1 demonstrate that the metathesis-
active intermediate A(C1) is not merely susceptible to
bimolecular decomposition, but that it is more so than
the corresponding H2IMes derivative. This was initially
unexpected: given the low lability of the CAAC catalysts,
relative to their H2IMes analogues,18,32 we anticipated
that slower pyridine (py) dissociation would retard
liberation and bimolecular coupling of A(C1). The
observed trend implies that the coupling step, rather
than py loss, is rate-determining.
Styrene self-metathesis (Figure 2), if carried out at Ru
concentrations sufficient for NMR detection, offers an
invaluable probe of MCB decomposition.37 -Elimination
of the MCB ring generates unique propenyl markers
The CAAC ligands are both more nucleophilic (-
donating), and more electrophilic (-accepting) than
diaminocarbenes.33,34 While the balance between these
properties as they relate to the Ru catalysts has not yet
been examined, strong ligand donicity is central to the
high metathesis activity of these carbene catalysts. Of
interest is the possibility that the electrophilicity of the
Ru center is heightened relative to the H2IMes analogue,
promoting bimolecular decomposition (i.e., attack on
A(C1) by the dative chloride donors of a second A(C1)
unit). Py re-uptake would likewise be favoured, but this
reaction is reversible, whereas dimerization is followed
by rapid, irreversible elimination of ethylene (Scheme
1a).6 Steric factors may also be relevant, however. The
bulk of the CAAC ligands relative to NHCs is not clear-
cut,35 but the extended “wingstips” of H2IMes, with its
(H2C=CHCH2R;
R
=
H, Ph), which are readily
distinguished from the products of metathesis (e.g.
RHC=CHR) by the odd number of backbone carbons
present. Styrene ensures the validity of this experiment
because, unlike most 1-olefins, it cannot isomerize, and
is therefore unable to generate “false” propenyl markers
via isomerization prior to metathesis.6 In addition, its
relatively low reactivity ensures complete catalyst
conscription even at 1 mol% Ru,37 maximizing yields of
the organic products of decomposition. Filling the NMR
tubes to 80% capacity is again important, to limit loss of
volatile propene to the headspace.
As shown in Figure 2a, and consistent with prior reports
for this and related Ru-NHC catalysts,8 nG readily
ACS Paragon Plus Environment

Journal of the American Chemical Society
undergoes -elimination. Propenes were detected in
Page 4 of 7
of the CAAC catalysts to -elimination, as well as their
susceptibility to bimolecular decomposition. Likewise of
keen interest is their robustness to Bronsted base, water,
and other contaminants to which the NHC catalysts are
vulnerable.37-39 Nevertheless, these catalysts hold great
promise for the broader implementation of metathesis
methodologies, particularly in contexts where ethylene is
required, or where its removal cannot be efficiently
achieved.
1
2
3
4
5
6
7
8
51% yield relative to the starting charge of nG.
(Bimolecular coupling is presumed to account for the
balance, but its ethylene marker is masked by the
ethylene liberated in metathesis). In striking contrast,
essentially zero propenes were eliminated from the
CAAC catalysts (2% for nG(C1); 0% for nG(C2)). The
CAAC ligand thus confers near-complete resistance to -
elimination. We speculate that heightened -donicity
could potentially stabilize the metallacyclobutane, and
hence raise the energy barrier to elimination.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
The rapid catalyst decomposition evident in the decay
curves of Figure 2b further underscores the ease with
which all of these methylidene intermediates undergo
bimolecular decomposition at high (20 mM) catalyst
concentrations. The slower net disappearance of nG(C2)
is an artifact of slower initiation of the dimethyl-CAAC
catalysts.17
PDF file: experimental data, rate plots, NMR spectra
AUTHOR INFORMATION
Corresponding Author
* dfogg@uottawa.ca
NO2
ACKNOWLEDGMENT
Ph
This work was funded by NSERC of Canada. Apeiron
Synthesis is thanked for a gift of nG and nG(C1), and
Umicore for a gift of C2•BF4. Vidar Jensen (Bergen) is
thanked for insightful discussions.
+
H
Cl
R
100
Cl
L
Ru
OiPr
Ph
+
Ph
L
Ru
25 °C, CDCl3
Cl
Cl
(20 mM; + IS)
-elimination
+ Ru products
REFERENCES
(1)
Grela, K., Olefin Metathesis-Theory and Practice. Wiley:
Hoboken, NJ, 2014.
(2)
Grubbs, R. H.; Wenzel, A. G., Handbook of Metathesis.
2nd ed.; Wiley-VCH: Weinheim, 2015.
(3)
(a) Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Olefin
Metathesis at the Dawn of Uptake in Pharmaceutical and
Specialty Chemicals Manufacturing. Angew. Chem., Int. Ed.
2016, 55, 3552–3565. (b) 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. (c)
Farina, V.; Horváth, A., Ring-Closing Metathesis in the Large-
Scale Synthesis of Pharmaceuticals. In Handbook of Metathesis,
Grubbs, R. H.; Wenzel, A. G., Eds. Wiley-VCH: Weinheim, 2015;
Vol. 2, pp 633–658.
Figure 2. Contribution of -Elimination (Propene
Formation) to Catalyst Decomposition. Metathesis
Products (C2H4, Stilbene) Not Shown.
These findings have several important implications. First,
the remarkable productivity of the CAAC catalysts is
clearly due to the stability of the ruthenacycle to -
elimination, not to the resistance of the methylidene
intermediate to bimolecular coupling. Indeed, the CAAC
catalysts are more susceptible to bimolecular
decomposition. Importantly, however, because they
resist -elimination, the CAAC catalysts can be used at
much lower catalyst loadings, which in turn minimizes
bimolecular decomposition. The remarkable productivity
of these catalysts thus originates in the fact that at low
catalyst loadings, both of the decomposition pathways of
Scheme 1 are inhibited.
(4)
(a) Schrodi, Y., Mechanisms of Olefin Metathesis
Catalyst Decomposition and Methods of Catalyst Reactivation.
In ref 2, pp 323–342. (b) Chadwick, J. C.; Duchateau, R.; Freixa,
Z.; van Leeuwen, P. W. N. M., Alkene Metathesis. In
Homogeneous Catalysts: Activity – Stability – Deactivation,
Wiley-VCH: Weinheim, 2011; pp 347-396.
(5)
In developing a production route to Simeprevir,
Janssen chemists added methanesulfonic acid to neutralize
basic impurities prior to mRCM. See: ref 3c. In GII-catalyzed
acrylate metathesis, a sacrificial proton source can prevent
deprotonation of the MCB by PCy3-generated enolates. See:
(a) Santos, A. G.; Bailey, G. A.; dos Santos, E. N.; Fogg, D. E.,
Overcoming Catalyst Decomposition in Acrylate Metathesis:
Poly-phenol Resins as Enabling Agents for Phosphine-Stabilized
Metathesis Catalysts. ACS Catal. 2017, 7, 3181−3189. (b) Bailey,
G. A.; Fogg, D. E., Acrylate Metathesis via the Second-
Fundamental studies now under way seek to deepen our
understanding of the factors that influence the stability
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Generation Grubbs Catalyst: Unexpected Pathways Enabled by a
Protease Inhibitor, by a Convergent Approach Based on Ring-
Closing Metathesis. J. Org. Chem. 2006, 71, 7133–7145.
(12) Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P., First
Scale-Up to Production Scale of a Ring Closing Metathesis
Reaction Forming a 15-Membered Macrocycle as a Precursor of
an Active Pharmaceutical Ingredient. Org. Process Res. Dev.
2005, 9, 513–515.
(13) Monfette, S.; Eyholzer, M.; Roberge, D. M.; Fogg, D. E.,
Getting RCM Off the Bench: Reaction-Reactor Matching
Transforms Metathesis Efficiency in the Assembly of Large
Rings. Chem. – Eur. J. 2010, 16, 11720–11725.
(14) Schrodi, Y.; Ung, T.; Vargas, A.; Mkrtumyan, G.; Lee, C.
W.; Champagne, T. M.; Pederson, R. L.; Hong, S. H., Ruthenium
Olefin Metathesis Catalysts for the Ethenolysis of Renewable
Feedstocks. Clean Soil, Air, Water 2008, 36, 669–673.
(15) Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.;
Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R. H., Cyclic
Alkyl Amino Carbene (CAAC) Ruthenium Complexes as
Remarkably Active Catalysts for Ethenolysis. Angew. Chem., Int.
Ed. 2015, 54, 1919–1923.
1
2
3
4
5
6
7
8
PCy3-Generated Enolate. J. Am. Chem. Soc. 2015, 137, 7318–
7321. In enyne metathesis, rapid catalyst decomposition is
inhibited by use of ethylene atmosphere. See: (c) Mori, M.;
Sakakibara, N.; Kinoshita, A., Remarkable Effect of Ethylene Gas
in the Intramolecular Enyne Metathesis of Terminal Alkynes. J.
Org. Chem. 1998, 63, 6082–6083. The beneficial effect is due to
inhibition of yne-yne reactions that result in catalyst
decomposition. See: (d) Grotevendt, A. G. D.; Lummiss, J. A. M.;
Mastronardi, M. L.; Fogg, D. E., Ethylene-Promoted versus
Ethylene-Free Enyne Metathesis. J. Am. Chem. Soc. 2011, 133,
15918–15921.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6)
Bailey, G. A.; Foscato, M.; Higman, C. S.; Day, C. S.;
Jensen, V. R.; Fogg, D. E., Bimolecular Coupling as a Vector for
Decomposition of Fast-Initiating Olefin Metathesis Catalysts. J.
Am. Chem. Soc. 2018, 140, 6931–6944.
(7)
Thiel, V.; Wannowius, K.-J.; Wolff, C.; Thiele, C. M.;
Plenio, H., Ring-Closing Metathesis Reactions: Interpretation of
Conversion–Time Data. Chem. - Eur. J. 2013, 19, 16403–16414.
(8)
For labelling evidence, see: (a) Romero, P. E.; Piers, W.
E., Mechanistic Studies on 14-Electron Ruthenacyclobutanes:
Degenerate Exchange with Free Ethylene. J. Am. Chem. Soc.
2007, 129, 1698–1704. For the first observation of propene
evolution from HII, see: (b) Nizovtsev, A. V.; Afanasiev, V. V.;
Shutko, E. V.; Bespalova, N. B., Metathesis Catalysts Stability And
Decomposition Pathway. NATO Sci. Ser. II 2007, 243, 125–135.
More unexpectedly, propene loss from GII was reported. See:
(c) van Rensburg, W. J.; Steynberg, P. J.; Meyer, W. H.; Kirk, M.
M.; Forman, G. S., DFT Prediction and Experimental Observation
of Substrate-Induced Catalyst Decomposition in Ruthenium-
Catalyzed Olefin Metathesis. J. Am. Chem. Soc. 2004, 126,
14332–14333. This is surprising given evidence for quantitative
abstraction of the methylidene ligand from A by PCy3, a potent
nucleophile. See: (d) McClennan, W. L.; Rufh, S. A.; Lummiss, J. A.
(16) Gawin, R.; Tracz, A.; Chwalba, M.; Kozakiewicz, A.;
Trzaskowski, B.; Skowerski, K., Cyclic Alkyl Amino Ruthenium
Complexes—Efficient Catalysts for Macrocyclization and
Acrylonitrile Cross Metathesis. ACS Catal. 2017, 7, 5443–5449.
(17) Gawin, R.; Kozakiewicz, A.; Guńka, P. A.; Dąbrowski, P.;
Skowerski, K., Bis(Cyclic Alkyl Amino Carbene) Ruthenium
Complexes:
A Versatile, Highly Efficient Tool for Olefin
Metathesis. Angew. Chem., Int. Ed. 2017, 56, 981–986.
(18) Nascimento, D. L.; Gawin, A.; Gawin, R.; Guńka, P. A.;
Zachara, J.; Skowerski, K.; Fogg, D. E., A Highly Reactive
Ruthenium-Indenylidene Catalyst for Olefin Metathesis. J. Am.
Chem. Soc. 2019, 141, 10626–10631.
(19) Bidange, J.; Fischmeister, C.; Bruneau, C., Ethenolysis: A
Green Catalytic Tool to Cleave Carbon–Carbon Double Bonds.
Chem. – Eur. J. 2016, 22, 12226–12244.
M.; Fogg, D. E.,
A General Decomposition Pathway for
Phosphine-Stabilized Metathesis Catalysts: Lewis Donors
Accelerate Methylidene Abstraction. J. Am. Chem. Soc. 2016,
138, 14668−14677. For the first observation of the [MePCy3]Cl
salt, see: (e) Hong, S. H.; Chlenov, A.; Day, M. W.; Grubbs, R. H.,
Double C-H Activation of an N-Heterocyclic Carbene Ligand in
a Ruthenium Olefin Metathesis Catalyst. Angew. Chem., Int. Ed.
2007, 46, 5148–5151. Methylidene abstraction in the van
Rensburg study was apparently prevented by the presence of
trace oxygen: ref (c) comments on the observation of O=PCy3.
(20) Chikkali, S.; Mecking, S., Refining of Plant Oils to
Chemicals by Olefin Metathesis. Angew. Chem., Int. Ed. 2012,
51, 5802−5808.
(21) Hess, S. K.; Lepetit, B.; Kroth, P. G.; Mecking, S.,
Production of Chemicals from Microalgae Lipids – Status and
Perspectives. Eur. J. Lipid Sci. Technol. 2018, 120, 1700152.
(22) For a recent study deploying a CAAC catalyst in
ethenolysis of ethyl oleate on 1 L scale, see: (a) Kajetanowicz, A.;
Chwalba, M.; Gawin, A.; Tracz, A.; Grela, K., Non-Glovebox
Ethenolysis of Ethyl Oleate and FAME at Larger Scale Utilizing a
Cyclic (Alkyl)(Amino)Carbene Ruthenium Catalyst. Eur. J. Lipid
Sci. Technol. 2019, 1900263. For the use of CAAC and
fluorinated NHC catalysts for ethenolysis of the terpene
squalene (which contains six trisubstituted olefinic units), see:
(b) Byun, S.; Seo, H.; Choi, J.-H.; Ryu, J. Y.; Lee, J.; Chung, W.-j.;
Hong, S., Fluoro-Imidazopyridinylidene Ruthenium Catalysts for
Cross Metathesis with Ethylene. Organometallics 2019, 38,
4121–4132.
(9)
Keitz, B. K.; Grubbs, R. H., Probing the Origin of
Degenerate Metathesis Selectivity via Characterization and
Dynamics of Ruthenacyclobutanes Containing Variable NHCs. J.
Am. Chem. Soc. 2011, 133, 16277–16284.
(10) Burdett, K. A.; Harris, L. D.; Margl, P.; Maughon, B. R.;
Mokhtar-Zadeh, T.; Saucier, P. C.; Wasserman, E. P., Renewable
Monomer Feedstocks via Olefin Metathesis: Fundamental
Mechanistic Studies of Methyl Oleate Ethenolysis with the First-
Generation Grubbs Catalyst. Organometallics 2004, 23, 2027–
2047.
(11) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos,
R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.;
Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.;
Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach,
K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W.,
Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV
(23) Butilkov, D.; Frenklah, A.; Rozenberg, I.; Kozuch, S.;
Lemcoff, N. G., Highly Selective Olefin Metathesis with CAAC-
Containing Ruthenium Benzylidenes. ACS Catal. 2017, 7, 7634–
7637.
(24) Molecular hydride species (including
a
dimer
identified in ref 8e) often cited as promoting competing
isomerization are insufficiently reactive to do so. For a kinetics
study, see: (a) Higman, C. S.; Plais, L.; Fogg, D. E., Isomerization
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
During Olefin Metathesis: An Assessment of Potential Catalyst
(30) The NMR spectrum showed no signals for propene,
the marker for decomposition of the unsubstituted
ruthenacyclobutane via b-elimination.
1
2
3
4
5
6
7
8
Culprits. ChemCatChem 2013, 5, 3548-3551. For GII, Ru
nanoparticles have been implicated. See: (b) Higman, C. S.;
Lanterna, A. E.; Marin, M. L.; Scaiano, J. C.; Fogg, D. E., Catalyst
Decomposition During Olefin Metathesis Yields Isomerization-
Active Ru Nanoparticles. ChemCatChem 2016, 8, 2446–2449.
For a critical review of isomerization in metathesis, see (c) van
Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E., Ring-Closing
Metathesis. In ref 1; pp 85–152.
(25) For evidence that the vinylphosphonium salt
[H2C=CHPCy3]Cl (1) lost on reaction with ethylene does not re-
enter metathesis, see: Leitao, E. M.; van der Eide, E. F.; Romero,
P. E.; Piers, W. E.; McDonald, R., Kinetic and Thermodynamic
Analysis of Processes Relevant to Initiation of Olefin Metathesis
by Ruthenium Phosphonium Alkylidene Catalysts. J. Am. Chem.
Soc. 2010, 132, 2784–2794.
(26) Carlson, R. G.; Gile, M. A.; Heppert, J. A.; Mason, M. H.;
Powell, D. R.; Vander Velde, D.; Vilain, J. M., The Metathesis-
Facilitated Synthesis of Terminal Ruthenium Carbide
Complexes: A Unique Carbon Atom Transfer Reaction. J. Am.
Chem. Soc. 2002, 124, 1580–1581.
(27) Romero, P. E.; Piers, W. E., Direct Observation of a 14-
Electron Ruthenacyclobutane Relevant to Olefin Metathesis. J.
Am. Chem. Soc. 2005, 127, 5032–5033.
(31) While the concentration of [Ru]=CH2 species (which
are more vulnerable than their alkylidene or benzylidene
[Ru]=CHR counterparts: ref 6) is higher in ethenolysis, the use
of ppm loadings in catalysis means that the absolute
concentrations of [Ru]=CH2 is orders of magnitude lower than
the 20 mM Ru concentration required for these NMR studies.
(32) Anderson, D. R.; Ung, T.; Mkrtumyan, G.; Bertrand, G.;
Grubbs, R. H.; Schrodi, Y., Kinetic Selectivity of Olefin Metathesis
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalysts
Organometallics 2008, 27, 563–566.
(33) Soleilhavoup, M.;
Bearing
Cyclic
(Alkyl)(Amino)Carbenes.
Bertrand, G., Cyclic
(Alkyl)(Amino)Carbenes (CAACs): Stable Carbenes on the Rise.
Acc. Chem. Res. 2015, 48, 256–266.
(34) Melaimi, M.; Jazzar, R.; Soleilhavoup, M.; Bertrand, G.,
Cyclic (Alkyl)(amino)carbenes (CAACs): Recent Developments.
Angew. Chem., Int. Ed. 2017, 56, 10046–10068.
(35) Paul, U. S. D.; Radius, U., What Wanzlick Did Not Dare
To Dream: Cyclic (Alkyl)(amino)carbenes (cAACs) as New Key
Players in Transition-Metal Chemistry. Eur. J. Inorg. Chem. 2017,
3362–3375.
(36) Anderson, D. R.; Lavallo, V.; O'Leary, D. J.; Bertrand, G.;
Grubbs, R. H., Synthesis and Reactivity of Olefin Metathesis
Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes. Angew. Chem.,
Int. Ed. 2007, 46, 7262–7265.
(28) van der Eide, E. F.; Romero, P. E.; Piers, W. E.,
Generation
and
Spectroscopic
Characterization
of
Ruthenacyclobutane
and Ruthenium
Olefin Carbene
Intermediates Relevant to Ring Closing Metathesis Catalysis. J.
Am. Chem. Soc. 2008, 130, 4485–4491.
(29) Restricting the headspace in the NMR tube to 20% of
the total tube volume represents a balance between tube
rupture and retention of C2H4 in solution. For calculations, see
the supporting information in ref 6. For a resource on safe
(37) Ireland, B. J.; Dobigny, B. T.; Fogg, D. E.,
Decomposition of a Phosphine-Free Metathesis Catalyst by
Amines and Other Nitrogen Bases: Metallacyclobutane
Deprotonation as a Major Deactivation Pathway. ACS Catal.
2015, 5, 4690−4698.
(38) Bailey, G. A.; Lummiss, J. A. M.; Foscato, M.; Occhipinti,
G.; McDonald, R.; Jensen, V. R.; Fogg, D. E., Decomposition of
handling of cryogenic liquids, including
a discussion on
condensable gases, see: Kuespert, D. R., Research Laboratory
Safety. de Gruyter: Haarlem, NL, 2016; pp 55–63. Losses to the
headspace occur over a timescale of hours. For C, 76% C2H4 was
detected when decomposition was complete within 20 min: ref
6.
Olefin
Metathesis
Catalysts
by
Brønsted
Base:
Metallacyclobutane Deprotonation as a Primary Deactivating
Event. J. Am. Chem. Soc. 2017, 139, 16446–16449.
(39) Guidone, S.; Songis, O.; Nahra, F.; Cazin, C. S. J.,
Conducting Olefin Metathesis Reactions in Air: Breaking the
Paradigm. ACS Catal. 2015, 5, 2697–2701.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
.
4
5
6
7
8
Cl
R
Cl
CAAC Ru
CAAC Ru
Cl
Cl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
+
0.5
decomposed
Ru products
ACS Paragon Plus Environment