Specialized ruthenium olefin metathesis catalysts bearing bulky unsymmetrical NHC Ligands: Computations, synthesis, and application

Article abstract of DOI:10.1021/acscatal.8b04783

Second-generation ruthenium olefin metathesis catalysts were investigated with systematic variation of the unsymmetrical uNHC ligands. Depending on the uNHC steric bulk, the catalysts exhibited different activity and selectivity in metathesis reactions. DFT calculations and X-ray crystallographic data were used to understand the influence of uNHC ligand structure on the catalyst properties. Furthermore, the catalysts were examined in the context of reactions that are problematic for general-purpose Ru catalysts, including industrially important self-cross metathesis of α-olefins and ethenolysis of ethyl oleate.

Full text of DOI:10.1021/acscatal.8b04783

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 587−598
Specialized Ruthenium Olefin Metathesis Catalysts Bearing Bulky
Unsymmetrical NHC Ligands: Computations, Synthesis, and
Application
‡
Paweł Małecki,† Katarzyna Gajda,† Roman Gajda,‡ Krzysztof Wozniak, Bartosz Trzaskowski,$
́
Anna Kajetanowicz,*,† and Karol Grela*,†
†
̇
Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Zwirki i Wigury Street 101, 02-089
Warszawa, Poland
‡Faculty of Chemistry, University of Warsaw, 02-089 Warszawa, Poland
$Centre of New Technologies, University of Warsaw, 02-097 Warszawa, Poland
S
* Supporting Information
ABSTRACT: Second-generation ruthenium olefin metathesis
catalysts were investigated with systematic variation of the
unsymmetrical uNHC ligands. Depending on the uNHC steric
bulk, the catalysts exhibited different activity and selectivity in
metathesis reactions. DFT calculations and X-ray crystallo-
graphic data were used to understand the influence of uNHC
ligand structure on the catalyst properties. Furthermore, the
catalysts were examined in the context of reactions that are
problematic for general-purpose Ru catalysts, including
industrially important self-cross metathesis of α-olefins and
ethenolysis of ethyl oleate.
KEYWORDS: olefin metathesis, ruthenium, ligands, N-heterocyclic carbenes, catalysis, selectivity, ethenolysis
INTRODUCTION
■
Olefin metathesis is an important catalytic reaction that allows
for preparation of various organic compounds.1 The milestone
enabling the introduction of metathesis methodology both for
general laboratory practices and large-scale industrial produc-
tion,1c was the introduction of well-defined catalysts, based on
molybdenum, tungsten, and ruthenium. Peculiarly, the second-
generation ruthenium catalysts Ru1−Ru5, in which one
phosphine ligand was replaced by N-heterocyclic carbene
(NHC) ligands (Figure 1, top), become very popular because
of their satisfactory stability toward air and moisture, and good
activity.1
The NHC moieties are among the most important ligands
used not only in olefin metathesis catalysts but also in other
transition-metals complexes commonly utilized in a variety of
coupling reactions,2−4 as well as in metal-free organo-
Figure 1. Selected popular second generation catalysts (Ru1−Ru5)
bearing privileged SIMes and SIPr ligands and complex (Ru6) bearing
catalysis.5,6 Such a high popularity of these ligands results
from their modularity and easy fine-tuning of their steric and
electronic properties, and thus the ability to modify the
properties of the resulted catalysts.7 Numerous ab initio and
experimental trial-and-error studies probing the relationship
between the structure of the NHCs and the stability and
activity of the resulted catalysts were conducted.8,9 In the
context of Ru-catalyzed olefin metathesis, it was proven that
the introduction of larger N-substituents (e.g., DIPP instead of
Mes, Figure 1) in the NHC ligand core not only improves the
more bulky IPr* ligand.
stability of the resulted Ru alkylidene catalyst but also affects
its activity. For example, many reports state that catalysts
Received: November 28, 2018
Revised: December 6, 2018
© XXXX American Chemical Society
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bearing more bulky SIPr ligands are much more stable and
productive than their SIMes analogues, although the latter
usually work better in the case of more crowded or less reactive
substrates.10−14 Interestingly, further enlargement of the NHC
ligand size does not always bring the improvement of the
properties of the resulted Ru catalyst, as for example complex
Ru6 (Figure 1, bottom) bearing IPr* moiety15 was shown to
be less active than their analogues with smaller SIPr and IPr
ligands.16 This result is of great theoretical importance as it
shows at its most extreme that when the bulk in the NHC
ligand sphere is too significant, the olefin metathesis catalysts
activity is reduced,17 which suggests that a perfect NHC ligand
shall combine enough bulkiness to protect the propagating 14-
electron Ru species from decomposition, with sufficient
flexibility to secure substrate unobstructed access. Herewith
we are describing our efforts to find such a “perfect match”
between the NHC ligand structure and efficiency of the
resulted Ru-complex as olefin metathesis catalysts (Figure 2),
first by ab initio and then by experimental methods.
In order to get a better picture of how the increasing size of
uNHC ligand would influence the stability and activity of the
corresponding catalysts, we envisioned a series of complexes
bearing N-aromatic substituents of gradually increasing steric
bulk in the uNHC ligand, while the other side kept small and
constant (Figure 2). To complete the series, two complexes
with never previously synthesized uNHC ligands, bearing 2,6-
bis(diphenylmethyl)-4-methylphenyl (Ru9) and 2,6-di(3-
pentyl)phenyl (Ru10) aromatic wings were proposed. Prior
to entering into synthesis, we decided to use computational
methods to predict performance in metathesis of these
complexes.
Ab Initio Studies. In order to assess the stability and
activity levels of the imagined complexes we performed state-
of-art computational study of their activation using the
B3LYP/DLPNO−CCSD(T) approach, described in detail in
SI. We considered only the dissociative path of initiation, as it
was shown that it is the only viable activation path for
Hoveyda-like catalysts for substrates of medium and large
size.23 As shown in Figure 3 the lowest Gibbs free energy of
Figure 3. Gibbs free energies of activation of complexes Ru7−Ru10
estimated at the B3LYP/DLPNO−CCSD(T) level.
activation was found for Ru7 (19.05 kcal/mol), and the
increase of the size of the aromatic substituent in the uNHC
ligand increases the activation barrier, with the exception of
Ru10. We can easily rationalize this results, as the larger
uNHC substituent makes it harder for the isopropoxybenzy-
lidene to rotate away in order to activate the complex due to
steric hindrance. The relatively low free energy of the
transition state for Ru10 (of 18.3 kcal/mol) is, in this view,
surprising and in disagreement with observed trends. The
reason for this discrepancy is the fact that all transition states
(defined as geometries with one imaginary frequency
corresponding to Ru−O bond breaking) here are “early”
with the average Ru−O distance of 3.4 Å, where the
isopropoxy moiety is still relatively close to the ruthenium
core. In order for the complex to activate the isopropox-
ybenzylidene part of it is required to rotate by another ∼90 deg
from ts to act conformation and this rotation may be hindered
by the bulky R groups. In order to verify this hypothesis, we
have performed a relaxed potential energy scan of the
isopropoxybenzylidene moiety rotation starting from the
transition state geometry. In the case of Ru7, Ru8, and Ru9,
the potential energy gets immediately lower when moving from
Figure 2. Structures of the uNHC Ru complexes used in this study.
RESULTS AND DISCUSSION
■
Recently we have synthesized two ruthenium 2-isopropox-
ybenzylidene complexes bearing N-aryl-N′-benzyl substituted
unsymmetrical NHC (uNHC) ligands. These complexes,
Ru718,19and Ru8,20 were found to be slower initiating but
more selective comparing to general-purpose Hoveyda−
Grubbs Ru2 and Ru3. Especially, the N-DIPP bearing complex
Ru820 was found to give promisingly good selectivity in
demanding21a self-CM of α-olefins. This finding was somehow
puzzling, as the more bulky, SIPr bearing catalysts (like Ru3)
were described to be more prone to induce the unwanted C−C
double bonds isomerization than their less sterically demand-
ing SIMes variants (e.g., Ru2).22
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ts to act, suggesting that the Gibbs free energy of the transition
state is the true energy barrier of activation. In the case of
Ru10, however, there is an additional barrier of 4.81 kcal/mol
required to make the rotation around the bulky phenyl groups.
As a result the true activation barrier of Ru10 is equal to 23.07
kcal/mol, suggesting that Ru10 is likely to be the slowest-
activating complex out of those four studied. These results can
be directly compared to the experimental ΔG‡ of Hoveyda-
Grubbs catalyst Ru2 equal to 20.69 kcal/mol (at 275 K).24
Given the obtained estimates we can predict that Ru7 and Ru8
should initiate with a similar rate to Ru2, while Ru9 and Ru10
are likely to initiate slower.
We also considered the possibility of the rotation of the
benzyl moiety, which upon activation of complexes could
inhibit olefin association, similarly to previously described
catalysts bearing N-phenylpyrrol uNHC ligands (e.g., Ru11).25
Unlike the latter system, for Ru7−Ru10 the Gibbs free energy
difference between the two conformations is around 5−6 kcal/
mol, rendering the conformation with the possible Ru−π
interaction unlikely from the energy point of view (Figure 4).
suggesting that it is less likely to be produced during the
catalytic cycle. Unfortunately the mechanism of Hoveyda−
Grubbs catalyst degradation in the absence of the olefinic
substrate and in nonpolar solvents is not fully understood, but
it likely involves the formation of the 14e species (either
benzylidene or methylidene), which are relatively unstable.26
Therefore, we can expect that also in this case the larger barrier
of initiation as well as higher energies of intermediates
correlate with the higher stability in a solution.
Synthesis and Structural Characterization. Encouraged
by the results of the ab initio study we decided to synthesize
the predicted catalysts (Ru9 and Ru10, Figure 2) and compare
them with previously obtained complexes. Such resulted
collection would compose of four structurally similar catalysts,
in which the N-aryl substituents are of gradually increasing
steric bulk, starting from Mes and DIPP in Ru7 and Ru8 and
finishing with very spacious Ru9 and Ru10 (Figure 2).
Unfortunately, the synthesis of new uNHC ligands carrying the
bulkier N-aryl substituents (3a,3b) using the previously
reported method22 failed. Therefore, we worked out an
alternative method based on the reaction between the
appropriate aniline derivatives 1a,1b and chloroacetyl chloride.
The resulting amides were then subjected to the reaction with
benzylamine and to subsequent reduction with lithium
aluminum hydride (LAH) to produce diamines that were
converted into the hydrochlorides 2a,2b in overall yield 56 and
73%, respectively. In the next step, the imidazoline rings were
formed upon reaction with triethyl orthoformate, to provide
with the expected products 3a,3b in almost 80% yields each
(Scheme 1). With both ligand precursors in hand the synthesis
of ruthenium complexes was attempted. In the first step, free
carbenes were generated from imidazoline salts 3a,3b in the
presence of potassium tert-amylate as the base and then reacted
Figure 4. Gibbs free energies of N-benzyl moiety rotation estimated
at the B3LYP/DLPNO−CCSD(T) level for complexes Ru7−Ru10.
The reason for the relatively high energy of this conformation
is the unfavorable interaction between the benzyl moiety and
Ru ion, estimated at +7.3 kcal/mol at the SAPT0 level of
theory. Clearly, dissimilar to the phenylpyrrol derived NHC
case,25 the benzyl group is not sufficiently flexible to position
the phenyl moiety close to the ruthenium to form a favorable
interaction. As most Hoveyda-type catalysts exhibit a direct
correlation between the initiation rate and their stability, we
can speculate that Ru10 is the most stable catalyst out of the
four studied complexes, while Ru7 is the least stable one
(relatively).
Scheme 1. Synthesis of uNHC and Ru Catalysts Ru7−
a
Ru10
The Gibbs free energy difference of initiation between Ru8
and Ru9 is below the expected accuracy of our calculations
(∼1 kcal/mol) so it is difficult to assess their relative stability,
aside from the fact that they should be more stable than Ru7
and less stable than Ru10. To better estimate the stabilities of
new complexes, we also calculated the relative Gibbs free
energies of their 14-electron methylidene intermediates (see
Figure 5). We found that while the free energies of Ru7−Ru9
are similar, and Ru10 is more than 1 kcal/mol higher in energy
a
Reaction conditions: (a) chloroacetyl chloride, K2CO3,
MeCN:DCM (1:1), 0 °C to RT, 2 h; (b) benzyl amine, K2CO3,
MeCN/PhMe (1:1), reflux, 24 h; (c) LAH, THF, −20 to 60 °C, 8 h;
(d) HCl, Et2O, −40 °C; (e) HC(OEt)3, 120 °C, 18 h; (f) t-AmOK,
hexane, RT, 2−5 min, then Ru12, 65 °C, 25 min; (g) t-AmOK,
toluene RT, 2−5 min, then Ru12, 75 °C, 5 min. NHC precursors for
Ru7 and Ru8 prepared according to ref 20.
Figure 5. Relative Gibbs free energies of 14e methylidene
intermediate for complexes Ru7−Ru10
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with the first generation Hoveyda−Grubbs catalyst (Ru12).
This process yielded Ru9 and Ru10 as greenish brown
microcrystalline solids, in yield of 63 and 68%, respectively
1
(Scheme 1). The H NMR for Ru9 showed a singlet peak at
16.23 ppm and for Ru10 at 16.96 ppm, which is a
characteristic region of the Hoveyda−Grubbs complexes, as
well as other peaks conformed presence of uNHC ligands (N-
CH2-CH2-N: for Ru9 3.61(dd); 3.99(dd) and for Ru10
2.00(dd); 2.77(dd)). First two complexes of the series, N-Mes
bearing Ru7 and N-DIPP substituted Ru8 were obtained
according to literature protocol,20 although with some
improvements (Scheme 1, method f) that allowed to shorten
and simplify their preparation, and also to improve yield of
Ru7 from 28% (previously reported)20 to 47% (see SI).
Single crystals, suitable for X-ray measurements, were
obtained from a mixture of dichloromethane (DCM) and
heptane. Both investigated catalysts, Ru9 and Ru10, crystallize
in, respectively, P21/c and P21/n space groups (with four
molecules in the unit cell in each case) of the monoclinic
crystal system. There are significant voids (V = 395 Å3) in the
structure of Ru10 filled in with highly disordered DCM
molecules. However, within the Ru9 structure, such voids are
not observed. To describe differences in conformation between
the investigated compounds, we defined a specific torsion
angle (T1), Cα−Cβ−Cγ−Nδ (see Figure 6). This angle
Figure 7. Par deux and all-four overlays of molecules: Ru7 (yellow),
Ru8 (red), Ru9 (green), and Ru10 (blue). Hydrogen atoms have
been omitted for clarity.
the resulted complexes. In addition, commercially available
Hoveyda−Grubbs second-generation catalyst Ru2 was added
to this set, as the example of the popular general-purpose
catalyst bearing a symmetrical NHC ligand. To quantify this
important catalyst’s property the following procedure for
measuring the decomposition rate in solution was used:
carefully weighed-out samples of the corresponding catalyst
and 1,3,5-trimethoxybenzene (used as an internal standard)
were dissolved in a CD2Cl2 in a glovebox and heated for 25
Figure 6. X-ray crystal structure of new catalysts with 50% probability
ellipsoids, and specific torsion angle T1 (Cα−Cβ−Cγ−Nδ) parameters.
describes the position of the benzyl substituents with respect
to the imidazolinium ring. Values of such defined angle are
−80.3(5)° for Ru9 and −44.32(15)° for Ru10, respectively. It
shows that access to the metallic center is open (see values of
this angle for similar catalysts in our previous paper).22 In the
case of Ru10, the phenyl rings substituted in the NHC ligand
are slightly disordered, but only for one of four rings this
disorder was so significant that it was possible to model it.
The overlay of four studied catalysts in a solid state visualizes
the increasing steric bulk caused by the augmented N- aryl
substituent (Figure 7). Importantly, the position of the second
(benzyl) “arm” of the uNHC stays in general constant, in
theory allowing for similarly unobstructed access to the
metallic center in each case. These results are in agreement
with computational data presented earlier, which suggest
similarly large barriers of rotation of the benzyl moiety for all
four studied systems (cf. Figure 4). As expected, the
computationally obtained geometries of complexes Ru7−
Ru10 are very similar to their crystal structures.
1
days at 40 °C. The H NMR spectra were recorded every
several days. The degree of degradation of the catalyst was
determined on the basis of the integration of benzylidene
signal coming from the complexes (peaks in the range of 16
17 ppm) and methoxy groups (6.15 ppm) coming from the
internal standard (Figure 8). Notably, the most stable complex
was Ru10 bearing the larger N-aryl substituent: after almost a
month in a solution warmed to 40 °C, only 1% of it was
decomposed! Just a tiny bit less stable were two other
complexes containing bulky aromatic substituents, namely,
Ru8 (with 2,6-diisopropylphenyl “wing”) and Ru9 (with 2,6-
diisopentylphenyl), that under the same conditions decom-
posed 2% each. Slightly less stable was complex Ru7
containing relatively the smallest substituent (mesityl),
however also in this case 95% of the initial complex survived.
For comparison, commercially available Ru2 under the same
conditions was visibly less stable, losing 25% of the initial
amount after only 15 days (Figure 8).
Comparative Stability Tests. Before the activity studies
of the uNHC Ru complexes were started, a set of standardized
decomposition tests were conducted to check whether the
introduced structural modifications improved the stability of
In addition, solid-state stability tests were performed. For
this purpose, catalysts samples were weighed into vials and left
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Figure 8. Degradation tests in CD2Cl2 solution at 40 °C under argon.
1
Monitored by H NMR spectroscopy with 1,3,5-trimetoxybenzene as
an internal standard. Lines are visual aids only.
open on a shelf on air at ambient temperature (22 °C). After 3
1
weeks of such “lousy storage” test, H NMR spectra were
recorded to show that all complexes containing uNHC ligands
(Ru7 to Ru10) were not changed, while Ru2 was partially
decomposed.
Olefin Metathesis Catalytic Activity Studies. High
stability, although welcome, is not enough to ensure a success
of a chemical catalyst. Therefore, the application profile of
complexes Ru7 to Ru10 in a diverse set of metathesis reactions
was explored and compared to that of Ru2. In the first stage of
this research the RCM reaction of the most commonly used
model substrate, diethyl 2,2-diallylmalonate (4),27 was
examined in the presence of 1 mol % of a catalyst. Initially,
the test reaction was performed at 50 °C (Figure 9a). As
expected, the least active catalyst was the one containing the
largest N-substituent in uNHC ligand (Ru10) as it reached
only about 50% conversion after 3 h. The complex bearing
second biggest substituent in this set (Ru9), gave almost twice
as good result reaching after the same time (>80% conversion).
All other catalysts, that is, Ru2, Ru7, and Ru8, reached full
conversion within less than an hour. These results are in
accordance with literature reports on other uNHC bearing 2-
isopropoxybenzylidene complexes that were usually charac-
terized as “thermally stable, latent”.28 To prove that the uNHC
complexes are thermoswitchable, the same model reaction was
repeated at higher temperature. Once the temperature was
raised up to 80 °C, all tested catalysts reacted much faster and
all of them achieved complete conversion within maximum 2 h,
what renders these complexes of practical usefulness. The
previously observed general trend of reactivity was preserved:
the slowest complex was Ru10, then Ru9, while compounds
containing less roomy mesityl and 2,6-diisopropylphenyl
substituents (Ru7 and Ru8, respectively) closed the five-
membered ring of 5 in less than 5 min (Figure 9b). In our
previous work18,20 we adopted the diastereoselctive ring
rearrangement metathesis reaction (DRRM) of cyclopentene
derivative 6 as a test for catalysts selectivity. This trans-
formation was previously studied in detail by Blechert et al.29
who concluded that the first generation of Ru catalysts (e.g.,
Ru12) produced an equimolar mixture of diastereoisomers,
while with the second generation complexes (Ru1 and Ru2)
the selectivity was slightly improved (up to trans:cis dr = 2:1).
Blechert demonstrated also that the highest selectivity in this
reaction (trans:cis dr = 9:1) may be obtained in the presence of
the Grubbs-type catalyst bearing unsymmetrical NHC ligand
based on tetrahydroquinoline moiety but at relatively low
Figure 9. Time/conversion curves for the RCM reaction of 4 with 1
mol % of Ru complexes at 50 (a) and 80 °C (b) (monitored by H
NMR). Lines are visual aids only.
1
conversion of 58%.29 Our previous studies on diastereose-
lective ring rearrangement metathesis of 6 showed that the
application of indenylidene complexes containing unsym-
metrical N-heterocyclic carbenes18−20 can increase the
selectivity of the reaction in comparison to standard second-
generation complexes (trans:cis dr ≈ 4:1 versus 2:1) at the
conversion exceeding 90−95%. Interestingly, similar result was
obtained in the present work with the 2-isopropoxybenzylidene
complex Ru7 bearing N-benzyl-N′-mesityl substituted uNHC,
which produced trans:cis isomers in dr 5:1 at full conversion
(Table 1, entry 2). The decrease of selectivity was
unfortunately observed in the case of more bulky uNHC
complexes Ru8 to Ru10 that reached only 1.4:1 to 1.2:1
a
Table 1. Results of DRRM Reaction of 6
entry
[Ru]
conversion [%]
trans:cis
1
2
3
4
5
6
Ru2
Ru7
Ru8
Ru9
Ru10
Ru3
99
>99
>99
>99
96
1.4:1
5.0:1
1.4:1
1.2:1
1.2:1
1.1:1
99
a
Monitored by 1H NMR spectroscopy and GC with durene as
internal standard. Conditions: 5 mol % of [Ru], CDCl3, c = 200 mM,
60 °C, 20 h.
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(trans:cis) while the conversion remained high (entries 3−5).
When Hoveyda−Grubbs catalyst with symmetrical bulky SIPr
NHC ligand (Ru3) was utilized, even lower selectivity was
observed (trans:cis 1.1:1, Table 1, entry 6). On the basis of
these results, one may conclude that while catalysts with small
(Ru2) and enlarged (Ru3) symmetrical NHC ligands fail in
providing good selectivity in DRRM, the catalyst bearing
unsymmetrical NHC containing relatively small N- aromatic
substituent, like Mes (Ru7) can led up to to 5:1
diastereoselectivity.
Table 2. Results of RCM and CM Comparative Study
Looking for potential application areas of the studied
catalysts, we decided to test them with a wider scope of
substrates, used in practical RCM and CM reactions (Table 2).
The comparison also included Ru2, one of the most popular
commercially available Ru-catalysts. First, the selected contest-
ants were tested in RCM reactions.
Diethyl 2-allyl-2-(but-3-en-1-yl)malonate (8) lead in 80−
90% isolated yield to cyclohexene derivative 9 in the presence
of all tested complexes. A slightly worse result was observed
when Ru10 was utilized; however, also in this case. the yield
reached almost 80%. All ruthenium compounds worked also
very well in the reaction of 2,2-diallyl-1H-indene-1,3(2H)-
dione (10) leading to spiro-compound 11 in over 95% yield.
So far, so normal. Somewhat different results, however, were
achieved in the RCM reaction of (S)-N,N-diallyl-1-tosylpyrro-
lidine-2-carboxamide (12), leading to 13an analogue of
promising prolyl endopeptidase inhibitor SUAM 1221.30
Indeed, when Ru2 were used in this transformation, some
amount of a byproduct with a migrated double bond (13′) was
formed as well. Importantly, uNHC-bearing catalysts Ru7 to
Ru10 promoted the same reaction in a fully selective fashion,
and no traces of byproduct 13′ were observed.
The unwanted formation of 13′ may be related to the
presence of small quantities of the ruthenium hydride or other
species, such as Ru dimeric complexes or even nanoparticles.
Such compoundsproducts of catalyst’s decompositionare
known to promote the migration of double bond.22,31−33 Since
Ru2 was the least stable catalyst in the series (see Figure 4), it
underwent degradation process the fastest; the other catalysts
were apparently stable enough, and the isomerization product
was not detected. Next, cross-metathesis reactions utilizing 1,4-
diacetoxybut-2-ene (15) were carried out (Table 2, entries 4−
6). With allyl benzene (14) as a cross-partner, it was found that
the bigger substituent on uNHC was, the higher amount of
(Z)-isomer was formed. Similarly, when the cross-partner was
a long-chain terminal olefin, 11-chloroundec-1-ene (17), the
most (Z)-selective catalysts was the most bulky Ru10.
However, in the case of allyl p-trifluorobenzene (19), a
relationship between the size of the N-substituent in the
uNHC ligand and the (Z)-selectivity was not preserved, as
relatively bulky Ru8 and Ru9 displayed (E)/(Z)-selectivity
level similar to that one exhibited by standard, SIMes-bearing
Ru2. We have no rationale for this observation, anyway, as in
previous examples (Table 2, entries 4 and 5) the highest
amount of (Z)-product was obtained for Ru10. (Table 2, entry
6). It shall be stressed that despite their latency, all tested
uNHC complexes delivered the expected products in high
isolated yield, similar or in some cases higher than the yield
obtained for faster initiating Ru2.
a
Isolated yield. Conditions: 1 mol % of [Ru], toluene, c = 100 mM,
b
c
80 °C, 20 h. Ratio 13:13’ = 87:5. 3 equiv of 15 were used. E:Z
ratios are given in parentheses.
important precursors to the specialty chemicals.34,35 Althought
CM of these substrates is know, it is considered as difficult.36
One of the challenges is the susceptibility of these substrates to
isomerization of the double bond during metathesis. For
example, a prior work aimed at the self-metathesis of estragole,
using Ru2 demonstrated that unintended isomerization of this
substrate can compete with metathesis.35,37 Being aware of this
hazard, we hoped that the studied catalysts can promote this
transformation more selectively. First, self-CM of 5-allyl-2-
hydroxy-3-methoxybenzaldehyde (21) was examined (Scheme
2). Indeed, in the presence of Ru2, the desired self-CM
product 22 was not observed, instead stilbene derivative 23
Encouraged by the above results, we decided to test catalysts
Ru7 to Ru10 in more demanding transformations. Function-
alized allylbenzenes (phenylpropenoids), such as estragole,
eugenol or safrole, readily available from essential oils, serve as
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a
a
Scheme 2. Selectivity in Self-CM of Eugenol Derivative 21
Scheme 3. Self-CM of Eugenol Derivatives 25a,b
a
Isolated yield.
a
b
Isolated yield. Inseparable mixture of 25, 26, 27 and other products
obtained.
(coming from self-CM reaction between two isomerized
substrate molecules) was isolated as a single (E)-isomer in
45% yield. On the contrary, when complexes Ru7 to Ru10
were utilized in the same reaction, the only observed product
was 22, obtained in 55−66% isolated yields (Scheme 2). In all
cases, (E)-isomer was obtained predominantly, and the highest
(E/Z)-selectivity was observed for Ru8 and Ru9, while Ru10
was less selective. Additional experiments were conducted
under milder conditions (40 °C; 0.5 mol % of catalyst) in a
hope to make this reaction more selective also with
nonspecialized catalysts, such as Ru2. While Ru8 under
these conditions still produced cleanly the expected product in
69% of isolated yield, the inseparable mixture of 22, stilbene 23
and other isomerization products (e.g., coming from the cross-
metathesis reaction between substrate and the isomerized
substrate molecules) were obtained for Ru2.
cases.38 Therefore, we decided to reinvestigate the subject
with a more selective catalyst. The study was started from
modification of simple 1-(oct-7-en-1-yl)-1H-indole with 3
equiv of 1,4-diacetoxybut-2-ene (15) or ethyl acrylate (28) as
CM partners, to deliver products 29 and 30 in high isolated
yields (Chart 1). Next targets were compounds 31 and 32
analogues of the designer drug 5F-PB-22.39 Despite the
a
Chart 1. CM Reaction of Indole Derivatives
In order to reveal whether such excellent selectivity of tested
uNHC catalysts is limited to this particular compound or the
trend is more general, a couple of additional eugenol
derivatives, namely acetylated (24a) and methylated eugenol
(24b) were tested (Scheme 3). In this examination, only Ru8
was used (and compared with Ru2). Despite that mild
conditions were used (40 °C; [Ru] 0.5 mol %), in the general-
purpose Ru2 catalyzed self-CM of 24a an inseparable mixture
of the desired product 25a, its isomer having shifted C−C
double bond 26a as well as shorter analogue 27a (coming from
CM reaction between 24a and isomerized 26a) and traces of
the corresponding stilbene were formed. The same compli-
cated mixture was observed in the case of 24b. In contrast,
when Ru8 was used as catalyst, the same reaction was fully
selective, leading to expected self-CM dimers in high isolated
yield (85 and 96% respectively), without formation of
isomerized or shortened products (Scheme 3).
Having successfully demonstrated good properties of the
new complexes in model RCM and CM reactions, we decided
to apply the methodology to other compounds with potential
biological activity. To do so, we attempted the CM reactions of
selected indole derivatives in the presence of Ru8, the catalyst
which exhibited so for the best balance between high activity
and selectivity with eugenol derivatives. Previously, we found
that modification of psychoactive indole derivatives that are
characterized by a presence of longer fatty chain substituents is
not always selective, leading to decrease of yields in some
a
Conditions: 1 mol % Ru8, 3 equiv of 15 or 28, toluene, c = 0.1 M, 80
°C, 8 h. Isolated yields.
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Figure 10. Self-metathesis of 1-octane (37). (a) Reaction scheme. PMP = primary metathesis product, IP = isomerization product, SMP =
secondary metathesis product; (b) GC traces after reaction with Ru10 vs Ru2. IS = internal standard (tetradecane); (c) Composition of the
reaction mixtures over time recorded for catalysts Ru2 and Ru7 to Ru10. Lines are visual aids only.
planned modification required the CM reaction at the eugenol
fragment, we were able to obtain more than satisfactory
(>90%) isolated yield of both indole products 31 and 32.
Another analogue sharing a similar structural motif, a derivative
of indole-based full agonist to CB1 and CB2 receptors named
NM-2201,40 was modified in CM with similar efficiency
leading to 33 and 34. Finally, 35 and 36two analogues of
well-known UR-144, a drug invented by Abbott Laboratories,
that acts as a selective full agonist of the peripheral
cannabinoid receptor with general weak cannabinoid-like
activity,41 were obtained. It shall be noted that in all cases
presented in Chart 1, the CM reactions catalyzed by Ru8 were
very clean, and the expected products were formed exclusively
and in good isolated yields.
Next, we explored the industrially relevant self-metathesis
reaction of α-olefins.42 These substrates are known to be prone
to migration of double bond along the carbon chain, especially
when the second generation complexes are used (Figure
10a).22 This usually undesired side process is invoked by the
products of decomposition of the catalysts, mainly ruthenium
hydrides,43 dimers,32 and nanoparticles.33 The most common
answer to this issue is the application of various additives, just
to mention: metallic mercury,33 quinones,44 chlorocatechol-
borane,45 and phenylphosphoric acid;46 however, none of
them is universal in each case. Recent developments in this
field have shown that the application of appropriate Ru
catalysts bearing either unsymmetrical NHC ligands21a,47,48 or
quinone fragment present in the catalyst structure49 can
significantly reduce the double bond migration during the
metathesis reaction, providing selectivity levels >90%.21a The
suppressed isomerization of double bond may be related to the
increased stability of the used complexes under the reaction
conditions, and thus their lower susceptibility to the
degradation to undesired ruthenium compounds. Encouraged
by the results obtained until now, we decided to check how the
newly obtained complexes would act in the self-CM reaction of
1-octene (37). All tests were carried out in the presence of 500
ppm of catalyst at 80 °C and without any solvent (in neat).
The reaction mixture composition was monitored by gas
chromatography (GC) during the reaction. The GC traces and
product composition charts presented in Figure 10b,c show
that the reaction outcome for standard Hoveyda−Grubbs
second-generation catalyst and the new catalysts containing
bulky uNHC ligands differ significantly. As expected, Ru2 was
the most active, as just after 5 min the full conversion of 1-
octene was reached; however, unfortunately, the selectivity was
very low. Practically from the very first minutes of the reaction,
the desired product 38 and the by-products (SMP:
homologues with shorter and longer carbon chain, and
possibly other products) were formed almost simultaneously.
The main product of the reaction (ca. 80%) was the unwanted
SMP, while the maximum content of expected 38 was only
20% (Figure 10b,c). The reactions catalyzed by complexes
containing enlarged substituent in the NHC ligand were
slightly slower compared to Ru2, but up to 120 min was
enough to obtain high conversion. On the other hand, all the
catalysts bearing uNHC ligand showed better selectivity than
Ru2. When Ru7 or Ru8containing the smallest N-aryl
substituents in the tested serieswere utilized in self-
metathesis of 1-octene, the maximum amount of the desired
(E)- and (Z)-isomers of the product 38 (77%) was obtained
after 20 and 30 min, respectively. However, in both cases the
side processes progressed too, unfortunately, which resulted in
a decrease of selectivity over time (Figure 10c). In contrast,
with Ru9 and Ru10 the reaction proceeded slower, but with
much higher selectivity, and in the best case of Ru10 product
38 was formed almost exclusively (Figure 10b,c). Therefore,
the use of catalysts containing unsymmetrical NHC ligand
seems to be preferential in the case of self-CM of α-olefins,
allowing to reach high selectivity without need of using
problematic additives.50
Fats and oils are very important renewable resources which
have many applications in industrial chemistry. Among the
many various metathesis-type reactions51,52 of oils and fats,
ethenolysis,53,54 has become a very promising transformation
which leads to terminal alkenes and unsaturated esters used in
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industry. Of the most commonly applied substrates are oleic
acid esters that, after ethenolysis and saponification lead to
dec-9-enoic acid (9-DA),55 used for example in production of
macrocyclic musks.56,57 However, due to known instability of
general purpose catalysts in ethylene, this process is not easy to
be implemented and industrial scale, so the existing plants
utilize 1-butene instead of ethylene.58
In order to reveal how the new uNHC catalysts might
perform in ethenolysis, first we investigated the stability of Ru7
to Ru10 in the atmosphere of ethylene. The complexes were
compared not only with Ru2, but also with CAAC Bertrand−
Grubbs catalyst (Ru13, Figure 11) because the latter exhibits
Figure 11. Degradation of catalysts Ru2 and Ru7 to Ru10 and Ru13
1
in CD2Cl2 at 40 °C under ethylene atmosphere. Monitored by H
NMR spectroscopy with 1,3,5-trimetoxybenzene as an internal
standard. Lines are visual aids only.
Figure 12. (a) Ethenolysis of 39. (b) Selectivity-temperature
dependence of various catalysts in ethenolysis of 39. Selectivity =
100 × (moles of 40 + moles of 41)/[(moles of 40 + moles of 41) + 2
× (moles of 42 + moles of 43)]. Lines are visual aids only.
one of the highest efficiency in ethenolysis noted so far.59 To
do so, the respective catalyst and 1,3,5-trimethoxybenzene
(internal standard) were dissolved in CD2Cl2 in glovebox in a
Young NMR tube. The tube was removed from the glovebox,
placed in an autoclave, and pressurized with ethylene.
Degradation of catalysts was conducted at 40 °C and
monitored by 1H NMR by comparing the integration of
benzylidene signal coming from the catalyst and methoxy
protons from the internal standard (formation of methylidene
[Ru]CH2 signals were not observed. For the detailed
procedure, see SI). Under these conditions, three complexes
bearing the biggest unsymmetrical NHC ligands (Ru8, Ru9,
and Ru10), and CAAC-type Ru13 were characterized by
practically the same high stability under an ethylene
atmosphere, as after 12 h at the elevated temperature, more
than 90% of each Ru-complex remained unchanged (Figure
11). As expected, Hoveyda−Grubbs second-generation catalyst
was much less stable under these conditions and after 10 h
only 30% of it remained unchanged. Notably, stability of Ru7
(bearing the smallest uNHC ligand) was much lower than
other tested uNHC complexes (after 6 h around half of Ru7
decomposed), but still higher than Ru2 (Figure 11).
In a model ethenolysis reaction complexes Ru8 to Ru10
were used (Ru7 was excluded due to its low stability toward
ethylene, vide supra), and the results were compared with
those obtained in the presence of state-of-the art Bertrand−
Grubbs catalyst Ru13. The challenge in the ethenolysis of ethyl
oleate (39) is formation of by-products (diethyl octadec-9-
enedioate, 42 and octadec-9-ene, 43), being “homodimers”
obtained in the unwelcome self-CM process that decrease the
yield of expected products: ethyl dec-9-enoate, 40 dec-1-ene,
41 (Figure 12). The ratio between ethenolysis and self-CM
products is usually defined as “reaction selectivity”.47,60 It is
known that the nature of catalyst and conditions of the
reaction have a great influence on the ratio of ethenolysis to
self-CM.61 In our tests, we decided to vary the temperature of
the reaction, in order to map the catalysts thermal stability
limits under real process conditions. To do so, ethenolysis
reactions were carried out in the presence of 50 ppm of
catalyst, under 20 bar of ethylene at temperature 50−70 °C. All
tested uNHC complexes exhibited similarly high selectivity in
this reaction (97−98%) regardless of temperature; however,
they were less active then CAAC complex Ru13. Interestingly,
selectivity exhibited by Ru13 decreased with temperature to
reach 87% at 70 °C (Figure 12). Under these conditions, Ru8
to Ru10 bearing unsymmetrical NHCs were still able to
promote ethenolysis highly selectively, allowing to convert 67−
45% of ethyl oleate (39) to expected products. Although the
very recently developed Apeiron’s bis(CAAC) indenylidene
complexes were reported to work even better in this reaction,62
the observed high thermal stability of the tested uNHC
complexes is of interest.
CONCLUSIONS
■
A series of ruthenium catalysts containing in the unsym-
metrical NHC ligand the N-aryl substituents of gradually
increasing bulk (Ru7 to Ru10) were studied computationally,
synthesized, and fully characterized. DFT calculations and X-
ray crystallographic data were used to understand the influence
of uNHC ligand structure on the catalyst properties.
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Depending of the size of the N-substituent, these complexes
are optimal to different applications. For example, while the
Mes-substituted Ru7 was giving best selectivity in the DRRM
reaction, it displayed the lowest stability in the presence of
ethylene. In contrast, Ru9 and Ru10 bearing much bulkier N-
aromatic wings were preferred for self-CM of α-olefins, where
they exhibited higher selectivity and thermal stability than their
smaller uNHC siblings as well as the commercial general
purpose catalyst Ru2. Similarly, the three most bulky uNHC
complexes were found to be perfectly stable in the presence of
ethylene and showed excellent selectivity in the ethenolysis of
ethyl oleate, even at increased temperature. The improved
selectivity of uNHC catalysts allows for metathesis reactions of
various functionalized substrates that sometimes are problem-
atic for the general purpose Ru catalysts. For example, when
self-metathesis reactions of eugenol derivatives were carried
out in the presence of the studied uNHC complexes, the
desired products were exclusively obtained, while the same
substrates with general SIMes-bearing catalyst led to non-
selective reactions and formation of products with shifted C−C
double bonds.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b04783.
Experimental, X-ray crystallographic and computational
methods and data (PDF)
3D rotatable images of all geometry-optimized structures
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: karol.grela@gmail.com.
*E-mail: anna.kajetanowicz@gmail.com.
ORCID
Roman Gajda: 0000-0002-9742-2941
́
Krzysztof Wozniak: 0000-0002-0277-294X
Karol Grela: 0000-0001-9193-3305
Notes
The authors declare no competing financial interest.
Crystallographic data (excluding structural factors) for the
structures reported in this paper has been deposited with the
Cambridge Crystallographic Data Centre and allocated the
deposition numbers: CCDC 1556136 (Ru9) and CCDC
1556135 (Ru10). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EW, UK (Fax: (+44)-1223-336-033; E-mail: deposit@
ccdc.cam.ac.uk.
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ACKNOWLEDGMENTS
■
Authors are grateful to the National Science Centre (Poland)
for the NCN MAESTRO Grant No. DEC-2012/04/A/ST5/
00594. The study was carried out at the Biological and
Chemical Research Centre, University of Warsaw, established
within the project cofinanced by European Union from the
European Regional Development Fund under the Operational
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