Ruthenium olefin metathesis catalysts featuring unsymmetrical N-heterocyclic carbenes

Article abstract of DOI:10.1039/c5dt03758a

New ruthenium Grubbs' and Hoveyda-Grubbs' second generation catalysts bearing N-alkyl/N-isopropylphenyl N-heterocyclic carbene (NHC) ligands with syn or anti backbone configuration were obtained and compared in model olefin metathesis reactions. Different catalytic efficiencies were observed depending on the size of the N-alkyl group (methyl or cyclohexyl) and on the backbone configuration. The presence of an N-cyclohexyl substituent determined the most significant reactivity differences between catalysts with syn or anti phenyl groups on the backbone. In particular, anti catalysts proved highly efficient, especially in the ring-closing metathesis (RCM) of encumbered diolefins, while syn catalysts showed low efficiency in the RCM of less hindered diolefins. This peculiar behavior, rationalized through DFT studies, was found to be related to the high propensity of these catalysts to give nonproductive metathesis events. Enantiopure anti catalysts were also tested in asymmetric metathesis reactions, where moderate enantioselectivities were observed. The steric and electronic properties of unsymmetrical NHCs with the N-cyclohexyl group were then evaluated using the corresponding rhodium complexes. While steric factors proved unimportant for both syn and anti NHCs, a major electron-donating character was found for the unsymmetrical NHC with anti phenyl substituents on the backbone.

Full text of DOI:10.1039/c5dt03758a

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Ruthenium olefin metathesis catalysts featuring
unsymmetrical N-heterocyclic carbenes†
Cite this: DOI: 10.1039/c5dt03758a
a
b
a
a
Veronica Paradiso, Valerio Bertolasi, Chiara Costabile and Fabia Grisi*
New ruthenium Grubbs’ and Hoveyda–Grubbs’ second generation catalysts bearing N-alkyl/N-isopropyl-
phenyl N-heterocyclic carbene (NHC) ligands with syn or anti backbone configuration were obtained and
compared in model olefin metathesis reactions. Different catalytic efficiencies were observed depending
on the size of the N-alkyl group (methyl or cyclohexyl) and on the backbone configuration. The presence
of an N-cyclohexyl substituent determined the most significant reactivity differences between catalysts
with syn or anti phenyl groups on the backbone. In particular, anti catalysts proved highly efficient,
especially in the ring-closing metathesis (RCM) of encumbered diolefins, while syn catalysts showed low
efficiency in the RCM of less hindered diolefins. This peculiar behavior, rationalized through DFT studies,
was found to be related to the high propensity of these catalysts to give nonproductive metathesis events.
Enantiopure anti catalysts were also tested in asymmetric metathesis reactions, where moderate enantio-
selectivities were observed. The steric and electronic properties of unsymmetrical NHCs with the
N-cyclohexyl group were then evaluated using the corresponding rhodium complexes. While steric
factors proved unimportant for both syn and anti NHCs, a major electron-donating character was found
for the unsymmetrical NHC with anti phenyl substituents on the backbone.
Received 25th September 2015,
Accepted 6th November 2015
DOI: 10.1039/c5dt03758a
www.rsc.org/dalton
ized ruthenium complexes (second generation catalysts) has
given a strong impetus to the development of this methodology,
Introduction
1
Since their introduction in the 1960s, N-heterocyclic carbenes which nowadays represents an indispensable synthetic tool for
4
(
NHCs) have gained increasing importance in modern chem- both organic and polymer chemists. Indeed, the use of NHCs
istry, with several applications in a large variety of research as ligands for ruthenium olefin metathesis has given access to
areas. Their steric and electronic properties make them excel- unprecedented reactivity pathways and has allowed significant
5–7
lent ancillary ligands for metal catalysts as well as effective advancements in a multitude of challenging reactions.
organocatalysts. The majority of applications of NHCs, Most of the efforts in designing new ruthenium catalysts
however, are related to their coordination to transition metals, involve manipulation of the NHC scaffold of commercial avail-
8
due to which efficient catalysts for a huge number of academi- able second generation catalysts. Indeed, the fine-tuning of
cally and industrially important processes have been found. steric and electronic properties of the NHC ligand can strongly
Indeed, the strong σ-donor capability of NHCs, combined with influence the catalytic behavior of the resulting ruthenium
a shielding steric pattern, leads to increased metal complex complexes. The development of unsymmetrical NHCs
2
stability and improved catalytic activity.
(uNHCs), able to differentiate steric bulkiness in the proximity
One of the most important and extensively studied trans- of the carbenic center, has led to important effects on the reac-
9
formations mediated by NHC–metal complexes is ruthenium- tivity and selectivity of the resulting catalysts. Among the
3
catalyzed olefin metathesis. The employment of NHC-stabil- numerous examples of ruthenium catalysts presenting uNHCs,
those characterized by N-alkyl/N-aryl substituents have attracted
1
0
much attention (Chart 1). A major breakthrough in this field
is represented by the introduction of a series of highly Z-selec-
tive ruthenium catalysts, incorporating a bidentate unsymmetri-
a
Dipartimento di Chimica e Biologia “Adolfo Zambelli”, Università di Salerno, Via
Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy. E-mail: fgrisi@unisa.it
b
Dipartimento di Chimica and Centro di Strutturistica Diffrattometrica, Università di
1
1
cal NHC ligand, by the Grubbs group (4, Chart 1).
Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
†
1
2
Electronic supplementary information (ESI) available: Experimental pro-
In this context, we recently reported on new olefin meta-
thesis catalysts bearing uNHCs, that combine N-cyclohexyl,
N-isopropylphenyl groups and phenyl substituents on the NHC
backbone with syn and anti relative orientation (7–10, Chart 2),
thus investigating for the first time the impact of changing the
cedures, figures giving NMR spectra of the new complexes, GC and HPLC chro-
matograms of 31, 32 and 36, tables and CIF files giving experimental details of
complexes 39 and 40, and Cartesian coordinates for the optimized structures.
CCDC 1414525 and 1414526. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5dt03758a
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Results and discussion
Synthesis and characterization of catalysts
The synthesis of complexes 7–10 was easily accomplished in
three synthetic steps, as described in our preliminary com-
1
2
munication. The Grubbs’ (7–8) and Hoveyda–Grubbs’ (9–10)
second generation type complexes were obtained in moderate
to good yields (45–64%). All the complexes were found to be
6 6
stable in the solid state for 5–6 months and in C D solution
1
4
over two weeks. Solution-state 1D and 2D NMR analyses of
the phosphine-containing complexes 7 and 8 showed the pres-
ence of two rotational isomers, syn and anti, corresponding to
different orientations of the benzylidene unit with respect to
the N-substituents of the uNHC ligand (syn: N-alkyl group
1
5
located on the same side as the benzylidene unit). These
rotamers did not display chemical exchange on the NMR time-
scale up to 70 °C, as proven by VT H NMR experiments.
Chart 1 Selected catalysts with N-alkyl/N-aryl substituted NHCs.
1
Attempts to obtain good-quality crystals of 7 and 8 for X-ray
crystallographic studies were unsuccessful.
As for phosphine-free complexes 9 and 10, the formation of
rotamers with only anti arrangement of the benzylidene
moiety was observed in solution as well as in the solid state.
The corresponding X-ray crystal structures were reported
1
2
previously.
Complexes 11–14 were synthesized according to the syn-
1
6a,b
thetic route reported by Collins
in very modest yields
(
12–22%). Attempts to improve yield by changing the reaction
conditions (e.g. the nature of base, solvent and temperature)
proved unfruitful. The replacement of a large-sized cyclohexyl
group with a sterically unencumbered methyl group led to
Chart 2 New N-alkyl/N-aryl NHC Ru catalysts.
17
diminished stability of 11–14 with respect to 7–10, as proven
1
by the disappearance from the H NMR spectrum of the diag-
nostic benzylidene signal in the course of 1 week. The solu-
tion-state studies carried out using 1D and 2D NMR
backbone configuration of uNHCs on catalytic behavior. As techniques showed the presence of two rotational isomers for
observed for Ru complexes bearing syn and anti backbone-sub- both 11 and 12. As already observed for complexes 7 and 8, the
8
h,13
stituted symmetrical NHCs,
the introduction of differently two rotamers are compatible with syn and anti disposal of the
oriented substituents on the backbone of uNHCs proved an benzylidene moiety with respect to the N-substituents of the
effective means of modulating the catalytic properties of the uNHC. Complex 11 was isolated in a 0.4 : 1 syn : anti ratio,
resulting complexes.
To offer a more complete picture of the relationship isomers. 2D-EXSY experiments at various mixing times showed
while complex 12 was isolated in a ratio of 0.5 : 1 syn : anti
1
8
between the NHC architecture and catalyst activity, herein we no exchange between syn and anti rotamers. Complexes 13
present an extended study on the catalytic behavior of 7–10 in and 14 were obtained as a single isomer, corresponding to the
1
2
the most common metathesis transformations. The catalytic anti rotamer, analogous to what was observed for 9 and 10.
performances of 7–10 are compared to those of newly syn- Unfortunately, owing to their high solubility in most common
thesized catalysts 11–14 (Chart 2), characterized by an N-alkyl polar and non-polar solvents, it was not possible to obtain
group of reduced steric hindrance with respect to the N-cyclo- crystals suitable for X-ray solid-state characterization.
hexyl, as the N-methyl group.
Ring-closing metathesis (RCM) activity
Furthermore, we report on the selectivity of enantiopure Ru
catalysts 8, 10, 12 and 14 in asymmetric metathesis transform- The catalytic ability of 7–14 was investigated in the RCM reac-
ations, such as asymmetric ring-closing metathesis (ARCM) tions of diethyl diallylmalonate (15) and diallyltosylamine (16).
and asymmetric ring-opening cross-metathesis (AROCM).
Finally, in order to gain more insight into the role of NHC 8, 11 and 12) were performed at 30 °C in CD Cl , while the
The RCM reactions promoted by Grubbs’ II type complexes (7,
2
2
backbone configuration in catalytic behavior, the steric and same ring-closures in the presence of Hoveyda–Grubbs’ II type
electronic properties of uNHCs featuring catalysts 7–10 are complexes (9, 10, 13 and 14) were carried out at 60 °C in C D .
6
6
evaluated using the corresponding rhodium complexes.
Indeed, the latter family of ruthenium catalysts generally
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shows slow initiation rates under the catalytic conditions profiles of the RCM of 15 and 16 promoted by GIItol, which
employed for the corresponding family of monophosphine indeed shows a trend opposite to that of 7–11.
complexes; therefore we selected reaction conditions more
suitable to promote their activation.
As for phosphine-free complexes, reactivity differences in
the RCM of 15 among 10, 13, 14 and HGIItol appeared to even
1
3b
The conversion of each substrate to products was moni- out, very likely as a consequence of the higher temperature
1
tored by H NMR spectroscopy. To put the results in a larger (Fig. 1C). Full conversions were reached in a range of 3–5 min,
context, we carried out parallel reactions with the symmetrical with anti catalysts 10 and 14 performing slightly better than
1
9
20
commercial catalysts GII-tol and HGII-tol, possessing less syn catalyst 13 with an N-methyl group, and rivaling the bench-
hindered N-aryl groups, as the catalysts 7–14. mark catalyst HGIItol. A much lower efficiency was shown by
The kinetic profiles of all these experiments are depicted in syn catalyst 9, bearing an N-cyclohexyl group, that produced
Fig. 1. Further details are reported in the ESI (Table S1†).
Interestingly, a different catalytic behavior among ruthe-
the cycloolefin 17 in full conversion within 20 min.
When the RCM of the N-tosylamine 16 was investigated, the
nium complexes with different NHC backbone configurations same reactivity trend as that observed in the previous RCM
was observed. The phosphine-containing catalysts 8 and 12 was registered (Fig. 1D). Catalysts 10, 13 and 14 were able to
with an anti disposal of the phenyl groups on the backbone complete cyclization in a range of 2–4 min, displaying a cata-
showed very similar activities in both the RCM, overcoming sig- lytic behavior comparable to that of HGIItol at a ten times
22
nificantly catalysts 7 and 11 with a syn-substituted backbone, lower catalyst loading (0.1 mol%). Also in this case, 9 proved
and displaying faster initial reaction rates than the benchmark to be the less efficient catalyst, not completing the RCM of 16
catalyst GIItol. In the RCM of tosylamine derivative 16 (Fig. 1B), within 60 min. As already observed for the monophosphine
8
and 12, despite their higher initial reaction rates, showed a complexes possessing equal NHC backbone configurations,
slightly inferior efficiency with respect to GIItol. the effect of the different bulkiness of the N-alkyl group is
Moreover, while for anti catalysts the size of the N-alkyl noticeable only for syn substituted catalysts.
group (methyl or cyclohexyl) seems not to play a substantial
The comparison on the catalytic behavior of catalysts 7–14
role in the examined ring-closures, for syn catalysts it assumes was then extended to the RCM of more hindered dienes 19
appreciable relevance (Fig. 1A and B). In fact, catalyst 11 and 20. The results for these reactions and for those promoted
bearing a smaller N-alkyl group performed much better than 7 by GIItol and HGIItol are depicted in Fig. 2 and summarized
possessing a more encumbered N-cyclohexyl group.
in Table S2 (ESI).† Again, phosphine-containing anti catalysts
Quite surprisingly, as a general trend shown by 7, 8, 11 and 8 and 12 gave better performances than their syn congeners
2, and more markedly for syn catalysts, the RCM reactions of (Fig. 2A and B), with anti 8, characterized by a bulkier N-cyclo-
1
malonate derivative 15 proved to be easier than those involving hexyl group, displaying the highest activity. Moreover, they
tosyl derivative 16. This finding is uncommon, since N-tosyl were found to be more efficient than GIItol in both transform-
derivatives are generally ring-closed with less difficulty with ations. As previously observed, the hindrance of the N-alkyl
2
1
respect to malonate derivatives.
Clear evidence of this substituent strongly influences the reactivity of syn catalysts;
anomaly can be immediately caught by observing the kinetic however, in the latter case, the catalytic performances of com-
plexes 7 and 11 were inverted, and the presence of the more
Fig. 1 RCM conversion of 15 (A, C) and 16 (B, D).
Fig. 2 RCM conversion of 19 (A, C) and 20 (B, D).
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encumbered N-alkyl group (N-Cy) resulted in better catalytic tered with the phosphine-containing anti catalyst 12,
activity. A careful analysis of the slope of the corresponding possessing the less bulky N-methyl group, which slightly sur-
curves in Fig. 2A and B strongly suggests a higher decompo- passed syn 7 with the N-cyclohexyl group, while the worst RCM
sition rate of 11 with respect to 7, very likely reflecting the performance was given by syn catalyst 11. A very similar cata-
different stabilities associated with each of them. It is worth to lytic behavior was noticed in the RCM of tosyl derivative 24
note that the reactivities of 7–12 towards malonate derivative (Fig. 3B), where anti 8, once again, turned out to be the most
1
9 were slightly lower than those towards tosyl derivative 20, active after GIItol. Differences among 7, 11 and 12 are instead
different from what was observed for the RCM of the less steri- nearly undetectable.
cally encumbered diolefins 15 and 16.
As depicted in Fig. 3C, the phosphine-free catalyst 10, suc-
The kinetic plots of the RCM of 19 and 20 promoted by cessfully accomplished the ring-closing of 23, equaling the per-
phosphine-free catalysts 9, 10, 13, and 14 (Fig. 2C and D, formance of the commercial benchmark HGIItol, which is one
respectively) showed a general reactivity trend in line with of the most efficient catalysts in RCM reactions of encumbered
6b
those previously observed for the RCM reactions carried out substrates, and significantly outperformed 9, 13 and 14. In
with this family of complexes. Very little marked differences in the RCM of 24 (Fig. 3D), 10 behaves as in the previous RCM,
the catalytic behavior were registered, and were slightly better but exhibiting inferior catalytic performance with respect to
appreciated in the ring-closure of 20 (see Table S2, ESI†). It HGIItol at a five times lower catalyst loading. Catalysts 9, 13 and
should be noted that between syn catalysts 9 and 13, syn 9 with 14 each gave the same value of conversion, displaying a slightly
the more encumbered N-substituent proved to be the less better efficiency than in the RCM of malonate derivative 23.
efficient catalyst in both the RCM reactions. This is in contrast
The above results suggest that catalysts with an anti dispo-
with the results obtained in the presence of the corresponding sal of the phenyl groups on the NHC backbone are more active
monophosphine catalysts, where the syn catalyst with the than their syn analogues, and that the size of the N-alkyl
N-methyl group showed a lower efficiency than the syn catalyst groups (methyl or cyclohexyl) plays an important role in deter-
with the N-cyclohexyl group. Very likely, the increased stability, mining catalytic behavior. Indeed, anti catalysts benefit from
typical of phosphine-free catalysts, strongly influences the cata- the steric hindrance offered by the N-cyclohexyl group in exhi-
lytic performance.
biting superior catalytic performances in almost all cases,
We also investigated the catalytic properties of 7–14 in the especially in the RCM of 23 and 24 leading to tetrasubstituted
challenging RCM of sterically encumbered dienes 23 and 24 olefins. On the contrary, the bulky N-cyclohexyl seems to be
and the results are reported in Table S3 in the ESI.† From the responsible for the mediocre RCM performances of syn cata-
corresponding kinetic data, depicted in Fig. 3, a striking reac- lysts, which disclosed an unexpectedly low activity in easier
tivity difference among anti catalysts 8 and 10, with the bulkier RCM reactions. To rationalize the peculiar behavior of syn cata-
N-cyclohexyl group, and all the other ones emerged. In the lysts toward the less hindered olefins as 15, we examined the
RCM of 23 (Fig. 3A), anti 8 was found to be inferior only to the possibility that RCM nonproductive events could play an
2
3
benchmark catalyst GIItol, which is actually particularly com- important role in influencing the outcome of the reaction.
petent in difficult RCM reactions. A lower conversion was regis- Therefore, to probe this hypothesis, molecular modeling
studies were carried out (see the ESI† for computational
details).
The free-energy profile for the RCM of a model of 15 (in
which the –COOEt group has been replaced by a –CH ) with
3
catalyst 7 was compared to a nonproductive event energy
profile. As depicted in Fig. 4, the rate determining transition
state for the RCM was found to be the first cross metathesis
between the substrate and the alkylidene species (P2 in Fig. 5),
1
3b,24
as already reported for analogous catalytic systems.
More
in detail, the minimum energy profile involves species charac-
terized by alkylidene oriented under the aryl moiety, while
higher energy transition states were located when the alkyli-
≠
dene is under the cyclohexyl group. ΔG of P2 was calculated
to be 15.2 kcal mol− in CH
1
Cl
, being significantly higher
2
2
than barriers found for 15 for analogous systems symmetri-
1
3b
cally substituted on nitrogen atoms.
On the contrary, the transition state for nonproductive
events (NP2 in Fig. 5) presents lower free energy, being favored
−
1
by 1.1 kcal mol (in CH Cl ) with respect to P2, with an absol-
2
2
ute barrier of 14.1 kcal mol− . Based on DFT calculation
results, the extraordinary low activity of catalyst 7 in the RCM
of the less hindered substrates seems to be dependent on the
1
Fig. 3 RCM conversion of 23 (A, C) and 24 (B, D).
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2 2
Fig. 4 Free energy profile in CH Cl solution of the RCM of a model of 15 promoted by catalyst 7, compared to the nonproductive event energy
profile.
Fig. 6 ROMP conversion of 27.
Fig. 5 Structures of the rate determining step transition state of RCM
of 15 (P2) and of the nonproductive event transition state (NP2).
high frequency of nonproductive events that appear to be
favored with respect to productive catalytic cycle. This hypo-
thesis is also corroborated by previous experimental studies that Entry
Table 1 ROMP of 27
a
b
Catalyst
Time (min)
Poly(35) yield (%)
E : Z
showed the increase of nonproductive events in the presence of
unsymmetrical NHCs with respect to symmetrical ones.
c
2
3
1
2
3
4
5
6
7
8
9
7
8
11
12
GIItol
9
10
13
14
30
20
14
9
4
12
5
8
4
2
98
>99
99
>99
>99
>99
>99
>99
>99
>99
1.0
1.0
0.8
0.5
1.3
2.0
2.5
0.9
2.0
3.8
c
c
c
Ring-opening metathesis polymerization (ROMP) activity
c
d
d
d
d
To further assess the reactivity of 7–14, we turned our attention
to the ROMP of 1,5-cyclooctadiene (27). This reaction was
1
monitored by H NMR (Fig. 6), and the results are summarized
d
in Table 1. All the catalysts were found to be efficient, with 10
HGIItol
the anti isomers again outperforming the corresponding syn
isomers. In particular, monophosphine catalysts 8 and 12,
with anti phenyl groups on the NHC backbone, quantitatively 0.1 mol%. Reactions in C
a
1
b
1
13
Determined by H NMR. E : Z ratios were determined by H and
C
c
NMR of isolated products. Reactions in CH
2
Cl
2
, at 30 °C, catalyst
d
6
D
6
, at 60 °C, catalyst 0.1 mol%.
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furnished poly(27) in 20 and 9 minutes, respectively, display- E/Z selectivity (entries 3 and 7, Table 2), resembling those of
2
5
ing activities lower than that of the reference catalyst GIItol classical symmetrical second generation catalysts.
Fig. 6A; entry 5, Table 1). Instead analogous syn isomers 7 and It is worth noting that yields in the desired cross-coupling
1 required 30 and 14 min, respectively, to successfully accom- product 30 are always higher for syn catalysts with respect to
(
1
plish the polymerization. Furthermore, the smaller the N-alkyl the anti analogues, although conversions of 28 are almost
group, the higher is the catalytic activity (entries 1–4, Table 1). quantitative (>90%). This suggests a major tendency of anti
Very likely, the presence of a less bulky methyl group facilitates catalysts to give the homocoupling product of 28 (1,4-diphenyl-
the approach of 27 to the ruthenium centre.
2-butene) rather than 30.
The same reactivity trend was observed with phosphine-free
The above results point out that the uNHC backbone con-
catalysts 9–14 (Fig. 6B), even if reactivity differences appeared figuration could cause profound alteration of the shape of the
to be leveled out. All the catalysts exhibited lower efficiency reactive pocket around the metal, thus addressing not only
than the benchmark catalyst HGIItol (entries 6–10, Table 1). As activity but also selectivity of the corresponding Ru complexes.
for E : Z selectivity, catalysts 7–14 disclosed E : Z ratios inferior Moreover, since marked differences in selectivity between anti
to those of GIItol and HGIItol, and a certain degree of Z and syn catalysts were registered only in the presence of the
selectivity could be appreciated in the ROMP reactions carried more encumbered N-cyclohexyl group, a combined effect of
out with catalysts bearing the less encumbered N-methyl group backbone configuration and bulkiness of N-substituents is
(
entries 3, 4, 8 and 9, Table 1). It is reasonable to suppose that unquestionable.
the high level of dissymmetry, created by substituents on the It is important to underline that we are unable to evaluate
nitrogen atoms with such a different steric hindrance, may the effect that each rotational isomer (syn and anti) of com-
1
0b,d
influence the selectivity of key metathesis intermediates.
plexes 7–12 exerts on catalyst properties due to the fact that
the syn : anti isomers cannot be separated. However, the strong
similitude of behavior between monophosphine and phos-
phine-free catalysts (obtained as anti rotational isomers only)
in both RCM and CM reactions strongly suggests the primary
role of the backbone configuration in influencing catalyst be-
havior with respect to the existence of rotamers.
Cross-metathesis (CM) activity
1
2
Afterwards, the catalytic behavior of 7–10 was compared to
that of newly synthesized 11–14 in the CM of allyl benzene (28)
and cis-1,4-diacetoxy-2-butene (29). The reaction is illustrated
in Scheme 1 and the results are reported in Table 2.
In contrast with the above experimental data, in this meta-
thesis reaction, catalysts with syn oriented phenyl groups on
Asymmetric metathesis transformations
the NHC backbone were found to be more competent than Finally, the enantiopure catalysts 8, 10, 12, and 14 were evalu-
their anti congeners, affording high yields combined with low ated in some model asymmetrical metathesis reactions, such
E/Z ratios (∼3) in the presence of catalysts 7 and 9, possessing as asymmetric ring-closing metathesis (ARCM) of achiral
an encumbered N-cyclohexyl group (entries 1 and 5, Table 2). trienes 31 and 32 (Scheme 2) and asymmetric ring-opening
Indeed, catalysts with a smaller N-methyl group gave worse cross-metathesis (AROCM) of the meso-norbornene 35 and
results, in terms of both conversion in the desired product and styrene (Scheme 3).
Scheme 1 CM of substrates 28 and 29.
Table 2 CM of 28 and 29 promoted by catalysts 7–14
Scheme 2 ARCM of 31 and 32.
a
b
Entry
Catalyst
38 Yield (%)
E : Z
1
2
3
4
5
6
7
8
7
8
88
53
66
53
72
67
86
57
3.6
8.5
7.4
9.5
2.6
7.6
8.0
8.6
11
12
9
10
13
14
a
b
1
Isolated yield. E : Z ratios were determined by H NMR spectroscopy.
Scheme 3 AROCM of 35 and side-products.
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The results for the ARCM of trienes 31 and 32 are summar- to be competent in this sterically demanding reaction, disclos-
ized in Table 3. All the catalysts were able to promote the ring ing opposite enantioselectivity with different values depending
closure of 31 in high yields. The enantiomeric excesses were on the N-alkyl substituents. Catalysts 8 and 10, characterized
modest (entries 1, 3, 5 and 7, Table 3); however, in analogy by an N-cyclohexyl group, furnished almost quantitatively the
with what was observed in the ARCM reactions with chiral cat- cyclic product 34 (42% ee, entries 11 and 15, Table 3), outper-
2
6
alysts bearing C
2
-symmetric NHCs, they were increased by forming catalyst 3 (8% ee, entry 19, Table 3) and mirroring the
employing NaI as an additive (entries 2, 4, 6 and 8, Table 3). best results reported by Collins with modified versions of cata-
1
6c
This finding is in contrast with the study by Collins on the lyst 3 (43% ee).
same ARCM reaction performed with chiral catalysts incorpor- On the other hand, catalysts 12 and 14 successfully accom-
ating C -symmetric NHCs, structurally very similar to the ones plished the RCM of 32 in 25% and 29% ee of the opposite
1
newly synthesized. Indeed, in that case, a deleterious impact enantiomer, respectively. This clearly indicates that the N-alkyl
of the use of NaI on enantioselectivity was observed (entries 9 group of the NHC ligand has a direct effect on the enantio-
1
6a,b
and 10).
meric excesses of the desymmetrization reaction. Also in this
As a further remark, by comparison of the results for the case, by changing the substituents on the NHC backbone (as
ring closure of 31 carried out with catalysts 12 and 3a, which from 3 to 12), catalyst properties changed (compare entry 10 to
differ only in the steric hindrance of the substituents on the entries 13 and 17 of Table 3). The addition of NaI to improve
NHC backbone (phenyl vs. t-butyl groups), a great difference enantioselectivity completely shuts down the reaction, very
−
in enantioselectivity emerged. A nearly negligible effect of the likely because the replacement of the Cl bound to ruthenium
size of N-substituents on enantiomeric excesses was detected with I− ligands makes the reactive pocket of the catalyst too
(entries 1 and 3, Table 3), and no substantial variations in congested, thus rendering difficult the approach of the bulky
yields and in enantioselectivities were noticed moving from substrate 32. As observed in the RCM of 31, Grubbs’ II and
phosphine-containing to phosphine-free catalysts (entries 1–4 Hoveyda–Grubbs II type catalysts showed the same catalytic
and 5–8). This suggests that enantioenrichment of 33 is deter- behavior.
mined by the same catalytic intermediate, independently of
Our attention was then focused on AROCM that represents
the fact that the phosphine-containing catalysts are a mixture a powerful method for the construction of enantioenriched
2
7
of rotamers, while phosphine-free catalysts consist of a single dienes, employed as the key step in several total syntheses.
rotational isomer. Table 4 describes the results for the AROCM of cis-5-norbor-
The good performances exhibited by catalysts 8, 10, 12, and nene-endo-2,3-dicarboxylic anhydride (35) with styrene as the
4 in the ring-closing of hindered substrates prompted us to model reaction (Scheme 3).
1
investigate their behavior in the challenging ARCM of 32 to
The meso-norbornene 35 was reacted with 10 equivalents of
generate tetrasubstituted olefin 34. All the catalysts were found styrene in the presence of monophosphine catalysts 8 and 12
and of phosphine-free catalysts 10 and 14 at room tempera-
ture, for 2 and 4 hours, respectively. The reactions promoted
by the more encumbered catalysts 8 and 10 gave 36 in moder-
ate enantioselectivity (entries 1 and 3, Table 4). The employ-
Table 3 ARCM of 31 and 32 with 8, 10, 12 and 14
a
b
c
ment of catalysts 12 and 14, with reduced steric hindrance,
resulted in lower enantiomeric excesses (entries 2 and 4,
Table 4). Except for stilbene arising from the cross-metathesis
of styrene, no polymer or homometathesis product was
detected in the reaction mixture. All the products showed trans
stereochemistry, and no cis isomers were observed.
Entry
Substrate Catalyst (mol%) Additive Yield (%) ee (%)
d
d
1
2
3
4
5
6
7
8
9
1
31
31
31
31
31
31
31
31
31
31
8 (2.5)
8 (4.0)
None
NaI
None
NaI
None
NaI
None
NaI
>98
>95
>98
>98
>98
>95
>98
>98
>95
>95
18 (S)
53 (S)
33 (S)
50 (S)
19 (S)
52 (S)
33 (S)
47 (S)
82 (S)
48 (S)
12 (2.5)
12 (4.0)
10 (2.5)
10 (4.0)
14 (2.5)
14 (4.0)
3a (2.5)
3a (4.0)
d
d
As reported by Grubbs for the analogous AROCM trans-
formation promoted by chiral N-aryl, N-alkyl NHC ruthenium
e
None
NaI
e
0
f
f
1
1
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
32
32
32
32
32
32
32
32
32
8 (2.5)
8 (4.0)
None
NaI
None
NaI
None
NaI
None
NaI
>95
—
>98
—
>95
—
>98
—
42 (S)
—
25 (R)
—
42 (S)
—
29 (R)
—
Table 4 AROCM of 35 with styrene
12 (2.5)
12 (4.0)
10 (2.5)
10 (4.0)
14 (2.5)
14 (4.0)
3a (2.5)
b
b
b
c
36 Yield
37 Yield
38 Yield
(%)
ee (36)
(%)
f
f
a
Entry
Cat.
(%)
(%)
d
e
1
2
3
4
8
45
46
20
35
10
15
5
10
10
11
24
32
13
29
10
10
12
14
g
d
e
None
95
8 (S)
7
a
2 2
Runs without additives were carried out in CH Cl , while runs with
NaI were performed in THF. Yields based on NMR analysis.
Enantiomeric excesses determined by chiral GC. Taken by ref. 12. excess determined by chiral HPLC. Reaction time: 2 h. Reaction
Ref. 16a,b. Taken by ref. 12. Ref. 16c.
b
a
b
c
[35]: 0.07 M in CH
2
Cl
2
; 10 eq. styrene. Isolated yield. Enantiomeric
c
e
d
d
e
f
g
time: 4 h.
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2
8
catalysts, the formation of AROCM side products 37 and 38
was observed. Grubbs’ II-type catalysts and the corresponding
Hoveyda–Grubbs’ II-type catalysts provided slightly different
ratios of products 36, 37 and 38.
Steric and electronic properties of uNHCs
The comparison among catalytic behaviors of ruthenium com-
plexes, with different NHC backbone configurations and
different N-alkyl substituents, highlighted major reactivity
differences mainly between syn and anti complexes character-
ized by a more encumbered N-cyclohexyl group. Intrigued by
this experimental evidence, we decided to gain more insight Fig. 7 ORTEP view of complexes 39 (A) and 40 (B) with the thermal
into the steric and electronic properties of the latter uNHCs
3
1
ellipsoids at 30% probability.
using the corresponding rhodium complexes. New rhodium
cyclooctadiene complexes (39, 40) and bis(carbonyl)complexes
8
d
(
(
41, 42) were prepared with previously described procedures
Scheme 4).
Table 5 Selected bond distances and angles (Å and degrees)
Deprotonation of dihydroimidazolium salts A and B with
potassium hexamethyldisilazide (KHMDS) in toluene at room
temperature, and subsequent treatment with [RhCl(COD)]
afforded, after purification by column chromatography, 39 and
Distances
39
40
Rh1–C1
Rh1–Cl1
Rh1–C(C4–C5)
2.016(2)
2.3825(8)
1.974(4)
2.099(4)
1.344(4)
1.337(4)
1.998(7)
2.388(2)
1.976(8)
2.102(8)
1.358(8)
1.348(7)
2
a
a
4
0 in 84% and 79% yields, respectively (Scheme 4). The Rh1–C(C8–C9)
C1–N1
desired products were isolated as yellow microcrystalline
solids.
C1–N2
1
13
H and C NMR spectroscopic analyses of complexes 39, Angles
C1–Rh1–Cl1
C1–Rh1–C(C4–C5)
C1–Rh1–C(C8–C9)
86.18(7)
95.0(1)
174.6(1)
176.8(1)
90.9(1)
90.0(2)
92.0(2)
177.8(2)
177.8(2)
91.0(2)
87.0(2)
107.2(5)
112.9(5)
113.4(5)
characterized by a syn disposal of phenyl groups on the NHC
backbone, revealed the presence of two isomers (molar ratio
1
: 0.2), due to a restricted rotation around the Rh–NHC bond Cl1–Rh1–C(C4–C5)
2
9
Cl1–Rh1–C(C8–C9)
C(C4–C5)–Rh1–C(C8–C9)
N1–C1–N2
or around the N-aryl bond.
88.1(1)
Only one rotamer was indeed observed for complex 40, with
anti phenyl groups on the backbone. The signals due to the C1–N1–C2
carbenic carbon coordinated to the metal were observed at
109.0(2)
113.1(2)
113.6(2)
C1–N2–C3
2
16.9 ppm (major isomer, d, JRh–C = 48.1 Hz) and 214.9 ppm
a
Centroids of the COD C4vC5 and C8vC9 double bonds.
(d, JRh–C = 47.2 Hz) for complexes 39 and 40, respectively.
Single crystals suitable for X-ray structure analysis were
obtained for both complexes by slow evaporation of concen-
trated solutions in CH Cl . The crystal structures are shown in
Fig. 7, and selected bond lengths and angles can be found in
Table 5. In both compounds, the Rh center adopts a square
planar coordination geometry. The chlorine atoms and the C1
symmetric space group C2/c; accordingly, the crystal contains a
racemic mixture of both the enantiomers having opposite con-
figurations of C2 and C3 carbon atoms (RS and SR) of the NHC
ligand. Conversely, complex 40 crystallizes in the ortho-
2
2
1 1 1
rhombic non-centrosymmetric space group P2 2 2 where
(NHC) atoms are trans oriented to the CvC π systems of the
both the asymmetric C2 and C3 atoms exhibit R chirality. It
was possible to determine the absolute configuration from the
crystallographic data by means of the calculated Flack para-
COD alkene molecule. Complex 39 crystallizes in the centro-
3
0
meter of −0.02(5).
In both complexes the distances of the Rh to the centroids
of the COD alkene bonds are longer for those trans to NHC
[2.099(4) Å for 39, 2.102(8) Å for 40] than for those trans to the
chlorine atom [1.974(4) Å for 39, 1.976(8) Å for 40]. This can be
ascribed to the greater trans influence of the NHC moiety. All
the other structural parameters are in good agreement with
3
2–35
those observed for other similar complexes.
The steric bulk, measured as the percentage of buried
volume (%VBur) of the N-cyclohexyl/N-o-isopropylphenyl NHC
ligands with syn or anti phenyl groups on the backbone, was
3
6
Scheme 4 Synthesis of Rh complexes 39–42.
extracted using the SambVca program developed by Cavallo,
Dalton Trans.
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using the crystal data of the corresponding Rh complexes 39
and 40. The %VBur values are 29.7 and 29.9 for syn uNHC and
Conclusion
anti uNHC ligands, respectively, and thus within the same In summary, we have presented herein the synthesis and
3
7
level of significance.
characterization of four new Grubbs’ and Hoveyda–Grubbs’
In order to study the electronic properties of these ligands, second generation catalysts (11–14) bearing unsymmetrical
the cis-dicarbonyl complexes 41 and 42 were synthesized by NHC ligands with N-methyl/N-isopropylphenyl substituents
replacing the COD ligand in 39 and 40 with carbon monoxide, and syn or anti phenyl groups on the backbone. The catalytic
1
as depicted in Scheme 4. The H NMR spectra of 41 and 42 behavior of these complexes was evaluated in standard RCM,
confirmed the disappearance of the signals because of the ROMP and CM reactions and compared to that of analogous
COD ligand. Complexes 41 and 42 were obtained as a mixture complexes presenting a more encumbered N-cyclohexyl group
of isomers (molar ratio 1 : 0.5 : 0.3 for 41 and 1 : 0.3 for 42), as (7–10). While anti substituted catalysts benefit from the steric
a consequence of a restricted rotation around the Rh–NHC hindrance offered by the N-cyclohexyl group, achieving the
2
9
13
bond and/or around the N–Ar bond. The C NMR spectra best catalytic efficiencies in almost all the metathesis trans-
showed the signals assigned to the carbene carbon at formations, and demonstrating to be particularly competent in
2
2
06.3 ppm (major isomer, d, JRh–C = 38.9 Hz) for 41, and at the most challenging RCM reactions, for syn catalysts the pres-
03.2 ppm (d, JRh–C = 40.4 Hz) for 42. The C NMR chemical ence of the bulkier N-cyclohexyl group is detrimental. In par-
1
3
shifts of the two carbonyl ligands were observed for the major ticular, catalysts 7 and 9 showed low activities in the easier
isomer of 41 at 186.8 (d, JRh–C = 53.4 Hz) and 183.5 ppm (d, RCM reactions, and this peculiar behavior, rationalized by
J
Rh–C = 75.5 Hz), while for 42 at 186.7 (d, JRh–C = 54.3 Hz) and DFT calculations, was ascribed to a major tendency of these
83.7 ppm (d, JRh–C = 73.9 Hz). catalysts to give nonproductive metathesis events. This feature
The IR spectra of dicarbonyl complexes 41 and 42 were strongly suggests to exploit these catalysts for targeted reac-
recorded in the solid-state (KBr) and carbonyl stretching fre- tions, such as ethenolysis.
1
quencies were found to be significantly dependent on the
The enantiopure catalysts 8, 10, 12 and 14 were also com-
NHC backbone configuration. More in detail, complex 41 with pared in asymmetric metathesis transformations, showing
syn phenyl groups on the NHC backbone showed signals due moderate enantioselectivity in both ARCM and AROCM. A
to the stretching of the two CO ligands at 2080 and 1999 cm−
1
,
clear influence of the bulkiness of the N-alkyl groups on the
whereas the anti isomer 42 exhibited the analogous signals at enantiomeric excesses was observed, encouraging further
1
38
2
075 and 1992 cm− . The Tolman electronic parameter (TEP)
of the uNHCs coordinated to 41 and 42 was then estimated size of N-alkyl substituents.
from the average stretching vibration wavenumber Finally, the steric and electronic properties of N-cyclohexyl/
2039.5 cm− for the uNHC from 41 and 2033.5 cm for the N-isopropylphenyl NHC ligands were evaluated from the
uNHC from 42), by using the well-accepted correlations corresponding rhodium cyclooctadiene (39, 40) complexes,
efforts towards the design of new chiral catalysts by varying the
1
−1
(
3
9
−1
reported in the literature. This led to a value of 2051.8 cm
characterized by X-ray analysis, and rhodium dicarbonyl (41,
−
1
for uNHC from 41 and of 2047.0 cm for uNHC from 42, 42) derivatives. To the best of our knowledge, this represents
suggesting a more electron-donating nature for the uNHC the first example of rhodium complexes bearing backbone-
bearing anti phenyl groups on the backbone than for the one substituted unsymmetrical NHCs. While the percentage of
bearing the syn oriented phenyl group.
buried volume (%VBur) indicates very similar steric properties
Bond-dissociation energies (BDE) for the uNHC ligand for the uNHCs with different backbone configurations, the
from Rh carbonyl complexes 41 and 42 were evaluated by DFT Tolman electronic parameter revealed a greater electron-donat-
calculations (see the ESI† for computational details) and were ing character for uNHCs with anti configuration, suggesting a
−1
−1
found to be 55.86 kcal mol for 41 and 56.44 kcal mol for direct correlation with the catalytic properties shown by the
2. Therefore, dissociation of the NHC ligand with anti phenyl corresponding catalysts.
groups on the backbone is more expensive by about 0.6 kcal A deeper investigation on the impact of unsymmetrical
4
−
1
mol than dissociation of NHC with syn phenyl groups, corro- NHC ligands differing in backbone configuration and N-alkyl/
borating the hypothesis that lower CO stretching frequencies N-aryl substituents on catalyst properties is in progress.
are associated with higher NHC–Rh bond strength. This is also
supported by the analysis of the NHC–Rh bond distances in
the corresponding rhodium–COD complexes 39 and 40, where
the bond distance between the NHC carbene carbon and the
Acknowledgements
Rh center is shorter in 40 (1.999 Å) than in 39 (2.016 Å).
The authors thank Dr Patrizia Iannece, Dr Ivano Immediata,
In the light of these results, it can be reasonably assumed and Patrizia Oliva for technical assistance and Dr Alessandra
that electronic factors outweigh steric factors for uNHCs pres- Perfetto for some experimental work. F.G. thanks Prof. Luigi
enting different backbone configurations, and that this feature Cavallo for his valuable suggestions on using the web appli-
could be related to the different efficiency shown by the corres- cation SambVca. Financial support from the Ministero dell’-
ponding ruthenium complexes 7–10 in the examined olefin Università e della Ricerca Scientifica e Tecnologica is gratefully
metathesis transformations.
acknowledged.
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Y. Schrodi, Org. Lett., 2007, 9, 1589; (b) J. M. Berlin,
K. Campbell, T. Ritter, T. W. Funk, A. Chlenov and
R. H. Grubbs, Org. Lett., 2007, 9, 1339.
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6
For sterically demanding reactions, see: (a) I. C. Stewart, 14 The stability of catalysts 7–10 was also monitored over time
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using 1,3,5-trimethoxybenzene as an internal standard.
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Experiments were performed, under nitrogen, at 30 °C in
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2
2
6 6
a week, only 7 was found to be fully decomposed.
28 R. M. Thomas and R. H. Grubbs, Chem. N.Z., 2011, 75, 65.
1
5 Complex 7 showed a syn : anti ratio of 0.3 : 1, while complex 29 (a) M. Iglesias, D. J. Beetstra, B. Kariuki, K. J. Cavell,
8
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2
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1
1
7 This finding is in line with the results reported by Collins
1996.
in ref. 8e. The catalyst stability increases with increasing 32 F. E. Hahn, M. Paas, D. Le Van and T. Lugger, Angew.
the size of the N-alkyl group. Chem., Int. Ed., 2003, 42, 5243.
8 A small amount of two minor carbenic species was 33 M. Alcarazo, S. J. Roseblade, E. Alonso, R. Fernandez,
1
detected in the H NMR spectrum of complex 13. However,
due to their low abundance, identification was not
possible.
E. Alvarez, F. J. Lahoz and J. M. Lassaletta, J. Am. Chem.
Soc., 2004, 126, 13242.
34 E. Jansen, M. Lutz, B. de Bruin and C. J. Elsevier, Organo-
metallics, 2014, 33, 2853.
35 C. Mejuto, G. Guisado-Barrios and E. Peris, Organometal-
lics, 2014, 33, 3205.
36 A. Poater, B. Cosenza, A. Correa, S. Giudice, F. Ragone,
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The default processing parameters of the SambVca web
application were kept unchanged.
1
2
2
9 Dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene]-
(
benzylidene) (tricyclohexylphosphine) ruthenium(II).
0 Dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene]-
2-isopropoxyphenylmethylene) ruthenium(II).
(
1 See for example: (a) L. Vieille-Petit, H. Clavier, A. Linden,
S. Blumentritt, S. P. Nolan and R. Dorta, Organometallics,
2
010, 29, 775; (b) A. Perfetto, C. Costabile, P. Longo and
F. Grisi, Organometallics, 2014, 33, 2747.
37 The %VBur values for the same NHC ligands were also cal-
culated using the crystal structures of 9 and 10, reported in
ref. 12, and they were found to be 29.9 for syn-uNHC and
29.1/29.4 for anti-uNHC (considering the two independent
molecules of 10).
2
2
2 At 1 mol%, the reaction is complete in less than two minutes.
3 I. C. Stewart, B. K. Keitz, K. M. Kuhn, R. M. Thomas and
R. H. Grubbs, J. Am. Chem. Soc., 2010, 132, 8534.
4 A. Perfetto, C. Costabile, P. Longo, V. Bertolasi and F. Grisi,
Chem. – Eur. J., 2013, 19, 10492.
2
2
38 C. A. Tolman, Chem. Rev., 1977, 77, 313.
5 (a) A. K. Chatterjee, T.-L. Choi, D. P. Sanders and 39 TEP was calculated using the equation: TEP = 0.8001 ν
COav
+ 420.0 cm− . For further details, see: (a) T. Dröge and
1
R. H. Grubbs, J. Am. Chem. Soc., 2003, 125, 11360;
b) T. Ritter, A. Hejl, A. G. Wenzel, T. W. Funk and
(
F. Glorius, Angew. Chem., Int. Ed., 2010, 49, 6940;
(b) A. R. Chianese, X. Li, M. C. Janzen, J. W. Faller and
R. H. Crabtree, Organometallics, 2003, 22, 1663;
(c) R. A. Kelly III, H. Clavier, S. Giudice, N. M. Scott,
E. D. Stevens, J. Bordner, I. Samardjiev, C. D. Hoff,
L. Cavallo and S. P. Nolan, Organometallics, 2008, 27, 202;
(d) S. Wolf and H. Plenio, J. Organomet. Chem., 2009, 694,
1487.
R. H. Grubbs, Organometallics, 2006, 25, 5740.
2
2
6 (a) T. J. Seiders, D. W. Ward and R. H. Grubbs, Org. Lett.,
2
001, 3, 3225; (b) T. W. Funk, J. M. Berlin and
R. H. Grubbs, J. Am. Chem. Soc., 2006, 128, 1840.
7 (a) D. G. Gillingham and A. H. Hoveyda, Angew. Chem., Int.
Ed., 2007, 46, 3860; (b) K. Takao, H. Yasui, S. Yamamoto,
D. Sasaki, S. Kawasaki, G. Watanabe and K. Tadano, J. Org.
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Dalton Trans.