Probing the relevance of NHC ligand conformations in the Ru-catalysed ring-closing metathesis reaction

Article abstract of DOI:10.1002/chem.201301540

Cat power: Judicious backbone substitution of N-heterocyclic carbenes (NHCs) leads to stable Ru metathesis catalysts with frozen NHC conformations. This finding not only permits the isolation of complexes that are among the most active catalysts in the ring-closing metathesis of hindered olefins (see graphic; Ts=p-toluenesulfonyl), but also provides fundamental mechanistic insights on the role of N-aryl substituent conformations on catalyst activity. Copyright

Full text of DOI:10.1002/chem.201301540

COMMUNICATION
Cat power: Judicious backbone substi-
tution of N-heterocyclic carbenes
(NHCs) leads to stable Ru metathesis
catalysts with frozen NHC conforma-
tions. This finding not only permits the
isolation of complexes that are among
the most active catalysts in the ring-
closing metathesis of hindered olefins
(see graphic; Ts=p-toluenesulfonyl),
but also provides fundamental mecha-
nistic insights on the role of N-aryl
substituent conformations on catalyst
activity.
Homogeneous Catalysis
A. Perfetto, C. Costabile, P. Longo,
V. Bertolasi, F. Grisi* ........ &&&& — &&&&
Probing the Relevance of NHC
Ligand Conformations in the Ru-Cata-
lysed Ring-Closing Metathesis Reac-
tion
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DOI: 10.1002/chem.201301540
Probing the Relevance of NHC Ligand Conformations in the Ru-Catalysed
Ring-Closing Metathesis Reaction
Alessandra Perfetto,[a] Chiara Costabile,[a] Pasquale Longo,[a] Valerio Bertolasi,[b] and
Fabia Grisi*[a]
Ring-closing metathesis (RCM) promoted by transition-
metal catalysts has become an indispensable tool in synthet-
ic organic chemistry.[1] The introduction of Ru complexes
bearing an N-heterocyclic carbene (NHC) ligand has
marked a turning point in the development of increasingly
efficient catalysts.[2] Successful design of NHC–Ru catalysts
has been achieved by fine-tuning of the stereoelectronic
properties of the NHC ligand and has led, inter alia, to a
series of ruthenium catalysts bearing NHCs with varying de-
Scheme 2. The syn NHC backbone substituted complexes.
grees of N-heterocyclic backbone and/or aryl side chain sub-
stitution (e.g., 1–4 in Scheme 1) that give positive enhance-
ment for RCM reactions.[3,4] In general, N-aryl bulk was
found to increase activity, whereas increased backbone sub-
stitution decreased activity but increased catalyst lifetime.
We have recently identified a class of Ru catalysts con-
taining N-heterocyclic carbene ligands with methyl groups
on the NHC backbone in a syn and anti orientation.[5,6] No-
tably, the syn complexes with o-tolyl N-substituents (5a and
6a, Scheme 2) are among the most efficient catalysts in the
formation of hindered olefins through RCM. The origin of
this enhanced reactivity has been ascribed to the syn dispos-
al of methyl groups on the backbone that induces a prefer-
ential syn orientation of the N-tolyl rings, thus providing a
more accessible active space at the metal.[6a,b] A preferred
syn orientation of N-tolyl substituents was already suggested
by Grubbs for catalysts 1 and 2.[7] Nevertheless, no direct
evidence has been up to now reported to confirm this hy-
pothesis.
In an attempt to further constrain N-aryl rings to adopt a
syn conformation, thus enhancing catalyst efficiency, we de-
cided to prepare monophosphine and phosphine-free NHC
Ru precatalysts with more encumbered syn backbone sub-
stituents, replacing methyl with phenyl groups. The synthesis
of the NHC ligand precursor with syn phenyl groups on the
backbone was easily accomplished in two steps starting from
the commercially available meso-1,2-diphenylethylenedia-
mine, allowing significant time saving with respect to the
five-step synthesis required for the analogous syn methyl
backbone substituted NHC (see the Supporting Informa-
tion).
Scheme 1. Backbone and/or N-aryl substituted complexes.
The phosphine-containing complex (7, Scheme 3) was pre-
pared by treatment of the appropriate imidazolinium tetra-
fluoroborate with (CF3)2CH3COK and RuCl
AHCTUNGTRENNUNG
2ACHTUNGTRNE(NUNG =CHPh)-
[a] A. Perfetto, Dr. C. Costabile, Prof. P. Longo, Dr. F. Grisi
Dipartimento di Chimica e Biologia, Universitꢁ degli Studi di Salerno
Via Giovanni Paolo II, 132, 84084 Fisciano, SA (Italy)
E-mail: fgrisi@unisa.it
(PCy3)2 in toluene at 608C.[8] Surprisingly, chromatographic
workup of the crude reaction mixture led to the isolation of
two isomeric compounds in 58% overall yield. The major
product (second eluted compound, 42%) was identified as
the isomer with syn-oriented N-tolyl groups (syn-7). The
minor isomer was assigned to be the conformation with the
two methyl groups of the N-tolyl substituents on the NHC
[b] Prof. V. Bertolasi
Dipartimento di Chimica e Centro di Strutturistica Diffrattometrica
Universitꢁ di Ferrara, Via L. Borsari 46, 44100 Ferrara (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301540.
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Olefin Metathesis Catalysts
COMMUNICATION
Scheme 3. NHC Ru complexes 7 and 8.
ligand disposed in an anti relationship (anti-7, 16%).[9] The
two isomers of 7 were both converted in the corresponding
phosphine-free complexes syn-8 and anti-8 (95 and 84%
yield, respectively) by treatment with 2-isopropoxystyrene
in the presence of CuCl.[11] Solution-state structure of com-
plex 8, determined by NMR analysis, revealed the presence
of only one isomer (syn-8). The structural assignment of
syn-8 was unambiguously established by X-ray diffraction
(Figure 1).[10a]
Figure 2. Isomers of complex 8. For each isomer internal and free
energies in CH2Cl2, obtained by DFT calculations, are reported in kcal
molÀ1. See the Supporting Information for further details.
located for complex 8. Internal and free energies in CH2Cl2
are reported in Figure 2, whereas structures are shown in
the Supporting Information. Lowest energy structure 8A
corresponds to the most abundant syn-8 isomer, character-
ised by X-ray diffraction as well. Moreover, 8B was found
to be more stable than 8C, possibly indicating 8B as the
major anti form. The high energy of 8D would explain the
presence of only three isomers experimentally observed.
Reaction thermodynamics for the isomerization process
from the minor isomer to the major isomer of anti-8 were
derived from VT 1H NMR analysis (DH8=À1.5 kcalmolÀ1
and DS8=À4.0 kcalmolÀ1 KÀ1; see the Supporting Informa-
tion). The comparison of calculated and experimental
energy differences strongly indicates 8B as the major anti
isomer. Indeed, calculated DE between 8B and 8C is
1.9 kcalmolÀ1 (Figure 2); this is in good agreement with ex-
perimental DH of 1.5 kcalmolÀ1.
To the best of our knowledge, this is the first time that
stable rotational isomers of N-tolyl complexes have been
isolated. In fact, the other known N-tolyl catalysts (1, 2, 5a
and 6a) exist as mixtures of conformational isomers in the
solid state as well as in solution.[3b,6a,7] Therefore, the high
degree of conformational stability observed is strictly corre-
lated to the presence of phenyl substituents on the NHC
backbone.
Figure 1. ORTEP[10b] view of complex syn-8 with the thermal ellipsoids at
30% probability.
1
Characterisation of complex anti-8 by H,13C and various
2D NMR experiments revealed the presence of two isomers,
corresponding to the different arrangement of the anti ori-
ented N-tolyl groups of the NHC (8B and 8C of Figure 2).
Unfortunately, in spite of numerous attempts, we were
unable to grow crystals of anti-8 suitable for X-ray analysis;
moreover, NMR characterisation of the complex did not
allow us to unambiguously assign the exact geometry to the
most stable species in solution.
The behaviour of the new complexes, 7 and 8, was tested
in some standard RCM reactions (Table 1). The RCM reac-
1
tion of each substrate was followed by using H NMR spec-
troscopy. Selected kinetic data are shown in Figure 3 (see
the Supporting Information for more details). Interestingly,
a marked difference in reactivity profiles is observed for 7
and 8 with different conformations of the NHC ligand.[12]
Indeed, syn-7 and syn-8 perform better than their anti ana-
logues in all the examined RCM reactions (Figure 3 and
According to density functional theory (DFT) studies on
the complex stability, four minimum energy structures were
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F. Grisi et al.
evidence that NHC ligands in-
corporating correctly oriented
N-tolyl groups are responsible
for enhanced reactivity in RCM
reactions.
The crucial role of N-tolyl
group orientation on catalyst
activity was furthermore con-
firmed by DFT calculations. In
particular, we compared the be-
haviour of syn- and anti-7, by
modelling
the
determining
energy transition state struc-
tures of the RCM catalytic
cycle of 13 for all possible N-
tolyl orientations. Indeed, as al-
ready reported by some of us,
highest energy transition states,
involved in the RCM of 13 pro-
moted by similar catalysts, such
as 5a (Scheme 2), were shown
to be those leading the coordi-
nated substrate structure to the
first metallacycle intermedia-
te.[6b]
Figure 3. Kinetic data for the RCM of 13 (A and B) and 19 (C and D).
The corresponding four pos-
sible structures and free and in-
Table 1), and the observed trend is more pronounced with
bulkier substrates that give tri- and tetrasubstituted cyclic
olefins. Figure 3A shows the results for the challenging
RCM of diethyl dimethallylmalonate 13 promoted by syn-7
and anti-8. For comparison, the plots of two other N-tolyl
complexes 1 and 5a, which are efficient catalysts for hin-
dered substrates, are also reported. Compound syn-7 not
only clearly outperforms anti-7, but it is also more efficient
than complexes 1 and 5a, reaching 92% conversion within
30 min. The latter represents the best result achieved in the
RCM of 13 with a monophosphine Ru complex to date. The
same reactivity profile is observed for the ring-closing of 13
carried out with the corresponding phosphine-free com-
plexes syn-8, anti-8, 2 and 6a (Figure 3B). Although the dif-
ferences in overall activity are less evident than for phos-
phine-based complexes, it is worth noting that syn-8 displays
the highest activity (98% conversion in 20 min), emerging
as one of the most efficient catalysts in the formation of tet-
rasubstituted olefins through RCM. Furthermore, syn-8 re-
veals a high ability to promote ring-closing metathesis reac-
tions at catalyst loadings as low as 0.5 to 0.05 mol%. Full
conversion is reached at catalyst loading 0.05 mol% for sub-
strates 15 and 17 (Table 1, entries 21 and 27), whereas
nearly quantitative yields are registered at 0.5 and 0.1 mol%
for the sterically demanding diolefins 13 and 19, respectively
(Table 1, entries 16 and 33). As for anti-8, the same low cat-
alyst loading experiments emphasise the striking difference
in activity compared with the syn isomer (Table 1). Notably,
comparison of separated syn and anti conformers of N-tolyl
catalysts 7 and 8 in RCM reactions provides the first direct
ternal energies of transition states for 7 are shown in
Figure 4. Lowest energy structure TS-A presents syn N-tolyl
groups in an anti relationship with respect to the backbone
phenyl groups. In fact, this N-group orientation minimises
the internal NHC repulsions as well as the repulsions of Ru
ligands with the incoming substrate 13 and accounts for the
higher activity of syn-7.[13]
Figure 4. Determining energy transition state structures of the RCM cata-
lytic cycle of 13 for all possible N-tolyl orientations of 7. Internal and
free energies, calculated in CH2Cl2, are in kcalmolÀ1
.
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Olefin Metathesis Catalysts
COMMUNICATION
Table 1. RCM reactions with catalysts 7 and 8.
ISCRA programme (code RCMMSCMO: HP10C8VOGT)
and financial support from the Ministero dell’Universitꢁ e
della Ricerca Scientifica e Tecnologica are gratefully acknowl-
edged.
Entry[a]
Substrate, Product
Catalyst
[mol%]
t [min]
Yield
[%][b]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
syn-7 (1)
anti-7 (1)
syn-8 (1)
syn-8 (0.1)
anti-8 (1)
anti-8 (0.1)
syn-7 (1)
anti-7 (1)
syn-8 (1)
syn-8 (0.1)
anti-8 (1)
anti-8 (0.1)
syn-7 (5)
anti-7 (5)
syn-8 (5)
syn-8 (0.5)
anti-8 (5)
syn-7 (1)
anti-7 (1)
syn-8 (0.1)
syn-8 (0.05)
anti-8 (1)
anti-8 (0.1)
syn-7 (1)
anti-7 (1)
syn-8 (0.1)
syn-8 (0.05)
anti-8 (1)
anti-8 (0.1)
syn-7 (1)
anti-7 (1)
syn-8 (1)
syn-8 (0.1)
anti-8 (1)
anti-8 (0.1)
30
60
5
30
12
60
35
60
6
60
60
60
30
60
30
180
120
25
60
5
>98
70
>99
>99
>99
97
>95
66
>99
95
95
74
92
44
99
96
94
>99
91
>99
>99
>99
94
99
71
>99
99
>99
97
97
60
Keywords: density
functional
calculations
·
homogeneous catalysis · N-heterocyclic carbenes ·
ring-closing metathesis · ruthenium
9
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separated, stable conformers of N-tolyl Ru complexes (7
and 8). Compounds syn-7 and syn-8 are among the most ef-
ficient catalysts in the RCM of hindered olefins, requiring
catalyst loadings as low as 0.05–0.5 mol%. Notably, the dif-
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and 8 provide the first unequivocal proof for the significance
of correctly disposed N-aryl groups to successfully accom-
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relationship between NHC architecture and catalyst activity,
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8 in other olefin metathesis reactions are underway and will
be reported in due course.
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Acknowledgements
The authors thank Dr. Patrizia Iannece and Patrizia Oliva for technical
assistance. Computational support from CINECA: High Performance
Computing Portal in the Framework of Class C awarded proposal to the
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F. Grisi et al.
[11] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
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[12] Intriguing reactivity differences between NHC–Ru complexes that
are only distinguished by the relative orientation of their side chains
(e.g., syn-4 and anti-4) were already observed; see ref. [4].
the substrate through the chlorine, leading to a torsion of the sub-
strate double bond axis with respect to Ru=CH2 axis and, as a con-
À
sequence, to an energy enhancement. As for substrate 13 model,
À
COOEt group has been replaced by CH3.
[13] In structures TS-B and TS-C, the repulsion between one of the phe-
nyls on the backbone and the eclipsed N-tolyl methyl are spread to
Received: April 23, 2013
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