The Key Role of the Nonchelating Conformation of the Benzylidene Ligand on the Formation and Initiation of Hoveyda-Grubbs Metathesis Catalysts

Article abstract of DOI:10.1002/chem.201501959

Experimental studies of Hoveyda-Grubbs metathesis catalysts reveal important consequences of substitution at the 6-position of the chelating benzylidene ligand. The structural modification varies conformational preferences of the ligand that affects its exchange due to the interaction of the coordinating site with the ruthenium center. As a consequence, when typical S-chelated systems are formed as kinetic trans-Cl₂ products, for 6-substituted benzylidenes the preference is altered toward direct formation of thermodynamic cis-Cl₂ isomers. Activity data and reactions with tricyclohexylphosphine (PCy₃) support also a similar scenario for O-chelated complexes, which display fast trans-Cl₂?cis-Cl₂ equilibrium observed by NMR EXSY studies. The presented conformational model reveals that catalysts, which cannot adopt the optimal nonchelating conformation of benzylidene ligand, initiate through a high-energy associative mechanism.

Full text of DOI:10.1002/chem.201501959

DOI: 10.1002/chem.201501959
Communication
&
Metathesis
The Key Role of the Nonchelating Conformation of the
Benzylidene Ligand on the Formation and Initiation of Hoveyda–
Grubbs Metathesis Catalysts
Bartosz Bieszczad and Michał Barbasiewicz*[a]
Abstract: Experimental studies of Hoveyda–Grubbs meta-
thesis catalysts reveal important consequences of substitu-
tion at the 6-position of the chelating benzylidene ligand.
The structural modification varies conformational prefer-
ences of the ligand that affects its exchange due to the in-
teraction of the coordinating site with the ruthenium
center. As a consequence, when typical S-chelated sys-
tems are formed as kinetic trans-Cl2 products, for 6-substi-
tuted benzylidenes the preference is altered toward direct
formation of thermodynamic cis-Cl2 isomers. Activity data
and reactions with tricyclohexylphosphine (PCy3) support
Scheme 1. Selected reactions of O- (top) and S-chelated (bottom) Hoveyda-
type complexes.[7,9] Mes=2,4,6-trimethylphenyl; Cy=cyclohexyl
also a similar scenario for O-chelated complexes, which
display fast trans-Cl2Qcis-Cl2 equilibrium observed by NMR
EXSY studies. The presented conformational model reveals
that catalysts, which cannot adopt the optimal nonchelat-
ing conformation of benzylidene ligand, initiate through
a high-energy associative mechanism.
olefin adduct evolves further into metallacyclobutane (MCB),
starting the initial turnover of the metathesis reaction.[2b,8] Intri-
guingly, as the initiation process was studied in detail, much
less is known about the formation of Hoveyda-type complexes.
Important details of the mechanism delivers synthesis of
sulfur-chelated analogs (e.g., 4).[9] Replacement into the heavi-
er coordinating heteroatom offers a unique opportunity to
follow conformational changes of the systems, which usually
form as kinetic trans-Cl2 products, slowly isomerizing to the
thermodynamic cis-Cl2 structures (Scheme 1, bottom).[10] Re-
cently, we observed that a S-chelating ligand with extended ar-
omatic framework adjacent to the olefinic substituent favors
direct formation of the cis-Cl2 isomer.[9b] In the current report
we explain the data by providing a concise mechanism based
on conformational considerations of the chelating benzylidene
ligand and its exchange in metathesis reactions. The presented
model is validated by experimental studies of formation and
initiation of S- and O-chelated Hoveyda–Grubbs complexes
bearing substituted benzylidene ligands.
Mechanistic studies play a dominant role in development of
catalytic systems, and olefin metathesis is one of the main
areas of the frontier research.[1] For the family of Hoveyda–
Grubbs complexes (e.g., 1), numerous studies that focused on
the catalytic cycle[2] revealed the importance of the initiation
step as a key process[3] responsible for release of active species,
and involved in the bimolecular deactivation pathway.[4] In ki-
netic studies Plenio demonstrated that the initiation proceeds
by dissociative (D) or interchange mechanism (Ia), depending
on structure of the substrate and coordinating alkoxy group of
the catalyst.[5] In both scenarios the chelate ring opens and
olefin binds preferably in a trans position to the N-heterocyclic
carbene (NHC).[6] Further insights were delivered by reaction of
1 with excess of PCy3, in which pentavalent adduct 2 adopts
a nonchelating conformation of benzylidene ligand (Scheme 1,
top).[7] As supported by ab initio calculations, in a real catalytic
cycle the system rearranges in a similar way, distancing the
OiPr coordinating site from the metal center; the so-formed
Our studies started from the preparation of S-chelating li-
gands with various groups attached at the 6-position of the
benzylidene ring, to probe their ligand-exchange processes
(R=H, SMe, OMe, Me; 5a–d; Figure 1).[11] The substrates were
subjected to the commercially available ruthenium precursor 6
1
(M2), and the reactions were analyzed using H NMR spectros-
copy (CD2Cl2, 408C). As expected, 2-(thiomethyl)styrene (5a;
R=H) led to the formation of the initial product attributed to
the kinetic trans-Cl2 isomer with a resonance peak of benzyli-
dene proton observed at 17.2 ppm, which slowly converted
into another one detected at 17.0 ppm (cis-Cl2).[12] In contrast,
for substituted ligands 5b–d (R¼ H) one predominant product
[a] B. Bieszczad, Dr. M. Barbasiewicz
Faculty of Chemistry, University of Warsaw
Pasteura 1, 02-093 Warsaw (Poland)
Fax: (+48)22 822 5996
E-mail: barbasiewicz@chem.uw.edu.pl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501959.
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portantly, chemical shifts of the minor forms were consistent
with traces of accompanying species observed in previous
NMR experiments (cf. Figure 1). In the next step the prepara-
tive experiments were repeated in toluene, which favors for-
mation of kinetic trans-Cl2 isomers of S-chelated systems.[10a] In-
terestingly, a reaction of ligand 5a afforded complex trans-7a,
isolated in 64% yield, whereas ligands 5b–d displayed essen-
tially no conversion under the same conditions (toluene, 408C,
16 h).[11] Attempts at forcing the processes at 808C overcame
the inhibitory effect, but again formation of cis-Cl2 products
was observed, and only for ligand 5c we isolated a small
amount of product characterized with NMR and X-ray studies
as trans-Cl2 complex 7c (11%).
Although all synthesized complexes cis-7a–d displayed very
little activity in model metathesis reactions,[11] more pro-
nounced differences between catalysts were observed for
trans-Cl2 isomers of 7a and 7c (Figure 2, left).
Figure 1. 1H NMR studies of synthesis of complexes 7a–d. The array experi-
ments were conducted in CD2Cl2 at 408C, and the NMR acquisitions were re-
peated at 30 min intervals.[11]
was formed in each case, with only trace amounts of accompa-
nying species. Analogously, in preparative experiments (CH2Cl2,
408C, 1 h) products 7b–d were isolated in good yields, and
characterized with NMR and X-ray studies as cis-Cl2 isomers
(Scheme 2). From the results we suspected that substitution of
benzylidene ring in a position adjacent to the vinyl group in-
fluences mechanism of the ligand-exchange process. In
a search for the missing trans-Cl2 isomers complexes cis-7b–d
were irradiated with UV light (366 nm), a technique used earli-
er for cis-to-trans-Cl2 isomerizations.[9a] In the mixtures we de-
tected formation of small amounts of products (expectedly
trans-Cl2 isomers), which remained stable under ambient con-
Figure 2. Activity profiles of 1.0 mol% of catalysts trans-7a,c in ring closing
metathesis (RCM) of diethyl diallylmalonate (DEDAM; c=0.2m; left), and iso-
merization studies of the complexes detected by 1H NMR (right).[11]
Complex trans-7a was moderately active, while trans-7c re-
mained inactive at 408C. Moreover, NMR studies revealed that
trans-7c isomerizes faster than trans-7a (t1/2 =13 h and 3 h for
7a and 7c, respectively; Figure 2, right), but the difference is
rather small, and thus cannot rationalize the observed lack of
activity of trans-7c by fast isomerization to the latent cis-Cl2
form. For the same reason, it is unlikely that in NMR and prep-
arative experiments performed in CD2Cl2 (cf. Figure 1 and
Scheme 2) complex cis-7c was formed by isomerization of the
transient trans-7c. A more plausible mechanism should involve
an alternative direct pathway to the cis-Cl2 form.
1
ditions and only slowly decayed, as detected by H NMR.[11] Im-
On the basis of the presented data we considered the pro-
cess of formation of S-chelated complexes, following a general-
ly accepted mechanism of metathesis reaction,[2b,8] with the ex-
changed olefin coordinated in a trans position to the NHC.[6]
The structure of the benzylidene ligand approaching the ruthe-
nium center was considered in two conformations: nonchelat-
ing (n-c) and chelating (c), and the two conformations led fur-
ther to parallel pathways of the ligand exchange process, as
presented in Scheme 3. In a less-hindered nonchelating confor-
Scheme 2. Preparative syntheses of complexes 7a–d, and results of UV irra-
diation experiments.[11]
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conformation, is more energetically preferred. Interestingly,
when considering initiation of complexes trans-7a and trans-
7c the same two mechanisms remain valid. For unsubstituted
catalyst 7a (independent of olefin participation in the chelate
opening) steps trans-7a!Dn-c!Cn-c lead to an adduct Bn-c, fol-
lowing a mechanism of initiation of O-chelated catalysts (cf.
Scheme 1, top).[2b,7,8] In turn, opening of the chelate and coor-
dination of the olefin in trans-7c (R=OMe) leads to an inter-
mediate E, which may enter the metathesis cycle only by a ro-
tation around the Ru=C bond, and recoordination of the SMe
group[14] (Scheme 4).
Scheme 4. Proposed mechanism of initiation of 6-substituted trans- and cis-
Cl2 complexes (R¼ H).
Therefore, instead of initiation by a six-coordinated structure
Bc, olefin may dissociate with the formation of cis-Cl2 isomer,
and thus no appreciable progress of the metathesis reaction is
observed. An important consequence of this reasoning is
a demand for an associative mechanism of initiation, when the
nonchelating conformation of benzylidene ligand is inaccessi-
ble. This may be the case for 6-substituted benzylidenes dis-
cussed here, or complexes for which cisQtrans-Cl2 equilibrium
is strongly shifted to the left.[9b,10a,15] Moreover, as in the disso-
ciative and interchange mechanism, a nonchelating conforma-
tion enables a stepwise decoordination of the ligand with
opening of the chelate ring separated from the metathesis
cycle; in the associative mechanism, a simultaneous breaking
of the Ru···heteroatom bond is required, making the process
difficult.[13]
Scheme 3. Proposed mechanism of formation of S-chelated Hoveyda-type
complexes. Typical benzylidene ligands are exchanged in a nonchelating
conformation giving kinetic trans-Cl2 products (left path), whereas ligands
substituted at the 6-position prefer a chelating conformation and, therefore,
thermodynamic cis-Cl2 isomers are formed directly (right path). Geometries
of the structures and their interconversion trajectories are idealized to em-
phasize key conformational changes.
mation (available for 5a; R=H), where interaction between
the SMe coordinating site and the metal center is reduced, the
olefin acts virtually as a monodentate ligand on steps An-c
!
To further verify the idea we synthesized a set of O-chelated
complexes 9a–c (Scheme 5). Activity data of the catalysts were
very similar to their S-chelated counterparts (Figure 3). As ex-
pected, complex 9a (R=H) was active under ambient condi-
tions, whereas substituted derivatives 9b and 9c (R¼ H) re-
mained intact, and required elevated temperature to initiate
Bn-c!Cn-c. However, a close parallel orientation of NHC and
benzylidene aromatic rings in Cn-c prevents a direct rotation
around the =CÀCAr bond, and thus a rotation around the Ru=C
bond leads to an intermediate Dn-c, which then cyclizes to
complex trans-Cl2. The mechanism agrees well with the ob-
served kinetic formation of trans-Cl2 isomer of 7a, and synthe-
ses of similar S-chelated complexes described in the litera-
ture.[9b,10a] In contrast, for ligands substituted at the 6-position
of the benzylidene ring (5b-d; R¼ H) an alternative mechanism
operates. Accordingly, when the chelating conformation pre-
vails in the exchange process, the SMe coordination site of the
chelating ligand begins to interact with the ruthenium center
in the initial steps, giving a transient structure Bc,[13] which de-
coordinates olefin directly to complex cis-Cl2. As ligand 5a (R=
H) forms a kinetic trans-Cl2 product, and the direct formation
of cis-Cl2 isomers is observed only for 5b–d (R¼ H), it becomes
apparent that the first pathway, realized by a nonchelating
Scheme 5. Syntheses of O-chelated complexes 9a–c, and their transQcis-Cl2
1
equilibria detected with H NMR EXSY at 808C.[11] [a] A longer reaction time
(4.5 h) was required to complete conversion of 6; [b] the structure of com-
plex 9b was confirmed with X-ray studies; [c] contents of the isomers ob-
1
served in CD2Cl2 at RT by H NMR.
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Acknowledgements
This work was financed by the Iuventus Plus program of the
Polish Ministry of Science and Higher Education (Grant No.
IP2012 001972, 2013–2015). NMR studies presented in the
report were carried out at the Biological and Chemical Re-
search Centre, University of Warsaw, established within the
project cofinanced by the European Union from the European
Regional Development Fund under the Operational Pro-
gramme Innovative Economy, 2007–2013. The authors thank
the Umicore AG & Co. KG for donation of the M2 complex, and
Prof. Karol Grela for support and the opportunity to perform
independent research in the field.
Figure 3. Activity profiles of complexes 9a–c in RCM of DEDAM in 0.2m sol-
1
utions detected by H NMR. The catalysts were tested at 0.2 mol% at 258C
Keywords: conformers · isomerization · mechanistic studies ·
metathesis · NMR spectroscopy
(left), and 1.0 mol% at 558C (in sealed tubes; right).[11]
(558C). Similar differences were observed also in reactions of
the complexes with excess of PCy3. As observed by 1H NMR
measurements, unsubstituted complex 9a easily transformed
into adduct, similar to 2 (cf. Scheme 1), whereas under the
same conditions 9b and 9c did not react, suggesting pro-
nounced difficulties for formation of 6-coordinated struc-
tures.[11] Interestingly, in contrast to properties of 1, the OMe-
chelated complexes existed in two forms in CD2Cl2 at RT, and
displayed equilibria observed with NMR EXSY studies at higher
temperatures. On the base of literature data[16] we assigned
the dynamic process to the fast transQcis-Cl2 isomerization in
solution.[9b,10,17] In this case the substitution of benzylidene ring
had only a limited effect on contents of the individual forms,
slightly destabilizing the minor cis-Cl2 isomers for complexes
9b and 9c (R¼ H).
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In conclusion, we have presented a conformational model,
which describes an exchange process of chelating benzylidene
ligand in Hoveyda–Grubbs metathesis catalysts. Accordingly,
the formation of S-chelated complexes proceeds through
a nonchelating conformation, which minimizes interaction of
the SMe coordinating site with the ruthenium center, giving ki-
netic trans-Cl2 isomers. However, substitution at the 6-position
of the benzylidene ring varies the preference toward a chelat-
ing conformation and, as a consequence, the complexes form
directly as cis-Cl2 structures. The differences concern also a re-
verse process of catalyst initiation. The nonchelating conforma-
tion of benzylidene ligand enables its stepwise decoordination
by opening of the chelate ring followed by a metathesis cycle.
However, when the conformation is not available, an associa-
tive mechanism operates, requiring formation of six-coordinat-
ed intermediate, and breaking of the Ru···heteroatom bond in
the course of the metathesis cycle.
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[14] An alternative mode of coordination by R group (for R=OMe and Me
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Experimental Section
CCDC 1044950, 1044951, 1044952, 1055099, and 1055105 (cis-7b,
9b, cis-7c, trans-7a, and trans-7c, respectively) contain the supple-
mentary crystallographic data for this paper. These data are provid-
ed free of charge by The Cambridge Crystallographic Data Centre.
Received: May 19, 2015
Published online on June 12, 2015
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