Synthesis, isolation, characterization, and reactivity of high-energy stereogenic-at-Ru carbenes: Stereochemical inversion through olefin metathesis and other pathways

Article abstract of DOI:10.1021/ja3056722

The synthesis, isolation, purification (routine silica gel chromatography), and spectroscopic characterization of high-energy endo stereogenic-at-Ru complex isomers, generated by ring-opening/cross-metathesis (ROCM) reaction of the corresponding exo carbe

Full text of DOI:10.1021/ja3056722

Communication
pubs.acs.org/JACS
Synthesis, Isolation, Characterization, and Reactivity of High-Energy
Stereogenic-at-Ru Carbenes: Stereochemical Inversion through
Olefin Metathesis and Other Pathways
R. Kashif M. Khan,† Adil R. Zhugralin,† Sebastian Torker, Robert V. O’Brien, Pamela J. Lombardi,
and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
findings in providing a better understanding of representative
previous observations.
Ru-based complexes bearing a bidentate N-heterocyclic
carbene (NHC) or phosphine ligand exist in two diastereo-
meric forms (Scheme 1) that are energetically distinct and can
ABSTRACT: The synthesis, isolation, purification (rou-
tine silica gel chromatography), and spectroscopic
characterization of high-energy endo stereogenic-at-Ru
complex isomers, generated by ring-opening/cross-meta-
thesis (ROCM) reaction of the corresponding exo
carbenes, are disclosed. We provide experimental evidence
showing that an endo isomer can undergo thermal or
Brønsted acid-catalyzed polytopal rearrangement, causing
conversion to the energetically favored exo carbene.
Scheme 1. OM-Induced Stereochemical Inversion
n the course of an olefin metathesis (OM) reaction,1 the
catalyst structure undergoes numerous changes, and the
I
metal center serves as the pivot around which these variations
occur.2 Many such alterations are unobservable in an achiral
complex. The study of stereogenic-at-metal complexes,
however, offers the opportunity to probe the nature of these
mechanistic nuances: stereochemical inversion might be
exploited to monitor structural modifications taking place
during a catalytic cycle.3 Investigations along these lines would
shed light on the inner workings of stereogenic-at-Ru carbenes,
represented by 1−34−6 (Figure 1), an emerging class of
play critical and complementary roles.11 In the case of exo- and
endo-4 derived from exo-1a, the former represents the resting
state of the complex, whereas the latter is less abundant but
more reactive (ΔE = 3−4 kcal/mol).12 We recently
demonstrated that in Z- and enantioselective reactions
involving the less active Fischer-type carbenes derived from
enol ethers, the higher-energy endo complex, which is
accessible by facile interconversion of the two diastereomeric
forms, is likely responsible for catalyzing OM (Curtin−
Hammett kinetics).12 In instances where the catalytic cycle
can commence with the lower-energy exo isomer, the endo
species reacts with another substrate molecule to regenerate the
more favored carbene, releasing the desired product. A more
extensive understanding of the attributes of the higher-energy
endo carbene and the factors that facilitate its isomerization to
the alternative exo isomer is critical for an appreciation of the
principles that control catalytic OM.
Figure 1. Stereogenic-at-Ru complexes used in olefin metathesis.
The OM reaction of an exo Ru complex (e.g., exo-4)
produces an endo carbene via a metallacyclobutane such as 5
(Scheme 1).13 The higher energy of the endo isomer accounts
for the fact that protocols for the preparation of stereogenic-at-
Ru complexes afford exo carbenes exclusively, without
detection of the endo isomers (as determined by spectroscopic
studies and X-ray crystallography).14 Several energetically
favored complexes bearing a bidentate o-alkoxybenzylidene
ligand have been isolated and characterized (including X-ray
complexes used for stereo- and sequence-selective OM.5,7,8
Herein we disclose the results of our studies regarding the
fluxionality9 of carbenes derived from 1a. We have synthesized,
isolated, and characterized the higher-energy stereogenic-at-Ru
endo isomers (cf. Scheme 1) generated by a single stereo-
chemical inversion through a ring-opening/cross-metathesis
(ROCM) reaction with the exo carbene (1a).10 By studying the
chemistry of the endo complex, we have established that
inversion can be induced thermally or catalyzed by a Brønsted
acid, all of which constitute non-OM-based polytopal rearrange-
ments. We briefly discuss the significance of the present
Received: June 11, 2012
Published: July 20, 2012
© 2012 American Chemical Society
12438
dx.doi.org/10.1021/ja3056722 | J. Am. Chem. Soc. 2012, 134, 12438−12441

Journal of the American Chemical Society
Communication
structures);4a,5,6,14 in contrast, data associated with a kinetically
stable and more reactive endo species do not exist.15 To
generate a well-defined endo carbene, we chose to probe the
reaction of exo-1a with cis-3,4-diisopropoxycyclobutene (6),
which was selected as the substrate for two reasons: the high
reactivity of the strained ring ensures facile ROCM, and
additionally, an isopropoxy group, by internal chelation with
the Ru center (cf. 1a), would improve stability, facilitating
isolation of the more reactive endo complex.
Treatment of exo-1a with cyclobutene 6 (22 °C, C6D6) led to
the disappearance of the exo carbene [16.0 ppm; Figure 2,
Figure 3. Reaction of endo-7a with styrene, leading to exo carbenes 9
and exo-7aanti, and 1H NMR spectra (C6D6) of (a) the reaction
mixture prior to purification and (b) the mixture from treatment of
pure 1a with 10 equiv of styrene (50 °C, 24 h). Percent values
correspond to conversion determined by analysis of 400 MHz 1H
NMR analysis of the unpurified mixture; 8% conv to 7asyn and 4%
conv to unidentified carbene. See the SI for details.
Figure 4c), the entity responsible for the signal at 16.41 ppm
[additionally, the minor carbene at 16.24 ppm is exo-7asyn; cf.
Figure 2. Syntheses of endo-7a and endo-7b by ROCM (yields are of
pure products), and H NMR spectra (C6D6) of (a) pure 1a, (b) the
mixture prior to purification, and (c) pure endo-7a after silica gel
chromatography. See the Supporting Information (SI) for details.
Figure 4].16 The relatively upfield chemical shift in exo-7aanti
,
1
similar to that in 1a and the related complexes,19 indicates that
the i-PrO ligand is chelated opposite to the NHC (carbene H
oriented toward Mes).
spectrum (a)] and generation of endo-7a,16 as indicated by the
It is doubtful that exo-7aanti is formed through OM via endo-
7a, as the two complexes differ only in the stereochemistry at
the Ru center. It is likely that exo-7aanti is generated by non-
OM-induced rearrangement of endo-7a. Another implication of
the transformation in Figure 3 is that the rate of endo-7a to exo-
7aanti isomerization can be competitive with OM. Given the
central roles of stereoisomeric complexes and the significance
of a possible nonmetathetic interconversion of the two
carbenes, we set out to assemble additional information on
non-OM-based isomerization processes.
1
appearance of a major signal at 17.07 ppm in the H NMR
spectrum [Figure 2, spectrum (b)].17 The downfield shift of the
peak is consistent with the formation of an endo complex, since
in an exo isomer the carbene proton would reside below the
face of the mesityl (Mes) moiety (anisotropic effect).18
Furthermore, we were able to isolate and purify samples of
endo-7a by routine silica gel chromatography (42% yield).
Similarly, F-substituted endo-7b (41% yield) was accessed by
the reaction of exo-1b with 6. With a sample of pure endo-7b
available, we secured additional support regarding the stereo-
chemical identity of the product of the aforementioned ROCM
reactions through 19F−1H heteronuclear Overhauser effect
spectroscopy (HOESY) experiments (Figure 2). The same
enhancement was not detected with exo-1b.
We heated a solution of endo-7a under the conditions shown
in Figure 3 (50 °C) but in the absence of styrene. After 6 h, as
1
indicated by the H NMR spectra in Figure 4, two major new
carbene signals appeared: one at 16.41 ppm, corresponding to
exo-7aanti, and another at 16.24 ppm. The latter peak was
transient: following an initial burst in intensity, it diminished
and then disappeared within 18 h, concomitant with an increase
An examination of the chemistry of endo-7a ensued.
Treatment of pure endo-7a with 11.0 equiv of styrene (C6D6,
50 °C, 12 h) led to the formation of cross-metathesis product 8
in the area corresponding to the signal for exo-7aanti
.
1
(51% yield; Figure 3). The H NMR spectrum of the mixture
Nonetheless, we isolated and purified the less stable carbene
(signal at 16.24 ppm) chromatographically, as it is considerably
more polar than exo complexes exo-1a and exo-7aanti as well as
endo-7a. By probing the identity of the relatively fleeting
complex by spectroscopic analysis,16 we established its identity
as exo-7asyn, in which the isopropoxy group is chelated syn to
the NHC ligand (Figure 4); the upfield shift of the carbene
proton of exo-7asyn relative to exo-7aanti is likely due to the
anisotropic effect induced by the proximal anionic aryloxide
exhibits one carbene signal at 17.68 ppm and another, with
higher intensity, at 16.41 ppm (Figure 3a). The more downfield
singlet likely arises from exo-benzylidene 9 formed by the
reaction with styrene; this contention is supported by the
observation that treatment of 1a with the aryl olefin led to the
appearance of the same signal (Figure 3b). Although we were
unable to isolate complex 9 because of its rapid decomposition,
we did succeed in purifying and characterizing exo-7aanti (cf.
12439
dx.doi.org/10.1021/ja3056722 | J. Am. Chem. Soc. 2012, 134, 12438−12441

Journal of the American Chemical Society
Communication
We then considered what other commonly encountered
conditions, in addition to elevated temperatures, might
promote non-metathesis-based interconversions of stereo-
genic-at-Ru complexes. Since a hallmark of Ru catalysts is
their constitutional (vs stereochemical) stability toward func-
tional groups that carry an acidic proton, we set out to establish
whether polytopal isomerization can occur in the presence of a
Brønsted acid. Such a possibility was founded on the hypothesis
that rearrangement of an endo carbene such as endo-7a to the
exo carbenes exo-7aanti and exo-7asyn likely proceeds via
complexes in which the carbene and the aryloxide ligand
both strong donor groupsare situated in an anti orientation
(cf. IV in Scheme 2). We envisioned that diminution of the
aryloxide’s donor ability, achieved through its interaction with
an appropriate Lewis acid, might lower the barrier needed for
the isomerization. The above deliberations led us to discover
that, as illustrated in Scheme 3, treatment of endo-7a with 12
Scheme 3. Acid-Catalyzed Polytopal Rearrangement
Figure 4. Thermal rearrangement of endo-7a, leading to exo-7asyn and
exo-7aanti, and H NMR spectra (C6D6) of (a) the reaction mixture
1
after 6.0 h, (b) isolated and purified exo-7asyn, and (c) isolated exo-
7aanti. See the SI for details.
ligand.20 The higher polarity of exo-7asyn probably results from
the syn orientation of the anionic iodide and aryloxide ligands
(anti in exo-1a, endo-7a, and exo-7aanti; isopropyl ether is a
neutral ligand).21 The calculated structure of exo-7asyn exhibits a
larger dipole moment than the other complexes (9.49 D for
exo-7asyn vs 2.76, 3.88, and 2.62 D for exo-1a, endo-7a, and exo-
7aanti, respectively). When pure exo-7asyn was heated for several
hours, it was transformed to exo-7aanti, showing that the
conversion of endo-7a to exo-7aanti can proceed via exo-7asyn.
Kinetic studies confirmed that the formation of exo-7aanti is
first-order in endo-7a and occurs by a unimolecular process.14
An OM reaction, as outlined in Scheme 2 (top), converts a
Ru−alkene complex, such as that derived from I (cf. endo-7a),
to a Ru carbene exemplified by III (cf. exo-7aanti) via
metallacyclobutane II (cf. 5 in Scheme 1); such a trans-
formation can be regarded as a series of polytopal rearrange-
ments22 that involve bond cleavage and formation and lead to
stereochemical inversion. As depicted in Scheme 2, endo-7a (cf.
I) can also be converted to exo-7aanti via IV−VI by a non-OM-
based process consisting of polytopal rearrangements.22 A key
conclusion of the present study is that in competition with
metathesis-based polytopal rearrangements, isomerizations by
nonmetathetic pathways can occur, impacting the efficiency and
selectivity of the overall process.
mol % HOAc at 22 °C (C6D6) resulted in 68% conversion to
exo-7asyn (cf. V in Scheme 2) within only 1 h (vs >98% conv to
exo-7aanti in 24 h by heating);22 with 1.0 equiv of HOAc,
isomerization was complete in less than 5 min. To ascertain
that conversion to exo-7asyn was not induced by coordination of
the Lewis basic23 carbonyl of acetic acid with the Ru center, we
treated endo-7a with acetone, dimethyl sulfoxide, and MeOH,
none of which led to any detectable change (<2%).
Unlike the conversion of endo-7a to exo-7asyn, the isomer-
ization of exo-7asyn to exo-7aanti is not facilitated by acetic acid
(Scheme 3). The latter rearrangement does not involve the
intermediacy of Ru complexes in which the aryloxide ligand is
positioned trans to the carbene (cf. VI in Scheme 2); the
presence of HOAc therefore does not impact the rearrange-
ment. In principle, generation of exo-7aanti via exo-7asyn can
occur by an isopropoxy group dissociation/carbene bond
rotation/reassociation pathway. Theoretical studies of quino-
line-chelated nonstereogenic-at-Ru complexes have revealed
that the aforementioned route and the polytopal rearragement
pathway might be energetically similar.24 Nonetheless, it is
unlikely that loss of chelation/rechelation is facile; otherwise,
isolation of exo-7asyn would not be feasible.
Scheme 2. Two Pathways for Stereochemical Inversion
The knowledge that Ru carbenes undergo competitive
stereoisomerizations that are not induced by OM provides
insight regarding the origin of some of the existing reactivity
and selectivity profiles. The present systems involve association
of oxygen-based chelates with the Ru center in place of an
alkene. It is thus likely that the less structurally rigid complexes
with a monodentate NHC and/or a carbene more readily
undergo polytopal isomerizations, including OM reactions.7a
12440
dx.doi.org/10.1021/ja3056722 | J. Am. Chem. Soc. 2012, 134, 12438−12441

Journal of the American Chemical Society
Communication
(5) (a) Bornand, M.; Chen, P. Angew. Chem., Int. Ed. 2005, 44, 7909.
(b) Bornand, M.; Torker, S.; Chen, P. Organometallics 2007, 26, 3585.
(c) Torker, S.; Muller, A.; Sigrist, R.; Chen, P. Organometallics 2010,
29, 2735.
(6) Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs, R. H.
J. Am. Chem. Soc. 2012, 134, 693 and references cited therein.
(7) For stereogenic-at-Mo catalysts, see: (a) Malcolmson, S. J.; Meek,
S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456,
933. (b) Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.;
Hoveyda, A. H. Nature 2011, 471, 461.
(8) For stereogenic-at-W catalysts, see: Yu, M.; Wang, C.; Kyle, A. F.;
Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011,
479, 88.
(9) (a) Berry, R. S. J. Chem. Phys. 1960, 32, 933. (b) Muetterties, E.
L. J. Am. Chem. Soc. 1969, 91, 1636. (c) Gillespie, P.; Hoffman, P.;
Klusacek, H.; Marquarding, D.; Pfohl, S.; Ramirez, F.; Tsolis, E. A.;
Ugi, I. Angew. Chem., Int. Ed. Engl. 1971, 10, 687.
The nonmetathetic interconversions of higher-energy carbenes
can account for errors in copolymerization of alkene substrates
performed with complexes such as 2 (Figure 1).5 Another
example pertains to catalytic ROCM performed with 1a; high
enantioselectivity likely demands that only one of the two
forms participate in the stereochemistry-determining RO step;
the less energetic exo species participates in RO of the strained
alkene, and the endo carbene is involved in product-releasing
CM.11b Conditions that promote out-of-sequence non-OM-
based isomerization of the higher-energy endo carbene
engender diminished enantioselectivities. Such considerations
provide a rationale for the enantioselectivity differences in
enantiomeric ratio (er) values in Ru-catalyzed ROCM of
oxabicyclic alkenes such as 10 with aryl- versus alkyl-substituted
terminal olefins (eq 1).25 Since there is minimal non-OM-based
(10) The designation is used according to whether the RuC bond
is exo or endo with respect to the azaoxaruthenacycle.
(11) (a) Reference 5a. (b) Hoveyda, A. H.; Malcolmson, S. J.; Meek,
S. J.; Zhugralin, A. R. Angew. Chem., Int. Ed. 2010, 49, 34.
(12) Khan, R. K. M.; O’Brien, R. V.; Torker, S.; Li, B.; Hoveyda, A.
H. J. Am. Chem. Soc. 2012, DOI: 10.1021/ja304827a.
(13) For studies regarding structures of Ru-based metallacyclobu-
tanes, see: (a) Romero, P. E.; Piers, W. E. J. Am. Chem. Soc. 2005, 127,
5032. (b) Wenzel, A. G.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128,
16048. (c) van der Eide, E. F.; Romero, P. E.; Piers, W. E. J. Am. Chem.
Soc. 2008, 130, 4485. (d) Van der Eide, E. F.; Piers, W. E. Nat. Chem.
2010, 2, 571.
isomerization with the faster-forming benzylidene intermedi-
ates, 11a is obtained in higher enantioselectivity than 11b (i.e.,
less out-of-sequence interconversion with the aryl olefin).
More detailed computational and mechanistic studies and
utilization of the concepts described above in the design of
more efficient catalysts and stereoselective OM protocols are
underway.
(14) See the Supporting Information (SI) for details.
(15) One endo isomer of a phosphine complex related to 2 (vs
bidentate benzylidenes as in 1−3) that is thermodynamically stabilized
by a C−H agostic interaction has been isolated and characterized (see
ref 5b).
(16) For detailed spectroscopic analyses to establish the identity of
Ru complexes, see the SI.
(17) The calculated shift for the signal corresponding to endo-7a is
similar in value to that measured experimentally (in CDCl3, calcd
17.01 ppm, exptl 16.82 ppm). See the SI for details.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral and analytical data for all
products, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(18) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791.
(19) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(20) Similar characteristics have been disclosed for a Ru-based
bidentate carbene with a sulfide bridge syn to the NHC complex. See:
Ben-Asuly, A.; Tzur, E.; Diesendruck, C. E.; Sigalov, M.; Goldberg, I.;
Lemcoff, N. G. Organometallics 2008, 27, 811.
AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
■
Author Contributions
†R.K.M.K. and A.R.Z. contributed equally.
(21) A Ru complex is more polar when a bidentate carbene is
chelated syn to the NHC than when associated anti to the same ligand.
See: (a) Benitez, E.; Goddard, W. A., III. J. Am. Chem. Soc. 2005, 127,
12218. (b) Correa, A.; Cavallo, L. J. Am. Chem. Soc. 2006, 128, 13352.
(22) For mechanistic aspects of polytopal rearrangements, see:
(a) Couzijn, E. P. A.; Slootweg, J. C.; Ehlers, A. W.; Lammertsma, K. J.
Am. Chem. Soc. 2010, 132, 18127 and references cited therein.
(b) Moberg, C. Angew. Chem., Int. Ed. 2011, 50, 10290. For related
isomerizations involving Ru complexes, see: (c) Hoffman, P. R.;
Caulton, K. G. J. Am. Chem. Soc. 1975, 97, 4221. (d) Krassowski, D.
W.; Nelson, J. H.; Brower, K. R.; Hauenstein, D.; Jaconson, R. A. Inorg.
Chem. 1988, 27, 4294.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSF (CHE-0715138
and 1111074). A.R.Z. and R.V.O. were LaMattina Graduate
Fellows and S.T. was a Swiss NSF Postdoctoral Fellow.
REFERENCES
■
(1) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
(2) For the mechanism of Ru-catalyzed OM, see: (a) Sanford, M. S.;
Love, J. A. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vol. 1, p 112. (b) Adlhart, C.; Chen, P. J.
Am. Chem. Soc. 2004, 126, 3496.
(23) Marinescu, S. C.; Schrock, R. R.; Li, B.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 58.
(24) Poater, A.; Ragone, F.; Correa, A.; Szadkowska, A.;
Barbasiewicz, M.; Grela, K.; Cavallo, L. Chem.Eur. J. 2010, 16,
14354.
(25) In regard to the slower reaction of alkyl- vs aryl-substituted
terminal olefins with Ru-based carbenes, see: Lane, D. R.; Beavers, C.
M.; Olmstead, M. M.; Schore, N. E. Organometallics 2009, 28, 6789.
(3) Meek, S. J.; Malcolmson, S. J.; Li, B.; Schrock, R. R.; Hoveyda, A.
H. J. Am. Chem. Soc. 2009, 131, 16407.
(4) (a) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 4954. (b) Van Veldhuizen, J. J.;
Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 12502. (c) Van Veldhuizen, J. J.; Campbell, J. E.;
Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877.
12441
dx.doi.org/10.1021/ja3056722 | J. Am. Chem. Soc. 2012, 134, 12438−12441