Nonproductive events in ring-closing metathesis using ruthenium catalysts

Article abstract of DOI:10.1021/ja1029045

The relative TONs of productive and nonproductive metathesis reactions of diethyl diallylmalonate are compared for eight different ruthenium-based catalysts. Nonproductive cross metathesis is proposed to involve a chain-carrying ruthenium methylidene. A second more-challenging substrate (dimethyl allylmethylallylmalonate) that forms a trisubstituted olefin product is used to further delineate the effect of catalyst structure on the relative efficiencies of these processes. A steric model is proposed to explain the observed trends.

Full text of DOI:10.1021/ja1029045

Published on Web 06/02/2010
Nonproductive Events in Ring-Closing Metathesis Using Ruthenium Catalysts
Ian C. Stewart, Benjamin K. Keitz, Kevin M. Kuhn, Renee M. Thomas, and Robert H. Grubbs*
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125
Received April 6, 2010; E-mail: rhg@caltech.edu
The widespread application of olefin metathesis in various fields
of chemical synthesis has fueled the continued search for transition
metal catalysts that exhibit high reactivity, selectivity, and stability.1
Studies have described the effect on reactivity upon modifying every
ligand of ruthenium-based catalysts. Generally, activity is reported as
yield or turnover number (TON) for the reaction of a substrate of
interest, which does not account for nonproductive metathesis events.
The role of nonproductive metathesis in the cross metathesis (CM)
of terminal olefins has been studied in detail for early hetero- and
homogeneous molybdenum and tungsten catalysts.2 In general, the rate
of degenerate metathesis greatly exceeds that of the productive
metathesis reactions and evidence suggests the chain-carrying inter-
mediate is a metal alkylidene (M)CHR), not a methylidene (M)CH2).
Thus, the TON determined from the amount of product formed is less
than the total number of metathesis events that the catalyst has
accomplished. An efficient catalyst must perform many turnovers and
be selective for productive pathways. Although degenerate reactions
do not result in a net change in concentration of the catalyst or the
substrate, they can provide additional opportunities for catalyst
decomposition and, therefore, can decrease efficiency. Recently,
Hoveyda and Schrock reported that degenerate processes in asymmetric
ring-closing metathesis (RCM) reactions are both prevalent and key
to achieving high levels of enantioselectivity.3
methylene exchange could take place via an R,R-disubstituted
metallacycle (13) by coordination of a substrate molecule to
ruthenium alkylidene 12 (eq 2).
To investigate these productive and nonproductive pathways,
diethyl d2-diethyldiallylmalonate (9-d2) was prepared and subjected
to catalysts 1-8. The conversion to cyclopentene 14 was monitored
by GC, while degenerate metathesis reactions were monitored by
the appearance of 9-d0 and 9-d4 by TOF-MS (Scheme 1).6,7
Scheme 1. Assay for Nonproductive RCM of 9
While measuring conversion of substrate is a common and
straightforward method of assessing catalyst activity in olefin
metathesis, and other catalytic reactions, degenerate metathesis
reactions must also be assayed to provide a more complete picture
of catalyst efficiency. No data on the rates of degenerate processes
are available for modern ruthenium-based catalysts (Chart 14), or
for RCM reactions. Herein we report studies aimed at understanding
the relative rates of degenerate and productive metathesis reactions.
Chart 1. Ruthenium-Based Olefin Metathesis Catalysts
Figure 1. Plot of nonproductive versus productive conversion for the RCM
reactions shown in Scheme 1. Reaction conditions were 50 °C in toluene
(1 mL) with substrate (0.1 mmol) and catalyst (1 - 1000 ppm, 2, 3, 4, 5
- 250 ppm, 6 - 500 ppm, 7 - 5000 ppm, 8 - 1000 ppm).
Diethyl diallylmalonate (9) and allylmethallylmalonate (15) have
become benchmark substrates for evaluation of olefin metathesis
catalysts in RCM.5 Besides the productive pathway, there are at
least two potential nonproductive pathways. The first begins with
a ruthenium methylidene (10) and forms a ꢀ-substituted metalla-
cycle (11); breakdown of this intermediate regenerates the starting
material but exchanges the methylene termini (eq 1). Alternatively,
Figure 1 shows the degenerate TON versus productive TON.
Surprisingly, significant levels of degenerate events were detected
with many catalysts. NHC-bearing catalysts 2-4 display degenerate/
9
8534 J. AM. CHEM. SOC. 2010, 132, 8534–8535
10.1021/ja1029045  2010 American Chemical Society

C O M M U N I C A T I O N S
productive ratios of approximately 1:10, while that for 5, which is
a catalyst containing the bulky 2,6-diisopropylphenyl (DIPP)
substituent, is closer to 1:4. Cyclic alkylaminocarbene (CAAC)-
containing catalyst 6 catalyzes a nearly equal number of degenerate
and productive metathesis events, as do N-alkyl catalysts 7-8.
Catalyst 5 was evaluated at two concentrations, and no change in
the ratio of degenerate to productive metathesis events was detected;
this is highly suggestive that nonproductive metathesis events are
catalyzed by a methylidene species (eq 1), as the alternative mechanism
(eq 2) is second order in substrate and would be expected to have
some concentration dependence.
to a productive turnover event; the second generates a ꢀ-substituted
metallacycle (path b), which exchanges the olefin termini but does
not generate a molecule of product. The nonproductive pathway is
especially facile with catalysts 6-8 due to the absence of any
significant steric interactions between the ligand and the approaching
olefin en route to the ꢀ-substituted metallacycle. Catalysts with
symmetric and bulky groups (e.g., N-2,6-iPr2Ph on both sides of 5)
would experience similar interactions along path a but increased steric
repulsion along path b, resulting in fewer nonproductive events and
thus higher overall efficiency.
Scheme 3. Steric Model for Ligand Effect on Nonproductive Metathesis
To evaluate the significance of degenerate metathesis in the RCM
of a more challenging substrate, deuterated dimethyl allylmethallyl-
malonate 15-d8 was prepared. A mixture of this isotopomer and the
per-protio compound (15-d0) was prepared and subjected to catalysts
1-8 (Scheme 2). Nonproductive metathesis was measured via TOF-
MS by monitoring the appearance of 15-d6 and 15-d2. Again, NHC
catalysts 2-4 perform the fewest degenerate events; in fact almost
none were detected with 4 (Figure 2). Bulky NHC-bearing complex 5
and diphosphine catalyst 1 perform around one degenerate event for
every two productive turnovers. Catalysts 6-8, however, perform two
or more nonproductiVe reactions for eVery productiVe RCM eVent.
As in the RCM of 9, no concentration dependence on the ratio of
degenerate to productive turnovers was detected with catalyst 5.
Herein we have described the study of nonproductive reactions
in ring-closing metathesis using ruthenium catalysts. The number
of nonproductive events in relatively simple substrates is strikingly
high but comparable with early work on hetereogeneous systems.
The steric model proposed can be applied to other important
metathesis processes where selectivity is important.
Scheme 2. Assay for Nonproductive RCM of 15
Acknowledgment. The NIH (K99GM084302 to I.C.S., 5RO1GM-
31332 to R.H.G.) for generous financial support, Hosea Nelson and Brian
M. Stoltz (Caltech) for assistance with and use of their TOF-MS
instrument, and Scott Virgil (Caltech Center for Catalysis and Chemical
Synthesis) for assistance with automation and analytical equipment.
Supporting Information Available: Experimental procedures and
details of quantitative analysis. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH:Weinheim, Germany,
2003 and references cited therein. (b) Hoveyda, A. H.; Zhugralin, A. R.
Nature 2007, 450, 243–251. (c) Schrodi, Y.; Pederson, R. L. Aldrichimica
Acta 2007, 40, 45–52. (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490–4527. (e) Grubbs, R. H. Tetrahedron 2004,
60, 7117–7140. (f) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013–3043.
(2) (a) Casey, C. P.; Tuinstra, H. E. J. Am. Chem. Soc. 1978, 100, 2270–2272.
(b) Casey, C. P.; Tuinstra, H. E.; Saeman, M. C. J. Am. Chem. Soc. 1976,
98, 608–609. (c) Handzlik, J. J. Mol. Catal. A 2004, 218, 91–100. (d)
McGinnis, J.; Katz, T. J.; Hurwitz, S. J. Am. Chem. Soc. 1976, 98, 605–
606. (e) Tanaka, K.; Takeo, H.; Matsumura, C. J. Am. Chem. Soc. 1987,
109, 2422–2425.
(3) Meek, S. M.; Malcolmson, S. J.; Li, B.; Schrock, R. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2009, 131, 16407–16409.
Figure 2. Plot of nonproductive TON versus productive TON for the RCM
reactions shown in Scheme 2. Reaction conditions were 50 °C in toluene
(1 mL) with substrate (0.1 mmol) and catalyst (1 - 1000 ppm, 2, 3, 4, 5
- 250 ppm, 6 - 500 ppm, 7 - 5000 ppm, 8 - 1000 ppm).
(4) For the original report of catalysts 1-6 used in this study, see, respectively: (a)
Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100–
110. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956. (c) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799. (d) Stewart, I. C.; Ung, T.;
Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9,
1589–1592. (e) Courchay, F. C.; Sworen, J. C.; Wagener, K. B. Macromol-
ecules 2003, 36, 8231–8239. (f) Anderson, D. R.; Lavallo, V.; O’Leary, D. J.;
Bertrand, G.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 7262–7265.
(5) (a) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. Organometallics
2006, 25, 5740–5745. (b) Kuhn, K. M.; Bourg, J.-B.; Chung, C. K.; Virgil,
S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 5313–5320.
(6) Note that exchanges of olefin termini that do not result in a change in isotopic
composition are also occurring. For a complete discussion of how degenerate
TONs were calculated see the Supporting Information. Isotope effects are
beyond the scope of the current discussion.
From these two data sets, it is plausible to propose that sterics is
the overriding determinant of the relative rates of degenerate to
productive events. Specifically, a catalyst bearing an unsymmetric
carbene ligand with significantly different-sized groups will favor
degenerate metathesis pathways (e.g., CMe2 vs N-2,6-Et2Ph in 6, N-Me
vs N-2,6-iPr2Ph in 7, N-Et vs N-2,4,6-Me3Ph in 8). Scheme 3 illustrates
this model beginning with the methylidene derived from catalyst 7.
Coordination of a terminal olefin can proceed with two possible
regiochemistries: the first generates an R-substituted metallacycle (path
a) and results in the formation of an alkylidene that ultimately leads
(7) For a discussion on the reversibility of the RCM reaction, see the Supporting
Information.
JA1029045
9
J. AM. CHEM. SOC. VOL. 132, NO. 25, 2010 8535