Olefin metathesis in homogeneous aqueous media catalyzed by conventional ruthenium catalysts

Article abstract of DOI:10.1021/ol7022505

(Chemical Equation Presented) Olefin metathesis in aqueous solvents is sought for applications in green chemistry and with the hydrophilic substrates of chemical biology, such as proteins and polysaccharides. Most demonstrations of metathesis in water, however, utilize exotic complexes. We have examined the performance of conventional catalysts in homogeneous water/organic mixtures, finding that the second-generation Hoveyda-Grubbs catalyst has extraordinary efficiency in aqueous dimethoxyethane and aqueous acetone. High (71-95%) conversions are achieved for ring-closing and cross metathesis of a variety of substrates in these solvent systems.

Full text of DOI:10.1021/ol7022505

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4885-4888
Olefin Metathesis in Homogeneous
Aqueous Media Catalyzed by
Conventional Ruthenium Catalysts
Joseph B. Binder,† Jacqueline J. Blank,‡ and Ronald T. Raines*,†,‡
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1322, and Department of Biochemistry, UniVersity of
Wisconsin-Madison, 433 Babcock DriVe, Madison, Wisconsin 53706-1544
raines@biochem.wisc.edu
Received September 13, 2007
ABSTRACT
Olefin metathesis in aqueous solvents is sought for applications in green chemistry and with the hydrophilic substrates of chemical biology,
such as proteins and polysaccharides. Most demonstrations of metathesis in water, however, utilize exotic complexes. We have examined the
performance of conventional catalysts in homogeneous water/organic mixtures, finding that the second-generation Hoveyda
−Grubbs catalyst
has extraordinary efficiency in aqueous dimethoxyethane and aqueous acetone. High (71−95%) conversions are achieved for ring-closing and
cross metathesis of a variety of substrates in these solvent systems.
As a highly effective means for creating carbon-carbon
bonds, olefin metathesis is a privileged reaction in the
armamentarium of synthetic and polymer chemists.1 Readily
available and highly active ruthenium catalysts 1-4 have
popularized metathesis chemistry in organic solvents (Figure
1).2,3 On the other hand, metathesis in aqueous solvents
largely remains the domain of catalysts designed expressly
for use in water (Figure 2).4-6 Despite the allure of aqueous
olefin metathesis for biological applications7 and green
chemistry,8 the synthesis of these water-soluble ligands and
complexes imposes barriers to their wider use. Developing
aqueous reaction conditions suitable for catalysts such as 1-4
is an alternative approach. In the initial work with well-
(4) (a) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996,
15, 4317-4325. (b) Binder, J. B.; Guzei, I., A.; Raines, R. T. AdV. Synth.
Catal. 2007, 349, 395-404.
(5) (a) Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508-
3509. (b) Jordan, J. P.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46,
5152-5155.
(6) Connon, S. J.; Rivard, M.; Zaja, M.; Blechert, S. AdV. Synth. Catal.
2003, 345, 572-575.
† Department of Chemistry.
‡ Department of Biochemistry.
(7) (a) Banasiak, D. S. J. Mol. Catal. A: Chem. 1985, 28, 107-115. (b)
Mortell, K. H.; Gingras, M.; Kiessling, L. L. J. Am. Chem. Soc. 1994, 116,
12053-12054. (c) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 9606-9614. (c) Jenkins, C. L.; Vasbinder, M. M.;
Miller, S. J.; Raines, R. T. Org. Lett. 2005, 7, 2619-2622. (d) Stymiest, J.
L.; Mitchell, B. F.; Wong, S.; Vederas, J. C. J. Org. Chem. 2005, 70, 7799-
7809.
(1) (a) Grubbs, R. H., Handbook of Metathesis; Wiley-VCH: Weinheim,
Germany, 2003. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D., Angew.
Chem., Int. Ed. 2005, 44, 4490-4527. (c) Schrock, R. R. Angew. Chem.,
Int. Ed. 2006, 45, 3748-3759. (d) Grubbs, R. H. Angew. Chem., Int. Ed.
2006, 45, 3760-3765.
(2) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110. (b) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.,
Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (c) Scholl,
M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
(3) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(8) (a) Streck, R. J. Mol. Catal. 1992, 76, 359-372. (b) Yao, Q.; Zhang,
Y. Angew. Chem., Int. Ed. 2003, 42, 3395-3398; Cornils, B.; Herrmann,
W. A. Aqueous-Phase Organometallic Catalysis, 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2004. (d) Clavier, H.; Grela, K.; Kirschning, A.;
Mauduit, M.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 6786-6801.
10.1021/ol7022505 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/19/2007

mixtures.6 Although they achieved high conversion in the
ring closure of N-tosyldiallylamine (8) in 3:1 water/methanol
and 3:1 water/DMF over an extended reaction time of 12 h,
these reactions were not accomplished in homogeneous
systems: neither the substrate nor the catalyst was dissolved
completely in the aqueous phase. In most cases detailed in
their report, the ruthenium complex was only sparingly
soluble in the aqueous reaction mixture.
Metathesis in homogeneous aqueous systems would likely
be faster and more versatile than in these heterogeneous
systems. An effective system for metathesis with com-
mercially available catalysts in homogeneous aqueous media
would not only make this chemistry more accessible but also
highlight the limitations of the standard catalysts in water,
informing catalyst-design efforts. Yet reports of the use of
common metathesis catalysts in an aqueous context are
limited. For these reasons, we chose to test the capabilities
of catalysts 1-4 in homogeneous aqueous media, and we
report the results of our exploration herein. First, we screened
various organic solvents as cosolvents for RCM of 8 in
homogeneous aqueous solution (Table 1). The solvents
Figure 1. Conventional ruthenium olefin metathesis catalysts.
defined catalysts in aqueous systems, Grubbs and co-workers
performed ring-opening metathesis polymerization (ROMP)
with 1 in aqueous emulsions,9 a method that allowed
Kiessling and co-workers to synthesize biologically active
glycopolymers.10 For ring-closing metathesis (RCM) and
cross metathesis (CM), Blechert and co-workers employed
commercially available 2 and complex 6c, a relative of
commercially available 4, in water/methanol and water/DMF
Table 1. RCM Catalyzed by 2 in Aqueous Media
solventa
4:1 THF/H2O
4:1 1,4-dioxane/H2O
4:1 DMF/H2O
conversion (%)
3
5
75
4:1 (CH3)2CO/H2O
4:1 DME/H2O
3:1 PEG-500 dimethyl ether/H2O
>95
>95
>95
a Mass:mass ratio.
typically used for olefin metathesis reactions, such as CH2Cl2,
1,2-dichloroethane, and toluene, are immiscible with water,
so we resorted to water-miscible solvents. Tetrahydrofuran
(THF), used previously as a solvent for ROMP and acyclic
diene metathesis with varying success,11 failed as a cosolvent
for RCM. On the other hand, the ethylene glycol ether based
solvents dimethoxyethane (DME or glyme) and poly(ethylene
glycol) (PEG) were excellent cosolvents. Their improved
results with respect to THF and dioxane could relate to their
better coordinating ability.12 Able to coordinate the tetra-
coordinate ruthenium complexes of the metathesis catalytic
(9) (a) Fraser, C.; Grubbs, R. H. Macromolecules 1995, 28, 7248-7255.
(b) Lynn, D. M.; Kanaoka, S.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118,
784-790 (c) Mecking, S.; Held, A.; Bauers, F. M. Angew. Chem., Int. Ed.
2002, 41, 544-561.
(10) (a) Manning, D. D.; Hu, X.; Beck, P.; Kiessling, L. L. J. Am. Chem.
Soc. 1997, 119, 3161-3162. (b) Kanai, M.; Mortell, K. H.; Kiessling, L.
L. J. Am. Chem. Soc. 1997, 119, 9931-9932.
(11) (a) Jin, W.; Fukushima, T.; Kosaka, A.; Niki, M.; Ishii, N.; Aida,
T. J. Am. Chem. Soc. 2005, 127, 8284-8285. (b) Tastard, C. Y.; Hodge,
P.; Ben-Haida, A.; Dobinson, M. React. Funct. Polym. 2006, 66, 93-107.
Figure 2. Metathesis catalysts adapted for aqueous solvents.
4886
Org. Lett., Vol. 9, No. 23, 2007

cycle, these ethers could more ably protect them from
detrimental coordination by water. Grubbs and co-workers
suggest that decomposition of metathesis intermediates in
water results from water coordination at ruthenium in the
methylidene-propagating species.13 Interestingly, these results
show that the protective environment of the PEG-bearing
ligand in 6a can also be provided by ethylene glycol ethers
in the bulk solvent.
coordinatively unsaturated intermediate, protecting it from
water to preserve the complex in solution.14 In addition to
helping select known catalysts for use in water/organic
systems, these results can inform the design of water-soluble
catalysts. The combination of a chelate and an NHC produces
a more effective catalyst for aqueous metathesis, as borne
out by complexes 6a, 6b, and 7. Future catalyst designs
should incorporate these features.
Next, we studied the performance of different com-
mercially available catalysts in the DME/water solvent
system with substrate 8 (Figure 3). Phosphine-free complex
Following the identification of 4 as the superior catalyst
in the water/DME system, the progress of RCM in acetone/
water was monitored to evaluate the rate of the reaction and
the lifetime of catalytically active species (Figure 4). The
Figure 4. Kinetics of RCM of 0.05 M substrate 8 catalyzed by
complex 4 in acetone/water monitored by H NMR spectroscopy.
Figure 3. RCM conversion of 0.05 M substrate 8 catalyzed by
complexes 1-4: 1 mol % [Ru], 2:1 DME/water, 24 h, rt, under
air.
1
majority of RCM occurred within 90 min of the beginning
of the reaction, as is typical for RCM of 8 with this catalyst
and temperature.16 Notably, this reaction is far faster than
the 12-h reaction time reported by Blechert and co-workers
for their heterogeneous systems.10 Nevertheless, catalyst
decomposition also proceeds quickly in the aqueous solvent,
with the results of the trial with 0.5 mol % catalyst indicating
that the majority of the catalytically active species is
destroyed within 90 min. In organic solvents, on the other
hand, complex 4 can be recovered after RCM reactions
requiring several hours.3
With optimized reaction conditions established, we probed
the RCM of a variety of dienes using complex 4 in aqueous
DME and acetone solutions. Under these homogeneous
conditions, substrates with a variety of substituents were
metathesized to form five-, six-, and seven-membered cyclic
products (Table 2). High conversion was consistently achieved
with traditional nonpolar substrates, except for diallyldi-
phenylsilane (14). Water-soluble substrates such as 11 and
16, a putative model for peptide substrates, were more
challenging, requiring increased catalyst loading and organic
cosolvent concentrations for high conversion. As it has with
many other metathesis systems, diallyldimethylammonium
chloride (12) resisted RCM.5,17
4 displayed the highest turnover, with both N-heterocyclic
carbene (NHC) complexes outperforming the first-generation
catalysts. The more σ-donating NHC ligand could aid olefin
coordination over attack by water, favoring metathesis with
the second-generation catalysts as opposed to decomposition.
The advantage of 4 over 2 is more difficult to rationalize
because both complexes produce the same propagating
species. The improved performance of 4 could be due to
the presence of the chelating isoproxy moiety, which could
potentially protect the catalyst from decomposition in water
prior to entry into the catalytic cycle, as suggested by
Blechert and co-workers for metathesis in organic solvents.14
Although the ether ligand binds more loosely than does the
phosphine of 2 (4 initiates >800-fold faster at 25 °C),15 its
rebinding to ruthenium prior to metathesis is unimolecular.
As a result, the ether ligand is more likely to rebind the
(12) Smid, J. In Ions and Ion-Pairs in Organic Reactions; Szwarc, M.,
Ed.; Wiley-Interscience: New York, 1972; Vol. 1, pp 85-151. (b) Seddon,
W. A.; Fletcher, J. W.; Catterall, R.; Sopchyshyn, F. C. Chem. Phys. Lett.
1977, 48, 584-586.
(13) Towards a second-generation aqueous Grubbs metathesis catalyst:
Understanding ruthenium methylidene decomposition in the presence of
water. Jordan, J. P.; Hong, S. H.; Grubbs, R. H. Presented at the 229th
National Meeting of the American Chemical Society, San Diego, CA, March
2005; Paper INOR-619.
Complex 4 is also capable of homodimerization of allyl
alcohol (18) in acetone/water, achieving good conversion
(14) Maechling, S.; Zaja, M.; Blechert, S. AdV. Synth. Catal. 2005, 347,
1413-1422.
(15) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035-4037.
(16) Zaja, M.; Connon, S. J.; Dunne, A. M.; Rivard, M.; Buschmann,
N.; Jiricek, J.; Blechert, S. Tetrahedron 2003, 59, 6545-6558.
(17) Lynn, D. M. Ph.D. Thesis. California Institute of Technology,
Pasadena, CA, 1999.
Org. Lett., Vol. 9, No. 23, 2007
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Table 2. RCM of Representative Dienes Catalyzed by 4 in
Table 3. CM Catalyzed by 4 in an Aqueous Medium under
Aqueous Media under Air
Air
time (h)
conversion (%)
2
6
71
75
sions can be drawn: homogeneous water/organic mixtures
could be advantageous for some olefin metathesis reactions,
and the principle advantage of current aqueous metathesis
catalysts is merely water solubility. Conventional catalysts
such as 4 are active in aqueous solvents and hence can be
used for metathesis of polar molecules if the substrate is
amenable to aqueous DME, PEG, or acetone. For instance,
some enzymes and polysaccharides are compatible with
aqueous DME,19 suggesting that these biomolecules might
be suitable for a metathesis strategy that avoids the synthesis
of specialized complexes. Moreover, we have found that
ribonuclease A is >90% soluble in 3:2 DME/phosphate-
buffered saline (PBS). In this solution, complex 4 not only
is soluble but also catalyzes the quantitative RCM of
N-tosyldiallylamine (8), even in the presence of ribonuclease
A.20 Thus, apart from its insolubility in pure water, 4 is nearly
as effective in the presence of water as are specialized
complexes such as 6b. Hence, additional advances in aqueous
metathesis will require enhanced ligands that not only provide
water solubility but also improve upon the NHC and
isopropoxy chelate in protecting the complex from water.
Acknowledgment. We are grateful to A. Choudhary
(University of Wisconsin-Madison) for critical review of
this manuscript. J.B.B. was supported by an NDSEG
Fellowship sponsored by the Air Force Office of Scientific
Research. This work was supported by grant GM44783
(NIH). NMRFAM was supported by grant P41RR02301
(NIH).
Supporting Information Available: Procedure for the
preparation of compound 16 and for performing metathesis
reactions and related analytical data. This material is available
free of charge via the Internet at http://pubs.acs.org.
over several hours (Table 3). Nevertheless, CM of other
substrates in aqueous solvents has proven elusive for us as
well as others.5,18
The effectiveness of 4 for RCM and CM in water/organic
solution is comparable to that of complex 6b, which is among
the best catalysts for metathesis in pure water. Two conclu-
OL7022505
(19) (a) Miller, J. F.; Graves, D. J. Biochem. Biophys. Res. Commun.
1981, 99, 1377-1383. (b) van Tol, J. B. A.; Stevens, R. M. M.; Veldhuizen,
W. J.; Jongejan, J. A.; Duine, J. A. Biotechnol. Bioeng. 1995, 47, 71-81.
(c) van Langen, L. M.; Oosthoek, N. H. P.; van Rantwijk, F.; Sheldon, R.
A. AdV. Synth. Catal. 2003, 345, 797-801. (d) Yoon, J. H.; McKenzie, D.
Enzyme Microb. Technol. 2005, 36, 439-446.
(20) Reaction conditions: 4 mol % 4, 0.025 M substrate 8, 0.2 mg/mL
ribonuclease A, 3:2 DME/PBS, 24 h, rt, under air. It is noteworthy that
water comprises 80% of the molecules in this reaction mixture.
(18) Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12,
1873-1876.
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