PQS: A new platform for micellar catalysis. RCM reactions in water, with catalyst recycling

Article abstract of DOI:10.1021/ol8027829

(Chemical Equation Presented) The first "designer" surfactant containing a covalently bound ruthenium catalyst is reported. This species dissolves freely in water, forming nanomicelles in which ring-closing metathesis reactions on water-insoluble dienic s

Full text of DOI:10.1021/ol8027829

ORGANIC
LETTERS
2009
Vol. 11, No. 3
705-708
PQS: A New Platform for Micellar
Catalysis. RCM Reactions in Water,
with Catalyst Recycling
Bruce H. Lipshutz* and Subir Ghorai
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received December 2, 2008
ABSTRACT
The first “designer” surfactant containing a covalently bound ruthenium catalyst is reported. This species dissolves freely in water, forming
nanomicelles in which ring-closing metathesis reactions on water-insoluble dienic substrates can occur in pure water at room temperature.
It can also be recycled continuously without reaction workup.
Development of environmentally innocuous processes is a
major theme associated with the “12 Principles of Green
Chemistry”.1a These guiding ideals, as espoused by Anastas
well over a decade ago, pose a challenge to synthetic
chemists worldwide: to devise chemistry that is “benign by
design”.1b Catalysis plays a huge role in furthering these
goals; indeed, Sheldon, Arends, and Hanefield in their recent
monograph link it prominently alongside green chemistry
in their title.2 Homogeneous catalysis, most notably in water,
offers unique opportunities to minimize solvent waste,
especially if a water-soluble catalyst can be reused in a
single-pot continuous process. Otherwise, catalyst separation
from the product can be problematic, and re-isolation is
oftentimes troublesome and costly. We now disclose new
technology that has been designed to accommodate all of
these features using the virtues of micellar catalysis,3 initially
applied to ring-closing metathesis (RCM). This new process
offers catalysis in water as the only medium, accommodation
of water-insoluble substrates, reactions run at room temper-
ature, no need for inert atmosphere or degassing, and
continuous batch processing with the catalyst remaining in
the water in the reaction vessel.
The three key elements of the newly designed platform,
amphiphile 1 (PQS; Figure 1), include (1) a lipophilic
component that serves as reaction “solvent” for water-
insoluble organic substrates; (2) a hydrophilic portion leading
to solubility in pure water; and (3) a free -OH residue within
the hydrophobic core capable of covalent linkage to a pendant
catalyst, in this case a Ru carbene, as in 2. Related catalysts,
(3) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005,
44, 7174–7199, and references therein. For examples of ligands attached
to surfactants capable of micelle formation, see: (a) Goedheijt, M. S.;
Hanson, B. E.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
J. Am. Chem. Soc. 2000, 122, 1650–1657. (b) Ding, H.; Hanson, B. E.;
Bakos, J. Angew. Chem., Int. Ed. 1995, 34, 1645–1647. (c) Ding, H.;
Hanson, B. E.; Bartik, T.; Bartik, B. Organometallics 1994, 13, 3761–3763.
(d) Bortenschlager, M.; Scho¨llhorn, N.; Wittmann, A.; Weberskirch, R.
Chem. Eur. J. 2007, 13, 520–528.
(1) (a) Anastas, P. T., Heine, L. G., Williamson T. C., Eds.; Green
Chemical Syntheses and Process; American Chemical Society: Washington,
DC, 2000. (b) Anastas, P. T., Farris, C. A., Eds.; Benign by Design:
AlternatiVe Synthetic Design for Pollution PreVention; ACS Symposium
Series 557; American Chemical Society: Washington, DC, 1994.
(2) Sheldon, R. A.; Arends, I. W. C. E.; Hanefeld, U. Green Chemistry
and Catalysis; Wiley-VCH: Weinheim, Germany, 2007.
10.1021/ol8027829 CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society

to room temperature afforded PQS (1) in 60% isolated yield
as a ca. 3:1 mix of inseparable regioisomers.8 PQS is a
colorless white solid, freely soluble in water in which it forms
9 nm micelles.9 Its critical micelle concentration is only 0.06
mg/mL at 25 °C,10 which corresponds to 1.97 × 10-5 M on
the basis of an average molecular weight of 3046.
Esterification of the free phenolic group in 1 using
Hoveyda’s acid 711 gave the carbene precursor 8 in high
isolated yield (Scheme 2). Exposure of newly formed triester
Figure 1. PQS-attached Grubbs-Hoveyda-1 metathesis catalyst for
RCM reactions in water.
Scheme 2. Preparation of PQS-Attached GH-1 Catalyst 2
including those that are polymer-bound4 (e.g., sol-gel)5 or
those bearing polar groups for achieving water solubility,6
offer no options for effecting dissolution of water-insoluble
educts and hence are used exclusively in organic media or
with water-soluble substrates.
The preparation of PQS combines two readily available
subsections: (1) the mixed, O-succinimide derivative 5,
formed by esterification using commercially available M-
PEG-2000 (3) and monocarbonyl-activated sebacic acid 4
(Scheme 1), and (2) ubiquinol 6, the hydroquinone form of
Scheme 1. Unoptimized Route to PQS (1)
8 to Grubbs first generation complex 9 in the presence of
CuCl11 inserted the desired Ru carbene, thereby arriving at
novel catalyst 2.12 Carbene 2 is a brown solid virtually
identical in appearance to catalyst 10.13 Upon addition of 2
to water (ca. 0.1 M) a solution is formed that contains, on
average, 44 nm micelles according to DLS measurements.9
To effect RCM, the substrate need only be added, neat.
Figure 2 illustrates representative examples, highlighting
several noteworthy features of this remarkably simple
process: (a) all cases studied to date, most of which involve
water-insoluble dienic substrates, led to excellent isolated
coenzyme Q10, which is formed quantitatively from its Zn/
HOAc reduction.7 Treatment of hydroquinone 6 with NaH
in THF at 0 °C followed by introduction of 5 and warming
(4) (a) Dowden, J.; Savovic´, J. Chem. Commun. 2001, 37–38. (b)
Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12, 1873–1876.
(c) Grela, K.; Tryznowski, M.; Bieniek, M. Tetrahedron Lett. 2002, 43,
9055–9059.
(8) Acylation of ubiquinol reproducibly leads to an inseparable 3:1
mixture of regioisomers, which is uneventfully carried through to “PQS”
and used as such. The ratio of regioisomers is discernible only by proton
NMR. Note that PEG-2000 represents an average molecular weight, as this
material is sold as a range of polyoxyethanyl-containing compounds.
(9) Determined by dynamic light scattering measurements using a
Brookhaven Laser Light Scattering instrument.
(10) Determined at Augustine Scientific, Newbury, Ohio by surface
tension measurements using the Wilhelmy Plate Method on a Kruss K100
Tensiometer.
(5) Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto,
M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2001, 40, 4251–4256.
(6) (a) Yao, Q.; Motta, A. R. Tetrahedron Lett. 2004, 45, 2447–2451.
(b) Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508–3509.
(c) Jordan, J. P.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 5152–
5155. (d) Rix, D.; Caijo, F.; Laurent, I.; GułajskiŁ.; Grela, K.; Mauduit,
´
M. Chem. Commun. 2007, 3771–3773. (e) GułajskiŁ.; Sledz´, P.; Lupa, A.;
(11) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
Grela, K. Green Chem. 2008, 10, 279–282. (f) GułajskiŁ.; Michrowska,
A.; Noraz˙nik, J.; Kaczmarska, Z.; Rupnicki, L.; Grela, K. Chem. Sus. Chem.
2008, 1, 103–109. (g) Burtscher, D.; Grela, K. Angew. Chem., Int. Ed. Epub
ahead of print. DOI: 10.1002/anie.200801451,
(12) Catalyst 2 was characterized by its carbene signal at δ 17.39 (d,
JPH ) 4.8 Hz), which is the only carbene peak observed, as well as the
methine proton at δ 5.26 of the Ru-bound isopropoxy ligand. The structural
assignment was further secured by comparison data with those of Grubbs-
Hoveyda catalyst 1013 (δ 17.44 of RudCHAr and 5.28 of OCHMe2).
(13) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799.
(7) Morgan, A. C.; Graves, S. S.; Woodhouse, C. S.; Sikorska, M.;
Walker, R.; Wilbur, D. S.; Borowy-Borowski, H. Water Soluble Ubiquinone
Compositions, Prodrugs, and Methods Relating Thereto. PCT 1996; CAN
125:123707.
706
Org. Lett., Vol. 11, No. 3, 2009

recycles. Unlike catalysts 9 and 10, which are compromised
after the first RCM in each case, PQS-derived carbene
complex 2 retains g92% of its original activity within this
(arbitrarily chosen) time frame and concentration in water.16
Lastly, rather than using standardized HPLC-grade water,
catalyst 2 was tested in seawater taken directly from the
Pacific Ocean. As illustrated in Scheme 3, for the challenging
case of seven-membered ring formation, essentially no
differences were observed, further indicative of the robust-
ness of this chemistry.
Scheme 3. RCM in Seawater at Room Temperature
Figure 2
Ru catalyst 2.
.
Products of RCM in water only, catalyzed by PQS-bound
In summary, a conceptually new platform for carrying out
micellar catalysis (PQS, 1) has been prepared, to which a
Ru carbene has been covalently linked. The resulting species
2 leads to an enabling technology that uniquely offers the
opportunity to effect ring-closing metathesis reactions in
water, or even seawater, with water-insoluble dienes, in air,
at room temperature, and with in-flask processing and
yields of the desired products; (b) the water need not be
degassed prior to use; (c) these reactions can be run fully
exposed to air; (d) reactions leading to five-, six-, and seven-
membered rings proceed smoothly under identical conditions;
(e) ring closures are fairly rapid, all taking place within 2 h
at ambient temperature; (f) workup and product isolation are
especially straightforward, simply involving addition of an
organic solvent (e.g., Et2O) to the reaction vessel and stirring,
followed by organic solvent removal directly from the
reaction vessel. Exposure of the solution obtained to charcoal
followed by product purification,14 using diene 12 (Table 1)
Table 1. Recycling of Catalyst 2 in RCM Reactions of 12a
cycle (% conversion)b
Figure 3
catalysis.
. Designer surfactants under development for asymmetric
catalyst
1
2
3
4
5
6
7
8
9
10
catalyst 2
>99 >99 >99 99 98 98 97 95 94 92
Grubbs-1 (9)
GH-1 (10)
93
94
79
73
5
<2
recycling (i.e., under green chemistry conditions).17 Catalysis
derives from self-organization of very small amounts of PQS
a The reactions were performed with 0.1 mmol substrate. b Determined
1
by H NMR spectroscopy at 400 MHz.
(16) It is appreciated that release and recapture (i.e., the boomerang
effect) is likely involved in these reactions; see: Hoveyda, A. H.; Gillingham,
D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8–23.
as a representative educt, affords material containing only
ca. 1.6 ppm Ru.15 With catalyst 2 remaining in the aqueous
layer, the process could be repeated for an additional 10
(17) (a) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 6786–6801. (b) Bruckmann, A.;
Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131–1141. For metathesis in
ionic liquids, see: (c) Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J.-
C. J. Am. Chem. Soc. 2003, 125, 9248–9249. (d) Yao, Q.; Zhang, Y. Angew.
Chem., Int. Ed. 2003, 42, 3395–3398. (e) Clavier, H.; Audic, N.; Mauduit,
M.; Guillemin, J.-C. Chem. Commun. 2004, 2282–2283.
(14) Hong, S. H.; Grubbs, R. H. Org. Lett. 2007, 9, 1955–1957.
(15) Determined by ICP-MS measurements at the Department of
Environmental Health Sciences, UCLA.
Org. Lett., Vol. 11, No. 3, 2009
707

into nanomicelles, with the lipophilic 50-carbon side chain
of a readily prepared18 ubiquinol derivative functioning as
the organic “solvent”. A myriad of opportunities exist for
covalent attachment of other species to PQS, such as BINAP
derivative 13 (e.g., for asymmetric Rh-catalyzed 1,4-addi-
tions)19 and proline 14 (for organocatalysis)20 as well as
pharmaceuticals (e.g., pacitaxel) for inclusion within micellar
environments in water (Figure 3). Results from these ongoing
and related studies in catalysis will be reported in due course.
Thus, in a broader sense, “designer” surfactants such as 2
have the potential to provide “green” solutions to selected
problems in organic synthesis.21
Acknowledgment. Financial support provided by Zymes,
LLC is warmly acknowledged with thanks.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8027829
RCM reaction were conducted at 0.1 M unless stated otherwise) was added
via syringe, and the resulting solution was allowed to stir at room
temperature for 3 h. The homogeneous reaction mixture was then diluted
with EtOAc (5 mL) and filtered through a bed of silica gel layered over
Celite, and the bed was further washed (2 × 10 mL) with EtOAc to collect
all of the cyclized material. The volatiles were removed in vacuo to afford
the crude product, which was subsequently purified by flash chromatography
using silica gel (4% EtOAc/hexanes) to afford the compound as a colorless
liquid (19 mg, 92%). IR (neat): 3085, 3001, 2940, 2840, 1598, 1463, 1428,
1349, 1295, 1242, 1204, 1155, 1054, 1020, 930 cm-1. 1H NMR (400 MHz,
CDCl3): δ 6.48 (d, J ) 2.4 Hz, 2H), 6.39 (t, J ) 2.4 Hz, 1H), 6.04-6.02
(m, 1H), 5.90-5.87 (m, 1H), 5.75-5.72 (m, 1H), 4.90-4.84 (m, 1H),
4.80-4.74 (m, 1H), 3.79 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 161.1,
144.7, 130.0, 126.9, 104.3, 99.9, 88.0, 76.1, 55.5. EI-MS m/z (%): 206 (100),
177 (30), 175 (35), 165 (57), 138 (48), 137 (19). HRMS (EI) calcd for
C12H14O3 [M]+ ) 206.0943, found 206.0952.
(18) A second generation, streamlined route to PQS has been developed;
Lipshutz, B. H.; Moser, R., unpublished work.
(19) (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844.
(b) Hayashi, T. Synlett 2001, 879–887. (c) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279–1300. (d) Nurihara, K.;
Sugishita, N.; Oshita, K.; Piao, D.; Yamamoto, Y.; Miyaura, N. J.
Organomet. Chem. 2007, 692, 428–435.
(20) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–
4660, and references therein.
(21) Representative Procedure. (Figure 2, compound 11) Precursor
diene (24 mg, 0.10 mmol) and catalyst 2 (7.5 mg, 0.002 mmol) were both
added into a Biotage 2-5 mL microwave reactor vial with a Teflon-coated
stir bar at room temperature and sealed with a septum. H2O (1.0 mL; all
708
Org. Lett., Vol. 11, No. 3, 2009