ISSN 2044-4753
Catalysis Science & Technologywww.rsc.org/catalysis Volume 2 | Number 12 | December 2012 | Pages 2391–2580
COVER ARTICLESkowerski et al.Highly active catalysts for olefi n metathesis in water
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2424 Catal. Sci. Technol., 2012, 2, 2424–2427 This journal is c The Royal Society of Chemistry 2012
Cite this: Catal. Sci. Technol., 2012, 2, 2424–2427
Highly active catalysts for olefin metathesis in waterw
Krzysztof Skowerski,*aGrzegorz Szczepaniak,
bCelina Wierzbicka,
a Łukasz Gu$ajski,a
Micha$ Bienieka and Karol Grelab
Received 15th May 2012, Accepted 16th June 2012
DOI: 10.1039/c2cy20320k
Preparation of novel, highly water soluble Ru complexes, which
contain quaternary ammonium chloride tags is presented. The
‘‘on-site’’ quaternisation method can be used to obtain polar
metathesis catalysts in an easy and efficient manner. Application
profiles of three representative catalysts are described.
Olefin metathesis found broad applications in many branches
of organic chemistry, and is rapidly becoming a stock item in
the toolbox of organic synthesis.1 However, conducting this
transformation in water still remains a challenge.2 Perfecting
metathesis in water would enable its wider use in many novel
applications, such as protein modification.3
Two basic approaches can be used to conduct metathesis
in water. The first one involves using standard, insoluble
catalysts in combination with surfactants2,4 or ultrasound.5 The
second approach, which is the primary focus of our group, is to
modify the catalyst itself to make it water soluble. Examples of
such catalysts are shown in the second and third row in Fig. 1.
Typically a highly hydrophilic tag, such as a poly(ethylene glycol)
chain (1)6 or a quaternary ammonium group (2–4),7 is added to
the molecule.
Furthermore, the recent pioneering work of Ward et al.,
who incorporated tagged Ru-catalysts into peptides (such as
biotin-tagged complex 5 bonded to streptavidin) to produce
artificial metalloenzymes active in RCM in aqueous solution,
shows an interesting future direction.8 Although these results
are impressive, still a lot of work must be invested to obtain a
really practical water-soluble olefin metathesis catalyst.
Because catalyst 2, synthesized earlier in our group,7a
suffered from low solubility in water (o1 mg mL�1), in the
current project we decided to search for its more water soluble
analogues. While catalyst 2 containing iodide counterions was
synthesised in a relatively inexpensive manner, there is no
simple and economic method for preparing such a complex
with chloride counterions.9 Also other published methods
of synthesis and purification of ammonium chloride tagged
Ru-catalysts are relatively difficult to scale-up.7c
Being interested in the development of new, stable and
efficient catalysts for olefin metathesis in neat water, we
decided to prepare a catalyst bearing ammonium tags in both
benzylidene and NHC parts of the complex. Having in mind
possible applications in biological systems under neutral pH,
we decided to synthesize catalysts containing in their structure
only quaternary ammonium groups (–NR3+Cl�), and not the
hydrochloride (–NH3+Cl�; compare with complex 3). To the
best of our knowledge, the Ru-catalysts bearing a quaternary
ammonium fragment in the NHC ligand are unknown.10
Unfortunately, we found previously that purification of a
catalyst bearing a quaternary ammonium chloride fragment
could be very difficult, probably due to interactions with
a CuCl�PCy3 complex formed during the reaction. Other
attempts, such as use of alternative ligand exchange protocols,11
were also ineffective in this case. It seems even more problematic
to place a quaternary ammonium cation on the NHC ligand,
due to strongly basic conditions required to generate the free
NHC from the corresponding imidazolinium salt (Scheme 1).
Therefore, we decided to develop a completely new, more
universal and user-friendly method of synthesis and purification
of ammonium-tagged olefin metathesis catalysts.
To do so, instead of using ligands with already present
hydrophilic groups, we decided to form quaternary ammonium
Fig. 1 Popular water-insoluble catalysts (Gru-II, Ind-I, Ind-II, Hov-II)
and complexes 1–5 designed for olefin metathesis in water (Mes = 2,4,6-
trimethylphenyl, Cy = cyclohexyl).
a Apeiron Synthesis Sp. z o.o., Klecinska 125, 54-413 Wroc!aw,Poland. E-mail: [email protected];Fax: +48-71-7985-622; Tel: +48-71-7985-621
bUniversity of Warsaw, Faculty of Chemistry, Pasteura 1,02-093 Warsaw, Poland. E-mail: [email protected];Tel: +48-22-822-28-92
w Electronic supplementary information (ESI) available: Full experi-mental data and copies of spectra. See DOI: 10.1039/c2cy20320k
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This journal is c The Royal Society of Chemistry 2012 Catal. Sci. Technol., 2012, 2, 2424–2427 2425
groups ‘‘on site’’ once the ruthenium complex is fully
assembled.12 This strategy should allow us to work (till the
final step) with uncharged non-polar compounds, which can
be conveniently purified by standard techniques (distillation,
column chromatography etc.). The synthesized Ru complexes
(6, 8, 10), bearing trialkylamino groups after treatment
with methyl chloride, shall yield ammonium tagged complexes
(7, 9, 11, Scheme 2).
First, we synthesized precursor 13 using the Mitsunobu
reaction and used it in a ligand exchange reaction with indenylidene
complex Ind-II to obtain compound 6 (Scheme 3). The yield of this
reaction was lower than yields usually observed in syntheses of
Hoveyda–Grubbs type catalysts.7 This might be associated with the
increased bulkiness of the etheral fragment in the benzylidene
ligand or with the presence of the basic amine, which could chelate
the Ru-metal, leading to the formation of Ru-oligomers.
The free-base 6 was then heated with methyl chloride in a
pressurised vessel to obtain 7 in high yield. After excess CH3Cl
was evaporated, the final purification of salt 7 was very simple
and involved only filtration through a short pad of neutral
aluminium oxide. Subsequently, we prepared catalysts 9 and 11
containing a quaternary ammonium chloride in the NHC
fragment. Salt 18 was synthesized in four steps in 20% overall
yield. Upon action of potassium tert-amylate, a free NHC was
generated, which was reacted in situ with Ind-I to yield 19. This
complex was then reacted with benzylidene ligand precursors 20
and 13, to give amine-containing catalysts 8 and 10. Quaterni-
zation of these neutral complexes afforded catalysts 9 and 11 in
high yields. These entities are, to the best of our knowledge, the
first reported metathesis catalysts with a quaternary ammonium
group placed in the NHC ligand. The alkylation reaction was
selective and affected only the less crowded piperazinic nitrogen
atom (Scheme 3).w
Catalysts 7 and 9 turned out to be sparingly soluble in water
(2 mg mL�1 and 3 mg mL�1, respectively), highlighting the
fact that one quaternary ammonium group is not sufficient to
provide good solubility. The presence of the second ammonium
group in 11 resulted, however, in a dramatic improvement in
solubility (35 mg mL�1).
The catalytic activity of 7, 9, and 11 was checked by
conducting a number of reactions in neat non-degassed D2O
under air. The results are summarized in Table 1. Complex 7
was generally highly active but surprisingly provided lowest
yield in RCM of 23. Complex 9 was less active in isomerization
of 21 but proved to be very effective in CM of 22 and RCM
of 23. Complex 11 exhibits the highest solubility, but this
property not always matched the highest catalytic activity in
water. All catalysts gave moderate yields in the cycloisomerisa-
tion of 25. According to our knowledge, this transformation is
the first successful enyne metathesis in neat water. Complexes 7
and 11 showed unprecedented activity in the isomerization of
(Z)-21 (Fig. 2).
This is probably due to sterical modification of the benzy-
lidene ligand or electronic activation through weakening of the
Ru–O bond by strongly electron withdrawing quaternary
ammonium groups.
In addition to metathesis in neat water, we decided to test
our polar catalysts with a model water-insoluble substrate
with the intention to extract 11 and any ruthenium containing
impurities in water. To do so, we conducted the RCM reaction
of diethyl diallylmalonate 27 promoted by 11 in non-degassed
DCM in air. After 30 min the reaction was completed (Fig. 3a).
To a yellow-green coloured reaction mixture D2O was added
(Fig. 3b) and the formed two phase mixture was vigorously
shaken. After the phases separated, we were pleased to find that
after this single extraction event the DCM phase containing
Scheme 1 Initial synthetic route to a bis-tagged Ru-complex.
Scheme 2 New route to ammonium tagged Ru-complexes.
Scheme 3 Synthetic route to tagged catalysts 7, 9, 11 (DIAD =
diisopropyl azodicarboxylate; TEOF = triethylorthoformate).
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2426 Catal. Sci. Technol., 2012, 2, 2424–2427 This journal is c The Royal Society of Chemistry 2012
product 28 became colourless, and the Ru complex migrated
to D2O (Fig. 3c). Similar approach to ruthenium residues
removal was reported by Grubbs et al.13 Next (Z)-21 was
added to the green D2O fraction and the reaction mixture was
analyzed by NMR. (E)-21 was obtained with 94% yield
after 1 h.
A more detailed study concerning product purification from
ruthenium residues and catalyst reuse is in progress.
In conclusion, we reported a simple synthetic protocol for
the preparation of quaternary ammonium chloride tagged
catalysts. The last step, quaternization of the preformed metal
complex, allows for very simple isolation of the resulted highly
polar catalyst. This method allows us to obtain Ru-complexes
containing quaternary ammonium groups in the NHC ligand.
Catalysts synthesized using this method are stable in water,
even in the presence of air, and promote CM, RCM, and
enyne reactions of various water-soluble substrates. The use of
water as a solvent for metathesis has significance for biological
applications, which are recently increasing in number. Moreover,
these catalysts can also be used in metathesis of water-insoluble
substrates in ‘‘classical’’ organic solvents, allowing for easy
purification of product and catalyst reuse.14a Immobilization
of these catalysts on solid supports14b or in ionic liquids15 will
be studied in due time.
Apeiron Synthesis acknowledges the National Centre
for Research and Development for financial support within
‘‘IniTech’’ programme. MB acknowledges the Foundation for
Polish Science for financial support within ‘‘INNOWATOR’’
programme.
KG and GS acknowledge the Foundation for Polish Science
for ‘TEAM’ Programme co-financed by the European
Table 1 Model metathesis reactions in neat water (D2O)a
Entry Substrate Product Catalyst (mol %) Time/h Yield (%)
1 7 (0.5) 0.13 94
2 9 (0.5) 1.1 71
3 11 (0.5) 0.16 94
4 7 (5) 24 74b
5 9 (5) 24 77b
6 11 (5) 24 38c
7 7 (2.5) 3.5 49
8 9 (2.5) 2.5 96
9 11 (2.5) 2.5 88
10 7 (5) 5 62
11 9 (5) 5 46
12 11 (5) 5 41
a Yields calculated from NMR. b E/Z = 16.7/1. c E/Z = 12.5/1.
Fig. 2 Isomerization of (Z)-21 with catalysts 7, 9, and 11.
Fig. 3 Example of catalyst 11 extraction and reuse.
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Notes and references
1 (a) For selected reviews, see: R. H. Grubbs, Handbook of Metathesis,Wiley-VCH, Weinheim, 2003, vol. 1–3; (b) M. Michalak, Ł. Gu"ajskiandK.Grela,AlkeneMetathesis, in Science of Synthesis: Houben–WeylMethods of Molecular Transformations, Alkenes, ed. A. de Meijere,Georg Thieme Verlag KG, 2010, vol. 47a, pp. 327–438; (c) Y.Vidavsky, A. Anaby and G. N. Lemcoff, Dalton Trans., 2012, 41,32–43; (d) G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2010,110, 1746–1787.
2 For selected reviews, see: (a) D. Burtscher and K. Grela, Angew.Chem., Int. Ed., 2009, 48, 442–454; (b) S. Zaman, O. J. Curnow andA. D. Abell, Aust. J. Chem., 2009, 62, 91–100; (c) C. Torborg,C. Samoj"owicz and K. Grela, Metathesis Reactions, in Science ofSynthesis: Methods of Molecular Transformations Vol. 2011/5:Water in Organic Synthesis, ed. S. Kobayashi, Georg ThiemeVerlag KG, Section 3.6, 2012, pp. 225–256.
3 For selected reviews, see: (a) Y. A. Lin, J. M. Chalker andB. G. Davis, ChemBioChem, 2009, 10, 959–969; (b) J. M. Chalker,G. J. L. Bernardes, Y. A. Lin and B. G. Davis, Chem.–Asian J.,2009, 4, 630–640; (c) Y. A. Lin and B. G. Davis, Beilstein J. Org.Chem., 2010, 6, 1219–1228.
4 For a review, see: B. H. Lipshutz and S. Ghorai, Aldrichimica Acta,2008, 41, 59–72.
5 Ł. Gu"ajski, P. Sledz, A. Lupa and K. Grela, Green Chem., 2008,10, 271–282.
6 (a) J. P. Gallivan, J. P. Jordan and R. H. Grubbs, TetrahedronLett., 2005, 46, 2577–2580; (b) S. H. Hong and R. H. Grubbs,J. Am. Chem. Soc., 2006, 128, 3508–3509.
7 (a) A. Michrowska, Ł. Gu"ajski, Z. Kaczmarska, K. Mennecke,A. Kirschning and K. Grela, Green Chem., 2006, 8, 685–688;(b) Ł. Gu"ajski, A. Michrowska, J. Naro_znik, Z. Kaczmarska,L. Rupnicki and K. Grela, ChemSusChem, 2008, 1, 103–109;(c) J. P. Jordan and R. H. Grubbs, Angew. Chem., Int. Ed., 2007,46, 5152–5155.
8 (a) C. Lo, M. R. Ringenberg, D. Gnandt, Y. Wilson andT. R. Ward, Chem. Commun., 2011, 47, 12065–12067;(b) C. Mayer, D. G. Gillingham, T. R. Ward and D. Hilvert,Chem. Commun., 2011, 47, 12068–12070.
9 Ł. Gu"ajski and K. Grela, Green Metathesis Chemistry, NATOScience for Peace and Security Series A: Chemistry and Biology,ed. V. Dragutan, A. Demonceau, I. Dragutan, E. Sh. FinkelshteinA. and Springer Science Netherlands, 2010, pp. 49–56.
10 A review on NHC-bearing Ru-metathesis catalysts:C. Samoj"owicz, M. Bieniek and K. Grela, Chem. Rev., 2009,109, 3708–3742.
11 S. Monsaert and F. Verpoort, Patent Application WO/2011/091980.
12 There are only few chemical transformations conducted onpreformed Ru-alkylidene complexes known, for example: (a) Bocdeprotection – ref. 7c; (b) esterification – M. Mayr, D. Wang,R. Kroll, N. Schuler, S. Pruhs, A. Furstner and M. R. Buchmeiser,Adv. Synth. Catal., 2005, 347, 484–492; (c) TMS deprotection –S. Pruhs, C. W. Lehmann and A. Furstner, Organometallics, 2004,23, 280 and Patent Application WO/2007/017047 A1.
13 S. H. Hong and R. H. Grubbs, Org. Lett., 2007, 9, 1955–1957.14 (a) M. R. Buchmeiser, Chem. Rev., 2009, 109, 303–321;
(b) H. Clavier, K. Grela, A. Kirschning, M. Mauduit andS. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 6786–6801.
15 P. Sledz, M. Mauduit and K. Grela, Chem. Soc. Rev., 2008, 37,2433–2442.
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