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: krzysztof.skowerski@apeiron-synthesis.com;Fax: +48-71-7985-622; Tel: +48-71-7985-621

bUniversity of Warsaw, Faculty of Chemistry, Pasteura 1,02-093 Warsaw, Poland. E-mail: klgrela@gmail.com;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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This journal is c The Royal Society of Chemistry 2012 Catal. Sci. Technol., 2012, 2, 2424–2427 2427

Regional Development Fund, Operational Program Innova-

tive Economy 2007–2013.

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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