SYNTHETIC METHOD
FIELD
The invention relates to a method of alkene metathesis. In the method, at least one
monoalkene is subjected to ethenolysis in the presence of a diene. The invention also
relates to the use of a diene to promote an ethenolysis reaction conducted on a monoalkene.
BACKGROUND
Olefin (alkene) metathesis is a very well-known synthetic technique, which allows the
exchange of substituents between alkenes by transalkylidenation. In recent years,
metathesis reactions have been the study of intense research. Indeed, the 2005 Nobel Prize
in Chemistry was awarded jointly to the chemists Yves Chauvin, Robert H. Grubbs and
Richard R. Schrock "for the development of the metathesis method in organic synthesis".
Such redistribution of carbon-carbon double bonds is catalysed by transition metalcontaining
catalysts. Although other transition metal-based catalysts can be used for
metathesis, such as molybdenum-based catalysts, the most common transition metal used is
ruthenium, in the form of alkylidene-containing complexes (so-called alkylidene ruthenium
complexes, or catalysts), more typically still alkylidene ruthenium complexes which comprise
two (generally) neutral ligands and two additional anionic ligands. For a comprehensive
review of such alkylidene ruthenium metathesis catalysts, the reader is referred to
Ruthenium-based Heterocyclic Carbene-Coordinated Olefin Metathesis Catalysts (GC
Vougioukalakis and RH Grubbs, Chem. Rev., 2010, 110, 1746-1787). In this review,
emphasis is, as it typically is in the art, focused on the use of catalysts comprising carbenecontaining,
in particular, N-heterocyclic carbene-containing (NHC-containing) catalysts, the
improved thermal and oxidative stability of such catalysts being believed to be attributable to
the decreased lability of such carbenes as compared with phosphine ligands, for example, as
well as other ligands coordinating through phosphorus atoms, such as phosphites,
phosphinites or phosphonites. Indeed, there has been a discernible move away from
metathesis catalysts comprising only phosphines as the neutral ligands in favour of
carbenes, in particular N-heterocyclic carbenes.
The earliest well-defined alkylidene- and ruthenium-containing metathesis catalysts
comprised two phosphine ligands and are often referred to as "First Generation" catalysts.
The archetypal First Generation Grubbs catalyst is 1. Developments in this technology led to
2 , the first of the so-called "Second Generation" metathesis catalysts, in which one of the
tri(cyclohexyl) phosphine ligands (P(Cy)3 ligands) of 1 has been replaced with an NHC.
Sometimes, including herein, catalysts of the type epitomised by 1 and 2 , i.e. alkylidene
ruthenium catalysts with two discrete neutral ligands are referred to as Grubbs metathesis
catalysts, or simply Grubbs catalysts. Still further evolution afforded the so-called Hoveyda-
Grubbs catalyst 3 (sometimes known as the Grubbs- Hoveyda catalyst), which was reported
in the year 2000. This phosphine-free catalyst comprises a coordinating isopropoxy
substituent attached to the aromatic ring of the benzylidene group, which replaces one of the
neutral ligands. This catalyst and variants of it have proven popular owing to their improved
thermal stability and oxygen-and moisture-tolerance in comparison with 1 and 2 .
Olefin metathesis reactions may be divided into a variety of subclasses. These
include, but are not limited to, so-called cross metathesis, ring-closing metathesis, ringopening
metathesis polymerisation (often referred to as ROMP) and self metathesis
reactions.
Cross metathesis appears to be subject to a variety of definitions in the literature,
including for example a metathesis reaction between two non-cyclic olefins, and an
intermolecular metathesis reaction between terminal alkenes. However, cross metathesis as
defined herein is any metathesis reaction between two alkenes. Typically the two alkenes
participating in a cross metathesis will be acyclic. It will be understood that, where the
participating alkenes are the same, such a cross metathesis reaction is an example of self
metathesis. Typically, however, cross metatheses are not self metathetic.
Ring-closing metathesis is a reaction whereby a ring is formed as a result of a
metathesis reaction between two carbon-carbon double bonds. For example, an acyclic
diene, typically in which the two participating C=C bonds are terminal may be ring-closed. In
contrast, ring-opening metathesis polymerisation involves, as the name implies, both ringopening
of a cycloalkene and polymerisation of the resultant diene.
Each of these (and other) classes of metathesis reactions are well-known to and
understood by the skilled person and, as discussed above, may be and often are catalysed
by alkylidene ruthenium complexes.
G S Forman et a (Organometallics, 2005, 24, 4528-4542) report enhancement to the
performance of certain olefin metathesis reactions catalysed by Grubbs catalysts by the
simple addition of phenol or a substituted phenol. In a published patent application (WO
2004/056728 A1), similar metathesis reactions are described. In neither of these
publications, however, is it in any way described or contemplated that the substituted phenol
may be tethered to a C=C bond participating in a metathesis reaction, in other words that a
phenol-comprising molecule participates in a metathesis reaction.
J A Mmongoyo et al. (Eur. J. Lipid Sci. Techno!., 114, 1183-1 192 (2012)) describe a
specific example of a cross metathesis reaction between ethylene and cardanol. Cardanol is
a term used to refer to a mixture of compounds each of which is a phenol having a C1
hydrocarbyl straight chain at the 3-position and which vary in the degree of internal
unsaturation in the chain, which has between 0 and 3 carbon-carbon double bonds. The
cross metathesis reaction described is catalysed by the Hoveyda-Grubbs catalyst (3, supra)
is described as providing a less than perfect yield, with the reaction giving undesired
quantities of other products believed to result from a series of side or competing reactions.
The type of scissile cross metathesis reaction described by J A Mmongoyo et al. Is
sometimes referred to as ethenolysis, since the metathesis reaction between ethylene and
an internal double bond serves to cleave the internal C=C bond.
In a recent study (R. M. Thomas, B. K. Keitz, T. M. Champagne and R. H. Grubbs, J.
Am. Chem. Soc, 201 1, 133, 7490-96), Grubbs-Hoveyda-type catalysts containing
unsymmetrical N-heterocyclic carbenes are described in which one N substituent is alkyl and
the other aryl. These are described as highly selective catalysts for the ethenolysis of methy
oleate, the best having di(2-propyl)phenyl and norbornyl substituents.
As is known (see for example the discussion by Thomas et a (immediately supra),
and the references cited therein), ethenolyses are particularly challenging metathesis
reactions to conduct. This is believed to be because the catalytic cycle involves reaction
between a methylidene complex and the internal alkene being subjected to ethenolysis.
Many alkene metathesis catalysts are understood to be unstable as methylidene complexes
and it is degradation of these intermediate species that is believed to give rise to the
difficulties encountered with ethenolysis reactions.
There is a continual need for modifications and/or improvements to existing
ethenolysis methodologies and the present invention addresses this need in the art.
SUMMARY
The present invention arises, in part, from the surprising finding that there is
advantageousness to conducting ethenolysis reactions in the presence of dienes. In
particular, we have found that the presence of dienes is of benefit to achieving good activity
and/or selectivity in ethenolysis reactions.
Viewed from a first aspect, therefore, the invention provides a method of ethenolysis of
a monoalkene, comprising introducing into a reaction vessel a monoalkene and a diene, and
subjecting the monoalkene to ethenolysis in the presence of a metathesis catalyst and the
diene.
Viewed from a second aspect, the invention provides the use of a diene to promote an
ethenolysis reaction conducted on a monoalkene.
Viewed from a third aspect, the invention provides an alkene obtained or obtainable by
a method of the first aspect of the invention or according to the use of the second aspect of
the invention.
Further aspects and embodiments of the present invention will become apparent from
the detailed discussion of the invention that follows below.
BRIEF DESCRIPTION OF THE FIGURES
Fig.1 shows oestrogen response curves for a variety of substrates obtained using a
yeast oestrogen screen (YES) assay (4-NP = 4-nonylphenol with mixed C chains; 4-n-NP =
4-nonylphenol with a linear chain; 3-NP = 3-nonylphenol prepared in this study by
hydrogenation of 3-nonenylphenol, cardanol and crude cashew nut shell liquid).
Fig. 2 shows oestrogen response curves for cardanol and CNSL compared with
oestrodiol using a YES assay.
DETAILED DESCRIPTION
As noted above, the present invention relates to ethenolysis reactions catalysed by
transition metal-containing metathesis catalysts. Whilst there is no particular limitation to the
nature of the metathesis catalysts may be used in accordance with the present invention, the
most common transition metal used in the metathesis catalysts is ruthenium, particularly in
the form of alkylidene-containing complexes (so-called alkylidene ruthenium complexes or
catalysts). Accordingly, the present invention focuses on such metathesis catalysts,
although the invention is not to be considered to be so limited unless the context specifically
indicates to the contrary. By this is meant that, where the discussion refers to alkylidene
ruthenium catalysts or complexes, its content may be extrapolated as appropriate to other
metathesis catalysts, e.g. molybdenum-based catalysts.
Generally, alkylidene ruthenium complexes, which may be used in accordance with
the various aspects of the present invention, comprise two (generally) neutral ligands and
two additional anionic ligands. The skilled person is well acquainted with such metathesis
catalysts (see the review article by Vougioukalakis and Grubbs (supra).
According to still more particular alkylidene ruthenium complexes useful according to
this invention, the invention makes use of a specific subclass of Grubbs catalyst, namely
those comprising two phosphine, phosphite, phosphinite or phosphonate ligands. In
particular, such catalysts may be defined as alkylidene ruthenium alkene metathesis
catalysts comprising two ligands P1 and P2, which may be the same or different and of
formula P(R1)3, in which P is a phosphorus atom coordinated to the ruthenium ion and each
R1 is independently an optionally substituted alkyl or alkoxy group; or two R1 groups within
one P1 or P2 ligand constitute an optionally substituted bicycloalkyl.
According to particular embodiments of the invention involving use of the ruthenium
alkene metathesis catalysts comprising two ligands P1 and P2 described in the immediately
preceding paragraph, P1 and P2 are each independently of formula P(R1)3, in which P is a
phosphorus atom coordinating to the ruthenium ion and each R1 is independently an
optionally substituted alkyl, alkoxy, aryl or aryloxy group; or two R1 groups within one P1 or P2
ligand of formula P(R1)3 constitutes an optionally substituted bicycloalkyl.
According to the invention, alkylidene ruthenium catalysts are used to catalyse
ethenolysis reactions. The expression "used to catalyse" herein indicates that that the
catalyst may be used to promote an ethenolysis reaction in a substoichiometric amount
(relative to the monoalkene undergoing metathesis, i.e. ethenolysis) , i.e. less than 1 molar
equivalent ( 100 mol %) relative to at least the monoalkene.
The expression "used to catalyse" does not require that the alkylidene ruthenium
catalysts with which the monoalkene is contacted is the actual catalytic species since,
without wishing to be bound by theory, the alkylidene group in such catalysts is believed to
be lost in the first catalytic cycle and the actual catalytic species may be formed in situ by
alkylidene exchange with a double bond. Typical substoichiometric amounts will be in the
range of about 0.0000001 to about 0.2 molar equivalents, e.g. about 0.00001 to about 0.2
molar equivalents, typically about 0.0001 to about 0.02 molar equivalents, relative to the
amount of the monoalkene.
Generally, the alkylidene ruthenium catalysts used according to the invention will be of
formula (I) :
wherein:
P1 and P2 are as herein defined;
X1 and X2 are anionic ligands, which may be the same or different; and
A is an alkylidene group.
Typically the alkylidene ruthenium catalysts used comprise ruthenium ions, generally in
oxidation state +2. It will be understood that these are may be formed in situ or ex situ.
Unless the context specifically suggests otherwise, the term "halide" refers to fluoride,
chloride, bromide or iodide, typically chloride, bromide or iodide.
The term aromatic used herein embraces within its scope heteroaromatic. As known to
those skilled in the art, and used herein, heteroaromatic moieties may be regarded a subset
of aromatic moieties that comprise one or more heteroatoms, typically O, N or S, in place of
one or more ring carbon atoms and any hydrogen atoms attached thereto. Such exemplary
heteroaromatic moieties, for example, include pyridine, furan, pyrrole and pyrimidine.
Aromatic moieties may be polycyclic, i.e. comprising two or more fused aromatic
(including heteroaromatic) rings. Naphthalene and anthracene are examples of polycyclic
aromatic moieties, and benzimidazole is an example of a polycyclic heteroaromatic moiety.
Unless the context herein specifically suggests otherwise, aromatic moieties, including
aryl and arylene radicals and diradicals (formed formally by abstraction of one or two
hydrogen atoms from an aromatic moiety) may be optionally substituted with one or more
substituents selected from halo (e.g. fluoro, chloro, bromo and iodo), alkyl, aryl (including
heteroaryl), hydroxy, nitro, amino, alkoxy, alkylthio, cyano, thio, formyl, ester, acyl, thioacyl,
amido, carbamido and sulfonamide. According to particular embodiments, aromatic moieties
herein are typically unsubstituted.
Unless the context herein specifically suggests otherwise, by alkyl is meant herein a
saturated hydrocarbyl moiety, which may be straight-chain, cyclic or branched. By alkylene
is meant an alkyl group from which a hydrogen atom has been formally abstracted. Typically
alkyl and alkylene groups will comprise from 1 to 25 carbon atoms, more usually 1 to 10
carbon atoms, more usually still 1 to 6 carbon atoms. Alkyl and alkylene groups may be
substituted, for example once, twice, or three times, e.g. once, i.e. formally replacing one or
more hydrogen atoms of the group. Examples of such substituents are halo (e.g. fluoro,
chloro, bromo and iodo), aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, cyano, thio,
formyl, ester, acyl, thioacyl, amido, carbamido, sulfonamido and the like. Examples of aryl
(e.g. heteroaryl) substituted alkyl (i.e. aralkyl (e.g. heteroaralkyl)) include CH2-aryl (e.g.
benzyl) and CH2-heteroaryl.
By alkene is meant a compound comprising one or more non-aromatic carbon-carbon
double bonds.
By alkyne is meant a compound comprising one or more carbon-carbon triple bonds.
By carboxy is meant herein the functional group C0 2H, which may be in deprotonated
form (C0 2
~) .
By acyl and thioacyl are meant the functional groups of formulae -C(0)-alkyl or -C(S)-
alkyl respectively, where alkyl is as defined hereinbefore.
By amido is meant a functional group comprising the moiety -N(H)C(=0)-;
By carbamido is meant a functional group comprising the moiety -N(H)C(=0)N(H)-;
By ester is meant a functional group comprising the moiety -OC(=0)-;
By sulfonamido is meant a functional group comprising the moiety -S0 2NH- in which
the hydrogen atom depicted may be replaced with alkyl or aryl.
Alkyloxy (synonymous with alkoxy) and alkylthio moieties are of the formulae -O-alkyl
and -S-alkyl respectively, where alkyl is as defined hereinbefore.
Aryloxy and arylthio moieties are of the formulae -O-aryl and -S-aryl respectively,
where aryl is as defined hereinbefore.
Alkylamino and dialkylamino moieties are of the formulae -N(H)-alkyl and
^alkyl
N
' y' respectively, where alkyl is as defined hereinbefore.
By amino group is meant herein a group of the formula -N(R )2 in which each R is
independently hydrogen, alkyl or aryl, e.g. an unsaturated, unsubstituted C -6 hydrocarbyl,
e.g. alkyl such as methyl or ethyl, or in which the two R s attached to the nitrogen atom N are
connected. One example of this is whereby - R -R - forms an alkylene diradical, derived
formally from an alkane from which two hydrogen atoms have been abstracted, typically from
terminal carbon atoms, whereby to form a ring together with the nitrogen atom of the amine.
As is known the diradical in cyclic amines need not necessarily be purely hydrocarbyl (the
alkylene chain - R -R - may be interrupted by, for example, one or more heteroatoms (e.g.
O, S or NR, wherein R is hydrogen, alkyl or aryl), or indeed saturated : morpholine (in which
- R -R - is -(CH 2)20(CH 2)2- ) is one such example of a cyclic amino in which an alkylene
chain is interrupted by oxygen.
References to amino herein are also to be understood as embracing within their ambit
quaternised or protonated derivatives of the amines resultant from compounds comprising
such amino groups. Examples of the latter may be understood to be salts such as
hydrochloride salts.
The alkylidene ruthenium catalysts of use according to the present invention typically
comprise two anionic ligands (X1 and X2 in formula (I)). These anionic ligands are not
particularly limited. Examples include those described in section 7 of GC Vougioukalakis and
RH Grubbs (supra) . For example, in addition to the often-used halides, anionic ligands may
be alkyl or aryl carboxylates or sulfonates, alkoxides or aryloxides optionally in which one or
more hydrogen atoms within the alkyl or aryl moieties of such ligands have been substituted
with halogen atoms, notably fluorine, for example in which the alkyl or aryl moieties of such
ligands have been perfluorinated (by which is meant that all of the hydrogen atoms of
hydrocarbyl group R are replaced with fluorine) . Specific examples of such anionic ligands
include acetate, monofluoroacetate, difluoroacetate, trifluoroacetate, propionate,
perfluoropropionate, C^alkoxides such as methoxide, ethoxide and terf-butoxide,
phenoxide, perfluorophenoxide, tosylate, mesylate and triflate. In many embodiments, X1
and X2 will be the same. In many embodiments, X1 and X2 will be halide, typically but not
necessarily chloride; bromide and iodide may also be used. In particular embodiments X1
and X2 are each chloride.
Ligands P1 and P2 are each independently of formula P(R1)3. Whilst these ligands may
be the same or different, typically they are the same.
Either or both of P1 and P2 may be a phosphine, phosphite, phosphinite or
phosphonite. In accordance with the skilled person's understanding of these four classes of
phosphorus-containing compound, the terms have their normal meanings: phosphine used
herein defines a compound of formula P(R1)3, in which each R1 is independently optionally
substituted alkyl; or two R1 groups within one P1 or P2 ligand of formula P(R1)3 constitutes an
optionally substituted bicycloalkyi; the term phosphite used herein defines a compound of
formula P(R1)3, in which each R1 is independently optionally substituted alkoxy; the term
phosphonite used herein defines a compound of formula P(R1)3, in which one R1 group is
optionally substituted alkyl and two R1 groups are independently optionally substituted
alkoxy; and the term phosphinite defines a compound of formula P(R1)3, in which two R1
groups are independently optionally substituted alkyl or together constitute an optionally
substituted bicycloalkyi and one R1 is independently optionally substituted alkoxy.
Typically, although not necessarily, each P1 and P2 is a phosphine or phosphite, for
example each P1 and P2 is a phosphine. In each of these embodiments, (i.e. wherein P1 and
P2 is a phosphine, phosphite, phosphinite or phosphonite; phosphine or phosphite; or a
phosphine) , P1 is typically the same as P2.
Typically, although not necessarily, each of the discrete R1 groups within the P1 and P2
ligands comprise from 1 to 20 carbon atoms. The term "discrete R1 groups" is intended to
exclude the possibility for two R1 groups together constituting an optionally substituted
bicycloalkyi, which optionally substituted bicycloalkyi typically comprises from 8 to 12 carbon
atoms. More commonly, at least two of the discrete R1 groups comprise between 5 and 10
carbon atoms, for example all of the discrete R1 groups comprise between 5 and 10 carbon
atoms.
The skilled person is very familiar with P1 and P2 ligands suitable for use in alkylidene
ruthenium metathesis catalysts. In particular, it is often advantageous for at least two R1
groups to be or comprise a branched alkyl or cycloalkyi group. According to particular
embodiments of the invention, P1 and P2 are tricycloalkylphosphines and
tricycloalkylphosphites, in particular tricyclopentylphosphine, tricyclopentylphosphite,
tricyclohexylphosphine and tricyclohexyphosphite. According to many embodiments of the
invention, at least one P(R1)3 group is, and typically both P(R1)3 groups are,
tricyclohexylphosphine. Notwithstanding this, however, the skilled person is well aware of
the suitability of many other phosphorus-coordinating ligands suitable for use with alkylidene
ruthenium metathesis catalysts. For example, reference may be made to tri(terfbutyl)
phosphine and tri(/so-propyl)phosphine.
Whilst attention is focused in the present discussion on the use of alkyl-based P1 and
P2 groups, the invention is not to be understand to be so limited, the discussion here of such
embodiments of the invention also applying mutatis mutandis to other embodiments of the
present invention in which one or more R1 groups of ligand P1 and/or P2 may be aryl or
aryloxy.
With regard to the possibility of two R1 groups within one ligand of formula P(R1)3 group
constituting a bicycloalkyi group, the skilled person will be aware of the description in the art
of the use of so-called phobanes - 9-phosphabicyclononanes - in metathesis catalysis. In
this regard, reference is made to F Boeda et al. (J. Org. Chem., 2008, 73(1) , 259-263), M
Carreira et al. (J. Am. Chem. So , 2009, 131 (8), 3078-3092), G S Forman et al. (J.
Organomet. Chem., 2006, 691 , 5513-5516) and WO 2007/010453 A2 (Sasol Technology
(UK) Limited) and the technology described therein. According to particular embodiments of
the invention one or both P(R1)3 groups may be a phobane. In these and other P1 and P2
ligands, the phosphorus atoms are in particular embodiments additionally attached to an
alkyl, e.g. cycloalkyi group, for example one comprising between 4 and 20 carbon atoms
(e.g. terf-butyl, sec-butyl, cyclohexyl or eicosyl). Phobane-containing metathesis catalysts
are available commercially, e.g. from Cytec or Umicore.
In many embodiments of the invention, the R1 groups within P1 and P2 are
unsubstituted. Where an R1 group is substituted, however (including embodiments in which
two R1 groups within one ligand of formula P(R1)3 is a substituted bicycloalkyl group) , such
R1 groups may comprise one or more substituents with which alkyl groups may generally be
substituted (vide supra). Notwithstanding this, an R1 group may according to particular
embodiments comprise one or more halo substituents; a sulfonate (-S0 3
~) , phosphate
(-OPO3
2 ) or carboxylate (-C0 2
~) group; a quaternary ammonium group; or a poly(ethylene
glycol)-containing (PEG-containing) substituent.
Where the substituent of a R1 group is halo, this may be, although not necessarily is,
fluoro. Moreover, in particular embodiments, multiple fluoro substitution may be effected, so
as to provide perfluorinated R1 groups, or R1 groups comprising perfluorinated portions. As
an example of the latter, reference is made to compound 421 in Vougioukalakis and RH
Grubbs (supra), and the references cited therein. Compound 421 comprises a partially
perfluorinated trialkyl phosphine in which each of the groups of the phosphine is a
perfluorodecylethyl moiety. As is described, such fluorine substitution can be advantageous
in effecting metathesis reactions in both monophasic and biphasic solvent mixtures (for
example in dichloromethane and dichloromethane/fluorine-containing solvent mixtures) with
improved reaction rates found when conducting metathesis reactions in such biphasic
solvent mixtures.
Where a substituent of an R1 group is a quaternary ammonium group, this may
typically be a group of the formula - N+(R2)3(X3) , wherein each R2 is alkyl or aryl, typically
alkyl; and X3 is any convenient anion. However, such R1 substitution is not so limited and the
skilled person will be aware of the possibility of substituting R1 with more structurally
complicated quaternary ammonium moieties such as alkylene- or alkyleneoxy-linked
imidazolium and pyrrolidinium cations.
Where a substituent of an R1 group is a PEG-containing substituent, wherein PEG
comprises a plurality, e.g. 2 to 2000, consecutive units of -CH2CH20-, typically only one of P1
and P2 will be substituted in this way.
Catalysts comprising sulfonate (-S0 3
~), phosphate (-OPO3
2 ) , carboxylate (-C0 2
~) or
quaternary ammonium groups or PEG-containing substituents can be advantageous, as is
known in the art, in permitting metatheses to be effected in water and/or protic solvents such
as alcohols (for example C -6 alcohols such as methanol or ethanol) , or combinations of such
solvents or mixtures of other solvents with other solvents with which these solvents or
mixtures of solvents are miscible, for example dimethylformamide (DMF) and dimethyl
sulfoxide (DMSO). Catalysts comprising sulfonate (-S0 3
~) , phosphate (-OPO3
2 ), carboxylate
(-C0 2
~) or quaternary ammonium groups also may be used to effect metathesis catalysis in
ionic liquids, as described in more detail below. Introduction of each of these substituents
into R1 groups is within the capability of those skilled in the art and, in this regard, reference
is made to the technology described in section 9 of the article by GC Vougioukalakis and RH
Grubbs (supra), and the references cited therein. The skilled person will understand that the
teaching in this reference (in relation to substitution of NHC-containing catalysts, both on the
NHC ligands themselves as well as other parts of alkylidene ruthenium metathesis catalysts,
may be applied mutatis mutandis to phosphorus-containing ligands in accordance with the
present invention. For example, there is described in WO 01/46096 (Sasol Technology (Pty)
Ltd) an alkylidene ruthenium metathesis catalyst comprising two dicyclohexyl
((trimethylammonium)ethyl)phosphine ligands having solubility in both water and methanol.
Where the substituent of a R1 group is a quaternary ammonium group, the nature of
the counteranion (to the quaternary ammonium group) is not of particular consequence. Any
convenient anion may be used. Halide anions such as chloride anions are typical although
the skilled person will be able to identify other suitable anions without difficulty.
Whilst substitution with a sulfonate, phosphate or carboxylate group is advantageous in
the context of conducting metathesis reactions in solutions comprising water and/or protic
solvents, as discussed supra, in which the identity of the countercation to these groups is not
of particular importance, and may for example be an alkali or alkaline earth cation (such as
Na+, Li+, K+ or Ca2+ , for example), the introduction of such substituents also offers the
possibility of conducting metathesis reactions in ionic liquids, in particular with the group is
sulfonate.
The alkylidene group (=A in formula (I)) may be any suitable alkylidene group for use in
ruthenium-catalysed metathesis. The skilled person is aware of a wealth of information
regarding the various possibilities for the alkylidene group, as well as methods of making
such alkylidene-containing catalysts. In this regard, reference is made yet again to G C
Vougioukalakis and R H Grubbs (supra), as well as P Schwab et al. (J. Am. Chem. Soc.
1996, 118, 100-1 10) and P Schwab et al. (Angew. Chem., Int. Ed. Engl., 1995, 34, 2039-
2041) and the description throughout these publications of various possibilities for the
alkylidene group in catalysts of this type, including the variants expressly described in section
5 of Vougioukalakis and Grubbs. Typically, the alkylidene group may be defined as a moiety
of formula =CR R , wherein "=C" indicates the bonding with the ruthenium ion. One of R
and R may be hydrogen and either or both of R and R may be alkyl, alkenyl, alkynyl, aryl
carboxyalkyl, alkoxy, alkenyloxy, alkynyloxy or alkoxycarbonyl, or R and R together form a
saturated, unsaturated or aromatic cyclic or bicyclic moiety. Those of skill in the art will
recognise that, where R and R together form a bicyclic moiety, this embraces the
indenylidene alkylidenes first reported by Nolan et al. in 1999, and which are often employed
in contemporary metathesis catalysis, in particular the 3-phenyl-1 H-inden-1 -ylidenes.
According to particular embodiments, the alkylidene group may be indenylidene, for example
an aryl-, e.g. phenyl-, substituted indenylidene, e.g. 3-phenyl-1 H-inden-1 -ylidene. However,
the invention should in no way be considered to be so-limited. For example, the alkylidene
group may embrace moieties of formula =CR R , wherein R is hydrogen, alkyl or aryl and R
is alkyl, alkenyl or aryl, more particularly wherein R is phenyl or vinyl, either an unsubstituted
or substituted with halo, nitro, amino (e.g. dimethylam ino) , alkyl (e.g. methyl) , alkoxy (e.g.
methoxy) and aryl (e.g. phenyl). As an example, the alkylidene group may be benzylidene
(the moiety of formula =CH(Ph)), which is the alkylidene moiety in Grubbs' First Generation
catalyst ( 1 , supra) and others.
The alkylidene ruthenium catalysts used may be formed in situ or ex situ. Catalysts
prepared ex situ are often referred to in the art as being well-defined. "Well-defined" means,
as is understood by those skilled in the art, and is meant herein, a complex that is prepared
ex situ, and is thus susceptible to characterisation (i.e. definition) . In other words, the use of
a well-defined complex means that the environment, for example, a reaction vessel, in which
the substrate(s) for the ethenolysis reaction are contacted with the catalyst of formula (I) is
charged a pre-formed transition metal catalyst of formula (I), rather than precursors to such
transition metal complexes formed in situ.
Alternatively, as is known, the catalyst of formula (I) may be formed in situ. Reference
is made in this regard, for example, to P O Nubel and C L Hunt (J. Molec. Catal. A:
Chemical, 1999, 145(1-2) , 323-327) and US patent number 6 ,159,890, which describe
catalyst systems from which catalytically active species may be generated in situ. As is
described in these publications, a source for the ruthenium ion in the metathesis catalyst, as
well as sources of the desired neutral ligands (which according to the present invention may
be the phosphorus-coordinating ligands P1 and P2 described herein) , anionic ligands and for
the alkylidene group, are brought into contact. In such in situ embodiments, the method of
the invention will thus typically involve bringing together these components in an
environment, for example, a reaction vessel, in which the substrates for the metathesis
reaction are to be contacted.
The source of the ruthenium ion is typically an inorganic salt such as ruthenium halide,
e.g. chloride, for example ruthenium ( III) chloride, optionally as a hydrate thereof.
Advantageously, such salts also provide anionic ligands X1 and X2, i.e. where these ligands
are the halide ions of the ruthenium halide. Alternatively, they may be introduced separately.
The source of the alkylidene A may be an alcohol. For example, where the alkylidene
is 3-phenyl-1 H-iden-1 -ylidene, this may be made by a reaction between a source for the
ruthenium ( I I) ion within the catalyst of formula (I) and 1,1-diphenyl-2-propyn-1 -ol. The
skilled person is well aware of how to make ruthenium indenylidene complexes (see, for
example, F Boeda et al. (Chem. Commun., 2008, 2726-2740).
The source of the ruthenium ion is typically an inorganic salt such as ruthenium halide,
e.g. chloride, for example ruthenium (III) chloride, optionally as a hydrate thereof.
Advantageously, such salts also provide anionic ligands X1 and X2, i.e. where these ligands
are the halide ions of the ruthenium halide. Alternatively, they may be introduced separately.
Whilst it is possible to make catalysts of formula (I) in situ, this is not at all essential,
the synthesis of well-defined alkylidene ruthenium catalysts for use in the present invention,
including those of formula (I), being at the disposal of the skilled person. Moreover, such
catalysts are readily available commercially, for example from Umicore AG & Co. KG,
Germany, and other suppliers of metathesis catalysts with which the skilled person is very
familiar. Specific examples of catalysts include the First Generation catalysts dichloro(3-
phenyl-1 H-inden-1-ylidene)bis(tricyclohexylphosphine) ruthenium (II) and (3-phenyl-1 H-idenl-
ylidene)bis(isobutylphobane) ruthenium (II), sold as M 1 and Ml respectively by Umicore.
Mention is now made of the nature of the monoalkene substrate for the ethenolysis
reaction, and of the ethenolysis reaction itself
By ethenolysis reaction is meant, as the term is understood by those in the art, a
metathesis reaction between ethylene and an internal alkene. By internal alkene is meant
that neither carbon atom of the carbon-carbon double bond of the alkene has two hydrogen
atoms attached to it. The internal alkenes that are subjected to ethenolysis in accordance
with the present invention are monoalkenes, by which it is meant that there is only one
alkenic carbon-carbon double bond in such compounds.
According to particular embodiments, the monoalkene substrate for the ethenolysis
reaction is located within a hydrocarbylene chain, optionally interrupted with ether, ester,
amide or amine groups, comprising from about 4 to about 100, e.g. from about 8 to about 30
30 carbon atoms. The optionally interrupted hydrocarbylene chain may be optionally
substituted. In many embodiments, however, it is unsubstituted. In many of these
embodiments, it is also not interrupted, i.e. is a hydrocarbylene chain that consists only of
carbon and hydrogen atoms.
According to particular embodiments, each carbon atom of the carbon-carbon double
bond of the monoalkene is attached to a typically unbranched, optionally interrupted
hydrocarbyl group, the carbon atoms of which are optionally interrupted with ether, ester,
amide or amine groups, each of which groups comprise between 1 and about 25, more
typically between about 1 and 10 atoms, from the first atom of the hydrocarbyl group
attached to the carbon-carbon bond and its terminal carbon atom. These optionally
interrupted hydrocarbyl groups may be optionally substituted. In some embodiments,
however, they are unsubstituted. In other embodiments, one is substituted and one is not.
In many of these embodiments, neither is interrupted, with one hydrocarbyl group being an
uninterrupted, unsubstituted hydrocarbyl group and the other an uninterrupted, substituted
hydrocarbyl group.
According to particular embodiments of the invention, the carbon-carbon double bond
of the monoalkene is a disubstituted carbon-carbon double bond (i.e. is of formula -CH=CH-).
According to these and other embodiments of the invention, each carbon atom of the carboncarbon
double bond is attached to an alkylene or alkyl moiety each of which independently
comprises from 2 to 7 carbon atoms. For example, the carbon-carbon double bond may be
flanked on either side by two ethylene (-CH2CH2-) moieties, by two propylene (-CH 2CH2CH2-)
moieties or by one propylene moiety and one ethylene moiety.
According to particular embodiments of the invention, the monoalkene is an optionally
esterified monounsaturated fatty acid, for example a fatty acid comprising from 4 to 28
carbon atoms. As is known, a fatty acid is a member of the series of open-chain carboxylic
acids including those found as esters in fats and oils. A monounsaturated fatty acid may be
regarded as a carboxylic acid comprising an alkenyl group having one carbon-carbon double
bond. Most naturally occurring fatty acids - it being understood that fatty acids need not be
naturally occurring - comprise an even number of carbon atoms.
According to particular embodiments of the invention, the monounsaturated fatty acid
comprises from 14 to 18 carbon atoms. The carbon-carbon double bond of these and other
monounsaturated fatty acids may be a cis or trans C=C bond. According to particular
embodiments, the carbon-carbon double bond of the fatty acid is a trans C=C bond.
Examples of monoalkene substrates for the ethenolysis may be selected from the group
consisting of oleic acid, sapienic acid, palmitoleic acid, myristoleic acid or erucic acid, and
esters thereof. According to particular embodiments of the invention, the monoalkene
substrate is oleic acid or an ester thereof.
Where reference is made to esters of carboxylic acids herein, in particular esters of
monounsaturated fatty acids, these esters may be alkyl or aryl esters. The alkoxy or aryloxy
moieties in these alkyl or aryl esters may be substituted or unsubstituted. According to
particular embodiments, these alkyl or aryl groups are unsubstituted. According to more
particular embodiments, the ester may be a phenyl ester or an alkyl ester. According to still
more particular embodiments, the alkyl ester is a C -6 alkyl ester, for example, methyl, ethyl
or n- or /sopropyl.
According to a specific embodiment, the monoalkene is methyl oleate, the ethenolysis
of which affords two industrially important chemicals: 1-decene and methyl 9-decenoate.
Other commercially relevant feedstocks may be provided by ethenolysis of other
monounsaturated fatty acids, including those described herein, and other internal
monoalkenes.
According to further embodiments, the carbon-carbon double bond of the monoalkene
is tethered to an aromatic moiety. By "tethered" is meant that the carbon-carbon double
bond is connected to a ring atom of the aromatic moiety, analogously to the carbon-carbon
double bond in a monounsaturated fatty acid being tethered to the carboxylic acid thereof.
The aromatic moiety may be monocyclic or polycyclic. According to particular embodiments,
the aromatic moiety is an optionally substituted monocyclic aromatic moiety, for example an
optionally substituted phenyl group.
According to particular embodiments, the aromatic moiety may be an aromatic alcohol.
According to such embodiments, the carbon-carbon double bond may be tethered to either
the same ring to which the hydroxyl group of the aromatic alcohol is attached, or to a ring
fused thereto. The carbon-carbon double bond may in some embodiments be directly
attached to the ring atom of the aromatic alcohol. Typically, however, it is connected to ring
atom of the aromatic alcohol by a typically straight-chain hydrocarbylene, optionally
interrupted with ether, ester, amide or amine groups, wherein between 1 and about 25, more
typically between about 1 and 10 atoms, separate the carbon-carbon double bond from the
aromatic ring. The optionally interrupted hydrocarbylene chain may be optionally
substituted. In many embodiments, however, it is unsubstituted. In many of these
embodiments, it is also not interrupted, i.e. is a hydrocarbylene chain. In particular
embodiments, such an uninterrupted, unsubstituted hydrocarbylene chain is an alkylene
chain comprising between 1 and about 25, more typically between about 1 and 10, carbon
atoms between the carbon-carbon double bond and the ring atom of the aromatic alcohol to
which the hydrocarbylene chain is attached.
In those embodiments of the invention in which the carbon-carbon double bond of the
monoalkene is tethered to a carboxylic acid or an aromatic moiety, the carbon atom of the
carbon-carbon double bond that is not so tethered is connected to a typically unbranched
hydrocarbyl group, the carbon atoms of which are optionally interrupted with ether, ester,
amide or amine groups, comprising between 1 and about 25, more typically between about 1
and 10 atoms, from the the first atom of the hydrocarbyl group attached to the carbon-carbon
bond and its terminal carbon atom. This optionally interrupted hydrocarbyl group may be
optionally substituted. In many embodiments, however, it is unsubstituted. In many of these
embodiments, it is also not interrupted, i.e. is a hydrocarbyl group consisting of carbon and
hydrogen atoms. In particular embodiments, such an uninterrupted, unsubstituted
hydrocarbyl group comprises between 1 and about 25, more typically between about 1 and
10, carbon atoms.
According to further embodiments of the present invention, the monoalkene may be a
cycloalkene for example a C .10cycloalkene, for example cyclohexene or cyclooctene.
By "aromatic alcohol" is meant herein a compound of formula R3OH in which R3, to
which the hydroxy group is attached, is an aromatic ring. As stated above, the term aromatic
embraces within its scope heteroaromatic. The complement to heteroaromatic, whereby to
refer to aromatic compounds not comprising any heteroatoms in the aromatic ring, is to refer
to aromatic hydrocarbons. It should be noted that use of this term does not exclude the
possibility that such aromatic compounds are substituted with heteroatom-containing
substituents. Typically, R3 is an optionally substituted aromatic hydrocarbon, by which is
meant that the aromatic hydrocarbon may comprise one or more additional substituents over
and above the alkene-containing moiety and the hydroxyl group.
The aromatic ring to which the hydroxyl group of the aromatic alcohol is attached may
be a monocycle, i.e. in which the aromatic ring to which the hydroxyl group is fused is not
fused to any other rings. Alternatively, this aromatic ring may be part of a polycyclic system,
i.e. in which it is fused to one or more aromatic (including heteroaromatic) or non-aromatic
rings. Napthalene, anthracene and phenanthrene are examples of fully aromatic polycyclic
hydrocarbons (a bicycle and two tricycles respectively), and benzimidazole is an example of
a fully aromatic polycyclic heteroaromatic compound. 1,2,3,4-tetrahydronaphthalene is an
example of a compound comprising an aromatic ring fused to a non-aromatic ring.
Typically, when the hydroxyl-bearing aromatic ring is part of a polycyclic system, this
will be a fully aromatic system. Examples of such aromatic alcohols include, for example,
napthol (1- or 2-) and phenanthrol (e.g. 9-phenanthrol).
Whilst the hydroxy-substituted aromatic ring of the aromatic alcohol may be part of a
polycyclic system, in many embodiments the aromatic alcohol is monocyclic, that is to say
the hydroxy-substituted aromatic ring is not fused to another ring. Within these embodiments
of the invention, the hydroxy-substituted aromatic ring may be a phenol.
The aromatic alcohol may be subject to additional substitution (i.e. over and above the
C=C-containing substituent). Such substituents may be, for example, those mentioned
above with which aromatic moieties may be substituted, for example halo, alkyl, aryl,
hydroxy, nitro, amino, alkoxy, cyano, formyl, ester, acyl, amido, carbamido and sulfonamide.
For example, the aromatic alcohol may be an aromatic diol or a hydroxybenzoic acid.
According to a particular embodiment of the invention, the ethenolysis may be of a
specific component of cardanol, a material found in cashew nut shell liquid (CNSL), the
byproduct of the cashew nut processing industry, which is available in an amount of
approximately 300,000 - 600,000 tonnes per year worldwide and which has so few uses that
it is generally considered to be a waste stream.
CNSL predominantly comprises four phenolic compounds, three of which predominate,
the proportions of which vary naturally and also depend on the method by which CNSL is
extracted from the shells of the cashew nuts. Typical compositions of CNSL (with the figures
being molar percentages) obtained by solvent extraction or by roasting are indicated in Table
A below:
(Legend to Table A overleaf)
Table A: Typical composition of CNSL obtained by solvent extraction or by roasting. R is
C1 hydrocarbyl chain with 1 to 3 double bonds, "* " indicating the end of the bond through
which the hydrocarbyl chains - R below are attached to the aromatic ring:
(b)
it will be understood from the numbering (1)-(4) and lettering (a)-(d) employed in
Table A that compound 2b, for example, denotes the monoalkene component of cardanol
and compound 2 denotes cardanol, i.e., the mixture of compounds.
Solvent extraction of the nuts gives predominately anacardic acid whilst roasting of
the nuts gives mainly cardanol (2), owing to the decarboxylation of anacardic acid on
heating. As may be appreciated from Table A, all four components have a fifteen carbon
linear chain in the meta-position to the phenolic group with a varying degree of saturation,
dependant on the origin of the cashew nuts.2 4
Anacardic acid (1) can be isolated from CNSL by precipitation with calcium hydroxide.
Separation and acidification of the calcium anacardate gives the pure acid 1, which can be
transformed to cardanol (2) by heating to 200 °C.5 Further purification by vacuum distillation
gives pure cardanol (2) without alteration of the side-chain. Its versatility as a renewable
starting material arises from its structure. Owing to the phenol group and the unsaturated
side-chain in the meta-position, it can be easily modified to valuable chemicals by introducing
novel functionalities, hence the particular discussion herein of the carbon-carbon double
bond of the monoalkene subject to ethenolysis according to the present invention being
tethered to an aromatic moiety in particular an aromatic alcohol.
Several applications of cardanol (2) or CNSL are known. For example, the synthesis
of biscardanol derivatives as monomers, additives in surface coatings and resins6 and the
synthesis of sodium cardanol sulfate as detergents. 7 2 can also be functionalised to its
corresponding ethers, which have been used as polymer additives8 or in nanofibers.9
However, the selective homogeneous catalysed transformation of cardanol (2) to valuable
intermediates is only rarely described and just few examples like the double bond metathesis
of cardanol (2) exist.6, Owing to its unsaturated side-chain, metathesis is an attractive tool
for functionalising 2 to intermediates of higher added-value. Vasapollo et al. reviewed the
transformation of cardanol 2 to new fine chemicals as well as new hybrid functional
materials, such as cardanol porphyrins, cardanol phthalocyanines and cardanol fullerenes
via olefin-metathesis. 9 However, no applications of the newly synthesised materials have
been reported.
It is thus of particular interest to convert cardanol (2) selectively to intermediates,
which can be used directly as substitutes in the value-added chain. For example, the
products of ethenolysis of cardanol monoene (2b) are 3-non-8-enylphenol (4) and 1-octene
(6), each of which is a potentially important product. 1-Octene 6 , is mainly used as a
comonomer for polyethylene and 3-nonylphenol has the potential for replacement of the 4-
nonylphenol, which makes an excellent detergent via ethoxylation, but has been banned in
Europe because of its endocrine disrupting properties. 12, 13
In the experimental section below, there is described a detailed study of the selective
ethenolysis of cardanol (2) . Unexpectedly, first generation catalysts in particular give very
high selectivities to the desired products and very high conversions. We also report
oestrogenicity studies on 3-nonyl phenol, which show that it is 2 orders of magnitude less
oestrogenic than 4-nonylphenol.
As is discussed by J A Mmongoyo et al. (supra), cardanol is generally used in the art,
and is used in the same sense herein, to refer to a composition comprising a mixtures of
compounds in which hydrocarbyl chain R varies in its degree of unsaturation, as indicated in
Table A above. Similarly, the other components of CNSL, anacardic acid, cardol and 2-
methylcardol are also used to refer to mixtures of compounds in which hydrocarbyl chain R
of Table A varies in its degree of unsaturation
The versatility of the components of CNSL, including but not limited to cardanol, as
starting materials in synthesis arises from their structure and, amongst other reactions J A
Mmongoyo et al. discuss, cross metathesis between ethylene and the unsaturated
components within cardanol may be used to afford 1-octene and 3-non-8-enylphenol.
According to particular embodiments of the invention the method comprises
contacting th
with an alkylidene ruthenium alkene or other metathesis catalyst described herein.
According to particular embodiments, the method comprises contacting this monoalkene with
an alkylidene ruthenium alkene metathesis catalyst. In this way, the invention permits the
preparation of 1-octene and 3-non-8-enylphenol. It will be understood from the foregoing
discussion that the latter of these may be used as a potential detergent precursor.
The monoene component of cardanol, which may, for example, be prepared by
selective transfer hydrogenation using RuCI3-xH20, as described by Perdriau et al. (S.
Perdriau, S. Harder, H. J. Heeres and J. G. de Vries, ChemSusChem, 5 , 2427 (2012)), who
report the selective transfer hydrogenation of cardanol to its monounsaturated component.
The transfer hydrogenation gives access to almost pure cardanol monoene, although some
double bond isomerisation occurs during the transfer hydrogenation reaction.
According to particular embodiments, where a 3-non-8-enylphenol, for example 3-
non-8-enylphenol, is prepared, this may be optionally subject to hydrogenation of the carboncarbon
double bond, whereby to provide a 3-nonylphenol, and further, ethoxylation of the
phenol to provide an ethoxy-3-nonylphenol or oligoethoxy-3-nonylphenol, in which the phenol
hydroxyl is replaced with -(OCH 2CH2)nOI-l, wherein n is an integer of between 1 and 20,
typically between 3 and 15, e.g. 9 . Suitable methods of hydrogenation and ethoxylation are
well within the capability of those skilled in the art. The invention also extends to ethoxy-3-
nonylphenol or oligoethoxy-3-nonylphenol obtainable or obtained by the method of the
invention. Prior to hydrogenation, the 3-non-8-enylphenol may be subject to optional
purification from other components (e.g. cyclohexadiene or other diene and/or 1-octene)
resultant from the ethenolysis reaction by which it is prepared, according to the normal ability
of those skilled in the art. Similarly, 1-octene may be readily subject to optional purification
from other components (e.g. cyclohexadiene or other diene and/or 3-non-8-enylphenol)
resultant from the ethenolysis reaction by which it is prepared.
A characterising feature of the present invention is the presence of the diene during
the ethenolysis of the monoalkene. In particular, according to the method of the first aspect
of the invention, the diene is introduced into the reaction vessel in which the ethenolysis
reaction is conducted. Generally, at least the monoalkene and ethylene are also introduced
into the reaction vessel in which the ethenolysis reaction is conducted. By being "introduced
into" is explicitly meant that the material concerned is transferred from outside the reaction
vessel to inside the reaction vessel in which the ethenolysis reaction takes place. In other
words, the diene, or other material that is introduced into the reaction vessel, is not
generated in situ. From the foregoing discussion, it will be understood that, according to
some embodiments, the ethenolysis catalyst is introduced into the reaction vessel.
According to other embodiments it is generated in situ.
The diene used need not be particularly limited, provided of course it comprises two
nonaromatic carbon-carbon double bonds. Typically, however, it will be a hydrocarbyl diene,
i.e. a diene consisting only of carbon and hydrogen atoms, typically comprising from 4 to 10
carbon atoms, for example from 6 to 8 carbon atoms. According to these and other
embodiments of the invention, the diene may be cyclic. According to more specific
embodiments, the diene may be selected from the group consisting of 1,4-cyclohexadiene,
1,4-hexadiene, 1,5-cyclooctadiene and 1,7-cyclooctadiene. According to specific
embodiments the diene is 1,4-cyclohexadiene.
The skilled person will be able to ascertain without undue burden appropriate
quantities of diene to introduce for any given ethenolysis reaction. For example, typical
amounts are in the range of 0.01 to 1 molar equivalents with respect to the monoalkene, for
example between about 0.05 and about 0.5 molar equivalents.
It will be understood that the introduction of a diene into a reaction vessel in which
cardanol (i.e. mixture 2) is subject to ethenolysis constitutes an embodiment of the invention.
General conditions for effecting ethenolysis reactions are well-known and an
illustrative procedure is described in the examples below. Typically, the reactions will be
conducted at temperatures ranging from about 10 ° to about 100 ° for example from about
20 ° to about 70 °C, dependent on solvent and other factors, for between about 5 minutes
and 24 hours, typically between about 1 hour and about 8 hours. (It will, however, be
appreciated that ethenolysis may be conducted at higher temperatures, for example when
using ionic liquids as solvents (vide infra). When conducting ethenolysis reactions,
pressurised reactors such as autoclaves for Fisher-Porter tubes or bottles are typically used,
the pressure at which the reaction is conducted generally being in the range of about 1 bar
(100 kPa) to about 100 bar (10,000 kPa), for example in the range of about 5 bar (500 kPa)
to about 15 bar ( 1 ,500 kPa).
As noted above, substitution of the P1 and/or P2 groups (of the relevant alkylidene
ruthenium catalysts described herein) with a charged or PEG-containing moiety offers the
opportunity to conduct the desired ethenolysis reactions in water and/or protic solvents.
Whilst substitution with a sulfonate, phosphate, carboxylate or quaternary ammonium group
is advantageous in the context of conducting ethenolysis reactions in solutions comprising
such solvents, in which the identity of the countercation to the negatively charged groups is
not of particular importance, and may for example be an alkali or alkaline earth cation (such
as Na+, Li+, K+ or Ca2+, for example) and the identity of the counteranion to the quaternary
ammonium group is also not of particular importance, and may for example be halide anion
(such as CI , for example), the introduction of such substituents also offers the possibility of
conducting ethenolysis reactions in ionic liquids.
Ionic liquids have in recent years been found to be of utility in a wide variety of
synthetic applications. These liquids can be advantageous for use as solvents or as other
types of continuous liquid phase reaction media (as discussed further below) on account of
their thermal stability, inflammability and lack of volatility. The nature of ionic liquids is well
known to those of skill in the art. Broadly speaking, an ionic liquid is salt, but one in which
the ions are insufficiently well-coordinated for the compound to be other than a liquid below
150 °C, more usually below 100 °C, and in some embodiments even at room temperature -
so-called room-temperature ionic liquids. In other words, ionic liquids are salts that form
stable liquids at temperatures below 150 °C or lower. There are no particular limitations as
to the specific types of ionic liquids that may be used as solvents for ethenolyses in
accordance with the present invention. One or more ionic liquids may be used. As will be
readily understood, one of the specific advantages that use of ionic liquids confers is removal
of the need to have a condenser in order to achieve a high-temperature liquid environment in
which the method of the present invention may be conducted. Ionic liquids, with inherently
low vapour pressure, allow the maintenance of constant temperature to be achieved over the
course of the method of the invention, in contrast to the significant vapour pressures of the
high-boiling point solvents typically used in the prior art. Such solvents inevitably cause a
decrease in the temperature of a reaction vessel when the solvent condenses back in. Ionic
liquids, therefore, permit not only an advantageously elevated temperature but allow a more
homogeneous temperature to be maintained throughout the reaction. Typically, ionic liquids
have either no, or negligible, vapour pressure.
Organic cations that may be present in ionic liquids may include, for example,
quaternary ammonium, phosphonium , heteroaromatic, imidazolium and pyrrolidinium
cations. The counteranions present in ionic liquids are likewise not particularly limited. For
example, suitable anions include halide (e.g. chloride or bromide), nitrate, sulfate,
hexafluorophosphate, tetrafluoroborate, s(triflylmethylsulfony l)imide, (the s (t r if ly lmethyl
sulfonyl)imide anion being abbreviated here as [NTf 2] ; it is also sometimes referred to as
N[Tf]2 or [Tf]2N) anions. Others will be evident to those of skill in the art.
Ionic liquids that may be used include 1-alkyl-3-methylimidazolium
s(trifluoromethylsulfonyl)imide, 1-alkyl-3-methylimidazolium hexafluorophosphate, 1,1,3,3-
tetralkylguanidinium lactate, alkylpyridinium tetrafluoroborate, 1-alkyl-3-alkylimidazolium
tetrafluoroborate, 1-alkyl-3-alkylimidazolium s(trif luoromethyl sulfonyl)imide 1-alkyl-3-alkylimidazolium
tetrafluoroborate, trialkyl-n-tetradecylphosphonium
s(trifluoromethylsulfonyl)imide, 1-alkyl-1 -alkyl-pyrrolidinium trifluoromethanesulfonate and
thiol-functionalised ionic liquids, wherein each alkyl is independently C1-20, for example C2-2o
or C2-12 . For example the ionic liquids may be 1-butyl-3-methylimidazolium
s(trifluoromethylsulfonyl)imide, 1-n-butyl-3-methylimidazolium hexafluorophosphate,
1,1,3,3-tetramethylguanidinium lactate, /V-butylpyridinium tetrafluoroborate, 1-butyl-3-
methylim idazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium s(trif luoromethyl
sulfonyl)imide 1-ethyl-3-methyl-imidazolium tetrafluoroborate, tri-n-hexyl-ntetradecylphosphonium
s(trifluoromethylsulfonyl)imide, 1-butyl-1 -methyl-pyrrolidinium
trifluoromethanesulfonate, all of the foregoing but in which the cation is instead 1-octyl-3-
methylim idazolium ; and thiol-functionalised ionic liquids. Ionic liquids are readily available
commercially, e.g. from Cytec Industries, Inc. and by contractual arrangement with the Ionic
Liquids Laboratory at the Queens University of Belfast (see quill.qub.ac. uk for further details) .
Ionic liquids can be engineered to tune their advantageous properties such as
stability, vapour low pressure and solvating ability so as to be safer and more
environmentally friendly than conventional volatile, organic compounds. Consequentially, and
because of the possibility of recycling, use of ionic liquids can simplify synthetic reactions
when it is possible to substitute such ionic liquids for conventional solvents.
As is known by those skilled in the art, certain ionic liquids are, notwithstanding their
advantages, susceptible to decomposition at elevated temperatures (for example in excess
of 240 °C) in a normal oxygen-containing atmosphere. However, such decomposition may
be mitigated where heating is conducted in an inert atmosphere. Suitable inert atmospheres
(e.g. those from which oxygen and/or moisture is substantially excluded) may be achieved by
means well known to those of skill in the art and may be provided through the use of purging
using argon, nitrogen or other gases. In certain embodiments, heating of mixtures to
temperatures of approximately 100 to 150 ° may be effected in order to remove any
residual oxygen or moisture prior to subsequent use.
Where the method of the invention is not conducted in an ionic liquid, the reaction
may be carried out in any convenient solvent. Protic solvents such as alcohols may be used,
as may aprotic solvents including chlorinated solvents such as dichloromethane;
hydrocarbon solvents such as hexane mixtures or toluene as appropriate; or others (e.g.
ethers such as diethyl ether and tetrahydrofuran (THF); ketones such as acetone or
butanone; and esters such as ethyl acetate). According to particular embodiments of the
invention, the solvent used may be a chlorinated solvent such as dichloromethane.
However, use of such solvents is not by any means mandatory and the ethenolysis reactions
may equally be practised with use of non-chlorinated solvents, for example toluene.
The selection of an appropriate solvent is well within the capability of a person of
normal skill. Alternatively, as is known to those familiar with metathesis chemistry, it may be
appropriate to conduct ethenolysis reactions of the invention in the absence of solvent. As
with many other aspects of the method of the invention, the skilled person is well able to
establish appropriate reaction conditions within his normal skill.
The method of the invention may be conducted in batch processing, i.e. in which the
desired reactant(s) for the metathesis reaction is/are introduced into a suitable vessel, for
example an autoclave, in view of the use of ethylene in accordance with the invention.
Alternatively, the method of the invention may be conducted on a non-batch, e.g.
continuous flow basis. Such non-batch methods may be achieved by dissolving well-defined
catalysts in ionic liquids, e.g. in a reactor, and introducing the substrate(s) for the metathesis
reaction in supercritical carbon dioxide.
Continuous processing is described by PB Webb et al. (J. Am. Chem Soc, 2003, 125,
15,577-15,588) in connection with hydroformylation of alkenes in supercritical fluid-ionic
liquid biphasic systems. However, the skilled person will understand that the principles
described therein as to how appropriate solubility of catalyst in ionic liquid may be achieved
are applicable to the present invention. In particular, the use of appropriate salts of
sulfonated phosphines is discussed in order to achieve effective solubility of catalysts in ionic
liquid. The skilled person will likewise understand that the teachings by Webb et al. may be
applied to sulfonated phosphites, phosphonates or phosphinates as well as phosphines, and
to phosphines, phosphites, phosphonates and phosphinates bearing phosphate or
carboxylate moieties, so as to maximise solubility in the ionic liquid and thereby activity of the
resultant catalysts.
Another example of continuous processing, again of hydroformylation, is described by
U Hintermair et al. (Dalton Trans., 2010, 39, 8501-8510). In this publication, microporous
silica-supported catalysts prepared from monosulfonated triphenylphosphine with an
imidazolium cation and an ionic liquid are described as being used in the continuous flow
hydroformylation of 1-octene in the presence of compressed carbon dioxide. In this way,
continuous flow of near critical or supercritical carbon dioxide allowed continuous flow
hydroformylation to be effected and it will be understood that the same principles described
in this publication may also be applied to the metathesis reactions to which the present
invention is directed. Reference is further made to the description of continuous flow
homogeneous alkene metathesis in a similar system (see R Duque et al., Green Chem.,
201 1, 13, 1187-1 195).
It will be readily appreciated by those skilled in the art that, if desired, recognised
methods of immobilisation of the catalysts described herein can be used to generate
heterogeneous catalysts which retain the important features of the metathesis catalysts
described herein, for example the phosphorus-coordinating ligands or catalysts may be
absorbed onto a suitable solid support or reacted with such a support to form a covalently
bound ligand or catalyst.
All publications (both patent and non-patent) referred to herein are hereby incorporated
by reference in their entirety.
The invention may be further understood with reference to the following non-limiting
clauses:
1. A method of ethenolysis of a monoalkene, comprising introducing into a reaction
vessel a monoalkene and a diene, and subjecting the monoalkene to ethenolysis in
the presence of a metathesis catalyst and the diene.
2 . The method of clause 1, wherein the metathesis catalyst is an alkylidene ruthenium
alkene metathesis catalyst.
3 . The method of clause 1 or clause 2 wherein the carbon-carbon double bond of the
monoalkene is a disubstituted carbon-carbon double bond.
4 . The method of any one preceding clause, wherein each carbon atom of the carboncarbon
double bond is attached to an alkylene or alkyl moiety each of which
independently comprises from 2 to 7 carbon atoms.
5 . The method of clause 4 wherein the carbon-carbon double bond is flanked by two
ethylene moieties.
6 . The method of clause 4 wherein the carbon-carbon double bond is flanked by two
propylene moieties.
7 . The method of any one preceding clause, wherein the monoalkene is an optionally
esterified monounsaturated fatty acid.
8 . The method of clause 7 , wherein the fatty acid comprises from 4 to 28 carbon atoms.
9 . The method of clause 8 , wherein the fatty acid comprises from 14 to 18 carbon atoms
10 . The method of any one of clauses 7 to 9 wherein the carbon-carbon double bond is a
cis C=C bond.
11. The method of of any one of clauses 7 to 9 wherein the carbon-carbon double bond
is a trans C=C bond.
12 . The method of clause 7 wherein the fatty acid is selected from the group consisting of
oleic acid, sapienic acid, palmitoleic acid, myristoleic acid or erucic acid.
13 . The method of clause 12 , wherein the fatty acid is oleic acid.
14 . The method of any one of clauses 7 to 13 , wherein the fatty acid is esterified
15 . The method of clause 14 , wherein the esterified fatty acid is an alkyl, aryl or
heteroaryl ester.
16 . The method of clause 15 , wherein the esterified fatty acid is an alkyl ester.
17 . The method of clause 7 , wherein the monoene is methyl oleate.
18 . The method of any one of clauses 1 to 6 , wherein the carbon-carbon double bond of
the monoalkene is tethered to an aromatic moiety.
19 . The method of clause 18 , wherein the aromatic moiety is an aromatic alcohol
20. The method of clause 19 wherein the aromatic alcohol is a phenol or a napthol.
2 1. The method of clause 19 wherein the aromatic alcohol is a phenol.
22. The method of any one of clauses 18 to 2 1 , wherein the carbon-carbon double bond
is tethered to the aromatic alcohol by a optionally substituted hydrocarbylene chain,
which is optionally interrupted with ether, ester, amide or amine groups.
23. The method of any of clauses 18 to 22 wherein the method comprises the ethenolysis
of cashew nut shell liquid, or one more components thereof.
24. The method of any one of clauses 18 to 23, wherein the method comprises the
ethenolysis of cardanol.
25. The method of clause 23 wherein the method comprises the ethenolysis of a
monoene component of cardanol.
26. The method of clause 23, wherein the method comprises the ethenolysis of
27. The method of any one of clauses 23 to 26, which is a method for preparing 1-octene.
28. The method of any one of clauses 18 to 26, which is a method of preparing 3-non-8-
enylphenol.
29. The method of clause 28 further comprising hydrogenating 3-non-8-enylphenol and
ethoxylating the resultant 3-nonylphenol to provide ethoxy-3-nonylphenol or
oligoethoxy-3-nonylphenol, in which the -oligoethoxy substituent is of formula
-(OCH 2CH2)nOH, wherein n is an integer of between 1 and 20.
The method of any one preceding clause wherein the alkylidene ruthenium alkene
metathesis catalyst comprises two ligands P1 and P2, which may be the same or
different and of formula P(R1)3, in which P is a phosphorus atom coordinated to the
ruthenium ion and each R1 is independently an optionally substituted alkyl or alkoxy
group; or two R1 groups within one P1 or P2 ligand constitute an optionally substituted
bicycloalkyl.
The method of clause 32 wherein the catalyst is of formula (I):
wherein:
P1 and P2 are as defined in clause 30;
X1 and X2 are anionic ligands, which may be the same or different; and
A is an alkylidene group.
The method of clause 30 or clause 3 1 wherein each R1 is independently a branched
C5-10 alkyl, C5-10 cycloalkyl, C5-10 alkoxy or C5-10 cycloalkoxy group optionally substituted
once with a sulfonate, phosphate carboxylate, quaternary ammonium or PEGcontaining
group.
The method of any one of clauses 30 to 32 wherein each R1 is unsubstituted and
independently a branched C -10 alkyl, C -10 cycloalkyl, branched C -10 alkoxy or C -10
cycloalkoxy group.
The method of clause 32 or clause 33 wherein each R1 is independently a C -10
cycloalkyl group.
The method of any one of clauses 30 to 34 wherein at least one of ligands P1 and P2
is tricyclohexylphosphine.
The method of any one of clauses 30 to 35 wherein both ligands P1 and P2 are the
same.
The method of any one of clauses 30 to 36 wherein the alkylidene group is a moiety
of formula =CR R and in which one of R and R may be hydrogen and either or both
of R and R may be alkyl, alkenyl, alkynyl, aryl carboxyalkyl, alkoxy, alkenyloxy,
alkynyloxy or alkoxycarbonyl, or R and R together form a saturated, unsaturated or
aromatic cyclic or bicyclic moiety.
38. The method of clause 37 wherein R is hydrogen, alkyl or aryl and R is alkyl, alkenyl
or aryl
39. The method of clause 37 wherein the alkylidene group is optionally substituted
indenylidene.
40. The method of clause 39 wherein the alkylidene group is a phenyl-substituted
indenylidene.
4 1. The method of clause 39 wherein the alkylidene group is 3-phenyl-1 H-inden-1-
ylidene.
42. The method of clause 4 1 wherein the catalyst is a dihalo(3-phenyl-1 H-inden-1-
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
43. The method of clause 42 wherein the catalyst is a dichloro(3-phenyl-1 H-inden-1-
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
44. The method of clause 37 wherein the alkylidene group is phenylidene.
45. The method of any one preceding clause wherein the diene is a diene consisting only
of carbon and hydrogen atoms.
46. The method of clause 45 wherein the diene is a cyclic diene.
47. The method of clause 46, wherein the diene is 1,4-cyclohexadiene.
48. Use of a diene to promote an ethenolysis reaction conducted on a monoalkene.
49. The use of clause 48, wherein the use comprises a method of any one of clauses 1 to
47.
50. An alkene obtained or obtainable by a method defined in any one of clauses 1 to 47
or according to the use defined in clause 48 or clause 49.
The invention is further illustrated by the following non-limiting examples below:
As homogeneous metathesis catalysts are very sensitive towards impurities, cardanol
(2) was purified prior to use. Following a known literature procedure anacardic acid (1) was
isolated from CNSL and heated to 200 ° for 3 h .3 After decarboxylation a brown viscous
liquid remained, which was further purified by distillation at 230 °C under vacuum. 2 could be
isolated as a pale yellow, slightly viscous liquid, which was stored under nitrogen
atmosphere. GC-MS and 1H-NMR analysis showed almost pure cardanol (2), which
contained 37.9 % monoene 2b, 19.9 % diene 2c, 37.5 % triene 2d and 4.7 % saturated
cardanol 2a. Separation of these various unsaturated compounds via column
chromatography proved difficult, so the cardanol mixture 2 was used without further
purification.
Cardanol ethenolysis
In a first set of experiments various homogeneous metathesis catalysts were
tested in the ethenolysis of cardanol 2. During ethenolysis, a propagating methylidene
species is formed, which reacts with cardanol (2) to release a terminal alkene 3-
nonenyl phenol (4) in the case of mono-unsaturated cardanol 2b. 15 Most alkene
metathesis catalysts are unstable as methylidene complexes and undergo rapid
decomposition, which affects the selectivity and productivity of the ethenolysis
reaction. 14 Therefore, 1st generation type, 2nd generation type and Grubbs-Hoveyda
type catalysts were screened in order to identify a suitable catalyst system for the
selective e
Grubbs 1
Owing to their varying stability and activity the performance of the metathesis
catalyst was investigated at various temperatures. Beside the expected ethenolysis
products, 3-non-8-enylphenol (4) and 1-octene (6), which are formed by crossmetathesis
of ethene with 2 containing only 1 double bond, 1,4-cyclohexadiene (7), 3-
dodecadienylphenol (5) and various isomeric ethenolysis products were also
observed in the reaction mixture:
cardanol (2)
isomeric ethenoysis products (e.g. 3-undecenylphenol)
The isomeric ethenolysis products are mainly formed via isomerisation of the
monounsaturated cardanol 2b, followed by cross-metathesis with ethene. Ethenolysis
at the unsaturated C -position of the diene 2c and triene 2d lead to the side-product
3-dodeca-8,1 1-dienylphenol (5). However, owing to their volatility the corresponding
side-products 1,4-pentadiene and 1-pentene were not observed.
Reacting 2 with MΊ at room temperature gives almost exclusive conversion (43
%) to 3-non-8-enylphenol (4, 8 1 % selectivity) and its isomers together with 1,4-
cyclohexadiene (7), the remaining unreacted cardanol (2) contains no 2d (absence of
peaks with m/e 298, [M]+; Entry 2, Table 1) . This reaction shows that 7 can be formed
by direct internal self-metathesis of the triene (2d) to 7 and 4 . However, 7 might also
be formed from the ethenolysis of the triene (2d) at the unsaturated C8,9-position,
giving 3-nonenylphenol (4) and 1,4,7-octatriene, followed by the internal selfmetathesis
of the 1,4,7-triene to ethene and 7.
Because of the high percentage of triene 2d in the starting material, the
amount of 1,4-cyclohexadiene (7) is significant and almost in the same range as 1-
octene (6).
As some of the side-products such as the diene (7) and the linear alkenes with
an alkyl chain < C7 are volatile, it was not possible reliably to determine their exact
amounts via GC analysis. Therefore, we analysed the distribution of the
corresponding alkenylphenols.
The results in Table 1 below show that the conversion and the selectivity in the
ethenolysis of cardanol (2) strongly depend on the metathesis catalyst and the
reaction temperature. Quite unexpectedly the best results were obtained with the MΊ
and the Grubbs 1st generation catalysts (Entries 1-6, Table 1) . Both catalytic systems
exhibited an excellent performance in the ethenolysis with yields and selectivities > 90
% towards the desired product, 4, (catalyst loading. 0.05 mol %). Only a minor
influence of the temperature on the activity was observed. And changing to the more
environmentally acceptable solvent, toluene from CH2CI2 was only slightly detrimental.
(Table 1, Entry 4) Furthermore, the metathesis reaction of cardanol (2) with M but
with no ethene present showed that 2 can undergo self-metathesis to form 1,4-
cyclohexadiene (7) and the desired 3-nonenylphenol (4) (Entry 2, Table 1). Only the
tri-unsaturated cardanol 2d is able to react to give 4 and 7 via self-metathesis, hence
the conversion of the reaction (43 %) is similar to the amount of tri-unsaturated
cardanol 2d in the substrate mixture (37.5 %; the slight difference is within the
experimental error of the GC measurements). This result indicates that metathesis of
2 with M and ethene probably proceeds by a combination of self-metathesis (for the
triene 2d) and ethenolysis (for the monoene 2b and diene 2c).
The N-heterocyclic carbene (NHC) bearing 2nd generation type16 19 catalysts
M2, M20 , M3 and Caz-1 (Entries 7-18, Table 1) were generally less active and
selective in the ethenolysis of cardanol mixture, 2, compared to the Grubbs 1st
generation catalyst and M especially at 20 °C where the conversion and the
selectivity were much lower in comparison to the 1st generation type catalysts. With
increasing temperature the activity and selectivity improved with M2 (Entries 8 and 9,
Table 1) and Caz-1 (Entries 17 and 18, Table 1) catalysts giving good performances
at 70 °C and 90 °C respectively.
Tab e c
ruthenium based catalysts.
Entry Catalyst T / ° Conv. 4 5 Isomeric
/ % / % / % products / %
1 M1 20 95 94 2 4
2b 20 43 8 1 0 19
3 40 96 93 3 4
4 20 84 87 8 5
5 Grubbs s 20 90 9 1 5 4
6 40 9 1 90 5 5
7 M 20 57 19 14 67
8 40 6 1 34 12 54
9 70 84 68 12 20
10 M20 20 26 43 25 32
11 40 83 54 20 27
12 70 87 49 15 37
13 M3 1 20 67 46 24 30
14 40 83 53 19 28
15 70 87 59 22 20
16 Caz-1 40 6 1 9 12 79
17 70 58 22 14 65
20 40 93 16 4 80
2 1 70 90 22 6 72
22 M52 20 88 23 7 70
23 40 95 24 10 66
24 70 89 22 7 72
a 2 (0.54 mmol), C2H4 (8 bar), CH2CI2 ( 1 .35 ml_), catalyst (0.05 mol%), Analysis via GC using
n-tetradecane as internal standard.6 h ; b no ethene.
This increased activity with higher reaction temperature could be related to the
activation energy of the catalyst since it is known that the latent Caz-1 must isomerise
from cis to trans before it becomes active. 20, For the metathesis reaction the catalyst
must provide a free coordination site, which is generated via dissociation of a ligand.
In contrast to the tricyclohexylphosphine ligands, which readily dissociate at room
temperature, methyl- or phosphite ligands are much less labile and need higher
temperature to leave the metal center. 20, Nevertheless, even at elevated
temperature the activities of the 2nd generation type catalysts are lower than those of
the 1st generation and MΊ catalysts. The reduced activity in the ethenolysis is not only
visible in the lower conversion, but is also seen in the lower selectivities to product 4.
The Grubbs-Hoveyda type catalysts show even less selectivity in the
ethenolysis of cardanol (2). Only in the case of M5 is significant selectivity towards
the desired 3-nonenylphenol (4) observed at 20 °C (Entry 19, Table 1) . Furthermore,
the activity and selectivity of M5 and M52 show only minor dependancies on the
reaction temperature (Entries 19-24, Table 1) . Both catalytic systems are active at 20
° and 40 ° respectively, but catalyse mainly the self-metathesis reactions of 2. In
comparison to the 2nd generation type catalysts, the boomerang-type ligand in M5
and M52 can easily dissociate to generate a free coordination site. It has been
proposed that the ligand remains close to the metal centre and re-coordinates after
the catalytic cycle to stabilise the complex, 15 but this recoordination has been
disputed. 22 In any case, they are much more active in the conversion of 2 than the 2nd
generation type catalysts. In general, NHC-based ruthenium catalyst are known to be
more active and stable than the first-generation catalyst but are significantly less
selective in ethenolysis, as they tend to promote self-metathesis. 14
Forman et al. showed that the performance of certain alkene metathesis
reactions by 1st generation catalysts could be enhanced by the addition of phenols.
In the presence of phenol only small quantities of undesired by-products were
detected and the activity of the catalytic system was significantly increased. We
reasoned, therefore, that the phenol present in cardanol (2) might be responsible for
the excellent activity and selectivity provided by 1st generation and MΊ catalysts in the
ethenolysis reaction. However, adding phenol to the ethenolysis reaction of 2 with MΊ
did not improve the catalytic performance. In contrast, we observed no conversion of
2 indicating that, in our case, the addition of phenol inhibits the cross-metathesis of
ethene and cardanol (2).
Metathesis of methyl protected cardanol 8
The effect of the phenolic group in cardanol (2) was further tested by etherification of
the phenolic -OH with methyl iodine,24 shown below:
cardanol (2)
3-nonenylphenylmethyl ether (9)
The methyl cardanol (8) was tested in the ethenolysis with MΊ under standard
reaction conditions. In comparison to the unprotected cardanol 2 the conversion (62.4
%) and selectivity towards the desired 3-nonenylphenol methyl ether (9) (84.0 %)
were both lower than when using cardanol (2) itself as substrate, but higher than
when using any of the other metathesis catalysts depicted above with it (i.e. Grubbs
1st , M2, M20 , M3 , Caz-1 , M5 and M52) . The result shows that, although the phenolic
structure of 2 may have some beneficial effect on the ethenolysis reaction, there must
also be some other reason for the excellent results obtained when using MΊ or
Grubbs 1st generation catalysts.
Ethenolysis of mono-unsaturated cardanol (2b)
Further information as to the important influences involved in the ethenolysis
reactions came from a study of monounsaturated cardanol (2b), which was originally
initiate to avoid the formation of 1,4-cyclohexadiene (7) and to maximise the
production of 1-octene (6).
Recently, Perdriau et al. reported the selective transfer hydrogenation of a
cardanol mixture 2 to mono-unsaturated compound 2b with RuCI3-xH20 in 2-
propanol. 25 The transfer-hydrogenation gives access to almost pure 2b, although
some double bond isomerisation occurs during the transfer hydrogenation reaction.
The mono-unsaturated cardanol 2b was tested in the ethenolysis with M Caz-1 and
M5 under the standard reaction conditions (Table 2).
Table eno
Entry Catalyst T / ° Conversion / % 4 / % Isomeric
products
/ %
1 M1 20 - - -
2 Caz-1 70 28 13 87
a Conditions as in Table 1
Surprisingly, we could not observe any conversion of the mono-unsaturated
cardanol with M . The catalytic system Caz-1 and M5 showed some conversion in the
ethenolysis, but in comparison to the unsaturated cardanol mixture 2 the activity and
selectivity were also much lower. This observation indicates that the di- and triunsaturated
cardanol (2c and 2d) are highly beneficial for the ethenolysis of cardanol.
Especially in the case of MΊ their presence seems to be essential.
A major difference between the mono-unsaturated compound 2b and the
natural cardanol mixture 2 is the formation of 1,4-cyclohexadiene (7) during the
metathesis reaction of 2d in the latter. To analyse the role of 1,4-cyclohexadiene (7) in
the ethenolysis reaction, we added 0.1 equivalent of 1,4-cyclohexadiene (7) to 2b and
repeated the metathesis reaction under the standard reaction conditions (cf Table 3):
Table 3 Ethenolysis of mono-unsaturated cardanol (2b) with additives.
Isomeric
Conversion /
Entry Additive 4 / % products
%
/ %
1 None - - -
2 1,4-cyclohexadiene (7) 64 55 46
3 1,4-hexadiene 63 46 55
4 1,5-cyclooctadiene 3 1 47 53
5 1,7-octadiene 69 46 54
Conditions as in Table 1; additive (0.1 equiv)
The addition of 1,4-cyclohexadiene (7) had a major impact on the ethenolysis
of monounsaturated cardanol (2b) (compare Entries 1 and 2 in Table 3). In the
presence of 1,4-cyclohexadiene 2b (64.4 %) underwent metathesis and 3-
nonenylphenol (4) was formed (54.5 % selectivity). The other products were mainly
isomeric metathesis products, which arose from double bond positional isomers of the
monoene 2b that were formed during the transfer hydrogenation reaction. 25 Since
without diene 7 we observed no reaction, these results indicate that 7 has a positive
effect on the MΊ catalyst during the ethenolysis reaction. We also tested other dienes
as additives in the metathesis of mono-unsaturated cardanol 2b (Table 3, Entries 3-5).
With all three additives we could see an improved activity of the MΊ catalyst in the
ethenolysis. The effect of 1,5-cyclooctadiene on the catalytic activity was less
pronounced, giving a lower conversion (31 .2 %, Entry 4, Table 1). This is possibly
because 1,5-cyclooctadiene can coordinate through both double bonds to the metal
centre and hence may block coordination of the double bond in 2. However, it still
gives better catalysis than is obtained in its absence. These results suggest that the
formation of 1,4-cyclohexadiene (7) in the ethenolysis of the natural cardanol mixture
2 is very important for the stabilisation of MΊ and its activity in the metathesis reaction
of cardanol (2) with ethene.
Caz-1 and M5 were also tested in the ethenolysis of mono-unsaturated
cardanol (2b) with 1,4-cyclohexadiene (7) as additive, see Table 4:
Table 4 Ethenolysis of mono-unsaturated cardanol 2b with different catalysts with or without
1,4-cyclohexadiene (7).
Entry Catalyst Conversion/ % 4 / % Isomeric products / %
1 Caz-1 28 13 87
2b Caz-1 78 11 90
+ 1,4-CHD
3C M51 72 7 93
4C M51 64 2 98
+ 1,4-CHD
a Conditions as in Table 1; b 70 ° c 40 °C.
In the case of Caz-1 the addition of 7 leads to an increase in conversion of 2b
up to 80 %. However, mainly isomeric products of cardanol (2) were formed and only
10.5 % of the desired 3-nonenylphenol (4) was detected. With M5 no enhancement of
the catalytic performance was observed. These results indicate that the effect of the
diene (7) strongly depends on the metal catalyst employed.
Owing to its positive effect in the ethenolysis of mono-unsaturated cardanol 2b
with M , we also analysed the influence of 1,4-cyclohexadiene (7) in the ethenolysis of
2b protected via etherification with methyl iodide (see Table 5).
Table 5 Ethenolysis of methyl-protected mono-unsaturated cardanol 8b with different
catalyts and 7 as additive.
Conversion / Isomeric
Entry Catalyst 4 / %
% products / %
1 M1 53 50 50
M1 2b 56 53 37
+ 1,4-CHD
3C Caz-1 7 1 6 94
Caz-1
4C 80 8 92
+ 1,4-CHD
5d M5 77 2 98-5
M5 6d 86 3 97
+ 1,4-CHD
Conditions as in Table 1; rt; c 70 ° d 40 °C.
Ethenolysis of oleate 10 and linoleate esters 12
The highly beneficial combination of MΊ + 1,4-cyclohexadiene (7) was also tested in
the ethenolysis of oleate and linolenate based substrates:
Me02
The results in Table 6 show that 7 also has a positive effect in the ethenolysis
of methyl oleate (10) (Entries 1 and 2, Table 6), increasing the conversion of 10 to the
ethenolysis product methyl 9-decenoate by more than 25 % However, MΊ is inactive
for the metathesis of methyl linolenate (12) in the presence or absence of the diene 7
(Entries 5 and 6, Table 6).
Table 6 Ethenolysis of different olefinic substrates (10-13) with M .a
Entry Substrate Conversion / % Selectivity / %
1 10 47 89
2 10+ 1,4-CHD 76 94
3 11 7 62
4 11+ 1,4-CHD 13 57
5 12 - -
6 12 + 1,4-CHD - -
7 13 36 75
8 13 + 1,4-CHD 5 -
Conditions as in Table 1.
To confirm that it was not the phenol in cardanol (2) that was allowing the
excellent results obtained in ethenolysis reactions using M1 we synthesised the
resorcinol esters of oleic (11) and linolenic (13) acids. Introducing the phenol moiety
into the oleic ester dramatically reduced the conversion and the selectivity towards the
desired non-8-enoic acid ester (Entry 3, Table 6), a result that was hardly improved by
adding 7 (Entry 4, Table 6). In the case of linolenate, there was some small
improvement as a result of using the resorcinol ester 13 (Entry 7, Table 6), but this
was nullified by adding the diene (7) (Entry 8, Table 6). Overall, the results of these
ethenolysis reactions with oleate and linoleate esters 10-13 confirm that the phenol
moiety is at best neutral or inhibiting to the reactions, but that 1,4-cyclohexadiene (7)
can provide a positive effect, even counteracting any negative effect of the phenyl
group.
Ethenolysis of anacardic acid (1) and its derivatives
Anacardic acid (1) can also be obtained directly from CSNL, but using fewer
steps than are required for the isolation of cardanol (2). It can potentially give the
desired 3-nonenylphenol (4) by ethenolysis followed by decarboxylation. Preliminary
studies on the ethenolysis of anacardic acid itself using MΊ catalyst (conditions
reported in Table 1, entry 1) showed no evidence for reaction. We therefore
methylated anacardic acid at both the phenolic and acidic positions. The ester 14
could then be purified by distillation without decarboxylation of the carboxyl group.
Because of the lower activity of MΊ in the ethenolysis of methyl cardanol (8, see
above) we directly investigated a range of Grubbs-Hoveyda type catalysts:
methyl 2-methoxy-6-(non-8-en-1-yl)benzoate (15)
a) Catalysts used for the ethenolysis of methylated anacardic acid (14);
b) Synthesis and ethenolysis of 14. D S = dimethylsulfate.
which showed high efficiency in our previously investigated isomerising ethenolysis of
methyl oleate 26 and of alkenyl benzenes, 27 :
The results of these studies, collected in Table 7, show that of all the catalysts
tested only the phosphine containing catalyst, HG shows high activity and selectivity
at 25 °C and a catalyst loading of 1 mol % over 16 h (Entry 1, Table 7).
Table 7 Ethenolysis of dimethylated anacardic acid 14.
Entry Metathesis catalyst T / °C Conversion / % Selectivity / %
1 H 25 93 93
2 M3 1
" 17 13
3 M4 1
" 30 18
4 M5
" 96 36
5 M74
" 90 37
7b M5
" 88 16
8b M3 1
" 56 11
9 M4 1
" 44 19
10* M 4
" 93 7
1 2 " 92 93
3c ί 78 93
a Conditions: 14 (0.25 mmol), cat. ( 1 mol %), CH2CI2 ( 1 ml_), 16 h ; a yields were determined
using n-dodecane as internal standard; ^THF ( 1 ml_); c reaction time 6 h ; d cat. (0.5 mol %); e
cat. (0.1 mol %); 'cat (0.05 mol %).
Amongst the other catalysts (Entries 3-8, Table 7), only M5 and M74 show good
activity (Entries 4 and 5, Table 7), but their selectivity towards the desired product 15
bearing an 8-nonenyl substituent is low. There is little or no improvement for any of
the catalysts at higher temperature (Entries 6-10, Table 7) but HGi is adversely
affected. At 25 °C HGi performs well even at lower catalysts loading (Entries 11-1 3,
Table 7) with a slight drop in activity but with the high selectivity being retained.
Test for oestrogenicity
Owing to their excellent properties, ethoxylated alkylphenols (APEs) are
widely used in various applications, for example as emulsifiers, detergents or
surfactants in household products. Nevertheless, they are being replaced by
ethoxylated alcohols because of environmental concerns. One of the most important
APEs has been banned in Europe because its precursor, 4 -nonylphenol is an
endocrine disrupter, 12, for example, it has been shown to induce testes-ova, and
intersex condition, in the post-hatching stages of development of male Japanese
Medaka fish. 28 The form of 4 -nonylphenol used has a variety of differently branched
C9 chains in the 4 position of the phenol and its endocrine disrupting properties have
been attributed t
oestradiol
We reasoned that 3 -nonylphenol might be less endocrine disrupting than 4 -
nonylphenol since it has a linear C9 chain in the 3 position and should not so readily
mimic oestradiol. Some of us have shown13 that the oestrogenicity of alkyl phenols
increases in the order 2<3<4 alkyl substitution on the ring and
primary~secondary98% pure) was purchased from Sigma Chemical
Company Ltd. (Dorset, UK) and ethanol (>99.7%) was purchased from Hayman Speciality
Products (Essex, UK). All other solvents were purchased from Sigma-Aldrich and were
distilled under N2 using the appropriate drying reagent. 29 CNSL was extracted from shells
collected from Naliendele in Mtwara, Tanzania. Anacardic acid was obtained from the oil by a
literature method3 and cardanol (2) from the anacardic acid (1) as previously published. 10
The cardanol (2) was vacuum dried before it was subjected to ethenolysis reactions.
Instrumentation
All weighing manipulations of air- and moisture-sensitive chemicals were
carried out in the glove box of model type FF1 00 Recirc 13649 series, where the port
was evacuated for 30 minutes and flooded with nitrogen gas for 3 cycles. All reactions
which used air sensitive chemicals were carried out under nitrogen atmosphere using
standard Schlenk line and catheter techniques.
GC-MS analyses were carried out using a Hewlett-Packard 6890 series gas
chromatograph instrument equipped with a flame ionization detector for quantitative
analysis and a Hewlett-Packard 5973 series mass selective detector fitted with hp1
film for mass spectral identification of products. Helium was used as the carrier gas
with initial flow of 1 imL/min. The H NMR and C NMR spectra were recorded on a
Bruker AM 400 NMR spectrometer at 400 and 100 MHz or a Bruker AM 300
spectrometer at 300 and 75 MHz, respectively. Samples were dissolved in deuterated
solvents which were referenced internally relative to tetramethylsilane (TMS) at d = 0
ppm. Chemical shifts, d , are reported in ppm relative to TMS. All 13C NMR spectra
were proton-decoupled.
Analysis of Cardanol (2). Cardanol was analysed via GC and NMR. H NMR(300
MHz, CDCI3): d 0.93 - 1.00 (m, 1.9 H, C 3/C ), 1.33 - 1.45 (m, 12.4 H, C ) , 2.05 -
2.14 (m, 2.1 H, C ) , 2.57 - 2.62 (m, 3.1 H, C ), 2.83 - 2.92 (m, 1.9 H, C ) , 5.03 -
5.16 (m, 0.8 H, CH) , 5.33 - 5.56 (m, 4.0 H, CH) , 5.82 - 5.95 (m, 0.4 H, CH), 6.70 -
7.22 (m, 4H, Ar-H) ppm. 3C (75 MHz, CDCI3): 14.3, 14.6 ( H3) , 32. 1, 23.3, 26.0, 26. 1,
27.6, 27.7, 29.4, 29.7, 29.8, 29.9, 30. 1, 30. 1, 30.2, 31.7, 32.0, 32.2, 36.3 (CH ) . 127.3,
128.0, 128.4, 128.6 129.7, 129.8 (CH), 130.4, 130.6, 130.8, 137.3, 145.3, 155.8 (Ar-
C) ppm. The integration of the H NMR-signals did not result in even numbers, as
cardanol is a mixture of compounds of different saturation . Furthermore, more than 2 1
C-signals can be observed due to the different degrees of saturation. The
composition of saturated, mono-, di- and tri-unsaturated cardanol was calculated from
integration of the olefinic proton signals the protons adjacent to the double binds and
the aromatic protons.
Monounsaturated cardanol (2d)25 RuCI3-xH20 (17 mg, 1.1 mmol) was dissolved in
2-propanol (5 ml) and cardanol (0.5 g, 1.66 mmol) was added. The reaction was
refluxed for 18 h under an N2 atmosphere. The resulting brown solution was cooled to
room temperature and the solvent removed to give a viscous brown oil. The oil was
dissolved in CH2CI2 (20 ml) and filtered over a 5 cm3 plug of silica to give a yellow oil.
Yield : 0.43 g, 1.4 mmol (86 %). H NMR (CDCI3): d 0.9 (t, 3H, CH3) 1.3 (m, 16 H,
C ); 2.0 (m, 4H, C -C=C) ; 2.6 (m, 2H, Ar-CH -) ; 5.4 (m, 2H, HC=CH) 6.7-7.2 (m,
4H, Ar) ppm. MS (m/z) : 302, 304 (saturated cardanol) .
Methyl protected monounsaturated cardanol (8b)24 Monounsaturated cardanol (1
g, 3.3 mmol) and potassium carbonate (0.9 g, 6.6 mmol) were suspended in dry
acetone (15 ml). Methyl iodide (0.4 ml, 6.6 mmol) was added dropwise and the
mixture allowed to reflux for 6 h. The reaction was then allowed to cool to room
temperature and the solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate (50 ml). The organic layer was washed with water (3 x 20
ml) , dried over MgS0 4, filtered and evaporated to give a yellow oil. The oil was then
purified over a silica column using hexane:EtOAc (5: 1) . Yield : 55 %. H NMR (CDCI3):
d 0.9 (t, 3H, CH3) 1.3 (m, 16 H, CH2) 2.0 (m, 4H, CH^C=C) 2.6 (m, 2H, Ar-CH^) ;
3.8 (s, 3H, OCH3); 5.4 (m, 2H, HC=CH) 6.7-7.2 (m, 4H, Ar) ppm. MS (m/z) : 316.
Methyl linolenate ( 12). Oleic acid (0.92 g, 3.5 mmmol) and polyethyleneglycol-750
(1,24 g) were dissolved in CH2CI2 (5 mL). KOH (0.37 g) was added and, after stirring
for 1 h, Mel (0.5 g, 0.22 mL, 3.4 mmol). After stirringfor 5 h, during which time a white
precipitate formed, water was added followed by NaCI to break the emulsion . The
organic phase was collected combined with CH2CI2 washings of the aqueous phase (2
x 5 mL), dried over anhydrous MgS0 4 and evaporated to dryness. The product was
separated on a silica column using hexane:EtOAc (4: 1) . GCMS analysis if the product
showed it to be contaminated with up to 50 % methyl linoleate and traces of methyl
oleate. NMR integration also suggests that significant amounts of methyl linoleate are
present.
3-hydroxyphenyl oleate ( 11) Oleic acid ( 1 .6 g, 4.21 mmol) and resorcinol (1.6 g,
14.82 mmol) were dissolved in THF (10 mL). The reaction mixture was cooled to 0 °C
and slowly N,N-dicyclohexylcarbodiimide (99 1 mg, 4.81 mmol ) and DMAP (22 mg,
0.18 mmol) were added. The reaction mixture turned turbulent and a white precipitate
was formed. The suspension was allowed to warm and was stirred for 85 h at room
temperature. Ethyl actate (25 mL) was added to the mixture and the precipitate was
collected by filtration . The filtrate was evaporated and the remaining residue was
purified via column chromatography with hexane/EtOAc (4: 1) as eluent. Yield : 62 %.
H NMR(CDCI3): d 0.9 1 (t, J = 6.9 Hz, 3 H, C 3) , 1.27 - 1.45 (m, 20 H, C ) , 1.75 -
1.79 (m, 2 H, C ), 2.0 1 - 2. 07 (m, 4 H, C ) , 2.57 (t, 3J = 7.8 Hz, C ), 5.36-5.42
(m, 2 H, CH) , 6.23 (b, 1 H, OH) , 6.57 - 6.70 (m, 3 H, Ar-H), 7.2 1 (t, = 9.0 Hz, 1 H,
Ar-H) ppm. ESMS (m/z) : 373 [M-H]+
3-hydroxyphenyl linolenate ( 13) was similarly prepared from linolenic acid (1.2 g,
4.43 mmol), resorcinol (1.6 g, 14.82 mmol), A/,A/-dicyclohexylcarbodiimide (998 mg,
4.84 mmol ) and DMAP ( 18.3 mg, 0.15 mmol). Yield: 58 %. H NMR(CDCI 3) : d 1.01 (t,
3 = 7.5 Hz, 3 H, C 3) , 1.29 - 1.46 (m, 8 H, CH2) , 1.73 - 1.82 (m, 2 H, CH2) , 2.06 -
2.16 (m, 4 H, CH2) , 2.58 (t, 3J = 7.5 Hz, 2 H, CH2) , 2.81 - 2.86 (m, 4 H, CH ) , 5.3 1 -
5.48 (m, 6 H, CH) , 6.03 (b, 1 H, OH), 7.56 (b, 1 H, Ar-H), 6.66 (t, 3J = 8.4 Hz, 2 H, Ar-
H) , 7.2 1 (t, 3J = 8.4 Hz, 1 H, Ar-H) ppm .
3-nonylphenol 3-nonenylphenol (1 g, 4.6 mmol) , in degassed toluene ( 10 ml) , was
added to a solution of [RhCI(PPh 3)3] (30 mg, 46 mi oI) dissolved in degassed toluene
(5 ml) and transferred to a Fischer-Porter bottle which was charged with 6 bar H2 and
left to stir overnight at 60 °C. The solution filtered over a plug of silica (5 cm3) using
CH2CI2 ( 100 ml). The solvent was removed to give a colourless oil. Yield : 0.96 g, 4.4
mmol (96 %). H NMR (CDCI3) : d 0.9 1 (t, 3 H, CH3) 1.3 (m, 12 H, CH2) 1.6 (m, 2H,
C CH Ar) ; 2.6 (m, 2H, C Ar) ; 4.7 (s, 1H, OH) ; 6.7 - 7.2 (m, 4H, Ar-H) ppm . C
NMR (CDCI3) : d 14.1 ( H3) ; 22.7 ( H ); 29.2 ( H ) ; 29.3 ( H ) ; 29.6 ( H ); 29.8
( H ); 31.2 ( H ); 31.9 ( H ); 36.0 (Ar- H ); 113.1 (Ar) ; 115.6 (Ar) ; 120.7 (Ar) ; 129.9
(Ar) ; 144.8 (qAr) ; 156. 1 (qAr) ppm. MS (m/z) : 220.
Hydrogenation of 3-nonenylphenol (4) with Pd/C 3-nonenylphenol (4) ((800 mg,
3.6 mmol) and Pd/ C (5 wt%, 39 mg) were placed in an autoclave and
dichloromethane (5 mL) was added. The autoclave was pressurized with hydrogen to
10 bar and the suspension was stirred at 4 0 °C for 6 h. The reaction wa sthen allowed
to cool to room temperature and the autoclave was slowly depressurized. The solvent
was removed under reduced pressure and the residue was purified via column
chromatography with hexane, ethylacetate and diethylether as eluent (7: 1 :1) . Yield 7 8
%. H NMR(300 MHz, CDCI3) : d 0.9 1 (t, 3J = 6.9 Hz, 3 H, C 3) , 1.19 - 1.40 (m, 12 H,
CHz), 1.54 - 1.67 (m, 2 H, CHz) , 5.57 (t, 3J = 8 .1 Hz, 2 H, CH2) , 4.94 (b, 1 H, OH),
6.64 - 6.71 (m, 2 H, Ar-H), 6.78 (bd, 3J = 8.4 Hz, 1 H, Ar-H), 7 .16 (t, 3 = 8.4 Hz, 1 H,
Ax-H) ppm. C (75 MHz, CDCI3) : 14.6 (CH3) , 23.2 (CH ) , 29.8 (CH2) , 30.0 (CH ) , 30. 1
(CHz), 30.2 (CHz), 3 1.8 (CH ) , 32.4 (CH ) , 36.3 (CH ) , 1 12.9 (Ar-CH), 1 15.9 (Ar-CH),
12 1.5 (Ar-CH), 129.8 (Ar-CH), 145.4 (Ar-C), 155.8 (Ar-C) ppm.
Some completely hydrogenated 3 -nonenylphenol to 3 -nonylcyclohexanol can be
observed in the NMR.
Anacardic acid ester (14)3 1 To a stirred solution of anacardic acid (1) (5.00 g, 14.6
mmol) in acetone (30 ml) was added potassium carbonate (8.07 g, 58.4 mmol).
Dimethylsulfate (3.72 g, 29.2 mmol) was added in portions for about 10 min at room
temperature. After the addition was complete, the solution was heated to reflux for
4 h. The solution was cooled to room temperature and quenched with ammonium
chloride ( 10 ml). Distilled water (30 ml) was added to the reaction mixture, which was
then extracted with ethyl acetate (3 3 0 ml). The organic layer was washed with
distilled water ( 1 10 ml), dried over anhydrous sodium sulfate, and concentrated in
vacuo. The crude product was further purified by Kugelrohr distillation (270 ° , \ c 10
mbar) to yield 4.3 1 g ( 1 1.6 mmol, 80 % ) of a bright yellow oil. H NMR (CDCI3) :
d = 0.9 (m, 1.77 H, CH3) 1.3 (m, 12.07 H, CH2) 1.6 (m, 2.23 H, CH2) 2.0 (m, 3.02 H,
C 2-C=C); 2.5 (m, 1.89 H, C=C-CH2-C=C); 2.8 (m, 2 H, Ar-CH2-); 3.8 (s, 3 H, OCH3)
3.9 (s, 3 H, COOCHs) ; 5.0 (m, 0.72 H, C=CH2) 5.4 (m, 2 H , C =C ) ; 5.8 (m, 0.72 H,
HC=CH ) ; 6.7-7.2 (m, 4H, Ar) ppm. MS (m/z): 374.
Typical catalytic experiments
The catalyst (M ; 2 mg, 2.2 mi oI) was weighed in the glove box and made up
to a standard solution in CH2CI2 (2 ml), in a Schlenk tube under dinitrogen
atmosphere. When required, the additive was added to the standard solution in
correct molar amounts ( 1,4 -cyclohexadienene; 2 7 m I, 55 mi oI) . The substrate
(Monoene; 0 .18 ml, 0.55 mmol) was degassed and added to a previously dried and
inert Fischer-Porter bottle with magnetic stirrer bar under dinitrogen atmosphere, in
CH2CI2 ( 1 .3 ml). The appropriate amount of catalyst was syringed from the standard
solution (0.26 ml) and added to the Fischer-Porter bottle to give the correct substrate
concentration (typically 0.35 M substrate, 1:2000 [catalyst: substrate]. The glass bottle
was sealed then flushed with ethene five times and pressurised to at 8 bar. The
solution was allowed to stir for 6 hrs at the predetermined temperature in the sealed
vessel. The reaction was quenched with ethylvinyl ether (0.05 ml) and taken for GC
analysis.
Recombinant yeast oestrogen screen
The recombinant hER yeast strain was developed by Glaxo Wellcome and
details of the yeast oestrogen screen have been described previously (Routledge and
Sumpter, 1996).
In brief, yeast cells were transfected with the human oestrogen receptor gene
together with expression plasmids; the oestrogen response element and the lac-Z
gene encoding the enzyme b-galactosidase. The yeast cells were incubated in
medium containing the test chemical and the chromogenic substrate, chlorophenol
red-p-D-galactosidase (CPRG), and active ligands induced b-gal expression. The b-
galactosidase secreted into the medium causes the yellow CPGR to change into a red
product, and this is measurable by absorbance.
Assay procedure
The medium components were prepared and the standard assay procedure
was followed. 32 Chemicals were serially diluted in ethanol and 10 m I volumes were
transferred to 96-well flat-bottom plates where the ethanol was allowed to evaporate
to dryness. Then, 200m I medium containing CPRG and yeast (final cell number of 5 x
105 cells/ml) was added to each well. Included with every assay was a negative
control, ethanol, and a positive control, 17 b-oestradiol (stock solution of 17 b-
oestradiol (2x1 0 7 mol dm 3) serially diluted in ethanol to achieve final concentrations
of 1 x 10 8 mol dm 3 to 4.88 x 10 12 mol dm 3 in the wells).
The plates were incubated at 32 °C for 3 days, after which absorbance
readings were taken at 540 and 620 nm (the second absorbance being a measure of
cell density and hence yeast growth). The absorbance values were corrected for cell
density using the following equation:
Corrected value = chemical 5 4onm-(chemical 62onm-ethanol blank 620 nm)-
All chemicals were tested in duplicate and each YES was carried out at least
three times.
Conclusion
We showed that MΊ is a very active and selective catalyst in the ethenolysis of
cardanol to 3-nonenylphenol, an intermediate for potential surfactants. The
unexpected high catalytic perfomance of MΊ is due to the side-product 1,4-
cyclohexadiene, which is formed during the ethenolysis from the tri-unsaturated
component of cardanol. 1,4-cyclohexadiene stabilises the catalytically active species
and prevents inhibition by the phenolic group. Absence of 1,4-cyclohexadiene leads to
a complete deactivation of M as the results of the ethenolysis of mono-unsatu rated
cardanol showed. The positive impact of 1,4-cyclohexadiene on the catalytic
performance was also observed with other substrates such as methyl oleate. It also
enables the use of less expensive homogeneous metathesis catalysts in the
ethenolysis reaction, one of the most challenging reactions in metathesis.
One application of 3-nonenylphenol is to hydrogenate to 3-nonylphenol as a
possible replacement for the banned, on the basis of its endocrine disrupting
properties, detergent precursor, 4-nonylphenol. A YES assay shows that 3-
nonylphenol prepared by ethenolysis of cardanol is at least 150 times les potent in
oestrogencity than the banned substance and some 10~6 times as oestrogenic as 17
b-oestradiol. Cradnol and cashew nut shell liquid are even less potent showing very
little oestrogenicuty in the YES assay. The significance of the loss of oestrogenicity of
3-NP, cardanol and CSNL in terms of their safety in use can only be determined
following the outcomes of internationally agreed and validated OECD test methods
developed for the identification of endocrine disrupters, including oestrogenicity,
(anti)androgenicity and thyroid disruption.
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CLAIMS
1. Use of a diene to promote an ethenolysis reaction conducted on a monoalkene.
2 . The use of claim 1, which comprises a method of ethenolysis of a monoalkene,
comprising introducing into a reaction vessel a monoalkene and a diene, and
subjecting the monoalkene to ethenolysis in the presence of a metathesis catalyst
and the diene.
3 . The use of claim 2 , wherein the metathesis catalyst is an alkylidene ruthenium alkene
metathesis catalyst.
4 . The use of any one of claims 1 to 3 wherein the carbon-carbon double bond of the
monoalkene is a disubstituted carbon-carbon double bond.
5 . The use of any one preceding claim, wherein each carbon atom of the carbon-carbon
double bond is attached to an alkylene or alkyl moiety each of which independently
comprises from 2 to 7 carbon atoms.
6 . The use of claim 5 wherein the carbon-carbon double bond is flanked by two ethylene
moieties.
7 . The use of claim 5 wherein the carbon-carbon double bond is flanked by two
propylene moieties.
8 . The use of any one preceding claim, wherein the monoalkene is an optionally
esterified monounsaturated fatty acid.
9 . The use of claim 8 , wherein the fatty acid comprises from 4 to 28 carbon atoms.
10 . The use of claim 9 , wherein the fatty acid comprises from 14 to 18 carbon atoms.
11. The use of any one of claims 8 to 10 wherein the carbon-carbon double bond is a cis
C=C bond.
The use of of any one of claims 8 to 10 wherein the carbon-carbon double bond is a
trans C=C bond.
The use of claim 8 wherein the fatty acid is selected from the group consisting of oleic
acid, sapienic acid, palmitoleic acid, myristoleic acid or erucic acid.
The use of claim 13, wherein the fatty acid is oleic acid.
The use of any one of claims 8 to 14, wherein the fatty acid is esterified.
The use of claim 15, wherein the esterified fatty acid is an alkyl, aryl or heteroaryl
ester.
The use of claim 16, wherein the esterified fatty acid is an alkyl ester.
The use of claim 8 , wherein the monoene is methyl oleate.
The use of any one of claims 1 to 7 , wherein the carbon-carbon double bond of the
monoalkene is tethered to an aromatic moiety.
The use of claim 19, wherein the aromatic moiety is an aromatic alcohol.
The use of claim 20 wherein the aromatic alcohol is a phenol or a napthol.
The use of claim 20 wherein the aromatic alcohol is a phenol.
The use of any one of claims 19 to 22, wherein the carbon-carbon double bond is
tethered to the aromatic alcohol by an optionally substituted hydrocarbylene chain,
which is optionally interrupted with ether, ester, amide or amine groups.
The use of any of claims 19 to 23 wherein the method comprises the ethenolysis of
cashew nut shell liquid, or one more components thereof.
The use of any one of claims 19 to 24, wherein the method comprises the ethenolysis
of cardanol.
The use of claim 24 wherein the method comprises the ethenolysis of a monoene
component of cardanol.
27. The use of claim 24, wherein the method comprises the ethenolysis of
The use of any one of claims 24 to 27, which is a method for preparing 1-octene.
The use of any one of claims 19 to 27, which is a method of preparing 3-non-8-
enylphenol.
The use of claim 29 further comprising hydrogenating 3-non-8-enylphenol and
ethoxylating the resultant 3-nonylphenol to provide ethoxy-3-nonylphenol or
oligoethoxy-3-nonylphenol, in which the -oligoethoxy substituent is of formula
-(OCH 2CH2)nOH, wherein n is an integer of between 1 and 20.
The use of any one of claims 3 to 30 wherein the alkylidene ruthenium alkene
metathesis catalyst comprises two ligands P1 and P2, which may be the same or
different and of formula P(R1)3, in which P is a phosphorus atom coordinated to the
ruthenium ion and each R1 is independently an optionally substituted alkyl or alkoxy
group; or two R1 groups within one P1 or P2 ligand constitute an optionally substituted
bicycloalkyl.
The use of claim 3 1 wherein the catalyst is of formula (I)
wherein:
P1 and P2 are as defined in claim 3 1 ;
X1 and X2 are anionic ligands, which may be the same or different; and
A is an alkylidene group.
33. The use of claim 3 1 or claim 32 wherein each R1 is independently a branched C -10
alkyi, C -10 cycloalkyl, C -10 alkoxy or C -10 cycloalkoxy group optionally substituted
once with a sulfonate, phosphate carboxylate, quaternary ammonium or PEGcontaining
group.
34. The use of any one of claims 3 1 to 33 wherein each R1 is unsubstituted and
independently a branched C -10 alkyi, C -10 cycloalkyl, branched C -10 alkoxy or C -10
cycloalkoxy group.
35. The use of claim 33 or claim 34 wherein each R1 is independently a C -10 cycloalkyl
group.
36. The use of any one of claims 3 1 to 35 wherein at least one of ligands P1 and P2 is
tricyclohexylphosphine.
37. The use of any one of claims 3 1 to 36 wherein both ligands P1 and P2 are the same.
38. The use of any one of claims 3 1 to 37 wherein the alkylidene group is a moiety of
formula =CR R and in which one of R and R may be hydrogen and either or both of
R and R may be alkyi, alkenyl, alkynyl, aryl carboxyalkyl, alkoxy, alkenyloxy,
alkynyloxy or alkoxycarbonyl, or R and R together form a saturated, unsaturated or
aromatic cyclic or bicyclic moiety.
39. The use of claim 38 wherein R is hydrogen, alkyi or aryl and R is alkyi, alkenyl or
aryl.
40. The use of claim 38 wherein the alkylidene group is optionally substituted
indenylidene.
4 1. The use of claim 40 wherein the alkylidene group is a phenyl-substituted
indenylidene.
42. The use of claim 40 wherein the alkylidene group is 3-phenyl-1 H-inden-1 -ylidene.
43. The use of claim 42 wherein the catalyst is a dihalo(3-phenyl-1 H-inden-1 -
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
44. The use of claim 43 wherein the catalyst is a dichloro(3-phenyl-1 H-inden-1-
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
45. The use of claim 38 wherein the alkylidene group is phenylidene.
46. The use of any one preceding claim wherein the diene is a diene consisting only of
carbon and hydrogen atoms.
47. The use of any one preceding claim wherein the diene is a cyclic diene.
48. The use of claim 47, wherein the diene is 1,4-cyclohexadiene.
49. A method of ethenolysis of a monoalkene, comprising introducing into a reaction
vessel a monoalkene and a diene, and subjecting the monoalkene to ethenolysis in
the presence of a metathesis catalyst and the diene, wherein the diene consists only
of carbon and hydrogen atoms; and/or is cyclic.
50. The method of claim 49, wherein the metathesis catalyst is an alkylidene ruthenium
alkene metathesis catalyst.
5 1. The method of claim 49 or claim 50 wherein the carbon-carbon double bond of the
monoalkene is a disubstituted carbon-carbon double bond.
52. The method of any one of claims 49 to 5 1 , wherein each carbon atom of the carboncarbon
double bond is attached to an alkylene or alkyl moiety each of which
independently comprises from 2 to 7 carbon atoms.
53. The method of claim 52 wherein the carbon-carbon double bond is flanked by two
ethylene moieties.
54. The method of claim 52 wherein the carbon-carbon double bond is flanked by two
propylene moieties.
55. The method of any of claims 49 to 54, wherein the monoalkene is an optionally
esterified monounsaturated fatty acid.
56. The method of claim 55, wherein the fatty acid comprises from 4 to 28 carbon atoms.
57. The method of claim 56, wherein the fatty acid comprises from 14 to 18 carbon
atoms.
58. The method of any one of claims 55 to 57 wherein the carbon-carbon double bond is
a cis C=C bond.
59. The method of of any one of claims 55 to 57 wherein the carbon-carbon double bond
is a trans C=C bond.
60. The method of claim 55 wherein the fatty acid is selected from the group consisting of
oleic acid, sapienic acid, palmitoleic acid, myristoleic acid or erucic acid.
6 1. The method of claim 60, wherein the fatty acid is oleic acid.
62. The method of any one of claims 55 to 6 1, wherein the fatty acid is esterified.
63. The method of claim 62, wherein the esterified fatty acid is an alkyl, aryl or heteroaryl
ester.
64. The method of claim 63, wherein the esterified fatty acid is an alkyl ester.
65. The method of claim 55, wherein the monoene is methyl oleate.
66. The method of any one of claims 49 to 54, wherein the carbon-carbon double bond of
the monoalkene is tethered to an aromatic moiety.
67. The method of claim 66, wherein the aromatic moiety is an aromatic alcohol.
68. The method of claim 67 wherein the aromatic alcohol is a phenol or a napthol.
69. The method of claim 67 wherein the aromatic alcohol is a phenol.
The method of any one of claims 66 to 69, wherein the carbon-carbon double bond is
tethered to the aromatic alcohol by an optionally substituted hydrocarbylene chain,
which is optionally interrupted with ether, ester, amide or amine groups.
The method of any of claims 66 to 70 wherein the method comprises the ethenolysis
of cashew nut shell liquid, or one more components thereof.
The method of any one of claims 66 to 7 1, wherein the method comprises the
ethenolysis of cardanol.
The method of claim 7 1 wherein the method comprises the ethenolysis of a monoene
component of cardanol.
The method of claim 7 1 , wherein the method comprises the ethenolysis of
The method of any one of claims 7 1 to 74, which is a method for preparing 1-octene.
The method of any one of claims 66 to 74, which is a method of preparing 3-
enylphenol.
The method of claim 76 further comprising hydrogenating 3-non-8-enylphenol and
ethoxylating the resultant 3-nonylphenol to provide ethoxy-3-nonylphenol or
oligoethoxy-3-nonylphenol, in which the -oligoethoxy substituent is of formula
-(OCH 2CH2)nOH, wherein n is an integer of between 1 and 20.
The method of any one of claims 49 to 77 wherein the alkylidene ruthenium alkene
metathesis catalyst comprises two ligands P1 and P2, which may be the same or
different and of formula P(R1)3, in which P is a phosphorus atom coordinated to the
ruthenium ion and each R1 is independently an optionally substituted alkyl or alkoxy
group; or two R1 groups within one P1 or P2 ligand constitute an optionally substituted
bicycloalkyl.
79. The method of claim 78 wherein the catalyst is of formula (I):
wherein:
P1 and P2 are as defined in claim 78;
X1 and X2 are anionic ligands, which may be the same or different; and
A is an alkylidene group.
80. The method of claim 78 or claim 79 wherein each R1 is independently a branched
C5-10 alkyl, C -10 cycloalkyl, C -10 alkoxy or C -10 cycloalkoxy group optionally substituted
once with a sulfonate, phosphate carboxylate, quaternary ammonium or PEGcontaining
group.
8 1. The method of any one of claims 78 to 80 wherein each R1 is unsubstituted and
independently a branched C -10 alkyl, C -10 cycloalkyl, branched C -10 alkoxy or C -10
cycloalkoxy group.
82. The method of claim 80 or claim 8 1 wherein each R1 is independently a C -10
cycloalkyl group.
83. The method of any one of claims 78 to 82 wherein at least one of ligands P1 and P2 is
tricyclohexylphosphine.
84. The method of any one of claims 78 to 83 wherein both ligands P1 and P2 are the
same.
85. The method of any one of claims 78 to 84 wherein the alkylidene group is a moiety of
formula =CR R and in which one of R and R may be hydrogen and either or both of
R and R may be alkyl, alkenyl, alkynyl, aryl carboxyalkyl, alkoxy, alkenyloxy,
alkynyloxy or alkoxycarbonyl, or R and R together form a saturated, unsaturated or
aromatic cyclic or bicyclic moiety.
86. The method of claim 85 wherein R is hydrogen, alkyi or aryl and R is alkyi, alkenyl
or aryl.
87. The method of claim 85 wherein the alkylidene group is optionally substituted
indenylidene.
88. The method of claim 87 wherein the alkylidene group is a phenyl-substituted
indenylidene.
89. The method of claim 87 wherein the alkylidene group is 3-phenyl-1 H-inden-1 -ylidene.
90. The method of claim 89 wherein the catalyst is a dihalo(3-phenyl-1 H-inden-1 -
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
9 1. The method of claim 90 wherein the catalyst is a dichloro(3-phenyl-1 H-inden-1 -
ylidene)bis(tricyclohexylphosphine) ruthenium (II).
92. The method of claim 85 wherein the alkylidene group is phenylidene.
93. The method of any one of claims 49 to 92, wherein the diene is 1,4-cyclohexadiene.
94. An alkene obtained or obtainable by a use defined in any one of claims 1 to 48 or
according to the method defined in any one of claims 49 to 93.