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\DOI{10.5802/crchim.319}
\datereceived{2024-02-09}
\daterevised{2024-04-08}
\datererevised{2024-04-10}
\dateaccepted{2024-05-17}
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\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{Challenges in biomass valorization by olefin metathesis}

\alttitle{Les D\'efis de la valorisation de la biomasse par m\'etath\`ese d'ol\'efines}

\author{\firstname{Antonio} \lastname{Del Vecchio}\CDRorcid{0000-0001-9759-4420}}
\address{Univ Rennes, Ecole Nationale Sup\'{e}rieure de Chimie de
Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France}
\curraddr[A. Del Vecchio]{Department of Chemistry and Industrial
Chemistry, University of Pisa, via G. Moruzzi 13, 56124 Pisa, Italy}
\email[A. Del Vecchio]{antonio.delvecchio@unipi.it}

\author{\firstname{Marc} \lastname{Mauduit}\CDRorcid{0000-0002-7080-9708}\IsCorresp}
\addressSameAs{1}{Univ Rennes, Ecole Nationale Sup\'{e}rieure de Chimie
de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France}
\email[M. Mauduit]{marc.mauduit@ensc-rennes.fr}

\begin{abstract}
The production of biosourced intermediates from renewable raw materials
represents a hot topic for the scientific community, which is engaged
in the development of more efficient and sustainable processes. In this
perspective, olefin metathesis (OM) is one of the best choices to
address societal issues, harnessing the conversion of compounds
extracted from plants into molecules of interest with a very low carbon
footprint. The aim of this article is to highlight and discuss two
relevant metathesis processes dedicated to biomass valorization (on the
one hand, the transformation of feedstocks resulting from
Fischer--Tropsch cuts of wood wastes, and on the other hand, the
transformation of unrefined unsaturated fatty esters from sunflower
oils) which involve highly efficient and selective ruthenium-based
catalysts. The recent development of continuous flow
\textit{Z}-selective metathesis processes applied to the synthesis of
biosourced odorant molecules and insect pheromones will also be
discussed.
\end{abstract}

\begin{altabstract}
La production d'interm\'{e}diaires biosourc\'{e}s \`{a} partir de
mati\`{e}res premi\`{e}res renouvelables repr\'{e}sente un sujet
d'importance pour la communaut\'{e} scientifique, qui pr\^{o}ne le
d\'{e}veloppement de processus plus efficaces et durables. Dans cette
perspective, la m\'{e}tath\`{e}se des ol\'{e}fines (MO) est l'un des
meilleurs choix pour r\'{e}pondre \`{a} ces enjeux soci\'{e}taux, en
exploitant la transformation de compos\'{e}s extraits de plantes en
mol\'{e}cules d'int\'{e}r\^{e}t avec une empreinte carbone tr\`{e}s
faible. L'objectif de cet article est de mettre en lumi\`{e}re et de
discuter deux processus de m\'{e}tath\`{e}se innovants d\'{e}di\'{e}s
\`{a} la valorisation de la biomasse (d'une part, la transformation de
mati\`{e}res premi\`{e}res r\'{e}sultant des coupes de Fischer--Tropsch
des d\'{e}chets de bois, et d'autre part, la transformation d'esters
gras insatur\'{e}s non raffin\'{e}s issus d'huiles de tournesol) qui
impliquent des catalyseurs \`{a} base de ruth\'{e}nium hautement
efficaces et s\'{e}lectifs. Le r\'{e}cent d\'{e}veloppement de
processus de m\'{e}tath\`{e}se \textit{Z}-s\'{e}lectifs en flux continu
appliqu\'{e}s \`{a} la synth\`{e}se de mol\'{e}cules odorantes
biosourc\'{e}es et de ph\'{e}romones d'insectes sera \'{e}galement
discut\'{e}.
\end{altabstract}

\keywords{\kwd{Olefin metathesis}
\kwd{Biomass valorization}
\kwd{Ruthenium}
\kwd{\textit{Z}-selectivity}
\kwd{Odorant molecules}
\kwd{Insect pheromones}
\kwd{Catalysis}}

\altkeywords{\kwd{M\'{e}tath\`{e}se des ol\'{e}fines}
\kwd{Valorisation de la biomasse}
\kwd{Ruth\'{e}nium}
\kwd{Catalyse}
\kwd{\textit{Z}-s\'{e}l\'{e}ctivit\'{e}}
\kwd{Mol\'{e}cules odorantes}
\kwd{Ph\'{e}romones d'insectes}}

\maketitle

\vspace*{5pt plus 1pt minus 1pt}

\twocolumngrid

\end{noXML}

\section{Introduction}

{Since its discovery in the 50s, the field of Olefin Metathesis (OM)
has been growing exponentially in terms of applications~\cite{1,2,3,4,5}. 
Early industrial applications were found in petrochemistry, where the use of
heterogeneous molybdenum or tungsten catalysts has proved effective in
the production of basic chemical intermediates}~\cite{6}. {Through the
years, metathesis reaction (MR) greatly enlarged its cohort of
applications, dramatically influencing the current way to think the
chemical synthesis (especially true for fine chemicals), and is an
invaluable tool in different\break industrial sectors, ranging from
oleochemistry, materials, pharmaceutical, agrochemical and perfume
industry}~\cite{7}. {Decades of efforts were finally recognized by the
international scientific community with the Nobel Prize awarded in 2005
to the pioneering work of Grubbs, Schrock, and Chauvin}~\cite{5}.

{With the isolation of the first stable alkylidene complexes based on
tantalum, molybdenum, and tungsten by Schrock in the 80s, the
metathesis catalysts are constantly evolving structurally, with a
strong progress in the 90s following the development of the first
Grubbs catalysts based on ruthenium, which are air-stable and tolerant
toward many organic functionalities. The emergence of stable and
isolable} {\textit{N}}{-heterocyclic carbene (NHC) ligands (e.g.,
SIMes, IMes, SIPr) has greatly contributed to improving the stability
and activity of Grubbs-type\break complexes, based on the work of Hermann,
Grubbs, and Nolan groups~\cite{8}. Another milestone in the structural
improvement of metal complexes, resulted in the introduction of
styrenyl ether carbenes by Hoveyda et~al.}~\cite{9}, {offering
an increased stability of the precatalyst, characterized by a reservoir
effect that greatly improved the catalytic efficiency upon
activation}~\cite{10}. {Later on, many other research groups, including
the Blechert, Grela, F\"{u}rstner, Pl\'{e}nio, and Mauduit groups,
contributed to the development of new catalytic species targeting both
stability and efficiency~\cite{8}. A plethora of ruthenium-based complexes
have been developed, constantly pushing the limits of the applications.
Many of these catalysts are commercially available and some of them are
now produced on multikilogram scale, with intense application in the
production of active pharmaceutical ingredients (APIs), notably for the
preparation of hepatitis C antivirals (e.g., Ciluprevir), kinase
inhibitors (e.g., Pacritinib), and Cathepsin K inhibitors (e.g.,
Relacatib) (Figure~\ref{fig1})~\cite{11,12}. Marketed since 2014 by Janssen
Pharmaceutical, Simeprevir (hepatitis C virus inhibitor) represents the
first API industrially produced by a metathesis route, demonstrating
the economic viability of this homogeneous transformation~\cite{13,14}.}

\begin{figure*}
\vspace*{5pt}
\includegraphics{fig01}
\vspace*{3pt}
\caption{\label{fig1}Examples of commercial ruthenium catalysts
(available in kg), frequently used in olefin metathesis and selected
APIs synthesized in kg scale.}
\vspace*{5pt}
\end{figure*}


{Although the pharmaceutical industry has already integrated the olefin
metathesis into manufacturing processes, the application of this
technology to the production of commodities from biomass still remains
underexploited}~\cite{11,15}. {Indeed, as Nature is unquestionably a source
of olefins, among whose terpene derivatives or triglycerides found in
vegetable oils}~\cite{16}, {the transformation of biomass by a
metathesis reaction is a promising approach to replace synthetic
petroleum derivatives in obtaining surfactants, lubricants, monomers
for the manufacture of materials, fragrances, or even insect pheromones\break
(Figure~\ref{fig2})~\cite{17,18}.}

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}Examples of molecules of interest for which at
least one synthesis step is accessible by biomass transformation via
olefin metathesis (in bold: bond formed by metathesis; in blue: carbon
chains from biomass).}
\vspace*{3pt}
\end{figure*}

{Nevertheless, olefin metathesis should ideally involve low-cost metal
catalysts with excellent efficiency (at ppm level) in terms of turnover
numbers (TON). Although some metal catalysts are available on a
multi-kg scale, the fluctuating market value of transition metals has
to be taken into account and the frequently excessive cost still
remains one of the weak points of this method}~\cite{12,19}. {Additionally,
the introduction of more complex ligands may greatly impact the overall
costs as well. The robustness and stability of metal complexes toward
the naturally occurring impurities in raw materials, especially when
these are of vegetable origin, is also a selection criterion. The
selectivity also plays a pivotal role for the right choice of the
catalyst to form the targeted metathesis product only, excluding
dimers, oligomers, or positional isomers (resulting from an
isomerization of the double bond, see Figure~\ref{fig9}). Low cost,
robustness and selectivity are therefore the catalyst
requirements}~\cite{20}.


{At present, the design of ruthenium-based catalysts has evolved
dramatically, leading to the synthesis of organometallic species
adaptable to the most common chemical challenges}~\cite{8}, {including
the transformation of biomass}~\cite{16,17}. {Listing all of them would
be extremely reductive, but some particular developments are worth
mentioning. With the Grubbs and Bertrand groups' pioneering work, it
was found that the replacement of the classic NHCs (see
Figure~\ref{fig1}) with cyclic(alkyl)(amino)carbenes (CAAC)~\cite{21},
successfully impacted on the stability of the methylidene intermediate,
thanks to peculiar steric and electronic properties of this carbene
(Figure~\ref{fig3})}~\cite{22}. {As such, the ethenolysis, a
cross-metathesis (CM) reaction between methyl oleate and ethylene,
could be successfully carried out, even using ppm or ppb of catalyst
loading, allowing the production of highly desirable biosourced
building blocks with very high TONs (up to 2.6 million)
(Figure~\ref{fig5})~\cite{22,23,24,25,26,27,28}. Of note, these
impressive TONs required the use of ultra-highly pure raw materials,
which severely impacts the production costs and is therefore not in
line with market expectations (Figure~\ref{fig3}).}

\begin{figure*}
\includegraphics{fig03}
\caption{\label{fig3}Ethenolysis of (\textit{Z})-methyl oleate
catalyzed by highly performant CAAC--Ru complexes.}
\end{figure*}


{Despite the numerous process patents filed over the last decade (e.g.,
by Elevance---Wilmar/Cargill, IFPEN, Croda, Versalis, and Arkema, to
name a few), there are only limited number of industrial-scale
operational production units for the valorization of biomass by
metathesis reaction~\cite{11,12,17}. Thus, the development of eco-efficient
metathesis processes dedicated to the valorization of biomass remains a
real economic and technological challenge. In this context, our
research group is involved in the development of eco-efficient
metathesis processes using robust and highly selective ruthenium
catalysts~\cite{20,29}, in partnership with companies (IFPEN, Ol\'{e}on,
ITERG, Demeta). The first aspect involves the transformation of
terminal olefins from light {Fischer--Tropsch} cuts derived from forest
residues. This process converts these olefins into
higher-molecular-weight internal olefins, which serve as precursors for
the production of plasticizers or lubricants}~\cite{30}. {The second
aspect is oriented toward the transformation of non-refined unsaturated
fatty esters from very high oleic sunflower oils (VHOSO) into diesters 
and unsaturated hydrocarbons, precursors of polyesters, polyamides and
high-tech lubricants}~\cite{31}. {Last but not least, continuous flow
synthesis has been engaged in the preparation of biosourced odorant
molecules and insect pheromones, thus exploiting for the first time
homogeneous} {\textit{Z}}{-selective or} {\textit{Z}}{-stereoretentive
Ru catalysts}~\cite{32}.\looseness=-1

\section{Selective metathesis of terminal olefins from biosourced
Fischer--Tropsch feeds} 

{To reduce the dependence on oil and limit greenhouse emissions, the
French Institute of Petroleum and Renewable Energies (IFPEN) has been
involved in an intensive research program on biofuels and chemical
intermediates production via biomass transformation. In this context,
many efforts have been made to develop a biomass-to-liquid process
(BtL) to produce biodiesel and biokerosene from agricultural and forest
residues}~\cite{33} {by means of a thermal gasification process~\cite{34,35,36}. 
The resulting synthetic gas (syngas) is further converted,
after additional purifications, into liquid hydrocarbons using the
Fischer--Tropsch process (FTp). The sixty-five percent of heavy
hydrocarbons (${>}$C}$_{10}${) are produced and directly used as
biofuels (diesel and kerosene) (Figure~\ref{fig4})}~\cite{37}. {The
FTp--BtL technology also produces lighter hydrocarbons (e.g., naphtha,
including saturated and unsaturated hydrocarbons with five to nine
carbon atoms, noted C}$_{5}${--C}$_{9}${), which naturally have a lower
market value and whose valorization would impact positively on the
overall production costs. In this perspective, olefin metathesis can be
successfully employed to convert light hydrocarbons into heavier
olefins (C}$_{10}${--C}$_{14}${), which are key intermediates for the
production of plasticizers, detergents and lubricants. The coproducts
of BtL may thus be used de facto as biosourced useful intermediates
(Figure~\ref{fig4}).}

\begin{figure*}
\includegraphics{fig04}
\caption{\label{fig4}Hydrocarbons from biomass and valorization of
lighter unsaturated hydrocarbons by olefin metathesis: an economic
challenge.}
\vspace*{3pt}
\end{figure*}


{However, the metathesis reaction applied to terminal olefins, which is
often considered as a simple transformation, raises important
technological issues when alkylidene-based ruthenium catalysts are
employed. These complexes, due to their limited robustness and
stability, are highly prone to generate ruthenium hydride species thus
promoting isomerization events, even in traces}~\cite{38,39}. {As a result
of this double bond migration, new internal olefins are generated and
prone to undergo another metathesis reaction to form undesired side
products. In this case, the final outcome is composed of a complex
mixture of primary metathesis products (PMP), isomerization (IP) and
random metathesis side products (RMP) (Figure~\ref{fig5}).}

\begin{figure*}
\includegraphics{fig05}
\caption{\label{fig5}Decomposition of ruthenium catalysts into metal
hydrides: the Achilles heel of ruthenium alkylidene for metathesis of
terminal olefins.}
\vspace*{3pt}
\end{figure*}


{While the incorporation of additives such as benzoquinone derivatives
has demonstrated some effectiveness in trapping ruthenium hydrides
within the reaction medium, this approach still presents 
challenges~\cite{39,40}. 
For example, considering the toxicity of benzoquinones and
their non-negligible costs, this solution may not be always adequate
for eco-efficient processes. In parallel, another drawback regarding
some of the catalysts concerns their low reactivity, which translates
into a consequent/significant increase in catalyst loading~\cite{41,42}. The
economic viability of the whole process may then be questioned since,
for instance, the costs of the catalysts are excessively high compared
to the value of the targeted olefins. Ideally, the transformation of
light olefins from the Fischer--Tropsch process should be carried out
at ppm-level catalyst loading (50 ppm maximum), thus in the presence of
robust metal complexes to avoid the formation of hydride species and
use of additional scavengers. With this objective in mind, our research
group, in collaboration with Olivier-Bourbigou et~al.\ from IFPEN, made
substantial efforts to develop an ecocompatible process to convert
lighter olefins (C}$_{4}${--C}$_{8}${) derived from the FTp of forest
residues, into heavier internal olefins
(C}$_{9}${--C}$_{14}$)~\cite{30}. {The investigations started with the
screening of various catalysts, including commercially available ones
(Figure~\ref{fig1}), on a benchmark self-metathesis reaction (SM)
involving oct-1-ene with a catalyst loading of 0.005 mol\% (50 ppm,
expressed as mole of Ru per mole of oct-1-ene) in the absence of
solvent. Among the studied Ru complexes (more than fifty complexes were
developed within the framework of the European FP7 EUMET program), the
home-made ruthenium complex} {\textbf{Ru-7}}~\cite{29}\break {demonstrated an
interesting reactivity, allowing a conversion of 70\% of oct-1-ene into
tetradec-7-ene with very high selectivity (98\%) and less than 2\%
isomerization, in stark contrast with the commercially available
catalysts} {\textbf{Ru-2b}} {and} {\textbf{Ru-3b}} {(85\% and 80\%
respectively) (Figure~\ref{fig6})}~\cite{30}. {The robustness of the
catalyst was the next parameter to be considered since, after the FTp,
the saturated hydrocarbon mixtures contain alcoholic impurities.
Remarkably, the selectivity was also maintained under diluted
conditions (60 vol\% of octane) and was marginally altered in the
presence of 10\% 1-pentanol (95\% vs.\ 98\%)~\cite{30}.}

\begin{figure*}
\includegraphics{fig06}
\caption{\label{fig6}Self-metathesis of oct-1-ene.}
\end{figure*}

{The reason for such a difference in selectivity can be explained by
the presence of a modified NHC ligand substituted by a cycloalkane unit
by design. This dissymmetric NHC can be prepared in four steps as a
tetrafluoroborate salt with an overall yield of 38\%
(Figure~\ref{fig7}A)}~\cite{29}. {In comparison, three synthetic steps
were necessary from the inexpensive glyoxal to obtain the symmetrical
imidazolinium salt (90\% yield), which is the precursor of the
1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes)
ligand used in many commercial complexes
(Figure~\ref{fig1})}~\cite{43}. {Although it can induce very high
selectivity, the production of} {\textbf{Ru-7}} {complex on a kilogram
scale would be already highly costly. Unsaturated NHCs, such as
1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2}{\textit{H}}{-imidazol-2-ylidene 
(IMes), are easily accessible in a single step following the well-known
Arduengo's protocol, by simply reacting an aniline with
paraformaldehyde and glyoxal in an aqueous acidic medium}~\cite{44}.
{Unfortunately, when two aliphatic amines are involved, the expected
dissymmetric salt is formed as a statistical mixture of two symmetric
salts}~\cite{45}. {Unexpectedly, by mixing an aryl amine (mesitylamine)
and an aliphatic amine (cyclododecylamine or cyclopentylamine), an
excellent selectivity in favor of the dissymmetric imidazolium salt was
observed (${>}$95\%), leading to good isolated yields (79--80\%)
(Figure~\ref{fig7}B)~\cite{46,47}.\ This highly\break selective multicomponent
reaction was extended to the synthesis of various dissymmetric salts
(about 30). All of them were isolated in very good yields,\break ensuring
inexpensive access to new precursors of novel dissymmetric unsaturated
NHC ligands, including chiral ones}~\cite{48}.

\begin{figure*}
\includegraphics{fig07}
\caption{\label{fig7}(A) Multistep synthesis of unsymmetrical
imidazolinium salts, precursors of saturated \textit{N}-heterocyclic
carbene (NHC) ligands; (B) Multicomponent synthesis of unsymmetrical
imidazolium, precursors of low-cost unsaturated NHC ligands; (C)
Evaluation in oct-1-ene self-metathesis of the related metathesis
complexes.}
\end{figure*}

With a highly competitive route to access dissymmetric unsaturated NHCs
in hand, the \textbf{Ru-8a} and \textbf{Ru-8b} complexes, bearing a
cyclododecyl and cyclopentyl moiety, respectively, were synthesized and
evaluated in the self-metathesis of oct-1-ene (Figure~\ref{fig7}C).
While the selectivity of the metathesis reaction was retained as
expected, a slight alteration of the conversion was also observed (59\%
vs.\ 70\%). Based on this result, the new \textbf{Ru-8b} complex was
selected to convert the light C$_{4}$ to C$_{8}$ Fischer--Tropsch cut
of 37 wt\% olefins, essentially terminal, into mainly C$_{11}$ and
C$_{12}$ internal olefins. With a catalyst loading of 50 ppm, the new
catalyst delivered the expected products with a conversion of 70\% and
the unprecedented selectivity of 98\%, with the distribution of olefins
unchanged over time (Figure~\ref{fig8})~\cite{30,49}. The resulting internal
olefins (mostly C$_{11}$, C$_{12}$) could thus be converted into the
corresponding linear alcohols via the OXO process (hydroformylation)
and thus potentially used as biosourced raw materials for the
production of plasticizers~\cite{50}.

\begin{figure*}
\includegraphics{fig08}
\caption{\label{fig8}Metathesis on a light hydrocarbon cut (C$_{4}$ to
C$_{8}$) from the Fischer--Tropsch process on forest residues.}
\end{figure*}

\section{Transformation of non-refined unsaturated fatty esters from
very high oleic sunflower Oils (VHOSO)} 


{Another biomass transformation of interest involves the olefin
metathesis of vegetable oils}~\cite{17}. {Compared to unsaturated
hydrocarbons from petrochemicals, vegetable oils contain carboxyl
functions which allow a greater modularity in the
post-functionalization and therefore to access a multitude of molecular
building blocks of interest (alcohols, amides, amines)}~\cite{18}. {The
Oleon company has been interested in using olefin metathesis to
transform unrefined} ({\textit{Z}}{)-methyl oleate from VHOSO into}
({\textit{E/Z}}{)-2-octadec-9-ene and} ({\textit{E/Z}}{)-3-dimethyl
octadec-9-enedioate (Figure~\ref{fig9}). These two synthons may be
further employed as basic ingredients for the preparation of
lubricants, plasticizers, waxes, fragrances, or even monomers for
materials (Figure~\ref{fig3})~\cite{51,52}.}

\begin{figure*}
\includegraphics{fig09}
\caption{\label{fig9}Self-metathesis of non-refined (\textit{Z})-methyl
oleate for the production of bio-based intermediates.}
\end{figure*}


{This self-metathesis reaction involving an internal olefin, albeit
simple on paper, requires the removal of certain technological barriers
to be attractive, in line with market expectations, with regard to the
very low added value of the targeted bio-based intermediates (a few
euros/kg). The first barrier concerns the efficiency of the metathesis
catalyst; the latter must be active below 0.0005 mol\% (5 ppm) and
capable of reaching a productive TON close to 100,000. The second
barrier is mostly related to the quality of the raw material. The state
of the art relates to a few examples where second-generation metathesis
catalysts such as} {\textbf{Ru-1}}, {\textbf{Ru-2b}}, {or}
{\textbf{Ru-4}} {allowed the reaction equilibrium with only 1 ppm of
catalyst loading, corresponding to TONs ranging between 250,000 and
440,000}~\cite{53}. {However, this remarkable efficiency was achieved
on the transformation of highly pure methyl oleate (${>}$99\%), thus
requiring distillation and/or prefiltration on alumina. Raw materials
of such quality are unsuitable for industrial scale since the
purification processes on a larger scale would be highly costly. Our
group has succeeded in refining the oil to a purity of 97\% on a
kilogram scale (in collaboration with ITERG). Albeit efficient, this
process involves a double cold crystallization, which is not feasible
on a larger scale. The metathesis reaction may be therefore
economically viable only if it is performed on unrefined methyl oleate
with a purity of only about 85\%}~\cite{54}. {The catalyst should be
robust, efficient, and productive in the presence of impurities
(Figure~\ref{fig11}). The key solution lies in the use of a very robust
catalyst but above all, in the implementation of an eco-efficient
pre-treatment process of the unrefined raw material, which would allow
the effective elimination of impurities that are deleterious to the
catalyst. Over the last decade, a few pre-treatment processes have been
developed by different companies operating in the field (e.g.,
Elevance, Croda, Arkema). However, they suffered either from a lack of
efficiency or an excessive cost of the catalyst, leading overall to a
non-negligible loss in raw material during the filtration 
processes~\cite{17,55}. Our group, in collaboration with industrial
partners (Oleon, ITERG, and Demeta), worked on the development of an
economically viable catalytic process for the transformation of
unrefined methyl oleate at 85\% purity}~\cite{31}.

{To determine the adequate pre-treatment, it was crucial to identify
the compounds present in the unrefined raw material (here sunflower
oil) likely to poison the catalyst. As depicted in Figure~\ref{fig10},
it was possible to classify those impurities into three main groups:
(1) those naturally present in the vegetable oil (sunflower lecithin,
tocopherol acetate and sterols); (2) the compounds resulting from the
hydrolysis and transesterification of the oil (oleic acid, glycerides,
glycerol, methanol, and water), and (3)~the residues resulting from the
oxidation of the oil (stand oils,} {\textit{n}}{-nonanal and
peroxidized methyl ester). As shown in Figure~\ref{fig11}, only
glycerides, oleic acid, nonanal, and peroxidized methyl ester (added up
to 10\% in mass) had a detrimental effect on the self-metathesis of
refined methyl oleate catalyzed by the M71} {\textbf{Ru-6a}} {complex
(500 ppm)}~\cite{56}, {where reaction equilibrium was reached in only 5
min in the absence of any additive, while normally this transformation
is highly slow or never complete.}

\begin{figure*}
\vspace*{7pt}
\includegraphics{fig10}
\vspace*{3pt}
\caption{\label{fig10}Compounds frequently detected in non-refined
unsaturated fatty esters that can poison the metathesis catalyst.}
\vspace*{8pt}
\end{figure*}

\begin{figure*}
\includegraphics{fig11}
\vspace*{-2pt}
\caption{\label{fig11}Effect of catalyst-killer molecules in the
self-metathesis of (\textit{Z})-methyl oleate: (A) from oil hydrolysis
and (B) from oil oxidation.}
\end{figure*}

Our group turned its attention to unrefined methyl oleate at 85\%
purity to identify the ideal pre-treatment that would inhibit the
deleterious effect of these impurities on catalyst efficiency. Our
choice was quickly made for bleaching earths, which are frequently used
in the refining of vegetable oils to eliminate pigments (chlorophyll,
carotenes) and other impurities (e.g., traces of metals or oxidation
products)~\cite{57}. As soon as the first test was carried out, beneficial
effects were noticed when 10 wt\% of tonsil$^{\text{\textregistered}}$ 110FF were
added (Clariant, composition: SiO$_{2}$ 75.5\%, Al$_{2}$O$_{3}$ 12\%,
Fe$_{2}$O$_{3}$ 2.4\%, CaO 0.4\%, MgO 1.4\%, Na$_{2}$O 0.3\%, K$_{2}$O
1\%), since the equilibrium was reached with a catalyst loading of 0.02
mol\% (200 ppm), whereas three times more catalyst was required in the
absence of treatment (Figure~\ref{fig12}). If the use of
tonsil$^{\text{\textregistered}}$ 110FF is combined with a thermal pre-treatment
(a well-known process to drastically reduce the naturally present
peroxides in fatty esters), equilibrium is reached after 1 h in the
presence of only 0.0005 mol\% (5 ppm) of \textbf{Ru-6a} complex only.
However, the abrasive character of the tonsil$^{\text{\textregistered}}$, which
is essentially composed of silica, represents an important
deterioration risk of the stainless steel reactors. With a significant
increase in contact time between tonsil$^{\text{\textregistered}}$ 110FF and
unrefined methyl oleate (from 15 to 120 min) prior to the addition of
the catalyst, it was possible to reduce the amount of
tonsil$^{\text{\textregistered}}$ 110FF by 1 wt\% without any loss of efficiency.
Under these optimal conditions, the limits of the catalytic process
were reached with a catalytic loading of 0.0001 mol\% (1 ppm),
representing an unprecedented maximum TON of 744,000 and a productive
TON approaching 360,000, despite the use of unrefined feedstock.

\begin{figure*}
\vspace*{-2pt}
\includegraphics{fig12}
\vspace*{-2pt}
\caption{\label{fig12}(A) Pre-treatment optimization and subsequent
self-metathesis of (\textit{Z})-methyl oleate. (B)~Screening of
commercially available Ru catalysts.}
\vspace*{-1pt}
\end{figure*}

After the pre-treatment optimization of raw materials, a screening of
various commercially available catalysts was carried out showing
significant differences in their reactivity profiles
(Figure~\ref{fig12}B). The first- and second-generation
phosphine-based ruthenium complexes \textbf{Ru-2a}, \textbf{Ru-2b},
\textbf{Ru-3a}, \textbf{Ru-3b} and \textbf{Ru-3c} proved to be
inefficient, most certainly due to too fast a degradation in the
reaction medium. Hoveyda-type catalysts showed higher robustness than
the phosphine-based ruthenium complexes, particularly complexes with a
sterically hindered NHC SIPr ligand (\textbf{Ru-5b} and
\textbf{Ru-6a}). The \textbf{Ru-6a} catalyst was selected for the
scale-up of the catalytic process, performed at ITERG and then by the
Oleon group (Figure~\ref{fig13}). The first test was performed on 1 kg
of raw material using 0.01 mol\% of \textbf{Ru-6a} complex. Under these
conditions, the reaction equilibrium was reached after 15 min. A test
on 3 kg and a catalytic load of 0.0005 mol\% provided a conversion of
88\% of methyl oleate after 1 h, consistently with the experiments
performed on a laboratory scale. Based on these results, two pilot
tests were performed on a 300 L reactor (Figure~\ref{fig13}). Two
batches of 200 kg of unrefined feedstock were successfully transformed,
with a conversion rate of 88\% at equilibrium (TON of 174,000) and
excellent productivity (productive TON of 95,000), thus demonstrating
the simplicity and\break robustness of the pre-treatment and overall
catalytic process~\cite{31}.

\begin{figure*}
\includegraphics{fig13}
\caption{\label{fig13}Scaling up of the catalytic process.}
\end{figure*}

{In order to avoid the drawbacks related to the high cost and reduced
performance of metal catalysts toward raw biosourced materials, our
group then focused in 2019 on the development of a straightforward
protocol for the in situ generation of an active ruthenium complex,
combining inexpensive commercially available reagents such as}
({\textit{p}}{-cymene)ruthenium(II) chloride dimer
([Ru(}{\textit{p}}{-cymene)Cl}$_{2}$]$_{2}${), SIPr·HCl, and}
{\textit{n}}{-BuLi in toluene~\cite{58,59}. The resulting 18-electron
species} {\textbf{Ru-9}} {is formed and directly used without any
purification step for a metathesis reaction in the presence of
activators such as alkynes, cyclopropenes, and diazoesters. The
diazoester} {\textbf{A1}} {was identified to be the most efficient
activator to convert the} ({\textit{Z}}{)-methyl oleate (99\% purity)
into highly valuable mono-unsaturated diester and hydrocarbon with a
catalyst loading under 0.01 mol\% (100 ppm) (Figure~\ref{fig14}, entry
1). This expedient protocol was applied to 2 kg-scale self-metathesis
of a non-refined\break technical grade} ({\textit{Z}}{)-methyl oleate (85\%
purity) using only 0.04 mol\% (400 ppm) of catalyst loading
(Figure~\ref{fig14}, entry 2)}~\cite{58}.

\begin{figure*}
\includegraphics{fig14}
\caption{\label{fig14}In situ generation of Ru-based metathesis
catalyst. Application to self-metathesis of (\textit{Z})-methyl oleate
(up to 2 kg).}
\end{figure*}

\section{Continuous flow \textit{Z}-selective olefin metathesis}

{As mentioned previously, vegetable oils have the advantage to be
easily post-functionalizable thanks to the intrinsic carboxyl function.
This feature provides access to a wide range of building blocks of
interest such as amides, amines, alcohols and ketones}~\cite{18}. {It
is worth mentioning that alcohols and ketones can be used as starting
materials to synthesize highly desirable insect pheromones~\cite{60} or
macrocyclic odorant molecules~\cite{61} via olefin metathesis. However, many
of these valuable molecules have an alkene group with a strict}
{\textit{Z}} {geometry, giving them a three-dimensional architecture
that matches with their biological activity. Since 2013, important
breakthroughs have been achieved in controlling}
{\textit{Z}}{-selectivity during the cross-metathesis and the macroring
closing metathesis, thanks to the development of efficient}
{\textit{Z}}{-selective and} {\textit{Z}}{-retentive ruthenium
catalysts based first on NHCs~\cite{62,63,64,65} and more recently on CAACs
(Figure~\ref{fig15})}~\cite{66}. {Unfortunately, besides their
exceptional utility, these catalysts remain extremely sensitive to
oxygen, air, and moisture, therefore they require the use of a glovebox
to perform the metathesis reaction, which could potentially limit their
applications in industrial settings.}

\begin{figure*}
\includegraphics{fig15}
\caption{\label{fig15}Top: Selected examples of \textit{Z}-selective
catalysts; bottom: \textit{Z}-retentive catalysts.}
\end{figure*}

To overcome the problems related to the manipulation of highly
sensitive catalysts, our team first developed a highly practical
in-situ protocol which is able to promote the \textit{Z}-selective
metathesis without the need of a glovebox
(Figure~\ref{fig16})~\cite{67}. By reacting commercially available
catechodithiol \textbf{L1} with\break diethylzinc, then adding the Hoveyda
catalyst \textbf{Ru-5a}, a solution of the expected dithiolate catalyst
\textbf{Ru-10} was obtained. This catalyst was then added to an alkene
in the presence of but-2-en-1,4-diol to give the desired
\textit{Z}-product in high yield and excellent stereochemical purity.
This operationally simple protocol was successfully applied to the
synthesis of valuable functionalized molecules (Figure~\ref{fig17}). 

\begin{figure*}
\includegraphics{fig16}
\caption{\label{fig16}In situ generation of \textit{Z}-retentive
catalysts and stereoretentive olefin metathesis.}
\end{figure*}

\begin{figure*}
\vspace*{1pt}
\includegraphics{fig17}
\vspace*{1pt}
\caption{\label{fig17}First developments in continuous flow
\textit{Z}-selective metathesis: selected applications in the synthesis
of (biosourced) insect pheromones and odorant molecules.}
\vspace*{1pt}
\end{figure*}

In a second stage, we focused on the implementation of the first
\textit{Z}-selective metathesis in continuous flow process in
collaboration with the Browne research group (UCL School of Pharmacy,
London)~\cite{32,68}. By using a Teflon AF-2400 tube-in-tube semi-permeable
membrane reactor, various semiochemicals (i.e, pheromones), acting as
potential\break biopesticides against pest insects, were efficiently
synthesized with high \textit{Z}-selectivity, even at 6 mmol scale,
thanks to the robust cyclometallated complex \textbf{Ru-11} featuring a
bulky unsaturated NHC. This method was also successfully applied to the
production of civetone and yuzu lactone, two highly desirable
macrocyclic odorant molecules. Interestingly, the in situ generation of
stereoretentive cathechodithiolate catalyst \textbf{Ru-10} 
(vide supra)~\cite{69} 
also proved to be highly efficient in continuous flow affording
the biosourced \textit{Tenebrio Molitor} pheromone in 49\% isolated
yield and with a \textit{Z}/\textit{E} ratio above 99:1 (not showed
here). 

\begin{figure*}
\includegraphics{fig18}
\caption{\label{fig18}Macro-ring closing metathesis catalyzed by
Blechert-type CAAC--Ru complex.}
\end{figure*}

{On the other hand, the search for more stable, easily accessible and
highly efficient ruthenium catalysts led to the design of new ligands
along with the investigation of other possible modifications on the
hemilabile styrenyl ether ligand}~\cite{66}. {Our group, in
collaboration with G. Bertrand and R. Jazzar (UCSD), very recently
developed a new ruthenium-based catalyst featuring a CAAC ligand and a
``Blechert-type'' styrenyl ether}~\cite{70}. {The combination of those
two elements led to the synthesis of an organometallic species which
summarizes the stability offered by the CAAC and the high initiation
rates peculiar for this styrenyl species. As a result, the
Blechert-type catalyst} {\textbf{Ru-12}} {was able to perform a series
of metathesis reactions at low catalyst loading (down to\break 0.005
mol\%)}~\cite{66}. {Particularly, the synthesis of civetone was
successfully achieved in 81\% isolated yield and with high purity
(99\%) (Figure~\ref{fig18}). Further developments will concentrate on
the synthesis of the corresponding catechodithiolate Ru complex for
promoting} {\textit{Z}}{-metathesis at very low catalyst loading.} 

\section{Conclusion}

Olefin metathesis rightly consolidated its position as an irreplaceable
versatile synthetic tool for chemists offering, when applicable,
numerous advantages such as reduced reaction time, simplification of
synthetic routes, and a lower carbon footprint. Today it seems
relatively straightforward to envisage applications of olefin
metathesis in biomass valorization or to convert renewable raw
materials into molecules of interest. However, due to the very low
added value of the targeted products, the implementation of metathesis
reaction on an industrial scale requires overcoming additional barriers
to become highly competitive. To meet this challenge, it is necessary
to design not only more robust, more selective and, above all, less
costly catalysts, but also to develop ingenious processes to
drastically reduce catalyst loading. Addressing these challenges, we
have explored the transformation of biosourced olefins. In the case of
unsaturated hydrocarbons coming from forest residues, use of innovative
ruthenium catalysts based on easily accessible dissymmetric unsaturated
NHC ligands, has enabled the efficient conversion of light linear
terminal olefins into linear heavier internal olefins. These olefins
serve as valuable precursors for plasticizers. The novelty lies not
only in the reduced costs of the catalyst and its use at very low
loadings (0.005 mol\%), but also costly and toxic additives were not
necessary to limit the formation of by-products. Similarly, in the case
of unsaturated fatty esters from vegetable oils, the development of a
pre-treatment based on bleaching earth, coupled with the use of a
robust catalyst, allowed an efficient conversion of unrefined methyl
oleate (85\% purity) into diester and unsaturated hydrocarbons,
precursors of polymers and lubricants. Unprecedented productivities
have been achieved (productive TON up to 360,000), despite the presence
of impurities that could poison the catalyst. The successful
performance on 200 kg pilot scale paved the way for potential
applications at industrial scale, thus impacting the production of
fragrances, pheromones and biofuels. Last but not least, by combining
\textit{Z}-stereoselective Ru catalysts with continuous flow processes,
the production of molecules of interest such as odorant molecules for
perfume industry or semiochemicals against insect pests can be achieved
efficiently. While increasing process productivity and reducing waste,
the continuous flow metathesis reaction can make a significant overall
impact on production costs.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could \mbox{benefit} from this article, and
have declared no affiliations other than their research organizations.

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