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\DOI{10.5802/crchim.301}
\datereceived{2023-09-11}
\daterevised{2023-12-21}
\datererevised{2024-02-07}
\dateaccepted{2024-02-12}
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\dateposted{2024-06-25}
\datepublished{2024-12-03}
\begin{document}

\begin{noXML}

\makeatletter
\def\TITREspecial{\relax}
\def\cdr@specialtitle@english{French/Nordic Special Issue on Materials and Coordination Chemistry}
\def\cdr@specialtitle@french{Num\'ero sp\'ecial franco-nordique sur les mat\'eriaux et la chimie de coordination}
\makeatother

\CDRsetmeta{articletype}{review}

\title{Polymeric nanoreactors for catalytic applications}

\alttitle{Nanor\'{e}acteurs polym\'{e}riques pour des applications
catalytiques}

\author{\firstname{Chantal Joseph} \lastname{Abou-Fayssal}\CDRorcid{0000-0002-8689-7319}}
\address{Centre for Catalysis and Sustainable Chemistry, Department of
Chemistry, Technical University of Denmark, Kemitorvet, Building 207,
2800 Kgs. Lyngby, Denmark}
\address{CNRS, Laboratoire de Chimie de Coordination (LCC),
Universit\'{e} de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099,
F-31077 Toulouse Cedex 4, France}
%\email[C. J. Abou-Fayssal]{abouf@kemi.dtu.dk}

\author{\firstname{Rinaldo} \lastname{Poli}\CDRorcid{0000-0002-5220-2515}\IsCorresp}
\addressSameAs{2}{CNRS, Laboratoire de Chimie de Coordination (LCC),
Universit\'{e} de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099,
F-31077 Toulouse Cedex 4, France}
\address{Institut Universitaire de France, 1, rue Descartes, 75231
Paris Cedex 05, France}
\email[R. Poli]{rinaldo.poli@lcc-toulouse.fr}

\author{\firstname{Karine} \lastname{Philippot}\CDRorcid{0000-0002-8965-825X}\IsCorresp}
\addressSameAs{2}{CNRS, Laboratoire de Chimie de Coordination (LCC),
Universit\'{e} de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099,
F-31077 Toulouse Cedex 4, France}
\email[K. Philippot]{karine.philippot@lcc-toulouse.fr}

\author{\firstname{Anders} \lastname{Riisager}\CDRorcid{0000-0002-7086-1143}\IsCorresp}
\addressSameAs{1}{Centre for Catalysis and Sustainable Chemistry,
Department of Chemistry, Technical University of Denmark, Kemitorvet,
Building 207, 2800 Kgs. Lyngby, Denmark}
\email[A. Riisager]{ar@kemi.dtu.dk}

\author{\firstname{Eric} \lastname{Manoury}\CDRorcid{0000-0001-7991-8890}\IsCorresp}
\addressSameAs{2}{CNRS, Laboratoire de Chimie de Coordination (LCC),
Universit\'{e} de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099,
F-31077 Toulouse Cedex 4, France}
\email[E. Manoury]{eric.manoury@lcc-toulouse.fr}

\shortrunauthors

\keywords{\kwd{Catalytic nanoreactors}\kwd{Biphasic
catalysis}\kwd{Macromolecular building blocks}\kwd{Polymers}}

\altkeywords{\kwd{Nanor\'{e}acteurs catalytiques}\kwd{Catalyse
biphasique}\kwd{Blocs de construction
macromol\'{e}culaires}\kwd{Polym\`{e}res}}

\thanks{European Research Council (grant agreement No. 860322)}

\begin{abstract} 
Mimicking Nature is one drive for chemists to design efficient
architectures matching the activity and selectivity of natural
catalytic systems, such as enzymes. To this extent, the developed
architectures need to have a selective and active site for the
transformation of a given substrate to a target product. In addition,
the catalyst must be recoverable and recyclable in order to improve the
efficiency and be sustainable. Nature achieves these goals by embedding
the catalytically active site in an adapted organic matrix that allows
controlling the confinement of the catalytic site and its access by the
substrate. Organic polymers allow confining diverse catalysts inside
organic nanodomains, following the concept of catalytic nanoreactors.
Anchoring the catalyst inside the polymer core protects it from the
surrounding environment. This strategy also provides an efficient way
to separate the catalyst from the products, thus permitting its
recovery and recycling. This review provides an overview of
unimolecular nanoreactor systems designed from macromolecular building
blocks and their application in biphasic catalysis.
\end{abstract} 

\begin{altabstract} 
Imiter la nature est une motivation pour les chimistes afin de
concevoir des architectures efficaces en harmonie avec l'activit\'{e}
et la s\'{e}lectivit\'{e} des syst\`{e}mes catalytiques naturels, tels
que les enzymes. \`{A} cet \'{e}gard, les architectures
d\'{e}velopp\'{e}es doivent disposer d'un site s\'{e}lectif et actif
pour la transformation d'un substrat donn\'{e} en un produit cible. De
plus, le catalyseur doit \^{e}tre r\'{e}cup\'{e}rable et recyclable
afin d'am\'{e}liorer son efficacit\'{e} et sa durabilit\'{e}. La nature
atteint ces objectifs en incorporant le site catalytiquement actif dans
une matrice organique adapt\'{e} qui permet de contr\^{o}ler le
confinement du site catalytique et son acc\`{e}s par le substrat. Les
polym\`{e}res organiques permettent de confiner divers catalyseurs
\`{a} l'int\'{e}rieur de nanodomaines organiques, suivant le concept de
nanor\'{e}acteurs catalytiques. Ancrer le catalyseur \`{a}
l'int\'{e}rieur du noyau polym\'{e}rique, le prot\`{e}ge de son
environnement. Cette strat\'{e}gie offre \'{e}galement un moyen
efficace pour la s\'{e}paration du catalyseur des produits, permettant
ainsi sa r\'{e}cup\'{e}ration et son recyclage. Cette revue offre un
aper\c{c}u des syst\`{e}mes de nanor\'{e}acteurs unimol\'{e}culaires
con\c{c}us \`{a} partir de blocs de construction macromol\'{e}culaires
et leur application en catalyse biphasique.
\end{altabstract} 

\maketitle
{\vspace*{2pt}}

\twocolumngrid

\end{noXML}

\section{Introduction}\label{sec1}

Catalysis is a key technology for our society with extensive
contributions in diverse areas such as energy, chemicals and food
production, cosmetics, health, etc.~\cite{1,2}. Heterogeneous
catalysis, where the catalyst and the substrate are in two different
phases, provides easy catalyst separation and reuse, which often
results in extended catalyst lifetime and use of 
lower amounts of solvents. These
features have made heterogeneous catalysts predominant in industry
(about 80\% of processes). However, heterogeneous catalytic systems
typically require harsher reaction conditions than homogeneous analogs
and this may lead to lower selectivities. Heterogeneous catalytic
systems may also suffer from mass transport limitations, which may
decrease the activity. In addition, the exploration of reaction
kinetics and mechanistic understanding are often more problematic for
heterogeneous catalysts. Conversely, homogeneous \mbox{catalysts} usually
provide high activities and selectivities under milder reaction
conditions. They also allow easier mechanistic investigations. However,
since the catalyst and the substrate coexist in the same physical phase
(typically a liquid phase), these systems inherently suffer from
difficult catalyst separation and reuse. Hence, down-stream separation
procedures such as precipitation, extraction or ultrafiltration are
typically required to recover the catalyst. These operations
need additional equipment and undesirable large amount of solvent and
entail extra costs.

\looseness=-1
To circumvent these issues, several strategies have been implemented
for the recycling of homogeneous catalysts in large-scale processes.
These strategies include: (1)~employing specially designed membranes
capable of selectively percolating catalyst-supporting molecules (such
as dendrimers or colloids) through micro-/ultra-/nanofiltration or
reverse osmosis processes~\cite{3,4}, tailored to the size and geometry
of the catalyst; (2)~utilizing biphasic catalysis, where the catalyst
is immobilized in a separate, immiscible liquid phase from that of the
reaction products~\cite{3} (for instance, the
Rh\^{o}ne-Poulenc/Ruhrchemie hydroformylation of propene and butene
involving water as the immiscible phase~\cite{5}); and (3)~employing
catalyst confinement techniques~\cite{6}, where the catalyst support
can be a solid phase with the molecular catalyst either grafted onto
the surface or enclosed within the pores of insoluble polymers (such as
resins), inorganic oxides (like silica and alumina), metal-organic
frameworks (MOFs) or carbon materials (including carbon black, carbon
nanotubes, and graphene), known as heterogenized homogeneous catalysis,
or a separate liquid phase, referred to as liquid/liquid biphasic
catalysis. The latter strategy is an effective and low-cost solution to
preserve the catalytic performance and facilitate catalyst recovery.
Whatever the catalyst support, solid or liquid, catalyst confinement
approaches combine the benefits of homogeneous and heterogeneous
catalysis. This is also possible {via} micro-heterogenization
using colloidal assemblies~\cite{3}, also referred to as nanoreactors.

Polymeric nanoreactors that contain covalently linked ligands in their
core architecture offer an interesting approach for anchoring and
protecting the catalyst from the surrounding environment, while
facilitating its recovery and \mbox{recycling}~\cite{4}. One of the
prominent techniques for catalyst recovery and recycling is
liquid/liquid biphasic catalysis using two immiscible liquid phases,
one containing the catalyst and the other one containing the reaction
products and any unreacted substrate~\cite{5,7,8}. In this approach,
the two phases can be separated by a simple decantation, thus
facilitating the reuse of the catalyst phase without the introduction
of any thermal or chemical stress. Four distinct operational modes may
be associated to the liquid/liquid biphasic approach, as listed for the
biphasic aqueous catalysis~\cite{5}: (i)~homogeneous in the aqueous
catalyst phase, if the substrate is sufficiently water-soluble;
(ii)~homogeneous in the substrate/product phase, if the catalyst is
sufficiently soluble in the substrate phase or can be transported there
by a temperature stimulus (thermomorphic approach)~\cite{9,10,11} or by
a phase-transfer agent; (iii)~interfacial when neither component is
sufficiently soluble in the other component phase and the
transformation occurs exclusively at the interface; (iv)~homogeneous
within the nanoreactors, which form a stable dispersion in a phase
different from that of the substrates/products~\cite{12,13}. The latter
approach, with the catalyst confinement within a small container, can
allow precise control over its interaction with the substrate. This can
lead to different reaction pathways compared to the free catalyst,
resulting in significantly improved selectivities compared to the
non-confined analogs~\cite{14,15}. The catalyst host can either be
molecular or macromolecular. This review deals with macromolecular
nanoreactors.\looseness=-1

Nanostructured materials can be produced for use as
nanoreactors~\cite{16,17,18,19}.\ They have a higher surface area
relative to their volume compared to complex and bulk materials. This
property allows for enhanced interactions with the surrounding
environment, leading to increased reactivity and improved performance
in various applications. Also, nanostructured materials often exhibit,
despite their small size, excellent mechanical properties like high
strength and hardness compared to their bulk counterparts~\cite{20}.
This is mainly due to their unique structural features, including the
presence of grain boundaries and interfaces, which can hinder
dislocation movement and improve overall material strength. In
addition, nanostructured materials can exhibit enhanced electrical
conductivity and optical properties \cite{21,22,23}, making them
suitable for various electronic and optoelectronic applications as well
as \mbox{favorable} for energy storage and conversion applications. For
example, a high surface area improves electrode--electrolyte
interactions in batteries and supercapacitors, resulting in enhanced
energy storage capabilities~\cite{24,25}. Most importantly, metal
nanomaterials with high specific surface area are often used as
catalysts~\cite{4,26,27} due to their ability to provide a large number
of active sites for chemical reactions. The increased surface area
allows for more efficient adsorption and reaction processes, leading to
enhanced catalytic activity and often also \mbox{selectivity}.

\begin{figure}
\includegraphics{fig01}
{\vspace*{-3pt}}
\caption{\label{fig1}Different polymeric nanoreactors for catalytic
applications.}
{\vspace*{-6pt}}
\end{figure}

A powerful toolbox is available to access a wide array of polymeric
nanoreactors~\cite{8,9} through controlled and living polymerization
techniques~\cite{28} such as reversible addition-fragmentation chain
transfer (RAFT) polymerization, ring-opening anionic, -cationic and
-metathesis polymerization (AROP, CROP and ROMP), and atom transfer
radical polymerization (ATRP). These polymerization methods have
successfully been used to synthesize various nanoreactor architectures
for application in catalysis, including self-assembled micelles,
multifunctional micelles~\cite{29},
polymersomes~\cite{30,31,32,33,34,35} and star polymers~\cite{36}
(Figure~\ref{fig1}). In all cases, a common aim is to embed and protect
the catalyst while allowing the substrate to easily reach the reactive
sites and the products to migrate back toward the bulk phase. This
review provides an overview of the currently known polymer-based
nanoreactor systems used in biphasic catalysis, designed from
macromolecular building blocks. Special attention is given to
core-crosslinked micelles (CCMs) obtained by RAFT polymerization. The
progress made on the synthesis of this particular type of unimolecular
nanoreactors and on their use in micellar-type aqueous biphasic
catalysis will be highlighted. 

\section{Catalysis within confined spaces} \label{sec2}

\looseness=-1
One of the captivating approaches in homogeneous biphasic catalysis is
micellar catalysis. Each micelle is an independent reaction locus and
can thus be{\break} described as a catalytic
``nanoreactor''~\cite{4,14,15,16,29,31,37,38,39,40,41}.\ Two
fundamentally different implementations of micelles in catalysis can be
distinguished \cite{42}. In the initially developed one, the catalyst
is dissolved in the aqueous phase, or held close to the micellar
surface by coulombic forces (if~the catalyst has an opposite charge to
that of the micelle surface) or by covalent grafting. The catalytic
reaction occurs at the interface between the bulk aqueous phase and the
nanoreactor core where the hydrophobic substrate is located. The
beneficial effect of the micelles is thus merely the increase of the
water/organic interface, thus improving mass transport kinetics in an
interfacial catalysis approach. This is what the ``micellar catalysis''
terminology has typically been referring to, but a more appropriate
description should be ``micelle-aided catalysis''. This topic has been
extensively reviewed and will not be considered
here~\cite{1,43,44,45,46,47,48}. The second type of micellar catalysis,
developed more recently, deals with systems where the catalyst is
embedded, by interaction with core-anchored ligands, in the hydrophobic
core of the micelles. The catalytic reaction occurs in the homogeneous
environment of the hydrophobic micellar core, benefitting from a high
local concentration of both substrate and catalyst~\cite{14,42}. The
kinetics of the overall transformation can thus favorably compare with
that of the analogous homogeneous process.

The first reports on micellar catalysis, based on micelles that are
self-assembled from a simple surfactant (e.g.\ potassium dodecanoate,
hexadecyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate,
etc.), date back to 1970~\cite{49}. Many additional investigations into
the preparation, \mbox{characterization} and catalytical applications have
followed~\cite{43,44,49,50,51,52,53,54,55,56,57}.

\section{Macromolecular nanoreactors} \label{sec3}

For micelles generated by amphiphilic macromolecules, typically named
``polymer micelles'', different morphologies exist depending on the
packing parameter $p$ that was defined by Israelachvili~\cite{58}
through Equation~(\ref{eq1}), where $v$ is the volume, $a_{0}$ is the
optimal area of the head group and $l_{c}$ is the length of the
hydrophobic tail.
{\begin{equation}\label{eq1}
p=v/a_{0}\cdot l_{c}
\end{equation}}\unskip
Spherical micelles are obtained when $p\leq 1/3$ whereas worm-like
micelles are formed when $1/3\leq p\leq 1/2$. If $p\geq 1/2$, 
vesicles result from the self-assembled micelles. Within each
morphology group, a smaller size leads to a higher interface area and
thus improves the kinetics of mass \mbox{transport} between the
hydrophobic bulk phase and the nanoobject core (Figure~\ref{fig2}). 

\begin{figure}
\includegraphics{fig02}
\caption{\label{fig2}Dependence of the morphology of the self-assembled
objects on the packing parameter~$p$. Reprinted with permission of
Wiley-VCH Verlag GmbH~\& Co. KGaA, Weinheim from~\cite{59}. Copyright
2019.}
\end{figure}

Another factor that also plays a major role is the hydrophobicity of
the local pocket~\cite{59}. Self-assembled nanoreactors are
non-covalent macromolecular entities assembled from their initial
building blocks~\cite{31,33,34,35,60}. They form good
compartmentalization of catalytic systems, providing advantages on the
kinetics (faster reaction rate) and on thermodynamics (lowering the
energy of the transitional state). In an aqueous medium, the formation of
amphiphilic micelles (Figure~\ref{fig3}) that tend to \mbox{assemble} above
the so-called ``critical aggregation concentration'' leads to complex
supramolecular architectures depending on the structure of the
molecular amphiphiles~\cite{61}.

\begin{figure*}
{\vspace*{2pt}}
\includegraphics{fig03}
\caption{\label{fig3}Self-assembly of amphiphilic micelles in water.}
\end{figure*}

As a function of the packing parameter $p$ defined above, three
different morphologies can be \mbox{observed}, combining the following
terms of Gibbs free energy~\cite{37}:
\begin{enumerate}[(i)]
\item a favorable entropic contribution resulting from the assembly of
the hydrophobic parts of the molecule,
\item a tendency of amphiphiles to minimize unfavorable
lipophilic--water interaction by closely packing and to spread apart as
the result of electrostatic repulsion between the hydrophilic head
groups, defined as surface term,
\item a limitation to the possible geometry of aggregation, requiring
that the hydrophobic cores only assemble in water or polar solvent,
defined as the packing parameter explained~above.
\end{enumerate}

\looseness=-1
These aggregates have dimensions in the nanometer regime. The inclusion
of catalytic sites in these aggregates, whether by the polymerization
or by the coordination of the pre-catalyst, results in the formation of
nanoreactors. In such nanoreactors, the reaction selectivity can be
modified by tuning the nature of the monomers in the core block. 

\vspace*{-2pt}
\subsection{Polymer micelles} \label{sec3.1}

Polymer micelles~\cite{62,63,64,65} (PMs) are described as aggregates
resulting from the self-association of amphiphilic polymers owing to
hydrophobic interactions between polymer molecules. However,
interactions may also be electrostatic or {via} hydrogen bonds
or coordination bonds. The morphology of these block copolymer micelles
resembles that of \mbox{molecular} surfactant micelles. They can be
spherical or cylindrical micelles, as well as vesicles, where the
hydrophobic polymer chains form the core and the hydrophilic polymer
chains form the shell when dispersed in aqueous media. The morphology
of the PMs depends on the ratio between the hydrophobic and hydrophilic
chains, capable of accommodating the catalyst~\cite{62}. PMs are
efficient systems for the encapsulation of hydrophobic compounds due to
the hydrophobic nature of their core and the hydrophilic corona, and
these nanoreactors have many applications besides catalysis, especially
in the medical field for, e.g. drug delivery~\cite{66,67} and magnetic
resonance imaging (MRI)~\cite{68}.

Chen and coworkers~\cite{69} have described the synthesis and
application of thermo-responsive polymer micelle-based nanoreactors
containing polyoxometalates (POMs) and
poly($N$-isopropylacrylamide)-$b$-poly(L-lysine) (PNIPAM-$b$-PLys-POM)
electrostatically linked {via} the POM and amino groups of
poly(L-lysine) for catalytic wet hydrogen peroxide oxidation (CWPO) of
phenol. Similarly, Suzuki et~al.~\cite{70} performed Pd-catalyzed
Mizoroki--Heck coupling of iodobenzene and $n$-butyl acrylate in aqueous
solution using thermo-responsive PMs based on
poly($N$-isopropyl-acrylamide) (PNIPAAm), which is known as an
efficient thermo-responsive polymer due to its lower critical solution
temperature (LCST) of 32~{\textdegree}C in water~\cite{71}
(Figure~\ref{fig4}).

\begin{figure*}
\includegraphics{fig04}
{\vspace*{.15pc}}
\caption{\label{fig4}Thermo-responsive micelles switched on/off by
temperature. Reprinted with permission of Elsevier from~\cite{70}.
Copyright 2019.}
\end{figure*}

The block copolymer~\textbf{2} with a thermo responsive NIPAAm block
and a neutral poly(ethylene glycol) (PEG) chain was prepared from
\textbf{1}\ {via} ATRP (Scheme~\ref{sch1}). The resulting block
copolymer had a narrow size distribution (15--20~nm at
25~{\textdegree}C) and was water-soluble at room temperature but when
heated up to 60~{\textdegree}C the polymer was insoluble, and the
solution became opaque. Characterization by dynamic light scattering
(DLS) demonstrated that the formation of the PMs by \textbf{2} was
thermo-induced and the switchable nature improved product extraction.
The PMs also limited the use of organic solvent for product separation
from the aqueous reaction mixture, but 2 mol\% of Pd was
required to obtain good product yield in the Pd-catalyzed
Mizoroki--Heck cross-coupling~\cite{70}.\looseness=-1

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{.8pc}}
\caption{\label{sch1}Preparation of NIPAAm-$b$-PEG \textbf{2} with
PEGylated ATRP agent. Reprinted with permission of Elsevier
from~\cite{70}. Copyright 2019.}
{\vspace*{-1pc}}
\end{scheme*}

NaCl was also introduced to the block polymer
containing proline to lower the solubility of the organic solute in the
aqueous phase and help directing it to the core of the PMs~\cite{70}.
This~``salting-out'' protocol led to the design of a new
thermo-responsive block copolymer with an anionic sodium sulfate
segment, PNIPAAm-$b$-PSSNa~\textbf{9}, also prepared using RAFT
polymerization. In the synthesis protocol, $N$-isopropylacrylamide and
sodium {$p$-styrenesulfonate} were polymerized in the presence of
the RAFT agent~\textbf{6} forming~\textbf{7}, followed by
depolymerization of $p$-styrenesulfonate by a radical desulfurization
process that led to the removal of trithiocarbonate moiety at the end
of the polymer-chain to yield the anionic-type copolymer
(Scheme~\ref{sch2}). A larger particle size was obtained with the
anionic PMs compared to the neutral one, likely due to electrostatic
repulsion among the anionic polymer chains. Further analysis also
showed that the anionic copolymer exhibited its LCST behavior at
\mbox{40--55}~{\textdegree}C. When the aqueous Pd-catalyzed
Mirozoki--Heck coupling of iodobenzene and $n$-butyl acrylate was
performed with \textbf{9} using 0.5~mol\% Pd, a better yield (though
moderate) was obtained compared to the previous reaction with the
neutral copolymer and 2~mol\% Pd (Scheme~\ref{sch2}), thus
demonstrating how rational PM design can improve catalytic performance.
To recover the catalyst, the authors investigated various solvents for
product extraction. In general, using diethyl ether proved less
effective than using ethyl acetate. Interestingly, polymer~\textbf{9}
demonstrated higher efficiency than polymer~\textbf{2}, despite the
fact that the recovered amount of \textbf{5a} was only half that
obtained with pure water. These findings suggested that
thermoresponsive block copolymers PNIPAAm-$b$-PEG~\textbf{2} and
PNIPAAm-$b$-PSSNa~\textbf{9} are not only effective in the Pd-catalyzed
Mirozoki--Heck reaction in water, but also in extracting the product
from the aqueous reaction mixture.\looseness=-1

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{.7pc}}
\caption{\label{sch2}Preparation of PNIPAAm-$b$-PSSNa~\textbf{9} by RAFT
polymerization. Reprinted with permission of Elsevier from~\cite{70}.
Copyright 2019; permission conveyed through Copyright Clearance Center,
Inc.}
{\vspace*{-.6pc}}
\end{scheme*}

The introduction of the catalyst in the core of the micellar
nanoreactors can be realized in \mbox{different} ways, either by polymerizing
a pre-catalyst-functionalized monomer into the hydrophobic compartment,
followed by self-assembly, or by ligand {exchange} between a
molecular pre-catalyst, introduced by mass transport inside the already
assembled micelles, to a core-anchored ligand. An example of
the former method~\cite{72} is the copolymerization of styrene and a
functionalized styrene containing a 4-(dimethylamino)pyridine (DMAP)
organocatalyst, using the RAFT technique, to yield a hydrophobic
macroRAFT agent~\textbf{2}, which was then chain-extended with a
hydrophilic poly($N$-isopropylacrylamide) (PNIPAM) block
(Scheme~\ref{sch3}). The catalytic activity of the compartmentalized
organocatalyst in the core was found to be high, improving the
DMAP-catalyzed acylation reaction of alcohols with anhydrides, with
rates up to 100 times compared to those for unsupported DMAP in organic
solvents (Table~\ref{tab1}). The authors explored catalyst recycling by
leveraging the system stimulus-responsive property. Following the
extraction of the synthesized product with diethyl ether, the aqueous
phase containing the \mbox{micellar} \mbox{catalyst} underwent heating to a
temperature over 50~{\textdegree}C. Hereby the polymer transformed into
a fine powder, which was subsequently gathered through centrifugation.
These catalytic nanoreactors were recycled up to six times without
losing catalytic activity.\looseness=-1

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{.61pc}}
\caption{\label{sch3}Four-step synthesis of micelles \textbf{4}
containing the DMAP functionality covalently attached to the
hydrophobic core. Reprinted with permission of American Chemical
Society from~\cite{72}. Copyright 2012.}
{\vspace*{-.3pc}}
\end{scheme*}

\begin{table*} %tab1
\tabcolsep7.8pt
\caption{\label{tab1}Acylation reactions in the micelles \textbf{4}
(adapted from~\cite{72})${}^{\mathrm{a}}$
\vspace*{4pt}\tpar{\protect\inlinefig{fx01}}\vspace*{-6pt}}
\begin{tabular}{ccccc}
\thead
Entry & R & $\text{R}'$ & Conversion (\%) (15~min) & Conversion (\%)
(24~h)\\
\endthead
1 & $\text{CH}_{3}$ & $\text{CH}_{3}$ & 26 & 32\\
2 & $\text{CH}_{2}\text{CH}_{3}$ & $\text{CH}_{3}$ & 28 & 29\\
3 & $\text{CH}_{3}$ & $\text{CH}_{2}\text{CH}_{2}\text{CH}_{3}$ & 47 & 53\\
4${}^{\mathrm{b}}$ & $\text{CH}_{3}$ & $\text{CH}_{2}\text{CH}_{2}\text{CH}_{3}$ & 65 & 66\\
5${}^{\mathrm{b}}$ & $\text{CH}_{2}\text{CH}_{3}$ & $\text{CH}_{2}\text{CH}_{2}\text{CH}_{3}$ & 94 & 98
\botline
\end{tabular}
\tabnote{${}^{\mathrm{a}}$~All reactions contained 8~mol\% DMAP, [OH]
$=$ 0.02~M, 1.5 equiv of auxiliary base (TEA), 1 equiv of alcohol, and
3 equiv of anhydride. Conversions determined by HPLC measurements with
mesitylene as the internal standard.
${}^{\mathrm{b}}$~$N$,$N$-Diisopropylethylamine (DIPEA) was used as
auxiliary base instead of TEA.}
\end{table*}

Despite successful applications, these and other micellar catalysts
have one major drawback: the equilibrium between micelles and free
surfactant macromolecules. This equilibrium can lead to undesired
formation of stable emulsions, slow micelle/product separation caused
by excessive swelling, and catalyst loss through the formation of
Langmuir--Blodgett films at the liquid/liquid interface and/or inverse
micelles in the bulk organic phase~\cite{73}. Another major drawback
related to the thermo-responsive PMs is their dynamic nature that
renders them sensitive to their environment. To circumvent these
issues, the micelles can be turned into unimolecular persistent objects
by crosslinking, which can be accomplished by various strategies as
described below. These cross-linked PMs constitute an attractive
alternative with improved characteristic and catalytical behavior.

\subsection{Polymersomes} \label{sec3.2}

The stability of micelle- and vesicle-based systems depends on the
environment, such as the temperature of the solution and the
concentration of the surfactant. To obtain better defined and more
stable systems, macromolecular polymers have been considered as
alternative nanoreactors, with a higher kinetic stability compared to
the self-assembled molecular surfactant (\textit{vide supra}). When
vesicles are self-assembled from macromolecular amphiphiles (or block
copolymers), they are referred to as polymersomes.
Polymersomes~\cite{74,75,76,77,78} have increased rigidity and
stability compared to micelles and vesicles, and their structure can
vary from simple coil-like diblock copolymers to rod-like, rod-coil
diblock or multiblock polymers with or without additional cross-linker
groups~\cite{79}. The variation in structuring can be tuned by varying
the relative block lengths, which results in modified size, structure,
polarity, and permeability of the polymersomes. 

Eisenberg and coworkers~\cite{80} were the first to generate a block
copolymer system with six different morphologies of ``crew-cut''
aggregates of polystyrene-$b$-poly(acrylic acid) block copolymers.
Shortly after, Meijer and coworkers~\cite{81} reported the synthesis of
polystyrene-poly(propylene)imine, thus starting a new research line
based on the relation between amphiphilic properties and molecular
structure towards the preparation of many other polymersomes by various
approaches~\cite{82,83,84} and with different application scope. For
enzymatic ring-opening polymerization, Nolte and coworkers~\cite{85}
developed polystyrene-polyisocyanopeptide (PS-PIAT) based polymersomes,
while van Hest and coworkers~\cite{86} reported a
polymersome-stabilized Pickering emulsion at the water/oil interface
that was later applied in biphasic enzymatic catalysis. Also,
Lecommandoux, van Hest and coworkers~\cite{87} reported a cascade
reaction in which small polymersomes were loaded into larger ones,
resulting in a multi-compartmentalized polymersome-in-polymersome
system (Figure~\ref{fig5}). 

\begin{figure*}
\includegraphics{fig05}
\caption{\label{fig5}Multi-compartmentalized polymersome-in-polymersome
system. Reprinted with permission of Wiley-VCH Verlag GmbH~\& Co. KGaA,
Weinheim from~\cite{87}. Copyright 2014.}
{\vspace*{.15pc}}
\end{figure*}

To demonstrate the functional and structural control of the system,
they investigated a model reaction with isolated enzymes in the
different compartments. The first step of the reaction was a
Baeyer-Villiger oxidation of a substituted hydroxyphenoxazinone
ketone~\textbf{1}. The resulting ester~\textbf{2} was then hydrolyzed
with a lipase (enzyme) to form the corresponding primary
alcohol~\textbf{3}, which was subsequently oxidized by alcohol
dehydrogenase and a cofactor nicotinamide adenine dinucleotide (NAD) to
yield the corresponding aldehyde product~\textbf{4}. The final step of
the catalytic transformation was a spontaneous ${\beta}$-elimination
leading to 7-hydroxy-3H-phenoxazin-3-one-10-oxide \textbf{5}
(Scheme~\ref{sch4}). The concept of enzyme compartmentalization in the
cascade reaction spatially separated incompatible enzymes to retain
their functionality, thus resembling the intracellular organization of
eukaryotic cells. This concept allows to separate and conduct
incompatible reactions simultaneously in a confined environment with
increased efficiency, and is a very powerful tool in material
chemistry. For the catalyst recovery, the sample was promptly subjected
to centrifugation (25~{\textdegree}C, 500~g force, 4~min).
Subsequently, the suspension of polymersomes-in-polymersomes in the
aqueous phase was retrieved from the lower layer.

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{.1pc}}
\caption{\label{sch4}Enzymatic cascade reactions in
multi-compartmentalized polymersomes. Reprinted with permission of
Wiley-VCH Verlag GmbH~\& Co. KGaA, Weinheim from~\cite{87}. Copyright
2014.}
{\vspace*{-.72pc}}
\end{scheme*}

Using the micellar or vesicular approaches, the formation of stable
emulsions may occur due to the excessive swelling of the micellar
core~\cite{88}. Parameters such as temperature, dilution, and the
composition of the mixed solvent~\cite{89,90,91,92} determine the
equilibrium between micelles/vesicles and single amphiphilic chains. An
alternative and promising method to overcome these disadvantages is to
cross-link all amphiphilic polymer chains to form unimolecular
nanoobjects, thus removing the dynamic micelle/single chain
equilibrium~\cite{42,60,93}.

\subsection{Unimolecular nanoreactors} \label{sec3.3}
\subsubsection{Shell cross-linked micelles} \label{sec3.3.1}

Wooley and coworkers~\cite{94} developed a method to prepare
functionalized micelles from low polydispersity macromolecules with a
defined structure and an immobilized permeable cross-linked shell and
labile core. Unlike dendrimers~\cite{95} these shell-cross-linked
knedel-like (SCK) particles have greater peripheral functions and
nanometer-size diameters, and are therefore more considered as hybrids
between dendrimers, hollow spheres, latex particles, and block
copolymer micelles (Figure~\ref{fig6}). The SCKs were prepared by a
two-step synthesis procedure using a block copolymer of polystyrene and
poly(4-vinyl pyridine), PSt-$b$-PVP, obtained by anionic
\mbox{polymerization.} The PSt served as the hydrophobic block and the
quaternized PVP generated the hydrophilic block and introduced the
cross-linkable group. \mbox{Besides} micellar catalysis~\cite{94}, the
SCKs find many applications in other fields such as, e.g. recording
materials, hydraulic fluids, delivery processes, phase transfer
reactions, solvation, coatings and fillers.

\begin{figure*}
\includegraphics{fig06}
{\vspace*{-.35pc}}
\caption{\label{fig6}Schematic representation of the basic approach for
the formation of SCK's. Micellization of amphiphilic~\textbf{2} is
followed by cross-linking through the styrene side chains located in
the peripheral water to yield~\textbf{1}. Reprinted with permission of
American Chemical Society from~\cite{94}. Copyright 1996.}
{\vspace*{-.28pc}}
\end{figure*}

O'Reilly and coworkers~\cite{96} reported the co-polymerization of an
amphiphilic copolymer in which the hydrophobic domain was selectively
functionalized with terpyridine groups using nitroxide mediated
polymerization (NMP) techniques, that has been extensively studied and
optimized by Schubert and coworkers~\cite{97,98} (Scheme~\ref{sch5}).
The resulting shell cross-linked micelles (SCMs) (Figure~\ref{fig7})
were then modified by metal ion complexation, notably $\text{Cu}^+$,
and used as catalysts for 1,3-dipolar cycloaddition reactions (``click
reactions'') of azido- and alkynyl-functionalized small
molecules~\cite{96}.

\begin{scheme*}
\includegraphics{sc05}
{\vspace*{-.2pc}}
\caption{\label{sch5}Synthesis of a \textit{tert}-butyl acrylate block
\textbf{6} using NMP, followed by chain extension to block
copolymer~\textbf{7} that incorporates terpyridine functionality, and
then formation of an amphiphilic diblock copolymer~\textbf{8} with
terpyridine functionality embedded within the hydrophobic segment.
Reprinted with permission of American Chemical Society from~\cite{96}.
Copyright 2008.}
{\vspace*{-.6pc}}
\end{scheme*}

\begin{figure}
{\vspace*{3pt}}
\includegraphics{fig07}
{\vspace*{3pt}}
\caption{\label{fig7}Representative transmission electron microscopy
(TEM) images of SCM. Reprinted with permission of American Chemical
Society from~\cite{96}. Copyright 2008.}
\end{figure}

Weck and coworkers~\cite{99} also reported the synthesis of various
SCMs and their catalytic applications~\cite{100}. Initially, they
reported the synthesis of poly(norbornene) block copolymer-based
amphiphilic ABC triblock copolymers {via} ROMP~\cite{99}. 
The middle block
(B~block) was functionalized with a photochemically active cinnamate
group for crosslinking, and the terminal hydrophobic block (C~block)
contained a Co-salen ligand. The Co-salen functionalized SCMs catalysts
were then used for hydrolytic kinetic resolution (HKR) of
epichlorohydrin. They showed that the structure of the SCM
catalysts was stabilized by the cross-linked shell, which assisted
recyclability of the catalysts. Then they also prepared SCMs containing
Co(III)-salen cores from amphiphilic poly(2-oxazoline) triblock
copolymers~\cite{100} and studied substrate selectivity in HKR with
various terminal epoxides. More recently, they also developed
trifunctional SCMs for enantioselective three-step tandem
catalysis~\cite{101}, which were based on poly(2-oxazoline) synthesized
through living CROP~\cite{102,103} that
permitted compartmentalization of three incompatible catalysts. The SCM
consisted of carboxylic acids in the hydrophilic outer shell, Rh-based
{$N$-tosylated} 1,2-diphenyl-1,2-ethylenediamine (Rh-TsDPEN) in the
intermediate cross-linked shell, and 4-dimethylaminopyridine (DMAP) in
the hydrophobic core. The spatial architecture of each catalyst was
designed to selectively exploit the path of the substrate during each
step of the reaction; the first step involved ketal hydrolysis to the
corresponding prochiral ketone, the second step asymmetric transfer
hydrogenation (ATH) to yield an enantio-enriched secondary alcohol, and
the final step selective acylation to the \mbox{desired} \mbox{ester} product
(Scheme~\ref{sch6}). Higher conversions were observed with more
hydrophobic ketals and anhydrides, and the role of the intermediate
shell cross-linked layer in preventing deactivation of the DMAP
catalyst supported inside the micellar core was also shown. The
conversion was determined from aliquots taken at certain time
intervals, extracted with ethyl acetate. No recyclability tests were\break
reported.

\begin{scheme*}
{\vspace*{4pt}}
\includegraphics{sc06}
{\vspace*{8pt}}
\caption{\label{sch6}Synthesis of the trifunctional SCM nanoreactor
COOH-Rh-DMAP. Reprinted with permission of Wiley-VCH Verlag GmbH~\& Co.
KGaA, Weinheim from~\cite{101}. Copyright 2018.}
{\vspace*{-.3pc}}
\end{scheme*}

Optimally, SCMs act as nano-incubators for loaded catalysts and protect
the catalyst from passivation or deactivation. However, the
cross-linked shell also introduces a physical barrier between the
hydrophobic core and the hydrophilic shell, which can lower the mass
transport of certain chemicals and limit SCMs applicability for certain
catalytical transformations.

\subsubsection{Core cross-linked micelles} \label{sec3.3.2}

To circumvent the mass transport restrictions of SCMs, other polymeric
structures have been developed. The first structure, called
core-crosslinked micelle (CCM), consists of ligand-functionalized
amphiphilic diblock copolymers that are cross-linked at the end of the
hydrophobic chain. This provides star-block unimolecular nano-objects
where the ligands are located on flexible arms outside of the
cross-linked area. The second structure, known as nanogel (NG),
features a fully cross-linked core, with the catalyst binding sites
being situated within the cross-linked core~\cite{88}. Various
strategies have been reported in the literature for the synthesis of
CCMs, including ATRP~\cite{104}, as used by Sawamoto and Terashima.
They were the first to use NG-type nanoreactors in catalysis and the
Ru-containing NG polymers made by ATRP~\cite{42,105,106,107,108}, and
RAFT-mediated polymerization-induced self-assembly (PISA)~\cite{109}.
The latter strategy is a particularly attractive approach as it allows
to produce block copolymer nano-objects with a full synthesis protocol
in one-pot. A survey of the different synthetic
approaches is beyond the scope of this review and the reader is
referred to the literature~\cite{110,111,112,113,114,115} for further
details.

\looseness=-1
Rieger and coworkers~\cite{116} reported the synthesis of a core--shell
NG using a previously established method involving RAFT radical
polymerization in{\break} an aqueous dispersion that provided
nanometer-sized, uniform core--shell particles with a cross-linkable
core.\ Poly($N$,$N$-dimethylacrylamide) served as the stabilizing shell,
and ($N$,$N$-diethylacrylamide) (PDEAAm) was used for the core matrix
through aqueous heterogeneous polymerization at a moderate temperature.
The NG was formed in water at 70~{\textdegree}C through RAFT dispersion
polymerization of $N$,$N$-diethylacrylamide (DEAAm; 85~mol\%), DMAEA
(10~mol\%), and $N$,$N$-methylenebis(acrylamide) (MBA; 5~mol\%), with a
stabilizing macromolecular RAFT agent based on
poly($N$,$N$-dimethylacrylamide) (PDMAAmmacroRAFT). The resulting
nanostructured core--shell NG demonstrated the ability to stabilize
$\text{Pd}^0$ nanoparticles (NPs) in its core. Pd NPs were incorporated
into the NG by adding a $\text{Pd}^{\mathrm{II}}$ salt, expected to
coordinate with the nitrogen functions of DMAEA units, \mbox{followed} by
metal reduction with ethanol. The \mbox{hybrid} PdNP@NG exhibited
stability in both solid and solution states, making it an effective
catalyst for the Mizoroki--Heck reaction between $n$-butylacrylate and
activated bromo- and iodoarenes. After catalysis, the hybrid NG
could be recovered, dried, and reused for three consecutive runs
without significant loss of the catalytic activity. However, after the
fourth reuse, a decline in catalytic activity was observed. Analysis of
the recovered hybrid PdNP@NG revealed the presence of large Pd
aggregates and significant oxidation of $\text{Pd}^0$ to
$\text{Pd}^{\mathrm{II}}$ (Figure~\ref{fig8}). Additionally, analysis
by inductively coupled plasma mass spectrometry (ICP-MS) showed a
substantial loss of Pd from the polymeric NG support. This suggested
that part of the catalysis occurred outside the NG, explaining the
observed limited\break recyclability.

\begin{figure*}
{\vspace*{-.2pc}}
\includegraphics{fig08}
{\vspace*{-.2pc}}
\caption{\label{fig8}(A)~TEM image and (B)~Pd 3d X-ray photoelectron
spectrum (XPS) of the hybrid PdNP@NG after four catalytic cycles (solid
black line) and its deconvolution into $\text{Pd}^0$ (dashed blue line)
and $\text{Pd}^{\mathrm{II}}$ (dotted red line). Reprinted with
permission of Wiley-VCH Verlag GmbH~\& Co. KGaA, Weinheim
from~\cite{116}. Copyright 2017.}
\end{figure*}

Stenzel and coworkers~\cite{117} used RAFT polymerization technique to
synthesize poly(2-hydroxyethyl acrylate)-poly($n$-butyl acrylate) block
copolymers using either poly(2-hydroxyethylacrylate) or poly($n$-butyl
acrylate) macromolecular RAFT (macroRAFT) agents with narrow molecular
weight distributions. These macroRAFT agents were further extended by
polymerization of a diacrylate monomer, yielding CCMs. 
No catalytic application was described for these CCMs.

Furthermore, three generations of CCMs with amphiphilic unimolecular
polymer-based nanoreactors~\cite{88} having neutral (CCM-N), cationic
(CCM-C) and anionic (CCM-A) shells, respectively, have been prepared by
RAFT PISA and used for aqueous biphasic catalysis
(Figure~\ref{fig9})~\cite{118}. In all cases, special attention was
devoted to the catalyst recovery using an optimized procedure.
Briefly, after phase separation, the latex was extracted with diethyl
ether or toluene, and the combined organic phases subjected to 
analysis by gas chromatography (GC).
For the recycling experiments, a fresh substrate solution
(same amount as in the initial run) was added to the same vial,
followed by reaction and product separation according to the same
\mbox{protocol}.

\begin{figure*}
\includegraphics{fig09}
{\vspace*{-.3pc}}
\caption{\label{fig9}Three generations of CCMs with triphenylphosphine
(TPP) core and different outer shell.}
{\vspace*{-.3pc}}
\end{figure*}

\begin{scheme*}
{\vspace*{2pt}}
\includegraphics{sc07}
{\vspace*{.15pc}}
\caption{\label{sch7}General strategy of RAFT-mediated emulsion
polymerization for the synthesis of various types of core-shell
nanoreactors. Reprinted with permission of Wiley-VCH Verlag GmbH~\& Co.
KGaA, Weinheim from~\cite{119}. Copyright 2014.}
{\vspace*{-.55pc}}
\end{scheme*}

The first generation CCM-N~\cite{119} was designed with an uncharged
water-soluble shell by copolymerization of methacrylic acid (MAA) and
poly(ethylene oxide) methyl ether methacrylate (PEOMA) to generate a
P(MAA-\textit{co}-PEOMA) macroRAFT agent (Scheme~\ref{sch7}). Addition
of styrene (St) and DPPS (diphenylphosphinostyrene) as core ligand
\mbox{generated}
P(MAA-\textit{co}-PEOMA)-b-P(St-\textit{co}-DPPS){\break}
\mbox{amphiphilic} block copolymers that self-assembled into
well-defined micellar particles ($d = 72$~nm), which was crosslinked
using diethylene glycol{\break} dimethacrylate (DEGDMA) forming CCM-N
($d = 79$~nm). The average formula of the single polymer chains is
$\text{R}_0$-(MAA${_{0.5}}$-\textit{co}-PEOMA${_{0.5}}$)${_{30}}b$-(St$_{1-
n}$-\textit{co}-{\ubreak}DPPS$_{n}$)$_{300}$-$b$-(St$_{0.9}
$-\textit{co}-DEGDMA$_{0.1}$)$_{100}$-SC(S)SPr,~with
the chain ends ($\text{R}_0 =
\text{C}(\text{CH}_{3})(\text{CN})\text{CH}_{2}\text{CH}_{2}
\text{COOH}$ and SC(S)SPr) provided by the RAFT 
chain transfer agent (CTA). The
uniformity of the CCM-Ns was demonstrated by size exclusion
chromatography (SEC), TEM and DLS analyses, which also evidenced the
latex stability. Moreover, nuclear magnetic resonance (NMR)
spectroscopy and DLS confirmed the transport of hydrophobic molecules
across the hydrophilic shell into the polymer core to be fast and
leading to increased particle size owing to the particle swelling ($d =
117$~nm).

As a proof-of-principle application, the CCM-Ns were loaded with
$[\text{Rh(acac)(CO)}_2]$ (acac $=$ acetylacetonate) and evaluated for
aqueous biphasic hydroformylation of 1-octene~\cite{120}. High
activity, low isomerization as well as good stability and recyclability
(Rh leaching of a few ppm) were found, but the system was moderately
mass-transfer limited at high Rh concentrations and non-negligeable
leaching appeared to result from particle aggregation. Subsequent
follow-up studies addressed the metal leaching mechanism~\cite{121},
metal migration and cross-exchange in amphiphilic core-shell polymer
latexes~\cite{122} and mass-transport limitations~\cite{123}. Later,
Poli, Manoury and coworkers~\cite{124} extended the family of
ligand-functionalized CCMs using the same synthesis protocol to include
the bidentate Nixantphos ligand in the CCM-N. After loading with
$[\text{Rh(acac)(CO)}_2]$ the system was also applied to the aqueous
biphasic hydroformylation of 1-octene, where only moderate activity
(mass-transfer limitation) but excellent regioselectivity was found for
the formation of $n$-nonanal.

\begin{scheme*}
\includegraphics{sc08}
{\vspace*{.3pc}}
\caption{\label{sch8}Synthesis of Rh-$\text{NHC}^{\mathrm{R}}$@CCMs
\textbf{5a} (R $=$ \textit{N}-methylimidazole (Me)) and \textbf{5b} (R
$=$ \textit{N}-mesitylimidazole (Mes)) by RAFT-PISA polymerization.
Reprinted with permission of The Royal Society of Chemistry
from~\cite{53}. Copyright 2021.}
{\vspace*{-1pt}}
\end{scheme*}

\begin{figure*}
\includegraphics{fig10}
{\vspace*{-1pt}}
\caption{\label{fig10}TEM images of Rh-$\text{NHC}^{\mathrm{R}}$@CCMs
\textbf{5a} (left) and \textbf{5b} (right) (numbers as in
Scheme~\ref{sch8}). Reprinted with permission of The Royal Society of
Chemistry from~\cite{53}. Copyright 2021.}
{\vspace*{-1pt}}
\end{figure*}

A convergent synthesis of polymeric nanoreactors containing
polymerizable Rh$^{\mathrm{I}}$-$\text{NHC}^{\mathrm{R}}$ 
complexes~\cite{53} was
then developed (Scheme~\ref{sch8}). TEM images of the resulting
Rh-$\text{NHC}^{\mathrm{R}}$@CCM nanoreactors with R $=$ Me
(\textbf{5a}) and R $=$ Mes (\textbf{5b}) (Figure~\ref{fig10}) revealed
formation of particles with a broad size distribution 
(diameter of $123.3 \pm 19.2$~nm).
Under optimized reaction conditions, the \textbf{5b}
nanoreactors yielded good activity and excellent recyclability for
styrene hydrogenation with Rh-leaching ${<}$0.6~ppm per reaction cycle
(measured by ICP-MS) after some initial decomposition of the Rh-complex
by cleavage of the Rh-NHC bond in the initial two runs
(Table~\ref{tab2}, entries~1 and~2). Despite the encouraging
recyclability results, mass-transfer limitations and impractical slow
separation of the catalyst and reaction mixture remained for this
catalyst, like for the other CCM-N catalysts.

\begin{table*} %tab2
\tabcolsep5.6pt
\caption{\label{tab2}Recycling study of
Rh-$\text{NHC}^{\mathrm{Mes}}$@CCM \textbf{5b} (number as in
Scheme~\ref{sch8}) catalyst in styrene hydrogenation (adapted
from~\cite{53})
\vspace*{12pt}\tpar{\protect\inlinefig{fx02}}\vspace*{-2pt}}
\begin{tabular}{cccccc}
\thead
Entry & Run & St/Rh & St Conversion${}^{\mathrm{a}}$ (\%) & EB
Selectivity${}^{\mathrm{a}}$ (\%) & Rh leaching${}^{\mathrm{b}}$
(ppm)\\
\endthead
1 & 1st & \morerows{4}{1000/1} & ${>}$99.5 & ${>}$99.5 & 0.87\\
2 & 2nd && ${>}$99.5 & ${>}$99.5 & 1.47\\
3 & 3rd && ${>}$99.5 & ${>}$99.5 & 0.24\\
4 & 4th && ${>}$99.5 & ${>}$99.5 & 0.34\\
5 & 5th && ${>}$99.5 & ${>}$99.5 & 0.21\vspace*{4pt}\\
6 & 1st & \morerows{4}{10,000/1} & 73 & ${>}$99.5 & 0.39\\
7 & 2nd && 77 & ${>}$99.5 & 0.61\\
8 & 3rd && ${>}$99.5 & ${>}$99.5 & 0.54\\
9 & 4th && ${>}$99.5 & ${>}$99.5 & 0.31\\
10 & 5th && 98 & ${>}$99.5 & 0.13
\botline
\end{tabular}
\tabnote{Conditions: styrene (79.3~mg, 0.75~mmol), CCM \textbf{5b}
(85~mg, $7.9 \times 10^{-7}$~mol of Rh for St/Rh $=$ 1000/1 or 8.5~mg,
$7.9 \times 10^{-8}$~mol of Rh for St/Rh $=$ 10,000/1), decane (31.5~mg,
0.225~mmol), toluene (1~mL)/water (0.5~mL). ${}^{\mathrm{a}}$~Measured
by GC. ${}^{\mathrm{b}}$~Measured by ICP-MS.\vspace*{6pt}}
\end{table*}

To circumvent the mass-transfer and separation issues with CCM-N, a
second generation of CCM nanoreactors with an outer polycationic
shell{\break} (CCM-C) based on poly(1-methyl-4-vinylpyridinium)
(CCM-Cs) was developed {via} RAFT polymerization~\cite{125}. The
macroRAFT agent was synthesized by RAFT polymerization of
4-vinylpyridine (4VP) in aqueous ethanol, followed by a chain extension
with a PSt block and quaternization of the P4VP block. A core-anchored
triphenylphosphine (TPP) ligand functionality, diluted in styrene was
introduced by chain extension in a fourth synthetic step and the CCM-C
was finally formed in a fifth step by core cross-linking by a
DEGDMA:St (10:90) mixture~\cite{126} (Scheme~\ref{sch9}). DLS and TEM
analyses showed that all obtained polymers ($x = 5$, 10 or 20\%) have
spherical morphology, a narrow size distribution ($d = 130$--150~nm)
and a positive zeta potential. 

\begin{scheme*}
{\vspace*{.2pc}}
\includegraphics{sc09}
{\vspace*{1.2pc}}
\caption{\label{sch9}Synthesis of CCM-C. Adapted with permission of
Wiley-VCH Verlag GmbH~\& Co. KGaA, Weinheim from~\cite{126}. Copyright
2019.}
{\vspace*{-.6pc}}
\end{scheme*}

After loading with $[\text{RhCl(COD)}]_2$ (COD $=$ 1,5-cyclooctadiene),
the aqueous biphasic hydrogenation of 1-octene and styrene revealed
improved mass transport properties and superior performance of the
CCM-Cs, in terms of both catalytic activity, stability, and recovery,
relative to the neutral-shell analogues~\cite{126}. Importantly, also
less catalyst leaching occurred due to an enhanced ability of the
polycationic shell to confine the nanoreactors in the aqueous phase.
Moreover, in \mbox{substrate} scope \mbox{investigations} where the catalytic
hydrogenation of acetophenone was attempted, the [RhCl(COD)(TPP@CCM-C)]
latex turned black, suggesting reduction of the molecular
$\text{Rh}^{\mathrm{I}}$ complex to $\text{Rh}^0$ metal. Actually, this
turned out to be an excellent approach to generate Rh NPs directly
inside the core of CCMs (Figure~\ref{fig11}), triggering further
investigations of biphasic hydrogenation with Rh~NPs~\cite{127}.

\begin{figure}
\includegraphics{fig11}
\caption{\label{fig11}TEM image of Rh~NPs generated in the core of
CCM-C. Reprinted with permission of The Royal Society of Chemistry
from~\cite{127}. Copyright 2021.}
\end{figure}

\begin{figure*}
{\vspace*{.5pc}}
\includegraphics{fig12}
{\vspace*{.2pc}}
\caption{\label{fig12}Recycling tests in the hydrogenation of styrene
with RhNP@CCM-C using diethyl ether (left) and toluene (right) as
extraction solvent (25~{\textdegree}C, 0.5~h, styrene/Rh $=$ 2000/1)
(top). TEM images of the recovered catalyst latexes after the final run
(bottom). Reprinted with permission of The Royal Society of Chemistry
from~\cite{127}. Copyright 2021.}
\end{figure*}

The RhNP@CCM-C system was initially tested for aqueous biphasic
hydrogenation of acetophenone, but only low conversions were obtained,
unless high temperature (90~{\textdegree}C) was used. The slow reaction
rate was attributed to a poor mass transport of the acetophenone into
the CCM-C core, resulting from a possible electrostatic interaction
between its \mbox{carbonyl} group and the cationic pyridinium functions
present in the shell~\cite{127}.
Conversely, the catalytic performances
were excellent when the catalyst system was applied to the
hydrogenation of \mbox{1-octene} and styrene, with full conversion and full
selectivity towards the hydrogenation of the olefinic group. Notably,
the catalytic activity was superior to that of molecular
$\text{Rh}^{\mathrm{I}}$ systems. The RhNP@CCM-C system proved also
recyclable for styrene hydrogenation up to four runs without loss of
activity and with the Rh~NPs remaining well-dispersed when toluene was
used for product recovery/catalyst recycling.
However, when using
diethyl ether as extraction solvent a dramatic loss of activity was
observed. This \mbox{phenomenon} was attributed to facilitated extraction of
the Rh~NPs from the CCM-C core by the oxygen-based solvent
(Figure~\ref{fig12}).

To address the substrate scope limitation of the CCM-C nanoreactors, a
third generation of phosphine-functionalized CCM nanoreactors was
developed with a polyanionic poly(styrene sulfonate)-based shell
(CCM-A)~\cite{12,118}. The synthesis route was identical to those used for
the syntheses of CCM-N and CCM-C described above, except for using the
water-soluble sodium styrene sulfonate monomer in the first step
(Scheme~\ref{sch10}, Figure~\ref{fig13}).

\begin{scheme*}
{\vspace*{2pt}}
\includegraphics{sc10}
\caption{\label{sch10}Synthesis route to CCM-A. Reprinted with
permission of Elsevier Ltd~\cite{12}. Copyright 2022.}
{\vspace*{-4pt}}
\end{scheme*}

\begin{figure*}
\vspace*{2pt}
\includegraphics{fig13}
\caption{\label{fig13}DLS (before and after swelling with toluene or
chloroform) and TEM image of the CCM-A. Color coding for the DLS size
distributions: number (red), volume (green) and intensity (blue).
Reprinted with permission of~\cite{118}.
MDPI (\url{https://creativecommons.org/licenses/by/4.0/}).}
\vspace*{2pt}
\end{figure*}

For application in aqueous biphasic styrene hydrogenation, the CCM-A
nanoreactors were loaded with $[\text{RhCl(COD)}]_2$, as previously
done for the CCM-N and CCM-C counterparts (\textit{vide supra}).
However, interaction between the Rh dimer complex and the outer shell
of the CCM-A limited the transfer of the metal complex to the core,
presumably {via} chelating $\text{Rh}^{\mathrm{I}}$-sulfonate
complex formation. This bottleneck was circumvented by ``dilution'' of
the shell with a neutral monomer (PEOMA), forming a mixed
polyanionic-neutral CCM, which allowed $\text{Rh}^{\mathrm{I}}$
complexation in the core. Nevertheless, the mixed polyanionic-neutral
CCM nanoreactors had inferior performance compared to equivalent
nanoreactors with neutral and polycationic shells, which seemed to stem
from catalyst alterations induced by migration of the Rh centers
towards the shell sulfonate groups~\cite{12,118}. Thus, despite
significant progress in the development of CCMs, further improvements
are still needed to obtain efficient and durable nanoreactor systems
for aqueous biphasic hydrogenation catalysis.

\section{Conclusion} \label{sec4}

Nanostructured materials with high specific surface area offer many
advantages, attributed to their unique properties, paving the way for
advances in various fields such as nanotechnology, materials
science, electronics, energy storage, and catalysis. This review has
highlighted major developments in the synthesis and catalytic
applications of self-assembled nanoreactors made from amphiphilic
macromolecules such as polymer micelles, polymersomes and unimolecular
nanoreactors. The approaches using macromolecular nanoreactors as
potential catalyst supports, hold many unique advantages owing to the
diverse synthesis strategies for the generation and tuning of the
nanoreactors, which could lead to unique industrial applications. 

In particular, unimolecular nanoreactors have been the topic of
extensive recent research. The perspectives of these systems are
numerous, owing to their modularity and simple syntheses, \mbox{notably} by
the PISA RAFT protocol, which provides access to ligand-functionalized
CCM nanoreactors. In such nanoreactors, the chemical nature and the
degree of polymerization of the core and the shell, the type and
density of the core-anchored ligands, as well as the nature of the
coordinated metal \mbox{pre-catalyst} can all be readily varied. This makes
the unimolecular nanoreactors highly adaptable and applicable to
aqueous biphasic catalysis, thus providing new avenues of research with
several potential{\break} applications.

{\vspace*{-2pt}}

\section*{Declaration of interest}

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

\section*{Funding}
This work has been supported by the European Research Council, as part
of the Horizon 2020 research and innovation program under the Marie
Skodowska-Curie grant agreement No. 860322.

\CDRGrant[ERC]{860322}

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