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\DOI{10.5802/crchim.277}
\datereceived{2023-11-16}
\daterevised{2023-11-28}
\datererevised{2023-11-30}
\dateaccepted{2023-11-30}
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\dateposted{2024-01-23}
\begin{document}

\begin{noXML}

%\makeatletter
%\def\TITREspecial{\relax}
%\def\cdr@specialtitle@english{French Women in Chemistry in 2024}
%%\def\cdr@specialtitle@french{Les chimistes fran\c{c}aises en 2024}
%\makeatother

\title{Selected properties of phosphorus dendrimers: green approaches
to catalysis}

\alttitle{Propri\'{e}t\'{e}s s\'{e}lectionn\'{e}es des dendrim\`{e}res
phosphor\'{e}s~: approches vertes de la catalyse}

\author{\firstname{Anne-Marie} \lastname{Caminade}\CDRorcid{0000-0001-8487-3578}\IsCorresp}
\address{Laboratoire de Chimie de Coordination (LCC) du CNRS, 
205 route de Narbonne, 31077 Toulouse Cedex 4, France}
\address{LCC-CNRS, Universit\'{e} de Toulouse, CNRS, Toulouse, France}
\email[A.-M. Caminade]{anne-marie.caminade@lcc-toulouse.fr}

\author{\firstname{Val\'{e}rie} \lastname{Maraval}\CDRorcid{0000-0003-0900-7332}}
\addressSameAs{1}{Laboratoire de Chimie de Coordination (LCC) du CNRS, 
205 route de Narbonne, 31077 Toulouse Cedex 4, France}
\addressSameAs{2}{LCC-CNRS, Universit\'{e} de Toulouse, CNRS, Toulouse, France}
\email[V. Maraval]{valerie.maraval@lcc-toulouse.fr}

\keywords{\kwd{Dendrimer}
\kwd{Dendron}
\kwd{Phosphorus chemistry}
\kwd{Catalysis}
\kwd{Organocatalysis}
\kwd{Nanoparticles}
\kwd{Green chemistry}}

\altkeywords{\kwd{Dendrim\`{e}re}
\kwd{Dendron}
\kwd{Chimie du phosphore}
\kwd{Catalyse}
\kwd{Organocatalyse}
\kwd{Nanoparticules}
\kwd{Chimie verte}}

\begin{abstract}
This review describes the synthesis of polyphosphorhydrazone (PPH)
dendrimers, which are highly branched macromolecules, having a
phosphorus atom at each branching point. The properties of these PPH
dendrimers in the field of catalysis are then described. The review is
organized to illustrate in the first part how the specificities of
dendrimers could contribute to green chemistry. This concerns in
particular the dendritic effect that is an increased efficiency (yield,
enantioselectivity, etc.) when the size of the dendrimer increases, the
recovery and reuse of the dendritic catalyst, the decreased leaching,
and the entrapping of nanoparticles. In a second part, some even
greener approaches of catalysis with dendrimers will be displayed, such
as catalysis in water, switchable catalysis, and organocatalysis (no
metal used). Different types of catalytic reactions have been studied,
such as Stille, Suzuki and Sonogashira couplings, Knoevenagel
condensations, Michael additions, asymmetric allylic alkylations, \textit{O}- and \textit{N}-arylation and vinylation reactions,
[2${+}$2${+}$2]-cycloaddition reactions, isomerization of 1-octan-3-ol,
Friedel--Crafts acylations, Heck reactions, hydrogenations, hydrations,
transfer hydrogenations, amination of $\rmbeta$-dicarbonyl compounds,
etc.
\end{abstract}

\begin{altabstract}
Cette revue d\'{e}crit la synth\`{e}se des dendrim\`{e}res
polyphosphorhydrazone (PPH), qui sont des macromol\'{e}cules hautement
ramifi\'{e}es, poss\'{e}dant un atome de phosphore \`{a} chaque point
de ramification. Les propri\'{e}t\'{e}s de ces dendrim\`{e}res PPH dans
le domaine de la catalyse sont ensuite d\'{e}crites. Dans une
premi\`{e}re partie seront illustr\'{e}es comment les
sp\'{e}cificit\'{e}s des dendrim\`{e}res peuvent contribuer \`{a} la
chimie verte. Ceci concerne en particulier l'effet dendritique qui est
un accroissement de l'efficacit\'{e} (rendement,
\'{e}nantios\'{e}lectivit\'{e}, etc{\,\ldots}) lorsque la taille du
dendrim\`{e}re augmente, la r\'{e}cup\'{e}ration et la
r\'{e}utilisation du catalyseur dendritique, la diminution de la
lixiviation et le pi\'{e}geage des nanoparticules. Dans une
deuxi\`{e}me partie, des approches encore plus vertes de la catalyse
avec des dendrim\`{e}res seront pr\'{e}sent\'{e}es, comme la catalyse
dans l'eau, la catalyse commutable et l'organocatalyse (aucun m\'{e}tal
utilis\'{e}). Diff\'{e}rents types de r\'{e}actions catalytiques sont
rapport\'{e}s, tels que les couplages de Stille, Suzuki et Sonogashira,
les condensations de Knoevenagel, les additions de Michael, les
alkylations allyliques asym\'{e}triques, les r\'{e}actions de \textit{O}- et
\textit{N}-arylation et de vinylation, les r\'{e}actions de cycloaddition 
[2${+}$2${+}$2], l'isom\'{e}risation du 1-octan-3-ol, les acylations de
Friedel--Crafts, les r\'{e}actions de Heck, les hydrog\'{e}nations, les
hydratations, l'hydrog\'{e}nation par transfert, l'amination de
compos\'{e}s $\rmbeta$-dicarbonyle, etc.
\end{altabstract}

\maketitle

\vspace*{-4pt}

\twocolumngrid

\end{noXML}

\section{Introduction}\label{sec1}

The word ``dendrimer'' was created by Tomalia  \mbox{\etal}~\cite{1} to name a
new class of hyperbranched polymers, constituted of branched monomers
associated stepwise and not by polymerization reactions. Most
dendrimers are synthesized by a divergent process, starting from a
multifunctional core, which is modified to become suitable for reaction
with a branched monomer. Such process affords the first generation of
the dendrimer. If both steps are quantitative, they can be repeated, by
modifying the terminal functions of the dendrimer, to render it
suitable for the reaction with the branched monomer, affording the
second generation of the dendrimer (Scheme~\ref{sch1}). Quantitative
reactions are the key-point for the synthesis of  dendrimers~\cite{2}.
Each time the number of terminal functions is multiplied, generally by 
two~\cite{3} or three~\cite{4}, a new generation is created. When the
number of generations increases, it becomes more and more difficult to
draw the full structures, thus dendrimers can also be represented by a
linear \mbox{structure,} with parentheses after each level of branching
points, associated to a number which corresponds to the number of
divergent ramifications for the branching point considered. Both the
full structure and the linear structure of the second-generation
dendrimer are represented in  Scheme~\ref{sch1}. Dendrimers have a
bowl-shaped structure, in particular for high generations. There is a
limit to the number of generations attainable with dendrimers, which
depends on the length of the  branches~\cite{5}. Indeed, the surface
available to accommodate the terminal functions increases more slowly
than the number of terminal functions. Polyamidoamine (PAMAM) 
dendrimers~\cite{6} and poly-L-lysine dendrimers~\cite{7} were the
first dendrimers synthesized up to the tenth generation.
Polyphosphorhydrazone (PPH)  dendrimers~\cite{8}, which will be the
main topic of this review, were synthesized up to generation 
12~\cite{9}, and were, for a long time, the largest type of dendrimers
ever synthesized. Relatively recently, generation 13 was obtained with
polytriazine  dendrimers~\cite{10}.

\begin{scheme*}
\vspace*{-3pt}
\includegraphics{sc01}
\vspace*{4pt}
\caption{\label{sch1}Divergent synthesis of dendrimers. Generation 2 is
represented twice: both the full structure, and the corresponding
linear representation with parentheses after each branching point.}
\vspace*{-7pt}
\end{scheme*}

The presence of a large number of functional groups, easily accessible
on the surface, and potentially modifiable at will, make dendrimers
unique objects in the field of nanotechnologies. Indeed, dendrimers
have a nanometric size, but contrarily to classical metal nanoparticles
of the same  size~\cite{11}, which pertain to hard matter, dendrimers
pertain to soft matter, as micelles and  liposomes~\cite{12}.
Modification of the terminal functions of diverse families of
dendrimers has already opened the way towards many potential
applications in the fields of catalysis, nanomaterials, 
biology~\cite{13}, and also sensors, or electronic, to name a
few~\cite{14}.

Most dendrimers comprise a nitrogen atom at each branching point. This
is the case of the PAMAM  dendrimers~\cite{15}, and poly-L-lysine
dendrimers~\cite{16}, but also of polypropyleneimine (PPI) 
dendrimers~\cite{17}. Besides, dendrimers constituted of more inorganic
elements such as  phosphorus~\cite{18} and silicon~\cite{19}
particularly carbosilane~\cite{20} are also known and have been 
reviewed~\cite{21,22}. The case of phosphorus is particularly
attractive for several reasons, due to the richness of its
chemistry~\cite{23}, the sensitivity and the wide window of
$\mbox{}^{31}$P  NMR~\cite{24}, as well as the potential
biocompatibility, as phosphates are for instance the cement of DNA.

In this review, we will present the synthesis of polyphosphorhydrazone
dendrimers, and then\unskip\break 
selected examples of their properties in the field
of catalysis, to illustrate the dendritic effect, the recycling, the
decreased leaching, and the entrapping of nanoparticles. In a second
part, other green approaches of catalysis with dendrimers will be
displayed, such as catalysis in water, switchable catalysis, and
organocatalysis. An overview of the different types of catalysis
carried out with phosphorhydrazone dendrimers has been 
published~\cite{25}, but no emphasis on their specific properties has
been reported.

\section{Synthesis of polyphosphorhydrazone (PPH) dendrimers}\label{sec2}
Two steps are used for the synthesis of polyphosphorhydrazone (PPH)
dendrimers, as for most dendrimers. The core bears P--Cl functions in
most cases, based either on the thiophosphoryl trichloride P(S)Cl$_{3}$
(\textbf{1a}-\textbf{G}$_{\mathbf{0}}$)~\cite{8} or the
hexachlorocyclotriphosphazene N$_{3}$P$_{3}$Cl$_{6}$
(\textbf{2a}-\textbf{G}$_{\mathbf{0}}$)~\cite{26}. Starting from the
core, the first step is the reaction with 4-hydroxybenzaldehyde
(\textbf{AB}) in basic conditions, either using NaH or cesium
carbonate. The second step is the condensation of the aldehydes of
\textbf{1b}-\textbf{G}$_{\mathbf{0}}$ or
\textbf{2b}-\textbf{G}$_{\mathbf{0}}$ with the thiophosphorhydrazide
H$_{2}$NNMeP(S)Cl$_{2}$ (\textbf{CD}$_{\mathbf{2}}$) used as branched
monomer, and obtained by reaction of methylhydrazine with P(S)Cl$_{3}$
at low temperature  $({-}60~\text{\textdegree}\mathrm{C})$. This second
reaction permits to double the number of chlorides compared to the core
\textbf{1a}-\textbf{G}$_{\mathbf{0}}$ or
\textbf{2a}-\textbf{G}$_{\mathbf{0}}$, and thus affords the first
generation of the dendrimer \textbf{1a}-\textbf{G}$_{\mathbf{1}}$ 
(Scheme~\ref{sch2}A) or \textbf{2a}-\textbf{G}$_{\mathbf{1}}$ 
(Scheme~\ref{sch2}B). Both steps are quantitative, thus they can be
used again to get the second generation
\textbf{1a}-\textbf{G}$_{\mathbf{2}}$ or
\textbf{2a}-\textbf{G}$_{\mathbf{2}}$, then the third
\textbf{1a}-\textbf{G}$_{\mathbf{3}}$ or
\textbf{2a}-\textbf{G}$_{\mathbf{3}}$, and so on. By starting from
N$_{3}$P$_{3}$Cl$_{6}$ as the core, by using the same principle, the
8th generation \textbf{2b}-\textbf{G}$_{\mathbf{8}}$ can be obtained 
(Scheme~\ref{sch2}B)~\cite{27}, whereas the 12th generation\unskip\break
\textbf{1a}-\textbf{G}$_{\mathbf{12}}$ can be obtained when
P(S)Cl$_{3}$ is used as the core  (Scheme~\ref{sch2}A)~\cite{9}. 

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc02}
\vspace*{4pt}
\caption{\label{sch2}Synthesis of polyphosphorhydrazone dendrimers,
starting from either P(S)Cl$_{3}$ (A) or N$_3$P$_{3}$Cl$_{6}$ (B) as
core.} 
\vspace*{-6pt}
\end{scheme*}

Several other methods to prepare phosphorus dendrimers have been
elaborated, often based on the Staudinger reaction~\cite{28} between
phosphines and azides, in particular using thiophosphoryl
azides~\cite{29}, for the synthesis of highly sophisticated dendritic
structures~\cite{30}. However, this family of phosphorus dendrimers has
not found any practical use up to now, and the selected properties of
PPH dendrimers in the field of catalysis will only be described.

\section{Specificities of dendrimers as catalysts}\label{sec3}
The very first examples of dendritic catalysts, were a silane dendrimer
functionalized with aryl nickel complexes, which was used in the
Kharasch addition of polyhalogenoalkanes to carbon--carbon double
bonds~\cite{31}, and a small polyphosphine dendrimer complexing
palladium used in the electrochemical reduction of CO$_{2}$ to
CO~\cite{32}.

Different types of ligands have been grafted very early on the surface
of PPH dendrimers, in particular phosphines~\cite{33} for the
complexation of metals such as gold, enabling the characterization by
High Resolution Transmission Electron Microscopy (HRTEM)~\cite{26}, but
also the complexation of iron and tungsten~\cite{34}, palladium,
platinum and rhodium~\cite{35}, ruthenium~\cite{36}, and
zirconium~\cite{37} but none of them were used as catalysts. The first
examples of PPH dendrimers used as catalysts concerned palladium and
ruthenium complexes which were utilized in Stille couplings,
Knoevenagel condensations, and Michael additions~\cite{38}. Other
examples of PPH dendritic catalysts concerned Pd complexes for
asymmetric allylic alkylations~\cite{39}, and C--C cross-coupling
reactions~\cite{40}.  

\begin{scheme*}
\includegraphics{sc03}
\vspace*{5pt}
\caption{\label{sch3}Illustration of the ``dendritic effect'' with
copper complexes of pyridine-imine ligands used for the arylation of
pyrazole, using the same quantity of copper.}
\vspace*{-2pt}
\end{scheme*}

\subsection{Dendritic effect in catalysis}\label{sec3.1}
One of the most intriguing properties of dendrimers is the so-called
``dendritic effect''~\cite{41}. This effect is observed when a
functional group behaves differently when it is alone or linked to a
dendrimer, and the effect is also depending on the generation of the
dendrimer. This effect is essentially unexplained, even if it is
believed that it is related to the multivalency effect, which is
well-known in biology~\cite{42}. In~the~case of catalysis, a
spectacular example of dendritic effect concerned the ester hydrolysis
catalyzed by peptide dendrimers composed of histidine--serine. The
generation 4 peptide dendrimer was 140,000-fold more efficient than the
reference catalyst for ester hydrolysis, with a 4500-fold acceleration
per histidine side-chain~\cite{43}. In~the~case of PPH dendrimers,
another intriguing example of the dendritic effect concerned
pyridine-imine ligands used for the complexation of copper. The monomer
and generations 1 to 3 of the PPH dendrimers were synthesized, and used
as catalysts for ${O}$- and ${N}$-arylation as well as for
vinylations. The most spectacular example concerned the arylation of
pyrazole, using the same quantity of copper (10~mol\%) for all the
generations used. The efficiency of 1 equiv of generation 3
(\textbf{2c}-\textbf{G}$_{\mathbf{3}}$) was compared to that of 2 equiv
of generation 2 (\textbf{2c}-\textbf{G}$_{\mathbf{2}}$), or 4 equiv of
generation 1 (\textbf{2c}-\textbf{G}$_{\mathbf{1}}$), or 48 equiv of
monomer (\textbf{2c}-\textbf{M}), as in all the examples displayed in
this review  (Scheme~\ref{sch3}). The monomeric catalyst
\textbf{2c}-\textbf{M} was found almost inactive as only 2\% yield in
1-phenylpyrazole \textbf{3} was obtained when pyrrole was treated with
phenylbromide. The yield in \textbf{3} was increased with generation 1
(40\% yield), generation 2 (44\% yield), and the best yield in
\textbf{3} was obtained with generation 3 (80\% yield)~\cite{44}. 

A strong positive dendritic effect has been also observed in both the
yield and the enantioselectivity of Rh-catalyzed
[2${+}$2${+}$2]-cycloadditions with dendritic phosphoramidite chiral ligands,
leading to axially chiral biaryl compounds. As previously, the same
quantity of catalytic sites is used in all cases~\cite{45} 
(Scheme~\ref{sch4}). The monomer complex 
\textbf{2d}-\textbf{M}-\textbf{Rh} and the branch complex
\textbf{2d}-\textbf{B}-\textbf{Rh} have practically no activity and no
selectivity in the synthesis of the biarylic compound \textbf{4}. On
the contrary, all the dendrimers are active, and display an increasing
efficiency on going from the first generation
\textbf{2d}-\textbf{G}$_{\mathbf{1}}$-\textbf{Rh} to the third
generation \textbf{2d}-\textbf{G}$_{\mathbf{3}}$-\textbf{Rh}, in both
yield and\unskip\break 
enantioselectivity.

\begin{scheme*}
\vspace*{-4pt}
\includegraphics{sc04}
\vspace*{2pt}
\caption{\label{sch4}Catalyzed [2${+}$2${+}$2]-cycloadditions using monomeric
(\textbf{2d}-\textbf{M}), branch (\textbf{2d}-\textbf{B}), and
dendritic (\textbf{2d}-\textbf{G}$_{\mathbf{1}}$ to
\textbf{2d}-\textbf{G}$_{\mathbf{3}}$) Rh complexes. Influence of the
generation on the yield and the enantioselectivity.}
\vspace*{-9pt}
\end{scheme*}

Other examples of positive dendritic effects have been observed in the
isomerization of 1-octan-3-ol catalyzed by dendritic
Ru-complexes~\cite{46}. However, it should be emphasized that a
positive dendritic effect is not always observed with dendrimers. In
some cases, there is no change when using a dendrimer compared to a
monomer~\cite{47}, or there is only a slight difference, which depends
on the reagents used~\cite{48}. In some cases, the absence of dendritic
effect is due to the cleavage of the catalytic entity from the
dendrimer when using hard conditions~\cite{49}. Some negative dendritic
effects have been also reported~\cite{50}, but there is probably a bias
in the reported number of positive dendritic effects, as most negative
results have never been published.

\subsection{Recovery and reuse of dendritic catalysts}\label{sec3.2}

Another important benefit of using dendritic catalysts is the
possibility to recover and reuse them in several catalytic runs. The
main reason is that dendrimers are quite large compared to the reagents
and products, and thus they can be less soluble in some solvents than
small molecules. This is in particular the case of phosphorhydrazone
dendrimers, which are soluble in several organic solvents, but not in
diethylether. Thus, the dendritic catalyst can be recovered by
precipitation in ether. This concept has been applied several times
generally for three runs  (see for example:~\cite{38,39,45,48}), but
such property was applied in particular to the 4th generation dendrimer
\textbf{2e}-\textbf{G}$_{\mathbf{4}}$ bearing terpyridine terminal
functions, suitable for the complexation of scandium. This dendrimer
was used in Friedel--Crafts acylations, under microwave irradiation. It
is worth mentioning that 12 runs can be achieved, with different
substrates at each run, and the efficiency of this dendrimer was still
very high even after 12 runs~\cite{51} (Scheme~\ref{sch5}). 

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc05}
\vspace*{4pt}
\caption{\label{sch5}Generation 4 dendrimer complexing scandium used as
catalyst in Friedel--Crafts acylation, under microwave irradiation.
Recovery and reuse of the dendritic catalyst in 12 runs, using
different substrates at each step. Blue arrows indicate the recycling.}
\vspace*{-6pt}
\end{scheme*}

Another example of the dendritic catalyst recovery concerned a biphasic
experiment (water/heptane 1:1), utilizing dendritic ruthenium complexes
of PTA (1,3,5-triaza-7-phosphaadamantane)~\cite{52} in the
isomerization of 1-octan-3-ol \textbf{5}. The dendrimers are soluble in
water, whereas the reagents and products are soluble in heptane.
Catalysis occurred at the interface, upon strong stirring. After
stopping the
magnetic stirring, two phases are rapidly formed and
easily separated, the organic phase containing the products, and the
water phase containing the dendritic catalysts. A positive dendritic
effect on the yield was observed from the monomer
\textbf{2f}-\textbf{M} (38\% conversion of \textbf{5}) to the third
generation \textbf{2f}-\textbf{G}$_{\mathbf{3}}$ (98\% conversion of
\textbf{5}). The water phase was recovered and reused in another run,
including for the first generation
\textbf{2f}-\textbf{G}$_{\mathbf{1}}$, which was efficiently reused for
3 runs~\cite{46}  (Scheme~\ref{sch6}). \looseness=-1

\begin{scheme*}
\includegraphics{sc06}
\vspace*{4pt}
\caption{\label{sch6}Water-soluble dendrimers used in catalyzed
biphasic isomerization of allylic alcohols to ketones. Positive
dendritic effect, and recycling of
\textbf{2f}-\textbf{G}$_{\mathbf{1}}$ by phase separation.}
\end{scheme*}

The third recycling method used to recover the dendritic
phosphorhydrazone catalysts is very original, as it uses magnetic
nanoparticles as supports of the dendritic catalysts, which are easily
recovered with a magnet~\cite{53}. The very first example concerning
the use of dendritic catalysts in such process was obtained with
generations 0 (\textbf{6}-\textbf{G}$_{\mathbf{0}}$) and 1
(\textbf{6}-\textbf{G}$_{\mathbf{1}}$) of PPH dendrimers having phosphine
palladium complexes on the surface and a single pyrene linked to the
core. At room temperature, the pyrene interacts by $\rmpi$-stacking
with a few graphene layers encapsulating the magnetic cobalt
nanoparticles. The efficiency of the $\rmpi$-stacking decreased when
heating, thus catalysis with these dendritic catalysts is performed in
solution. After completion of the catalysis, the reaction medium is
cooled down to room temperature, the dendrimers go back to the graphene
entrapping magnetic nanoparticles, which are easily recovered using a
magnet, as illustrated in  Scheme~\ref{sch7}. Such process has been
applied to Suzuki couplings of boronic acids with various aryl
bromides, and in particular for the synthesis of an anti-inflammatory
drug, Felbinac, which was isolated in 100\% yield even after 
12~runs~\cite{54}.\looseness=-1

\begin{scheme*}
\includegraphics{sc07}
\vspace*{4pt}
\caption{\label{sch7}Magnetic cobalt nanoparticles covered by graphene
interacting with a pyrene catalytic dendron at room temperature, and
used for the synthesis of Felbinac. Recovery using a magnet was carried
out 11 times.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc08}
\vspace*{4pt}
\caption{\label{sch8}Two types of dendrimers suitable for the
complexation of palladium, and used in Suzuki couplings. Recycling was
only efficient with the dendrimer bearing the thiazolyl phosphine
complexes, thanks to undetectable palladium leaching.}
\vspace*{-4pt}
\end{scheme*}

\subsection{Decreased metal leaching}\label{sec3.3}
Leaching of metals during catalytic processes is an important problem
for both the loss of precious/expensive metals, and the difficult
purification of products, especially for the pharmaceutical
industry~\cite{55}. As shown in the previous paragraphs, it is possible
to recover and reuse dendritic catalysts with a good efficiency even
after several runs, thus it is presumed that leaching should be reduced
when using dendrimers compared to monomers, but it might also depend on
the type of ligands. Two families of dendrimers (monomer, generations~1
and~3) were synthesized, decorated with either triphenylphosphine
(\textbf{2g}-\textbf{MPPh}$_{\mathbf{3}}$,
\textbf{2g}-\textbf{G}$_{\mathbf{1}}$\textbf{PPh}$_{\mathbf{3}}$,
\textbf{2g}-\textbf{G}$_{\mathbf{3}}$\textbf{PPh}$_{\mathbf{3}}$) or
thiazolyldiphenyl phosphine (\textbf{2h}-\textbf{MthiazolP},
\textbf{2h}-\textbf{G}$_{\mathbf{1}}$\textbf{thiazolP},
\textbf{2h}-\textbf{G}$_{\mathbf{3}}$\textbf{thiazolP}). They were
involved in Suzuki coupling reactions, after complexation of palladium.
Both families demonstrated a better efficiency of the first
generations, compared to the corresponding monomers 
(Scheme~\ref{sch8}). Thus, their recycling was studied. It was shown
that the 1st generation dendrimer decorated with Pd complexes of
thiazolyl phosphine
(\textbf{2h}-\textbf{G}$_{\mathbf{1}}$\textbf{thiazolP-Pd}) was
efficiently recovered and reused, without loss of activity for at least
5 runs. On the contrary, the efficiency of the 1st generation dendrimer
decorated with Pd complexes of triphenylphosphine
(\textbf{2g}-\textbf{G}$_{\mathbf{1}}$\textbf{PPh}$_{\mathbf{3}}$-\textbf{Pd})
decreased rapidly, and disappeared after 3 runs. To elucidate this
difference, palladium leaching with the monomers and the 1st generation
dendrimers was measured by Inductively Coupled Plasma Mass Spectrometry
(ICP-MS). Leaching was found very high with both monomers, reduced for
the triphenylphosphine linked to the dendrimer, and undetectable for
the thiazolyl phosphine linked to the dendrimer  (Scheme~\ref{sch8}).
Such a low level of palladium leaching is very rare for Suzuki
reactions in homogeneous conditions, and explains the efficiency of the
recovery and reuse of the dendritic catalyst~\cite{56}.

\begin{scheme*}
\includegraphics{sc09}
\vspace*{4pt}
\caption{\label{sch9}Macrocycles on the surface of dendrimers, used for
complexing palladium as discrete complexes or as palladium
nanoparticles. Heck coupling reactions, and recycling.}
\vspace*{-4pt}
\end{scheme*}

\subsection{Entrapping catalytic nanoparticles}\label{sec3.4}
Beside the grafting of discrete complexes on the surface of dendrimers,
examples of dendrimers incorporating metal nanoparticles used for
catalysis have been largely explored~\cite{57}. Most generally, the
starting complex has to be reduced to generate the nanoparticles and to
stabilize them, by entrapping them inside the dendrimers or in between
dendrimers. A series of phosphorhydrazone dendrimers was functionalized
with 15-membered triolefinic triazamacrocycles, generation 0 built from
P(S)Cl$_{3}$ as core (\textbf{1i}-\textbf{G}$_{\mathbf{0}}$) and
generations 0, 1 and 4, built from N$_{3}$P$_{3}$Cl$_{6}$ as
core (\textbf{2i}-\textbf{G}$_{\mathbf{0}}$,
\textbf{2i}-\textbf{G}$_{\mathbf{1}}$, and
\textbf{2i}-\textbf{G}$_{\mathbf{4}}$). These macrocycles are suitable
for complexing Pd(0), issued from Pd$_{2}$(dba)$_{4}$ (dba $=$
dibenzylidene acetone). The use of a stoichiometric amount of palladium
(1~Pd per macrocycle) induces the formation of discrete complexes,
whereas the use of an excess of Pd induces the formation of Pd(0)
nanoparticles, stabilized by the dendrimers. The average diameters of
the nanoparticles are between 3 and 5 nm, irrespective of the size
(generation) of the dendrimers. Both the discrete complexes and the
nanoparticles stabilized by the dendrimers were tested as catalysts in
Heck reactions, using the same quantity of palladium in all cases.
Generation 0 built from the P(S) trifunctional core (compound
\textbf{1i}-\textbf{G}$_{\mathbf{0}}$) was found the most efficient
after 4~h, with both the discrete complex and the nanoparticles.
However, no large differences were observed after 24~h. In both cases,
recycling was attempted 5 times  (Scheme~\ref{sch9}). The most
important differences were observed after 4~h. The discrete complex is
easily recovered and reused with the same efficiency. Surprisingly, the
nanoparticles complexed by the generation 0 dendrimers
(\textbf{1i}-\textbf{G}$_{\mathbf{0}}$) displayed an increasing
activity with the number of recycling runs, with a yield in butyl
cinnamate after 4~h increasing from 36\% after run 1 to 98\% after run
6. This contra-intuitive result is due to the decrease of 
the\unskip\break
nanoparticles size, with an average size from 4.1 nm at the first run
to 2.3~nm at the sixth run~\cite{58}.

Another way to generate catalytic nanoparticles consisted in milling,
under air, ruthenium chloride (RuCl$_{3}$), sodium borohydride
(NaBH$_{4}$) and polyphosphorhydrazone (PPH) dendrons of generations 0
to 2, having an alkyl chain (C12 or C16) at the focal point and
triarylphosphines on the surface (compounds\unskip\break
\textbf{7}-\textbf{G}$_{\mathbf{0}}$,
\textbf{7}-\textbf{G}$_{\mathbf{1}}$, and
\textbf{7}-\textbf{G}$_{\mathbf{2}}$). Ru nanoparticles obtained in
these conditions, were then used as efficient catalysts in the
hydrogenation of styrene, to afford ethylbenzene \textbf{8} 
(Scheme~\ref{sch10}). No effect of the alkyl chain length on the
efficiency was observed. However, a positive dendrimer effect was
observed, as the Ru particles stabilized with the second generation
dendron (\textbf{Ru@7}-\textbf{G}$_{\mathbf{2}}$) were the most
efficient (85\% yield with generation 0; 96\% yield with generation 2).
This is probably due to the fact that the surface of the nanocomposite
systems is less hindered when higher generation dendrons are involved,
as illustrated in  Scheme~\ref{sch10}~\cite{59}.

\begin{scheme*}
\vspace*{1pt}
\includegraphics{sc10}
\vspace*{4pt}
\caption{\label{sch10}Dendrons for the synthesis of Ru nanoparticles.
Catalysts for the hydrogenation of styrene.}
\end{scheme*}

\section{Additional green approaches of catalysis}\label{sec4}
The different specificities of dendrimers in catalysis shown in Section
3 are all relevant for green chemistry processes by decreasing the
leaching of metal, and by decreasing either the time or the temperature
of the reaction, reusing the catalyst to decrease the quantity of metal
needed, and simplifying the purification of the products. Other types
of green approaches are more classical and are known also with
monomeric catalysts.

\subsection{Catalysis in water}\label{sec4.1}
Water can be considered as a green solvent, compared to classical
organic solvents. As the internal structure of the phosphorhydrazone
dendrimers contains numerous aromatic cycles, they are rather
hydrophobic, and can be soluble in water only if the terminal functions
are hydrophilic, bearing either positive charges such as
ammoniums~\cite{60,61,62} or negative charges such as
carboxylates~\cite{63,64,65}, phosphonates~\cite{66,67} or
sulfonates~\cite{68}, or neutral polyethyleneglycol (PEG)~\cite{69,70}.

As shown in Scheme~\ref{sch6}, the positive charge on the PTA
(PhosphaTriazaAdamantane) ligand induces a solubilization of the
dendrimers in water and at the interface between water and
heptane~\cite{46}. Generations 0
(\textbf{2f}-\textbf{G}$_{\mathbf{0}}$) to 3
(\textbf{2f}-\textbf{G}$_{\mathbf{3}}$) of the same family of PTA
dendrimers have been also investigated, both as catalysts for the
hydration of phenylacetylene in H$_{2}$O/$i$PrOH, and for their
interaction in phosphate buffer (excepted
\textbf{2f}-\textbf{G}$_{\mathbf{3}}$) with supercoiled DNA, to afford
relaxed DNA~\cite{71}. 

Scorpionates such as tris(pyrazolyl) ligands, have been grafted to the
surface of a 1st generation dendrimer
\textbf{2j}-\textbf{G}$_{\mathbf{1}}$, and used for the complexation of
palladium. Complexes of the dendrimer
(\textbf{2j}-\textbf{G}$_{\mathbf{1}}$-\textbf{Pd}) and of the
corresponding monomer (\textbf{2j}-\textbf{M}-\textbf{Pd}) have been
used as catalysts in both Sonogashira and Heck C--C cross-coupling
reactions in a H$_{2}$O/CH$_{3}$CN (1:6) mixture 
(Scheme~\ref{sch11})~\cite{72}. Monomer
\textbf{2j}-\textbf{M}-\textbf{Pd} and dendrimer
\textbf{2j}-\textbf{G}$_{\mathbf{1}}$-\textbf{Pd} complexes afford
analogous efficiency in the Sonogashira coupling, whereas the dendrimer
\textbf{2j}-\textbf{G}$_{\mathbf{1}}$-\textbf{Pd} is more efficient
than the monomer \textbf{2j}-\textbf{M}-\textbf{Pd} in Heck coupling.

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc11}
\vspace*{4pt}
\caption{\label{sch11}Monomer and dendrimer bearing scorpionates for
the complexation of palladium. Sonogashira and Heck coupling reactions.}
\vspace*{-7pt}
\end{scheme*}

\subsection{Switchable catalysts}\label{sec4.2}
Redox-switchable catalysis concerns an emerging field of research, in
which a redox-active functionality is incorporated within a ligand
framework. As the redox process influences the electron-donating
ability of the ligands, the coordinated metal centers can be influenced
\textit{in situ}, thus modifying the catalytic activity~\cite{73}. It
has never been applied to dendritic catalysts before our work.
Ferrocene is a widely used redox-active group, which displays a high
degree of reversibility. Furthermore, it can be easily functionalized
and has been frequently grafted to dendrimers, including to phosphorus
dendrimers~\cite{74}. The presence of an additional functionalization
such as phosphine complexes of palladium, enabled their use in
asymmetric allylic substitution reactions~\cite{47}. Later on, a
monomer and a 1st generation dendrimer
(\textbf{2k}-\textbf{G}$_{\mathbf{1}}$) were functionalized with
unsymmetrically disubstituted 1,1$'$-ferrocenylphosphine, in which one
cyclopentadienyl (Cp) ring is substituted with a phenol for the
grafting to the dendrimer, and the other Cp is substituted with an aryl
phosphine.\unskip\break 
The phosphines were then used for complexing ruthenium, and
the complexes efficiently catalyzed the isomerization of 1-octen-3-ol
to 3-octanone. Upon oxidation of the ferrocene
(\textbf{2k}-\textbf{G}$_{\mathbf{1}}$-\textbf{Red}) to ferrocenium
(\textbf{2k}-\textbf{G}$_{\mathbf{1}}$-\textbf{Ox}), the experimental
rate constant dramatically decreased, due to the precipitation of the
oxidized dendritic catalysts
\textbf{2k}-\textbf{G}$_{\mathbf{1}}$-\textbf{Ox} in the medium. Upon
reduction to \textbf{2k}-\textbf{G}$_{\mathbf{1}}$-\textbf{Red}, the
dendritic catalysts became again soluble, and the rate constant
dramatically increased, displaying an ON/OFF/ON switching process 
(Scheme~\ref{sch12})~\cite{75}. This family of redox-switchable
dendrimers was expanded up to generation 3, and with the use of either
no linker or a biphenyl linker between the ferrocene and the
phosphine~\cite{76}. 

\begin{scheme*}
\includegraphics{sc12}
\vspace*{4pt}
\caption{\label{sch12}Dendrimer bearing redox switchable phosphines
complexing ruthenium, and its use as catalyst in the isomerization of
1-octen-3-ol to 3-octanone. Influence of the oxidation and reduction of
the ferrocenes on the catalytic rate.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc13}
\vspace*{4pt}
\caption{\label{sch13}Dendrimers and cobalt nanoparticles as support of
the J\o{}rgensen--Hayashi organocatalyst. Coupling of propanal to
$\rmbeta$-nitrostyrene. Comparison of the efficacy in recycling
experiments.}
\vspace*{-8pt}
\end{scheme*}

More recently, the same switching process was successfully applied to
dendrimers bearing chiral ferrocenyl phosphines as terminal functions
for ruthenium-catalyzed transfer hydrogenation~\cite{77} of
acetophenone~\cite{78}.

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc14}
\vspace*{4pt}
\caption{\label{sch14}$({+})$-Cinchonine derivative linked to a monomer
(\textbf{2m}-\textbf{M}), a branch (\textbf{2m}-\textbf{B}) and to
generation 1 of dendrimer (\textbf{2m}-\textbf{G}$_{\mathbf{1}}$), and
their use as organocatalysts for the $\rmalpha$-amination of
$\rmbeta$-dicarbonyl compounds.}
\vspace*{-6pt}
\end{scheme*}

\subsection{Organocatalysis}\label{sec4.3}
Organocatalysis, i.e. catalysis in the absence of any metal, is
particularly attractive in relation to the principles of ``green
chemistry'', being both cheaper and safer. The use of dendrimers as
organocatalysts has been recognized early and reviewed~\cite{79}.
Phosphorhydrazone dendrimers have been used as supports of known
organocatalysts in several cases.\unskip\break
In a first example, small polymers
linked to the surface of cobalt nanoparticles \textbf{2l}-\textbf{NP}
(identical to those used in  Scheme~\ref{sch7}) as well as dendrimers
of generations 1 to 3 (\textbf{2l}-\textbf{G}$_{\mathbf{1}}$,
\textbf{2l}-\textbf{G}$_{\mathbf{2}}$ and
\textbf{2l}-\textbf{G}$_{\mathbf{3}}$) were functionalized with the
J\o{}rgensen--Hayashi catalyst
[($S$)-$\rmalpha$,$\rmalpha$-diphenylprolinol trimethylsilyl ether].
Both families of compounds were used as catalysts in the Michael
additions of a wide range of aldehydes to different nitroolefins. The
addition of propanal to  $\rmbeta$-nitrostyrene was particularly
studied to demonstrate the recycling ability  (Scheme~\ref{sch13}).
Among the dendrimers, generation 3
(\textbf{2l}-\textbf{G}$_{\mathbf{3}}$) was the most efficient at the
first run, and remained highly efficient over 4 runs. The cobalt
nanoparticles covered with the catalysts \textbf{2l}-\textbf{NP} were
found as efficient as the dendrimer
\textbf{2l}-\textbf{G}$_{\mathbf{3}}$, but the recycling was
surprisingly poorly efficient. Indeed, at run 4, the catalytic
efficiency of the dendrimer \textbf{2l}-\textbf{G}$_{\mathbf{3}}$ was
still 98\%, whereas that of the nanoparticles \textbf{2l}-\textbf{NP}
was only 34\%~\cite{80}.

\begin{scheme*}
\includegraphics{sc15}
\vspace*{4pt}
\caption{\label{sch15}Alkylation of the nitrogen of the quinuclidine of
$({+})$-cinchonine for the grafting to the 1st generation dendrimer.
Phase transfer catalyst in the asymmetric alkylation of a glycinate
Schiff base with benzyl bromide. Influence of the temperature and the R
substituent. Recycling experiments with
\textbf{2n}-\textbf{G}$_{\mathbf{1}}$\textbf{b}.}
\end{scheme*}

Cinchona alkaloids are natural products, which derivatives have been
used in many catalytic asymmetric reactions~\cite{81}. One of these
derivatives, $({+})$-cinchonine, has been grafted on the surface of
phosphorhydrazone (PPH) dendrimers in two different ways for two
different purposes. In the first attempt, $({+})$-cinchonine was modified
with a phenol, to be reacted with the P(S)Cl$_{2}$ terminal functions
of the dendrimers of generations 1
(\textbf{2m}-\textbf{G}$_{\mathbf{1}}$) and 4
(\textbf{2m}-\textbf{G}$_{\mathbf{4}}$). A branch derivative
(\textbf{2m}-\textbf{B}) was also synthesized as a model compound
bearing two $({+})$-cinchonine derivatives  (Scheme~\ref{sch14}). These
compounds were tested in the $\rmalpha$-amination of several
$\rmbeta$-dicarbonyl compounds. The reactions were very fast, even with
only 4 mol\% of catalyst (to be compared with 20~mol\% in the case of
the monomer  \textbf{2m}-\textbf{M}), and went to completion in 2 min
at 25~\textdegree C, and in 10~min at
${-}25~\text{\textdegree}\mathrm{C}$ with the smallest
compounds (branch \textbf{2m}-\textbf{B}, and 1st generation dendrimer
\textbf{2m}-\textbf{G}$_{\mathbf{1}}$). The best enantiomeric excesses
were obtained with the branch and the 1st generation dendrimer.
Recycling experiments were successfully carried out with the 1st
generation \textbf{2m}-\textbf{G}$_{\mathbf{1}}$, and ten runs were
carried out without loss of activity and enantioselectivity. The scope
of the catalytic enantioselective amination of various active methylene
compounds was then evaluated, using cyclic and noncyclic esters, cyclic
$\rmbeta$-diketones and opened chain esters~\cite{82}.

The second way to graft $({+})$-cinchonine required the modification of
the surface of the dendrimers in three steps from the aldehydes, e.g.
reduction with BH$_{3}{\cdot}$SMe$_{2}$, transformation to benzylic
chloride with SOCl$_{2}$~\cite{83}, and reaction with NaI to give
benzyl iodide terminal functions. The next step was the quaternization
of the nitrogen of the quinuclidine of $({+})$-cinchonine, containing
different R groups in the O-9 hydroxy group of the cinchonine unit. A
small quantity (0.1 mol\%) of these functionalized dendrimers
\textbf{2n}-\textbf{G}$_{\mathbf{1}}$\textbf{a}-\textbf{d} was then
used as a phase transfer catalyst in the asymmetric alkylation of a
glycinate Schiff base with benzyl bromide, at  25~\textdegree C, 
0~\textdegree C, and even ${-}20~\text{\textdegree}\mathrm{C}$ 
(Scheme~\ref{sch15}). To simplify the analysis, the resulting imines
\textbf{9} were derivatized to the corresponding trifluoroacetamides
\textbf{10} by their hydrolysis with citric acid, followed by the
protection of the generated primary amines by reaction with
trifluoroacetic anhydride. The best results concerning the yield and
the enantiomeric excess were obtained for
\textbf{2n}-\textbf{G}$_{\mathbf{1}}$\textbf{b} (R $=$ allyl). This
dendrimer was also used in recycling experiments, at  0~\textdegree C.
Five runs were carried out, and yields were similar for each run, but a
slight decrease of ee was observed. The scope of the catalytic
enantioselective alkylation of the
${N}$-(diphenylmethylene)glycine \textit{tert}-butyl ester with
various alkylating agents was then also evaluated. Good yields
(76--87\%) and enantioselectivities (76--89\%) were obtained in most
cases~\cite{84}.

\section{Conclusions}\label{sec5} 
We have shown in this review different aspects of the use of dendrimers
in catalysis. Very positive influences on the yield, the
enantioselectivity, the easy recovery and reuse, make dendrimers
especially attractive in the field of catalysis. However, it should be
emphasized that catalysis is only a part of the fields that benefit
from the use of dendrimers. The PPH (polyphosphorhydrazone) dendrimers
in particular gave birth to two start-ups, one in the field of
materials, in particular biosensors for diagnosis~\cite{85,86}, and one
in the field of biology, in particular an anti-inflammatory
drug~\cite{87,88}. Thus, there is still plenty of room to expand the
use of dendrimers in general, and more specifically of PPH dendrimers. 

\section*{Declaration of interests}
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.

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