Metal-Containing Dendritic Polymers

Fiona J. Stoddart and Thomas Welton*

Department of Chemistry, Imperial College of Science, Technology and Medicine, South

Kensington, London SW7 2AY, UK.

Abstract

Metal-containing dendrimers (metallodendrimers) have attracted a great deal of attention recently and their study is becoming a growing field. Many workers have entered the field and it is rapidly developing. In this review, the preparation, characterisation and applications of metal-containing denrimers are discussed. The principal methodologies for the preparation of dendrimers are first demonstrated and then the derivatisation of organic dendrimers to form suitable potential ligands is presented. Finally the formation of transition-metal complexes of the dendrimers is discussed. The manuscript is organised such that the metallodendrimers are discussed by donor element in the dendrimer. As one might expect, phoshine and nitrogen-donor complexes have dominated this initial phase of synthesis.

However, there are reports of metallodendrimers with a wide variety of donor atoms. In the few years since the first metallodendrimers were prepared the field has moved rapidly towards potential applications, and this has been noted.

1 Introduction

Over the last twenty years, a new class of polymers known as dendrimers has fascinated many chemists. This review concentrates on those dendrimers that contain metals. However, a brief introduction to dendrimers in general and the major approaches to their syntheses is given. More detailed reviews on this subject have been given elsewhere.1

The term dendrimer is derived from the Greek word dendra meaning tree. These highly branched macromolecules have compelling molecular structures that are reminiscent of patterns often observed in nature and particularly those found in trees and in coral.

Dendrimers – also called arborols2 or cascade3 molecules – exhibit controlled patterns of branching and ideally are monodisperse, i.e.; all the molecules should have exactly the same molecular masses, constitutions and average dimensions. The larger dendrimers, which have globular structures, carry many close-packed surface end groups and contain internal cavities.

The interest in dendritic polymers stems from the possibility that their architectures, which differ from those of traditional linear step-growth polymers, offer exciting prospects of new applications.4

Before 1940, branched molecular structures had been considered to be responsible for the insoluble and intractable materials formed during polymerisations.Error: Reference source not foundb These materials were largely ignored since it was invariably impossible to isolate discrete molecular compounds and assign them definite structures.

In 1978 Vögtle and co-workers published a synthetic strategy which involved the

“cascade-like” synthesis of acyclic, branched polyamines.5 The synthesis, which is illustrated in Scheme 1, began with an exhaustive Michael addition of the monoamine 1 to acrylonitrile, leading to the annexation of two branches per amino group, thus affording the bisnitrile 2.

The nitrile groups were then reduced to amine functions, using cobalt(II)/sodium borohydride to give the bisamine 3. Repetition of these two steps afforded the hexa-branched tetraamine 2 5, via the tetranitrile 4. Although this synthesis was not continued beyond this point because of problems encountered in the reduction step, the principle that repeated cycles of reactions could lead to controlled polymer growth had been demonstrated.

R R R N C N N C o ( I I I ) / N a B H 4 N H 2 A c O H M e O H

N C C N H 2 N N H 2 1 2 3 R R N N

C N C o ( I I I ) / N a B H 4 N N A c O H M e O H N N

N C N C C N C N H 2 N N H 2 H 2 N N H 2 4 5

Scheme 1. “Cascade-like” synthesis of acyclic, branched polyamines

In 1981, Denkewalter et al.6 patented the synthesis of highly branched polylysine derivatives.

Each member of this series of compounds was monodisperse, consisting of branching units of differing lengths. From 1985 onwards, two research groups, one headed by Tomalia7 and the other by Newkome,Error: Reference source not found,8 simultaneously developed families of dendrimers synthesised using this divergent method (see below). In 1990, Fréchet and

Hawker9 employed a different method, the convergent approach (see below), to prepare poly(aryl ether) dendrimers.

3 Dendritic Structure

Figure 1 depicts the structure of a typical dendrimer. The following points must be considered and, where appropriate, adapted when describing the structures of dendrimers:-

(i) There is a central point known as the initiator core: in the dendrimer shown in Figure

1, four branches emanate from a core and so the core multiplicity (Nc) is four.

(ii) Each branch contains further branching sites: in the example illustrated in Figure 1,

the degree of branching (Nb) is two.

(iii) Each new layer of branches that are constructed upon old branch points is called a

generation (G): generations are numbered at 0, 1, 2, 3 ... and so on.

(iv) The branch cell unit lengths (l) are determined by the choice of branched monomers.

l G = 1

Figure 1. Schematic representation of a dendrimer

4 The number of monomer units in a dendrimer increases exponentially as a function of the generation. As the dendrimer grows in size, the end groups reside closer and closer to one another. Eventually, this branch-growing process results in surface congestion, a feature that prevents further growth from all branch points with the consequence that the dendrimer can no longer be monodisperse. The highest generation at which the dendrimer is still potentially monodisperse is described as its “starburst limit”.

5 Dendrimer Synthesis

Dendrimers are constructed in stages using repetitive synthetic strategies. Both the divergent and convergent approaches to dendrimer synthesis have advantages and disadvantages.

The Divergent Approach

The synthetic approach to dendrimer formation, which has become known as the divergent method, emerged during the period 1978-1987 with many of the seminal contributions coming from Newkome Error: Reference source not found,Error: Reference source not found and Tomalia.Error:

Reference source not found The basic concept, which is that of starting at the core and working outwards in a divergent fashion to create a highly branched structure, has subsequently been developed and exploited by many research groups world-wide.10 An illustration of the divergent approach to the synthesis of a dendrimer is shown in Scheme 2.

4 x 8 x

C o r e F i r s t - g e n e r a t i o n S e c o n d - g e n e r a t i o n m o l e c u l e d e n d r i m e r m o l e c u l e

Scheme 2. Schematic representation of the divergent synthesis of dendrimers

6 A multifunctional core molecule – in this case, one with four functional groups – is reacted with four monomer molecules to give the first generation dendrimer. Repetitive addition of similar building blocks – usually achieved by a protection-deprotection procedure – affords successive generations. It is important to ensure that each set of reactions leading to these new generations has been completed before the next cycle of reactions is commenced, if defects in the dendritic structure are to be avoided.

Using the divergent approach, it is possible to prepare up to tenth generation dendrimers with molecular weights of the order of 700,000 and with more than 3,000 end groups per molecule.11 The advantage of the divergent method is that the production of several grams of dendrimer is easily attainable since, with each subsequent generation, the molar mass of the dendrimer is greatly increased.

This method is not without its drawbacks. As the dendrimer grows in size, the number of end groups involved in the reaction increases and the likelihood of incomplete growth steps leading to defects in the structure becomes greater. It is often difficult to detect the precise extent of conversion from one generation to the next. As a consequence, imperfect samples of dendrimers, which are virtually impossible to purify and characterise, since they may differ only slightly from the desired monodisperse samples, are obtained.

Therefore, if the divergent method is to be employed successfully, extremely efficient and high-yielding reactions are required in order to ensure the production of dendrimers with low polydispersities. This often poses a great synthetic challenge.

The Convergent Approach

Fréchet and Hawker first proposed an alternative approach to dendrimer syntheses, known as the convergent method.Error: Reference source not found,12 Here, the reverse of the divergent method is applied; the synthesis starts at what will eventually become the periphery 7 of the dendrimer and progresses inwards. Surface units are linked together increasingly with more monomers until a wedge-shaped molecule is generated, carrying a reactive group at its apex. The final step of the synthesis involves attaching the desired number of wedges to a multifunctional core. This approach is illustrated in Scheme 3.

The attraction of the convergent method lies in the fact that only a small number of molecules are involved in the reaction steps that form each successive generation. In contrast, increasing numbers of molecules are involved in the reactions in the later stages of a synthesis using the divergent approach. Large excesses of reagents and slight impurities can also be avoided, without sacrificing high yields and, because of easier purification, reactions no longer need to be as efficient, meaning that a much larger choice of reaction types are available.

T w o o f I

T w o o f I I R e p e a t T h r e e w e d g e s

n t i m e s + +

W e d g e D e n d r i m e r

Scheme 3. Schematic representation of the convergent synthesis of dendrimers

8 The main disadvantage of the convergent approach is that it is not accompanied, after each reaction cycle, by the marked increase in molar mass, which is observed in the case of the divergent method. The total number of steps involved in the construction of the dendrimer using the convergent method is not actually reduced compared with that needed in the divergent approach, yet significantly more starting material is required. Also the higher generation dendritic wedges can experience severe steric problems when reactions to attach their reactive apex groups to core molecules are attempted. Thus, the convergent approach has been found to be less useful than the divergent one for the synthesis of dendrimers approaching their starburst limit.

Metallodendrimers

During the last decade, those working with dendrimers have switched their focus from the initial synthetic directions explored mainly by organic chemists to a more applied emphasis.

Thus, metallodendrimers are becoming of interest from a materials science perspective because of their unique physical properties, leading to potential photophysical and catalytic applications. Metallodendrimers show substantial structural diversity and their properties and applications are wide-ranging. Metallodendrimers may be classified by where the metal appears in the dendrimer, at the centre, as connectors, as branching units, or as peripheral units of the dendrimer.13 However, here the metallodendrimers are classified by ligand type, i.e., the particular ligand which complexes the metal centre to/within the dendrimer – thus viewing them from the perspective of the inorganic chemist. In many of the following illustrations, only one section of the dendrimer has been portrayed and a “W” within a wedge-shaped motif represents other dendritic arms identical to the one which has been drawn out in full.

9 Dendrimers as Counter ions

Perhaps the simplest way in which to include metals in a dendritic structure is to use the dendrimer as a counterion for a well-defined metal or metal complex. The metal may bind to a surface site on the dendrimer (exo-receptor) or to a site within the internal cavaties of the dendrimer (endo-receptor).

Hydrolysis of ester-terminated PAMAM dendrimers with Group 1 metal (Na+, K+, Cs+ and Rb+) hydroxides resulted in the formation of salts as white hygroscopic powders.Error:

Reference source not foundd Direct observation of these single dendrimer molecules by

Channel Tunelling Electron Microscopy has been achieved. Further studies were conducted using carboxylate-terminated PAMAMs and their complexes with Fe3+, Gd3+, Mn2+, Pr3+ and

Y3+ ions.Error: Reference source not foundg

In another investigation,14 which sought to support the molecular mechanics simulations with experimental evidence, the properties of the carboxylate salts of the half- generation PAMAM dendrimers were likened to those of anionic micelles. The ability of these anionic dendrimers to effect the kinetics of the electron-transfer quenching of

2+ 15 photoexcited Ru(phen)3 has been examined. The emission decay of the metal-to-ligand

2+ charge transfer (MLCT) excited state of the probe – Ru(phen)3 bound to half-generation

3+ PAMAMs was analysed in the presence and absence of the quencher – Co(phen)3 . The studies showed that the probe lifetimes were enhanced when the complexes were bound to dendrimers as compared with unbound complexes. It was concluded that the quenching of

2+ 2+ dendrimer-bound Ru(phen)3 by Co(phen)3 occurs at the surface of the dendrimer. These

2+ results indicate that the cationic Ru(phen)3 binds strongly to the negative surface of the

2+ dendrimer. This has been confirmed by another study study of Ru(phen)3 labeled with a

16 nitroxide radical, via –NHC(O)OCH2- or –O(CH2)8O- units, as an EPR probe. More recently, similar results using protonated amino-terminated PAMAMs and Ru(4,7- 10 4- 17 (SO3C6H5)2-phen)3 as the probe have been reported. Hence, these systems provide examples of a dendrimer acting as an exo-receptor.

Phosphorus-Donor Metallodendrimers

Phosphorus-containing dendrimers, in which the core and subsequent branch points are pentavalent phosphorus atoms and which possess peripheral aldehyde groups have been prepared by Majoral et al.Error: Reference source not foundd The dendrimers – up to the tenth generation – were functionalised with phosphino groups and then reacted with

AuCl(tetrahydrothiophene) to give dendrimers with AuCl moieties as the peripheral units.18

The authors note that the reactivity of all generations towards gold complexation is similar, and therefore, independent of the size of dendrimer used. Most recently, Majoral et al.19 have reported the incorporation of gold into different generational layers of dendritic molecules.

Complexation occurs both at the sulfur-donor P=N-P=N-P=S fragments and the terminal

CH2PPh2 moieties. The dendritic fragment, shown in Figure 2, has been modified at the generation 1 level to introduce ligands, which are able to coordinate gold. The metallodendrimer has eighteen internal AuCl units – six at the P=N-P=N-P=S linkages and twelve at the phosphino groups. The complexes formed can be characterised unambiguously by 31P NMR spectroscopy. Studies are currently underway to extend this methodology to incorporate a variety of different metals within the cascade structure of dendrimers.

11 O A r M e P O A r N H N S C

S M e O W P W N O M e N H O A r H C C N N P P O A r N N M e S O O W P P C N N C P N P M e S N H H 2 O P O A r N N C N O A r C l - A u S P C M e H H N O O N O P O S H C M e N S C H H C N P O A r N N O A r P h P h N N M e A u - C l C l - A u P M e P P h P h

Figure 2. Gold complexation within the cascade structure of a dendrimer

Majoral et al.20 have also prepared diphosphino-terminated dendrimers complexed to rhodium, palladium, platinum and ruthenium. Addition of hydrazine to dendrimers – generations 1-3 – with terminal aldehyde groups produced CH=NNH2 end groups and subsequent reaction with Ph2PCH2OH (2 equivalents per NH2 group) led to the formation of the desired diphosphine ligands. Reaction of these ligands with RuH2(PPh3)4 gave the metallodendrimers shown in Scheme 4. The reactivity of these dendritic complexes was found to be very limited, compared with the reactivity of the monomeric starting material complex. However, the metallodendrimers reacted slowly with CO to give dihydrido carbonyl derivatives, where the CO ligand is located trans to one of the hydrides. In order to produce a more reactive ruthenium site, the diphosphino-terminated dendrimers were reacted with RuH2(H2)2(PCy3)2 to give the isomeric dihydride dihydrogen derivatives shown in

Scheme 4. The isomer produced is dependent on the reaction conditions employed, but all of the isomers reacted with CO to give one unique dihydrido carbonyl complex. Majoral et al.Error: Reference source not found are currently investigating the extent of the chemical 12 reactivity displayed by these complexes and their application as catalysts for ketone hydrogenation.

P P h 3 C O P P h P h P P P h P h 2 P P P h 3 2 R u H 2 ( P P h 3 ) 4 2 3 C O N N R u N R u P P h 2 P h 2 P H P h 2 P H n H n H n

R u H 2 ( H 2 ) 2 ( P C y 3 ) 2

H H H P C y 3 P h 2 P H P h 2 P P C y 3 P h P H N R u 2 N R u N R u P h 2 P P C y 3 P h 2 P H P h 2 P H H H H n n H H n C O C O C O C O P h 2 P P C y 3 N R u P h 2 P H H n

= D e n d r i m e r G = 1 , n = 6 ; G = 2 , n = 1 2 ; G = 3 , n = 2 4

Scheme 4. Reactivity of diphosphine-terminated dendrimers

Schmidbaur et al.21 have used “spacers”, e.g., -(diphenylphosphino)propionic acid, to functionalise third and fourth generation poly(propylene)imine dendrimers with terminal diphenylphosphino groups. Subsequent addition of (dimethyl sulfide)gold chloride gave the metallodendrimers as stable colourless solids (Scheme 5). Monomeric model compounds were also synthesised from methylamine and ethylenediamine in order to ascertain suitable coupling conditions for the synthesis of the dendritic N-alkylamides. Schmidbaur et al.Error:

Reference source not found envisage applications for these metallodendrimers in biochemical diagnostics and imaging and as antiflammatory and antitumour drugs.

13 O O H O O C - C 2 H 4 - P P h 2 M e 2 S A u C l H P P h 2 H P P h 2 A u C l N H 2 N C N C n n n E D C , N E t 3

= D e n d r i m e r G = 3 , n = 1 6 ; G = 4 , n = 3 2

Scheme 5. Synthesis of chlorogold(I)diphenylphosphino-terminated dendrimers

Second and third generation polypropylene(imine)22 dendrimers have also been surface functionalised by Reetz et al.23 In this case, a double phosphinomethylation – similar to that of Majoral et al.Error: Reference source not found described above – of each of the peripheral primary amine functions was achieved. A variety of palladium, iridium, nickel and rhodium complexes were reacted with the diphosphino-terminated dendrimers. The palladium-containing dendrimers were employed as catalysts in the Heck reaction. A significantly higher catalytic activity was observed for the dendritic catalysts compared with the activities of the monomeric analogues. The authors attributed this enhancement of activity to the thermal stability of the dendrimers which prevents the undesired formation of elemental palladium from occurring – a major problem for the monomeric complexes. By contrast, the rhodium-containing dendrimers display comparable catalytic activities in hydroformylations to that of the monomeric complex.

14 P H O O 2 O P ( O R ) P 2 L A H P ( O R ) 2 L A H P ( O R ) 2 P H 2 P H P h P 2 P h P H 2 P h P O P h P P H 2 P ( O R ) 2 P H 2 P

6 7 8 9 P H 2

N C M e P d R R 2 P R 2 P P R 2 2 P N C M e P R 2 P P d P P R 2 P R 2 [ P d ( M e C N ) 4 ] ( B F 4 ) 2 P P R 2 P P R 2 P P P h P P h P P d M e C N P P P P R 2 P R P 2 P P R 2 P d P N C M e P R 2 P R P P R R R 2 P 2 P d 2 2 N C M e 1 0 a , b 1 1 a , b R = P h , E t

Scheme 6. Synthesis of palladium-containing dendrimers

Palladium complexes of several small organophosphine dendrimers synthesised by

DuBois et al.Error: Reference source not foundc exhibit catalytic activity for the electrochemical reduction of CO2 to CO. The synthesis of one example of these metallodendrimers is shown in Scheme 6. Addition of diethyl vinylphosphonate to the primary phosphine 6 gave the phosphonate 7 and subsequent reduction with lithium aluminium hydride resulted in the phosphine 8. Repetition of these two steps afforded the phosphine 9 which undergoes reaction with vinyldiphenylphosphine or vinyldiethylphosphine to give dendrimers 10a and 10b, respectively. The reaction of 10a,b with [Pd(MeCN)4]

[BF4]2 formed the metallodendrimers 11a,b containing five square planar metal centres.

These dendritic acetonitrile complexes catalyse electrochemical CO2 reduction with rates and selectivities which are similar to analogous monomeric catalysts. 15 16 Nitrogen-Donor Metallodendrimers

The majority of the metallodendrimers described in the literature belong to this category, with many examples involving polypyridine-type ligands.

Balzani et al.24 have developed a synthetic procedure in which a complex is used as a ligand and another is used as a metal (“complexes as ligands/complexes as metals”) to prepare luminescent and redox-active metallodendrimers. Dendrimers that incorporate specific “pieces of information” in their building blocks, such as the abilities to absorb and emit visible light and to undergo reversible multielectron redox processes, have potential applications in molecular electronics and photochemical molecular devices.

Both the divergent and convergent approaches to the synthesis of nitrogen-containing metallodendrimers have been employed and are illustrated in Scheme 7. Using the divergent

2+ method, the first step is the construction of the core, [Ru(2,3-dpp)3] (12), which has three chelate sites available and is, therefore, a “complex as ligand.” The building block, [Ru(2,3-

2+ Medpp)2Cl2] (13) has two labile chlorides – therefore representing a “complex as metal” – and two bridging ligands, which have been protected to prevent further metal coordination.

The reaction of 12 with 13 gives the first generation metallodendrimer 14 and deprotection of the six peripheral chelating sites yields compound 15. The second generation dendrimer 17, which has ten ruthenium centres, is formed by the reaction of 15 with the capping unit,

[Ru(bpy)2Cl2] 16. In the convergent approach, the dendritic wedge 18 – “complex as metal” is reacted with the core compound 12 to give the metallodendrimer 17.

17 18 19 + 4 + N N 2 0 N N N R u N R u N N N N N N C l N N N N N N N C l R u N R u R u R u N N N N N N N N N N N N N N + N N 2 N N N N N N N R u N N R u N N R u N N N N N N N N N N R u N N N N N N N N N N N R u R u R u 1 8 N N N N N N N N N N N N N N 1 2 N N N R u N N N 1 7 + M e 2 N N N N N M e N N R u N N N C l C l N R u N C l C l 1 3 1 6

M e 1 4 + + N N N N 8 N N N N N N M e N N R u N N R u N M e N N N N N N N N N N N N N D e p r o t e c t i o n N N N N R u R u N R u N N R u N N N N N N N N N N N N N N N N N N N N N M e R u N N R u N N M e N N N N N N N N N N M e 1 4 1 5 N N

Scheme 7. Convergent and divergent synthesis of the Balzani dendrimers

The absorption spectrum and redox patterns of the dendrimer resemble the sum of those of its mononuclear component units and each of these units brings its own redox properties

20 into the macromolecular structure. By varying the metals and/or ligands of the building blocks employed, it is possible to design dendrimers with predetermined redox patterns.

Thus, synthetic control of the number of electrons exchanged at a certain given potential is achieved and their application as multielectron-transfer catalysts is of potential interest.

Constable and co-workers25 have prepared a variety of metallodendrimers employing terpyridine-based ligands using both divergent and convergent methodologies. Their latest development, using convergent assembly, is shown in Scheme 8. A ruthenium complex 19 is reacted with an electrophile – bis(bromomethyl)benzene – to give complex 20 possessing an electrophilic site remote from the metal centre. Reaction with a nucleophile – 4,4- dihydroxy-2,2-bipyridine – yields the binuclear dendritic wedge 21 which has a bipyridine ligand at its focal point. Thus, rapid coordination with either iron(II) or cobalt(II) leads to the formation of the heptanuclear metallodendrimer 22.

Vögtle and Balzani26 have employed a similar strategy to that described above in the synthesis of ruthenium complexes of dendritic bipyridine ligands. The ligands have been prepared by the attachment of branches at the 4 and 4 positions of bipyridine using a procedure reported by Newkome et al.Error: Reference source not found The dendritic bipyridines – generations 1-3 – were reacted with Ru(III) chloride to produce a metallodendrimer where the metal is only present in the core. These complexes exhibit similar absorption and emission properties to those of an unsubstituted Ru(II) bipyridine complex. However, a longer excited-state lifetime was observed for the higher generation dendrimers because of the shielding effect of the dendritic branches on the metal core, which limits the quenching effect of molecular oxygen.

21 N N N R u N N N B r O H O N O N N N N N N N N B r O H R u R u N N N N N N N O

O O H O N N N R u N N 1 9 2 0 2 1 N B r

N N N R u N N N

O N N N N N N R u R u N N N N N N O O O

O O N N N M N N N O O

O O O N N N N N N R u R u N N N N N O N M = F e , C o N N N R u N N 2 2 N

Scheme 8. Convergent synthesis of a Constable dendrimer

Recently, more attention has been focused on the ability to incorporate predetermined subunits into the dendritic structure, thus possessing the synthetic control necessary to create 22 series of “dendritic assemblies.” With this aim in view, Newkome et al.27 investigated the connection of two different sized dendritic fragments to a ruthenium centre, thus forming a bis-dendrimer. A recent publication by Newkome et al.28 describes the connection of two different dendritic fragments to two separate dendritic core molecules to give the snowflake- like metallodendrimers shown in Figure 3. This shift in focus from the synthesis of traditional dendrimers, where the repeat/branching units are identical, to the preparation of macromolecular dendritic assemblies is becoming more apparent in recent research.

Chemists are interested in tailor-made dendritic molecules that allow a greater control of the properties exhibited by the macromolecular array.

A convergent synthesis of organoplatinum dendrimers developed by Puddephatt et al.29 is illustrated in Scheme 9. An oxidative addition reaction of the bromomethyl groups on bipyridine 24 to two square planar dimethylplatinum centres on 23 gave the dendritic unit 25.

The diimine group at the centre of the molecule was then complexed to a different dimethylplatinum centre 26 to yield the trinuclear complex 27. These two steps were repeated to give the dendritic wedge 28 and subsequent reaction with the core compound 29 –

1,2,4,5-tetrakis(bromomethyl)benzene – yielded metallodendrimer 30 containing 28 platinum centres.

Dendrimers that possess a metal porphyrin unit as the core have the potential to mimic the biological functions of haemoproteins and act as sterically hindered oxidation catalysts.

Dendrimers (generations 1-3) with a zinc-porphyrin core and Newkome-typeError: Reference source not found polyether amide branches synthesised by Diederich et al.30 can be viewed as encapsulated redox-active centres. The influence of the close-packed dendritic branches on the redox properties of the central zinc porphyrin unit was studied by cyclic voltametry. A decrease in the first reduction potential of the zinc-porphyrins with increasing dendrimer generation was observed. Thus, the dendritic fragments serve to shield the porphyrin centre 23 and hinder the addition of electrons to it. More recently, Diederich et al.31 have modified the peripheral groups on the dendrimer to prepare water-soluble dendritic iron-porphyrins and similar electrochemical behaviour was observed.

Fréchet et al.32 have also investigated the effects of the dendrimer generation on the properties of a porphyrin core. They discovered that although higher generation dendrimers can bury the core site and hinder electron-transfer to it, small molecules such as benzylviologen are able to penetrate the dendritic shell. Photophysical studies revealed that the dendritic shell does not interfere with the ability of benzylviologen to quench the fluorescence of the metalloporphyrin. This result suggests that dendrimers with metalloporphyrin cores could be employed as catalysts. Modification at the periphery of the dendrimer, or incorporation of rate enhancing ligands into the dendritic structure, would allow their fine-tuning for specific catalytic applications.

These, apparently contradictory, results can be explained by the methods used to study the electron transfer (cyclic voltametry) and excited state quenching (fluorescence spectroscopy). The former is an interfacial experiment where the metal centre is required to come into close contact with a large solid electrode. The dendritic structure around the metal porphyrin prevents this close contact and hence inhibits electron transfer. The latter is a solution experiment where the flexibility of the dendritic arms allows the probe molecule to approach the metal centre.

Suslick et al.33 have studied the role of dendritic porphyrins as regioselective catalysts in the epoxidation of olefins. The metallodendrimer shown in Figure 4 and its first generation equivalent were prepared using a convergent synthesis. The peripheral tert-butyl groups served to increase steric hinderance and enhance solubility. Epoxidation of nonconjugated dienes and mixtures of linear and cyclo-alkenes were carried out using iodosylbenzene as the oxygen donor. Using 1:1 alkene mixtures, the dendrimer- 24 metalloporphyrins showed greater selectivity for epoxidation of 1-alkenes over cyclooctene.

This selectivity was higher for the second generation metallodendrimer than for the first generation one. The reason for this increase in selectivity shown by the dendritic catalyst was attributed to the steric influence of the bulky second generation dendrimer which led to preferential penetration of the linear alkenes.

The synthesis and properties of dendrimer porphyrins have also been reported by Aida et al.34 Most recently, they have used negatively and positively charged dendrimer- metalloporphyrins to construct electrostatic assemblies.35 Studies on these systems showed that the spatial arrangement of these two communicating functionalities could be controlled with nanometric precision. Thus, their potential application in nanomaterials science can be anticipated.

O O O O O O O O O O O O O O

O O O O O O O O O O

O O N N O O W M n C l W N N

25 Figure 4. A dendrimer-metalloporphyrin

Porphyrin-functionalised dendrimers have also been investigated for their potential biological/therapeutic uses. The use of antibodies, modified with radioisotopes or cytotoxic drugs in cancer imaging and therapy, is of great interest on account of the inherent specificity of the antibody-antigen interaction. However, these modifications often diminish or eliminate the biological activity of the macromolecule, therefore destroying its targeting potential. In order to prevent these problems, intermediate linker molecules, which can be highly modified with a drug, but which will only modify a single site on the surface of the antibody, would be of great advantage. Roberts et al.36 have used PAMAM dendrimers to covalently couple synthetic copper-chelated porphyrins to antibody molecules. The antibody-dendrimer-porphyrin conjugate is illustrated in Figure 5.

Gansow et al.37 have attached the nitrogen-donor macrocycle 1,4,7,10- tetraazacyclododecanetetraacetic acid to PAMAM dendrimers and then formed antibody conjugates. The chelator-dendrimer-antibody constructs were easily labeled with 90Y, 111In and 212Bi, suggesting that these types of complexes could be used in radiotherapy and imaging. In a more detailed study, dendritic magnetic resonance imaging contrast agents, consisting of Gd(III) complexes of the chelator 2-(4-isothiocyanatobenzyl)-6-methyl- diethylenetriaminepentaacetic acid anchored to amino-terminated PAMAMs, were developed by Tomalia et al.38 These complexes enhanced magnetic resonance images and were found to be more effective contrast agents than other commercially available macromolecule-chelate complexes, such as those formed using albumin, polylysine and dextran.

26 A n t i b o d y

C H 2 D e n d r i m e r N H N H 2

N O 2 H 2 N N H 2

H N 2 H N O C H 2 – C S O 3

N H N N P o r p h y r i n H N

– – O 3 S S O 3

Figure 5. Representation of an antibody-dendrimer-porphyrin conjugate

Nickel-containing dendritic catalysts have been designed and tested for their catalytic activity in the Kharasch addition by van Koten et al.39 The catalysts – a second generation example of which is shown in Figure 6 – are carbosilane dendrimers, which have been surface-functionalised with nickel complexes. Although the catalytic activities of the dendrimers were found to be lower than that of the monomeric analogue, the catalysts could be easily precipitated from solution and therefore recycled. More recently, van Koten et al.40 have reported the preparation of platinum-containing dendrimers which possess the same surface functionalities as those of the dendrimer shown in Figure 6, yet contain aryl-ester branching units instead of carbosilane backbones. The complexes reversibly bind SO2 both in the solid state and in solution and can therefore be used as molecular sensors for this toxic

27 gas. Desorption of SO2 is achieved using mild conditions, thus regenerating the “detector” compounds.

M e 2 N B r N i

N M e 2 O N H O

M e O S i M e O N M e 2 M e O S i S i S i O N N i B r M e H M e N M e 2 S i O M e O O H N N M e 2

N i B r N M e 2

Figure 6. Second generation silane dendrimer functionalised with nickel complexes

Chow and Mak41 have prepared dendritic bis(oxazoline) copper complexes (generations 0-3) which catalyse the Diels-Alder reaction. The catalytic centre is at the focal point of a dendritic wedge constructed of Fréchet-typeError: Reference source not found polyaryl ether dendrons. The catalysis of the Diels-Alder reaction between cyclopentadiene and crotonyl imide (Scheme 10) was studied. Lower rates of reaction were observed using generation 3 dendrimer catalysts than when generations 0-2 were used. This observation is thought to be a consequence of the morphological change shown by the dendrimer as the generation increases. The catalytic core is essentially open to the surroundings at lower generations but

28 is partially buried in the interior of the dendritic branches at generation 3. These and other studies discussed above indicate that a variety of types of dendritic catalyst can be synthesised but further work on the dendritic structure is needed before superior catalysts can be prepared.

O O N N O O C u O ( O T f ) 2 N O N O O

Scheme 10. Diels-Alder reaction catalysed by bis(oxazoline)copper(II) dendrimers

Organometallic Dendrimers

42 + Astruc et al. reported the synthesis of ferrocenyl star polymers using the Fe(-C5H5) induced perfuctionalisation of polymethylaromatics. Very recently,43 they have reacted amino-terminated dendrimers with ferrocenylcarbonylchlorides to give amidoferrocenes such as the example illustrated in Figure 7. A dendritic effect in molecular recognition has been demonstrated using these metallodendrimers. The binding of several inorganic anions to the ferrocenyl units was investigated by examining the shift in the position of the cyclic voltammetric wave. The apparent association constants were found to increase in the order

- - - - NO3 < Cl < HSO4 < H2PO4 . In addition, the magnitude of the interaction of higher generation dendrimers with the anions was greater than that of the lower generation analogues.

29 F e

C O N H F e O C N N H

C O O N H F e

C O O N N H F e

F e N N H O C

H N F e C O

Figure 7. An amidoferrocene dendrimer

Organosilicon dendrimers with ferrocenyl peripheral units have been prepared by Cuadrado et al.44 and their electrochemical properties studied. Cyclic voltammograms of the first and second generation dendrimers show a unique wave corresponding to the oxidation of all of the redox centres. Therefore, the ferrocenyl moieties are electrochemically equivalent non- interacting redox centres. Cuadrado et al.45 have also surface-functionalised poly(propylene imine) dendrimers with ferrocenyl units. In order to prepare inclusion complexes where the dendritic terminal groups act as the guests, the binding of cyclodextrin – a well known molecular host – to the ferrocene moieties in these dendrimers was studied. The authors discovered that although the aqueous solubility of the dendrimers was enhanced by the 30 presence of cyclodextrin, it decreased with increasing dendrimer generation. In addition to this, they also observed two different voltammetric waves for the highest generation dendrimer, indicating that complexed and uncomplexed ferrocene units were present and thus, complete complexation of all surface moieties was not possible. Both these observations were attributed to the steric congestion present at the surface of the larger dendrimer, which limits the number of ferrocene residues that can be included by the bulky cyclodextrin hosts.

Pugin et al.46 have attached chiral diphosphine ferrocenyl complexes to dendritic ligands in order to examine their catalytic activity in hydrogenation reactions. The rhodium- catalysed asymmetric hydrogenation of dimethyl itaconate was studied using different sizes of dendritic complexes. The enantioselectivities shown by the dendritic catalysts were found to be slightly lower than that of the corresponding mononuclear catalyst. Pugin et al.Error:

Reference source not found are currently investigating the use of larger dendrimers in other catalytic reactions in order to ascertain the influence of the dendrimer backbone on the selectivities of reactions.

31 O O O O O O

O N H O O O O O O N N H H F e O O N H O O

O O O O O

Figure 8. Asymmetric redox-active dendrimer with ferrocene subunit

Another recent report by Kaifer et al.47 describes the synthesis of asymmetric redox- active dendrimers. A single ferrocene unit is appended to a dendritic branch of variable size to form compounds such as the one illustrated in Figure 8. The electrochemical behaviour of these dendrimers is similar to that described by Diederich and co-workersError: Reference source not found for their porphyrin-based systems. Again, the redox-active centre is partially shielded by the higher generation dendritic branches, thus hindering electron transfer to the ferrocene unit.

C N O N H

O O O O P h S S P h P h S S P h P d P d P d P d C l C l C l C l S S S S P h P h A g B F 4 P h P h 3 1 3 2

O O P h S S P h P h P h P d P d S S N C l N P d C l S S N H P d O P h P h S P h O O P h S O N H

P h S P d S P h P h S P d S P h C l C l 3 3

Scheme 11. Convergent synthesis of palladium-containing dendritic wedge

Reinhoudt et al.48, 49 have utilised palladium-containing building blocks to construct metallodendrimers using both convergent and divergent approaches. Dendritic growth was achieved by the substitution of an N-donor ligand for a chloride in a two-step process.

Scheme 11 shows the convergent synthesis of a second generation dendritic wedge. Firstly, the palladium complex 31 was activated by removing the chloride ion using Ag[BF4].

Subsequent addition of two equivalents of pyridine-based building block 32 gave a second generation dendritic wedge 33 with a cyano group at its focal point. Repetition of these two steps afforded a third generation wedge. In the final stage of the synthesis, the dendritic wedges were coupled to a trifunctional palladium-containing core molecule. In one report, 33 the dendrimers were synthesised using a combination of both coordinative and hydrogen bonds.50

Another type of organopalladium dendrimer has been prepared by van Koten et al.51 via the insertion of palladium into peripheral carbon-iodine bonds of carbosilane dendrimers.

The organopalladium moieties were attached to the periphery of the dendrimer exclusively via palladium-carbon bonds. Reactions of these complexes with transmetalation reagents

LiMe and SnMe4 were attempted but were unsuccessful.

B u 3 P P t P B u 3

P B u 3 P h P t P h P B u 3

P B u 3 B u 3 P P t P t P B u 3 B u 3 P

P B u 3 P t

P B u 3

B u 3 P P B u 3 P t P t P B u 3 B u 3 P

P B u 3 P h P h P t

P B u 3

P B u 3 P t B u 3 P

Figure 9. Organoplatinum dendrimer

Stang et al.52 and Takahashi et al.53 have also employed metal-carbon bonds to construct their organoplatinum dendrimers. In these examples, the metals are present in every generational layer of the dendrimer. Stang et al.Error: Reference source not found used 34 a stepwise divergent approach to synthesise first and second generation metallodendrimers with a backbone of -bonded tri- and tetra-ethynylbenzene units. A similar strategy devised by Takahashi et al.Error: Reference source not found used triethynyl-trimethylbenzene as a building block to form metallodendrimers such as the one illustrated in Figure 9.

A final example of the use of metal-carbon -bonds in the construction of organotransition metal dendrimer synthesis has been reported by Liao and Moss.54 They have prepared dendrimers with the functional group (CpM(CO)2CH2CH2CH2-) – where M = Fe,

Ru – located exclusively at the periphery. Using the convergent approach, the metal complexes were attached to a Fréchet-typeError: Reference source not found poly(aryl ether) dendritic wedge. The largest dendrimer synthesised – generation 4 – contained 48 ruthenium atoms and has an estimated diameter of about 5 nm.

Sulfur-Donor Dendrimers

Majoral et al.Error: Reference source not found have prepared gold chloride containing dendrimers with the gold atom coordinated to sulfur in the internal cavaties of the dendrimer and to phosphorus at the surface (see Figure 2). The palladacycle dendrimers of Reinhouldt et. al.Error: Reference source not found,Error: Reference source not found,Error: Reference source not found also use sulfur donors in S-C-S double pincer ligands.

Welton et al. have prepared PAMAM dendrimers with a terminal secondary amine rather than the normal primary amine.55 They have then used these to prepare sodium dithiocarbamate dendrimers that they then coordinated to a variety of ruthenium complexes

(Scheme 12).

35 Conclusions

These aesthetically pleasing macromolecules known as dendrimers are attracting an increasingly large amount of attention from chemists and biochemists in all research areas.

Over 600 papers in this field were published during 1998 alone. Metallodendrimers are beginning to show real promise in catalysis, with catalytic activities per metal centre being equivalent to those of monomeric analogues. The possibility of using dendrimers to prevent catalyst losses from reaction mixtures could soon lead to commercialisation of these materials.

Future progress will undoubtedly include the formation of tailor-made dendritic assemblies where predetermined properties can be introduced into specific sites in the dendritic structure. The synthetic control and fine-tuning of the dendrimer needed to produce molecules with specific properties should lead to the proposed applications of these molecules becoming a reality.

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