54
1 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS Charles N. Moorefield, Sujith Perera, and George R. Newkome “There are many beautiful molecular architectures, it is just that some are easier to access than others.” Roald Hoffman, Nobel Prize in Chemistry, 1981 1.1. INTRODUCTION 1.1.1. Historical Background Dendritic chemistry, from its initial development to its application in the construction of utilitarian devices and materials, has provided a great amount of proverbial cement for interdisciplinary integration. Similar to polymer (or macromolecular) chemistry, conceptualized and postulated by luminaries such as Flory [1–3] (Nobel—1974) and Staudinger (Nobel—1953) who provided a new foundation for material sciences, dendrimer chemistry has generated another new level of scaffolding upon which a myriad of potential uses are being explored and exploited. First introduced as “cascade” molecules due to their repeating motif by Vogtle and coworkers [4] in 1978, materials analogously termed arborols (derived from the Latin word arbor for tree) and dendrimers (derived from the Greek word dendro for tree) were reported by Newkome et al. [5] and Tomalia et al. [6] both in 1985, respectively. While these reports specifically addressed the potential to craft branching molecular architectures with multiple terminal functionality and repetitive branch junctures Dendrimer-Based Drug Delivery Systems: From Theory to Practice, First Edition. Edited by Yiyun Cheng. Ó 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc. 1 COPYRIGHTED MATERIAL

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Page 1: DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES …€¦ · 1 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS CharlesN.Moorefield,SujithPerera,andGeorgeR.Newkome

1DENDRIMER CHEMISTRY:SUPRAMOLECULAR PERSPECTIVESAND APPLICATIONS

Charles N.Moorefield, Sujith Perera, and George R. Newkome

“There aremany beautifulmolecular architectures, it is just that some are easier to access

than others.”

Roald Hoffman, Nobel Prize in Chemistry, 1981

1.1. INTRODUCTION

1.1.1. Historical Background

Dendritic chemistry, from its initial development to its application in the construction

of utilitarian devices andmaterials, has provided a great amount of proverbial cement

for interdisciplinary integration. Similar to polymer (or macromolecular) chemistry,

conceptualized and postulated by luminaries such as Flory [1–3] (Nobel—1974) and

Staudinger (Nobel—1953) who provided a new foundation for material sciences,

dendrimer chemistry has generated another new level of scaffolding upon which a

myriad of potential uses are being explored and exploited.

First introduced as “cascade”molecules due to their repeatingmotif by V€ogtle andcoworkers [4] in 1978, materials analogously termed arborols (derived from the Latin

word arbor for tree) and dendrimers (derived from the Greek word dendro for tree)

were reported by Newkome et al. [5] and Tomalia et al. [6] both in 1985, respectively.

While these reports specifically addressed the potential to craft branching molecular

architectures with multiple terminal functionality and repetitive branch junctures

Dendrimer-BasedDrugDelivery Systems: FromTheory to Practice, First Edition. Edited byYiyun Cheng.� 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

1

COPYRIG

HTED M

ATERIAL

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(Tomaila, 1 ! 2 branching based on linear building blocks; Newkome, 1 ! 3

branching based onmodular building blocks with preconstructed branching centers)

another notable report appeared by Aharoni and coworkers [7] in 1982 describing the

“Size and Solution Properties of Globular tert-Butoxycarbonyl-poly(a,e-L-lysine).”Their study involved the characterization of 1 ! 2, asymmetrically branched

materials that were termed “nondraining globular biopolymers” that were iteratively

prepared and reported in 1981 (U.S. patent 4289872, Denkewalter et al. [8]). Other

notable and interesting reports prior to the explosive advent of dendritic chemistry,

include the iterative synthesis of ultralong, linear paraffins reported by Bidd and

Whiting [9], the early observation by Ingold and Nickolls [10] of the entrapment of

gas molecules by methanetetraacetic acid, and Lehn’s elegant modular approach [11]

to cryptate syntheses.

1.1.2. Architectural Concepts

Dendritic molecules can be envisioned by considering the repetitive layering of

multifunctional building blocks based on a protection and deprotection scheme or the

addition of increasing numbers of linear, complementary monomers. This generally

results in a branched, tree- or fractal-like, molecular motif whereby each incorporated

layer provides a foundation for the successive layer. Since the number of reactive sites

and branching centers increases with each layer, a “mushrooming” framework is

produced. The synthetic protocol can be visualized (Scheme 1.1) by considering

the attachment of a generic 1 ! 3 branched building block 1 that possesses three

reactive sites differentiated from the 4th. Thus, treatment of monomer 1 with three

equivalents of a like monomer produces a new monomer 2 with the same functional

SCHEME 1.1 Divergent and convergent routes to branched architecture.

2 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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group characteristics as the starting materials, except that the periphery has now

grown and expanded to a 1 ! 9 branched construct.

The iterative dendritic strategy has developed into two general modes of con-

struction. The divergent route, initially introduced by V€ogtle et al. [4], whereby

molecular growth essentially proceeds from the “inside outward” and the convergent

route, introduced in 1990 by Frechet et al. [12], resulting in growth from the “outside

inward.” Differences in the two methods arise from building block order of addition

and can be affected by the control over functional group activation and deactivation.

Thus, logical choices of protection–deprotection strategies derived from classical

synthetic chemistry are a prime importance in dendritic chemistry. Addition of nine

equivalents of a triprotected monomer 1 to the surface of a growing specie 2will lead

to the progressively greater branched construct 3. The same material (i.e., 3) can be

derived convergently by inverting the process to add three equivalents of the 1 ! 9

higher–order, branched monomer to the simple monomer. Both methods allow the

construction of dendritic material and also have their individual strengths and

weaknesses. For example, divergent syntheses requires an ever increasing number

of monomer attachment reactions leading to a higher probability of incomplete

reactions at the ever-expanding periphery leading to a greater number of imperfec-

tions; whereas, convergent methods instill a greater probability to generate perfect

structures due to few required reactions for layer construction, albeit at lower

molecular weights. The potential to locate and connect at a single site within a

growing multifunctional monomer diminishes with size and the attendant steric

hindrance. Predicated on these features and a comprehensive mass spectrometry

analysis, divergent and convergent methods have been compared to polymer and

organic syntheses, respectively, by Meijer et al. [13].

As with most other unique areas that attract much attention, descriptive termi-

nology has been developed within the dendritic chemistry community.While much is

intuitive, a brief discussion is warranted. The central point from which all branching

emanates is described as a core; whereas, the outer surface, or peripheral region, is

populated with terminal groups (4; Fig. 1.1). Branching centers define the branching

multiplicity based on the number of functional groups or reactive sites that they

possess (i.e., 2, 3, or greater) and layers are often referred to as generations to easily

denote the number of iterations used in construction. Notably, dendritic void volume

is a valuable and useful property and has been employed by many research groups for

purposes such as micellar entrapment, host–guest interactions, and catalytic site

construction, to mention but a few. This feature has given rise to a new area of study

upon which this book is largely based—drug delivery and pharmacological agents

using dendritic species.

Branched monomers, or building blocks, used in dendritic construction are now

commonly referred to as dendrons, in analogy to synthons in classical organic

chemistry. Many dendrimers have been reported [14] using nonbranched monomers;

however, their monomers are usually not described as dendrons owing to their linear

characteristic. Arising from the convergent protocol, the single reactive site on a

multifunctional dendron is described as the focal site. The individual layers of

building blocks that comprise dendritic structures are generally denoted as

INTRODUCTION 3

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generations, which in turn allow for easy descriptive terminology and a ready

understanding of the potential number of surface moieties provided the multiplicity

of the core and dendron(s) are known. The concept of dense packing arises from the

consideration of increasing numbers of surface groups and a proportionately decreas-

ing amount of available surface area; hence, at some level of construction there will

not be enough surface area to accommodate a stoichiometric number of building

blocks. This aspect may ormay not be problematic andwill depend on the desired end

characteristics of the material(s) in question.

Ultimately, consideration of dendritic generation leads to the question – struc-

turally, what constitutes a dendrimer? Numerous reports in the literature describe

new dendritic species comprising only a single generation. In many cases, a zeroth-

generation construct is reported. The importance, elegance, and usefulness of these

materials notwithstanding, they are not dendrimers in an historical or idealized sense.

They do not possess repeating architectural details at different generations. Therefore,

we will herein only describe those materials possessing the attributes of greater than

two generations as belonging to a dendrimer family and they must be structurally

characterized.

1.1.3. Initial Reduction to Practice

In 1978, a branched covalent molecular architecture was initially reported

(Scheme 1.2) by V€ogtle et al. [4]. Their scheme represented the first report of a

repetitively branched, polyfunctional molecule whereby all to the intermediates were

isolated, purified, and substantially characterized in contrast to the traditional

synthesis of a polymer whereby only the starting materials and products are isolated

and verified. The synthetic protocol utilized Michael-type, nucleophilic amine

FIGURE 1.1 2D and 3D representations of dendritic components.

4 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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addition to an electron-poor cyanoalkene followed by reduction of the cyano groups to

generate new amine moieties used for further reaction. Thus, for example, amine 5

was treated with acrylonitrile in the presence of glacial acetic acid to give bis-nitrile 6

that was then reducedwithNaBH4 andCoCl2�6H2O to afford diamine 7. Repetition of

the sequence generated polynitrile 8 and subsequently polyamine 9 possessing 3

tertiary and 4 primary amino moieties. The procedure was also undertaken with

diamines such as 2,6-diaminomethylpyridine and diaminoethane to give the corre-

sponding 16 amine constructs.

The authors described these new materials as cascade- or nonskid-chain-like

owing to the repeating pathway for bond formation and they devised the scheme for

the construction of large molecular cavities capable of host–guest interactions. This

general procedure was also applied to diaza-monocyclic rings for the construction of

polycyclic medium- and large-ring materials.

Approximately 1 year later, in 1979, Denkewalter et al. [8] reported in a patent

the construction of high molecular weight materials based on step-wise coupling

(Scheme 1.3). This was the first example of dendritic materials construction using a

protection–deprotection strategy and a preformed 1 ! 2 C-branching center inherent

in the building block. Their scheme employed the 4-nitrophenol-activated ester of N,

N-bis(tert-butoxycarbonyl)-L-lysine (11), a chiral-protectedaminoacid, as thedendron.

Treatment of an initial diamine 10 with the BOC-protected diamino-activated ester

11followedbyremovaloftheBOCgroups(CF3CO2H)affordedthetetraaminetrisamide

12. Repetition of the sequence generated the octaamine 13 and eventually led to

dendrimers with theoretically 512 terminal lysine groups corresponding to nine

generations. With no characterization reported in the patent, Aharoni et al. [7] sub-

sequently aided in the characterization of these impressive materials by examining the

viscosity, photo correlation spectroscopy (PCS), and size exclusion chromatography

(SEC). Itwas concluded that eachgenerationwasmonodisperse and that thesematerials

behaved as nondraining spheres.

NHR 2

CN

NR

CN

CN

NR

NH2

NH2

NaBH4Co(II)

NR

N

NH2

NH2

N

NH2

NH2

NaBH4Co(II)

CN

NR

N

CN

CN

NCN

CN

765

98

SCHEME 1.2 V€ogtle’s original cascade preparation of a 1 ! 2 N-branched polyamine.

INTRODUCTION 5

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During 1985, Newkome and coworkers [5] published the first example of a 1 ! 3

C-branched dendrimer, then termed an arborol for its likeness to tree architecture

(specifically, the Leeuwenberg model [15] that branched 1 ! 3 in a similar manner to

that of tetrahedral, tetravalent carbon) and its terminal alcohol groups. In the sameyear,

Tomalia and coworkers [6] reported their work with 1 ! 2 N-branched materials,

which they described as starburst dendrimers (derived from the Greek root dendro- for

tree-like); these were the first series of polyamines to be prepared in high generation.

These twodendritic examples are the first fractal families thatwere fully characterized.

Newkome’s synthesis [5] (Scheme 1.4) began with a polyalcohol (14) that was

extended by reactionwith chloroacetic acid, under basic conditions, and subsequently

esterified to give triester 15. Reduction with LiAlH4 and treatment with tosyl chloride

afforded the activated triol 16 that was next reacted with the Naþ salt of methane-

tricarboxylic triethyl ester (17) to generate the nonaester 19 followed by amidation

with tris(hydroxymethyl)aminomethane (18); the resulting 27-alcohol 20 was iso-

lated as a white solid that was freely soluble in water. The requisite extension of the

alcohol moieties was necessary due to substitution of the bulky triester nucleophile,

which precluded repetition of the scheme, however, this was the first example of

dendrons possessing preconstructed 1 ! 3 branching centers.

Other arborols constructed using these building blocks included the bolaamphi-

phile, dumbbell-shaped [9]-(CH2)n-[9] and [6]-(CH2)n-[6] series [16,17], where [9]

or [6] denotes the number of hydroxyl groups connected by alkyl chains with n

HNO

H2NNH2 O

O

BocNNBoc

O2N Boc=

O

O

1)

2) CF3CO2HHN

O

NH

ONH2

NH2

HNO

H2N

NH2

OO

BocNNBoc

O2N

1)

2) CF3CO2HHN

O

NH

O

HNO

HN

ONH2

NH2

NH

O

NH2

NH2

NH

ONH2

NH2

HN

OH2N

H2N

10

11

12

13

SCHEME 1.3 Synthetic method for Denkewalter et al. polylysine dendrimers.

6 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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equal 8 to 12 carbons. These materials formed thermally reversible gels upon cooling

of aqueous and alcoholic solutions at low concentrations. Gel formation was

characterized by electron microscopy and predicated on maximizing lipophilic–

lipophilic and hydrophilic–hydrophilic interactions [28]. Arborols [18] constructed

with an aromatic benzene core also formed spherical aggregates in solution with

diameters of approximately 20 nm and have recently been shown to assemble into

large, hollow, spherical motifs [18]. Notably, the globular shape was postulated to be

reminiscent of a unimolecular micelle [5].

Tomalia’s protocol [6] was similar to that of V€ogtle’s [4] in that it relied on the

reaction of linear monomers and generated branching centers by the Michael-type

reaction of electron-poor alkeneswith a nucleophilic amine during the construction of

successive layers. Thus, in an early example (Scheme 1.5), three equivalents of

methyl acrylate (21) were reacted with ammonia to give the triester 22 followed by

generation of a new triamine core (24) by treatment with diaminoethane (23). Based

on the minimally sterically demanding building blocks, repetition of the sequence

to afford hexamine 25 and higher generations was smoothly facilitated. This initial

report described the second instance of an iterative synthesis accessing materials up

to seven generations.

These manuscripts provided the foundation for the burgeoning field that dendritic

chemistry is today, however, as it is with most scientific advances, chemistry before

and after has played a major role. Thus, advances in the field of macromolecular

sciencebypioneers such asFlory,who reported theoretical [1–3] andexperimental [19]

evidence for the existence of branched-chain, three-dimensional materials in 1941 and

1942, respectively, began to focus attention on the potential that macromolecules

n-C5H11

OH

OH

OH n-C5H11

O

O

O

CO2CH3

CO2CH3

CO2CH3

n-C5H11

O

O

O

OTs

OTs

OTs

n-C5H11

O

O

O

EtO2CCO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et

CO2EtEtO2C

n-C5H11

O

O

OH

OH OH

NH

HNHO

HOHO

HN

HO OHHO

HN

OH

OH

OH

NH

OH

OH

OH

HN

OH

OH

OH

O

O

O

O

O

O

O

HNHO

HOHO

HN

HO OHHO

HN

OH

OH

OH

O

O

O

1) ClCH2CO2H,Base

2) CH3OH,H+

2) TsCl,Pyridine

1) LiAlH4

CO2EtCO2Et

CO2EtNa H2N

OH

OH

OH

Base

161514

19 20

1817

SCHEME 1.4 Newkome’s preliminary 1 ! 3 C-branched dendritic scheme.

INTRODUCTION 7

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might eventually play in the chemical and materials science arenas. Stockmayer [20]

added to the interest by developing equations for branched-chain size distribution and

the extent of reaction where a “gel,” or network, should be formed. Flory [21] later

considered the formation of 1 ! 2 branched polymers and their scaling properties,

notably describing what has now become the well-known area of “hyperbranched”

dendrimers. Along with growing interest in macromolecules during the formative

years of polymer chemistry, scientists such as Staudinger [22] postulated thatmaterials

like rubber were really high molecular weight polymers and not aggregates of smaller

species. Studies by Carothers [23] on condensation polymerizations supported this

idea. Lehn [11] subsequently introduced step-wise strategies for the construction of

macrocyclic rings in 1973 and later received the Nobel Prize in Chemistry (1987) for

work on the host–guest chemistry of designedmolecular cavities [24] (e.g., cryptands).

Following these initial reports of V€ogtle [4], Newkome [5], Denkwalter [8],

and Tomalia [6], research into dendrimer properties and chemistry began to

accelerate. Balzani and coworkers [25] introduced metallodendrimers; Hawker

and Frechet [26] developed the convergent protocol; Masamune et al. [27] reported

the first preparation of silicon-based dendrimers; de Gennes (Nobel 1991) and

Hervet [28] described the first theoretical study of dendrimers; Seebach et al. [29]

delineated their work in the preparation of chiral dendrimers; Hudson and

Damha [30] described the construction of DNA-based dendrimers; Moore and

NH3

O

OCH3

N

CO2CH3

CO2CH3

H3CO2C

H2NNH2

N

HNO

NH2

NH

O

H2N

HN

O

NH2

HNO

NHO

NH2

N NH

ONH2

NH

O

NH

OH2N N

HN O

NH2

NHN

O

HN

O

NH2

N

NH

O

H2N

RepeatRepeat

21

22

23

24

25

SCHEME 1.5 Tomalia’s original dendrimer synthesis based on linear building blocks.

8 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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Xu [31] exploited phenylacetylene chemistry for dendrimer construction; Meijer

and de Brabander-van den Berg [32,33] along with W€orner and M€ulhaupt [34]reported, in back-to-back manuscripts, improved procedures for the large-scale

preparation of V€ogtle-type, polypropylenimine (PPI) dendrimers; Majoral and

coworkers [35] reported the first phosphorous-based dendrimers; Zimmerman

et al. [36] described the self-assembly of a complex dendrimer based on hydrogen-

bonding at the core; and Schl€uter et al. [37] reported their work on dendrimeriza-

tion of a classic polymer framework.

This abbreviated historical account, while not all-inclusive, is intended to give the

reader a flavor of the beginnings, or roots, of the current dendritic arena. There are

many scientist and researchers, who have contributed to the milestones of dendritic

chemistry, which not only strives for new synthetic methods for theoretical and

utilitarian applications, but also include an element of artistic style. It is the relative

simplicity of design and construction of these complex polyfunctional architectures

along with their ease of integration and synergy with other areas of chemistry that

affords dendritic chemistry its unique position among materials building blocks.

Numerous accounts of the history [38], theory [39], syntheses [40], and applica-

tions [38,41] of dendrimers exist in the literature and it is assumed the reader will

pursue their topic of choice; a selected survey is herein presented.

1.2. SUPRAMOLECULAR PERSPECTIVES

1.2.1. Unimolecular Micelles—The Advent of the Container

Early reports heralding the potential of dendritic architecture include Newkome and

coworkers [42,43] construction of the first example of a unimolecularmicelle (defined

in the seminal 1985 report [18]) possessing an all saturated hydrocarbon infrastructure

and charged carboxylate surface groups. The unimolecular micelle concept (28) is

illustrated in (Fig. 1.2) along with representations of a classical micelle (26)

comprising a collection of associated long chain hydrocarbons with polar head

groups that are bound together by noncovalent van der Waals- and ionic-based forces

and a surface-networked,micellar aggregate 27 accessed from a classicalmicellewith

polymerizable head groups. Surfactant-based, micellar aggregates have been known

and used in numerous applications formany years, however, structural dependence on

temperature, surfactant concentration, ionic strength, and hydrophilic–hydrophobic

environment adds several “degrees-of-freedom” to their utilitarian considerations.

Thus, dendrimer chemistry has provided a means to eliminate or control these

aggregate phenomena.

Synthesis of the unimolecular micelle [42] was facilitated by the crafting of 1 ! 3

C-branched dendrons (Scheme 1.6) possessing functional groups sufficiently

removed (3 CH2 moieties) from the quaternary branching center to allow for smooth

end group transformation [44]. Beginning with the Michael-type addition of acry-

lonitrile to nitromethane to generate a nitrotrinitrile, followed by hydrolysis of the

nitrile groups to carboxylic acids and subsequent reduction to the corresponding

SUPRAMOLECULAR PERSPECTIVES 9

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FIGURE 1.2 Idealized representations of a micelle, a polymerized aggregate, and a unim-

olecular micelle.

Acrylonitrile,NH + HSO ¯NH4

+ HSO4 ,

H2O, dioxane,KOH

HCl BH3⋅ THF

BzClAcrylonitrile,AIBN,

O2NCH3

29

n-Bu4SnH

1) KOH2) BH3⋅ THF

3) SOCl2

30 314) Li Acetylide

HBr,H2SO4

32

O2N

O2N O2N

O2N

CO2H

CO2H

CO2H

CN

CN

CN

OBz

OBzOBz

HOBz

OBzOBz

OBz

OBzOBz

OBz Br

Br

Br

BrOBz

OBz

OH

OH

OH

NC

HO

SCHEME 1.6 Synthesis of 1 ! 3 C-branched, hydrocarbon-based dendrons.

10 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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alcohols, the nitrotriol 29was obtained. Relying on electron-transfer and free-radical

chemistry developed by Newkome et al. [45], Ono et al. [46], and Geise et al. [47], a

novel route to the synthesis of quaternary carbon centers was developed. This new

method allowed the preparation of dendrons with differentiated functionality in

contrast to a 17 step synthesis reported by Rice et al. [48] leading to a similar

framework with identical termini (i.e., tetrabromide 32).

Thus, benzyl protection of the alcohol groups in triol 29 allowed radical initiated

substitution of the nitro group with acrylonitrile (AIBN, toluene, n-Bu4SnH) to give

the mononitrile trisbenzyl ether 30. Reaction with (1) KOH, (2) BH3-THF, (3) SOCl2,

and lithium acetylide–TMEDAcomplex then afforded the desired terminal alkyne 31;

whereas, treatment of an intermediate monoalcohol trisbenzyl ether with HBr in

H2SO4 gave the starting tetrabromide core 32.Reaction of the monoalkyne with the tetrabromide (LDA, TMEDA, and HMPA)

followed by concomitant Pd-C-mediated benzyl ether hydrogenation and alkyne

reduction afforded the first-generation 12 alcohol construct 33. Subsequent bromina-

tion (HBr, H2SO4) and treatment with more of the alkyne dendron (LDA, TMEDA)

gave the second-generation, benzyl-protected alcohol dendrimer that was reduced

(Pd-C, H2), oxidized (RuO4), and treated with tetramethyl ammonium hydroxide to

give the 36 tetramethyl ammonium carboxylate 34 (Scheme 1.7). This dendrimer was

described as a [82�3] micellanoate, where 82�3 represents two generations of an eightcarbon spacer with 1 ! 3 branching.

Dendrimer aggregation promoted in solution by carboxylic acid H-bonding was

inhibited by ion exchange to the tetraalkylammonium carboxylate as evidenced in the

observed 30A�diameters in electronmicrographs of 34 that compared favorably to the

calculated values [43]. Fluorescence lifetime and anisotropy decay values obtained by

phase resolved anisotropy experiments with diphenylhexatriene (DPH) as a molec-

ular probe were similar to that observed with DPH in phosphatidylcholine vesicles

demonstrating the micellar host–guest relationship in an aqueous environment [43].

Other molecular probes used to explore the micellar properties of these dendrimers

include chlortetracycline (fluorescence), phenol blue, naphthalene (UVabsorbance),

and pinacyanoyl chloride (color change).

Newkome and coworkers [49] also reported the construction of the unique dendron

tetraacid core [50] 35 (prepared by reaction of pentaerythritol and acrylonitrile

followed by hydrolysis) and aminotriester [51] 36 (accessed byMichael-type addition

of tert-butyl acrylate to nitromethane; commonly referred to as Behera’s amine [51]

in honor of Prof. Rajani K. Behera who, while working in Prof. Newkome’s

laboratories, first prepared and used this material) that were employed for the

construction of a series of amide-based dendrimers [52,53]. The stable isocyanate

ofBehera’s amine hasbeenused for facile combinatorial surfacemodification [54,55].

Coupling of the amine under standard peptide conditions (DCC, 1-HOBT, DMF)

afforded the first-generation, 12 tert-butyl ester dendrimer 37 (Scheme 1.8). Liber-

ation of the carboxylic acid surface groups (HCO2H) generated the new acid-

terminated periphery 38 that could be treated with more aminotriester. Dendrimers

in this family were prepared and isolated through generations 1 to 5 corresponding to

12, 36 (i.e., 39), 108, 324, and 972 theoretical terminal groups.

SUPRAMOLECULAR PERSPECTIVES 11

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Initial studies [56] of these amide-based dendrimers involved the systematic

evaluation of the pH effect on the hydrodynamic radii using two-dimensional,

diffusion-ordered 1H NMR spectroscopy (DOSY NMR). Termination of the car-

boxylic acid series with dendrons crafted to incorporate amine and hydroxylated

surfaces [56] (Fig. 1.3; 40 and 41, respectively) generated the complementary basic

and neutral surfaces, respectively. Accordingly, the acid-terminated dendrimers

were found to be largest or in an expanded state in neutral and basic pH; whereas,

OHOH

OHHO

HOHO 33

Br

Br

Br

Br

OBz I

OBz IOBz I

H

+

OH

OHOHHOHO

HO

32 31

-O2C-O2C

CO2-

CO2-

CO2-

CO2-

CO2-

CO2-

-O2C

-O2C

-O2C

CO2-

-O2C-O2C

CO2-

CO2-

-O2C

CO2-

CO2-

CO2-

-O2C

CO2-

CO2--O2C

CO2- CO2

-

-O2CCO2

-CO2

--O2C

-O2C

CO2-

-O2C

-O2C

-O2C

CO2-

(CH3)4N+

(CH3)4N+

+N(CH3)4(CH3)4N+

+N(CH3)4

+N(CH3)4

+N(CH3)4

+N(CH3)4

(CH3)4N+

(CH3)4N+

(CH3)4N+ +N(CH3)4

(CH3)4N+(CH3)4N+

(CH3)4N+

+N(CH3)4

+N(CH3)4

+N(CH3)4

+N(CH3)4

(CH3)4N+

+N(CH3)4

(CH3)4N+

(CH3)4N+

(CH3)4N+

+N(CH3)4

+N(CH3)4

+N(CH3)4

+N(CH3)4 +N(CH3)4

+N(CH3)4

+N(CH3)4

+N(CH3)4

(CH3)4N+

(CH3)4N+

(CH3)4N+

+N(CH3)4

1) HBr,

2 4

2) 12 equiv 31

3) [H]4) RuO4

5) Me4N OH

1) LDA, HMPA,TMEDA

2) Pd-C, H2,EtOH

34

SOH

SCHEME1.7 Newkome’s synthesis of a unimolecular micellewith a saturated hydrocarbon

infrastructure.

12 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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the amine-terminated species exhibited contraction in basic media; the hydroxyl-

terminated constructs showed a constant hydrodynamic radius over the range from

basic to acidic pH. A study of dendrimer expansion and contraction based on ionic

strength has also been reported [57].

HO O OHO

OHO

OO

O O

HOO

H2N

O

OO

O

OO t-Bu

t-Bu

t-Bu

OO

O

O

OOOO

O

O

OO

HN ONHO

NH O

HNO

OO

O O

O

O

OOO

O

O

O

O O O

O t-Bu

t-Bu

t-Bu

t-Bu

t-But-Bu

t-But-Bu

t-Bu

t-Bu

t-Bu

t-Bu

O O

O

O

OOOO

O

O

OO

HN ONHO

NH O

HNO

OO

O O

OH

OH

OHHOHO

HO

HO

HO

HO O OH

OH

+

DCC, 1-HOBT

DMF

HCO2H

O NH

HO OHOO

HO

O

ONH

HO

OOH

O

OHO

OH

OOHO

OH

O

HN

O

O

NH

OH

OOH

O

OHO

O

HN

OH

OOHO

OH

O

OH

OHO

O

HOO

NHOOHN

OHOOHO

OH

O

O

HN

OH

OHO

O

HOO

HO

OHO O

HO

O

NH

O

O

HN

HO

OHO

O

HO O

O

NH

HO

OHO O

HO

O

HOO

OH

O

OHO

HNO

HN ONHO

NH O

HNO

OO

O O

H2N

O

OO

O

OO t-Bu

t-Bu

t-Bu

DCC, 1-HOBTDMF

HCO2H

3635

37

38

39

SCHEME 1.8 1 ! 3 C-branched dendrimers constructed using amide-connectivity.

SUPRAMOLECULAR PERSPECTIVES 13

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Kuzdzal and coworkers [58,59] have used these acid-terminated dendrimers based

on Behera’s amine as a micellar substitute for the pseudostationary phase in

electrokinetic capillary chromatography for the separation of a series of parabens.

Tanaka et al. [60] were the first to report the use of dendrimers in electrokinetic

chromatography, and Muijselaar et al. [61], have also investigated this dendritic

property.Newkome et al. [62] further reported the incorporation ofH-bonding sites on

the arms of the interior dendritic framework; the encapsulation of AZT based on

complementary H-bonding was achieved. The micellar properties were also

employed by Miller et al. [63] to construct an “electronic nose,” whereby selective

dendritic encapsulation of organic solvents provided a means of detection.

Meijer and coworkers [64] studied extensively the polypropylenimine (PPI)

dendrimers and reported the “dendritic box,” whereby the amine termini were capped

with the activated ester of aBoc-protected chiral amino acid (42) to generate stericallydemanding surface that traps molecular guests (Scheme 1.9; 42). Molecular probes

used to investigate entrapment include 3-carboxypropyl radical 43, tetracyanoqui-

nodimethane (TCNQ) 44, andRose bengal 45 alongwith the corresponding analytical

techniques of EPR, UV, and fluorescence spectra, respectively. Notably, the diffusion

of guest molecules after being locked in was unmeasurable.

Zimmerman et al. [65,66] have provided the first example of dendrimer con-

struction employing self-assembly based onH-bonding of isophthalic acid moieties

attached at the focal positions (Scheme 1.10) of Frechet-type dendrons [26].

Synthesis of the requisite dendrons (generations 1 to 4) began with conversion

of pyridine dibromide 46 to the bis-boronic acid that was then transformed to the bis

(dimethyl isophthalate) using aryl iodide Pd(0) coupling. Attachment of the

dendritic wedge to the phenolic position of 47was accomplished byKOH-promoted

substitution at the focal benzylic bromide 48 to give the poly(isophthalic acid)

substituted dendron 49. Self-assembly into ordered hexameric aggregates (i.e., 50)

was studied by SEC, VPO, and LLS. Molecular weights determined by SEC

retention times using polystyrene for calibration were in agreement with NMR

data that showed monomeric species in THF and hexameric structure in noncom-

peting CH2Cl2 solution. However, observed SEC traces for the lower generation

H2N

O

O

O

Me

Me

Me

O

O

O

H2N

NH

NH

NH

O

O

O

O

O

O

t-Bu

t-Bu

t-Bu

4140

FIGURE 1.3 1 ! 3 C-Branched dendrons for the incorporation of amine and hydroxylated

surfaces.

14 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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dendrons suggested a greater percentage existed in linear and dimeric forms due to

less steric pressure to form the hexameric species.

Zimmerman and coworkers [67] have explored the potential to use chromogeni-

cally modified, peripherally cross-linked dendrons as amine chemosensors. Their

strategy involvedcouplingFrechet-typedendronsmodifiedat the terminiwithalkene

groups (either homoallyl or allyl ether moieties) attached to the phenolic positions

of a trifluoroacetylazo dye that has been shown to be an amine chemosensor, based

64

NH2

O

O

N

O

O

64N O

O

H

64

N

ON O

O

H

HCH2Cl2, Et3N

42

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

OR

O

N

O

N

OR

O

N

O

N

OR

O

N

O

NO

R O

ON

OR

O

ON

OR O

N

N

NN

N

N

NN

N

N

N

NN

NN

N

N

N

N

N

N

N

N

N

O NO

RO

O N O

RO

O N O

R O

O NO

RO

ON

O

RO

O

NO

RO

O

NO

RO

O

NO

R

OO

NO

R

OO

NO

R

OO

N

O

R

O

N

O

N

O

R

O

N

O

N

O

R

O

N

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

N

N

N

N

N

N

N

N

N

N

NN

N

NN

N

NN

NN

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

O

N

OR

O

N

O

N

OR

O

N

O

N

OR

O

N

O

NO

RO

ON

OR

O

ON

ORO

N

N

NN

N

N

NN

N

N

N

NN

NN

N

N

N

N

N

N

N

ONO

RO

ONO

RO

ONO

RO

ONO

RO

ON

O

RO

O

NO

RO

O

NO

RO

O

NO

R

O O

NO

R

OO

NO

R

OO

N

O

R

O

N

O

N

O

R

O

N

O

N

O

R

O

N

O

N

O

R

O

O

N

O

R

O

O

N

O

R

O

N

N

N

N

N

N

N

N

N

N

NN

N

NN

NN

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N

N N

N

N

N

N

N

N

N

N

N

R =42

N

OHO

43

CN

CN

NC

NC

44

O

ClClCl

Cl OH

O

O

I

I

I

HOI

45

SCHEME 1.9 Topological trapping of guest molecules in a “Molecular Box.”

SUPRAMOLECULAR PERSPECTIVES 15

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on its ability to trap amines by reaction with the trifluoroacetyl unit, thereby

exhibiting a 50 nm shift in lmax in the visible region from red-orange to yellow

(l¼ 475–425 nm for uncomplexed to complexed, respectively). The requisite

sensor-modified dendrons (Scheme 1.11) were prepared by standard Frechet-based

attachment (KF promoted coupling with 18-crown-6) of two dendrons to the

dye. Treatment of two equivalents of the dendron-substituted dye 51 with butane

1,4-diazide in the presence of triphenylphosphine produced the bis-imino

N

BrBr

NO

OMe

O Me

OO

Me

OO Me

+

OMeO

HO

O

OO

Me

OO Me

4647

48

O

O

O

O

O

O

OO O

O

O

O

O

O

O

O

O

O

O

OO

O

O

Br

O

O

NO

OMe

OO Me

OK2CO3

KOH,THF,H2O

O

O

O

O

O

49

SCHEME 1.10 Self-assembly of dendrimer architecture based on H-bonding.

16 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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didendron 52. Metathesis with Grubbs catalyst then effected the surface cross-

linking (Scheme 1.12) to give the encapsulated amine active site 53. Treatment with

aqueous HCl transformed the trifluoroimine moieties to the starting trifluoroacetyl

groups54. Extensive systematichost–guest studiesusing theseuniquematerialswith

a library of amines and alcohols revealed the selective signaling of certain diamines,

although it was determined not to arise due to template-mediated imprinting.

Zimmerman and coworkers [68] have used dendrimer surface cross-linking based

on Grubbs-promoted alkene metathesis for the modification of nanoparticles. They

showed that the degree of dendrimer cross-linking can be controlled, thereby leading

to nanoparticles with predictable rigidity. Control over cross-linking has also been

examined by internal placement of the alkene moieties [65]. The distribution of

alkene cross-linking placement between subunits on 1 ! 2 branched, aryl ether

dendrons has also been studied [69] along with the reversibility of dendrimer

metathesis [70] and cross-linked arylether dendrimers with arylester cores have been

hydrolytically decored without significant degradation [71].

Zimmerman and coworkers [66] initially reported the use of dendrimer-based

surface metathesis chemistry in concert with the potential to co-facially connect and

linearly arrange porphyrin moieties with the goal of creating new organic nanotubes

(Scheme 1.13). Treatment of dendrimerized, Sn-metallated porphyrin 55, with

succinic acid and excess Ag2O generated the oligomerized dendrimer 56; it was

noted that successful oligomerization hinged on reaction mixture concentration by

solvent evaporation during the transformation. Notably, the oligomerwas treatedwith

Grubbs catalyst without delay due to an observed increase in molecular weight over

time. Following metathesis, the newly formed rod 57 was reacted with NaOMe to

liberate the porphyrin core and generate the decored organic nanotube 58. SECcomparison of the hollow constructs to polystyrene and dendrimer standards revealed

tetramer and dodecamer formation with corresponding molecular weights of 23,000

and 72,600 Da, respectively.

O H OO H

where R =

O

OO

H O O OH O

HHO O

O

OO

O

O

O

O

O

OO O

O

OO

OO

O O

O

H

H

O

OOO

OO

O O

H

H HH

O

O

O

O

H

H

O

O OO

HO

H OH

HO O

O

O

OHO

OO

O

O O

H

H HH

R

R

R

RR

50

OHOOR

SCHEME 1.10 (Continued)

SUPRAMOLECULAR PERSPECTIVES 17

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Percec et al. [40,72] investigated dendrimer supramolecular self-assembly by

constructing a library of conical dendrons, whereby the focal groups embed into the

central core of spherical motifs that can be envisioned as the dendritic equivalent of a

surfactant based micelle. Porous columns were also obtained. The dendritic library

was constructed using 1 ! 2 arylether, Frechet-type synthesis with C4 to C12 chiral

or achiral carbon chains attached to the periphery with ester, alcohol, or dipeptides as

focal units. The self-assembly process is exemplified in Scheme1.14where the benzyl

alcohol dendron 59 with C6 alkyl chain termini assembles into a hollow sphere 60

with an 83.5A�diameter and core diameter of 26.4� 4A

�. Further assembly based on

spherical packing into a Pm3n cubic lattice 61was determined. Whereas, the starting

dendrons were fully characterized by NMR, HPLC, and MALDI-TOF; the

O O

O

O

O

O

O

OO

OO

OO

OO

OO

O

O

OO

O

O

O

O

O

O

O

OO

O

CF3

NN

NMe

Me

52

N3 N3

PPh3, Et2O

51

O O

O

O

O

O

O

OO

OO

OO

OO

OO

O

O

OO

O

O

O

O

O

O

O

OO

N

CF3

NN

NMe

Me

2

Ru

P(cyhx)3Cl

Cl P(cyhx)3Ph

PhH

SCHEME 1.11 Coupling of dendrimerized chromogenic sites as chemosensors.

18 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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supramolecular assemblies were analyzed by small-angle X-ray diffraction andDSC.

Reconstruction of the electron density maps afforded three-dimensional mapping of

the hollow cubic phases showing the electron density profiles; aliphatic and aromatic

regions were clearly discernible. Low temperature TEM imaging combined with

electron diffraction also revealed circular objects arranged in square lattices. A

dendritic crown derived fromdendron-modified cyclotriveratrylenes [73], semifluori-

nated, Janus-type, dendritic benzamides that form bilayer pyramidal columns [74],

dendritic crown ethers [75], dendronized poly(carbazoles) [76], dendritic dipep-

tides [77], dendronized polyphenylacetylenes [78], p-stacked, semifluorinated den-

drons [79], and thixotropic dendritic organogelators [80] have also been studied; a

comprehensive review [40] is available.

Hirsch and coworkers [81] have reported the switchable supramolecular assembly

(Fig. 1.4) based on an amphiphilic fullerene possessing Newkome-type, carboxylic

acid-terminated dendrons. In contrast to an amphiphilic fullerene 62with ester-based

dendron connectivity and in comparison to the calixarene-cored analog [82] 63, the

dendronized fullerene 64 has been shown to exhibit globular micellar character at

basic pH and predominately rod-shaped character at near neutral pH. Using electron

cryogenic microscopic data (cryo-TEM), a three-dimensional reconstruction of the

pseudospherical shape was obtained. The globular motif (diameter¼ 85� 5A�) was

O

O

NN

Me2N

NF3C

O

ON N

NMe2

N CF3

O

O

NN

Me2N

OF3C

O

ON N

NMe2

O CF3

aq. HCl, THF

= polymerized

matrix 5453

SCHEME 1.12 Idealized representation of matrix encapsulated, chemosensor site for

diamine recognition.

SUPRAMOLECULAR PERSPECTIVES 19

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O

O

O

O

O

O

O

O

OO

O

O

OO

NNN N

M

O

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

OO

OO

OO

O

O

O

O

OO

O

O

O

OO

OO

OO

O

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

O

O

O

OO

O

O

O

ONN

N N

O

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

O

O

O

O

O

OO

OO

OO

O

O

O

O

O

O

O

O

O

OO

O

OO

O O

Sn

55

HO

O

OH

O

Ag 2

O,

TH

F

56

SCHEME1.13

Anovel

adaptationofself-assem

bly

fortheconstructionoforganic

nanotubes.

20 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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RuP(c

yhx)

3

Cl C

lP

h

Sn

P(c

yhx)

3

NaO

Me

5857

SCHEME1.13

(Continued)

SUPRAMOLECULAR PERSPECTIVES 21

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modeled as a packed aggregate of eight molecules of 64 in a C2-symmetrical

arrangement consisting of two interlocked, U-shaped species, each consisting of

four molecules, with 180� opposing domes, essentially capping one another, and

perpendicular planes. At a lower pH of 7.2, rod-shaped, double-layered aggregation

was observed in electron micrographs (diameter¼ 65� 5A�with variable lengths).

The spherical aggregation possesses the expected attributes of a micellar structure in

that as arranged all of the hydrophobic alkyl chains are shielded from the aqueous

environment and aid in the structural stability by solubilizing each other on the

interior of the superstructure. A later report discussed the control of self-assembly of

the structurally persistent micelles by specific-ion effects and hydrophobic guests,

while a dendronized fullerene and porphyrin hybrid have also been studied with

respect to their electrostatic attraction and resulting 1.1 ms charge separated state [83]and their efficient light harvesting and charge-transfer character [84].

Hirsch and coworkers [85] have also reported the dendronization with Newkome-

type dendrons of perylene bis-imides that exhibit electronic communication with

graphene in solution or following surface deposition. Noncovalent p-system binding

provided the association and facilitated the interaction. Perylene dendronization and its

utility as a rigid spacer for terpyridine-based metal connectivity used in metallosupra-

molecular self-assembly have also been reported byW€urthner and coworkers [86–89].

1.2.2. Framework Conformational Control

Supramolecular self-assembly predicated on complementary H-bonding interactions

has also been investigated by Hirsch and coworkers [90]. Employing a 2,20-bipyr-idinyl-4,40-dicarboxylic acid as the starting point formetal-centered core construction

SCHEME 1.14 Using dendron shape for the assembly of complex architectures.

22 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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O

O

HN

O

H NO

H

O

OH

O

OH

O

O

OH

O

HO

O

OH

OH

NH

O

O

HO

OH

OO

O

NH

O

OH

N

OH

NOH

OH

O

O

OH

OO

HO

O

HO

OH

OO

HN

HO

OO

H

O

HO

O

O

H N

OO

O

OO

OO

O

O

O

OO

OO

O

O

O OOO

OO

NH

O

H NO

H

O

OH

O

OH

OO

OH

OH

O

O

OH

OH

N

HO

O

HO

OH

OO

O

NH

NH

O

O

NH

O

HN

OH

OHO

O

OH

OO

HO

O

HO

OH

OO

HN

HO

OO

H

O

HO

O

O

H N

NH

O

O

OO

OO 63

62

NH

O

HN

O

H NO

H

O

OH

O

OH

O

O

OH

O

HO

O

OH

OH

NH

O

O

HO

OH

OO

O

NH

HN

OH

N

OH

NOH

OH

O

O

OH

OO

HO

O

HO

OH

OO

HN

HO

OO

H

O

HO

O

O

H N

OO

O

OO

OO

O

O

O

OO

OO

O

O

O OO

O

OO

64

FIG

URE1.4

Dendronized

fullerenes

that

exhibitpH

switchable,globularmicellaraggregationandlinear,rod-shaped

assembly.

SUPRAMOLECULAR PERSPECTIVES 23

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(Scheme 1.15), a 1 ! 2 aryl branched, bis(2,6-diamidopyridine) receptor 65 was

attached by standard coupling procedures to diacid 66 to generate the bipyridine

dendron 67. Reaction with RuCl3 afforded the trisbipyridine Ru(II) core that was

subsequently coordinated at the binding sites with cyanuric acid-modified dendrons

that introduce potential repetition for continued dendritic growth, chirality, or

electronic possibilities (68). Generation of the final, poly(H-bonded), Ru complex

N

N

O

O

NH

HN

OH

O

OH

OH

H2N

O

O

NH

NH

N

N

NH

NH

O

ON

N

O

O

NH

HN

O

OH

HN

O

O

NH

HN

N

N

NH

HN

O

O

NHO

O

NH

NH

N

N

NH

NH

O

O

N

NRu

NN

NN

O HN

ONH

O

O

NH

HN

N

N

NH

HN

O

O

HN

ONH

O O

NH HN

N N

NHHN

OO

O

O

NHO

HN

O

O

HN

HN

N

N

HN

HN

O

O

HN

OHN

O

O

HN

NH

N

N

HN

NH

O

O O

H2N

OHN

OOHNNH

NNHNNH OO

O

HNO

HN

O

O

NH

NH

N

N

NH

NH

O

O

O

NH

NHNO

O

O

RO

HN N

HNO O

O RO

HNN

NHO

OO

RO

HN

N NHO

O

O

RO

NHNNH

OO

OR

O

NHN

HNO

O O

R O

HNN

HNO

O

O

R

O

1) RuCl3

2)

HN

O O

O

OOO

HN

O O

O

OOO

HNO

O

O O

O

OO

O

O

OO

R = , , or

65

6766

68

SCHEME 1.15 An innovative use of H-bonding for dendritic construction.

24 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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was accomplished both by sequential addition or in a single-step reaction.

The complementary H-bonding was monitored by NMR titration and determination

of the stepwise formation constants K1–K6.

Parquette and Huang [91] demonstrated conformational restriction of the dendritic

framework based on the incorporation of internal H-bonding. Their sequence for

convergent dendron construction focused on 4-chloropyridine-2,6-dicarbonyl chloride

(Scheme 1.16; 69, obtained from the treatment of chelidamic acid with POCl3), which

was initially treated with dodecyl anthranilate to generate the terminal species 70.

Subsequent reaction with NaN3, followed by hydrogenation (H2, Pd-C), and treatment

with more diacid dichloride 69 afforded the second-generation dendron 71; repetition

gave generation 4 72. X-ray structure determination of the second-generation dendron

revealed amonoclinic asymmetric unit exhibiting aP21/c space group and a propeller-

like secondary motif resulting from symmetrical assembly of entwined dimers in the

solid state. Along with the X-ray data, 1H NMR and IR spectra further evidenced

the pyridine N–H amide structure; distances ranged from 2.13 to 2.33A�.

NCl

O

O

Cl

Cl

NHO

O

O

OH

OH

69

O OR

H2N

R = (CH2)11CH3

NX

O

O

OORN

H

ORO

NH

70

N

O

O

O

OR

NH

ORO

NH

NX

O

O

NH

N

O

O

O OR

NH

OR

ONH

N

HA

B

B

C

C

D

D

1) NaN3

2) H2, Pd-C3) 69

71

NX

O

O

NH

N

H

NO

O

O

OR

N H

OR

O

NH

N

O

O

N H

N

O

O

O

ORN

H

ORO

NHN

H

N

O

O

O ORNH

OR

ONH

N

O

O

NH

NO

O

O

OR

NH

OR

O

N H

NH

1) NaN3

2) H2, Pd-C3) 69

72

SCHEME 1.16 H-bonding-based conformational framework restriction.

SUPRAMOLECULAR PERSPECTIVES 25

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Parquette and coworkers [92] have also investigatedH-bond-based dendrons using

a 2-methoxyisophthalamide moiety that were designated as 2-OMe-IPA (i.e., 76)

and compared it to the corresponding 2,6-dicarboxamidopyridine-based dendrons

that were designated as 2,6-Pydic (i.e., 77). The 2-OMe-IPA building blocks were

prepared (Scheme 1.17) starting with 2,6-dimethylanisole, which was sequentially

oxidized (KMnO4), nitrated (HNO3, H2SO4), and carbonylated [(COCl)2] to give the

nitrobis(carbonyl chloride) 73. Introduction of the capping species, provided by the

tetraethyleneglycol ester of anthranilic acid 74, afforded the first-generation den-

dron 75. Two iterative treatments with SnCl2 for reduction of the aryl nitro group

followed by reaction with the bis(acid chloride) 73 gave the third-generation

dendron 76. The 2,6-pydic-based materials were accessed using 4-chloropyridine-

2,6-dicarbonyl chloride. Both materials were evaluated computationally with respect

to the energy requirements for syn–syn, syn–anti, and anti–anti conformations.

Although subtle differences were found, both systems exhibited organization, based

on the syn–syn conformations; thus, the carboxamide protons were oriented inward.

This preference in 2-OMe-IPAwas attributed entirely to H-bonding; whereas, dipole

moment minimization effects also played a part in the 2,6-pydic dendrons. Although

it was noted that “solvophobic compression was deemed to be a more important

effect on hydrodynamic properties than solvent-based shifts in repeat unit confor-

mational equilibria for both series.”

Using the 2,6-dicarboxamidopyridine-based protocol for dendron construction

and oxazoline capping groups, Preston et al. [93] described the synthesis and

properties of folded metallodendrons exhibiting “shell-selectivity” toward metal

coordination. Circular dichroism and X-ray studies verified the selectivity and

confirmed the helical properties of these dendrons. This offers added flexibility to

design and construct dendrimers with redox potential gradients and the ability to fine

tune dendritic electronic materials and components. Conformational properties of the

folded metallodendrons have also been reported [94].

2,6-Dicarboxamidopyridine-type dendrons integrated with alanine-based oligo-

mers (denoted as peptide–dendron hybrids, PDHs) have been reported [95] to undergo

a reversible conversion from an amyloid fibrillar structure to a nanotube assembly in

water effected by a change in pH or ionic strength; the phenomena was exploited for

the encapsulation and release of a dye (Nile Red) upon a pH change from high to low.

Dendrons crafted with these unique building blocks have been used as catalysts for

Aldol reactions [95] where the dendritic effects on stereoselectivity were analyzed.

1.2.3. Harnessing Electronic Properties

Nierengarten and coworkers [96] have described the self-assembly of fulleroden-

drimers using the four-fold H-bonding specie 2-ureido-4-[1H]pyrimidinone. Syn-

thesis of the requisite building block (Scheme 1.18) was accomplished [97,98]

beginning with the alkylation of 3,5-dihydroxybenzyl alcohol using 1-bromohex-

adecane to give the dialkylated benzyl alcohol 78 that was subsequently treated with

Meldrum’s acid affording the malonic acid 79. Coupling with the di(benzyl alcohol)

80 (accessed from dimethyl 5-hydroxyisophthalate in two steps [98] using DIBAL

26 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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CH3H3COMe

CO2HHO2COMe

KMnO4

1) HNO3,H2SO4

OO

O O O OCH3NHH

OMe

OO

ClCl

NO2

O

O

O

O2N

OO

O O O OCH3NH

Me

OCH3OOOONOH

1) SnCl2

2)73

3) Repeat 1) and 2)

O

ON

O

O O

N

O

O

O

O

O

H3CO

NH

Me

OCH3

O

O

O

O

N

OH

O

O

O

N

O

O

OO

OOCH3

NH

Me OCH3OO

OON

OH

O

O

N

O

O

O

N OO OO

OOCH3

NH

Me

OCH3

OO

OO

N OH

O

OO

N

O

O

O

O

O

OCH3

NH

Me

H3CO

O

O

O

O

N

OH

O

O

O2N

OMe

H

H

OMeH

H

O MeH

H

73

74

75

76

2) (COCl)2,DMF

N

N

N

O

O

ClH

H

O

O

n

OCH3OOOO

O O O O OCH3

77

SCHEME1.17 BothH-bonding systemswere determined to exist in syn–syn conformations.

SUPRAMOLECULAR PERSPECTIVES 27

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HO

HO

OH

O OO

H

C16

H33

C16

H33

Bas

e

O OO

C16

H33

C16

H33

OH

OO

Mel

drum

’sac

id

7879

OH

HO

O

CO

2-t-B

u

DC

C, D

MA

P

80O

O

O

CO

2-t-B

u

O

OO

C16

H33

C16

H33

O

OO

O

C16

H33

C16

H33

OO

O

81

O

CO

2t-B

u

ZO

OZ

ZO

ZO

O

OOO

OO O

OC 60

, I2

DB

U

CF 3

CO

2H

82

1-B

rC16

H33

O

CO

2H

ZO

OZ

ZO

ZO

O

OO

O

OO O

O

83

O

CO

2t-B

u

OO

O

O

O

OOO

OO O

O

OH

OH

HO

OH

84

O

CO

2t-B

u

O

O

OO

O

O OOO

OO O

O

O

O

O

O

OR

RO

OR

OR

O

O OOO

OOO

OO

OR

RO

OR

OR

O

O

OO

OOO O

O

O

OR

RO RO

OR

O

OO

O

O OO

O

OO

RO R

O

OR

RO

OO

OO

OOO

O

O

85

SCHEME1.18

Supramolecularself-assem

bly

ofafullerodendrimer.

28 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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O

O

OOO

O

OO

O

OOO

O

OH

O

O

O

O

ZO

OZ

OZ

ZO

O

OO

OO

OO

O

O

O

ZO

ZO

OZ

ZO

OO

OO

OOO

O

O

O

OZ

ZOO

Z

OZ

O

O OO

OOOO

O

O

ZO

OZ

OZ

ZO

O

OO

O

OO

OO

O

O

O

O OO

O

OO

O

O OO

O

HO

O

O

O

O

OZ

ZO

ZO

OZ

O

OO

O O OO

O

O

O

OZ

OZ

ZOO

Z

OO

OO

O OO

O

O

O

ZO

OZ

ZO

ZO

O

OOO

OO

OO

O

O

OZ

ZO

ZO

OZ

O

OO

O

O

OO

O

O

NN

O

NO

HN

NN

O

NO

HN

H

H HH

OO

OO

87

1) C

F 3C

O2H

2) D

CC

, DM

AP

,

N

NH

O

N HO

OH

O

3) a

) C

F3C

O2H

b) H

17C

8NC

O

86

Z =

C16

H33

SCHEME1.18

(Continued)

SUPRAMOLECULAR PERSPECTIVES 29

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reduction, followed by reaction with tert-butyl bromoacetate) gave the bis-malonate

81, which when reacted (I2, DBU) with C60, generated the tert-butyl-protected

dendron 82; deprotection with CF3CO2H afforded the carboxylic acid-modified,

fullerodendron 83. Reaction with the tetraalcohol dendron 84 (prepared [99] in an

analogous procedure to that of 82, whereby 2-bromo-6-benzyloxyhexane is used in

place of 1-bromohexadecane for alkylation of 3,5-dihydroxybenzyl alcohol, followed

by debenzylation) with the focal acidmoieties of 83 gave the pentafullerodendron 85.

Transformation of the focal tert-butyl ester to the corresponding acid [CF3CO2H

(TFA)], coupling (DCC, DMAP) to BOC-protected, 2-amino-6-(4-hydroxybutyl)-

[1H]pyrimidine-4-one (86), followed by amine liberation (TFA) and alkylation with

octylisocyanate (H17C8NCO) produced the desired 2-ureido-pyrimidone-modified,

dodecaC60, fullerodendron dimer (87). Proof-of-dimerization was verified by mass

spectrometry, albeit in low abundance (5%), and 1H NMR, which clearly revealed the

large downfield shifts corresponding to the relevant protons positioned between theH-

bonding units (i.e., ureaNHs, 11.81 and 10.06 ppm; pyrimidoneNH, 13.23 ppm). The

corresponding smaller diC60dimer was also prepared. These materials demonstrated

the potential to craft novel supramolecular architectures exhibiting fullerene-based

photoinitiated properties. Mass spectrometry, along with electrochemical analysis

(CV) of fullerodendrons possessing 3, 5, and 7 C60 moieties, revealed independent

redox behavior of the methanofullerene groups [99]. A review on the use of [61]

fullerenes as photoactive cores for dendrimers is available [100].

Connection of the pentaC60 dendrons (85) acid focal group followed by coupling to

third-generation, PEG-terminated, Frechet-type dendron generated amphiphilic

diblock dendrimers that were examined [97,101] for their ability to form Langmuir

and Langmuir–Blodgett films. The potential to form ordered films arises largely from

the hydrophilic and hydrophobic peripheral chains on the opposing hemispheres of

the dendrimers and also provided structural attributes to facilitate efficient transfer to

a multilayer Langmuir–Blodgett array. Langmuir films have also been prepared by

attachment of these methanofullerenes to bipyridine, followed by generation of a tris

(2,20-bipyridine)Ru(II) complex to act as a polar head group [102]. Ruthenium(II)

complexes attached to C60 through polyethylene glycol units, based on bipyridine and

terpyridine, have been reported as well [103]. A bis-phenanthrolene–Cu(I) complex

used as a tetradirectional core with grafted G1 through G3, C60-based, dendrons has

been reported [104]; the encapsulation of fullerene-modified dendritic frameworks

was shown to isolate the central complex from electrode oxidation and electrochem-

ical oxidation was not observed for the G2 and G3 constructs, leading to a “dendritic

black box” description. Additional reviews are available regarding the supramolec-

ular and photophysical aspects of fullerene-rich dendrimers [105,106].

Ceroni and coworkers have investigated the electronic and excited state attributes

of fullerene-modified phenyleneethynylene dendrons characterized by 1 ! 2 aryl

branching employing either a 1,2,4- or 1,3,5-substitution pattern (88–91; Fig. 1.5).

Synthesis of these phenylacetylenes is exemplified by the preparation of the 1,3,

4-motif 89, which beganwith Corey–Fuchs dibromoolefination (CBr4, PPh3, Zn) of 3,

4-dibromobenzaldehyde followed by transformation to the alkyne (LDA) and trap-

ping with triethylsilyl chloride (TESCl) to give the protected dibromoalkyne 92

30 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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(Scheme 1.19). Sonogashira coupling [Pd(PPh3)2Cl2, Cu(I)] of the capping agent 93

then gave the silated alkyne 94 which was next deprotected (TBAF) to afford the

terminal alkyne 95. Repetitive couplingwith the Sonogashira reagents and the startingdibromoaldehyde generated the G2 dendron 96. Treatment of the aldehyde moiety

with N-methylglycine to give an intermediate azomethine ylide facilitated reaction

with fullerene to afford the desired C60-modified dendron 89. Whereas all these

dendron hybrids were shown to facilitate ultrafast energy transfer, the 1,2,4- versus

1,3,5-branching motifs showed dramatic differences in their absorption and emission

spectra with the former pattern exhibiting a lower absorption commencement and a

broadened profile relative to the latter pattern; thus, the 1,2,4-architecture was

revealed to possess enhanced light-harvesting potential.

Frechet et al. [107] synthesized a multichromophoric light-harvesting dendrimer

possessing two complementary donor dyes. The donors absorb a broad spectrum of

light energy in the UVand visible regions as well as facilitate red region emission by a

porphyrin core through a florescence resonance energy transfer mechanism. Dyes

chosen as chromophores include the carboxylic acid-modified, naphthopyranone

[Scheme 1.20; prepared by Peckmann condensation of 2,7-dihydroxynaphthalene

and ethyl trifluoroacetoacetate, followed by reaction with tert-butyl bromoacetate

(K2CO3) with subsequent acid-mediated, tert-butyl group removal] and commer-

cially available coumarin 3-carboxylic acid. The dye-functionalized, 1 ! 3

C-branched building blocks were derived by carbodiimide-based coupling (EDC

NMe

OR

OR

OR

OR

88

NMe

OR

OR

OR

OR

ORRO

OR

OR

89

NMe

OR

OR

RO OR

OR

OR

RO OR90

NMe

OR

OR

OR

OR

91

R = C12H25

FIGURE 1.5 Different branching patterns have explored for optimum energy transfer.

SUPRAMOLECULAR PERSPECTIVES 31

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CHO

BrBr

Br

BrBr

BrCBr3

PPh3

Zn

Br

Br SiEt3a) LDA

b) TESCl

92

RO

RO H

93SiEt3

RO

RO

RO

RO94

H

RO

RO

RO

RO

TBAFPd(PPh3)2Cl

CuI

CHO

BrBr

Pd(PPh 3)2Cl,CuI

RO

RO

RO

RO

RO

RO

RO OR

CHO

95

96R = C12H25

N-Methylglycine

C60

89

92

SCHEME 1.19 Synthesis of a phenylacetylene-based dendron.

O

O NH2

OH

OO

O

HO OF3C

97

HOBT, EDC,DMF

O

O NH

OH

OO

O OF3C

O O

OH

O

EDC, CH2Cl2

98

99

OO

O

O

O NH

OH

O OO

DMAP,MeCN

O

O NH

O

OO

O OF3C

OOH

O

100

OO

O

O

O NH

O

OOH

O

101

O OO

DMAP,MeCN,

SCHEME 1.20 Dye incorporation into dendritic building blocks.

32 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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with 1-HOBT being used in the case of the naphthopyranone) of each dye to

5-amino-5-hydroxymethyl-2,2-dimethyl-1,3-dioxane [108] (97) [prepared by treat-

ment of tris(hydroxymethyl)aminomethane (TRIS) with commercially available 2,2-

dimethoxypropane] to generate the intermediate alcohols 98 and 99, followed

treatment with succinic anhydride, in the presence of DMAP to give the desired

functional dendrons 100 and 101.

Dendritic preparation proceeded (Scheme 1.21) by polystyrene-carbodiimide

coupling of the hydroxyl-terminated porphyrin 102 with the naphthopyranone

building block 100 in the presence of pyridine to generate the first-generation polyol

N HN

NNH

OO

O O

O

O

O

O

O

O

OO

O

HNO

O

O

O

F3CO

O

O O

OOHN

O

O

OO

CF3

OO

O O

O

NHO

O

O

O

CF3

O

O

OO

O

O

O

HN

O

O

O

O

F3C

O

O O

OO

NHO

O

OO

CF3

O

OO

O O NH

OO

OO

F3C

O O

O O

O

O

O

O

ONH

O

O

O

O

CF3O

O O

OO

OO

HNO

O

O O

F3C

OO

O

O

ON

OO O

OO

O

O

O

HN

OO

O

O

OO O

ON

O

OO

O

O

O

OO

HN

O

O

O

O

OO

O

O

NO

O

OO

O

O

O O

HN

O

O

O

OO

O

O O

NO

O

O

O

O OO

O

NHO

OO

OO

O

OO

N

O

O

O

O

OO

O

O

NH

O

OO

O

O

OO

O N

O

OO

O

O

O

O

O NH

OO

O

O

O O

OO

NO

O

OO

O

O

OO

NH

O

O

O

O

OOO

O

HNO

OO

O

OO

OO

NO

O

O

1) PS-Carbodiimide,Pyridine, 101

2) (NH4)2Ce(NO3)6

Buffer

N HN

NNH

OO

OHOH

O

O

OH

OH

O O

OH OH

O

O

HO

HO

NHN

NNH

OO

O O

O

O

O

O

O

O

OO

O

HNO

O

O

O

F3CHO

HO

O O

OO

HN

O

O

OO

CF3

OHOH

O O

O

NHO

O

O

O

CF3OH

OH

OO

OHO

HO

HN

OO

O

OF3C

O

OO

HOHOHN O

O

OO

F3C

O

OO

O O NH

OO

OO

F3C

HO HO

OO

O O

O

OH

OH

NH

O

OO

O

CF3O

OO

OO

OH OH

HNO

O

O O

CF3102

1) PS-Carbodiimide,Pyridine, 100

2) (NH4)2Ce(NO3)6

Buffer

103

104

SCHEME 1.21 Construction of a dye-based gradient within a dendritic framework.

SUPRAMOLECULAR PERSPECTIVES 33

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103 after removal of the acetonide protecting moieties with (NH4)2Ce(NO3)2.

Attachment of the coumarin-based, dye 101 layer, thereby generating the 24 dye-

modified dendrimer 104, was conducted similarly to the octa(naphthopyranone) dye

dendrimer. Fluorescence spectra recorded after excitation at 335 or 358 nm (coumarin

and naphthopyranone absorbance values, respectively) reveal predominant emission

at 651 and 717 nm corresponding only to the porphyrin core. This modular approach

to dendritic construction is a notable example of framework modification employing

preconstructed, application-oriented dendrons, thereby instilling a “gradient” prop-

erty characteristic, in this case, light absorption.

1.2.4. Drug Delivery Systems

Frechet and coworkers [109] have employed dendrimer–polymer hybrids as micel-

lar capsules for event-triggered drug release. Dendrimer assembly (Scheme 1.22)

relied on the use of benzylidene-protected, 2,2-bis(hydroxymethyl)propionic anhy-

dride 105 (prepared [110] by treatment of 2,2-bis(hydroxymethyl)propionic acid

with benzaldehyde dimethyl acetal, followed by coupling and dehydration with

DCC), as the dendritic building block, followed by Pd-C hydrogenolysis of the

resulting polybenzylidene surface to give a new polyhydroxy periphery that could

be further elaborated. Using this protocol and starting with the polyethyleneoxide

(PEO) core 106, the PEO–dendrimer composite 107 was generated, which was

next capped with diazonaphthoquinone to afford a dendritic framework (108) thatwas able to undergo Wolff rearrangement to an indene carboxylic acid, upon

irradiation with UV light; hence, the transformation would change the micellar

character and disrupt the aggregation. Since Nile Red excimer fluorescence could

be used to follow micelle formation in the noncapped PEO-dendrimer hybrids, it

was reasoned that the capped hybrid upon irradiation and rearrangement would

provide a release mechanism useful for drug delivery. Upon irradiation at 355 nm

and termini rearrangement, the resulting indene carboxylic moieties changed the

dendritic character from hydrophobic to hydrophilic, disrupted micellar formation,

and released the encapsulated dye as revealed using fluorescence emission studies

and dynamic light scattering experiments.

Gillies and Frechet [111] have also used a micelle disruption mechanism for the

controlled release of doxorubicin. As an example, the micelle-forming, diblock

copolymer 109 (Scheme 1.23) comprised a polyethylene chain (� 10,000MW) and a

third-generation dendron terminated with 2,4,6-trimethoxybenzaldehyde acetal moi-

eties (prepared [110,112–116] by iterative reaction of hydroxyl terminal groups with

benzylidene-protected, 2,2-bis(hydroxymethyl)propionic anhydride, treatment with

an aminodiol and subsequent acetal formation) was subjected to a pH decrease.

Following the pH change, the surface acetals begin to hydrolyze and generate a polar

protic dendron surface 110 that changes the polar character of the micelle thereby

releasing the doxorubicin. Several variations of these polyester dendrimers have been

reported [117–120]. A marvelous example of dendritic utility is realized in the

report [121] of one dose of a doxorubicin-modified dendrimer acting to cure mice

inflicted with C-26 colon tumors.

34 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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1.2.5. Dendritic Self-Assembly, Sensors, and Devices

Chow and coworkers [122] have crafted 1 ! 2 C-branched, all hydrocarbon den-

drons, focally attached to bis(2-ureido-4-pyridinone) (UPy)2, which can self-assem-

ble to form novel dendronized polymers [123]. Synthesis of the aliphatic dendrons

(Scheme 1.24) began by diallylation of diethyl malonate with dimethyl allyl chloride

111 followed by Pd(OH)2-mediated reduction of the alkene moieties to give the

dialkylated malonic ester 112. Subsequent saponification (KOH), decarboxylation

(pyridine, H2O, heat), and reduction (LAH), followed by PCC oxidation, bis(tri-

methoxy)phosphonoacetate homologation, and finally DIBAL reduction afforded the

OO

O

OH

OH

n

O

O

H

O

O

O

O

O

H105

DMAP,1)

2) H2, Pd-C

3) repeat 1) and 2)2 times

OO

O

n

O

OO

O

O

O OO

OHOH

O

OHOH

O

O

O

O OH

OH

O

OH

OH

OO

OO

OO

O

O

OH

OH

OOH

OH

OO

O

O

OH

OH

O

OH

OH

106 107

DABCO,CH2Cl2

ON2

SO2Cl

OO

O

n

O

OO

O

O OO

OO

O

OO

O

ON2

O2S

O N2

SO2

O

N2

O2S

O

N2SO2

O O

O

OO

O

O

O

O

O

N2

O2SO

N2

SO2

O

N2

O2S

O

N2

O2S

O

O

O O

O

O

O

O

O

OO

O

O

N2

O2S

O

N2

SO2

ON2

SO2

ON2

O2S

O

OOO

O O

O

O O

ON2

SO2

ON2

O2S

O

N2SO2

O

N2O2S

O

108

SCHEME 1.22 Surface modification able to undergo light-induced degradation.

SUPRAMOLECULAR PERSPECTIVES 35

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O

O O

O

O

O

OO

NHOO

NH

O

O

OO

O

NH

O

O

NH

OMe

OMeMeO

OO OMe

OMe

MeO

O

O

OMe

OMe

MeO

O

O

OMe

MeO

MeO

O

O

OO

O

O

O

HN

O

O

HNO

O

OO

HN

OO

NH

OMe

MeO

MeO

O

O

OMeMeO

OMeO

O

OMeMeO

OMeO

O

OMe

MeO OMe

O O

OO

O

O

OO

n

O

OH3OC

OH

OH

OOH

O

OH3C

OHNH2

O

OH3OC

OH

OH

OOH

O

OH3C

OHNH2

O

OH3OC

OH

OH

OOH

O

OH3C

OHNH2

O

OH3OC

OH

OH

OOH

O

OH3C

OHNH2

O

O O

O

O

O

OO

NHOO

NH

O

O

OO

O

NH

O

O

NH

OHOH

OH

OH

OH

OH

OH

OH

OO

O

O

O

HN

O

O

HNO

O

OO

HN

OO

NH

OH

OH

OH

OH

OH

OH

OH OH

OO

O

O

OO

OMe

MeO

MeO

O

H

Drug releaseby aggregate disruption

O

OH3OC

OH

OH

OOH

O

OH3C

OHNH2

+

+

H+

109

110

SCHEME 1.23 Dendrimer-based micelles modified for acid-promoted drug release.

36 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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first-generation allylic alcohol 113. Reaction of 113withMeldrum’s acid using Shin’s

modification [124] of the Mitsunobu reaction [PPh3, diisopropylazodicarboxylate,

(DIAD)] gave predominantly the C-alkylated product, which was then subjected to

the same sequence beginning with the Pd(OH)2-mediated reduction of the alkene

moieties and ending with the DIBAL reduction to generate the second tier dendron

114; the third-generation construct 115 was obtain analogously stopping at the focal

carboxylic acid, prior to the homologation steps.

Construction of the H-bonding, dimeric (2-ureido-4-pyridinone) units with all

aliphatic dendrons [122], exemplified using the third-generation dendron,

(Scheme 1.25) was achieved by coupling [(PPh3)2PdCl2, Cu(I), NEt3] the alkyne-

modified dendron 116, prepared by transforming the corresponding focal aldehyde

obtained from 115 (Scheme 1.24) with vinyl dibromide (CBr4, PPh3, K2CO3),

followed by n-BuLi elimination using the Corey–Fuchs method to ditriflate 117

(accessed by treatment of the corresponding diol with trifluoromethylacetic anhy-

dride) affording the dendronized aryl diester 118. Reduction of the alkyne moieties

(H2, Pd-C) gave the alkyl-modified diester 119 that was subsequently saponified to the

diacid 120 and treated with diphenyl phosphorazidate (DPPA) and NEt3 to produce,

via a Curtius rearrangement, the diisocyanate 121 in situ.

Attempts to obtain the desired di(2-ureido-4-pyridinone) by reaction with 6-

methylisocytosine proved difficult due to solubility, reduced nucleophilic character of

the aryl amine, and decompositionwhen forcing conditions were employed. Use of an

O-benzyl protected, 2-amino-6-methylpryimidine, a method for the synthesis of 2-

ureido-4-pyridinones reported by Meijer [125], allowed the desired transformations.

Thus, treatment of commercially available 2-amino-4-chloro-6-methylpyrimidine

with benzyl alcohol in the presence of base (NaH) gave the O-benzyl-protected

aminopyrimidine 122 (Scheme 1.26), which was subsequently reacted with the

1), 2)

1) KOH2) Pyr,H2O,

Cl

O O

OEt OEt

1)

2) Pd-C, H2

111

OEtOEt

OO

112

3) LAH4) PCC5) (MeO)2POCH2CO2Me

NaH6) DIBAL

OH

113

1) –6)

OH114 COOH 115

SCHEME 1.24 Synthetic protocol for 1 ! 2 C-branched, aliphatic dendrons.

SUPRAMOLECULAR PERSPECTIVES 37

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dendronized diisocyanate 121 to afford the dibenzyl ether 123. Hydrogenolysis [Pd

(OH)2, H2] to remove the benzyl groups generate the H-bondedmotif, and the desired

supramolecular polymer 124 was effected under dilute conditions to enable the

removal of the catalyst and avoid product precipitation. Notably, upon isolation of

the dendronized polymers, the first- and second-generation materials were difficult to

resolubilize with the second-generation construct being described as “devoid of

solubility in any solvents.” However, the third-generation polymer exhibited excel-

lent characteristics and was highly soluble in nonpolar solvents. For this third-

generation, supramolecular polymer 124, the specific viscosity showed a nonlinear

increase with increasing concentration; above 26mM, a very strong monomer

association was observed—a behavior consistent with other 2-ureido-4-pyridi-

none-based polymers [125]. The UV-vis absorption maximum of the polymer

exhibited a significant bathochromic shift with increasing polymer concentration;

thus, the fibers formed by spin coating and imaged by SEM were described as J-type

aggregates (i.e., end-to-end arrangement and narrow, red-shifted absorption peak). A

model proposed for fiber assembly suggests adjacent, linear H-bonded arrays with

alternating dendritic wedge interdigitation.

An interesting use of branched architecture has been reported by Tang and

coworkers [126], based on the construction of materials that possess high molecular

compressibility and exhibit aggregation-induced emission (AIE). These polymer

nanoaggregates were shown to detect explosive material with a superamplification

effect. Theoretical and experimental evidence has shown the main cause of AIE

to arise from restriction of intermolecular rotation of the phenyl moieties in

such propeller-shaped molecules as tetraphenylethylene and hexaphenylsilole;

DPPA, NEt3

(Ph3P)2PdCl2

CuI, NEt3

G3 H

OTf

OTf

CO2H

HO2C

CO2H

HO2C

G3

G3

DMF, THF

CO2H

HO2C

CH2G3

G3H2C

H2, Pd-black

EtOH, THF

116

811711 119

CO2Et

EtO2C

CH2G3

G3H2C

KOH (G1 and G2)or KOt-Bu (G3)

MeOH, H2O, THF

121021

toluene

+

G3 = third-generation dendron

NCO

OCN

CH2G3

CH2G3

SCHEME 1.25 Construction of a dendritic monomer for use in polymeric, H-bonding,

self-assembly.

38 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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thus, they are nonemissive when in the dissolved state and emit efficiently in the

aggregate state.

Construction of the hyperbranched polymers was envisioned to incorporate

spring-like flexibility between the triazine-based sites of connectivity, thereby

introducing an element of compressibility, which was deemed necessary for

AIE. Synthesis began with the preparation of triazides 125a and b [Scheme 1.27;

where, a¼ hexamethylene and b¼ tetramethylene spacers] accessed by the based-

promoted (K2CO3) alkylation of tris(4-hydroxyphenyl)methane with either

N

N

NH2BnO

N N

N

BnO

NN

N

OBn

CH2G3

G3H2CHN

NH

OOH

H

121

PhCH3,

122 123

H2, Pd(OH)2-C

CHCl3/CH3OHN

N

N

OH

OH

NH

N NH H

OH

N

N O

N

N

N

OH

O

HNH

NNHH

OHN

NO

124

NCO

OCN

CH2G3

CH2G3

SCHEME 1.26 Generation of aH-bonding-based, supramolecular polymer with a dendritic,

all-hydrocarbon coating.

SUPRAMOLECULAR PERSPECTIVES 39

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1,6-dibromohexane and 1,4-dibromobutane, respectively, to give the triaryloxy-

tribromide, followed by transformation of the alkyl bromide groups to the

corresponding azides (NaN3, DMSO). The required divalent tetraphenylethylene

dialkyne monomer 126 was prepared by TiCl4–Zn coupling of a monobromodi-

phenyl ketone to give the dibromotetraphenylethylene that was converted to the

desired alkyne by coupling [Pd(PPh3)2Cl2, Cu(I), PPh3] with trimethylsilyl

acetylene followed by base-mediated (KOH) deprotection.

Synthesis of the hyperbranched constructs 127a and b was effected (Scheme 1.27)

using the high yield “click” chemistry [127–129] based on Cu-catalyzed [Cu

(PPh3)3Br] triazine formation between alkyne and triazide moieties. The Mw of

9800 and 12,400 and polydispersity indexes (PDIs) of 4.32 and 4.28 were obtained

for the hexamethylene and tetramethylene materials hyperbranched materials, respec-

tively. Photoluminescence (PL) experiments revealed the absence of emission when

dissolved in THF and the presence of an emission peak at 490 nm that increased in

intensity with the addition of water, indicative of AIE behavior.

TiCl4, ZnPd(PPh3)Cl2,CuI KOH

HO

NaN3

126

OH

K2CO3

Cu(PPh3)3Br

+ Where,

R = b = (CH2)4

R = a = (CH2)6

126a or b 127a or b

125a or b

125a or b

O

BrSi

Si

Si

OH

Br

Br Br

Br O

O

Br

O

O

N3

N3

R

R

R OR

R

O

N

NN N

N

N

O

NN

N

N3

RO

O

O

BrR

R

R

R

R

SCHEME 1.27 Branched, tetraphenylenes exhibit aggregation induced emission that has

led to new chemosensors for explosives.

40 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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Investigation of materials, as chemosensors, led to an examination of the effect of

picric acid (PA) and trinitrotoluene (TNT) addition to the polymer aggregates in an

effort to find new explosives detection methods. Upon addition, the aggregate

emission decreased progressively with analyte concentration. The phenomena were

attributed to cavities in the aggregates that allowed the analytes entrance in com-

bination with diffusion channels for exciton migration that facilitated the explosive–

exciton contact and subsequent quenching.

Biocompatible, polyglycerol dendrons [130,131] provided the branched scaffold-

ing for dendrimer self-assembly based on a zwitterionic, guanidiniocarbonylpyrole

carboxylate core. Synthesis of the dendritic polyglycerol units was achieved starting

with tandem nucleophilic substitution (NaH, 15-crown-5, 18-crown-6, KI) of 3-

chloro-2-chloromethyl-1-propene [methallyl dichloride (MDC); 128, Scheme 1.28]

using bis(acetal-protected) triglycerol 129 [accessed by either direct bis(acetal)

formation using p-TSA and acetone dimethylacetal or a three-step procedure

involving coupling two equivalents of acetal-modified glycerol with methallyl

dichloride]. Notably, the former method, starting from commercially available,

technical grade triglycerol, easily allowed generation of large-scale, pure quantities

NaH,15-Crown-5,

1) O3

2) NaBH4128

18-Crown-6,KI

130129

1) MsCl

2) NaN3,DMSO

132131

O

CI

CI

O

O

O

OO O

O

O

O

O

O O

O

O

O

O

OO

O

O

O

OO

ON3

O

O

O O

O

O

O

O

O

OO

OHO

O

O

O

O

OO

O

O

O

O

OHO

SCHEME 1.28 Preparation of polyglycerol dendrons.

SUPRAMOLECULAR PERSPECTIVES 41

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of this crucial building block.Use of 15-crown-5 and 18-crown-6 in concert facilitated

the deprotonation of the focal hydroxyl moiety and generated a more reactive

alcoholate anion. Conversion of the disubstituted alkene 130 to the corresponding

alcohol 131was then achieved by ozonolysis (O3), followed hydroboration (NaBH4).

Repetition of the sequence allowed the construction of higher generations. Trans-

formation of the focal hydroxyl moiety to the azide group (132) used for subsequent

“click” coupling to the alkyne-modified core was effected by conversion to the

mesylate (MsCl) and reaction with NaN3.

The H-bonding-based core was prepared starting from the differentiated diester,

pyrrolecarboxylic acid 133 (Scheme 1.29) that was treated with PyBOP (benzo-

triazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), as the coupling

agent, and BOC-protected guanidine to give the guanidinium precursor 134.

Selective methyl ester deprotection (LiOH) gave the corresponding acid, followed

by PyBOP-promoted coupling to propargylamine afforded the desired alkyne 135.

Cu-mediated (CuSO4) attachment of dendron 132, followed by concomitant acid,

alcohol, and amine deprotection (TFA) subsequently generated the zwitterionic

NH

tBuO2CO

HN

NH

NHBoc

ONH

NH

tBuO2C

CO2Me

O

HN

NH

NHBocNH

tBuO2C CO2H

CO2Me

NH

O

HNNH2

NH2

ONH N N

O O

O

HOHO

OH

OH

O

OO

OHOH

OH

OH

N

O

O

PyBOPPyBOP

Boc-guanidine propargylamine

N O

NNH

N

O

NH

N N

O

OO

OHHO

OH

OH

O

O

O

OHHO

OH

OH

NO

O

H

HH

H

H

HNO

NN

N

O

HN

NN

O

OO

HO OH

HO

HO

O

O

O

HO OH

HO

HO

NO

O

H

HH

H

H

H

O

OO

O

O

OO

O O

O

O

O OO

N3

CuSO4, DIPEA,Sodium ascorbate

~ pH 6

135134133

132

136

137

SCHEME1.29 Zwitterionic carboxylate-guanidinium self-assembly provides a unique core.

42 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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aminoacid core 136; control of the pH within the range of 5 to 8 allowed dimer

formation and supramolecular assembly of ionic-based dendrimer 137.

A fascinating study by Loeb and coworkers [132] has provided further insight into

the utility of dendritic architecture of positional in multicomponent molecular

devices. Whereas, studies focusing on the use of large dendrimer units as end-

capping, stoppers to secure the wheel component on molecular shuttles have been

reported [133], attachment of dendrons to both the axle and wheel provides a new

method to control wheel positioning on the axle (Fig. 1.6). Thus, the major

conformation in the Frechet-type, polyarylether-modified 1,2-bis(pyridinium)eth-

ane [25] crown-8-based shuttle is the “short” conformation 138 that was postulated to

arise due to dendron interdigitation; in contrast, the “long” conformation 139 exists as

N NN N

N N

O

OO

O

OO

O

O OO

OOO

O

O

O

O

OO

O

N NN N

N N

O

OO

O

OO

O

O OO

OOO

O

O

O

O

OO

O

138

139

“minor” long conformation

“major” short conformation

FIGURE 1.6 Dendrimer-based, positional control of molecular shuttle components.

SUPRAMOLECULAR PERSPECTIVES 43

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Cl

N

SO3

N

O3SNa

N

SO O

O

N

SO3

NH

NH

Cl

Cl

O1) POCl3,

DMF

2) Aniline

141140

142

143

SCHEME 1.30 Synthesis of a dye with near-IR fluorescence for the construction of

imaging agents.

NO2CH3

O

O

O2N

O

O O2N

OO

O

O

OO

O2N

OHO

O

O

OHO

H2N

OO

O

O

OO

O

O

O2N

O

O

O

O

NH

OO OO

O

O

NH

OO OO

O

O

O2N

O

OH

O

O

NH

OO OO

O

O

NH

OO OO

O

O

O2N

O

NH

O

O

NH

OO OO

O

O

NH

OO OO

O

O

NH2

H2NNHBoc

DIPEA Triton B

HCO2H

1-HOBT,DCC

Pd-C, H2

1) HATU,DIPEA,

Cl

N

SO3

N

O3SNa

O2N

O

NH

O

O

NH

OO OO

O

O

NH

OO OO

O

O

HN

NSO3

NSO3

Na+

2) HCO2H

144

146

147

145

148 149

SCHEME 1.31 Construction of dendrons with site-specified attachment points.

44 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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the minor conformation, where the dendrons are separated. For example, variable

temperature (VT) NMR studies, comparing the integration ratios for the major versus

minor tert-butyl proton absorptions reveal an 88:12 major-to-minor conformational

mixturewhen both stoppers are generation 2.Varying the generation size on the crown

component from G0 to G1 gave similar major-to-minor results of 83:17 and 87:13,

respectively.

H2N

O

O

O

NH

OO OO

O

O

NH

OO OO

O

O

NH

OO

O

O

OO

H2N N3

1) FMOC-linker-CO2H

NH

O

O

O

NH

OH

O OHOOH

O

NH

OH

O OHOOH

O

NH

OHO

OH

O

OHO

O

O

HNO

OOH2N

2) Formic acid

1)

HATU

3) Near-IR dye 143

2) Piperidine

NH

O

O

O

NH

OO

O

NH

OO

O

NH

O

O

O

O

O

HNO

OO

NH

N3

NH

N3

NH

N3

NH

N3

NH

N3

NH

N3HN

N3

HN

N3

HN

N3

HN

N

O3S

NO3S

Na+

150

151

152

SCHEME 1.32 A dendronized, aminocyanine dye prepared as a near-IR imaging agent.

SUPRAMOLECULAR PERSPECTIVES 45

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Weck and coworkers [134,135] have employed Newkome-type dendrons for the

construction of imaging agents, based on aminocyanine dyes that possess fluores-

cence in the near-IR (NIR) region of the spectrum, cyanine-based materials that

fluoresce in the NIR range are of great interest for in vivo optical imaging due, in part,

to overcoming background fluorescence from deep tissue biomolecules and their

proven biocompatibility with regards to safe use.

The cyanine dye, that is essentially a “push-pull” alkene, was accessed starting

from trimethylindolenine 140 (Scheme 1.30) that was reacted with 1,3-propanesul-

tone to give the indolinium salt 141, which was subsequently treated (NaOAc, EtOH)

with the iminium chloride salt 142 (prepared by reaction of cyclohexanone with

POCl3, DMF, and aniline) to generate the desired zwitterionic cyanine dye 143.

A series of dendrimer-based cyanines were prepared from dendrons utilizing

terminal site-specific and focal dye attachment. Dendrons capable of single-site dye

connectivity (Scheme1.31)were constructedwith 1 ! 3C-branched building blocks

starting with nitrobenzyl ester 144 (prepared by treatment of the MeNO2 with one

equivalent of benzyl acrylate), which was further elaborated with tert-butyl acrylate

to give the functionally differentiated triester 145. Following removal of the tert-butyl

moieties (HCO2H) and coupling (DCC, HOBT) with the aminotriester 146

(“Behera’s” amine), the hexa-tert-butyl ester was derived, which was next debenzy-

lated (Pd-C,H2) to give themonoacid 147 and treatedwith amono-Boc-protected 1,6-

diaminohexane. Liberation of the Boc-protected amine (HCO2H) afforded the

modified dendron 148 that was finally treated with the cyanine dye to give the

dendronized dye 149.

Focally-modified dendrons allowing further functionalization at the dendritic

surface were prepared (Scheme 1.32) utilizing second-generation, Newkome-type,

amide-based dendrons 150 (prepared by treatment of the nitrotriacid analog of 146

with three equivalents of Behera’s amine). Thus, reaction of 150with a Fmoc-amino-

protected polyethylene glycol linker afforded the amino-protected nonaester. Depro-

tection of the carboxylic acids (HCO2H) to give the poly acid 151 and reaction with an

azidoamine gave the polyazidoamide that was subsequently treated with piperidine to

remove the Fmoc group and attached to the cyanine dye yielded the desired modified

imaging agent 152. Monomeric and H and J aggregates were observed in the

absorption spectra with their formation observed to be strongly independent on

linker length and dendron structure. Cytotoxicity studies of these hybrid structures

indicated their nontoxic nature.

1.3. CONCLUSIONS

It is hoped that the reader has gained an appreciation of the vast utilitarian

potential that dendritic chemistry offers, especially in light of current develop-

ments in the nanoscience arena. It is clear that the dendritic architecture will

continue to play an important role in the structural foundations in many fields,

including spectroscopy, electronic, and molecular devices, and drug delivery.

From our perspective, the ability to integrate iterative synthetic methodology

46 DENDRIMER CHEMISTRY: SUPRAMOLECULAR PERSPECTIVES AND APPLICATIONS

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with more mature chemistry regimes will be a major driving force in material

science for foreseeable future.

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