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
(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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
RuP(c
yhx)
3
Cl C
lP
h
Sn
P(c
yhx)
3
NaO
Me
5857
SCHEME1.13
(Continued)
SUPRAMOLECULAR PERSPECTIVES 21
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
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
(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
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
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
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
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
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
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
(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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
with more mature chemistry regimes will be a major driving force in material
science for foreseeable future.
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