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385
MOLECULAR RECOGNITION
IN DENDRIMERS
Introduction
Dendrimers are highly branched polymers that can be obtained with a very high
degree of control (1–10). The degree of control that is obtainable in dendrimers
is often touted as being matched by those only seen with biopolymers. Ever since
the first report of dendrimer synthesis (11), a number of possible applications for
these molecules were envisioned (7,12). Several of those imaginative ideas are
being brought to practice with these new macromolecular architectures. The sem-
inal work of Newkome and Tomalia also has to be credited for bringing this area of
research to the forefront (13,14). A particular theme that has emerged out of these
new molecules is to use these scaffolds for molecular recognition (15). Structurally,
dendrimers have three different locations of interest: a core, highly branched inte-
rior building blocks, and functionalities in the periphery. The features that render
these macromolecules as ideal candidates for molecular recognition are that (1)
dendrimers can be obtained in a highly monodisperse form, ie, with a high degree
of control over molecular weight; (2) They adapt a globular conformation at higher
generations, thereby generating space in its interior for binding guest molecules;
(3) The core of the dendrimer is often well-encapsulated from the solvent environ-
ment; (4) The ability to functionalize the periphery of the dendrimers allows for a
high density presentation of functionalities.
Encyclopedia of Polymer Science and Technology. Copyright John Wiley & Sons, Inc. All rights reserved.
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MOLECULAR RECOGNITION IN DENDRIMERS
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Binding events between two molecules (a host and a guest) occur due to
certain attractive forces. These could be dispersion forces such as
π-stacking,
metal–ligand interactions, hydrogen bonding, hydrophobic interaction, ionic in-
teraction, or other electrostatic attractions. In this article, we will focus mainly on
hydrogen-bonding-based recognition and hydrophobic forces. We will make occa-
sional reference to ionic interactions and
π-stacking within the two topics above.
Dendrimers based on metal–ligand interactions are not included in this review
and interested readers are referred to other recent review articles on this topic
(6,16,17) (see also D
ENDRONIZED
P
OLYMERS
).
Synthesis of Dendrimers
Syntheses of dendrimers can be achieved mainly through two complementary
methods: (1) a divergent approach and (2) a convergent approach (18). Both
approaches use AB
n
monomer units and utilize protection–deprotection (or
masking–unmasking methodologies) to grow the dendrimer. The divergent syn-
thesis starts from the core and the periphery grows as more synthetic iterations
are performed on the same molecule (Fig. 1). Therefore, the reactive functionalities
are always in the periphery of the dendrimer. In the convergent synthesis, the den-
dritic growth occurs at the focal point of the dendron or dendrimer, since the growth
takes place from the periphery to the core (Fig. 2). The divergent approach and
the convergent approach are shown schematically in Figures 1 and 2, respectively.
There are advantages and disadvantages to both of these approaches. Since
the reactive functionalities are in the periphery of the growing dendrimer in the
divergent approach, the reactivity of these groups is retained even at high gener-
ations. However, in the convergent synthesis, since the reactive functional group
is at the focal point of the dendrimer, this functionality tends to get encapsulated
at higher generations. Therefore, it becomes less reactive and it is difficult to
Fig. 1.
Schematic representation of the divergent approach.
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MOLECULAR RECOGNITION IN DENDRIMERS
387
Fig. 2.
Schematic representation of the convergent approach.
produce very high generations using the convergent approach. Also, note that the
number of reactions that needs to be done on a single dendrimer molecule doubles
with each generation in the divergent synthesis (Fig. 1). This results in defects in
the dendrimer structures at higher generations. In the convergent synthesis, the
number of reactions to be performed in a particular molecule always remains the
same, independent of the generation. Therefore, achieving a pure, monodisperse
dendrimer is more likely. Dendritic systems such as the commercially available
polyamidoamine (PAMAM) and poly(propylene)imine (PPI) dendrimers are syn-
thesized through a divergent approach. Dendrimers such as the Newkome den-
drimer, silane-based dendrimers, and the phosphorus based dendrimers are also
made using a divergent approach (13,19,20). Benzyl ether and phenylacetylene
dendrimers are the two main classes of dendrimers that have been synthesized
using a convergent approach (4,5).
Since dendrimers are often pursued as globular protein mimics, it is useful
to be able to vary each monomer unit from the other, ie introduce sequences within
dendrimers. For achieving such a possibility, the convergent approach is an ideal
synthetic protocol. The Thayumanavan group has developed two synthetic pro-
tocols in which the peripheral functionalities of the dendrimers are all different
from each other (21,22). In the first approach, we used an AB
2
monomer unit in
which one of the B units is protected. This approach was demonstrated by the
monoprotection of one of the phenolic groups of 3,5-dihydroxybenzyl alcohol with
an allyl moiety. The resultant monomer was treated with one alkylating agent to
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Fig. 3.
Schematic representation of ABB
p
sequencing methodology.
cleanly afford the monosubstituted compound. The allyl group was deprotected
and the resultant phenol was then treated with a second electrophile to afford the
differentially substituted G1 dendron. Conversion of the hydroxymethyl moiety
to bromomethyl group and iterations of the above-mentioned steps resulted in
higher generation dendrons, as schematically shown in Figure 3.
In an alternate approach, an ABB
monomer was used as the building block
unit. In this monomer, under a certain condition the functionality B reacts with
A selectively, while A can react with B
under a different set of conditions. The
repeat unit used for this purpose was ethyl 3-hydroxy-5-hydroxymethylbenzoate.
Here B is the phenol, B
is the primary alcohol, and the masked form of A is the
ester group. This approach is schematically shown in Figure 4. Another facile
route that is capable of introducing sequences within dendrimers was developed
by Simanek, where three different functionalities can be reacted one at a time
with a traizine core (23).
Fig. 4.
Schematic representation of ABB
sequencing methodology.
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Hydrogen Bonding
Hydrogen bonding has been a fascinating tool for molecular recognition for
chemists, since it is ubiquitous in nature’s recognition processes and is highly
directional. The directional nature of hydrogen bonds allows control over the rela-
tive orientation of the host–guest molecular framework. Hydrogen-bonding-based
interactions are often weak in the presence of polar and/or protic solvents or in the
presence of other competitive guest molecules. This feature has led to the design of
the reversible incorporation of guest molecules that could find use in applications
such as catalysis, separations, and controlled drug release.
Hydrogen Bonding within Dendritic Interiors.
Newkome and co-
workers incorporated 2,6-diaminopyridine units as the host recognition func-
tionalities within dendrimers (24). The dendrimer host containing the donor–
acceptor–donor (DAD) hydrogen-bonding receptor was able to bind glutarimide
containing the complementary acceptor–donor–acceptor (ADA) units with 1:1
functional stoichiometry (Fig. 5). The apparent association constant was found
to be about 62–70 M
− 1
. Newkome also noted that the analysis was complicated
by additional complexation sites within the dendrimer backbone, as they weakly
compete for the guest molecule. Similarly, Santo and Fox have also studied the
hydrogen-bonding interaction between dendrimers and several heterocyclic guest
molecules (25). These authors noticed that the binding efficiency depends on the
nature of the peripheral functionalities of PAMAM dendrimers. It is also inter-
esting to note that PAMAM dendrimers have been shown to be capable of accom-
modating guest molecules such as 2-naphthol in their interior, which can then be
released upon a pH change (26). These interactions are presumed to be due to
hydrogen bonding.
Specific binding between a dendrimer host and a complementary guest
molecule was also achieved by Zimmerman and co-workers, where they used
benzyl ether or phenyleneethynylene dendrimer backbone (27). In this work,
naphthyridine units were incorporated into the focal point of dendrimers, and
complementary benzamidinium-based molecules were used as guests (Fig. 6).
The authors found the association constant (K
a
) of this host–guest interaction
to be independent of the dendrimer generation and is dependent only on the na-
ture of the solvent in which it is measured. These results were taken to suggest
Fig. 5.
Structure of the Newkome dendrimer that binds glutarimide.
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Fig. 6.
Structure of the dendrimer with a naphthyridine core.
that dendrimers are highly porous in nature and that the dendritic interiors are
solvent-filled. This is an interesting result, considering the report by Fr´echet,
where the solvatochromic shifts of a chromophore incorporated in the core sug-
gests that the polarity of the dendritic interior is dictated by the dendrimer back-
bone and not the bulk solvent (28).
Diederich and co-workers incorporated optically active binaphthol at the core
of benzyl ether dendrimers (29). The diol moiety in the core was converted to the
corresponding phosphates, which were used for carbohydrate recognition (30).
Although, they observed a 1:1 association with glycosidic guest molecules, the
binding selectivity was observed to be weak. Also, the association strength did not
change significantly with dendrimer generation. This observation is consistent
with Zimmerman’s results mentioned above. Fluorescence-based enantioselective
recognition of amino alcohols was also attempted with BINOL-cored dendrimers
(31). The proof-of-principle for such a possibility is reported, although the enan-
tiodiscrimination using these dendrimers is moderate. The fact that the fluores-
cence quenching is not dependent on amino alcohol concentration leads to the
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391
Fig. 7.
Structure of a dendrocleft.
conclusion that the quenching occurs because of the hydrogen bonding between
the core of the dendrimer and the amino alcohols.
Carbohydrate recognition has also been achieved with dendrimers by
Smith and Diederich (32). These so-called dendroclefts are made up of a
9,9
-spirobi[9H-fluorene] initiator core containing 2,6-di(carboxamido)pyridine
moieties (Fig. 7). Upon increasing the dendrimer generation, it was noted that
the discrimination of enantiomeric guest molecules became poorer, whereas dis-
crimination between diastereomeric guest molecules became better. This was at-
tributed to the difference in steric demands of the dendritic shell or to the possible
participation of the peripheral functionalities in the host–guest hydrogen-bonding
network.
Molecularly imprinted polymers have been approached as a possible mode of
performing host–guest chemistry in recent years (33). However, the limitations of
these methods include incomplete template removal, broad guest affinities, and
slow mass transfer. The molecular homogeneity, monodispersity, and large solu-
bility of dendrimers make them good choice for the molecular imprinting process.
Recently, Zimmerman and co-workers used their cored-dendrimer concept (34)
to template porphyrins with benzyl ether dendrimer (35). The hollow core of the
dendrimer contained eight carboxyl groups inside the dendritic core, capable of
hydrogen bonding with complementary guest molecules. They showed that dif-
ferent porphyrin-based guest molecules can bind reversibly to the host structure
(Fig. 8) (36).
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 8.
Molecularly imprinted dendrimers.
Hydrogen Bonding in the Dendritic Periphery.
While host–guest in-
teraction in the dendritic interior is interesting because of the unique environ-
ment that dendrimers often provide in their interiors, reversible modification
of dendritic periphery is also interesting. Meijer and co-workers showed that
PPI dendrimers with modified urea functionalities can be utilized to bind guest
molecules that are also urea-based (37). It was also shown later that a thiourea-
based host functionality is better than urea itself for the urea-based guests (Fig. 9)
(38). The observation was confirmed by isothermal calorimetry studies. Since both
host and guest molecules are based on urea functionalities and since the periph-
ery of the dendrimers contains a high density of the urea functionalities, there is
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393
Fig. 9.
Binding of urea guest molecules with thiourea functionalities in the dendritic
periphery.
an obvious opportunity for intramolecular hydrogen bonding in these dendrimers.
When there is an increased intramolecular hydrogen-bonding interaction, it was
observed that the host–guest interaction is weaker. The authors attributed this
observation as the probable reason for thiourea being a better host. They suggest
that the soft interaction between the molecules owing to the presence of sulfur
compared to oxygen provides a less dense structure, which is more accessible to
guest molecules.
An elegant application of this method was shown by Reek and Meijer, where
this type of dendrimer was used as catalytic support for palladium-catalyzed al-
lylic amination reactions (39). The periphery of the dendrimer contains many
adamantyl-functionalized urea groups (Fig. 10), and the catalyst was designed
to have complementary hydrogen-bonding elements along with a triphenyl phos-
phine moiety, a ubiquitous ligand in organometallic catalysis. The presence of
multiple catalytic sites in a single dendrimeric support did not hamper the reac-
tion rate, showing that the phosphine ligands were independent of each other. It
was also easy to recover the ligand from the support, which could then be reused.
An interesting work by Kim showed that the periphery of the dendrimers
can be reversibly manipulated through noncovalent interactions (40). They used
Cucurbituril as the molecular bead that encapsulates the amino butane periph-
eral units (Fig. 11). The pseudorotaxane-terminated dendrimers not only gave a
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Fig. 10.
A recoverable catalyst using hydrogen-bonded host–guest dendrimer.
topologically novel dendritic structure but also suggested that these structures
can be useful for applications such as drug delivery upon appropriate redesign.
Intramolecular hydrogen bonding among the periphery units in dendrimers
has been effectively used for binding guest molecules. Meijer’s group has shown
that the intramolecular hydrogen bonding among the peripheral units can be
used to construct a so-called dendritic box. Intramolecular hydrogen bonding is
Fig. 11.
Dendrimers with noncovalently bound cucurbiturils (the cylindrical objects de-
note cucurbiturils).
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395
shown to result in dendrimers with a solid-shell structure and a flexible core
(41,42). The hydrogen bonding units were generated from the derivatization of
the primary amino groups in PPI dendrimers with Boc-protected amino acids.
Guests were incorporated inside the dendrimers while functionalizing the pe-
ripheral amino groups. Typical guest molecules used include 3-carboxy-PROXYL
radical, erichrome black, and rose bengal. All these guest molecules contain car-
boxylic or sulfonic acid functionalities, which bind to the dendritic interior con-
taining tertiary amines presumably through acid–base interactions. Note that the
role of hydrogen-bonding periphery in these dendrimers is not to provide specific
interactions with the guest molecules, but rather to provide a solid shell to trap
the guest molecules. Meijer noted that size-selective release of the trapped guest
molecules is possible by first deprotecting the Boc groups and then by hydrolyz-
ing the amino acids from the dendrimer under rather harsh conditions (Fig. 12)
(43,44).
Biomimetic Materials.
The large structure of dendrimers and their glob-
ular shape has attracted significant attention because of its potential application
as biomimetics, especially as enzyme mimics. The work by Aida and co-workers
showed the function of dendrimers as a hemoglobin mimic (45). Aryl ether den-
drimers were used to encapsulate iron(II)–porphyrin 1-methylimidazole complex
(Fig. 13). The oxygen-binding ability of the complex increased with the dendrimer
generation where the dioxygen molecule binds to the complex, instead of the
µ-
oxo-dimer formation observed for lower generations of the dendrimers. Another
important result from this study was that the oxygenated complex was very sta-
ble toward carbon monoxide, which holds exciting possibilities in itself. However,
in this work, the use of 1-methylimidazole apparently complicated the study of
oxygen affinity measurements.
Interestingly, Collman and co-workers used 1,2-dimethylimidazole (dimim)
which formed 1:1 high spin iron(II) adduct (Fig. 14) (46). It was found that the ratio
of the two binding constants K
CO
/K
O2
of this complex was very low, as compared to
T-state hemoglobin and the picket fence Fe(II)–dimim complex. The probable rea-
son is that the bound dioxygen molecule formed hydrogen bonding with the amide
NH-groups of the dendritic backbone used. The destabilization of the CO ligand
was thought to be an unfavorable steric interaction between the CO and the den-
dritic branch. These results were further supported in a later publication, where
the O
2
binding studies were performed (47). It was noted that the complexation
of first and second generation of the amide-based dendrimers show efficient O
2
binding, whereas the control molecule without the amide bonds showed reduced
stability for the dioxygen complex. Also for the first and second generation of the
amide-based dendrimer, it was seen that in the presence of solvents like water,
the oxygen affinity of these compounds decreased, clearly showing the effect of
competing hydrogen bonding between water and the dendritic branches.
The emission properties of tryptophan (Trp) have been widely used in bio-
physical studies of proteins. Recently, Smith and M ¨
uller used Trp to probe the
dendritic microenvironment by attaching the amino acid to polyether dendrimers
and studying their fluorescence spectra (Fig. 15) (48). It was observed that in the
presence of non-hydrogen-bonding solvents, the dendritic effect (shift of
λ
max
) was
profound. The argument was that in presence of non-hydrogen bonding solvents,
there was effective hydrogen-bonding interaction between the amide H-atom of
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 12.
Dendritic box and selective guest release.
Trp and the carbonyl groups of the dendrimer, which leads to the shift in the emis-
sion spectra. It was seen that the hydrogen bond acceptor solvents do not change
the character of the spectra much, which is understandable. Also, the hydrogen
bond donor–acceptor solvents showed negative dendritic effect owing to the com-
petition faced by the Trp, from the solvents. It was proposed that strong hydrogen
bonding between the Trp and dendritic branch resulted in a change of the polar-
ity of Trp’s microenvironment, resulting in an emission shift. This proposal was
further supported in a later publication where they took Trp along with another
compound where the
NH group of the indole ring has been changed to N Me
(49). No dendritic effect was observed in this case.
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397
Fig. 13.
Porphyrin dendrimer with oxygen-binding ability.
Parquette and Huang showed that the hydrogen-bonding effects within the
dendritic interior could result in a particular helical bias in a dendrimer, and
that the chirality can be transferred from the core to the periphery. Working with
pyridine-2,6-dicarboxamide, they first showed the synthesis and characterization
of dendrimers whose conformations at different levels are somewhat restricted
because of intramolecular hydrogen bonding (Fig. 16) (50). The stability of helical
secondary structure in these dendrimers is dramatically enhanced by linking each
generational shell through an anthranilamide turn unit (51). Circular dichroism
studies on these intramolecularly hydrogen-bonded dendrimers revealed that the
interconversion between the two diastereomeric helical conformations (M and P
helices) relating a pair of anthranilamide termini depends on solvent, temper-
ature, and dendrimer generation (52). More recently, they have shown that the
compaction levels of these dendrimers can be modified by varying the linkers in
the central core of the dendrimer (53).
Sensors.
An obvious application of molecular recognition is in the area
of sensory materials. Several aspects described above can be exploited to gen-
erate sensors. There have been a particular interest in anion sensing with den-
dritic structures. Significant contributions in this field have been made indepen-
dently by Astruc and Kaifer. Astruc and co-workers studied the binding effect
of several anions, including HSO
4
−
, H
2
PO
4
−
, and Cl
−
, on different dendrimer
generations (54). The dendritic effect was most pronounced with H
2
PO
4
−
an-
ions. Using polyamido ferrocene dendrimers, they showed that with increase in
generations, the E
1
/2
value for ferrocene wave increased with the addition of the
H
2
PO
4
−
anions (Fig. 17). It was proposed that the H
2
PO
4
−
anion interacts with
the dendrimers via a synergy between electrostatic and hydrogen-bonding inter-
actions. The fact that more H
2
PO
4
−
anions are needed for higher generations
of dendrimer was taken to suggest that the H
2
PO
4
−
units are interacting with
the amide moieties present in the dendritic backbone. The sensory effect was
maximum for the dendrimer with 18 ferrocene units, indicating that the steric
factors become important in larger generations. This work was extended further
by attaching AB3 phenol units p-OH C
6
H
4
C(CH
2
CH CH
2
)
3
and p-OH C
6
H
4
C
[(CH
2
)
3
SiMe
2
CH
2
NHCOFc]
3
, with different generations of polypropyleneimine
dendrimers (55). The molecules here were assembled by hydrogen bonding. The
characterization by cyclic voltammetry (CV) and NMR methods proved that the
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Fig. 14.
Iron–porphyrin dendrimer by Collman and Diederich.
sudden wave changes, alterations of half stoichiometry, and decrease of peak in-
tensity in CV are all affected by dendrimer generations. On a similar note, Kaifer
and co-workers showed that similar hydrogen-bonding-mediated anion sensing
can be performed via ferrocenyl urea dendrimers (56). The results here are sig-
nificant since all the studies were done in DMSO, where the competing solvent
effects would seem to make the anion sensing less feasible.
Dendrimer Assemblies.
Supramolecular assembly is not a new area of
research and chemists have been involved in this field for a long time. However,
controlled assembly of well-defined macromolecules is often seen only in nature.
Dendrimers are ideal scaffolds as artificial proteins and enzyme mimics, since
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399
Fig. 15.
Tryptophan dendrimers.
they have large molecular weights, are monodisperse, and are easy to functionally
manipulate. Zimmerman showed that hydrogen-bonding-mediated assembly of di-
dendrons can be achieved by complexing monodendrons with a 1,9,10-anthyridine
core and ditopic complementary guest molecule (Fig. 18). A 2:1 complex was
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 16.
Dendrimers with helical bias due to intramolecular hydrogen bonding.
observed between the anthyridine core with three hydrogen bond acceptor func-
tionalities (AAA) and guest molecules containing benzamidine groups with two
hydrogen bond donor abilities (DD). High association constants were observed
between these complementary hydrogen-bonding motifs. A small molecule con-
taining two benzamidine group was used to assemble two dendrons containing
the naphthyridine core (57).
Similarly, Smith and co-workers showed the scope of dendritic assembly
through the interaction between a crown-ether core and divalent ammonium ions
(58). Lysine-based dendrons were built with crown ethers at the focal point. These
dendrons assembled into didendrons upon a 2:1 binding with a guest molecule
containing two ammonium moieties. This supramolecular assembly of dendrons
was easily dislodged using K
+
ions, as the latter competes for the crown ether
(Fig. 19). In a later publication, the same group reported the supramolecu-
lar assembly of the similar dendrimers based on aliphatic diamines (59). The
two-component gel-phase materials reported here are attributed to the length
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Fig. 17.
Anion sensing ferrocene dendrimers.
Fig. 18.
Dendron with the DDD motif and the complementary guest.
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 19.
Deaggregation of crown-cored dendrons.
of the hydrophobic spacer and the potential hydrogen-bonding units within the
amino acid branches. Similarly, Gibson reported a tritopic R
2
NH
2
+
moiety, which
exhibited the ability to assemble dendrons cooperatively (60,61).
Another interesting dendrimeric assembly strategy was shown by Stoddart
and co-workers, where they introduced the concept of mechanically interlocked
branching units in the dendrimer (62,63). Here the dendrons are attached to par-
ticular components, which are involved in mechanical bonding with catenanes or
rotaxanes. A bis-dibenzo[24]crown-8 core was attached to R
2
NH
2
+
type compound,
where R is a benzylic group. The association constant for those assemblies was
found to be quite high. After association, benzyl ether dendrimers were attached
while maintaining the association in good yield (Fig. 20). Stoddart also reported
a similar assembly of dendrimers by a slippage methodology (64).
Assemblies higher than dimeric and trimeric ones have also been re-
ported with dendrimers. Zimmerman attached benzyl ether dendrimers to a core
containing two-isophthalic acid units (65). The self-complementary nature of car-
boxylic acids is expected to provide either a polymeric or a hexameric aggregate
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403
Fig. 20.
Dendrimers with mechanical branching.
via hydrogen bonding (Fig. 21). The SEC and NMR data showed the hexameric
structure to be predominant. An advantage for the hexamer aggregation was the
subtle interplay between favorable hydrogen bonding and van der Waal’s interac-
tion, and the unfavorable steric interactions between the adjacent dendrimers in
competing aggregates. The hexameric aggregate structure was further supported
by SANS (small-angle neutron scattering) studies (66).
The hexameric assembly based on carboxylic acid moieties mentioned above
exhibited low stability in moderately competitive solvents like THF. Also, only cer-
tain generations of dendrimers (G2 and G3) formed hexameric aggregates, while
G1 did not form any stable hexameric assembly. Keeping this in mind and also
the fact that nature has chosen heterocycles to form hydrogen bonds in nucleic
acids, Zimmerman and Kolotuchin synthesized and characterized a new molecule
capable of forming hexameric assemblies (Fig. 22) (67). This compound formed
hexameric aggregates and were stable in dilute THF solutions. Encouraged by
this result, they attached different generation dendrons to this species and char-
acterized the assemblies (68). From NMR titration data, it was shown that the
stability of the hexameric assemblies was (A)6-G1
> (A)6-G2 > (A)6-G3. Also
when (A)6-G1 and (A)6-G3 were mixed together, they formed one structure out
of about 13 possible structures. This indicated that the discrete aggregates were
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Fig. 21.
Carboxylic acid based hexameric dendrimer assembly.
self-selected, and one can play with the supramolecular structures by making sub-
tle variations in different parameters like temperature, solvent, and steric effects
(69). Even higher order assemblies using liquid crystalline dendrimers have been
achieved by the elegant work of Percec and co-workers (70,71). Discussion of those
structures is beyond the scope of this review. Similarly, dendrimers also have been
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405
Fig. 22.
Stable hexameric assemblies designed by Zimmerman.
shown to form hydrogen-bonding-based network assemblies with themselves or
with other polymers, the discussion of which is not included in this article (72–77).
Host–Guest Interaction Based on Amphiphilicity
The globular nature of dendrimers at high generations provides significant op-
portunities for dendrimers to be used as hosts in a variety of ways. One of the
most prominent interactions involves the formation of dendrimers with micel-
lar or inverse-micellar characteristics. In this section, we will discuss host–guest
interactions based on hydrophobic or solvophobic pressure. We will also discuss
binding based on ionic attractions including acid–base interactions within this
section, since these have been used along with amphiphilicity to enhance binding
in several cases.
Dendrimers as Micelles.
In their seminal work, Newkome and co-
workers designed and synthesized a dendrimer called micellanoic acid with an all-
hydrocarbon interior and carboxylic acid periphery (Fig. 23) (78). They showed that
these dendrimers are water-soluble and are capable of sequestering hydrophobic
substituents in their interior. The guest molecules include spectral probes such
as phenol blue, naphthalene, pinacyanol chloride, and diphenylhexatriene. By
comparison with classical amphiphiles such as SDS, it was shown that the crit-
ical micelle concentration (cmc) of these dendrimers is very low. Therefore, they
called these dendrimers as unimolecular micelles (79). Binding abilities of some
of these amphiphilic dendrimers have also been investigated using electrokinetic
chromatography and electrochemistry (80–83).
Similarly, amphiphilic dendrimers with carboxylic acid peripheral groups
and benzyl ether interior were synthesized by Fr´echet and co-workers (Fig. 24)
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 23.
Structure of micellanoic acid.
(84). The carboxylate salts of these dendrimers are water-soluble and are capable
of sequestering apolar guest molecules, such as pyrene. Spectral analysis indi-
cated that about 0.45 molecules of pyrene was found per dendrimer. Fr´echet also
demonstrated that this could be increased to 0.7 molecule of pyrene per dendrimer
by increasing the ionic strength of the solvent. This is a significant number and
is comparable to classical micelles based on small molecule amphiphiles. The cmc
values for these dendrimers seem to be nonexistent or below the detectable lim-
its, reiterating the ability of dendrimers to function as unimolecular micelles.
These dendrimers also demonstrated the ability to act as recyclable solubilizing
agents.
Kraska and Seyferth synthesized water-soluble carbosilane dendrimers
based on simple hydrosilation and alkylation reactions (19). The sulfonate-
terminated and tetralkylammonium-terminated amphiphilic dendrimers have
been shown to act as micelles. These dendrimers are capable of sequestering alkyl
benzenes (toluene, ethyl benzene, or propyl benzene). It was estimated that a
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MOLECULAR RECOGNITION IN DENDRIMERS
407
Fig. 24.
Structure of micellar benzyl ether dendrimer.
second-generation dendrimer with 16 sulfonate groups in the periphery was able
to sequester about two to three alkyl benzene molecules in its interior.
Turro and co-workers studied amphiphilic PAMAM dendrimers with dif-
ferent alkyl chain lengths at their core (85). Specifically, diamino derivatives of
ethane, butane, octane, and dodecane were studied. The amino groups were placed
at the terminal carbons of these n-alkanes. The ability of these dendrimers to
sequester hydrophobic derivatives was studied by using Nile red as the guest
molecule. They observed that the sequestering ability depends both on the den-
drimer generation and the length of the alkyl chain in the core. They were able to
demonstrate that the dye molecule is bound closer to the alkyl chain at the core, in
case of long alkyl chains. It was also shown that the ability of the dendrimers to se-
quester apolar guest molecules is enhanced by adding a surfactant to the aqueous
solution of the dendrimer. The location of the dye molecule in this case also de-
pends on the length of the alkyl chain at the core, as shown in Figure 25. Note that
the ability to generate both amine-terminated and carboxylic-terminated PAMAM
dendrimers render them capable of sequestering guest molecules based on ionic
interactions. This capability has been exploited by the research groups of Turro
and Tomalia (86,87).
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 25.
Location of the dye in amphiphilic PAMAM dendrimers and surfactant mixture.
An interesting variation to the amphiphilic dendrimers shown above was
synthesized by Pan and Ford (88,89). PPI dendrimers were derivatized at their
periphery with both alkyl chains and triethyleneglycol monomethyl ether (TEG)
moieties (Fig. 26). They observed that these dendrimers are not soluble in water,
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MOLECULAR RECOGNITION IN DENDRIMERS
409
Fig. 26.
Structure of amphiphilically modified peripheries designed by Ford.
surprisingly even at low pH. However, they were able to render these den-
drimers soluble in water by further derivatizing these dendrimers into qua-
ternary ammonium salts. Aqueous solutions of these dendrimers were able to
accommodate apolar guests such as pyrene or Reichardt’s dye. Furthermore, these
dendrimers also exhibited the ability to catalyze the decarboxylation reaction of
6-nitrobenzoisoxazole-3-carboxylate ion. A rate increase of 200–500 times was ob-
served in the presence of the dendrimer, compared to the rate of the reaction in
pure water.
In proteins, almost all the side chains of hydrophobic amino acids are directed
toward the interiors in globular proteins. Similarly, the hydrophilic amino acid side
chains are directed toward the exterior of these proteins with significant consis-
tency. These biomacromolecules can therefore be also considered as unimolecular
micelles as well. Noting this structural theme in proteins, it is clear that an im-
portant structural requirement that will further enhance dendrimers’ repertoire
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 27.
The possible conformations (A and B) of the amphiphilic dendrimer in polar and
apolar solvents respectively.
in this arena involves the ability to selectively functionalize the concave interi-
ors of these macromolecules, ie, selectively direct functional groups toward the
interior of the globular dendrimer. A flexible backbone is a prerequisite to obtain
globular shape at high generations. Attaining conformational control over the ori-
entation of the functional groups is nontrivial, when the molecules are built with
flexible linkers. Thayumanavan and co-workers proposed an approach to achieve
control over functional group orientation by rendering the macromolecules fa-
cially amphiphilic (90). In this design, the dendrimers are uniformly amphiphilic
over the entire globular surface; that is, when the convex face of the dendrimer
is hydrophilic, the concave face will be hydrophobic and vice versa. The nature of
the functional groups directed toward the concave interior of the dendrimer will
be driven by solvophobic interactions. In this design, the inherent flexibility of
the dendritic backbone can be expected to yield the different solvent-dependent
conformations 27A and 27B, as shown in Figure 27.
The monomer design involves a unit that has the AB
2
functional groups for
the dendrimer growth and the amphiphilic functional groups in orthogonal planes
(Fig. 28). The amphiphilic substituents are placed on opposite sides of the plane
containing the AB
2
moieties. Such relative placement of the functional groups
dictates that the amphiphilic moieties are in a plane perpendicular to that of
the macromolecular backbone upon assembly of the dendrimer. The geometric ar-
rangement of the dendrimer also dictates that the hydrophobic and the hydrophilic
functionalities are in opposite faces of the globular dendrimer, and thus the struc-
tures 27A and 27B should result (Figs. 27 and 28). A monomer unit that satisfies
these structural requirements is represented by the biphenyl molecule shown in
Figure 28, in which the hydrophilic unit is a TEG moiety and the hydrophobic unit
is an n-butyl group. Synthesis of dendrons up to the fourth generation has been re-
ported. However, solubility problems hampered the studies that would support the
structural hypothesis proposed. Experiments are under way to modify the func-
tional groups and render the dendrimers soluble in both polar and apolar solvents.
In addition to utilizing dendrimers themselves as micelles, there have been
several reports on utilizing block-co-polymers containing a hydrophilic linear
polymer and a hydrophobic dendrimer. These studies are not included in this
review. We recommend some key references in this area for an interested reader
(91–104).
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MOLECULAR RECOGNITION IN DENDRIMERS
411
Fig. 28.
Cartoon of the AB
2
monomer with the amphiphilic groups on the orthogonal
plane, the dendrimer growth, and its conformation in a hydrophilic solvent is represented.
Biomimetic Dendritic Amphiphiles.
The active sites of globular pro-
teins are often buried in their hydrophobic binding pockets. Inspired by globular
proteins, Diederich has developed a class of dendrimers called dendrophanes (105).
These are dendrimers that contain a hydrophobic cyclophane cavity and polar pe-
ripheral functionalities. Diederich showed that the size of the guest molecules
that could be accommodated in these hydrophobic cavities depend on the size of
the cyclophane core. Two different cyclophanes were reported; one that is capable
of binding benzene and naphthalene guests and a larger one that is capable of
binding large steroidal substrates (106,107). Guest molecules were shown to be
bound specifically at the cyclophane core and the nonspecific binding, if any, is
negligible. The binding constants were found to be independent of the dendrimer
generation. The micropolarity of the cyclophane core is significantly reduced and
is comparable to ethanol. The exchange kinetics of the host–guest binding events
were found to be fast. The combination of these properties led to the idea of devel-
oping these molecules into possible artificial globular enzymes. In order to mimic
the enzyme pyruvate oxidase, Diederich and co-workers incorporated thiazolium
ions into the cyclophanes and studied the catalytic ability of these compounds
in the oxidation of naphthalene-2-carboxyaldehyde to naphthalene-2-carboxylate
(Fig. 29) (108). The observed acceleration of the reaction was attributed to both
the reduced polarity in the dendritic interior and fast exchange rates.
More recently, Hecht and Fr´echet have synthesized an amphiphilic den-
drimer that is capable of acting as a photoreactor to catalyze a cycloaddition
reaction between cyclopentadiene and singlet oxygen (109). In this case, an ap-
olar functionality capable of sensitizing singlet oxygen (benzophenone) was at-
tached to dendrons containing hydrophilic peripheral groups. The cyclopentadiene
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 29.
Structure of the dendritic enzyme.
substrate was concentrated closer to the benzophenone core owing to the relatively
apolar nature of the core. Since the singlet oxygen is also generated near the ben-
zophenone core, the dendrimer was able to serve as a nanoreactor for this reaction
(Fig. 30).
Dendrimers as Inverted Micelles.
The inherently polar building blocks
of PAMAM and poly(propylene imine) dendrimers make these molecules attrac-
tive candidates for the creation of unimolecular inverted micelles. Meijer modified
the PPI dendrimers with apolar end groups such as the palmitoyl chains and stud-
ied the inverted micellar character of these dendrimers (Fig. 31) (110,111). These
dendrimers are capable of sequestering anionic guest molecules from aqueous so-
lutions. The binding process is attributed to the combination of hydrophobic effect,
hydrogen bonding, and ionic interactions. It was also noted that the efficiency of
binding is dependent on pH and were better at lower pH. It is also interesting to
note that these dendrimers exhibited significant selectivity in the sequestration
of guest molecules from the aqueous solution. For example, a fifth-generation den-
drimer was able to extract only 1 or 2 molecules of fluorescein, whereas the same
host was able to extract about 50 molecules of rose bengal. This selectivity is
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MOLECULAR RECOGNITION IN DENDRIMERS
413
Fig. 30.
Structure of the dendrimer with a singlet oxygen sensitizing core.
magnified in an experiment where it was demonstrated that even at pH 10, the
dendrimer was able to selectively extract rose bengal out of a mixture containing
a 10,000:1 ratio of fluorescein to rose bengal. Meijer also utilized PPI dendrimers
that are modified with oligo(p-phenylenevinylenes) as the peripheral apolar func-
tionality to study energy transfer in supramolecular assemblies containing the
dendrimer host and an anionic dye molecule as the guest (112). Similarly, Balzani
and V¨ogtle have shown that PPI dendrimers functionalized with dansyl groups in
their periphery can extract eosin red from aqueous solutions into the organic layer
(113,114). When dendrimers are functionalized with fluorocarbon chains at their
periphery, these macromolecules were soluble in supercritical carbon dioxide and
fluorocarbon solvents and were capable of solubilizing polar substrates in these
solvents (115,116). This is of considerable significance, since this process could
have implications in environmentally benign catalytic processes.
Tomalia and co-workers reported the hydrophobic modification of PAMAM
dendrimers by treating the terminal primary amines with various epoxyalka-
nes (117). Similar to the PPI dendrimers reported above, these dendrimers also
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MOLECULAR RECOGNITION IN DENDRIMERS
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Fig. 31.
Inverted micelles based on poly(propylene imine) dendrimer.
exhibited the inverted micelle properties that are capable of sequestering polar
guest molecules. More specifically, Tomalia showed that these dendrimers are ca-
pable of transporting copper(II) ions from an aqueous solution into an organic
phase.
An elegant experiment by Crooks showed that the hydrophobic modification
of PAMAM dendrimers by noncovalent interactions could also result in macro-
molecules that behave like inverted micelles (118). The spontaneous assembly
between the fatty acids and amino periphery of the PAMAM dendrimer was
driven by ionic interactions (Fig. 32). These dendrimers were shown to be capa-
ble of extracting hydrophilic dyes such as methyl orange from water into toluene.
Similarly, these dendrimers were also shown to be excellent molecular contain-
ers for catalytically active metal nanoparticles. The inverted micellar nature of
various dendrimers have been used by Crooks and others for the preparation of
a variety of nanoparticles (119–122). A related macromolecule, but an architec-
ture with less of a control, is a hyperbranched polymer. Hydrophobically modified
hyperbranched polymers have also been shown to be capable of acting as inverted
micelles (123,124).
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MOLECULAR RECOGNITION IN DENDRIMERS
415
Fig. 32.
Supramolecular assembly of inverted micelles by Crooks.
Binding at the Dendritic Periphery.
Dendrimers with ferrocene substi-
tutions at their periphery have been synthesized to achieve new electrochemical
sensors for anions such as H
2
PO
4
−
(54–56,125). These ferrocene dendrimers are
often insoluble in aqueous media. However, if the peripheral ferrocenes are ef-
ficiently complexed with cyclodextrins, the resultant complex can be rendered
water-soluble (Fig. 33). Kaifer and co-workers were able to demonstrate that such
complexes are indeed more soluble (126). They also noted that the solubility de-
pends on the efficiency of complexation, which decreased with increasing gen-
eration possibly because of steric crowding. Since the binding of ferrocene with
cyclodextrin is based on the hydrophobic effect, there is a significant difference in
binding between ferrocene and ferrocenium ions. The weaker binding of ferroce-
nium ions provides the opportunity to release these complexes with electrochem-
ical control. Similarly, the difference in association constants between cobaltoce-
nium ion and cabaltocene provides a system in which the binding increases upon
an electrochemical trigger (127).
Similar to ferrocene, admantane is also considered an excellent guest moiety
for
β-cyclodextrin. Reinhoudt showed that adamantyl-terminated PPI dendrimers
can bind to several
β-cyclodextrin molecules (128–130). The complex was most
416
MOLECULAR RECOGNITION IN DENDRIMERS
Vol. 10
Fig. 33.
Dendrimer with cyclodextrin caps.
stable at pH 2, at which point the internal tertiary amines are all protonated. The
possible extended conformation of the protonated dendrimer is suggested to be
responsible for the complete complexation of cyclodextrins with dendrimers up to
the fourth generation. Reinhoudt was able to show that the stoichiometry of bind-
ing up to fourth-generation dendrimer between the cyclodextrin and adamantyl
groups was 1:1. This ratio decreased in the fifth generation and is attributed to
the possible steric crowding.
Small surfactant molecules also have been used as guest molecules to bind
to the surface of the dendrimers, often through the combination of hydrophobic
effect and ionic interactions (131–136). Ottaviani and co-workers studied the char-
acteristics of the PAMAM dendrimers using noncovalently incorporated nitroxide
radical based surfactant (131). The dendrimers were terminated with carboxy-
late moieties, while the nitroxide radical was functionalized with a quaternary
ammonium functionality. They noted that the nitroxide surfactants were able to
act as micellar hosts for low generation dendrimers. However, for higher genera-
tion dendrimers (
>3.5), the dendrimer was able to act as a host for the nitroxide
surfactant molecule. The binding was proposed to be due to ionic and hydropho-
bic interactions. Using EPR (electron paramagnetic resonance) studies, they were
also able to show that the nitroxide radical probes are trapped in a restricted space
in proximity to the dendrimer surface. On the basis of this observation, a mode
of binding was proposed as seen in Figure 34 (132). Similarly, Majoral has uti-
lized this strategy to functionalize the periphery of phosphorus-based dendrimers
noncovalently with carbohydrates (136).
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MOLECULAR RECOGNITION IN DENDRIMERS
417
Fig. 34.
Binding small molecule surfactants in dendrimers with hydrophobic chains
buried inside.
Catalysis with Amphiphilic Dendrimers.
An example of biomimetic
catalysis with amphiphilic dendrimers has already been mentioned above (108).
Similarly other micellar dendrimers have been used to catalyze reactions either
within the hydrophobic interior or at the interface. An interesting example was
provided by the research group of Rico-Lattes, in which PAMAM dendrimers
were functionalized using
D
-gluconolactone (137–139). The resultant chiral den-
drimers were tested for their capabilities in the asymmetric reduction of prochiral
ketones using sodium borohydride as the reagent. While these dendrimers pro-
vide moderate or poor asymmetric induction in a homogeneous phase (water),
the chiral induction was very high in THF. The selectivity is attributed to the
supramolecular ordering of the prochiral ketone at the chiral solvating interface.
The third-generation dendrimer was found to be a particularly suitable vehicle for
this chiral induction. Similarly, binding based on hydrophobic interaction is also
attributed to the catalysis of aminolysis reactions of p-nitrophenyl esters using
amine-terminated PAMAM dendrimers (140,141).
Hawker and co-workers reported the synthesis of unimolecular inverse mi-
celles based on benzyl ether dendrimers with hydroxyl groups in its interior (142).
They showed that this dendrimer was able to catalyze the E1 elimination reac-
tion of 2-iodo-2-methylheptane. The tridendron of G4 seems to be particularly
effective in catalyzing this reaction. The conversions to products were found to be
greater than 90%. The regioselectivity of the elimination was moderate. Turnover
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MOLECULAR RECOGNITION IN DENDRIMERS
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numbers as high as 17,400 were observed with these dendrimers. The catalysis
of the dendrimer was attributed to the ability of the internal hydroxy groups to
stabilize the cationic transition state of the elimination reaction.
Dendrimer Assembly Based on Hydrophobic Interactions.
Nonco-
valent assembly of dendrimers using hydrogen-bonding interactions was dis-
cussed earlier in this article. Noncovalent assembly of dendrimers based on
hydrophobic interactions is also very attractive, since these assemblies can be
achieved in aqueous solutions or other polar solvents. The strong association
between adamantyl groups and
β-cyclodextrin is a well-known phenomenon.
Newkome and co-workers used this interaction in an attempt to assemble den-
drimers (83). They synthesized a bis-ester of admantane carboxylic acid with
tetraethyleneglycol and attempted to complex this bis(adamantane ester) to a
β-cyclodextrin derivatized with amide dendrons (Fig. 35). On the basis of a dye-
displacement assay, the efficiency of the dendrimer assembly was found to be
not very high. They attributed this to the possible steric encumbrance of the
bis(admantane ester) owing to the chain compaction by the sodium ions present
in solution.
Diederich has used the previously described association between steroids
and cyclophanes to noncovalently assemble dendrimers (143). A bis(testosterone)
derivative that contains a rigid phenylacetylene-based linker is used as the ditopic
ligand (Fig. 36). The linker contains positively charged amino groups, which are
useful both to solubilize these compounds in aqueous solutions and to have ionic
interactions with the negatively charged periphery of the dendrons. Using
1
H
NMR, it was ascertained that the steroid, not the phenylacetylene linker, is bound
to the cyclophane. The association constants for a 1:1 complex were high in all
cases. However, the association for a 2:1 complex was dependent on the length
of the bis(steroid) linker. It was observed that for higher generation dendrimers,
the possible repulsion between the negative charges of the dendrons inhibits the
Fig. 35.
Cyclodextrin cored dendrimer synthesized by newkome.
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MOLECULAR RECOGNITION IN DENDRIMERS
419
Fig. 36.
Structure of the ditopic steroidal guest molecule (structure of the dendrimer is
similar to the one shown in Fig. 29, but with a larger cyclophane core).
formation of a 2:1 complex. This repulsive interaction is reduced for dimerizing
the dendrons by using a longer phenylacetylene linker.
Summary
Ever since the first reports on the synthesis of dendrimers, these macromolecules
have attracted the attention of researchers from biology to engineering. The com-
pactness of the three-dimensional architecture, the opportunity to present a high
density of functional groups in the periphery, the opportunity to encapsulate func-
tionalities in the core, and the globular structure of these molecules make them
extremely versatile. Each of these features makes these molecules attractive for
different applications in a variety of areas. Some of these features make them ideal
architectures for binding guest molecules in its interior, periphery, or the interface.
In this article, we have mainly discussed hydrogen bonding and amphiphilic inter-
actions with frequent inference to ionic interactions. Molecular recognition using
dendritic scaffolds will have lasting implications in nanotechnology and biology
(144–154).
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S
UBHADEEP
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ASU
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S. S
ANDANARAJ
S. T
HAYUMANAVAN
University of Massachusetts