Self-Assembly of a β-Cyclodextrin Bis-Inclusion Complex into a Highly Crystalline Fiber Network. An Effective Strategy for Null Aggregate Design

Article abstract of DOI:10.1021/acs.jpcb.9b05430

The present work deals with the tight molecular packing of a bis-inclusion complex into rigid, 1D nanofibers. The bis-adamantane (AD) linked anthracene derivative AD-AN-AD readily formed the β-CD bis-inclusion complex, β-CD?AD-AN-AD?β-CD, which spontaneously assembled into a nanofiber network. The wide angle X-ray scattering pattern of the dried nanofibers indicated that these are highly crystalline in nature. Spectroscopic data of the aggregate are identical to those of the monomeric species, suggesting that the aggregate is not a regular H- or J-aggregate. We propose that the nanofibers constitute another example of the recently proposed class of "null" aggregates, based on the crystal structure and molecular packing in compound 3, which is the precursor of AD-AN-AD. The molecular packing in 3 actually provides a strategy for the design of null aggregates. We propose that the nanofibers are formed from null aggregates of β-CD?AD-AN-AD?β-CD, wherein the anthracene moieties are twisted in the range of 60-72°, and this assignment is in line with the spectroscopic studies and NMR titration experiments.

Full text of DOI:10.1021/acs.jpcb.9b05430

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B: Fluid Interfaces, Colloids, Polymers, Soft Matter, Surfactants, and Glassy Materials
Self-Assembly of a #-Cyclodextrin Bis-Inclusion Complex Into Highly
Crystalline Fiber Network. An Effective Strategy for Null Aggregate Design
Nagaraj Nayak, and Karical Raman Gopidas
J. Phys. Chem. B, Just Accepted Manuscript • Publication Date (Web): 03 Sep 2019
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Self-assembly of a β-cyclodextrin Bis-inclusion Complex into Highly Crystalline Fiber
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Network. An Effective Strategy for Null Aggregate Design
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Nagaraj Nayak and Karical Raman Gopidas*
Photosciences and Photonics Section, Chemical Sciences and Technology Division,
CSIR-National Institute for Interdisciplinary Science and Technology, Trivandrum 695 019 (India)
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ABSTRACT: The present work deals with the tight molecular packing of a bis-inclusion complex into
rigid, 1-D nanofibers. The bis-adamantane linked anthracene derivative AD-AN-AD readily formed the
β-CD bis-inclusion complex, β-CDAD-AN-ADβ-CD, which spontaneously assembled into a nano-
fiber network. WAXS pattern of the dried nanofibers indicated that these are highly crystalline in
nature. Spectroscopic data of the aggregate are identical to those of the monomeric species, suggesting
that the aggregate is not a regular H- or J-aggregate. We propose that the nanofibers constitute another
example of the recently proposed class of “null” aggregates, based on the crystal structure and
molecular packing in compound 3 which is the precursor of AD-AN-AD. The molecular packing in 3
actually provides a strategy for the design of null aggregates. We propose that the nanofibers are formed
from null aggregates of β-CDAD-AN-ADβ-CD, wherein the anthracene moieties are twisted in the
range 60-720, and this assignment is in line with the spectroscopic studies and NMR titration
experiments.
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1. INTRODUCTION
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Bolaamphiphiles are amphiphilic molecules that contain two polar head groups connected by a
hydrophobic linker.1-5 Because of their propensity to self-assemble into various morphologies, they are
considered as important building blocks for the construction of various nanostructures. For example,
bolaamphiphiles are known to self-assemble into spheres,6-9 gels,3,10-14 discs,15-18 vesicles,19-25 helical
structures,26-29 tubes28-33 etc. Construction of supramolecular amphiphiles and study of their self-
assembly into various morphological structures is an important aspect of current supramolecular
chemistry.2,34-40 Bis-inclusion complexes of cyclodextrins (CD), where the included moieties are present
at the two ends of a sufficiently hydrophobic linker unit, can be considered as supramolecular
bolaamphiphiles.36-37, 41-45 The high water solubility of CDs makes both ends of these bis-inclusion
complexes hydrophilic. Although supramolecular amphiphiles are known to self-assemble in to various
types of morphologies, bis-inclusion complexes of CDs are known to self-assemble only into vesicles.46-
50 In this paper we present self-assembly of a β-CD bis-inclusion complex into crystalline fibers for the
first time.
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Recently we reported the unusual self-assembly of a β-CD bis-inclusion complex into vesicles
capable of encapsulating and releasing drug molecules.49 We prepared the molecule AD-AD (Figure 1)
which has adamantane (AD) units at both ends. Because of the propensity of AD derivatives to form
inclusion complexes with β-CD, the molecule forms the bis-inclusion complex β-CDAD-ADβ-CD.
We have observed that the β-CDAD-ADβ-CD spontaneously aggregated into vesicles. The self-
assembly was unusual because, in all the reported cases of vesicle formation from bis-inclusion
complexes, these complexes were identified as supramolecular bola-amphiphiles, with the CD acting as
the hydrophilic head group and the alkyl or aryl residue acting as the hydrophobic core. In the case of β-
CDAD-ADβ-CD, both the end groups and the central 1,2-bis(4-pyridyl)ethane moieties are
hydrophilic. The +ve charges on the pyridinium nitrogens of adjacent layers are expected to repel each
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other and hence the inclusion complex β-CDAD-ADβ-CD was not expected to stack one over the
other to give vesicles. However, vesicle formation was observed and confirmed by dynamic light
scattering, AFM, SEM and TEM. We also showed that these vesicles could be loaded with the
anticancer drug doxorubicin and the loaded drug can be released upon addition of a competitive binding
agent such as adamantane carboxylate.49
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Herein we report the synthesis and inclusion complexation of AD-AN-AD (Figure 1) in which
an anthracene moiety replaces the central 1,2-bis(4-pyridyl)ethane moiety of AD-AD. AD-AN-AD
differs from our previous molecule in few respects. The central 1,2-bis(4-pyridyl)ethane moiety is
replaced by a more hydrophobic and rigid anthracene unit. The central unit is devoid of any charges, but
the two AD moieties at the ends now carry positive charges. These changes have made the end units
more hydrophilic and the central units more hydrophobic compared to AD-AD, and the overall length of
the molecule is reduced. We observed that AD-AN-AD readily forms the bis-inclusion complex β-
CDAD-AN-ADβ-CD, which spontaneously self-assembled into highly crystalline fibrous networks.
In order to explain the crystalline nature of the fibers and the absence of excitonic coupling in the
aggregate, we have invoked the newly introduced concept of “null” aggregates. We propose that β-
CDAD-AN-ADβ-CD packs one over the other with a twist angle in the range of 60-720 so as to
avoid steric hindrance and achieve a π-π stacking distance of 3.64 Å. In this report, details of the
inclusion complexation and further self-assembly into fibers are presented along with a discussion of the
aggregation process.
H2N
Cl
O
Cl
NH2
N
Br
N
Br
O
AD-AD
AD-AN-AD
Figure 1. Structures of AD-AD and AD-AN-AD.
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2. METHODS
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General Methods. β-CD and all other chemicals were purchased from Aldrich and used as
received. The solvents and reagents were dried and purified by standard methods prior to use. Aqueous
sample solutions were prepared using double distilled water. The electronic absorption spectra were
recorded on a Shimadzu 2401PC UV-VIS-NIR scanning spectrophotometer. ITC data were obtained
using microcal iTC 200. The raw data obtained were fitted and analyzed using origin 7.0 software
provided along with the instrument. In order to analyze the data, one site (or two identical sites) binding
model was assumed and the thermogram was fitted using nonlinear regression procedure.51 The standard
deviations reported for the parameters are those obtained from the fit. All NMR data were recorded in
D2O purchased from Aldrich, using a 500 MHz Bruker Avance DPX spectrometer. AFM measurements
were carried out using Bruker multimode 8-HR instrument using micro fabricated TiN cantilever tips
(NSG-10) with a resonating frequency of 299 kHz and a spring constant of 20-80 Nm-1 using tapping
mode techniques. The samples for AFM were prepared by drop casting the solution on freshly cleaved
mica surface and the excess solvent was evaporated. TEM analyses were performed using a FEI-
TECNAI T30 G2S-TWIN, 300 kV HRTEM microscope with an accelerating voltage of 100 kV and the
samples were prepared by drop casting the solution on a formvar coated copper grid (400 mesh) and
evaporating excess solvent. The 2D X-ray measurements were carried out with Xeuss SAXS/WAXS
system using a dried film of the sample cast on aluminium foil. Steady-state fluorescence experiments
were performed with a SPEX Fluorolog F112X spectrofluorimeter by using optically dilute solutions.
Time-resolved fluorescence experiments were performed by using an IBH picosecond single-photon-
counting system employing a 375 nm nanoLED excitation source and a Hamamatsu C4878-02
microchannel plate detector. A single crystal of molecule 3 was grown in CHCl3/CH3OH solvent
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mixture and the crystal was analyzed by Saturn 724+ HG single crystal x-ray diffractometer using Mo
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Kα (λ = 0.71073 Å) X-rays.
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3. RESULTS AND DISCUSSION
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Synthesis and Characterization of AD-AN-AD. AD-AN-AD was synthesized as shown in
Scheme 1. Anthracene was converted into 9,10-bisbromomethylanthracene using paraformaldehyde and
HBr in glacial acetic acid.52 This was treated with two equivalents of adamantylamine in the presence of
n-butyllithium. The bisadamantyl adduct 3 was converted to its hydrochloride salt (AD-AN-AD) by
1
treatment with dry HCl gas. All the intermediates and final products were characterized by H NMR,
13C NMR and HRMS techniques [see experimental section and supporting information (Figures S1-S6)
for more details]. Structure of the intermediate 3 was also confirmed by single crystal X-ray analysis.
AD-AN-AD was found to be sufficiently soluble in aqueous medium because of the two positive
charges in the molecule.
(HCHO)n,
HBr/AcOH
Br
RT, 2 h
Br
2.
1.
NH2
n-BuLi
THF, 0 0C
HN
H2N
Cl
Cl
NH2
Dry HCl
CHCl3
NH
3.
AD-AN-AD
Scheme 1. Scheme for the synthesis of AD-AN-AD.
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Host-Guest Complexation Studies of AD-AN-AD and β-CD. Addition of two equivalents of
β-CD to an aqueous solution of AD-AN-AD resulted in the formation of the bis-inclusion complex β-
CDAD-AN-ADβ-CD, in which the adamantane moieties of AD-AN-AD are encapsulated inside β-
CD cavity, as shown in Scheme 2. Formation of the bis-inclusion complex was studied using isothermal
titration calorimetry (ITC) and 1H NMR spectroscopy.
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H2N
Cl
H2N
Cl
Cl
NH2
Cl
NH2
2 β – CD
AD-AN-AD
β-CDAD-AN-ADβ-CD
Scheme 2. Formation of bis-inclusion complex β-CDAD-AN-ADβ-CD.
Isothermal Titration Calorimetry. The ITC experiment was carried out by taking β-CD (10
mM, 40 µL) in the syringe and AD-AN-AD (0.1 mM, 200 µL) in the cell. Heat changes observed for
AD-AN-AD/β-CD complexation was moderately high. The raw data and fit are shown in Figure 2. The
fit parameters obtained are: Ka = (6.07 ± 0.1) × 103 M-1, ∆H = -24.4 ± 0.2 kJ mol-1 and ∆S = -9.61 J mol-
1 K-1 and n = 1.93. The value of n (2) indicates that AD-AN-AD has two binding sites for β-CD. Thus,
ITC studies confirmed that a 1:2 complex is formed between the two as shown in Scheme 2. The Ka
value obtained in this case is somewhat lower compared to the previous systems studied by us49, 53-56 and
+
others.57-58 This is attributed to the presence of positively charged -NH2 - moieties close to the AD
groups in AD-AN-AD. It is reported that Ka for the formation of 1-adamantane ammonium chloride
(ADAC)/β-CD complex is less compared to several other adamantane/β-CD systems.59-60 This is
explained to be due to shallow penetration of the AD moiety in ADAC in the β-CD cavity, leaving the
ammonium terminus projecting above the wider rim.59 In this configuration the ammonium head group
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is better solvated and a considerable percentage of the cavity near the narrow rim will remain
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unoccupied.
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Time (min)
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0.00
-0.50
-1.00
-1.50
-2.00
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-2.50
0.0
-1.0
-2.0
-3.0
0
5
10
15
20
Molar Ratio
Figure 2. The ITC titration curve and fit obtained for the titration of β-CD with AD-AN-AD.
1H NMR titration studies. 1H NMR spectra of AD-AN-AD in the presence of varying amounts
of β-CD, where the β-CD concentration changed from 0 – 2 equivalents, are shown in Figure 3a.
Assignments of the various protons based on literature reports49, 61 are also shown in Figure 3a. In
Figure 3a the dotted vertical lines indicate the original peak positions and the changes in peak positions
are indicated by arrows in the top panel. The AD protons are labeled Ha (6H), Hb (3H) and Hc (6H). In
the absence of β-CD, the Ha protons appeared as doublet of doublet at  1.84 ppm, Hc and Hb protons
appeared as singlets at  2.25 and 2.35 ppm, respectively.49 When inclusion of AD occurs, the Ha and Hb
protons will be deeply inserted into the cavity and the Hc protons will remain close to the wider rim of
β-CD. The inclusion process affects the signals due to all these protons. The doublet of doublet pattern
of Ha changed into a broad singlet and shifted down field to  1.95 ppm. Signal due to Hb down-shifted
to  2.55 ppm and Hc protons down-shifted to  2.39 ppm along with broadening, clearly providing
evidence for inclusion of the AD moieties in the β-CD cavity.
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Presence of a guest molecule in the CD cavity can also be confirmed by monitoring the changes
in the chemical shifts of CD protons. The H-3, H-5 and one of the H-6 protons of -CD are directed
towards the interior of the cavity and the H-2, H-4 and one H-6 protons are on the outside (Figure S6, S.
I.). Presence of a guest inside the cavity affects the chemical shifts of all these protons, but signals of the
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inside protons are affected more. The bottom panel in Figure 3b shows H NMR signals for H-2 – H-6
protons of -CD56,57 and the other panels show the shifts of these signals upon addition of AD-AN-AD
(0.5, 1.0 and 2.0 eq. of AD-AN-AD w.r.t. -CD). The figure shows that addition of AD-AN-AD lead to
moderate upfield shifts for H-3 and H-5 protons and downfield shifts for H-2 and H-6 protons. The H-4
signal is not affected much. The H-2 proton is placed at the wider rim of the CD and in this case H-2 is
also affected because penetration of the AD moiety into the CD cavity is very shallow and part of this
moiety projects outside the wider rim (vide supra). Based on the NMR chemical shifts discussed so far
and the 1:2 stoichiometry derived from the ITC experiments , the structure of the inclusion complex can
be written as in Scheme 2, with both the AD moieties included in the -CD cavities and the AN unit
+
placed in between the CDs. Since there are -NH2 - groups, which are highly hydrated on either side of
the AN moiety, we assume that AN is fully exposed to water. If this is the case, the AN protons should
not be affected by the presence of -CD.
We, however, observed that in the presence of -CD, the AN protons also exhibited chemical
shift changes. The He and Hf protons of the AN appeared as multiplets in the absence of β-CD (A
multiplet pattern is observed for these protons in few 9,10-dimethylene-substituted anthracene
derivatives.62 In order to confirm the assignments we obtained the single crystal X-ray structure of 3
(which is the precursor of AD-AN-AD, Scheme 1). The X-ray structure of 3 is presented in the
supporting information along with its 1H NMR spectrum (Figure S1, S2), which also exhibited multiplet
patterns for He and Hf). Up on addition of β-CD, the He and Hf protons of AD-AN-AD coalesced into
broad singlets and shifted down field (inset in Figure 3a), although these protons are away from the site
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of inclusion (Scheme 2). The Hd protons (CH2 protons linked to 9- and 10- positions of anthracene) also
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exhibited considerable down field shifts from  5.33 to 5.45 ppm. These NMR shifts have prompted us
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to consider other probable structures shown in Figure S7, for the AD-AN-AD/-CD complex.
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(a)
He
Hc
Hc
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Hf
Hb
Ha
H2N
Hd
Ha
NH2
Hd
8.40
8.30
8.20
8.10
8.00
7.90
7.80
f1 (ppm)
H
H
a
c
(E)
H
b
H
H
f
e
H
(D)
(C)
(B)
(A)
d
H
H
H
H
H H
c,
d
b
f
e
a
(b)
H3
H6
H2
H2
H4
H4
β-CD + 2 eq.
AD-AN-AD
H5
H5
H3, H6
β-CD + 1 eq.
AD-AN-AD
H6
H3
H2
H4
H5
H5, H6
β-CD + 0.5 eq.
AD-AN-AD
H3
H2
H4
β-CD alone
1
Figure 3. (a) H NMR spectra of AD-AN-AD (1 mM) in the absence (A) and presence (B-E) of β-CD
(0.5 – 2 eq.) in D2O. The insets show the shift of adamantyl and aromatic protons. (b) Selected area 1H
NMR spectra showing changes in β-CD (0.5 mM) protons as [AD-AN-AD] is varied.
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Ka value for anthracene/-CD inclusion complexation is 2.04  103 M-1.63 In the case of AD-
1
2
3
AN-AD the anthracene unit cannot be fully included in the cavity as its 9- and 10- positions are
substituted by bulky groups. The AN moiety, however, can be partially included as shown in Figure
S7a, where the terminal benzene rings of AN are included in -CD. In this case the relevant Ka is that
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for benzene/-CD interaction, for which the value is only 170 M-1.63 The Ka value for adamantane/-CD
interaction is >104 M-1.63 Hence if the binding stoichiometry is 1:2, inclusion of AD moiety as shown in
Scheme 2 is highly favored over Figure S7a. Further, we have previously shown that even partial
inclusion of anthracene in -CD will lead to changes in the absorption and emission profiles of the
molecule.64 We have observed that the photophysical properties of AD-AN-AD are unaffected by
complexation with -CD (vide infra). Because of these reasons the 1:2 and 1:4 complexes shown in
Figure S7a,b can be ruled out. In addition, these structures also cannot explain the NMR shift observed
for the Hd protons, as the molecular dimensions of -CD will not allow entry of these protons into the
cavity.
In the case of the β-CDAD-ADβ-CD system reported previously by us, we observed
chemical shift changes for protons that are placed much away from the site of inclusion binding.49 These
changes were attributed to secondary interactions leading to the formation of vesicles. The finding here
is similar to that observed for the β-CDAD-ADβ-CD system, and accordingly we attribute these
changes to secondary interactions of the bis-inclusion complex. In order to probe whether such
secondary interactions are taking place in the present system, we have subjected the β-CD/AD-AN-AD
system to microscopic investigations.
Microscopic Studies. Aqueous solution of the bis-inclusion complex β-CDAD-AN-ADβ-
CD, prepared by mixing AD-AN-AD (1  10-5 M) and β-CD (2  10-5 M) was drop-casted onto freshly
cleaved mica and air-dried for AFM analysis. The same aqueous solution was drop-casted on carbon-
coated copper grid for TEM imaging. AFM and TEM images displayed largely interwoven fibrous
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structures (Figure 4, see Figures S8 and S9, S.I. also). The TEM images showed highly rigid fibers
exhibiting fairly uniform width ranging from 50-200 nm and length reaching several micrometers. The
SAED pattern obtained in the TEM showed small spots in a ring pattern, suggesting that the fibers are
polycrystalline in nature (Figure S8c, S.I.). AFM images also showed nano-fibers of several
micrometers length and 50-150 nm width, which is in good agreement with the results obtained from
TEM experiments. The AFM height images suggested that these fibers have heights varying in a small
range of 4-8 nm. The AFM 3D image was also obtained for better visualization of rigidity of fibers,
which is shown in Figure 4b. The confocal laser scanning microscopy (CLSM) images of the fibers
(Figure 4d) showed fluorescent fibers indicating that the fluorescent anthracene moiety is incorporated
into the fibers.
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Figure 4. (a) AFM height, (b) AFM 3-D, and (c) TEM images of AD-AN-AD (10-5 M)/β-CD (2  10-5
M) system in water. The (d) CLSM image of fluorescent nanofibers drop cast from AD-AN-AD (10-3
M) and β-CD (2  10-3 M) aqueous solution.
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Wide Angle X-ray Scattering (WAXS) Studies. The microscopic experiments suggested that
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the bis-inclusion complex β-CDAD-AN-ADβ-CD self-assembled into long fibrous structures. In
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order to understand the molecular level packing of the bis-inclusion complex β-CDAD-AN-ADβ-
CD within the assembly, we carried out the WAXS studies on a dried film and the pattern obtained is
shown in Figure 5 (the corresponding 2D plot is shown in the inset). The WAXS pattern showed several
distinct X-ray scattering peaks, thereby suggesting that the observed fibers are highly crystalline.65 We
propose that scattering from different planes of self-assembled nano-fibers occurred to yield the
observed multiple peak pattern. Among these, we could identify scattering peaks at 2θ of 5.830 and
11.020 which correspond, respectively, to d values of 15.14 Å and 7.89 Å. These could be assigned to
molecular dimensions of β-CD. Also, sharp scattering occurred at a 2θ angle of 8.90 (d = 9.5 Å) which
corresponds to the molecular length of anthracene unit. We also could identify a set of four peaks in the
2θ range of 23.50 –26.070 which correspond to d values of 3.8 Å, 3.6 Å, 3.47 Å and 3.41 Å.
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Figure 5. The WAXS pattern obtained for AD-AN-AD (5 × 10-4 M)/β-CD (1  10-3 M) self-assembled
system with inset showing the corresponding 2D plot.
It is reported in the literature that the π-stacking of anthracene occurs at distances of 3.3 - 3.87
Å,65 and hence we assign these peaks to π-π stacking of the anthracene core of β-CDAD-AN-ADβ-
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CD. We believe that the tendency of the anthracene core for -stacking in the aqueous medium drives
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the self-assembly of β-CDAD-AN-ADβ-CD into the fiber system. Thus the WAXS experiment
confirmed the crystalline nature of nanofibers which is in agreement with the crystalline morphology
obtained by TEM and AFM experiments.
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Self-Assembly of β-CDAD-AN-ADβ-CD. The bis-inclusion complex β-CDAD-AN-
ADβ-CD is a supramolecular bola-amphiphile with a hydrophobic and rigid anthracene at the core and
adamantane-included β-CD moieties at both ends as shown in Scheme 2. The terminal groups are
hydrophilic due to the presence of the β-CDs and positively charged ammonium groups attached to the
adamantane moieties. Self-assembly of the bis-inclusion complex into the long fibers most probably has
its origin in the tendency for the anthracene core for aggregation in the aqueous environment.
Aggregates are classified as J-aggregates when the absorption spectrum is red-shifted with respect to the
monomer peak, and H-aggregate when it is blue shifted.67-68 H-aggregates are generally non-emissive
but J-aggregates emit with enhanced rates. In order to see if any H- or J-aggregates were formed in the
AD-AN-AD/β-CD system the photophysical properties of this system were investigated. Figure 6 shows
the absorption and emission spectra of AD-AN-AD in the absence and presence of two equivalents of β-
CD. The inset of Figure 6 shows the fluorescence decay profiles of AD-AN-AD in the absence and
presence of β-CD. From Figure 6 it is clear that formation of the bis-inclusion complex and further self-
assembly into the fibrous networks had no influence on the absorption and emission properties of AD-
AN-AD. These results, in turn, ruled out the possibility of H- and J-aggregate formation in the AD-AN-
AD/β-CD system. As mentioned previously, this also ruled out the possibility of full or partial inclusion
of the AN moiety in the CD cavity.
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Figure 6. Absorption (a) and emission (b) spectra of AD-AN-AD in the absence (blue trace) and
presence (red trace) of 2 eq. of β-CD. For the absorption spectra [AD-AN-AD] was 8  10-5 M, and for
(b) OD at the excitation wavelength (354 nm) was 0.06. Inset (c) shows the corresponding fluorescence
decay profiles monitored at 420 nm.
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According to Kasha, H-aggregates arise when molecules stack with their transition moments
parallel and side-by-side and J-aggregation takes place when the transition dipoles are oriented head-to-
tail.67-68 A closer look at the molecular dimensions of β-CDAD-AN-ADβ-CD (see Figure S10, S.I.),
would reveal that this complex cannot form H- or J-aggregates because of geometrical restrictions. The
edge-to-edge distance in β-CDAD-AN-ADβ-CD is 2.6 nm. The outer diameter of β-CD is 1.5 nm
and the edge-to-edge distance in anthracene is 0.97 nm, as shown in Figure S10 (S.I.). The large size
of the β-CD compared to anthracene does not allow close packing of β-CDAD-AN-ADβ-CD into H-
or J- aggregates. Given the molecular dimensions in Figure S10, the probable molecular stacking in H-
and J-aggregates would be as shown in Figure S11a,b (S.I.). In the H-aggregate, the anthracene groups
are -stacked vertically one over another. Since the outer diameter of β-CD at the wider rim is 1.5 nm,
the separation between adjacent anthracene residues will also be 1.5 nm, if we assume that these
residues are placed along the central plane of the β-CD. At this distance -stacking interaction is not
possible. In the J-aggregate shown, the anthracene chromophores are stacked in a head-to-tail fashion.
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Using the molecular dimensions in Figure S10 (S.I.), we propose that the distance between the edge
hydrogens of adjacent anthracene groups is 5 Å. The -clouds of the anthracene rings are also far apart
to have any interaction. Thus, Figure S11 shows that geometrical restrictions do not allow formation of
H- or J-aggregates of β-CDAD-AN-ADβ-CD.
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Kasha proposed H- and J- aggregation based on the spatial dependence of the Coulombic
coupling between the monomers.67 Spano and co-workers recently pointed out that, in addition to long
range Coulombic coupling, short range charge transfer (CT) mediated interactions must also be
considered in molecular aggregates.69-70 Since Coulombic and CT-mediated couplings exist
simultaneously in tightly packed molecular aggregates, the interference between these two interactions
must be considered when defining J- and H- aggregates. Spano’s group recently put forward the concept
of “null” aggregates where the Coulomb and CT couplings destructively interfere and effectively cancel
out. Such systems will have spectroscopic properties closely resembling those of unaggregated
molecules in solution.69 Null aggregation arises due to translational displacements (“slips”) and twists
between neighboring chromophores which influences the short range interaction severely.
The first example of null-aggregate is recently reported by Würthner and co-workers in the case
of bis(perylene bisimide) (PBI) foldamers in which two PBI chromophores are covalently linked in the
bay position by spacer moieties of different length and steric demand.71 The authors claimed that one of
the foldamers, where the torsional angle () between the foldamers is 250 and the centers of the
chromophores is displaced by 2.1 Å, exhibited properties characteristic of null-aggregates as demanded
by Spano’s theory. Very recently, Hariharan and co-workers have reported a novel Greek cross (+)
assembly ( = 900) of 1,7-dibromoperylene-3,4,9,10-tetracarboxylic tetrabutyl ester (PTE-Br2), which
exhibited null exciton coupling-mediated monomer-like optical characteristics in the crystalline state.72
We propose that the fiber networks formed in the AD-AN-AD/β-CD solution are null-aggregates
of β-CDAD-AN-ADβ-CD. Our proposal is based on the molecular stacking observed for 3, which is
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the precursor of AD-AN-AD. 3 has bulky adamantane groups on either side and stacks in such a way to
avoid steric interactions between adamantane groups, as shown by the molecular packing in the crystals
(Figure 7). The anthracene groups are stacked in parallel planes with their long axis rotated by 56.060
with respect to the preceding and succeeding neighbors. The rotation angle is close to the magic angle of
54.70. Average  stacking distance in the assembly is 3.64 Å, which is the value normally observed
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for aromatic -stacked systems.66 The molecular packing in 3 also provides us with a strategy for the
design of null aggregates. Planar chromophores such as anthracene can be substituted with bulky
adamantane moieties so that the molecules can pack in the crystals only in the crisscross manner
exhibited in the case of 3.
Figure 7. Molecular packing in the crystals of 3.
If the stacking in β-CDAD-AN-ADβ-CD is same as in 3, β-CDAD-AN-ADβ-CD will
stack as shown in Figure 8a. The third stack will be exactly over the first one. The center-to-center
distance between AD groups in the first and third stacks is 7.28 Å in Figure 7. When the AD groups are
replaced by -CD, a center-to-center distance of 15.3 Å would be required between the first and third
layers to stack one -CD over another -CD. If this is the case there will not be any  stacking
interaction as the anthracene groups in successive stacks would be separated by about 7.65 Å. In order
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to keep the -stacking distance at 3.6 Å and to accommodate the steric bulk of the -CD groups, the β-
CDAD-AN-ADβ-CD molecules in successive layers will be twisted such that -CD molecules in
one stack will come above another -CD only in the fifth or sixth stack, meaning that there will be a
twist angle of 60 – 720 between β-CDAD-AN-ADβ-CD molecules in successive stacks. A probable
schematic of the assembly is shown in Figure 8b.
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Figure 8. Probable stacking modes of β-CDAD-AN-ADβ-CD in the fiber networks (The nitrogen
atoms are not shown).
Several authors have reported cross-dipole stacks of aromatic chromophores where the twist
angle  varied from 0 to 900.72-75 In these systems non-zero exciton coupling leads to perturbations in
the spectroscopic properties. For example, a PTE system reported by Hariharan and co-workers
exhibited red shifts in the absorption and emission spectra compared to the monomer when  = 70.20.72
Ma et al also reported small red shifts in the absorption and emission spectra for a system where  =
620.75 In the present case we propose that the anthracene chromophores are twisted in the range of 60-
720 as shown in Figure 8b, and this does not lead to any perturbation in the spectroscopic properties. In
other words, these aggregates exhibit properties of null aggregates in the proposed twist angle.
In this study we have investigated only the -CD complex of AD-AN-AD and proposed that the
larger size of -CD compared to anthracene does not allow the type of packing observed for 3 (Figure
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7). In this context, it may be important to investigate the behavior of -CD and -CD complexes of AD-
AN-AD. The outer diameter of -CD is 13.7 Å at the wider rim and this may allow better packing of the
AD-AN-AD/-CD bis-inclusion complex. Since -CD is larger, stacking of AD-AN-AD/-CD bis-
inclusion complex would be more difficult. Such considerations, however, have to take into account the
lower stabilities of AD/-CD and AD/-CD complexes. Cromwell et al. have studied the complexation
of adamantane carboxylate with -, - and -CDs and found that complexation with -CD is the most
exergonic (G0 = -5.85 kcal mol-1) and exothermic (H0 = -4.85 kcal mol-1).58 G0 for the binding of -
CD was 140-fold lower and binding with -CD was found to be endothermic. This study highlighted the
importance of an optimum matching of the cavity size and guest size in determining the strength of
binding. Since the strength of AD/-CD and AD/-CD systems are very low, we may not observe the
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fiber-type assembly for AD-AN-AD/-CD or AD-AN-AD/-CD systems.
If fibers are formed by stacking of bis-inclusion complexes as in Figure 8b, the outer diameter of
the fiber would be around 2.6 nm (see Figure S10). The fibers observed in AFM have diameters in the
50-200 nm range. This suggest that the fibers are bundled together, which most probably would involve
hydrogen bonding interactions between fibers. The fibers formed by stacking as shown in Figure 8b will
have their outer surface covered by the narrow rims of -CD. The narrow rim of -CD is made up of
seven primary hydroxyl groups which can readily form hydrogen bonds with solvent molecules or other
fibers. Since there are large numbers of narrow rims on the outer surface of every fiber, large number of
fibers can come together and get stabilized through hydrogen bonding to give the observed fiber
network. We could not confirm the structure of the null aggregate by X-ray crystallography because β-
CDAD-AN-ADβ-CD did not crystallize from aqueous medium and formed the fiber networks even
at very low concentrations (≤ 10-5 M). The anthracene groups are buried inside the fibers and their outer
surface is loaded with the narrow rims of -CD having primary hydroxyl groups even in the bundled
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state, which makes them highly hydrophilic. Thus, these fibers are soluble in water and do not form
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The stacking modes presented in Figure 8b also explains the chemical shift changes observed in
the NMR titration experiment (Figure 3a). The π-π stacking distance in the assembly is < 4 Å, which
explains the observed chemical shift changes for the ring protons. The Hd protons are sandwiched
between aromatic rings and hence experience large shifts. The photophysical properties of the aggregate
and monomer are identical because the assembly is a null aggregate.
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4. CONCLUSIONS
The bis-adamantane derivative of anthracene, AD-AN-AD, where the adamantane groups are connected
to the 9- and 10- positions of anthracene through a short linker, readily formed a bis-inclusion complex
in aqueous solution, in the presence of two equivalents of β-CD. The bis-inclusion complex, β-CDAD-
AN-ADβ-CD, which is a bola-amphiphile, spontaneously self-assembled in to a nanofiber network.
Images of the nanofiber assemblies were obtained in AFM, TEM and CLSM experiments. The
nanofibers were highly crystalline as confirmed from WAXS studies. We presumed that tight packing of
the anthracene moieties in β-CDAD-AN-ADβ-CD into a crystalline aggregate is responsible for the
crystallinity of the fibers. We proposed that β-CDAD-AN-ADβ-CD tightly packed into null
aggregates where the stacking distance between anthracene molecules is ~3.6 Å and the long axis of
anthracene in one stack is rotated in the range of 60-720 with respect to anthracenes in the preceding and
succeeding layers. The null aggregate can stack together to give the observed 1-D fiber networks.
Photophysical properties of the fiber system were identical to those of the monomer units, and this is in
conformity with the definition of null aggregate. The proposal of the null aggregate is based on the
observed crystal packing in the precursor of AD-AN-AD, where the molecules stacks in a crisscross
fashion to avoid steric crowding. In this mode of stacking the stacking distance is 3.64 Å and the
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crisscross angle  = 56.06◦. In short, this study also provides a simple and effective strategy for
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designing null aggregates of planar chromophores in solution and solid state.
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Supporting Information.
1
Synthesis, H, 13C NMR and ESI-HRMS of AD-AN-AD, Single crystal structure of molecule 3 (in
scheme 1), Molecular dimensions of β-CDAD-AN-ADβ-CD complex, Additional TEM, AFM
images nanofibers. This material is available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
* E-mail:gopidaskr@gmail.com
Present Addresses
Dr. Nagaraj Nayak
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai – 400 076 (India)
ACKNOWLEDGEMENTS
We thank CSIR, Government of India (project no. HCP0012) for financial support. We are also
thankful to Dr. Sunil Varughese for single crystal X-ray analysis, Mr. Kiran Mohan for TEM and Mr.
Aswin Maheswar for AFM analysis. K.R.G. thanks CSIR for Emeritus scheme and N. N. thanks CSIR
for a research fellowship.
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Table of Contents Graphic
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Null Aggregates
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