Special Issue | October 2014 187

BARC NEWSLETTERFounder’s DaySTIMULI-RESPONSIVE CUCURBITURIL-ADORNED SUPRMOLECULAR MICELLAR ASSEMBLIES OF

CETYLPYRIDINIUM CHLORIDE

Jyotirmayee MohantyRadiation & Photochemistry Division

Abstract

The molecular recognition behavior of versatile macrocyclic receptors, cucurbiturils (CBs) have been investigated in

relation to their host-guest interaction with amphiphilic molecules, especially cationic surfactants having widespread

technological importance. Construction of novel cucurbituril (CB)-adorned supramolecular micellar assemblies

of a cationic surfactant, cetylpyridinium chloride (CPC), through noncovalent host-guest interactions has been

demonstrated. The distinct cation receptor features and cavity dimensions of the CB5 and CB7 homologues assert

that the macrocyclic hosts remain complexed with the CPC monomers and take part in the micelle formation with

a shift in cmc, a unique observation in contrast to that of classical host, b-cyclodextrin, and has been characterized

by photochemical, surface tension, conductivity, DOSY NMR and SANS measurements. The reversible response of

these soft supramolecular micellar structures to thermal-stimuli, which project their utility for on-demand smart

drug-delivery vehicles, has also been established.

Key Words: Host-guest interaction, cucurbiturils, surfactant, supramolecular-micellar assemblies, stimuli-

responsive

This Paper received the Samanta Chandra Sekhar Award 2011, at the Annual Meeting of the Odisha Bigyan Academy

Introduction

Supramolecular encapsulation of guest molecules

through macrocyclic hosts presents a convenient

pathway for modulation of molecular properties, as

it can introduce pronounced effects on the physico-

chemical properties of the included guest.1 Host-

guest interaction finds immense importance in

obtaining photostability, drug delivery, catalysis, and

sensor applications. Cucurbiturils (CBs), relatively new

addition to the repertoire of macrocyclic hosts, are

a unique class of water soluble macrocyclic receptor

molecules consisting of methylene bridged glycoluril

units (Chart 1).1,2 Structurally, the pumpkin-shaped

CBs constitute highly symmetrical hydrophobic cages

of low polarity and polarizability with two identical

dipolar portal ends comprised of carbonyl functional

groups.1,2 As a macrocyclic host, CBs have attracted

considerable attention in recent years owing to their

excellent binding abilities for varieties of guests.

Among different CBs, the homologue cucurbit[7]uril

(CB7, with 7 glycoluril units) forms stable inclusion

complexes with several guest molecules, like organic

dyes, protonated alkyl and aryl amines and cationic

dyes, via a combination of hydrophobic and ion-dipole

interactions.1-4 The lower homologue cucurbit[5]uril

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CONTENTS

188 Special Issue | October 2014

BARC NEWSLETTERFounder’s Day(CB5), having a smaller cavity size, interacts with metal

ions or forms exclusion complex with cationic organic

guests through its highly polarized carbonyl portals.2 In

this article, the supramolecular interactions of CB5 and

CB7 hosts with a cationic surfactant, cetylpyridinium

chloride, have been described in relation to the

modulation in the critical micelle concentration (cmc),

temperature-responsive tunability and their potential

applications.

concentrations, the cmc gradually increases from its

normal value of 1 mM to 1.63 mM in the presence of

2 mM CB7 (Fig.1 a-c). In contrast, the titration of NR

with CPC in the presence of CB5 (1 mM), displayed a

downward shift in the cmc (0.57mM) (Fig.1 d, e).5 The

shift in cmc of CPC in the presence of CB5/CB7 was

also confirmed by surface tension and conductivity

measurements.

Chart 1: Chemical structures of the cucurbituril hosts and CPC surfactant.

Cucurbituril-adorned Suprmolecular Micellar Assemblies

Cetylpyridinium chloride (CPC, Chart 1) belongs to

a class of frequently used cationic surfactants and

exhibits intriguing microstructural changes with

anionic additives such as hydrotropes, electrolytes, bile

salts, etc. Owing to its vast applications, we attempted

to explore its intriguing assembly features in the

presence of supramolecular host, CBs, to have control

for an on demand uptake and release.

In the photochemical approach, we employ a

fluorescent probe, Nile Red (NR), which shows

characteristic changes in its spectral properties due

to its preferential positioning in the interfacial region

of the micelle. As shown in Fig. 1, the micellization

behavior was examined in the presence of the

macrocyclic host, CB7 and CB5. With increasing CB7

Fig.1: Fluorescence titration curves of NR (~2 mM) with different concentrations of CPC in the absence and presence of CB hosts: absence of CBs (a); 1.5 mM CB7 (b); 2.0 mM CB7 (c); and 0.5 mM CB5 (d); 1 mM CB5 (e). lex = 550 nm, lmon = 660 nm.

Considering the dimensions of the CB portals (portal

diameter ~5.4 Å and ~2.4 Å for CB7 and CB5,

respectively),2 and CPC (width of pyridinium group

<5 Å and length of hydrocarbon chain ~17 Å), it is

apparent that the pyridinium group of CPC can be

accommodated within the CB7 cavity. CPC cannot

be accommodated inside the CB5 cavity, however, an

exclusion complex based on ion-dipole interactions

is possible. Earlier studies using cyclodextrin (CD)/

CB7 hosts and other surfactant molecules have

suggested that the reduction in the surfactant-

monomer concentration is the prevailing mechanism

for the upward cmc shift where the host-bound

surfactant monomers do not participate in the micelle

formation.6,7 However, a similar mechanism in the

present case cannot explain the contrasting cmc shifts

observed with the CB7 and CB5 hosts, which points to

possible participation of the CB-bound CPC monomers

in the micelle formation.

Special Issue | October 2014 189

BARC NEWSLETTERFounder’s DayThe participation of the CB hosts in the micelle

structure has also been confirmed by DOSY NMR

measurements. If the cucurbiturils remain attached to

the CPC as inclusion or exclusion (in the vicinity of the

CPC head group) complexes, the diffusion coefficients

of both the CPC protons as well as the CB7 protons

would get affected on micellization. The average

diffusion coefficient of the –CH protons of CPC in the

presence of CB5 or CB7, decreases with increasing

CPC concentrations. While the diffusion coefficient

of CB5 protons remain unchanged, CB7 protons

show a gradual decrease even beyond the cmc (Fig.

2), indicating that the CB7-CPC unit is incorporated

within the micellar assembly. However, similar studies

with b-cyclodextrin (bCD) displayed such changes after

an initial slight decrease, which was expected for its

involvement with the monomers.5

Fig.2: Plot of the diffusion coefficient values for the b-CD (a), CB7 (b) and the CB5 (c) protons with CPC concentration.

significant decrease in the surface charge on the

micelle (0.17 to 0.10). This is very much in line with

the existence of CB7 beaded CPC micelle. On the

other hand, in the CB5-CPC system, though the SANS

data indicated a significant reduction in the surface

charge, the micellar dimensions remained unchanged,

suggesting an externally embedded CB5 on the CPC

micelle. Based on the above results, the positioning of

the CB7/CB5 hosts in the CPC micelle can be visualized

as in Fig. 3. In the case of CB5, the macrocycle remains

in the periphery of the micellar structure, whereas in

the case of CB7, the CB7-CPC complex is incorporated

within the micellar structure leading to the formation

of mixed micelles. The incorporation of CB7 at the

neck of the pyridinium head group provides optimum

interaction for the negatively polarized CB portals with

the cationic charge of the pyridinium head group. In

addition a part of the alkyl chain is included in the

cavity of the macrocycle due to favorable hydrophobic

interactions. The partial encapsulation of alkyl chain of

CPC within the CB7 host can reduce the hydrophobicity

of the alkyl chain and can lead to an increase in the

cmc.5

Stimuli-responsive Tuning

The advantages of the contrasting supra-molecular cmc

shift established in CPC on using CB7 or CB5 has been

explored further to demonstrate a supramolecularly

tunable cmc, which has implications in drug transport,

binding and release strategy, etc. The effect of

increasing CB7 concentration or solution temperature

on the cmc of CPC in a solution containing 1 mM

Fig.3: Schematic representation of the distinct cucurbituril adorned micellar assemblies formed by CPC (a), in presence of CB7 (b), and CB5 (c).

Small-angle neutron scattering

(SANS) measurements on the

CB7-CPC system revealed that

the micellar structure of CPC is

prolate ellipsoidal with axes 34.3

Å (a) and 18.5 Å (b). However,

in the presence of CB7, there is

slight elongation along the major

axis from 34.3 to 35.9 Å with a

190 Special Issue | October 2014

BARC NEWSLETTERFounder’s DayCB5 has been investigated. The fluorescence titration

curves progressively shifted with the addition of CB7

or increasing temperature and the corresponding cmc

values demonstrated a tunable range from 0.57 to

1.6 mM (Fig. 4).5 The addition of CB7 or increase in

temperature at the above discussed conditions disrupts

the CB5-CPC micellar structure, which establishes a

facile host/temperature-induced release mechanism

having direct relevance in drug delivery applications.

demonstrates a continuous tunable range for the

micellization of CPC. The supramolecular modulation

of the surfactant aggregates, envisioned in the present

work is very potent and promising for pharmacological

applications and for designing tunable artificial

molecular devices or nanoreactors.

Acknowledgements

I acknowledge all my collaborators and co-authors of

our published works. I also thank the colleagues in

RPCD and CG, BARC for their constant encouragement

and support.

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Fig. 4: Micellization curve for the CB5 or CB7 adorned CPC surfactant and the proposed release mechanism for the CB5 assembly.

Conclusion

The established cucurbituril-adorned, thermo-

responsive on/off supramolecular micellar assemblies

of the cationic surfactant, CPC, is schematically shown

in figure 4. While the supramolecular additive, CB5,

exhibits an early micellization of CPC at ~0.57 mM,

the CB7 host delays the same to about 1.6 mM of

CPC. Response of these systems to external stimuli,

such as, temperature or the combination of CB5/CB7,