Surfactants Possessing Multiple Polar Heads. A Perspective on their

PERSPECTIVE pubs.acs.org/JPCL

Surfactants Possessing Multiple Polar Heads. A Perspective on their Unique Aggregation Behavior and Applications Santanu Bhattacharya*,§ and Suman K. Samanta Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India ABSTRACT: Surfactants containing more than one head group are known to exhibit a wide range of interesting properties as they undergo aggregation in water. The correlation between the molecular structure of these surfactants and their properties (for example, critical micellar concentration, aggregation number, morphology, counterion dissociation, fractional charge, etc.) can provide useful information to define the structure
activity relationship. The influence of the number of head groups on the surfactant aggregation is further evident from interesting interfacial behavior, seen in biological applications. This Perspective highlights recent trends in surfactant aggregation effects and focuses on emerging challenges in the field.

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urfactants are useful in a number of household, industrial, and scientific applications, including oil recovery, drug delivery, chemical warfare decontamination, cleaning, waterproofing, and lubricating, or as additives for food, cosmetics, paint, and so forth. Surfactants self-organize in water,1 producing aggregates called micelles above a certain concentration [critical micellar concentration (CMC)],2 and form lyotropic mesophases at higher concentrations. The polar head groups (cationic, anionic, or zwitterionic) of these aggregates lie near the bulk aqueous phase, whereas the hydrocarbon chains or hydrophobic parts extend inwardly to avoid unfavorable water contacts.3 Surfactants, the compounds that lower the surface tension of a liquid, allow easier spreading and lowering of the interfacial tension between two liquids or between a liquid and a solid.4 Electrostatic interactions at the level of head groups determine their relative locations and separations in an aggregate. In comparison with a single-head group/single-chain surfactant, the single-chained ones with multiple head groups have a larger and more hydrophilic end. This tends to reduce the activity of the latter significantly and thus manifests several unique properties in its aggregate states. Owing to their unique physical chemical properties, many natural forms of multihead amphiphiles (I, II) possess important biological functions,5 while their synthetic equivalents (III, IV)6,7 show useful medicinal properties (Figure 1). Thus, the design of diverse types of surfactant molecules of increasing number of head groups provides an opportunity for tailoring their aggregation behavior and the resulting aggregate properties. Various new types of surfactant architectures have appeared in recent literature. These include multihead surfactants (having more than one head group connected to a single hydrocarbon tail), including facial amphiphiles (more than one polar head on one face of the surfactants), multimeric gemini surfactants (dimeric, r 2011 American Chemical Society

trimeric, and tetrameric), bola-form surfactants, star-like trimeric cationic surfactants, and so forth. In the following, we discuss some of these exotic classes of surfactants and draw a correlation between each of their molecular structures and properties. Influence of the Number of Head Groups on the Surfactant Aggregation. When a progressively increasing number of head groups is added to a single aliphatic chain, single-head (1a, d), double-head (1b, e), and triple-head surfactants (1c, f) are obtained (Chart 1).8,9 With a greater number of head groups, the micellar sizes and the aggregation numbers (N) decrease; the CMCs, the degrees of counterion dissociation (R), and the fractional charges (R), on the other hand, increase. This may be rationalized as follows. With larger head group charges and sizes, enhanced electrostatic repulsions among surfactant molecules are experienced within an aggregate. In such a situation, greater micellar surfaces are required, and progressively fewer surfactant molecules can be accommodated in a single micellar aggregate. The hydrocarbon chains in such multihead surfactants therefore remain highly folded in the micelles, as depicted in Figure 2. This renders the resulting micelles more “wet” than their single-chain/single-head group counterparts. A single-head pyridinium surfactant (1d) forms lamellae upon solubilization in water, whereas the corresponding surfactants with double (1e) and triple (1f) head groups form micelles in water.10 The aggregates shrink in size, aggregation numbers continually decrease, and the fractional charges increase with every increase in the number of head groups on the surfactants. This is only possible if a bent conformation is adopted by the hydrocarbon tails in such Received: February 3, 2011 Accepted: March 25, 2011 Published: April 05, 2011 914

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multihead surfactant micelles. Increasing the surfactant concentrations does not affect the lamellar structure for 1d, but the

Double-head amphiphiles (3a) with a rigid aromatic core form micelles in water where log(CMC) values decrease linearly with increasing chain length (n), with a slightly lower dependence on n than that for the corresponding single-head analogues (3b).12 The ionization degrees (R) of the micelle-dwelling surfactant in this series decrease with increasing chain length, consistent with an increase in micelle size. Comparison with two analogous single-head surfactants shows that incorporation of a second head group leads to an increase in the CMC and a decrease in the Krafft temperature. Interfacial Properties. The interfacial behavior of a series of double-head ammonium surfactants (4) has also been examined.13 The adsorption and the nature of the surfactant layers formed strongly depend on their molecular structures. Due to the strong repulsion between the electric surface charges of the double-head surfactant ions in the adsorption layer and in the solution, the single-head/single-tail surfactants are more surfaceactive and exhibit lower surface area occupied by a surfactant at the interface than the corresponding double-head compounds possessing an identical alkyl chain length. Moreover, the methylsulfate derivatives are slightly more surface-active than the corresponding bromide compounds, which also coincides with the Hofmeister series effect. Anions, which can easily penetrate the surface layer, neutralize the charge of adsorbed surfaceactive cations more effectively and lower the surface potential of the electric double layer. As a consequence of surface charge neutralization, more surfactant ions can be adsorbed at the interface. Surface and aggregation properties of another type of two multihead surfactants (5, n = 8, 18) have been examined.14 These reduce aqueous surface tension, decrease the CMC, and increase the micellar size as their alkyl chain lengths increase.15 It has been

With larger head group charges and sizes, enhanced electrostatic repulsions among surfactant molecules are experienced within an aggregate. In such a situation, greater micellar surfaces are required, and progressively fewer surfactant molecules can be accommodated in a single micellar aggregate. aggregation number and the size of the micelles increase for both 1e and 1f. Upon increasing temperature, however, a transition from lamellae to rod-like micelles is observed for 1d, but for 1e and 1f, the micellar size and the aggregation number decrease. Facial amphiphiles based on cholic acid (2) with permanent charges, on the other hand, act as three-head surfactants, forming small “primary” (3
6 nm) and larger “secondary” (15
60 nm) spherical micelles.11 The secondary micelles might form upon clustering of the small, primary micelles, similar to the known two-step aggregation behavior of the cholic acid itself.

Figure 1. Molecular structures of some naturally occurring (I and II) and synthetic multihead amphiphiles (III and IV). 915

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Chart 1. Molecular Structures of an Assorted Variety of Multihead Surfactantsa

a

Each family is shown inside a separate box.

Figure 2. Schematic representation of multihead surfactant micelles where chain coiling is required to alleviate the intersurfactant head group repulsion within the aggregate.

suggested that the hydrophobic “tails” of these surfactants do not end at the first nitrogen as expected but extend to two or three carbons into the “head” region. Interestingly, these multihead surfactants act as effective capping agents for the stabilization of Ag nanoparticles originally synthesized in water, allowing their transfer into organic solvents. Wang et al. also studied their pHdependent aggregation in water. The morphology of the resulting molecular assemblies changes first from micelle to globular vesicles and then into elongated multilayer lyotropic mesophases as the pH of the dispersed medium is increased. Multihead Geminis. Dimeric or oligomeric surfactants that consist of two or more conventional monomeric surfactant units connected through head groups by a suitable spacer exhibit unusual aggregation properties.5,16,17 These are popularly known as gemini surfactants, which possess many unusual properties and have been the subject of many reviews.18 Herein, we discuss a few recent examples of gemini surfactants where multiple charges at the head groups are incorporated. Surfactant 6a forms micelles at a very low CMC and is efficient in lowering oil
water

interfacial tension in comparison to its conventional single-chain counterpart.19 Cationic trimeric surfactant 6b acts as a good structure-directing agent for the synthesis of mesoporous materials.20 The oligomeric surfactants with short spacer [(
CH2
)n, n = 2 or 3] exhibit high propensity to assemble at the air/water interface. These surfactants have a very low CMC and form either a worm-like micelle (dimer), a branched threadlike micelle (trimer), or a ring-like micelle (tetramer). First, a short spacer makes the distance between the head groups (caused by the repulsion among the cationic heads) decrease. Second, this also increases the van der Waals interactions between their alkyl chains. The relative microviscosity increases nearly linearly with the degree of oligomerization in going from DTAB to the surfactant dimer, trimer, and tetramer (6c),21 and the CMC values decrease progressively with increasing degree of oligomerization in the series. The molecular conformational transition driven by the hydrophobic interactions controls their aggregate formation and transition of the star-like trimeric cationic surfactants 7 in 916

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water.22 They first form vesicles just beyond the critical aggregation concentration (CAC) because of the “loose” packing of the hydrocarbon chains caused by the electrostatic repulsion and due to the presence of a spacer around the head groups. When the hydrophobic interactions of the long alkyl chains become strong enough to turn the molecular conformation into a pyramid-like shape, the vesicles transfer to micelles. Gemini surfactants, 8b and 8c exhibit stronger aggregation ability at pH 9.2 in comparison with their monomeric analogue 8a.23 This is due to the enhanced hydrophobic interaction and reduced electrostatic repulsion owing to the existence of a spacer in the geminis. Vesicles form beyond the CAC in all of the investigated surfactants. The water-mediated intermolecular H-bonding interactions between the tertiary N's assist 8a and 8b in their vesicle formation, and the π
π interactions between the aromatic rings could be additional driving force for the vesicle formation in the case of 8c. Meanwhile, the above-mentioned noncovalent interactions provide the possibility of multilayer formation for 8c and 8b at the air/water interface. Due to the very low Krafft temperature and CAC values, these gemini surfactants offer good potential for applications in tertiary oil recovery and as detergents. Thermodynamics and Theoretical Aspects of Aggregation. The relationship between the CMC of the surfactant in solution and its free energy of micellization (ΔGm) was also investigated in detail, and ΔGm was obtained using eq 1 ΔGm ¼ RTð1 þ nβÞ ln CMC þ nRTβ ln n

tendency to form associates with the investigated double-head surfactants than the bromide ions. Aggregate Growth. The addition of salts (organic or inorganic) is known to influence the association behavior of the surfactants in solution. The presence of counterions in the vicinity of the micellar surface contributes to the stabilization of micelles of the ionic surfactants. This, in turn, facilitates the growth of micelles, often leading to the formation of a nonspherical, rod-like shape. Counterions reduce the repulsive forces between the like charges on the heads of the surfactants, stabilizing the micellar organization with reference to a solution of free surfactants. Dramatic micellar growth upon addition of salts [KBr and sodium salicylate (Na-Sal)] occurs with monovalent surfactants (CTABr), leading to a pronounced increase in the viscosity of the resulting micellar solutions.8,27 Although the transition of spherical to rod-like morphology is observed for 1a, shapes of micellar 1b and 1c notably remain unaffected even after the addition of KBr and Na-Sal. Clearly, the charge density at the surfactant head groups markedly influences their micellar aggregation properties. With an increase in the number of head groups, the tightly “bound” pre-existing counterions per cation around the micelle may be responsible for this unusual micellar behavior of the multihead surfactants, which help “screen” the latter from the added salts. Biological Applications. The multihead cationic amphiphiles (1a
f) were also tested for possible antimicrobial activities against both Gram-positive and Gram-negative bacteria. The killing effects of the single-head amphiphiles (1a and 1d) were slightly lower than those of CTAB and CPB.28 However, with an increase in the number of head groups in the surfactants, the killing effects increased dramatically for both sets of the compounds. This could be first due to their higher solubility in water and second due to greater positive charge density per molecule, both of which enable them to interact better with the bacterial cell surface, leading to more efficient killing of the bacteria. Interestingly, the multihead pyridinium amphiphiles are more efficacious antimicrobials compared to their Me3Nþ counterparts.28 Further, the multicationic heads in these amphiphiles are covalently attached via scissile ester-type linkages that can be hydrolyzed spontaneously at physiological pH. This property enables such multihead surfactants to be readily metabolized, reducing their toxicity significantly. Therefore, such multihead surfactants have the potential to be superior disinfectants and antiseptics for food and body surfaces. Analogously the facial amphiphiles (2) have also manifested certain antimicrobial activity.11 A series of cationic surfactants composed of a single hydrocarbon tail and three positive head groups was developed (9) with the purpose of achieving optimal condensation of DNA and enhancing transfection.29,30 The R groups in 9 were varied in terms of the aliphatic chain length (from
C5H11 to
C23H47), or the chains possessed a double bond in the middle, or even the hydrophobic part was derived from cholesterol. When each of these compounds was mixed with DNA or RNA in an aqueous solution, electrostatic and hydrophobic interactions led to a spontaneous self-assembly into a surfactant
nucleic acid complex (lipoplex).31 Although single-chained agents induce the complexation of DNA by forming micelles, such vectors were more toxic and less efficient than their double-tailed counterparts. Indeed, the use of multicationic vectors could offer an accelerated means of allowing endosomal disruption and thus enhanced DNA escape. For example, the transfection efficiency of the multihead cationic lipid (III) surpasses that of the commercially available

ð1Þ

where β is the fraction of charges and n = number of head groups. The changes in the free energy of micellization (ΔGm) gradually became less negative from 1a to 1c and 1d to 1f with an energy increase in the number of head groups. This implies that micelle formation becomes progressively less favorable as more head groups are incorporated into the surfactant. The micelles are more hydrated, and the micropolarity of the micelles and the degrees of micellar ionization increase with the increase in the number of heads.24,25 A coarse-grained model has been developed recently to understand the aggregation behavior of the multihead surfactants in water and also to find out the maximum number of head groups that can be attached onto a single hydrocarbon chain of identical length such that micelle formation is still feasible. Molecular-level pictures of the aggregates obtained using MD simulations indicate that with every rise in the number of head groups, the CMC values increase gradually, and the size and aggregation number of the micelles decrease progressively for the surfactants with a constant hydrophobic unit. The coarse-grained model is thus in good agreement with the available experimental results.26 Importantly, micelle formation with a very low N value of the four-head surfactant has been predicted, but no experimental data exist yet. Theoretical calculations of double-head surfactants (4) have been carried out to examine the effect of the counterion on their interfacial behavior.13 The studies indicate that the CH3OSO3
ions, due to their higher polarizability, exhibit stronger interactions with the electric field at the interface than the Br
ions. Bromide activity measurements indicate that the concentration of Br
ions at higher surfactant concentrations but still below their CMCs was lower than that predicted for fully dissociated surfactant molecules. This phenomenon is also confirmed by molecular dynamic simulations, which demonstrate that the methylsulfate ions have a higher 917

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micelles are first formed, which undergo clustering to larger aggregates, a property inherent to cholic-acid-based scaffolds.11 For a related double-head surfactant, the surface activity is lowered, the CMC increases, and the Krafft temperature decreases as a larger number of head groups is added to it.12,13 The formation of a variety of shapes and sizes in a wide range of pH value suggests 5 (n = 18) to be a kind of surfactant that may offer potential in drug delivery as well as in the fabrication of biosensors and biomolecular devices.14 The magnitude of the negative free energy of micellization decreases with increasing number of head groups.24,25 MD simulations suggest that even a single-chain surfactant with four charged head groups can still form micelles, albeit with a very small N value.26 Salt-induced micellar growth, a property well-known for conventional singlehead ionic surfactants, is impeded in the case of the multihead surfactant micelles.27 Importantly, the multihead cationic surfactants show potent antimicrobial properties against a range of stubborn organisms and also manifest effective gene transfection activity compared to their single-head counterparts.28
30 The above findings clearly demonstrate that an incorporation of multiple heads into amphiphile brings about ramifications far exceeding the seemingly small modification at the molecular level. Therefore, further modification and evolution of their structure
property relationships need to be assessed in order to reap practical benefits. Depending on the choice of the head group, one can deposit such multihead surfactants onto suitable surfaces to render them antibacterial or antifungal. Corresponding self-assembled

single-head DOTAP (N-[1-(2, 3-dioleoyloxy)-propyl]-N,N,N-trimethyl ammonium)-based lipid.6 In particular, DNA complexes of (III) are significantly more effective transfectants in mouse embryonic fibroblasts, a cell line empirically known to be hard to transfect. Neutral and cationic series of trimeric β-hydroxyamino or ammonium surfactants 10 show good surface-active properties.32 Solubility of the cationic compounds in water at 20 °C exceeds by >600 times their neutral counterparts. Thus, cationic surfactants in the series 10b exhibit clear solutions, well-defined CMCs, and a linear relationship between the CMCs and the number of carbon atoms in the alkyl chains of the homologues. A relatively lower head group surface area (for the cationic series, 10b) indicates a flexibility of the spacing group and stronger intermolecular van der Waals interactions with increasing chain lengths. These lead to the formation of a more close-packed arrangement. The antimicrobial potency of these surfactants depends on the target microorganism (Gram-positive bacteria > fungi > Gram-negative bacteria), as well as on both the neutral or ionic nature (cationic > neutral) and alkyl chain length (tri-C12 > tri-C18 > tri-C8) of the compounds. Future Challenges. In summary, the incorporation of multiple heads into a single chain of constant length surfactant results into lowering of aggregate size and aggregation number while their fractional charge, counterion dissociation, and CMCs increase irrespective of their nature of the head groups.8
11 Even in the case of corresponding facial multihead amphiphiles, smaller

Figure 3. Schematic representation of multihead surfactant-induced nanoparticle aggregation in different modes. Depending on the number of head groups on the surfactant, the density of the hydrophobic chains in the periphery of the nanoparticle can be made to vary. The mode and the extent of interfacial interactions decide the extent of growth, giving rise to different shapes. 918

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The Journal of Physical Chemistry Letters monolayers, surfaces and coatings will have fewer hydrocarbon chains per unit area compared to the conventional surfactants. Investigation of interactions between such coatings and surfaces will therefore be interesting. On the other hand, if the charged ammonium or pyridinium head groups are replaced by suitable naturally occurring amino acids, glycoclusters, or nucleic-acidbased functional groups, the resulting multihead surfactants could be considerably more biocompatible and less toxic and may find use in tissue engineering or as bioadhesives.

Depending on the choice of the head group, one can deposit such multihead surfactants onto suitable surfaces to render them antibacterial or antifungal. One can even extend the utility of such multihead surfactants for the stabilization of nanoparticles toward photothermal ablation therapy (PTA) of cancer.33 Several single-head/single-tail surfactants have already been used to stabilize silver and gold nanoparticles and their use as PTA. However, the use of multihead surfactants for the stabilization of nanoparticles is hitherto unknown. We have already proposed a suitable modification of multihead surfactants with the biocompatible less toxic, targetable head groups for better biological activity. The choice of appropriate multihead surfactants having biocompatible and targetable heads is crucial for achieving optimum PTA. Along similar lines, one can decorate SWNTs to achieve better transfection efficacy and other biological applications. Multihead surfactant-capped nanoparticles may also be exploited to self-organize to produce structure-directing architectures in different dimensions. Achieving controlled manipulation of these properties will lead to applications in many areas. The effective head group size increases with the appendage of additional head groups for a particular hydrophobic tail. In that situation, the surfactant with single head/single tail will have greater number of alkyl chains in the periphery of the stabilized nanoparticle compared to that of their multihead analogues. This in turn should induce formation of altered nanoparticle aggregate structures depending on the interactions with the hydrocarbon tails on their surfaces. Thus, one can end up with nanorods of high aspect ratio in the case of the single-head surfactant, smaller aspect ratio rods or nanoparticles in the case of the double-head surfactants, and predominantly spherical nanoparticles in case of the surfactant cap with a higher number of head groups (Figure 3).34
38 Clearly, much needs to be done to exploit such exciting possibilities.

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’ BIOGRAPHIES Santanu Bhattacharya obtained his Ph.D. (Prof. Robert A. Moss) from Rutgers University, New Brunswick, NJ. He was a NIH postdoctoral fellow at MIT under the tutelage of Prof. H. Gobind Khorana. He is now a senior Professor at the Indian Institute of Science and an honorary faculty of the Chemical Biology Unit, JNCASR, Bangalore. He has authored more than 165 research articles. His research interests include various aspects of chemical biology, supramolecular chemistry, molecular sensors, physical gels, self-assemblies, and chemistry of nanomaterials. Suman K. Samanta received his M.Sc. in Chemistry from the University of Calcutta in 2006, and currently, he is working towards his Ph.D. under the guidance of Prof. Santanu Bhattacharya at the Indian Institute of Science. His research interests include synthesis of functional organic molecules, self-assembly, physical gels, photophysical properties, novel surfactants, and theoretical studies. ’ ACKNOWLEDGMENT S.B. thanks DST, New Delhi, for the J. C. Bose Fellowship and Dr. Kevin L. Caran for useful discussions. S.K.S. thanks CSIR for a senior research fellowship. ’ REFERENCES (1) Chevalier, Y. New Surfactants: New Chemical Functions and Molecular Architectures. Curr. Opin. Colloid Interface Sci. 2002, 7, 3–11. (2) Israelachvili, J. N. Physics of Amphiphiles: Micelles, Vesicles, and Microemulsions. Elsevier: Amsterdam, The Netherlands, 1985; p 24. (3) Menger, F. M.; Shi, L.; Rizvi, S. A. A. Self-Assembling Systems: Mining a Rich Vein. J. Colloid Interface Sci. 2010, 344, 241–246. (4) Rosen, M. J. Surfactants and Interfacial Phenomena, 3rd ed.; Wiley: New York, 2004. (5) Bhattacharya, S.; De, S. Synthesis and Vesicle Formation from Dimeric Pseudoglyceryl Lipids with (CH2)m Spacers: Pronounced mValue Dependence of Thermal Properties, Vesicle Fusion, and Cholesterol Complexation. Chem.—Eur. J. 1999, 5, 2335–2347. (6) Ewert, K. K.; Evans, H. M.; Zidovska, A.; Bouxsein, N. F.; Ahmad, A.; Safinya, C. R. A Columnar Phase of Dendritic Lipid-Based Cationic Liposome
DNA Complexes for Gene Delivery: Hexagonally Ordered Cylindrical Micelles Embedded in a DNA Honeycomb Lattice. J. Am. Chem. Soc. 2006, 128, 3998–4006. (7) Jayaprakash, K. N.; Lu, J.; Fraser-Reid, B. Synthesis of a Lipomannan Component of the Cell-Wall Complex of Mycobacterium tuberculosis Is Based on Paulsen’s Concept of Donor/Acceptor “Match”. Angew. Chem., Int. Ed. 2005, 44, 5894–5898. (8) Haldar, J.; Aswal, V. K.; Goyal, P. S.; Bhattacharya, S. Molecular Modulation of Surfactant Aggregation in Water: Effect of the Incorporation of Multiple head groups on Micellar Properties. Angew. Chem., Int. Ed. 2001, 40, 1228–1232. (9) Haldar, J.; Aswal, V. K.; Goyal, P. S.; Bhattacharya, S. Role of Incorporation of Multiple head groups in Cationic Surfactants in Determining Micellar Properties. Small-Angle-Neutron-Scattering and Fluorescence Studies. J. Phys. Chem. B 2001, 105, 12803–12808. (10) Haldar, J.; Aswal, V. K.; Goyal, P. S.; Bhattacharya, S. Aggregation Properties of Novel Cationic Surfactants with Multiple Pyridinium Headgroups. Small-Angle Neutron Scattering and Conductivity Studies. J. Phys. Chem. B 2004, 108, 11406–11411. (11) Willemen, H. M.; de Smet, L. C. P. M.; Koudijs, A.; Stuart, M. C. A.; Heikamp-de Jong, I. G. A. M.; Marcelis, A. T. M.; Sudholter, E. J. R. Micelle Formation and Antimicrobial Activity of Cholic Acid Derivatives with Three Permanent Ionic Head Groups. Angew. Chem., Int. Ed. 2002, 41, 4275–4277.

’ AUTHOR INFORMATION Corresponding Author

*Phone: þ(91)-080-2293-2664. Fax: þ(91)-080-2360-0529. E-mail: [email protected]. Notes §

Also at the Chemical Biology Unit, Jawaharlal Nehru Centre of Advanced Scientific Research, Bangalore 560 012, India. 919

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