Self-Assembly of Amphiphilic Calix[4]arenes in Aqueous Solution

FULL PAPER 

DOI: 10.1002/adfm.200500212 

Self-Assembly of Amphiphilic Calix[4]arenes in Aqueous Solution** 

By Michael Strobel, Katarzyna Kita-Tokarczyk, Andreas Taubert, Corinne Vebert, Paul A. Heiney, 

Mohamed Chami, and Wolfgang Meier* 

The self-assembly of amphiphilic calix[4]arenes with either a carboxylic acid or a trimethyl ammonium head group and different 

alkyl chains in aqueous solution was investigated. The carboxylated calixarene forms vesicles in dilute solution and stable 

monolayers on water. In contrast, the ammonium head group provides high water solubility with no observed aggregation. At 

high concentrations, all calixarene amphiphiles form lyotropic liquid crystals. 

1. Introduction 

Calixarenes are monodisperse, easily synthesized, and easily 

purified in large amounts. Amphiphilic calixarenes are “surfactants 

with a host–guest recognition site”, [1] which is attractive 

for applications where a guest molecule must be stabilized, 

transported, or protected in aqueous media. As amphiphilic calixarenes 

can interact with aqueous systems, they are of particular 

interest for biological and environmental applications, e.g., 

wastewater treatment, medical diagnosis, and highly sensitive 

and selective sensors. [2,3] There have thus been some studies on 

amphiphilic calixarenes in aqueous solution, [1,4–15] but few calixarene-based 

gels have been reported, [16,17] although such gels 

could, for example, enable the incorporation of pharmaceutically 

active compounds into ointments. In the same context, 

liquid-crystalline calixarenes are interesting, but so far only a 

few calixarene-based LCs have been reported. [18–26] 

Most reports on amphiphilic calixarenes have been on dilute 

aqueous solutions. For example, in an early small-angle X-ray 

scattering (SAXS) study of sulfonated calix[6]arene amphiphiles, 

Shinkai et al. [1] observed micelles. More recently, Kellermann 

et al. [5] have reported uniform and monodisperse micelles; 

mixed micelles have also been described, [27] and Capuzzi 

– [*] Prof. W. Meier, Dr. M. Strobel, Dr. K. Kita-Tokarczyk, [+] 

Dr. A. Taubert, Dr. C. Vebert 

Department of Chemistry, Biozentrum, University of Basel 

CH-4056 Basel (Switzerland) 

E-mail: wolfgang.meier@unibas.ch 

Prof. P. A. Heiney 

Department of Physics and Astronomy, University of Pennsylvania 

Philadelphia, PA 19104 (USA) 

Dr. M. Chami 

M.E. Müller Institute for Microscopy, Biozentrum, University of Basel 

CH-4056 Basel (Switzerland) 

[+] Current address: Faculty of Chemistry, Jagiellonian University, 

Ingardena 3, PL-30-060 Krakow, Poland. 

[**] We acknowledge Prof. W. B. Stern (University of Basel) for preliminary 

X-ray experiments at the Earth Sciences Department. This work 

was funded by the Swiss National Science Foundation and the NCCR 

Nanosciences. P. A. H. acknowledges financial support by the National 

Science Foundation (DMR-0102459). Supporting Information 

is available online from Wiley InterScience or from the author. 

et al. [11] have investigated selective counterion complexation 

by calix[4]arene-crown ether micelles. While most of these 

studies report the formation of micelles, three studies describe 

the formation of vesicles from calixarenes. [6,8,9] Vesicular structures 

should attract attention because they may have applications 

similar to lipid vesicles or self-assembled polymers, which 

have been widely promoted as, e.g., drug-delivery systems. [28–30] 

The goal of this current study was thus to synthesize amphiphilic 

calixarenes and to study their self-assembly in aqueous 

solution. We have studied the amphiphilic calix[4]arenes 4, 5a, 

and 5b (Scheme 1) in aqueous solution and at the air/water 

interface using a wide variety of experimental techniques. For 

the reasons mentioned above, a particular focus was the formation 

and investigation of vesicular structures. 

2. Results 

2.1. Self-Assembly in Dilute Solutions 

We will first present the results obtained from dilute calixarene 

solutions. Figure 1 shows the static and dynamic light scattering 

(LS) data of calixarene 4 in 0.1 M NH3(aq). The hydrodynamic 

radius R h of the aggregates is 43 nm, as calculated 

from the Stokes–Einstein equation using the diffusion coefficient 

obtained after extrapolation to zero concentration, Figure 

1a. [31] The polydispersity index is approximately 1.2 for all 

samples, which is common for vesicles. 

The concentration (c) profile of the inverse scattering intensity, 

Figure 1b, is linear. As a result, the critical aggregation 

concentration (cac) is below the detection limit of our lightscattering 

experiments. Zimm analysis yielded a radius of gyration 

R g of 58 nm and a weight-average molecular weight (M w) 

of about 10 7 g mol –1 for the aggregates, i.e., the aggregation 

number is ca. 7800. Interestingly, the scattering intensity of solutions 

of 5a and 5b was too low for analysis even at a concentration 

of 500 mg mL –1 . These LS measurements are further 

complicated by the low index of refraction increment. 

Figure 2 is a cryo-TEM (transmission electron microscopy) 

image of 4 in 0.1 M NH 3(aq). The sample is a mixture of large 

and small vesicles, distorted vesicles, and isolated lamellae; the 

252 © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Funct. Mater. 2006, 16, 252–259

M. Strobel et al./Self-Assembly of Amphiphilic Calix[4]arenes in Aqueous Solution 

Scheme 1. Calixarene amphiphile synthesis. 

Figure 1.a) Scaleddiffusioncoefficient(KD)andb) inversescatteringintensity 

(Kc/R),Kistheopticalconstant,RistheRayleighratio)of4in0.1 MNH3(aq). 

Figure 2. Cryo-TEM image of self-assembled structures of 4 in 0.1 N 

NH 3(aq): 1) large vesicle, 2) small vesicle, 3) distorted vesicle, and 4) isolated 

lamella or rod-like micelle. 

latter can also be interpreted as rod-like micelles. As in previous 

studies, multilayer vesicles are not observed. [6,8,9] It must 

be stressed at this point that, unlike in other studies, the vesicles 

form spontaneously, i.e., simply after dissolution in aqueous 

solvents without further treatment, such as sonication etc. 

Despite the wide variety of shapes and sizes, the membrane 

thickness of the vesicles and the diameter of the presumed rodlike 

micelles is uniform, ranging from 37 to 50 Å. Simple calculations 

of the length of the monomeric unit of 4, 5a, and 5b 

using ChemOffice Chem3D give lengths of 17.1, 19.9, and 

22.0 Å, respectively, if the alkyl chain is fully extended, Figure 

3. These calculations are consistent with the bilayer thickness 

observed in the TEM: a bilayer of 4 is approximately 40 Å 

thick from the calculations, which is consistent with the 37 to 

50 Å observed in the TEM. 

2.2. Self-Assembly at the Air/Water Interface 

Before presenting the results from concentrated bulk aqueous 

solutions, we will focus on the self-assembly of the calixarenes 

at the air/water interface. These studies provide further 

insight into why, in dilute solution, 4 forms vesicles and 5a,5b 

do not seem to form any aggregates that can be detected either 

with LS analysis or TEM. 

Figure 4 shows the surface pressure (p)–area (A) isotherms 

and the corresponding surface potentials of 4 and 5a on water. 

4 and 5a form condensed monolayers and exhibit no evident 

phase transitions in the low-surface-pressure region. However, 

the isotherms vary strongly as a function of the head group. 

i) Only the isotherm of 5a has a distinct and reproducible plateau 

at high p. ii) 5a has a larger lift-off area than 4 (50 Å 2 versus 

20 Å 2 , respectively). iii) The mean area per unit monomer 

of 4 and 5a differs with the number of molecules spread at the 

interface and with the compression speed (data not shown). 

The lift-off area is smaller upon slow compression, and when a 

small amount of 4 or 5a is spread. These differences are more 

significant in the case of 5a, the compound of higher water 

Adv. Funct. Mater. 2006, 16, 252–259 © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.afm-journal.de 253 

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Figure 3. Calculated monomeric units with fully extended alkyl tails. The 

head group of 4 is ca. 4.4 Å wide if one takes into account that the benzene 

rings cannot be closer than their outermost hydrogens. The head 

groups of 5a and 5b are ca. 4.3 Å wide. Element code: gray—carbon, 

red—oxygen, dark blue—nitrogen, light blue—hydrogen, green—chlorine. 

Figure 4. p–A isotherms of 4 and 5a with corresponding surface potentials. 


solubility. iv) The surface potential (DV) increases before p 

increases. The surface potential increase of 4 is linear in the 

expanded phase region, and a small kink is observed at the liftoff 

area. Maximum surface potential, corresponding to the 

most-vertical orientation of the hydrophobic chains, is reached 

at ca. 20 Å 2 . Further compression leads to a p increase, 

whereas DV slightly decreases. 5a already exhibits a linear DV 

increase in the expanded phase, but at the onset of the plateau 

in the p isotherm, DV decreases slightly. 

Not only the isotherms but also the film stability varied 

strongly with the head group: during subsequent compression/ 

expansion cycles, a significant amount of 5a desorbed irreversibly 

into the subphase, as is shown in a constant-area experiment 

(see Supporting Information). 

At the Brewster angle (53° for the air/water interface), the 

monolayer morphology can be imaged based on the intensity 

of the p-polarized light reflected from the interface. The image 

grayscale can be related to different organization of the molecules 

at the interface. Figure 5 shows that at zero surface pressure, 

gaseous (dark) and expanded liquid (gray) phases coexist 

in monolayers of 4. At the lift-off area (ca. 18 Å 2 ) the gaseous 

phase disappears, but no ideally homogeneous monolayer 

forms. Instead, monolayer fragments and a ‘rough’ (more reflecting) 

texture are visible, indicating a change in molecular 

packing. Bright stripe-like structures appear and grow above 

the ‘kink’ pressure at 42 mN m –1 . Eventually, the monolayer 

collapses. With 5a (data not shown), we observed an ideally 

smooth monolayer throughout the compression, but no larger 

features. 

Figure 5. Brewster angle microscopy (BAM) images of 4 at increasing surface 

pressures. 

254 www.afm-journal.de © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Funct. Mater. 2006, 16, 252–259


2.3. Self-Assembly in Concentrated Solution 

Figures 6,7 are optical micrographs of 5a in water (70:30 w/w) 

and 4 in 5 N NH 3(aq) (63:37 w/w), respectively. All images 

show birefringence indicative of a liquid crystal (LC); the textures 

are however rather non-descript, which makes it difficult 

to definitely assign a LC phase to the materials. We explain the 

lack of a characteristic texture with the high viscosity of the respective 

samples. The LCs are stable between 50 and 80 wt.-% 

(calixarene 4) and 55 and 80 wt.-% (calixarene 5a) from 5 to 

80 °C. Figure 8 is an approximate phase diagram of 4 and 5a. 

This is, to the best of the authors’ knowledge, the first lyotropic 

LC of calixarenes reported. 

Figure 9 is an X-ray pattern of a 60:40 (w/w) mixture of 4 

in 3 N NH3(aq). The pattern exhibits a single sharp peak at 

q =0.161 Å –1 , corresponding to a d-spacing of 39 Å. Such a 

pattern is characteristic of a lamellar lyotropic LC, and the 

Figure 6. A 70:30 (w/w) mixture of 5a in water between crossed polarizers. 

Figure 7. A 63:37 (w/w) mixture of 4 in 5 N NH 3(aq) between crossed polarizers. 

Figure 8. Phase diagrams of 4 and 5a. 

Figure 9. X-ray pattern of a 60:40 (w/w) mixture of 4 in 3 N NH3(aq) at 

room temperature. 

d-spacing is consistent with the cryo-TEM measurements on 

dilute solutions of 4, which indicate vesicle wall thickness of 

37–50 Å. The X-ray data are also consistent with the calculated 

bilayer thickness of ca. 40 Å. However, due to the 

absence of higher-order peaks this assignment must be considered 

preliminary. 

In contrast to 4, the X-ray pattern of 5a (see Supporting 

Information) exhibits a more complex pattern with at least 

5 distinct (albeit broad) peaks. A complete analysis requires 

more diffraction peaks and further experimental data on 

the aggregate shape in solution from LS. However, the 

X-ray pattern is consistent with a rectangular columnar 

structure. 


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3. Discussion 

3.1. Dilute Solutions 

Unlike many lipids, surfactants, or amphiphilic block copolymers 

in dilute aqueous solution, 4 spontaneously self-assembles 

into unilamellar vesicles. Rg (58 nm) and Rh (43 nm) of 4 in dilute 

solution yield a q value (q = Rg/Rh) of 1.35. A q value of 1 is 

characteristic for hollow spheres, i.e., vesicles, and q = 2 is obtained 

for anisometric objects such as rods, however sample 

polydispersities of ca. 1.2 also affect q. [32] LS analysis thus indicated 

the presence of a polydisperse mixture of objects with several 

shapes and sizes in dilute solutions of 4. Cryo-TEM confirmed 

the formation of vesicles and long thin features that 

could possibly be rod-like micelles. The vesicle shell thickness 

(or rod diameter) obtained from cryo-TEM was between 37 and 

50 Å. We concluded that the shells are calixarene bilayers because 

their thickness is similar to lipid bilayers (30 to 50 Å). [29] 

Furthermore, the calculated thickness of a bilayer of 4 is just below 

40 Å, also in agreement with the observed shell thickness. 

The uniform thickness indicates that no multilayers form. 

The wide variety of shapes and sizes is consistent with a 

system with rather slow dynamics: in general, highly dynamic 

systems at or close to equilibrium rapidly undergo surfactant 

exchange and show uniform aggregate shapes and sizes. Systems 

with slow dynamics, however, exhibit rather broad shape 

and size distributions. The cryo-TEM images are therefore 

snapshots of assemblies attempting to reach equilibrium rather 

than assemblies at equilibrium. 

In contrast to 4, we did not observe aggregation of 5a or 5b. 

This suggests that 5a and 5b either do not aggregate or—more 

likely—form aggregates that are invisible in LS analysis and 

TEM. The calculated micelle radius (i.e., the length of one molecule) 

is 17 (5a) to22(5b) Å. These dimensions are too small for 

our LS setup, which has a lower detection limit of ca. 40 Å, but 

could be detected with small-angle X-ray scattering, small-angle 

neutron scattering (SANS), or improved cryo-TEM. Indeed 

some studies have detected calixarene micelle sizes between 30 

and 90 Å. [5,6,10,11] We therefore conclude that, as the hydrophobic 

parts of 4 and 5b are the same, the key parameter controlling 

calixarene amphiphile self-assembly in aqueous solution is the 

head group. For vesicle formation, comparatively small head 

groups with relatively low charges are necessary. In our case, 

–COOH (or –COO – ) is smaller than the –CH 2N(CH 3) 3Cl group 

and is only partly ionized because it is a weak acid. 

Our findings thus support observations in which relatively 

hydrophobic calixarenes form vesicles with a single bilayer 

membrane, and highly hydrophilic derivatives or derivatives 

with rather large hydrophilic groups form micelles. For example, 

Lee at al. [6] have shown that amphiphilic calixarenes with 

triethylene glycol tails at the head groups form micelles. In contrast, 

hydroxyethyl or diethylene glycol groups favor vesicles. 

The same group has also shown that protonation (increase of 

the head group charge) of tertiary amine head groups drives 

the transition from vesicles to micelles. 

Our experiments at the air/water interface confirm that the 

head group is a key parameter governing self-assembly: the 


(apparently) small lift-off area of 20 Å 2 for 4 is the area per 

monomer, i.e., a quarter of the whole calixarene. As the width 

of the head group of 4 is ca. 4.4 Å, the calculated mean molecular 

area is ca. 19.4 Å 2 , which agrees reasonably well with the 

experiment. The monomeric units of 4, 5a, and 5b are essentially 

surfactants with straight hydrocarbon chains, and their 

mean molecular area is indeed comparable to simple straightchain 

amphiphiles at the air/water interface. The values also 

agree with other calixarenes. For example, the lift-off area of a 

calix[4]arene with a crown ether head group is 23 Å 2 /monomer, 

[12] and 30 Å 2 /monomer has been reported for a tert-butyl 

calix[6]arene. [33] The latter area increase is due to the bulky 

t-butyl group. 

Possible explanations for the lift-off area differences between 

4 and 5a are i) ionic repulsion between the quaternary 

head groups and hence an increase of the ammonium–ammonium 

group distance, and ii) the formation of hydrogen bonds in 

monolayers of 4. This last interaction could facilitate the formation 

of more compact layers with the carboxy head group 

than with the trimethyl ammonium head group and could lead 

to a decrease in the lift-off area of 4. In contrast, ionic repulsion 

will increase the calixarene–calixarene distance and thus 

increase the lift-off area of 5a. 

A broad plateau at ca. 35 mN m –1 characterizes the surface 

pressure isotherm of 5a. Such a plateau can indicate a first-order 

phase transition, yet such transitions are normally observed 

at a lower p. Plateau regions in calixarene monolayers have 

been observed before. For example, the p–A isotherm of 1,3-dioctyloxy-calix[4]arene-crown-6-ether 

[12] has a plateau region at 

ca. 40 mN m –1 , which is attributed to monolayer collapse. On 

the other hand, He at al. [34] report the coexistence of monoand 

multilayers at 47 mN m –1 with 5,11,17,23-tetra-tert-butyl- 

25,27-di{[(2′-amino-4′-methylthio)butyryl]aminoethoxy}-26,28dihydroxycalix[4]-arene. 

These authors suggest that there is a 

folding of the monolayer that leads to the formation of multilayers 

or other three-dimensional (3D) aggregates. 

For 5a, Brewster angle microscopy (BAM) rules out monolayer 

collapse at ca. 35 mN m –1 pressure, as the film remains 

smooth throughout the plateau and no domains are visible. We 

thus suggest that the plateau is not related to a monolayer transition 

or crystallization (LC formation). On the other hand, 

with the high solubility of the compound in water, the plateau 

at high surface pressure could be attributed to dissolution of 

the monolayer material in the subphase, especially when no 

morphological changes are observed with BAM at 33 mN m –1 , 

where the plateau begins. Additionally, this result is supported 

by the decreasing surface potential in this region and the constant-area 

experiment, where p decreases over time (see Supporting 

Information). 

3.2. Self-Assembly in Concentrated Solution 

All the studied calixarenes exhibited bulk lyotropic LC 

phases above ca. 50 wt.-% calixarene. They are layered in 4 

and rectangular in 5a,5b. For a layered lyotropic LC, the molecules 

must form bilayers, and indeed, TEM shows evidence for 



spontaneous bilayer formation with 4. Moreover, calculations 

of the molecular dimensions support the experimental results 

because the calculated vesicle wall thickness (40 Å, 4) and micelle 

radii (17.1 Å, 5a, and 22 Å, 5b) correspond well to our 

observations and interpretations. We can thus directly relate 

the self-assembly of 4 in dilute solution with its self-assembly 

in concentrated solution: vesicles are essentially closed bilayers, 

which open up and form a layered LC at higher concentrations. 

In contrast, there is (although indirect) evidence for 

micelle formation with 5a and 5b. We thus suspect that the 

X-ray pattern of the corresponding LC originates from the 

stacking and aggregation of calixarene micelles into columns 

which then self-organize in a rectangular lattice. 

As in the dilute regime, experiments at the air/water interface 

support the above interpretation of our data. Film compression 

of 4 leads to 3D stripe-like crystalline domains at high 

surface pressure, which is indicated as a ‘kink’ at 42 mN m –1 in 

the p–A isotherms. Unlike other crystalline aggregates, the aggregates 

observed in this study are not the collapsed form of 

the monolayer, because the collapse pressure is 51 mN m –1 . 

Therefore, with the high transition pressure, a plausible explanation 

of such a morphology is a LC phase, thereby supporting 

our optical polarized microscopy (OPM) and X-ray results. 

4. Conclusions 

Amphiphilic calixarenes have a complex self-assembly behavior 

in aqueous media. Our results support a recent study [6] 

demonstrating that the nature of the (ionic) head group of amphiphilic 

calixarenes is a key parameter to control and tune the 

self-assembly in aqueous solution. We have also provided evidence 

that the symmetry of the assemblies is independent of 

the calixarene concentration: carboxylated calixarenes form 

bilayer-based structures (vesicles and lamellar LCs), whereas 

calixarenes with trimethyl ammonium head groups most likely 

form micelles that are below 50 Å in diameter, which aggregate 

at higher concentrations into rectangular lyotropic LCs. 

5. Experimental 

Synthesis: Solvents were dried and purified according to established 

procedures and stored under argon. Calix[4]arene 1 was purchased 

from Fluka and used without further purification. 

25,26,27,28-Tetrahydroxycalix[4]arene 2: 15 g (23.1 mmol) of p-tertbutylcalix[4]arene 

and 13.2 g of phenol were dissolved in 330 mL of 

toluene. 24 g (180 mmol) of AlCl3 were added and the mixture was 

stirred at 60 °C for 6 h. After cooling, 300 mL of HCl (3 %) was added 

and the reaction mixture was stirred for 30 min. The aqueous phase 

was washed with toluene once and the organic phases were dried with 

Na2SO4 before toluene removal via rotary evaporation. 100 mL of 

MeOH (Me = CH3) were added to the semisolid residue. After filtration 

and drying a white residue was obtained, which was recrystallized 

from CHCl3/MeOH yielding 9.2 g (21.7 mmol, 93 %) of 2. 1 H NMR 

(300 MHz, CDCl3): d= 10.19 (s, 4H, –OH), 7.05 (d, J = 7.60 Hz, 8H, 

ArH), 6.73 (t, J = 7.61 Hz, 4H, ArH), 4.26 (s [broad], 4H, Ar–CH2–Ar), 

3.55 (s [broad], 4H, Ar–CH 2–Ar). 

25,26,27,28-Tetra-n-octyloxy calix[4]arene 3a: 1.6 g of NaH (60 % 

dispersion in mineral oil) were washed with hexane and added to a so- 

lution of 3.86 g (9.1 mmol) of 2 in 40 mL of dry dimethylformamide 

under argon. For complete deprotonation of the OH group, the mixture 

was heated to 60 °C for 30 min. After cooling to 30 °C, 7.5 mL 

(41.2 mmol) of n-iodooctane were slowly added and the mixture was 

stirred for 5 h at 30 °C. A further 1.0 g of washed NaH and 3 mL of 

n-iodooctane were added. The mixture was stirred for 12 h at 30 °C, 

the reaction was quenched with water, and the product was extracted 

with CHCl3. The organic layer was evaporated and the white product 

was recrystallized twice from iPrOH/CHCl3 yielding 6.1 g (76 %) of 3a. 

1 H NMR (300 MHz, CDCl3): d= 6.59 (m, 12H, ArH), 4.44 (d, 

J = 13.38 Hz, 4H, Ar–CH2–Ar), 3.88 (t, J = 7.46 Hz, 8H, –CH2–O–Ar), 

3.13 (d, J = 13.38 Hz, 4H, Ar–CH2–Ar), 1.91 (m, 8H, –CH2–CH2–O– 

Ar), 1.31 (m, 40H, alkyl-H), 0.89 (t, J = 6.91 Hz, 12H, CH3–CH2–). 13 C 

NMR (75 MHz, CDCl3): d= 156.62, 135.18, 128.09, 121.86, 75.16 (O– 

CH2–), 32.01, 31.02, 30.38, 29.95, 29.65, 26.40, 22.73, 14.11 (CH3–). 

25,26,27,28-Tetra-n-dodecyloxy calix[4]arene 3b: 2 was reacted with 

n-iodododecane according to the procedure above to afford 8.12 g 

(78 %) of 3b. 1 H NMR (400 MHz, CDCl 3): d= 6.59 (m, 12H, ArH), 

4.43 (d, J = 13.38 Hz, 4H, Ar–CH 2–Ar), 3.88 (t, J = 7.46 Hz, 8H, –CH 2– 

O–Ar), 3.14 (d, J = 13.38 Hz, 4H, Ar–CH 2–Ar), 1.90 (m, 8H, –CH 2– 

CH 2–O–Ar), 1.31 (m, 72H, alkyl-H), 0.88 (t, J = 6.91 Hz, 12H, CH 3– 

CH 2–). 13 C NMR (100 MHz, CDCl 3): d= 156.63, 135.18, 128.09, 121.86, 

75.16 (O–CH 2–), 31.99, 31.02, 30.38, 30.01, 29.89, 29.85, 29.78, 29.47, 

26.40, 22.73, 14.13 (CH 3–). 

25,26,27,28-Tetra-n-dodecyloxy calix[4]arene-5,11,17,23-tetrabromide: 

3.20 g (17.98 mmol) N-bromosuccinimide was added to a solution 

of 2.48 g (2.26 mmol) 3b in 50 mL of butanone. The reaction mixture 

was stirred at room temperature for 14 h. The solvent was 

evaporated and the raw product was recrystallized from acetone/benzene, 

yielding 2.70 g (84 %) of 25,26,27,28-tetra-n-dodecyloxy calix[4]arene-5,11,17,23-tetrabromide. 

1 H NMR (400 MHz, CDCl3): d= 6.8 (s, 

8H, Ar–H), 4.33 (d, J = 13.28 Hz, 4H, Ar–CH2–Ar), 3.82 (t, J = 7.5 Hz, 

8H, –CH2–O–Ar), 3.07 (d, J = 13.28 Hz, 4H, Ar–CH2–Ar), 1.84 (m, 8H, 

–CH2–CH2–O–Ar), 1.26 (m, 72H, alkyl-H), 0.88 (t, J = 6.66 Hz, 12H, 

CH3–CH2–). 

25,26,27,28-Tetra-n-dodecyloxy calix[4]arene-5,11,17,23-tetracarboxylic 

acid 4: To a solution of 2.0 g (1.42 mmol) of 3b in 63 mL tetrahydrofuran 

(THF) under argon, 11.25 mL of t-butyl lithium (1.7 M in 

pentane) was added at –78 °C under argon. The reaction mixture was 

stirred for 30 min. An excess of CO 2 gas dried over P 2O 5 was bubbled 

through the mixture while the cooling was removed. After reaching 

room temperature, the mixture was quenched with water and acidified 

with 6 N HCl. The precipitate was filtered, washed with methanol/ 

water, and recrystallized from THF/acetone yielding 1.60 g (88 %) of 4. 

1 H NMR (400 MHz, THF-d8): d= 10.99 (s, broad, 4H, COOH), 7.38 (s, 

8H, ArH), 4.49 (d, J = 13.45 Hz, 4H, Ar–CH2–Ar), 3.99 (t, J = 7.40 Hz, 

8H, –CH2–O–Ar), 3.31 (d, J = 13.67 Hz, 4H, Ar–CH2–Ar), 1.93 (m, 8H, 

–CH2CH2–O), 1.31 (m, 72H, alkyl CH2), 0.89 (t, J = 6.85 Hz, 12H, 

CH3–). 13 C NMR (100 MHz, THF-d8): d= 166.55 (CO2H), 159.02, 

133.26, 128.76, 123.11, 73.77, 30.50, 29.27, 28.85, 28.54, 28.49, 28.41, 

28.31, 27.99, 24.88, 21.17, 12.04. Matrix-assisted laser desorption ionization 

time-of-flight mass spectrometry, m/z 1272 (M + ); mp > 350 °C (decomp.). 

5,11,17,23-Tetrakis(chloromethyl)-25,26,27,28-tetra-n-octyloxy calix[4]arene: 

To a solution of 4.0 g (4.58 mmol) 3a in a mixture of 

100 mL dioxane, 68 mL H 3PO 4 (85 %), 36 mL acetic acid, and 74 mL 

concentrated hydrochloric acid, 6.6 g (220 mmol) of paraformaldehyde 

were added. The resulting suspension was stirred at ca. 110 °C under argon 

for 36 h. The mixture was added to ca. 400 mL of an ice/water mixture 

and extracted with CHCl 3. The CHCl 3 phase was washed with 

water and NaHCO 3 until a neutral pH was reached. The CHCl 3 phase 

was dried with Na2SO4 and the solvent was removed via rotary evaporation 

and high-vacuum (HV) drying. The white precipitate was recrystallized 

twice from CHCl3/acetone yielding 3.9 g (79 %) of 

5,11,17,23-tetrakis(chloromethyl)-25,26,27,28-tetra-n-octyloxy calix[4]arene. 

1 H NMR (300 MHz, CDCl3): d= 6.64 (s, 4H, ArH), 4.40 (d, 

J = 13.28 Hz, 4H, Ar–CH2–Ar), 4.30 (s, 8H, CH2–Cl), 3.87 (t, 

J = 7.5 Hz, 8H, –CH2–O–Ar), 3.13 (d, J = 13.28 Hz, 4H, Ar–CH2–Ar), 

1.88 (m, 8H, –CH2–CH2–O–Ar), 1.31 (m, 40H, alkyl-H), 0.89 (t, 

J = 6.66 Hz, 12H, CH3–CH2–). 


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5,11,17,23-Tetrakis(chloromethyl)-25,26,27,28-tetra-n-dodecyloxy calix[4]arene: 

4.0 g (3.65 mmol) of 3b was reacted according to the above 

procedure to give 3.5 g (2.71 mmol, 74 %) of 5,11,17,23-tetrakis(chlor- 

omethyl)-25,26,27,28-tetra-n-dodecyloxy calix[4]arene. 

1 H NMR 

(400 MHz, CDCl 3): d= 6.64 (s, 4H, ArH), 4.40 (d, J = 13.28 Hz, 4H, Ar– 

CH 2–Ar), 4.30 (s, 8H, CH 2–Cl), 3.86 (t, J = 7.5 Hz, 8H, –CH 2–O–Ar), 

3.13 (d, J = 13.28 Hz, 4H, Ar–CH2–Ar), 1.89 (m, 8H, –CH2–CH2–O– 

Ar), 1.27 (m, 72H, alkyl-H), 0.88 (t, J = 6.66 Hz, 12H, CH3–CH2–). 

5,11,17,23-Tetrakis(trimetylammoniomethyl)-25,26,27,28-tetra-n-octyloxy 

calix[4]arene tetrachloride 5a: A solution of 3.3 g (3.09 mmol) 

5,11,17,23-tetrakis(chloromethyl)-25,26,27,28-tetra-n-dodecyloxy calix[4]arene 

and 20 mL trimethylamine (45 % in water) in 70 mL of 

THF was stirred under argon at room temperature for 24 h. The white 

precipitate was filtered, dried under vacuum, and recrystallized from 

CHCl3/CH3CN yielding 3.0 g (74 %) of 5a. 1 H NMR (400 MHz, dimethylsulfoxide 

(DMSO)-d6): d= 6.89 (s, 8H, ArH), 4.50 (s, 8H, Ar– 

CH2–N), 4.34 (d, J = 12.29 Hz, 4H, Ar–CH2–Ar), 3.87 (t, J = 7.5 Hz, 

8H, Ar–O–CH 2–), 3.30 (d, J = 12.29 Hz, 4H, Ar–CH 2–Ar), 2.92 (s, 36H, 

N(CH 3) 3), 1.87 (m, 8H, –CH 2–CH 2–O–Ar), 1.26 (m, 40H, alkyl-CH 2), 

0.85 (t, 6.7 Hz, 12H, CH 3–CH 2–); mp > 350 °C (decomp.). 

5,11,17,23-Tetrakis(trimetylammoniomethyl)-25,26,27,28-tetra-n-dodecyloxy 

calix[4]arene tetrachloride 5b: 4.5 g (3.49 mmol) of 

5,11,17,23-tetrakis(chloromethyl)-25,26,27,28-tetra-n-dodecyloxy calix[4]arene 

(4.5 g, 3.49 mmol) was reacted according to the procedure 

above to give 3.6 g (67 %) 5b. 1 H NMR (400 MHz, DMSO-d 6): 

d = 6.89 (s, 8H, ArH), 4.50 (s, 8H, Ar–CH2–N), 4.34 (d, J = 12.29 Hz, 

4H, Ar–CH2–Ar), 3.87 (t, J = 6.5 Hz, 8H, Ar–O–CH2–), 3.30 (d, 

J = 12.29 Hz, 4H, Ar–CH2–Ar), 2.92 (s, 36H, N(CH3)3), 1.87 (m, 8H, 

–CH2–CH2–O–Ar), 1.26 (m, 40H, alkyl-CH2), 0.85 (t, 6.9 Hz, 12H, 

CH3–CH2–); mp > 350 °C (decomp.). 

Light Scattering: Compound 4 was dissolved in a 0.1 M NH3(aq) 

solution and compounds 5a and 5b were dissolved in water to a final 

concentration of 2 mg mL –1 . Static and dynamic LS experiments were 

performed with a commercial goniometer (ALV) with a frequency 

doubled Nd:YAG (yttrium aluminum garnet) laser (ADLAS, wavelength 

k = 532 nm). Scattering angles ranged from 30 to 150° and the 

photon intensity autocorrelation function g 2 (t) was determined with an 

ALV-5000E correlator. Samples were filtered through Millipore filters 

(0.45 lm, Millex-HV) into 10 mm quartz cells mounted in an optical 

matching bath. The experiments were performed at T = 293 ± 0.02 K. 

The refractive index increment dn/dc was obtained at 293 K and 

532 nm with an ALV-DR1 differential refractometer. Data were analyzed 

via Zimm plot and cumulative analysis. 

Cryo-TEM:A5lL aliquot of 4 at 2 mg mL –1 in 0.1 M NH3 (aq.) was 

adsorbed for 30 s onto holey carbon film 400 mesh grids, blotted with 

Whatman 4 filter paper, and frozen into liquid ethane at –178 °C using 

a Leica CPC station. Frozen grids were transferred to a Philips CM200 

FEG electron microscope using a Gatan 626 cryo-station. Electron micrographs 

were recorded at 200 kV at 50 000× under low-dose conditions. 

Defocus was –1 lm. Micrographs were recorded on Kodak SO- 

163 film. Staining with heavy metals failed because of the affinity of 4, 

5a, and 5b to metal ions; regular TEM failed because of the low contrast. 

Langmuir Monolayers: Monolayers of 4 and 5a were prepared by 

spreading an aliquot of a calixarene solution (0.7 mg mL –1 in THF and 

0.26 mg mL –1 in CHCl 3, respectively; spectroscopy grade solvents) on 

bi-distilled water of pH 5.5 on a mini Langmuir–Blodgett trough (total 

area 242 cm 2 ) from KSV, Finland, placed on an anti-vibration table in a 

dust-free room. After spreading, 5 min were allowed for the solvent to 

evaporate, followed by compression of the film at 15 mm min –1 

(11.3 cm 2 min –1 ). Other surface studies with calixarenes have used discontinuous 

compression, but we believe that 15 mm min –1 is slow 

enough for the relatively small calixarene molecules to adopt the most 

favorable conformation at the interface. For comparison, compression 

isotherms of film-forming polymers at the air/water interface have been 

normally measured at higher rates, even though the polymer dynamics 

is much slower [35,36]. The surface pressure of the monolayers was 

measured to ±0.01 mN m –1 with a Wilhelmy plate (chromatography paper, 

ashless Whatman Chr 1) on an electrobalance. Monolayers were 

compressed at 20 °C; the subphase temperature was controlled to ±1°C 


with a Haake circulating water system. The surface potential was recorded 

using a SPOT 1 (KSV, Finland) measuring head. The vibrating 

plate was located ca. 2 mm above the water surface. The reference 

electrode was placed in the water subphase. Surface potential measurements 

were reproducible within 10 mV. 

Brewster Angle Microscopy: Monolayer morphology was visualized 

with a BAM2plus Brewster angle microscope (Nanofilm, Germany), 

with a 50 mW laser at the wavelength of 532 nm. With a 10× Nikon 

long-distance objective, the microscope has a resolution of 2 lm; recorded 

images correspond to 430 lm in width. 

Optical Polarization Microscopy: OPM experiments were carried 

out on a Leica DM-RP with a Leitz 350 hot stage and a Lauda RS20 

cryostat allowing temperatures down to –30 °C. Mixtures of water and 

calixarene were weighed in Teflon capsules with a stainless-steel ball 

and homogenized in a Perkin–Elmer vibration mill. Samples were investigated 

from 5 to 80 °C with a ramping speed of about 2 °C per minute. 

X-Ray Diffraction: X-ray diffraction experiments utilized Cu Ka1 radiation 

from a rotating anode (Bruker AXS FR591) X-ray generator, 

focused and monochromatized via mirror-monochromator optics, and 

measured with a wire area detector (Bruker AXS Hi-Star), as previously 

described [37]. To minimize attenuation and background scattering, 

an integral vacuum was maintained along the length of the flight 

tube and within the sample chamber. The X-ray data were analyzed 

using Datasqueeze. 

Received: April 13, 2005 

Published online: September 13, 2005 

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Self-Assembly of Amphiphilic Calix[4]arenes in Aqueous Solution

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