Novel Dimeric Cholesteryl Derivatives and Their Smart Thixotropic Gels

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Novel Dimeric Cholesteryl Derivatives and Their Smart Thixotropic Gels Xiaoyu Hou, Di Gao, Junlin Yan, Ying Ma, Kaiqiang Liu, and Yu Fang* Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710062, China

bS Supporting Information ABSTRACT: Three novel LS2-type dimeric-cholesteryl derivatives (1
3), where S is a steroidal residue and L stands for a linker connecting the two S residues and contains three benzene rings and two amide and two carbamate groups, were designed and prepared. The compounds can gel a wide variety of organic solvents via three different ways, including mixing at room temperature, a heating
cooling cycle, and ultrasound treatment. SEM measurements revealed that the structures and the concentrations of the gelators, the nature of the solvent, and the preparation method employed have a great effect on the morphologies of the gel networks. It was revealed that 1 is a supergelator for DMSO (cgc = 0.04% w/v) and that the 1/DMSO gel can be prepared via any of the three methods mentioned above. Furthermore, the gel possesses excellent mechanical strength and a very smart thixotropic property. FT-IR and temperature- and concentration-dependent 1H NMR spectroscopy studies revealed that hydrogen bonding and π
π stacking among the molecules of 1 are two important driving forces for the physical gelation of DMSO. In addition, XRD analysis confirmed the layered packing structure of 1 in its DMSO gel.

1. INTRODUCTION Unlike in chemical gels, in which the gelator molecules are cross-linked via chemical bonds, in particular, covalent bonds, the gelator molecules in physical gels, particularly those based upon low-molecular-mass gelators (LMMGs), self-assemble into 3D network structures via nonchemical bonding interactions, that is, supramolecular weak interactions such as van der Waals interactions,1 hydrogen bonding,2 π
π stacking,3 electrostatic interactions,4 solvophobic interactions,5 coordination interactions,6 and host
guest interactions,7 in suitable solvents. The weak interaction nature in physical gels causes their formation and de-formation to be controlled by some physical stimuli, including heating or cooling, changing pH,8 light irradiation,9 ultrasound treatment,10 proton transfer,11 and the shear force.12 These smart properties may bring about real-life applications of the LMMG-based physical gels in drug delivery,13 tissue engineering,14 templates,15 sensors,16 the oil industry,17 light-harvesting materials,9 and dye-sensitized solar cells.18 Among the LMMGs reported, cholesterol-based LMMGs have attracted a considerable amount of attention because of their versatility in gelation and diversity of structures. Historically, these LMMGs have been classified as ALS, A(LS)2, LS, and LS2 types according to the numbers of aromatic (A) moieties, and steroids (S), and functionalized linkers (L). The structures of the LMMGs have been regulated successfully by changing the components of L or A, and the gelators as gained can gel a range of solvents including protic/aprotic and polar/nonpolar solvents.19,20 In particular, our group reported several cholesterolbased LMMGs bearing smart behavior, such as gelation and r 2011 American Chemical Society

phase-selective gelation at room temperature21
23 and gel emulsion and gel film formation,24,25 which are necessities in spilled-oil recovery, water purification, and template preparation of low-density materials. Actually, molecular gels formed by other LMMGs with no cholesterol structure may also possess smart properties and find important applications.26
32 It is known that most of the LMMG-based supramolecular gels are prepared via a heating
cooling cycle.19,33
35 Recently, other competitive preparation methods have also been developed, such as light irradiation9 and sonication10 and chemical, mechanical, or even electronic-/magnetic-field treatment at room temperature.11,12,25 For example, Zhang36 and Naota10,37 and their co-workers reported, separately, ultrasound-induced gelation. Their studies demonstrated that the weak noncovalent interaction between the gelator molecules has been partially broken, which favors the establishment of a balance between aggregation and dis-aggregation, a necessity for the gelation of a system. Moreover, the network structure of the gelator in the gels can be also controlled by changing the intensity and frequency of the ultrasound wave employed.38 In fact, the development of smart, adaptive gels whose properties can be controlled or even switched by external stimuli has always been appealing, promising, and challenging. Very recently, the structure of benzene was intentionally introduced into the linkers of cholesterol-based LMMGs in an Received: June 18, 2011 Revised: August 24, 2011 Published: August 25, 2011 12156

dx.doi.org/10.1021/la2022819 | Langmuir 2011, 27, 12156–12163

Langmuir

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Scheme 1. Schematic Representation of the Synthesis of Compounds 1
3 and Their Intermediates a
c, Respectively

A(LS)2 structure, of which the structures of the compounds were changed by varying the relative positions of the two linkers on the benzene ring. It was demonstrated that changes in the positions of the substrates resulted in great changes in the gelation behaviors of the compounds and their gel properties.21 Therefore, it is of interest to imagine what will happen if another or more benzene structures were introduced and more variations were added to the connecting structures between the two cholesterol units. Accordingly, three novel cholesterol-based LMMGs were designed and prepared by introducing three benzene rings, two amide structures, and two carbamate groups into the connecting structures of a new series of dicholesteryl derivatives. We are lucky to find that some of the compounds as designed and prepared possess exceptional gelation and mechanical properties. We believe that the present findings may provide additional data regarding the cholesterol-based gelators, a well-studied class of LMMGs. This article reports the details.

2. EXPERIMENTAL SECTION 2.1. Gelation Test. A known weight of the potential gelator and a measured aliquot of liquid were placed into a sealed glass tube (d = 8 mm, v = 0.5 mL), and the system was heated in an oil or water bath until all solid materials were dissolved completely. Then the solution was slowly cooled to room temperature in air, and the test tube was inversed to determine if a gel had formed. When a white or transparent gel is formed at this stage, it is denoted as G or TG. In some cases, a solution and gel may coexist within a system, and they are referred to as partial gels (PG). For the systems in which only solution remained until the end of the tests, they are referred to as solution (S). The system in which the potential gelator could not be dissolved even at the boiling point of the solvent is considered to be an insoluble system (I). For some of the systems, heating results in the dissolution of the gelators, but cooling results in their precipitation. These systems are denoted as P. In a few cases, a viscous solution (VS) was also observed at 2.5% (w/v) gelator. Molecular gels obtained by simple shaking or sonication at room temperature are denoted as G (rt) or G*, respectively. The critical gelation concentration (cgc) refers to the minimum concentration of the gelator needed for the gelation of the relevant solvent. 2.2. SEM Measurement. SEM images of the xerogel were taken on a Quanta 200 scanning electron microscope (Philips-FEI). The accelerating voltage was 15.0 kV, and the emission was 10.0 mA. The xerogel for the measurement was prepared by freezing the gel formed in a concerned solvent at a concentration of 2.5% (w/v) in liquid nitrogen and

freeze drying for 12
24 h. The sample as obtained was attached to a copper holder by conductive adhesive tape and shielded with gold. It is to be noted that the morphologies of the xerogels as obtained may not be necessarily the real structures of the molecular gel networks, from which the xerogels were obtained. However, it is believed that this kind of measurement does provide useful information for an understanding of the gel networks. 2.3. Rheological Measurement. Rheological measurements were carried out with a stress-controlled rheometer (TA Instruments, AR-G2) equipped with steel-coated parallel-plate geometry (20 mm diameter). The gap distance was fixed at 1000 μm. A solvent-trapping device was placed above the plate to avoid evaporation. All measurements were made at room temperature (25 °C). Stress sweep at a constant angle frequency (6.28 rad s
1) was performed in the 1.0
6000.0 Pa stress range to determine the linear viscoelastic region (LVER) of the gel sample. A frequency sweep was performed in a 1.0
628.0 rad s
1 angle frequency range at a certain shear force (500 Pa) within LVER that can bring about small strains in the tested materials. A thixotropic study was conducted to examine the recovery behavior of a supramolecular gel after deformation. This process includes two steps: (1) Deformation: a constant oscillatory shear stress (6000.0 Pa) that is enough to destroy the gel is applied to the fresh gel in the sample holder for 2 min. (2) Modulus recovery in a time sweep: the recovery of the storage modulus is monitored at 6.28 rad s
1 under a low shear force (10.0 Pa) placed on the above destroyed gel. The storage modulus G0 and the loss modulus G00 are recorded as functions of time in the recovery process. A temperature sweep began from 20 °C to 75 °C at 6.28 rad s
1 under a constant stress (10 Pa) in order to reach the gel
sol transition temperature. The following procedure was used to load the fresh gel sample: 2.0 mL of a solution containing solvent and gelator was heated to 90 °C, closed using a tight cone, and then cooled to 25 °C. The measurements started 1 h later after the gels had formed. 2.4. 1H NMR Measurement. The gel sample containing one gelator and CDCl3 was prepared in an NMR tube, and the chemical shifts of the sample were detected with a Fourier digital NMR spectrometer (Avance, 300 MHz) at a given temperature of between 298 and 318 K or at a given concentration range between 1.0% (w/v) and 2.5% (w/v) at 298 K. 2.5. FT-IR Measurements. All FT-IR measurements were performed on a Brucher Equinx55 spectrometer in transmittance mode. KBr pellets were obtained by mixing small amounts of the dried gel samples and anhydrous KBr powder. 12157

dx.doi.org/10.1021/la2022819 |Langmuir 2011, 27, 12156–12163

Langmuir 2.6. X-ray Diffraction (XRD) Measurement. Diffraction patterns were obtained on a Japan Rigaku D/max-III diffractometer with Cu Kα X-rays generated (λ = 1.5418 A) under a voltage of 40 kV and a current of 40 mA. The scan rate was 0.5°/min.

3. SYNTHESIS OF THREE CHOLESTERYL DERIVATIVES 3.1. Intermediate (a). o-Phenylenediamine (8.64 g, 80 mmol) and triethylamine (0.58 mL, 4 mmol) were both dissolved in THF (150 mL). To the solution, 80 mL of a THF solution of cholesteryl chloroformate (1.8 g, 4 mmol) was added dropwise under stirring in an ice bath. After the addition, the mixture was stirred at room temperature for 18 h. Then, the mixture was filtered, and the filtrate was evaporated in vacuum to dryness, and the residues were dissolved in dichloromethane. The dichloromethane solution was washed with water at least 10 times. The organic phase was separated and dried by using anhydrous magnesium sulfate. The dried and purified organic solution was concentrated in vacuum to dryness. The solid as obtained was recrystallized twice from methanol, and the desired product (a) was obtained as a white powder in 70% yield with mp 204
205 °C. 1H NMR (CDCl3/Me4Si, 300 MHz): δ 7.27
7.30 (1H, d, J = 8.0 Hz, benzene ring), 6.99
7.04 (1H, t, J = 15 Hz, benzene ring), 6.80
6.83 (1H, t, J = 8.2 Hz, benzene ring), 6.77
6.79 (1H, d, J = 7.8 Hz, benzene ring), 6.31 (1H, s, CONH), 5.40 (1H, s, alkenyl), 4.56
4.63 (1H, m, oxy-cyclohexyl), 3.49 (2H, s,
NH2), 0.68
2.41 (43H, m, cholesteryl protons). FT-IR, νmax/cm
1: 3394 (NH), 2938 (CH), 1705 (CdO,
O), 1628 (CdO,
NH), 1536 (NH, bending), and 1254 (
C
O). Anal. Calcd for C34H52N2O2: C, 78.41; H, 10.06; N, 5.38. Found: C, 78.41; H, 10.09; N, 5.02. MS (ESI): m/z calcd for [M + Na+], 543.3921; found, 543.3926. 3.2. Intermediate (b). The synthesis procedures for intermediate b are similar to those for intermediate a and produce a powder product (b) in 35% yield with mp 183
184 °C. 1H NMR (CDCl3/Me4Si, 300 MHz): δ 7.02
7.07 (1H, t, J = 16 Hz, benzene), 6.97 (1H, s, benzene ring), 6.56
6.59 (1H, d, J = 7.9 Hz, benzene ring), 6.48 (1H, s, CONH), 6.36
6.39 (1H, d, J = 7.6 Hz, benzene ring), 5.40 (1H, s, alkenyl), 4.58
4.60 (1H, m, oxy-cyclohexyl), 3.60 (2H, s,
NH2), 0.68
2.41 (43H, m, cholesteryl protons). FT-IR, νmax/cm
1: 3411 (NH), 2946 (CH), 1728 (CdO,
O), 1635 (CdO,
NH), 1530 (NH, bending), and 1208(
C
O). Anal. Calcd for C34H52N2O2: C, 78.41; H, 10.06; N, 5.38. Found: C, 78.69; H, 9.72; N, 5.33. MS (ESI): m/z calcd for [M + Na+], 543.3921; found: 543.3929. 3.3. Intermediate (c). The synthesis procedures for intermediate c are similar to those for both a and b and give a powder product in 38% yield with mp 172
173 °C. 1H NMR (CDCl3/Me4Si, 300 MHz): δ 7.12
7.15 (2H, d, J = 6.8 Hz, benzene ring), 6.61
6.63 (2H, d, J = 8.4 Hz, benzene), 6.46 (1H, s, CONH), 5.39 (1H, s, alkenyl), 4.54
4.61 (1H, m, oxy-cyclohexyl), 3.42 (2H, s,
NH2), 0.68
2.40 (43H, m, cholesteryl protons). FT-IR, νmax/cm
1: 3411 (NH), 2946 (CH), 1728 (CdO,
O), 1635 (CdO,
NH), 1530 (NH, bending), and 1208(
C
O). Anal. Calcd for C34H52N2O2: C, 78.41; H, 10.06; N, 5.38. Found: C, 78.49; H, 9.93; N, 4.99. MS (ESI): m/z calcd for [M + Na+], 543.3921; found, 543.3924. 3.4. Compound 1. Compound a (1.04 g, 2 mmol) and triethylamine (0.29 mL, 2 mmol) were dissolved in 150 mL of THF, and the mixture was stirred at room temperature. To the solution, 80 mL of a THF solution of isophthaloyl chloride (0.203 g, 1.0 mmol) was added dropwise. After the addition, the mixture was stirred at 65 °C for 6 h. Then the reaction mixture was filtered, and the filtrate was evaporated to dryness. The resulting solid was washed with hot acetone five times and then dried in vacuum to give the desired product (1) in 55% yield as a white powder with mp 212
213 °C. 1H NMR (CDCl3/Me4Si, 300 MHz): δ 9.27 (s, 2H, CONH), 8.50 (s, 1H, benzene), 8.09
8.12 (d, 2H, J = 7.7 Hz, benzene), 7.55
7.60 (t, 1H, J = 15 Hz, benzene), 7.50
7.53 (d, 2H, J = 6.3 Hz, benzene), 7.39
7.41 (d, 2H, J = 7.4 Hz, benzene),

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7.33 (s, 2H, CONH), 7.07
7.13 (t, 4H, J = 13 Hz, benzene), 5.33 (s, 2H, alkenyl), 4.55
4.57 (m, 2H, oxy-cyclohexyl), 0.67
2.34 (m, 86H, cholesteryl protons). FT-IR, vmax/cm
1: 3423 (NH), 2945 (CH), 1738 (CdO,
O), 1644 (CdO,
NH), 1527 (NH, bending), and 1226 (
C
O). Anal. Calcd for C34H52N2O2: C, 77.91; H, 9.12; N, 4.78. Found: C, 77.66; H, 9.02; N, 4.83. MS (ESI): m/z calcd for [M + Na+], 1193.8005; found, 1193.7981. 3.5. Compound 2. Compound b (1.04 g, 2 mmol) and triethylamine (0.29 mL, 2 mmol) were dissolved in 150 mL of THF, and the mixture was stirred in an ice
water bath. To the solution, 80 mL of a THF solution of isophthaloyl chloride (0.203 g, 1.0 mmol) was added dropwise. Then the reaction mixture was stirred at room temperature for 18 h, the reaction mixture was filtered, and the filtrate was evaporated to dryness. The resulting solid was recrystallized from acetone twice and then dried in vacuum to give the desired product (2) in 77% yield as a white powder with mp 225
226 °C. 1H NMR (CDCl3/Me4Si, 300 MHz): δ 8.69 (s, 2H, CONH), 8.15 (s, 1H, benzene), 7.84
7.87 (d, J = 7.1 Hz, 2H, benzene), 7.77 (s, 2H, benzene), 7.39
7.44 (t, 1H, J = 15 Hz, benzene), 7.30
7.33 (t, 2H, J = 7.1 Hz, benzene), 7.18
7.21 (d, 2H, J = 7.6 Hz, benzene), 7.12
7.15 (d, 2H, J = 9.1 Hz, benzene), 6.78 (s, 2H, CONH), 5.36 (s, 2H, alkenyl), 4.51
4.53 (m, 2H, oxycyclohexyl), 0.68
2.34 (m, 86H, cholesteryl protons). FT-IR, vmax/cm
1: 3432 (NH), 2944 (CH), 1730 (CdO,
O), 1616 (CdO,
NH), 1540 (NH, bending), and 1219 (
C
O). Anal. Calcd for C34H52N2O2: C, 77.91; H, 9.12; N, 4.78. Found: C, 77.58; H, 9.09; N, 4.62. MS (ESI): m/z calcd for [M + Na+], 1193.8005; found, 1193.7987. 3.6. Compound 3. Compound c (1.04 g, 2 mmol) and triethylamine (0.29 mL, 2 mmol) were dissolved in 150 mL of THF, and the mixture was stirred in an ice
water bath. To the solution, 80 mL of a THF solution of isophthaloyl chloride (0.203 g, 1.0 mmol) was added dropwise. Then the reaction mixture was stirred at room temperature for 18 h. After the reaction, the mixture was filtered, and the filtrate was evaporated to dryness. The resulting solid was washed with hot acetone five times and then dried in vacuum to give the desired product (3) in 55% yield as a white powder with mp 280
281 °C. 1H NMR (THF-d8/ Me4Si, 300 MHz): δ 9.57 (s, 2H, CONH), 8.70 (s, 2H, CONH), 8.51 (s, 1H, benzene), 8.09
8.12 (d, 2H, J = 7.3 Hz, benzene), 7.73
7.76 (d, 4H, J = 8.3 Hz, benzene), 7.55
7.60 (t, 1H, J = 15 Hz, benzene), 7.47
7.50 (d, 4H, J = 8.1 Hz, benzene), 5.44 (s, 2H, alkenyl), 4.56 (m, 2H, oxy-cyclohexyl), 0.77
2.79 (m, 86H, cholesteryl protons). FT-IR, vmax/cm
1: 3440 (NH), 2944 (CH), 1704 (CdO,
O), 1647 (CdO,
NH), 1522 (NH, bending), and 1225 (
C
O). Anal. Calcd for C34H52N2O2: C, 77.91; H, 9.12; N, 4.78. Found: C, 77.45; H, 8.87; N, 4.78. MS (ESI): m/z calcd for [M + Na+], 1193.8005; found, 1193.8002.

4. RESULTS AND DISCUSSION 4.1. Design of the Gelators. It has been demonstrated in previous work that some A(LS)2-type gelators gel some organic solvents efficiently (