WO2003044008A1

WO2003044008A1 - Light-switchable gelator

Info

Publication number: WO2003044008A1
Application number: PCT/NL2002/000747
Authority: WO
Inventors: Linda Nienke Lucas; Johannes Henricus Van Esch; Richard Morrison Kellogg; Bernard Lucas Feringa
Original assignee: Applied Nanosystem B.V.
Priority date: 2001-11-22
Filing date: 2002-11-18
Publication date: 2003-05-30
Also published as: AU2002343253A1

Abstract

The invention relates to a novel class of compounds which are capable of producing a gel in certain solvents upon contact with light. The gellation behaviour is reversible in that the gel may be dissolved again by contact with light. The invention also relates to a process for preparing the compounds and to their use in microfluidics or to create gel patterns.

Description

Title: Light-switchable gelator

The invention relates to a novel class of gelling agents, a process for producing them and to their application in preparing gels for various applications.

Reversible gelling of organic solvents by low molecular weight compounds are of particular interest for many technical applications. The self assembly of these gelator molecules often occurs by means of non-covalent interactions such as hydrophobic interaction, π-π interactions, electronic interactions, hydrogen bonding or combinations thereof.

One area where reversible gelling may be employed is the field of microfluidics. The first functional microfluidic devices were made from elastomers and were used for performing DNA analysis and cell sorting. These devices used flow control based on electrokinetics. Although electric fields are a powerful tool for molecular separations, they have drawbacks as a general method of fluidic manipulation. For instance, electrophoretic demixing may occur when pumping of heterogeneous solutions is attempted.

It has also been proposed to employ hydrogels for autonomous flow control inside microfluidic channels. Hydrogels have been developed to respond to a wide variety of stimuli, but their use in macroscopic systems has been hindered by slow response times. The rate-limiting factor in the formation of the gel is diffusion. Based on the fact that there are many natural examples of chemically driven actuation that rely on short diffusion paths to produce a rapid response, it has been suggested that scaling down objects to micrometer scale would sufficiently improve response times.

Although several gelator molecules have been identified during the last decade, there is still interest in stable gelators that can be synthesized easily from cheap, renewable sources and gelate a wide variety of solvents. There is a particular interest in gelators that produce a reversible gelling effect, wherein a gel can be dissolved again at will. Most reversible gelators reported in the art are thermally reversible. The present invention aims to provide a new class of gelators that can be used to prepare stable gels in a wide variety of solvents, and which' action is light reversible.

Photo-controlled gelation has been reported by Murata et al., J. Am. Chem. Soc, (1994), 116, 6664-6676. They disclose certain cholesterol- azobenzene derivatives which isomerize from the trans-state into the cis-state upon irradiation with light.

In accordance with the invention, a light-switchable gelator is provided having the formula (I):

wherein

- X is chosen from the group of the moieties -(CH2)_n-, -(CF2)_n-, -C(=0)-0-C(=0)- and — C(=0)-NR-C(=0)-, wherein n is 3 or 4 and wherein R is hydrogen, a (cyclo)alkyl group or an aryl group;

- Y and Z each are nitrogen or sulfur; - Ri and R3 each are an alkyl group;

- R₂ and R₄ each are hydrogen or an alkyl group;

- Ai and A₂ each are absent or are an aryl group;

- R5, Re, R7, and Rs each are hydrogen, an alkyl group or an aryl group;

- m and o each are integers chosen from the group of 0, 1, 2, 3, and 4; - Bi and B₂ are hydrogen bonding moieties; and

- Mi and M₂ each are an aryl group, a (cyclo)alkyl group, or -CRgRioRπ, wherein R9, Rio and Rn each are hydrogen, a (cyclo)alkyl group, an aralkyl group or an aryl group. It is to be noted that all symbols defined above may be chosen to have a meaning as defined, independent on the meaning of any of the other symbols, unless otherwise indicated herein. A compound according to the invention can be used to form a stable gel. The gellation phenomenon can be induced by light and has been found to be reversible. This opens a wide range of possible applications of a compound according to the invention, including flow control of liquids in microchannels (microfluidics).

As used herein, the term alkyl group refers to a straight-chain or a branched-chain alkyl radical containing from 1 to 10, preferably from 1 to 8, carbon atoms. The term (cyclo)alkyl group refers to an alkyl group or a cyclic alkyl radical. The latter includes saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radicals wherein each cyclic moiety contains 3 to 8 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, cyclopentyl, cyclopentenyl, cyclohexenyl and cyclohexyl.

The term aryl group refers to an aromatic or hetero-aromatic ring system, such as a phenyl, naphtyl or anthracene group, preferably a phenyl, radical which optionally carries one or more substituents chosen from the group of alkyl, methoxy, halogen, hydroxy, amino, nitro, and cyano. Examples of such radicals include phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy) phenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphtyl, and 2-naphtyl. It is to be noted that fused and connected rings, as well as 5, 6, 7 or 8-membered rings, such as cyclopentadienyl, imidazolyl, thiophenyl, thienyl, etc., are included.

The term aralkyl group means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, or 2-phenylethyl. In a preferred embodiment, the invention relates to a light- switchable gelator as defined above having the formula (II):

wherein Ri and R3 are both methyl, and the other symbols having the same meanings as defined above. It is further preferred that R₂ and R each are hydrogen or a methyl group. Preferably, R2 and R have the same meaning. In another preferred embodiment of the invention, Mi and M2 have the same meaning. Preferably, Mi and M2 are phenyl or -CRgRioRn, wherein R₉ is hydrogen, Rio is cyclohexyl, cyclopentyl, or an aryl group, and Ru is an alkyl group. Even more preferred is an embodiment wherein Mi and M2 are phenyl, -CH(CH₃)(C₆H₅), or -CH(CH₃)(C₆H₁₁). The invention further relates to a process for preparing a light- switchable gelator as described above. In accordance with this process, suitable starting materials are materials having formula (I) wherein X is (CH₂)3, Y and Z are sulfur, Ri and R3 represent a CH3 group, R₂ and R are hydrogen, and Ai and A₂ are each chosen from the group of hydrogen, chloride, bromide and iodide. These materials may be prepared using any known method. Suitable ways of preparing them have been disclosed in Lucas et al., Chem. Commun., 2001, 759, and Lucas et al., Chem. Commun., 1998, 2313, the contents of which are incorporated herein by reference. It is to be noted that the compounds disclosed in the first mentioned publication are molecular switches which may be used as viscosifiers. However, they do not have any gelating properties.

The starting materials may be converted to produce a gelator according to the invention according to the reaction scheme shown in Figure 1, which illustrates a convenient preparation method starting from the above mentioned starting materials wherein Ai and A2 are both chloride (compound Z, figure 1).

In a first step, these materials may be converted to their corresponding formyl derivatives (compound A, Figure 1), for instance by reaction with n-butyl Uthium and dimethylformamide. It will be understood that other lithiating agents can also be used. As a solvent any ether may be employed. Preferred solvents are tetrahydrofuran (THF) and diethyl ether. The temperature at which the lithiation reaction can be performed may range from -80°C to 50°C, but is preferably between -10°C and 10°C, more preferably around 0°C.

In a second step, the formyl group may be converted to a carboxylic acid group to produce a diacid derivative (compound B, Figure 1). This is may be done using any oxidizing agent, but is preferably involves silver oxide in water under reflux conditions as described by Gronowitz et al., Heterocycles, 1981, 15, 947.

In an alternative embodiment, the starting material is directly converted to the diacid derivative by quenching the reaction mixture with solid or gaseous carbon dioxide after lithiation has taken place, as described by Norsten et al., J. Am. Chem. Soα, 2001, 123, 1784. It is furthermore possible to perform this step by quenching with a carbamate in order to obtain the corresponding ester, which can be hydrolysed to the diacid.

The final step involves the transformation of the carboxylic acid derivative to the desired amide derivative, by known methods involving first the activation of the carboxylic acid, and secondly reaction of the activated carboxylic acid with the amine (Figure 1) (see e.g. J. March, Advanced Organic Chemistry, Wiley, NY, 1992) Preferably, the diacid derivative (B) is treated with N-methylmorpholine and subsequently activated with 2-chloro-4,6- dimethoxytriazine in any chlorinated solvent, such as CH2CI2, or ether or dimethylformamide, at a temperature which may vary between -50°C and 30°C, but is preferably between -5°C and 5°C. After the activation N-methyl- morpholine is added again and subsequently the desired amine, like phenyl- ethylamine and the reaction is raised to room temperature. Of course, N- methylmorpholine can be substituted for any other suitable base.

Compounds with Ai and A2 groups present can be synthesized via a cross coupling reaction, preferably the Suzuki-coupling. The same compound as described above (Z) can be used as starting material. The compound is lithiated first (see above) and subsequently quenched with a boronic ester, preferably n-butyl boronic ester. The formed bis boronic ester derivative is directly used in the cross coupling reaction with a compound of the formula Qι,2-Ai,2-(CR5,7R6,8)m,o-Pι,2 , in which Qi,2 can be Cl, Br or I, but preferably Br or I, and Pi,2 is an amine or carboxylic acid, or any functional group which can be converted to an amine or carboxylic acid.

The solution of the bis boronic ester may be added, preferably dropwise, to a mixture of Qi,2-Ai,2-(CR5,7R6,8)m,o-Pι,2, a catalyst, base and a few drops of ethylene glycol just below reflux temperatures. The solvent is preferably THF, but also other ethers, or aromatic solvents like toluene can be used. The catalyst can be any palladium-, iron- or nickel catalyst, but is preferably palladium tetrakistriphenylphosphine (Pd(PPli3)4). As a base, a solution of Na₂Cθ3 in H2O or Na₂Cθ3 XH2O is preferably used, however, any other inorganic base can also be used. After the solution of the bis boronic ester has been added, this mixture is preferably refluxed for a suitable time such as two hours, and subsequently worked-up, to give a compound with Ai-(CR5R6)m- Pi = A2-(CR₇R8)o-P2 present.

In order to synthesize compounds in which -Ai-(CR5R6)m-Bi-Mi ≠ - A2-(CR₇R8)₀-B2-M2 a modified Suzuki reaction can be used in which only one side of the molecule undergoes this reaction. This can be accomplished by using the procedure described above for the synthesis of the bis boronic ester derivative wherein only one equivalent of the lithiating agent is used. In this way only one boronic ester per molecule is formed (bis and no substitution less than 5%). This mono boronic ester derivative is then coupled to one equivalent of Qi-Ai-(CR5R6)m-Pι. This reaction sequence can be repeated with a different Q2-A2-(CR₇R8)o-P2 to give a the non-symmetrical substituted precursor for the objective gelator.

Functional group P can be converted to a carboxylic acid group or an amine (Figure 2). For instance if P is a halogen it can be transformed to an azide, which can be reduced to an amine or it can react with succinimide to form a protected amine. Another example is when P is a nitro group, which can be reduced to an amine. Further, P can be an aldehyde which can be oxidized to a carboxylic acid. When P is a nitrile group, it can be hydrolysed to a carboxylic acid. The amine in its turn can be converted to a urea group or an amide by known methods (ref J. March, Advanced Organic Chemistry, Wiley, NY, 1992). (Figure 2). The carboxylic acid can be converted to an amide (Figure 2). The carboxylic acid precursors are then converted to the corresponding carboxylic acid azides, which in an Curtius rearrangement are converted to the corresponding isocyanates by known methods (ref J. March, Advanced Organic Chemistry, chapter 18, Wiley, NY, 1992). The isocyanate can be turned into an urea group by means of an amine.

In a preferred embodiment for the symmetric precursor compound Pi, 2 is a methyl ester. After the Suzuki reaction has been carried out, the ester can be hydrolysed to the corresponding carboxylic acid. The hydrolysis can be carried out using any standard saponification conditions, e.g. with a base in water or a water/organic solvent mixture. Preferably, 4M NaOH in a water/THF mixture is used (Figure 3). This compound can thus be treated in the same way as described above in order to obtain the amide derivatives, or used as starting material to prepare a bis-urea derivative or -NHCO- group (see above and Figure 2). Another example is given in which 1,4- dibromobenzene is used in a Suzuki reaction with compound Z (Figure 4). In this way a precursor with a halogen is synthesized (example 10).

If Pi ≠ P2 and have different reactivities, a sequence of selective reactions can be used to prepare the desired compounds. The invention further relates to the use of a light-switchable gelator as described herein to prepare a gel. According to the invention, a gel may be prepared by dissolving the gelator in a suitable solvent by heating (if necessary), and subsequently inducing gel formation by cooling and/or irradiating it with light.

Suitable solvents may be chosen from the group of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, non- aromatic hydrocarbons, aromatic solvents, alcohols, ethers, esters, aldehydes, alkanoic acids, epoxides, amines, silicon oils, vegetable oils, phosporic esters, sulfoxides, ketones and mixtures thereof. Preferred solvents are hydrocarbons, aromatic hydrocarbons and other aromatic solvents.

A gelator according to the invention will typically be present in the solution in a concentration of between 0.01 and 10 wt.%, based on the weight of the solution. The temperature needed in order to form a gel will depend on the solvent chosen as well as on the exact structure of the gelator and its concentration. In a preferred embodiment the mixture of the gelling agent and the solvent is heated to dissolve the gelling agent, and subsequent cooling allows the formation of a gel. Typically, the heating will involve raising the temperature of the mixture to about 30 - 175°C. Typically, the minimal temperature needed to achieve gelation will lie in the range of -10 to 100°C, preferably in the range of 30 to 80°C.

The gelation process can be monitored by rheology, microscopic methods, and spectroscopic methods. In the non-restrictive case that Mi and/or M2 are chiral, gelation results in a strong enhancement of the elipticity of the samples as measured by circular dichroism (CD) spectroscopy (see example 11).

An important property of the gelators according to the present invention is that they can exist as two thermally stable valence isomers, which can be converted into each other by irradiation with light in the range of 200- 800 nm (Figure 5). It will be understood that both valence isomers are encompassed by the invention.

Irradiation of the open form of the gelator (see Formula (I) above) with light of a lower wavelength (λi) causes conversion to a photostationary state (PSS) in which the ring closed form is predominant, and irradiation of the PSS with light of higher wavelength (λ2) causes conversion to the open form of the gelator. Here, λi is preferably in the range of 250 to 600 nm, and even more preferably 300 to 450 nm, whereas λ2 is preferably in the range of 350 to 900 nm, and even more preferably 450 to 700 nm. The isomerization process can be monitored by spectroscopic methods, and especially UN- VIS spectroscopy, due to the presence of a strong absorption of the closed form with a maximum between 400 and 700 nm, which is absent for the open form (see example 12).

Most remarkably, photoswitching between the two valence isomers of the gelator has a pronounced effect on thermal stability of the gels, as well as on the kinetics of gel formation. In an preferred embodiment, a gelator with the structure of formula II can be switched from the open form to the closed form by irradiation with light between 300nm and 450 nm, which is accompanied by an change of the melting point of the gel by 5-50°C, the exact value depending on the structure of the gelator, the solvent used, and the concentration of the gelator. In an even more preferred embodiment the melting point of the closed form of a gelator according to Formula II is by 5- 50°C higher than that of the open form, and gel formation in solutions of the closed form of the gelling agent is faster than gel formation in solutions of the open form.

In accordance with the present invention, the differences in thermal stability and kinetics of gelation between the open and closed form of the gelators may be exploited to induce gel formation by irradiation with light. When the melting point of a gel of the closed form is lower than that of the open form, photoinduced gelation can be achieved at a temperature between the melting point of the open and closed form, by irradiation of such a solution with light of wavelength λ₂ which causes isomerization from the closed to the open form. In another case, a gel of the open form has a lower melting temperature than that of the closed form, and gelation can be achieved at a temperatures between the melting point of the open and closed form, by irradiation of such a solution with light of wavelength λi which causes isomerization from the open to the closed form (see example 12).

It is also possible to make use of the differences in kinetics of gelation between the open and closed form to induce gelation by irradiation with light. In general, gelation at a set temperature below the melting point of the gels, is faster for gels of the valence isomer of the gelator having the higher melting point. Irradiation of a supercooled solution of an isomer of the gelator having the lower melting point with light of a wavelength causing isomerization to the other isomer of the gelator, results in a strong acceleration of the gelation process. In a preferred embodiment, a solution of a gelator according to Formula II is cooled to 10-50°C below the melting point, and irradiation of such a solution with light of wavelength λi causing isomerization to the PSS (see above) together with gelation within 10 minutes, whereas a similar non-irradiated solution does not turn into a gel within this period (see example 12).

Another important aspect of the invention is that gelation by a gelator according to the invention is reversible. This reversibility also holds for the photo-induced isomerization processes, and all the photo-induced gelation processes described above can be reversed by performing the back- isomerization by irradiation with light as depicted in Figure 5.

Due to its advantageous properties a light-switchable gelator according to the invention can be employed to control the flow of a liquid in a microchannel. In this regard, a microchannel is defined a passage, tube or duct for flow of a liquid having a diameter in the range of 0.1 to 500 μm, preferably of 1 to 100 μm. According to the invention, the flow of a liquid in a microchannel may be controlled by dissolving a small amount in the liquid flowing through it, and by irradiating part of the microchannel with light at a suitable temperature to locally form a gel as described above, which stops or at least reduces the flow of the liquid. The flow can be reinstated or increased by dissolving the gel again, by irradiation with light of a wavelength causing the reversed isomerization reaction as described above.

In another application the advantageous properties of a light- switchable gelator according to the invention are exploited to create gel patterns or gel objects of defined geometry by irradiation of only selected regions in a solution of the gelator. In a preferred embodiment, a film of a solution of the gelator with a thickness typically between 0.1 μm and 1 mm is used to prepare a network of liquid channels in a gel matrix by irradiation by light, and of which network the geometry can be changed by thermally-induced or light induced dissolution or gelation as described above. To this end the solution film of the gelator is kept at a fixed temperature and irradiated with light of a wavelength which induces gelation as described above, through a mask covering the regions of the gelator solution which should remain fluid, to induce gelation only in the non-covered regions, resulting in the desired gel- fluid network. The invention will now be further elucidated by the following non- restrictive examples.

Example 1: l,2-Bis(5'-formyl-2'-methylthien-3'-l)cyclopentene (A) n-Butyllithium (7.85 ml of 1.6M solution in hexane, 12.56 mmol) was added to a stirred solution of l,2-bis(5'-chloro-2'-methylthien-3'-l)cyclopentene (compound Z in Figure 3) (1.97 g, 5.98 mmol) in anhydrous THF (20 ml) under nitrogen at room temperature. One hour after the addition the reaction mixture was quenched with anhydrous dimethylformamide (0.97 ml, 12.56 mmol). The mixture was stirred then for an additional hour at room temperature, before it was poured into HC1 (2N, 50 ml). The mixture was extracted with diethyl ether (3 x 25 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (2x 25 ml) and H2O (1 x 25 ml), and dried (Na2S0 ), filtered and evaporated in vacuo to yield a brown solid (1.89 g, 90%). Chromatography of the solid over silica gel (hexane/ethyl acetate = 9/1) afforded the compound as a brown/orange solid (0.98 g, 52%). In the first step also other lithiating agents can be used, as a solvent all ethers can be used but preferably THF and diethyl ether. The temperature at which the lithiation reaction can be performed ranges from -80°C to 50°C, but preferably at 0°C.

Example 2: l,2-bis(5'-carboxylic acid-2'-methylthien-3'-l)cyclopentene (B)

Silver oxide was used to oxidize dithienylcyclopentene bisaldehyde (compound A)which was prepared as described in Example 1. This was done in situ by adding AgN0 (1.64 g, 9.6 mmol) to a solution of NaOH (0.75g, 18.7 mmol) in H2O (15 ml). Silver oxide immediately precipitated. This suspension was then added to compound A (0.74 g, 2.34 mmol) and refluxed for lh, subsequently filtered over a glass filter and rinsed with hot water. The filtrate was cooled and acidified with 2M HC1 in an ice bath. The compound precipitated and was filtered over a glassfilter (G4). The residual water was azeotropically removed with toluene to yield an off-white solid (0.51g, 62%).

Example 3: l,2-Bis(5'-(anilinocarbonyl)-2'-methyl-thien-3'-yl) cyclopentene (C) Dicarboxylic acid-thienylcyclopentene derivative (Compound B, 0.5 g, 1.44 mmol), which was prepared as described in Example 2, was suspended in CH2CI2 (5 ml) and placed in an ice bath. Subsequently N-methylmorpholine (0.31 ml, 2.9 mmol) was added and the suspension became a solution. Then 2- chloro-4,6-dimethoxytriazine (0,48 g, 2.9 mmol) was added, and a white precipitate was formed immediately after this addition. The reaction mixture was stirred for 2h at 0°C, and then another two equivalents of N- methylmorpholine (0.31ml, 2.9 mmol) were added followed by aniline (0.28 ml, 2.9 mmol). Stirring was continued for lh at 0°C, and the reaction mixture was then stirred overnight at room temperature. CH2CI2 (50 ml) was added and the solution was washed with, respectively, IM HCl (2 x 20ml), brine (lx 20 ml), saturated aqueous bicarbonate solution (1 x 20ml) and H2O (1 x 20ml). The organic phase was dried (Na₂S0 ) and after evaporation of the solvent gave a solid product. After purification, refluxing in CH2Cl2/diethylether (excess), filtration (G4-glassfilter) and drying under vacuum at 50°C, a white solid was obtained (0.27g, 37%).

Example 4: l,2-Bis(2'-methyl-5'-{[((R)-l-phenylethyl) amino]carbonyl} thien-3'-yl)cyclopentene (D)

This compound was prepared as described above for C, starting from diacid B (0.5 g, 1.44 mmol) and (R)-phenylethylamine (0.37 ml, 2.9 mmol). After purification by (CH₂Cl₂/MeOH = 60:1), stirring in MeOH/ diethyl ether (excess) and filtration (G4-glass filter), a white solid was obtained (0.28g, 35%). molecular formula C33H34N2O2S2.

Example 5: l,2-Bis(2'-methyl-5'-{[((R)-l-cyclohexylethyl) amino] carbonyl}thien-3'-yl)cyclopentene (E)

This compound was prepared as described above for C, starting from diacid B (1.34 g, 3.85 mmol) and (R)-cyclohexylamine (1.1 ml, 7.7 mmol). After purification by stirring in CH2Cl2/MeOH (60/1), filtration (G4-glass filter) and drying under vacuum at 50°C, a white solid was obtained (0.59g, 44%) molecular formula C33H46N2O2S2.

Example 6: l,2-Bis(5'-boronyl-2'-methylthien-3'-yl)cyclopentene (F)

Compound Z (l.Og, 3.04 mmol) was dissolved in anhydrous THF (12 ml) under a nitrogen atmosphere, and n-BuLi (5.0ml of 1.6M solution in hexane, 8 mmol) was added at once using a syringe. This solution was stirred for 30 min at r.t., and B(rc-OBu)3 (2.25 ml, 8.3 mmol) was added at once. The resulting solution was stirred for 1 h at room temperature and was used directly in the Suzuki cross coupling-reaction.

Example 7: l,2-Bis(5'-[methyl 5-(2-thienyl)-acetic acid]-2'-methylthien- 3'-yl)cyclopentene (G)

Methyl 2-(5-bromo-2-thienyι)acetic acid (2.94 g, 12.4 mmol) was dissolved in THF (75 ml) and Pd(PPh₃)₄ (0.42 g, 6 mol%) was added, this solution was stirred for 15 minutes at r.t.. Then aqueous Na2Cθ3 (36 ml, 2M) and 6 drops of ethylene glycol were added. This two-phase system was heated in an oilbath just below reflux (60°C) and the solution of compound F (6.07 mmol) in THF (20 ml) was added dropwise via a syringe in a short time-period. After that the mixture was refluxed for 2 hr. Subsequently cooled down and diethylether (100 ml) and H₂0 (50 ml) were added. The organic layer was washed with IM HCl (2 x 50 ml), brine (2 x 50 ml) and dried (Na₂S0₄). After evaporation the compound was purified by column chromatography (CH2CI2/ hexane = 4/1) on silica to yield an oil (2.13 g, 62%). (C₂9H28θ₄S₄)

Example 8: 1,2-Bis(5'- [5-(2-thienyl)-acetic acid]-2'-methylthien-3'- yl)cyclopentene (H)

Compound G (0.81 g, 1.23 mmol) was dissolved in MeOH (20 ml) and THF (20 ml), then 4M NaOH (2.7 ml) was added. This mixture was stirred for 2 hr at r.t.. After evaporation of the solvent H2O (25 ml) was added and the mixture was acidified in an ice-bath with 2M HCl. A precipitate was formed immediately, which was filtrated over a glasfilter. After removal of the residual water by forming an azeotrope with toluene, an off-white solid was obtained (0.28 g, 76%). (C27H₂4θ₄S ) Example 9: l,2-Bis(5'-{N-dodecyl-N^,-[4-(2-thienyl)methyl]urea}-2'- methylthien-3'-yl)cyclopentene (I)

Dry CH2CI2 (20 ml) and Et₃N (0.11 ml, 0.76 mmol) were added under a nitrogen atmosphere to Compound H (0.204 g, 0.38 mmol). When a solution was obtained diphenylphosphorylazide (0.16 ml, 0.76 mmol) was added in one time. This mixture was stirred for 2 h at room temperature and subsequently the temperature was raised to 50°C to stir for another 2 h. Then dodecylamine (0.17 ml, 0.76 mmol) was added and the mixture was refluxed for 2 hr and finally stirred at r.t. for 16 hr. The mixture was diluted with diethylether (80 ml) and washed with saturated bicarbonate solution (2 x 25 ml), H2O (2 x 25 ml), IM HCl (1 x 25 ml), brine (2 x 25 ml) and dried (Na₂S0₄). After evaporation of the solvent in vacuo, the obtained solid This solid was submitted to column chromatography (CHCI3/ MeOH = 20/1) on silica was refluxed in CHCI3 /diethylether (excess) and filtrated (G4) to yield a purple solid (36 mg, 10 %). (C₅ιH₇₆N₄0₂S₄).

Example 10: l,2-Bis[5'-(4"-bromophenyl)-2'-methylthien-3'-yl] cyclopentene (J)

1,4-dibromobenzene (3.4 g, 14.4 mmol)was dissolved in THF (12 ml) and after addition of Pd(PPh3)₄ (0.4 g, 0.3 mmol), the solution was stirred for 15 min at r.t.. Then aqueous Na2Cθ3 (17 ml, 2M) and 6 drops of ethylene glycol were added, and the resulting two-phase system was heated in an oil bath till reflux (60°C). The solution of compound F was added dropwise by a syringe in a few minutes. After addition was complete, the reaction mixture was refluxed for 2 h, and then allowed to cool to r.t.. Diethyl ether (50 ml) and H₂O (50 ml) were added, and the organic layer was collected and dried (Na2S0₄). After evaporation of the solvent the product was purified by column chromatography (Si0₂, hexane) to gave a yellowish solid (1.30 g, 76%).

Example 11: Gelation experiments

In a typical gelation experiment, a carefully weighed amount of the dithienylcyclopentene derivative under investigation and 1 ml of the solvent are placed in a test tube, which is sealed and then heated until the compound is dissolved. The solution is allowed to cool to room temperature. Gelation was considered to have occurred when a homogeneous solid substance was obtained, which exhibited no gravitational flow. Gelation did occur in the following non-limiting cases of solutions of Compound C in 1-phenyloctane, toluene, n-butylether, benzene, tetralin; Compound D in cyclohexane, 1- phenyloctane, toluene, n-butyl ether, benzene, tetralin; Compound E in hexadecane, cyclohexane, 1-phenyloctane, toluene, n-butylether, benzene, tetralin, 1,4-dioxane, and n-butyl acetate. The gelation process could be followed by UV-vis and CD spectroscopy as depicted in Figure 6. At low concentrations (0.35 mM) compound D is dissolved in toluene and this solution did not show a CD effect. Increasing the concentration to 1.8 mM causes gelation of the solvent, which is accompanied by a change of the UN- visible spectrum, together with the appearance of a strong CD signal at 323 nm (Figure 5 A and B). Similar changes in the UV-vis and CD spectrum are observed upon gelation of the 1.8 mM solution of D in toluene by cooling to a temperature below the sol-gel phase transition(from here on referred to as gel(o). From a plot of the increase of the CD signal versus the temperature the sol-gel phase transition temperature of gel(o) was determined to be 29°C for a 1.8 mM solution of D in toluene.

Example 12: Photoswitching of gels of compound D

In a typical photoswitching experiment a solution (1.8 mM) of Compound D in toluene was prepared by cooling from 70°C to the desired temperature (typically between 30°C and 60°C, i.e. above the gel-sol phase transition temperature of the open form of D) in a cuvette of 1 mm path length. This solution was then irradiated at λi = 313 nm to convert the ring-open form of Compound D to the ring-closed form. By using a 150 W Xe lamp and a 313 nm bandpass filter, the photostationary state (PSS) was reached typically within 10 minutes, which consist of 60mol% of the closed form and 40mol% of the open form. During this irradiation process the solution of D was transformed into a deeply purple colored gel (from here referred to as gel(c,I), which could be monitored by UV-vis and CD spectroscopy (Figure 6 D and D). From a plot of the increase of the CD signal versus the temperature the sol-gel phase transition temperature of gel(c,I) was determined to be 62°C, showing that the thermal stability has increased by more than 30°C compared to that of gel(o). It should be noted that dissolving gel(c,I) by heating and subsequent cooling to again a temperature below the gel-sol phase transition, resulted in a CD spectrum different to that of gel(c,I), indicating that gels of the closed form of D can adopt an alternate structure, which is from hereon referred to as gel(c,II) (see Figure 6D). Gels of the closed form of D can also be dissolved by converting the closed form to the open form by irradiation with light of wavelength λ₂. Irradiation of gel(c,I) or gel(c,II) with λ₂ > 450 nm at while keeping the temperature between 30°C and 60°C causes dissolution of the gel to give a solution of the open form D, of which the UV-vis and CD spectra are identical to that of the starting solution. This process of gelation-dissolution by alternating irradiations with UV (313 nm) and Vis (> 450 nm) light can be repeated many times, showing that the photo-induced gelation process is fully reversible.

In another experiment, a solution (1.8 mM) of Compound D in toluene was prepared by cooling from 70°C to a temperature below the gel-sol phase transition temperature of the open form of (typically between 20°C and 29°C) in a cuvette of 1 mm path length. This solution was then irradiated at λi = 313 nm to convert the ring-open form of Compound D to the ring-closed form, whereas solutions which have been kept in the dark stay colorless and did not form a gel within 1 hour. This clearly shows that gelation of a solution of D can be accelerated by converting the open to the closed form by irradiation with light of wavelength λi.

To demonstrate the possibility to create gel patterns by irradiation with light, a 11 mM toluene solution of the open form of compound D was prepared in a cuvette of 0.2 mm path length by keeping the temperature at 43°C, i.e. at a temperature above the gel-sol phase transition temperature of the open form but below the phase transition temperature of the closed form. In a first irradiation experiment the solution was exposed to light of λj=313 through a mask which causes conversion of the open form to the closed form and subsequent gelation of the closed form, only at the irradiated areas (see Figure 7). In a second irradiation experiment also the previously unexposed areas were irradiated with light of λj=313. No further changes were observed, which shows that already during the first irradiation experiment a photo- stationary state has been obtained.

Claims

1. A light-switchable gelator having the formula (I):

wherein

- X is chosen from the group of the moieties -(CH2)_n-, -(CF2)_n-, -C(=0)-0-C(=0)- and -C(=0)-NR-C(=0)-, wherein n is 3 or 4 and wherein R is hydrogen, a

(cyclo)alkyl group or an aryl group;

- Y and Z each are nitrogen or sulfur;

- Ri and R3 each are an alkyl group;

- R2 and R₄ each are hydrogen or an alkyl group; - Ai and A2 each are absent or are an aryl group;

- R5, Re, R7, and Re each are hydrogen, an alkyl group or an aryl group;

- m and o each are integers chosen from the group of 0, 1, 2, 3, and 4;

- Bi and B2 are hydrogen bonding moieties; and

- Mi and M2 each are an aryl group, a (cyclo)alkyl group, or -CR₉R₁₀R₁₁, wherein R9, Rio and Rπ each are hydrogen, a (cyclo)alkyl group, an aralkyl group or an aryl group.

2. A light-switchable gelator having the formula (III):

wherein

- X is chosen from the group of the moieties -(CH2)_n-, -(CF2)_n-, -C(=0)-0-C(=0)- and -C(=0)-NR-C(=0)-, wherein n is 3 or 4 and wherein R is hydrogen, a (cyclo)alkyl group or an aryl group;

- Y and Z each are nitrogen or sulfur;

- Ri and R3 each are an alkyl group;

- R2 and R₄ each are hydrogen or an alkyl group;

- Ai and A2 each are absent or are an aryl group;

- R5, Re, R7, and Rs each are hydrogen, an alkyl group or an aryl group;

- m and o each are integers chosen from the group of 0, 1, 2, 3, and 4;

- Bi and B2 are hydrogen bonding moieties; and

- Mi and M₂ each are an aryl group, a (cyclo)alkyl group, or -CR9R10R11, wherein R9, Rio and Rn each are hydrogen, a (cyclo)alkyl group, an aralkyl group or an aryl group.

3. A light-switchable gelator according to claim 1 or 2, wherein the hydrogen bonding moieties Bi and B₂ are chosen from the group of -NH-C(=0)-, -C(=0)-NH-, and -NH-C(=0)-NH-.

4. A light-switchable gelator according to claim 1 or 3 having the formula (II):

wherein Ri and R3 are both methyl.

5. A light-switchable gelator according to claim 4, wherein R₂ and R₄ are hydrogen or methyl.

6. A light-switchable gelator according to claim 5, wherein R₂ and R₄ are the same.

7. A light-switchable gelator according to any of the claims 4-6, wherein Mi and M2 are the same.

8. A light-switchable gelator according to claim 7, wherein Mi and M2 are phenyl or -CR9R10R11, wherein R9 is hydrogen, Rio is cyclohexyl, cyclopentyl, or an aryl group, and Rπ is an alkyl group.

9. A light-switchable gelator according to claim 8, wherein Mi and M2 are phenyl, -CH(CH₃)(C₆H₅), or -CH(CH₃)(C₆Hn).

10. A process for preparing a light-switchable gelator according to claim 1 or 3, comprising the steps of: - converting a compound having formula (I), wherein X is (CH2)3, Y and Z are sulfur, Ri and R3 represent a CH3 group, R2 and R4 are hydrogen, and Ai and A2 are each chosen from the group of hydrogen, chloride, bromide and iodide to its corresponding dialdehyde derivative by reaction with a lithiating agent and dimethylformamide; - converting the dialdehyde derivative to a diacid derivative by oxidation;

- converting the diacid derivative into a diisocyanate derivative through a Curtius rearrangement; and

- converting the diisocyanate derivative into the light-switchable gelator by treatment with a base followed by activation with a carboxylic acid activator and reaction with M1NH2 and M2NH2.

11. A process for preparing a light-switchable gelator according to any of the claims 4-9, comprising the steps of:

- converting a compound having formula (I), wherein X is (CH2)₃, Y and Z are sulfur, Ri and R3 represent a CH3 group, R2 and R₄ are hydrogen, and Ai and A₂ are each chosen from the group of hydrogen, chloride, bromide and iodide to its corresponding dialdehyde derivative by reaction with a lithiating agent and dimethylfo mamide;

- converting the dialdehyde derivative to a diacid derivative by oxidation; and - converting the diacid derivative to the light-switchable gelator by treatment with a base followed by activation with a carboxylic acid activator and reaction

12. A process according to claim 10 or 11, wherein the lithiating agent is n-butyl lithium.

13. A process according to claims 10-12, wherein the oxidation is carried out using silver oxide.

14. A process according to claims 10-13, wherein the base is N-methyl morpholine and the carboxylic acid activator is 2-chloro-4,6-dimethoxytriazine.

15. A process for preparing a gel, wherein a light-switchable gelator according to any of the claims 1-9 is dissolved in a suitable solvent and gel formation is induced by cooling and/or irradiation with light.

16. A process according to claim 15, wherein the solvent is chosen from the group of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, non-aromatic hydrocarbons, aromatic solvents, alcohols, ethers, esters, aldehydes, alkanoic acids, epoxides, amines, silicon oils, vegetable oils, phosporic esters, sulfoxides, ketones and mixtures thereof.

17. A process according to claim 15 or 16, wherein the light has a wavelength between 200 and 800 nm.

18. A gel obtainable by a process according to any of the claims 15-17.

19. A process for dissolving a gel according to claim 18, wherein the gel is irradiated with light.

20. A process according to claim 19, wherein the light has a wavelength between 200 and 800 nm.

21. Use of a light-switchable gelator according to any of the claims 1-9 for controlling the flow of a liquid in a microchannel.

22. Use of a light-switchable gelator according to any of the claims 1-9 to create gel patterns or objects by irradiation of selected regions of a solution of the gelator with light.