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Selective surface adsorption versus imprinting in amorphous microporous silicas
Microporous and Mesoporous Materials 29 (1999) 389–403
Selective surface adsorption versus imprinting in amorphous microporous silicas M. Hunnius, A. Rufin´ska, W.F. Maier * Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim an der Ruhr, Germany Received 25 September 1998; received in revised form 4 December 1998; accepted 4 December 1998
Abstract Selective adsorption of organic molecules on inorganic solids is an attractive property of inorganic materials. It was attempted to control molecular adsorption on inorganic surfaces by the preparation of porous silicas through a sol–gel process developed for the generation of selective adsorption sites by molecular imprinting. The materials were prepared by co-polycondensation of tetraethyl orthosilicate with R–Si(OR) , with R as a removable template. In 3 competitive adsorption experiments on such imprinted porous oxides with mixtures of (−)-borneol, (−)-camphor and (+)-fenchol, selective adsorption of individual components has been observed. Detailed control experiments, however, confirmed that the adsorption selectivity is independent of the comonomer used in the sol–gel process, but dependent on the method of preparation. Adsorption selectivities are found to be dependent on the specific pore surfaces created by different preparation procedures. No evidence was found for the presence of selective cavities due to imprint effects. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Hybrid materials; Inorganic molecular imprinting; Selective surface adsorption; Silica; Sol–gel
1. Introduction Molecular recognition is one of the basic concepts in nature. In enzymes this recognition is a prerequisite for molecules to gain access to the active site, thus enforcing the high substrate selectivities enzymes are known for. This recognition is often initiated by the lock and key mechanism first discussed by Pauling [1,2] and refined by what is termed induced fit. The generation of sites capable of molecular recognition in inorganic materials is very attractive, because such materials could be * Corresponding author. Tel: +49-208-306-2447; Fax: +49-208-306-2987. E-mail address: [email protected] ( W.F. Maier)
used for molecular separations including enantiomeric enrichments and selective sensors, as well as selective catalysts. The target is to generate structures in the form of cavities complementary to the molecule to be recognised. A simple approach to generate such a complementary cavity is molecular imprinting by the use of a removable template. Such molecular imprinting has been approached in several ways. As early as 1931, Poljakov [3] removed water from a silica gel in an atmosphere of benzene, toluene or xylene. He found that the pore structure was influenced by the size and shape of the molecules in the gas atmosphere. On a silica gel dried in a benzene atmosphere, benzene adsorbed faster than toluene or xylene. In 1949 Dickey [4,5] prepared imprinted gels from acidified
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silica solutions in the presence of methyl orange, which, after extraction, adsorbed methyl orange better than a blank gel. Curti et al. in 1952 expanded the concept of Dickey to the separation of enantiomers by imprinting silica with an enantiomer [6 ]. These authors used a silica gel that was precipitated in the presence of 4–5% of (S)-10-camphorsulfonic acid, and were able to resolve racemic camphorsulfonic acid with an ee of 30%, while with mandelic acid an ee of 10% was reached. In the early 1960s Klabunovskii et al. further expanded the concept of molecular recognition to the resolution of racemic mixtures. During the hydrolysis of alkoxysilanes, they were the first to use chiral silanes [i.e., tetra-(2-methylbutoxy) silanes] as templating agents [7]. The adsorption of racemic 2-butanol and of the pure isomer, (S)2-butanol, was measured by gravimetric adsorption [8]. In every case more of the racemic alcohol than of the (S )-2-butanol was adsorbed on all the samples, indicating that the racemic mixture is adsorbed preferentially on the silica surface. No evidence for stereospecific adsorption was obtained. Erlenmeyer and Bartels [9,10] and Haldeman and Emmett [11] repeated Dickey’s experiments and not only confirmed his observations, but carried out further investigations to support the imprint theory. Erlenmeyer’s group especially engaged in the problem of similarity. They recognised that the specificity of adsorption on imprinted silicas is not limited to the associated template, but that also other molecules of similar structure are adsorbed in preference to other molecules non-similar in structure. Another concept of molecular imprinting was first presented by Wulff and Sarhan [12] in 1972, who used an organic polymer network as matrix instead of silica. Here a template linked to a properly chosen binding site was copolymerised to give (after removal of the template) a cavity in the polymer, where several functional groups of the binding site are prearranged in a fixed position. The main difference to all former concepts is that it does not rely on the shape selectivity of the imprint cavity, but on highly specific binding sites in defined cavity positions, which allow well-
defined interactions between the reactants and several functional groups of the polymer. This area has grown rapidly [13,14] and imprinted polymers have been used successfully for selective adsorption [15,16 ], chiral recognition and an ever-increasing number of applications including selectively catalysed reactions [17]. In 1988 Morihara et al. [18–21] published the use of transition-state analogues ( TSAs) as template to form cavities with an intrinsic selective catalytic activity. Dibenzamide was used as a template to serve as a TSA for the butanolysis of benzoic anhydride. Several reports followed in which, with such ‘‘footprint catalysts’’, rate enhancements were observed [18–21]. Evidence for an imprint effect was obtained by Michaelis– Menten kinetics and inhibition of the catalysed reaction with the imprint molecule. Some of the results have been questioned by Kaiser and Anderson [22] who also chose aluminium-doped silica as catalytic material but were unable to find any catalytic effect for their desired reaction. In our studies on the preparation of new catalyst materials by the sol–gel process, we discovered that amorphous microporous oxides with a narrow pore-size distribution (0.8 nm diameter) comparable to zeolites can be obtained by careful control of the sol–gel process followed by drying and calcination. The narrow pore-size distribution was attributed to transport pores of the alcohol formed during the hydrolysis–polycondensation reactions in the sol–gel process which, after calcination, remain an integral part of the microstructure of the final material. In other words, the amorphous microstructure of the final glass remembers the kinetic diameter of the alcohol. It was rationalised then, that if this polycondensation can so precisely adopt the transport diameter of diffusing ethanol, it may also be able to remember the molecular shape of imprinted molecules and thus provide another entry to molecular imprinting in inorganic oxides. Our approach is summarised in Fig. 1. First experiments relied on imprinting of a phosphonate as transition-state analogue of the transesterification of ethyl phenylacetate with hexanol. The TSA was connected to a triethoxysilyloxy group as co-polycondensable anchor. The material showed not only a higher activity for the transester-
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Fig. 1. Molecules used as comonomers in the sol–gel process for imprinting purposes. Schematic description of the sol–gel process leading to imprinted porous materials.
ification reaction [23] compared with a control catalyst, but also a significantly higher selectivity, implying that the observed catalysis was the result of an imprint. However, no inhibition of the catalyst by adding the TSA to the catalytic reaction was noted [23]. Detailed investigation of the imprinted gel by 31P magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy showed that, in the untreated gel, the imprint molecule was not covalently bound to the polymer network but only physically embedded in the gel [24], which rendered the imprint hypothesis impossible. Since the initial selectivities reported were reproducible at the time, it was concluded that selective diffusion may have been responsible for the observed selectivities [24]. To prove molecular imprinting indirectly by the
effect of catalysis is more difficult than to show this effect with adsorption or even competitive adsorption, since selective catalysis exploits kinetic differences and therefore differentiation at the imprinted site must be very high. On the other hand, pore-size effects having a direct influence on diffusion constants may compensate all imprint effects, leaving the question of imprinting unanswered. With competitive adsorption this is not the case. For a competitive adsorption experiment the two components have sufficient time to diffuse through the pores and adsorb on the recognition site. By using the same approach as mentioned above, (−)-borneol was copolymerised with tetraethoxysilane and methyltriethoxysilane to give, after calcination, a microporous gel that was able to selectively adsorb the imprinted molecule,
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(−)-borneol [25,26 ]. In contrast to the initial success, these results could not be reproduced [26 ]. Pinel et al. [27] used (−)-menthol as template and did not find any enantiomeric enrichment but some regiorecognition was observed. All these results prompted a systematic investigation of the phenomena of molecular imprinting by co-polycondensation.
2. Prerequisites of imprinting Reliable evidence for successful imprinting has so far only been provided for polymeric materials. Polymeric networks are usually amorphous and the cavities are randomly distributed in the solid material, rendering characterisation of such cavities difficult. Presently there are only two possible ways to prove an imprint effect: selective catalysis and competitive adsorption. The formation of an imprint includes formally several steps: first the template molecule has to be evenly distributed in the monomer solution, so that a solid matrix can be built around each single template providing the sites of a complementary three-dimensional structure. Secondly, the template has to be removed from the matrix. Therefore, the polymeric material has to have a porous structure and the van der Waals’ or covalent bond of the template molecule to the polymer network has to be broken. The empty cavity has to be stable under adsorption or reaction conditions. Another important point is that the adsorption site must not be blocked by any other molecule that adsorbs better on a silica surface than the template molecule. Since water in particular tends to block the silica surface, traces of water should be removed from the imprint material prior to experiments and the solvent used should be chosen with care. The adsorption or the catalysed reaction must take place inside the cavity formed during the polymerisation process. This means that the matrix needs to be flexible or needs to have pores that are larger than the template or the reactants. In addition to that, the cavity itself should be fairly flexible to allow the molecules to enter or, in the case that the material is rather rigid, the imprinted site needs to have a large opening. To produce a material capable of molecu-
lar recognition, all the properties listed here should be taken into account to ensure that the material may function properly.
3. Experimental 3.1. General All chemicals were used as received from the suppliers without further purification if not stated differently. Only phenyldodecane (Aldrich) was purified by means of preparative gas chromatography (GC ). 3.2. Preparation of the imprint materials At room temperature, 9.49 ml (42.5 mmol ) of tetraethoxysilane ( TEOS) together with 1.5 ml (7.5 mmol ) of methyltriethoxysilane were stirred, while 10 ml of ethanol was added. After stirring for 15 min, 1 ml (3 mmol ) of the comonomer was added according to Table 1. Afterwards, HCl diluted in the appropriate amount of water was added as listed in Table 1 (given as equivalents relative to the amount of TEOS used). The sol usually started to gel after 3 to 4 days and was left to dry for another 3 days prior to calcination. The gels were then heated slowly from room temperature to 65°C at a rate of 0.1°C min−1. This temperature was maintained for 300 min before the temperature was increased to 250°C at the same rate of 0.1°C min−1. This temperature was kept for 300 min before the oven was allowed to cool down. The solid was then milled in a ballmill to particle sizes smaller than 200 mm. This material was used for the adsorption experiments. By means of the same method, the material containing a chiral comonomer was obtained. First, 11.7 ml (52.3 mmol ) of tetraethoxysilane together with 1.75 ml (9.2 mmol ) of methyltriethoxysilane were stirred, while 12.5 ml of ethanol was added. After stirring for 15 min, 185 mg (0.5 mmol ) of 2-(4-methoxy-phenyl )-3,3-dimethylbutan-1-yloxytriethoxysilylane was added. Afterwards, 2.25 ml of 0.4 N HCl was added. The calcination and milling processes were identical to those described above.
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Table 1 Adsorption properties and surface areas of gels co-condensed with either (−)-bornyloxytriethoxysilane, (+)-fenchyloxytriethoxysilane or without additional comonomer [(−)-camphor, control ]. The molar amounts of TEOS:water:HCl:ethanol are usually 1:2:0.35:3. The amounts of HCl and water (given in equivalents relative to the amount of TEOS ) were varied according to this table, giving different surface areas and adsorption properties Gel
A-1 A-2 A-3 B-1 B-2 B-3 C-1 C-2 C-3 D-1 D-2 D-3 E-1 E-2 E-3 F-1 F-2 F-3 G-1 G-2 G-3 H-1 H-2 H-3
Equiv. HCl
0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13
Equiv. water
14.2 14.2 14.2 6.9 6.9 6.9 3.2 3.2 3.2 1.4 1.4 1.4 6.9 6.9 6.9 3.2 3.2 3.2 1.4 1.4 1.4 0.7 0.7 0.7
Imprinting molecule
(−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none
Adsorption propertiesa
Surface area (m2 g−1)
(−)-Borneol
(+)-Fenchol
(−)-Camphor
−6 −7.8 −8 −5.3 −8.1 −6.7 0.8 1.7 −5.2 −0.4 −0.2 −0.4 −4.4 −2.5 −2.5 0.8 1 1.6 −0.1 0.2 0 no gelation
6.4 10.9 7.2 3.8 6.8 8.4 −3.7 −3.5 7.3 0.5 −0.5 0.4 1.9 2.3 2.8 −3 −2.5 −1.4 0.2 −0.4 0.2
−0.5 −3.2 0.8 1.4 1.2 −1.7 3 1.7 −2.1 −0.1 0.7 0 2.5 0.2 −0.3 2.1 1.5 −0.2 −0.3 0.3 −0.3
556.1 502.5 476.94 438.5 438.5 401.5 248.3 348.2 446.7 125.1 147 33.2 302.6 248.2 341.4 115.6 261 372.1 71.5 5.8 46.2
a Change of GC (%) compared with the standard.
3.2.1. Oxidative treatment of the imprint materials for the removal of (−)-borneol To remove the imprinted molecule, 300 mg of the gel was mixed with 7 ml of a 1:1 mixture of H O and i-propanol. The mixture was stirred and 2 2 heated to 75°C for 24 h. Afterwards, the gels were centrifuged and washed several times with i-propanol. 3.2.2. General procedure for the synthesis of organyloxytriethoxysilanes A quantity (100 mmol ) of alcohol (borneol or fenchol ) was dissolved under an argon atmosphere in 500 ml of dry pentane, the solution was cooled to −35°C and 7.91 g (8.1 ml, 100 mmol ) of dry pyridine was added slowly. The reaction mixture was cooled to −60°C and then 29.4 g (148 mmol )
of chlorotriethoxysilane was added dropwise. After the mixture reached room temperature, it was filtered under argon over a P4 frit and washed with 50 ml of pentane. Traces of the solvent were removed under reduced pressure.
3.2.2.1. (−)-Bornyloxytriethoxysilane. Yield: 28.4 g (90 mmol, 90.0%). 1H- and 13CP-NMR, infrared (IR) and elemental analyses are consistent with the proposed structure.
3.2.2.2. (+)-Fenchyloxytriethoxysilane. Yield: 29.0 g (90 mmol, 91.6%). 1H- and 13C-NMR, IR and elemental analysis are consistent with the proposed structure.
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3.2.3. 1-(4-Methoxy-phenyl)-2,2-dimethyl-propan1-one [28] Dimethylpropionyl chloride (44.8 g, 370 mmol ), dissolved in 80 ml of dry pentane, was slowly added to a stirred mixture of the catalyst AlCl 3 (74.4 g, 560 mmol ) and anisole (80 g, 740 mmol ) in 400 ml of pentane, which was cooled with ice. After 45 min of stirring the reaction mixture reached room temperature and was poured onto 400 ml of ice. The resulting pink complex was destroyed by the addition of hydrochloric acid. The water phase was washed three times with pentane. The combined organic phases were dried over MgSO , filtered and the pentane was removed 4 under vacuum. The 1-(4-methoxy-phenyl )-2,2dimethyl-propan-1-one was further purified by distillation (T =72°C at p=0.002 mbar). s Yield: 54.1 g (276 mmol, 74.6%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.4. 1-(4-Methoxy-phenyl)-2,2-dimethyl-propan1-ol [29] At 0°C, 9.55 g (50 mol ) of 1-(4-methoxyphenyl )-2,2-dimethyl-propan-1-one was added to a solution of 0.756 g (20 mmol ) of sodium borohydride which was dissolved in a mixture of isopropanol and 10 ml of water. The reaction was stopped after 15 min by the addition of acetone (250 ml ). While the flask reached room temperature, the solution was well stirred. It was then washed with a saturated solution of NaHCO and 3 extracted three times with ether. The combined organic phases were dried over Na SO , filtered 2 4 and the solvent was removed under vacuum. Yield: 7.9 g (41.2 mmol, 82.4%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.5. 2-(4-Methoxy-phenyl)-3,3-dimethyl-but1-ene Triphenylmethylphosphonium bromide (171.6 g, 160 mmol ) was suspended in 800 ml of ether. Next, 30.72 g (480 mmol ) of n-butyllithium in 300 ml pentane (1.6 M ) was added to this solution. The mixture was stirred overnight before 23.04 g of 1-(4-methoxy-phenyl )-2,2-dimethyl-propan-1-one was added slowly. After stirring for 1 h at room
temperature, the mixture was refluxed at 60°C for 6 h. For the work-up the mixture was poured into 2000 ml of water and extracted three times with ether. The combined organic phases were dried over Na SO , filtered and the solvent was removed 2 4 under vacuum. Besides the desired product, the reaction mixture contains phosphine oxide as well. Via distillation (0.005 mbar, 52°C ), the product was purified. Yield: 16.3 g (85.6 mmol, 71.4%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.6. 2-(4-Methoxy-phenyl)-3,3-dimethyl-butan1-ol [30,31] To 27.9 g (148.8 mmol ) of 2-(4-methoxyphenyl )-3,3-dimethyl-but-1-ene dissolved in 85 ml of diglyme in a flask equipped with a condenser, 2.418 g (63.9 mmol ) of NaBH was added under 4 argon. Using a dropping funnel, 10.27 ml (11.5 g, 81.4 mmol ) of boron trifluoride diethyletherate were added over 30 min while the reaction mixture was kept at room temperature. The excess of NaBH was destroyed by the addition of 20 ml 4 water. By the addition of 16.5 ml of 3 N NaOH, followed by the dropwise addition of 16.5 ml of H O (30%), the organoborane was oxidised. Prior 2 2 to extraction with ether the mixture was stirred for another hour. The organic phase was extracted five times with water to remove the diglyme. The organic phases were dried over MgSO , filtered 4 and the solvent was removed under vacuum. Yield: 21.4 g (102.9 mmol, 69.2%). 1H- and 13C-NMR, IR and elemental analysis are consistent with the proposed structure. 3.2.7. (R)-3-Oxo-4,4,7-trimethyl2-oxabicyclo[2.2.1]heptan-1-carboxylic acid2-(4-methoxy-phenyl)-3,3-dimethylbutylester [32] To a solution of 20 g (96 mmol ) of the racemic alcohol (±)2-(4-methoxy-phenyl )-3,3-dimethylbutan-1-ol in 300 ml pyridine at 0°C, 22.8 g (105.7 mmol, 10% excess) of (−)-camphanoyl chloride was added. To dilute further, 150 ml of pyridine was added. After the solution was stirred for 19 h at room temperature, CH Cl was added and 2 2 the organic layer was first washed with cold 2 N hydrochloric acid and then with NaHCO solution. 3
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After removal of the solvent, a white powder was obtained. Yield: 34.8 g (89.8 mmol, 93.5%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. The diastereomers containing about 4.5% of the starting material have been separated by preparative high-performance liquid chromatography (HPLC ); 26.8 g of the mixture of diastereomers was separated. The first diastereomer was isolated with a purity of over 96% (8.1 g, yield 64%). For the other diastereomer 8.5 g of the same purity was obtained, corresponding to a yield of 69%.
3.2.8. Enantiomerically pure 2-(4-methoxyphenyl)-3,3-dimethyl-butan-1-ol by ester hydrolysis A quantity (50 ml ) of 2 N KOH was added to a solution of 1440.0 mg (2.7 mmol ) of one of the diastereomers of (R)-3-oxo-4,4,7-trimethyl2-oxabicyclo[2.2.1]heptan-1-carboxylic acid2-(4-methoxy-phenyl )-3,3-dimethylbutylester, obtained from HPLC separation, in 120 ml of ethanol. After 24 h of refluxing (T~100°C ) the mixture was allowed to cool down. The alcohol was evaporated at reduced pressure and the water phase was extracted with ether. Afterwards, the ether was removed under vacuum. Yield: 0.499 g (2.4 mmol, 89.1%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure.
3.2.9. 2-(4-Methoxy-phenyl)-3,3-dimethyl-butan1-yloxytriethoxy silane 2-(4-Methoxy-phenyl )-3,3-dimethyl-butan-1-ol (2.15 g, 10.3 mmol ) was dissolved in 400 ml of dry heptane under an argon atmosphere, cooled to −5°C and then 3.05 g (15.5 mmol ) of chlorotriethoxysilane in 5 ml of heptane was added dropwise. Afterwards, 8.26 ml (10.3 mmol ) of dry pyridine in 5 ml of dry heptane was added. The solution was allowed to warm to room temperature and was then stirred for 15 h before the reaction mixture was filtered under argon over a P4 frit. The precipitate was washed with 50 ml of heptane and dried under reduced pressure to remove traces of the solvent.
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Yield: 3.2 g (8.7 mmol, 85.0%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure.
3.3. HPLC 3.3.1. Analysis conditions Apparatus: Column: Temperature: Mobile phase: Flow: Pressure: Detection:
DuPont 8800, Shimadzu SpD-6A 250 mm LiChrospher Si100, 4.5 mm diameter, D494 35°C hexane/2-propanol=99/1 (v/v) 1.0 ml min−1 2.4 MPa UV, 220 nm, E=16
3.3.2. Preparative HPLC separation Apparatus: Column: Stationary phase: Temperature: Mobile phase: Flow: Pressure: Detection:
Shimadzu LC-8A Gradientensystem 230 mm×36 mm Bu¨chiColumn LiChroprep Si 100, 25–40 mm, Charge 730F852704 room temperature dichloromethane (water-saturated ) 35 ml min−1 1.8 MPa UV, 220 nm, E=1.28
3.4. 13C cross-polarisation (CP)/MAS NMR studies Solid-state 13C CP/MAS NMR spectra were recorded on a Bruker MSL-300 spectrometer, equipped with a double-bearing probe. The ZrO rotor 2 (7 mm internal diameter) was charged with the samples and sealed by a Kel-F inset. The optimal contact time for 13C cross-polarisation was 2–3 ms. The spinning rate was between 2 and 5 kHz. The external standard for 13C NMR was adamantane [d(CH )=38.40, relative to tetramethylsilane]. 2
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3.5. Adsorption experiments For competitive adsorption experiments of (−)-borneol, (−)-camphor and (+)-fenchol, 10 mg of each compound was dissolved in 10 ml of phenyldodecane. For the adsorption experiment 2 ml of the solution was stirred together with 200 mg of the imprinted material for 24 h. Afterwards, samples were taken and analysed by GC. For competitive adsorption measurements of silica imprinted with 2-(4-methoxyphenyl )-3,3dimethylbutan-1-ol, 20 mg of the racemate used for adsorption experiments was dissolved in purified phenyldodecane. The adsorption experiment was carried out in the same manner as described above. 3.6. GC measurements Samples taken from adsorption experiments of the (−)-borneol/(−)-campher/(+)-fenchol system were analysed by GC on an HP 5890 (OV-1, 10 m), FID, integrator HP-3394. Samples from material imprinted with 2-(4-methoxyphenyl )-3,3dimethylbutan-1-ol were analysed on a Carlo Erba 4100/2; 521 (30 m ter. But. Beta CD/SE-54; FS 595), FID, recorder Kipp&Zonen 5 mV. 3.7. Argon physisorption studies Argon adsorption isotherms were obtained on an Omnisorb 360 (Coulter). Fig. 2 shows the isotherms obtained from a typical powder sample together with the pore-size distribution calculated from such isotherms according to the method of Horva´th and Kawazoe [33]. All materials prepared displayed type I isotherms typical for microporous materials with a narrow pore-size distribution.
4. Results and discussion The starting point of the present investigation has been severe problems encountered in the reproduction of the results achieved for the competitive adsorption of (−)-borneol and (+)-fenchol. To produce an imprinted site in a silica matrix, the sol–gel chemistry described above has been used.
Fig. 2. Typical pore-size distributions calculated according to the Horva´th–Kawazoe method for a (−)-borneol (dashed line) and a (+)-fenchol (solid line) imprinted material prepared under equal conditions. The isotherms shown as inset were measured with argon at the temperature of liquid argon. The differences between the two sorption data have no interpretable significance.
The approach is outlined in Fig. 1. In an HClcatalysed co-condensation reaction of tetraethoxysilane, methyltriethoxysilane and (−)-bornyloxytriethoxysilane or (+)-fenchyloxytriethoxysilane, respectively, a clear gel was formed. During the calcination procedure the microporous structure is formed and the imprinted molecule could be removed thermally from the cavities. Investigations of this material by temperature-dependent mass spectrometry (MS) showed desorption of unfragmented template molecules identified by the molecular ion and fragmentation pattern, indicating that at least a portion of the imprinted molecule is leaving the material undestroyed upon heating. This implies that if the former binding sites of the templates remain as cavities, these should be accessible and therefore selective adsorption should be possible. In a competitive adsorption experiment, equal amounts of (−)-borneol and (+)-fenchol and, for reference reasons, (−)-camphor were used to detect any difference in adsorption. These materials did not show selective adsorption of any of these compounds regardless of its chemical nature. The sol–gel process used here is essentially controlled by three factors: the relative amount of acid, water and alcohol, with the last factor being
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of lesser importance. A systematic investigation was carried out to examine the effects of HCl and water on the final materials. It was known that too high a concentration of an acid leads to decomposition of the modified silane and to the cleavage of its ether bond [27]. On the other hand, too low a concentration of water and HCl prevented gelation of the sol (H in Fig. 3 and Table 1). The amount of HCl was varied at two different levels, the amount of water at four different levels. For each of these eight materials a blank gel with no template, a gel with a (−)-borneol imprint and a gel with a (+)-fenchol imprint were prepared. After calcination, these gels exhibit selective adsorption of (−)-borneol and (+)-fenchol. As shown in Table 1 and Fig. 4, the adsorption found does not correlate with the template molecule used during the preparation of the gel. Apparently only the different preparation conditions resulted in these drastic selectivity changes in the adsorption experiments, emphasising the importance of Erlenmeyer’s work [9,10] on the problems associated with similarity of the adsorbents. For the preparation of all gels the same ratio of tetraethoxysilane and methyltriethoxysilane was used. So, in all the calcined gels, the amount of methyl groups was identical. The methyl groups increase the
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hydrophobicity of the material which is necessary to achieve a significant adsorption of a non-polar material such as borneol, fenchol or camphor. The amount of methyl groups was not varied so the hydrophobicity of the samples did not change. The hydrophobicity index, HI, the quotient of the amount of octane over the amount of water adsorbed by the sample, is – within experimental error – identical for all the samples, indicating that imprinting does not influence the hydrophobic properties of the material. So the different adsorption properties cannot be associated with differences in surface polarity. Apparently it is possible to produce silica materials capable of adsorbing selectively (−)-borneol or (+)-fenchol. A comparison of gels produced with the same amounts of water and HCl shows clearly that the adsorption properties of these gels are much more similar than of gels where the same molecule for imprinting was used. It is interesting to note that some gels exhibit a specific adsorption of (−)-borneol while others adsorb (+)-fenchol selectively. The adsorption difference is highest for gels with high amounts of HCl and high amounts of water. These gels (e.g., A, B and E ) adsorb preferentially (−)-borneol. Gels with a low amount of HCl and water show only a small difference for
Fig. 3. Display of the sol parameters varied in the preparation of the imprint materials.
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Fig. 4. Adsorption properties of imprinted materials (‘‘gels’’) prepared with different imprint molecules under different conditions. It is clearly visible that gels which have different imprints but were prepared under similar conditions are more similar than those imprinted with the same molecule.
the adsorption: these gels adsorb mainly (+)-fenchol (e.g., D and G). There are no gels that adsorb selectively (−)-camphor in competition with the two alcohols. Fig. 2 shows the adsorption isotherms and pore-size distributions of gels A-1
and A-2. The pore-size distribution is narrow with the maximum for both materials at the same position of 0.8 nm. The adsorption selectivity observed must be attributed to differences in the surface of the gels
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caused by the different amounts of HCl and water used. Apparently, larger amounts of the gelation catalyst HCl result in a more selective surface (compare A, B and C with E, F and G in Fig. 4), while the decreasing amount of water (AD and EH ) has little effect on selectivity. Significant are the experiments with understoichiometric amounts of water (D, G and H ), which show very poor selective adsorption, and gelation either takes a very long time or did not happen in the case of H1-3. With these gels water must have been consumed from the air to complete the hydrolysis. Since the HIs of all materials are similar, no good explanation for these significant changes in adsorption behaviour of all calcined gels can be given at this time. To obtain information on the mobility of the template molecule in the gel and the covalent bond of the template to the pore-wall silica atoms, another set of gels was prepared. Because of the limited sensitivity of solid-state 13C-NMR, the amount of template in the gels was increased to 5% (−)-borneol groups together with 20% methyl groups, which served as internal reference. The use of the Me–Si groups as internal standard is beneficial, because they are not affected by a calcination procedure (as long as the calcination temperature does not exceed 400°C ). It therefore becomes possible to estimate the amount of template remaining in the material after calcination. We investigated first an uncalcined gel (I ), a gel calcined at 130°C (II ) as well as a gel calcined at 250°C (III ). The 13C-CP/MAS NMR spectra are shown in Fig. 5. In the uncalcined gel the (−)-borneol can clearly be identified. With increasing calcination temperature the line width of all signals in the spectra increases. In the uncalcined gel (I ) the line width of resonances of silica bound to methyl groups is around 170 Hz, in gel (II ) it is 250 Hz and in gel (III ) it rises to 320 Hz. This can be explained by the increasing rigidity of the matrix material due to increased crosslinking with increasing temperature, which limits the movement of the (−)-borneol group. Clearly, calcination does not remove all the imprint molecules. All materials still contain most of the template molecule as well as ethanol and ethoxy groups. This shows that it is impossible to remove the imprint molecule only
399
Fig. 5. 13C-CP/MAS NMR spectra of gels prepared from 75% ( EtO) Si+20% MeSi(OEt) +5% (−)-bornyloxytriethoxy4 3 silane. The three samples were calcined under different conditions: (a) gel (I ), non-calcined; (b) gel (II ), calcined at 130°C; and (c) gel (III ), calcined at 250°C. All spectra are taken under the same conditions with nearly the same number of scans (NS#7300). It is clearly visible that it is not possible to remove the imprint molecule by calcination.
by a calcination process. In previous experiments temperature-programmed MS [26 ] was used to detect upon heating the qualitative desorption of unfragmented (−)-borneol. Since MS is extremely sensitive this might just have been traces. On the other hand, the calcination process is necessary in order to form the three-dimensional network and
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the microporosity. This led us to the conclusion that, after calcination, the imprint molecule has to be removed by another process, such as extraction or oxidative extraction. For an oxidative extraction procedure a mixture of H O and i-propanol was 2 2 heated with the imprint material for 24 h, then dried and calcined at 250°C. The 13C-CP/MAS NMR spectra are shown in Fig. 6. Only traces of (−)-borneol groups were left in the gel (IV ) dried at room temperature prior to extraction, as well as in the gel ( V ) calcined at 130°C prior to extraction. Only the third gel ( VI ), which was calcined to 250°C (prior to extraction) and in which the microporous structure was formed prior to extraction, still contains (−)-borneol groups corresponding to the internal standard, but to a far lesser extent than prior to the oxidative extraction procedure. The fact that even under harsher conditions not all of the (−)-borneol groups could be removed indicates that some of the (−)-borneol groups in the rigid polymeric network are not accessible to the oxidising agent H O , most likely 2 2 encapsulated in the material. Different approaches such as repetitive extractions with i-propanol have been tried, but the H O treatment was most 2 2 effective for the removal of (−)-borneol. It is also possible to remove partially the (−)-borneol groups by extraction in a Soxhlet apparatus with i-propanol. The removal of the template molecule was most effective in the materials calcined at temperatures up to 130°C prior to the extraction. However, template removal was less effective than with the oxidative treatment described above. Nevertheless, after this nondestructive removal of most of the (−)-borneol molecules groups through the pores, the remaining imprint material should have empty cavities accessible to (−)-borneol groups from a solution. These sites should exhibit selective adsorption. However, no indication of correct adsorption selectivity could be obtained. It seems to be impossible to unambiguously prove an imprint effect by competitive adsorption of two different molecules. To overcome the problem of adsorption differences of different compounds, a chiral molecule was designed to suit the needs. The molecule should exhibit a distinct three-dimensional chirality. The chiral centre should be close to the anchor-
2. Extraction with i-propanol 3. DT=250°C
ppm Fig. 6. 13C-CP/MAS-NMR spectra of gels (I )–(III ) after oxidative treatment with a mixture of H O and i-propanol followed 2 2 by calcination at 250°C: (a) gel (IV ) starting from gel (I ); (b) gel ( V ) starting from gel (II ); and (c) gel ( VI ) starting from gel (III ).
ing OH group. The molecule should also have a second polar group to allow specific interactions with altogether two points in the pore or cavity wall via hydrogen bonds or polar interactions. The molecule has to be small enough to be transported through the pores to the site of selective adsorption. The molecule chosen was 2-(4-methoxy-
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phenyl )-3,3-dimethylbutan-1-ol (1), shown in Fig. 7. Another important consideration is that, by hydrolytic cleavage, the C–O–Si bond is replaced with a C–OH and a HO–Si bond. This means that, for adsorption, the actual distance between the carbon and the silicon atom will be longer than in the case of the template itself. This effect could result in poor adsorption on the selective site. Therefore, the molecule to be used for selective adsorption was 1-(4-methoxy-phenyl )2,2-dimethylpropan-1-ol (2), which contains one CH group less than the imprint molecule. This 2 should result in a more correct distance for selective adsorption ( Fig. 7). The chiral alcohols 1 and 2 were synthesised as described in Section 3. At first 1-(4-methoxyphenyl )-2,2-dimethyl-propan-1-one was prepared by Friedel–Crafts acylation from anisole and dimethylpropionyl chloride with AlCl as catalyst. 3 This ketone was reduced to provide the racemic alcohol 2. For imprinting, an additional CH group 2 between the C–OH bond was introduced. This was accomplished with the ketone as starting material by a Wittig reaction with triphenylphospho-
401
nium bromide and n-butyllithium in ether to give 2-(4-methoxyphenyl )-3,3-dimethylbut-1-ene. Via hydroboration with boron trifluoride diethyletherate and NaBH in diglyme, the racemic alcohol 4 2-(4-methoxyphenyl )-3,3-dimethylbutan-1-ol was produced. To resolve the racemic mixture the alcohol was converted to diastereoisomers with camphanoyl chloride in pyridine. The diastereomeric mixture was resolved by HPLC to give the diastereomers with a purity of over 96%. The diastereomers were then converted back to the two enantiomerically pure esters of 1 (no absolute assignment of the stereochemistry was obtained). The comonomer for the sol–gel process was formed by hydrolysis of one of the enantiomerically pure ester and then converted to the desired enantiomerically pure silane 3 with chlorotriethoxysilane and pyridine in n-heptane (Fig. 7). With 3 as comonomer, gels were prepared using the optimised amount of water and HCl which gave the compound adsorption difference between (−)-borneol and (+)-fenchol. For this gel the amount of comonomer was reduced to a percentage of 0.8% which corresponds to a ratio of 123
Reduction
-HCl
Fig. 7. Molecules chosen for chiral imprinting and their basic preparation route.
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formal SiO units to one imprint molecule. The 2 lower concentration should help to avoid coagulation of imprint molecules which could result in poor adsorption properties. As solvent for the competitive adsorption, dodecylbenzene was used in the same way as in former experiments. This non-polar solvent molecule is too big to enter the pores so that only the racemic mixture of 2 is small enough to enter the pores. This prevents solvent molecules from blocking active sites. A blank gel containing no comonomer was produced for reference purposes. For the adsorption experiments, gels were prepared with the enantiomerically pure compound 3 as comonomer in the sol–gel process with TEOS. After calcination at 250°C adsorption experiments with the racemic compound 2 were carried out. These gels did not show any enantiomeric enrichment of the solution. By the use of enantiomerically pure (+)-1-phenylethanol it was tested whether these gels show acidic properties after calcination which could cause racemisation at the chiral centres, leading to wrong conclusions concerning enantiomeric enrichment in solution. It was found that, indeed, there were acidic sites in the gel capable of racemising the pure (+)1-phenylethanol within 24 h to the racemic mixture. Therefore, the original compound 2 could not be used for the adsorption experiments but compound 1 had to be used. To completely remove the imprinted molecule and to avoid any possible misinterpretation, which could be caused by the chiral 1 leaching into solution, these gels were extracted oxidatively after calcination to 250°C. For adsorption experiments a solution of the racemic compound 1 in phenyldodecane was used, but again no trace of enrichment of one of the enantiomers in the solution was detectable.
effect observed with competitive adsorption of the mixture of (−)-borneol, (+)-fenchol and (−)-camphor is therefore most likely a surface effect and not an imprint effect. Such selective adsorptions of structurally similar molecules was avoided by the selective adsorption of one enantiomer from a racemic mixture on a silica imprinted with the associated chiral template. However, with the racemic mixture of compound 1 no selective adsorption was detectable. This leads to the conclusion that, under the conditions we have been using for the preparation of imprinted silicas, an imprint effect either does not exist or, if so, it is too small to be detectable within the experimental error. We also have to state that, to our knowledge, none of the studies published in the area of molecular imprinting in inorganic solids has provided a rigid proof for the presence of such an imprint, nor have there been sufficient control experiments to rule out artefacts of the type we have reported here. Nevertheless, we believe that imprinting is a potentially important area of materials preparation and new approaches should be pursued. With this study we hope, by no means, to discourage other scientists who are actively involved in imprinting research. Our intention here is to outline potential pitfalls and to clarify the problems encountered with the use of sol–gel and our co-polycondensation concept for imprint generation.
Acknowledgement We acknowledge support from Katalyseverbund Nordrhein–Westfalen.
the
References 5. Conclusions Depending on the preparation conditions, microporous silica can show surprising adsorption selectivities. These selectivities are apparently not related to imprint effects and must be attributed to yet unpredictable changes in surface polarity of the final porous materials. The selective adsorption
[1] [2] [3] [4] [5] [6 ]
L. Pauling, J. Am. Chem. Soc. 62 (1940) 2643. L. Pauling, Chem. Eng. News 10 (1946) 1375. M.W. Poljakow, J. Phys. Chem. 2 (1931) 799. F.H. Dickey, Proc. Nat. Acad. Sci. 35 (1949) 227. F.H. Dickey, J. Phys. Chem. 59 (1955) 659. R. Curti, U. Colombo, F. Clerici, Gazz. Chim. Ital. 82 (1952) 491. [7] E.I. Klabunovskii, A.E. Agronomov, L.M. Volkova, A.A.
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[8] [9] [10] [11] [12] [13] [14] [15] [16 ] [17] [18] [19] [20] [21]
Balandin, Izv. Akad. Nauk SSSr, Otd. Khim. Nauk (1963) 228. E.I. Klabunovskii, A.E. Agronomov, Byul. Izobret. I Tovarnykh Znakov 16 (1963) 13. H. Erlenmeyer, H. Bartels, Helv. Chim. Acta 47 (1964) 47. H. Erlenmeyer, H. Bartels, Helv. Chim. Acta 49 (1966) 1621. R.G. Haldeman, P.H. Emmett, J. Phys. Chem. 59 (1955) 1039. G. Wulff, A. Sarhan, Angew. Chem. 84 (1972) 364. J. Steinke, D.C. Scherrington, I.R. Dunkin, Adv. Polym. Sci. 124 (1995) 81. G. Wulff, Angew. Chem. 107 (1995) 1958. H. Bartels, B. Prijs, Adv. Chromatogr. 11 (1974) 115. H. Bartels, J. Chromatogr. 30 (1967) 113. G. Wulff, T. Gross, R. Scho¨nfeld, Angew. Chem. Int. Ed. Engl. 36 (1997) 1962. K. Morihara, S. Kurihara, J. Suzuki, Bull. Chem. Soc. Jpn 61 (1988) 3991. K. Morihara, M. Kurokawa, Y. Kamata, T. Shimada, J. Chem. Soc., Chem. Commun. (1992) 358. K. Morihara, Bull. Chem. Soc. Jpn 67 (1994) 748. K. Morihara, M. Kurokawa, Y. Kamata, T. Shimada, J. Chem. Soc., Chem. Commun. (1992) 358.
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[22] G.G. Kaiser, J.T. Anderson, Fres. J. Anal. Chem. 342 (1992) 834. [23] J. Heilmann, W.F. Maier, Angew. Chem. 106 (1994) 491. [24] W.F. Maier, W. BenMustapha, Catal. Lett. 46 (1997) 137. [25] W.F. Maier, F.M. Bohnen, J. Heilmann, S. Klein, H.-C. Ko, M.F. Mark, S. Thorimbert, I. Tilgner, M. Wiedorn, in J.F. Harrod, R.M. Laine ( Eds.), Applications of Organometallic Chemistry in the Preparation and Processing of Advanced Materials, NATO ASI Series, Kluwer Academic Publishers, Dordrecht, 1995, p. 27. [26 ] F.M. Bohnen, Ph.D. thesis, Universita¨t GH Essen, Essen, 1996. [27] C. Pinel, P. Loisil, P. Gallezot, Adv. Mater. 9 (1997) 582. [28] E. Rothstein, R.W. Saville, J. Chem. Soc. (1949) 1950. [29] Autorenkollektiv, Organikum, Deutscher Verlag d. Wissenschaften, Berlin, 1990, p. 495. [30] G. Zweifel, H.C. Brown, Org. React. 13 (1963) 29. [31] E. Schenker, Neue Meth. 4 (1996) 173. [32] H.-G. Capraro, C. Ganter, Helv. Chim. Acta 63 (1980) 1347. [33] G. Horva´th, K. Kawazoe, J. Chem. Eng. Jpn 16 (1983) 470.
Selective surface adsorption versus imprinting in amorphous microporous silicas M. Hunnius, A. Rufin´ska, W.F. Maier * Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim an der Ruhr, Germany Received 25 September 1998; received in revised form 4 December 1998; accepted 4 December 1998
Abstract Selective adsorption of organic molecules on inorganic solids is an attractive property of inorganic materials. It was attempted to control molecular adsorption on inorganic surfaces by the preparation of porous silicas through a sol–gel process developed for the generation of selective adsorption sites by molecular imprinting. The materials were prepared by co-polycondensation of tetraethyl orthosilicate with R–Si(OR) , with R as a removable template. In 3 competitive adsorption experiments on such imprinted porous oxides with mixtures of (−)-borneol, (−)-camphor and (+)-fenchol, selective adsorption of individual components has been observed. Detailed control experiments, however, confirmed that the adsorption selectivity is independent of the comonomer used in the sol–gel process, but dependent on the method of preparation. Adsorption selectivities are found to be dependent on the specific pore surfaces created by different preparation procedures. No evidence was found for the presence of selective cavities due to imprint effects. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Hybrid materials; Inorganic molecular imprinting; Selective surface adsorption; Silica; Sol–gel
1. Introduction Molecular recognition is one of the basic concepts in nature. In enzymes this recognition is a prerequisite for molecules to gain access to the active site, thus enforcing the high substrate selectivities enzymes are known for. This recognition is often initiated by the lock and key mechanism first discussed by Pauling [1,2] and refined by what is termed induced fit. The generation of sites capable of molecular recognition in inorganic materials is very attractive, because such materials could be * Corresponding author. Tel: +49-208-306-2447; Fax: +49-208-306-2987. E-mail address: [email protected] ( W.F. Maier)
used for molecular separations including enantiomeric enrichments and selective sensors, as well as selective catalysts. The target is to generate structures in the form of cavities complementary to the molecule to be recognised. A simple approach to generate such a complementary cavity is molecular imprinting by the use of a removable template. Such molecular imprinting has been approached in several ways. As early as 1931, Poljakov [3] removed water from a silica gel in an atmosphere of benzene, toluene or xylene. He found that the pore structure was influenced by the size and shape of the molecules in the gas atmosphere. On a silica gel dried in a benzene atmosphere, benzene adsorbed faster than toluene or xylene. In 1949 Dickey [4,5] prepared imprinted gels from acidified
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silica solutions in the presence of methyl orange, which, after extraction, adsorbed methyl orange better than a blank gel. Curti et al. in 1952 expanded the concept of Dickey to the separation of enantiomers by imprinting silica with an enantiomer [6 ]. These authors used a silica gel that was precipitated in the presence of 4–5% of (S)-10-camphorsulfonic acid, and were able to resolve racemic camphorsulfonic acid with an ee of 30%, while with mandelic acid an ee of 10% was reached. In the early 1960s Klabunovskii et al. further expanded the concept of molecular recognition to the resolution of racemic mixtures. During the hydrolysis of alkoxysilanes, they were the first to use chiral silanes [i.e., tetra-(2-methylbutoxy) silanes] as templating agents [7]. The adsorption of racemic 2-butanol and of the pure isomer, (S)2-butanol, was measured by gravimetric adsorption [8]. In every case more of the racemic alcohol than of the (S )-2-butanol was adsorbed on all the samples, indicating that the racemic mixture is adsorbed preferentially on the silica surface. No evidence for stereospecific adsorption was obtained. Erlenmeyer and Bartels [9,10] and Haldeman and Emmett [11] repeated Dickey’s experiments and not only confirmed his observations, but carried out further investigations to support the imprint theory. Erlenmeyer’s group especially engaged in the problem of similarity. They recognised that the specificity of adsorption on imprinted silicas is not limited to the associated template, but that also other molecules of similar structure are adsorbed in preference to other molecules non-similar in structure. Another concept of molecular imprinting was first presented by Wulff and Sarhan [12] in 1972, who used an organic polymer network as matrix instead of silica. Here a template linked to a properly chosen binding site was copolymerised to give (after removal of the template) a cavity in the polymer, where several functional groups of the binding site are prearranged in a fixed position. The main difference to all former concepts is that it does not rely on the shape selectivity of the imprint cavity, but on highly specific binding sites in defined cavity positions, which allow well-
defined interactions between the reactants and several functional groups of the polymer. This area has grown rapidly [13,14] and imprinted polymers have been used successfully for selective adsorption [15,16 ], chiral recognition and an ever-increasing number of applications including selectively catalysed reactions [17]. In 1988 Morihara et al. [18–21] published the use of transition-state analogues ( TSAs) as template to form cavities with an intrinsic selective catalytic activity. Dibenzamide was used as a template to serve as a TSA for the butanolysis of benzoic anhydride. Several reports followed in which, with such ‘‘footprint catalysts’’, rate enhancements were observed [18–21]. Evidence for an imprint effect was obtained by Michaelis– Menten kinetics and inhibition of the catalysed reaction with the imprint molecule. Some of the results have been questioned by Kaiser and Anderson [22] who also chose aluminium-doped silica as catalytic material but were unable to find any catalytic effect for their desired reaction. In our studies on the preparation of new catalyst materials by the sol–gel process, we discovered that amorphous microporous oxides with a narrow pore-size distribution (0.8 nm diameter) comparable to zeolites can be obtained by careful control of the sol–gel process followed by drying and calcination. The narrow pore-size distribution was attributed to transport pores of the alcohol formed during the hydrolysis–polycondensation reactions in the sol–gel process which, after calcination, remain an integral part of the microstructure of the final material. In other words, the amorphous microstructure of the final glass remembers the kinetic diameter of the alcohol. It was rationalised then, that if this polycondensation can so precisely adopt the transport diameter of diffusing ethanol, it may also be able to remember the molecular shape of imprinted molecules and thus provide another entry to molecular imprinting in inorganic oxides. Our approach is summarised in Fig. 1. First experiments relied on imprinting of a phosphonate as transition-state analogue of the transesterification of ethyl phenylacetate with hexanol. The TSA was connected to a triethoxysilyloxy group as co-polycondensable anchor. The material showed not only a higher activity for the transester-
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391
Fig. 1. Molecules used as comonomers in the sol–gel process for imprinting purposes. Schematic description of the sol–gel process leading to imprinted porous materials.
ification reaction [23] compared with a control catalyst, but also a significantly higher selectivity, implying that the observed catalysis was the result of an imprint. However, no inhibition of the catalyst by adding the TSA to the catalytic reaction was noted [23]. Detailed investigation of the imprinted gel by 31P magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy showed that, in the untreated gel, the imprint molecule was not covalently bound to the polymer network but only physically embedded in the gel [24], which rendered the imprint hypothesis impossible. Since the initial selectivities reported were reproducible at the time, it was concluded that selective diffusion may have been responsible for the observed selectivities [24]. To prove molecular imprinting indirectly by the
effect of catalysis is more difficult than to show this effect with adsorption or even competitive adsorption, since selective catalysis exploits kinetic differences and therefore differentiation at the imprinted site must be very high. On the other hand, pore-size effects having a direct influence on diffusion constants may compensate all imprint effects, leaving the question of imprinting unanswered. With competitive adsorption this is not the case. For a competitive adsorption experiment the two components have sufficient time to diffuse through the pores and adsorb on the recognition site. By using the same approach as mentioned above, (−)-borneol was copolymerised with tetraethoxysilane and methyltriethoxysilane to give, after calcination, a microporous gel that was able to selectively adsorb the imprinted molecule,
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(−)-borneol [25,26 ]. In contrast to the initial success, these results could not be reproduced [26 ]. Pinel et al. [27] used (−)-menthol as template and did not find any enantiomeric enrichment but some regiorecognition was observed. All these results prompted a systematic investigation of the phenomena of molecular imprinting by co-polycondensation.
2. Prerequisites of imprinting Reliable evidence for successful imprinting has so far only been provided for polymeric materials. Polymeric networks are usually amorphous and the cavities are randomly distributed in the solid material, rendering characterisation of such cavities difficult. Presently there are only two possible ways to prove an imprint effect: selective catalysis and competitive adsorption. The formation of an imprint includes formally several steps: first the template molecule has to be evenly distributed in the monomer solution, so that a solid matrix can be built around each single template providing the sites of a complementary three-dimensional structure. Secondly, the template has to be removed from the matrix. Therefore, the polymeric material has to have a porous structure and the van der Waals’ or covalent bond of the template molecule to the polymer network has to be broken. The empty cavity has to be stable under adsorption or reaction conditions. Another important point is that the adsorption site must not be blocked by any other molecule that adsorbs better on a silica surface than the template molecule. Since water in particular tends to block the silica surface, traces of water should be removed from the imprint material prior to experiments and the solvent used should be chosen with care. The adsorption or the catalysed reaction must take place inside the cavity formed during the polymerisation process. This means that the matrix needs to be flexible or needs to have pores that are larger than the template or the reactants. In addition to that, the cavity itself should be fairly flexible to allow the molecules to enter or, in the case that the material is rather rigid, the imprinted site needs to have a large opening. To produce a material capable of molecu-
lar recognition, all the properties listed here should be taken into account to ensure that the material may function properly.
3. Experimental 3.1. General All chemicals were used as received from the suppliers without further purification if not stated differently. Only phenyldodecane (Aldrich) was purified by means of preparative gas chromatography (GC ). 3.2. Preparation of the imprint materials At room temperature, 9.49 ml (42.5 mmol ) of tetraethoxysilane ( TEOS) together with 1.5 ml (7.5 mmol ) of methyltriethoxysilane were stirred, while 10 ml of ethanol was added. After stirring for 15 min, 1 ml (3 mmol ) of the comonomer was added according to Table 1. Afterwards, HCl diluted in the appropriate amount of water was added as listed in Table 1 (given as equivalents relative to the amount of TEOS used). The sol usually started to gel after 3 to 4 days and was left to dry for another 3 days prior to calcination. The gels were then heated slowly from room temperature to 65°C at a rate of 0.1°C min−1. This temperature was maintained for 300 min before the temperature was increased to 250°C at the same rate of 0.1°C min−1. This temperature was kept for 300 min before the oven was allowed to cool down. The solid was then milled in a ballmill to particle sizes smaller than 200 mm. This material was used for the adsorption experiments. By means of the same method, the material containing a chiral comonomer was obtained. First, 11.7 ml (52.3 mmol ) of tetraethoxysilane together with 1.75 ml (9.2 mmol ) of methyltriethoxysilane were stirred, while 12.5 ml of ethanol was added. After stirring for 15 min, 185 mg (0.5 mmol ) of 2-(4-methoxy-phenyl )-3,3-dimethylbutan-1-yloxytriethoxysilylane was added. Afterwards, 2.25 ml of 0.4 N HCl was added. The calcination and milling processes were identical to those described above.
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Table 1 Adsorption properties and surface areas of gels co-condensed with either (−)-bornyloxytriethoxysilane, (+)-fenchyloxytriethoxysilane or without additional comonomer [(−)-camphor, control ]. The molar amounts of TEOS:water:HCl:ethanol are usually 1:2:0.35:3. The amounts of HCl and water (given in equivalents relative to the amount of TEOS ) were varied according to this table, giving different surface areas and adsorption properties Gel
A-1 A-2 A-3 B-1 B-2 B-3 C-1 C-2 C-3 D-1 D-2 D-3 E-1 E-2 E-3 F-1 F-2 F-3 G-1 G-2 G-3 H-1 H-2 H-3
Equiv. HCl
0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.26 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13
Equiv. water
14.2 14.2 14.2 6.9 6.9 6.9 3.2 3.2 3.2 1.4 1.4 1.4 6.9 6.9 6.9 3.2 3.2 3.2 1.4 1.4 1.4 0.7 0.7 0.7
Imprinting molecule
(−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none (−)-borneol (+)-fenchol none
Adsorption propertiesa
Surface area (m2 g−1)
(−)-Borneol
(+)-Fenchol
(−)-Camphor
−6 −7.8 −8 −5.3 −8.1 −6.7 0.8 1.7 −5.2 −0.4 −0.2 −0.4 −4.4 −2.5 −2.5 0.8 1 1.6 −0.1 0.2 0 no gelation
6.4 10.9 7.2 3.8 6.8 8.4 −3.7 −3.5 7.3 0.5 −0.5 0.4 1.9 2.3 2.8 −3 −2.5 −1.4 0.2 −0.4 0.2
−0.5 −3.2 0.8 1.4 1.2 −1.7 3 1.7 −2.1 −0.1 0.7 0 2.5 0.2 −0.3 2.1 1.5 −0.2 −0.3 0.3 −0.3
556.1 502.5 476.94 438.5 438.5 401.5 248.3 348.2 446.7 125.1 147 33.2 302.6 248.2 341.4 115.6 261 372.1 71.5 5.8 46.2
a Change of GC (%) compared with the standard.
3.2.1. Oxidative treatment of the imprint materials for the removal of (−)-borneol To remove the imprinted molecule, 300 mg of the gel was mixed with 7 ml of a 1:1 mixture of H O and i-propanol. The mixture was stirred and 2 2 heated to 75°C for 24 h. Afterwards, the gels were centrifuged and washed several times with i-propanol. 3.2.2. General procedure for the synthesis of organyloxytriethoxysilanes A quantity (100 mmol ) of alcohol (borneol or fenchol ) was dissolved under an argon atmosphere in 500 ml of dry pentane, the solution was cooled to −35°C and 7.91 g (8.1 ml, 100 mmol ) of dry pyridine was added slowly. The reaction mixture was cooled to −60°C and then 29.4 g (148 mmol )
of chlorotriethoxysilane was added dropwise. After the mixture reached room temperature, it was filtered under argon over a P4 frit and washed with 50 ml of pentane. Traces of the solvent were removed under reduced pressure.
3.2.2.1. (−)-Bornyloxytriethoxysilane. Yield: 28.4 g (90 mmol, 90.0%). 1H- and 13CP-NMR, infrared (IR) and elemental analyses are consistent with the proposed structure.
3.2.2.2. (+)-Fenchyloxytriethoxysilane. Yield: 29.0 g (90 mmol, 91.6%). 1H- and 13C-NMR, IR and elemental analysis are consistent with the proposed structure.
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3.2.3. 1-(4-Methoxy-phenyl)-2,2-dimethyl-propan1-one [28] Dimethylpropionyl chloride (44.8 g, 370 mmol ), dissolved in 80 ml of dry pentane, was slowly added to a stirred mixture of the catalyst AlCl 3 (74.4 g, 560 mmol ) and anisole (80 g, 740 mmol ) in 400 ml of pentane, which was cooled with ice. After 45 min of stirring the reaction mixture reached room temperature and was poured onto 400 ml of ice. The resulting pink complex was destroyed by the addition of hydrochloric acid. The water phase was washed three times with pentane. The combined organic phases were dried over MgSO , filtered and the pentane was removed 4 under vacuum. The 1-(4-methoxy-phenyl )-2,2dimethyl-propan-1-one was further purified by distillation (T =72°C at p=0.002 mbar). s Yield: 54.1 g (276 mmol, 74.6%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.4. 1-(4-Methoxy-phenyl)-2,2-dimethyl-propan1-ol [29] At 0°C, 9.55 g (50 mol ) of 1-(4-methoxyphenyl )-2,2-dimethyl-propan-1-one was added to a solution of 0.756 g (20 mmol ) of sodium borohydride which was dissolved in a mixture of isopropanol and 10 ml of water. The reaction was stopped after 15 min by the addition of acetone (250 ml ). While the flask reached room temperature, the solution was well stirred. It was then washed with a saturated solution of NaHCO and 3 extracted three times with ether. The combined organic phases were dried over Na SO , filtered 2 4 and the solvent was removed under vacuum. Yield: 7.9 g (41.2 mmol, 82.4%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.5. 2-(4-Methoxy-phenyl)-3,3-dimethyl-but1-ene Triphenylmethylphosphonium bromide (171.6 g, 160 mmol ) was suspended in 800 ml of ether. Next, 30.72 g (480 mmol ) of n-butyllithium in 300 ml pentane (1.6 M ) was added to this solution. The mixture was stirred overnight before 23.04 g of 1-(4-methoxy-phenyl )-2,2-dimethyl-propan-1-one was added slowly. After stirring for 1 h at room
temperature, the mixture was refluxed at 60°C for 6 h. For the work-up the mixture was poured into 2000 ml of water and extracted three times with ether. The combined organic phases were dried over Na SO , filtered and the solvent was removed 2 4 under vacuum. Besides the desired product, the reaction mixture contains phosphine oxide as well. Via distillation (0.005 mbar, 52°C ), the product was purified. Yield: 16.3 g (85.6 mmol, 71.4%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. 3.2.6. 2-(4-Methoxy-phenyl)-3,3-dimethyl-butan1-ol [30,31] To 27.9 g (148.8 mmol ) of 2-(4-methoxyphenyl )-3,3-dimethyl-but-1-ene dissolved in 85 ml of diglyme in a flask equipped with a condenser, 2.418 g (63.9 mmol ) of NaBH was added under 4 argon. Using a dropping funnel, 10.27 ml (11.5 g, 81.4 mmol ) of boron trifluoride diethyletherate were added over 30 min while the reaction mixture was kept at room temperature. The excess of NaBH was destroyed by the addition of 20 ml 4 water. By the addition of 16.5 ml of 3 N NaOH, followed by the dropwise addition of 16.5 ml of H O (30%), the organoborane was oxidised. Prior 2 2 to extraction with ether the mixture was stirred for another hour. The organic phase was extracted five times with water to remove the diglyme. The organic phases were dried over MgSO , filtered 4 and the solvent was removed under vacuum. Yield: 21.4 g (102.9 mmol, 69.2%). 1H- and 13C-NMR, IR and elemental analysis are consistent with the proposed structure. 3.2.7. (R)-3-Oxo-4,4,7-trimethyl2-oxabicyclo[2.2.1]heptan-1-carboxylic acid2-(4-methoxy-phenyl)-3,3-dimethylbutylester [32] To a solution of 20 g (96 mmol ) of the racemic alcohol (±)2-(4-methoxy-phenyl )-3,3-dimethylbutan-1-ol in 300 ml pyridine at 0°C, 22.8 g (105.7 mmol, 10% excess) of (−)-camphanoyl chloride was added. To dilute further, 150 ml of pyridine was added. After the solution was stirred for 19 h at room temperature, CH Cl was added and 2 2 the organic layer was first washed with cold 2 N hydrochloric acid and then with NaHCO solution. 3
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After removal of the solvent, a white powder was obtained. Yield: 34.8 g (89.8 mmol, 93.5%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure. The diastereomers containing about 4.5% of the starting material have been separated by preparative high-performance liquid chromatography (HPLC ); 26.8 g of the mixture of diastereomers was separated. The first diastereomer was isolated with a purity of over 96% (8.1 g, yield 64%). For the other diastereomer 8.5 g of the same purity was obtained, corresponding to a yield of 69%.
3.2.8. Enantiomerically pure 2-(4-methoxyphenyl)-3,3-dimethyl-butan-1-ol by ester hydrolysis A quantity (50 ml ) of 2 N KOH was added to a solution of 1440.0 mg (2.7 mmol ) of one of the diastereomers of (R)-3-oxo-4,4,7-trimethyl2-oxabicyclo[2.2.1]heptan-1-carboxylic acid2-(4-methoxy-phenyl )-3,3-dimethylbutylester, obtained from HPLC separation, in 120 ml of ethanol. After 24 h of refluxing (T~100°C ) the mixture was allowed to cool down. The alcohol was evaporated at reduced pressure and the water phase was extracted with ether. Afterwards, the ether was removed under vacuum. Yield: 0.499 g (2.4 mmol, 89.1%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure.
3.2.9. 2-(4-Methoxy-phenyl)-3,3-dimethyl-butan1-yloxytriethoxy silane 2-(4-Methoxy-phenyl )-3,3-dimethyl-butan-1-ol (2.15 g, 10.3 mmol ) was dissolved in 400 ml of dry heptane under an argon atmosphere, cooled to −5°C and then 3.05 g (15.5 mmol ) of chlorotriethoxysilane in 5 ml of heptane was added dropwise. Afterwards, 8.26 ml (10.3 mmol ) of dry pyridine in 5 ml of dry heptane was added. The solution was allowed to warm to room temperature and was then stirred for 15 h before the reaction mixture was filtered under argon over a P4 frit. The precipitate was washed with 50 ml of heptane and dried under reduced pressure to remove traces of the solvent.
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Yield: 3.2 g (8.7 mmol, 85.0%). 1H- and 13CNMR, IR and elemental analysis are consistent with the proposed structure.
3.3. HPLC 3.3.1. Analysis conditions Apparatus: Column: Temperature: Mobile phase: Flow: Pressure: Detection:
DuPont 8800, Shimadzu SpD-6A 250 mm LiChrospher Si100, 4.5 mm diameter, D494 35°C hexane/2-propanol=99/1 (v/v) 1.0 ml min−1 2.4 MPa UV, 220 nm, E=16
3.3.2. Preparative HPLC separation Apparatus: Column: Stationary phase: Temperature: Mobile phase: Flow: Pressure: Detection:
Shimadzu LC-8A Gradientensystem 230 mm×36 mm Bu¨chiColumn LiChroprep Si 100, 25–40 mm, Charge 730F852704 room temperature dichloromethane (water-saturated ) 35 ml min−1 1.8 MPa UV, 220 nm, E=1.28
3.4. 13C cross-polarisation (CP)/MAS NMR studies Solid-state 13C CP/MAS NMR spectra were recorded on a Bruker MSL-300 spectrometer, equipped with a double-bearing probe. The ZrO rotor 2 (7 mm internal diameter) was charged with the samples and sealed by a Kel-F inset. The optimal contact time for 13C cross-polarisation was 2–3 ms. The spinning rate was between 2 and 5 kHz. The external standard for 13C NMR was adamantane [d(CH )=38.40, relative to tetramethylsilane]. 2
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3.5. Adsorption experiments For competitive adsorption experiments of (−)-borneol, (−)-camphor and (+)-fenchol, 10 mg of each compound was dissolved in 10 ml of phenyldodecane. For the adsorption experiment 2 ml of the solution was stirred together with 200 mg of the imprinted material for 24 h. Afterwards, samples were taken and analysed by GC. For competitive adsorption measurements of silica imprinted with 2-(4-methoxyphenyl )-3,3dimethylbutan-1-ol, 20 mg of the racemate used for adsorption experiments was dissolved in purified phenyldodecane. The adsorption experiment was carried out in the same manner as described above. 3.6. GC measurements Samples taken from adsorption experiments of the (−)-borneol/(−)-campher/(+)-fenchol system were analysed by GC on an HP 5890 (OV-1, 10 m), FID, integrator HP-3394. Samples from material imprinted with 2-(4-methoxyphenyl )-3,3dimethylbutan-1-ol were analysed on a Carlo Erba 4100/2; 521 (30 m ter. But. Beta CD/SE-54; FS 595), FID, recorder Kipp&Zonen 5 mV. 3.7. Argon physisorption studies Argon adsorption isotherms were obtained on an Omnisorb 360 (Coulter). Fig. 2 shows the isotherms obtained from a typical powder sample together with the pore-size distribution calculated from such isotherms according to the method of Horva´th and Kawazoe [33]. All materials prepared displayed type I isotherms typical for microporous materials with a narrow pore-size distribution.
4. Results and discussion The starting point of the present investigation has been severe problems encountered in the reproduction of the results achieved for the competitive adsorption of (−)-borneol and (+)-fenchol. To produce an imprinted site in a silica matrix, the sol–gel chemistry described above has been used.
Fig. 2. Typical pore-size distributions calculated according to the Horva´th–Kawazoe method for a (−)-borneol (dashed line) and a (+)-fenchol (solid line) imprinted material prepared under equal conditions. The isotherms shown as inset were measured with argon at the temperature of liquid argon. The differences between the two sorption data have no interpretable significance.
The approach is outlined in Fig. 1. In an HClcatalysed co-condensation reaction of tetraethoxysilane, methyltriethoxysilane and (−)-bornyloxytriethoxysilane or (+)-fenchyloxytriethoxysilane, respectively, a clear gel was formed. During the calcination procedure the microporous structure is formed and the imprinted molecule could be removed thermally from the cavities. Investigations of this material by temperature-dependent mass spectrometry (MS) showed desorption of unfragmented template molecules identified by the molecular ion and fragmentation pattern, indicating that at least a portion of the imprinted molecule is leaving the material undestroyed upon heating. This implies that if the former binding sites of the templates remain as cavities, these should be accessible and therefore selective adsorption should be possible. In a competitive adsorption experiment, equal amounts of (−)-borneol and (+)-fenchol and, for reference reasons, (−)-camphor were used to detect any difference in adsorption. These materials did not show selective adsorption of any of these compounds regardless of its chemical nature. The sol–gel process used here is essentially controlled by three factors: the relative amount of acid, water and alcohol, with the last factor being
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of lesser importance. A systematic investigation was carried out to examine the effects of HCl and water on the final materials. It was known that too high a concentration of an acid leads to decomposition of the modified silane and to the cleavage of its ether bond [27]. On the other hand, too low a concentration of water and HCl prevented gelation of the sol (H in Fig. 3 and Table 1). The amount of HCl was varied at two different levels, the amount of water at four different levels. For each of these eight materials a blank gel with no template, a gel with a (−)-borneol imprint and a gel with a (+)-fenchol imprint were prepared. After calcination, these gels exhibit selective adsorption of (−)-borneol and (+)-fenchol. As shown in Table 1 and Fig. 4, the adsorption found does not correlate with the template molecule used during the preparation of the gel. Apparently only the different preparation conditions resulted in these drastic selectivity changes in the adsorption experiments, emphasising the importance of Erlenmeyer’s work [9,10] on the problems associated with similarity of the adsorbents. For the preparation of all gels the same ratio of tetraethoxysilane and methyltriethoxysilane was used. So, in all the calcined gels, the amount of methyl groups was identical. The methyl groups increase the
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hydrophobicity of the material which is necessary to achieve a significant adsorption of a non-polar material such as borneol, fenchol or camphor. The amount of methyl groups was not varied so the hydrophobicity of the samples did not change. The hydrophobicity index, HI, the quotient of the amount of octane over the amount of water adsorbed by the sample, is – within experimental error – identical for all the samples, indicating that imprinting does not influence the hydrophobic properties of the material. So the different adsorption properties cannot be associated with differences in surface polarity. Apparently it is possible to produce silica materials capable of adsorbing selectively (−)-borneol or (+)-fenchol. A comparison of gels produced with the same amounts of water and HCl shows clearly that the adsorption properties of these gels are much more similar than of gels where the same molecule for imprinting was used. It is interesting to note that some gels exhibit a specific adsorption of (−)-borneol while others adsorb (+)-fenchol selectively. The adsorption difference is highest for gels with high amounts of HCl and high amounts of water. These gels (e.g., A, B and E ) adsorb preferentially (−)-borneol. Gels with a low amount of HCl and water show only a small difference for
Fig. 3. Display of the sol parameters varied in the preparation of the imprint materials.
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Fig. 4. Adsorption properties of imprinted materials (‘‘gels’’) prepared with different imprint molecules under different conditions. It is clearly visible that gels which have different imprints but were prepared under similar conditions are more similar than those imprinted with the same molecule.
the adsorption: these gels adsorb mainly (+)-fenchol (e.g., D and G). There are no gels that adsorb selectively (−)-camphor in competition with the two alcohols. Fig. 2 shows the adsorption isotherms and pore-size distributions of gels A-1
and A-2. The pore-size distribution is narrow with the maximum for both materials at the same position of 0.8 nm. The adsorption selectivity observed must be attributed to differences in the surface of the gels
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caused by the different amounts of HCl and water used. Apparently, larger amounts of the gelation catalyst HCl result in a more selective surface (compare A, B and C with E, F and G in Fig. 4), while the decreasing amount of water (AD and EH ) has little effect on selectivity. Significant are the experiments with understoichiometric amounts of water (D, G and H ), which show very poor selective adsorption, and gelation either takes a very long time or did not happen in the case of H1-3. With these gels water must have been consumed from the air to complete the hydrolysis. Since the HIs of all materials are similar, no good explanation for these significant changes in adsorption behaviour of all calcined gels can be given at this time. To obtain information on the mobility of the template molecule in the gel and the covalent bond of the template to the pore-wall silica atoms, another set of gels was prepared. Because of the limited sensitivity of solid-state 13C-NMR, the amount of template in the gels was increased to 5% (−)-borneol groups together with 20% methyl groups, which served as internal reference. The use of the Me–Si groups as internal standard is beneficial, because they are not affected by a calcination procedure (as long as the calcination temperature does not exceed 400°C ). It therefore becomes possible to estimate the amount of template remaining in the material after calcination. We investigated first an uncalcined gel (I ), a gel calcined at 130°C (II ) as well as a gel calcined at 250°C (III ). The 13C-CP/MAS NMR spectra are shown in Fig. 5. In the uncalcined gel the (−)-borneol can clearly be identified. With increasing calcination temperature the line width of all signals in the spectra increases. In the uncalcined gel (I ) the line width of resonances of silica bound to methyl groups is around 170 Hz, in gel (II ) it is 250 Hz and in gel (III ) it rises to 320 Hz. This can be explained by the increasing rigidity of the matrix material due to increased crosslinking with increasing temperature, which limits the movement of the (−)-borneol group. Clearly, calcination does not remove all the imprint molecules. All materials still contain most of the template molecule as well as ethanol and ethoxy groups. This shows that it is impossible to remove the imprint molecule only
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Fig. 5. 13C-CP/MAS NMR spectra of gels prepared from 75% ( EtO) Si+20% MeSi(OEt) +5% (−)-bornyloxytriethoxy4 3 silane. The three samples were calcined under different conditions: (a) gel (I ), non-calcined; (b) gel (II ), calcined at 130°C; and (c) gel (III ), calcined at 250°C. All spectra are taken under the same conditions with nearly the same number of scans (NS#7300). It is clearly visible that it is not possible to remove the imprint molecule by calcination.
by a calcination process. In previous experiments temperature-programmed MS [26 ] was used to detect upon heating the qualitative desorption of unfragmented (−)-borneol. Since MS is extremely sensitive this might just have been traces. On the other hand, the calcination process is necessary in order to form the three-dimensional network and
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the microporosity. This led us to the conclusion that, after calcination, the imprint molecule has to be removed by another process, such as extraction or oxidative extraction. For an oxidative extraction procedure a mixture of H O and i-propanol was 2 2 heated with the imprint material for 24 h, then dried and calcined at 250°C. The 13C-CP/MAS NMR spectra are shown in Fig. 6. Only traces of (−)-borneol groups were left in the gel (IV ) dried at room temperature prior to extraction, as well as in the gel ( V ) calcined at 130°C prior to extraction. Only the third gel ( VI ), which was calcined to 250°C (prior to extraction) and in which the microporous structure was formed prior to extraction, still contains (−)-borneol groups corresponding to the internal standard, but to a far lesser extent than prior to the oxidative extraction procedure. The fact that even under harsher conditions not all of the (−)-borneol groups could be removed indicates that some of the (−)-borneol groups in the rigid polymeric network are not accessible to the oxidising agent H O , most likely 2 2 encapsulated in the material. Different approaches such as repetitive extractions with i-propanol have been tried, but the H O treatment was most 2 2 effective for the removal of (−)-borneol. It is also possible to remove partially the (−)-borneol groups by extraction in a Soxhlet apparatus with i-propanol. The removal of the template molecule was most effective in the materials calcined at temperatures up to 130°C prior to the extraction. However, template removal was less effective than with the oxidative treatment described above. Nevertheless, after this nondestructive removal of most of the (−)-borneol molecules groups through the pores, the remaining imprint material should have empty cavities accessible to (−)-borneol groups from a solution. These sites should exhibit selective adsorption. However, no indication of correct adsorption selectivity could be obtained. It seems to be impossible to unambiguously prove an imprint effect by competitive adsorption of two different molecules. To overcome the problem of adsorption differences of different compounds, a chiral molecule was designed to suit the needs. The molecule should exhibit a distinct three-dimensional chirality. The chiral centre should be close to the anchor-
2. Extraction with i-propanol 3. DT=250°C
ppm Fig. 6. 13C-CP/MAS-NMR spectra of gels (I )–(III ) after oxidative treatment with a mixture of H O and i-propanol followed 2 2 by calcination at 250°C: (a) gel (IV ) starting from gel (I ); (b) gel ( V ) starting from gel (II ); and (c) gel ( VI ) starting from gel (III ).
ing OH group. The molecule should also have a second polar group to allow specific interactions with altogether two points in the pore or cavity wall via hydrogen bonds or polar interactions. The molecule has to be small enough to be transported through the pores to the site of selective adsorption. The molecule chosen was 2-(4-methoxy-
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phenyl )-3,3-dimethylbutan-1-ol (1), shown in Fig. 7. Another important consideration is that, by hydrolytic cleavage, the C–O–Si bond is replaced with a C–OH and a HO–Si bond. This means that, for adsorption, the actual distance between the carbon and the silicon atom will be longer than in the case of the template itself. This effect could result in poor adsorption on the selective site. Therefore, the molecule to be used for selective adsorption was 1-(4-methoxy-phenyl )2,2-dimethylpropan-1-ol (2), which contains one CH group less than the imprint molecule. This 2 should result in a more correct distance for selective adsorption ( Fig. 7). The chiral alcohols 1 and 2 were synthesised as described in Section 3. At first 1-(4-methoxyphenyl )-2,2-dimethyl-propan-1-one was prepared by Friedel–Crafts acylation from anisole and dimethylpropionyl chloride with AlCl as catalyst. 3 This ketone was reduced to provide the racemic alcohol 2. For imprinting, an additional CH group 2 between the C–OH bond was introduced. This was accomplished with the ketone as starting material by a Wittig reaction with triphenylphospho-
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nium bromide and n-butyllithium in ether to give 2-(4-methoxyphenyl )-3,3-dimethylbut-1-ene. Via hydroboration with boron trifluoride diethyletherate and NaBH in diglyme, the racemic alcohol 4 2-(4-methoxyphenyl )-3,3-dimethylbutan-1-ol was produced. To resolve the racemic mixture the alcohol was converted to diastereoisomers with camphanoyl chloride in pyridine. The diastereomeric mixture was resolved by HPLC to give the diastereomers with a purity of over 96%. The diastereomers were then converted back to the two enantiomerically pure esters of 1 (no absolute assignment of the stereochemistry was obtained). The comonomer for the sol–gel process was formed by hydrolysis of one of the enantiomerically pure ester and then converted to the desired enantiomerically pure silane 3 with chlorotriethoxysilane and pyridine in n-heptane (Fig. 7). With 3 as comonomer, gels were prepared using the optimised amount of water and HCl which gave the compound adsorption difference between (−)-borneol and (+)-fenchol. For this gel the amount of comonomer was reduced to a percentage of 0.8% which corresponds to a ratio of 123
Reduction
-HCl
Fig. 7. Molecules chosen for chiral imprinting and their basic preparation route.
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formal SiO units to one imprint molecule. The 2 lower concentration should help to avoid coagulation of imprint molecules which could result in poor adsorption properties. As solvent for the competitive adsorption, dodecylbenzene was used in the same way as in former experiments. This non-polar solvent molecule is too big to enter the pores so that only the racemic mixture of 2 is small enough to enter the pores. This prevents solvent molecules from blocking active sites. A blank gel containing no comonomer was produced for reference purposes. For the adsorption experiments, gels were prepared with the enantiomerically pure compound 3 as comonomer in the sol–gel process with TEOS. After calcination at 250°C adsorption experiments with the racemic compound 2 were carried out. These gels did not show any enantiomeric enrichment of the solution. By the use of enantiomerically pure (+)-1-phenylethanol it was tested whether these gels show acidic properties after calcination which could cause racemisation at the chiral centres, leading to wrong conclusions concerning enantiomeric enrichment in solution. It was found that, indeed, there were acidic sites in the gel capable of racemising the pure (+)1-phenylethanol within 24 h to the racemic mixture. Therefore, the original compound 2 could not be used for the adsorption experiments but compound 1 had to be used. To completely remove the imprinted molecule and to avoid any possible misinterpretation, which could be caused by the chiral 1 leaching into solution, these gels were extracted oxidatively after calcination to 250°C. For adsorption experiments a solution of the racemic compound 1 in phenyldodecane was used, but again no trace of enrichment of one of the enantiomers in the solution was detectable.
effect observed with competitive adsorption of the mixture of (−)-borneol, (+)-fenchol and (−)-camphor is therefore most likely a surface effect and not an imprint effect. Such selective adsorptions of structurally similar molecules was avoided by the selective adsorption of one enantiomer from a racemic mixture on a silica imprinted with the associated chiral template. However, with the racemic mixture of compound 1 no selective adsorption was detectable. This leads to the conclusion that, under the conditions we have been using for the preparation of imprinted silicas, an imprint effect either does not exist or, if so, it is too small to be detectable within the experimental error. We also have to state that, to our knowledge, none of the studies published in the area of molecular imprinting in inorganic solids has provided a rigid proof for the presence of such an imprint, nor have there been sufficient control experiments to rule out artefacts of the type we have reported here. Nevertheless, we believe that imprinting is a potentially important area of materials preparation and new approaches should be pursued. With this study we hope, by no means, to discourage other scientists who are actively involved in imprinting research. Our intention here is to outline potential pitfalls and to clarify the problems encountered with the use of sol–gel and our co-polycondensation concept for imprint generation.
Acknowledgement We acknowledge support from Katalyseverbund Nordrhein–Westfalen.
the
References 5. Conclusions Depending on the preparation conditions, microporous silica can show surprising adsorption selectivities. These selectivities are apparently not related to imprint effects and must be attributed to yet unpredictable changes in surface polarity of the final porous materials. The selective adsorption
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