In this study, an E2-based imprinted inorganic-organic hybrid, which exhibited high adsorption and recognition capability, was successfully fabricated by using a polymerization process followed by a sol-gel processes. While methyl methacrylate (MMA) was used to create a hydrophobic imprinted environment, methacrylic acid (MAA) and styrene were used as the functional monomers to interact with the target (E2) by hydrogen bonding and π-π interaction, respectively. Tetraethyl orthosilicate (TEOS) was used as the precursor for silica source and 3-(methacryloyloxy) propyl trimethoxysilane (MPS) was used as the coupling agent. The MMA-based molecularly imprinted hybrid (MIH) showed the highest E2 adsorption, followed by the styrene-based and the MAA-based MIHs, indicating hydrophobic environmental exhibit higher affinity toward E2. Introduction of styrene and MAA into the poly-MMA chains greatly enhanced the adsorption ability. The optimal molar ratio of E2/styrene/MAA/MMA/TEOS/MPS was 1/1/1/5/5/15, at which the adsorption capacity reached 35.08 mg/g. Relative to the adsorption ability for the estrone, estriol, and bisphenol A, the MIH showed respectively 1.08, 5.17, 5.9 times higher adsorption ability for E2. After six (6) times of adsorption-desorption cycles, the MIH still exhibited stable adsorptions with a small standard deviation of 4%.

In this study, an E2-based imprinted inorganic-organic hybrid, which exhibited high adsorption and recognition capability, was successfully fabricated by using a polymerization process followed by a sol-gel processes. While methyl methacrylate (MMA) was used to create a hydrophobic imprinted environment, methacrylic acid (MAA) and styrene were used as the functional monomers to interact with the target (E2) by hydrogen bonding and π-π interaction, respectively. Tetraethyl orthosilicate (TEOS) was used as the precursor for silica source and 3-(methacryloyloxy) propyl trimethoxysilane (MPS) was used as the coupling agent. The MMA-based molecularly imprinted hybrid (MIH) showed the highest E2 adsorption, followed by the styrene-based and the MAA-based MIHs, indicating hydrophobic environmental exhibit higher affinity toward E2. Introduction of styrene and MAA into the poly-MMA chains greatly enhanced the adsorption ability. The optimal molar ratio of E2/styrene/MAA/MMA/TEOS/MPS was 1/1/1/5/5/15, at which the adsorption capacity reached 35.08 mg/g. Relative to the adsorption ability for the estrone, estriol, and bisphenol A, the MIH showed respectively 1.08, 5.17, 5.9 times higher adsorption ability for E2. After six (6) times of adsorption-desorption cycles, the MIH still exhibited stable adsorptions with a small standard deviation of 4%.

Abstract I
Figure Caption IV
Table Caption VI
Chapter 1. Introduction 1
1-1 Motivation 1
1-2 Objectives 2
Chapter 2. Literature Review 4
2-1 Estradiol 4
2-2 Imprinted Materials 5
2-2-1 Covalent Bonding 7
2-2-2 Non-covalent Bonding 7
2-2-3 Organic MIPs 9
2-2-4 Inorganic MIPs 9
2-2-5 Organic-Inorganic (hybrid) MIPs 10
2-3 Effects of Functional Monomers 12
2-3-1 Single Functional Monomer 13
2-3-2 Double Functional Monomers 13
2-4 Applications of Molecular Imprinted Polymers. 15
Chapter 3. Experimental Section 17
3-1 Experimental Flowchart 17
3-2 Chemicals 18
3-3 Preparation of MIHs 19
3-4 Adsorption 20
3-5 Characterization 21
3-5-1 Fourier Transform Infrared Spectrometer (FTIR) 21
3-5-2 Specific Surface Area (BET) 21
3-5-3 Thermal Gravimetric Analysis (TGA) 22
Chapter 4. Results and Discussion 23
4-1 Optimization 23
4-1-1 Effects of Hydrophobic and Hydrophilic Environment on the Adsorption of E2 23
4-1-2 Dual Functional Monomers 24
4-1-3 Multi-Functional Monomers 25
4-2 Characterizations 27
4-2-1 Functional Groups 27
4-2-3 Texture 29
4-3 Adsorptions 30
4-3-1 solvent 30
4-4 Adsorption Isotherm 33
4-5 Scatchard Analysis 36
4-6 Selectivity Test 37
4-7 Regeneration 38
Chapter 5. Conclusions 39
Reference 40

1. Diamante, G.; Menjivar-Cervantes, N.; Leung, M. S.; Volz, D. C.; Schlenk, D., Contribution of G protein-coupled estrogen receptor 1 (GPER) to 17beta-estradiol-induced developmental toxicity in zebrafish. Aquatic toxicology (Amsterdam, Netherlands) 2017, 186, 180-187.
2. Wang, S.; Huang, W.; Fang, G.; Zhang, Y.; Qiao, H., Analysis of steroidal estrogen residues in food and environmental samples. International Journal of Environmental Analytical Chemistry 2008, 88 (1), 1-25.
3. Scheller, F. W.; Zhang, X.; Yarman, A.; Wollenberger, U.; Gyurcsányi, R. E., Molecularly imprinted polymer based electrochemical sensors for Biopolymers. Current Opinion in Electrochemistry 2018.
4. Adeel, M.; Song, X.; Wang, Y.; Francis, D.; Yang, Y., Environmental impact of estrogens on human, animal and plant life: A critical review. Environment International 2017, 99, 107-119.
5. Le Noir, M.; Lepeuple, A. S.; Guieysse, B.; Mattiasson, B., Selective removal of 17beta-estradiol at trace concentration using a molecularly imprinted polymer. Water Res 2007, 41 (12), 2825-31.
6. Kim, Y. H.; Lee, B.; Choo, K. H.; Choi, S. J., Selective Adsorption of Bisphenol A by Organic–Inorganic Hybrid Mesoporous Silicas. Microporous Mesoporous Mater. 2011, 138 (1), 184.
7. Udomsap, D.; Brisset, H.; Culioli, G.; Dollet, P.; Laatikainen, K.; Siren, H.; Branger, C., Electrochemical molecularly imprinted polymers as material for pollutant detection. Materials Today Communications 2018, 17, 458-465.
8. Hammam, M. A.; Wagdy, H. A.; El Nashar, R. M., Moxifloxacin hydrochloride electrochemical detection based on newly designed molecularly imprinted polymer. Sensors and Actuators B: Chemical 2018, 275, 127-136.
9. Qader, B.; Baron, M.; Hussain, I.; Sevilla, J. M.; Johnson, R. P.; Gonzalez-Rodriguez, J., Electrochemical determination of disulfoton using a molecularly imprinted poly-phenol polymer. Electrochimica Acta 2019, 295, 333-339.
10. Jin, Y.; Jiang, M.; Shi, Y.; Lin, Y.; Peng, Y.; Dai, K.; Lu, B., Narrowly dispersed molecularly imprinted microspheres prepared by a modified precipitation polymerization method. Analytica Chimica Acta 2008, 612 (1), 105-113.
11. Wei, S.; Molinelli, A.; Mizaikoff, B., Molecularly imprinted micro and nanospheres for the selective recognition of 17beta-estradiol. 2006; Vol. 21, p 1943-51.
12. Chin, K.-Z.; Chang, S.-m., SiO2-Coated Molecularly Imprinted Copolymer Nanostructures for the Adsorption of Bisphenol A. ACS Applied Nano Materials 2019, 2 (1), 89-99.
13. Borthakur, P.; Boruah, P. K.; Das, M. R.; Kulik, N.; Minofar, B., Adsorption of 17α-ethynyl estradiol and β-estradiol on graphene oxide surface: An experimental and computational study. Journal of Molecular Liquids 2018, 269, 160-168.
14. Celiz, M. D.; Aga, D. S.; Colón, L. A., Evaluation of a molecularly imprinted polymer for the isolation/enrichment of β-estradiol. Microchemical Journal 2009, 92 (2), 174-179.
15. Sarafraz-Yazdi, A.; Razavi, N., Application of molecularly-imprinted polymers in solid-phase microextraction techniques. TrAC Trends in Analytical Chemistry 2015, 73, 81-90.
16. Li, Q.; Ling, B.; Jiang, L.; Ye, L., A paradigm shift design of functional monomers for developing molecularly imprinted polymers. Chemical Engineering Journal 2018, 350, 217-224.
17. Huang, D. L.; Wang, R. Z.; Liu, Y. G.; Zeng, G. M.; Lai, C.; Xu, P.; Lu, B. A.; Xu, J. J.; Wang, C.; Huang, C., Application of molecularly imprinted polymers in wastewater treatment: a review. Environmental science and pollution research international 2015, 22 (2), 963-77.
18. Hongyuan, Y.; Row, K., Characteristic and Synthetic Approach of Molecularly Imprinted Polymer. 2006; Vol. 7.
19. Ye, N.; Wang, X.; Liu, Q.; Hu, X., Covalent bonding of Schiff base network-1 as a stationary phase for capillary electrochromatography. Analytica Chimica Acta 2018, 1028, 113-120.
20. Alberti, E.; Zampakou, M.; Donghi, D., Covalent and non-covalent binding of metal complexes to RNA. Journal of Inorganic Biochemistry 2016, 163, 278-291.
21. Kashyap, C.; Ullah, S. S.; Mazumder, L. J.; Kanti Guha, A., Non-covalent interaction in benzene and substituted benzene: A theoretical study. Computational and Theoretical Chemistry 2018, 1130, 134-139.
22. Wulff, G., Molecular Imprinting in Cross-Linked Materials with the Aid of Molecular Templates— A Way towards Artificial Antibodies. 1995, 34 (17), 1812-1832.
23. Zheng, J.; Huang, J.; Yang, Q.; Ni, C.; Xie, X.; Shi, Y.; Sun, J.; Zhu, F.; Ouyang, G., Fabrications of novel solid phase microextraction fiber coatings based on new materials for high enrichment capability. TrAC Trends in Analytical Chemistry 2018, 108, 135-153.
24. Zhang, L.; Wang, G.; Xiong, C.; Zheng, L.; He, J.; Ding, Y.; Lu, H.; Zhang, G.; Cho, K.; Qiu, L., Chirality detection of amino acid enantiomers by organic electrochemical transistor. Biosensors and Bioelectronics 2018, 105, 121-128.
25. Uniyal, S.; Sharma, R. K., Technological advancement in electrochemical biosensor based detection of Organophosphate pesticide chlorpyrifos in the environment: A review of status and prospects. Biosensors and Bioelectronics 2018, 116, 37-50.
26. Holthoff, E. L.; Bright, F. V., Molecularly templated materials in chemical sensing. Analytica Chimica Acta 2007, 594 (2), 147-161.
27. Farrington, K.; Regan, F., Molecularly imprinted sol gel for ibuprofen: An analytical study of the factors influencing selectivity. Talanta 2009, 78 (3), 653-659.
28. Wang, H.-F.; Zhu, Y.-Z.; Yan, X.-P.; Gao, R.-Y.; Zheng, J.-Y., A Room Temperature Ionic Liquid (RTIL)-Mediated, Non-Hydrolytic Sol–Gel Methodology to Prepare Molecularly Imprinted, Silica-Based Hybrid Monoliths for Chiral Separation. 2006, 18 (24), 3266-3270.
29. Burak Özkan, M.; Tscheuner, S.; Ozkan, E., Diagnostic accuracy of MIP slice modalities for small pulmonary nodules in paediatric oncology patients revisited: What is additional from the paediatric radiologist approach? The Egyptian Journal of Radiology and Nuclear Medicine 2016, 47 (4), 1629-1637.
30. Derradji, M.; Wang, J.; Liu, W., 3 - X-Functional Phthalonitrile Monomers and Polymers. In Phthalonitrile Resins and Composites, Derradji, M.; Wang, J.; Liu, W., Eds. William Andrew Publishing: 2018; pp 107-174.
31. Qiujin, Z.; Tang, J.; Dai, J.; Gu, X.; Chen, S., Synthesis and characteristics of imprinted 17‐β‐estradiol microparticle and nanoparticle with TFMAA as functional monomer. 2007; Vol. 104, p 1551-1558.
32. Mayes, A. G.; Whitcombe, M. J., Synthetic strategies for the generation of molecularly imprinted organic polymers. Advanced Drug Delivery Reviews 2005, 57 (12), 1742-1778.
33. Anantha-Iyengar, G.; Shanmugasundaram, K.; Nallal, M.; Lee, K.-P.; Whitcombe, M. J.; Lakshmi, D.; Sai-Anand, G., Functionalized conjugated polymers for sensing and molecular imprinting applications. Progress in Polymer Science 2019, 88, 1-129.
34. Chen, L.; Li, B., Magnetic molecularly imprinted polymer extraction of chloramphenicol from honey. Food Chemistry 2013, 141 (1), 23-28.
35. Zheng, X.; Xu, T.; Shi, R.; Lu, N.; Zhang, J.; Jiang, C.; Zhang, C.; Zhou, J., Preparation of hollow porous molecularly imprinted polymers for N-nitrosamine adsorption. Materials Letters 2018, 211, 21-23.
36. Li, Z.; Lei, C.; Wang, N.; Jiang, X.; Zeng, Y.; Fu, Z.; Zou, L.; He, L.; Liu, S.; Ao, X.; Zhou, K.; Chen, S., Preparation of magnetic molecularly imprinted polymers with double functional monomers for the extraction and detection of chloramphenicol in food. Journal of Chromatography B 2018, 1100-1101, 113-121.
37. Wang, S.; Li, Y.; Ding, M.; Wu, X.; Xu, J.; Wang, R.; Wen, T.; Huang, W.; Zhou, P.; Ma, K.; Zhou, X.; Du, S., Self-assembly molecularly imprinted polymers of 17β-estradiol on the surface of magnetic nanoparticles for selective separation and detection of estrogenic hormones in feeds. Journal of Chromatography B 2011, 879 (25), 2595-2600.
38. Peng, H.; Luo, M.; Xiong, H.; Yu, N.; Ning, F.; Fan, J.; Zeng, Z.; Li, J.; Chen, L., Preparation of photonic-magnetic responsive molecularly imprinted microspheres and their application to fast and selective extraction of 17β-estradiol. Journal of Chromatography A 2016, 1442, 1-11.
39. Watabe, Y.; Kubo, T.; Nishikawa, T.; Fujita, T.; Kaya, K.; Hosoya, K., Fully automated liquid chromatography–mass spectrometry determination of 17β-estradiol in river water. Journal of Chromatography A 2006, 1120 (1), 252-259.
40. Xiong, H.; Wu, X.; Lu, W.; Fu, J.; Peng, H.; Li, J.; Wang, X.; Xiong, H.; Chen, L., Switchable zipper-like thermoresponsive molecularly imprinted polymers for selective recognition and extraction of estradiol. Talanta 2018, 176, 187-194.
41. Zhu, W.; Peng, H.; Luo, M.; Yu, N.; Xiong, H.; Wang, R.; Li, Y., Zipper-like magnetic molecularly imprinted microspheres for on/off-switchable recognition and extraction of 17β-estradiol from food samples. Food Chemistry 2018, 261, 87-95.
42. Wan, Y.; Wang, M.; Fu, Q.; Wang, L.; Wang, D.; Zhang, K.; Xia, Z.; Gao, D., Novel dual functional monomers based molecularly imprinted polymers for selective extraction of myricetin from herbal medicines. Journal of Chromatography B 2018, 1097-1098, 1-9.
43. Tran, M.; Turner, E. B.; Segro, S. S.; Fang, L.; Seyyal, E.; Malik, A., Tantala-based sol-gel coating for capillary microextraction on-line coupled to high-performance liquid chromatography. Journal of Chromatography A 2017, 1522, 38-47.
44. Neelon, K.; Roberts, Mary F.; Stec, B., Crystal Structure of a Trapped Catalytic Intermediate Suggests that Forced Atomic Proximity Drives the Catalysis of mIPS. Biophysical Journal 2011, 101 (11), 2816-2824.
45. Uzuriaga-Sánchez, R. J.; Khan, S.; Wong, A.; Picasso, G.; Pividori, M. I.; Sotomayor, M. D. P. T., Magnetically separable polymer (Mag-MIP) for selective analysis of biotin in food samples. Food Chemistry 2016, 190, 460-467.
46. Tse Sum Bui, B.; Belmont, A.-S.; Witters, H.; Haupt, K., Molecular recognition of endocrine disruptors by synthetic and natural 17??-estradiol receptors: A comparative study. 2008; Vol. 390, p 2081-8.
47. Waffo, A. F. T.; Yesildag, C.; Caserta, G.; Katz, S.; Zebger, I.; Lensen, M. C.; Wollenberger, U.; Scheller, F. W.; Altintas, Z., Fully electrochemical MIP sensor for artemisinin. Sensors and Actuators B: Chemical 2018, 275, 163-173.
48. Weber, P.; Riegger, B. R.; Niedergall, K.; Tovar, G. E. M.; Bach, M.; Gauglitz, G., Nano-MIP based sensor for penicillin G: Sensitive layer and analytical validation. Sensors and Actuators B: Chemical 2018, 267, 26-33.
49. Lian, L.; Zhang, X.; Hao, J.; Lv, J.; Wang, X.; Zhu, B.; Lou, D., Magnetic solid-phase extraction of fluoroquinolones from water samples using titanium-based metal-organic framework functionalized magnetic microspheres. Journal of Chromatography A 2018, 1579, 1-8.
50. Hashemi, S. H.; Kaykhaii, M.; Keikha, A. J.; Sajjadi, Z., Application of Box-Behnken design in response surface methodology for the molecularly imprinted polymer pipette-tip solid phase extraction of methyl red from seawater samples and its determination by spectrophotometery. Marine Pollution Bulletin 2018, 137, 306-314.
51. Sandle, T., Chapter 16 - Risk Assessment and Investigation for Environmental Monitoring. In Biocontamination Control for Pharmaceuticals and Healthcare, Sandle, T., Ed. Academic Press: 2019; pp 261-285.
52. Cantarella, M.; Carroccio, S. C.; Dattilo, S.; Avolio, R.; Castaldo, R.; Puglisi, C.; Privitera, V., Molecularly imprinted polymer for selective adsorption of diclofenac from contaminated water. Chemical Engineering Journal 2019, 367, 180-188.
53. Wang, J.; Huyan, Y.; Yang, Z.; Zhang, H.; Zhang, A.; Kou, X.; Zhang, Q.; Zhang, B., Preparation of surface protein imprinted thermosensitive polymer monolithic column and its specific adsorption for BSA. Talanta 2019, 200, 526-536.
54. Abolghasemi-Fakhri, L.; Ghanbarzadeh, B.; Dehghannya, J.; Abbasi, F.; Adun, P., Styrene monomer migration from polystyrene based food packaging nanocomposite: Effect of clay and ZnO nanoparticles. Food and Chemical Toxicology 2019, 129, 77-86.
55. Kingsley, K.; Shevchuk, O.; Demchuk, Z.; Voronov, S.; Voronov, A., The features of emulsion copolymerization for plant oil-based vinyl monomers and styrene. Industrial Crops and Products 2017, 109, 274-280.
56. Sharma, A. K.; Pasini, D., Fluorinated styrene-based monomers for cyclopolymerizations. Journal of Fluorine Chemistry 2011, 132 (11), 956-960.
57. Lee, S.-H.; Doong, R.-a., Adsorption and selective recognition of 17ß-estradiol by molecularly imprinted polymers. 2012; Vol. 19.
58. Spivak, D. A., Optimization, evaluation, and characterization of molecularly imprinted polymers. Advanced Drug Delivery Reviews 2005, 57 (12), 1779-1794.
59. Shivraj; Siddlingeshwar, B.; Thomas, A.; Kirilova, E. M.; Divakar, D. D.; Alkheraif, A. A., Experimental and theoretical insights on the effect of solvent polarity on the photophysical properties of a benzanthrone dye. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2019, 218, 221-228.
60. Inglezakis, V. J.; Poulopoulos, S. G.; Kazemian, H., Insights into the S-shaped sorption isotherms and their dimensionless forms. Microporous and Mesoporous Materials 2018, 272, 166-176.
61. Ali, I.; Alothman, Z. A.; Alwarthan, A., Supra molecular mechanism of the removal of 17-β-estradiol endocrine disturbing pollutant from water on functionalized iron nano particles. Journal of Molecular Liquids 2017, 241, 123-129.
62. Xiao, L.; Zhang, Z.; Wu, C.; Han, L.; Zhang, H., Molecularly imprinted polymer grafted paper-based method for the detection of 17β-estradiol. Food Chemistry 2017, 221, 82-86.
63. Wen, T.; Wang, M.; Luo, M.; Yu, N.; Xiong, H.; Peng, H., A nanowell-based molecularly imprinted electrochemical sensor for highly sensitive and selective detection of 17β-estradiol in food samples. Food Chemistry 2019, 297, 124968.
64. Han, Q.; Shen, X.; Zhu, W.; Zhu, C.; Zhou, X.; Jiang, H., Magnetic sensing film based on Fe3O4@Au-GSH molecularly imprinted polymers for the electrochemical detection of estradiol. Biosensors and Bioelectronics 2016, 79, 180-186.
65. Zaib, Q.; Khan, I. A.; Saleh, N. B.; Flora, J. R. V.; Park, Y.-G.; Yoon, Y., Removal of Bisphenol A and 17β-Estradiol by Single-Walled Carbon Nanotubes in Aqueous Solution: Adsorption and Molecular Modeling. Water, Air, & Soil Pollution 2012, 223 (6), 3281-3293.
66. Gao, R.; Cui, X.; Hao, Y.; Zhang, L.; Liu, D.; Tang, Y., A highly-efficient imprinted magnetic nanoparticle for selective separation and detection of 17β-estradiol in milk. Food Chemistry 2016, 194, 1040-1047.
67. Dong, X.; He, L.; Hu, H.; Liu, N.; Gao, S.; Piao, Y., Removal of 17β-estradiol by using highly adsorptive magnetic biochar nanoparticles from aqueous solution. Chemical Engineering Journal 2018, 352, 371-379.