DOI: 10.17344/acsi.2017.3841 Acta Chim. Slov. 2017, 64, 747-762 Scientific paper Iodine-catalyzed Transformation of Aryl-substituted Alcohols Under Solvent-free and Highly Concentrated Reaction Conditions Marjan Jereb1* and Dejan Vražič2 1 Chair of Organic Chemistry, Faculty of Chemistry and Chemical Technology, Večna pot 113, 1000 Ljubljana, Slovenia 2 Present address: Krka, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia * Corresponding author: E-mail: marjan.jereb@fkkt.uni-lj.si Tel.: (++386) 1 479 8577 Fax: (++386) 1 241 9144 Received: 18-09-2017 Dedicated to Professor Emeritus Miha Tišler, University of Ljubljana, on the occasion of his 90th birthday. Abstract Iodine-catalyzed transformations of alcohols under solvent-free reaction conditions (SFRC) and under highly concentrated reaction conditions (HCRC) in the presence of various solvents were studied in order to gain insight into the behavior of the reaction intermediates under these conditions. Dimerization, dehydration and substitution were the three types of transformations observed with benzylic alcohols. Dimerization and substitution reactions were predominant in the case of primary- and secondary alcohols, whereas dehydration prevailed in the case of tertiary alcohols. The relative reactivity of substituted 1-phenylethanols in I2-catalyzed dimerization under SFRC provided a good Hammett plot p+ = -2.8 (r2 = 0.98), suggesting the presence of electron-deficient intermediates with a certain degree of developed charge in the rate-determining step. Keywords: Alcohols, catalysis, green chemistry, Hammett correlation, iodine 1. Introduction Green chemistry is currently a popular topic in chemistry. Numerous serious efforts have been made to improve and simplify existing methods and procedures, especially in terms of atom-economy, process-efficiency, health, risk and waste-minimization.1-3 Transformations of neat reactants under solvent-free reaction conditions (SFRC) are one of the best solutions in this regard.4-7 In the solid/solid system, a remarkable reaction rate enhancement was observed just by introducing small amounts of solvent vapor into the reaction mixture.8 Moreover, the course of the reaction can be dramatically influenced under highly concentrated reaction conditions (HCRC).9 It has been documented that water can remarkably affect the course of the reaction,10-12 including enantioselectivity.13-15 Water has become a reaction solvent of immense importance for the selectivity/reactivity studies of nucleophiles and electrophiles,16-18 where carbocation intermediates play an important role.19-21 Mixtures of water with organic solvents have been employed to determine the geometry of the transition states,22 with the hydrophobic effect attracting attention in studies of organic reactions in the presence of water.23-25 In recent years, iodine26,27 has emerged as remarkable catalyst exhibiting high water tolerance in diverse types of reactions. One of beneficial properties of iodine is its high affinity towards molecular oxygen as well as functional groups bearing at least one oxygen atom.28,29 It has been established that iodine is an efficient catalyst for the transformation of alcohols under SFRC, with tertiary alcohols being dehydrated;30 while primary and secondary transformed into ethers or esters.31-33 This protocol has been already applied under various conditions34-36 all indicating participation of the reaction intermediates having a partial positive charge. Recently, important mechanistic studies on the iodine-catalyzed reactions in solution have been published,37,38 but the knowledge of the behavior of iodine under SFRC and HCRC remains largely undis- covered.39 The above reasons prompted us to investigate the reactivity of several model substrates in iodine-catalyzed transformations of alcohols under SFRC and HCRC. The alcohol substrates were selected to study different electronic effects and geometry. The role of the potentially present heteroatom and antiaromaticity of intermediates on transformations will be validated on sterically hindered dibenzo-substituted alcohols. Stereochemistry and regi-oselectivity of dehydration reactions and the role of the reaction medium polarity (protic vs. aprotic), nucleop-hilicity and pKa under HCRC will be examined as well. 2. Experimental 2. 1. General 1-Phenylethanol 1a, 1,1-diphenylethanol 1d and 4-methoxybenzyl alcohol 1m are commercially available, the other alcohols were prepared by various methods. A) Modified Grignard procedure,40 a typical experiment: under inert atmosphere, one crystal of iodine was added to magnesium turnings (60 mmol) in 5 mL of dry THF, and a few drops of the corresponding halogenide (PhCH2Cl, PhBr or EtI) (60 mmol). The rest of the halogenide was diluted with 25 mL of dry THF and slowly added at room temperature. The reaction mixture was refluxed for 90 minutes, then cooled to room temperature, diluted with 50 mL of dry THF and a solution of the appropriate carbonyl molecule (PhCOMe, Ph2CO, 4'-methoxyacetophenone, 2'-methoxyacetophenone, 4-methoxybenzaldehyde, 4,4'-dimethoxybenzophenone or 9-fluorenone) (20 mmol) in 50 mL of dry THF was slowly added and the reaction mixture was refluxed for two hours. After cooling, THF was evaporated and the reaction mixture diluted with Et2O and water. The organic phase was separated, washed with water, dried over anhydrous Na2SO4; the solvent evaporated and pure products were obtained after column chromatogra-phy or crystallization. Alcohols prepared by method A: 1,2-diphenyl-2-propanol41 1c, 1,1-diphenyl-1-propanol42 1e, 1-(4-methoxyphenyl)-2-phenylethanol43 1i, 1-(4-me-thoxyphenyl)-1-phenylethanol44 1j, 1-(2-methoxyphenyl)-1-phenylethanol45 1k, 1,1-bis(4-methoxyphenyl)-2-phen-ylethanol46 1l, 2-(4-methoxyphenyl)-1-phenyl-2-propa-nol47 1n, 9-ethyl-9-fluorenol48 4a, 9-benzyl-9-fluorenol49 4b and 9-benzyl-9-xanthenol50 4f. B) Na/RX/carbonyl molecule, a typical experiment: xanthone or dibenzosub-erone (20 mmol) was dissolved in toluene (40 mL), followed by the addition of ethyl iodide or benzyl chloride (60 mmol) and sodium (120 mmol). The reaction mixture was refluxed for one hour, cooled to room temperature, diluted with toluene; water was added in small portions. The organic phase was separated, washed with water, dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. Alcohols prepared by method B: 5-ethyl-10,11-di-hydro-5H-dibenzo[a,d]cyclohepten-5-ol 4c, 9-ethyl-9-xanthenol51 4e, and 5-benzyl-10,11-dihydro-5H-diben- zo[a,d]cyclohepten-5-ol 4d. C) By reduction of commercially available ketones with NaBH4: 1,2-diphenylethanol41 1b, 1-(4-methoxyphenyl)ethanol52 1h, 1-(4-fluorophenyl) ethanol52 1o, 1-(3-methylphenyl)ethanol52 1p, 1-(3-me-thoxyphenyl)ethanol52 1q, 1-(4-chlorophenyl)ethanol52 1r, 1-(4-bromophenyl)ethanol52 1s. D) By reduction using Al-KOH:53 Xanthydrol54 10. E) By halohydroxylation:55-56 1,1-diphenyl-2-bromoethanol57 1f and 1,1-diphenyl-2-flu-oroethanol58 1g. Pure products were usually obtained using column chromatography (CC) at given conditions using Fluka 60 silica gel (63-200 ^m, 70-230 mesh ASTM). Reaction progress was monitored by thin-layer chroma-tography on Merck 60 F254 TLC plates or by 1H NMR spectroscopy. NMR spectra were recorded on Bruker Avance 300 DPX, and Bruker Avance III 500 Instrument (1H: 300 MHz, 13C: 75.5 MHz and 125 MHz). The 1H spectra were referred to an internal standard (0 ppm for TMS) or to the residual 1H signal of CHCl3 at 7.26 ppm. The 13C spectra were referred to the central line of CDCl3 (77.00 ppm). New compounds were characterized by 1H NMR, 13C NMR and IR spectroscopy, HRMS and/or elemental analysis, and also with the melting points when solid. Known products were characterized by 1H NMR and IR spectros-copy, melting point when solid and by LRMS in most of the cases. Additionally, 13C NMR spectra were recorded for those products, whose13C NMR data were not found in the literature. Melting points were determined on Buchi 535 apparatus and are not corrected. Mass spectra were obtained with the electron ionization (EI). Elemental combustion analyses were performed on Perkin-Elmer analyser 2400 CHN. 2. 2. General Procedure for Iodine-catalyzed Transformation of Alcohols Under SFRC The procedure is the same for solid and liquid substrates. Alcohol (1 mmol) and iodine (3 mol%) were mixed together in a 5 mL conical reactor and the reaction mixture stirred at 25 °C or 55 °C for various times (5 min to 192 h), progress was monitored by TLC or by 1H NMR spectroscopy. The crude reaction mixture was diluted with ferf-butyl methyl ether, washed with an aqueous solution of Na2S2O3, water, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude reaction mixture was subjected to column chromatography or preparative TLC using hexane or petroleum ether/ferf-bu-tyl methyl ether mixtures and pure product(s) were obtained. Conversions were determined by 1H NMR spec-troscopy. The effects of reaction variables on the type of transformation and conversions are stated in Tables and Figures. In order to obtain the information (role) of the reaction variables and structure of substrate, the data (reaction times with lower conversion) are presented in some Tables. In the experimental section, the best reaction conditions are named; 3 mol% of I2 were used, giving the highest yield. 2. 3. General Procedure for Iodine-catalyzed Transformation of Alcohols Under HCRC The procedure is the same for solid and liquid substrates. To the mixture of alcohol (1 mmol) and various amounts of solvent (CH2Cl2, MeOH, EtOH, ¿-PrOH, TFE, HFIP, HCOOH, AcOH and H2O 3-300 mmol) iodine (3 mol%) was added in 5 mL conical reactor and the reaction mixture stirred at 25 °C from five minutes to 360 hours. Isolation and purification procedure was the same as described above. Conversions were determined by 1H NMR spectroscopy. Results are presented in Tables, Figures and Schemes. Isolation procedure is given for the best yield. 2. 4. Determination of Hammett Reaction Constant p+ for the I2-catalyzed Dimerization of 1-phenylethanols 1-phenylethanols (0.5 mmol) (1a, 1o, 1p, 1q, 1r, 1s) were separately placed in the conical reactors, transformation was induced by iodine (0.015 mmol, 3.8 mg, 3 mol %) at 55 °C. Alcohols 1o and 1p were stirred for two hours, and alcohols 1q, 1r and 1s were stirred for three hours. The transformation was stopped by cooling, the reaction mixture was analyzed by 1H NMR spectroscopy and relative rate constants calculated from the equation59 kr = kA/kB = log ((A - X)/A)/log ((B - Y)/B), derived from the Ingold-Shaw relation60 where A and B are the amounts of starting material and X and Ythe amounts of products derived from them. The relative rate factors thus obtained, collected in Figure 1, are the averages of at least two measurements, giving a good reproducibility, deviation of ke ranged (± 3%). The reaction of reference substrate 1-phenylethanol 1a was quenched separately after 2 h and 3 h and relative rate constants were obtained by means of 1H NMR spectroscopy utilising internal standard 1,1-di-phenylethene. 2. 5. Volumetric Determination of Iodine After the I2-catalyzed Reaction of 1n Under HCRC in MeOH To a mixture of 1-(4-methoxyphenyl)-2-pheny-lethan-1-ol 1n (1 mmol, 228 mg) and methanol (3 mmol, 96 mg) iodine (0.03 mmol, 7.6 mg) was added and the mixture stirred for 30 minutes at 25 °C. A reaction mixture was diluted with acetonitrile (5 mL) and titrated with a standard solution of Na2S2O3 (c = 0.1022 mol/L, V = 0.58 mL). 2. 6. Volumetric Determination of Iodine After the I2-catalyzed Reaction of 1n Under HC2RC in CH2Cl2 To a mixture of 1-(4-methoxyphenyl)-2-pheny-lethan-1-ol 1n (1 mmol, 228 mg) and dichloromethane (3 mmol, 255 mg) iodine (0.03 mmol, 7.6 mg) was added and the mixture stirred for 30 minutes at 25 °C. A reaction mixture was diluted with acetonitrile (5 mL) and titrated with a standard solution of Na2S2O3 (c = 0.1022 mol/L, V = 0.57 mL). 2. 7. Spectroscopic and Analytical Data of Novel Compounds Bis[1-(4-fluorophenyl)ethyl] ether 2o SFRC (r.t. = 4.5 h, 55 °C), CC (SiO2, petroleum ether), colorless oil (90%), as a mixture of stereoisomers in ratio 1/0.39; IR (neat): 2976, 2930, 1604, 1508, 1371, 1224, 1156, 1091, 949, 836 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.23-7.12 (m, 8H), 7.05-6.87 (m, 8H), 4.42 (q, J = 6.4 Hz, 2H), 4.13 (q, J = 6.5 Hz, 2H, major), 1.41 (d, J = 6.4 Hz, 6H), 1.32 (d, J = 6.5 Hz, 6H, major); 13C NMR (75.5 MHz, CDCl3): 5 162.2 (d, J = 245 Hz, 2C, major), 162.0 (d, J = 245 Hz, 2C, minor), 139.8 (d, J = 3 Hz, 2C, minor), 139.6 (d, J = 3 Hz, 2C, major), 127.8 (d, J = 8 Hz, 4C, major), 127.7 (d, J = 8 Hz, 4C, minor), 115.3 (d, J = 22 Hz, 4C, major), 115.0 (d, J = 22 Hz, 4C, minor), 74.1 (minor), 73.9 (major), 24.7 (major), 23.1 (minor); MS m/z (EI): 262 (M+, <1%), 247 (4), 123 (100), 103 (20); HRMS: Calcd for C,,H.,F,O 262.1169; found 262.1172. 16 16 2 Bis[1-(3-methylphenyl)ethyl] ether 2p SFRC (r.t. = 4.5 h, 55 °C), CC (SiO2, hexane/CH2-Cl2), colorless oil (87%), as a mixture of stereoisomers in ratio 1/0.37; IR (neat): 2973, 2924, 1607, 1487, 1447, 1368, 1160, 1092, 1034, 786, 705 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.22-6.93 (m, 16H), 4.42 (q, J = 6.4 Hz, 2H), 4.14 (q, J = 6.5 Hz, 2H, major), 2.36 (s, 6H, major), 2.30 (s, 6H, minor), 1.41 (d, J = 6.4 Hz, 6H, minor), 1.32 (d, J = 6.5 Hz, 6H, major); 13C NMR (75.5 MHz, CDCl3): 5 144.2, 144.2, 137.9, 137.7, 128.3, 128.1, 128.1, 127.8, 127.0, 126.9, 123.3, 123.3, 74.6 (major), 74.4 (minor), 24.7 (major), 22.9 (minor), 21.5 (major), 21.4 (minor); MS m/z (EI): 254 (M+, <1%), 135 (23), 119 (100), 105 (13), 91 (16); HRMS: Calcd for C18H22O 254.1671; found 254.1677. Anal. Calcd for C18H22O: C, 84.99; H, 8.72. Found: C, 84.65; H, 9.03. 18 22 Bis[1-(4-bromophenyl)ethyl] ether 2s SFRC (r.t. = 18 h, 55 °C), CC (SiO2, hexane), white solid (81%), as a mixture of stereoisomers in ratio 1/0.53; mp 68-74 °C; IR (neat): cm-1; 1H NMR (300 MHz, CDCl3): 5 7.45 (d, J = 8.4 Hz, 4H), 7.38 (d, J = 8.4 Hz, 4H), 7.11 (d, J = 8.4 Hz, 4H), 7.09 (d, J = 8.4 Hz, 4H), 4.42 (q, J = 6.4 Hz, 2H, minor), 4.13 (q, J = 6.5 Hz, 2H, major), 1.41 (d, J = 6.4 Hz, 6H, minor), 1.32 (d, J = 6.5 Hz, 6H, major); 13C NMR (75.5 MHz, CDCl3): 5 143.1, 142.9, 131.7, 131.4, 128.0, 127.9, 121.3, 121A 74.2, 74.2, 24.5 (major), 23.0 (minor); MS m/z (EI): 382 (M+, 2%), 367 (5), 226 (6), 199 (21), 185 (100), 104 (35); HRMS: Calcd for C16H16Br2O 381.9568; found 381.9578. 5-Ethyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ol 4c (20 mmol (4.17 g) dibenzosuberone, 120 mmol (2.76 g) Na, 60 mmol (9.36 g) EtI, 40 mL toluene, 1 h, reflux), CC (SiO2, CH2Cl2/petroleum ether, 1/4) and crystallization (petroleum ether), white solid (82%); mp 61.0-62.0 °C; IR (KBr): 3400, 2932, 1485, 1455, 1317, 1080, 1041, 965, 924, 889, 750 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.91-7.88 (m, 2H), 7.26-7.08 (m, 6H), 3.41-3.31 (m, 2H), 3.01-2.91 (m, 2H), 2.23 (q, J = 7.4 Hz, 2H), 2.14 (s, 1h), 0.69 (t, J = 7.4 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): 5 144.6, 138.8, 130.2, 127.2, 127.1, 126.1, 79.4, 38.2, 34.6,8.8; MS m/z (EI): 237 (M+ - H, 2%), 220 (1), 209 (100), 131 (26), 103 (26), 91 (15); Anal. Calcd for C17H18O: C, 85.67; H, 7.61. Found: C, 85.88; H, 7.83. 5-Benzyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol 4d (20 mmol (4.17 g) dibenzosuberone, 120 mmol (2.76 g) Na, 60 mmol (7.59 g) PhCH2Cl, 40 mL toluene, 1 h, reflux), CC (SiO2, CH2Cl2/petroleum ether, 1/4) and crystallization (petroleum ether), white solid (85%); mp 61.663.7 °C; IR (KBr): 3468, 2924, 1599, 1486, 1450, 1275, 1077, 1012, 766, 700, 673 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.73-7.70 (m, 2H), 7.19-7.04 (m, 9H), 6.73-6.70 (m, 2H), 3.47 (s, 2H), 3.46-3.37 (m, 2H), 3.07-2.97 (m, 2H), 2.32 (s, 1H); 13C NMR (75.5 MHz, CDCl3): 5 143.9, 139.1, 136.2, 130.7, 130.0, 127.7, 127.6, 127.3, 1226.5, 126.2, 79.1, 51.9, 35.1; MS m/z (EI): 300 (M+ - H, 1%), 282 (<1), 209 (100), 131 (49), 103 (19), 91 (27); Anal. Calcd for C22H20O: C, 87.96; H, 6.71. Found: C, 87.84; H, 6.83. 2-Methoxy-2-(4-methoxyphenyl)-1-phenylpropane 6na HCRC (MeOH, r.t. = 4 h, 25 °C), CC (SiO2, petroleum ether), colorless viscous oil (39%); IR (neat): 2937, 2824, 1610, 1510, 1455, 1371, 1299, 1249, 1088, 832, 701 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.18-7.13 (m, 5H), 6.87-6.82 (m, 4H), 3.81 (s, 3H), 3.08 (s, 3H), 3.02 (d, J = 13.1 Hz, 1H), 2.95 (d, J = 13.1 Hz, 1H), 1.46 (s, 3H); 13C NMR (75.5 MHz, CDCl3): 5 158.5, 137.6, 136.2, 130.7, 127.9, 127.5, 126.0, 113.2, 79.5, 55.2, 50.7, 50.3, 21.3; MS m/z (EI): 224 (M+ - MeOH, 88%), 209 (20), 165 (56), 133 (100), 128 (18). Anal. Calcd for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.22; H, 7.87. 17 20 2 2-Ethoxy-2-(4-methoxyphenyl)-1-phenylpropane 6nb (EtOH, 30 mmol, r.t. = 19 h, 25 °C), CC (SiO2, petroleum ether), viscous colorless oil (73%); IR (neat): 2975, 1609, 1510, 1454, 1300, 1250, 1179, 1091, 1034, 833, 702 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.13-7.07 (m, 5H), 6.83-6.80 (m, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.79 (s, 3h), 3.30 (dq, J = 14.2 Hz, J = 7.0 Hz, 1H), 3.09 (dq, J = 14.2 Hz, J = 7.0 Hz, 1H), 2.96 (d, J = 13.1 Hz, 1H), 2.87 (d, J = 13.1 Hz, 1H), 1.43 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): 5 158.4, 137.7, 137.0, 130.8, 127.7, 127.4, 126.0, 113.2, 79.1, 57.6, 55.2, 51.0, 21.8, 15.8; MS m/z (EI): 225 (M+ - OEt, 5%), 179 (100), 151 (41). Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.75; H, 8.56. 1,2-Diphenylethyl formate 7ba HCRC (HCOOH, without I2, r.t. = 23 h, 25 °C), CC (SiO2, petroleum ether), viscous colorless oil (81%); IR (neat): 3064, 3031, 2925, 1724, 1495, 1450, 1167, 755, 699 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.99 (s, 1H), 7.327.16 (m, 8H), 7.07-7.04 (m, 2H), 6.02 (dd, J = 7.7 Hz, J = 6.2 Hz, 1H), 3.21 (dd, J = 13.8 Hz, J = 7.7 Hz, 1H), 3.06 (dd, J = 13.8 Hz, J = 6.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): 5 160.1, 139.3, 136.6, 129.5, 128.4, 128.3, 128.2, 126.7, 126.6, 76.5, 42.8; MS m/z (EI): 180 (M+ - HCOOH, 61%), 135 (50), 107 (100), 91 (44), 79 (86), 77 (50). Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.66; H, 6.27. 1-(4-Methoxyphenyl)-2-phenylethyl formate 7ia HCRC (HCOOH, without I2, r.t. = 30 min, 25 °C), preparative chromatography (SiO2, CH2Cl2), white solid (55%); mp 63.0-63.8 °C; IR (KBr): 2910, 2837, 1710, 1512, 1242, 1163, 1035, 977, 831, 734, 698 cm-1; 1H NMR (300 MHz, CDCl3): 5 8.01 (s, 1H), 7.28-7.18 (m, 5H), 7.14-7.08 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.02 (dd, J = 7.8 Hz, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.24 (dd, J = 13.8 Hz, J = 7.8 Hz, 1H), 2.82 (dd, J = 13.8 Hz, J = 6.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): 5 160.2, 159.5, 136.7, 131.4, 129.5, 128.3, 128.1, 126.6, 113.8, 76.3, 55.2, 42.6; MS m/z(EI): 256 (M+, 3%), 211 (10), 165 (91), 137 (100), 109 (20), 69 (27); HRMS: Calcd for C16H16O3 256.1099; found 256.1102. Anal. Calcd for C.,H.,O,: C, 74.98; H, 6.29. Found: C, 16 16 3 74.71; H, 6.27. (E)-1,5-Diphenyl-4-methyl-2,4-di(4-methoxyphenyl) pent-1-ene 9a SFRC (r.t. = 30 min, 25 °C), CC and separation by preparative chromatography (SiO2, petroleum ether/t-bu-tyl methyl ether = 97.5/2.5), whit2e solid (23%), mp 92.794.6 °C; IR (KBr): 2932, 2834, 1607, 1510, 1454, 1290, 1248, 1180, 1034, 824, 699 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.31-7.19 (m, 3H), 7.16-7.10 (m, 4H), 7.05-6.97 (m, 3H), 6.87 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.67-6.57 (m, 4H), 6.54 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3h), 3.24 (d, J = 13.9 Hz, 1H), 3.17 (d, J = 13.9 Hz, 1H), 2.83 (d, J = 13.1 Hz, 1H), 2.66 (d, J = 13.1 Hz, 1H), 0.92 (s, 3H); 13C NMR (75.5 MHz, CDCl3): 5 158.4, 157.2, 141.0, 138.9, 138.6, 137.6, 131.4, 130.5,128.9, 128.2, 128.1, 128.0, 127.3, 126.2, 125.7, 113.3, 112.8, 55.2, 55.1, 50.0, 43.0, 42.8, 23.3; MS m/z (EI): 448 (M+, <1%), 357 (<2), 225 (100), 91 (15). Anal. Calcd for C32H32O2: C, 85.68; H, 7.19. Found: C, 85.37; H, 7.38. 32 32 2 (Z)-1,5-Diphenyl-4-methyl-2,4-di(4-methoxyphenyl) pent-1-ene 9b SFRC (r.t. = 30 min, 25 °C), CC and separation by preparative chromatography (SiO2, petroleum ether/1- butyl methyl ether = 97.5/2.5), white solid (29%), mp 74.6-75.5 °C; IR (KBr): 2930, 2834, 1607, 1510, 1454, 1288, 1247, 1180, 1033, 826, 699 cm-1; 1H NMR (300 MHz, CDCl3): 5 7.08-6.99 (m, 8H), 6.85-6.63 (m, 9H), 6.15 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.06 (d, J = 13.1 Hz, 1H), 3.02 (d, J = 13.1 Hz, 1H), 2.85 (d, J = 13.1 Hz, 1H), 2.78 (d, J = 13.1 Hz, 1H), 1.12 (s, 3H); 13C NMR (75.5 MHz, CDCl3): 5 158.1, 157.3, 139.6, 138.6, 138.4, 137.7, 134.3, 130.5, 130.0, 128.9, 128.2, 127.7, 127.3, 125.9, 125.8, 113.5, 112.9, 55.2, 55.1, 53.6, 50.4, 42.9, 23.3; MS m/z (EI): 448 (M+, <1%), 357 (1), 225 (100), 91 (17). Anal. Calcd for C32H32O2: C, 85.68; H, 7.19. Found: C, 85.52; H, 7.44. 3. Results and Discussion Most of the published I2-catalyzed transformations of alcohols were conducted in relatively diluted solution, in a concentration range of 23 mol to 157 mol of solvent per mol of alcohol.61,62 In contrast, we examined the behavior of substituted benzylic alcohols in highly-concentrated Table 1. The effect of the alcohol structure 1 and reaction conditions (SFRC vs. HCRC) on the type of iodine-induced transformation Entry Alcohol Reaction conditionsa Conversionb Dimerization / Dehydration Ar R1 R2 1 and time [%] 2 / 3 1 Ph H H a A, 165 h 38 100 2 B, 165 h 90 100 3 Ph H Ph b A, 67 h 88 81 19 4 B, 67 h 10 100 5 Ph CH3 Ph c A, 20 h 100 100c 6 B, 48 h 100 100d 7 Ph Ph H d A, 10 min 100 100 8 B, 1 h 97 100 9 Ph Ph CH3 e A, 3 he 100 100 10 B, 1 h 10 100 11 Ph Ph Br f A, 96 he 98 100 12 B, 1 h 0 13 Ph Ph F g A,192 he 57 100 14 B, 1 h 0 15 p-An H H h A, 15 min 92 100 16 B, 15 min 92 100 17 p-An H Ph i A, 230 min 100 73 27 18 B, 1 h 95 100 19 p-An Ph H j A, 5 min 100 100 20 B, 5 min 100 100 21 o-An Ph H k A, 15 min 100 100 22 B, 15 min 100 100 23 p-An p-An Ph l A, 200 min 31 100 24 B, 200 min 100 100 a A: SFRC; 1 mmol of 1 and 0.03 mmol of I determined by 'H NMR spectroscopy. B: HCRC; 1 mmol of 1, 3 mmol of CH CI and 0.03 mmol of T. . b Conversion and product distribution c 4% of (Z)-isomer relatively to (E)-alkene, traces of the Hofmann alkene. d 5% of (Z)-isomer relatively to (E)-alkene, Zaitsev vs. Hofmann = 85/15. 1c remained intact without iodine under conditions A and B. e Reaction temperature was 55 °C, in all other cases was 25 °C. reaction medium, that contained only 3 mol of solvent per mol of the reactant. Variously substituted secondary and tertiary benzylic alcohols 1a-l, possessing different structural features were selected as substrates (Scheme 1). Groups Ar, R1, and R2 having electron-releasing substitu-ents should enhance the stability of electron-deficient intermediates, whereas ^-halogen atom R2 in 1f and 1g should increase the acidity of the methylene protons. The results of the iodine catalyzed transformation under SFRC and HCRC with alcohols 1a-l are summarized in Table 1 indicating that tertiary alcohols underwent dehydration, while secondary alcohols predominantly dimerized into ether derivatives 2. The aggregate state of alcohols played an important role; reaction mixtures in the case of solid alcohols 1 became pasty, which proved to be essential for the reaction progress. On the other hand, liquid alcohols were less challenging in terms of their aggregate state. 1-Phenylethanol 1a yielded exclusively ether 2a under both types of the reaction conditions (entries 1 and 2, A=SFRC, B=HCRC-CH2Cl2). Introduction of an additional phenyl group at C-2 (1b) increased the reactivity affording dimer 2b as the major product (81%), and trans-stilbe-ne (19%) as the sole dehydration product (entry 3). Enhanced reactivity of 1b could be ascribed to the stabilizing effect of the additional phenyl group. A remarkable decrease in reactivity was observed for fluoro-substituted analogues of 1a: 1-(2,3,4,5,6-pentafluorophenyl)ethanol and 1-phenyl-2,2,2-trifluoroethanol remained intact after three days at 85 °C under SFRC. Tertiary alcohols 1c, 1d and 1e only underwent dehydration into alkene 3 (Table 1, entries 5-10). A mixture of (Z)- and (£)-1,2-diphenylpropene was formed from 1c, with the latter being the major product. The transformation of 1c was accompanied by the formation of 2,3-diphe-nyl-1-propene (entries 5 and 6). 1c remained intact without iodine under conditions A and B, signifying the role of iodine. The role of acidity of the hydroxyl group and the C-2 hydrogen atom of C-2 halogenated tertiary alcohols 1f and 1g in I2-catalyzed transformation was examined (Table 1, entries 11-14). Reactivity was diminished in both cases, but fluoro derivative 1g (entry 13) reacted considerably more sluggishly than the bromo analogue 1f (entry 11), suggesting the ease of the proton removal from C-2 not being the most crucial in the process of dehydration, but the electron-accepting properties of the halomethyl group on the stability of the electron-deficient reaction intermediates. The introduction of methoxy group to the aromatic ring did not alter the reaction pathway in the case of 1-(4-me-thoxyphenyl)ethanol 1h, but dimerization was remarkably faster than with 1-phenylethanol 1a (entries 15 and 16). A similar enhancement of reactivity, induced by methoxy group, was observed also in the case of 1-(4-methoxy-phenyl)-2-phenylethanol 1i; dimerization was the major process, the proportion of the dehydration grew to 27% (Table 1, entry 17) when compared with 1b (entry 3) under SFRC. Interestingly, 1i gave dimeric ether 2i as the sole product under HCRC (entry 18). Tertiary alcohols 1j and 1k underwent dehydration, while position of the methoxy group (p-MeO vs. o-MeO) did not play a substantial role on the type of transformation and reaction rate (entries 19-22). The substantially lower reactivity of triaryl-substi-tuted alcohol 1l could be ascribed to the fact that substrate has the highest melting point and the lowest solubility Table 2. The effects of geometry, ring size and substituents on the iodine-catalyzed dehydration of tertiary alcohols 4 HO CH2R fyYS ^ K^yS^ HCRC 4 S Entry Alcohol Y R 4 Reaction timea Conversion [%]b 1 / ch3 a 15 min 3 2 23 h 100 3 / Ph b 15 min 0 4 96 h 0 5 ch2ch2 ch3 c 15 min 79 6 154 min 100 7 ch2ch2 Ph d 15 min 35 8 154 min 100 9 O ch3 e 15 min 67 10 60 min 100 11 O Ph f 15 min 65 12 30 min 100 a Reaction conditions: 1 mmol of 4, 3 mmol of CH2Cl2 and 0.03 mmol of I2 stirred at 25 °C. b Determined by 'H NMR spectroscopy. among alcohols 1, and the reaction mixture required a longer time to become pasty under SFRC (31% conversion, entry 23). In spite of the poor solubility of 1l in CH2Cl2, enhanced molecular migration was achieved, reflecting in a considerably higher degree of conversion under HCRC (entry 24). In general, the reactivity of the secondary and the tertiary alcohols differs drastically regardless on the conditions SFRC or HCRC. The secondary alcohols have a strong tendency of dimerization into ethers, while the tertiary alcohols underwent dehydration into alkenes. Such a clear-cut might be surprising; however, it could be somehow anticipated.31 One of the reasons for smooth dehydration of the tertiary-, in comparison with the secondary alcohols, might be the formation of the thermodynamically more stable alkenes. In addition, dimerization of the steri-cally hindered tertiary alcohols is disfavored. It could be concluded that substantially higher reactivity of me-thoxy-substituted alcohols (Table 1, entries 15-24) is likely a consequence of stabilization of the intermediates involved - the electron deficient species. Furthermore, we examined the role of geometry, ring size and heteroatom on I2-catalyzed transformation of the dibenzo-substituted tertiary alcohols 4 under HCRC-CH2Cl2; the results are collected in Table 2. Fluorene derivative 4a yielded 9-ethylidenefluorene 5a (Table 2, entries 1 and 2) but phenyl-substituted derivative 4b was not reactive under these conditions (entries 3 and 4). The low reactivity of 4a and 4b might be associated with the geometry and formation of the potential anti-aromatic fluorenyl carbocation.31,63,64 Dibenzosuberan deriva- tives 4c and 4d are not planar and were considerably more reactive than 4a an additional phenyl group did not enhance the reactivity of 4d. The substitution of a CH2CH2 group in the dibenzosuberan derivative with an O-atom decreased the reactivity of 9-ethyl-xanthen-9-ol 4e, while phenyl derivative 4f was more reactive than 4e. The results showed the importance of the geometry of the structure of the electron-deficient intermediates in dehydration reactions under HCRC. Further, we examined the role of nucleophilic, protic solvents (possessing different acidity, ionizing power, hy-drophobicity, and solubility of 1 and I2) on iodine-catalyzed transformations of secondary benzylic alcohols under HCRC (Table 3). Three reaction pathways were operative: dimeriza-tion, dehydration and substitution. The important role of solvent added on the type of transformation was demonstrated on 1,2-diphenylethanol 1b (entries 1-4). No reaction took place in MeOH, in the presence of HCOOH, only substitution occurred yielding 7ba (entry 3); in contrast, in the presence of H2O, dimerization was the dominant process (entry 4). Substrate 1b is considerably hydro-phobic and does not possess a strong electron-donating group, which is reflected in its relatively low reactivity. Introduction of methoxy group to the para position of the phenyl ring remarkably enhanced the reactivity and selectivity of reaction of 1-(4-methoxyphenyl)-2-phenyletha-nol 1i under HCRC (entries 5-8); contrary to 1b, in the case of MeOH, the methyl ether 6ia was obtained. Another surprising difference was established in the presence of Table 3. The effect of hydroxy-substituted solvent on the iodine-catalyzed transformations of alcohols 1 under HCRC OH |2 HCRC [DIMERIZATION] (DEHYDRATION] (SUBSTiTUTIONj Ar—|—CHjR1 H 1 7 R2 = CHO Entry Ar Alcohol R1 1 Reaction conditions" Conversion [%]b Product distribution11 2 3 6/7 1 Ph Ph b CH2Cl2 / 67 h 10 100 2 MeOH / 67 h 0 3 HCOOH / 23 h 89 100 4 H2O / 67 h 14 90 10 5 p-An Ph i CH2Cl2 / 60 min 97 100 6 MeOH / 20 h 100 5 95 7 HCOOH / 30 min 100 87 13d 8 H2O / 230 min 100 88 12 9 p-An H h CH2Cl2 / 15 min 92 100 10 MeOH / 180 min 95 5 95 11 HCOOH / 30 min 98 8 92 12 H2O / 15 min 96 100 a 1 mmol of 1, 3 mmol of solvent and 0.03 mmol of I2 stirred at 25 °C. b Conversion and product distribution determined by 'H NMR spectroscopy. c Dimerization vs. Dehydration vs. Substitution. d A ratio 2/7 without I2 was 23/77. HCOOH, where dimerization was the main process (entry 7), while transformation without I2 furnished a mixture of 2i and 7ia in reversed ratio (23/77). The contrasting result suggests that iodine activated 1i. Results of reactivity of 1i (entries 5-8) suggest that iodine activated 1i which di-merized predominantly in the absence of good nucleop-hiles (entries 5, 7 and 8). In the presence of MeOH, a me-thoxy ether 6ia was the major product (entry 6), while a small extent of dehydration was observed in the cases of 1,2-diaryl-substituted alcohols only. 1-(4-methoxyphenyl) ethanol 1h, the least hydrophobic and sterically-hindered in this series, was the most reactive (entries 9-12), but with altered selectivity. In the presence of CH2Cl2 and H2O, dimerization took place (entries 9 and 12), while substitution was the main process in the presence of MeOH and HCOOH, giving 6ha and 7ha, respectively (entries 10 and 11). 1h was esterified with HCOOH under SFRC without iodine,32 thus signifying the role of pKa, and iodine has little influence on reaction of 1h with HCOOH (entry 11). The reactivity pattern of 1h is similar to 1i, where substitution predominantly took place in the presence of relatively good nucleophiles, whereas dimerization is prevalent in their absence. The alcohols and alkenes substituted with electron rich-aromatic groups might be sensitive to polymerization and are known to undergo different types of transformation. Indeed, 4-methoxybenzyl alcohol 1m proved to be the right target in this regard (Table 4); under SFRC, dimerization giving 2m was the main process (entry 1), ipso-substitution also took place, however polymerization completely prevailed after 200 minutes producing tar material only. Similar product distribution was obtained under HCRC-CH2Cl2 (entry 2). No other alkylation of the aromatic ring was noted. The third reaction channel was substitution; it occurred in the presence of MeOH giving 6ma, and a small proportion of dimer 2m was also formed, but no polymerization was noted, even after 190 hours (entry 3). Di-merization was the main process in the absence of a nucle-ophile, and ipso-substitution appeared as minor, but additional reaction channel. Considering that ipso-substitution is often related with cationic intermediates,65 it could be assumed that formation of 8 is another suggestion of involvement of electron-deficient intermediates. Next, we studied the transformation of sterically hindered and hydrophobic tertiary alcohol with the electron-rich aromatic ring, 1-phenyl-2-(4-methoxyphenyl)-2-propanol 1n in the presence of a catalytic amount of iodine (Table 5). 1n is a substrate of choice because it possesses an activated aromatic ring for good reactivity and it could form a well stable potential intermediate to study its fate under SFRC and HCRC. Reaction mixture after 30 minutes at room temperature under SFRC contained at least three products. The major product was easily identified as the Zaitsev-type product, (E)-2-(4-methoxyphenyl)-1-phe-nyl-1-propene 3na (entry 1). However, the two other products had very similar physicochemical properties, reflecting in almost identical retention factors; the molecular mass of 448 indicated that dimerization occurred. The structures of these two alkenes were elucidated on the basis of 1D and 2D NMR spectra and identified as (E)-1,5-diphenyl-4-methyl-2,4-bis(4-methoxyphenyl)pent-1-ene 9a and its (Z)-isomer 9b. The explanation of the formation of these two alkenes is presented in Table 5. The results suggest that iodine likely induced the formation of tertiary electron-deficient intermediate or related species, probably similar to the intermediate A; its subsequent dehydra- Table 4. The effect of the reaction conditions on the iodine-catalyzed transformation of 4-methoxybenzyl alcohol Entry Reaction conditions" Conversion [%]b Dimerization / Ipso / Substitution11 2m / 8 /6ma 1 SFRC / 150 min 54 82 / 8 2 HCRC-CH2Cl2 / 150 min 37 86 / 14 3 HCRC-MeOH / 190 h 91 10 / 90 a SFRC: 1 mmol of 1m and 0.03 mmol of I2, HCRC: 1 mmol of 1m, 3 mmol of solvent and 0.03 mmol of I2 stirred at 25 °C. b Conversion and product distribution determined by 1H NMR spectroscopy. c Dimerization vs. Ipso substitution vs. Substitution. Table 5. The effect of the reaction conditions on the iodine-catalyzed transformations of 1n MeO 9b Entry Reaction conditions" Conversion [%]b 3na'+3nac 3nb Product distribution 9a 9b 6d 1 SFRC 100 57 23 20 2 CH2Cl2-3 mmol 100 58 21 21 3 CH2Cl2-30 mmol CHp^OO mmol 98 70 12 8 10 4 0 5 MeOH-3 mmol 78 30 15 55 6 MeOH-30 mmol 68 100 7 MeOH-300 mmol 0 8 EtOH-3 mmol 61 44 23 33 9 (CH3)2CHOH-3 mmol 77 67 33 10 (CF3)2CHOH-3 mmol 100 72 14 14 a SFRC; 1 mmol of 1n and 0.03 mmol of I2, HCRC; 1 mmol of 1n, 3, 30 or 300 mmol of solvent and 0.03 mmol of I2 stirred at 25 °C for 30 min. b Conversion determined by 'H NMR spectroscopy. c Data refer to the sum of 3na and 3na', with (E)/(Z) = 95/5 (entries 1, 5, 8-10) and (E)/(Z) = 90/10 in entries 2 and 3. d Methoxy ether 6na in the case of MeOH and ethoxy ether 6nb in the case of EtOH were formed. tion predominantly led to the mixture of (Z)- and (E)-2-(4-methoxyphenyl)-1-phenyl-1-propene 3na and 3na', the Hofmann type dehydration furnished 2-(4-methoxy-phenyl)-3-phenyl-1-propene 3nb. However, the latter 3nb was not stable under the studied conditions and further attacked primarily formed species A, resulting in a cation-ic-like intermediate B or a related species, and removal of the benzylic proton furnished the isomeric alkenes 9a and 9b. Continuing, we examined the effect of 3 mmol of CH2Cl2 on the transformation of 1 mmol of 1n. The added solvent had no significant impact on the type of transformation (entry 2). Alkene 3nb was isolated and treated in an independent experiment with 3 mol% of I2 in di-chloromethane until the full consumption of 3nb. Alkenes 3na, 3na', 9a and 9b were formed in this process potentially via A'. A could furnish 3na and 3na' or it could add to the rest of 3nb producing 9a and 9b. In contrast, an independent transformation of a mixture of the isolated alkenes 3na and 3na' with 3 mol% of I2 failed, since 3na and 3na' remained intact. Alkenes 3na and 3na' are thermodynam-ically more stable than 3nb and were not be activated by iodine. In contrast, a larger amount (30 mmol) of CH2Cl2 suppressed addition of the species A to alkene 3nb and favored the formation of the Zaitsev type product 3na (entry 3). Interestingly, 1n remained unreacted in a highly diluted solution of 300 mmol of dichloromethane (entry 4). It is obvious that the vicinity of the reacting species is of the prime importance, demonstrating a crucial role of the concentration. In the presence of 3 mmol of MeOH, dehydration and substitution processes were observed, giving alkenes 3na, 3na' and 3nb and methoxy ether 6na (entry 5). Methanol blocked the addition of A to alkene 3nb, the selectivity Zaitsev vs. Hofmann decreased (entry 5) in comparison with the entries 1-3. Turnover in transformation occurred in the presence of a 10-fold higher amount of MeOH, and only ether 6na was obtained (entry 6); no reaction took place in the presence of 300 mmol of methanol (entry 7). In the presence of 3 mmol of ethanol (entry 8), the same reaction pathways were observed as in the presence of methanol (entry 5). In the presence of ¿-PrOH and (CF3)2CHOH (HFIP), no substitution occurred (entries 9 and 10); the Zaitsev alkene was more favored than in EtOH (entry 8), and finally reached 72% in the presence of HFIP, where alkene 3nb was further transformed to 9a and 9b (entry 10). It could be concluded that dehydration and further reaction of the formed intermediates took place under SFRC and HCRC in the presence of a non-nu-cleophilic solvent (CH2Cl2) and HFIP. The latter solvent is known to stabilize the carbocationic intermediates,66,67 and this could be an indication that our intermediates may be similar. The competition between dehydration and substitution took place under HCRC (3 mmol of alcohol, entries 5 and 8) in a nucleophilic solvent (MeOH and EtOH), while in the presence of 30 mmol of methanol, substitution took place exclusively. It is noteworthy to say that certain processes take place under SFRC and HCRC, but not under classical diluted conditions in a solution - the formation of 9a and 9b is such an example. 4-methoxybenzyl alcohol 1m proved to be very reactive substrate under the studied conditions, and it tended to yield insoluble, probably polymerized products after prolonged reaction time. Consequently, we decided to explore the reactivity of exceedingly acid sensitive 9H-xan-thene-9-ol 10 in the presence of catalytic amount of I2 (Table 6). 2 Alcohol 10 was found to be very reactive; the reaction under SFRC was accomplished in 15 minutes at room temperature in spite of a solid reactant and catalyst. To our surprise, disproportionation took place giving the product 11a and 11b as the only products (entry 1). Similar observation could be made in detritylation of ethers using I2 in methanol.68 We published a detailed iodine-catalyzed dis-proportionation of ethers under SFRC.39 Disproportion-ation took place also in the presence of dichloromethane under HCRC, and it was even faster probably due to the higher migration of the reactants (entry 2). Transformation of 10 under HCRC in the presence of MeOH yielded the related methoxy ether 11c, a very acid sensitive compound, too (entry 3). In order to obtain information about the role of geometry (cyclic 9-xanthhydrol vs. acyclic diphenyl methanol) and substituents, the transformation of diphenyl methanol and bis(4-methoxyphenyl)methanol was studied under HCRC-CH2Cl2. Only dimerization took place, and no disproportionation was noted. Dimerization of bis(4-methoxyphenyl)methanol to bis[bis(4-methoxyphe-nyl)methyl] ether occured in five minutes, while bis(di-phenylmethyl) ether was obtained in 71% yield after two days at room temperature. In MeOH, substitution took place, and bis(4-methoxyphenyl)methyl methyl ether was formed in 77% yield. Diphenyl methanol yielded the corresponding methyl ether as the main product, and a small amount of bis(diphenylmethyl)ether. Bis(pentafluorophe-nyl)methanol was found inert in the I2-catalyzed reaction; no conversion was noted after two days at 85 °C under SFRC. It can be concluded that reactivity is essentially dependent on the structure and geometry of the alcohol; the electron-accepting groups tend to disfavor the transformation. 4-Methoxyphenyl-substituted alcohols 1m and 1h were proved very sensitive to the reaction conditions; for that reason, we investigated the role ofpKa of alcohols added under HCRC, Table 7. Dimerization of 4-methoxybenzyl alcohol 1m was the main process in the absence of a good nucleophile (HCRC-CH2Cl2), while ¿pso-substitution took place as CQO 11b Entry Reaction conditions Conversion (%)c Distibution of products 11a / 11b / 11c 1 SFRCa / 15 min 100 50 / 50 2 CH2Cl2b / 5 min 100 50 / 50 3 MeOHb / 5 min 100 100 a 1 mmol of 10, 0.03 mmol of I2, T = 25 °C. b 1 mmol of 10, 3 mmol of solvent, 0.03 mmol I2, T = 25 °C. c Conversion and product distribution determined by 'H NMR spectroscopy. Table 6. The effect of the reaction conditions on iodine-catalyzed transformation of 10 O 11c Table 7. The effect of the HCRC on the transformation of 1m and 1h Entry 1 R2OH Reaction timea Conversion (%)b 2 6 / i^au 8 1 1m MeOH 190 h 91 10 90 2 1m EtOH 360 h 80 16 80 / 4 3 1m ¿-PrOH 360 h 67 29 64 / 7 4 1m cf3ch2oh 1 h 40 77 / 23 5 1m (cf3)2choh 1 h 30 65 / 35 6 1h MeOH 15 min 43 14 86 7 1h MeOH 3 h 95 5 95 8 1h EtOH 15 min 49 61 39 9 1h EtOH 25 h 98 12 88 10 1h ¿-PrOH 15 min 37 80 20 11 1h ¿-PrOH 25 h 98 25 75 12 1h cf3ch2oh 15 min 83 20 80 13 1h CF3CH2OH 2.5 h 96 8 92 14 1h (cf3)2choh 15 min 60 100 a1 mmol of 1, 3 mmol of R2OH, 0.03 mmol of I2, T = 25 °C. bConversion and product distribution determined by 'H NMR spectroscopy. well (Table 4, entry 2). The addition of alcohols extensively retarded transformation of 1m (Table 7, entries 1-3); the proportion of substitution is decreasing with the growing sterical hindrance and the reducing nucleophilicity of the solvent. A noteworthy modulation of the reactivity was noted in the case of more acidic and low nucleophilic 2,2,2-trifluoroethanol (TFE) and HFIP. Starting 1m displayed a strong tendency of polymerization in the latter two alcohols, and after too long reaction time, the tar material was only isolated. The reaction time was consequently limited to one hour and dimerization and ¿pso-substitu- tion were the only processes (entries 4 and 5). Both alcohols are poor nucleophiles, and no substitution took place. An additional methyl group contributed to the substantially higher reactivity of 1-(4-methoxyphenyl)ethanol 1h in comparison with 1m, dimerization and substitution became the only reaction channels. Dimerization was the exclusive transformation in the absence of a good nucleo-phile (HCRC-CH2Cl2) (Table 3, entry 9). In the presence of MeOH, EtOH and ¿-PrOH substitution and dimerization took place (Table 7, entries 7, 9 and 11), exhibiting a similar reactivity pattern as in the case of 1m. It is evident that Table 8. The effect of the hydroxy-substituted solvent on the conversion of 2h under HCRC Entry ROH Reaction timea Conversion (%) 6 1h MeOH EtOH ¿-PrOH cf3ch2oh ŒLCOOH 3 h 15 h 15 h 1.5 h 6 h 75 74 52 91 79 97 97 96 95 88c 3 3 4 5 12 a Reaction conditions: 1 mmol of 2h, 3 mmol ROH, 0.03 mmol of I2, T = 25 °C, R. t. (reaction time). b Conversion and product distribution determined by 1H NMR spectroscopy. c The product is 1-(4-methoxyphenyl)ethyl acetate 6he. / the dimeric ether 2 is a kinetically controlled product (entries 6-11), and iodine could catalyze its transetherifica-tion.69 Transformations of 1h were faster in presence of the fluorinated solvents; in the case of a better nucleophile TFE, substitution almost completely prevailed (entries 12 and 13), while in the presence of HFIP dimerization was the only process (entry 14). It could be concluded that reactivity patterns of 1m and 1h in the presence of iodine under SFRC and HCRC are similar. Dimerization of both alcohols is the key process in the absence of a good nucleophile, while substitution took place predominantly in the presence of a good nucleophile. It is evident in the Table 7 that dimerization is followed by transetherification, and we decided to further investigate this rather unexplored process, Table 8. Functionalization of 2h in the presence of methanol under HCRC yielded the corresponding methyl ether 6ha (97%) and 3% of the alcohol 1h (entry 1). This is an indication that relation between 1h and 2h is reversible. The conversion roughly corresponds with the nucleophilicity of the alcohols (entries 1-3); in the case of the most sterically hindered and least nucleophilic ¿-PrOH the lowest conversion was achieved. A surprising turning point was observed in CF3CH2OH (entry 4). Although considerably more acidic and worse nucleophile than ethanol, the highest conversion was achieved in CF3CH2OH. The result reflects the much stronger stabilization of the reaction intermediates in comparison with the simple alkyl alcohols. Transformation of 2h in the presence of acetic acid yielded the corresponding acetate ester 6he (entry 5), demonstrating the carboxylic acids are suitable nucleophiles in this reaction. Products 6 were considerably more stable than 2h, and remained intact in the presence of iodine. The Hammett correlation70,71 is a convenient tool for the estimation of the nature of the reaction intermediates and the type of bond cleavage, and in the case of ionic in- termediates, the degree of the charge developed. It is determined under homogenous conditions in diluted solution; however, we decided to examine the relative reactivity of the substituted 1-phenylethanols in I2-catalyzed dimeriza-tion under SFRC (Figure 1). The SFRC conditions are challenging, and therefore the Hammett correlation has been rarely studied.72 The relative reactivity of 1-phenylethanol 1a toward its substituted 4-F 1o, 3-Me 1p, 3-MeO 1q, 4-Cl 1r and 4-Br 1s derivatives was studied at 55 °C, all the alcohols are liquid at given temperature. In all cases, dimeric ethers 2a and 2o-s were formed and good Hammett correlation (r2 = 0.98) was obtained utilizing a+ substituent constants. The slope p+ = -2.8 suggests the transition state involving electron-deficient intermediates with a partial developed charge in a rate-determining step. A similar value of p = -2.76 was obtained in I2-catalyzed dihydroperoxidation of benzaldehydes in acetonitrile at 22 °C.73 It can be summarized that iodine has a remarkable feature of generation of species that would normally require the use of a strong acid. In order to demonstrate the role of iodine, reactivity of different catalytic systems were examined on an exceedingly acid-sensitive substrate 9H-xanthene-9-ol 10, giving 11a and 11b smoothly,74 Table 9. Entries 1 and 2 were added from Table 6 for easier comparison. Transformation of 10 in the presence of phosphomolybdic acid hydrate under SFRC was much less effective in comparison with the I2-catalyzed reaction (entry 3), while reaction in the presence of methanol yielded the methoxy ether 11c with 84% selectivity (entry 4). Ex-pectedly, disproportionation of 10 in the presence of 57 % aqueous solution of HI was the only process75 (entry 5), whereas in the presence of methanol 80% of 11c was formed (entry 6); displaying similar reactivity in the presence of heteropoly acid and HI (entries 3-6). Reaction of Entry R 1 o+ l0g krel 1 4-F 1o -0.07 0.30 2 3-Me 1P -0.07 0.24 3 H 1a 0 0 4 3-OMe 1q 0.05 -0.10 5 4-Cl 1r 0.11 -0.24 6 4-Br 1s 0.15 -0.37 Figure 1. Hammett correlation analysis on I2-catalyzed dimerization of 1. Acta Chim. Slov. 2017, 64, 747-762 Table 9. Comparison of activity of different catalysts on the transformation of 10a OH 0 OMe iTYS . -rViPi + f YTI+n conditions s a? 0 0 ^ 10 11a 11Ö 11c Entry Catalyst Reaction time, rt Conversion (%)b 11a 11b 11c 1 3% I2/SFRCc 15 min 100 50 50 2 3% yMeOH 5 min 100 100 3 PMA/SFRCd 15 min 29e 7 7 4 PMA/MeOHf 5 min 100 8 8 84 5 3% HI (57%)« 15 min 100 50 50 6 3% HI (57%)/MeOHh 5 min 100 10 10 80 7 3% I2/3% H2O/MeOH' 5 min 100 100 8 3% y3% KI/SFRO 15 min 100 50 50 9 3% I2/3% KI/MeOHk 5 min 100 100 10 3% I2/3% Bu4NI/SFRC' 15 min 40m 2 2 11 3% I/3% BuNI/MeOH" 2 4 5 min 95 100 a Reaction conditions: 10 (1 mmol, 198 mg) and various catalysts, rt. b Conversion and product distribution determined by 'H NMR spectroscopy. c Entries 1 and 2 from Table 6. d 10 (1 mmol, 198 mg) and phosphomolybdic acid hydrate (PMA, H3[P(Mo3O10)4] • xH2O), 60 mg. e 71% of unreacted 10 and 15% of a new, unidentified product presumably a ROR type dimer of 10. f 10 (1 mmol, 198 mg), methanol (3 mmol, 96 mg) and PMA (60 mg). g 10 (1 mmol, 198 mg) and HI (57 % aqueous solution, 0.03 mmol, 6.7 mg). h 10 (1 mmol, 198 mg), methanol (3 mmol, 96 mg) and HI (57% aqueous solution, 0.03 mmol, 6.7 mg). i 10 (1 mmol, 198 mg), H2O (0.03 mmol, 0.6 mg), methanol (3 mmol, 96 mg) and I2 (0.03 mmol, 7.6 mg). j KI (0.03 mmol, 5 mg) and I2 (0.03 mmol, 7.6 mg) were stirred for 20 minutes, 10 (1 mmol, 198 mg) was added. k KI (0.03 mmol, 5 mg), I2 (0.03 mmol, 7.6 mg) were stirred for 20 minutes, 10 (1 mmol, 198 mg) and methanol (3 mmol, 96 mg) were added. l I2 (0.03 mmol, 7.6 mg) and Bu4NI (0.03 mmol, 11.1 mg) were stirred for 20 minutes, 10 (1 mmol, 198 mg) was added. m 60% of unreacted 10 and 36% of a new product, presumably a ROR type dimer of 10. n I2 (0.03 mmol, 7.6 mg), Bu4NI (0.03 mmol, 11.1 mg) were stirred for 20 minutes, 10 (1 mmol, 198 mg) and methanol (3 mmol, 96 mg) were added. 10 in a mixture of 3% of I2, 3 % of water and 3 mmol of methanol furnished 11c as the only product (entry 7). The result indicates that iodine is relatively highly water tolerant76 and retains its catalytic activity in contrast to the numerous other Lewis acids. Iodine and KI were stirred together before 10 were added in order to establish the effect of iodine complexation. Disproportionation took place quantitatively, indicating at least two possible scenarios. Complexation of iodine and potassium iodide might be poor; on the other hand, triiodide could possibly catalyze the disproportionation (entry 8). Reaction of 10 with the system I2/KI/MeOH yielded the methoxy ether 11c as a (substitution) Scheme 1. A suggested role of iodine in transformation of alcohols under SFRC and HCRC. sole product (entry 9). Additional complexation of I2 with Bu4NI almost completely suppressed disproportionation, suggesting that formation of triiodide was a key (entry 10). Reaction of 10 with I2/Bu4NI in the presence of methanol yielded the methoxy ether 11c only, while no disproportionation took place (entry 11). In reactions in entries 3 and 10 an unidentified product appeared, seemingly a di-meric ether of 10. There is often speculated, though not experimentally proven, that the in-situ formed HI is the actual catalyst in the iodine-catalyzed transformations.77 A potential formation of HI would probably result in a loss of the reaction selectivity (comparison of entries 2 and 6). The results indicate that iodine was the active catalyst, where complexation changed the reaction pathway considerably. Additionally, iodine was titrated with a standard solution of Na2S2O3 after the end of the disproportionation of 10. The entire amount of iodine was present at the end of the reaction. Similar observation was made in the case of dimerization of a secondary alcohol and substitution reaction with methanol, strongly indicating iodine as the active catalyst in these reactions. A tentative explanation of the reaction pathways is presented on Scheme 2. The driving force in all cases is presumably polarization of the reactants by iodine. We proposed such halogen bond78 activation in disproportionation of ethers under SFRC39, which is in agreement with recent computational37 and experimental studies.38 A simultaneous TS-1 or two separated activation processes TS-2, including carbenium ion TS-3 could be proposed as the key steps in the dimerization process. In the absence of a better nucleophile, the starting alcohol took over a role of an attacking nucleophile, affording the dimer 2. The dehydration process of the tertiary alcohols might be initiated by polarization of the starting alcohol as shown in TS-4. The substitution step is suggested as a concomitant activation TS-5 or a divided activation TS-6 or by carbenium ion TS-7. In the presence of added stronger nucleophile, substitution products 6 and 7 substantially prevailed over the dimerization products 2. ary alcohols. The difference in thermodynamic stability of the alkenes, derived from the tertiary and the secondary alcohols, is supposedly a driving force for the observed selectivity. Substitution was another process observed in the presence of the hydroxylic solvents; their acidity, nucleop-hilicity and hydrophobicity were important parameters for studying the reactivity of those alcohols. 4-Methoxyphe-nyl-substituted alcohols possessed higher reactivity than phenyl analogues; their pentafluorophenyl counterparts were unreactive under the studied conditions. The results indicated the electron-deficient intermediates to be likely involved in these processes, the geometries of the molecule and heteroatom share an important part in reactivity. 4-Methoxybenzyl alcohol yielded its dimeric ether and bis(4-methoxyphenyl)methane, a product derived via the I2-catalyzed ipso-substitution. 4-Methoxybenzyl alcohol exhibited higher reactivity in TFE and HFIP than in EtOH and in i-PrOH under HCRC, thus indicating stronger stabilization of the reaction intermediates in the fluorinated alcohols. A tertiary benzylic alcohol 1n was demonstrated to possess a special reactivity. It appears that upon its dehydration all three possible alkenes were obtained. The thermodynamically less stable alkene unexpectedly reacted with the initially formed intermediate, furnishing two dimeric alkenes. It is worth mentioning that certain processes take place under SFRC and HCRC, but not under the classical diluted conditions. This is an indication that reacting species have to be in close vicinity. Iodine catalyzed the disproportionation of 9H-xanthene-9-ol 10 under SFRC and HCRC, and in contrast, the substitution took place in the presence of MeOH. Iodine is a convenient catalyst for transetherification under mild conditions, it has a potential for interconversion of ether to ester. The Hammett correlation analysis of the I2-catalyzed dimerization of substituted 1-phenylethanols under SFRC (T = 55 °C) furnished straight-line p+ = -2.8 (r2 = 0.98). This fact strongly suggests the involvement of the electron-deficient intermediates with a certain degree of the developed charge in the transition state. 4. Conclusions To summarize, we have studied iodine-catalyzed transformations of aryl-substituted alcohols under SFRC and under HCRC, the concentration was proved to have an exceptional impact on the transformation. 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Ryu, Synthesis 1998, 835-836. 78. G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati, G. Terraneo, Chem. Rev. 2016, 116, 2478-2601. DOI: 10.1021/acs.chemrev.5b00484 Povzetek Preučevali smo z jodom katalizirane pretvorbe alkoholov pri reakcijskih pogojih brez topil (RPBT) in pri visoko koncentriranih pogojih (VKP) v prisotnosti različnih topil, da bi dobili vpogled v obnašanje reakcijskih intermediatov pri takšnih pogojih. Ugotovili smo, da z benzilnimi alkoholi potečejo trije različni tipi pretvorb: dimerizacija, dehidratacija in substitucija. Dimerizacija in substitucija pretežno potečeta v primeru primarnih in sekundarnih alkoholov, medtem, ko dehidratacija prevladuje v primeru terciarnih alkoholov. Relativna reaktivnost substituiranih 1-feniletanolov pri z jodom katalizirani dimerizaciji pri RPBT daje dobro Hammettovo korelacijo p+ = -2.8 (r2 = 0.98), ki kaže na prisotnost elektronsko siromašnih intermediatov z določeno stopnjo razvitega naboja v prehodnem stanju.