Direct and efficient synthesis of unsymmetrical ethers from alcohols catalyzed by Fe(HSO4)3 under solvent-free conditions

Article abstract of DOI:10.1007/s11164-015-2098-y

Highly efficient Fe(HSO₄)₃ catalyzed etherification of primary, secondary and tertiary benzylic alcohols with primary and secondary aliphatic alcohols is reported. The reaction affords unsymmetrical benzyl ethers in good to excellent yields under solvent-free conditions.

Full text of DOI:10.1007/s11164-015-2098-y

Res Chem Intermed
DOI 10.1007/s11164-015-2098-y
Direct and efficient synthesis of unsymmetrical ethers
from alcohols catalyzed by Fe(HSO4)3 under
solvent-free conditions
Bashir Nazari Moghadam1 Batool Akhlaghinia1
•
•
Soodabeh Rezazadeh1
Received: 27 November 2014 / Accepted: 6 May 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Highly efficient Fe(HSO4)3 catalyzed etherification of primary, sec-
ondary and tertiary benzylic alcohols with primary and secondary aliphatic alcohols
is reported. The reaction affords unsymmetrical benzyl ethers in good to excellent
yields under solvent-free conditions.
Keywords Etherification Á Ferric hydrogen sulphate [Fe(HSO4)3] Á Alcohols Á
Unsymmetrical ethers
Introduction
Ethers are essential compounds in organic chemistry, serving as products and
important precursors in organic synthesis. Ether bond formation has a fundamen-
tally important and central position in organic chemistry, and there are many
synthetic routes for practical preparation of ethers. The Williamson ether synthesis
is still the best general method for the preparation of symmetrical and unsymmet-
rical ethers [1–7]. This method generally involves the preparation of halides,
followed by their substitution with alkoxides under strong basic conditions, which
cause undesired side reactions such as elimination of the alkylating agent and the
generation of large amounts of waste that leads to reduction of both selectivity and
yield. However, the Williamson ether synthesis is impractical because the starting
halide compounds are not easily available or they are too expensive. Alternatively,
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2098-y)
contains supplementary material, which is available to authorized users.
&
Batool Akhlaghinia
akhlaghinia@um.ac.ir
1
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad,
9177948974 Mashhad, Iran
123

B. N. Moghadam et al.
the direct preparation of ethers from alcohols is more environmentally friendly, and
has attracted much attention because of its advantages, such as easy work-up
procedures, low costs and the formation of water as the only by-product [8–38]. The
dehydration of alcohols using many homogeneous catalysts such as Brønsted acid or
Lewis acid have been reported in the etherification of alcohols [8–29]. Ethers are
also prepared through hydroalkoxylation of alkenes, [39–41] alcoholysis of
epoxides, and [42–44] reductive etherification of carbonyl compounds with
triethylsilane and alkoxytrimethylsilane [45–50].
Today, because of strict environmental legislation, heterogeneous catalysis has
become attractive in view of their isolation and separation from the reaction media.
The reported heterogeneous catalysts have been mostly applied to the synthesis of
symmetrical ethers, while the heterogeneous catalysts for the synthesis of
unsymmetrical ethers are still rare [16–18].
Under this purview, we have been motivated to develop a convenient and
efficient protocol for the synthesis of a wide range of unsymmetrical ethers using
heterogeneous catalysts.
Experimental
General
The products were purified by column chromatography. The purity determinations
of the products were accomplished by TLC on silica gel polygram STL G/UV 254
plates. The melting points of products were determined with an Electrothermal Type
9100 melting point apparatus. The FT-IR spectra were recorded on an Avatar 370
FT-IR Therma Nicolet spectrometer. The NMR spectra were provided on Brucker
Avance 400 MHz instruments in CDCl3. Mass spectra were recorded with a
Shimadzu GC–MS-QP5050 and CH7A Varianmat Bremem instruments at 70 eV; in
m/z (rel %). All the products were characterized by IR, 1H NMR spectroscopy, mass
spectrometry and comparison of their melting points (or those of the derivatives)
with authentic samples. The catalyst were prepared and purified by the method
described in the literature [51].
Preparation of 1-(1-butoxyethyl) benzene in the presence of Fe(HSO4)3
To a mixture of 1-butanol (0.074 g, 1 mmol) and Fe(HSO4)3 (0.024 g, 7 mol%)
taken into a round-bottomed flask at room temperature, 1-phenyl ethanol (0.122 g,
1 mmol) was added dropwise. The mixture was stirred and heated in an oil bath at
90 °C for the given period of time (45 min). After completion of the reaction (TLC
monitoring), the reaction mixture was cooled to room temperature. EtOAc (15 mL)
was added to the reaction mixture, stirred for a while, and filtered. The filtrate was
washed with saturated NaHCO3 (2 9 10 mL) and H2O (3 9 10 mL). The organic
phase was dried over anhydrous Na2SO4, and concentrated in vacuo to give the
crude product which was then purified by thin layer chromatography using n-
hexane/EtOAc (20/1) to afford 1-(1-butoxyethyl) benzene(0.169 g, 95 %).
123

Direct and efficient synthesis of unsymmetrical ethers…
1-(1-Ethoxyethyl)benzene [52] (Table 2, entry 1) Oil; IR (neat): (t/cm-1) 3083,
3062, 3028, 2974, 2928, 2867, 1949, 1878, 1809, 1750, 1603, 1492, 1450, 1368,
ꢀ
1
1350, 1304, 1282, 1206, 1093 (C–O), 1027, 947, 911, 854, 760, 700, 632, 542; H
NMR (CDCl3, 400 MHz) d: 7.40–7.28 (m, 5H, Ph), 4.44 (q, J = 6.5 Hz, 1H, CH),
3.39 (q, J = 7.0 Hz, 2H, CH2), 1.48 (d, J = 6.4 Hz, 3H, CH3), 1.22 (t, J = 6.8 Hz,
3H, CH3); MS(EI): m/z (%) 150(5)[M]?, 121(87), 105(100), 77(75), 29(70).
1-(1-Butoxyethyl)benzene [52] (Table 2, entry 2) Oil; IR (neat): (tꢀ/cm-1) 3084,
3062, 3028, 2960, 2930, 2868, 2765, 2603, 1947, 1876, 1807, 1751, 1602, 1492,
1451, 1369, 1350, 1302, 1281, 1206, 1102 (C–O), 1030, 971, 948, 910, 841, 760,
1
700, 632, 610, 557, 542; H NMR (CDCl3, 400 MHz) d: 7.38–7.29 (m, 5H, Ph),
4.42 (q, J = 6.4 Hz, 1H, CH), 3.34 (t, J = 10.0 Hz, 2H, O-CH2), 1.61–1.56 (m, 2H,
CH2), 1.55 (d, J = 6.4 Hz, 3H, CH3), 1.44–1.31 (m, 2H, CH2), 0.91 (t, J = 7.2 Hz,
3H, CH3); MS(EI): m/z (%) 178(37)[M]?, 163(90), 105(27), 73(20), 57(60), 15(7).
ꢀ
1-(2-(1-Phenylethoxy)ethyl)benzene [53] (Table 2, entry 3) Oil; IR (neat): (t/
cm-1) 3084, 3062, 3027, 2975, 2928, 2863, 2765, 1947, 1877, 1807, 1753, 1603,
1545, 1494, 1452, 1391, 1369, 1351, 1323, 1304, 1282, 1206, 1177, 1102 (C–O),
1029, 1006, 994, 911, 829, 759, 699, 611, 587, 552, 506; 1H NMR (CDCl3,
400 MHz) d: 7.40–7.10 (m, 10 H, Ph), 4.42 (q, J = 6.3 Hz, 1H, CH), 3.52 (t,
J = 7.5 Hz, 2H, aCH2), 2.90 (m, 2H, bCH2), 1.48 (t, J = 6.3 Hz, 3H, CH3);
MS(EI): m/z (%) 226(97)[M]?, 211(5), 121(40), 105(80), 15(7).
-1
ꢀ
1-(1-Hexan-2-yloxy)ethyl)benzene (Table 2, entry 4) Oil; IR (neat): (t/cm
)
3084, 3063, 3028, 2972, 2929, 2870, 1948, 1876, 1807, 1753, 1602, 1492, 1451,
1370, 1350, 1303, 1281, 1206, 1142, 1091 (C–O), 1029, 948, 910, 857, 759, 699,
1
632, 613, 542, 514; H NMR (CDCl3, 400 MHz) d: 7.40–7.20 (m, 5H, Ph), 4.42
(q, J = 6.4 Hz, 1H, O(CH)Ph), 3.49 (m, 1H, O(CH)CH2), 1.60–1.25 (m, 9H,
3CH2 and CH3), 1.19 (d, J = 6.4 Hz, 3H, CH3), 0.88 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3) d: 144.2, 128.3, 127.1, 126.3, 75.2, 74.4, 69.5, 36.3,
27.8, 22.7, 19.6, 14.1; MS(EI): m/z (%) 206(7)[M]?, 121(25), 105(100), 101(10),
85(20).
Butoxydiphenylmethane [54] (Table 2, entry 5) Oil; IR (neat): (t/cm-1) 3086,
ꢀ
3062, 3028, 2957, 2931, 2869, 1600, 1493, 1452, 1343, 1303, 1185, 1095 (C–O),
1029, 763, 740, 699, 653, 612; 1H NMR (CDCl3, 400 MHz) d: 7.40–7.20 (m, 10H,
Ph), 5.40 (s, 1H, CH), 3.51 (t, J = 7.0 Hz, 2H, aCH2), 1.70–1.60 (m, 2H, bCH2),
1.50–1.40 (m, 2H, cCH2), 0.95 (t, J = 7.0 Hz, 3H, CH3); MS(EI): m/z (%)
240(7)[M]?, 183(15), 167(90), 163(25), 77(87), 57(5).
ꢀ
(3-Phenylpropoxy)diphenylmethane [55] (Table 2, entry 6) Oil; IR (neat): (t/
cm-1) 3085, 3061, 3026, 2941, 2859, 2771, 1949, 1889, 1807, 1738, 1601, 1585,
1494, 1452, 1396, 1343, 1303, 1263, 1184, 1155, 1100 (C–O), 1074, 1028, 922,
1
1
833, 746, 697, 653, 613, 583, 557, 492, 466; H NMR (CDCl3, 400 MHz) d: H
NMR (CDCl3, 400 MHz) d: 7.46–7.25 (m 15H, 3Ph), 5.45 (s, 1H, CH), 3.57 (t,
J = 7.0 Hz, 2H, aCH2), 2.84 (t, J = 7.0 Hz, 2H, cCH2), 2.10–2.03 (m, 2H, bCH2);
123

B. N. Moghadam et al.
MS(EI): m/z (%) 302(12)[M]?, 225(10), 183(70), 167(100), 135(25), 119(40),
77(70).
-1
ꢀ
(Phenethyloxy)diphenylmethane [55] (Table 2, entry 7) Oil; IR (neat): (t/cm
)
3084, 3061, 3027, 2939, 2861, 2764, 1949, 1889, 1807, 1748, 1601, 1544, 1493,
1451, 1391, 1344, 1304, 1264, 1183, 1156, 1096 (C–O), 1075, 1028, 913, 870, 834,
741, 699, 654, 614, 583, 544, 504, 469, 404; 1H NMR (CDCl3, 400 MHz) d:
7.37–7.20 (m, 15H, 3Ph), 5.37 (s, 1H, CH), 3.69 (t, J = 8.0 Hz, 2H, aCH2), 2.99 (t,
J = 8.0 Hz, 2H, bCH2); MS(EI)3: m/z (%) 288(5)[M]?, 211(5), 183(15), 167(80),
121(5), 105(100), 77(25).
-1
ꢀ
(Isopentyloxy)diphenylmethane [34] (Table 2, entry 8) Oil; IR (neat): (t/cm
3086, 3062, 3028, 2955, 2926, 2867, 1492, 1452, 1384, 1345, 1303, 1184, 1095 (C–
)
1
O), 1075, 1027, 1004, 756, 739, 699, 653, 614; H NMR (CDCl3, 400 MHz) d:
7.40–7.20 (m, 10H, 2Ph), 5.4 (s, 1H, CH), 3.54 (t, J = 6.4 Hz, 2H, aCH2), 1.87
(sept, J = 5.7 Hz, 1H, CH(CH3)2), 1.64–1.59 (m, 2H, bCH2), 0.99 (d, J = 6.7 Hz,
6H, 2CH3); MS(EI): m/z (%) 254(2)[M]?, 183(15), 177(10), 167(90), 87(10),
77(60).
(Hexan-2-yloxy)diphenylmethane (Table 2, entry 9) Oil; IR (neat): (t/cm-1) 3086,
ꢀ
3062, 3027, 2959, 2930, 2860, 1947, 1891, 1806, 1600, 1492, 1451, 1376, 1337,
1302, 1260, 1218, 1184, 1136, 1115, 1086 (C–O), 1060, 1028, 983, 923, 879, 842,
1
755, 740, 699, 653, 612, 571; H NMR (CDCl3, 400 MHz) d: 7.40–7.20 (m, 10H,
2Ph), 5.60 (s, 1H, CH(Ph)2), 3.70–3.40 (sept, 1H, CH(CH3)(CH2)), 1.80–1.30 (m,
6H, 3CH2), 1.34 (d, J = 7.0 Hz, 3H, CH3), 0.81 (t, J = 7.0 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3) d: 142. 9, 128.3, 127.4, 126.3, 80.5, 72.7, 36.6, 27.7, 22.9,
19.8, 14.2; MS(EI): m/z (%) 268(2)[M]?, 191(5), 183(20), 167(95), 101(5), 85(10),
77(65).
ꢀ
1-(Butoxymethyl)-4-methoxybenzene [36] (Table 2, entry 10) Oil; IR (neat): (t/
cm-1) 2999, 2957, 2932, 2863, 1612, 1585, 1513, 1462, 1361, 1300, 1247, 1175,
1
1096 (C–O), 1037, 821, 754, 578, 515; H NMR (CDCl3, 400 MHz) d: 7.30 (d,
J = 4 Hz, 2H, Ph), 6.90 (d, J = 4 Hz, 2H, Ph), 4.42 (s, 2H, CH2), 3.80 (s, 3H,
OCH3), 3.40 (t, J = 6.4 Hz, 2H, aCH2), 1.60–1.50 (m, 2H, bCH2), 1.40–1.30 (m,
2H, cCH2), 0.90 (t, J = 7.0 Hz, 3H, CH3); MS(EI): m/z (%) 194(10)[M]?, 163(5),
137(20), 121(100), 57(25).
1-3-(4-Methoxybenzyloxy)propyl)benzene [20] (Table 2, entry 11) Oil; IR
ꢀ
(neat): (t/cm-1) 3083, 3061, 3026, 3000, 2934, 2857, 2792, 2541, 2059, 1883,
1723, 1612, 1585, 1512, 1454, 1363, 1301, 1248, 1174, 1098 (C–O), 1034, 918,
1
820, 746, 699, 632, 578, 507; H NMR (CDCl3, 400 MHz) d: 7.30–7.27 (m, 4H,
Ph), 7.21–7.18 (m, 3H, Ph), 6.90–6.80 (m, 2H, Ph), 4.46 (s, 2H, CH2(O)(Ph)), 3.84
(s, 3H, OCH3), 3.49 (t, J = 6.6 Hz, 2H, aCH2), 2.72 (t, J = 7.3 Hz, 2H, cCH2),
1.94 (m, 2H, bCH2); MS(EI): m/z (%) 256(37)[M]?, 225(5), 137(10), 121(100),
119(5), 35(5).
1-(2-(4-Methoxybenzyloxy)ethyl)benzene [56] (Table 2, entry 12) Oil; IR (neat):
(t/cm-1) 3084, 3062, 3027, 3002, 2934, 2860, 2786, 1944, 1879, 1805, 1736, 1611,
ꢀ
123

Direct and efficient synthesis of unsymmetrical ethers…
1585, 1513, 1454, 1360, 1300, 1247, 1174, 1090 (C–O), 1034, 955, 822, 747, 699,
1
604, 575, 514; H NMR (CDCl3, 400 MHz) d: 7.31–7.19 (m, 7H, Ph), 6.88–6.83
(m, 2H, Ph), 4.45 (m, 2H, OCH2), 3.80 (s, 3H, OCH3), 2.92 (t, J = 7.2 Hz, 2H,
aCH2), 2.85 (t, J = 7.2 Hz, 2H, bCH2); MS(EI): m/z (%) 242(10)[M]?, 211(5),
137(5), 121(100), 105(90), 31(25).
1-((Isopentyloxy)methyl)-4-methoxybenzene [28] (Table 2, entry 13) Oil; IR
(neat): (tꢀ/cm-1) 3031, 2999, 2955, 2930, 2867, 2836, 2790, 1612, 1585, 1512,
1464, 1383, 1365, 1301, 1247, 1173, 1095 (C–O), 1036, 943, 820, 756, 578, 514; 1H
NMR (CDCl3, 400 MHz) d: 7.28 (d, J = 9.0 Hz, 2H, Ph), 6.90 (d, J = 9.0 Hz, 2H,
Ph), 4.43 (s, 2H, OCH2), 3.80 (s, 3H, OCH3), 3.40 (t, J = 7.2 Hz, 2H, aCH2), 1.70
(m, 1H, CH(CH3)2), 1.53–1.48 (m, 2H, bCH2), 0.90 (d, J = 7.0 Hz, 6H, 2CH3);
MS(EI)7: m/z (%) 208(10)[M]?, 137(20), 121(100), 87(30), 71(45), 31(20).
1-((Cyclohexyloxy)methyl)-4-methoxybenzene [56] (Table 2, entry 14) Oil; IR
(neat): (t/cm-1) 3035, 2998, 2931, 2855, 1612, 1584, 1511, 1450, 1364, 1300, 1246,
ꢀ
1
1174, 1087 (C–O), 1037, 959, 811, 747, 583, 514; H NMR (CDCl3, 400 MHz) d:
7.27 (d, J = 9.0 Hz, 2H, Ph), 6.89 (d, J = 9.0 Hz, 2H, Ph), 4.48 (s, 2H, OCH2),
3.78 (s, 3H, OCH3), 3.35–3.33 (m, 1H, OCH), 1.96–1.22 (m, 10H, cyclohexyl);
MS(EI): m/z (%) 220(25)[M]?, 137(20), 121(100), 99(10), 83(70), 31(25).
1-(sec-Butoxymethyl)-4-methoxybenzene [17] (Table 2, entry 15) Oil; IR (neat):
(t/cm-1) 3064, 3039, 2966, 2932, 2873, 2836, 1612, 1585, 1512, 1463, 1373, 1300,
ꢀ
1247, 1173, 1110, 1067 (C–O), 1036, 902, 820, 743, 579; 1H NMR (CDCl3,
400 MHz) d: 7.20 (d, J = 8.6 Hz, 2H, Ph), 6.80 (d, J = 8.6 Hz, 2H, Ph), 4.44 (s,
2H, OCH2), 3.80 (s, 3H, OCH3), 3.22–3.21 (m, 1H, OCH), 1.90–1.80 (m, 2H, CH2),
1.59 (s, 3H, CH3), 0.93 (t, J = 7.4 Hz, 3H, CH3); MS(EI)8: m/z (%) 194(20)[M]?,
137(20), 121(100), 73(7), 57(30), 31(25).
1-((Hexan-2-yloxy)methyl)-4-methoxybenzene (Table 2, entry 16) Oil; IR (neat):
ꢀ
(t/cm-1) 3063, 3031, 3002, 2958, 2932, 2859, 2836, 2059, 1989, 1879, 1612, 1585,
1512, 1464, 1374, 1338, 1300, 1247, 1174, 1113, 1072 (C–O), 1037, 924, 821, 750,
1
641, 578, 513; H NMR (CDCl3, 400 MHz) d: 7.28 (d, J = 8.4 Hz, 2H, Ph), 7.10
(d, J = 8.4 Hz, 2H, Ph), 4.51 (d, J = 12.0 Hz, 1H, OCH2), 4.41 (d, J = 12.0 Hz,
1H, OCH2) 3.81 (s, 3H, OCH3), 3.79–3.74 (m, 1H, OCH), 1.70–1.30 (m, 6H, 3CH2),
1.19 (d, J = 7.2 Hz, 3H, CH3), 0.91 (t, J = 7.5 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) d: 159.0, 131.3, 129.2, 113.8, 74.6, 69.9, 55.2, 36.4, 27.8, 22.8,
19.6, 14.1; MS(EI): m/z (%) 222(2)[M]?, 137(5), 121(100), 85(10), 31(15).
1-Methoxy-4-((octan-2-yloxy)methyl)benzene [57] (Table 2, entry 17) Oil; IR
ꢀ
(neat): (t/cm-1) 2957, 2930, 2856, 1613, 1586, 1512, 1464, 1373, 1339, 1301, 1247,
1172, 1119, 1083 (C–O), 1038, 931, 821, 752, 722, 579, 513; H NMR (CDCl3,
1
400 MHz) d: 7.27 (d, J = 8.4 Hz, 2H, Ph), 6.86 (d, J = 8.4 Hz, 2H, Ph), 4.50 (d,
J = 11.2 Hz, 1H, OCH2) 4.39 (d, J = 11.2 Hz, 1H, OCH2), 3.80 (s, 3H, OCH3),
3.50–3.46 (m, 1H, OCH), 1.43–1.27 (m, 10H, 5CH2), 1.17 (d, J = 6.0 Hz, 3H,
CH3), 0.88 (t, J = 6.8 Hz, 3H, CH3); MS(EI): m/z (%) 250(5)[M]?, 137(37),
121(100), 113(42).
123

B. N. Moghadam et al.
1-(Butoxymethyl)benzene [30] (Table 2, entry 18) Oil; IR (neat): (t/cm-1) 2999,
2957, 2932, 2863, 1612, 1585, 1513, 1462, 1361, 1300, 1247 (C–O), 1175, 1096,
ꢀ
1
1037, 821, 754, 578, 515; H NMR (CDCl3, 400 MHz) d: 7.37–7.25 (m, 5H, Ph),
4.50 (d, J = 6.3 Hz, 2H, OCH2), 3.48 (t, J = 6.4 Hz, 2H, aCH2), 1.64–1.57 (m, 2H,
bCH2), 1.45–1.36 (m, 2H, cCH2), 0.94 (t, J = 7.2 Hz, 3H, CH3); MS(EI): m/z (%)
164(15)[M]?, 107(5), 91(40), 77(5), 73(10), 57(95).
1-((Hexan-2-yloxy)methyl)benzene [58] (Table 2, entry 19) Oil; IR (neat): (tꢀ/
cm-1) 2960, 2931, 2860, 1732, 1601, 1491, 1465, 1375, 1339, 1274, 1117, 1086
1
(C–O), 1015, 923, 807, 739, 673, 481; H NMR (CDCl3, 400 MHz) d: 7.37–7.27
(m, 5H, Ph), 4.58 (d, J = 12.0 Hz, 1H, OCH2), 4.49 (d, J = 12.0 Hz, 1H, OCH2),
3.53–3.49 (m, 1H, CH), 1.63–1.30 (m, 6H, 3CH2), 1.21 (d, J = 6.0 Hz, 3H, CH3),
0.91 (t, J = 6.8 Hz, 3H, CH3); MS(EI): m/z (%) 192(2)[M]?, 107(57), 91(100),
77(42), 85(15).
ꢀ
1-(Butoxymethyl)-4-chlorobenzene [30] (Table 2, entry 20) Oil; IR (neat): (t/
cm-1) 3063, 3031, 3002, 2958, 2932, 2859, 2836, 2059, 1989, 1879, 1612, 1585,
1512, 1464, 1374, 1338, 1300, 1247 (C–O), 1174, 1113, 1072, 1037, 924, 821, 750,
1
641, 578, 513; H NMR (CDCl3, 400 MHz) d: 7.32–7.24 (m, 4H, Ph), 4.46 (s, 2H,
OCH2), 3.47 (t, J = 6.5 Hz, 2H, aCH2), 1.62–1.56 (m, 2H, bCH2), 1.45–1.36 (m,
2H, cCH2), 0.91 (t, J = 7.2 Hz, 3H, CH3); MS(EI): m/z (%) 198(2)[M]?, 141(5),
125(5), 111(10), 57(95).
ꢀ
1-Chloro-4-((hexan-2-yloxy)methyl)benzene (Table 2, entry 21) Oil; IR (neat): (t/
cm-1) 3084, 3027, 2960, 2931, 2860, 1896, 1777, 1719, 1598, 1576, 1491, 1464,
1408, 1375, 1338, 1297, 1250, 1205, 1143, 1117, 1087 (C–O), 1015, 922, 807, 729,
668, 482; 1H NMR (CDCl3, 400 MHz) d: 7.30–7.20 (m, 4H, Ph), 4.52 (d,
J = 12.0 Hz, 1H, OCH2), 4.40 (d, J = 12.0 Hz, 1H, OCH2), 3.52–3.40 (m, 1H,
CH), 1.46–1.29 (m, 6H, 3CH2), 1.18 (d, J = 6.0 Hz, 3H, CH3), 0.90 (t, J = 6.8 Hz,
3H, CH3); 13C NMR (100 MHz, CDCl3) d: 137.7, 133.0, 128.8, 128.4, 75.2, 69.5,
36.3, 27.7, 22.8, 19.6, 14.1; MS(EI): m/z (%) 226(2)[M]?, 141(5), 125(100), 111(7),
101(7), 85(10).
(Phenethyloxy)triphenylmethane [59] (Table 2, entry 22) mp 85–87 °C (lit.
87 °C); IR (KBr): (t/cm-1) 3057, 3022, 2932, 2873, 1596, 1489, 1445, 1392,
1222, 1193, 1153, 1058 (C–O), 1027, 982, 898, 767, 702, 629, 510, 477; H NMR
ꢀ
1
(CDCl3, 400 MHz) d: 7.38–7.18 (m, 20H, 4Ph), 3.31–3.28 (m, 2H, aCH2),
2.91–2.87 (m, 2H, bCH2); MS(EI): m/z (%) 364(5)[M]?, 259(2), 243(100),
105(100), 77(75).
(Cyclohexyloxy)triphenylmethane [60] (Table 2, entry 23) mp 78–80 °C (lit.
80 °C); IR (KBr): (tꢀ/cm-1) 3084, 3059, 3025, 2974, 2927, 2878, 1737, 1597, 1492,
1447, 1374, 1266, 1245, 1156, 1115, 1067 (C–O), 1003, 918, 898, 845, 745, 702,
1
632, 605, 481; H NMR (CDCl3, 400 MHz) d: 7.47–7.10 (m, 15H, 3Ph), 3.10 (m,
1H, OCH), 1.95 (m, 2H, cyclohexyl), 1.76 (m, 2H, cyclohexyl), 1.51–1.23 (m, 6H,
cyclohexyl); MS(EI): m/z (%) 342(10)[M]?, 259(5), 243(100), 83(5), 77(75).
123

Direct and efficient synthesis of unsymmetrical ethers…
Results and discussion
Recently, we demonstrated that Fe(HSO4)3 acted as an efficient solid acid catalyst
for C-alkylation of 1,3-dicarbonyl compounds [61]. The scope of this article was to
study the direct synthesis of unsymmetrical ethers from different classes of alcohols
under mild reaction conditions in the presence of Fe (HSO4)3 as an effective, easily
available, cheap, and reusable catalyst (Scheme 1).
Etherification of 1-phenyl ethanol with 1-butanol was chosen as the model
reaction to optimize the reaction conditions in the presence of Fe (HSO4)3 (Table 1).
At room temperature, in the absence of any catalyst and solvent, no reaction
occurred between 1-phenyl ethanol and 1-butanol (Table 1, entry 1). In the presence
of 10 mol% of Fe (HSO4)3 at ambient temperature, no reaction was observed
between 1-phenyl ethanol and 1-butanol (Table 1, entry 2). To improve the
efficiency of the catalyst, the effect of temperature was studied in etherification
reaction. Temperature has an essential effect on the reaction rate, so at 90 °C the
1-(1-butoxyethyl)benzene was obtained in 45 min (Table 1, entry 3). At the same
reaction conditions, using Fe (HSO4)3/silica leads to the formation of 1-(1-
butoxyethyl)benzene in a longer reaction time (Table 1, entry 4). Temperatures over
90 °C were not suitable for etherification reaction in the presence of Fe (HSO4)3,
because of the formation of by-products (Table 1, entry 5). The effect of different
solvents was investigated on the etherification reaction by performing the reaction in
CH3CN, 1,4-dioxane, and toluene (Table 1, entries 6–8). As can be seen, in
comparison with solvent-free condition, performing the etherification reaction in
different solvents does not lead to the formation of 1-(1-butoxyethyl) benzene in a
reasonable rate and yield. The effect of different amounts of catalyst was studied on
etherification reaction of 1-phenyl ethanol with 1-butanol (Table 1, entries 9–12).
Applying 7 mol% of Fe (HSO4)3 at 100 °C leads to the formation of by-products,
whilst applying 7 mol% of catalyst at 90 °C produced the desired product in 45 min
without the formation of any by-products (Table 1, entries 9, 10). By performing the
reaction in the presence of 5 mol% of Fe (HSO4)3 at 90 °C, etherification was
completed in a longer reaction time (Table 1, entries 11). Additional amounts of
catalyst accelerated the etherification reaction but the formation of by-products
decreased the yield of the reaction (Table 1, entry 12). A 1/1 molar ratio of 1-phenyl
ethanol/1-butanol was the optimized amount of reactants. Treatment of additional
amounts of 1-butanol with 1-phenyl ethanol did not increased the reaction rate
(Table 1, entries 13).
R1OH
Fe (HSO4)3 (7 mol%)
R2OH
R1-O-R2
+
90 °C, solvent free
R1=PhCHCH3 ,PhCHPh , p-CH3O-PhCH2 , PhCH2 , p-Cl-PhCH2 ,(Ph)3C.
R2=CH3CH2 ,CH3(CH2)2CH2 ,PhCH2CH2 ,Ph(CH2)2CH2 , (CH3)2CHCH2CH2 ,
CH3CH2CHCH3 , CH3(CH2)3CHCH3 , CH3(CH2)5CHCH3 , (CH2)5CH.
Scheme 1 Etherification of different classes of alcohols by Fe(HSO4)3
123

B. N. Moghadam et al.
Table 1 Synthesis of 1-(1-butoxyethyl) benzene in the presence of Fe(HSO4)3 under different reaction
conditions
Entry Molar ratio of Catalyst
1-phenylethanol/ 1-buthanol (mol%)
Solvent
Temperature Time
(oC)
Isolated
Yield (%)
(min)
1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
None
10
None
None
None
None
None
CH3CN
r.t
24 (h)
24 (h)
45
0
0
2
r.t
3
10
90
97
95
75
90
98
4a
5b
6
10
90
1 (h)
25
10
100
Reflux
Reflux
10
36 (h)
2 (h)
7
10
1,4-
Dioxane
8
1:1
1:1
1:1
1:1
1:1
1:1.2
10
7
Toluene
None
None
None
None
None
90
100
90
90
90
90
4 (h)
30
98
75
95
95
80
90
9b
10
11
12b
13
a
7
45
5
75
13
7
30
60
The reaction was performed in the presence of Fe(HSO4)3/silica
b
The etherification reaction is accompanied with formation of by-products
To show the general application of the protocol and with the optimal conditions
at hand (Table 1, entry 10), the substrate scope of the etherification reaction was
investigated. We have studied the etherification of primary, secondary and tertiary
benzylic alcohols with primary and secondary aliphatic alcohols. All the reactions
proceeded well in short reaction times with the production of benzyl alkyl ethers in
excellent yields (Table 2). From this Table, it is clear that, in the presence of
Fe(HSO4)3, condensation of tertiary and secondary benzylic alcohols (triphenyl-
methanol, 1-phenyl ethanol and benzhydrol) with primary aliphatic alcohols was
completed faster than with secondary aliphatic alcohols owing to the steric
hindrance (compare entries 1–3, 5–8 and 22 with entries 4 and 9, 23 respectively).
Comparatively, the etherification reaction of triphenylmethanol and benzhydrol with
aliphatic alcohols was performed in a shorter reaction time than 1-phenyl ethanol
(compare entries 5–9 and 22–23 with entries 1–4). This result led us to conclude that
the more stable carbocation improved the reaction rate. We also tested the
etherification reaction of the highly reactive primary p-methoxybenzyl alcohol with
primary and secondary aliphatic alcohols in the presence of Fe(HSO4)3 (Table 2,
entries 10–17). Due to the greater stability and also lack of steric hindrance of the
corresponding carbocation, the etherification reaction of p-methoxybenzyl alcohol
was achieved in a high yield and short reaction time. The catalyst was also effective
in promoting the reaction of benzyl alcohol and p-chloro benzyl alcohol with the
primary and secondary aliphatic alcohols (Table 2, entries 18–22). The correspond-
ing ethers were obtained with good yields but in longer reaction times. With
effective conditions established for the etherification reaction, we next investigated
123

Direct and efficient synthesis of unsymmetrical ethers…
Table 2 Etherification of primary, secondary and tertiary benzylic alcohols with primary and secondary
aliphatic alcohols in the presence of Fe(HSO4)3 under solvent free condition
Isolated
Time
Entry
1
Alcohol(1)
Alcohol(2)
Ethanol
Product
Yield%
(min)
1-phenyl
ethanol
45
85
1-phenyl
ethanol
2
3
4
5
1-butanol
45
45
60
30
95
90
80
95
1-phenyl
ethanol
2-phenyl-1-
ethanol
1-phenyl
ethanol
2-hexanol
1-butanol
benzhydrol
benzhydrol
3-phenyl-l-
propanol
6
7
8
9
30
30
30
45
95
95
90
2-phenyl-1-
ethanol
benzhydrol
benzhydrol
3-methyl-1-
butanol
benzhydrol
2-hexanol
90
123

B. N. Moghadam et al.
Table 2 continued
Isolated
Time
Entry
10
Alcohol(1)
Alcohol(2)
1-butanol
Product
Yield%
(min)
4-methoxy
benzyl
15
15
97
95
alcohol
4-methoxy
benzyl
3-phenyl-l-
propanol
11
alcohol
4-methoxy
benzyl
2-phenyl-l-
propanol
12
13
14
15
15
45
85
90
90
alcohol
4-methoxy
benzyl
3-methyl 1-
butanol
alcohol
4-methoxy
benzyl
cyclohexanol
alcohol
4-methoxy
benzyl
15
16
2-butanol
2-hexanol
45
45
90
98
alcohol
4-methoxy
benzyl
alcohol
4-methoxy
benzyl
17
18
2-octanol
1-butanol
45
95
95
alcohol
benzyl
4(h)
alcohol
123

Direct and efficient synthesis of unsymmetrical ethers…
Table 2 continued
Isolated
Yield%
Time
(min)
Entry
19
Alcohol(1)
Alcohol(2)
2-hexanol
Product
benzyl
5(h)
5(h)
90
80
alcohol
4-chloro
benzyl
20
21
1-butanol
2-hexanol
alcohol
4-chloro
benzyl
7(h)
15
75
98
alcohol
triphenyl
methanol
2-phenyl-1-
ethanol
22
23
triphenyl
methanol
cyclohexanol
35
98
the ability of Fe(HSO4)3 to catalyze the formation of unsymmetrical ethers from a
series of benzylic alcohol with phenol. After a long period of time, phenol did not
react with benzylic alcohol under optimized reaction conditions. Comparatively,
low activity of phenol towards benzylic alcohols in the presence of Fe(HSO4)3 was
attributed to the low nucleophilicity of phenols. To test the scope of the reaction
further, we attempted an etherification reaction of t-butyl alcohol with 2-phenyl-1-
ethanol and 2-hexanol. Unfortunately, the catalyst was ineffective in etherification
of tertiary aliphatic alcohols with primary and secondary aliphatic alcohols even
under forced conditions (10 mol% of catalyst).
The present protocol, in its entirety, simply involves the addition of a primary/or
secondary/or tertiary benzylic alcohol to primary/or secondary aliphatic alcohols in
the presence of a catalytic amount of Fe(HSO4)3, and warming the reaction mixture
to afford the corresponding ether. The reactions are reasonably fast, but because of
acidic media, to prevent formation of any by-products (symmetrical ethers or
alkenes in the case of 1-phenyl ethanol), the addition of benzylic alcohols should be
carried out drop by drop, which prolonged the reaction times.
123

B. N. Moghadam et al.
R1OH
R1 = primary or secondary benzyl
Fe (HSO4)3
R1OH2
I
-H2O
R1OH
R1
II
R1 = PhCHCH3
if
R1-O-R1
+ H+
R2OH
R2 = primary or secondary alkyl
IV
+ H+
PhCH = CH2
V
R1-O-R2
III
Scheme 2 Mechanism for etherification of alcohols by Fe(HSO4)3
The final verification of the products’ identity which can be achieved
1
spectroscopically (FT-IR, H NMR and 13C NMR) are found to be comparable in
all respects with pure samples. The melting points and mass spectrometric data also
compared favorably with data previously reported in the literature.
Although the mechanism of the present catalytic etherification remains to be
elucidated, we are prompted to propose the following mechanism (Scheme 2) for
the catalytic etherification of primary, secondary and tertiary benzylic alcohols with
primary and secondary aliphatic alcohols in the presence of 7 mol% of Fe(HSO4)3
at 90 °C. It is seen that the etherification reaction is in fact a Brønsted acid catalyzed
reaction with fast generation of the protonated species I which subsequently
generates the corresponding stable benzylic carbocation II. This idea is supported
by performing the reaction in the absence of a catalyst. Without any catalyst, the
etherification reaction is not performed even after a long period of time (Table 1,
123

Direct and efficient synthesis of unsymmetrical ethers…
Table 3 Reaction of benzhydrol with 1-butanol in the presence of reused catalyst
Run
Time (min)
Conversion (%)
Isolated yield (%)
1
2
3
4
5
6
7
8
9a
a
30
100
100
100
100
100
100
100
100
85/100
95
30
92
30
97
30
98
30
95
30
90
30
90
30
95
30/60
80/92
The second numbers in the third and fourth columns correspond to conversion and yield after 1 h
Table 4 Etherification of 1-phenyl ethanol with 1-butanol under optimized conditions in the presence of
other catalysts
Entry
Catalyst
Time (min)
Isolated Yield (%)
1
2
FeCl3Á6H2O
Fe(NO3)3Á9H2O
Cu(SO4)2Á5H2O
Cu(OAc)2ÁH2O
CuCl2
60
105
120
120
120
120
100
60
45
45
0
3
4
0
5
80
0
6
NiCl2Á6H2O
AlCl3
7
80
50
50
95
8
ZnBr2
9
ZnCl2
60
10
Fe(HSO4)3
45
entries 1). Nucleophilic attack of aliphatic alcohols to II affords the desired
unsymmetrical ether III, H2O and releases the proton for the next catalytic cycle. As
addition of benzylic alcohol to the reaction mixture was performed drop by drop, the
formation of any symmetric ether IV as by product was prohibited. Also,
dehydration of II, which leads to alkene V, did not happen in the etherification
reaction in the presence of Fe(HSO4)3. Further investigation on the elucidation of
the mechanism and scope of this reaction are currently underway in our laboratory.
Recovery of Fe(HSO4)3 was accomplished by simple filtration followed by
washing thoroughly with ethyl acetate (3 9 10) to remove all organic compounds
and then dried at 100 °C for 1 h. Using this treatment, the recyclability of the
catalyst was evaluated for the reaction of benzhydrol with 1-butanol (Table 3). The
recovered catalyst was reused at least 8 times without any decrease in the yield of
butoxydiphenyl methane. The 9th run gave 85 % conversion after 30 min, but
complete conversion and similar yield was obtained after 1 h.
123

B. N. Moghadam et al.
To show novel catalytic activity of Fe(HSO4)3 in direct etherification of alcohols,
the model reaction in the presence of Fe(HSO4)3 was compared with various metal
catalysts such as FeCl3Á6H2O, Fe(NO3)3Á9H2O, Cu(SO4)2Á5H2O, Cu(OAc)2ÁH2O,
CuCl2, NiCl2Á6H2O, AlCl3, ZnBr2, ZnCl2 (Table 4).
Performing the reaction in the presence of Cu(SO4)2Á5H2O Cu(OAc)2ÁH2O and
NiCl2Á6H2O did not produce the desired product in quantitative yield (Table 4,
entries 3, 4, 6). Comparatively, direct etherification in the presence of FeCl3Á6H2O
and Fe(NO3)3Á9H2O produced the corresponding ether in low yield after a long
reaction time (Table 4, entries 1, 2). Reaction of 1-phenyl ethanol with 1-butanol in
the presence of CuCl2, AlCl3, ZnBr2 and ZnCl2 required long reaction times to
achieve reasonable yields concomitant with the formation of by-products (Table 4,
entries 5, 7, 8, 9).
Conclusions
The present study demonstrates the ability of Fe(HSO4)3 to act as the simplest and
least expensive heterogeneous catalyst for dehydration of two different alcohols to
produce unsymmetrical ethers under solvent-free conditions. The significant
features of this environmentally benign and cost-effective straightforward protocol
for direct conversion of alcohols into unsymmetrical ethers include operational
simplicity, low reagent loading, high product yields, short reaction time and mild
reaction conditions, which do not require any solvent and distilled and/or dry
reagents, and consequently minimizes the generation of toxic waste. We believe the
Fe(HSO4)3-promoted etherification of alcohols is a straightforward exercise that
could be easily incorporated into any synthetic methodologies.
Acknowledgment The authors gratefully acknowledge the partial support of this study by Ferdowsi
University of Mashhad Research Council (Grant No. p/3/29889).
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