Ethylene Glycol1

[107-21-1]  · C2H6O2  · Ethylene Glycol  · (MW 62.08)

(formation of acetals;1 stereoselective aldol reactions;2 solvent for Diels-Alder reaction;3 solvent for Fischer indole reaction;4 preparation of tertiary alcohols from trialkylboranes5)

Alternate Name: ethane-1,2-diol.

Physical Data: bp 197 °C; d 1.11 g cm-3.

Solubility: completely sol H2O, low MW alcohols, acetone; insol benzene, chlorinated hydrocarbons.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: harmful or fatal if swallowed. Prolonged or repeated breathing of vapor harmful. Causes eye irritation. May cause kidney and nervous system damage. Causes birth defects in laboratory animals. Use in a fume hood.

Acetal Formation.1

The dioxolane group is one of the most widely used protecting groups for carbonyl compounds. Dioxolanes are generally stable to bases, Grignard reagents, alkyl lithium reagents, metal hydrides, Na/NH3, Wittig reagents, hydrogenation conditions, oxidants, and bromination and esterification reagents.1 This wide range of stability has been especially useful in steroid synthesis.6 The ease of formation of dioxolanes roughly follows the order: aldehydes > acyclic ketones and cyclohexanones > cyclopentanones > a,b-unsaturated ketones > a-mono- and disubstituted ketones >> aromatic ketones. Ketones generally require stronger acids than aldehydes, such as sulfuric, hydrochloric, or TsOH.7-11 A typical protection procedure involves heating a benzene or toluene solution of the ketone and p-Toluenesulfonic Acid (eq 1).9 Alternatively, a Lewis acid catalyst, such as Boron Trifluoride Etherate12-14 may be used (eqs 2 and 3).13,14

Water removal can be accomplished by using Dean-Stark distillation,15 molecular sieves,16 CaSO4,17 CuSO4,18 or water scavengers such as Triethyl Orthoformate19-21 or dialkyl sulfites (eq 4).22

Compounds that are stable under strongly acidic conditions can be derivatized using a mixture of ethylene glycol and HCl (eq 5).23,24

Many procedures have also been developed for acid-sensitive compounds. Use of either adipic25 or Oxalic Acid26 gives good yields of sensitive steroid D4-3-ethylene acetals. Selenium(IV) Oxide has also been used effectively for steroid acetalization (eq 6).27

Pyridinium salts are mild catalysts for ethylene acetal formation.28-31 Pyridinium p-Toluenesulfonate (PPTS) catalyzes acetal formation with less than 4% epimerization, whereas use of TsOH led to 34% epimerization (eq 7).30

The use of a hindered pyridinium salt, such as 2,4,6-Collidinium p-Toluenesulfonate (CTPS), allows acetalization of a,b-unsaturated ketones in the presence of saturated carbonyl systems (eq 8).31

N,N-Dimethylformamide/Dimethyl Sulfate is another mild acetalization catalyst.32 Metal catalysts, such as Rh complexes33 and Palladium on Carbon1a have also been used effectively (eqs 9 and 10). Ion-exchange resins offer significant advantages for the preparation of sensitive steroid acetals (eq 11).34 An especially convenient method involves running a solution of the ketone and ethylene glycol through a column of Amberlyst.35 Zeolites have also been used to prepare acetals.36

Ketones that react slowly under normal acetalization conditions can be converted into dioxolanes at high pressure (eq 12).37 A procedure has also been developed for the dioxolanation of ketones in the presence of aldehydes using a bis-silyl ether of ethylene glycol (eq 13).38 The selective acetalization of aldehydes in the presence of ketones has been accomplished using ethylene glycol and alumina or silica gel.39

In addition to their use as protecting groups, dioxolanes have been employed as intermediates. One example is a ring expansion of cyclopentanones via Grob fragmentation of the acetal (eq 14).40 A novel synthesis of glycerol from formaldehyde and ethylene glycol involves dioxolane intermediates.41

Dioxolane formation is not limited to aldehydes and ketones. Amide acetals have been prepared directly and by the alcohol interchange method (eq 15).42

The interchange of carbonyl protecting groups can be quite valuable in organic synthesis. For example, replacing a thioacetal with an acetal would allow a subsequent oxidation or hydrogenation which is not possible in the presence of a sensitive sulfur-containing group. Reacting the thioacetal with MeOSO2F, followed by treatment with ethylene glycol, achieves this transformation under mild conditions.43 Ethylene Chloroboronate, prepared from BCl3 and ethylene glycol, has been used for stereoselective aldol reactions with aliphatic and aromatic aldehydes (eq 16).2

Solvent Effects.1d

Ethylene glycol is an excellent solvent for many reactions and its high boiling point (197.6 °C) and low freezing point (-13 °C) permit a wide range of operating temperatures. Both NaOH and KOH are very soluble in ethylene glycol. Examples are the hydrolysis of t-butylurea,44 the dehydrochlorination of monovinylacetylene,45 and the Wolff-Kishner deoxygenation.46 Dehydroxylations of (R,R)-tartrates with Samarium(II) Iodide are best accomplished in ethylene glycol.47 The conversion of alkyl bromides to alkyl fluorides has been carried out in ethylene glycol.48 Removal of the acetonide group can be accelerated by substituting ethylene glycol for H2O.49 The Fischer indole synthesis can be performed without the addition of an acid catalyst by heating a phenylhydrazone in ethylene glycol.4,50 Ethylene glycol has also been used as a substrate for the synthesis of indoles and other heterocycles.51 The Ru complex catalyzed reaction of substituted anilines and ethylene glycol offers an alternative route to the indoles under milder conditions than conventional methods (eq 17).51a,b

Ethylene glycol is superior to benzene, MeCN, DMSO, MeOH, and H2O for the Diels-Alder reaction involving relatively hydrophobic dienes and dienophiles. The increased reaction rate in ethylene glycol is attributed to the improved aggregation of the diene and dienophile (eq 18).3

The synthesis of tertiary alcohols from trialkylboranes and CO at 100-150 °C has been improved in the presence of ethylene glycol5,52-54 (eq 19).54a The purpose of the ethylene glycol is to trap the intermediate boronic anhydride, which can form a polymer that is difficult to oxidize.

1. (a) Meskens, A. J. S 1981, 501. (b) Greene, T. W. Protective Groups in Organic Synthesis; Wiley: New York, 1981. (c) McOmie, J. F. W. Protective Groups in Organic Chemistry; Plenum: New York, 1973. (d) Fieser, L. F.; Fieser, M. FF 1967, 1, 375.
2. (a) Gennari, C.; Colombo, L.; Poli, G. TL 1984, 25, 2279. (b) Gennari, C.; Cardani, S.; Colombo, L.; Scolastico, C. TL 1984, 25, 2283.
3. Dunams, T.; Hoekstra, W.; Pentaleri, M.; Liotta, D. TL 1988, 29, 3745.
4. Fitzpatrick, J. T.; Hiser, R. D. JOC 1957, 22, 1703.
5. Brown, H. C. ACR 1969, 2, 65.
6. (a) Loewenthal, H. J. E. T 1959, 6, 269. (b) Keana, J. F. W. Steroid Reactions; Djerassi, C., Ed.; Holden-Day: San Francisco, 1963; pp 1-87.
7. Salmi, E. J. CB 1938, 71, 1803.
8. Sulzbacher, M.; Bergmann, E.; Pariser, E. R. JACS 1948, 70, 2827.
9. Johnson, W. S.; Rogier, E. R.; Szmuszkovicz, J.; Hadler, H. I.; Ackerman, J.; Bhattacharyya, B. K.; Bloom, B. M.; Stalmann, L.; Clement, R. A.; Bannister, B.; Wynberg, H. JACS 1956, 78, 6289.
10. Campbell, J. A.; Babcock, J. C.; Hogg, J. A. JACS 1958, 80, 4717.
11. Daignault, R. A.; Eliel, E. L. OSC 1973, 5, 303.
12. Fieser, L. F.; Stevenson, R. JACS 1954, 76, 1728.
13. Engel, C. R.; Rakhit, S. CJC 1962, 40, 2153.
14. Swenton, J. S.; Blankenship, R. M.; Sanitra, R. JACS 1975, 97, 4941.
15. Sakane, K.; Otsuji, Y.; Imoto, E. BCJ 1974, 47, 2410.
16. Roelofsen, D. P.; van Bekkum, H. S 1979, 419.
17. Stenberg, V. I.; Kubik, D. A. JOC 1974, 39, 2815.
18. Hanzlik, R. P.; Leinwetter, M. JOC 1978, 43, 438.
19. Caserio, F. F., Jr.; Roberts, J. D. JACS 1958, 80, 5837.
20. (a) Marquet, A.; Dvolaitzky, M.; Kagan, H. B.; Mamlok, L.; Ouannes, C.; Jacques, J. BSF 1961, 1822. (b) Marquet, A.; Jacques, J. BSF 1962, 90.
21. Doyle, P.; Maclean, I. R.; Murray, R. D. H.; Parker, W.; Raphael, R. A. JCS 1965, 1344.
22. Hesse, G.; Förderreuther, M. CB 1960, 93, 1249.
23. Vogel, E.; Schinz, H. HCA 1950, 33, 116.
24. Howard, E. G.; Lindsey, R. V., Jr. JACS 1960, 82, 158.
25. (a) Brown, J. J.; Lenhard, R. H.; Bernstein, S. E 1962, 18, 309. (b) Brown, J. J.; Lenhard, R. H.; Bernstein, S. JACS 1964, 86, 2183.
26. Andersen, N. H.; Uh, H.-S. SC 1973, 3, 125.
27. Oliveto, E. P.; Smith, H. Q.; Gerold, C.; Weber, L.; Rausser, R.; Hershberg, E. B. JACS 1955, 77, 2224.
28. Rausser, R.; Lyncheski, A. M.; Harris, H.; Grocela, R.; Murrill, N.; Bellamy, E.; Ferchinger, D.; Gebert, W.; Herzog, H. L.; Hershberg, E. B.; Oliveto, E. P. JOC 1966, 31, 26.
29. Bond, F. T.; Stemke, J. E.; Powell, D. W. SC 1975, 5, 427.
30. Sterzycki, R. S 1979, 724.
31. Nitz, T. J.; Paquette, L. A. TL 1984, 25, 3047.
32. Kantlehner, W.; Gutbrod, H.-D. LA 1979, 1362.
33. Ott, J.; Tombo, G. M. R.; Schmid, B.; Venanzi, L. M.; Wang, G.; Ward, T. R. TL 1989, 30, 6151.
34. Jones, E. R. H.; Meakins, G. D.; Pragnell, J.; Müller, W. E.; Wilkins, A. L. JCS(P1) 1979, 2376.
35. Dann, A. E.; Davis, J. B.; Nagler, M. J. JCS(P1) 1979, 158.
36. Corma, A.; Climent, M. J.; Hermenegildo, C.; Primo, J. CA 1990, 113, 61 675x.
37. Dauben, W. G.; Gerdes, J. M.; Look, G. C. JOC 1986, 51, 4964.
38. Kim, S.; Kim, Y. G.; Kim, D.-i. TL 1992, 33, 2565.
39. Kamitori, Y.; Hojo, M.; Masuda, R.; Yoshida, T. TL 1985, 26, 4767.
40. Sakai, K. CA 1992, 117, 130 946h.
41. Sanderson, J. R.; Lin, J. J.; Duranleau, R. G.; Yeakey, E. L.; Marquis, E. T. JOC 1988, 53, 2859.
42. Bredereck, H.; Sinchen, G; Rebstat, S.; Kantlehner, W.; Horn, P.; Wohl, R.; Hoffman, H.; Grieshaber; P. CB 1968, 101, 41.
43. Corey, E. J.; Hase, T. TL 1975, 3267.
44. Pearson, D. E.; Baxter, J. F.; Carter, K. N. OSC 1955, 3, 154.
45. Hennion, G. F.; Price, C. C.; McKeon, T. F., Jr. OSC 1963, 4, 683.
46. Georgiadis, M. P.; Tsekouras, A.; Kotretsou, S. I.; Haroutounian, S. A.; Polissiou, M. G. S 1991, 929.
47. Kusuda, K.; Inanaga, J.; Yamaguchi, M. TL 1989, 30, 2945.
48. Vogel, A. I.; Leicester, J.; Macey, W. A. T. OSC 1963, 4, 525.
49. Hampton, A.; Fratantoni, J. C.; Carroll, P. M.; Wang, S. JACS 1965, 87, 5481.
50. Borch, R. F.; Newell, R. G. JOC 1973, 38, 2729.
51. (a) Tsuji, Y.; Huh, K.-T.; Watanabe, Y. JOC 1987, 52, 1673. (b) Tsuji, Y.; Huh, K.-T.; Watanabe, Y. TL 1986, 27, 377. (c) Kondo, T.; Kotachi, S.; Watanabe, Y. CC 1992, 1318.
52. (a) Hillman, M. E. D. JACS 1962, 84, 4715. (b) Hillman, M. E. D. JACS 1963, 85, 982.
53. (a) Puzitskii, K. V.; Pirozhkov, S. D.; Ryabova, K. G.; Pastukhova, I. V.; Eidus, Ya. T. BAU 1972, 21, 1939. (b) Puzitskii, K. V.; Pirozhkov, S. D.; Ryabova, K. G.; Pastukhova, I. V.; Eidus, Ya. T. BAU 1973, 22, 1760.
54. (a) Brown, H. C.; Rathke, M. W. JACS 1967, 89, 2737. (b) Negishi, E.; Brown, H. C. OS 1983, 61, 103.

W. Christopher Hoffman

Union Carbide, South Charleston, WV, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.