Phenyllithium1

PhLi

[591-51-5]  · C6H5Li  · Phenyllithium  · (MW 84.05)

(organometallic agent useful as nucleophile for addition and substitution reactions,1,3-20 and in the preparation of organolithium building blocks via metalation32 and lithium-metalloid exchange reaction1)

Physical Data: X-ray structures of the PMDTA-complexed monomer,2i the TMEDA-complexed dimer,2a the diethyl ether-complexed tetramer,2b and the PhLi:LiBr (3:1) mixed tetramer2b have been reported. Cryoscopic2h and NMR2c-e studies have shown that a monomer-dimer equilibrium exists in THF solution and that monomers exist in THF/HMPA2f and THF/PMDTA.2c PhLi is tetrameric in ether.

Solubility: sol ether solvents; sol hydrocarbon solvents only by the addition of donor solvents/additives such as ether or TMEDA.2a

Form Supplied in: commercially available in cyclohexane/ether solution.

Analysis of Reagent Purity: standard titration methods should be used.

Preparative Methods: prepared from phenyl halide (PhCl,2j PhBr,2k,l PhI2m) and lithium metal in ether. Several procedures have been used to prepare solid, salt-free PhLi.2n-r The synthesis of 13C-labeled PhLi (ipso carbon only) has been described.2h

Handling, Storage, and Precautions: moisture and oxygen sensitive. Concentrated solutions are pyrophoric. Ether solutions slowly undergo proton abstraction to generate benzene and should be stored in the freezer.

Addition and Substitution Reactions.

The greatest number of synthetic methodologies using PhLi involve carbon-carbon single bond formation through nucleophilic addition and substitution reactions. PhLi undergoes nucleophilic addition in a 1,2-fashion to a variety of carbonyl containing compounds including 1,4-Benzoquinone,3a,b cyclobutenediones,3c g-amino enals,3d N-(alkyl)phthalimides,3e optically-active dienone-iron tricarbonyl complexes,3f a-silyl ketones4 (eq 1),4a and b-lactams (eq 2).5 PhLi adds similarly to cumulated carbonyl groups: isocyanates afford amides,1 ketenes6 yield enolates (eq 3),6b and Carbon Dioxide7 produces phenyl ketones (eq 4).7b

In general, organolithium compounds preferentially undergo addition to the carbonyl of a,b-unsaturated carbonyl compounds rather than Michael addition. However, conjugate addition is promoted by increased solvent polarity, delocalized organolithium compounds, and lower temperatures which allow for thermodynamic control.1,9 Conjugate addition of PhLi to vinyl sulfones8 and a,b-unsaturated esters,10a ketones,10b and imines11 has been reported. Thiophilic attack of thiocarbonyl compounds by PhLi has been observed for thioketones,12 thioketenes (eq 5),13 and thiocarbonates.14 Addition of PhLi to carbon-nitrogen double and triple bonds, including the formal carbon-nitrogen double bond of azaaromatic heterocycles such as pyridine15a and quinoline,15b is general.15 Arylation of 3,4-dihydro-b-carboline was accomplished by activation with Boron Trifluoride Etherate (eq 6).15c Similarily, the addition of PhLi to 2-isoxazolines15d and oxime ethers15e in the presence of boron trifluoride has been demonstrated. Addition reactions to nitriles containing no a-hydrogens have been reported to effectively afford ketimines and ketones.16 Lithium aldimines have been prepared through the addition of PhLi to isocyanides.17

PhLi undergoes alkylation with primary halides, allylic halides (eq 7),18a and benzyl halides.1a-c,18 Although not nearly as prevalent, displacement of sulfonate has also been reported.1,19 Nucleophilic ring opening of epoxides with PhLi is general.20 The reaction of PhLi with a,b-epoxy silanes yields b-hydroxy silanes which subsequently undergo Peterson reaction to afford alkenes (eq 8).20d Addition reactions to oxetanes21a and substituted aziridines21b are known, but have comparatively little utility.

Nucleophilic addition and substitution reactions with PhLi often may be accompanied or followed by other reactions such as lithium-metalloid exchange, enolization, metalation, or carbanionic rearrangements.

Lithium-Metalloid Exchange Reaction.

Phenyllithium undergoes lithium metalloid exchange1 which is a reversible process with an equilibrium constant that reflects the difference in stability of PhLi and the new organolithium species generated. Mechanistic studies of this reaction abound.1d,e Lithium-halogen exchange is most prevalent, although related transmetalations involving selenium,22 tellurium,23 tin,24 and mercury25 are also common. In general, PhLi/M exchange is characteristically fast (I > Te, Sn > Br > Se > Cl)1d even at low temperatures. Exchange rates increase with increased solvent polarity, but are slowed by the presence of lithium salts.2f,26 PhLi/M exchange reactions have been utilized for the preparation of functionalized aryllithiums (e.g. 4-methoxyphenyllithium,27a lithio-nitrobenzenes),27b,c substituted benzyllithiums (eq 9),28 3-thienyllithium derivatives (eq 10),29 Vinyllithium,24c 2-lithiophosphinines,30 and other stabilized organolithium reagents which are not readily available by metalation or the reduction of halides. Allyllithium generated through reaction of PhLi and Tetraallylstannane,24d,e can be converted with Potassium t-Butoxide to the more reactive allylpotassium which subsequently undergoes conjugate addition to vinyl sulfones (eq 11).31

Lithiation Reactions.32-36

Replacement of hydrogen by lithium in an organic compound is perhaps the most versatile method for preparing organolithium compounds. Although not nearly as prevalent as n-Butyllithium, PhLi has been used as a base in heteroatom-facilitated lithiations, lithiations of relatively strong hydrocarbon acids (pKa of benzene = 43),37 and in the formation of stabilized anions where a milder reagent is warranted. Thiophenes,32 sulfones,8 nitriles,33 1,3-dimethoxybenzenes,34 and a-methylpyridines35 (eq 12)35a have been metalated with PhLi. Reaction of 2 equiv of PhLi with a b-epoxy sulfone resulted in base-catalyzed b-elimination and subsequent conjugate addition to produce a dianion which was alkylated with Iodomethane (eq 13).8 PhLi has been used to deprotonate secondary amines to form lithium amides.36

Related Reagents.

Lithium Diphenylcuprate; Lithium Di-p-tolylcuprate; Phenylmagnesium Bromide.


1. (a) Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon: Oxford, 1974. (b) Wakefield, B. J. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel E. W., Eds.; Pergamon: Oxford, 1982; Vol. 7, Chapter 44. (c) Wardell, J. L. In The Chemistry of the Metal-Carbon Bond; Wiley: New York, 1987; Vol. 4, Chapter 1. (d) Bailey, W. F.; Patricia, J. J. JOM 1988, 352, 1. (e) Reich, H. J.; Green, D. P.; Phillips, N. H.; Borst, J. P.; Reich, I. L. PS 1992, 67, 83.
2. (a) Weiss, E.; Thoennes, D. CB 1978, 111, 3157. (b) Hope, H.; Power, P. P. JACS 1983, 105, 5320. (c) Bauer, W.; Winchester, W. R.; Schleyer, P. v. R. OM 1987, 6, 2371. (d) Reich, H. J.; Green, D. P.; Phillips, N. H. JACS 1991, 113, 1414. (e) Jackman, L. M.; Scarmoutzos, L. M. JACS 1984, 106, 4627. (f) Reich, H. J.; Green, D. P. JACS 1989, 111, 8729. (g) Bauer, W.; Seebach, D. HCA 1984, 67, 1972. (h) Seebach, D.; Hässig, R.; Gabriel, J. HCA 1983, 66, 308. (i) Weiss, E.; Schümann, U.; Kopf, J. AG(E) 1985, 24, 215. (j) Esmay, D. I., Adv. Chem. Ser. 1959, 23, 47. (k) Gilman, H.; Morton, J. W. OR 1954, 8, 286. (l) Gilman, H.; Caj, B. J. JOC 1957, 22, 1165. (m) Müller, E.; Ludsteck, D. CB 1954, 87, 1887. (n) Wittig, G.; Meyer, F. J.; Lange, G. LA 1951, 571, 167. (o) Waack, R.; Doran, M. A. JACS 1963, 85, 1651. (p) Fraenkel, W. E.; Dagagi, S.; Kobayashi, S. J. Phys. Chem. 1961, 83, 3585. (q) Schlosser, M. JOM 1967, 8, 193. (r) Wehman, E.; Jastrzebski, J. T. B. H.; Ernsting, J.; Grove, D. M.; van Koten, G. JOM 1988, 353, 133.
3. (a) Alonso, F.; Yus, M. T 1991, 47, 7471. (b) Alonso, F.; Yus, M. TL 1992, 48, 2709. (c) Liebeskind, L. S.; Wirtz, K. R. JOC 1990, 55, 5350. (d) Reetz, M. T.; Wang, F.; Harms, K. CC 1991, 1309. (e) Braun, L. L.; Torian, B. E. JHC 1984, 21, 293. (f) Franck-Neumann, M.; Chemla, P.; Martina, D. SL 1990, 641.
4. (a) Ruden, R. A.; Gaffney, B. L. SC 1975, 5, 15. (b) Barrett, A. G. M.; Flygare, J. A. JOC 1991, 56, 638.
5. Kano, S.; Ebata, T.; Shibuya, S. CPB 1979, 27, 2450.
6. (a) Beel, J. A.; Vejvoda, E. JACS 1954, 76, 905. (b) Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. JACS 1985, 107, 5391. (c) Seebach, D.; Laube, T.; Häner, R. JACS 1985, 107, 5396.
7. (a) Levine, R.; Karten, M. J.; Kadunce, W. M. JOC 1975, 40, 1770. (b) Breitmaier, E.; Zadel, G. AG(E) 1992, 31, 1035.
8. Fuchs, P. L.; Conrad, P. C. JACS 1978, 100, 346.
9. Cohen, T.; Abraham, W. D.; Myers, M. JACS 1987, 109, 7923.
10. (a) Tanaka, J.; Kanemasa, S.; Ninomiya, Y.; Tsuge, O. BCJ 1990, 63, 476. (b) Stern, A. J.; Swenton, J. S. CC 1988, 1255.
11. (a) Meyers, A. I.; Barner, B. A. JOC 1986, 51, 120. (b) Kundig, E. P.; Liu, R. G.; Ripa, A. HCA 1992, 75, 2657.
12. (a) Beak, P.; Worley, J. W. JACS 1970, 92, 4142. (b) Ohno, A.; Nakamura, K.; Uohama, M.; Oka, S. CL 1975, 983.
13. Schaumann, E.; Walter, W. CB 1974, 107, 3562.
14. Beak, P. Worley, J. W. JACS 1972, 94, 597.
15. (a) Overberger, C. G.; Lombardino, J. G.; Hiskey, R. G. JACS 1957, 79, 6430. (b) Uno, H.; Okada, S.; Suzuki, H. JHC 1991, 28, 346. (c) Nakagawa, M.; Kawate, T.; Yamazaki, H.; Hino, T. CC 1990, 991. (d) Uno, H.; Terakawa, T.; Suzuki, H. CL 1989, 1079. (e) Uno, H.; Terakawa, T.; Suzuki, H. SL 1991, 559.
16. (a) Itsuno, S.; Hachisuka, C.; Kitano, K.; Ito, K. TL 1992, 33, 627. (b) Zimmerman, H. E.; Wright, C. W. JACS 1992, 114, 363. (c) Walborsky, H. M.; Niznik, G. E. JOC 1972, 37, 187.
17. Walborsky, H. M.; Periasamy, M. P. JOC 1974, 39, 611.
18. (a) Peterson, P. E.; Grant, G. JOC 1991, 56, 16. (b) Brown, H. C.; Rangaishenvi, M. V. TL 1990, 31, 7115. (c) Merkel, D.; Köbrich, G. CB 1973, 106, 2040.
19. (a) Tomalia, D. A.; Falk, J. C. JHC 1972, 9, 891. (b) Kasatkin, A. N. IZV 1988, 2159.
20. (a) Cristol, S. J.; Douglass, J. R.; Meek, J. S. JACS 1951, 73, 816. (b) Aithie, G. C. M.; Miller, J. A. TL 1975, 4419. (c) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. JOC 1991, 56, 5161. (d) Ukaji, Y.; Yoshida, A.; Fujisawa, T. CL 1990, 157.
21. (a) Searles, S. JACS 1951, 73, 125. (b) Eis, M. J.; Ganem, B. TL 1985, 26, 1153.
22. (a) Reich, H. J. In Organoselenium Chemistry; Liotta, D., Ed.; Wiley: New York, 1987; p 243. (b) Dumont, W.; Bayet, P.; Krief, A. AG(E) 1974, 13, 243.
23. Tomoki, H.; Kambe, N.; Ogawa, A.; Miyoshi, N.; Murai, S.; Sonoda, N. AG(E) 1987, 26, 1187.
24. (a) Reich, H. J.; Phillips, N. H. PAC 1987, 59, 1021. (b) Seyferth, D.; Weiner, M. A. OSC 1973, 5, 452. (c) Seyferth, D.; Weiner, M. A. JACS 1961, 83, 3583. (d) Bristow, G. S. Aldrichim. Acta 1984, 17, 75. (e) Eisch, J. J. OS 1981, 2, 92.
25. (a) Eaton, P. E.; Cunkle, G. T.; Marchioro, G.; Martin, R. M. JACS 1987, 109, 948. (b) Maercker, A.; Dujardin, R. AG 1984, 96, 222.
26. (a) Batalov, A. P.; Rostokin, G. A. JGU 1971, 41, 154, 1740, 1743. (b) Batalov, A. P.; Rostokin, G. A. JGU 1973, 43, 959. (c) Winkler, H. J. S.; Winkler, H. JACS 1966, 88, 964, 969.
27. (a) Gilman, H.; Towle, J. L.; Spatz, S. M. JACS 1946, 68, 2017. (b) Köbrich, G.; Buck, P. CB 1970, 103, 1412. (c) Lucchesini, F. T 1992, 48, 9951.
28. Tashiro, M.; Yamato, T. CL 1982, 61.
29. Frejd, T.; Karlsson, J. O.; Gronowitz, S. JOC 1981, 46, 3132.
30. (a) Lefloch, P.; Carmichael, D.; Mathey, F. OM 1991, 10, 2432. (b) Lefloch, P.; Carmichael, D.; Ricard, L.; Mathey, F.; Jutand, A.; Amatore, C. OM 1992, 11, 2475.
31. Fuchs, P. L.; Anderson, M. B. JOC 1990, 55, 337.
32. (a) Gilman, H.; Morton, J. W. OR 1954, 8, 286. (b) Gschwend, H. W.; Rodriguez, H. R. OR 1976, 26, 1. (c) Beak, P.; Snieckus, V. ACR 1982, 15, 306. (d) Beak, P.; Zajdel, W. J.; Reitz, D. B. CRV 1984, 84, 471.
33. (a) Weinstock, J.; Boekelheide, V. OSC 1963, 4, 641. (b) Cason, J.; Sumrell, G.; Mitchell, R. S. JOC 1950, 15, 850.
34. (a) Catlin, E. R.; Hassell, C. H. JCS(C) 1971, 460. (b) Lambooy, J. P. JACS 1956, 78, 771.
35. (a) Compagnon, P.-L.; Gasquez, F.; Kimny, T. S 1986, 948. (b) Lee, J. W.; Anderson, W. K. SC 1992, 22, 369.
36. (a) Huisgen, R.; Konig, H. CB 1959, 92, 203. (b) Iida, H.; Yuasa, Y.; Kibayashi, C. S 1977, 879.
37. Streitwieser, A., Jr.; Scannon, P. J.; Niemeyer, H. M. JACS 1972, 94, 7936.

D. Patrick Green

The Dow Chemical Co., Midland, MI, USA



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