Lithium Chloride

LiCl

[7447-41-8]  · ClLi  · Lithium Chloride  · (MW 42.39)

(source of Cl- as nucleophile and ligand; weak Lewis acid that modifies the reactivity of enolates, lithium dialkylamides, and other Lewis bases)

Physical Data: mp 605 °C; bp 1325-1360 °C; d 2.068 g cm-3.

Solubility: very sol H2O; sol methanol, ethanol, acetone, acetonitrile, THF, DMF, DMSO, HMPA.

Form Supplied in: white solid, widely available. Drying: deliquescent; for most applications, drying at 150 °C for 3 h is sufficient; for higher purity, recrystallization from methanol, followed by drying at 140 °C/0.5 mmHg overnight, is recommended.

Handling, Storage, and Precautions: of low toxicity; take directly from the oven when dryness is required.

Source of Chloride Nucleophile.

The solubility of LiCl in many organic dipolar solvents renders it an effective source of nucleophilic chloride anion. Lithium chloride converts alcohols to alkyl chlorides1 under Mitsunobu conditions,2 or by way of the corresponding sulfonates3 or other leaving groups.4 This salt cleanly and regioselectively opens epoxides to chlorohydrins in the presence of acids and Lewis acids such as Acetic Acid,5 Amberlyst 15 resin,6 and Titanium(IV) Chloride.7 In the presence of acetic acid, LiCl regio- and stereoselectively hydrochlorinates 2-propynoic acid and its derivatives to form the corresponding derivatives of (Z)-3-chloropropenoic acid.8 Oxidative decarboxylation of carboxylic acids by Lead(IV) Acetate in the presence of 1 equiv of LiCl generates the corresponding chlorides.9

In wet DMSO, LiCl dealkoxycarbonylates various activated esters (eq 1).10,11 If the reaction is performed in anhyd solvent the reaction generates a carbanion intermediate, which can undergo inter- or intramolecular alkylation or elimination. Other inorganic salts (NaCN, NaCl, Lithium Iodide) and other dipolar aprotic solvents (HMPA, DMF) can also be employed. Under similar conditions, lithium chloride cleaves alkyl aryl ethers having electron-withdrawing substituents at the ortho or para positions.12

Source of Chloride Ligand.

In palladium-catalyzed reactions, LiCl is often the reagent of choice as a source of chloride ligand. Lithium chloride is a necessary component in palladium-catalyzed coupling and carbonylative coupling reactions of organostannanes and vinyl triflates.13,14 Lithium chloride has a dramatic effect on the stereochemical course of palladium-catalyzed 1,4-additions to 1,3-dienes.15 Treatment of 1,3-cyclohexadiene with Palladium(II) Acetate and LiOAc and the oxidizing agents 1,4-Benzoquinone and Manganese Dioxide affords 1,4-trans-diacetoxy-2-cyclohexene (eq 2). In the presence of a catalytic quantity of LiCl, the cis isomer is formed (eq 3). If 2 equiv LiCl are added, the cis-acetoxychloro compound forms (eq 4). These methods are general for both cyclic and acyclic dienes, and have recently been extended to the stereospecific formation of fused heterocycles.16 Lithium chloride is also used in the preparation of Dilithium Tetrachloropalladate(II)17 and zinc organocuprate reagents.18

Weak Lewis Acid.

Lithium chloride is a weak Lewis acid that forms mixed aggregates with lithium dialkylamides, enolates, alkoxides, peptides, and related hard Lewis bases.19 Thus LiCl often has a dramatic effect on reactions involving these species. In the deprotonation of 3-pentanone by Lithium 2,2,6,6-Tetramethylpiperidide (LTMP), addition of 0.3 equiv LiCl increases the (E)/(Z) selectivity from 9:1 to 52:1 (eq 5).20 Enhancement in the enantioselectivity of deprotonation of prochiral ketones by a chiral lithium amide has also been reported.21 Lithium chloride stabilizes anions derived from a-phosphonoacetates, permitting amine and amidine bases to be used to perform Horner-Wadsworth-Emmons reactions on base-sensitive aldehydes under exceptionally mild conditions.22 Lithium chloride and other lithium salts disrupt peptide aggregation and increase the solubilities of peptides in THF and other ethereal solvents, often by 100-fold or greater.23 These effects render LiCl a useful additive in the chemical modification of peptides (e.g. by the formation and alkylation of peptide enolates).19,24 Lithium chloride has also shown promise as an additive in solid-phase peptide synthesis, increasing resin swelling and improving the efficiencies of difficult coupling steps.25

Related Reagents.

Lithium Chloride-Diisopropylethylamine; Lithium Chloride-Hexamethylphosphoric Triamide.


1. Magid, R. M. T 1980, 36, 1901.
2. Manna, S.; Falck, J. R.; Mioskowski, C. SC 1985, 15, 663.
3. (a) Owen, L. N.; Robins, P. A. JCS 1949, 320. (b) Owen, L. N.; Robins, P. A. JCS 1949, 326. (c) Eglinton, G.; Whiting, M. C. JCS 1950, 3650. (d) Collington, E. W.; Meyers, A. I. JOC 1971, 36, 3044. (e) Stork, G.; Grieco, P. A.; Gregson, M. TL 1969, 18, 1393.
4. (a) Czernecki, S.; Georgoulis, C. BSF 1975, 405. (b) Camps, F.; Gasol, V.; Guerrero, A. S 1987, 511.
5. Bajwa, J. S.; Anderson, R. C. TL 1991, 32, 3021.
6. Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L. SC 1992, 22, 1863.
7. Shimizu, M.; Yoshida, A.; Fujisawa, T. SL 1992, 204.
8. (a) Ma, S.; Lu, X. TL 1990, 31, 7653. (b) Ma, S.; Lu, X.; Li, Z. JOC 1992, 57, 709.
9. (a) Kochi, J. K. JACS 1965, 87, 2500. (b) Review: Sheldon, R. A., Kochi, J. K. OR 1972, 19, 279.
10. Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E., Jr.; Lovey, A. J.; Stephens, W. P. JOC 1978, 43, 138.
11. Reviews: (a) Krapcho, A. P. S 1982, 805. (b) Krapcho, A. P. S 1982, 893.
12. Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A. S 1989, 287.
13. (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. JACS 1984, 106, 4630. (b) Crisp, G. T.; Scott, W. L.; Stille, J. K. JACS 1984, 106, 7500.
14. Reviews: (a) Stille, J. K. AG(E) 1986, 25, 508. (b) Scott, W. J.; McMurry, J. E. ACR 1988, 21, 47.
15. (a) Bäckvall, J. E.; Byström, S. E.; Nordberg, R. E. JOC 1984, 49, 4619. (b) Bäckvall, J. E.; Nyström, J. E.; Nordberg, R. E. JACS 1985, 107, 3676.
16. (a) Bäckvall, J. E.; Andersson, P. G. JACS 1992, 114, 6374. (b) Review: Bäckvall, J. E. PAC 1992, 64, 429.
17. Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135.
18. (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. JOC 1988, 53, 2390. (b) Jubert, C.; Knochel, P. JOC 1992, 57, 5431. (c) Ibuka, T.; Yoshizawa, H.; Habashita, H.; Fujii, N.; Chounan, Y.; Tanaka, M.; Yamamoto, Y. TL 1992, 33, 3783. (d) Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. JOC 1992, 57, 1024. (e) Knochel, P.; Rozema, M. J.; Tucker, C. E.; Retherford, C.; Furlong, M.; AchyuthaRao, S. PAC 1992, 64, 361.
19. Seebach, D. AG(E) 1988, 27, 1624.
20. (a) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. JACS 1991, 113, 9571. (b) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. JACS 1991, 113, 9575.
21. Bunn, B. J.; Simpkins, N. S. JOC 1993, 58, 533.
22. (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. TL 1984, 25, 2183. (b) Rathke, M. W.; Nowak, M. JOC 1985, 50, 2624.
23. Seebach, D.; Thaler, A.; Beck, A. K. HCA 1989, 72, 857.
24. Seebach, D.; Bossler, H.; Gründler, H.; Shoda, S.-i.; Wenger, R. HCA 1991, 74, 197.
25. (a) Thaler, A.; Seebach, D.; Cardinaux, F. HCA 1991, 74, 617. (b) Thaler, A.; Seebach, D.; Cardinaux, F. HCA 1991, 74, 628.

James S. Nowick

University of California, Irvine, CA, USA

Guido Lutterbach

Johannes Gutenberg University, Mainz, Germany



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