[294-93-9] · C8H16O4 · 12-Crown-4 · (MW 176.21)
(lithium-selective complexing agent, useful for activation and solubilization of lithium salts such as cyanide, diisopropylamide, and aluminium hydride, as well as organolithium reagents and lithium enolates)
Physical Data: bp 67-70 °C/0.5 mmHg, 118-119 °C/15 mmHg; IR (neat, NaCl plates) 2925, 1465, 1365, 1280, 1250, 1130, 1100, 1095, and 920 cm-1; 1H NMR 3.65 ppm (sharp singlet); 13C NMR (CDCl3) 70.621 ppm.
Preparative Methods: 12-crown-4 has been synthesized by a variety of modified Williamson ether procedures;1,2 12-crown-4 is also formed in the cyclic oligomerization of Ethylene Oxide using gaseous Boron Trifluoride;3 commercially available.
Handling, Storage, and Precautions: hygroscopic; use in a fume hood.
The cavity diameter of 12-crown-4 is estimated to be 1.2-1.5 Å, which is ideal for complexing with a lithium cation which has an ionic diameter of 1.36 Å. While the selectivity of 12-crown-4 for lithium salts is well documented, this macrocyclic multidentate ligand will also effectively complex with other alkali metal cations.4,6 The selectivities of 12-crown-4 for a wide variety of metal cations have been estimated from solvent extraction studies of metal picrates.5
The cycloaddition of 2-phenylallylmagnesium phenoxide and trans-stilbene in THF is better catalyzed by 15-Crown-5 than 12-crown-4.6 No reaction takes place in the absence of a ligand or in the presence of 18-crown-6.
12-Crown-4 dissolves the alkali metals Sodium, Potassium, rubidium, and cesium to produce blue solutions containing metal cations, metal anions, electrons, and cation-electron pairs.7
The reaction of Lithium Cyanide with enol trifluoromethanesulfonates in benzene solvent at rt in the presence of 12-crown-4 and Tetrakis(triphenylphosphine)palladium(0) gives good to excellent yields of the corresponding unsaturated nitrile (eq 1).8
Deprotonation of tropinone with Lithium Diisopropylamide followed by reaction with Methyl Cyanoformate in the presence of 12-crown-4 resulted in ring opening with the formation of a pyrrolidine derivative (eq 2).9
1,1-Dichloroallyllithium preferentially reacts at the g-position with substituted benzaldehydes and acetophenone. In the presence of 12-crown-4 the selectivity toward the a-position is significantly increased.10
The regiochemistry of ring opening of 1,2-epoxides can be controlled by the presence of a chelating species. cis-4-(Benzyloxy)-1,2-epoxycyclohexane reacts with Lithium Aluminum Hydride to produce 3-benzyloxycyclohexanol almost exclusively. In the presence of premixed LAH and 12-crown-4 the major product was 4-benzyloxycyclohexanol (eq 3).11
12-Crown-4 enhances the rate of the a-chymotrypsin-catalyzed transesterification of N-acetyl-L-phenylalanine ethyl ester with propan-1-ol in octane. Studies with subtilisin indicate that the catalytic effects of crown are much less pronounced.12
The lithium enolate of the acetonide of (S,S)-dimethyl tartrate was prepared by treatment with LDA in the presence of 12-crown-4. Addition of this enolate to acetonylacetone followed by treatment of the product with acid gave a mixture of cyclized adducts from which a single diastereoisomer was isolated (eq 4).13 The reaction failed in the absence of 12-crown-4.
Charles L. Liotta & Joachim Berkner
Georgia Institute of Technology, Atlanta, GA, USA