Carbanions, generally involved as ion pairs or aggregates, are important intermediates in the organic synthesis of many biologically active natural products, pharmaceuticals, drugs, etc. A common synthetic procedure is the metallation of a substrate with an alkyllithium or lithium amide in an ether followed by reaction with a suitable electrophile. We propose to put this largely empirical technique on a quantitative scientific basis by continuing our determination of equilibrium constants for the reactions, R-M+ + R'H = R'-M+ + RH, for indicator hydrocarbons (e.g., fluorenes, arylmethanes, etc.) in tetrahydrofuran (THF) with cesium and lithium as gegenions. These indicator systems will be used to determine equilibria for carbon acids with various functional groups important in synthesis. Important emphasis will be placed on functional groups used to control regio- and stereochemistry in synthesis of biologically active compounds and natural products, such as oxime ethers and dimethylhydrazone derivatives of carbonyl compounds. The study will include other carbonyl compounds and derivatives such as amides and oxazolines as well as sulfur, selenium and silicon derivatives, vinyl, allyl, benzyl and aryl compounds heterocyclic compounds, and related dianions such as oxime dianions. Determinations as a function of concentration will provide quantitative estimates of the degree of aggregation. For those systems shown to exist as monomer and dimer ion pairs, kinetic studies of alkylation and condensation will be accomplished as a function of concentration to show the role of both species in such reactions. Equilibrium measurements as a function of temperature will provide thermodynamic quantities and comparison of the cesium equilibria, which are known to involve contact ion pairs, with the corresponding lithium equilibria, in which a variety of types of ion pairs are possible, will facilitate understanding of the more complex lithium cases. Conductivity studies will relate the ion pairs to dissociated ions. The results will be interpreted with the help of related kinetic acidity measurements, studies of aggregated systems, theoretical quantum chemical calculations and computer graphics analysis of electron density distributions. The theoretical studies include ab initio computations of structure and reaction paths.
| Streitwieser, Andrew (2009) Perspectives on computational organic chemistry. J Org Chem 74:4433-46 |
| Streitwieser, Andrew; Husemann, Marc; Kim, Yeong-Joon (2003) Aggregation and reactivity of the dilithium and dicesium enediolates of 1-naphthylacetic acid. J Org Chem 68:7937-42 |
| Facchetti, A; Kim, Y J; Streitwieser, A (2000) Comparisons of ion pair acidities of some acidic carbon acids. J Org Chem 65:4195-7 |
| Kim, Y J; Streitwieser, A; Chow, A et al. (1999) Aggregation and C-N rotation of the lithium salt of N,N-dimethyldiphenylacetamide. Org Lett 1:2069-71 |
| Streitwieser, A; Leung, S S; Kim, Y J (1999) Role of aggregates in Claisen acylation reactions of imidazole, pyrazole, and thioesters with lithium enolates in THF. Org Lett 1:145-7 |
