The principal investigator notes that the Aldol addition reaction is one of the most important carbon-carbon bond forming reactions in synthetic organic chemistry, that it is widely used in the synthesis of drugs and other biologically active molecules and that the reaction is now most often run in non-polar solvents, such as tetrahydrofuran (THF), frequently with lithium salts of carbonyl compounds (lithium enolates). He reports that the aggregation of these compounds has been characterized by solution properties, NMR and by X-ray crystallography and that such aggregates have been proposed as the reactive species in the Aldol-type additions with other carbonyl derivatives but there have been very few studies on the actual role of such aggregates in reactions. He goes on to note that by a combination of UV-vis spectroscopic and proton transfer equilibrium studies of some lithium enolates, aggregation constants have been obtained even in dilute solution and that spectra as a function of concentration are analyzed by """"""""Singular Value Decomposition"""""""" to determine the number of different species present and to permit deconvolution to give the spectrum of each component. For this purpose a glovebox-spectrometer apparatus has been developed in which the sample compartment built into the glovebox is connected with a spectrometer with fiber-optic cables. It is noted that the apparatus permits spectroscopy of solutions prepared and studied under the inert atmosphere of the glovebox. The results thus far are said to suggest that the monomeric ion pairs might play an important kinetic role in reactions. It is proposed to extend such studies to additional enolates of interest and to measure the reaction kinetics of their Aldol additions to aldehydes and ketones and of Michael addition reactions with unsaturated carbonyl compounds. It is indicated that the kinetic studies will show the state of aggregation of the enolate reactive species and that knowledge of the relative roles of ion pair monomers and aggregates will lead to more complete reaction mechanisms and to the better understanding required for sophisticated synthesis design. The principal investigator notes that in particular, the roles of solvent addends, such as lithium salts, hexamethylphosphoric triamide, and di- and triamines will be studied under carefully controlled conditions to determine the role of coordination of lithium in the stereochemistry of the addition reactions. It is also proposed to apply the same techniques of spectroscopic study, proton transfer equilibria and reaction kinetics of Aldol and Michael addition reactions to the dilithium salts of carboxylic acids and beta- diketones. It is noted that these dilithium salts are also being used increasingly in organic synthesis but that the reaction mechanisms are virtually unstudied. It is reported that these salts are also aggregated but nothing is known about the relative reactivities of monomers and aggregates. The proposed studies are to provide unique information about these reactions, which would be difficult to obtain in any other way. It is suggested that subsequent extension to other salts of alkali and alkaline earth metals, early and late transition metals and lanthanides is also proposed since many of these salts have found use in some stereospecific syntheses.
| 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 |
