Tautomerism and Keto Enol Equilibrium

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2 Tautomerism and Keto Enol Equilibrium Enols & enolates are important nucleophiles in organic & biochemistry. Keto-Enol Equilibrium: Tautomerisation can be catalyzed by either acids or bases. Relative stability of keto and enol forms Enamines & metalloenamines, their nitrogen counterparts, are (almost) as important For simple ketones and aldehydes, keto form is favored by 10 5 to Enol form can be stabilized by increased substitution and conjugation of the alkene. Tautomers: Structural isomers generated as a consequence of the a proton shift. For example:

3 Formation of Metal Enolates General methods for enolate formation The Ireland Model Deprotonation properties of metal enolates Soft Enolization Reduction of a-halocarbonyls Reformatsky reaction Reduction of enones Decarboxylation Acidity of Carbonyls Bulky secondary amines favor formation of E enolates. Large R substituent on carbonyls and weaker amide bases that lead to latter transition states, favor formation of Z enolates. Unless stated otherwise, kinetic distribution of products obtained. Kresge, J. Am. Chem. Soc. 1984, 106, 460. Diastereoselectivity in Enolate Formation Z and E descriptors are used without regard for the nature of the R substituent. It is the matter of definition (convention). Lithium amides are usually used in etherial solvents, THF being the most common. Z enolates are thermodynamically more stable, but the preference is usually small. Proper choice of reaction conditions allows selective formation of either dieastereoisomer.

4 Regioselectivuty: Kinetic vs. Thermodynamic Control Influence of the carbonyl structure. Collum Results Collum, D. B. J. Am. Chem. Soc. 2003, 125, The observed rate acceleration in the presence of Et 3 N has been attributed to the relief of strain in going from the initial complex with a carbonyl to the TS. Only one of the two possible regioisomers is observed. Why? Regioselectivity: Kinetic vs. Thermodynamic control Collum, D. B. J. Am. Chem. Soc. 2008, 130, Aggregation of the lithium amide, its complex with the carbonyl and the TS are all factors in determining the diastereoselectivity of enolization. Every combination of the solvent, Li ligand, and the amide base can in principle lead to a different set of intermediates and TSs. Number of experimental techniques including 6 Li NMR indicate that Ireland model is relevant only for LDA, THF combination. A Sterically hindered and strong bases, and low temperature favor the formation of the less substituted enolate. B More substituted enolates are thermodynamically more stable. Weaker base, small excess of the carbonyl, higher temperature and longer reaction times, all promote equilibration of the enolates and lead to the formation of a thermodynamic mixture of enolates.

5 Dramatic difference in kinetic and thermodynamic selectivity. Enolate Structure For alkali metal enolates (M = Li, Na, K etc.) the O-metal tautomer is strongly favored. This generalization holds for most alkaline earth enolates (Mg+2) as well. These are the generally useful enolate nucleophiles. For some late transition metals C-Metal tautomer is prefered. High selectivity can usually be achieved in deprotonation of enones. General method for the formation of thermodynamic enolates.

6 For NMR solution structures see: Collum, D. B. J. Am. Chem. Soc. 2008, 130, 4859.

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8 Soft Enolization Lewis acid complexation dramatically enhances acidity of carbonyls. Examples Lithium enolates possible only with relatively acidic carbonyls Horner-Wadsworth-Emmons Reaction Kurti & Czako, Named Reactions in Organic Synthesis p 212. Magnesium enolates Horner-Wadsworth-Emmons Reaction Combination of Lewis acid and week base can also effect enolization. Approach complementary to the use of strong base. Enolate Carboxylation Acid-base complexation has to be reversible Rathke, M. W. J. Org. Chem. 1985, 50, Titanium enolates Kurti & Czako, p Knoevenagel condensation Lehnert, W. Tetrahedron Lett. 1970, 4723.

9 Evans Study Boron enolates More acidic boron reagents favor formation of Z enolate. Larger dialkylboron acids favor E enolates. Structure of the carbonyl compounds has a strong influence on the diastereoselectivity. i-pr 2 NEt, Et 3 N, N-Ethylpiperidine are suitable bases. DBU and tetramethylguanidine do not provide enolate. CH 2 Cl 2 is the only suitable solvent for these enolizations. Order of addition of reagents is important for TiCl 4. Enolization model: Order of addition of reagents is not important for i-proticl 3 or (i-pro) 2 TiCl 2. Enolizable substrates: Problematic substrates: Favored for triflate Favored for chloride

10 Reduction of a-halocarbonyls Reformatsky Reaction Kurti & Czako, Named Reactions in Organic Synthesis p Enolization can be achieved chemoselectively in the presence of other carbonyl compounds. Ideally suited for intramolecular reactions Reduction of Enones Solution of alkali metals (Li, Na, K) in NH 3 used as a reducing reagent at low temperature. Allows regioselective formation of both kinetic and thermodynamic enolates. The oldest method used to control regioselectivity. Other reducing reagents can be used including: L- and K-slectride, triethysilane in the presence of a metal catalyst, hydrogen with a catalyst (and many others). Even relatively sterically hindered ketones can be used. Decarboxylation Decarboxylative enolate formation is one of the key steps in biosynthesis of polyketides and fatty acids. Metals other than zinc can be used, and allow the reaction to be performed at a lower temperature. Sm(II) most commonly used. Molander, "Reductions with Samarium (II) Iodide." Org. Reactions 1994, 46, 211.

11 The timing of the decarboxylation is not firmly established but the order of events depicted below is most commonly encountered. Kinetic Acylation with methyl cyanoformate (The Mender reagent) At low temperature decomposition of the tetrahedral intermediate is much slower than acylation. Enolate Acylation Jaz, J. M. et al. Chem. Biol. 2000, 7, 919. Carbon Acylation with N-Methoxy-N-methylamides Nucleophilic addition to Weinreb amide results in the formation of a particularly stable tetrahedral intermediate. Reaction Thermodynamics: Overall Keq ~ 1 Final enolization Step: Keq ~ final enolization step does not render the process irreversible just thermodynamically favorable

12 In reactions with organometallic reagents ketones are formed. Aldehydes obtained in reactions with strong hydride donors. The Dieckmann Condensation Provide a detailed explanation for the observed selectivity in the two reactions.