1.3. OTHER MEANS OF GENERATING ENOLATES

1. 1.3. OTHER MEANS OF GENERATING ENOLATES Experimental conditions in which lithium enolates are stable and do not equilibrate with their regioisomers were developed. So, besides deprotonation, other methods are available to generate the desidered enolate. a) The reaction of trimethyl silylenolethers or enol acetates with methillithium is a synthetic pathway that depends on the availability of this molecules in high purities

2. b) Trimethyl silylenolethers give enolates also reacting with quaternary ammonium fluorides. The driving force of this reaction is the formation of the strong Si-F bond (142 kcal/mol). Trimethyl silylenolethers can be prepared starting from ketones, in conditions of kinetic or thermodynamic control, purified and then used as regioselective enolate precursors. c) It is possible to obtain enolates regioselectively, by reduction of a,b-unsatured ketones, with lithium and liquid ammonia.

3. 1.4. ALKYLATION OF ENOLATES • Alkylation of enolate is an important synthetic method. • Methylene groups can be dialkylated if sufficient base and alkylating agent are used. Dialkylation can be an undesirable side reaction if the monoalkyl derivative is the desired product. Use of dihaloalkanes as the alkylating reagent leads to ring formation. • The relative rates of cyclization for w-haloalkyl malonate esters are 650,000 : 1 : 6500 : 5 for formation of three-, four-, five-, and six-membered rings, respectively.

4. Relatively acidic carbon acids such as malonic esters and b-keto esters were the first class of carbanions for which reliable conditions for alkylation were developed, because these carbanions are formed using easily accessible alkoxide ions. 2-Substituted b-keto esters and 2-substituted derivatives of malonic ester are useful precursors of ketones and carboxylic acids, since both b-ketoacids and malonic acids undergo facile decarboxylation: X = alkyl, aryl: b-ketoacid → ketone X = OH: malonate → substituted acetic acid

5. STEREOSELECTIVITY a) TRANS / CIS = 20 / 1 b) Y = 59% c) Y = 43%

6. 1.5. GENERATION AND ALKYLATION OF DIANIONS In the presence of a sufficiently strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations. • Alkylation reactions of dianions occur at the more basic carbon. • This technique allows alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. • Because, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and and nature of the base.

7. Alkylation of the more acid position Alkylation of the more basic position Same examples, using different bases and different substrates MONOANION DIANION

8. Relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide: THF DME DMF DMSO SOLVENT DIELECTRIC CONSTANT 2.3 7.3 6.8 37 47 RELATIVE RATE 1 14 80 970 1420 1.6. MEDIUM EFFECTS IN THE ALKYLATION OF ENOLATES The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried.

9. HIGH DIELECTRIC CONSTANTS have HYDROXYL GROUPS OR OTHER HYDROGEN-BONDING GROUPS lack EXCELLENT METAL-CATION COORDINATION ABILITY possess can SOLVATE AND DISSOCIATE ENOLATES AND OTHER CARBANIONS FROM IONS PAIRS AND CLUSTERS Polar aprotic solvents have high dielectric constants but lack hydroxyl groups or other hydrogen-bonding groups. Polar aprotic solvents possess excellent metal-cation coordination ability, so they can solvate and dissociate enolates and other carbanions from ion pairs and clusters. POLAR APROTIC SOLVENTS

10. REACTIVITY OF Li+, Na+, K+ ENOLATES STATE OF AGGREGATION depends on depends on CATION STRONGLY SOLVATED MAXIMUM REACTIVITY ENOLATE VERY WEAKLY SOLVATED The reactivity of Li+, Na+, K+ enolates is very sensitive to the state of aggregation, which is, in turn, influenced by the reaction medium. The highest level of reactivity is that of the "bare“ unsolvated enolate anion. REACTION MEDIA For an enolate-metal ion pair in solution, the maximum reactivity would be expected in a medium in which the cation was strongly solvated and the enolate was very weakly solvated. ENOLATE-METAL ION PAIR IN SOLUTION

11. GOOD CATION SOLVATORS POOR ANION SOLVATORS POLAR APROTIC SOLVENTS DMSO, DMF, HMPA, and NMP have all a negatively polarized oxygen available for coordination to the alkali-metal cation. At the same time the positively polarized atom of these molecules , that can coordinate cations, is not nearly as exposed as the oxygen. Thus, these solvents provide a medium in which enolate-metal ion pairs are dissociated to give a less encumbered, more reactive enolate.

12. Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogen-bonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO.

13. THF and DME are slightly polar solvents which are moderately good cation solvators. Coordination to the metal cation involves the oxygen lone pairs. These solvents, because of their lower dielectric constants, are less effective at separating ion pairs and higher aggregates than the polar aprotic ones. They can be used in the presence of co-solvents, molecules containing donors groups, more efficient in coordinating metal cations.

14. The reactivity of enolates is also affected by the metal counterion. Among the most commonly used ions, the order of reactivity is. Mg2+ <Li+ < Na+ < K+ The factors that are responsible for this order are closely related to those described for solvents. The smaller, harder Mg2+ and Li+ cations are more tightly associated with the enolate than are the Na+ and K+ ions. The tighter coordination decreases the reactivity of the enolate and gives rise to more highly associated species.