Revised Organic synthesis via

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  • ORGANIC CHEMISTRY

    Organic synthesis via enolates

    Dr. Vimal Rarh Lecturer

    Dept. of Chemistry S.G.T.B. Khalsa College

    Delhi

    (14.06.2007)

    CONTENTS Acidity of Alpha HydrogensAcidity of -dicarbonyl CompoundsHydrogen-Deuterium ExchangeAlkylation of Enolate AnionsAlkylation Reactions of Enolate AnionsRegioselectivity in Enolate Anion Formation and ReactionKeto-enol tautomerism of Ethyl AcetoacetateEquilibrium of keto-enol MixturesEnolisationModern Theories of TautomerismPosition of Equilibrium in keto-enol TautomerismFactors affecting the Enol ContentSynthesis of Ethyl Acetoacetate: the Claisen CondensationAlkylation of Diethyl Malonate and Ethyl AcetoacetateAlkylation of 1,3-DithianesAlkylation and Acylation of EnaminesEnamines, Enols and Enolate Ions

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  • Acidity of Alpha Hydrogens The (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as -carbon atom) adjacent to the carbonyl carbon. The next carbon is the -carbon and the hydrogen atoms attached to it are called as -hydrogen atoms and so on.

    Aldehydes and ketones are weak acids and have remarkably low pKa values (between 15 and 20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base. But, aldehydes and ketones are much stronger acids than alkanes. Due to the only minor difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are hardly polarized. Thus, hydrogens of alkanes are in fact not acidic. The pKa values of alkanes are around 50.

    The acidity of -hydrogens of aldehydes and ketones is much less than carboxylic acids, which have pKa values around 3 to 4. Reason for acidity: The - hydrogen of carbonyl compounds is acidic, as it is connected with the -carbon that is directly bound to the electron withdrawing carbonyl group. The carbonyl compounds' relatively high acidity (as compared to alkanes) may be explained by the resonance stabilization of the conjugate base by the carbonyl group, or, in other words, through the stabilization of the anion formed by deprotonation. This anion is called an enolate anion. The negative charge is mainly distributed among the -carbon and the carbonyl oxygen, by resonance, which leads to the stabilization of the otherwise highly, energized carbanion. The distribution of the negative charge and the nucleophilic qualities are at the carbon (in carbanion) and at the oxygen (in enolate anion). As a result, the - carbon and the carbonyl oxygen are the nucleophilic positions of enolate anions.

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  • Further, as the negative charge is more stable at more electronegative oxygen, than at electropositive carbon, the negative charge is bound more strongly and closely to the oxygen atom than is the case with the carbon. Thus, the carbon (as anion) is a soft base, while the carbonyl oxygen (as anion) is a hard base. As a result, soft Lewis acids (electrophiles), such as alkyl halides and the carbonyl carbon of carbonyl compounds, tend to be nucleophilically attacked by the enolate's carbon. In simple words, an enolate anion has two nucleophilic positions, namely the - carbon and the carbonyl oxygen. Enolate anions are hence ambident, that is, they possess two reactive (nucleophilic) centres. Protonation of an enolate may yield two different products, the enol (enolic form of a carbonyl compound), or the carbonyl compound (keto form).

    Variation of acidity: The acidities of these hydrogen atoms is enhanced if an electron withdrawing group is attached to the carbon atom.

    On the other hand, the acidity of the hydrogen atoms decreases if an electron donating group is attached to the carbon atom.

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  • Keto-enol tautomerism The keto form and enolic form are in equilibrium called as keto-enol tautomerism.

    The establishment of equilibrium may be catalyzed by both acids and bases. Through suitable means, such as by fractional crystallization or careful distillation in the absence of any acid and any base, the keto and the enolic form may be separated from each other. The keto and enolic form of a carbonyl compound are constitutional isomers. The separation must be carried out in the absence of all acids and bases, as the equilibrium reaction would otherwise proceed too rapidly. As a result, the separated, pure keto and enolic form would immediately be "contaminated" at least to some degree by the other form again. The various structural formulas of an enolate, in which the negative charge is located at various positions, are actually merely resonance formulas of one and the same compound! Equilibrium position in keto-enol tautomerism : The position of the keto-enol equilibrium is influenced by the temperature and the solvent (if present). The keto form usually exceeds the enolic form to a considerable degree. For example, Acetone contains only 1.5 x 10-4 % of the enolic form. Ketones are usually not enolized to such a degree as aldehydes are. However, -dicarbonyl compounds are significantly much more enolized, as the double bond of a monoenolized -dicarbonyl compound is additionally stabilized through resonance with the second carbonyl group. As a result, the - hydrogen between the two carbonyl groups of -dicarbonyl compounds is much more acidic. On the other extreme, the classic example of a compound that is virtually completely enolized is phenol. The equilibrium constant of keto-enol tautomerism equilibrium of phenol amounts to roughly 1010. It follows that the enolic form of phenol predominates to over 99.99 %. Due to the strikingly high resonance stabilization of the aromatic system, the enolic form of phenol is much

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  • more stable than the non-aromatic keto form (cyclohexadienone). Also, phenol's enolate is much more stable than non-aromatic enolates are, as its negative charge is stabilized through resonance with the aromatic system. As a result, phenol is considerably more acidic than other enols or alcohols. The pKa value of is 9.95.

    Fig: keto and enol form of phenol

    Acidity of -dicarbonyl compounds The acidity of -dicarbonyl compounds is considerably higher than that of monocarbonyl compounds and other dicarbonyl compounds. In keto-enol equilibrium of -dicarbonyl compounds, the (mono)enolic form usually exceeds the keto form. For example, 2,4-Pentadione consists of about 76 % enolic form.

    The reason for this is the noticeably higher stabilization of the enol in comparison to other carbonyl compounds. On the one hand, a -dicarbonyl compound's enol is additionally stabilized through resonance of the enol's carbon-carbon double bond with the second carbonyl group. On the other hand, the enol's hydroxyl hydrogen is connected to the carbonyl oxygen by an intramolecular hydrogen bond. The formation of this hydrogen bond is further facilitated by the six membered planar structure of the enol-carbonyl resonance system.

    Hydrogen-Deuterium Exchange Due to the acidity of the -hydrogens of enolizable carbonyl compounds, the hydrogen may easily be exchanged for deuterium (H/D exchange). H/D exchange may, for instance, occur when the carbonyl compound is treated with heavy water (D2O).

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  • Whenever a carbonyl compound is treated with a large excess of D2O, for instance, if it is dissolved in D2O, virtually all hydrogens of the carbonyl compound are exchanged. A large excess of D2O is essential, since H/D exchange is an equilibrium reaction. The H/D exchange happens faster in the presence of acids or bases.

    Alkylation of enolate anions Enolate anions are nulceophiles. Thus, they can participate in SN2 reactions. If reacted with alkyl halides as electrophiles, alkylation of the enolate occurs. Due to the enolate's ambident character, O-alkylation or C-alkylation may take place. The practicality of the reaction therefore depends on the selectivity for one of the alkylation variations. The question is which position in the enolate displays the highest nucleophilicity? Nucelophilicity also depends on the electrophile. C-alkylation or O-alkylation? In alkylation with alkyl halides, the electrophile is a relatively soft Lewis acid. For that reason, C-alkylation of the enolate is favored, as, due to carbon's lower electronegativity, the enolate's carbon position is a much softer Lewis base than the oxygen position. According to the HSAB concept, a soft Lewis base tends to react with a soft Lewis acid, while a hard Lewis base tends to react with a hard Lewis acid.

    On the other hand, if it is reacted with a harder base as an electrophile, O-alkylation is the preferential route.

    The complexity between reaction at C or at O in enolates is illustrated by the following example:

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  • Reactant Important Factors

    CH3I

    The negative charge density is greatest at the oxygen atom (greater electronegativity), and coordination with the sodium cation is stronger there. Because methyl iodide is only a modest electrophile, the SN2 transition state resembles the products more than the reactants. Since the C-alkylation product is thermodynamically more stable than the O-alkylated enol ether, this is reflected in the transition state energies.

    (CH3)3SiCl

    Trimethylsilyl chloride is a stronger electrophile than methyl iodide (note the electronegativity difference between silicon and chlorine). Relative to the methylation reaction, the SN2 transition state will resemble the reactants more than the products. Consequently, reaction at the site of greatest negative charge (oxygen) will be favored. Also, the high SiO bond energy (over 25 kcal/mole greater than SiC) thermodynamically favors the silyl enol eth