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22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

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  • Page ID
    91009
  • Objectives

    After completing this section, you should be able to

    1. explain why the alpha hydrogens of carbonyl compounds are more acidic than the hydrogens in a typical hydrocarbon.
    2. list the properties that make lithium diisopropylamide a suitable reagent for converting a wide range of carbonyl compounds into their enolate anions.
    3. arrange a given list of carbonyl compounds in order of increasing or decreasing acidity.
    4. determine whether a given carbonyl‑containing compound is more or less acidic than selected other compounds, such as water, ammonia, alcohols, alkanes, alkenes, alkynes and amines.
    5. explain why dicarbonyl compounds, such as β‑diketones, are more acidic than compounds that contain only a single carbonyl group.

    Key Terms

    Make certain that you can define, and use in context, the key terms below.

    • β‑diketone
    • β‑keto ester

    For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases that have been used for enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and LiN[CH(CH3)2]2 (lithium diisopropylamide, LDA, pKa 36).  Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane. 

    Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application, one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid. Although the reaction of carbonyl compounds with sodium hydride is heterogeneous and slow, sodium enolates are formed with the loss of hydrogen, and no other organic compounds are produced.

    The presence of these overlapping p orbitals gives \(\alpha\) hydrogens (Hydrogens on carbons adjacent to carbonyls) special properties. In particular, \(\alpha\) hydrogens are weakly acidic because the conjugate base, called an enolate, is stabilized though conjugation with the \(\pi\) orbitals of the carbonyl. The effect of the carbonyl is seen when comparing the pKa for the \(\alpha\) hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to the pKa of an alkane (~50).

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    Of the two resonance structures of the enolate ion the one which places the negative charge on the oxygen is the most stable. This is because the negative change will be better stabilized by the greater electronegativity of the oxygen.

    Functional Group Structure pKa
    carboxylic acid HO–(C=O)R 5
    nitro RCH2–NO2 9
    β-diketone * R(O=C)–CH2–(C=O)R 9
    β-ketoester * R(O=C)–CH2–(C=O)OR 11
    β-diester * RO(O=C)–CH2–(C=O)OR 13
    amide RNH–(C=O)R 15
    alcohol RCH2–OH 16
    aldehyde RCH2–(C=O)H 17
    ketone RCH2–(C=O)R 20
    thioester RCH2–(C=O)SR 21
    ester RCH2–(C=O)OR 25
    nitrile RCH2–C≡N 25
    sulfone RCH2–SO2R 25
    amide RCH2–(C=O)N(CH3)2 30
    alkane CH3–R 50

    * Note methylene groups bridging between two electron withdrawing groups are more acidic than alpha protons next to only one carbonyl group.

    Examples

    If the formed enolate is stabilized by more than one carbonyl it is possible to use a weaker base such as sodium ethoxide.

    NaOCH2CH3 = Na+  -OCH2CH3 = NaOEt


    Because of the acidity of α hydrogens, carbonyls undergo keto-enol tautomerism.  Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.

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