22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

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 S_N2 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 (pK_a > 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, pK_a > 45), NaNH₂ (sodium amide, pK_a = 34), and LiN[CH(CH₃)₂]₂ (lithium diisopropylamide, LDA, pK_a 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 pK_a for the \(\alpha\) hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to the pK_a of an alkane (~50).

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.

Contributors and Attributions

• Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

• Prof. Steven Farmer (Sonoma State University)

• William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry