Mechanisms keto-enol tautomerism, catalyzed

Problem 17.3 Compare the mechanisms for (a) base-catalyzed and (b) acid-catalyzed keto-enol tautomerism. 

The initial product has a hydroxy group attached to a carbon-carbon double bond. Compounds such as this are called enols (ene + ol) and are very labile—they cannot usually be isolated. Enols such as this spontaneously rearrange to the more stable ketone isomer. The ketone and the enol are termed tautomers. This reaction, which simply involves the movement of a proton and a double bond, is called a keto—enol tautomerization and is usually very fast. In most cases the ketone is much more stable, and the amount of enol present at equilibrium is not detectable by most methods. The mechanism for this tautomerization in acid is shown in Figure 11.6. The mercury-catalyzed hydration of alkynes is a good method for the preparation of ketones, as shown in the following example ... 

Compare the base-catalyzed and acid-catalyzed mechanisms shown for keto-enol tautomerism. In base, the proton is removed from the a carbon, then replaced on oxygen. In acid, oxygen is protonated first, then the a carbon is deprotonated. Most proton-transfer mechanisms work this way. In base, the proton is removed from the old location, then replaced at the new location. In acid, protonation occurs at the new location, followed by deprotonation at the old location. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

Show how enols and enolate ions act as nucleophiles. Give mechanisms for acid-catalyzed and base-catalyzed keto-enol tautomerisms. 

The mechanism of the acid-catalyzed aldol reaction involves an initial acid-catalyzed keto-enol tautomerization to provide the enol form protonation of a second molecule on the carbonyl oxygen creates an electrophilic oxonium ion that is then attacked by the nucleophilic enol, followed by loss of a proton to give the j8-hydroxy aldehyde or ketone product. 

Tautomerizations involve the shift of a hydrogen atom across a tt system. The most typical tautomerization is a 1,3-shift, and the focus of this section is the interconversion of a ketone (or aldehyde) and an enol, often termed keto-enol tautomerization. The reaction can be catalyzed by acid or base, and it is technically an isomerization, a class of reactions we will cover later in this chapter. However, knowledge of the mechanism of keto-enol tautomerizations is crucial to understanding enol and enolate chemistry, and therefore we cover it here. 

DRAWING THE MECHANISM OF ACID-CATALYZED KETO-ENOL TAUTOMERIZATION... 

Know how to recognize or draw the keto and enol forms of a molecule, and know the mechanism of a keto-enol tautomerization under acid- and base-catalyzed conditions. 

Drawing the Mechanism of Acid-Catalyzed Keto-Enol Tautomerization... 

These oscillatory changes were observed not only for the optically pure enantiomers but also with the racemic 2-phenyl propionic acid sample. The molecular mechanism was attributed to keto-enol tautomerism that is acid catalyzed as well. All the profens are carboxylic acids with relatively well-pronounced electrolytic dissociation. Thus, the keto-enol transenantiomerization of profens in aqueous media was considered justified because of the self-catalytic effect of the protons originating from the dissociated carboxyl groups. Since reducing the temperature stabilizes the short-lived tautomers there was greater amplitude of oscillation at 6°C than at 22- C. 

Equilibrium favors the keto form largely because a C=0 is much stronger than a C=C. Tautomerization, the process of converting one tautomer into another, is catalyzed by both acid and base. Under the strongly acidic conditions of hydration, tautomerization of the enol to the keto form occurs rapidly by a two-step process protonation, followed by deprotonation as shown in Mechanism 11.3. 

Hydration of an internal alkyne with strong acid forms an enol by a mechanism similar to that of the acid-catalyzed hydration of an alkene (Section 10.12). Mechanism 11.4 illustrates the hydration of 2-butyne with H2O and H2SO4. Once formed, the enol then tautomerizes to the more stable keto form by protonation followed by deprotonation. 

A plausible overall mechanism for the reactions leading to 29 is shown in Scheme 18.5. 2-Methylpropanal (26) first undergoes acid-catalyzed tautomerization to its enol form 30, in which the adelocalized cation 31, which is more electrophilic than the unprotonated form. Because 30 is a weak nucleophile relative to an enolate ion, the formation of 31 facilitates the next stage of the reaction, which results in a new carbon-carbon bond between 26 and 27 to give the enol 32. The boldfaced atoms in structure 32 show that the a-C-H bond of 26 has added in a conjugate-, or 1,4-, manner to 27. Acid-catalyzed tautomerization of 32 leads to the thermodynamically more stable keto form 28. 

In the first step of acid-catalyzed tautomerization of the keto form, hydronium ion proton-ates the carbonyl oxygen atom. Then, water removes the a-hydrogen atom to give the enol. Each of the reactions is reversible, so the acid-catalyzed conversion of the enol into the keto form occurs by the reverse of each step of the mechanism. 

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