chem a225 notes page 87 chapter 22: enolate reactions (part one)€¦ · chapter 22: enolate...

Chem A225 Notes Page 87

Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.

Chapter 22: Enolate Reactions (Part One)

I. Acidity of Carbonyl Compounds: Enolates

• We can use greek letters to indicate positions in a carbon chain relative to a functional group (FG = –OH, –X, –C=O). If we treat the C=O carbon as a functional group, then the carbon attached to C=O would be the alpha (α) carbon:

• The hydrogens on the α carbons of carbonyls (α hydrogens) are more acidic than most hydrogens attached to carbon. For example, an alkane usually has a pKa around 50, while the pKa of an α carbon of a carbonyl is around 17–22.

• An acid’s strength increases when the electron density in the conjugate base is stabilized. (We will study this more in Chapter 21)

• We can explain this by looking at the stability of the conjugate base of a carbonyl compound. The conjugate base produced by deprotonation of the α carbon of a carbonyl compound is called an enolate.

• There are two factors which stabilize the electron density in an enolate:

1) Resonance delocalization of the negative charge. In general, a species with more resonance structures is usually more stable.

2) Resonance moves electron density from carbon (low electronegativity) onto oxygen (high electronegativity) where it is much more stable. Excess electron density (negative charge) is more stable when it is on an atom with a high electronegativity.

Chem A225 Notes Ch 22: Alpha Carbon Chemistry (Part One) Page 88


II. Keto-Enol Tautomers

• Tautomers: structural (constitutional) isomers that can chemically interconvert.

• Ketones and aldehydes exist as a mixture of tautomers:

• In most cases, isolated ketones and aldehydes prefer the keto tautomer:

• However, intramolecular (inside the same molecule) hydrogen bonding can help increase the amount of enol present:

• Base-Catalyzed mechanism of keto-enol tautomerization:

• Acid-catalyzed mechanism of keto-enol tautomerization:



III.Reactions of Enolates

A. Aldol Addition and Aldol Condensation

• Aldol Addition (Observed Reaction) (also called aldol reaction)

• Aldol Condensation (Observed Reaction)

• Mechanism:

• Two carbonyl molecules react. One is the electron donor. It will be the molecule that forms the enolate. The other is the electron acceptor. It will accept electrons of a nucleophile at the carbonyl carbon (C+).

• The new bond will be formed between the alpha carbon of the donor and the C+ carbon of the acceptor.

• The reaction steps are reversible up until the step that forms the double bond (in the condensation).

• Equilibrium for the aldol reaction (stopping at the aldol) is disfavored for ketones; therefore, ketones almost always must be dehydrated (aldol condensation) or no products will be isolated.



• Crossed aldol reaction: an aldol reaction in which the two carbonyl compounds are not identical.

• For most pairs of carbonyl reactants, crossed aldol reactions are impractical because they result in a bad mixture of different products:



• We can do a crossed aldol when carbonyl A (the acceptor) has no α hydrogens (so that products A–D and A–A cannot be formed):

• We can also use a ketone as carbonyl D (the donor) with an aldehyde acceptor that has no α hydrogens (this is called the Claisen-Schmidt Reaction):

• Aldol cyclization: an intramolecular aldol condensation that forms a ring.

• When a compound contains two carbonyls, treatment with base can form a ring:



• In the cyclization, 5 or 6 membered rings are preferred instead of 3, 4 or 7 membered rings:

• When the compound contains an aldehyde and a ketone, the ketone forms the enolate and the aldehyde is the acceptor:

• Problem-solving Strategy: Analyzing an Aldol Reaction or Condensation

• The product of an aldol addition will have a carbonyl and a hydroxyl group. The carbonyl is from the donor. The hydroxyl group is attached to C+ of the acceptor.



• The product of an aldol condensation is an α,β-unsaturated carbonyl. The carbonyl is from the donor; the enolate was on the α carbon. The β-carbon was C+ of the acceptor.

B. Acid-Catalyzed Halogenation

• Observed Reaction

• Mechanism:

• Usually halogenation on the more substituted side is preferred (the more substituted enol is formed preferentially because it is more stable).



C. Base-Promoted Halogenation


• Base-promoted: base increases the rate of the reaction, but it is consumed (different from a catalyst, which increases reaction rate but is not consumed).

• When a reaction is promoted by acid or base, a full equivalent of the acid or base is required.

• Mechanism:

• The enolate is formed in the presence of the electrophile, and it reacts immediately after forming. Because the less-substituted enolate (kinetic enolate) is formed first, it will react before it can equilibrate to the more-substituted (thermodynamic) enolate. Therefore, halogenation should occur on the less-substituted side.

• Polyhalogenation is a problem with this reaction:

Chem A225 Notes Ch 22: Alpha Carbon Chemistry (Part One) 5


D. Haloform Reaction


• Mechanism

• Only works on methyl ketones and 2-alcohols:



• Iodoform Test: A chemical test for methyl ketones (and 2-alcohols)

E. Enamine Reactions

• Observed Reaction: Formation of the Enamine

• Observed Reaction: Alkylation of Enamines (similar to enolate alkylation)

• Works for both aldehydes and ketones. The more substituted enamine is usually preferred, which gives alkylation on the more substituted (thermodynamic) side.

• Examples:



• Mechanism of Enamine Formation

• Add R2NH --> Remove OH

• Mechanism of Enamine Alkylation and Hydrolysis



F. Enolate Alkylation

• Observed Reactions

• Only works on ketone enolates (aldehydes have too many side reactions, use enamine instead).

• Alkyl halide (R–X) must be able to do SN2 reaction (must not be sterically hindered).

• Mechanism



• Many compounds can form two possible regioisomeric enolates:

• The more substituted enolate would be more stable. Increasing the number of alkyl substituents on the enolate increases the stability of the enolate. This is explained by comparing the enolate to an alkene; recall that more substituted alkenes are more stable.

• The less substituted enolate would be formed faster, because of decreased steric hindrance to deprotonation on the less substituted α carbon.

• Whenever there is a reaction with two possible products, one of which is more stable and the other of which is formed faster, we have the possibility of controlling the selectivity of the products.

• The more stable product is called the thermodynamic product because it is thermodynamically (according to ΔG) more stable.

• The faster formed product is called the kinetic product.

• Under reversible, equilibrium conditions, the thermodynamic product will be preferred.

Why? Because when any of the kinetic product is formed, it will eventually be converted (by reverse reaction) back to the reactant. This will give another opportunity for the thermodynamic product to be formed. The thermodynamic product reacts more slowly in the reverse reaction (Why? higher Ea for its reverse reaction, look at the energy profile above to see), so over time more of it accumulates, making it the preferred product.



• The kinetic product is favored by rapid, irreversible reaction conditions.

Why? Because the kinetic product is formed faster. Once it is formed, the product is trapped as the kinetic product because the reaction won’t go in the reverse direction.

• When making lithium enolates, we can control formation of the kinetic and thermodynamic enolates.

1) Kinetic enolate is favored by using a strong base (like lithium diisopropyl amide, LDA) in slight excess (1.02 equivs) at low temperature. The conj. acid of LDA has a pKa of 35, so Keq will be large and positive. Enolate formation will be irreversible.

2) The thermodynamic enolate can also be formed by using slightly less than one equiv (usually about 0.98 equivs) of strong base (like LDA), and letting the reaction sit for 30 min. Under these conditions, the small amount of unreacted aldehyde/ketone acts like an acid and reacts with the enolate. This sets up a new enolate-forming acid-base reaction, where the Keq is equal to 1. Over time, the reaction equilibrates to give the thermodynamic enolate.

chem a225 notes page 87 chapter 22: enolate reactions (part one)€¦ · chapter 22: enolate...

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