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CHAPTER 23: ENOLS + ENOLATES

KETO-ENOL TAUTOMERISM

TAUTOMERISM

ACIDIC MECHANISM

BASIC MECHANISM

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EQUILIBRIUM CONSTANTS

K 1 1 × 10–5 8 × 10–8 1.7 × 10–8

K 1 0.23 (water solvent) 29 (CCl4 solvent) 20 (water solvent) >50

1 Carey, F.A., Sundberg, R.J., Advanced Organic Chemistry, 4th ed., Kluwer Academic/Plenum Publishing, 2000, pp. 429.

RC

O

CR

OH K= [enol] [keto]

H3CC

O

H H2CC

OH

H H3CC

CH3

O

CH3C

H2C

OH

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1H NMR spectra can be used to generate K’s:

Problem: Below are various tautomers of Vitamin C (ascorbic acid). Choose the major form at equilibrium.

BIOCHEMISTRY APPLICATION

Glucose Phosphoenol pyruvate (PEP)

Last step of Glycolysis

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ALPHA RACEMIZATION

WHY THIS OCCURS IN BASE

WHY THIS OCCURS IN ACID

APPLICATION

Odilute HCl (aq)

dilute KOH (aq)or

[α] = +x˚

[α] = 0˚

N

O

O

NHO

O N

O

O

NHO

O

Thalidomide

Helps morning sickness Serious birth defects

(These racemize in the body.)

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ALPHA HYDROGEN ACIDITY

FORMATION OF ENOLATES

Lithium diisopropyl amide (LDA)

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DIFFERENCES IN ALPHA ACIDITY

pKa 15-17

pKa

O O

+ NaOH

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REACTIONS AT THE ALPHA CARBON

ALPHA HALOGENATION

REACTION + MECHANISM

X = Cl, Br, I

HALOFORM REACTION

Note: Purification of water using chlorine sometimes creates CHCl3 (carcinogen) from reaction of organic impurities that contain methyl ketones.2

2 Solomons, G., Fryhle, C.B., Organic Chemistry, 8th ed., Wiley, 2004, pp. 778.

Iodoform Test for Methyl Ketones (Left = Negative, Right = Positive)

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EXAMPLES

ALPHA ALKYLATION

REACTION + MECHANISM

Oa. 1 equiv. LDA

b. CH3X

Oa. 1 equiv. LDA

b. I

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APPLICATION

MALONIC ESTER SYNTHESIS

THE PROCESS

STEPS A+B (ALKYLATION)

Tamoxifen (anticancer drug, has been successful against breast cancers)

O

OCH3

O

OCH3 ON(CH3)2

Malonic ester

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STEP C (DECARBOXYLATION)

EXAMPLES

Design a synthesis of each:

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BIOCHEMISTRY APPLICATIONS

Step 3 of the citric acid cycle:

Pentose Phosphate Pathway3:

Synthesis of 5-Carbon Carbohydrates (like what is used in DNA + RNA) from 6-Carbon Glucose

ACETOACETIC ESTER SYNTHESIS

THE PROCESS

EXAMPLE

3 McMurry, J., Begley, T., The Organic Chemistry of Biological Pathways, 2nd edition, 2016, pp. 228.

–O2C CO2–

OH

CO2–

NAD+ –O2C CO2–

O

CO2–

O

O

OO O

O

O=

OOH

POHOHO

OH

Glucose-6-phosphate

O

O

POHOHO

OH

NADP+ H2OOH

O

POHOHO

OH

OOH

O

POHO

O OH

O

NADP+

Acetoacetic ester

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SUMMATIVE PROBLEM

Use one of the reagents shown to synthesize the following ketone: