Enolates, Enols, and Enamines Part 3

Transcription

1 Enolates, Enols, and Enamines Part 3 Guanine Tautomerize 2 2 Thymine C 3 Tautomerize C 3 Thursday March 21, 8:00-11:00 AM Final Exam Topics Part A: Carbonyl Fundamentals Carbonyl Survey Enolates, Enols, and Enamines Part B: Comprehensive (entire course) Rooms Last name A-Me in CS50 Last name Mo-Z in CS24 **Discussion board user name** Part A/Part B/Both Parts ption Part A only or Part B only: 90 minutes exam time; exam score doubled Both parts: 3 hours Tools Pen and/or pencil (not red) Eraser Molecular model kit o calculators or cell phones Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 1

2 Enols ame Resonance contributors Resonance hybrid Enolate δ α β ucleophilic at β-carbon Enol alkene + alcohol δ+ Enamine alkene + amine R 2 R 2 R 2 δ+ Enols: Tautomerization and Stability C 3 C C 23 Keto form as -C-C= K eq ~ 10-6 Enol form as C=C-- Constitutional isomers differing in position of pi bond and proton = Tautomers Interconversion of tautomers = Tautomerization Increasing stability of enol shifts equilibrium: K eq ~ 1 C 3 C C 2 Keto form has higher bond energy sum Therefore Keto form more stable than enol form Enol stabilized by... Increased conjugation Intramolecular hydrogen bond K eq >> 1 Aromaticity Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 2

3 Enols: Formation First guess: Does not occur because Acid-catalyzed tautomerization: Most common tautomerization mechanism Base-catalyzed tautomerization: Rarely important due to enolate self-condensation + By decarboxylation: + C Can be any C= functional group Enols: Reactions δ+ General reaction pattern: React with electrophile at β-carbon Similar to enolates Examples: Acid-catalyzed aldol reaction aq. 2 S 4 Acid-catalyzed bromination Ph C 3 Br 2 aq. Br Ph Br C 3 Mechanisms: ew bond adjacent to C= in presence of strong acid suggests enols are involved Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 3

4 Enols: Acid-Catalyzed Aldol Reaction Mechanism aq. 2 S 4 Mechanism: ew C-C adjacent to C= in presence of acid suggests enol is involved 2 2 Acid-catalyzed tautomerization 2 Enol is... Strong nuc More electrophilic? Ketone Weak nuc Protonated ketone Can - be LG? Yes o 2 Enols: Acid-Catalyzed Bromination Br 2 Ph C Ph aq. Br C 3 C 3 Br Student exercises: Work out the mechanism Solution in CATSA Chapter 27 Why bromination at PhC 2 instead of at C 3? Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 4

5 Formation Enamines: Formation Usually from secondary amine (R 2 ) with aldehyde or ketone Example: (C 3 ) 2 2 S 4 (C 3 ) 2 Student exercises: Work out the mechanism Solution in WLS and CATSA Chapter 25 Why is enamine formed instead of imine? Enamines: Reactions R 2 R 2 R 2 δ+ General reaction pattern: React with electrophile at β-carbon Similar to enolates and enols Example: The Stork acylation reaction aq. 2 S 4 Cl + Student exercise Work out the mechanism Solution in Enolates WLS and CATSA Chapter 27 Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 5

6 Which Mechanism is perating? C C C C X α Which mechanism? Reaction at carbonyl α-carbon usually indicates enolate, enol, or enamine mechanism Strong base is present mechanism probably enolate Strong acid is present mechanism is probably enol Amine present mechanism might be enamine Exceptions exist Examples: ew C-C next to C= ew C-C next to C= a aq. 2 S = strong base Mechanism is: enolate enol enamine 3 + = strong acid Mechanism is: enolate enol enamine Enolates, Enols, and Enamines in Biology Enolates generally too strongly basic to exist under physiological conditions. Enolates are common in lab scale and industrial scale organic synthesis. Enols and enamines are plentiful in biology. Biological examples: Vitamin C (ascorbic acid) An enol 2 Tryptophan (an amino acid) An enamine C Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 6

7 Enolates, Enols, and Enamines in Biology Tautomers frustrate Watson and Crick's quest to solve the DA structure problem... Considered 'best' before 1953 Corrected structures Guanine Tautomerize 2 2 Thymine C 3 Tautomerize C 3 Do not fit hydrogen-bonded base-paired double helix Fit hydrogen-bonded, basepaired double helix perfectly. Enolates, Enols, and Enamines in Biology Example: Thioester Claisen reaction, an early step in steroid biosynthesis Acetoacetyl-CoA transferase SCoA SCoA Student exercise Propose a mechanism for this reaction. Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 7

8 Enolates, Enols, and Enamines in Biology Example: Glycolysis (metabolism of glucose) Enz-B = enzyme basic site Enz-B = enzyme acidic site C 2 several steps P 3 Enz- 2 P 3 Enz Glucose P 3 P 3 Enz-B reverse aldol Further metabolism 3 P Pyruvic acid + Enz o direct pathway Enz-B Enz-B 2 P 3 P 3 P 3 Enolates, Enols, and Enamines Part 3 Lecture Supplement -- Page 8