A. Review of Acidity and pk a Common way to examine acidity is to use the Bronsted-Lowry acid-base equation:

Transcription

1 1 Chapter 22: Reactions of Enols and Enolates I. Alpha Substitution verview: A. Review of Acidity and pk a Common way to examine acidity is to use the Bronsted-Lowry acid-base equation: Recall that the Bronsted-Lowry acid-base reaction is a reversible reaction, with an equilibrium constant K eq : To compare the strength of different acids, we use water (H 2 ) as the base and compare the value of K eq for different acids reacting with water. We can also estimate K eq of an acid-base equilibrium using pk a s:

2 2 A table of standard pk a values is listed below. Please memorize all the acids and their pk a values on this table. Acid pk a Conjugate Base Strong Acids HI -10 I Weak Bases HBr -8 Br HCl -7 Cl H 2 S 4-5 HS 4 H H 2 CCl 3 CH 0.6 CCl 3 C H 3 P H 2 P 4 HF 3.2 F CH 3 CH 4.8 CH 3 C H 2 C HC 3 H 2 S 7.0 HS HCN 9.1 CN + NH NH 3 CH 3 H 15.5 CH 3 H H CH 3 CH 2 H 16 CH 3 CH 2 CH 3 CH 17 CH 2 CH (CH 3 ) 3 CH 18 (CH 3 ) 3 C CH 3 CCH 3 20 CH 3 CCH 2 CH 3 C 2 R 24.5 CH 2 C 2 R R-C C-H 25 R-C C H-H 35 H NH 3 36 NH 2 CH 2 =CH 2 44 CH 2 =CH Weak Acids CH 3 CH 3 50 CH 3 CH 2 Strong Bases Examples:

3 3 B. Acidity of Carbonyl Compounds: Enolates Greek lettering is used to indicate positions in a carbon chain relative to a functional group (FG = H, X, C=). II. Enolate Formation: Kinetic vs. Thermodynamic Enolates Many compounds can form two possible regioisomeric enolates:

4 4 CASE #1: Favoring the Kinetic Product CASE # 2: Favoring the Thermodynamic Product. Let s look at the three different sets of conditions we can use to form enolates.

5 5 1) Formation of the Thermodynamic Product: Use Alkoxide bases (R or H ) 2) Formation of the Kinetic enolate ) (less sterically hindered). Use a slight excess (1.02 eq) of a VERY strong base (like lithium diisopropyl amide, LDA)

6 6 3) Fromation of the thermodynamic enolate Use slightly less than one equiv (usually about 0.98 equivs) of strong base (like LDA), and letting the reaction sit for 30 min. III. Keto-Enol Tautomers Tautomers: structural (constitutional) isomers that can chemically interconvert. Ketones and aldehydes exist as a mixture of tautomers:

7 7 CASE #1 CASE #2

8 8 Reactions of Enolates I. Acid or 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. CASE #1: Base-Promoted Mechanism: Alpha-Halogenation

9 9 CASE #2: Acid-Catalyzed Mechanism: Alpha-Halogenation Halogens are good oxidizing agents and aldehydes are easily oxidized. II. Haloform Reaction Mechanism: (iodoform test works for 2 o alcohols also) III. Alkylation of Enolates nly works on ketone enolates (aldehydes have too many side reactions). Alkyl halide (R X) must be able to do S N 2 reaction (must not be sterically hindered, etc ). Since we use a base, we must consider kinetic and thermodynamic products. Mechanism:

10 10 IV. Enamine Reactions bserved Reaction A) Enamine Formation Mechanism: B) Enamine Alkylation

11 11 C) Enamine Hydrolysis: V. Aldol Condensation of Ketones and Aldehydes bserved Reaction Biological Example: steps are reversible with an enzyme Fructose-1,6-biphosphate Dihydroxyacetone-P + Glyceraldehyde-3-P H 2 C P C H CH HC H HC H Enzyme H 2 C C H 2 C P H + HC HC H 2 C H P H 2 C P Fructose-1,6-biphosphate Dihydroxyacetone Phosphate + Glyceraldehyde 3-phosphate

12 12 Part I- Formation of Aldol Product CASE #1: Base-Catalyzed Mechanism CASE #2: Acid-Catalyzed Mechanism PART II- Dehydration of Aldol Products (Needs heat): CASE #1: Basic Conditions CASE #2: Acidic Conditions

13 13 VI. 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: EXAMPLE We can do a crossed aldol when one of the carbonyl containing compounds has no hydrogens:

14 14 VII. Aldol cyclization: When a compound contains two carbonyls, treatment with base can form a ring: When the compound contains an aldehyde and a ketone, the ketone forms the enolate and the aldehyde is the acceptor in an intramolecular reaction:

15 15 VIII. Planning an Aldol Condensation

16 16 IX. Trends in Acidity of Carbonyl Compounds (esters and -dicarbonyls) Esters are less acidic than ketones or aldehydes. The ester group is already stabilized: -Dicarbonyls are much more acidic than simple esters, aldehydes, or ketones. Why? More resonance to stabilize their conjugate bases (remember, more stable conjugate base makes a stronger acid). -Dicarbonyls can be almost completely deprotonated using hydroxide or alkoxide bases (instead requiring very strong bases such as LDA). These are useful conditions in biological systems.

17 17 X. The Claisen-Ester Condensation bserved Reaction The alkyl group (R) on the ester must be the same as the alkyl group (R) on the alkoxide base; if they are different, we can get undesired transesterification. Mechanism

18 18 XI. Crossed Claisen Condensation The crossed Claisen condensation works best when one of the esters has no acidic - hydrogens (similar to a crossed aldol): Methyl Formate Dimethyl Carbonate Methyl Benzoate Example: A similar crossed Claisen condensation occurs between a ketone and an ester. The ketone is the stronger acid, so it is deprotonated and acts as the donor Predict the products:

19 19 XII. Malonic Ester Synthesis bserved Reaction Mechanism:

20 20 XIII. Acetoacetic Synthesis bserved Reaction and Mechanism

21 21 XIV. Addition to,-unsaturated Carbonyls (Michael Reaction) A. 1,2 vs. 1,4 Addition (Conjugate Addition) An,-unsaturated carbonyl compound has a carbon-carbon double bond conjugated with the C= pi bond. Resonance delocalizes the + charge that is on the C= carbon: Nucleophiles can add to either the C= carbon or the beta carbon. Addition to the C= carbon is called 1,2-addition: Addition to the beta carbon is called 1,4-addition or conjugate addition or Michael addition: The properties of the nucleophile determine where it will prefer to add. CASE #1: Nucleophiles (Michael Donors) with high polarizability prefer to add 1,4. Nucleophile (aka Michael Donor) RSH, R 2 CuLi, enolates

22 22 CASE #2: Nucleophiles (Michael Donors) with low polarizability prefer to add 1,2. Nucleophiles (Michael Donors) RH, H: -- (from LiAlH 4 ), R: MgX + and R: Li +. Michael donors (nucleophiles): enolate ions stabilized by two electron-withdrawing groups. o -diketone, -keto ester, enamine, dialkylcuprate, -keto nitrile, -nitro ketone. Michael acceptors (electrophiles): C=C conjugated with carbonyl, cyano, or nitro group. o conjugated aldehyde, ketone, ester, amide, nitrile, or a nitroethylene and often MVK (methyl vinyl ketone) but-3-en-2-one aka MVK

23 23 XV. Robinson Annulation (Nobel Prize in 1947) Annulation: Defiinition Ring forming reaction Michael Addition followed by Aldol Condensation Useful in preparing a 6-membered rings (like steroids) bserved Reaction