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 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 3 + -1.7 H 2 CCl 3 CH 0.6 CCl 3 C H 3 P 4 2.1 H 2 P 4 HF 3.2 F CH 3 CH 4.8 CH 3 C H 2 C 3 6.4 HC 3 H 2 S 7.0 HS HCN 9.1 CN + NH 4 9.4 NH 3 CH 3 H 15.5 CH 3 H 2 15.7 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 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 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 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 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 CASE #1 CASE #2
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 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 IV. Enamine Reactions bserved Reaction A) Enamine Formation Mechanism: B) Enamine Alkylation
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 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 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 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 VIII. Planning an Aldol Condensation
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 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 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 XII. Malonic Ester Synthesis bserved Reaction Mechanism:
20 XIII. Acetoacetic Synthesis bserved Reaction and Mechanism
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 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 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