Chapter 23. Carbonyl Alpha Substitution Reactions

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1 Chapter 23. Carbonyl Alpha Substitution eactions Alpha-substitution reactions occur at the position NEXT to the carbonyl group- the α position- and involve substitution of the α- by an electrophile E through either an ENL or ENLATE IN. The α-c of carbonyls can act as a nucleophile in a number of reactions via either the enol tautomer or via the enolate anion.! ' E + ' E no alpha-proton Keto-Enol Tautomerization and Enol eactivity S. 8.5: A ketone with alpha is in equilibrium with its corresponding enol tautomer: There is a rapid interconversion between the two forms which is a special kind of isomerism called: tautomerism (Greek: the same) ketone % enol % Under most conditions the enol form is present in very small amounts. owever, it is very important for synthetic reasons because they are so reactive. The formation of the enol component is catalyzed by both acids and bases such that it can be present in amounts that allow for synthetically useful reactions:

2 Acid Catalyzed Base Catalyzed B - - -B + B - Alpha halogenation of enols ne important reaction of enols: alpha halogenation Aldehydes and ketones can be halogenated with Cl 2, 2, and I 2 under acidic conditions: 2 / + Mechanism: + - C 2 - nly NE alpha- is replaced by a halogen

3 If a ketone is unsymmetrically substituted, the halogen is delivered to the more substituted side, via the more substituted and more nucleophilic enol: Cl 2 / + Cl Alpha-halogenated ketones and aldehydes are easily converted in their corresponding α,β-unsaturated compounds by elimination: 2 / + tbuk E2 Acidity of Alpha : Enolate ion formation Discuss pka A + 2 A C C! pka = 17 3 C C 2 Ka = [A- ][ 3 + ] [A] pka = 60 C C! pka = 20 pka = -logka Difference: ~40 pka units ketone is times more acidic than alkane. (USA budget (2006) ~$2 trillion (10 12 ) ) Lower pka due to resonance stabilization : ' B ' ' enolate

4 EDG, less enolate stabilization pka = 20 pka = 17 Cl pka = 16 pka = 25 N pka = 30 N 2 pka = 8.6 C N pka = 25 N C C C N pka = 12 2,4 pentane dione pka = 9 Weaker bases, such as Na and NaEt generate an equilibrium mixture of enolate and carbonyl compound: Ethyl-3-oxobutyrate pka = 11 Why higher? Discuss 99.9 % NaEt or Na 0.1 % Even though the generated enolate is not much it can still be used in reactions. A more powerful base, LDA, can be used to completely convert a ketone or aldehyde to their corresponding enolate:

5 LDA: lithium diisopropylamide LDA ~ 100% + N Li N N pka ~ 40 + nbuli weak acid conjugated base is strong Li N bulky base good base, bad nucleophile Enolates are more useful than enols for two reasons: 1. Unlike enols, enolates can be generated as stable, pure solutions 2. Due to their negative charge, enolates are more reactive nucleophiles than enols

6 Enolates can react either at the alpha carbon or at the oxygen carbon. (We will only study reactions at the alpha carbon) reaction at! carbon ' reaction at oxygen ' E + E + not discussed E ' E '

7 Two reactions of Enolates to discuss: 1. alpha alogenation Already saw enol halogenation (under acidic conditions): Compare to enolate halogenation (basic conditions): + / 2 + much less nucleophilic enol due to EW bromine monohalogenation Na Na 2 perhalogenation - more acidic due to EW So: Under basic conditions every alpha- is replaced by a halogen: Na Cl 2 Cl Cl

8 aloform eaction: NLY with methyl ketones, same conditions afford carboxylic acids /Na Mechanism Na 2 CB3 Na C C 3 2. Alkylation of Enolate Ions LDA S N 2 Aldehydes, Ketones, Lactones, Esters, Nitriles can all be alkylated on the alpha C this way.

9 Examples:!- lactone 1. LDA 2. C 3 C 2 Cl!-!- 1. LDA 2. Ph I Ph symmetric!-!- 1. LDA 2. C 3 C 2 Cl or asymmetric Kinetic vs Thermodynamic Enolate LDA + more hindered less hindered more stable thermodynamic enolate faster kinetic enolate

10 LDA (2 eq) faster kinetic enolate Cl LDA (<1 eq) Cl more stable thermodynamic enolate Dicarbonyl Compounds emember: pka = 20 pka = 17 2,4 pentane dione pka = 9 So, dicarbonyl compounds will form enolates easier (no need for strong base like LDA, softer bases (NaEt, Na) would do) Ethyl-3-oxobutyrate pka = NaEt 2. Ph Ph Very useful synthetic indermediates

11 Two useful reactions (need to memorize the names of the compounds): 1. The Malonic Ester synthesis (Provides Carboxylic Acids) Et Et diethyl malonate 1. NaEt 2. Et Et -C heat ester hydrolysis Example Et Et 1. NaEt 2. Ph heat Ph 2. The Ethyl Acetoacetate synthesis (Provides Methyl Ketones) Et ethyl acetoacetate 1. NaEt 2. Et -C heat ester hydrolysis Example 1. NaEt 2. Et heat

12 Both reaction proceed through a decarboxylation rxn (loss of C2) - 3-oxo-carboxylic acids can decarboxylate if heated under acidic or basic conditions: - bad leaving group + C 2 + C 2 enolatestabilized Example: Na, heat C 2

13 Chapter 24. Carbonyl Condensation eactions Nu electrophile Nu Base E + nucleophile E Carbonyls can act as both Electrophiles and Nucleophiles, so: Na used to be carbonyl "! "-hydroxyaldehyde 2 C-C bond formation - Self Aldol Condensation Similar rxn with ketones affords beta-hydroxyketones

14 Na!-hydroxyketone heat dehydration ",! unsaturated enone ydroxy compounds can dehydrate under acidic conditions, heat Aldol products can dehydrate under acidic or basic conditions and heat easier, since the product is a conjugated system. Some Aldol products do not need heat. They dehydrate since they will have extra conjugation. For example, aromatic systems: - - Dehydrated Aldols are called Aldol Condensations used to be carbonyl

15 Mixed (Crossed) Aldols When two non identical carbonyls are used in an aldol rxn Typically, what is isolated is a statistical mixture of four products: two self-aldol products and two mixed aldol products. + Na (If asymmetric ketones used, even worse mess!) Two possible solutions: 1. If one participant has no α hydrogens + Na + Two products, better yield of 1 st if excess benzaldehyde used.

16 2. Better solution: Generate the enolate of one carbonyl compound completely with LDS and then add the 2 nd carbonyl compound. 1. LDA -78 o C Examples: carbonyl 1. LDA -78 o C LDA, -78 o C kinetic enolate

17 Intramolecular Aldol eactions When the same molecule has two aldehydes or ketones Driving force: Formation of 5 or 6 membered rings. Na 23.8 Claisen Condensation Condensation of two esters: Note: Base has to be same as ester otherwise transesterification 1. NaC NaC 3!-ketoster - Example: Et Et

18 Mixed Claisens: 1. Useful only if one of the two esters has no α-. That ester is used in excess to avoid homocoupling: excess 1. NaMe Works the best if you 1 st generate one enolate and then add the second ester. 1. LDA, -78 o C Ph Ph 2. Et 3. Useful if ester is used to condense with ketone/aldehydes (α- pka is less), use ester in excess excess + 1. C 3 C 2 Na 2. +!-diketone 1. C 3 C 2 Na 2. +!-ketoaldehyde

19 23.10 Dieckmann Condensation (Intramolecular Claisen) Diesters can cyclize to form cyclic β-keto esters (5, 6 m. rings) NaC The Michael eaction emember addition to unsaturated compounds: 1,2 for strong bases (Grignard) 1,4 for weaker bases Michael eaction combines enolate chemistry with the reactivity of α,β-unsaturated carbonyls. Works well with enolates of betadicarbonyls, since they are relatively acidic.

20 Mechanism: Examples: NaC 3 CN Na CN 1,4 addition does not take place readily with enolates of ketones/aldehydes (too basic). beta-diketone Na no 1,4 product (Weʼll see Stork Enamine xn for forming 1,4 diketones, dialdehydes )

21 ow to prepare α,β unsaturated carbonyls a. Elimination of alpha halogen carbonyls (Not very good) b. Aldol c. BETTE WAY. 1. LDA 2. PhSeCl SePh selene nylation SePh 2 2 SePh Works well for ketones, esters, nitriles 1. LDA 2. PhSeCl

22 23.12 The Stork Enamine eaction Michael rxn with an enamine nucleophile instead of an enolate: N N nucleophilic!-c Enamines behave similarly to enolates in that they have a partial negative charge on their alpha-c. N N 3 + protonates the enolate and hydrolyzes the iminium N N

23 23.13 The obinson Annulation eaction Combination of a Michael xn followed by an intramolecular aldol Always makes six-membered rings, α,β-unsaturated ketones: Na mechanism Michael Aldol To analyze a obinson annulation product: Cut between β, γ and through double bond! "! "

Chapter 22 Carbonyl Alpha-Substitution Reactions

John E. McMurry www.cengage.com/chemistry/mcmurry Chapter 22 Carbonyl Alpha-Substitution Reactions The α Position The carbon next to the carbonyl group is designated as being in the α position Electrophilic