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CHEM 2222 Chapter 20 Notes

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CHEM 2222 Chapter 20 Notes Chem 212 - Organic Chemistry II

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Organic Chemistry (Carey) Chapter 20
Organic Chemistry II
Dr. Alissa Hare
Class Notes
enols, enolates, Organic Chemistry
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This 32 page Class Notes was uploaded by annafen on Sunday May 29, 2016. The Class Notes belongs to Chem 212 - Organic Chemistry II at Vanderbilt University taught by Dr. Alissa Hare in Spring 2016. Since its upload, it has received 8 views. For similar materials see Organic Chemistry II in Chemistry at Vanderbilt University.


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Date Created: 05/29/16
20.1 Enol Content and Enolization Keto-Enol Tautomerization 1 Acid-Catalyzed Enolization 2 Halogenation of Ketones • The enol form of the carbonyl contributes to reactivity at the α-carbon 3 20.2 Enolates Acidity of Carbonyl Compounds 4 Acidity of Carbonyl Compounds • Two reasons for increased acidity of carbonyl molecules relative to alkanes – • The inductive effect of the carbonyl causes the α-protons to be more acidic • Once deprotonated, the negative charge of the enolate ion (the conjugate base) is stabilized by resonance delocalization 5 Acidity of Carbonyl Compounds • Remember the acid-base equilibrium favors the weaker acid. 6 Acidity of Carbonyl Compounds • Lithium diisopropylamide (LDA) is a strong base that can deprotonate the α-hydrogen • The equilibrium lies almost entirely to the right – quantitative enolate formation 7 Kinetic and Thermodynamic Enolates • Less hindered enolates are formed faster: Kinetic enolate. • More stable (more substituted) enolates are favored at equilibrium: Thermodynamic enolate • The thermodynamic enolate is formed under reversible conditions – with an alkoxide base • The kinetic enolate is formed by irreversible conditions – with a strong base and cryogenic temperatures 8 20.3 The​ Aldol​ Condensation Aldol Addition • An enolate of one carbonyl (nucleophile) reacts with the carbonyl carbon (electrophile) of a second carbonyl compound resulting in the formation of a new C-C bond aldol reactions involving α-monosubstituted aldehydes are generally favorable aldol reactions involving α,α-disubstituted aldehydes are generally unfavorable aldol reactions involving ketones are generally unfavorable 9 Mechanism of Aldol Reaction 10 Aldol Reaction of Ketones • Equilibrium is less favorable for ketones, but you can drive the reaction forward using heat • The dehydration product is formed under these conditions and is irreversible – called a thermodynamic sink 11 20.4 ​ Mixed​ and​ Directed ​Aldol​ Reactions Mixed​ ​Aldol ​Reactions • Two different aldehydes give four possible products (not very useful) • Aldehydes with no α-protons can only act as the electrophile 12 Directed Aldol Reactions • The enolate is first formed from one reactant quantitatively and then the second reactant is added 13 20.5 Acylation​ of​ Enolates:​ The​ Claisen​ Condensation Claisen Condensation Reaction • An enolate of one ester reacts via nucleophilic acyl substitution with a second ester 14 Mechanism 15 Related Mixed Condensations • Ideally one ester has no α-hydrogens so it can’t act as a nucleophile 16 Cyclic Claisen • Dieckmann Cyclization is an intramolecular Claisen condensation • Works best with 1,6 -diesters, to give a 5-membered cyclic β-keto ester product • 1,7-diestersto give 6-membered cyclic β-keto ester product 17 20.6 Alkylation​ of​ Enolates:​ The​ Acetoacetic​ and​ Malonic Ester ​​Syntheses Alkylation of Ketones and β-Diketones • Ketones can be alkylated using the strong hindered base LDA to deprotonate the α-position quantitatively • The alkylating reagent is usually an alkyl halide • Occurs via a SN2 mechanism 18 Acetoacetic Ester Synthesis • Ethyl acetoacetate can be alkylated using an alkyl halide • The product, a β-keto ester, is then hydrolyzed to the β-keto acid and decarboxylated to the ketone • This method can be used as a ketone equivalent 19 Acetoacetic Ester Synthesis • β-keto esters that result from the Claisen or Dieckmann can also be used and then decarbonylated 20 Malonic Acid Synthesis 21 20.7 The​ Haloform​ Reaction The Haloform Reaction • Aldehydes and ketones undergo α-halogenation in neutral or acidic conditions via an enol intermediate • In base the reaction continues to polyhalogenation, which is then hydrolyzed to the carboxylic acid • Called the haloform reaction because the products are chloro- form, bromoform or iodoform. 22 The Haloform Reaction 23 Acid-Catalyzed Halogenation • The acid-catalyzed reaction with Cl , Br 2 or 2 , pr2ceeds through an enol • Generally followed by elimination under these conditions 24 20.8 Conjugation​ Effects ​in​ α,β-Unsaturated​ Aldehydes ​and​ Ketones Conjugation and Stability • Conjugated α,β-unsaturated ketone is more stabilized by resonance • α,β -Unsaturated ketones and aldehydes are prepared by 1. Aldol reactions with dehydration of the aldol 2. α-halogenation of a ketone or aldehyde followed by elimination 25 Conjugated Ketones and Nucleophilic Addition • Strongly basic nucleophiles react at the carbonyl carbon (1,2-addition) • Organolithium reagents, Grignard reagents and LiAlH 4 • Less basic nucleophiles react at the β-carbon, called conjugate addition or 1,4-addition • Organocopper reagents, enolates, amines, thiolates, and cyanide 26 Conjugate Addition • When a reaction can take two possible path, it is said to be under kinetic control when the products are reflective of the path that reacts fastest • The reaction is said to be under thermodynamic control when the most stable product is obtained from the reaction • In the case of 1,2- versus 1,4 addition of an α,β-unsaturated carbonyl, 1,2-addition is kinetically favored and 1,4-addition is thermodynamically favored 27 Michael Addition • Conjugate addition of an enolate to α,β-unsaturated ketones • Robinson Annulation - Michael addition is followed by a intramolecular aldol condensation to give a cyclohexenone containing product. 28 Robinson Annulation 29 Enamines • Recall that the reaction of a ketone with a 2º amines gives an enamine • Read pages 910-913 • Enamines are reactive equivalents of enols and enolates and can undergo α-substituion reaction with electrophiles. The enamine (iminium ion) is hydrolyzed to the ketone after alkylation. 30 Enamines • Reaction of enamine with α,β-unsaturated ketones (Michael reaction) • Enamines react on the less hindered side of unsymmetrical ketones 31 C H e o h e 2 a X r o O 2 O 0 n a C 3 a O O O O H + O X e O H e 3O H H H c X d O 2 O h c a H i H t e O d O H e t R r O O O O O N 3 O O N H 2O O a 3 l C 2 O 3 O 3 h 3 + O 3 t O + O 3 H h R O H H n C e 3 H a H H H R t O R B O i O O r O O D O C 3 N 3 A H + O T h 3O h 3O+ F n n - H H R 8 1 C 2 s , O a H H N O O d uc a u O i dN M e n Har + N g p h 3O+ O 1. 3 c Lr l n 2.H A s H H w o u o 1. t2C e x 2. Soft R L p m O H3O+N u O O i i e O c R s s O N C 2O H N S 2 C N , O c e h 3O+ C H O o n t H s


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