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The Α-Carbon Atom and Its Pka the Inductive Effect of the Carbonyl

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The Α-Carbon Atom and Its Pka the Inductive Effect of the Carbonyl Chapter 18: Enols and Enolates O E+ O H Enolate O E carbonyl H O E+ Enol 18.1: The α-Carbon Atom and its pKa O "' " #' !' ! # 126 The inductive effect of the carbonyl causes the α-protons to be more acidic. The negative charge of the enolate ion (the conjugate base of the aldehyde or ketone) is stabilized by resonance delocalization. The pKa of the α-protons of aldehydes and ketones is in the range of 16-20 (Table 18.1, p. 754) resonance effect ! - inductive O O !+ O + B effect C H C C + H-B !+ C C C carbonyl Enolate anion H C C C C C C O O O O H3C CH3 C H3CH2COH H3C CH3 ethane acetone ethanol 127 pKa= 50-60 pKa= 19 pKa= 16 65 O O O O O C C Cl C C C H3C CH3 H3C C H3C C H3C C CH3 H H H H H H pKa 19 14 16 9 O O + H O C + H3O C 2 H C CH H3C CH3 3 2 acid base conjugate conjugate base acid pKa 19 -1.7 (weaker acid) (weaker base) (stronger base) (stronger acid) O O + HO C + H O C H C CH 2 H3C CH3 3 2 acid base conjugate conjugate base acid pKa 19 15.7 (weaker acid) (weaker base) (stronger base) (stronger acid) 128 O O O O C C + H2O C C + HO H C C CH H C C CH 3 3 3 3 H H H acid base conjugate conjugate base acid pKa 9 15.7 (stronger acid) (stronger base) (weaker base) (weaker acid) 18.2: The Aldol Condensation- 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 O OH O 2 H C C H + HO + HO 3 H3C CH CH2 C H acetaldehyde 3-hydroxybutanal (!-hydroxy aldehyde) 129 66 Mechanism of the base-catalyzed aldol condensation (Fig. 18.1) The position of the equilibrium for the aldol reaction is highly dependent on the reaction conditions, substrates, and steric considerations of the aldol product. Low temperature tends to favor the aldol product. 130 O H O NaOEt HO H aldol reactions involving α-monosubstituted R C C H R C C EtOH C C H aldehydes are generally favorable H H H H R O H O NaOEt HO H aldol reactions involving α,α-disubstituted R C C H R C C aldehydes are generally unfavorable EtOH C C H R R H R R O H O NaOEt HO R aldol reactions involving ketones are R C C R R C C generally unfavorable EtOH C C R H H H R H The aldol product can undergo base-catalyzed dehydration to an α,β-unsaturated carbonyl. The dehydration is essentially irreversible. The dehydration is favored at higher temperatures. (mechanism Fig. 18.2) 131 67 18.3: Mixed Aldol Reactions - Aldol reaction between two different carbonyl compounds Four possible products (not very useful) HO H O HO H O C C C C O O NaOH, H3CH2CH2CH2C C H H3CH2C C H H2O H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C H C H H H H H HO H O HO H O C C C C H3CH2C C H H3CH2CH2CH2C C H H3C H H H3CH2CH2C Aldehydes with no α-protons can only act as the electrophile O HO H O O O NaOH, HO H C C C + H3C C H2O + C C H C H C H H3CH2C C H H H H3C H H3C H Preferred reactivity HO H O O O NaOH, C C C C H2O H + C CH3 H3C CH 3 H H 132 Discrete generation of an enolate with lithium diisopropyl amide (LDA) under aprotic conditions (THF as solvent) THF O H3C C HO H O O O Li+ C H LDA, THF, -78°C C C H CH CH C C H H 3 2 2 H3CH2CH2C C H3CH2C C H C H C H H then H2O H CH CH C H H H 3 2 2 O H3CH2CH2C C O O Li+ C H HO H O LDA, THF, -78°C H H C C H3C C H3C C C H C H H3CH2CH2CH2C C H H C H H H H then H2O 3 Lithium diisopropylamide (LDA): a very strong base O O C + N Li C + N H H3C CH3 H3C CH2 pKa= 19 pKa= 40 (stronger acid) (stronger base) (weaker base) (weaker acid) + H CH CH CH C N H + H3CH2CH2CH2C Li N Li 3 2 2 3 133 pKa= 40 pKa= 60 68 18.4: Alkylation of Enolate Ions - enolate anions can react with other electrophiles such as alkyl halides and tosylates to form a new C-C bonds. The alkylation reaction is an SN2 reaction. Reaction works best with the discrete generation of the enolate by LDA in THF, then the addition of the alkyl halide 18.5: Enolization and Enol Content Tautomers: isomers, usually related by a proton transfer, that are in equilibrium 134 Keto-enol tautomeric equilibrium lies heavily in favor of the keto form. H O O C C H C C enol keto C=C ΔH° = 611 KJ/mol C=O ΔH° = 735 KJ/mol C-O 380 C-C 370 O-H 426 C-H 400 ΔH° = -88 KJ/mol OH O C H H3C C H3C CH3 H 99.9999999 % 0.0000001% Enolization is acid- and base-catalyzed 135 69 Base-catalyzed mechanism (Figure 18.3, 9.764): Acid-catalyzed mechanism (Figure 18.4, p. 765): 18.6: Stabilized enols (please read) 136 18.7: α Halogenation of Aldehydes and Ketones- α-proton of aldehydes and ketones can be replaced with a -Cl, -Br, or -I (-X) through the acid-catalyzed reaction with Cl2 , Br2 , or I2 , (X2) respectively. The reaction proceeds through an enol. O O H X2, H-X X H H + H-X X= Cl, Br, I 18.8: Mechanism of α Halogenation of Aldehydes and Ketones Acid-catalyzed mechanism (Fig. 18.5, p. 769) Rate= k [ketone/aldehyde] [H+] 137 rate dependent on enol formation and not [X2] 70 α,β-unsaturated ketones and aldehydes: α -bromination followed by elimination O O O CH3 CH - + 3 Br2, CH3CO2H (H3C)3CO K CH3 Br E2 Why is one enol favored over the other? OH O OH + CH3 H CH3 CH3 18.9: The Haloform Reaction. Mechanism of the base-promoted α-halogenation of aldehydes and ketones (Fig. 18.6, p. 770) 138 In the base promoted reaction, the product is more reactive toward enolization and resulting in further α-halogenation of the ketone or aldehyde. For methyl ketone, an α, α, α -trihalomethyl ketone is produced. O O O O NaOH, NaOH, H2O X C X 2 C X H2O, X2 C X C X C C C C H H H X X X H pKa ~14 pKa ~12 The α, α, α -trihalomethyl ketone reacts with aquous hydroxide to give the carboxylic acid and haloform (HCX3) Iodoform reaction: chemical tests for a methyl ketone O O NaOH, H2O + HCI Iodoform: bright yellow C C 3 139 R CH3 I2 R O Iodoform precipitate 71 18.10: Some Chemical and Stereochemical Consequences of Enolization (please read) O O NaOD, D2O D D -or- D D + D3O O O O (R) (R) (S) NaOD, D2O + H -or- CH H3C + H3C H H 3 D3O 50 : 50 18.11: Effects of Conjugation in α,β-Unsaturated Aldehydes and Ketones. α,β -Unsaturated carbonyl have a conjugated C=C 1 O "' R= H, α,β-unsaturated aldehyde= enal 3 R 2 4 R≠ H, α,β-unsaturated ketone= enone ! # Conjugation of the π-electrons of the C=C and C=O is a stabilizing interaction 140 α,β -Unsaturated ketones and aldehydes are prepared by: a. Aldol reactions with dehydration of the aldol b. α-halogenation of a ketone or aldehyde followed by E2 elimination 18.12: Conjugate Addition to α,β-Unsaturated Carbonyl Compounds. The resonance structures of an α,β-unsaturated ketone or aldehyde suggest two sites for nucleophilic addition; the carbonyl carbon and the β-carbon 141 72 Organolithium reagents, Grignard reagents and 1 O "' LiAlH4 reaction α,β-unsaturated ketone and 3 R 2 4 aldehydes at the carbonyl carbon. This is referred ! # to as 1,2-addition. Organocopper reagents, enolates, amines, cyanide react at the β-carbon of α,β-unsaturated ketone and aldehydes. This is referred to a 1,4-addition or 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. 142 1,2 vs 1,4-addition α,β-unsaturated ketone and aldehydes NOTE: conjugation to the carbonyl activates the β-carbon toward nucleophilic addition. An isolated C=C does not normally react with nucleophiles O 1) Nu: :Nu + O Nu 2) H3O Nu: C C C C No Reaction R C R C C H 143 73 18.13: Addition of Carbanions to α,β-Unsaturated Carbonyl Compounds: The Michael Reaction. The conjugate addition of a enolate ion to an α,β-unsaturated carbonyl.
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