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Chapter 23. Carbonyl Condensation Reactions

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Chapter 23. Carbonyl Condensation Reactions Chapter 23. Carbonyl Condensation Reactions As a result of the large dipole of the carbonyl group: 1. The carbonyl carbon is electrophilic and is the site of addition reactions by nucleophiles; O OH O + H3O C C C Chapters 19 & 20 Nu Nu Nu: Ketone/aldehyde (electrophile) 2. The α-protons are acidic and can be deprotonated by strong bases to give an enolate, which are nucleophiles and react with electrophiles. B O O E O C H C C E Chapter 21 C C C Enolate anion (nucleophile) 256 23.1 Mechanism of Carbonyl Condensation Reactions An enolate of one carbonyl (nucleophile) reacts with the carbonyl carbon (electrophile) of a second carbonyl compound (1,2-addition reaction) resulting in the formation of a new C-C bond General mechanism (Fig. 23.1, page 855): Nucleophilic carbonyl: aldehydes, ketones, esters, amides and nitrile Electrophilic carbonyl: aldehydes, ketones, α,β-unsaturated 257 ketones, and esters 130 23.2 Condensations of Aldehydes and Ketones: The Aldol Reaction The base-catalyzed self-condesnation reaction of acetaldehyde gives 3-hydroxybutanal (aldol) O NaOEt OH O 2 H3C C H H C CH CH C H EtOH 3 2 acetaldehyde 3-hydroxybutanal (!-hydroxy aldehyde) General mechanism of the aldol reaction (Fig. 23.2, page 857) The base-catalyzed aldol reaction (NaOEt, EtOH) is reversible 258 The position of the equilibrium for the aldol reaction is highly dependent on the reaction conditions, substrates, and steric considerations of the aldol product. O H O NaOEt HO H aldol reactions involving R C C H R C C α-monosubstituted aldehydes EtOH C C H H H H H R are generally favorable O H O NaOEt HO H aldol reactions involving -disubstituted aldehydes R C C H R C C α,α EtOH C C H are generally unfavorable R R H R R O H O NaOEt HO R aldol reactions involving R C C R R C C ketones are generally EtOH C C R H H H R H unfavorable 259 131 23.3 Carbonyl Condensation Reactions versus Alpha-Substitution Reactions O HO O O CH2R + RCH2X How do you suppress carbonyl condensation during an α-alkylation reaction?? O O Li O LDA, THF, -78 °C RCH2X CH2R The enolate is discretely and quantitatively generated with LDA at low temperature, then the alkyl halide is added to the solution of the enolate. 260 23.4 Dehydration of Aldol Products: Synthesis of Enones The β-hydroxy carbonyl product of the aldol reaction can undergo dehydration to yield a conjugated enones; this step is irreversible and is catalyzed by either acid or base. Mechanisms (p. 859) 261 132 The aldol reaction can be driven toward products by dehydration O R O H O NaOEt HO R - H2O R C C R C C R C C R C C R EtOH C C R H H H R H H H R O NaOH O EtOH HO 22% O NaOH O O EtOH HO D 92% The π-orbitals of the C=C and C=O are in conjugation, which is a stabilizing influence of α,β-unsaturated carbonyls • • • C • O C C 262 Synthesis of α,β-unsaturated carbonyl compounds MgBr + then H3O R C N O α,β-unsaturated ketones O R C R Cl CuLi 2 O O (H C) CO- K+ O Br2, AcOH 3 3 α,β-unsaturated R R R ketones and aldehydes Br Br , PBr (H C) CO- K+ O O 2 3 O 3 3 α,β-unsaturated acids, then H O, or HO 2 Y Y esters and amides ROH, or R2NH R R2 O -unsaturated ketones, H O NaOEt, EtOH α,β 1 1 2 R C C R C C R C C R2 aldehydes and esters - H2O H H H R1 263 133 23.6 Mixed Aldol Reactions Aldol reaction between two different carbonyl compounds Four possible products HO H O HO H O C C C C O O EtONa, H3CH2CH2CH2C C H H3CH2C C H EtOH 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 C 5 C3 H3CH2C C H H3CH2CH2CH2C C H H3C H H H3CH2CH2C Aldehydes with no α-protons can only act as the electrophile EtONa, O HO H O O EtOH C C H3C C (H C) C C H H3CH2CH2C C C H 3 3 C H + H C CH H CH CH C H H H 3 3 3 2 2 O O EtONa, HO H O EtOH C C C + H3C C H C H C H H H H3C H 264 One of the carbonyl compounds is significantly more acidic EtONa, O O O EtOH H O H3CH2CH2C C C C H3CH2CH2C C C H + H3C C OEt C C CH3 H H H H H H CO2Et Discrete (in situ) generation of an enolate with LDA 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 3 265 134 23.7 Intramolecular Aldol Reactions Treatment of a dicarbonyls compound can lead to an intramolecular aldol condensation. Formation of five- and six-membered rings are favorable. O O O O EtONa, EtOH EtOH - H2O O O OH O O O O EtONa, EtOH EtOH - H2O O O OH 266 More favorable ring sizes (less strained) are made from intramolecular reactions O O O - H2O O O OH O O O O H - H O 2 less favored O OH pathway O O O - H2O O O OH O O O O H less favored - H2O O pathway OH 267 135 Figure 4.8 (page 111) !Hcomb !Hcomb per -CH2- Total Strain Cycloalkane Ring Size (n) KJ/mol KJ/mol Energy Strained 3 2090 698 115 rings 4 2744 686 110 5 3220 664 27 Common rings 6 3952 659 0 7 4637 662 27 8 5310 664 42 Medium rings Cyclononane 9 5981 665 54 Cyclodecane 10 6636 664 50 < 12 Large rings Cyclopentadecane 15 9985 659 0 Alkane reference 659 0 268 23.5 Using Aldol Reactions in Synthesis Very important C-C bond forming reaction. Readily make large carbon skeletons from smaller ones aldol OH O O O reaction O + -or- aldol R1 R1 H H R1 H products H R R1 R1 1 H2, Pd/C R2 O -or- O Wittig !-alkylation reaction + R1 R1 R1 H H X R 1 R1 R1 Grignard addition OH R1 R2 R1 Robert B. Woodward (Harvard): 1965 Nobel Prize in Chemistry "for his outstanding achievements in the art of organic synthesis" 269 136 OH 2-ethyl-1-hexanol O H O O O OH H H H two n-C4 units O X H 270 Problem 23.5: Which of the following are aldol condensation products? a. 2-hydroxy-2-methylpentanal b. 5-ethyl-4-methyl-4-hepten-3-one HO CH3 O CHO Problem 23.8: Which of the following can probably be prepared by a mixed aldol reaction? a. b. O c. O O 271 137 23.8 The Claisen Condensation Reaction Base catalyzed condensation of two esters to give a β-keto-ester product NaOEt O O O 2 H3C C OEt EtOH H3C CH CH2 C OEt + then H3O Ethyl acetate Ethyl 3-oxobutanoate (Ethyl acetoacetate) Mechanism: has features of the aldol and nucleophilic acyl substitution reactions (Fig. 23.5, page 866) 272 The product β-keto ester product of the Claisen condensation is more acidic than the reactants; deprotonation of the product drives the reaction forward. One full equivalent of base must be used in the Claisen condensation. 23.9 Mixed Claisen Condensation Strategies are similar to that of the mixed aldol reaction. Four possible products O O O O C C C C O O EtONa, H3CH2CH2CH2C C OEt H3CH2C C OEt EtOH H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C OEt C OEt + H H H H then H3O O O O O C C C C C 5 C3 H3CH2C C OEt H3CH2CH2CH2C C OEt H3C H H H3CH2CH2C Esters with no α-protons can only act as the electrophile O O O EtONa, O EtOH C C C + H3C C OEt C OEt C OEt H H then H O+ H3C H 3 273 138 Discrete (in situ) generation of an ester enolate with LDA O H3C C O O O O Li+ C OEt LDA, THF, -78°C H H C C H3CH2CH2C C H3CH2CH2C C H3CH2C C OEt C OEt C OEt + H then H2O H CH CH C H H H 3 2 2 O H3CH2CH2C C O O Li+ C OEt O O LDA, THF, -78°C H H C C H3C C H3C C C OEt C OEt H3CH2CH2CH2C C OEt + H C H H H H then H3O 3 Mixed Claisen condensations with a ketone enolate and esters O EtONa, O O EtOH O CH CH + C 2 3 H3CH2C OEt + then H3O EtONa, O O O O EtOH C H + H OEt + then H3O EtONa, O O O O EtOH C OEt + EtO OEt 274 + then H3O 23.10 Intramolecular Claisen Condensations: The Dieckmann Cyclization Dieckmann cyclization is an intramolecular Claisen condensation.
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