Chapter 23 - Substitution Reactions of Carbonyl Compounds at the α CarbonAll following reactions are w/ aldehydes and ketones.Formation of Enolate

NaH or LDA = non-catalytic bases, react once, essentially 100% yield of enolate NaOH, KOH, NaOR = catalytic bases, react repeatedly

Kinetic enolate is favored by:1. A strong nonnucleophilic base. Strong enolate forms rapidly. Bulky (like LDA) removes more accessible proton.2. Polar aprotic solvent. Polar dissolve polar starting materials and intermediates. Aprotic doesn’t protonate any enolate that is formed. (Ex. THF)3. Low temperature (–78 °C)  Keep kinetic enolate from equilibrating to thermodynamic enolate.

Thermodynamic enolate is favored by:1.  A strong base. Na+ –OCH2CH3, K+ –OC(CH3)3, or other alkoxides are common.2.  Protic solvent. EtOH or other alcohols.3.  Room temperature (25 °C).

Halogenation X2 and acid or base add X to α carbon

o Acid enol intermediate; acetic acid is a common acid; acid adds 1 X to α carbono Base enolate intermediate; (base negative); don’t use base because it reacts x2, adding 2

Xs to α carbon

Haloform Rxn Methyl ketone and excess X2 in base carboxylate anion and HCX3 (haloform)

o Iodoform is yellow salt o Only with *methyl* ketones

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Elimination Bases that eliminate X from α-halo carbonyl, creating alpha-beta unsaturated carbonyl:

o Pyridineo Li2CO3o LiBr and DMFo NaH and NaNH2

Hell-Volhard Zelinsky Rxn [1] Br2, PBr2 and [2] H2O adds Br to α carbon of COOH After adding Br to COOH:

o NaOH, then H+ substitutes OH for Bro KOH (alc), then H+ eliminates Br, creating alpha-beta unsaturationo NH3 substitutes NH2 for Br, forming amino acid

Direct Enolate Alkylation Base and alkyl halide adds alkyl group to α carbon

o SN2 reaction, best with unhindered methyl and 1° alkyl halides R3CX, CH2=CHX, and C6H5X do not undergo alkylation rxn w/ enolates, because they

are unreactive in SN2 reactionso Can add to esters and nitriles, as well as aldehydes and ketoneso Forms new stereogenic center racemic productso Unsymmetrical ketone use kinetic/thermodynamic conditions to select product

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Malonic Ester Synthesis Diethyl malonate (Nu) and [1] NaOEt and [2] alkyl halide or carbonyl compound (electrophile)

adds alkyl group or carbonyl compound (at carbonyl C) to center of diethyl malonateo OEt deprotonates diethyl malonate, forming enolate

Diethyl malonate and [1] acid and [2] heat carboxylic acido Acid: CO2Et COOHo Heat: eliminates one of the COOHs; produces CO2 and 2 equiv. EtOH

Acetoacetic Ester Synthesis Ethyl acetoacetate (Nu) and [1] NaOEt and [2] alkyl halide or carbonyl compound (electrophile)

adds alkyl group or carbonyl compound (at carbonyl C) to center of ethyl acetoacetate Ethyl acetoacetate and acid and heat hydrolyze and decarboxylate, forming carboxylic acid

o Acid: CO2Et COOHo Heat: eliminates COOH; produces CO2 and EtOH

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Chapter 24 - Carbonyl Condensation ReactionsAldol

2 aldehydes/ketones in base (usually NaOEt) aldol (aldehyde/alcohol) aka β-hydroxy carbonyl compound

o Aldols dehydrate to form α,β-unsaturated carbonyl compound

Retro-Aldol Aldol in heat and base aldehydes/ketones

Directed Aldol 2 different ketones/aldehyde and ketone 1 aldol product

o Not 2 aldehydes, because that produces 4 products See kinetic/thermodynamic conditions from Chapter 23

Claisen 2 esters and [1] alkoxide base (usually NaOEt) and [2] H3O+ β-keto ester

o Characteristic rxn of esters is nucleophilic substitution

Dieckmann = intramolecular Claiseno 1,6-Diesters 5-membered ringso 1,7-Diesters 6-membered ring

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Michael Enolate (Michael donor) and α,β-unsaturated carbonyl compound (Michael acceptor) enolate adds

to β carbon of α,β-unsaturated carbonyl compoundo 1,4 / conjugate addition

Michael product and acid and heat hydrolyze and decarboxylate, forming 1,5 dicarbonyl compound

Robinson Annulation Michael addition, followed by intramolecular aldol Michael: Enolate and α,β-unsaturated carbonyl compound dicarbonyl compound Intramolecular Aldol: dicarbonyl compound and base aldol dehydrates to form α,β-unsaturated

carbonyl compound

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