Chapter 17 Carbonyl Alpha-Substitution and Condensation Reactions

a-Substitution and Carbonyl Condensation Reactions Alpha-substitution reactions occur at the carbon next to the carbonyl carbon – the a position Involve substitution of a-hydrogen by electrophile Proceed through enol or enolate ion intermediate Carbonyl condensation reactions occur between two carbonyl partners Combination of a-substitution and nucleophilic addition steps Gives b-hydroxy carbonyl compound

17.1 Keto-Enol Tautomerism Carbonyl compounds with a-hydrogens rapidly equilibrate with corresponding enol (ene + alcohol) Interconversion known as keto-enol tautomerism Greek tauto, meaning “the same,” and meros, meaning “part” Individual isomers called tautomers

Keto-Enol Tautomerism Tautomers are constitutional isomers Isomers are different compounds with different structures Atoms arranged differently Different from resonance structures that differ only in the position of their electrons Most carbonyl compounds exist almost exclusively in the keto form at equilibrium

Keto-Enol Tautomerism Mechanism of acid-catalyzed enol formation Protonated intermediate can lose H+, either from the oxygen atom to regenerate the keto tautomer or from the a carbon atom to yield an enol tautomer

Keto-Enol Tautomerism Mechanism of base-catalyzed enol formation The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to generate the starting keto tautomer or on oxygen to give an enol tautomer

Keto-Enol Tautomerism Only a-hydrogens are acidic a-Hydrogens are acidic because the enolate ion that results from deprotonation is resonance stabilized with the electronegative oxygen of the carbonyl b-, g-, d-Hydrogens (and so on) are not acidic because the ion that results from deprotonation is not resonance stabilized

17.2 Reactivity of Enols: a-Substitution Reactions Enols are nucleophiles that react with electrophiles There is a substantial build-up of electron density on the a carbon of the enol

Reactivity of Enols: a-Substitution Reactions Mechanism of carbonyl a-substitution reaction on an enol Enol is formed with acid catalysis Electron pair from C=C bond of enol attacks an electrophile (E+), forming new C-E bond and a resonance stabilized intermediate Loss of H+ from oxygen yields the neutral alpha- substitution product and restores the C=O bond

Reactivity of Enols: a-Substitution Reactions Acid-catalyzed a-halogenation (Cl2, Br2, and I2) of aldehydes and ketones is a common laboratory reaction a-Halogenation occurs in biological systems a-Halogenation of ketones in marine alga

Reactivity of Enols: a-Substitution Reactions Mechanism of acid-catalyzed bromination of acetone

Reactivity of Enols: a-Substitution Reactions Isotopic labeling experiments support reaction mechanism of acid-catalyzed halogenation For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation Enol intermediate involved in both processes

Reactivity of Enols: a-Substitution Reactions a-Bromoketones are dehydrobrominated by base to yield a,b-unsaturated ketones E2 reaction mechanism 2-Methylcyclohexanone gives 2-methylcyclohex-2-enone on heating in pyridine

17.3 Acidity of a Hydrogen Atoms: Enolate Ion Formation Presence of neighboring carbonyl group increases the acidity of the ketone over the alkane by a factor of 1040 Proton abstraction from carbonyl occurs when the a C-H bond is oriented parallel to the p orbitals of the carbonyl group A carbon of the enolate ion has a p orbital that overlaps neighboring p orbitals of the carbonyl group Negative charge shared with oxygen atom by resonance

Acidity of a Hydrogen Atoms: Enolate Ion Formation Strong base required for enolate formation If NaOCH2CH3 is used the extent of enolate formation is only about 0.1% If sodium hydride, NaH, or lithium diisopropylamide (LDA), [LiN(i-C3H7)2], is used the carbonyl is completely converted to its enolate conjugate base LDA is prepared by reaction of butyllithium with diisopropylamine

Acidity of a Hydrogen Atoms: Enolate Ion Formation A C-H bond flanked by two carbonyl groups is even more acidic Enolate ion is stabilized by delocalization of negative charge over both carbonyl groups Pentane-2,4-dione has three resonance forms

Acidity of a Hydrogen Atoms: Enolate Ion Formation

Acidity of a Hydrogen Atoms: Enolate Ion Formation

Worked Example 17.1 Identifying Acidic Hydrogens in a Compound Identify the most acidic hydrogens in each of the following compounds, and rank the compounds in order of increasing acidity:

Worked Example 17.1 Identifying Acidic Hydrogens in a Compound Strategy Hydrogens on carbon next to a carbonyl group are acidic. In general, a b-dicarbonyl compound is most acidic, a ketone or aldehyde is next most acidic, and a carboxylic acid derivative is least acidic. Remember that alcohols, phenols, and carboxylic acids are also acidic because of their –OH hydrogens

Worked Example 17.1 Identifying Acidic Hydrogens in a Compound Solution The acidity order is (a) > (c) > (b). Acidic hydrogens are shown in red:

17.4 Alkylation of Enolate Ions Enolate ions are resonance hybrides of two nonequivalent contributors Enolate ions are vinylic alkoxides (C=C–O-) Reaction on the oxygen yields an enol derivative Enolate ions are a-keto carbanions (-C–C=O) Reaction on the carbon yields an a-substituted carbonyl compound

Alkylation of Enolate Ions Enolate ions undergo alkylation by treatment with an alkyl halide or tosylate Nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction Leaving group displaced by backside attack

Alkylation of Enolate Ions Alkylations are subject to all constraints that affect all SN2 reactions Alkyl group R should be primary or methyl and preferably allylic or benzylic Secondary alkyl halides react poorly and tertiary are unreactive due to competing E2 reaction

Alkylation of Enolate Ions The Malonic Ester Synthesis Preparation of carboxylic acids from alkyl halides while lengthening the carbon chain by two atoms

Alkylation of Enolate Ions Diethyl propanedioate, commonly known as diethyl malonate, or malonic ester is more acidic than monocarbonyl compounds (pKa = 13) because its a hydrogens are flanked by two carbonyl groups Easily converted to enolate ion by sodium ethoxide in ethanol “Et” is used as an abbreviation for –CH2CH3

Alkylation of Enolate Ions Malonic ester contains two a hydrogens Product of a-alkylation can itself undergo alkylation

Alkylation of Enolate Ions Alkylated of dialkylated malonic ester undergoes hydrolysis to yield the diacid followed by decarboxylation (loss of CO2) to yield the monoacid

Alkylation of Enolate Ions Decarboxylation is unique to carboxylic acids with a second carbonyl group located at the b position Decarboxylation occurs via a cyclic mechanism Involves initial formation of an enol

Alkylation of Enolate Ions Overall result of malonic ester synthesis is the conversion of an alkyl halide into a carboxylic acid while lengthening the carbon chain by two carbons

Alkylation of Enolate Ions Malonic ester synthesis can be used to prepare cycloalkane-carboxylic acids Three-, four-, five-, and six-membered rings can all be prepared in this way

Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid How would you prepare heptanoic acid using a malonic ester systhesis?

Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane

Worked Example 17. 2 Using the Malonic Ester Synthesis to Prepare a Worked Example 17.2 Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid Solution

Alkylation of Enolate Ions The Acetoacetic Ester Synthesis The acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons

Alkylation of Enolate Ions Ethyl-3-oxobutanoate, commonly called ethyl acetoacetate or acetoacetic ester, contains a hydrogens flanked by two carbonyl groups Enolate ion is readily formed and alkylated under SN2 reaction conditions A second alkylation product can be derived from monoalkylated product

Alkylation of Enolate Ions Alkylated or dialkylated acetoacetic ester is hydrolyzed in aqueous acid to a b-keto acid b-Keto acid undergoes decarboxylation to yield ketone product

Alkylation of Enolate Ions Ketone product formed in three-step sequence: Enolate formation Alkylation Hydrolysis/decarboxylation Sequence applicable to all b-keto esters with acidic a hydrogens

Alkylation of Enolate Ions Cyclic b-keto esters such as ethyl 2-oxocyclohexanecarboxylate can be alkylated and decarboxylated to give 2-substituted cyclohexanones

Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone How would you prepare pentan-2-one by an acetoacetic ester synthesis?

Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone Strategy The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide: Thus, the acetoacetic ester synthesis of pentan-2-one must involve reaction of bromoethane

Worked Example 17.3 Using the Acetoacetic Ester Synthesis to Prepare a Ketone Solution

Alkylation of Enolate Ions Direct Alkylation of Ketones, Esters, and Nitriles A strong, sterically hindered base such as LDA converts a ketone, ester, or nitrile to its enolate ion Use of a sterically hindered base avoids nucleophilic addition A nonprotic solvent such as THF is required Aldehydes rarely give high yields of alkylation products because their enolate ions undergo carbonyl condensation reactions

Alkylation of Enolate Ions Example alkylations

Alkylation of Enolate Ions Example alkylations

Alkylation of Enolate Ions Example alkylations

Worked Example 17. 4 Using an Alkylation Reaction to Prepare a Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester How might you use an alkylation reaction to prepare ethyl 1-methylcyclohexanecarboxylate?

Worked Example 17. 4 Using an Alkylation Reaction to Prepare a Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester Strategy An alkylation reaction is used to introduce a methyl or primary alkyl group onto the a position of a ketone, ester, or nitrile by SN2 reaction of an enolate ion with an alkyl halide. Look at the target molecule and identify any methyl or primary alkyl groups attached to an a carbon. The target has an a methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane

Worked Example 17. 4 Using an Alkylation Reaction to Prepare a Worked Example 17.4 Using an Alkylation Reaction to Prepare a Substituted Ester Solution

Alkylation of Enolate Ions Biological Alkylations Alkylations are not common in biological systems a-Methylation occurs in the biosynthesis of the antibiotic indolmycin from indolylpyruvate

17.5 Carbonyl Condensations: The Aldol Reaction Carbonyl condensation reactions occur between an electrophilic carbonyl group of one partner and the nucleophilic enolate ion of the other partner Combination of a-substitution and nucleophilic addition steps

Carbonyl Condensations: The Aldol Reaction Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction Treatment of acetaldehyde with sodium ethoxide yields 3-hydroxybutanal (an aldol)

Carbonyl Condensations: The Aldol Reaction Position of the aldol equilibrium depends both on reaction condition and substrate structure Equilibrium favors condensation product in the case of aldehydes with no a substituent (RCH2CHO)

Carbonyl Condensations: The Aldol Reaction Equilibrium favors reactant for disubstituted aldehydes (R2CHCHO) and most ketones

Carbonyl Condensations: The Aldol Reaction Aldol reactions occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule Resultant tetrahedral intermediate is protonated to give an alcohol product The reverse process occurs when base abstracts the –OH hydrogen from the aldol to yield a b-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound

Worked Example 17.5 Predicting the Product of an Aldol Reaction What is the structure of the aldol product from propanal?

Worked Example 17.5 Predicting the Product of an Aldol Reaction Strategy An aldol reaction combines two molecules of reactant, forming a bond between the a carbon of one partner and the carbonyl carbon of the second partner

Worked Example 17.5 Predicting the Product of an Aldol Reaction Solution

Carbonyl Condensations: The Aldol Reaction Carbonyl Condensations versus a-Substitutions Carbonyl condensation reactions and a substitutions take place under basic conditions and involve enolate-ion intermediates Alpha-substitution reactions require a full equivalent of strong base and are carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at low temperature before addition of the electrophile

Carbonyl Condensations: The Aldol Reaction Carbonyl condensation reactions require only a catalytic amount of a relatively weak base Enolate ion is generated in the presence of unreacted carbonyl compound

17.6 Dehydration of Aldol Products b-Hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield a,b-unsaturated products, or conjugated enones Aldol reactions were named condensation reactions due to the loss of water

Dehydration of Aldol Products Aldol products dehydrate easily because of carbonyl group Under basic conditions, an acidic a hydrogen is removed, yielding an enolate ion that expels the –OH leaving group in an E1cB reaction Under acidic conditions an enol is formed, the –OH group is protonated, and water is expelled in an E1 or E2 reaction

Dehydration of Aldol Products Reaction condition needed for aldol dehydration are often only slightly more vigorous than conditions for aldol formation Conjugated enones are often obtained directly from aldol reactions without isolating the intermediate b-hydroxy carbonyl compounds Conjugated enones are more stable than nonconjugated enones Interaction between p electrons of C=C bond and the p electrons of the C=O bond

Dehydration of Aldol Products Removal of water from reaction mixture drives the aldol equilibrium toward product

Worked Example 17.6 Predicting the Product of an Aldol Reaction What is the structure of the enone obtained from aldol condensation of acetaldehyde?

Worked Example 17.6 Predicting the Product of an Aldol Reaction Strategy In the aldol reaction, H2O is eliminated and a double bond is formed by removing two hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner.

Worked Example 17.6 Predicting the Product of an Aldol Reaction Solution

17.7 Intramolecular Aldol Reactions Some dicarbonyl compounds react when treated with base in an intramolecular aldol reaction Leads to formation of cyclic product

Intramolecular Aldol Reactions Intramolecular aldol reactions may lead to product mixtures Most thermodynamically stable product formed selectively All reaction steps are reversible Most thermodynamically stable product predominates at equilibrium

17.8 The Claisen Condensation Reaction Reversible condensation reaction between two esters is called the Claisen condensation reaction Esters have weakly acidic a hydrogens When an ester with an a hydrogen is treated with 1 equivalent of a base a b-keto ester is formed

The Claisen Condensation Reaction Claisen condensation mechanism proceeds through a tetrahedral intermediate The tetrahedral intermediate expels an alkoxide leaving group to yield an acyl substitution product If the product b-keto ester has another acidic a proton, 1 full equivalent of base is used for deprotonation Deprotonation of b-keto ester drives reaction to the product side giving high yields of Claisen product

Worked Example 17. 7 Predicting the Product of a Claisen Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction What product would you obtain from Claisen condensation of ethyl propanoate?

Worked Example 17. 7 Predicting the Product of a Claisen Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction Strategy The Claisen condensation of an ester results in loss of one molecule of alcohol and formation of a product in which an acyl group of one reactant bonds to the a carbon of the second reactant.

Worked Example 17.7 Predicting the Product of a Claisen Condensation Reaction Solution

17.9 Intramolecular Claisen Condensations Intramolecular Claisen condensations are called Deickman cyclizations Reaction works best for 1,6 and 1,7 diesters 1,6 Diester gives a five-membered cyclic b-keto ester 1,7 Diester gives a six-membered cyclic b-keto ester

Intramolecular Claisen Condensations Mechanism of Dieckmann cyclization Same as Claisen reaction mechanism

Intramolecular Claisen Condensations The cyclic b-keto ester produced in an intramolecular Claisen cyclization can be further alkylated and decarboxylated 2-cyclohexanones and 2-cyclopentanones are prepared by the following sequence: Intramolecular Claisen cyclization b-Keto ester alkylation Decarboxylation

17.10 Conjugate Carbonyl Additions: The Michael Reaction The conjugate addition of a nucleophilic enolate ion to an a,b-unsaturated carbonyl compound is known as the Michael reaction Best reactions are derived from addition of a b-keto ester or other 1,3-dicarbonyl compound to an unhindered a,b-unsaturated ketone Ethyl acetoacetate reacts with but-3-en-2-one in the presence of sodium ethoxide to yield the Michael addition product

Conjugate Carbonyl Additions: The Michael Reaction Conjugate addition of a nucleophilic enolate ion to b carbon of an a,b-unsaturated carbonyl compound Best Michael reactions between stable enolate ions and unhindered a,b-unsaturated ketones

Conjugate Carbonyl Additions: The Michael Reaction Michael reaction occurs with a variety of a,b-unsaturated carbonyl compounds

Worked Example 17.8 Using the Michael Reaction How might you obtain the following compound using a Michael reaction?

Worked Example 17.8 Using the Michael Reaction Strategy A Michael reaction involves the conjugate addition of a stable enolate ion donor to an a,b-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product Usually the stable enolate ion is derived from a b-diketone, b-keto ester, malonic ester or similar compound The C-C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the b carbon of the unsaturated acceptor

Worked Example 17.8 Using the Michael Reaction Solution

17.11 Carbonyl Condensations with Enamines: The Stork Reaction Enamine nucleophiles add to a,b-unsaturated acceptors in Michael-like reactions Reactions are particularly important in biological chemistry Enamines are prepared by reaction between a ketone and a secondary amine

Carbonyl Condensations with Enamines: The Stork Reaction Enamines are electronically similar to enolate ions Overlap of the nitrogen lone-pair orbital with the double-bond p orbitals leads to an increase in electron density on the a carbon atom

Carbonyl Condensations with Enamines: The Stork Reaction Enamine adds to an a,b-unsaturated carbonyl acceptor in a Michael-like reaction Initial product is hydrolyzed by aqueous acid to yield a 1,5-dicarbonyl compound Overall reaction is a three-step sequence: Enamine formation from a ketone Michael addition to an a,b-unsaturated carbonyl compound Enamine hydrolysis back to ketone

Carbonyl Condensations with Enamines: The Stork Reaction The net effect of the Stork reaction is a Michael addition of a ketone to an a,b-unsaturated carbonyl compound

Carbonyl Condensations with Enamines: The Stork Reaction Two advantages to the enamine-Michael reaction that make the pathway useful in biological systems Enamine is neutral and easily prepared and handled Enolate is charged and difficult to prepare and handle Enamine from a monoketone can be used in the Michael addition Only enolate ions from b-dicarbonyl compounds can be used

Worked Example 17.9 Using the Stork Enamine Reaction How might you use an enamine reaction to prepare the following compound?

Worked Example 17.9 Using the Stork Enamine Reaction Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an a,b-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product The C-C bond made in the Michael addition step is the one between the a carbon of the ketone donor and the b carbon of the unsaturated acceptor

Worked Example 17.9 Using the Stork Enamine Reaction Solution

17.12 Some Biological Carbonyl Condensation Reactions Biological Aldol Reactions Aldol reactions are particularly important in carbohydrate metabolism Enzymes called aldolases catalyze addition of a ketone enolate ion to an aldehyde Type I aldolases occur primarily in animals and higher plants Operate through an enolate ion Type II aldolases occur primarily in fungi and bacteria

Some Biological Carbonyl Condensation Reactions Mechanism of Type I aldolase in glucose biosynthesis Dihydroxyacetone phosphate is first converted into an enamine by reaction with the –NH2 group on a lysine amino acid in the enzyme Enamine adds to glyceraldehyde 3-phosphate Resultant iminium ion is hydrolyzed

Some Biological Carbonyl Condensation Reactions Mechanism of Type II aldolase in glucose biosynthesis Aldol reaction occurs directly Ketone carbonyl group of glyceraldegyde 3-phosphate complexed to a Zn2+ ion to make it a better acceptor

Some Biological Carbonyl Condensation Reactions Biological Claisen Condensations Claisen condensations occur in a large number of biological pathways In fatty acid biosynthesis an enolate ion generated by decarboxylation of malonyl ACP adds to the carbonyl group of another acyl group bonded through a thioester linkage to a synthase enzyme The tetrahedral intermediate expels the synthase, giving acetoacetyl ACP

Some Biological Carbonyl Condensation Reactions Mixed Claisen consensations occur frequently in living organisms Butyryl synthase, in the fatty-acid biosynthesis pathway, reacts with malonyl ACP in a mixed Claisen condensation to give 3-ketohexanoyl ACP