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1: Keto-Enol Tautomerization o Carbonyl compounds with a hydrogen on the α-carbon (carbon next to the carbonyl) rapidly equilibrate between the keto form (carbonyl) and the enol form (C=C bond with OH). This process formally involves the movement of a proton from the α-carbon to the oxygen and the π-bond from C-O to C-C Note, that this is not resonance since an atom is moving. This type of isomerization is called tautomerization, which is any rapid equilibrium that involves movement of one or more atoms (usually protons)
o Simple ketones or aldehydes exist almost exclusively in the keto form. For ketones the typical ratio is 10,000-10,000,000:1 ketone/enol. Even though the enol is present in very small amounts, it will be responsible for several reactions that we will discuss. o The keto/enol tautomerization can be catalyzed using acid or base. Acid-Catalyzed: The first step is protonation of the carbonyl group. This makes the carbonyl group a stronger electron-withdrawing group and increases the acidity of the α-protons. Water then removes a proton from the α-position to give the enol (recall that in E1 elimination, the C-H bond next to a carbocation is easily deprotonated). Base-Catalyzed: Protons in the α-position of a carbonyl are more acidic than a typical C-H bond due to the electron-withdrawing effect of the carbonyl (only the α-position is made more acidic). With hydroxide, the first step is deprotonation of the α-position to give an enolate. Protonation at oxygen by water gives the enol.
22.2: Reactivity of Enols o The α-carbon of an enol is nucleophilic. If we consider an alternate resonance structure where the OH donates a pair of electrons to generate a C=O double bond and place a negative charge on the α-carbon. o The α-position will react with electrophiles to give α-substituted carbonyl derivatives.
22.3: α-Halogenation of aldehydes and ketones o Treatment of ketones or aldehydes with at least one proton on an α-carbon with a halogen (Cl2, Br2, or I2) under acidic conditions results in halogenation of the αposition. The mechanism involves acid-catalyzed formation of an enol. The enol then acts as a nucleophile and attacks the halogen. Deprotonation of the carbonyl gives the halogenated carbonyl. α-Bromoketones are useful precursors because they allow the synthesis of α,ßunsaturated ketones. Treatment of an α-bromoketone with pyridine leads to an E2 elimination.
3-diester (malonic ester) has a pKa of 13. Note that any nucleophile could be used to react with the acid bromide (i. Because the acid bromide is much more electrophilic than a carboxylic acid. such as lithium diisopropyl amide (LDA) are able to completely deprotonate ketones and other carbonyl derivatives (the pKa of diisopropylamine is around 40). so only about 1% of the enolate can be formed if hydroxide is reacted with a ketone. the enol form is formed more easily. The enol then reacts with bromine to give the α-brominated acid bromide. The carbanion is stabilized by resonance electron-withdrawal by the carbonyl.4Pentanedione has a pKa of 9 for the C-H bonds between the two ketones. the C-H bonds α to a carbonyl are considerably more acidic than a normal C-H bond. o The acidity of the α-position of a carbonyl group is dependent on the positive charge on the carbonyl carbon.3. Hydroxide is sufficiently basic to completely deprotonate these 1. acid chloride = 16 aldehyde = 17 ketone = 19 ester = 25 amide = 30 o If a carbon is α to two carbonyl groups it's protons are considerably more acidic. Treatment with water gives the αbromoacid. so it is formed preferentially. the bromination occurs on the more substituted side. 2. More electrophilic carbonyls (more positive) will be more acidic.4: α-Bromination of carboxylic acids-Hell-Volhard-Zelinskii reaction o Treatment of carboxylic acids with PBr3. For example. o Weak bases such as hydroxide or alkoxides are much weaker bases than an enolate. In unsymmetrical ketones. Thus. Remember alcohols and water have pKa values around 16 compared to the pKa value of the ketone (19). such as acetone.3-dicarbonyls. Br2 followed by treatment with water produces a α-brominated carboxylic acid The mechanism involves the formation of acid bromide with the PBr3. . A 3ketoester has a pKa of 11. Deprotonation gives a carbanion that is known as an enolate. acetone has a pKa of 19. • 22. The alternate resonance structure with a C=C bond and an oxygen anion is relatively stable (hence the name enolate). o The α-C-H bonds are more acidic because of the electron-withdrawing effect of the carbonyl group. The more substituted enol is more stable (same as for alkenes). while ethane has a pKa of 60.e. • 22. while a 1. the more substituted side of the ketone (assuming there is an α-proton) will react. o A strong bases.5: Acidity of α-hydrogen atoms-enolate formation o As mentioned previously. an alcohol to give an ester or an amine to give an amide).
Thus. Because the resonance forms have negative charge on both the oxygen and the α-carbon. loss of CO2 occurs to give a carboxylic acid. Methyl ketones treated with a halogen under basic conditions converts the methyl group to a CX3 group. the process can be repeated with a second alkyl group. Treatment of a ketone with sodium hydroxide and bromine results in bromination of the α-position. Hydrolysis of the ester under acidic conditions gives a malonic acid derivative (diacid). which is a yellow solid.3-dicarbonyl with sodium ethoxide provides an enolate. The dialkyl malonate is deprotonated and alkylated. The base generates an enolate. Secondary alkyl halides react poorly because they often give elimination. complete replacement of all α-C-H bonds occurs. The negative charge is primarily located on the oxygen. o 1. Thus treatment of a 1. this reaction allows synthesis of an acetic acid derivative with 1 or 2 alkyl groups added to the α-carbon.• 22. Instead. When iodine is used. If a second proton is present. o Ketones can be halogenated under basic conditions. which can then be alkylated. which then reacts with the bromine. o Malonic Ester Synthesis: The malonic ester synthesis is a method to convert a malonic ester (1. The alkyl group should be methyl or primary and preferably allylic or benzylic with a good leaving group (halide or tosylate). Instead. o The haloform reaction is an example of this type of reaction. This was historically used as a way to test for the presence of a methyl ketone.3-diester) to an alkylated acetic acid derivative. A nucleophilic acyl substitution occurs leading to formation of a carboxylate and HCX3. but most electrophiles react at the carbon to give α-substituted carbonyl products. • Carboxylic acids with carbonyls in the ß-position undergo rapid loss of CO2. The acidic proton is transferred to the ß-carbonyl with elimination of CO2. . which allows carbon groups to be added to the α-position of a carbonyl compound. Because the brominated ketone is now more acidic. but it produces a substituted acetone derivative. which gives an enol. electrophiles could potentially add to each site. Tautomerization to the carbonyl form then occurs. which is not isolated. • 22.3-Dicarbonyls are particularly good substrates for alkylation reactions because they are easily deprotonated using an alkoxide base. the reaction can usually not be stopped after a single bromination. o Acetoacetic Ester Synthesis: The acetoacetic ester synthesis is the same as the malonic ester synthesis. This process is repeated if a second alkyl group is needed. the product is iodoform (HCI3). A further reaction occurs because the CX3 group is now a reasonable leaving group.6: Reactivity of enolate ions o Enolates are more reactive than enols because they are negatively charged.7: Alkylation of enolate ions o Enolates are good nucleophiles for SN2 reactions.
which will undergo decarboxylation. Unsymmetrical ketones are deprotonated on the less substituted side. . such as ketones. it is easier to remove the proton from the less-substituted side. esters. Because LDA is large. the ester can be hydrolyzed to give a 3ketoacid. The resulting product is a methyl ketone. Deprotonation with LDA gives the enolate. Acetoacetic ester is 3-ketoester. and nitriles. It can be alkylated with one or two alkyl groups in the same way as a malonic ester. and nitriles can be alkylated. o Direct alkylation of ketones. but a stronger base (LDA) is required. esters. After the alkyl groups are added. Other 3-ketoesters can be used in the same way to generate alkylated ketones. The LDA generates a kinetically preferred enolate. Less acidic carbonyl derivatives. which can be alkylated.
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