Carbonyl Alpha-Substitution Reactions Capter-22

1. Carbonyl Alpha-Substitution ReactionsCapter-22 Chem. 233 Fall 2004 Dr. Zand Farshid Zand

2. Sneak Peek: • Keto-Enol Tautomerism • Reactivity of Enols: Mech. of Alpha-Substitution Rxns. • Alpha Halogenation of Aldehydes and Ketones • Alpha Bromination of Carboxylic Acids: The Hell-Volhard-Zelinskii Rxn. • Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Reactivity of Enolate Ions • Halogenatation of Enolate Ions: The Haloform Rxn. • Alkylation of Enolate ions Farshid Zand

3. : :O:- C E+ C :O: O E C C H α C C : :OH E+ C C α-substitution Reaction An enolate ion An alpha-substituted carbonyl compound A carbonyl compound An enol Farshid Zand

4. Keto-Enol Tautomerism A. Natures of tautomerism. 1. Carbonyl compounds with hydrogens bonded to their α carbons equilibrate with their corresponding enols. 2. This rapid equilibration is called tautomerism, and the individual isomers are tautomers. 3. Unlike resonance forms, tautomers are isomers. 4. Despite the fact that very little of the enol isomer is present at room temperature, enols are very important because they are reactive. B. Mechanism of tautomerism. 1. In acid-catalyzed enoliztion, the carbonyl α carbon is protonated to form an intermediate that can lose a hydrogen from its carbon to yield a neutral enol. 2. In base-catalyzed enol formation, an acid-0base reaction occurs between a base and an α hydrogen. a. The resultant enolate is potonated to yield an enol. b. Protonation can occur either on carbon or on oxygen. c. Only hydrogen on the α positions of carbonyl compounds are acidic. Farshid Zand

5. :O: C H C H H : +:O :O C C H H + C C H : :O C C Acid-catalyzed Enol Formation H—A Acid-catalyzed enol formation. The protonated intermediate can lose H+, either from the oxygen atom to regenerate keto tautomer or from the α carbon atom to yield an enol. Keto tautomer Protonation of the carbonyl oxygen atom by an acid catalyst HA yield a cation that can be represented by two resonance structures. :A- Loss of H+from the α position by reaction with a base A-then yields the enol tautomer and regenerates HA catalyst. + HA Enol tautomer Farshid Zand

6. :O: : -:OH : C H C : :O: :O:- : H—O—H : C C I: C C H : :O C C Base-catalyzed Enol Formation Base-catalyzed enol formation. The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to regenerate the starting keto tautomer or on oxygen to give an enol. Keto tautomer Base removes an acidic hydrogen from the α position of the carbonyl compound, yielding an enolate anion that has two resonance structures. Protonation of the enolate anion on the oxygen atom yields an enol and regenerates the base catalyst. + OH- Farshid Zand Enol tautomer

7. Reactivity of Enols: Mech. of Alpha-Substitution Rxns 1. The electron-rich double bonds of enols cause them to behave as nucleophiles. (The electron-donating enol -OH groups make enols more reactive then alkenes) 2. When an enol reacts with an electrophile, the initial adduct loses -H from oxygen to give a substituted carbonyl compound Farshid Zand

8. :O H H : Electron-rich +:O C C I: C C Enol tautomer Farshid Zand

9. Alpha Halogenation of Aldehydes and Ketones 1. Aldehydes and ketones can be halogenated at their α positions by reaction of X2 in acidic solution. 2. The reaction proceeds by acid-catalyzed formation of an enol intermediate. 3. Halogen isn’t involved in the rate-limiting step: the rate doesn’t depend on the identity of the halogen, but only on [ketone] and [H+]. 4. α-Bromo ketones are useful in synthesis because they can be dehydrobrominated by base treatment to from α,β-unsaturated ketones. Farshid Zand

10. H :O: : :O C H C C C Acid catalyst :Base H + H :O : :O E C E C C + C O E C C Carbonyl α-substitution Rxn. Acid-catalyzed enol formation occurs by the usual mechanism. E+ Carbonyl α–substitution Rxn. The initial formed cation loses H+ to regenerate a carbonyl compound. An electron pair from the enol oxygen attacks an electrophile (E+), forming a new bond and leaving a cation intermediate that is stabilized by resonance between two forms. Loss of a proton from oxygen yields the neutral α-substitution product as a new C=O bond is formed. Farshid Zand

11. O O C C CH3CO2H solvent CH3 + Br2 CH2Br+ HBr Acetophnone α- Bromoacetophenone (72%) O O Cl Cl2 H2O, HCl + HCl 2- Chlorocyclohexanone (66%) Cyclohexanone Examples:Aldehydes and ketones can be halogenated at their α positions by reaction with Cl2, Br2, or I2 in acidic solution. Bromine in acetic acid solvent is often used. Farshid Zand

12. H . . H :O: :O: + :O :O :Base C C H3C H3C CH2Br CH3 H H C C C C H3C H3C H H H :Base H . . H + :O : O Br Br C C C + C H3C H3C H H H H Acid-catalyzed bromination of acetone H—Br Br—Br + Br- Enol The carbonyl oxygen atom is protpnated by acid catalyst. Loss of an acidic proton from the alpha carbon takes place in the normal way to yield an enol intermediate An electron pair from the enol attacks bromine, giving an intermediate cation that is stabilized by resonance between two forms. Loss of the –OH proton then gives the alpha-halongenated product and generates more acid catalyst. + HBr Farshid Zand

13. Alpha Bromination of Carboxylic Acids: The Hell-Volhard-Zelinskii Rxn 1. In the Hell-Volhard-Zelinskii (HVZ) reaction, a mixture of Br2 and PBr3 can be used to brominate carboxylic acids in the α position. 2. The initially formed acid bromide reacts with Br2 to form an α–bromo acid bromide, which is hydrolyzed by water to give the α–bromo carboxylic acid. 3. The reaction proceeds through an acid bromide enol. Farshid Zand

14. O H C C OH R R PBr3 OH O O H R C Br2 C C Br C Br C Br C R Br R R R R H2O O Br C C OH R R The Hell-Volhard-Zelinskii Rxn 1st step takes place between PBr3 and a carboxylic acid to yield an intermediate acid bromide plus HBr. The Hell-Volhard-Zelinskii Rxn. The overall result of the reaction is the transformation of an acid into an α-bromo acid. Note, though, that the key step involves α substitution of an acid bromide enol rather than a carboxylic acid enol. Acid bromide Acid bromide enol The HBr catalyzes enolization of the acid bromide and the resultant enol reacts rapidly with Br2in an α-substitution rxn. Addition of H2O results in hydrolysis of the α-bromo acid bromide and gives the α-bromo carboxylic acid product. Farshid Zand

15. Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation 1. Hydrogens α to a carbonyl group are weakly acidic. a. This stability is due to overlap of a vacant ρ orbital with the carbonyl group ρ orbitals, allowing the carbonyl group to stabilize the negative charge by resonance. b. The two resonance forms aren’t equivalent; the form with the negative charge on oxygen is of lower energy. 2. Strong bases are needed for enolate ion formation. a. Alkoxide ions are too weak to use in enolate formation. b. Lithium diisopropylamide (LDA) is used for forming enolates because it is a very strong base, it is soluble in THF, it is hindered and it can be used at low temperatures. c. LDA can be used to form the enolate of many different carbonyl compounds. 3. When a hydrogen is flanked by two carbonyl groups, it is much more acidic. (Both carbonyl groups can stabilize the negative charge.) Farshid Zand

16. Acidity Constants for Some Organic Compounds Farshid Zand

17. Reactivity of Enolate Ions 1. Enolates are more useful than enols for two reasons: a. Unlike enols, stable solutions of enlolates are easily prepared. b. Enolates are more reactive then enols because they are more neucleophilic. 2. Enolates can react either at carbon or at oxygen. a. Reaction at carbon yields an α-substituted carbonyl compound. b. Reaction at oxygen yields an enol derivative. Farshid Zand

18. Reaction here or Reaction here : :O: :O:- C C I: C C E+ E+ E O O E C C C C Reactivity of Enolate Ions Relativity of Enolate Ions. Two modes of reaction of an enolate ion with an electrophile, E+. Reaction on carbon to yield an α-substituted carbonyl product is more common. Α-Keto canbanion Vinylic alkoxide An α-substituted carbonyl compound An enol derivative Farshid Zand

19. Halogenatation of Enolate Ions: The Haloform Rxn 1. Base-promoted halogenation of aldehydes and ketones proceeds readily because each halogen added makes the carbonyl compound more reactive. 2. Consequently, polyhalogenated compounds are usually produced. 3. This reaction is only useful with methyl ketones, which form HCX3 when reacted with halogens. a. The HCX3 is a solid that can be identified. b. The last step of the reaction involves a carbanion leaving group. Farshid Zand

20. O C R CH3 X2 NaOH O OH O C C C R CX3 R CX3 R OH -:O: -:OH : : : O C R O- Where X = Cl, Br, I The Haloform Rxn The Haloform Rxn. If excess base and halogen are used, a methyl ketone is triply halogenate and then cleaved by a base. The products are a carboxylic acid plus a so-called haloform. Note, that the 2nd step of the rxn is a nucleophillic acyl substitution of –CX3 by –OH. That is, a carbanion acts as a leaving grp. A methyl ketone + -CX3 + CHX3 Farshid Zand

21. Alkylation of Enolate ions 1. General features. a. Alkylatons are useful because they form a new C—C bond. b. Alkylations have the same limitations as SN2 reactions; the alkyl groups must be methyl, primary, allylic or benzylic. 2. The malonic ester synthesis. a. The malonic ester synthesis is used for preparing a carboxylic acid from a halide while lengthening the chain by two atoms. b. Diethyl malonate is useful because its enolate is easily prepared by reaction with sodium ethoxide. c. Since diethyl malonate has two acidic hydrogens, two alkylations can take place. d. Heating in aqueous HCL causes hydrolysis and decarboxylation of the alkylated malonate. (Decarboxylations are common only to β–keto acids and malonic acids.) e. Cycloalkanecarboxylic acids can also be prepared. Farshid Zand

22. CO2Et CO2Et CO2Et Na+-OEt EtOH RX CO2Et CO2Et CO2Et H R C Na+ - :C C H H H R—X{ —X: Tosylate > — I > — Br > — Cl R—: Allylic ≈ Benzylic > H3C— > RCH2— CO2Et H H3O+ Heat CO2Et CO2Et R R C C H H The Malonic Ester Synthesis Sodio malonic ester Diethyl propanedioate (malonic ester) An alkylated malonic ester + CO2+ 2 EtOH Farshid Zand

23. Alkylation of Enolate ions cont... 3. The acetoacetic ester synthesis. a. The acetoacetic ester synthesis is used for converting an alkyl halide to a methyl ketone, while lengthening the the carbon chain by 3 atoms. b. As with malonic ester, acetoacetic ester has two acidic hydrogens which are flanked by a ketone and an ester, and two alkylations can take place. c. Heating in aqueous HCL hydrolyzes the ester and decarboxylate the acid to yield the ketone. d. All β–keto esters can undergo this type of reaction. 4. Direct alkylation of ketones, esters, and nitriles. a. LDA in a nonprotic solvent can be used to convert the above compounds to their enolates. b. Alkylation of an unsymmetrical ketone leads to a mixture of products, but the major product is alkylated at the less hindered position. Farshid Zand

24. H O H O O Na+-OEt EtOH RX R I: C C CH3 H H C C CH3 C C CH3 CO2Et CO2Et CO2Et R’ O H O O Na+-OEt EtOH R’X R I: C C CH3 R R C C CH3 C C CH3 CO2Et CO2Et CO2Et The Acetoacetic Ester Synthesis Acetoacetic ester A monoalkylated acetoacetic ester A monoalkylated acetoacetic ester A dialkylatedn acetoacetic ester Farshid Zand

25. R’X O O O H LDA THF R’ C C C I: C C R C R R Alkylation of ketones Farshid Zand

26. LDA THF R’X O O O H R’ C C C I: C C R O C R O R O Alkylation of esters Farshid Zand

27. LDA THF RX N N N H R C C C I: C C C Alkylation of nitriles Farshid Zand