CHAPTER 18 ENOLS AND ENOLATES n the preceding chapter you learned that nucleophilic addition to the carbonyl group is one of the fundamental reaction types of organic chemistry. In addition to its own reactivity, a carbonyl group can affect the chemical properties of aldehydes and ketones other ways. Aldehydes and ketones are in equilibrium with their enol isomers RoCHCR′、RC=CR′ In this chapter you'll see a number of processes in which the enol, rather than the alde hyde or a ketone, is the reactive species. There is also an important group of reactions in which the carbonyl group acts as a powerful electron-withdrawing substituent, increasing the acidity of protons on the adjacent carbons R2CCR This proton is far more acidic than a hydrogen in an alkane Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
701 CHAPTER 18 ENOLS AND ENOLATES I n the preceding chapter you learned that nucleophilic addition to the carbonyl group is one of the fundamental reaction types of organic chemistry. In addition to its own reactivity, a carbonyl group can affect the chemical properties of aldehydes and ketones in other ways. Aldehydes and ketones are in equilibrium with their enol isomers. In this chapter you’ll see a number of processes in which the enol, rather than the aldehyde or a ketone, is the reactive species. There is also an important group of reactions in which the carbonyl group acts as a powerful electron-withdrawing substituent, increasing the acidity of protons on the adjacent carbons. This proton is far more acidic than a hydrogen in an alkane. R2CCR H O Aldehyde or ketone R2CHCR O Enol R2C CR OH Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTEr EIGHTEEN Enols and enolates As an electron-withdrawing group on a carbon-carbon double bond, a carbonyl group renders the double bond susceptible to nucleophilic attack: R,C=CHCR Normally, carbon-carbon double bonds are attacked by electrophiles; a carbon-carbon double bond that is conjugated to a carbonyl group is attacked by nucleophiles. The presence of a carbonyl group in a molecule makes possible a number of chem- ical reactions that are of great synthetic and mechanistic importance. This chapter is com- plementary to the preceding one; the two chapters taken together demonstrate the extra- ordinary range of chemical reactions available to aldehydes and ketones. 18.1 THE Q-CARBON ATOM AND ITS HYDROGENS It is convenient to use the Greek letters a, B, Y, and so forth, to locate the carbons in a molecule in relation to the carbonyl group. The carbon atom adjacent to the carbonyl is the a-carbon atom, the next one down the chain is the B carbon, and so on. Butanal, for example, has an a carbon, a p carbon, and a y carbon Carbonyl group CH3CH,CH,CH no greek letter assigned to Hydrogens take the same Greek letter as the carbon atom to which they are attached. A hydrogen connected to the a-carbon atom is an a hydrogen. Butanal has two a protons, two B protons, and three y protons. No Greek letter is assigned to the hydro- gen attached directly to the carbonyl group of an aldehyde PROBLEM 18.1 How many a hydrogens are there in each of the following? (a)3, 3-Dimethyl-2-butanon (c) Benzyl methyl ketone (b)2, 2-Dimethylpropanal SAMPLE SOLUTION (a) This ketone has two different a carbons, but only one of them has hydrogen substituents. There are three equivalent a hydrogens. the other nine hydrogens are attached to B-carbon atoms CH3-C--C--CH3 3, 3-Dimethyl-2-butanone her than nucleophilic addition to the carbonyl group, the most important reac- tions of aldehydes and ketones involve substitution of an a hydrogen. A particularly well studied example is halogenation of aldehydes and ketones Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
As an electron-withdrawing group on a carbon–carbon double bond, a carbonyl group renders the double bond susceptible to nucleophilic attack: The presence of a carbonyl group in a molecule makes possible a number of chemical reactions that are of great synthetic and mechanistic importance. This chapter is complementary to the preceding one; the two chapters taken together demonstrate the extraordinary range of chemical reactions available to aldehydes and ketones. 18.1 THE -CARBON ATOM AND ITS HYDROGENS It is convenient to use the Greek letters , , , and so forth, to locate the carbons in a molecule in relation to the carbonyl group. The carbon atom adjacent to the carbonyl is the -carbon atom, the next one down the chain is the carbon, and so on. Butanal, for example, has an carbon, a carbon, and a carbon. Hydrogens take the same Greek letter as the carbon atom to which they are attached. A hydrogen connected to the -carbon atom is an hydrogen. Butanal has two protons, two protons, and three protons. No Greek letter is assigned to the hydrogen attached directly to the carbonyl group of an aldehyde. PROBLEM 18.1 How many hydrogens are there in each of the following? (a) 3,3-Dimethyl-2-butanone (c) Benzyl methyl ketone (b) 2,2-Dimethylpropanal (d) Cyclohexanone SAMPLE SOLUTION (a) This ketone has two different carbons, but only one of them has hydrogen substituents. There are three equivalent hydrogens. The other nine hydrogens are attached to -carbon atoms. Other than nucleophilic addition to the carbonyl group, the most important reactions of aldehydes and ketones involve substitution of an hydrogen. A particularly well studied example is halogenation of aldehydes and ketones. 3,3-Dimethyl-2-butanone CH3±C±C±CH3 CH3 CH3 O X W W Carbonyl group is reference point; no Greek letter assigned to it. O CH3CH2CH2CH Normally, carbon–carbon double bonds are attacked by electrophiles; a carbon–carbon double bond that is conjugated to a carbonyl group is attacked by nucleophiles. O R2C CHCR 702 CHAPTER EIGHTEEN Enols and Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
18.3 Mechanism of a Halogenation of Aldehydes and Ketones 18.2 C HALOGENATION OF ALDEHYDES AND KETONES Aldehydes and ketones react with halogens by substitution of one of the a hydrogens R,CCR+ X2 →R,CCR HX Aldehyde Halo a-Halo aldehyde Hydrogen The reaction is regiospecific for substitution of an a hydrogen. None of the hydrogens farther removed from the carbonyl group are affected Cl HCl Cyclohexanone Chlorine 2-Chlorocyclohexanone Hydrogen (61-66%) chloride Nor is the hydrogen directly attached to the carbonyl group in aldehydes affected Only the a hydrogen is replace CH CHCI3 HBr Cyclohexanecarbaldehyde Bromine 1-Bromocyclohexanecarbaldehyde(80%) Hydrogen PROBLEM 18.2 Chlorination of 2-butanone yields two isomeric products, each having the molecular formula CaH,Clo. Identify these two compounds a Halogenation of aldehydes and ketones can be carried out in a variety of sol- vents(water and chloroform are shown in the examples, but acetic acid and diethyl ether are also often used). The reaction is catalyzed by acids. Since one of the reaction prod- ucts, the hydrogen halide, is an acid and therefore a catalyst for the reaction, the proces is said to be autocatalytic. Free radicals are not involved, and the reactions occur at room temperature in the absence of initiators. Mechanistically, acid-catalyzed haloge nation of aldehydes and ketones is much different from free-radical halogenation of alkanes. Although both processes lead to the replacement of a hydrogen by a halogen, they do so by completely different pathways 18.3 MECHANISM OF C HALOGENATION OF ALDEHYDES AND KETONES In one of the earliest mechanistic investigations in organic chemistry, Arthur Lapworth discovered in 1904 that the rates of chlorination and bromination of acetone were the same. Later he found that iodination of acetone proceeded at the same rate as chlorination Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
18.2 HALOGENATION OF ALDEHYDES AND KETONES Aldehydes and ketones react with halogens by substitution of one of the hydrogens: The reaction is regiospecific for substitution of an hydrogen. None of the hydrogens farther removed from the carbonyl group are affected. Nor is the hydrogen directly attached to the carbonyl group in aldehydes affected. Only the hydrogen is replaced. PROBLEM 18.2 Chlorination of 2-butanone yields two isomeric products, each having the molecular formula C4H7ClO. Identify these two compounds. Halogenation of aldehydes and ketones can be carried out in a variety of solvents (water and chloroform are shown in the examples, but acetic acid and diethyl ether are also often used). The reaction is catalyzed by acids. Since one of the reaction products, the hydrogen halide, is an acid and therefore a catalyst for the reaction, the process is said to be autocatalytic. Free radicals are not involved, and the reactions occur at room temperature in the absence of initiators. Mechanistically, acid-catalyzed halogenation of aldehydes and ketones is much different from free-radical halogenation of alkanes. Although both processes lead to the replacement of a hydrogen by a halogen, they do so by completely different pathways. 18.3 MECHANISM OF HALOGENATION OF ALDEHYDES AND KETONES In one of the earliest mechanistic investigations in organic chemistry, Arthur Lapworth discovered in 1904 that the rates of chlorination and bromination of acetone were the same. Later he found that iodination of acetone proceeded at the same rate as chlorination O Cyclohexanone Cl2 Chlorine H2O O Cl 2-Chlorocyclohexanone (61–66%) Hydrogen chloride HCl Aldehyde or ketone R2CCR H O R2CCR X O -Halo aldehyde or ketone Halogen X2 Hydrogen halide HX H 18.3 Mechanism of Halogenation of Aldehydes and Ketones 703 HBr Hydrogen bromide CH O H Cyclohexanecarbaldehyde Br2 Bromine CH O Br 1-Bromocyclohexanecarbaldehyde (80%) CHCl3 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTEr EIGHTEEN Enols and enolates and bromination. Moreover, the rates of all three halogenation reactions, although first order in acetone, are independent of the halogen concentration. Thus, the halogen does not participate in the reaction until after the rate-determining step. These kinetic obser vations, coupled with the fact that substitution occurs exclusively at the a-carbon atom, ed Lapworth to propose that the rate-determining step is the conversion of acetone to a more reactive form. its enol isomer: this chapter is an electrostatic CHACHa= Acetone Propen-2-o1(enol Once formed, this enol reacts rapidly with the halogen to form an a-halo ketone OH CH3C= 2 CH3 CCH2X HX Propen-2-0 Halogen a-Halo derivative Hydrogen form of ac of acetone halide PROBLEM 18.3 Write the structures of the enol forms of 2-butanone that react with chlorine to give 1-chloro-2-butanone and 3-chloro-2-butanone far ahead of Both parts of the Lapworth mechanism, enol formation and enol halogenation, are new to us. Lets examine them in reverse order. We can understand enol halogenation ow organic reactions occur. by analogy to halogen addition to alkenes. An enol is a very reactive kind of alkene. Its For an account of Lapworth's carbon-carbon double bond bears an electron-releasing hydroxyl group, which activates nistry, see the it toward attack by electrophiles ovember 1972 issue of the OH on,pp.750-752. CHSC-CH, +Br-Br: ICH3-C-CH,Br:+Br Bromine Stabilized carbocation (enol form The hydroxyl group stabilizes the carbocation by delocalization of one of the ared electron pairs of oxygen: CH, Br CH3-C-CH, Br able resonance More stable 6 electrons on form: all aton tively charged c Participation by the oxygen lone pairs is responsible for the rapid attack on the carbon-carbon double bond of an enol by bromine. We can represent this participation explicitly: Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
and bromination. Moreover, the rates of all three halogenation reactions, although firstorder in acetone, are independent of the halogen concentration. Thus, the halogen does not participate in the reaction until after the rate-determining step. These kinetic observations, coupled with the fact that substitution occurs exclusively at the -carbon atom, led Lapworth to propose that the rate-determining step is the conversion of acetone to a more reactive form, its enol isomer: Once formed, this enol reacts rapidly with the halogen to form an -halo ketone: PROBLEM 18.3 Write the structures of the enol forms of 2-butanone that react with chlorine to give 1-chloro-2-butanone and 3-chloro-2-butanone. Both parts of the Lapworth mechanism, enol formation and enol halogenation, are new to us. Let’s examine them in reverse order. We can understand enol halogenation by analogy to halogen addition to alkenes. An enol is a very reactive kind of alkene. Its carbon–carbon double bond bears an electron-releasing hydroxyl group, which activates it toward attack by electrophiles. The hydroxyl group stabilizes the carbocation by delocalization of one of the unshared electron pairs of oxygen: Participation by the oxygen lone pairs is responsible for the rapid attack on the carbon–carbon double bond of an enol by bromine. We can represent this participation explicitly: Less stable resonance form; 6 electrons on positively charged carbon. CH3 CH2Br C O More stable resonance form; all atoms (except hydrogen) have octets of electrons. CH3 C CH2Br H O H Br Bromide ion CH3 CH2Br C OH Stabilized carbocation very fast Br Br Bromine CH3C CH2 OH Propen-2-ol (enol form of acetone) -Halo derivative of acetone CH3CCH2X O Halogen X2 Hydrogen halide HX Propen-2-ol (enol form of acetone) CH3C CH2 OH fast Acetone CH3CCH3 O Propen-2-ol (enol form of acetone) CH3C CH2 OH slow 704 CHAPTER EIGHTEEN Enols and Enolates The graphic that opened this chapter is an electrostatic potential map of the enol of acetone. Lapworth was far ahead of his time in understanding how organic reactions occur. For an account of Lapworth’s contributions to mechanistic organic chemistry, see the November 1972 issue of the Journal of Chemical Education, pp. 750–752. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
18.4 Enolization and Enol Content OH CH3C=CH2 CH3C—CH,Br:+ Br-br Writing the bromine addition step in this way emphasizes the increased nucleophilicity of the enol double bond and identifies the source of that increased nucleophilicity as the lic PROBLEM 18 4 Represent the reaction of chlorine with each of the enol forms of 2-butanone (see Problem 18.3)according to the curved arrow formalism just described The cationic intermediate is simply the protonated form(conjugate acid) of the a-halo ketone. Deprotonation of the cationic intermediate gives the product -H: Br CH3, Br Hy Having now seen how an enol, once formed, reacts with a halogen, let us consider the process of enolization itself 18.4 ENOLIZATION AND ENOL CONTENT Enols are related to an aldehyde or a ketone by a proton-transfer equilibrium known as keto-enol tautomerism. (Tautomerism refers to an interconversion between two struc- The keto and enol forms are tures that differ by the placement of an atom or a group. constitutional isomers. Using each other RCH, CR RCHECR Keto form Enol form The mechanism of enolization involves two separate proton-transfer steps rather than a one-step process in which a proton jumps from carbon to oxygen. It is relatively slow in neutral media. The rate of enolization is catalyzed by acids as shown by the mechanism in Figure 18.1. In aqueous acid, a hydronium ion transfers a proton to the carbonyl oxygen in step l, and a water molecule acts as a Bronsted base to remove a proton from the a-carbon atom in step 2. The second step is slower than the first. The first step involves proton transfer between oxygens, and the second is a proton transfer from carbon to oxygen. You have had earlier experience with enols in their role as intermediates in the hydration of alkynes (Section 9. 12). The mechanism of enolization of aldehydes and ketones is precisely the reverse of the mechanism by which an enol is converted to a carbonyl compound The amount of enol present at equilibrium, the enol content, is quite small for sim- ple aldehydes and ketones. The equilibrium constants for enolization, as shown by the following examples, are much less than 1 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Writing the bromine addition step in this way emphasizes the increased nucleophilicity of the enol double bond and identifies the source of that increased nucleophilicity as the enolic oxygen. PROBLEM 18.4 Represent the reaction of chlorine with each of the enol forms of 2-butanone (see Problem 18.3) according to the curved arrow formalism just described. The cationic intermediate is simply the protonated form (conjugate acid) of the -halo ketone. Deprotonation of the cationic intermediate gives the products. Having now seen how an enol, once formed, reacts with a halogen, let us consider the process of enolization itself. 18.4 ENOLIZATION AND ENOL CONTENT Enols are related to an aldehyde or a ketone by a proton-transfer equilibrium known as keto–enol tautomerism. (Tautomerism refers to an interconversion between two structures that differ by the placement of an atom or a group.) The mechanism of enolization involves two separate proton-transfer steps rather than a one-step process in which a proton jumps from carbon to oxygen. It is relatively slow in neutral media. The rate of enolization is catalyzed by acids as shown by the mechanism in Figure 18.1. In aqueous acid, a hydronium ion transfers a proton to the carbonyl oxygen in step 1, and a water molecule acts as a Brønsted base to remove a proton from the -carbon atom in step 2. The second step is slower than the first. The first step involves proton transfer between oxygens, and the second is a proton transfer from carbon to oxygen. You have had earlier experience with enols in their role as intermediates in the hydration of alkynes (Section 9.12). The mechanism of enolization of aldehydes and ketones is precisely the reverse of the mechanism by which an enol is converted to a carbonyl compound. The amount of enol present at equilibrium, the enol content, is quite small for simple aldehydes and ketones. The equilibrium constants for enolization, as shown by the following examples, are much less than 1. Keto form RCH2CR O Enol form RCH CR OH tautomerism Cationic intermediate Br O CH3CCH2Br H CH3CCH2Br O Bromoacetone H Br Hydrogen bromide Br CH3 C CH2Br Br Br CH3C CH2 OH OH 18.4 Enolization and Enol Content 705 The keto and enol forms are constitutional isomers. Using older terminology they are referred to as tautomers of each other. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website