CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group Consider first the electronic effect of alkyl groups versus hydrogen atoms attached to C=O. Recall from Section 17.2 that alkyl substituents stabilize C=O, making a ketone carbonyl more stable than an aldehyde carbonyl. As with all equilibria, factors that stabilize the reactants decrease the equilibrium constant. Thus, the extent of hydra- tion decreases as the number of alkyl groups on the carbonyl Increase Increasing stabilization of carbonyl group decreasing K for hydration HCH CH3CH CH3 CCH3 Acetaldehyd Acetone almost completel (comparable amounts of (hardly any hydrate hydrated in water) hyde and hydrate present in water) present in water) example of bility and its relation to the equilibrium constant for hydration in the case of hexafluoroacetone In con- trast to the almost negligible hydration of hexafluoroacetone is completely hydrated OH CF3CCF3 CF3CCF Khy Hexafluoroacetone Water 1. 1. 1.3.3. 3-Hexafluoro- Instead of stabilizing the carbonyl group by electron donation as alkyl substituents de trifluoromethyl groups destabilize it by withdrawing electrons. A less stabilized carbonyl group is associated with a greater equilibrium constant for addition PROBLEM 17.5 Chloral is one of the common names for trichloroethanol a solution of chloral in water is called chloral hydrate; this material has featured prominently in countless detective stories as the notorious"Mickey Finn"knock out drops. Write a structural formula for chloral hydrate Now lets turn our attention to steric effects by looking at how the size of the groups that were attached to C=O affect Hydr. The bond angles at carbon shrink from 120 to=109.5 as the hybridization changes from sp- in the reactant (aldehyde or ketone) to sp in the product (hydrate). The increased crowding this produces in the hydrate is better tolerated, and Khydr is greater when the groups are small(hydrogen) than when they are large(alkyl) easing crowding in hydrate; decreasing k for formation HC CH H Hydrate of acetaldehyde Hydrate of acetone Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Consider first the electronic effect of alkyl groups versus hydrogen atoms attached to CœO. Recall from Section 17.2 that alkyl substituents stabilize CœO, making a ketone carbonyl more stable than an aldehyde carbonyl. As with all equilibria, factors that stabilize the reactants decrease the equilibrium constant. Thus, the extent of hydration decreases as the number of alkyl groups on the carbonyl increase. A striking example of an electronic effect on carbonyl group stability and its relation to the equilibrium constant for hydration is seen in the case of hexafluoroacetone. In contrast to the almost negligible hydration of acetone, hexafluoroacetone is completely hydrated. Instead of stabilizing the carbonyl group by electron donation as alkyl substituents do, trifluoromethyl groups destabilize it by withdrawing electrons. A less stabilized carbonyl group is associated with a greater equilibrium constant for addition. PROBLEM 17.5 Chloral is one of the common names for trichloroethanal. A solution of chloral in water is called chloral hydrate; this material has featured prominently in countless detective stories as the notorious “Mickey Finn” knockout drops. Write a structural formula for chloral hydrate. Now let’s turn our attention to steric effects by looking at how the size of the groups that were attached to CœO affect Khydr. The bond angles at carbon shrink from 120° to 109.5° as the hybridization changes from sp2 in the reactant (aldehyde or ketone) to sp3 in the product (hydrate). The increased crowding this produces in the hydrate is better tolerated, and Khydr is greater when the groups are small (hydrogen) than when they are large (alkyl). Increasing crowding in hydrate; decreasing K for formation C H H HO OH Hydrate of formaldehyde C H3C H HO OH Hydrate of acetaldehyde C H3C CH3 HO OH Hydrate of acetone CF3CCF3 O Hexafluoroacetone H2O Water CF3CCF3 OH OH 1,1,1,3,3,3-Hexafluoro- 2,2-propanediol Khydr 22,000 Increasing stabilization of carbonyl group; decreasing K for hydration HCH O X Formaldehyde (almost completely hydrated in water) CH3CH O X Acetaldehyde (comparable amounts of aldehyde and hydrate present in water) CH3CCH3 O X Acetone (hardly any hydrate present in water) 664 CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
17.6 Principles of Nucleophilic Addition: Hydration of Aldehydes and Ketones Electronic and steric effects operate in the same direction. Both cause the equilibrium constants for hydration of aldehydes to be greater than those of ketones Mechanism of Hydration: Hydration of aldehydes and ketones is a rapid reaction quickly reaching equilibrium, but faster in acid or base than in neutral solution. Thus instead of a single mechanism for hydration, well look at two mechanisms, one for basic and the other for acidic solution The base-catalyzed mechanism(Figure 17. 4)is a two-step process in which the first step is rate-determining. In it, the nucleophile, a hydroxide ion, attacks the carbon of the carbonyl group and bonds to it. The product of this step is an alkoxide ion, which abstracts a proton from water in the second step, yielding the geminal diol. The second step, like all the other proton transfers between oxygens that we have seen, is fast The role of the basic catalyst(Ho )is to increase the rate of the nucleophilic addi tion step. Hydroxide ion, the nucleophile in the base-catalyzed reaction, is much more reactive than a water molecule, the nucleophile in neutral media Aldehydes react faster than ketones for almost the same reasons that their eq librium constants for hydration are more favorable. The sp2- sp hybridization change that the carbonyl carbon undergoes on hydration is partially developed in the transition state for the rate-determining nucleophilic addition step(Figure 17.5). Alkyl groups at the reaction site increase the activation energy by simultaneously lowering the energy of the starting state(ketones have a more stabilized carbonyl group than aldehydes) and raising the energy of the transition state(a steric crowding effect) Three steps are involved in the acid-catalyzed hydration reaction, as shown in Figure 17.6. The first and last are rapid proton-transfer processes. The second is the nucleophilic addition step. The acid catalyst activates the carbonyl group toward attack by a weakly nucleophilic water molecule Protonation of oxygen makes the carbonyl carbon of an alde- hyde or a ketone much more electrophilic. Expressed in resonance terms, the protonated carbonyl has a greater degree of carbocation character than an unprotonated carbonyl cludes models of formaldehyde (H2C-O)and its protonat rm( H, C-OH). Compare the ect to their elec- H degree of positive charge at carbon Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group Aldehyde Step 2: Proton transfer from water to the intermediate formed in the first step R′R HO Water Geminal diol Hydroxide ion FIGURE 17. 4 The mechanism of hydration of an aldehyde or ketone in basic solution Hydrox- ide ion is a catalyst; it is consumed in the first step, and regenerated in the second Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Electronic and steric effects operate in the same direction. Both cause the equilibrium constants for hydration of aldehydes to be greater than those of ketones. Mechanism of Hydration: Hydration of aldehydes and ketones is a rapid reaction, quickly reaching equilibrium, but faster in acid or base than in neutral solution. Thus instead of a single mechanism for hydration, we’ll look at two mechanisms, one for basic and the other for acidic solution. The base-catalyzed mechanism (Figure 17.4) is a two-step process in which the first step is rate-determining. In it, the nucleophile, a hydroxide ion, attacks the carbon of the carbonyl group and bonds to it. The product of this step is an alkoxide ion, which abstracts a proton from water in the second step, yielding the geminal diol. The second step, like all the other proton transfers between oxygens that we have seen, is fast. The role of the basic catalyst (HO) is to increase the rate of the nucleophilic addition step. Hydroxide ion, the nucleophile in the base-catalyzed reaction, is much more reactive than a water molecule, the nucleophile in neutral media. Aldehydes react faster than ketones for almost the same reasons that their equilibrium constants for hydration are more favorable. The sp2 → sp3 hybridization change that the carbonyl carbon undergoes on hydration is partially developed in the transition state for the rate-determining nucleophilic addition step (Figure 17.5). Alkyl groups at the reaction site increase the activation energy by simultaneously lowering the energy of the starting state (ketones have a more stabilized carbonyl group than aldehydes) and raising the energy of the transition state (a steric crowding effect). Three steps are involved in the acid-catalyzed hydration reaction, as shown in Figure 17.6. The first and last are rapid proton-transfer processes. The second is the nucleophilic addition step. The acid catalyst activates the carbonyl group toward attack by a weakly nucleophilic water molecule. Protonation of oxygen makes the carbonyl carbon of an aldehyde or a ketone much more electrophilic. Expressed in resonance terms, the protonated carbonyl has a greater degree of carbocation character than an unprotonated carbonyl. C O H C H O 17.6 Principles of Nucleophilic Addition: Hydration of Aldehydes and Ketones 665 Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group Step 2: Proton transfer from water to the intermediate formed in the first step R HO C O slow R Hydroxide Aldehyde or ketone HO C O R R HO C R R O H OH fast C O R R H OH Water Geminal diol Hydroxide ion HO FIGURE 17.4 The mechanism of hydration of an aldehyde or ketone in basic solution. Hydroxide ion is a catalyst; it is consumed in the first step, and regenerated in the second. Learning By Modeling includes models of formaldehyde (H2CœO) and its protonated form (H2CœOH). Compare the two with respect to their electrostatic potential maps and the degree of positive charge at carbon. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
FIGURE 17.5 Potential or base- R ion of an aldehyde HO H RCRHO. HO FIGURE 17.6 The nism of hydration Step 1: Protonation of the carbonyl aldehyde or ketone in R solution Hydronium ion is catalyst; it is consumed in c=6:+H0四c-b: HOH ated in the third H jugate acid of Step 2: Nucleophilic addition to the protonated aldehyde or ketone RIR H Conjugate acid of Step 3: Proton transfer from the conjugate acid of the geminal diol to a water molecule H,O: H,O Conjugate acid of Water Geminal diol Hydronium minal diol 56 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
666 , H2O δ – Potential energy R R R' R R' R C C C C HO HO HO R R' sp3 sp3 sp2 HO O OH O O – H2O RCR', H2O, HO– OH, – OH H Eact O δ – δ – δ – Step 1: Protonation of the carbonyl oxgyen C R R O H O fast O H Hydronium ion Conjugate acid of carbonyl compound Water H Aldehyde or ketone C R R H HOH Step 2: Nucleophilic addition to the protonated aldehyde or ketone H O H Water O Conjugate acid of carbonyl compound C R R H slow C O R R H O H H Conjugate acid of geminal diol Step 3: Proton transfer from the conjugate acid of the geminal diol to a water molecule C O R R H O H H Conjugate acid of geminal diol H2O fast C O R R H O H Geminal diol H3O Hydronium ion Water FIGURE 17.5 Potential energy diagram for basecatalyzed hydration of an aldehyde or ketone. FIGURE 17.6 The mechanism of hydration of an aldehyde or ketone in acidic solution. Hydronium ion is a catalyst; it is consumed in the first step, and regenerated in the third. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
17.7 Cyanohydrin Formation Steric and electronic effects influence the rate of nucleophilic addition to a proton ated carbonyl group in much the same way as they do for the case of a neutral one, and protonated aldehydes react faster than protonated ketones With this as background, let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones. We'll begin with the addition of hydrogen cyanide 17.7 CYANOHYDRIN FORMATION The product of addition of hydrogen cyanide to an aldehyde or a ketone contains both a hydroxyl group and a cyano group bonded to the same carbon Compounds of this type are cd led cyanohydrins RCR′+HC≡N→>RCR′ C≡N Aldehyde Hydrogen Cyanohydrin or ketone cya The mechanism of this reaction is outlined in Figure 17.7. It is analogous to the mech anism of base-catalyzed hydration in that the nucleophile(cyanide ion) attacks the car- bonyl carbon in the first step of the reaction, followed by proton transfer to the carbonyl oxygen in the second step The addition of hydrogen cyanide is catalyzed by cyanide ion, but HCN is too weak an acid to provide enough: C=N: for the reaction to proceed at a reasonable rate. Cyanohydrins are therefore normally prepared by adding an acid to a solution containing cyanide ion is always present in amounts sufficient to increase the rate of the reacton the carbonyl compound and sodium or potassium cyanide. This procedure ensures that ranohydrin formation is reversible, and the position of equilibrium depends on In sub IUPAC nomen- the steric and electronic factors governing nucleophilic addition to carbonyl groups clature, cyanohydrin described in the preceding section. Aldehydes and unhindered ketones give good yields named as hydroxy deriva- of cyanohydrins will refer to cyanohydrins NaCN. ether-water CH CHC≡N in the examples. This con forms to the practice of most 2,4-Dichlorobenzaldehyde 2, 4-Dichlorobenzaldehyde cyanohydrin(100%) CHCCH CH3CCH3 Ac Acetone cyanohydrin(77-78%) Converting aldehydes and ketones to cyanohydrins is of synthetic value for two rea- sons:(1)a new carbon-carbon bond is formed, and (2) the cyano group in the product can be converted to a carboxylic acid function( CO2 H) by hydrolysis( to be discussed in Section 19.12)or to an amine of the type CH2NH2 by reduction( to be discussed in Section 22.10) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Steric and electronic effects influence the rate of nucleophilic addition to a protonated carbonyl group in much the same way as they do for the case of a neutral one, and protonated aldehydes react faster than protonated ketones. With this as background, let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones. We’ll begin with the addition of hydrogen cyanide. 17.7 CYANOHYDRIN FORMATION The product of addition of hydrogen cyanide to an aldehyde or a ketone contains both a hydroxyl group and a cyano group bonded to the same carbon. Compounds of this type are called cyanohydrins. The mechanism of this reaction is outlined in Figure 17.7. It is analogous to the mechanism of base-catalyzed hydration in that the nucleophile (cyanide ion) attacks the carbonyl carbon in the first step of the reaction, followed by proton transfer to the carbonyl oxygen in the second step. The addition of hydrogen cyanide is catalyzed by cyanide ion, but HCN is too weak an acid to provide enough for the reaction to proceed at a reasonable rate. Cyanohydrins are therefore normally prepared by adding an acid to a solution containing the carbonyl compound and sodium or potassium cyanide. This procedure ensures that free cyanide ion is always present in amounts sufficient to increase the rate of the reaction. Cyanohydrin formation is reversible, and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described in the preceding section. Aldehydes and unhindered ketones give good yields of cyanohydrins. Converting aldehydes and ketones to cyanohydrins is of synthetic value for two reasons: (1) a new carbon–carbon bond is formed, and (2) the cyano group in the product can be converted to a carboxylic acid function (CO2H) by hydrolysis (to be discussed in Section 19.12) or to an amine of the type CH2NH2 by reduction (to be discussed in Section 22.10). NaCN, ether–water then HCl Cl CH Cl O 2,4-Dichlorobenzaldehyde Cl CHC Cl OH N 2,4-Dichlorobenzaldehyde cyanohydrin (100%) NaCN, H2O then H2SO4 CH3CCH3 O Acetone OH CH3CCH3 C N Acetone cyanohydrin (77–78%) C N RCR O Aldehyde or ketone Hydrogen cyanide HC N Cyanohydrin RCR OH C N 17.7 Cyanohydrin Formation 667 In substitutive IUPAC nomenclature, cyanohydrins are named as hydroxy derivatives of nitriles. Since nitrile nomenclature will not be discussed until Section 20.1, we will refer to cyanohydrins as derivatives of the parent aldehyde or ketone as shown in the examples. This conforms to the practice of most chemists. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group FIGURE 17.7 The mecha nism of cyanohydrin forma The overall reaction tion from an aldehyde or a ketone. Cyanide ion is a cat- first step, and regenerated C=0+H-( H Aldehyde or ketone Hydrogen cyanide Cvanohyd Step 1: Nucleophilic attack by the negatively charged carbon of cyanide ion at the carbonyl carbon of the aldehyde or ketone. Hydrogen cyanide itself is not very nucleophilic and does not ionize to form cyanide ion to a significant extent. Thus, a source of cyanide ion such as Nacn or Kcn is used. N≡C-C Cyanide ion Aldehyde or Conjugate base of cyanohydrin Step 2: The alkoxide ion formed in the first step abstracts a proton from hydrogen yanide. This step yields the cyanohydrin product and regenerates cyanide ion. R N≡C-C-0 →:N≡C-C-OH+C≡N R Conjugate base of Hydr Cyanohydrin Cyanide ion cyanohydrin PROBLEM 17.6 The hydroxyl group of a cyanohydrin is also a potentially read tive site. Methacrylonitrile is an industrial chemical used in the production of plas- tics and fibers. One method for its preparation is the acid-catalyzed dehydration of acetone cyanohydrin. Deduce the structure of methacrylonitrile A few cyanohydrins and ethers of cyanohydrins occur naturally millipede stores benzaldehyde cyanohydrin, along with an enzyme catalyzes its cleavage to benzaldehyde and hydrogen cyanide, in separate compartments above its legs. When attacked, the insect ejects a mixture of the cyanohydrin and the enzyme. repelling the invader by spraying it with hydrogen cyanide 17.8 ACETAL FORMATION Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions. An example is the reaction of aldehydes with alcohols under cor Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 17.6 The hydroxyl group of a cyanohydrin is also a potentially reactive site. Methacrylonitrile is an industrial chemical used in the production of plastics and fibers. One method for its preparation is the acid-catalyzed dehydration of acetone cyanohydrin. Deduce the structure of methacrylonitrile. A few cyanohydrins and ethers of cyanohydrins occur naturally. One species of millipede stores benzaldehyde cyanohydrin, along with an enzyme that catalyzes its cleavage to benzaldehyde and hydrogen cyanide, in separate compartments above its legs. When attacked, the insect ejects a mixture of the cyanohydrin and the enzyme, repelling the invader by spraying it with hydrogen cyanide. 17.8 ACETAL FORMATION Many of the most interesting and useful reactions of aldehydes and ketones involve transformation of the initial product of nucleophilic addition to some other substance under the reaction conditions. An example is the reaction of aldehydes with alcohols under con- 668 CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group Step 1: Nucleophilic attack by the negatively charged carbon of cyanide ion at the carbonyl carbon of the aldehyde or ketone. Hydrogen cyanide itself is not very nucleophilic and does not ionize to form cyanide ion to a significant extent. Thus, a source of cyanide ion such as NaCN or KCN is used. R R C O Aldehyde or ketone Hydrogen cyanide Cyanohydrin H N C N C C OH R R The overall reaction: Cyanide ion O Aldehyde or ketone C R R N C O Conjugate base of cyanohydrin N C C R R Step 2: The alkoxide ion formed in the first step abstracts a proton from hydrogen cyanide. This step yields the cyanohydrin product and regenerates cyanide ion. O Conjugate base of cyanohydrin N C C R R Hydrogen cyanide H N C N C C OH R R Cyanohydrin C N Cyanide ion FIGURE 17.7 The mechanism of cyanohydrin formation from an aldehyde or a ketone. Cyanide ion is a catalyst; it is consumed in the first step, and regenerated in the second. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website