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19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 907

19.7 REVERSIBLE ADDITION REACTIONS OF AND 907

REVERSIBLE ADDITION REACTIONS 19.7 OF ALDEHYDES AND KETONES

One of the most typical reactions of aldehydes and ketones is addition to the carbon– oxygen double bond. To begin with, let’s focus on two simple addition reactions: addition of hydrogen (HCN) and hydration (addition of water). Addition of HCN: O OH S pH 9–10 H3CCCH3 H CN' H3CC" CH3 (19.15) LLacetone + L LL "C ' N cyanohydrin (77–78% yield)

The product of HCN addition to an or is called a cyanohydrin. Cyanohydrins constitute a special class of (organic ). (The chemistry of nitriles is discussed in Chapter 21.) The preparation of cyanohydrins is another method of forming carbon–carbon bonds. Addition of water (hydration): O OH S H3CCH H OH H3CH"C (19.16) acetaldehydeLL + L LL "OH acetaldehyde hydrate

The product of water addition to an aldehyde or ketone is called a hydrate, or gem-diol. (The prefix gem stands for geminal, from the Latin word for twin, and is used in chemistry when two identical groups are present on the same carbon.) In all carbonyl-addition reactions, the more electropositive species (for example, the hydro- gen of H CN or H OH) adds to the carbonyl oxygen, and the more electronegative species (for example,L the LCN or the OH) adds to the carbonyl carbon. L L A. Mechanisms of Carbonyl-Addition Reactions Carbonyl-addition reactions occur by two general types of mechanisms. The first mechanism, called nucleophilic carbonyl addition, involves the reaction of a nucleophile at the carbonyl carbon. In cyanohydrin formation (Eq. 19.15), the nucleophile is cyanide ion, which is formed by the ionization of HCN:

(19.17a) H CN _OH _ CN H2O pKLa 9.4 + 3 + = cyanide ion Cyanide ion donates electrons to the carbonyl carbon of the aldehyde or ketone, and the car- bonyl oxygen accepts the displaced electron pair and assumes a negative charge. We can think of this process in the same way that we think of nucleophilic reactions at saturated carbon atoms (Sec. 3.4B). The electrophile is the carbonyl carbon, and the “leaving group” is one of the two carbon–oxygen bonds of the . Because the other carbon–oxygen bond remains intact, the “leaving group” doesn’t actually leave. 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 908

908 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS

one carbon–oxygen bond O serves as the “leaving group” O _ electrophile 3 3 3 2 3 C CN nucleophile H3C "C CH3 (19.17b) H C CH _ 3 % % 3 3 LL "CN

To complete the , the negatively charged oxygen—an alkoxide ion, and a relatively strong base—is protonated by either water or HCN.

O _ H CN OH 332 L 3 2 H3C"C CH3 H3C "C CH3 _ CN (19.17c) LL LL + 3 "CN "CN

The nucleophilic carbonyl-addition mechanism finds no analogy in additions to ordinary carbon–carbon double bonds. Yet, nucleophilic carbonyl addition occurs even though the car- 1 1 STUDY GUIDE LINK 19.1 bon–oxygen p bond is 62 kJ mol_ (15 kcal mol_ ) stronger than the carbon–carbon p bond Why Nucleophiles of an alkene. The stronger bond is more reactive because the unshared electron pair (and neg- React at the Carbonyl Carbon ative charge) formed in the carbonyl-addition mechanism is transferred to a very electronega- tive atom, oxygen. The same reaction of an alkene would place an unshared pair and negative charge on a carbon, a much less electronegative atom.

additional unshared pair and unshared pair and

negative charge on oxygen negative charge on carbon

% %

O O _ C "C _ 3S3 332 S L 3 C "C C "C % % LL % % L L "CN "CN _ CN _ CN 3 observed 3 not observed with ordinary alkenes

The reaction of a nucleophile with the carbonyl group, then, is driven by the ability of oxygen to accept the unshared electron pair. For this reason, a nucleophile cannot add to the carbonyl oxygen. Nucleophiles always react with carbonyl groups at the carbonyl carbon. The geometry of nucleophilic addition and the reason for it are shown in Fig. 19.8. The car- bonyl group and the two atoms bound to the carbonyl carbon define a reference plane. The nu- cleophile approaches the carbonyl carbon from above or below this plane, as shown in Fig. 19.8a. As a result of this reaction, the carbonyl carbon changes hybridization from sp2 to sp3, the oxygen accepts an electron pair, and the geometry at the carbonyl carbon changes from trig- onal planar to tetrahedral. In other words, the angle between the bonds to the carbonyl carbon, initially about 120 , compresses to about 109 , the tetrahedral angle. As a result of the reaction, then, the groups bound° to the carbonyl carbon° become closer together. The reason for the addition geometry is similar to the reason for backside substitution in the

SN2 reactions of halides (Sec. 9.4C, Fig. 9.3). The curved-arrow notation might convey the impression that the nucleophile reacts at the p bond. However, the bonding p molecular orbital of the carbonyl group (Fig. 19.1) is fully occupied with two electrons and cannot ac- commodate any more electrons. The electron pair of the nucleophile interacts instead with the unoccupied MO of lowest energy (LUMO), which, in the case of the carbonyl group, is the an- tibonding p* molecular orbital. This MO is shown in Fig. 19.8b. This MO has lobes above and 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 909

19.7 REVERSIBLE ADDITION REACTIONS OF ALDEHYDES AND KETONES 909

sp2-hybridized sp3-hybridized

carbon carbon

≈109Њ ..

1 R .. O.. ≈120Њ R´ 1 Nuc _ Nuc 3 (a)

antibonding (p*) MO

.. bonding overlap

Nuc

(b)

Figure 19.8 (a) The geometry of nucleophilic reaction with the carbonyl carbon of , with the nu-

cleophile represented by Nuc _. The reference plane (gray) is the plane defined by the carbonyl group and the atoms attached to the carbonyl3 carbon.The nucleophile approaches this carbon from above or below this plane. As a result, the carbonyl carbon changes hybridization from sp2 to sp3,the bond angles at the carbonyl carbon compress from 120 to 109 ,and the groups attached to the carbonyl carbon move as shown by the green arrows. (b) The interaction °of a nucleophile° with the p* antibonding MO of formaldehyde.The lobes of this MO are con- centrated above and below the plane of the molecule.The interaction of the nucleophile with this MO defines the direction of nucleophilic approach to the carbonyl carbon.

below the reference plane. The nucleophile, then, must begin its bonding interaction with the carbonyl carbon from the direction along which the LUMO is concentrated, as shown in Fig. 19.8a. When the antibonding p* MO is filled, even with electrons from another molecule, the CAO p bond is weakened. (Remember that when an antibonding molecular orbital is popu- lated, the energetic advantage of bonding disappears.) This is the reason that the p bond breaks. The energetic “trade-off” for loss of this bonding is formation of the new bond to the nucleophile. The second mechanism for carbonyl addition occurs under acidic conditions and is closely analogous to the mechanism for the addition of acids to alkenes (Secs. 4.7 and 4.9B). Acid- catalyzed hydration of aldehydes and ketones (Eq. 19.16) is an example of this mechanism.

The first step in hydration is protonation of the carbonyl oxygen (Sec. 19.6).

|1 | O H OH2 O H 1

S S 3 3 L 3 L 1 C C OH2 (19.18a) H3CH% % H3CH% % + 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 910

910 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS

A positively charged oxygen attracts electrons even more strongly than the oxygen of an un- protonated carbonyl group. In other words, the protonated carbonyl compound is a much stronger Lewis acid (electron acceptor) than an unprotonated carbonyl compound. As a result,

even the relatively weak base H2O can react at the carbonyl carbon. Loss of a proton to solvent

completes the reaction.

| 1 O H 1 O H OH

S L 3 L 1 3 2 H2O 3 2 C OH2 H3C "C HH3 3CH"C H3O| (19.18b) H C H LL LL + 3 3 % % "O| H "OH 3 L 3 "H 2 Hydration of aldehydes and ketones also occurs in neutral and basic solution (Prob- lem 19.15). The direction of approach of the nucleophile to the protonated carbonyl group is the same as it is for approach to the unprotonated carbonyl group (Fig. 19.8)—from above or below the reference plane. This is explained by the shape of the LUMO of the protonated carbonyl group, which is very similar to the shape of the LUMO of the carbonyl group itself.

PROBLEMS 19.15 (a) Write a curved-arrow mechanism for the hydroxide-catalyzed hydration of acetalde- hyde. (b) Write a curved-arrow mechanism for the decomposition of (Eq. 19.15) in aqueous hydroxide. Explain why the ketone–cyanohydrin equilibrium favors the ketone at high pH. 19.16 Write a curved-arrow mechanism for (a) the acid-catalyzed addition of methanol to benzaldehyde. (b) the methoxide-catalyzed addition of methanol to benzaldehyde.

B. Equilibria in Carbonyl-Addition Reactions Hydration and cyanohydrin formation are both reversible reactions. (Not all carbonyl addi- tions are reversible.) Whether the equilibrium for a reversible addition favors the addition product or the carbonyl compound depends strongly on the structure of the carbonyl com- pound. For example, cyanohydrin formation favors the cyanohydrin addition product in the case of aldehydes and methyl ketones, but the equilibrium favors the carbonyl compound when aryl ketones are used. The effect of aldehyde or ketone structure on the addition equilibrium for hydration is il- lustrated by the data in Table 19.2. Note the following trends in the table. 1. Addition is more favorable for aldehydes than for ketones. 2. Electronegative groups near the carbonyl carbon make carbonyl addition more favorable. 3. Addition is less favorable when groups are present that donate electrons by resonance to the carbonyl carbon. The trends in this table and the reasons behind them are important for two reasons. First, the equilibria for all addition reactions show similar effects of structure. Second, and more impor- tant, the rates of carbonyl-addition reactions—that is, the reactivities of carbonyl com- pounds—follow similar trends (Sec. 19.7C). 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 911

19.7 REVERSIBLE ADDITION REACTIONS OF ALDEHYDES AND KETONES 911

TABLE 19.2 Equilibrium Constants for Hydration of Aldehydes and Ketones

O OH

S Keq H2O RCR´ RC" R´ + LL LL "OH

Aldehydes Keq Ketones Keq

3 3 H2 CAO2.2 10 (CH3)2CAO1.4 10- X X CH3CHAO1.0 O S Ph C CH3 6 (CH3)2CHCHAO0.51.0 6.6 10- - LL X 3 7 PhCHAO8.3 10- Ph2CAO1.2 10- X X ClCH2CHAO37(ClCH2)2CAO10

4 Cl3CCHAO2.8 10 (CF3)2CAOtoo large to measure X

What is the reason for the effect of structure on carbonyl addition? The relative stabilities of the carbonyl compound and the addition product govern the DG for addition. This point is illustrated in Fig. 19.9. As shown in this figure, the primary effect° on the hydration equilib- rium is the difference in the stabilities of the carbonyl compounds. Added stability in the car- bonyl compound increases the energy change DG , and hence decreases the equilibrium con- stant, for formation of an addition product. °

OH OH

CH3CCH3 CH3CH2CH OH OH ∆G° (aldehyde) O

∆G° (ketone) CH3CH2CH + H2O stabilization of the ketone relative O to the aldehyde STANDARD FREE ENERGY STANDARD

CH3CCH3 + H2O

larger ∆G° smaller ∆G° smaller Keq larger Keq

Figure 19.9 The greater stability of a ketone relative to an aldehyde causes the ketone to have a greater stan- dard free energy of hydration and therefore a smaller equilibrium constant for hydration. (The two hydrates have been placed at the same energy level for comparison purposes.) 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 912

912 CHAPTER 19 • THE CHEMISTRY OF ALDEHYDES AND KETONES. CARBONYL-ADDITION REACTIONS

The major factors that stabilize carbonyl compounds can be understood by considering the resonance structures of the carbonyl group:

O O _ 33S 332 R CR R "CR (19.19) LL LL| The structure on the right, although not as important a contributor as the one on the left, reflects the polarity of the carbonyl group and has the characteristics of a carbocation. There- fore, anything that stabilizes carbocations also tends to stabilize carbonyl compounds. Be- cause alkyl groups stabilize carbocations, ketones (R alkyl) are more stable than aldehydes (R H). This stability is reflected in the relative heats= of formation of aldehydes and ketones. = 1 1 1 For example, acetone, with DHf 218 kJ mo1_ ( 52.0 kcal mo1_ ), is 29 kJ mo1_ (6.9 1 ° =- - 1 kcal mo1_ ) more stable than its isomer propionaldehyde, for which DHf 189 kJ mo1_ 1 °=- ( 45.2 kcal mo1_ ). Because alkyl groups stabilize carbonyl compounds, the equilibria for additions- to ketones are less favorable than those for additions to aldehydes (trend 1). Formaldehyde, with two hydrogens and no alkyl groups bound to the carbonyl, has a very large equilibrium constant for hydration. Electronegative groups such as halogens destabilize carbocations by their polar effect and for the same reason destabilize carbonyl compounds. Thus, halogens make the equilibria for addition more favorable (trend 2). In fact, chloral hydrate (known in medicine as a hypnotic) is a stable crystalline compound.

O OH S Cl3C CH H2O Cl3C "CH (19.20) L + L chloral "OH (2,2,2-trichloroethanal) chloral hydrate

Groups that are conjugated with the carbonyl group, such as the phenyl group of benzalde- hyde, stabilize carbocations by resonance, and hence stabilize carbonyl compounds.

O _ O _ O _ O _ 332 332 332 | 332 "C H A"C H A"C H A"C H | L | L L L L | (19.21) A similar resonance stabilization cannot occur in the hydrate because the carbonyl group is no longer present. Consequently, aryl aldehydes and ketones have relatively unfavorable hydra- tion equilibria (trend 3). A steric effect also operates in carbonyl addition. As the size of the groups bound to the car- bonyl carbon increases, van der Waals repulsions in the corresponding addition compounds become more important. We can see why this should be so from Fig. 19.8a. The groups at the carbonyl carbon are closer together in the addition compound than in the carbonyl compound; hence, van der Waals repulsions are more pronounced in the addition compound. These van der Waals repulsions, in turn, raise the energy of the addition compound relative to the car- bonyl compound and increase the DG for addition. ° 19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 913

19.7 REVERSIBLE ADDITION REACTIONS OF ALDEHYDES AND KETONES 913

C. Rates of Carbonyl-Addition Reactions The trends in relative rates of addition can be predicted from the trends in equilibrium con- stants. That is, compounds with the most favorable addition equilibria tend to react most rapidly in addition reactions. Thus, aldehydes are generally more reactive than ketones in ad- dition reactions; formaldehyde is more reactive than many other simple aldehydes. The reason for the parallel trends in rates and equilibria is that the transition states for ad- dition reactions resemble addition products. Thus, it is a convenient approximation to think of the addition compounds in Fig. 19.9 as transition states, and the standard free energies DG as standard free energies of activation G ‡. Just as destabilization of aldehydes or ketones °de- STUDY GUIDE LINK 19.2 D Ground-State Energies creases the DG for their addition reactions,° the same destabilization decreases the free ener- and Reactivity ‡ gies of activation° DG for addition and thus increases the rate of addition. This section has covered° two examples of addition to the carbonyl group. Subsequent sec- tions deal with other addition reactions as well as more complex reactions that have mecha- nisms in which the initial steps are addition reactions. These addition reactions all have mech- anisms similar to the ones discussed in this section, and the trends in reactivity are the same. Addition to the carbonyl group is a common thread that runs throughout most of aldehyde and ketone chemistry.

PROBLEMS 19.17 Which carbonyl compound should form the greater proportion of cyanohydrin at equilib- rium? Draw the structure of the cyanohydrin, and explain your reasoning.

CHA O or CH3CH2CHA O L propanal benzaldehyde

19.18 The compound ninhydrin exists as a hydrate. Which carbonyl group is hydrated? Explain, and give the structure of the hydrate.

O * A O

@O ninhydrin

19.19 Within each set, which compound should be more reactive in carbonyl-addition reactions? Explain your choices. (a) O O S S H3CCCH2CH2Br or H3CCCH2Br LL LL (b) O O O S S S

H3CCC CH3 or H3CCCH2CH3 LLL LL1 (c)

O2NOCH A or CH3O CHA O L L 1 L L (d) A O or A O

(Hint: Note the change in bond angles in Fig. 19.8a.)