17. 4 Sources of Aldehydes and Ketones 17. 4 SOURCES OF ALDEHYDES AND KETONES As we'll see later in this chapter and the next, aldehydes and ketones are involved in many of the most used reactions in synthetic organic chemistry. Where do aldehydes and ketones come from? Many occur naturally. In terms of both variety and quantity, aldehydes and ketones rank among the most common and familiar natural products. Several are shown in Igure Many are made in the laboratory from alkenes, alkynes, arenes, and alcohols by reactions that you already know about and are summarized in Table 17.1 To the synthetic chemist, the most important of the reactions in Table 17.1 are th last two: the oxidation of primary alcohols to aldehydes and secondary alcohols to ketones. Indeed, when combined with reactions that yield alcohols, the oxidation meth ods are so versatile that it will not be necessary to introduce any new methods for prepar- ing aldehydes and ketones in this chapter A few examples will illustrate this point Let's first consider how to prepare an aldehyde from a carboxylic acid. There are no good methods for going from RCO2H to RCHO directly. Instead, we do it indirectly by first reducing the carboxylic acid to the corresponding primary alcohol, then oxidiz ing the primary alcohol to the aldehyde CHOH →>RCH Carboxylic acid Primary alcohol Aldehyde O L LIAIH PDC COH CHOH CH Benzoic acid Benzyl alcohol (81%) Benzaldehyde (83%) (sex pheromone of greater wax moth) (component of alarm pheromone of bees) (alarm pheromone of myrmicine ant) (present in lemon grass oil) (found in oil of jasmine) FIGURE 17.3 African civet cat) naturally occurring Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
17.4 SOURCES OF ALDEHYDES AND KETONES As we’ll see later in this chapter and the next, aldehydes and ketones are involved in many of the most used reactions in synthetic organic chemistry. Where do aldehydes and ketones come from? Many occur naturally. In terms of both variety and quantity, aldehydes and ketones rank among the most common and familiar natural products. Several are shown in Figure 17.3. Many are made in the laboratory from alkenes, alkynes, arenes, and alcohols by reactions that you already know about and are summarized in Table 17.1. To the synthetic chemist, the most important of the reactions in Table 17.1 are the last two: the oxidation of primary alcohols to aldehydes and secondary alcohols to ketones. Indeed, when combined with reactions that yield alcohols, the oxidation methods are so versatile that it will not be necessary to introduce any new methods for preparing aldehydes and ketones in this chapter. A few examples will illustrate this point. Let’s first consider how to prepare an aldehyde from a carboxylic acid. There are no good methods for going from RCO2H to RCHO directly. Instead, we do it indirectly by first reducing the carboxylic acid to the corresponding primary alcohol, then oxidizing the primary alcohol to the aldehyde. COH O Benzoic acid CH2OH Benzyl alcohol (81%) CH O Benzaldehyde (83%) 1. LiAlH4 2. H2O PDC CH2Cl2 RCO2H Carboxylic acid RCH2OH Primary alcohol RCH O Aldehyde reduce oxidize 17.4 Sources of Aldehydes and Ketones 659 O O O Undecanal (sex pheromone of greater wax moth) 2-Heptanone (component of alarm pheromone of bees) O trans-2-Hexenal (alarm pheromone of myrmicine ant) O Citral (present in lemon grass oil) O Civetone (obtained from scent glands of African civet cat) Jasmone (found in oil of jasmine) H H H FIGURE 17.3 Some naturally occurring aldehydes and ketones. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
TABLE 17.1 Summary of Reactions Discussed in Earlier Chapters That Yield Aldehydes and Ketones Reaction(section) and comments General equation and specific example Ozonolysis of alkenes(Section 6. 19)This H cleavage reaction is more often seen in structural analysis than in synthesis. The RCR+RCH 2. H-O. Zn substitution pattern around a double R bond is revealed by identifying the carbonyl-containing compounds that Alkene Two carbonyl compounds make up the product Hydrolysis of the ozonide intermediate in the presence of CH3 zinc(reductive workup) permits alde- CH3 CCH3 HCCH2 CH2 CHCH2CH3 hyde products to be isolated without further oxidation 2, 6-Dimethyl-2-octene Acetone 4-Methylhexanal (91%) Hydration of alkynes(Section 9.12)Reac- ate formed by Markovnikov addition of RC=CR+H,o HS0a, RCCH2R tion occurs by way of an enol intermedi ater to the triple bond Alkyne Ketone HC=C(CH2)5 CH3+h. aC(CH2)sCH 1-Octyne 2-Octanone(91%) Friedel-Crafts acylation of aromatic compounds(Section 12.7) Acyl chloride and carboxylic acid anhydrides acylate ArH+RCCl Ch ArCR +Hcl o aromatic rings in the presence of alum num chloride. The reaction is electrophile ic aromatic substitution in which acylium ArH+ RCOCR RCO2H ions are generated and attack the ring (90-94% Oxidation of primary alcohols to alde- hydes(Section 15.10)Pyridinium dichro- mate( PDo) or pyridinium chlorochro- RCH2OH DC or PCC mate(PCC)in anhydrous media such as Primary alcohol Aldehyde dichloromethane oxidizes primary alco- hols to aldehydes while avoiding overox CH3(CH2)CH2OH CH2)&CH 1-Decanol Oxidation of secondary alcohols to tones (Section 15.10)Many oxidizing agents are available for converting sec- RCHR ondary alcohols to ketones. PDC or PCC may be used as well as other cr(vi)- based agents such as chromic acid or Secondary alcohol Ketone potassium dichromate and sulfuric acid C6HsCHCH2 CH2 H2 CH3 -i CsHs CH2CH2 CH OH 1-Phenyl-1-pentanol 1-Phenyl-1-pentanone(93%) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
TABLE 17.1 Summary of Reactions Discussed in Earlier Chapters That Yield Aldehydes and Ketones Reaction (section) and comments Ozonolysis of alkenes (Section 6.19) This cleavage reaction is more often seen in structural analysis than in synthesis. The substitution pattern around a double bond is revealed by identifying the carbonyl-containing compounds that make up the product. Hydrolysis of the ozonide intermediate in the presence of zinc (reductive workup) permits aldehyde products to be isolated without further oxidation. Friedel-Crafts acylation of aromatic compounds (Section 12.7) Acyl chlorides and carboxylic acid anhydrides acylate aromatic rings in the presence of aluminum chloride. The reaction is electrophilic aromatic substitution in which acylium ions are generated and attack the ring. Oxidation of primary alcohols to aldehydes (Section 15.10) Pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in anhydrous media such as dichloromethane oxidizes primary alcohols to aldehydes while avoiding overoxidation to carboxylic acids. Oxidation of secondary alcohols to ketones (Section 15.10) Many oxidizing agents are available for converting secondary alcohols to ketones. PDC or PCC may be used, as well as other Cr(VI)- based agents such as chromic acid or potassium dichromate and sulfuric acid. Hydration of alkynes (Section 9.12) Reaction occurs by way of an enol intermediate formed by Markovnikov addition of water to the triple bond. General equation and specific example Two carbonyl compounds RCR O X RCH O X 1. O3 2. H2O, Zn Alkene CœC ± ± ± ± R H R R Acetone CH3CCH3 O X HCCH2CH2CHCH2CH3 O X W CH3 4-Methylhexanal (91%) 1. O3 2. H2O, Zn 2,6-Dimethyl-2-octene Alkyne RCPCR H2O H2SO4 HgSO4 RCCH2R O X Ketone ArH HCl or AlCl3 ArCR O X RCCl O X RCH2OH Primary alcohol PDC or PCC CH2Cl2 Aldehyde RCH O X RCHR W OH Secondary alcohol Cr(VI) Ketone RCR O X C6H5CHCH2CH2CH2CH3 W OH 1-Phenyl-1-pentanol CrO3 acetic acid/ water 1-Phenyl-1-pentanone (93%) C6H5CCH2CH2CH2CH3 O X CH3(CH2)8CH2OH 1-Decanol PDC CH2Cl2 Decanal (98%) CH3(CH2)8CH O X ArH RCO 2H AlCl3 ArCR O X RCOCR O X O X 1-Octyne HCPC(CH2)5CH3 H2O H2SO4 HgSO4 CH3C(CH2)5CH3 O X 2-Octanone (91%) AlCl3 CCH3 O X CH3O p-Methoxyacetophenone (90–94%) CH3COCCH3 O X O X Acetic anhydride CH3O Anisole Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
17.5 Reactions of Aldehydes and Ketones: A Review and a Preview PROBLEM 17.3 Can catalytic hydrogenation be used to reduce a carboxylic acid to a primary alcohol in the first step of this sequence? It is often necessary to prepare ketones by processes g carbon-carbon bond formation In such cases the standard method combines of a Grignard reagent to an aldehyde with oxidation of the resulting secondary OH 1. RMgX, diethyl eth Aldehyde Secondary alcohol OH I CH3(CH,)3MgBr →CH2CH2CHCH2)CH2C CH3CH,C(CH2)3CH 3-Heptanol 3-Heptanone PROBLEM 17.4 Show how 2-butanone could be prepared by a procedure in hich all of the carbons originate in acetic acid (CHa,H) Many low-molecular-weight aldehydes and ketones are important industrial chemi- The name aldehyde was in. cals. Formaldehyde, a starting material for a number of plastics, is prepared by oxidation of vented to stand for alcohol methanol over a silver or iron oxide/molybdenum oxide catalyst at elevated temperature. that aldehydes are related to CH3OH+ Jo, cataly HCH H,O Methanol Oxygen Formaldehyde Water Similar processes are used to convert ethanol to acetaldehyde and isopropyl alcohol to acetone The "linear a-olefins described in Section 14 15 are starting materials for the preparation of a variety of aldehydes by reaction with carbon monoxide. The process is called hydroformylation RCH=CH,+ CO H RCH,,CH Alkene Carbon Excess hydrogen brings about the hydrogenation of the aldehyde and allows the process to be adapted to the preparation of primary alcohols. Over 2 X 10 lb/year of a variety of aldehydes and alcohols is prepared in the United States by hydroformylation. A number of aldehydes and ketones are prepared both in industry and in the lab- oratory by a reaction known as the aldol condensation, which will be discussed in detail in Chapter 18. 17.5 REACTIONS OF ALDEHY DES AND KETONES: A REVIEW AND A PREVIEW Table 17.2 summarizes the reactions of aldehydes and ketones that you ve seen in ear- lier chapters. All are valuable tools to the synthetic chemist. Carbonyl groups provide access to hydrocarbons by Clemmensen of Wolff-Kishner reduction(Section 12. 8),to Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 17.3 Can catalytic hydrogenation be used to reduce a carboxylic acid to a primary alcohol in the first step of this sequence? It is often necessary to prepare ketones by processes involving carbon–carbon bond formation. In such cases the standard method combines addition of a Grignard reagent to an aldehyde with oxidation of the resulting secondary alcohol: PROBLEM 17.4 Show how 2-butanone could be prepared by a procedure in which all of the carbons originate in acetic acid (CH3CO2H). Many low-molecular-weight aldehydes and ketones are important industrial chemicals. Formaldehyde, a starting material for a number of plastics, is prepared by oxidation of methanol over a silver or iron oxide/molybdenum oxide catalyst at elevated temperature. Similar processes are used to convert ethanol to acetaldehyde and isopropyl alcohol to acetone. The “linear -olefins” described in Section 14.15 are starting materials for the preparation of a variety of aldehydes by reaction with carbon monoxide. The process is called hydroformylation. Excess hydrogen brings about the hydrogenation of the aldehyde and allows the process to be adapted to the preparation of primary alcohols. Over 2 109 lb/year of a variety of aldehydes and alcohols is prepared in the United States by hydroformylation. A number of aldehydes and ketones are prepared both in industry and in the laboratory by a reaction known as the aldol condensation, which will be discussed in detail in Chapter 18. 17.5 REACTIONS OF ALDEHYDES AND KETONES: A REVIEW AND A PREVIEW Table 17.2 summarizes the reactions of aldehydes and ketones that you’ve seen in earlier chapters. All are valuable tools to the synthetic chemist. Carbonyl groups provide access to hydrocarbons by Clemmensen of Wolff–Kishner reduction (Section 12.8), to RCH2CH2CH O Aldehyde Co2(CO)8 Hydrogen H2 Carbon monoxide CO Alkene RCH CH2 CH3OH Methanol HCH O Formaldehyde H2O Water catalyst 500°C Oxygen O2 1 2 RCH O Aldehyde RCHR OH Secondary alcohol RCR O Ketone 1. RMgX, diethyl ether 2. H3O oxidize CH3CH2CH O Propanal CH3CH2CH(CH2)3CH3 OH 3-Heptanol CH3CH2C(CH2)3CH3 O 3-Heptanone (57% from propanal) 1. CH3(CH2)3MgBr diethyl ether 2. H3O H2CrO4 17.5 Reactions of Aldehydes and Ketones: A Review and a Preview 661 The name aldehyde was invented to stand for alcohol dehydrogenatum, indicating that aldehydes are related to alcohols by loss of hydrogen. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group TABLE 17.2 Summary of Reactions of Aldehydes and Ketones Discussed in Earlier Chapters Reaction(section) and comments General equation and specific example Reduction to hydrocarbons(Section 12.8) Two methods for converting carbonyl groups to methylene units are the Clem- ensen reduction(zinc amalgam and con- Aldehyde centrated hydrochloric acid) and the or ketone Wolff-Kishner reduction(heat with hydra- zine and potassium hydroxide in a high ing alcohol). glycol, heat Citronellal 2, 6-Dimethyl-2-octene Reduction to alcohols (Section 15.2)Alde- hydes are reduced to primary alcohols, and ketones are reduced to secondary alcohols RCR RCHR by a variety of reducing agents. Catalytic hydrogenation over a metal catalyst and eduction with sodium borohydride or Aldehyde Alcohol lithium aluminum hydride are genera CHO ->CH laO p-Methoxybenzaldehyde p-Methoxybenzyl alcohol (96%) Addition of Grignard reagents and organolithium compounds(Sections 14.6-14.7)Aldehydes are converted to RCR′+R"M )RCR H RCR' secondary alcohols and ketones to tertiary HO CH2CH CHICH,MgBr 1 die toether Cyclohexanone Ethylmagnesiun 1-Ethylcyclohexanol alcohols by reduction(Section 15. 2)or by reaction with Grignard or organolithium The most important chemical property of the carbonyl group is its tendency to undergo nucleophilic addition reactions of the type represented in the general equation Aldehyde Product of Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
alcohols by reduction (Section 15.2) or by reaction with Grignard or organolithium reagents (Sections 14.6 and 14.7). The most important chemical property of the carbonyl group is its tendency to undergo nucleophilic addition reactions of the type represented in the general equation: C O Aldehyde or ketone X Y C Y O X Product of nucleophilic addition 662 CHAPTER SEVENTEEN Aldehydes and Ketones: Nucleophilic Addition to the Carbonyl Group TABLE 17.2 Summary of Reactions of Aldehydes and Ketones Discussed in Earlier Chapters Reaction (section) and comments Reduction to hydrocarbons (Section 12.8) Two methods for converting carbonyl groups to methylene units are the Clemmensen reduction (zinc amalgam and concentrated hydrochloric acid) and the Wolff–Kishner reduction (heat with hydrazine and potassium hydroxide in a highboiling alcohol). Addition of Grignard reagents and organolithium compounds (Sections 14.6-14.7) Aldehydes are converted to secondary alcohols and ketones to tertiary alcohols. Reduction to alcohols (Section 15.2) Aldehydes are reduced to primary alcohols, and ketones are reduced to secondary alcohols by a variety of reducing agents. Catalytic hydrogenation over a metal catalyst and reduction with sodium borohydride or lithium aluminum hydride are general methods. General equation and specific example NaBH4 CH3OH CH O X CH3O p-Methoxybenzaldehyde CH3O CH2OH p-Methoxybenzyl alcohol (96%) Hydrocarbon RCR RCH2R O X Aldehyde or ketone H2NNH2, KOH diethylene glycol, heat Citronellal 2,6-Dimethyl-2-octene (80%) CH O X RCHR OH W Alcohol RCR O X Aldehyde or ketone RCR R OM W W RCR R OH W W RCR O X RM H3O CH3CH2MgBr Ethylmagnesium bromide Cyclohexanone O 1. diethyl ether 2. H3O 1-Ethylcyclohexanol (74%) HO CH2CH3 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
17.6 Principles of Nucleophilic Addition: Hydration of Aldehydes and Ketones A negatively polarized atom or group attacks the positively polarized carbon of the car- bonyl group in the rate-determining step of these reactions. Grignard reagents, organo- lithium reagents, lithium aluminum hydride, and sodium borohydride, for example, all react with carbonyl compounds by nucleophilic addition. The next section explores the mechanism of nucleophilic addition to aldehydes and ketones. There we'll discuss their hydration a reaction in which water adds to the c=o group. After we use this reaction to develop some general principles, we'll then survey a number of related reactions of synthetic, mechanistic, or biological interest. 17.6 PRINCIPLES OF NUCLEOPHILIC ADDITION: HYDRATION OF ALDEHYDES AND KETONES Effects of structure on Equilibrium: Aldehydes and ketones react with water in a d equilibrium: RCR′+H2O [carbonyl compound][water] Aldehyde Water Geminal diol Overall. the reaction is classified as an addition. The elements of water add to the car- bonyl group. Hydrogen becomes bonded to the negatively polarized carbonyl oxyger hydroxyl to the positively polarized carbon. Table 17.3 compares the equilibrium constants Khydr for hydration of some simple aldehydes and ketones. The position of equilibrium depends on what groups are attached to C=O and how they affect its steric and electronic environment. Both effects con- tribute, but the electronic effect controls Khvdr more than the steric effect. TABLE 17.3 Equilibrium Constants(Khyd )for Hydration of Some Aldehydes and Ketones Percent conversion Hydrate K HCH CH2(OH)2 CHCH CHa CH(OH)2 1.8×10-2 CH3)3CCH (CH3)aCCH(OH)2 4.1×10-3 CHaCCH (CH3)2C(OH)2 25×10-5 0.14 Total concentration(hydrate plus carbonyl compound) assumed to be 1 M. Water concentration is 55.5 M. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
A negatively polarized atom or group attacks the positively polarized carbon of the carbonyl group in the rate-determining step of these reactions. Grignard reagents, organolithium reagents, lithium aluminum hydride, and sodium borohydride, for example, all react with carbonyl compounds by nucleophilic addition. The next section explores the mechanism of nucleophilic addition to aldehydes and ketones. There we’ll discuss their hydration, a reaction in which water adds to the CœO group. After we use this reaction to develop some general principles, we’ll then survey a number of related reactions of synthetic, mechanistic, or biological interest. 17.6 PRINCIPLES OF NUCLEOPHILIC ADDITION: HYDRATION OF ALDEHYDES AND KETONES Effects of Structure on Equilibrium: Aldehydes and ketones react with water in a rapid equilibrium: Overall, the reaction is classified as an addition. The elements of water add to the carbonyl group. Hydrogen becomes bonded to the negatively polarized carbonyl oxygen, hydroxyl to the positively polarized carbon. Table 17.3 compares the equilibrium constants Khydr for hydration of some simple aldehydes and ketones. The position of equilibrium depends on what groups are attached to CœO and how they affect its steric and electronic environment. Both effects contribute, but the electronic effect controls Khydr more than the steric effect. RCR O Aldehyde or ketone H2O Water RCR OH OH Geminal diol (hydrate) fast Khydr [hydrate] [carbonyl compound][water] 17.6 Principles of Nucleophilic Addition: Hydration of Aldehydes and Ketones 663 TABLE 17.3 Equilibrium Constants (Khydr) for Hydration of Some Aldehydes and Ketones Hydrate CH2(OH)2 CH3CH(OH)2 (CH3)3CCH(OH)2 (CH3)2C(OH)2 Khydr* 41 1.8 102 4.1 103 2.5 105 Percent conversion to hydrate† 99.96 50 19 0.14 Carbonyl compound HCH O X CH3CH O X (CH3)3CCH O X CH3CCH3 O X † Total concentration (hydrate plus carbonyl compound) assumed to be 1 M. Water concentration is 55.5 M. *Khydr . Units of Khydr are M1 . [hydrate] [carbonyl compound][water] Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website