Aldehydes and Ketones: Nucleophilic Addition Reactions PDF
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Summary
This is a chapter on aldehydes and ketones. It covers the naming, preparation, oxidation, and nucleophilic addition reactions of these crucial organic compounds. The chapter also touches on biological occurrences and industrial applications of aldehydes and ketones.
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19 Aldehydes and Ketones: Nucleophilic Addition Reactions 19-1 Naming Aldehydes and Ketones 19-2 Preparing Aldehydes and Ketones 19-3 Oxidation of Aldehydes and Ketones 19-4 Nucleophilic Addition Reactions of Aldehydes and Ketones 19-5 Nucleophilic Addition of H2O: Hydration 19-6 Nucleo...
19 Aldehydes and Ketones: Nucleophilic Addition Reactions 19-1 Naming Aldehydes and Ketones 19-2 Preparing Aldehydes and Ketones 19-3 Oxidation of Aldehydes and Ketones 19-4 Nucleophilic Addition Reactions of Aldehydes and Ketones 19-5 Nucleophilic Addition of H2O: Hydration 19-6 Nucleophilic Addition of HCN: Cyanohydrin Formation 19-7 Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation 19-8 Nucleophilic Addition of Amines: Imine and Enamine Formation 19-9 Nucleophilic Addition of Hydrazine: The Wolff– Kishner Reaction 19-10 Nucleophilic Addition of Alcohols: Acetal Formation 19-11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction ©Loskutnikov/Shutterstock.com contents Few flowers are more beautiful or more fragrant than roses. Their perfumed odor is due to several simple organic compounds, including the ketone -damascenone. Much of organic chemistry is the chemistry of carbonyl compounds. Aldehydes and ketones, in particular, are intermediCHAPTER? ates in the synthesis of many pharmaceutical agents, in almost all biological pathways, and in numerous industrial processes, so an understanding of their properties and reactions is essential. In this chapter, we’ll look at some of their most important reactions. WHY THIS Aldehydes (RCHO) and ketones (R2CO) are among the most widely occurring of all compounds. In nature, many substances required by living organisms are aldehydes or ketones. The aldehyde pyridoxal phosphate, for instance, is a coenzyme involved in a large number of metabolic reactions; the ketone hydrocortisone is a steroid hormone secreted by the adrenal glands to regulate fat, protein, and carbohydrate metabolism. 19-12 Biological Reductions 19-13 Conjugate Nucleophilic Addition to ␣,-Unsaturated Aldehydes and Ketones 19-14 Spectroscopy of Aldehydes and Ketones SOMETHING EXTRA Enantioselective Synthesis CH2OH 2–O PO 3 HO C +N OH CH3 O OH CH3 O H CH3 H H H H H O Pyridoxal phosphate (PLP) Hydrocortisone In the chemical industry, simple aldehydes and ketones are produced in large quantities for use as solvents and as starting materials to prepare a host of other compounds. For example, more than 30 million tons per year of formaldehyde, H2C P O, is produced worldwide for use in building insulation 604 !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-1 naming aldehydes and ketones materials and in the adhesive resins that bind particle board and plywood. Acetone, (CH3)2C P O, is widely used as an industrial solvent; approximately 6 million tons per year is produced worldwide. Formaldehyde is synthesized industrially by catalytic oxidation of methanol, and one method of acetone preparation involves oxidation of 2-propanol. OH C H O Catalyst H C Heat H H Methanol Formaldehyde OH H3C H3C C H O ZnO H 380 °C C H3C 2-Propanol CH3 Acetone 19-1 Naming Aldehydes and Ketones Aldehydes are named by replacing the terminal -e of the corresponding alkane name with -al. The parent chain must contain the ᎐ CHO group, and the ᎐ CHO carbon is numbered as carbon 1. Note in the following examples that the longest chain in 2-ethyl-4-methylpentanal is actually a hexane, but this chain does not include the ᎐ CHO group and thus is not the parent. O CH3CH CH3 O O 2 CH3CH2CH CH3CHCH2CHCH 5 4 3 1 CH2CH3 Ethanal (acetaldehyde) Propanal (propionaldehyde) 2-Ethyl-4-methylpentanal For cyclic aldehydes in which the ᎐ CHO group is directly attached to a ring, the suffix -carbaldehyde is used. CHO Cyclohexanecarbaldehyde 1 2 CHO 2-Naphthalenecarbaldehyde A few simple and well-known aldehydes have common names that are recognized by IUPAC. Several that you might encounter are listed in TABLE 19-1. !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 605 606 chapter 19 aldehydes and ketones: nucleophilic addition reactions TABLE 19-1 Common Names of Some Simple Aldehydes Formula Common name Systematic name HCHO Formaldehyde Methanal CH3CHO Acetaldehyde Ethanal H2C P CHCHO Acrolein Propenal CH3CH P CHCHO Crotonaldehyde 2-Butenal Benzaldehyde Benzenecarbaldehyde CHO Ketones are named by replacing the terminal -e of the corresponding alkane name with -one. The parent chain is the longest one that includes the ketone group, and the numbering begins at the end nearer the carbonyl carbon. As with alkenes (Section 7-3) and alcohols (Section 17-1), the locant is placed before the parent name using older rules but before the suffix with the newer IUPAC guidelines. For example: O O O CH3CH2CCH2CH2CH3 CH3CH 3-Hexanone (New: Hexan-3-one) 4-Hexen-2-one (New: Hex-4-en-2-one) 1 2 34 5 6 6 CHCH2CCH3 5 4 3 21 O CH3CH2CCH2CCH3 6 5 43 21 2,4-Hexanedione (New: Hexane-2,4-dione) A few ketones are allowed by IUPAC to retain their common names. O O C CH3CCH3 Acetone O C CH3 Acetophenone Benzophenone When it’s necessary to refer to the R ᎐ C⫽O as a substituent, the name acyl (a-sil) group is used and the name ending -yl is attached. Thus, ᎐ COCH3 is an acetyl group, ᎐ CHO is a formyl group, ᎐ COAr is an aroyl group, and ᎐ COC6H5 is a benzoyl group. O O C R An acyl group C H3C Acetyl O O C C H Formyl Benzoyl !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-2 preparing aldehydes and ketones If other functional groups are present and the double-bonded oxygen is considered a substituent on a parent chain, the prefix oxo- is used. For example: O O CH3CH2CH2CCH2CH 5 6 4 32 3-Oxohexanal 1 PROBLEM 19-1 Name the following aldehydes and ketones: O (a) (b) CH2CH2CHO (c) O O CH3CCH2CH2CH2CCH2CH3 CH3CH2CCHCH3 CH3 (d) H (e) CH3 H O CH3CH CHCH2CH2CH O (f) H3C H CHO H CH3 PROBLEM 19-2 Draw structures corresponding to the following names: (a) 3-Methylbutanal (c) Phenylacetaldehyde (e) 3-Methyl-3-butenal (b) 4-Chloro-2-pentanone (d) cis-3-tert-Butylcyclohexanecarbaldehyde (f) 2-(1-Chloroethyl)-5-methylheptanal 19-2 Preparing Aldehydes and Ketones Preparing Aldehydes One of the best methods of aldehyde synthesis is by oxidation of primary alcohols, as we saw in Section 17-7. The reaction is often carried out using the Dess–Martin periodinane reagent in dichloromethane solvent at room temperature: AcO I OAc OAc O H O CH2OH Geraniol C CH2Cl2 O Geranial (84%) A second method of aldehyde synthesis is one that we’ll mention here just briefly and then return to in Section 21-6. Certain carboxylic acid derivatives !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 607 608 chapter 19 aldehydes and ketones: nucleophilic addition reactions can be partially reduced to yield aldehydes. The partial reduction of an ester by diisobutylaluminum hydride (DIBAH, or DIBAL-H), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related processes also occur in biological pathways. The reaction is normally carried out at ⫺78 °C (dry-ice temperature) in toluene solution. O O 1. DIBAH, toluene, –78 °C 2. H O+ CH3(CH2)10COCH3 CH3(CH2)10CH 3 Methyl dodecanoate Dodecanal (88%) H where DIBAH = CH3CHCH2 Al CH2CHCH3 CH3 CH3 PROBLEM 19-3 How would you prepare pentanal from the following starting materials? (a) CH3CH2CH2CH2CH2OH (c) CH3CH2CH2CH2CO2CH3 (b) CH3CH2CH2CH2CH P CH2 (d) CH3CH2CH2CH P CH2 Preparing Ketones For the most part, methods of ketone synthesis are similar to those for aldehydes. Secondary alcohols are oxidized by a variety of reagents to give ketones (Section 17-7). The choice of oxidant depends on such factors as reaction scale, cost, and acid or base sensitivity of the alcohol. Either the Dess–Martin periodinane or a Cr(VI) reagent such as CrO3 is a common choice. O OH CrO3 H3C H3C CH2Cl2 C H3C H3C CH3 4-tert-Butylcyclohexanol C CH3 4-tert-Butylcyclohexanone (90%) Other methods include the ozonolysis of alkenes in which one of the unsaturated carbon atoms is disubstituted (Section 8-8) and Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (Section 16-3). O O O CH2 1. O3 CH3 + 2. Zn/H3O+ CH3 H 2C O 70% !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-3 oxidation of aldehydes and ketones O O + Benzene C AlCl3 CH3CCl CH3 Heat Acetyl chloride Acetophenone (95%) In addition to those methods already discussed, ketones can also be prepared from certain carboxylic acid derivatives, just as aldehydes can. Among the most useful reactions of this sort is that between an acid chloride and a lithium diorganocopper reagent, as we saw in Section 10-7. We’ll discuss this reaction in more detail in Section 21-4. O O (CH3)2Cu– Li+ C CH3CH2CH2CH2CH2 C Ether Cl CH3CH2CH2CH2CH2 Hexanoyl chloride CH3 2-Heptanone (81%) PROBLEM 19-4 How would you carry out the following reactions? More than one step may be required. (a) (b) (c) (d) 3-Hexyne n 3-Hexanone Benzene n m-Bromoacetophenone Bromobenzene n Acetophenone 1-Methylcyclohexene n 2-Methylcyclohexanone 19-3 Oxidation of Aldehydes and Ketones Aldehydes are easily oxidized to yield carboxylic acids, but ketones are generally inert toward oxidation. The difference is a consequence of structure: aldehydes have a ᎐ CHO proton that can be abstracted during oxidation, but ketones do not. Hydrogen here Not hydrogen here O [O ] C R H An aldehyde R O O C C OH A carboxylic acid R [O ] No reaction R′ A ketone Many oxidizing agents, including KMnO4 and hot HNO3, convert aldehydes into carboxylic acids, but CrO3 in aqueous acid is a more common !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 609 610 chapter 19 aldehydes and ketones: nucleophilic addition reactions choice. The oxidation occurs rapidly at room temperature and generally has good yields. O CH3CH2CH2CH2CH2CH O CrO3, H3O+ Acetone, 0 °C CH3CH2CH2CH2CH2COH Hexanal Hexanoic acid (85%) Aldehyde oxidations occur through intermediate 1,1-diols, or hydrates, which are formed by a reversible nucleophilic addition of water to the carbonyl group. Even though it’s formed to only a small extent at equilibrium, the hydrate reacts like any typical primary or secondary alcohol and is oxidized to a carbonyl compound (Section 17-7). OH O H2O C R C R H O OH CrO3 H O+ C R 3 H An aldehyde A hydrate OH A carboxylic acid Ketones are inert to most oxidizing agents but undergo a slow cleavage reaction of the C ᎐ C bond next to the carbonyl group when treated with hot alkaline KMnO4. The reaction is not often used and is mentioned here only for completeness. O 1. KMnO4, H2O, NaOH 2. H O+ 3 Cyclohexanone CO2H CO2H Hexanedioic acid (79%) 19-4 Nucleophilic Addition Reactions of Aldehydes and Ketones As we saw in the Preview of Carbonyl Chemistry, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction. As shown in FIGURE 19-1 , a nucleophile, :Nuⴚ, approaches the carbonyl group from an angle of about 105° opposite the carbonyl oxygen and forms a bond to the electrophilic C⫽O carbon atom. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the C⫽O bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced. Protonation of the alkoxide by addition of acid then gives an alcohol. !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-4 nucleophilic addition reactions of aldehydes and ketones MECHANISM FIGURE 19-1 A nucleophilic addition reaction to an aldehyde or ketone. The nucleophile approaches the carbonyl group from an angle of approximately 75° to the plane of the sp2 orbitals, the carbonyl carbon rehybridizes from sp2 to sp3, and an alkoxide ion is formed. Protonation by addition of acid then gives an alcohol. O 1 An electron pair from the nucleophile adds to the electrophilic carbon of the carbonyl group, pushing an electron pair from the C=O bond onto oxygen and giving an alkoxide ion intermediate. The carbonyl carbon rehybridizes from sp2 to sp3. Aldehyde or ketone C Nu – R R′ 75° 1 O Nu C – R R′ Alkoxide ion 2 Protonation of the alkoxide anion intermediate gives the neutral alcohol addition product. 2 H3O+ OH Nu C R R′ + H2O Alcohol The nucleophile can be either negatively charged (:Nuⴚ) or neutral (:Nu). If it’s neutral, however, it usually carries a hydrogen atom that can subsequently be eliminated, :Nu ᎐ H. For example: HO – (hydroxide ion) H – (hydride ion) Some negatively charged nucleophiles R3C – (a carbanion) RO – (an alkoxide ion) N C – (cyanide ion) HOH (water) Some neutral nucleophiles ROH (an alcohol) H3N (ammonia) RNH2 (an amine) !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 611 612 chapter 19 aldehydes and ketones: nucleophilic addition reactions Nucleophilic additions to aldehydes and ketones have two general variations, as shown in FIGURE 19-2. In one variation, the tetrahedral intermediate is protonated by water or acid to give an alcohol as the final product. In the second variation, the carbonyl oxygen atom is protonated and then eliminated as HOⴚ or H2O to give a product with a C⫽Nu double bond. FIGURE 19-2 Two general reaction pathways following addition of a nucleophile to an aldehyde or ketone. The top pathway leads to an alcohol product; the bottom pathway leads to a product with a C⫽Nu double bond. O Nu– R – OH H C A O C R Nu R′ Nu R′ C R R′ H Aldehyde or ketone Nu O H R C R′ – OH + Nu H R C Nu –H2O Nu R′ H H C R R′ Aldehydes are generally more reactive than ketones in nucleophilic addition reactions for both steric and electronic reasons. Sterically, the presence of only one large substituent bonded to the C⫽O carbon in an aldehyde versus two large substituents in a ketone means that a nucleophile is able to approach an aldehyde more readily. Thus, the transition state leading to the tetrahedral intermediate is less crowded and lower in energy for an aldehyde than for a ketone (FIGURE 19-3). (a) (b) Nu Nu 75° FIGURE 19-3 Steric hindrance in nucleophilic addition reactions. (a) Nucleophilic addition to an aldehyde is sterically less hindered because only one relatively large substituent is attached to the carbonyl-group carbon. (b) A ketone, however, has two large substituents and is more hindered. The approach of the nucleophile is along the C⫽O bond at an angle of about 75° to the plane of the carbon sp2 orbitals. Electronically, aldehydes are more reactive than ketones because of the greater polarization of aldehyde carbonyl groups. To see this polarity difference, recall the stability order of carbocations (Section 7-9). A primary carbocation is higher in energy and thus more reactive than a secondary carbocation since it has only one alkyl group inductively stabilizing the positive charge rather than two. In the same way, an aldehyde has only one alkyl group inductively stabilizing the partial positive charge on the carbonyl carbon rather !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-4 nucleophilic addition reactions of aldehydes and ketones than two, and is a bit more electrophilic, and, therefore, more reactive than a ketone. H R H C+ H 1° carbocation (less stable, more reactive) O R C C+ R R′ 2° carbocation (more stable, less reactive) ␦– O ␦+ H C R Aldehyde (less stabilization of ␦+, more reactive) ␦– ␦+ R′ Ketone (more stabilization of ␦+, less reactive) One further comparison: aromatic aldehydes, such as benzaldehyde, are less reactive in nucleophilic addition reactions than aliphatic aldehydes because the electron-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic. Comparing electrostatic potential maps of formaldehyde and benzaldehyde, for example, shows that the carbonyl carbon atom is less positive (less blue) in the aromatic aldehyde. O O C C H + Formaldehyde – O C H – O + H C – H + Benzaldehyde PROBLEM 19-5 Treatment of an aldehyde or ketone with cyanide ion (ⴚ:C⬅N), followed by protonation of the tetrahedral alkoxide ion intermediate, gives a cyanohydrin. Show the structure of the cyanohydrin obtained from cyclohexanone. PROBLEM 19-6 p-Nitrobenzaldehyde is more reactive toward nucleophilic additions than p-methoxybenzaldehyde. Explain. !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 613 614 chapter 19 aldehydes and ketones: nucleophilic addition reactions 19-5 Nucleophilic Addition of H2O: Hydration Aldehydes and ketones react with water to yield 1,1-diols, or geminal (gem) diols. The hydration reaction is reversible, and a gem diol can eliminate water to regenerate an aldehyde or ketone. OH O H3C C + CH3 H2O Acetone (99.9%) H3C H3C C OH Acetone hydrate (0.1%) The position of the equilibrium between a gem diol and an aldehyde or ketone depends on the structure of the carbonyl compound. Equilibrium generally favors the carbonyl compound for steric reasons, but the gem diol is favored for a few simple aldehydes. For example, an aqueous solution of formaldehyde consists of 99.9% gem diol and 0.1% aldehyde at equilibrium, whereas an aqueous solution of acetone consists of only about 0.1% gem diol and 99.9% ketone. OH O H C + H Formaldehyde (0.1%) H2O C H OH H Formaldehyde hydrate (99.9%) The nucleophilic addition of water to an aldehyde or ketone is slow under neutral conditions but is catalyzed by both base and acid. Under basic conditions (FIGURE 19-4a), the nucleophile is negatively charged (OHⴚ) and uses a pair of its electrons to form a bond to the electrophilic carbon atom of the C⫽O group. At the same time, the C⫽O carbon atom rehybridizes from sp2 to sp3 and two electrons from the C⫽O bond are pushed onto the oxygen atom, giving an alkoxide ion. Protonation of the alkoxide ion by water then yields a neutral addition product plus regenerated OHⴚ. Under acidic conditions (FIGURE 19-4b), the carbonyl oxygen atom is first protonated by H3Oⴙ to make the carbonyl group more strongly electrophilic. A neutral nucleophile, H2O, then uses a pair of electrons to bond to the carbon atom of the C⫽O group, and two electrons from the C⫽O bond move onto the oxygen atom. The positive charge on oxygen is thereby neutralized, while the nucleophile gains a positive charge. Finally, deprotonation by water gives the neutral addition product and regenerates the H3Oⴙ catalyst. Note the key difference between the base-catalyzed and acid-catalyzed reactions. The base-catalyzed reaction takes place rapidly because water is converted into hydroxide ion, a much better nucleophile. The acid-catalyzed reaction takes place rapidly because the carbonyl compound is converted by protonation into a much better electrophile. !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% 19-5 nucleophilic addition of h2o: hydration 615 FIGURE 19-4 MECHANISM The mechanism for a nucleophilic addition reaction of aldehydes and ketones under both basic and acidic conditions. (a) Under basic conditions, a negatively charged nucleophile adds to the carbonyl group to give an alkoxide ion intermediate, which is subsequently protonated. (b) Under acidic conditions, protonation of the carbonyl group occurs first, followed by addition of a neutral nucleophile and subsequent deprotonation. (a) Basic conditions (b) Acidic conditions ␦– ␦– O ␦+ C 1 The negatively charged nucleophile OH– adds to the electrophilic carbon and pushes electrons from the C=O bond onto oxygen, giving an alkoxide ion. ␦+ C – 1 The carbonyl oxygen is protonated by acid H3O+, making the carbon more strongly electrophilic. OH 1 H 1 + H O O – C H O H OH Alkoxide ion intermediate 2 The alkoxide ion is protonated by water to give the neutral hydrate as the addition product and regenerating OH–. + H O H O 2 2 The neutral nucleophile OH2 adds to the electrophilic carbon, pushing the electrons from the C=O onto oxygen. The oxygen becomes neutral, and the nucleophile gains the + charge. O H2O H H 2 OH2 OH C OH C + C + H O H OH Hydrate (gem diol) + –OH 3 Water deprotonates the intermediate, giving the neutral hydrate addition product and regenerating the acid catalyst H3O+. 3 OH C OH + Hydrate (gem diol) The hydration reaction just described is typical of what happens when an aldehyde or ketone is treated with a nucleophile of the type H ᎐ Y, where the Y atom is electronegative and can stabilize a negative charge (oxygen, halogen, or sulfur, for instance). In such reactions, the nucleophilic addition is reversible, with the equilibrium generally favoring the carbonyl reactant !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#% H3O+ 616 chapter 19 aldehydes and ketones: nucleophilic addition reactions rather than the tetrahedral addition product. In other words, treatment of an aldehyde or ketone with CH3OH, H2O, HCl, HBr, or H2SO4 does not normally lead to a stable alcohol addition product. OH O + C R H Y R R′ C Y R′ Favored when Y = –OCH3, –OH, –Br, –Cl, –OSO3H PROBLEM 19-7 When dissolved in water, trichloroacetaldehyde exists primarily as its hydrate, called chloral hydrate. Show the structure of chloral hydrate. PROBLEM 19-8 The oxygen in water is primarily (99.8%) 16O, but water enriched with the heavy isotope 18O is also available. When an aldehyde or ketone is dissolved in 18O-enriched water, the isotopic label becomes incorporated into the carbonyl group. Explain. R2C P O ⫹ H2O ^ R2C P O ⫹ H2O where O ⫽ 18O 19-6 Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C ⬅ N. Studies carried out in the early 1900s by Arthur Lapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CNⴚ. Addition of CNⴚ takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CNⴚ. – O O C H Benzaldehyde – C CN C N H Tetrahedral intermediate HO CN C HCN H + – C N Mandelonitrile (88%) Cyanohydrin formation is somewhat unusual because it is one of the few examples of the addition of a protic acid (H ᎐ Y) to a carbonyl group. As noted in the previous section, protic acids such as H2O, HBr, HCl, and H2SO4 don’t !*#% # %$$#'* % !$ #&! % ( # !#%&% %# #%$$ %#!#%* % % *$&!!#$$# % # !%#$ % # #'($ %% *$&!!#$$ % % $ % %# *%% '# # )!# # #$#'$%#%% # '% % %% *% $&$"& %#%$#$%#% $#"&#%
