Aldehydes and Ketones, Lecture notes of Chemistry

Download Aldehydes and Ketones and more Lecture notes Chemistry in PDF only on Docsity! 416 Ethanol from alcoholic beverages is first metabolized to acetaldehyde before being broken down further in the body. The reactivity of the carbonyl group of acetaldehyde allows it to bind to proteins in the body, the products of which lead to tissue damage and organ disease. Inset: A model of acetaldehyde. (Novastock/ Stock Connection/Glow Images) 12 Aldehydes and Ketones 12.1 What Are Aldehydes and Ketones? 12.2 How Are Aldehydes and Ketones Named? 12.3 What Are the Physical Properties of Aldehydes and Ketones? 12.4 What Is the Most Common Reaction Theme of Aldehydes and Ketones? 12.5 What Are Grignard Reagents, and How Do They React with Aldehydes and Ketones? 12.6 What Are Hemiacetals and Acetals? 12.7 How Do Aldehydes and Ketones React with Ammonia and Amines? 12.8 What Is Keto–Enol Tautomerism? 12.9 How Are Aldehydes and Ketones Oxidized? 12.10 How Are Aldehydes and Ketones Reduced? H O W T O 12.1 How to Predict the Product of a Grignard Reaction 12.2 How to Determine the Reactants Used to Synthesize a Hemiacetal or Acetal C H E M I C A L C O N N E C T I O N S 12A A Green Synthesis of Adipic Acid K E Y Q U E S T I O N S IN THIS AND several of the following chapters, we study the physical and chemical properties of compounds containing the carbonyl group, C O. Because this group is the functional group of aldehydes, ketones, and carboxylic acids and their derivatives, it is one of the most important functional groups in organic chemistry and in the chemistry of biological systems. The chemical properties of the carbonyl group are straightforward, and an understanding of its characteristic reaction themes leads very quickly to an understanding of a wide variety of organic reactions. 4171 2 . 2 How Are Aldehydes and Ketones Named? 12.1 What Are Aldehydes and Ketones? The functional group of an aldehyde is a carbonyl group bonded to a hydrogen atom (Section 1.7C). In methanal (common name: formaldehyde), the simplest aldehyde, the carbonyl group is bonded to two hydrogen atoms. In other aldehydes, it is bonded to one hydrogen atom and one carbon atom. The functional group of a ketone is a carbonyl group bonded to two carbon atoms (Section 1.7C). Following are Lewis structures for the alde- hydes methanal and ethanal, and a Lewis structure for propanone, the simplest ketone. Under each in parentheses is its common name: Methanal (Formaldehyde) ‘ CH3CCH3 O ‘ CH3CH O ‘ HCH O Ethanal (Acetaldehyde) Propanone (Acetone) A carbon–oxygen double bond consists of one sigma bond formed by the overlap of sp 2 hybrid orbitals of carbon and oxygen and one pi bond formed by the overlap of parallel 2p orbitals. The two nonbonding pairs of electrons on oxygen lie in the two remaining sp2 hybrid orbitals (Figure 1.20). 12.2 How Are Aldehydes and Ketones Named? A. IUPAC Nomenclature The IUPAC system of nomenclature for aldehydes and ketones follows the familiar pattern of selecting the longest chain of carbon atoms that contains the functional group as the parent alkane. We show the aldehyde group by changing the suffix -e of the parent alkane to -al, as in methanal (Section 3.5). Because the carbonyl group of an aldehyde can appear only at the end of a parent chain and numbering must start with that group as carbon-1, its position is unambiguous; there is no need to use a number to locate it. For unsaturated aldehydes, the presence of a carbon–carbon double bond is indicated by the infix -en-. As with other molecules with both an infix and a suffix, the location of the suffix determines the numbering pattern. H O 3 24 1 3-Methylbutanal H O 3 2 1 2-Propenal (Acrolein) H O 57 3 2468 1 (2E )-3,7-Dimethyl-2,6-octadienal (Geranial) For cyclic molecules in which CHO is bonded directly to the ring, we name the molecule by adding the suffix -carbaldehyde to the name of the ring. We number the atom of the ring bearing the aldehyde group as number 1: CHO Cyclopentanecarbaldehyde HO CHO14 trans -4-Hydroxycyclohexanecarbaldehyde Among the aldehydes for which the IUPAC system retains common names are benzalde- hyde and cinnamaldehyde. Note here the alternative ways of writing the phenyl group. Aldehyde A compound containing a carbonyl group bonded to hydrogen (a CHO group). Ketone A compound containing a carbonyl group bonded to two carbons. C H A P T E R 1 2 Aldehydes and Ketones420 T A B L E 1 2 . 1 Increasing Order of Precedence of Six Functional Groups Functional Group Suffix Prefix Example of When the Functional Group Has Lower Priority Carboxyl -oic acid — Aldehyde -al oxo- 3-Oxopropanoic acid H O COOH 3 2 1 Ketone -one oxo- 3-Oxobutanal H OO 3 24 1 Alcohol -ol hydroxy- 4-Hydroxy-2-butanone O HO 3 24 1 Amino -amine amino- 2-Amino-1-propanol NH2 OH3 2 1 Sulfhydryl -thiol mercapto- 2-Mercaptoethanol HS OH 2 1 E X A M P L E 12.3 Write the IUPAC name for each compound: O H O (a) H2N COOH(b) O HO H(c) S T R AT E G Y First determine the root name from the longest chain of car- bons that contains the carbonyl group. Use the priority rules in Table 12.1 to determine the suffix and prefix. For benzene ring compounds, remember to use any common names that have been retained in the IUPAC system. S O L U T I O N (a) An aldehyde has higher precedence than a ketone, so we indicate the presence of the carbonyl group of the ketone by the prefix oxo-. The IUPAC name of this com- pound is 5-oxohexanal. (b) The carboxyl group has higher precedence, so we indicate the presence of the amino group by the prefix amino-. The IUPAC name is 4-aminobenzoic acid. Alternatively, the compound may be named p-aminobenzoic acid, abbrevi- ated PABA. PABA, a growth factor of microorganisms, is required for the synthesis of folic acid. (c) The C O group has higher precedence than the OH group, so we indicate the OH group by the prefix hydroxy-. The IUPAC name of this compound is (R)-6- hydroxy-2-heptanone. See problems 12.17, 12.18 P R O B L E M 12.3 Write IUPAC names for these compounds, each of which is important in intermediary metabolism: )a( (c) Lactic acid H2N OH O )b( O ‘ CH3CCOOH OH ƒ CH3CHCOOH Pyruvic acid g-Aminobutyric acid The name shown is the one by which the compound is more commonly known in the biological sciences. 4211 2 . 3 What Are the Physical Properties of Aldehydes and Ketones? C. Common Names The common name for an aldehyde is derived from the common name of the corre- sponding carboxylic acid by dropping the word acid and changing the suffix -ic or -oic to -aldehyde. Because we have not yet studied common names for carboxylic acids, we are not in a position to discuss common names for aldehydes. We can, however, illustrate how they are derived by reference to two common names of carboxylic acids with which you are familiar. The name formaldehyde is derived from formic acid, and the name acetal- dehyde from acetic acid: Formaldehyde CH3 O ‘ C OH CH3 O ‘ C H H O ‘ C OH H O ‘ C H Formic acid Acetaldehyde Acetic acid Common names for ketones are derived by naming each alkyl or aryl group bonded to the carbonyl group as a separate word, followed by the word ketone. Groups are generally listed in order of increasing atomic weight. (Methyl ethyl ketone, abbreviated MEK, is a common solvent for varnishes and lacquers): O Methyl ethyl ketone (MEK) O Diethyl ketone O Dicyclohexyl ketone the lower-molecular-weight group bonded to the carbonyl comes first in the common name for a ketone 12.3 What Are the Physical Properties of Aldehydes and Ketones? Oxygen is more electronegative than carbon (3.5 compared with 2.5; Table 1.4); therefore, a carbon–oxygen double bond is polar, with oxygen bearing a partial negative charge and carbon bearing a partial positive charge: Polarity of a carbonyl group C O d+ d– A carbonyl group as a resonance hybrid the more important contributing structure C O C O+ The electron density model shows that the partial positive charge on an acetone molecule is distributed both on the carbonyl carbon and on the two attached methyl groups as well. – In addition, the resonance structure on the right emphasizes that, in reactions of a carbonyl group, carbon acts as an electrophile and a Lewis acid. The carbonyl oxygen, by contrast, acts as a nucleophile and a Lewis base. Because of the polarity of the carbonyl group, aldehydes and ketones are polar com- pounds and interact in the liquid state by dipole–dipole interactions. As a result, aldehydes and ketones have higher boiling points than those of nonpolar compounds with compa- rable molecular weight. C H A P T E R 1 2 Aldehydes and Ketones422 12.4 What Is the Most Common Reaction Theme of Aldehydes and Ketones? The partially positive charge on the carbonyl carbon (Section 12.3) is the cause of the most common reaction theme of the carbonyl group, the addition of a nucleophile to form a tetrahedral carbonyl addition intermediate. In the following general reaction, the nucleo- philic reagent is written as Nu: to emphasize the presence of its unshared pair of electrons: R C R ONu +– – ¡ O Nu C R R Tetrahedral carbonyl addition intermediate d+ d- this is the common mechanism pattern: Reaction of a nucleophile and an electrophile to form a covalent bond T A B L E 1 2 . 2 Boiling Points of Six Compounds of Comparable Molecular Weight Name Structural Formula Molecular Weight Boiling Point (°C) Diethyl ether CH3CH2OCH2CH3 74 34 Pentane CH3CH2CH2CH2CH3 72 36 Butanal CH3CH2CH2CHO 72 76 2-Butanone CH3CH2COCH3 72 80 1-Butanol CH3CH2CH2CH2OH 74 117 Propanoic acid CH3CH2COOH 72 141 T A B L E 1 2 . 3 Physical Properties of Selected Aldehydes and Ketones IUPAC Name Common Name Structural Formula Boiling Point (°C) Solubility (g 100 g water) Methanal Formaldehyde HCHO 21 infinite Ethanal Acetaldehyde CH3CHO 20 infinite Propanal Propionaldehyde CH3CH2CHO 49 16 Butanal Butyraldehyde CH3CH2CH2CHO 76 7 Hexanal Caproaldehyde CH3(CH2)4CHO 129 slight Propanone Acetone CH3COCH3 56 infinite 2-Butanone Methyl ethyl ketone CH3COCH2CH3 80 26 3-Pentanone Diethyl ketone CH3CH2COCH2CH3 101 5 although the “solubilities” of methanal and ethanal are reported as “infinite,” it should be noted that 99% of initial methanal and 57% of initial ethanal are converted to compounds known as hydrates upon addition of water C O H H H2O HO H HO H C Hydrate of methanal Table 12.2 lists the boiling points of six compounds of comparable molecular weight. Pentane and diethyl ether have the lowest boiling points of these six compounds. Both bu- tanal and 2-butanone are polar compounds, and because of the intermolecular attraction between carbonyl groups, their boiling points are higher than those of pentane and diethyl ether. Alcohols (Section 8.1C) and carboxylic acids (Section 13.3) are polar compounds, and their molecules associate by hydrogen bonding; their boiling points are higher than those of butanal and 2-butanone, compounds whose molecules cannot associate in that manner. Because the carbonyl groups of aldehydes and ketones interact with water molecules by hydrogen bonding, low-molecular-weight aldehydes and ketones are more soluble in water than are nonpolar compounds of comparable molecular weight. Table 12.3 lists the boiling points and solubilities in water of several low-molecular-weight aldehydes and ketones. 4251 2 . 5 What Are Grignard Reagents, and How Do They React with Aldehydes and Ketones? C. Addition of Grignard Reagents to Aldehydes and Ketones The special value of Grignard reagents is that they provide excellent ways to form new carbon–carbon bonds. In their reactions, Grignard reagents behave as carbanions. A carbanion is a good nucleophile and adds to the carbonyl group of an aldehyde or a ketone to form a tetrahedral carbonyl addition intermediate. The driving force for these reactions is the attraction of the partial negative charge on the carbon of the organome- tallic compound to the partial positive charge of the carbonyl carbon. In the examples that follow, the magnesium–oxygen bond, which forms after the tetrahedral carbonyl addition intermediate is formed, is written O [MgBr] to emphasize its ionic charac- ter. The alkoxide ions formed in Grignard reactions are strong bases (Section 8.2C) and form alcohols when treated with an aqueous acid such as HCl or aqueous NH4Cl during workup. Addition to Formaldehyde Gives a 1° Alcohol Treatment of a Grignard reagent with formaldehyde, followed by hydrolysis in aqueous acid, gives a primary alcohol: CH3CH2 ¬ MgBr ++ - H ¬ C ¬ H CH3CH2 ¬ CH2 ether O ‘ O ƒ ƒ [MgBr]+ H¬O ¬ ¬ H H CH3CH2 ¬ CH2 OH Mg2+ Formaldehyde A magnasium alkoxide 1-Propanol (a 1 alcohol) recall that hydronium is the active agent in HCl/H2O + Addition to an Aldehyde (Except Formaldehyde) Gives a 2° Alcohol Treatment of a Grignard reagent with any aldehyde other than formaldehyde, followed by hydrolysis in aqueous acid, gives a secondary alcohol: H ¬ O ¬ H H ¬ MgBr+CH3¬ C ¬ H O ‘ CHCH3 [MgBr]±O ƒ CHCH3+Mg2± OH ƒ 1-Cyclohexylethanol (a 2 alcohol) A magnesium alkoxide Acetaldehyde – ether + Addition to a Ketone Gives a 3° Alcohol Treatment of a Grignard reagent with a ketone, followed by hydrolysis in aqueous acid, gives a tertiary alcohol: H ¬ O ¬ H H +¬ MgBr+CH3¬ C ¬ CH3 2-Phenyl-2-propanol (a 3 alcohol) A magnesium alkoxide Acetone CCH3+Mg2± OH ƒ CCH3 [MgBr]±– O ƒ ƒ CH3 ƒ CH3 O ‘ ether C H A P T E R 1 2 Aldehydes and Ketones426 H O W T O 1 2. 1 (a) Using the fact that a Grignard reaction involves the formation of a carbon– carbon bond, identify the nucleophilic carbon (i.e., the carbon bonded to the magnesium atom). MgBr + R ¬ C ¬ R ether O ‘ the carbon bonded to the Mg is the nucleophile and will be part of the new C¬C bond (b) Check to see that there are no O H, N H, or S H groups in the reagents or solvent. These will undergo proton transfer with the Grignard reagent and prevent the reaction with the carbonyl from occurring. MgBr + Et OH ¬OH, ¬NH, or ¬SH groups will prevent a Grignard reaction from proceeding as planned O ‘ C NH2R + (c) Create a new bond between the carbon identified in (a) and the carbonyl carbon. The nucleophilic carbon from the Grignard reagent will no longer be bonded to MgBr. Instead, the MgBr should be shown to be ionically coordinated with the negatively charged oxygen that was part of the car- bonyl. If there is a workup step, the magnesium salt is converted to an alcohol. MgBr + R ¬ C ¬ R O ‘ draw a new bond between the nucleophilic carbon and the carbonyl carbon 3 24 1 3 24 1¬ C OH R R ¬ workup step ¡HCl H2O3 24 1 ¬ C – O R R ¬ [MgBr]+ the new bond ether Predict the Product of a Grignard Reaction E X A M P L E 12.5 2-Phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. S T R AT E G Y The Grignard reagent used to synthesize any alcohol can be determined by identifying a C C bond connecting the alcohol carbon to the continuing carbon chain. Remove this bond, convert the C OH to C O, and convert the other piece to a Grignard reagent. 4271 2 . 6 What Are Hemiacetals and Acetals? S O L U T I O N Curved arrows in each solution show the formation of the new carbon–carbon bond and the alkoxide ion, and labels on the final product show which set of reagents forms each bond: [MgBr]± ¡HCl H2O C ¬ CH2CH3 OH ƒ ƒ CH3 ƒ CH3 MgBr+CCH2CH3(a) O ‘ ƒ CH3 C+CH2CH3(b) O ‘ MgBr ƒ ƒ CH3 C ¬ CH2CH3 O ƒ ƒ CH3 CCH2CH3+MgBr(c) O ‘ (a) (b) (c) P R O B L E M 12.5 Show how these three compounds can be synthesized from the same Grignard reagent: (a) OH (b) OH (c) HO See problems 12.21, 12.22 12.6 What Are Hemiacetals and Acetals? A. Formation of Acetals The addition of a molecule of alcohol to the carbonyl group of an aldehyde or a ketone forms a hemiacetal (a half-acetal). This reaction is catalyzed by both acid and base: Oxygen adds to the carbonyl carbon and hydrogen adds to the carbonyl oxygen: H+ or OH- A hemiacetal CH3 O ƒ C ƒ C H OCH 2CH3 H3 CH3 O ‘ C CH3 + H ƒ O CH2CH3 The functional group of a hemiacetal is a carbon bonded to an OH group and an OR or OAr group: Hemiacetals from a ketone R ¬ OH ƒ C ƒ R – ¬ OR ¿ R ¬ O ƒ C ƒ H H ¬ OR ¿ from an aldehyde ⁄⁄ Hemiacetal A molecule containing an OH and an OR or OAr group bonded to the same carbon. C H A P T E R 1 2 Aldehydes and Ketones430 Mechanism Acid-Catalyzed Formation of an Acetal STEP 1: Add a proton. Proton transfer from the acid, H A, to the hemiacetal OH group gives an oxonium ion: An oxonium ion H R O C H O CH3 H A H R O C H H O CH3 A STEP 2: Break a bond to form a stable ion or molecule. Loss of water from the oxonium ion gives a resonance-stabilized cation: A resonance-stabilized cation O CH3 H2O C H RO CH3 C H R H R O C H H O CH3 STEP 3: Reaction of an electrophile and a nucleophile to form a new covalent bond. Reaction of the resonance-stabilized cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal: A protonated acetal H R O C H CH3 O CH3 3 H O CH3 C H O CHR (an electrophile)(a nucleophile) STEP 4: Take a proton away. Proton transfer from the protonated acetal to A gives the acetal and generates a new molecule of H A, the acid catalyst: A protonated acetal An acetal HA R O C H CH3 O CH3 A H R O C H CH3 O CH3 Formation of acetals is often carried out using the alcohol as a solvent and dissolving either dry HCl (hydrogen chloride) or arenesulfonic acid (Section 9.6B), ArSO3H, in the alcohol. Because the alcohol is both a reactant and the solvent, it is present in large molar excess, which drives the reaction to the right and favors acetal formation. Alternatively, the reaction may be driven to the right by the removal of water as it is formed: 4311 2 . 6 What Are Hemiacetals and Acetals? A diethyl acetal R ¬ O ƒ C ƒ R CH2CH3 ¬ OCH 2CH3 + H2O H+ R ¬ O ‘ C ¬ R + 2CH3CH2OH An excess of alcohol pushes the equilibrium toward acetal formation Removal of water favors acetal formation H O W T O 1 2. 2 (a) Identify the carbon atom that is bonded to two oxygen atoms. This carbon atom is the carbonyl carbon that was converted to the carbon of the acetal or hemiacetal group. O O the carbon that is bonded to two oxygen atoms is the former carbonyl carbon O O (b) Remove both C O bonds and add back a hydrogen to each oxygen to obtain the alcohol reagent(s) used. Then convert the carbon identified in (a) to a carbonyl group. convert the former acetal carbon to a carbonyl group O O remove the C¬ O bond OH OH O H add an H to each oxygen remove the C¬ O bond convert the former acetal carbon to a carbonyl groupremove the C¬O bond remove the C¬O bond O O OH OH O add an H to each oxygen Determine the Reactants Used to Synthesize a Hemiacetal or Acetal E X A M P L E 12.6 Show the reaction of the carbonyl group of each ketone with one molecule of alcohol to form a hemiacetal and then with a second molecule of alcohol to form an acetal (note that, in part (b), ethylene glycol is a diol, and one molecule of it provides both OH groups): O +2 CH3CH2OH(a) H± Δ Ethylene glycol HO OH O +(b) H± Δ C H A P T E R 1 2 Aldehydes and Ketones432 Like ethers, acetals are unreactive to bases, to reducing agents such as H2 M, to Grignard reagents, and to oxidizing agents (except, of course, those which involve aque- ous acid). Because of their lack of reactivity toward these reagents, acetals are often used to protect the carbonyl groups of aldehydes and ketones while reactions are carried out on functional groups in other parts of the molecule. B. Acetals as Carbonyl-Protecting Groups The use of acetals as carbonyl-protecting groups is illustrated by the synthesis of 5-hydroxy- 5-phenylpentanal from benzaldehyde and 4-bromobutanal: H O Br H O OH H O + ¡?? Benzaldehyde 4-Bromobutanal 5-Hydroxy-5-phenylpentanal One obvious way to form a new carbon–carbon bond between these two molecules is to treat benzaldehyde with the Grignard reagent formed from 4-bromobutanal. This Grignard reagent, however, would react immediately with the carbonyl group of another molecule of 4-bromobutanal, causing it to self-destruct during preparation (Section 12.5B). A way to avoid this problem is to protect the carbonyl group of 4-bromobutanal by converting it to an acetal. Cyclic acetals are often used because they are particularly easy to prepare. Br H O H2O+ +Δ H± HO OH Ethylene glycol Br O O A cyclic acetal the carbonyl is protected by converting it to an acetal S T R AT E G Y In forming the hemiacetal, one molecule of the alcohol is added to the carbonyl carbon, resulting in an OR group and an OH group bonded to the carbon that was previously part of the carbonyl. In forming an acetal, two molecules of the alcohol are added to the carbonyl carbon, resulting in two OR groups bonded to the carbon that was previously part of the carbonyl. S O L U T I O N Here are structural formulas of the hemiacetal and then the acetal: HO OC2H5 C2H5O OC2H5 (a) ¡ O O O OH OH (b) ¡ +H2O +H2O See problems 12.23–12.26 P R O B L E M 12.6 The hydrolysis of an acetal forms an aldehyde or a ketone and two molecules of alcohol. Following are structural formulas for three acetals: CH3O OCH3 OCH3 (a) O O (b) O OCH3 (c) Draw the structural formulas for the products of the hydrolysis of each in aqueous acid (i.e., provide the carbonyl compound and alcohol(s) from which each acetal was derived). 4351 2 . 7 How Do Aldehydes and Ketones React with Ammonia and Amines? A tetrahedral carbonyl addition intermediate O C H2N R O C H N H R O C H N H R STEP 2: Add a proton. Protonation of the OH group to form OH2 , a good leaving group. O H+ C N R C N R H H ± ± H O O HH HH STEP 3: Take a proton away and break a bond to form a stable molecule. Loss of water and proton transfer to solvent gives the imine. Notice that the loss of water and the proton transfer have the characteristics of an E2 reaction. Three things happen simultaneously in this dehydration: a base (in this case a water molecule) removes a proton from N, the carbon–nitrogen double bond forms, and the leaving group (in this case, a water molecule) departs: the flow of electrons here is similar to that in an E2 reaction Δ ± H ƒ √ √ C “ N ¬ R+H2O +H ¬ O ¬ H An imineH O ƒ H √ ¬ C ¬ N ¬ R ± O ƒ ƒ H ƒ H √ H √ To give but one example of the importance of imines in biological systems, the active form of vitamin A aldehyde (retinal) is bound to the protein opsin in the human retina in the form of an imine called rhodopsin or visual purple (see Chemical Connections 4B). The amino acid lysine (see Table 18.1) provides the primary amino group for this reaction: C H O C H N ¬ Opsin Rhodopsin (Visual purple) 11-cis -Retinal +H2N ¬ Opsin ¡ E X A M P L E 12.8 Predict the products formed in each reaction: O NH2 + H± –H2O(a) (1 equiv.)(b) +H2OCH2N HCl C H A P T E R 1 2 Aldehydes and Ketones436 P R O B L E M 12.8 Predict the products formed in each reaction. Note: Acid-catalyzed hydrolysis of an imine gives an amine and an aldehyde or a ketone. When one equivalent of acid is used, the amine is converted to its ammonium salt. (a) CH “ NCH2CH3+H2O ¡HCl O H2N OCH3+ H± –H2O(b) S T R AT E G Y In an imine-forming reaction, the C O group is converted to a C N group and the nitrogen of the former 1° amine loses both of its hydrogens. In the reverse process, the C N group is converted back to a C O group and two hydrogens are added back to the nitrogen to form a 1° amine. S O L U T I O N Reaction (a) is an imine-forming reaction, while reaction (b) is the acid-catalyzed hydrolysis of an imine to an ammonium salt and a ketone: N(a) (b) OCH2NH3Cl- + + See problems 12.29–12.32 B. Reductive Amination of Aldehydes and Ketones One of the chief values of imines is that the carbon–nitrogen double bond can be reduced to a carbon–nitrogen single bond by hydrogen in the presence of a nickel or other tran- sition metal catalyst. By this two-step reaction, called reductive amination, a primary amine is converted to a secondary amine by way of an imine, as illustrated by the conversion of cyclohexylamine to dicyclohexylamine: O H2N N N H + H± –H2O H2/Ni Cyclohexanone Cyclohexyl- amine (a 1 amine) Dicyclohexylamine (a 2 amine) (An imine) H2 adds across the C “ N bond Conversion of an aldehyde or a ketone to an amine is generally carried out in one labora- tory operation by mixing together the carbonyl-containing compound, the amine or am- monia, hydrogen, and the transition metal catalyst. The imine intermediate is not isolated. Reductive amination The formation of an imine from an aldehyde or a ketone, followed by the reduction of the imine to an amine. E X A M P L E 12.9 Show how to synthesize each amine by a reductive amination: (a) (b) NH2 N H 4371 2 . 8 What Is Keto–Enol Tautomerism? P R O B L E M 12.9 Show how to prepare each amine by the reductive amination of an appropriate aldehyde or ketone: (a) (b)N H NH2 See problems 12.29–12.32 S T R AT E G Y Identify the C N bond formed in the reductive amination. The carbon of the C N bond is part of the carbonyl starting material, and the nitrogen is part of the 1° amine. S O L U T I O N Treat the appropriate compound, in each case a ketone, with ammonia or an amine in the presence of H2 Ni: (a) (b) O O H2N+NH3 + 12.8 What Is Keto–Enol Tautomerism? A. Keto and Enol Forms A carbon atom adjacent to a carbonyl group is called an A carbon, and any hydrogen atoms bonded to it are called A hydrogens: -hydrogens -carbonsa CH3 ¬ O ‘ C ¬ CH2 ¬ CH3 a ⁄ ⁄ ⁄ ⁄ An aldehyde or ketone that has at least one a hydrogen is in equilibrium with a constitu- tional isomer called an enol. The name enol is derived from the IUPAC designation of it as both an alkene (-en-) and an alcohol (-ol): Acetone Acetone (keto form) (enol form) O OH ‘ ƒ CH3 ¬ C ¬ CH3 Δ CH3 ¬ C “ CH2 Keto and enol forms are examples of tautomers—constitutional isomers that are in equilibrium with each other and that differ in the location of a hydrogen atom and a double A-Carbon A carbon atom adjacent to a carbonyl group. A-Hydrogen A hydrogen on an a carbon. Enol A molecule containing an OH group bonded to a carbon of a carbon–carbon double bond. Tautomers Constitutional isomers that differ in the location of hydrogen and a double bond relative to O, N, or S. C H A P T E R 1 2 Aldehydes and Ketones440 C. A-Halogenation Aldehydes and ketones with at least one a hydrogen react with bromine and chlorine at the a carbon to give an a haloaldehyde or a haloketone. Acetophenone, for example, reacts with bromine in acetic acid to give an a bromoketone: CH3COOH O O Br Acetophenone a -Bromoacetophenone +Br2 +HBr a Halogenation is catalyzed by both acid and base. For acid-catalyzed halogenation, the HBr or HCl generated by the reaction catalyzes further reaction. Mechanism Acid-Catalyzed A-Halogenation of a Ketone STEP 1: Keto–enol tautomerism (Section 12.8A). A small amount of enol is formed under acid-catalyzed conditions: Keto form O Enol form OH STEP 2: Reaction of an electrophile with a nucleophile to form a new covalent bond. Nucleophilic attack of the enol on the halogen molecule: Br O H H + Br ¬ Br + Br¡ ± ‘ O STEP 3: Take a proton away. Proton transfer generates HBr and gives the a-haloketone: ‘Br H + +¡ ± Br - Br HBr O ‘ O The value of a halogenation is that it converts an a carbon into a center that now has a good leaving group bonded to it and that is therefore susceptible to attack by a variety of good nucleophiles. In the following illustration, diethylamine (a nucleophile) reacts with the a bromoketone to give an a diethylaminoketone: 441 C ha rle s D . W in te rs A silver mirror has been deposited in the inside of this flask by the reaction of an aldehyde with Tollens’ reagent. 1 2 . 9 How Are Aldehydes and Ketones Oxidized? O Br +H ¬ N +HBr An a - diethylaminoketoneAn a -bromoketone ¡ O N In practice, this type of nucleophilic substitution is generally carried out in the presence of a weak base such as potassium carbonate to neutralize the HX as it is formed. 12.9 How Are Aldehydes and Ketones Oxidized? A. Oxidation of Aldehydes to Carboxylic Acids Aldehydes are oxidized to carboxylic acids by a variety of common oxidizing agents, in- cluding chromic acid and molecular oxygen. In fact, aldehydes are one of the most easily oxidized of all functional groups. Oxidation by chromic acid (Section 8.2F) is illustrated by the conversion of hexanal to hexanoic acid: Hexanal Hexanoic acid H O OH O H2CrO4 Aldehydes are also oxidized to carboxylic acids by silver ion. One common labora- tory procedure uses Tollens’ reagent, prepared by dissolving AgNO3 in water, adding sodium hydroxide to precipitate silver ion as Ag2O, and then adding aqueous ammonia to redissolve silver ion as the silver–ammonia complex ion: Ag NO3 2NH3 NH3, H2O Ag(NH3)2 NO3 When Tollens’ reagent is added to an aldehyde, the aldehyde is oxidized to a carboxylic anion, and Ag is reduced to metallic silver. If this reaction is carried out properly, silver precipitates as a smooth, mirrorlike deposit—hence the name silver-mirror test: Precipitates as silver mirror R O ‘ CO- + 2Ag + 4NH3 NH3, H2O R O ‘ C H + 2Ag(NH3)2 + Nowadays, Ag is rarely used for the oxidation of aldehydes, because of the cost of silver and because other, more convenient methods exist for this oxidation. The reaction, how- ever, is still used for silvering mirrors. In the process, formaldehyde or glucose is used as the aldehyde to reduce Ag . Aldehydes are also oxidized to carboxylic acids by molecular oxygen and by hydrogen peroxide. O ‘ O ‘ CH+O2 ¡ Benzaldehyde Benzoic acid 2 COH2 Molecular oxygen is the least expensive and most readily available of all oxidizing agents, and, on an industrial scale, air oxidation of organic molecules, including aldehydes, is common. Air oxidation of aldehydes can also be a problem: Aldehydes that are liquid at room temperature are so sensitive to oxidation by molecular oxygen that they must be protected from contact with air during storage. Often, this is done by sealing the aldehyde in a container under an atmosphere of nitrogen. C H A P T E R 1 2 Aldehydes and Ketones442 E X A M P L E 12.11 Draw a structural formula for the product formed by treating each compound with Tollens’ reagent, followed by acidifica- tion with aqueous HCl: (a) Pentanal (b) Cyclopentanecarbaldehyde S T R AT E G Y Aldehydes are oxidized to carboxylic acids by Tollens’ reagent. S O L U T I O N The aldehyde group in each compound is oxidized to a car- boxyl group: (a) (b) OH O Pentanoic acid COOH Cyclopentanecarboxylic acid See problems 12.36, 12.37 P R O B L E M 12.11 Complete these oxidations: (a) 3 Oxobutanal O2 (b) 3 Phenylpropanal Tollens’ reagent Chemical Connections 12A A GREEN SYNTHESIS OF ADIPIC ACID Cyclohexene Hexanedioic acid (Adipic acid) +4H2O2 +4H2O Na2WO4 [CH3(C8H17)3N]HSO4 COOH COOH In this process, cyclohexene is mixed with aqueous 30% hydrogen peroxide, and sodium tungstate and methyl- trioctylammonium hydrogen sulfate are added to the resulting two-phase system. (Cyclohexene is insoluble in water.) Under these conditions, cyclohexene is oxidized to adipic acid in approximately 90% yield. While this route to adipic acid is environmen- tally friendly, it is not yet competitive with the nitric acid oxidation route because of the high cost of 30% hydrogen peroxide. What will make it competitive is either a considerable reduction in the cost of hydrogen peroxide or the institution of more stringent limitations on the emission of nitrous oxide into the atmosphere (or a combination of these). Question Using chemistry presented in this and previous chapters, propose a synthesis for adipic acid from cyclohexene. The current industrial production of adipic acid relies on the oxidation of a mixture of cyclohexanol and cyclohexanone by nitric acid: Cyclohexanol Hexanedioic acid (Adipic acid) Nitrous oxide OH 4 4 + 6HNO3 ¡ + 3N2O + 3H2O COOH COOH A by-product of this oxidation is nitrous oxide, a gas considered to play a role in global warming and the depletion of the ozone layer in the atmosphere, as well as contributing to acid rain and acid smog. Given the fact that worldwide production of adipic acid is approximately 2.2 billion metric tons per year, the production of nitrous oxide is enormous. In spite of technological advances that allow for the recovery and recycling of nitrous oxide, it is estimated that approximately 400,000 metric tons escapes recovery and is released into the atmosphere each year. Recently, Ryoji Noyori (2001 Nobel Prize in Chem- istry) and coworkers at Nagoya University in Japan developed a “green” route to adipic acid, one that in- volves the oxidation of cyclohexene by 30% hydrogen peroxide catalyzed by sodium tungstate, Na2WO4 : 445Summary of Key Questions Selective reduction of a carbon–carbon double bond using a protecting group: H2 Rh HCl, H2O RCH CHCR O OH HO H H H O O R C C C R O O RCH2CH2 C R O RCH2CH2CR E X A M P L E 12.12 S O L U T I O N The carbonyl group of the aldehyde in (a) is reduced to a primary alcohol, and that of the ketone in (b) is reduced to a secondary alcohol: (a) OH (b) CH3O OH Complete these reductions: (a) H O 1) LiAIH4 2) H2O (b) 1) NaBH4 2) H2O CH3O O S T R AT E G Y Consider all the functional groups that can react with each reducing reagent. Alkenes, ketones, aldehydes, and imines are just some examples of functional groups that can be reduced. See problems 12.36, 12.37 P R O B L E M 12.12 What aldehyde or ketone gives each alcohol upon reduction by NaBH4 ? (a) (b) (c)OH CH2CH2OH OH OH SUMMARY OF KEY QUEST IONS An aldehyde contains a carbonyl group bonded to a hydrogen atom and a carbon atom. A ketone contains a carbonyl group bonded to two carbons. 12.1 What Are Aldehydes and Ketones? An aldehyde is named by changing -e of the parent alkane to -al. A CHO group bonded to a ring is indicated by the suffix -carbaldehyde. A ketone is named by changing -e of the parent alkane to -one and using a number to locate the carbonyl group. In naming compounds that contain more than one func- tional group, the IUPAC system has established an order of precedence of functional groups. If the carbonyl group of an aldehyde or a ketone is lower in precedence than other functional groups in the molecule, it is indicated by the infix -oxo-. 12.2 How Are Aldehydes and Ketones Named? C H A P T E R 1 2 Aldehydes and Ketones446 Aldehydes and ketones are polar compounds and interact in the pure state by dipole–dipole interactions. Aldehydes and ketones have higher boiling points and are more soluble in water than are nonpolar compounds of comparable molecular weight. 12.3 What Are the Physical Properties of Aldehydes and Ketones? The common reaction theme of the carbonyl group of aldehydes and ketones is the addition of a nucleophile to form a tetrahedral carbonyl addition intermediate. 12.4 What Is the Most Common Reaction Theme of Aldehdyes and Ketones? Grignard reagents are organomagnesium compounds with the generic formula RMgX. The carbon–metal bond in Grignard reagents has a high degree of partial ionic character. Grignard reagents behave as carbanions and are both strong bases and good nucleophiles. They react with aldehydes and ketones by adding to the carbonyl carbon. 12.5 What Are Grignard Reagents, and How Do They React with Aldehydes and Ketones? The addition of a molecule of alcohol to the carbonyl group of an aldehyde or a ketone forms a hemiacetal. Hemiacetals can react further with alcohols to form ace- tals plus a molecule of water. Because of their lack of reactivity toward nucleophilic and basic reagents, acetals are often used to protect the carbonyl groups of aldehydes and ketones while reactions are car- ried out on functional groups in other parts of the molecule. 12.6 What Are Hemiacetals and Acetals? Ammonia, 1° aliphatic amines (RNH2), and 1° aromatic amines (ArNH2) react with the carbonyl group of alde- hydes and ketones in the presence of an acid catalyst to give imines, compounds that contain a carbon–nitrogen double bond. 12.7 How Do Aldehydes and Ketones React with Ammonia and Amines? A carbon atom adjacent to a carbonyl group is called an A-carbon, and any hydrogen atoms bonded to it are called A-hydrogens. An aldehyde or a ketone, which is said to be in its keto form, that has at least one a-hydrogen is in equilibrium with a constitutional isomer called an enol. This type of isomerism is called tautomerism. Tautomerism, catalyzed by trace amounts of acid or base, is the cause of racemization of chiral aldehydes and ketones when a stereocenter exists at an a-carbon. The enol form allows aldehydes and ketones to be haloge- nated at the a-position. 12.8 What Is Keto–Enol Tautomerism? Aldehydes are oxidized to carboxylic acids by a variety of common oxidizing agents, including chromic acid, the Tollens’ reagent, and molecular oxygen. Ketones are much more resistant to oxidation than are aldehydes. However, they undergo oxidative cleavage, via their enol form, by potassium dichromate and potas- sium permanganate at higher temperatures and by higher concentrations of HNO3. 12.9 How Are Aldehydes and Ketones Oxidized? Aldehydes are reduced to primary alcohols and ketones to secondary alcohols by catalytic hydrogenation or through the use of the metal hydrides NaBH4 or LiAlH4. 12.10 How Are Aldehydes and Ketones Reduced? 447Key Reactions 1. In a compound that contains both an aldehyde and a C C double bond, each functional group can be reduced exclusive of the other. (12.10) 2. Nucleophiles react with aldehydes and ketones to form tetrahedral carbonyl addition intermediates. (12.4) 3. The carboxyl group (COOH) has a higher priority in naming than all other functional groups. (12.2) 4. A stereocenter at the -carbon of an aldehyde or a ketone will undergo racemization over time in the pres- ence of an acid or a base. (12.8) 5. Acetone is the lowest-molecular-weight ketone. (12.3) 6. Aldehydes can be oxidized to ketones and carboxylic acids. (12.9) 7. Ketones are less water soluble than alcohols with com- parable molecular weight. (12.3) 8. A Grignard reagent cannot be formed in the presence of an NH, OH, or SH group. (12.5) 9. Ketones have higher boiling points than alkanes with comparable molecular weight. (12.3) 10. An aldehyde has a higher priority in naming than a ketone. (12.2) 11. A Grignard reagent is a good electrophile. (12.5) 12. Any reaction that oxidizes an aldehyde to a carboxylic acid will also oxidize a ketone to a carboxylic acid. (12.9) 13. Aldehydes are more water soluble than ethers with comparable molecular weight. (12.3) 14. Aldehydes react with Grignard reagents (followed by acid workup) to form 1° alcohols. (12.5) 15. An imine can be reduced to an amine through catalytic hydrogenation. (12.7) 16. Sodium borohydride, NaBH4, is more reactive and less selective than lithium aluminum hydride, LiAlH4. (12.10) 17. An acetal can only result from the base-catalyzed addi- tion of an alcohol to a hemiacetal. (12.6) 18. A Grignard reagent is a strong base. (12.5) 19. Acetal formation is reversible. (12.6) 20. An imine is the result of the reaction of a 2° amine with an aldehyde or a ketone. (12.7) 21. Ketones react with Grignard reagents (followed by acid workup) to form 2° alcohols. (12.5) 22. Aldehydes and ketones can undergo tautomerism. (12.8) 23. Acetaldehyde is the lowest-molecular-weight aldehyde. (12.3) 24. A ketone that possesses an a-hydrogen can undergo a-halogenation. (12.8) 25. A carbonyl group is polarized such that the oxygen atom is partially positive and the carbon atom is par- tially negative. (12.3) 26. Acetals are stable to bases, nucleophiles, and reducing agents. (12.6) 27. A “carbaldehyde” is an aldehyde in which the carbonyl group is adjacent to a C C double bond. (12.1) 28. A hemiacetal can result from the acid-catalyzed or base- catalyzed addition of an alcohol to an aldehyde or a ketone. (12.6) QUICK QUIZ Answer true or false to the following questions to assess your general knowledge of the concepts in this chapter. If you have difficulty with any of them, you should review the appropriate section in the chapter (shown in parenthe- ses) before attempting the more challenging end-of-chapter problems. Detailed explanations for many of these answers can be found in the accompanying Solutions Manual. Answers: (1) T (2) T (3) T (4) T (5) T (6) T (7) T (8) T (9) T (10) T (11) F (12) F (13) T (14) F (15) T (16) F (17) F (18) T (19) T (20) F (21) F (22) T (23) F (24) T (25) F (26) T (27) F (28) T 1. Reaction with Grignard Reagents (Section 12.5C) Treatment of formaldehyde with a Grignard reagent, followed by hydrolysis in aqueous acid, gives a primary alcohol. Similar treatment of any other aldehyde gives a secondary alcohol: C6H5 O ƒ C H HCH 3 1) C6H5MgBr 2) HCl, H2O CH3 O ‘ C H Treatment of a ketone with a Grignard reagent gives a tertiary alcohol: C6H5 O ƒ C H (CH3)2 1) C6H5MgBr 2) HCl, H2O CH3 O ‘ C CH3 2. Addition of Alcohols to Form Hemiacetals (Section 12.6) Hemiacetals are only minor components of an equilib- rium mixture of aldehyde or ketone and alcohol, except where the OH and C O groups are parts of the same molecule and a five- or six-membered ring can form: OCH3 OHCH3CHCH2CH2CH O ‘ ƒ OH 4-Hydroxypentanal A cyclic hemiacetal 3. Addition of Alcohols to Form Acetals (Section 12.6) The formation of acetals is catalyzed by acid: O CH2 CH2 O O+HOCH2CH2OH +H2O Δ H± KEY REACT IONS C H A P T E R 1 2 Aldehydes and Ketones450 12.23 5-Hydroxyhexanal forms a six-membered cyclic hemiacetal that predominates at equilibrium in aque- ous solution: (See Example 12.6) OH H O 5-Hydroxyhexanal Δ a cyclic hemiacetal H± (a) Draw a structural formula for this cyclic hemi- acetal. (b) How many stereoisomers are possible for 5-hydroxyhexanal? (c) How many stereoisomers are possible for the cyclic hemiacetal? (d) Draw alternative chair conformations for each stereoisomer. (e) For each stereoisomer, which alternative chair conformation is the more stable? 12.24 Draw structural formulas for the hemiacetal and then the acetal formed from each pair of reactants in the presence of an acid catalyst: (See Example 12.6) (a) +CH3CH2OH O (b) +CH3CCH3 O ‘ OH OH (c) CHO+CH3OH 12.25 Draw structural formulas for the products of hydroly- sis of each acetal in aqueous acid: (See Example 12.6) (b)(a) CH3O OCH3 O H OCH3 Section 12.6 Addition of Oxygen Nucleophiles (c) O O CHO (d) O O 12.26 The following compound is a component of the fra- grance of jasmine: From what carbonyl-containing compound and alcohol is the compound derived? (See Example 12.6) O O 12.27 Propose a mechanism for the formation of the cyclic acetal by treating acetone with ethylene glycol in the presence of an acid catalyst. Make sure that your mechanism is consistent with the fact that the oxy- gen atom of the water molecule is derived from the carbonyl oxygen of acetone. + H± +H2O¡O HO OH O O Acetone Ethylene glycol 12.28 Propose a mechanism for the formation of a cyclic acetal from 4-hydroxypentanal and one equivalent of methanol: If the carbonyl oxygen of 4-hydroxy- pentanal is enriched with oxygen-18, does your mechanism predict that the oxygen label appears in the cyclic acetal or in the water? Explain. H± ¡ OH H 18O O OCH3 +CH3OH +H2O 12.29 Show how this secondary amine can be prepared by two successive reductive aminations: (See Examples 12.8, 12.9) Section 12.7 Addition of Nitrogen Nucleophiles ¡(1) ¡(2) Ph O Ph NH2 Ph N Ph H 451Problems 12.30 Show how to convert cyclohexanone to each of the following amines: (See Examples 12.8, 12.9) NH(c) NHCH(CH3)2(b) NH2(a) *12.31 Following are structural formulas for amphetamine and methamphetamine: (See Examples 12.8, 12.9) (b)(a) NH2 N H CH3 Amphetamine Methamphetamine The major central nervous system effects of amphet- amine and amphetaminelike drugs are locomotor stimulation, euphoria and excitement, stereotyped behavior, and anorexia. Show how each drug can be synthesized by the reductive amination of an appro- priate aldehyde or ketone. *12.32 Rimantadine is effective in preventing infections caused by the influenza A virus and in treating estab- lished illness. The drug is thought to exert its antiviral effect by blocking a late stage in the assembly of the virus. Following is the final step in the synthesis of rimantadine: (See Examples 12.8, 12.9) O NH2 Rimantadine (an antiviral agent) ¡ (a) Describe experimental conditions to bring about this final step. (b) Is rimantadine chiral? *12.33 Methenamine, a product of the reaction of formal- dehyde and ammonia, is a prodrug—a compound that is inactive by itself, but is converted to an active drug in the body by a biochemical transformation. The strategy behind the use of methenamine as a prodrug is that nearly all bacteria are sensitive to formaldehyde at concentrations of 20 mg/mL or higher. Formaldehyde cannot be used directly in medicine, however, because an effective concentra- tion in plasma cannot be achieved with safe doses. Methenamine is stable at pH 7.4 (the pH of blood plasma), but undergoes acid-catalyzed hydrolysis to formaldehyde and ammonium ion under the acidic conditions of the kidneys and the urinary tract: N N N+H2O ¡ CH2O+NH4 ±H± N Methenamine Thus, methenamine can be used as a site-specific drug to treat urinary infections. (a) Balance the equation for the hydrolysis of methenamine to formaldehyde and ammonium ion. (b) Does the pH of an aqueous solution of methen- amine increase, remain the same, or decrease as a result of the hydrolysis of the compound? Explain. (c) Explain the meaning of the following state- ment: The functional group in methenamine is the nitrogen analog of an acetal. (d) Account for the observation that methenamine is stable in blood plasma, but undergoes hydrolysis in the urinary tract. 12.34 The following molecule belongs to a class of com- pounds called enediols: Each carbon of the double bond carries an OH group: An enediol a-hydroxyaldehyde Δ HC ¬ OH ‘ C ¬ OH ƒ CH3 Δ a-hydroxyketone Draw structural formulas for the a hydroxyketone and the a hydroxyaldehyde with which this enediol is in equilibrium. (See Example 12.10) Section 12.8 Keto–Enol Tautomerism 12.35 In dilute aqueous acid, (R)-glyceraldehyde is converted into an equilibrium mixture of (R,S)-glyceraldehyde and dihydroxyacetone: (R)- Glyceraldehyde C ƒ C ƒ C H2OH “ O H2OH + C ƒ C ƒ C HO HOH H2OH H2O, HCl C ƒ C ƒ HO HOH CH2OH Dihydroxyacetone(R,S)- Glyceraldehyde Propose a mechanism for this isomerization. C H A P T E R 1 2 Aldehydes and Ketones452 12.36 Draw a structural formula for the product formed by treating butanal with each of the following sets of reagents: (See Examples 12.11, 12.12) (a) LiAlH4 followed by H2O (b) NaBH4 in CH3OH H2O (c) H2 Pt Section 12.9 Oxidation/Reduction of Aldehydes and Ketones (d) Ag(NH3)2 in NH3 H2O and then HCl H2O (e) H2CrO4 (f) C6H5NH2 in the presence of H2 Ni 12.37 Draw a structural formula for the product of the reaction of p-bromoacetophenone with each set of reagents in Problem 12.36. (See Examples 12.11, 12.12) 12.38 Show the reagents and conditions that will bring about the conversion of cyclohexanol to cyclohexane- carbaldehyde: (See Example 12.7) CHO OH Cl ¡(1) ¡(2) MgCl OH ¡(3) ¡(4) 12.39 Starting with cyclohexanone, show how to prepare these compounds (in addition to the given start- ing material, use any other organic or inorganic reagents, as necessary): (See Example 12.7) (a) Cyclohexanol (b) Cyclohexene (c) Bromocyclohexane (d) 1-Methylcyclohexanol (e) 1-Methylcyclohexene (f) 1-Phenylcyclohexanol (g) 1-Phenylcyclohexene (h) Cyclohexene oxide (i) trans-1,2-Cyclohexanediol 12.40 Show how to bring about these conversions (in addition to the given starting material, use any other organic or inorganic reagents, as necessary): (See Example 12.7) (a) C6H5CH “ CHCH 3 ¡ C6H5 O ƒ C H HCH 2CH3¡ C6H5 O ‘ C CH2CH3 Synthesis (b) ¡ ¡O OH ¡Cl CH2OH (c) ¡O OH (d) ¡O N H *12.41 Many tumors of the breast are estrogen dependent. Drugs that interfere with estrogen binding have anti- tumor activity and may even help prevent the occur- rence of tumors. A widely used antiestrogen drug is tamoxifen: (See Example 12.7) O O N CH3 CH3 O N CH3 CH3 ¡? Tamoxifen (a) How many stereoisomers are possible for tamoxifen? (b) Specify the configuration of the stereoisomer shown here. (c) Show how tamoxifen can be synthesized from the given ketone using a Grignard reaction, fol- lowed by dehydration. 455Spectroscopy ¡(k) OH ¡ (l) Cl N H ¬ (m) ¡ O O O (n) ¡ NH2Br ¡(o) CH3¬C‚C¬H ‘ O ¡ (p) ¡ (q) Cl HO O ¡(r) OH H N SPECTROSCOPY 12.47 Compound A, C5H10O, is used as a flavoring agent for many foods that possess a chocolate or peach flavor. Its common name is isovaleraldehyde, and it 12.48 Following are 1H NMR and IR spectra of compound B, C6H12O2 : 10 9 8 7 6 5 4 3 2 1 0 (300 MHz,CDCl3) ppm Chemical Shift ( ) C6H12O2 Compound B 1H 2H 3H 6H 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 450 2.5 2.6 2.7 2.8 2.9 3 3.5 4 4.5 5 5.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 21 22 WAVENUMBERS (cm ) MICROMETERS 0 10 20 30 40 50 60 70 80 90 100 % T R A N S M I T T A N C E -1 C6H12O2 Compound B Propose a structural formula for compound B. gives 13C NMR peaks at 202.7, 52.7, 23.6, and 22.6. Provide a structural formula for isovaleraldehyde and give its IUPAC name. C H A P T E R 1 2 Aldehydes and Ketones456 12.49 Compound C, C9H18O, is used in the automotive industry to retard the flow of solvent and thus improve the application of paints and coatings. It yields 13C NMR peaks at 210.5, 52.4, 24.5, and 22.6. Provide a structure and an IUPAC name for compound C. 12.50 Reaction of a Grignard reagent with carbon dioxide, followed by treatment with aqueous HCl, gives a carboxylic acid. Propose a structural formula for the bracketed intermediate formed by the reaction of phenylmagnesium bromide with CO2 , and propose a mechanism for the formation of this intermediate: MgBr C OH O +CO2 intermediate (not isolated) HCl, H2O 12.51 Rank the following carbonyls in order of increasing reactivity to nucleophilic attack, and explain your reasoning. O O O N O 12.52 Provide the enol form of this ketone and predict the direction of equilibrium: keto–enol tautomerism O an enol LOOKING AHEAD 12.53 Draw the cyclic hemiacetal formed by reaction of the highlighted OH group with the aldehyde group: Glucose Ribose OH H HO HO H H H OHH O OH OH O H HOCH2 H H OH H OH (a) (b) 12.54 Propose a mechanism for the acid-catalyzed reaction of the following hemiacetal, with an amine acting as a nucleophile: H3O± H2N ¬ CH2CH3 O OH O NHCH2CH3 +H2O GROUP LEARNING ACT IV IT IES 12.55 Pheromones are important organic compounds in agriculture because they represent one means of baiting and trapping insects that may be harmful to crops. Olean, the sex pheromone for the olive fruit fly, Dacus oleae, can be synthesized from the hydroxyenol ether shown by treating it with a Brønsted acid (H–A). H–A O Olean OH O O As a group, answer the following questions related to this agriculturally important product: (a) Name the functional group in Olean. (b) Propose a mechanism for the reaction. Hint: The mechanism consists of the following patterns: (1) add a proton, (2) reaction of an electrophile and a nucleophile to form a new covalent bond, and (3) take a proton away. (c) Is Olean chiral? If so, how many stereoisomers are possible? Hint: Build a model of olean. Then build a second model in which the two central C O bonds are swapped. (d) Predict the product formed by acid-catalyzed hydrolysis of Olean.