Both (S)-citronellal and isopulegol are naturally

Predict the position of the following equilibrium. O2Na1 Acetophenone O C CH3 1 Na CH2 1 NH3 1NH2 2 C

Draw a structural formula for the keto form of each enol. (a) (b) (c) O OH OH OH OH

Complete the equations for these oxidations. (a) Hexanal 1 H2O2h (b) 3-Phenylpropanal 1 Tollens reagent h

What aldehyde or ketone gives these alcohols on reduction with NaBH4? OH OH (mixture of three stereoisomers) OH OH (a) (b) (c)

Complete the following reactions. O H (a) O (b) Zn/Hg, HCl heat N2H4, KOH diethylene glycol, heat Civetone (from the civet cat; used in perfumery) Citronellal (from citronella and lemon grass oils)

Name each compound, showing stereochemistry where relevant. (a) (b) (c) (d) (e) (f) O CHO OH H CH2OH CH3 C CHO O O O (g) (h) OHC CHO (i) O O Br O

Draw a structural formula for each compound. (a) 1-Chloro-2-propanone (b) 3-Hydroxybutanal (c) 4- Hydroxy-4-methyl-2-pentanone (d) 3-Methyl-3-phenylbutanal (e) 1,3-Cyclohexanedione (f) 3-Methyl-3- buten-2-one (g) 5-Oxohexanal (h) 2,2-Dimethylcyclohexanecarbaldehyde (i) 3-Oxobutanoic acid

The infrared spectrum of Compound A, C6H12O, shows a strong, sharp peak at 1724 cm1. From this information and its 1 H-NMR spectrum, deduce the structure of compound A. 634 Chapter 16 Aldehydes and Ketones 10 9 8 7 6 5 4 3 2 1 0 ppm Chemical Shift ( ) C6H12O Compound A 3H 3H 3H 1H 2H

Following are 1 H-NMR spectra for compounds B (C6H12O2) and C (C6H10O). On warming in dilute acid, compound B is converted to compound C. Deduce the structural formulas for compounds B and C. 10 9 8 7 6 5 4 3 2 1 0 ppm C6H12O2 Compound B 3H 6H 1H 2H Chemical Shift ( ) 10 9 8 7 6 5 4 3 2 1 0 ppm C6H10O Compound C 3H 1H 6H Chemical Shift ( )

Draw structural formulas for the product formed by treating each compound with propylmagnesium bromide followed by aqueous HCl. O (a) CH2O (b) (c) (d) O O

Suggest a synthesis for the following alcohols starting from an aldehyde or ketone and an appropriate Grignard reagent. Below each target molecule is the number of combinations of Grignard reagent and aldehyde or ketone that might be used. (a) (b) (c) OH 3 Combinations (racemic) 2 Combinations (racemic) 2 Combinations (racemic) OH OH OCH3

Show how to synthesize the following alcohol using 1-bromopropane, propanal, and ethylene oxide as the only sources of carbon atoms. O several steps Br CHO OH (racemic) 1 1

1-Phenyl-2-butanol is used in perfumery. Show how to synthesize this alcohol from bromobenzene, 1- butene, and any necessary inorganic reagents. several steps Bromobenzene 1-Phenyl-2-butanol (racemic) 1-Butene Br 1 OH

With organolithium and organomagnesium compounds, approach to the carbonyl carbon from the less hindered direction is generally preferred. Assuming this is the case, predict the structure of the major product formed by reaction of methylmagnesium bromide with 4-tert-butylcyclohexanone.

Draw structural formulas for (1) the alkyltriphenylphosphonium salt formed by treatment of each haloalkane with triphenylphosphine, (2) the phosphonium ylide formed by treatment of each phosphonium salt with butyllithium, and (3) the alkene formed by treatment of each phosphonium ylide with acetone. Cl O Ph Cl Br O Br Br Cl (a) (b) (c) (d) (e) (f)

Show how to bring about the following conversions using a Wittig reaction. O O OCH3 (a) (b) (c) O CH OCH3

The Wittig reaction can be used for the synthesis of conjugated dienes, as for example, 1-phenyl-1,3- pentadiene. 1-Phenyl-1,3-pentadiene CH"CHCH"CHCH3 Propose two sets of reagents that might be combined in a Wittig reaction to give this conjugated diene.

Wittig reactions with the following a-chloroethers can be used for the synthesis of aldehydes and ketones. CH3 ClCH2OCH3 (A) ClCHOCH3 (B) (a) Draw the structure of the triphenylphosphonium salt and Wittig reagent formed from each chloroether. (b) Draw the structural formula of the product formed by treating each Wittig reagent with cyclopentanone. Note that the functional group is an enol ether or, alternatively, a vinyl ether. (c) Draw the structural formula of the product formed on acid- catalyzed hydrolysis of each enol ether from part (b).

It is possible to generate sulfur ylides in a manner similar to that used to produce phosphonium ylides. For example, treating a sulfonium salt with a strong base gives the sulfur ylide. A sulfonium bromide salt A sulfur ylide 1S CH Br2 Ph Ph CH3 CH3 12 S C Ph Ph CH3 CH3 strong base Sulfur ylides react with ketones to give epoxides. Suggest a mechanism for this reaction. O O 12 1 S 1 C Ph Ph (Ph)2S CH3 CH3 CH3 CH3

Propose a structural formula for Compound D and for the product, C9H14O, formed in this reaction sequence. O 1 BuLi S Br2 D C9H14O C6H5 C6H5

5-Hydroxyhexanal forms a six-membered cyclic hemiacetal, which predominates at equilibrium in aqueous solution. (a) Draw a structural formula for this cyclic hemiacetal. (b) How many stereoisomers are possible for 5-hydroxyhexanal? (c) How many stereoisomers are possible for this cyclic hemiacetal? (d) Draw alternative chair conformations for each stereoisomer and label groups axial or equatorial. Also predict which of the alternative chair conformations for each stereoisomer is the more stable.

Draw structural formulas for the hemiacetal and then the acetal formed from each pair of reactants in the presence of an acid catalyst. (a) 1 EtOH (b) (c) OH OH O 1 "O O H 1 MeOH

Draw structural formulas for the products of hydrolysis of the following acetals in aqueous HCl. OMe OMe H MeO (a) (b) (c) CHO O O O

Propose a mechanism to account for the formation of a cyclic acetal from 4-hydroxypentanal and one equivalent of methanol. If the carbonyl oxygen of 4-hydroxypentanal is enriched with oxygen-18, do you predict that the oxygen label appears in the cyclic acetal or in the water? 4-Hydroxypentanal A cyclic acetal (racemic) OH H1 1 1 CH3OH H2O O O OCH3 H

Propose a mechanism for this acid-catalyzed hydrolysis. H1 1 H2O 1 CH3OH OCH3 O

In Section 11.5 we saw that ethers, such as diethyl ether and tetrahydrofuran, are quite resistant to the action of dilute acids and require hot concentrated HI or HBr for cleavage. However, acetals in which two ether groups are linked to the same carbon undergo hydrolysis readily, even in dilute aqueous acid. How do you account for this marked difference in chemical reactivity toward dilute aqueous acid between ethers and acetals?

Show how to bring about the following conversion. O H HO OH (racemic) O H

A primary or secondary alcohol can be protected by conversion to its tetrahydropyranyl ether. Why is formation of THP ethers by this reaction limited to primary and secondary alcohols?

Which of these molecules will cyclize to give the insect pheromone frontalin? O Frontalin (A) (B) (C) O O O OH O HO O O OH O

Draw a structural formula for the product of each acid-catalyzed reaction. (a) Phenylacetaldehyde 1 hydrazine h (b) Cyclopentanone 1 semicarbazide h (c) Acetophenone 1 2,4-dinitrophenylhydrazine h (d) Benzaldehyde 1 hydroxylamine h

Following are structural formulas for amphetamine and methamphetamine. Amphetamine (racemic) Methamphetamine (racemic) (a) NH2 (b) N H CH3 The major central nervous system effects of amphetamine and amphetamine-like drugs are locomotor stimulation, euphoria and excitement, stereotyped behavior, and anorexia. Show how each drug can be synthesized by reductive amination of an appropriate aldehyde or ketone and amine. For the structural formulas of several more anorexics, see Problems 23.62 and 23.63

Following is the fi nal step in the synthesis of the antiviral drug Rimantidine (Problem 7.19). O NH2 (a) Describe experimental conditions to bring about this conversion. (b) Is Rimantidine chiral? How many stereoisomers are possible for it?

The following molecule belongs to a class of compounds called enediols; each carbon of the double bond carries an !OH group. Draw structural formulas for the a-hydroxyketone and the a- hydroxyaldehyde with which this enediol is in equilibrium. An enediol a -Hydroxyaldehyde C9OH CH9OH CH3 a -Hydroxyketone

When cis-2-decalone is dissolved in ether containing a trace of HCl, an equilibrium is established with trans-2-decalone. The latter ketone predominates in the equilibrium mixture. 5498X_16_ch16_p581- 648.indd 638 12/13/10 4:43:05 PM.Problems 639 cis-2-Decalone H H O trans-2-Decalone O HCl H H Propose a mechanism for this isomerization and account for the fact that the trans isomer predominates at equilibrium

Draw a structural formula for the product formed by treating butanal with each reagent. (a) LiAlH4 followed by H2O (b) NaBH4 in CH3OH/H2O (c) H2/Pt (d) Ag(NH3)2 1 in NH3/H2O (e) H2CrO4, heat (f) HOCH2CH2OH, HCl (g) Zn(Hg)/HCl (h) N2H4, KOH at 250C (i) C6H5NH2 (j) C6H5NHNH2

Draw a structural formula for the product of the reaction of acetophenone with each reagent given in Problem 16.43

The following bicyclic ketone has two a-carbons and three a-hydrogens. When this molecule is treated with D2O in the presence of an acid catalyst, only two of the three a-hydrogens exchange with deuterium. The a-hydrogen at the bridgehead does not exchange. These two a-hydrogens exchange H H H O This a-hydrogen does not exchange How do you account for the fact that two a-hydrogens do exchange but the third does not? You will fi nd it helpful to build models of the enols by which exchange of a-hydrogens occurs.

Propose a mechanism for this reaction. O 1 Cl2 Cl O 1 HCl (racemic)

The base-promoted rearrangement of an a-haloketone to a carboxylic acid, known as the Favorskii rearrangement, is illustrated by the conversion of 2-chlorocyclohexanone to cyclopentanecarboxylic acid. NaOH THF NaOH THF HCl H2O O Cl O O A proposed intermediate CO2Na1 O COH It is proposed that NaOH fi rst converts the a-haloketone to the substituted cyclopropanone shown in brackets, and then to the sodium salt of cyclopentanecarboxylic acid. 5498X_16_ch16_p581-648.indd 639 12/13/10 4:43:05 PM . 640 Chapter 16 Aldehydes and Ketones (a) Propose a mechanism for base-promoted conversion of 2-chlorocyclohexanone to the proposed intermediate. (b) Propose a mechanism for base-promoted conversion of the proposed intermediate to sodium cyclopentanecarboxylate.

If the Favorskii rearrangement of 2-chlorocyclohexanone is carried out using sodium ethoxide in ethanol, the product is ethyl cyclopentanecarboxylate. O Cl O OEt EtOH EtO2Na1 Propose a mechanism for this reaction.

(R)-Pulegone, readily available from pennyroyal oil, is an important enantiopure building block for organic syntheses. Propose a mechanism for each step in this transformation of pulegone. Br2 CH3O2Na1 CH3OH (R)-(1)-Pulegone O O Br Br COCH3 O

(R)-Pulegone is converted to (R)-citronellic acid by addition of HCl followed by treatment with NaOH. HCl (R)-Pulegone (R)-Citronellic acid O Cl O 1. NaOH 2. HCl OH O Propose a mechanism for each step in this transformation, and account for the regioselectivity of HCl addition.

Starting with cyclohexanone, show how to prepare these compounds. In addition to the given starting material, use any other organic or inorganic reagents as necessary. (a) Cyclohexanol (b) Cyclohexene (c) cis-1,2-Cyclohexanediol (d) 1-Methylcyclohexanol (e) 1-Methylcyclohexene (f) 1- Phenylcyclohexanol (g) 1-Phenylcyclohexene (h) Cyclohexene oxide (i) trans-1,2-Cyclohexanediol

Show how to convert cyclopentanone to these compounds. In addition to cyclopentanone, use any other organic or inorganic reagents as necessary. (a) OH (b) Cl (c) (d) OH

Disparlure is a sex attractant of the gypsy moth (Porthetria dispar). It has been synthesized in the laboratory from the following Z alkene. (Z)-2-Methyl-7-octadecene Disparlure H H H O (a) Propose two sets of reagents that might be combined in a Wittig reaction to give the indicated Z alkene. (b) How might the Z alkene be converted to disparlure? (c) How many stereoisomers are possible for disparlure? How many stereoisomers are formed in hesequence you chose?

Propose structural formulas for compounds A, B, and C in the following conversion. Show also how to prepare compound C by a Wittig reaction. (A) C7H10O C7H12O C7H10 H2 Lindlar catalyst KHSO4 heat O 1.HC#CH, NaNH2 2.H2O (B) (C)

Following is a retrosynthetic scheme for the synthesis of cis -3-penten-2-ol. O H Iodomethane Acetaldehyde (racemic) (racemic) Acetylene OH H H 1 1 CH3I O Write a synthesis for this compound from acetylene, acetaldehyde, and iodomethane.

Following is the structural formula of Surfynol, a defoaming surfactant. Describe the synthesis of this compound from acetylene and a ketone. How many stereoisomers are possible for Surfynol? Surfynol OH OH

Propose a mechanism for this isomerization. OH H1 O H

Propose a mechanism for this isomerization. O ArSO3H O

Starting with acetylene and 1-bromobutane as the only sources of carbon atoms, show how to synthesize the following. (a) meso-5,6-Decanediol (b) racemic 5,6-Decanediol (c) 5-Decanone (d) 5,6-Epoxydecane (e) 5-Decanol (f) Decane (g) 6-Methyl-5-decanol (h) 6-Methyl-5-decanone

Following are the fi nal steps in one industrial synthesis of vitamin A acetate. H2SO4 (1) Ph3P, HBr (4) Pseudoionone -Ionone (racemic) (racemic) Vitamin A acetate O PPh3 Br2 (2) O (5) (3) OH 1 OH b OCCH3 O (a) Propose a mechanism for the acid-catalyzed cyclization in Step 1. (b) Propose reagents to bring about Step 2. (c) Propose a mechanism for formation of the phosphonium salt in Step 4. (d) Propose reagents to bring about Step 3. (e) Show how Step 5 can be completed by a Wittig reaction.

Following is the structural formula of the principal sex pheromone of the Douglas fi r tussock moth (Orgyia pseudotsugata), a severe defoliant of the fi r trees of western North America. (Z)-6- Heneicosene-11-one ( ) O 9 11 7 6 1 Several syntheses of this compound have been reported, starting materials for three of which are given here, Br O OH ( ) 1 1 8 Br (c) Br ( ) 1 O 9 (b) (a) H 1 OH 9 ( ) O Show a series of steps by which each set of starting aterials could be converted into the target molecule.

Both (S)-citronellal and isopulegol are naturally occurring terpenes (Section 5.4). When (S)-citronellal is treated with tin(IV) chloride (a Lewis acid) followed by neutralization with aqueous ammonium chloride, isopulegol is obtained in 85% yield. Problems 643 1. SnCl4, CH2Cl2 2. NH4Cl O (S)- Citronellal (C10H18O) Isopulegol (C10H18O) OH H (a) Show that both compounds are terpenes. (b) Propose a mechanism for the conversion of (S)-citronellal to isopulegol. (c) How many stereocenters are present in isopulegol? How many stereoisomers are possible for a molecule with this number of stereocenters? (d) Isopulegol is formed as a single stereoisomer. Account for the fact that only a single stereoisomer is formed.

At some point during the synthesis of a target molecule, it may be necessary to protect an !OH group (that is, to prevent its reacting). In addition to the trimethylsilyl, tert-butyl-dimethylsilyl, and other trialkylsilyl groups described in Section 11.6, and the tetrahydropyranyl group described in Section 16.7D, the ethoxyethyl group may also be used as a protecting group. ArSO3H An ethoxyethyl group RCH2OH 1 RCH29O9 O O Ethyl vinyl ether (a) Propose a mechanism for the acid-catalyzed formation of the ethoxyethyl protecting group. (b) Suggest an experimental procedure whereby this protecting group can be removed to regenerate the unprotected alcohol

Both 1,2-diols and 1,3-diols can be protected by treatment with 2-methoxypropene according to the following reaction. OH O OH 2-Methoxypropene A protected 1,2-diol HBr OCH3 1 1 CH3OH O (a) Propose a mechanism for the formation of this protected diol. (b) Suggest an experimental procedure by which this protecting group can be removed to regenerate the unprotected diol.

All rearrangements we have discussed so far have involved generation of an electrondefi cient carbon followed by a 1,2-shift of an atom or group of atoms from an adjacent atom to the electron-defi cient carbon. Rearrangements by a 1,2-shift can also occur following the generation of an electron-defi cient oxygen. Propose a mechanism for the acid-catalyzed rearrangement of cumene hydroperoxide to phenol and acetone. H2SO4 Cumene hydroperoxide Phenol Acetone 9OOH 9OH 1 O"

In dilute aqueous base, (R)-glyceraldehyde is converted into an equilibrium mixture of (R,S)- glyceraldehyde and dihydroxyacetone. Propose a mechanism for this isomerization. NaOH CHOH CHO CH2OH (R)-Glyceraldehyde CHOH 1 CHO CH2OH (R,S)-Glyceraldehyde C"O CH2OH CH2OH Dihydroxyacetone

Treatment of b-d-glucose with methanol in the presence of an acid catalyst converts it into a mixture of two compounds called methyl glucosides (Section 25.3A). O H1 2H2O CH2OH H H OH HO H OH OH H H 4 1 1 CH3OH 3 2 5 6 O CH2OH H H OCH3 HO H OH -D-Glucose Methyl -D-glucoside OH H H 4 1 1 3 2 5 6 O CH2OH H OCH3 H HO H OH Methyl -D-glucoside OH H H 4 1 3 2 5 6 In these representations, the six-membered rings are drawn as planar hexagons. (a) Propose a mechanism for this conversion, and account for the fact that only the !OH on carbon 1 is transformed into an !OCH3 group. (b) Draw the more stable chair conformation for each product. (c) Which of the two products has the chair conformation of greater stability? Explain.

Treating a Grignard reagent with carbon dioxide followed by aqueous HCl gives a carboxylic acid. intermediate HCl,H2O (not isolated) O 1 CO2 [ ] MgBr C OH Propose a structural formula for the bracketed intermediate and a mechanism for its formation.

As we saw in Chapter 6, carbon-carbon double bonds are attacked by electrophiles but not by nucleophiles. An exception to this generalization is the reactivity of a,b-unsaturated aldehydes and ketones toward nucleophiles. Even though an isolated carbon-carbon double bond does not react with 2 amines such as dimethylamine, 3-buten-2-one reacts readily by regioselective addition. O Et2NH 1 CH2"CH9CH29CH3 Et2NH 1 CH2"CH9C9CH3 O Et2N9CH29CH29C9CH3 Diethylamine 3-Buten-2- one (Methyl vinyl ketone) no reaction Account for the addition of nucleophiles to the carbon-carbon double bond of an a,b-unsaturated aldehyde or ketone and the regioselectivity of the addition.

Ribose, a carbohydrate with the formula shown, forms a cyclic hemiacetal, which, in principle, could contain either a four-membered, a five-membered, or a sixmembered ring. When d-ribose is treated with methanol in the presence of an acid catalyst, two cyclic acetals, A and B, are formed, both with molecular formula C6H12O5. These are separated, and each is treated with sodium periodate (Section 10.8C) followed by dilute aqueous acid. Both A and B yield the same three products in the same ratios. 1. NaIO4 2. H3O1 OOH HO H 1 CH3OH A 1 B 1 1 CHOH CH3OH CHO CH2OH CHO CHO OH D-Ribose (C5H10O5) Isomeric cyclic acetals with molecular formula C6H12O5 OH From this information, deduce whether the cyclic hemiacetal formed by d-ribose is four membered, fi ve membered, or six membered.

The favorite nuclide used in positron emission tomography (PET scan) to follow glucose metabolism is fl uorine-18, which decays by positron emission to oxygen-18 and has a half-life of 110 minutes. Fluorine-18 is administered in the form of fl udeoxyglucose F-18; the product of this molecules decay is glucose. O HO H OH H HO H 18F OH H H 1 11 0 Fludeoxyglucose F-18 O HO H OH H HO H 18OH OH H H D-Glucose A positron Draw the alternative chair conformations for fl udeoxyglucose F- 18, and select the more stable of the two.

Use the roadmap you made for problem 15.19, and update it to contain the reactions in the Key Reactions section of this chapter. Because of their highly specifi c nature, do not use reactions 7, 12, 13, 14, and 26 on your roadmap.

Write the products of the following sequences of reactions. Refer to your roadmaps to see how the combined reactions allow you to navigate between the different functional groups. Note that you will need both your old Chapters 611 roadmap and your new Chapters 1516 roadmap for these. (a) 2. HCl, H2O 3. PCC 5. HCl, H2O 1. MgBr 4. MgBr O An epoxide (b) 1. O3 2. (CH3)2S 4. Excess H2, Pd 3. 2 Equivalents Ph3P CH2 1 2 An alkene (c) 1. 1 Equivalent of NaNH2 3. H2CrO4 5. HCl, H2O CH3 C C H O 2. H 4. MgBr An alkyne 646 Chapter 16 Aldehydes and Ketones (d) 1. H2O, catalytic H2SO4 2. H2CrO4 3. CH3NH2 4. NaBH3CN 5. Br An alkene (e) 1. NaOH, H2O 2. OsO4 3. NaHSO3 Br O 4. , catalytic H2SO4 A haloalkane (f) MgBr 6. 1. Cl2, hn 2. NaOH/H2O 3. BH3 4. H2O2 5. PCC An alkane 7. HCl, H2O

Using your roadmaps as a guide, show how to convert 1-butanol into racemic 4-octanol. You must use 1-butanol as the source of all carbon atoms in the target molecule. Show all reagents and all molecules synthesized along the way. 1-Butanol 4-Octanol (racemic) OH OH OH

Using your roadmaps as a guide, show how to convert ethylene into 2-methyl-1,3- dioxolane. You must use ethylene as the source of all carbon atoms in the target molecule. Show all reagents and all molecules synthesized along the way. Ethylene 2-Methyl-1,3-dioxolane O O

Using your roadmaps as a guide, show how to convert (2-bromoethyl)benzene into 2-chloro-1- phenylethanone. Show all reagents and all molecules synthesized along the way. Br (2-Bromoethyl) benzene 2-Chloro-1-phenylethanone Cl O

Using your roadmaps as a guide, show how to convert acetaldehyde into racemic 3-hydroxybutanal. You must use acetaldehyde as the source of all carbon atoms in the target molecule. Show all reagents and all molecules synthesized along the way. . Problems 647 Acetaldehyde 3- Hydroxybutanal (racemic) ? O O H H O H OH OH

Cetrizine is a nonsedating antihistamine. The first step in a synthesis of cetrizine involves the following Grignard reaction. (a) Draw the product of this Grignard reaction. 1. Ether 2. H2O, HCl Cl MgBr H O (b) Cetrizine is chiral. Like many chiral drugs, one enantiomer of cetrizine is more active than the other enantiomer or the racemic mixture. The levorotatory (S) enantiomer of cetrizine is more active, and syntheses have been developed that produce only the desired enantiomer in high yield. Label the chiral center of cetrizine with an asterisk. Cetrizine Cl CO2H O N N

Wittig reactions are widely used in drug synthesis. Write the predominant product of the following Wittig reaction used in the fi rst step of a synthesis of elitriptan, which is used to treat migraine headaches. O H O O O O Ph3P + O S O N N H3C H Elitriptan

Complete the following Wittig reactions. (a) O O O Ph3P + CH3 CH3 CH3 H3C H (b) O Ph3PCH2 + CH3 CH3 C

Complete the following Grignard reaction. The starting material is chiral and present as a single enantiomer. Using models, predict which product enantiomer predominates and include that stereochemical prediction in your answer. 1. 2. H2O, HCl O H H MgBr