964 Chapter 20 Carboxylic Acid Derivatives

7. The functional group of nitriles is somewhat similar to that of the alkynes. The two component 2 atoms are sp hybridized. The IR stretching vibration appears at about 2250 cm 1. The hydrogens next to the cyano group are deshielded in 1H NMR. The 13C NMR absorptions for nitrile carbons are at relatively low fi eld (d , 112 – 126 ppm), a consequence of the electronegativity of nitrogen. Problems 30. Name (IUPAC system) or draw the structure of each of the following compounds. COCl O OO BB CH3 (a) I (b) (c) CF3COCCF3

OO O O BB B B

(d) COCCH2CH3 (e) (CH3)3CCOCH2CH3 (f) CH3CNH

(g) Propyl butanoate (h) Butyl propanoate (i) 2-Chloroethyl benzoate (j) N,N-Dimethylbenzamide (k) 2-Methylhexanenitrile (l) Cyclopentanecarbonitrile 31. Name each of the following compounds according to IUPAC or Chemical Abstracts rules. Pay attention to the order of precedence of the functional groups. CONH O O 2 OH

(a) OCH3 (b) CO2CH2CH3 (c) NHCH3 (d) H Cl O CONH2 O 32. (a) Use resonance forms to explain in detail the relative order of acidity of carboxylic acid derivatives, as presented in Section 20-1. (b) Do the same, but use an argument based on inductive effects. O B 33. In each of the following pairs of compounds, decide which possesses the indicated property to

CH3CN(CH3)2 the greater degree. (a) Length of C – X bond: acetyl fl uoride or acetyl chloride. (b) Acidity of the i boldface H: CH2(COCH3)2 or CH2(COOCH3)2. (c) Reactivity toward addition of a nucleophile: (i) an amide or (ii) an imide (as shown in the margin). (d) High-energy infrared carbonyl stretching O O B B frequency: ethyl acetate or ethenyl acetate. CH CNCCH 34. 3 A 3 Give the product(s) of each of the following reactions.

CH3 O NH2 ii B (a) CH3CCl ϩ 2

O THF ϩ (b) ΂ ΂ CuLi Cl 2

O H3C O B A B Ϫ ° 2 CH2OH, N LiAl[OC(CH3)3]3H, THF, 78 C CH OCCl (c) H CCOOCCl (d) 2 3 A A CH2 OCCl H3C B O OCH3

H3C

LiAl[OC(CH3)3]3H, THF, Ϫ78°C (e) H C CCl 3 B O Problems Chapter 20 965

35. Formulate a mechanism for the reaction of acetyl chloride with 1-propanol shown on p. 932. 36. Give the product(s) of the reactions of acetic anhydride with each of the following reagents. Assume in all cases that the reagent is present in excess.

(a) (CH3)2CHOH (b) NH3

ϩ 1 (c) MgBr, THF; then H , H2O (d) LiAlH4, (CH3CH2)2O; then H , H2O

37. Give the product(s) of the reaction of butanedioic (succinic) anhydride with each of the reagents in Problem 36. 38. Formulate a mechanism for the reaction of butanedioic (succinic) anhydride with methanol shown on p. 935. 39. Give the products of reaction of methyl pentanoate with each of the following reagents under the conditions shown. 1 1 (a) NaOH, H2O, heat; then H , H2O (b) (CH3)2CHCH2CH2OH (excess), H 1 (c) (CH3CH2)2NH, heat (d) CH3MgI (excess), (CH3CH2)2O; then H , H2O 1 1 (e) LiAlH4, (CH3CH2)2O; then H , H2O (f) [(CH3)2CHCH2]2AlH, toluene, low temperature; then H , H2O 40. Give the products of reaction of g-valerolactone (5-methyloxa-2-cyclopentanone, Section 20-4) with each of the reagents in Problem 39. 41. Draw the structure of each of the following compounds: (a) b-butyrolactone; (b) b-valerolactone; (c) d-valerolactone; (d) b-propiolactam; (e) a-methyl-d-valerolactam; (f) N-methyl-g-butyrolactam. 42. Formulate a mechanism for the acid-catalyzed transesterifi cation of ethyl 2-methylpropanoate (ethyl isobutyrate) into the corresponding methyl ester. Your mechanism should clearly illustrate the catalytic role of the proton. 43. Formulate a mechanism for the reaction of methyl 9-octadecenoate with 1-dodecanamine shown on p. 939. 44. Reaction review. Suggest reagents to convert each of the following starting materials into the indicated product: (a) hexanoyl chloride into acetic hexanoic anhydride; (b) methyl hexanoate into N-methylhexanamide; (c) hexanoyl chloride into hexanal; (d) hexanenitrile into hexanoic acid; (e) hexanamide into hexanamine; (f) hexanamide into pentanamine; (g) ethyl hexanoate into

3-ethyl-3-octanol; (h) hexanenitrile into 1-phenyl-1-hexanone [C6H5CO(CH2)4CH3]. 45. Give the product of each of the following reactions.

COOCH3 % 1. KOH, H2O ϩ H C 2. H , H2O 3 % O (CH ) CHNH , CH OH, ⌬ (a) (b) 3 2 2 3

0 O ´ COOCH3 CH3CH2

O 1. (CH3CH2)2O, 20°C B ϩ MgBr 2. H , H2O ϩ (c) CH3COCH3 excess

1. LDA, THF, Ϫ78°C CH A 3 CH 2. CH3I, HMPA Ϫ ° 3 ϩ COOCH 1. (CH3CHCH2)2AlH, toluene, 60 C D 3. H , H O 3 ϩ 2 2. H , H O (d) CHG (e) 2 COOCH2CH3 46. For each of the naturally occurring lactones below, draw the structure of the compound that would result from hydrolysis using aqueous base.

Sedanenolide, major contributor to the fl avor of celery (a) O

O 966 Chapter 20 Carboxylic Acid Derivatives

H ´ Nepetalactone, major active component in catnip (b) (Caution: Do you notice anything unusual about one of the O ≥ functional groups after hydrolysis? H

O

O O g-Valerolactone, impotant in the fragrance industry (c) and a potential biofuel

(d) A novel “green” process converts levulinic acid (4-oxopentanoic acid, CH3COCH2CH2COOH), which is readily obtained from waste biomass, into g-valerolactone by treatment with gaseous

H2 in the presence of a special hydrogenation catalyst. Speculate on how this reaction may CH3 take place. O 47. N,N-Diethyl-3-methylbenzamide (N,N-diethyl-m-toluamide), marketed as DEET, is perhaps the most widely used insect repellent in the world and is especially effective in interrupting the transmission (CH3CH2)2N of diseases by mosquitoes and ticks. Propose one or more preparations of DEET (see structure, DEET margin) from the corresponding carboxylic acid and any other appropriate reagents. 48. Like many chiral pharmaceuticals, Ritalin, widely used to treat attention defi cit disorder, is synthe- sized and marketed as a racemic mixture. In 2003, a new and potentially practical synthetic route to

0 CO2CH3 the active enantiomer (see structure, margin) was described. The fi rst step is shown below, the reac- N ´ tion of dimethyl sulfate with a six-membered ring lactam. Propose a mechanism for this reaction. H C6H5 O Ritalin B CH OOOS OCH (Active stereoisomer) 3 B 3 O

N O N OCH3 H

O B 49. Formulate a mechanism for the formation of acetamide, CH3CNH2, from methyl acetate and ammonia. 50. Give the products of the reactions of pentanamide with the reagents given in Problem 39(a, e, f). Repeat for N,N-dimethylpentanamide. 51. Formulate a mechanism for the acid-catalyzed hydrolysis of 3-methylpentanamide shown on p. 948. (Hint: Use as a model the mechanism for general acid-catalyzed addition – elimination presented in Section 19-7.) 52. What reagents would be necessary to carry out the following transformations? (a) Cyclohexanecar- bonyl chloride y pentanoylcyclohexane; (b) 2-butenedioic (maleic) anhydride y (Z)-2-butene- 1,4-diol; (c) 3-methylbutanoyl bromide y 3-methylbutanal; (d) benzamide y 1-phenylmethanamine; (e) propanenitrile y 3-hexanone; (f) methyl propanoate y 4-ethyl-4-heptanol. 53. Nylon-6,6 was the fi rst completely synthetic fi ber, initially prepared in the mid-1930s at DuPont. It is a copolymer whose subunits are alternating molecules of 1,6-hexanediamine and hexanedioic (adipic) acid, linked by amide functions. (a) Write a structural representation of Nylon-6,6. (b) Hexanedinitrile (adiponitrile) may be used as a common precursor to both 1,6-hexanediamine and hexanedioic acid. Show the reactions necessary to convert the dinitrile into both the diamine and the diacid. (c) Formulate a mechanism for the conversion into the diacid under the reaction conditions that you chose in (b). 54. Upon treatment with strong base followed by protonation, compounds A and B undergo cis-trans isomerization, but compound C does not. Explain.

[ COOCH3 [ CON(CH3)2 [ CONH2

) ) ) COOCH3 CON(CH3)2 CONH2 A B C Problems Chapter 20 967

55. 2-Aminobenzoic (anthranilic) acid is prepared from 1,2-benzenedicarboxylic anhydride (phthalic anhydride) by using the two reactions shown here. Explain these processes mechanistically.

O O O B ° 1. NaOH, Br2, 80 C COH ϩ NH3, 300°C 2. H , H2O O NH

NH2 O O 1,2-Benzenedicarboxylic 1,2-Benzenedicarboximide 2-Aminobenzoic acid anhydride (Phthalimide) (Anthranilic acid) (Phthalic anhydride)

56. On the basis of the reactions presented in this chapter, write reaction summary charts for esters and amides similar to the chart for acyl halides (Figure 20-1). Compare the number of reactions for each of the compound classes. Is this information consistent with your understanding of the relative reactivity of each of the functional groups? 57. Show how you might synthesize chlorpheniramine, a powerful antihistamine used in several decongestants, from each of carboxylic acids A and B. Use a different carboxylic amide in each synthesis.

N N N

CHCH2COOH CHCH2CH2COOH CHCH2CH2N(CH3)2

Cl Cl Cl A B Chlorpheniramine

2 58. Although esters typically have carbonyl stretching frequencies at about 1740 cm 1 in the infra- O O red spectrum, the corresponding band for lactones can vary greatly with ring size. Three exam- ples are shown in the margin. Propose an explanation for the IR bands of these smaller ring O O lactones. 59. Upon completing a synthetic procedure, every chemist is faced with the job of cleaning glassware. 1735 cm؊1 1770 cm؊1 Because the compounds present may be dangerous in some way or have unpleasant properties, a little serious chemical thinking is often benefi cial before “doing the dishes.” Suppose that you O have just completed a synthesis of hexanoyl chloride, perhaps to carry out the reaction in Problem O 34(b); fi rst, however, you must clean the glassware contaminated with this acyl halide. Both hexanoyl chloride and hexanoic acid have terrible odors. (a) Would cleansing the glassware with 1840 cm؊1 soap and water be a good idea? Explain. (b) Suggest a more pleasant alternative, based on the chemistry of acyl halides and the physical properties (particularly the odors) of the various carboxylic acid derivatives.

60. Show how you would carry out the following transformation in which the ester function at the lower left of the molecule is converted into a hydroxy group but that at the upper right is preserved. (Hint: Do not try ester hydrolysis. Look carefully at how the ester groups are linked to the steroid and consider an approach based on transesterifi cation.)

CH OCH CH OCH 3 D 3 3 D 3 C ? C CH3 M CH3 M % O % O

CH3 CH3 O % % B ECH } } H3CO HO 968 Chapter 20 Carboxylic Acid Derivatives

61. The removal of the C17 side chain of certain steroids is a critical element in the synthesis of a number of hormones, such as testosterone, from steroids in the relatively readily available preg- nane family.

CH3 O OH H3C CH3% % 17 % 17 H C H H C H 3 % ≥ % ≥ Several steps 3 % ≥ % ≥ H H H H } HO O H3C O Pregnan-3␣-ol-20-one Testosterone OH How would you carry out the comparable transformation, shown in the margin, of acetylcyclo- ? pentane into cyclopentanol? (Note: In this and subsequent synthetic problems, you may need to use reactions from several areas of carbonyl chemistry discussed in Chapters 17 – 20.) 62. Propose a synthetic sequence to convert carboxylic acid A into the naturally occurring sesquiter- pene a-curcumene.

CH3 CH3

?

CO2H CH3 CH3

H3CCH3 A ␣ -Curcumene

63. Propose a synthetic scheme for the conversion of lactone A into amine B, a precursor to the naturally occurring monoterpene C.

CH3 CH3 CH3 CH3 CH3 CH3 ? H C H3C H3C 3 CH3 CH3 CH3 O HO HO

O N(CH3)2 AB C

64. Propose a synthesis of b-selinene, a member of a very common family of sesqui- terpenes, beginning with the alcohol shown here. Use a nitrile in your synthesis. Inspection of a model may help you choose a way to obtain the desired stereochemistry. (Is the 1-methylethenyl group axial or equatorial?) CH CH % 3 % 3 ?

≥ ' ≥ CH2 OH H H H2C H2C CH3 ␤-Selinene

65. Give the structure of the product of the fi rst of the following reactions, and then propose a scheme that will ultimately convert it into the methyl-substituted ketone at the end of the scheme. This example illustrates a common method for the introduction of methyl groups into synthetically prepared steroids. (Hint: It will be necessary to protect the carbonyl function.) CH O % 3 O HCN ? C11H15NO ≤ IR: 1715, 2250 cm؊1 ≤ H H Problems Chapter 20 969

66. Spectroscopic data for two carboxylic acid derivatives are given in NMR-A and Mass Spectrum of NMR-B. Identify these compounds, which may contain C, H, O, N, Cl, and Br but no other ele- Unknown A ments. (a) 1H NMR: spectrum A (one signal has been amplifi ed to reveal all peaks in the multi- 2 plet). IR: 1728 cm 1. High-resolution mass spectrum: myz for the molecular ion is 116.0837. See 2 Intensity relative table for important MS fragmentation peaks. (b) 1H NMR: spectrum B. IR: 1739 cm 1. High- m/z to base peak (%) resolution mass spectrum: The intact molecule gives two peaks with almost equal intensity: myz 5 179.9786 and 181.9766. See table for important MS fragmentation peaks. 116 0.5 101 12 1 1 H NMR H NMR 75 26 6 H 3 H 57 100 3 H 43 66 29 34

3 H 4.44.3 4.2

2 H (CH3)4Si 5.15.0 4.9 2 H 1 H

1 H (CH3)4Si Mass Spectrum of Unknown B

5.0 4.5 4.0 3.5 3.0 2.52.0 1.5 1.0 0.5 0.0 5.0 4.5 4.0 3.5 3.0 2.52.0 1.5 1.0 0.5 0.0 Intensity relative 300-MHz 1H NMR spectrum ppm (δ ) 300-MHz 1H NMR spectrum ppm (δ ) m/z to base peak (%) A B 182 13 Team Problem 180 13 67. Friedel-Crafts acylations are best carried out with acyl halides, but other carboxylic acid deriva- 109 78 tives undergo this process, too, such as carboxylic anhydrides or esters. These reagents may have 107 77 some drawbacks, however, the subject of this problem. 101 3 Before you start, discuss as a group the mechanisms for forming acylium ions from acyl 29 100 halides and carboxylic anhydrides in Section 15-13. Then divide your group in two and analyze the outcome of the following two reactions. Use the NMR spectral data given to confi rm your product assignments. (Hint: D is formed via C.)

O O AlCl3 ϩ A (C H O)ϩ B (C H O) O 8 8 10 12

O AlCl3 ϩ A (C H O)ϩ C (C H ) ϩ D (C H O) O 8 8 8 10 10 12

Compound A: 1H NMR: d 2.60 (s, 3H), 7.40 – 7.50 (m, 2H), 7.50 – 7.60 (m, 1H), 7.90 – 8.00 (m, 2H). Compound B: 1H NMR: d 2.22 (d, 6H), 3.55 (sep, 1H), 7.40 – 7.50 (m, 2H), 7.50 – 7.60 (m, 1H), 7.90 – 8.00 (m, 2H). Compound C: 1H NMR: d 1.20 (t, 3H), 2.64 (q, 2H), 7.10 – 7.30 (m, 5H). Compound D: 1H NMR: d 1.25 (t, 3H), 2.57 (s, 3H), 2.70 (q, 2H), 7.20 (d, 2H), 7.70 (d, 2H). 970 Chapter 20 Carboxylic Acid Derivatives

Reconvene to share your solutions. Then specifi cally address the nature of the complications ensuing when using the reagents shown. Finally, all together, consider the following reaction sequence. Again, use a mechanistic approach to arrive at the structures of the products.

O

⌬ ϩ AlCl3 Zn(Hg), HCl, SOCl2 AlCl3 O C10H10O3 C10H12O2 C10H11ClO C10H10O

O Preprofessional Problems F 68. What is the IUPAC name of the compound shown in the margin? (a) Isopropyl 2-fluoro- A 3-methylbutanoate; (b) 2-fl uoroisobutanoyl 2-propanoate; (c) 1-methylethyl 2-fl uorobutyrate; (CH ) CCO CH(CH ) 3 2 2 3 2 (d) 2-fl uoroisopropyl isopropanoate; (e) 1-methylethyl 2-fl uoro-2-methylpropanoate. O B 18 69. Saponifi cation of (CH3)2CHC OCH2CH2CH3 with aqueous NaOH will give 2 1 1 18 (a) (CH3)2CHCO2 Na CH3CH2CH2 OH; O B 18 2 1 1 1 q 18 (b) (CH3)2CHC O Na CH3CH2CH2OH; (c) (CH3)2CHOCH2CH2CH3 C O; 1 18 (d) (CH3)2CHCHO CH3CH2CH2 OH. 70. JO The best description for compound A (see margin) is (a) an amide; (b) a lactam; (c) an ether; H COC (d) a lactone. 2 A A 71. H2C OO Which of the three compounds below would be the most reactive toward hydrolysis with A aqueous base? O O O B B B

COCH3 CCl CNH2 (a) (b) (c)