482 Chapter 17 Solutions to Problems 1. The lactone would be a three-membered ring, which is too strained to form, 2. a butanenitrile ¢. isobutyl butanoate propyl cyanide isobutyl butyrate b. ethanoie propanoic anhydride f. N,N-dimethylhexanamide acetic propionic anhydride . potassium butanoate }-butyrolactam or potassium butyrate 2-azacyclopentanone 4d. pentanoyl chloride h. cyclopentanecarboxylic acid valeryl chloride i. B-methyl-6-valerolactone or 5-methyl-2-oxacyclohexanone 3. ° g i L a. cy cuo€ 4. cH’ wc ¢_Y & cHycucry, SNH, Br 9 § o oO A i b. ~ S \ nn @ CHCH,CHCH,CH” “OK on ca’ S/cH,cH én is oO peg Be tea, yemethylcaproie acid ° i eS, & CH,CH,CH;C=N —f CHCH.CH,CH” OCH,CH, a 4. The carbon-oxygen single bond in an alcohol is longer because, as a result of resonance, the carbon-oxygen single bond in a carboxylic acid has some double-bond character. i I C, d ra =z5. Chapter 17483, a, The bond between oxygen and the methyl group is the longest because itis a pure single bond, whereas the other two carbon-oxygen bonds have some double-bond character, ‘The bond between carbon and the carbonyl oxygen is the shortest because it has the most double bond character. The more electronegative the base (Y) attached to the carbonyl carbon, the greater the double bond character of the C=O bond. ay ox RY The weaker the base (Y) attached to the carbonyl carbon the less well it shares it electrons. ‘When Y shares its electrons, it decreases the double bond character of the C=O bond, making it easier to stretch. O: i RY ‘Therefore, the compounds have the indicated carbonyl IR absorption bands. ‘The carbonyl group of the acyl chloride stretches at the highest frequency because the chlorine atom is the most electronegative atom and the weakest base. The carbonyl group of the amide stretches at the lowest frequency because the nitrogen atom is the least electronegative atom and the strongest base. acyl chloride ~ 1800 em’! acid anhydride ~ 1800 and 1750 em"! ester ~ 1730cm? amide ~ 1640 em"484 Chapter 17 ‘The resonance contributors show why the acid anhydride has two carbonyl IR absorption bands. AN R” %O “p 1 a a + NaCl ——= — noreaction CHY *OCH; g i i b. eC, + NOH ——> c + NaCl cHY Scr cu? ‘ou 9 o fo, f af as Jn Cc. US + NaCl cHY “cl cHY ‘o cxf” So” ‘cu, ? 9 a. hg Nec ——> no reaction N cué ‘o” ‘cu, 8 Itis.a true statement. If the nucleophile is the stronger base, it will be harder to eliminate the nucleophile from the tetrahedral intermediate (B) than to eliminate the group attached to the acyl group in the reactant. In other words, the hill that has to be climbed from the intermediate (B to A) back to the reactants is higher than the hill that has to be climbed from the intermediate (B to C) to the products. Since the transition state with the highest energy is the transition state of the rate- limiting step, the first step is the rate-limiting step.10. i. 12. Chapter 17485 Free Energy See Progress of the Reaction a, anew carboxylic acid derivative b. no reaction ¢. a mixture of two carboxylic acid derivatives Solved in the text. A protonated amine has a pKa ~ LL. Therefore, the amine will be protonated by the acid that is produced in the reaction, and a protonated amine is not a nucleophile. Excess amine is used in order to have some unprotonated amine available to react as a nucleophile. A protonated alcohol has a pkg ~ ~2. Therefore, the alcohol will not be protonated by the acid that is produced in the reaction. c cu’ “on486 Chapter 17 6 108 5 b. t I 1 . + CNH, CH G—Br CHET + HB’ CHy te / c_NHCH, NHCH; . Buy | 6 é + Br cHY/ ~NHCH, 13. t a, CHyCH,CH,OH . (CH),NE e. CH;CO™ b. CHjCH,NH, d. 1,0 f. wok Y-n0, 14. Ste ~ i - Il a. CHj;C—O—CCH, + 1,0: == CHG O-EC, = CHCTQ-CCH, . N74 Cy AS asa Ro Ghar R~ SNHR492 31. 32. Chapter 17 Therefore, we should let the nucleophile attack the electrophile and then see if that product helps us figure out how we can arrive at the given product (the nitrile. cl + SO, + R-C=N anitrile The relative reactivities of the amides depend on the basicities of their leaving groups: the weaker the base, the more reactive the amide. Q Q og g cutnn-€_Y-vo, > cutn€ 9 > cusenn-€_Y > ontxX_) A para-nitro-substituted aniline is less basic than a meta-substituted aniline because when the nitro group is in the para position, electrons can be delocalized onto the nitro group. 0, 9 WON x cnt he KTV oO a, pentyl bromide —b. isohexyl bromide ¢. benzyl bromide d. cyclohexyl bromide The reaction of an alkyl halide with ammonia leads to primary, secondary, and tertiary amines, and even quaternary ammonium ions. Thus, the yield of primary amine could be relatively low. NES pi, ——= pn, BBS R,NH, ——> R,NH + HY +H {Ree RBr RN Be «REO RN <— R,NH +H35. Chapter 17493 In contrast, the Gabriel synthesis forms only primary amines, The reaction of an alkyl halide with azide ion also forms only primary amines because the compound formed from the initial reaction of the two reagents is not nucleophilic, so polyalkylation does not occur. CH,CH,CH,Br-—b. CH)GHCHBr Cs CH; P BrCH,CH,CH,CHCH,CH, —Na» CN Oy o7 TCHLCHs CH; Ch g AIC, ‘CH,CH,CH,CHCH, © = OO CH,CH,CH,CH,CI peroxide {sou F494° Chapter 17 Na . BrCH,CH,CH,CHCH,CH=CH, = —S8= CM Be RES Rateindecray ea 2 7 ~CH:CHECH, oH ' Qramman Hear OM 0% CERCH=CH2 20, H,0,, H,0 (07 CHaCH)CH;0H product of e 36. Oo oO 090 “00 ‘Ors, O tl ih. il Tf = Il a, HOCCH,CH,COH + CH;COCCH; ——>= cusepecn, — Sa 7 “4 HB 6 . o=¢ ont + HB CH,CH,COH CH,CH,COH | ° i - Pf CHSC OCCH; 6 o-H <— a NA B CHCH,COH 0 9 0 + CH,CO b. Without acetic anhydride, the leaving group would be hydroxide ion. Acetic anhydride causes the reaction to take place via two successive acy! substitution reactions. In both reactions the leaving group is acetate ion, which is much less basic than hydroxide ion.37. Chapter 17495 9 é a. (CH;CH,))N~ ~N(CH;CH;), e © AIL © Ay H,N~ ~NHCH; f. CH,CH, 0 d. no reaction ° 1 ir a. CHCH,CH,CHACH,CNCH, —f, CHCO™ Na cH; Cis 9 ° 9 b. CHCH,CH,CCH,CNH, e ()-b0-t¢y CH; 9° u a \ d. CHjCH,C=N 1 © CH,CH,CBr496 39, 40. 41. Chapter 17 a, S-cthylheptanoic acid b. propyl propanoate propyl propionate ¢. pentanenitrile butyl cyanide 4. propanoic anhydride propionic anhydride ¢. N.N-dimethylbutanamide N.N-dimethylbutyramide e F f. pentanoyl chloride valery! chloride g. acetic benzoic anhydride h, N-methyl-3-butenamide i. ()-3-methylpentanoic acid (S)-B-methylvaleric acid 4. (R)-3-methylhexanenitrile Q=0 OO O+O-= 9 1 €S—Loguien, CH; C-ban- a, The weaker the base attached to the acyl group, the easier itis to form the tetrahedral intermediate. (para-Chlorophenol is a stronger acid than phenol so the conjugate base of, para chlorophenol is a weaker base than the conjugate base of phenol, etc.) t a q cxgo_Y-a > onto’ > cxyto-_Y—cn, > Oo i cate)Chapter 17 497 . ‘The tetrahedral intermediate collapses by eliminating the “OR group of the tetrahedral intermediate. The weaker the basicity of the “OR group, the easier it is to eliminate it Thus, the rate of both formation of the tetrahedral intermediate and collapse of the tetrahedral intermediate is decreased by increasing the basicity of the “OR group. i i . ceo Va aa) > cnsto-¥ Yc, > t cco) 42, a. Methyl acetate has a resonance contributor that butanone does not have, and this resonance Contributor causes methyl acetate to be more polar than butanone. Because butanone is less polar, it has the lower dipole moment. Cin, IL ia CH,—C—CH,CH CH;—C—OCH; <—= CH,—C=0cH, >. Because itis more polar, the intermolecular forces holding methyl acetate molecules together ‘are stronger, so we would expect methyl acetate to have a higher boiling point. 43. Propyl formate is easy to distinguish because itis the only ester that will show four signals. The other three esters show three signals. Isopropyl formate can be distinguished by i unique ° a u@ ocH,cH,cH, 4 signals Oo QO i i ; LN vai ¢. ‘OcKCH, ‘OCH,CH, oN H CHCH, CH, ACH, CH,CH,” OCH, cH; 3 signals 3 signals 3 signals singlet, doublet, septet singlet, triplet, quartet singlet, triplet, quartet The peak farthest downfield The peak farthest downfield is a quartet. isa singlet498 Chapter 17 44. The reaction of methylamine with propionyl chloride generates a proton that will protonate unreacted amine, thereby destroying its nucleophilicity. If two equivalents of CH3NHp are used, ‘one equivalent will remain unprotonated and be able to react with propionyl chloride to form N-methylpropanamide. ° ° i i + - CH,CH,CCl + CH;NH) ——> CH,CH,CNHCH, + H* + CI [ons CHNH3 45. b. Only one isotopically labeled oxygen can be incorporated into the ester because the bond between the methyl group and the labeled oxygen does not break, so there is no way for the carbonyl oxygen to become labeled. cannot become labeled bond does not breakChapter 17499 46. a. isopropyl alcohol and HCL cc. ethylamine b. aqueous sodium hydroxide water and HCI 47, The offset in the NMR spectrum shows that there is a signal at ~ 10 ppm, which is where the proton of a COOH group shows a signal. The two triplets and the multiplet are characteristic of a propyl group. The compound is butanoic acid. ‘O om CH,CH,CHY OH ‘The molecular formula shows that the unknown compound has one more carbon atom than butanoic acid. Since butanoic acid is formed from acid hydrolysis of the compound, the compound must be the methyl ester of butanoic acid. fo) I c, CH,CH,CHY ocH, C5H 902 48. Aspartame has an amide group and an ester group that will be hydrolyzed in an aqueous solution of HCI, Because the hydrolysis is carried out in an acidic solution, the carboxylic acid groups and the amino groups will be in their acidic forms. I tl i 1 il + il HOCCHCHCNHCHCOCH, ic HOCCH;CHCOH + HNCHCOH, +*NH, CH) z +NHy CH) + CH,OH 49. a. 1,3, 4,6, 7, 9 will not form the indicated products under the given conditions. b. 9 will form the product shown in the presence of an acid catalyst.500 50. St. 52. Chapter 17 ‘The tertiary amine is a stronger nucleophile than the alcohol, so formation of the charged amide will be faster than formation of the new ester would have been. The charged amide is more reactive than an ester, so formation of the new ester by reaction of the alcohol with the charged ‘amide will be faster than formation of the ester by reaction of the alcohol with the starting ester ‘would have been. In other words, both reactions that occur in the presence of the tertiary amine are faster than the single reaction that occurs in the absence of the tertiary amine. Oo oO oO i i 1 ROH > Ay ot NOONE SC pi a a cHY ~ocH; =\_/ cHy “WN it cH’ or | \_/ VS + CH,OH ‘The amine is a stronger nucleophile than the alcohol, but since the acyl chloride is very reactive, it can react easily with both nucleophiles. Therefore, steric hindrance will be the most important factor in determining the products. The amino group is less sterically hindered than the alcohol ‘group so that will be the group most easily acetylated. 9 i .CH,OH g ,CH,OH ,CH,OCCH, CFencr, + CHC "CH,CH; C Fens 'N’ N N H ¢=0 G0 Pyridine is used for the CH CH; sécond equivalent of amine. major product © minor product CH,OCCH, CKeuscx, N’ H minor product Bromobutane undergoes an Syy2 reaction with NH to form butylamine (A). Bromobutane can then react with butylamine to form dibutylamine (B). The amines each form an amide upon reaction with acetyl chloride. The IR spectrum of C exhibits an NH stretch at about 3300 cm"! while the IR spectrum of D does not exhibit this absorption band, because the nitrogen in D is not bonded to a hydrogen. CH,CH,CH,CH,Br + NH; ——* CH,CH,CH,CH,NH, A {es (CH;CH,CH,CH,).NH B53. 54, 55. Chapter 17501 9 ° i il CH;CCl + CH;CH;CH,CH,NH, ——» CH,CNHCH,CH,CH,CH, A c q i CH,CCl + (CH;CH,CH,CH,),NH —s — CH,CN(CH,CH,CH,CH;) B D I q 1. CICOCH, 3. CHyCH,CH,NHCNHCH,CH,CH; O° 1 1 2. CH;OCOCH; — 4. CHyCH,OCNHCH e 9° 9° i Ih NN + moioneneye + Ba > a LN G +H +cr re \° 1 SO . oO. 0 0. oO wt TN + 5008 + or 1 CH,CF r , O Oo b ° -O ,Z & UL te HOCCH,CH,CH,NH; Cr 1 ? f. HOCCH,CH,CH,OH 0 © Cp exes ° 9° ° - 1 8 CH,CCH,O + CH;OCCH, j, CGH 5 1 t oO HOCCH,CH,COH h al 07 ~ocn;502 56. 37. 58. 59. Chapter 17 9 i i CICH;CH,CH,CCl + CH,0OH ——» CICH,CH,CH,COCH, Compound A t t iy a, CH,CNHCHCH,CH,OCCH, + CH;COH CH; iL b. CHyCNHCHCH,CH,OH CHy Because the amino group is a stronger nucleophile than the OH group, the predominant product ‘will be the amide if the reaction is stopped prematurely. If the amine is tertiary, the nitrogen atom in the amide cannot get rid of its positive charge by losing a proton, An amide with a positively charged amino group is very reactive because the positively charged amino group is a weak base and, therefore, an excellent leaving group. ‘Water will immediately react with the amide, and because the positively charged amine 1s a better leaving group than the OH group, the amine will be expelled and the product will be a carboxylic acid. oO oO i 2NRs, 4h cay ci CH “Nr, cHY Oo HNR; Cl a. The steric hindrance provided by the methyl groups prevents methyl alcohol from attacking, the carbonyl carbon. b. No, because there would be no steric hindrance. Coon COOCH; © coo HC. CH 5 AGC. CH, HC. CH CH,NEN CH, CH CH, CH; 2,60. 61. Chapter 17 503 The spectrum shows that the compound has four different kinds of hydrogens with relative ratios 2: 1:16. The doublet at 0.9 ppm and the ratio of 6 hydrogens suggests that the compound has an iso group. The signal at 3.4 ppm indicates hydrogens on a carbon that is attached to an oxygen atom. The shape of the signal at 2.4 ppm suggests an OH group. We can conclude that the spectrum is a spectrum of isobutyl alcohol. The molecular formula indicates the compound that undergoes hydrolysis is an ester. Subtracting the atoms due to the isobutyl group lets us identify the ester as isobutyl benzoate. 9 ° i HCI i ‘C—OCH,CHCHs aro" C-OH + HOCH,CHCH, CH, > CH, The more electronegative the base (Y) attached to the carbonyl carbon, the greater the double bond character of the C=O bond. ‘The weaker the base (Y) attached to the carbonyl carbon the less well it shares it electrons. when Y shares its electrons, it decreases the double bond character of the C=O bond, making it easier to stretch. 20: b N RK YY ‘Therefore, the carbonyl IR absorption band decreases in the order: oO i I 1 1 CH;CCl > CH;COCH, > CH;CH > CH,CNH, ‘The carbonyl group of the acyl chloride stretches at the highest frequency because the chlorine atom is the most electronegative atom and the weakest base. The predominant effect of the oxygen of an ester is inductive electron withdrawal, so its carbonyl group stretches at a higher frequency than the carbonyl group of the aldehyde. ‘The carbonyl group of the amide stretches at the lowest frequency because the nitrogen atom is the strongest base, so itis best at sharing its electrons.504 Chapter 17 a 4.02 = x 2.00 = (=x) 2-2x = x 2 3x x = 0.667 [ethyl acetate] = 0.667 times the concentration of acetic acid used b. 2 x 4.02 = ——~—_ 0-2) =x) x = 0.974 [ethyl acetate] = 0.974 times the concentration of acetic acid used « 402 = ——~___ (00= x) =x) x = 0,997 [ethyl acetate] = 0.997 times the concentration of acetic acid used Each of the NMR spectra has signals between about 7-8 ppm, indicating that the compound has a benzene ring with one substituent (the benzene ring has hydrogens in three different environments) and one additional signal that is a singlet. From the molecular formulas it can be determined that the esters have the following structures. The singlet in each spectrum is due to a methyl group. Because the methyl group is farther downfield in the spectrum on the right, itis, the spectrum of the compound on the right, since its methyl group is adjacent to an electron- withdrawing oxygen atom. t t culo Y €S—tocn, The ester on the left will hydrolyze faster because phenol is a much weaker base than methyl alcohol. i + if 11 a. CH3CH,CNH, er cacn,con S°C% cHcH,Cci AChapter 17505 Soci. b. CH;CH,CH,CH,OH CC® cH,c,cH,cH,c1 S2% cH,cH,CH,CH,C=N H,0 [rc A a NH, + CH;CH,CH,CH,COH 9 9 1 AICI; ° s il © CHYCH), CoH SOCK CHs(CH,) gC] 5 cuseny,.t—¢_Y . Hy Zn(Hg) ,,|NH)NH, HC, & A SO, ener, )—son 2 229 cay, _Y NaOH a ‘ cxyeriy, €_Y-sos Na’ CHy Gnu, excess CHANHS 9 tt NH, a i zy Il _ e CHSCCL = mao Pyridine 2.H,O0 2 HO q506 Chapter 17 65. The acid-catalyzed hydrolysis of acetamide forms acetic acid and ammonium ion, Itis an irreversible reaction, because the pK, of a acetic acid is less than the pK, of the ammonium ion. ‘Therefore, it is impossible to have the carboxylic acid in its reactive acidic form and ammonia in its reactive basic form. If the solution is sufficiently acidic to have the carboxylic acid is in its acidic form, ammonia will also be in its acidic form so it will not be a nucleophile. If the pH of the solution is sufficiently basic to have ammonia in its nucleophilic basic form, the carboxylic acid will also be its basic form; a negatively charged carboxylic acid is not attacked by nucleophiles I * CH,COH + NH, ——> noreaction The ammonium ion is not nucleophilic. i CH,CO” + NH; ——> noreaction The carboxylate ion is not attacked by nucleophiles. AWG RC-NH-R) —<—— RC=NH-R' “= RC=N-R’ > ‘c EES bn a 4 RE-NH-R’ + BBY ° b. The Ritter reaction does not work with primary alcohols, because primary alcohols do not form carbocations. ¢. The only difference in the two reactions is the electrophile that attaches to the nitrogen of the nitrile: itis a carbocation in the Ritter reaction and a proton in the acid-catalyzed hydrolysis of a nitrile.67. 68. J - CH; + HO Chapter 17 + CH;CH,OH 507508 Chapter 17 69. HNO; iH; 'H: 2 Cp tee Opn 28 Open 1,80, Pd/C pyridine 1,804 9° ° ° i PCI; tt i cis NHCCH; Hos NHCCH; 3 0 {rts 9 ° . 1) 1." 1,0 t HNS NHCCH, ——— HANS NH, 2. HO" MI oO 70. CH; a HNO. —> aoe as CS H)SO, 9 COOH f 00 occH; tT x CH,COCCH, OH 0 NaN aaa eo coChapter 17509 CH;CH, CH3CH, CH,CHBr L(CHy,cHeCI, b. a CBSCHBr Alc, NBS. A ‘AIC, a0 “peroxide OFCRHCH; O=CCHCH; oy d tl i) CH,CHCOH CH,CHCOH excess HCI 2. HCI H,0, A CHCHCH, O=CCHCHs O=CCHCHs CH; CH, CH; 71. A B-lactamase enzyme provides resistance to penicillin by reacting with it, opening the four- membered ring. yt ° a The inhibitor of the f-iactamase enzyme has an excellent leaving group, so it is readily attacked by nucleophiles. When the enzyme attacks the inhibitor, a relatively stable phosphonyl-enzyme is formed, so its OH group is no longer available to react with penicillin510 Chapter 17 toe 9 ° 9 9° i) iA il 1 oHeNTCti "0 —> CH,CNHCH,P—OCH coo” a phosphonyl-enzyme wXQ coo” Hydroxylamine (HNOH) reactivates the enzyme by liberating the enzyme from the phosphonyl- enzyme. Spenser ne WA i nae — i Cp retsbsncial on, ¢ }ewou a HO. HOD CI sco ~ NHCO,CH; 2CO3CH3 N—CO,CH3Chapter 17511 to ec Vor — L 0" oO, ON KC 7 CRO NOz TB. HNO. 8 Cyn te Crm ae Oude Tso, Pac pyridine CH;Cl rcs ° HOG Hi NOHO oy NHCCH. ~~ NI Ha, SHO <<. 5 5 : ° arte ~<— (CH;CH,),NH + 7 \ CH3CH, 9 CH3QH,, ° I + Ho \ I _JNHICH,CHO' NH; HO, / NCHACHOC NH CH,CH, CH;CH,$12. Chapter 17 74, NO, 75. COOH Os excess SOCI, t ° cca cl v Loo Oe = OF Pr76. Chapter 17513 Because electron-withdrawing substituents have positive substituent constants and electron- donating substituents have negative substituent constants, a reaction with a positive p value is one in which compounds with electron-withdrawing substituents react more rapidly than compounds with electron-donating substituents, and a reaction with a negative pvalue is one in which compounds with electron-donating substituents react more rapidly than compounds with electron-withdrawing substituents electron withdrawal increases electron donation increases the rate of the reaction the rate of the reaction z e 2 2 0 2 a, In the hydroxide-ion-promoted hydrolysis of a series of ethyl benzoates, electron-withdrawing substituents will increase the rate of the reaction by increasing the amount of positive charge on the carbonyl carbon, thereby making it more readily attacked by hydroxide ion. The p value for this reaction is, therefore, positive. 9 i xf ¥—Locircrs + H In amide formation with a series of anilines, electron donation will increase the rate of the reaction by increasing the nucleophilicity of the aniline. The p value for this reaction is, therefore, negative. ° 1 (¥-bo + uy \—« — NY b. Because ortho substituents are close to the site of the reaction, they introduce steric factors into the rate constant for the reaction. In other words, the presence of an ortho substituent can slow a reaction down, not because it can donate or withdraw electrons but because it can get in the way of the reactants, Therefore, any change in the rate is due to a combination of steric effects and the electron-donating or electron-withdrawing ability of the substituent. Because the change in rate cannot be attributed solely to the electron-donating or electron- withdrawing ability of the substituent, ortho-substituted compounds were not included in the study. ¢. An electron-withdrawing substituent will make it easier for benzoic acid to lose a proton, so ionization will show a positive p value.