Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
18 Organic Chemistry William H. Brown & Christopher S. Foote 18-1 18 Carboxyl Derivatives 18-2 18 Carboxyl Derivatives In this chapter, we study five classes of organic compounds • under the structural formula of each is a drawing to help you see its relationship to the carboxyl group O RCCl An acid chloride O RC- OH H- Cl O O RCOCR' An acid anhydride O O RC- OH H- OCR' O RCOR' An ester O RC- OH H- OR' 18-3 18 Carboxyl Derivatives • an amide is formally related to a carboxyl group by loss of -OH from the carboxyl and -H from ammonia • loss of -OH and -H from an amide gives a nitrile O RCN H2 An amide O RC- OH H- NH 2 RC N A nitrile HO H RC= N The enol of an amide 18-4 18 Structure: Acid Chlorides The functional group of an acid halide is an acyl group bonded to a halogen • to name, change the suffix -ic acid to -yl halide O O RCAn acyl group O CH3 CCl Ethanoyl chloride (Acetyl chloride) RCCl An acyl chloride (An acid chloride) O CCl Benzoyl chloride O O ClC(CH2 ) 4 CCl Hexanedioyl chloride (Adipoyl chloride) 18-5 18 Acid Chlorides • replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride O CH3 SOH O Methanesulfonic acid O CH3 SCl O Methanesulfonyl chloride (Mesyl chloride, MsCl) O H3 C SOH O p-Toluenesulfonic acid O H3 C SCl O p-Toluenesulfonyl chloride (Tosyl chloride, TsCl) 18-6 18 Acid Anhydrides The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom • the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups) • to name, replace acid of the parent acid by anhydride O O CH3 COCCH3 O O O O COC CH3 COC Acetic anhydride Benzoic anhydride Acetic benzoic anhydride 18-7 18 Acid Anhydrides Cyclic anhydrides are named from the dicarboxylic acids from which they are derived O O O Succinic anhydride O O O Maleic anhydride O O O Phthalic anhydride 18-8 18 Acid Anhydrides A phosphoric acid anhydride contains two phosphoryl groups bonded to an oxygen atom O O O - HO- P-O- P-OH OH OH Diphosphoric acid (Pyrophosphoric acid) O O O- O- OTriphosphoric acid O- P-O-P- O O- - O- Diphosphate ion (Pyrophosphate ion) O O HO- P-O- P-O-P- OH O - O O O- P-O-P- O-P- O O- O- OTriphosphate ion - 18-9 18 Esters The functional group of an ester is an acyl group bonded to -OR or -OAr • name the alkyl or aryl group bonded to oxygen followed by the name of the acid • change the suffix -ic acid to -ate O O O O O Ethyl ethanoate (Ethyl acetate) O O O Isopropyl benzoate Diethyl butanedioate (Diethyl succinate) 18-10 18 Esters Cyclic esters are called lactones • name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone 2 3 H3 C O O 1 O 3-Butanolactone -Butyrolactone) 1 2 O 3 4 4-Butanolactone -Butyrolactone) O 2 3 1 4 O 5 CH3 5-Hexanolactone -Caprolactone) 18-11 18 Amides The functional group of an amide is an acyl group bonded to a nitrogen atom • IUPAC: drop -oic acid from the name of the parent acid and add -amide • if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by NO CH3 CN H2 O CH3 CN HCH3 O HCN ( CH3 ) 2 Acetamide (a 1° amide) N-Methylacetamide (a 2° amide) N,N-Dimethylformamide (DMF) (a 3° amide) 18-12 18 Amides Cyclic amides are called lactams Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam H3 C O 2 1 3 NH 3-Butanolactam -Butyrolactam) O 2 1 3 4 NH 5 6 6-Hexanolactam -Caprolactam) 18-13 18 Penicillins penicillins are a family of -lactam antibiotics The the penicillins differ in the group bonded to the acyl carbon H CH2 C O Penicillin G N O H H S CH3 N CH3 COOH 18-14 18 Penicillins Amoxicillin HO O H H S HN N H2 N O COOH 18-15 18 Cephalosporins The cephalosporins are also -lactam antibiotics the cephalosporins differ in the group bonded to the acyl carbon and the side chain bonded to the thiazine ring H S H 2N Cefetamet N C N CH3 O H H N N O S CH3 COOH 18-16 18 Cefetamet H S H 2N N C N N H H O OCH3 N S CH3 COOH 18-17 18 Nitriles The functional group of a nitrile is a cyano group IUPAC: name as an alkanenitrile Common: drop the -ic acid and add -onitrile CH3 C N Ethanenitrile (Acetonitrile) C N Benzonitrile CH2 C N Phenylethanenitrile (Phenylacetonitrile) 18-18 18 Acidity of N-H bonds Amides are comparable in acidity to alcohols • water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water soluble salts Sulfonamides and imides are more acidic than amides O CH3 CNH2 O O SNH2 NH O NH O Acetamide pKa 15-17 Benzenesulfonamide pKa 10 O Succinimide pK a 9.7 O Phthalimide pKa 8.3 18-19 18 Acidity of N-H bonds Imides are more acidic than amides because 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and 2. the imide anion is stabilized by resonance delocalization of the negative charge O N -H + H2 O O Phthalimide O N- O+ N + H3 O O O A resonance-stabilized anion 18-20 18 Acidity of N-H • imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts O O N H + N aOH O pKa 8.3 (stronger acid) - N Na + + H2 O O (stronger base) (weaker base) pKa 15.7 (weaker acid) 18-21 18 IR Spectroscopy C=O Stretch Cmpd (cm-1 ) O O 1740-1760 and RCOCR 1800-1850 O RCOR 1735-1800 O 1700-1725 RCOH O RCN H2 1630-1680 Additional Stretchings (cm -1) C-O at 900-1300 C-O at 1000-1100 and 1200-1250 O-H at 2400-3400 C-O at 1210-1320 N-H at 3200 and 3400 (1° have two N-H peaks) (2° have one N-H peak) 18-22 18 NMR Spectroscopy 1H-NMR • H on the -carbon to a C=O group are slightly deshielded and come into resonance at 2.1-2.6 • H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at 3.7-4.7 2.33(q) O 3.68(s) CH3 -CH2 -C-O-CH3 13C-NMR Methyl propanoate • the carbonyl carbons of esters show characteristic resonance at 160-180 18-23 18 Characteristic Reactions Nucleophilic acyl substitution: an additionelimination sequence resulting in substitution of one nucleophile for another O + C R Y : N u- R : O- O C C Nu Y Tetrahedral carbonyl addition intermediate R + :Y- Nu Substitution product 18-24 18 Characteristic Reactions • in this general reaction, we have shown the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group R2 N - RO - O RCO - X- Increasing leaving ability Increasing basicity 18-25 18 Characteristic Reactions • halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution • amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution O RCN H2 Amide O RCOR' Ester O O RCOCR' O RCX Anhydride Acid halide Increasing reactivity toward nucleophilic acyl substitution 18-26 18 Rexn with H O - RCOCl 2 • low-molecular-weight acid chlorides react rapidly with water • higher molecular-weight acid chlorides are less soluble in water and react less readily O CH3 CCl + O H2 O CH3 COH + HCl 18-27 18 Rexn with H O - RCO OR 2 2 • low-molecular-weight acid anhydrides react readily with water to give two molecules of carboxylic acid • higher-molecular-weight acid anhydrides also react with water, but less readily O O CH3 COCCH3 + H2 O O O CH3 COH + HOCCH3 18-28 18 Rexn with H O - Esters 2 Esters are hydrolyzed only slowly, even in boiling water Hydrolysis becomes more rapid if they are heated with either aqueous acid or base Hydrolysis in aqueous acid is the reverse of Fischer esterification • the role of the acid catalyst is to protonate the carbonyl oxygen and increase its electrophilic character toward attack by water to form a tetrahedral carbonyl addition intermediate • collapse of this intermediate gives the carboxylic acid and alcohol 18-29 18 Rexn with H O - Esters 2 Acid-catalyzed R O C ester hydrolysis OH C + + OCH3 H2 O H R H + OH R O C + OH CH3 OH OCH3 Tetrahedral carbonyl addition intermediate 18-30 18 Rexn with H O - Esters 2 Hydrolysis of an esters in aqueous base is often called saponification • each mole of ester hydrolyzed requires 1 mole of base; for this reason, ester hydrolysis in aqueous base is said to be base promoted O RCOCH3 + NaOH H2 O O - RCO Na + + CH3 OH • hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer 18-31 18 Rexn with H O - Amides 2 Hydrolysis of an amide in aqueous acid requires 1 mole of acid per mole of amide O O NH2 + H2 O + HCl Ph 2-Phenylbutanamide H2 O heat OH + NH4 + Cl - Ph 2-Phenylbutanoic acid 18-32 18 Rexn with H O - Amides 2 Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide O CH3 CNH + N-Phenylethanamide (N-Phenylacetamide, Acetanilide) NaOH H2 O heat O CH3 CO-Na+ Sodium acetate + H2 N Aniline 18-33 18 Rexn with H O - Nitriles 2 The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion CH2 C N + 2 H2 O + H2 SO 4 H2 O heat Phenylacetonitrile O CH2 COH Phenylacetic acid + + N H4 H SO 4 - Ammonium hydrogen sulfate 18-34 18 Rexn with H O - Nitriles 2 • protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid • keto-enol tautomerism of the imidic acid gives the amide + R-C N + H2 O H OH R-C O NH An imidic acid (enol of an amide) R-C-NH2 An amide 18-35 18 Rexn with H O - Nitriles 2 • hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid CH3 ( CH2 ) 9 C N + H2 O + N aOH Undecanenitrile H2 O heat O + CH3 ( CH2 ) 9 CO Na Sodium undecanoate HCl H2 O O CH3 ( CH2 ) 9 COH Undecanoic acid 18-36 18 Rexn with H O - Nitriles 2 Hydrolysis of nitriles is a valuable route to carboxylic acids O CH HCN , KCN ethanol, water Benzaldehyde HO CC N H2 SO 4 , H2 O H Benzaldehyde cyanohydrin (Mandelonitrile) heat HO O CHCOH 2-Hydroxyphenylacetic acid (Mandelic acid) 18-37 18 Rexn with Alcohols Acid halides react with alcohols to give esters • acid halides are so reactive toward even weak nucleophiles such as alcohols that no catalyst is necessary • where the alcohol or resulting ester is sensitive to HCl, reaction is carried out in the presence of a 3° amine to neutralize the acid O Cl + HO Butanoyl chloride Cyclohexanol O O + HCl Cyclohexyl butanoate 18-38 18 Rexn with Alcohols • sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol O H3 C S- Cl O p-Toluenesulfonyl chloride (Tosyl chloride; TsCl) H3 C + C OH pyridine H C6 H1 3 (R)-2-Octanol H3 C H O C O-S C6 H1 3 CH3 O (R)-2-Octyl p-t oluenesulfonate [(R)-2-Octyl tosylate] 18-39 18 Rexn with Alcohols Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid O O CH3 COCCH3 + Acetic anhydride HOCH2 CH 3 Ethanol O O CH3 COCH2 CH3 + CH3 COH Ethyl acetate Acetic acid 18-40 18 Rexn with Alcohols • cyclic anhydrides react with alcohols to give one ester group and one carboxyl group O O O Phthalic anhydride + HO 2-Butanol (sec-Butyl alcohol) O O OH O 1-Methylpropyl hydrogen phthalate (sec-Butyl hydrogen phthalate) 18-41 18 Rexn with Alcohols • aspirin is synthesized by treatment of salicylic acid with acetic anhydride COOH OH O O + CH COCCH 3 3 Acetic 2-Hydroxybenzoic anhydride acid COOH (Salicylic acid) O CH3 O Acetylsalicylic acid (Aspirin) + O CH3 COH Acetic acid 18-42 18 Rexn with Alcohols Esters react with alcohols in the presence of an acid catalyst in a reaction called transesterification, an equilibrium reaction O + OCH3 Methyl propenoate (Methyl acrylate) (bp 81°C) HCl HO 1-Butanol (bp 117°C) O O Butyl propenoate (Butyl acrylate) (bp 147°C) + CH3 OH Methanol (bp 65°C) 18-43 18 Rexn with Ammonia, etc. Acid halides react with ammonia, 1° amines, and 2° amines to form amides • 2 moles of the amine are required per mole of acid chloride O Cl + 2 NH3 Hexanoyl Ammonia chloride O + NH2 + NH4 Cl Hexanamide Ammonium chloride 18-44 18 Rexn with Ammonia, etc. Acid anhydrides react with ammonia, and 1° and 2° amines to form amides. • 2 moles of ammonia or amine are required O O CH3 COCCH3 + 2 NH3 Ammonia Acetic anhydride O O CH3 CNH2 + CH3 CO - NH4 + Ethanamide Ammonium (Acetamide) acetate 18-45 18 Rexn with Ammonia, etc. Esters react with ammonia, and 1° and 2° amines to form amides • esters are less reactive than either acid halides or acid anhydrides O Ph O O + Ethyl phenylacetate Amides N H3 Ph N H2 + HO Phenylacetamide Ethanol do not react with ammonia, or 1° or 2° amines 18-46 18 Interconversions QuickTime™ and a Photo - JPEG decompressor are needed to see this picture. 18-47 18 Acid Chlorides with Salts Acid chlorides react with salts of carboxylic acids to give anhydrides • most commonly used are sodium or potassium salts O CH3 CCl + N a Acetyl chloride + - O O O OC CH3 COC Sodium benzoate + N a+ Cl - Acetic benzoic anhydride 18-48 18 Rexns with Grignards • treatment of a formic ester with 2 moles of Grignard reagent followed by hydrolysis with aqueous acid gives a 2° alcohol O HCOCH3 + 2 RMgX An ester of formic acid magnesium H O, HCl OH 2 alkoxide HC- R + CH3 OH salt R A secondary alcohol 18-49 18 Rexn with Grignards • treatment of an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol O CH3 COCH3 + 2 RMgX An ester other than a formate magnesium H2 O, HCl alkoxide salt OH CH3 C- R + CH3 OH R A tertiary alcohol 18-50 18 Rexns with Grignards 1. addition of 1 mole of RMgX to the carbonyl carbon gives a TCAI 2. collapse of the TCAI gives a ketone (an aldehyde from a formic ester) O CH3 -C- OCH 3 + R Mg Br O – [ MgBr ] + CH3 -C OCH3 R A magnesium salt (a TCAI) O CH3 -C + CH3 O - [ MgBr] + R A ketone 18-51 18 Reaction with Grignards • 3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI • 4. treatment with aqueous acid gives the alcohol O CH3 -C R A ketone + R Mg Br O - [ MgBr] + CH3 -C- R R Magnesium salt H2 O, HCl OH CH3 -C- R R A tertiary alcohol 18-52 18 Rexns with RLi Organolithium compounds are even more powerful nucleophiles than Grignard reagents • they react with esters to give the same types of 2° and 3° alcohols as do Grignard reagents • and often in higher yields O RCOCH3 1 . 2 R' Li 2 . H2 O, HCl OH R- C-R' + CH3 OH R' 18-53 18 Gilman Reagents Acid chlorides at -78°C react with Gilman reagents to give ketones. • under these conditions, the TCAI is stable, and it is not until acid hydrolysis that the ketone is liberated O 1 . ( CH3 ) 2 CuLi, ether, -78°C Cl 2 . H O 2 Pentanoyl chloride O 2-Hexanone 18-54 18 Gilman Reagents • Gilman reagents react only with acid chlorides • they do not react with acid anhydrides, esters, amides, or nitriles under the conditions described O H 3 CO O 1 . ( CH3 ) 2 CuLi, ether, -78°C Cl 2 . H O 2 O H 3 CO O 18-55 18 Redn - Esters by LiAlH 4 Most reductions of carbonyl compounds now use hydride reducing agents • esters are reduced by LiAlH4 to two alcohols • the alcohol derived from the carbonyl group is primary O Ph OCH3 Methyl 2-phenylpropanoate 1 . LiAlH4 , e t he r 2 . H2 O, HCl Ph OH + CH3 OH 2-Phenyl-1propanol Methanol 18-56 18 Redn - Esters by LiAlH 4 Reduction occurs in three steps plus workup : O– O R- C-OR' + :H- An ester (1) H R- C-OR' H O R- C + - :OR' H A tetrahedral carbonyl An addition intermediate aldehyde : O- O R- C + :H- (2) (3) R- C-H H H2O (4) OH R- C-H H A primary alcohol 18-57 18 Redn - Esters by LiAlH 4 NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones Selective reduction is often possible by the proper choice of reducing agents and experimental conditions O O O NaBH4 Et OH OH O O 18-58 18 Redn - Esters by DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78°C selectively reduces an ester to an aldehyde • at -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated O OCH3 Methyl hexanoate 1 . DIBALH , toluene, -78°C 2 . H2 O, HCl O H + CH3 OH Hexanal 18-59 18 Redn - Amides by LiAlH 4 LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide O N H2 Octanamide 1 . LiA lH4 2 . H2 O N H2 1-Octanamine O N 1 . LiA lH4 2 . H2 O N,N-Dimethylbenzamide N N,N-Dimethylbenzylamine 18-60 18 Redn - Amides by LiAlH 4 The mechanism is divided into 4 steps • Step 1: transfer of a hydride ion to the carbonyl carbon • Step 2: formation of an oxygen-aluminum bond AlH3 O H C R N H2 (1) A lH3 :O R C H N H2 (2) A lH3 O R C H NH2 18-61 18 Redn - Amides by LiAlH 4 • Step 3: redistribution of electrons gives an iminium ion • Step 4: transfer of a second hydride ion completes the reduction to the amine A lH3 O R C H (3) R C H (4) N H H H An iminium ion H R C H N : H : N H: - H H 18-62 18 Redn - Nitriles by LiAlH 4 The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine 1 . LiA lH4 CH3 CH= CH( CH 2 ) 4 C N 2 . H2 O 6-Octenenitrile CH3 CH= CH ( CH2 ) 4 CH2 N H2 6-Octen-1-amine 18-63 18 Interconversions Problem: show reagents and experimental conditions to bring about each reaction O PhCH2 CCl O PhCH2 COH (a) (d) (b) (c) (f) O PhCH2 COCH3 (j) PhCH2 CH2 OH (e) (h) (k) (i) O PhCH2 CNH2 (g) PhCH2 CH2 NH2 O PhCH2 CH 18-64 18 Hofmann Rearrangement When a 1° amide is treated with bromine or chlorine in aqueous NaOH or KOH, • the carbonyl carbon is lost as carbonate ion, and • the amide is converted to an amine of one fewer carbon atoms O Ph N H2 H3 C H (S)-2-Phenylpropanamide Br2 , N aOH H2 O Ph N H2 + N a2 CO 3 H3 C H (S)-1-Phenylethanamine 18-65 18 Hofmann Rearrangement Stage 1: acid-base reaction gives an amide anion, which reacts as a nucleophile with Br2 H O R C N: Br Br O C N : N H - : HO : O R C R Br + :Br - H H An amide anion An N-bromoamide Stage 2: a 2nd acid-base reaction followed by elimination of Br- gives a nitrene, an electron-deficient species, that rearranges to an isocyanate - :Br - An acyl nitrene : O R- C-N : : - H2 O O R- C-N -Br : HO - : : O R- C-N -Br H R- N= C= O An isocyanate 18-66 18 Hofmann Rearrangement • Stage 3: reaction of the isocyanate with water gives a carbamic acid R- N= C= O + H2 O An isocyanate O R- N- C-OH H A carbamic acid • Stage 4: decarboxylation of the carbamic acid gives the primary amine O R- N- C-OH H R- NH 2 + H2 O 18-67 18 Prob 18.19 Propose a structural formula for each compound. (a) C5 H1 0 O 2 (b) C7 H1 4 O 2 1 1 13 H-NMR C-NMR 0.96 (d, 6H) 161.11 1.96 (m, 1H) 70.01 3.95 (d, 2H) 27.71 8.08 (s, 1H) 19.00 H-NMR 13 C-NMR 0.92 (d, 6H) 171.15 1.52 (m, 2H) 63.12 1.70 (m, 1H) 37.31 2.09 (s, 3H) 25.05 4.10 (t, 2H) 22.45 21.06 18-68 18 Prob 18.19 (cont’d) Propose a structural formula for each compound. (c) C6 H1 2 O 2 (d) C7 H1 2 O 4 1 H-NMR 13 C-NMR 1.18 (d, 6H) 177.16 1.26 (t, 3H) 60.17 2.51 (m, 1H) 34.04 4.13 (q, 2H) 19.01 14.25 (e) C4 H7 ClO 2 1 13 H-NMR C-NMR 1.28 (t, 6H) 166.52 3.36 (s, 2H) 61.43 4.21 (q, 4H) 41.69 14.07 (f) C4 H6 O2 1 H-NMR 13 C-NMR 1.68 (d, 3H) 170.51 3.80 (s, 3H) 52.92 4.42 (q, 1H) 52.32 21.52 1 H-NMR 13 C-NMR 2.29 (m, 2H) 177.81 2.50 (t, 2H) 68.58 4.36 (t, 2H) 27.79 22.17 18-69 18 Prob 18.20 Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent. (a) (b) OH, py ridine SH , py r idine (d) N H2 (two equivalents) - (f) ( CH3 ) 2 CuLi, then H 3 O+ OH (c) O (e) (g)CH3 O O Na + N H2 , pyridine (h) C6 H5 MgBr (two equivalents), then H 3 O+ 18-70 18 Prob 18.26 Draw a structural formula for the product of treating this ,-unsaturated ketone with each reagent. O O OEt (a) (c) H2 ( 1 mol) Pd, EtOH 1 . LiA lH4 , THF 2 . H2 O (b) (d) N aBH4 CH3 OH 1 . DIBALH , - 7 8 ° 2 . H2 O 18-71 18 Prob 18.28 Draw a structural formula for the product of treating this anhydride with each reagent. H O O H (a) H2 O, HCl heat (d) CH3 OH (b) (e) O H2 O, N aOH heat (c) 1 . LiA lH4 2 . H2 O N H3 ( 2 m ole s) 18-72 18 Prob 18.31 Show how to bring about each step in this conversion of nicotinic acid to nicotinamide. O O COH COCH 2 CH 3 N Nicotinic acid (Niacin) ? N Ethyl nicotinate O ? CNH 2 N Nicotinamide 18-73 18 Prob 18.32 Complete these reactions. (a) CH3 O O O NH2 + CH3 COCCH3 O (b) CH3 CCl + 2HN O (c) CH3 COCH3 + HN (d) O NH2 + CH3 (CH2 ) 5 CH 18-74 18 Prob 18.35 Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid. O (a) H 2 N O O O O N H2 H N O NH (b) O Meprobamate O H N Phenobarbital O NH (c) O Pentobarbital 18-75 18 Prob 18.36 Show reagents to bring about each step in this synthesis of anthranilic acid. O O (1) O Phthalic anhydride O + CO NH 4 (2) CNH 2 O O COH CNH 2 O O COH (3) N H2 Anthranilic acid 18-76 18 Prob 18.37 Propose a mechanism for each step in this sequence. O RCN H2 + Br2 A primary amide - CH3 O N a + RN = C= O CH3 OH An isocyanate CH3 OH O RN HCOCH 3 A carbamate 18-77 18 Prob 18.38 Propose a mechanism for each step in this sequence. Br O O O CH3 O - N a+ Br2 Br COCH 3 CH3 OH (R)-(+)-Pulegone 18-78 18 Prob 18.39 Show how to prepare the insect repellent DEET from 3methyltoluic acid. O O OH 3-Methylbenzoic acid (m-Toluic acid) N N,N-Diethyl-m-toluamide DEET) 18-79 18 Prob 18.40 Show how to prepare isoniazid from 4-pyridinecarboxylic acid. O O ? N COH 4-Pyridinecarboxylic acid N CNH NH2 4-Pyridinecarboxylic acid hydrazide (Isoniazid) 18-80 18 Prob 18.41 Show how to bring about this conversion. C CH Phenylacetylene O CH2 COCH 2 CH = CH 2 Allyl phenylacetate 18-81 18 Prob 18.42 Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane Br ring. COOH COOH CH3 COOH Br2 O CH3 A bromolactone O many steps O HO COOH OH PGE 1 (alprostadil) 18-82 18 Prob 18.43 Propose a mechanism for this reaction. O H2 N OEt O + OEt O Diethyl diethylmalonate - H2 N Urea 1 . Et O Na + 2 . H2 O O 6 5 NH 1 4 3 2 O + 2 Et OH NH O 5,5-Diethylbarbituric acid (Barbital) 18-83 18 Prob 18.44 Propose a synthesis of this -chloroamine from anthranilic acid. Cl N H2 + 2 COOH 2-Aminobenzoic acid (Anthranilic acid) O several steps N O O 18-84 18 Prob 18.45 Show reagents for the synthesis of 5-nonanone from 1bromobutane as the only organic starting material. O O OH 5-Nonanone C N Br 1-Bromobutane 18-85 18 Prob 18.46 Describe a synthesis of procaine from the three named starting materials. O O H 2N Procaine N O OH H 2N 4-Aminobenzoic acid N + HO O + Ethylene oxide N H Diethylamine 18-86 18 Prob 18.47 The following sequence converts (R)-2-octanol to (S)-2octanol. Propose structural formulas for A and B, and specify the configuration of each. H3 C C OH H C6 H1 3 p- Ts Cl pyridine - A CH3 COO Na + DMSO (R)-2-Octanol B 1 . LiA lH4 2 . H2 O CH3 HO C H C6 H1 3 (S)-2-Octanol 18-87 18 Prob 18.48 Propose a mechanism for this reaction. O Et O OEt + H 2 N Diethyl carbonate Butylamine O Et O N + Et OH H Ethyl N-butylcarbamate 18-88 18 Prob 18.49 Propose a mechanism for this reaction. O O S N H- N a+ Sodium salt of p-toluenesulfonamide O + Et O N H A carbamic ester O O O S N N H H H3 C Tolbutamide (Oramide, Orinase) 18-89 18 Prob 18.50 Show how each hypoglycemic drug can be synthesized by converting an appropriate amine to a carbamate ester, and then treating its sodium salt with a substituted benzenesufonamide. (a) O O O N S N N H H Tolazamide (Tolamide, Tolinase) (b) O O O N S N N H H Gliclazide (Diamicron) 18-90 18 Prob 18.51 Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine. Br CH3 C N in H2 SO4 ( 1) 1-Bromoadamantane O NHCCH3 ( 2) NH2 Amantadine 18-91 18 Prob 18.52 • Propose structural formulas for intermediates A-F and for the configuration of the bromoepoxide. H OH 1 COOH HOOC (S)-Malic acid C (C9 H1 8 O4 ) 4 A ( C8 H1 4 O5 ) D 5 E 2 B 3 6 F (C4 H8 OBr 2 ) 7 O Br A bromoepoxide 1 . CH3 CH2 OH, H+ + 2. ,H O 3 . LiAlH4 , then H2 O 4 . TsCl, pyridine 6 . H2 O, CH3 COOH 7 . KOH 5 . NaBr, DMSO 18-92 18 Prob 18.53 Show reagents for the synthesis of (S)-Metolachlor from the named starting materials O Cl N O 1 O Cl O HN 2 OH + O N Chloroacetic acid (S)-Metolachlor O Acetone 3 5 O Cl + CH3 OH Methanol 4 N H2 O OCH3 + 2-Ethyl-6-methylaniline 18-93 18 Derivatives of Carboxylic Acids End Chapter 18 18-94