Chapter18

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Chapter18

  1. 1. OrganicChemistry William H. Brown Christopher S. Foote Brent L. Iverson 18-1
  2. 2. FunctionalDerivatives ofCarboxylic 18-2
  3. 3. Carboxyl Derivativesx 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 O group O O O O RCCl RCOCR RCOR RCNH2 RC N An acid An acid An ester An amide A nitrile chloride anhydride -H2 O -H2 O -H2 O -H2 O -H2 O O O O O O HO HRC-OH H-Cl RC-OH H-OCR RC-OH H-OR RC-OH H-NH2 RC=N The enol of an amide 18-3
  4. 4. Structure: Acid Chloridesx The functional group of an acid halide is an acyl group bonded to a halogen • the most common are the acid chlorides • to name, change the suffix -ic acid to -yl halide O O O O Cl Cl Cl RC- CH3 CCl O An acyl Ethanoyl chloride Benzoyl chloride Hexanedioyl chloride group (Acetyl chloride) (Adipoyl chloride) 18-4
  5. 5. Sulfonyl Chlorides • replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride O O CH3 SOH CH3 SCl O O Methanesulfonic Methanesulfonyl chloride acid (Mesyl chloride, MsCl) O O H3 C SOH H3 C SCl O O p-Toluenesulfonic p-Toluenesulfonyl chloride acid (Tosyl chloride, TsCl) 18-5
  6. 6. Acid Anhydridesx 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 O O CH3 COCCH3 COC Acetic anhydride Benzoic anhydride 18-6
  7. 7. Acid Anhydridesx Cyclic anhydrides are named from the dicarboxylic acids from which they are derived O O O O O O O O O S u c c in ic M le ic a P h t h a lic a n h y d r i d ea n h y d r i d e n h y d r i d e a 18-7
  8. 8. Phosphoric Anhydridesx A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom O O O O - - HO-P-O-P-OH O- P-O-P-O OH OH O- O- D ip h o s p h o r ic a c D ip h o s p h a t e io n id ( P y r o p h o s p h o r i c (a cyir o p h o s p h a t e i o n ) P d) O O O O O O - - HO-P-O-P-O-P-OH O- P-O-P-O-P-O O- O- O- O- O- O- T r i p h o s p h o r i c a c iT r i p h o s p h a t e i o n d 18-8
  9. 9. Estersx 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 OEt EtO O O Ethyl ethanoate Isopropyl Diethyl butanedioate (Ethyl acetate) benzoate (Diethyl succinate) 18-9
  10. 10. Estersx Cyclic esters are called lactones • name the parent carboxylic acid, drop the suffix -ic acid and add -olactone O a O a O b 2 2 1 1 3 1 a 2 O b3 O g 4 O H3 C 3 4 5 6 b g d e 3-Butanolactone 4-Butanolactone 6-H exanolactone (b-Butyrolactone) (g-Butyrolactone) (e-Caprolactone) 18-10
  11. 11. Esters of Phosphoric Acid • phosphoric acid forms mono-, di-, and triesters • name by giving the name of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate • in more complex phosphoric esters, it is common to name the organic molecule and then indicate the presence of the phosphoric ester by the word phosphate CHOthe prefix phospho- O or CHO O O HO C-H O HO CH2 O-P-O- CO- O CH3 OPOH - CH2 -O-P-O- O- C O P O OCH3 O- H3 C N CH2 O- Dimethyl Glyceraldehyde Pyridoxal phosphate Phosphoenol- phosphate 3-phosphate pyruvate 18-11
  12. 12. Amidesx 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 N - O O H O CH3 CH3 CNH2 CH3 C-N H-C-N CH3 CH3 Acetamide N-Methylacetamide N,N-Dimethyl- (a 1¡ amide) (a 2¡ amide) formamide (DMF) (a 3¡ amide) 18-12
  13. 13. Amidesx Cyclic amides are called lactams • name the parent carboxylic acid, drop the suffix -ic acid and add -lactam α O a O β 2 3 1 2 1 b3 γ 4 NH NH 5 6 H3 C δ ε 3-Butanolactam 6-Hexanolactam (b-Butyrolactam) (e-Caprolactam) 18-13
  14. 14. Penicillins • the penicillins are a family of β-lactam antibiotics HO Ο Τηε πενιχιλ ιν σ λ H H διφφερ ιν τηε NH S γρουπ βονδ εδ H2 N το τηε αχψλ χαρ ον β N β− αχταµ λ O COOH Amoxicillin (a β− αχταµ αν τιβ ιοτιχ) λ 18-14
  15. 15. Cephalosporins • the cephalosporins are also β-lactam antibiotics The cephalosporins differ in the group bonded to the acyl carbon and the side chain of the thiazine ring O H H S N NH2 H N O Me β− αχταµ λ COOH Cephalexin (Keflex) 18-15
  16. 16. Imidesx The functional group of an imide is two acyl groups bonded to nitrogen • both succinimide and phthalimide are cyclic imides O O NH NH O O Succinimide Phthalimide 18-16
  17. 17. Nitrilesx The functional group of a nitrile is a cyano group • IUPAC names: name as an alkanenitrile • common names: drop the -ic acid and add CH3 C N C N CH2 C N -onitrile Ethanenitrile Benzonitrile Phenylethanenitrile (Acetonitrile) (Phenylacetonitrile) 18-17
  18. 18. Acidity of N-H bondsx Amides are comparable in acidity to alcohols • water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water- soluble saltsx Sulfonamides and imides are more acidic than amides O O O O SNH2 NH NH CH3 CNH2 O O O Acetamide Benzenesulfonamide Succinimide Phthalimide pKa 15-17 pKa 10 pKa 9.7 pKa 8.3 18-18
  19. 19. Acidity of N-H bondsx 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 O O N N N O O O A resonance-stabilized anion 18-19
  20. 20. Acidity of N-H • imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts O O - + NH + NaOH N Na + H 2 O O O p Ka8 . 3 p Ka15 . 7 ( s t r o n g e r( s t r o n g e r (w eaker (w eaker a c id ) bas e) bas e) a c id ) 18-20
  21. 21. Characteristic Reactionsx Nucleophilic acyl substitution: an addition- elimination sequence resulting in substitution of one nucleophile for another - O :O O - - C + :Nu C C + :Y R Y R Nu R Nu Y Tetrahedral carbonyl Substitution addition intermediate product 18-21
  22. 22. Characteristic Reactions • in the general reaction, we showed the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group O - - - - R2 N RO RCO X Increasing leaving ability Increasing basicity 18-22
  23. 23. 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 18-23
  24. 24. Reaction with H 2 O - Acid Chlorides • low-molecular-weight acid chlorides react rapidly with water • higher molecular-weight acid chlorides are less soluble in water and react less readily O O CH3 CCl + H2 O CH3 COH + HCl Acetyl chloride 18-24
  25. 25. Reaction with H 2 O - Anhydrides • 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 O O CH 3 COCCH3 + H2 O CH3 COH + HOCCH3 Acetic anhydride 18-25
  26. 26. Reaction with H 2 O - Anhydrides • Step 1: addition of H 2 O to give a TCAI H + H O O H O O O +CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 CH3 -C-O-C-CH3 + H-O-H + O H O H O-H H H O-H Tetrahedral carbonyl H H addition intermediate • Step 2: protonation followed collapse of the TCAI H H H H H H +O O +O H H H H H + H O O O O O OCH3 -C-O-C-CH3 CH3 C O C CH3 CH3 C + O C CH3 O O O H H H 18-26
  27. 27. Reaction with H 2 O - Estersx Esters are hydrolyzed only slowly, even in boiling water • hydrolysis becomes more rapid if they are heated with either aqueous acid or basex 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 (a weak nucleophile) to form a tetrahedral carbonyl addition intermediate • collapse of this intermediate gives the carboxylic acid and alcohol 18-27
  28. 28. Reaction with H 2 O - Estersx Acid-catalyzed ester hydrolysis O + OH + O C H C H C + H2 O + CH3 OH R OCH3 R OH R OH OCH3 Tetrahedral carbonyl addition intermediate 18-28
  29. 29. Reaction with H 2 O - Estersx 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 O said to be base promoted O H2 O - + RCOCH 3 + NaOH 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 18-29
  30. 30. Reaction with H 2 O - Esters • Step 1: attack of hydroxide ion (a nucleophile) on the carbonyl carbon (an electrophile) • Step 2: collapse of the TCAI • Step 3: proton transfer to the alkoxide ion; this step is irreversible and drives saponification to completion O O O O (1) (2 )R-C-OCH3 + OH R-C OCH3 R-C + OCH3 (3 ) R-C + HOCH3 OH O O H 18-30
  31. 31. Reaction with H 2 O - Amidesx Hydrolysis of an amide in aqueous acid requires 1 mole of acid per mole of amide • reaction is driven to completion by the acid-base reaction between the amine or ammonia and the acid O O H2 O + - N H 2 + H 2 O + HCl heat OH + N H4 Cl Ph Ph 2-Phenylbutanamide 2-Phenylbutanoic acid 18-31
  32. 32. Reaction with H 2 O - Amidesx Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide • reaction is driven to completion by the irreversible formation of the carboxylate sale O O H2 O - + CH3 CNH + NaOH CH 3 CO Na + H2 N hea t N-Phenylethanamide Sodium Aniline (N-Phenylacetamide, acetate Acetanilide) 18-32
  33. 33. Reaction with H 2 O - Amides • Step1: protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate O +R C NH2 + H O H H +H H H O O O + R C NH2 R C NH2 R C NH2 + H2 O + Resonance-stabilized cation intermediate 18-33
  34. 34. Reaction with H 2 O - Amides • Step 2: addition of water (a nucleophile) to the carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI proton OH transfer from OH OH + O to N R C NH2 + O H R C NH2 R C NH3 + H O+ O H H H • Step 3: collapse of the TCAI and proton transfer H O + H O O + R C NH3 + R C + NH3 R C OH + NH4 OH OH 18-34
  35. 35. Reaction with H 2 O - Nitrilesx The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion O H2 O + - Ph CH 2 C N + 2 H2 O + H2 SO4 Ph CH2 COH + NH4 HSO4 he atPhenylacetonitrile Phenylacetic Ammonium acid hydrogen sulfate • protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid • keto-enol tautomerism gives the amide + OH O H R-C N + H2 O R-C NH R-C-NH2 An imidic acid An amide (enol of an amide) 18-35
  36. 36. Reaction with H 2 O - Nitriles • hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid O NaOH, H O 2 - + CH3 ( CH2 ) 9 C N CH3 ( CH 2 ) 9 CO Na + NH3 heat Undecanenitrile Sodium undecanoate HCl H 2 O O CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl Undecanoic acid 18-36
  37. 37. Reaction with H 2 O - Nitriles • hydrolysis of nitriles is a valuable route to carboxylic acids O KCN H2 SO4 , H2 O CH3 ( CH2 ) 8 CH2 Cl CH3 (CH2 ) 9 C N CH3 ( CH2 ) 9 COH ethanol, heat1-Chlorodecane Undecanenitrile Undecanoic acid water OH OH CHO HCN, KCN CN H2 SO4 , H2 O COOH ethanol, heat water Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid (Mandelonitrile) (Mandelic acid) (racemic) (racemic) 18-37
  38. 38. Reaction with Alcoholsx 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 O Cl + HO O + HCl Butanoyl Cyclohexanol Cyclohexyl butanoate chloride 18-38
  39. 39. Reaction with Alcohols • sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride (Section 18.1A) with an alcohol or phenol • the key point here is that OH - (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center OH OTs + TsCl pyridine (R)-2-Octanol p-Toluenesulfonyl (R)-2-Octyl p-toluenesulfonate chloride [(R)-2-Octyl tosylate] (Tosyl chloride) 18-39
  40. 40. Reaction with Alcoholsx Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid O O O CH3 COCCH3 + HOCH2 CH3 CH3 COCH2 CH 3 + CH3 COH Acetic anhydride Ethanol Ethyl acetate Acetic acid • cyclic anhydrides react with alcohols to give one O O and one carboxyl group ester group O O + HO OH O O Phthalic 2-Butanol anhydride (sec-Butyl alcohol) (sec-Butyl hydrogen phthalate 18-40
  41. 41. Reaction with Alcohols • aspirin is synthesized by treating salicylic acid with acetic anhydride COOH OH O O + CH COCCH 3 3 A e t ic c2 - H y d r o x y b e n z o acn h y d r i d e i a c id ( S a lic y lic a c id ) COOH O CH 3 O + CH 3 COH O A c e t y l s a l i c y l i c a A i de t i c a c i d c c ( A s p ir in ) 18-41
  42. 42. Reaction with Alcoholsx Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification O + HCl OCH 3 HO M e t h y l p r o p e n o a t1- B u t a n o l e ( M e t h y l a c r y l a t e () b p 117 ° C ) ( b p 8 1° C ) O O + CH 3 OH B u t y l p r o p e n o a tM e t h a n o l e ( B u t y l a c r y la t e ) b p 6 5 °C ) ( ( b p 14 7 ° C ) 18-42
  43. 43. Reaction with Ammonia, etc.x 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 O + - Cl + 2 NH3 NH2 + NH4 Cl Hexanoyl Ammonia Hexanamide Ammonium chloride chloride 18-43
  44. 44. Reaction with Ammonia, etc.x Acid anhydrides react with ammonia, and 1° and 2° amines to form amides • 2 moles of ammonia or amine are required O O O O CH3 COCCH3 + 2 NH3 CH3 CNH2 + CH3 CO- NH 4 + Acetic Ammonia Acetamide Ammonium anhydride acetate 18-44
  45. 45. Reaction with Ammonia, etc.x Esters react with ammonia, and 1° and 2° amines to form amides • esters are less reactive than either acid halides or acid anhydrides O O Ph Ph OEt + NH3 NH2 + Et OH Ethyl phenylacetate Phenylacetamide Ethanolx Amides do not react with ammonia, or 1° or 2° amines 18-45
  46. 46. Acid Chlorides with Saltsx Acid chlorides react with salts of carboxylic acids to give anhydrides • most commonly used are sodium or potassium salts O O O O + - CH3 CCl + Na OC CH3 COC + Na + Cl - Acetyl Sodium benzoate Acetic benzoic chloride anhydride 18-46
  47. 47. Interconversions 18-47
  48. 48. Reaction with Grignard Reagents • treating a formic ester with 2 moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol O magnesium H O, HCl OH HCOCH3 + 2 RMgX alkoxide 2 HC-R + CH 3 OH salt R An ester of A 2¡ alcohol formic acid 18-48
  49. 49. Reaction with Grignard Reagents • treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol O magnesium H O, HCl OH CH3 COCH3 + 2 RMgX alkoxide 2 CH3 C-R + CH3 OH salt R An ester of any acid A 3¡ alcoholother than formic acid 18-49
  50. 50. Reaction with Grignard Reagents 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) - + 1 O 2 O [MgX] O - +CH3 -C-OCH3 + R MgX CH3 -C OCH3 CH3 -C + CH3 O [ MgX] R 2 R 1 A magnesium salt A ketone (a tetrahedral carbonyl addition intermediate) 18-50
  51. 51. Reaction with Grignard Reagents 3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI 4. treatment with aqueous acid gives the alcohol - + O 3 O [MgX] OH 3 CH3 -C + R MgX CH 3 -C-R H2 O, HCl CH 3 -C-R R R (4) R A ketone Magnesium salt A 3¡ alcohol 18-51
  52. 52. Reactions with RLix 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 OH O 1 . 2 R Li RCOCH 3 R- C-R + CH3 OH 2 . H2 O, HCl R 18-52
  53. 53. Gilman Reagentsx 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 O 1 . (CH 3 ) 2 CuLi, ether, -78 °C Cl 2 . H O 2P e n t a n o y l c h lo r id e 2 -H e x a n o n e 18-53
  54. 54. 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 1 . ( CH3 ) 2 CuLi, ether, -78¡ C H3 CO Cl 2 . H2 O O O H3 CO O 18-54
  55. 55. Reduction - Esters by LiAlH 4x Most reductions of carbonyl compounds now use hydride reducing agents • esters are reduced by LiAlH 4 to two alcohols • the alcohol derived from the carbonyl group is primary O Ph Ph 1 . LiAlH 4 , e t her OH + CH 3 OH OCH 3 2 . H 2 O, HCl 2 - P h e n y l - 1- M t h a n o l eM e t h y l 2 -p h e n y l- propa nol p ro p a no a te 18-55
  56. 56. Reduction - Esters by LiAlH 4x Reduction occurs in three steps plus workup • Steps 1 and 2 reduce the ester to an aldehyde O O O (1) (2) R C OR + H R C OR R C + OR H H A tetrahedral carbonyl addition intermediate • Step 3 reduction of the aldehyde followed by work up gives a 1° alcohol O O OH (3) (4) R C + H R C H R C H H H H A 1¡ alcohol 18-56
  57. 57. Reduction - Esters by NaBH 4x NaBH 4 does not normally reduce esters, but it does reduce aldehydes and ketonesx Selective reduction is often possible by the proper choice of reducing agents and experimental conditions O O OH O NaBH4 OEt EtOH OEt (racemic) 18-57
  58. 58. Reduction - Esters by DIBAlHx 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 1 . DIBALH , toluene, -78¡C OCH 3 2 . H2 O, HCl Methyl hexanoate O H + CH3 OH Hexanal 18-58
  59. 59. Reduction - Amides by LiAlH 4x LiAlH 4 reduction of an amide gives a 1° , 2° , or 3° amine, depending on the degree of substitution of the amide O 1 . LiAlH4 NH2 NH2 2 . H2 O Octanamide 1-Octanamine O NMe2 NMe 2 1 . LiAlH4 2 . H2 O N,N-Dimethylbenzamide N,N-Dimethylbenzylamine 18-59
  60. 60. Reduction - Amides by LiAlH 4x The mechanism is divided into 4 steps • Step 1: transfer of a hydride ion to the carbonyl carbon • Step 2: a Lewis acid-base reaction and formation of an oxygen-aluminum bond O O AlH3 O (1) (2) R C NH2 + H AlH3 R C NH2 + AlH3 R C NH2 H H 18-60
  61. 61. Reduction - Amides by LiAlH 4 • Step 3: redistribution of electrons and ejection of H 3 AlO - gives an iminium ion • Step 4: transfer of a second hydride ion to the iminium ion completes the reduction to the amine AlH3 H O (3) (4) R C N H R C N H R-CH2 -NH2 H H H H An iminium ion A 1¡ amine 18-61
  62. 62. Reduction - Nitriles by LiAlH 4x The cyano group of a nitrile is reduced by LiAlH 4 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 18-62
  63. 63. Interconversions Problem: show reagents and experimental conditions to bring about each reaction O Ph Cl (a) (b) (c) O O OPh (d) (e) Ph OH Ph NH2 OMe Phenylacetic acid (g) (h) (f) Ph Ph NH2 OH 18-63
  64. 64. Derivatives ofCarboxylic Acids End Chapter 18 18-64

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