Organic chemistry fundamentals

1. 18-1
Carboxyl Derivatives
Classes shown, formally, via dehydration.
H-NH2H-Cl H-OR'RC-OH
O
H-OCR'
O
RC=N
HO H
RC-OH
O
RC-OH
O
RC-OH
O
-H2 O -H2 O -H2 O -H2 O
-H2 O
RC NRCNH2
O
RCCl
O
RCOR'
O
RCOCR'
O O
The enol of
an amide
An acid
chloride
An esterAn acid
anhydride
An amide A nitrile

2. 18-2
Structure: Acid Chlorides
 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 -oic acid to -oyl halide.
CH3CCl
OO
RC-
Cl
O
Cl
O
Cl
O
Benzoyl chlorideEthanoyl chloride
(Acetyl chloride)
An acyl
group
Hexanedioyl chloride
(Adipoyl chloride)

3. 18-3
Related: Sulfonyl Chlorides
• Replacement of -OH in a sulfonic acid by -Cl gives a
sulfonyl chloride.
SOHH3 C
O
O
CH3SOH
O
O
SClH3 C
O
O
CH3 SCl
O
O
Methanesulfonic
acid
p-Toluenesulfonic
acid
Methanesulfonyl chloride
(Mesyl chloride, MsCl)
p-Toluenesulfonyl chloride
(Tosyl chloride, TsCl)

4. 18-4
Structure: Acid Anhydrides
 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.
COC
O O
CH3 COCCH3
O O
Benzoic anhydrideAcetic anhydride

5. 18-5
Acid Anhydrides
 Cyclic anhydrides are named from the
dicarboxylic acids from which they are derived.
Maleic
anhydride
O
O
O
Phthalic
anhydride
Succinic
anhydride
O
O
O
O
O
O

6. 18-7
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
EtO
O
OEt
O
O
O
Ethyl ethanoate
(Ethyl acetate)
Diethyl butanedioate
(Diethyl succinate)
Isopropyl
benzoate

7. 18-8
Esters; Lactones
 Lactone: A cyclic ester.
• name the parent carboxylic acid, drop the suffix -ic
acid and add -olactone.
4-Butanolactone
-Butyrolactone)
3-Butanolactone
-Butyrolactone)



O O
O
O
H3 C
2
3
1
2
1
3 4
6-Hexanolactone
-Caprolactone)




O
O
2
13
4
5 6

8. 18-10
Amides
 The functional group of an amide is an acyl
group bonded to a nitrogen atom.
• drop -oic acid from the name of the parent acid and
add -amide. (For the common acid name, drop -ic of
the acid name and add -amide.)
• an alkyl or aryl group bonded to the N: name the group
and show its location on nitrogen by N-.
CH3CNH2
O
CH3 C-N
H
CH3
O
H-C-N
CH3
CH3
O
N-Methylacetamide
(a 2° amide)
Acetamide
(a 1° amide)
N,N-Dimethyl-
formamide (DMF)
(a 3° amide)
ethanamide

9. 18-11
Amides: resonance

10. 18-12
Amides; Characteristics

11. 18-13
Amides; Lactams
 Lactams: A cyclic amides are called lactams.
• Name the parent carboxylic acid, drop the suffix -ic
acid and add -lactam.



 
6-Hexanolactam
-Caprolactam)


H3 C
O
NH
O
NH
1
2 1
2
3
4
5 6
3
3-Butanolactam
-Butyrolactam)
Indicates where the N is located.

12. 18-14
Imides
 The functional group of an imide is two acyl
groups bonded to nitrogen.
• Both succinimide and phthalimide are cyclic imides.
PhthalimideSuccinimide
NH NH
O O
OO

13. 18-15
Related: Nitriles
 The functional group of a nitrile is a cyano group
• IUPAC names: name as an alkanenitrile.
• common names: drop the -ic acid and add -onitrile.
CH3 C N C N CH2 C N
Ethanenitrile
(Acetonitrile)
Benzonitrile Phenylethanenitrile
(Phenylacetonitrile)

14. 18-16
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.
CH3CNH2
O
O
O
SNH2 NH
O
O
NH
O
O
pKa 8.3pKa 9.7pKa 10
PhthalimideSuccinimideBenzenesulfonamideAcetamide
pKa 15-17

15. 18-17
Acidity of N-H bonds
 Effect of neighboring carbonyl groups.
1.0

16. 18-18
Acidity of N-H
• Imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts.
(stronger
acid)
(weaker
acid)
(weaker
base)
(stronger
base)
pKa 15.7pKa 8.3
++
O
O
NH N
-
Na
+
O
O
NaOH H2 O

17. 18-19
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. More resonance delocalization of the negative charge.
O
O
N N
O
O
A resonance-stabilized anion
N
O
O

18. 18-20
Lab related: Sulfonamides (Hinsberg)
Experimental test to distinguish primary, secondary and
tertiary amines.
In acidIn base
Reaction replaces one H with the sulfonyl group. In
an H remains it is soluble in base.
1
2
3
soluble
soluble
insoluble
insoluble

19. 18-21
Characteristic Reactions: Ketones & Aldehydes
 Nucleophilic acyl Addition:
Protonation makes carbonyl better electrophile. Ok with
poor nucleophile.
Carbonyl weaker electrophile.
Need good nucleophile.

20. 18-22
Characteristic Reactions: Derivatives
 Nucleophilic acyl substitution: An addition-
elimination sequence resulting in substitution of
one nucleophile for another.
Tetrahedral carbonyl
addition intermediate
++ C
NuR
C
Y R
C
NuR
O
Y
O
:Nu :Y
Substitution
product
O
Dominant for derivatives due to good leaving group (Y),
uncommon for ketones or aldehydes.

21. 18-23
Characteristic Reactions
Poor bases make good leaving groups.
R2 N-
RO-
O
RCO-
X-
Increasing basicity
Increasing leaving ability
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.

22. 18-24
Water and 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.
CH3CCl
O
H2O CH3COH
O
HCl++
Acetyl chloride

23. 18-25
Water and Anhydrides
• Low-molecular-weight anhydrides react readily with
water to give two molecules of carboxylic acid.
• Higher-molecular-weight anhydrides also react with
water, but less readily.
CH3COCCH3
O O
H2O CH3COH
O
HOCCH3
O
++
Acetic anhydride

24. 18-26
Mechanism- Anhydrides
• Step 1: Addition of H2O to give a TCAI. (Addition)
O
CH3 -C- O-C- CH3
H
H
O-H
O
O HH
CH3 -C- O-C- CH3
H
H
O-H
CH3 -C- O-C- CH3
O
O
H
H
H- O-H
H
+
+
+
Tetrahedral carbonyl
addition intermediate
+
OO
Acid makes carbonyl better electrophile.

25. 18-27
Mechanism- Anhydrides
• Step 2: Protonation and collapse of the TCAI. (Elimination)
O
CH3 -C-O-C-CH3
O
H
O
H
H
+ O
H H
CH3 C
O
O
O C
O
CH3
H
H
O
H
H
+
CH3 C O
O
O
C CH3
O
H
H
H
H
H+ H
+
O
Acid sets up better leaving group.

26. 18-28
Water and Esters
 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.
• acid catalyst protonates the carbonyl oxygen and
increases 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.

27. 18-29
Mechanism: Acid/H2O - Esters (1o and 2o alkoxy)
 Acid-catalyzed ester hydrolysis.
R OCH3
C
O
H2 O
H+
OH
C
R
OCH3
OH
H+
R OH
C
O
CH3 OH+ +
Tetrahedral carbonyl
addition intermediateAcid makes
carbonyl
Better
electrophile.
Acid sets up
leaving group.

28. 18-30
Mechanism: Reaction with Acid/H2O – Esters (3o alkoxy)
alcohol
water
But wait!!!!!!!

29. 18-31
Reaction with Base/H2O - Esters
 Saponification: The hydrolysis of an esters in
aqueous base.
• 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
+
CH3OH++

30. 18-32
Mechanism of Reaction with Base/H2O – Esters
• Step 1: Attack of hydroxide ion (a nucleophile) on the
carbonyl carbon (an electrophile). (Addition)
• Step 2: Collapse of the TCAI. (Elimination)
• Step 3: Proton transfer to the alkoxide ion; this step is
irreversible and drives saponification to completion.
R- C-OCH3
O
OH R- C
O
OH
OCH3
R- C
O
O
H
R- C
O
O
HOCH3
(1)
+
(2) (3)
+ +OCH3

31. 18-33
Acidic Reaction with H2O - Amides
 Hydrolysis of an amide in aqueous acid requires
one 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.
2-Phenylbutanoic acid2-Phenylbutanamide
++ +
heat
H2 O HCl
H2 O
NH4
+
Cl
-
Ph
NH2
O
Ph
OH
O

32. 18-34
Basic Reaction with H2O - Amides
 Hydrolysis of an amide in aqueous base requires
one mole of base per mole of amide.
• Reaction is driven to completion by the irreversible
formation of the carboxylate salt.
CH3 CNH
O
NaOH
H2O
CH3 CO-
Na+
O
H2N
AnilineSodium
acetate
N-Phenylethanamide
(N-Phenylacetamide,
Acetanilide)
++
heat

33. 18-35
Mechanism: Acidic H2O - Amides
• Step1: Protonation of the carbonyl oxygen gives a
resonance-stabilized cation intermediate.
R C
O
NH2 OH H
H
O
C NH2R
H
O
C NH2R
H
C
O
NH2R
H
H2 O
Resonance-stabilized cation intermediate
+
+
+
+
+
+

34. 18-36
Acidic H2O - Amides
• Step 2: Addition of water (a nucleophile) to the carbonyl carbon
(an electrophile) followed by proton transfer gives a TCAI.
• Step 3: Collapse of the TCAI and proton transfer. (Elimination)
R C
OH
C OHRNH3
H
C
O
NH3
+
R
OH
NH4
+
++
O
+
O
H
+
+ O
H
H C
OH
NH2R
O
H H
C
OH
NH3
+
R
O
+
C
OH
NH2R
H
proton
transfer from
O to N

35. 18-37
Mechanism: Reaction with Basic H2O - Amides
Amide
hydroxide ion
Dianion!

36. 18-38
Acidic H2O and Nitriles
 The cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion.
• Protonation of the cyano nitrogen gives a cation that
reacts with water to give an imidic acid.
• Keto-enol tautomerism gives the amide.
Ph CH2C N 2H2O H2 SO4
H2O
Ph CH2COH
O
NH4
+
HSO4
-
Ammonium
hydrogen sulfate
Phenylacetic
acid
Phenylacetonitrile
+
heat
++
R-C N H2 O H
+
NH
OH
R-C R-C-NH2
O
An imidic acid
(enol of an amide)
+
An amide
Acid
+
Ammonium
ion

37. 18-39
Basic H2O and Nitriles
• 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) 9C N
NaOH, H2O
O
CH3( CH2) 9COH
CH3( CH2)9 CO
-
Na
+
O
HCl H2 O
NaCl
NH3
NH4 Cl
Sodium undecanoateUndecanenitrile
+
heat
Undecanoic acid
+ +

38. 18-40
Synthesis: Reaction with H2O - Nitriles
• Hydrolysis of nitriles is a valuable route to carboxylic
acids.
CHO HCN, KCN CN
OH
H2 SO4 , H2 O COOH
OH
heat
Benzaldehyde Benzaldehyde cyanohydrin
(Mandelonitrile)
(racemic)
2-Hydroxyphenylacetic acid
(Mandelic acid)
(racemic)
ethanol,
water
CH3( CH2 ) 8 CH2 Cl
KCN H2 SO4 , H2 O
CH3 ( CH2 ) 9COH
heatethanol,
water
O
CH3 ( CH2 ) 9C N
1-Chlorodecane Undecanenitrile Undecanoic acid

39. 18-41
RCR'
NH
Synthesis: Grignards + Nitriles ->ketone 1
 Grignard reagents add to carbon-nitrogen triple
bonds in the same way that they add to carbon-
oxygen double bonds.
 The product of the reaction is an imine.
RC N
R'MgX
RCR'
NMgX
H2O
diethyl
ether

40. 18-42
Synthesis: Grignards + Nitriles ->ketone 2
RC N
R'MgX
RCR'
NMgX
H2O
RCR'
NH
diethyl
ether
RCR'
O
H3O+
Imines hydrolyzed to ketones.

41. 18-43
Reaction of Alcohols and Acid Halides
 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.
Butanoyl
chloride
Cyclohexyl butanoate
+
Cyclohexanol
HO HClCl
O
+ O
O

42. 18-44
Reaction with Alcohols, Sulfonic Esters
• Sulfonic acid esters are prepared by the reaction of an
alkane- or arenesulfonyl chloride 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.
(R)-2-Octanol p-Toluenesulfonyl
chloride
(Tosyl chloride)
(R)-2-Octyl p-toluenesulfonate
[(R)-2-Octyl tosylate]
OH
+ TsCl pyridine
OTs

43. 18-45
Reaction of Alcohols and Acid Anhydrides
 Acid anhydrides react with alcohols to give one
mole of ester and one mole of a carboxylic acid.
• Cyclic anhydrides react with alcohols to give one ester
group and one carboxyl group.
(sec-Butyl hydrogen
phthalate
2-Butanol
(sec-Butyl alcohol)
+
Phthalic
anhydride
O
O
O
O
OHHO
O
O
Acetic acidEthyl acetateEthanolAcetic anhydride
++CH3 COCCH3 HOCH2 CH3 CH3 COCH2 CH3 CH3 COH
O O OO

44. 18-46
Reaction of Alcohols and Esters
 Esters react with alcohols in the presence of an
acid catalyst in an equilibrium reaction called
transesterification.
Butyl propenoate
(Butyl acrylate)
(bp 147°C)
1-Butanol
(bp 117°C)
Methyl propenoate
(Methyl acrylate)
(bp 81°C)
+
+
HCl
CH3 OH
Methanol
(bp 65°C)
OCH3
O
HO
O
O

45. 18-47
Reaction of Ammonia, etc. and Acid Halides
 Acid halides react with ammonia, 1° amines, and
2° amines to form amides.
• Two moles of the amine are required per mole of acid
chloride.
Cl
O
2NH3 NH2
O
NH4
+
Cl
-
+ +
Hexanoyl
chloride
Ammonia Hexanamide Ammonium
chloride

46. 18-48
Reaction of Ammonia, etc. and Anhydrides.
 Acid anhydrides react with ammonia, and 1° and
2° amines to form amides.
• Two moles of ammonia or amine are required.
CH3 COCCH3
O O
2NH3 CH3 CNH2
O
CH3 CO-
NH4
+
O
+ +
Acetic
anhydride
Ammonia Acetamide Ammonium
acetate

47. 18-49
Ammonia, etc. and Esters
 Esters react with ammonia and with 1° and 2°
amines to form amides.
• Esters are less reactive than either acid halides or acid
anhydrides.
 Amides do not react with ammonia or with 1° or
2° amines.
Ph
OEt
O
NH3
Ph
NH2
O
Et OH
PhenylacetamideEthyl phenylacetate
+ +
Ethanol

48. 18-50
Acid Chlorides with Salts
 Acid chlorides react with salts of carboxylic
acids to give anhydrides.
• Most commonly used are sodium or potassium salts.
+ +CH3 CCl -
OC CH3 COC Na+
Cl -Na
+
O O O O
Acetyl
chloride
Sodium
benzoate
Acetic benzoic
anhydride

49. 18-51
Interconversions of Acid Derivatives

50. 18-52
Grignard and an Ester.
Look for two kinds of reactions.
R' OEt
O
R-Mg-X
R' OEt
O
R
R' R
O
R-Mg-X
R' R
OMgX
R
R' R
OH
R
But where does an ester
come from?
R'COCl
EtOH
Acid
chloride
R'CO2H
SOCl2
Perhaps this carboxylic
acid comes from the
oxidation of a primary
alcohol or reaction of a
Grignard with CO2.
Substitution
Addition
Any
alcohol
will do
here.

51. 18-53
Grignard Reagents and Formic Esters
• Treating a formic ester with two moles of Grignard
reagent followed by hydrolysis in aqueous acid gives a
2° alcohol.
HCOCH3
O
2RMgX
H2O, HCl
HC-R
R
OH
CH3 OH+
magnesium
alkoxide
salt
A 2° alcoholAn ester of
formic acid
+

52. 18-54
Reactions with RLi
 Organolithium compounds are even more
powerful nucleophiles than Grignard reagents.
RCOCH3
1 . 2 R' Li
2 . H2 O, HCl
R- C-R'
O
R'
OH
+ CH3 OH

53. 18-55
Gilman Reagents
 Acid chlorides at -78°C react with Gilman
reagents to give ketones.
1 . ( CH3 ) 2 CuLi, ether, -78°C
2 . H2 O
Pentanoyl chloride 2-Hexanone
Cl
O O
Gilman Reagents do not react with acid
anhydrides, esters, amides or nitriles under these
conditions. Selective reaction.

54. 18-56
Synthesis: Reduction - Esters by LiAlH4
 Most reductions of carbonyl compounds use
hydride reducing agents.
• Esters are reduced by LiAlH4 to two alcohols.
• The alcohol derived from the carbonyl group is
primary.
Methanol2-Phenyl-1-
propanol
(racemic)
Methyl 2-phenyl-
propanoate
(racemic)
+1 . LiAlH4 , et her
2 . H2 O, HCl
CH3 OHPh
OCH3
O Ph
OH

55. 18-57
Mechanism: Reduction - Esters by LiAlH4
 Reduction occurs in three steps plus workup:
• Steps 1 and 2 reduce the ester to an aldehyde.
• Step 3: Work-up gives a 1° alcohol derived from the
carbonyl group.
A 1° alcohol
R C
H
O
+ H
(3)
R C H
O
H
(4)
R C H
OH
H
A tetrahedral carbonyl
addition intermediate
(1)
R C OR'
O
+ H R C OR'
O
H
R C
H
O
(2)
OR'+

56. 18-58
Synthesis: Selective Reduction by NaBH4
 NaBH4 reduces aldehydes and ketones. It does
not normally reduce esters. LiAlH4 reduces all.
 Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions.
OEt
O O NaBH4
EtOH OEt
OH O
(racemic)

57. 18-59
Synthesis: Reduction - Esters by DIBAlH -> Aldehyde
 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.
Hexanal
Methyl hexanoate
+
1 . DIBALH, toluene, -78°C
2 . H2 O, HCl
CH3 OH
OCH3
O
H
O

58. 18-60
Synthesis: Reduction - Amides by LiAlH4
 LiAlH4 reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution
of the amide.
NH2
O
1. LiAlH4
2. H2O
1. LiAlH4
2. H2O
NMe2
O
NMe2
NH2
Octanamide 1-Octanamine
N,N-Dimethylbenzamide N,N-Dimethylbenzylamine

59. 18-61
Synthesis: Reduction - Nitriles by LiAlH4
 The cyano group of a nitrile is reduced by LiAlH4
to a 1° amine.
6-Octenenitrile
6-Octen-1-amine
CH3 CH= CH( CH2 ) 4 C
1 . LiAlH4
2 . H2 O
CH3 CH= CH( CH2 ) 4 CH2 NH2
N
Can use catalytic hydrogenation also.

60. 18-62
Interconversions
Problem: Show reagents and experimental conditions to
bring about each reaction.
Ph
OH
O
OMe
O
Ph
Ph
OH
Ph
Cl
O
Ph
NH2
Ph
NH2
O
Phenylacetic
acid
(a) (b) (c)
(d) (e)
(f)
(g) (h)