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CH-5Organic Chemistry-2
Prepared By
Dr. Khalid Ahmad Shadid & Prof Dr. Abdelfattah Haikal
Islamic University in Madinah
Department of Chemistry
Carboxylic Acids and Their DerivativesCarboxylic Acids and Their DerivativesNucleophilic Addition–Elimination at the Acyl Nucleophilic Addition–Elimination at the Acyl
CarbonCarbon
1. Introduction Carboxylic Acid Derivatives
O
R Clacid chloride
O
R OHcarboxylic acid
O
R OR'ester
O
R NR'2amide
O
R O R'
O
acid anhydride
2. Nomenclature and Physical Properties
Nomenclature of Carboxylic Acids ● Rules
Carboxylic acid as parent (suffix): ending with “–oic acid”
Carboxylic AcidsCarboxylic Acids
ExamplesExamples
O
OHEthanoic acid(acetic acid)
O
OH
( E )-2-Hexenoic acid
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Carboxylate SaltsCarboxylate Salts Nomenclature of Carboxylic Salts
● Rules Carboxylate as parent (suffix): ending with “–
oate”
ExamplesExamples
Sodium benzoate
O Na
O
Potassium butanoateO
O K
Acidity of Carboxylic AcidsAcidity of Carboxylic AcidsMost unsubstituted carboxylic acids have Ka values in the range of lit 10-4 - 10-5 (pKa 4-5).
These relative acidities mean that carboxylic acids react readily with aqueous solutions of sodium hydroxide and sodium bicarbonate to form soluble sodium salts.
Carboxylic acids having electron-withdrawing groups are stronger than unsuhslituled acids. The chloroacetic acids, show the following order of acidities:
pKa 0.70 1.48
O
OH
ClCl
ClO
OH
HCl
ClO
OH
HH
ClO
OH
HH
H> > >
2.86 4.76
Stability of conjugate bases
O
O
ClCl
ClO
O
HCl
Cl>
O
O
HH
Cl>
O
O
HH
H>>>
> >> >
The acid-strengthening effect of electron- withdrawing groups arises from a combination of inductive effects and entropy effects.
The acid-strengthening effect decreases as distance between the electron-withdrawing group and the carboxyl group increases.
4-Chlorobutanoic acid(pKa = 4.50)
O
OHCl
2-Chlorobutanoic acid(pKa = 2.85)
O
OH
Cl3-Chlorobutanoic acid
(pKa = 4.05)
O
OH
Cl
>
> > >> > >>
>
Dicarboxylic AcidsDicarboxylic AcidsDicarboxylic acids are named as alkanedioic acids in the IUIPAC systematic or substitutive system.
HO2C CO2H
HO2CCH2CO2H
HO2C(CH2)4CO2H
CO2H
CO2H
StructureCommon
Name mp (oC) pK1
pKa
(at 25oC)
pK2
Oxalic acid
Malonic acid
Adipic acid
Phthalic acid
189 dec
136
153
206-208 dec
1.2
2.9
4.4
2.9
4.2
5.7
5.6
5.4
EstersEsters
The names of esters are derived from the names of the alcohol (with the ending -yl) and the acid (with the ending -ate or -oate). The portion of the name derived from the alcohol comes first.
O
OCH3
Methyl propanoate
O
O
Ethyl ( E )-2-butenoate
Esters are polar compounds, but, lacking a hydrogen attached to oxygen, their molecules cannot form hydrogen bonds to each other. As a result, esters have boiling points that are lower than those of acids and alcohols of comparable molecular weight.
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Carboxylic AnhydridesCarboxylic Anhydrides Nomenclature of Carboxylic Anhydrides
● Rules Most anhydrides are named by dropping the
word acid from the name of the carboxylic acid and then adding the word “anhydride”
Example O
O
OEthanoic anhydride(acetic anhydride)
Acyl Chlorides
Acyl chlorides are also called acid chlorides. They are named by dropping -ic acid from the name of the acid and then adding -yl chloride.
Acyl chlorides and carboxylic anhydrides have boiling points in the same range as esters of comparable molecular weight.
Cl
O
Benzoyl chloride
AmidesAmides that have no substituent on nitrogen are named by dropping -ic acid from the common name of the acid (or -oic acid from the substitutive name) and then adding -amide. Alkyl groups on the nitrogen atom of amides are named as substituents, and the named substituent is prefaced by N- or N, N-.
O
NH'2Ethanamide
NitrilesCarboxylic acids can he converted to nitriles and vice versa. In IUPAC substitutive nomenclature, acyclic nitriles are named by adding the suffix -nitrile to the name of the corresponding hydrocarbon. The carbon atom of the -CN group is assigned number 1.
Ethanenitrile
H3C C N
Preparation of Carboxylic Acids1. By oxidative cleavage of alkenes
● Using KMnO4
Ph
Ph O
O
OH
OH
1. KMnO4, HO , heat
2. H3O+
+
● Using ozonolysis
1. O3
2. H2O2
OHOHO O
2. By oxidation of aldehydes & 1o alcohols
H
O
OH
O
1. Ag2O
2. H3O+
OH O
OH
1. KMnO4, HO , heat
2. H3O+
H
O
OHorH2CrO4
OH
O
3. By oxidation of alkyl benzene
1. KMnO4, HO , heat
2. H3O+
ROH
O
(R = 1o or 2o alkyl groups)
4. By Oxidation of methyl Ketones
5. By oxidation of Cyanohydrines and other Nitriles
Nitriles can also be prepared by nucleophilic substitution reactions of alkyl halides with sodium cyanide. Hydrolysis of the nitrile yields a carboxylic acid with a chain one carbon atom longer than the original alkyl halide.
6. By Carbonation of Grignard Reagent
Problem
Show how each of the following compounds could be converted to benzoic acid.
(a) Ethylbenzene (b) Acetophenone
(c) Benzyl alcohol (d) Bromobenzene
(e) Phenylethene (f) Benzaldehyde
Nucleophilic Addition-Elimination at the Acyl Carbon A characteristic reaction of aldehydes and ketones is one
of nucleophilic addition to the carbon-oxygen double bond. Carboxylic acids and their derivatives are characterized by a nueleophilic addition-elimination mechanism that takes place at their acyl (carbonyl) carbon atoms.
It is after the initial nucleophilic attack has taken place that the two reactions differ. The tetrahedral intermediate formed from an aldehyde or ketone usually accepts a proton to form a stable addition product.
In contrast, the intermediate formed from an acyl compound usually eliminates a leaving group; this elimination leads to regeneration of the carbon-oxygen double bond and to a substitution product. The overall process in the case of acyl substitution occurs, therefore, by a nucleophilic addition-elimination mechanism.
Nucleophilic Addition-Elimination at the Acyl Carbon
NuO
R Y+
O
RY
Nu
Y
O
R Nu+
(Y = leaving group, e.g. OR, NR2, Cl)
NuO
R Y+ Y
O
R Nu+
(Y = leaving group, e.g. OR, NR2, Cl)
This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism
This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives
O
R Clacid chloride
O
R OHcarboxylic acid
O
R OR'ester
O
R NR'2amide
O
R O R'
O
acid anhydride
Unlike carboxylic acids and their derivatives, aldehydes and ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of an acyl leaving group
O
R Ya carboxylic acid
derivative
O
R H
O
R R'
A good leaving group
Not a good leaving group
Acyl compounds react as they do because they all have good, or reasonably good, leaving groups (or they can be protonated to have good leaving groups) attached to the carbonyl carbon atom. An acyl chloride, for example, generally reacts by losing a chloride ion- a very weak base and thus a very good leaving group.
Relative Reactivity of Acyl Compounds
The general order of reactivity of acid derivatives can be explained by taking into account the basicity of the leaving groups. When acyl chlorides react, the leaving group is a chloride ion, and when amides react, the leaving group is an amine (or ammonia). The chloride ions are the weakest bases and acyl chlorides are the must reactive acyl compounds. Amines (or ammonia) are the strongest bases and amides are the least reactive acyl compounds.
Acyl ChloridesAcyl Chloridessynthesis of acyl chloridessynthesis of acyl chlorides
(COCl)2
Oxalyl chloride
OCl
O
O
R
O
Cl
OCl
O
O
R
O
Cl
O
R OH
ClCl
O
O
Mechanism
OCl
O
O
R
O
O
R Cl+ CO2 + CO + Cl
Cl
Oxalyl chloride
Reactions of Acyl Chlorides
Acyl chlorides also react with water and (even more Acyl chlorides also react with water and (even more rapidly) with rapidly) with aqueous base.aqueous base.
O
R OHB H +
O
R OH
H
OH
R OHCl
O
RCl
OH
H
O
R Cl H2O
MechanismMechanism
B:
Carboxylic Acid AnhydridesSynthesis of Carboxylic AcidSynthesis of Carboxylic Acid AnhydridesAnhydrides
O
R' Cl
O
R OH N
+
+ +
O
R O R'
O
N
H
Cl
Carboxylic acids react with acyl chlorides in the presence of pyridine to give carboxylic acid anhydrides.
O
R' Cl
O
R O Na++
O
R O R'
ONa Cl
OH
OH
O
O
300oC+O
O
OSuccinicacid
Succinicanhydride
H2O
230oC
OH
OHO
O
O
O
O
H2O
Phthalicacid
Phthalic anhydride(~100%)
+
Sodium salts of carboxylic acids
anhydrides
Cyclic anhydrides
dicarboxylic acid
Cyclic anhydrides
dicarboxylic acid
Reactions of Carboxylic Acid AnhydridesReactions of Carboxylic Acid Anhydrides
Conversion of acid anhydrides to carboxylic acids by hydrolysis
O
HO R'
O
R OH+
O
R O R'
O+ H2O
H+
O
R OH
O
R O R'
OH
OH
R O R'
O
OHH
O
R O R'
O H+
Mechanism
H2O
OH
R O R'
O
OHH
R'COOH+
O
R OH
HH2O
Reactions of Carboxylic Acid AnhydridesBecause carboxylic acid anhydrides are highly reactive they can be used to prepare esters and amides.
EstersSynthesis of Esters: EsterificationCarboxylic acids react with alcohols to form esters through a condensation reaction known as esterification:
Mechanism
Acid-Catalyzed Ester Hydrolysis
Esters from Acyl Chlorides
Esters from Carboxylic Acid Anhydrides
Cyclic anhydrides react with one molar equivalent of an alcohol to form compounds that are both esters and acids.
Base-Promoted Hydrolysis of Esters: Saponification
Lactones
Carboxylic acids whose molecules have a hydroxyl group on a or carbon undergo an intramolecular esterification to give cyclic esters known as or -lactones. The reaction is acid catalyzed:
O H
O H
O H
R
R OH
HO O
a -hydroxyacid
H AO
OHO H
R
H
O
O
R
+ O H
H
H
O
O
R
++A O H
H
H
a -lactone
Lactones are hydrolyzed by aqueous base just as Lactones are hydrolyzed by aqueous base just as other esters are. other esters are.
AmidesSynthesis of Amides
Amides from Acyl Chlorides
Amides from Acyl ChloridesAmides from Acyl Chlorides
O
R Cl
:NHR'R"
O
R ClN
R'
R"H
O
R N R'
H
R":Cl:
R"R'HN:
Cl + R'R"NH2 +
O
R NR"
R'
+
Amides from Carboxylic AnhydridesAmides from Carboxylic Anhydrides
R O R
O O+ N
R"
H R'2
N
R"
R'R
O O
R O
H
N R'H
R"
+
R', R" can be H, alkyl, or aryl.
+
Amides from Esters
Amides from Carboxylic Acids and Ammonium Carboxylates
Hydrolysis of Amides
Problem
What products would you obtain from acidic and basic hydrolysis of each of the following arnides?
Nitriles from the Dehydration of Amides
Amides react with P4H10 (a compound that is often called phosphorus pentoxide and written P2O5 or with boiling acetic anhydride to form nitriles.
NH2
O
P4O10
dehydration
C N
Hydrolysis of Nitriles
Catalyzed by both acid and base
Examples
CNOH
O
H2SO4
H2O,
(82%)
CNOH
O2. H3O+
1. NaOH, H2O,
(68%)
R C N:H
OH H:
Mechanism
H2O
:
R C NH +R C NH
H
O H::
slow
O
CR NH
H
H
:
:
O
CR NH
H:
:
:H
OH H: +O
CR NH2
H:
:
:
O
CR NH2
H:
O
R OH
+ NH4several steps
(amide hydrolysis)
protonated nitrile
protonatedamide
amidetautomer
O
R
O
NH2
:
HH OH OH
O
R
OH
NH2
:
H
NH
R OH
:
+ O H:::
O
R
O
NH2
:
R C N:
O H:::
MechanismN
R OH
:: H OH
OH
R
OH
NH::HHOHO
HOHHO
O
R O+ NH3 + OH
H OH
LactamsLactams
NH
O
NHNH
OO
a -lactam a -lactam a -lactam
Penicillin G
Ampicillin
Penicillin V
N
S CH3
CH3
CO2HO
N
H
R
O
R = C6H5CH2
R = C6H5CH
NH2
R = C6H5OCH2
Cyclic amides are called lactams. The size of the lactam ring is designated by Greek letters in a way that is analogous to lactone nomenclature
-Halo Acids-Halo AcidsThe Hell-volhard-Zeliniski The Hell-volhard-Zeliniski reactionreactionAliphatic carboxylic acids react with bromine or chlorine in the presence of
phosphorus (or a phosphorus halide) to give -halo acids through a reaction known as the Hell-Volhard-Zelinski (or HVZ) reaction.
-Halo acids are important synthetic intermediates because they are capable of reacting with a variety of nucleophiles;
Decarboxylation of Carboxylic Acids
The reaction whereby a carboxylic acid loses CO2 is called a decarboxylation.
Acids whose molecules have a carbonyl group one carbon removed from the carboxylic acid group, called -keto acids, decarboxylate readily when they are heated to 100-150°C. (Some -keto acids even decarboxylate slowly at room temperature.)
1. When the carboxylate anion decarboxylates, it forms a resonance-stabilized enolate anion:
CO2
R
O
O
OH
R
OH
O
R
-keto acid enol ketone
CO2
R
O
O
O O
R
: : :
: :
:
O
R
: :HA
O
R
: ::
acylacetate ion
resonance-stabilizedanion
2. When the acid itself decarboxylates, it can do so through a six-membered cyclic transition state:
This reaction produces an enol directly and, the enol then tautomerizes to a methyl ketone.
CO2
R
O
O
OH
R
OH
O
R
-keto acid enol ketone
Malonic acids also decarboxylate readily for similar reasons.
Chemical Tests for Acyl Compounds
OH
O OH
OH
> >
Recall: acidity of
O
R OH Na OH+
O
R O Na+ H2O
(soluble in water)
OH
+ NaOH
OH
+ NaOH
(immisciblewith H2O)
O Na
(soluble in water)
No Reaction
O
OH
+ NaHCO3
O
O Na
+ CO2(g) + H2O
(gas evolved)O
H+ NaHCO3 No Reaction
OH
+ NaHCO3 No Reaction
Summary of the Reactions of Carboxylic Acids and Their
Derivatives
GOOD GOOD LUCKLUCK
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