Carboxylic Acids and Their Derivatives (Ch. 20 & 21 McMurry). Acyl group: R – C
= O. IR: C = O stretch in 1650 – 1750 cm. -1 range. Carboxylic acids: R – COOH.
Carboxylic Acids and Their Derivatives (Ch. 20 & 21 McMurry) IR: C = O stretch in 1650 – 1750 cm-1 range
Acyl group: R – C = O Carboxylic acids: R – COOH
IR: C = O stretch in 1680 – 1725 cm-1 range C – O stretch in 1100 – 1310 cm-1 range O – H stretch broad, 3400 – 2500 cm-1 range
O R
COOH = “carboxyl group”
C OH
Nomenclature of carboxylic acids: IUPAC 1. Name based on corresponding alkane; remove the “e” and add “oic acid” 2. For substituents, number chain beginning at the carboxyl carbon. 3. For unsaturated carboxylic acids number the location of the double bond: CH3 – CHOH – CH2 – COOH 3-hydroxybutanoic acid
CH3 – CH = CH – COOH 2-butenoic acid
Common names are really common with small acids (more in table 20.1) formic acid:
H – COOH
acetic acid:
propionic acid:
CH3CH2COOH
butyric acid:
CH3COOH CH3-CH2-CH2-COOH
γ
β
α
O
benzoic acid:
C OH
long-chain acids = “fatty acids” are further discussed in Ch. 27 Derivatives of carboxylic acids: Esters
Amides
C
R O
C R
Acid anhydrides
O
O
O R
Acid halides
C
R N
O
R
O
C Cl
R
C O
R
R
A fairly good leaving group in place of the OH makes allows these to undergo nucleophilic substitution at the carbonyl carbon (Ch. 21)
Structure, nomenclature and occurrence of acid derivatives: Esters:
Typically originate from a carboxylic acid and an alcohol
O C
Nomenclature: Name consists of 2 parts: alkyl group name (R’)+ acid salt name (R – COO-)
R
R
O O C
H 3C
O
O H2 C O
C O CH 3
CH 3
C O
H 3C
Salts of carboxylic acids are named similarly: sodium acetate =
O H3C
C O Na+
Occurrence: -- Natural fragrances & flavorings, plants, fruit (isoamyl acetate, methyl salicylate) -- Fats and oils are esters of glycerol IR:
2 C – O stretches: 1 C = O stretch
1050 – 1150 and 1150 – 1300 cm-1 1740 cm-1 (lower for aromatic esters)
Variations on a theme: Lactones = cyclic esters; most frequently 5 or 6-member rings
Acyl halides (“acid halides”): Occurrence:
Not normally found in nature! Acid chlorides and acid bromides are typically synthesized and used as starting reagents for preparation of other acid derivatives
Nomenclature:
Acid name: replace “ic acid” with “yl”
Ex:
Benzoyl chloride
IR:
C = O stretch
Anhydrides:
+
Halide name
Propanoyl bromide
typically higher than other carbonyl compounds 1785 – 1815 cm-1 for aliphatic, 1740 – 1775 cm-1 for aryl Formed from two carboxylic acid molecules by loss of a water
Occurrence:
R
IR:
O
O
C
C O
Not found in nature (they don’t like water!) Nomenclature: acid name(s) + “anhydride” R = R’ = “symmetrical anhydride” (acetic anhydride)
R'
1820 + 1750 cm-1
2 C = O stretches:
Nitriles:
R
C
Nomenclature: IUPAC:
N
IR: 2220 – 2260 cm-1
Alkane name
+
“nitrile”
Common: Use acid name, replace “ic acid” with “onitrile”
Amides:
Formed from condensation of a carboxylic acid with an amine Nomenclature is based on acid name, classification as 1o, 2o or 3o
1o amides: From 1o amines, no alkyl on the N
2o amides: From 2o amines, one R group on N O
O
Root of acid name + “amide”
C
C R
R
NH 2
R' N H O
3o amides:
From 3o amines, two R groups on N
C R
R N R
IR:
C = O stretch is lower than usual; 1630 – 1700 cm-1 depending on structure N – H stretch occurs in 1o and 2o amides, around 3300 cm-1
Occurrence: Amides are very common in nature -- “Backbone” of protein structure (formed from condensation of amino acids) HOOC – CHR – NH2 -- Nucleic acids (DNA, RNA), Vitamins & cofactors, alkaloids -- "Lactams" are cyclic amides - β-lactams are a class of antibiotics
Properties of Carboxylic Acids 1)
Strong hydrogen bonding - Polar C = O and O – H make hydrogen bonding occur readily with water and other RCOOH (forms dimers) Boiling points are higher than alcohols of equivalent molecular weight
2) Acidic behavior: Carboxylic acids readily react with bases to form salts and water: CH3COOH
+
CH3COO- Na+
NaOH
+
H2O
Equilibrium constant for dissociation in water is given by Ka O R
C OH + H2O
O R
HA
C O
+ H3
O+
A-
Like phenols, acids form a resonance-stabilized conjugate base: "carboxylate anion"
Ka = [A-][H3O+] pKa = - log Ka [HA] pKa < 5.0 more acidic than alcohols or phenols
O H3C
C O
At a given pH, the relative amounts of undissociated/dissociated forms are given by the Henderson-Hasselbalch equation: pH = pKa + log [A-] / [HA]
3) Substituent effects on acidity: Electron-withdrawing groups on the α−carbon stabilize the carboxylate ion; favor dissociation Compare pKas of trifluoroacetic, chloroacetic and acetic acid As EWG moves farther away, effects decrease Electron donors have the opposite effect of EWG EWG on benzoic acid (deactivators) increase acidity, decrease pKa (Table 20.4)
Preparing Carboxylic Acids 1) By oxidation (review) a. Oxidative cleavage of alkenes KMnO4, H3O+ b. Oxidation of alkyl groups on a benzene ring: c. Oxidation of a 1o alcohol or aldehyde with a strong oxidizer (Na2Cr2O7, H3O+) Going in the opposite direction: Reduction of acids back to alcohols a. LiAlH4 (reduces everything, requires heating)
b. BH3/THF (rapid & selective for COOH group)
2) From nitriles by hydrolysis (addition of water) Ex:
(Hydrolysis of esters, anhydrides and amides also produces carboxylic acids) 3) Grignard addition to CO2 : the “carboxylation reaction” Mg
H 3C
Br
+
O
C
O
O
H 3 O+ H 3C
C H2
C C H2
OH
This reaction is an effective way to functionalize benzene starting with a halobenzene: 1) Mg, 2) CO2 H 3C
Br
3) H3O
+
H 3C
COOH
Nitrile reactions Nitriles are electronically similar to acids, esters & amides due to the three bonds from the central carbon to an electronegative atom. The cyano carbon is electrophilic. Prep. of simple nitriles is best accomplished by SN2 reaction of RX with CNCH3CH2CH2-Br
+
NaCN
CH3CH2CH2-CN
Sterically hindered nitriles can be prepared by dehydration of 1o amides O CH3 H 3C
C
C
CH3
SOCl2, benzene NH2
80oC
H 3C
C
CH3
C
N
+ SO 2 + HCl
CH3
Preparation of cyanohydrins or α-hydroxy-nitriles from RCHO: (Ch. 19)
The cyano group of a nitrile can be hydrolyzed to an acid: H3O+ CH3CH2CH2CN
CH3CH2CH2COOH
or reduced to a 1o amine: LiAlH4 CH3CH2CH2CN
CH3CH2CH2CH2NH2
Nitrile to ketone: Since the cyano carbon is electrophilic, it will also undergo Grignard addition reactions, followed by loss of nitrogen in a hydrolysis step, yielding a ketone. CH3MgBr C
N
N C
H2O CH3
O C
CH3
+ NH3
How could you prepare these acids?
Chapter 21:
Reactivity of carboxylic acids & derivatives
Hybridization & geometry: sp2 hybridization: allows for resonance forms Polarity leads to reactivity: carbonyl carbon is reactive toward nucleophiles
R C O Y
Mechanism: Nucleophilic acyl substitution rather than addition, due to leaving ability O
O
Nu:-
C R
Y
C
O Y
R
Y:-
C R
Nu
Nu
short-lived tetrahedral intermediate Factors controlling reactions of acid derivatives: 1) Basicity of nucleophile: Equilibrium favors replacement when incoming nucleophile is more basic than Y:2) Leaving group: Reaction occurs more readily when Y:- is a good leaving group (Weaker base = better leaving group) When Y group is a weak base, inductive e- withdrawal increases electrophilicity of the carbonyl C. Result: Elimination of Y:- (forward reaction) occurs more easily Relative reactivities of carboxylic acid derivatives: acyl halide > acid anhydride > ester > carboxylic acid
>
amide
A group on the left can be converted readily to the groups to its right • • • •
Acyl chlorides are great starting materials to prepare other derivatives Anhydrides are hydrolyzed to acids more easily than esters or amides Amides are the least suitable for preparing other derivatives Acyl halides & anhydrides are unstable in water, hydrolyze to carb. acids
Effect of R group: Bulky, e- rich groups decrease reactivity of C = O
General mechanisms for all nucleophilic acyl substitution reactions: 1) When the nucleophile is negatively charged (hydroxide, amide ion, alkoxide, etc): O
O -
HO:
C R
O
C
Y
R
Y
Y:-
C R
OH
OH
2) When the nucleophile is neutral (water, alcohols, amines, etc): O
O
HOH
C R
C
Y
+ H+ Y
C
R
Y
O
O R
R H OH
HY
C OH
OH
Common types of nucleophilic acyl substitutions: These reactions may occur more readily for certain Y groups than others. O C
Hydrolysis:
O
H 2O
R
Y
O
may require acid or base
R
OH
O
ROH
C
Alcoholysis:
C
R
Y
O
Aminolysis:
R
C Y
R
O C Y
O
O
2) H3O+
C R
Y
H3O+
H
O
R'MgBr
C R
NHR
1) LiAlH4
R
Grignard:
OR
O
:NH2R
C R
Reduction:
+ HY
C
C R
R'
Reactions of carboxylic acids to make derivatives: Since carboxylic acids aren’t very reactive, these reactions take some “encouraging” 1) Preparation of acid chlorides: similar to converting alcohols to alkyl halides SOCl2 or PBr3 converts OH to better leaving group (chlorosulfite, bromophosphite) O
SOCl2
C R
OH
2) Preparation of anhydrides: Heat promotes a condensation reaction between two carboxylic acid groups O
2
200oC
C R
O
O
C
C
R
OH
O
+ H2O R
3) Preparation of esters: Fischer esterification Since the –OH and –OR groups have similar basicities, the equilibrium reaction of carboxylic acids with alcohols must be driven forward to obtain esters H+
O
ROH
C R
O
Y
H2O
C R
O
R'
Acid-catalyzed: The H+ protonates the carbonyl to increase its electrophilicity Mechanism for laboratory reaction: formation of banana oil (isoamyl acetate)
Reactions of acid halides: Preparation of acids and derivatives Since Cl- is readily eliminated, acid chlorides make very good starting reactants: 1. Acid chloride +
2. Acid chloride
water or -OH
+ alcohol or -OR
carboxylic acid
ester
3. Acid chloride +
ammonia 1o or 2o amines
1o amide 2o or 3o amides
4. Acid chloride +
carboxylic acid salt
anhydride
5. Acid chloride +
hydride donor
alcohols or aldehydes
LiAlH4, ether H+
O C R
Cl
LiAlH[(OtBu)3]3, ether H+ 6. Acid chloride +
carbon donor
R’MgBr, ether H+
O C R
Cl
R2CuLi, ether (-78oC) H+
alcohols or ketones
Reactions of anhydrides & amides Acid anhydrides aren’t that common and are easily hydrolyzed; however, they can be used in esterification reactions with alcohols, such as synthesis of aspirin (acetylsalicylic acid) O
O C
OH
OH
O
O
C
C
H 3C
O
OH
C
C
O
O
CH 3
O
H3 C
OH
CH 3
The anhydride can be cleaved in half, which makes it useful for these rxns: Hydrolysis: anhydride + water = acids Aminolysis: anhydride + amine = amides Reduction: anhydride + hydride = RCHO, ROH Amides Preparation: Acyl nucleophilic substitution of acid chlorides with amines Reactions: Amides are unreactive & unsuitable for most conversions except for: O
1. Reduction to amines:
LiAlH4
C R
NR2
O
2. Hydrolysis: (ex: protein digestion)
H3O+
R
NR2
H3O+
NR2
O
Base or
C R
H2 C
NHR2
C R
OH
Esters: Hydrolysis and transesterification Hydrolysis reactions of esters: • Hydrolysis of esters produces carboxylic acids & alcohols • Ester hydrolysis can be speeded up by using acid as a catalyst. • H+ works by first protonating the carbonyl oxygen to make it more reactive • Like the reverse rxn (esterification) hydrolysis is an equilibrium process with a tetrahedral intermediate • Both OH- and OR- groups are equally likely to leave the intermediate. • Excess water pushes equilibrium to the right; removal of water pushes toward ester. H+
O
H2O
C R
O
ROH
C R
O R
OH
Mechanism: Figure 21.8
• Ester hydrolysis occurs in digestion of fats and oils (tri-esters) - see Ch. 27 • Hydrolysis can also be base catalyzed (see saponification) • Phenyl esters are very reactive - phenolate leaving group is a weak base.
Alcoholysis: The alkyl group on the incoming alcohol replaces the original group on the ester (a transesterification). Excess alcohol forces equilibrium O C H3 C
O
HO
O
H+
H2 C
H2 C
C CH3
(excess)
H3 C
O
HO CH2
Hydroxide-ion promoted (aka: "Base-catalyzed") ester hydrolysis: Saponification OH- is a better nucleophile than H2O, so the initial step of ester hydrolysis occurs more rapidly. O H2 H 3C C C
O
CH3
NaOH
Mechanism of reaction: Fig 21.7
O H2 H 3C C C O Na+
H O
CH3
Note that carrying out hydrolysis in base results in formation of acid salts The reaction of fats to release fatty acid salts that act as detergents is called "saponification" (27.2)
Salts of fatty acids and soap behavior: Fatty acid salts have a charged "head" that interacts with water and a nonpolar "tail" that is repelled by water. The tails therefore interact with each other through London dispersion forces. This is known as "hydrophobic" interaction, forming a “micelle”
Since most dirt is oilbased, it is attracted to the center of the micelle and the soap micelles therefore break up dirt particles (but remain soluble due to charged outer layer) Reduction of esters: Esters can also be reduced to alcohols or carboxylic acids using H- donors:
O C H 3C
LiAlH4, H3O +
H2 C O
CH 3
DIBAH in toluene H 3 O+
Step-growth polymers Polymers: Large molecules (chains, branched chains) built up by bonding together many smaller units called monomers Hydrocarbon (chain-growth) polymers from alkenes were introduced in Ch. 7 Polymers form by chain reactions (free radical or electrophilic addition) started by an initiator These include polyethylene, polystyrene, polypropylene & rubber In step-growth polymerization, bonds between monomers form independently and the polymer may grow in small sections 2 common types of condensation polymers have amide or ester linkages between units --These linkages require two different types of units --Monomers have a functional group on each end --Several other types are shown in Table 21.2 1) Polyamides (Nylons) Dicarboxylic acid + Diamine = repeating amide links between R groups (or diacid chloride)
Peptides & proteins are natural polymers with amide linkages between amino acids
2) Polyesters: Diester or diacid chloride + Diol = repeating ester links between R groups
Step-growth allows for more structural variation, compared to polymer structures formed by free radical addition of alkenes (example: polypropylene)
Versatility of carboxylic acid derivatives
How would you prepare the analgesic butacetin from p-bromonitrobenzene?
Br
NO 2
C5H9ClO2
C11H12O2
