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 COOH = “carboxyl group”

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 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 CH3 – CH = CH – COOH 3-hydroxybutanoic acid 2-butenoic acid Common names are really common with small acids (more in table 20.1) formic acid: H – COOH acetic acid: CH3COOH propionic acid: CH3CH2COOH butyric acid: CH3-CH2-CH2-COOH γ β α benzoic acid: long-chain acids = “fatty acids” are further discussed in Ch. 27 Derivatives of carboxylic acids: Esters Amides Acid halides Acid anhydrides A fairly good leaving group in place of the OH makes allows these to undergo nucleophilic substitution at the carbonyl carbon (Ch. 21)

C

O

OH

RC

OR

O

RC

NR

O

RC

Cl

O

R

RC

OC

O O

R

R C

O

OH

Structure, nomenclature and occurrence of acid derivatives: Esters: Typically originate from a carboxylic acid and an alcohol

Nomenclature: Name consists of 2 parts: alkyl group name (R’)+ acid salt name (R – COO-)

Salts of carboxylic acids are named similarly: sodium acetate = Occurrence: -- Natural fragrances & flavorings, plants, fruit (isoamyl acetate, methyl salicylate) -- Fats and oils are esters of glycerol IR: 2 C – O stretches: 1050 – 1150 and 1150 – 1300 cm-1 1 C = O stretch 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” + Halide name Ex: Benzoyl chloride Propanoyl bromide IR: C = O stretch typically higher than other carbonyl compounds

1785 – 1815 cm-1 for aliphatic, 1740 – 1775 cm-1 for aryl Anhydrides: Formed from two carboxylic acid molecules by loss of a water

RC

OR

O

H3C CO

O Na+

H3CC

O

H2C

O

C

O

O CH3CH3 H3C

CO

O

Occurrence: Not found in nature (they don’t like water!) Nomenclature: acid name(s) + “anhydride”

R = R’ = “symmetrical anhydride” (acetic anhydride)

IR: 2 C = O stretches: 1820 + 1750 cm-1 Nitriles: R C N IR: 2220 – 2260 cm-1 Nomenclature: IUPAC: 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: 2o amides: From 1o amines, no alkyl on the N From 2o amines, one R group on N Root of acid name + “amide” 3o amides: From 3o amines, two R groups on N 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

RC

OC

O O

R'

RC

NR

O

R

RC

NH

R'

O

RC

NH2

O

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 + NaOH CH3COO- Na+ + H2O Equilibrium constant for dissociation in water is given by Ka

HA A- Like phenols, acids form a resonance-stabilized conjugate base: "carboxylate anion" 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)

R CO

OH R CO

O+ H2O + H3O+

H3C CO

O

Ka = [A-][H3O+] pKa = - log Ka [HA] pKa < 5.0 more acidic than

alcohols or phenols

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”

This reaction is an effective way to functionalize benzene starting with a halobenzene:

H3CCH2

Mg Br O C OH3O+

H3CCH2

C

O

OH+

BrH3C COOHH3C1) Mg, 2) CO2

3) H3O+

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 CN- CH3CH2CH2-Br + NaCN CH3CH2CH2-CN Sterically hindered nitriles can be prepared by dehydration of 1o amides

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.

CH3C

CH3

CH3

C

O

NH2

SOCl2, benzene

80oC CH3C

CH3

CH3

C N + SO2 + HCl

C NCH3MgBr

C

N

CH3

H2OC

O

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 Mechanism: Nucleophilic acyl substitution rather than addition, due to leaving ability

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

RC

Y

O

RC Y

O

RC

Nu

OY:-Nu:-

Nu

RC

Y

O

General mechanisms for all nucleophilic acyl substitution reactions: 1) When the nucleophile is negatively charged (hydroxide, amide ion, alkoxide, etc):

RC

Y

O

RC Y

O

RC

OH

OY:-

OH

HO:-

2) When the nucleophile is neutral (water, alcohols, amines, etc):

RC

Y

O

RC Y

O

RC

OH

O

HY

O

HOH

H HR

C Y

O

OH

+ H+

Common types of nucleophilic acyl substitutions: These reactions may occur more readily for certain Y groups than others. Hydrolysis: Alcoholysis: Aminolysis: Reduction: Grignard:

RC

Y

O

RC

OH

OH2O+ HY

may requireacid or base

RC

Y

O

RC

OR

OROH

RC

Y

O

RC

NHR

O:NH2R

RC

Y

O

RC

H

O1) LiAlH4

2) H3O+

RC

Y

O

RC

R'

OR'MgBrH3O+

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) 2) Preparation of anhydrides: Heat promotes a condensation reaction between two carboxylic acid groups

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 Acid-catalyzed: The H+ protonates the carbonyl to increase its electrophilicity Mechanism for laboratory reaction: formation of banana oil (isoamyl acetate)

RC

OH

OSOCl2

RC

OH

O200oC

RC

O

O

RC

O2 + H2O

RC

Y

O

RC

O

O

ROHH+

R'H2O

Reactions of acid halides: Preparation of acids and derivatives Since Cl- is readily eliminated, acid chlorides make very good starting reactants: 1. Acid chloride + water or -OH carboxylic acid 2. Acid chloride + alcohol or -OR ester 3. Acid chloride + ammonia 1o amide

1o or 2o amines 2o or 3o amides 4. Acid chloride + carboxylic acid salt anhydride 5. Acid chloride + hydride donor alcohols or aldehydes LiAlH4, ether

H+

LiAlH[(OtBu)3]3, ether H+ 6. Acid chloride + carbon donor alcohols or ketones

R’MgBr, ether H+

R2CuLi, ether (-78oC) H+

RC

Cl

O

RC

Cl

O

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) 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: 1. Reduction to amines: 2. Hydrolysis: (ex: protein digestion)

C

O

OH

O CH3

O

C

O

OH

OH

H3CC

O

OHH3C

CO

O

CH3

C

O

RC

NR2

O

R

H2C

NR2

LiAlH4

H3O+

RC

NR2

O

RC

OH

Base or

H3O+

ONHR2

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. 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

H3CC

O

H2C

O

CH2H3CC

O

O H+

HO

H2C

CH3

HO

(excess)

RC

O

O

RC

O

OHROH

H+

H2OR

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. Mechanism of reaction: Fig 21.7

H3CH2C C

O

O CH3 H3CH2C C

O

O CH3O HNaOH

Na+

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”

Reduction of esters: Esters can also be reduced to alcohols or carboxylic acids using H- donors:

H3CC

O

H2C

O

CH3

LiAlH4, H3O+

DIBAH in toluene

H3O+

Since most dirt is oil-based, 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)

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

NO2Br

How would you prepare the analgesic butacetin from p-bromonitrobenzene?

C5H9ClO2

C11H12O2