Carboxylic acids and their derivatives

Carboxylic acids and their derivatives

Synthesis of acidsProperties of acidsNomenclature of acidsReactions of acidsAcid derivatives and their propertiesNomenclature of acid derivativesReactions of acid derivatives

Carboxylic acids

The carboxylic acid functional group consist of a carbonyl group that has a hydroxyl group attached to the carbonyl carbon.

Carboxylic acid groups are generally written as R-COOH or

R-CO2H

Carboxylic acids are generally weak acids that are only partially ionized.

C O

O

R H + H2O RO

O-R

O-

O+ H3O+[ ]

Properties of carboxylic acids

Boiling PointsHigher boiling points than similar alcohols, due to dimer formation.

Acetic acid, b.p. 118C

Melting Points

Aliphatic acids with more than 8 carbons are solids at room temperature. Double bonds (especially cis) lower the melting point. Note these 18-C

acids: Stearic acid (saturated): 72C Oleic acid (one cis double bond): 16C Linoleic acid (two cis double bonds): -5 (cis,cis-9,12-octadecadienoic

acid)

Properties of carboxylic acids

Solubility

Water solubility decreases with the length of the carbon chain.

Up to 4 carbons, acid is miscible in water. More soluble in alcohol. Also soluble in relatively nonpolar solvents like chloroform

because it dissolves as a dimer.

Acidity

Structure of Carboxyl

Carbon is sp2 hybridized. Bond angles are close to 120. O-H eclipsed with C=O, to get overlap of

orbital with orbital of lone pair on oxygen.

Substituent Effects on Acidity

Acid + Base salt + “water”

Naming Carboxylic acids

Historical names are commonly used for many carboxylic acids.

Positions of substituents on the chain are labeled with Greek letters.

CH3COH

O

acetic acid

Common Carboxylic acid Names

CO2H CO2H

CO2H

formic acid acetic acid propionic acid butyric acid

Benzoic acid phthalic acid

HO

OH

CH3

O

OHCH3CH2

O

OH

CH3CH2CH2

O

OH

Common Carboxylic acid Names

OH

OHO

O

CH2

O

HO

O

OHCH2

O

HOCH2

O

OH

oxalic acid malonic acid succinic acid

O

HO

O

OH

adipic acid IUPAC: hexanedioic acid

Naming Carboxylic acids

IUPAC Names

Remove -e from alkane (or alkene) name, add -oic acid. The carboxylic acid group has priority over all over groups.

The carbon of the carboxyl group is #1.

CH3CH2CHC

Cl

OH

O

2-chlorobutanoic acid

PhC

HC

H

COOH

trans-3-phenyl-2-propenoic acid (cinnamic acid)

Naming Cyclic Acids

When the -CO2H is bonded to a cycloalkane ring the compound is named as a cycloalkanecarboxylic acids.

Aromatic acids are named based on benzoic acids.

COOH

CH(CH3)2

2-isopropylcyclopentanecarboxylic acid

COOH

OH

o-hydroxybenzoic acid(salicylic acid)

Dicarboxylic Acids

Aliphatic diacids are usually called by their common names (to be memorized).

For IUPAC name, number the chain from the end closest to a substituent.

Two carboxyl groups on a benzene ring indicate a phthalic acid.

HOOCCH2CHCH2CH2COOH

Br

3-bromohexanedioic acid

-bromoadipic acid

COOH

COOH

1,3-benzenedicarboxylic acid m-phthalic acid

Common Carboxylic acid Names

Long chain carboxylic acids are called fatty acid. Fatty acids are generally found as ester in nature.

Fat - a triglyceride - three fatty acids esterified to glycerol (propane-1,2,3-triol) - that is solid at room temperature. Generally animal source. Fatty acid chains are generally saturated.

Oil - a triglyceride that is liquid at room temperature. Generally plant source. Fatty acid chains are generally unsaturated.

See handout for the composition of different fats and oils.

Common Carboxylic acid Names

For fatty acids containing double bonds, the location of the double bond is sometimes specified relative to the last carbon in the chain - the omega () carbon.

CH3(CH2)4 CH2

HH

(CH2)7-COOH

HH

Linoleic acid (an -6 fatty acid)

OH

O

Alpha-linolenic acid (an -3 fatty acid)

Common Carboxylic acid Names

A deprotonated acid is a carboxylate ion. The -oic acid becomes -oate in the deprotonated form. The name of the metal counterion comes first in the compound name.

CH3CO2H + NaOH CH3CO2Na + H2O

Acetic acid Sodium acetate

+ NaOH + H2O

CO2HCO2Na

benzoic acid Sodium benzoate

Acidity of Carboxylic acids

Ka = [RCOO][H+][RCOOH]

The larger the Ka values the stronger the acid.

Since most carboxylic acids have small Ka values (104 and lower), acid strength is often expressed using pKa values.

C O

O

R H + H2O RO

O-+ H3O+

Acidity of Carboxylic acids

pKa = log Ka

pKa and acid strength are inversely related

Strong acids have small pKas

Most carboxylic acids have pKa vales in the 4.0 to 5.0 range.

HCOOH pKa = 3.75

CH3COOH pKa = 4.74

Benzoic acid pKa = 4.19

Acidity of Carboxylic acids

CO2H CO2H

OCH3

CO2H

NO2

Which to the stronger acid?

pKa 4.19 4.46 3.41

Acidity of Carboxylic acids

The proximity of electron withdrawing groups has an effect.

Cl

COOH

Cl

COOHCH2 CH CH2 CH2CH3 CH2

pKa = 2.86 pKa = 4.52

Acid-Base reaction

spectroscopy of carboxylic acids

C=O of COOH 1710 cm1 (conjugation lowers )

-O-H stretch of carboxylic acid 2500 - 3500 cm1

-O-H stretch of alcohol 3300 cm1

(2800 - 3200 cm1)

Proton NMRO

CH3-CH2-CH2-C-O-H

10-12 ppm2.41.61.0

13C-NMRO

CH3-CH2-CH2-CH2-CH2-C-O-H

181 ppm

34

25

31

2214

Synthesis of acids

Synthesis of acids

Synthesis of acids

Synthesis of acids

Synthesis of acids

R CN R CO2HH+ / H2O

R CN R CO2-

OH - / H2O

Nitriles can undergo either acid or base catalyzed hydrolysis to form carboxylic acids or carboxylates.

RCH2-X + CN - RCH2-CNacetone

Nitriles can easily be prepared from the corresponding halides.

Synthesis of acids

Malonic ester synthesis:

CO2Et

CH2

CO2Et

1) CH3CH2O- Na+

2) R-X

CO2Et

CH

CO2Et

R

Diethyl malonate

CO2Et

CH

CO2Et

R2) H + , heat

1) OH - CO2H

CH2R

This second step is a decarboxylation reaction.

Synthesis of acids

CH2CH3

Br

conc. KMnO4 / heat

1) Mg / ether

2) CO2

3) H+

CHCH3

Br

CO2H

CO2HNa2Cr2O7 / H2SO4

Synthesis of acids Commercial sources

Many carboxylic acids are derived commercially from natural sources. Straight chain acid with 6 to 18 are readily obtained from fats and oil. Fats and oils are composed of triesters of glycerol (triglyceride). The acid is obtained by either acid or base hydrolysis of the ester groups. The base hydrolysis is called saponification (the making of soap) produces the carboxylate salt. Acid hydrolysis gives the free acid.

Synthesis of acids Commercial sources

Acetic acid is produced via both fermentation and catalytic processes.

Other acids such as benzoic acid, phthalic acid and adipic acid are produced via oxidation of an appropriate substrate.

Reactions of acids

The reactivity of these acid derivatives is dependent on the basicity of the leaving group. (List the leaving groups in order of increasing basicity.)

Synthesis of acid chlorides

Synthesis of esters from acids

Ester synthesis

Esterification under acid conditions (Fischer esterification)

R O H

OH

OR

H+

R O+

OH

OR H

HR

O+

OR

H

H2OR

O

OR

Esterification using diazomethane

Yields of the methyl ester are very good. However, diazomethane is a toxic, explosive gas. The reagent is generated just before it is used. Ether solutions of this reagent are relatively safe to work with.

Ester from acid Chlorides

What is the mechanism for this reaction?

Synthesis of amide from acids

The initial formation of the ammonium carboxylate salt is an exothermic reaction. The reaction mixture is then typically heated to 125-150°C to convert the salt to the amide with loss of water.

Synthesis of amide from acid chlorides

The HCl that is generated by this reaction must be neutralized or scavenged from the reaction mixture to prevent the protonating of unreacted amine. This is often done with pyridine, NaOH or Na2CO3. The reaction must be kept dry since acid chloride will react with water to give the acid.

Synthesis of acid anhydrides

RO

Cl+ R'

O

HOR O R'

O O

+ HCl

Acid anhydride

Acid anhydrides react similarly to acid chlorides to form esters and amides.

Reduction of Acids

Note that esters undergo an analogous reaction with LAH.

Reduction of Acid Chlorides

Nomenclature and reactions of acid derivatives

Naming Esters

Esters are named as alkyl carboxylates. Alkyl from the alcohol, carboxylate from

the carboxylic acid precursor.

Cyclic Esters

Reaction of -OH and -COOH on same molecule produces a cyclic ester, lactone.

To name, add word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone.

O

OH

OH

H+

O

O

+ H2O

4-hydroxybutanoic acid lactone γ -hydroxybutyrolactone

4-hydroxybutanoic acid γ-hydroxybutyric acid

Reactions of Esters

OO

H

O

R-C-O-R' R''-NH2

H3O+

R''-OH , H+

OH-

R-C-N-R'' + R'-OH

R-C-O-R'' + R'-OH

R-COOH + R'-OH

R-COO-+ R'-OH

transesterification

saponificaton

O

R''

OHR-C-O-R'

1) LiAlH4

2) H2O

1) 2 R''MgX, ether

2) H3O+

R-OH + R'-OH

R-C-R"

Amides

Product of the reaction of a carboxylic acid and ammonia or an amine.

Not basic because the lone pair on nitrogen is delocalized by resonance.

Classes of Amides

1 amide has one C-N bond (two N-H). 2 amide or N-substituted amide has two

C-N bonds (one N-H). 3 amide or N,N-disubstituted amide has

three C-N bonds (no N-H).

R

O

N H

H

R

O

N R'

R'

R

O

N H

R'

Classes of Amides

DMF is a common polar and aprotic solvent that is often used in the laboratory. Because of the very strong hydrogen bonding in 1° and 2° amides they have very high melting and boiling points.

Naming Amides

For 1 amide, drop -ic or -oic acid from the carboxylic acid name, add -amide.

For 2 and 3 amides, the alkyl groups bonded to nitrogen are named with N- to indicate their position.

CH3CHC N

O

CH2CH3

CH3

CH3

N-ethyl-N,2-dimethylpropanamideN-ethyl-N-methylisobutyramide

Cyclic Amides

Reaction of -NH2 and -COOH on same molecule produces a cyclic amide, lactam.

To name, add word lactam to the IUPAC acid name or replace the -ic acid of common name with -olactam.

4-aminobutanoic acid lactam-butyrolactamN

O

H

Reactions of Amides

O

O

O

H

H3O+

OH-R-C-O + R'-NH2

R-C-OH + R'-NH3+

-

1) LiAlH4

2) H2O

R-C-N-R' -

R-CH2-NH-R'

POCl3

X2 , OHR-NH2

R-CN(or P2O5)

(only work with 1 amides)

Naming Nitriles

For IUPAC names, add -nitrile to the alkane name.

Common names come from the carboxylic acid. Replace -ic acid with -onitrile.

CH3CHCH2CH2CH2CN

Br

5-bromohexanenitrile-bromocapronitrile

C N

Cyclohexanecarbonitrile

Nitriles synthesis

Unlike other acid derivatives nitriles do not contain a carbonyl.

Nitriles can be prepared by treating an amide with POCl3 or at high temperature over an alumina catalyst.

R C

O

NH2 R CN POCl3

R C

O

NH2 R CN Al2O3 / NH3 / 300 C

+ H2O

Reactions of Nitriles

R-X + NaCN

ketone or aldehyde + NaCN, HCN

Ar-N2+ + CuCN

amide + POCl3

nitrile (or cyanohydrin)

O1) R'MgX , ether

2) H3O+

1) LiAlH4

2) H2O

H2O

H+ or OH -

R-CN

R-C-R'

R-CH2-NH2

R-COOH (or R-COO )-

(Note: shorter periods of hydrolysis can yield an intermediate amide)

Acid Halides

Named by replacing -ic acid with -yl halide.

C

O

Cl CH3CHCH2C

Br O

Br

benzoyl chloride

3-bromobutanoyl bromide-bromobutyryl bromide

Acid Halides

R

O

Cl

OOO

O

O

HO

C

R'-C-OHR-C-O-C-R'

R'-OH

R'-NH2

H2O

R-C-O-R'

R-C-N-R'

R-C-OH

( + HCl )

( + HCl )

( + HCl )

( + HCl )

(Pyridine or NaHCO3(aq) is used to help control acidity since protonating the N stops the reaction.

R

O

ClOC

LiAlH(O-tBu)3

R'2CuLi

R-CHO

R-C-R'

Acid Anhydrides

Two molecules of acid combine with the loss of water to form the anhydride.

A carboxylate ion is the leaving group in nucleophilic acyl substitution reactions.

To name an anhydride drop the word acid and replace with anhydride.

R C

O

O H RC

O

OH R C

O

O C

O

R

CH3 C

O

O C

O

CH3

ethanoic anhydrideacetic anhydride

Acid Anhydrides

1,2-benzenedicarboxylic anhydridephthalic anhydride

O

O

O

Acid Anhydrides

O

OO

O

O

H

O O

O

R-C-OH

R-C-O-C-R

R'-OH , H+

R'-NH2

H2O

R-C-O-R'

R-C-N-R'

R-C-OH

+

R-C-OH+

R-C-OH+

OO O

C-R OR-C-O-C-R , AlCl31)

2) H2O R-C-OH+

(Note: The benzene ring cannot be strongly deactivated.)

Multifunctional Compounds

The functional group with the highest priority determines the parent name.

Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne.

C

CN

O

OCH2CH3 ethyl o-cyanobenzoate

Solubility

Acid chlorides and anhydrides are too reactive to be used with water or alcohol.

Esters, 3 amides, and nitriles are good polar aprotic solvents.

Solvents commonly used in organic reactions: Ethyl acetate Dimethylformamide (DMF) Acetonitrile

1H NMR Spectroscopy

13C NMR Spectroscopy

Acid Chloride to Anhydride

Acid or carboxylate ion attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is

abstracted.

+ HClC

O

R OC

O

R'

_

C

O

R Cl

OH C

OR'

C

O

R ClR' C

O

O H+

- H+

Acid Chloride to Ester

Alcohol attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is

abstracted.

+ HClC

O

R OR'

_

C

O

R Cl

OH R'

C

O

R Cl+

- H+

R' O H

Acid Chloride to Amide

Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide

Anhydride to Ester

Alcohol attacks one C=O of anhydride. Tetrahedral intermediate forms. Carboxylate ion leaves, C=O is restored,

H+ is abstracted.

Anhydride to Amide

Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide

Ester to Amide

Nucleophile must be NH3 or 1 amine. Prolonged heating required.

Transesterification

One alkoxy group can be replaced by another with acid or base catalyst.

Use large excess of preferred alcohol.