CHEM 4113 ORGANIC CHEMISTRY II CHAPTER 20

1. Introduction

LECTURE NOTES

Of the organic compounds that show appreciable acidity, by far the most important are the carboxylic acids. These compounds contain the carboxyl group (-COOH). Carboxylic acids and their derivatives rank with the aldehydes and ketones as among the most important organic compounds because they occur widely in nature, and because they serve important roles in organic synthesis. This chapter is concerned with the structure, properties and reactivities of carboxylic acids. 2. a. Nomenclature Common System

Common nomenclature is widely used for the simpler carboxylic acids. A carboxylic acid is generally named by adding the suffix ic and the word acid to the prefix for the appropriate group. Common names, such as formic ( from Latin word for ant), acetic (from the Latin word for vinegar) and butyric (from the Latin word for butter) are based on the natural source for the acid. The common names for the first four linear acids are used as much as their IUPAC names. Substitution in the common system is denoted by letters of the Greek alphabet rather than numbers. The position adjacent to the carboxyl group is denoted as and so on. Acids with two carboxyl groups are called dicarboxylic acids ( or diacids). The unbranched, linear diacids are particularly important, and are invariably known by their common names. Phthalic acid is an important aromatic diacid. The first four monocarboxylic acids are: formic, acetic,propionic and butyric. O HC OH O CH3 C OH O O CH3CH2 C OH CH3CH2CH2CH2 C OH

With common nomenclature, the positions adjacent to the carbonyl group are designated with letters from the greek alphabet. HO CO2H -Hydroxybutyric acid

Dicarboxylic acids are important synthetic materials. Names of several of the most common of these are shown below. O n= Common Name C OH 0 oxalic acid (CH2)n 1 malonic acid 2 succinic acid C OH O COOH COOH phthalic acid HOOC COOH HOOC fumaric acid COOH

maleic acid

Common Nomenclature of Carboxylic Acids

b.

IUPAC System

A carboxylic acid is named in the IUPAC system by finding the longest chain which contains the carboxyl group of the acid, dropping the final -e from the name of the hydrocarbon of the same number of carbon atoms, and adding the suffix -oic acid. However, the final -e is not dropped in the name of the diacids. The chain is always numbered such that the carbon of the carboxyl group is given the no. 1 position. When a carboxylic acid is derived from a cyclic hydrocarbon, the suffix -carboxylic acid is added to the name of the hydrocarbon. This nomenclature is similar to that of the corresponding aldehydes. In such systems the numbering of the ring begins at the carbon bearing the carboxyl group. One exception to this nomenclature is benzoic acid, for which the IUPAC recognizes the common name ( thus it is NOT called benzenecarboxylic acid). Carboxylic acids have priority over aldehydes, ketones, alcohols and all other functional groups learned to date.
Acyclic Systems The name of the principal chain containing the acid functional group is specified by dropping the -e and adding the suffic -oic acid. In IUPAC nomenclature, all carbons are numbered starting with the carboxylic acid carbon as number 1.

CH3 O
4 3 2

3-methyl-4-phenylpentanoic acid
1

OH

Ring Systems

5 CH3

When the carboxylic acid is external to the position of the ring, the suffix -carboxylic acid is used, the ring is numbered starting from the position of attachemnt of the carboxylic acid.
3 2

cis-3-isopropylcyclohexanecarboxylic acid

COOH
Priority of groups

O OH

O H O

>

>

>

OH

>

OR

H3C O COOH

H 2-(2-oxopropyl)-7-oxo-heptanoic acid

IUPAC Nomenclature of Carboxylic Acids

3.

Acidity of Carboxylic Acids

Although much weaker than the strong mineral acids ( i.e. sulfuric acid, hydrochloric acid), the carboxylic acids are tremendously stronger than the weak organic acids we have studied thus far (i.e. alcohols, acetylenes). Carboxylic acids are strong organic acids because of the ease of ionization of the O-H bond of the carboxyl group to give a proton (H+) and a carboxylate anion (RCOO-).

Carboxylic acids are much stronger than other functional groups which contain an O-H bond such as alcohols and phenols. This increased acidity is due to two factor. First is the polar effects of the carbonyl group, because of its sp2 hybridized atoms and an electronegative oxygen atom the carbonyl weakens the O-H bond by inductive removal of electron density. The second, and much more important factor, is the resonance stabilization of the conjugate base carboxylate ion. Carboxylic acids are strong enough acids that they are completely deprotonated by relatively weak bases such as NaOH (i.e. RCOOH + -OH RCOO- + H 2 O).
pKa's of some common organic compounds

CH3 H
pKa = 55

CH3O H
pKa = 18 Increasing Acidity

O CH3CO H
pKa = 5

Resonance effects on carboxyl acidity

O R O H R

O
H+ +

O R O R

O O

O H

Delocalization of the lone-pair onto the carbonyl oxygen serves to weaken the O-H bond.

Delocalization of the carboxylate anion places the negative charge on two equal electronegative oxygens.

Acidity of Carboxylic Acids

As with alcohols, inductively electron withdrawing groups situated close to the carboxyl group cause an increase in acidity. The presence of several such electron-withdrawing groups can result in carboxylic acids as strong as typical mineral acids. The inductive effect is much less when the electron-withdrawing groups are some distance for the carboxyl group.

Inductive effects on carboxylic acid acidity

CH3
pKa =

O C

FCH2

O C

F2CH

O C

CF3

O C
0.23

4.67

2.66 INCREASING ACIDITY

1.24

CH2 + O F O C
pKa =

O C

Electron withdrawing groups close to the carbonyl cause an increase in acidity. This is due to the increase in positive charge on the carbonyl carbon due to inductive effects. The inductive effect is much less when the substituents are removed from the carbonyl group.

H Cl

O C

Cl O H

O C

H Cl

O C

4.82

4.55

4.06

2.84

Inductive Effects

4.

Synthesis of Carboxylic Acids.

The most common routes to the carboxylic acids involve oxidation processes. Oxidation of alkyl benzene side chains and oxidative cleavage of alkenes result in acids with fewer carbons than present in the precursor compounds. Oxidative cleavage of terminal alkenes is a particularly useful method for preparing an acid with one-less carbon than the starting material. Work-up of this reaction product is simplified by the fact that one of the reaction carbons is lost as CO2 . Oxidation of primary alcohols and aldehydes are the standard ways of making acids with the same number of carbons as the starting materials. Aldehydes are particularly easy to oxidize to acids. In fact, older bottles of aldehydes which have been exposed to the O2 and water vapor in the atmosphere, often have significant amounts of acid present (O2 is a powerful oxidizing agent). One very useful, selective oxidizing agent for aldehydes is Tollen's Reagent made from silver hydroxide and dilute aqueous ammonia solution. This will selectively oxidize aldehydes to acids in the presence of other functional groups such as multiple bonds and alcohols..

Oxidation of alkylbenzene side-chains

H R R
KMnO4 H+, H20 heat

O C OH

At least one benzylic hydrogen must be present for oxidaation to occur.

R = H, or alkyl

Oxidative cleavage of alkenes KMnO4 H+, H20 heat

R CH CH R
Vinyl Hydrogens

O 2 R C OH

There must be at least one vinylic hydrogen for an acid be formed.

R CH CH2

KMnO4 H+, H20 heat

O R C OH + CO2

Terminal alkenes afford acids with one less carbon atom in the chain.

Oxidation of primary alcohols

OH R CH2

CrO3 H2SO4

O R C OH

Any aqueous solution of Cr(+6) will carry out the oxidation.

Oxidation of aldehydes

O Ag(NH3)2OH R CH
Tollen's Reagent

O R C OH + Ag

Aldehydes are the easiest functional group to oxidize to a carboxylic acid. The weak Ag ion of Tollen's Reagent is reduced to Ag(s).

Preparation of Carboxylic Acids

a.

Nitrile Hydrolysis to Carboxylic Acids

The cyanide anion (-CN) is a good nucleophile and may be reacted with alkyl halides (R-X, either primary or unhindered secondary) via an SN2 substitution process to prepare nitriles (R-CN). The nitrile will react with hot, aqueous acid to from the carboxylic acid and ammonia. The mechanism is presented here, but will be considered in detail in chapter 21. This procedure allows for the preparation of carboxylic acids with one more carbon than the alkyl halide precursor ( the carbon of the carboxyl group comes from the cyanide anion).

Acid hydrolysis of nitriles

R X

NaCN acetone SN2

R C N

H3O+ heat

O R C OH

Since the reaction involves and SN2 reaction the R group must be a primary or unhindered secondary alkyl group Mechanism of hydrolysis

R C

H+

R C

N H

OH2

H O H R C N H
Proton Transfer

The system of the nitrile is polarized such that the nitrogen is basic, and the carbon is an electrophile

H O R C O H

H N H H

H O H Proton R C N H Transfer O H H
-H+

H2O

H O R C

H N H

H O - NH3 R C O H Acid Hydrolysis of Nitriles b.

O R C OH

Carboxylation of Grignard Reagents to form Carboxylic Acids.

Another method for preparing the next higher carboxylic acid from an alkyl halide is through a carboxylation of the Grignard derived from the haloalkane. Carbon dioxide may be considered as a "diketone" of carbon, and as such, organometallic reagents attack it as much as they would aldehydes or ketones. Aqueous acidic work-up yields the carboxylic acid. Mg
+

R Br

R MgBr

O R C O

MgBr

H3O+ Note that the Grignard addition to carbon dioxide is another example of a 1,2-addition to a carbonyl O R C OH

Synthesis of Acids via Carboxylation of Grignards Although the Grignard procedure, at first glance appears to have no particular advantage over the nitrile hydrolysis procedure, they are in fact complimentary. For example, the Grignard approach allows us to employ tertiary alkyl halides which would not be feasible with the SN2 substitution based nitrile hydrolysis method. Likewise, hydroxy and carbonyl groups present in the molecule do not have to be protected in the nitrile hydrolysis approach as they do in the Grignard method. 5. Reactions of Carboxylic Acids

The reactions of carboxylic acids can be categorized into five types: 1. Reactions at the carboxylate oxygen(deprotonation) 2. Reactions involving the carbon (alpha substitution 3. Reactions at the carbonyl group (nucleophilic acyl substitution) 4. Reactions at the carbonyl group (reduction) 5. Loss of the carboxyl group as CO2 (decarboxylation). We will discuss the first three in chapter 21 a. Reductions of Carboxylic Acids to Alcohols.

Carboxylic acids are reduced to primary alcohols by LiAlH4 but not by NaBH4 . The reaction is difficult and requires heating to drive it to completion. The reduction requires two equivalents of LiAlH4 for every acid functional group in the molecule. O R C O H
LiAlH4 H- acting as a base VERY FAST Aldehyde Intermediate

O R C O

O
+ AlH3

R C H O Al H2
Hydride delivery to carboxylate carbonyl SLOW

NET REACTION

OH R CH2

1) LiAlH4 2) H3O+

O R C H

O
- LiOAlH2

Li

R C H

LiAlH4 Reduction of Acids to Primary Alcohols

O AlH2

Surprisingly borane (BH3 ) is a very useful reducing agent for carboxylic acids. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations. O C O OH 1) BH3, THF 2)H3O+ O C OH CH2

Note that neither the ketone carbonyl nor the alkene double bond are affected in this reaction. Selective Reduction of Carboxylic Acids by BH3 b. Decarboxylation of Carboxylic Acids

Carboxylic acids undergo decarboxylation - loss of CO2 - under certain conditions to give a product having one less carbon than the starting acid had. i. -Keto Acids While most acids are very stable, several special types of carboxylic acid are prone to decarboxylation at temperatures slightly higher than room temperature. The most common of these

are -keto acids and malonic acids. It is the availability of a 6-membered cyclic transition state leading to the enol of a ketone are carboxylic acid that enables the decarboxylation to occur.
Decarboxylation of -keto acids

O HO C O

temp above 25C

O C + O

OH
tautomerization ENOL INTERMEDIATE

KETONE

Decarboxylation of malonic acids

O HO

H O C O
temp above 25C

O C + HO O

OH
tautomerization

O HO
CARBOXYLIC ACID

ENOL INTERMEDIATE

Decarboxylation of -Keto- and Malonic Acids ii. Hunsdiecker Reaction O

AgOH OH Br2 Ag+ OH-

Br + CO2 + AgBr + H2O O O - Ag+ + H2O O

Step 1: SIlver carboxylate formation

O OH

Step 2: Hypopromite formation

O O - Ag+

Br Br

O Br

+ Br-

Step 3: Radical formation and loss of CO2

O O Br
Br +

O O
+ CO2

Step 4: Radical Combination Br +

Br

Hunsdiecker Decarboxylation