Carboxylic acids overview

1. SPC 251 – Organic
Pharmaceutical
Chemistry (II)
By
Gideon Akolgo (Mr.)

2. Course Content
1. Dicarboxylic Acids: reactions, condensation, polymerisation, and malonic ester synthesis.
2. Hyroxy Acids: Reformatsky reaction, lactides, lactones
3. Keto Acids and Esters: Claisen’s condensation, keto-enoltautomerism, acetoacetic ester synthesis
4. Heterocyclic Compounds: Thiophene, pyrrole, furan, pyridine – aromatic and other chemical
properties. Fused ring heterocyclics eg. Quinoline, isoquinoline, purine etc. Examples of drugs
containing above ring systems.
5. Alicyclic compounds: preparations. Diels-Alder reaction ring stability. Bayer’s theory,
conformations of cyclohexane and derivatives and cyclopentane, fused rings: reactions, effect of
conformation, ring expansion and contractions.
6. Biologically important macromolecules and their interactions; Amino acids, Peptides, Proteins,
Nucleosides, Nucleotides, RNA, and DNA: Structure of proteins, i.e. primary, secondary, tertiary
and quaternary structure determination, sequence analysis, bio- synthesis and importance in
Pharmacy.
7. Glycols: preparation, properties, periodic acid oxidation pinacol rearrangement.
8. Stereochemistry; Optical Isomerism: compounds with more than one chiral centre, diastereomers.
Meso-compounds: resolution of racemates, asymmetric synthesis.
9. Carbohydrates: nomenclature, glucose structure, configurational and stereo chemical, absolute
configuration: aldose reactions, oxidations, additions, Keller-Kiliani Fischer synthesis, cyclic
structure of D-glucose, muta-rotation, pyranose, furanose and configurations, rings size
determination: disaccharides, structure and structure determination.

3. Introduction
• In SPC 152, you studied the chemistry of monocarboxylic acids in detail including
acidic behaviour, preparations, properties, functional derivatives of carboxylic acids,
general reactions of- carboxyl group, etc.
• In this course (SPC 251), we will study the change in their properties caused by the
introduction of a second functional group.
• The second functional group may be a second carboxyl group (–C=O), halogen, a hydroxyl
group (–OH), an amino group (–NH2), a double or triple bond.
• Where the 2nd functional group is…
Carbonyl group (–C=O) – Dicarboxylic acid
Hydroxyl group (–OH) – Hydroxyacid
Halogen (F, Cl, Br) – Haloacid
An amino group (–NH2) – Amino acid
Double or triple bond – Keto acid
• We will study the chemistry of each of these classes of substituted carboxylic acids.

4. Carboxylic Acids – Revision
• Carboxylic acids are organic compounds that contain the carboxyl (–COOH)
functional groups.
• The name carboxylic is derived from carbonyl (–C=O) and hydroxyl (–OH) because
in the carboxyl group, these two groups are directly bonded to each other.
• Carboxyl group are further classified as monocarboxylic acid, dicarboxylic acids,
tricarboxylic acids.
• Classified according to the substituents bonded to the carboxyl group.
1. Aliphatic (general formula is RCOOH)
2. Aromatic (general formula is ArCOOH)
Acetic acid
(aliphatic,
monocarboxylic)
Benzoic acid
(aromatic,
monocarboxylic)
Oxalic acid
(Dicarboxylic)
Citric acid
(Tricarboxylic)

5. Nomenclature of Carboxylic Acids
1. Select the longest carbon chain containing carboxyl group.
2. Drop the final –e from the hydrocarbon name.
3. Add the suffix –oic acid.
4. Number the carbon of parent chain starting with the carboxylic
group. Carboxylic group is always at the beginning of the carbon
chain.
5. Name other groups attached to parent chain as usual.
Examples:
CH4 – methane; HCOOH – methanoic acid
CH3CH3 – ethane; CH3COOH – ethanoic acid
CH3CH2CH3 – propane; CH3CH2COOH – propanoic acid
CH3CH2CH2CH3 – butane; CH3CH2CH2COOH – butanoic acid

6. Name the following Carboxylic Acids

7. Nomenclature of Carboxylic Acids using Greek alphabets

8. Write formula for the following

9. Physical properties of Carboxylic acids

10. Classification of Carboxylic acids

11. Classification of Carboxylic acids

12. Classification of Carboxylic acids

13. Classification of Carboxylic acids

14. Carboxylic Acids – Revision
Basicity of carboxylic acids
• Basicity of an acid = number of protons
1. Monobasic carboxylic acid:- has one carboxyl group with one proton to
participate in acid-base reactions.
2. Dibasic carboxylic acid:- has two carboxyl groups with two protons.
3. Tribasic carboxylic acid:- has three carboxyl groups with three protons.
Acetic acid
(monobasic)
Benzoic acid
(monobasic)
Oxalic acid
(Dibasic)
Citric acid
(Tribasic)
Acidity of carboxylic acids
• Carboxylic acids are weak acids and ionize in water according to the following
equation;

15. Reactions of Carboxylic Acids
1. Acidity of carboxylic acid:- The most obvious property of carboxylic acids is implied by
their name: carboxylic acids are acidic.
• They react with bases such as NaOH and NaHCO3 to give metal carboxylate salts, RCO2
-M+.
Like other Brønsted–Lowry acids, carboxylic acids dissociate slightly in dilute aqueous
solution to give H3O+ and the corresponding carboxylate anions, RCO2
- . The extent of
dissociation is given by an acidity constant, Ka.

16. Acidity of Carboxylic Acids
• Carboxylic acids are weakly acidic – one of their most important properties.
• Bronsted Acidity: Carboxylic acids ionize in water by the transfer of a proton to
water to give H3O+ and carboxylate anions, RCO2- according to the equation;
Acidity of carboxylic acids
• Carboxylic acids are weak acids and ionize in water according to the following
equation;
• pKa values of carboxylic acids fall within the range 4 -5. They are significantly more acidic than water
or alcohols e.g. pKa of acetic acid = 4.76.

17. 1. Carboxylic acids have lesser pKa than alcohols. The lesser the pKa, the greater
the acidity. pKa values for acids is 4 – 5 and that of alcohols is 14 – 16.
2. Carboxylic acids dissociate in water to form carboxylate ions and hydronium
ions.
2. The carboxylate ion formed is stabilized through resonance by effective
delocalization or shifting of negative charge from one oxygen to another.
3. The equilibrium shifts to the right side and carboxylic acids ionize faster than
alcohols.
Acidity of Carboxylic Acids

18. Why Carboxylic Acid is more acidic than alcohol
1. Carboxylic acids have lesser pKa than alcohols. The lesser the pKa, the greater
the acidity. pKa values for acids is 4 – 5 and that of alcohols is 14 – 16.
2. The greater acidity of carboxylic acids is attributed to greater stabilization of
carboxylate ion by:
(a) Inductive effect of the C=O group
(b) Resonance stabilization of the carboxylate ion

19. Carboxylic Acids

20. pKa values of some Carboxylic Acids

21. Effects of Substitution on Acidity
1. The pKa of a carboxylic acid can be influenced by substituents on the a-carbon,
largely through inductive effects.
2. Electron withdrawing groups (EWG) (Cl, Br, F) increase acidity (lower pKa) :- EWGs
withdraw electron density from the carboxylic group shifting the equilibrium to the
right thus increasing the acidity of carboxylic acids.
4. Electron-donating groups (EDG) (OH,NH2) decrease the acidity (higher pKa):- EDGs add
electron density to carboxyl group and equilibrium shifts to the left thus decreasing the
acidity of carboxylic acid.
3. Inductive effects work through σ-bonds, and the effect falls off dramatically with distance.

22. Effects of Substitution on Acidity
1. Substituent effects on acidity
are also found in substituted
benzoic acids.
• Substituents on the aromatic
ring strongly affect reactivity.
• Aromatic rings with electron-
donating (activating) groups
are activated such as methoxy
decreases acidity by
destabilizing the carboxylate
anion.
• Similarly, aromatic rings with
electron-withdrawing
(deactivating) groups such as
nitro increases acidity by
stabilizing the carboxylate
anion.

23. Methods of preparation of Carboxylic Acids
1. Oxidation of alkenes
2. Hydrolysis of nitriles
3. Side Chain Oxidation of Alkylbenzenes
4. Oxidation of primary alcohols and aldehydes
5. Hydrolysis of esters
6. Carboxylation of Grignard method.
7. Carboxylation of alkenes
8. From malonic esters

24. Methods of preparation of Carboxylic Acids
1. Oxidation of alkenes:- Basic potassium permangate (KMnO4) cleaves alkenes to
two carbonyl compounds. gives the corresponding carboxylic acid.
• If one of the substituents at the double bond is hydrogen, the cleavage product
is an aldehyde which is rapidly oxidized to a carboxylic acid under the reaction
conditions, i.e.

25. Methods of preparation of Carboxylic Acids
2. Hydrolysis of nitriles:- Nitriles on hydrolysis in acidic or basic conditions
yields the carboxylic acid
• Also, 1° and 2° alkyl halides may be converted to carboxylic acids containing one
more carbon atom using a two-step process. The first step involves the preparation
of nitriles or alkyl cyanide.

26. Preparation of Carboxylic Acids
3. Side-chain oxidation of alkylbenzenes:- side-chain alkylbenzenes upon
oxidation with sodium or potassium dichromate (Na2Cr2O7 or K2Cr2O7) and
sulphuric acid (H2SO4), or potassium permangate (KMnO4) gives the
corresponding aromatic carboxylic acid.
• Note: Regardless of length of the alkyl chain, It is oxidized to a COOH group.
However, tert-akyl substituents do not undergo oxidation under these
conditions. Why?

27. Methods of preparation of Carboxylic Acids
2. Side-chain oxidation of alkylbenzenes:-

28. 4. Oxidation of primary alcohols and aldehydes:- Primary alcohols and aldehydes
are readily oxidized to carboxylic acid using strong oxidizing agents such as
sodium or potassium dichromate (Na2Cr2O7 or K2Cr2O7) and sulphuric acid
(H2SO4), HNO3, or potassium permangate (KMnO4).
• The carboxylic acid obtained contains the same number of carbon atoms as present in
the starting alcohol.
• The initial product of oxidation is an aldehyde. However, when aqueous KMnO4 is
used, the aldehyde is rapidly oxidized and the carboxylic acid is obtained.
• This is what happens when wine is left exposed to the air, and bacteria converts
the ethanol (wine) into ethanal (vinegar) and the wine goes “bad”.
Preparation of Carboxylic Acids

29. 4. Oxidation of primary alcohols and aldehydes:- Primary alcohols and aldehydes
are readily oxidized to carboxylic acid using strong oxidizing agents such as
sodium or potassium dichromate (Na2Cr2O7 or K2Cr2O7) and sulphuric acid
(H2SO4), HNO3, or potassium permangate (KMnO4).
Preparation of Carboxylic Acids

30. Preparation of Carboxylic Acids

31. Preparation of Carboxylic Acids
• Oxidation of methylketones:- The haloform reaction is occasionally used
to prepare carboxylic acids from readily available methylketones.

32. Preparation of Carboxylic Acids
1. Carboxylation of Grignard method:- Organometallic compounds such as
Grignard reagents and organolithium compounds can be used for
the synthesis of carboxylic acids. Grignard or organometallic reagents react
with carbon dioxide.
• Organometallic reagents react with carbon dioxide to give
salts of carboxylic acids.
• The salt is treated with a strong mineral acid to yield the
carboxylic acid.

33. Methods of preparation of Carboxylic Acids
2. Hydrolysis of nitriles:- Nitriles on hydrolysis in acidic or basic conditions yields
the carboxylic acid
QUESTION: How would you prepare phenylacetic acid (PhCH2CO2H) from benzyl
bromide (PhCH2Br)?

34. Methods of preparation of Carboxylic Acids
QUESTION: How would you prepare phenylacetic acid
(PhCH2CO2H) from benzyl bromide (PhCH2Br)?
Solution:

35. Reactions of Carboxylic Acids
Four general reaction categories are
represented here:
1. As carboxylic acids are easily deprotonated,
they readily form a carboxylate salt which
can then potentially be reacted with an
electrophile to complete a substitution of
the hydroxyl hydrogen.
2. Nucleophilic acyl substitution reactions
allow substitution of the hydroxyl group
which leads to several carboxylic acid
derivatives (e.g. acid halides, esters,
amides, thioesters, acid anhydrides, etc.).
3. Like other carbonyl compounds, carboxylic
acids can be reduced by reagents such as
LiAlH.
4. While the proton on the carbon alpha to the
carbonyl group is not as acidic as the
hydroxyl hydrogen, it can be removed
leading to substitution at the alpha
position.

36. Thank you