NTA Level 5 • Semester 1 • PST05106

Carboxylic Acids of Pharmaceutical Importance

Pharmaceutical Organic Chemistry • Source Session/Topic 12

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Session 12: Carboxylic Acids of Pharmaceutical Importance.

Total Session Time: 120 minutes

Prerequisites

• None

Learning Tasks.

By the end of this session students are expected to be able to:

• Define carboxylic acids

• Explain nomenclature of carboxylic acids

• Draw chemical structure of carboxylic acids

• List chemical properties of carboxylic acids

• Explain chemical reactions of carboxylic acids

Resources Needed:

• Flip charts, marker pens, and masking tape.

• Black/white board and chalk/whiteboard markers.

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Definition of Carboxylic Acids (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What is carboxylic acid? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• The combination of a carbonyl group and a hydroxyl on the same carbon

atom is called a carboxyl group.

• Compounds containing the carboxyl group are distinctly acidic and are

called carboxylic acids.

[pic]

Condensed structures

[pic]

• Therefore, carboxylic acids are acidic organic compounds containing the

carboxyl group as a functional group, attached to hydrogen HCOOH or an

alkyl group as RCOOH or an aryl group as ArCOOH

• The general formula would be CnH(2n+1)COOH or R-CO2H.

STEP 3: Nomenclature of Carboxylic Acids (15 minutes).

IUPAC Names

• The IUPAC nomenclature for carboxylic acids uses the name of the alkane

that corresponds to the longest continuous chain of carbon atoms.

• The final -e in the alkane name is replaced by the suffix -oic acid.

• The chain is numbered, starting with the carboxyl carbon atom, to give

positions of substituents along the chain.

In naming, the carboxyl group takes priority over any of the functional

groups discussed previously

=Examples

[pic]

Some more examples of traditional names most widely used are:

• Formic acid- HCOOH

• Acetic acid – CH3COOH

• Propionic acid – CH3CH2COOH

• Butyric acid – CH3(CH2)2COOH

• Valeric acid – CH3(CH2)3COOH

• Caproic acid – CH3(CH2)4COOH

• Capyrylic acid – CH3(CH2)6COOH

• Capric acid – CH3(CH2)8COOH

STEP 4: Chemical Structure of Carboxylic Acids (15 minutes)

• The CO2H unit is planar and consistent with sp2 hybridization and a

resonance interaction of the lone pairs of the hydroxyl oxygen with the π

system of the carbonyl.

| Carboxylic Acid | | |

| |Structure | |

|Ethanoic acid |CH3CO2H | |

|Propanoic acid |CH3CH2CO2H | |

|Fluoroethanoic acid |CH2FCO2H | |

|Chloroethanoic acid |CH2ClCO2H | |

|Dichloroethanoic acid |CHCl2CO2H | |

|Trichloroethanoic acid |CCl3CO2H | |

|Nitroethanoic acid |O2NCH2CO2H | |

STEP 5: Chemical Properties of Carboxylic Acids (15 minutes).

|Activity: Buzzing (10minutes) |

| |

|ASK students to pair up and buzz on the following question for 5 |

|minutes |

| |

|What are the chemical properties of carboxylic acid? |

| |

|ALLOW pairs to respond on the question |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content in the table 1 below |

The following are chemical properties of carboxylic acids;

Acidity of Carboxylic Acids

Carboxylic acids are weak acids and their carboxylic anions are strong

conjugate bases are slightly alkaline due to the hydrolysis of carboxylate

anion compared to other species, the order of acidity and basicity or

corresponding conjugate bases are as follows:

Acidity RCOOH > HOH > ROH > HC[pic] CH > NH3 > RH

Basicity RCOO– < HO– < RO– < HCC– < NH2-< R–

Reaction of Carboxylic Acids with Metals

• The carboxylic acids react with metals to liberate hydrogen and are

soluble in both NaOH and NaHCO3 solutions.

For example;

▪ 2CH3COOH + 2Na → 2CH3COO–Na+ + H2

▪ CH3COOH + NaOH → CH3COO–Na+ + H2O

▪ CH3COOH + NaHCO3 → CH3COO–Na+ + H2O + CO2

• Carboxylic acids dissociate in water to give resonance stabilised

carboxylate anions and hydronium ion.

[pic]

Effect of substituents on the acidity of Carboxylic Acids

• Any factor that stabilizes the anion more than it stabilizes the acid

would increase the acidity of carboxylic acids.

• While any factor that decreases the stability of anion would decrease the

acidity of carboxylic acids.

• Electron withdrawing groups disperse the negative charge and thus

stabilize the anion which results in increase in acidity of the

carboxylic acids.

• Electron donating groups intensify the negative charge and destabilize

the anion which results in decrease in acidity of carboxylic acid.

[pic]

Conversion of Carboxylic Acids into functional derivatives

• Carboxylic acids can be converted into number of other compounds (known

as derivatives of carboxylic acids or simply acid derivatives)

by replacement of its –OH group by a Cl, OR or NH2 .

o Replacement of -OH by -Cl forms acid chlorides.

o Replacement of -OH by -OR forms ester.

o Replacement of -OH by -NH2 forms amide.

• Carboxylic acid can be recovered simply by hydrolysis of the acid

derivatives or one can say that the functional derivatives are all

readily reconverted into the acid by simple hydrolysis.

Conversion of Carboxylic Acids into Amide

• Reaction of carboxylic acids with ammonia results in formation of give

ammonium salt which on further heating at high temperature give

amides.

[pic]

Conversion of Carboxylic Acids into Acid Anhydrides

Lower monocarboxylic acid on heating with dehydrating agent (say P2O5)

forms anhydrides

[pic]

Note: Anhydride of formic acid is not known, it gives CO and H2O on

heating with conc. H2SO4.

HCOOH +Conc. H2SO → H2O + CO

Reduction of Carboxylic Acids to Alcohols

Lithium aluminium hydride can reduce an acid to an alcohol; the

initial product is an alkoxide from which the alcohol is liberated by

hydrolysis.

4 R–COOH + 3LiAlH4 → 4H2 + 2LiAlO2 + (RCH2O)4 AlLi + H2

Hydrolysis of (RCH2O)4 → alcohols

STEP 6: Chemical Reactions involving Carboxylic Acids (40 minutes).

|Activity: Small Group Discussion (20 minutes) |

| |

|DIVIDE students into small groups. |

| |

|ASK students to discuss in groups on the following questions |

|What are the chemical reactions involving carboxylic acids? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW each group to present for 5 minutes |

| |

|CLARIFY and SUMMARIZE by using the contents below |

An overview of the chemical reactions involving carboxylic acids

[pic]

Acid chloride (ROCl)

• Acid chlorides are formed when carboxylic acids react with thionyl

chloride (SOCl2).

• They are the most reactive derivatives of carboxylic acid.

[pic]

Ester (RCOOR’)

• Esters are derived when a carboxylic acid reacts with an alcohol.

• Esters containing long alkyl chains (R) are main constituents of animal

and vegetable fats and oils.

• Many esters containing small alkyl chains are fruity in smell and are

commonly used in fragrances.

[pic]

The acid-catalyzed esterification of carboxylic acids with alcohols to give

esters is termed Fischer esterification.

Thioester (RCOSR’)

• Thioesterification: A thioester is formed when a carboxylic acid

reacts with a thiol (RSH) in the presence of an acid.

[pic]

• Thioesters are commonly found in biochemistry, the best-known example

being acetyl CoA.

Acid anhydride

• An acid anhydride is a compound that has two acyl groups (R-C=O) bonded

to the same oxygen atom.

• Anhydrides are commonly formed when a carboxylic acid reacts with an acid

chloride in the presence of a base.

[pic]

• The mechanism by which a carboxylic acid anhydride is synthesized is as

follows;

[pic]

• This reaction follows an addition-elimination mechanism in which the

chloride anion (Cl-) is the leaving group.

o In the first step, the base abstracts a proton (H+) from the

carboxylic acid to form the corresponding carboxylate anion (1).

o The carboxylate anion's negatively charged oxygen attacks the

considerably electrophilic acyl chloride's carbonyl carbon.

o As a result, a tetrahedral intermediate (2) is formed.

o In the final step, chloride – a good leaving group – is eliminated

from the tetrahedral intermediate to yield the acid anhydride.

Amide

• The direct conversion of a carboxylic acid to an amide is difficult

because amines are very basic and tend to convert carboxylic acids to

their highly unreactive carboxylate ions.

o Therefore, DCC (Dicyclohexylcarbodiimide) is used to drive this

reaction.

[pic]

• A carboxylic acid first adds to the DCC molecule to form a good leaving

group, which can then be displaced by an amine during nucleophilic

substitution to form the corresponding amide.

Relative reactivity of the carboxylic acid derivatives towards a

nucleophilic substitution reaction

[pic]

• Consider the carboxylic acid derivatives as an acyl group, R-C=O,

attached to a substituent (X).

o These derivatives also undergo a nucleophilic substitution reaction

with a nucleophile (Nu) as shown above.

o The reactivity of these derivatives towards nucleophilic substitution

is governed by the nature of the substituent X present in the acid

derivative.

o If the substituent (X) is electron donating, it reduces the

electrophilic nature of the carbonyl group by neutralizing the partial

positive charge developed on the carbonyl carbon, and thus makes the

derivative less reactive to nucleophilic substitution.

o If the substituent (X) is electron withdrawing, then it increases the

electrophilic nature of carbonyl group by pulling the electron density

of the carbonyl bond towards itself, making the carbonyl carbon more

reactive to nucleophilic substitution.

|Derivative |

|Substituent (X) |

|Electronic effect of X |

|Relative reactivity |

| |

|Acid chloride |

|-Cl |

|electron withdrawing |

|1 (most reactive) |

| |

|Acid anhydride |

|-OC=OR |

|electron withdrawing |

|2 (almost as reactive as 1) |

| |

|Thioester |

|-SR |

|weakly electron donating |

|3 |

| |

|Ester |

|-OR |

|alkoxy (-OR) group is weakly electron donating |

|4 |

| |

|Amide |

|-NH2 |

|very strongly donating |

|5 |

| |

|Carboxylate ion |

|-O |

|Carboxylate ions are not reactive because their negative charge |

|repels the approach of other nucleophiles |

|6 (least reactive) |

| |

• Thus, on a reactivity scale, the order of reactivity of various

carboxylic acid derivatives towards nucleophilic substitution is as

follows:

Acid halide > acid anhydride > thioester > ester > amide

STEP 7: Key Points (10 minutes)

• A carboxylic acid is an organic compound that contains a carboxyl

group (C(=O)OH).

• The general formula of a carboxylic acid is R–COOH, with R referring

to the rest of the molecule.

• Carboxylic acids are generally more acidic than other

organic compounds containing hydroxyl groups but are generally weaker

than the familiar mineral acids (e.g., hydrochloric acid,

HCl, sulfuric acid, H2SO4, etc.).

• The chemical reactions involving carboxylic acids include conversion

of carboxylic acids into esters, amides, carboxylate salts, acid

chlorides, and alcohols.

• Carboxylic acids react with bases to form carboxylate salts, in which

the hydrogen of the hydroxyl (–OH) group is replaced with a

metal cation.

STEP 8: Evaluation (10 minutes)

• What are carboxylic acids?

• Write chemical five structures of carboxylic acids

• What are the chemical properties of carboxylic acids?

• Mention three chemical reactions involving carboxylic acids.

References

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New

Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). California, United

States: Lippincott Williams

Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Services

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