ORGANIC CHEMISTRY II

CHM301

CHAPTER 4
CARBOXYLIC ACIDS DERIVATIVES

Puan Nordiana Suhada Mohmad Tahiruddin

1
SUBTOPICS
◦General formula
◦Nucleophilic acyl substitution
- mechanism
◦Reactivity of carboxylic acid derivatives
toward nucleophilic acyl substitution
reaction
 GENERAL FORMULA

◦Carboxylic acid derivatives:

- groups of compounds which the acyl group (RCO-)

attached to electronegative atom or substituent.

◦The –OH group in carboxylic acid is replaced

by nucleophiles (Cl-, RCOO2-, RO- or NH2-).
 O O
R C OH R C Y
Carboxylic acid Carboxylic acid derivatives

o Four common derivatives:

- acyl chlorides / acid chlorides, acid anhydrides,
esters and amides.
 CARBOXYLIC ACID DERIVATIVES
Group replacing Classes of General Example
the –OH group compound formula
of RCOOH
-Cl Acyl O O
chloride/acid R C Cl H3C C CI
chlorides ethanoyl chloride

-OR’ Ester O
O
H3C C OC2H5
R C OR' ethyl ethanoate

-NH2 Amide O
O
H3C C NH2
R C NH2 ethanamide

O Acid anhydride O O O O
H3C C O C CH3
O C R' R C O C R'
ethanoic anhydride
 NUCLEOPHILIC ACYL SUBSTITUTION
REACTION
O O
R C Y Nu-H R C Nu H-Y

◦ Carboxylic acids (and their derivatives) more

commonly react by nucleophilic acyl substitution.
- one nucleophile replaces another on the acyl (C=O) carbon
atom.
◦ The nucleophile forms a new bond with nucleophilic
site and the leaving group (Y = Cl-, Br-, RO- or RNH-)
detaches from the molecule.
 MECHANISM OF NUCLEOPHILIC ACYL
SUBSTITUTION
◦ Occurs through an addition-elimination process in which a
nucleophile forms a bond with the electrophilic carbonyl
carbon atom forming a tetrahedral intermediate.

◦ The tetrahedral intermediate undergoes an elimination to

yield the products.

◦ STEP 1: Nucleophile attacks on carbonyl carbon results in

the π – bond cleaved.
O O
R C Y Nuc-H R C Y
Nuc-H
o Step 2: The regeneration of the double bond and the
leaving group Y detaches from the molecule.

O O
R C Y R C Nuc H Y

Nuc-H
o Step 3: H+ ion is removed from the molecule by the
leaving group Y.

O O
R C Nuc H Y R C Nuc HY

Nuc = OH, OR, OCOR, NH2, NHR

Y = Cl, Br, OCOR, OR, NHR
 ACID CATALYZED VARIATION
MECHANISM

◦ STEP 1: Protonation of carbonyl oxygen to

increase the reactivity which carbonyl carbon
becomes more positive for the nucleophilic attack.

O OH
R C Y HA R C Y A
• STEP 2: The π-bond breaks as nucleophile
attached to the molecule.

OH OH
R C Y Nuc H R C Y A

Nuc H
• STEP 3: As H+ ion bonded to nucleophile
detaches, double bonds regenerates and the
leaving group is pushed out from the molecule.

OH OH
R C Y R C Nuc Y
Nuc
• STEP 4: The leaving group, Y- removes the H+
ion, reestablishes carbonyl carbon in the
product.

O H O
R C Nuc Y R C Nuc HY
 RELATIVE REACTIVITIES OF CARBOXYLIC ACID
DERIVATIVES TOWARD NUCLEOPHILIC ACYL
SUBSTITUTION REACTION

 Example: Hydrolisis of carboxylic acid derivatives.

- Carboxylic acid derivatives, RCOY undergoes
hydrolysis with water.

- During hydrolysis, the C-Y bond is broken.

- The rate of hydrolysis depends on the bond

strength of C-Y.
The bond length decreases in the order:

C-Cl (in acyl chlorides) > C-O (in anhydride) > C-O (in ester) > C-N (in amide)
(longest bond) (shortest bond)

Bond strength is inversely proportional to bond length. The

longest bond is the weakest bond. Bond strength increases
in the order:

C-Cl (in acyl chlorides) > C-O (in anhydride) > C-O (in ester) > C-N (in amide)
(weakest bond) (strongest bond)
• Reactivity carboxylic acid derivatives decreases
in the order:

RCOCl > (RCO)2O > RCOOR’ > RCONH2

(most reactive) (least reactive)

• Carboxylic acids and esters are very similar in

reactivity.
• The less reactive acid derivatives can be
prepared from the more reactive ones.
- Example, anhydrides, esters and amides can be
prepared from acid chlorides.
- Esters, anhydrides and acid chlorides cannot be
prepared from amides.
• The order of reactivity can be explained by
considering the basicity of the leaving group.
- strong bases are not good leaving groups.
- the reactivity of derivatives decreases as the
leaving group become more basic.
- example: Cl- is a weakest base and a good
leaving group. Acyl chlorides is the most reactive
compared to other carboxylic acid derivatives.
• The reactivity of the carboxylic acid derivatives
are influences by the substituents:

i) if the substituent is electron donating, the

carbonyl carbon becomes less reactive.

ii) if the substituents is electron withdrawing,

the carbonyl carbon become more reactive.
@nsmt2016