Subject Chemistry

Paper No and Title 14: Organic Chemistry – IV (Advance Organic

Synthesis and Supramolecular Chemistry and
carbocyclic rings)
Module No and 12: Disconnection approach for normal to large
Title carbocyclic rings

Module Tag CHE_P14_M12

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Table of Content

1. Learning outcomes
2. Introduction
3. Synthesis of common/normal ring compounds
4. Synthesis of medium and large ring compounds
5. Summary

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 1. Learning Outcomes

After studying this module, you shall be able to

 Know the importance of normal, medium and large carbocyclic and related compounds
 Design the synthesis of five and six-membered ring compounds and their derivatives
 Design the synthesis of medium and large ring compounds and their derivatives

2. Introduction

The carbocyclic compounds have played and going to play very important role in
chemistry. The interest towards macrocycles has increased due to their wide applications. The
development is mainly due to their fascinating structural symmetries and new stereochemical
aspects. They are also helpful as building blocks in supramolecular chemistry. The saturated
alicyclic compounds have the general formula CnH2n (same as that of the alkene and are isomers
of alkene); they do not have double bond but possess a ring structure.
Monocyclic compounds have been classified on the basis of number of carbon atoms in
the ring in the following way:
Small rings: 3-4 carbon atoms
Common/normal rings: 5-7 carbon atoms
Medium rings: 8-11 carbon atoms
Large rings: >12 carbon atoms
The carbocyclic rings are present in many natural product compounds. For example,
paclitaxel is a plant derived terpenoid. This is a multi-ring structured compound and possesses
four-, six- and eight-membered rings.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Paclitaxel

3. Synthesis of normal ring compounds

Synthesis of cyclopentane
Retrosynthetic analysis:
The retrosynthetic analysis of cyclopentane (1) is given in figure 1. The functional group
interconversion shows that the cyclopentane can be obtained from cyclopentanone (2) which
further can be obtained from 2-oxocyclopentanecarboxylic acid ethyl ester (3). The C-C
disconnection of 2-oxocyclopentanecarboxylic acid (4) shows that this can be obtained from
diethyl hexanedioate (5).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 1

Synthesis:
Cyclopentane is synthesized from diethyl hexanedioate using Dieckmann condensation
on the basis of retrosynthetic analysis (Figure 2).
Step 1: Diethylhexadioate (5) on reaction with a base forms the corresponding anion (6), which
undergoes cyclization, followed by ethoxide ion (-OEt) removal to form 2-
oxoethylcyclopentanoate (3).
Step 2: 2-Oxoethylcyclopentanoate (3) upon hydrolysis forms 2-oxocyclopentanoic acid (4).
Step 3: 2-Oxocyclopentanoic acid (4) on heating undergoes decarboxylation and form
cyclopentanone (2).
Step 4: Cyclopentanone (2) undergoes Clemmenson’s reduction using Zn-Hg/HCl and forms
cyclopentane (1).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 2

Synthesis of cyclohexane
Retrosynthetic analysis:
The retrosynthetic analysis of cyclohexane (7) is given in figure 3. The functional group
interconversion shows that the cyclohexane can be obtained from cyclohexanone (8) which
further can be obtained from 2-oxocyclohexanecarboxylic acid ethyl ester (9). The C-C
disconnection of 2-oxocyclohexanecarboxylic acid (9) shows that this can be obtained from
diethylheptanedioate (11).

Synthesis:
Cyclohexane is synthesized from diethyl heptanedioate (11) using Dieckmann
condensation as shown in figure 4.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Step 1: Diethylheptandioate (11) on reaction with a base forms the corresponding anion (12),
which undergoes cyclization, followed by ethoxide ion (-OEt) removal to form 2-
oxoethylcyclohexanoate (9).
Step 2: 2-Oxoethylcyclohexanoate (9) upon hydrolysis forms 2-oxocyclohexanecarboxylic acid
(10).
Step 3: 2-oxocyclohexanecarboxylic acid (10) on heating undergoes decarboxylation and form
cyclohexanone (8).
Step 4: Cyclohexanone (8) undergoes Clemmenson’s reduction using Zn-Hg/HCl and forms
cyclohexane (7).

Figure 3

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 4

Synthesis of cyclohex-4-ene-1,2-dicarboxylic acid

Retrosynthetic analysis:
The retrosynthetic analysis of cyclohex-4-ene-1,2-dicarboxylic acid (13) is given in
figure 5. The disconnection approach explains that the cycloaddition of ‘diene’ and ‘en’ can built
a cyclohexane ring.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 5

Synthesis:
Cyclohex-4-ene-1,2-dicarboxylic acid is synthesized from 1,3-butadiene and eth-1,2-
dienoic acid using Diels-Alder reaction (Figure 6). When buta-1,3-diene and eth-1,2-dienoic acid
are heated, they form the cyclohex-4-ene-1,2-dicarboxylic acid.

Figure 6

4. Synthesis of medium and large ring compounds

Figures 7 and 8 show the general retrosynthetic and synthetic pathways for the design and
synthesis of medium and large ring compounds.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Retrosynthetic analysis
The retrosynthetic analysis of carbocyclic ring compounds possessing medium to large
rings is given in figure 7. These compounds can be synthesized from aliphatic dicyanides. The
functional group interconversion (FGI) on carbocyclic compound 16 shows that it can be
prepared from compound of the type 17. The compound 17 can be obtained from 18 which on C-
C disconnection give synthon 19. The synthetic equivalent of synthon 19 is the dicyanide
compound 20.

Figure 7

Synthesis

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 The synthetic pathways of carbocyclic ring compounds possessing medium to large rings
is given in figure 8. These compounds can be synthesized from aliphatic dicyanides through
intramolecular condensation of aliphatic dicyanides.
Step 1: Aliphatic dicyanide (20) in the presence of base gives a carbanion 21 which is stabilized
with metal ion (lithium metal, in present case).
Step 2: The carbanion 21 undergoes cyclization to give the carbocyclic ring 22.
Step 3: The carbocyclic ring 22 undergoes acidic hydrolysis where C=NH get converted to C=O
and –CN get converted to –COOH (compound 17).
Step 4: The decarboxylation of compound 17 gives cyclic ketone 23, which can be further
reduced to cyclic alkanes via Clemmensen reduction using Zn-Hg and HCl.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 8

Synthesis of 2-methylcyclohept-3-enol (24)

The retrosynthetic pathway of 2-methylcyclohept-3-enol (24) is given in figure 9.

Figure 9

Synthesis

The synthesis of 2-methylcyclohept-3-enol (24) is given in figure 10. In this case,

allylsilane-based strategies have been utilized to build up cycloheptane derivatives. The
intramolecular cyclization of functionalised allylsilanes has been utilized for the synthesis of
seven membered hydroxycycloalkenes and oxacycloalkenes. The functionalised allylsilanes (26)
has been achieved from allylic alcohols (27).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 Figure 10

The other possible methods for the synthesis of carbocyclic compounds include
expanding or contracting an existing ring. Using these methods it is possible to access structures
that would be difficult with a single cyclization reaction due to slow rate of formation. The
expansion of rings is usually done either by a migration or insertion or opening of a bicycle to a
single larger ring.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings
 5. Summary
 Monocyclic compounds have been classified as small rings (3-4 carbon atoms),
common/normal rings (5-7 carbon atoms), medium rings (8-11 carbon atoms) and large
rings (>12 carbon atoms).
 Cyclopentane is synthesized from diethylhexanedioate using Dieckmann condensation.
 Dieckmann condensation is also being used for the synthesis of cyclohexane.
 Cyclohex-4-ene-1,2-dicarboxylic acid is synthesized from 1,3-butadiene and eth-1,2-
dienoic acid using Diels-Alder reaction.
 The general retrosynthetic and synthetic pathways for the design and synthesis of
medium and large ring compounds has been discussed.
 The allylsilane-based strategies have been utilized to build up cycloheptane derivatives.
 The expanding or contracting an existing ring method can also be employed for the
synthesis of carbocyclic rings.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic

Synthesis and Supramolecular Chemistry and carbocyclic
rings)
Module No. 12: Disconnection approach for normal to
large carbocyclic rings