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Subject Chemistry

Paper No and Title Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

Module No and Title Module-11, Michael Reaction and Addition to Cyclopropane

Ring
Module Tag CHE_P9_M11

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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TABLE OF CONTENTS
1. Learning Outcomes
2. The Michael Reaction
2.1 What is Michael Reaction
2.2 Mechanism of Michael Addition
2.3 Asymmetric Michael Addition
3. Additions to Cyclopropane Ring
3.1 Structure and Bonding in the Cyclopropane Ring
3.2 Addition Reactions of Cyclopropane Ring
3.3 Mechanism of Electrophilic Addition to Cyclopropane
3.4 Nucleophilic Addition to Cyclopropane
3.5 Addition of Free radicals to Cyclopropane
6. Summary

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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1. Learning Outcomes
After studying this module, you shall be able to

• Know about Michael conjugate addition reaction

• Learn about Michael acceptors and donors used for the reaction
• Familiarize with the mechanistic aspects of Michael reaction
• Acquire an understanding about Asymmetric variants of Michael reaction
• Identify the reasons for enhanced reactivity of cyclopropane ring
• Acquaint yourself with the various types of additions that cyclopropane systems undergo

2. The Michael Reaction

2.1 What is Michael Reaction

The Michael reaction can be understood as a base catalysed 1,4-conjugate addition of an

activated methylene (termed Michael Donor) and a conjugated olefin (Michael acceptor) as
represented below.

The activated methylene , the methylene donor is a methylene group which is bonded to two
electron withdrawing groups. These two groups can be same or different. The
electronwithdrawing groups help in stabilising the negative charge that forms after the removal
of proton from methylene group by the base. Thus, aldehydes, ketones, diketones, esters and
diesters, keto-esters, carboxylic acids and dicarboxylic acids, nitriles and nitro compounds can act
as efficient Michael donors.

Initially, the Michael reaction was done with an α,β-unsaturated   carbonyl compounds (Michael
acceptor) only. Later, it was extended to a variety of substrates including esters; nitriles;
sulfones; and compounds with activated double bonds like alkyl acrylates, Vinyl ketones, acrylo
nitrile, etc.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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The conjugation of a double bond to a carbonyl group due to resonance exhinits the electrophilic
or electron deficient character to the β-carbon of the double bond. It is due to this, that the
nucleophile may easily react with this and result in formation of the 1,4-addition product. A
strong base is used to generate the enolate which acts as the nucleophile from the Michael donor.
The commonly used bases in the reaction are alkoxides, NaOH, KOH , LDA, etc. in the presence
of protic solvents like alcohols.

For example, as shown below, the two electron wthdrawing esters group in diethy malonate help
the methylene group to act as Micheal acceptor. On the other hand, the second molecule .acts as
Michael acceptor where the phenyl and ester group are attached on the double bond.

2.2 Mechanism of Michael Addition

Let us understand how the Michael reaction takes place with the help of its mechanism which is
as depicted below.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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• The first step involves proton abstraction by the base to yield the reactive intermediate
(enolate ion).
• In the next step, the nucleophilic enolate attacks the conjugated ketone at the electrophilic
alkene carbon thereby transfering the electrons to the electronegative Oxygen, yielding an
intermediate enolate adduct. Thus, the conjugate 1,4-addition occurs.
• Finally, the enolate product gets protonated (by extracting a H+ from the protic solvent or
from the active methylene or during acid work-up) and which usually tautomerizes to the
more stable keto-form.

Even though the presence of a protic solvent aids proton-transfer steps shown in the mechanism,
protic solvents are not a necessity for successful Michael addition reactions.

The conjugate 1,4-addition product is thermodynamically controlled and takes place at relatively
higher temperatures. On the other hand, a 1,2-addition which is kinetically controlled takes place
at lower temperatures as shown below.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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Carbanions are weak bases, and favour 1,4-addition. However, strong bases like RLi, RMgX etc.
give 1,2 addition i.e., directly to the C=O bond , unless the C=O group is sterically hindered by
large groups.

It must be noted that the product of Michael addition can also further act as a potential Michael
donor. Hence the further reaction of the product donor further with the acceptor must be
controlled or else it will lead to polymerization.
In the classical Michael reaction, the enolate formed as the product is much more basic than the
donor enolate. As a result, it is thus rapidly discharged by protonation by solvent, other proton
donors or by the starting β-dicarbonyl compound.
• With unsymmetrical ketones, a mixture of regioisomeric enolates may be formed,
resulting in a mixture of Michael adducts. Generally, the more substituted alpha-carbon
of Michael donor are involved in the addition to avodi the further reaction.

• With β,β-­‐disubstituted acceptors, the rate of reaction is quite slow due to increased steric
hindrance. However, with doubly-activated acceptors (i.e. with two strong electron-
withdrawing substituents) this is not such of a problem.

• When both the Michael donor as well as th acceptor groups are located within the same
molecule, an intramolecular Michael addition reaction can take place.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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• The use of various other nucleophiles like amines (aza-Michael), S (thia-Michael) to

form C-N and C-S bond, respectively has also been done as extension of Michael
addition.

• In place of enolates, enamines can also be used as Michael donors in a very similar
manner. The reaction with enamines is called as Stork-enamine reaction.

2.3 Asymmetric Michael Addition

Recent research has focussed on the asymmetric variant of the Michael reaction which has not
only expanded the scope of this classical reaction but also increased its utility for the synthesis of
various natural products and compounds of pharmaceutical importance. There are essentially 2
major ways for obtaining a chiral Michael product:

1. Use of chiral substrates i.e. one can use a chiral Michael donor or a chiral Michael
acceptor or a combination of both to get an adduct in which the substrate essentially

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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controls its stereochemistry. An example of a Michael reaction with a chiral acceptor is

shown below:

2. Use of a chiral catalyst which induces chirality in the reaction product. Of these, the use
of chiral enamine catalysis has received great attention. Initially, stoichiometric amounts
of catalyst were used but now even 10-20 mol% (or even less) of the organocatalyst is
sufficient to bring about a successful asymmetry.

The chiral catalyst may induce chirality in the substrate through various mechanisms. For
example, use of chiral secondary amines (e.g. Proline based organocatlysts) may lead to a chiral
Michael adduct via 3 mechanisms:
I. Activation of the Michael acceptor via formation of an iminium species (I)
II. It may act as a base forming a complex with enolate to react with the acceptor (II)
III. Activation of ketone donors through formation of an enamine intermediate (III)
These are as shown below:

Thus, in all these cases, there is a discrimination of attack by either the acceptor or donor towards
one of the enantio-face of the chiral intermediate formed with the catalyst which in turn results in
the generation of asymmetric centres in the product.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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For example, the asymmetric Michael addition of aldehydes to nitrostyrenes was catalysed by
Pyrrolidine-sulfonamide catalyst which exhibited excellent enantioselectivity (94–99% ee),
diastereoselectivity (≥20:1 d.r.), and high yields (63–99%) as shown below.

Initially the catalyst forms an enamine with the aldehyde and due to which the nitrostyrene
attacks favourably through one of the faces to form a most stable transition-state as shown in
which the enamine and β-nitrostyrene are co-facial, with the nitro group hydrogen-bonded to the
protonated sulphonamide. This subsequently leads to the product with desired enantioselectivity.

Other catalysts used for asymmetric Michael addition include organocatalysts such as chiral
diamines, chiral crown ethers, chiral aminoacids, chiral alkaloids and chiral oxazolines or
heterogenous catalysts like polymer supported catalysts, organometallic complexes etc.

3. Additions to Cyclopropane Ring

The readers might wonder that why a section on cyclopropane ring system has popped up while
discussing the addition reactions to C—C multiple bonds. Actually, the cyclopropane ring-
system, although an alkane, shows reactivity akin to an alkene towards various electrophiles,
nucleophiles or free radicals. What is the reason for this type of reactivity of cyclopropane ring
system can be explained by having a close observation of its structure and bonding properties.

3.1 Structure and Bonding in the Cyclopropane Ring

Cyclopropane has a triangular planar structure due to which , the bond angles between carbon-
carbon bonds are expected to be 60°. This is far less than the thermodynamically stable angle of
109.5° as per the sp3 hybridisation of the carbon atoms. Due to this there is a considerable amount
of ring strain in the cyclopropane molecule. In addition to this angular strain, cyclopropane also
suffers additional torsional-strain. The torsional strain is due to the coplanar arrangement of the

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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carbon atoms wherein leading to the eclipsed arrangement of the C-H bonds. Important
characteristics of cyclopropane ring are as given below:

• C—C bonds are shorter than in alkanes (1.51 Å vs. 1.54 Å).
• H—C—H angle opened up (115 Å vs. 106 Å in propane)
• C—H bonds are more acidic (pKa=46, vs. 51 in propane
• Strain energy = 27.5 kcal/mol.
• The C-C bond strength in cyclopropane is considerably weaker (65 kcal/mol) than for a
typical C-C bond (80-85 kcal/mol).

It has been suggested that significant re-hybridization occurs in cyclopropane and bonding
between the carbon centres occurs in terms of ‘bent’ bonds (Coulson-Moffitt model) wherein the
carbon-carbon bonds are bent outwards so that the inter-orbital angle is 104° which consequently
reduces the level of bond strain. So it is intermediate between σ and π bonding. These bonds are
also sometimes called "banana bonds" (Fig.1a). Thus, the C—C bonds have more p- character
than normal while C—H bonds have more s character. Thus, it can be seen that ring strain
substantially weakens the C-C bonds of the cyclopropane ring. Hence, cyclopropane is much
more reactive than alkanes or other higher ring systems.

(i) (ii)

a) Coulson-Moffitt model b)Walsh model

Fig. 1: Models for bonding in cyclopropane

Another model viz. Walsh model based on M.O. considerations, envisions cyclopropane as
being constructed from three sp2-hybridized methylenes (CH2), (Fig. 1b). Two of these sp2-
orbitals are used for C−H-bonds (not shown) and one forms an inner two-electron-three-centre σ
bond, leaving p-orbitals to form some kind of degenerate π-like orbitals. Thus, Walsh
cyclopropane has considerable sp2 character and should react in analogy to olefins. Fig. 1b(ii)

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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shows the Molecular Orbital diagram for cyclopropane as formed up of 3 methylenes, in

inceasing order of energy.

3.2 Addition Reactions of Cyclopropane Ring

From the preceding discussion, it becomes clear that cyclopropane ring system suffers from a
large ring strain (which is a combination of angle strain and torsional strain) which leads to a
significant weakening of the C—C bond. Thus, C—C bonds show a greater p-character, while
C—H bonds have more s character. Thus, in effect, the cyclopropane ring undergoes any such
reaction which can subsequently help in relieving the ring strain. Most of these reactions are
similar to those of alkenes and most common of these are addition reactions (electrophilic
nucleophilic or free-radical) which lead to opening of the ring. The following figure illustrates
some of the addition reactions of cyclopropane.

In each of these reactions, a C—C bond is broken leading to ring fission and the atoms of the
reagent attach at two terminals of the resulting propane chain. Depending upon the substitution of
cyclopropane ring , which can be electron donors or acceptors, any of its three bonds are likely to
undergo cleavage. The reagent must be able to polarize itself into nucleophilic and electrophilic
centres for the subsequent addition to occur. This is as shown in the following figure (note: this is
not the full mechanism!!). Thus, propylene reacts more readily with Br2 or Cl2 while for reaction
with cyclopropane a Lewis acid is required (FeCl3 or FeBr3) to effect sufficient polarization of the
Cl2 or Br2 molecule.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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3.3 Mechanism of Electrophilic Addition to Cyclopropane

Before discussing the mechanism, there are two important points to be noted for addition reaction
of cyclopropane:

1. The mechanism must be stepwise as reaction of D2SO4 with cyclopropane yields along
with the expected product (I), minor amounts of 2 more products (II and III) as shown
below:

2. The electrophilic addition in substituted cyclopropanes generally follows Markovnikov's

rule wherein hydrogen adds to the carbon which already contains more hydrogens.

This suggests that the mechanism comprises of an initial attack by the electrophile (e.g. H+) on
the ring carbon with the most hydrogens, generating a positive charge on the carbon
(carbocation). This positive charge may be transferred on to the other carbons of the ring and the
most favourable intermediate would be the one in which the positive charge is on the most
substituted carbon (most stable carbocation). This cation is subsequently trapped by its reaction
with the nucleophile as shown below.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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Another type of mechanism has been suggested which depicts an edge-protonated cyclopropane:

3.4 Nucleophilic Addition to Cyclopropane

Ring-fission of cyclopropane by nucleophiles is possible only when an electron-withdrawing

group (W) is present on the ring.

This reaction has been used widely in organic synthesis and can be used as a homologous variant
to a Michael-type addition to generate a 5-membered ring as shown.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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Similarly, secondary amines or alcohols can also effect the opening of the cyclopropane ring as
shown below.

3.5 Addition of Free radicals to Cyclopropane

Free radicals also add to the cyclopropane ring system. Thus, Br2 can add to a cyclopropane ring
in presence of UV light via a free radical mechanism. Initially, Br● attacks the least hindered
carbon, to yield the most stable radical, and the second one goes to the most substituted carbon.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring
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6. Summary
• The Michael reaction is essentially a 1,4-conjugate addition and is one of the most
powerful carbon-carbon bond-forming reactions in organic synthesis.

• Both the Michael donor and Michael acceptor have activating groups (electron
withdrawing nature) that can also serve as points for further functionalization.

• In place of enolates, enamines can be used as Michael donors and the resulting reaction is
called as Stork-enamine reaction.

• The mechanism of Michael reaction involves proton abstraction of the Michael donor
resulting in a stable carbanion and conjugate 1,4-addition with the Michael acceptor
molecule followed by subsequent proton abstraction and tautomerism to yield the stable
Michael product.

• Various catalysts have been used for the asymmetric Michael addition which has
expanded the scope of this classical reaction.

• Cyclopropane ring system suffers from a large ring strain (which is a combination of
angle strain and torsional strain) which leads to a significant weakening of the C—C
bond.

• Various models for the structure and bonding of cyclopropane have been suggested. The
Coulson-Moffitt model depicts the rehybridisation of the molecule in terms of bent
“banana” C—C bonds while the Walsh MO treatment considers it as made up of 3
methylene groups.

• Cyclopropane undergoes many reactions similar to those of alkenes such as

electrophilic/nucleophilic or free radical addition reactions which result in relieving of
the ring strain via ring fissure.

• The electrophilic addition to cyclopropane follows Markovnikov’s rule.

CHEMISTRY PAPER No. : Paper-9, Organic Chemistry-III (Reaction Mechanism-2)

MODULE No. : Module-11, Michael Reaction and Addition to
Cyclopropane Ring