UNIT-IV: Addition to Carbon Multiple Bonds and Mechanisms:

4.1 Addition to carbon-carbon multiple bonds- Addition reactions involving 4.1.1 electrophiles, 4.1.2
nucleophiles, 4.1.3 free radicals, 4.1.4 carbenes and 4.1.5 cyclic mechanisms-4.1.6 Orientation and reactivity,
4.1.7 hydrogenation of double and triple bonds, 4.1.8 Michael reaction, 4.1.9 addition of oxygen and Nitrogen;

4.2 Addition to carbon-hetero atom multiple bonds: 4.2.1 Mannich reaction, 4.2.2 acids, 4.2.3 esters, 4.2.4
nitrites, 4.2.5 addition of Grignard reagents, 4.2.6 Wittig reaction, 4.2.7 Prins reaction. 4.2.8 Stereochemical
aspects of addition reactions.

4.3 Addition to Carbon-Hetero atom Multiplebonds: 4.3.1 Addition of Grignard reagents, 4.3.2 organozinc
and 4.3.3 organolithium reagents to carbonyl and unsaturated carbonyl compounds.

4.4 Mechanism of condensation reactions involving enolates – 4.4.1 Stobbe reactions.4.4.2 Hydrolysis of
esters and 4.4.3 amides, 4.4.4 ammonolysis ofesters.

4.1 ADDITION TO CARBON – CARBON MULTIPLE BONDS

The addition to a double or triple bond can take place by electrophlic (+ve or neutral Species),
nucleophilic (-ve Species), free-radical mechanism or simultaneous attack of electrophlic, nucleophilic on both
carbon atoms. The nature of mechanism occur in an reaction depends on the nature of the substrate, the reagent
and the reaction conditions.

4.1.1 Electrophilic addition In this mechanism a positive species approaches the double or triple bond and in
the first step forms a bond by converting the pi-pair of electrons into a sigma pair.

Y may be the positive ion, positive end of a dipole or an induced dipole, with the negative part breaking
off either during the 1st step or shortly after. The second step is a combination of carbocation with species carrying
an electorn pair.

But in bromination, the intermediate carbocation rapidly cyclises to a bromonium ion

The addition of electrophilic is stereospecific or stereo selective.

4.1.2 Nucleophilic addition

The first step of nucleophilic addition, a nucleophile brings it pair of electrons to one c atom of the
double or triple bond, creating a carbanion. The second step is combination of this carbanion with a positive
species.

Step 1 : Step 2 :

The neucleophilic addition to double bond is non stereospecifc. Because the carbanion has a short life
time assume most favourable conformation before the attack of w.

4.1.3 Free radical addition

The first step involves the formation of free radicals usually by homolytic cleavage of bond i.e. a
cleavage in which each fragment retains one electron.

Initiation step:

⎯hυ
⎯⎯ or
→
Spontaneous dissociation
YW Y. + W. This is called an initiation step.

Propagation

The 2nd step is called propagation in which case one must be a molecule and one a F.R. but in any case a new
radical is generated.
•

Y. + H2C = CH2 → YH2C – C H2 The

Termination

3rd step is called termination.

This usually happens by a process of combination of two like radicals or a radical and a molecule to
form a new bond.

Y Y W
| | |
• •
H2C- C H2 + YW → H2C – CH2 + Y
The FR addition should be non steroeospecific, because intermediate has short life time.

4.1.4 Carbene
 A carbene is a compound that has two unshared valence electrons and a neutral carbon atom with a
valency of two. Generally written as “R2C:”. Carbenes, which have six electrons in their outer orbital, have a
nonbonding pair of electrons and their formal charge is zero. They are short-lived and exhibit extreme reactivity
because of electron deficiency.

Structure and reactivity : Generally, carbenes have two bonding electrons (both in sp2-orbitals) and two non-
bonding electrons. There are two classes of carbenes called singlet or triplet carbene depending on whether the
non-bonding electrons are in the same or different orbitals, respectively as shown in Figure. The diradical form
is known as a triplet carbene, while the structure with a lone pair is called a singlet carbene.

Carbene Synthesis : The two most popular methods for the synthesis of carbenes are from alpha-elimination of a
halo compound and from decomposition of a diazo compound. A common example of the alpha-elimination
reaction is the deprotonation reaction of chloroform with hydroxide to yield dichlorocarbene.

Cyclopropanation Reactions: The most important carbene reactions are ones that enable formation of
cyclopropanes. Depending on the structure of the target cyclopropane, different carbene starting materials are
employed. If a dihalocyclopropane is the target, then a standard alpha-elimination reaction is used. As shown
below, treating the starting alkene with chloroform and a base readily yields a dichlorocyclopropane product. The
reaction mechanism is a stereospecific, concerted process.

1)

2)
4.1.5 Cyclic mechanism

In this mechanism both c atoms are attacked simultaneously by Y - W and the addition is syn and
stereospecific. The cyclic mechanism takes place by four , five or six centered transition state

4.1.7 Hydrogenation of Double or Trible bonds

4.1.8 MICHAEL ADDITIONS

 Compounds containing electron withdrawing groups add in the presence of base to olefins of the form H 2C
= CHZ (Z electrone withdrawing group). This is called the Michael reaction.

CH2 (COOC2 H5)2 + C6H5.CH=CH.COOCH3 base C6 H5.CH.CH2.COOCH3

ehyl malonate α, β – unsaturated ester |
CH.(COOC2H5)2

The mechanism is nucleophilic addition

Step 1 Formation of Nucleophile

CH2. (COOC2 H5)2+ C2H5O- CH. (COOC2H5)2 + C2H5OH

Diethyl malonate

Step 2 Attack of Nucleophile on the substrate

O
||
C6 H5.CH = CH.C.OCH3 + CH.(COOC2H5)2
O
C6 H5.CH.CH = C – OCH3
|
CH(COOC2H5)2

Step 3 Attack of H+ from C2H5OH and followed by keto-enol tautomerism

O O
||
C6 H5.CH.CH = C – OCH3 C2H5OH C6H5CH.CH2-C.OCH3
| |
CH(COOC2H5)2 CH (COOC2H5)2

The reaction has been carried out with malonates, cyanoacetates, aceto acetates, other  -
Keto ester. Etc, Michael reactions are sometimes applied to substrate of the type – C  C-Z e.g.,

HC  C. COOEt + H3C.CO.CH.COOEt + C2H5OH

H C = CH. COOEt
|
CH3CO.CH.COOEt
4.1.9 1.3 – DIPOLAR ADDITION (ADDITION OF O,N,C)

Azides add to double bonds to give triazolines. This reaction is an example for (2+3)
addition in which 5 membered heterocylic compounds are prepared by addition of 1,3. dipolar
compounds to double bonds.

1,3 dipolar compounds have a sequence of three atoms a-b-c of which ‘a’ has a sextet of
electrons in the outer shell and ‘c’ an octet with atleast one unshared pair.

Mechanism

The addition is stereospecific and syn and the mechanism is probably a one step
synchronous process. The rate of reaction do not very with changes in solvent. There are no
simple rule covering orientation in 1,3- dipolar additions. Regioselectivities are complicated but
have been explained by molecular orbital treatments.

Since compounds with 6 electrons in the outer shell of an atom are usually not stable the
a-b-c system is actually one canonical form of a resonance hybrid for which at least one other
form can be drawn e.g. for azides.
− − +
R – N – N = N+ R N – N N

1,3 – dipolar compounds can be divided into two main types. 1. Those in which the dipolar
canonical form has a double bond on the sextet atom and the other canonical form has a triple
bond on that atom
− + − +
a –b= c a – b  c

If we limit ourselves to the first row of the periodic table, b can only be nitrogen, c can be
carbon or nitrogen and a can be carbon, oxygen or nitrogen. Hence there are six types among
these are azides (a = b = c = N) and diazoalkanes (R2C – N = N R2C – N  N).
2. Those in which the dipolar canonical form has a single bond on the sextet atom and the other
from has a double bond.
− + − +
a –b− c a – b =c

Here b can be nitrogen or oxygen and a and c can be nitrogen, oxygen or carbon but there
are only 12 types since, for example N – N – C is only another form of C – N – N Of the 18
systems some of which are unstable and must be generated in situ, the reaction has been
accomplished for atleast 15, though not in all cases with a c-c double bond and also with other
double bonds. Not all olefins undergo 1,3 dipolar addition equally well. The reaction is most
successful for those that are good dienophiles in the Diels Alder reaction.

Conjugated dienes generally give exclusive 1,2 addition though 1,4 addition (3+4) Cyclo
addition) has been reported.

C – C triple bonds can also undergo 1,3 dipolar addition for example azides give triazoles

1,3 dipolar reagent can in some cases be generated by the in situ opening of a suitable 3
membered ring system. For example, aziridines can add to activated double bonds to give
pyrrolidines. E.g

Aziridines also add to c – c triples bonds as well as to other unsaturated linkages including
C=O, C=N and C  N. In some of these reactions it is a C-N bond of the aziridine that opens rather
than the C-C bond.
4.2 Addition to carbon-hetero atom multiple bonds:

4.2.1 The Mannich Reaction

The Mannich reaction is a three-component acid-catalyzed reaction of aldehydes or ketones with 1° or 2°

amines to produce β-amino-carbonyl compounds

The Mannich reaction is the organic reaction in which an acidic H+ ion (proton), which is positioned next
to a carbonyl group, undergoes an amino alkylation with the help of formaldehyde and ammonia (a primary or
secondary amine can be used instead of NH 3). The product of this reaction is a beta-amino carbonyl compound.
An example of the Mannich reaction between an amine or ammonia with formaldehyde and an alpha acidic proton
from a carbonyl compound to give a beta-amino carbonyl compound is illustrated below.

Mannich Reaction Mechanism

The Mannich reaction mechanism proceeds via two steps:

Step 1

The reaction between formaldehyde and amine leads to the formation of the iminium ion. This formation of an
iminium ion is illustrated below.

Step 2

The compound containing the carbonyl group (which is a ketone in this illustration for the mechanism of the
Mannich reaction) undergoes tautomerization to give its enol form. This enol form of the compound with a
carbonyl functional group now proceeds to execute an attack on the iminium ion. This attack finally yields the
required beta-amino-carbonyl compound or Mannich base. The illustration for this step is given below.
Thus, the amino alkylation of an acidic proton which is placed alongside a carbonyl group by formaldehyde and
a primary or secondary amine or ammonia is achieved, and the required beta-amino carbonyl compound (or
Mannich base) is produced. From the mechanism illustrated above, it can be observed that the Mannich reaction
is an example of the nucleophilic addition of an amine to a carbonyl group.

Many active hydrogen compounds give the reaction.

e.g.

The active hydrogen underlined.

According to this mechanism it is the free amine, not the salt that reacts, even in acid solution and the
active hydorgen compound reacts as the enol when it is possible. There is kinetic evidence for the intermediacy
of the iminium ion.

The Mannish reaction is an important biosynthetic route to natural products, mainly alkaloids, Robinson (1917)
synthesized tropinone by a Mannich reaction involving succin dialdehyde, methylamine and acetone.

4.2.2 Reduction of acids

Since relatively few methods exist for the reduction of carboxylic acid derivatives to aldehydes, it would
be useful to modify the reactivity and solubility of LAH to permit partial reductions of this kind to be achieved.
The most fruitful approach to this end has been to attach alkoxy or alkyl groups on the aluminum. This not only
modifies the reactivity of the reagent as a hydride donor, but also increases its solubility in nonpolar solvents.
Two such reagents will be mentioned here; the reactive hydride atom is in bold.

Lithium tri-tert-butoxyaluminohydride (LtBAH), LiAl[OC(CH3)3]3H : Soluble in THF, diglyme & ether.

Diisobutylaluminum hydride (DIBAH), [(CH3)2CHCH2]2AlH : Soluble in toluene, THF & ether.

Each of these reagents carries one equivalent of hydride. The first (LtBAH) is a complex metal hydride,
but the second is simply an alkyl derivative of aluminum hydride. In practice, both reagents are used in equimolar
amounts, and usually at temperatures well below 0 ºC. The following examples illustrate how aldehydes may be
prepared from carboxylic acid derivatives by careful application of these reagents. A temperature of -78 ºC is
easily maintained by using dry-ice as a coolant.

Although carboxylic acids are more difficult to reduce than aldehydes and ketones, there are several
agents that accomplish this reduction, the most important being lithium aluminum hydride (LiAlH4)
and borane (BH3). The product is a primary alcohol (RCOOH → RCH2OH).

Diborane (B 2H 6) also can be used to reduce carboxylic acids to alcohols.

 Carboxylic acids can be converted to 1o alcohols using Lithium aluminum hydride (LiAlH4). Note that
NaBH4 is not strong enough to convert carboxylic acids or esters to alcohols. An aldehyde is produced as an
intermediate during this reaction, but it cannot be isolated because it is more reactive than the original carboxylic
acid.

Mechanism

1) Deprotonation

2) Nucleopilic attack by the hydride anion

3) Leaving group removal

4) Nucleopilic attack by the hydride anion

5) The alkoxide is protonated

4.2.3 Reduction of Esters

Esters can be converted to aldehydes using diisobutylaluminum hydride (DIBAH). The reaction is
usually carried out at -78 oC to prevent reaction with the aldehyde product.

Esters can be converted to 1o alcohols using LiAlH4, while sodium borohydride (NaBH4) is not a strong
enough reducing agent to perform this reaction.

Mechanism

1) Nucleophilic attack by the hydride

2) Leaving group removal

3) Nucleopilic attack by the hydride anion

4) The alkoxide is protonated

4.2.4 Metal Hydride Reduction of Nitriles

The nitriles’ reduction may simply be defined as the chemical transformation in which a nitrile is reduced
to either an aldehyde or an amine by the use of a suitable reagent. Many metal hydrides can be used to reduce the
nitrile compounds to amines but LiBH4 and LiAlH4 are most common.
1. Reduction by lithium borohydride: The lithium borohydride (LiBH4) is one of the most common sources of
the hydride nucleophile. The hydride anion is produced during the reaction because of the polar nature of the
metal-hydrogen bond.

The hydride anion’s addition to nitrile compounds results in an anion which in turn gives rise to a
reduced product. Two subsequent additions of hydride anions to the carbon-nitrogen bond result in a lithium
salt which in turn gives rise to primary (1º) amines on protonation

The mechanism for the nitriles’ reduction by metal hydride (LiAlH4 in this case ) that involves the nucleophilic
addition of the hydride ion to the carbon-nitrogen bond is given below.

2. Reduction by Lithium aluminium hydride: The lithium aluminium hydride (LiAlH4) is one of the most common
sources of the hydride nucleophile. The hydride anion is produced during reaction because of the polar nature of
the metal-hydrogen bond.
The hydride anion’s addition to nitrile compounds results in an anion which in turn gives rise to a reduced
product. Two subsequent additions of hydride anions to the carbon-nitrogen bond result in a lithium salt which
in turn gives rise to primary (1º) amines on protonation

The mechanism for the nitriles’ reduction by metal hydride (LiAlH4 in this case ) that involves the nucleophilic
addition of the hydride ion to the carbon-nitrogen bond is given below.

4.2.5 Addition of Grignard reagents

Grignard reagents are formed by the reaction of magnesium metal with alkyl or alkenyl halides. They’re
extremely good nucleophiles, reacting with electrophiles such as carbonyl compounds (aldehydes, ketones, esters,
carbon dioxide, etc) and epoxides. They’re also very strong bases and will react with acidic hydrogens (such as
alcohols, water, and carboxylic acids).

Grignard reagents are made through the addition of magnesium metal to alkyl or alkenyl halides. The
halide can be Cl, Br, or I (not F)
 Reaction with aldehyde to form secondary alcohol

Reaction with ketone to form tertiary alcohol

Reactions with esters to give tertiary alcohol

Mechanism

The relative electronegativities of carbon (2.5) and magnesium (1.1), the bond between carbon and
magnesium is polarized toward carbon. That means that carbon is more electron rich than magnesium and is
actually nucleophilic.
 In the reaction of Grignards with aldehydes, the carbon attacks the carbonyl carbon and performs a 1,2-
addition to give an alkoxide. In the second step, acid is added to give you the alcohol.

4.2.6 Wittig reaction

Wittig reaction is an organic chemical reaction wherein an aldehyde or a ketone is reacted with a Wittig
Reagent (a triphenyl phosphonium ylide) to yield an alkene along with triphenylphosphine oxide.

The conversion of aldehydes and ketones to alkenes is one of the most common uses of Wittig
reactions. Usually, the Wittig reaction is employed to add a methylene group using Ph 3P=CH2
(methylenetriphenylphosphorane or Wittig reagent).

A principal advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is
absolutely fixed, in contrast to the mixtures often produced by alcohol dehydration.

Mechanism

Following the initial carbon-carbon bond formation, two intermediates have been identified for the
Wittig reaction, a dipolar charge-separated species called a betaine and a four-membered heterocyclic structure
referred to as an oxaphosphatane. Cleavage of the oxaphosphatane to alkene and phosphine oxide products is
exothermic and irreversible.

1) Nucleophillic attack on the carbonyl

2) Formation of a 4 membered ring

3) Formation of the alkene

(OR)
 If we want to get (E)-alkene but from a destabilized ylide, the Schlosser modification of the Wittig
reaction can be employed. Otherwise, the (E)-alkene selectively can also be obtained via Julia olefination and
its different variants. Since the (E)-enoate (α, β-unsaturated ester) are prepared via Horner-Wadsworth-Emmons
reaction, the same can be used as a substitute for the Wittig reaction. On a final note, the Still-Gennari
modification of the Horner-Wadsworth-Emmons reaction can be used to get (Z)-enoate.

In the case of aldehydes, the geometry around double bonds can easily be predicted by analyzing the
ylide’s nature. With unstable ylides (R3 = alkyl), (Z)-alkenes are formed with reasonable to very high selectivity.
With stable ylides (R3 = ester or ketone), (E)-alkenes are formed with a very high magnitude of selectivity. The
selectivity ratio (E/Z) is usually very poor with semi-stabilized ylides (R3 = aryl).

It has been observed that the Wittig reagents usually tolerate carbonyl compounds with numerous types
of functional groups like OH, OR, epoxide, aromatic nitro, and ester group

4.2.7 Prins reaction

The addition of an olefin to formaldehyde in the presence of an acid catalyst is called the Prins reaction.
Three main products are possible, which one predominates depends on the olefin and conditions.
 When the product is the 1,3 diol or the dioxane, the reaction involves addition to the C=C as well as to
the C=O. The mechanism is one of electophilic attack on both double bonds. The acid first protonates the C= O,
and the resulting carbocation attacks the C=C.

1) may undergo loss of H+ to give the olefin or may add water to give the diol. It has been proposed that
1 is stabilized by neighbouring group attraction with either the oxygen or a carbon stabilizing the charge (2 & 3
respectively). This stabilization is postulated to explain the fact that with 2. butene with cyclohexenes the
addition is anti.

2 1 3 4

A backside attack of H2O on the 3 or 4 membered ring would account for it. Other products are obtained
too, which can be explained on the basis of 2 or 3. Additional evidence for the intermediacy 2. is the finding 4
that oxetanes 4 subjected to the reaction conditions give essentially the same product ratios as the
corresponding alkenes. An argument against the intermediacy of 2 and 3 is that not all alkenes show the
antistereo selectivity. Indeed the stereochemical results are often quite complex with syn, anti and nonstereo
selective addition reported depending on the nature of the reagents and the reaction conditions. Since addition
to the C=C bond, is eletrophilic, the reactivity of the olefin increases with alkyl substitution and Markovnikovs
rule is followed.

The dioxan product may arise from a reaction between 1, 3 diol and HCHO or even between the olefin
and a formaldehyde dimer HO.CH2OCH+2.

4.2.8 Stereochemical aspects of addition reactions

For addition to c-x multiple bonds, the reactions are addition to the C – O, C-N C-S double
bonds and C-N triple bond. The mechanistic study of these reaction is much simpler than addition to c-c
multiple bonds. Since C=O, C=N and C  N bonds are strongly polar, with the carbon always the positive end
(except for isonitriles) there is never any doubt about orientation of unsymmetrical addition to these bonds.
Nucleophilic attacking species always go to the carbon and electrophilic ones to the oxygen or nitrogen.
Additions to C = S bonds are much less common but in these cases the addition can be in the other direction.
e.g. thiobenzophenone Ph2C = S when treated with phenyl lithium gives, after hydrolysis, benzhydryl phenyl
surfide Ph2CH SPh

Stereochemistry

It is not possible to determine whether the addition is syn or anit In addition of YH to a ketone
e.g.

The product has a chiral c but unless there is chirality in R or R1 or YH is optically active, the product
must be a racemic mixture there is no way to tell from its steric nature whether the addition of Y and H was syn
or anti. The same holds true for C = N and C = S bonds, since in none of these cases can chirality be present at
the hetero atom

The addition of a single YH to the C-N triple bonds gives the product in E & Z forms. If R or R1 is
chiral, a racemic mixture will not always arise and stereochemistry of addition can be studied in such cases.
Cram’s rule predict the direction of attack of Y in many cases. However, even in this the relative directions of
attack Y and H are not determined but only the direction of attack of Y with respect to the rest of the substrate
molecule.

4.3 Addition of Grignard Reagents, Organozinc and Organolithium Reagents to Carbonyl and
Unsaturated Carbonyl Compounds

As far as the addition to carbon-heteroatom multiple bonds is concerned, three organometallic

reagents are much more important than the others; organomagnesium (Grignard reagents), organozinc, and
oreganolithium compounds. In this section, we will discuss the addition of these three types of reagents to
carbonyl and unsaturated carbonyl compounds.

4.3.1 Addition of Grignard Reagents to Carbonyl and Unsaturated Carbonyl Compounds

The typical addition mode of organomagnesium compounds (Grignard reagent) to common carbonyl
compounds like ketone and aldehydes is given below.
 The halomagnesium alkoxide thus formed can react with H 2O (when an HX type mineral acid is available)
to result in alcohols; which in turn, could be susceptible to dehydration (acid-catalyzed) if it is tertiary-type. To
stop the alcohol’s dehydration, we need to add some ammonium chloride (NH 4Cl) to the water so that because its
acidic character can be employed to transform ROMgX to ROH.

It is also worthy to note that bulky groups in the keto group, or in the reagent itself, greatly affect the
nucleophilic addition in a negative way, or gets completely prohibited in some cases.
 However, if a beta hydrogen is present in the bulky group of Grignard reagent, the transfer of hydride ion
can result in the reduction of even highly hindered ketone. The transfer of hydride ion takes place via the cyclic
transition state having six member.

Also, if the Grignard addition takes place in cyclic ketones, the nucleophilic attack will happen
from the carbonyl’s face with less steric hindrance.
 On a final note, if the aldehyde or the ketone used is α-, β-unsaturated, the nucleophilic addition of
Grignard reagents becomes must faster and effective than normal carbonyl compounds, yielding 1, 4- and 1, 2-
adddition products simultaneously. Moreover, these α-, β-unsaturated ketone and aldehydes give 1, 4- and 1, 2-
adducts as the major products, respectively.
 Since the Grignard reagents are very strong bases, they are not suitable to act as nucleophiles with substrate
containing acidic hydrogens. In other words, Grignard reagents will act as a base and will abstract the acidic
hydrogen instead of participating as a nucleophile to attack the carbonyl group.

4.3.2 Addition of Organozinc Reagents to Carbonyl and Unsaturated Carbonyl Compounds

The rate of reaction for carbonyl compounds with dialkylzinc reagents is quite slow. It has also been
observed that the rate for higher dialkylzinc is even lesser than lower dialkylzinc reagents. For instance, the
reaction of diethylzinc with acetaldehyde takes hours for completion whereas the higher homologs may even take
weeks. Nevertheless, allylzinc reagents show greater reactivity towards nucleophilic addition than normal
dialkylzinc systems. Furthermore, the metal halide Lewis acids have been shown to enhance the rate of addition
via dialkylzinc reagents.

The heteroatoms presence at the alpha-site (relative to C=O group) has also been found to be supportive
of nucleophilic addition of organizinc reagents.

On a final note, it has also been proved that many titanium catalysts are supportive of the reactivity of
organozinc reagents, specially TiCl4 and Ti(OiPr)4.

4.3.3 Addition of Organolithium Reagents to Carbonyl and Unsaturated Carbonyl Compounds

Organolithium reagents react with organic carbonyl derivatives to generate lithium alkoxide, which in turn
gives rise to alcohols upon hydrolysis.
 Sometimes a bioproduct via the α-deprotonation can also be obtained because besides being a nucleophilic
attacker, organolithium is a powerful base too.

Furthermore, it is also worthy to note that organolithium reagents are better than their organomagnesium
counterparts; and therefore, some highly hindered carbonyls (who were unable to react at all with Grignard
reagents) can also be used as a substrate to produces quite stable products.

On a final note, the conjugated addition doesn’t happen in the case of organolithium, leaving 1, 2-adducts
as the only products.

4.4 Mechanism of condensation reactions involving enolates :

4.4.1 Stobbe Condensation

 The Stobbe condensation may simply be defined as a modification to Claisen condensation where the
diethylesters of succinic acid react with aldehydes (or ketones) to give rise to alkylidene succinic acids or their
monoesters in presence of a relatively less strong base.

This reaction is a modification to Claisen condensation and was invented by a German chemist Hans
Stobbe; and therefore, is also named after him. The initial reaction was observed in 1893 when H. Stobbe observed
that the reaction between acetone and diethyl succinate (in the presence of C2H5ONa) yielded an α-, β-unsaturated
ester (tetraconic acid) and its monoethyl ester, instead of a 1-, 3-diketone product via normal Claisen
condensation.

Mechanism of Stobbe Condensation: The most widly accepted mechanism for Stobbe condensation that can
explain the generation of an ester group, as well as the formation of a carboxylic acid group is a function of a
lactone intermediate as shown below.

The carbonyl component isn’t restricted in Stobbe condensation; and therefore, it even can have α-
hydrogens. Nevertheless, if α-hydrogens are present in the carbonyl component, the double bond migration can
trigger the formation of many types of final products.

Stereochemistry of Stobbe condensation: Only one alkene stereoisomer will be obtained if

symmetrical ketones are used; nevertheless, unsymmetrical ketones will give rise to a mixture of alkene
stereoisomers.
Examples of Stobbe condensation

1. Reaction between acetone and dimethylsuccinate

2. The reaction between benzophenone and diethyl succinate to give corresponding monoethyl ester is
also an example of Stobbe condensation.

3. One more example of Stobbe condensation includes the generation of acids and monoethyl esters
from the reaction between alkyl aryl ketone with diethyl succinate.
4.4.2 Hydrolysis of Esters

Although the esters are derived from acids, they are generally neutral compounds. In an archetypal ester
reaction, the OR group (i.e., alkoxy) of the ester is swapped by another group. One such type of reaction is the
ester hydrolysis where the OH group (generated by the water-splitting) replaces the alkoxy group of esters under
consideration. The ester hydrolysis can either be catalyzed by an acid or by a base.

Illustrative Reaction: The typical organic chemical reaction depicting acid hydrolysis of esters is shown
below

Mechanism involved: Since the ester hydrolysis can either be catalyzed by an acid or by a base; a brief
overview for both kinds must be understood for a better understanding.

i) Acid-catalyzed mechanism of ester hydrolysis:

The mechanism for acid-catalyzed ester hydrolysis is a case of ‘less reactive system type’, and all the
steps involved are shown below.
 Furthermore, it is also worthy to note that the acidic hydrolysis of esters is just the reverse of
esterification where an ester is heated with a large amount of water in the presence of a strongly acidic catalyst.
Also, acidic ester hydrolysis is a reversible process and does not complete with 100% yield (like esterification).

ii) Base catalyzed mechanism of ester hydrolysis:

The mechanism for base-catalyzed ester hydrolysis is a case of ‘reactive system type’, and all the steps
involved are shown below.

The mechanism given above gives rise to the breakage of the acyl-oxygen bond (second step); and is supported
by experimental pieces of evidence through if the compound is isotopically labeled (i.e., 18O). A similar
conclusion was drawn if esters of chiral alcohols were used. The base-catalyzed ester hydrolysis is popularly
known as the "saponification" process due to its use of soap-synthesis.

4.4.3 Hydrolysis of Amides

Amides are derivatives of carboxylic acid where the OH group has been substituted by NR 2, NH2, NHR,
or amine. Since the reaction between an amine and a carboxylic acid giving amide occurs via the release of the
water molecule (condensation reaction), the amides’ hydrolysis can be labeled as the reverse of
condensation reaction as the amine and acid are being reproduced. The amides’ hydrolysis isn’t easy and
requires conditions like the heating of amide with aqueous acid for a long interval of time. Like the hydrolysis of
esters, the amide hydrolysis can either be catalyzed by an acid or by a base.

Illustrative Reaction: The typical organic chemical reaction depicting acid hydrolysis of amides is shown below.

Mechanism involved: Since the amide hydrolysis can either be catalyzed by an acid or by a base; a brief
overview for both kinds must be discussed for a better understanding.
i) Acid-catalyzed mechanism of amide hydrolysis:

The mechanism for acid catalyzed amide hydrolysis is a case of ‘less reactive system type’, and all the
steps involved are shown below

It is obvious from the mechanism given above that the acid catalysed amide hydrolysis is quite
analogous to the acid catalysed esters’ hydrolysis; and proceed via the protonation of the carbonyl group and
not the amide one.

ii) Base catalyzed mechanism of amide hydrolysis:

The base-catalyzed amide hydrolysis is extremely difficult to carry out but possible if the amide is
heated for a very long span of time. All the steps involved in the base-catalyzed hydrolysis of amide are shown
below.

It is obvious that the major problem in the way of substitution to happen is the need for a good leaving
group; however, the deprotonated amine so strongly basic that it is almost the opposite of a good leaving group.
Consequently, the breaking of amide is proved to be extremely difficult even if we couple very high
temperatures with a base like KOH.
4.4.4 Ammonolysis of Esters

Before we study the ammonolysis of esters, we need to distinguish the term ‘ammonolysis’ from the term ‘aminolysis’ first. The
precise definition of ‘ammonolysis’ includes the chemical reactions in which a compound is split into two parts by its reaction with
ammonia; however, in broader terms, admins can also be used. On the other hand, the precise definition of ‘aminolysis’ includes the
chemical reactions in which a compound is split into two parts by its reaction with amine; nevertheless, in broader terms, ammonia can
also be used. Hence, we can conclude that the terms ‘ammonolysis’ and ‘aminolysis’ are pretty much similar not only w.r.t names but
also in their approach; and therefore, are used in an exchangeable manner in different textbooks.

Definition and Examples Reactions of Ammonolysis of Esters

Now we come to the ‘ammonolysis’ of esters, which popularly means that the esters can be converted into
primary, secondary, and tertiary amides (along with alcohols) by treating them with ammonia, primary amines,
and secondary amines respectively.

Since the RO– is a very poor leaving group, the conventional nucleophilic addition-elimination pathway
will not be useful as far the practicality is concerned. Hence, unlike the reaction of acyl chlorides with amines,
the corresponding nucleophilic addition-elimination in case esters requires much stronger conditions.

Mechanism of Ammonolysis of Esters

Before we discuss the mechanism of ammonolysis of esters, we understand different outcomes first.
Initially, an ammonia molecule (or amine) attacks the carbonyl via nucleophilic addition; whilst a large amount
of ammonia still present in the reaction solution, followed by the formation of an anionic tetrahedral
intermediate due to deprotonation.
 2 amide (NH –)
At this point, C=O double bond can only be restored only if either the alkoxy (RO–) or the
group is detached. Now although both are very poor leaving groups; the pKa values of alcohol and ammonia
suggested that alkoxy groups (RO–) are much weaker bases than ammonia’s conjugate base (i.e., 2
NH –), and
therefore, is a better leaving group. Consequently, the reassortment of the C=O bond will happen via loss of
alkoxy group giving rise to an amide product.

However, it is also worthy to note that the relative betterment of alkoxy as a leaving group doesn’t make
it a good leave group on the absolute scale; and therefore, the ammonolysis of esters isn’t a very effective route
for the amides’ synthesis, indicating acyl chlorides as more suitable substrates.