CY 2102

Course structure
Substitution Reactions at sp3 Carbons: Types (SN1, SN2, SNi), neighbouring group
participation, factors affecting SN reaction, Competition between SN1 and SN2
reactions, Substitution reactions of alcohols, alkyl halides, reactions with epoxides.

Addition Reactions at sp2 Carbons: Addition of Carbon, Hydrogen, oxygen, sulphur

and Nitrogennucleophiles to Carbonyl Compounds, Wittig reaction, Schiff’s base-
hydrazone, oxime,Cannizzarro’sreaction, acetal Synthesis, α,β-unsaturated carbonyl
compounds-preparation and properties, Michael addition, 1,2 Vs 1,4- addition
reaction.
Acidity of α-hydrogen: Keto-enoltautomerism, alkylation, acylation, halogenation,
Aldolcondensation, Robbinson annulation, Perkin’s reaction, Claisen condensation,
Dieckmanncondensation Reaction, Stobbe Condensation Reaction, Moritas-Baylis-
Hilmann reaction, Bamford-Steven, Shapiro reaction, base catalyzed halogenations
reaction of ketones (Iododform reaction,) active methylene compounds and their
reactions, Malonic ester, acetoacetic ester.

Carboxylic acid and its derivatives (esters, anhydrides, acid halides, amides):
Relative Reactivities, Nucleophilic acyl substitution reactions, Synthesis and
reactions
 Nucleophilic substitution reactions

Nucleophilic substitution reactions bimolecular (SN2)

rate of reaction = k2[n-BuBr][HO ]

–

rate = k2[n-BuBr][HO–]

rate
rate

[n-BuBr]
[NaOH]

But why are the slopes different?

Because we have incorporated a constant concentration of one of the
reagents into what appears to be the rate constant for the reaction.
Whether a reaction follows the SN2 or the SN1 pathway for substitution is determined
mainly by the degree of substitution at the center of reactivity.

A good leaving group on a tertiary carbon is going to go through the S N1 pathway

because the steric hindrance prevents it from the SN2 pathway.

However, SN1 pathways use a dissociative mechanism to form an intermediate

carbocation. Carbocation form more readily on tertiary carbons because this is more
stable.
• SN2 primarily occurs on primary carbon atoms which favor backside attack.
SN2 reactions are preferred when there is a good, nucleophile and a good
leaving group.
• A good leaving group on a primary carbon is going to go through the SN2
pathway.
SN1 Mechanism

Rate of reaction of tertbutyl bromide with water to be relatively slow

because water is a poor nucleophile and tert-butyl bromide is sterically
hindered to attack by a nucleophile
rate = k[alkyl halide]

An SN1 reaction is based on the following experimental evidence:

1. The rate law shows that the rate of the reaction depends only on the
concentrationof the alkyl halide. This means that we must be observing a
reaction whose rate-determining step involves only the alkyl halide.

5
2. When the methyl groups of tert-butyl bromide are successively replaced
by hydrogens, the rate of the reaction decreases progressively . This
is opposite to the order of reactivity exhibited by alkyl halides in reactions.

3. The reaction of an alkyl halide in which the halogen is bonded to an

asymmetric carbon forms two stereoisomers: one with the same relative
configuration at the asymmetric carbon as the reacting alkyl halide, the other
with the inverted configuration.
When choosing SN1 or SN2, it is often useful to look at how substituted the reactive
center is because a tertiary carbon will be too hindered to allow the leaving group to
leave in an SN2. Because a primary carbon would create an unstable carbocation, SN2
will be favored over SN1 in this instance.
The type of solvent used is very important in competition between S N1 and SN2
reactions. Polar protic solvents prefer heterolytic cleavage which is characteristic of SN1
reactions because this forms a carbocation. Aprotic solvents are used in S N2 reactions
because they are good nucleophiles and promote backside attack.
Give the configuration(s) of the substitution product(s) that will be obtained from the
reactions of the following secondary alkyl halides with the indicated nucleophile.
1.

2.

3.

4.
Q. 1.

Because a high concentration of a good nucleophile is used, we can predict that the
reaction is an SN2 reaction. Therefore, the product will have the inverted configuration
relative to the configuration of the reactant.

Q.2.

Because a poor nucleophile is used, we can predict that the reaction is an SN1
reaction. Therefore, we will obtain two substitution products, one with the retained
configuration and one with the inverted configuration, relative to the configuration of
the reactant.
Q.3.

The relatively poor nucleophile suggests that the reaction is an SN1 reaction. However,
the product does not have an asymmetric carbon, so it does not have stereoisomers

Q.4.

Because a high concentration of a good nucleophile is employed, we can predict that the
reaction is an SN2 reaction. Therefore, the product will have the inverted configuration
relative to the configuration of the reactant. But since the configuration of the reactant is
not indicated, we do not know the configuration of the product.

Q.5.

Because a poor nucleophile is employed, we can predict that the reaction is an S N1

reaction. Therefore, both stereoisomers will be formed, regardless of the configuration
of the reactant.
Nucleophilic substitutions of alcohols:
• Since, Hydroxide ion is very basic, very reactive, and a bad leaving group. Alcohols do
not react with nucleophiles.
• If the nucleophile were strong enough to produce hydroxide ion, it would be more
than strong enough to remove the proton from the alcohol.

• The preparation of t-BuCl from t-BuOH simply by shaking it with concentrated HCl is a
good example. This is obviously an SN1 reaction with the t-butyl cation as intermediate.
• Similar methods can be used to make secondary alkyl bromides with HBr alone and
primary alkyl bromides using a mixture of HBr and H2SO4. The second is certainly an
SN2 reaction and we show just one stage in a two-step process that is very efficient.

• Another way is to convert the OH group into a better leaving group by combination
with an element that forms very strong bonds to oxygen. The most popular choices
are phosphorus and sulfur. Making primary alkyl alcohol with PBr3 usually works well.
Br-
 Substitution reactions of alcohols
An alcohol cannot undergo a nucleophilic substitution reaction because it has a strongly
basic leaving group (–OH)that cannot be displaced by a nucleophile.

An alcohol is able to undergo a nucleophilic substitution reaction if its OH group is

converted into a group that is a weaker base (i.e., a better leaving group). One way to

Because the OH group of the alcohol has to be protonated before it can be displaced by
a nucleophile, only weakly basic nucleophiles (I-, Br -, Cl-) can be used in the substitution
reaction.
Moderately and strongly basic nucleophiles (NH3 , RNH2 , CH3O-) would be protonated
in the acidic solution and, once protonated, would no longer be nucleophiles (NH 4+
RNH3+ ) 4 or would be poor nucleophiles (CH3OH).

Primary, secondary, and tertiary alcohols all undergo nucleophilic substitution

reactions with HI, HBr, and HCl to form alkyl halides.
 Secondary and tertiary alcohols undergo SN1 reactions.

It can combine with a nucleophile and form a substitution product, or it can lose a proton
and form an elimination product.

However, only the substitution product is actually obtained, because any alkene formed in
an elimination reaction will undergo a subsequent addition reaction with HX to form more
of the substitution product.
Tertiary alcohols undergo substitution reactions with hydrogen halides faster than
do secondary alcohols because tertiary carbocations are easier to form than
secondary carbocations.

Thus, the reaction of a tertiary alcohol with a hydrogen halide proceeds readily at
room temperature, whereas the reaction of a secondary alcohol with a hydrogen
halide would have to be heated to have the reaction occur at the same rate.

Primary alcohols cannot undergo reactions because primary carbocations are

too unstable to be formed . Therefore, when a primary alcohol reacts
with a hydrogen halide, it must do so via an reaction.
Only the substitution product is obtained. No elimination product is formed because
the halide ion, although a good nucleophile, is a weak base, and strong base is needed
in an E2 reaction to remove a proton from a carbon.

When HCl is used instead of HBr or HI, the reaction is slower because Cl- is a poorer
nucleophile.

Because the reaction of a secondary or a tertiary alcohol with a hydrogen halide is

an reaction, a carbocation is formed as an intermediate. Therefore, we must check
for the possibility of a carbocation rearrangement when predicting the product of the
substitution reaction.
Answer the following the questions.
Whether Amines undergo substitution reaction ??

Amines are even less reactive than alcohols.

The relative reactivities of an alkyl fluoride (the least reactive of the alkyl halides), an
alcohol, and an amine can be appreciated by comparing the pKa values of the conjugate
acids of their leaving groups.

The leaving group of an amine is such a strong base that amines cannot undergo
substitution or elimination reactions.

When protonated amine becomes a good leaving group.

Better yields are obtained and carbocation rearrangements can be avoided if a
phosphorus trihalide (PX3 or thionyl chloride (SOCl2 ) is used instead. These reagents
all act in the same way.

They convert an alcohol into an alkyl halide by converting the alcohol into an
intermediate with a leaving group that is readily displaced by a halide ion.
Thionyl chloride converts an OH group into a chlorosulfite group that can be displaced by
Cl-

Pyridine is generally used as the solvent in these reactions because it prevents the
build up of HBr or HCl and it is a relatively poor nucleophile.

The foregoing reactions work well for primary and secondary alcohols, but tertiary alcohols
give poor yields because the intermediate formed by a tertiary alcohol is sterically hindered
to attack by the halide ion.
Alcohols can be activated for subsequent reaction with a nucleophile, besides being
converted into an alkyl halide, is to be converted into a sulfonate ester. A sulfonate ester is
formed when an alcohol reacts with a sulfonyl chloride.

The reaction is a nucleophilic substitution reaction. The alcohol displaces the chloride
ion. Pyridine is used both as the solvent and to prevent HCl from building up.
A sulfonic acid is a strong acid (pKa = -1)because its conjugate base is particularly
stable due to delocalization of its negative charge over three oxygen atoms

Several sulfonyl chlorides are available to activate OH groups. The most common one
is para-toluenesulfonyl chloride.

A para-toluene sulfonate ion is about 100 times better than a chloride ion as a leaving
group
Example 1

Explain why the ether obtained by treating an optically active alcohol with followed
by sodium methoxide has the same configuration as the alcohol, whereas the ether
obtained by treating the alcohol with tosyl chloride followed by sodium methoxide has a
configuration opposite that of the alcohol.
 reacts with nucleophiles 106 times as fast as

Nearby groups can evidently increase the rate of substitution reactions significantly.
The mechanism by which they speed up the reactions is known as neighbouring
group participation.

A common feature of all mechanisms involving neighbouring group participation is the formation of a cyclic
intermediate
Simple substitution or substitution with participation of neighbouring group ??
Why is first case there is retention and in 2nd case
there is inversion of configuration ?

In first case the substitution OTS s assisted by

neighbouring OAc group
 Two sequential SN2 reactions taking place—in other words neighbouring group participation.

Neighbouring group participation is impossible, and substitution goes simply by intermolecular

displacement of OTs by AcOH. Just one SN2 step means overall inversion of configuration, and no
participation means a slower reaction.
 Retention of configuration is an indication of neighbouring group participation

on the other hand, the reaction is run using Ag 2O and a low concentration of sodium hydroxide, (S)-lactic acid is
obtained—there is overall retention of stereochemistry.
Sulfides, esters, carboxylates. Ethers and amines can also assist substitution reactions through neighbouring
group participation.

The important thing that they have in common is an electron-rich heteroatom with a lone
pair that can be used to form the cyclic intermediate. Sulfides, esters, carboxylates. Ethers and amines can
also assist substitution reactions through neighbouring group participation. The important thing
that they have in common is an electron-rich heteroatom with a lone pair that can be used to
form the cyclic intermediate. Sulfides
Addition Reactions at sp2 Carbons

CY-2102

Co-ordinator: Prof. Sasmita Mohapatra

Department of Chemistry
Room No: MC-329
Email: [email protected]
Phone: 0661-2462661
 Carbonyl compounds:
 Carbonyl compounds have a planar trigonal framework of a sp2
carbon atom and an sp2 oxygen atom. Each uses one sp2 orbital to
form a  bond to the other atom and a p orbital to form a  bond to
the other atom.

Bond between R and Sp2 carbon of carbonyl

 The carbon uses two sp2 orbitals to form  bonds to the substituents.
There are two lone pairs of electrons on the oxygen atom.
Molecular orbitals of carbonyl compounds:

 Carbonyl compounds have a

low-energy bonding -orbital
and also have a dipole because in
this filled orbital the electrons
are more on electronegative
oxygen than on carbon. This
orbital is rarely involved in
reactions.

 Going up the energy scale we next have two degenerate (equal in energy) lone
pairs in nonbonding orbitals. These are the highest-energy electrons in the
molecule (HOMO) and are the ones that react with electrophiles
When we consider the carbonyl group as an electrophile?
 we must look at antibonding orbitals. The only one that concerns us is the
relatively low-energy * orbital of the C=O double bond (the LUMO). This
orbital is biased towards the carbon to compensate for the opposite bias in the
filled  orbital.

 Simply because nucleophiles, whether charged or not, attack carbonyl groups at

the carbon atom. They get the best overlap with the larger orbital component of
the  * orbital.
  The lone pair electrons on the nucleophile move into the  * orbital of the C=O
double bond and break the  bond not the  bond.

 The lone pair electrons on oxygen interact better with empty orbitals such as the
1s of the proton and so carbonyl compounds are protonated on oxygen.
 The resulting cation is even more electrophilic because of the positive charge but
nucleophiles still attack the carbon atom of the carbonyl group because the  *
orbital still has more contribution from carbon.

ii.
i.
 Nucleophile, which we have represented as ‘Nu–’ approaches the
carbon atom, the electron pair in its HOMO starts to interact with the
LUMO (antibonding *) to form a new  bond.

 Filling antibonding orbitals breaks bonds and, as the electrons

enter the antibonding  * of the carbonyl group, the  bond is
broken, leaving only the C–O  bond intact.
 But electrons can’t just vanish, and those that were in the  bond
move off on to the electronegative oxygen, which ends up with the
negative charge that started on the nucleophile.
The angle of nucleophilic attack on aldehydes and ketones:

 Nucleophiles attack not from a direction perpendicular to the plane of the

carbonyl group but at about 107° to the C=O bond.
 This approach route is known as the Bürgi–Dunitz trajectory after the authors
of the elegant crystallographic methods that revealed it.
Additions to carbonyl groups:
Additions to carbonyl groups generally consist of two mechanistic steps:
1. Nucleophilic attack on the carbonyl group.
2 .Protonation of the anion that results.

For example:
 Nucleophilic attack by ‘hydride’on aldehydes and ketones:
 Addition of H– to the carbon atom of a C=O group would result in the
formation of an alcohol, which is a type of reduction.

 The most important of these compounds is sodium borohydride, NaBH4. This is

a water-soluble salt containing the tetrahedral BH4– anion.

 Since all of the electrons are in B–H  orbitals, it is from a B–H bond that arrow
was started to indicate reaction of BH4– as a nucleophile.
 The hydrogen atom, together with the pair of electrons from the B–H bond, will
be transferred to the carbon atom of the C=O group.

Questions:
1. 3.

2.
4.
 Answers:
1.

2.

3.
4.

o If a molecule contains both an aldehyde and an ester, only the aldehyde

will be reduced.
o Sodium borohydride is one of the weakest hydride donors available.
o Sodium borohydride reacts with both aldehydes and ketones, though the
reaction with ketones is slower.
o Sodium borohydride does not react at all with less reactive carbonyl
compounds such as esters or amides.
Addition of carbon to carbonyl compounds:
 For addition of carbon to carbonyl compounds we need to consider
addition of organometallic reagents to aldehydes and ketones.
 Lithium and magnesium are very electropositive metals, and the Li–C or
Mg–C bonds in organolithium or organo-magnesium reagents are highly
polarized towards carbon.
 They are therefore very powerful nucleophiles, and attack the carbonyl
group to give alcohols, forming a new C–C bond.
 At first, MeLi is added to the aldehyde in a THF solvent, where MeLi adds to
the aldehyde to give an alkoxide.
 Then (and only then) water is added to protonate the alkoxide.
 In fact, water must not be present during the
addition of MeLi (or of any other
organometallic reagent) to a carbonyl group
because water destroys organometallics very
rapidly by protonating them to give alkanes.
 Most common and commercially available organolithium reagents include
n-butyllithium and phenyl-lithium and they react with both aldehydes and ketones.
 It is very important to note that addition to an aldehyde gives a secondary alcohol
while addition to a ketone gives a tertiary alcohol.
 Organo-magnesium reagents known as Grignard reagents (RMgX) react in a
similar way.
 Some simple Grignard reagents, such as methyl magnesium chloride(MeMgCl)
and phenyl magnesium Bromide (PhMgBr) are commercially available and they
react with carbonyl compound to form c-c bond.
 Addition of OXYGEN nucleophiles to carbonyl compounds:
 Aldehydes and ketones react with alcohols to form hemiacetals and acetals
by an equilibrium reaction.
Hemiacetals:
 The essential structural features of a hemiacetal are an −OH and an −OR group attached to
the same carbon atom.
 A hemiacetal results by nucleophilic addition of an alcohol oxygen to the carbonyl carbon of
an aldehyde or ketone.
 Cyclic hemiacetals with five- or six-membered rings form very readily and can be
isolated.

 Dissolving an aldehyde in water causes the establishment of an equilibrium

between the aldehyde and its hydrate. This hydrate is 1,1-diol, called a geminal
diol.

 Compounds with strong electron-withdrawing groups attached to the carbonyl group

can form stable gem-diols, however. An example is the compound called chloral
hydrate.
Questions:
Among the following which has the highest hydration rate constant?
(chloral, acetone, acetaldehyde, formaldehyde, hexafluoroacetone)

Answer: Hexafluoroacetone
Acetals
 An acetal has two −OR groups attached to the same carbon atom.
 An acetal forms when an aldehyde or ketone is treated with an
excess of alcohol in the presence of an acid catalyst.
 Although a hemiacetal is an intermediate, it usually cannot be
isolated because it continues on to become an acetal.

 The mechanism involves acid-catalyzed formation of a hemiacetal,

then acid-catalyzed elimination of water followed by addition of a
second alcohol group.
 When an acetal is placed in water and added a catalytic amount of acid, all of the
steps are reversed.
 With an excess of water, the equilibrium favors the formation of the aldehyde.

 Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an

excess of a 1,2-diol and a trace of nonaqueous acid.
Addition of SULPHUR nucleophiles to carbonyl compounds:
 Aldehydes and ketones react with thiols under acid catalysis to form thioacetals.

 Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney

nickel gives us an additional method for converting carbonyl groups of aldehydes
and ketones to yield –CH2- group.
 Sodium bisulfite(NaHSO3) adds to aldehydes and some ketones to give bisulfite
addition compound.
 The reaction occurs by nucleophilic attack of a lone pair on the carbonyl group and
leaves a positively charged sulfur atom but a simple proton transfer leads to the
product.

 It is proposed by Vogel’s practical book that when acetone first react with sodium
bisulfite and then with sodium cyanide give a good yield (70%) of the cyanohydrin.

cyanohydrin
Mechanism: cyanohydrin
Addition of NITROGEN nucleophiles to carbonyl compounds:
 Aldehydes and ketones react with primary amines to form imines and with
secondary amines to form enamines.
 Imines have a carbon–nitrogen double bond. Enamines have an amino group
joined to a carbon–carbon double bond

 Imine formation is acid catalyzed, and the product can form as a mixture of (E)
and (Z) isomers. Imine formation generally takes place fastest between pH 4 and 5
and is slow at very low or very high pH.
Mechanism:
 What is phosphonium ylid ?
 An ylid (or ylide) is a species with positive and negative charges on
adjacent atoms and a phosphonium ylid carries its positive charge on
phosphorus.
 Phosphonium ylids are made from phosphonium salts by deprotonating
them with a strong base.
 Wittig reaction:
 The Wittig reaction is named after its discoverer
Georg Wittig (1897–1987), who won the Nobel
Prize in 1979.
 The Wittig reaction is a reaction between a carbonyl
compound (aldehyde or ketone only) and a species
known as a phosphonium ylid.
 Basically, the reaction starts with a phosphonium
salt, which is treated with sodium hydride and then
with a carbonyl compound to form ALKENE.
Georg Friedrich Karl Wittig
Mechanism:
 The reaction begins with an attack on the carbonyl group by a nucleophile i.e. the
carbanion part of the phosphonium ylid.
 This reaction generates a negatively charged oxygen that attacks the positively
charged phosphorus and gives a four-membered ring called an oxaphosphetane.
 The formed oxaphosphetane is a four-membered ring, which is quite unstable.

oxaphosphetane
 Since, the formed oxaphosphetane is a four-membered ring and is unstable. So
it collapses in a way that forms two double bonds along with a phosphine oxide.

Basically, the Wittig reaction is a type of concerted [2 + 2] cycloaddition reaction

Stereoselectivity in the Wittig reaction
 Ylides can be divided into two types : one with conjugating or anion-stabilizing
substituents adjacent to the negative charge (such as carbonyl groups) and the other
one is without any conjugation or anion stabilizing substituents.
 The first one, whose negative charge is stabilized not only by the phosphorus atom
but by the adjacent functional group is called stabilized ylids.
 When Wittig reaction is taking place with stabilized ylids, then the stereochemistry
is E selective.
 The second one without any conjugation or anion stabilizing substituents is
called unstabilized ylids.
 When Wittig reaction is taking place with unstabilized ylids, then the
stereochemistry is Z selective.
Predict the product of the followings:

1.

2.
Answers:
1.

Unstabilized ylid are used to make the Z-isomer selectively

2.

Stabilized ylid are used to make the E-isomer selectively

Q.
Predict the reactants to synthesize 2-methyl-1-phenylprop-1-en,
using a Wittig reaction.

Solution:
Retrosynthetic Analysis
Schiff’s base:
 Aldehydes and ketones react with a primary amine(RNH2) to form an imine. An
imine is a compound with a carbon–nitrogen double bond.
 The imine obtained from the reaction of a carbonyl compound and a primary
amine is often called a Schiff base.
Bonding in an imine:
 The orbital model of a C=N group is similar to the orbital model of a C=O group.
The imine nitrogen is sp2 hybridized.
 One of its sp2 orbitals forms a  bond with the imine carbon, one forms a  bond
with a substituent and the third contains a lone pair. The p orbital of nitrogen and
the p orbital of carbon overlap to form a p bond.
 Hydrazone formation
 The imine obtained from the reaction of aldehyde and ketone with hydrazine is
called a hydrazone.
Addition Reactions at sp2 Carbons

CY-2102

Co-ordinator: Prof. Sasmita Mohapatra

Department of Chemistry
Room No: MC-329
Email: [email protected]
Phone: 0661-2462661
Schiff’s base:
 Aldehydes and ketones react with a primary amine(RNH2) to form an imine. An
imine is a compound with a carbon–nitrogen double bond.
 The imine obtained from the reaction of a carbonyl compound and a primary
amine is often called a Schiff base.
Bonding in an imine:
 The orbital model of a C=N group is similar to the orbital model of a C=O group.
The imine nitrogen is sp2 hybridized.
 One of its sp2 orbitals forms a  bond with the imine carbon, one forms a  bond
with a substituent and the third contains a lone pair. The p orbital of nitrogen and
the p orbital of carbon overlap to form a p bond.
 Hydrazone formation
 The imine obtained from the reaction of aldehyde and ketone with hydrazine is
called a hydrazone.
Oxime formation:
 The imine obtained from the reaction with hydroxylamineis called an oxime.
Cannizzaro reaction:
 Aldehydes that have no α hydrogen undergo an intermolecular oxidation–reduction
i.e. undergo disproportionation, called the Cannizzaro reaction.

 Usually the reaction takes place in presence

Disproportionation means one
of a strong base. half of the sample is oxidized by
 Here half of the aldehyde reduces to the the other half, which is itself
primary alcohol and the other half oxidized reduced.
to the carboxylic acid.
Mechanism:
When the reaction is carried out in D2O , what will be the product ?
 Acetal Synthesis:
 Acetals are compounds with two single bonded oxygen atoms attached to the
same carbon atom.

 In the presence of acid, Acetals are formed from aldehydes or ketones along
with alcohols.
 A solution of acetaldehyde in methanol forms a new compound i.e. a
hemiacetal.

Hemi-acetal
 But, if a catalytic amount of acid is added to our acetaldehyde–methanol mixture,
then the rate of reaction of the acetaldehyde with the methanol increases to
produce an acetal.

 In the presence of acid (but not base) hemiacetals can undergo an elimination
reaction, losing the oxygen atom that once belonged to the parent aldehyde’s
carbonyl group.

 The stages include:

1. Protonation of the hydroxyl group of the hemiacetal.
2. Loss of water by elimination, which leads to an unstable and highly reactive
oxonium ion.
3. Addition of methanol to the oxonium ion.
4. Loss of a proton to give the acetal
Mechanism:

unstable oxonium ion

unstable oxonium ion

 The formed oxonium ions are powerful electrophiles and can react rapidly
with a second molecule of alcohol to form new, stable compounds known as
acetals.

Hemiacetal formation is catalysed by acid or base, but acetal

formation is possible only with an acid catalyst because an OH
group must be made into a good leaving group.
 Cyclic acetals

 Cyclic acetals, formed by reaction of a single molecule of a diol, a compound

containing two hydroxyl groups, are also important.
 When the diol is ethylene glycol the five-membered cyclic acetal is known as a
dioxolane.

dioxolane.
Acetals hydrolyse only in the presence of acid:

 Acetals can be hydrolysed only by using an acid catalyst. With aqueous acid, the
hydrolysis of acyclic acetals is very easy.
 Acetals can be hydrolysed in acid but are stable to base
 What will be the product of the followings?

1.

2.

3.

4.
Answers:

1.

2.
3.

4.
Conjugate addition or direct addition to the carbonyl
group?

The contrast between the two products is this-

 cyanohydrin is formed faster than the conjugate addition product, but the
conjugate addition product is the more stable compound.
 Kinetic control involves lower temperatures and shorter reaction times, which
ensures that only the fastest reaction has the chance to occur.
 Thermodynamic control involves higher temperatures and long reaction times to
ensure that even the slower reactions have a chance to occur, and all the material
is converted to the most stable compound.
 Why is direct addition faster than conjugate addition?
 The carbon atom b to the C=O group carries some positive charge, the carbon
atom of the carbonyl group carries more.
 Electrostatic attraction for the charged nucleophiles will encourage it to attack the
carbonyl group directly rather than undergo conjugate addition.
 Structural factors:
The site of nucleophilic attack is determined simply by reactivity:
 The more reactive the carbonyl group, the more direct addition to C=O will
result.
 Comparing the way butyllithium adds to this ,-unsaturated aldehyde and ,-
unsaturated amide.

 Both additions are irreversible, and BuLi attacks the reactive carbonyl group of
the aldehyde, but prefers conjugate addition to the less reactive amide.
 Ammonia reacts with this acyl chloride to give Reactivity order
an amide product that derives from direct
addition to the carbonyl group.

 The ester undergoes conjugate addition to give

an amine.
 Sodium borohydride is a nucleophile that you have seen reducing simple
aldehydes and ketones to alcohols .
 It usually reacts with a,b-unsaturated aldehydes in a similar way, giving
alcohols by direct addition to the carbonyl group.
 The borohydride has reduced not only the carbonyl group but the double bond as
well.
 In fact, it’s the double bond that’s reduce first in a conjugate addition, followed
by addition to the carbonyl group.
 The more substituents there are at the b carbon, the less likely a nucleophile is
to attack there.
The nature of the nucleophile: hard and soft
 Among the best nucleophiles of all at doing conjugate addition are thiols, the
sulfur analogues of alcohols.

 With the use of THIOL, no acid or base catalyst is needed and the product is
obtained in 94% yield under quite mild reaction conditions.
Hard/Soft nucleophile:
 Hard nucleophiles are typically from the early rows of the periodic table and
have higher charge density.
 Soft nucleophiles are from the later rows of the periodic table. i.e, they are
either uncharged or have larger atoms with higher-energy, more diffuse
orbitals.
Copper(I) salts have a remarkable effect on
organometallic reagents:
 Grignard reagents add directly to the carbonyl group of a,b-unsaturated
aldehydes and ketones to give allylic alcohols.
 The hard Grignard reagent prefers to attack the harder C=O rather than the
softer C=C electrophilic centre.

 e.g., The addition of MeMgI to a cyclic ketone to give an allylic alcohol along
with a diene that arises from this alcohol by loss of water (dehydration).
 Here is the same reaction, to which a very small amount (just 0.01 equivalents,
that is, 1%) of copper(I) chloride has been added.
 The effect of the copper is dramatic: it makes the Grignard reagent undergo
conjugate addition, with only a trace of the diene.
Organocopper reagents undergo conjugate addition:
 The copper works by trans-metallating the Grignard reagent to give an
organocopper reagent.
 Organo-coppers are softer than Grignard reagents, and add in a conjugate fashion
to the softer C=C double bond.

 Once the organocopper has added, the copper salt is available to trans-metallate
some more Grignard, and only a catalytic amount is required.