Chapter Four

Major Organic Reactions

Nucleophilic Substitution
• A type of reaction a in which nucleophile (Nu:-) replaces a leaving group
(LG) in the molecule that undergoes substitution (called the substrate).

 Nucleophile- any negative ion, uncharged molecule with an unshared

electron pair or π bond.
 A base that donate electron to the substrate
The SN2 (Nucleophilic Substitution Bimolecular] Reaction
• Exhibits second-order kinetics
• Reaction is bimolecular
• Both the substrate and the nucleophile appear in the rate equation.
• The reaction is concerted reaction bond breaking and bond making occur
1 at the same time.
 Rate = k[Nu-][Substrate] The rate equation is second order.
o Nucleophile; - More reactive and unhindered is important.
• Strength of RNH- > RO- > HO- > RCO2- > NH3, H2O other neutral species
o Substrate- Unhindered because as the number of R groups on the carbon
with the leaving group increases, the rate of an SN2 reaction decreases.
CH3-X > RCH2-X > R2CH-X > R3C-X
Methyl 1o 2o 3o
o Leaving Group- A good leaving group leave as a relatively stable,
• Weakly basic molecule or ion, the more stable, the weaker base.
I- > Br- > Cl- > F-
• Steric hindrance decreases nucleophilicity but not basicity
• Steric hindrance is when the spatial arrangement of atoms or bulky
groups at or near a reacting site of a molecule hinders or retards a reaction
2
 Stereochemistry of the SN2 Reaction
• The nucleophile approaches the carbon bearing the leaving group from
the backside, that is, from the side directly opposite the leaving group.
• Because the leaving group blocks the approach of the nucleophile to the
front side of the molecule.
• As the nucleophile forms a bond and the leaving group departs, the
substrate carbon atom undergoes inversion of configuration its
tetrahedral bonding configuration is turned inside out.
 The SN2 reaction proceeds in a single step (without any intermediates)
through an unstable arrangement of atoms called the transition state
 The reaction leads to an inversion (or change) of stereochemistry at a
chiral center (i.e. an R-enantiomer will be converted to an S-enantiomer).
The configuration is inverted
relative to that of the reactant

3
 SN1 (Nucleophilic Substitution unimolecular] Reaction
• Mechanism involves more than one step, and the slow step is unimolecular.
• Carbocations are formed as reactive intermediates.
Step I. The C–Br bond is broken.

Step II. The C–O bond is formed. Rate = k[(CH3)3CBr]

Substrate
• As the number of R groups on the carbon with the leaving group increases,
the rate of an SN1 reaction increases..
• Increasing rate of an SN1 reaction CH3-X < RCH2 –X < R2CH X < R3CX
• Carbocations stability primary (1°) < secondary (2°), < tertiary (3°)
4
 Nucleophiles
• Weak nucleophiles H2O and ROH favor SN1 reactions
• Nucleophilic attack carbocation from both direction
Leaving Group
• Better leaving group increases the rate of both SN1 and SN2 reactions.
Stereochemistry of the SN1 Reaction
• Nucleophilic attack carbocation from both direction, an equal amount of
the two enantiomers is formed.
• The reaction leads to the racemization of a stereogenic center
• Racemization is the formation of equal amounts of two enantiomeric
(50:50 mixture of R- and S-enantiomers) products from a single starting
material
Inverted configuration Retained configuration

+ HBr

(S)-2-bromobutan (R)-2-butanol (S)-2-butanol

5
 Synthesis of Alcohol

+- CH3CH2CH2 OH + Na +Br-
Na OH + CH3CH2CH2 Br

Synthesis of Ethers.
• Symmetrical Ethers are prepared by acid-catalyzed (H2SO4) condensation
of the corresponding alcohols

Synthesis of unsymmetrical Ethers

• Synthesis of unsymmetrical Ethers under basic condition based on the
principles of SN2 is known as the Williamson Synthesis.
• Nucleophilic substitution of an alkyl halide (less substituted such as 1o alky
halide) by an alkoxide gives ether.
• The alkoxide ion for the Williamson ether synthesis is prepared by using
sodium metal or sodium hydride (NaH) to remove a proton from an alcohol.
• Methyl halides and primary alkyl halides are the best substrates.
6
 Synthesis of Amines.
• If alkyl halide is treated with ammonia alkyl ammonium halide results.
• The free amine can be released by neutralization of salt with NaOH

CH3 Br + NH3 CH3 NH3 + -OH CH3NH2 + H2O

CH3 Br + CH3NH2 CH3 NH3 + -OH CH3NHCH3 + H2O

• Amines act as nucleophiles in nucleophilic acyl substitution reactions

7
 Synthesis of Carboxylic Acid
• Nitriles can be prepared by SN2 reaction between a 1o or 2o halide and NaCN
• Nitriles group then hydrolyzed to Carboxylic acids in either strong acid or base.
O
H2O
R C N R C OH + NH4+
HO- or H3O+
Nitrile carboxylic acid ammonium cation
Heat

Synthesis of Alkynes, Alkenes and Alkanes

H C C H + NaNH2 H C C-Na+ + NH3
Acetylene sodium amide sodium acetylide Ammonia

H C C-Na+ + R X H C CR + NaX
Sodium acetylide 1o alkyl halide Alkyne Sodium halide

8
• Internal alkynes can be converted into trans alkenes using sodium (or
lithium) in liquid ammonia.

• Addition of hydrogen to an internal alkyne in the presence of Lindlar

catalyst forms a cis alkene
• Prepared by precipitating palladium on calcium carbonate and treating it
with lead(II) acetate and quinoline

Synthesis of Epoxide and Epoxide Ring Opening

• Epoxide can be prepared by treating olefins with an oxidizing agent per-acid

9
 Acid-Catalyzed Epoxide Opening

2-methoxy-1-propanol 1-methoxy-2-propanol
major product minor product
• The more substituted carbon is more likely to be attacked because, after the
epoxide is protonated, it is so reactive that one of the bonds begins to break
before the nucleophile has a chance to attack.
• The protonated epoxide breaks preferentially in the direction that puts the
partial positive charge on the more substituted carbon, because a more
substituted carbocation is more stable
• H2O and ROH can open an epoxide ring in the presence of acid.
• Trans-1,2-disubstituted cycloalkanes are formed. (same for base also)

10
 Base-Catalyzed Epoxide Opening
• Because of the strain in the three-membered ring, epoxides are reactive
enough to open without first being protonated
• When a nucleophile attacks an unprotonated epoxide, the reaction is a pure
SN2 type reaction.
• That is, the bond does not begin to break until the carbon is attacked by
the nucleophile.
• The nucleophile is more likely to attack the less substituted carbon
because the less substituted carbon is more accessible to attack. (It is less
sterically hindered.)

11
Methylenecyclohexane oxide 1-Hydroxymethyl cyclohexanol (70%)
 The Malonic Ester Synthesis
• The malonic ester synthesis converts diethyl malonate to a carboxylic acid
• Alkylation of an α-carbon of diethyl propanedioate (diethyl malonate), or
malonic ester and decarboxylation of a β dicarboxylic acid can be used to
prepare carboxylic acids of any desired chain length.,

SN2 reaction

Resonance-stabilized enolate

SN2 reaction

-CO2
Decarboxylation
Hydrolysis
12 Dialkylmalonic acid
 • Deprotonation of the ester to form an enolate

• SN2 of the enolate upon an alkyl halide, forming a new C-C bond

• Acidic hydrolysis of the ester to give a carboxylic acid

13
 • Decarboxylation of the carboxylic acid to give an enol

• Tautomerization of the resulting enol to a carboxylic acid

Acetoacetic ester synthesis

• Acetoacetic ester (β-keto ester), it is a β-dicarbonyl compound, react with
alkyl halide and converted to methyl ketone rather than a carboxylic acid.

14
Acetoacetic ester Sodioacetoacetic ester Monoalkylacetoacetic ester
 aqueous NaOH
heat

15
 Chapter 5 Elimination Reactions
• All elimination reactions involve loss of subsituents from adjacent atoms
of the reactant to form a new π bond in the product
• Type of organic reaction in which two substituents are removed from a
molecule in either a one or two-step mechanism

B: H 
(Base)
C C C C + H-B+ + X:-

x
 There are three fundamental events in these elimination reactions
• Removal of proton by Base (B-, mostly negatively charged oxygen
compounds, –OR, called alkoxides), on the β carbon, thus forming H–B.
• Formation of the CC π bond (the electron pair in the β C – H bond forms
the new π bond between the α and β carbons).
• Breaking of the bond to the leaving group (the electron pair in the C – X
bond ends up on halogen, forming the leaving group :X–.
• The two main mechanisms for elimination reactions of are E1 and E2.
16
 E2 Elimination Mechanism (elimination, bimolecular) reaction

• Reaction is a concerted, one-step reaction, no intermediate is formed.

• The proton and the bromide ion are removed in the same step.
• The reaction exhibits second-order kinetics (bimolecular)
• Rate depends on the conc. of base and alkyl halide. Rate= k [RX] [B]
• The reaction is regioselective because more substituted alkene is the stable
of the two alkenes will be the major product
Unhindered base/not bulky base

17 More stable of the two alkenes will be the major product of the reaction
 Relative reactivities of alkyl halides in an E2 reaction

 Zaitsev’s rule - the major product is the alkene with the more substituted
double bond
 Hofmann rule;-the major alkene has the less substituted double bond.
• In some elimination reactions, the less stable alkene is the major product.
• E.g., if the base is sterically bulky and the alkyl halide is sterically hindered,
the base will preferentially remove the most accessible hydrogen.
• It is easier for the bulky tert-butoxide ion to remove one of the more exposed
terminal hydrogens, which leads to formation of the less substituted alkene

E2

18
 E1 Elimination Mechanism (elimination, unimolecular) reaction

base removes a proton from a β-carbon

• First-order elimination reaction because the rate of the reaction depends
only on the concentration of the alkyl halide.
• Rate = k[alkyl halide]
• The more substituted alkene is the more stable

19
• Relative reactivities of alkyl halides in an E1 reaction = relative stabilities
of carbocation

• Because they are positively charged, carbocations are stabilized by

electron-donating groups.
• Alkyl groups stabilize carbocations because alkyl groups are more electron
donating than a hydrogen.
• Tertiary carbocations are the most stable and methyl cations are the least
stable
Competition Between E2 and E1 Reactions
• Primary alkyl halides undergo only E2 elimination reactions
• Secondary and tertiary alkyl halides undergo both E2 and E1 reactions
• E2 reaction is favored by a high conc. of a strong base and an aprotic
polar solvent (e.g., DMSO or DMF),
20
• E1 reaction is favored by a weak base and a protic polar solvent (e.g., ,
H2O or ROH).
 Competition Between Substitution and Elimination
• SN2/E2 reactions are favored by a high conc. of a good nucleophile/strong
base, whereas SN1/E1 reactions are favored by a poor nucleophile/weak base
1. Primary Substrate
• When the base is strong and unhindered, substitution is highly favored

• 1o alkyl halide is the most reactive in an SN2 reaction and the least reactive
in an E2 reaction,
• If the 1o alkyl halide or nucleophile/base is sterically hindered, the
nucleophile will have difficulty getting to the back side of the α-carbon.
Then elimination will win the competition,

21
 Secondary Substrate
With strong base and bulkier the base, elimination is highly favored
because steric hindrance in the substrate makes substitution more difficult.
EtONa
CH3 CH CH3 o CH3 CH CH2 + CH3 CH CH3
Br
EtOH, 55 C OCH CH
2 3

Secondary E2 Major (79%) SN2 Minor (21%)

The stronger and bulkier the base, the greater the percentage of the
elimination product, whereas no elimination product is formed with the
weakly basic acetate ion

100%

• A tertiary alkyl halide is the least reactive of the alkyl halides in an SN2
reaction and the most reactive in an E2 reaction.
• In SN1/E1 reactions, the alkyl halide dissociates to form a carbocation,
which can then either combine with the nucleophile to form the substitution
22product or lose a proton to form the elimination product
 1. Dehydration of Alcohols or Synthesis of Alkene
• Reactions are stereoselective and regioselective, so the most stable alkene is
usually formed as the major product.
• Alcohols undergo dehydration is in the following order 3o > 2o > 1o.
• Dehydration of 2° and 3° alcohols occurs via an E1 while 1o is an E2
• 1o alcohols are the most difficult to dehydrate.
• Dehydration of ethanol requires conc. H2SO4 and a temperature of 180°C
H2SO4
CH3CH2 OH
o CH2 CH2 + H2O
180 C
• 2o alcohols usually dehydrate under milder conditions. E.g. Cyclohexanol,
OH
85% H3PO4
165-170oC
• Dehydration reactions that occur in biological processes are catalyzed by
enzymes.

23
• 3o alcohols - easily dehydrated extremely so mild conditions can be used.
CH3 CH2
CH3 C OH
85% H3PO4 + H2O
C
165-170oC H3C CH3
CH3
CH3 CH3
• Protonation of OH CH3 C O H + H OSO3 CH3 C OH2 + HSO4-
CH3 CH3
CH3 CH3
• Heterolytic C-O bond slow
CH3 C + H2O
CH3 C OH2
cleavage and formation
CH3 CH3
of carbocation
3o Carbocation

• Removal a proton from

the β-carbon π- bond is
24 formed
 Rearrangements during Dehydration of Secondary Alcohols

• Formation of the
protonated alcohol.

• Loses of water
and carbocation
rearranges to a
more stable 3o
carbocation:
Less stable
• Formation alkene
an alkene + HA

More stable
alkene
25
 2. Dehydrohalogenation of Alkyl Halides or Synthesis of Alkene
• Zaitsev’s Rule: Formation of the More Substituted Alkene is favored with
a Small Base (unhindered base) . E.g EtONa/ EtOH at 70°C

69% (more stable)

2-Methyl-2-butene

31% (less stable)

2-Methyl-1-butene
• Hofmann Elimination - Dehydrohalogenations carrying out with a bulky
base such as potassium tertbutoxide (t-BuOK) in tert-butyl alcohol (t-
BuOH) favors the formation of the less substituted alkene:

26
2-Methyl-2-butene (27.5%) 2-Methyl-1-butene (72.5%)
(more substituted) (less substituted)
 Elimination of vicinal dihalides
• Reduction of vicinal dihalide by Zn-metal processed by way of oxidative
insertion of Zn(0) in to a C-X bond.
CH3 CH3
Zn H3C CH3
H3C C C CH3 C C + ZnBr2
EtOH or CH3COOH
Br Br H3C CH3

Acetate pyrolysis
• A chemical transformation produced by applying heat to a single compound
is called a pyrolysis reaction.
• Acetates are esters of acetic acid which can be prepared by treating alcohols
with acetic anhydride

27
 Cope Reaction
• When a tertiary amine is treated with 30% hydrogen peroxide, an amine
oxide is formed.
CH2
CH2 N CH3 Heat
CH2 N CH3 H2 O 2 CH3
160o
+ N(CH3)2OH
-
CH3 H O
for 2hrs
amine oxide
• Cope reaction is an excellent means of converting an amine into an olefin.
• In general, the yields are better than those of the hofmann elimination
which performs the same function.

28
 Chapter 6 Addition Reactions
• Addition Reaction characteristics of compound with carbon-carbon
double bond
• Because the C–C π bond of an alkene is much weaker than a C–C σ bond,
the characteristic reaction of alkenes is addition: the π bond is broken and
two new δ-bonds are formed
• Two characteristics of the double bond help us understand why these
addition reactions occur.
• Because alkenes are electron rich, simple alkenes do not react with
nucleophiles or bases, reagents that are themselves electron rich.
• Alkenes react with electrophiles
• The conversion of one π-bond and one σ-bond into two σ- bonds and
electrons of the pi bond are exposed.
• Electrons in the pi-bond of alkenes react with electrophiles.
• Electrophiles are electron-seeking reagents.

nucleophile the π bond has broken and

σ bond and a π bond electrophile
29 new σ bonds have formed
 Addition of Hydrogen Halides to Alkenes (Markovnikov’s Rule)
• The addition of HX to an unsymmetrical alkene, the H- atom adds to the
carbon atom of the double bond that has the greater number of H-n atoms.

1o Carbocation
(less stable)
2o Carbocation (more stable)
• Stability of a carbocation increases as the number of alkyl substituents bonded to
the positively charged carbon increases, the more alkyl groups there are attached
to the positively charged carbon, the more electron density shifts toward the
charge and the more inductive stabilization of the cation occurs

Most stable Least stable

30
• Markovnikov’s rule: “When a HX adds to an unsymmetrical alkene, the
addition occurs , the halogen attaches itself to the double-bonded carbon
atom of the alkene bearing the lesser number of hydrogen atoms
• The H-n adds to the carbon that is bonded to the greater number of hydrogen
• Electrophile adds to the carbon that bonded to greater number of hydrogens.

• Rearrangement of the 2° carbocation by a 1,2-methyl shift forms a more

stable 3° carbocation

31
 Hydration of Alkene-Electrophilic Addition of Water
• When water is added to an alkene, no reaction takes place, because there is
no electrophile present to start a reaction by adding to the nucleophilic alkene
• If, however, an acid (e.g., or HCl) is added to the solution, a reaction will
occur because the acid provides an electrophile
• The product of the reaction is an alcohol.
• The first two steps of the mechanism are the same as the two steps of the
mechanism for the addition of a hydrogen halide to an alkene:
• The electrophile adds to the carbon that is bonded to the greater number of
hydrogens, and the nucleophile adds to the other carbon

- H+

- H+
32
 Michael Addition
• The addition of nucleophiles to α,β-unsaturated carbonyl compounds at
the β-position.
• When HX adds to a double bond conjugated with a carbonyl group, the X
ends up on the β- carbon
H2C CH C CH3 HX XCH2CH2CCH3
O O
methyl vinyl ketone

H
H2C CH C CH3 CH2 CH C CH3 CH2 CH C CH3
O OH OH
methyl vinyl ketone

X
H2C CH C CH3 X CH2 CH C CH3 XCH2CH2CCH3
HO OH
+ O
methyl vinyl ketone enol Ketone
33
 Halogenation-Addition of Halogen
• Addition of halogen X2 (X = Cl or Br) to an alkene, forming a vicinal dihalide.
• Bromination is a simple chemical test for the presence of π bonds
• When bromine, a red liquid, is added to an alkene dissolved in the solvent
CCl4, the bromine adds to the double bond and the red color disappears.
• The disappearance of the red color is therefore a positive test for π bonds.
• The bond joining the two halogen atoms is relatively weak and, easily broken.
• When the electrons of the alkene approach a molecule, one of the halogen
atoms accepts the electrons and releases the shared electrons to the other
halogen atom.

Br Br
Br2 in CCl4
(Enantiomers)
Br Br
34 (Red)
(Colorless)
 Addition of hypolous acids
• The reaction of alkenes with the hypohalous acids HOX (HOCl or HOBr)
to yield 1,2-halo alcohols, called halohydrins.
• The oxygen of Hypohalous acid (HOX) bears a partial negative charge
(HO--X+) because oxygen is more electronegative than the halogens except
for fluorine.
• Therefore, Markonikov addition of HOX results in the bonding of the
oxygen to the more substituted carbon

Bromohydrin major product minor product

35
 Radical reaction
• When a bond breaks such that each of the atoms retains one of the bonding
electrons, the process is called homolytic bond cleavage or homolysis.
• A radical is a reactive intermediate with a single unpaired electron, formed
by homolysis of a covalent bond
• Radical contains an atom that does not have an octet of electrons, making it
highly reactive and unstable.
• A radical (also called a free radical) is a species with an unpaired electron
• Radical processes involve single electrons, so half-headed arrows are used
to show the movement of electrons.
• The stability of a radical increases as the number of alkyl groups bonded to
the radical carbon increases

• The formation of 1-bromo-3-methylbutane requires the anti Markovnikov

addition of HBr.
• If an alkyl peroxide (ROOR) is added to the reaction mixture, the product
36 of the addition reaction will be the desired 1-bromo-3-methylbutane.
 • Initiation- generation of radical, the akyl peroxide contains a weak O–O single
bond that is readily broken homolytically to form radicals.
• Abstraction of H from HBr occurs by a two-step process.

• Propagation-The π-bond is broken and the C–H and C–Br σ bonds are formed

• Termination-Two radicals react to form a bond.

37
 Chapter 7 Reactions of Carbonyl Compounds
• The carbonyl (C=O )bond is polarized, and the oxygen atom is slightly
negative, while the carbon atom is slightly positive (electron deficient or
electrophile).
• Carbonyl carbon can be easily attacked by nucleophile (Nu-) or electron
rich species in nucleophilic addition reactions.
-
: O:
 bond + electron deficient (electrophilic carbon)

product of
nucleophilic
addition
• The carbonyl group of an aldehyde or a ketone is attached to a group that is
too strong a base ( or ) to be eliminated under normal conditions, so it
cannot be replaced by another group.
• Thus, aldehydes and ketones undergo nucleophilic addition reactions, while
38 carboxylic acid derivatives undergo nucleophilic acyl substitution reactions.
 Carbonyl addition-Eliminationl/ Rection with Carbon Nucleophiles
• Aldehydes and ketones undergo nucleophilic addition reactions
• If the nucleophile that adds, Z is not electronegative (Z is an H or a C
nucleophile), the tetrahedral addition product will be stable
• Otherwise addition to aldehydes or ketones is often reversible, an added
nucleophile may be eliminated and the carbonyl group re-formed

• When the nucleophile added to aldehyde or ketone is one EN (Z is an O or

an N nucleophile), the tetrahedral addition product will not be stable and
water will be eliminated from the addition product (nucleophilic addition–
elimination)

39
 But, carboxylic acid derivatives undergo nucleophilic acyl substitution reactions
• Acyl halide (most reactive) > acid anhydride > aldehyde > ketone > ester
∼ carboxylic acid > amide (least reactive)
Cyanohydrins
• Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins.
• This reaction forms a product with one more carbon atom than the reactant.
• The alkoxide ion accepts a proton from an undissociated hydrogen cyanide

• Because hydrogen cyanide is a toxic gas, the best way to carry out this
reaction is to generate hydrogen cyanide during the reaction by adding HCl
to a mixture of the aldehyde or ketone and excess sodium cyanide.
• Excess NaCN is used in order to make cyanide ion act as a nucleophile.
• Basic solutions, a
cyanohydrin is converted to
40 the carbonyl compound
• Acid-catalyzed hydrolysis of a cyanohydrin forms α-hydroxycarboxylic acid

Reaction with Grignard Reagents

• Versatile reaction that leads to the formation of a new C-C bond.
• Can be prepared by adding an alkyl halide to Mg shavings in diethyl ether.

1o alcohol

2o alcohol

41 3o alcohol
 Reactions of Carbonyl Compounds with Hydride Ion
• Addition of hydride ion to an aldehyde or ketone forms an alkoxide ion.
• Subsequent protonation by an acid produces an alcohol.
• The overall reaction adds H2 to the carbonyl group, reduction reaction

• Aldehydes and ketones are generally reduced using sodium borohydride

(NaBH4) as the source of hydride ion.
• Aldehydes are reduced to 1o alcohols and ketones are reduced to 1o alcohols
• The acid is not added to the reaction mixture until the reaction with the
hydride donor is complete.
• NaBH4 is not a sufficiently
strong hydride donor.
• Only reduce aldehydes and
ketones)
• Not reduce, carboxylic acids
42
and its derivatives
• Because lithium aluminum hydride (LiAlH4) is more reactive than NaBH4,
it is not as safe or as easy to use.
• Since it reacts violently with protic solvents, lithium aluminium hydride
must be used in a dry, aprotic solvent.
• The reaction of an ester with produces two alcohols, one corresponding to
the acyl portion of the ester and one corresponding to the alkyl portion.

43
 • The reaction of a carboxylic acid with forms a single primary alcohol.

• Acyl chlorides, like esters and carboxylic acids, undergo two successive
additions of hydride ion when treated with LiAlH4

• Amides also undergo two successive additions of hydride ion when they
react with
• The product of the reaction is an amine

44
 Acetal and ketal Formation
• Hemiacetal-product formed when one an alcohol adds to an aldehyde
• Acetal- product formed when alcohol is added to hemiacetal
• Alcohol is a poor nucleophile, so an acid catalyst is required for the reaction
to take place at a reasonable rate.

A hemiacetal has a carbon atom bonded to one OH group and one OR group.
• Ketones react with one equivalent of alcohol to form hemiketal
• Ketones react with two equivalents of alcohol to form ketals

45
• In an acidic solution, the acid protonates an oxygen of the acetal.
• This creates a weak base that can be expelled by the other group.
• When the group is expelled, water can attack the reactive intermediate,
and you are then on your way back to the ketone (or aldehyde)

46
 Ester hydrolysis and formation in acid media
• Esters are fairly stable in neutral aqueous media but are cleaved when
heated with water in the presence of strong acids or bases.
• The hydrolysis of esters in dilute aqueous acid is the reverse of the Fischer
esterification.

47
 Wittig reaction
• Reaction of an aldehyde or ketone with phosphonium ylide to form alkene.
• An ylide is a compound that has opposite charges on adjacent bonded atoms

48
 Reactions of Aldehydes and Ketones with Nitrogen Nucleophiles
• Aldehydes and ketones react with a primary amine 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

49
• Aldehydes and ketones react with secondary amines to form enamines.
• Like imine formation, the reaction requires a trace amount of an acid
catalyst.

50
51
 Acidity of Hydrogens on carbon adjacent to a carbonyl carbon
• When a proton is removed from a carbon adjacent to a carbonyl carbon,
two factors combine to increase the stability of the base that is formed.
• 1st the electrons are delocalized, and electron delocalization increases the
stability of a compound (aldehydes & ketones are more acidic than esters)
• 2nd the electrons are delocalized onto an oxygen, an atom that is better able
to accommodate the electrons because it is more EN than carbon.

• If the α-carbon is between two carbonyl groups, the acidity of α-hydrogen is

even greater

52
 Halogenation of the α-Carbon of Aldehydes and Ketones
1. When excess Br2, Cl2 or I2 is added to a basic solution of an aldehyde or
a ketone, the halogen replaces all α-hydrogens

Haloform Reaction
• In the presence of excess base and excess halogen, a methyl ketone is first
converted into a trihalo-substituted ketone, then hydroxide ion attacks the
carbonyl carbon of the trihalo-substituted ketone.
• Because the trihalomethyl ion is a weaker base than hydroxide ion, the
trihalomethyl ion is the group more easily expelled from the tetrahedral
intermediate, so the final product is a carboxylic acid.

53
 Alkylation of the α-crbon of Carbonyl Compounds
• Alkylation of the α-carbon of a carbonyl compound is an important
reaction because it gives us another way to form a carbon–carbon bond.
• Alkylation is carried out by first removing a proton from the α-carbon with
a strong base such as LDA (lithium diisopropylamide) and then adding
the appropriate alkyl halide
• Because the alkylation is an SN2 reaction, it works best with methyl halides
and primary alkyl halides

54
 • Two different products can be formed when the ketone is not symmetrical,
because either can be alkylated.

• How could you prepare 4-methyl-3-hexanone from a

ketone containing no more than six carbon atoms?
• Two sets of ketone and alkyl halide could be used
for the synthesis: 3-hexanone and a methyl halide
or 3-pentanone and an ethyl halide.

55
 Aldol condensation
• Two molecules of an aldehyde or ketone react with each other in the
presence of base to form a β-hydroxy carbonyl compound
• The β-hyrdoxyaldehyde and β-hyrdoxyketone products of aldol addition
reactions are easier to dehydrate than many other alcohols because the
double bond formed as the result of dehydration is conjugated with a
carbonyl group

• Base removes an α-proton from the carbonyl, creating an enolate.

• The enolate adds to the carbonyl carbon of a second carbonyl, and the
resulting negatively charged oxygen is protonated by the solvent.

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 • Ketones are less susceptible than aldehydes to attack by nucleophiles so
aldol additions occur more slowly with ketones.
• The relatively high reactivity of aldehydes in competing aldol addition
reactions is what causes them to give low yields of α-alkylation products

• Dehydration of an aldol addition product leads to a conjugated α, β,

unsaturated carbonyl system.
• The overall process is called an aldol condensation, and the product can
be called an enal (alkene aldehyde) or enone (alkene ketone), depending
on the carbonyl group in the product.

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 • β-Hydroxyaldehydes, β-hydroxyketones dehydrated under basic condition
• The product of dehydration is called an enone—“ene” for the double bond
and “one” for the carbonyl group.

• The mechanism begins with

the acid-catalyzed formation of
the enol.

• Then the enol adds to the

protonated carbonyl group of
another molecule of acetone.

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 Mannich condensation
• Compounds capable of forming an enol react with imines from
formaldehyde and a primary or secondary amine to yield β-aminoalkyl
carbonyl compounds called Mannich bases.

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 Claisen Condensation
• When two molecules of an ester undergo a condensaion reaction, the
reaction is called a Claisen condensation and condensation is β –keto ester.
• One molecule of carbonyl compound is converted into an enolate when an
α-hydrpgen removed by a strong base.
• The enolate attacks the carbonyl carbon of a second molecule of ester.
• The base employed corresponds to the leaving group of the ester so that the
reactant is not changed if the base acts as a nucleophile and attacks the
carbonyl group

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• It is easy to remove a proton from the β-keto ester b/c its central α- carbon
is flanked by two carbonyl groups, making its much more acidic than the a-
hydrogens of the ester starting material.

• Because the of a ketone are more acidic than an ester, ketone and the base
are each added slowly to the ester form β-diketone

• A β-keto aldehyde is formed when a ketone condenses with a formate ester.

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 Perkin condensation
• Analogous to aldol condensation in which an aromatic aldehyde (ArCHO)
reacts with a acid anhydride to give an α, β-unsaturated aromatic acid.
• In the presence of an alkali salt of the same carboxylic acid from which
acid anhydride is made.

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