Organic Chemistry – Chemistry of Life and Beyond…..

Synthesis

Functional Groups Reactions Mechanisms

electron
movement

Molecules
formula
shape
name

bonding

Atoms

1
Nucleophilic substitution reactions occur when nucleophiles
displace leaving groups, resulting in the substitution of one
group for another.

Nucleophiles are species with non-bonding electrons that

can be donated to electrophilic centers.

Nucleophilicity is affected by the structure of the nucleophile

and by the solvent used in the reaction.

Nucleophilic strength (in water) - reacts faster with the electrophile:

SH- > CN- > I- > HO- > N3- > Br- > PhO- > CH3COO- > Cl- > F- > NO3- > H2O

Leaving groups are stable species that can be removed with

their bonding electrons from a molecule during reaction.
2
Nucleophilicity - important factors in determining nucleophilicity:

it depends on availability of electron pairs (related to basicity)

Depends on electronegativity (CH3:- > H2N:- > HO:- > F:-)

Depends on charge (HO:- > H2O:)

Depends on polarizability (HS:- > HO:-)

Depends on solvation:

Protic polar solvents that can hydrogen bond make the

nucleophilic electrons less available.

Aprotic polar solvents that can not hydrogen bond make the
electrons more available.

3
Acid-catalyzed ring opening of epoxides:
H
H2C CH2 + H2O HOCH2CH2OH
O

OH
H Nucleophile attacks anti
O + H2O
OH
to the leaving group
+ enantiomer

4
Review: the SN2 reaction.
1°, 2° halides, carbon
Substitution, nucleophilic, bimolecular with good leaving group

Second order kinetics

R = k [alkylhalide][nuc:]

• One step - pentacoordinate transition state.

• substitution is slowed by substitution at the 

and  carbons of the reagent.

• If the carbon atom is chiral an SN2 reaction

results in inversion of configuration.

5
Review: the SN1 reaction.
3° and benzylic halides
Substitution, nucleophilic, unimolecular (sometimes 2°
halides).
First order kinetics
R = k [alkylhalide]
• Two-step reaction.

• Rate-determining step - formation of carbocation.

• Second step - reaction of carbocation with nucleophile -

fast SN1 product (in competition with the carbocation
losing a proton to give the E1 elimination product).

• If the carbon atom is chiral an SN1 reaction results in

racemization of configuration.

Carried out in ionizing solvents able to

stabilize the carbocation
6
 Nucleophilic Substitution Reactions

SN2 versus SN1

RX: R = methyl, 1° & 2° RX: R = 3° & 2°

Strong nucleophile Weak nucleophile

Aprotic solvents Polar, protic solvents

7
Elimination reactions generate alkenes:

H
  base
C C C C
X
X = Cl, Br, I

Dehydrohalogenation reaction: loss of HX

It is the reverse of an electrophilic addition reaction.

8
 Elimination Reactions
Two possible mechanisms

Elimination bimolecular Elimination unimolecular

E2 E1
HO H H
H 1) C C C C X
C C C C H 2O X X

X H2 O
H
2) C C C C H3O

The C-X and C-H bonds break and The C-X bond breaks first (slow
the C=C bond forms simultaneously: step), then the C-H breaks and the
a CONCERTED mechanism C=C bond forms: a STEPWISE
mechanism 9
An elimination reaction may be either E1 or E2.

An E1 reaction involves loss of a proton from a carbocation

intermediate and is first order.

E2 reactions are second order.

Elimination reactions compete with substitution reactions and are

promoted by strong bases and high temperatures.

For elimination reactions that can give rise to more than one alkene, the
more highly substituted alkene is the major product.

E2 reactions proceed most easily when the leaving group and the
proton to be removed are in the anti orientation.

The order of reactivity for alkyl halides in elimination reactions is:

3° > 2° > 1°
10
 Elimination Reactions
E2 E1

Kinetics of the E2 reaction: Kinetics of the E1 reaction:

rate = k[R-X][base] rate = k[R-X]

overall kinetics are second order. overall kinetics are first order.

Intermediate carbocation

Ea2
Ea R+ + X-

Ea1
R-X + HO- R-X
R=R’ + H2O R=R’
reaction coordinate reaction coordinate 11
E2

12
E1

13
 C-C
-bonds

sp2-sp2 1 1 1 1

sp2-sp3 4 3 2 1

sp3-sp3 0 1 2 3
Most stable least stable
a terminal alkene
internal alkenes
Bonds with more ‘s’ character are more stable (lower energy
orbital)
sp2-sp3 bonds have more ‘s’ character than sp3-sp3 bonds
The more substituted the alkene is the more stable.
18
 C-C
-bonds

sp2-sp2 1 1 1 1

sp2-sp3 4 3 2 1

sp3-sp3 0 1 2 3
Most stable least stable
a terminal alkene
internal alkenes
Bonds with more ‘s’ character are more stable (lower energy
orbital)
The more substituted the alkene is the more stable.
The elimination reaction preferentially produces the most substituted alkene
possible - this is called Saytzeff elimination 19
 Elimination Reactions
E2

HO
H

Ea C C

X 
R-X + HO-
R=R’ + H2O
reaction coordinate

The transition state resembles the alkene product (partial double bond),
therefore the reaction results in the formation of the more stable alkene.

The most substituted alkene is the most stable.

20
 H H H Br
C C H
H C C
Stereochemistry of H H H H
the E2 reaction
2-bromobutane

H
+ H2O + Br-
Br
H3 C H3C H
C C
H H
CH3
H CH3

H O (E)-2-butene and (Z)-2-butene

H Br
H H H
C C
H H + H2O + Br-
CH2CH3
H CH2CH3

H O
1-butene

21
BUT: when a highly branched base is used, a smaller percentage of
the Saytzeff elimination is observed.

This is because the bulky base preferentially attacks the least

sterically hindered hydrogens.

Br

Base Product ratio

H3CH2C O
79% 21%
CH3
H3C C O
27% 73%
CH3
CH3
H3 C C O 19% 81%
CH2CH3

CH2CH3
H3CH2C C O 8% 92%
CH2CH3 22
Branching in the base (bulky base) has two effects:

1) it increases the relative proportion of E2 to SN2 products.

2) In the elimination reaction, it increases the proportion of alkenes with less

branching

23
 Stereochemistry of the E2 elimination reaction

In an E2 reaction, the stereochemistry of the alkene that is formed is

governed by the conformation of the starting material.

The leaving group and the proton being removed by the base are anti
to each other.

H H3 C EtO-Na+ H3C CH3


H
H3 C H H
C C C C
TsO CH3 ethanol
H3 C C6 H 5 C6 H 5 H C6 H 5
OTs

C 6 H5 

This is called an anti elimination reaction.

24
 H H H EtO-Na+ H CH3


H CH3 H3 C
C C C C
TsO CH3 ethanol
H3 C C6 H5 C6 H 5 H3C C 6 H5
OTs

C 6 H5 

25
 H
H OTs
H
CH3 CH3
H OTs OTs
H
H H H CH3
H

CH3
DMSO H3 C C O K
55 °C The diequatorial conformation is the most
CH3 stable, but the leaving group must be axial
in order to have an anti hydrogen atom
required for the E2 elimination reaction.
H
CH3

26
 H H H C6 H 5
TsO C6 H 5 TsO H

trans cis
CH3 CH3
H3 C C O K H3 C C O K
50 °C 50 °C
CH3 CH3

C 6 H5 C 6 H5

fast slow

anti elimination syn elimination

27
The elimination reaction and the nature of the base:

The rate of the E2 reaction depends on the base - The stronger

the base, the faster the reaction.

Elimination reactions are promoted by high temperatures.

The rate of the E1 reaction does not depend on the strength of

the base. The base is not involved in the rate determining step.

The nature of the leaving group:

E1 and E2 reactions are faster when the leaving group is better:

ROTs > RI > RBr > RCl > RF

28
 Does the substrate have good leaving group?

No Yes
Is the nucleophile/base strong?
No Rxn

No Yes
Nature of Substrate? Nuclophile or base?

1° 2° 3°
Nucleophile base
No Rxn SN1/E1 SN1/E1 Nature of substrate? Nature of substrate?

1° 2° 3°
1° 2°
SN2 SN2/SN1? SN1
bulky base and or/heat? E1
Nature of solvent?

polar protic polar aprotic Yes No

SN1 favored SN2 favored E2 SN2/E2
29
Electrophilic addition of acids to alkenes

C
C
H Br H C H Br
C
H CH2Cl CH2Cl

nucleophile electrophile electrophile nucleophile

H3C CH3 H3C CH3

Br Br
H2C C C CH2

H C H H C H

CH2Cl CH2Cl

The reaction is regioselective but not enantioselective 30

 Rearrangement of carbocations

Sometimes, a secondary carbocation can rearrange to give a more

stable tertiary carbocation.

When this occurs, mixtures of products are usually obtained.

CH3 CH3

H3C C CH CH2 H3 C C CH CH3

H H
H Cl Cl

31
 CH3
H3 C C CH CH3

32
 CH3
+
+
H3 C C CH CH3

33
 CH3
+
+
H3 C C CH CH3

34
 CH3
+ +
H3 C C CH CH3

35
 CH3
+ +
H3 C C CH CH3

36
 CH3
+ +
H3 C C CH CH3

37
 CH3
+ +
H3 C C CH CH3

38
 CH3
+ +
H3 C C CH CH3

39
 CH3
+ +
H3 C C CH CH3

40
 CH3
H3 C C CH CH3

41
 CH3 CH3
1,2-hydride shift
H3C 1C CH CH3 H3 C C CH CH3
2
H H

A hydrogen atom with a pair of electrons is a hydride ion.

A hydride shift is when a hydride ion moves from one carbon atom to
another carbon atom that has a deficiency of electrons.

When it takes place between adjacent carbon atoms, it is known as a

1,2-hydride shift.

42
 CH3 CH3

H3C CH CH2 H3 C C CH CH3

H H
H Cl Cl

CH3 CH3
H3 C C CH CH3 H3C C CH CH3
H H Cl
Cl

CH3
CH3 CH3
H3 C C CH CH3
H 3C C CH CH3 H3C C CH CH3
H
H Cl H
Cl
43
 The hydration reaction is reversible.

CH3
H3 C CH3
C H2O/H2SO4 H3 C C OH
C H C H
H H
H

• When alcohols are heated in acid, they are converted to alkenes in

an elimination reaction (E1 mechanism).

• First, you have to protonate the alcohol to make it a good leaving

group.

• Second, a water molecule leaves to give a carbocation.

• Third, the carbocation loses a proton to water (acting as a base).

44
DEHYDRATION OF ALCOHOLS

Acid catalysed dehydration of a simple alcohol like ethanol to

give an alkene.

The dehydration of ethanol

Ethanol can be dehydrated to give ethene by heating it with an

excess of concentrated sulfuric acid at about 170°C.
Concentrated phosphoric acid, H3PO4, can also be used.

In the first stage, one of the lone pairs of electrons on the

oxygen picks up an hydrogen ion from the sulphuric acid. The
alcohol is said to be protonated.
45
Dehydration of cyclopentanol
H
O
H3PO4
+ H2O


46
 H H
O O O H
O P OH
+ + O P O
H OH OH
H
O

47
 H H H H
O O O
O H
+O P OH
+ H + H2OP
O O
H OH OH
H
O

H H
O
H H H
H
+ O

H H
O H H
O
H +
+ H H

48
Hydration of a double bond

49
Question: In a dehydration reaction, how do we explain the predominant
formation of: CH3CH=CHCH3 when CH3CH2CH2CH2-OH reacts with acid?
1) protonate to make a good leaving group.
2) form an unstable primary carbocation

50
 H

This 1° carbocation undergoes a 1,2-hydride

shift to form a more stable 2° carbocation.

51
H

52
H

53
H

54
H

55
H

56
 H
+

Now we have a more stable 2° carbocation.

57
H
O
H
H
+
CH3CH CHCH3

CH3CH CHCH3
CH3CH CHCH3
58
 CH3

1 °

Carbon atoms can also shift to form more

stable carbocations.

This results in a rearrangement of the

carbon skeleton.
59
CH3

60
CH3

61
CH3

62
CH3

63
CH3

64
 CH3
+

1o 2o
carbocation

65
An electrophilic addition reaction with a 1,2-methyl shift

CH3 CH3 CH3

H3C C CH CH2 H3C C CH CH3 H3C C CH CH3

CH3 CH3 CH3 Cl

H Cl Cl

CH3 CH3 CH2

H 3C C CH CH3 H3 C C CH CH3 H3C C CH CH3

Cl CH3
CH3 CH3

Cl

The shift of a methyl group along with the pair of electrons that
binds it, from one carbon atom to an adjacent carbocation is
known as a 1,2-methyl shift.
66
The carbocation intermediate can be formed from the
addition of a proton to an alkene.

OR from the loss of a water molecule from an alcohol

under acidic conditions.

Carbocations can rearrange to more stable

carbocations in equilibrium reactions (i.e. there is a
mixture present).

Carbocations react as Lewis acids with electron rich

species.

OR as Brønsted acids to lose a proton to a base

(elimination).
67
 Formation and reactions of carbocations

CH3 CH2 CH3

H3C C C CH3 H2 C C C CH3 H3 C C CH CH3
CH3 OH CH2 OH2 CH3

CH3 CH3
H
H3 C C CH CH2 H3 C C CH CH2 O H
H
CH3 H CH3

O H 3%
H

68
 Formation and reactions of carbocations
H
O
CH3 H
CH3 H CH2
H3 C C CH CH3 H3 C C CH CH3 H3 C C CH CH3
H
CH3 CH3 CH3

H
O
CH3 H CH2
H
H3 C C C CH3 H3C C CH CH3

CH3 CH3

31%

CH3 CH3
H3C C CH CH2 H3C C C CH3
CH3 CH3

3% 61%
Formation and reactions of carbocations

CH3
CH3
+
CH3 H
OH
CH3

?
CH3 CH3
CH3 H+
OH
CH3