Reaction mechanisms

1
Ionic Reactions

2
Ionic Reactions

3
Ionic Reactions

4
Ionic Reactions

5
 Bond Polarity
Partial charges

6
Nucleophiles and Electrophiles

7
Leaving Groups

8
Radical Reactions

9
Type of Reactions

10
 Nucleophilic reactions:
nucleophilic substitution (SN)
Nucleophilic substitution: -> reagent is nucleophil
-> nucleophil replaces leaving group
-> competing reaction (elimination + rearrangements)

leaving
group
nucleophilic
substitution
C Nu +
-
Nu
-
+ C X X
Nucleophile

• in the following general reaction, substitution takes place on an sp3 hybridized

(tetrahedral) carbon

11
 Nucleophilic Substitution

• Some nucleophilic substitution reactions

Reaction: Nu -
+ CH3 X CH3 Nu + X-

-
HO CH3 -OH An alcohol
-
RO CH3 -OR An ether
-
HS CH3 -S H A thiol (a mercaptan)
-
RS CH3 -S R A sulfide (a thioether)
-
I CH3 -I An alkyl iodide

NH3 CH3 -NH3

+
An alkylammonium ion
+
HOH CH3 -O-H An alcohol (after proton transfer)
H
12
 Mechanism

• Chemists propose two limiting mechanisms for nucleophilic displacement

– a fundamental difference between them is the timing of bond breaking and
bond forming steps

• At one extreme, the two processes take place simultaneously; designated SN2
– S = substitution
– N = nucleophilic
– 2 = bimolecular (two species are involved in the rate-determining step)
– rate = k[haloalkane][nucleophile]
• In the other limiting mechanism, bond breaking between carbon and the leaving
group is entirely completed before bond forming with the nucleophile begins.
This mechanism is designated SN1 where
– S = substitution
– N = nucleophilic
– 1 = unimolecular (only one species is involved in the rate-determining step)
– rate = k[haloalkane]
13
 SN2 reaction: bimolecular nucleophilic substitution

– both reactants are involved in the transition state of the

rate-determining step
– the nucleophile attacks the reactive center from the side
opposite the leaving group

H
H - - H
HO + C Br HO C Br HO C + Br
-

H
H H
HH H

Transition state with

simultaneous bond breaking
and bond forming

14
 SN2

• An energy diagram for an SN 2 reaction

– there is one transition state and no reactive intermediate

15
 SN1 reaction: unimolecular nucleophilic substitution

• SN1 is illustrated by the solvolysis of tert-butyl bromide

– Step 1: ionization of the C-X bond gives a carbocation intermediate

H3 C slow, rate CH3

determining
C Br C+ + Br
H3 C
H3 C H 3 C CH3
A carbocation intermediate;
carbon is trigonal planar

16
 SN1
– Step 2: reaction of the carbocation (an electrophile) with methanol
(a nucleophile) gives an oxonium ion
CH3 H3 C CH3 H3 C CH3
fast
CH3 O + C+ + OCH3 O C + C O
CH3 H3 C
H H H H3 C H
H3 C CH3 CH3
– Step 3: proton transfer completes the reaction

H3 C H3 C CH3 H
CH3 H
+ + fast +
C O O C O + H O
H3 C CH3 H3 C
H H3 C CH3
H3 C

17
 SN1

• An energy diagram for an SN1 reaction

18
 SN1

• For an SN1 reaction at a stereocenter, the product is a racemic mixture

• the nucleophile attacks with equal probability from either face of the
planar carbocation intermediate

C6 H5 C6 H5 C6 H5 C6 H5
-
-Cl CH3 OH
C Cl C+ + CH3 O C + C OCH3
-H H
H H H

Cl Cl Cl
Cl (S)-Enantiomer (R)-Enantiomer
(R)-Enantiomer Planar carbocation
(achiral)
A racemic mixture

19
 Effect of variables on SN Reactions

– the nature of substituents bonded to the atom attacked by

nucleophile
– the nature of the nucleophile
– the nature of the leaving group
– the solvent effect

20
Effect of substituents on SN2

21
Effect of substituents on SN1

22
 Effect of substituents on SN reactions

• SN1 reactions
– governed by electronic factors, namely the relative
stabilities of carbocation intermediates
– relative rates: 3° > 2° > 1° > methyl

• SN2 reactions
– governed by steric factors, namely the relative ease of
approach of the nucleophile to the site of reaction
– relative rates: methyl > 1° > 2° > 3°

23
 Effect of substituents on SN reactions

• Effect of electronic and steric factors in competition between S N1 and

SN2 reactions

24
 Nucleophilicity

• Nucleophilicity: a kinetic property measured by the rate at

which a Nu attacks a reference compound under a standard set
of experimental conditions
– for example, the rate at which a set of nucleophiles displaces
bromide ion from bromoethane

CH3 CH2 Br + NH3 CH3 CH2 NH3

+
+ Br-

Two important features:

- An anion is a better nucleophile than a uncharged conjugated acid
- strong bases are good nucleophiles

25
 Nucleophilicity

Effectiveness Nucleophile
Br-, I -
good CH3 S- , RS-
HO-, CH3 O-, RO-
O O
CH3 CO-, RCO-
moderate
CH3 SH, RSH, R2 S
NH3 , RNH2 , R2 NH, R3 N
H2 O
CH3 OH, ROH
poor O O
CH3 COH, RCOH

26
Nucleophilicity

27
Leaving Group

28
Leaving Group

29
 The Leaving Group

– the best leaving groups in this series are the halogens I-, Br-,
and Cl-
– OH-, RO-, and NH2- are such poor leaving groups that they are
rarely if ever displaced in nucleophilic substitution reactions

Rarely act as leaving groups

in nucleophilic substitution
Greater ability as leaving group and -elimination reactions
O
I- > Br- > Cl- >> F- > CH3 CO- > HO- > CH3 O- > NH2 -

Greater stability of anion; greater strength of conjugate acid

30
 Solvent Effect

• Protic solvent: a solvent that contains an -OH group

– these solvents favor SN1 reactions; the greater the polarity of the
solvent, the easier it is to form carbocations in it

Protic Polarity
Solvent Structure of Solvent
Water H2 O
Formic acid HCOOH
Methanol CH3 OH
Ethanol CH3 CH2 OH
Acetic acid CH3 COOH

31
 Solvent Effect

• Aprotic solvent: does not contain an -OH group

– it is more difficult to form carbocations in aprotic solvents
– aprotic solvents favor SN2 reactions

Aprotic Polarity of
Solvent Structure Solvent
O
Dimethyl sulfoxide CH3 S CH3
(DMSO)
O
Acetone CH3 CCH3
Dichloromethane CH2 Cl2
Diethyl ether (CH3 CH2 ) 2 O

32
 Summary of SN1 and SN2
Type of
Haloalkane SN 2 SN 1
Methyl SN 2 is favored. SN 1 does not occur. The methyl
CH3 X cation is so unstable that it is
never observed in solution.
Primary SN 2 is favored. SN 1 does not occur. Primary
RCH2 X carbocations are so unstable that
they are never observed in solution.
Secondary SN 2 is favored in aprotic SN 1 is favored in protic solvents
R2 CHX solvents with good with poor nucleophiles.
nucleophiles.
Tertiary SN 2 does not occur because SN 1 is favored because of the ease of
R3 CX of steric hindrance around formation of tertiary carbocations.
the substitution center.
Substitution Inversion of configuration. Racemization. The carbocation
at a The nucleophile attacks intermediate is planar, and attack by
stereocenter the stereocenter from the the nucleophile occurs with equal
side opposite the leaving probability from either side.
group.

33
 Competing Reaction: Elimination

-Elimination: removal of atoms or groups of atoms from adjacent

carbons to form a carbon-carbon double bond
– we study a type of b-elimination called dehydrohalogenation
(the elimination of HX)

 
C C + CH3 CH2 O-Na+
CH3 CH2 OH
H X
Base
An alkyl
halide
+ -
C C + CH3 CH2 OH + Na X

An alkene
34
 b-Elimination

• There are two limiting mechanisms for β-elimination reactions

• E1 mechanism: at one extreme, breaking of the C-X bond is

complete before reaction with base breaks the C-H bond
– only R-X is involved in the rate-determining step

• E2 mechanism: at the other extreme, breaking of the C-X and C-

H bonds is concerted
– both R-X and base are involved in the rate-determining step

35
 E2 Mechanism

• A one-step mechanism; all bond-breaking and bond-forming

steps are concerted

36
 E1 Mechanism

– Step 1: ionization of C-X gives a carbocation intermediate

CH3 slow, rate CH3

determining –
CH2 -C-CH3 CH3 -C-CH3 + Br
+
Br (A carbocation
intermediate)
– Step 2: proton transfer from the carbocation intermediate to a
base (in this case, the solvent) gives the alkene

CH3 CH3
H fast H +
O + H-CH2 -C-CH3 O H + CH2 =C-CH3
+
H3 C H3 C
Nucleophile
-> acting as a
strong base

37
 Elimination

• Saytzeff rule: the major product of a elimination is the more

stable (the more highly substituted) alkene

Br CH3 CH2 O-Na +

+
CH3 CH2 OH
2-Bromo-2- 2-Methyl-2-butene 2-Methyl-1-
methylbutane (major product) butene

Br -
CH3 O Na
+

+
CH3 OH
1-Bromo-1-methyl- 1-Methyl- Methylene-
cyclopentane cyclopentene cyclopentane
(major product)

38
 Elimination Reactions

• Summary of E1 versus E2 Reactions for Haloalkanes

Haloalkane E1 E2
Primary E1 does not occur. E2 is favored.
RCH2 X Primary carbocations are
so unstable that they are
never observed in solution.

Secondary Main reaction with weak Main reaction with strong

R2 CHX bases such as H2 O and ROH. bases such as OH- and OR-.

Tertiary Main reaction with weak Main reaction with strong

R3 CX bases such as H2 O and ROH. bases such as OH- and OR-.

39
 Substitution vs Elimination

• Many nucleophiles are also strong bases (OH- and RO-) and SN
and E reactions often compete
– the ratio of SN/E products depends on the relative rates of
the two reactions
nucleophilic
substitution H C C Nu + X-
H C C X + Nu-
-elimination C C + H-Nu + X-

What favors Elimination reactions:

- attacking nucleophil is a strong and large base
- steric crowding in the substrate
- High temperatures and low polarity of solvent

40
 SN1 versus E1

• Reactions of 2° and 3° haloalkanes in polar protic solvents give

mixtures of substitution and elimination products
CH3
E1
CH2 C + H+
CH3 CH3
CH3 C I
-I- CH3 CH3
CH3 SN 1
CH3 C+ CH3 C OH + H+
H2 O
CH3 -Cl- CH3 CH3
CH3 C Cl
CH3
CH3 SN 1
CH3 C OCH3 + H+
CH3 OH
CH3

41
 SN2 versus E2

• It is considerably easier to predict the ratio of SN2 to E2

products

Attack of base on a -hydrogen by

E2 is only slightly affected by R R
branching at the -carbon; alkene
H C
formation is accelerated
C leaving group
SN2 attack of a nucleophile is R
impeded by branching at the R
- and -carbons

42
 Summary of S vs E for Haloalkanes

– for methyl and 1°haloalkanes

Methyl S N2 The only substitution reactions observed

CH3 X S N1 SN1 reactions of methyl halides are never observed.
The methyl cation is so unstable that it is never
formed in solution.
Primary S N2 The main reaction with strong bases such as OH- and
RCH2 X EtO-. Also, the main reaction with good
nucleophiles/weak bases, such as I- and CH3 COO-.

E2 The main reaction with strong, bulky bases, such as

potassium tert-butoxide.
SN 1 / E1 Primary cations are never formed in solution; therefore,
S N1 and E1 reactions of primary halides are never observed.

43
 Summary of S vs E for Haloalkanes

– for 2° and 3° haloalkanes

Secondary SN 2 The main reaction with weak bases/good nucleophiles,

R2 CHX such as I- and CH3COO-.
E2 The main reaction with strong bases/good nucleophiles
such as OH- and CH3CH2O-.
SN1 / E1 Common in reactions with weak nucleophiles in polar
protic solvents, such as water, methanol, and ethanol.

Tertiary SN 2 SN 2 reactions of tertiary halides are never observed

R3 CX because of the extreme crowding around the 3° carbon.
E2 Main reaction with strong bases, such as HO- and RO-.
SN1 / E1 Main reactions with poor nucleophiles/weak bases.

44
 Summary of S vs E for Haloalkanes
– Examples: predict the major product and the mechanism for
each reaction

Cl 80°C
1. + NaOH Elimination, strong base, high temp.
H2 O

30°C
2. + ( C2 H5 ) 3 N SN2, weak base, good nucleophil
Br CH2 Cl2

Br
- +
3. + CH3 O Na SN1 (+Elimination), strong base, good
methanol
nucleophil, protic solvent

Cl
4. + -
+ Na I No reaction,
acetone I is a weak base (SN2)
I better leaving group than Cl
45
 Carbocation rearrangements

Also 1,3- and other shifts are possible

The driving force of rearrangements is -> to form a more stable carbocation !!!
Happens often with secondary carbocations -> more stable tertiary carbocation

46
Carbocation rearrangements in SN + E reactions

Rearrangement

47
 Carbocation rearrangements in SN + E reactions
-> Wagner – Meerwein rearrangements

Rearrangement of a secondary carbocations -> more stable tertiary carbocation

Plays an important role in biosynthesis of molecules, i.e. Cholesterol -> (Biochemistry)

48
Carbocation rearrangements in Electrophilic
addition reactions

49