Reaction mechanisms
1
Ionic Reactions
2
Bond Polarity
Partial charges
3
Nucleophiles and Electrophiles
4
Nucleophile Examples
Br
Anions
OH
C N
H
H
Pi bonds
H
H
H C C H
C C
H
H
H
C
C
C
C
C
C
H
H
H
Atoms with lone pairs
H O
H
H
N
O
H
H
H3C
C
CH3
5
6
7
8
9
10
11
12
13
14
15
Leaving Groups
16
17
18
Radical Reactions
19
Type of Reactions
20
Nucleophilic reactions:
nucleophilic substitution (SN)
Nucleophilic substitution: -> reagent is nucleophile
-> nucleophile replaces leaving group
-> competing reaction (elimination + rearrangements)
leaving
group
-
+
Nu
N ucleoph ile
•
C X
nucleoph ilic
sub stitution
C Nu +
-
X
in the following general reaction, substitution takes place on an sp3 hybridized
(tetrahedral) carbon
21
Nucleophilic Substitution
•
Some nucleophilic substitution reactions
Reactio n: Nu
HO
RO
HS
RS
I
-
-
+ CH3 X
CH3 Nu + X
-
CH3 -OH
An alcoh ol
-
CH3 -OR
An eth er
-
CH3 -SH
A thiol (a mercap tan)
-
CH3 -SR
A su lfid e (a th ioeth er)
-
CH3 -I
An alk yl iodide
NH3
CH3 -NH3
+
An alk ylammoniu m ion
+
HOH
CH3 -O-H
An alcoh ol (after p roton tran sfer)
H
22
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
–
–
–
–
•
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]
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]
23
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
HO
+
C
H
H
Br
-
H
-
HO
C
Br
HH
H
+
HO C
Br
-
H
H
Trans ition s tate w ith
s imu ltaneou s bond breaking
an d bond forming
24
SN2
• An energy diagram for an SN 2 reaction
– there is one transition state and no reactive intermediate
25
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
H 3C
C
Br
slow , rate
d etermining
CH3
C+
+
Br
H3 C
H3 C
H 3 C CH3
A carbocation intermediate;
carbon is trigonal p lanar
26
SN1
– Step 2: reaction of the carbocation (an electrophile) with methanol
(a nucleophile) gives an oxonium ion
CH3
CH3 O
H
+
H3 C
+
C+
H3 C CH3
fast
OCH3
CH3
O
H
H
H3 C
+
C
CH3
CH3
CH3
C O
H3 C
H3 C
H
– Step 3: proton transfer completes the reaction
H3 C
H3 C
H3 C
+
C O
CH3
H
H
+
O
CH3
H3 C
fas t
H3 C
H3 C
CH3
C O
+
+ H O
H
CH3
27
SN1
•
An energy diagram for an SN1 reaction
28
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
C
C6 H5
Cl
H
Cl
(R)-Enantiomer
-Cl
-
C+
H
C6 H5
CH3 OH
-H
Cl
Planar carbocation
(achiral)
+
C6 H5
+
CH3 O C
H
C OCH3
H
Cl
Cl
(S)-Enantiomer(R)-Enantiomer
A racemic mixture
29
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
30
Effect of substituents on SN2
31
Effect of substituents on SN1
32
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°
33
Effect of substituents on SN reactions
•
Effect of electronic and steric factors in competition between SN1 and
SN2 reactions
34
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
35
Nucleophilicity
Ef fectiv eness N ucl eoph ile
g oo d
Br-, I CH3 S , RS
-
-
-
HO , CH3 O , RO
mo derate
O
O
CH3 CO-, RCOCH3 SH, RSH, R2 S
NH3 , RNH2 , R2 NH, R3 N
H2 O
po or
CH3 OH, ROH
O
O
CH3 COH, RCOH
36
Nucleophilicity
37
Leaving Group
38
Leaving Group
39
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 leavi ng gro ups
in nucleo phil ic substi tutio n
G reater abi lity as leavi ng gro up and -el imin atio n reaction s
O
-
I > Br
-
-
-
-
-
-
> Cl >> F > CH3 CO > HO > CH3 O > NH2
-
Greater stabi li ty o f ani on; greater stren gth o f co njug ate acid
40
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
Solven t
Water
Formic acid
Methanol
Ethan ol
Acetic acid
Structure
H2 O
Polarity
of Solvent
HCOOH
CH3 OH
CH3 CH2 OH
CH3 COOH
41
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
Solvent
Stru cture
Polarity of
Solvent
O
Dimethyl su lfoxide CH3 SCH3
(D MS O)
O
CH3 CCH3
Acetone
Dichloromethane
CH2 Cl2
Dieth yl eth er
(CH3 CH2 ) 2 O
42
Summary of SN1 and SN2
Type of
Haloalkane
SN 2
SN 1
Methyl
CH3 X
SN 2 is favored .
SN 1 does not occur. The methyl
cation is s o u nstab le th at it is
never ob served in solution .
Primary
RCH2 X
SN 2 is favored .
SN 1 does not occur. Primary
carbocations are so un stable that
they are never observed in s olution.
Secon dary
R2 CHX
SN 2 is favored in aprotic
solvents w ith good
nu cleophiles.
SN 1 is favored in protic solven ts
w ith poor n ucleoph iles .
Tertiary
R3 CX
SN 2 does not occur because
of s teric h indrance around
the s ubstitu tion center.
SN 1 is favored becau se of th e ease of
formation of tertiary carbocation s.
Su bstitution Invers ion of configu ration.
at a
The n ucleophile attacks
stereocenter the s tereocenter from the
sid e op pos ite the leavin g
group .
Racemization. Th e carbocation
intermediate is plan ar, and attack b y
the n ucleophile occurs w ith equ al
probability from either sid e.
43
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 -elimination called dehydrohalogenation
(the elimination of HX)


C C
H X
An alkyl
halide
+
CH3 CH2 O-Na+
CH3 CH2 OH
Bas e
C
C
+
CH3 CH2 OH
+
+
Na X
-
An alken e
44
-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 CH bonds is concerted
– both R-X and base are involved in the rate-determining step
45
E2 Mechanism
• A one-step mechanism; all bond-breaking and bond-forming
steps are concerted
46
E1 Mechanism
– Step 1: ionization of C-X gives a carbocation intermediate
CH3
CH2 -C-CH3
s low , rate
determin ing
Br
CH3
CH3 -C-CH3 +
+
(A carb ocation
in termediate)
Br
–
– Step 2: proton transfer from the carbocation intermediate to a
base (in this case, the solvent) gives the alkene
H
O
H3 C
CH3
+ H-CH2 -C-CH3
+
fas t
CH3
H +
O H + CH2 =C-CH3
H3 C
Nucleophile
-> acting as a
strong base
47
Elimination
• Saytzeff rule: the major product of a elimination is the more
stable (the more highly substituted) alkene
-
Br
CH3 CH2 O Na
2-Bromo-2methylbutan e
+
+
CH3 CH2 OH
Br
-
2-Meth yl-2-bu tene
(major p roduct)
+
CH3 O Na
+
CH3 OH
1-Bromo-1-methylcyclopentane
2-Meth yl-1b utene
1-Methylcyclopen tene
(major product)
Methylenecyclop entane
48
Elimination Reactions
• Summary of E1 versus E2 Reactions for Haloalkanes
Haloalkane
Primary
RCH2 X
E1
E1 d oes not occur.
Primary carbocations are
so un stable that th ey are
never ob served in solution .
E2
E2 is favored.
Secon dary Main reaction w ith w eak
Main reaction w ith s trong
R2 CHX bas es su ch as H 2 O and ROH. bas es su ch as OH - an d OR-.
Tertiary
R3 CX
Main reaction w ith w eak
Main reaction w ith s trong
bas es su ch as H 2 O and ROH. bas es su ch as OH - an d OR-.
49
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
nucleop hilic
sub stitution H C
H C
C X +
Nu
C Nu +
X-
-
-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
50
SN1 versus E1
• Reactions of 2° and 3° haloalkanes in polar protic solvents give
mixtures of substitution and elimination products
E1
CH3
CH3
C I
CH3
CH3
CH3 C Cl
CH3
-
-I
CH3
-
-Cl
CH3
C+
CH3
SN 1
H2 O
SN 1
CH3 OH
CH3
CH2 C
+ H+
CH3
CH3
+
CH3 C OH + H
CH3
CH3
CH3 C OCH3 + H+
CH3
51
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 sligh tly affected by
bran chin g at the -carbon; alken e
formation is accelerated
R R
H
C
C leavin g grou p
SN 2 attack of a nu cleop hile is R
R
imped ed by branching at the
- and -carbons
52
Summary of S vs E for Haloalkanes
– for methyl and 1°haloalkanes
Methyl
CH3 X
SN2
The only sub stitution reactions observed
SN1
SN 1 reactions of methyl halid es are n ever observed.
The meth yl cation is so uns table that it is never
formed in solution .
Primary
RCH2 X
SN2
The main reaction w ith strong bases such as OH - an d
EtO -. Als o, th e main reaction w ith good
nu cleophiles/w eak bas es, su ch as I- and CH 3 COO -.
E2
The main reaction with stron g, bu lky bases , such as
potas sium t ert-butoxide.
SN 1 / E1
Primary cation s are n ever formed in s olution; th erefore,
S N 1 and E1 reaction s of p rimary h alid es are never obs erved.
53
Summary of S vs E for Haloalkanes
– for 2° and 3° haloalkanes
Secondary SN 2
R2 CHX
Tertiary
R3 CX
The main reaction w ith w eak b ases/good nu cleophiles,
such as I- and CH 3COO -.
E2
Th e main reaction w ith s trong bases /good nucleoph iles
su ch as OH - an d CH 3CH 2O -.
SN1 / E1
Common in reactions w ith w eak nucleop hiles in p olar
protic s olvents, s uch as w ater, methan ol, an d ethanol.
SN 2
SN 2 reactions of tertiary halides are n ever observed
because of th e extreme crow ding aroun d the 3° carbon.
Main reaction w ith strong bas es, su ch as HO - an d RO -.
E2
SN1 / E1
Main reactions w ith poor nu cleophiles/w eak b ases.
54
Summary of S vs E for Haloalkanes
– Examples: predict the major product and the mechanism for
each reaction
1.
Cl
80°C
H2 O
+ NaOH
+ ( C2 H5 ) 3 N
Br
2.
Br
-
3.
Elimination, strong base, high temp.
30°C
CH2 Cl2
SN2, weak base, good nucleophil
+
+ CH3 O Na
methanol
SN1 (+Elimination), strong base, good
nucleophil, protic solvent
Cl
4.
+ -
+ Na I
acetone
No reaction,
I is a weak base (SN2)
I better leaving group than Cl
55
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
56
Carbocation rearrangements in SN + E reactions
Rearrangement
57
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)
58
Carbocation rearrangements in Electrophilic
addition reactions
59