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1
Reaction mechanisms
2
Ionic Reactions
3
Ionic Reactions
4
Ionic Reactions
5
Ionic Reactions
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Bond PolarityPartial charges
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Nucleophiles and Electrophiles
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Leaving Groups
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Radical Reactions
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Type of Reactions
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Nucleophilic reactions: nucleophilic substitution (SN)
Nucleophilic substitution: -> reagent is nucleophil
-> nucleophil replaces leaving group
-> competing reaction (elimination + rearrangements)
nucleophilicsubstitution
Nucleophile
++ C NuC XNu - X-
leavinggroup
• in the following general reaction, substitution takes place on an sp3 hybridized (tetrahedral) carbon
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Nucleophilic Substitution
• Some nucleophilic substitution reactions
CH3-I
HO -
Nu -
RO -
HS -
RS -
I -
NH3
HOH
CH3-SH
CH3-SR
CH3-OH
CH3-OR
H
CH3-O-H
CH3-NH3+
CH3X CH3Nu X-
+An alcohol (after proton transfer)
An alkylammonium ion
An alkyl iodide
A sulfide (a thioether)
A thiol (a mercaptan)
An ether
An alcohol
Reaction: + +
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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 SSNN22
– 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 SSNN11 where
– S = substitution– N = nucleophilic– 1 = unimolecular (only one species is involved in the rate-determining
step)– rate = k[haloalkane]
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SN2 reaction: bimolecular nucleophilic substitution
C Br
H
HH
HO + C
H
H H
HO Br
- -
Transition state withsimultaneous bond breaking
and bond forming
C
H
HH
HO + Br -
– 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
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SN2
• An energy diagram for an SN 2 reaction
– there is one transition state and no reactive intermediate
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• SN1 is illustrated by the solvolysis of tert-butyl bromide
– Step 1: ionization of the C-X bond gives a carbocation intermediate
C
CH3
CH3H3C
+C
H3C
H3C
Br
H3C
slow, ratedetermining
A carbocation intermediate; carbon is trigonal planar
+ Br
SN1 reaction: unimolecular nucleophilic substitution
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SN1
– Step 2: reaction of the carbocation (an electrophile) with methanol (a nucleophile) gives an oxonium ion
– Step 3: proton transfer completes the reaction
CH3O
H H3C
C
CH3
CH3
OCH3
H
C
CH3
CH3
CH3
O
H3C
HH3C
H3C
C
H3C
O
CH3
H
fast ++ ++
++++ fastC
H3CH3C
O
H3C
OCH3
HOHO
CH3CH3
H
H
CH3
H3C
CH3C
H3C
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SN1
• An energy diagram for an SN1 reaction
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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
(R)-EnantiomerPlanar carbocation (achiral)
C
H
Cl
C6H5
Cl
C+
C6H5
H
Cl
CH3OH-Cl-
-H+
+
A racemic mixture
Cl
C6H5 C6H5
C OCH3
H
CH3O CH
Cl(R)-Enantiomer(S)-Enantiomer
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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
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Effect of substituents on SN2
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Effect of substituents on SN1
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• SN1 reactions
– governed by electronic factorselectronic factors, namely the relative stabilities of carbocation intermediates
– relative rates: 3° > 2° > 1° > methyl
• SN2 reactions
– governed by steric factorssteric factors, namely the relative ease of approach of the nucleophile to the site of reaction
– relative rates: methyl > 1° > 2° > 3°
Effect of substituents on SN reactions
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Effect of substituents on SN reactions
• Effect of electronic and steric factors in competition between SN1 and SN2 reactions
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Nucleophilicity
• NucleophilicityNucleophilicity: 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
CH3CH2Br NH3 CH3CH2NH3+ Br
-++
Two important features:
- An anion is a better nucleophile than a uncharged conjugated acid
- strong bases are good nucleophiles
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Nucleophilicity
good
poor
Br-, I -
HO-, CH3O-, RO-
CH3S-, RS-
H2O
CH3OH, ROH
CH3COH, RCOH
O O
NH3, RNH2, R2NH, R3N
CH3SH, RSH, R2S
Effectiveness Nucleophile
moderateCH3CO-, RCO-
O O
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Nucleophilicity
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Leaving Group
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Leaving Group
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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
I- > Br- > Cl- >> F- > CH3CO- > HO- > CH3O- > NH2-
Greater ability as leaving group
Greater stability of anion; greater strength of conjugate acid
Rarely act as leaving groups in nucleophilic substitution and -elimination reactions
O
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Solvent Effect
• Protic solventProtic 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
CH3COOHCH3CH2OHCH3OHHCOOH
H2OStructure
Acetic acid
Formic acid
EthanolMethanol
Water
ProticSolvent
Polarity of Solvent
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Solvent Effect
• Aprotic solventAprotic solvent: does not contain an -OH group – it is more difficult to form carbocations in aprotic
solvents
– aprotic solvents favor SN2 reactions
(CH3CH2)2O
CH2Cl2
OCH3CCH3
OCH3SCH3
Diethyl ether
Dichloromethane
AproticSolvent Structure
Dimethyl sulfoxide (DMSO)
Acetone
Polarity ofSolvent
33
Summary of SN1 and SN2
CH3X
RCH2X
R2CHX
R3CX
Type of Haloalkane
Methyl
Primary
Secondary
Tertiary
SN2 SN1
Substitutionat a stereocenter
SN2 is favored. SN1 does not occur. The methylcation is so unstable that it is never observed in solution.
SN1 does not occur. Primary carbocations are so unstable thatthey are never observed in solution.
SN1 is favored in protic solventswith poor nucleophiles.
SN2 is favored in aproticsolvents with goodnucleophiles.
SN2 does not occur becauseof steric hindrance aroundthe substitution center.
SN1 is favored because of the ease of formation of tertiary carbocations.
Inversion of configuration.The nucleophile attacksthe stereocenter from theside opposite the leavinggroup.
Racemization. The carbocationintermediate is planar, and attack bythe nucleophile occurs with equalprobability from either side.
SN2 is favored.
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Competing Reaction: Elimination
--EliminationElimination: removal of atoms or groups of atoms from adjacent carbons to form a carbon-carbon double bond– we study a type of -elimination called
dehydrohalogenationdehydrohalogenation (the elimination of HX)
C CH X
CH3CH2O-Na+
C C
CH3CH2OH
CH3CH2OH Na+X -+
+
+
An alkyl halide
Base
An alkene
35
-Elimination
• There are two limiting mechanisms for β-elimination reactions
• E1 mechanism: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: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
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E2 Mechanism
• A one-step mechanism; all bond-breaking and bond-forming steps are concerted
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E1 Mechanism
– Step 1: ionization of C-X gives a carbocation intermediate
– Step 2: proton transfer from the carbocation intermediate to a base (in this case, the solvent) gives the alkene
CH2-C-CH3
Br
CH3
CH3-C-CH3
CH3
Br –slow, rate
determining
+(A carbocation intermediate)
+
HO
H3CH-CH2-C-CH3
CH3
HOH
H3CCH2=C-CH3
CH3fast+
+ ++
Nucleophile
-> acting as a strong base
38
Elimination
• Saytzeff rule:Saytzeff rule: the major product of a elimination is the more stable (the more highly substituted) alkene
Br CH3CH2O-Na+
CH3CH2OH2-Methyl-2-butene (major product)
2-Bromo-2-methylbutane
2-Methyl-1-butene
+
Br CH3O-Na+
CH3OH+
1-Methyl-cyclopentene
(major product)
1-Bromo-1-methyl-cyclopentane
Methylene-cyclopentane
39
Elimination Reactions
• Summary of E1 versus E2 Reactions for Haloalkanes
RCH2X
R2CHX
R3CX
Haloalkane E1 E2
Primary
Secondary
Tertiary
E1 does not occur.Primary carbocations areso unstable that they are never observed in solution.
E2 is favored.
Main reaction with strong bases such as OH- and OR-.
Main reaction with weak bases such as H2O and ROH.
Main reaction with strong bases such as OH- and OR-.
Main reaction with weak bases such as H2O and ROH.
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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
nucleophilicsubstitution
-eliminationC CH X + Nu-
C CH Nu +
C C H-Nu+ +
X-
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
41
SN1 versus E1
• Reactions of 2° and 3° haloalkanes in polar protic solvents give mixtures of substitution and elimination products
CH3
CH3
ICCH3 -I-
CH3 C
CH3 SN1
CH3-Cl-H2O
CH3OH
SN1ClCH3
CH3
CH3C
CH2
CH3
CH3
C
C
CH3
CH3
CH3
CCH3
CH3
CH3
OH
OCH3
H+
H+
H+
E1
+
+
+
+
42
SN2 versus E2
• It is considerably easier to predict the ratio of SN2 to E2 products
leaving groupC
C
RR
H
RRAttack of base on a -hydrogen by E2 is only slightly affected by branching at the -carbon; alkene formation is accelerated
SN2 attack of a nucleophile isimpeded by branching at the- and -carbons
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Summary of S vs E for Haloalkanes
– for methyl and 1°haloalkanes
RCH2X
CH3X
SN1 and E1 reactions of primary halides are never observed.
SN2
SN1 reactions of methyl halides are never observed.The methyl cation is so unstable that it is never formed in solution.
SN2
E2 The main reaction with strong, bulky bases, such as potassium tert-butoxide.
Primary cations are never formed in solution; therefore,
Methyl
Primary
SN1/E1
SN1
The only substitution reactions observed
The main reaction with strong bases such as OH- andEtO-. Also, the main reaction with good nucleophiles/weak bases, such as I- and CH3COO-.
44
Summary of S vs E for Haloalkanes
– for 2° and 3° haloalkanes
The main reaction with strong bases/good nucleophiles
R3CX
such as I- and CH3COO-.R2CHX
Main reaction with strong bases, such as HO- and RO-.
Main reactions with poor nucleophiles/weak bases.
The main reaction with weak bases/good nucleophiles,
E2
SN2
E2
SN2 reactions of tertiary halides are never observed
SN1/ E1
Secondary
Tertiarybecause of the extreme crowding around the 3° carbon.
SN1/ E1 Common in reactions with weak nucleophiles in polarprotic solvents, such as water, methanol, and ethanol.
such as OH- and CH3CH2O-.
SN2
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Summary of S vs E for Haloalkanes
– Examples: predict the major product and the mechanism for each reaction
ClNaOH 80°C
H2O+1.
Br(C2H5)3N
30°CCH2Cl2
+2.
BrCH3O
- Na
+
methanol3. +
Cl
Na+
I-4. + acetone
Elimination, strong base, high temp.
SN2, weak base, good nucleophil
SN1 (+Elimination), strong base, good nucleophil, protic solvent
No reaction, I is a weak base (SN2)I better leaving group than Cl
46
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
47
Carbocation rearrangements in SN + E reactions
Rearrangement
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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)
49
Carbocation rearrangements in Electrophilic addition reactions