chapter 7 substitution reactions '13 bw(1)
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Chapter 7. Substitution Reactions
Junha Jeon
Department of ChemistryUniversity of Texas at Arlington
Arlington, Texas 76019
Chem 2321, Fall
13
7.1. Substitution Reactions
Change of one functional group for another:
Substitution Reactions
Change of one functional group for another:
Substitution Reactions
Leaving groups:
Substitution Reactions
Leaving groups:
polarizability
The ease of distortion of the electron cloud
of a molecular entity (by an electric eld)
7.2. Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups).
3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
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Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups).
3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups).
3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
Alkyl Halides: Nomenclature
1. Leaving groups: Identify and name the parent chain.
2. Identify the name of the substituents (side groups).
3. Assign a locant (number) to each substituent.
4. Assemble the name alphabetically.
Alkyl Halides: Nomenclature
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Mechanisms for Substitution Reactions
1. Concerted process:
2. Stepwise process:
Mechanisms for Substitution Reactions
What is wrong?
Mechanisms for Substitution Reactions
What is wrong?
7.4 S N2 Mechanism
Kinetics:
7.4 S N2 Mechanism: Kinetics
Kinetics:
7.4 S N2 Mechanism
Kinetics:
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S N2: Substitution, Nucleophilic, 2 nd order kinetics (bimolecular)
Concerted mechanism
Back-side Attack
S N2: Substitution, Nucleophilic, 2 nd order kinetics (bimolecular)
Concerted mechanism
Back-side attack by nucleophile
Transition state
Stereospecic: Inversion of conguration
S N2: Substitution, Nucleophilic, 2 nd order kinetics (bimolecular)
Back-side attack by nucleophile
Transition state
Stereospecic: Inversion of conguration
S N2: Substitution, Nucleophilic, 2 nd order kinetics (bimolecular)
S N2: Substitution, Nucleophilic, 2 nd order kinetics (bimolecular)
Concerted mechanism
Back-side attack by nucleophile
Transition state
Stereospecic: Inversion of conguration (Walden inversion/ Umbrella ip)
Question
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S N2: Substrate: Sensitive toward Steric Hindrance S N2: Substrate: Sensitive toward Steric Hindrance
S N2: Substrate: Sensitive toward Steric Hindrance Substrate: Sensitive toward Steric Hindrance
Neopentyl Bromide: No S N2 Due to the Steric Hindrance
MeBr
Me
Me
Neopentyl Bromide: No S N2 Due to the Steric Hindrance
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7.5. S N1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)
Stepwise mechanism: Rate = k [electrophile]
Loss of a leaving group is the slowest step [rate determining step(RDS)]
Intermediate
7.5. S N1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)
Stepwise mechanism: Rate = k [electrophile]
Loss of a leaving group is the slowest step [rate determining step(RDS)]
Intermediate
7.5. S N1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)
Stepwise mechanism: Rate = k [electrophile]
Loss of a leaving group is the slowest step [rate determining step(RDS)]
Intermediate
7.5. S N1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)
Stepwise mechanism: Rate = k [electrophile]
Loss of a leaving group is the slowest step [rate determining step(RDS)]
Intermediate
S N1: Energy Prole
RDS
Substrate: Stability of the Resulting Carbocation
H H
H
H H
Me
Me Me
Me
H Me
Me
vis--vis S N2 (see p32)
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Substrate: Stability of the Resulting Carbocation
H H
H
H H
Me
Me Me
Me
H Me
Me
Substrate: Stability of the Resulting Carbocation Hyperconjugation
H H
H
H H
Me
Me Me
Me
H Me
Me
Substrate: Stability of the Resulting Carbocation Substrate: Stability of the Resulting Carbocation
Recall S N2 Mechanism
Concerted mechanism
Back-side attack by nucleophile
Transition state
Stereospecic: Inversion of conguration
S N1: Stereochemistry
Generation of the carbocation intermediate
Non-stereospecic
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S N1: Stereochemistry
Non-stereospecic: Production of racemic mixture of inversion of conguration +retention of conguration
S N1: Stereochemistry
Non-stereospecic: Production of racemic mixture of inversion of conguration +retention of conguration
Would a ratio of two products be 50:50?
Formation of an Ion Pair Formation of an Ion Pair
Summary: S N2 and S N1 7.6 The Mechanistic Steps in S N2 and S N1
Junha~ Back to the white board
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S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
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S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism Product Distribution
How fast does the rearrangement take place?
In most cases, the rearranged product predorminates!
The C + rearrangement (intramolecular) vs. the nucleophilic attack (intermolecular)
Product Distribution
How fast does the rearrangement take place?
In most cases, the rearranged product predominates!
The C + rearrangement (intramolecular) vs. the nucleophilic attack (intermolecular)
Product Distribution
How fast does the rearrangement take place?
In most cases, the rearranged product predominates!
The C + rearrangement (intramolecular) vs. the nucleophilic attack (intermolecular)
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S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
Neutral Nu
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
Neutral Nu
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S N1: Two Core Steps + Three Additional Steps - Detailed Mechanism
not a good LG
Neutral Nu
S N1: Two Core Steps + Three Additional Steps Energy Diagram
the rst intermediate
S N1: Two Core Steps + Three Additional Steps Energy Diagram S N1: Two Core Steps + Three Additional Steps Energy Diagram
S N1: Two Core Steps + Three Additional Steps Energy Diagram S N1: Two Core Steps + Three Additional Steps Energy Diagram
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S N1: Summary
Summary of considerations to make:
Will proton transfers be necessary?
Look at the quality of the leaving group.
Look at the stability of the nal product.
Will the mechanism be S N1 or S N2?
Look at how crowded the electrophilic site is .
Look at how stable the resulting carbocation would be.
Are rearrangements likely?
Look for ways to improve the stability of the carbocation.
Will the product have inversion or racemization?
S N1=racemization while S N2=inversion.
S N1: Summary
Summary of considerations to make:
Will proton transfers be necessary?
Look at the quality of the leaving group.
Look at the stability of the nal product.
Will the mechanism be S N1 or S N2?
Look at how crowded the electrophilic site is .
Look at how stable the resulting carbocation would be.
Are rearrangements likely?
Look for ways to improve the stability of the carbocation.
Will the product have inversion or racemization?
S N1=racemization while S N2=inversion.
S N1: Summary
Summary of considerations to make:
Will proton transfers be necessary?
Look at the quality of the leaving group.
Look at the stability of the nal product.
Will the mechanism be S N1 or S N2?
Look at how crowded the electrophilic site is .
Look at how stable the resulting carbocation would be.
Are rearrangements likely?
Look for ways to improve the stability of the carbocation.
Will the product have inversion or racemization?
S N1=racemization while S N2=inversion.
S N1: Summary
Summary of considerations to make:
Will proton transfers be necessary?
Look at the quality of the leaving group.
Look at the stability of the nal product.
Will the mechanism be S N1 or S N2?
Look at how crowded the electrophilic site is .
Look at how stable the resulting carbocation would be.
Are rearrangements likely?
Look for ways to improve the stability of the carbocation.
Will the product have inversion or racemization?
S N1=racemization while S N2=inversion.
S N1: Summary
Summary of considerations to make:
Will proton transfers be necessary?
Look at the quality of the leaving group.
Look at the stability of the nal product.
Will the mechanism be S N1 or S N2?
Look at how crowded the electrophilic site is . Look at how stable the resulting carbocation would be.
Are rearrangements likely?
Look for ways to improve the stability of the carbocation.
Will the product have inversion or racemization?
S N1 = racemization while S N2 = inversion .
7.7 S N2: One Core Steps + Two Additional Steps
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S N2: One Core Steps + Two Additional Steps S N2: One Core Steps + Two Additional Steps
S N2: One Core Steps + Two Additional Steps S N2: One Core Steps + Two Additional Steps
S N2: One Core Steps + Two Additional Steps
Is a reverse reaction possible?i.e. Is this reversible reaction?
S N2 vs. S N1 ? Four Factors
1. The substrate
2. The nucleophile (Nu)
3. The leaving group (LG)
4. The solvent
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S N2 vs. S N1 ? Four Factors: 1. The Substrate
S N2 (see p32): S N1 (see p42):
S N2 vs. S N1 ? Four Factors: 1. The Substrate
S N2 (see p32):steric
S N1 (see p42):carbocation stability
S N2 vs. S N1 ? Four Factors: 1. The Substrate
Special Cases:
Allylic and Benzylic Halides
vs.
Vinyl and Aryl Halides
S N2 vs. S N1 ? Four Factors: 1. The Substrate
Special Cases:
Allylic and Benzylic Halides: Both S N 2 vs. S N 1
Vinyl and Aryl Halides: No S N 2 vs. S N 1
S N2 vs. S N1 ? Four Factors: 1. The Substrate
Secondary substrate and allylic/benzylic can react via either mechanism
S N2 vs. S N1 ? Four Factors: 2. The Nucleophile
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
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S N2 vs. S N1 ? Four Factors: 2. The Nucleophile
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
! A strong nucleophile favors S N2.
! A weak nucleophile disfavors S N2
(and thereby allows S N1 to compete successfully).
S N2 vs. S N1 ? Four Factors: 2. The Nucleophile
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
! A strong nucleophile favors S N2.
! A weak nucleophile disfavors S N2
(and thereby allows S N1 to compete successfully).
What makes a nucleophile strong or weak?
1. Stability (induction, resonance, solvation)
2. Sterics
S N2 vs. S N1 ? Four Factors: 2. The Nucleophile
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
S N2 vs. S N1 ? Four Factors: 2. The Nucleophile
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
S N2 vs. S N1 ? Four Factors: 3. The Leaving Group
RDS
S N2: A good
LG
S N1: An excellent
LG
S N2 vs. S N1 ? Four Factors: 3. The Leaving Group
RDS
S N2: A good
LG
S N1: An excellent
LG
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S N2 vs. S N1 ? Four Factors: 3. The Leaving Group S N2 vs. S N1 ? Four Factors: 3. The Leaving Group
Sulfonate Ions (cf. H2SO 4)
H3C SO
OO
Tosylate
H3C SO
OO
Mesylate
F3C SO
OO
Triate
Making OH a Better Leaving Group in an S N2 Reaction by TsCl
R OH
H3C S ClO
O
N
(pyridine)
4-methylbenzene-1-sulfonyl chloridep- tolylsulfonyl chloride
tosyl chloride (TsCl)
R O S
O
O
CH3
R O Ts
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
# - # -
# - # +
# - # +
# + # -
# - # +
# - # +
# + # -
# - # +
# + # - # - # + # + # -
# - # +
# - # +
# - # +
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
S N2 S N1
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
S N2 S N1
(CH 3CN)
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S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
(azide)
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects Why?
I + Na Cl Cl + Na I
DMSO
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
I + Na Cl Cl + Na IDMSO
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
I + Na Cl Cl + Na IDMSO
naked Nu: ready to attack
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
I + Na Cl Cl + Na IDMSO
naked Nu: ready to attack
E a
E a
S N2 vs. S N1 ? Four Factors: 4. Solvent Effects
OTf + Na ClH 2 O
Cl + Na OTf
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Recall the Hammond Postulate
The structure of a transition state resembles the structure of the nearest stablespecies. Transition states for endergonic steps structurally resemble products,and transition states for exergonic steps structurally resemble reactants.
2. The Nucleophile: Basicity $ Nucleophilicity ?
S N2: Rate = k [nucleophile][electrophile]
S N1: Rate = k [electrophile]
2. The Nucleophile: Basicity
I < Br < Cl < F
Basicity : recall ARIO
I is the most stable base, which means the weakest base .
Therefore, I would be the weakest anion??
I > Br > Cl > F
in polar
protic
solvent
: opposite trend
I < Br < Cl < F
in polar
aprotic
solvent
: agree with basicity
Nucleophilicity
2. The Nucleophile: Nucleophilicity Trend
I < Br < Cl < F
Basicity : recall ARIO
I is the most stable base, which means the weakest base .
Therefore, I would be the weakest anion??
I > Br > Cl > F
in polar
protic
solvent
: opposite trend
I < Br < Cl < F
in polar
aprotic
solvent
: agree with basicity
Nucleophilicity
2. The Nucleophile: Nucleophilicity Trend
I < Br < Cl < F
Basicity : recall ARIO
I is the most stable base, which means the weakest base .
Therefore, I would be the weakest anion??
I
> Br
> Cl
> F
in polar
protic
solvent
: opposite trend
I < Br < Cl < F
in polar
aprotic
solvent
: agree with basicity
Nucleophilicity
2. The Nucleophile: Nucleophilicity Trend
I > Br > Cl > F
in polar
protic
solvent
: opposite trend
Solvation of the small atom such as F is more effective than I ;
F is not available to function as a nucleophile (the weakest Nucleophile)
I < Br < Cl < F
in polar
aprotic
solvent
: agree with basicity
Solvation effect is minimal;
F is free to function as a nucleophile (the strongest Nucleophile)
Nucleophilicity
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2. The Nucleophile: Nucleophilicity Trend
I > Br > Cl > F
in polar
protic
solvent
: opposite trend
Solvation of the small atom such as F is more effective than I ;
F is not available to function as a nucleophile (the weakest Nucleophile)
I < Br < Cl < F
in polar
aprotic
solvent
: agree with basicity
Solvation effect is minimal;
F is free to function as a nucleophile (the strongest Nucleophile)
Nucleophilicity
Nucleophilicity: Another Consideration Polarizability
The degree of nucleophilicity increases down the periodic table, which is generally applicable to various nucleophiles.
Polarizability
H2S > H 2O
PH 3 > NH 3
Example Example
Example Example
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Example Example
Substitution Reactions: Synthesizing Various Products Summary
Polar AproticSolvent Polar Protic
Nuclephile Substrate Electrophile
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