Chapter 7 Substitution Reactions '13 BW(1)

8/13/2019 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

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7.1. Substitution Reactions

Change of one functional group for another:

Substitution Reactions

Change of one functional group for another:


Leaving groups:


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


2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituent.




2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituent.



















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Mechanisms for Substitution Reactions

1. Concerted process:

2. Stepwise process:


What is wrong?


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


Concerted mechanism

Back-side attack by nucleophile

Transition state

Stereospecic: Inversion of conguration



Transition state




Concerted mechanism


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




Intermediate




Intermediate




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


Transition state


S N1: Stereochemistry

Generation of the carbocation intermediate

Non-stereospecic


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Non-stereospecic: Production of racemic mixture of inversion of conguration +retention of conguration


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


Neutral Nu


Neutral Nu


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 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


In most cases, the rearranged product predominates!


Product Distribution


In most cases, the rearranged product predominates!



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not a good LG


not a good LG

Neutral Nu


not a good LG

Neutral Nu


not a good LG


not a good LG

Neutral Nu


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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












S N1: Summary












S N1: Summary












S N1: Summary






Look at how crowded the electrophilic site is . Look at how stable the resulting carbocation would be.




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 (see p32):steric

S N1 (see p42):carbocation stability


Special Cases:

Allylic and Benzylic Halides

vs.

Vinyl and Aryl Halides


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


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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! A strong nucleophile favors S N2.

! A weak nucleophile disfavors S N2

(and thereby allows S N1 to compete successfully).




! 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: 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 S N1


S N2 S N1

(CH 3CN)


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(azide)

S N2 vs. S N1 ? Four Factors: 4. Solvent Effects Why?

I + Na Cl Cl + Na I

DMSO


I + Na Cl Cl + Na IDMSO



naked Nu: ready to attack



naked Nu: ready to attack

E a

E a


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 ?



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




I > Br > Cl > F

in polar

protic

solvent

: opposite trend

I < Br < Cl < F

in polar

aprotic

solvent


Nucleophilicity


I < Br < Cl < F




I

> Br

> Cl

> F

in polar

protic

solvent

: opposite trend

I < Br < Cl < F

in polar

aprotic

solvent


Nucleophilicity


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


Solvation effect is minimal;

F is free to function as a nucleophile (the strongest Nucleophile)

Nucleophilicity


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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


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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Chapter 7 Substitution Reactions '13 BW(1)