7.1. Substitution Reactions!

Chapter 7. Substitution Reactions! ! "

Junha Jeon !
Department of Chemistry ! University of Texas at Arlington ! Arlington, Texas 76019 ! " ! Chem 2321, Fall 13 !

Change of one functional group for another:!

Substitution Reactions!
Change of one functional group for another:!

Substitution Reactions!
Leaving groups:!

Substitution Reactions!
Leaving groups:!

7.2. Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

polarizability ! The ease of distortion of the electron cloud of a molecular entity (by an electric eld) !

1 !

Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

Alkyl Halides: Nomenclature!

1." 2." 3." 4." ! Leaving groups: Identify and name the parent chain.! Identify the name of the substituents (side groups).! Assign a locant (number) to each substituent.! Assemble the name alphabetically.!

Alkyl Halides: Nomenclature!

2 !

Structure of Alkyl Halides!

Recall? Chapter 6. Rearrangement !

Carbocation stability: depending upon # of alkyl groups attached directly to the carbocation explained by Hyperconjugation" ! ! ! ! ! ! ! !

Structure of Alkyl Halides!

Structure of Alkyl Halides!

7.3 Mechanisms for Substitution Reactions!

Mechanisms for Substitution Reactions!

1. Concerted process:!

! 2. Stepwise process:!

3 !

Mechanisms for Substitution Reactions!

1. Concerted process:!

Mechanisms for Substitution Reactions!

What is wrong?! ! ! ! ! 2. Stepwise process:! ! ! ! ! !

Mechanisms for Substitution Reactions!

7.4 SN2 Mechanism!

What is wrong?! ! ! ! ! ! ! ! ! Kinetics: !

7.4 SN2 Mechanism: Kinetics!

7.4 SN2 Mechanism!

Kinetics: !

Kinetics: !

4 !

SN2: Substitution, Nucleophilic, 2nd order kinetics (bimolecular)!

SN2: Substitution, Nucleophilic, 2nd order kinetics (bimolecular)!

" Concerted mechanism!

" Concerted mechanism!

" Back-side Attack

" Back-side attack by nucleophile! " Transition state! " Stereospecic: Inversion of conguration!

SN2: Substitution, Nucleophilic, 2nd order kinetics (bimolecular)!

SN2: Substitution, Nucleophilic, 2nd order kinetics (bimolecular)!

" Back-side attack by nucleophile! " Transition state! " Stereospecic: Inversion of conguration!

SN2: Substitution, Nucleophilic, 2nd order kinetics (bimolecular)!

Question!

" Concerted mechanism!

" Back-side attack by nucleophile! " Transition state! " Stereospecic: Inversion of conguration (Walden inversion/ Umbrella ip)!

5 !

SN2: Substrate: Sensitive toward Steric Hindrance!

SN2: Substrate: Sensitive toward Steric Hindrance!

SN2: Substrate: Sensitive toward Steric Hindrance!

Substrate: Sensitive toward Steric Hindrance!

Neopentyl Bromide: No SN2 Due to the Steric Hindrance!

Neopentyl Bromide: No SN2 Due to the Steric Hindrance!

Me Me

Me Br

6 !

7.5. SN1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)!

7.5. SN1: 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!

" Stepwise mechanism: Rate = k [electrophile]! " Loss of a leaving group is the slowest step [rate determining step (RDS)]! " Intermediate!

7.5. SN1: Substitution, Nucleophilic, 1st order kinetics (unimolecular)!

7.5. SN1: 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!

" Stepwise mechanism: Rate = k [electrophile]! " Loss of a leaving group is the slowest step [rate determining step (RDS)]! " Intermediate!

SN1: Energy Prole!

Substrate: Stability of the Resulting Carbocation !

Me H H H H

Me Me Me

Me Me

RDS!

vis--vis SN2 (see p32)!

7 !

Substrate: Stability of the Resulting Carbocation !

Substrate: Stability of the Resulting Carbocation Hyperconjugation!

H H H H

Me H H

Me Me Me

Me Me H

H H H

Me H H

Me Me Me

Me Me

Substrate: Stability of the Resulting Carbocation!

Substrate: Stability of the Resulting Carbocation!

Recall SN2 Mechanism!

SN1: Stereochemistry!
Non-stereospecic!

" Concerted mechanism!

" Back-side attack by nucleophile! " Transition state! " Stereospecic: Inversion of conguration!

Generation of the carbocation intermediate!

8 !

SN1: Stereochemistry!
Non-stereospecic: Production of racemic mixture of inversion of conguration + retention of conguration!

SN1: 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: SN2 and SN1!

7.6 The Mechanistic Steps in SN2 and SN1!

Junha~! Back to the white board!

9 !

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

not a good LG! Neutral Nu! Neutral Nu!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

Neutral Nu!

Neutral Nu!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

10 !

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: 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!

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)!

How fast does the rearrangement take place?! ! In most cases, the rearranged product predominates!! ! The C+ rearrangement (intramolecular) vs. the nucleophilic attack (intermolecular)!

11 !

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

not a good LG!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

not a good LG! Neutral Nu!

not a good LG! Neutral Nu!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

not a good LG!

not a good LG! Neutral Nu!

12 !

SN1: Two Core Steps + Three Additional Steps - Detailed Mechanism!

SN1: Two Core Steps + Three Additional Steps Energy Diagram!

not a good LG! Neutral Nu! the rst intermediate!

SN1: Two Core Steps + Three Additional Steps Energy Diagram!

SN1: Two Core Steps + Three Additional Steps Energy Diagram!

SN1: Two Core Steps + Three Additional Steps Energy Diagram!

SN1: Two Core Steps + Three Additional Steps Energy Diagram!

13 !

SN1: 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 SN1 or SN2?! " 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?! " SN1=racemization while SN2=inversion.!

SN1: 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 SN1 or SN2?! " 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?! " SN1=racemization while SN2=inversion.!

SN1: 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 SN1 or SN2?! " 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?! " SN1=racemization while SN2=inversion.!

SN1: 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 SN1 or SN2?! " 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?! " SN1=racemization while SN2=inversion.!

SN1: 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 SN1 or SN2?! " 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?! " SN1 = racemization while SN2 = inversion.!

7.7 SN2: One Core Steps + Two Additional Steps !

14 !

SN2: One Core Steps + Two Additional Steps !

SN2: One Core Steps + Two Additional Steps !

SN2: One Core Steps + Two Additional Steps !

SN2: One Core Steps + Two Additional Steps !

SN2: One Core Steps + Two Additional Steps !

SN2 vs. SN1 ? Four Factors!

1." The substrate! Is a reverse reaction possible? ! i.e. Is this reversible reaction?! 2." The nucleophile (Nu)! 3." The leaving group (LG)! 4." The solvent!

15 !

SN2 vs. SN1 ? Four Factors: 1. The Substrate!

SN2 vs. SN1 ? Four Factors: 1. The Substrate!

SN2 (see p32):!

SN1 (see p42):!

SN2 (see p32): ! steric!

SN1 (see p42): ! carbocation stability!

SN2 vs. SN1 ? Four Factors: 1. The Substrate!

SN2 vs. SN1 ? Four Factors: 1. The Substrate ! Special Cases:"

Special Cases:" " Allylic and Benzylic Halides! vs.! Vinyl and Aryl Halides!

Allylic and Benzylic Halides: Both SN2 vs. SN1! ! ! ! ! Vinyl and Aryl Halides: No SN2 vs. SN1 !

SN2 vs. SN1 ? Four Factors: 1. The Substrate!

SN2 vs. SN1 ? Four Factors: 2. The Nucleophile !

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]! ! ! !

Secondary substrate and allylic/benzylic can react via either mechanism!

16 !

SN2 vs. SN1 ? Four Factors: 2. The Nucleophile !

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]! ! ! ! !" A strong nucleophile favors SN2.!

SN2 vs. SN1 ? Four Factors: 2. The Nucleophile !

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]! ! ! ! !" A strong nucleophile favors SN2.!

!!" A weak nucleophile disfavors SN2 !

(and thereby allows SN1 to compete successfully).! !

!!" A weak nucleophile disfavors SN2 !

(and thereby allows SN1 to compete successfully).! !

What makes a nucleophile strong or weak? ! 1. Stability (induction, resonance, solvation)! 2. Sterics! !

SN2 vs. SN1 ? Four Factors: 2. The Nucleophile!

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]!

SN2 vs. SN1 ? Four Factors: 2. The Nucleophile!

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]!

SN2 vs. SN1 ? Four Factors: 3. The Leaving Group!

SN2 vs. SN1 ? Four Factors: 3. The Leaving Group!

SN2:!
A good! LG!

SN2:!
A good! LG!

SN1:!
An excellent! LG!

SN1:!

RDS!

An excellent" LG!

RDS!

17 !

SN2 vs. SN1 ? Four Factors: 3. The Leaving Group!

SN2 vs. SN1 ? Four Factors: 3. The Leaving Group!

Sulfonate Ions! (cf. H2SO4)!
O S O O Tosylate O H3C S O O Mesylate O F3C S O O Triate

H3C

Making OH a Better Leaving Group in an SN2 Reaction by TsCl !

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

H3C

O S Cl O CH3 O R N (pyridine) R OTs O S O

4-methylbenzene-1-sulfonyl chloride p-tolylsulfonyl chloride tosyl chloride (TsCl) R OH

#+! #-! #+! #-! #+! #-! #+!

#-! #+! #-! #+! #-!

#+! #-!

#-! #+!

#-! #+! #-! #+! #-!

#-! #+! #-! #+! #-! #+! #-!

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

(CH3CN)!

SN1!

SN2!

SN1!

SN2!

18 !

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

(azide)!

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects Why?!

I + Na Cl Cl + Na I

DMSO

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

I + Na Cl Cl + Na I

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

I + Na Cl Cl + Na I

DMSO

DMSO

naked Nu:! ready to attack!

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

I + Na Cl Cl + Na I

SN2 vs. SN1 ? Four Factors: 4. Solvent Effects!

OTf + Na Cl H2O Cl + Na OTf

DMSO

naked Nu:! ready to attack!

Ea! Ea!

19 !

Recall the Hammond Postulate!

The structure of a transition state resembles the structure of the nearest stable species. Transition states for endergonic steps structurally resemble products, and transition states for exergonic steps structurally resemble reactants.!

2. The Nucleophile: Basicity $ Nucleophilicity ?!

SN2: Rate = k [nucleophile][electrophile]! SN1: Rate = k [electrophile]!

2. The Nucleophile: Basicity!

I < Br < Cl < F
!

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??!

Basicity: recall ARIO!

I is the most stable base, which means the weakest base.! Therefore, I would be the weakest anion??!

Nucleophilicity"
I > Br > Cl > F : opposite ! trend " ! ! I < Br < Cl < F : agree with basicity "
!

! !

Nucleophilicity"
!

! !

I > Br > Cl > F : opposite ! trend " ! ! I < Br < Cl < F : agree with basicity "

! solvent! in polar protic

! solvent! in polar protic

in polar aprotic solvent!

in polar aprotic solvent!

2. The Nucleophile: Nucleophilicity Trend!

I I < Br < Cl < F
!

2. The Nucleophile: Nucleophilicity Trend!

Nucleophilicity"
I > Br > Cl > F : opposite trend " Solvation of the small atom such as F is more effective than I ; "
! !

Basicity: recall ARIO!

is the most stable base, which means the weakest base.! Therefore, I would be the weakest anion??!

in polar protic solvent!

Nucleophilicity"
I > Br > Cl > F : opposite ! trend " ! ! I < Br < Cl < F : agree with basicity "
!

! !

F is not available to function as a nucleophile (the weakest Nucleophile)" ! I < Br < Cl < F
!

! solvent! in polar protic

in polar aprotic solvent! : agree with basicity " Solvation effect is minimal; " F is free to function as a nucleophile (the strongest Nucleophile)" "

in polar aprotic solvent!

20 !

2. The Nucleophile: Nucleophilicity Trend!

Nucleophilicity"
I > Br > Cl > F : 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
! !

Nucleophilicity: Another Consideration Polarizability!

The degree of nucleophilicity increases down the periodic table, which" is generally applicable to various nucleophiles. " "

in polar protic solvent!

Polarizability "
" H 2S > H 2O ! ! PH3 > NH3!

in polar aprotic solvent! : agree with basicity " Solvation effect is minimal; " F is free to function as a nucleophile (the strongest Nucleophile)" "

Example!

Example!

Example!

Example!

21 !

Example!

Example!

Substitution Reactions: Synthesizing Various Products!

Summary!

Solvent"

Polar Aprotic ! Substrate!

Polar Protic ! Nuclephile! Electrophile!

22 !