9-1 organic chemistry william h. brown christopher s. foote brent l. iverson william h. brown...

9-9-11

Organic Organic ChemistryChemistry

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

William H. BrownWilliam H. Brown

Christopher S. FooteChristopher S. Foote

Brent L. IversonBrent L. Iverson

9-9-22

Nucleophilic Nucleophilic Substitution and Substitution and -Elimination-Elimination

Chapter 8

Chapter 9Chapter 9

9-9-33

Nucleophilic SubstitutionNucleophilic Substitution

Nucleophilic substitution:Nucleophilic substitution: any reaction in which one nucleophile substitutes for another at a tetravalent carbon

Nucleophile:Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base

nucleophilicsubstitution

Nucleophile

++ C NuC LvNu:- Lv

Leavinggroup

9-9-44

Nucleophilic SubstitutionNucleophilic Substitution

Some nucleophilic substitution reactions

I -

HS -

RO -

HO -

- C N

HC C -

Nu

NH3

HOH

CH3I

CH3SH

CH3OH

CH3OR

CH3O-HH

CH3C N

CH3Br

CH3NH3+

CH3C CH

CH3Nu Br

+an alcohol (after proton transfer)

an alkylammonium ion

an alkyl iodide

a nitrile

an alkyne

::

:

:

:::

:

a thiol (a mercaptan)

an ether

an alcohol

Reaction: + +: :

:

:

:

: :

9-9-55

SolventsSolvents

Protic solvent:Protic solvent: a solvent that is a hydrogen bond donor • the most common protic solvents contain -OH groups

Aprotic solvent:Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor• nowhere in the molecule is there a hydrogen bonded

to an atom of high electronegativity

9-9-66

Dielectric ConstantDielectric Constant

Solvents are classified as polar and nonpolar• the most common measure of solvent polarity is

dielectric constant

Dielectric constant:Dielectric constant: a measure of a solvent’s ability to insulate opposite charges from one another• the greater the value of the dielectric constant of a

solvent, the smaller the interaction between ions of opposite charge dissolved in that solvent

• polar solvent: dielectric constant > 15• nonpolar solvent: dielectric constant < 15

9-9-77

Protic SolventsProtic Solvents

H2OHCOOH

CH3OH

CH3CH2OH

CH3COOH

Solvent Structure

DielectricConstant(25°C)

WaterFormic acid

Methanol

Ethanol

7959

33

24

Acetic acid 6

9-9-88

Aprotic SolventsAprotic Solvents

CH2Cl2CH3CH2OCH2CH3

CH3C N

CH3(CH2)4CH3

(CH3)2S=O

(CH3)2NCHO

(CH3)2C=O

C6H5CH3 2.3Toluene

4.3Diethyl ether

9.1Dichloromethane

SolventDielectricConstantStructure

Dimethyl sulfoxide (DMSO)

Acetonitrile

Acetone

N,N-Dimethylformamide (DMF)

48.9

37.5

36.7

20.7

Polar

Nonpolar

Hexane 1.9

9-9-99

MechanismsMechanisms

Chemists propose two limiting mechanisms for nucleophilic substitution• 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 SN2• S = substitution• N = nucleophilic• 2 = bimolecular (two species are involved in the rate-

determining step)

9-9-1010

Mechanism - SMechanism - SNN22

• both reactants are involved in the transition state of the rate-determining step

C Br

H

HH

HO:- + C

H

H H

HO Brδ- δ-

Transition state with simultaneous bond breaking and bond forming

C

H

HH

HO + Br::

: :::

::

::

::: : ::

9-9-1111


9-9-1212


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)

9-9-1313


• Step 1: ionization of the C-X bond gives a carbocation intermediate

C

CH3

CH3H3C

+C

H3C

H3CBr

H3C

slow, ratedetermining

A carbocation intermediate; its shape is trigonal planar

+ Br

9-9-1414


• Step 2: reaction of the carbocation (an electrophile) with methanol (a nucleophile) gives an oxonium ion

• Step 3: proton transfer completes the reaction

C

CH3

CH3H3C

OCH3

H

C

CH3

CH3

O

H3C

H CH3

C

H3C

H3C

O

H3CH

CH3

+

Electrophile Nucleophile

fast

Oxonium ions

+ + ::

: :

:+

+++ fastC

H3CH3C

OH3C

OCH3

HOHO

CH3CH3

H

H

CH3

H3C

CH3C

H3C

:: : ::

9-9-1515


9-9-1616

Evidence of SEvidence of SNN reactions reactions

1. What is relationship between the rate of an SN reaction and: • the structure of Nu?• the structure of RLv?• the structure of the leaving group?• the solvent?

2. What is the stereochemical outcome if the leaving group is displaced from a chiral center?

3. Under what conditions are skeletal rearrangements observed?

9-9-1717

KineticsKinetics

For an SN1 reaction• reaction occurs in two steps• the reaction leading to formation transition state for

the carbocation intermediate involves only the haloalkane and not the nucleophile

• the result is a first-order reaction

CH3CBrCH3

CH3

CH3OH

d[(CH3)3CBr]dt

Rate = - = k[(CH3)3CBr]

CH3COCH3

CH3

CH3

HBr+ +

2-Bromo-2-methylpropane

Methanol 2-Methoxy-2-methylpropane

9-9-1818

KineticsKinetics

For an SN2 reaction, • reaction occurs in one step• the reaction leading to the transition state involves the

haloalkane and the nucleophile• the result is a second-order reaction; first order in

haloalkane and first order in nucleophile

d[CH3Br]

dtrate = = k[CH3Br][OH-]

CH3Br + Na+OH- CH3OH + Na+Br-

Bromomethane Methanol

9-9-1919

NucleophilicityNucleophilicity

Nucleophilicity:Nucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions

Basicity:Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction

Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity

9-9-2020


Good

Poor

Br-, I-

HO-, CH3O-, RO-CH3S

-, RS-

CH3COO-, RCOO-

H2OCH3OH, ROHCH3COOH, RCOOH

NH3, RNH2, R2NH, R3NCH3SH, RSH, R2S

Nucleophile

Moderate

CN-, N3-

Effectiveness

Cl-, F-

9-9-2121


Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents

How do we account for these differences?

Increasing Nucleophilicity

Solvent

Polar aprotic

Polar protic F- < Cl- < Br- < I-

I- < Br- < Cl- < F-

9-9-2222


A guiding principle is the freer the nucleophile, the greater its nucleophilicity

Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF) • are very effective in solvating cations, but not nearly

so effective in solvating anions. • because anions are only poorly solvated, they

participate readily in SN reactions, and

• nucleophilicity parallels basicity: F- > Cl- > Br- > I-

9-9-2323


Polar protic solvents (e.g., water, methanol)• anions are highly solvated by hydrogen bonding with

the solvent• the more concentrated the negative charge of the

anion, the more tightly it is held in a solvent shell• the nucleophile must be at least partially removed

from its solvent shell to participate in SN reactions

• because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F-

9-9-2424


Generalization• within a row of the Periodic Table, nucleophilicity

increases from left to right; that is, it increases with basicity

Increasing NucleophilicityPeriod

Period 2

Period 3

F- < OH- < NH2- < CH3

-

Cl- < SH- < PH2-

9-9-2525


Generalization• in a series of reagents with the same nucleophilic

atom, anionic reagents are stronger nucleophiles than neutral reagents; this trend parallels the basicity of the nucleophile


ROH < RO-H2O < OH-

NH3 < NH2-

RSH < RS-

9-9-2626


Generalization• when comparing groups of reagents in which the

nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity

Nucleophile RCOO-

HO-

RO-

Conjugate acid

pKa

RCOOH4-5

ROHHOH

16-1815.7

Hydroxide ion

Alkoxide ion

Carboxylate ion

Increasing Acidity


9-9-2727

StereochemistryStereochemistry

For an SN1 reaction at a chiral center, the R and S enantiomers are formed in equal amounts, and the product is a racemic mixture

C

H

Cl

Cl

-Cl-

C+

H

Cl

CH3OH

-H+ CH3O C

H

Cl Cl

C OCH3

H

R EnantiomerS Enantiomer

+

R EnantiomerA racemic mixture

Planar carbocation (achiral)

9-9-2828


For SN1 reactions at a chiral center• examples of complete racemization have been

observed, but• partial racemization with a slight excess of inversion is

more common

Approach of the nucleophile from this side is less hindered

+

R1

C

HR2

Cl-

Approach of the nucleophile fromthis side is partially blocked by leaving group, which remains associated with the carbocation as anion pair

9-9-2929


For SN2 reactions at a chiral center, there is inversion of configuration at the chiral center

Experiment of Hughes and Ingold

Iacetone

SN2-131+

I I131

I-+

2-Iodooctane

9-9-3030

Hughes-Ingold ExptHughes-Ingold Expt

• the reaction is 2nd order, therefore, SN2

• the rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131

I:- CH

I

C6H13

H3CH

CH3

C6H13

I C ISN2

acetone+131 131

+

(S)-2-I odooctane (R)-2-Iodooctane

9-9-3131

Structure of RXStructure of RX

SN1 reactions: governed by electronic factors • the relative stabilities of carbocation intermediates

SN2 reactions: governed by steric factors • the relative ease of approach of a nucleophile to the

reaction siteGoverned byelectronic factors

Governed bysteric factors

SN1

SN2

R3CX R2CHX RCH2X CH3X

Access to the site of reaction

(3°) (methyl)(2°) (1°)

Carbocation stability

9-9-3232

Effect of Effect of -Branching-Branching

1.2 x 10-51.2 x 10-3Relative Rate

Alkyl Bromide

-Branches 0 1 2 3

1.0 4.1 x 10-1

Br Br Br Br

9-9-3333

Effect of Effect of -Branching-Branching

CH3CH2Br

freeaccess

Bromoethane(Ethyl bromide)

CH3CCH2Br

CH3

CH3

1-Bromo-2,2-dimethylpropane(Neopentyl bromide)

blockedaccess

9-9-3434

Allylic HalidesAllylic Halides

Allylic cations are stabilized by resonance delocalization of the positive charge• a 1° allylic cation is about as stable as a 2° alkyl cation

+ +

Allyl cation(a hybrid of two equivalent contributing

structures)

CH2=CH-CH2 CH2-CH=CH2

9-9-3535

Allylic CationsAllylic Cations

• 2° & 3° allylic cations are even more stable

• as also are benzylic cations

• adding these carbocations to those from Section 6.3

C6H5-CH2+CH2

+

Benzyl cation(a benzylic carbocation)

The benzyl cation is also writtenin this abbreviated form

CH2=CH-CH-CH3

CH3

CH2=CH-C-CH3

++

A 2° allylic carbocation A 3° allylic carbocation

Increasing stability of carbocations

2° alkyl1° allylic1° benzylic

methyl < 1° alkyl < < 3° alkyl2° allylic2° benzylic

<3° allylic3° benzylic

9-9-3636

The Leaving GroupThe Leaving Group

The more stable the anion, the better the leaving ability• the most stable anions are the conjugate bases of

strong acids

I- > Br- > Cl- > H2O >> F- > CH3CO- > HO- > CH3O- > NH2-

Reactivity as a leaving group

Stability of anion; strength of conjugate acid

rarely function as leaving groups

O

9-9-3737

The Solvent - SThe Solvent - SNN22

The most common type of SN2 reaction involves a negative Nu and a negative leaving group

• the weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of SN2

+ +

Transition state

negatively chargednucleophile

negatively chargedleaving group

negative charge dispersed in the transition state

LvC LvCNu CNuNu:-δ−δ−

Lv

9-9-3838


Br N3-

CH3C N

CH3OHH2O

(CH3 )2S=O

(CH3 )2NCHO

N3 Br-

SolventType

polar aprotic

polar protic

5000

2800

1300

71

k(methanol)

k(solvent)

Solvent

+solvent

SN2+

9-9-3939


SN1 reactions involve creation and separation of unlike charge in the transition state of the rate-determining step

Rate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cation

Polar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions

9-9-4040


water

80% water: 20% ethanol

40% water: 60% ethanolethanol

Solvent

solvolysis++

k(solvent)

k(ethanol)

1

100

14,000

100,000

CH3

CH3 CH3

CH3

CH3CCl ROH CH3COR HCl

9-9-4141

Rearrangements in SRearrangements in SNN11

Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one

2-Methoxy-2-phenylbutane2-Chloro-3-phenylbutane

++ CH3OH + Cl -

CH3OHCH3OH

HCl

OCH3

+

9-9-4242

Rearrangements in SRearrangements in SNN11

Mechanism of a carbocation rearrangement

Cl

H

O-CH3

H

H

O

H

CH3

Cl+

+

A 2° carbocation

++

A 3° benzylic carbocation

+++

An oxonium ion

:

:

(1)

(2)

(3)

9-9-4343

Summary of SSummary of SNN1 & S1 & SNN22

CH3X

RCH2X

R2CHX

R3CX

Type of Alkyl Halide

Methyl

Primary

Secondary

Tertiary

SN2 SN1

Substitution at a stereocenter

SN2 is favored. SN1 does not occur. The methyl cationis so unstable, it is never observedin solution.

SN1 rarely occurs. Primary cations are so unstable, that they are never observed in solution.

SN1 is favored in protic solvents withpoor nucleophiles. Carbocation rearrangements may occur.

SN2 is favored in aproticsolvents with goodnucleophiles.

SN2 does not occur becauseof steric hindrance aroundthe reaction 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 is favored. The carbocationintermediate is planar, and attack of thenucleophile occurs with equalprobability from either side. There is often some net inversion of configuration.

SN2 is favored.

9-9-4444

SSNN1/S1/SNN2 Problems2 Problems

• Problem 1:Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product

• Problem 2:Problem 2: predict the mechanism of this reaction

+ +Na+CN- Na+Br -DMSOBr CN

Cl

CH3OH/ H2O

OH OCH3

HCl+(R)-2-Chlorobutane

+ +

9-9-4545


• Problem 3:Problem 3: predict the mechanism of this reaction and the configuration of product

• Problem 4:Problem 4: predict the mechanism of this reaction and the configuration of the product

Br

CH3S-Na+

SCH3

Na+Br-+ +acetone(R)-2- Bromobutane

Br CH3COH

O

OCCH3

O

HBr+ acetic acid +

(R)-3-Bromo-cyclohexene

9-9-4646


• Problem 5:Problem 5: predict the mechanism of this reaction

++

toluene(CH3 )3P P(CH3)3 Br-Br

9-9-4747

-Elimination-Elimination

-Elimination:-Elimination: a reaction in which a molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons

C C

X

H

CH3CH2O-Na+

C C

CH3CH2OH

CH3CH2OH Na+X -

α+

+ +

A haloalkane Base

An alkene

9-9-4848


Zaitsev rule:Zaitsev rule: the major product of a -elimination is the more stable (the more highly substituted) alkene

2-Methyl-2-butene (major product)

CH3CH2O-Na+

CH3CH2OH 2-Bromo-2-methylbutane

2-Methyl-1-butene

Br+

+

1-Methyl-cyclopentene

(major product)

CH3O-Na+

CH3OH

1-Bromo-1-methyl-cyclopentane

Br

Methylene-cyclopentane

9-9-4949


There are two limiting mechanisms for -elimination reactions

E1 mechanism:E1 mechanism: at one extreme, breaking of the R-Lv bond to give a carbocation is complete before reaction with base to break the C-H bond• only R-Lv is involved in the rate-determining step

E2 mechanism:E2 mechanism: at the other extreme, breaking of the R-Lv and C-H bonds is concerted• both R-Lv and base are involved in the rate-determining step

9-9-5050

E1 MechanismE1 Mechanism

• ionization of C-Lv gives a carbocation intermediate

• proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene

CH3-C-CH3

Br

CH3

CH3-C-CH3

CH3

Br


+(A carbocation intermediate)

+

O:

H

H3CH-CH2-C-CH3

CH3

O

H

H3CH CH2=C-CH3

CH3fast

+

++ +

9-9-5151


9-9-5252


9-9-5353

Kinetics of E1 and E2Kinetics of E1 and E2

E1 mechanism • reaction occurs in two steps• the rate-determining step is carbocation formation• the reaction is 1st order in RLv and zero order is base

E2 mechanism• reaction occurs in one step• reaction is 2nd order; first order in RLv and 1st order

in based[RLv]

dtRate = = k[RLv][Base]

d[RLv]

dtRate = = k[RLv]

9-9-5454

Regioselectivity of E1/E2Regioselectivity of E1/E2

E1: major product is the more stable alkene E2: with strong base, the major product is the

more stable (more substituted) alkene• double bond character is highly developed in the

transition state• thus, the transition state of lowest energy is that

leading to the most stable (the most highly substituted) alkene

E2: with a strong, sterically hindered base such as tert-butoxide, the major product is often the less stable (less substituted) alkene

9-9-5555

Stereoselectivity of E2Stereoselectivity of E2

E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar

CH3O:-

C C

H

Lv

CH3OH

C C

Lv-H and -Lv are anti and coplanar

(dihedral angle 180°)

9-9-5656

Stereochemistry of E2Stereochemistry of E2

Consider E2 of these stereoisomers

Cl

CH3O-Na+

CH3OH

CH3O-Na+

CH3OHCl

+

(R)-3-Isopropyl-cyclohexene

1-Isopropyl-cyclohexene

(major product)

cis-1-Chloro-2-isopropyl-

cyclohexane

trans-1-Chloro-2-isopropyl-

cyclohexane


9-9-5757


• in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial

CH3O:-

H

H

H

H

Cl

CH3OH :Cl

1-Isopropyl-cyclohexene

2

1

6 + +E2

9-9-5858


• in the more stable chair of the trans isomer, there is no H anti and coplanar with Lv, but there is one in the less stable chair

More stable chair (no H is anti and coplanar to Cl)

Less stable chair(H on carbon 6 is

anti and coplanar to Cl)

2

2

11

6 6Cl

H

H

H

H

Cl

HH

HH

9-9-5959


• it is only the less stable chair conformation of this isomer that can undergo an E2 reaction

H

Cl

HH

HCH3O:

-

CH3OH Cl


21

6E2

+ +

9-9-6060


Problem:Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E alkene

C6H5CH-CHC6H5

Br BrCH3O- Na+

CH3OH

C C

Br H

C6H5C6H5

meso-1,2-Dibromo-1,2-diphenylethane

(E)-1-Bromo-1,2-diphenylethylene

9-9-6161

Summary of E2 vs E1Summary of E2 vs E1

RCH2X

R2CHX

R3CX

Alkyl halide E1 E2

Primary

Secondary

Tertiary

E1 does not occur.Primary carbocations areso unstable, they are neverobserved in solution.

E2 is favored.

Main reaction with strong bases such as OH- and OR-.

Main reaction with weak bases such as H2O, ROH.

Main reaction with strong bases such as OH- and OR-.

Main reaction with weak bases such as H2O, ROH.

9-9-6262

SSNN vs E vs E

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

-elimination

C CH Lv + Nu-

C CH Nu +

C C H-Nu+ +

Lv

Lv

9-9-6363

SSNN vs E vs E

CH3X

RCH2X bases such as I- and CH3COO-.

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 observeded in solution and,therefore, SN1 and E1 reactions of primary halides are never observed.

Halide Reaction Comments

Methyl

Primary The main reaction with good nucleophiles/weak

9-9-6464

SSNN vs E (cont’d) vs E (cont’d)

The main reaction with bases/nucleophiles where the

R3CX

pKa of the conjugate acid is 11 or less, as for exampleI- and CH3COO-.

R2CHX

Main reaction with strong bases such as HO- and RO-.

Main reactions with poor nucleophiles/weak bases.

The main reaction with bases/nucleophiles where

E2

SN2

E2

SN2 reactions of tertiary halides are never observed

SN1/E1

Secondary

Tertiary

because of the extreme crowding around the 3° carbon.

SN1/E1Common in reactions with weak nucleophiles in polarprotic solvents, such as water, methanol, and ethanol.

pKa of the conjugate acid is 11 or greater, as for exampleOH- and CH3CH2O

-.

9-9-6565

Neighboring GroupsNeighboring Groups

In an SN2 reaction, departure of the leaving group is assisted by Nu; in an SN1 reaction, it is not

These two types of reactions are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st order

But some substitution reactions are 1st order and yet involve two successive SN2 reactions

9-9-6666

Mustard GasesMustard Gases

Mustard gases • contain either S-C-C-X or N-C-C-X

• what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile

ClS

Cl 2H2O HOS

OH 2HCl+ +

Bis(2-chloroethyl)sulfide(a sulfur mustard gas)

Bis(2-chloroethyl)methylamine(a nitrogen mustard gas)

ClS

Cl ClN

Cl

9-9-6767

Mustard GasesMustard Gases

• the reason is neighboring group participation by the adjacent heteroatom

• proton transfer to solvent completes the reaction

ClS

Cl

ClS O-H

H

ClS

ClS

O

H

H

Cl+

+

A cyclic sulfonium ion

an internal SN2 reaction


++

a secondSN2 reaction

fast+

:

:

:

9-9-6868

Phase-Transfer CatalysisPhase-Transfer Catalysis

A substance that transfers ions from an aqueous phase to an organic phase

An effective phase-transfer catalyst must have sufficient• hydrophilic character to dissolve in water and form an

ion pair with the ion to be transported• hydrophobic character to dissolve in the organic

phase and transport the ion into it

The following salt is an effective phase-transfer catalysts for the transport of anions

(CH3CH2CH2CH2)4N+Cl-

Tetrabutylammonium chloride(Bu4N

+Cl- )

9-9-6969

Phase-Transfer CatalysisPhase-Transfer Catalysis

9-9-7070

Nucleophilic Substitution Nucleophilic Substitution and and


End Chapter 9End Chapter 9

9-1 organic chemistry william h. brown christopher s. foote brent l. iverson william h. brown...

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