nucleophilic substitution and elimination reactions of

Chapter 6

Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

Ch. 6 - 1

Ch. 6 - 2

1. Organic Halides

Halogens are more electronegative than carbon

C Xδ+ δ−

X = Cl, Br, I

Ch. 6 - 3

C FH

HH C Cl

H

HH C Br

H

HH C I

H

HH

C–X BondLength (Å) 1.39 1.78 1.93 2.14

C–X BondStrength(kJ/mol)

472 350 293 239

Carbon-Halogen Bond Lengthsand Bond Strength

increase

decrease

Ch. 6 - 4

Chloride

-23.8

13.1

78.4

68

69

51

Group

Me

Et

Bu

sBu

iBu

tBu

Fluoride

-78.4

-37.7

32

-

-

12

Bromide

3.6

38.4

101

91.2

91

73.3

Iodide

42.5

72

130

120

119

100(dec)

1A. Physical Properties of Organic Halides:Boiling Point (bp/oC)

Ch. 6 - 5

Chloride

0.92

0.91(15)

0.89

0.87

0.87

0.84

Group

Me

Et

Bu

sBu

iBu

tBu

Fluoride

0.84(-60)

0.72

0.78

-

-

0.75(12)

Bromide

1.73(0)

1.46

1.27

1.26

1.26

1.22

Iodide

2.28

1.95

1.61

1.60

1.60

1.57(0)

Physical Properties of Organic Halides:Density (ρ)

Ch. 6 - 6

Different Types of Organic Halides Alkyl halides (haloalkanes)

Cl Br Ia 1o chloride a 2o bromide a 3o iodide

Attached to1 carbon atom

C

Attached to2 carbon atoms

C

C

Attached to3 carbon atoms

C

C

C

sp3C X

Ch. 6 - 7

Vinyl halides (Alkenyl halides)

Aryl halides

Acetylenic halides (Alkynyl halides)

sp2

X

sp2

X

benzene or aromatic ring

sp

X

Ch. 6 - 8

C X

sp3

δ+ δ−

Alkyl halides

Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E) (the focus of this Chapter)

sp2

X X X

sp2sp

Different reactivity than alkyl halides, and do not undergo SN or E reactions

Ch. 6 - 9

Nu + C Xδ+ δ− CNu + X

(nucleophile) (substrate) (product) (leavinggroup)

The Nu⊖

donatesan e⊖ pairto thesubstrate

The bondbetweenC and LGbreaks,giving bothe⊖ from thebond to LG

The Nu⊖ usesits e⊖ pair toform a newcovalent bondwith thesubstrate C

The LGgains thepair of e⊖

originallybondedin thesubstrate

2. Nucleophilic Substitution Reactions

Ch. 6 - 10

Two types of mechanisms● 1st type: SN2 (concerted mechanism)

R

C Br

RR

δ+ δ−HO

R

C

RR

BrHOδ− δ−

transition state (T.S.)+ Br-

R

CHO

RR

Timing of The Bond Breaking & Bond Making Process

Ch. 6 - 11

RC BrRR

RCRR

Br(k1)

Step (1):

+slowr.d.s.

H2O(k3)

RCRR

OH

H RCRR

OH H3O+

Step (3)

+ +

RCRR

H2O(k2)

RCRR

OH

HStep (2)

+

k1 << k2 and k3

fast

fast

● 2nd type: SN1 (stepwise mechanism)

Ch. 6 - 12

C Xδ+ δ−

A reagent that seeks a positive center Has an unshared pair of e⊖

e.g.: HO , CH3O , H2N

(negative charge)

H2O, NH3 (neutral)

This is the positivecenter that theNu⊖ seeks

3. Nucleophiles

Ch. 6 - 13

Examples:

HO + CCl

ClH H

CH3(substrate) (product) (L.G.)(Nu )

COH

H H

CH3+

O + CCl

ClH H

CH3(substrate) (L.G.)(Nu )

CO

H H

CH3+

H H H

H

COH

H H

CH3H3O+

(product)

Ch. 6 - 14

To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3

OMs =

OTs = O SO

OCH3

O SO

OCH3

(Tosylate)

(Mesylate)

4. Leaving Groups

Ch. 6 - 15

The rate of the substitution reaction is linearly dependent on the concentration of OH⊖ and CH3Br

Overall, a second-order reaction ⇒bimolecular

HO + CH3 Br HO CH3 +

Rate = k[CH3Br][OH-]

Br

5. Kinetics of a Nucleophilic SubstitutionReaction: An SN2 Reaction

Ch. 6 - 16

The rate of reaction can be measured by● The consumption of the reactants

(HO⊖ or CH3Cl) or● The appearance of the products

(CH3OH or Cl⊖) over time

HO + C Cl HO C +

(Nu )

ClH

H

H

H

H

H

(substrate) (product)(leavinggroup)

e.g.:

5A. How Do We Measure the Rate of This Reaction?

Ch. 6 - 17

Time, t

Conc

entr

atio

n, M [CH3Cl] ↓

[CH3OH] ↑

Graphically…

Rate =Δ[CH3Cl]

Δt= −

[CH3Cl]t=t − [CH3Cl]t=0

Time in seconds

[CH3Cl] ↓[CH3OH] ↑

Ch. 6 - 18

Time, t

Conc

entr

atio

n, M

[CH3Cl]

Initial Rate

[CH3Cl]t=0

[CH3Cl]t=t

Initial Rate(from slope) = −

[CH3Cl]t=t − [CH3Cl]t=0

Δt

Ch. 6 - 19

Example:

HO + Cl CH3 HO CH3 + Cl60oCH2O

[OH⊖]t=0 [CH3Cl]t=0Initial rate

mole L-1, s-1 Result

1.0 M 0.0010 M 4.9 10-7

1.0 M 0.0020 M 9.8 10-7 Doubled

2.0 M 0.0010 M 9.8 10-7 Doubled

2.0 M 0.0020 M 19.6 10-7 Quadrupled

Ch. 6 - 20

Conclusion:


● The rate of reaction is directly proportional to the concentration of either reactant.

● When the concentration of either reactant is doubled, the rate of reaction doubles.

Ch. 6 - 21

The Kinetic Rate Expression

Rate α [OH⊖][CH3Cl]


[OH⊖][CH3Cl]

Initial Ratek =

= 4.9 10-7 L mol-1 s-1

Rate = k[OH⊖][CH3Cl]

Ch. 6 - 22

H

C Br

HH

δ+ δ−HO

H

C

HH

BrHOδ− δ−

transition state (T.S.)+ Br-

H

CHO

HH

negative OH⊖

brings an e⊖pair to δ+ C; δ–

Br begins to move away with an e⊖ pair

O–C bond partially formed; C–Br bond partially broken. Configuration of C begins to invert

O–C bond formed; Br⊖

departed. Configuration of C inverted

6. A Mechanism for the SN2 Reaction

Ch. 6 - 23

A reaction that proceeds with a negative free-energy change (releases energy to its surroundings) is said to be exergonic

A reaction that proceeds with a positivefree-energy change (absorbs energy from its surroundings) is said to be endergonic

7. Transition State Theory:Free Energy Diagrams

Ch. 6 - 24

At 60oC (333 K)

CH3 Br + OH CH3 OH + Cl

∆Go = -100 kJ/mol

● This reaction is highly exergonic

● This reaction is exothermic

∆Ho = -75 kJ/mol

Ch. 6 - 25

CH3 Br + OH CH3 OH + Cl

● Its equilibrium constant (Keq) is

∆Go = –RT ln Keq

ln Keq =–∆Go

RT=

–(–100 kJ/mol)

(0.00831 kJ K-1 mol-1)(333 K)

= 36.1

Keq = 5.0 ╳ 1015

Ch. 6 - 26

A Free Energy Diagram for a Hypothetical SN2Reaction That Takes Place with a Negative ∆Go

Ch. 6 - 27

The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products

The top of the energy curve corresponds to the transition state for the reaction

The free energy of activation (∆G‡) for the reaction is the difference in energy between the reactants and the transition state

The free energy change for the reaction (∆Go) is the difference in energy between the reactants and the products

Ch. 6 - 28

A Free Energy Diagram for a HypotheticalReaction with a Positive Free-Energy Change

Ch. 6 - 29

A 10°C increase in temperature will cause the reaction rate to double for many reactions taking place near room temperature

7A. Temperature, Reaction Rate, and the Equilibrium Constant

Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.

Ch. 6 - 30

The relationship between the rate constant (k) and ∆G‡

is exponential :


k = k0 e−∆G‡/RT

e = 2.718, the base of natural logarithms

k0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25oC,k0 = 6.2 ╳ 1012 s−1 )

Ch. 6 - 31

A reaction with a lower free energy of activation (∆G‡) will occur exponentially faster than a reaction with a higher ∆G‡, as dictated by


k = k0 e−∆G‡/RT

Ch. 6 - 32

HO- + CH3Br

T.S.

CH3OH + Br-

Free

Ene

rgy

Reaction Coordinate

∆Go

∆G∆G =

∆Go =

free energy of activationfree energy change

Exothermic (∆Go is negative) Thermodynamically favorable process

Free Energy Diagram of SN2 Reactions

Ch. 6 - 33

(R)

(S)

CH3

C Br

CH2CH3

HHO +

+ BrCH3

CHO

CH2CH3

H

(inversion)

Inversion of configuration

8.The Stereochemistry of SN2 Reactions

Ch. 6 - 34

CH3 OCH3 + I

Example:

CH3 I + OCH3

Nu⊖ attacks from the TOP face.

(inversion of configuration)

Ch. 6 - 35

+ BrCN

Example:

+ CNBr

Nu⊖ attacks from the BACK face.

(inversion ofconfiguration)

Ch. 6 - 36

CH3C BrCH3CH3

H2OCH3C OHCH3CH3

HBr+ +

9. The Reaction of tert-Butyl Chloridewith Hydroxide Ion: An SN1 Reaction

The rate of SN1 reactions depends only on concentration of the alkyl halide and is independent on concentration of the Nu⊖

Rate = k[RX] In other words, it is a first-order reaction⇒ unimolecular nucleophilic substitution

Ch. 6 - 37

In a multistep reaction, the rate of the overall reaction is the same as the rate of the SLOWEST step, known as the rate-determining step (r.d.s)

For example:

Reactant Intermediate1

Intermediate2

Product(slow)

k1 k2 k3

(fast) (fast)

k1 << k2 or k3

9A. Multistep Reactions & the Rate-Determining Step

Ch. 6 - 38

The opening A is much smaller than openings B and C

The overall rate at which sand reaches to the bottom of the hourglass is limited by the rate at which sand falls through opening A

Opening A is analogous to the rate-determining step of a multistep reaction

A

B

C

Ch. 6 - 39

A multistep process

CH3C BrCH3CH3

CH3CCH3CH3

Br(k1)

Step (1):

+

(ionization of alkyl halide)

slowr.d. step

10. A Mechanism for the SN1 Reaction

Ch. 6 - 40


T.S. (1)

(CH3)3C-OH

+ Br-

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

T.S. (3)

(CH3)3C -OH2

+ Br-

(CH3)3C

+ Br-

(CH3)3CBr

+ H2O

∆G1

intermediate

Ch. 6 - 41

CH3CCH3CH3

H2O(k2)

CH3CCH3CH3

OH

H

Step (2)

+fast

Ch. 6 - 42


T.S. (1)

(CH3)3C-OH

+ Br-

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

T.S. (3)

(CH3)3C -OH2

+ Br-

(CH3)3C

+ Br-

(CH3)3CBr

+ H2O

∆G1

intermediate

Ch. 6 - 43

H2O(k3)

CH3CCH3CH3

OH

H CH3CCH3CH3

OH

H3O+

Step (3)

+

+

CH3CCH3CH3

H2O(k2)

CH3CCH3CH3

OH

H

Step (2)

+fast

fast

Ch. 6 - 44


T.S. (1)

(CH3)3C-OH

+ Br-

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

T.S. (3)

(CH3)3C -OH2

+ Br-

(CH3)3C

+ Br-

(CH3)3CBr

+ H2O

∆G1

intermediate

Ch. 6 - 45

H2O(k3)

CH3CCH3CH3

OH

H CH3CCH3CH3

OH

H3O+

Step (3)

+

+

CH3CCH3CH3

H2O(k2)

CH3CCH3CH3

OH

H

Step (2)

+

k1 << k2 and k3

fast

fast

Ch. 6 - 46

2 intermediates and 3 transition states (T.S.)

CH3

CCH3

CH3

Brδ+ δ−

The most important T.S. for SN1 reactions is T.S. (1) of the rate-determining step (r.d.s.)

Ch. 6 - 47

Carbocations are trigonal planar

The central carbon atom in a carbocation is electron deficient; it has only six e⊖ in its valence shell

The p orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction

11A. The Structure of Carbocations11. Carbocations

CH3C

H3C CH3

sp2-sp3 π bond

Ch. 6 - 48

General order of reactivity (towards SN1 reaction)● 3o > 2o >> 1o > methyl

The more stable the carbocation formed, the faster the SN1 reaction

11B. The Relative Stabilities ofCarbocations

Ch. 6 - 49

Stability of cations

R

CR R

R

CR H

R

CH H

H

CH H

> > >

most stable (positive inductive effect)

Resonance stabilization of allylic and benzylic cations

CH2 CH2etc.

Ch. 6 - 50

Ph

BrCH2CH3

CH3

CH3OH

(S)

Ph

C

CH2CH3CH3

(trigonal planar)

CH3OHattack from left

CH3OHattack from right

CH3OHPh

CCH3 OCH3

CH2CH3(R) and (S)

racemic mixture

50:50chance

12. The Stereochemistry of SN1 Reactions

Ph

CH3OCH2CH3

CH3

(R)

Ph

OCH3CH2CH3

CH3

(S)(1 : 1)

Ch. 6 - 51

Example:

Br

(R) H2O(SN1)

slowr.d.s.

(one enantiomer)

(carbocation)

H2O

attack from TOP face

H2O attack from BOTTOM face

OH H

OH H

OH

(R)

OH

(S)+

H2O

H2O

racemic mixture( 1 : 1 )

Ch. 6 - 52

tBuCH3⊕

⊕

tBu

O

Me

Me H

tBu

Me

O H

Me

tBu

I

Me MeOH

Example:

slowr.d.s.

MeOH

MeOH

trigonal planar

tBu

OMe

Me tBu

Me

OMe+

MeOH

MeOH

Ch. 6 - 53

The structure of the substrate

The concentration and reactivity of the nucleophile (for SN2 reactions only)

The effect of the solvent

The nature of the leaving group

13. Factors Affecting the Rates of SN1 and SN2 Reactions

Ch. 6 - 54

13A. The Effect of the Structure of the Substrate

General order of reactivity (towards SN2 reaction)

● Methyl > 1o > 2o >> 3o > vinyl or aryl

DO NOT undergo

SN2 reactions

Ch. 6 - 55

Relative Rate (towards SN2)

methyl 1o 2o neopentyl 3o

2 × 106 4 × 104 500 1 < 1Most

reactiveLeast

reactive

CH3 Br CH3CH2 Br CH3CH BrCH3

C CH2BrCH3

CH3CH3 C Br

CH3

CH3CH3

R Br HO+ R OH Br+

For example:

Ch. 6 - 56

HC Br

CH3

CH3

δ+ δ−

HC Br

HH

δ+ δ−

Compare

HO + BrH

CHO

HHfaster

HO + BrH

CHO

CH3

CH3slower

HO

Ch. 6 - 57

+ BrCH3

CHO

CH3

CH3extremely

slow

+ BrH

CHO

CH3

tBuveryslow

HC Br

HtBu

δ+ δ−

CH3

C Br

CH3

CH3

δ+ δ−

HOHO

HOHO

Ch. 6 - 58

Note NO SN2 reaction on sp2 or sp carbons

e.g.

H

H

H

I+ Nu No reaction

No reaction+ NuI

I No reaction+ Nu

sp2

sp2

sp

Ch. 6 - 59

General order of reactivity (towards SN1 reaction)● 3o > 2o >> 1o > methyl

The more stable the carbocationformed, the faster the SN1 reaction

Reactivity of the Substrate in SN1 Reactions

Ch. 6 - 60

Stability of cations

R

CR R

R

CR H

R

CH H

H

CH H

> > >

most stable (positive inductive effect)

Allylic halides and benzylic halides also undergo SN1 reactions at reasonable rates I

Br

an allylic bromide a benzylic iodide

Ch. 6 - 61

Resonance stabilization for allylic and benzylic cations

CH2 CH2etc.

Ch. 6 - 62

For SN1 reactionRecall: Rate = k[RX]● The Nu⊖ does NOT participate in

the r.d.s.● Rate of SN1 reactions are NOT

affected by either the concentration or the identity of the Nu⊖

13B. The Effect of the Concentration& Strength of the Nucleophile

Ch. 6 - 63

For SN2 reactionRecall: Rate = k[RX][RX]● The rate of SN2 reactions depends

on both the concentration and the identity of the attacking Nu⊖

Ch. 6 - 64

Identity of the Nu⊖

● The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the relative rate of its SN2 reaction with a given substrate

rapidCH3O + CH3I CH3OCH3 + I

Good Nu⊖

VeryslowCH3OH + CH3I CH3OCH3 + I

Poor Nu⊖

Ch. 6 - 65

The relative strength of a Nu⊖ can be correlated with 3 structural features● A negatively charged Nu⊖ is always a

more reactive Nu⊖ than its conjugated acid e.g. HO⊖ is a better Nu⊖ than H2O

and RO⊖ is better than ROH● In a group of Nu⊖s in which the

nucleophilic atom is the same, nucleophilicities parallel basicities e.g. for O compounds,

RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O

Ch. 6 - 66

● When the nucleophilic atoms are different, then nucleophilicities may not parallel basicities e.g. in protic solvents HS⊖, CN⊖,

and I⊖ are all weaker bases than HO⊖, yet they are stronger Nu⊖sthan HO⊖

HS⊖ > CN⊖ > I⊖ > HO⊖

Ch. 6 - 67

Solvents

Non-polar solvents(e.g. hexane, benzene)

Polar solvents

Polar protic solvents(e.g. H2O, MeOH)

Polar aprotic solvents(e.g. DMSO, HMPA)

Classification of solvents

13C. Solvent Effects on SN2 Reactions:Polar Protic & Aprotic Solvents

Ch. 6 - 68

SN2 Reactions in Polar Aprotic Solvents● The best solvents for SN2 reactions

are Polar aprotic solvents, which

have strong dipoles but do not have OH or NH groups

Examples

OS

CH3 CH3

O

H NCH3

CH3

OP

Me2N NMe2NMe2

CH3CN

(DMSO) (DMF) (HMPA) (Acetonitrile)

Ch. 6 - 69

Polar aprotic solvents tend to solvate metal cations rather than nucleophilic anions, and this results in “naked” anions of the Nu⊖ and makes the e⊖ pair of the Nu⊖ more available

NaDMSO

+ DMSO Na"naked anion"

CH3O CH3O

Ch. 6 - 70

CH3Br + NaI CH3I + NaBr

Solvent Relative Rate

MeOH 1

DMF 106

Tremendous acceleration in SN2 reactions with polar aprotic solvent

Ch. 6 - 71

HNu HH

H

OR

OR

ORRO

SN2 Reactions in Polar Protic Solvents● In polar protic solvents, the Nu⊖

anion is solvated by the surrounding protic solvent which makes the e⊖

pair of the Nu⊖ less available and thus less reactive in SN2 reactions

Ch. 6 - 72

Halide Nucleophilicity in Protic Solvents● I⊖ > Br⊖ > Cl⊖ > F⊖

Thus, I⊖ is a stronger Nu⊖ in proticsolvents, as its e⊖ pair is more available to attack the substrate in the SN2 reaction.

H

H

H

HH

H

OR

OR

ORRO

RO

RO

(strongly solvated)

δ+ δ+

δ+ δ+

δ+ δ+F- H

H

H

RO

OR

OR(weakly solvated)

I-

Ch. 6 - 73

Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO)● F⊖ > Cl⊖ > Br⊖ > I⊖

Polar aprotic solvents do not solvate anions but solvate the cations

The “naked” anions act as the Nu⊖

Since F⊖ is smaller in size and the charge per surface area is largerthan I⊖, the nucleophilicity of F⊖ in this environment is greater than I⊖

Ch. 6 - 74

Solvent plays an important role in SN1 reactions but the reasons are different from those in SN2 reactions

Solvent effects in SN1 reactions are due largely to stabilization or destabilization of the transition state

13D. Solvent Effects on SN1 Reactions:The Ionizing Ability of the Solvent

Ch. 6 - 75

Polar protic solvents stabilize the development of the polar transition state and thus accelerate this rate-determining step (r.d.s.):

CH3

CCH3 ClCH3

slowr.d.s. C Cl

δ+ δ−

H

H

OR

OR

ORH

δ+δ−

δ+

CH2

CCH3

CH3

H3CCH3

CH3

+Cl-

Ch. 6 - 76

13E. The Nature of the Leaving Group

The better a species can stabilize a negative charge, the better the LG in an SN2 reaction

C Xslowr.d.s.

δ−δ+C X

C X

C X+

slowr.d.s.

δ−C XNu

δ−

Nu:

C X+Nu

SN1 Reaction:

SN2 Reaction:

Ch. 6 - 77

CH3O + CH3–X → CH3–OCH3 + X

OH, NH2

, RO

F Cl Br I TsO

~ 0 1 200 10,000 30,000 60,000

Relative Rate:

<< < < < <Worst X⊖ Best X⊖

Note: Normally R–F, R–OH, R–NH2, R–OR’ do not undergo SN2 reactions.

Examples of the reactivity of some X⊖:

Ch. 6 - 78

NuR OH +R Nu OH

R OH

H Nu+R Nu H2O

H

a strongbasic anion

a poorleaving group

weakbase

✔a good

leaving group

Ch. 6 - 79

14. Organic Synthesis: Functional GroupTransformation Using SN2 Reactions

HO

Br

OH

MeO

Me

HS

SH

MeS

SMe

CNCN

Ch. 6 - 80

Br

C CMe

Me

MeCOO

O Me

O

Me3N

NMe3 Br

N3

N3

II

Ch. 6 - 81

Examples:

Br O

??NaOEt, DMSO

I SMe??NaSMe, DMSO

Ch. 6 - 82

Examples:

I CN

(optically active, chiral) (optically active, chiral)

??

● Need SN2 reactions to control stereochemistry

● But SN2 reactions give the inversion of configurations, so how do you get the “retention” of configuration here??

● Solution: “double inversion” ⇒ “retention”

Ch. 6 - 83

Br

I CN

(optically active, chiral) (optically active, chiral)

??

(Note: Br⊖ is a stronger Nu thanI⊖ in polar aprotic solvent.)

NaBrDMSO

NaCNDMSO

(SN2 withinversion)

(SN2 withinversion)

Ch. 6 - 84

Vinylic and phenyl halides are generally unreactive in SN1 or SN2 reactions

14A. The Unreactivity of Vinylic andPhenyl Halides

C

X

CX

vinylic halide phenyl halide

Ch. 6 - 85

Examples

I

BrNaCN

DMSO

NaSMe

HMPA

No Reaction

No Reaction

Ch. 6 - 86

Substitution

15. Elimination Reactions of AlkylHalides

Elimination

C CH

BrBr-C C

H OCH3+(acts as a

Nu )

OCH3

C CH

H

BrC C CH3OH Br-(acts as a

base)

+ +OCH3

Ch. 6 - 87

Substitution reaction (SN) and elimination reaction (E) are processes in competition with each other

tBuOKtBuOH

e.g.

I +OtBu

SN2: 15% E2: 85%

Ch. 6 - 88

15A. Dehydrohalogenation

CH

CX halide as LG

β carbon

β hydrogenα carbon

H

BrtBuOK

tBuOH, 60oC+ KBr + tBuOHαβ

LG

β hydrogen⊖OtBu

Ch. 6 - 89

Conjugate base of alcohols is often used as the base in dehydrohalogenations

15B. Bases Used in Dehydrohalogenation

R−O⊖ + Na⊕ + H2

R−O−HR−O⊖ + Na⊕ + H2

Na

NaH

EtO Na tBuO K

sodium ethoxide potassium tert-butoxide

e.g.

Ch. 6 - 90

Rate = k[CH3CHBrCH3][EtO⊖]

Rate determining step involves both the alkyl halide and the alkoxide anion

A bimolecular reaction

16. The E2 ReactionBr

H

EtO + + EtOH + Br

Ch. 6 - 91

Mechanism for an E2 Reaction

Et O

C CBr

H

HH

CH3H

Et O

C CBr

H

HH

CH3Hδ−

δ−C C

H

H

H

CH3

Et OH + Br

+βα

EtO⊖ removes a β proton; C−H breaks; new π bond forms and Br begins to depart

Partial bonds in the transition state: C−H and C−Br bonds break, new πC−C bond forms

C=C is fully formed and the other products are EtOH and Br⊖

Ch. 6 - 92

CH3CHBrCH3

+ EtO-

T.S.

CH2=CHCH3

+ EtOH + Br-

Free

Ene

rgy

Reaction Coordinate

Free Energy Diagram of E2 Reaction

∆G‡ E2 reaction has ONEtransition state

Second-order overall ⇒ bimolecular

Rate = k[CH3CHBrCH3][EtO⊖]

Ch. 6 - 93

E1: Unimolecular elimination

C ClCH3

CH3

CH3 H2O

slowr.d.s

CCH3

CH3

CH3H2O as

nucleophile

(major (SN1))

C OHCH3

CH3

CH3

H2O asbase

+CH2 CCH3

CH3

(minor (E1))

17. The E1 Reaction

Ch. 6 - 94

Mechanism of an E1 Reaction

ClH2O

HH2O

slowr.d.s.

α carbonβ hydrogen

+ H3O(E1 product)fast

H2Ofast

OH

H H2OOH + H3O

(SN1 product)

Ch. 6 - 95


T.S. (1)

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

(CH3)3C

+ Cl-

(CH3)3CCl

+ H2O

∆G1(CH3)2C=CH2

+ H3O + Cl-

Ch. 6 - 96

CH3C ClCH3CH3

CH3CCH3CH3

Cl(k1)

Step (1):

+H2O

slowr.d. stepAided by the

polar solvent, a chlorine departs with the e⊖ pair that bonded it to the carbon

Produces relatively stable 3o carbocation and a Cl⊖. The ions are solvated (and stabilized) by surrounding H2O molecules

Ch. 6 - 97


T.S. (1)

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

(CH3)3C

+ Cl-

(CH3)3CCl

+ H2O

∆G1(CH3)2C=CH2

+ H3O + Cl-

Ch. 6 - 98

H3C

CH3C

H2O(k2)

H OH

H

Step (2)

+C H CH2H3C

H3C

+

H

Hfast

H2O molecule removes one of the β hydrogens which are acidic due to the adjacent positive charge. An e⊖ pair moves in to form a double bond between the β and αcarbon atoms

Produces alkene and hydronium ion

Ch. 6 - 99

18. How To Determine Whether Substitution or Elimination Is Favoured

All nucleophiles are potential bases and all bases are potential nucleophiles

Substitution reactions are always in competition with elimination reactions

Different factors can affect which type of reaction is favoured

Ch. 6 - 100

CNu

C X

H

E2

(b)

(a)

SN2(b)

(a)

C

CNu

H+ X

C+ X

C+ Nu H

18A. SN2 vs. E2

Ch. 6 - 101

With a strong base, e.g. EtO⊖

● Favor SN2

Primary Substrate

BrNaOEtEtOH

OEt

+

E2: (10%)

SN2: 90%

Ch. 6 - 102


● Favor E2

Secondary Substrate

Br

NaOEtEtOH

OEt

+

+

E2: 80%

SN2: 20%

Ch. 6 - 103


● E2 is highly favored

Tertiary Substrate

Br OEt

NaOEtEtOH

+

E2: 91% SN1: 9%

Ch. 6 - 104

Unhindered “small” base/Nu⊖

Base/Nu⊖: Small vs. Bulky

Hindered “bulky” base/Nu⊖

BrKOtButBuOH

OtBu+

E2: 85%SN2: 15%

BrNaOMeMeOH OMe+

E2: 1%SN2: 99%

Ch. 6 - 105

Basicity vs. Polarizability

Br

O CH3

O

+

OCCH3 O

(weak base)E2: 0%SN2: 100%

EtO(strong base)

OEt+

E2: 80%SN2: 20%

Ch. 6 - 106

Tertiary Halides: SN1 vs. E1 & E2

EtO

Br

OEt+

SN1: 0%E2: 100%(strongbase)

EtOHheat

OEt+

SN1: 80%E1 + E2: 20%

Ch. 6 - 107

E2E1SN2SN1CH3X

RCH2X

RCHXR'

RCXR'

R"

Mostly SN2 withweak bases;e.g. with CH3COO⊖

Very favorablewith weak bases;e.g. with H2O;MeOH

Hindered bases givemostly alkenes;e.g. with tBuO⊖

Mostly

Very little;Solvolysis possible;e.g. with H2O;MeOH

Very littleStrong basespromote E2;e.g. with RO⊖, HO⊖

Strong basespromote E2;e.g. with RO⊖, HO⊖

──

─ Always competeswith SN1

─Very fast ──

19. Overall Summary

Ch. 6 - 108

Review Problems

Br

DMF, 25oCtBu

Na CN(1)CN

tBu

NaHEt2OI O

H(2)

I O

O

H⊖

Intramolecular SN2

SN2 with inversion

Ch. 6 - 109

Cl

tBu

CH3

CH3

tBu

Cl

+

( 50 : 50)

OH

tBu

HClCH3(3)

CH3

tBu

O

tBu

CH3

H

H

sp2 hybridizedcarbocation

Cl⊖ attacksfrom top face

Cl⊖ attacksfrom bottomface

SN1 with racemization

Ch. 6 - 110

END OF CHAPTER 6

nucleophilic substitution and elimination reactions of

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