Created byProfessor William Tam & Dr. Phillis

Chang Ch. 6 - 1

Chapter 6Nucleophilic

Substitution and Elimination Reactions of

Alkyl Halides

About The AuthorsThese PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.

Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.

Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

Ch. 6 - 2

Ch. 6 - 3

1. Organic Halides

Halogens are more electronegative than carbon

C X

X = Cl, Br, I

Ch. 6 - 4

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 - 5

Chloride

-23.8

13.1

78.4

68

69

51

Group

Me

Et

BusBuiButBu

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 - 6

Chloride

0.92

0.91(15)

0.89

0.87

0.87

0.84

Group

Me

Et

BusBuiButBu

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 (r)

Ch. 6 - 7

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 - 8

Vinyl halides (Alkenyl halides)

Aryl halides

Acetylenic halides (Alkynyl halides)

sp2

X

sp2

X

benzene or aromatic ring

spX

Ch. 6 - 9

C Xsp3

Alkyl halides

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

sp2

X X Xsp2

sp

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

Ch. 6 - 10

Nu + C X

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 - 11

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

mechanism)

RC Br

RR

HO

R

CRR

BrHO

transition state (T.S.)+ Br-

RCHO

RR

Timing of The Bond Breaking & Bond Making Process

Ch. 6 - 12

RC BrRR

RCRR

Br(k1)

Step (1):

+slowr.d.s.

H2O(k3)R

CRR

OH

H RCRR

OH H3O+

Step (3)

+ +

RCRR

H2O(k2) R

CRR

OH

HStep (2)

+

k1 << k2 and k3

fast

fast

●2nd type: SN1 (stepwise mechanism)

Ch. 6 - 13

C X

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 - 14

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 - 15

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 - 16

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 - 17

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 - 18

Time, tConc

entra

tion,

M [CH3Cl] ↓[CH3OH] ↑

Graphically…

Rate =Δ[CH3Cl]

Δt = −[CH3Cl]t=t − [CH3Cl]t=0

Time in seconds

[CH3Cl] ↓[CH3OH] ↑

Ch. 6 - 19

Time, tConc

entra

tion,

M

[CH3Cl]

Initial Rate[CH3Cl]t=0

[CH3Cl]t=t

Initial Rate(from slope)= −

[CH3Cl]t=t − [CH3Cl]t=0

Δt

Ch. 6 - 20

Example:HO + Cl CH3 HO CH3 + Cl60oC

H2O

[OH⊖]t=0 [CH3Cl]t=0

Initial ratemole L-1, s-

1Result

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 - 21

Conclusion:

HO + Cl CH3 HO CH3 + Cl60oCH2O

●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 - 22

The Kinetic Rate Expression

Rate α [OH⊖][CH3Cl]

HO + Cl CH3 HO CH3 + Cl60oCH2O

[OH⊖][CH3Cl]Initial Ratek =

= 4.9 × 10-7 L mol-1 s-1

Rate = k[OH⊖][CH3Cl]

Ch. 6 - 23

HC Br

HH

HO

H

CHH

BrHO

transition state (T.S.)+ Br-

HCHO

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 - 24

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 positive free-energy change (absorbs energy from its surroundings) is said to be endergonic

7. Transition State Theory:Free Energy Diagrams

Ch. 6 - 25

At 60oC (333 K)CH3 Br + OH CH3 OH + Cl

DGo = -100 kJ/mol●This reaction is highly

exergonic

●This reaction is exothermic

DHo = -75 kJ/mol

Ch. 6 - 26

CH3 Br + OH CH3 OH + Cl

●Its equilibrium constant (Keq) isDGo = –RT ln Keq

ln Keq =–DGo

RT= –(–100 kJ/mol)

(0.00831 kJ K-1 mol-1)(333 K)= 36.1

Keq = 5.0 ╳ 1015

Ch. 6 - 27

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

Ch. 6 - 28

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 (DG‡) for the reaction is the difference in energy between the reactants and the transition state

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

Ch. 6 - 29

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

Ch. 6 - 30

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 - 31

The relationship between the rate constant (k) and DG‡ is exponential :

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.

k = k0 e DG‡/RT

e = 2.718, the base of natural logarithmsk0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25oC,k0 = 6.2 ╳ 1012 s1 )

Ch. 6 - 32

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

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.

k = k0 e DG‡/RT

Ch. 6 - 33

HO- + CH3Br

T.S.

CH3OH + Br-Free

Ene

rgy

Reaction Coordinate

DGo

DGDG =

DGo =

free energy of activationfree energy change

Exothermic (DGo is negative) Thermodynamically favorable

process

Free Energy Diagram of SN2 Reactions

Ch. 6 - 34

(R)

(S)

CH3C BrCH2CH3

HHO +

+ BrCH3

CHOCH2CH3

H

(inversion)

Inversion of configuration8.The Stereochemistry of SN2 Reactions

Ch. 6 - 35

CH3 OCH3 + I

Example:

CH3 I + OCH3

Nu⊖ attacks from the TOP face.

(inversion of configuration)

Ch. 6 - 36

+BrCN

Example:

+ CNBr

Nu⊖ attacks from the BACK face.

(inversion ofconfiguration)

Ch. 6 - 37

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 - 38

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 Intermediate

1Intermediate

2Product(slow)

k1 k2 k3(fast) (fast)

k1 << k2 or k3

9A.Multistep Reactions & the Rate-

Determining Step

Ch. 6 - 39

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 - 40

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 - 41

Free Energy Diagram of SN1 ReactionsT.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

DG1

intermediate

Ch. 6 - 42

CH3CCH3CH3

H2O(k2) CH3

CCH3CH3

OH

H

Step (2)

+ fast

Ch. 6 - 43

Free Energy Diagram of SN1 ReactionsT.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

DG1

intermediate

Ch. 6 - 44

H2O(k3)CH3

CCH3CH3

OH

H CH3CCH3CH3

OH

H3O+

Step (3)

+

+

CH3CCH3CH3

H2O(k2) CH3

CCH3CH3

OH

H

Step (2)

+ fast

fast

Ch. 6 - 45

Free Energy Diagram of SN1 ReactionsT.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

DG1

intermediate

Ch. 6 - 46

H2O(k3)CH3

CCH3CH3

OH

H CH3CCH3CH3

OH

H3O+

Step (3)

+

+

CH3CCH3CH3

H2O(k2) CH3

CCH3CH3

OH

H

Step (2)

+

k1 << k2 and k3

fast

fast

Ch. 6 - 47

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

CH3CCH3CH3

Br

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

Ch. 6 - 48

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 Carbocations

11. Carbocations

CH3C

H3C CH3

sp2-sp3 p bond

Ch. 6 - 49

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 of Carbocations

Ch. 6 - 50

Stability of cations

RC

R R

RC

R H

RC

H H

HC

H H> > >

most stable (positive inductive effect)

Resonance stabilization of allylic and benzylic cations

CH2 CH2etc.

Ch. 6 - 51

Ph

BrCH2CH3

CH3

CH3OH

(S)

PhC

CH2CH3CH3(trigonal planar)

CH3OHattack from left

CH3OHattack from right

CH3OHPhCCH3 OCH3

CH2CH3(R) and (S)

racemic mixture

50:50chance

12. The Stereochemistry of SN1 Reactions

Ph

CH3O CH2CH3

CH3

(R)

Ph

OCH3CH2CH3

CH3

(S)(1 : 1)

Ch. 6 - 52

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)+

H2OH2O

racemic mixture

( 1 : 1 )

Ch. 6 - 53

tBuCH3

tBuO

Me

Me H

tBuMe

O HMe

tBuI

Me MeOH

Example:

slowr.d.s. MeOH

MeOH

trigonal planar

tBuOMe

Me tBuMe

OMe+

MeOH

MeOH

Ch. 6 - 54

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 - 55

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 - 56

Relative Rate (towards SN2)

methyl 1o 2o neopentyl

3o

2 106

4 104

500 1 < 1

Most reactiv

e

Least reactiv

e

CH3 Br CH3CH2 Br CH3CH BrCH3

C CH2BrCH3

CH3CH3 C Br

CH3

CH3CH3

R Br HO+ R OH Br+ For example:

Ch. 6 - 57

HC Br

CH3CH3

HC Br

HH

Compare

HO + BrH

CHO

HHfaster

HO + BrH

CHO

CH3CH3

slowerHO

Ch. 6 - 58

+ BrCH3

CHO

CH3CH3

extremelyslow

+ BrH

CHO

CH3

tBuveryslow

HC Br

HtBu

CH3C Br

CH3CH3

HOHO

HOHO

Ch. 6 - 59

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 - 60

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

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

Reactivity of the Substrate in SN1 Reactions

Ch. 6 - 61

Stability of cations

RC

R R

RC

R H

RC

H H

HC

H H> > >

most stable (positive inductive effect)

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

Bran allylic bromide a benzylic iodide

Ch. 6 - 62

Resonance stabilization for allylic and benzylic cations

CH2 CH2etc.

Ch. 6 - 63

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 - 64

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 - 65

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 substraterapid

CH3O + CH3I CH3OCH3 + IGood Nu⊖

VeryslowCH3OH + CH3I CH3OCH3 + I

Poor Nu⊖

Ch. 6 - 66

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 - 67

●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⊖s than HO⊖

HS⊖ > CN⊖ > I⊖ > HO⊖

Ch. 6 - 68

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 - 69

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

ExamplesOSCH3 CH3

OH N

CH3

CH3

OP

Me2N NMe2NMe2 CH3CN

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

Ch. 6 - 70

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

Na DMSO + DMSO Na"naked anion"

CH3O CH3O

Ch. 6 - 71

CH3Br +NaI CH3I +NaBr

Solvent Relative Rate

MeOH 1DMF 106

Tremendous acceleration in SN2 reactions with polar aprotic solvent

Ch. 6 - 72

HNu HHH

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 - 73

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

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

HH

HHH

HOR

OR

ORRO

RO

RO

(strongly solvated)

F- H

H

H

RO

OR

OR(weakly solvated)

I-

Ch. 6 - 74

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 larger than I⊖, the nucleophilicity of F⊖ in this environment is greater than I⊖

Ch. 6 - 75

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 - 76

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

CH3CCH3 ClCH3

slowr.d.s. C Cl

H

H

OR

OR

ORH

CH2CCH3CH3

H3CCH3

CH3

+Cl-

Ch. 6 - 77

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 X slowr.d.s.

C X

C X

C X+

slowr.d.s.

C XNu

Nu:C X+Nu

SN1 Reaction:

SN2 Reaction:

Ch. 6 - 78

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 - 79

NuR OH +R Nu OH

R OHH Nu +R Nu H2O

H

a strong

basic aniona poor

leaving group

weakbase

✔a goodleaving group

Ch. 6 - 80

14. Organic Synthesis: Functional GroupTransformation Using SN2 Reactions

HO

Br

OH

MeOMe

HS

SH

MeS

SMe

CNCN

Ch. 6 - 81

Br

C CMe

Me

MeCOO

O MeO

Me3N

NMe3 Br

N3

N3

II

Ch. 6 - 82

Examples:

Br O??NaOEt, DMSO

I SMe??NaSMe, DMSO

Ch. 6 - 83

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 - 84

Br

I CN(optically active, chiral) (optically active, chiral)

??

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

NaBrDMSO NaCN

DMSO(SN2 withinversion)

(SN2 withinversion)

Ch. 6 - 85

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

14A. The Unreactivity of Vinylic and Phenyl Halides

CX

CX

vinylic halide phenyl halide

Ch. 6 - 86

Examples

I

BrNaCNDMSO

NaSMeHMPA

No Reaction

No Reaction

Ch. 6 - 87

Substitution

15.Elimination Reactions of AlkylHalides

Elimination

C CH

BrBr-C C

H OCH3+(acts as a

Nu )

OCH3

C CHH

BrC C CH3OH Br-(acts as a

base)+ +OCH3

Ch. 6 - 88

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 - 89

15A. Dehydrohalogenation

CH

CX halide as LG

β carbon

β hydrogenα carbon

H

Br tBuOKtBuOH, 60oC + KBr + tBuOHαβ

LG

β hydrogen⊖OtBu

Ch. 6 - 90

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 Ksodium ethoxidepotassium tert-butoxide

e.g.

Ch. 6 - 91

Rate = k[CH3CHBrCH3][EtO⊖]

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

A bimolecular reaction

16.The E2 ReactionBr

HEtO + + EtOH + Br

Ch. 6 - 92

Mechanism for an E2 ReactionEt O

C CBr

H

HH

CH3H

Et O

C CBr

H

HH

CH3H

C C

HH

HCH3

Et OH +Br+

βα

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

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

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

Ch. 6 - 93

CH3CHBrCH3+ EtO-

T.S.

CH2=CHCH3+ EtOH + Br-

Free

Ene

rgy

Reaction Coordinate

Free Energy Diagram of E2 Reaction

DG‡ E2 reaction has ONEtransition state

Second-order overall bimolecular

Rate = k[CH3CHBrCH3][EtO⊖]

Ch. 6 - 94

E1: Unimolecular elimination

C ClCH3

CH3CH3 H2O

slowr.d.s

CCH3

CH3CH3 H2O as

nucleophile

(major (SN1))

C OHCH3

CH3CH3

H2O asbase

+CH2 CCH3

CH3

(minor (E1))

17.The E1 Reaction

Ch. 6 - 95

Mechanism of an E1 Reaction

ClH2O

HH2O

slowr.d.s

.

α carbonβ hydrogen

+ H3O(E1 product)fast

H2Ofast

OH

H H2O OH+H3O

(SN1 product)

Ch. 6 - 96

Free Energy Diagram of E1 ReactionT.S. (1)

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

(CH3)3C+ Cl-

(CH3)3CCl+ H2O

DG1 (CH3)2C=CH2+ H3O + Cl-

Ch. 6 - 97

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 - 98

Free Energy Diagram of E1 ReactionT.S. (1)

Free

Ene

rgy

Reaction Coordinate

T.S. (2)

(CH3)3C+ Cl-

(CH3)3CCl+ H2O

DG1 (CH3)2C=CH2+ H3O + Cl-

Ch. 6 - 99

H3CC

H3CH2O

(k2)

H OH

H

Step (2)

+C H CH2H3C

H3C

+

H

H fastH2O molecule removes one of the b hydrogens which are acidic due to the adjacent positive charge. An e⊖ pair moves in to form a double bond between the b and a carbon atoms

Produces alkene and hydronium ion

Ch. 6 - 100

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 - 101

CNu C X

H

E2(b)

(a)SN2(b)

(a)

CCNu

H + X

C + XC

+Nu H

18A. SN2 vs. E2

Ch. 6 - 102

With a strong base, e.g. EtO⊖

●Favor SN2

Primary Substrate

BrNaOEtEtOH

OEt

+

E2: (10%)

SN2: 90%

Ch. 6 - 103

With a strong base, e.g. EtO⊖

●Favor E2

Secondary Substrate

BrNaOEtEtOH

OEt

+

+E2: 80%

SN2: 20%

Ch. 6 - 104

With a strong base, e.g. EtO⊖

●E2 is highly favored

Tertiary Substrate

Br OEt

NaOEtEtOH +

E2: 91% SN1: 9%

Ch. 6 - 105

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 - 106

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 - 107

Tertiary Halides: SN1 vs. E1 & E2

EtO

Br

OEt+SN1: 0%E2: 100%

(strongbase)

EtOHheat

OEt+SN1: 80%E1 + E2: 20%

Ch. 6 - 108

E2E1SN2SN1CH3XRCH2X

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 - 109

Review ProblemsBr

DMF, 25oCtBu

Na CN(1) CN

tBu

NaHEt2OI O

H(2)

I O

O

H⊖

Intramolecular SN2

SN2 with inversion

Ch. 6 - 110

CltBu

CH3CH3

tBu

Cl

+

( 50 : 50)

OHtBu

HClCH3(3)

CH3

tBu

OtBu

CH3

HH

sp2 hybridizedcarbocation

Cl⊖ attacksfrom top face

Cl⊖ attacksfrom bottomface

SN1 with racemization

Ch. 6 - 111

END OF CHAPTER 6