chapter 9 nucleophilic substitution & -elimination

9-1Chapter 9 Nucleophilic Substitution & -Elimination

1. Nucleophilic Aliphatic Substitution 2. Solvents for Nucleophilic Substitution Reactions3. Mechanisms of Nucleophilic aliphatic substitution4. Evidence of Sn1 / Sn2 Mechanisms5. Analysis of some Nucleophilic Substitution Rx’s

IC

H

H3C DNC

CH

H3CD

(-):CN:

(-)I

6. -Elimination7. -Elimination mechanism8. Evidence for E1 and E29. Substitution vs Elimination

C

CBr

H R

CH2

CH R Br

+tBu

OHH

H

tBuO H

+ +

9-2substitution

-elimination

rxs can compete leads to by-products (additional products)

C C HC

H3C

HHNa(+) (-)Br+

Br

C C HC

H3C

Br HH

Na

+

H

H C C H+ C C HH+ Na(+) (-)Br+

4

9-3

Product(s)

Leaving group - stable with pair of e’ss, weak B:

9 Nucleophilic Substitution

Nu: + R3C-X R3C-Nu + X:(-)

conditions

Reactions with Lewis :Bases / :Nucleophiles

Conditions - solvent, temperature, etc

H-OR C C H3N,, [e- rich]

9-4

Nucleophilic SubstitutionNucleophilic Substitution(see Table 9.1 for more examples)

Rx:

H OH3C Br

H-O CH3 alcohol

H3C X Nu CH3Nu: + + :X:

H3C BretherO CH3H3C OH3C

N CH3C Br

C CH3 nitrileN

C CH3C Br

C CH3 acetyleneCH H (Chap 7)

4

9-5

Nucleophilic SubstitutionNucleophilic Substitutionexamples Table 9.1 continued

H SH3C Br

H-S CH3 thiol (mercaptan)

O

CO

CH2

CH3

C

H

Br

H

H+O

CO

CH2

CH3

C

H

H

H

ester

N

H

C

H

CH3

Br

+

H

C

H

H3C

N NNN Nazide

2

9-6

OCH2

C

CH3

C

H

I

H

H

+ C

H H

HH3C

H H

OCH2

C

CH3

H3C

H

H

OHCHIHH+ CHHHH OHH

OHCHIHH+ CHHHH OHH

OHCHIHH+ CHHHHOHH

OHCHIHH+ CHHHHOHH

H

OH

HC

H

H

I

+H

CH

H

OH

H

H

NH

HC

H

CH3

I

+H

CH

H3C

NH

H

H

H

Nucleophilic SubstitutionNucleophilic Substitutionexamples Table 9.1 continued

amine

alcohol

ether

(after -H+)

6

9-7

APROTIC

2. Solvents2. Solvents

PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

9-8

APROTIC PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

DMSO 48.9acetonitrile 37.5DMF 36.7acetone 20.7

dichloromethane 9.1

diethyl ether 4.3toluene 2.3hexane 1.9

2. Solvents of reaction (rx)2. Solvents of reaction (rx)

9-9

water 79formic acid 59methanol 33ethanol 24

acetic acid 6.2

APROTIC

2. Solvents2. Solvents

PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

9-10

3. Substitution Mechanisms3. Substitution Mechanisms

Difference: timing of bond-breaking and making

One simultaneous breaking & making; [SN2]

Other, break then make bonds stepwise; [SN1]

2 limiting mechanisms for substitution

(SN2, SN1)

5

9-11

CHO Br

HH

H

t.s. simultaneous bond breaking and making

C

H

H

H+H-O Br

Mechanism - SMechanism - SNN22

C

H

H

HBr+H-O

sp2

C

3

9-12

CH3CH2C

CH3

H3CBr

+ Na I

polarsolvent

CH3CH2C

CH3

H3CI

BrNa

+

C

CH2

CH3

H3C

Br+

CH3

+ other products[important!]

Mechanism - SMechanism - SNN11

4

9-13

SSNN reactions reactions

Reactant structure have on mechanism/rate?

Structure of Nu: have on mechanism/rate?

Leaving group have on rate?

What effect does the:

What is: The stereochemical course of SN reaction?

The role of the solvent?

When or why: Does rearrangement occur?

5

9-14

Kinetics/NucleophilicityKinetics/Nucleophilicity

:Nucleophilicity - kinetic, speed of rxn.

timeNu: C X

H

HHCNu

H

HH+ X(-)

+

-

Nu: or B: H B-H+

:Basicity - equilibrium

Nucleophiles are also bases

:Nucleophilicity and :Basicity have correlations

4

9-15

Reaction rate depends on [RX] unimolecular rx

rate = k[(CH3)3CBr]

k - rate constant

1st order kinetics / stepwise

CH3CH2C

CH3

H3CBr

+ Na I

polarsolvent

CH3CH2C

CH3

H3CI

BrNa

+

C

CH2

CH3

H3C

Br+

CH3

Kinetics - SKinetics - SNN11

4

9-16

both reactants in rate limiting step bimolecular reaction

rate = k[ CH3Br ][ -OH ] 2nd order kinetics

CHO Br

HH

H

C

H

H

H+H-O Br

kinetics - Skinetics - SNN22

C

H

H

HBr+H-O

9-17rx profile:

t.s.1

t.s.2

SM products

prog of rx

H

R+

SN1

E

t.s.

SM products

prog of rx

H

C

CH3

CH3

H3CC

H

H

H

Br

OH

SN2

2

9-18substitution SN1 or SN2?

Br CNa+ + Na+ -BrN::C N: polarsolv.

:C N:Br

OR

:C N:Br

2

9-19SSNN1 or S1 or SNN2 with a 22 with a 2oo RX is RX is on nucleophile on nucleophile

nu

cleo

pil

icit

y

moderate

strong

weak

H3CSH, RSH, R2SH3N, RNH2,R2NH, R3N

H3CC OO-

RC OO-,

Cl-, F-

H2OH3COH, ROH

H3CC OOH

RC OOH

,

Br-, I-

H3CS-, RS-

HO-, H3CO-, RO-, [H2N-,(CH3)3C-O-

R C C-, R-]N C-, N3

-

strongbases

9-20

:C N:Br

substitution SN1 or SN2?

Br CNa+ + Na+ -BrN::C N: polarsolv.

:C N:Br

OR

√

9-21

APROTIC

2. Solvents2. Solvents

PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

E+ -Nu E+ -Nupolar

3

9-22

Solvents effects on Nu:Solvents effects on Nu:--

Protic AproticThe greater the the solvent’s dielectric

constant, the better ions of opposite charge are separated.

Polar and Nonpolar Solvents

E+ -Nu E+ -Nupolar

2

9-23

POLAR APROTIC solvents effective in solvating cations

but poorly solvate anions, e.g.:

Solvents effects on Nu:Solvents effects on Nu:--

The freer the Nucleophile’s e(-)s

the greater its Nucleophilicity

2

9-24

SO

SO

APROTIC solvents solvate cations

F-

Na+

Na+S O

SO

Na+

S

O

S

O

S O SO

SO

SO

SO

SO

F- “free” of Na+

3

9-25

APROTIC PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

DMSO 48.9acetonitrile 37.5DMF 36.7acetone 20.7

solvents of Ssolvents of SNN2 rx2 rx

9-26PROTIC solvents solvate cations & anions

e.g. CH3OH

F-

Na+H

OH3C

H O CH3F-

Na+H

OH3C

HO

H3C

HO

CH3

H O CH3HOH3C F-H

O CH3

HO

H3C

Na+H

OH3C H

OCH3

HO

CH3

HO

H3C

2

9-27SN1rx on separating charges (+/-) in t.s.

C

CH3

CH3

H3C Cl Br(-) insolvent C

CH3

CH3

H3C Br

rx rateTHF* - 0.05Acetone - 0.5

H2O - 4x103

*dielectric constant 7

protic polar solvents separate cations & anions

tBu-X tBu X tBu + X+ -

:Nu(-)tBu-Nu

4

9-28

water 79formic acid 59methanol 33ethanol 24

APROTIC

2. Solvents2. Solvents

PROTIC [H+]

NON-POLAR

dielectric constant

≥ 15

≤ 5

9-29StereochemistryStereochemistry S SNN11

RCH2

CCl

CH3

PhH3C

CH3OH RCH2

CO

CH3

PhCH3

H3C

CH2

CO

CH3

PhH3C CH3

S+

CH2

C

CH3

PhH3C

H3CO

H

CH2

CO

CH3

PhCH3

H3C

H

CH2

CO

CH3

PhH3C CH3

H

+

[ -H+ ]

4

9-30Stereochemistry SStereochemistry SNN2 -2 - inversion

C

CH3

BrDH

IC

H3C

I DH

+ Bracetone

S R

inversion of configuration S->R & R->S BUT . . .

C

CH3

BrD

H

I-

- t.s.

backside attack,

5

9-31

C

C

N

DH

CCH

SN2 product is clearly inverted but substituent priorities changed

C

C

N

Br

DH

C CH +

S rotation product S

backside attack, inversion of configuration

2

9-32

Structure of RXStructure of RX

R3CXR2CHX

RCH2XCH3X

Reactivities for SN1 and SN2 opposite

increasing stability of carbocationSN1

SN2decreasing steric hindrance

governed by steric factors

governed by electronic factors

5

9-33

SSNN2 sterics - 12 sterics - 1oo

Br C

H

H

H:Nu(-)

3o backside blocked SN1

C

CBrC

C

H HH

HHH

H

H

H

:Nu(-)

6

9-34

C

CBrC

C

H HH

HHH

H

H

H

SSNN2 sterics2 sterics

Br C

H

H

H

:Nu(-)

3o backside blocked SN1

5

9-35

hard to formeasy to form

RX - Carbocations (SRX - Carbocations (SNN1)1)

3o R-X reacts by R+ (SN1) H3C

C Br

H3CH3C

CH3

C

CH3

H3CRDS

etc.

R3C > R2CH > RCH2 > CH3

3

9-36

(S(SNN1) Other Cations1) Other Cations

allylic & benzylic cation- resonance stabilized - delocalizated (+) charge [SN1]

CC

C

H

H

H H

H

1o allylic ≈ 2o alkyl CC

C

H

H

H H

HH

H

9-37

CC

H

H

H CCH3

HC

C

H

H

H CCH3

CH3

2o & 3o allylic cations are even more sable

(S(SNN1) Other Cations1) Other Cations

allylic & benzylic cation- resonance stabilized - delocalizated + charge [SN1]

CC

C

H

H

H H

H

1o allylic

9-38

mech.

What is the effect of resonance on SN1?

CC

H

H

H3C C CH3

H

H

OH

CC

H

H

CH3CH3C

H

OH H

CC

H

H

CH3C

H3C

H

H

OH

CC

H

H

H3C C CH3

H

O HH

-H+

same

write either

CC

H

H

H3C C CH3

H

Br

CC

H

H

H3C C CH3

H

OH

H2O+ H-BrSN1rx

6

9-39

(S(SNN1) Other Cations1) Other Cations

allylic & benzylic cation- resonance stabilized - delocalizated (+)-charge [SN1]

CR2 CR2 CR2 CR2

CR2

or hybrid

4

9-40

allylic allylic (benzylic)(benzylic) facilitates S facilitates SNN22

H

H

H

H:Br:H3C-O:

Br: H3CO+ :Br:H3CO: - +

2

9-41

Leaving group

X - gains e(-)s (Lewis base ) - less basic or more stable with e(-)s

better leaving gp. e.g. (-)OH

vs (-)Cl

Nu: + R-X Nu R X Nu-R + :X

strong base

“neutral”

as leaving gp Cl(-) >>> (-)OH

8

9-42

I(-) > Br(-) > Cl(-) ~ H2O > F(-) > AcO(-) > HO(-) > RO(-) > R2N(-)

good leaving gp.

stability of group with e(-)s

special casesnot leaving gp.

Leaving group

9-43

OH

NH2

I

Cl

OCH3

Na+ -SCH3

DMF

Which of the given substrates would undergo SN2 substitution? Product(s)? Reason?

SCH3

NaI or NaCl+

strong bases: (-)OH, (-)OCH3; (-)NH2 even stronger!

not leaving groups3

9-44Other concerns - Rearrangements SN1 yes (R+); SN2 no

HBr O-CH3

O-CH3

+ + otherO CH3

H

H

O CH3

H

O

H

CH3

O-CH3

H

H

O CH3

H

H

6

9-45

Summary of SSummary of SNN Rx’s Rx’sAlkyl Halide

CH3Xmethyl

SN2 SN1

SN1 does not occur. methyl cation too unstable

SN2

R2CHXsecondary SN1 favored with poor

nucleophiles.

SN2 favored inwith good nucleophiles

RCH2Xprimary No SN1 , 1° cations

rarely observed SN2

TertiaryR3CX

SN2 does notoccur; sterichindrance

SN1 - ease offormation of 3o carbocations

stereocenter substitution

inversion racemization4

9-46

polar protic

unimolecular

Guidelines for Substitution & Elimination

H3C-X

SSNN22

C C XH

H

H

HR

weak

SSNN11 & & E1E1

C C XR'

H

H

HR C C X

R'

R"

H

HR

SSNN22

Nu:- B:-

polar aprotic bimolecular

SSNN11 & & E1E1

weak

B:- Nu:-B:- Nu:-

med. B:good

SSNN22

Nu:-

inversion racemicrearrange

8

9-47SSNN1/S1/SNN2 Problems2 Problems

Predict: products, and show (arrows) the mechanism.

+

Na+ -CN

CBr

CH3

H

DMF

+

Na+ -Br

C

CN

CH3H

SN2

CBr

CH3

H

HOCH3 SN1+ HBrC OCH3

CH3

H

C

CH3H

C

CH3HC

CH3H

C

CH3H

-H+

H

O CH3C OCH3

CH3

H H

11

9-48

a reaction in which a small

molecule (HCl, HBr, HI, or HOH) is eliminated.-Elimination-Elimination

+

C

C

(major )

CH3O-Na+

CH3OH

BrH

HH

HH

CH

H

HH

H

H

HH

9-49

E2: concerted break/make bonds

bimolecular, rate [R-X] [ B: or (Nu:)]

E1: break bond, then make bond unimolecular, rate [ R-X ]

2 limiting mechanisms for -elimination rxs

-Elimination-Elimination

9-50

Br

CH

H

HH H

CH

HH

H

:B:B

CH

H

H H

Zaitsev rule:

major -elimination product = the more stable alkene

(more substituted) .

--eliminationelimination

a

a

a

b

bb

9-51Mechanisms (2) timing of bond

breaking/making differs

:B

H

Br

CH

HH

H

E2

H

Br

CH

HH

H

B -

-

C

H

HHH

9-52

H

Br

CH

HH

H

H

Br

CH

HH

H

B -

-

C

H

HHH

E1

H

C

HHH

H

H

Br

CH

HH

H

-

+

Mechanisms (2) timing of bond breaking/making differs

E2

9-53

CHH

H

H

ionization, rate determining step (same as SN1)

E1 mechanismE1 mechanism

H

SM productprogress of reaction

R+

Eac

t

t.s.1t.s.2

H

Br

CH

HH

H

H

C

HHH

H

3

9-54

E2 mechanismE2 mechanismone-step mechanism; concerted bond-breaking

and bond-forming

t.s.

SM productsprog of rx

H

+O

CH2

H3CBr

HH CH3

+ +Br-

OCH2

H3C

H

H CH3

2

9-55

Stereoselectivity of E2Stereoselectivity of E2

E2 most favorable (lowest Ea) - H and X are anti and coplanar

C C

H

XH

H

HR

ButO-

C C

X-

HH

HR

ButOH

1

9-56

Stereoselectivity of E2Stereoselectivity of E2

C CHH

HR

ButO-

X

H

C C

X-

HH

HR

ButOH

E2 most favorable (lowest Ea) - H and X are anti and coplanar

9-57

Regioselectivity of E1/E2Regioselectivity of E1/E2

E1: major product is the more stable alkene

E2: the major product is usually the more stable alkene, but on orientation of H and X

(1.)

(2.)

CH3

Br

H

H

CH3

H

H

Br

*also SN1 products

CH3

H

HK+ -OtBu

CH3

HK+ -OtBu

HOEt* or

HOEt* how?

4

9-58

CH3

H

H

Br

CH3

Br

H

H

EtOH

Stereochemistry of E1Stereochemistry of E1

CH3

H

CH3

HH

CH3

H

H

(1.)

(2.)

3

9-59

CH3

H

H

H

H

CH3Br

tBuO-H

H

H

Stereochemistry of E2Stereochemistry of E2

The only anti-coplanar H to X arrangement forces formation of less stable olefin

(2.)

9-60

E2

branching hinders SN2

X

H

H3CH

HCH3

SN2Nu:-Nu:-

X -

H

H3CH

HCH3

Nu -

H3CH H

CH3

Nu:-

X -

H

H3CH

HCH3

Nu -

H

H3CH H

CH3

Nu

Nu:-

6

9-61

SSNN vs E vs E

Many nucleophiles are also strong bases (OH- and RO-), thus SN and E reactions often compete.

C CH X + Nu-

C CH Nu X-+

C C H-Nu+ X-+E

SN

9-62Guidelines for Substitution & Elimination

H3C-X

SSNN22

C C XH

H

H

HR

E2E2

strongbulky

(tBuO-)

weak

SSNN11 & & E1E1

SSNN11 & & E1E1

weak

C C XR'

H

H

HR C C X

R'

R"

H

HR

B:- Nu:-

E2E2

strong B:

med. B:good

SSNN22

E2E2strong

B:- Nu:-

SSNN22

Nu:- B:-

polar protic

unimolecular

polar aprotic bimolecular

Nu:-

inversionstereochem

racemicrearrange

11