I, Br, Cl - WebAssignncsu/CH221_ssii_02/...R X R X Section 8.1 Nucleophilic Substitution (NS) © Kay Sandberg NS d+ d-d+ d+ R O R O R X d+ d+ d-d-d-d-O O O R O H S H S R N C N C R

1

Which configuration?

1. A

2. B

3. C

4. D

5. E

6. F

1. 2. 3. 4. 5. 6.

3% 2% 0%

94%

0%1%

Which one has the (R)-configuration?

(S)-3-bromo-3-methylhexane (S)-3-bromo-3-methylhexane

(S)-3-bromo-3-methylhexane (R)-3-bromo-3-methylhexane

(S)-3-bromo-3-methylhexane(S)-3-bromo-3-methylhexane

2

Objectives

©Dr. Kay Sandberg

Last lecture

This lecture

Chirality

Reactions that create stereoisomers

Different factors that affect the reaction

SN2

Nucleophilic substitution bimolecular

3

SN2 components

© Kay Sandberg

Section 8.0

Now that we understand chirality and chiral carbonswe are ready to examine the SN2 mechanism ingreat detail.

R LGNu Nu R LG++

nucleophile

substrate substitutionproduct

leaving group

4

Positive & negative sites

R X

© Kay Sandberg

Section 8.1Nucleophilic Substitution (NS)

Functional Group Transformation by NS

d+ d-

I, Br, Cl

R XY Y R X+M+ M+

Li+, Na+, K+

5

Various transfomrationsR X

R X

R X

R X

R X

© Kay SandbergSection 8.1 Nucleophilic Substitution (NS)

Funct

ional G

roup T

ransf

orm

ation b

y N

S

d+ d-

d+

d+

R OR O

R

X

d+

d+

d-

d-

d-

d-

O

O

O

R

O

X

H S H S

R

X

N C N C R X

N N NN N RN

X

alkyl halidealkoxide ion ether

acetate ion ester

hydrogen sulfide ion

thiol

cyanide ionnitrile

azide ion

alkyl azide

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

LQ #1: A) Draw major substitution product formed when 1-iodopentane is treated with sodium propoxide. B) ID FG.

Good trade in charge?

6

Example

ppp

© Kay Sandberg

Section 8.1

Cl

NaCN MOP

C NNa

d+

d-

2

7

SN2 kinetics

© Kay Sandberg

Section 8.4SN2 mechanism: the kinetics

Substitution bimolecularnucleophilic

OH1- + CH3Br HOCH3 + Br1-

Observed rate is second order over all

1st order in nucleophile & 1st order in substrate

Rate = k[OH1-][CH3Br]

8

SN2 trajectory

© Kay Sandberg

Section 8.4SN2 mechanismSubstitution bimolecularnucleophilic

OH1- + CH3Br HOCH3 + Br1-

In the mechanism, does the nucleophile:come in the “back-door” or the “front-door”?

H O BrC

d- d-

H

H H

HO

Br

C

d-

d-

H

HH

Bond forming

Bond breaking

9

Backside attack trajectory

SN2 mechanismIn the mechanism, does the nucleophile:attack from the back-door or the front-door?

BrC

H3CH

H O

CH3CH2

(S)-2-bromobutane

© Kay Sandberg

Section 8.4

H O BrC

d- d-CH2CH3

H3CH

H O C

CH2CH3

CH3

HBr

inversion of configuration

(R)-butan-2-ol

10

Frontside attack trajectory

SN2 mechanism

BrC

H3CH

HO

CH3CH2

(S)-2-bromobutane

© Kay Sandberg

Section 8.4

BrC

d-

H3CH

H

OCH3CH2d-

Br

H3CH

H

OC

CH3CH2

retention of configuration

(S)-butan-2-ol

11

Experimental result

© Kay Sandberg

Section 8.4SN2 mechanism

C

CH3

HO

H (CH2)5CH3

C

H3C

Br

HCH3(CH2)5

NaOHin ethanol-water(S)-2-bromooctane

(R)-octan-2-ol

Experimental Results:

In the mechanism, does the nucleophile:attack from the back-door or the front-door?

12

SN2 proposed mechanism

C BrO +H

H

HH BrO +C

H H

HH

Concerted rxn:

© Kay Sandberg

Section 8.5SN2 mechanism

Direct displacement

stereospecific (back-door)

H O BrC

d- d-

H

H HTransition state

•single elementary step•one transition state •bimolecular •second order overall

OH1-, CH3Br

CH3OH, Br1-

TS

E

Reaction Coordinate

3

13

SN2 TS characteristics

C BrO +H

H

HH

BrO +C

H H

HH

H O BrC

d- d-

H

H H

Transition state

© Kay SandbergSection 8.5

SN2 mechanism bond“makeage”

bond“breakage”TS

E

Reaction Coordinate

14

ExampleD

C

H

BrS

R

© Kay Sandberg

R

SN2 mechanism: Stereospecific

NaSR

Br

D

MOP*

1

2

3

4

15

D

C

H

Brd

S

R d

© Kay Sandberg

16

D

C

H

Brd

S

Rd

© Kay Sandberg

17

D

C

H

BrdS

Rd

© Kay Sandberg

18

Configuration?

1. 2.

99

%

1%

1. R

2. SS

R D

C

H

Br

© Kay Sandberg

What is the configuration of the chiral carbon?

4

19

Product analysis

S

R D

C

H

Br

© Kay Sandberg

What is the configuration of the chiral carbon?

1

2

3

SN2 is stereospecific: the nucleophile attacks fromthe back while the leaving group leaves from the front.

Stereospecific consequence: when attacked carbon is chiral, there will be inversionof configuration.*

*provided the nucleophile and LG have same priority ranking and attacked carbon remains chiral.

S

20

Example againD

C

H

BrS

R

© Kay Sandberg

Focus on the D as the Nu and LG bonds are kept in plane of screen.

21

D

C

H

Brd

S

R d

© Kay Sandberg

22

D

C

H

Brd

S

Rd

© Kay Sandberg

23

D

C

H

BrdS

Rd

© Kay Sandberg

24

S

R D

C

H

Br

© Kay Sandberg

5

25

Product analysis

D

C

H

Br

© Kay Sandberg

When Nu and LG bonds are in the plane of screen,inversion of configuration occurs as the D, ethyl and H keep their bond characteristics(i.e., wedge stays wedge), but switch their angles (all initially angled to left with heavy group on right, ended up angled to right with heavy group on left) .

D

C

H

BrS

RS

S

RR

26

Another perspective

© Kay Sandberg

When Nu and LG bonds are not in the plane of screen,inversion of configuration occurs when the Nu has the opposite bond characteristic of the LG

D

SR

D

BrS

R

SR

Br

provided the stick bonds have the same orientation.

LQ #2: Draw major SN2 product from a rxn between hydroxide ion + (S)-2-bromohexane.

27

Which one?

1. 2. 3. 4.

15%

2%2%

81%

SN2 product

1. A

2. B

3. Neither

4. Both

A B

28

Example

R

© Kay Sandberg

SN2 product

R

X

R

O

O

Dash changed to wedgebut stick orientation also changed

S

S

O

O

Br

NaOCH3

Hey! You can only change 1 thing!!

29

Various representationsC

H

Br

© Kay Sandberg

Is the configuration of the chiral carbonR or S?

Br

1

2

3

Br

Br

BrR

R

R

R

Notice: there are always 2 sticks!!!BrR

BrR

30

Preparations of the substrate

© Kay SandbergSection 8.1Nucleophilic Substitution (NS)


R X

Alkyl halide

Prepared from:

Alkanes - free radical halogenation

Alcohols - nucleophilic substitution

Alkenes - hydrohalogenation

d+ d-

I, Br, Cl

6

31

Characteristics to be considered

© Kay SandbergSection 8.3

Dissect Nucleophilic Substitution (NS)

I. LG characteristics

III. Solvent characteristics

II. Substrate characteristics

IV. Nucleophile characteristics

Elimination is almost always in competition with substitution.

E vs NS

(provided there is a b-H.)

32

Energetic considerations

© Kay Sandberg


Smallest Eact (DG‡) has fastest rate

E

Reaction progress

R

P

R

P

R

P P

R

33

LG characteristics

© Kay Sandberg

Section 8.2Factor #1: LG characteristics

Also the order of reactivity for elimination rxns

RF RCl RBr RI

Increasing rate ofsubstitution by nucleophiles

Poorestleavinggroup Weakest

C-X bond

Most basic Least basic

Strongest C-X bond

Bestleavinggroup

<< < <

34

Halide-halide exchange

© Kay Sandberg




Y R X Y R X+

halideion

alkyl halide alkyl halide halideion

35




BrCH3CH2CH2CH2CH2FK+

F Br+CH3CH2CH2CH2CH2 K+

+

ethyleneglycol

120o

Le Châtelier’s principle:

•C-F bond stronger than C-Br

•Low boiling alkyl fluorides - distilled off

Bp 129oC

Bp 50oC

36




C Cl

H

HH

INa+ +

CI

H

H H

ClCI

H

HH

Cld- d-

CH3-Cl: BDE 349 kJ/molCH3-I: BDE 234 kJ/mol

7

37

Importance of acetone solvent

© Kay Sandberg

Section 8.1

Nucleophilic Substitution (NS)


ClCH2=CHCH2INa+

I Cl+CH2=CHCH2 Na+

+

acetone

•Sodium chloride (& sodium bromide) are insoluble in acetone

O

precipitates

38

Practice

Br

© Kay Sandberg

Section 8.5

NaI

O

SN2 MOP

39

Solution

I

Br

© Kay Sandberg

Section 8.5

NaI

O

RRS

I

R

IRR

IRR

I

RR40

What to do and not to do

© Kay Sandberg

I

Br

No!No!No!

IYes!Yes!Yes!

Yes!Yes!Yes!

Geometry needs to reflect

realistic bond angles!

on same side

Br

No!No!No!

41

Substrate leaving group trend

© Kay Sandberg

Section 8.2Rate dependence in NS

RF << RCl < RBr < RI

Increasing rate ofsubstitution by nucleophiles

Poorestleavinggroup Weakest

C-X bondStrongest C-X bond

Bestleavinggroup

Factor #1: Substrate leaving group

42

Energetic comparisons for leaving

group

© Kay Sandberg


Characteristics of the SN2 reaction: LG


E

Reaction progress

R-F

R-I

LQ #3: Draw major SN2 product when 1-bromo-5-chloropentane

is treated with only 1 equivalent of NaI in acetone.

8

43

Substrate electrophilic carbon

hybridization


Factor #2: substrate characteristics

X X X

sp3sp2

sp2

Alkyl halide Alkenyl halide(vinylic halide)

Aryl halide

Unreactive under SN2 conditions

44

Substrate stereics

© Dr. Kay Sandberg

Section 8.2Rate dependence in NS

Factor #2: Substrate sterics

R-Br R-I+ LiI + LiBracetone

CH3-Br: methyl

RCH2-Br: primary

R2CH-Br: secondary

R3C-Br: tertiary

relative rate 1

45

Methyl vs primary

Section 8.6 Steric effects in SN2 rxns

Relative rate of NS:

221,000


© Dr. Kay Sandberg

1,350

X

46

Secondary vs tertiary


Section 8.6© Dr. Kay Sandberg

1

Too smallto measure

X

47

Methyl vs tertiary



Too smallto measure

221,000X

48

Methyl vs tertiary



Too smallto measure

221,000X

9

49

Steric effect trends

© Kay Sandberg


Steric effects

R3CX < R2CHX < RCH2X < CH3X

Increasing rate ofsubstitution by SN2 mechanism

methyl

Least reactive Most reactive

3o

Most crowded Least crowded

221,0001 1350too small

50

NeopentylBr

© Kay Sandberg

Section 8.6


Substrate characteristics: Steric effects


R3CX << R2CHX < RCH2X < CH3X

neopentyl bromide?

methyl3o 2o 1o

X

51

Neopentyl in the trend

© Kay Sandberg


Substrate characteristics: Steric effects

(CH3)3CX < (CH3)3CCH2X < (CH3)2CHX < CH3CH2X < CH3X


methyl3o neopentyl 2o 1o

too small 1 500 40000 2000000

52


© Kay Sandberg

Characteristics of the SN2 reaction: substrate


E

3oR-X 1oR-X

SN2 is governed by steric effects


LQ #4) Draw the major SN2 product when 1 equivof NaI in acetone is used.

Reaction progress

53

Solvent considerations

© Kay Sandberg


III. Solvent:

Major effect is on the rate of NS

What properties of the solvent influence the rate?

How does the activation energy of the RDS respond to these properties?

54

Solubility considerations

© Kay Sandberg



Solvent systems:

R XYM+

salt Alkyl halide

Water soluble Water insoluble

Ethanol-water mixture

DMSO (dimethyl sulfoxide)

O

S

10

55

Protic vs aprotic

© Kay Sandberg


Solvent characteristics:

vs

H3C O

H

H O

H

What do the red have in common with the blue?

H3CS

CH3

O

NC

H

O

H3C

H3C

C NH3C

d+

d+

d+

d+

d+

d-

d-

d-

d-

d-

How are they different?

All are polar solvents

protic

aprotic

Polar solvents neededto dissolve ionic species

56

Protic

© Kay Sandberg

HO

H

Na+

Cl-

Aaaahhhhhh!!

HO

H

H

O

H

H

O

H

HO

H

HO

H

HO

H H

O

H

H

O

H

Solvates Nu: & cation Lowers Nu: E


protic solvent (water or alcohol)

CH2

Br

57

Aprotic

© Kay Sandberg


aprotic solvent (DMSO)

Solvates cation (+), but not much for Nu:-

Raises Nu: E

S O

C

C

H

H

H

H

H

H

Na+

S

O

C C

H

HH

H

H

H

S

O

CC

H

HH

H

H

H

SO

CH2

CH2

H

H

Cl-

Urrrrggggg!!

CH2

Br

Cl-

58

Rate comparison

© Kay Sandberg


Aprotic vs protic

S O

C

C

H

H

H

H

H

H

Na+

Cl-

H

O

H

E

TS

protic

aprotic

103 X faster

59

Conjugate comparisons

© Kay Sandberg

Section 8.7Nucleophilic Substitution (NS)Factor #4: Nucleophile characteristics: nucleophilicity

vs

vs

R O R OH

RC O

O

RC OH

O

i

ii

A B

A Brelationship?

Which in each pair is more nucleophilic?

60

Nucleophile

1. 2. 3. 4.

92%

3%0%5%

© Kay Sandberg



vs

vs

R O R OH

RC O

O

RC OH

O

i

ii

A B

A Brelationship?

i ii1. A A

2. A B

3. B A

4. B B

11

61

Conjugate comparisons

© Kay Sandberg



vs

vs

R O R OH

RC O

O

RC OH

O

i

ii

A B

A Brelationship?

Bases are stronger nucleophiles than their conjugate acids

62

Energetic comparison

© Kay Sandberg


Characteristics of the SN2 reaction: nucleophile


E

Reaction progress

neutralanionic

conjugates

63

Same atom comparisons

© Kay Sandberg

Section 8.8Nucleophile characteristics: nucleophilicity

Which is more nucleophilic?

R ORC O

O

vs

pKaROH = 16pKaRCOOH = 5

A B

SA WA

carboxylate ionWB

alkoxide ionSB

64

Nucleophile1. 2.

76

%

24

%

1. A

2. B

© Kay Sandberg



R ORC O

O

vs


A B

SA WA

carboxylate ionWB

alkoxide ionSB

65

Same atom comparisons

© Kay Sandberg


Which is more nucleophilic?

R ORC O

O

vs


A B

SA WA

carboxylate ionWB

alkoxide ionSB

The more basic the nucleophile the stronger the nucleophile (if nucleophilic atom is the same).

CO

O

RC

O

O

RC

O

O

R

-½

-½

66

Energetic comparisons

© Kay Sandberg




E

Reaction progress

less

basic

More

basic

Same type of atom

12

67

Nucleophile?

1. 2. 3. 4.

7% 6%

57%

30%

1. A A

2. A B

3. B A

4. B B

© Kay Sandberg


vs

vs

Nucleophile characteristics: nucleophilicity


H O F

H2O NH3

iA B

iiA B

i ii

Same period

68

Nucleophile?

© Kay Sandberg


vs

vs



H O F

H2O NH3

Within the same period, the less electronegative thenucleophilic atom, the stronger the nucleophile.

iA B

iiA B

69


© Kay Sandberg




E

Reaction progress

more

EN

less

EN

Same period

70

Same family comparisons

© Kay Sandberg


vs



F I

H S H Ovs

A B

A BSame family

In protic solvents(solvents such asalcohol or water)

i.

ii.

71

Nucleophile

1. 2. 3. 4.

0% 0%0%0%

1. A A

2. A B

3. B A

4. B B

© Kay Sandberg


vs



F I

H S H Ovs

A B

A BSame family


i ii

10

i

ii

72


© Kay Sandberg


vs



F I

H S H Ovs

A B

A BSame family


Within the same family, the larger nucleophileis the stronger the nucleophile.

13

73


© Kay Sandberg


vs

Within the same family, the larger the nucleophilic atom,the stronger the nucleophile.

1) The larger nucleophilic atom is more polarizable,(it can form a partial bond at a greater distancewhich helps stabilize the TS).



F I

H S H Ovs

A B

A B


74


© Kay Sandberg




vsF I

Within the same family, the larger the nucleophilic atom,the stronger the nucleophile.

2) The larger nucleophilic atom is less solvatedin protic solvents, (it can break away from the solvent easier to displace the leaving group).

H S H OvsIn protic solvents(solvents such asalcohol or water)

75

Protic solvents

© Kay Sandberg

O H

H

O

H

H

OH

H

OH

H

O H

H

O

H

H

OH

H

OH

H

Go

Cl-

F-

strongerbase

weakerbase

weakernucleophile

strongernucleophile

stronger H-bond

weaker H-bond

In aprotic solvents, nucleophilicity follows basicity(F- stronger nucleophile)

Protic solvent

76


© Kay Sandberg




E

smaller

bigger

Same family

More stableTS

Reaction progress

Protic solvent

Opposite trend for aprotic solvents

77

Stabilization types

© Kay Sandberg

Nucleophilic Substitution (NS) Characteristics of the SN2 reaction


E

Reaction progress

P

R

R

P

R

P P

R

Two different factors

Stabilization of reactant

More stable reactant –higher E hill to climb

Stabilization of TS

More stable TS –lower E hill to climb

78

Nucleophilicity chart

© Kay Sandberg


Nucleophile characteristics: nucleophilicity(rate comparison when substrate is methyl iodideand solvent is methanol – a protic solvent)

Very good nucleophiles

Reactivity class Nucleophile

Good nucleophiles

I-, HS-, RS-

Br-, HO-, RO-, CN-, N3-

Fair nucleophiles NH3, Cl-, F-, RCO2-

Weak nucleophiles H2O, ROH

Very weak nucleophiles RCO2H

Only strong bases in list(all others are weak bases)

Watch out for E2 competition

14

79

Nucleophilicity trends

© Kay Sandberg


Characteristics of the SN2 reaction

IV. Nucleophile: nucleophiles with higher energyground states are more reactive

neutral < negatively charged

less basic < more basic (same atom)

more EN < less EN (same period)

smaller size < bigger size(protic solvents like water or alcohols)

(same family)

(conjugates)

weaker base < stronger base(aprotic solvents like DMSO)

(same family)

I, Br, Cl - WebAssignncsu/CH221_ssii_02/...R X R X Section 8.1 Nucleophilic Substitution (NS) © Kay Sandberg NS d+ d-d+ d+ R O R O R X d+ d+ d-d-d-d-O O O R O H S H S R N C N C R

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