chap10

CHAPTER 10Nucleophilic Substitution

The SN1 and SN2 Mechanisms

Sect. 10.1: Overview of nucleophilic substitution• The substitution reaction: SN1 and SN2• Primary halides = SN2 • Secondary halides = both mechanisms!• Tertiary halides = SN1• Leaving groups: halogens most common• There are a number of different nucleophiles!!

Nucleophilic Substitution (SN2)

R-CH2-X + Nu_

R-CH2-Nu + X_

substrate nucleophile product leaving group

Oxygen Nucleophiles (SN2)

O-H_

R-CH2-O-Halcoholhydroxide

R-CH2-X +_

+ X

O-R_

R-CH2-O-RR-CH2-X +_

+ X

etheralkoxide

O-C-R_

R-CH2-R-CH2-X +_

+ X

estercarboxylateO

O-C-R

O

Nitrogen as a nucleophile (SN2)

R-CH2-X + Nu_

R-CH2-Nu + X_


NH3 R-CH2-NH3ammonia

R-CH2-X ++

X_

R-CH2-NH3

+X

_

R-CH2-NH2 + H-Xprimaryamine

Carbon as a nucleophile (SN2)

R-CH2-X + Nu_

R-CH2-Nu + X_


C_

nitrilecyanideR-CH2-X +

_+ X

R-CH2-R-CH2-X +_

+ Xalkyne

CH2-C-R_

R-CH2-X +

O

N C NR-CH2

C_

C-H

CH2-C-R

O

R-CH2 + X_

ketone

C C-H

energy

Reaction coordinate

CH

H

Br-

OH

R

..:..

__H O

C H

H

Br

R

Br

H O

CH

HR

The SN1 Mechanism

1)

2)

: :..

slow

++ : Br :

..

..

_

++ :

fast

CH3 C CH3

CH3

Br

CH3 C CH3

CH3

CH3 C CH3

CH3

CH3 C CH3

CH3

Nu

Nu_

carbocation

energy

Reaction coordinate

C

R

Br

RR

R CRR

Br

R CR

R

R CR

R

Nu

CR

R

Nu

R

intermediate

Sect. 10.2: SN2 Mechanism

•reaction and mechanism•kinetics•stereochemistry•substrate structure•nucleophiles• leaving groups•solvents

The SN2 Reaction

+ + Br: :..

..

_

:..

..

_ ..

..CH3 Br O H CH3 OH

Sterically accessible compounds reactby this mechanism!!

Methyl group is small

SN2 Mechanism: kinetics

• The reactions follows second order (bimolecular) kinetics

• Rate = k [R-Br]1 [OH-]1

energy

Reaction coordinate

CH

H

Br-

OH

R

..:..

__H O

C H

H

Br

R

Br

H O

CH

HR

SN2 Reaction: stereochemistry

.. _

:..

3

C BrH

Et

CHH O

(R)- enantiomer

H O C

CH

EtH

Br

3

..

..H O C

CH

HEt

Br_

+3

(S) enantiomer

Inversion of configuration

For an SN2 Reaction:

EVERY REACTION EVENT ALWAYS LEADS TO

INVERSION OF CONFIGURATION

SN2 Reaction: substrate structure (Table 10-5)

krel

150

1

0.008

unreactive!

CH3 Br

CH3 CH2 Br

CH3 CH Br

CH3

CH3 C Br

CH3

CH3

KI in Acetone at 25°

Chloromethane + Iodide as the Nucleophile

I-

Fast

tert-Butyl Chloride + Iodide as the Nucleophile

I-

No reaction

SN2 Reaction: substrate structure

> > C

primary secondary tertiary

CH3-Br CH3-CH2-Br CH3 CH

CH3

Br > CH3

CH3

CH3

Br

Reactivity order---- fastest to slowest!

Predict which is more nucleophilic

CH3-O- or CH3-S-

CH3-S-is more nucleophilic!

Relative Nucleophilicity

Increasing Nucleophilicty

H2O

CH3OH_ _

OCH3

_I_ _

SH

_

C N

OH_

CH3 C O

O

O

1) In general, stronger bases are better nucleophiles

2) However, iodide doesn’t fit that pattern (weak base, but great

nucleophile!)

3) Cyanide is an excellent nucleophile because of its linear

structure

4) Sulfur is better than oxygen as a nucleophile

SN2 Reaction: Leaving Groups

• Best leaving groups leave to form weak Lewis bases.

• Good leaving groups:• Br, I, Cl, OTs, OH2

+

• “Lousy” leaving groups:• OH, OR, NH2,, F

Sulfonate Leaving Groups

S CH3OR

O

O

S BrOR

O

O

para-Toluenesulfonate Tosylate

para-Bromobenzenesulfonate Brosylate

R OTs

R OBs

Tosylate leaving groupTosylate leaving group

(S)-(+)-1-Phenyl-2-propanol

(S)-(+)-1-Methyl-2-phenylethyl tosylate

C2H5O

2-Ethoxy-1-phenylpropaneIs this ether (R) or (S)?

C OH

CH2

CH3

H

CH3 S Cl

O

O

C O

CH2

CH3

H Ts

C O

CH2

CH3

H Ts

CH2 CH O CH2 CH3

CH3_

+ H-Cl

Retention of configuration

Retention or inversion?

[Ts-Cl]

Inversion of Configuration

CH2

CH

CH3

O S

O

O

CH3 CH2

CH3 CH2 O C

CH2

HCH3

+ CH3 S O

O

O

(S)

(R)

_

O_ CH3

SN2 Reaction: solvents

SN2 reactions are accelerated in polar, aprotic solvents. Consider Na+ -OEt as an example of a nucleophile.

Why are reactions accelerated? The Na+ cation is complexed by the negative part of the aprotic solvent molecule pulling it away from –OEt.Now that the sodium ion is complexed, the oxygen in the nucleophile –OEt is more available for attack.

Aprotic solvents• These solvents do not have OH bonds in them. They complex the cation through the lone pairs on oxygen or nitrogen:

AcetoneH3C

O

CH3

Dimethyl sulfoxide (DMSO)H3C

S

O

CH3

Dimethylformamide (DMF) H

O

NCH3

CH3

Acetonitrile C NH3C

How cations are complexed with aprotic solvents

H3CS

O

CH3

Na

H3C S CH3

O

Now that the Na+ is complexed, the –

OEt can react more easily

Et O H3C Br Et O CH3 Br

SN2 Reaction: solventsSN2 reactions are retarded (slowed) in polar, protic solvents. Protic solvents have O-H groups.

Why are reactions retarded? Nucleophile is hydrogen bonded to solvent!

Et O H OEt

The nucleophile ishydrogen bondedto ethanol - reducesnucleophilicity

Protic solvents Typical protic solvents:

WaterH

OH

Methanol HO

CH3

HO

CH2CH3

HOEtEthanol

HO

C

O

CH3Acetic acid HOAc

HO

C

O

HFormic acid

HOMe

abbreviations

Sect. 10.4: SN1 Mechanism

• reaction and mechanism• kinetics• stereochemistry• substrate structure• nucleophiles• leaving groups• solvents

Solvolysis of tert-Butyl Bromide

+ H2O +

+ other products

acetoneCH3 C CH3

CH3

Br

CH3 C CH3

CH3

OH

H Br

Acetone is used to dissolve everything! Water is the Acetone is used to dissolve everything! Water is the

solvent and nucleophile (solvolysis). solvent and nucleophile (solvolysis).

The SN1 Mechanism

1)

2)

3)

: :..

slow

++ : Br :

..

..

_

++ : :

fast

:+

:+

fast

:..

+ H+

CH3 C CH3

CH3

Br

CH3 C CH3

CH3

CH3 C CH3

CH3

CH3 C CH3

CH3

O H

H

O

H

H

CH3 C CH3

CH3

O H

H

CH3 C CH3

CH3

O H

1935: Hughes & Ingold

carbocation

energy

Reaction coordinate

C

R

Br

RR

R CRR

Br

R CR

R

R C

R

O

R

H H

CR

R

OH

R

intermediate

intermediate

SN1 Reaction: kinetics

•The reactions follows first order (unimolecular) kinetics

•Rate = k [R-Br]1

SN1 Reaction: stereochemistry

With chiral R-X compounds, the product will be racemic (50% of

each enantiomer).

Stereochemistry in SN1 reactions – racemic product

CH3

H

CH3C

Et

BrPr CH3-O-H

CH3C

Et

OPr

3o substrate

polarproticsolvent!

C

Pr

H3C Et

(S) enantiomerplanar carbocation

C

Pr

H3C Et

front sideattack

back sideattack

CH3-O-H

CH3-O-H

Slow

Pr

CH3Et

OH3C

H

Pr

CH3Et

OH3C

CHEt

OPr CH3H

H

50% (S)

50% (R)

Fast fast

fast

energy

Reaction coordinate

C

R

Br

RR

R CRR

Br

R CR

R

R C

R

O

R

H3C H

CR

R

O-CH3

R

intermediate

intermediate


krel

no reaction

1.00

11.6

61.2 x 10

CH3 Br

CH3 CH2 Br

CH3 CH Br

CH3

CH3 C Br

CH3

CH3

Solvolysis in water at 50°C


tertiary>secondary>primary > methyl

Primary and methyl halides are very unreactive! They don’t go by SN1 reactions.

C

tertiary

C

tertiary secondary

>

primary

+

carbocation (very stable)

secondarycarbocation

+

CH3

>Br

CH3

CH3

CH3 CH

CH3

Br

CH3 CH

CH3

CH3CH3-CH2-Br

CH3

+

primarycarboc

CH3

carbocation(unstable)

CH3

+

CH3-Br>

very unstable carbocation

three methyl groups

two methyl groups

one methyl group

no methyl groups

CH3 CH2

Nucleophiles• Usually SN1 reactions are run in polar protic solvents;

compounds with O-H groups.• The polar protic solvent acts as BOTH nucleophile as well

as the solvent. • Common solvent/nucleophiles include:

water, ethanol, methanol, acetic acid, and formic acid.

A protic solvent acts as both a solvent and nucleophile in SN1 reactions - solvolysis:

WaterH

OH

Methanol HO

CH3

HO

CH2CH3

HOEtEthanol

HO

C

O

CH3Acetic acid HOAc

HO

C

O

HFormic acid

HOMe

abbreviations

Typical solvolysis reaction

CH3

H

CH3C

Et

BrPr CH3-O-H

CH3C

Et

OPr

3o substrate

polarproticsolvent!

C

Pr

H3C Et

(S) enantiomerplanar carbocation

C

Pr

H3C Et

front sideattack

back sideattack

CH3-O-H

CH3-O-H

Slow

Pr

CH3Et

OH3C

H

Pr

CH3Et

OH3C

CHEt

OPr CH3H

H

50% (S)

50% (R)

Fast fast

fast

Polar solvent

stabilizes

the carbocation!Solvent is the

nucleophile

Leaving groups

• Leaving groups are the same as in SN2 reactions:

• Cl, Br, I, OTs are the usual ones.

SN1 Reaction: solvent polarity

•SN1 solvolysis reactions go much faster in trifluoroacetic acid and water (high ionizing power).

•SN1 solvolysis reactions go slower in ethanol and acetic acid (lower ionizing power).

•See table 10-9.

SN2 versus SN1 Reactions• A primary alkyl halide or a methyl halide should react by an SN2 process. Look for a good nucleophile, such as hydroxide, methoxide, etc. in an polar aprotic solvent.

• A tertiary alkyl halide should react by an SN1 mechanism. Make sure to run the reaction under solvolysis (polar protic solvent) conditions! Don’t use strong base conditions -- it will give you nothing but E2 elimination!

• A secondary alkyl halide can go by either mechanism. Look at the solvent/nucleophile conditions!!

SN2 versus SN1 Reactions (continued)• If the reaction medium is KI or NaI in acetone, this demands an SN2 mechanism.

• If the reaction medium is AgNO3 in ethanol, this demands an SN1 mechanism.

• If the medium is basic, look for SN2.

• If the medium is acidic or neutral, expect SN1.

Comparison of SN1 and SN2 Reactions

•See Table 10-10 on page 936. Great table!!

•Section 10-5: Solvent effects; been there done that!!

Sect. 10.6: classification tests

•Sodium iodide and potassium iodide in acetone are typical SN2 reagents!!

•Silver nitrate in ethanol is a typical SN1 reagent!!

Sect. 10.7: Special Cases

Neopentyl compounds are very unreactive in SN2 reactions.

Effect of -substitution on SN2 reactivity (Table 10-11)

KI in Acetone at 25°

krel

1.0

0.65

0.15

0.000026

CH2 CH2 Br

CH2 CH2 Br

CH3 C CH2 Br

CH3

CH3

Neopentyl bromide

CH3

CH3 CH CH2 Br

CH3

H

Neopentyl Transition State

C C

Y

Nu

R1

R2

R3

Nu

YR1

H

H

Allylic and Benzylic compounds

Allylic and benzylic compounds are especially reactive in SN1 reactions.Even though they are primary substrates, they are more reactive most other halides! They form resonance stabilized carbocations.

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

Solvolysis Rates: SN1Table 10-13

krel

Ethyl chlorideIsopropyl chlorideAllyl chlorideBenzyl chloridetert-Butyl chloride

very small 1 74 140 12,000

80% Ethanol-water at 50°

Allylic and Benzylic compounds

Allylic and benzylic compounds are especially reactive in SN2 reactions.They are more reactive than typical primary compounds!

CH2-Br CH2=CH-CH2-Br

benzyl bromide allyl bromide

Reaction with KI in Acetone: SN2Table 10-14

krel

Ethyl chlorideAllyl chlorideMethyl chlorideBenzyl chloride

1 33 93 93

60° C

Vinyl and Phenyl Compounds

Vinyl and Phenyl compounds are completely inert in both

SN1 and SN2 reactions!!

vinyl phenyl

CCH2

Cl

H Cl

Reactivity order for SN1

RC

R R

Br>

CH2Br

C CCH2

Br

HH

H

>

3o

BenzylAllyl

RCH

RBr

2o

>

1o

R CH2 Br> >> CH3-Br

methyl

>> Br

CBr

R

R

H

phenylvinyl

Inert!!No reaction

Reactivity order for SN2

RC

R R

Br

CH2Br

C CCH2

Br

HH

H

3o

BenzylAllyl

RCH

RBr

2o1o

R CH2 BrCH3-Br

methyl

>> Br

CBr

R

R

H

phenylvinyl

Inert!!No reaction!!

>> >

Can not undergoSN2

= >> >

About same reactivity

Sect. 10.8: Cyclic Systems

•Cyclopropyl and cyclobutyl halides are very unreactive in both SN1 and SN2

reactions

•Cyclopentyl halides are more reactive than cyclohexyl halides in SN1 and SN2 reactions.

Bicyclic systems: Bredt’s Rule

You can’t have p orbitals on a bridgehead position in a rigid bicyclic molecule.

-- You cannot form a carbocation at a bridgehead position.

--You cannot have a double bond at a bridgehead position.

+

bridgehead

bridgehead

Cl

AgNO3

Ethanol

No reaction!

Sect. 10.9: Carbocation Rearrangement

1)

slow

++ Br

_

2)

+ +

3)

++ ROH + H

+

CH3 C CH CH3

CH3

CH3 Br

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3OR

a carbocation

A Closer Look...

+ +

+

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

transition state

Carbocation Rearrangement

CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3


CH3 C CH CH3

CH3

CH3

Sir Christopher Ingold

Source: Michigan State University, Department of Chemistry

http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

Saul Winstein

Source: Michigan State University, Department of Chemistry

http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

Sect. 10.10 Competing Reactions: Elimination -- Table 10-16• Lower temperatures favor substitution; higher

temperatures give more elimination. • Highly branched compounds (secondary and tertiary

compounds) give mostly elimination with strong bases. Weaker bases give more substitution. A basic medium favors E2; a more nucleophilic medium favors SN2.

• Primary compounds give mostly substitution with non-bulky nucleophiles. A bulky base (tert-butoxide) gives elimination.

• Tertiary compounds should be reacted under solvolysis conditions to give substitution!!!

Sect. 10.11: Neighboring group participation

+ CH3O_

> 0.5 M

_ _

+ CH3O_

< 0.1 M

_ _

(R)-(+) (S)-(-)

(R)-(+)(R)-(+)

+ Br_

+ Br_

CH3OH

CH3OH

!!!

CH3 CH C O

Br

O

CH3 CH C O

OCH3

O

CH3 CH C O

Br

O

CH3 CH C O

OCH3

O

inversion

retention

Under SN2 Conditions

_

_

(R)

..:..

- -

_

+ Br_

_

(S)

Inversion of configuration

C Br

CH3

HC

OO

CH3 OCH3

C

H C

BrO

OO

CH3

CH3 O C

CH3

HC

OO

Internal SN2 reaction followed by an external SN2 reaction

.._

:..

(R)

slow

: :

_ ..:

..

..

..

+ H+

+ Br_

(R)

Retention of Configuration

C Br

CH3

HC

O

O

C

C

O

CH3H

O

OCH3 H

C O CH3

CH3

CH

OO

Neighboring Group Participation

slow+ : X :

..

..

_

fast

Nu :

1)

2)

C C

G:

X

C C

G

C C

G

C C

G:

Nu

G:

X

Neighboring group participation: Summary•Retention of configuration•Enhanced rate of reaction

Mustard gas• Mustard gas is a substance that causes tissue blistering (a

vesicant). It is highly reactive compound that combines with proteins and DNA and results in cellular changes immediately after exposure. Mustard gas was used as a chemical warfare agent in World War I by both sides.

S

ClCl

S

Cl

Neighboringgroup participationInternal SN2

S

Cl O-Enzyme

External SN2S

O-EnzymeCl

Cl

ClCl

Mustard gas

Sect. 10.13: Ion-pair mechanisms (skip!!)• SN1 reactions are “expected” to give a 50-50 (racemic) mixture of the two enantiomers!!

• But, if the leaving group doesn’t get out of the way, you will get more inversion than retention, which makes it “look like” SN2.

• In the extreme, you could have a carbocation give only inversion of configuration by an SN1 mechanism!!

In-Class Problem

For the following reaction,

CH3 CH CH CH2 OTs H2O

acetone

A) Identify the mechanism of this reaction.

B) Predict the product(s) of this reaction, and identifythem as major or minor, if appropriate.

The following table may be helpful as a review

Substitution versus EliminationSN1 SN2 E1 E2

Substrate Strong effect; reaction favored by tertiary halide

Strong effect; reaction favored by methyl or primary halide

Strong effect; reaction favored by tertiary halide

Strong effect; reaction favored by tertiary halide

Reactivity – primary

Does not occur Highly favored Does not occur Occurs with strong base!

Reactivity – tertiary

Favored when nucleophile is the solvent – solvolysis

Does not occur Occurs under solvolysis conditions or with strong acids

Highly favored when strong bases (OH-, OR-) are used

Reactivity – secondary

Can occur in polar, protic solvents

Favored by good nucleophile in polar, aprotic solvents

Can occur in polar, protic solvents

Favored when strong bases are used

Solvent Very strong effect; reaction favored by polar, protic solvents

Strong effect; reaction favored by polar, aprotic solvents

Very strong effect; reaction favored by polar, protic solvents

Strong effect; reaction favored by polar, aprotic solvent

Nucleophile/Base Weak effect; reaction favored by good nucleophile/weak base

Strong effect; reaction favored by good nucleophile/weak base

Weak effect; reaction favored by weak base

Strong effect; reaction favored by strong base

Leaving Group Strong effect; reaction favored by good leaving group

Strong effect; reaction favored by good leaving group



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