Chapter 10

WWU -- ChemistryWWU -- Chemistry

Chapter 10Chapter 10

Nucleophilic Substitution:

The SN1 and SN2Mechanisms


Assignment for Chapter Assignment for Chapter 1010

• We will cover all the sections in this chapter, except Sections 10.12 and 10.13


Problem Assignment Problem Assignment for Chapter 10for Chapter 10

In-Text Problems1 - 15 17, 18 19 (SN2 react)

20 (SN1 reaction), 21, 22, 24, 25, 26,27, 28

End-of-Chapter Problems30 - 37 39 - 42 44 – 49

51 - 55


Sect. 10.1: Sect. 10.1: Nomenclature of alkyl Nomenclature of alkyl

halides -- common halides -- common namesnames

methylene chloride CH2Cl2chloroform CHCl3carbon tetrachloride CCl4


More common and IUPAC More common and IUPAC namesnamesisopropyl chloride (2-chloropropane)sec-butyl chloride (2-chlorobutane)isobutyl chloride (1-chloro-2-methylpropane)tert-butyl chloride (2-chloro-2-methylpropane)allyl chloride (3-chloro-1-propene)vinyl chloride (chloroethene)

benzyl chloride (chloromethylbenzene)phenyl chloride (chlorobenzene)


Sect. 10.2: Overview of Sect. 10.2: Overview of nucleophilic nucleophilic substitutionsubstitution

• 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 Nucleophilic Substitution (S(SNN2)2)

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 Nitrogen as a nucleophile (S(SNN2)2)

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 Carbon as a nucleophile (S(SNN2)2)

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 SThe SNN1 Mechanism1 Mechanism1)

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. 10.3: SSect. 10.3: SNN2 2 MechanismMechanism

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


The SThe SNN2 Reaction2 Reaction

+ + Br: :..

..

_

:..

..

_ ..

..CH3 Br O H CH3 OH

Sterically accessible compounds reactby this mechanism!!

Methyl group is small


SSNN2 Mechanism: 2 Mechanism: kineticskinetics

•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


.. _

:..

3

C BrH

Et

CHH O

(R)- enantiomer

H O C

CH

EtH

Br

3

..

..H O C

CH

HEt

Br_

+3

(S) enantiomer

SSNN2 Reaction: 2 Reaction: stereochemistrystereochemistry

Inversion of configuration


For an SFor an SNN2 Reaction:2 Reaction:

EVERY REACTION EVENT ALWAYS LEADS TO

INVERSION OF CONFIGURATION


SSNN2 Reaction: substrate 2 Reaction: substrate structure (Table 10-5)structure (Table 10-5)

KI in Acetone at 25°

krel

150

1

0.008

unreactive!

CH3 Br

CH3 CH2 Br

CH3 CH Br

CH3

CH3 C Br

CH3

CH3


Chloromethane + Chloromethane + Iodide as the Iodide as the NucleophileNucleophile

I-

Fast


terttert-Butyl Chloride + -Butyl Chloride + Iodide as the Iodide as the NucleophileNucleophile

I-

No reaction


SSNN2 Reaction: 2 Reaction: substrate structuresubstrate structure

> > C

primary secondary tertiary

CH3-Br CH3-CH2-Br CH3 CH

CH3

Br > CH3

CH3

CH3

Br

Reactivity order---- fastest to slowest!


SSNN2 Reaction: 2 Reaction: nucleophilicitynucleophilicity

Basicity Nucleophilicity


Predict which is more Predict which is more nucleophilicnucleophilic

CH3-O- or CH3-S-

CH3-S-is more nucleophilic!


Relative NucleophilicityRelative 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


SSNN2 Reaction: Leaving 2 Reaction: Leaving GroupsGroups

• 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 Sulfonate Leaving GroupsGroups

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 Inversion of ConfigurationConfiguration

CH2

CH

CH3

O S

O

O

CH3 CH2

CH3 CH2 O C

CH2

HCH3

+ CH3 S O

O

O

(S)

(R)

_

O_ CH3


SSNN2 Reaction: solvents2 Reaction: solventsSN2 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 solventsAprotic 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 How cations are complexed with aprotic complexed with aprotic

solventssolvents

H3CS

O

CH3

Na

H3C S CH3

O


Now that the NaNow that the Na++ is is complexed, the complexed, the ––OEt can OEt can

react more easilyreact more easily

Et O H3C Br Et O CH3 Br


SSNN2 Reaction: solvents2 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 solventsProtic 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: SSect. 10.4: SNN1 1 MechanismMechanism

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


Solvolysis of Solvolysis of terttert-Butyl -Butyl BromideBromide

+ 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 SThe SNN1 Mechanism1 Mechanism1)

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


SSNN1 Reaction: kinetics1 Reaction: kinetics

•The reactions follows first order (unimolecular) kinetics

•Rate = k [R-Br]1


SSNN1 Reaction: 1 Reaction: stereochemistrystereochemistry

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

each enantiomer).


Stereochemistry in SStereochemistry in SNN1 1 reactions – racemic reactions – racemic

productproduct

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


SSNN1 Reaction: substrate 1 Reaction: substrate structurestructure

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


SSNN1 Reaction: 1 Reaction: substrate structuresubstrate structure

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


NucleophilesNucleophiles

• 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 A protic solvent acts as both a solvent and nucleophile in Ssolvent and nucleophile in SNN1 1

reactions - solvolysis:reactions - solvolysis:Water

HO

H

Methanol HO

CH3

HO

CH2CH3

HOEtEthanol

HO

C

O

CH3Acetic acid HOAc

HO

C

O

HFormic acid

HOMe

abbreviations


Typical solvolysis Typical solvolysis reaction 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 groupsLeaving groups

• Leaving groups are the same as in SN2 reactions:

• Cl, Br, I, OTs are the usual ones.


SSNN1 Reaction: solvent 1 Reaction: solvent polaritypolarity

• 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.


SSNN2 2 versusversus S SNN1 1 ReactionsReactions

• 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!!


SSNN2 2 versusversus S SNN1 Reactions 1 Reactions (continued)(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 SComparison of SNN1 and 1 and SSNN2 Reactions2 Reactions

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

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


Sect. 10.6: Sect. 10.6: classification tests 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 Sect. 10.7: Special CasesCases

Neopentyl compounds are very unreactive in SN2 reactions.


Effect Effect of of -substitution-substitution on S on SNN2 reactivity (Table 10-2 reactivity (Table 10-

11)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 Neopentyl Transition StateState

C C

Y

Nu

R1

R2

R3

Nu

YR1

H

H


Allylic and Benzylic Allylic and Benzylic compoundscompounds

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: SSolvolysis Rates: SNN11Table 10-13Table 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 Allylic and Benzylic compounds 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 Reaction with KI in Acetone: SAcetone: SNN22Table 10-14Table 10-14

krel

Ethyl chlorideAllyl chlorideMethyl chlorideBenzyl chloride

1 33 93 93

60° C


Vinyl and Phenyl Vinyl and Phenyl CompoundsCompounds

Vinyl and Phenyl compounds are completely inert in both

SN1 and SN2 reactions!!

vinyl phenyl

CCH2

Cl

H Cl


Reactivity order for SReactivity order for SNN11

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 SReactivity order for SNN22

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 Sect. 10.8: Cyclic SystemsSystems

• 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 Bicyclic systems: Bredt’s RuleRule

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: Sect. 10.9: Carbocation Carbocation RearrangementRearrangement

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...A Closer Look...

+ +

+

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

CH3 C CH CH3

CH3

CH3

transition state


Carbocation Carbocation RearrangementRearrangement

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 IngoldSir Christopher Ingold

Source: Michigan State University, Department of Chemistry

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


Saul WinsteinSaul Winstein

Source: Michigan State University, Department of Chemistry

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


Sect. 10.10 Competing Sect. 10.10 Competing Reactions: Elimination Reactions: Elimination

-- Table 10-16-- 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: Sect. 10.11: Neighboring group Neighboring group

participationparticipation+ 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 SUnder SNN2 Conditions2 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 SInternal SNN2 reaction 2 reaction followed by an external followed by an external

SSNN2 reaction2 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 Neighboring Group ParticipationParticipation

slow+ : X :

..

..

_

fast

Nu :

1)

2)

C C

G:

X

C C

G

C C

G

C C

G:

Nu

G:

X


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


Mustard gasMustard 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 Sect. 10.13: Ion-pair mechanisms (skip!!)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 ProblemIn-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 The following table may be helpful as a review be helpful as a review


Substitution Substitution versusversus EliminationElimination

SN1 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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