WWU -- Chemistry

CHAPTER 10
Nucleophilic Substitution The SN1 and SN2 Mechanisms

WWU -- Chemistry

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!!

WWU -- Chemistry

Nucleophilic Substitution (SN2)

Oxygen Nucleophiles (SN2)
_

R-CH 2-X
substrate

+ _

Nu

R-CH2-Nu
product

nucleophile

leaving group

R-CH 2-X +

O-H hydroxide _ R-CH 2-X + O-R alkoxide R-CH 2-X + _ O-C-R

R-CH 2-O-H + alcohol R-CH 2-O-R + ether R-CH 2-O-C-R + O ester

O carboxylate

WWU -- Chemistry

Nitrogen as a nucleophile (SN2)

_

R-CH 2-X
substrate

Nu

R-CH2-Nu
product
+

nucleophile

leaving group
_

R-CH 2-X +

NH 3 ammonia
_

R-CH2-NH3

R-CH 2-NH3 X

R-CH 2-NH2 primary amine

H-X

WWU -- Chemistry

Carbon as a nucleophile (SN2)

_

R-CH 2-X
substrate

Nu

R-CH2-Nu
product

nucleophile

leaving group

_ C N R-CH 2-X + cyanide _ R-CH 2-X + C C-H _ R-CH 2-X + CH2-C-R O

R-CH 2 C N + nitrile R-CH 2- C C-H + alkyne

X
_

R-CH 2 CH2-C-R + X ketone O

WWU -- Chemistry

H
R

d-

O
H H

C Br

d-

energy
.. __ O: .. R

C Br

OH R C H H Br

Reaction coordinate

WWU -- Chemistry

The SN1 Mechanism

1) CH3 CH3 C : Br: .. 2) CH3 CH3 C + CH3 + : Nu _ fast CH3 CH3 C Nu CH3 CH3 slow CH3 CH3 C + CH3 + .. _ : Br : ..

carbocation

WWU -- Chemistry

R C R

d+ R

d+
R

d-

Br

d+R

C R R Nu

energy

R C R

intermediate
R C R Nu

R
R R C R Br

Reaction coordinate

WWU -- Chemistry

Sect. 10.2: SN2 Mechanism

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

WWU -- Chemistry

The SN2 Reaction

Sterically accessible compounds react by this mechanism!!
_ CH3 Br + .. :O .. H .. CH3 OH .. + .. _ : Br : ..

Methyl group is small

WWU -- Chemistry

SN2 Mechanism: kinetics

The reactions follows second

order (bimolecular) kinetics

Rate = k [R-Br]1 [OH-]1

WWU -- Chemistry

H
R

d-

O
H H

C Br

d-

energy
.. __ O: .. R

C Br

OH R C H H Br

Reaction coordinate

WWU -- Chemistry

SN2 Reaction: stereochemistry

H .. _ O: .. CH3 C H Et Br
H CH3 dO H C Et dBr

(R)- enantiomer

Inversion of configuration

.. O ..

CH3 C
+

Br

H Et

(S) enantiomer

WWU -- Chemistry

For an SN2 Reaction:

EVERY REACTION EVENT ALWAYS LEADS TO INVERSION OF CONFIGURATION

WWU -- Chemistry

SN2 Reaction: substrate structure (Table 10-5)

krel CH3 Br 150 1

CH3 CH2 Br

CH3 CH Br CH3 CH3 CH3 C CH3 Br

0.008

unreactive! KI in Acetone at 25

WWU -- Chemistry

Chloromethane + Iodide as the Nucleophile

Fast

I-

WWU -- Chemistry

tert-Butyl Chloride + Iodide as the Nucleophile

No reaction I-

WWU -- Chemistry

SN2 Reaction: substrate structure

CH3 CH3-Br > CH3-CH2-Br > CH3 CH CH3 primary secondary Br > CH3 C CH3 tertiary Br

Reactivity order---- fastest to slowest!

WWU -- Chemistry

Predict which is more nucleophilic

CH3-O or CH3-S
-

CH3-S

is more nucleophilic!

WWU -- Chemistry

Relative Nucleophilicity
_ OH _ O _ O _ OCH3 _ I _ SH _ N C

CH3OH H2O

O CH3 C

Increasing Nucleophilicty

1) In general, stronger bases are better nucleophiles 2) However, iodide doesnt 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

WWU -- Chemistry

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

WWU -- Chemistry

Sulfonate Leaving Groups

O R O S O para-Toluenesulfonate O R O S O para-Bromobenzenesulfonate Brosylate Br R OBs Tosylate CH3 R OTs

WWU -- Chemistry

Tosylate leaving group

CH3 H C OH CH3 CH2 O S O Cl [Ts-Cl] CH3 H C O Ts CH2 + H-Cl

Retention of configuration

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

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

CH3 H C O Ts CH3 CH2 CH O CH2 CH3 CH2 C2H5O

_

Retention or inversion? 2-Ethoxy-1-phenylpropane

Is this ether (R) or (S)?

WWU -- Chemistry

Inversion of Configuration
CH3 CH2 O_ H CH3 C CH2 O O S O CH3

(S)

CH3 CH2 O

CH3 H C CH2 + CH3

O S O O
_

(R)

WWU -- Chemistry

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:

O Acetone H3 C CH3 O S O Dimethylf ormamide (DMF) H N CH 3 CH 3

Dimethyl sulfoxide (DMSO)

H3 C

CH3

Acetonitrile

H3 C C N
WWU -- Chemistry

WWU -- Chemistry

How cations are complexed with aprotic solvents

H3C S CH3 O Na O S

H3C

CH3

WWU -- Chemistry

Now that the Na+ is complexed, the OEt can react more easily

Et O

H3C Br

Et O CH3

Br

SN2 Reaction: solvents

SN2 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 O Et The nucleophile is hydrogen bonded to ethanol - reduces nucleophilicity

WWU -- Chemistry

Protic solvents
Typical protic solvents:
Water H O H O CH3 HOMe

abbreviations

Methanol

Ethanol

CH2 CH3

HOEt

Acetic acid

C CH3 O

HOAc

Formic acid

C H O
WWU -- Chemistry

WWU -- Chemistry

Sect. 10.4: SN1 Mechanism

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

WWU -- Chemistry

Solvolysis of tert-Butyl Bromide

Acetone is used to dissolve everything! Water is the solvent and nucleophile (solvolysis).

CH3 CH3 C Br CH3 + H2O acetone

CH3 CH3 C OH + other products CH3 + H Br

WWU -- Chemistry

The SN1 Mechanism

1) CH3 CH3 C : Br: .. 2) CH3 CH3 C + CH3 + :O: H H CH3 fast CH3 C :O H 3) CH3 CH3 C :O H + CH3 H
fast

CH3 CH3 slow CH3 C + CH3 +

.. _ : Br : ..

carbocation

CH3 + H

CH3 CH3 C :O .. CH3 H + H +

1935: Hughes & Ingold

WWU -- Chemistry

R C R

d+ R

dR R C R O H intermediate H

Br

energy

R C R

+ R

intermediate
R
R R C R Br

R C R OH

Reaction coordinate

WWU -- Chemistry

SN1 Reaction: kinetics

The reactions follows first order

(unimolecular) kinetics
Rate = k [R-Br]1

WWU -- Chemistry

SN1 Reaction: stereochemistry

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

WWU -- Chemistry

Stereochemistry in SN1 reactions racemic product

Slow Pr CH3-O-H C Br polar H3C protic Et 3o substrate solvent! (S) enantiomer CH3-O-H front side attack Pr C H3C Et CH3-O-H Fast back side attack Pr C H3C Et planar carbocation Pr H3C Et C O CH3 H Pr H Et C O CH3

H fast

50% (S) Pr O CH3 Et 50% (R)

H3C H

Pr O CH3 Et H fast

H3C

WWU -- Chemistry

R C R

d+ R

dR R C R O H intermediate H3C

Br

energy

R C R

+ R

intermediate
R
R R C R Br

R C R O-CH3

Reaction coordinate

WWU -- Chemistry

SN1 Reaction: substrate structure

krel CH3 Br CH3 CH2 Br CH3 CH Br CH3 CH3 CH3 C CH3
Solvolysis in water at 50C

no reaction

1.00

11.6

Br

6 1.2 x 10

WWU -- Chemistry

SN1 Reaction: substrate structure

tertiary>secondary>primary > methyl Primary and methyl halides are very unreactive! They dont go by SN1 reactions.

WWU -- Chemistry

CH3 CH3 C CH3 tertiary Br > CH3 CH CH3 secondary primary Br > CH3-CH2-Br > CH3-Br

CH3 CH3 C+ CH3 tertiary carbocation (very stable) three methyl groups CH3

+
CH CH3 CH3

+
CH 2

+
CH3

secondary carbocation

primary carboc carbocation (unstable) one methyl group

very unstable carbocation no methyl groups

two methyl groups

WWU -- Chemistry

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:
Water H O H O CH3 HOMe

abbreviations

Methanol

Ethanol

CH2 CH3

HOEt

Acetic acid

C CH3 O

HOAc

Formic acid

C H O
WWU -- Chemistry

WWU -- Chemistry

Typical solvolysis reaction

Polar solvent stabilizes the carbocation!
Pr C H3C Et planar carbocation Pr H3C Et C O CH3 H Pr H Et C O CH3

Slow Pr CH3-O-H C Br polar H3C protic Et 3o substrate solvent! (S) enantiomer CH3-O-H front side attack Pr C H3C Et CH3-O-H Fast back side attack

Solvent is the nucleophile

H fast

50% (S) Pr O CH3 Et 50% (R)

H3C H

Pr O CH3 Et H fast

H3C

WWU -- Chemistry

Leaving groups
Leaving groups are the same as in SN2 reactions: Cl, Br, I, OTs are the usual ones.

WWU -- Chemistry

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.

WWU -- Chemistry

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! Dont 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!!

WWU -- Chemistry

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.

WWU -- Chemistry

Comparison of SN1 and SN2 Reactions

See Table 10-10 on page 936. Great

table!!
Section 10-5: Solvent effects; been

there done that!!

WWU -- Chemistry

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!!

WWU -- Chemistry

Sect. 10.7: Special Cases

Neopentyl compounds are very unreactive in SN2 reactions.

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

krel

WWU -- Chemistry

b H CH2 CH2 Br b CH3 CH2 CH2 Br

CH3 CH3 CH CH2 Br b CH3 CH3 C

1.0

0.65

0.15

b CH3

CH2 Br

Neopentyl bromide

0.000026

KI in Acetone at 25

WWU -- Chemistry

Neopentyl Transition State

Y Y H C H R1 R1

C
R2 R3

Nu Nu

WWU -- Chemistry

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 allyl bromide

benzyl bromide

WWU -- Chemistry

Solvolysis Rates: SN1 Table 10-13

krel Ethyl chloride Isopropyl chloride Allyl chloride Benzyl chloride tert-Butyl chloride very small 1 74 140 12,000

80% Ethanol-water at 50

WWU -- Chemistry

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 allyl bromide

benzyl bromide

WWU -- Chemistry

Reaction with KI in Acetone: SN2 Table 10-14

krel Ethyl chloride Allyl chloride Methyl chloride Benzyl chloride 1 33 93 93

60 C

WWU -- Chemistry

Vinyl and Phenyl Compounds

Vinyl and Phenyl compounds are completely inert in both SN1 and SN2 reactions!!

H CH2 C Cl vinyl phenyl

Cl

WWU -- Chemistry

Reactivity order for SN1

CH2 R C R R Br

Br

>
H H C C CH2 Br H

>

R CH Br R

>>

R CH2

Br

>> CH3-Br >>

methyl
R R

2o

1o

Br H C Br

Benzyl Allyl

phenyl vinyl Inert!! No reaction

WWU -- Chemistry

Reactivity order for SN2

About same reactivity

CH2

Br

CH3-Br

>

R CH2

Br

>
R

CH Br

>>>

R C R R

Br

>> >
R R

H H C C CH2 Br H

methyl

1o

2o

3o
Can not undergo SN2

Br H C Br

Benzyl Allyl

phenyl vinyl Inert!! No reaction!!

WWU -- Chemistry

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.

WWU -- Chemistry

Bicyclic systems: Bredts Rule

You cant have p orbitals on a bridgehead position in a rigid bicyclic molecule. -- You cannot form a carbocation at a bridgehead position.
bridgehead

bridgehead

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

WWU -- Chemistry

AgNO 3 Ethanol Cl

No reaction!

WWU -- Chemistry

Sect. 10.9: Carbocation Rearrangement

1) CH3 CH3 C CH CH3 slow CH3 CH3 C CH3 CH CH3 + _ + Br CH3 Br

a carbocation
2) CH3 CH3 C CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3

3)

CH3 CH3 C + CH CH3 CH3 + ROH

CH3 CH3 C CH CH3 + + H

OR CH3

WWU -- Chemistry

A Closer Look...
CH3 CH3 C CH3 CH3 CH3 C + CH CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3

CH3
transition state

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH3 CH CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH3 CH CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH3 CH CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH CH3

CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH CH3 CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH CH3 CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH CH3 CH3

WWU -- Chemistry

Carbocation Rearrangement

CH3 CH3 C CH CH3 CH3

WWU -- Chemistry

Sir Christopher Ingold

Source: Michigan State University, Department of Chemistry http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

WWU -- Chemistry

Saul Winstein

Source: Michigan State University, Department of Chemistry http://www.chemistry.msu.edu/Portraits/PortraitsHH_collection.shtml

WWU -- Chemistry

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 nonbulky nucleophiles. A bulky base (tert-butoxide) gives elimination. Tertiary compounds should be reacted under solvolysis conditions to give substitution!!!

WWU -- Chemistry

Sect. 10.11: Neighboring group participation

O CH3 CH C Br (R)-(+) _ O _ + CH3O > 0.5 M CH3OH inversion O CH3 CH C OCH3 (S)-(-) _ O + Br _

O CH3 CH C Br (R)-(+) _ O _ + CH3O < 0.1 M CH3OH retention

O CH3 CH C OCH3 (R)-(+) !!! _ O _ + Br

WWU -- Chemistry

Under SN2 Conditions

_ .. CH3 O : .. CH3 H C _O (R) O C Br dCH3 O H _O CH3 C C O dBr

CH3 Inversion of configuration CH3 O C H C _O (S) O +

_ Br

WWU -- Chemistry

Internal SN2 reaction followed by an external SN2 reaction

CH3 _ .. :O .. C H C O (R) Br slow O C O :O : CH3 H Retention of Configuration H C _ + Br H _ .. C :O .. O (R) CH3 CH3 C .. O CH3 + H

..

WWU -- Chemistry

Neighboring Group Participation

1)

G: C C X slow C

G C +

.. _ :X: ..

2) C

G C fast

G: C C Nu

G:

Nu :

WWU -- Chemistry

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.

Cl S

Cl

Cl S

Cl

Mustard gas

Neighboring group participation Internal SN2 O-Enzyme External SN2

Cl Cl S

Cl S

O-Enzyme

Cl

WWU -- Chemistry

WWU -- Chemistry

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 doesnt 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!!

WWU -- Chemistry

In-Class Problem
For the following reaction,

H2O CH3 CH CH CH2 OTs acetone

A) B)

Identify the mechanism of this reaction. Predict the product(s) of this reaction, and identify them as major or minor, if appropriate.

WWU -- Chemistry

The following table may be helpful as a review

Substitution versus Elimination

SN1
Substrate Strong effect; reaction favored by tertiary halide Does not occur Favored when nucleophile is the solvent solvolysis Can occur in polar, protic solvents Very strong effect; reaction favored by polar, protic solvents Weak effect; reaction favored by good nucleophile/weak base Strong effect; reaction favored by good leaving group

SN2
Strong effect; reaction favored by methyl or primary halide Highly favored Does not occur

E1
Strong effect; reaction favored by tertiary halide Does not occur Occurs under solvolysis conditions or with strong acids Can occur in polar, protic solvents Very strong effect; reaction favored by polar, protic solvents Weak effect; reaction favored by weak base

E2
Strong effect; reaction favored by tertiary halide Occurs with strong base! Highly favored when strong bases (OH-, OR-) are used Favored when strong bases are used Strong effect; reaction favored by polar, aprotic solvent Strong effect; reaction favored by strong base Strong effect; reaction favored by good leaving group

Reactivity primary Reactivity tertiary

Reactivity secondary Solvent

Favored by good nucleophile in polar, aprotic solvents Strong effect; reaction favored by polar, aprotic solvents Strong effect; reaction favored by good nucleophile/weak base Strong effect; reaction favored by good leaving group

Nucleophile/Base

Leaving Group

Strong effect; reaction favored by good leaving group

WWU -- Chemistry