Nucleophilic Substitution: The SN1 and SN2 Mechanisms

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Nomenclature of alkyl halides -- common names

methylene chloride chloroform carbon tetrachloride CH2Cl2 CHCl3 CCl4

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Nomenclature of alkyl halides -- common names

methylene chloride chloroform carbon tetrachloride CH2Cl2 CHCl3 CCl4

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More common and IUPAC names

isopropyl chloride sec-butyl chloride isobutyl chloride tert-butyl chloride allyl chloride vinyl chloride benzyl chloride phenyl chloride (2-chloropropane) (2-chlorobutane) (1-chloro-2-methylpropane) (2-chloro-2-methylpropane) (3-chloro-1-propene) (chloroethene) (chloromethylbenzene) (chlorobenzene)

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Sect. 9.1: 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!!
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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

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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

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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

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H
R

d-

O
H H

C Br

d-

energy
.. __ O: .. R

C Br

OH R C H H Br

Reaction coordinate
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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

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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
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Sect. 9.2 SN2 Mechanism

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents
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The SN2 Reaction

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

Methyl group is small

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SN2 Mechanism: kinetics

The reactions follows second order (bimolecular) kinetics

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

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H
R

d-

O
H H

C Br

d-

energy
.. __ O: .. R

C Br

OH R C H H Br

Reaction coordinate
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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
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(S) enantiomer

For an SN2 Reaction:

EVERY REACTION EVENT ALWAYS LEADS TO INVERSION OF CONFIGURATION

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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

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Chloromethane + Iodide as the Nucleophile

Fast

I-

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tert-Butyl Chloride + Iodide as the Nucleophile

No reaction I-

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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!

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Relative Nucleophilicity
O CH3 C _ O _ O _ OH _ OCH3 _ I _ SH _ N C

CH3OH H2O

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
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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

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Sulfonate Leaving Groups

O R O S O para-Toluenesulfonate O R O S O para-Bromobenzenesulfonate Brosylate
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CH3

OTs

Tosylate

Br

OBs

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)?

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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)

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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.
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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
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How cations are complexed with aprotic solvents

H3C S CH3 O Na O S

H3C

CH3
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Now that the Na+ is complexed, the OEt can react more easily

Et O

H3C Br

Et O CH3

Br

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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
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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
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Sect. 9.3: SN1 Mechanism

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents
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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

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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

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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
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SN1 Reaction: kinetics

The reactions follows first order (unimolecular) kinetics

Rate = k
1 [R-Br]

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SN1 Reaction: stereochemistry

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

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Stereochemistry in SN1 reactions racemic product

Slow Pr CH3-O-H C Br polar H3C protic Et o 3 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

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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
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SN1 Reaction: substrate structure

krel CH3 Br CH3 CH2 Br CH3 CH Br CH3 CH3 CH3 C CH3
Solvolysis in water at 50C
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no reaction

1.00

11.6

Br

6 1.2 x 10

SN1 Reaction: substrate structure

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

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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

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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.
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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
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Typical solvolysis reaction

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

Polar solvent stabilizes the carbocation!

Solvent is the nucleophileCH -O-H

3

planar carbocation Pr H3C Et C O CH3 H Pr H Et C O CH3

H fast

Pr C H3C Et

front side attack

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

CH3-O-H Fast

back side attack

H3C H

Pr O CH3 Et H fast

H3C

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

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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).

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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!!
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 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.

SN2 versus SN1 Reactions (continued)

If the medium is acidic or neutral, expect SN1.

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Effect of b-substitution
on SN2 reactivity
krel

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

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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

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benzyl bromide

Solvolysis Rates: SN1

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

80% Ethanol-water at 50
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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

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Reaction with KI in Acetone: SN2

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

60 C
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Vinyl and Phenyl Compounds

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

H CH2 C Cl vinyl phenyl

Cl

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Reactivity order for SN1

CH2 R C R R Br Br R CH Br R

>
H H C C CH2 Br H

>

>>

R CH2

Br

>> CH3-Br >>

methyl
R R

Br H C Br

3o

Benzyl Allyl

phenyl vinyl Inert!! No reaction

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Reactivity order for SN2

About same reactivity
CH2 Br = CH3-Br R CH2 Br R R C R R Br

>

>
R

CH Br

>>>

>> >
R R phenyl vinyl

Br H C Br

H H C C CH2 Br H

methyl

2o

3o
Can not undergo SN2

Benzyl Allyl

Inert!! No reaction!!

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Sect. 9.4: 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
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A Closer Look...
CH3 CH3 C CH3 CH3 CH3 C + CH CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3

CH3
transition state
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Carbocation Rearrangement

CH3 CH3 C CH3

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CH

CH3

Carbocation Rearrangement

CH3 CH3 C CH3

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CH

CH3

Carbocation Rearrangement

CH3 CH3 C CH3

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CH

CH3

Carbocation Rearrangement

CH3 CH3 C CH CH3

CH3
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Carbocation Rearrangement

CH3 CH3 C CH CH3

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CH3

Carbocation Rearrangement

CH3 CH3 C CH CH3

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CH3

Carbocation Rearrangement

CH3 CH3 C CH CH3

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CH3

Carbocation Rearrangement

CH3 CH3 C CH CH3

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CH3

Sect. 9.5: 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)-(+) !!!

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_ O

_ + Br

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

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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

..

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Neighboring Group Participation

1) G: C C X slow C G C + .. _ :X: ..

2) C

G C fast

G: C C Nu

G:

Nu :

X
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Neighboring group participation: Summary

Retention of configuration Enhanced rate of reaction

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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 S

Cl

Cl

Mustard gas

Neighboring group participation Internal SN2 O-Enzyme External SN2

Cl Cl S

Cl S

O-Enzyme

Cl

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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.

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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

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