chap10

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CHAPTER 10 Nucleophilic Substitution The SN1 and SN2 Mechanisms

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Sect. 10.1: Overview of nucleophilic substitution • The

substitution reaction: SN1 and SN2 substitution • Primary halides = S N2 • Secondary halides = both mechanisms! • Tertiary halides = SN1 • Leaving groups: halogens most common • There are a number of different nucleophiles!!

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Sect. 10.1: Overview of nucleophilic substitution • The

substitution reaction: SN1 and SN2 substitution • Primary halides = S N2 • 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

nucleophile

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

_

R-CH2-Nu product

+

leaving group

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

X

_

X X

_

X

_

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Nitrogen as a nucleophile (SN2) _

R-CH 2-X

+

substrate

nucleophile

R-CH2-Nu product

+

NH 3 ammonia

X

leaving group _

+

R-CH 2-X +

+

Nu

_

R-CH2-NH3

X

_

R-CH 2-NH3 X

R-CH 2-NH2 primary amine

+

H-X

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Carbon as a nucleophile (SN2) _

R-CH2-X substrate

+

Nu

nucleophile

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

_

R-CH2-Nu product

+

X

leaving group

R-CH2 C N + nitrile

X

_

_

R-CH2- C C-H + alkyne

X _

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

O

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H

R

d-

O

C

H H

Br

d-

energy

H

 _  ..  _  O: .. R

H

C

H

Br

Reaction coordinate

OH R C H H Br

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The SN1 Mechanism 1)

CH3 CH3 C

CH3 CH3

slow

CH3 C +

CH3

..  _  : Br : ..

+

carbocation

: Br: .. 2) CH3 CH3 C +

CH3 CH3

+ : Nu

_

fast

CH3 C Nu

CH3

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d+R

R C R

d+ R

Br

d-

C R R Nu

d+R

R C

R

energy

intermediate

R R R C R Br

R C R Nu

Reaction coordinate

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Sect. 10.2: 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

Methyl group is small

.. CH3 OH ..

+

..  _  : Br : ..

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SN2 Mechanism: kinetics • The

reactions follows second order (bimolecular) kinetics

• Rate

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

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H

R

d-

O

C

H H

Br

d-

energy

H

 _  ..  _  O: .. R

H

C

H

Br

Reaction coordinate

OH R C H H Br

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SN2 Reaction: stereochemistry H

..  _  O: ..

CH3

CH3 C H

d-

Br

H

d-

O

Et

C H

Et

(R)- enantiomer

Inversion of configuration

H

.. O ..

CH 3 _

C

H Et

(S) enantiomer

+

Br

Br

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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

CH3 CH2 Br

1

CH3 CH Br

0.008

CH3 CH3 CH3 C CH3

Br

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

Br >

CH3 primary

secondary

Reactivity order---- fastest to slowest!

CH3

C CH3 tertiary

Br

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Predict which is more nucleophilic -

-

CH3-O or CH3-S -

CH3-S

is more nucleophilic!

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Relative Nucleophilicity

CH3OH H2O

O CH3 C

 _  OH  _  O

 _  O

 _  OCH3

 _   _  I

SH  _  N C

Increasing Nucleophilicty

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

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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

CH3

R

OTs

O para -Toluenesulfonate

Tosylate

O R

O

S

Br

R

OBs

O para -Bromobenzenesulfonate

Brosylate

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Tosylate leaving group CH3 H

C

OH CH3

CH2

CH3

O

H

S

Cl

O

[Ts-Cl]

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

CH2 C2H5O

 _ 

Retention or inversion?

CH3 CH2 CH

O CH2 CH3

2-Ethoxy-1-phenylpropane

Is this ether (R) or (S)?

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Inversion of Configuration CH3 CH2

H

O _ 

O

CH3 C

CH2

O

S

CH3

O

(S)

CH3 CH2 O

CH3 H C

O

CH2 +

R

CH3

S O

O

 _ 

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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.

Aprotic solvents • These

solvents solve nts do do not have OH OH bonds in them. them. They complex the cation through the lone pairs on oxygen or nitrogen: O Acetone H3 C

CH3 O

Dimet imethy hyll sulfox sulfoxide ide (DMSO) DMSO)

H3 C

S

CH3

O Dimethy Di methylf lforma ormamid mide e (DMF)

Acetonitrile

H3 C C N

H

N

CH3 CH3

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How cations are complexed with aprotic solvents H3C S CH3 O Na

H3C

O S

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

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

Protic solvents Typical protic solvents: Water

H

O

Methanol

H

Ethanol

H

Acetic acid

Formic acid

abbreviations

H

H

H

O

CH3

HOMe

O

CH2 CH3

HOEt

O

C CH3 O

O

C H O

HOAc

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Sect. 10.4: 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 CH3 C Br

CH3

+

H2O

acetone

CH3 C

CH3

+

H

Br

OH + other products

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The SN1 Mechanism 1)

CH3 CH3 C

CH3 CH3

slow

CH3 C +

: Br: .. 2)

+

carbocation

CH3 CH3 C +

CH3

..  _  : Br : ..

H CH3

+ :O:

CH3 fast

CH3 C

H

:O

CH3 +

H

H 3)

CH3

CH3 CH3 C :O H

CH3 +

H

fast

CH3 C :O ..

CH3

+

H

+

H

1935: Hughes & Ingold

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d+R

R C R Br

d-

+ R

R R C R O H intermediate H

R C R

energy

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 [R-Br]1

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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 C

CH3-O-H

Pr C Br H3C Et 3o substrate

polar protic solvent!

(S) enantiomer

H3C Et planar carbocation

CH3-O-H front side attack Pr C H3C Et CH3-O-H Fast

back side attack

Pr H3C Et

H3C H

C O

CH3 H

Pr

H fast

Pr H

O CH3 Et

fast

H Et

H3C

C O

CH3

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

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d+R

R C R Br

d-

+ R

R R C R O H intermediate H3C

R C R

energy

intermediate R

R C R O-CH3

R R C R Br

Reaction coordinate

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SN1 Reaction: substrate structure CH3 Br

krel no reaction

CH3 CH2 Br

1.00

CH3 CH Br

11.6

CH3 CH3 CH3 C

Br

6 1.2 x 10

CH3 Solvolysis in water at 50°C

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SN1 Reaction: substrate structure tertiary>secondary>primary > methyl Primary and methyl halides are very unreactive! They don’t go by S N1 reactions.

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CH3 CH3

C

Br

>

CH3

secondary

CH3 CH3

C+ CH3

tertiary carbocation (very stable) three methyl groups

Br >

CH3-CH2-Br

> CH3-Br

CH3

CH3 tertiary

CH

primary

+

CH3

CH

+

CH3

CH 2

+

CH3

CH3

secondary carbocation

two methyl groups

primary carbocation (unstable) one methyl group

very unstable carbocation no 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. •

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

H

O

Methanol

H

Ethanol

H

Acetic acid

Formic acid

abbreviations

H

H

H

O

CH3

HOMe

O

CH2 CH3

HOEt

O

C CH3 O

O

C H O

HOAc

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Typical solvolysis reaction

Slow Pr C

CH3-O-H

Pr C Br H3C Et 3o substrate

Solvent is the (S) enantiomer nucleophile

polar protic solvent!

H3C Et planar carbocation

CH3-O-H front side attack Pr C H3C Et CH3-O-H Fast

back side attack

Pr H3C Et

H3C H

C O

CH3 H

Pr

H fast

Pr H

O CH3 Et

fast

H Et

H3C

C O

CH3

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

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Leaving groups •

Leaving groups are the same as in S N2 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).

• See

table 10-9.

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SN2 versus SN1 Reactions • A primary alkyl

halide or a methyl halide should react by an S N2 process. Look for a good nucleophile, such as hydroxide, methoxide, etc. in an polar aprotic solvent. • A tertiary alkyl halide should react by an S N1 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!!

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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 S N2.

• If

the medium is acidic or neutral, expect S N1.

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Comparison of SN1 and SN2 Reactions • See

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

• Section

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

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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!!

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Sect. 10.7: Special Cases Neopentyl compounds are very  unreactive in SN2 reactions.

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

H CH 2 CH 2 Br

1.0

b

CH 3 CH 2 CH 2 Br

0.65

CH 3 CH 3 CH CH 2 Br

0.15

b

CH 3 CH 3 C

b

CH 2 Br

Neopentyl bromide

0.000026

CH 3 KI in Acetone at 25°

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Neopentyl Transition State Y Y

R1 R1

H C

C R2

H

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

benzyl bromide

CH2=CH-CH2-Br allyl bromide

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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°

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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

benzyl bromide

CH2=CH-CH2-Br allyl bromide

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Reaction with KI in Acetone: SN2 Table 10-14 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!!

Cl

H CH2

C Cl

vinyl

phenyl

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Reactivity order for SN1

CH2 R C R R

3

o

Br

Br

>

> H H C C CH2 Br H

Benzyl Allyl

R CH Br

>>

R CH2

Br

>> CH3-Br >>

Br H C Br

R

2o

1o

methyl

R R

phenyl vinyl Inert!! No reaction

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Reactivity order for SN2  About same reactivity

CH2

Br

H H C C CH2 Br H

Benzyl Allyl

=

CH3-Br

methyl

>

R CH2

1o

Br

>

R CH Br R

2o

>>>

R C R R

Br

3o Can not undergo SN2

>>>

Br H

R

C

Br

R phenyl vinyl Inert!! No reaction!!

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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.

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Bicyclic systems: Bredt’s Rule p orbitals on a bridgehead position in a rigid bicyclic molecule.

 You can’t have

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

+ bridgehead

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

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AgNO 3 Ethanol Cl

No reaction!

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Sect. 10.9: Carbocation Rearrangement 1)

CH3 CH3 C

CH3 slow

CH CH3

CH3 Br

CH3 C CH3

CH CH3 +

 _  + Br

a carbocation 2)

CH3 C CH3

3)

CH3

CH3

CH3 C +

CH CH3 +

CH3

CH3

CH3 CH3 C +

CH CH3

CH CH3 CH3

+

ROH

CH3 C

CH CH3

OR CH3

+

+ H

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A Closer Look... CH3 CH3 C CH3

CH3 CH CH3 +

CH3 C +

CH3 CH3

C

+

CH CH3

CH3 transition state

CH CH3 CH3

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Carbocation Rearrangement

CH3 CH3 C CH3

CH

CH3

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Carbocation Rearrangement

CH3 CH3 C CH3

CH

CH3

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Carbocation Rearrangement

CH3 CH3 C CH3

CH

CH3

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Carbocation Rearrangement

CH3 CH3 C

CH

CH3

CH3

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Carbocation Rearrangement

CH3 CH3 C

CH CH3

CH3

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Carbocation Rearrangement

CH3 CH3 C

CH CH3

CH3

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Carbocation Rearrangement

CH3 CH3 C

CH CH3

CH3

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Carbocation Rearrangement

CH3 CH3 C

CH CH3

CH3

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Sir Christopher Ingold

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

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Saul Winstein

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

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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 S N2. • 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!!! •

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Sect. 10.11: Neighboring group participation O CH3 CH C Br

O  _   _  O + CH O 3 > 0.5 M 

CH3OH inversion

CH3 CH C Br (R)-(+)

OCH3 (S)-(-)

(R)-(+)

O

CH3 CH C

 _   _  O + Br

O  _   _  O + CH O 3 < 0.1 M 

CH3OH retention

CH3 CH C

 _   _  O + Br

OCH3 (R)-(+)

!!!

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Under SN2 Conditions  _  .. CH3 O : ..

CH3 C

H

Br

C  _ O

O

CH3

CH3 O

Br

C H  _ O

C O

(R)

CH3 Inversion of configuration

CH3 O

C C

 _ O (S)

H O

+

Br

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Internal SN2 reaction followed by an external SN2 reaction H

CH3  _ 

C ..

:O ..

H

Br

slow

C

O C

C

C H  _ 

..

:O ..

:O :

CH3

CH3  _  + Br

O

O (R)

CH3 ..

O ..

C O

+

H (R)

Retention of Configuration

CH3 + H

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Neighboring Group Participation 1)

G

G: C

C

slow

C

C

+

..  _  :X: ..

X

2) C

G:

G:

G C

fast

C

C Nu

Nu :

X

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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

Cl S

Mustard gas

Cl

Cl S

Cl

Cl S

Neighboring group participation Internal SN2

O-Enzyme External SN2

O-Enzyme

Cl S

Cl

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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” S N2. • In the extreme, you could have a carbocation give only inversion of configuration by an S N1 mechanism!!

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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 identify them as major or minor , if appropriate.

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The following table may be helpful as a review