chap10

CHAPTER 10

CHAPTER 10

Nucleophilic Substitution

Nucleophilic Substitution

The S

Sect.

Sect. 10.1: 10.1: Overview Overview of of nucleophilicnucleophilic

substitution

substitution

•

• The The substitutiosubstitution n reaction: reaction: SS_NN1 and S1 and S_NN22

•

• Primary halides = SPrimary halides = S_NN22

•

• Secondary halides = both mechanisms!Secondary halides = both mechanisms!

•

• Tertiary halides = STertiary halides = S_NN11

•

• Leaving Leaving groups: groups: halogens halogens most most commoncommon

•

• There are a number of differentThere are a number of different

nucleophiles!!

nucleophiles!!

WWU -- Chemistry

Sect.

Sect. 10.1: 10.1: Overview Overview of of nucleophilicnucleophilic

substitution

substitution

•

• The The substitutiosubstitution n reaction: reaction: SS_NN1 and S1 and S_NN22

•

• Primary halides = SPrimary halides = S_NN22

•

• Secondary halides = both mechanisms!Secondary halides = both mechanisms!

•

• Tertiary halides = STertiary halides = S_NN11

•

• Leaving Leaving groups: groups: halogens halogens most most commoncommon

•

• There are a number of differentThere are a number of different

nucleophiles!!

Nucleophilic Substitution (S Nucleophilic Substitution (S_NN22)) WWU -- Chemistry WWU -- Chemistry R-CH R-CH₂₂-X-X ++ NuNu _ _ R-CH R-CH₂₂-Nu-Nu ++ XX _ _ substrate

substrate nnuucclleeoopphhiillee pprroodduucctt lleeaavviinng g ggrroouupp Oxygen Nucleophiles (S Oxygen Nucleophiles (S_NN2)2) O-H O-H  _   _  R-CH R-CH₂₂-O-H-O-H alcohol alcohol hydroxide hydroxide R-CH R-CH₂₂-X-X ++ _{+ + XX} __ O-R O-R  _   _  R-CH R-CH₂₂-O-R-O-R R-CH R-CH₂₂-X-X ++ + + XX__ ether ether alkoxide alkoxide O-C-R O-C-R  _   _  R-CH R-CH₂₂ --R-CH R-CH₂₂-X-X ++ + + XX__ ester ester carboxylate carboxylate O O O-C-R O-C-R O O

Nitrogen as a nucleophile (S Nitrogen as a nucleophile (S_NN22)) R-CH R-CH₂₂-X-X ++ NuNu _ _ R-CH R-CH₂₂-Nu-Nu + + XX _ _ substrate

substrate nucleophilenucleophile productproduct leaving groupleaving group

N NHH_{33 R-CHR-CH22-NH-NH33} ammonia ammonia R-CH R-CH₂₂-X-X ++ + + X X _ _ R-CH R-CH₂₂-NH-NH₃₃ + + X X _ _ R-CH R-CH₂₂-NH-NH₂₂ + + H-XH-X primary primary amine amine

Carbon as a nucleophile (S_N2) WWU -- Chemistry R-CH₂-X + Nu _ R-CH₂-Nu + X _

substrate nucleophile product leaving group

C  _  nitrile cyanide R-CH₂-X + _{+ X}_ R-CH₂ -R-CH₂-X + _{+ X} _ alkyne CH₂-C-R  _  R-CH₂-X + O N _{R-CH2 C N} C  _  C-H CH₂-C-R O R-CH₂ + X _ ketone C C-H

energy Reaction coordinate C H H Br -OH R .. : ..  _  _  H O C H H Br R Br C H H R

d-The S_N1 Mechanism WWU -- Chemistry 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 R R R C _R Br d -R C R R + R C R R Nu d+ d-C R R Nu R intermediate

Sect. 10.2: S_N2 Mechanism

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

The S_N2 Reaction + + : Br: .. ..  _  : .. ..  _  _.. .. CH₃ Br O H CH3 OH

Sterically accessible compounds react by this mechanism!!

S_N2 Mechanism: kinetics

•

The reactions follows second

order (bimolecular) kinetics

•

Rate = k [R-Br]

[OH

]

energy Reaction coordinate C H H Br -OH R .. : ..  _  _  H O C H H Br R Br C H H R

d-S_N2 Reaction: stereochemistry WWU -- Chemistry ..  _  : .. 3 C Br H Et CH H O (R)- enantiomer d- d-H O C CH Et H Br 3 .. .. H O C CH H Et Br _ + 3 (S) enantiomer Inversion of configuration

For an S_N2 Reaction:

EVERY REACTION EVENT ALWAYS LEADS TO

S_N2 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 WWU -- Chemistry KI in Acetone at 25°

Chloromethane + Iodide as the Nucleophile

I

tert -Butyl Chloride + Iodide as the Nucleophile WWU -- Chemistry I -No reaction

S_N2 Reaction: substrate structure

> > _C

primary secondary _tertiary CH₃-Br _CH 3-CH2-Br CH₃ CH CH₃ Br > CH₃ CH₃ CH₃ Br

Predict which is more nucleophilic

CH₃-O- or CH₃-S

-WWU -- Chemistry

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

S_N2 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, NH_2,, F

Sulfonate Leaving Groups S CH₃ O R O O S Br O R O O

para -Toluenesulfonate Tosylate

para -Bromobenzenesulfonate Brosylate R OTs

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Tosylate leaving group

(S)-(+)-1-Phenyl-2-propanol (S)-(+)-1-Methyl-2-phenylethyl tosylate C2H5O 2-Ethoxy-1-phenylpropane Is 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 CH₂CH₃ CH₃  _  + H-Cl Retention of configuration Retention or inversion? [Ts-Cl]

Inversion of Configuration CH₂ C H CH3 O S O O CH₃ CH₂ CH₃ CH₂ O C CH₂ H CH₃ + CH3 S O O O (S) R  _  O _  _CH3

S

S_NN2 2 Reaction: Reaction: solventssolvents

S

S_NN2 reactions are2 reactions are accelerated accelerated  in polar, aproticin polar, aprotic

solvents.

solvents. Consider Consider NaNa++ --_{OEt as an example of aOEt as an example of a}

nucleophile.

nucleophile.

Why are reactions accelerated? The Na

Why are reactions accelerated? The Na++

cation is complexed by the negative part of

cation is complexed by the negative part of

the aprotic solvent molecule pulling it away

the aprotic solvent molecule pulling it away

from

from – –

OEt.

OEt.

Now that the sodium ion is

Now that the sodium ion is complexed, thecomplexed, the

oxygen in the nucleophile

oxygen in the nucleophile – –

OEt is more

OEt is more

available for attack.

available for attack.

WWU -- Chemistry

•

• These solveThese solvents dnts do not o not have Ohave OH bonds H bonds in thin them. em. TheyThey

complex the cation through the lone pairs on

complex the cation through the lone pairs on oxygenoxygen

or nitrogen: or nitrogen: Acetone Acetone H H₃₃CC O O CH CH₃₃ D

Dimimetethyhyll susulfoxlfoxideide ((DMSDMSO)O)

H H₃₃CC SS O O CH CH₃₃ Di

Dimethymethylflformaormamidmidee (DMF)(DMF) _HH O O N N CHCH33 CH CH₃₃ Acetonitrile Acetonitrile _{HH CC NN} 3 3CC

How cations are complexed with aprotic

How cations are complexed with aprotic

solvents solvents H H₃₃CC SS O O CH CH₃₃ Na Na H H₃₃C_{C SS CH}CH₃₃ O O WWU -- Chemistry WWU -- Chemistry

Now that the Na

Now that the Na is complexed, theis complexed, the OOEEtt

can react more easily

can react more easily

E

S_N2 Reaction: solvents

S_N2 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

Typical protic solvents: Water H O H Methanol _H O _CH3 H O CH₂ CH3 HOEt Ethanol H O C O CH₃

Acetic acid HOAc

H O C O H Formic acid HOMe abbreviations

Sect. 10.4: S_N1 Mechanism

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

Solvolysis of tert -Butyl Bromide + _H2O + + other products acetone CH₃ C CH₃ CH₃ Br CH₃ C CH₃ CH₃ OH H Br

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

The S_N1 Mechanism WWU -- Chemistry 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

energy Reaction coordinate C R Br R R R C _R Br d -R C R R R C R O R H H C R R OH R intermediate + intermediate

S_N1 Reaction: kinetics

•

The reactions follows first order

(unimolecular) kinetics

•

Rate = k [R-Br]

S_N1 Reaction: stereochemistry

With chiral R-X compounds, the

product will be racemic (50% of each enantiomer).

Stereochemistry in S_N1 reactions – racemic product CH3 H C H3C Et Br Pr CH3-O-H C H3C Et O Pr 3osubstrate polar protic solvent! C Pr H3C Et

(S) enantiomer planar carbocation

C Pr H3C Et front side attack back side attack CH3-O-H CH3-O-H Slow Pr CH3 Et O H3C H Pr CH3 Et O H3C C H Et O Pr _CH3 H H 50% (S) 50% (R) Fast fast fast WWU -- Chemistry

energy Reaction coordinate C R Br R R R C _R Br d -R C R R R C R O R H₃C H C R R O-CH₃ R intermediate + intermediate

S_N1 Reaction: substrate structure WWU -- Chemistry krel no reaction 1.00 11.6 6 1.2 x 10 CH₃ Br CH₃ CH₂ Br CH₃ CH Br CH₃ CH₃ C Br CH₃ CH₃ Solvolysis in water at 50°C

S_N1 Reaction: substrate structure

tertiary>secondary>primary > methyl Primary and methyl halides are very

unreactive! They don’t go by S_N1 reactions.

WWU -- Chemistry C tertiary C tertiary secondary > primary + carbocation (very stable) secondary carbocation + CH₃ > Br CH₃ CH₃ CH₃ CH CH₃ Br CH₃ CH CH₃ CH₃ CH₃-CH₂-Br CH₃ + primary 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 S_N1 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:

A protic solvent acts as both a solvent and nucleophile in S_N1 reactions - solvolysis:

Water H O H Methanol _H O _CH3 H O CH₂ CH3 HOEt Ethanol H O C O CH₃

Acetic acid HOAc

H O C O H Formic acid HOMe abbreviations

Typical solvolysis reaction CH3 H C H3C Et Br Pr CH3-O-H C H3C Et O Pr 3osubstrate polar protic solvent! C Pr H3C Et

(S) enantiomer planar carbocation

C Pr H3C Et front side attack back side attack CH3-O-H CH3-O-H Slow Pr CH3 Et O H3C H Pr CH3 Et O H3C C H Et O Pr _CH 3 H H 50% (S) 50% (R) Fast fast fast Solvent is the nucleophile

Polar solvent stabilizes the carbocation!

Leaving groups

• Leaving groups are the same as in S_N2 reactions:

• Cl, Br, I, OTs are the usual ones.

S_N1 Reaction: solvent polarity

•S_N1 solvolysis reactions go much

faster in trifluoroacetic acid and water (high ionizing power).

•S_N1 solvolysis reactions go slower

in ethanol and acetic acid (lower ionizing power).

S_N2 versus S_N1 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!!

S_N2 versus S_N1 Reactions (continued)

• If the reaction medium is KI or NaI in acetone,

this demands an S_N2 mechanism.

• If the reaction medium is AgNO₃ in ethanol,

this demands an S_N1 mechanism.

• If the medium is basic, look for S_N2.

Comparison of S_N1 and S_N2 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 S_N2 reagents!!

• Silver nitrate in ethanol is a typical S_N1

Sect. 10.7: Special Cases

Neopentyl compounds are very 

unreactive in S_N2 reactions.

on S_N2 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 b b b b

Neopentyl Transition State WWU -- Chemistry C C Y Nu R₁ R₂ R₃ Nu Y R₁ H H

Allylic and Benzylic compounds

Allylic and benzylic compounds are especially reactive in S_N1 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

Solvolysis Rates: S_N1 Table 10-13 WWU -- Chemistry k_rel Ethyl chloride Isopropyl chloride Allyl chloride Benzyl chloride tert-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 S_N2 reactions.

They are more reactive than typical primary compounds!

CH₂-Br CH₂=CH-CH₂-Br

Reaction with KI in Acetone: S_N2 Table 10-14 WWU -- Chemistry k_rel Ethyl chloride Allyl chloride Methyl chloride Benzyl 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 C CH₂ Cl H Cl

Reactivity order for S_N1 R C R R Br > CH2 Br C C CH2 Br H H H > 3o Benzyl Allyl R CH R Br 2o > 1o R CH2 Br > >> CH3-Br methyl >> Br C Br R R H phenyl vinyl Inert!! No reaction WWU -- Chemistry

Reactivity order for S_N2 R C R R Br CH2 Br C C CH2 Br H H H 3o Benzyl Allyl R CH R Br 2o 1o R CH2 Br CH3-Br methyl >> Br C Br R R H phenyl vinyl Inert!! No reaction!! > > > Can not undergo SN2 = >> _>

Sect. 10.8: Cyclic Systems

• Cyclopropyl and cyclobutyl halides are

very unreactive in both S_N1 and S_N2

reactions

• Cyclopentyl halides are more reactive

than cyclohexyl halides in S_N1 and S_N2

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

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Cl

AgNO₃ Ethanol

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 CH₃ OR a carbocation

A Closer Look... WWU -- Chemistry + ₊ + 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

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

Carbocation Rearrangement

CH₃ C CH CH₃ CH₃

CH₃

Sir Christopher Ingold

Source: Michigan State University, Department of Chemistry

Saul Winstein

WWU -- Chemistry

Source: Michigan State University, Department of 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 S_N2.

• Primary compounds give mostly substitution with

non-bulky nucleophiles. A non-bulky base (tert-butoxide) gives elimination.

• Tertiary compounds should be reacted under solvolysis

Sect. 10.11: Neighboring group participation WWU -- Chemistry + 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 S_N2 Conditions  _   _  (R) .. : .. - - _  + Br  _  (S) Inversion of configuration C Br CH₃ H C O O CH₃ O CH₃ C H C Br O O O CH₃ CH₃ O C CH₃ H C O O

Internal S_N2 reaction followed by an external S_N2 reaction WWU -- Chemistry ..  _  : .. (R) slow : :  _  _.. : .. .. .. + H+ + Br  _  (R) Retention of Configuration C Br CH₃ H C O O C C O CH₃ H O O CH₃ H C O CH₃ CH₃ C H O O

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 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 Cl Cl S Cl Neighboring group participation Internal S_N2 S Cl O-Enzyme External S_N2 S O-Enzyme Cl Cl Cl Cl Mustard gas

Sect. 10.13: Ion-pair mechanisms (skip!!)

• S_N1 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!!

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.

The following table may be helpful as a review