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Reaction mechanisms

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Bond PolarityPartial charges

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Type of Reactions

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Nucleophiles and Electrophiles

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8

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Leaving Groups

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Radical Reactions

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13

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Nucleophilic reactions:

Nucleophilic substitution: -> reagent is nucleophil-> nucleophil replaces leaving group-> competing reaction (elimination +

rearrangements)

nucleophilicsubstitution

Nucleophile++ C NuC XNu - X-

leavinggroup

• in the following general reaction, substitution takes place on an sp3 hybridized (tetrahedral) carbon

1. nucleophilic substitution (SN)

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• Some nucleophilic substitution reactions

CH3-I

HO -

Nu -

RO -

HS -

RS -

I -

NH3

HOH

CH3-SH

CH3-SR

CH3-OH

CH3-OR

HCH3-O-H

CH3-NH3+

CH3X CH3Nu X-

+An alcohol (after proton transfer)

An alkylammonium ion

An alkyl iodide

A sulfide (a thioether)

A thiol (a mercaptan)

An ether

An alcohol

Reaction: + +

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Mechanism• Chemists propose two limiting

mechanisms for nucleophilic displacement– a fundamental difference between them

is the timing of bond breaking and bond forming steps

At one extreme, the two processes take place simultaneously; designated SSNN22

S = substitutionN = nucleophilic2 = bimolecular (two species are involved in the rate-determining step)rate = k[haloalkane][nucleophile]

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• In the other limiting mechanism, bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins.

• This mechanism is designated SSNN11 where– S = substitution– N = nucleophilic– 1 = unimolecular (only one

species is involved in the rate-determining step)

– rate = k[haloalkane]

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SN2 reaction: bimolecular nucleophilic

substitution

C BrH

HH

HO + C

H

H H

HO Br- -

Transition state withsimultaneous bond breaking

and bond forming

CH

HH

HO + Br -

– both reactants are involved in the transition state of the rate-determining step

– the nucleophile attacks the reactive center from the side opposite the leaving group

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SN2• An energy diagram for an SN 2 reaction

– there is one transition state and no reactive intermediate

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• SN1 is illustrated by the solvolysis of tert-butyl bromide– Step 1: ionization of the C-X bond gives a carbocation intermediate

C

CH3

CH3H3C

+C

H3C

H3CBr

H3C

slow, ratedetermining

A carbocation intermediate; carbon is trigonal planar

+ Br

SN1 reaction: unimolecular nucleophilic substitution

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SN1– Step 2: reaction of the carbocation (an

electrophile) with methanol (a nucleophile) gives an oxonium ion

– Step 3: proton transfer completes the reaction

CH3OH H3C

C

CH3

CH3

OCH3

H

CCH3

CH3

CH3O

H3C

H H3CH3C

CH3C

OCH3

H

fast ++ ++

++++ fastC

H3CH3C

OH3C

OCH3

HOHO

CH3CH3

H

H

CH3

H3CCH3C

H3C

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• An energy diagram for an SN1 reaction

SN1

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• For an SN1 reaction at a stereocenter, the product is a racemic mixture

• the nucleophile attacks with equal probability from either face of the planar carbocation intermediate

(R)-EnantiomerPlanar carbocation (achiral)

CH

Cl

C6H5

Cl

C+

C6H5

H

Cl

CH3OH-Cl-

-H++

A racemic mixture

Cl

C6 H5 C6 H5

C OCH3H

CH3 O CH

Cl(R)-Enantiomer(S)-Enantiomer

SN1

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Effect of variables on SN Reactions– the nature of substituents bonded to the atom

attacked by nucleophile– the nature of the nucleophile– the nature of the leaving group – the solvent effect

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Effect of substituents on SN2

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Effect of substituents on SN1

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• SN1 reactions – governed by electronic factorselectronic factors, namely the relative

stabilities of carbocation intermediates– relative rates: 3° > 2° > 1° > methyl

• SN2 reactions– governed by steric factorssteric factors, namely the relative ease of

approach of the nucleophile to the site of reaction– relative rates: methyl > 1° > 2° > 3°

Effect of substituents on SN reactions

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Effect of substituents on SN reactions

• Effect of electronic and steric factors in competition between SN1 and SN2 reactions

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Nucleophilicity• NucleophilicityNucleophilicity: a kinetic property measured by the rate

at which a Nu attacks a reference compound under a standard set of experimental conditions– for example, the rate at which a set of nucleophiles

displaces bromide ion from bromoethane

CH3CH2Br NH3 CH3CH2NH3+ Br-++

Two important features:- An anion is a better nucleophile than a uncharged conjugated acid- strong bases are good nucleophiles

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good

poor

Br-, I -

HO-, CH3O-, RO-CH3S-, RS-

H2OCH3OH, ROH

CH3COH, RCOHO O

NH3, RNH2, R2NH, R3NCH3SH, RSH, R2S

Effectiveness Nucleophile

moderateCH3CO-, RCO-

O O

Nucleophilicity

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Nucleophilicity

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Leaving Group

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Leaving Group

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The Leaving Group

– the best leaving groups in this series are the halogens I-, Br-, and Cl-

– OH-, RO-, and NH2- are such poor leaving groups that

they are rarely if ever displaced in nucleophilic substitution reactions

I- > Br- > Cl- >> F- > CH3CO- > HO- > CH3O- > NH2-

Greater ability as leaving group

Greater stability of anion; greater strength of conjugate acid

Rarely act as leaving groups in nucleophilic substitution and -elimination reactions

O

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Solvent Effect

• Protic solventProtic solvent: a solvent that contains an -OH group – these solvents favor SN1 reactions; the greater the polarity of

the solvent, the easier it is to form carbocations in it

CH3COOHCH3CH2OHCH3OHHCOOHH2OStructure

Acetic acid

Formic acid

EthanolMethanol

Water

ProticSolvent

Polarity of Solvent

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Solvent Effect

• Aprotic solventAprotic solvent: does not contain an -OH group – it is more difficult to form carbocations in aprotic

solvents– aprotic solvents favor SN2 reactions

(CH3CH2)2OCH2Cl2

OCH3CCH3

OCH3SCH3

Diethyl etherDichloromethane

AproticSolvent Structure

Dimethyl sulfoxide (DMSO)

Acetone

Polarity ofSolvent

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Summary of SN1 and SN2

CH3X

RCH2X

R2CHX

R3CX

Type of HaloalkaneMethyl

Primary

Secondary

Tertiary

SN2 SN1

Substitutionat a stereocenter

SN2 is favored. SN1 does not occur. The methylcation is so unstable that it is never observed in solution.SN1 does not occur. Primary carbocations are so unstable thatthey are never observed in solution.SN1 is favored in protic solventswith poor nucleophiles.

SN2 is favored in aproticsolvents with goodnucleophiles.SN2 does not occur becauseof steric hindrance aroundthe substitution center.

SN1 is favored because of the ease of formation of tertiary carbocations.

Inversion of configuration.The nucleophile attacksthe stereocenter from theside opposite the leavinggroup.

Racemization. The carbocationintermediate is planar, and attack bythe nucleophile occurs with equalprobability from either side.

SN2 is favored.

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Competing Reaction: Elimination--EliminationElimination: removal of atoms or groups of atoms from

adjacent carbons to form a carbon-carbon double bond– we study a type of -elimination called

dehydrohalogenationdehydrohalogenation (the elimination of HX)

C CH X

CH3CH2O-Na+

C C

CH3CH2OH

CH3CH2OH Na+X -+

+

+

An alkyl halide

Base

An alkene

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-Elimination

• There are two limiting mechanisms for β-elimination reactions

• E1 mechanism:E1 mechanism: at one extreme, breaking of the C-X bond is complete before reaction with base breaks the C-H bond– only R-X is involved in the rate-determining step

• E2 mechanism:E2 mechanism: at the other extreme, breaking of the C-X and C-H bonds is concerted– both R-X and base are involved in the rate-determining

step

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E2 Mechanism

• A one-step mechanism; all bond-breaking and bond-forming steps are concerted

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E1 Mechanism

– Step 1: ionization of C-X gives a carbocation intermediate

– Step 2: proton transfer from the carbocation intermediate to a base (in this case, the solvent) gives the alkene

CH2-C-CH3

Br

CH3CH3-C-CH3

CH3

Br –slow, rate

determining+

(A carbocation intermediate)

+

HO

H3CH-CH2-C-CH3

CH3HO

H

H3CCH2=C-CH3

CH3fast+

+ ++

Nucleophile-> acting as a strong base

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Elimination

• Saytzeff rule:Saytzeff rule: the major product of a elimination is the more stable (the more highly substituted) alkene

Br CH3CH2O-Na+

CH3CH2OH2-Methyl-2-butene (major product)

2-Bromo-2-methylbutane

2-Methyl-1-butene

+

Br CH3O-Na+

CH3OH +

1-Methyl-cyclopentene

(major product)

1-Bromo-1-methyl-cyclopentane

Methylene-cyclopentane

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Elimination Reactions

• Summary of E1 versus E2 Reactions for Haloalkanes

RCH2X

R2CHX

R3CX

Haloalkane E1 E2Primary

Secondary

Tertiary

E1 does not occur.Primary carbocations areso unstable that they are never observed in solution.

E2 is favored.

Main reaction with strong bases such as OH- and OR-.

Main reaction with weak bases such as H2O and ROH.

Main reaction with strong bases such as OH- and OR-.

Main reaction with weak bases such as H2O and ROH.

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Substitution vs Elimination

• Many nucleophiles are also strong bases (OH- and RO-) and SN and E reactions often compete– the ratio of SN/E products depends on the relative rates

of the two reactionsnucleophilicsubstitution

-eliminationC CH X + Nu-

C CH Nu +

C C H-Nu+ +

X-

X-

What favors Elimination reactions:- attacking nucleophil is a strong and large base- steric crowding in the substrate- High temperatures and low polarity of solvent

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SN1 versus E1

• Reactions of 2° and 3° haloalkanes in polar protic solvents give mixtures of substitution and elimination products

CH3

CH3

ICCH3 -I-

CH3 CCH3 SN1

CH3-Cl-H2O

CH3OHSN1

ClCH3CH3

CH3C

CH2

CH3

CH3

C

C

CH3

CH3

CH3CCH3

CH3

CH3

OH

OCH3

H+

H+

H+

E1

+

+

+

+

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SN2 versus E2

• It is considerably easier to predict the ratio of SN2 to E2 products

leaving groupCC

R R

HRR

Attack of base on a -hydrogen by E2 is only slightly affected by branching at the -carbon; alkene formation is accelerated

SN2 attack of a nucleophile isimpeded by branching at the- and -carbons

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Summary of S vs E for Haloalkanes

– for methyl and 1°haloalkanes

RCH2X

CH3X

SN1 and E1 reactions of primary halides are never observed.

SN2SN1 reactions of methyl halides are never observed.The methyl cation is so unstable that it is never formed in solution.

SN2

E2 The main reaction with strong, bulky bases, such as potassium tert-butoxide.

Primary cations are never formed in solution; therefore,

Methyl

Primary

SN1/E1

SN1The only substitution reactions observed

The main reaction with strong bases such as OH- andEtO-. Also, the main reaction with good nucleophiles/weak bases, such as I- and CH3COO-.

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Summary of S vs E for Haloalkanes

– for 2° and 3° haloalkanes

The main reaction with strong bases/good nucleophiles

R3CX

such as I- and CH3COO-.R2CHX

Main reaction with strong bases, such as HO- and RO-.Main reactions with poor nucleophiles/weak bases.

The main reaction with weak bases/good nucleophiles,

E2

SN2

E2

SN2 reactions of tertiary halides are never observed

SN1/ E1

Secondary

Tertiarybecause of the extreme crowding around the 3° carbon.

SN1/ E1 Common in reactions with weak nucleophiles in polarprotic solvents, such as water, methanol, and ethanol.

such as OH- and CH3CH2O-.

SN2

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Summary of S vs E for Haloalkanes– Examples: predict the major product and the mechanism

for each reaction

ClNaOH 80°C

H2O+1.

Br (C2H5)3N 30°CCH2Cl2

+2.

BrCH3O- Na+

methanol3. +

ClNa+ I-4. + acetone

Elimination, strong base, high temp.

SN2, weak base, good nucleophil

SN1 (+Elimination), strong base, good nucleophil, protic solvent

No reaction, I is a weak base (SN2)I better leaving group than Cl

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Penataan ulang via Carbocation (Rearrangements)

Also 1,3- and other shifts are possible

The driving force of rearrangements is -> to form a more stable carbocation !!!Happens often with secondary carbocations -> more stable tertiary carbocation

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Via Carbocation SN + E reactions

Rearrangement

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Via SN + E reactions -> Wagner – Meerwein rearrangements

Rearrangement of a secondary carbocations -> more stable tertiary carbocation

Plays an important role in biosynthesis of molecules, i.e. Cholesterol -> (Biochemistry)

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Via Electrophilic addition reactions

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Ionic Reactions

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Ionic Reactions

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Ionic Reactions

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Ionic Reactions