ReactionsReactions

R X R+ + X-

Ionic reactions:Ionic reactions:

Bond breaking and bond Bond breaking and bond making take place in a making take place in a heterolytic fashionheterolytic fashion

R X R. + X.

Bond breaking and bond Bond breaking and bond making take place in amaking take place in ahomolytic fashionhomolytic fashion

Radical reactions:Radical reactions:

Ionic Reactions :

1) substitution :

3) addition :

Y R X R Y X+ +

R = aliphatic as well as aromatic

X

R2

R1

Y

X

R2 Y

R1H XH

R2 Y

R1

+

X = O , NH

2) elimination :

Nucleophilic Nucleophilic SubstitutionSubstitution

NucleophilicNucleophilic SubstitutionSubstitution

Y R X R Y X+ +

R = aliphatic as well as aromatic

Nucleophile + Substrate Product + Leaving group

NucleophilicNucleophilic SubstitutionSubstitution

SN1 SN2

S: Substitution N: Nucleophilic1: unimolecular

S: SubstitutionN: Nucleophilic2: Bimolecular

Y C X C Y X++ C+

leaving group goes first and nucleophile comes later

Y C X C Y X++

nucleophile attacks and leaving group goes simultaneously

SN2

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

SN2 reaction and mechanism

9

Synthetic Utility of the SN2 ReactionA variety of functional groups can be prepared employing a good

nucleophile and an electrophile with a good leaving group:

SN2 reaction : Kinetics

12

The Rate Law of an SN2 Reaction

Obtained experimentally:

Rate law includes both the alkyl halide and the nucleophile, a second-order process

SN2 reaction : Stereochemistry

SSNN2 MECHANISM2 MECHANISM

O

C

R

HCH3

H O:....attacks

back lobe

nucleophilic attack

(R)-config

(S)-config

C

R

HCH3

Br: :....H :..

..

INVERSION

Stereochemistry of SStereochemistry of SNN22Walden inversionWalden inversion

=>

C

R

HCH3

Br:C

R

HCH3

HO :

C

HCH3

R

BrHO

H O:....

activated complexis trigonal planar (sp2 )

(R)-configuration(S)-configuration

configurationis inverted

Ea

HO C B

partial bonding

2pTHE INVERSIONTHE INVERSIONPROCESSPROCESS

sp3

sp3

sp2

SN2 reaction : substrate substrate structurestructure

Less bulky

Should stabilize the transition state

SN2 Reaction: substrate structure

KI in Acetone at 25°krel

150

1

0.008

unreactive!

CH3 Br

CH3 CH2 Br

CH3 CH Br

CH3

CH3 C Br

CH3

CH3

Relative rates of SN2 reactions of alkyl chlorides with the iodide ion

Alkyl chloride relative rate

Me Cl 200

Cl0.02

MeO Cl

920

Cl

O

1,00,000

The rates are given with respect to n-BuCl

RHal

ONu-

RNu

O

R = alkyl, aryl, OR'

Me ClCl

O

H

H

Cl* of the C=O

* of of the C-Cl

Nu

only SN2, no SN1

Relative rates of SN2 reactions with iodide ion

1:500

Nu

Cl

H

H

++* of the C=O

C=O group stabilizes the T.S. by Overlap of its * orbital with full P-orbital of the C-atom under attack

SN2 reaction : Effect of Nucleophile Effect of Nucleophile

The nucleophilicity may be correlated with the availability of the electron pairs and the ease with which it is donated

Trends in Nuc. Trends in Nuc. StrengthStrength

Increases down Periodic Table, as Increases down Periodic Table, as size and polarizability increase: size and polarizability increase: II-- > Br > Br-- > Cl > Cl-- >F >F- -

Of a conjugate acid-base pair, the Of a conjugate acid-base pair, the base is stronger: base is stronger: OHOH-- > H > H22O, NHO, NH22

-- > NH > NH33

Polarizability and nucleophilicity - increased polarizability makes for a better nucleophile

I- > Br- > Cl- >F-I- > Br- > Cl- >F-

Effect of Nucleophile :

The nucleophilicity may be correlated to its basicity as both involve the availability of the electron pairs and the ease with which it is donated

CH3O H3C I

CH3OH H3C I

CH3OCH3

CH3OCH3 HI

I+ +rapid

very

slow++

Nucleophilicity of CH3O CH3OH> A negatively charged nucleophile is always stronger than its conjugate acid.

Stronger base weaker basebetter nucleophile poorer nucleophile

HO > H2O

CH3O > CH3OH

H2N > NH3

The direct relationship between basicity and nucleophilicity is maintained if the reaction occurs in the gas phase

SSNN2: Nucleophilic Strength2: Nucleophilic Strength Stronger nucleophiles react faster.Stronger nucleophiles react faster. Strong bases are strong nucleophiles, Strong bases are strong nucleophiles,

but not all strong nucleophiles are but not all strong nucleophiles are basic.basic.

=>

SN2 reaction : Effect of leaving Effect of leaving groupgroup

31

•A good leaving group needs to be a Stable anions that are weak bases which can delocalize charge

The Leaving Group

Sulfonate Leaving Groups

S CH3OR

O

O

S BrOR

O

O

para-Toluenesulfonate Tosylate

para-Bromobenzenesulfonate Brosylate

R OTs

R OBs

SN2 reaction : Effect of Solvent Effect of Solvent

Solvent

Polar Solvent nonpolar Solvent

Polar protic Solvent Polar aprotic Solvent

SN2 reaction prefers polar aprotic solvent

Solvent Effects (1)Solvent Effects (1)Polar protic solvents (O-H or N-H) reduce Polar protic solvents (O-H or N-H) reduce

the strength of the nucleophile. the strength of the nucleophile. Hydrogen bonds must be broken before Hydrogen bonds must be broken before nucleophile can attack the carbon.nucleophile can attack the carbon.

=>

Solvent Effects (2)Solvent Effects (2) Polar aprotic solvents (no O-H or N-H) do Polar aprotic solvents (no O-H or N-H) do

not form hydrogen bonds with nucleophilenot form hydrogen bonds with nucleophile Examples: Examples:

CH3 C Nacetonitrile C

O

H3C CH3

acetone =>

dimethylformamide (DMF)

CH

O

NCH3

CH3

Me I + Me N3N3-Na+ + NaI

solvent

Rate in MeOH ( 33) 1 DMF ( 37) 4.5X104 DMF: HCONMe2

Marked effect on the rate of SN2 reaction, when that transferred from polar protic solvent to polar aprotic solvent.

• In MeOH both Na+ and N3- are solvated.

• In DMF only Na+ is solvated, but not N3-.

• So, unsolvated N3- is a much more powerful

nucleophile

DMSO ( 46) 1X109 DMSO: Me2SO

SN1

reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

SN1: reaction and mechanism

Solvolysis of tert-Butyl Bromide

+ H2O +

+ other products

acetoneCH3 C CH3

CH3

Br

CH3 C CH3

CH3

OH

H Br

SN1: Mechanism

1935: Hughes & Ingold

carbocation

SN1 reaction : Kinetics

SN1 Reaction: kinetics

The reactions follows first order (unimolecular) kinetics

Rate = k [R-Br]1

R LG R R NuNu

LGslow

+fast

Rate = K[R-LG]

Reaction profile for SN1 reaction

SN1 reaction : Stereochemistry

SN1: Hydrolysis of t-butyl chloride by base proceed according to

Rate = k1[t-BuCl] or independent of [OH-]

1. Halide undergoes slow ionization to yield the ion pair R+ and Cl- followed by first attack by –OH or solvent or nuleophile.

2. The energy necessary to effect the initial ionization is largely recovered from the energy evolved through solvation of the resultant ion-pair.

ClMe

MeMe

Me

MeMe+

slow

sp3 sp2

fast

fast

OHMe

MeMe

HOMe

MeMe

-OH

-OH

SN1 reaction : substrate substrate structurestructure

Stability of carbocation

C

tertiary

C

tertiary secondary

>

primary

+

carbocation (very stable)

secondarycarbocation

+

CH3

>Br

CH3

CH3

CH3 CH

CH3

Br

CH3 CH

CH3

CH3CH3-CH2-Br

CH3

+

primarycarboc

CH3

carbocation(unstable)

CH3

+

CH3-Br>

very unstable carbocation

three methyl groups

two methyl groups

one methyl group

no methyl groups

CH3 CH2

SN1 Reaction: substrate structure

krel

no reaction

1.00

11.6

61.2 x 10

CH3 Br

CH3 CH2 Br

CH3 CH Br

CH3

CH3 C Br

CH3

CH3

Solvolysis in water at 50°C

SN1 reaction : Effect of Nucleophile Effect of Nucleophile

Nucleophiles in SN1

Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile (weak nucleophile)

A protic solvent acts as both a solvent and nucleophile in SN1

reactions - solvolysis:Water

HO

H

Methanol HO

CH3

HO

CH2CH3

HOEtEthanol

HO

C

O

CH3Acetic acid HOAc

HO

C

O

HFormic acid

HOMe

abbreviations

SN1 reaction : Effect of leaving Effect of leaving groupgroup

Leaving groups

Leaving groups are the same as in SN2 reactions:

SN1 reaction : Effect of Solvent Effect of Solvent

Dielectric constant (, at 25 C): H2O 79

EtOH 25

Solvent effect

Increase in dielectric constant and/or ion-solvating ability result in a marked increase in reaction rate

Polar protic solvents favoring the SN1 reaction since it stabilizes carbocation of the transition state

Protic solvents disfavor the SN2 reaction by stabilizing the ground state

Transfer from polar, protic to polar, aprotic solvents can change the reaction mode from SN1 SN2

Things to remember

SSNN22 or or SSNN1?1? Primary or methylPrimary or methyl Strong Strong

nucleophilenucleophile Polar aprotic Polar aprotic

solventsolvent Rate = Rate = k k [halide] [halide]

[Nuc][Nuc] Inversion Inversion No No

rearrangementsrearrangements

TertiaryTertiary Weak nucleophile Weak nucleophile

(may also be (may also be solvent)solvent)

Polar protic solvent, Polar protic solvent, silver saltssilver salts

Rate = Rate = k k [halide][halide] Racemization Racemization Rearranged products Rearranged products

=>=>

Competition reaction in SN1

RearrangementsRearrangements

Carbocations can rearrange to form a Carbocations can rearrange to form a more stable carbocation.more stable carbocation.

Hydride shift: HHydride shift: H-- on adjacent carbon on adjacent carbon bonds with Cbonds with C++..

Methyl shift: CHMethyl shift: CH33-- moves from adjacent moves from adjacent

carbon carbon ifif no H’s are available. no H’s are available.

=> =>

Hydride ShiftHydride Shift

CH3 C

Br

H

C

H

CH3

CH3CH3 C

H

C

H

CH3

CH3

CH3 C

H

C

H

CH3

CH3CH3 C

H

C

CH3

CH3

H

CH3 C

H

C

CH3

CH3

HNuc

CH3 C

H

C

CH3

CH3

H Nuc

=>

Methyl ShiftMethyl Shift

CH3 C

Br

H

C

CH3

CH3

CH3CH3 C

H

C

CH3

CH3

CH3

CH3 C

H

C

CH3

CH3

CH3CH3 C

H

C

CH3

CH3

CH3

CH3 C

H

C

CH3

CH3

CH3

NucCH3 C

H

C

CH3

CH3

CH3 Nuc

=>

Important substrates……..

Allylic and Benzylic compounds

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

benzyl bromide allyl bromide

CH2 CH2 etc+

+

++

etcCH2 CH2

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

benzyl bromide allyl bromide

For SN2: stabilisation of TS by conjugation with allylic -bond

Br

Nu

H

Nu

Br

H

(-)

(-)

Nu

++

T.S.

Nu

Br

H

H

++

T.S.

(-)

(-)

BENZYL ( GOOD FOR SBENZYL ( GOOD FOR SNN1 ) 1 ) IS ALSO A GOOD SIS ALSO A GOOD SNN2 SUBSTRATE2 SUBSTRATE

CH2 Br + NaI CH2 I + NaBr

primary, but faster than other primary

overlap inthe activatedcomplexlowers theactivationenergy

I

Br

H

H

criticaloverlap

Vinyl and aryl halides

76

Vinyl and aryl halides do not undergo SN1 because:

77

Vinyl and aryl halides do not undergo SN2 because:

Cyclic systems

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

You can’t have p orbitals on a bridgehead position

rigid bicyclic molecule.

+

+

cannot becomeplanar

X

“steric rigidity”

Br +

Problems :

BrBr Br

1 10-6 10-14

Explain?

2) Rate of solvolysis in EtOH :

CH3CH2 Br Me2HCCH2 Br Me3CCH2 BrCH3CH2CH2 Br

relative rate 1 2.8X10-1 3.0X10-2 24.2X10-6

1) SN2 reaction by EtO- in EtOH:

Explain ?

Br Br

1 10-23

Explain ?

1-bromotriptycene

Rigid structure, cation empty p-orbitals are at right angles to orbitals of Ph

cc at bridge head, less stable, difficult to attain planarity due to rigidity

A)

A)B)