lecture 11

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Lecture -11

Substitution Reactions

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2

Energy diagram of an SN 1 reaction

SN 1 Mechanism

StereochemistrySN 1 reactions are not stereospecific.The intermediate, carbocation is planar

and achiralSince there is no preference for

nucleophilic attack from either direction, equal amounts of the two enantiomers are formed — a racemic mixture

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The attack on one side results in a product with retention of configuration and the other side attack forms inversion product.

Racemization is simply combination of retention and inversion.

SN 1 Mechanism

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SN 1 Mechanism

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When racemization occurs, the product is rarely completely racemic.

There is often more inversion than retention of configuration.

As the leaving group leaves it partially blocks the front side of the carbocation.

The backside is unhindered, so attack is more likely there.

SN 1 Mechanism

More than 50%More than 50% Less than 50%Less than 50%

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Leaving group shieldsLeaving group shields one face of one face of carbocationcarbocation;; nucleophilenucleophile attacks attacks faster at opposite face.faster at opposite face.

Example:Bromine atom is cis to deuterium in the

reactant, so nucleophile is cis to deuterium in the retention product

The nucleophile is trans to deuterium in the inversion product.

SS NN 1 Mechanism1 Mechanism

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cis40% retention of configuration

trans60% inversion of

configuration

Attack fromthe top

Attack fromthe bottom

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General reaction :

R –X + CF3 COOH →

R –OCOCF3 + H –X

R ter-butyl isopropyl ethyl methyl

Rel. rate 106 1.0 10-4 10-5

SN 1 Mechanism

Reactivity of substratesUnder conditions that greatly favour SN 1,

the following results have been obtained:

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REARRANGEMENTS IN SN 1 REACTIONS

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Carbocations can rearrange to form a more stable carbocation.

Hydride shift (~H) : The movement of hydrogen with its bonding pair of electrons.

Methyl shift (~CH3 ): CH3- moves

from adjacent carbon if no H’s are available.

Rearrangements in SN 1 Reactions

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Rearrangements in SN 1 Reactions

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Rearrangements in SN 1 Reactions

An alkyl group can rearrange to make a carbocation more stable.

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Rearrangements in SN 1 ReactionsWhen neopentyl bromide is boiled in

ethanol, it gives only a rearranged productThis product results from a methyl shift

(~CH3 )

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Wagner-Meerwein Rearrangements

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Increasing the stability of carbocation intermediates is not the only factor that leads to molecular rearrangement.

If angle strain , torsional strain or steric crowding in the reactant structure is relieved by an alkyl or aryl shift to a carbocation site, such a rearrangement is commonly observed.

Rearrangements in SN 1 Reactions

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Although a 3º-carbocation is initially formed, the angle and torsional strain of the four-membered ring is reduced by a methylene group shift resulting in ring expansion to a 2º-carbocation.

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SolvolysisSubstitution reactions in which the

nucleophile is the solvent in which the reaction is carried out.

If the solvent is water, then reaction can be called hydrolysis.

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FACTORS AFFECTING THE RATES OF SN 1 AND SN 2 REACTIONS

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STRUCTURE OF THE SUBSTRATESTRUCTURE OF THE SUBSTRATESN 1

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SSNN 1 1 -- SUBSTRATE AND CARBOCATIONSUBSTRATE AND CARBOCATION

R-X R+ + X-slow

R+ + Nu- R-Nufast

The better ion will have the lower energy pathway.

The energy of the carbocationintermediate is an important factor for an SN 1 reaction.

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CH

H

H

Br CCH3

H

H

Br CCH3

H

CH3

Br CCH3

CH3

CH3

Br

relativerate

1.0 1.7 45

RBr + H2 O ROH + HBrHCOOH

increasing rate

rel rate = rate CH3 Brrate

Effect of increasing substitution Effect of increasing substitution -- SSNN 11

methyl primary secondary tertiary

108

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STRUCTURE OF THE SUBSTRATESTRUCTURE OF THE SUBSTRATESN 2

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SSNN 2 2 -- SUBSTRATESUBSTRATE

C

R

Br:H O:..

..

RR

large groupsintroduce sterichindrance

C

H

Br:H O:..

.. H

H

easy accessno sterichindrance

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BrCH3 CH2 BrCH3 CH BrCH3

CH3

C BrCH3

CH3

CH3

R B r + N a I R I + N a B racetoneH 2O

150 1 0.01 0.001

decreasing rate

Effect of Degree of Substitution Effect of Degree of Substitution -- SSNN 22

methyl primary secondary tertiary

rel rate = rate EtBrrate

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IS THE NUCLEOPHILE IMPORTANTIS THE NUCLEOPHILE IMPORTANTIN BOTH SIN BOTH SNN 1 AND S1 AND SNN 2 REACTIONS ?2 REACTIONS ?

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Nucleophilicityis determined here Basicity is

determined here

Different places on the energy profile Different places on the energy profile determine determine nucleophilicitynucleophilicity and and basicitybasicity

faster is better

lower energy is better

NUCLEOPHILES

BASES

NUCLEOPHILICITY

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Nucleophiles are unimportant in an SN 1 reaction; they are not involved in the rate- determining step.

SN 1 rate = K1 [RX]

The nature of a nucleophile is only important to an SN 2 reaction.

SN 2 rate = K2 [RX][Nu]

NUCLEOPHILESNUCLEOPHILESIMPORTANCE IN SIMPORTANCE IN SNN 1 AND S1 AND SNN 2 REACTIONS2 REACTIONS

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WHAT IS A WHAT IS A GOOD NUCLEOPHILE ?GOOD NUCLEOPHILE ?

SN 2 REACTIONS

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C

R

Br:

RR

Y: :..

..

WHAT IS THE IDEAL NUCLEOPHILE ?WHAT IS THE IDEAL NUCLEOPHILE ?

no way ! badno way ! badSTERIC PROBLEMS

LARGE

SMALL

SN 2 REACTIONS

For an SN 2 reaction the nucleophile must find the back lobe of the sp3 hybrid orbital that the leaving group is bonded to.

:....X: -

goodgood

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FFF Cl Br I

1.36 A 1.81 A 1.95 A 2.16 A

--- - - -

smallestion

and we would expect the smallest one (fluoride) to be the best nucleophile,

….. however, that is not usually the case.

OUR NAÏVE EXPECTATIONOUR NAÏVE EXPECTATIONWe would expect the halides to be good nucleophiles:

ionic radii:

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F- 5 x 102

Cl- 2.3 x 104

Br- 6 x 105

I- 2 x 107

slowest

fastest

k

CH3 -I + NaX CH3 -X + NaI

Rate = k [CH3 I] [X-]

EXPERIMENTAL RESULTS: relative rates relative rates of reaction for the halidesof reaction for the halides

MeOH

* MeOH solvates like water but dissolves everything better.

SN 2

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SOLVATIONSOLVATION

Solvation reverses our ideas of size.

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FFF

- 120 Kcal / mole

--- gas phase F- (g) F- (aq)

HEAT OF SOLVATIONHEAT OF SOLVATION

Solvation lowers the potential energy of the nucleophile making it less reactive.

FFF---H O

H

HO

H

HO

H

H O

H

The interaction between the ion and the solventis a type of weak bond.Energy is released when it occurs.

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FFF Cl Br I

1.36 A 1.81 A 1.95 A 2.16 A

HALIDE IONSHALIDE IONS

Heats ofsolvationin H2 OKcal / mole

- 120 - 90 - 65

X(H2 O)n-

--- - - -

increasing solvation

- 75

Small ions solvate more than large ions

IONICRADIUS

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WATER AS A SOLVENTWATER AS A SOLVENT

Water is a polar molecule. Negative on the oxygen end, and

positive on the hydrogen end.It can solvate both cations and anions.

OHHδ+

δ+ δ-δ-

X-

H OH

H OHH

OH

M+

H OH

HOH

HO

H

HO

H

polar OH bonds

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SOLVATIONSOLVATION

solventshell

- -

BETTERNUCLEOPHILE

IF - -

“Effective size” is larger.

H OH

H OHH

OH H

OH

HOH H

OH

HO H

H OH

H OHH

OH

Heavy solvation lowers the potential energy of the nucleophile. It is difficult for the solvated nucleophile to escape the solvent shell.

strong interactionwith the solvent

weak interactionwith the solvent

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PROTIC SOLVENTSPROTIC SOLVENTS

water methanol ethanol amines

CH3CH2 OH

H OH

NRH

HCH3 O

H

Water is an example of a “protic” solvent.Protic solvents are those that have

Protic solvents can form hydrogen bonds and can solvate both cations and anions.

O-H, N-H or S-H bonds.

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1. In protic solvents the larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potential energy.

2. Since the solvent shell is smaller in a larger ion it can more easily “escape” from the surrounding solvent molecules during reaction. There is morepotential energy.

LARGER IONS ARE BETTER NUCLEOPHILES LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTSIN PROTIC SOLVENTS

THREE FACTORS ARE INVOLVED :

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C Br

3. The larger ions are thought to be more “polarizable”.

Polarizability assumes larger ions are able to easily distort the electons in their valence shell, and that smaller ions cannot.

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NUCLEOPHILICITY TRENDS IN PROTIC SOLVENTS

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In polar protic solvents, nucleophilicity increases down a column of the periodic table.This is the opposite of basicity.

Right-to-left-across a row of the periodic table, nucleophilicity increases.

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APROTIC SOLVENTSAPROTIC SOLVENTS

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APROTIC SOLVENTSAPROTIC SOLVENTS

SCH3 CH3

OCH N

O

CH3

CH3

N P N

O

N

H3C

H3C

CH3

CH3CH3H3C

CCH3 CH3

O

CH3 C N

acetone acetonitrile

if scrupulouslyfree of water

+- -

+

DMSODMF

HMPA

Aprotic solvents do not have OH, NH, or SH bonds

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APROTIC SOLVENTS SOLVATE CATIONS,APROTIC SOLVENTS SOLVATE CATIONS,BUT NOT ANIONS (NUCLEOPHILES)BUT NOT ANIONS (NUCLEOPHILES)

The nucleophile is “free” (unsolvated),and therefore is small and not hindered by a solvent shell.

-

-

+

+

X-M+

S

O

CH3 CH3

S

O

H3C CH3

SOCH3

CH3

S O

H3C

H3C

crowded

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In polar aprotic solvents, nucleophilicity parallels basicity, and the stronger base is the stronger nucleophile.

Because basicity decreases with size down a column, nucleophilicity decreases as well.

The Nucleophile

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Crown Ethers

• Solvate the cation, so nucleophilic strength of the anion increases.

• Fluoride becomes a good nucleophile.

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SOLVENTSSOLVENTS

what are good solvents for sN 1 and sN 2 ?

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SN 1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step.

R-X R+ + X-

rate-determiningstep

solvation of both ionsspeeds the ionization

SSNN 1 SOLVENTS = POLAR1 SOLVENTS = POLAR

Carbocation

ions

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SN 2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile.

C

R

Br:

:....

RR

X:

smaller is better !

SMALL,UNSOLVATED

SSNN 2 SOLVENTS = NONPOLAR2 SOLVENTS = NONPOLAROR POLAROR POLAR--APROTICAPROTIC

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SN

2 or SN

1?

•

Primary or methyl•

Strong nucleophile

•

Polar aprotic

solvent•

Rate = k[halide][Nuc]

•

Inversion at chiral carbon

•

No rearrangements

•

Tertiary•

Weak nucleophile (mayalso be solvent)

•

Polar protic

solvent •

Rate = k[halide]

•

Racemization of optically active compound

•

Rearranged products