Lecture 11

Lecture -11

Substitution Reactions

+

1

Energy diagram of an SN1 reaction

2

SN1 Mechanism Stereochemistry SN1 reactions are not stereospecific. The intermediate, carbocation is planar and achiral Since there is no preference for nucleophilic attack from either direction, equal amounts of the two enantiomers are formed — a racemic mixture

SN1 Mechanism 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.

4

5

SN1 Mechanism

SN1 Mechanism 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. 7

Leaving group shields one face of carbocation; nucleophile attacks faster at opposite face. +

More than 50%

Less than 50%

SN1 Mechanism

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.

Attack from the top

Attack from the bottom

cis 40% retention of configuration

trans 60% inversion of 10 configuration

SN1 Mechanism Reactivity of substrates Under conditions that greatly favour SN1, the following results have been obtained: General reaction : R –X + CF3COOH → R –OCOCF3 + H –X R Rel. rate

ter-butyl isopropyl 106

1.0

ethyl methyl 10-4

10-5 11

REARRANGEMENTS IN SN1 REACTIONS

12

Rearrangements in SN1 Reactions 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. 13

Rearrangements in SN1 Reactions

14

Rearrangements in SN1 Reactions An alkyl group can rearrange to make a carbocation more stable.

15

Rearrangements in SN1 Reactions When neopentyl bromide is boiled in ethanol, it gives only a rearranged product This product results from a methyl shift (~CH3)

16

Wagner-Meerwein Rearrangements

17

Rearrangements in SN1 Reactions 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.

18

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.

19

Solvolysis Substitution 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.

20

FACTORS AFFECTING THE RATES OF SN1 AND SN2 REACTIONS

21

STRUCTURE OF THE SUBSTRATE S N1

22

SN1 - SUBSTRATE AND CARBOCATION slow

R-X R+

+

Nu-

R+ fast

+

X-

R-Nu

The energy of the carbocation intermediate is an important factor for an SN1 reaction. The better ion will have the lower energy pathway. 23

Effect of increasing substitution - SN1 RBr + H2O methyl H

primary

H

H

CH 3 C Br

CH 3

CH 3 C Br

H

1.0

ROH + HBr

secondary tertiary

H

H C Br

relative rate

HCOOH

CH 3 C Br CH 3

CH 3

1.7

45

108

increasing rate rate rel rate = rate CH3Br 24

STRUCTURE OF THE SUBSTRATE S N2

25

SN2 - SUBSTRATE R

.. : H O ..

C R

large groups : Br introduce steric hindrance

R .. : H O ..

H C H H

: Br

easy access no steric hindrance 26

Effect of Degree of Substitution - SN2 RBr

+ NaI

methyl primary

acetone H 2O

RI + NaBr

secondary

tertiary CH 3

CH 3 Br

150

CH 3 CH 2 Br CH 3 CH Br CH 3

1

C Br

CH 3

CH 3

0.01

0.001

decreasing rate rate rel rate = 27 rate EtBr

IS THE NUCLEOPHILE IMPORTANT IN BOTH SN1 AND SN2 REACTIONS ?

28

NUCLEOPHILICITY Different places on the energy profile determine nucleophilicity and basicity NUCLEOPHILES Nucleophilicity is determined here faster is better

BASES Basicity is determined here lower energy is 29 better

NUCLEOPHILES IMPORTANCE IN SN1 AND SN2 REACTIONS Nucleophiles are unimportant in an SN1 reaction; they are not involved in the ratedetermining step. SN1 rate = K1 [RX] The nature of a nucleophile is only important to an SN2 reaction. SN2 rate = K2 [RX][Nu] 30

WHAT IS A GOOD NUCLEOPHILE ? SN2 REACTIONS 31

WHAT IS THE IDEAL NUCLEOPHILE ? 2 REACTIONS S N LARGE .. :Y : STERIC PROBLEMS .. no way ! bad R SMALL

.. :.. X: good

C

: Br

R

R For an SN2 reaction the nucleophile must find the back lobe of the sp3 hybrid orbital that the leaving group is bonded to.

32

OUR NAÏVE EXPECTATION We would expect the halides to be good nucleophiles: ionic radii: 1.36 A 1.81 A 1.95 A 2.16 A F-

Cl

-

Br

I

smallest ion and we would expect the smallest one (fluoride) to be the best nucleophile, ….. however, that is not usually the case. 33

EXPERIMENTAL RESULTS: relative rates of reaction for the halides MeOH CH -X + NaI CH -I + NaX 3

3

Rate = k [CH3I] [X-] SN2

k F-

5 x 102

Cl-

2.3 x 104

Br-

6 x 105

slowest

fastest I2 x 107 * MeOH solvates like water but dissolves everything better.

34

SOLVATION

Solvation reverses our ideas of size. 35

HEAT OF SOLVATION F

gas phase

F- (g)

F- (aq)

- 120 Kcal / mole O

H

H H O

H

H

O

F

H

H

O

H

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

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

36

HALIDE IONS IONIC 1.36 A RADIUS

1.81 A

F Heats of solvation in H2O Kcal / mole

X(H2O)n

- 120

Cl

-

- 90

1.95 A

2.16 A

Br

- 75

I

- 65

increasing solvation

Small ions solvate more than large ions

37

WATER AS A SOLVENT H δ+

δ-

H O

δ-

H δ+ polar OH bonds

H

H O H

O

M

H O H

+

O H

H

H O H -

X

O

H H

H H O

Water is a polar molecule. Negative on the oxygen end, and positive on the hydrogen end. It can solvate both cations and anions. 38

SOLVATION F

-

strong interaction with the solvent

O H H H O H H H O O H H H H H O H O O H H

-

solvent shell “Effective size” is larger.

I

BETTER NUCLEOPHILE H O

H O H

-

H H

H O

weak interaction with the solvent

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

39

PROTIC SOLVENTS H H

O

C H3 C H 2

C H3 O H

water

O

N

H

H

methanol

R

ethanol

H

amines

Water is an example of a “protic” solvent. Protic solvents are those that have O-H, N-H or S-H bonds. Protic solvents can form hydrogen bonds and can solvate both cations and anions. 40

LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTS

THREE FACTORS ARE INVOLVED : 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 more potential energy. 41

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.

C

Br 42

43

44

NUCLEOPHILICITY TRENDS IN PROTIC SOLVENTS

45

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.

46

APROTIC SOLVENTS

47

APROTIC SOLVENTS O CH 3

-

S+ CH 3

O H C N CH 3

DMSO

O

H3C CH 3

DMF

H3C

-

P+ N

N H 3C

N

CH 3 CH 3

CH 3

HMPA

O CH 3

C CH 3

acetone

CH 3 C N

acetonitrile

if scrupulously free of water Aprotic solvents do not have OH, NH, or SH bonds 48

APROTIC SOLVENTS SOLVATE CATIONS, BUT NOT ANIONS (NUCLEOPHILES)

H 3C

O

H 3C S H 3C

S + CH3 CH3

-

O M+ O O

CH3

crowded

S

+

X-

CH3

S CH 3

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

49

The Nucleophile 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.

50

Crown Ethers • Solvate the cation, so nucleophilic strength of the anion increases. • Fluoride becomes a good nucleophile.

51

SOLVENTS what are good solvents for sN1 and sN2 ? 52

SN1 SOLVENTS = POLAR SN1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. R-X rate-determining step

ions R + + Xsolvation of both ions speeds the ionization Carbocation 53

SN2 SOLVENTS = NONPOLAR OR POLAR-APROTIC SN2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile. .. :.. X: SMALL, UNSOLVATED smaller is better !

R C

: Br

R R

54

S N2

or

SN1?

• Primary or methyl • Strong nucleophile

• Tertiary • Weak nucleophile (may also be solvent)

• Polar aprotic solvent

• Polar protic solvent

• Rate = k[halide][Nuc] • Rate = k[halide] • Inversion at chiral carbon

• Racemization of optically active compound

• No rearrangements

• Rearranged products 55