nucleophilic substitution reactions part 1

NUCLEOPHILIC SUBSTITUTION REACTIONS

Part 1CHEM 2101

Module 6

Susan Morante

1. Some Definitions

• Nucleophile (symbol Nu):

• Electrophile (symbol E):

• Leaving Group (symbol L):

• R Group (symbol R):

2. The General Reaction

Nu:¯ + R – L Nu – R +:L¯

• Example of an R – L (a substrate):

2. The General Reaction

– C is sp3 hybridized (tetrahedral)– Cl is more electronegative than C making the

C electrophilic and the C-Cl bond polar– Nu is attracted to the electron-deficient site

and becomes bonded to it in the product

2. The General Reaction

• In general, we use Nu:¯ to indicate a strong Nucleophile and Nu: (without the negative charge) to indicate a weak Nucleophile

• Halides are the most common leaving groups in substrates used for Nucleophilic substitution reactions

• We can use alkyl halides as examples to explore some more terminology

2. The General Reaction

Type of substrate

Explanation Example

Methyl Leaving group attached to methyl group CH3Cl

Primary Leaving group attached to primary carbon Cl

2. The General Reaction

Type of substrate

Explanation Example

Secondary Leaving group attached to secondary carbon

Tertiary Leaving group attached to tertiary carbon

Cl

Cl

2. The General Reaction

Type of substrate

Explanation Example

Allylic Leaving group attached to a carbon (primary, secondary or tertiary) that is adjacent to a pi bond or pi system

Aryl Leaving group is attached to a benzene ring

ClCl Cl

1o 2o3o

Cl

2. The General Reaction

Type of substrate

Explanation Example

Vinylic Leaving group attached to a carbon that is part of a double bond

Benzylic Leaving group attached to a carbon (primary, secondary or tertiary) that is attached to a benzene ring

Cl

Cl

Cl

R

Cl

R

R'

2. The General Reaction

• There are two possible mechanisms for the substitution reaction which will be discussed in detail later in these notes– Bimolecular Nucleophilic substitution (SN2)

– Unimolecular Nucleophilic substitution (SN1)

3. Possible Stereochemistry of Substitution Reactions

• Retention of configuration:

– Not usually seen• inversion of

configuration:– seen in all SN2

reactions involving chiral reactants and products

• racemization– seen in all SN1

reactions involving chiral reactants and products

4. Bimolecular Nucleophilic substitution (SN2)

• Generic Reaction:

Nu:¯ + R – L Nu – R +:L¯

4. Bimolecular Nucleophilic substitution (SN2)

• Specific Example:

HO:¯+CH3CH2Cl→CH3CH2OH+Cl¯

• Rate Equation: Rate = k [EtCl] [OH¯]

Cl OHHO-Cl-

4. Bimolecular Nucleophilic substitution (SN2)

• For any SN2: Rate = k [substrate] [Nu]

– The reaction rate depends on the concentration of the nucleophile and the substrate

– Second order rate law (In general, the order of a reaction is equal to the sum of the exponents in the rate equation.)

– Reaction is bimolecular (two species involved in rate-determining step)

4. Bimolecular Nucleophilic substitution (SN2)

• Concerted reaction –

4. Bimolecular Nucleophilic substitution (SN2)

• Energy diagram –

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction:– SN2 occurs through a back side attack

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction cont’d:– The nucleophile must approach the carbon

from the side opposite to the leaving group

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction:– HOMO of Nu attacks LUMO of E

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction cont’d:– Bond between

Nu and E strengthens

– Bond between E and L weakens

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction cont’d:– Inversion of configuration

4. Bimolecular Nucleophilic substitution (SN2)

• Mechanism of the reaction cont’d:– During transition state – C becomes sp2

hybridized– Transition state – a fleeting arrangement (one

molecular vibration, 10-12s) of atoms

p. 262

The Hammond Postulate

• The structure of the transition state for a reaction step is most similar to (or looks most like) the structure of the species (reactant or product) to which it is closer in energy.

The Hammond Postulate

• For an exergonic step: if a bond is forming in the step, that bond is less than half formed in the transition state, and if a bond is breaking, it is less than half broken (i.e. TS resembles reactants).

• the transition state is closer in energy to the reactants thus the transition state most resembles the reactants

The Hammond Postulate

The Hammond Postulate

• For an endergonic step this means that if a bond is forming in the step, that bond is more than half formed in the transition state, and if the bond is breaking, it is more than half broken (i.e. TS resembles products).

• the transition state is closer in energy to the products thus the transition state most resembles the products

The Hammond Postulate

Effect of Substituents on the Rate of the SN2 reaction

• The rate of the SN2 reaction decreases dramatically each time one of the hydrogens of the electrophilic carbon of the substrate is replaced by an alkyl group.

Effect of Substituents on the Rate of the SN2 reaction

• This result of the larger size of the alkyl group on the rate of reaction, as compared to the size of hydrogen, is called steric effect.

• Steric effect – the effect on the rate caused by space-filling properties of parts of the molecule near the reacting site.

Fig. 8-5, p. 267

Table 8-1, p. 264

Effect of Substituents on the Rate of the SN2 reaction

• Exceptions– neopentyl substrates – react many times

slower than other primary substrates because the tert-butyl group attached to the electrophilic carbon hinders the back – side attack of the Nu

Effect of Substituents on the Rate of the SN2 reaction

• Exceptions– allylic and benzylic substrates – react faster

than other primary substrates because there is resonance stabilization of the transition state possible

Effect of Substituents on the Rate of the SN2 reaction

• Exceptions– Vinylic and aryl substrates – do not

undergo nucleophilic substitution reactions• No good direction of approach for Nu• Inability to form the transition state• C-L bond not easily broken

Intramolecular Nucleophilic substitution reactions using SN2

• An example of an SN2 reaction and a lesson in how to make alkoxides

• An alkoxide is an alcohol (ROH) that has had the H removed to form (RO‾)

ROH + Na(s) → RO¯Na+ + ½ H2(g)

Alcohol Alkoxide

Intramolecular Nucleophilic substitution reactions using SN2

Br OHBr O

O

e.g.1

+ Na

cyclic ether

redox

Cl O

O

Cl O

O

O O

H

e.g.2

+ Na+OH-

(cyclic ester)

lactone

acid-base

Intramolecular Nucleophilic substitution reactions using SN2

• Intramolecular reactions tend to be faster than intermolecular reactions because collisions between the Nu and the E happen more rapidly.

p. 293

4. Bimolecular Nucleophilic substitution (SN2)

• Various examples:

4. Bimolecular Nucleophilic substitution (SN2)

• Various examples:

5. Unimolecular Nucleophilic Substitution (SN1)

• Generic Reaction:

R – L → R+ + L¯

R+ + :Nu → R – Nu

• Proceeds with racemization if electrophilic C is chiral

5. Unimolecular Nucleophilic Substitution (SN1)

• Carbocation formation is the rate determining step because it is slightly endothermic and thus very slow

5. Unimolecular Nucleophilic Substitution (SN1)

• Mechanism:

5. Unimolecular Nucleophilic Substitution (SN1)

• Specific Example:

• Rate Equation:Rate = k [t-BuCl]

5. Unimolecular Nucleophilic Substitution (SN1)

• Rate Equation cont’d:

For any SN1 Rate = k [substrate]

– This is a first order reaction– The reaction rate depends only on the

concentration of the substrate– Only the substrate is present in the transition

state for the rate determining step

5. Unimolecular Nucleophilic Substitution (SN1)

• Non – Concerted reaction –

5. Unimolecular Nucleophilic Substitution (SN1)

• Energy diagram –

5. Unimolecular Nucleophilic Substitution (SN1)

• Reaction intermediate – – Product of an elementary step– Often a high energy reactive species

Effect of Substituents on the Rate of the SN1 reaction

• Anything that makes the carbocation more stable will all make the transition state more stable

• Anything that makes the transition state more stable will result in a faster reaction

• Increased substitution on the electrophilic carbon stabilizes the carbocation

Table 8-2, p. 272

Effect of Substituents on the Rate of the SN1 reaction

• Stability of carbocations:

• How does the presence of alkyl groups on a carbon stabilize the carbocation?

Effect of Substituents on the Rate of the SN1 reaction

• HYPERCONJUGATION

Effect of Substituents on the Rate of the SN1 reaction

• HYPERCONJUGATION

HH

H H

H

HH

H

H

Effect of Substituents on the Rate of the SN1 reaction

• Stabilization due to the partial overlap of a sigma bonding MO from the adjacent carbon with the empty p orbital of the carbocation

• The sigma MO and the empty p AO are coplanar, so they overlap in a manner similar to a pi bond, even though they are not parallel. This overlap provides a path for the electrons of the sigma bond to be delocalized into the empty p orbital, thus helping to stabilize the carbocation (i.e. it lowers the energy)

Effect of Substituents on the Rate of the SN1 reaction

• Exceptions– Vinylic and aryl substrates – do not undergo

nucleophilic substitution reactions

– methyl groups cannot undergo SN1 reactions (methyl cation is too unstable)

– allylic and benzylic substrates – react faster than other primary substrates because there is resonance stabilization of the carbocation intermediate

Effect of Substituents on the Rate of the SN1 reaction

Effect of Substituents on the Rate of the SN1 reaction

+

Rearrangements of Carbocations during SN1 reactions:

• rearrangements are structural changes that increase stability– 1,2 – hydride shift

Rearrangements of Carbocations during SN1 reactions:

• e.g.

Rearrangements of Carbocations during SN1 reactions:

– 1,2 – alkyl shift

Rearrangements of Carbocations during SN1 reactions:

• e.g.

Rearrangements of Carbocations during SN1 reactions:

• allylic carbocations

• e.g.

Rearrangements of Carbocations during SN1 reactions:

• allylic carbocations cont’d:– sometimes molecules undergo hydride or

alkyl shifts to give an allylic cation– these are very stable due to a delocalised pi

system

Rearrangements of Carbocations during SN1 reactions:

• e.g.H H

H

HH

H+

+

5. Unimolecular Nucleophilic Substitution (SN1)

• Various examples:

5. Unimolecular Nucleophilic Substitution (SN1)

• Various examples: