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):


– 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


• 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


Type of substrate

Explanation Example

Methyl Leaving group attached to methyl group CH3Cl

Primary Leaving group attached to primary carbon Cl


Type of substrate

Explanation Example

Secondary Leaving group attached to secondary carbon

Tertiary Leaving group attached to tertiary carbon

Cl

Cl


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


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'


• 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¯


• Specific Example:

HO:¯+CH3CH2Cl→CH3CH2OH+Cl¯

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

Cl OHHO-Cl-


• 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)


• Concerted reaction –


• Energy diagram –


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


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

from the side opposite to the leaving group


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


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

Nu and E strengthens

– Bond between E and L weakens


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


• 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.


• 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


• 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

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.


• 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


• 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


• Exceptions– allylic and benzylic substrates – react faster

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


• 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


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

p. 293


• 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


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


• Mechanism:


• Specific Example:

• Rate Equation:Rate = k [t-BuCl]


• 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


• Non – Concerted reaction –


• Energy diagram –


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


• 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


• Stability of carbocations:

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


• HYPERCONJUGATION


• HYPERCONJUGATION

HH

H H

H

HH

H

H


• 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)


• 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


+

Rearrangements of Carbocations during SN1 reactions:

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


• e.g.


– 1,2 – alkyl shift


• e.g.


• allylic carbocations

• e.g.


• 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


• e.g.H H

H

HH

H+

+


• Various examples:

nucleophilic substitution reactions part 1

Documents

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reaction contd

substrate nuthe reaction

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leaving group4