NUCLEOPHILIC SUBSTITUTION REACTIONS Part 1
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Transcript of 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: