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Lecture 7 Nucleophilic Substitution

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23 views21 pages

Lecture 7 Nucleophilic Substitution

Chem lecture

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Deekshã Dee
Copyright
© © All Rights Reserved
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Principles of Organic Chemistry

CH1113

Topic: Nucleophilic Substitution Reactions


Lecture 7: 21.10.2024
Boopathy Gnanaprakasam
[email protected]

Organic Chemistry by J. Clayden, N. Greeves, S. Warren, P. Wothers; Oxford Press, Second Edn.
Chapter-15, page: 328-359
Solvents

Polar aprotic solvents: DMSO,


Polar protic solvents: water,
Acetonitrile, Dimethylformamide,
alcohols, acetic acid, ammonia Hexamethyl phosphoramide, Acetone
Solvent Effect on SN2
• The rates of SN2 reactions are strongly affected by the solvent.
Protic solvents—those that contain an OH or NH group—are
generally the worst for SN2 reactions, while polar aprotic solvents,
which are polar but don’t have an OH or NH group, are the best

S N2 The solvent molecules hydrogen bond


to the nucleophile and form a cage
around it, thereby lowering its energy
and reactivity.

• Polar aprotic solvents increase the rates of SN2 reactions by raising the
ground-state energy of the nucleophile

• These solvents can dissolve many salts because of their high polarity,
but they tend to solvate metal cations rather than nucleophilic anions.
Solvent Effect on SN1
Solvent effects in the SN1 reaction are due largely to
stabilization or destabilization of the transition state.

Any factor stabilizing the intermediate carbocation


should increase the rate of an SN1 reaction.
Stabilization through the interaction
of the ion with solvent molecules

S N1
Strength of Nucleophiles

Remember the Kinetics

SN2 depends
nucleophile

SN1 is not
dependent on
nucleophile

Strong Nucleophiles
Weak Nucleophiles
Strong Nucleophiles favours SN2 Weak nucleophiles disfavour
SN2 depends on substrate
Effect of Nucleophiles on SN1 or SN2
• Nucleophiles affect the SN2 reaction, strong nucleophiles promote SN2 reaction
• Nucleophiles does not affect the SN1 reaction. Because the SN1 reaction occurs
through a rate limiting step in which the added nucleophile has no part
Nucleophile AcO- Cl- PhO- OH- PhS-
Rate (10-5 s-1) 3.9 4.0 3.8 74 107
Inference SN1 SN1 SN1 SN2 SN2
Strength of Nucleophiles

Nucleophile AcO- Cl- PhO- OH- PhS-


Rate (s-1) 900 1100 2000 1.2x104 5X107
Inference SN2 SN2 SN2 SN2 SN2
Strength of leaving groups: Good leaving groups are
conjugate base of the strong acids

Among halides, Iodides is best leaving group


Bad leaving groups
Among sulfonate, Nosylate and triflate are best
Both SN1 and SN2 depends Leaving group
Effect of Leaving Group on SN1 or SN2
The greater the extent of charge stabilization by the leaving group, the lower the
energy of the transition state and the more rapid the SN2 reaction.

S N2

Leaving group effect on SN1


reactivity order is S N1
Energy diagram for Effect of Substrate, Nucleophile, Leaving
Group and Solvents on SN2
What if the leaving group and electron donating group
on adjacent carbons? {Clayden Book Chapter 37} Neighbouring
SN2 Group Participation
SN2
(NGP)
Neighboring groups:
Inversion COO, COOR, COAr, OCOR, OR,
Inversion Overall Retention OH, O-, NH2, NHR, NR2,
NHCOR, SH, SR, S-, I, Br, and Cl
• Higher reaction rate than expected
• Retention of configuration
• Group having unshared pair of electrons β to the leaving group
• Two SN2 reactions

Retention
X is leaving group

Pi bond in NGP Pi bond not in NGP


Sigma bond in NGP

C-C sigma orbitals are in Pi orbitals are not in


Pi orbitals are in proper
proper position to interact position to interact with position to interact with
with Sigma* orbital of C-X Sigma* orbital of C-X Sigma* orbital of C-X
What if the leaving group present in bicyclic
compounds? {Clayden Book Chapter 37}
Compound I undergoes Acetolysis
140,000 times faster than the
saturated analog II due to
anchimeric assistance or NGP of
alkene
I II

Neighbouring Group Participation (NGP)


Nucleophilic Substitution in Cyclohexane Derivative
The nucleophile must attack the s* of the leaving group, that is, directly behind
the C–X bond. In the case of an equatorially substituted compound, this line of
attack is hindered by the (green) axial hydrogens—it passes directly through the
region of space they occupy. For an axial leaving group, the direction of attack is
parallel with the (orange) axial hydrogens anti-periplanar to the leaving group,
and approach is much less hindered.

S N2
SN1 with Ion-Pair Mechanism
Nucleophilic Substitution with Internal Return: SNi

SN i

SN 2
What if the leaving group and electron donating group
on the same carbon?
What if the leaving group and Electron withdrawing
Group on the same carbon
Exclusively SN2
How about Allylic Systems

Steric effect
How about Benzylic Systems: Stabilize the SN1
Intermediate
S N1

Weak Nucleophiles
Favours SN1
Benzylic and Allylic Stabilize the Transition State of SN2
S N2

Strong Nucleophiles Favours SN2


SN1 or SN2

S N2

SN1

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