CHEM 261 - Substitution and Elimination Theory

I didn't think this would be as important as the mechanism itself, but it is (unfortunately)

Nucleophile

• Is any negative ion or neutral molecule which possesses a long-pair of electrons and are attracted to a positive center.

• Is also a base (lewis base).

Substrate

• The alkyl halide that is being attacked by the nucleophile.

Inversion of Configuration

• The process in which the configuration of a chiral center is reversed during a substitution (S_N2) reaction, resulting in a product with opposite stereochemistry.

Substitution (Bimolecular) S_N2

• Reaction involves a backside attack by a nucleophile on the sp³ carbon.

• It is a concerted reaction - bond making and bond breaking at the same time.

• A transition state is formed in the reaction - the nucleophile, sp³ and the leaving group lie in a straight line.

• The sp³ carbon becomes sp² hybridized and the three substituents all lie on the same plane.

• A good leaving group is a weak base.

Reactivity towards S_N2

• Methyl > 1° > 2° > 3°.

• Reaction is also sensitive to steric effect - too much crowding slows the reaction and too much steric hindrance can stop the reaction altogether.

  • Alters rate of reaction.

Leaving Group

• A atom or group that can be easily displaced in reaction.

• The weaker the basicity, the better the leaving group.

  • Fluorine is a poor LG, whereas I is a good LG.

• Other good LG’s include H₂SO₄, HSO₄⁻, TsO⁻ (used when H₂SO₄ is too acidic).

Nucleophilicity

• Usually parallels basicity - a strong base is usually a strong nucleophile.

  • A negative charged nucleophile is always stronger than its conjugate acid.

• Across a period, nucleophilicity (basicity) decreases from left to right.

• Basicity normally decreases with atomic size (down the table). But in a polar solvent, nucleophilicity increases down the periodic table (large anion would become a strong nucleophile).

• Decreases when there’s a bulky group present.

Solvation

• Intermolecular interactions (h-bonds, dipole-dipole, ion-dipole) between the solvent molecules and the reagents/transition states.

  • When the solvent is water, the solvation is referred to as hydration.

• The intermolecular forces (solvation) is largest for smaller anions.

• Solvation of the anions decreases the nucleophilicity.

Protic Solvent

• A solvent which possesses hydrogen attached to electronegative elements.

  • i.e. water and methanol.

• They form hydrogen bonds and nucleophiles.

• Protic solvents solvates anion.

• Nucleophilicity is therefore decreased - energy is needed to strip off the solvent molecules.

• The strong interaction between methanol (a polar protic solvent) and anion lowers its reactivity.

Aprotic Solvent

• Is a solvent whose molecules do not possess hydrogen attached to electronegative elements.

• Some common polar aprotic solvents are N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

• The type of solvent greatly affects the rate of reaction.

• Aprotic solvents solvates cation only, leaving the anion “naked.”

  • Nucleophilicity of anion is therefore increased.

Solvation of the Anion

• The strong interaction between methanol (a polar protic solvent) and anion lowers its reactivity.

Factors Affecting S_N2 Reaction

• The substrate: CH₃ > 1° > 2° > 3°.

• The nucleophile: Strong (usually strong bases).

• The leaving group: Weak bases.

• The solvent: Aprotic.

Intramolecular Substitution Reactions

• A functional group within a molecule is replaced by another atom or group within the same molecule, leading to the formation of new cyclic structures.

Substitution Unimolecular (S_N1)

• Tertiary alkyl halides undergo S_N1 substitution. Enhanced by polar protic solvents.

• Rate = k[alkyl halide]; nucleophile strength doesn't affect rate, so weak nucleophiles can participate.

• The slow, rate-determining step forms a carbocation.

• A weak nucleophile then rapidly attacks the carbocation from either side (no steric hindrance).

• Finally, the solvent is deprotonated and attaches to the substrate.

Hyperconjugation

• Delocalization of electrons from a bonding orbital to an adjacent unfilled orbital.

• Stabilizes the transition state; the more stable the carbocation, the lower its activation energy.

• As a result, it increases the reaction rate.

Summary of S_N1 and S_N2 Reactions

Factors	SN1	SN2
Alkyl Groups	CH3 and 1°	3°
Leaving Groups	Good leaving groups	Good leaving groups
Nucleophile	Strong Nucleophile	Weak Nucleophile
Solvents	Polar aprotic solvent	Polar protic solvent

Elimination Reaction

• The loss of two atoms or groups from a group from a substrate to the formation of a π bond.

Dehydrohalogenation

• A reaction in which a hydrogen atom and a halogen atom are removed from adjacent atoms in a molecule, forming (usually) an alkene or an alkyne.

  • Bases commonly used for this reaction include KOH and a conjugate base of alcohol (i.e. a sodium salt).

Dehydration

• The chemical reactions in which a water molecule is eliminated from the reactant molecule.

• Can result in a alkene.

Orientation of Carbon

• The carbon atom bonded to the leaving group X is called the α-carbon.

• The adjacent carbon atom is called the β-carbon.

• The next carbon atom in the chain is termed the γ-carbon.

Unimolecular Elimination (E1)

• A two step-reaction. The first step entails the formation of a carbocation.

• The second step is the loss of a hydrogen on a β-carbon.

• Since the rate-determining step is the same for both S_N1 and E1 by the formation of a carbocation, an E1 reaction always results in the formation of a S_N1 side product.

  • There are major and minor products though - elimination reactions favour heat.

  • The more substituted alkene is always the major product.

• Rate = k[RX]/

Bimolecular Elimination (E2)

• E2 is a one-step, concerted reaction with rate = k[RX][Base].
  A strong base drives elimination with no substitution by-products.
  Simultaneously:

  • Base forms ROH.

  • β-H is removed (H–C bond breaks).

  • C=C π bond forms.

  • C–Br bond breaks (leaving group exits).

Zaitsev’s Rule

• if more than alkene product is possible, the most stable alkene (with most substituents) is formed as the major product.

Stability of Alkenes

• The preferred product is the alkene with the breater number of alkyl groups attached to the carbon atoms with the double bond.

• Trans-alkene is more stable than the cis-alkene.

Condition for a π Bond Formation

• The p-orbitals must be on the same plane for effective side-to-side overlapping.

• Overlapping is not possible if the p-orbitals are not on the same plane.

Syn-Periplanar Elimination

• The spatial arrangement in which atoms or groups involved in a chemical reaction, specifically in an E2 elimination reaction, are on the same side and in the same plane.

Stereochemistry for E2 Reaction

• E2 mechanism is concerted.

• β-hydrogen, the leaving group must lie in the same plane for reaction for that a π bond can be formed effectively.

• The elimination reaction takes place when β-hydrogen and the leaving group are anti (anti-elimination) to each other in the Newman projection.

• If the β-hydrogen and the leaving group are not on the same plane and anti to each other, E2 mechanism is not possible.

Elimination Vs. Substitution Table

Types of Alkyl Halides	Weak Nucleophile/Base	Strong Base Nucleophiles	Strong and Bulky Base Nucleophiles
Methyl	No reaction.	SN2	SN2
1°	No reaction.	SN2	E2
2°	E1 and SN1	SN2	E2
3°	E1 and SN1	E1 and SN1	E2