Substitution Reactions

Why are halides good leaving groups?

• They are electronegative, which makes C more electrophilic when they leave

• They are stable → very weak bases → won’t react after leaving

What is the rate law of S_N2 reactions?

rate = k [alkyl halide] [nucleophile]

Why does an inversion of configuration occur in S_N2 reactions?

Due to the back-side attack

• nucleophile attacks C at opposite side of LG

What are the reasons for a back-side attack in S_N2 reactions?

1. LG lone pairs repel nucleophile lone pairs

2. The molecular orbital of the alkyl halide has a lobe at the back with which the nucleophile’s orbital can overlap to form a bond

Why might there not be an inversion of configuration in an S_N2 reaction?

Although a back-side attack will always occur, there will not be an inversion of configuration if:

1. The electrophilic C is achiral → no inversion is possible

2. The priority/identity of the LG/nucleophile does not lead to an inversion

What are the substrate (organic reactant) effects on rate?

Sterics:

If there are substituents on the α (directly attached to LG) and/or β (one C away from LG) carbons, the rxn rate decreases

methyl > primary > secondary >> tertiary

Tertiary-substituted α carbons are considered not reactive

Tertiary-substituted β carbons are prohibitively slow

What is the kinetics explanation for substrates with more substituents having slower rxn rates?

More substitution → T.S. is higher E (less stable) → greater E_a → nucleophile forms weaker partial bond due to sterics

• Weaker C---Nuc → higher E T.S.

• More sterically-hindered = harder for Nuc to reach the C

What makes a good leaving group?

1) Electron withdrawing (electronegativity) → makes C more electrophilic (greater δ⁺)

2) Stable → not a strong base → won’t react in solution

3) Polarizable to stabilize T.S. → electron cloud can extend to keep partial bond with substrate

• lower E T.S. due to stronger partial bond

• polarizability tends to take priority for alkyl halides

What is nucleophilicity?

the rate at which the nucleophile attacks the electrophile

strong nucleophiles → fast S_N2 (good for S_N2)

weak nucleophiles → slow S_N2

What does nucleophilicity depend on?

1) Charge: negatively charged nucleophiles are stronger than neutral

2) Polarizability: more polarizable, stronger nucleophile → better bonding in T.S. → lower E_a (in same group)

3) Basicity: more basic, stronger nucleophile; basicity increases right to left (less EN)

4) Sterics: less sterically hindered, stronger nucleophile

Which nucleophiles are good for S_N2?

I^-, Br^-, Cl^-

HS^-, RS^-, H₂S

HO^-, RO^-

^-CN

What are weak nucleophiles?

H₂O and ROH

What solvents are suitable for S_N2?

S_N2 rxns generally need polar solvents to solvate ionic nucleophiles and LGs

What is a protic solvent?

A solvent in which a H is bonded to an EN atom

Ex: CH₃OH, NH₃

What is a polar aprotic solvent?

A polar solvent that does not contain H atoms bonded to EN atoms

Ex: acetone, DMF, CH₃CN (acetonitrile), HMPA, DMSO

Is S_N2 quicker in protic or polar aprotic?

Polar aprotic

• protic solvents “tie up” the nucleophile due to hydrogen bonding, which causes the reactant (nucleophile) to be stabilized relative to aprotic solvent → increases E_a

What is the effect of H-bonding stabilizing reactants in protic solvents?

Their starting energies are lower, so their E_a is higher and they are less reactive