OCHEM Ch. 4 Substitution & Elimination

nucleophile

electron-rich (has lone pair or π); donates electrons

electrophile

electron-poor; accepts electrons

nucleophile strength increases _ to _ across a row in both polar protic and polar aprotic solvents

R, L

polar protic solvents

• solvents that form H-bonds

• nucleophilicity increases down a group

  • Ex: H₂O, CH₃OH

polar aprotic solvents

• solvents that cannot donate H-bonds

• nucleophilicity decreases down a group

  • ex: acetone, THF, DMSO

leaving groups (LG)

• atoms that detach from molecule, taking electrongs

• best LG = weak bases

S_N2 Reaction

bimolecular nucleophillic substitution

• 1 step (concerted): backside attack

• sterospecific: inversion (umbrella flip)

• rate = k[nucleophile][substrate]

S_N2 reactions are favored by

• strong nucleophile

• primary/secondary carbon substrate type

• polar aprotic solvents (ex: DMSO, acetone)

S_N1 Reaction

unimolecular nucleophilic substitution

• 3 steps: LG leaves → carbocation forms → nucleophile attacks

• forms racemic mix (not stereospecific)

• rate = k[substrate]

• rate-determining step: formation of a carbocation

S_N1 reactions are favored by

• weak nucleophile

• tertiary > secondary > never primary carbon substrate

• polar protic solvents (ex: H₂O, ROH)

_____ stable carbocations = faster S_N1 reactions

more

going L to R, are the carbocation arrangements getting less or more stable?

more

Zaitsev vs. Hofmann Products

• Zaitsev = thermodynamic product (more stable)

  • more substituted alkene, greater stability

  • favored by small bases: EtO^-, MeO^-

• Hofmann = kinetic product (forms faster with bulky base)

  • less substituted alkene, decreased steric hindrance

  • favored by bulky bases: tBuO^-

Zaitsev product

more substituted alkene in an elimation rxn → greater stability

Hofmann product

less substituted alkene in an elimation rxn

1. least

2. ethene

3. mono

4. di

5. cis-

6. trans-

7. geminal-

8. tri

9. tetra

10. most

E2 Reaction

bimolecular elimination

• 1 step (concerted): base removes β-Hydrogen, LG leaves, forms alkene

• rate = k[base][substrate]

• stereoselectivity when two β-protons are available

• stereospecificity when only one β-proton is available

E2 reactions are favored by

• strong base (ex: NaOet, NaOMe)

• tertiary, secondary, or primary carbon

• polar aprotic solvents

stereoselectivity

• when two β-protons are available

  • E (trans) = major product → more stable

  • Z (cis) = minor product → increase steric hindrance

stereospecificity

• when only one β-proton is available

  • LG & β-H must be anti-periplanar

E1 Reaction

unimolecular elimination

• 3 steps: LG leaves → carbocation forms → proton removal

• rate = k[substrate]

E1 reactions are favored by

• weak base (ex: H₂O, ROH)

• tertiary/secondary carbons

• heat

acid-catalyzed dehydration of alcohols

reagent: H₂SO₄ + heat

• OH → H₂O (good LG), then E1 mechanism (or E2 for 1° alcohol)

• forms Zaitsev alkene

carbocation rearrangements

• only in S_N1/E1

• hydride/methyl shift to form more stable carbocation

How to Choose: S_N1, S_N2, E1, E2

1. Degree of Substitution (on C bonded to LG)

   1. 1°: S_N2 / E2 only

   2. 2°: all possible

   3. 3°: S_N1 / E1 / E2 only

2. Strength of Nucleophile/Base

   1. Strong = S_N2 / E2

   2. Weak = S_N1 / E1

3. Bulky Base: Hofmann Product + E2 favored

4. Solvent

   1. Protic → S_N1 / E1

5. Heat: Elimination (E1 / E2)

1. E2

2. S_N2 / E2

3. S_N2 / E2 (E2 favored)

4. E2

5. S_N2

6. S_N1

7. No Reaction

8. S_N1

9. E1

1. S_N2

2. S_N2 (polar aprotic solvent) / S_N1 (polar protic solvent

3. S_N1

4. E2

5. E2 (polar protic solvent) and S_N2 (polar aprotic solvent)

6. E2 only due to steric hindrance

7. Not straightforward

8. S_N1 and E1 - Heat favors elimination

regiochemical and sterochemical outcome: S_N2

• regiochemical: Attack at the alpha position, kick out leaving group in same step.

• sterochemical: Inversion of configuration (flip like an umbrella).

regiochemical and sterochemical outcome: S_N1

• regiochemical: Nucleophilic attack of the carbocation. Carbocation could be where the leaving group was, or it could have rearranged.

• sterochemical: Since the carbocation intermediate is planar, nucleophile can attack from either face with equal probability. Produces a racemic mixture if the product is chiral.

regiochemical and sterochemical outcome: E2

• regiochemical

  • Zaitsev Product: more substituted alkene is favored if base is unhindered.

  • Hofmann Product: less substituted alkene is favored if base is bulky.

• sterochemical

  • Stereoselective if there are 2 protons on the appropriate beta carbon can form E or Z alkene, but the major product is the E alkene.

  • Stereospecific if there is only 1 proton on the appropriate beta carbon need to draw the Newman projection so that the leaving group and hydrogen being pulled are antiperiplanar.

regiochemical and sterochemical outcome: E1

• regiochemical: Zaitsev Product- more substituted alkene is favored.

• stereochemical: Stereoselective- E alkene will be favored over Z (no antiperiplanar requirement).

strong base, weak nucleophile examples

NaH, DBN, DBU, LDA, t-BuOK, triethlamine, diisopropylethylamine

strong base, strong nucleophile examples

RO-, HO-, MeO-, EtO-

weak base, strong nucleophile examples

I-, Br-, Cl-, RS-, HS-, RSH, H₂S

weak base, weak nucleophile examples

H₂O, MeOH, EtOH, ROH

most nucleophilic molecule will be the ________ or _____ reactive base

strongest, most

Negatively charged bases are more reactive than neutral ones