Organic Reactions & Mechanisms

🟢 Lite — Quick Review (1h–1d)

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Organic Reactions & Mechanisms — Key Facts for Makerere University (Uganda) Core concept: Understanding reaction mechanisms allows you to predict products, explain reactivity, and account for stereochemical outcomes High-yield points: SN1 vs SN2 vs E1 vs E2 mechanisms; electrophilic addition to alkenes; nucleophilic addition to carbonyls; radical halogenation of alkanes; free energy diagrams ⚡ Exam tip: When asked to predict products, always identify the mechanism type first by examining substrate, nucleophile/base strength, and solvent

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🟡 Standard — Regular Study (2d–2mo)

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Organic Reactions & Mechanisms — Makerere University (Uganda) Study Guide

1. Bond Breaking and Making in Organic Reactions

Homolytic vs Heterolytic Cleavage

Homolytic cleavage (equal sharing of electrons): A:B → A• + B• (each gets one electron)

• Produces free radicals
• Occurs in non-polar bonds under heat or UV light
• Bond dissociation energy: Energy needed for homolytic cleavage

Heterolytic cleavage (unequal sharing, one atom takes both electrons): A:B → A⁺ + :B⁻ (or A:⁻ + B⁺)

• Produces carbocations (A⁺) or carbanions (A:⁻)
• Occurs in polar bonds, especially in polar solvents
• Carbocation: electron-deficient, sp² hybridized, 6 electrons
• Carbanion: electron-rich, pyramidal shape, like NH₃

Types of Reagents

Electrophiles (electron-loving): Electron-deficient species that accept electron pairs

• H⁺, NO₂⁺, AlCl₃, FeBr₃, Br₂ (in reactions where Br–Br bond is polarized)
• Carbocations: R⁺

Nucleophiles (nucleus-loving): Electron-rich species that donate electron pairs

• Anions: OH⁻, CN⁻, Cl⁻, Br⁻, NH₂⁻, RCOO⁻
• Neutral with lone pairs: NH₃, H₂O, ROH, ROR
• Carbanions: R:MgX (Grignard), RLi

2. Reaction Energy Profiles

Activation Energy (Ea)

The minimum energy required for reactants to reach the transition state (activated complex).

Transition state: The highest energy point on the reaction coordinate — a point of no return where bonds are partially broken and partially formed.

Reaction Profiles

Exothermic reactions: Products are more stable than reactants; ΔH is negative; energy is released.

Energy
  |  ∆H < 0
  |  ╱╲
  | ╱  ╲
  |╱    ╲
  └──────→ Reaction coordinate

Endothermic reactions: Products are less stable than reactants; ΔH is positive; energy is absorbed.

Rate Laws

• Molecularity: Number of molecules/entities involved in the rate-determining step
• Unimolecular: 1 molecule → rate = k[A]
• Bimolecular: 2 molecules → rate = k[A][B]

3. Nucleophilic Substitution Reactions

SN2 Mechanism (Bimolecular Nucleophilic Substitution)

Characteristics:

• One-step mechanism (concerted)
• Nucleophile attacks from the BACK (anti) to the leaving group
• Walden inversion of configuration at the carbon
• Rate = k[substrate][nucleophile] (second order)
• No intermediate (just transition state)

Mechanism:

        Nu⁻              Nu⁻
          \              /
           C–X    →     C–X
          /              \
         H                H
    (substrate)      (product, inverted)

Favored by:

• Methyl and primary (1°) halides (less steric hindrance)
• Strong nucleophiles (I⁻, CN⁻, RS⁻, OH⁻)
• Polar aprotic solvents (acetone, DMSO, DMF) — solvate cations, not nucleophilic anions

SN2 reactivity order: CH₃X > 1°RX > 2°RX > 3°RX (steric hindrance) I⁻ > Br⁻ > Cl⁻ > F⁻ (weaker C–X bond = better leaving group)

SN1 Mechanism (Unimolecular Nucleophilic Substitution)

Characteristics:

• Two-step mechanism (stepwise)
• First step: slow ionization to form carbocation (rate-determining)
• Second step: fast attack by nucleophile
• Rate = k[substrate] only (first order)
• Racemization occurs (planar carbocation attacked from both sides)

Mechanism: Step 1 (slow): R₃C–X → R₃C⁺ + X⁻ (carbocation intermediate) Step 2 (fast): R₃C⁺ + Nu⁻ → R₃C–Nu

Carbocation Stability: 3° > 2° > 1° > methyl (more alkyl groups = more stable via hyperconjugation)

Favored by:

• Tertiary (3°) and secondary (2°) substrates
• Weak nucleophiles (H₂O, ROH, halides)
• Polar protic solvents (water, carboxylic acids) — stabilize ions through solvation

Carbocation Rearrangements:

• Hydride shift: H⁻ moves from adjacent carbon to stabilize carbocation
• Methyl shift: CH₃ group moves
• Always shifts toward MORE stable carbocation

Example: (CH₃)₃C–CH(Br)–CH₃ (2-bromo-2-methylbutane) Ionization → tertiary carbocation at C-2 Or rearranged: (CH₃)₂C⁺–CH(CH₃)–CH₃ (even more stable tertiary at C-2 after methyl shift from C-3)

SN1 vs SN2 — Decision Tree

Factor	Favors SN2	Favors SN1
Substrate	Methyl, 1°, 2°	3°, 2°
Nucleophile	Strong	Weak
Leaving group	Good (I⁻ > Br⁻ > Cl⁻)	Good
Solvent	Polar aprotic	Polar protic
Stereochemistry	Inversion	Racemization

⚠️ Important: 3° substrates almost always undergo E2 (with strong base) or SN1 (with weak nucleophile), NOT SN2 (too sterically hindered).

4. Elimination Reactions

E2 Mechanism (Bimolecular Elimination)

Characteristics:

• One-step, concerted (anti-periplanar geometry required)
• Strong base abstracts H⁺ while leaving group departs simultaneously
• Rate = k[substrate][base] (second order)
• Hofmann product favored with bulky bases (夺取more substituted = more hindered)

Anti-periplanar requirement: The H and leaving group must be on opposite sides (180° dihedral angle) for the orbital overlap needed to form the π bond.

Mechanism:

    H           H
     \         /
      C=====C   →   C≡C + H–B + X⁻
     /         \
    R           R
  (E2 elimination)

Zaitsev’s Rule: The more substituted alkene (more alkyl groups on double-bond carbons) is the major product.

• Exception: Hofmann product (less substituted) dominates when bulky bases (t-BuOK, NaNH₂) are used

E1 Mechanism (Unimolecular Elimination)

Characteristics:

• Two-step (same as SN1: ionization to carbocation, then H⁺ abstraction by base)
• Rate = k[substrate] (first order)
• Usually competes with SN1 when carbocation is formed
• Zaitsev product favored (less substituted carbons lose H⁺ faster if selectivity exists)

Mechanism: Step 1 (slow): R–X → R⁺ + X⁻ (carbocation) Step 2 (fast): R⁺ + B⁻ → alkene + BH

E1 vs E2 vs SN1 vs SN2 — Competition

Primary substrate (1°):

• With strong base → E2 (predominant) or SN2
• With weak base → SN2

Secondary substrate (2°):

• With strong base → E2 (predominant) or SN2
• With weak base → mixture of E1/SN1 (but E1 requires ionizing conditions)

Tertiary substrate (3°):

• With strong base → E2 (predominant)
• With weak base → SN1 (or E1)
• Almost NEVER SN2

Elimination vs Substitution factors:

• Higher temperature → favors elimination (more endothermic)
• Bulky base → favors E2 (dehydrohalogenation)
• Weak nucleophile + polar protic → SN1/E1

5. Electrophilic Addition to Alkenes

General Mechanism (Two-step)

1. Electrophilic attack: The π electrons of the C=C attack the electrophile E⁺ → forms carbocation intermediate
2. Nucleophilic attack: The nucleophile (X⁻) attacks the carbocation → addition product

Anti-addition: In alkenes, addition across the double bond is usually anti (from opposite sides) due to the mechanism.

Addition of HX (Hydrohalogenation)

Regioselectivity — Markovnikov’s Rule:

• H adds to the carbon with MORE hydrogen atoms
• X adds to the carbon with FEWER hydrogen atoms

Mechanism with carbocation rearrangement: If the initially formed carbocation can rearrange to a more stable one, it will:

• Secondary carbocation → tertiary carbocation (via hydride or methyl shift)
• The rearranged carbocation then captures the nucleophile

Example: 2-methylbut-2-ene + HBr → 2-bromo-2-methylbutane (after rearrangement from secondary to tertiary carbocation, if formed)

Addition of X₂ (Halogenation)

• Anti-addition (bromine adds anti to each other across the double bond)
• Cyclic bromonium ion intermediate (three-membered ring with Br⁺)
• Nucleophilic attack opens the ring from the back → trans product

Bromination stereochemistry:

      Br           Br
       \         /
        C=====C    →   trans-1,2-dibromocyclohexane
       /         \
      H           H

For cyclohexene: trans-1,2-dibromo product (both Br on opposite faces).

Addition of H₂O (Hydration)

• Acid-catalyzed addition of water
• Markovnikov addition (H to carbon with more H, OH to carbon with fewer H)
• Reverse reaction: dehydration of alcohols

Addition of H₂ (Hydrogenation)

• Requires metal catalysts: Pt, Pd, Ni (Raney Ni)
• Syn-addition (both H add to same face)
• Saturation of double bond: alkene → alkane

Heat of hydrogenation (measure of stability):

• Ethene: −136 kJ/mol
• Propene: −124 kJ/mol
• 2-methylpropene: −119 kJ/mol
• Benzene: −208 kJ/mol (much less than expected for cyclohexatriene!)

6. Nucleophilic Addition to Carbonyl Compounds

General Mechanism

1. Nucleophile attacks carbonyl carbon (electrophilic due to O’s electronegativity)
2. π bond electrons move to oxygen → tetrahedral alkoxide intermediate
3. Alkoxide is protonated → alcohol product

Rate enhanced by:

• More electrophilic carbonyl carbon (electron-withdrawing groups)
• Less hindered carbonyl (sterics)

Acid-Catalyzed Nucleophilic Addition

1. Protonate the carbonyl oxygen → makes carbonyl carbon MORE electrophilic
2. Nucleophile attacks
3. Deprotonate to give product

Nucleophiles in Carbonyl Addition

Water (Hydration): R–CHO + H₂O ⇌ R–CH(OH)₂ (gem-diol) Equilibrium favors gem-diol for chloral (Cl₃C–CHO) due to electron-withdrawing Cl₃C– group.

Alcohols (Acetal Formation): R–CHO + 2R’OH ⇌ R–CH(OR’)₂ + H₂O (acetal) R–CO–R’ + 2R”OH → R–C(OR”)₂–R’ + H₂O (ketal) Reaction requires acid catalysis and removal of water.

Hydrogen Cyanide (HCN): R–CHO + HCN → R–CH(OH)–CN (cyanohydrin) Base-catalyzed (CN⁻ is the nucleophile). Used in industrial synthesis of hydroxy acids.

Grignard Reagents (RMgX): R–CHO + R’MgX → R–CH(OMgX)–R’ → (H₃O⁺) → R–CH(OH)–R’

• Formaldehyde → 1° alcohol
• Aldehyde → 2° alcohol
• Ketone → 3° alcohol

Amines: R–CHO + R’NH₂ → R–CH=N–R’ (imine/schiff base) R–CO–R’ + R”NHNH₂ → R–C=N–NHR” (hydrazone)

7. Radical Reactions

Free Radical Halogenation of Alkanes

Reaction: RH + X₂ → RX + HX (requires UV light or heat)

Mechanism: Initiation: X₂ → 2X• (radicals generated) Propagation:

• X• + RH → HX + R• (hydrogen abstraction)
• R• + X₂ → RX + X• (halogen abstraction) Termination:
• X• + X• → X₂
• R• + R• → R–R
• R• + X• → RX

Selectivity: 3° > 2° > 1° > CH₄ (based on C–H bond strength)

• CH₃–H: 435 kJ/mol (strongest)
• 1° C–H: 410 kJ/mol
• 2° C–H: 397 kJ/mol
• 3° C–H: 389 kJ/mol (weakest → most reactive to abstraction)

Multiple substitution: Products include mono-, di-, tri- halogenated compounds. To get monohalogenated product, use large excess of alkane relative to halogen.

Allylic Bromination (NBS)

Reagent: N-bromosuccinimide (NBS) + light (hv) Selectivity: Brominates allylic (C adjacent to C=C) positions Mechanism: Involves allylic radical stabilization

8. Oxidation and Reduction

Oxidation (LOSS of electrons, or GAIN of O, LOSS of H)

• Primary alcohol → aldehyde → carboxylic acid
• Secondary alcohol → ketone
• Aldehyde → carboxylic acid
• Alkene → diol (cold dilute KMnO₄) or CO₂ (hot conc. KMnO₄)
• Alkylbenzene → benzoic acid (hot KMnO₄)

Reduction (GAIN of electrons, or LOSS of O, GAIN of H)

• Aldehyde → primary alcohol
• Ketone → secondary alcohol
• Carboxylic acid → alcohol (LiAlH₄, not NaBH₄)
• Ester → alcohol (LiAlH₄)
• Amide → amine (LiAlH₄)
• Nitro → amine (Sn/HCl or H₂/Pd)
• C=C → C–C (H₂/Pt or H₂/Ni) — but NOT aromatic ring

Oxidizing Agents

• K₂Cr₂O₇/H₂SO₄: Orange → green; oxidizes 1° alcohol to acid (via aldehyde), 2° alcohol to ketone
• KMnO₄: Purple → brown MnO₂ (or colorless in dilute/cold); similar uses to dichromate
• Tollens’ Reagent (Ag(NH₃)₂⁺): Oxidizes aldehydes only → Ag⁰ (silver mirror); ketones don’t react
• Fehling’s Solution (Cu²⁺ tartrate): Oxidizes aldehydes → Cu₂O (red precipitate)

Reducing Agents

• NaBH₄: Reduces aldehydes and ketones to alcohols; does NOT reduce esters, acids, or amides
• LiAlH₄: Stronger than NaBH₄; reduces esters, amides, carboxylic acids; requires dry conditions (reacts with water)
• H₂/Ni or Pt or Pd: Catalytic hydrogenation; reduces C=C, C≡C, C=O, nitro groups
• Sn/HCl: Reduces nitro groups to amines

9. Exam-Style Questions & Tips

Common exam question patterns at Makerere:

1. “Draw the mechanism for [reaction] and name the intermediate(s)”
2. “Predict the major product and mechanism for the reaction of [substrate] with [reagent]”
3. “State whether the reaction proceeds by SN1, SN2, E1, or E2 mechanism and give your reasoning”
4. “Draw an energy diagram for [reaction type]”
5. “Explain why [substrate] reacts faster/slower than [other substrate] in [type] reactions”
6. “When 2-bromopropane is treated with NaOH, which reaction predominates: substitution or elimination? Explain.”

⚡ Exam tips:

• When drawing mechanisms, ALWAYS show curly arrows correctly — from electron pair to electrophile/nucleophile
• In elimination, anti-periplanar geometry is required for E2 — draw Newman projections to check
• Carbocation rearrangements can only occur if they lead to a MORE stable carbocation — never less stable
• Remember: LiAlH₄ reduces more functional groups than NaBH₄

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

10. Curly Arrow Conventions — Mastering Arrow Pushing

Arrow types:

1. Single-headed fishhook (↔): Electron pair movement (homo-cleavage: radical reactions)
2. Double-headed arrow (→): Two-electron movement (heterolysis or nucleophilic attack)
3. Resonance arrows (↔): Electron delocalization, same energy structures

Rules for drawing mechanistic arrows:

• Arrows start FROM a lone pair or bond, point TO where the new bond forms or electrons go
• Never exceed the octet rule in the arrow-pushing mechanism
• Positive charges attract electron flow (electrophiles attack electron-rich sites)
• In carbocation rearrangements: show hydride or methyl shift with two fishhook arrows

11. Carbanion Chemistry

Formation of Carbanions

Carbanions are negatively charged carbon species (R:⁻).

Sources:

• Grignard reagents (RMgX): C is nucleophilic (carbanion-like)
• Organolithium (RLi): Strongly nucleophilic carbanion
• acetylides (R–C≡C:⁻)

Reactions of Carbanions

• Attack electrophilic centers (SN2, carbonyl addition)
• As bases in E2 reactions

12. Reaction Coordinate Diagrams — Detailed Analysis

For an SN1 reaction:

          Energy
            |         Carbocation + Nu⁻
            |        ╱
            |       ╱  (after rate-determining step)
            |      ╱
            |     ╱
            |    ╱
            |   ╱  Transition state 2
            |  ╱
            | ╱
            |╱ Transition state 1
            ●
            |__________________→ Reaction coordinate
         R–X (reactants)

Transition state 1 (highest point of first step): Formation of [R…X]‡ Intermediate: Carbocation R⁺ + X⁻ (in a “valley”) Transition state 2: [R…Nu]‡

For SN2:

          Energy
            |    [R...Nu...X]‡
            |   ╱
            |  ╱
            | ╱
            |╱
            ●
            |__________________→ Reaction coordinate
         R–X (reactants)       R–Nu + X⁻ (products)

One transition state, no intermediate.

13. Concerted vs Stepwise Reactions

Concerted reactions: All bond-making and bond-breaking occur in a single step (e.g., SN2, E2, Diels-Alder). Stepwise reactions: Intermediate(s) formed between steps (e.g., SN1, E1).

Practice Problems

Q1: 1-bromo-1-methylcyclohexane undergoes elimination with ethanolic KOH. Draw all possible alkene products and name them. Which would be major?

Q2: When 3-bromo-2-methylbutane is treated with NaOH, a mixture of products forms. Draw and name all possible organic products. Which mechanisms operate?

Q3: Draw the reaction profile diagram for an SN1 reaction. Label: reactants, products, intermediates, transition states, activation energies for each step, ΔH.

Q4: Explain why 2-bromo-2-methylpropane undergoes hydrolysis (with AgNO₃ in ethanol/water) much faster than 2-bromopropane.

Q5: In the addition of HBr to propene, if the carbocation at C-2 could form (secondary), why might rearrangement to a more stable intermediate occur?

Common Mistakes to Avoid

1. Drawing curly arrows incorrectly: Arrows ALWAYS point from electron source to electron sink. Don’t draw arrows pointing toward electrons.
2. Forgetting anti-periplanar geometry for E2: If the leaving group and β-hydrogen are not anti-periplanar, E2 cannot occur — the reaction may be slow or may not happen.
3. Confusing SN1/SN2 rate laws: SN1 rate depends only on substrate; SN2 rate depends on substrate AND nucleophile.
4. Thinking carbocations rearrange to ANY more stable form: They only rearrange once — the new carbocation may not rearrange further if it’s already very stable.
5. Forgetting the role of solvent: Polar protic solvents favor SN1/E1 (stabilize ions); polar aprotic solvents favor SN2 (don’t solvate nucleophiles as well).
6. Miscounting the number of beta-hydrogens for elimination: A carbon adjacent to the leaving group may have 0, 1, 2, or 3 hydrogens to abstract — the most substituted alkene is usually favored.

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