Organic Chemistry - Reaction Mechanisms, Nucleophilic Substitution & Stereochemistry Flashcards

Question 1

$S_N2$ Mechanism & Stereochemistry

Accepted Answer

**Bimolecular Nucleophilic Substitution ($S_N2$):**
- **Mechanism:** Concerted (single-step) backside attack by a nucleophile while the leaving group leaves.
- **Rate Law:** $	ext{Rate} = k[	ext{substrate}][	ext{nucleophile}]$
- **Stereochemistry:** Inversion of configuration (100% Walden inversion, converting $R ightarrow S$ or $S ightarrow R$ if priority order is preserved).
- **Favored Substrates:** Methyl > $1^\circ$ > $2^\circ$ ($3^\circ$ substrates cannot undergo $S_N2$ due to steric hindrance).

Question 2

$S_N1$ Mechanism & Stereochemistry

Accepted Answer

**Unimolecular Nucleophilic Substitution ($S_N1$):**
- **Mechanism:** Stepwise mechanism via a planar trigonal carbocation intermediate.
  1. Rate-determining step (RDS): Loss of leaving group $ightarrow$ carbocation.
  2. Nucleophilic attack from either face.
  3. Deprotonation (if neutral nucleophile used).
- **Rate Law:** $	ext{Rate} = k[	ext{substrate}]$
- **Stereochemistry:** Racemization (mix of inversion and retention) due to the achiral planar carbocation intermediate.
- **Favored Substrates:** $3^\circ > 2^\circ > 	ext{allylic/benzylic}$ (unstable on $1^\circ$ or methyl).

Question 3

Carbocation Stability Rules

Accepted Answer

**Relative Stability:** $	ext{Methyl} < 1^\circ < 2^\circ < 3^\circ < 	ext{Allylic/Benzylic}$

**Key Stabilizing Factors:**
1. **Hyperconjugation:** $\sigma$-bonds from adjacent $	ext{C-H}$ or $	ext{C-C}$ bonds donate electron density into the empty $p$-orbital.
2. **Induction:** Electronegativity differences push electron density through $\sigma$-bonds toward the positively charged carbon.
3. **Resonance:** Delocalization of positive charge into adjacent $\pi$-systems (e.g., allylic/benzylic carbocations).

Question 4

Carbocation Rearrangements (Hydride & Alkyl Shifts)

Accepted Answer

**Overview:** Occur during reactions involving carbocation intermediates ($S_N1$, $E1$, electrophilic additions) to yield a more stable carbocation.

- **1,2-Hydride Shift:** A hydrogen atom migrates with its electron pair ($	ext{H}^-$) to an adjacent carbocation center ($2^\circ \rightarrow 3^\circ$).
- **1,2-Methyl/Alkyl Shift:** An alkyl group migrates with its bonding electrons when no adjacent hydrogens are available to increase stability ($2^\circ \rightarrow 3^\circ$ or ring expansion).

Question 5

Polar Protic vs. Polar Aprotic Solvents

Accepted Answer

- **Polar Protic Solvents:** Contain $	ext{O-H}$ or $	ext{N-H}$ bonds (e.g., $	ext{H}_2	ext{O}$, $	ext{MeOH}$, $	ext{EtOH}$). Form hydrogen bonds with nucleophiles, solvating them, which weakens nucleophilicity. **Favors $S_N1$ / $E1$.**
- **Polar Aprotic Solvents:** Lack $	ext{O-H}$/$	ext{N-H}$ bonds (e.g., DMSO, Acetone, DMF, acetonitrile). Solvate cations well but leave nucleophiles bare ("naked") and highly reactive. **Favors $S_N2$ / $E2$.**

Question 6

Nucleophilicity vs. Basicity

Accepted Answer

- **Basicity:** Thermodynamic property measured by $K_a$ ($pK_a$); capacity to donate electron pairs to a proton ($	ext{H}^+$).
- **Nucleophilicity:** Kinetic property; speed of electron pair donation to an electrophilic carbon atom.

**Trends:**
- Parallel in same row: Stronger base = Stronger nucleophile (e.g., $	ext{HO}^- > 	ext{H}_2	ext{O}$).
- Steric Hindrance: Bulky bases (e.g., $t$-BuO$^-$) are strong bases but poor nucleophiles.
- Solvents: In polar protic solvents, larger polarizable atoms are better nucleophiles ($	ext{I}^- > 	ext{Br}^- > 	ext{Cl}^- > 	ext{F}^-$).

Question 7

$E2$ Elimination Mechanism & Stereochemistry

Accepted Answer

**Bimolecular Elimination ($E2$):**
- **Mechanism:** Concerted deprotonation of a $\beta$-hydrogen by a base while the leaving group departs to form a $\pi$-bond.
- **Rate Law:** $	ext{Rate} = k[	ext{substrate}][	ext{base}]$
- **Stereospecificity Requirement:** The $\beta$-hydrogen and the leaving group must be **anti-periplanar** (dihedral angle = $180^\circ$).
- In cyclohexane rings, both the leaving group and $\beta$-H must be in trans-diaxial orientation.

Question 8

$E1$ Elimination Mechanism

Accepted Answer

**Unimolecular Elimination ($E1$):**
- **Stepwise Mechanism:**
  1. Loss of leaving group $ightarrow$ carbocation intermediate (RDS).
  2. Weak base deprotonates the $\beta$-carbon to form an alkene.
- **Rate Law:** $	ext{Rate} = k[	ext{substrate}]$
- **Regioselectivity:** Follows Zaitsev's rule (forms the most substituted, stable alkene).
- **Competition:** Always competes with $S_N1$ because both share the same rate-determining carbocation formation step.

Question 9

Zaitsev's Rule vs. Hofmann's Rule

Accepted Answer

- **Zaitsev's Rule:** Elimination yields the **more substituted**, thermodynamically more stable alkene.
  - *Conditions:* Small, unhindered bases (e.g., $	ext{NaOEt}$, $	ext{NaOH}, 	ext{NaOMe}$).
- **Hofmann's Rule:** Elimination yields the **less substituted**, sterically less hindered alkene.
  - *Conditions:* Bulky, hindered bases (e.g., Potassium $tert$-butoxide, $	ext{K}^{+-}	ext{O}t	ext{Bu}$, LDA) or poor leaving groups like fluorides/ammonium salts.

Question 10

Cahn-Ingold-Prelog (CIP) Priorities & $R/S$ Determination

Accepted Answer

1. **Assign Priorities (1-4):** Assign based on atomic number ($Z$) directly bonded to chiral center ($	ext{I} > 	ext{Br} > 	ext{Cl} > 	ext{S} > 	ext{P} > 	ext{F} > 	ext{O} > 	ext{N} > 	ext{C} > 	ext{H}$).
2. **Tie-Breaker:** Compare atoms at the next point of difference.
3. **Multiple Bonds:** Treat multiple bonds as duplicate single bonds (e.g., $-	ext{CH}=	ext{O}$ is treated as $-	ext{CH}(	ext{O})_2$).
4. **Orient & Read:** Point priority 4 group to the back (dashed wedge).
   - **Clockwise (1 $ightarrow$ 2 $ightarrow$ 3):** $R$ (Rectus)
   - **Counter-clockwise (1 $ightarrow$ 2 $ightarrow$ 3):** $S$ (Sinister)

Question 11

Enantiomers vs. Diastereomers

Accepted Answer

- **Enantiomers:** Non-superimposable mirror images.
  - All chiral centers inverted ($R,R \leftrightarrow S,S$).
  - Same physical properties (bp, mp, solubility), but rotate plane-polarized light in equal and opposite directions ($[\alpha]$).
- **Diastereomers:** Stereoisomers that are non-superimposable and non-mirror images.
  - At least one, but not all, chiral centers inverted ($R,R \leftrightarrow R,S$).
  - Different physical and chemical properties.

Question 12

Meso Compounds

Accepted Answer

**Definition:** Molecules containing two or more stereocenters that are achiral due to an **internal plane of symmetry** (or center of inversion).

- **Properties:** Optically inactive ($[\alpha] = 0^\circ$).
- **Stereocenters:** Opposite configurations across symmetry plane (e.g., $1R, 2S$).
- **Formula Check:** Maximum number of stereoisomers $= 2^n - 1$ when a meso form is present (where $n$ is the number of stereocenters).

Question 13

Electrophilic Addition: Markovnikov's Rule

Accepted Answer

**Markovnikov's Rule:** In the addition of $	ext{HX}$ to an unsymmetrical alkene, the electrophilic proton ($	ext{H}^+$) adds to the carbon with **more hydrogens**, forming the more stable carbocation intermediate.

- **Product:** Halide ($	ext{X}^-$) attaches to the **more substituted** carbon atom.
- **Exceptions:** Addition of $	ext{HBr}$ in the presence of peroxides ($	ext{ROOR}$) proceeds via a radical mechanism yielding **Anti-Markovnikov** addition.

Question 14

Hydroboration-Oxidation Mechanism & Stereochemistry

Accepted Answer

**Reagents:** 1) $	ext{BH}_3 \cdot 	ext{THF}$, 2) $	ext{H}_2	ext{O}_2, 	ext{NaOH}$

- **Regioselectivity:** Anti-Markovnikov (hydroxyl group $-	ext{OH}$ attaches to the *less substituted* carbon).
- **Stereochemistry:** **Syn-addition** (both $-	ext{H}$ and $-	ext{OH}$ add to the *same face* of the alkene via a 4-membered cyclic transition state).
- **Intermediate:** No carbocation is formed (no rearrangements).

Question 15

Halogenation & Halohydrin Formation Stereochemistry

Accepted Answer

- **Halogenation ($	ext{X}_2$ in $	ext{CCl}_4$):** Forms a cyclic **halonium ion** intermediate. Nucleophilic attack by $	ext{X}^-$ occurs from the opposite face $ightarrow$ **Anti-addition** product.
- **Halohydrin Formation ($	ext{X}_2$ in $	ext{H}_2	ext{O}$):** Water attacks the more substituted carbon of the halonium ion $ightarrow$ **Anti-addition** with $-	ext{OH}$ on the more substituted carbon.

Question 16

Leaving Group Ability Trends

Accepted Answer

**Rule:** Good leaving groups are **weak bases** (conjugate bases of strong acids).

- **Trend:** $	ext{I}^- > 	ext{Br}^- > 	ext{Cl}^- \gg 	ext{F}^-$
- **Sulfonates:** $	ext{OTs}^-$, $	ext{OMs}^-$, $	ext{OTf}^-$ are exceptional leaving groups due to resonance stabilization of the negative charge.
- **Poor Leaving Groups:** $-	ext{OH}$, $-	ext{NH}_2$, $-	ext{OR}$ (Must be protonated or activated to leave, e.g., converting $-	ext{OH} ightarrow -	ext{OH}_2^+$ or $-	ext{OTs}$).

Question 17

Oxymercuration-Demercuration

Accepted Answer

**Reagents:** 1) $	ext{Hg(OAc)}_2, 	ext{H}_2	ext{O}$, 2) $	ext{NaBH}_4$

- **Regioselectivity:** Markovnikov addition of $-	ext{OH}$ and $-	ext{H}$.
- **Intermediate:** Cyclic **mercurinium ion** intermediate prevents carbocation rearrangements.
- **Stereochemistry:** Anti-addition of $	ext{Hg(OAc)}$ and $	ext{OH}$ in step 1; overall regiosecondary alcohol formation without rearrangement.

Question 18

Epoxidation & Anti-Dihydroxylation of Alkenes

Accepted Answer

- **Epoxidation:** Alkene treated with a peroxyacid (e.g., $	ext{mCPBA}$) forms an epoxide via a concerted mechanism (**Syn-addition**).
- **Ring-Opening (Anti-Dihydroxylation):** Acid-catalyzed ($	ext{H}_3	ext{O}^+$) nucleophilic ring opening of an epoxide proceeds via anti-attack, yielding a **trans-1,2-diol**.

Question 19

Summary: Matrix for $S_N1, S_N2, E1, E2$ Pathways

Accepted Answer

| Substrate | Strong Base / Strong Nuc | Strong Base / Weak Nuc | Weak Base / Strong Nuc | Weak Base / Weak Nuc |
| :--- | :--- | :--- | :--- | :--- |
| **Primary ($1^\circ$)** | $S_N2$ | $E2$ | $S_N2$ | No reaction |
| **Secondary ($2^\circ$)** | $E2$ | $E2$ | $S_N2$ | $S_N1 / E1$ (slow) |
| **Tertiary ($3^\circ$)** | $E2$ | $E2$ | $S_N1$ | $S_N1 / E1$ (heat favors $E1$) |

Organic Chemistry - Reaction Mechanisms, Nucleophilic Substitution & Stereochemistry

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