Organic Chemistry - Reaction Mechanisms: Nucleophilic Substitution & Elimination ($S_N1$, $S_N2$, $E1$, $E2$) Flashcards

Question 1

$S_N2$ Mechanism Overview

Accepted Answer

A concerted, bimolecular nucleophilic substitution mechanism. The nucleophile attacks the electrophilic carbon at the same time the leaving group leaves. Rate law: $	ext{Rate} = k[	ext{substrate}][	ext{nucleophile}]$.

Question 2

$S_N2$ Stereochemistry & Walden Inversion

Accepted Answer

Proceeds exclusively via **backside attack** to avoid electronic repulsion with the leaving group, causing a complete inversion of stereochemical configuration at a chiral carbon (**Walden Inversion**).

Question 3

$S_N1$ Mechanism Overview

Accepted Answer

A stepwise, unimolecular nucleophilic substitution mechanism. The rate-determining step is the loss of the leaving group to form a carbocation intermediate. Rate law: $	ext{Rate} = k[	ext{substrate}]$.

Question 4

$S_N1$ Stereochemistry

Accepted Answer

Proceeds via an $sp^2$-hybridized, planar carbocation intermediate. The nucleophile can attack equally from either face, yielding a racemic mixture (**racemization**) of enantiomers.

Question 5

Substrate Reactivity Order for $S_N2$

Accepted Answer

$	ext{Methyl} > 1^\circ > 2^\circ \gg 3^\circ$.
Steric hindrance around the electrophilic carbon dramatically decreases the rate of backside attack. Tertiary ($3^\circ$) substrates do not undergo $S_N2$.

Question 6

Substrate Reactivity Order for $S_N1$

Accepted Answer

$3^\circ > 2^\circ \gg 1^\circ > 	ext{Methyl}$.
Driven by carbocation stability. Hyperconjugation and inductive electron donation stabilize $3^\circ$ carbocations best ($3^\circ > 2^\circ > 1^\circ$).

Question 7

Polar Protic Solvents vs. $S_N1$/$S_N2$

Accepted Answer

Solvents containing $-	ext{OH}$ or $-	ext{NH}$ bonds (e.g., $	ext{H}_2	ext{O}$, $	ext{MeOH}$, $	ext{EtOH}$). They solvate nucleophiles via hydrogen bonding, lowering nucleophilicity (favors $S_N1$/$E1$ by stabilizing carbocation intermediates).

Question 8

Polar Aprotic Solvents vs. $S_N1$/$S_N2$

Accepted Answer

Solvents without hydrogen-bond donors (e.g., DMSO, DMF, acetone, acetonitrile). They solvate cations but leave nucleophiles naked and highly reactive, dramatically accelerating $S_N2$ reactions.

Question 9

Nucleophilicity vs. Basicity

Accepted Answer

**Nucleophilicity** is a kinetic measurement (rate of attack on an electrophilic carbon atom). **Basicity** is a thermodynamic measurement (position of equilibrium when abstracting a proton, $	ext{H}^+$).

Question 10

$E2$ Mechanism Overview

Accepted Answer

A concerted, bimolecular elimination reaction where a strong base removes a $\beta$-hydrogen while the leaving group departs, forming a $\pi$ bond. Rate law: $	ext{Rate} = k[	ext{substrate}][	ext{base}]$.

Question 11

$E2$ Stereospecificity: Anti-Periplanar Requirement

Accepted Answer

The $\beta$-hydrogen and the leaving group must be arranged **anti-periplanar** ($180^\circ$ dihedral angle) to allow proper orbital overlap for double bond formation.

Question 12

$E1$ Mechanism Overview

Accepted Answer

A stepwise unimolecular elimination mechanism. The leaving group departs first to form a carbocation intermediate, followed by deprotonation by a weak base to form an alkene. Rate law: $	ext{Rate} = k[	ext{substrate}]$.

Question 13

Zaitsev's Rule (Regioselectivity)

Accepted Answer

In elimination reactions, the **more substituted, thermodynamically stable alkene** is formed as the major product. Favored when using small, unhindered bases (e.g., $	ext{NaOCH}_3$, $	ext{KOH}$).

Question 14

Hofmann's Rule (Regioselectivity)

Accepted Answer

In elimination reactions, the **less substituted, sterically less hindered alkene** is formed as the major product. Favored when using strong, bulky bases (e.g., potassium $tert$-butoxide, $	ext{KO}t	ext{-Bu}$).

Question 15

Leaving Group Ability Trend

Accepted Answer

Good leaving groups are weak, stable bases (conjugate bases of strong acids). Order of leaving group ability: $	ext{I}^- > 	ext{Br}^- > 	ext{Cl}^- > 	ext{H}_2	ext{O} > 	ext{F}^-$. Tosylates ($	ext{OTs}^-$) and mesylates ($	ext{OMs}^-$) are also excellent.

Question 16

Converting Poor Leaving Groups ($-	ext{OH}$)

Accepted Answer

Hydroxyl groups ($-	ext{OH}$) are strong bases and poor leaving groups. They must be activated by **protonation** with acid (forming $-	ext{OH}_2^+$) or converted to a **tosylate** ($-	ext{OTs}$) using $	ext{TsCl/pyridine}$.

Question 17

Carbocation Rearrangements ($S_N1$ & $E1$)

Accepted Answer

If a carbocation intermediate forms ($S_N1$ or $E1$), it can undergo a **$1,2$-hydride shift** or **$1,2$-methyl shift** to rearrange into a more stable carbocation (e.g., $2^\circ \rightarrow 3^\circ$).

Question 18

Primary ($1^\circ$) Substrate Reaction Pathway Selection

Accepted Answer

- Strong nucleophile/strong base (e.g., $	ext{NaOH}$): **$S_N2$**
- Bulky strong base (e.g., $t	ext{-BuOK}$): **$E2$**
- Weak nucleophile/weak base (e.g., $	ext{H}_2	ext{O}$): **No reaction** (primary carbocation too unstable for $S_N1$/$E1$).

Question 19

Tertiary ($3^\circ$) Substrate Reaction Pathway Selection

Accepted Answer

- Strong base (e.g., $	ext{NaOEt}$ or $t	ext{-BuOK}$): **$E2$**
- Weak nucleophile/base + heat (e.g., $	ext{EtOH, } \Delta$): **$E1$**
- Weak nucleophile/base (e.g., $	ext{H}_2	ext{O}$ or $	ext{MeOH}$): **$S_N1$**
- **$S_N2$ is impossible** due to severe steric hindrance.

Question 20

Secondary ($2^\circ$) Substrate Pathway Rules

Accepted Answer

- Strong base/strong nucleophile (e.g., $	ext{OH}^-$): **$E2$ major, $S_N2$ minor**
- Strong nucleophile/weak base (e.g., $	ext{I}^-$, $	ext{N}_3^-$): **$S_N2$**
- Strong bulky base (e.g., $t	ext{-BuO}^-$): **$E2$ (Hofmann)**
- Weak base/weak nucleophile (e.g., $	ext{H}_2	ext{O}$): **$S_N1$ / $E1$ mixture**

Organic Chemistry - Reaction Mechanisms: Nucleophilic Substitution & Elimination ($S_N1$, $S_N2$, $E1$, $E2$)

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