Organic Chemistry - Reaction Mechanisms, Electrophilic Additions & Stereochemistry Flashcards

Question 1

What do curved arrows represent in organic reaction mechanisms, and what is the cardinal rule regarding arrow direction?

Accepted Answer

Curved arrows represent the **movement of electron pairs** (not atomic nuclei or positive charges).

- **Source:** The tail begins at an electron-dense region (a lone pair or a $\pi$/$\sigma$ bond).
- **Sink:** The head points to an electron-deficient center or atom forming a new bond or receiving an electron pair.

Question 2

Rank the relative stability of carbocations and explain the underlying electronic factors.

Accepted Answer

**Stability Order:** $	ext{Benzylic/Allylic} \approx 3^\circ > 2^\circ > 1^\circ > 	ext{Methyl}$

- **Hyperconjugation:** $\sigma$-electrons from adjacent $	ext{C-H}$ or $	ext{C-C}$ bonds delocalize into the empty $p$-orbital of the carbocation.
- **Inductive Effect:** Electron-donating alkyl groups push electron density toward the positively charged carbon.
- **Resonance:** Allylic and benzylic cations delocalize the positive charge across $\pi$-systems.

Question 3

What are the key mechanistic steps, kinetics, and stereochemical outcomes of an $S_N1$ reaction?

Accepted Answer

- **Mechanism:** 2-step unimolecular substitution via a discrete carbocation intermediate (leaving group leaves, then nucleophile attacks).
- **Kinetics:** First-order: $	ext{Rate} = k[	ext{substrate}]$.
- **Stereochemistry:** **Racemization** (mixture of enantiomers) because nucleophilic attack can occur from either face of the planar, $sp^2$-hybridized carbocation intermediate.

Question 4

What are the key mechanistic steps, kinetics, and stereochemical outcomes of an $S_N2$ reaction?

Accepted Answer

- **Mechanism:** 1-step concerted bimolecular substitution via a pentacoordinate transition state (backside attack).
- **Kinetics:** Second-order: $	ext{Rate} = k[	ext{substrate}][	ext{nucleophile}]$.
- **Stereochemistry:** Complete **inversion of configuration** (Walden inversion) at the target stereocenter.

Question 5

How do $E1$ and $E2$ elimination mechanisms differ in kinetics, intermediates, and geometric requirements?

Accepted Answer

- **$E1$ Mechanism:** 2-step unimolecular elimination via a carbocation intermediate; $	ext{Rate} = k[	ext{substrate}]$; requires no special spatial alignment.
- **$E2$ Mechanism:** 1-step concerted bimolecular elimination; $	ext{Rate} = k[	ext{substrate}][	ext{base}]$; strictly requires an **anti-periplanar** geometry (dihedral angle $	heta = 180^\circ$) between the $\beta$-hydrogen and the leaving group.

Question 6

How do substrate structure and reagent strength dictate substitution ($S_N1/S_N2$) vs. elimination ($E1/E2$)?

Accepted Answer

- **Strong Base / Strong Nucleophile** (e.g., $	ext{HO}^-$, $	ext{RO}^-$): $1^\circ ightarrow S_N2$; $2^\circ ightarrow E2$; $3^\circ ightarrow E2$.
- **Weak Base / Strong Nucleophile** (e.g., $	ext{I}^-$, $	ext{RS}^-$): $1^\circ, 2^\circ ightarrow S_N2$; $3^\circ ightarrow S_N1$.
- **Strong Bulky Base** (e.g., $t	ext{-BuO}^-$): $1^\circ, 2^\circ, 3^\circ ightarrow E2$ (Hofmann product).
- **Weak Base / Weak Nucleophile** (e.g., $	ext{H}_2	ext{O}$, $	ext{ROH}$): $1^\circ ightarrow 	ext{No reaction}$; $3^\circ ightarrow S_N1/E1$ mixture (heat favors $E1$).

Question 7

What determines Zaitsev vs. Hofmann elimination regioselectivity?

Accepted Answer

- **Zaitsev's Rule:** Form the **more substituted, thermodynamically stable alkene** as the major product (favored by small, unhindered bases like $	ext{NaOEt}$ or $	ext{NaOH}$).
- **Hofmann's Rule:** Form the **less substituted alkene** as the major product (favored by sterically hindered bases like $t	ext{-BuOK}$ or bulky leaving groups like fluoride or quaternary ammonium salts).

Question 8

Describe the regioselectivity, intermediate, and potential rearrangements in alkene hydrohalogenation ($	ext{HX}$).

Accepted Answer

- **Regioselectivity:** Follows **Markovnikov's rule**—the electrophile ($	ext{H}^+$) adds to the carbon with more hydrogens, forming the more stable carbocation intermediate.
- **Intermediate:** Open carbocation.
- **Rearrangements:** Possible via 1,2-hydride or 1,2-alkyl shifts if a more stable carbocation can form.

Question 9

How does addition of $	ext{HBr}$ in the presence of peroxides ($	ext{ROOR}$) alter regioselectivity?

Accepted Answer

- **Regioselectivity:** **Anti-Markovnikov** addition of $	ext{HBr}$.
- **Mechanism:** Radical chain pathway. Peroxides undergo homolysis to generate $	ext{Br}^\bullet$, which adds first to the double bond to generate the **more substituted (more stable) alkyl radical intermediate**.
- *Note:* Applies exclusively to $	ext{HBr}$ (not $	ext{HCl}$ or $	ext{HI}$).

Question 10

What are the intermediates and stereochemical outcomes for alkene bromination ($	ext{Br}_2$) and halohydrin formation ($	ext{Br}_2/	ext{H}_2	ext{O}$)?

Accepted Answer

- **Intermediate:** Cyclic **bromonium ion** ($3$-membered ring).
- **Stereochemistry:** Exclusive **anti-addition** due to nucleophilic attack from the face opposite the bromonium ion.
- **Halohydrin Regioselectivity:** $	ext{H}_2	ext{O}$ acts as the nucleophile and attacks the **more substituted carbon** (which carries more partial positive charge).

Question 11

Compare Oxymercuration-Demercuration and Hydroboration-Oxidation of alkenes.

Accepted Answer

- **Oxymercuration-Demercuration** ($1.	ext{ Hg(OAc)}_2, 	ext{H}_2	ext{O} / 2.	ext{ NaBH}_4$): Yields **Markovnikov** alcohol via mercurinium ion intermediate; anti-addition; **no carbocation rearrangements**.
- **Hydroboration-Oxidation** ($1.	ext{ BH}_3\cdot	ext{THF} / 2.	ext{ H}_2	ext{O}_2, 	ext{NaOH}$): Yields **Anti-Markovnikov** alcohol via concerted 4-center transition state; **syn-addition**; **no carbocation rearrangements**.

Question 12

Compare the stereochemical outcomes of anti-dihydroxylation and syn-dihydroxylation of alkenes.

Accepted Answer

- **Anti-Dihydroxylation:** Epoxidation with a peroxyacid (e.g., $	ext{mCPBA}$) followed by acid-catalyzed ($ 	ext{H}_3	ext{O}^+$) ring opening $ightarrow$ **trans-1,2-diol**.
- **Syn-Dihydroxylation:** Reaction with catalytic $	ext{OsO}_4$ / $	ext{NMO}$ or cold, dilute $	ext{KMnO}_4$ forming a cyclic osmate/manganate ester $ightarrow$ **cis-1,2-diol**.

Question 13

What products are formed from the ozonolysis of alkenes under reductive vs. oxidative workup?

Accepted Answer

- **Reductive Workup** ($1.	ext{ O}_3 / 2.	ext{ Zn/AcOH}$ or $	ext{(CH}_3)_2	ext{S}$): Cleaves $C=C$ to yield **aldehydes** (if $	ext{H}$ was attached to the alkene carbon) and/or **ketones**.
- **Oxidative Workup** ($1.	ext{ O}_3 / 2.	ext{ H}_2	ext{O}_2$): Cleaves $C=C$ to yield **carboxylic acids** (if $	ext{H}$ was attached) and/or **ketones**.

Question 14

How does hydration of a terminal alkyne differ using $	ext{HgSO}_4/	ext{H}_2	ext{SO}_4$ vs. Hydroboration-Oxidation?

Accepted Answer

- **$	ext{HgSO}_4/	ext{H}_2	ext{SO}_4/	ext{H}_2	ext{O}$:** Markovnikov addition forms an enol that tautomerizes to a **methyl ketone**.
- **Hydroboration-Oxidation** (using hindered borane like $	ext{Sia}_2	ext{BH}$): Anti-Markovnikov addition forms an enol that tautomerizes to an **aldehyde**.

Question 15

What are the Cahn-Ingold-Prelog (CIP) priority rules for assigning $R$ or $S$ configuration?

Accepted Answer

1. Rank 4 substituents by atomic number of directly attached atom ($I > Br > Cl > S > P > O > N > C > H$).
2. In case of ties, compare atoms at the next point of difference.
3. Treat double/triple bonds as duplicate/triplicate single bonds.
4. Orient lowest priority group (4) to the back (dashed bond).
5. Trace path $1 \rightarrow 2 \rightarrow 3$:
   - **Clockwise** = **$R$** (Rectus)
   - **Counterclockwise** = **$S$** (Sinister)

Question 16

How are $E$ and $Z$ stereodescriptors assigned to substituted alkenes?

Accepted Answer

Assign CIP priority to the two groups attached to **each** double-bonded carbon separately.

- **$Z$ (zusammen = together):** The highest priority group on Carbon 1 and highest priority group on Carbon 2 are on the **same side** of the $C=C$ double bond.
- **$E$ (entgegen = opposite):** The highest priority groups are on **opposite sides** of the $C=C$ double bond.

Question 17

Define enantiomers, diastereomers, and meso compounds, noting their optical activity.

Accepted Answer

- **Enantiomers:** Non-superimposable mirror images; inverted at *all* stereocenters; **optically active** ($[\alpha] 
eq 0$).
- **Diastereomers:** Non-superimposable non-mirror images; inverted at *some* (not all) stereocenters; **optically active** ($[\alpha] 
eq 0$).
- **Meso Compounds:** Possess multiple stereocenters AND an **internal plane of symmetry**; achiral and **optically inactive** ($[\alpha] = 0$).

Question 18

What is the formula for Enantiomeric Excess ($ee$) and how does it relate to observed optical rotation?

Accepted Answer

$$ee = \frac{|	ext{mole fraction } R - 	ext{mole fraction } S|}{	ext{total mole fraction}} 	imes 100\%$$

$$ee = \frac{[\alpha]_{	ext{observed}}}{[\alpha]_{	ext{pure enantiomer}}} 	imes 100\%$$

A racemic mixture ($50:50$ ratio) has $ee = 0\%$ and zero optical rotation.

Question 19

When and how do carbocation rearrangements occur?

Accepted Answer

Occur spontaneously whenever a secondary ($2^a$) or primary ($1^a$) carbocation can transform into a more stable tertiary ($3^a$), allylic, or benzylic carbocation via:

- **1,2-Hydride Shift:** Migration of $	ext{H}^-$ with its electron pair from an adjacent carbon.
- **1,2-Alkyl (Methyl) Shift:** Migration of an alkyl group with its electron pair when no $\beta$-hydrogen is available.

Question 20

How do polar protic vs. polar aprotic solvents affect the rates of $S_N1$ and $S_N2$ reactions?

Accepted Answer

- **Polar Protic Solvents** (e.g., $	ext{H}_2	ext{O}, 	ext{MeOH}, 	ext{EtOH}$): Hydrogen-bond with nucleophiles, forming a solvation shell that lowers nucleophilicity. Stabilize carbocations, favoring **$S_N1/E1$** pathways.
- **Polar Aprotic Solvents** (e.g., $	ext{DMSO}, 	ext{DMF}, 	ext{acetone}$): Solvate cations but leave nucleophiles naked/unsolvated, dramatically accelerating **$S_N2$** pathways.

Question 21

What is the key functional difference between nucleophilicity and basicity?

Accepted Answer

- **Basicity:** A **thermodynamic** property measuring a species' equilibrium affinity for a proton ($	ext{H}^+$).
- **Nucleophilicity:** A **kinetic** property measuring the rate at which a species attacks an electrophilic carbon atom.
- **Steric Hindrance Effect:** Sterically bulky bases (e.g., $t	ext{-BuO}^-$) are strong bases but **poor nucleophiles** due to spatial crowding.

Question 22

What stereochemical requirement must be met for an $E2$ elimination on a cyclohexane ring?

Accepted Answer

The leaving group and the adjacent $\beta$-hydrogen **must both occupy axial positions** (trans-diaxial arrangement) to be anti-periplanar ($	heta = 180^\circ$). If the leaving group is in an equatorial position, the chair must undergo a **chair flip** before $E2$ elimination can occur.

Organic Chemistry - Reaction Mechanisms, Electrophilic Additions & Stereochemistry

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