Organic Reactions: Detailed Notes and Questions & Answers

These notes are derived from “Organic Chemistry” by Clayden, Greeves, and Warren (Second Edition). They cover fundamental organic reaction types, mechanisms, and key concepts, followed by a set of 40 questions and answers to reinforce your understanding.

Part 1: Detailed Notes on Organic Reactions

Chapter 5: Organic Reactions – Fundamentals

• Chemical Reactions: Molecules react due to incessant motion and collisions. For a reaction to occur, molecules must overcome an activation energy barrier, requiring sufficient energy to overcome electronic repulsion.
• Nucleophiles and Electrophiles:
  • Nucleophiles (Nu): “Nucleus-loving” species that are electron-rich and seek positive centers. They have a filled orbital (HOMO – Highest Occupied Molecular Orbital) that donates electrons. Examples include negative charges (anions), lone pairs, π bonds, and sometimes σ bonds.
  • Electrophiles (E): “Electron-loving” species that are electron-deficient and seek electron-rich centers. They have an empty orbital (LUMO – Lowest Unoccupied Molecular Orbital) that accepts electrons. Examples include positive charges (cations) or atoms with partial positive charges (e.g., carbonyl carbon).
  • Key Principle: Most organic reactions involve the interaction between a filled orbital of a nucleophile and an empty orbital of an electrophile.
• Curly Arrows: Represent the movement of a pair of electrons in a reaction mechanism.
  • Start from a source of electrons (negative charge, lone pair, bond).
  • End at the destination of electrons (where a new bond forms, or an electronegative atom that can bear a negative charge).
  • Conservation of Charge: Overall charge is always conserved in each step of a reaction.
  • Octet Rule: Atoms like C, N, O, B rarely exceed four bonds (or eight valence electrons). If a new bond forms to one of these atoms, an existing bond often must break simultaneously.

Chapter 6: Nucleophilic Addition to the Carbonyl Group

• Carbonyl Group (C=O): Highly reactive electrophilic center due to the electronegativity difference between carbon and oxygen, creating a dipole with a partial positive charge on carbon and a partial negative charge on oxygen. The LUMO is the π∗ orbital of the C=O bond.
• Mechanism: Nucleophilic attack on the carbonyl carbon, pushing electrons from the C=O π bond onto the oxygen atom, forming a tetrahedral intermediate (alkoxide). This is typically followed by protonation of the alkoxide.
• Examples of Nucleophilic Addition:
  • Addition of Cyanide (HCN/NaCN): Forms cyanohydrins. The cyanide ion (⁻CN) attacks the carbonyl carbon.
    RCHO+NaCNH+​RCH(OH)CN
  • Addition of Hydride (e.g., NaBH$_4$): Reduces aldehydes/ketones to alcohols. The hydride ion (H⁻) effectively acts as the nucleophile.
    R2​CO+NaBH4​H2​O​R2​CHOH
  • Addition of Organometallic Reagents (Grignard reagents R-MgX, Organolithiums R-Li): Forms new C-C bonds and alcohols. These are very strong nucleophiles.
    R1​R2​CO+R3​MgBr1.Et2​O,2.H3​O+​R1​R2​(R3​)COH
  • Addition of Water: Forms hydrates (geminal diols). Equilibrium often favors the carbonyl compound unless the hydrate is cyclic.
    R2​CO+H2​O⇌R2​C(OH)2​
  • Addition of Alcohols: Forms hemiacetals (from aldehydes/ketones) and then acetals (from aldehydes/ketones with acid catalyst). Cyclic hemiacetals (e.g., sugars) are often stable.
    RCHO+ROH⇌RCH(OH)ORRCHO+2ROHH+​RCH(OR)2​+H2​O
• Catalysis: Acid and base catalysis increase the rate of nucleophilic addition by making the carbonyl group more electrophilic (acid) or the nucleophile more nucleophilic (base).

Chapter 9: Using Organometallic Reagents to Make C-C Bonds

• Organometallic Compounds: Contain a carbon-metal bond (e.g., R-MgX, R-Li). The carbon atom is typically nucleophilic due to the polarity of the C-metal bond.
• Making Organometallics: Often by reaction of alkyl halides with metals (e.g., Li, Mg).
  RX+2Li→RLi+LiXRX+Mg→RMgX
• Reactions to Make C-C Bonds: Primarily addition to carbonyl groups (aldehydes, ketones, esters, CO$_2$) as discussed in Chapter 6. These reactions are highly effective for forming new carbon-carbon bonds.
  • Addition to Aldehydes/Ketones: Yields alcohols (primary, secondary, or tertiary depending on the starting carbonyl).
  • Addition to Esters: Typically yields tertiary alcohols by adding two equivalents of the organometallic reagent, as the initially formed ketone is more reactive than the ester.
  • Addition to CO$_2$: Forms carboxylic acids after protonation.

Chapter 10: Nucleophilic Substitution at the Carbonyl Group

• Mechanism: Nucleophilic attack on the carbonyl carbon to form a tetrahedral intermediate, followed by the loss of a leaving group (typically a stable anion like Cl⁻, RO⁻, RCO$_2$⁻), regenerating a carbonyl group. This is often called addition-elimination.
• Carboxylic Acid Derivatives: Reactivity order: Acyl Chlorides > Acid Anhydrides > Esters > Carboxylic Acids > Amides. This order is largely determined by the leaving group ability. Good leaving groups (e.g., Cl⁻) correspond to more reactive derivatives.
  • Interconversions: Can typically be converted to less reactive derivatives. To go to more reactive derivatives, one usually converts to the carboxylic acid and then to the acyl chloride.
  • Hydrolysis: Reaction with water (often with acid/base catalysis) to form carboxylic acids.
  • Alcoholysis: Reaction with alcohols to form esters.
  • Aminolysis: Reaction with amines to form amides.
• Making Ketones from Esters: Generally problematic with Grignard/organolithium reagents because the ketone product is more electrophilic than the ester starting material, leading to over-addition and formation of tertiary alcohols.
  • Solutions: Use less reactive organometallics (e.g., Gilman reagents, organocuprates) or Weinreb amides, which form stable tetrahedral intermediates that only collapse upon acid work-up.
• Making Aldehydes from Esters/Nitriles: Similar strategies using specific reagents like DMF for aldehydes from organometallics, or reduction of nitriles.

Chapter 11: Nucleophilic Substitution at C=O with Loss of Carbonyl Oxygen

• Key Concept: Carbonyl oxygen is replaced by another atom (e.g., nitrogen) or group of atoms. This often involves acid catalysis.
• Acetals Formation (from aldehydes/ketones + alcohols):
  • Aldehydes and ketones react reversibly with alcohols in the presence of acid to form acetals. These are stable protecting groups for aldehydes and ketones as they are unreactive to many nucleophiles and bases.
  • Mechanism involves protonation of the carbonyl oxygen to increase electrophilicity, nucleophilic attack by alcohol, loss of water (protonated hydroxyl group), and then attack by another alcohol molecule.
• Imine Formation (from aldehydes/ketones + amines):
  • Aldehydes and ketones react with primary amines to form imines (RHC=NR’, R₂C=NR’). This reaction is also acid-catalyzed and reversible.
  • Mechanism involves nucleophilic attack by the amine, proton transfer, and loss of water (from the hemiaminal intermediate).
  • pH Dependence: The reaction rate for imine formation is sensitive to pH, typically showing a maximum around pH 6. Too much acid protonates the amine (reducing nucleophilicity), too little acid means the leaving group (OH) is not sufficiently protonated to leave as water.
• Wittig Reaction: Forms alkenes from aldehydes/ketones and phosphonium ylids. This reaction is highly stereoselective (often producing a specific alkene isomer) and irreversible, driven by the formation of a very strong P=O bond.
  R1​R2​CO+Ph3​P=CHR3​→R1​R2​C=CHR3​+Ph3​PO

Chapter 15: Nucleophilic Substitution at Saturated Carbon (S$_N1andS_N$2)

• Nucleophilic Substitution: A nucleophile replaces a leaving group on a saturated carbon atom.
• S$_N$2 Mechanism (Bimolecular Nucleophilic Substitution):
  • Concerted: Bond formation and bond breaking occur simultaneously in a single step.
  • Stereochemistry: Inversion of configuration at the reacting carbon (Walden inversion).
  • Rate Law: Rate = k[substrate][nucleophile] (second-order).
  • Substrate Reactivity: Methyl > Primary > Secondary. Tertiary substrates do not undergo S$_N$2 due to steric hindrance.
  • Leaving Group: Must be able to depart as a stable anion (e.g., Cl⁻, Br⁻, I⁻, TsO⁻, H$_2$O from protonated alcohols). Good leaving groups are weak bases.
  • Nucleophile: Strength is important. Strong nucleophiles favor S$_N$2.
  • Solvent: Polar aprotic solvents (e.g., DMSO, DMF, acetone) favor S$_N$2 by solvating cations but not anions, making the nucleophile more active.
• S$_N$1 Mechanism (Unimolecular Nucleophilic Substitution):
  • Two-step Process:
    1. Ionization of the substrate to form a carbocation (rate-determining step).
    2. Nucleophilic attack on the carbocation.
  • Stereochemistry: Racemization (loss of stereochemical information) if the carbocation is chiral, due to nucleophilic attack from either face.
  • Rate Law: Rate = k[substrate] (first-order).
  • Substrate Reactivity: Tertiary > Secondary > Primary > Methyl. Stabilized carbocations (allylic, benzylic) also favor S$_N$1.
  • Leaving Group: Crucial for the initial ionization. Good leaving groups are essential.
  • Nucleophile: Strength is less important; concentration matters.
  • Solvent: Polar protic solvents (e.g., water, alcohols) favor S$_N$1 by solvating and stabilizing the developing carbocation.

Chapter 17: Elimination Reactions (E1 and E2)

• Elimination: Loss of two atoms or groups from adjacent carbons, typically forming a π bond (double or triple bond). Often competes with substitution.
• E2 Mechanism (Bimolecular Elimination):
  • Concerted: Base removes a proton, and the leaving group departs simultaneously.
  • Stereochemistry: Requires an anti-periplanar arrangement of the proton and the leaving group (180° dihedral angle). This is crucial for regioselectivity and stereoselectivity.
  • Rate Law: Rate = k[substrate][base] (second-order).
  • Substrate Reactivity: Tertiary > Secondary > Primary (due to steric factors and stability of forming alkene).
  • Base: Strong bases favor E2.
  • Leaving Group: Same as S$_N2/S_N$1.
  • Regioselectivity: Favors the more substituted (Zaitsev) alkene product, unless a bulky base is used (Hofmann product).
• E1 Mechanism (Unimolecular Elimination):
  • Two-step Process:
    1. Formation of a carbocation (rate-determining step), identical to the first step of S$_N$1.
    2. Deprotonation of an adjacent carbon by a weak base (often the solvent) to form the alkene.
  • Stereochemistry: Less selective than E2, often leading to mixtures of E and Z isomers.
  • Rate Law: Rate = k[substrate] (first-order).
  • Substrate Reactivity: Tertiary > Secondary. Primary substrates typically don’t undergo E1.
  • Base: Weak bases or solvent act as bases.
  • Regioselectivity: Favors the more substituted (Zaitsev) alkene.
• Competition (S$_N1/E1,S_N$2/E2):
  • Strong, bulky bases (e.g., t-BuOK): Favor E2.
  • Strong, small nucleophiles/bases (e.g., NaOH, NaOEt): Favor S$_N$2 or E2 depending on substrate.
  • Weak bases/nucleophiles (e.g., H$_2$O, ROH): Favor S$_N$1/E1, especially with tertiary substrates.
  • Temperature: Higher temperatures favor elimination (due to entropy).

Chapter 19: Electrophilic Addition to Alkenes

• Key Concept: Alkenes (C=C double bonds) are nucleophilic due to their π electrons, and react with electrophiles. The π bond breaks, and new σ bonds are formed.
• Mechanism: Typically involves the formation of a carbocation or a cyclic intermediate (e.g., bromonium ion, mercurinium ion), followed by nucleophilic attack.
• Examples:
  • Addition of HX (H-Cl, H-Br, H-I): Forms alkyl halides.
    • Regioselectivity (Markovnikov’s Rule): The H adds to the carbon with more hydrogens (to form the more stable carbocation), and the X adds to the carbon with fewer hydrogens.
    • RCH=CH2​+HX→RCHXCH3​
  • Addition of Br$_2$/Cl$_2$: Forms vicinal dihalides.
    • Mechanism: Formation of a cyclic halonium ion (e.g., bromonium ion), followed by backside attack of halide ion.
    • Stereospecificity: Anti-addition (trans product from cis alkene, cis product from trans alkene).
    • RCH=CHR′+Br2​→RCHBrCHBrR′ (anti-addition)
  • Formation of Epoxides (Oxidation): Reaction with peroxy acids (e.g., m-CPBA) to form a three-membered cyclic ether.
    • RCH=CHR′+RCO3​H→epoxide
  • Dihydroxylation (Adding two OH groups):
    • Syn-dihydroxylation: Using OsO$_4$ followed by NaHSO$_3$/H$_2O,orcold,diluteKMnO_4$. Both OH groups add to the same face.
    • Anti-dihydroxylation: Via epoxidation followed by acid-catalyzed ring opening with water.
  • Ozonolysis (O$_3$): Cleaves the C=C bond to form aldehydes and/or ketones. A powerful method for determining alkene structure.

Chapter 20: Formation and Reactions of Enols and Enolates

• Tautomerism (Keto-Enol Tautomerism): Aldehydes and ketones are in equilibrium with their enol forms (contains C=C-OH). The keto form is usually more stable.
  • Enols: Activated alkenes (nucleophilic).
  • Enolates: Deprotonated enols (anions, even more nucleophilic). The negative charge is delocalized over the α-carbon and oxygen.
• Enolization: Catalyzed by both acids and bases.
  • Acid-catalyzed: Protonation of carbonyl oxygen, then deprotonation of α-carbon.
  • Base-catalyzed: Deprotonation of α-carbon to form enolate, then protonation of carbonyl oxygen.
• Reactions involving Enols/Enolates: Enols and enolates react primarily at the α-carbon as nucleophiles.
  • Halogenation (α-Halogenation): Reaction of aldehydes/ketones with halogens (e.g., Br$_2$) via enol or enolate intermediate.
  • Deuterium Exchange: Evidence for enol/enolate formation, as α-hydrogens are exchanged with deuterium in D$_2$O under acidic or basic conditions.
  • Alkylation of Enolates: Forms new C-C bonds (discussed in Chapter 25).
  • Aldol and Claisen Reactions: Reactions of enolates with carbonyl compounds (discussed in Chapter 26).

Chapter 21: Electrophilic Aromatic Substitution (EAS)

• Key Concept: Aromatic rings are electron-rich and thus nucleophilic, reacting with strong electrophiles to replace a hydrogen atom on the ring with an electrophile. The aromaticity is preserved.
• Mechanism:
  1. Attack of the π electrons of the aromatic ring on the electrophile to form a carbocationic sigma complex (arenium ion) – rate-determining step. Aromaticity is temporarily lost.
  2. Loss of a proton from the sigma complex to restore aromaticity.
• Common EAS Reactions:
  • Nitration: With HNO$_3$/H$_2SO_4$ (electrophile: NO$_2^+$ – nitronium ion).
    • ArH+HNO3​H2​SO4​​ArNO2​+H2​O
  • Halogenation: With X$_2$/FeX$_3$ (X=Cl, Br; electrophile: X-X-FeX$_3$ complex).
    • ArH+Br2​FeBr3​​ArBr+HBr
  • Sulfonation: With fuming H$_2SO_4$ (electrophile: SO$_3$).
    • ArH+H2​SO4​(fuming)⇌ArSO3​H+H2​O
  • Friedel-Crafts Alkylation: With RX/AlX$_3$ (electrophile: R⁺ carbocation).
    • ArH+RXAlX3​​ArR+HX
    • Limitations: Carbocation rearrangements can occur, and polyalkylation is common because the alkylated product is more reactive than the starting material.
  • Friedel-Crafts Acylation: With RCOCl/AlCl$_3$ (electrophile: RCO⁺ – acylium ion).
    • ArH+RCOClAlCl3​​ArCOR+HCl
    • Advantages: No rearrangements, and product is less reactive than starting material, preventing polyacylation.
• Substituent Effects (Directing Groups):
  • Activating Groups (o,p-directing): Electron-donating groups (e.g., -OH, -NH$_2$, -OR, alkyl groups). Increase electron density of the ring, especially at ortho and para positions, stabilizing the sigma complex.
  • Deactivating Groups (m-directing): Electron-withdrawing groups (e.g., -NO$_2$, -CN, -COOH, -CHO). Decrease electron density of the ring, especially at ortho and para positions, making meta attack relatively more favorable. (Halogens are deactivating but o,p-directing due to resonance effects).

Chapter 22: Conjugate Addition and Nucleophilic Aromatic Substitution

• Conjugate Addition (1,4-Addition to α,β-Unsaturated Carbonyls):
  • Substrate: α,β-unsaturated carbonyl compounds (enones, enals, esters, etc.) are electrophilic at both the carbonyl carbon (1,2-addition) and the β-carbon (1,4-addition).
  • Nucleophile Type:
    • Hard Nucleophiles (e.g., Grignard reagents, RLi): Favor 1,2-addition to the carbonyl carbon (kinetic control).
    • Soft Nucleophiles (e.g., Gilman reagents R$_2$CuLi, enolates, amines): Favor 1,4-addition to the β-carbon (conjugate addition, thermodynamic control).
  • Mechanism (1,4-addition): Nucleophilic attack at the β-carbon, pushing electrons through the π system to the oxygen of the carbonyl, forming an enolate intermediate, followed by protonation.
• Nucleophilic Aromatic Substitution (S$_N$Ar):
  • Requirement: Strong electron-withdrawing groups (e.g., -NO$_2$) ortho or para to a leaving group (e.g., -Cl, -F) on an aromatic ring.
  • Mechanism (Addition-Elimination):
    1. Nucleophilic attack on the carbon bearing the leaving group, forming a resonance-stabilized anionic Meisenheimer complex (rate-determining step).
    2. Loss of the leaving group.
  • Alternative Mechanisms:
    • S$_N$1 (via Diazonium Salts): Involves formation of an aryl diazonium ion (ArN$_2^+),whichcanloseN_2$ to form a highly unstable aryl cation, followed by nucleophilic attack. Used for making aryl halides, phenols, nitriles, etc.
    • Benzyne Mechanism: Occurs with very strong bases and no activating groups, involving a highly reactive triple bond intermediate within the ring.

Part 2: 40 Questions and Answers

Section A: Multiple Choice / Short Answer (20 Questions)

1. Q: What is the primary characteristic that defines a nucleophile? A: A nucleophile is an electron-rich species that seeks positive centers and has a filled orbital to donate electrons.
2. Q: What is the activation energy in a chemical reaction? A: The minimum energy required for molecules to overcome superfi cial repulsion and react when they collide.
3. Q: What is the main structural feature responsible for the electrophilic nature of a carbonyl group? A: The partial positive charge on the carbonyl carbon due to the electronegativity difference between carbon and oxygen.
4. Q: Name two common types of organometallic reagents used to form C-C bonds. A: Grignard reagents (R-MgX) and Organolithium reagents (R-Li).
5. Q: How does a primary alcohol typically react with a Grignard reagent? A: Grignard reagents are strong bases and will deprotonate the acidic proton of the alcohol, rather than adding to a carbonyl (if one were present). If there’s no carbonyl, it acts as a base to produce an alkane.
6. Q: In nucleophilic substitution at a carbonyl group (addition-elimination), what determines the relative reactivity of carboxylic acid derivatives? A: The ability of the group attached to the carbonyl carbon to act as a leaving group.
7. Q: What is the major problem when attempting to synthesize a ketone from an ester using a Grignard reagent, and what is a common solution? A: The ketone product is more reactive than the ester starting material, leading to over-addition and tertiary alcohol formation. A common solution is using Weinreb amides.
8. Q: What type of compound is formed when an aldehyde reacts with an alcohol in the presence of an acid catalyst, and is this product stable under neutral conditions? A: An acetal is formed. Yes, acetals are generally stable under neutral conditions but are easily hydrolyzed under acidic conditions.
9. Q: What is the name of the reaction that forms an alkene from a carbonyl compound and a phosphonium ylid? A: The Wittig reaction.
10. Q: What is the key stereochemical outcome of an S$_N$2 reaction at a chiral center? A: Inversion of configuration (Walden inversion).
11. Q: Which type of solvent (polar protic or polar aprotic) favors S$_N$2 reactions, and why? A: Polar aprotic solvents, because they solvate cations but leave anions (nucleophiles) relatively unsolvated and more reactive.
12. Q: What is the rate-determining step in an S$_N$1 reaction? A: The formation of a carbocation from the substrate (ionization).
13. Q: For an E2 elimination reaction, what specific geometric arrangement is required between the proton and the leaving group? A: Anti-periplanar.
14. Q: According to Markovnikov’s rule, where does the hydrogen atom add in the electrophilic addition of HX to an unsymmetrical alkene? A: To the carbon atom of the double bond that already has more hydrogen atoms (leading to the more stable carbocation intermediate).
15. Q: What type of addition (syn or anti) is observed during the bromination of an alkene to form a vicinal dibromide? A: Anti-addition.
16. Q: What is keto-enol tautomerism? A: An equilibrium between a carbonyl compound (keto form) and its enol form (a compound with a hydroxyl group directly attached to an alkene carbon).
17. Q: What is the electrophile in the nitration of benzene? A: The nitronium ion (NO$_2^+$).
18. Q: How do electron-donating groups affect the rate and directing ability in Electrophilic Aromatic Substitution (EAS)? A: They activate the ring, increasing the rate of reaction, and are typically ortho, para-directing.
19. Q: What is the primary limitation of Friedel-Crafts alkylation, and how can it be overcome using Friedel-Crafts acylation? A: Limitations include carbocation rearrangements and polyalkylation. Friedel-Crafts acylation avoids these because the acylium ion doesn’t rearrange and the ketone product is deactivating, preventing further acylation.
20. Q: What class of nucleophiles (hard or soft) typically favors 1,4-conjugate addition to α,β-unsaturated carbonyl compounds? A: Soft nucleophiles.

Section B: Conceptual / Explanatory (20 Questions)

21. Q: Explain why curly arrows must always start from a filled orbital or a negative charge. A: Curly arrows represent the movement of a pair of electrons. Electrons reside in filled orbitals (HOMO) or are associated with negative charges (lone pairs or formal charges). Thus, the starting point of a curly arrow must be an electron-rich site that can donate electrons.
22. Q: Discuss the role of the solvent in S$_N1andS_N$2 reactions. A:
    • S$_N$1: Favored by polar protic solvents (e.g., water, alcohols). These solvents stabilize the highly polar transition state and the resulting carbocation intermediate through hydrogen bonding and dipole-dipole interactions, lowering the activation energy.
    • S$_N$2: Favored by polar aprotic solvents (e.g., DMSO, DMF, acetone). These solvents can solvate cations effectively (through their dipole moments) but do not extensively hydrogen bond with and solvate anions (nucleophiles), leaving the nucleophiles “naked” and highly reactive.
23. Q: Compare and contrast the stereochemical outcomes of S$_N1andS_N$2 reactions at a chiral center. A:
    • S$_N$2: Leads to complete inversion of configuration at the chiral center (Walden inversion). This is because the nucleophile attacks from the backside, opposite to the leaving group, in a concerted manner.
    • S$_N$1: Leads to racemization, forming a racemic mixture of enantiomers. This is because the carbocation intermediate is planar, allowing the nucleophile to attack from either face with equal probability (though some retention can occur if the leaving group temporarily shields one face).
24. Q: Explain why imine formation is often sensitive to pH and has an optimal pH range. A: Imine formation involves two key steps: nucleophilic addition and dehydration.
    • Low pH (too acidic): The amine nucleophile becomes protonated (RNH$_3^+$), losing its nucleophilicity, thus slowing down the initial addition step.
    • High pH (too basic): The acid catalysis required for the dehydration step (loss of water) is diminished, making the leaving group (OH) difficult to depart.
    • The optimal pH balances these two competing effects, typically around pH 6, where there’s enough free amine for addition and enough acid for efficient dehydration.
25. Q: Describe the difference between 1,2-addition and 1,4-addition (conjugate addition) to α,β-unsaturated carbonyl compounds, and what factors influence which pathway is favored. A:
    • 1,2-Addition: Nucleophilic attack occurs directly at the carbonyl carbon. This is typically faster and kinetically favored, especially with hard nucleophiles (e.g., Grignard, RLi).
    • 1,4-Addition (Conjugate Addition): Nucleophilic attack occurs at the β-carbon of the double bond, and the electrons are delocalized to the carbonyl oxygen, forming an enolate. This is often thermodynamically favored and occurs with soft nucleophiles (e.g., Gilman reagents, enolates). The difference lies in the “hardness” or “softness” of the nucleophile, relating to their polarizability and charge density.
26. Q: Why are Friedel-Crafts alkylations prone to carbocation rearrangements, while Friedel-Crafts acylations are not? A:
    • Alkylation: The electrophile is a carbocation (R$^+$), which can undergo hydride or alkyl shifts to form a more stable carbocation before reacting with the aromatic ring.
    • Acylation: The electrophile is an acylium ion (RCO$^+$). This ion is resonance-stabilized and the positive charge is delocalized onto the oxygen, making it much less prone to rearrangement.
27. Q: Discuss the concept of “leaving group” in organic reactions. What makes a good leaving group? Provide examples. A: A leaving group is an atom or group of atoms that detaches from a molecule, typically taking a pair of bonding electrons with it, as a stable species (usually an anion).
    • Characteristics of a good leaving group: It must be a weak base (stable anion) and capable of dispersing the negative charge it acquires.
    • Examples: Halides (I⁻ > Br⁻ > Cl⁻ > F⁻), sulfonate esters (TsO⁻, MsO⁻, TfO⁻), water (H$_2$O) from protonated alcohols. Strong bases like HO⁻ or RO⁻ are generally poor leaving groups.
28. Q: Explain why electron-withdrawing groups are meta-directing in Electrophilic Aromatic Substitution (EAS). A: Electron-withdrawing groups deactivate the aromatic ring by pulling electron density away from it. This deactivation is more pronounced at the ortho and para positions due to resonance effects. Therefore, the meta position, while still deactivated, is relatively less deactivated, making it the preferred site for electrophilic attack.
29. Q: Describe the role of acid catalysis in the formation of acetals from aldehydes/ketones and alcohols. A: Acid catalysis protonates the oxygen atom of the carbonyl group. This increases the partial positive charge on the carbonyl carbon, making it a stronger electrophile and more susceptible to nucleophilic attack by the weakly nucleophilic alcohol. It also helps in the departure of water as a leaving group during the second stage of acetal formation.
30. Q: How can infrared (IR) spectroscopy be used to distinguish between a ketone and an ester? A: Both ketones and esters contain a carbonyl (C=O) group, which shows a strong absorption in the IR spectrum. However, their characteristic C=O stretching frequencies differ. Esters typically show a higher frequency (around 1735-1750 cm⁻¹) due to the electron-withdrawing effect of the ester oxygen, while ketones appear slightly lower (around 1715-1725 cm⁻¹). (Refer to Chapter 18 for more details on spectroscopic distinctions).
31. Q: What is the significance of the “anti-periplanar” requirement in E2 elimination reactions? A: The anti-periplanar geometry (dihedral angle of 180° between the leaving group and the proton being removed) allows for optimal overlap between the developing p-orbital on the carbon losing the leaving group and the developing p-orbital on the carbon losing the proton, leading to the formation of a stable π bond. This specific geometry dictates the stereochemistry and sometimes the regioselectivity of the E2 reaction.
32. Q: Explain the concept of “thermodynamic control” versus “kinetic control” in organic reactions. A:
    • Kinetic Control: The product distribution is determined by the relative rates of formation of competing products. The major product is the one that forms fastest, typically via the lowest energy transition state. Reactions under kinetic control are often irreversible or run at low temperatures.
    • Thermodynamic Control: The product distribution is determined by the relative stabilities of the competing products. The major product is the most stable one, regardless of its formation rate. Reactions under thermodynamic control are often reversible and run at higher temperatures or for longer durations, allowing equilibrium to be established.
33. Q: What is the purpose of using “protecting groups” in organic synthesis? Provide a simple example. A: Protecting groups are temporarily introduced into a molecule to mask or deactivate a reactive functional group, preventing it from reacting during a subsequent synthetic step. Once the necessary reaction is complete, the protecting group is removed to reveal the original functional group.
    • Example: A common protecting group for an alcohol (R-OH) is a silyl ether (R-OSiR$_3$). If you have a molecule with both an alcohol and a ketone, and you want to react the ketone with a Grignard reagent, the alcohol’s acidic proton would quench the Grignard. Protecting the alcohol as a silyl ether allows the Grignard to react only with the ketone.
34. Q: How does temperature generally affect the competition between substitution and elimination reactions? A: Higher temperatures generally favor elimination reactions over substitution reactions. This is because elimination reactions typically involve an increase in the number of molecules (e.g., one molecule breaking into two or three in E1 or E2, respectively), leading to a more positive change in entropy (ΔS). Since ΔG=ΔH−TΔS, an increase in temperature (T) makes the −TΔS term more significant, favoring reactions with a positive ΔS (elimination).
35. Q: Describe the process of ozonolysis of an alkene and its utility in determining the structure of an unknown alkene. A: Ozonolysis is a reaction where an alkene (C=C) is reacted with ozone (O$_3$), followed by a reductive or oxidative work-up (e.g., with DMS or H$_2O_2$). This process cleaves the carbon-carbon double bond entirely, forming carbonyl compounds (aldehydes and/or ketones). By identifying the resulting carbonyl fragments, one can deduce the original structure of the alkene. For example, if ozonolysis yields acetone and acetaldehyde, the original alkene must have been 2-methylbut-2-ene.
36. Q: What are “enolates” and why are they important in organic synthesis? A: Enolates are anions formed by the deprotonation of an α-hydrogen from a carbonyl compound. They are resonance-stabilized, with the negative charge delocalized between the α-carbon and the carbonyl oxygen. Enolates are highly important in organic synthesis because they are powerful carbon nucleophiles, allowing for the formation of new carbon-carbon bonds (e.g., in aldol and Claisen reactions, and alkylation of enolates).
37. Q: In electrophilic addition to conjugated dienes, why can both 1,2- and 1,4-addition products be observed? A: When an electrophile adds to a conjugated diene, it forms a resonance-stabilized allylic carbocation. This carbocation has two electrophilic centers where a nucleophile can attack:
    • 1,2-addition: Nucleophilic attack at the carbon directly adjacent to where the electrophile added. This product often forms faster (kinetic control).
    • 1,4-addition: Nucleophilic attack at the carbon at the end of the conjugated system. This product is often more stable (thermodynamic control) due to forming a more substituted or stable double bond. The relative amounts depend on reaction conditions (temperature, time).
38. Q: Explain why halogens (like Cl and Br) are deactivating but ortho, para-directing in electrophilic aromatic substitution. A: Halogens are unique because they have opposing effects.
    • Deactivating: They are electronegative and withdraw electron density from the aromatic ring through inductive effects, making the ring less reactive overall.
    • Ortho, Para-Directing: They possess lone pairs of electrons that can be donated to the ring via resonance. This resonance effect is more significant at the ortho and para positions, stabilizing the intermediate sigma complex for attack at these positions, making them preferred, even though the overall rate is slower than for benzene. The inductive deactivation dominates the rate, while the resonance donation dictates the regioselectivity.
39. Q: What are acetals often used for in organic synthesis, and how are they typically deprotected? A: Acetals are widely used as protecting groups for aldehydes and ketones. They are stable to strong bases, nucleophiles, and reducing agents, allowing reactions to occur elsewhere in the molecule. They are typically deprotected (hydrolyzed back to the carbonyl compound) under acidic aqueous conditions, as the formation of acetals is reversible under these conditions.
40. Q: Briefly describe “curly arrows” and their fundamental rules. A: Curly arrows are a symbolic representation of electron movement in reaction mechanisms.
    • Rule 1: Always show the movement of a pair of electrons.
    • Rule 2: Start the tail of the arrow at the source of electrons (a lone pair, a negative charge, or the middle of a bond).
    • Rule 3: Point the head of the arrow to where the electrons are moving to (where a new bond is forming, or onto an atom that will bear a negative charge).
    • Rule 4: Do not exceed the octet rule for second-row elements (C, N, O, B). If a new bond forms, an existing bond often must break simultaneously.
    • Rule 5: Charge is conserved in each individual step of a mechanism.