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Organic Chemistry Flashcards

Carbocation Reactions (9.9)
  • Less stable carbocations rearrange to more stable ones via hydrogen or alkyl group shifts.

  • Carbocations also react with:

    • Nucleophiles (7.12)

    • Bases (8.7)

  • 1,2-shifts occur where a group (R or H) moves to an adjacent carbon.

Preparation of Alcohols, Ethers, and Epoxides (9.6)

[1] Preparation of Alcohols

  • R-X + OH⁻ → R-OH + X⁻

  • Mechanism: SN2

  • Best for CH₃X and 1° RX.

[2] Preparation of Alkoxides (Brønsted-Lowry Acid-Base Reaction)

  • R-OH + NaH → R-O⁻Na⁺ + H₂

  • Alkoxides are formed by deprotonating alcohols with a strong base.

[3] Preparation of Ethers (Williamson Ether Synthesis)

  • R-X + O⁻R' → R-OR' + X⁻

  • Mechanism: SN2

  • Best for CH₃X and 1° RX.

[4] Preparation of Epoxides (Intramolecular SN2 Reaction)

  • Involves a halohydrin intermediate.

  • Two-step reaction sequence:

    1. Removal of a proton from the alcohol of halohydrin with a base to form an alkoxide.

    2. Intramolecular SN2 reaction to form the epoxide.

    [1] Halohydrin + B: → BH⁺ + :O⁻
    [2] Intramolecular SN2 reaction forms Epoxide

Reactions of Alcohols

[1] Dehydration to Form Alkenes

a. Using Strong Acid (9.8, 9.9)

  • Alcohol H₂SO₄ or TSOH→ Alkene + H₂O

  • Mechanism for 2° and 3° ROH: E1- Carbocations are intermediates; rearrangements can occur.

  • Mechanism for 1° ROH: E2- The Zaitsev rule is followed.

b. Using POCl3 and Pyridine (9.10)

  • Alcohol POCl₃, pyridine→ Alkene + H₂O

  • Mechanism: E2

  • No carbocation rearrangements occur.

[2] Reaction with HX to Form RX (9.11)

  • R-OH + H-X → R-X + H₂O

  • Order of reactivity: R₃COH > R₂CHOH > RCH₂OH

  • Mechanism for 2° and 3° ROH: SN1- Carbocations are intermediates; rearrangements occur.

  • Mechanism for CH₃OH and 1° ROH: SN2

[3] Reaction with Other Reagents to Form RX (9.12)

  • R-OH + SOCl₂ pyridine→ R-Cl

  • R-OH + PBr₃ → R-Br

  • Reactions occur with CH₃OH, 1° and 2° ROH.

  • Mechanism: SN2

[4] Reaction with Tosyl Chloride to Form Alkyl Tosylates (9.13A)

  • R-OH + Cl-SO₂C₆H₄CH₃ pyridine→ R-O-SO₂C₆H₄CH₃ (R-OTs)

  • The C-O bond is not broken; the configuration at a stereogenic center is retained.

Reactions of Alkyl Tosylates (9.13B)
  • Undergo either substitution or elimination depending on the reagent.

  • Strong nucleophiles favor substitution (SN2).

  • Strong bases favor elimination (E2).

  • 2° and 3° R groups favor SN1.

  • CH₃ and 1° R groups favor SN2.

Reactions of Ethers (9.14)
  • Only useful reaction: Cleavage with strong acids (HX, where X = Br or I).

  • R-O-R' + H-X 2 equiv→ R-X + R'-X + H₂O

Reactions Involving Thiols and Sulfides (9.15)

[1] Preparation of Thiols

  • R-X + SH⁻ → R-SH + X⁻

  • Mechanism: SN2

  • Best for CH₃X and 1° RX.

[2] Oxidation and Reduction Involving Thiols

a. Oxidation of Thiols to Disulfides

  • 2R-SH Br₂ or I₂→ R-S-S-R

b. Reduction of Disulfides to Thiols

  • R-S-S-R Zn, HCl→ 2R-SH

[3] Preparation of Sulfides

  • R-X + SR'⁻ → R-SR' + X⁻

  • Mechanism: SN2

  • Best for CH₃X and 1° RX.

[4] Reaction of Sulfides to Form Sulfonium Ions

  • R'₂S + R-X → R'₂S⁺-R + X⁻

  • Mechanism: SN2

  • Best for CH₃X and 1° RX.

Reactions of Epoxides (9.16)
  • Epoxide rings are opened by nucleophiles (:Nu) and acids (HZ).

  • Epoxide + :Nu → Nu-C-C-OH or Epoxide + HZ → HO-C-C-Z

  • Backside attack occurs, resulting in trans or anti products.

  • With :Nu, mechanism is SN2- Nucleophilic attack occurs at the less substituted C.

  • With HZ, mechanism is between SN1 and SN2- Attack of Z occurs at the more substituted C.

Addition Reactions of Alkenes

[1] Hydrohalogenation - Addition of HX (X = Cl, Br, I) (10.9-10.11)

  • Alkene + H-X → Alkyl Halide

  • Two-step mechanism

  • Carbocations are intermediates; rearrangements possible.

  • Markovnikov's rule is followed: H bonds to the less substituted C.

  • Syn and anti addition occur.

[2] Hydration and Related Reactions - Addition of H2O or ROH (10.12)

  • Alkene + H-OH H₂SO₄→ Alcohol

  • Alkene + H-OR H₂SO₄→ Ether

  • Three-step mechanism

  • Carbocations are intermediates; rearrangements possible.

  • Markovnikov's rule is followed: H bonds to the less substituted C.

  • Syn and anti addition occur.

[3] Halogenation - Addition of X2 (X = Cl or Br) (10.13–10.14)

  • Alkene + X-X → Vicinal Dihalide

  • Two-step mechanism

  • Bridged halonium ions are intermediates.

  • No rearrangements occur.

  • Anti addition occurs.

[4] Halohydrin Formation - Addition of OH and X (X = Cl, Br) (10.15)

  • Alkene + X-X H₂O→ Halohydrin

  • Three-step mechanism

  • Bridged halonium ions are intermediates.

  • No rearrangements occur.

  • X bonds to the less substituted C.

  • Anti addition occurs.

  • NBS in DMSO and H₂O adds Br and OH in the same fashion.

[5] Hydroboration-Oxidation - Addition of H₂O (10.16)

  • Alkene BH₃ or 9-BBN, H₂O₂, HO⁻→ Alcohol

  • One-step mechanism

  • No rearrangements occur.

  • OH bonds to the less substituted C.

  • Syn addition of H₂O occurs.

Addition Reactions of Alkynes

[1] Hydrohalogenation - Addition of HX (X = Cl, Br, or I) (11.7)

  • Alkyne + H-X 2 equiv→ Geminal Dihalide

  • Markovnikov's rule is followed.

[2] Halogenation - Addition of X₂ (X = Cl or Br) (11.8)

  • Alkyne + X-X 2 equiv→ Tetrahalide

  • Anti addition of X₂ occurs.

[3] Hydration - Addition of H₂O (11.9)

  • Alkyne + H₂O H₂SO₄, HgSO₄→ Enol → Carbonyl Group

  • Markovnikov's rule is followed.

  • The unstable enol rearranges to a carbonyl group.

[4] Hydroboration-Oxidation - Addition of H₂O (11.10)

  • Alkyne R₂BH, H₂O₂, HO⁻→ Enol → Carbonyl Group

  • The unstable enol rearranges to a carbonyl group.

Reactions Involving Acetylide Anions

[1] Formation of Acetylide Anions from Terminal Alkynes (11.6B)

  • R-C≡C-H + B⁻ → R-C≡C:⁻ + BH⁺

  • Typical bases: NaNH₂ and NaH

[2] Reaction of Acetylide Anions with Alkyl Halides (11.11A)

  • H-C≡C:⁻ + R-X → H-C≡C-R + X⁻

  • Mechanism: SN2

  • Best with CH₃X and RCH₂X.

[3] Reaction of Acetylide Anions with Epoxides (11.11B)

  • H-C≡C:⁻ + Epoxide H₂O→ H-C≡C-CH₂CH₂OH

  • Mechanism: SN2

  • Ring opening occurs from the back side at the less substituted end of the epoxide.

Reduction Reactions

[1] Reduction of Alkenes - Catalytic Hydrogenation (12.3)

  • Alkene + H₂ Pd, Pt, or Ni→ Alkane

  • Syn addition of H₂ occurs.

  • Increasing alkyl substitution on the C=C decreases the rate of reaction.

[2] Reduction of Alkynes

a.

  • Alkyne + 2H₂ Pd-C→ Alkane

  • Two equivalents of H₂ are added.

b.

  • Alkyne + H₂ Lindlar Catalyst→ cis-Alkene

  • Syn addition of H₂ occurs.

  • The Lindlar catalyst is deactivated so that reaction stops after one equivalent of H₂ has been added.

c.

  • Alkyne + Na NH₃→ trans-Alkene

  • Anti addition of H₂ occurs.

[3] Reduction of Alkyl Halides (12.6)

  • R-X LiAlH₄, H₂O→ R-H

  • Mechanism: SN2

  • CH₃X and RCH₂X react faster than more substituted RX.

[4] Reduction of Epoxides (12.6)

  • Epoxide LiAlH₄, H₂O→ Alcohol

  • Mechanism: SN2

  • In unsymmetrical epoxides, H (from LiAlH₄) attacks at the less substituted carbon.

Oxidation Reactions

[1] Oxidation of Alkenes

a. Epoxidation (12.8)

  • Alkene + RCO₃H → Epoxide

  • One-step mechanism

  • Syn addition of an O atom occurs.

  • The reaction is stereospecific.

b. Anti Dihydroxylation (12.9A)

  • Alkene RCO₃H, H₂O (H⁺ or HO⁻)→ 1,2-Diol

  • Ring opening of an epoxide intermediate with OH⁻ or H₂O forms a 1,2-diol with two OH groups added in an anti fashion.

c. Syn Dihydroxylation (12.9B)

  • Alkene OsO₄ or KMnO₄, NaHSO₃, H₂O→ 1,2-Diol

  • Each reagent adds two new C-O bonds to the C=C in a syn fashion.

d. Oxidative Cleavage (12.10)

  • Alkene O₃, Zn, H₂O or CH₃SCH₃→ Ketone + Aldehyde

  • Both the σ and π bonds of the alkene are cleaved to form two carbonyl groups.

[2] Oxidative Cleavage of Alkynes (12.11)

a. Internal Alkyne

  • Alkyne O₃, H₂O→ Carboxylic Acids

  • The σ bond and both π bonds of the alkyne are cleaved.

b. Terminal Alkyne

  • Alkyne O₃, H₂O→ Carboxylic Acid + CO₂

[3] Oxidation of Alcohols (12.12, 12.13)

a. 1° Alcohol to Aldehyde

  • 1° Alcohol PCC→ Aldehyde

  • Oxidation of a 1° alcohol with PCC stops at the aldehyde stage.

  • Only one C-H bond is replaced by a C-O bond.

b. 1° Alcohol to Carboxylic Acid

  • 1° Alcohol CrO₃, H₂SO₄, H₂O→ Carboxylic Acid

  • Oxidation of a 1° alcohol under harsher reaction conditions affords a RCO₂H.

  • Two C-H bonds are replaced by two C-O bonds.

c. 2° Alcohol to Ketone

  • 2° Alcohol PCC or CrO₃→ Ketone

  • A 2° alcohol has only one C-H bond on the carbon bearing the OH group, so all Cr⁶⁺ reagents oxidize a 2° alcohol to a ketone.

[4] Asymmetric Epoxidation of Allylic Alcohols (12.15)

  • Using chiral catalysts like (-)-DET or (+)-DET to achieve stereoselective epoxidation.

Reduction Reactions of Aldehydes and Ketones

[1] Reduction of Aldehydes and Ketones to 1° and 2° Alcohols (17.4)

  • Aldehyde/Ketone NaBH₄, CH₃OH or LiAlH₄, H₂O or H₂, Pd-C→ 1°/2° Alcohol

[2] Reduction of α,β-Unsaturated Aldehydes and Ketones (17.4C)

  • Selective reduction of C=O or C=C possible with different reagents.

[3] Enantioselective Ketone Reduction (17.6)

  • Using chiral CBS reagents to form a single enantiomer of a 2° alcohol.

[4] Reduction of Acid Chlorides (17.7A)

  • Acid Chloride LiAlH₄, H₂O→ 1° Alcohol

  • Acid Chloride LiAlH[OC(CH₃)₃]₃, H₂O→ Aldehyde

Oxidation Reactions of Aldehydes
  • Aldehyde CrO₃, Na₂Cr₂O₇, K₂Cr₂O₇, KMnO₄ or Ag₂O, NH₄OH→ Carboxylic Acid

  • Tollens reagent oxidizes aldehydes only; alcohols do not react.

Preparation of Organometallic Reagents (17.9)

[1] Organolithium Reagents

  • R-X + 2Li → R-Li + LiX

[2] Grignard Reagents

  • R-X + Mg (CH₃CH₂)₂O→ R-Mg-X

[3] Organocuprate Reagents

  • R-X + 2Li → R-Li + LiX 2R-Li + CuI → R₂CuLi + LiI

[4] Lithium and Sodium Acetylides

  • R-C≡C-H + NaNH₂ → R-C≡CNa⁺ + NH₃

  • R-C≡C-H + R-Li → R-C≡C-Li + R-H

Reactions with Organometallic Reagents

[1] Reaction as a Base (17.9C)

  • R-M + H-O-R' → R-H + M⁺OR'⁻ (R-M = RLi, RMgX, R₂CuLi)

  • This acid-base reaction occurs with H₂O, ROH, RNH₂, R₂NH, RSH, RCOOH, RCONH₂, and RCONHR.

[2] Reaction with Aldehydes and Ketones to Form 1°, 2°, and 3° Alcohols (17.10)

  • Aldehyde/Ketone R''MgX or R''Li, H₂O→ 1°, 2°, or 3° Alcohol

[3] Reaction with Esters to Form 3° Alcohols (17.13A)

  • Ester R''Li or R''MgX (2 equiv), H₂O→ 3° Alcohol

[4] Reaction with Acid Chlorides (17.13)

  • Acid Chloride R''Li or R''MgX (2 equiv), H₂O→ 3° Alcohol

  • Acid Chloride R'₂CuLi, H₂O→ Ketone

[5] Reaction with Carbon Dioxide - Carboxylation (17.14A)

  • R-MgX CO₂, H₃O⁺→ Carboxylic Acid

[6] Reaction with Epoxides (17.14B)

  • Epoxide RLi, RMgX, or R₂CuLi, H₂O→ Alcohol

[7] Reaction with α,β-Unsaturated Aldehydes and Ketones (17.15B)

  • α,β-Unsaturated Carbonyl R'Li or R'MgX, H₂O→ Allylic Alcohol (1, 2-addition)

  • α,β-Unsaturated Carbonyl R'₂CuLi, H₂O→ Ketone (1, 4-addition)

  • More reactive organometallic reagents (RLi & RMgX) yield 1,2-addition.

  • Less reactive organometallic reagents (R₂CuLi) yield 1,4-addition.

Protecting Groups (17.12)

[1] Protecting an Alcohol as a tert-Butyldimethylsilyl Ether

  • Alcohol Cl-TBS, N N→ tert-Butyldimethylsilyl Ether ([R-O-TBS])

[2] Deprotecting a tert-Butyldimethylsilyl Ether to Re-form an Alcohol

  • [R-O-TBS] Bu₄N⁺F⁻→ Alcohol

Five Examples of Electrophilic Aromatic Substitution

[1] Halogenation - Replacement of H by Cl or Br (16.3)

  • Benzene + X₂ FeX₃→ Aryl Halide (X = Cl, Br)

  • Polyhalogenation occurs on benzene rings substituted by OH and NH₂.

[2] Nitration - Replacement of H by NO₂ (16.4)

  • Benzene + HNO₃ H₂SO₄→ Nitro Compound

[3] Sulfonation - Replacement of H by SO₃H (16.4)

  • Benzene + SO₃ H₂SO₄→ Benzenesulfonic Acid

[4] Friedel-Crafts Alkylation - Replacement of H by R (16.5)

  • Benzene + RCl AlCl₃→ Alkyl Benzene (Arene)

  • Rearrangements can occur.

  • The reaction does not occur on benzene rings substituted by meta deactivating groups or NH₂ groups.

  • Polyalkylation can occur.

Variations

  • Using alcohols or alkenes as alkylating agents.

[5] Friedel-Crafts Acylation - Replacement of H by RCO (16.5)

  • Benzene + RCOCl AlCl₃→ Ketone

  • The reaction does not occur on benzene rings substituted by meta deactivating groups or NH₂ groups.

Reduction of Esters

[5] Reduction of Esters (17.7A)

  • Ester LiAlH₄, H₂O→ 1° Alcohol

  • Ester DIBAL-H, H₂O→ Aldehyde

  • LiAlH₄ reduces to a 1° alcohol, while DIBAL-H stops at the aldehyde stage.

[6] Reduction of Carboxylic Acids to 1° Alcohols (17.7B)

  • Carboxylic Acid LiAlH₄, H₂O→ 1° Alcohol

[7] Reduction of Amides to Amines (17.7B)

  • Amide LiAlH₄, H₂O→ Amine

Nucleophilic Aromatic Substitution (16.13)

[1] Nucleophilic Substitution by an Addition-Elimination Mechanism

  • Two-step mechanism.

  • Strong electron-withdrawing groups at the ortho or para position are required.

  • Increasing the number of electron-withdrawing groups increases the rate.

  • Increasing the electronegativity of the halogen increases the rate.

[2] Nucleophilic Substitution by an Elimination-Addition Mechanism

  • Harsh reaction conditions are required.

  • Benzyne is formed as an intermediate.

Other Reactions of Benzene Derivatives

[1] Benzylic Halogenation (16.14A)

  • Alkylbenzene Br₂ or NBS, hν or Δ→ Benzylic Bromide

  • A benzylic C-H bond is needed for reaction.

[2] Oxidation of Alkyl Benzenes (16.14B)

  • Alkylbenzene KMnO₄→ Benzoic Acid

  • A benzylic C-H bond is needed for reaction.

[3] Reduction of Ketones to Alkyl Benzenes (16.14C)

  • Ketone Zn(Hg), HCl or NH₂NH₂, OH⁻→ Alkyl Benzene

[4] Reduction of Nitro Groups to Amino Groups (16.14D)

  • Nitrobenzene H₂, Pd-C or Fe, HCl or Sn, HCl→ Aniline

Nucleophilic Addition Reactions

[1] Addition of Hydride (H⁻) (18.7)

  • Aldehyde/Ketone NaBH₄, CH₃OH or LiAlH₄, H₂O→ 1°/2° Alcohol

[2] Addition of Organometallic Reagents (R⁻) (18.7)

  • Aldehyde/Ketone R''MgX or R''Li, H₂O→ Alcohol

[3] Addition of Cyanide (⁻CN) (18.8)

  • Aldehyde/Ketone NaCN, HCl→ Cyanohydrin

[4] Wittig Reaction (18.9)

  • Aldehyde/Ketone + Wittig Reagent → Alkene + Ph₃P=O

[5] Addition of 1° Amines (18.10)

  • Aldehyde/Ketone + 1° Amine mild acid→ Imine

[6] Addition of 2° Amines (18.11)

  • Aldehyde/Ketone + 2° Amine mild acid→ Enamine

[7] Addition of H₂O - Hydration (18.12)

  • Aldehyde/Ketone + H₂O H⁺ or OH⁻→ Geminal Diol

[8] Addition of Alcohols (18.13)

  • Aldehyde/Ketone + Alcohol H⁺→ Acetal/Ketal

Other Reactions

[1] Synthesis of Wittig Reagents (18.9A)

  • R-X Ph₃P:, BuLi→ Wittig Reagent

  • Step [1] is best with CH₃X and RCH₂X.

  • A strong base is needed for proton removal in Step [2].

[2] Conversion of Cyanohydrins to Aldehydes and Ketones (18.8)

  • Cyanohydrin OH⁻→ Aldehyde/Ketone + CN⁻

  • Reverses cyanohydrin formation.

[3] Hydrolysis of Nitriles (18.8)

  • Nitrile H₂O, H⁺ or OH⁻→ Carboxylic Acid

[4] Hydrolysis of Imines and Enamines (18.11B)

  • Imine/Enamine H₂O, H⁺→ Aldehyde/Ketone + Amine

[5] Hydrolysis of Acetals (18.13)

  • Acetal/Ketal H⁺, H₂O→ Aldehyde/Ketone + Alcohol

Nitrile Synthesis (19.12)
  • R-X + CN⁻ S₂N→ R-CN + X⁻

  • R = CH₃, 1°

Reactions of Nitriles (19.12)

[1] Hydrolysis

  • R-CN H₂O, H⁺ or OH⁻→ Carboxylic Acid

[2] Reduction

a.

  • R-CN LiAlH₄, H₂O→ 1° Amine

b.

  • R-CN DIBAL-H, H₂O→ Aldehyde

[3] Reaction with Organometallic Reagents

  • R-CN R'MgX or R'Li, H₂O→ Ketone

Nucleophilic Acyl Substitution Reactions

[1] Reaction that Synthesizes Acid Chlorides (RCOCl) From RCOOH (20.9A)

  • RCOOH + SOCl₂ → RCOCl + SO₂ + HCl

[2] Reactions That Synthesize Anhydrides [(RCO)2O]

a. From RCOCl (20.7)

  • RCOCl + R'COO⁻ → (RCO)₂O + Cl⁻

b. From Dicarboxylic Acids (20.9B)

  • Dicarboxylic Acid Δ→ Cyclic Anhydride

[3] Reactions That Synthesize Carboxylic Acids (RCOOH)

a. From RCOCl (20.7)

  • RCOCl + H₂O pyridine→ RCOOH + HCl

b. From (RCO)2O (20.8)

  • (RCO)₂O + H₂O → RCOOH

c. From RCOOR' (20.10)

  • RCOOR' + H₂O H⁺ or OH⁻→ RCOOH + R'OH

d. From RCONR'2 (R' = H or Alkyl, 20.12)

  • RCONR'₂ + H₂O H⁺ or OH⁻→ RCOOH + R'₂NH₂

[4] Reactions that Synthesize Esters (RCOOR')

a. From RCOCl (20.7)

  • RCOCl + R'OH pyridine→ RCOOR' + HCl

b. From (RCO)2O (20.8)

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