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: S_N2

• 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: S_N2

• Best for CH₃X and 1° RX.

[4] Preparation of Epoxides (Intramolecular S_N2 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 S_N2 reaction to form the epoxide.

  [1] Halohydrin + B: → BH⁺ + :O⁻
  [2] Intramolecular S_N2 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: S_N1- Carbocations are intermediates; rearrangements occur.

• Mechanism for CH₃OH and 1° ROH: S_N2

[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: S_N2

[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 (S_N2).

• Strong bases favor elimination (E2).

• 2° and 3° R groups favor S_N1.

• CH₃ and 1° R groups favor S_N2.

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: S_N2

• 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: S_N2

• Best for CH₃X and 1° RX.

[4] Reaction of Sulfides to Form Sulfonium Ions

• R'₂S + R-X → R'₂S⁺-R + X⁻

• Mechanism: S_N2

• 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 S_N2- Nucleophilic attack occurs at the less substituted C.

• With HZ, mechanism is between S_N1 and S_N2- 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: S_N2

• Best with CH₃X and RCH₂X.

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

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

• Mechanism: S_N2

• 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: S_N2

• CH₃X and RCH₂X react faster than more substituted RX.

[4] Reduction of Epoxides (12.6)

• Epoxide LiAlH₄, H₂O→ Alcohol

• Mechanism: S_N2

• 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)

-