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.
[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:
Removal of a proton from the alcohol of halohydrin with a base to form an alkoxide.
Intramolecular SN2 reaction to form the epoxide.
[1] Halohydrin + B: → BH⁺ + :O⁻
[2] Intramolecular SN2 reaction forms Epoxide
[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.
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.
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
[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.
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.
[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.
[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.
[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.
[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.
[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.
[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
Aldehyde CrO₃, Na₂Cr₂O₇, K₂Cr₂O₇, KMnO₄ or Ag₂O, NH₄OH→ Carboxylic Acid
Tollens reagent oxidizes aldehydes only; alcohols do not react.
[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
[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.
[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
[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.
[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
[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.
[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
[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
[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
R-X + CN⁻ S₂N→ R-CN + X⁻
R = CH₃, 1°
[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
[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)
-