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Chapter 18. Amines and Others

Recommended Article: 【Organic Chemistry】 Organic Chemistry Table of Contents

1. Amines

2. Imines

3. Azides

4. Nitric Acids

1. Amines

⑴ Overview

① Definition: Derivatives of NH3

② Nomenclature

○ Add “amine” after the corresponding alkane carbon number

○ For 2nd and 3rd amines, substitute groups attached to other nitrogen atoms are named with N - prefixed

○ Amine substituents are denoted by “amino-“

③ Boiling Point

○ Hydrogen bonding is possible between primary and secondary amines

○ Boiling and melting points of tertiary amines are lower than those of primary or secondary amines: Tertiary amines cannot form intramolecular hydrogen bonds themselves

○ Boiling points of amines are relatively lower compared to alcohols with similar molecular weight: Due to lower electronegativity of nitrogen

○ Boiling point of trimethylamine > boiling point of triethylamine: Alkyl groups hinder intermolecular forces

○ Boiling point of triethylamine < boiling point of triethylphosphine: Polarizability is more important than electronegativity

④ Acidity

○ Comparison of amine basicity in the gaseous state: Tertiary > Secondary > Primary amines (Due to the electron-donating alkyl groups enhancing amine’s basicity)

○ Comparison of amine basicity in aqueous solutions: Secondary > Tertiary > Primary amines (Considering stabilizing effects from solvents)

○ pK_a of alkyl amine conjugate acids is around 10-11

○ pK_a of aryl amine conjugate acids is around 4-5

○ Basicity of aryl amines

○ Basicity of heterocyclic amines

⑤ Amine Inversion

⑵ Reaction 1. Acid-Base Reaction: Amines act as bases

⑶ Reaction 2. S_N2 Nucleophilic Substitution Reaction

① 2-1. Amine protection and deprotection reactions

○ Protection reaction: -NH₂ → -NHBoc

○ Deprotection reaction: -NHBoc → -NH₂

Figure 1. Deprotection reaction mechanism

② 2-2. Thiourea bond formation reaction

Figure 2. Thiourea bond formation reaction

③ 2-3. Reactions of secondary and tertiary amines with nitrous acid

⑷ Reaction 3. Electrophilic Aromatic Substitution Reaction (S_EAr)

① 3-1. Electrophilic Aromatic Substitution of Anilines

⑸ Reaction 4. Hydrogenation Reduction Reaction

① Reaction 4-1. Acylation reaction: 1. SOCl₂, 2. NH₃, 3. LiAlH₄, ether, 4. H₂O

② Reaction 4-2. NaBH₃CN: Reduces imines to amines

Figure 3. Reduction reaction of imines using NaBH₃CN

③ Reaction 4-3. H₂ / Pt: Reduces imines to amines

⑹ Reaction 5. Other Reactions

① Oxidation reactions of amines

② Diazonium salt production reaction with sodium nitrite (NaNO₂)

Figure 4. Diazonium salt production reaction with sodium nitrite

③ Nitrosonium (N≡O⁺) production reaction with sodium nitrite (NaNO₂)

Figure 5. nitrosonium production reaction with nitrite

④ Tiffeneau-Demjanov Rearrangement

⑤ Diazotization and Sandmeyer Reaction

⑥ Hinsberg test: Reaction with sulfonyl chlorides

⑦ Hofmann Elimination Reaction: Converts amines to alkenes

Figure 6. Hofmann elimination reaction of amines

○ (Formula 1) Conversion of amine to a good leaving group, i.e. trimethylamine, using 1. excess CH₃I, base, 2. Ag₂O, H₂O, Δ conditions, followed by elimination reaction.

○ (Formula 2) Formation of alkene with smaller substituents

○ Zaitsev’s rule: Highly substituted alkenes are major products in elimination reactions due to alkene stability

○ Hofmann’s rule: Less substituted alkenes are major products in elimination reactions due to steric effects

○ Hofmann Elimination Reaction: When the substituent is a quaternary ammonium or tertiary sulfonium ion, the Hofmann product is the major product upon elimination

⑦ Cope Elimination Reaction

○ Hofmann Elimination Reaction is based on the E2 elimination reaction. Hofmann Elimination Reaction is based on the E2 elimination reaction. It proceeds through a stereospecific anti-periplanar mechanism.

○ Cope Elimination Reaction involves a pentagonal transition state

○ Treatment of tertiary amines with peroxides results in syn elimination of amine and formation of amine oxide

⑺ Synthesis Methods

① Haber-Bosch Process

○ Industrial production of ammonia

○ Preparing N₂: H₂ in a 1:3 ratio

○ Reaction 1: Air equilibrium: N₂:O₂ = 78%:21%

○ Reaction 2: Methane oxidation: 2CH₄ + O₂ → 2CO + 4H₂

○ Reaction 3: Methane oxidation: CH₄ + H₂O → CO + 3H₂

○ Reaction 4: Reaction with vapor: CO + H₂O → CO₂ + H₂

○ By combining these reactions, a N2 to H2 molar ratio of 1:3 can be achieved

○ Haber-Bosch Process

○ Catalyst: Iron powder

○ Accounts for 1-2% of the total CO2 emissions produced by humans

② Direct S_N2 reaction of alkyl halides with ammonia for primary amine synthesis: NH₃

③ S_N2 reaction of alkyl halides with azide ion for primary amine synthesis

○ Alkyl azide intermediates are explosive

④ Gabriel Synthesis

○ (Formula) Potassium phthalimide, base (e.g., OH^-), H₂O

○ A type of S_N2 reaction

Figure 7. Gabriel synthesis

⑤ Reduction of nitrobenzene to aniline using reduction of substituent

⑥ Amide Reduction Reaction

⑦ Nitrile Reduction Reaction

⑧ Imin Reduction Reaction

⑨ Hofmann Rearrangement: Br₂, H₂O

⑩ Curtius Rearrangement: Generation of isocyanate and nitrogen gas from acyl azides

⑪ Schmidt Rearrangement: H⁺, -N₂, H₂O, -CO₂

⑫ Lossen Rearrangement: Et₃N, H₂O, EtOH, H₂O

⑬ Eschweiler-Clarke Reaction: HCOOH, CH₂O

2. Imines

⑴ Overview

① Imines refer to -C=NR₂

② Imines are also known as Schiff bases

⑵ Reactions

① Reaction 1. Hydration and Dehydration Reactions

○ 1-1. Hydration of imines: Reversible reaction

Figure 8. Nucleophilic substitution reaction of amines

○ 1-2. Dehydration reaction: Reacting HRC=N-OH with an acid anhydride forms R-C≡N

② Reaction 2. Reduction Reactions

○ 2-1. Hydrogenation reaction of imines

Figure 9. Hydrogenation reduction reaction of imines

○ 2-2. Reduction of imines by organometallic reagents: Reduction using NaBH₄, LiAlH₄, etc. Forms a racemic mixture

Figure 10. Organic metal reagent reduction reaction of imines

○ 2-3. Selective reduction of imines: Using reagents like LiBH₃CN, NaBH(OCOCH₃)₃

○ 2-4. Oxime reduction (e.g., cyclohexanone oxime → cyclohexanamine)

③ Reaction 3. Wolff-Kishner Reduction Reaction

○ When -C=N-NH₂ (hydrazone) is treated with a base

○ Commonly used as a reaction to remove ketone groups in problems

Figure 11. Amine addition reaction to ketone + Wolff-Kishner reduction reaction

○ 3-1. Arndt-Eistert Reaction: Reaction where a carboxylic acid increases its carbon number by one

④ Reaction 4. Beckmann Rearrangement Reaction

○ When -C=N-OH (oxime) is treated with an acid

○ Nitrilium ion is stable due to resonance structures

Figure 12. Beckmann rearrangement reaction mechanism

⑶ Synthesis Methods

3. Azides

⑴ Overview

⑵ Reaction 1. Diazonium Reactions

① 1-1. Sandmeyer Reaction

○ Ph-N₂⁺ + CuBr → Ph-Br + N₂ (g)

○ Ph-N₂⁺ + KI → Ph-I + N₂ (g)

○ Ph-N₂⁺ + CuC≡N → Ph-C≡N + N₂ (g)

○ Ph-N₂⁺ + H₃O⁺ → Ph-OH + HCl + N₂ (g) (conditions: Δ)

○ Ph-N₂⁺ + CuCl → Ph-Cl + N₂ (g)

○ Ph-N₂⁺ + Cu₂O, Cu(NO₃)₂, H₂O → Ph-OH + N₂ (g)

○ Ph-N₂⁺ + H₃PO₂ → benzene + N₂ (g)

② 1-2. Schiemann Reaction

○ Ph-N₂⁺ + HBF₄ → Ph-F + BF₃ + N₂ (g) (conditions: Δ)

③ 1-3. Azo coupling of aryl diazonium salts

○ The N=N bond formation is called an azo coupling

○ Azo coupling is used to synthesize extended conjugated compounds as dyes: congo red, para red, etc.

⑶ Reaction 2. Rearrangement Reactions

① Reaction 2-1. Curtius Rearrangement Reaction

Figure 13. Curtius rearrangement reaction

② Reaction 2-2. Wolff Rearrangement Reaction

Figure 14. Wolff rearrangement reaction

⑷ Reaction 3. Azide-Alkyne Cycloaddition

① Also known as click chemistry, initiated by K. Barry Sharpless in 1998

② Reaction 3-1. 1,3-dipolar azide-alkyne cycloaddition

○ Above 100 °C, takes hours to days, a thermally driven conjugation reaction

○ Reaction proceeds quickly when R₂ and R₃ are electron-withdrawing groups

Figure 15. 1,3-dipolar cycloaddition

○ Application 1. Azide + cyclooctyne

Figure 16. Cycloaddition with azide and cyclooctyne

○ Application 2. Tetrazine + trans-cyclooctene

Figure 17. Cycloaddition with tetrazine and trans-cyclooctene

Figure. 18. Cycloaddition with tetrazine and trans-cyclooctene

③ Reaction 3-2. CuAAC (Copper Catalyzed Azide-Alkyne Cycloaddition)

Figure 19. CuAAC reaction

④ Reaction 3-3. RuAAC (Ruthenium Catalyzed Azide-Alkyne Cycloaddition)

Figure 20. RuAAC reaction

⑤ Reaction 3-4. SPAAC (Copper-Free Stain-Promoted Azide-Alkyne Cycloaddition)

○ Recently introduced technique

○ Cycloaddition reaction suitable for soft molecules like biomolecules

⑸ Synthesis Methods

4. Nitric Acids

⑴ Reaction 1. Hydrogenation of Nitrobenzene

Figure 21. Hydrogenation of Nitrobenzene

⑵ Synthesis Methods

Input: 2019.06.11 20:53

Modified: 2023.07.30 23:06