Amines

Amines: Organic derivatives of $NH_3$ where one or more H is replaced by alkyl/aryl groups.

Classification (based on number of R groups on N):

Also:

• Aliphatic ($R$ = alkyl): methylamine, ethylamine
• Aromatic ($R$ = aryl): aniline ($C_6H_5NH_2$)
• Mixed: N-methylaniline ($C_6H_5NHCH_3$)

Structure: N is $sp^3$ hybridized; pyramidal (like $NH_3$); lone pair on N.

• Bond angle ~$107°$ (slightly less than tetrahedral due to lp-bp repulsion)

Nomenclature:

Suffix: replace last 'e' of alkane with -amine. Substituents on N: prefix N-.

Preparation:

1. Reduction of Nitro Compounds: $RNO_2 + 6[H] \xrightarrow{Sn/HCl \text{ or } Fe/HCl \text{ or } H_2/Pt} RNH_2 + 2H_2O$

• For aniline: $C_6H_5NO_2 + 6[H] \to C_6H_5NH_2 + 2H_2O$
• Common reagents: $Sn + HCl$, $Fe + HCl$, $H_2/Ni$, $Zn/HCl$

2. Reduction of Nitriles ($RCN$): $RCN + 4[H] \xrightarrow{Na/C_2H_5OH \text{ or } LiAlH_4 \text{ or } H_2/Ni} RCH_2NH_2$

• Adds one C; 1° amine
• $CH_3CN \to CH_3CH_2NH_2$ (ethylamine, from methyl cyanide)

3. Reduction of Amides: $RCONH_2 + 4[H] \xrightarrow{LiAlH_4} RCH_2NH_2 + H_2O$

• Note: same number of C; 1° amine

4. Ammonolysis of Alkyl Halides (Hofmann's Method): $RX + NH_3 \to RNH_2 + HX$ (further alkylation possible)

• Gives mix of $1°, 2°, 3°$ amines and quaternary salt
• Order of reactivity: $RI > RBr > RCl$
• Industrial way for simple amines

Problems: over-alkylation. Solution: excess NH₃ for $1°$ amine; excess RX for higher amines.

5. Hofmann Bromamide Degradation: $RCONH_2 + Br_2 + 4NaOH \to RNH_2 + Na_2CO_3 + 2NaBr + 2H_2O$

• Amide → $1°$ amine with one fewer C
• Specific for $1°$ amine; no other isomers
• e.g., $CH_3CH_2CONH_2 \to CH_3CH_2NH_2$

6. Gabriel Phthalimide Synthesis: For pure $1°$ amines only.

1. Potassium phthalimide + RX → N-alkyl phthalimide
2. Hydrolyze (or hydrazine — Ing-Manske) → $RNH_2$ + phthalic acid

$\text{Phthalimide}-K + RX \to \text{Phthalimide}-R \xrightarrow{NaOH \text{ or } NH_2NH_2} RNH_2 + \text{phthalate}$

Limitations: Doesn't work with aryl halides (aryl C-X bond is unreactive in $S_N2$); doesn't give aryl amines.

Physical Properties:

• Lower amines: gases or liquids; pungent (fishy) smell
• BP: $RNH_2$ > $R_2NH$ > $R_3N$ (more H-bonding with more N-H bonds)
• BP order: $RNH_2 \approx ROH > R_3N \approx RH$ (alkanes)
• Solubility: lower amines very soluble in water (H-bond with water); decreases with chain length
• Aniline: oily liquid; turns brown on air exposure (auto-oxidation)

Basicity: Ability to donate lone pair to H⁺. Lone pair on N is key.

Comparison of Basicity:

• Amines are weaker bases than NaOH, KOH
• Amines are stronger bases than NH₃ (in general)
• $pK_b$ (or $pK_a$ of conjugate acid) measures basicity

Factors Affecting Basicity:

1. Inductive Effect (+I from alkyl): Alkyl groups donate electrons through sigma bonds → increases electron density on N → makes N more basic. Predicted order: $3° > 2° > 1° > NH_3$.

2. Resonance Effect: In aromatic amines, lone pair on N can delocalize into ring; reduces availability → less basic.

• Aniline < methylamine in basicity.

3. Steric Effect: Bulky groups around N prevent approach of H⁺ → decreases basicity. $(CH_3)_3N$ less basic than $(CH_3)_2NH$ in some scenarios.

4. Solvation Effect (Aqueous): $1°$ amine cation ($RNH_3^+$) has more H's available for H-bonding with water → better solvated → more stable → more basic effective. $3°$ amine cation ($R_3NH^+$) has only one N-H; less solvated → less stable → less basic in water.

Order of Basicity:

In Gas Phase (no solvation; only +I effect): $3° > 2° > 1° > NH_3$ $(CH_3)_3N > (CH_3)_2NH > CH_3NH_2 > NH_3$

In Aqueous Solution (combines +I and solvation): Generally: $2° > 1° > 3° > NH_3$ $(CH_3)_2NH > CH_3NH_2 > (CH_3)_3N > NH_3$

(Sometimes $1° > 2° > 3°$ if bulky groups cause more steric and less solvation.)

$pK_b$ values (aqueous, 25°C):

Basicity of Aromatic Amines:

Aniline < methylamine because:

1. Lone pair on N delocalized into benzene ring via resonance (mesomeric effect)
2. Lone pair less available for protonation
3. Conjugate acid (anilinium ion) loses this resonance stabilization → less stable → less basic

Substituent Effects on Aniline:

Effects in different positions:

• p-toluidine ($p$-$CH_3$): more basic than aniline (+I)
• p-nitroaniline: much less basic than aniline (-R, -I)
• o-nitroaniline: weakest of three nitroanilines (ortho effect, H-bonding internal)

Reactions of Amines:

1. With Mineral Acids (Salt formation): $RNH_2 + HCl \to RNH_3^+Cl^-$ (alkyl ammonium chloride)

• Salts soluble in water; amines extracted by acidic workup

2. Alkylation (Hofmann's Method): $RNH_2 + R'X \to RR'NH + HX$ (→ further alkylation → $R_3N$ → $R_4N^+X^-$ quaternary salt)

• Gives mixture; isolated by fractional distillation/separation

3. Acylation (with acid chlorides or anhydrides): $RNH_2 + R'COCl \to R'CONHR + HCl$ (amide; "protected" amine) $RNH_2 + (R'CO)_2O \to R'CONHR + R'COOH$

• $3°$ amines don't acylate (no N-H)
• Acetylation of aniline → acetanilide ($C_6H_5NHCOCH_3$) — used in some old drugs

4. Carbylamine Reaction (Isocyanide Test) — for $1°$ amines: $RNH_2 + CHCl_3 + 3KOH \xrightarrow{\Delta} RNC + 3KCl + 3H_2O$

• Gives isocyanide with very offensive smell
• Specific test for $1°$ amines (both aliphatic and aromatic)
• $2°$ and $3°$ amines don't give this

5. Hinsberg Test (with Benzenesulfonyl Chloride):

• Distinguishes $1°, 2°, 3°$ amines.

6. Reaction with Nitrous Acid (Diazotization):

(a) $1°$ Aliphatic amines + HNO₂ (cold) → unstable diazonium → loses $N_2$ → alcohol/alkene mix: $RNH_2 + HNO_2 \xrightarrow{0-5°C} ROH + N_2 + H_2O$ (Diazonium too unstable at any T)

(b) $1°$ Aromatic amines + HNO₂ at 0-5°C → stable arenediazonium salt: $ArNH_2 + HNO_2 + HCl \xrightarrow{0-5°C} ArN_2^+Cl^- + 2H_2O$

• Stable below $5°C$ (called diazotization)

(c) $2°$ amines + HNO₂ → N-nitrosoamines (yellow oily; carcinogenic): $R_2NH + HNO_2 \to R_2N-NO + H_2O$

(d) $3°$ amines + HNO₂: only protonates (no reaction at N-H since none).

7. Oxidation:

• Aniline + chromic acid → mostly degradation products; benzoquinone with some oxidants
• Aliphatic amines can give various products; not commonly used

Aromatic Diazonium Salts ($ArN_2^+ X^-$): Extremely useful synthetic intermediates.

Preparation (Diazotization): $ArNH_2 + HNO_2 + HCl \xrightarrow{0-5°C} ArN_2^+Cl^- + 2H_2O$ (or $HNO_2$ generated in situ from $NaNO_2 + HCl$)

Conditions: low T (0-5°C); diazonium salt decomposes above 10°C.

Reactions of Diazonium Salts (extremely versatile):

A. Replacement of $N_2^+$ by Other Groups:

1. Sandmeyer Reaction: $ArN_2^+Cl^- + CuCl \to ArCl + N_2 + CuCl$ $ArN_2^+Br^- + CuBr \to ArBr + N_2 + CuBr$ $ArN_2^+Cl^- + CuCN \to ArCN + N_2$

• Replaces $N_2^+$ with Cl, Br, or CN

2. Gattermann Reaction: Variant with Cu/HCl or Cu/HBr (cheaper than Sandmeyer's Cu(I) salts): $ArN_2^+Cl^- + Cu/HCl \to ArCl + N_2 + CuCl$

3. Replacement by -I: With KI: $ArN_2^+Cl^- + KI \to ArI + N_2 + KCl$ (no catalyst needed; smooth)

4. Replacement by -F (Schiemann): $ArN_2^+BF_4^- \xrightarrow{\Delta} ArF + N_2 + BF_3$

5. Replacement by -OH (Hydrolysis): $ArN_2^+ + H_2O \xrightarrow{warm} ArOH + N_2 + H^+$ (gives phenol; warm dilute acid solution)

6. Replacement by -H (Deamination): $ArN_2^+ + H_3PO_2 \to ArH + N_2 + H_3PO_3$ (or hypophosphorous acid; useful for removing $-NH_2$ from ring)

7. Replacement by -NO₂: With Cu/NaNO₂.

B. Azo Coupling Reactions (Retention of $N_2$):

Diazonium ions are weak electrophiles; couple with strongly activated aromatics (phenols, anilines):

$ArN_2^+ + Ar'H \to Ar-N=N-Ar' + H^+$

Conditions:

• With phenols: alkaline solution (pH 9-10): the phenoxide $Ar'O^-$ is highly activated; couples at para position.
• With aromatic amines: acidic to neutral (pH 5-7): amine itself activated.

Examples:

• Aniline + diazonium → orange dye (methyl orange in industry made from diazotized sulfanilic acid + N,N-dimethylaniline)
• Phenol + diazonium → orange-red dye (p-hydroxyazobenzene)

Reactivity: Used in azo dyes industry (clothes, paper, food coloring).

Importance of $ArN_2^+$: Convert $-NH_2$ to many functional groups (-OH, -X, -CN, -NO₂, -H, -Ar) — making it a versatile route in aromatic synthesis.

Aromatic Amines Reactions Summary:

Aniline ($C_6H_5NH_2$) Properties:

1. Lone pair on N donates to ring → strong activator, o/p director (for EAS).
2. Less basic than aliphatic amines (resonance lock-up of lp).
3. Cannot undergo Friedel-Crafts directly (Lewis acid forms complex with lone pair on N, deactivating ring).

• Solution: protect $-NH_2$ as $-NHCOCH_3$ (acetanilide) first.

EAS on Aniline:

• Bromination ($Br_2$/water): 2,4,6-tribromoaniline (uncontrolled; aniline very activated).
• Mono-bromination requires acetanilide protection, then deprotection.
• Nitration:
• Direct $HNO_3 + H_2SO_4$: aniline gets protonated ($-NH_3^+$, m-director) → m-nitroaniline major (~50%) + o, p
• To get p-nitroaniline: protect as acetanilide → nitrate → mostly para → hydrolyze.

Coupling reactions:

• Aniline + nitrous acid → diazonium salt (then various reactions above)
• Diazonium coupling with phenol/amine → azo dye