Chapter 20 Amines Notes

Nomenclature of Amines

• 1° Amines:

  • Butylamine: $NH_2$

  • Cyclohexylamine: $NH_2$

• 2° Amines:

  • Butylethylamine: $N(H)$

  • Diethylamine: $N(H)$

• 3° Amines:

  • Triethylamine: $N$

  • Butylethylmethylamine: $N$

Arylamines

• Aniline: $NH_2$

• N,N-Dimethylaniline: $N$

• p-Toluidine (4-Methylbenzeneamine): $NH<em>2$ with a $CH</em>3$ group at the para position.

Heterocyclic Amines

• Aziridine: $N(H)$

• Pyrrole: $N(H)$

• Pyridine: $N$

• Indole: $N(H)$

• Quinoline: $N$

Physical Properties and Structure of Amines

• Physical Properties

• Structure of Amines:

  • Nitrogen is $sp^3$ hybridized.

  • Trigonal pyramidal geometry.

  • Bond angles are close to $109.5^o$.

• 3° Amines with three different groups:

  • Two enantiomeric forms interconvert rapidly.

  • Impossible to resolve enantiomers due to pyramidal or nitrogen inversion.

  • Barrier is approximately $25 kJ/mol$, low enough to occur rapidly at room temperature.

• Ammonium salts with four different groups:

  • Enantiomers can be resolved.

Basicity of Amines: Amine Salts

• Equilibrium:

  • $RNH<em>2 + H</em>3O^+ \rightleftharpoons RNH<em>3^+ + H</em>2O$

• $K<em>a = \frac{[RNH</em>2][H<em>3O^+]}{[RNH</em>3^+]}$

• $pK<em>a = -log K</em>a$

• The aminium ion of a more basic amine will have a larger $pK_a$ than the aminium ion of a less basic amine.

  • $NH<em>3^+$ has $pK</em>a = 9.26$

  • $CH<em>3NH</em>3^+$ has $pK_a = 10.64$

  • $CH<em>3CH</em>2NH<em>3^+$ has $pK</em>a = 10.75$

• Alkyl groups stabilize the alkylaminium ion through dispersal of charge.

  • $R-N(H<em>2)^+ + H</em>2O \rightleftharpoons R-NH<em>2 + H</em>3O^+$

• Basicity in gas phase vs. aqueous solution:

  • Gas phase basicity: (CH3)3N > (CH3)2NH > CH3NH2 > NH_3 (3° > 2° > 1°)

  • Aqueous solution basicity: (CH3)2NH > CH3NH2 > (CH3)3N > NH_3 (2° > 1° > 3°)

Basicity of Arylamines

• $C<em>6H</em>5NH<em>3^+$ has $pK</em>a = 4.58$. The $pK<em>a$ of $CH</em>3C<em>6H</em>4NH_3^+$ is 5.08

• Resonance structures of aniline:

  • Five resonance structures, delocalizing the electron density.

• Resonance structures of anilinium ion:

  • Only two resonance structures, less stabilization.

• Anilinium ion formation:

  • $NH<em>2 + H</em>2O \rightleftharpoons NH_3^+ + OH^-$

Basicity of Heterocyclic Amines

• Order of basicity:

  • The $pK_a$ of the conjugate acid of pyridine is 5.2

  • The $pK_a$ of the conjugate acid of pyrrole is 0.4

  • The $pK<em>a$ of the conjugate acid of Et3N is 9.7 (c.f. Et3N, $pK</em>a$ of the conjugate acid 11.2)

• Reaction of imidazole with a proton:

  • Imidazole is a very common base in organic synthesis as it remains aromatic.

  • $N: + H^+ \rightleftharpoons NH^+$

Amines versus Amides

• Amides are far less basic than amines (even less basic than arylamines).

  • The $pK_a$ of the conjugate acid of a typical amide is ~zero

• Resonance stabilization:

  • Larger resonance stabilization in amides compared to smaller resonance stabilization in N-protonated amides.

  • Amide resonance structures.

  • N-Protonated amide resonance structures.

• Equilibrium:

  • $R-CO-NH<em>2 + H</em>3O^+ \rightleftharpoons R-CO-NH<em>3^+ + H</em>2O$

Aminium Salts and Quaternary Ammonium Salts

• $R_4N^+$ $OH^-$ are strong bases (as strong as NaOH).

• Aminium salts cannot act as bases.

• Aminium salt formation:

  • $R<em>2N(R</em>1)R<em>3 + HCl \rightleftharpoons R</em>2N(H)(R<em>1)R</em>3 Cl^-$

• Quaternary ammonium salt formation:

  • $R<em>2N(R</em>1)R<em>3 + R</em>4Br \rightleftharpoons R<em>2N(R</em>1)R<em>3R</em>4 Br^-$

Solubility of Amines in Aqueous Acids

• Amines are more soluble in aqueous acids due to the formation of water-soluble salts.

  • $RNH<em>2 + HX \rightleftharpoons RNH</em>3^+ X^-$ (water soluble)

• Ethers (or unprotonated organic molecules) are generally water insoluble.

  • $R-O-R + HX \rightleftharpoons ROH^+ X^-$ (water insoluble)

Amines as Resolving Agents

• Enantiomerically pure amines are often used to resolve racemic forms of acidic compounds by the formation of diastereomeric salts.

• Example:

  • Using an (R)-amine to resolve a racemic (R,S)-acid.

  • Separating (R,R)-salt and (S,R)-salt.

  • Regenerating (R)-acid and (S)-acid with $H_3O^+$.

Preparation of Amines

• Through Nucleophilic Substitution Reactions:

  • Alkylation of ammonia leads to over-alkylation.

    • $NH<em>3 + RX \rightarrow NH</em>2R + HX$
      alternately leads to dialkylation or trialkylation

  • Alkylation of azide ion followed by reduction.

    • $NaN<em>3 + RX \rightarrow RN</em>3 \xrightarrow[Na/EtOH \text{ or } LiAlH<em>4]{} RNH</em>2$

  • The Gabriel synthesis:

    • Phthalimide alkylation followed by hydrolysis.

    • 2 steps: imide to amine using$NH<em>2NH</em>2$

  • Alkylation of 3° amines:

    • SN2 reaction to form quaternary ammonium salts.

    • NR3 + R'X --> NR3R'^+ X^-

Preparation of Aromatic Amines through Reduction of Nitro Compounds

• Reduction of nitro compounds to aromatic amines.

  • $R-NO<em>2 \xrightarrow[H</em>2, catalyst \text{ or } Fe, HCl, then NaOH]{} R-NH_2$

Preparation of 1°, 2°, & 3° Amines through Reductive Amination

• Using aldehydes or ketones with ammonia or amines.

  • Aldehyde or ketone + $NH_3 \xrightarrow[[H]]{} 1°$ amine.

  • Aldehyde or ketone + $R''NH_2 \xrightarrow[[H]]{} 2°$ amine.

• Mechanism:

  • Formation of a hemiaminal intermediate, followed by imine formation and reduction.

• Examples:

  • Using $NH<em>3$ and $H</em>2/Ni$ with heat and pressure.

  • Using $NaBH_3CN$ as the reducing agent.

  • $NaBH_3CN$

Preparation of 1°, 2°, & 3° Amines through Reduction of Nitriles, Oximes, and Amides

• Reduction of nitriles, oximes, and amides to amines.

  • Nitrile: $R-C≡N \xrightarrow[[H]]{} RCH<em>2NH</em>2$.

  • Oxime: $R<em>2C=N-OH \xrightarrow[[H]]{} R</em>2CHNH_2$ .

  • Amides: $RCONR'R'' \xrightarrow[[H]]{} RCH_2NR'R''$.

• Examples:

  • Reduction of an oxime using Na/EtOH.

  • Reduction of an amide using $LiAlH<em>4$ followed by $H</em>2O$.

Oxidation of Amines

• Tertiary amines can be oxidized to amine oxides using $H<em>2O</em>2$ or a peroxyacid.

  • $R<em>3N: + O \rightarrow R</em>3N-O$

Reactions of Amines with Nitrous Acid

• Nitrous acid formation:

  • $HCl(aq) + NaNO_2(aq) \rightarrow HONO(aq) + NaCl(aq)$

  • $H<em>2SO</em>4(aq) + 2NaNO<em>2(aq) \rightarrow 2HONO(aq) + Na</em>2SO_4(aq)$

Reactions of Primary Arylamines with Nitrous Acid

• Formation of arenediazonium salts (stable at < $5^oC$).

• Mechanism involves multiple proton transfers and the formation of a diazonium ion.

Reactions of Secondary Amines with Nitrous Acid

• Formation of N-Nitroso-amines.

Reactions of Tertiary Amines with Nitrous Acid

• Complicated reactions, often leading to decomposition or salt formation.

  • Et3N + NaNO2 + HCl --> Et3NHCl + Et3NNOCl

Replacement Reactions of Arenediazonium Salts

• Diazonium salts can be replaced with various groups.

• Replacement by —I

  • Example: Conversion of p-Nitroaniline to p-Iodonitrobenzene using $H<em>2SO</em>4$, $NaNO_2$, and KI (81% overall yield).

• Replacement by -F

  • Example: Conversion of m-Toluidine to m-Fluorotoluene using $HONO$, $HBF_4$, and heat (69% yield).

• Replacement by —OH

  • Example: Conversion of p-Toluenediazonium hydrogen sulfate to p-Cresol using $Cu<em>2O$, $Cu^{2+}$, and $H</em>2O$ (93% yield).

Coupling Reactions of Arenediazonium Salts

• Arenediazonium salts react with electron-rich aromatic compounds (Q = $NR_2$ or OH) to form azo dyes.

• Examples:

  • Formation of an orange solid dye.

  • Formation of a yellow solid dye.

Summary of Preparations and Reactions of Amines

• Preparation of amines

  • Gabriel synthesis

    • $R NH<em>2 \longleftarrow \text{N O O H} \xrightarrow{1. KOH} \xrightarrow{2. R-X} \xrightarrow{3. NH</em>2NH_2, EtOH, heat}$

  • From alkyl halides

    • $R NH_2 \longleftarrow R Br$

      1. $NaN_3$

      2. $LiAlH_4$

  • From nitro compounds

    • $R NH<em>2 \longleftarrow R NO</em>2 \xrightarrow{H_2, cat. or 1. Fe, HCl 2. NaOH}$

  • Reductive amination

    • $R NH<em>2 \longleftarrow \text{O R1 R2 R = R1 R2 }\xrightarrow{NH</em>3} \xrightarrow{[H]}$

  • From oximes

    • $N R1 R2 R = R1 R2 OH \xrightarrow{Na EtOH}$

  • Amide reduction

    • $R NH_2 \longleftarrow \text{1. LiAlH4 2. H2O R C N}$

  • Hoffman rearrangement

    • $R NH<em>2 \longleftarrow O R Cl \xrightarrow{Br</em>2} \xrightarrow{ NaOH} \xrightarrow{1. NaN3} \xrightarrow{2. heat} \xrightarrow{3. H2O}$