Chapter 19: Amines - Comprehensive Lecture Notes

Introduction to Amines

• Amines are biologically active compounds.
• Alkaloids are synthesized by plants as a defense mechanism against insects and animals; many addictive drugs are alkaloids.
• Examples of biologically active amines:
  • Dopamine: A neurotransmitter.
  • Epinephrine: An adrenal hormone.
  • L-tryptophan: An amino acid.
  • Piperazine: Kills intestinal worms.
  • Nicotinic acid (Niacin): A vitamin.
  • Pyridoxine: Vitamin B6.
  • Histamine: Dilates blood vessels.

Classes of Amines

• Primary (1°): One alkyl group bonded to the nitrogen (RNH2).
• Secondary (2°): Two alkyl groups bonded to the nitrogen (R2NH).
• Tertiary (3°): Three alkyl groups bonded to the nitrogen (R3N).
• Quaternary (4°): Four alkyl groups bonded to the nitrogen, with the nitrogen bearing a positive charge (R4N+).

Nomenclature of Amines

• Primary (1°) amines: e.g., cyclohexylamine, tert-butylamine.
• Secondary (2°) amines: e.g., N-ethylaniline, piperidine.
• Tertiary (3°) amines: e.g., N,N-diethylaniline, quinuclidine.

Quaternary Ammonium Salts

• The nitrogen atom has four alkyl groups attached and is positively charged.

Common Names

• Formed from the names of the alkyl groups bonded to nitrogen, followed by the suffix -amine.

Amine as Substituent

• When an amine is on a molecule with a higher-priority functional group, it is named as a substituent.

IUPAC Names

• Based on the longest carbon chain.
• The -e of the alkane is replaced with -amine.

Aromatic Amines

• In aromatic amines, the amino group is bonded to a benzene ring.
• The parent compound is called aniline.

Heterocyclic Amines

• When naming a cyclic amine, the nitrogen is assigned position number 1.

Structure of Amines

• Nitrogen is sp3 hybridized with a lone pair of electrons.
• The bond angle is less than 109.5°.

Interconversion of Chiral Amines

• Nitrogen may have three different groups and a lone pair, but enantiomers cannot be isolated due to inversion around N.

Chiral Amines

• Amines whose chirality stems from the presence of chiral carbon atoms.
• Inversion of the nitrogen is not relevant because it will not affect the chiral carbon.

Chiral Quaternary Ammonium Salts

• Quaternary ammonium salts may have a chiral nitrogen atom if the four substituents are different.
• Inversion of configuration is not possible because there is no lone pair to undergo nitrogen inversion.

Chiral Cyclic Amines

• If the nitrogen atom is contained in a small ring, it is prevented from attaining the 120° bond angle that facilitates inversion.
• Such a compound has a higher activation energy for inversion; the inversion is slow, and the enantiomers may be resolved.

Physical Properties of Amines

• N—H is less polar than O—H, resulting in weaker hydrogen bonds. Amines have lower boiling points than corresponding alcohols.
• Tertiary amines cannot hydrogen-bond, so they have lower boiling points than primary and secondary amines.

Boiling Points

• Comparison of boiling points:
  • (CH3)3N (tertiary amine): 3 °C, Molecular Weight 59
  • CH3–O–CH2–CH_2 (ether): 8 °C, Molecular Weight 60
  • CH3–NH–CH2–CH_2 (secondary amine): 37 °C, Molecular Weight 59
  • CH3CH2CH2–NH2 (primary amine): 48 °C, Molecular Weight 59
  • CH3CH2CH_2–OH (alcohol): 97 °C, Molecular Weight 60

Solubility and Odor

• Small amines (< six carbons) are soluble in water.
• All amines accept hydrogen bonds from water and alcohol.
• Branching increases solubility.
• Most amines smell like rotting fish.

Basicity of Amines

• The lone pair of electrons on nitrogen can accept a proton from an acid.
• Aqueous solutions are basic to litmus.
• Ammonia pK_b = 4.74.
• Alkyl amines are usually stronger bases than ammonia.
• Increasing the number of alkyl groups decreases solvation of the ion, so 2° and 3° amines are similar to 1° amines in basicity.
• Reaction of an amine as a nucleophile: R-N: + CH3I → R-N-CH3 + I^-
• Reaction of an amine as a proton base: R-N: + HX → R-NH + X^-

Base-Dissociation Constant of Amines

• Amines are strongly basic and can abstract a proton from water, giving an ammonium ion and a hydroxide ion.
• The equilibrium constant for this reaction is called the base-dissociation constant for the amine, symbolized by K_b.

Amine Basicity Constants

• Ammonia: Kb = 1.8 Imes 10^{-5}, pKb = 4.74, pK_a = 9.26
• Primary alkyl amines (e.g., methylamine, ethylamine, n-propylamine, isopropylamine, cyclohexylamine, benzylamine) generally have pK_b values around 3.3 to 4.7.
• Secondary amines (e.g., dimethylamine, diethylamine, di-n-propylamine) generally have pK_b values around 3.0 to 3.3.
• Tertiary amines (e.g., trimethylamine, triethylamine, tri-n-propylamine) generally have pK_b values around 3.2 to 4.3.
• Aryl amines (e.g., aniline, N-methylaniline, N,N-dimethylaniline, p-bromoaniline, p-methoxyaniline, p-nitroaniline) generally have much lower Kb values, with pKb values ranging from 8.7 to 13.0.
• Heterocyclic amines (e.g., pyrrole, pyrrolidine, imidazole, pyridine, piperidine) have a wide range of basicity, with pK_b values ranging from -0.3 to 14.3.

Factors Affecting Amine Basicity

• Alkyl groups stabilize the ammonium ion, making the amine a stronger base.
• Any delocalization of the electron pair weakens the base.
• Protonation of pyrrole is unfavorable because pyrrole loses its aromatic stabilization.
• Pyridine is less basic than aliphatic amines, but it is more basic than pyrrole because it does not lose its aromaticity on protonation.

Ammonium Salts

• Ionic solids with high melting points.
• Soluble in water.
• No fishy odor.

Purifying an Amine

• Extraction process using ether and water to separate the amine from other organics and impurities.
• Treatment with dilute HCl to form water-soluble ammonium salts, followed by addition of NaOH to regenerate the free amine.

Spectroscopy of Amines

• IR Spectroscopy:
  • N—H stretch between 3200 and 3500 cm–1.
  • Two peaks for 1° amine, one for 2°.
• NMR Spectroscopy:
  • Nitrogen is not as electronegative as oxygen, so the protons on the α carbon atoms of amines are not as strongly deshielded.
• Carbon NMR Chemical Shifts of Some Representative Amines:
  • Methanamine: 26.9
  • Ethanamine: 17.7, 35.9
  • Propan-1-amine: 11.1, 27.3, 44.9
  • Butan-1-amine: 14.0, 20.4, 36.7, 42.3
• Mass Spectroscopy of Amines:
  • Nitrogen has an odd valence and an even mass number.
  • When a nitrogen atom is present in a stable molecule, the molecular weight is odd.
  • Whenever an odd number of nitrogen atoms are present in a molecule, the molecular ion has an odd mass number.

Alpha Cleavage of Amines

• The most common fragmentation of amines is α cleavage to give a resonance-stabilized cation—an iminium ion.

Reactions of Amines

• Amines react with ketones and aldehydes.

Alkylation of Amines by Alkyl Halides

• Proceeds by the SN2 mechanism.
• Secondary alkyl halides will give elimination products.
• Multiple alkylations are a major problem, leading to complex mixtures.

Exhaustive Alkylation

• Forms the tetraalkylammonium salt.
• Mild basic conditions (NaHCO3) are used to deprotonate the intermediates and neutralize the acid formed.

Alkylations with Excess Ammonia

• Reaction with a large excess of NH3 to form the primary amine in good yields.
• Excess ammonia is allowed to evaporate after reaction.

Acylation of Amines

• Primary and secondary amines react with acid halides to form amides.
• This reaction is a nucleophilic acyl substitution.
• Mechanism of Acyl Substitution:
  • Step 1: Nucleophile attacks the carbonyl carbon, forming the tetrahedral intermediate.
  • Step 2: Expulsion of the chloride ion.
  • Step 3: Loss of a proton gives the amide.

Acylation of Aromatic Amines

• The resulting amide is still activating and ortho, para-directing.
• The acyl group can be removed later by acidic or basic hydrolysis.

Amines as Leaving Groups: The Hofmann Elimination

• Amines can undergo elimination reactions to form alkenes.
• The –NH2 or –NHR groups are not good leaving groups because they are very strong bases.
• Exhaustive methylation can convert the amino group into a quaternary ammonium salt, which can leave as the neutral amine.

Exhaustive Methylation of Amines

• Methyl iodide is usually used as a methylating agent.
• The leaving group is the neutral amine.

Conversion to the Hydroxide Salt

• The iodide salt is converted to the hydroxide salt by treatment with silver oxide and water.
• The hydroxide will serve as the base in the elimination step.

Hofmann Elimination

• A quaternary ammonium salt has a good leaving group—a neutral amine.
• Heating the hydroxide salt produces the least substituted alkene.

Mechanism of the Hofmann Elimination

• The Hofmann elimination is a one-step, concerted E2 reaction in which the amine is the leaving group.

Regioselectivity of the Hofmann Elimination

• The least substituted product is the major product of the reaction (Hofmann product).

Oxidation of Amines

• Amines are easily oxidized, even in air.
• Common oxidizing agents: H2O2, MCPBA.
• 2° amines oxidize to hydroxylamine (—NOH).
• 3° amines oxidize to amine oxide (R_3N^+—O^–).

Preparation of Amine Oxides

• Tertiary amines are oxidized to amine oxides, often in good yields.
• Either H2O2 or peroxyacid may be used for this oxidation.
• The N-oxide can undergo elimination to form alkenes in a reaction analogous to the Hofmann elimination.

Cope Rearrangement

• E2 mechanism.
• The amine oxide acts as its own base through a cyclic transition state, so