Amines

• Amine is one of the common N-containing functional groups in organicchemistry.
• It is abundant in nature and a common component of proteins,enzymes, nucleic acid, and alkaloidal drugs (N-containing activecompounds).
• Heterocyclic amines are also common in which a nitrogen is present ina ring system. This amines are either aromatic or anti-aromatic.
• Amines are derivatives of NH3 (ammonia). One H- of ammonia isreplaced by a carbon group (R), yielding an amine.
• Alkaloids are naturally-occurring amines. They are plant derivedconstituents which contains a nitrogen molecule that has a wide variety ofbiological properties.
• Atropine from Atropa belladonna

  Reserpine from Rauwolfia serpentina
• Amines can be either alkyl-substituted (alkylamines) or aryl-substituted(arylamines).
• There are also instances where a N atom has 4 groups attached to it and the N atom carries a positive charge, they are called quaternaryammonium salts.
• Amines are water-soluble, forms hydrogen bonds (for 1° and 2° amines),and have a distinct putrid odor.
• Amines are basic by nature defined as K b (basicity constant). Amines in a solution can receive a proton from water (acting as acid).
• Alkyl-substituted amines are more basic compared than aryl-substitutedamines.
• N-atom’s lone-pair in aryl-substituted amines are delocalized andparticipates in p orbital overlap, making aryl-amines less basic.
• Synthesis and Reaction of Amines

  • reduction of nitrobenzene
  • reduction of nitriles
  • reduction of amides
  • Sn2 alkylation with haloalkanes
  • reductive amination
• Reduction of Nitrobenzene is mechanism to synthesize amines from anaromatic molecule via two-step sequence SE nitration followed by nitro-reduction.
• Reduction of Nitrobenzene

  Benzene -> Nitration (HNO3/H2SO4) -> Reduction (H2/Pd or SnCl2 or Fe/H+) -> Amine
• Reduction of Nitriles is an amine synthesis via SN2 mechanism with RXand -CN ion, followed by reduction with strong reducing agent.• This method always produces a 1° amine product.
• Reduction of Nitriles

  RCH2X (NaCN) -> RCH2CN (LiAlH4/Ether or H2O) ->RCH2C2N2
• Reduction of Amides is an amine synthesis via SNAcyl mechanism withRCOOH and NH3 , followed by reduction with strong reducing agent.• This method always produces a 1° amine product without an additionalcarbon added into the structure.
• Reduction of Amides

  any carboxylic derivative (SOCl2 or DCC/NH3) -> primary amide (LiAlH4/ether or H2O) -> primary amine
• Reduction of Amides

  Acid Halides = Excess Ammonia with Pyridine with a by-product = NH4Cl

  Acid Anhydrides = 1 mol Ammonia with a by-product = RCOOH
• Acid halides and Acid anhydrides can use NH3, 1° amines, and 2° aminesto yield different amide products, which will lead to substituted amines.
• Alkylation via S N2 mechanism uses RX and amines (NH3, 1° amines, 2°amines) to synthesize other amines.
• SN 2 reactions can also take place with alkyl halides where other amines (from ammonia to 3◦ amines) can be used to synthesize other amines.
• NH3 → 1° amine1° amine → 2° amine2° amine → 3° amine3° amine → 4° amine
• Sn2 Alkylation with Haloalkanes

  RX + NH3/NaOH = Primary Amine

  RX + RNH2/NaOH = Secondary Amine

  RX + R2NH/NaOH = Tertiary Amine

  RX + R3N/NaOH = Quarternary Amine (with a positive charge since it has more than it can handle)
• SN2 alkylation using azide ion (N 3-) reacting with RX.
• NH3 and Primary Amine have similar reactivity, overalkylation can occur and Primary Amine maybe difficult to form.
• An azide (-N3) salt is a better reagent to create Primary Amine since the alkyl azide is not nucleophilic, thus overalkylation is prevented.
• Azide ion creates a more stable product for production of primary amine
• Sn2 alkylation using azide ion

  RX + NaN3/ethanol -> alkyl azide -> LiAlH4/ether or H2O -> primary amine
• Reductive amination is one-step synthesis reaction of amines fromaldehydes and ketones reaction with NH3, 1° amines, and 2° amines in the presence of a reducing agent (NaBH 4 or H2/Ni).
• Reductive Amination

  Ketone or Aldehyde + NH3 -> Carbinolamine intermediate* -> Imine intermediate + H2/Ni or NaBH4 -> Primary Amine

  *with a by-product of H2O