(May 1) Amines and Amides Lecture Notes

Naming Amines and Ammonium Salts

• Naming charged amines (ammonium salts) can be tricky.

• Example: Treating an amine with $HCl$ results in a positively charged species with chloride as the counter ion.

• Butyl methylammonium chloride is formed by butyl and methyl groups bonded to a charged nitrogen (ammonium).

• The naming is derived from $NH<em>3$ (ammonia) and $NH</em>4^+$ (ammonium ion).

• The behavior of amines closely mimics ammonia, leading to the use of "ammonium" in naming charged amine salts.

• Examples:

  • $NH_4Cl$: Ammonium chloride.

  • $CH<em>3CH</em>2NH_3Cl$: Ethylammonium chloride (one hydrogen replaced by an ethyl group).

  • $(CH<em>3CH</em>2)<em>2NH</em>2Cl$: Diethylammonium chloride (two hydrogens replaced by ethyl groups).

  • $(CH<em>3CH</em>2)_3NHCl$: Triethylammonium chloride (three hydrogens replaced by ethyl groups).

  • $(CH<em>3CH</em>2)_4NCl$: Tetraethylammonium chloride (four hydrogens replaced by ethyl groups).

Physical Properties of Amines

• Comparison of boiling points: pentyl alcohol vs. pentylamine (1-pentanamine).

• Alcohols generally have higher boiling points than corresponding amines due to greater electronegativity of oxygen (3.5) compared to nitrogen (3.0).

• This results in larger partial negative and positive charges in alcohols, leading to stronger intermolecular forces.

• Amines are still capable of hydrogen bonding due to the electronegativity of nitrogen.

• Boiling point ranking (keeping sizes the same):

  1. Alkane (lowest).

  2. Amine (intermediate).

  3. Alcohol (highest).

• If an amine is treated with acid to form an ammonium salt, the boiling point becomes very high due to strong ionic interactions.

• Water solubility of pentylamine is higher than expected, despite being less polar than pentanol.

• Amines are mimics of ammonia, which is a base.

• When ammonia is placed in water, it forms ammonium and hydroxide ions (approximately 5% ionization at equilibrium).

• Amines behave similarly in water, forming ammonium ions.

• This ionization offsets the lower polarity of amines, enhancing their water solubility.

• Solubility Rule of Thumb

  • Marginally solubilize approximately 5 Carbons per Nitrogen.

  • Marginally solubilize approximately 2 Carbons per Oxygen.

• Solubility in water increases significantly upon treatment with acid, forming ionic salts.

• Ions have much higher boiling points and water solubility compared to neutral molecules.

Reactions of Amines

• Reaction with common acids (e.g., $HCl$) to form amine salts.

• Example: Aniline reacting with $HCl$ forms anilinium chloride.

• Nitrogen with four bonds carries a positive charge.

• Amines are weak bases (only a small percentage ionizes in water).

• Amine salts (ionized form) react with strong bases (e.g., hydroxide) to regenerate the free amine.
  $ArNH<em>3Cl + NaOH \rightarrow ArNH</em>2 + NaCl + H_2O$

• If drugs are in salt form to enhance water solubility, exposure to strong bases can cause them to precipitate out of solution, which can lead to health problems when administered intravenously.

Practical Applications of Amines

• Example: Cocaine as a starting point for local anesthetics.

• Cocaine-derived anesthetics (e.g., lidocaine, bupivacaine) share a structural base with cocaine: a benzene ring, an ester or amide linkage, a couple of carbons, and a nitrogen.

• Cocaine is clinically used to reduce blood flow during messy procedures due to its vasoconstrictive properties.

• Cocaine is used in the salt form, which prevents it from vaporizing.

• To "freebase" cocaine, it must be reacted with a base (e.g., ammonia, hydroxide) to remove the proton from the nitrogen.

Acetaminophen and Liver Toxicity

• Acetanilide (acetylation of aniline) is less toxic than aniline itself, and has analgesic and antipyretic properties.

• Acetaminophen (Tylenol) is derived from the core aniline structure.

• The CYP2E1 enzyme pathway converts acetaminophen into a reactive metabolite that is toxic to the liver.

• Glutathione (GSH) can deactivate this metabolite by reacting with it.

• Excessive alcohol consumption increases the levels of CYP2E1, leading to a larger fraction of acetaminophen being converted into the toxic metabolite.

Reaction with Carboxylic Acids

• At room temperature, mixing an amine with a carboxylic acid results in an acid-base reaction to form the salt, not an amide.

• To form an amide, high temperatures (250-300 °C) are needed.

• Heating causes two carboxylic acids to combine and release water, forming an acid anhydride. The amine can then attack the anhydride to form the amide, releasing the other acid

• Amino acids (examples: glycine, cysteine) form proteins via amide bonds (peptide bonds).

• In the body, amide bonds are formed by the transfer RNA which bring in a specific amino acid, and they keep an acid base reaction from screwing everything up.

• Transfer RNAs (tRNAs) bring in specific amino acids and prevent acid-base reactions from interfering with protein synthesis.