Amines and Amino Acids Notes

Amines and its Reactions (Learning Guide 5.2)

Target

• Relate the structure of amines with their properties.
• Predict the products from a given set of starting materials in two general reactions of amines: alkylation, acylation, and Hoffman elimination; and vice-versa.

Amines

• Derivatives of ammonia.
• One or more of the hydrogens are replaced by an alkyl or aryl group.
• Nitrogen atom with a lone pair of electrons.
• Thus, both basic and nucleophilic.

Why Amines are Basic and Nucleophilic?

• The amino group (:N) attracts protons (in the form of H+) from acid.
• Can attack/attach to a carbocation.

Examples of Substances with Amines

• Trimethylamine: $\text{CH}<em>3\text{N(CH}</em>3)_2$
• Nicotine: $\text{C}<em>{10}\text{H}</em>{14}\text{N}_2$
• Cocaine: $\text{C}<em>{17}\text{H}</em>{21}\text{NO}_4$

Amines in Living Organisms

• Trimethylamine:
  • In animal tissues and partially responsible for the distinctive odor of fish.
• Nicotine:
  • Found in tobacco, the addictive component of cigarettes.
• Cocaine:
  • Stimulant found in the South American coca bush.
• Amino acids:
  • Building blocks of all proteins.
• Cyclic amine bases:
  • Component of nucleic acids
• Cadaverine (1,5-diaminopentane):
  • A poisonous, viscous liquid present in rotting flesh; produced during the decomposition of the amino acid lysine; partially responsible for the odor of urine and bad breath.
• Putrescine (1,4-diaminobutane):
  • A poisonous oil present in rotting flesh; produced during the decomposition of the amino acid arginine; also partially responsible for the odor of urine and bad breath.

Classifications of Amines

Degree of Substitution on the Nitrogen Center

• Ammonia: 0 carbons attached to the nitrogen.
• Primary (1°) amine: 1 carbon directly attached to the nitrogen (e.g., $\text{CH}<em>3\text{NH}</em>2$).
• Secondary (2°) amine: 2 carbons attached to the nitrogen (e.g., $\text{(CH}<em>3)</em>2\text{NH}$).
• Tertiary (3°) amine: 3 carbons attached to the nitrogen (e.g., $\text{(CH}<em>3)</em>3\text{N}$).
• Quaternary (4°) amine (ammonium): 4 carbons attached to the nitrogen (e.g., $\text{(CH}<em>3)</em>4\text{N}^+$).

Type of Substituent

• Alkyl-Substituted Amines:
  • Amines with alkyl groups attached to the nitrogen (e.g., trimethylamine, N-methylethylamine, tert-butylamine).
• Aryl-Substituted Amines:
  • Amines with aryl groups (benzene rings) attached to the nitrogen (e.g., aniline, diphenylamine, para-chloroaniline).
• Heterocyclic Amines:
  • Amines in which the nitrogen atom is part of a ring structure (e.g., piperidine, indole).

Smell of Amines

• Low MW amines exhibit sharp penetrating odors similar to ammonia.
• High MW amines smell like rotting fish and are found in decaying animal tissues (Cadaverine, Putrescine).

Properties of Amines

• Amines are gases for low molecular weight cases (e.g., trimethylamine) and many heavier ones are liquids at room temperature.
• Intermediate boiling points relative to alcohols and alkanes of similar molar mass.
• N-H bond(s) in 1° and 2° amines allow hydrogen-bonding, but N is not as electronegative as O, so N-H bond is not as polar as an O-H bond thus, has weaker H-bonding.
• Boiling point:
  • Increases with increasing chain length (molecular weight).
  • Decreases with increasing degree of N-substitution.
• The polar amino group is hindered with more substituents, meaning more nonpolar regions (London dispersion forces), which have low BPs/MPs.
• Higher melting points and boiling points are observed with less substituted amines (1°, 2°) due to their hydrogen-bonding capability.
• Solubility:
  • Increasing chain length, lower solubility.
  • The five-carbon rule: when less than five carbon atoms are present in the amine structure, the amine is generally water soluble.
  • Water-solubility decreases as:
    • chain length increases
    • the degree of N-substitution increases

Basicity of Amines

• Ammonia is a weak base; reacts with water molecules to produce OH- ions, resulting in a basic solution.
• Chemical reactivity of amines derives from the lone pair of electrons on the nitrogen atom, which gives the amine both basic (proton acceptor) and nucleophilic (electron pair donor) characteristics.
• In aqueous solution, amines accept hydrogen from water, forming a quaternary ammonium ion and hydroxide:
  • $\text{RNH}<em>2 + \text{H}</em>2\text{O} \rightleftharpoons \text{RNH}_3^+ + \text{OH}^-$
• The equilibrium expression for amine yielding the equilibrium constant Kb:
  • $K<em>b = \frac{[\text{RNH}</em>3^+][\text{OH}^-]}{[\text{RNH}_2]}$
  • $pK<em>b = -\log K</em>b$
• small Kb- weak base; large Kb- strong base
• The basicity of amines is measured in terms of the acidity of the ammonium ion:
  • $\text{RNH}<em>3^+ + \text{H}</em>2\text{O} \rightleftharpoons \text{RNH}<em>2 + \text{H}</em>3\text{O}^-$
  • $K<em>a = \frac{[\text{RNH}</em>2][\text{H}<em>3\text{O}^+]}{[\text{RNH}</em>3^+]}$
  • $pK<em>a = -\log K</em>a$
  • If Ka is small→ Kb is large → the base is strong
• $K<em>a \cdot K</em>b = [\text{H}<em>3\text{O}^+][\text{OH}^-] = K</em>w = 1.00 \times 10^{-14}$
• $pK<em>a + pK</em>b = 14$
• Primary, Secondary and Tertiary amines are more basic than ammonia, $\text{NH}_3$. Because alkyl groups donate electrons to the more electronegative nitrogen. The inductive effect makes the electron density on the alkylamine's nitrogen greater than the nitrogen of ammonium. Correspondingly, primary, secondary, and tertiary alkyl amines are more basic than ammonia.
• Alkyl amines are more basic than aryl amines because some electron density provided by the nitrogen atom is distributed throughout the aromatic system.

Summary of Basicity of Amines

• The physical and chemical properties of amines primarily stem from the substitution on the nitrogen center of the compound and on its lone pair of electrons.
• The lone pair of electrons on the nitrogen gives cause the basicity and nucleophilicity of amines. These characteristics are also augmented by the type of substituents connected to the amine.
• Electron donating groups like alkyl chains serve to increase both the nucleophilicity and basicity of amines.

Reactions of Amines (Learning Guide 5.2)

• Two common reactions:
  • $\text{S}_N2$ reactions with alkyl halides to form alkylamines
  • Nucleophilic acyl substitution to form amides.
• Alkylation via $\text{S}_N2$ → reaction with RX → forms more substituted alkylamines
  • Further, oxidation of the monoalkylated amine product forms mixture of products except for a 3° amine.
• Acylation of amines: nucleophilic acyl substitution → reaction with either acid chloride or acid anhydride → forms amides
  • N in the amide product does not undergo further acylation.
  • Unlike amines, amides are non-basic and are poor nucleophiles.
• Hoffman Elimination Reaction → amines into alkenes → amine is methylated ⇢ into 4 ammonium ($\text{NH}<em>4$ +) salt (good leaving group) → the ammonium salt is heated with a base ($\text{Ag}</em>2\text{O}$).
• Amide is resonance stabilized whereas an amine is not - in amides, the lone-pair of electrons on the N is delocalized.

Structure of Amino Acids and Levels of Protein Structure (Learning Guide 5.3)

Target

• Describe the structure of naturally occurring amino acids in terms of their stereochemistry.
• Explain how intermolecular forces and covalent bonding lead to the different levels of protein structure.

Proteins

• Proteins are large biomolecules or macromolecules that are composed of one or more long chains of amino acid residues.
  • Are polyamides.
  • Monomeric units are composed of about 20 different α-amino acids.

Amino Acids: The Building Blocks of Proteins

• General structure of amino acids:
  • Stereogenic carbon
  • With an unsubstituted amine
  • A carboxylic acid
  • A hydrogen
  • And a characteristic side chain (R).

Physical Properties of Amino Acids

1. Solubility: Most of the amino acids are usually soluble in water, and insoluble in organic solvents.
2. Melting Point: Amino acids generally melt at a higher temperature above 200°C.
3. Taste: Amino acids may be sweet (Gly, Ala & Val), tasteless (Leu) or Bitter (Arg & Ile).
4. Optical Properties: All amino acids possess optical isomers due to the presence of asymmetric α-carbon atoms.

Chemical Properties of Amino Acids

• Chemical reactions of amino acids due to carboxyl and amino groups:
  • Reaction due to carboxyl groups
  • Reaction due to amino groups
  • Reaction due to carboxyl and amino groups
• D- and L- notations
  • The configuration of the stereogenic α- carbon in amino acids is expressed through the D- and L- notations.
  • Naturally occurring amino acids exhibit the L- configuration and are referred to as L- amino acids.
• Amino acids, in their dry solid states, exist as zwitterions
  * carboxyl group is negatively charged ⇢ as carboxylate –COO-
  * amino group is positively charged ⇢ as ammonium –NH3 +
• isoelectric point, pI
  * pH at which the maximum concentration of the zwitterion occurs
  * average of the pKa values of α-COOH and α-NH3 + groups
  *20 amino acids
  * essential amino acids: Phenylalanine. Valine.
• The unsubstituted amine -NH2 and the carboxylic acid -COOH give the amino acid its basic and acidic properties, respectively
• Classification of amino acids
  * Acidic Amino Acids – These amino acids have an additional carboxylic acid group in their R side chain.
  * Basic Amino Acids – These amino acids have an additional amine group in their R side chain.
  * Neutral Amino Acids – These amino acids have neither additional carboxylic acids nor additional amine groups in their R side chain.

Levels of Protein Structure

• Primary:
  • Amino acid sequence.
• Secondary:
  • Alpha helix: the peptide chain twists into a right-handed or clockwise spiral.
  • Beta-pleated sheet: two or more peptide chain (strands) line up side-by-side.
• Tertiary:
  • The three-dimensional shape adopted by the entire peptide chain.
    • Folding ⇢ “conformation” maximize stability
    • In aqueous environment
      • Polar sites ⇢ outer surface
      • Maximize H-bonding with water
• Quaternary:
  • The shape adopted when two or more polypeptide chains aggregate into a protein complex.