Chapter 26 (Amino Acids)

Question 1

Amino Acid

Answer 1

A compound possessing a terminal carboxylic acid (—COOH) group and a terminal amine (—NH₂) group.

The amine group (—NH₂) of amino acids is termed an amino group.

Question 2

α-Amino Acid

Answer 2

The most common type of amino acid found in nature that possesses the amino group on the α-Carbon.

The 20 most common α-amino acids have the (S)-configuration at the α-Carbon (except for Cysteine and Glycine).

Question 3

Configuration of Amino Acids

α-Carbon Configuration

Answer 3

(S)-Configuration

L-Configuration

• Cysteine = (R)-Configuration
• Glycine = Achiral

Question 4

Relative Configuration ⟶ Absolute Configuration

Answer 4

• D-Configuration ⟶ (R)-Configuration
• L-Configuration ⟶ (S)-Configuration

Question 5

Fischer Projection: L-Amino Acids

(S)-Amino Acids

Answer 5

• Top: Carboxylic Acid Group (—COOH)
• Bottom: R Group (—R)
• Left: Amino Group (—NH₂)
• Right: Hydrogen (—H)

Wedges are assigned to the horizontal substitutents of the Fischer projections (i.e. the amino group and the Hydrogen).

Question 6

Fischer Projection: D-Amino Acids

(R)-Amino Acids

Answer 6

• Top: Carboxylic Acid Group (—COOH)
• Bottom: R Group (—R)
• Left: Hydrogen (—H)
• Right: Amino Group (—NH₂)

Wedges are assigned to the horizontal substitutents of the Fischer projections (i.e. the amino group and the Hydrogen).

Question 7

Amino Acid State: Neutral Conditions

Answer 7

Zwitterionic Form: The amino group is protonated to form an ammonium group (—NH₃⁺) and the carboxylic acid group is deprotonated to form a carboxylate group (—CO_2^–).

The Zwitterionic form of amino acids is the most stable state within neutral conditions.

Question 8

Amino Acid State: Strongly Acidic Conditions

pH < 2

Answer 8

α-Ammonium Carboxylic Acid: The amino group is protonated to form an ammonium group (—NH₃⁺) and the carboxylic acid group remains protonated to form a carboxylic acid (—CO_2H).

pK_a of α-Carboxylic Acid ≈ 2: The carboxylic acid group remains protonated under strongly acidic conditions.

Question 9

Strongly Acidic Conditions

Answer 9

pH < 2

α-Ammonium Carboxylic Acid

Question 10

Basic Conditions

Answer 10

pH > 10

α-Amino Carboxylate

Question 11

Amino Acid State: Basic Conditions

pH > 10

Answer 11

α-Amino Carboxylate: The amino group remains deprotonated to form an amine group (—NH₂) and the carboxylic acid group is deprotonated to form a carboxylate (—CO_2^–).

pK_a of Ammonium ≈ 9–10: The amino group remains deprotonated under basic conditions.

Question 12

pK_a: α-Carboxylic Acid

Amino Acids

Answer 12

pK_a ≈ 2

The pK_a of α-Carboxylic Acids (of amino acids) is lower than typical carboxylic acids (pK_a ≈ 4) due to the ammonium-facilitated stabilization of the α-Amino Acid’s conjugate base.

Question 13

Why are α-Carboxylic Acids more acidic than typical carboxylic acids?

α-Carboxylic Acid = Amino Acid Carboxylic Acid

Answer 13

The electron-withdrawing character of the α-ammonium (—NH₃⁺) substituent stabilizes the negative charge on the amino acid’s conjugate base.

The positive charge on the α-ammonium substituent allows it to delocalize the carboxylate group’s negative charge.

Question 14

Amino Acid Synthesis

Answer 14

1. Aldehyde Reaction w/ NH₃ + HCN
2. Acidic/Basic Nitrile Hydrolysis

Question 15

Aldehyde ⟶ Amino Acid

Answer 15

Amino Acid Synthesis

The Amino Acid Synthesis mechanism yields a racemic mixture of both amino acid enantiomers (since the aldehyde starting reagent is achiral).

Question 16

Reagents: Amino Acid Synthesis

Starting Material = Aldehyde

Answer 16

1. NH₃, HCN
2. H₂SO₄, H₂O, Δ

Question 17

Simple Mechanism: Amino Acid Synthesis

Answer 17

1. NH₃ adds to the aldehyde’s carbonyl Carbon to yield an imine.
2. HCN protonates the imine’s Nitrogen to yield an iminium cation.
3. CN^{– adds to the iminium’s central Carbon to yield a tetrahedral Aminonitrile intermediate.}
4. Nitrile Hydrolysis yields an amino acid (by replacing the cyanide group with a carboxylate group and protonating the amino group).

Question 18

Peptide Bond

Answer 18

The amide bond that connects connects one amino acid’s carboxylic acid group to another amino acid’s amino group.

The peptide bond is a C_Carbonyl—N bond that is planar, relatively short, and resistant to rotation.

Question 19

Peptide Bond: Characteristics

C_Carbonyl—N

Answer 19

• Planar: Conjugation between the Nitrogen lone-pair and the carbonyl π electrons.
• Short: Strong conjugation across the amide group due to the readily donatable Nitrogen lone-pair electrons.
• High Barrier to Rotation: Strong conjugation across the amide group that requires large activation energy to overcome.

Question 20

Most Stable Configuration of (Di)Peptides

Answer 20

Trans Configuration

The trans configuration places the α-Carbons of adjacent amino acids on opposite sides of the peptide bond, which minimizes steric repulsion.

Question 21

Instability of Cis Configuration Peptides

Answer 21

The cis configuration creates steric strain/repulsion between the α-Carbons of adjacent amino acids (by placing these Carbons on the same side of the peptide bond).

Question 22

N–Terminus

Answer 22

The end of the peptide chain that contains the amino group (—NH₂).

Question 23

C–Terminus

Answer 23

The end of the peptide chain that contains the carboxylic acid group (—CO₂H).

Question 24

Naming of Peptides

Answer 24

The naming of peptides always begins from the N–terminus and ends at the C–terminus.

N’ ⟶ C’

Question 25

Amino Acid ⟶ Peptide

Answer 25

Peptide Synthesis

Question 26

Reagents: Peptide Synthesis

Answer 26

1. Boc₂O, N(Et)₃ (Amino Group Protection)
2. Benzyl Chloride (Carboxylic Acid Protection)
3. DCC (Peptide Bond Formation)
4. H₂SO₄, H₂O (Boc Deprotection)
5. H₂, Pd-C (Benzylic Deprotection)

Question 27

Mechanism: Peptide Synthesis

Answer 27

1. Boc₂O reacts with the amino group (of one amino acid) in the presence of N(Et)₃ to yield a Boc-protected amino group.
2. Benzyl Chloride adds to the carboxylate group (of another amino acid) via SN2 attack to yield a Benzyl-protected carboxylic acid group.
3. The Boc-protected amino acid and Benzyl-protected amino acid react together in the presence of DCC to create a peptide bond.
4. The terminal-protected peptide undergoes acid-catalyzed hydrolysis to remove the Boc protecting group.
5. The Benzyl-protected peptide undergoes hydrogenolysis to remove the Benzylic protecting group (and produce the unprotected peptide).

Question 28

Boc₂O

Answer 28

Di-tert-Butyl Dicarbonate

Question 29

DCC

Answer 29

N, N′-Dicyclohexylcarbodiimide

DCC is used to promote amide formation (between two individual amino acids) under mild conditions.

Question 30

Boc–Protection

N–Protection

Answer 30

The “protection” of an amino acid’s —NH₂ group that results in the formation of an amide bond involving the amino group’s Nitrogen.

The Boc–deprotection process involves acid-catalyzed hydrolysis of the O_Boc—N amide bond.

Question 31

Benzylic Protection

O–Protection

Answer 31

The “protection” of an amino acid’s —COOH group that results in the formation of an ether bond involving the carboxylic acid group’s hydroxyl Oxygen.

The Benzylic deprotection process involves hydrogenolysis of the C_Benzylic—O bond (at room temperature).

Question 32

Conditions: Peptide Synthesis

Answer 32

Mild Conditions

Strongs acids/bases and high temperatures must be avoided during peptide synthesis reactions.

Question 33

Why does acid-catalyzed hydrolysis of the Boc-protected peptide only occur at the O_Boc—N amide bond (and not the amidic peptide bond)?

Answer 33

The O_Boc—N amide bond is more reactive (than the amidic peptide bond) due to the electron-donating character of the Boc Oxygen_Ester. As a result, the Boc Oxygen_Carbonyl is more readily protonated than a typical amidic Oxygen_Carbonyl.

Because the Boc Oxygen_Carbonyl is more readily protonated, it will be preferentially (over the amidic peptide Oxygen_Carbonyl) “activated” and undergo hydrolysis via nucleophilic H₂O.