Amino Acids - MCAT Organic Chemistry

Amino Acids

Updated Apr 17, 2026

Amino acids are the building blocks of proteins. Each has an alpha-carbon with four attachments: a hydrogen, an amine group (-NH₂), a carboxylic acid (-COOH), and a variable side chain (-R). At physiological pH, the amine is protonated and the carboxylic acid is deprotonated, giving the characteristic zwitterionic form.

Amino acid zwitterion showing protonated amine (NH3+) and deprotonated carboxylate (COO-) at physiological pH — The zwitterionic form of an amino acid at physiological pH: alpha-amine protonated (NH₃⁺), alpha-carboxylate deprotonated (COO⁻). Net charge is zero despite both groups being ionized. *Credit: Wikimedia Commons, CC BY-SA*

General Structure

H₂N-CHR-COOH (neutral form, theoretical)

⁺H₃N-CHR-COO⁻ (zwitterion, actual form at pH 7.4)

The alpha-carbon is chiral (except in glycine, where R = H). All 20 proteinogenic amino acids in proteins are in the L configuration (S absolute configuration for all except cysteine, where the CIP priority of the sulfur flips the label to R).

Key pKa Values

Simple (non-ionizable side chain) amino acid:

alpha-COOH: pKa ~2 (lowered from 4-5 by the adjacent protonated amine’s inductive pull).
alpha-NH₃⁺: pKa ~9 (lowered from ~10 of a simple amine by the adjacent negative carboxylate’s inductive pull).

At pH 7.4, both groups are fully ionized (COOH deprotonated, NH₃ protonated) → zwitterion.

Isoelectric Point (pI)

The isoelectric point is the pH at which the amino acid has net zero charge on average. For simple amino acids:

pI = (pKa₁ + pKa₂) / 2

For glycine: pI = (2.35 + 9.78) / 2 = 6.06.

For amino acids with ionizable side chains (e.g., lysine, aspartate), pI is calculated by averaging the two pKa values bracketing the zwitterionic form.

Titration Curve

A plot of pH vs. equivalents of base added shows three regions:

Below pKa₁ (~2): COOH is protonated; molecule is NH₃⁺-COOH (net +1 charge).
Between pKa₁ and pKa₂: zwitterion dominates (NH₃⁺-COO⁻, net zero).
Above pKa₂ (~9): NH₂ is deprotonated; molecule is NH₂-COO⁻ (net -1 charge).

Each pKa corresponds to an inflection point on the titration curve, and the midpoint between them is the pI.

Titration curves for the 20 amino acids organized by side chain, showing characteristic buffering regions at each pKa — Titration curves for all 20 amino acids grouped by side chain type. The flat "buffering" plateaus correspond to pKa values; steep vertical segments are the equivalence points. Amino acids with ionizable side chains show a third plateau/buffer region around their side chain pKa. *Credit: Wikimedia Commons, CC BY-SA*

Strecker Synthesis of Amino Acids

Starting materials: an aldehyde, NH₃, and HCN.

Aldehyde + NH₃ → imine (R-CH=NH).
Imine + HCN → aminonitrile (R-CH(NH₂)-CN).
Acid hydrolysis of nitrile → carboxylic acid: R-CH(NH₂)-COOH.

Net: RCHO + NH₃ + HCN + H₂O (acid) → alpha-amino acid.

Named after the 19th-century chemist Adolph Strecker. On the AAMC content outline.

Strecker synthesis of an alpha-amino acid from an aldehyde, ammonia, and HCN via imine and aminonitrile intermediates — Strecker synthesis: aldehyde + NH₃ → imine; imine + HCN → alpha-aminonitrile; acid hydrolysis of the nitrile → alpha-amino acid. A classical route to racemic amino acids from simple starting materials. *Credit: Wikimedia Commons, CC BY-SA*

Gabriel Synthesis of Primary Amines (and by extension, amino acids)

Problem with direct alkylation of ammonia: over-alkylation (product mixture of 1°, 2°, 3° amines). Gabriel synthesis solves this using potassium phthalimide.

Potassium phthalimide (a “masked” ammonia where the nitrogen is flanked by two carbonyls, preventing further alkylation) + R-X → N-alkyl phthalimide.
Hydrolysis with hydrazine (N₂H₄) or strong acid/base → primary amine + phthalhydrazide (or phthalic acid).

For amino acid synthesis: use an alkyl halide with a pre-installed -COOH (like diethyl alpha-bromomalonate). Phthalimide displaces Br, giving an N-alkyl phthalimide with the ester. Hydrolysis gives the amino acid with clean 1° amine.

D and L Amino Acids

Naturally occurring amino acids are almost exclusively L-amino acids (S configuration at alpha-C for 19 of 20; R for cysteine). D-amino acids appear in bacterial cell walls (peptidoglycan) and a few natural products.

The strict L-selectivity of biology is enforced by aminoacyl-tRNA synthetases, which only accept L-amino acids for protein synthesis. Racemized (D) amino acids cannot be incorporated into standard proteins.

At pH 1, pH 7, and pH 12, what are the ionization states and net charges of glycine (alpha-COOH pKa 2.35, alpha-NH₃⁺ pKa 9.78)?

Click to reveal answer

At pH 1: NH₃⁺-CH₂-COOH (COOH protonated below its pKa, NH₃⁺ protonated far below its pKa). Net charge: +1. At pH 7: NH₃⁺-CH₂-COO⁻ (zwitterion - COOH deprotonated, NH₃⁺ still protonated). Net charge: 0. At pH 12: NH₂-CH₂-COO⁻ (above both pKas - NH₃⁺ deprotonated to NH₂, COO⁻ is still deprotonated). Net charge: -1.