Kaplan MCAT Organic Chemistry Review

1. Master IUPAC nomenclature and functional group priority to decode MCAT questions

The highest-priority functional group (with the most oxidized carbon) will provide the suffix.

Oxidation dictates priority. The IUPAC system establishes an unambiguous relationship between a molecule's name and its structure. Priority is determined by the oxidation state of the carbon, meaning that more oxidized carbons (those with more bonds to heteroatoms like oxygen, nitrogen, or halogens) take precedence.

Systematic naming steps. To name any compound, you must follow a strict five-step protocol. This ensures that no two distinct compounds share the same name:

• Identify the longest carbon chain containing the highest-priority functional group.
• Number the chain starting closest to the highest-priority group.
• Name and number the substituents alphabetically.
• Assemble the full name, separating numbers with commas and words with hyphens.

Common names matter. The MCAT frequently uses common names alongside IUPAC names, requiring pre-meds to recognize both. For instance, methanal is formaldehyde, ethanal is acetaldehyde, and ethanoic acid is acetic acid.

2. Differentiate spatial isomers to predict optical activity and molecular behavior

Isomers have the same molecular formula, but different structures.

Structural versus spatial. Isomers are divided into structural (constitutional) isomers, which share only a molecular formula, and stereoisomers, which share atomic connectivity but differ in spatial arrangement. Stereoisomers are further split into conformational isomers (differing by simple rotation about a single bond) and configurational isomers (requiring bond breakage to interconvert).

Chirality and optical activity. Chiral molecules lack an internal plane of symmetry and have non-superimposable mirror images. These molecules rotate plane-polarized light, a property known as optical activity:

• Enantiomers: Nonsuperimposable mirror images with opposite configurations at every chiral center.
• Diastereomers: Non-mirror-image stereoisomers that differ at some, but not all, chiral centers.
• Meso compounds: Molecules with chiral centers and an internal plane of symmetry, rendering them optically inactive.

Absolute configuration rules. The Cahn-Ingold-Prelog priority rules assign (R) or (S) designations to chiral centers. By orienting the lowest-priority group to the back, a clockwise circle from highest to lowest priority indicates (R), while a counterclockwise circle indicates (S).

3. Understand orbital hybridization and resonance to evaluate molecular geometry and stability

Hybridization is a way of making all of the bonds to a central atom equivalent to each other.

Orbital mixing shapes molecules. Carbon's tetravalency is explained by orbital hybridization, where s and p atomic orbitals merge to form equivalent hybrid orbitals. The type of hybridization determines the spatial geometry and bond angles of the carbon atom.

Hybridization states compared. The three primary hybridization states of carbon dictate its bonding capabilities:

• sp3: 25% s character, tetrahedral geometry, 109.5° bond angles, found in alkanes.
• sp2: 33% s character, trigonal planar geometry, 120° bond angles, found in alkenes.
• sp: 50% s character, linear geometry, 180° bond angles, found in alkynes.

Resonance stabilizes charge. Conjugation occurs when single and multiple bonds alternate, aligning unhybridized p-orbitals. This allows π electrons to delocalize across the system, creating a resonance hybrid that is more stable than any individual contributing structure.

4. Analyze reaction mechanisms through the lens of nucleophiles, electrophiles, and leaving groups

Almost all reactions in organic chemistry can be divided into one of two groups: oxidation−reduction reactions or nucleophile−electrophile reactions.

Opposites attract molecularly. Nucleophile-electrophile reactions are driven by electrostatic attractions between electron-rich and electron-poor species. Nucleophiles ("nucleus-loving") possess lone pairs or π bonds, while electrophiles ("electron-loving") carry a positive charge or positive polarization.

Key reactivity determinants. Several physical properties dictate how effectively these species interact during a chemical reaction:

• Charge: More negative charge increases nucleophilicity.
• Electronegativity: Highly electronegative atoms are worse nucleophiles because they resist sharing electrons.
• Steric hindrance: Bulkier molecules are less nucleophilic due to physical crowding.
• Solvent: Protic solvents can hinder nucleophiles by protonating them.

Leaving group stability. Leaving groups are molecular fragments that retain electrons after bond cleavage. The best leaving groups are weak bases (the conjugate bases of strong acids) because they can stably hold the negative charge.

5. Contrast SN1 and SN2 mechanisms to predict substitution kinetics and stereochemistry

In both SN1 and SN2 reactions, a nucleophile forms a bond with a substrate carbon and a leaving group leaves.

Unimolecular versus bimolecular. Nucleophilic substitution occurs via two distinct pathways: SN1 and SN2. The SN1 pathway is a two-step process where the leaving group departs first to form a carbocation intermediate, whereas the SN2 pathway is a concerted, single-step backside attack.

Kinetics and substrates. The structural preferences and rate laws of these two mechanisms are completely opposed:

• SN1: Prefers highly substituted carbons (tertiary > secondary) to stabilize the carbocation; rate depends only on substrate concentration.
• SN2: Prefers methyl or primary carbons to minimize steric hindrance; rate depends on both substrate and nucleophile concentrations.

Stereochemical outcomes. Because the SN1 intermediate is a planar carbocation, the nucleophile can attack from either side, yielding a racemic mixture. Conversely, the SN2 backside attack forces an inversion of relative configuration, making it a stereospecific reaction.

6. Evaluate oxidation-reduction states to track electron flow in organic and biological systems

In organic chemistry, it is often easier to view oxidation as increasing the number of bonds to oxygen or other heteroatoms (atoms besides carbon and hydrogen).

Tracking carbon oxidation. Oxidation states in organic chemistry are determined by the heteroatoms bonded to carbon. Oxidation involves increasing bonds to oxygen, nitrogen, or halogens, while reduction involves increasing bonds to hydrogen.

Reagent strengths compared. Different oxidizing and reducing agents achieve varying levels of carbon oxidation or reduction:

• PCC: A mild anhydrous oxidant that stops at the aldehyde stage for primary alcohols.
• Dichromate/CrO3: Strong oxidants that convert primary alcohols fully to carboxylic acids.
• LiAlH4: A strong reducing agent capable of reducing carboxylic acids, esters, and amides to alcohols or amines.
• NaBH4: A mild reducing agent that can reduce aldehydes and ketones but not carboxylic acids.

Biological redox carriers. In biochemistry, these same redox principles govern metabolic pathways. Molecules like ubiquinone (coenzyme Q) utilize conjugated rings to undergo reversible reduction to ubiquinol, facilitating electron transport.

7. Leverage carbonyl chemistry and enolate intermediates for carbon-carbon bond formation

The carbonyl group is one of the most common functional groups in organic chemistry for two reasons.

Carbonyl dipole reactivity. The polarization of the C=O bond makes the carbonyl carbon highly electrophilic. When a nucleophile attacks, it breaks the π bond, pushing electrons onto the oxygen and forming a tetrahedral intermediate.

Enolate carbanion formation. The α-hydrogens of aldehydes and ketones are exceptionally acidic due to resonance stabilization of the resulting enolate. This deprotonation creates a powerful nucleophile:

• Kinetic enolate: Formed rapidly, less stable, favored at low temperatures with strong, bulky bases.
• Thermodynamic enolate: Formed slowly, more stable, favored at high temperatures with weak, small bases.

The aldol condensation. In an aldol condensation, an enolate nucleophile attacks a keto electrophile to form a carbon-carbon bond. Subsequent dehydration eliminates water, yielding an α,β-unsaturated carbonyl.

8. Predict the reactivity of carboxylic acids and their derivatives using electronic and steric effects

Regardless of the carboxylic acid derivative at hand, there are some rules that govern the reactivity of these molecules.

Nucleophilic acyl substitution. Carboxylic acids and their derivatives undergo nucleophilic acyl substitution rather than addition. Because these molecules contain a leaving group, the tetrahedral intermediate can collapse to reform the carbonyl, expelling the leaving group.

Derivative reactivity hierarchy. The reactivity of carboxylic acid derivatives toward nucleophilic attack follows a strict thermodynamic hierarchy:

• Anhydrides: Most reactive due to induction from three electronegative oxygens and resonance.
• Esters/Carboxylic Acids: Moderately reactive, lacking one carbonyl oxygen.
• Amides: Least reactive due to the electron-donating amino group.

Steric and strain effects. Steric hindrance can shield carbonyl carbons from nucleophilic attack, a property exploited by protecting groups. Conversely, ring strain in cyclic derivatives like β-lactams dramatically increases reactivity, making them highly susceptible to hydrolysis.

9. Utilize laboratory synthesis pathways to construct chiral amino acids

In the lab, several simple reaction mechanisms are exploited to make amino acids neatly and efficiently.

Strecker synthesis mechanism. The Strecker synthesis is a classic two-step laboratory method to generate amino acids from an aldehyde. It begins with the condensation of an aldehyde with ammonium chloride to form an imine, which is then attacked by cyanide to yield an aminonitrile.

Gabriel synthesis mechanism. The Gabriel synthesis is an alternative pathway that avoids over-alkylation by using a bulky nucleophile. It relies on a series of coordinated steps:

• An SN2 reaction where potassium phthalimide attacks diethyl bromomalonate.
• A second SN2 reaction to introduce the amino acid's specific R group via an alkyl halide.
• Hydrolysis of the esters and phthalimide group using a strong base.
• Decarboxylation of the resulting dicarboxylic acid with heat and acid.

Stereochemical stereorandomness. Both the Strecker and Gabriel syntheses utilize planar starting materials (aldehydes and malonic esters). Because the nucleophilic attacks can occur from either side with equal probability, both methods produce a racemic mixture of L- and D-amino acids.

10. Apply spectroscopy and separation techniques to identify and purify organic compounds

Different types of spectroscopy measure different types of molecular properties, allowing us to identify the presence of specific functional groups and to detect the connectivity (backbone) of a molecule.

Spectroscopic identification. Spectroscopy uses electromagnetic radiation to probe molecular structures. Infrared (IR) spectroscopy identifies functional groups by measuring bond vibrations, while Proton NMR (1H-NMR) determines the carbon-hydrogen backbone and chemical environments.

Key spectroscopic signatures. Memorizing specific spectroscopic peaks is essential for rapid molecular identification on the MCAT:

• IR O-H peak: Broad peak around 3300 cm−1 (3000 cm−1 for carboxylic acids).
• IR C=O peak: Sharp peak around 1750 cm−1.
• NMR Aldehyde: Peak downfield at 9 to 10 ppm.
• NMR Carboxylic Acid: Peak downfield at 10.5 to 12 ppm.

Separation and purification. Once identified, compounds are isolated using physical properties. Extraction separates compounds by solubility, distillation separates miscible liquids by boiling point, and chromatography (TLC, column, GC, HPLC) separates mixtures based on their differential affinity for a stationary versus a mobile phase.