Difficulty: Introductory to Intermediate | Prerequisites: General chemistry (Lewis structures, electronegativity, acid-base equilibria)
Chapters 1-7 lay the groundwork for everything else in organic chemistry. Physical properties tell you how molecules behave in the lab (what boils when, what dissolves in what). Acid-base chemistry governs proton transfers and determines ionisation states. Stereochemistry tells you about the 3D arrangement of atoms, which matters for biological activity and reaction outcomes. Conformational analysis explains why certain molecular shapes are more stable than others.
These concepts reappear constantly. When you predict an SN2 product's stereochemistry, you are using Ch. 5. When you run an acid-base extraction in the lab, you are using Ch. 2-3. When you assess ring strain or steric interactions, you are using Ch. 4.
Boiling points depend on intermolecular forces (hydrogen bonding > dipole-dipole > London dispersion). Water solubility depends on polarity and the ability to hydrogen-bond. Acid-base chemistry and pKa determine ionisation states at a given pH, which controls solubility and separation behaviour. Stereochemistry (R/S, enantiomers, diastereomers) determines biological activity and reaction outcomes. Conformational analysis of cyclohexanes and open-chain molecules predicts which shape is lowest in energy.
Functional group
A specific grouping of atoms within a molecule that determines its chemical reactivity. Examples: alcohol (OH), alkene (C=C), ketone (C=O), alkyl halide (C-X), amine (NH₂). In simple terms, the functional group is the reactive part of the molecule.
Polar bond
A covalent bond between atoms of different electronegativity, creating a partial positive charge (δ+) on the less electronegative atom and a partial negative charge (δ-) on the more electronegative atom. Common polar bonds: C-O, C-F, C-Cl, O-H, N-H.
Electronegativity
An atom's ability to attract bonding electrons. Increases across a period (left to right) and up a group. F (4.0) > O (3.5) > N, Cl > C (2.5) > H (2.1).
Stereocentre (chiral centre)
A carbon bonded to four different groups. This carbon has a non-superimposable mirror image, making the molecule chiral. In simple terms, if all four groups are different, the carbon is a stereocentre.
Enantiomers
Non-superimposable mirror images of each other. They have identical physical properties except for the direction they rotate plane-polarised light (+ or -).
Diastereomers
Stereoisomers that are not mirror images. They have different physical properties (different melting points, boiling points, solubilities).
R/S configuration
The Cahn-Ingold-Prelog system for assigning absolute configuration at a stereocentre. Assign priority to the four groups (by atomic number), orient the lowest priority group away from you, and trace the remaining three from highest to lowest: clockwise = R, anticlockwise = S.
Optical rotation
The ability of a chiral compound to rotate plane-polarised light. Dextrorotatory (+) rotates clockwise, levorotatory (-) rotates anticlockwise. There is no reliable way to predict the sign of rotation from the R/S designation without experimental data.
pKa
The negative log of the acid dissociation constant. A lower pKa means a stronger acid. For an amine, the pKa value given is typically for the conjugate ammonium ion (e.g. RNH₃⁺ has pKa ~9-10).
Newman projection
A way of viewing a molecule along a C-C bond axis. Used to analyse steric interactions and torsional strain between substituents on adjacent carbons.
Boiling point
Depends on intermolecular forces. Stronger forces mean higher boiling points.
Hydrogen bonding (O-H, N-H) > dipole-dipole > London dispersion forces.
Among molecules of similar molecular weight, an alcohol (has O-H, can hydrogen-bond) will have a higher boiling point than an ether (dipole-dipole only) or an alkane (London dispersion only).
Among molecules with similar functional groups, higher molecular weight generally means a higher boiling point (more surface area, stronger London dispersion forces).
Branching lowers boiling point by reducing surface area and weakening London dispersion forces.
Water solubility
"Like dissolves like" is the principle, but the exam expects more than that phrase.
Water-soluble molecules can form hydrogen bonds with water. Small alcohols, amines, and carboxylic acids are water-soluble.
As the hydrocarbon portion of a molecule grows, water solubility decreases. Roughly, molecules with more than 5-6 carbons per polar group become insoluble in water.
Charged species (ions) are generally water-soluble. This is why ionisation state matters for solubility: a charged form of a compound is more water-soluble than its neutral form.
Exam application
Given three or four structures, identify which has the highest and lowest boiling point by comparing functional groups, molecular weight, and branching.
Given structures, identify highest and lowest water solubility by comparing polarity, hydrogen-bonding ability, and the ratio of polar groups to hydrocarbon bulk.
Determining ionisation state at a given pH
If pH < pKa, the protonated (acidic) form predominates.
If pH > pKa, the deprotonated (basic/conjugate base) form predominates.
For a phenol with pKa = 10 at pH 6: pH < pKa, so the phenol is in its neutral (protonated, OH) form.
For an amine with pKa = 9 (this is the pKa of the conjugate ammonium ion, RNH₃⁺) at pH 6: pH < pKa, so the ammonium form (RNH₃⁺) predominates. The amine is protonated and positively charged.
Solubility consequences
At pH 6, a phenol (pKa 10) is neutral and relatively nonpolar. An amine (pKa 9 for its conjugate acid) is protonated to RNH₃⁺, making it charged and water-soluble.
The charged ammonium form of the amine would be expected to be water-soluble because ions interact strongly with water through ion-dipole interactions.
Acid-base extraction
This technique separates compounds by exploiting differences in ionisation state at different pH values.
At pH 12 (strongly basic): a phenol (pKa 10) is deprotonated to its phenoxide form (ArO⁻), making it charged and water-soluble. An amine (pKa 9 for the ammonium ion) is in its neutral free-base form (RNH₂), making it uncharged and more soluble in organic solvents.
In a separatory funnel with hexane and water at pH 12: the phenoxide (charged) dissolves in the water layer, and the free-base amine (uncharged) dissolves in the hexane layer. They are in different layers.
Functional groups in complex molecules
The exam asks you to identify functional groups in steroids and other complex structures. Look for: alcohols (OH), ketones (C=O in a chain/ring), alkenes (C=C), alkyl halides (C-F, C-Cl, C-Br), and amines.
Fluoxymesterone (from the exam) contains: alcohol, ketone, alkene, and alkyl fluoride, alongside the alkane framework.
Polar bonds
A bond is polar when the electronegativity difference between the two atoms is significant (roughly > 0.4).
Given electronegativity values C = 2.5, H = 2.1, O = 3.5, F = 4.0: C-F bonds are the most polar, followed by C-O and O-H bonds. C-H bonds are weakly polar. C-C bonds are nonpolar.
R/S assignment
Assign priorities to the four groups on a stereocentre using Cahn-Ingold-Prelog rules (highest atomic number = highest priority).
Orient the molecule so the lowest-priority group points away from you.
Trace a path from highest to second to third priority: clockwise = R, anticlockwise = S.
Stereoisomer counting
Maximum number of stereoisomers = 2ⁿ, where n = number of stereocentres.
Fluoxymesterone (from the exam) has 7 stereocentres, giving a maximum of 2⁷ = 128 stereoisomers (including the one drawn).
Meso compounds (internal planes of symmetry) reduce the count, but for most complex molecules like steroids, 2ⁿ is the answer.
Stereochemical correlation
Used to determine absolute configuration of a compound by relating it to a compound of known configuration.
If a reaction does not break a bond at the stereocentre (e.g. catalytic hydrogenation of a distant double bond), the configuration at that centre is retained.
If a reaction inverts the configuration (e.g. SN2), the product has the opposite R/S at that centre.
Example from the exam: a chloroalkene with measured rotation (+) and known R = (+). Hydrogenation (H₂/Pd) reduces the double bond without touching the stereocentre. The product retains the same configuration. If the starting material is R and (+), the product is also R and (+).
Another example: a bromoalkane with measured rotation (+) undergoes SN2 with NaOH to give an alcohol with measured rotation (-) and known S = (-). Since SN2 inverts configuration, the starting bromide must have had the opposite configuration at that centre. The alcohol is S, so the bromide was R.
Optical rotation
The sign of optical rotation (+ or -) cannot be predicted from R/S configuration. It must be measured experimentally or looked up.
A racemic mixture (50:50 R and S) has zero optical rotation.
The exam provides literature data correlating R/S with + or - for one compound, and asks you to deduce the R/S of the other compound using the reaction mechanism (retention or inversion).
Newman projections and steric strain
Staggered conformations are more stable than eclipsed conformations.
Anti conformations (largest groups 180° apart) are generally the most stable.
Gauche interactions (large groups 60° apart) are destabilising but less so than eclipsed.
Cyclohexane conformations
Substituents prefer equatorial positions to avoid 1,3-diaxial interactions.
Larger substituents have a stronger equatorial preference.
When two substituents are present, the more stable chair places the larger group equatorial. If both cannot be equatorial, the conformation where the largest group is equatorial wins.
Example from the exam: comparing two Newman projections of a disubstituted compound. The more stable conformer has the larger groups anti to each other, minimising steric interactions.
Ring strain
Cyclopropane (3-membered ring) has significant angle strain (bond angles forced to 60° instead of the ideal 109.5° for sp³ carbon) and torsional strain (all C-H bonds are eclipsed).
Cyclobutane (4-membered ring) has less angle strain but still substantial.
Cyclopentane has minimal angle strain but some torsional strain.
Cyclohexane (6-membered ring) in its chair conformation has no angle strain and minimal torsional strain, making it the most stable common ring size.
Example from the exam: cyclopropane is less stable than cyclobutane due to greater angle strain. Both are less stable than cyclohexane.
Stability of alkene isomers
More substituted alkenes are more stable (hyperconjugation stabilises the double bond).
Trans alkenes are generally more stable than cis alkenes (less steric strain between groups on the same side).
Example from the exam: comparing two methylcyclohexane isomers with different positioning of a methyl group. The isomer with the methyl in the equatorial position is more stable.
Students often state "like dissolves like" as an explanation for water solubility. The exam explicitly says this is not sufficient. You must explain the specific intermolecular interactions (hydrogen bonding, ion-dipole interactions for charged species) that make a compound water-soluble.
Students confuse the pKa of an amine with the pKa of its conjugate acid. When you see "pKa = 9 for an amine," that is the pKa of the protonated ammonium form (RNH₃⁺). At pH below 9, the amine is protonated (charged).
Students assume R = (+) and S = (-). There is no general correlation. The sign of optical rotation must be determined experimentally.
Students sometimes think that all reactions at a stereocentre invert the configuration. Only SN2 inverts. Reactions that do not break a bond at the stereocentre (such as hydrogenation of a distant double bond) retain configuration.
⚠️ The ionisation-state / acid-base extraction question is a multi-part problem that builds on itself. If you get the ionisation state wrong in part (a), the rest falls apart.
⚠️ Functional group identification in complex molecules (steroids) is straightforward points if you know your groups. Do not overlook alkyl fluoride or alkene within a ring.
⚠️ Stereochemical correlation requires you to reason through whether the reaction retains or inverts configuration, and then work backwards to assign R/S. Draw out the stereochemistry with wedges and dashes.
⚠️ Conformational analysis questions ask "which is more stable" and require a brief explanation. The answer is almost always about minimising steric strain (1,3-diaxial interactions, gauche interactions, or eclipsing).
True or False: A molecule with two stereocentres always has exactly 4 stereoisomers.
Fill in the blank: At pH 6, an amine with a conjugate acid pKa of 9 is in its ______ (protonated/deprotonated) form.
True or False: Branching increases boiling point.
Fill in the blank: The maximum number of stereoisomers for a molecule with n stereocentres is ______.
True or False: In a cyclohexane chair, a substituent in the axial position experiences more steric strain than one in the equatorial position.
Answers: 1. False (it can be fewer if the molecule has a meso form). 2. Protonated (pH < pKa). 3. False (branching decreases boiling point). 4. 2ⁿ. 5. True.
Q: A phenol (pKa = 10) and an amine (conjugate acid pKa = 9) are at pH 6. What is the ionisation state of each?
A: At pH 6, the phenol (pKa 10) has pH < pKa, so it remains protonated (neutral OH form). The amine's conjugate acid (pKa 9) has pH < pKa, so the amine is protonated to its ammonium form (RNH₃⁺, positively charged).
Q: Which of those two compounds at pH 6 would you expect to be water-soluble, and why?
A: The protonated amine (RNH₃⁺) is water-soluble because it is charged. Ions interact strongly with water through ion-dipole interactions. The neutral phenol is less water-soluble because, although it can hydrogen-bond through its OH group, its large aromatic ring makes it predominantly nonpolar.
Q: At pH 12, you place the same mixture in a separatory funnel with hexane and water. Are the two compounds in the same layer or different layers?
A: Different layers. At pH 12: the phenol (pKa 10) is deprotonated to phenoxide (ArO⁻), which is charged and dissolves in the water layer. The amine (conjugate acid pKa 9) is in its neutral free-base form (RNH₂), which is uncharged and dissolves in the hexane layer.
Q: Fluoxymesterone has 7 stereocentres. Including the structure drawn, how many stereoisomers does it have?
A: 2⁷ = 128 stereoisomers.
Q: A compound with a stereocentre has [α] = (+) and literature data shows R = (+). It undergoes catalytic hydrogenation (H₂/Pd) of a distant double bond. The product also measures (+). What is the R/S configuration of the product?
A: R. Catalytic hydrogenation does not break any bonds at the stereocentre, so configuration is retained. The starting material is R (because R = (+) and it measured (+)), and the product retains R.
Physical properties (boiling point, solubility) connect directly to acid-base extraction techniques you will use in the CHEM 241 lab. Understanding ionisation states at different pH values is what makes extraction work: you separate compounds by toggling them between charged (water-soluble) and neutral (organic-soluble) forms.
Stereochemistry from these chapters is the foundation for every reaction mechanism in Ch. 8-9 and beyond. When you predict inversion in SN2, retention in hydrogenation, or racemisation in SN1, you are applying the R/S and enantiomer/diastereomer concepts from Ch. 5. Conformational analysis feeds into E2 elimination (anti-periplanar geometry requires specific axial/equatorial arrangements in cyclohexane rings) and into understanding why certain reaction products are favoured over others.
boiling point, water solubility, intermolecular forces, hydrogen bonding, dipole-dipole, London dispersion forces, van der Waals, polar bond, electronegativity, functional group, alcohol, ketone, alkene, alkyl halide, alkyl fluoride, amine, pKa, conjugate acid, conjugate base, ionisation state, protonation, deprotonation, acid-base extraction, separatory funnel, phenol, phenoxide, ammonium ion, stereocentre, chiral centre, enantiomer, diastereomer, meso compound, R/S configuration, Cahn-Ingold-Prelog, optical rotation, dextrorotatory, levorotatory, stereochemical correlation, racemic mixture, Newman projection, staggered, eclipsed, anti, gauche, 1,3-diaxial interaction, axial, equatorial, chair conformation, ring strain, angle strain, torsional strain, cyclopropane, cyclohexane, fluoxymesterone, CHEM 237 foundations, organic chemistry fundamentals