Acids, Bases and Stereoisomerism, CHEM 210 – Study Notes
Difficulty: Foundational to Intermediate | Prerequisites: Nomenclature and structure notes; familiarity with electronegativity, Lewis structures.
Acid-base chemistry is the lens through which organic chemists predict the direction of proton transfers and the stability of charged intermediates. Stereoisomerism is the reason that molecules with identical connectivity can behave completely differently in biological systems. These two topics sit underneath nearly every reaction mechanism you will study: acids and bases tell you which proton moves and why, while stereochemistry tells you the spatial outcome. Both are heavily tested and both require systematic thinking rather than memorisation.
Acids donate protons; bases accept them. Lower pKa = stronger acid = weaker conjugate base, and equilibrium always favours the weaker acid side. Stereoisomers share the same connectivity but differ in 3D arrangement: enantiomers are non-superimposable mirror images (assign R/S using CIP priorities), while diastereomers are stereoisomers that are not mirror images.
Bronsted-Lowry acid
A proton (H+) donor. In simple terms, an acid is anything that gives up a hydrogen ion.
Bronsted-Lowry base
A proton acceptor. A base is anything with a lone pair that can grab a hydrogen ion.
pKa
The negative log of the acid dissociation constant. Lower pKa = stronger acid = weaker conjugate base. This is the single most useful number for predicting acid-base equilibria.
Conjugate base
What remains after an acid donates its proton. The stability of the conjugate base determines how strong the acid is.
Lewis acid
An electron pair acceptor (e.g. BF3, AlCl3, carbocations). Think of it as anything with an empty or electron-poor orbital.
Lewis base
An electron pair donor (lone pairs, pi bonds, nucleophiles). Think of it as anything with electrons to share.
Stereoisomers
Molecules with the same connectivity but different spatial arrangement. The umbrella term that includes enantiomers, diastereomers, conformational isomers, and geometric isomers.
Stereocenter (chiral center)
An sp3 carbon bearing four different substituents. The point at which mirror-image non-superimposability arises.
Enantiomers
Non-superimposable mirror images of each other. They have identical physical properties except for the direction they rotate plane-polarised light.
Diastereomers
Stereoisomers that are not mirror images. They have different physical properties (melting point, boiling point, solubility).
Meso compound
A molecule that has stereocentres but is achiral due to an internal plane of symmetry. Identical to its mirror image and optically inactive.
Racemic mixture
A 50:50 mixture of R and S enantiomers. Optically inactive because the rotations cancel out.
Enantiomeric excess (ee)
The percentage by which one enantiomer exceeds the other: ee = |%R - %S|. An ee of 100% means optically pure; 0% means racemic.
Acid = proton donor. Base = proton acceptor.
The pKa scale measures acid strength: lower pKa = stronger acid = weaker conjugate base.
Equilibrium always favours the weaker acid/base side. If pKa(reactant acid) > pKa(product acid), products are favoured.
This is the single most reliable tool for predicting which way a proton transfer goes.
Lewis acid = electron pair acceptor. Examples: BF3, AlCl3, FeBr3, carbocations, any electrophile.
Lewis base = electron pair donor. Examples: anything with a lone pair or a pi bond, nucleophiles.
Lewis acid-base interactions are central to electrophilic aromatic substitution and coordination chemistry.
The Lewis definition is broader than Bronsted-Lowry: every Bronsted acid is a Lewis acid, but not every Lewis acid donates a proton.
Five factors determine how acidic a given X-H bond is. Each one is about how well the conjugate base handles the negative charge.
Electronegativity. A more electronegative atom stabilises the negative charge on the conjugate base. Across a row: HF > H2O > NH3 > CH4.
Size/polarisability. Going down a group, a larger atom spreads the charge over a bigger volume. HI > HBr > HCl > HF in water (size dominates over electronegativity down a group).
Resonance. Delocalisation of the negative charge across multiple atoms stabilises the conjugate base. Carboxylic acids (pKa ~5) are far more acidic than alcohols (pKa ~16) because the carboxylate anion has two equivalent resonance structures. Phenols (pKa ~10) are more acidic than aliphatic alcohols for the same reason.
Induction. Electron-withdrawing groups near the acidic site pull electron density away, stabilising the conjugate base. ClCH2COOH (pKa ~2.9) is more acidic than CH3COOH (pKa ~4.8).
Hybridisation. More s-character = more electronegative carbon = more acidic C-H bond. sp C-H (pKa ~25) > sp2 C-H (pKa ~44) > sp3 C-H (pKa ~50).
H2SO4 ~ -3
HCl ~ -7
RCOOH ~ 5
ArOH ~ 10
ROH ~ 16 to 18
Alpha-H of ketone ~ 20
Terminal alkyne ~ 25
NH3 ~ 38
sp3 C-H ~ 50
Knowing these approximate values lets you predict the direction of any proton transfer at a glance.
Constitutional (structural) isomers. Same molecular formula, different connectivity. Example: butanol and diethyl ether are both C4H10O.
Stereoisomers. Same connectivity, different spatial arrangement. Subcategories: enantiomers, diastereomers, conformational isomers, geometric (cis/trans) isomers.
A stereocenter is an sp3 carbon with four different substituents. To assign R or S configuration using CIP rules:
Rank the four substituents by atomic number (higher = higher priority). Break ties by moving outward to the next set of atoms.
Orient the molecule so the lowest-priority group (usually H) points away from you.
Trace a path from priority 1 to 2 to 3. Clockwise = R. Counterclockwise = S.
If the lowest-priority group was pointing toward you when you traced the path, reverse the assignment.
For alkenes: cis = same groups on the same side of the double bond; trans = opposite sides. E/Z is more general and always works.
For cycloalkanes: cis = substituents on the same face; trans = opposite faces.
Non-superimposable mirror images. Identical physical properties (boiling point, melting point, solubility) except optical rotation: they rotate plane-polarised light by equal magnitude in opposite directions. A racemic mixture (50:50 R/S) is optically inactive. Enantiomeric excess (ee) = |%R - %S|.
Stereoisomers that are not mirror images. They have different physical properties (different melting points, boiling points, solubility). Cis/trans isomers of cycloalkanes and alkenes are diastereomers. A compound with n stereocentres has at most 2^n stereoisomers (fewer if meso forms exist).
Achiral despite having stereocentres, because an internal plane of symmetry makes the molecule identical to its mirror image. Classic example: meso-tartaric acid (2R,3S). Optically inactive.
Rotational isomers about single bonds. They are not true stereoisomers because they interconvert rapidly at room temperature. Newman projections show the key conformations:
Staggered conformations: anti (most stable, 180 degrees between large groups) and gauche (60 degrees).
Eclipsed conformations: least stable (0 degrees between groups, torsional strain).
Cyclohexane ring-flipping: chair interconverts with chair; axial positions become equatorial and vice versa. Larger substituents strongly prefer equatorial positions to avoid 1,3-diaxial strain. The A-value quantifies the free energy preference for equatorial placement.
Students often think a lower pKa means a weaker acid. It is the opposite: lower pKa = stronger acid.
Students sometimes believe that size always trumps electronegativity. It does not. Size dominates going down a group (same column of the periodic table). Electronegativity dominates going across a row.
Students sometimes assign R/S without orienting the lowest-priority group away from the viewer first. Skipping this step inverts the answer.
Students often assume that any molecule with stereocentres is chiral. A meso compound has stereocentres but is achiral due to an internal plane of symmetry.
Students confuse conformational isomers with configurational stereoisomers. Conformers interconvert freely by bond rotation at room temperature; you cannot isolate them separately. Enantiomers and diastereomers require bond breaking to interconvert.
⚠️ pKa comparison questions are on nearly every exam. Memorise the common values and know how to reason about unfamiliar ones using the five factors.
⚠️ R/S assignment is a guaranteed exam topic. Practise until the CIP procedure is automatic.
⚠️ Meso compounds are a favourite trick question. If you see an internal plane of symmetry, the compound is achiral regardless of the number of stereocentres.
⚠️ Newman projection and chair flip questions test whether you understand conformational analysis. The most stable chair puts the largest substituent equatorial.
⚠️ Optical activity questions: know that a racemic mixture is optically inactive and that ee tells you how far from racemic you are.
True or false: A compound with a pKa of 3 is a weaker acid than a compound with a pKa of 10. (False. pKa 3 is the stronger acid.)
Fill in the blank: An sp3 carbon with four different substituents is called a ______. (stereocenter / chiral center)
True or false: Diastereomers have identical physical properties. (False. They have different physical properties.)
Fill in the blank: In a cyclohexane chair, larger substituents prefer the ______ position. (equatorial)
True or false: A meso compound is optically active. (False. It is optically inactive despite having stereocentres.)
Q: Predict the direction of equilibrium: CH3COOH (pKa 4.8) + NaOH. Which side is favoured?
A: Products are favoured. NaOH is a strong base; the conjugate acid of OH- is water (pKa ~15.7). Since the reactant acid (pKa 4.8) is stronger than the product acid (pKa 15.7), equilibrium lies to the right.
Q: Rank the following in order of increasing acidity: ethanol, acetic acid, phenol.
A: Ethanol (pKa ~16) < phenol (pKa ~10) < acetic acid (pKa ~5). Phenol is more acidic than ethanol because the phenoxide anion is resonance-stabilised. Acetic acid is more acidic than phenol because the carboxylate has two equivalent resonance structures sharing the charge equally.
Q: A molecule has two stereocentres with configurations 2R,3S. Its mirror image is 2S,3R. Are these enantiomers or a meso compound?
A: It depends on whether an internal plane of symmetry exists. If the groups on C-2 and C-3 are the same (as in tartaric acid), then 2R,3S = meso, and it is identical to its mirror image. If the groups differ, they are enantiomers.
Q: Draw the most stable chair conformation of trans-1,4-dimethylcyclohexane.
A: In trans-1,4-dimethylcyclohexane, both methyl groups can be equatorial simultaneously (one up, one down on opposite sides). The most stable chair places both methyls equatorial.
Q: Why is HI a stronger acid than HF in water, even though fluorine is more electronegative?
A: Because iodine is much larger than fluorine. The iodide anion spreads the negative charge over a larger volume, stabilising the conjugate base. Going down a group, size/polarisability dominates over electronegativity.
Acid-base chemistry is the foundation for understanding nucleophilicity and leaving group ability in the substitution and elimination unit. The pKa table tells you whether a base is strong enough to deprotonate a given substrate, which determines whether you get SN2/E2 or SN1/E1. Stereoisomerism connects directly to reaction stereochemistry: every time a new stereocenter forms, you need to predict whether the product is racemic, inverted, or retained.
Bronsted-Lowry, Lewis acid, Lewis base, pKa, conjugate acid, conjugate base, proton transfer, acid strength, electronegativity, size, polarisability, resonance stabilisation, induction, electron-withdrawing group, hybridisation and acidity, stereoisomers, enantiomers, diastereomers, meso compound, chiral center, stereocenter, R/S configuration, CIP priority, optical rotation, racemic mixture, enantiomeric excess, constitutional isomers, conformational isomers, Newman projection, chair conformation, axial, equatorial, 1,3-diaxial strain, A-value, ring flip