Difficulty: Intermediate | Prerequisites: CHEM 210 (Organic Chemistry I), familiarity with pKa values and functional groups.
Over 80% of organic reaction mechanisms include a Bronsted-Lowry acid-base step, and every biochemical pathway involves acid-base chemistry. This material is the backbone of reaction prediction in Organic Chemistry II. You need to be comfortable identifying electron-rich and electron-poor atoms, understanding how reaction conditions (acidic vs basic) dictate what intermediates and reagents are allowed, and using pKa values to predict equilibrium direction. If you skipped the pKa table review from CHEM 210, do that first.
Acid-base chemistry is the single most recurring mechanistic step in organic reactions. Every functional group behaves differently depending on whether conditions are acidic or basic, and the key to predicting outcomes is identifying electron-rich sites (nucleophiles/bases) and electron-poor sites (electrophiles/acids), then using pKa values to determine which direction equilibrium favours. If you can match the right reagent to the right functional group under the right conditions, you can predict virtually any reaction outcome in this course.
Bronsted-Lowry acid
A species that donates a proton (H+) to another molecule. In simple terms, it is anything that gives away a hydrogen ion.
Bronsted-Lowry base
A species that accepts a proton (H+) from another molecule. Think of it as the electron-rich partner that grabs the proton.
Lewis acid
An electron-pair acceptor. It has an empty or partial orbital ready to receive electrons. In simple terms, it is electron-hungry.
Lewis base
An electron-pair donor. It has a lone pair or electron density available to share. Think of it as the molecule with electrons to give.
ARIO
A mnemonic for the four factors that stabilise conjugate bases (and therefore affect acid strength): Atom (electronegativity and size), Resonance, Induction, and Orbital effects. This is how you rank acid strength when pKa values are not given.
Keq (equilibrium constant)
The ratio of product concentrations to reactant concentrations at equilibrium. For acid-base reactions, equilibrium favours the side with the weaker acid and weaker base (higher pKa on the acid side of the products).
pKa
A logarithmic measure of acid strength. Lower pKa means a stronger acid. The difference in pKa values between the acid on the reactant side and the acid on the product side tells you which direction equilibrium favours.
pKaH
The pKa of the conjugate acid of a base. A higher pKaH means the base is stronger (its conjugate acid is weaker). Used to compare base strength directly.
Nucleophile
An electron-rich species that donates electrons to an electron-poor atom, forming a new bond. Think of it as the attacker in a bond-forming step.
Electrophile
An electron-poor species that accepts electrons from a nucleophile. It is the target of nucleophilic attack.
Curved arrow mechanism
A notation showing the movement of electron pairs during a reaction. Arrows always flow from the electron-rich source (nucleophile/base) to the electron-poor sink (electrophile/acid). Full arrows represent two-electron movements.
Under acidic conditions, charged organic intermediates can only be positively charged. You will never draw a negatively charged organic intermediate in acid.
Under basic conditions, charged organic intermediates can only be negatively charged. You will never draw a positively charged organic intermediate in base.
This single rule eliminates half the possible mistakes on an exam. Memorise it.
An acid catalyst protonates a substrate, making the electrophile more reactive (it lowers the LUMO energy, making it easier for nucleophiles to attack).
A base deprotonates a substrate, generating a stronger nucleophile (it raises the HOMO energy, making it a better electron donor).
Every acid-base interaction in this course falls into one of four patterns. For each, start by identifying electron-rich atoms (potential nucleophiles/bases) and electron-poor atoms (potential electrophiles/acids).
Pattern 1: Proton transfer (PT)
A molecule with a lone pair (M:) attacks H+ from an acid. The lone pair forms a new bond to hydrogen, and M becomes positively charged. Arrow flows from the lone pair on M to the H.
Pattern 2: Nucleophilic attack on an electrophile
A molecule with a lone pair (M:) attacks a partially or fully positive electrophile. The lone pair forms a new bond, and M picks up a positive charge. Examples include water attacking a protonated carbonyl, or water attacking a carbocation.
Pattern 3: Deprotonation by a base
A base (B:-) removes a proton from M-H. The electrons from the M-H bond stay on M, giving M a negative charge, and the base picks up the proton to form B-H. Arrow flows from B:- to the H, and from the M-H bond to M.
Pattern 4: Nucleophilic substitution
A nucleophile (nuc:-) attacks a partially positive atom in M-X, displacing the leaving group X as X:-. The nucleophile forms a new bond to M, and X leaves with the bonding electrons.
Nucleophiles available in base:
Hydride (H:-)
Carbanions (R:-)
Hydroxide (HO-)
Alkoxides (RO-)
Enolates (from deprotonation of carbonyls at the alpha carbon, pKaH > 11)
Carboxylates (pKaH around 5)
All of these are negatively charged, consistent with the cardinal rule.
Electrophiles available in base:
Aldehydes (R-CHO)
Ketones (R-CO-R')
Esters (R-CO-OR')
Alkyl halides (R-X)
Alkyl tosylates (R-OTs)
These electrophiles are neutral but have electron-poor carbon centres.
Nucleophiles available in acid:
Alkenes (pi electrons)
Alcohols (ROH)
Water (H2O)
These are all neutral or weakly nucleophilic, consistent with the cardinal rule (no negative charges in acid).
Electrophiles available in acid:
Carbocations (from protonation steps)
Protonated aldehydes, ketones, esters, and carboxylic acids (protonation of the carbonyl oxygen makes the carbonyl carbon far more electrophilic)
Protonated alcohols (the OH2+ group is a much better leaving group than OH)
All of these are positively charged or bear partial positive charges enhanced by protonation.
Under basic conditions, deprotonation raises the HOMO energy of the nucleophile, making it a better electron donor (higher-energy HOMO).
Under acidic conditions, protonation lowers the LUMO energy of the electrophile, making it a better electron acceptor (lower-energy LUMO).
This is the orbital-level explanation for why acids activate electrophiles and bases activate nucleophiles.
Students often draw a negatively charged intermediate (like an alkoxide) under acidic conditions. This is not allowed. Under acidic conditions, only positively charged organic intermediates exist.
Students confuse nucleophiles with bases. A nucleophile attacks an electrophilic atom (typically carbon), while a base removes a proton. The same species can act as either, but the outcome is different.
Students assume that a stronger base is always a better nucleophile. Basicity is about affinity for protons (thermodynamic), while nucleophilicity is about the rate of attack on carbon (kinetic). Bulky bases like LDA are strong bases but poor nucleophiles.
Students forget that curved arrows always point from the electron source to the electron sink. Drawing the arrow backwards is one of the most common errors on exams.
You will almost certainly be asked to predict whether a reaction proceeds under acidic or basic conditions, and to draw the mechanism with correct curved arrows.
Predicting the equilibrium direction using pKa values is a core exam skill. Equilibrium favours the side with the weaker acid (higher pKa). If the product acid has a higher pKa than the reactant acid, equilibrium lies to the left (unfavourable).
Knowing which nucleophiles and electrophiles are available under each set of conditions is essential for multi-step synthesis problems. Using a reagent that does not exist under those conditions (e.g. an alkoxide in acid) will cost you marks.
The distinction between H2O vs H3O+ and HOEt vs H2OEt+ matters. In acidic conditions, neutral species are protonated. The protonated form is the active electrophile or leaving group.
True or False: Under acidic conditions, you can have a carbanion intermediate. (Answer: False. Only positively charged intermediates under acidic conditions.)
Fill in the blank: An acid catalyst makes an electrophile ________ reactive by lowering its ________ energy. (Answer: more, LUMO)
True or False: Equilibrium in an acid-base reaction favours the side with the stronger acid. (Answer: False. Equilibrium favours the weaker acid and weaker base.)
Fill in the blank: Curved arrows always point from the ________ source to the ________ sink. (Answer: electron, electron)
True or False: Hydroxide (HO-) is an appropriate nucleophile to use under acidic conditions. (Answer: False. Negatively charged species do not exist under acidic conditions.)
Q: A reaction is performed under basic conditions. A student proposes a carbocation intermediate. Is this reasonable? Explain.
A: No. Under basic conditions, charged organic intermediates can only be negatively charged. A carbocation (positively charged) cannot exist under basic conditions.
Q: Given that the pKa of HBr is -9 and the pKa of H3O+ is -1.7, predict the equilibrium direction for the reaction of HBr with water.
A: HBr is the stronger acid (lower pKa). The equilibrium favours the products (H3O+ and Br-), because the product acid (H3O+, pKa = -1.7) is weaker than the reactant acid (HBr, pKa = -9). The reaction is product-favoured.
Q: Why does protonating a carbonyl oxygen make the carbonyl carbon more electrophilic?
A: Protonation places a formal positive charge on the oxygen, which strongly withdraws electron density from the carbon through the C=O bond. This lowers the LUMO energy of the carbonyl carbon, making it much more susceptible to nucleophilic attack.
Q: Draw the curved arrow mechanism for hydroxide (HO-) deprotonating ethanol (CH3CH2OH). Label the acid, base, conjugate acid, and conjugate base.
A: The curved arrow goes from the lone pair on HO- to the O-H proton of ethanol, and a second arrow goes from the O-H bond to the oxygen of ethanol. HO- is the base, ethanol is the acid, water (H2O) is the conjugate acid, and ethoxide (CH3CH2O-) is the conjugate base. Note: this reaction is not very favourable because the pKa of ethanol (around 16) and water (around 14/15.7) are close, with equilibrium slightly favouring the reactants.
Q: Name the four factors in ARIO and briefly explain what each one assesses.
A: Atom: considers electronegativity and size of the atom bearing the negative charge. Resonance: whether the negative charge can be delocalised across multiple atoms. Induction: whether nearby electronegative atoms stabilise the charge through sigma bonds. Orbital: the s-character of the orbital holding the electrons (more s-character means more stable).
This material connects directly to nucleophilic substitution (SN1, SN2) and elimination (E1, E2) from CHEM 210, because the choice of acidic vs basic conditions determines which nucleophiles and leaving groups are available. It also sets the stage for carbonyl chemistry (aldehydes, ketones, carboxylic acid derivatives), where every mechanism begins with either protonation of the carbonyl (acidic) or nucleophilic attack (basic). Understanding HOMO/LUMO interactions here prepares you for molecular orbital arguments in pericyclic reactions later.
Acid-base reactions, Bronsted-Lowry, Lewis acid, Lewis base, proton transfer, nucleophile, electrophile, pKa, pKaH, conjugate acid, conjugate base, ARIO, equilibrium constant, Keq, curved arrow mechanism, electron-pushing arrows, acidic conditions, basic conditions, charged intermediates, HOMO, LUMO, organic chemistry II, CHEM 212, reaction prediction, Penn State