Difficulty: Intermediate to Advanced | Prerequisites: General chemistry acid-base concepts, Lewis structures, resonance (see companion notes).
Acid-base chemistry is the engine that drives most of organic chemistry. Proton transfers are the simplest reactions, but they set the stage for understanding nucleophilic addition, elimination, and substitution. This material also introduces Lewis acid-base reactions (no proton involved) and curved-arrow mechanisms, which are the notation system for every reaction mechanism you will encounter. If you are not comfortable with pKa values and their meaning, this is the place to build that foundation.
pKa measures acid strength (lower = stronger acid). The relationship Keq = 10^(pKa of product acid minus pKa of reactant acid) lets you predict whether a proton transfer is favourable. At a given pH, compare the pH to each pKa to determine which protonation state dominates. Lewis acids accept electron pairs (no proton needed). Curved arrows show electron flow from nucleophile to electrophile, always drawn from the electron source to the electron sink.
Bronsted acid
A proton (H+) donor. In simple terms, any species that can give away a hydrogen ion.
Bronsted base
A proton (H+) acceptor. In simple terms, any species with a lone pair that can grab a hydrogen ion.
Lewis acid
An electron-pair acceptor. This is broader than Bronsted: metal halides like TiCl4 and AlCl3 are Lewis acids even though no proton is involved. Think of it as: anything with an empty or electron-poor orbital that can accept electrons.
Lewis base
An electron-pair donor. Any species with a lone pair that it can share with a Lewis acid. Every Bronsted base is also a Lewis base, but not every Lewis base is a Bronsted base.
pKa
The negative log of the acid dissociation constant (Ka). Lower pKa = stronger acid. A pKa of -12 is an extremely strong acid; a pKa of 49 is an extremely weak acid.
Keq (equilibrium constant)
The ratio of products to reactants at equilibrium. For a proton transfer: Keq = 10^(pKa(product acid) minus pKa(reactant acid)). If Keq is greater than 1, the reaction favours products.
Proton transfer reaction
The simplest organic reaction: an acid donates H+ to a base. Always produces a conjugate acid and a conjugate base. The equilibrium favours formation of the weaker acid and the weaker base.
Curved arrow
A notation showing the movement of an electron pair. The arrow starts at the electron source (lone pair or bond) and points to the electron sink (an atom or bond that can accept them). Double-barbed arrows move two electrons; single-barbed (fishhook) arrows move one.
Nucleophile
An electron-rich species that attacks an electron-poor centre. In mechanisms, the curved arrow starts from the nucleophile.
Electrophile
An electron-poor species that accepts electrons from a nucleophile. In mechanisms, the curved arrow points towards the electrophile.
For any proton transfer reaction: HA + B- goes to A- + HB.
Keq = 10^(pKa(HB) - pKa(HA))
This means the equilibrium always favours formation of the weaker acid (higher pKa product). If the product acid is weaker than the reactant acid (pKa product > pKa reactant), Keq > 1 and the reaction is favourable.
Worked example from the exam: arsine (AsH3) reacts with a base in a reaction with Keq = 10^(-21). To find arsine's pKa, rearrange: pKa(arsine) = pKa(product acid) + 21. If the product acid can be identified from the reaction and its pKa looked up on the table, you solve directly.
Molecule 1 (a serotonin metabolite) has two acidic protons with pKa values of approximately 2 and 9.5.
At pH 3 (acidic gut environment): pH 3 is above pKa 2 but below pKa 9.5. The group with pKa 2 is mostly deprotonated (pH > pKa means the conjugate base form dominates). The group with pKa 9.5 is mostly protonated (pH < pKa means the acid form dominates). So the dominant species has the carboxylic acid deprotonated (carboxylate) and the amine protonated (ammonium). This is the zwitterionic form.
At pH 9.4: pH 9.4 is just below pKa 9.5. Both species (protonated and deprotonated at that site) exist, but the protonated form is at slightly higher concentration because pH < pKa. The group with pKa 2 is fully deprotonated at this pH.
The general rule: if pH < pKa, the protonated (acid) form dominates. If pH > pKa, the deprotonated (base) form dominates.
For bufotenin (most acidic pKa approximately 8.5), a base deprotonates it with Keq > 10^3 when:
Keq = 10^(pKa(bufotenin) - pKa(conjugate acid of the base)) > 10^3
This requires pKa of the base's conjugate acid > 8.5 + 3 = 11.5. So any base whose conjugate acid has pKa > 11.5 will work. From the pKa table, identify bases with conjugate acid pKa values above 11.5.
Buffothionine has a most acidic pKa of approximately -3. HF has a pKa of 3.2. For the reaction of bufothionine with NaF (F- is the base, conjugate acid is HF):
Keq = 10^(pKa(bufothionine) - pKa(HF)) = 10^(-3 - 3.2) = 10^(-6.2)
The equilibrium strongly favours reactants because HF is a stronger acid than bufothionine's conjugate acid (NaF is too weak a base to deprotonate bufothionine effectively).
Both TiCl4 and AlCl3 are Lewis acids (electron-pair acceptors). When they react:
A chloride lone pair on AlCl3 donates to the electron-deficient Ti in TiCl4 (curved arrow from Cl lone pair to Ti).
This forms a complex where chloride bridges the two metals.
The complex then breaks apart, with a chloride transferring from Ti to Al (or vice versa), showing the relative Lewis acid strengths.
The product distribution tells you which metal is the stronger Lewis acid: the metal that ends up with more chlorides is the stronger Lewis acid (it holds onto the electron-rich chloride more effectively).
Methyl-2-cyanoacrylate polymerises by anionic addition:
Hydroxide (a nucleophile) attacks the electrophilic alkene carbon. Curved arrow goes from the OH lone pair to the carbon of the C=C.
This generates a carbanion (negative charge on carbon), stabilised by delocalisation into the cyano group and the ester carbonyl.
The carbanion then attacks the next monomer's alkene in the same way, and the chain grows.
Water reduces adhesion because water can act as a proton source, quenching the growing anionic chain end (protonating the carbanion) and terminating polymerisation before long chains form. Shorter chains mean weaker adhesion.
The pKa concept governs drug design: most drugs must cross cell membranes, which requires the uncharged (protonated for bases, deprotonated for acids) form. Knowing the pKa tells you what fraction is uncharged at physiological pH (7.4). Super Glue's polymerisation mechanism is the basis of forensic fingerprint development: cyanoacrylate fuming deposits polymer on the oils left by fingerprints, making them visible.
Students often confuse the direction of the pKa/Keq formula. Remember: Keq = 10^(pKa of product acid minus pKa of reactant acid). If you subtract in the wrong order, your Keq will be inverted.
"Lower pKa means stronger acid" is often memorised but misapplied. Students sometimes think a lower pKa means a stronger base. It does not. A lower pKa means a stronger acid, which means its conjugate base is weaker.
Curved arrows must start from the electron source. A common error is drawing the arrow from the electrophile to the nucleophile (backwards). The arrow always flows from the species that has electrons to give.
Students frequently forget to balance proton transfer reactions. Both sides must have the same atoms and the same total charge.
The pKa table provided with the exam is your most important reference. Nearly every acid-base question can be solved by looking up the relevant pKa values and applying the Keq formula.
"Draw the most significant resonance contributor" in the context of a mechanism means the product you draw should show the most stable electron arrangement.
Curved-arrow mechanism questions specify "accurately and efficiently," meaning use the fewest arrows needed and make sure each arrow starts and ends in the correct place.
Questions that say "balance your reaction" are checking whether you remembered to include all products (including the conjugate acid or base of the reagent).
Fill in the blank: Keq for a proton transfer = 10 to the power of (pKa of ___ minus pKa of ___). (Product acid; reactant acid.)
True or false: if pH is below the pKa, the deprotonated form dominates. (False. The protonated form dominates when pH < pKa.)
Fill in the blank: a Lewis acid is an electron-pair ___. (Acceptor.)
True or false: curved arrows point from the nucleophile to the electrophile. (True.)
Fill in the blank: an acid with pKa -3 is ___ than an acid with pKa 4. (Stronger.)
Q: Molecule 1 has acidic protons with pKa values of approximately 2 and 9.5. At pH 3, what is the dominant protonation state?
A: The group with pKa 2 is mostly deprotonated (pH 3 > pKa 2). The group with pKa 9.5 is mostly protonated (pH 3 < pKa 9.5). The dominant form is the zwitterion: the carboxylate is deprotonated (negative) and the ammonium is protonated (positive).
Q: At pH 9.4, two species of Molecule 1 coexist. Which is at higher concentration?
A: pH 9.4 is just below the pKa of 9.5. Since pH < pKa, the protonated form is at slightly higher concentration than the deprotonated form.
Q: Bufotenin has a most acidic pKa of approximately 8.5. Which bases from the pKa table can deprotonate it with Keq > 10^3?
A: Any base whose conjugate acid has a pKa greater than 11.5 (because 8.5 + 3 = 11.5). From the table, candidates include: NaNH2 (conjugate acid NH3, pKa 36), alkoxide bases like sodium ethoxide (conjugate acid ethanol, pKa 17), and potassium tert-butoxide (conjugate acid tert-butanol, pKa approximately 19).
Q: Given a proton transfer with Keq = 10^(-21) and one known pKa, how do you find the unknown pKa?
A: Use Keq = 10^(pKa product acid - pKa reactant acid). Plug in the known Keq and known pKa, then solve for the unknown. For arsine: -21 = pKa(product acid) - pKa(arsine), so pKa(arsine) = pKa(product acid) + 21.
Q: In the Super Glue polymerisation mechanism, where does the first curved arrow start and end?
A: The first arrow starts from a lone pair on hydroxide (the nucleophile) and ends at the electrophilic carbon of the C=C double bond in methyl-2-cyanoacrylate. Simultaneously, a second arrow shows the pi electrons of the C=C being displaced onto the adjacent carbon.
Q: Why does water reduce the adhesive strength of Super Glue?
A: Water can protonate the carbanion at the growing chain end, terminating the polymerisation. Shorter polymer chains produce weaker adhesion.
Acid-base chemistry connects to resonance because the stability of a conjugate base (and therefore the strength of the acid) depends on how well the negative charge is delocalised. It connects to hybridisation because sp-hybridised C-H bonds are more acidic than sp3 C-H bonds (more s-character stabilises the conjugate base). Curved-arrow mechanisms are the foundation for every reaction mechanism in Organic Chemistry II, from nucleophilic addition to elimination to substitution.
The exam provides a full pKa table, but these benchmark values are worth memorising for speed:
Strong mineral acids (HI, HCl, H2SO4): pKa around -9 to -7
Protonated alcohols, protonated ethers: pKa around -2 to -4
Carboxylic acids: pKa around 4 to 5
Ammonium ions (R-NH3+): pKa around 9 to 11
Phenols: pKa around 10
Alcohols: pKa around 15 to 17
Terminal alkynes (sp C-H): pKa around 25
Ammonia (NH3): pKa 36
Alkenes (sp2 C-H): pKa around 44
Alkanes (sp3 C-H): pKa around 49 to 51
pKa, Ka, Keq, equilibrium constant, Bronsted acid, Bronsted base, Lewis acid, Lewis base, proton transfer, acid-base equilibrium, conjugate acid, conjugate base, Henderson-Hasselbalch, protonation state, zwitterion, curved arrow mechanism, nucleophile, electrophile, electron pair donor, electron pair acceptor, TiCl4, AlCl3, Lewis acid strength, Super Glue, cyanoacrylate, anionic polymerisation, serotonin metabolite, bufotenin, bufothionine, arsine, organic chemistry II, CHEM 210, CHEM 215, University of Michigan