Difficulty: Intermediate to Advanced | Prerequisites: Acid-base foundations (Doc 1) and alkene/alcohol/alkyl halide reactivity (Doc 2) from this set.
This final set of notes covers aldehydes, ketones, carboxylic acids and their derivatives (esters, amides, anhydrides, acid chlorides) under acidic and basic conditions, plus how multifunctional compounds behave when they contain more than one reactive site. This is where the acid-base framework comes together for the most complex reaction predictions in the course.
Aldehydes and ketones are electrophilic at the carbonyl carbon and weakly acidic at the alpha carbon (pKa around 17 to 20). Under acidic conditions, protonation of the carbonyl oxygen makes them even more electrophilic. Under basic conditions, they can be deprotonated at the alpha carbon to form enolates, or attacked by nucleophiles at the carbonyl carbon. Carboxylic acids and their derivatives follow a similar pattern but add an extra wrinkle: the acidic O-H (pKa around 5) gets deprotonated before nucleophilic addition can occur, so any nucleophile with pKa > 5 will deprotonate first. Multifunctional compounds react at their most reactive site first, which you determine by comparing pKa values of all the acidic and basic sites present.
Aldehyde
A carbonyl compound with at least one hydrogen on the carbonyl carbon (R-CHO). More electrophilic than ketones because the hydrogen provides less steric shielding and less electron donation than an alkyl group.
Ketone
A carbonyl compound with two carbon substituents on the carbonyl carbon (R-CO-R'). Slightly less electrophilic than aldehydes due to greater steric bulk and inductive donation from two alkyl groups.
Alpha carbon
The carbon adjacent to the carbonyl. Hydrogens on this carbon are weakly acidic (pKa around 17 to 20) because the resulting carbanion is stabilised by resonance with the carbonyl (forming an enolate).
Enolate
The conjugate base formed by deprotonating the alpha carbon of a carbonyl compound. The negative charge is delocalised across the alpha carbon and the carbonyl oxygen. Enolates are both nucleophilic and basic.
Enol
The tautomer of a carbonyl compound where the proton has moved from the alpha carbon to the oxygen, creating a C=C double bond adjacent to an OH group. Enols are nucleophilic at the double bond, similar to alkenes.
Enamine
The nitrogen analogue of an enol. Formed by replacing the OH of an enol with NR2. The nitrogen lone pair donates into the pi system, making the beta carbon nucleophilic. Protonation with one equivalent of acid gives an iminium ion.
Carboxylic acid
A compound with both a carbonyl and a hydroxyl on the same carbon (R-COOH). The O-H is significantly acidic (pKa around 5) because the conjugate base (carboxylate) is resonance-stabilised across two equivalent oxygens.
Ester
A carboxylic acid derivative where the O-H is replaced by O-R' (R-COOR'). No acidic proton, so nucleophilic acyl substitution can occur without competing deprotonation.
Nucleophilic addition
The mechanism for reactions at aldehyde and ketone carbonyls. A nucleophile attacks the carbonyl carbon, breaking the pi bond, and the electrons go to the oxygen. The result is a tetrahedral alkoxide intermediate.
Nucleophilic acyl substitution
The mechanism for reactions at carboxylic acid derivative carbonyls. A nucleophile attacks the carbonyl carbon (addition), forming a tetrahedral intermediate, and then a leaving group departs (elimination). The net effect is substitution of the leaving group by the nucleophile.
Reactive sites: the carbonyl carbon (electrophilic, partial positive charge), the carbonyl oxygen (lone pairs, weakly basic), and the alpha C-H (weakly acidic, pKa around 17 to 20).
With H+ (acid):
The carbonyl oxygen is protonated (pKa of the protonated carbonyl is around -6). This requires a strong acid with pKa < 0. Protonation dramatically increases the electrophilicity of the carbonyl carbon by lowering its LUMO energy. This is a key activation step for reactions like acid-catalysed nucleophilic addition.
With an electrophile:
Limited reactivity. The carbonyl carbon is already electrophilic, so it does not attack other electrophiles. The oxygen lone pairs could in theory act as a nucleophile toward a very strong electrophile, but this is uncommon.
With a base (deprotonation at the alpha carbon):
A base removes an alpha-hydrogen (pKa around 17) to form an enolate.
Reversible with hydroxide (HO-, pKaH around 14): the pKa gap is only about 3 units, so the equilibrium only slightly favours products. The enolate forms in small amounts.
Irreversible with NaH (pKaH = 35): the pKa gap is about 18 units, so the reaction goes fully to completion. All of the carbonyl is converted to enolate.
This distinction between reversible and irreversible enolate formation is critical for controlling selectivity in aldol reactions and alkylation reactions later in the course.
With a nucleophile (nucleophilic addition):
A nucleophile attacks the electrophilic carbonyl carbon, breaking the C=O pi bond and pushing electrons onto oxygen to form an alkoxide intermediate.
Reversible with water (H2O, pKa = 14): forms a hydrate (geminal diol) that easily reverts.
Irreversible with HCN (forms a cyanohydrin): the C-CN bond is strong and the cyanide is a good nucleophile, so the reaction proceeds to completion.
The reversibility depends on the nucleophile's leaving ability. Weak nucleophiles that are also good leaving groups (like water) give reversible additions. Strong nucleophiles that are poor leaving groups (like cyanide, hydride, organometallics) give irreversible additions.
Reactive sites: the carbonyl carbon (electrophilic), the carbonyl oxygen (weakly basic, most basic site on the molecule), and for carboxylic acids the O-H (acidic, pKa around 5).
Derivatives include: esters (R-COOR'), amides (R-CONR2), anhydrides (RCO-O-COR), and acid chlorides (R-COCl).
With H+ (acid):
The carbonyl oxygen is protonated (pKa of the protonated form is around -6). This requires a strong acid (pKa < 0) such as HI (pKa = -10), H2SO4 (pKa = -5), or a protonated alcohol (pKa around -6.5). Protonation activates the carbonyl for nucleophilic attack, just as with aldehydes and ketones.
The most basic site on the carboxylic acid is the carbonyl oxygen (the C=O oxygen), not the hydroxyl oxygen. This is because protonation at the carbonyl oxygen gives a resonance-stabilised cation with three contributing structures.
With an electrophile:
Not common. The carboxylate oxygen can act as a nucleophile in some cases, but direct electrophilic attack on carboxylic acids is rare.
With a base (deprotonation):
A base with a conjugate acid pKa > 5 will deprotonate the carboxylic acid O-H to form a carboxylate anion (RCO2-). This is fast and favourable. Suitable bases include ammonia (NH3), hydroxide (OH-), alkoxides (OR-), and methyl anions (CH3-).
For the alpha C-H (pKa around 18 to 20), a stronger base is needed (pKaH > 18). The base must be strong enough to reach the alpha position, which is less acidic than the O-H. In practice, deprotonation of the O-H always happens first.
With a nucleophile:
This is where the critical distinction arises. For carboxylic acids, any nucleophile with a conjugate acid pKa > 5 will deprotonate the O-H instead of attacking the carbonyl. Deprotonation is faster than nucleophilic addition. This is similar to the alcohol problem: acid-base chemistry dominates over substitution when an acidic proton is available.
For esters, anhydrides, and acid chlorides (no acidic O-H proton), nucleophilic acyl substitution can proceed. The nucleophile attacks the carbonyl carbon, forms a tetrahedral intermediate, and the leaving group departs.
When a molecule has more than one reactive functional group, the most acidic proton is removed first and the most basic site is protonated first. You must compare pKa values across all sites to predict the outcome.
Amino acid at pH 7.4:
An amino acid has both a carboxylic acid (pKa around 2 to 5) and an amine (pKaH around 10.6). At physiological pH (7.4), both groups react: the carboxylic acid is deprotonated (because 7.4 > pKa of about 2 to 5), and the amine is protonated (because 7.4 < pKaH of about 10.6). The result is a zwitterion: a molecule with both a negative charge (carboxylate) and a positive charge (ammonium).
At pH 1 (strongly acidic), both groups are protonated: the carboxylic acid stays as COOH, and the amine is protonated to NH3+. The molecule carries a net positive charge.
Under basic conditions, both groups are deprotonated: the carboxylic acid becomes COO-, and the amine stays as NH2. The molecule carries a net negative charge.
Hydroxy acid with NaH:
A molecule with both an alcohol (pKa around 16) and a carboxylic acid (pKa around 5) reacts differently depending on equivalents of NaH:
1 equivalent of NaH: the more acidic proton (carboxylic acid, pKa = 5) is removed first, forming a carboxylate while leaving the alcohol intact. The carboxylate can then undergo SN2 with CH3I to form a methyl ester.
2 equivalents of NaH: both protons are removed. The carboxylic acid is deprotonated first (pKa = 5), then the alcohol (pKa = 16). With 1 equivalent of CH3I, alkylation occurs on the more nucleophilic carboxylate, and acid workup (H3O+) reprotonates the remaining carboxylate to give the final product.
Enamine in HCl:
An enamine (H2N-CH=CH-R) has a basic nitrogen (lone pair) and a nucleophilic double bond.
1 equivalent of HCl: the nitrogen is protonated first (it is more basic, pKa of the ammonium is around -8 for the protonated form shown), forming an iminium ion.
2 equivalents of HCl: after nitrogen protonation, the second equivalent protonates the double bond (since the enamine pi system is nucleophilic).
Enol in HCl:
An enol (HO-CH=CH-R) treated with HCl will be protonated at the double bond, since the C=C acts as the nucleophile. The resulting carbocation is stabilised by the adjacent oxygen lone pair. This produces the protonated ketone/aldehyde (tautomerisation to the keto form).
Students often try to attack the carbonyl of a carboxylic acid with a nucleophile like hydroxide, forgetting that the O-H proton (pKa around 5) will be removed first. Deprotonation is always faster than nucleophilic addition when an acidic proton is available.
Students confuse nucleophilic addition (what happens to aldehydes and ketones) with nucleophilic acyl substitution (what happens to carboxylic acid derivatives). The difference is the presence of a leaving group: esters, acid chlorides, and anhydrides have one, so the tetrahedral intermediate collapses by ejecting the leaving group. Aldehydes and ketones do not, so they stay at the tetrahedral stage.
Students assume that the hydroxyl oxygen is the most basic site on a carboxylic acid. The carbonyl oxygen is actually more basic because protonation there gives a resonance-stabilised cation with three contributing structures.
With multifunctional compounds, students often forget to rank all the acidic sites by pKa before deciding what reacts first. The most acidic proton is always removed first, and the most basic site is always protonated first.
The reversible vs irreversible distinction for enolate formation (hydroxide vs NaH) is a perennial exam topic. Know the pKa values and be prepared to justify your answer with the arithmetic.
Predicting the behaviour of multifunctional compounds (amino acids, hydroxy acids, enamines, enols) under specific conditions is a classic exam question format. You will be given a molecule with two or more functional groups and asked to predict the product with a given number of equivalents of reagent.
The most basic site on a carboxylic acid (the carbonyl oxygen, not the hydroxyl oxygen) is commonly tested.
Knowing that nucleophilic acyl substitution works on esters, anhydrides, and acid chlorides but not on carboxylic acids (because deprotonation dominates) is essential for synthesis problems.
True or False: The pKa of the alpha C-H of a ketone is around 17, so hydroxide (pKaH around 14) can irreversibly form the enolate. (Answer: False. The pKa gap is only about 3 units, making enolate formation reversible with hydroxide.)
Fill in the blank: The most basic site on a carboxylic acid is the ________ oxygen. (Answer: carbonyl)
True or False: A nucleophile with pKa > 5 attacking a carboxylic acid will primarily deprotonate the O-H rather than add to the carbonyl. (Answer: True.)
Fill in the blank: At pH 7.4, an amino acid exists as a ________, with the carboxylic acid ________ and the amine ________. (Answer: zwitterion, deprotonated, protonated)
True or False: Nucleophilic acyl substitution can occur on acid chlorides under basic conditions. (Answer: True. Acid chlorides have no acidic proton to compete, and Cl- is an excellent leaving group.)
Q: An aldehyde is treated with NaOH. What happens at the alpha carbon, and is the reaction reversible or irreversible? Justify with pKa values.
A: Hydroxide (pKaH around 14) deprotonates the alpha C-H (pKa around 17) to form an enolate and water. The reaction is reversible because the pKa gap is only about 3 units. At equilibrium, only a small fraction of the aldehyde is converted to enolate.
Q: An aldehyde is treated with NaH. Same question.
A: NaH (pKaH = 35) deprotonates the alpha C-H (pKa around 17) to form an enolate and H2 gas. The reaction is irreversible because the pKa gap is about 18 units, and H2 escapes as a gas, driving the equilibrium fully to products.
Q: Why does treating a carboxylic acid with sodium hydroxide produce a carboxylate salt rather than a nucleophilic addition product?
A: The O-H proton of the carboxylic acid (pKa around 5) is much more acidic than the carbonyl is electrophilic. Hydroxide (a base with pKaH around 14) deprotonates the O-H in a fast, thermodynamically favourable proton transfer. Deprotonation is faster than nucleophilic addition, so the carboxylate salt forms exclusively.
Q: A hydroxy acid (HO-CH2-CH2-COOH) is treated with exactly 1 equivalent of NaH, followed by CH3I. Predict the product.
A: The 1 equivalent of NaH deprotonates the most acidic proton first, which is the carboxylic acid O-H (pKa = 5), not the alcohol O-H (pKa = 16). This forms the carboxylate. The carboxylate then acts as a nucleophile in an SN2 reaction with CH3I, forming the methyl ester while the alcohol remains untouched. Product: HO-CH2-CH2-COOCH3.
Q: Draw the structure of glycine (H2N-CH2-COOH) at pH 7.4, pH 1, and pH 13.
A: At pH 7.4 (physiological): zwitterion form, H3N+-CH2-COO-. The carboxylic acid is deprotonated (pH > pKa of about 2) and the amine is protonated (pH < pKaH of about 10.6). At pH 1 (strongly acidic): fully protonated, H3N+-CH2-COOH. Both groups carry their protons, net charge +1. At pH 13 (strongly basic): fully deprotonated, H2N-CH2-COO-. Both groups have lost their protons, net charge -1.
Enolate chemistry is the foundation for aldol reactions, Claisen condensations, and alpha-alkylation, all of which appear in the next unit. Carboxylic acid derivative reactivity leads directly into ester hydrolysis, amide bond formation (peptide chemistry), and transesterification. The multifunctional compound analysis (ranking pKa values across multiple sites) is exactly the skill needed for understanding amino acid chemistry and biochemical pathways, which rely on the same acid-base logic at physiological pH.
Aldehyde, ketone, carbonyl electrophile, alpha carbon, enolate, enol, enamine, nucleophilic addition, reversible addition, irreversible addition, cyanohydrin, carboxylic acid, carboxylate, ester, amide, anhydride, acid chloride, nucleophilic acyl substitution, zwitterion, amino acid, pKa ranking, multifunctional compound, hydroxy acid, NaH equivalents, CHEM 212, organic chemistry II, reaction prediction, Penn State