Chapter 25 — Nucleophilic Addition to Aldehydes and Ketones

"An aldehyde meets a nucleophile and gets a new bond at carbon. That is the entire chapter, summarized in one sentence." — organic chemistry teaching maxim

"All of biology builds molecules by adding things to carbonyls. Every glycolytic intermediate, every fatty acid, every nucleotide — somewhere in their synthesis, a nucleophile attacked an aldehyde or a ketone."

This is the first carbonyl reactivity family from Section 24.2: addition. Aldehydes and ketones cannot undergo acyl substitution because their carbonyl carbon has only carbon-based substituents (R, H) and no leaving group. So when a nucleophile attacks, the nucleophile stays bonded to carbon, the C=O π electrons collapse onto oxygen, and a tetrahedral intermediate forms. After protonation, the result is some kind of alcohol or alcohol-derivative.

This is the simplest reaction pattern in carbonyl chemistry — and arguably the most important. Every reaction in this chapter follows the same two-step cartoon: (1) nucleophile to carbon; (2) protonation of oxygen. The variety comes from what the nucleophile is, what happens after the alkoxide forms (sometimes water is lost; sometimes a second equivalent of nucleophile adds), and whether the conditions are acid or base.

By the end of Chapter 25 you should be able to: - Predict the product of nucleophilic addition to any aldehyde or ketone, given the nucleophile. - Draw the full mechanism (with arrows) for: hydration, hemiacetal/acetal formation, imine/enamine formation, cyanohydrin formation, Grignard addition, hydride reduction, and the Wittig reaction. - Recognize protected carbonyls (acetals, ketals) and predict what they will do under acid or base. - Predict the stereochemistry of nucleophilic addition (Bürgi-Dunitz angle, π-face selectivity, the Felkin-Anh model). - Explain why some additions are reversible (hydration, hemiacetal) while others are not (Grignard, hydride). - Recognize this family in biology (glucose chemistry, amino acid metabolism, vision biochemistry).

25.1 The mechanism in detail

Every reaction in this chapter follows the same two-step cartoon, with variations on the back end.

Step 1: Nucleophilic attack

The nucleophile (anything with a lone pair or a polarized bond — water, alcohol, amine, cyanide, hydride, organometallic) approaches the electrophilic carbonyl carbon. The C-Nu bond forms; simultaneously the C=O π bond breaks, sending two electrons onto oxygen. The carbon goes from sp² (planar) to sp³ (tetrahedral). The oxygen, now bearing a negative charge (and three lone pairs), is the tetrahedral alkoxide intermediate.

This step is rate-limiting in most additions and is reversible: the alkoxide can in principle expel the nucleophile and regenerate the carbonyl. Whether the equilibrium favors forward or back depends on the nucleophile, the carbonyl substituents, and the solvent.

Mechanism Map 25.1: The universal addition step.

Nu⁻ + R₂C=O → R₂C(Nu)(O⁻) (Nu attacks C; C=O π → O lone pair; sp² → sp³)

This is the operation you will draw for every reaction in this chapter. Every variation is just (a) what the Nu is and (b) what happens to the alkoxide afterward.

Step 2: Protonation (or further reaction) of the alkoxide

The tetrahedral alkoxide is a strong base (pKa of the conjugate acid alcohol is ~16). It will pick up a proton from any acid present — water, alcohol solvent, the conjugate acid of the nucleophile, or an acid added in workup.

After protonation, the result is an alcohol (or its variant) with the nucleophile bonded to what was the carbonyl carbon.

For some reactions (hemiacetal, hemiaminal), the story stops here. For others (acetal, imine), step 2 is followed by loss of water and a second equivalent of nucleophile (or a tautomerization), giving the final product.

The Bürgi-Dunitz angle

When the nucleophile approaches the planar carbonyl carbon, it does so at an angle of about 107° from the C=O bond axis (rather than perpendicular at 90°). This is the Bürgi-Dunitz angle, derived from crystal structures of aminoketones in the 1970s by Bürgi, Dunitz, and Lehn (Chemistry Nobel laureate, 1987).

Why 107°? Because the new C-Nu bond forms with the π orbital of the carbonyl, which has a node at the C-O axis. Approach from above (pure perpendicular) overlaps poorly with π; approach at ~107° off the C-O bond gives optimal overlap. This angle has consequences: - For prochiral carbonyls (one face vs the other not the same), the Bürgi-Dunitz approach selects which face is attacked. - For cyclic carbonyls (cyclohexanone), the steric environment of axial vs equatorial substituents matters. - For amino acid synthesis with Strecker (cyanide) or transamination (PLP-mediated), the trajectory of attack determines stereochemistry.

The Bürgi-Dunitz angle returns in Chapter 25 (Felkin-Anh model) and Chapter 28 (aldol stereochemistry).

25.2 Hydration: the simplest addition

Water is the simplest nucleophile. Adding water to an aldehyde or ketone gives a gem-diol (two OH groups on the same carbon):

$$R_2C{=}O + H_2O \rightleftharpoons R_2C(OH)_2$$

The reaction is reversible. The equilibrium constant depends critically on the substituents:

What drives this dramatic span? Two effects:

1. Steric: gem-diol has two OH groups crowding the central carbon. Going from sp² (planar) to sp³ (tetrahedral) increases substituent congestion. Methyl groups (in acetone) are bigger than H's (in formaldehyde), so acetone's hydrate is destabilized.

2. Electronic: the carbonyl is destabilized (energy raised) by electron-withdrawing groups; the gem-diol does not have the C=O stabilization. Electron-withdrawing groups like CCl₃ or CF₃ destabilize the C=O preferentially, shifting the equilibrium toward the hydrate.

Hydration is rarely a productive synthesis (gem-diols revert to the carbonyl on isolation), but the equilibrium matters for understanding aqueous chemistry of carbonyls and the role of acid/base catalysis. The mechanism is also the simplest example of the universal addition pattern — making it the place to first learn the arrow-pushing.

Worked Problem 25.1: Why is the hydrate of formaldehyde the dominant species in water (>99.9%) but the hydrate of acetone is minor (~0.14%)?

Solution: Two methyl groups in acetone hyperconjugate with the C=O π* and stabilize the carbonyl. Hydration removes that stabilization. The two methyls also crowd each other in the sp³ gem-diol. Both effects push the equilibrium back to the carbonyl. Formaldehyde has only H's — no hyperconjugative stabilization, no steric crowding — so the equilibrium goes the other way.

25.3 Hemiacetals and acetals: protecting the carbonyl

When the nucleophile is an alcohol rather than water, the same chemistry plays out.

Hemiacetal formation (one alcohol)

$$R_2C{=}O + R'OH \rightleftharpoons R_2C(OH)(OR')$$

The product, a hemiacetal, has one OH and one OR' on the same carbon. Like hydration, this reaction is reversible and the equilibrium often favors the carbonyl (especially for ketones). Acid or base catalysis accelerates the equilibration.

Glucose's pyranose form is a hemiacetal — and an intramolecular one, where one C-OH within the same glucose molecule attacks the C=O of the same molecule. The intramolecular nature makes the equilibrium dramatically favor the cyclic form (~99.98% pyranose, see Ch 24 case study 1).

Acetal formation (two alcohols, acid catalyzed)

Continuing past the hemiacetal under acid catalysis with excess alcohol:

$$R_2C(OH)(OR') + R'OH \xrightarrow{H^+} R_2C(OR')_2 + H_2O$$

The OH of the hemiacetal is protonated (becomes a leaving group), water leaves, an oxocarbenium intermediate forms, the second alcohol attacks, deprotonation, and finally the acetal is born — two OR groups on one carbon, no OH.

Acetals are stable under basic conditions but hydrolyze back to the aldehyde under acidic conditions. This stability profile makes them excellent protecting groups: when you want to perform some other reaction (e.g., a Grignard, which tolerates the OR but would attack a free C=O), you can protect the carbonyl as an acetal first, do the reaction, then hydrolyze the acetal back to the carbonyl.

A common protecting strategy uses a diol (e.g., ethylene glycol) to form a cyclic acetal (a 5- or 6-membered ring). The cyclic version is more stable than the open-chain dimethyl acetal because of the chelate effect — both OR' groups are tied together in one ring.

Mechanism Map 25.2: Acetal formation. 1. R₂C=O + H⁺ → R₂C=OH⁺ (protonation makes the C more electrophilic) 2. R'OH attacks C; alkoxide is now -O⁺HR' (protonated) 3. Deprotonation gives R₂C(OH)(OR') (hemiacetal) 4. Reprotonate the OH → R₂C(OH₂⁺)(OR') (this OH is now a leaving group) 5. Water leaves → R₂C⁺(OR') (an oxocarbenium ion stabilized by the lone pairs on the remaining OR') 6. Second R'OH attacks → R₂C(OR')(O⁺HR') (protonated acetal) 7. Deprotonation → R₂C(OR')₂ (acetal) + H⁺ (regenerated catalyst)

Note: the mechanism is reversible. Driving forward by removing water (Dean-Stark trap, molecular sieves) shifts the equilibrium to the acetal.

Why glucose isn't an acetal in water

Glucose has the C5-OH and another OH that could in principle form an acetal at C1. Why is glucose mostly a hemiacetal (~99.98% cyclic hemiacetal) rather than an acetal? Because acetal formation requires acidic conditions plus loss of water, and at neutral pH (water solvent, no driving force to remove water), the hemiacetal is the thermodynamic resting place. To form an acetal of glucose (e.g., methyl glucoside), one acidifies and reacts with methanol, removing water as it forms. This is the standard glycosidic bond synthesis (Ch 32).

25.4 Imines and enamines: addition with loss of water

When the nucleophile is an amine instead of an alcohol, the same hemiketal-style intermediate forms, but the nitrogen has a different fate than oxygen would.

Primary amines give imines (Schiff bases)

A primary amine ($R'NH_2$) attacks an aldehyde or ketone to give a hemiaminal ($R_2C(OH)(NHR')$), which loses water to form an imine (also called a Schiff base):

$$R_2C{=}O + R'NH_2 \to R_2C{=}NR' + H_2O$$

The imine has a C=N double bond — analogous to the C=O carbonyl. Under acidic conditions, imines protonate to iminium ions ($R_2C{=}N^+(H)R'$), which are excellent electrophiles in their own right (more reactive than the parent C=O because nitrogen donates more weakly than oxygen — wait, that's wrong: actually, iminium is more electrophilic at C than the imine, but imine is comparable to C=O in electrophilicity).

Imine formation is reversible. The equilibrium and kinetic optimum are at pH ~5: acidic enough to protonate the OH leaving group during loss of water, but not so acidic that the amine itself is fully protonated (and so no longer nucleophilic). At pH 7 (physiological), the kinetics of imine formation are slow but nonzero — relevant to the Maillard browning reactions and to glycosylation of hemoglobin (HbA1c).

Secondary amines give enamines

A secondary amine ($R'R''NH$) cannot form an imine after addition (no H to lose from N for the C=N). Instead, the hemiaminal intermediate loses water by deprotonating the α-carbon:

$$R_2C{=}O + R'R''NH \to (R)_2HC{-}C(R){=}N(R')(R'') \to R_2C{=}CR{-}N(R')(R'')$$

Wait, let me redo. The hemiaminal is $R_2C(OH)(NR'R'')$. Acid protonates the OH; water leaves giving an iminium ion ($R_2C^{=}N^+R'R''$). The α-carbon's hydrogen is now α to the iminium and is acidic (because removal gives an enamine that is conjugated). Deprotonation of α-H gives the enamine:

$$R_2C{=}CR{-}N(R')(R'')$$

The C=C double bond is shifted to the α-position. Enamines are nucleophilic at the α-carbon (because the lone pair on nitrogen can delocalize through the C=C, putting electron density on the α-carbon). They react with electrophiles like alkyl halides, giving alkylation products. We'll return to this in Chapter 27.

Reductive amination: an indispensable synthetic tool

If you want to make an amine from a ketone, the classic method is reductive amination: form the imine, then reduce in situ (often with NaBH₃CN, which reduces iminium but not the parent C=O):

$$R_2C{=}O + R'NH_2 \xrightarrow{\text{cat. H}^+} R_2C{=}NR' \xrightarrow{NaBH_3CN} R_2CH{-}NHR'$$

The reduction is selective for the protonated iminium (which is more electrophilic than the C=O). So you can do this in one pot at pH 5–6: the carbonyl forms imine first, the imine protonates and reduces faster than the C=O does.

Reductive amination is one of the most-used reactions in pharmaceutical synthesis. Hundreds of FDA-approved drugs are made (in some step) by reductive amination of a ketone with an amine.

Biological Connection 25.1: Vision and the Schiff base of retinal.

The light-detecting molecule in your retina is rhodopsin: opsin (a protein) covalently bonded to retinal (a polyunsaturated aldehyde, the oxidized form of vitamin A) by an imine. The retinal aldehyde forms a Schiff base with a lysine residue on opsin. When a photon hits, the retinal isomerizes from 11-cis to all-trans, the Schiff base hydrolyzes, and a signaling cascade fires. The whole apparatus relies on the reversibility of imine formation — perfectly tuned to the requirements of vision.

Other PLP (pyridoxal phosphate) enzymes work the same way. PLP, an aldehyde, forms a Schiff base with the substrate amine. The geometry of the bound substrate determines whether transamination, decarboxylation, or racemization occurs. The amino acid metabolic pathways depend on this single chemistry, applied in many variations.

25.5 Cyanohydrins: extending the carbon chain

Cyanide ($CN^-$) is a particularly interesting nucleophile. It attacks the carbonyl, gives an alkoxide, and protonation gives a cyanohydrin:

$$R_2C{=}O + HCN \to R_2C(OH)(CN)$$

In practice, the catalyst is a small amount of base (or KCN with HCN); the equilibrium favors the cyanohydrin for most aldehydes and many ketones.

What makes this useful? The CN group can be: - Hydrolyzed to a COOH (Ch 26): R₂C(OH)(CN) → R₂C(OH)(COOH). - Reduced with LiAlH₄ to a primary amine: R₂C(OH)(CN) → R₂C(OH)(CH₂NH₂).

Either way, the cyanohydrin extends the carbon chain by one and installs a useful functional group (COOH or CH₂NH₂) at the new position. This is the basis of the Strecker synthesis of amino acids: aldehyde + ammonia + HCN gives an α-aminonitrile, which hydrolyzes to an α-amino acid. Strecker is one of the oldest amino acid syntheses (dating to 1850).

25.6 Grignard reagents: forging C-C bonds

Carbon nucleophiles are the most synthetically powerful — they make new C-C bonds, the heart of synthesis. The most accessible are the Grignard reagents ($R-MgX$, where X = Cl, Br, I) and organolithiums ($R-Li$).

A Grignard reagent forms by reacting an alkyl halide with magnesium metal in dry ether: $$R-X + Mg \to R-MgX$$

The R-Mg bond is highly polarized (Mg is electropositive, R is electronegative-ish). The carbon end is carbanion-like — a carbon nucleophile. When mixed with a carbonyl, the Grignard adds:

$$R'-MgX + R_2C{=}O \to R_2C(R')(OMgX)$$

Followed by aqueous workup ($H_3O^+$) to protonate the alkoxide:

$$R_2C(R')(OMgX) + H_3O^+ \to R_2C(R')(OH)$$

The result is a new C-C bond and a new alcohol. With: - Aldehyde + Grignard: secondary alcohol. - Ketone + Grignard: tertiary alcohol. - Formaldehyde + Grignard: primary alcohol. - Ester + 2 Grignard: tertiary alcohol (ester goes through a ketone intermediate that gets attacked again).

Grignard addition is irreversible — the C-C bond is strong, and the alkoxide is a poor leaving group. This is in stark contrast to hydration (reversible) or hemiacetal (reversible).

Limitations: - Grignards do not tolerate acidic protons (would deprotonate first instead of adding). So no -OH, -NH, -SH, -COOH in the substrate. These groups must be protected first. - Grignards do not tolerate other electrophiles (would attack them too). So no -NO₂, no other carbonyls except the target. - Grignards require dry, oxygen-free conditions (water/oxygen rapidly destroy them).

Worked Problem 25.2: Predict the product of cyclohexanone + ethylmagnesium bromide, followed by aqueous workup. Then predict the product of methyl benzoate (an ester) + 2 equivalents of phenylmagnesium bromide.

Solution: First reaction: cyclohexanone + EtMgBr → 1-ethylcyclohexanol (a tertiary alcohol). Second reaction: methyl benzoate + 2 PhMgBr → triphenylmethanol (Ph₂C(Ph)(OH)). The ester reacts with one Ph⁻ to form a ketone (PhCOPh, benzophenone) which is too reactive to isolate; the second PhMgBr attacks benzophenone to give the trityl alcohol.

Organolithiums (R-Li) are even more reactive than Grignards, useful for slightly different cases. The chemistry is qualitatively the same.

25.7 Hydride reduction

Hydride sources are reagents that effectively deliver $H^-$ to the carbonyl:

Mechanism: hydride attacks the carbonyl C; π electrons go to O; alkoxide protonates on workup; alcohol product.

NaBH₄ selectivity: in MeOH, NaBH₄ reduces aldehydes and ketones quickly (minutes) but leaves esters/amides/COOH untouched (they don't react in days). This is because ester/amide C=O is less electrophilic (Ch 24 reactivity ordering).

LiAlH₄ has no such selectivity: the high charge density and aggressive H-delivery overcome the lower electrophilicity of esters/amides.

Common Mistake 25.1: Mixing up which hydride does what. Memorize: NaBH₄ does aldehydes and ketones only; LiAlH₄ does everything. When in doubt, use the milder NaBH₄ first; only escalate to LiAlH₄ if you need more reactivity.

In biology, the analogous reagent is NADH/NADPH — a nicotinamide cofactor that delivers a "hydride equivalent" to a carbonyl. Examples: lactate dehydrogenase reduces pyruvate (a ketone) to lactate using NADH. The mechanism is essentially the same as NaBH₄'s, just enzyme-catalyzed.

25.8 The Wittig reaction: aldehyde or ketone → alkene

The Wittig reaction (Nobel Prize 1979 to Wittig) is a beautiful method for converting an aldehyde or ketone into an alkene with control of the alkene geometry.

The reagent is a phosphorus ylide ($R_3P^+{-}CR'_2^-$), generated by deprotonating a phosphonium salt with a strong base:

$$R_3P{=}CR'_2 + R''_2C{=}O \to R''_2C{=}CR'_2 + R_3P{=}O$$

The ylide attacks the carbonyl C; an oxaphosphetane (4-membered ring with P-O and C-C) forms; it collapses to alkene + triphenylphosphine oxide.

Why Wittig matters: - Highly chemoselective (tolerates many other groups). - Geometry-controlled: with stabilized ylides (R' = ester, ketone, aryl), trans (E) alkene predominates. With non-stabilized ylides (R' = alkyl, H), cis (Z) alkene predominates. - Atom-economical: phosphine oxide is the byproduct, easy to remove. - Compatible with most other functional groups.

Used in the synthesis of vitamins, terpenes, hormones, and many drugs. The cis-Wittig is especially valuable for natural products with embedded cis double bonds (e.g., insect pheromones).

25.9 Stereochemistry of nucleophilic addition

When a nucleophile adds to a prochiral aldehyde or ketone (one face is different from the other), it produces a stereocenter. Two patterns to know:

π-face selectivity in cyclic ketones

In a substituted cyclohexanone, the nucleophile can attack from the axial or equatorial face. For small, hindered nucleophiles like LiAlH₄, equatorial attack is preferred (less steric clash). For bulky nucleophiles like L-Selectride, axial attack is preferred (Bürgi-Dunitz angle from the less-hindered axial direction). The result: NaBH₄ on 4-tert-butylcyclohexanone gives ~90% trans (axial OH, equatorial t-Bu), while L-Selectride gives ~95% cis.

Felkin-Anh model for acyclic carbonyls

For an aldehyde with a stereocenter at the α-carbon (the carbon next to C=O), the nucleophile approaches the carbonyl carbon at the Bürgi-Dunitz angle, and the α-substituents are oriented to minimize steric clash with the incoming nucleophile. The largest α-substituent points away from the incoming Nu; the medium-sized substituent goes "near" the Nu; the smallest substituent stays "near" the carbonyl. The result is one diastereomer preferred over the other — typically the anti (Felkin-Anh) diastereomer.

Felkin-Anh predicts the stereochemistry of dozens of important reactions in synthesis, including aldol condensations and reductions of α-substituted aldehydes/ketones.

Computational Exercise 25.1: Build cyclohexanone in Avogadro. Compute the optimum geometry. Identify the axial and equatorial faces of the C=O. Place a hydride at the Bürgi-Dunitz angle of 107° from above; compute the steric energy of attack from each face. Compare to L-Selectride (replace H with a bulky boronate). Verify the predicted face preference.

25.10 Spectroscopy of products

When a carbonyl is converted to an alcohol (e.g., by reduction or Grignard), the IR C=O stretch (around 1720 cm⁻¹) disappears and a broad O-H stretch around 3300 cm⁻¹ appears. ¹H NMR: the aldehyde H at δ 9–10 ppm is gone; an OH (broad, exchangeable) appears at δ 0.5–4 ppm.

When a carbonyl is converted to an imine, the C=O at 1720 → C=N at 1640 cm⁻¹. ¹H NMR: the imine H at δ 7–9 ppm replaces the aldehyde H.

When a carbonyl is converted to an acetal, the C=O is gone; both ¹H and ¹³C show the new C-H and C-O environments. The acetal carbon resonates at δ 95–105 ppm in ¹³C — diagnostic.

Spectroscopy Clue 25.1: An aldehyde shows IR at 1720 cm⁻¹ and ¹H NMR at δ 9.7. After NaBH₄, the IR loses the 1720 peak and gains a broad 3300 peak; the NMR loses the 9.7 peak and gains an OH (exchangeable) and a new -CH(OH)- multiplet at δ 3.5–4. These changes confirm reduction has occurred.

25.11 Biology of nucleophilic addition

Carbonyl addition is everywhere in biology. A few examples:

• Glucose hemiacetal formation (Ch 24): intramolecular addition of C5-OH to C1 aldehyde forms the pyranose ring.
• Hemoglobin glycation (HbA1c): a slow imine formation between glucose's C1 aldehyde and the N-terminal amine of hemoglobin. The imine isomerizes to a Amadori product (a stable amino-ketone). Used as a long-term diabetes marker because RBC turnover is ~120 days.
• Vision (rhodopsin, Biological Connection 25.1): retinal Schiff base.
• Thiamine and pyruvate decarboxylation: thiamine's ylide attacks pyruvate's α-keto carbonyl, forming a reactive intermediate that decarboxylates. This is the first step of fermentation.
• NADH-mediated reductions: lactate dehydrogenase, alcohol dehydrogenase, malate dehydrogenase — all use NADH to reduce a carbonyl, exactly as NaBH₄ would in vitro.
• Retro-aldol: aldolase enzymes catalyze the reverse of an aldol (Ch 28) by abstracting an α-H to form an enol/enolate, then breaking the C-C bond between α and β. Glycolysis step 4.

25.12 Why this chapter matters

Nucleophilic addition to aldehydes and ketones is the foundational transformation of synthesis. Once you have it, you can: - Make alcohols from carbonyls (NaBH₄, LiAlH₄). - Make C-C bonds (Grignard, organolithium). - Make alkenes from carbonyls (Wittig). - Make imines and amines (reductive amination). - Protect a carbonyl as an acetal during other reactions.

These tools are used in every drug synthesis. Appendix F lists ~100 named reactions; perhaps 30 are direct variants of nucleophilic addition. Master them here, and the rest of carbonyl chemistry will feel like elaborations on a theme.

25.13 Summary

1. Nucleophilic addition: Nu attacks C; π electrons go to O; alkoxide protonates; alcohol or its derivative results.
2. Hydration: water + carbonyl → gem-diol. Equilibrium favors carbonyl for most carbonyls except formaldehyde and electron-poor aldehydes.
3. Hemiacetal: alcohol + carbonyl, reversible. Glucose's pyranose is an example.
4. Acetal: alcohol + carbonyl + acid + remove water. Used as protecting group.
5. Imine: primary amine + carbonyl. Reversible. pH ~5 optimal.
6. Enamine: secondary amine + carbonyl. C=C-N functional group, used in alkylation chemistry (Ch 27).
7. Cyanohydrin: HCN + carbonyl. Extends carbon chain.
8. Grignard: R-MgX + carbonyl → new C-C, new alcohol. Aldehyde → 2° OH; ketone → 3° OH; ester → 3° OH (after 2 equiv).
9. Hydride: NaBH₄ (aldehydes, ketones); LiAlH₄ (almost everything).
10. Wittig: ylide + carbonyl → alkene. Geometry depends on ylide stability.
11. Stereochemistry: Bürgi-Dunitz angle, π-face selectivity, Felkin-Anh model.
12. Biology: glucose, vision, glycation, NADH reductions — all examples of this chemistry.

Chapter 26 introduces the second carbonyl reactivity family: acyl substitution. The same nucleophilic attack on C=O, but now with a leaving group on C — so the nucleophile substitutes for the leaving group instead of just adding.