Source: Brown, Iverson, Anslyn, Foote, Organic Chemistry 8th ed., Chapters 16, 17, 18 + Carbohydrate supplement
Difficulty: Intermediate–Advanced | Prerequisites: Module 1 (spectroscopy, aromaticity), CHM 25500 (nucleophilic addition, acid-base chemistry, stereochemistry)
Tags: aldehydes, ketones, carbonyl chemistry, nucleophilic addition, carboxylic acids, acyl substitution, acid derivatives, esters, amides, anhydrides, acid chlorides, carbohydrates, hemiacetal, acetal, Fischer projection, Haworth projection
This is the heart of CHM 25600. The carbonyl group (C=O) is the most important functional group in organic chemistry: its reactivity drives everything from simple addition reactions in aldehydes and ketones to the substitution chemistry of carboxylic acid derivatives, and it underpins the biological chemistry of carbohydrates, peptides, and metabolic pathways. Module 1 gave you the tools to identify these groups spectroscopically. This module teaches you what they do. You should already be comfortable with curved-arrow mechanisms, acid-base equilibria, and the idea that nucleophiles attack electrophilic carbons.
Aldehydes and ketones undergo nucleophilic addition at the carbonyl carbon. Carboxylic acids and their derivatives (acid chlorides, anhydrides, esters, amides) undergo nucleophilic acyl substitution, where a nucleophile adds and then a leaving group departs. The reactivity order of acid derivatives tracks with leaving-group ability. Carbohydrates are polyhydroxy aldehydes or ketones whose chemistry is built on hemiacetal and acetal formation.
Carbonyl Group
A C=O double bond. The carbon is sp² hybridised and electrophilic because oxygen is more electronegative and pulls electron density away from carbon. In simple terms, the carbon of a C=O is a magnet for nucleophiles.
Nucleophilic Addition
The characteristic reaction of aldehydes and ketones: a nucleophile attacks the electrophilic carbonyl carbon, breaking the pi bond and forming a tetrahedral alkoxide intermediate. No leaving group departs.
Nucleophilic Acyl Substitution
The characteristic reaction of carboxylic acid derivatives: a nucleophile attacks the carbonyl carbon to form a tetrahedral intermediate, then a leaving group is expelled, regenerating the C=O. The net result is substitution of the leaving group by the nucleophile.
Tetrahedral Intermediate
The sp³ carbon species formed when a nucleophile adds to a carbonyl. In acyl substitution, this intermediate collapses by expelling the best available leaving group.
Hemiacetal
The product of adding one equivalent of alcohol to an aldehyde or ketone: a carbon bonded to both an –OH and an –OR group. Hemiacetals are usually unstable in open-chain form but are the basis of cyclic sugar structures.
Acetal
The product of adding a second equivalent of alcohol to a hemiacetal (replacing the –OH with another –OR). Acetals are stable under basic and neutral conditions but cleave in aqueous acid. They are commonly used as protecting groups for carbonyls.
Hydrate (Geminal Diol)
The product of adding water to a carbonyl: a carbon bearing two –OH groups. Most hydrates are thermodynamically unfavourable and revert to the carbonyl, but formaldehyde and some highly electrophilic aldehydes form stable hydrates.
Imine (Schiff Base)
The product of reacting an aldehyde or ketone with a primary amine (RNH₂). Contains a C=N double bond. Formation requires mildly acidic conditions (pH ~4–5) to protonate the intermediate but not the amine.
Enamine
The product of reacting an aldehyde or ketone with a secondary amine (R₂NH). Contains a C=C double bond adjacent to nitrogen.
Cyanohydrin
The product of adding HCN (or NaCN + acid) to a carbonyl. Contains an –OH and –CN on the same carbon.
Wittig Reaction
Converts a C=O to a C=C using a phosphorus ylide (Wittig reagent). The by-product is triphenylphosphine oxide. Think of it as a way to place a double bond exactly where a carbonyl used to be.
Carboxylic Acid
R–COOH. A weak organic acid whose acidity comes from resonance stabilisation of the carboxylate anion (RCO₂⁻). Typical pKa values are 4–5.
Acid Chloride (Acyl Chloride)
R–COCl. The most reactive carboxylic acid derivative. Chloride is an excellent leaving group.
Acid Anhydride
(RCO)₂O. The second most reactive derivative. One carboxylate unit acts as the leaving group.
Ester
R–COOR'. Moderate reactivity. The leaving group is an alkoxide (RO⁻), which is a poorer leaving group than Cl⁻ or RCO₂⁻.
Amide
R–CONR'₂. The least reactive carboxylic acid derivative because nitrogen donates its lone pair into the carbonyl, increasing the electron density on carbon and reducing its electrophilicity. The leaving group (NR₂⁻) is a very poor one.
Fischer Esterification
Acid-catalysed reaction of a carboxylic acid with an alcohol to form an ester and water. Reversible; driven forward by excess alcohol or removal of water.
Saponification
Base-promoted hydrolysis of an ester to give a carboxylate salt and an alcohol. Irreversible because the carboxylate anion is resonance-stabilised and non-electrophilic.
Lactone
A cyclic ester. Five- and six-membered lactones form readily.
Lactam
A cyclic amide. The beta-lactam ring is the core of penicillin antibiotics.
Carbohydrate (Sugar, Saccharide)
A polyhydroxy aldehyde (aldose) or polyhydroxy ketone (ketose). In simple terms, sugars are carbonyl compounds decorated with multiple hydroxyl groups, and their ring forms are intramolecular hemiacetals or hemiketals.
Anomeric Carbon
The carbon derived from the carbonyl carbon in the open-chain form of a sugar. It becomes the hemiacetal/hemiketal centre in the cyclic form and is bonded to two oxygen atoms.
Anomer
Stereoisomers that differ in configuration at the anomeric carbon only. Alpha and beta anomers differ in whether the –OH at the anomeric position is axial or equatorial (in the pyranose chair).
Mutarotation
The change in optical rotation observed when a pure anomer dissolves in water and equilibrates between alpha and beta forms through the open-chain intermediate.
Glycosidic Bond
An acetal linkage between the anomeric carbon of one sugar and a hydroxyl group of another molecule (another sugar or an aglycone). This is how disaccharides and polysaccharides are built.
The carbonyl carbon is electrophilic (δ+) because of the C=O dipole
Aldehydes are more reactive than ketones toward nucleophilic addition:
Less steric hindrance (one H vs. two R groups flanking the carbonyl)
One fewer electron-donating alkyl group, so the carbon is more electrophilic
Mechanism (general, under neutral/basic conditions):
Nucleophile attacks the carbonyl carbon
Pi bond breaks; electrons go to oxygen, forming an alkoxide
Alkoxide is protonated (by solvent or acid workup)
Under acidic conditions, the carbonyl oxygen is protonated first, making the carbon more electrophilic, and then the nucleophile attacks
Reactions to know:
Hydration (H₂O): gives a geminal diol; usually thermodynamically unfavourable except for formaldehyde and chloral
Hemiacetal/acetal formation (ROH, acid catalyst): one equivalent of ROH gives a hemiacetal; a second equivalent gives an acetal. Acetals are stable under neutral/basic conditions, cleaved by aqueous acid
Cyanohydrin formation (HCN or NaCN/H⁺): gives a cyanohydrin (alpha-hydroxy nitrile)
Grignard reaction (RMgBr then H₃O⁺): adds an alkyl or aryl group; primary/secondary/tertiary alcohol depending on the carbonyl
Reduction (NaBH₄ or LiAlH₄): hydride delivery gives an alcohol (aldehyde to primary alcohol, ketone to secondary alcohol)
Imine formation (RNH₂, mild acid): gives a C=N with loss of water
Enamine formation (R₂NH, mild acid): gives a C=C–NR₂ with loss of water
Wittig reaction (Ph₃P=CR₂): gives an alkene, replacing C=O with C=C
Monosaccharides are classified by:
Number of carbons: triose (3), tetrose (4), pentose (5), hexose (6)
Carbonyl type: aldose (aldehyde) or ketose (ketone)
D and L designation: based on the configuration of the highest-numbered stereocentre (the one closest to the bottom –CH₂OH in a Fischer projection). D-sugars have the –OH on the right in a Fischer projection; most biological sugars are D
Important monosaccharides: D-glucose, D-galactose, D-mannose, D-fructose, D-ribose
Cyclic forms:
Five-membered ring: furanose
Six-membered ring: pyranose
Formed by intramolecular hemiacetal (aldoses) or hemiketal (ketoses) cyclisation
Creates a new stereocentre at the anomeric carbon: alpha (–OH axial in glucose) and beta (–OH equatorial in glucose)
Haworth projections and chair conformations are both used to represent cyclic sugars
Mutarotation: pure alpha-D-glucose ([α] = +112°) or pure beta-D-glucose ([α] = +18.7°) equilibrates in water to a mixture with [α] = +52.5°
Glycosides: acetals formed at the anomeric position. Stable to base; cleaved by aqueous acid or enzymes
Disaccharides: two monosaccharides joined by a glycosidic bond
Maltose: alpha-1,4 link between two glucose units (reducing sugar)
Cellobiose: beta-1,4 link between two glucose units (reducing sugar)
Sucrose: alpha-1,2 link between glucose and fructose (non-reducing, because both anomeric carbons are tied up in the glycosidic bond)
Structure: R–COOH, pKa typically 4–5
Acidity is enhanced by:
Resonance stabilisation of the conjugate base (two equivalent C–O bonds in RCO₂⁻)
Electron-withdrawing substituents (halogens, nitro groups) via inductive effects
Proximity of the electron-withdrawing group to the carboxyl (alpha > beta > gamma)
Nomenclature: IUPAC uses "-oic acid" suffix; common names are widely used (formic, acetic, propionic, butyric, etc.)
Key reactions:
Deprotonation with base to form a carboxylate salt
Fischer esterification with an alcohol (acid-catalysed, reversible)
Conversion to acid chloride with SOCl₂ or oxalyl chloride
Reduction with LiAlH₄ to a primary alcohol (NaBH₄ does not reduce carboxylic acids)
Decarboxylation of beta-keto acids and malonic acid derivatives (loss of CO₂ via a six-membered cyclic transition state)
Reactivity order (most to least reactive toward nucleophilic acyl substitution):
Acid chloride > Anhydride > Ester ≈ Carboxylic acid > Amide
This tracks with leaving-group ability: Cl⁻ > RCO₂⁻ > RO⁻ > NR₂⁻
General mechanism (for all derivatives):
Nucleophile attacks the carbonyl carbon
Tetrahedral intermediate forms
Leaving group departs, regenerating C=O
Under basic conditions, the nucleophile attacks directly
Under acidic conditions, the carbonyl is first protonated to activate it
Interconversions:
You can always convert a more reactive derivative to a less reactive one (downhill in the reactivity series)
Going uphill requires activation (e.g. converting an ester to an acid chloride requires SOCl₂, not just adding Cl⁻)
Key reactions of acid chlorides:
H₂O → carboxylic acid (hydrolysis)
ROH → ester (alcoholysis)
RNH₂ → amide (aminolysis)
R₂CuLi → ketone (Gilman reagent, stops at the ketone stage)
LiAlH₄ → primary alcohol (over-reduction through the aldehyde)
LiAl(OtBu)₃H → aldehyde (controlled reduction)
Key reactions of esters:
Acid-catalysed hydrolysis (reversible) → carboxylic acid + alcohol
Saponification (NaOH or KOH, irreversible) → carboxylate salt + alcohol
Transesterification (new ROH, acid catalyst)
Reduction with LiAlH₄ → two alcohols (one from the acyl portion, one from the OR)
Reduction with DIBAL-H at low temperature → aldehyde
Grignard reagent (2 equivalents) → tertiary alcohol
Amides are the least reactive:
Hydrolysis requires prolonged heating in strong acid or base
This stability is why peptide bonds (amide bonds) persist under physiological conditions
Reactivity order of carbonyl compounds: Acid chlorides > Anhydrides > Aldehydes ≈ Ketones > Esters > Amides
(Note: aldehydes and ketones undergo addition, not substitution, because they lack a leaving group.)
Fischer esterification equilibrium: RCOOH + R'OH ⇌ RCOOR' + H₂O (acid catalyst, reversible)
Saponification: RCOOR' + NaOH → RCOONa + R'OH (irreversible)
Acetal formation: RCHO + 2 R'OH ⇌ RCH(OR')₂ + H₂O (acid catalyst)
Ester hydrolysis is the chemistry behind soap making (saponification of fats). Aspirin is an ester of salicylic acid and acetic acid, and its hydrolysis in the body releases the active salicylate. Glycosidic bonds in starch and cellulose are the reason you can digest bread but not wood: human enzymes cleave alpha-glycosidic bonds but not beta ones.
Students often think NaBH₄ and LiAlH₄ do the same thing. NaBH₄ is milder: it reduces aldehydes and ketones but not carboxylic acids or esters. LiAlH₄ reduces all of these. Choosing the wrong reagent is a common exam error.
Students frequently forget that acetal formation requires acid catalysis. Under basic conditions, hemiacetals can form but the conversion to the acetal does not proceed.
A common mistake is treating the reactivity order of acid derivatives as optional trivia. It is the single most tested concept in this section: you must know that you can go downhill (acid chloride to ester to amide) but not uphill without special activation.
Students often confuse reducing and non-reducing sugars. A reducing sugar has a free anomeric centre (hemiacetal) that can open to the aldehyde and act as a reducing agent. If both anomeric carbons are locked in glycosidic bonds (as in sucrose), the sugar is non-reducing.
⚠️ Nucleophilic addition (aldehydes/ketones) vs. nucleophilic acyl substitution (acid derivatives) is a fundamental distinction. Know which mechanism applies and why.
⚠️ The reactivity ranking of acid derivatives and the logic behind it (leaving-group ability) appears on virtually every exam covering this material.
⚠️ Acetal and hemiacetal chemistry connects directly to carbohydrate ring closure. If you understand acetal formation, sugar cyclisation makes sense; if you do not, it will feel arbitrary.
⚠️ Be able to draw full curved-arrow mechanisms for Fischer esterification, saponification, and amide hydrolysis. These are high-frequency exam questions.
⚠️ Know the reducing agents and what each one can and cannot reduce: NaBH₄ (aldehydes, ketones), LiAlH₄ (all carbonyls including acids and esters), DIBAL-H at −78 °C (ester to aldehyde).
True or false: Ketones are more reactive than aldehydes toward nucleophilic addition.
Fill in the blank: The least reactive carboxylic acid derivative toward nucleophilic acyl substitution is the ____.
True or false: An acetal is stable in aqueous base but cleaved in aqueous acid.
Fill in the blank: In a cyclic sugar, the anomeric carbon is bonded to ____ oxygen atoms.
True or false: Sucrose is a reducing sugar.
Answers: 1. False (aldehydes are more reactive). 2. Amide. 3. True. 4. Two. 5. False (both anomeric centres are involved in the glycosidic bond).
Q: Rank the following in order of decreasing reactivity toward nucleophilic acyl substitution: amide, ester, acid chloride, anhydride.
A: Acid chloride > anhydride > ester > amide. The ranking follows leaving-group ability.
Q: Draw the product of reacting butanal with excess methanol in the presence of an acid catalyst.
A: The product is butanal dimethyl acetal, CH₃CH₂CH₂CH(OCH₃)₂, plus water.
Q: Why does LiAlH₄ reduce esters but NaBH₄ does not?
A: LiAlH₄ is a much stronger nucleophilic hydride donor and a more powerful reducing agent. NaBH₄ cannot deliver hydride to the less electrophilic carbonyl of an ester (where the lone-pair donation from oxygen into the carbonyl reduces electrophilicity). LiAlH₄ is reactive enough to overcome this.
Q: D-Glucose forms a six-membered ring (pyranose). Which hydroxyl group attacks which carbon to form the ring?
A: The –OH on C-5 attacks the aldehyde carbon (C-1) in an intramolecular nucleophilic addition, forming a hemiacetal and creating the pyranose ring with an oxygen bridge between C-1 and C-5.
Q: What distinguishes a reducing sugar from a non-reducing sugar?
A: A reducing sugar has at least one free anomeric centre (a hemiacetal or hemiketal) that can open to expose the aldehyde (or alpha-hydroxy ketone), which can then reduce mild oxidising agents such as Tollens' reagent or Benedict's solution. A non-reducing sugar has all anomeric centres locked in acetal (glycosidic) linkages.
Carbonyl chemistry is the foundation for Module 3 (enolate anions), where you will learn how the alpha carbon of a carbonyl becomes nucleophilic. Carbohydrate chemistry connects to Module 4 (biological molecules), where polysaccharides, nucleic acids, and glycoproteins all depend on glycosidic bonds and hemiacetal/acetal logic. The spectroscopic tools from Module 1 (especially IR identification of C=O and NMR chemical shifts of aldehydic protons near 9.5 ppm) are used constantly to confirm the products of these reactions.
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