Nucleophilic Addition
Aldehydes and ketones both contain the carbonyl group (C=O), a polar double bond in which the electronegative oxygen atom draws electron density away from the carbon atom. This creates a partial positive charge (δ+) on the carbonyl carbon, making it an electrophilic centre readily attacked by nucleophiles — electron-rich species that donate a pair of electrons to form a new covalent bond. The resulting reaction class is called nucleophilic addition, and it is the defining reaction type of carbonyl compounds. In nucleophilic addition, the π bond of the C=O breaks heterolytically. The two electrons move onto oxygen (forming an alkoxide intermediate), while the nucleophile bonds to carbon. A proton source then protonates the alkoxide to give the final product — usually an alcohol or its derivative. Because ketones have two carbon substituents flanking the carbonyl, they are generally less reactive than aldehydes (more steric hindrance, greater electron donation from two alkyl groups reducing the δ+ charge). The four main nucleophilic addition reactions you need to know are: (1) addition of hydrogen cyanide (HCN) to give cyanohydrins; (2) addition of Grignard reagents (organomagnesium halides) to give alcohols; (3) addition of alcohols to give hemiacetals/hemiketals and then acetals/ketals; and (4) addition of ammonia derivatives (e.g. hydroxylamine, 2,4-dinitrophenylhydrazine, semicarbazide) to give condensation products collectively called imines or their derivatives. Each reaction follows the same fundamental mechanism but gives different useful products.
- General Mechanism of Nucleophilic Addition
- Reaction with HCN — Cyanohydrin Formation
- Grignard Reagents — Synthesis of Alcohols
- Reaction with Alcohols — Hemiacetals, Acetals, and Ketals
- Reaction with Ammonia Derivatives — Condensation to Imines and Derivatives
General Mechanism of Nucleophilic Addition
Step 1 – Nucleophilic attack: The nucleophile (Nu⁻ or Nu:) donates its lone pair or bonding electrons to the electrophilic carbonyl carbon. The C=O π bond breaks; both electrons move onto oxygen, generating a tetrahedral alkoxide intermediate (sp³ carbon, O⁻). Step 2 – Protonation: The alkoxide is protonated by water or acid to give the hydroxyl-containing product. Overall: R₂C=O + Nu⁻ → R₂C(Nu)(O⁻) → R₂C(Nu)(OH). Aldehydes react faster than ketones because they have less steric crowding around the carbonyl carbon and less electron donation destabilising the transition state.
Reaction with HCN — Cyanohydrin Formation
HCN adds across the C=O bond in the presence of a catalytic base (CN⁻ is the actual nucleophile; pure HCN reacts very slowly). The cyanide ion attacks the carbonyl carbon, giving a cyanohydrin: RCH=O + HCN → RCH(OH)CN. The product gains one carbon (chain extension), making this reaction synthetically valuable. For example, ethanal + HCN → 2-hydroxypropanenitrile (acetaldehyde cyanohydrin, pKₐ of HCN ≈ 9.2). The CN group can be hydrolysed to –COOH or reduced to –CH₂NH₂, enabling synthesis of α-hydroxy acids and amino acids. CAUTION: HCN is extremely toxic (LC₅₀ ~100 ppm inhalation).
Grignard Reagents — Synthesis of Alcohols
Grignard reagents (RMgX, where X = Cl, Br, or I) are prepared by reacting an alkyl or aryl halide with magnesium metal in dry diethyl ether. The C–Mg bond is highly polarised (δ–C–Mgδ+), so the carbon acts as a carbanion nucleophile. Addition to methanal (HCHO) gives a primary alcohol; to any other aldehyde gives a secondary alcohol; to a ketone gives a tertiary alcohol. For example: CH₃MgBr + CH₃CHO → (after H₃O⁺ workup) CH₃CH(OH)CH₃ (propan-2-ol). The reaction must be performed under strictly anhydrous conditions because Grignard reagents are destroyed by water (RMgX + H₂O → RH + Mg(OH)X). This is the most powerful method for building C–C bonds at a carbonyl carbon in introductory organic chemistry.
Reaction with Alcohols — Hemiacetals, Acetals, and Ketals
An alcohol (ROH) is a weak nucleophile; it attacks the carbonyl under acid catalysis. Step 1: One equivalent of alcohol adds to the aldehyde to give a hemiacetal [RCH(OH)(OR')]. This is an equilibrium favouring the open-chain form for most aldehydes (glucose is a notable exception — it exists predominantly as a cyclic hemiacetal). Step 2: Under acidic conditions with excess alcohol, the –OH of the hemiacetal is protonated and water is lost, forming an oxocarbenium ion, which is then attacked by a second alcohol molecule to give an acetal [RCH(OR')₂]. Acetals are stable to base and nucleophiles, making them excellent protecting groups for aldehydes in multi-step synthesis. Ketones give analogous hemiketals and ketals. The overall reaction is reversible; acetals are hydrolysed back to aldehydes/ketones by dilute aqueous acid.
Reaction with Ammonia Derivatives — Condensation to Imines and Derivatives
Ammonia (H₂N–) and its derivatives (H₂N–G, where G = OH, NHC₆H₄NO₂, NHCONH₂, etc.) react with carbonyl compounds in a two-stage process: (a) nucleophilic addition of N to carbonyl carbon gives a carbinolamine (hemiaminal); (b) acid-catalysed elimination of water gives a C=N double bond. The overall reaction (addition + elimination = condensation) is called nucleophilic addition–elimination. Products: aldehyde/ketone + NH₃ → imine (Schiff base, R₂C=NH); + H₂NOH (hydroxylamine) → oxime (R₂C=NOH); + H₂NNHC₆H₃(NO₂)₂ (2,4-DNPH) → 2,4-dinitrophenylhydrazone (bright orange/yellow precipitate, used as a qualitative test for carbonyls); + H₂NNHCONH₂ (semicarbazide) → semicarbazone. These derivatives have sharp, characteristic melting points used to identify unknown carbonyl compounds before modern spectroscopy was available.
The Key Equation
- \ce{R-CHO} — Aldehyde (mol): The carbonyl compound; the electrophilic C=O carbon is attacked by the nucleophile.
- \ce{HCN} — Hydrogen cyanide (mol): Source of the cyanide nucleophile (CN⁻). A catalytic base deprotonates HCN to release CN⁻.
- \ce{R-CH(OH)-CN} — Cyanohydrin (α-hydroxy nitrile) (mol): Product of nucleophilic addition; contains a new C–C bond, a hydroxyl group, and a nitrile group. One carbon longer than the starting aldehyde.
Worked Example
Problem. Predict the organic product formed when phenylmagnesium bromide (C₆H₅MgBr) reacts with propanal (CH₃CH₂CHO) in dry diethyl ether, followed by aqueous acid workup (H₃O⁺). Name the product and classify the alcohol type.
Answer. The product is 1-phenylpropan-1-ol, a secondary alcohol.
Origins · 1 minVictor Grignard and how this was discovered
Victor Grignard discovered organomagnesium halide reagents (now universally called Grignard reagents) in 1900 while working in Lyon under Philippe Barbier. He showed that alkyl halides react with magnesium in dry ether to form RMgX, which adds nucleophilically to carbonyl compounds to build C–C bonds — a reaction of enormous synthetic importance. For this discovery he was awarded the Nobel Prize in Chemistry in 1912, sharing it with Paul Sabatier. Grignard initially struggled to find academic employment; his breakthrough discovery came from improving upon a failed experiment by his supervisor Barbier. During World War I, he also contributed to French chemical warfare research, a stark contrast to his elegant peacetime organic chemistry.
Related Concepts
- Aldehydes & Ketones: Structure and Properties — Understanding carbonyl polarity, hybridisation (sp²), and reactivity differences between aldehydes and ketones is prerequisite knowledge for nucleophilic addition.
- Oxidation and Reduction of Carbonyl Compounds — Reduction of aldehydes and ketones by NaBH₄ or LiAlH₄ also proceeds via nucleophilic addition (H⁻ as nucleophile), linking directly to this concept.
- Nucleophilic Substitution (SN1 and SN2) — Contrasting nucleophilic addition (carbonyl retains all atoms) with nucleophilic substitution (a leaving group departs) deepens understanding of nucleophile reactivity.
- Carboxylic Acids and Their Derivatives — Cyanohydrin nitrile groups can be hydrolysed to carboxylic acids; Grignard additions to esters give tertiary alcohols — connecting carbonyl addition to carboxylic acid chemistry.
- Imines and Enamines — Addition of nitrogen nucleophiles to carbonyls forms imines and enamines via the nucleophilic addition–elimination pathway, a direct extension of this topic.