Difficulty: Intermediate | Prerequisites: Spectroscopy notes, basic understanding of nucleophiles and electrophiles.
Carbonyl compounds (aldehydes and ketones) are central to organic chemistry because the C=O bond is both polar and unsaturated, making the carbon a natural electrophile. Nucleophiles attack this carbon, and the oxygen picks up a proton. The result is a new bond to carbon and a change in functionality: from carbonyl to alcohol, diol, acetal, imine, or alkene, depending on the nucleophile and conditions. This set of reactions is the core of Organic Chemistry II synthesis strategy. You should already be comfortable with nucleophile/electrophile concepts and curved-arrow mechanisms.
Nucleophiles add to the electrophilic carbon of aldehydes and ketones. Depending on the nucleophile (water, alcohol, Grignard, hydride, amine, ylide, cyanide), you get diols, acetals, alcohols, imines, enamines, alkenes, or cyanohydrins. Each reaction has a characteristic oxidation-state change (or none) that helps you classify it.
Nucleophilic addition
The general mechanism for reactions at aldehyde and ketone carbonyls: a nucleophile attacks the electrophilic carbon, the pi bond breaks, and the oxygen becomes an alkoxide (which is then protonated).
In simple terms, something electron-rich attacks the carbon of C=O and pushes electrons onto the oxygen.
Diol (geminal diol / hydrate)
The product of water adding across a carbonyl: a carbon bearing two OH groups. Formed under both acidic and basic conditions. No net change in oxidation state.
Acetal
The product of two equivalents of alcohol adding to an aldehyde, with loss of water. An acetal has two OR groups on the same carbon. Formed under acid catalysis. Acetals are stable under basic conditions and are used as protecting groups for carbonyls.
Ketal
The same as an acetal, but starting from a ketone rather than an aldehyde. The term is sometimes used interchangeably with acetal.
Cyclic ketal
Formed when a 1,2-diol or 1,3-diol reacts with a carbonyl under acid catalysis. Produces a five- or six-membered ring containing two oxygen atoms. Commonly used as a protecting group.
Grignard reagent (RMgBr)
An organomagnesium halide that acts as a strong carbon nucleophile. Adds to carbonyls in a 1-electron-pair reduction, forming a new C-C bond and ultimately an alcohol after aqueous workup.
Think of it as a carbanion delivery system.
Wittig reagent / ylide
A phosphorus ylide (R₂C⁻-PPh₃⁺) that reacts with aldehydes and ketones to replace the C=O with a C=C. This is a 2-electron-pair reduction and produces a regiospecific alkene plus triphenylphosphine oxide.
Cyanohydrin
The product of HCN (with catalytic NaCN) adding to a carbonyl. The carbon now bears both an OH and a CN group. A 1-electron-pair reduction.
Sodium borohydride (NaBH₄)
A mild reducing agent that delivers hydride (H⁻) to carbonyls. Reduces aldehydes and ketones to alcohols. Will not reduce esters or carboxylic acids. A 2-electron-pair reduction.
Lithium aluminium hydride (LiAlH₄ / LAH)
A powerful reducing agent that reduces nearly all carbonyl-containing functional groups, including esters, carboxylic acids, amides, and nitriles, in addition to aldehydes and ketones.
Imine (Schiff base)
Formed when a primary amine (RNH₂) reacts with an aldehyde or ketone at pH 4.5, losing water. Contains a C=N bond. No net change in oxidation state.
Enamine
Formed when a secondary amine (R₂NH) reacts with an aldehyde or ketone at pH 4.5. Contains a C=C-N arrangement. A 1-electron-pair reduction. Reversible back to the carbonyl with H₃O⁺.
Oxime
Formed when hydroxylamine (NH₂OH) reacts with a carbonyl at pH 4.5. Contains a C=N-OH group. No net change in oxidation state.
Hydrazone
Formed when hydrazine (NH₂NH₂) reacts with a carbonyl at pH 4.5. Contains a C=N-NH₂ group.
Wolff-Kishner reduction
Conversion of a carbonyl to a methylene group (CH₂) using hydrazine and strong base (KOH) at high temperature. A 4-electron reduction. Proceeds through a hydrazone intermediate that loses N₂.
Aldehyde or ketone + catalytic KOH + H₂O → geminal diol.
Mechanism: hydroxide attacks the carbonyl carbon, forming an alkoxide, which is protonated by water.
No net oxidation state change.
Aldehyde or ketone + catalytic H₃O⁺ + H₂O → geminal diol.
Mechanism: the carbonyl oxygen is protonated first (activating the carbonyl), then water attacks the carbon, followed by proton transfers to reach the diol.
Also no net oxidation state change.
The equilibrium generally favours the carbonyl form for most aldehydes and ketones. Formaldehyde is an exception where the hydrate is favoured.
Aldehyde + 2 equivalents of alcohol + H₃O⁺ (acid catalyst) → acetal + H₂O.
Mechanism: protonation of carbonyl oxygen → alcohol attacks carbon → proton transfer gives hemiacetal → protonation of the OH → loss of water → second alcohol attacks the oxocarbenium ion → deprotonation gives the acetal.
No net change in oxidation state.
Ketone + a 1,2-diol (e.g. ethylene glycol) + HCl → cyclic ketal + H₂O.
The diol wraps around to form a five-membered ring with two oxygen atoms.
Mechanism follows the same steps as linear acetal formation, but the second alcohol attack is intramolecular.
Acetals are stable under basic and nucleophilic conditions but are cleaved by aqueous acid. This makes them ideal protecting groups for carbonyls: convert to an acetal, carry out reactions elsewhere on the molecule, then remove the acetal with H₃O⁺ to regenerate the carbonyl.
The lecture notes give the example of protecting one carbonyl in a molecule so that a Grignard reagent reacts at the other carbonyl, not the protected one.
Grignard reagents (RMgBr) are carbon nucleophiles. They add to carbonyls in a 1-electron-pair reduction, forming a new C-C bond.
The carbanion (R⁻) from the Grignard attacks the carbonyl carbon.
The oxygen picks up MgBr⁺, forming a magnesium alkoxide.
Aqueous workup (H₂O or dilute acid) protonates the alkoxide to give the alcohol.
Formaldehyde + RMgBr → primary alcohol (one more carbon than the Grignard).
Aldehyde + RMgBr → secondary alcohol.
Ketone + RMgBr → tertiary alcohol.
There are many ways to make the same alcohol by choosing different Grignard/carbonyl combinations. Retrosynthetic thinking: look at the alcohol, identify which C-C bond was formed, and work backwards to the Grignard and carbonyl starting materials.
The Wittig reaction converts a C=O into a C=C. It is a 2-electron-pair reduction and a regiospecific alkene addition.
Start with an alkyl halide (e.g. CH₃Br).
React with triphenylphosphine (PPh₃) in an SN2 reaction → phosphonium salt (CH₃-PPh₃⁺).
Deprotonate with a strong base (e.g. CH₃Li or n-BuLi) → ylide (⁻CH₂-PPh₃⁺).
The ylide carbon (carbanion) attacks the carbonyl carbon.
A four-membered ring intermediate (betaine / oxaphosphetane) forms.
The ring collapses, expelling triphenylphosphine oxide (O=PPh₃) and yielding the alkene.
The beauty of the Wittig is that you know exactly where the double bond ends up: it replaces the C=O. No ambiguity about regiochemistry.
Aldehyde or ketone + HCN (catalytic NaCN) → cyanohydrin (OH and CN on the same carbon).
1-electron-pair reduction.
The cyanide ion (CN⁻) is the actual nucleophile. It attacks the carbonyl, then HCN protonates the alkoxide.
The CN group can be further transformed: LiAlH₄ reduces it to a vicinal amino-alcohol. Acid hydrolysis converts it to an alpha-hydroxy acid.
NaBH₄ delivers H⁻ to the carbonyl carbon of aldehydes and ketones.
Produces primary alcohols from aldehydes, secondary alcohols from ketones.
2-electron-pair reduction.
Key limitation: NaBH₄ will not reduce esters or carboxylic acids. For those, you need LiAlH₄.
Aldehyde or ketone + primary amine (RNH₂) at pH 4.5 → imine (C=N-R) + H₂O.
Mechanism: amine attacks carbonyl → carbinolamine intermediate → protonation of OH → loss of water → imine.
Changes functionality (carbonyl to imine). No net oxidation state change.
pH 4.5 is optimal: acidic enough to protonate the OH leaving group, but not so acidic that the amine is fully protonated and unreactive.
Aldehyde or ketone + secondary amine (R₂NH) at pH 4.5 → enamine (C=C-NR₂) + H₂O.
1-electron-pair reduction. Changes functionality.
The mechanism is similar to imine formation, but because the nitrogen has no N-H left to lose, elimination occurs from the carbon adjacent to nitrogen, forming the C=C.
Reversible: treating the enamine with H₃O⁺ regenerates the original carbonyl.
Oxime: carbonyl + hydroxylamine (NH₂OH) at pH 4.5 → C=N-OH. No net oxidation change.
Hydrazone: carbonyl + hydrazine (NH₂NH₂) at pH 4.5 → C=N-NH₂.
Carbonyl + NH₂NH₂ + KOH, with heat → alkane (the C=O becomes CH₂) + N₂.
4-electron reduction. Proceeds via the hydrazone, which is then deprotonated and loses N₂ under strongly basic, high-temperature conditions.
This is the complement of the Clemmensen reduction (Zn/Hg, HCl), which achieves the same transformation under acidic conditions.
Not all carbonyls are equally reactive toward nucleophilic addition. The order from most reactive to least reactive is:
Acid chlorides > Aldehydes > Ketones > Esters > Amides
Steric argument: Aldehydes (one R group, one H) are more accessible to a nucleophile than ketones (two R groups). Less steric crowding at carbon means easier attack.
Electronic / resonance argument: The substituent on the carbonyl can donate electron density into the C=O through resonance, stabilising the carbonyl and making it less electrophilic (less reactive).
Acid chloride: Chlorine is a poor resonance donor (poor orbital overlap between 3p on Cl and 2p on C). The carbonyl is not stabilised much, so it is very reactive. Less stable = more reactive.
Aldehyde: Only one alkyl group donating into the carbonyl. Moderately reactive.
Ketone: Two alkyl groups stabilise the carbonyl more than one. Less reactive than aldehydes.
Ester: The OR oxygen lone pairs donate into the carbonyl through resonance (good 2p-2p overlap), significantly stabilising it. Much less reactive.
Amide: Nitrogen is an even better resonance donor than oxygen (less electronegative, more willing to share electrons). The carbonyl is highly stabilised. Amides are the least reactive carbonyls. Most stable = least reactive.
Ketones and aldehydes undergo nucleophilic addition (the nucleophile stays). Acid chlorides, esters, and amides undergo nucleophilic acyl substitution (the nucleophile replaces the leaving group). The leaving group ability follows the reverse of stability: Cl⁻ leaves easily, NR₂⁻ does not.
Students often assume NaBH₄ can reduce any carbonyl-containing compound. It cannot. NaBH₄ reduces aldehydes and ketones but will not touch esters or carboxylic acids. For those, you need LiAlH₄.
Acetal formation requires acid catalysis. Students sometimes try to form acetals under basic conditions, which does not work. Conversely, acetals are stable to base, which is precisely why they serve as protecting groups.
The Wittig reaction does not produce an alcohol. It replaces C=O with C=C. Students sometimes confuse it with Grignard addition.
Students often forget that imine and enamine formation both require pH 4.5. Too acidic and the amine is protonated (unreactive). Too basic and the water-loss step does not happen.
⚠️ You will be given a target molecule and asked how to make it. Know which reagent builds which product: Grignard → alcohol, Wittig → alkene, NaBH₄ → alcohol (mild), imine → C=N, enamine → C=C-N.
⚠️ Protecting groups (acetals) come up in multi-step synthesis problems. If a molecule has two carbonyls and you only want to react one, protect the other as an acetal.
⚠️ The carbonyl reactivity order (acid chloride through amide) is frequently tested. Be able to explain it using both steric and resonance arguments.
⚠️ Oxidation-state bookkeeping: know which reactions change the oxidation state and by how many electron pairs. Grignard and cyanohydrin are 1e⁻-pair reductions. NaBH₄ and Wittig are 2e⁻-pair. Wolff-Kishner is 4e⁻.
Grignard reactions are used extensively in pharmaceutical synthesis to build carbon frameworks. Acetals protect sensitive carbonyls during multi-step industrial processes. The Wittig reaction is one of the most reliable methods for making alkenes with defined regiochemistry, used in the synthesis of vitamin A and many drug intermediates.
True or False: An acetal can be formed under basic conditions.
False. Acid catalysis is required.
Fill in the blank: A Grignard reagent + formaldehyde gives a ______ alcohol.
Primary.
True or False: NaBH₄ reduces esters to alcohols.
False. You need LiAlH₄ for that.
Fill in the blank: The Wittig reaction converts a C=O into a ______.
C=C (alkene).
True or False: Enamine formation uses a primary amine.
False. Enamines use secondary amines. Primary amines give imines.
Q: Propose a synthesis of 2-methyl-2-butanol from a ketone and a Grignard reagent. Give two different combinations.
A: (1) Acetone (propan-2-one) + CH₃CH₂MgBr, then H₂O. (2) 2-Butanone (methyl ethyl ketone) + CH₃MgBr, then H₂O. Both give the same tertiary alcohol.
Q: You have a diketone and want to react only one carbonyl with a Grignard reagent. How do you do it?
A: Protect one carbonyl as a cyclic acetal (using ethylene glycol + HCl), perform the Grignard addition on the unprotected carbonyl, then remove the acetal with aqueous acid (H₃O⁺).
Q: What product forms when cyclohexanone is treated with (a) NH₂CH₃ at pH 4.5, and (b) (CH₃)₂NH at pH 4.5?
A: (a) An imine (C=N-CH₃). (b) An enamine (the double bond migrates to the carbon adjacent to nitrogen).
Q: Rank the following in order of decreasing reactivity toward nucleophilic addition: ester, aldehyde, amide, acid chloride, ketone.
A: Acid chloride > aldehyde > ketone > ester > amide.
These carbonyl addition reactions connect directly to nucleophilic acyl substitution (covered in the next set of notes), where the same nucleophilic attack at a carbonyl is followed by expulsion of a leaving group. Grignard and Wittig reactions will reappear in retrosynthesis problems throughout the rest of the course. Enamine chemistry leads into alpha-functionalisation (covered in the alpha-carbonyl chemistry notes).
Nucleophilic addition, carbonyl addition, aldehyde reactions, ketone reactions, diol, geminal diol, hydrate, hemiacetal, acetal, ketal, cyclic ketal, protecting group, Grignard reagent, RMgBr, Grignard addition, Wittig reaction, phosphorus ylide, triphenylphosphine oxide, cyanohydrin, HCN addition, NaBH4, sodium borohydride, LiAlH4, lithium aluminium hydride, LAH, hydride reduction, imine, Schiff base, enamine, oxime, hydrazone, Wolff-Kishner reduction, carbonyl reactivity, steric argument, resonance stabilisation, acid chloride reactivity, CHEM 212, organic chemistry II carbonyl reactions