Premed · Premed · Organic Chemistry 2
Lecture 7: Nucleophilic Addition to Carbonyls
Organic Chemistry II
Learning Objectives
By the end of this lecture, students will be able to:
- Describe the general mechanism of nucleophilic addition to aldehydes and ketones
- Explain the factors affecting the reactivity of carbonyls toward nucleophilic addition
- Predict the products of reactions with hydride reagents, Grignard reagents, and organolithium reagents
- Write mechanisms for cyanohydrin formation, hydration, acetal formation, and imine/enamine formation
- Describe the Wittig reaction and its use in alkene synthesis
- Distinguish between reversible and irreversible nucleophilic additions
Lecture Content
I. General Mechanism of Nucleophilic Addition
The carbonyl carbon is electrophilic because of the C=O dipole, which places a significant partial positive charge on carbon. Nucleophilic addition can proceed under two sets of conditions. Under basic or neutral conditions, the nucleophile attacks the carbonyl carbon directly, forming a tetrahedral alkoxide intermediate, which is then protonated to give the product. Under acidic conditions, the carbonyl oxygen is protonated first, which activates the C=O bond by making the carbon even more electrophilic, and then the nucleophile attacks the activated carbonyl.
The nucleophile approaches the trigonal planar sp2 carbon from either face at the Burgi-Dunitz angle of approximately 107 degrees. If the addition creates a new stereocenter, a racemic mixture results unless a chiral catalyst or chiral auxiliary is employed.
II. Factors Affecting Reactivity
Steric effects play a major role in determining reactivity. Less substituted carbonyls react faster because the transition state involves compression of bond angles from approximately 120 degrees to approximately 109.5 degrees, and bulkier substituents increase the strain associated with this rehybridization. The overall reactivity order is formaldehyde > other aldehydes > ketones.
Electronic effects also influence reactivity. Electron-withdrawing groups increase the electrophilicity of the carbonyl carbon, making the compound more reactive. Chloral (trichloroacetaldehyde, Cl3CCHO) is so reactive that it reacts with water to form a stable hydrate. Conversely, electron-donating groups decrease reactivity by reducing the partial positive charge on carbon. Conjugation with additional pi systems, such as an aromatic ring or an extended enone, decreases reactivity because the electron density of the carbonyl is partially delocalized. Taking all these factors together, the overall reactivity order is H2C=O > RCHO > ArCHO > R2C=O > ArCOR > Ar2C=O.
III. Reduction with Hydride Reagents
Sodium borohydride (NaBH4) is a mild reducing agent that selectively reduces aldehydes and ketones while leaving esters, carboxylic acids, and amides untouched under standard conditions. It is typically used in methanol or ethanol as solvent. The mechanism involves delivery of a hydride ion (H-) from the BH4- anion to the carbonyl carbon, producing an alkoxide intermediate that is subsequently protonated. Aldehydes are reduced to primary alcohols, and ketones to secondary alcohols.
Lithium aluminum hydride (LiAlH4) is a far more powerful reducing agent that reduces virtually all carbonyl-containing functional groups, including aldehydes, ketones, esters, carboxylic acids, amides, acid chlorides, and epoxides. Because LiAlH4 reacts violently with water, it must be used in anhydrous ether solvents such as diethyl ether or THF, followed by a careful aqueous workup. DIBAL-H, when used at -78 degrees C, occupies an intermediate niche, selectively reducing esters to aldehydes without proceeding further.
IV. Addition of Organometallic Reagents
Grignard reagents (RMgX), prepared from alkyl or aryl halides with magnesium in ether, function as carbanion equivalents and attack carbonyl carbons to form new carbon-carbon bonds. The product depends on the carbonyl substrate: formaldehyde yields a primary alcohol, an aldehyde yields a secondary alcohol, and a ketone yields a tertiary alcohol (all after aqueous workup). Organolithium reagents (RLi), formed from RX with two equivalents of lithium metal, are more reactive than Grignard reagents but give the same types of products.
These reagents have important limitations. They cannot be used in protic solvents such as water, alcohols, or amines, and the substrate must not contain acidic protons (N-H, O-H, S-H, or terminal alkyne C-H), as these would protonate and destroy the organometallic species. Acetylide anions (RC triple bond C:- Na+) add to carbonyls to give propargylic alcohols, providing a useful method for extending carbon chains while incorporating a triple bond.
<image>Reaction summary diagram showing three types of carbonyl compounds (formaldehyde, aldehyde, ketone) each reacting with RMgBr. Formaldehyde gives a primary alcohol, an aldehyde gives a secondary alcohol, and a ketone gives a tertiary alcohol. Each pathway shows the intermediate magnesium alkoxide and the aqueous acid workup step. A note indicates that organolithium reagents give the same products.</image>
V. Nucleophilic Addition of Water and Alcohols
Hydration of an aldehyde or ketone with water produces a geminal diol (gem-diol) in a reversible equilibrium process. For most carbonyl compounds, the equilibrium strongly favors the carbonyl form. Notable exceptions include formaldehyde, which is more than 99% hydrated in aqueous solution, and chloral (trichloroacetaldehyde), where the three electron-withdrawing chlorine atoms stabilize the hydrate. The reaction is catalyzed by acid or base.
Addition of one equivalent of alcohol gives a hemiacetal (or hemiketal), a process that is generally unfavorable at equilibrium except when five- or six-membered cyclic hemiacetals can form. These cyclic hemiacetals are ubiquitous in carbohydrate chemistry, where they constitute the pyranose and furanose ring forms of sugars. Under acid catalysis, the mechanism involves protonation of the carbonyl, nucleophilic attack by the alcohol, and deprotonation.
Treatment of a hemiacetal with a second equivalent of alcohol under acid catalysis, with removal of water, produces an acetal. Acetals contain two -OR groups on the same carbon and have the general formula RCH(OR')2 or R2C(OR')2. The acid-catalyzed mechanism proceeds in five steps: protonation of the carbonyl, alcohol attack to form the hemiacetal, protonation of the hemiacetal hydroxyl, loss of water to generate an oxocarbenium ion, and attack by a second alcohol molecule. Acetals are stable under basic conditions and toward nucleophilic reagents, making them excellent protecting groups for aldehydes and ketones during reactions at other functional groups in the molecule. They are cleanly removed by treatment with aqueous acid. The use of 1,2-diols or 1,3-diols produces cyclic acetals such as 1,3-dioxolanes and 1,3-dioxanes.
<image>Step-by-step acid-catalyzed mechanism for acetal formation from an aldehyde and two equivalents of methanol. Five steps are shown with curved arrows: (1) protonation of C=O by H+, (2) nucleophilic attack by methanol to form the hemiacetal, (3) protonation of the -OH of the hemiacetal, (4) loss of water to form the oxocarbenium ion resonance-stabilized intermediate, (5) attack by a second methanol molecule and deprotonation to give the dimethyl acetal product. Each intermediate is clearly labeled.</image>
VI. Addition of Nitrogen Nucleophiles
Primary amines (RNH2) react with aldehydes and ketones to form imines (Schiff bases) with loss of water. The mechanism involves initial nucleophilic addition to give a carbinolamine intermediate, followed by acid-catalyzed dehydration. The optimal pH is around 4 to 5, providing enough acid to catalyze the dehydration step without protonating the amine so heavily that it can no longer act as a nucleophile. Imines, which contain a C=N bond, are important in biological chemistry; retinal in the visual cycle and pyridoxal phosphate (PLP) enzyme chemistry both rely on imine intermediates.
Secondary amines (R2NH) undergo the same initial addition, but because the nitrogen bears no hydrogen after adding to the carbonyl, dehydration cannot occur at nitrogen. Instead, an alpha-hydrogen is lost to form a carbon-carbon double bond adjacent to the nitrogen, producing an enamine. Enamines are valuable nucleophilic intermediates used in the Stork enamine synthesis.
Hydroxylamine (NH2OH) reacts with carbonyls to form oximes (R2C=NOH), which can undergo the Beckmann rearrangement to produce amides upon treatment with acid. Hydrazine (NH2NH2) forms hydrazones (R2C=NNH2), which are substrates for the Wolff-Kishner reduction, converting the carbonyl to a methylene group upon treatment with KOH at high temperature. Semicarbazide (NH2NHCONH2) produces semicarbazones.
VII. The Wittig Reaction
The Wittig reaction converts a carbonyl group (C=O) into a carbon-carbon double bond (C=C), making it one of the most powerful methods for alkene synthesis. An aldehyde or ketone reacts with a phosphonium ylide (the Wittig reagent) to give an alkene and triphenylphosphine oxide as a byproduct.
Preparation of the Wittig reagent begins with an SN2 reaction between an alkyl halide and triphenylphosphine to form a phosphonium salt. Treatment of the phosphonium salt with a strong base such as n-BuLi, NaH, or NaHMDS generates the ylide (phosphorane), in which a carbanion is stabilized by the adjacent phosphorus atom. The mechanism of the Wittig reaction involves attack of the ylide on the carbonyl carbon to form a betaine intermediate, cyclization to a four-membered oxaphosphetane ring, and retro [2+2] fragmentation to release the alkene and triphenylphosphine oxide.
The stereochemistry of the product depends on the nature of the ylide. Unstabilized ylides (those without electron-withdrawing groups on the carbanion carbon) predominantly give Z-alkenes (cis). Stabilized ylides (bearing EWGs such as esters) favor E-alkenes (trans). The Horner-Wadsworth-Emmons (HWE) modification, which uses phosphonate esters instead of phosphonium salts, provides high E-selectivity.
The Wittig reaction offers significant synthetic advantages. The double bond is placed unambiguously at the position of the former carbonyl, eliminating the regiochemistry concerns that plague elimination reactions. There is no ambiguity about which beta-hydrogen is removed, as there is with E2 eliminations exhibiting Zaitsev or Hofmann selectivity.
<image>Panel A: Complete Wittig reaction sequence showing (1) preparation of the phosphonium salt from an alkyl halide and PPh3, (2) deprotonation with n-BuLi to form the ylide, and (3) reaction of the ylide with an aldehyde through the betaine and oxaphosphetane intermediates to give the alkene product and triphenylphosphine oxide. Panel B: Comparison of products from stabilized vs. unstabilized ylides, showing the E-selectivity of stabilized ylides and Z-selectivity of unstabilized ylides.</image>
