[75-07-0]  · C2H4O  · Acetaldehyde  · (MW 44.05)

(reagent used as two-carbon electrophilic component in a wide array of reactions)

Physical Data: mp -123.5 °C; bp 21 °C; d 0.788 g cm-3.

Solubility: sol H2O, alcohol, ether, and most organic solvents.

Form Supplied in: colorless liquid; widely available.

Purification: shaken with powdered NaHCO3 for 30 min; dried over CaSO4, and fractionally distilled at 760 mmHg through a 70 mm Vigreux column.

Handling, Storage, and Precautions: bottles may develop pressure and should be cooled before opening. To help prevent polymerization and autoxidation, store under nitrogen atmosphere and refrigerate. Acetaldehyde is a cancer suspect agent and should be used only in a well-ventilated fume hood. Toxicity (oral) rat LD50: 661 mg kg-1. Incompatible with strong acids, strong bases, oxidizing and reducing agents. Decomposes on prolonged exposure to air.


Acetaldehyde reacts with a myriad of nucleophilic reagents, generally providing excellent yields of the two-carbon extended secondary alcohols. Aryl-,1 alkynyl-,2 and alkyllithiums3 react rapidly with acetaldehyde even at low temperature. A chiral vinyllithium reagent at low temperature reacts stereoselectively to afford a 10:1 mixture of diastereomeric alcohols (eq 1).4 Aryl5 or alkyl6 Grignard reagents behave in an analogous manner with acetaldehyde to give the secondary alcohols or the methyl ketones7 upon subsequent oxidation. Allyl organometallics react with varying degrees of stereocontrol depending on the metal and conditions to give the corresponding homoallylic alcohols.8 Chiral allylboronates also react with acetaldehyde at -78 °C to afford the homoallylic alcohols with high enantioselectivity.9 trans-Epoxides are produced selectively through the Darzens reaction of acetaldehyde with halomethyl sulfones under basic phase transfer conditions.10 Classical Wittig reagents11 and Horner-Emmons phosphonate12 ylides react with acetaldehyde to give the alkene.

Aldol Additions.

Acetaldehyde serves as an electrophilic partner in the aldol condensation with a wide array of enolates.13 Knoevenagel condensation of acetaldehyde with active methylene compounds in the presence of base provides good yields of the ethylidene substituted compounds.14 Addition of two equivalents of an active methylene compound to acetaldehyde results in a Michael addition of the second equivalent to the initially formed ethylidene.15 Tollens reaction of acetaldehyde with formaldehyde gives pentaerythritol.16 The addition of acetaldehyde in a Baylis-Hillman condensation with Ethyl Acrylate using 1,4-Diazabicyclo[2.2.2]octane (DABCO) as catalyst gives a 90% yield of the allylic alcohol.17 The stereoselective aldol reaction of acetaldehyde with achiral18 and chiral19 imide enolates has received much attention and is a proven method for controlling acyclic relative and absolute stereochemistry.13 For example, the boron enolate of a norephedrine-derived propionyloxazolidine reacts with acetaldehyde to afford in 90% yield and >98% de the syn aldol product (eq 2).19a Acetaldehyde also smoothly undergoes nitro-aldol condensation to the corresponding nitro alcohols.20 The lithium enolates of a variety of heterocycles react with acetaldehyde to give good yields of product alcohols.21 In addition, the zinc,22 copper,23 and boron24 enolates of esters and ketones provide aldol products with acetaldehyde.

Mannich and Mannich-Type Reactions.

Although not as commonly used as Formaldehyde, acetaldehyde undergoes many synthetically useful Mannich reactions. Intramolecular Mannich reaction of acetaldehyde has been utilized to produce the natural product myrtine (eq 3).25 The intramolecular Mannich reaction has also been used in the synthesis of proline derivatives.26 Nucleophiles as diverse as dialkyl phosphites27 and amines28 or aryl radicals29 may also add to the intermediate imine of acetaldehyde in Mannich-type reactions. A historically significant reaction of acetaldehyde in this mode is the Strecker synthesis of alanine, whereby cyanide is added to the adduct of ammonia and acetaldehyde followed by hydrolysis of the intermediate a-aminonitrile.30 The Pictet-Spengler reaction utilizing acetaldehyde is an important ring-forming reaction. Acetaldehyde has been extensively used in the synthesis of the biologically active b-carbolines from tryptophan derivatives through this cyclization.31 Other ring systems such as tetrahydroisoquinolines32 and dihydrooxazines33 have also been formed employing Pictet-Spengler cyclization with acetaldehyde.

Metal and Other Promoted Condensations.

In the mixed Tishchenko reaction using Aluminum Isopropoxide as promoter, acetaldehyde is predominately the oxidized partner. Thus when condensed with benzaldehyde, benzyl acetate is the major product.34 Recently an interesting and synthetically useful stereoselective intramolecular Tishchenko reduction of b-hydroxy ketones using acetaldehyde and promoted by Samarium(II) Iodide, affording anti-1,3-diol monoacetates, has been reported (eq 4).35 The stereoselective pinacol cross-coupling of acetaldehyde with other higher-order aldehydes that contain chelating functionalities has been achieved using a vanadium(II) reagent.36 The photochemical addition of acetaldehyde in the presence of molecular oxygen to a,b-unsaturated esters and ketones provides excellent yields of the 1,4-dicarbonyl compounds (eq 5).37

Pericyclic Reactions.

The thermal ene reactions of acetaldehyde and other aliphatic aldehydes with alkenes are generally not very productive.38 However, acetaldehyde can be induced to undergo ene reactions with a variety of alkenes under Lewis acid activation. Dimethylaluminum Chloride has been used to promote the ene reaction between the relatively reactive 1,1-di-, tri-, and tetrasubstituted alkenes (eq 6).39 With the more unreactive monosubstituted terminal alkenes, the more Lewis acidic Ethylaluminum Dichloride must be employed to obtain reasonable yields of ene products with acetaldehyde.40 Acetaldehyde is a relatively unreactive dieneophile towards dienes. The hetero-Diels-Alder reaction of acetaldehyde has been reported under high pressure acceleration with 1-alkoxydienes to afford good yields of dihydropyrans with modest endo selectivity.41

Paraldehyde and Other Acetaldehyde Derivatives.

Paraldehyde has historically been used as a stabile and less volatile form of acetaldehyde in a wide array of chemical reactions.42 However, since its classification as a controlled substance, its restricted availability has led to its limited use in modern synthetic organic chemistry. Acetaldehyde can be generated from paraldehyde through acid catalyzed degradation of the trimer and isolated by distillation.43 The diethyl acetal of acetaldehyde, commonly known as acetal, may be generated from acetaldehyde or paraldehyde, ethanol, and calcium chloride.44 Acetaldehyde and paraldehyde have also been used for the protection of diols as their ethylidene acetals.45

Related Reagents.

Acetaldehyde N-t-Butylimine; Acetaldoxime; Crotonaldehyde; Dimethylaluminum Chloride; Ethyl Vinyl Ether; Formaldehyde; Formaldehyde-Dimethylamine; Vinyl Acetate.

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Thomas J. Sowin & Laura M. Melcher

Abbott Laboratories, Abbott Park, IL, USA

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