Acrolein

[107-02-8]  · C3H4O  · Acrolein  · (MW 56.06)

(electrophile in 1,2- and 1,4-addition reactions; diene; dienophile)

Alternate Name: propenal.

Physical Data: mp -87 °C; bp 53 °C; d 0.839 g cm-3; nD 1.4017.

Solubility: sol water, alcohols, most organic solvents.

Form Supplied in: colorless liquid (stabilized with 0.1 wt % hydroquinone); widely available.

Purification: purified by fractional distillation under nitrogen, drying with anhydrous CaSO4, and then distilling under vacuum, preferably in the dark. To avoid formation of diacryl, a small amount of catechol or hydroquinone should be placed in the receiver flask.

Handling, Storage, and Precautions: the liquid is flammable. Polymerization occurs in the presence of base or strong acids or upon exposure to light. Therefore it must be stored in the dark in the presence of 0.1 wt % catechol or hydroquinone. The liquid has a pungent odor and is highly toxic. Skin and mucous membranes become irritated upon exposure, while inhalation may cause lachrymation and an asthmatic reaction. Use in a fume hood.

Oxidations and Reductions.

Each functional group in acrolein can react selectively and in some cases both react. Acetal formation has been achieved using transacetalization conditions.1 Oxidation with Hydrogen Peroxide in the presence of a catalytic amount of SeO2 leads to acrylic acid.2 while oxidation under controlled pH conditions gives glycidaldehyde in excellent yield.3 Selective reduction of the alkene can be achieved with Octacarbonyldicobalt/H24 or via treatment with Triethylsilane in the presence of Wilkinson's catalyst (Chlorotris(triphenylphosphine)rhodium(I)) followed by hydrolysis of the silyl enol ether.5a Selective reduction using hydrogen and a PdII/ferrocenylamine sulfide catalyst has been described.5b

Addition Reactions.

Acrolein undergoes addition reactions at the carbonyl group (1,2-addition) and/or the electron deficient alkene (1,4-addition). The site of attack depends on the nucleophile and the reaction conditions. Under equilibrating conditions the 1,4-addition product is preferred.

The ratio of 1,2- to 1,4-addition of carbon nucleophiles to acrolein is strongly dependent on the nature of the organometallic species, especially on the polarity of the carbon-metal bond (eq 1). In general, the proportion of 1,2-addition product increases with more electropositive metal counterions. Moreover, due to the high reactivity of aldehydes, 1,2-addition often competes in processes where 1,4-addition is usually the favored pathway.

Organolithium reagents react with acrolein exclusively via 1,2-addition when the reaction is performed in THF at -78 °C.6 Grignard reagents give mainly carbonyl addition products.7 Organoberyllium, -zinc, and -cadmium also add exclusively to the carbonyl group,8 as do organocerium and -titanium reagents.9 Low enantioselectivity (24%) was observed in the addition of n-Butyllithium to acrolein in the presence of a chiral tetraamine ligand (DEB).10

Phosphonate anions react at the carbonyl group to yield substituted butadienes ultimately.11

Thiols undergo selective 1,4-addition to acrolein, whereas Triphenylphosphine induces polymerization.12 Cyanide ion adds to acrolein but it is more efficient to react the a,b-unsaturated imine followed by hydrolysis.13

Stabilized carbanions, such as malonate and other active methylene compounds, undergo 1,4-addition (Michael reaction) to give 1,5-dicarbonyl compounds under mild conditions.14 Phase transfer catalysts have been used to promote the reaction.14c When the reaction is carried out between unsaturated aldehydes and (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane, a 3 + 3 cyclohexenone annulation occurs to give cyclohexenones (eq 2).15 The yield is modest for acrolein, but improves upon substitution at the a- or b-positions.

Substituents on the malonate can result in additional transformations of the Michael adducts. For example, if the nucleophile has a 2-substituent bearing a ketone, the intermediate aldehyde enolate closes onto the ketone providing a formylcyclopentene in 50% yield.16 Reaction of bromomalonates with acrolein in the presence of NaOEt results in an efficient route to formylcyclopropanes. Similar products are formed in the reaction of a stabilized S-ylide with acrolein (eq 3).17 Carbene addition to acrolein has also been achieved using nickel catalysts.18

A highly enantioselective rhodium catalyzed version of the Michael addition to acrolein has been recently developed.19 The catalyst, prepared in situ from RhH(CO)(PPh3)3 and the chelating chiral diphosphine ligand TRAP (TRAP = 2,2-bis[1-(diphenylphosphino)ethyl]-1,1-biferrocene), provides high yields and good ee's using 1 mol % of rhodium (eq 4).

While scattered examples of 1,4-additions of nonstabilized carbanions have been described, the first systematic study of cuprate addition to enals was carried out by Normant.20 Cuprates derived from organolithium reagents gave low yields,21 whereas the best results were obtained using cuprates prepared from Grignard reagents. Chlorotrimethylsilane improved the 1,4-addition process (eq 5).20

Aryl halides react with acrolein in the presence of palladium catalysts to give aryl and diaryl derivatives via a mono or double Heck process respectively.22

Organoboranes undergo 1,2- or 1,4-addition to acrolein depending on the R group. Alkylboranes undergo 1,4-addition in a reaction which is catalyzed by the presence of water. There is considerable evidence for a radical chain mechanism.23 Allylboranes undergo selective 1,2-addition with a variety of aldehydes including acrolein. Chiral boranes (R2 = Me, OMe, R1 = H, Me) derived from a-pinene react to give the alcohols in up to 90% ee (eq 6).24

In contrast, allylic silanes undergo stereoselective 1,4-addition (Sakurai reaction), silyl migration, and ring closure in a novel cyclopentane annulation reaction (eq 7).25

Carbon radicals also add to electron deficient alkenes including acrolein.26 A key feature of this reaction is the compatibility of several functional groups which would not be tolerated using carbanion chemistry. Furthermore, the reaction can be carried out in organic as well as aqueous media, depending on the mode of radical preparation. With 2-iodoethanol, a conjugate addition-cyclization sequence occurs providing six-membered lactols in good yield (eq 8).27 It is noteworthy that no elimination of the b-oxygen occurs under these conditions.

Hydrogen Bromide adds efficiently to the alkene in acrolein.28 Treatment of acrolein with HBr and 1,3-Propanediol provides a route to g-bromoacetals,29a which have been widely used as b-homoenolate equivalents. Thus g-ketoaldehydes are prepared by a three-step procedure involving conversion of the bromide to the Grignard reagent, addition of an acid chloride, and hydrolysis of the acetal.29b

Aldol Condensation Reactions.

Reaction of the magnesium enolate of a thioamide with acrolein gives predominantly (73-89%) the syn aldol adduct.30 Similar results were obtained with a ketone enolate, though little selectivity was noted for an enolate derived from an a-alkoxypropionate.31,32 Selectivities exceeding 50:1 were noted in the reaction of a lithium enolate of a chiral thioester.33 Asymmetric aldol condensation using an enolate bearing the Evans chiral auxiliary has also been reported with acrolein to give a single diastereomer in high yield (eq 9).30

Pericyclic Reactions.

The ene reaction of (-)-b-pinene with acrolein was shown to proceed at 135 °C in 17 h to give 30% of the ene adduct (a formal conjugate addition).34 However, Lewis acid catalysis allowed the reaction to be run at a much lower temperature.35 Thus an alkylidenecycloalkane such as 1-methylene-2,6-dimethylcyclohexane reacts with acrolein in the presence of Dimethylaluminum Chloride at 0 °C, to provide a decalin system in 57% yield (eq 10). This annulation procedure is based on two sequential ene reactions in which acrolein serves as the double enophile partner.36

b-Alkylation of acrolein has been achieved by indirect multi-step methods. One approach uses a [3,3]-sigmatropic rearrangement of an allylic thionocarbamate as the key step.37 For example, addition of n-BuLi to acrolein, followed by treatment with thiocarbamoyl chloride, provides 2-heptenal after sulfenylation and hydrolysis.

A second method is based on the umpolung strategy. An acetal of 3-phenylsulfonylpropanal, which can be prepared in three steps from acrolein and Thiophenol, can be deprotonated, alkylated, and the acetal hydrolyzed to provide a b-sulfonylated aldehyde, which undergoes a retro-Michael addition to give the (E)-b-substituted acrolein.12

Cycloadditions.

Acrolein has been used as both a dienophile and a diene in Diels-Alder reactions as illustrated below. The dimer of acrolein is formed under thermal conditions providing a single regioisomer.38 The dimer is a useful building block in organic synthesis.38 Cycloaddition between acrolein and vinyl ethers typically requires heating in an autoclave at 160-200 °C.39 The reaction temperature can be reduced to 50 °C when mild Lewis acid catalysts such as Yb(fod)340 are used, providing a powerful synthetic route to dihydropyrans.41 The hetero Diels-Alder reaction very efficiently leads to spiroacetal compounds when the appropriate vinyl ether is used (eq 11).42 Enamines43 and ynamines44 also react to yield amino-dihydropyrans and aminopyrans respectively. Both 5,6- and 5,5-spiroacetals can be obtained using acrolein as the diene component.

There are many examples in which acrolein is used as a dienophile.45 Electron rich,46 electron poor,47 as well as a variety of substituted dienes react smoothly with acrolein at temperatures ranging from rt to 120 °C to yield substituted cyclohexene derivatives, often with complete regiocontrol.48 Cyclohexadienes,49 dimethylenehexahydropyrazines,50 and various furans51 provide rapid entry into bicyclo[2.2.2]octanes, octahydroquinoxalines, and oxabicyclo[2.2.1] compounds, respectively. While Diels-Alder cycloadditions of dienes with acrolein can be slow at elevated temperatures and atmospheric pressure, rates can be increased by factors of 10-1000 by application of higher pressures52 or using a Lewis acid catalyst.53 However, very mild Lewis acids are required since polymerization occurs readily with stronger Lewis acids.54 The increase in reaction rates is accompanied by improved regioselection. Yb,40 Fe,54 W,55 and Ru56 based complexes are among the mildest catalysts reported to date (eq 12).

There are a few reports of asymmetric cycloadditions with acrolein. A diastereomeric excess of 64% was obtained using an (S)-O-methylmandeloxy substituted diene.57 Cycloadditions mediated by a chiral Lewis acid have also been described.58 An 80% enantiomeric excess was observed in the cycloaddition between cyclohexadiene and acrolein catalyzed by a chiral (acyloxy)borane.

A cycloaddition between acrolein and a pyrilium ion was reported to be highly regioselective and moderately stereoselective, yielding an oxabicyclo[3.2.1]octene.59


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Patrick H. M. Delanghe & Mark Lautens

University of Toronto, Ontario, Canada



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