Ketene1

H2C=C=O

[463-51-4]  · C2H2O  · Ketene  · (MW 42.04)

(mild acetylating reagent;1 performs [2 + 2] cycloadditions with alkenes and alkynes;1c performs nucleophilic addition to acetyl chlorides;2 capable of certain organometallic transformations3)

Physical Data: mp -150 °C; bp -56 °C.

Solubility: generally introduced as a gas but is soluble in a wide variety of solvents.

Preparative Methods: by the thermal decomposition of acetone,4 diketene,5 acetic anhydride,6 alkoxy7 or siloxy acetylenes,8,9 and carboxylic acid over zeolites.10 Acetic anhydride gives the purest stream of this gas. The use of acetone, diketene, or acetic acid may leave impurities such as acetone and carbon monoxide.

Handling, Storage, and Precautions: poisonous gas with a toxicity approximately eight times greater than phosgene.11 All operations utilizing ketene should be carried out in an appropriate isolated apparatus in a well-ventilated fume hood.5,11

Acetylating Reagent.

The electrophilic nature of the sp carbon in ketene makes it a powerful yet mild acetylating reagent.1,12,13 Unlike other reagents such as Acetic Anhydride, ketene has no leaving group; the opening of the double bond being its equivalent.14 This feature ensures fewer byproducts in the reaction mixture, allowing for easier purification of the product. Ketene will acetylate a wide variety of functional groups, including carboxylic acids, alcohols, amines, amides, thiols and 1,3-dione systems.1a,14-16 One of the more recent uses of ketene in this area is the acetylation of b-diketone CuII intermediates (eq 1).12 This reaction proceeds quickly at room temperature, without the need of a catalyst, the sole product being that arising from C-acetylation. Other attempts to introduce substitution into this system using alternative reagents not only required higher temperatures and the use of catalysts, but have resulted in the formation of both C- and O-acetylated products.17,18 These reactions also resulted in the loss of the Cu-O bond, which the ketene reaction does not affect.

Ketene has also been used in acetylating cyclic diones to form the corresponding 1,3-cycloalkadienes (eq 2).15,16 The formation of the 1,3-cycloalkadienes was previously accomplished by a Birch reduction of the corresponding aromatic derivatives.15 For rings larger than six atoms in size, the use of ketene will result in C-acetylation as well as O-acetylation, and Isopropenyl Acetate has been shown to be more effective in this case.

Ketene is also a good acetylating reagent in reactions where the starting material has been absorbed onto a solid medium. The acetylation of phenol usually requires the use of high temperatures and a catalyst.19 Even under these conditions, the reaction proves to be inconsistent. If phenol is first absorbed onto silica, however, acetylation may take place in good yield by passing a stream of ketene through the medium as a gas at room temperature. Phenol derivatives absorbed on alumina have also been shown to acetylate quantitatively at 0 °C when exposed to ketene gas.19 This reaction has been shown to be quite versatile and may accommodate a wide variety of alcohols on many absorbants including celite, magnesium oxide, and zinc oxide.20 The ease of acetylation using ketene may also be shown by the following example (eq 3). The thermal fragmentation of 1-alkoxyalkynes in chloroform allows for the easy formation of ketene in situ. When this process is carried out in the presence of an amine, the ketene is trapped upon formation, giving the resulting amide.7 As shown in eq 3, this reaction offers a mild process for acetylation which should be suitable for a wide variety of nucleophiles.7

Cycloadditions.

Cycloaddition involving ketene and its derivatives is probably the most characteristic reaction involving this reagent. Examples of 1,2-cycloaddition to form four-membered rings are known to occur between ketene and C&tbond;C, C=C, C=O, C=N, C=S, N=N, N=O, N=S, and P=N groups.1c,1a These reactions are generally considered to proceed via a p2s + p2a thermally allowed cycloaddition following the Woodward-Hoffmann rules.1c The cycloaddition proves to be highly selective,13 the most nucleophilic alkenic carbon becoming bonded to the sp carbon of ketene in the product. Addition occurs with retention of configuration of the alkene.1a In many cases, ketene proves to be too unreactive for the task at hand and Dichloroketene has become the reagent of choice in recent years. The relative reactivities of some ketenes in reference to cycloadditions are shown in Scheme 1.1a

Alkene Addition.

There are few examples of alkene addition to ketene itself. The alkene generally has to be activated either through the use of an EDG or strain in the system, such as the case with cyclopentadiene (eq 4)21,22 and 1,3-cyclohexadiene (eq 5).22 Linear conjugated dienes will sometimes react with ketene but yields are generally quite low and the reaction is not synthetically useful. Again, dichloroketene is generally used in this case due to its greater reactivity (eq 6).1c,23

One example of the use of ketene with an activated alkene is in the case of vinyl ethers.24,25 Staudinger had shown in 1920 that Diphenylketene would add to ethyl vinyl ether to form the 1,2-cycloaddition product.1c This reaction was repeated by others,26,27 and in 1960 Hurd was able to show that ketene itself would also add to a vinyl ether.24 Seija built upon this methodology later when he used a variety of vinyl ethers along with ketene to gain access to the synthetically interesting bicyclo[1.1.0]butane systems, as shown in eq 7.25 The reaction is regiospecific in that the methylene group in the product is bonded to the carbon attached to the ether oxygen.24,25

Alkyne Addition.

The alkyne bond is sufficiently high in energy to perform 1,2-cycloadditions with ketene in the formation of cyclobutenones.28 Wasserman29 and Pericás30 utilized this reaction in the formation of 1,3-cyclobutanedione. The latter synthesis used the alkyne as a source of ketene as well as the cycloaddition partner (eq 8). More recently, siloxyalkynes have been shown to undergo the same type of reaction utilizing a wide variety of R groups (eq 9); a multitude of cyclobutenone systems can thereby be constructed.31

C=X Cycloaddition.

The cycloaddition reaction of ketene to a C=O bond is a very synthetically useful reaction which allows formation of the 2-oxetanone system (b-lactone).1 The rate of reaction is controlled somewhat by the polarization of the carbonyl bond. The greater the positive charge of the carbonyl carbon, the greater the rate of reaction.32 The cycloaddition of ketene with the carbonyl bond requires a catalyst for reaction to occur.1a Ketene will readily couple with chloral in the presence of a catalyst to form b-(trichloromethyl)-b-propiolactone.33 Using chiral cinchona alkaloid catalysts, it is possible to form the chiral 4-(trichloromethyl)-2-oxetanone beginning with ketene and chloral. Acid hydrolysis of the cyclic product allows the formation of optically pure (S)- or (R)-malic acid in 79% yield (eq 10).32,34

This compares quite well with more involved routes which begin with chiral tartaric acids35 or the use of enzymatic catalysts, which allow for synthesis of the (S)-isomer but not the unnatural (R)-isomer.36 Chiral polymeric cinchona alkaloids have also been employed in the reaction.37 The use of polymeric catalysts allows greater ease of recycling and in some cases, such as poly(cinchona alkaloidacrylate), the enantioselectivity and yields were comparable to their monomeric counterparts.37

The cycloaddition of ketene to a C=N bond was first discovered by Staudinger in 1907 and is often referred to by that name.38 The reaction proceeds regioselectively via a nonconcerted mechanism to give the b-lactam (eq 11).39-41 Ketene itself is quite unreactive towards the imine group;1c,42 however, reactions with the disubstituted ketenes proceed well.42 Among the more popular ketenes utilized for this reaction are diphenyl-, chlorophenyl-, and dibromoketene.42

Diazomethane Cycloaddition.

The reaction of ketene with Diazomethane offers a simple, high yielding synthesis of cyclopropanone, a molecule of both theoretical and synthetic interest.43 In the presence of methanol and excess ketene, cyclopropanone may be further acetylated, as shown in eq 12. Reaction with excess diazomethane results in the formation of cyclobutanone.43,44 Earlier methods to prepare cyclopropanone from cyclobutanediones met with little success.45

1,3- and 1,4-Cycloaddition.

Cyclizations of this type are quite rare using ketene itself, although ketene derivatives have been known to undergo 1,3- and 1,4-cyclizations.1

Allene Formation.

The reaction of ketene with an ylide proves to be a convenient method for the formation of allenes. In the reaction with the ylide shown in eq 13, the a-vinylidene-g-butyrolactone, which holds biological interest, may be formed in high yield.46

The same methodology has been employed in more complex systems, such as the formation of 4,5-dihydropyrazolo[1,5-a]pyridine beginning with azine phosphoranes (eq 14).47

If a ketene derivative is utilized (phenylacetoxyketene or monophenyoxyketene), the product will spontaneously eliminate acetic acid or phenol to aromatize, giving the pyridine ring.47 The ability to use either ketene or its derivatives offers good flexibility in the synthesis of these molecules.

Organometallic Compounds.

Although not as well known as the organic chemistry of ketene, the organometallic chemistry of ketene does occur in a wide variety of systems.3 An example is the insertion of ketene into metal hydrides, as shown in eq 15.3,48

Ketene will also insert into metal-alkyl bonds.3 The mechanism of these reactions is unknown, but it should be noted that the products follow the same type of pattern as the acetylation reactions. Some more recent work in the organometallic area is the formation of disilver ketenide (eq 16).49 This complex was formed via reaction of silver acetate with ketene gas formed from pyrolysis of acetone or via in situ formation of ketene using acetic anhydride. The latter method could be run at temperatures as low as -28 °C in the presence of an amine base for a catalyst. The reaction was also run using enol acetates as the ketene source.49 The formation of this complex shows the potential carbon acidity of the hydrogen atoms attached to ketene. The silver ketenide complex is quite stable but undergoes the transformations shown in eqs 17-19.

Although silver ketenide is more inert than expected, it has the potential of being a useful synthetic reagent for the introduction of disubstituted ketenes or regeneration of ketene itself.49

Ketene as a Nucleophile.

In acetylation reactions, ketene behaves as an electrophilic agent, but in the presence of hemiacetal chlorides,2 acid chlorides, acetals,2 etc., ketene behaves as a nucleophile. In a study by Hurd and Kimbrough, ketene was mixed with the hemiacetal chloride in the presence of Zinc Chloride to give, after workup, the corresponding acid.50 Hurd went on to extend the study to acetals as well as the chloro derivatives.2 More recently, Goure reacted Trifluoroacetyl Chloride with ketene followed by addition of ethyl 3-amino-4,4,4-trifluoro-2-butenoate. Subsequent rearrangement of this intermediate led to the pyridinecarboxylate in 86% yield.51 The use of ketene in this reaction allows a two-step, one-pot synthesis of the previously unknown 2-hydroxy-4,6-bis(trifluoromethyl)pyridine-5-carboxylate (eq 20). Other methods utilized to form this compound lack the ability to incorporate a functional group in the 5 position of the pyridine ring.51,52

Miscellaneous.

Recently, ketene has become a tool for mechanistic probes and the formation of high energy molecules. It is known that the transformation of methanol to hydrocarbons goes through a ketene intermediate at some point. With this in mind, the thermal decomposition of ketene is being studied on metal surfaces in an effort to further elucidate this, as yet, unknown mechanism.53,54

Ketene is also used to form singlet methylene (1CH2) in an effort to study the insertion reactions of this short-lived intermediate.55 Its use is also noted in the formation of distonic ions: ions that have a separated charge and radical site. The use of ketene in this instance offers an advantage over the known methods in that it allows greater ease of formation of the distonic ions and greater flexibility over the type of ion formed.56


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Thomas M. Mitzel

The Ohio State University, Columbus, OH, USA



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