Volume 12 (1962) 1. Cyclobutane Derivatives from Thermal Cycloaddition Reactions - John D. Roberts and Clay M. Sharts 2. The Preparation of Olefins by the Pyrolysis of Xanthates. The Chugaev Reaction - Harold R. Nace 3. The Synthesis of Aliphatic and Alicyclic Nitro Compounds - Nathan Kornblum 4. Synthesis of Peptides with Mixed Anhydrides - Noel F. Albertson 5. Desulfurizatioand Eugene nE . witvanh TameleRaney nNicke l - George R. Pettit Preparation of substituted cyclobutanes and cyclobutenes by cycloaddition reactions of alkene to alkene and alkene to alkyne has become an important synthetic reaction and, in fact, where applicable, is now the method of choice for synthesis of four-membered carbon ring compounds. Such cycloadditions may be achieved thermally under autogenous pressure in the presence of free-radical inhibitors or photochemically by irradiation with visible or ultraviolet light. This chapter does not include photochemical cycloadditions or the thermal dimerizations of ketenes since these have been well reviewed elsewhere.1-3 Historically, the establishment of cyclobutane structures for cycloaddition products provides an enlightening example of the waxing and waning of fashions in the interpretation of organic reactions. Some of the interesting and important landmarks will be briefly noted here.* First, the early work of Liebermann4 (1889) on the truxillic acids provided a strong measure of confidence for later workers in assigning cyclobutane structures to a variety of cycloadducts, and, when Kraemer5 discovered dicyclopentadiene (1896), he suggested that it was a cyclobutane derivative. This was followed by proposals of cyclobutane structures for dimers from 1,5-cycloöctadiene (Willst tter,6 1905), substituted ketenes (Staudinger,7 1906–1912), unsaturated acids (Doebner,8 1907), and allenes (Lebedev,9 1911–1913). Publication by Staudinger10 of Die Ketene in 1912 appeared to complete the conditioning of chemical thought, and postulation of formation of cyclobutanes by cycloaddition reactions was both fashionable and respectable over the next two decades. The skies darkened briefly in 1928 when Diels and Alder11 demonstrated the generality of their reaction and suggested that dicyclopentadiene resulted from 1,4 and not 1,2 addition. However, Bergel12 in 1928 reaffirmed faith in the cyclobutane structure, and comparative peace reigned until 1931 when Alder and Stein13 proved beyond reasonable doubt that dicyclopentadiene actually had the bridged-ring structure. With this development, cyclobutane structures for cycloadducts rapidly became unfashionable and fell into general disfavor. The tide was partially stemmed in 1934 when Cupery and Carothers14 oxidized the dimer of divinylacetylene to cyclobutane-1,2-dicarboxylic acid—the first time a cyclobutane derivative of known structure was isolated as a degradation product of a cycloadduct. None the less, the tenor of thought in the late thirties was such that when Simonsen15 showed that Staudinger's diphenyl-ketene- cyclopentadiene adduct contained a four-membered ring, this result was “not anticipated.” The pessimism which then prevailed is well illustrated by Bergmann's review article of 193916 in which many postulated cyclobutane structures (some correct, some incorrect) were flatly rejected. The era of doubt drew to a close late in the forties when new experimental results led to general recognition of the usefulness of thermal cycloaddition reactions as a synthetic route to cyclobutane derivatives. The breakthrough was greatly facilitated by the discovery by du Pont research groups17, 18 that octafluorocyclobutane can be formed readily by thermal dimerization of tetrafluoroethylene. This development inspired several extensive investigations of cycloadditions involving fluoroalkenes. A typical reaction is the addition of tetrafluoroethylene to 1,3-butadiene at 125° to afford 3-vinyl-1,1,2,2- tetrafluorocyclobutane in 90% yield.19 This cycloaddition illustrates two important points. First, flucrinated alkenes may add to non-fluorinated unsaturated compounds much more readily than they dimerize. Second, when fluorinated alkenes are given a choice between four- and six-membered ring formation, as is possible with a conjugated diene, the formation of the four-membered ring is favored. It seems significant that ethylene20 and tetracyanoethylene21 apparently give only the normal Diels-Alder, six-membered ring products with butadiene. The experimental conditions for the addition of tetrafluoroethylene to butadiene are very similar to those commonly used for Diels-Alder reactions involving volatile addends, and a further similarity is provided by the aforementioned fact that two dissimilar compounds, tetrafluoroethylene and butadiene, are found to react with each other much more readily than they react with themselves. Like Diels-Alder reactions,22 the cycloadditions leading to four-membered rings may present orientational and stereochemical problems. For example, dimerization of trifluorochloroethylene can give two structural isomers, the “head-to-head” (I) and “head-to-tail” (II) adducts, and each of these may be the cis or the trans isomer. It is of considerable practical and theoretical significance that the principal product in this23 and other cases is the result of head-to-head addition (I) with the chlorine atoms predominantly cis to one another. This mode of addition is not at all peculiar to fluoroalkenes. Allene dimerizes to give predominantly 1,2-dimethylenecyclobutane9, 24 (head-to-head), and acrylonitrile affords cis- and trans- 1,2-dicyanocyclobutane.25 As will be shown, these facts are strong evidence against ionic mechanisms for this type of cycloaddition (except possibly ketene dimerizations); in addition, they may well provide new understanding of factors governing cycloadditions in general, including the Diels-Alder reaction. The cycloaddition reactions of fluoroalkenes have provided a dazzling array of unusual fluorinated cyclobutane and cyclobutene derivatives that would be extraordinarily difficult to synthesize by conventional means. Many of these substances possess great intrinsic interest; but, generally speaking, they are not useful intermediates for the synthesis of nonfluorinated cyclobutanes since almost all contain gem-fluorine atoms that are characteristically rather inert chemically. None the less, some success has been achieved in utilizing the beneficial effect of gem-fluorine atoms on formation of four-membered rings and then removing the fluorine by hydrolysis to yield carbonyl groups. In this way, practical laboratory syntheses have been developed of substituted cyclobutenones (III, IV),26-28 cyclobutenediones (V to VII),29-31 and tropolone (VIII),32 as illustrated in the following equations. The cycloadduct IX from ketene and cyclopentadiene, even though formed in rather poor yield, has been used as an intermediate for the synthesis of a bicyclo[3.3.0]octadiene as part of a projected route to pentalene33 and has also been converted to cycloheptatriene.34 The very reasonable yields of cyclobutane derivatives recently demonstrated for the addition of allene to various substituted alkenes35 have substantially broadened the synthetic usefulness of the cycloaddition reaction for the preparation of non-fluorinated, four-membered-ring compounds. The adduct X from allene and acrylonitrile has already proved useful in syntheses for 1,3-dimethylenecyclobutane,36, 37 3-methylenecyclobutanone,38 and 1,3-cyclobutanedione.39 It has been suggested that formation of octafluorocyclobutane from tetrafluoroethylene during the pyrolysis of polytetrafluoroethylene (Teflon) involves a diradical intermediate.18 A similar explanation was offered to account for the head-to-head dimerization of acrylonitrile.25 Formation of the diradical XI was expected to be substantially more favorable than formation of the diradical XII, which would also lead to head-to-head cycloaddition, or XIII, which would give the head-to-tail product because of stabilization resulting through interaction of the unpaired electrons with the adjacent unsaturated cyano groups as may be symbolized by the resonance forms XIV to XVI, etc. Such stabilization would be possible for only one of the unpaired electrons of diradical XIII and would be impossible for XII. The head-to-head orientation produced with acrylonitrile appears to exclude an ionic mechanism since the electrical polarization of the double bond by the cyano group would be expected to lead exclusively to head-to-tail addition. Furthermore, an ionic intermediate (XVII) analogous to the diradical XI would have a cationic center immediately adjacent to a cyano group, and there seems to be no reason to suppose that this unfavorable juxtaposition of electron-withdrawing groups would necessarily be more than counterbalanced by the concomitant establishment of an anionic center adjacent to the other cyano group. An additional argument against ionic mechanisms is that these cycloadditions proceed well in non-polar solvents and with fluoroalkenes even in the gas phase.23 The reasonable alternative to the stepwise diradical mechanism is a more or less concerted breaking of the multiple bonds of the addends and formation of the new bonds of the adduct. If the 1,4 bond has only a very slight single-bond character in the transition state when formation of the 2,3 bond is nearly complete, we have what might be termed a “virtual” diradical mechanism. The distinction between this formulation and the “bona fide” diradical process proposed