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This Account highlights William von Eggers Doering's important discoveries in many fields of chemistry. His synthetic and mechanistic studies have contributed to areas including non-benzenoid aromatics, carbenes, pericyclic reactions, and diradical intermediates. Doering's synthesis with L. H. Knox of the highly stable tropylium ion and their investigation of its reactivity were the starting point for the development of the field of non-benzenoid aromatics. Working with A. K. Hoffmann, Doering demonstrated the synthesis of dichloro- and dibromocarbene by base-induced alpha elimination of HCl or HBr from CHCl3 or CHBr3 under anhydrous conditions. These results allowed for the synthesis of a variety of cyclopropanes and derivatives including allenes. Using 14C labeling experiments, Doering and Prinzbach showed that the mechanism of insertion of singlet methylene into a C-H bond was a concerted process.In their work on the Cope rearrangement, Doering and Roth's outstanding stereochemical analysis showed that the rearrangement of acyclic 1,5-hexadienes proceeds concertedly, passing over a chairlike transition state. This work has had an enormous impact on the understanding of stereochemical control in synthetic organic chemistry, and many fruitful applications in synthesis have stemmed directly from this finding. Transition-state resonance structures analogous to those for ground-state aromatics can qualitatively explain the relatively large substituent effects on the rate of the Cope rearrangement. However, quantum chemical calculations have quantitatively described these effects. The rapid degenerate Cope rearrangements in the cis-divinylcyclopropane units of 3,4-homotropilidene, barbaralone, and bullvalene establish these molecules as having fluxional structures. The unique molecule bullvalene has more than 1.2 million possible structures interconnected by degenerate Cope rearrangements, which average all H and all C atoms. Doering has also examined stepwise thermal reorganizations that pass through intermediary 1,3- or 1,4-diradicals and do not show conformational equilibration as would be expected for classical intermediates. Doering calls these processes "not-obviously concerted". He discusses "continuous diradicals" as transition states and rationalizes the course of these reactions through the concept of a "caldera" (a flat surface with small energy wells as found on the top of volcanoes).The understanding of fundamental chemical reactions remains the focus of Doering's research. In his terms, "understanding" means not only gaining deep insight but also the intellectual control that allows researchers to predict a reaction's course. Because the interplay between theory and experiment has led to great progress in this predictive ability, Doering's experimental work has provided an important input for computational chemistry and to the essential understanding of chemical reactions.

Pyrolysis of 1,6-diphenylhexa-1,5-diyne-cis-3-ene at 800–1000°C leads to a mixture of 1- and 2-phenylbiphenylene, along with triphenylene. Formation of the two biphenylenes is taken as strong evidence of the rearrangement of a p-benzyne into a m-benzyne through a shift of one of the phenyl groups. Copyright © 2004 John Wiley & Sons, Ltd.

Pyrolysis of two differently labeled versions of 3-phenylphthalic anhydride shows that a m-benzyne can form the related o-benzyne through shift of a phenyl group. The highest energy point in the process is the transition structure for a reverse carbon-hydrogen insertion in an intermediate benzopentalene. With the minor addition of an intermediate alkyne formed through a Roger Brown rearrangement, the original mechanism for formation of acenaphthalene accommodates the labeling results.

3,5,7-trimethyl-1 -azatricyclo[3.3.1.1(3,7)]decan-2-ylidene, an aminocarbene without pi conjugation, has been generated from the corresponding tosylhydrazone salt. Addition of the carbene to alkenes is stereospecifically cis, thus showing that the reacting state is singlet. Competition studies reveal that the carbene is somewhat nucleophilic, implying a measure of overlap between the lone pair on nitrogen and the empty orbital on carbon. In turn, such overlap implies a pyramidal structure for the divalent carbon.

Photolysis of ‘naphtho-o-carborane’ under oxygen leads to the quinone, 5,8-diketonaphthocarborane. Photolysis in the presence of hydrogen donors such as acetonitrile or 1,4-cyclohexadiene leads both to the quinone and 5-ketodihydronaphthocarborane. By contrast, photolysis of ‘benzocarborane’ under similar conditions leads only to a highly stereo- and regiospecific dimerization.

Photolysis of ‘naphtho-o-carborane’ in the presence of excellent hydrogen donors such as 1,4-cyclohexadiene leads to quantitative double hydrogen abstraction. Other molecules, including supercoiled DNA, similarly act as hydrogen atom donors towards photolyzed naphtho-o-carborane. A diradical intermediate is proposed.

Cyclohept-1-en-3-yne rearranges thermally to toluene via cycloheptatriene, and to a mixture of 1- and 2-vinylcyclopentadiene an intermediate allene, 1-ethenylidenecyclo-2-pentene.

A simple vinyl group is sufficient to induce a stepwise mechanism for the ring expansion of cyclopropylcarbenes.

The benzophenone-photosensitized decomposition of ethyl diazomalonate in 1,3-cyclooctadiene led to trans -bicyclo[6.1.0]non- cis -2-ene, a new strained ring system. The function of the photosensitizer is to convert Z,Z -1,3-cyclooctadiene into the E,Z -isomer.

Almost thirty years after the first (and only) description of 1,4-addition of a carbene to cyclooctatetraene, we report that direct photolysis of ethyl diazomalonate in cyclooctatetraene leads to 13% of the product of 1,4-addition. When the decomposition of the diazo compound is photosensitized by benzophenone, 1,4-addition becomes virtually the sole reaction pathway.

Generation of benzocyclohex-1-en-3-yne in two ways leads to naphthalene and methyleneindene (benzofulvene). Labeling studies favor a multistep mechanism involving an initial electrocyclic ring opening, and carbene−alkene interconversions.

Decomposition of a naphtho-fused cyclopropyldiazomethane leads to benzocyclooctatetraene, 1-vinylnaphthalene, 2-vinylnaphthalene, and small amounts of benzobarrelene. Diradical intermediates are postulated.

Generation of bicyclo[2.2.1]heptan-1-ylcarbene from a hydrocarbon precursor avoids the problems that attend generation from nitrogenous molecules and allows the determination that such carbenes can ring expand to bridgehead alkenes.

Photolysis of naphtho[b]cyclopropene in hydrocarbons leads to products derived from hydrogen abstraction by a diradical. Photolysis in a cryogenic matrix allows ESR detection of this diradical, which has zero field spliting parameters D/hc = 0.057, E/hc −1 .

Methylene has been shown not to react with the carbon-carbon bonds of spiropentane and spiro[3.3]heptane. © 1997 Elsevier Science Ltd.

The details of the nitroxylation of 2-nitroxy- endo -tetrahydrodicyclopentadiene with nitric acid were studied. A bridged carbocation is suggested as the intermediate responsible for the parallel and irreversible formation of 2,6-dinitroxy- endo -tetrahydrodicyclopentadiene and 2,7-dinitroxy-1,7-trimethylenenorbornane.

Between 200 and 400 million lb of citric acid are produced annually in the USA by fermentation of molasses and other sugars using the microorganism Aspergillus niger. A lesser quantity of itaconic acid is manufactured by a similar technology using Aspergillus terreus. The recovery of citric acid from its fermentation broth via calcium salt precipitation is a costly, highly complex, sophisticated operation. USDOE estimates the cost of dry citric acid produced from a new plant to be about $0.59/lb, whereas the estimated cost of wet citric acid (in its fermentation broth) from a new plant is about $0.19/lb and from an old plant is about $0.15/lb. Citric acid rapidly reacts in hot (250 C), compressed (34.5 MPa) liquid water to form itaconic and citraconic acids with a combined selectivity that exceeds 90%. At higher temperatures (360 C), in the absence and presence of NaOH, itaconic acid decarboxylates to form methacrylic acid. The yield of methacrylic acid depends on the temperature, pH, and buffer strength of the medium, reaching a maximum of about 70% (by mole) of the itaconic acid feed. Conditions which favor the production of methacrylic acid also lead to the formation of its hydration product: hydroxyisobutyric acid. Undermore » optimum conditions the combined yield of methacrylic acid and hydroxyisobutyric acid from itaconic acid exceeds 80%. Results are consistent with well-established dehydration and decarboxylation mechanisms.« less

In contrast to photolysis or thermal decomposition in solution, which is dominated by ionic reactions, flash vacuum pyrolysis of alkylchlorodiazirines in the gas phase generates radicals. The cyclopropylcarbinyl system is re-examined and the 1-norbornylcarbinyl system is studied for the first time.

An investigation of the reactions of three boron-substituted carbenes with alkened and alkanes uncovers substantial triplet reactivity. The triplet reveals itself not through addition or insertion reactions, but by abstraction to give a radical that abstracts again to give, ultimately, methyl-o-carboranes

Reactions of 1,2-dehydro-o-carborane, a benzyne analogue, and three boron-substituted o-carboranylcarbenes are described. Dehydro-o-carborane contains a reactive, but normal "dehydro" bond. The carbenes show exceptional triplet reactivity.

Bicyclo[2.2.2]octylidene is formed in four quite different ways. Reactions of the precursors do not complicate the chemistry of the carbene. The products are tricyclo[2.2.2.02,6]octane and bicyclo[2.2.2]octene, formed in approximately a 70:30 ratio.

A simple vinyl group is sufficient to induce a stepwise mechanism for the ring expansion of cyclopropylcarbenes.

Bicyclo[2.2.2]octylidene is formed in four quite different ways. Reactions of the precursors do not complicate the chemistry of the carbene. The products are tricyclo[2.2.2.02,6]octane and bicyclo[2.2.2]octene, formed in approximately a 70:30 ratio.

9-Carboranylcarbene is formed by reaction of carbon atoms with o-carborane. The triplet state reacts with alkenes by hydrogen abstraction, not the more usual addition reaction.

The phonylcarbene rearrangement is used to produce carbenes that are compared to the intermediates formed on photolysis and pyrolysis of diazo compounds.

Benzyne reacts with enamines through a combination of ene and 2+2 cycloadditions. One of the two possible ene reactions is greathly favored. The three-dimensional intermediate, 1,2-dehydro-o-carborane, 1 eschews the 2+2 reaction in favor of the ene reaction that is less favored in the benzyne reactions. This preference is rationalized in terms of the different steric demands of the two intermediates

The factors influencing the carbon-hydrogen insertion reaction of dichlorocarbene into tertiary carbon-hydrogen bonds are discussed.

Both methylene and carboethoxycarbene react with p-carborane to give the products of boron-hydrogen insertion.

Singlet carbenes are known to react with bicyclobutanes to yield 1,4-diene products, as in the addition of dichlorocarbene to bicyclobutane to yield 1,1-dichloro-1,4-pentadiene. At least two mechanisms have been proposed to explain this unusual reaction: (1) a concerted process and (2) a stepwise process involving a zwitterionic intermediate. Ab initio electronic structure calculations have been performed in order to help distinguish between these two mechanistic possibilities. In the parent system, the concerted pathway and the corresponding transition structure are readily located. On the other hand, the hypothesized zwitterionic intermediate does not correspond to a minimum at most levels of theory, even in the presence of a polar medium representing the solvent. Instead, this structure corresponds to a transition state or, at best, an extremely shallow minimum. The two pathways--one unambiguously concerted, the other possibly leading through an extremely shallow minimum (intermediate)--have very similar barriers and are expected to be competitive. In the substituted 1,2,2-trimethylbicyclobutane system, five regioisomeric concerted pathways exist and lead to four different diene products. Two of these pathways lie well below the others in energy, and they alone are expected to play a significant role at ordinary temperatures. Of these two pathways, the one calculated to have the slightly lower barrier leads to the only product that is reported experimentally. In addition, a sixth geometry of approach exists, leading over a transition structure of comparable energy to a shallow minimum that corresponds to a zwitterionic intermediate. The calculated potential energy surface suggests that the reaction can proceed through this intermediate both to the observed diene product and to one of the other isomers. It therefore appears that the concerted and stepwise mechanisms are competitive in the substituted system. Taken together, the calculated pathways and barriers do not adequately account for the very pronounced regioselectivity observed experimentally; only modest regioselectivity would be predicted at best. Examination of a calculated potential energy surface defined over two relevant internal coordinates sheds further light on the reaction and suggests that the experimentally observed regioselectivity might derive in considerable part from dynamic effects.

A combination of chemical trapping and laser flash photolysis experiments is used to demonstrate that homocub-9-ylidene and homocub-1(9)-ene are in equilibrium. The equilibrium constant can be shown to be close to unity at +20°C (0.23≤K≤4)

A carborane version of dehydrobenzene, 1,2-dehydro-o-carborane, has been generated from (2-bromo-o-carboranyl) lithium. This new intermediate undergoes the ene reaction as well as 2+2 and 2+4 cycloadditions. The 2+2 cycloaddition is nonstereospecific, whereas the 2+4 cycloaddition likely proceeds with retention of stereochemistry

PREFACE. CONTRIBUTORS. PART 1 REACTIVE INTERMEDIATES. 1. Tetrahedral Intermediates Derived from Carbonyl Compounds, Pentacoordinate Intermediates Derived from Phosphoryl and Sulfonyl Compounds, and Concerted Paths Which Avoid Them (J.P. Guthrie). 2. Silicon-, Germanium-, and Tin-Centered Cations, Radicals, and Anions (V.Y. Lee and A. Sekiguchi). PART 2 METHODS AND APPLICATIONS. 3. An Introduction to Time-Resolved Resonance Raman Spectroscopy and Its Application to Reactive Intermediates (D.L. Phillips, W.M. Kwok, and C. Ma). 4. Time-Resolved Infrared (TRIR) Studies of Organic Reactive Intermediates (J.P. Toscano). 5. Studies of the Thermochemical Properties of Reactive Intermediates by Mass Spectrometric Methods (P.G. Wenthold). 6. Reactive Intermediates in Combustion (J.K. Merle and C.M. Hadad). 7. Reactive Intermediates in Crystals: Form and Function (L.M. Campos and M.A. Garcia-Garibay). 8. The Chemical Reactions of DNA Damage and Degradation (K.S. Gates). 9. Conical Intersection Species as Reactive Intermediates (M.J. Bearpark and M.A. Robb). 10. Quantum Mechanical Tunneling in Organic Reactive Intermediates (R.S. Sheridan). INDEX.

Pyrolysis of 1,6-diphenylhexa-1,5-diyne-cis-3-ene at 800–1000°C leads to a mixture of 1- and 2-phenylbiphenylene, along with triphenylene. Formation of the two biphenylenes is taken as strong evidence of the rearrangement of a p-benzyne into a m-benzyne through a shift of one of the phenyl groups. Copyright © 2004 John Wiley & Sons, Ltd.

Spiro[5.7]trideca-1,4-dien-3-one intermediate: 1-(cyclooctylidenemethyl)piperidine reactant: methyl vinyl ketone (6.44 g, 0.092 mol) intermediate: spiro[5.7]tridec-1-en-3-one product: spiro[5.7]trideca-1,4-dien-3-one Keywords: addition, to CO; annulation, carbocyclic-[6]; cyclization, condensation; elimination, dehydrogenation; enamine or imine formation; dioxane; methyl vinyl ketone; piperidine

Laser flash photolysis of diadamantyldiazomethane produces diadamantylcarbene which reacts with oxygen to form a carbonyl oxide with λ max=307 nm