Quest for even higher stabilized foiled carbenes.

Foiled carbene structures comprising strong stabilizing interactions between the divalent carbon and the intramolecular double bond have been located by DFT calculations. These tetracyclic species bearing fused five-membered rings impeding intramolecular rearrangements are theoretically predicted to lie in a deep potential energy well. A suitable dibromocyclopropane precursor for this type of foiled carbene has been prepared in 12 steps. Its treatment with methyllithium led to the isolation of a product of a formal carbene dimerization, a bicyclopropylidene.

Efforts toward distorted spiropentanes.

Tetravinylbenzene 4 was prepared in nearly quantitative yield from commercially available tetrabromobenzene; the improved, one-step procedure now employs Suzuki-Miyaura cross-coupling conditions. Intermolecular cyclopropanation of 4 with dibromocarbene gave a series of gem-dibromide adducts. Intramolecular cyclopropanation of monoadduct 5, putatively by its methyllithium-generated cyclopropylidene(oid), produced compound 11, which features a highly distorted spiropentane having a C-C-C bond angle of 163.5°. The stability of the reported spiropentanes was investigated using DFT calculations.

2H-Azirines from a concerted addition of alkylcarbenes to nitrile groups.

Photolysis of aziadamantanes in the presence of fumaronitrile (FN) unexpectedly afforded conjugated 2H-azirines resulting from addition of the carbene to the CN triple bond. This represents the first example of a direct azirine formation starting from an alkylcarbene for which a concerted pathway is postulated. The novel outcome of the reaction is favored by the prior formation of a carbene-alkene complex, a type of adduct that only recently has been described.

Controllable selective functionalization of a cavitand via solid state photolysis of an encapsulated phenyl azide.

Phenyl azide (1) has been encapsulated within cavitand 2 to form a 1:1 complex of 1@2 in the solid state. Subsequent irradiation affords two diastereomeric nitrene addition products 5 and 7. The ratio of 5 and 7 can be reversed by thermally induced valence isomerization to 1H-azepine 8 followed by photolysis. In sharp contrast, phenylnitrene generation by photolysis of the corresponding 1.5:1 complex results mainly in the regioselective formation of C-H insertion product 4. The supramolecular approach to phenylnitrene chemistry provides good yields, in contrast to the generally low yield reactions of this species in solution.

Carbene-alkene complexes between a nucleophilic carbene and electron-poor alkenes.

Spirooxadiazoline 5 is a clean thermal source of tricyclo[6.2.1.0 (2,7)]undec-9-en-11-ylidene (7), a typical foiled carbene. Species 7 can be trapped efficiently at 165 degrees C by electron-deficient alkenes like acrylonitrile and fumaronitrile whereby the anti addition products are obtained exclusively. Higher temperatures, however, favor intramolecular reactions. Density functional theory (DFT) calculations predict the formation of a strong complex between both reactants which actually is a minimum on the free energy scale. These results confirm the nucleophilic character of foiled carbenes and the presence of a significant barrier toward rearrangement.

Substituent effects on the ring-opening mechanism of lithium bromocyclopropylidenoids to allenes.

The ring-opening reactions of lithium bromocyclopropylidenoids to allenes have been investigated computationally at the B3LYP/6-31G(d) level of theory. Formally, two pathways can be considered: the reaction may either proceed in a concerted fashion or stepwise with the intermediacy of a free cyclopropylidene. In both cases, the loss of the bromide ion determines the kinetic of the reaction. The stability of the reactive intermediate, i.e., the carbene, is dependent on the substituent. Cyclopropylidenes bearing an electron-donating group (+M) are extremely unstable and ring-open readily to the allene. In contrast, bromocyclopropylidenoids with electron-withdrawing groups are particularly stable species. Here, a high energy barrier needs to be overcome in order to split off bromide and to generate the corresponding carbene or allene. Still, for most of the monosubstituted cyclopropylidenes investigated during this study, the activation energy for the cyclopropylidene to allene rearrangement is lower than the energy required for parent compound (X = H) except for X = -SiH3 and -CF3.

Intermolecular reactions of foiled carbenes with N-H bonds: evidence for an ylidic pathway.

The chemistry of endo-tricyclo[6.2.1.0 (2.7)]undec-9-en-11-ylidene (10), an archetypal foiled carbene, has been investigated. The intermolecular reactions of 10 are most conveniently performed with oxadiazoline 6 because the corresponding diazirine can be obtained only in very low yield. Furthermore, the aziridinyl imine is difficult to decompose and the tosylhydrazone sodium salt poorly soluble in common organic solvents. Photolysis of 6 in diethylamine leads merely to a reduction of the diazo group and regeneration of acetyl hydrazone 5, whereas thermolysis cleanly affords tertiary amine 12(anti) in 77% yield. Calculations show that even stabilized-nucleophilic carbenes react with amines through an ylidic pathway and not by a concerted insertion into the N-H bond. Nevertheless, in the gas phase, norbornen-7-ylidene (13) is predicted to be stabilized by one molecule of NH3 more efficiently through a hydrogen bond than by ylide formation.

The carbene reactivity surface: a classification.

A new two-dimensional classification of singlet carbenes based on the difference in reactivity of their insertion reactions into the C-H bonds of acetonitrile and isobutane is presented. This classification combines the stability and the philicity of divalent species. Until now all of the experimentally based philicity scales are based on the addition to alkenes. Moreover, a new terminology for describing the reactivity of carbenes is introduced. Among the alkyl carbenes, acetyl carbene (2) and cyclopentadienylidene are shown as highly reactive electrophilic carbenes, whereas the other alkylidenes and alkenylidenes investigated are all less active than 2 and more nucleophilic. The stabilized-nucleophilic bicyclo[2.1.1]hex-2-en-5-ylidene (13) possesses a stability similar to that of cyclic alkyl amino carbene (CAAC) 18 and aminophosphoniocarbene 7. Strong hydrogen bridging is found between a C-H bond of acetonitrile and the nucleophilic carbenes 13 and 14.

Toward selective reactions with C-H bonds: a rationale for the regio- and stereochemistry of dichlorocarbene insertions into cyclic hydrocarbons.

DFT calculations have been performed to study the course of dichlorocarbene insertion reactions into alkanes and to better understand the regio- and stereoselectivities observed. At the B3LYP/6-31G(d) level of theory, the selectivity of dichlorocarbene insertions into a number of hydrocarbons agrees well with the obtained experimental results. The reactivity of a specific C-H bond is determined by the capacity of the remaining alkyl fragment to effectively delocalize the partial positive charge buildup during the reaction. This activity can readily be estimated by calculation of the hydride transfer potential (HTP). A comparison with the structure and the stability of the corresponding cation is useful to emphasize the origins of the selectivity. Dichlorocarbene is also predicted to react efficiently with acidic C-H bonds through a nucleophilic-electrophilic mechanism. In principle, an attack of a carbene on an appropriately substituted three-membered ring may lead to fragmentation of the molecule.

Dihalocarbene insertion reactions into C-H bonds of compounds containing small rings: mechanisms and regio- and stereoselectivities.

Novel insertion reactions of dichloro- and dibromocarbene into carbon-hydrogen bonds adjacent to cyclopropane rings are reported. It is found that the predominant isomers formed in the reactions with bicyclo[4.1.0]heptane result from insertion into the endo carbon-hydrogen bonds alpha to the three-membered ring. In the reactions of bicyclo[3.1.0]hexane, however, the exo dihalocarbene insertion products are formed as the major isomers. In some compounds cyclopropane rings "activate" adjacent carbon-hydrogen bonds, whereas other systems containing three-membered rings do not. Moreover, the influence of various substituents (methyl, geminal dimethyl, phenyl, methoxy, and ethoxy) attached to bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane in dihalocarbene reactions has been studied. The findings can be explained by the concept of maximum orbital overlaps of Walsh orbitals of the cyclopropane rings and the alpha carbon-hydrogen bonds. In stark contrast, selective insertion into the tertiary carbon-hydrogen bonds of the cyclobutane ring in bicyclo[4.2.0]octane is observed.

Foiled carbenes revisited: When sigma-stabilization surpasses pi-stabilization.

The bicyclic alkenylidenes 9 (bicyclo[3.2.1]oct-2-en-8-ylidene) and 17 (bicyclo[3.3.1]non-2-en-9-ylidene) were claimed to be stabilized foiled carbenes. Our B3LYP and MP2 computations confirm previous experimental data. Moreover, they show that these carbenes are very reactive and rearrange rapidly, mainly through a 1,2-vinyl shift by overcoming a low barrier (1.2 to 5.4 kcal/mol). This is in contrast to the high barriers (up to 30 kcal/mol) predicted for the same type of rearrangements in norborn-2-en-7-ylidene derivatives. In 17 and bicyclo[4.1.1]oct-2-en-7-ylidene (23), the divalent carbon atom is even bent away from the double bond!

Cope rearrangement versus a novel tandem retro-Diels-Alder-Diels-Alder reaction with role reversal.

[reaction: see text] A reinvestigation of the thermolysis of 4,4-dibromotetracyclo[6.2.1.0(2,7).0(3,5)]undec-9-ene (2) affords diene 8 with a completely rearranged hydrocarbon skeleton via the isolable intermediate 4, along with cyclopentadiene and bromobenzene. DFT calculations show that the novel tandem retro-Diels-Alder-Diels-Alder reaction with role reversal is slightly less favored than the overall single-step Cope rearrangement.

The nature and extent of pi-stabilization within foiled carbenes.

B3LYP/6-311+G(d,p) computations of the stabilization energies, singlet-triplet energy gaps, and lowest transition states for a set of cyclic alkenylidenes were performed in order to find the strongest interactions between the C-C double bond and the carbene center. The results suggest that among the alkenylidenes investigated in this study, those with a norbornenylidene structure represent strongly stabilized carbenes with a reduced reactivity toward intermolecular reactions. Further stabilization is found when the double bond is electron-rich or pyramidalized. Thus, for the rearrangement of syn-34 to take place, an activation barrier of about 22 kcal/mol needs to be overcome. The inclination to undergo a retro-Skattebøl rearrangement, which to our knowledge has never been observed experimentally, is characteristic for highly stabilized foiled carbenes.

A tether controlled exo-selective trans-annular Diels-Alder (TADA) reaction.

[reaction: see text] A fully substrate controlled stereoselective route to construct cis-hexahydronaphthalene 4 is described starting from nonracemic butenolide 6. The key step is an exo-selective transannular Diels-Alder reaction (TADA) of tetraene 5, whose intrinsic constraint allows selective formation of one stereodefined product. Compound 4 is a key intermediate in the synthesis of the novel antibiotic branimycin (1).

Reactions of endo-3-diazotricyclo[3.2.1.0 2,4]oct-6-ene, a potential precursor for the generation of a neutral C8H8 molecule with a pyramidally coordinated carbon.

endo-3-Diazotricyclo[3.2.1.0(2,4)]oct-6-ene (endo-6) has already been prepared in solution. According to B3LYP/6-311+G(d,p) computations, the corresponding carbene endo-7 easily produces the highly strained neutral C8H8 compound 4 comprising a pyramidally tetracoordinated carbon which then rearranges to bridgehead alkene 15 through a cascade of rearrangements. Nonplanar diazocyclopropane structures are predicted for endo- and exo-6. Furthermore, their ring-opened isomers 27 are the first representatives of a new class of non-Kekulé compounds, the diazoallyls.

On the existence of uncharged molecules with a pyramidally coordinated carbon: the cases of pentacyclo[4.3.0.0(2,9).0(3,8).0(7,9)]non-4-ene and heptacyclo- [7.6.0.0(1,5).0(5,15).0(6,14).0(10,14).0(10,15)]pentadecane.

[reaction: see text] B3LYP/6-31G(d) and MP2 calculations predict interactions between the divalent carbon and one double bond in tricyclo[3.2.2.0(2,4)]nona-6,8-dien-3-ylidene (3). Carbene 3 easily forms the more stable 4, a species with a pyramidal geometry. Moreover, the kinetic stability of 4 has been investigated, and some of its decay products are described. Interestingly, 3,3-dibromotricyclo[3.2.2.0(2,4)]nona-6,8-diene (1), the precursor of carbenoid 3, has already been reported and shown to undergo a formal dimerization to give 2. In addition, 15, a compound structurally related to 4, is expected to have a substantially greater stability toward further rearrangement.

Supramolecular recognition and structural elucidation of inclusion complexes of an achiral carbene precursor in beta- and permethylated beta-cyclodextrin.

[structure: see text] Inclusion of achiral carbene precursor endo-8-azibicyclo[3.2.1]octan-3-ol (1) in chiral beta-cyclodextrin (7-Cy) and tri-O-methyl-beta-cyclodextrin (TRIMEB) leads to 1:1 complexes 1@7-Cy and 1@TRIMEB, respectively. The combined methods of induced circular dichroism, NMR spectroscopy, and X-ray structure determination were employed for the first time for structural elucidation of the complexes in solution and the solid state. Significantly different orientations of 1 were observed. Compared with 1@7-Cy, 1@TRIMEB exhibits a different guest orientation and an association constant one-twentieth lower.

Regioselective formation of alkylidenecyclopropanes from 2-substituted cyclobutylidenes generated from geminal dibromocyclobutanes and methyllithium.

Four different 2-substituted geminal dibromocyclobutanes were reacted with methyllithium at -78 degrees C. In contrast to previous studies using diazocyclobutanes as carbene precursors at temperatures above 200 degrees C via reaction of the corresponding tosylhydrazone sodium salts, the organometallic route in each case produces only an alkylidenecyclopropane that could be isolated in good yields. B3LYP calculations were employed to rationalize the observed regioselective ring contraction of the generated cyclobutyliden(oid)s. [reaction: see text]