Through-space effects of substituents on the stability of the 1-bicyclo[3.1.1]heptyl cation.

γ-Substituents, are shown to have a dramatic effect on the stabilisation of the cationic transition state for solvolysis of 5-substituted bicyclo[3.1.1]heptyl bromides.     

Methyl substituent effects in radical cation Diels-Alder reactions

The effect of methyl substitution on the Diels-Alder radical cation reaction was studied using B3LYP with a 6-31G* basis set. Five separate pathways, one concerted and four stepwise, were examined for each possible position of a methyl substituent. None of the concerted transition structures could be located without symmetry constraints, and all but one of the structures obtained under these conditions were destabilized by a second-order Jahn-Teller distortion. A concerted pathway with simultaneous bond formation at C1 and C4 is therefore excluded. Stepwise pathways that had the methyl group either on a carbon involved in the initial bond formation or in a position where it could not stabilize the radical/cation were a few kcal/mol above alternate pathways. High transition state energies for the formation of vinylcyclobutane derivatives cause it to be a minor product in general. The pathway that proceeds through an anti-intermediate is the most favored, while the pathways forming the gauche-out intermediate that converts to the anti-intermediate is also strongly represented. Both of the major pathways lead directly to the formation of the methylcyclohexene product.     

Remote substituent effects upon the rearrangements of housane cation radicals

The rearrangement of a series of housane-derived cation radicals was investigated. Surprisingly, 2-aryl-substituted systems rearranged regioselectively and in a process whose selectivity proved to be independent of the electronic character of para substituents. The major reaction pathway is suggested to be the one that allows maximum delocalization, and allows it to be maintained for as long as possible. Bridging is invoked to account for the regio- and stereoselectivity. When a nonbridging trimethylsilylmethyl substituent is appended to C2, the regioselectivity is eroded entirely. B3LYP/6-31G(d) calculations corroborate the notion that bridging plays a role. While bridging ought to stabilize an intermediate by allowing delocalization of the charge/spin, there should be an accompanying entropic penalty. To determine the relative importance of enthalpic and entropic factors in determining the product selectivity, the rearrangement of the p-methoxyphenyl-substituted housane was investigated as a function of temperature. Enthalpic factors dominated over the entire temperature range that was explored. Overall, the results indicate that it is possible to influence the direction of migration in housane-derived cation radical rearrangements even when the regiochemical control unit is not directly appended to the migration terminus. This finding suggests that there may be other substituents that can be placed at C2 that could do the same, perhaps more efficiently.     

Nature of the 2-bicyclo[3.2.1]octanyl and 2-bicyclo[3.2.2]nonanyl cations.

Density functional and ab initio calculations have been employed to explore the nature of the cations formed in the solvolysis of 2-bicyclo[3.2.1]octanyl tosylate the 2-bicyclo[3.2.2]nonanyl tosylate. In contrast to recent conclusions in the literature, the various proposed classical carbocations postulated to explain the products of the 2-bicyclo[3.2.2]nonanyl tosylate solvolysis were found to have nonclassical structures.     

NMR isotope shifts in the 2-methyl-2-bicyclo[2.1.1]hexyl cation and related systems

NMR isotope shifts at ¹³C nuclei due to deuteriation in the 2-methyl-2-bicyclo[2.1.1]hexyl cation are reported. Comparisons are made to the 2-methyl-2-bicyclo[2.2.1]heptyl and 2-methyl-2-bicyclo[2.2.2]octyl cations, and also to neutral molecules containing the bicyclo[2.1.1]hexyl framework. The combination of isotope effects with temperature dependence of ¹³C chemical shifts allows predictions of the shapes of the energy surfaces along the bending coordinate corresponding to bridging in these cations.     

Coping with substituent effects in divinylcyclopropyl diazene rearrangements

Surprising differences between the chemistry of ester and ketone derivatives of C-7-substituted divinylcyclopropyl [2.2.1]diazenes was discovered. While the ester does not, the ketone undergoes facile Cope rearrangement. These topics, the chemistry of the product, and mechanistic implications are discussed.     

Stereochemical assignments of the 7-phenyl-2-oxabicyclo[4.1.0]heptanes

A rapid method for making stereochemical assignments based on variant temperature nmr data for the 7-phenyl-2-oxabicyclo[4.1.0]heptanes is described.     

Electron-impact fragmentation of the bicyclo[4.1.0]heptane-2-one system: Correlations with photochemistry

The low resolution and complete high resolution mass spectra of a series of methyl and deuterium substituted bicyclo[4.1.0]heptane-2-one derivatives have been measured. An attempt has been made to test the operation of a fragmentation process analogous to the known photochemical rearrangement, and to determine if the substitution effects critical to the photorearrangement also influence the electron-impact process. The fragmentation pattern of these conjugated cyclopropyl ketones is detailed and the influence of the cyclopropyl ring is discussed. It is suggested that electron-impact-induced rearrangements which are analogous to photochemical transformations will be relatively low energy processes and will remain prominent at low ionizing voltages.     

Interconversion of bicyclo[2.2.1]hept-2-yne and 5-bicyclo[2.1.1]hexylidenecarbene

This work provides unambiguous results for the full equilibration of cycloalkyne 2 with its isomeric ring-contracted vinylidene 3 prior to their reaction with 2,3-dihydropyran (4), as evidenced by the products formed when 2 and 3 are produced directly from their precursors having bicyclo[2.2.1]heptyl and bicyclo[2.1.1]hexyl skeletons, respectively.     

Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.     

Synthesis and dynamic NMR studies of the 3,7-diazabicyclo[4.1.0]heptane system

A new bicyclic system, 3,7-diazabicyclo[4.1.0]heptane, has been prepared from 3-(ethoxycarbonyl)-7,3-oxazabicyclo[4.1.0]heptane by reaction with sodium azide and reduction of the resulting tosyloxy azide with lithium aluminum hydride. The molecule can exist in four stereoisomeric half-chairs, depending on the configuration of the two nitrogen atoms. Half-chair ring reversal and piperidine nitrogen inversion are fast on the NMR time scale at all observed temperatures. Inversion of the secondary aziridine nitrogen becomes slow as the temperature is lowered (T_c= ?10°C). Complete analysis of the ¹H spectrum was possible with the 1,5,5-trideuteriated analog. At slow exchange, two aziridine invertomers are present with an exo/endo ratio of approximately 0.7 in toluene-d₈, 0.7 in CH₂Cl₂ and 1.7 in CHCl₃/CH₂Cl₂. The free energy of activation for nitrogen inversion is 13.2 kcal mol^?1 at ?10°C in CHCl₃/CH₂Cl₂.     

Preparation of N-arylamines from 2-oxo-7-azobicyclo[4.1.0]heptanes

A wide range of N-phenylated secondary amines were prepared directly from 2-oxo-7-azobicyclo[4.1.0]heptanes using 4-nitrobenzoic acid as acid catalyst. The intermediate enol esters could also be isolated under similar conditions. A catalytic cycle is proposed.     

Remote substituent effects in ruthenium-catalyzed [2+2] cycloadditions: an experimental and theoretical study

The effects of a remote substituent on the regioselectivity of ruthenium-catalyzed [2+2] cycloadditions of 2-substituted norbornenes with alkynes have been investigated experimentally and theoretically using density functional theory. Most of the cycloadditions occurred smoothly at room temperature, giving the exo cycloadducts in excellent yields. Regioselectivities of 1.2:1 to 15:1 were observed with various substituents on the C-2 position of the norbornenes. Exo-C-2-substituents usually showed greater remote substituent effects on the regioselectivities of the cycloadditions than the corresponding endo-C-2-substituents. The regioselectivity of the cycloadditions with C-2 substituents containing an exocyclic double bond (sp2 hybridized carbon at C-2) are much higher than the cycloadditions with the exo and endo 2-substituted norbornenes. Theoretical studies predicted the same trends as experiment and matched the experimental product ratios well. The nature of the regioselectivity in this reaction is discussed. Different strengths of the pi(C5-C6)-->pi(C2-Y) or pi(C5-C6)-->sigma(C2-Y) orbital interactions in 2-substituted norbornenes result in different degrees of C5-C6 double bond polarization. Stronger C5-C6 polarization will increase the difference in the activation energies between the major and minor pathways and thus lead to greater regioselectivities.     

Chemo-enzymatic preparation of optically active endo-bicyclo[4.1.0]heptan-2-ols

Resolutions of endo-bicyclo[4.1.0]heptan-2-ols were achieved by acylation in the presence of lipase from Candida antarctica (Novozym^®). The (1S,2R,6R) enantiomers reacted faster and the enantiomeric ratios were between 60 and 800 for the 6-substituted bicycloalkanols.     

Captodative substituent effects — Part XXXI olefins with captodative substitution in [2+2] cycloadditions

Olefins with captodative substitution are excellent partners in [2+2] cycloadditions leading to cyclobutane derivatives. The reaction rates increase with the radical stabilising power of the substituents. Thio- and selenoalkyl(aryl) substituted gemdifluoroolefins allow the synthesis of new cyclobutane derivatives.     

Methyl substituent effects for methyltryptophans in 13C nmr

The ¹³C and ¹H nmr spectra of methyltryptophans 2–5 in 0.1 N sodium deuteroxide methanol-d₄ were assigned based on 1-D and 2-D nmr techniques, including COSY, inverse-detected direct (HMQC) and long-range (HMBC) correlation. Methyl substituent effects in chemical shifts (SCS) for the indole ring of tryptophan were calculated and compared with those of indole. The correlations were linear except for 4-methyltryptophan, which suggest structural changes in the indole ring of 4-methyltryptophan and 4-methylindole. The results of molecular modeling and NOE experiments supported that suggestion.