Effects of halo substituents on electron-impact induced fragmentation of cyclopropanes

Bromine, fluorine and/or chlorine atoms on one cyclopropyl ring jointly influence the dominant primary modes of electron-impact induced fragmentation. Decomposition ions include CBrX, C₂HQ₂X and C₃HQ₂X₂, where × is an halogen atom and Q is from the group of an halogen atom, an hydrogen atom and a methyl group. For none of the compounds studied was formation of an ionic CBrX the dominant primary process. Gem-dibromo-gem-dihalocyclopropanes preferentially eliminated dibromo divalent carbon and formed decomposition products of gem-dihalogenated C₂HQ₂X′s. In cases where more stable allyl ions were formed, fragmentation was through C₃HQ₂X₂. Upon electron-impact, the ions CF, CHF₂ and CF₃ were produced in abundances directly related to the fluorine content of their cyclopropyl precursors. When fragmentation patterns for internally generated radical ions of the composition C₂HQ₂X were compared with patterns obtained by direct introduction of the same fluoroolefins into a mass spectrometer, incomplete correspondence was found. Variation in the mode of decomposition can be a consequence of differences in the energy levels of the olefin fragmented. Addition of two hydrogen atoms from water to quinones and to s-tetrazines is well established in the literature. Reaction of an additional cyclic series, polyhalocyclopropanes, with water prior to electron-impact is suggested.     

Ionization energies of homologous organic compounds and correlation with molecular size

The empirical relationship IE ∝? 1/n, between the ionization energy (IE) and molecular size (as represented by the number of atoms, n) in homologous series of organic compounds has been confirmed for n-alkanes, alkyl halides, cyclic ethers and alkyl-subsiituted cycloalkanes. For each series, the plot of IE vs. 1/n produces a line of characteristic slope. The only exception is the cycloalkanes themselves, whose IE values (from C₃ to C₈) are closely similar. The possible relationship between the IE, the polarizability of the molecules and the energy of the highest occupied molecular orbital is briefly discussed.     

Synthesis of Selectively gem-Difluorinated Molecules; Chiral gem-Difluorocyclopropanes via Chemo-Enzymatic Reaction and gem-Difluorinated Compounds via Radical Reaction

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem-difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2-difluorinated-esters by visible light-driven radical addition of 2,2-difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem-difluorinated compounds via the ring-opening of gem-difluorocyclopropanes. We further developed a novel method of synthesizing gem-difluorohomoallylic alcohols via the ring-opening of gem-difluorocyclopropane and aerobic oxidation by photo-irradiation in the presence of an organic pigment. Since gem-difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem-difluorinated cyclic alkenols via the ring-closing-metathesis (RCM) reaction.     

Impact of Fluoroalkyl Substituents on the Physicochemical Properties of Saturated Heterocyclic Amines

The physicochemical properties (pK_a(H), log P, and aqueous solubility) of fluoroalkyl-substituted heterocyclic amines were profiled to facilitate the amines’ rational application in medicinal chemistry research. The features of fluorine-containing compounds were compared to those of the corresponding parent non-fluorinated heterocycles and the corresponding fluorinated n-alkylamines. Amine basicity was observed to change in a monotonic fashion depending on the fluorination pattern. Although the introduction of fluoroalkyl groups had complex effects on the lipophilicity and aqueous solubility of the compounds, possible contributions of the fluorination pattern, ring size, and conformation of the substituent in the ring were addressed for a series of derivatives. The summarized data provide a useful guideline for the application of fluorinated motifs for fine-tuning a compound's properties related to drug discovery.     

Copper-Catalyzed Enantioselective Hydrosilylation of gem-Difluorocyclopropenes Leading to a Stereochemical Study of the Silylated gem-Difluorocyclopropanes

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper-catalyzed enantioselective hydrosilylation of gem-difluorocyclopropenes to provide the corresponding chiral gem-difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me₂PhSi-Bpin accompanying sodium tert-butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three-membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio-enriched gem-difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C−C bond leading to the transient acyclic intermediates.     

Mass spectrometric investigation of polyfluorinated C60. Evidence for the existence of C60F2n (n = 0–30)

Electron-capture negative ion chemical ionization (EC-NICI) and field desorption (FD) mass spectrometric techniques were utilized to examine polyfluorinated C₆₀. Two different samples from the same preparation, one prior to sublimation and the other sublimed material, were investigated. From the raw non-sublimed product in EC-NCI six series of ions corresponding to different numbers of attached oxygen atoms were obtained, which are represented by the formula [C₆₀F_2nO_m]^?, where n ranged from 0 to 30 and m from 0 to 5. The sublimed material in EC-NICI produced the same six series of ions with up to 48 fluorine atoms attached to C₆₀. The field desorption of the same sample produced similar results, but the signal-to-noise ratios of the spectra were low. Both samples, in the two different techniques examined, yielded C₆₀F₆₀ ions with only an even number of fluorine atoms attached. The present investigation, for the first time, provides direct experimental evidence for the existence of higher fluorinated C₆₀ up to C₆₀F₆₀ and multiple oxides of polyfluoro-C₆₀ with up to five oxygen atoms attached.     

Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and 6a – 6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and their enantiomers 6a – 6i , together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.     

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene by chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone, affording gem-difluorinated 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.     

Molecular structure and thermal stability of α-halogen-<Emphasis Type="Italic">gem</Emphasis>-dithiols

The electronic structure of α-halogen-gem-dithiols RC(SH)₂CH₂X (R = Me, Ph; X = F, Cl, Br, I) was studied by quantum chemistry methods. Four most stable rotamers were located, differing in the mutual orientation of the thiol groups and the halogen atom. The thermodynamic and kinetic characteristics of the thermolysis of α-halogen-gem-dithiols were obtained. Thermolysis of chlorine- and bromine-substituted gem-dithiols depends on the properties of the medium, namely, in aprotic media aromatic dithiols form trithianorbornane derivatives while aliphatic dithiols form thiirane derivatives. In an aqueous medium (R = Me, Ph), water promoted elimination of hydrogen sulfide with the formation of corresponding thiones is more preferable. Thermolysis of aliphatic iodine-substituted gem-dithiols proceeds as bimolecular deiodination resulting in the formation of a new C-C bond.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 559–568, March, 2005.     

Some Reactions of gem‐Dibromocyclopropanes and Metal Carbonyls

A series of gem‐dibromocyclopropanes were treated with various metal complexes. Among the metal complexes, Ru(CO)₂(PPh₃)₃, Ru(CO)₃(PPh₃)₂, and Mo(CO)₆ were able to remove a bromine atom from 1,1‐dibromo‐2‐phenylcyclopropanes ( 1 ) to yield a series of corresponding of 1‐bromo‐2‐phenylcyclopropanes ( 2 ). Upon the treatment of 1 with Cr(CO)₆ in DMSO, a series of allenes were obtained in good yields. The correlation between the rate of formation of allenes and the substituents on the benzene gives a negative coefficient which suggests the dibromocyclopropanes possesses as an electrophile toward to Cr(CO)₆. In the presence of Cr(CO)₆, gem‐dibromobicyclo[n,1,0]alkanes ( 4 ) in DMF or DMSO solution underwent the cleavage of carbon‐bromine bond followed by ring‐expansion and coupling reaction to form bicycloalkenes 7 .     

Theoretical Analysis and Experimental Study of the Spatial Structure and Isomerism of Acetone Azine and Its Cyclization to 3,5,5-Trimethyl-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole

An ab initio (RHF/6-31G*and MP2/6-31G*) study has been undertaken to investigate the spatial structure and relative stability of the acyclic isomers of acetone azine (acetone N-(1-methylethylidene) hydrazone (CH₃)₂C=N-N=C(CH₃)₂), differing in the position of multiple bonds, and of the cyclic isomer 3,5,5-trimethyl-4,5-dihydro-1H-pyrazole. In the series of structures under study, the latter possesses the greatest thermodynamic stability so that formation of acyclic isomers such as 1-isopropenyl-2-isopropyldiazene, acetone N-isopropenylhydrazone, and 1,2-diisopropenylhydrazine from acetone azine is thermodynamically unfavorable. For each structure, stable conformations have been found, and the internal rotation barriers of molecules relative to the N-N, C-N, and C-C single bonds have been estimated. The noncoplanar goshconformer of acetone azine was found to possess the greatest thermodynamic stability. The acetone azine molecule is considered in comparison with model hydrazine, butadiene, and vinylamine molecules. Acetone azine is conformationally preferable not only because of steric factors, but also due to the interaction of the lone electron pair (LEP) of nitrogen atoms with adjacent N=C multiple bonds.Original Russian Text Copyright © 2004 by V. B. Kobychev, N. M. Vitkovskaya, N. V. Pavlova, E. Yu. Schmidt, and B. A. Trofimov__________Translated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 5, pp. 792–799, September–October, 2004.     

O‐Alkyl S‐3,3‐Dimethyl‐2‐oxobutyl Dithiocarbonates as Versatile Sulfur‐Transfer Agents in Radical C(sp3)?H Functionalization

Boiling of the title compounds in ethereal solvents or cycloalkanes in the presence of a radical initiator leads to radical C(sp³)? H functionalization, by which a sulfur atom is introduced into the ethereal solvents at the oxygenated carbon atom or into the cycloalkanes. Both acyclic and cyclic ethers, such as [18]crown‐6 and [D₈]THF, undergo the sulfur transfer. The reaction is useful for the synthesis of monothioacetals, thiols, and sulfides from simple starting materials.     

A quantum chemical study of the structure of fluorinated silver acetate(I) monomers and dimers

Quantum chemical calculations of the equilibrium structure, potential energy surface cross-sections along the nonrigid degrees of freedom of (CF₃COOAg)₂, (CHF₂COOAg)₂, (CH₂FCOOAg)₂, and (CH₃COOAg)₂ dimers and the corresponding monomers are presented. The B3LYP method with the augmented cc-pVTZ basis set for C, O, F atoms and the Stuttgart 1997 RSC basis set together with the relativistic effective potential for Ag atoms is used. It is shown that in all dimers the eight-membered ring is a rather rigid planar fragment, and the Ag atoms can be bonded with the bond order of 0.2 in dimers. Almost free rotation of acyclic groups around the C-C bond in (CH₃COOAg)₂ and (CF₃COOAg)₂ dimers transforms into a hindered one in the (CHF₂COOAg)₂ dimer, and further into the existence of syn- and anti-structures divided by a high rotation barrier in the (CH₂FCOOAg)₂ dimer. In monomers, the ratio of the internal rotation barriers is similar. With increasing number of fluorine substitution for hydrogen atoms in dimers the Ag-Ag bond length is found to increase (2.79 Å, 2.81 Å, 2.83 Å, 2.84 Å) and the ring rigidity to simultaneously decrease in the acetate-triflouroacetate series.     

X-ray photoelectron spectroscopy as detection tool for coordinated or uncoordinated fluorine atoms demonstrated on fluoride systems NaF,K2TaF7, K3TaF8, K2ZrF6, Na7Zr6F31 and K3ZrF7

While systems K₃TaF₈ and K₃ZrF₇ were prepared by modified molten salt method modified wet pathway was used for reproducible preparation of Na₇Zr₆F₃₁. Its congruently melting character was demonstrated on simultaneous TG/DSC measurements and XRD patterns. X-ray photoelectron spectroscopy was applied for identification of differently bonded fluorine atoms in series of compounds NaF, K₂TaF₇, K₃TaF₈, K₂ZrF₆, Na₇Zr₆F₃₁ and K₃ZrF₇. Three different types of fluorine atoms were described qualitatively and quantitatively. Uncoordinated fluorine atoms (F⁻) provide signals at lowest binding energies, followed by signals from terminally coordinated fluorine atoms (M–F) and then bridging fluorine atoms (M–F–M) at highest energy. Based on XPS F 1s signals assigned to fluorine atoms in compounds with correctly determined structure it was suggested that fluorine atoms in K₃ZrF₇ have partially bridging character.     

Why is benzyl‐gem‐diacetate remarkably stable in aqueous solution?

Benzyl‐gem‐diacetate is synthesized and performed its solvolysis in water at 25°C. It did not solvolize even for a year, whereas its counterparts benzyl‐gem‐diazide and dihalides underwent spontaneous cleavage through a S_N1 mechanism in aqueous solution to give benzaldehydes as the final product through α‐azido benzyl and α‐halo benzyl carbocation intermediates, respectively. The possible explanations are offered for the extraordinary stability of the benzyl‐gem‐diacetate in water. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 554–557, 2009     

Mutual correlation between gas chromatographic retention indices of unsaturated and saturated hydrocarbons found by molecular dynamics

It is shown that gas Chromatographic retention indices for cycloalkenes can be calculated from the corresponding data for cycloalkanes (and vice versa) using computer simulation of intramolecular vibrational and rotational processes by molecular dynamics. For organic compounds structurally related asA → B, the total internal energy differences δE = E(B)-E(A) correlate with the corresponding differences in retention indices δI = I(B)-I(A), and a linear relationship exists δI =aδE + b (a < 0, |ρ| > 0.9). Limitations are found for the use of molecular dynamics for compounds havingn-alkyl radicals with no less than four carbon atoms. In these cases, a simpler model for the evaluation of dynamic molecular parameters should be preferred for the calculation of retention indices of acyclic alkenes and alkanes. The reliability of the retention indices evaluated by the proposed technique is comparable to their interlaboratory reproducibility found using standard nonpolar poly(dimethylsiloxane) stationary phases.     

1H NMR studies of 3,8-dioxatricyclo-[3.2.1.02,4]octane derivatives

A series of 6-X-3,8-dioxatricyclo[3.2.1.0^2,4]octanes (X?CO₂CH₃, CN, Cl and CN) are studied by NMR, after their syntheses by epoxidation of the corresponding 7-oxabicyclo[2.2.1]heptenes. The NMR parameters (J, δ) are determined, and also the anisotropy effects of methyl groups at the 1,5 bridgehead positions. The results allow an unambiguous identification of the diastereo-isomers having a gem-chlorocyano group in the 6 position.     

Grubbs Metathesis Enabled by a Light-Driven gem-Hydrogenation of Internal Alkynes

[(NHC)(cymene)RuCl₂] (NHC=N-heterocyclic carbene) complexes instigate a light-driven gem-hydrogenation of internal alkynes with concomitant formation of discrete Grubbs-type ruthenium carbene species. This unorthodox reactivity mode is harnessed in the form of a “hydrogenative metathesis” reaction, which converts an enyne substrate into a cyclic alkene. The intervention of ruthenium carbenes formed in the actual gem-hydrogenation step was proven by the isolation and crystallographic characterization of a rather unusual representative of this series carrying an unconfined alkyl group on a disubstituted carbene center.     

Thermodynamics of solutions of iodine and perfluorocarbons in cycloalkanes

The solubilities of iodine from 9 to 30°C were measured in the C₅, C₆, C₇, C₈, and C₁₀ cycloalkanes. The solubilities were found to increase smoothly with ring size and to be greater than these of corresponding n-alkane. The results are analyzed in terms of the solubility parameter version of the regular solution theory and, unlike the n-alkanes, good agreement is found suggesting that the cycloalkanes are good model substances for testing theoretical predictions of the effect of molecular size on the thermodynamics of liquid mixtures and that molecular shape and flexibility need not be considered, at least in equilibrium properties governed by the free energy. A similar analysis of the upper critical solution temperatures of cyloalkane + perfluorotributylamine, cycloalkane + perfluorocyclohexane, and n-alkane + perfluorotributylamine mixtures leads to the same conclusion.