Structures of some fluorinated benzenes determined by ab initio computation

The structures of fluorobenzene, 1,3-difluorobenzene, 1,3,5-trifluorobenzene, 1,2,3-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene have been determined by the ab initio gradient method with a 4-21 basis set. Approximate corrections have been developed to yield r_e and r₀ structures so that comparison can be made with the available experimental information. The C? F bond distance decreases in a uniform manner with increasing fluorination of the ring, either on adjacent or on meta sites. The ring structure also shows systematic deformation, with a decrease of about 0.01 Å in the C? C bond length adjacent to the point of substitution and an increase of about 2.5? in the ring angle at the substitution site in those cases where the requirement of ring closure permits.     

Selective fluorination of pyridine and its derivatives in the presence of high-oxidation-state transition metals

The oxidative fluorination of pyridine and 4-ethylpyridine under chemical and electro-chemical conditions in the presence of transition metal (high-oxidation-state nickel, cobalt, and silver) salts was studied. The chemical fluorination affords 2-fluoropyridine in all cases, while the electrochemical fluorination results in 2-fluoroor 3-fluoropyridine depending on the catalyst used.     

Gas-phase reactions of divalent Ni complex ions with acetonitrile: Chelate ring size,inductive, and steric effects

Ni(II) complexes of a series of pentadentate polyamine ligands have been reacted with CH₃CN in the gas phase using a modified quadrupole ion trap mass spectrometer. The ligands have structural features such that upon complexation, chelate ring size, sterics, and inductive effects can be evaluated in the gas phase. Rate and equilibrium constants for CH₃CN addition to the metal complexes show that there is a general decrease in the gas-phase reactivity as the chelate ring size is increased. Density functional theory calculations at the B3LYP/LANL2DZ level of theory have been used to obtain minimum energy structures and Mulliken charges for the complexes. The decreased reactivity observed as the chelate ring size is increased correlates with a decrease in the atomic charge on the metal. A larger chelate ring size enhances ligand flexibility and improves the overlap of the ligand’s donor atoms with the metal center. Adding methyl groups adjacent to or on the nitrogen donor groups of a ligand also decreases the rate and equilibrium constants for the reactions of a given complex with CH₃CN. Analysis of Mulliken charges for these complexes indicates that both inductive and steric effects are responsible for lower complex reactivity. These results suggest that while the gas-phase reactivity of a metal complex with CH₃CN is very dependent on the functional groups directly bound to the metal, in some cases steric effects can conceal the correlation between reactivity and coordination structure.     

Chemoselective,Substrate‐directed Fluorination of Functionalized Cyclopentane β‐Amino Acids

This work describes a substrate‐directed fluorination of some highly functionalized cyclopentane derivatives. The cyclic products incorporating CH₂F or CHF₂ moieties in their structure have been synthesized from diexo‐ or diendo‐norbornene β‐amino acids following a stereocontrolled strategy. The synthetic study was based on an oxidative transformation of the ring carbon–carbon double bond of the norbornene β‐amino acids, followed by transformation of the resulted ?all cis“ and ?trans“ diformyl intermediates by fluorination with ?chemodifferentiation“.     

Fluorination of poly(p-phenylene) using TbF4 as fluorinating agent

The fluorination using TbF₄ as fluorinating agent was successfully performed on poly(p-phenylene). The method allows the fluorine content of the polymer to be controlled and the formation of structural defects, such as dangling bonds, to be significantly decreased by comparison with the direct fluorination using pure F₂ gas. The aromatic character of the phenyl ring is partly maintained through the fluorination contrary to the direct fluorination (using pure F₂ gas), for which a quasi-perfluorination and a partial decomposition of the polymer occur. Complementary analytical techniques have been used, such as ¹⁹F and ¹³C solid state NMR, FT-IR and EPR to compare the samples as a function of the reaction conditions.     

Influence of peripheral substituents on the stability of sandwich-type complexes of crown ether-containing anthraquinoneimines

Benzo-15-crown-5 ether derivatives of 1-hydroxy-9,10-anthraquinone-9-imine bearing a substituted benzoylamino group, NHCO(p-C₆H₄NO₂) or NHCOC₆F₅, in position 2 were synthesized by a photochemical method. The structure of the fluorine-containing compound was determined by single-crystal X-ray diffraction. Both synthesized dyes, as well as their analogue without substituents on the benzoyl ring, are capable of binding Sr²⁺ and Ba²⁺ to form sandwich-type 2:1 (ligand:metal) complexes. In MeCN, these complexes exhibit higher stability constants (K_2:1) than the corresponding 1:1 complexes (K_1:1). The para-substitution of the benzoyl ring with a nitro group leads to a significant increase in both the K_2:1 constant and the K_2:1/K_1:1 ratio. The fluorination of the benzoyl ring insignificantly affects the stability of sandwich complexes. Density functional theory calculations showed that this is related to steric interactions in the benzoylamino group. The calculated structures of the dyes and their sandwich complexes with Ba²⁺ are consistent with the 2D NOESY data.     

Conformational analysis. XIII—A 300 MHz 1H NMR study of 2-methyl-, 2-phenyl-, 2-(2-chlorophenyl)-and 2-(4-chlorophenyl)-oxetanes

The 300 MHz spectra of 2-methyl-, 2-phenyl-, 2-(2-chlorophenyl)- and 2-(4-chlorophenyl)-oxetanes were recorded in CCl₄ and C₆D₆. The chemical shifts and the proton-proton coupling constants were solved through iterative calculations. The results were discussed in the light of structural factors and theoretical calculations. The average angle of pucker for the oxetane ring was estimated at c. 5°, in fair agreement with the value of 3·3° derived from a microwave study.     

An improved Balz-Schiemann reaction enabled by ionic liquids and continuous processing

A Balz-Schiemann reaction was developed to convert 2-cyano-5-aminopyridine to 2-cyano-5-fluoropyridine. The use of an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF₄) as a solvent was found to be critical in achieving high assay yields and high selectivity for the fluorination vs. protonation. A process was developed to recycle and reuse the ionic liquid enabling its cost-effective use as a solvent. Finally, the optimal conditions were demonstrated under as a continuous process to address process safety risks associated with diazonium intermediates and the product was used to access a key intermediate in the synthesis of β-amyloid cleaving enzyme 1 inhibitor, verubecestat.     

How Does the Fluorination of the Linker Affect the Structural Chemistry of Trimesate-Based Metal-Organic Frameworks (MOFs)?

FMOFs, i.e. metal-organic frameworks with linkers with fluoro substituents, were supposed to show enhanced thermal and chemical stability as well as high gas affinity and hydrophobicity. However, at least for aromatic carboxylate ligands it was shown in a subsequent work that fluoro substituents weaken the C(phenyl)-COO^– bond and thus facilitate decarboxylation leading to a decreased chemical and thermal stability. Nonetheless, it was concluded that linker fluorination leads to a rich structural chemistry, as the torsion angle between the phenyl ring and the carboxylate group is significantly increased in these compounds. Here, we present the very first examples of four MOFs all based on Sr²⁺ cations and trimesate-based linkers with three different degrees of fluorination as well as the known non-fluorinated counterpart: [Sr(HL)(H₂O)] · n H₂O [ 1 : L = mF-BTC^3–, n = 0.5, P1 , Z = 2; 2 : L = dF-BTC^3–, n = 0.5, C2/c, Z = 8; 3 : L = pF-BTC^3–, n = 1.5, C2/c, Z = 8; 4 : L = BTC^3–, n = 0.5, P1 , Z = 2; BTC^3– ≡ 1,3,5-benzenetricarboxylate (trimesate); mF-BTC^3– ≡ monofluorinated trimesate, dF-BTC^3– ≡ difluorinated trimesate, pF-BTC^3– ≡ per-(tri-)fluorinated trimesate]. Whereas 1 and known 4 are found to crystallize in isotypic structures and 2 in a very similar structural arrangement [all CN(Sr²⁺) = 9], 3 with the highest degree of fluorination exhibits a completely different crystal structure [CN(Sr²⁺) = 8], which is already obvious from the different composition. It is shown that the torsion angles between the phenyl ring and the carboxylate groups play an important structure-directing role. DSC/TGA investigations confirm that with increasing fluorination the thermal stability is decreased. However, the release temperature of water, i.e. the affinity to water, increases with the number of fluoro substituents.     

Hyperconjugative Interactions in Bicyclo[2.2.1]heptane Derivatives. Effects on the Diels-Alder Reactivity of the s-cis-Butadiene Group of 2, 3-Dimethylidene-norbornanes

Chemical and spectroscopic properties of the s-cis-butadiene chromophore in 2, 3-dimethylidene-norbornane can be modified without direct substitution of the diene moiety. Introduction of an etheral bridge for the H₂C(7) bridge ( 2 , 4 , 6 ) and/or introduction of a double bond ( 5 , 6 ) or of an exo-epoxide ring ( 3 , 4 ) for the H₂C(5)–H₂C(6) bridge causes rate decreases in the Diels-Alder cycloaddition with dimethyl acetylenedicarboxylate. The differences of reactivity observed between the dienes 1 – 6 are briefly discussed. Variation of the ability of the puckered cyclopentane ring of the bicyclo[2.2.1]heptane skeleton to hyperconjugate with the adjacent π-system is offered as a possible rationalization of the electronic effects.     

Characterization,crystal structure and cytotoxic activity of a rare iridoid glycoside from Lonicera saccata

A new iridoid glycoside, methyl (3R,4R,4aS,7S,7aR)‐3‐hydroxy‐7‐methyl‐5‐oxooctahydrocyclopenta[c]pyran‐4‐carboxylate‐3‐O‐β‐d ‐(1′S,2′R,3′S,4′S,5′R)‐glucopyranoside, named loniceroside A, C₁₇H₂₆O₁₀, ( 1 ), was obtained from the aerial parts of Lonicera saccata. Its structure was established based on an analysis of spectroscopic data, including 1D NMR, 2D NMR and HRESIMS, and the configurations of the chiral C atoms were determined by X‐ray crystallographic analysis. The single‐crystal structure reveals that the cyclopenta[c]pyran scaffold is formed from a five‐membered ring and a chair‐like six‐membered ring connected through two bridgehead chiral C atoms. In the solid state, the glucose group of ( 1 ) plays an important role in constructing an unusual supramolecular motif. The structure analysis revealed adjacent molecules linked together through intermolecular O—H…O hydrogen bonds to generate a banded structure. Furthermore, the banded structures are linked into a three‐dimensional network by interesting hydrogen bonds. Biogenetically, compound ( 1 ) carries a glucopyranosyloxy moiety at the C‐3 position, representing a rare structural feature for naturally occurring iridoid glycosides. The growth inhibitory effects against human cervical carcinoma cells (Hela), human lung adenocarcinoma cells (A549), human acute mononuclear granulocyte leukaemia (THP‐1) and the human liver hepatocellular carcinoma cell line (HepG2) were evaluated by the MTT method.     

Reaction of 4‐benzylidene‐2‐methyl‐5‐oxazolone with amines,Part 2: Influence of substituents in para‐position in the phenyl ring and a substituent on amine nitrogen atom on the reaction kinetics

An influence of a structure of the amine (benzylamine, N‐methyl‐benzylamine, N‐isopropyl‐benzylamine, N‐methyl‐butylamine, N‐ethyl‐butylamine, sec‐butylamine, and tert‐butylamine) on a rate constant of the ring‐opening reaction of 4‐benzylidene‐2‐methyl‐5‐oxazolone (Ox) was studied. The good correlation between logarithm of the rate constants and Charton's steric substituent constant ν as well as good correlation with a form of the simple branching equation indicate that there is a steric effect because of substitution at C1 carbon atom of nucleophile which decreases the reaction rate. Additionally, an influence of a structure of the benzylidene moiety of Ox on a rate of the oxazolone ring‐opening reaction was studied. The substituents (? OH, ? OCH₃, ? N(CH₃)₂, ? Cl, ? NO₂) in para‐position of the phenyl ring of Ox substantially modified the rate of the reaction with benzylamine in acetonitrile. The rate of the Ox ring‐opening reaction decreased with increase of the electron‐donating properties of the substituent. A good correlation between the rate constants of the reaction of 4‐(4′‐substituted‐benzylidene)‐2‐methyl‐5‐oxazolones with benzylamine and the electron density at the reaction center (carbon C5 of the oxazolone ring), calculated using ab initio method, and the Hammett substituent constants, and CR equation were established. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 148–155, 2002; DOI 10.1002/kin.10039     

Kinetic Evaluation of Hyperbranched A2 + B3 Polycondensation Reactions

The kinetics of hyperbranched A₂ + B₃ systems is discussed theoretically with respect to the development of the 7 different structural units, the degree of branching, DB, and the monomer sequences considering the adjacent groups of a structural unit. For A₂ + B₃ systems, the comonomer ratio, the relative rate constants and the process conditions have an influence on the resulting structure as shown by numerical simulations. With increasing A:B ratios f_A/B, the degree of branching will be increased. Also the relative reaction rate constants have a strong impact on the distribution of structural units, especially when the reaction rate constants for the pathway of the B₃ monomer are changed. On the other hand, differences in the reaction rate constants for the pathway of the A₂ monomer do not have any influence on the degree of branching. The simulation indicates that slow addition of either both monomers or just the B₃ monomer has the strongest effect on the resulting DB. In all cases, the conversion is a critical issue to obtain high molecular weight products.

Degree of branching (DB) versus conversion of A‐functionalities (p_A) for various monomer compositions.     

Syndones and syndoneimines. The alkaline splitting reaction with 3- and 3, 4 -substituted syndoneimines

Alkaline splitting reaction equilibrium constants are determined polarographically for a series of 3 -and 3, 4-substituted syndoneimines. The stability of these heterocyclic compounds increases with decrease in electronegativity and increase in volume of substituents at positions 3 and 4. The steric effect is explained by a broadening of substituents at N₃ and C₄, Equilibrium constants for 3-substituted syndoneimines are correlated with Taft inductive and steric effects constants. The data obtained made it possible to determine the value of the energy of non-polar conjugation between the syndoneimine ring and the 4-phenyl ring, and it was found to be of the order of 2 kcal.     

Structural and Conformational Aspects of Equatorial and Axial Trifluoromethyl,Difluoromethyl, and Monofluoromethyl Groups

The X‐ray crystal structures of cis‐ and trans‐1‐(indol‐3‐yl)‐4‐methyl cyclohexane and its congeners with stepwise fluorination of the methyl group are reported. The trans‐configured compounds adopted diequatorial conformations, whereas the cis analogues adopted regular cyclohexane chair conformations with the methyl group preferentially assuming the axial position, even in the case of the CF₃ group. Surprisingly, although the axial CF₃ derivative displayed distinct valence deformations in the cyclohexane moiety, the observed structural changes were relatively modest. The cis derivatives with axial mono‐ and difluorinated methyl groups exhibited conformational disorder in the crystals with significant population levels for the staggered conformations that had one fluorine atom in the endo position; their respective trans counterparts adopted unique conformations, but again with one fluorine atom in the endo position. Theoretical calculations for a series of cis‐ and trans‐1,4‐dimethyl cyclohexane model compounds with stepwise fluorination of one equatorial or axial methyl group reproduced the experimentally observed structural response patterns very well, reproduced the experimentally determined nonlinear correlation of the axial–equatorial energy difference with the degree of methyl fluorination in a satisfactory manner, and provided further insights into important conformational aspects of partially fluorinated methyl groups.     

The x-ray structure analysis of 17-beta-bromoacetoxy-9-beta, 10-alpha-androst-4-en-3-on

The structure of 17β-bromacetoxy-9β, 10α-androst-4-en-3-one has been determined by three-dimensional X-ray crystallographic methods. The crystals of the restrosteroid belong to the orthorhombic space group P2₁2₁2₁ with four molecules per unit cell. The cell constants are a = 11.32 Å, b = 13.71 Å and c = 12.52 Å. The absolute configuration of the molecule has been determined by the anomalous dispersion method. Bond length, bond angles and distances of atoms from ‘best planes’ are given. Ring A represents a distorted half-chair, ring B and C a chair and ring D an envelope conformation. The molecule shows, contrary to normal 9α, 10β-steroids, a bent shape.     

Dipole moments,Kerr constants,and structure of oxides of substituted norbornenes

The molar Kerr constants and dipole moments at infinite dilution in CCl₄ have been measured for these compounds and also for dicyclopentadiene dioxide and the oxides of ethylene, propylene, and tetramethylethylene. The dipole moment indicates an exo-oxide structure for endo-cyanonorbornene, and this fact is used with the Kerr constants for endo-cyanonorbornene and ethylene oxide to calculate the axes of the polarizability ellipsoid for the oxide ring: b₁ (along the symmetry axis), b₂ (in plane of ring), and b₃ (perpendicular to plane of ring). The Kerr constants for propylene and tetramethylethylene oxides have been used to determine the anisotropy in the polarizability of the C-C bond adjoining the oxide ring. The results demonstrate an exo mode of oxidation of all substituted norbornenes and an exo-exo structure for dicyclopentadiene dioxide.     

Nitro derivatives of <Emphasis Type="Italic">N</Emphasis>-alkylbenzoaza-15-crown-5: synthesis,structures, and complexation with metal and ammonium cations

A number of N-alkylnitrobenzoaza-15-crown-5 with the macrocycle N atom conjugated with the benzene ring were obtained. The structural and complexing properties of these compounds were compared with those of model nitrobenzo- and N-(4-nitrophenyl)aza-15-crown-5 using X-ray diffraction, ¹H NMR spectroscopy, and DFT calculations. The macrocyclic N atom of benzoazacrown ethers are characterized by a considerable contribution of the sp3-hybridized state and a pronounced pyramidal geometry; the crownlike conformation of the macrocycle is preorganized for cation binding, which facilitates complexation. The stability constants of the complexes of crown ethers with the NH₄ ⁺, EtNH₃ ⁺, Na⁺, K⁺, Ca²⁺, and Ba²⁺ ions were determined by 1H NMR titration in MeCN-d₃. The most stable complexes were obtained with alkaline-earth metal cations, which is due to the higher charge density at these cations. The characteristics of the complexing ability of N-alkylnitrobenzoaza-15-crown-5 toward alkaline earth metal cations are comparable with analogous characteristics of nitrobenzo-15-crown-5 and are much better than those of N-(4-nitrophenyl)aza-15-crown-5.     

Chlorine substituent effects for indole and tryptophan in 13C NMR

The ¹³C and ¹H nmr spectra of chloroindoles and chlorotryptophans in methanol-d₄ were assigned based on 1-D and 2-D nmr techniques, including COSY, inverse-detected direct (HMQC) and long-range (HMBC) correlation. Chlorine substitutent effects in chemical shifts (SCS) for chlorotryptophans and chloroindoles were calculated and compared. The correlations were linear except for 4-chlorotryptophan, which suggests structural changes on the indole ring between 4-chlorotryptophan and 4 chloroindole. The conformational analysis based on the coupling constants of the side chain also showed a change in the fractional population of the rotamers between 4-chlorotryptophan and the other chlorotryptophans.     

Kinetic isotope effects in the thermal gas phase reactions of 1, 2-epoxycyclohexane-3, 3, 6, 6-d4

First-order rate constants for formation of cyclohexanone and 2-cyclohexen-1-ol from 1,2-epoxycyclohexane and 1,2-epoxycyclohexane-3,3,6,6-d₄ have been determined over the temperature range of 677–746°K. The observed kinetic isotope effects are used in an attempt to determine the mechanism for formation of products. A distinction between a biradical and a concerted mechanism for the alcohol formation could not be made. However, if a common biradical is the precursor of both cyclohexanone and 2-cyclohexenl-ol then the rate of ring closure of this biradical must be much faster than the rates of hydrogen transfer to give the ketone and the alcohol.