Novel Ortho effects detected in the fast atom bombardment mass spectra of substituted bisaryl phosphate antagonists of platelet-activating factor

A series of substituted bisaryl phosphate compounds, (R¹CH₂)⁺ ArOP = O(O^?)(OArR²R₃), was analyzed and characterized by fast atom bombardment mass spectrometry. Abundant fragment ions were observed and correlated with the proposed structures. From fragmentation pattersn, ‘ortho effect’ reactions were demonstrated to have occurred when the phosphoryl oxygen reacted with the (CH₂R¹)⁺ and C?O(OCH₃) substituents in the ortho position, relative to the phosphate group, and displaced the R¹ and OCH₃ groups, respectively, to produce phosphorus containing six-membered rings fused to the aryl moiety. When the (CH₂R¹)⁺ substituents were in the meta position relative to the phosphate group, the ‘ortho effect’ reactions were not observed. However, when the C?O(OCH₃) substituent was in the meta position relative to the phosphate group, an abundant fragment ion containing a five-membered phosphate ring fused to the aryl ring was detected with the original phosphoryl oxygen ortho to both the phosphate oxygen and a formyl group, formed from the original C?O(OCH₃) substituent. All other fragmentations not involving the ‘ortho effect’ reactions were nearly identical for the different structural isomers of the substituted bisaryl phosphate compounds.     

Efficient double bond migration of allylbenzenes catalyzed by Pd(OAc)2-HFIP system with unique substituent effect

A novel catalyst system of Pd(OAc)₂-HFIP induces double-bond migration of allylbenzenes under mild conditions with low catalytic loading to afford 1-propenylbenzenes. The reaction shows a unique substituent effect that is highly dependent on the distance of substituents from the allylic moiety. Thus, the reactivity of substrates bearing a methyl group is ordered in para > meta > ortho, whereas it is entirely reversed as ortho > meta > para for methoxy and chloro substituents.     

Pulsed fourier transform NMR of substituted aryltrimethyltin derivatives : II. (119Sn-13C) coupling constants and 13C chemical shifts of meta- and para-derivatives

Carbon-13 NMR data are reported for thirteen para- and meta-substituted phenyltrimethyltin compounds, RC₆H₄Sn(CH₃)₃, where R = para-N(CH₃)₂, para-OCH₃, para-OC₂H₅, para-CH₃, meta-CH₃, -H, para-F, meta-OCH₃, para-Cl, para-Br, meta-F, meta-Cl and para-Sn(CH₃)₃. In the para-derivatives, correlation coefficients with Hammet σ-constants of greater than ca. 0.9 are obtained with the tin-carbon couplings to methyl, C₁ and C₄ carbons, and with the carbon-13 chemical shifts δ(C(1)). In the meta-derivatives, the couplings |J(Sn-CH₃)|:, |:J(Sn-C(1))|:, |:J(Sn-C(3))|: and |:J(Sn-C(6))|:, and the shifts δ(C(1)) and δ(C(5)) correlate well with Hammett σ. In the para-derivatives, sensitivity to change in substituent falls off C(4) > C(3, 5) > C(1) > C(2, 6) > CH₃ as registered by the δ(C), while in the meta-derivatives δ(C) changes decrease C(3) > C(2), C(4) > C(1) > C(5), C(6) > CH₃. The magnitudes of the tin coupling constants decrease C(1) > CH₃ > C(3, 5) > C(2, 6) > C(4) in the para-derivatives, while in the meta-series the order is C(1) > CH₃ > C(3), C(5) > C(2) > C(6) > C(4). The two sets of one-bond |:J(Sn-CH₃)|: and |:J(Sn-C(1)|: values correspond closely to the 0.25/0.33 ratio of coefficients in the LCAO approach, and are interpreted in terms of s-electron redistributions at the tin atom with change in substituent.     

Retrieval and analysis of transition states in electrophilic substitution reactions of the carborane(12) series

The transition states of the reaction of electrophilic substitution in a series of ortho-, meta-, and para-carboranes were found by calculations in the B3PW91/6-31G(d,p) and B3LYP/6-31G(d,p) approximations. The key role of catalyst was demonstrated in the reactions of halogenation and alkylation. The reaction selectivity of electrophilic alkylation by CH₃Br in the presence of AlCl₃ should be lower than that of the chlorination reaction.     

Quantum Chemical Calculation of Conformations and Rotation Barriers of Functional Groups in Arylsulfonyl Halides

The semiempirical PM3 method is used to calculate the potential functions of internal rotation of the functional groups –SO₂Cl, –NO₂, –CH₃, –OCH₃, and –NH₂ of benzenesulfonyl halide molecules (PhSO₂Hal, Hal = F, Cl, Br, I) and twelve substituted derivatives of benzenesulfonyl chloride. Molecular conformations have been determined and internal rotation barriers of the functional groups have been calculated. For meta- and para-substituted benzenesulfonyl chlorides, the projection of the S–Hal bond is perpendicular to the plane of the benzene ring. The rotation barriers of the –SO₂Hal group of benzenesulfonyl halides increase in the series Hal = F, Cl, Br, I. The rotation barriers of the –SO₂Cl group of benzenesulfonyl chloride with meta- and para-substituents slightly increase with the electron-donor properties of the substituent. The rotation barriers of the functional groups of ortho-substituted benzenesulfonyl chlorides are 3 or 4 times as high as those of the meta- and para-isomers. For para-substituted benzenesulfonyl chlorides, the rotation barriers of the functional groups increase in the order –CH₃, –NO₂, –SO₂Cl, –OCH₃, –NH₂.     

Carboranylphosphites—new effective ligands for rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate

Novel monodentate phosphites containing ortho- and meta-closo-dodecarboranyl groups have been synthesized and applied in the asymmetric Rh-catalyzed hydrogenation of dimethyl itaconate, providing excellent enantioselectivities (up to 99.8% ee in CH₂Cl₂ and up to 93% ee in supercritical CO₂).     

Modified palladium-catalyzed regioselective ortho-arylation of sp C-H bond substrates with a low catalyst loading

A novel and generally applicable system for ortho-arylation of a broad range of sp² C-H bond substrates such as arylated benzoxazoles, acylated anilines, and pyridines has been developed. The arylation was performed in trifluoroacetic acid (TFA) under air by using PdCl₂ as the catalyst with a low catalyst loading of 1 mol %. And it was found for the first time that the addition of weak base K₃PO₄ to the acidic solvent could remarkably enhance the reaction rate. The arylated products were isolated in moderate to good yields with high regioselectivity for the substrates containing a meta-substituent. This arylation is tolerant with various functional groups such as CH₃, CH₃O, CH₃CO, Br, and Cl.     

The Loss of a hydroxyl group from the molecular ions of alkylnitrobenzenes

It is confirmed that the loss of HO˙ from the molecular ion of o-nitrotoluene involves exclusively a hydrogen from the methyl group. However, in higher homologues hydrogen atoms from non-benzylic sites are also implicated. With such compounds this fragmentation mode is shown not only by the ortho but, to a lesser extent, by the meta and para isomers as well. The proportion of the total ion current borne by the [M – 17]⁺ ion follows the order ortho > meta > para, which is attributed to substituent migration around the ring with a hydroxyl radical only being lost when the groups are on adjacent ring atoms. Other ions present in the spectra point to interaction between substituents to form a new heterocyclic ring.     

The thermodynamic studies of the molecular interactions of methyltin(IV) tribromide with free base meso-tetraarylporphyrins

The thermodynamic parameters for the interactions of MeSnBr₃ with para- and meta-substituted meso-tetraphenylporphyrins (H₂T(4-X)PP; X=OCH₃, CH₃, H, Cl, NO₂ and H₂T(3-X)PP; X=CH₃, Cl) have been studied. The formation constants have been elucidated by using spectrophotometric titration and computer squad program data refinement. The adducts of composition 2:1 and 1:1 of MeSnBr₃ to H₂T(4-X)PP with stability constants K₁ and K₂ coexist in solution, but meta-substituted porphyrins form adducts of the composition 1:1 of MeSnBr₃ to H₂T(3-X)PP with stability constant K₁. Formation constants decrease with decreasing electron donation of para-substituted porphyrins as follow: H₂T(4-CH₃O)PP>H₂T(4-CH₃)PP>H₂TPP>H₂T(4-Cl)PP>H₂T(4-NO₂)PP. Despite the electron donation of the methyl group, H₂T(3-Cl)PP forms more stable adducts than H₂T(3-CH₃)PP with MeSnBr₃.     

meta-Nitration of Arenes Bearing ortho/para Directing Group(s) Using C−H Borylation

Herein, we report the meta-nitration of arenes bearing ortho/para directing group(s) using the iridium-catalyzed C−H borylation reaction followed by a newly developed copper(II)-catalyzed transformation of the crude aryl pinacol boronate esters into the corresponding nitroarenes in a one-pot fashion. This protocol allows the synthesis of meta-nitrated arenes that are tedious to prepare or require multistep synthesis using the existing methods. The reaction tolerates a wide array of ortho/para-directing groups, such as −F, −Cl, −Br, −CH₃, −Et, −iPr −OCH₃, and −OCF₃. It also provides regioselective access to the nitro derivatives of π-electron-deficient heterocycles, such as pyridine and quinoline derivatives. The application of this method is demonstrated in the late-stage modification of complex molecules and also in the gram-scale preparation of an intermediate en route to the FDA-approved drug Nilotinib. Finally, we have shown that the nitro product obtained by this strategy can also be directly converted to the aniline or hindered amine through Baran's amination protocol.     

Methyl propionate radical cation

Examination of the reactions of the long-lived (>0.5-s) radical cations of CD₃CH₂COOCH₃ and CH₃CH₂COOCD₃ indicates that the long-lived, nondecomposing methyl propionate radical cation CH₃CH₂C(O)OCH ₃ ^+· isomerizes to its enol form CH₃CH=C(OH)OCH ₃ ^+· (ΔH _{isomerization} ? ?32 kcal/mol) via two different pathways in the gas phase in a Fourier-transform ion cyclotron resonance mass spectrometer. A 1,4-shift of a β-hydrogen of the acid moiety to the carbonyl oxygen yields the distonic ion ^·CH₂CH₂C⁺ (OH)OCH₃ that then rearranges to CH₃CH=C(OH)OCH ₃ ^+· probably by consecutive 1,5- and 1,4-hydrogen shifts. This process is in competition with a 1,4-hydrogen transfer from the alcohol moiety to form another distonic ion, CH₃CH₂C⁺(OH)OCH ₂ ^· , that can undergo a 1,4-hydrogen shift to form CH₃CH=C(OH)OCH ₃ ^+· . Ab initio molecular orbital calculations carried out at the UMP2/6-31G** + ZPVE level of theory show that the two distonic ions lie more than 16 kcal/mol lower in energy than CH₃CH₂C(O)OCH ₃ ^+· . Hence, the first step of both rearrangement processes has a great driving force. The 1,4-hydrogen shift that involves the acid moiety is 3 kcal/mol more exothermic (ΔH _{isomerization}=?16 kcal/mol) and is associated with a 4-kcal/mol lower barrier (10 kcal/mol) than the shift that involves the alcohol moiety. Indeed, experimental findings suggest that the hydrogen shift from the acid moiety is likely to be the favored channel.     

Site of protonation in the chemical ionization mass spectra of olefinic methyl esters

The H₂ and CH₄ chemical ionization mass spectra of the olefinic esters methyl acrylate, methyl methacrylate, methyl crotonate, methyl 3-butenoate, methyl 2-methyl-2-butenoate, methyl 3-methyl-2-butenoate and methyl cinnamate have been determined. In addition to the expected loss of CH₃OH from [MH]⁺, in many cases the protonated molecules also show loss of CO or CH₂CO with methoxy group migration to the positive ion centre, indicative of protonation at the double bond. These rearrangement reactions, which have analogies in electron impact mass spectra, result in chemical ionization mass spectra of isomeric molecules which show more substantial differences than the electron impact mass spectra. In the case of methyl cinnamate, isotopic labelling experiments show considerable interchange of the added proton with the ortho and meta phenyl hydrogens prior to CH₃OH or CH₂CO loss, although the extent of interchange is not the same for both cases.     

Novel formation of a fluorinated aziridino[60]fullerene

Reaction of MEMN₃ (methoxyethoxymethylazide) with C₆₀F₁₈ results in replacement of two fluorines by the >NCH₂OCH₂CH₂OMe function giving a C_s symmetrical aziridinofluorofullerene, C₆₀F₁₆NCH₂OCH₂CH₂OMe.     

Role of positional isomers on receptor-anion binding and evidence for resonance energy transfer

New urea-based sensors show a strong affinity for F⁻, CH₃COO⁻, and H₂PO₄⁻ with an appreciable color change in the presence of excess F⁻. The position of the nitro group in the urea derivative influences the relative affinity toward anionic analytes. Spectral and ab initio studies showed the difference in the deprotonation sites for the ortho- and meta/para-isomers in these cases. Photophysical studies confirmed the resonance energy transfer in the case of the ortho-isomer. The ortho-isomer can act as a dual emission probe for F⁻.     

Novel perfluoroalkylated oligo(oxyethylene) methyl ethers with high hemocompatibility and excellent co-emulsifying properties for potential biomedical uses

Two series of novel perfluoroalkylated amphiphilic compounds were synthesized from monomethyl ethers of mono-, di- and tri-(oxyethylene) glycols. The first series CH₃(OCH₂CH₂)_nOCH₂CH(OH)CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) bearing the hydroxy group at the spacer between hydrophilic and hydrophobic parts was prepared by the reactions of the monomethyl ethers with 2-(perfluoroalkylmethyl)oxiranes in 76-97% yields. The second series CH₃(OCH₂CH₂)_nOCH₂CH₂CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) possessing the non-hydroxylated spacer was synthesized from allyl methyl ethers of oligo(oxyethylene) glycols using radical additions of perfluoroalkyl iodides and subsequent selective reductions of the C-I bond in the adducts in overall yields of 23-69%. Some of the novel amphiphilic compounds displayed very low hemolytic activity to erythrocytes and excellent co-emulsifying properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. 1-O-(2-Hydroxy-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-d-xylitol was prepared by a novelized synthesis and employed as a standard compound in the testing.     

Chemical polarization of nuclei. Proton polarization during thermal decomposition reaction of dimethyl perdiglutarate

Proton chemical polarization was observed in methyl butyrate, γ-butyrolactone and in some other products of the dimethyl perdiglutarate decomposition reaction. The polarization pattern of the α-CH₂ and β-CH₂ groups in butyrolactone is just as one would expect in the products of the CH₃OCH₂CH₂?H₂ radical which has left the pair of identical radicals. Thus butyrolactone is formed from the CH₃OCH₂CH₂?H₂ radical by means of intramolecular cyclization and elimination of the methyl radical.     

Bromination of phenols in bromoperoxidase-catalyzed oxidations

Phenol and ortho-substituted derivatives furnish products of selective para-bromination, if treated with sodium bromide, hydrogen peroxide, and the vanadate(V)-dependent bromoperoxidase I from the brown alga Ascophyllum nodosum. Relative rates of bromination in morpholine-4-ethane sulfonic acid (MES)-buffered aqueous tert-butanol (pH 6.2) increase by a factor 32, as the ortho-substituent in a phenol changes from F via Cl, OCH₃, C(CH₃)₃, and H to CH₃. The polar effect in phenol bromination by the enzymatic method, according to a Hammett-correlation (ρ=−3), compares to reactivity of molecular bromine under identical conditions (ρ=−2). Hypobromous acid is not able to electrophilically substitute bromine for hydrogen at pH 6.2 in aqueous tert-butanol. The tribromide anion behaves in MES-buffered aqueous tert-butanol as electrophile (ρ∼−3), showing a similar polar effect in phenol bromination as molecular bromine.     

Novel Copolymers of Alkyl and Alkoxy Ring‐Substituted Ethyl 2‐Cyano‐3‐phenyl‐2‐propenoates and Styrene

Abstract

Electrophilic trisubstituted ethylenes, ring‐substituted ethyl 2‐cyano‐3‐phenyl‐2‐propenoates, RC₆H₄CH?C(CN)CO₂C₂H₅ (where R is 2‐CH₃, 3‐CH₃, 4‐CH₃, 2‐OCH₃, 3‐OCH₃, and 4‐OCH₃) were prepared and copolymerized with styrene (ST). The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring‐substituted benzaldehydes and ethyl cyanoacetate, and characterized by CHN analysis, IR, ¹H and ¹³C NMR. All the ethylenes were copolymerized with ST (M₁) in solution with radical initiation (AIBN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, ¹H and ¹³C NMR. The order of relative reactivity (1/r ₁) for the monomers is 3‐OCH₃ (0.88)?>?4‐CH₃ (0.71)?>?2‐OCH₃ (0.68)?>?3‐CH₃ (0.55)?>?2‐CH₃ (0.47)?>?4‐OCH₃ (0.40). Higher T _g of the copolymers in comparison with that of polystyrene indicates a decrease in chain mobility of the copolymer due to the high dipolar character of the TSE structural unit. Gravimetric analysis indicated that the copolymers decompose in the 257–287°C range.     

Chemical shifts for tritons in the ortho,meta and para positions of toluene as determined by tritium NMR spectroscopy

Chemical shifts for tritons in ortho, meta and para positions in toluene have been determined using a 64 MHz tritium NMR spectrometer. The order of shift is meta>para>ortho, whereas the calculated shift order for protons is meta>ortho>para.     

A ‘meta effect’ in the fragmentation reactions of ionised alkyl phenols and alkyl anisoles

The competition between benzylic cleavage (simple bond fission [SBF]) and retro‐ene rearrangement (RER) from ionised ortho, meta and para RC₆H₄OH and RC₆H₄OCH₃ (R = n‐C₃H₇, n‐C₄H₉, n‐C₅H₁₁, n‐C₇H₁₅, n‐C₉H₁₉, n‐C₁₅H₃₁) is examined. It is observed that the SBF/RER ratio is significantly influenced by the position of the substituent on the aromatic ring. As a rule, phenols and anisoles substituted by an alkyl group in meta position lead to more abundant methylene‐2,4‐cyclohexadiene cations (RER fragmentation) than their ortho and para homologues. This ‘meta effect’ is explained on the basis of energetic and kinetic of the two reaction channels. Quantum chemistry computations have been used to provide estimate of the thermochemistry associated with these two fragmentation routes. G3B3 calculation shows that a hydroxy or a methoxy group in the meta position destabilises the SBF and stabilises the RER product ions. Modelling of the SBF/RER intensities ratio has been performed assuming two single reaction rates for both fragmentation processes and computing them within the statistical RRKM formalism in the case of ortho, meta and para butyl phenols. It is clearly demonstrated that, combining thermochemistry and kinetics, the inequality (SBF/RER)_meta < (SBF/RER)_ortho < (SBF/RER)_para holds for the butyl phenols series. It is expected that the ‘meta effect’ described in this study enables unequivocal identification of meta isomers from ortho and para isomers not only of alkyl phenols and alkyl anisoles but also in other alkyl benzene series. Copyright © 2012 John Wiley & Sons, Ltd.