Fluorinated phosphorus compounds: Part 9. The reactions of bis(fluoroalkyl) phosphorochloridates with oxygen nucleophiles

Twenty nine bis(fluoroalkyl) phosphates (R_FO)₂P(O)OR were prepared in 18-75% yield by treating phosphorochloridates (R_FO)₂P(O)Cl, where R_F was HCF₂CH₂, HCF₂CF₂CH₂, H(CF₂)₄CH₂, C₂F₅CH₂, C₃F₇CH₂, (CF₃)₂CH, (FCH₂)₂CH and (CH₃)₂CF₃C with methanol, ethanol, propanol and isopropanol in diethyl ether in the presence of triethylamine. The bulky chloridate [(CH₃)₂CF₃CO]₂P(O)Cl reacted with methanol, ethanol and propanol, but not with isopropanol - even on heating in the presence of the catalyst 4-dimethylaminopyridine - due to steric hindrance at phosphorus. The relative reactivities of three of the chloridates decreased in the order [(CF₃)₂CHO]₂P(O)Cl > [(FCH₂)₂CHO]₂P(O)Cl > [(CH₃)₂CF₃CO]₂P(O)Cl. Also described is the synthesis of phosphates (CF₃CH₂O)₂P(O)OCH₂R, where R = CH₂Br, CH₂Cl, CH₂F and CHF₂, and diphosphates [H(CF₂)_nCH₂O]₂P(O)OCH₂(CF₂)₂CH₂OP(O)[OCH₂(CF₂)_nH]₂, where n = 1, 2 and 4.     

Fluorinated phosphorus compounds: Part 6. The synthesis of bis(fluoroalkyl) phosphites and bis(fluoroalkyl) phosphorohalidates

Reaction of phosphorus trichloride with tert-butanol and fluoroalcohols gave bis(fluoroalkyl) phosphites (R_FO)₂P(O)H in 42-89% yield, where R_F=HCF₂CH₂, H(CF₂)₂CH₂, H(CF₂)₄CH₂, CF₃CH₂, C₂F₅CH₂, C₃F₇CH₂, (CF₃)₂CH, (FCH₂)₂CH, CF₃(CH₃)₂C, (CF₃)₂CH₃C, CF₃CH₂CH₂, C₄F₉CH₂CH₂ and C₆F₁₃CH₂CH₂. Treatment of these with chlorine in dichloromethane gave the bis(fluoroalkyl) phosphorochloridates (R_FO)₂P(O)Cl in 49-96% yield. The chloridate (CF₃CH₂O)₂P(O)Cl was isolated in much lower yield from the interaction of thionyl chloride with bis(trifluoroethyl) phosphite. Heating the latter in dichloromethane with potassium fluoride and a catalytic amount of trifluoroacetic acid gave the corresponding fluoridate (CF₃CH₂O)₂P(O)F in 84% yield. Treatment of bis(trifluoroethyl) phosphite with bromine or iodine gave the bromidate (CF₃CH₂O)₂P(O)Br and iodidate (CF₃CH₂O)₂P(O)I in 51 and 46% yield, respectively. The iodidate is the first dialkyl phosphoroiodidate to have been isolated and characterised properly—its discovery lags behind the first isolation of a dialkyl phosphorochloridate by over 130 years. The fluoroalkyl phosphoryl compounds are generally more stable than known unfluorinated counterparts.     

Fluorinated phosphorus compounds: Part 8. The reactions of bis(fluoroalkyl) phosphorochloridates with sulfur nucleophiles

The reactivity of bis(fluoroalkyl) phosphorochloridates to nucleophiles is summarised. Previous data and the results described here indicate that reactivities decrease in the order: amines>alcohols>thiols. The synthesis of CF₃CH₂OP(O)(SEt)₂ in 30% yield was accomplished by treating CF₃CH₂OP(O)Cl₂ with two molar equivalents of EtSH and Et₃N in ether. The chloridates (CF₃CH₂O)₂P(O)Cl and (C₂F₅CH₂O)₂P(O)Cl did not react with MeSH in ether at −78 °C or when heated with Pb(SMe)₂ in benzene. Ethanethiol and propanethiol reacted with fluorinated chloridates in the presence of triethylamine to give thiolates (R_FO)₂P(O)SR in 13-41% yield where R_F was CF₃CH₂, C₂F₅CH₂, C₃F₇CH₂ or (CF₃)₂CH and R was Et or n-Pr. Similarly, reaction of phosphorobromidates (R_FCH₂O)₂P(O)Br, made by brominating the corresponding bis(fluoroalkyl) H-phosphonates, with benzenethiol gave derivatives (R_FCH₂O)₂P(O)SPh in 43 and 46% yield where R_F was CF₃ and C₂F₅, respectively. Treatment of the chloridothiolate Cl(EtO)P(O)SMe, prepared in two steps from triethyl phosphite, with fluoroalcohols and triethylamine in ether gave species R_FO(EtO)P(O)SMe in 62-74% yield where R_F was CF₃CH₂, C₂F₅CH₂, C₃F₇CH₂ or (CF₃)₂CH. The reactions of bis(trifluoroethyl) phosphorochloridate with 2-mercaptoethanol, 3-mercaptopropanol and ethane-1,2-dithiol gave several unexpected products whose structures were tentatively assigned.     

Fluorinated phosphorus compounds: Part 11. The reactions of some fluorinated amines with dialkyl and bis(fluoroalkyl) phosphorochloridates

Dimethyl phosphorochloridate reacted with R_FCH₂NH₂ in ether in the presence of Et₃N to afford (MeO)₂P(O)NHCH₂R_F, where R_F = CF₃ and C₂F₅, in 39 and 47% yield, respectively. Similar reactions with di-n-propyl and diisopropyl phosphorochloridates could be effected only with H₂NCH₂CF₃ when 4-dimethylaminopyridine catalyst was added and (n-PrO)₂P(O)NHCH₂CF₃ and (i-PrO)₂P(O)NHCH₂CF₃ were isolated in 49 and 25% yield, respectively. Treatment of POCl₃ with one molar equivalent each of H₂NCH₂CF₃ and Et₃N permitted the synthesis of Cl₂P(O)NHCH₂CF₃ in 43% yield. Bis(fluoroalkyl) phosphorochloridates (R_FO)₂P(O)Cl, where R_F = C₂F₅CH₂, C₃F₇CH₂ and (CF₃)₂CH, reacted with 2,2,2-trifluoroethylamine and 2,2,3,3,3-pentafluoropropylamine to furnish phosphoramidates (R_FO)₂P(O)NHCH₂R, where R = CF₃ or C₂F₅, in yields of 32-67%.     

Fluorinated phosphorus compounds: Part 10. Bis(fluoroalkyl) S-alkyl phosphorothiolates and tris(fluoroalkyl) phosphorothionates

Treatment of bis(fluoroalkyl) phosphites (R_FCH₂O)₂P(O)H, where R_F was CF₃ or C₂F₅ with sulfur in pyridine at 80 °C gave salts of structure [(R_FCH₂O)₂P(O)SH]NC₅H₅ in 90 and 88% yield, respectively. The salts reacted with alkyl iodides in acetonitrile at 50 °C to furnish bis(fluoroalkyl) S-alkyl phosphorothiolates (R_FCH₂O)₂P(O)SR, where R was Me, Et, n- and i-Pr (when R_F = CF₃) and Me (when R_F = C₂F₅). Yields ranged from 21 to 57%. Bis(trifluoroethyl) S-methyl phosphorothiolate (CF₃CH₂O)₂P(O)SMe underwent fluorination by silver(I) fluoride in acetonitrile at room temperature to yield the phosphorofluoridate (CF₃CH₂O)₂P(O)F in 75% yield. Tris(fluoroalkyl) phosphorothionates (R_FCH₂O)₃P = S, where R_F was CF₃, C₂F₅ and C₃F₇, were prepared in 30-34% yield by heating the tris(fluoroalkyl) phosphites (R_FCH₂O)₃P and sulfur to 200 °C in a sealed tube for 8 h.     

Polyhalogenoheterocyclic compounds: Part 54: [1] Suzuki reactions of 2,4,6-tribromo-3,5-difluoropyridine

Palladium catalysed Suzuki cross-coupling reactions between 2,4,6-tribromo-3,5-difluoropyridine and a short series of aromatic boronic acid derivatives gave 4-bromo-3,5-difluoro-2,6-diphenylpyridine derivatives arising from displacement of bromine atoms attached to positions ortho to ring nitrogen or the corresponding triaryl systems depending on the reaction conditions. Consequently, the use of polybromofluoropyridine scaffolds for the synthesis of polyfunctional heteroaromatic derivatives is expanded further.     

Enzyme immobilization procedures on screen-printed electrodes used for the detection of anticholinesterase pesticides: Comparative study

A comparison between several acetylcholinesterase (AChE) immobilization procedures on the 7,7,8,8-tetracyanoquinodimethane (TCNQ)-modified graphite working electrodes is presented. The immobilization methods employed crosslinking with glutaraldehyde in presence of BSA protein and photopolymerization with poly(vinyl alcohol) bearing styrylpyridinium groups (PVA-SbQ). The main variations were related to the enzyme charge in each electrode and the enzyme conditioning and storage conditions after immobilization. Initially, the enzyme-substrate reaction was carried out and the following parameters were chrono-amperometrically and -coulometrically monitored: current intensities, time to stabilize the current response, and the mass transfer represented by the Coulomb charge. The screen-printed biosensors that presented best characteristics were then used to perform the inhibition assays and to verify the sensitivity against the following NMC insecticides: aldicarb, carbaryl, carbofuran, and methomyl.In general, diffusion of electrons into the sensitive layer, mass transfer, and time to stabilize the current were adequate in all cases. The Cottrell law was followed before the 1 min of enzyme-substrate reaction. Adequate reproducibility within electrochemical measurements was also observed, with relative standard deviations varying from 6.5 to 18.6%.AChE immobilization with glutaraldehyde allow to obtain robust and reproducible biosensors, but they need a much higher enzyme content (80 mUA per electrode) to achieve current values comparable to that constructed by immobilizing the AChE through photopolymerization with PVA-SbQ (0.7 to 1 mUA per electrode). The limits of detection were determined with a minimum 10% inhibition, and varied from 10⁻⁹ to 8×10⁻⁹ M (0.2 to 1.5 ppb) by employing the enzyme immobilization through photopolymerization with PVA-SbQ. In practice, this kind of immobilization procedure is much simpler and produces good results: fast response, adequate reproducibility, large pesticides working ranges, and excellent sensitivities to N-methylcarbamates (NMCs) which in general do not present enzyme inhibition power as elevated as for the organophosphate pesticides.     

Canonical Measure of Correlation (CMC) and Canonical Measure of Distance (CMD) between sets of data: Part 2. Variable reduction

This paper proposes a new method for determining the subset of variables that reproduce as well as possible the main structural features of the complete data set. This method can be useful for pre-treatment of large data sets since it allows discarding variables that contain redundant information. Reducing the number of variables often allows one to better investigate data structure and obtain more stable results from multivariate modelling methods.The novel method is based on the recently proposed canonical measure of correlation (CMC index) between two sets of variables [R. Todeschini, V. Consonni, A. Manganaro, D. Ballabio, A. Mauri, Canonical Measure of Correlation (CMC) and Canonical Measure of Distance (CMD) between sets of data. Part 1. Theory and simple chemometric applications, Anal. Chim. Acta submitted for publication (2009)]. Following a stepwise procedure (backward elimination), each variable in turn is compared to all the other variables and the most correlated is definitively discarded. Finally, a key subset of variables being as orthogonal as possible are selected. The performance was evaluated on both simulated and real data sets. The effectiveness of the novel method is discussed by comparison with results of other well known methods for variable reduction, such as Jolliffe techniques, McCabe criteria, Krzanowski approach and its modification based on genetic algorithms, loadings of the first principal component, Key Set Factor Analysis (KSFA), Variable Inflation Factor (VIF), pairwise correlation approach, and K correlation analysis (KIF). The obtained results are consistent with those of the other considered methods; moreover, the advantage of the proposed CMC method is that calculation is very quick and can be easily implemented in any software application.     

Polyhalogenoheterocyclic compounds: Part 51. [1] Macrocycles from 4-alkoxy-tetrafluoropyridine derivatives

4-Alkoxy-tetrafluoropyridine derivatives were used as building blocks for the synthesis of 14- and 16-membered macrocyclic ring systems comprising pyridine and either poly-ether or amine subunits; two of the macrocycles were characterised by X-ray crystallography.     

Mechanisms of reactions of halogenated compounds: Part 7. Effects of fluorine and other groups as substituents on nucleophilic aromatic substitution

The effect of fluorine as a substituent group on nucleophilic aromatic substitution is discussed, where a fluorine atom located ortho to the point of substitution may be of variable activating influence, whereas fluorine located para is slightly deactivating and meta is activating. A rationale of these effects is presented and evidence to support polar influences by ortho fluorine is advanced. The influence of CN, CF₃, CF₂H and CFH₂ is also established by comparison of appropriate measured rate constants and compared with the activation effects of ring nitrogen.     

Phenomenology of Polymorphism: IV. The Trimorphism of Ferrocene and the Overall Metastability of Its Triclinic Phase

Structural and thermodynamic data reported in the literature for the three crystalline phases of ferrocene are used to build a topological representation of its (p, T) phase diagram. Two phases (orthorhombic and monoclinic) exhibit stable phase regions whose temperature ranges increase with increasing pressure. The triclinic phase is found to be metastable at any temperature and pressure. In fact, in the (p, T) diagram, it is not associated with any state of lowest energy although it transforms into the monoclinic phase according to a transition which is reversible. This transition occurs in the phase region where the orthorhombic phase is the stable one.     

pH-stat techniques in titrimetric analysis: Part 3. The principles of pH-stat chelatometric titrations

Chelatometric titrations can be effectively monitored by means of the pH-stat technique. During the addition of the primary titrant (the chelating agent), the pH of the titrated solution is kept at a pre-selected value by adding a strong base as the auxiliary titrant. The equivalence point is characterised by a sudden change in the ratio between the added volumes of auxiliary and primary titrant solutions, i.e. in the slope of the linearly segmented titration plot representing the volume of the base against the volume of the chelating agent. The slope of the linear segments depends on the reactions involving proton exchange, which accompany the primary complexation reaction. The dependence of the shape of the plots on the imposed pH for typical titrations (magnesium(II) and copper(II)) is examined and the conditions for the feasibility of pH-stat chelatometric titrations are discussed.     

Polyhalogenated heterocyclic compounds: Part 52. [1] Macrocycles from 3,5-dichloro-2,4,6-trifluoropyridine

Model studies show that displacement of fluorine, rather than chlorine, occurs upon reaction of 3,5-dichloro-2,4,6-trifluoropyridine with sodium methoxide and phenoxide. Subsequent hydro-dechlorination can be achieved by reaction with lithium aluminium hydride whereas reaction of sodium in iso-propanol leads to formation of the tri-iso-propoxy pyridine derivative, via nucleophilic substitution of the methoxy group, rather than the dechlorinated products. Macrocycles can be synthesised by reactions of appropriate difunctional oxygen nucleophiles with 3,5-dichloro-2,4,6-trifluoropyridine, one of which was characterised by X-ray crystallography.     

Fluorinated stannanes : Part 2. The stereospecific synthesis of fluorinated stannanes via a Barbier-type reaction between fluorinated halides and tributyltin chloride mediated by zinc or cadmium

Fluorinated stannanes are valuable synthons in synthetic organofluorine chemistry. Fluorinated vinyl, alkyl and aryl halides reacted efficiently with tri-n-butyltin chloride in the presence of zinc or cadmium to yield the corresponding stannanes in good yields. In some cases, yield of the stannanes showed a dramatic improvement over the transmetalation method. In all other cases, comparable yields were obtained.     

Fluorinated pyridine derivatives: Part 1. The synthesis of some mono- and bis-quaternary pyridine salts of potential use in the treatment of nerve agent poisoning

Experiments were performed to determine whether F- and CF₃-substituted pyridines undergo quaternization with iodomethane (1:1 molar ratio in THF) and 1,3-diiodopropane (2:1 molar ratio in MeCN). 2-Fluoropyridine and 2-(trifluoromethyl)pyridine did not react with MeI even under prolonged reflux, while 3-fluoropyridine, 3,5-difluoropyridine, 3-(trifluoromethyl)pyridine and 4-(trifluoromethyl)pyridine gave methiodide salts in 28-72% yield. 2-Fluoropyridine did not react with I(CH₂)₃I, 3-fluoropyridine gave the bis-quaternary salt and 3,5-difluoropyridine yielded a mono-quaternary derivative. Both 3- and 4-(trifluoromethyl)pyridine furnished the bis-quaternary products in 53 and 55% yield, respectively. The bis-quaternary salts are potentially useful in the treatment of organophosphorus nerve agent poisoning.     

Incorporation of siloxanes in hydrolytically degradable structures: I. Poly(anhydride)s synthesis

New poly(anhydride)s containing amino acids and siloxane segments have been synthesized. The synthetic method involves the polycondensation in solution of the organic diacids (N-trimellitylimidoglycine, 1a, N-trimellitylimido-γ-aminobutiric acid, 1b, and N-trimellitylimido-ε-aminocapronic acid, 1c) obtained from the proper amino acids with a siloxane diacid (1,3-bis(3-carboxypropyl)tetramethyldisiloxane, 2a, α,ω-bis(3-carboxypropyl)oligodimethylsiloxane, 2b, or 1,3-bis(sebacomethyl)tetramethyl-disiloxane, 2c). The acetylation method was used for the activation of the two types of diacids (organic and siloxanic). Optimization of synthesis parameters was made.The structures and morphology of partial and final products were determined by IR and ¹H NMR spectroscopy and differential scanning calorimetry. Inherent viscosities were determined and some preliminary solubility and hydrolytic stability tests were also performed.     

Fluorinated phenylcyclopropylamines: Part 6. Effects of electron withdrawing or donating aryl substituents on the inhibition of tyramine oxidase from Arthrobacter sp. by diastereomeric 2-aryl-2-fluoro-cyclopropylamines

Diastereomeric arylcyclopropylamines substituted with fluorine in the 2-position and with electron donating or electron withdrawing groups at the aromatic ring were evaluated as inhibitors of microbial tyramine oxidase. The trans-isomers were consistently more potent inhibitors of the enzyme than the cis-isomers. Electron donating substituents increased the potency of tyramine oxidase inhibition, while electron withdrawing substituents decreased the activity. The results obtained are discussed in terms of pK_a and log D values of the inhibitors as well as the mechanism of action of tranylcypromines and the geometry of the active site of the enzyme.     

Palladium complexes with ethylene-bridged bis(N-heterocyclic carbene) for C-C coupling reactions

A series of new ethylene-bridged bis(imidazolium) halides with various N-substitutions were synthesized. Complexation of these imidazolium halides with Pd(OAc)₂ produced new Pd(II) ethylene-bridged bis(carbene) complexes. Crystallographic analyses of some of the new imidazolium salts and Pd(II) complexes were determined. Applications of these seven-member palladacycles in Suzuki and Heck coupling reactions produced comparable catalytic activities to those of six-member analogs.     

Fluorinated butanolides and butenolides : Part 9. Synthesis of 2-(trifluoromethyl)butan-4-olides by Wittig reaction using methyl 3,3,3-trifluoropyruvate

2-(Trifluoromethyl)butan-4-olides 13 and 14 were prepared by a three-step synthesis starting from a Wittig reagent and methyl 3,3,3-trifluoropyruvate (1) as a building block. The Wittig reaction of (2-oxoalkyl)triphenylphosphonium bromides with pyruvate 1 gave intermediate 4-oxobutenoates 8 and 9, which were stepwise selectively reduced with zinc borohydride firstly at the double bond and subsequently at the oxo group to afford unstable 4-hydroxy-2-trifluoromethylalkanoates 11 and 12, which cyclised spontaneously to the end butenolides 13 and 14.