Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters

Carbon-carbon and carbon-heteroatom bond formations constitute the central events in organic synthesis. In view of this, much of the research in organic synthesis has been focused on devising novel and efficient methods for such bond constructions. In general, polar, pericyclic and radical methodologies are employed for this purpose. The polar and radical reactions proceed via reactive intermediates such as carbanions, enols/enolates, enamines, carbocations, radical cations, radical anions, carbenes, zwitterions etc. In recent years, there has been enormous interest in the chemistry of zwitterionic species largely from the standpoint of their applications in multicomponent reactions (MCRs) and organocatalytic reactions. Zwitterions formed by the addition of nucleophiles to electrophilic π-systems such as acetylenic esters and azoesters have been the subject of extensive investigations; their synthetic utility, however, remained largely unexplored. Investigations in a number of laboratories, including our own, have shown that zwitterions of the type mentioned above on reaction with electrophiles give rise to carbo- and heterocyclic products by 1,3- or 1,4-dipolar cycloadditions. Recently, allenoates, another class of active π-systems were introduced to this field. Against this background, a systematic investigation of the reactions of various zwitterions derived from allenoates with different electrophiles especially 1,2-diones, were carried out. The results of these studies are embodied in the thesis entitled “Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters”.

Organometallic macrocyclic chemistry. 8.(1) : an unusual metallacycle derived from phosphine−alkynyl thioether coupling

The α,ω-diyne 4,7,10-trithiatrideca-2,11-diyne reacts with [RuCl2(PPh3)3] and KPF6 to form the phosphonio-substituted metallatricyclic salt [RuCl(PPh3){κ4C,S,S′,S′′-S(C≡CMe)C2H4SC2H4SC(PPh3)CMe}]PF6 arising from the activation of one alkynyl group toward nucleophilic attack by extraneous phosphine.

Simulation of phosphine flow in vertical grain storage : a preliminary numerical study

To fumigate grain stored in a silo, phosphine gas is distributed by a combination of diffusion and fan-forced advection. This initial study of the problem mainly focuses on the advection, numerically modelled as fluid flow in a porous medium. We find satisfactory agreement between the flow predictions of two Computational Fluid Dynamics packages, Comsol and Fluent. The flow predictions demonstrate that the highest velocity (>0.1 m/s) occurs less than 0.2m from the inlet and reduces drastically over one metre of silo height, with the flow elsewhere less than 0.002 m/s or 1% of the velocity injection. The flow predictions are examined to identify silo regions where phosphine dosage levels are likely to be too low for effective grain fumigation.

Structure, magnetism and colour in simple bis­(phosphine)nickel(II) dihalide complexes : an experimental and theoretical investigation

The complex [1,2-bis­(di-tert-butyl­phosphan­yl)ethane-[kappa]2P,P']di­iodido­nickel(II), [NiI2(C18H40P2] or (dtbpe-[kappa]2P)NiI2, [dtbpe is 1,2-bis­(di-tert-butyl­phosphan­yl)ethane], is bright blue-green in the solid state and in solution, but, contrary to the structure predicted for a blue or green nickel(II) bis­(phos­phine) complex, it is found to be close to square planar in the solid state. The solution structure is deduced to be similar, because the optical spectra measured in solution and in the solid state contain similar absorptions. In solution at room temperature, no 31P{1H} NMR resonance is observed, but the very small solid-state magnetic moment at temperatures down to 4 K indicates that the weak paramagnetism of this nickel(II) complex can be ascribed to temperature independent paramagnetism, and that the complex has no unpaired electrons. The red [1,2-bis­(di-tert-butyl­phosphan­yl)ethane-[kappa]2P,P']di­chlorido­nickel(II), [NiCl2(C18H40P2] or (dtbpe-[kappa]2P)NiCl2, is very close to square planar and very weakly paramagnetic in the solid state and in solution, while the maroon [1,2-bis­(di-tert-butyl­phosphan­yl)ethane-[kappa]2P,P']di­bromido­nickel(II), [NiBr2(C18H40P2] or (dtbpe-[kappa]2P)NiBr2, is isostructural with the diiodide in the solid state, and displays paramagnetism inter­mediate between that of the dichloride and the diiodide in the solid state and in solution. Density functional calculations demonstrate that distortion from an ideal square plane for these complexes occurs on a flat potential energy surface. The calculations reproduce the observed structures and colours, and explain the trends observed for these and similar complexes. Although theoretical investigation identified magnetic-dipole-allowed excitations that are characteristic for temperature-independent paramagnetism (TIP), theory predicts the mol­ecules to be diamagnetic.

Prospects for predicting insect mortality in relation to changing phosphine concentrations

Typically, in bag-stack or silo fumigations the concentration of phosphine is not constant, and yet most of what is known about phosphine efficacy against grain insects comes from studies with fixed concentrations. Indeed, where changing concentration experiments have been performed, researchers have been unable to explain observed efficacy on the basis of data from fixed concentrations. The ability to predict insect mortality in relation to changing phosphine concentrations would facilitate the development of effective fumigation protocols. In this paper, we explore the prospects for making such predictions. After reviewing published and new results, we conclude that the commonly used concentration x time (Ct) product is unreliable for this purpose. New results, for a strongly resistant strain of Rhyzopertha dominica from Australia, suggest that the relationship Cnt = k may be useful for predicting mortality of this type of insect in changing concentrations. However, in the case of a strain of Sitophilus oryzae with a type of resistance common in Australian S. oryzae, the relationship Cnt = k proved to be less reliable.

Effect of fumigation temperature on the efficacy of phosphine against strongly resistant psocids liposcelis bostrychophila (Pscodoptera: Liposcelididae)

Species of Liposcelis psocids have emerged as major pests of stored grain in Australia in recent years. Several populations have been detected with high resistance to phosphine, the major chemical treatment. Highest resistance has been detected in the cosmopolitan species Liposcelis bostrychophila. As part of a national resistance management strategy to maintain the viability of phosphine, we are developing minimum effective dosage regimes (concentration x time) required to control all life stages of resistant L. bostrychophila at a range of grain temperatures. Four concentrations of phosphine, 0.1, 0.17, 0.3 aid 1 mg/L, were evaluated for their effectiveness against strongly resistant L. bostrychophila at a series of fumigation temperatures: 20, 25, 30 and 35°C. Results were recorded as the least number of days taken to achieve population extinction. We found that, at any fixed concentration of phosphine, time to population extinction decreased as fumigation temperature increased from 20 to 30°C. For example, at 0.1 mg/L, it took more than 14 days at 20°C to completely control these insects, whereas at 30°C it took only seven days. Increase in fumigation temperature from 25OC to 30°C dramatically reduced the exposure period needed to achieve population extinction of resistant psocids. For example, a dose of 0.17 mg/L over six days at 30°C completely controlled strongly resistant L. bostrychophila populations that can survive at 1 mg/L and 25°C over the same exposure period. Findings from our study will be used to formulate recommendations for registered dosage rates and fumigation periods for use in Australia.

Developments in phosphine resistance in China and possible implications for Australia

Resistance to phosphine was characterised in strains of rice weevil, Sirophilus oryzae, and the psocids Liposcelis entomophila and L. decolor from China and Australia. Mixed-age cultures (containing all life stages) of insects were tested using a flow-through apparatus. The criterion of response was 'time to population extinction' defined as the exposure period, in days, at which 100% mortality of adults and no live progeny were achieved. Chinese S. oryzae took 11 and 7 days for population extinction at 200 and 700 ppm phosphine, respectively, compared with the Australian strain, which was controlled in 7 and 5 days, respectively. Similarly, the Chinese strains L. Enfornophila and L. decolor were generally more difficult to control than the corresponding Australian strains. The Chinese strains of L. decolor showed resistance levels stronger than any grain storage insect pest species so far detected in Australia. This research allows us to evaluate the likely significance of potential new resistance to the Australian grain industry and to prepare effective fumigation dosages and resistance management strategies to combat new strong resistances before they emerge here.

Predicting mortality of phosphine-resistant adults of Sitophilus oryzae (L) (Coleoptera: Curculionidae) in relation to changing phosphine concentration

Adults of a phosphine-resistant strain of Sitophilus oryzae (L) were exposed to constant phosphine concentrations of 0.0035-0.9 mg litre(-1) for periods of between 20 and 168 h at 25 °C, and the effects of time and concentration on mortality were quantified. Adults were also exposed to a series of treatments lasting 48, 72 or 168 h at 25 °C, during which the concentration of phosphine was varied. The aim of this study was to determine whether equations from experiments using constant concentrations could be used to predict the efficacy of changing phosphine concentrations against adults of S oryzae. A probit plane without interaction, in which the logarithms of time (t) and concentration (C) were variables, described the effects of concentration and time on mortality in experiments with constant concentrations. A derived equation of the form C^nt = k gave excellent predictions of toxicity when applied to data from changing concentration experiments. The results suggest that for resistant S oryzae adults there is nothing inherently different between constant and changing concentration regimes, and that data collected from fixed concentrations can be used to develop equations for predicting mortality in fumigations in which phosphine concentration changes. This approach could simplify the prediction of efficacy of typical fumigations in which concentrations tend to rise and then fall over a period of days.

Effect of exposure period on degree of dominance of phosphine resistance in adults of Rhyzopertha dominica (Coleoptera: Bostrychidae) and Sitophilus oryzae (Coleoptera: Curculionidae)

Degree of dominance of phosphine resistance was investigated in adults of Rhyzopertha dominica F and Sitophilus oryzae L. Efficacy of the grain fumigant phosphine depends on both concentration and exposure period, which raises the possibility that dominance levels vary with exposure period. New and published data were used to test this possibility in adults of R dominica and S oryzae fumigated for periods of up to 144 h. The concentrations required for control of homozygous resistant and susceptible strains and their F1 hybrids decreased with increasing exposure period. For both species the response lines for the homozygous resistant and susceptible strains and their F1 hybrids were parallel. Therefore, neither dominance level nor resistance factor was affected by exposure period. Resistance was incompletely recessive and the level of dominance, calculated at 50% mortality level, was -0.59 for R dominica and -0.65 for S oryzae. The resistant R dominica strain was 30.9 times more resistant than the susceptible strain, compared with 8.9 times for the resistant S oryzae strain. The results suggest that developing discriminating doses for detecting heterozygote adults of either species will be difficult.

Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans

The aim of this study is to identify the biochemical mechanism of phosphine toxicity and resistance, using Caenorhabditis elegans as a model organism. To date, the precise mode of phosphine action is unclear. In this report, we demonstrate the following dose-dependent actions of phosphine, in vitro: (1) reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), (2) release of iron from horse ferritin, (3) and the peroxidation of lipid as a result of iron release from ferritin. Using in situ hybridization, we show that the ferritin genes of C. elegans, both ferritin-1 and ferritin-2, are expressed along the digestive tract with greatest expression at the proximal and distal ends. Basal expression of the ferritin-2 gene, as determined by quantitative PCR, is approximately 80 times that of ferritin-1. However, transcript levels of ferritin-1 are induced at least 20-fold in response to phosphine, whereas there is no change in the level of ferritin-2. This resembles the reported pattern of ferritin gene regulation by iron, suggesting that phosphine toxicity may be related to an increase in the level of free iron. Indeed, iron overload increases phosphine toxicity in C. elegans at least threefold. Moreover, we demonstrate that suppression of ferritin-2 gene expression by RNAi, significantly increases sensitivity to phosphine. This study identifies similarities between phosphine toxicity and iron overload and demonstrates that phosphine can trigger iron release from storage proteins, increasing lipid peroxidation, leading to cell injury and/or cell death.

Effect of phosphine dose on sorption in wheat

BACKGROUND: In spite of the extensive use of phosphine fumigation around the world to control insects in stored grain, and the knowledge that grain sorbs phosphine, the effect of concentration on sorption has not been quantified. A laboratory study was undertaken, therefore, to investigate the effect of phosphine dose on sorption in wheat. Wheat was added to glass flasks to achieve filling ratios of 0.25-0.95, and the flasks were sealed and injected with phosphine at 0.1-1.5 mg L-1 based on flask volume. Phosphine concentration was monitored for 8 days at 25°C and 55% RH. RESULTS: When sorption occurred, phosphine concentration declined with time and was approximately first order, i.e. the data fitted an exponential decay equation. Percentage sorption per day was directly proportional to filling ratio, and was negatively correlated with dose for any given filling ratio. Based on the results, a tenfold increase in dose would result in a halving of the sorption constant and the percentage daily loss. Wheat was less sorptive if it was fumigated for a second time. CONCLUSIONS: The results have implications for the use of phosphine for control of insects in stored wheat. This study shows that dose is a factor that must be considered when trying to understand the impact of sorption on phosphine concentration, and that there appears to be a limit to the capacity of wheat to sorb phosphine.

New tools for management of phosphine resistance

Phosphine is the primary fumigant used to protect the majority of the world' s grain and a variety of other stored commodities from insect pests. Phosphine is playing an increasingly important role in the protection of commodities for two primary reasons. Firstly, use of the alternative fumigant, methyl bromide, has been sharply curtailed and is tightly regulated due to its role in ozone depletion, and secondly, consumers are becoming increasingly intolerant of contact pesticides. Niche alternatives to phosphine exist, but they suffer from a range of factors that limit their use, including: 1) Limited commercial adoption due to expense or slow mode of action; 2) Poor efficacy due to low toxicity, rapid sorption, limited volatility or high density; 3) Public health concerns due to toxicity to handlers or nearby residents, as well as risk of explosion; 4) Poor consumer acceptance due to toxic residues or smell. These same factors limit the prospects of quickly identifying and deploying a new fumigant. Given that resistance toward phosphine is increasing among insect pests, improved monitoring and management of resistance is a priority. Knowledge of the mode of action of phosphine as well as the mechanisms of resistance may also greatly reduce the effort and expense of identifying synergists or novel replacement compounds.

Gene interactions constrain the course of evolution of phosphine resistance in the lesser grain borer, Rhyzopertha dominica

Phosphine, a widely used fumigant for the protection of stored grain from insect pests, kills organisms indirectly by inducing oxidative stress. High levels of heritable resistance to phosphine in the insect pest of stored grain, Rhyzopertha dominica have been detected in Asia, Australia and South America. In order to understand the evolution of phosphine resistance and to isolate the responsible genes, we have undertaken genetic linkage analysis of fully sensitive (QRD14), moderately resistant (QRD369) and highly resistant (QRD569) strains of R. dominica collected in Australia. We previously determined that two loci, rph1 and rph2, confer high-level resistance on strain QRD569, which was collected in 1997. We have now confirmed that rph1 is responsible for the moderate resistance of strain QRD369, which was collected in 1990, and is shared with a highly resistant strain from the same geographical region, QRD569. In contrast, rph2 by itself confers only very weak resistance, either as a heterozygote or as a homozygote and was not discovered in the field until weak resistance (probably due to rph1) had become ubiquitous. Thus, high-level resistance against phosphine has evolved via stepwise acquisition of resistance alleles, first at rph1 and thereafter at rph2. The semi-dominance of rph2 together with the synergistic interaction between rph1 and rph2 would have led to rapid selection for homozygosity. A lack of visible fitness cost associated with alleles at either locus suggests that the resistance phenotype will persist in the field.