Activation organophosphorus compounds

The present review summarizes recent studies carried out at Princeton which have dealt with the stereochemistry of displacement reactions at phosphorus. The review is divided into two principal sections. The first part (Sect. 2) describes primarily the development of general synthetic methods for the stereospecific conversion of phosphinates -> phosphine oxides -> phosphines, and the configurational intercorrelations of these optically active organophosphorus compounds. The second part (Sect. 3) evaluates the role of pseudorotation in the stereochemistry of various displacement reactions at tetracoordinate phosphorus. The influence of steric and electronic factors is discussed with the aid of a general topological representation which maps the stereochemistry of displacement reactions at tetracoordinate centers. 

Hu LM, Zhang YM, He HW et al (1997) Studies on biological active organophosphorus compounds XIL Synthesis of a-(2-substituted benzainidofonnyloxy)hydiocarbyl phosphonate. Chin J Synthesis Chem 5 287-291... 

He HW, Wang J, Liu ZJ et al (1994) Study on biologically active organophosphorus compounds V Synthesis and properties of a-(substituted phenoxyacetoxyjalkyl phosphonates. Chin J Appl Chem 11 21-24... 

Organophosphorus compounds. Phosphorus-carbon bond fonnation takes place by the reaction of various phosphorus compounds containing a P—H bond with halides or tritlates. Alkylaryl- or alkenylalkylphosphinates are prepared from alkylphosphinate[638]. The optically active isopropyl alkenyl-methylphosphinate 778 is prepared from isopropyl methylphosphinate with retention[639]. The monoaryl and symmetrical and asymmetric diarylphosphi-nates 780, 781, and 782 are prepared by the reaction of the unstable methyl phosphinate 779 with different amounts of aryl iodides. Tnmethyl orthoformate is added to stabilize the methyl phosphinate[640]. 

Many organophosphorus compounds are highly toxic and frequently lethal. They have been actively developed for herbicides, pesticides and more sinister purposes such as nerve gases which disorient, harass, paralyse or kill. ... 

Chen HH, Sirianni SR, Huang CC. 1982. Sister chromatid exchanges in Chinese hamster cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation system. Environ Mutagen 4 621-624. 

Maxwell DM, Brecht KM. 1992. Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analougues of organophosphorus compounds. Chem Res Toxicol 5 66-71. 

Ohkawa H, Oshita H, Miyamoto J. 1980. Comparison of inhibitory activity of various organophosphorus compounds against acetylcholinesterase and neurotoxic esterase of hens with respect to delayed neurotoxicity. Biochem Pharmacol 29 2721-2727. 

All these observations underscore the potential for application of appropriate OPAs to the destruction of organophosphorus compounds with anticholinesterase activity (Cheng and Calomiris 1996). However, since, hydrolysis results in release of fluoride, the possibility of its subsequent incorporation into organic substrates to produce fluoroacetate and 4-fluorothreonine (Reid et al. 1995) may be worth consideration. 

The unique combination of double bonds in the molecules of those compounds, each with different reactivity along with the easy preparation, makes phosphorylated allenes useful substrates for the synthesis of different cyclic and noncyclic organophosphorus compounds. Recent investigations increase the scope of application of phosphorylated allenes as precursors in organic syntheses. Most of them are accompanied by the formation of five- or six-membered phosphorus heterocycles, which in many cases demonstrate certain biological activity. 

Diazinon (phosphorothioic acid 0,0-diethyl 0-(6-mcthyl-2-(l-mcthylcthyl)-4-pyrimidinyl) ester) is an organophosphorus compound with an anticholinesterase mode of action. It is used extensively to control hies, lice, insect pests of ornamental plants and food crops, as well as nematodes and soil insects in lawns and croplands. Diazinon degrades rapidly in the environment, with half-time persistence usually less than 14 days. But under conditions of low temperature, low moisture, high alkalinity, and lack of suitable microbial degraders, diazinon may remain biologically active in soils for 6 months or longer. 

In spite of heavy activity in the study of organophosphorus chemistry, it remains relatively rare to find university courses taught on the topic of synthesis of organophosphorus compounds. This Second Edition retains a purpose embodied in the First Edition to provide a working guide for the practicing chemist with a need to perform organophosphorus syntheses. 

Another different class of inhibitors binds covalently to specific amino acids in the enzyme and these are referred to as irreversible inhibitors. The organophosphorus compounds, of which nerve gases are examples, inactivate enzymes which rely on the hydroxyl group of serine residues for their activity, e.g. cholinesterase (EC 3.1.1.8). 

Phosphatases are numerous and important enzymes (see also Chapt. 2). They are classified as phosphoric monoester hydrolases (phosphatases, EC 3.1.3), phosphoric diester hydrolases (phosphodiesterases, EC 3.1.4), triphosphoric monoester hydrolases (EC 3.1.5), diphosphoric monoester hydrolases (pyrophosphatases, EC 3.1.7), and phosphoric triester hydrolases (EC 3.1.8) [21] [63]. Most of these enzymes have a narrow substrate specificity restricted to endogenous compounds. However, some of these enzymes are active toward xenobiotic organophosphorus compounds, e.g., alkaline phosphatase (EC 3.1.3.1), acid phosphatase (EC 3.1.3.2), aryldialkylphosphatase (para-oxonase (PON1), EC 3.1.8.1) and diisopropyl-fluorophosphatase (tabunase, somanase, EC 3.1.8.2) [64 - 70]. However, such a classification is far from definitive and will evolve with further biochemical findings. Thus, a good correlation has been found in human blood samples between somanase and sarinase activities on the one hand, and paraoxonase (PON1) type Q isozyme concentrations on the other [71]. 

Limitations of MNDO. From its inception, some important limitations of MNDO were apparent. Sterically crowded molecules were calculated too unstable for example, the AHf of neopentane is predicted by MNDO to be —24.6 kcal/mol, compared with the observed -40.3 kcal/mol. On the other hand, four—membered rings were predicted to be too stable, this reaching a limit in cubane, which was predicted to be 49.6 kcal/mol too stable. Later on, other limitations were discovered, the most important from a biochemical standpoint being the virtually complete lack of a hydrogen bond. Other deficiencies included the extreme instability of hypervalent molecules. This effectivdy precluded the application of MNDO to organophosphorus compounds of biologic interest. Finally, activation barriers were predicted to be too high. 

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