Background: Organophosphorus flame retardants (OPFRs) are a group of chemical substances used in building materials and plastic products to suppress or mitigate the combustion of materials. Although OPFRs are generally used in mixed form, information on their mixture toxicity is quite scarce.Objectives: This study aims to elucidate the toxicity and determine the types of interaction (e.g., synergistic, additive, and antagonistic effect) of OPFRs mixtures.Methods: Nine organophosphorus flame retardants, including TEHP (tris(2-ethylhexyl) phosphate) and TDCPP (tris(1,3-dichloro-2-propyl) phosphate), were selected based on indoor dust measurement data in South Korea. Nine OPFRs were exposed to the luminescent bacteria Aliivibrio fischeri for 30 minutes and the human hepatocyte cell line HepG2 for 48 hours. Chemicals with significant toxicity were only used for mixture toxicity tests in HepG2. In addition, the observed EC x values were compared with the predicted toxicity values in the CA (concentration addition) prediction model, and the MDR (model deviation ratio) was calculated to determine the type of interaction.Results: Only four chemicals showed significant toxicity in the luminescent bacteria assays. However, EC 50 values were derived for seven out of nine OPFRs in the HepG2 assays. In the HepG2 assays, the highest to lowest EC 50 were in the order of the molecular weight of the target chemicals. In the further mixture tests, most binary mixtures show additive interactions except for the two combinations that have TPhP (triphenyl phosphate), i.e., TPhP and TDCPP, and TPhP and TBOEP (tris(2-butoxyethyl) phosphate).
Conclusions:Our data shows OPFR mixtures usually have additivity; however, more research is needed to find out the reason for the synergistic effect of TPhP. Also, the mixture experimental dataset can be used as a training and validation set for developing the mixture toxicity prediction model as a further step.
Malic acid is the active ingredient in many sour foods and found mostly in unripe fruits. The dicarboxylic acid is relatively inexpensive and commercially available in both enantiomeric forms. The application of malic acid derivatives as a chiral auxiliary is, however, not well known in the area of asymmetric synthesis.1 We herein report the first example of L-malate-mediated dynamic kinetic resolution of α-bromo esters in nucleophilic substitution with various arylamines.
2Treatment of diisopropyl L-malate with racemic α-bromo phenylacetic acid in the presence of DCC and DMAP provided α-bromo phenylacetate (αRS)-1 in 77% yield with about 50:50 diastereomeric ratio (dr). When the two diastereomeric mixture of (αRS)-1 was treated with p-anisidine (1.5 equiv), tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH 2 Cl 2 at room temperature for 12 h, N-aryl amino ester 2 was produced in 81% yield with 90:10 dr as shown in Scheme 1. Subsequent removal of diisopropyl L-malate with MeOH and Et 3 N gave N-aryl phenylglycinate (R)-3 in 71% yield with 89:11 enantiomeric ratio (er).3a,c The yield and stereoselectivity of the substitution imply that α-bromo stereogenic center is configurationally labile with respect to the rate of substitution and (αRS)-1 is dynamically resolved under the reaction condition.In order to understand the effect of additives and reaction pathway, we carried out a series of reactions as shown in Table 1. In the absence of both TBAI and DIEA, the substitution of 1 was very slow to provide 2 with 71:29 dr in 27% yield after 12 h (entry 1). Also, the rate of the substitution was substantially decreased in the absence of DIEA to provide 2 in 47% yield with 90:10 dr, whereas the reaction in the absence of TBAI gave 2 with both lower yield and stereoselectivity (entries 2-3). The results in entries 1-3 show the importance of the presence of halide ion and base for sufficient rate acceleration and selectivity. When the mixture of two diastereomers of 1 (70:30 dr) was allowed to reach thermodynamic equilibrium in the presence of TBAI and DIEA, the diastereomeric ratio of recovered 1 was analyzed by 1
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