Evaluation of compounds for insecticidal activity on adult mosquitos. 2. Toxicity to adult mosquitos and the physical properties of some new carbamates.

Bull. Org. mond. Sant) 1970, 42, 369-375 Bull. Wld Hlth Org. Evaluation of Compounds for Insecticidal Activity on Adult Mosquitos* 2. Toxicity to Adult Mosquitos and the Physical Properties of Some New Carbamates A. B. HADAWAY, F. BARLOW, J. E. H. GROSE, C. R. TURNER & L. S. FLOWER The N,N-dimethylcarbamates are much less toxic and much more volatile than the corresponding N-methylcarbamates. N-acylation of N-methylcarbamates is also generally accompanied by a loss in intrinsic toxicity to adult mosquitos by topical application, but the reduction in toxicity may be relatively small and in some N-acetyl derivatives may not occur at all. N-acylation is also accompanied by changes in physical properties such as lipid solubility and partition coefficient, which influence contact toxicity, and volatility, which affects residual activity. In the series of compounds examined, contact toxicity is maximal in the N-acetyl derivatives but their volatility is often so high that they lack the persistence required of residual insecticides. This does not apply, however, to the N-acetyl derivatives of OMS-597 and OMS-708 because the volatility of the parent compound is so low that some degree of persistence can be sacrificed to obtain some improvement in contact activity. OMS-1064 is the only N-chloroacetyl derivative tested so far that shows promise as a residual insecticide. The relative toxicities to adult mosquitos of numerous substituted N-methylcarbamates and some N-acyl derivatives were recorded previously (Hadaway & Barlow, 1965, 1966b). Additional compounds obtained through the World Health Organization programme for the evaluation of insecticides or synthesized by one of us (F. B.) have now been examined and relationships between chemical structure, physical properties and insecticidal activity have been studied further. MATERIALS AND METHODS N-acylcarbamates were usually prepared by the method of Robertson, Fraser & Clinch (1963) using the appropriate acid anhydride and trace amounts of sulfuric acid as a catalyst. However, chloroacetates could not be made from chloroacetic anhydride by this procedure. Instead, the carbamate was dissolved in xylene containing 1.5 equivalents of chloroacetyl chloride and the solution was refluxed * From the Ministry of Overseas Development, Tropical Pesticides Research Unit, Porton Down, England. 2477 for 24 hours. Part of the xylene was usually distilled before the liquid residue was diluted with petroleum ether to precipitate the N-chloroacetyl derivative. This method frequently produced a mixture of which about 70 % was the required compound. Solids therefore required several recrystallizations before the melting-point was constant. Elemental analyses were obtained for some of the new compounds when it was essential to check on identity (Table 1), although the method of preparation and the physical properties left little doubt that they were the expected compounds. Gas-liquid chromatography gave single peaks with the expected retention times. The compounds investigated, together with some of their physical properties, are listed in Table 2 which also includes, for comparison, compounds previously examined and reported. All the solids, whether synthesized or obtained from commercial sources, were purified by recrystallization. Liquids were prepared from pure reactants and were redistilled except for the sample of OMS-1064 which was provided by the makers and described as pure. 369- 370 A. B. HADAWAY AND OTHERS TABLE 1 ELEMENTAL ANALYSES OF SOME NEW COMPOUNDS TESTED FOR INSECTICIDAL PROPERTIES Calculated (%) Compound N-chloroacetyl derivative of OMS-174 Found (%) I C H N 49.7 4.52 4.83 Cl 5.02 N-chloroacetyl derivative of OMS-29 5.62 S -C 50.0 H N Cl 4.87 4.60 4.70 5.44 12.7 12.8 12.9 57.8 N-acetyl derivative of OMS-708 57.8 N-propionyl derivative of OMS-708 59.3 4.98 5.32 N-butyryl derivative of OMS-708 N-acetyl derivative of OMS-1094 N-acetyl derivative of OMS-1029 60.6 5.45 5.05 62.0 5.62 61.4 6.15 69.5 | 5.40 69.0 5.49 OMS-1028 had a wide melting range despite repeated crystallization; gas-liquid chromatography did not show the presence of any isomers and the compound had the correct amount of esterified phenol. Solubility in n-hexane and partition between n-hexane and water were determined by the methods described previously (Hadaway & Barlow, 1966a) and the rate of evaporation from glass-fibre filterpapers by the method given by Hadaway & Barlow (1966b). Median lethal doses ot compounds were determined by the topical application of solutions in di-isobutyl ketone to female Anopheles stephensi and Aedes aegypti mosquitos, 1-2 days old. Contact toxicity tests were carried out with blood-fed female An. stephensi, 2-3 days old, and deposits from water-dispersible-powder formulations on plywood and plaster of Paris panels. Wettable powders of newly synthesized compounds were prepared with the following general composition although small variations were sometimes made to suit the properties of individual insecticides: Composition of powder by weight 50 Piercentage Active ingredient Talc (BDH) or Speswhite china-clay Hisil 233 or Neosyl LM GA5590, a polyethyleneoxide Empicol LZ (sodium lauryl sulfate) 38 6 4 2 Talc was the preferred filler for compounds such as the N-chloroacetyl derivatives which decomposed on the more acidic china-clay. After hand-mixing, the powders were air-milled. 11.6 59.1 5.15 4.91 60.9 5.74 4.88 IS 12.8 11.1 RESULTS Physical properties The newer NH-methylcarbamates such as OMS1094 and OMS-708, which are derived from fusedring phenols, were notable for their high melting points, low volatilities, low hexane solubilities and more favourable water-partitioning behaviour. In structure and properties, they are therefore similar to OMS-29 (carbaryl). As previously observed (Hadaway & Barlow, 1966b), replacement of the hydrogen atom on the carbamoyl portion of the molecule by a methyl or alkanoyl group results in marked reductions in melting points and increases in volatilities and hexane-solubility. Further substitution within the alkanoyl group itself can reverse these effects to a considerable extent. Thus the N-chloroacetyl compounds all have higher melting points and are less volatile and more soluble than the corresponding acetates. Chemical properties The N,N-dimethylcarbamates are very resistant to base-catalysed hydrolysis as compared with the corresponding N-methylcarbamates. N-acyl groups, however, do not stabilize the ester and are themselves relatively labile, the rate of de-acylation depending upon the nature of the acyl group. If this is acetyl, for example, base-catalysed de-acylation proceeds at a similar rate to ester hydrolysis and the end-products are the phenol and methylcarbamic acid. If it is chloroacetyl, however, the de-acylation is accelerated by a factor of about 10' and occurs at pH levels as low as 7, yielding only 371 EVA (...truncated)