title: Neonicotinoid nitroguanidine insecticide metabolites: synthesis and nicotinic receptor potency of guanidines, aminoguanidines, and their derivatives.
abstract: Four neonicotinoid nitroguanidine insecticides (imidacloprid, thiamethoxam, clothianidin, and dinotefuran) acting as nicotinic agonists account for 10-15% of worldwide insecticide sales. General methods are needed for synthesis of their guanidine and aminoguanidine metabolites so they may be used as analytical standards and for evaluation of nicotinic receptor potency. The guanidines are obtained by treating the parent nitroguanidines with Fe powder in aqueous C2H5OH containing NH4Cl and isolated by silica chromatography. The aminoguanidines are prepared as mixtures with the guanidines on reaction of the parent nitroguanidines and Zn powder in glacial acetic acid. The imidacloprid aminoguanidine is isolated as the acetone imine or trifluoroacetamide and the clothianidin and dinotefuran aminoguanidines as the acetone imines using silica chromatography. Deprotection under acidic conditions then leads to the aminoguanidine.HCl salts. Because of stability considerations, a pH partitioning method is used to separate thiamethoxam aminoguanidine and guanidine. An alternate procedure to the aminoguanidine of imidacloprid (but not thiamethoxam, clothianidin, or dinotefuran) is reaction with hydrazine hydrate and NH4Cl in anhydrous C2H5OH. Ambiguities in further biological reactions are clarified by synthesizing authentic standards of three purported metabolites formed via the imidacloprid aminoguanidine: the 1,2,4-triazol-3-one derivative with ethyl chloroformate or ethyl pyrocarbonate, the acetaldehyde imine with acetaldehyde, and the 3-methyl-1,2,4-triazin-4-one derivative with ethyl pyruvate in refluxing toluene. The purported triazolone metabolite is reassigned as the aminoguanidine acetaldehyde imine probably formed as an artifact from acetaldehyde present in the ethyl acetate used for metabolite extraction. Potency at the Drosophila nicotinic receptor is greatly decreased on converting a nitroguanidine to a guanidine or aminoguanidine. In sharp contrast, potency at the vertebrate alpha4beta2 nicotinic receptor is generally increased on conversion from the nitroguanidine to aminoguanidine and particularly guanidine derivatives.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Kanne
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Dick
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000586:Amination; D000818:Animals; D004331:Drosophila melanogaster; D019791:Guanidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D007306:Insecticides; D011978:Receptors, Nicotinic; C506414:neonicotinoid nitroguanidine; D019791:Guanidine