Aclonifen is a diphenyl ether herbicide which has been used in agriculture since the 1980s. Its mode of action has been uncertain, with evidence suggesting it might interfere with carotenoid biosynthesis or inhibit the enzyme protoporphyrinogen oxidase (PPO). Both mechanisms could result in the observed whole-plant effect of bleaching (removal of leaf colour) and the compound includes chemical features (a nitro group attached to a diphenyl ether) that are known to result in PPO effects, as seen with acifluorfen, for example.[1][3][4] In 2020, further research revealed that aclonifen has a different and novel mode of action, targeting solanesyl diphosphate synthase which would also cause bleaching.[5][6]
History
The nitrophenyl ethers are a well-known class of herbicides, the oldest member of which was nitrofen, invented by Rohm & Haas and first registered for sale in 1964.[7] This area of chemistry became very competitive, with the Mobil Oil Corporation's filing in 1969 and grant in 1974 of a patent to the structural analog with a COOCH3 group adjacent to the nitro group of nitrofen.[8] This product, bifenox, was launched in 1981. Meanwhile, Rohm & Haas introduced acifluorfen (as its sodium salt) in 1980.[9] It had much improved properties including a wider spectrum of herbicidal effect and good safety to soybean crops. The first patent for this material was published in December 1975,[10]
Nitrofen
Bifenox
Acifluorfen
Celamerck scientists were also working on analogs retaining the 4-nitrodiphenyl ether framework and in 1978 filed a patent of relatively narrow scope which claimed compounds having an amine group adjacent to the nitro substituent and also having an additional chlorine atom between the amine and the oxygen of the diphenyl ether. 2-Chloro-3-phenoxy-6-nitroaniline was described as having selectivity, so that important grass weeds could be controlled within dicot crops and this lack of damage to the crop extended to some cereals.[11] Aclonifen was subsequently developed and marketed by Rhône-Poulenc under the code number RPA099795 and launched in 1983 in Europe.[1][12]
Synthesis
The synthesis of aclonifen
The preparation of aclonifen first described in Celamerck patents starts from 2,3,4-trichloronitrobenzene. This is reacted in an autoclave with ammonia in dimethyl sulfoxide. The intermediate aniline is treated with potassium phenolate in an Ullmann ether synthesis using acetonitrile as solvent.[11]
Mechanism of action
The detailed mechanism of action for nitro diphenyl ether herbicides such as acifluorfen was unknown at the time they were invented. The effects visible on whole plants are chlorosis and desiccation: in 1983 several hypotheses were advanced regarding the molecular-level interactions which might explain these symptoms.[13] By 1992, it was becoming clear that most compounds of this class inhibit the enzyme protoporphyrinogen oxidase (PPO), which leads to an accumulation of protoporphyrin IX in the plant cells. This is a potent photosensitizer which activates oxygen, leading to lipid peroxidation. Both light and oxygen are required for this process to kill the plant.[14][15][16]
Aclonifen was shown to be an inhibitor of PPO but in addition had effects on carotenoid synthesis, by inhibition of phytoene desaturase at similar concentrations in vitro.[3] This led to the conclusion that it expressed a dual mode of action.[4][17] In 2020, further research revealed that it is likely to have a completely different and novel mode of action, targeting solanesyl diphosphate synthase.[5] This has led to its being classified in its own group for the purposes of resistance management.[18]
Uses
Aclonifen is registered for use in the European Union, where a two-tiered approach is used for approval and authorisation. Before a formulated product can be developed for market, the active substance must be approved. Then authorisation for the specific product must be sought from every Member State that the applicant wants to sell it to. Afterwards, there is a monitoring programme to make sure the pesticide residues in food are below the limits set by the European Food Safety Authority. The active ingredient is registered for use against weeds in crops including cereals, potato and sunflower.[1][19] It is particularly safe to sunflower, owing to the metabolism which occurs in that crop.[20][21]
^Pesticide Properties Database. "Nitrofen". University of Hertfordshire. Retrieved 2021-03-03.
^US patent 3784635, Theissen R.J., "Herbicidal 4-trifluoromethyl-4'-nitrodiphenyl ethers", issued 1974-01-08, assigned to Mobil Oil Corporation
^Pesticide Properties Database. "Acifluorfen-sodium". University of Hertfordshire. Retrieved 2021-03-03.
^US patent 3928416, Bayer H. O.; Swithenbank C. & Yih R. Y., "Herbicidal 4-trifluoromethyl-4'-nitrodiphenyl ethers", issued 1975-12-23, assigned to Rohm & Haas
^ abUS patent 4394159, Buck W.; Linden G. & Lust S. et al., "2-Chloro-3-(phenoxy or phenylthio)-6-6-nitro-anilines", issued 1981-09-16, assigned to Celamerck GmbH and Co KG
^Matringe, M.; Clair, D.; Scalla, R. (1990). "Effects of peroxidizing herbicides on protoporphyrin IX levels in non-chlorophyllous soybean cell culture". Pesticide Biochemistry and Physiology. 36 (3): 300–307. doi:10.1016/0048-3575(90)90039-5.
^Nandihalli, Ujjana B.; Duke, Mary V.; Duke, Stephen O. (1992). "Quantitative structure-activity relationships of protoporphyrinogen oxidase-inhibiting diphenyl ether herbicides". Pesticide Biochemistry and Physiology. 43 (3): 193–211. doi:10.1016/0048-3575(92)90033-V.
^Dayan, Franck E.; Reddy, Krishna N.; Duke, Stephen O. (1999). "Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. pp. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN978-3-642-63674-5.
