Current Contributions of Organofluorine Compounds to the Agrochemical Industry

Abstract

Currently, more than 1,200 agrochemicals are listed and many of these are regularly used by farmers to generate the food supply to support the expanding global population. However, resistance to pesticides is an ever more frequently occurring phenomenon, and thus, a continuous supply of novel agrochemicals with high efficiency, selectivity, and low toxicity is required. Moreover, the demand for a more sustainable society, by reducing the risk chemicals pose to human health and by minimizing their environmental footprint, renders the development of novel agrochemicals an ever more challenging undertaking. In the last two decades, fluoro-chemicals have been associated with significant advances in the agrochemical development process. We herein analyze the contribution that organofluorine compounds make to the agrochemical industry. Our database covers 424 fluoro-agrochemicals and is subdivided into several categories including chemotypes, mode of action, heterocycles, and chirality. This in-depth analysis reveals the unique relationship between fluorine and agrochemicals.

Keywords: Agricultural Science; Chemistry; Industrial Chemistry; Organic Chemistry.

Graphical abstract

Figure 1

Early Examples of Synthetic Pesticides and Fluoro-pharmaceuticals (A) DDT. (B) DFDT. (C) Trifluralin. (D) Florinef acetate.

Figure 2

Contributions of Fluorine-Containing Compounds (A) To pharmaceuticals (1991–2019). (B) To agrochemicals (data based on the Pesticide Manual, 18th edition).

Figure 3

Prevalence of Fluoro/Non-fluoro-Agrochemicals Assigned New ISO Common Names (1998–2020 (June)) The list of all agrochemicals (238 compounds) including the fluoro-agrochemicals (127 compounds) is provided in Table S4. (A) Pie chart. (B) Bar chart depending on the year.

Figure 4

The 28 Fluoro-Agrochemicals Assigned New ISO Common Names in the last Five Years (2016-2020 (June))

Figure 5

Classification of Agrochemicals with New ISO Common Names (238 Compounds, 1998–2020 (June)) into Nine Categories: Fungicides, Herbicides, Insecticides, Acaricides, Nematicides, Plant Growth Regulators, Herbicide Safeners, Rodenticides, and Others (244 Entries) The names of all agrochemicals (238 compounds) with their agrochemical types is provided in Table S4.

Figure 6

Distribution of Chemotypes of Fluoro-Agrochemicals (424 Compounds, 541 Entries, 33 Groups)

Figure 7

Chemotype Distribution of Fluoro-Agrochemicals Focusing on the Number of Fluorine Atoms Present Per Functional Group (424 Compounds, 541 Entries, 8 Groups)

Figure 8

Classification of Fluoro-Agrochemicals by Agrochemical Type (A) For all fluoro-agrochemicals (424 compounds, 477 entries). (B) For fluoro-agrochemicals with more than six fluorine atoms in their structures (57 compounds, 72 entries).

Figure 9

Examples of Fluoro-Agrochemicals with More than Eight Fluorine Atoms in Their Structures

Figure 10

Distribution of Fluoro-Agrochemicals According to the “Rule of Five” (A) Molecular weight. (B) log P (calculated). (C) Clog P (calculated). Details are provided in Table S3.

Figure 11

HRAC Classification for Fluoro-Herbicides, including Herbicide Safeners and Plant-Growth Regulators (167 Compounds Selected) A: Inhibition of acetyl CoA carboxylase (ACCase); B: Inhibition of acetolactate synthase ALS (acetohydroxyacid synthase AHAS); C1,2,3: Inhibition of photosynthesis at photosystem II; D: Photosystem-I-electron diversion; E: Inhibition of protoporphyrinogen oxidase (PPO); F1: Inhibition of the phytoene desaturase (PDS); F2: Inhibition of 4-hydroxyphenyl-pyruvatedioxygenase (4-HPPD); F3: Inhibition of carotenoid biosynthesis (unknown target); F4: Inhibition of 1-deoxy-d-xylulose 5-phosphate synthase (DOXP synthase); G: Inhibition of EPSP synthase; H: Inhibition of glutamine synthetase; I: Inhibition of DHP (dihydropteroate) synthase; K1: Inhibition of microtubule assembly; K2: Inhibition of mitosis/microtubule organization: Inhibition of VLCFAs (inhibition of cell division); L: Inhibition of cell wall (cellulose) synthesis; M: Uncoupling (membrane disruption); (N): Inhibition of lipid synthesis—not ACCase inhibition; O: Action like indole acetic acid (synthetic auxins): P; Inhibition of auxin transport.

Figure 12

IRAC Classification for Fluoro-Insecticides, including Acaricides, and Molluscicides (102 Compounds Selected) Code 1: Acetylcholine esterase inhibitors (Nerve action); Code 2: GABA-gated chloride channel antagonists (Nerve action); Code 3: Sodium channel modulators (Nerve action); Code 4: Nicotinic acetylcholine receptor agonists (Nerve action); Code 5: Nicotinic acetylcholine receptor agonists (Nerve action) (Nicotinic acetylcholine receptor allosteric activators); Code 6: Chloride channel activators (Nerve and muscle action); Code 7: Juvenile hormone mimics (Growth regulation); Code 8: Miscellaneous non-specific (multi-site) inhibitors; Code 9: Selective Homopteran feeding blockers (Nerve action); Code 10: Mite growth inhibitors (Acaricides); Code 11: Microbial disrupters of insect midgut membranes (includes transgenic crops expressing Bacillus thuringiensis toxins); Code 12: Inhibitors of mitochondrial ATP synthase (energy metabolism); Code 13: Uncoupler of oxidative phosphorylation via disruption of the proton gradient (energy metabolism); Code 14: Nicotinic acetylcholine receptor channel blockers (nerve action); Code 15: Inhibitors of chitin biosynthesis, type 0, Lepidopteran (growth regulation); Code 16: Inhibitors of chitin biosynthesis, type 1, Homopteran (growth regulation); Code 17: Molting disruptor, Dipteran (growth regulation); Code 18: Ecdysone receptor agonists (growth regulation); Code 19: Octopamine agonists (nerve action); Code 20: Mitochondrial complex III electron transport inhibitors (coupling site II) (energy metabolism); Code 21: Mitochondrial complex I electron transport inhibitors (energy metabolism); Code 22: Voltage-dependent sodium channel blocker (nerve action); Code 23: Inhibitors of acetyl CoA carboxylase (lipid synthesis, growth regulation); Code 24: Mitochondrial complex IV electron transport inhibitors (energy metabolism); Code 25: Mitochondrial complex II electron transport inhibitors (energy metabolism); Code 28: Ryanodine receptor modulators (nerve and muscle action) (Ryanodine receptor [RyR] calcium channel disruptor); Code 29: Chordotonal Organ Modulators—undefined target site; Code 30: GABA-gated chloride channel allosteric modulators (nerve action).

Figure 13

FRAC Classification for Fluoro-Fungicides (61 Compounds Selected) A: Nucleic acids metabolism; B: Cytoskeleton and motor proteins; C: Respiration; D; Amino acids and protein synthesis; E: Signal transduction; F: Lipid synthesis or transport/membrane integrity or function; G: Sterol biosynthesis in membranes; H: Glucan synthesis; I: Melanin synthesis in cell wall; P: Host plant defense induction; M: Chemicals with multi-site activity; Others: Biologicals with multiple modes of action

Figure 14

Fluoro-Agrochemicals with/without Heterocycles (A) Distribution of fluoro-agrochemicals with (259 compounds) or without (165) heterocycles. (B) Distribution of heterocyclic moieties with (134 compounds) or without (125) fluoro-functional groups.

Figure 15

Diversity of Fluoro-Functional Groups Directly Attached to the Heterocyclic Cores of Fluoro-Agrochemicals

Figure 16

Fluralaner (Bravecto) (A) Structure of fluralaner. (B) Asymmetric synthesis of (S)-fluralaner using asymmetric organo-catalysis.

Figure 17

Fluoro-Agrochemicals with/without a Stereogenic Carbon Center (A) Distribution of fluoro-agrochemicals with (41 chiral compounds, 103 racemic compounds) or without (280) a stereogenic carbon center. (B) Distribution of fluoro-agrochemicals with fluorine or fluoro-functional groups directly connected to a stereogenic carbon center, which includes racemic compounds (14 compounds) and others (410 compounds).

Figure 18

Fluoro-Agrochemicals Having a Fluoro-Functionalized Stereogenic Carbon Center

Figure 19

Fluorine-Containing Inorganic Agrochemicals: Hexaflurate, Sodium Fluoride, Cryolite, Sodium Silicofluoride, and Barium Hexafluorosilicate

Figure 20

Persistent Organic Pollutants (POPs) Stockholm Convention Annex A: Parties must take measures to eliminate the production and use of the chemicals listed under Annex A. Annex B: Parties must take measures to restrict the production and use of the chemicals listed under Annex B in light of any applicable acceptable purposes and/or specific exemptions listed in the Annex. See the website of Stockholm Convention. (A) PFOA. (B) PFOSs. Fluorous agrochemicals such as LIPO, sulfluramid, and flursulamid belong to this group. (C) All POP agrochemicals according to the Stockholm Convention (2020, August).

Figure 21

The Distributions of Chemicals and Their Categories in the List of POPs Stockholm Convention The 35 POPs are expanded to 38 entries owing to the 3 duplications. Pesticides: 18; industrial chemicals: 13; unintentional productions: 7. See the full list in Table S11.