The unique role of halogen substituents in the design of modern agrochemicals

Abstract

The past 30 years have witnessed a period of significant expansion in the use of halogenated compounds in the field of agrochemical research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochemical with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, especially in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the number of commercial products containing 'mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochemicals throughout the twenty-first century. A number of these recently developed agrochemical candidates containing halogen substituents represent novel classes of chemical compounds with new modes of action. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compound, depending on its changed mode of action, physicochemical properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a molecule at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilisation of halogens and their unique role in the design of modern agrochemicals, exemplified by various commercial products from Bayer CropScience coming from different agrochemical areas.

α‐Fluoro‐o‐cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen‐Bond Acidity

“…The effects of fluorination on molecular properties are well established, and their use in compound property optimisation in many fields like material 1, 2 and medicinal chemistry, [3][4][5][6] as well as crystal engineering 7,8 and agrochemistry 9,10 benefit from this strong influence. After the debate about the effective ability of fluorine to act as a hydrogen-bond (H-bond, HB) acceptor, [11][12][13][14][15] the occurrence of intermolecular OHF H-bonding is now clearly established through experimental and theoretical evidences.…”

Uptake, Translocation, and Dose Response of Postemergence Applied Diclosulam to Bristly Starbur (Acanthospermum hispidum)

“…Diclosulam is a weak acid (pKa 5 4.09) (Senseman, 2007), and was anionic in charge for this experiment as the pH of the spray solution was 4.9. Upon application to the bristly starbur leaf surface, the anionic molecule was absorbed across the leaf cuticle via increased lipophilicity due to the halogens F and Cl on opposite ends of the diclosulam molecule (Jeschke, 2009). Once the diclosulam molecule entered the bristly starbur leaf cell, it was phloem translocated to the apical growing points.…”

Fluorination of pyrrole derivatives by Selectfluor™

“…[2][3][4][5][6] Consequently, fluorine-containing drugs are now prevalent within the life science industries and a considerable number of blockbuster pharmaceuticals and agrochemicals now contain at least one fluorine atom. [7][8][9] In particular, fluorinated azaheterocycles are very important subunits within life science products and a growing number of pharmaceuticals that contain fluoroheteroaromatic motifs such as Voriconazole (antifungal, Pfizer), Capecitabine (anticancer, Roche) and Diclosulam (herbicide, Dow) have now reached the commercial market [10][11][12] with many others in clinical trials such as Abemaciclib (anticancer, Eli Lilly), Riociguat (heart failure, Bayer) and Verubecestat (Alzheimers, Merck). 13 Notably, these pharmaceuticals all contain a fluorinated six-membered azaheterocycle, such as fluoro-pyridine or -pyrimidine structural sub-unit, and effective synthetic procedures at both discovery and manufacturing scales are well reported in the literature.…”