Unique fluoroalkyl substituents: is there life after CF₃?

Over the past few decades, the trifluoromethyl group (CF₃) has become one of the most prevalent in applied chemistry, frequently appearing in approved drugs and even more commonly in agrochemicals. However, this widespread use has led to the accumulation of trifluoroacetic acid (TFA) in the environment as a byproduct of metabolic and environmental degradation, prompting legislative actions to restrict certain chemicals and even entire compound classes of so-called "forever chemicals". Hence, this has created a growing demand for alternative motifs that retain the beneficial molecular properties of the trifluoromethyl group but avoid forming trifluoroacetate during degradation. This review summarizes the current state of the application of trifluoromethyl-free, partially fluorinated fluoroalkyl groups in the development of drugs and agrochemicals. We focus on nine moieties that have shown presence in already approved and investigational structures. We also present data on fifteen innovative fragments promising for current and future research. We believe this guide will be valuable for industrial and academic researchers seeking sustainable and ecologically responsible solutions for biomolecular engineering, especially in applications that create risks of environmental pollution.