Discovered serendipitously in 1951, ferrocene features a sandwich-like structure with two parallel cyclopentadienyl (Cp) rings coordinated to a central Fe(II) ion. In the ferrocene structure, the Fe(II) ion acts as an "atomic ball-bearing" that enables the Cp rings to rotate freely in solution (Figure ). This allows ferrocene-based structures to dynamically change their conformation through thermal rotation with a low energy barrier of just 0.9 kcal mol -1 . The preferred conformation of ferrocene derivatives depends on various factors. In structures like 1,1′-disubstituted ferrocenes, the short distance between the Cp ring planes (3.3 Å) brings lateral substituents close together, facilitating supramolecular interactions such as hydrogen bonding and π-π interactions, which could favour the cis conformation. These interactions are generally weak, and external factors can induce controllable switching between cis and trans conformations (Figure ). For example, in ferrocene-conjugated dipeptides, the side chains formed a parallel β-sheet that shifted from cis to trans in aqueous media, a behaviour linked to hydration resulting in hydrogen bond rearrangement between the side chains (Figure ). Ferrocene is an important structural core in (bio-)organometallic chemistry because of its inherent stability, excellent redox properties, and low toxicity making it a versatile platform in various fields, including nanotechnology, catalysis and medicinal chemistry. The nontoxic and lipophilic nature makes ferrocene a particularly attractive motif, especially for incorporation in bioactive compounds. For instance, ferroquine (Figure ), now in phase II of clinical trials, is one of the most notable contributions of ferrocene to medicinal chemistry with remarkable antimalarial properties. Inspired by the peculiar molecular properties of ferrocene, we envisaged its potential applications into linkers for bifunctional molecules. We hypothesised that the ferrocene scaffold could enable controlled modulation of the conformational landscape, via "chameleonicity" as a strategy to fine-tune physicochemical properties, and we aimed to investigate and exemplify this concept with PROTACs (Figure ). Our goal in designing FerroTACs was to minimise the disruption from the newly introduced ferrocene moiety, by preserving approximately the same linker length and number of amide bonds as in the reference compounds whenever feasible. VHL-targeting homo-FerroTACs AS1 and cisAS1 (Figure ) were synthesised by incorporating ferrocene into the reference structures of CM11 and its non-degrading analogue CMP98, respectively. Given the evidence that a benzylic methylated VHL ligand (MeVH032) demonstrated a significant increase in binding affinity and proved a favourable modification as part of PROTACs, we , , , , also studied CM11`s benzyl-methylated analogue (MeCM11), resulting in the design of the VHL-targeting FerroTAC AS2. Building on MeVH032, we developed the CRBN-VHL-targeting hetero-PROTACs AS3 and AS4 (Figure ) from a ferrocene dicarboxylic precursor. Both structures incorporated linkers of varying lengths (i.e., alkyl C-3 and C-6 and PEG-3) on each side of the ferrocene motif. Furthermore, to reduce the number of hydrogen bond donors (HBD) and enhance the feasibility of asymmetrical chemical derivatisation, we employed an alternative strategy by introducing an alkyne as a chemical handle for click chemistry on the ferrocene building block resulting in the incorporation of a 1,2,3-triazole as amide bioisostere (Figure ). Using click chemistry, we synthesised 1,1-disubstituted ferrocenes with a triazole linkage for CRBN/VHL (AS5) and BET-targeting analogues containing JQ1: AS6, which incorporates a PEG-3 linker, and AS7, featuring a shorter C-3 alkyl linker on the JQ1 side (Figure ).