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. Author manuscript; available in PMC: 2025 Oct 7.
Published before final editing as: Trends Chem. 2025 Oct 2:10.1016/j.trechm.2025.09.006. doi: 10.1016/j.trechm.2025.09.006

Transition Metal Catalysis Drives Innovative Activity-Based Sensing Systems

Autumn I Giger 1,2, Ramandeep Kaur 1,2, Nicholas J Dacon 1,2, Brian W Michel 1,*
PMCID: PMC12498564  NIHMSID: NIHMS2111996  PMID: 41059046

Abstract

Through mechanistic understanding, transition metal catalysis has evolved into a key component of organic chemists’ toolbox. Improvements in ligand design continue to push the boundaries of applications beyond targeted synthesis. This forum contextualizes how mechanistic insight has influenced recent developments in transition metal-based molecular sensing.

The modern synthetic chemist has a variety of transition metal-catalyzed transformations that enable conversion of relatively inert functional groups under mild conditions. Many of these transformations have been enabled by mechanistic studies focused on improving catalyst selectivity and stability. Recently, researchers have adapted these findings to develop innovative molecular sensing tools for the detection of biologically relevant small molecules such as carbon monoxide, formate, and ethylene.

Molecular sensing strategies can be broadly categorized as coordination-based, where sensing occurs by the analyte binding with a recognition element, or activity-based, where binding is followed by a chemical transformation to induce signal transduction. Although both strategies offer distinct advantages, activity-based sensors (ABS) can provide enhanced molecular selectivity by virtue of kinetic constraints of the chemical transformation.[1] A promising subset of ABS integrate signal transduction with transition metal-mediated transformations for detection of analytes that would be challenging to detect with main group chemistry. This Forum article highlights the connections between mechanistic insights from catalyst design and the development of transition metal ABS.

Sensing One Carbon Metabolites

Due to limited inherent reactivity, carbon monoxide (CO) is a prototypical analyte for necessitating transition metal-mediated detection. In 2012, Michel, Lippert, and Chang reported a profluorescent CO Probe (COP-1, Figure 1A),[2] which is based on a cyclopalladated complex reminiscent of important precatalysts for Pd(0) and C–H activation adducts.[3] Fluorescence of the boron-dipyrromethene (BODIPY) is quenched in the palladated complex. Upon binding CO, Pd mediates carbonylation, which releases Pd(0) and results in a large increase in fluorophore quantum yield. The dual purpose served by palladium here, modulating fluorescence and mediating reaction with the analyte, is a common theme in transition metal-based ABS.

Figure 1.

Figure 1.

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Examples of transition metal-catalysis inspired strategies for activity-based sensing (ABS) of small molecules: (A) Cyclopalladated ABS for CO[2]; (B) An Ir-mediated ABS system for formate[4]; (C) Wacker oxidation ABS for ethylene[7]; and (D) A cyclorhodinated ABS for ethylene[10].

Similar to CO, formate is another interesting one-carbon metabolite with significant transition metal-mediated activity. Formate is regularly used as a reductive hydride source in transition metal-catalyzed transfer hydrogenations. Inspired by this, Chang and coworkers evaluated a range of Ru, Os, and Ir complexes for their ability to mediate the reduction of aldehyde containing fluorophores (Figure 1B).[4] A sulfonamide amine tethered iridium complex demonstrated selectivity for formate over NADH, proposed to arise from an unfavorable steric interaction with NADH. Notably, related organoiridium complexes demonstrated transfer hydrogenation on fluorogenic BODIPY substrates in the presence of endogenous NADPH.[5]

Ethylene Sensing – A Century in the Making

Despite its small size and minimal functionality, ethylene performs critical hormone signaling in plants and represents a biomarker of oxidative stress in mammalian systems. Due to lack of mild main group chemistry, it is not surprising that ethylene is detected in plants by copper containing proteins. Likewise, transition metals have been integral in the molecular detection of ethylene and the field is dominated by well-studied systems with long histories of industrial and synthetic applications.[6]

Classically, the Wacker oxidation utilizes palladium to catalytically oxidize olefins into carbonyls under aerobic conditions. In 2020, Swager and coworkers developed a chemiresistive sensor for detecting ethylene via Wacker oxidation (Figure 1C).[7] Electron rich Pd(0) generated upon ethylene oxidation acts as an n-dopant to modulate the electronic properties of single-walled carbon nanotubes (SWCNTs). Inspired by an aldehyde selective system reported by Grubbs and coworkers,[8] a nitrite cocatalyst system was found to provide greater signal generation as compared to traditional Cu-cocatalysts. Although ethylene oxidation mediated by Pd(II) has been known for more than 100 years, it is remarkable that a mechanistically driven variant reported in 2013 was key to the development of this sensitive ABS system.

In 2011 Guimond, Gorelsky, and Fagnou reported a Rh-catalyzed C–H activation-annulation system that utilized a sacrificial N–O bond to oxidize Rh following reductive elimination, thereby negating the need for external oxidants.[9] Inspired by this and continued efforts by others, in 2021 Ye and coworkers employed an isolated Rh(III) complex, effectively a C–H activation adduct derived from a fluorescent coumarin, for ethylene detection (Figure 1D).[10] The presence of Rh yields a quenched ABS, which upon exposure to ethylene in the presence of alcohol as a co-solvent provides a fluorescent response.

Olefin Metathesis – Mechanism Driven Sensing

Owing to decades of mechanistic insight and iterative improvements, Ru-mediated olefin metathesis is a versatile and robust transformation. The substitution of both phosphine ligands present in early well-defined metathesis complexes (e.g. G1) is a prime example of mechanism-based catalyst improvements (Figure 2A). In the Grubbs 2nd generation complex G2, N-heterocyclic carbenes (NHCs) provide greater σ-donating character and steric bulk, resulting in higher initiation rates. The serendipitous isolation of an isopropyl ether chelated complex facilitated the development of phosphine free complexes (e.g. HG2), thereby eliminating catalyst inhibition and phosphine mediated decomposition pathways. These primary improvements to the ligand environment remain viable a quarter-century later due to good oxygen and moisture tolerance.

Figure 2.

Figure 2.

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(A) Initial trends in olefin metathesis complexes; (B) BEPs reactivity with ethylene[11]; (C); RCM triggered ROMP with Ru-S-I[12]; (D) Ethylene autocatalysis enables ADE[13].

The robust nature of HG2 and its proclivity for rapid reaction with small electron rich olefins made it an obvious framework for our first BODIPY Ethylene Probes (BEPs) (Figure 2B).[11] Here the fluorophore was appended to the isopropoxy benzylidene ligand. Fluorescence is significantly quenched upon metalation with Ru, which also provides the ethylene recognition element. Ethylene coordinates and undergoes a metathesis reaction, which cleaves Ru from the fluorophore, inducing a significant increase in fluorescence. Interestingly, BEP-5 achieves a greater response per unit time than BEP-4 despite lower overall turn-on. This highlights a correlation between sensitivity and catalyst initiation rates. Such features are commonly considered in catalyst optimization studies and are likely transferable to other related sensing methods.

The identity of the anionic halogen ligands has been evaluated for Ru-metathesis catalysts and in most cases has not inspired extensive follow-up. However, some noteworthy exceptions arise from the increased steric bulk provided by iodide,[14] and fortunately these interesting observations did not escape prepared minds. For the catalyst systems described below, researchers considered the mechanistic implications, designed probing experiments, and more importantly, reported their findings.

Lemcoff and coworkers have demonstrated remarkable latency for sulfur chelated complexes with both photo and thermal initiation. When an iodide complex (Ru-S-I) was evaluated, surprisingly unique reactivity was observed (Figure 2C).[12] In RCM reactions, terminal olefins such as diethyldiallylmalonate (DEDAM) underwent efficient cyclization. In direct contrast, more reactive ROMP substrates such as cyclooctene (COE) and dicyclopentadiene (DCPD) were completely inert. Interestingly, when DEDAM was present in equimolar amounts, highly efficient COE conversion was observed. It reasons that the bulky iodides block access of the disubstituted alkene to the Ru-alkylidene metal center. However, initial RCM of DEDAM provides the less encumbered Ru=CH2, which is capable of reacting with COE.

Another notable example that demonstrates reactivity attributable to the X-ligands, Skowerski and coworkers explored iodide complexes to improve catalyst stability.[15] Diiodo catalysts demonstrated an induction period with slow initial reaction velocity followed by rapid substrate consumption. Further, high substrate conversion suggests greater stability of the Ru=CH2 species. In experiments to better understand the delayed onset of substrate conversion, an atmosphere of ethylene ablated the induction period observed for the iodide complexes.

Although the Lemcoff and Skowerski teams were not evaluating catalyst modifications in search of sensing systems, their reports inspired us to evaluate Ru-iodide complexes in the context of Amplificative Detection of Ethylene (ADE).[13] Specifically, we sought partial activation of the precatalyst pool at low ethylene concentrations. Modifying Skowerski’s experiments, varied amounts of injected ethylene demonstrated a dose-dependent attenuation of the induction period (Figure 4D). Here RCM provides product and regenerates ethylene as a byproduct, amplifying sub-stoichiometric ethylene via catalyst turnover and analyte feedback. This combined with the use of profluorescent substrates facilitated signal transduction. The autocatalytic nature of ADE improved sensitivity by an order of magnitude compared to stoichiometric systems, with utility demonstrated in the detection of ethylene from biologically relevant samples.

Concluding Remarks

Significant impact is achieved when studies and experiments contribute beyond the borders of one’s own subfield. We find this particularly evident in the translation of transition metal catalysis to small molecule detection. The catalyst-inspired sensing systems described above are not possible without the thorough reports that motivated them.

Of course this extends beyond molecular sensing, and we should continue to emphasize strong fundamental understanding to push interdisciplinary boundaries. Considering olefin metathesis again as an example, the plethora of diverse catalysts with finely tuned properties has enabled innovative applications across chemistry disciplines. We hope this forum inspires chemists to conduct and report curiosity driven experiments, as it only takes a spark of inspiration to light the fire of innovation.

Acknowledgement

This work was supported by the NIGMS National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM150937 and the USDA National Institute of Food and Agriculture, AFRI project award no. 2023-67018-39467.

Footnotes

Conflict of Interest

The authors declare the following competing financial interest(s): The University of Denver has submitted U.S. Provisional Patent Application Serial # 63/683,597, which covers various aspects of the amplificative ethylene detection technology discussed in this manuscript. This pending application names Brian Michel, Brady Worrell, Autumn Giger, and Jaiden Voldrich as inventors.

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