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The Mills Laboratory is tackling real-world synthetic problems with Earth-abundant transition metal catalysts

Key research objectives

Transition metal catalysis has enriched the toolbox of synthetic chemistry, particularly for pharmaceutical synthesis. Historically, transition metal catalysis has typically employed well-behaved second- and third-row transition metals. First-row transition metals, however, have emerged as an important area of catalyst study given their relatively greater abundance, lower cost, and unique reactivity that is often defined by single-electron behavior. While first-row transition metals offer diverse reactivity due to accessible oxidation and spin-states, their uptake is traditionally challenged due to their sometimes unpredictable nature. Our research seeks to address these challenges.

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Cross-coupling partners from abundant functionality

The most useful synthetic methods expand access to new chemical space.

In synthesis of organic molecules, the cross-coupling strategy catalyzed by transition metals represents the joining of nucleophilic and electrophilic coupling partners that would otherwise not react without the transition metal catalyst. We use a mechanism-driven approach to develop new catalysts to break bonds of abundant functionality, opening new strategies to use new substrates to increase possibilities for molecular synthesis.

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Selective C(sp3)–H activation for pharmaceutical derivatization

C–H functionalization reactions entail direct transformations of unfunctionalized molecules, providing a way to rapidly diversify organic compounds.

While nature has developed intricate enzymes for C(sp3)–H oxidation, state-of-the-art synthetic C(sp3)–H oxidation reactions often involve highly reactive free radical intermediates with unpredictable selectivity in molecules with many C(sp3)–H bonds. Inspired by nature, we develop modular C(sp3)–H functionalization catalysts based on naturally abundant Fe, Mn, and Cr to tackle selective derivatization of complex, pharmaceutically-relevant molecules.

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First-row organometallic catalysts and reagents

Earth-abundant, first-row transition metal complexes of Fe, Mn, and Co are defined by their ability to traverse oxidation states, offering opportunity to react with nucleophilic or electrophilic functionality depending on synthetic need.

While first-row transition metals are often taken for granted as commodity, “base” metals, for us, this abundance is an advantage that relates to low toxicity and low cost. Using techniques based on spectroscopy, crystallography, and kinetic investigation, we study the bond-forming and bond-breaking mechanisms of these versatile transition metals, to establish their reactivity rules and to aid the rational design of robust, efficient catalysts and organometallics.

Recent publications

  • Development of Persistent Cobalt(II)–Aryl Catalysts for C(sp2)–C(sp3) Cross-Coupling Involving Redox-Active Alkyl Electrophiles

    Development of Persistent Cobalt(II)–Aryl Catalysts for C(sp2)–C(sp3) Cross-Coupling Involving Redox-Active Alkyl Electrophiles

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    Kavita Choudhary, L. Reginald Mills

    Synlett 2026, eFirst, DOI: 10.1055/a-2877-3982

    Publication Abstract

    Cross-coupling of alkyl electrophiles by first row transition metal catalysts represents a productive approach of incorporating C(sp3) fragments into pharmaceutically relevant organic molecules. This Account highlights the development of cobalt-catalyzed Negishi C(sp2)–C(sp3) cross-coupling reactions of redox active electrophiles, particularly thiol-derived unactivated alkyl(pyridyl)sulfones. Informed by catalyst characterization and mechanistic investigation, this account proposes key principles of substrate and catalyst design, which may enable development of future methodologies and robust cobalt catalysts for medicinal and process chemistry applications.

  • Spin-State Dichotomy of On-Cycle Cobalt(II) Organometallics Informs Polar Cobalt(0/II) Versus Radical Cobalt(I/II/III) Cross-Coupling Mechanisms

    Spin-State Dichotomy of On-Cycle Cobalt(II) Organometallics Informs Polar Cobalt(0/II) Versus Radical Cobalt(I/II/III) Cross-Coupling Mechanisms

    5

    Kavita Choudhary, Bhaswati Paul, L. Reginald Mills

    Angew. Chem. Int. Ed. 2026, e6050863

    Publication Abstract

    A well-defined, single-component precatalyst N,N,N′,N′-tetramethylethylenediamine (TMEDA)cobalt(II) dibromide catalyzed Negishi arylation reactions of alkyl bromide, N-hydroxyphthalimide ester, and (hetero)aryl halide electrophiles, exhibiting both C(sp2)─C(sp2) and C(sp2)─C(sp3) bond-formation. Organometallic reactions of relevant weak field ligand cobalt(II) dihalide complexes with arylzinc reagents demonstrated monoarylation, yielding a series of isolable high spin (S = 3/2) cobalt(II)–monoaryl bromide compounds supported by TMEDA, 3,5-lutidine, or bis(oxazoline) (BOX) ligands. Relevant to C(sp2)–C(sp2) cross-coupling, cobalt(II)–monoaryl bromide complexes reacted with arylzinc nucleophiles to yield TMEDA-supported and bpy-supported low-spin (S = 1/2) cobalt(II)–diaryl complexes, which underwent reductive elimination in acetonitrile to provide direct evidence for cobalt(0/II) cycles. In C(sp2)─C(sp3) Negishi cross-coupling reactions, the isolated TMEDA-supported and BOX-supported cobalt(II)–monoaryl complexes were determined to be catalyst resting states by 1H and 19F NMR spectroscopies in acetonitrile-d3. Stoichiometric reactions demonstrated high spin (TMEDA)cobalt(II)–monoaryl to be competent for alkyl bromine atom abstraction and for alkyl radical capture, yielding C(sp2)─C(sp3) product by reductive elimination at (TMEDA)cobalt(III). These data demonstrated the versatile reactivity of high-spin (S = 3/2) cobalt(II)–monoaryl and low-spin cobalt(II)–diaryl (S = 1/2) complexes, engaging productive closed-shell cobalt(0/II) or open-shell cobalt(I/III) cross-coupling mechanisms depending on the aryl or alkyl electrophile substrate.

  • Crystallographic evidence of a trinuclear (salen)manganese(iv/iii/iv)–μ-oxo formed during catalytic C(sp3)–H oxidation reactions

    Crystallographic evidence of a trinuclear (salen)manganese(iv/iii/iv)–μ-oxo formed during catalytic C(sp3)–H oxidation reactions

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    Bhaswati Paul, Kusalvin Dabare, Joshua D. Bocarsly, and L. Reginald Mills

    Dalton Trans. 2026, 55, 845–853

    Publication Abstract

    The formation of manganese–oxo catalysts involved in C(sp3)–H bond oxidation was explored in the targeted synthesis of (salen/salophen)manganese complexes that varied axial ligand identity and varied oxidation state of the manganese center. Isolated compounds included dinuclear (salen/salophen)manganese(III)–μ-hydroxo and trinuclear (salen)manganese(IV/III/IV)–μ-oxo, the latter of which formed by oxidation with catalytically relevant oxidant iodosylbenzene. The X-ray structure of trinuclear complex (salen)manganese(IV/III/IV)–μ-oxo indicated a Mn(IV)–O–Mn(III)–O–Mn(IV) motif, with nearly linear Mn–O–Mn angles of 166.19(12)° and 172.47(15)°, Mn(IV)–O bond lengths of 1.948(2) and 1.998(2) Å, and Mn(III)–O bond lengths of 2.102(2) and 2.118(2) Å. All well-defined (salen/salophen)manganese hydroxo and oxo compounds served as precatalysts for oxidation of C(sp3)–H substrates 9,10-dihydroanthracene (>99% conversion), fluorene (52–70% conversion), and phenylcyclohexane (with lower 18–23% conversion), albeit with lower rate of activity for the isolated trinuclear μ-oxo compound, allowing its assignment as an off-cycle catalyst aggregate. These data supported the proposal of a manganese(III/V) cycle for C(sp3)–H oxidation, which involved monomerization of the dinuclear (salen)manganese(III)-μ-hydroxo catalyst prior to rate-determining C(sp3)–H activation.

All Publications
Mills Lab team, Feb 2026

Our team

The Mills Lab is led by Principal Investigator, Reginald Mills. We are currently building out our team and are actively recruiting exceptional scholars at all levels. Please see below for application requirements for your particular level.

Postdoctoral scholars

Postdoctoral applicants should send their application by email to Reggie at lrmills2@uh.edu. Applications should include a cover letter, CV, contact information for two references, and a one-page summary of prior research.

Graduate students

Prospective students must first be admitted to the Department of Chemistry Graduate Studies at the University of Houston. Potential applicants should feel free to reach out to Reggie by email at lrmills2@uh.edu to learn more.

Undergraduate students

Current University of Houston undergraduate students interested in conducting research during the semester or over the summer should reach out to Reggie by email at lrmills2@uh.edu to learn more.

Team Members
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Our research is devoted to the use of Earth-abundant, first-row transition metals as a platform for synthesis, catalysis, and the fundamental understanding of organic and inorganic reactivity.

Projects in the Mills Lab include cross-coupling of abundant feedstock chemicals, synthesis of new catalysts for C–H activation, and development of aromatic chelates for small molecule sensing.

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