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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

  • Thermal Bimolecular Homodimerization Initiates Nickel(I) Catalysis from 2,6-Aryl-Unsubstituted Bipyridyl Nickel(II) Oxidative Addition Complexes

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    Bhaswati Paul, L. Reginald Mills

    ACS Catal. 2026, Articles ASAP. DOI: 10.1021/acscatal.6c05021

    Publication Abstract

    A procedure for the general synthesis of nickel(II)–aryl bromide oxidative addition complexes without aryl substitution at the 2,6-positions was achieved by inverse addition of the requisite bipyridyl nickel(0)–1,5-cyclooctadiene (COD) complex to the aryl bromide, yielding 2,2’-bipyridyl (bpy) and 4,4’-di-tert-butyl-2,2’-bipyridyl (dtbbpy) supported nickel(II)–aryl bromide compounds in 38–93% yield. During reductive C(sp2)–C(sp3) cross-electrophile cross-coupling in DMA at 60 °C, UV-vis absorbance spectroscopy determined (dtbbpy)nickel(II)–aryl bromide complexes to be the predominant catalyst resting states. The observed catalyst resting states were implicated in forming the organic products of C(sp2)–C(sp3) cross-coupling and of C(sp2)–C(sp2) homocoupling, homocoupling of which was more predominant with electron-donating aryl substituents. Dissolution of (dtbbpy)nickel(II)–aryl bromide compounds in 0.5 mM DMA in the absence of excess aryl bromide established decay of the compounds within minutes to form aryl homodimer and dimeric (dtbbpy)nickel(I) bromide as the exclusive products, in which compounds with the fastest rates of decay were those bearing electron-donating substituents (OMe, t-Bu), correlated with more nucleophilic character of the aryl and weaker Ni–Aryl bond strength. Determination of concentration-dependence for homodimerization of (dtbbpy)NiBr(4-F-C6H4) and (bpy)NiBr(4-F-C6H4) compounds measured by UV-visible absorbance spectroscopy exhibited 1.5-order and 1.3-order dependence, respectively, rationalized as exhibiting concurrent bimolecular and unimolecular mechanisms, namely bimolecular transmetalation/reductive elimination, and unimolecular autoreduction, the latter of which was informed by rapid comproportionation of nickel(II)–aryl with nickel(0) yielding nickel(I)–aryl intermediates detected by X-band EPR spectroscopy at 77 K. These studies informed kinetically relevant aryl homodimerization as the predominant mechanism for low-valent nickel formation, initiating the nickel(I/II/III) alkyl radical chain mechanism by homogeneous turnover of the (dtbbpy)nickel(II)–aryl bromide catalyst.

  • Bisphosphine–Cobalt(II)-Catalyzed C(sp2)–O Bond Activation in Kumada Arylation of Heteroaryl Ethers

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    Khanh Truong Chau, L. Reginald Mills

    J. Org. Chem. 2026, Articles ASAP. DOI: 10.1021/acs.joc.6c01325

    Publication Abstract

    Synthesized from benzothiazolones, 2-alkoxy benzothiazoles served as competent C(sp2)–O electrophiles in (bisphos-phine)cobalt(II)-catalyzed Kumada arylation, forming 2-arylbenzothiazole products. Employing catalytic (5 mol%) bis(diphenylphosphino)propane (dppp)–cobalt(II) dibromide precatalyst, the Kumada arylation of heteroaryl ethers was gen-eral towards 2-alkoxybenzoxazole, 2-alkoxyquinoline, and 2-alkoxythiazole substrates (17–65% yield). Investigation of cata-lytically relevant precatalysts indicated kinetic incompetence of cobalt(I) and cobalt(0) complexes, supporting proposal of a redox-neutral cobalt(II)-catalyzed reaction involving rate-determining heteroaryl ether substitution.

  • 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.

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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