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

Insight into Arylboronate Transmetalation Enables Pentacarbonylmanganese(I)-Mediated Carbonylative Amination of Arylboronic Acids

10

Jia-Chun Lee, L. Reginald Mills

Submitted

October 29, 2026

Publication Abstract

In situ formation of arylboronate nucleophiles from suitable arylboronic acid, sodium methoxide, and triisopropyl borate allowed aryl transmetalation at pentacarbonylmanganese(I) bromide, yielding pentacarbonylmanganese(I)–aryl compounds. Employing 4-fluorophenylboronic acid, kinetic studies by ¹⁹F NMR spectroscopy indicated rate-limiting arylboron transmetalation at cationic manganese(I), informing the mechanism of productive arylboronic acid functionalization involving nucleophilic arylboronates. In a one-pot protocol, arylboronic acids, pentacarbonylmanganese(I) bromide, and amines reacted in a three-component carbonylative coupling, enabling modular amide synthesis tolerant of aldehyde, nitrile, and aryl bromide functionality.
Cross-Selective Alkyl–Alkyl Negishi Coupling at Isolable, High-Spin (S = 3/2) Cobalt(II)–Alkyl Catalysts

9

Kavita Choudhary, Bhaswati Paul, Khanh Truong Chau, L. Reginald Mills

Submitted

October 29, 2026

Publication Abstract

A high-spin (S = 3/2) cobalt(II)–dialkyl complex supported by weak-field ligand N,N,N’,N’-tetramethylethylenediamine (TMEDA) served as precatalyst for alkyl–alkyl Negishi cross-coupling of alkyl bromide electrophiles. Organometallic studies indicated isolability of cross-coupling resting state (TMEDA)cobalt(II)–monoalkyl bromide complex, which was resistant against deleterious β-hydride elimination due to high-spin (S = 3/2) electronic configuration disfavoring β-agostic H-to-Co interactions. During catalytic cross-coupling, kinetic studies indicated rate-determining formation of cobalt(II)–dialkyl, which was kinetically competent for bromine atom abstraction of bromocyclohexane to (re)initiate alkyl radical formation. The combined catalytic and organometallic studies evidenced a radical chain mechanism for alkyl–alkyl cross-coupling, which engages productive alkyl radical capture at stable at (TMEDA)cobalt(II)–monoalkyl bromide and subsequent bond-forming reductive elimination. The competent (TMEDA)cobalt(II) dibromide precatalyst enabled alkyl–alkyl Negishi cross-coupling reactions of a variety of substrates, including tertiary 1-adamantyl bromides and secondary dialkylzinc reagents, demonstrating that the open-shell character of high-spin cobalt(II)–alkyl catalysts promotes successful, cross-selective alkyl–alkyl radical coupling.
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, 16, 15, 15420–15433

July 23, 2026

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.

All Publications

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

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.

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