About

Kenneth D. Karlin is the Ira Remsen Professor of Chemistry at Johns Hopkins University and has served as the department Chair. He earned his B.S. from Stanford University in 1970 and his Ph.D. from Columbia University in 1975. Following a N.A.T.O. postdoctoral fellowship at Cambridge University, he began his academic career as an Assistant Professor of Chemistry at SUNY Albany in 1977. He joined Johns Hopkins University as a professor in 1990. Dr. Karlin's research focuses on bioinorganic chemistry, particularly coordination chemistry relevant to biological and environmental processes involving copper and heme (porphyrin-iron) complexes. His work investigates the chemistry of these metal complexes with molecular oxygen, nitrogen oxides, and pollutants, aiming to understand their reactivity, structure, and mechanisms. His research includes synthetic modeling of enzyme active sites, spectroscopic and structural characterization, and mechanistic studies of oxygen-binding, reduction, and oxidation processes. Dr. Karlin has made notable contributions to understanding reversible copper-dioxygen interactions, models for heme-copper oxidases, and the development of biomimetic catalysts for oxidation and pollutant reduction. He is the Editor-in-Chief of Progress in Inorganic Chemistry, has held advisory roles with prominent chemical societies, and has received awards including the 2009 F. Albert Cotton Award in Synthetic Inorganic Chemistry. His work advances the understanding of metalloprotein active sites and the development of practical catalytic systems.

Research topics

• Stereochemistry
• Chemistry
• Photochemistry
• Organic chemistry
• Inorganic chemistry
• Medicinal chemistry
• Physical chemistry

Selected publications

• Experimental electronic structures of the Fe ^IV =O bond in S=1 heme vs. nonheme sites: Effect of the porphyrin ligand

  Proceedings of the National Academy of Sciences · 2025-02-21 · 6 citations

  articleOpen access

  High-valent Fe IV =O species are common intermediates in biological and artificial catalysts. Heme and nonheme S=1 Fe IV =O sites have been synthesized and studied for decades but little quantitative experimental comparison of their electronic structures has been available, due to the lack of direct methods focused on the iron. This study allows a rigorous determination of the electronic structure of a nonheme Fe IV =O center and its comparison to an Fe IV =O heme site using 1s2p resonant inelastic X-ray scattering (RIXS) and Fe L-edge X-ray absorption spectroscopy (XAS). Further, variable temperature magnetic circular dichroism (VT-MCD) of the ligand field transitions, combined with nuclear resonance vibrational spectroscopy of the two S=1 Fe IV =O systems show that the equatorial ligand field decreases from a nonheme to a heme Fe IV =O site. Alternatively, RIXS and Fe L-edge XAS combined with MCD show that the Fe d π orbitals are unperturbed in the Fe IV =O heme relative to the nonheme site because the strong axial Fe-O bond uncouples the Fe d π orbitals from the porphyrin π -system. As a consequence, the thermodynamics and kinetics of the H-atom abstraction reactions are actually very similar for heme compound II and nonheme Fe IV =O active sites.

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• Reactivity of a heterobinuclear heme–peroxo–Cu complex with <i>para</i>-substituted catechols shows a p<i>K</i>_a-dependent change in mechanism

  Chemical Science · 2024-12-30

  articleOpen accessSenior authorCorresponding

  Reactions of para -R-catechols with a cytochrome c oxidase synthetic model compound, a heme-peroxo-copper species, are p K a -dependent, suggesting O–O bond homolysis occurs via a hydrogen-bond assisted stepwise proton/electron transfer pathway.

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• Dioxygenase Chemistry in Nucleophilic Aldehyde Deformylations Utilizing Dicopper O₂-Derived Peroxide Complexes

  Journal of the American Chemical Society · 2024-08-14 · 10 citations

  articleOpen accessSenior authorCorresponding

  The chemistry of copper-dioxygen complexes is relevant to copper enzymes in biology as well as in (ligand)Cu–O2 (or Cu2–O2) species utilized in oxidative transformations. For overall energy considerations, as applicable in chemical synthesis, it is beneficial to have an appropriate atom economy; both O-atoms of O2(g) are transferred to the product(s). However, examples of such dioxygenase-type chemistry are extremely rare or not well documented. Herein, we report on nucleophilic oxidative aldehyde deformylation reactivity by the peroxo-dicopper(II) species [Cu2II(BPMPO–)(O22–)]1+ {BPMPO-H = 2,6-bis{[(bis(2-pyridylmethyl)amino]methyl}-4-methylphenol)} and [Cu2II(XYLO–)(O22–)]1+ (XYLO– = a BPMPO– analogue possessing bis(2-{2-pyridyl}ethyl)amine chelating arms). Their dicopper(I) precursors are dioxygenase catalysts. The O2(g)-derived peroxo-dicopper(II) intermediates react rapidly with aldehydes like 2-phenylpropionaldehyde (2-PPA) and cyclohexanecarboxaldehyde (CCA) in 2-methyltetrahydrofuran at −90 °C. Warming to room temperature (RT) followed by workup results in good yields of formate (HC(O)O–) along with ketones (acetophenone or cyclohexanone). Mechanistic investigation shows that [Cu2II(BPMPO–)(O22–)]1+ species initially reacts reversibly with the aldehydes to form detectable dicopper(II) peroxyhemiacetal intermediates, for which optical titrations provide the Keq (at −90 °C) of 73.6 × 102 M–1 (2-PPA) and 10.4 × 102 M–1 (CCA). In the reaction of [Cu2II(XYLO–)(O22–)]1+ with 2-PPA, product complexes characterized by single-crystal X-ray crystallography are the anticipated dicopper(I) complex, [Cu2I(XYLO–)]1+ plus a mixed-valent Cu(I)Cu(II)-formate species. Formate was further identified and confirmed by 1H NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS) analysis. Using 18O2(g)-isotope labeling the reaction produced a high yield of 18-O incorporated acetophenone as well as formate. The overall results signify that true dioxygenase reactions have occurred, supported by a thorough mechanistic investigation.

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• Coordination Variations within Binuclear Copper Dioxygen-Derived (Hydro)Peroxo and Superoxo Species; Influences upon Thermodynamic and Electronic Properties

  Journal of the American Chemical Society · 2024-04-30 · 15 citations

  articleOpen accessSenior authorCorresponding

  Copper ion is a versatile and ubiquitous facilitator of redox chemical and biochemical processes. These include the binding of molecular oxygen to copper(I) complexes where it undergoes stepwise reduction-protonation. A detailed understanding of thermodynamic relationships between such reduced/protonated states is key to elucidate the fundamentals of the chemical/biochemical processes involved. The dicopper(I) complex [CuI2(BPMPO–)]1+ {BPMPOH = 2,6-bis{[(bis(2-pyridylmethyl)amino]methyl}-4-methylphenol)} undergoes cryogenic dioxygen addition; further manipulations in 2-methyltetrahydrofuran generate dicopper(II) peroxo [CuII2(BPMPO–)(O22–)]1+, hydroperoxo [CuII2(BPMPO–)(−OOH)]2+, and superoxo [CuII2(BPMPO–)(O2•–)]2+ species, characterized by UV–vis, resonance Raman and electron paramagnetic resonance (EPR) spectroscopies, and cold spray ionization mass spectrometry. An unexpected EPR spectrum for [CuII2(BPMPO–)(O2•–)]2+ is explained by the analysis of its exchange-coupled three-spin frustrated system and DFT calculations. A redox equilibrium, [CuII2(BPMPO–)(O22–)]1+ ⇄ [CuII2(BPMPO–)(O2•–)]2+, is established utilizing Me8Fc+/Cr(η6-C6H6)2, allowing for [CuII2(BPMPO–)(O2•–)]2+/[CuII2(BPMPO–)(O22–)]1+ reduction potential calculation, E°′ = −0.44 ± 0.01 V vs Fc+/0, also confirmed by cryoelectrochemical measurements (E°′ = −0.40 ± 0.01 V). 2,6-Lutidinium triflate addition to [CuII2(BPMPO–)(O22–)]1+ produces [CuII2(BPMPO–)(−OOH)]2+; using a phosphazene base, an acid–base equilibrium was achieved, pKa = 22.3 ± 0.7 for [CuII2(BPMPO–)(−OOH)]2+. The BDFEOO–H = 80.3 ± 1.2 kcal/mol, as calculated for [CuII2(BPMPO–)(−OOH)]2+; this is further substantiated by H atom abstraction from O–H substrates by [CuII2(BPMPO–)(O2•–)]2+ forming [CuII2(BPMPO–)(−OOH)]2+. In comparison to known analogues, the thermodynamic and spectroscopic properties of [CuII2(BPMPO–)] O2-derived adducts can be accounted for based on chelate ring size variations built into the BPMPO– framework and the resulting enhanced CuII-ion Lewis acidity.

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• Intramolecular Phenolic H-Atom Abstraction by a N₃ArOH Ligand-Supported (μ-η²:η²-Peroxo)dicopper(II) Species Relevant to the Active Site Function of oxy-Tyrosinase

  Journal of the American Chemical Society · 2024-05-22 · 6 citations

  articleOpen accessSenior authorCorresponding

  Synthetic side-on peroxide-bound dicopper(II) (SP) complexes are important for understanding the active site structure/function of many copper-containing enzymes. This work highlights the formation of new {CuII(μ-η2:η2-O22–)CuII} complexes (with electronic absorption and resonance Raman (rR) spectroscopic characterization) using tripodal N3ArOH ligands at −135 °C, which spontaneously participate in intramolecular phenolic H-atom abstraction (HAA). This results in the generation of bis(phenoxyl radical)bis(μ-OH)dicopper(II) intermediates, substantiated by their EPR/UV–vis/rR spectroscopic signatures and crystal structural determination of a diphenoquinone dicopper(I) complex derived from ligand para-C═C coupling. The newly observed chemistry in these ligand–Cu systems is discussed with respect to (a) our Cu-MeAN (tridentate N,N,N′,N′,N″-pentamethyldipropylenetriamine)-derived model SP species, which was unreactive toward exogenous monophenol addition (J. Am. Chem. Soc. 2012, 134, 8513–8524), emphasizing the impact of intramolecularly tethered ArOH groups, and (b) recent advances in understanding the mechanism of action of the tyrosinase (Ty) enzyme.

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• Synthetic Copper-(Di)oxygen Complex Generation and Reactivity Relevant to Copper Protein O&lt;sub&gt;2&lt;/sub&gt;-Processing

  Bulletin of Japan Society of Coordination Chemistry · 2024-06-20

  articleOpen access1st authorCorresponding

  Synthetic copper-dioxygen complex design, generation and characterization, play a crucial role in elucidating the structure/function of copper-based metalloenzymes, including dopamine β-monooxygenase, lytic polysaccharide monooxygenases, particulate methane monooxygenase, tyrosinase, hemocyanin, and catechol oxidase. Designing suitable ligands to closely mimic the variable active sites found in these enzymes poses a challenging task for synthetic bioinorganic chemists. In this review, we have highlighted a few representative ligand systems capable of stabilizing various copper-dioxygen species such as CuII-(O2•-)(superoxide), Cu2II-(μ-η1:η1-O22-) (trans/cis-peroxide), Cu2II-(μ-η2:η2-O22-) (side-on peroxide) and CunII-–OOH (hydroperoxide)species. Here, we discuss the ligand type utilized, syntheses, and spectroscopic characterization of these species. We also delineate reactivity patterns, particularly electrophilic arene hydroxylation by a side-on peroxo species which occurs via a “NIH shift” mechanism and thermodynamic-kinetic relationships among Cu2-(O2•-)/O22-/ -OOH moieties.

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• Reductive Coupling of Nitric Oxide by Cu(I): Stepwise Formation of Mono- and Dinitrosyl Species <i>En Route</i> to a Cupric Hyponitrite Intermediate

  Journal of the American Chemical Society · 2023-01-18 · 14 citations

  articleOpen accessSenior authorCorresponding

  Transition-metal-mediated reductive coupling of nitric oxide (NO(g)) to nitrous oxide (N2O(g)) has significance across the fields of industrial chemistry, biochemistry, medicine, and environmental health. Herein, we elucidate a density functional theory (DFT)-supplemented mechanism of NO(g) reductive coupling at a copper-ion center, [(tmpa)CuI(MeCN)]+ (1) {tmpa = tris(2-pyridylmethyl)amine}. At −110 °C in EtOH (<−90 °C in MeOH), exposing 1 to NO(g) leads to a new binuclear hyponitrite intermediate [{(tmpa)CuII}2(μ-N2O22–)]2+ (2), exhibiting temperature-dependent irreversible isomerization to the previously characterized κ2-O,O′-trans-[(tmpa)2Cu2II(μ-N2O22–)]2+ (OOXray) complex. Complementary stopped-flow kinetic analysis of the reaction in MeOH reveals an initial mononitrosyl species [(tmpa)Cu(NO)]+ (1-(NO)) that binds a second NO molecule, forming a dinitrosyl species [(tmpa)CuII(NO)2] (1-(NO)2). The decay of 1-(NO)2 requires an available starting complex 1 to form a dicopper-dinitrosyl species hypothesized to be [{(tmpa)Cu}2(μ-NO)2]2+ (D) bearing a diamond-core motif, en route to the formation of hyponitrite intermediate 2. In contrast, exposing 1 to NO(g) in 2-MeTHF/THF (v/v 4:1) at <−80 °C leads to the newly observed transient metastable dinitrosyl species [(tmpa)CuII(NO)2] (1-(NO)2) prior to its disproportionation-mediated transformation to the nitrite product [(tmpa)CuII(NO2)]+. Our study furnishes a near-complete profile of NO(g) activation at a reduced Cu site with tripodal tetradentate ligation in two distinctly different solvents, aided by detailed spectroscopic characterization of metastable intermediates, including resonance Raman characterization of the new dinitrosyl and hyponitrite species detected.

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• Fenton-like Chemistry by a Copper(I) Complex and H₂O₂ Relevant to Enzyme Peroxygenase C–H Hydroxylation

  Journal of the American Chemical Society · 2023-05-17 · 57 citations

  articleOpen accessSenior authorCorresponding

  Lytic polysaccharide monooxygenases have received significant attention as catalytic convertors of biomass to biofuel. Recent studies suggest that its peroxygenase activity (i.e., using H2O2 as an oxidant) is more important than its monooxygenase functionality. Here, we describe new insights into peroxygenase activity, with a copper(I) complex reacting with H2O2 leading to site-specific ligand–substrate C–H hydroxylation. [CuI(TMG3tren)]+ (1) (TMG3tren = 1,1,1-Tris{2-[N2-(1,1,3,3-tetramethylguanidino)]ethyl}amine) and a dry source of hydrogen peroxide, (o-Tol3P═O·H2O2)2 react in the stoichiometry, [CuI(TMG3tren)]+ + H2O2 → [CuI(TMG3tren-OH)]+ + H2O, wherein a ligand N-methyl group undergoes hydroxylation giving TMG3tren-OH. Furthermore, Fenton-type chemistry (CuI + H2O2 → CuII-OH + ·OH) is displayed, in which (i) a Cu(II)-OH complex could be detected during the reaction and it could be separately isolated and characterized crystallographically and (ii) hydroxyl radical (·OH) scavengers either quenched the ligand hydroxylation reaction and/or (iii) captured the ·OH produced.

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• Heme-copper and Heme O2-derived synthetic (bioinorganic) chemistry toward an understanding of cytochrome c oxidase dioxygen chemistry

  Journal of Inorganic Biochemistry · 2023-09-09 · 12 citations

  reviewOpen accessSenior authorCorresponding
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• CCDC 2245700: Experimental Crystal Structure Determination

  The Cambridge Structural Database · 2023-05-17

  datasetOpen accessSenior author

  An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

  PublisherDOI

Recent grants

• Reactivity-Activation of O(2) or NO in Copper and Heme-Cu Coordination Complexes

  NIH · $2.9M · 2021–2027

• Bioinorganic Copper Coordination Chemistry

  NIH · $8.4M · 1991–2023

• NIH Grant R01GM045971

  NIH · $295k · 1995

• NIH Grant R01GM034909

  NIH · $242k · 1988

• NIH Grant R37GM028962

  NIH · $3.7M · 2003

Frequent coauthors

• Edward I. Solomon

  SLAC National Accelerator Laboratory

  359 shared

• Arnold L. Rheingold

  University of California, San Diego

  230 shared

• Andreas D. Zuberbühler

  University of Basel

  184 shared

• Susan Kaderli

  149 shared

• Keith O. Hodgson

  Stanford Synchrotron Radiation Lightsource

  127 shared

• Pierre Moënne‐Loccoz

  Oregon Health & Science University

  125 shared

• Britt Hedman

  Stanford Synchrotron Radiation Lightsource

  124 shared

• Amy A. Sarjeant

  Bristol-Myers Squibb (United States)

  112 shared

Awards & honors

• F. Albert Cotton Award in Synthetic Inorganic Chemistry (200…
• fellow of the American Association for the Advancement of Sc…
• 2013 DIC Chair (elected)
• Collaborative Research in Environmental Molecular Science (C…