About

Isaac Garcia Bosch is an Associate Professor of Chemistry at Carnegie Mellon University within the Mellon College of Science. His research group, the Garcia-Bosch lab, takes inspiration from metalloenzymes to develop metal complexes capable of catalyzing organic transformations under environmentally benign conditions. The lab focuses on using cheap reagents such as first-row transition metals like copper, and green oxidants such as O2 or H2O2, to create practical bio-inspired catalysts for organic synthesis. His work includes designing functional synthetic models of Cu-dependent monooxygenases and exploring catalysis with copper complexes bearing redox-active ligands with tunable hydrogen-bonding donors. Dr. Garcia Bosch's research aims to understand and harness the reactivity of metal complexes to facilitate environmentally friendly chemical processes, contributing to advancements in catalysis, energy, and biological chemistry.

Research topics

• Chemistry
• Organic chemistry
• Photochemistry
• Materials science
• Nanotechnology
• Medicinal chemistry
• Combinatorial chemistry
• Stereochemistry
• Biochemistry
• Inorganic chemistry

Selected publications

• Synthesis and Characterization of Copper Complexes Featuring a Redox-Active ONO Ligand in Three Molecular Oxidation States

  Inorganic Chemistry · 2025-05-30 · 2 citations

  articleOpen accessSenior authorCorresponding

  In this research article, we report the synthesis, characterization, and reactivity of a family of Cu complexes bearing a tridentate iminosemiquinone ligand and ancillary amine ligands ((sqONO)CuII(L)n, n: 1 or 2). The complexes were obtained following a one-pot synthetic protocol by mixing CuII, 3,5-di-tert-butylcatechol, and aqueous ammonia in the presence of an amine base. The Cu complexes were structurally characterized by single-crystal X-ray diffraction analysis (SC-XRD). Cyclic voltammetry measurements showed that the Cu complexes reached three molecular oxidation states in a reversible fashion. The reaction between the Cu-iminosemiquinone complex (sqONO)CuII(L) with cobaltocene (1e– donor) and ferrocenium (1e– acceptor) produced the corresponding reduced and oxidized complexes. Structural and spectroscopic characterization (SC-XRD, UV–vis, and EPR) of the Cu complexes in the three oxidation states, namely, [(catONO)CuII(L)]−, (sqONO)CuII(L), and [(bqONO)CuII(L)]+, suggest that the redox events are ligand-based. DFT computations also formulated the complexes as CuII species with the ONO ligand in different oxidation states. For the CuII-iminosemiquinone complexes, we calculated small energetic differences between their singlet and triplet states (S = 0 vs S = 1), which explain their magnetic behavior in solution. Our results provide evidence of how Cu-radical metalloenzymes might tune their electronic structure to modulate their reactivity.

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• Machine Learning-Accelerated Screening of Hydroquinone Analogs for Proton-Coupled Electron Transfer

  ChemRxiv · 2025-11-05

  preprintSenior author

  Proton-coupled electron transfer (PCET) mediated by hydroquinone and related molecules is key to natural and artificial energy conversion. The reactivity of these molecules depends on their bond dissociation free energy (BDFE), but studying the relationship between structure and thermochemistry across chemical space has been limited by computational expense. Here, we present the first use of the AIMNet2 neural network potential to calculate average BDFE (BDFEavg) values for the 2H+/2e− dehydrogenation of about 200,000 hydroquinone-like compounds, including vicinal diamines, diols, and dithiols. Benchmarking against DFT calculations for 168 substituted ortho-phenylenediamines (opda) shows good agreement (R² > 0.9). Our analysis finds that BDFEavg ranges from 50 to 80 kcal/mol and can be systematically tuned by modifying the backbone and N-substitution: electron-withdrawing groups raise BDFEavg by up to 15 kcal/mol, while lower aromaticity in furan and thiophene backbones decreases BDFEavg by approximately 10 kcal/mol compared to phenyl systems. We developed an additive "offset model" that allows separate investigation of backbone and sidechain effects. Validation through cyclic voltammetry and reactivity studies with quinone oxidants for selected compounds supports the computational results. This extensive thermochemical database and web-based prediction tool offer valuable resources for designing PCET reagents for catalysis, energy storage, and biomedical uses.

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• Characterization of Three Intermediates in an Unusual Copper-Dependent Enzyme

  ACS Central Science · 2025-05-06 · 1 citations

  articleOpen accessSenior author

  Three intermediates in the formylglycine-generating enzyme are characterized at the molecular level.

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• Stepwise 6H⁺/6e^– Electron-Coupled Proton Buffers Based on Fe and Redox-Active Ligands

  Inorganic Chemistry · 2025-09-22

  articleOpen accessSenior authorCorresponding

  Herein, we report electron-coupled-proton buffers (ECPBs) based on Fe and redox-active ortho-phenylenediamine (opda) ligands that perform stepwise and reversible 6H+/6e– transformations. Four of the Fe complexes involved in the PCET transformation (namely X62+, X8H22+, X10H42+ and X12H62+) were structurally and/or spectroscopically characterized. The reductive protonation of X62+ to X12H62+ and the oxidative deprotonation of X12H62+ to X62+ were carried out using PCET reagents, which indicate that these 6H+/6e– transformations occurred in a 2H+/2e– fashion, accumulating the intermediate species X8H22+and X10H42+. The thermochemistry of the 2H+/2e– and overall 6H+/6e– transformations was studied by open-circuit potential measurements and comproportionation reactions. Interestingly, the Fe-based ECPBs depicted redox unleveling, in which the average bond dissociation free energy (BDFEavg) of the 2H+/2e– reductive protonation of X62+ to X8H22+ was substantially higher than the BDFEavg of the 6H+/6e– conversion of X62+ to X12H62+. We also show that the BDFEavg of the PCET transformations involving the Fe system bearing unsubstituted opda are higher than the systems bound by 4,5-Me2-opda and 4,5-(MeO)2-opda, a manifestation of redox decompensation. The capability of the Fe-based ECPBs to accept and donate H-atom equivalents, as well as their ability to dehydrogenate organic substrates using O2 as oxidant in a decoupled fashion, was also evaluated.

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• Recent Advances in Bioinspired Cu-Directed C–H Hydroxylation Reactions

  Accounts of Chemical Research · 2025-08-27 · 3 citations

  articleOpen accessSenior authorCorresponding

  ConspectusCu-dependent metalloenzymes catalyze a wide array of oxidative transformations using O2 as an oxidant under mild conditions. These include the hydroxylation of challenging organic substrates (e.g., oxidation of methane to methanol in particulate methane monooxygenase) and the regio- and enantioselective hydroxylation of complex molecules (e.g., benzylic hydroxylation of dopamine to noradrenaline in dopamine-β-monooxygenase). Lytic polysaccharide monooxygenase enzymes (LPMOs) promote the C–H hydroxylation and subsequent cleavage of the polysaccharide chains found in natural materials such as cellulose or chitin. Recent reports on the reactivity of LPMOs suggest that, instead of O2, these Cu-dependent metalloenzymes utilize H2O2 as an oxidant. In 2015, our research lab reported that the catalytic hydroxylation of strong C–H bonds (e.g., cyclohexane) using Cu and H2O2 proceeded via formation of nonselective Fenton-like oxidants (hydroxyl and hydroperoxyl radicals). To achieve regioselectivity, LPMOs bind the organic substrate before exposing the Cu center to the oxidant, a reaction that leads to the formation of a highly organized ternary complex prior to substrate hydroxylation (i.e., metal–substrate–oxidant adduct). Based on this concept, our research lab has pioneered the use of Cu, directing groups, and green oxidants to promote the site-selective hydroxylation of ketones and aldehydes. In our first report on this topic, we carried out an extensive mechanistic analysis on the Cu-directed sp3 C–H hydroxylation reactions developed by Schönecker and co-workers. Our findings suggested that the reaction between CuI and O2 did not lead to the formation of dinuclear Cu2O2 (as it was previously suggested) but produced CuII and H2O2, which generated mononuclear CuII-hydroperoxide oxidants. Based on our mechanistic analysis, we redesigned the reaction conditions to utilize CuII and H2O2, which improved the yield, cost, and practicability of the Schönecker oxidations. Since then, our research lab has broadened the scope of substrates that can be oxidized using Cu, H2O2, and bidentate directing groups to include the γ-hydroxylation of sp2 C–H bonds and β-hydroxylation of sp3 C–H bonds. Our latest reports have focused on the regioselective hydroxylation of substituted unsymmetrical benzophenones (which occurred via the formation of an electrophilic CuOOH species) and, for the first time, enantioselective C–H hydroxylation reactions via the formation of Cu/O2 species. Our work highlights the importance of a mechanistic understanding to improve oxidation processes as well as underlines the use of metal-directed transformations to study the mechanisms by which metalloenzymes functionalize organic molecules.

  PublisherOA PDFDOI

• Oxidation of C–H and O–H bonds by a copper complex inspired by the Cu( <scp>ii</scp> )–tyrosyl species formed in LPMOs

  Chemical Science · 2025-01-01 · 1 citations

  articleOpen accessSenior author

  towards C-H bonds. This work describes the first example of Cu complex bound by a redox-active ligand able to oxidize C-H bonds, and provides evidence of the involvement of similar species in the oxidation of organic substrates catalyzed by Cu-dependent metalloenzymes such as lytic polysaccharide monooxygenases.

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• Mimicking the Reactivity of LPMOs with a Mononuclear Cu Complex

  European Journal of Inorganic Chemistry · 2024-01-08 · 8 citations

  articleOpen accessSenior authorCorresponding

  Abstract Lytic polysaccharide monooxygenases (LPMOs) are Cu‐dependent metalloenzymes that catalyze the hydroxylation of strong C−H bonds in polysaccharides using O 2 or H 2 O 2 as oxidants (monooxygenase/peroxygenase). In the absence of C−H substrate, LPMOs reduce O 2 to H 2 O 2 (oxidase) and H 2 O 2 to H 2 O (peroxidase) using proton/electron donors. This rich oxidative reactivity is promoted by a mononuclear Cu center in which some of the amino acid residues surrounding the metal might accept and donate protons and/or electrons during O 2 and H 2 O 2 reduction. Herein, we utilize a podal ligand containing H‐bond/proton donors (LH 2 ) to analyze the reactivity of mononuclear Cu species towards O 2 and H 2 O 2 . [(LH 2 )Cu I ] 1+ ( 1 ), [(LH 2 )Cu II ] 2+ ( 2 ), [(LH − )Cu II ] 1+ ( 3 ), [(LH 2 )Cu II (OH)] 1+ ( 4 ), and [(LH 2 )Cu II (OOH)] 1+ ( 5 ) were synthesized and characterized by structural and spectroscopic means. Complex 1 reacts with O 2 to produce 5 , which releases H 2 O 2 to generate 3 , suggesting that O 2 is used by LPMOs to generate H 2 O 2 . The reaction of 1 with H 2 O 2 produces 4 and hydroxyl radical, which reacts with C−H substrates in a Fenton‐like fashion. Complex 3 , which can generate 1 via a reversible protonation/reduction, binds H 2 O and H 2 O 2 to produce 4 and 5 , respectively, a mechanism that could be used by LPMOs to control oxidative reactivity.

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• Expanding the Clip-and-Cleave Concept: Approaching Enantioselective C–H Hydroxylations by Copper Imine Complexes Using O₂ and H₂O₂ as Oxidants

  Journal of the American Chemical Society · 2024-09-06 · 10 citations

  articleOpen accessCorresponding

  Copper-mediated aromatic and aliphatic C–H hydroxylations using benign oxidants (O2 and H2O2) have been studied intensively in recent years to meet the growing demand for efficient and green C–H functionalizations. Herein, we report an enantioselective variant of the so-called clip-and-cleave concept for intramolecular ligand hydroxylations by the application of chiral diamines as directing groups. We tested the hydroxylation of cyclohexanone and 1-acetyladamantane under different oxidative conditions (CuI/O2; CuI/H2O2; CuII/H2O2) in various solvents. As an outstanding example, we obtained (R)-1-acetyl-2-adamantol with a yield of 37% and >99:1 enantiomeric excess from hydroxylation in acetone using CuI and O2. Low-temperature stopped-flow UV–vis measurements in combination with density functional theory (DFT) computations revealed that the hydroxylation proceeds via a bis(μ-oxido) dicopper intermediate. The reaction product represents a rare example of an enantiopure 1,2-difunctionalized adamantane derivative, which paves the way for potential pharmacological studies. Furthermore, we found that 1-acetyladamantane can be hydroxylated in a one-pot reaction under air with isolated yields up to 36% and enantiomeric ratios of 96:4 using CuII/H2O2 in MeOH.

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• Enhanced Proton-Coupled Electron-Transfer Reactivity by a Mononuclear Nickel(II) Hydroxide Radical Complex

  Inorganic Chemistry · 2024-12-16 · 4 citations

  articleOpen accessSenior authorCorresponding

  The synthesis, characterization, and reactivity of a NiOH core bearing a tridentate redox-active ligand capable of reaching three molecular oxidation states is presented in this paper. The reduced complex [LNiOH]2– was characterized by single-crystal X-ray diffraction analysis, depicting a square-planar NiOH core stabilized by intramolecular H-bonding interactions. Cyclic voltammetry measurements indicated that [LNiOH]2– can be reversibly oxidized to [LNiOH]− and [LNiOH] at very negative reduction potentials (−1.13 and −0.39 V vs ferrocene, respectively). The oxidation of [LNiOH]2– to [LNiOH]− and [LNiOH] was accomplished using 1 and 2 equiv of ferrocenium, respectively. Spectroscopic and computational characterization suggest that [LNiOH]2–, [LNiOH]−, and [LNiOH] are all NiII species in which the redox-active ligand adopts different oxidation states (catecholate-like, semiquinone-like, and quinone-like, respectively). The NiOH species were found to promote H-atom abstraction from organic substrates, with [LNiOH]− acting as a 1H+/1e– oxidant and [LNiOH] as a 2H+/2e– oxidant. Thermochemical analysis indicated that [LNiOH] was capable of abstracting H atoms from stronger O–H bonds than [LNiOH]−. However, the greater thermochemical tendency of [LNiOH] reactivity toward H atoms did not align with the kinetics of the PCET reaction, where [LNiOH]− reacted with H-atom donors much faster than [LNiOH]. The unique stereoelectronic structure of [LNiOH]− (radical character combined with a basic NiOH core) might account for its enhanced PCET reactivity.

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• Daniel-Ankita

  ioChem-BD Computational Chemistry Datasets · 2024-09-29

  datasetOpen accessSenior author
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Frequent coauthors

• Maxime A. Siegler

  79 shared

• Marcel Swart

  Institució Catalana de Recerca i Estudis Avançats

  38 shared

• Khashayar Rajabimoghadam

  Yale University

  35 shared

• Xavi Ribas

  University of Girona

  35 shared

• Miguel Costas

  University of Girona

  34 shared

• Sidney Eichelberger

  27 shared

• Anna Company

  University of Girona

  26 shared

• Umyeena Bashir

  24 shared

Labs

• Garcia-Bosch GroupPI

Education

• B.S., Chemistry

  University of Girona

  2006

• M.S., Inorganic Chemistry

  University of Girona

  2008

• Ph.D., Chemistry

  University of Girona

  2011

• Other

  Johns Hopkins University

  2012

Awards & honors

• NSF CAREER Award
• John & Nancy Harrison Legacy Graduate Fellowship in Chemistr…