Electron Transfer-proton Transfer Research Articles

A DFT study on OH radical scavenging activities of eriodictyol, Isosakuranetin and pinocembrin

Flavonoids are natural compounds with antioxidant properties that have positive effects on human health, which reduce toxic effects of reactive oxygen species (ROS) and partially oxidative damage. In the work, the density functional theory (DFT/BMK) calculations were performed for antioxidant activity evaluation of pinocembrin (P), isosakuranetin (I) and eriodictyol (E). Four main mechanisms were examined: hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer-proton transfer (SET-PT) and Sequential proton loss electron transfer (SPLET). HAT and SPLET are thermodynamically the most probable process in gas phase and water. The three flavonoids examined + •OH HAT and RAF mechanisms for each possible location were investigated theoretically for the first time. The results were discussed by considering thermodynamic, kinetic and structural data of various reaction paths using IRC approach. Communicated by Ramaswamy H. Sarma

Electrocatalytic Reduction of C-C π-Bonds via a Cobaltocene-Derived Concerted Proton-Electron Transfer Mediator: Fumarate Hydrogenation as a Model Study.

Reductive concerted proton-electron transfer (CPET) is poorly developed for the reduction of C-C π-bonds, including for activated alkenes that can succumb to deleterious pathways (e.g., a competing hydrogen evolution reaction or oligomerization) in a standard electrochemical reduction. We demonstrate herein that selective hydrogenation of the C-C π-bond of fumarate esters can be achieved via electrocatalytic CPET (eCPET) using a CPET mediator comprising cobaltocene with a tethered Brønsted base. High selectivity for electrocatalytic hydrogenation is observed only when the mediator is present. Mechanistic analysis sheds light on two distinct kinetic regimes based on the substrate concentration: low fumarate concentrations operate via rate-limiting CPET followed by an electron-transfer/proton-transfer (ET/PT) step, whereas high concentrations operate via CPET followed by a rate-limiting ET/PT step.

Influence of the proton relay spacer on hydrogen electrocatalysis by cobalt hangman porphyrins

A cobalt hangman porphyrin system with a phenyl spacer between the porphyrin ring and an internal carboxylic acid group as well as its non-hangman analogue were synthesized and utilized for the study of the proton-coupled electron transfer (PCET) kinetics attendant to electrocatalytic hydrogen evolution. Cyclic voltammetry (CV) together with simulations show that a short distance between the proton relay and the redox active cobalt center as well as the increased proton donating strength results in superior catalytic activity. The mechanism of hydrogen generation is at the nexus of proton transfer–electron transfer (PTET) and concerted proton–electron transfer (CPET), as opposed to an ETPT mechanism that is characteristic of hangman systems with longer proton relay networks.

Theoretical investigations on the antioxidant potential of a non-phenolic compound thymoquinone: a DFT approach.

Thymoquinone (TQ) is a natural compound present in black cumin which possesses potent antioxidant activity without having any phenolic hydroxyl group which is responsible for antioxidant activity. In the present study, computational calculation based on density functional theory (DFT) was executed to assess systematically the antioxidant behavior of this compound by considering geometrical characteristics, highest occupied molecular orbital - lowest unoccupied molecular orbital (HOMO-LUMO), and molecular electrostatic potential (MEP) surface. Thermochemical parameters correlated to the leading antioxidant mechanisms such as hydrogen atom transfer (HAT), single electron transfer-proton transfer (SETPT), and sequential proton loss electron transfer (SPLET) were studied in gas and water media. In addition, the changes of thermochemical parameters such as free energy change (∆G) and enthalpy change (∆H) were computed for hydrogen abstraction (HA) from TQ to hydroxyl radical in gas and water phases to investigate its free radical scavenging potency. The low and comparable values of bond dissociation enthalpy (BDE), proton dissociation enthalpy (PDE), ionization potential (IP), proton affinity (PA), and electron transfer enthalpy (ETE) revealed the antioxidant activity. The ∆G and ∆H also indicated apposite thermodynamic evidence in favor of antiradical capability of TQ. The attack of the free radical occurred preferentially at 3CH position of the molecule.

Investigation of antioxidant activity of epigallocatechin gallate and epicatechin as compared to resveratrol and ascorbic acid: experimental and theoretical insights

Antioxidants are molecules that help the human body to fight oxidative stress caused by excess free radicals that trigger a number of diseases. Understanding the structure–activity relationship of antioxidants and their mechanisms of action is important for designing more powerful antioxidants. Polyphenols from Vitis vinifera L. have shown several biological activities among which antioxidant activity. Among polyphenolic compounds having potent biological activities, we find resveratrol (RSV) which is a stilbene and epigallocatechin gallate (EGCg) and epicatechin (EC) which are catechins or flavanols. We report here a comparative study of the antioxidant potential of EGCg and EC as compared to RSV. The most favorable mechanism by which each molecule exerts the antioxidant activity is determined. Ascorbic acid (AA) was included as a reference. DPPH and FRAP assays were used for experimental evaluation of antioxidant activity and for theoretical calculations, density functional theory (DFT) method was chosen. Three mechanisms were investigated: hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET). Calculated thermodynamic parameters correlate well with percentage inhibition (I%) and half maximal inhibitory concentration (IC50) values given by the DPPH test. Both experimental and theoretical approaches showed that EGCg is more potent antioxidant than EC and RSV. The most preferential sites are gallate moiety and 4′-OH in EGCg and OH sites of the B ring in EC. The pKa values confirm this finding. All proposed mechanisms are favored for EGCg, and SET-PT is preferred antioxidant mechanism for EC and it is the most suitable in the first step for RSV. Flavanols are more potent antioxidants than the stilbene, RSV.

Predicting the antioxidant activity of some flavonoids of Arbutus plant: A theoretical approach

In this work, the antioxidant activity, free radical-scavenging capacity, molecular geometry and intramolecular hydrogen bonding interaction were explored for three natural flavonoid compounds of Arbutus unedo L. plant, Fisetin (3,3′,4′,7-tetrahydroxy flavone), Catechin (Flavan-3,3′,4′,5,7-pentol) and Apigenin (4′,5,7-trihydroxy flavone). Three potential mechanisms of antioxidant activity, hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET), have been explored. The physicochemical parameters (BDE, IP, PA, PD, ETE, HOMO and LUMO), as well spin density distribution, were calculated in different solvents. The mechanisms involved in the radical scavenging activity, taking into account the position of the most active OH hydroxyl group, are in accordance with the experimental tests. HAT mechanism is most favorable in the gas phase and benzene solvent. B-ring of the three flavonoids is the active center for the antioxidant activity. Fisetin presents the best antioxidant activity with high free radical scavenging capacity followed by Catechin and Apigenin, respectively.

DFT investigation of pachypodol for exploring anti-oxidant action – Performance of B3LYP and M06-2X

Anti-oxidant mechanism of the pachypodol is computed with the aid of density functional theory (DFT) in the light of B3LYP (B3, Lee-Yang-Parr correlation function) and M06-2X (highly parameterized, exchange correlation function) using 6-311G(d,p) basis set in the Gaussian 09 software package. This investigation aims to prove the better reaction enthalpies among hydrogen atom transfer (HAT), sequential proton-loss electron-transfer (SPLET) and single electron transfer-proton transfer (SET-PT) in gas and solvent phases with both the level of theories (B3LYP and M06-2X). The result shows that the preferred anti-oxidant mechanism is found to be HAT in both gas and solvent phases. The analysis of bond dissociation enthalpy (BDE) has been carried out in gas and solvent phases. Molecular descriptors are analyzed and computed in the light of both the level of theories. The radical scavenging of pachypodol is well established with B3LYP theory, since it yields appreciable results with respect to BDE, IP and PDE than M06-2X level of theory. Preferred electrophilic and nucleophilic sites of pachypodol are analyzed using MEP. The weak and strong intramolecular bonds are examined with the aid of NBO.

Overcoming Redox Reactions at Perovskite-Nickel Oxide Interfaces to Boost Voltages in Perovskite Solar Cells

Summary Nickel oxide (NiOx) hole transport layers (HTLs) are desirable contacts for perovskite photovoltaics because they are low cost, stable, and readily scalable; however, they deliver lower open-circuit voltages (VOCs) compared to organic HTLs. Here, we characterize and mitigate electron transfer-proton transfer reactions between NiOx HTLs and perovskite precursors. Using XPS and UPS characterization, we identify that Ni≥3+ metal cation sites in NiOx thin films act both as Bronsted proton acceptors and Lewis electron acceptors, deprotonating cationic amines and oxidizing iodide species, forming PbI2−xBrx-rich hole extraction barriers at the perovskite-NiOx interface. Titrating reactive Ni≥3+ surface states with excess A-site cation salts during perovskite active layer deposition yielded an increase in VOC values to 1.15 V and power conversion efficiencies of ∼20%. This may be a general finding for metal oxide contacts that act as Bronsted and Lewis acid-base reactants toward perovskite precursors, an observation that has also been made recently for TiO2 and SnO2 contacts.

Phenol Oxidation by a Nickel(III)-Fluoride Complex: Exploring the Influence of the Proton Accepting Ligand in PCET Oxidation.

In order to gain insight into the influence of the H+ -accepting terminal ligand in high-valent oxidant mediated proton coupled electron transfer (PCET) reactions, the reactivity of a high valent nickel-fluoride complex [NiIII (F)(L)] (2, L=N,N'-(2,6-dimethylphenyl)-2,6-pyridinecarboxamidate) with substituted phenols was explored. Analysis of kinetic data from these reactions (Evans-Polanyi, Hammett, and Marcus plots, and KIE measurements) and the formed products show that 2 reacted with electron rich phenols through a hydrogen atom transfer (HAT, or concerted PCET) mechanism and with electron poor phenols through a stepwise proton transfer/electron transfer (PT/ET) reaction mechanism. The analogous complexes [NiIII (Z)(L)] (Z=Cl, OCO2 H, O2 CCH3 , ONO2 ) reacted with all phenols through a HAT mechanism. We explore the reason for a change in mechanism with the highly basic fluoride ligand in 2. Complex 2 was also found to react one to two orders of magnitude faster than the corresponding analogous [NiIII (Z)(L)] complexes. This was ascribed to a high bond dissociation free energy value associated with H-F (135 kcal mol-1 ), which is postulated to be the product formed from PCET oxidation by 2 and is believed to be the driving force for the reaction. Our findings show that high-valent metal-fluoride complexes represent a class of highly reactive PCET oxidants.

Design, synthesis, biological evaluation, molecular docking, DFT calculations and in silico ADME analysis of (benz)imidazole-hydrazone derivatives as promising antioxidant, antifungal, and anti-acetylcholinesterase agents

Ten hydrazone derivatives bearing a (benz)imidazole nucleus were designed, synthesized and evaluated for their antioxidant, antifungal, and anti-acetylcholinesterase activities. All the synthesized compounds (1-10) showed good to excellent antioxidant activity. Among them, compound 10 was found to be the best acetylcholinesterase inhibitor with an IC50 value comparable to that of the galantamine. Compound 5 was found to be the best antifungal agent against Fusarium oxysporum fungal strain when compared to the commercial fungicide carbendazim. DFT calculations, for representative molecules 1 and 6, were also performed to investigate the antioxidant mechanisms, and it was found that SETPT (sequential electron transfer-proton transfer) is the most favorable mechanism in ethanol. Molecular docking studies of the most active compounds were carried out, and results showed reasonable binding modes in the active site of Fusarium oxysporum FGB1 enzyme and acetylcholinesterase. Finally, in silico predictions of ADME and pharmacokinetic parameters indicated that these compounds should have good oral bioavailability.

Flavones' and Flavonols' Antiradical Structure-Activity Relationship-A Quantum Chemical Study.

Flavonoids are known for their antiradical capacity, and this ability is strongly structure-dependent. In this research, the activity of flavones and flavonols in a water solvent was studied with the density functional theory methods. These included examination of flavonoids’ molecular and radical structures with natural bonding orbitals analysis, spin density analysis and frontier molecular orbitals theory. Calculations of determinants were performed: specific, for the three possible mechanisms of action—hydrogen atom transfer (HAT), electron transfer–proton transfer (ETPT) and sequential proton loss electron transfer (SPLET); and the unspecific—reorganization enthalpy (RE) and hydrogen abstraction enthalpy (HAE). Intramolecular hydrogen bonding, catechol moiety activity and the probability of electron density swap between rings were all established. Hydrogen bonding seems to be much more important than the conjugation effect, because some structures tends to form more intramolecular hydrogen bonds instead of being completely planar. The very first hydrogen abstraction mechanism in a water solvent is SPLET, and the most privileged abstraction site, indicated by HAE, can be associated with the C3 hydroxyl group of flavonols and C4’ hydroxyl group of flavones. For the catechol moiety, an intramolecular reorganization to an o-benzoquinone-like structure occurs, and the ETPT is favored as the second abstraction mechanism.

Studies on the oxidative degradation of paracetamol by a μ-oxo-diiron(III) complex

In higher organisms, metalloenzymes like cytochrome P450, containing a Fe(III) metal center, play an active role in metabolism of paracetamol (APAP). Here, we have chosen a mimicking μ-oxo-diiron complex, [Fe(III)2(μ-O)(phen)4(H2O)2]4+(1, phen = 1,10-phenanthroline), to study spectrophotometrically the kinetics of the redox interactions with APAP. In acidic buffer media (pH = 3.4–5.1), APAP quantitatively reduces 1 following first-order reaction kinetics. Each molecule of 1 accepts two electrons from APAP and is reduced to ferroin [Fe(phen)3]2+. On oxidation, APAP produces N-acetyl-p-benzoquinone imine (NAPQI), which on hydrolysis results in a mixture of benzoquinone, quinone oxime, acetamide, and acetic acid. In reaction media due to successive deprotonations, 1 exists in equilibrium with the species [Fe(III)2(μ-O)(phen)4(H2O)(OH)]3+(1a) and [Fe(III)2(μ-O)(phen)4(OH)2]2+(1b) (pKa= 3.71 and 5.28, respectively). The kinetic analyses suggest for an unusual reactivity order as 1 < 1a ≫ 1b. The mechanistic possibilities suggest that although 1 is reduced by concerted electron transfer (ET) – proton transfer (PT) mechanism, 1a and 1b may be reduced by a concerted PT–ET mechanism where a slow proton-abstraction step is followed by a rapid ET process. It seems that the initial activation of the bridging μ-oxo group by a proton-abstraction results in the higher reactivity of 1a.

Insight into Antioxidant and Photoprotective Properties of Natural Compounds from Marine Fungus.

This computational and experimental work aims to elucidate physicochemical and photophysical natures of free radical scavenging and ultraviolet radiation (UVR) filtering activities of five terpenoids available in the extract of marine fungus. The antioxidant activities of ochraceopone F (C1), aspertetranone D (C2), cycloechinulin (C3), wasabidienone E (C4), and mactanamide (C5) are evaluated by using density functional theory (DFT) at the M05-2X/6-311++G(d,p) level of theory in the gas phase, water, and pentyl ethanoate (PEA). Double antioxidant mechanisms allowing the second (H+/e-) donation such as double hydrogen atom transfer (dHAT), double single electron transfer-proton transfer (dSET-PT), and double sequential proton loss-electron transfer (dSPL-ET) are considered. Reaction enthalpies (ΔrH0), standard Gibbs free energies (ΔrG0) and potential energy surfaces of reactions toward HOO• radical are then established to evaluate the hydrogen transfer (HT) and radical adduct formation (RAF) mechanisms. The computational results are supported by DPPH• and ABTS•+ antioxidant essays. Results show that all compounds C1-C5 are able to scavenge two free radicals via dHAT, dSET-PT, and dSPL-ET mechanisms. Among the compounds, C3 and C4 represent the most potential antioxidants, especially via HAT and RAF mechanisms in all the reaction media. Their rate constants for both HAT and RAF reactions are remarkably higher than that of Trolox and ascorbic acid. The kinetic calculations on activation Gibbs free energies (ΔG⧧) and rate constants (kTST) based on conventional transition state theory (TST) reveal that HAT and RAF processes are in competition in solvents. Photophysical processes occurring during UVR exposure are investigated using the time dependent density functional theory (TD-DFT) combined with UV-vis experiments. The obtained results highlight the promising activities of C1-C5 in UVR absorption in the ranges of UVA and UVB. Among them, C3 and C4 also show better UV absorption properties with the easiest excitations (band gaps equal to 4.06 and 3.65 eV). This study suggests the natural candidates possibly used in organic sunscreen.

A DFT mechanistic, thermodynamic and kinetic study on the reaction of 1, 3, 5-trihydroxybenzene and 2, 4, 6-trihydroxyacetophenone with •OOH in different media

A theoretical investigation on the reactions of 1, 3, 5-trihydroxybenzene (PG) and 2, 4, 6-trihydroxyacetophenone (ACPG) with •OOH has been performed with the aim of elucidating the peroxyl radical scavenging properties of PG and its acylated derivative. The study has considered the hydrogen atom transfer (HAT), the single electron transfer-proton transfer and the sequential proton loss-electron transfer mechanisms and determined the geometric, energetic and electronic properties of the reaction species as well as the kinetic parameters for the HAT mechanism. DFT/M06-2X, DFT/MPW1K and DFT/BHHLYP calculation methods have been utilized in combination with the 6-311++G(3df, 2p) basis set. The DFT methods were benchmarked using the CBS-QB3 method. Thermodynamic parameters such as bond dissociation enthalpy (BDE) and ionization energy suggest that the thermodynamically preferred mechanism is the HAT mechanism. The geometric, electronic and energetic parameters suggest that the preferred site for the abstraction of the free phenolic H atom in ACPG is the ortho position. Spin density and branching ratio values indicate that the most stable and preferable product formed is for the reaction of ACPG [Formula: see text] •OOH at the ortho position. The estimated rate constants obtained indicate that the reaction of ACPG [Formula: see text] •OOH is kinetically preferred to the reaction of PG [Formula: see text] •OOH, which is in agreement with experimental findings.

Radical Rebound Hydroxylation Versus H-Atom Transfer in Non-Heme Iron(III)-Hydroxo Complexes: Reactivity and Structural Differentiation.

The characterization of high-valent iron centers in enzymes has been aided by synthetic model systems that mimic their reactivity or structural and spectral features. For example, the cleavage of dioxygen often produces an iron(IV)-oxo that has been characterized in a number of enzymatic and synthetic systems. In non-heme 2-oxogluterate dependent (iron-2OG) enzymes, the ferryl species abstracts an H-atom from bound substrate to produce the proposed iron(III)-hydroxo and caged substrate radical. Most iron-2OG enzymes perform a radical rebound hydroxylation at the site of the H-atom abstraction (HAA); however, recent reports have shown that certain substrates can be desaturated through the loss of a second H atom at a site adjacent to a heteroatom (N or O) for most native desaturase substrates. One proposed mechanism for the removal of the second H-atom involves a polar-cleavage mechanism (electron transfer-proton transfer) by the iron(III)-hydroxo, as opposed to a second HAA. Herein we report the synthesis and characterization of a series of iron complexes with hydrogen bonding interactions between bound aquo or hydroxo ligands and the secondary coordination spherein ferrous and ferric complexes. Interconversion among the iron species is accomplished by stepwise proton or electron addition or subtraction, as well as H-atom transfer (HAT). The calculated bond dissociation free energies (BDFEs) of two ferric hydroxo complexes, differentiated by theirnoncovalent interactions and reactivity, suggest that neither complex is capable of activating even weak C-H bonds, lending further support to the proposed mechanism for desaturation in iron-2OG desaturase enzymes. Additionally, the ferric hydroxo species are differentiated by their reactivity toward performing a radical rebound hydroxylation of triphenylmethylradical. Our findings should encourage further study of the desaturase systems that may contain unique H-bonding motifs proximal to the active site that help bias substrate desaturation over hydroxylation.

Effect of Side Chain Functional Groups on the DPPH Radical Scavenging Activity of Bisabolane-Type Phenols.

Methods for improving the antioxidant activity of phenolic compounds have been widely investigated; however, most studies have focused on the structure–activity correlations of substituents on the aromatic rings of catechols or flavonoids. We investigated the influence of side chain functional groups on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of xanthorrhizol and curcuphenol analogues. These compounds were synthesised by the side chain functional group conversion of curcumene, followed by direct oxidation of the aromatic ring. We determined the DPPH radical scavenging activity from the half-maximal effective concentration (EC50) obtained from a DPPH assay in methanol. The positional relationships of the side chain with the aromatic ring and phenolic OH group were determined using density functional theory calculations, and the stability of different conformations was compared. Electron transfer-proton transfer was determined to be the dominant mechanism in the DPPH reaction with xanthorrhizol analogues, based on the correlation between the EC50 and ionisation potential. The radical cation was greatly stabilised in the structure where the side chain functional group was close to the aromatic ring. Stabilisation also depended on the phenolic OH group position. In future antioxidant design, aromatic ring substituent conversion and the use of functional groups far from the OH group or ring should be explored.

The influence of the H5⋯O[dbnd]C4 intramolecular hydrogen-bond (IHB) on the antioxidative activity of flavonoid

Flavonoids widely found in natural foods are characterized by acting as antioxidants compounds. There are close relationship between the antiradical activities and structural properties of flavonoids. In this work, density functional theory (DFT) methods were applied to investigate the influence of the H5⋯OC4 intramolecular hydrogen-bond (IHB) on the antiradical activity of flavonoid based on three prevalently accepted radical scavenging mechanisms: hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton-loss electron-transfer (SPLET). The thermodynamic properties: bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) related with these mechanisms were calculated to elucidate the antiradical activity. The results showed that the 5−OH group is most influenced and its antiradical capacity was weakened by the H5⋯OC4 IHB. In the gas, benzene and chloroform phases, H5⋯OC4 IHB would reduce the antiradical activity of flavonoid via increasing the bond dissociation enthalpy. While, in the DMSO and H2O phases, the opposite result occurs by lowering the proton affinity.

Substituent Effects on the Radical Scavenging Activity of Isoflavonoid.

Understanding the role of substituents is of great importance for the preparation of novel phenolic compounds with enhanced antioxidative properties. In this work, the antioxidative activity of isoflavonoid derivatives with different substituents placed at the C2 position was determined by density functional theory (DFT) calculations. The bond dissociation enthalpy (BDE), ionization potential (IP), and proton affinity (PA) related to hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanisms were calculated. The strongest antioxidative group of isoflavonoid is not altered by the substituents. Excellent correlations were found between the BDE/IP/PA and Hammett sigma constants. Equations obtained from linear regression can be useful in the selection of suitable candidates for the synthesis of novel isoflavonoids derivatives with enhanced antioxidative properties. In the gas and benzene phases, the electron-donating substituents would enhance the antioxidative activity of isoflavonoids via weakening the BDE of 4′−OH. In water phase, they will reduce the antioxidative by strengthening the PA of 7−OH. Contrary results occur for the electron-withdrawing groups. In addition, the electronic effects of substituents on the BDE/IP/PA have also been analyzed.

Direct Molecular Evidence of Proton Transfer and Mass Dynamics at the Electrode-Electrolyte Interface.

Proton transfer has been widely regarded as a key step in many electrochemical and biological processes. However, direct molecular evidence has long been lacking. In this work, we chose the electrochemical oxidation of acetaminophen (APAP) as a model system and utilized in situ liquid time-of-flight secondary ion mass spectroscopy (ToF-SIMS) to molecularly examine proton solvation and transfer in this process. In addition, we successfully captured and identified the transient radical intermediate, providing solid molecular evidence to resolve an important debate in electron transfer-proton transfer oxidation mechanism of APAP. Moreover, the potential-dependent behaviors of both inert ions and electroactive species during the dynamic potential scanning were chemically monitored in real time and the mass diffusion mechanism regarding the electroactive and nonelectroactive species was revealed under polarized conditions. The results are consistent with our computer simulations. The observations in this work greatly improved our understanding of proton transfer and mass dynamics occurring at the electrode-electrolyte interface in complex electrochemical processes.

Interplay between Substrate and Proton Donor Coordination in Reductions of Carbonyls by SmI2-Water Through Proton-Coupled Electron-Transfer.

The reduction of a carbonyl by SmI2-water is the first step in a range of reactions of synthetic importance. Although the reduction is often proposed to proceed through an initial stepwise electron-transfer-proton-transfer (ET-PT), recent work has shown that carbonyls and related functional groups are likely reduced though proton-coupled electron-transfer (PCET). In the present work, the reduction of an activated ester, aldehyde, a linear and cyclic ketone, and related sterically demanding carbonyls by SmI2-H2O was examined through a series of mechanistic experiments. Kinetic studies demonstrate that all substrates exhibit significant increases in the rate of reduction by SmI2 as [H2O] is increased. Under identical conditions, ketones and an aldehyde containing a methyl adjacent to the carbonyl are reduced slower than an unsubstituted variant by an order of magnitude, demonstrating the importance of substrate coordination. In the case of unactivated substrates, rates of reduction show excellent correlation with the calculated bond dissociation free energy of the O-H bond of the intermediate ketyl and the calculated free energy of intermediate ketyl radical anions derived from unhindered substrates: findings consistent with concerted PCET. Activated esters derived from methylbenzoate are likely reduced through stepwise or asynchronous PCET. Overall, this work demonstrates that the combination of the coordination of substrate and water to Sm(II) provides a configuration uniquely suited to a coupled electron- and proton-transfer process.