Ru-Catalyzed Asymmetric Reductive Amination of Aryl-Trifluoromethyl Ketones for Synthesis of Primary α-(Trifluoromethyl)arylmethylamines.

The ruthenium-catalyzed asymmetric reductive amination of aryl-trifluoromethyl ketones affording high value primary α-(trifluoromethyl)arylmethylamines using cheap NH4OAc as the nitrogen source and H2 as the reductant is reported. This user-friendly and simple catalytic method tolerates various aromatic functions with electron-withdrawing or -donating substituents at the para- or meta-positions and as well challenging heteroaromatic functions, yielding primary α-(trifluoromethyl)arylmethylamines with excellent chemoselectivities, enantioselectivities, and useful yields (80-97% ee, 51-92% isolated yields). Finally, scalable and concise synthesis of key drug intermediates using this methodology is presented.

[Exhaustive Syntheses of Deuterium-labelled Compounds].

Deuterium (2H, D) is a stable isotope of hydrogen (1H). Deuterium-incorporated (labelled) compounds are widely utilized in various scientific fields such as mechanistic studies of organic reactions, elucidation of drug metabolism, application as tracers for microanalysis. Recently, development of heavy drugs and molecular imaging using techniques such as neutron scattering and Raman spectroscopy are spotlighted. We have developed various deuterium-incorporated compounds using D2O as an inexpensive deuterium source to construct novel functional materials. The use of platinum group metals on carbon as catalysts could result in the multi-deuteration of compounds in the mixed solvents of 2-propanol and D2O, and site-selectively deuterated compounds can be synthesized by organocatalytic methods. In this review, the latter deuteration methods using organocatalysts and their applications are summarized. Terminal alkynes smoothly underwent deuterium incorporation by using triethylamine as an organic base or a solid resin possessing the tertiary amine moiety in the same molecule to give mono-deuterated alkynes. These compounds were partially reduced over our prepared specific palladium catalyst under atmospheric D2 gas to produce tri-deuterated alkenes. Achiral or chiral di-deuterated ß-nitro alcohols were also prepared by the organic-base-catalyzed deuteration of nitromethane, followed by nitroaldol reactions in a one pot manner. The mono-deuteration of aromatic aldehyde could be effectively catalyzed by N-heterocyclic carbene. Furthermore, the α-deuteration of aliphatic aldehydes using a basic resin catalyst and the subsequent Knoevenagel condensation with malononitrile could provide γ-deuterium-incorporated α,ß-unsaturated nitrile derivatives. The deuterated compounds thus obtained can be important synthetic precursors to construct the deuterium-incorporated target functional materials.

Visible-light-mediated catalyst-free synthesis of unnatural α-amino acids and peptide macrocycles.

The visible light induced, photocatalysts or photoabsorbing EDA complexes mediated cleavage of pyridinium C-N bond were reported in the past years. Here, we report an ionic compound promote homolytic cleavage of pyridinium C-N bond by exploiting the photonic energy from visible light. This finding is successfully applied in deaminative hydroalkylation of a series of alkenes including naturally occurring dehydroalanine, which provides an efficient way to prepare ß-alkyl substituted unnatural amino acids under mild and photocatalyst-free conditions. Importantly, by using this protocol, the deaminative cyclization of peptide backbone N-terminals is realized. Furthermore, the use of Et3N or PPh3 as reductants and H2O as hydrogen atom source is a practical advantage. We anticipate that our protocol will be useful in peptide synthesis and modern peptide drug discovery.

Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 ß-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity.

Structure-activity relationship study of hydroxyethylamine isostere and P1' site structure of peptide mimetic BACE1 inhibitors.

An aromatic substituent has been introduced into a known hydroxyethylamine (HEA)-type BACE1 inhibitor containing the superior substrate sequence to enhance inhibitory activity. The HEA-type isosteres bearing different hydroxyl group and methyl group configurations were prepared through a branched synthesis approach using intra- and inter-molecular epoxide opening reactions. The effect of their configuration was evaluated, showing that an R-configuration improved the inhibitory activity, while introduction of a methyl group on the isostere decreased the activity. Based on the non-substituted isostere with an R-configuration, 21 derivatives containing various substituents at the P1' site were synthesized. Our evaluation of the derivatives showed that the structure of the P1' site had a clear effect on activity, and highly potent inhibitor 40g, which showed sub-micromolar activity against recombinant BACE1 (rBACE1), was identified. The docking simulation of 40g with rBACE1 suggested that a carboxymethyl group at the para-position of the P1' benzene ring interacted with Lys285 in the S1' pocket.

Overcoming GNA/RNA base-pairing limitations using isonucleotides improves the pharmacodynamic activity of ESC+ GalNAc-siRNAs.

We recently reported that RNAi-mediated off-target effects are important drivers of the hepatotoxicity observed for a subset of GalNAc-siRNA conjugates in rodents, and that these findings could be mitigated by seed-pairing destabilization using a single GNA nucleotide placed within the seed region of the guide strand. Here, we report further investigation of the unique and poorly understood GNA/RNA cross-pairing behavior to better inform GNA-containing siRNA design. A reexamination of published GNA homoduplex crystal structures, along with a novel structure containing a single (S)-GNA-A residue in duplex RNA, indicated that GNA nucleotides universally adopt a rotated nucleobase orientation within all duplex contexts. Such an orientation strongly affects GNA-C and GNA-G but not GNA-A or GNA-T pairing in GNA/RNA heteroduplexes. Transposition of the hydrogen-bond donor/acceptor pairs using the novel (S)-GNA-isocytidine and -isoguanosine nucleotides could rescue productive base-pairing with the complementary G or C ribonucleotides, respectively. GalNAc-siRNAs containing these GNA isonucleotides showed an improved in vitro activity, a similar improvement in off-target profile, and maintained in vivo activity and guide strand liver levels more consistent with the parent siRNAs than those modified with isomeric GNA-C or -G, thereby expanding our toolbox for the design of siRNAs with minimized off-target activity.

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach.

The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6 M03, 6LU7, 2GZ7, 6 W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n = 40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of âˆ¼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.

Synthesis of molecularly imprinted polymers based on boronate affinity for diol-containing macrolide antibiotics with hydrophobicity-balanced and pH-responsive cavities.

In this research, in order to separate and purify diol-containing macrolide antibiotics, like tylosin, from complex biological samples, molecularly imprinted polymer (MIP) based on boronate affinity for tylosin was synthesized by using precipitation polymerization method with 4-vinylphenylboronic acid (VPBA) and dimethyl aminoethyl methacrylate (DMAEMA) as pH-responsive functional monomers, and N,N'-methylene bisacrylamide (MBAA)/ ethylene glycol dimethacrylate (EGDMA) as the co-crosslinkers that balance the hydrophobicity of the MIP. The synthesized tylosin-MIP had the advantages of high adsorption capacity (120 mg/g), fast pH-responsiveness responsible for the accessibility of imprinted cavities, and high selectivity coefficient towards tylosin versus its analogues (2.8 versus spiramycin, 7.3 versus desmycosin) in an aqueous environment. The mechanism of boronate affinity between tylosin and VPBA in the form of charged hydrogen bonding was analyzed via density functional theory (DFT). MIPs were used to successfully separate diol-containing macrolides through molecularly imprinted solid phase extraction (MISPE). The results show that MIPs prepared in this method have a good application prospect in the separation and purification of the diol-containing macrolide antibiotics.

Dynamic Manipulation of DNA-Programmed Crystals Embedded in a Polyelectrolyte Hydrogel.

DNA is a powerful tool for programming the three-dimensional organization of nanomaterials, where the specificity of nucleotide base-pairing can enable precise, complex, and dynamically addressable structures like colloidal crystals. However, because these DNA-programmed materials are often only stable in solution, their organization can be easily disrupted by changes to its local environment. Methods to stabilize these materials have been developed, but often come at the expense of altering or permanently fixing the materials' structures, removing many of the benefits of using DNA interactions to program assembly. Thus, these methods limit the application of DNA-assembled structures as dynamic and programmable material components. Here, a method is presented to resolve these drawbacks for DNA-grafted nanoparticles, also known as Programmable Atom Equivalents (PAEs), by embedding assembled lattices within a hydrogel matrix. The preformed lattices are exposed to polymerizable residues that electrostatically bind to the charged backbone of the DNA ligands and form a continuous, permeating gel network that stabilizes the colloidal crystals upon introduction of a radical initiator. After embedding PAEs in a hydrogel, deformation of the macroscopic matrix results in concomitant deformation of the PAE lattices, allowing superlattice structural changes to be induced by chemical methods (such as changing solute concentration to alter swelling pressure) or by application of mechanical strain. Changes to the structure of the PAE lattices are reversible and repeatable over multiple cycles and can be either isotropic (such as by swelling) or anisotropic (such as by mechanical deformation). This method of embedding nanoparticle crystals inside of a flexible and environmentally responsive hydrogel is therefore a useful tool in extending the utility of PAEs and other micro- and nanostructures assembled with DNA.

Activation of Ligand Reaction on an Iron Complex: H/D Exchange Reaction of a Low-Spin Bis[2-(Pyridylmethylidene)-1-(2-pyridyl)methylamine]iron(II) Complex.

With the aim of shedding some light on the still scarcely investigated mechanism of transformation of imines in metal complexes, this study describes the investigation of the hydrogen-deuterium (H/D) exchange reaction of a bis[2-(pyridylmethylidene)-1-(2-pyridylmethylamine]iron(II) complex ([Fe(PMAP)2]2+), following our previous work on a low-spin iron(II) complex bearing two molecules of S-2-pyridylmethylidene-1-(2-pyridyl)ethylamine. This complex has been proven to undergo successive transiminations in acetonitrile, yielding a bis[1-(2-pyridyl)ethylidene-2-pyridylmethylamine]iron(II) complex. In the analogous [Fe(PMAP)2]2+ complex, a 1,3-hydrogen rearrangement occurs in a 10% deuterium oxide-acetonitrile-d3 (D2O-CD3CN) solution. The H/D exchange reaction of [Fe(PMAP)2]2+ was examined in the presence of various concentrations of 2,6-dimethylpyridine as a base in a 10% D2O-CD3CN solution at 45 °C, and the reaction mechanism was investigated.

Suitable analysis of α-amino acids by a direct combination of thin-layer chromatography and matrix-assisted laser desorption/ionization mass spectrometry in conjunction with post-chromatographic fixed-charge derivatization.

On-spot fixed-charge derivatization has been suggested for the modification of α-amino acids for their analysis by thin layer chromatography/matrix-assisted laser desorption ionization (TLC/MALDI) mass spectrometry. The approach was based on post-chromatographic treatment of separated analytes by tris(2,6-dimethoxyphenyl)methenium salt and triethylamine. The reaction proceeded smoothly in mild conditions and gave rise to pink-red colored derivatives, containing permanent positive charge. Their MALDI mass spectra, recorded directly from TLC plates, revealed intense peaks corresponding to decarboxylated cationic parts. All derivatives are characterized by high ionization efficiency, which indicates the high sensitivity of the developed method for analyzing amino acids. Applicability of the method to analysis of amino acids was demonstrated on artificial mixtures and dietary supplement.

A micro-solid phase extraction device to prepare a molecularly imprinted porous monolith in a facile mode for fast protein separation.

A molecularly imprinted polymeric monolith was synthesized in an aqueous environment in 15 min via UV-irradiation. The imprinted monolith was composed of hydroxyethyl methacrylate as monomer, dimethyl amino ethyl methacrylate as functional monomer, methylene bisacrylamide and piperazine diacrylamide as crosslinkers and human serum albumin as template molecule. The synthesis took place in a PDMS-based device (2.5 cm long) yielding a micro-solid phase extraction column (3 × 5 mm) with two built-in fingertight connectors for an infusion pump and fraction collector. The imprinted monolith displayed the characteristic features of a porous polymeric monolith, had dimethyl amino ethyl methacrylate and human serum albumin as functional groups within the monolith and showed high permeability (0.51 × 10-13 m2). 85% of the imprinted cavities were readily available for rebinding of human serum albumin with an imprinting factor of 1.3. In comparison to a non-imprinted monolith, molecular imprinting increased human serum albumin adsorption by > 30%. Imprinted monolith displayed selectivity for human serum albumin over other competing proteins (human transferrin, ovalbumin and carbonic anhydrase) with similar or different isoelectric points and size. Human serum albumin was adsorbed (in dynamic mode) with > 98% selectivity from diluted human plasma using the imprinted monolith device. Device to device reproducibility and reusability of the device for 5 cycles showcase the imprinted monolith micro-device efficiency.

Synthesis of Novel Aryloxyethylamine Derivatives and Evaluation of Their in Vitro and in Vivo Neuroprotective Activities.

A series of aryloxyethylamine derivatives were designed, synthesized and evaluated for their biological activity. Their structures were confirmed by 1 H-NMR, 13 C-NMR, FT-IR and HR-ESI-MS. The preliminary screening of neuroprotection of compounds in vitro was detected by MTT, and the anti-ischemic activity in vivo was tested using bilateral common carotid artery occlusion in mice. Most of these compounds showed potential neuroprotective effects against the glutamate-induced cell death in differentiated rat pheochromocytoma cells (PC12 cells), especially for (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone, (4-bromophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone, (4-chlorophenyl)(1-{2-[(naphthalen-2-yl)oxy]ethyl}piperidin-4-yl)methanone, (4-chlorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone and {1-[2-(4-bromophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone, which exhibited potent protection of PC12 cells at three doses (0.1, 1.0, 10 µM). Compounds (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, (4-fluorophenyl){1-[2-(naphthalen-2-yloxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone and {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone possessed the significant prolongation of the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all five doses tested (200, 100, 50, 25, 12.5 mg/kg) and had significant neuroprotective activity. In addition, (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone and {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone possessed outstanding neuroprotection in vitro and in vivo. These compounds can be used as a promising neuroprotective agents for future development of new anti-ischemic stroke agents. Basic structure-activity relationships are also presented.

Cationised dextran and pullulan modified with diethyl aminoethyl methacrylate for gene delivery in cancer cells.

This work describes the synthesis and characterisation of cationised dextran and pullulan modified with diethyl aminoethyl methacrylate (DEAEM) for gene delivery in cancer cells. To dextran and pullulan, PEI was conjugated to impart cationicity. These cationised polysaccharides were then modified with DEAEM monomer via Michael addition reaction and synthesised four different derivatives viz DPD I, DPD II, PPD I and PPD II. These vectors form nanocomplexes with DNA exhibiting positive zeta potential. These nanoplexes are cytocompatible in C6, HeLa and L929 cells. Transfection efficiency of these vectors was evaluated using p53 plasmid which demonstrated good transfection in cancer cells (C6 and HeLa) alone. Biodistribution studies of DPD II and PPD II in BALB/c mice shows its tendency to accumulate in liver tissue and not in any vital organs like brain, lungs and heart. In addition, these derivatives also exhibit good renal clearance.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Switchable-hydrophilicity solvent liquid-liquid microextraction versus dispersive liquid-liquid microextraction prior to HPLC-UV for the determination and isolation of piperine from Piper nigrum L.

Switchable-hydrophilicity solvent liquid-liquid microextraction and dispersive liquid-liquid microextraction were compared for the extraction of piperine from Piper nigrum L. prior to its analysis by using high-performance liquid chromatography with UV detection. Under optimum conditions, limits of detection and quantitation were found as 0.2-0.6 and 0.7-2.0 µg/mg with the two methods, respectively. Calibration graphs showed good linearity with coefficients of determination (R2 ) higher than 0.9962 and percentage relative standard deviations lower than 6.8%. Both methods were efficiently used for the extraction of piperine from black and white pepper samples from different origins and percentage relative recoveries ranged between 90.0 and 106.0%. The results showed that switchable-hydrophilicity solvent liquid-liquid microextraction is a better alternative to dispersive liquid-liquid microextraction for the routine analysis of piperine in food samples. A novel scaled-up dispersive liquid-liquid microextraction method was also proposed for the isolation of piperine providing a yield of 102.9 ± 4.9% and purity higher than 98.0% as revealed by NMR spectroscopy.

Effect of Four Novel Bio-Based DES (Deep Eutectic Solvents) on Hardwood Fractionation.

Using the basic principle of construction between a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD), four bio-based deep eutectic solvents (DESs) were prepared in a 1:2 molar ratio of HBA:HBD. 2,3-Dihydroxypropyl-1-triethylammonium chloride ([C9H22N+O2]Cl-) was synthesized from raw glycerol and used as an HBA. Lactic acid, urea, pure glycerol, and ethylene glycol were selected as HBD. Attempts to prepare DESs, using citric acid and benzoic acid as HBDs, were unsuccessful. All these DESs were characterized using FTIR and NMR techniques. Besides, physicochemical parameters such as pH, viscosity, density, and melting point were determined. The behavior of these DES to fractionate olive pomace was studied. Lignin recovery yields spanned between 27% and 39% (w/w) of the available lignin in olive pomace. The best DES, in terms of lignin yield ([C9H22N+O2]Cl- -lactic acid), was selected to perform a scale-up lignin extraction using 40 g of olive pomace. Lignin recovery on the multigram scale was similar to the mg scale (38% w/w). Similarly, for the holocellulose-rich fractions, recovery yields were 34% and 45% for mg and multi-gram scale, respectively. Finally, this DES was used to fractionate four fruit pruning samples. These results show that our novel DESs are alternative approaches to the ionic liquid:triethylammonium hydrogen sulfate and the widely used DES: choline chloride:lactic acid (1:10 molar ratio) for biomass processing.

Continuous-Flow Accelerated Sulfation of Heparan Sulfate Intermediates.

We report for the first time a continuous-flow strategy to execute O-sulfation modification of heparan sulfate (HS) oligosaccharides. A systematic investigation of the influence of the flow parameters on the installation of the sulfate group on glucosamine monosaccharide can aid the development of a comprehensive, quick, and reliable strategy for O-sulfation of HS oligosaccharide precursors. Deprotection of the sulfated heparin intermediates led to the development of a comprehensive biologically inspired oligosaccharide library to understand the crucial structure-function relationship of HS.

Tracing the Full Bimolecular Photocycle of Iron(III)-Carbene Light Harvesters in Electron-Donating Solvents.

Photoinduced bimolecular charge transfer processes involving the iron(III) N-heterocyclic carbene (FeNHC) photosensitizer [Fe(phtmeimb)2]+ (phtmeimb = phenyltris(3-methyl-imidazolin-2-ylidene)borate) and triethylamine as well as N,N-dimethylaniline donors have been studied using optical spectroscopy. The full photocycle of charge separation and recombination down to ultrashort time scales was studied by investigating the excited-state dynamics up to high quencher concentrations. The unconventional doublet ligand-to-metal charge transfer (2LMCT) photoactive excited state exhibits donor-dependent charge separation rates of up to 1.25 ps-1 that exceed the rates found for typical ruthenium-based systems and are instead more similar to results reported for organic sensitizers. The ultrafast charge transfer probed at high electron donor concentrations outpaces the solvent dynamics and goes beyond the classical Marcus electron transfer regime. Poor photoproduct yields are explained by donor-independent, fast charge recombination with rates of ∼0.2 ps-1, thus inhibiting cage escape and photoproduct formation. This study thus shows that the ultimate bottlenecks for bimolecular photoredox processes involving these FeNHC photosensitizers can only be determined from the ultrafast dynamics of the full photocycle, which is of particular importance when the bimolecular charge transfer processes are not limited by the intrinsic excited-state lifetime of the photosensitizer.