Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues.

Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the "theranostic pair" concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.

[Level and health evaluation of rare earth elements in human blood and hair in the mining areas in Northwest Hubei].

OBJECTIVE: To investigate the content of rare earth elements(REs)in blood and hair of residents in a RE mining area in Northwest Hubei, and evaluate the impact of REs on the health status of local residents. METHODS: A total of 191 residents from the core area of RE mining areas and 186 residents from non RE mining areas, aged 20-69, were selected. The content of REs in the blood and hair of the survey subjects was measured using inductively coupled plasma mass spectrometry, and compared with existing literature values. At the same time, blood tests and questionnaire surveys will be conducted on the health status of residents to examine whether human RE enrichment can lead to endemic diseases. RESULTS: The average total content of REs in the blood of residents in the mining area was 60.22 ng/mL, which was 3.35 times that of the control area; The average total content of REs in hair was 1197.91 ng/g, which was 6.32 times higher than the control area. As age increasing, the abundance of REs in the blood and hair of both men and women in mining areas increased. The proportion of Yttrium and Scandium in the blood and hair were much higher than that in the soil. Compared to hair, Yttrium and Scandium were more easily enriched in the blood. There was no significant difference in the probability of fatty liver, hepatitis B, hypoglycemia, hypotension, hypertension and heart disease and the average life span between residents in RE mining areas and those in the control area. CONCLUSION: The high daily average dietary intake of REs in residents leads to a relatively large accumulation of REs in human blood and hair, but no significant and substantial human health damage has been found at present.

Scandium Ion-Promoted Electron-Transfer Disproportionation of 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-Oxide (PTIO•) in Acetonitrile and Its Regeneration Induced by Water.

2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO•), a persistent nitronyl nitroxide radical, has been used for the detection and trapping of nitric oxide, as a redox mediator for batteries, for the activity estimation of antioxidants, and so on. However, there is no report on the reactivity of PTIO• in the presence of redox-inactive metal ions. In this study, it is demonstrated that the addition of scandium triflate, Sc(OTf)3 (OTf = OSO2CF3), to an acetonitrile (MeCN) solution of PTIO• resulted in an electron-transfer disproportionation to generate the corresponding cation (PTIO+) and anion (PTIO-), the latter of which is suggested to be stabilized by Sc3+ to form [(PTIO)Sc]2+. The decay of the absorption band at 361 nm due to PTIO•, monitored using a stopped-flow technique, obeyed second-order kinetics. The second-order rate constant for the disproportionation, thus determined, increased with increasing the Sc(OTf)3 concentration to reach a constant value. A drastic change in the cyclic voltammogram recorded for PTIO• in deaerated MeCN containing 0.10 M Bu4NClO4 was also observed upon addition of Sc(OTf)3, suggesting that the large positive shift of the one-electron reduction potential of PTIO• (equivalent to the one-electron oxidation potential of PTIO-) in the presence of Sc(OTf)3 may result in the disproportionation. When H2O was added to the PTIO•-Sc(OTf)3 system in deaerated MeCN, PTIO• was completely regenerated. It is suggested that the complex formation of Sc3+ with H2O may weaken the interaction between PTIO- and Sc3+, leading to electron-transfer comproportionation to regenerate PTIO•. The reversible disproportionation of PTIO• was also confirmed by electron paramagnetic resonance (EPR) spectroscopy.

New insights on scandium separation from scandium concentrate with titanium dioxide wastewater.

In this study, a scandium concentrate with Sc2O3 content of 66.24 g/t was obtained from V-Ti magnetite tailings by physical concentration, and the main Sc-bearing minerals were augite and hornblende. A novel process of roasting and leaching was proposed to extract scandium from scandium concentrate with titanium dioxide wastewater. Scandium concentrate was pretreated by roasting, and titanium dioxide wastewater was used to directly leach scandium from the roasted ore. The effects of roasting and leaching parameters such as roasting temperature, roasting time, roasting agents, leaching temperature, leaching time, liquid-to-solid ratio, and leaching agents on scandium separation were thoroughly researched in the experimental procedure. The results show that a scandium leaching efficiency of 85.89% was obtained, and the scandium content of leaching residue decreased to 9.31 g/t under the optimal conditions: a roasting temperature of 1123 K, a roasting time of 120 min, a leaching temperature of 343 K, a leaching time of 120 min, and a m (titanium dioxide wastewater)∶m (roasted ore)∶m (ammonium fluoride) ratio of 8∶1∶0.09. The main findings of the scandium separation mechanism show that Sc-bearing minerals can effectively decompose and release scandium element after roasting, and created favorable conditions for scandium leaching with titanium dioxide wastewater to achieve the purpose of scandium recovery.

Revisiting the isolation and characterisation of Entamoeba histolytica lipopeptidophosphoglycan.

The parasite Entamoeba histolytica is the cause of amoebic dysentery and liver abscess in humans. On the protozoan cell surface, a variety of glycosylated molecules are involved in the interaction with the environment, such as attachment to the colonic mucus. One of these molecules is the lipopeptidophosphoglycan (LPPG), a complex surface component with antigenic properties. Its structure is only partly known, it is a glycosylphosphatidylinositol (GPI)-linked glycoprotein with a large amount of O-glycosylation. To date, the sequence of a core protein has not been identified. In this study, we further investigated this complex surface molecule aided by the availability of the monoclonal antibody EH5, which had been raised in our laboratory. We studied the extraction of LPPG in various solvent mixtures and discovered that 2-butanol saturated water was simple and superior to other solvents used in the past. The isolated LPPG was subjected to treatment with several proteases and the Ser/Thr specific cleavage agent scandium (III) trifluoromethanesulfonate (scandium triflate). The products were probed with antibody EH5 and the blots showed that the LPPG preparation was largely resistant to standard proteases, but could be cleaved by the scandium compound. These observations could point to the existence of a Ser- or Thr-rich core protein structure.

44Sc production from enriched 47TiO2 targets with a medical cyclotron.

44Sc is a ß+-emitter which has been extensively studied for nuclear medicine applications. Its promising decay characteristics [t1/2 = 3.97 h, E [Formula: see text] = 632 keV (94.3%), Eγ = 1157 keV (99.9%); 1499 keV (0.91%)] make it highly attractive for clinical PET imaging, offering an alternative to the widely used 68Ga [t1/2 = 67.7 min, E [Formula: see text] = 836 keV (87.7%)]. Notably, its nearly fourfold longer half-life opens avenues for applications with biomolecules having extended biological half-lives and enables the centralized distribution of 44Sc radiopharmaceuticals. An additional advantage of employing 44Sc as a diagnostic radioisotope lies in its counterpart, the ß--emitter 47Sc, which is currently under investigation for targeted radiotherapy. Together, they form an ideal theranostic pair, providing a comprehensive solution for both diagnostic imaging and therapeutic applications in nuclear medicine. At the Bern medical cyclotron, a study to optimize the production of scandium radioisotopes is currently ongoing. In this context, proton irradiation of titanium targets has been investigated, exploiting the reactions 47Ti(p,α)44Sc and 50Ti(p,α)47Sc. This approach enables the production of Sc radioisotopes within a single PET medical cyclotron facility, employing identical chemical procedures for target preparation and post-irradiation processing. In this paper, we report on cross-section measurements of the 47Ti(p,α)44Sc nuclear reaction using 95.7% enriched 47TiO2 targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Production tests were performed to confirm these findings.

Toxicokinetic study of scandium oxide in rats.

Canada has recently invested in the large-scale exploitation of scandium oxide. However, there are no studies available to date to understand its toxicokinetics in the animal or human body, which is necessary to assess exposure and health risks. The aim of this research was to investigate the toxicokinetics of absorbed scandium oxide (Sc2O3) using the rat as an experimental model. Male Sprague-Dawley rats were injected intravenously with 0.3 or 1 mg Sc2O3/kg body weight (bw). Blood and excreta (urine and feces) were collected sequentially during a 21-day period, and main organs (liver, spleen, lungs, kidneys, brain) were withdrawn at sacrifice on day 21. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for the measurement of Sc element in the different samples. The mean residence time (MRTIV) calculated from the blood profile was 19.7 ± 5.9 h and 43.4 ± 24.6 h at the lower and higher doses, respectively. Highest tissue levels of Sc were found in the lungs and liver; respective lung values of 10.6 ± 6.2% and 3.4 ± 2.3% of the Sc dose were observed at the time of sacrifice while liver levels represented 8.9 ± 6.4% and 4.6 ± 1.1%. Elimination of Sc from the body was not complete after 21 days. Cumulative fecal excretion over the 21-day collection period represented 12.3 ± 1.3% and 5.9 ± 1.0% of the lower and higher Sc doses, respectively, and showed a significant effect of the dose on the excretion; only a small fraction of the Sc dose was recovered in urine (0.025 ± 0.016% and 0.011 ± 0.004% in total, respectively). In addition to an effect of the dose on the toxicokinetics, results highlight the importance of the lung as a site of accumulation and retention of Sc2O3, which raises the question of the risks of effects related to respiratory exposure in workers. The results also question the relevance of urine as a matrix for biological exposure monitoring. A more in-depth inhalation toxicokinetic study would be necessary.

Scandium Radioisotopes-Toward New Targets and Imaging Modalities.

The concept of theranostics uses radioisotopes of the same or chemically similar elements to label biological ligands in a way that allows the use of diagnostic and therapeutic radiation for a combined diagnosis and treatment regimen. For scandium, radioisotopes -43 and -44 can be used as diagnostic markers, while radioisotope scandium-47 can be used in the same configuration for targeted therapy. This work presents the latest achievements in the production and processing of radioisotopes and briefly characterizes solutions aimed at increasing the availability of these radioisotopes for research and clinical practice.

Comparison of micromorphological changes in enamel using SEM analysis after conventional and erbium, chromium:yttrium, scandium, gallium, and garnet hard-tissue laser fissurotomy: An in vitro study.

Background: Well articulated by John Knowles - "Everything has to evolve or else it perishes." With the paradigm shift of emphasis toward the prevention of dental caries, it has been proven that laser irradiation protects against both caries initiation and caries progression. Aim: The aim of the study was to evaluate and compare the micromorphology of caries-free extracted premolars using a Scanning electron microscope (SEM) after fissurotomy by conventional fissurotomy bur and erbium, chromium: yttrium, scandium, gallium, and garnet (ER, CR: YSGG) hard-tissue laser. Methodology: Sixty caries-free premolars extracted atraumatically for orthodontic treatment were included in the study. The samples were divided into two groups randomly (Group 1: fissurotomy by bur, n = 30, and Group 2: fissurotomy by hard-tissue laser, n = 30). Each sample was further divided into halves from the occlusal surface wherein one-half of the occlusal surface received fissurotomy procedure and the other half was control. Samples were analyzed by scanning electron microscopy (SEM) for micromorphological changes. Results: Profile image of control samples revealed the disorganization of enamel surface at the junction of fissures forming a heterogeneous tissue and agglomeration of enamel with deep pit and fissure. On the contrary, the image of experimented samples (with laser fissurotomy) showed smooth enamel surface and homogeneous enamel subsurface with wider pit and fissure owing to self-cleansing ability. Conclusion: On the grounds of the present study results, it could be concluded that the intervention of ER, CR: YSGG hard-tissue laser possesses self-cleansable pit and fissures for caries prevention and has the potential to irradicate the smear layer entirely for superior attachment of remineralizing agents.

A combined inorganic-organic titanium-44/scandium-44g radiochemical generator.

Scandium-44g (t1/2 = 4.0 h) is an emerging radioisotope for positron emission tomography. It can be produced with a radiochemical generator using its long-lived parent, titanium-44 (t1/2 = 59.1 years). This work presents a new inorganic substrate for 44Ti/44gSc radiochemical generator design based on porous TiO2 microbeads (80 µm and 110 µm particle size, 60 Å pores). Comprehensive evaluation of conditions optimal for generator construction (44Ti loading) and use (44gSc elution) is provided in three steps. For stable 44Ti loading onto titania, heat-treatment at 180 °C for 90 min is shown to be effective while 0.3 M HCl(aq) is identified as the medium of choice for 44gSc elution. Two titania-based 3.6 MBq generators prepared under optimized conditions are characterized with respect to 44gSc recovery and 44Ti breakthrough. Each of these generators employed a different guard substrate to minimize 44Ti breakthrough, TiO2 microbeads and ZR resin. Both are shown to provide comparable 44gSc recoveries close to 50% but differ in 44Ti breakthrough, which is significantly lower with the organic ZR resin guard substrate at 0.0002%. This concept represents a new inorganic-organic approach to 44Ti/44gSc generator design. Benefits of both substrates are exploited: TiO2 has potential for durability necessary for utilizing the long half-life of the 44Ti parent while ZR resin guard segments minimize 44Ti breakthrough.

Photo-induced scandium-catalyzed biomimetic skeleton conversion of lathyrane to naturally rare eupholathone Euphorbia diterpenes.

The naturally scarce eupholathone-type euphornin E (1) was efficiently prepared from abundant lathyrane-type Euphorbia factor L1via a visible-light-induced Sc(OTf)3-catalyzed tandem process. Eupholathones 2 and 3 were also smoothly obtained by changing the reaction solvent. This route provides a convenient method for easily constructing scarce eupholathone- from lathyrane-type Euphorbia diterpenes, and confirms the biogenetic relationship between them from a chemical standpoint. Notably, compound 1 exhibited good anti-HIV activity.

Erbium, chromium:Yttrium-scandium-gallium-garnet (Er, Cr:YSGG) laser versus diode laser in the treatment of pericoronitis.

Background: There are limited number of studies about the lasers used for the treatment of pericoronitis infection. Aim: To compare the Er, Cr:YSGG laser and diode laser applications clinically in the treatment of pericoronitis infection. Patients and Methods: Sixty patients with pericoronitis infection were divided into three groups using block randomization: Er, Cr:YSGG + antibiotic group, n = 20 (mean age: 24.20 ± 6.13; 14 females, 6 males); diode group + antibiotic, n = 20 (mean age: 23.45 ± 2.96; 14 females, 6 males); and antibiotic, n = 20 (mean age: 22.45 ± 3.02; 11 females, 9 males). In addition, laser application was performed for patients in the Er, Cr:YSGG and diode laser groups on the 1st and 2nd days until the extraction day. Tooth extractions were performed on the 3rd day for all patients. Patients' pain (with visual analog scale [VAS]), lymphadenopathy, and local edema were clinically evaluated in the first 3 days and on the 7th day of treatment. Results: Pain score on the 2nd day of treatment was determined to be significantly lower in the Er, Cr:YSGG + antibiotic laser group as compared with the other two groups (P = 0.019). Although regression of lymphadenopathy on the 3rd day was highest (P = 0.025) in the Er, Cr:YSGG group, there was no significant difference between the groups regarding local edema. Conclusion: Er, Cr:YSGG laser improved the healing process in the treatment of pericoronitis and made an important contribution to the treatment.

Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics.

In the field of nuclear medicine, the ß+ -emitting 43Sc and ß- -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented.

Water-Induced Regeneration of a 2,2-Diphenyl-1-picrylhydrazyl Radical after Its Scandium Ion-Promoted Electron-Transfer Disproportionation in an Aprotic Medium.

A neutral, stable radical, 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•), has been frequently used to estimate the activity of antioxidants for more than 60 years. However, the number of reports about the effect of metal ions on the reactivity of DPPH• is quite limited. We have recently reported a unique electron-transfer disproportionation of DPPH• to produce the DPPH cations (DPPH+) and anions (DPPH-) upon the addition of scandium triflate [Sc(OTf)3 (OTf = OSO2CF3)] to an acetonitrile (MeCN) solution of DPPH•. The driving force of this reaction is suggested to be an interaction between DPPH- and Sc3+. In this study, it is demonstrated that the addition of H2O to the DPPH•-Sc(OTf)3 system in MeCN resulted in an increase in the absorption band at 519 nm due to DPPH•. This indicated that an electron-transfer comproportionation occurred to regenerate DPPH•. The regeneration of DPPH• was also confirmed by electron paramagnetic resonance (EPR) spectroscopy. The amount of DPPH• increased with an increasing amount of added H2O to reach a constant value. The detailed mechanism of regeneration of DPPH• was proposed based on the detailed spectroscopic and kinetic analyses, in which the reaction of DPPH+ with [(DPPH)2Sc(H2O)3]+ generated upon the addition of H2O to [(DPPH)2Sc]+ is the rate-determining step.

Alpha-induced production and robust radiochemical separation of 43Sc as an emerging radiometal for formulation of PET radiopharmaceuticals.

Scandium-43 is an emerging PET radiometal that was produced by α-particle bombardment on natural CaCO3 target via natCa (α,p) 43Sc and natCa (α,n) 43Ti→43Sc reactions using K-130 cyclotron at VECC. A robust radiochemical procedure based on selective precipitation of 43Sc as Sc(OH)3 was developed for separation of the radioisotope from the irradiated target. The overall yield of the separation process was >85% and it was obtained in a form suitable for preparation of target specific radiopharmaceuticals for PET imaging of cancer.

Record High 36 K Transition Temperature to the Superconducting State of Elemental Scandium at a Pressure of 260 GPa.

Elemental materials provide clean and fundamental platforms for studying superconductivity. However, the highest superconducting critical temperature (T_{c}) yet observed in elements has not exceeded 30 K. Discovering elemental superconductors with a higher T_{c} is one of the most fundamental and challenging tasks in condensed matter physics. In this study, by applying high pressure up to approximately 260 GPa, we demonstrate that the superconducting transition temperature of elemental scandium (Sc) can be increased to 36 K from the transport measurement, which is a record-high T_{c} for superconducting elements. The pressure dependence of T_{c} implies the occurrence of multiple phase transitions in Sc, which is in agreement with previous x-ray diffraction results. Optimization of T_{c} is achieved in the Sc-V phase, which can be attributed to the strong coupling between d electrons and moderate-frequency phonons, as suggested by our first-principles calculations. This study provides insights for exploring new high-T_{c} elemental metals.

Light-activated carbon dot nanozyme with scandium for a highly efficient and pH-universal bio-nanozyme cascade colorimetric assay.

Nanozyme-based colorimetric assays have attracted much attention due to their cost-effectiveness, high stability, and sensitivity. In particular, the catalytic cascade imparted by the biological enzyme is highly selective. However, developing an efficient, one-pot, and pH-universal bio-nanozyme cascade remains challenging. Considering the tunable activity of the photo-activated nanozyme, we herein demonstrated a pH-universal colorimetric assay based on the Sc3+-boosted photocatalytic oxidation of carbon dots (C-dots). As a strong Lewis acid, Sc3+ shows ultra-fast complexation with OH- over a broad pH range and dramatically decreases the pH of the buffer solutions. In addition to regulating the pH, Sc3+ also binds to the C-dots to produce a persistent and strongly oxidizing intermediate based on photo-induced electron transfer. The proposed Sc3+-boosted photocatalytic system was successfully used in a cascade colorimetric assay with biological enzymes for assessing their activity as well as the detection of enzyme inhibitors at neutral and alkaline pH. Instead of designing new nanozymes for catalytic cascades, this work suggests that introducing promoters can be a convenient strategy in practical applications.

4,5-Dihydro-1,2,4-oxadiazole as a Single Nitrogen Transfer Reagent: Synthesis of Functionalized Isoxazoles Assisted by Sc(OTf)3 or Au(I)/Sc(OTf)3 Synergistic Catalysis.

A five-membered N-O heterocycle, 4,5-dihydro-1,2,4-oxadiazole, was found to act as a single nitrogen atom transfer reagent via elimination of a ketone/aldehyde and a nitrile. This reagent was successfully applied for the synthesis of isoxazoles from ynones promoted by Sc(OTf)3 or through Au(I)/Sc(OTf)3 synergistic catalysis. The efficiency of this protocol was also demonstrated by its application in modifications of structurally complex natural products and pharmaceuticals.

Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).

PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Mechanism and Origin of Site Selectivity and Regioselectivity of Scandium-Catalyzed Benzylic C-H Alkylation of Tertiary Anilines with Alkenes.

Benzylic C(sp3)-H alkylation of tertiary anilines with alkenes by an anilido-oxazoline-ligated scandium alkyl catalyst was recently reported with C-H site selectivity and alkene-dependent regioselectivity. Revealing the mechanism and origin of selectivity is undoubtedly of great importance for understanding experimental observations and developing new reactions. Herein, density functional theory (DFT) calculations have been carried out on the model reaction of Sc-catalyzed benzylic C(sp3)-H alkylation of N,N-dimethyl-o-toluidine with allylbenzene. The reaction generally undergoes the generation of active species, alkene insertion, and protonation steps. The difference of the distortion energy of the aniline moiety in transition states, which is related to the ring size of the forming metallacycles, accounts for the site selectivity of C-H activation. Benzylic C(sp3)-H activation possessing less strained five-membered metallacycle compared to the ortho-C(sp2)-H and α-methyl C(sp3)-H activation results in benzylic C(sp3)-H alkylation observed experimentally. Both steric and electronic factors are responsible for the 1,2-insertion regioselectivity for alkyl-substituted alkenes, while electronic factors control the 2,1-insertion manner for vinylsilanes. The analysis of original alkene substrates further strengthens the understanding of the alkene-dependent regioselectivity. These results help us to obtain the mechanistic understanding and are expected to be conducive to the development of new C-H functionalization reactions.