Comprehensive Summary

The deuteration of organic compounds has attracted more attentions in recent years for the potential applications in new drug discovery and synthetic chemistry. For this purpose, many efficient deuterium labeling methodologies have been developed, including hydrogen isotope exchange (HIE), reductive deuteration, and dehalogenative deuteration that allow for the synthesis of selectively deuterated compounds. In the last few years, great breakthroughs in selective isotope labeling have been achieved and the interest in new methodologies for the deuteration of organic molecules is rising. In this review, we summarized the recent developments in the selective deuteration of organic molecules since 2021. Several types of key processes in deuterium incorporation reactions, including H/D exchange, reductive deuteration and dehalogenative deuteration, are introduced and discussed.

Key Scientists

In the 2000s, Derdau and Atzrodt's group have made great contributions to the directing group assisted noble-metal catalyzed hydrogen isotope exchange of arenes and applications of labeled compounds. During the same period, Sajiki and co-workers completed a series of deuteration reactions by heterogeneous platinum-group metal catalysts. Since 2015, Gregory Pieters and co-workers have developed ruthenium catalysts for selective hydrogen isotope exchange. In 2016, Chirik's group achieved hydrogen isotope exchange in the presence of a homogeneous iron complex. David MacMillan and coworkers have made breakthroughs in photocatalyzed HIE reactions for α-amino C(sp³)–H bonds. From 2020, a series of nanoelectrodes were designed for selective dehalogenative deuterations and reductive deuteration of unactivated unsaturated bonds by Zhang's group. Recently, Beller's group developed several efficient strategies for isotopic labeling using heterogeneous earth-abundant catalysts. Our review summarized the latest and important developments since 2021.

Recent developments have led to the emergence of Frustrated Radical Pairs (FRPs) as an extension of the radical family. FRPs are formed from FLPs through Single Electron Transfer (SET) and exhibit the ability to activate a variety of chemical bonds. This review highlights the current state of FRPs in organic synthesis, delves into mechanistic insights, explores their potential, and underscores the challenges in this emerging field.

Abstract

Frustrated Lewis Pairs (FLPs) represent a unique class of interactions in Lewis acid-base chemistry, driven by spatial hindrance or incongruent orbital energy levels that hinder the formation of effective coordination bonds. FLPs have received significant attention for their application in activating small molecules and facilitating organic synthesis reactions. Recent developments have led to the emergence of Frustrated Radical Pairs (FRPs) as an extension of the radical family. FRPs are formed from FLPs through Single Electron Transfer (SET) and exhibit the ability to activate a variety of chemical bonds. While research on FLPs is well-established, investigations into FRPs in organic reactions remain limited. This review highlights the current state of FRPs in organic synthesis, delves into mechanistic insights, explores their potential, and underscores the challenges in this emerging field.

The invention of a well-defined Cu(III) fluoride complex Me₄N⁺[Cu(CF₃)₃(F)]^- 1 enabled to access a versatile of functionalized Cu(III) complexes [Me₄N]⁺[Cu(X)(CF₃)₃]^- (X = C₆F₅, C₆F₅C≡C, CN, Cl, N₃, ^t BuOO, SCN, OAc, SAr), many of them for the first time. The availability of these complexes allowed us to evaluate the the trans-influence order of ligand in Cu(III) complexes: Bn > CF₃ ^– > C₆F₅ ^– > N₃ ^– > py ~ CH₃ ^– ~ C₆F₅C≡C > NO₂PhO^– ~ ^t BuOO^– ~ CH₃COO^– > F^–.

Comprehensive Summary

The invention of a well-defined Cu(III) fluoride complex Me₄N⁺[Cu(CF₃)₃(F)]^- 1 enabled to access a versatile of functionalized Cu(III) complexes [Me₄N]⁺[Cu(X)(CF₃)₃]^- (X = C₆F₅, C₆F₅C≡C, CN, Cl, N₃, ^t BuOO, SCN, OAc, SAr), many of them for the first time. The availability of these complexes allowed us to evaluate the trans-influence order of ligand in Cu(III) complexes: Bn > CF₃ ^– > C₆F₅ ^– > N₃ ^– > py ~ CH₃ ^– ~ C₆F₅C≡C > NO₂PhO^– ~ ^t BuOO^– ~ CH₃COO^– > F^–.

Introducing homochirality provides an effective and universal strategy to precisely design molecular ferroelectrics. This review summarizes the recent progress on the chemical design of molecular ferroelectrics through the strategy of introducing homochirality.

What is the most favorite and original chemistry developed in your research group?

We originally proposed the design principle for molecular ferroelectrics: ferroelectrochemistry, including quasi-spherical theory, the introduction of homochirality, and H/F substitution. Ferroelectrochemistry changed the blind search for molecular ferroelectrics into targeted chemical design, which will develop into a new discipline.

How do you get into this specific field? Could you please share some experiences with our readers?

I have been devoted to the field of molecular ferroelectrics for more than 20 years. In the early stage, I worked on non-centrosymmetric metal-organic complexes, which are potential molecular ferroelectrics. This laid a foundation for my further study of molecular ferroelectrics. Non-centrosymmetric crystal symmetry is only one of the necessary requirements for ferroelectrics, which must adopt one of the 10 polar crystallographic point groups and should also generally undergo symmetry-breaking phase transitions. Due to the lack of a feasible method, the discovery of molecular ferroelectrics has long depended on blindly searching. This process is like finding a needle in a haystack. After years of exploration in this field, I fully understood the Landau phase transition phenomenological theory, Curie symmetry, and Neumann principle from a chemical perspective, and proposed the design principle for molecular ferroelectrics: ferroelectrochemistry, transforming the discovery of molecular ferroelectrics from blind search to targeted chemical design. Never give up no matter how much difficulty you have met, because maybe there is an opportunity the next second.

What is the most important personality for scientific research?

Curiosity, divergent thinking, perseverance, team spirit, and gratitude.

How do you supervise your students?

Emphasis on independent problem-solving abilities. Encourage students to read professional books frequently while doing research.

What are your hobbies? What’s your favorite book(s)?

Jogging, reading, and swimming. My favorite book is The Journey to the West.

Comprehensive Summary

Molecular ferroelectrics have attracted tremendous attention in the past decades due to their excellent ferroelectric performance and superiorities of easy processability, mechanical flexibility, and good biocompatibility. However, the discovery of molecular ferroelectrics is a great challenge and has long relied on blind search. This situation changed recently, with the development of ferroelectrochemistry proposed by our group. As a major design approach in ferroelectrochemistry, introducing homochirality, which facilitates the crystallization of materials in polar crystallographic point groups, greatly improves the probability of being ferroelectrics. Various new molecular ferroelectrics with splendid properties have been precisely synthesized by using this efficient and universal strategy. In this review, we summarize the advances in the chemical design of molecular ferroelectrics through the strategy of introducing homochirality.

Key Scientists

Comprehensive Summary

Construction of C—F bonds is a direct and efficient method for introducing fluorine into pharmaceuticals, agrochemicals, and materials. Strategies such as nucleophilic, electrophilic, radical, and transition-metal catalyzed fluorination have been developed to meet the demand of diverse C—F bond formation. Among them, radical fluorination has been witnessed with substantial advancement in a recent decade. Herein, we reviewed methods for formation of C—F bonds with carbon-centered radicals as key intermediates, especially in recent five years. We introduce in the paper with different fluorinating reagents, strategies for radical generation, and application in late-stage functionalization and synthesis of PET tracers. We also indicate the current limitations and propose the direction of the field for the future development.

Key Scientists

Radical fluorination was recognized as an old and uncontrolled reaction that may date back to the time when element fluorine was first mixed with organic compounds by Henri Moissan in 1891. The development of the field was slow in combination with discovery of new fluorinating reagents. Substantial changes took place in 2012, when the first example of carbon radical fluorination with robust and mild fluorinating reagents, such as NFSI and Selectfluor, was reported by the Sammis group. In the same year, Groves, Lectka, Li, and Boger led the pioneering works on aliphatic C—H fluorination, decarboxylative fluorination, and fluorofunctionalization of alkenes in a radical manner. Photoredox catalysis was introduced to radical fluorination in 2013 by the Chen group, which opens up a new avenue for diverse fluorinative transformations. Most of the previous works focus on radical fluorination to form C(sp³)–F bonds. In 2018, the challenging non-directed aromatic C—H fluorination was solved by Ritter and coworkers. Direct arene fluorination with fluoride ion was later disclosed by the Nicewicz group in 2019. There are many other scientists that have also made tremendous contribution to the development of radical fluorination, with too limited space to list them all. We only list those with first discoveries that may point to the new direction of radical fluorination.

Bioassay-guided investigation led to the discovery of eight novel guaiane-type sesquiterpenoid trimers, artemsieverolactones A—H, which can be classified into four different types based on the connecting models of three guaianolide units. Most of the compounds showed inhibitory activity on HSC-LX2 cells. Artemsieverolactone B (2) exhibited significant inhibition on HSC-LX2 with an IC₅₀ value of 37.8 μmol/L, and inhibited the deposition of human collagen type I (Col I), human hyaluronicacid (HA) and human laminin (HL) with IC₅₀ values of 40.4, 47.3 and 55.1 μmol/L, respectively.

Comprehensive Summary

Eight new guaiane-type sesquiterpenoid trimers, artemsieverolactones A—H, possessing unprecedented scaffolds via biocatalyzed [4+2] Diels−Alder cycloaddition reactions were identified from Artemisia sieversiana. Their structures were determined by comprehensive spectroscopic data, single-crystal X-ray diffraction analyses, and ECD calculations. In terms of structure, artemsieverolactones A—H are first examples of sesquiterpenoid trimers from guaiane-type sesquiterpenoid through four different [4+2] Diels−Alder cycloaddition models. Antihepatic fibrosis assay suggested that five compounds exhibited activity against HSC-LX2 with IC₅₀ values ranging from 37.8 to 117.1 μmol/L. The most active artemsieverolactone B (2) displayed significant inhibitory activity against HSC-LX2 with IC₅₀ value of 37.8 μmol/L, which was 3 times more active than the positive drug silybin (IC₅₀, 139.7 μmol/L). Preliminary mechanism study revealed that artemsieverolactone B could inhibit the deposition of human collagen type I (Col I), human hyaluronic acid (HA), and human laminin (HL) with IC₅₀ values of 40.4 μmol/L (Col I), 55.1 μmol/L (HL), 47.3 μmol/L (HA), which was 2 to 3-fold more potent than silybin.

A new family of dibenzoullazine derivatives was synthesized through 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with alkynylbenziodoxoles followed by oxidation. The benziodoxole moiety in the resulting products was used as a versatile linchpin for the synthesis of structurally diverse functional dibenzoullazines that are difficult to access by other synthetic methods.

Comprehensive Summary

A new family of dibenzoullazine derivatives was synthesized through 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with alkynylbenziodoxoles followed by oxidation. The benziodoxole moiety in the resulting products was used as a versatile linchpin for the synthesis of structurally diverse functional dibenzoullazines that are difficult to access by other synthetic methods.

A disposable monolithic column mass spectrometry analysis kit was developed for direct whole blood analysis. The monolithic column can clean whole blood matrix in 30 s as well as avoid analyte exposure to oxygen, moisture and sunlight for sample storage. This MS kit has been successfully applied to the quantitative analysis of procainamide hydrochloride in 2 μL rat blood, proving it a cost-effective and powerful tool for in vitro diagnostics in the future.

Comprehensive Summary

A monolithic column-based mass spectrometry (MS) analysis kit was prepared for whole blood analysis with MS. The kit is disposable and can be used for purification, storage, transportation and direct analysis of whole blood. The kit mainly consists of a capillary for quantitative microsampling, a cation exchange monolithic column for purification and storage, and a syringe for loading sample. This kit is very friendly to various users that one can easily siphon the blood in the kit followed by rapid clean-up. We established a quantitative method using the kit with a limit detection as low as 0.33 nmol/L, and achieved more than five orders of magnitude enhancement in sensitivity compared to direct nanoelectrospray ionization MS analysis. The column can avoid analyte exposure to environment, which helps the storage of the sample for laboratory analysis. The relative standard deviation of immediate blood analysis and storage blood analysis within 10 d was less than 10%. This method has been successfully applied to the quantitative analysis of procainamide hydrochloride in 2 μL rat blood. These results indicate that this disposable kit does have the potential to achieve highly sensitive quantitative MS analysis in biological samples, which is expected to become a cost-effective and powerful tool for in vitro diagnostics.

We used Ru(II)-catalyst to perform ortho C—H allylation of N-aryl-7-azaindole with 2-methylenecyclic carbonate. The range of reactions is quite wide, and reactions can also be carried out on other heterocyclic compounds, and different carbonates can be used.

Comprehensive Summary

A Ru(II)-catalyzed ortho allylation reaction of N-aryl-7-azaindole with readily available 2-methylidene cyclic carbonate has been developed. This reaction is an effective pathway for synthesizing 7-azaindole derivatives with a wide scope of substrates and high yields. In addition, the method can be extended to the allylation of other heterocyclic compounds and several cyclic carbonates, highlighting the practicality of this strategy for synthesis.

Comprehensive Summary

Stereoselective synthesis of multi-substituted cyclobutanes with different substituents is still a daunting challenge in organic synthesis. We report here a practical and facile approach to synthesizing all-trans 2,3,4-trisubstituted cyclobutanones from readily available dichlorocyclobutanones. The substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic conditions. Further transformation to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was also explored.

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