Nucleophilic Reagents Research Articles

Froth flotation separation of phosphate ore using a novel hammer-like amidoxime surfactant

Phosphate fertilizer, as a necessary nutrient for crops in agriculture, plays a vital role in addressing global food security concerns. The source of phosphate fertilizer is mainly obtained through the production of phosphate ore, which has caused widespread concern. However, in the traditional process, the low production efficiency and high dosage of common surfactants have severely restricted the development and utilization of phosphate rock resources. In this work, a new designed hammer-like amidoxime surfactant (DPA) was characterized and introduced as an outstanding collector to recover high quality phosphate ore. The micro-flotation tests indicated that DPA had more excellent collecting ability and selectivity(The phosphorite recovery was always lower than 15%) than common monomolecular collector 1-dodecylamine (DA). Bench-scale flotation tests showed that a high quality phosphorite concentrate with higher grade and recovery (33.65% and 79.46%, respectively) could be enriched using lower dosage DPA. Economic estimate for a 5000 t/d phosphorite ore concentrator would result in an annual profit increase of approximately $8675330.65 by DPA collector. Density functional theory(DFT) calculations revealed that DPA reacted with Nucleophilic reagent (Phosphorite) by the reactive site of –CH2NH(CH2)2C(NOH)N+H3 group and more easily absorbed on the surface of Phosphorite than DA. Therefore, the above results prove that amidoxime surfactant DPA is an efficient and economic collector to recover high quality phosphate ore, which provides an important guarantee for the production of phosphate fertilizer.

Interaction of the anion [2-B<sub>10</sub>H<sub>9</sub>O(CH<sub>2</sub>)<sub>4</sub>O]− with secondary amines

Objectives. One of the most promising methods of treating malignant tumors is 10B-neutron capture therapy. While compounds based on cluster boron anions [BnHn]2− (n = 10, 12) are often used as boron-containing agents due to the very high specific concentration of boron atoms per particle, the use of such compounds is associated with the need to develop new methods for the functionalization of boron clusters associated with the production of boron-containing derivatives containing biologically active functional groups. One of the most convenient methods of modification of [BnHn]2− (n = 10, 12) anions is the interaction of their derivatives containing cyclic oxonium-type substituents with negatively charged or neutral nucleophilic reagents. The disclosure of substituents of this type leads to the formation of closo-borates with functional groups separated from the cluster by an alkoxyl spacer chain. The purpose of this study is to develop methods for the synthesis of derivatives of the closo-decaborate anion [B10H10]2− with pendant nitrogen-containing groups.Methods. The general control of the reactions of the disclosure of cyclic substituents was carried out on the basis of 11B nuclear magnetic resonance (NMR) spectroscopy data. The structure of the obtained derivatives, including the nature of the attached functional groups, was determined using 1H, 13C attached proton test (APT) NMR and infrared (IR) spectroscopy data. The molecular weight of the synthesized compounds was confirmed by electrospray ionization mass-spectrometry (ESI–MS).Results. The interaction of the anion [2-B10H9O(CH2)4O]− with secondary amines (dimethylamine, dipropylamine, diallylamine, dibutylamine, diisobutylamine, morpholine, di-sec-butylamine) in an ethanol environment is investigated. As a result of the reactions, a cyclic substituent is shown to expand with the addition of a nucleophilic reagent. Seven new derivatives of the closodecaborate anion with pendant nitrogen-containing groups have been synthesized.Conclusions. A developed method for obtaining closo-decaborates with ammonium groups separated from the boron cluster by an alkoxyl spacer group is presented. It is shown that the use of amines of various structures does not fundamentally affect the course of the reactions, allowing the composition and structure of the target derivatives to be effectively regulated. The resulting compounds can be involved in further modification reactions due to a reactive pendant group, as well as being suitable for use as effective polydentate ligands. Closo-decaborates with pendant nitrogen-containing groups and their derivatives are of considerable interest in the synthesis of compounds for use in 10B-neutron capture therapy of malignant tumors.

Synthesis, spectral characterization, DFT and in silico ADME studies of the novel pyrido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines

The chemical behavior of 3-substituted-6,8-dimethylchromones 1-3 was studied towards two selected nucleophiles namely 1H-benzimidazol-2-ylacetonitrile (R1) and 5-amino-2,4-dihydro-3H-pyrazol-3-one (R2). A diversity of pyrido[1,2-a] benzimidazoles and pyrazolo[3,4-b]pyridines was efficiently synthesized through different transformation reactions; depending on the functional group present at C-3 position of the chromone moiety. The two nucleophiles reacted with acrylonitrile 1 through γ-pyrone ring opening at C-2 position followed by recyclization, while compounds 2 and 3 reacted with the two nucleophiles through addition onto the exocyclic double bonds followed by cycloaddition onto the nitrile functions. All theoretical computations were calculated by using Density Functional Theory (DFT) B3LYP method with the help of 6-311G(d,p) basis set. In theoretical studies, the global chemical activity descriptors (FMOs, electron affinity, ionization potential, hardness, softness, etc.) and MEP were calculated to predict the important information related with the stability and reactivity of the prepared molecules. Compound 7 which obtained through ring opening and recyclization of compound 1 by reagent R2 is the more stable product. Fukui functions (FFs) for the starting substrates 1-3 were determined by using the same level of theory. With the aid of local based descriptors in the form of condensed Fukui functions, the sites available for nucleophilic attack for compound 1 were C10 then at C8, and for compounds 2 and 3 were C14 then at C26. The electrons transfer occurs from the nucleophilic reagents (R1 and R2) to the starting substrates 1-3 as deduced from electrophilicity-based charge transfer study (ECT > 0). To explain the nonlinear optical (NLO) properties of the synthesized compounds, the dipole moment, polarizability, and first hyperpolarizability values (in the range 0.84 × 10−30 - 3.85 × 10−30 esu) have been calculated and compared with urea as a reference material. In addition, the 1H NMR chemical shifts of prepared compounds were simulated by GIAO manner and compared with experimental chemical shifts results. The “drug-likeness” and ADME appeared in good agreement with the Lipinski, Ghose and Veber rules, indicating the ability of the prepared compounds to be predictively orally active and bioavailable.

Theoretical Validation of In Chemico Skin Sensitization Assay "ADRA" Using the Products Formed by Nucleophilic Reagents and Chemicals.

Amino acid derivative reactivity assay (ADRA) is an in chemico assay for assessing the skin sensitization potential of chemicals by evaluating the reactivity of nucleophilic reagents that mimic skin proteins. N-(2-(1-Naphthyl)acetyl)-l-cysteine (NAC) and α-N-(2-(1-naphthyl)acetyl)-l-lysine (NAL), used as nucleophilic reagents, are small-molecule derivatives of two different amino acids, each with a naphthalene ring attached. The rate of decrease in the amount of NAC or NAL in the reaction solution is evaluated in this assay as an indicator of the test substance's skin sensitization ability. However, the products formed between the nucleophilic reagent and the test substance, which play an important role in vivo, are not directly identified. Therefore, six highly reactive chemicals, including the proficiency substances listed in the OECD Test Guidelines─squaric acid diethyl ester, 2-methyl-2H-isothiazol-3-one (MI), p-benzoquinone, palmitoyl chloride, diphenylcyclopropenone (DPCP), and imidazolidinyl urea (IU)─were used to determine each formed product. Samples were prepared according to the standard ADRA method, and the formed products were predicted on the basis of the reaction mechanism. Excluding DPCP, the estimated structures were validated using mass spectrometry and nuclear magnetic resonance spectrometry on the synthesized samples. In this manner, the products of each nucleophile were confirmed for all examined test substances. The estimated structure products were obtained through a series of reactions initiated by the nucleophilic attack of NAC's thiol group or NAL's amino group on the test substance's electron-deficient carbonyl carbon. However, contrary to expectations, disulfide-linked-type ring-opened products were detected in the case of MI, and products with free formaldehyde in solution were detected in the case of IU. In summary, all skin sensitizers tested herein reacted with NAC and/or NAL to give products. This supports the theoretical validity of ADRA, which provides an indirect evaluation of the formed products based on a decrease in nucleophilic reagents.

Toward efficient functionalization of polystyrene backbone through ketene chemistry: Synthesis, characterization, and DFT study

AbstractIn this study, polystyrene was functionalized with Meldrum's acid toward the introduction of the ketenes (CCO) system to its backbone for producing a dramatically reactive intermediate. Meldrum's acid, as a ketene source, was reacted by poly(styrene‐co‐p‐chloromethyl styrene) through a simple nucleophilic reaction to synthesize poly(styrene‐co‐styryl Meldrum's acid). Then, the pendant Meldrum's acid under thermal treatment converted to ketene intermediate resulting in highly reactive polystyrenes derivatives, which rapidly reacted by nucleophilic reagents to afford ultimate organic building blocks. The polystyrene derivatives were characterized using elemental analysis, FT‐IR, high‐resolution solid‐state NMR, thermogravimetric analysis (TGA), and differential thermogravimetric analysis (DTG). To clarify the evolutionary mechanisms of polystyrene products, density functional theory (DFT) method B3LYP with the 6–311++G(2d,p) basis set was used. We studied the preparation of polystyrene model compounds through Meldrum's acid thermolysis and nucleophilic substitution. The kinetic and thermodynamic parameters in all reactions and the structural and electronic properties of all molecules were calculated. These data exhibited that based on Gibbs Free energy values, the structure of syndiotactic polystyrene is more stable than that of isotactic polystyrene. Furthermore, it was found that the presence of an electron donor or acceptor substituent on the polystyrene structure affects the electronic bandgap.

Self-Plasticized PVC Prepared by Introducing Fatty Acid to the PVC with Triglycidyl Isocyanurate as an Intermediate Bridge.

The phthalate-free self-plasticization of poly(vinyl chloride) (PVC) conforms to the concept of green chemistry. In this work, phthalate-free, biocontaining, self-plasticized PVC with nonmigration (4-an-TG-X-PVC; X = R, P, or O) was prepared by covalent attachment of ricinoleic acid, palmitic acid, and oleic acid, respectively, to the PVC matrix with 4-aminothiophenol and triglycidyl isocyanurate (TGIC) as intermediate bridges. 4-Aminothiophenol and TGIC acted as the nucleophilic reagent and the thermally stable substance, respectively. The 4-an-TG-X-PVC was observed by diverse characterization methods. Specifically, Fourier transform infrared spectra, 1H nuclear magnetic resonance, gel permeation chromatography, and migration stability tests proved the successful synthesis of 4-an-TG-X-PVC. Compared to the neat PVC, the mechanical property of 4-an-TG-X-PVC is better. The glass transition temperature (Tg) of PVC is 81.24 °C, while that of 4-an-TG-X-PVC decreased to 41.88, 31.49, and 46.91 °C. The 4-an-TG-X-PVC showed higher elongation at break and lower tensile strength than neat PVC. Simultaneously, the thermal property of 4-an-TG-X-PVC got a boost. Thermogravimetry–infrared and thermogravimetry–mass spectrometry showed that 4-an-TG-X-PVC released less HCl than neat PVC in a thermal environment. Discoloration experiments demonstrated that 4-an-TG-P-PVC had better heat stabilization and better color than 4-an-TG-O-PVC and 4-an-TG-R-PVC. This work provides a viable solution to the dependence on phthalates, reduced human health and ecological risks, and endowed PVC with improved thermal stability and nonmigration performance.

COMPARATIVE STUDIES OF THE CHEMICAL INTERACTION OF GUANIDINE WITH DIALDEHYDE CELLU-LOSE AND PECTIN

The presence of reactive aldehyde groups in the elementary units of dialdehyde polysaccharides enables to enter easily into a condensation reaction with reagents containing primary amino groups in the structure. This naturally expands the possibilities of obtaining new derivatives of polysaccharides with physiologically active properties. In this study, we synthesized azomethine derivatives of cellulose and pectin differing in the degree of substitution and the content of the nucleophilic reagent in the composition of the reaction products through chemical interaction of guanidine with macromolecules of dialdehyde polysaccharides. Therefore, regularities of the reaction of nucleophilic substitution of aldehyde groups of oxidized polysaccharides with guanidine were revealed. It was found that the interaction of guanidine amino groups with oxidized pectin in contrast to dialdehyde cellulose occurs through the formation of azomethine and ionic bonds. Moreover, the possibility of obtaining guanidine-containing derivatives of cellulose and pectin with different structural characteristics by varying the molar ratio of the nucleophile and the oxidation state of the starting polysaccharides was proved. The composition and structure of the reaction products were studied by physicochemical methods of analysis. The stability and rate of cleavage of guanidine groups from the macromolecules of dialdehyde cellulose and dialdehyde pectin were studied by hydrolysis of the synthesized samples in acidic and alkaline media.

Cover Feature: Recent Developments in Nucleophilic Fluorination with Potassium Fluoride (KF): A Review (Asian J. Org. Chem. 9/2022)

Potassium fluoride (KF) as a nucleophilic fluorinating reagent with various promoters or catalysts has received immense popularity in the last decade owing to low cost, easy availability, high reactivity, high selectivity, mild reaction conditions, and high functional group tolerance towards various functional groups. This review delineates all the recent developments made in the fluorination of different compounds such as aliphatic, aromatic, and heteroatomic using KF as a nucleophilic fluorinating agent. More information can be found in the Review by Rama Kanwar Khangarot et al.

Promotion of biomass pyrolytic saccharification and lignin depolymerization via nucleophilic reagents quenching of the carbonium ions

The condensation of lignin under acidic conditions inhibited the subsequent value-added utilization of lignin, and the condensed lignin covered the biomass surface. Here, a method of benzenesulfonic acid pretreatment combined with nucleophilic reagents promoted pyrolytic saccharification and lignin hydrogenation was reported. The anhydrosugar content in the pyrolysis bio-oil increased from 66.91% to 69.00%, 72.88%, and 72.16% via adding methanol, propionaldehyde, 3-hydroxylic-2-naphthoic acid, respectively. The characterization of the biomass surface structure and the calculation of bond lengths indicated that carbonium ions prefer to bind with the added nucleophilic reagent rather than the lignin fragment. Furthermore, the quenching of the carbonium ions preserved the β-O-4 bond, as demonstrated in 2D NMR. In the subsequent hydrogenation reaction, it was found that methanol facilitated the production of lignin monomer. The calculation also revealed that the quenching of the carbonium ions with methanol reduced the bond-breaking energy of the β-O-4 bond.

Synthesis and evaluation of a new series of spiro aryl dioxolane compounds: A new scaffold as potential poly(ADP‐ribose)polymerase‐1 (PARP‐1) inhibitors

AbstractA new series of spiro aryl dioxolane derivatives were synthesized and evaluated to find a new scaffold as potential poly(ADP‐ribose)polymerases‐1 (PARP‐1) inhibitors. This key starting compound, 2,6‐bis(methoxybenzylidene)cyclohexanone, was functionalized with different nucleophilic reagents via cyclocondensation reactions to obtain new benzylidene scaffolds containing diverse aryl groups such as spiroindazoleorquinazoline [1,3]dioxolane compounds. Furthermore, the Michael addition reaction of bis‐benzylidene with some active methylene compounds afforded spirochromene‐ or naphthalene‐[1,3]dioxolane compounds. All the synthesized compounds revealed promising inhibition with IC50 values in the nanomolar range (0.997–2.698 nM), not significantly different from that of Olaparib (IC50 = 0.861 nM). Compounds 5b and 15 (IC50 = 1.009 and 0.997 nM) showed the highest potency among all the prepared compounds and accordingly their ability to inhibit the growth of BRCA1 mutated breast cancer cell line MDA‐MB‐436 was tested, where compound 5b (IC50 = 0.67 μM) showed a potency ten folds higher than that of Olaparib but compound 15 (IC50 = 7.47 μM) exerted lower activity but still comparable to that of Olaparib (IC50 = 6.84 μM). Both resulted in the arrest of cell cycle at S phase and caused cell apoptosis. In silico studies including absorption, distribution, metabolism, excretion (ADME) properties, drug‐likeness, and molecular docking were carried out to support the above‐mentioned findings. This work presents compounds 5b and 15 as promising scaffolds as PARP‐1 inhibitors.

Revealing the Role of the Cyaphide Ion as a Bridging Ligand in Heterometallic Complexes.

The synthesis of heterometallic transition metal complexes featuring bridging cyaphide ions (C≡P−) is reported. These are synthesized from reactions of Au(IDipp)(CP) (IDipp=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene) with electron‐rich, nucleophilic transition metal reagents, affording Au(IDipp)(μ2−C≡P)Ni(MeI i Pr)2 (MeI i Pr=1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene) and Au(IDipp)(μ2−C≡P)Rh(Cp*)(PMe3). These studies reveal that, in contrast to the cyanide ion, bimetallic cyaphido complexes strongly favor a η1 : η2 coordination mode that maximizes the interaction of the second metal (Ni, Rh) with the π‐manifold of the ion (and not the phosphorus atom lone pair). End‐on bridging can be effectively unlocked by blocking the π‐manifold, as demonstrated by reaction of Au(IDipp)(μ2−C≡P)Rh(Cp*)(PMe3) with an electrophilic transition metal reagent, W(CO)5(THF), which affords the heterotrimetallic compound Au(IDipp)(μ3−C≡P)[Rh(Cp*)(PMe3)][W(CO)5].

Revealing the Role of the Cyaphide Ion as a Bridging Ligand in Heterometallic Complexes

AbstractThe synthesis of heterometallic transition metal complexes featuring bridging cyaphide ions (C≡P−) is reported. These are synthesized from reactions of Au(IDipp)(CP) (IDipp=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene) with electron‐rich, nucleophilic transition metal reagents, affording Au(IDipp)(μ2−C≡P)Ni(MeIiPr)2 (MeIiPr=1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene) and Au(IDipp)(μ2−C≡P)Rh(Cp*)(PMe3). These studies reveal that, in contrast to the cyanide ion, bimetallic cyaphido complexes strongly favor a η1 : η2 coordination mode that maximizes the interaction of the second metal (Ni, Rh) with the π‐manifold of the ion (and not the phosphorus atom lone pair). End‐on bridging can be effectively unlocked by blocking the π‐manifold, as demonstrated by reaction of Au(IDipp)(μ2−C≡P)Rh(Cp*)(PMe3) with an electrophilic transition metal reagent, W(CO)5(THF), which affords the heterotrimetallic compound Au(IDipp)(μ3−C≡P)[Rh(Cp*)(PMe3)][W(CO)5].

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

Renewable Reagent for Nucleophilic Fluorination.

Herein, we report a study on the reactivity of three 1,3-diarylimidazolium-based fluoride reagents, with a general formula of [IPrH][F(HF)n] (n = 0, 1, or 2), that tackle the challenges of limited solubility, hygroscopicity, instability, and laborious preparation procedures of nucleophilic fluoride reagents. Fluorination of 4-tert-butylbenzyl bromide reveals that trifluoride [IPrH][F(HF)2] is the most selective reagent. Microwave-assisted activation coupled with the addition of sterically hindered amine DIPEA or alkali metal fluorides increases the rate of fluorination with [IPrH][F(HF)2], making it an excellent reagent for the fluorination of various organic substrates. The scope of substrates includes benzyl bromides, iodides, chlorides, aliphatic halides, tosylates, mesylates, α-haloketones, a silyl chloride, acyl and sulfuryl chlorides, and a nitroarene. The exceptional stability of the air-stable and nonhygroscopic [IPrH][F(HF)2] reagent is illustrated by its convenient synthesis and detailed experimental regeneration protocol using hydrofluoric acid without organic solvents.

Synthesis of Altenuene Backbones through Iodine(III)-Participated Umpolung Diesterification and Insights into the General [1,5]-H Shift in para-Dearomatization of Phenols via Quantum Chemical Calculations.

Through PhI(OAc)2-oxidized dearomatization and diesterification of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acids, a series of polycyclic compounds possessing an altenuene backbone were obtained in moderate to good yields. The Umpolung diesterification reaction was completed under mild reaction conditions without an additional nucleophilic reagent. This work offers a concise method for the synthesis of diverse natural altenuene analogues. The mechanism was proposed, and the [1,5]-H shift was studied in isomerization from the ketone-form structure to a phenol employing computational studies.

Coupled adsorption-catalytic reduction of permanganate on Co–Al-layered double hydroxide for dye removal

Permanganate (MnO4−) ions were catalytically reduced to MnO2 by water molecules after adsorption on the surface of carbonate intercalated Co–Al-LDH. This reaction was very slow under experimental conditions in the absence of catalyst and was catalyzed by Co–Al-LDH and Co(II) ion had a key role in this process in the pH range of 2.8–13. But, at pH = 14, MnO4− ions reacted with Co(II) ion of adsorbent and produced Co(III). At all pHs, adsorption sites of Co–Al-LDH for MnO4− ions were Co–OH groups. These adsorption sites were located in micropores and mesopores of Co–Al-LDH and were called MI and ME adsorption sites, respectively. MnO4− ions were adsorbed on both adsorption sites in neutral aqueous solutions and only on ME sites at other pHs. Adsorption experiments were carried out at different temperatures, ionic strengths, pHs and initial adsorbate concentrations. Co–Al-LDH acted as a superadsorbent for MnO4− ions and maximum adsorption capacity was 347.9 mg g−1 (2.2 mmol g−1) in neutral aqueous solution at 318 K. The adsorption binding constants and thermodynamic parameters of adsorption of MnO4− ions on Co–Al-LDH were analyzed by ARIAN (adsorption isotherm regional analysis) model. This model determined the boundaries of adsorption of MnO4− ions on Co–Al-LDH under different conditions and showed that this process was endothermic in regions I and II of its isotherms in neutral solution and at pH = 13. This process obeyed ARIAN–Hinshelwood mechanism and water molecules in the pH range of 2.8–13 and hydroxide ions at pH = 14 participated as nucleophile reagents. Reaction in the pH range of 2.8–13 was as follows2MnO4−+ H2O →2MnO2(ad)+32O2+2OH− and at pH = 14 was as2MnO4−+2Co(II)–OH+H2O→2Co(III)–OH+2MnO2ad+32O2+2OH−This adsorbent was used for selective separation of permanganate from cationic safranin O and methylene blue dyes. However, it could not separate anionic methyl orange dye from MnO4− ions.This work further successfully demonstrated an approach to recycle the used Co–Al-LDH using a reducing agent.

Synthesis of novel polymer quaternary ammonium salt derived from glucose as a phase transfer catalyst

Abstract. Alrubaie I, Salim AT, Majeed MM, Radhi AJ. 2022. Synthesis of novel polymer quaternary ammonium salt derived from glucose as a phase transfer catalyst. Nusantara Bioscience 14: 25-33. Some new polymer containing quaternary ammonium salts based-carbohydrate starting from methyl-4,6-O-benzylidene-glucopyranoside have been prepared. The ammonium groups are connected to the glucose structure in various positions (2 and 3). Our synthesis used methyl-4,6-O-benzylidene-a-D-glucopyranoside through nucleophilic reagents to produce the main intermediates. The monomer glucose- quaternary ammonium salts are immobilized on the polyvinyl azide to give the final structure of the Polymer-Supported quaternary ammonium salts. In certain new kinds of phase transfer catalysts, the effectiveness of the polymer glucose-quaternary ammonium salts was tested in the Williamson etherification. The ether synthesis is a typical example of using a phase transfer catalyst. The reactions were performed in a liquid-liquid two-phase system, applying a mixture of toluene and 50% solution of aqueous sodium hydroxide in the presence of a 20 mg/mmol catalyst (compound 9). Compared to other derivatives, the reaction of 4-nitrophenol with dibromoethylene gives the highest yields. On the other hand, compound 9 with the C16 chain gives high activity in the phase transfer catalyst.

Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

Automated iterative Csp3-C bond formation.

Fully automated synthetic chemistry would substantially change the field by providing broadon-demandaccess to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of Csp3-C bonds would expand access to many important types offunctional organic molecules1. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp2-Csp2 bonds and were effective building blocks for automating the synthesis of many small molecules2, but they are incompatible with stereospecific Csp3-Csp2 and Csp3-Csp3 bond-forming reactions3-10. Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N-methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis11-13 revealed that redistribution of electron density increases covalency of the N-B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage2, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp3-Csp2 and Csp3-Csp3 bond formation. These findings will enable increasingly complex Csp3-rich small molecules to be accessed via automated assembly.

Electrochemical Fluorination of Vinyl Boronates through Donor-Stabilized Vinyl Carbocation Intermediates.

The electrochemical generation of vinyl carbocations from alkenyl boronic esters and boronates is reported. Using easy-to-handle nucleophilic fluoride reagents, these intermediates are trapped to form fully substituted vinyl fluorides. Mechanistic studies support the formation of dicoordinated carbocations through sequential single-electron oxidation events. Notably, this electrochemical fluorination features fast reaction times and Lewis acid-free conditions. This transformation provides a complementary method to access vinyl fluorides with simple fluoride salts such as TBAF.