Radical Nucleophilic Substitution Research Articles

Denitrative Hydroxylation of Unactivated Nitroarenes.

A one-step method for the conversion of nitroarenes into phenols under operationally simple, transition-metal-free conditions is described. This denitrative functionalization protocol provides a concise and economical alternative to conventional three-step synthetic sequences. Experimental and computational studies suggest that nitroarenes may be substituted by an electron-catalysed radical-nucleophilic substitution (SRN 1) chain mechanism.

Radical nucleophilic substitution/cyclization: A novel strategy for selective and ultrafast fluorescence imaging of cysteine levels in ferroptosis process

Diphenylisoindolo[2,1-a]quinoline can be used to detect cysteine among homocysteine, glutathione, and other 19 natural amino acids. Unlike other reported probes, the response mechanism involves sulfhydryl radical nucleophilic substitution and cyclization, and thus the differences in ring-formation kinetics enable high selectivity. After treated with Cys, the response process was completed rapidly and the maximum fluorescence intensity (at 496 nm) was reached extremely fast (<1 s) when excited at 380 nm in MeCN-PBS buffer (10.0 mM, pH = 7.4, 3:7 (v/v)). The quantum yield after the reaction was increased almost 7 times to be 0.02 from 0.003. Fluorescence intensity displayed a good quantitative linear relationship in the range 1–10 μM Cys with a detection limit of 270 nM. Furthermore, the probe was demonstrated for real-time monitoring of intracellular cysteine levels within HepG2 cells in ferroptosis process.

Construction of S-CF2/ O-CF2 bonds via inter/intramolecular radical nucleophilic substitution reaction

A facile and efficient method for construction of S-CF2 or O-CF2 bonds through intermolecular radical nucleophilic substitution (SRN1) reaction of 2-bromo-2,2-difluoro-N-phenylacetamide and thiophenols or phenols was developed, which has also been successfully utilized in the intramolecular SRN1 reaction to generate a new O-CF2 bonds for synthesis of biologically important 2,2-difluoro-2H-benzo [1,4]oxazin-3-one. The protocol enables an efficient access to gem-difluoromethylene-containing thioethers or ethers and oxazin heterocycles with good to excellent yields by inter/intramolecular radical nucleophilic substitution reaction under mild reaction conditions.

Propagation chains in photocatalyzed radical nucleophilic substitutions of thiolates with perfluoroalkyl groups

Quantum yields and radical chain lengths have been investigated in photocatalyzed radical nucleophilic perfluorobutyl group substitution reactions of 2-mercaptothiolate anion under three different photocatalytic systems operating in reductive and quenching manners. Important propagation chain lengths have been uncovered with photocatalysts under both scenarios, reductive and oxidative. The different overall quantum yields and chain lengths observed demonstrate the balance between the efficiency of the photoinitiation events, propagation and termination steps. Theoretical calculations provide a better understanding and throw light into whether a closed or an open catalytic cycle is operating in photoinitiated perfluoroalkyl group- thiolate coupling reaction.

Fluoroalkylation of Various Nucleophiles with Fluoroalkyl Sulfones through a Single Electron Transfer Process.

The fluoroalkylation of various nucleophilic reagents with (phenylsulfonyl)difluoromethyl (PhSO2CF2)-substituted phenanthridines was achieved to give fluorinated phenanthridine derivatives, which enables the construction of both carbon-heteroatom and carbon-carbon bonds via the substitution of the phenylsulfonyl group. Mechanistic studies indicated that these reactions proceed through a unimolecular radical nucleophilic substitution (SRN1) mechanism. It is worthwhile noting that in the cases of O-nucleophiles ( t-BuO- and PhO-), the addition of t-BuOK/PhCHO could significantly promote the reactions, due to the in situ formation of a highly reactive electron donor species through the interaction of t-BuOK, PhCHO, and the solvent DMF, which can effectively initiate the single electron transfer process.

2,4-Disubstituted 5-Nitroimidazoles Potent against Clostridium difficile.

Metronidazole is one of the first-line treatments for non-severe Clostridium difficile infections (CDI). However, resistance limits its use in cases of severe and complicated CDI. Structure-activity relationships previously described for the 5-nitroimidazole series have shown that functionalization at the 2- and 4-positions can impart better activity against parasites and anaerobic bacteria than metronidazole. Herein we report the synthesis of new 2,4-disubstituted 5-nitroimidazole compounds that show potent antibacterial activity against C. difficile. We used a vicarious nucleophilic substitution of hydrogen (VNS) reaction to introduce a phenylmethylsulfone at the 4-position and a unimolecular radical nucleophilic substitution (SRN 1) reaction to introduce an ethylenic function at the 2-position of the 5-nitroimidazole scaffold.

Intra- versus intermolecular electron transfer in radical nucleophilic aromatic substitution of dihalo(hetero)arenes - a tool for estimating π-conjugation in aromatic systems.

In this paper, the application of the double radical nucleophilic aromatic substitution (SRN1) in various dihalogenated, mostly diiodinated, π-conjugated systems as a tool for qualitatively estimating their π-conjugation is described. This approach uses electron delocalisation as a measure of π-conjugation. Electron injection into the π-system is achieved via reaction of an intermediate aryl radical, itself generated from a dihalogenated π-system via SET-reduction of the C-I bond and subsequent reaction with a thiolate anion. The generated arene radical anion can then further react with the second aryl-halogen moiety within the π-system via an intramolecular electron transfer process. The efficiency of this intramolecular electron transfer is related to the π-conjugation of the radical anion. If the π-conjugation within the aromatic unit is weak, the arene radical anion reacts via an intermolecular ET with the starting dihalide. The intramolecular ET process delivers a product of a double SRN1 substitution whereas the intermolecular ET pathway provides a product of a mono- SRN1 substitution. By simple product analysis of mono- versus double substitution, π-conjugation can be qualitatively evaluated. This mechanistic tool is applied to various dihalogenated π-conjugated systems and the results are discussed within the context of π-conjugation. The conjugation mode within the π-system and the length of the aromatic system are varied, and the effect of relative positioning of the two halides within small π-systems is also addressed.

ChemInform Abstract: Designing New 5‐Nitroimidazoles: Towards Safer Anti‐infectious Agents

AbstractReview: 146 refs.

Designing New 5-Nitroimidazoles: Towards Safer Anti-infectious Agents

5-Nitroimidazoles are drugs having both antiprotozoal and antibacterial activity, but show mutagenicity and development of resistance particularly with metronidazole. For the development of new potentially safer derivatives, we investigated new strategies of synthesis: such as Vicarious Nucleophilic Substitution of hydrogen (VNS), palladiumcatalyzed cross-coupling reactions (Suzuki-Miyaura, Sonogashira…) and electron transfer reactions (Unimolecular Radical Nucleophilic Substitution (SRN1), TDAE methodology) applied in 5-nitroimidazole series.

Nucleophile-Dependent Regioselective Reaction of (S)-4-Benzyl-2-Fluoroalkyl-1,3-Oxazolines

Nucleophile-dependent regioselectivities in the nucleophilic reaction of (S)-4-benzyl-2-fluoroalkyl-1,3-oxazoline to different types of fluorinated compounds were investigated experimentally and theoretically. The ring opening of (S)-4-benzyl-2-bromodifluoromethyl-1,3-oxazoline by arenethiolates exclusively occurred at the C5 position of the 1,3-oxazoline ring, whereas completely different regioselectivity was observed for a unimolecular radical nucleophilic substitution (S(RN)1) at the terminal bromine atom of the CF2Br group when arenolates were employed as the nucleophiles. The reaction of (S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline with nucleophiles such as arenethiols, arenols, and TMSCl underwent nucleophilic ring opening in a regiospecific way, while the use of TMSCF3 was determined to proceed through nucleophilic addition to the C═N bond.

Construction of Dendritic-Linear Brushes on Silica Nanoparticles by Electrostatic Assembly

Using dendritic bromide poly (benzyl ether), G2-Br, as macroinitiator, dendritic-linear polymer (G2-PS-NHSO3Na) was obtained via atom transfer radical polymerization and nucleophilic substitution of G2-PS-Br. G2-PS-NHSO3Na was constructed on cationic silica by both electrostatic attraction and steric effort coming from dendritic block of G2-PS-NHSO3Na. 1H-NMR and differential scanning calorimetry were used to characterize the structure and thermal behavior of G2-PS-NHSO3Na; thermo-gravimetric analysis and TEM were applied to analysis the assembly amount of G2-PS-NHSO3Na and the dispersibility of silica before and after assembly. The results show that G2-PS-NHSO3Na can be synthesized successfully and has exact structure; it can be constructed on cationic silica with 27% assembly amount; the aggregation of silica can be prevented effectively by the dendritic-linear brushes, but the molecular weight of linear segment and the generation of dendritic block will influence the assembly behavior and the amount of the dendritic-linear brushes.

Separation and Identification of Photolysis Products of Clothianidin by Ultra-Performance Liquid Tandem Mass Spectrometry

Photolysis of clothianidin by Xenon lamp was investigated by Ultra-Performance Liquid Chromatography Electrospray Ionization tandem mass spectrometry (UPLC-ESI/MS/MS). Quantitative study on the photodegradation of clothianidin found that the photodegradation obeyed first order kinetics (C = 9.9917e – 0.187t, R² = 0.994). The half-life was about 3.6 hours. Qualitative study on photolysis products of clothianidin were taken by checking all total ion spectra of different sample time. A total of eight products was found in this study. The structure of each product was determined by the total ion spectrometry spectrum and daughter-scan spectrum. The mechanism of photodegradation of this pesticide included radical denitration, nucleophilic substitution, and rearrangement, ring-open, and ring-close. Through the analysis of the change of every product and the mass information, the photolysis pathway was drawn. From this study, products of V, VI, and VII seemed more stable than clothianidin.

ChemInform Abstract: The SRN1 Reaction

AbstractReview: 181 refs.

Synthesis of α,α-diaryl nitriles by radical nucleophilic substitution

The present study shows that the anion of 2-naphthylacetonitrile is substituted selectively at its Cα by aromatic halides, through a radical nucleophilic substitution mechanism, to give the corresponding α,α-diaryl nitriles in good yields. The regioselectivity of this ambident nucleophile changes with the steric hindrance at the radical centre from the aromatic substrate. The selectivity observed was investigated through a computational model of the key reaction step.

Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S(RN)1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC(50) > 100 μM).

Directed aromatic functionalization.

The title of this Thematic Series brings to the minds of most organic chemists the beautifully logical aromatic electrophilic substitution (SEAr) [1–5] and, to a lesser extent, nucleophilic aromatic substitution (SNAr) [2,6–7] reactions as taught to many generations of students in their first organic chemistry courses [8] (Fig. 1). Being less steeped in history, radical nucleophilic substitution (SRN1) [9] and vicarious nucleophilic substitution (VNS) [10–12], in spite of their considerable synthetic utility, are given sparse mention. By the time students reach the upper years of study, aromatic chemistry receives the label “classical” and is disregarded or relegated to brief coverage. Apart from in English schools [13], heteroaromatic chemistry suffers the same fate. As a consequence, a fresh graduate entering the pharmaceutical industry, who invariably faces a complex aromatic or heteroaromatic as his or her first target molecule, is either lost or must grope around with insufficient background knowledge.

Selective synthesis of mono- and distannylpyridines from chloropyridinols via an S RN1 mechanism

A selective two-step synthesis of either mono- or distannylated pyridines from commercially available pyridinols, involving its conversion to the corresponding diethyl pyridyl phosphates (pyDEP) followed by the reaction with Me 3SnNa in liquid ammonia, is described. The results obtained clearly indicate that the reactions proceed through an unimolecular radical nucleophilic substitution mechanism (S RN1) with intermediacy of a monosubstitution product.

ChemInform Abstract: Arylation of Heterocyclic Ketene Aminals with 2,4-Dinitrohalobenzenes by a Radical Nucleophilic Substitution Mechanism.

The anions of heterocyclic ketene aminals reacted with 2,4-dinitrohalobenzenes to give arylated products by a radical nucleophilic substitution mechanism. The SRN1 mechanism was confirmed by EPR spectroscopy, EPR spin trapping, and by depression of the reaction rate by the addition of an inhibitor.

Regioselectivity of methyl chlorobenzoate analogues with trimethylstannyl anions by radical nucleophilic substitution: theoretical and experimental study

Reactions of methyl 2,5-dichlorobenzoate, methyl 4-chlorobenzoate, methyl 2-chlorobenzoate and methyl 3-chlorobenzoate with Me3Sn− ions gave the corresponding substitution products by an SRN1 mechanism. Competition experiments showed that the relative reactivity of chlorine as the leaving group with respect to the ester group in methyl chlorobenzoate is para ≥ ortho ≫ meta toward Me3Sn− ions. Theoretical studies were able to explain the observed reactivity on the basis of the energetic properties of the transition states of the radical anions formed in these reactions.

Competitive Reaction Pathways foro-Anilide Aryl Radicals: 1,5- or 1,6-Hydrogen Transfer versus Nucleophilic Coupling Reactions. A Novel Rearrangement to Afford an Amidyl Radical

The photoinduced reactions of o-iodoanilides (o-IC6H4N(Me)COR, 4a-d) with sulfur nucleophiles such as thiourea anion (1, -SCNH(NH2)), thioacetate anion (2, MeCOS-), and sulfide anion (3, S(2-)) follow different reaction channels, giving the sulfides by a radical nucleophilic substitution or the dehalogenated products by hydrogen atom transfer pathways. After an initial photoinduced electron transfer (PET) from 1 to iodide 4, the o-amide aryl radicals 12 are generated. These aryl radicals 12 afford alternative reaction pathways depending on the structure of the alpha-carbonyl moiety: (a) 12b (R = Me) adds to 1 to render the methylthio-substituted compounds by quenching the thiolate anion intermediate with MeI after irradiation; (b) 12c (R = -CH2Ph) follows a 1,5-hydrogen transfer to give a stabilized alpha-carbonyl radical (17); and (c) 12d (R = t-Bu) affords 1,6-hydrogen transfer, followed by a 1,4-aryl migration to render an amidyl radical (20), which is reduced to the N-benzyl-N,2-dimethylpropanamide (10). Together with this last rearranged product, the ipso substitution derivative was also observed. Similar results were obtained in the PET reactions of 4d (R = t-Bu) with anions 2 and 3 under entrainment conditions with the enolate anion from cyclohexenone (5) or the tert-butoxide anion (6). From this novel rearrangement, and only under reductive conditions by PET reaction with anion 5, iodide 4d (R = t-Bu) affords quantitatively the propanamide 10. The energetic of the intramolecular rearrangements followed by radicals 12b-d were rationalized by B3LYP/6-31+G* calculations.