Nucleophilic Adducts Research Articles

Cover Feature: Diiminium Nucleophile Adducts Are Stable and Convenient Strong Lewis Acids (Chem. Eur. J. 58/2023)

Cover Feature: Diiminium Nucleophile Adducts Are Stable and Convenient Strong Lewis Acids (Chem. Eur. J. 58/2023)

Diiminium Nucleophile Adducts Are Stable and Convenient Strong Lewis Acids.

Strong Lewis acids are essential tools for manifold chemical procedures, but their scalable deployment is limited by their costs and safety concerns. We report a scalable, convenient, and inexpensive synthesis of stable diiminium-based reagents with a Lewis acidic carbon centre. Coordination with pyridine donors stabilises these centres; the 2,2'-bipyridine adduct shows a chelation effect at carbon. Due to high fluoride, hydride, and oxide affinities, the diiminium pyridine adducts are promising soft and hard Lewis acids. They effectively produce acylpyridinium salts from carboxylates that can acylate amines to give amides and imides even from electronically intractable coupling partners.

Visible-light-driven graphene supported Cu/Pd alloy nanoparticle-catalyzed borylation of alkyl bromides and chlorides in air

A highly efficient photocatalytic protocol for borylation of alkyl bromides and chlorides with graphene supported Cu/Pd alloy nanoparticles as a heterogeneous catalyst is reported. This photocatalytic system operates with visible light in air, providing a wide range of primary and secondary alkyl halides with B2pin2 or B2neop2 in high yields at low temperatures, thereby demonstrating its broad utility and functional group tolerance. The high performance is attributed to a synergistic effect of localized surface plasmon resonance (LSPR) of Cu and charge transfer from Cu to Pd due to the alloy surface charge heterogeneity. Transfer of energetic electrons from Pd to electrophilic alkyl halides lead to the formation of the alkyl radicals, which quickly react with a nucleophilic adduct of a diboron compound with base adsorbed on the positively charged Cu sites to form the corresponding borylation product.

Theoretical investigation on the mechanism and enantioselectivity of organocatalytic asymmetric Povarov reactions of anilines and aldehydes

AbstractThe mechanism is investigated for organocatalytic asymmetric Povarov reaction of anilines and aldehydes using M06‐2X functional. Two molecule of aldehyde condense with aniline and catalyst giving N‐arylimine and enamine. The reaction is stepwise involving [2 + 2] cycloaddition and ring‐opening/cyclization. Four competitive paths exist in step 1 leading to isomers of quaternary nitrogen heterocycle as cycloadduct. Step 2 is sequential with proton transfer and concerted ring‐opening/cyclization in two feasible orders. Each path in step 1 divides into two in step 2 producing isomers of tetrahydroquinoline (THQ) bonded with catalyst as cyclization product. The reactive nucleophilic adduct with two charge centers in step 1 supports the recovery of catalyst and generation of aldehyde assisted by water. THQ alcohol is obtained in the following intramolecular Friedel–Crafts reaction. The enantio‐ and diastereoselectivity are both thermodynamic control with preferred path yielding the most stable isomer with 2S3S or 1R2S3S configuration. The path bias is in line with the reduction degree of energy barrier in solvent compared with gas phase. Our conclusion is verified by Multiwfn analysis and the predicted ee, dr value of THQ scaffold in experiment.

A novel, green and safe ultrasound-assisted emulsification liquid phase microextraction based on alcohol-based deep eutectic solvent for determination of patulin in fruit juices by spectrophotometry

In the study, a novel, green and safe microextraction procedure was developed for the determination and extraction of patulin, α, β-unsaturated lactone (4-hydroxy-4H-furo[3,2-c] pyran-2-(6H)-one), in fruit juice samples by using ultrasound-assisted emulsification liquid phase microextraction based on alcohol-based deep eutectic solvent coupled to micro-volume ultraviolet-visible spectrophotometry. The method is based on formation of chelate complex or nucleophilic adduct formation between patulin and Mg(II) in presence of nucleophilic metal chelating tris-buffer at pH 8.0, and then extraction of the formed complex into the micro-drops of deep eutectic solvent by donor-acceptor mechanism. The optimum conditions for the effective extraction of patulin from fruit juices were 500 μL of deep eutectic solvent, 75 μmol L−1 of Mg(II) solution, pH 8.0, ultrasound time of 12 min, respectively. The patulin in enriched phase was detected by micro-volume ultraviolet-visible spectrophotometry at 304 nm. Under optimal conditions, the linear response range of the method was from 7.5 to 420 μg L−1 with a detection limit of 2.2 μg L−1. After the validation study, the applicability of the method were tested by analysis of the fruit juice samples. The average recovery for spiked fruit juices was ranged from 90.2% to 106.9%, with relative standard deviations lower than 4.2%.

Time-Resolved Spectroscopic Study of N,N-Di(4-bromo)nitrenium Ions in Selected Solutions.

Nitrenium ions are important reactive intermediates in chemistry and biology. In this work, femtosecond and nanosecond transient absorption (fs-TA and ns-TA) along with nanosecond time-resolved resonance Raman (ns-TR3) experiments were employed to examine the photochemical pathways of N-(4,4′-dibromodiphenylamino)-2,4,6-trimethylpyridinium BF4− (salt (DN) from just absorption of a photon of light to the production of the important N,N-di(4-bromophenyl)nitrenium ion 2. In acetonitrile (MeCN), the formation of halogenated diarylnitrenium ion 2 was observed within 4 ps, showing the vibrational spectra with strong intensity. The nucleophilic adduct reaction of ion 2 with H2O was also examined in aqueous solutions. The direct detection of the unique ortho adduct intermediate 3 shows that there is an efficient and exclusive reaction pathway for 2 with H2O. The results shown in this paper give new characterization of 2, which can be used to design time-resolved spectroscopy investigations of covalent addition reactions of nitrenium ions with other molecules in future studies.

Detection and Structural Characterization of Nucleophiles Trapped Reactive Metabolites of Limonin Using Liquid Chromatography-Mass Spectrometry.

Limonin (LIM), a furan-containing limonoid, is one of the most abundant components of Dictamnus dasycarpus Turcz. Recent studies demonstrated that LIM has great potential for inhibiting the activity of drug-metabolizing enzymes. However, the mechanisms of LIM-induced enzyme inactivation processes remain unexplored. The main objective of this study was to identify the reactive metabolites of LIM using liquid chromatography-mass spectrometry. Three nucleophiles, glutathione (GSH), N-acetyl cysteine (NAC), and N-acetyl lysine (NAL), were used to trap the reactive metabolites of LIM in in vitro and in vivo models. Two different types of mass spectrometry, a hybrid quadrupole time-of-flight (Q-TOF) mass spectrometry and a LTQ velos Pro ion trap mass spectrometry, were employed to acquire structural information of nucleophile adducts of LIM. In total, six nucleophile adducts of LIM (M1–M6) with their isomers were identified; among them, M1 was a GSH and NAL conjugate of LIM, M2–M4 were glutathione adducts of LIM, M5 was a NAC and NAL conjugate of LIM, and M6 was a NAC adduct of LIM. Additionally, CYP3A4 was found to be the key enzyme responsible for the bioactivation of limonin. This metabolism study largely facilitates the understanding of mechanisms of limonin-induced enzyme inactivation processes.

Swain-Scott Relationships for Nucleophile Addition to Ring-Substituted Phenonium Ions.

The products of the reactions of 2-(4-methoxyphenyl)ethyl tosylate (MeO-1-Ts) and 2-(4-methyphenyl)ethyl tosylate (Me-1-Ts) with nucleophilic anions were determined for reactions in 50/50 (v/v) trifluoroethanol/water at 25°C. In many cases the nucleophile selectivity kNu/ks (M-1) for reactions of nucleophile and solvent, calculated from the ratio of product yields, depends upon [Nu-]. This demonstrates the existence of competing reaction pathways, which show different selectivities for reactions with nucleophiles. A carbon-13 NMR analysis of the products of the reactions of substrate enriched with carbon-13 at the α-carbon, X-1-[α-13C]Ts, (X = -OCH3, -Me) with nucleophilic anions in 50/50 (v/v) trifluoroethanol/water at 25°C shows the formation of X-1-[β-13C]OH, X-1-[β-13C]OCH2CF3 and X-1-[β-13C]Nu (Nu = Br, Cl, CH3CO2, Cl2CHCO2) from the trapping of symmetrical 4-substituted phenonium ion reaction intermediates X-2+ . The observation of excess label in the α-position, [α-13C]/[β-13C] > 1.0, for both the water and nucleophile adducts, shows that water and anionic nucleophiles also react by direct substitution at X-1-[α-13C]Ts. The ratios of product yields, [α-13C]/[β-13C], and observed nucleophile selectivity (kNu/ks)obs were used to dissect the contribution of direct nucleophile addition at Me-1-Ts and trapping of X-2+ to the product yields. The product yields from partitioning of the intermediate gave the nucleophile selectivity kNu/ks (M-1) for X-2+ . Swain-Scott plots of log (kNu/ks) are correlated by slopes of s = 0.78 and s = 0.73 for reactions of MeO-2+ and Me-2+ , respectively. This shows that the sensitivity of bimolecular substitution at X-2+ to changes in nucleophile reactivity is smaller than for nucleophilic substitution at the methyl iodide. Evidence is presented that nucleophile addition to X-2+ proceeds through an "exploded" transition state.

Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis

Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4-naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor.

Structure, Luminescence, and Vapochromism of Bridged Cationic Copper(I) Dimers and Polymers

The dimeric complex of Cu(I) [Cu2(PPh3)4(MeCN)2(Bpy)](BF4)2 (1a, Bpy = 4,4′-dipyridyl) self-assembles in CH2Cl2 or acetone and shows intense photoluminescence (excitation λmax = 356 nm, emission λmax = 486 nm, ϕ = 0.47). The MeCN ligands are readily removed from 1a, producing [Cu2(PPh3)4(Bpy)](BF4)2 (1b) and altering the photophysical behavior (excitation λmax = 336 nm, emission λmax = 568 nm, ϕ = 0.07). The desolvated compound 1b reversibly absorbs many vapor phase nucleophiles, as revealed by thermogravimetry. Intense luminescence emission is restored for 1b/Nu, Nu = MeCN (1a), acetone, tetrahydrothiophene (THT), and Et2S. Films of 1b are produced when CH2Cl2 solutions of 1a are cast onto glass. The films also react with Nu vapor, again producing intense emission. The pyrazine-bridged dimer [Cu2(PPh3)4(MeCN)2(Pyz)](BF4)2 (2a) is produced in CH2Cl2, while [Cu2(PPh3)4(MeCN)(acetone)(Pyz)](BF4)2∙½[Cu2(PPh3)4(MeCN)2(Pyz)](BF4)2 (2b) is formed in acetone. The crystal structure of the polymer {[Cu(PPh3)2(Bpy)](BF4)∙acetone} n (3) is reported, as is the mixed polymer/dimer structure {[Cu(PPh3)2(Pyz)](BF4)} n ∙½n[Cu2(PPh3)4(BF4)2(Pyz)] (4b) in which the dimer units show Cu–FBF3 coordination. The Pyz dimer and the Pyz and Bpy polymers show much weaker luminescence behavior than that of Bpy dimers 1a and the related 1b/Nu adducts. Nucleophile adduct structures [Cu2(PPh3)4(THT)2(Bpy)](BF4)2∙½ethyl ether (5) and [Cu2(PPh3)4(Py)2(Bpy)](BF4)2∙CH2Cl2 (6) confirmed the coordination of one Nu per Cu to 1b.

Fast Controlled Living Polymerization of Arylisocyanide Initiated by Aromatic Nucleophile Adduct of Nickel Isocyanide Complex.

The fast living polymerization of chiral arylisocyanide in the presence of the aromatic nucleophile adduct of tetra(t-butylisocyano)nickel(II) complex as an initiator gave the predominantly one-handed helical polyisocyanide with narrow polydispersity. X-ray crystal structures of initiators and MALDI-TOF MS and NMR studies of the polymer products elucidated the key role of the aromatic substituents in the initiator and monomer achieving narrow polydispersity. The aromatic groups in the initiator and monomer stabilized the electronic structure of the carbene-like ligand to suppress dissociation of the active nickel complex that leads to chain transfer and termination. The aromatic groups also controlled the reactivity of the active site for initiation and propagation.

Density Functional Study on the Cytochrome-Mediated S-Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6-311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds.

A higher energy conformer of ( S)-proline is the active catalyst in intermolecular aldol reaction: Evidence from DFT calculations

Full catalytic cycle of the stereoselective ( S)-proline catalyzed aldol reaction of acetone and acetaldehyde in DMSO solvent has been investigated using three different DFT methods, viz. B3LYP, MPWB1K and B97D in conjunction with the polarizable continuum (PCM) method. At all the levels of theory, one of the higher energy conformers of the catalyst, 1b showed higher activity than the most stable conformer, 1a. On the basis of Δ G # of 39.8 kcal/mol observed for the reaction of 1a with acetone, 1a is considered to be inactive in the catalytic cycle while the same reaction with 1b showed 22.7 kcal/mol (B97D-PCM level) lower value for Δ G # than 1a. All the possibilities for enamine formation and C–C bond formation step have been considered for describing the most appropriate stereoselective catalytic cycle which showed that the full cycle is made up of a relay of eight proton transfer steps and the reaction is categorized under hydrogen bond catalysis. The hydration across the iminium bond of the second nucleophilic adduct – an intermediate formed subsequent to the aldehyde addition to the enamine – is the rate limiting step of the reaction with Δ G # = 21.7 kcal/mol (B97D-PCM level).

Structural diversity of nucleophilic adducts from flavanols and oak wood aldehydes

The reactions between (+)-catechin and a representative oak wood aldehyde (furfuraldehyde, 5-(hydroxymethyl)furfuraldehyde, 5-methylfurfuraldehyde, vanillin, or syringaldehyde) in a wine-like model solution were studied and the formed condensation products were characterized by LC/MS and LC/MS/MS.

Substituents on Quinone Methides Strongly Modulate Formation and Stability of Their Nucleophilic Adducts

Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron-deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron-donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 h. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span 5 orders of magnitude with electron-rich species reacting most slowly and electron-deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application.

Fenton-enhanced γ-radiolysis of cyanuric acid

Degradation of cyanuric acid (OOOT), a stable end product of oxidative decomposition of atrazine, is investigated in a combined field of gamma radiolysis and fenton reaction. The reaction of hydroxyl radical ( OH) at pH 6 was carried out by irradiating N 2O saturated aqueous solutions containing OOOT (1 × 10 −3 mol dm −3), and this resulted only a marginal degradation (20%). However, when the same reaction was carried out in the presence of varying concentrations of ferrous sulfate ((5–10) × 10 −5 mol dm −3), the decay of OOOT has been enhanced to more than 80%. This decay followed a first order kinetics. Nearly similar effects were observed with another triazine derivative, 2,4-dioxohexahydro-1,3,5-triazine (DHT). Two major reaction mechanisms are proposed for the enhanced decay of OOOT. The formation of unstable hydroxyl radical adducts from the reaction of OH which is the result of gamma radiolysis and the Fenton reaction (resulting from the reaction of the added Fe(II) and of the H 2O 2 from the radiolysis of water), is proposed as the first mechanism. The second mechanism, which is likely the major contributor to degradation, is proposed as the reaction of a nucleophilic adduct, Fe(II)OOH, which could directly react with the electron deficient triazine ring. It is highlighted that such degradation reactions must be explored for the complete degradation of the byproducts of the oxidative decomposition of atrazine.

Potentiometric and theoretical studies of the carbonate sensors based on 3-bromo-4-hexyl-5-nitrotrifluoroacetophenone.

Novel carbonate ionophore, trifluoroacetophenone derivative (TFA) substituted by two acceptor substituents in the phenyl ring (3-bromo-4-hexyl-5-nitrotrifluoroacetophenone), was synthesized. Solvent polymeric membrane sensors based on this ionophore exhibited heightened selectivity to carbonate ions in the presence of the most important interfering anions. A wide range of potentiometric properties were studied and compared with those of sensors based on mono-substituted ionophores. Special attention was paid to pH dependence of sensor responses and to elaboration of appropriate conditions for carbonate analysis. A segmented-sandwich membrane method was applied for determination of the stoichiometry of ionophore-carbonate complexes, which was determined to be 1:3, and apparent complex formation constants which were 14.4 and 13.6 for DOS- and NPOE-plasticized membranes, respectively. Theoretical studies on TFA derivatives by semi-empirical (AM1 and PM3) and ab initio(6-31+G*) methods were performed, considering different types of possible ionophore-ion interactions. The formation of hydrogen bonds between carbonate and hydrated TFA was proved to be much more favourable in terms of energy compared to tetrahedral nucleophilic adducts that earlier were postulated to being formed in the membrane phase. The final conclusion on the mechanism of carbonate sensing by TFA-based solvent polymeric membrane sensors was made on the basis of computational data and detailed analysis of the literature.

Structure−Reactivity Relationships and Intrinsic Reaction Barriers for Nucleophile Additions to a Quinone Methide: A Strongly Resonance-Stabilized Carbocation

Second-order rate constants kNu (M-1 s-1) were determined for addition of a wide range of nucleophiles to the simple quinone methide 4-[bis(trifluoromethyl)methylene]cyclohexa-2,5-dienone (1) to give the nucleophile adduct 1-Nu in water. Equilibrium constants were determined for the overall addition of HBr and HI to 1 to give H-1-Nu, and the data were used to calculate equilibrium constants for the addition of Br- and I- to 1, and to estimate equilibrium constants for the addition of Cl- and AcO-. The values of log kNu show a linear correlation with the Ritchie nucleophilicity parameter N+ with a slope s = 0.92 ± 0.10 that is essentially the same as the electrophile-independent value of 1.0 for highly resonance-stabilized carbocations. Marcus intrinsic barriers Λ of 12.4, 13.9, 15.4, and 19.8 kcal/mol are reported for the addition of I-, Br-, Cl-, and AcO- to 1, respectively. The thermodynamic barriers ΔG° and intrinsic barriers Λ for addition of Br-, Cl-, and AcO- to 1 are 8.4 ± 1.0 and 5.2 ± 0.2 kcal/mol larger, respectively, than the corresponding barriers for addition of these nucleophiles to the triphenylmethyl carbocation. It is concluded that, by the criterion of its chemical reactivity, 1 behaves as a highly resonance-stabilized carbocation. Values of N+ = 4.0, 2.2, 1.2 and 0.60, respectively, are reported for I-, Br-, Cl-, and AcO-, which do not form stable adducts to Ritchie electrophiles. The slope of 2.0 (r = 0.98) for the linear correlation between Ritchie (N+) and Swain−Scott (n) nucleophilicity parameters shows that there is substantially greater bonding between the nucleophile and carbon at the transition state for nucleophile addition to sp2-hybridized carbon than for addition to sp3-hybridized carbon. Azide ion and nucleophiles with a nonbonding electron pair(s) at atoms adjacent to the nucleophilic site (α-effect nucleophiles) exhibit significant positive deviations from this correlation.

Radical-chain reductive alkylation of electron-rich alkenes mediated by silanes in the presence of thiols as polarity-reversal catalysts

In the presence of a thiol catalyst, triphenylsilane mediates the reductive alkylation of electron-rich terminal alkenes R1R2CCH2 by organic halides R3Hal via electrophilic carbon-centred radicals R3˙. Reactions were carried out in benzene or dioxane solvent using di-tert-butyl hyponitrite (at 60 °C) or dilauroyl peroxide (at 80 °C) as initiators and good yields of the adducts R1R2CHCH2R3 were obtained with either methyl thioglycolate or triphenylsilanethiol as catalysts (5–10 mol% based on alkene). In the presence of the thiol, the slow direct abstraction of hydrogen from the silane by the nucleophilic adduct radical R1R2ĊCH2R3 is replaced by a cycle of more rapid polarity-matched reactions in which hydrogen-atom transfer to the adduct radical from the thiol is followed by abstraction of hydrogen from the silane by the derived thiyl radical, to regenerate the catalyst. In the absence of thiol, negligible yields of reductive alkylation products were obtained. The homochiral thiols, 1-thio-β-D-mannopyranose tetraacetate and 1-thio-β-D-glucopyranose tetraacetate, and the tetrapivalate and tetrabenzoate analogues of the latter were effective catalysts and reductive carboxyalkylation products with enantiomeric excesses up to 72% were obtained from prochiral alkenes. Homochiral samples of two of these adducts were obtained by recrystallisation and their absolute configurations were determined by X-ray diffraction.

Alkylation of Pyridinium Acceptors via Thermal and Photoinduced Electron Transfer in Charge-Transfer Salts with Organoborates

Colored salts of pyridinium tetraalkylborates [Py+,BR4-] are readily isolated by the metathesis of LiBMe4, LiBMePh3, or NaBPh4 with a series of pyridinium triflates in aqueous solution. The interionic charge-transfer (CT) interaction between the organoborate anions and the pyridinium cations is established by their characteristic charge-transfer absorption bands and X-ray crystal structures. Thermal and photochemical CT activations of the salts lead to efficient methyl transfer from tetramethylborate (or methyltriphenylborate) to the pyridinium cations to afford the various nucleophilic adducts (Py-Me) in good yields. Contact charge-transfer ion pairs are identified as the critical intermediates in the formal nucleophilic addition and thus play important roles in determining the regiochemistry of the alkylation and the solid-state reactivity of the [Py+,BR4-] salts.