Addition-elimination Mechanism Research Articles

Acyl Transfer Reactions of 2,4-Dinitrophenyl Furoates: Comparative Effects of Nucleophiles and Non-Leaving Groups

This study investigated the acyl group transfer reactions of 2,4-dinitrophenyl 5-substituted-2-furoates, promoted by 4-substituted phenoxides/phenols in a 20 mol% DMSO aqueous solution at 25 °C. The reactions yielded nucleophilic substitution products and displayed second-order kinetics, with βacyl values ranging from −2.24 to −2.50, ρ(x) values between 3.18 and 3.56, and βnuc values of 0.81 to 0.84. These findings indicate an addition–elimination mechanism where the initial step is rate-determining. Comparative analysis with previous data revealed that the transition state structure remained largely consistent when altering the non-leaving group from thienyl to furyl under similar conditions. Notably, a shift in the rate-determining step was observed when changing the nucleophile from secondary amines/ammonium ions to 4-substituted phenoxides/phenols, highlighting the significant impact of nucleophile selection on the reaction kinetics and mechanisms in acyl transfer reactions.

Gas-Phase Alcoholysis of Benzylic Halides in the Atmospheric Pressure Ionization Source.

The present study investigates the gas-phase alcoholysis reaction of benzylic halides under atmospheric pressure chemical ionization (APCI) conditions. The APCI corona discharge is used to initiate the novel reaction, which is monitored by ion trap mass spectrometry (IT-MS). The model compound α,α,α-trifluorotoluene is applied to observe the cascade methoxylation reaction during the +APCI-MS analysis, resulting in the formation of [PhC(OCH3)2]+. Based on the results of isotopic labeling and substrate expansion experiments, an addition-elimination mechanism is proposed: initially, the reaction was initiated by the dissociation of fluorine from PhCF3 under APCI condition, leading to the formation of [PhCF2]+; subsequently, two methanol molecules nucleophilicly attack [PhCF2]+ stepwisely, accompanied by the elimination of HF, yielding the product ion [PhC(OCH3)2]+. The proposed mechanism was further corroborated by theoretical calculations. The results of substrate scope expansion experiments suggest that this in-source reaction has the potential to differentiate the positional isomers of alcohols and phenols.

Tuneable thiol exchange linkers for traceless drug release applications in prodrugs and ADCs.

We describe a versatile and tuneable thiol responsive linker system using thiovinylketones, which relies on the conjugate addition-elimination mechanism of Michael acceptors for the traceless release of therapeutics. In a proof-of-principle study, we translate our findings to exhibit potent thiol-cleavable antibiotic prodrugs and antibody-drug conjugates.

Nazarov reaction triggered by active lithium salts in cyclopentyl methyl ether

Abstract In this study, we developed a lithium-activated Nazarov reaction of highly activated divinyl ketones in the presence of mixed lithium salts by combining LiClO4 with either LiOMe or LiI in cyclopentyl methyl ether (CPME). This reaction produces LiOPh in the reaction mixture, exhibiting aspects of a Nazarov reaction in the presence of base. The additives LiOMe and LiI not only facilitated the dissolution of LiClO4 aggregates but also promoted the addition–elimination mechanism, thereby accelerating the reaction and preventing side reactions.

Formation Mechanism of the Unsubstituted Chlorophosphazene Cl3P═NH: A Theoretical Study via Quantum Mechanical Calculations.

Although the synthesis of chlorophosphazene polymers has been explored for more than 100 years, the shortest yet most illusive monomer, Cl3P═NH, has never been isolated and fully characterized. Here we investigate the formation of Cl3P═NH from PCl5 and NH3 in chlorobenzene through quantum mechanical calculations. The potential energy surface was mapped using the MP2 Hamiltonian in conjunction with Dunning's correlation-consistent basis sets (aug-cc-pVXZ, where X = D and T). Along with HOMO/LUMO frontier molecular orbitals and natural bond orbital analyses, we found that instead of following the SN1 path proposed in the literature, the reaction proceeds via an addition-elimination mechanism. Our results also indicate that due to the low-lying stable intermediates (IM), most steps are exothermic such that the production of Cl3P═NH·2HCl can be completed once the energy barrier for the formation of [PCl4-NH3]+Cl- is overcome. Therefore, our theoretical work might explain the challenges in isolating any of the IMs in a typical chlorophosphazene reaction in chlorobenzene.

Reactions of 2,4‐dinitrophenyl 5‐substituted‐2‐thiophenecarboxylate promoted by 4‐ZC6H4O−/4‐ZC6H4OH in 20 mol% DMSO(aq). Effects of leaving group and nucleophile on the acyl transfer reactions

AbstractThe kinetics of nucleophilic substitution reactions involving 2,4‐dinitrophenyl 5‐substituted‐2‐thiophenecarboxylate were studied kinetically with 4‐Z‐C6H4O−/4‐Z‐C6H4OH, which facilitated the reactions, in 20 mol% DMSO(aq). The reactions followed second‐order kinetics and exhibited βacyl = −2.34 to −2.92, ρ(Y) = 2.71–3.39, βnuc = 0.74–0.83, and |βlg| = 0.40–0.57. Based on the interpretation of the results, we have concluded that the reaction follows an addition–elimination mechanism in which the first step is the rate‐determining step (rds). The transition state structures for the 4‐ZC6H4O−‐promoted reactions remained nearly the same with a change in the leaving group from 4‐nitrophenoxide to 2,4‐dinitrophenoxide. The mechanism of the 4‐ZC6H4O−‐promoted reaction was similar to that of R2NH‐promoted reactions, except that the former proceeded with the 1st step being the rds and the latter proceeded with a change in the rds from the second to the first step with a stronger nucleophile.

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

Diverse Synthesis of 2H-Isoindole-Based Polycyclic Aromatic Compounds.

1,3-Disubstituted N-aryl-2H-isoindoles have been synthesized by a cascade reaction of divinyl ethers, which are derived from easily available 4-bromoisocoumarins, with substituted anilines in HFIP. This cascade reaction consists of a ring-opening step through addition-elimination mechanism and the following 5-exo-tet type ring-closing step via the intramolecular nucleophilic substitution reaction. Thus obtained 2H-isoindoles have been derivatized to high-order nitrogen-containing polycycles including less accessible benzo[a]ullazines.

DFT investigations on the mechanisms and kinetics for the DMS + O3 reaction

AbstractThe potential energy surface (PES) for the reaction of ozone with dimethyl sulfide (DMS) was calculated at the CCSD(T)/6‐311++G(3df,2pd)//M06‐2X/6‐311++G(d,p) levels of theory. Result shows that on the singlet PES the addition–elimination mechanism is dominant, and H‐abstraction mechanism is less competitive. The major channel starts from the addition of ozone and DMS leading to a weak intermediate IM1, which decomposes subsequently to DMSO and 1O2 via a barrier around 38.8 kJ/mol. With a barrier of 64.0 kJ/mol, the formation of HO3 + CH3SCH2 via H‐abstraction mechanism is subdominant. Besides, DMSO + 1O2 can take place further reactions to produce several products. The substitution mechanism was located on the triplet PES, however, with a rather high barrier it is negligible. Furthermore, the rate constants for the two channels leading to DMSO + 1O2 and HO3 + CH3SCH2 were calculated from 200 to 1000 K. The total rate constant is 1.13 × 10‐20 cm3·molecule‐1·s‐1 at 298 K and 1 atm, in good agreement with previous experimental data. The overall rate constants are positive temperature dependent in the whole temperature range.

An Ab Initio RRKM-Based Master Equation Study for Kinetics of OH-Initiated Oxidation of 2-Methyltetrahydrofuran and Its Implications in Kinetic Modeling

Cyclic ethers (CEs) can be promising future biofuel candidates. Most CEs possess physico-chemical and combustion indicators comparable to conventional fuels, making them suitable for internal combustion engines. This work computationally investigates the kinetic behaviors of hydrogen abstraction from 2-methyl tetrahydrofuran (2MTHF), one of the promising CEs, by hydroxyl radicals under combustion and atmospheric relevant conditions. The various reaction pathways were explored using the CCSD(T)/cc-pVTZ//M06-2X/aug-cc-pVTZ level of theory. The Rice–Ramsperger–Kassel–Marcus-based master equation (RRKM-ME) rate model, including treatments for hindered internal rotation and tunneling, was employed to describe time-dependent species profiles and pressure and temperature-dependent rate coefficients. Our kinetic model revealed that the H-abstraction proceeds via an addition-elimination mechanism forming reaction complexes at both the entrance and exit channels. Eight different reaction channels yielding five radical products were located. The reaction exhibited complex kinetics yielding a U-shaped Arrhenius behavior. An unusual occurrence of negative temperature dependence was observed at low temperatures, owing to the negative barrier height for the hydrogen abstraction reaction from the C-H bond at the vicinity of the O-atom. A shift in the reaction mechanism was observed with the dominance of the abstraction at Cα-H of 2MTHF ring (causing negative-T dependence) and at CH3 (positive-T dependence) at low and high temperatures, respectively. Interestingly, the pressure effect was observed at low temperatures, revealing the kinetic significance of the pre-reaction complex. Under atmospheric pressure, our theoretical rate coefficients showed excellent agreement with the available literature data. Our model nicely captured the negative temperature-dependent behaviors at low temperatures. Our predicted global rate coefficients can be expressed as k (T, 760 Torr) = 3.55 × 101 × T−4.72 × exp [−340.0 K/T] + 8.21 × 10−23 × T3.49 × exp [918.8 K/T] (cm3/molecule/s). Our work provides a detailed kinetic picture of the OH-initiated oxidation kinetics of 2MTHF. Hence, this information is useful for building a kinetic me chanism for methylated cyclic ethers.

Chemo- and regioselectivities of the TBAF-catalyzed C[sbnd]F bond allylation of trifluoromethylalkenes: A theoretical view

Selective CF bond activation and functionalization of readily available polyfluorinated groups is a classical and effective way to access high value-added organofluorine compounds. Insights into origin of the selectivities could provide valuable guidance to precise manipulation and so as to get desired products. In this study, the mechanism and causation of the selective mono-CF bond allylation of trifluoromethylalkenes with tetrabutylammonium fluoride (TBAF) as catalyst has been investigated by using the density functional theory (DFT) methods. It is unveiled that the SN2′-type nucleophilic substitution going through the addition-elimination mechanism is more favorable than the concerted SN2 pathway. According to the calculation results, allyl anions would kinetically identify the trifluoromethylalkene, ammonium cation (TBA+), and difluoromethylalkene in turn, which guarantees the mono-CF bond activation under the conditions of excessive nucleophiles. Furthermore, as a specific point, the regioselectivity of the reaction using asymmetric allyl anion as the nucleophile has also been studied. The Parr function calculations and non-covalent interaction analysis reveals that the more significant nucleophilicility of the benzyl carbon atom in allyl anion and the π…π interaction between the aryl substituents on the two reacting fragments leads to favor of the reaction at the benzyl site.

Preparation of Vinylphosphonates from Ketones Promoted by Tf2O.

An efficient triflic anhydride promoted phosphorylation of ketone was disclosed, and vinylphosphorus compounds were prepared under solvent- and metal-free conditions. Both aryl and alkyl ketones could perform smoothly to give vinyl phosphonates in high to excellent yields. In addition, the reaction was easy to carry out and easy to scale up. Mechanistic studies suggested that this transformation might involve nucleophilic vinylic substitution or a nucleophilic addition-elimination mechanism.

The electrophilic aromatic bromination of benzenes: mechanistic and regioselective insights from density functional theory.

The HBr-assisted electrophilic aromatic bromination of benzene, anisole and nitrobenzene was investigated using static DFT calculations in gas phase and implicit apolar (CCl4) and polar (acetonitrile) solvent models at the ωB97X-D/cc-pVTZ level of theory. The reaction profiles corresponding to either a direct substitution reaction or an addition-elimination process were constructed and insight into the preferred regioselectivity was provided using a combination of conceptual DFT reactivity indices, aromaticity indices, Wiberg bond indices and the non-covalent interaction index. Our results show that under the considered reaction conditions the bromination reaction preferentially occurs through an addition-elimination mechanism and without formation of a stable charged Wheland intermediate. The ortho/para directing effect of the electron-donating methoxy-group in anisole was ascribed to a synergy between strong electron delocalisation and attractive interactions. In contrast, the preferred meta-addition on nitrobenzene could not be traced back to any of these effects, nor to the intrinsic reactivity property of the reactant. In this case, an electrostatic clash between the ipso-carbon of the ring and the nitrogen atom resulting from the later nature of the rate-determining step, with respect to anisole, appeared to play a crucial role.

One-Pot Protolignin Extraction by Targeted Unlocking Lignin-Carbohydrate Esters via Nucleophilic Addition-Elimination Strategy.

Protolignin extraction can facilitate structure elucidation and valorization of lignin in biorefinery, but is rather challenging due to the complex chemical bonds present. Here, we developed the insitu generated NH3-reline (IGNR) system to realize one-pot protolignin extraction from lignocellulose. In the IGNR system, reline consisting of choline chloride and urea acted as both a solvent and a nucleophile generator, and the nucleophilic addition-elimination mechanism was verified by model compound studies. The insitu generated NH3 could precisely cleave the lignin-carbohydrate esters in lignocellulose with a near-quantitative retention of carbohydrates. The extracted IGNR-Protolignin exhibited native lignin substructure with high molecular weight and high β-O-4' content (41.5 per 100 aromatic units). In addition, the up-scaled kilogram reaction demonstrated the feasibility of the IGNR system for potential industrial application in a green and sustainable pathway. This work represents a breakthrough toward protolignin extraction in practice with the future goal of achieving total biorefinery.

Nucleophilic Substitution at Tricoordinate Sulfur-Alkaline Hydrolysis of Optically Active Dialkoxysulfonium Salts: Stereochemistry, Mechanism and Reaction Energetics.

Optically active dialkoxyisopropylsulfonium salts were obtained by methylation (ethylation) of optically active alkyl isopropanesulfinates using methyl (ethyl) trifluoromethanesulfonate. Alkaline hydrolysis of a series of methoxy(alkoxy)sulfonium salts afforded the two sulfinate products methyl isopropanesulfinate and alkyl isopropanesulfinate, both formed with a slightly prevailing inversion of configuration at the sulfur atom. DFT calculations revealed that this substitution reaction proceeded stepwise according to an addition-elimination (A-E) mechanism involving the formation of high tetracoordinate SIV sulfurane intermediates. In addition, the DFT calculations showed that recombination of the hydroxy anion with the methoxy(alkoxy)sulfonium cation-leading to the parallel formation of the two most stable primary sulfuranes, with the hydroxy and alkoxy groups in apical positions and their direct decomposition-is the most energetically favorable pathway.

Computational investigation of thermochemistry and kinetics of the reaction between n-butyl peroxy and hydroperoxyl radicals

The energetics, thermochemistry and kinetics for the reaction between n-butyl peroxy radical and HO2 radical was computed using CCSD(T)/aug-cc-pVDZ// B3LYP/6-311G(d,p) level of theory coupled with Canonical Variational Transition state theory incorporating small curvature tunnelling corrections. The H abstraction pathway involving addition–elimination mechanism on the triplet energy surface was found to be most feasible reaction pathway. The calculated rate coefficients showed a negative temperature dependency in the studied range of 200 to 400 K. The Arrhenius expression for the title reaction was derived as, ktotal = 1.35 × 10−16 exp(3703/T) cm3molecule−1 s−1.

Sulfite-Catalyzed Nucleophilic Substitution Reactions with Thiamin and Analogous Pyrimidine Donors Proceed via an SNAE Mechanism.

When treated with SO32-, thiamin undergoes a substitution reaction to release a thiazole leaving group and the corresponding sulfonate. Although this reaction could proceed via a simple SN2-like mechanism, a multistep addition-elimination (SNAE) mechanism involving the addition of SO32- to C6' of the 4-aminopyrimidine of thiamin has also been proposed. Although this reaction has potential utility in the synthesis of substituted pyrimidines and provides a direct analogue to reactions catalyzed by thiaminases, a detailed mechanistic picture of the SO32--catalyzed cleavage of thiamin has remained elusive. Here, DFT calculations have been used to probe the relative energetics and the factors that shape the potential energy surfaces that define the possible mechanisms of substitution. These calculations provide clear support for the SNAE mechanism over an SN2-like process and illustrate that the unique ability of SO32- to activate thiamin toward nucleophilic displacement is due to the combined nucleophilicity and relatively poor leaving group ability of SO32-. Both of these factors favor the forward partitioning of the sulfite adduct toward the cleavage products whereas adducts formed with other nucleophiles overwhelmingly revert to reactants. Calculations performed with a range of substrates with various electrophilicities and nucleofugalities consistently suggest that the SNAE pathway is significantly lower in energy than the direct substitution, illustrating that this SO32--catalyzed multistep process is likely to be broadly applicable both in solution and in catalysis by thiaminases.

Environment-friendly transesterification to seawater-degradable polymers expanded: Computational construction guide to breaking points

Marine plastic pollution caused by non-biodegradable polymers is a major worldwide concern. So-called “biodegradable” polymers should reduce plastic pollution in the environment by the safeguard of biodegradation. However, many polyesters degrade very slowly in seawater. We therefore designed a systematic library of “breaking points” that are installed into a polylactide backbone and simulated their degradation mechanisms, including internal and external SN2 mechanisms, Addition-Elimination (AE) mechanisms, and RNA-inspired mechanisms. The breaking points are composed of phosphoesters with pendant nucleophiles directly at the P-atom, or structurally similar silicones, or side-chain functional polyesters. All P-containing breaking points react via the RNA-inspired mechanism, while Si-containing linkers undergo decomposition via the A-E mechanism. For C-containing linkers, only when a long pendant chain (4 carbon atoms) is present can the reaction proceed via the RNA-inspired mechanism. In cases of shorter pendants, the Addition-Elimination (AE) mechanism is energetically favorable. We believe that these calculations will pave the way for the synthesis of exceptionally seawater-degradable polyesters in the future that can act as a safeguard to prevent microplastic formation after eventual littering.

Quantum-Chemical Study of Reactions between Dimethyl Carbonate and Methylamine Proceeding through an Addition–Elimination Mechanism on Zinc Oxide Catalysts

Quantum-Chemical Study of Reactions between Dimethyl Carbonate and Methylamine Proceeding through an Addition–Elimination Mechanism on Zinc Oxide Catalysts

Complexities of Regioselective Ring-Opening vs Transcarbonylation-Driven Structural Metamorphosis during Organocatalytic Polymerizations of Five-Membered Cyclic Carbonate Glucose Monomers.

Rigorous investigations of the organobase-catalyzed ring-opening polymerizations (ROPs) of a series of five-membered cyclic carbonate monomers derived from glucose revealed that competing transcarbonylation reactions scrambled the regiochemistries of the polycarbonate backbones. Regioirregular poly(2,3-α-d-glucose carbonate) backbone connectivities were afforded by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed ROPs of three monomers having different cyclic acetal protecting groups through the 4- and 6-positions. Small molecule studies conducted upon isolated unimers and dimers indicated a preference for Cx–O2 vs Cx–O3 bond cleavage from tetrahedral intermediates along the pathways of addition–elimination mechanisms when the reactions were performed at room temperature. Furthermore, treatment of isolated 3-unimer or 2-unimer, having the carbonate linkage in the 3- or 2-position as obtained from either Cx–O2 or Cx–O3 bond cleavage, respectively, gave the same 74:26 (3-unimer:2-unimer) ratio, confirming the occurrence of transcarbonylation reactions with a preference for 3-unimer vs. 2-unimer formation in the presence of organobase catalyst at room temperature. In contrast, unimer preparation at −78 °C favored Cx–O3 bond cleavage to afford a majority of 2-unimer, presumably due to a lack of transcarbonylation side reactions. Computational studies supported the experimental findings, enhancing fundamental understanding of the regiochemistry resulting from the ring-opening and subsequent transcarbonylation reactions during ROP of glucose carbonates. These findings are expected to guide the development of advanced carbohydrate-derived polymer materials by an initial monomer design via side chain acetal protecting groups, with the ability to evolve the properties further through later-stage structural metamorphosis.