Phenoxide Nucleophiles Research Articles

Dearomative Alkylation-Based Two-Step cis-Diastereoselective Synthesis of Indoline-2,3-Fused Chromans and Tetrahydropyrans.

Herein, we describe a two-step, cis-diastereoselective synthesis of indoline-2,3-fused chromans from 3-substituted indoles. The method proceeds without intermediacy of ortho-quinone methides and leverages the dual function of TBS-protected 2-hydroxybenzyl iodides both as highly reactive alkylating agents in a t-BuONa/Et3B-promoted dearomative alkylation step and as a source of masked phenoxide nucleophiles in a subsequent TBAF-induced one-pot deprotection-cyclization step of the resulting indolenines. Importantly, this two-step protocol can also be extended to access indoline-2,3-fused tetrahydropyrans. These syntheses of indoline-2,3-fused chromans and tetrahydropyrans proceed with operational convenience, use easily accessible substrates and reagents, and feature broad substrate scope, high yields and complete diastereoselectivity. Furthermore, the synthesized products have the potential to undergo late-stage functionalization.

Determination of the Mechanism of Nucleophilic Reaction of Fenitrothion Using Substituted Phenoxide Nucleophiles in Aqueous Media

The mechanism of the nucleophilic displacement reaction at the phosphorus centre of organophosphates was determined. Phenoxide nucleophiles were reacted with fenitrothion (O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate) in water at 25oC and pseudo-first order rate constant measurements taken. Second-order rate constant (kNuc) was determined for the different concentrations of nucleophiles while the second-order rate constant (klg) for the investigation of 2,4-dichlorophenoxide ion with and series of aryl phosphorothioate esters was also determined. Linear free energy relationship was further determined using the Brϕnsted-type plot. The plots are linear over a range of pKaNuc of 7.15-11.10 that straddles the pKa of the leaving 3-methyl-4-nitrophenoxide ion (pKa = 7.20) with statistically acceptable linear correlations (R2 = 0.987) and (R2 = 0.980). The linearity in the traditional Brϕnsted-type plots shows the sensitivity of the nucleophilic displacement to the basicity of the nucleophiles and hence is consistent with a single transition-state mechanism whose barrier to decomposition is low hence concerted. Analysis of the values of βNuc, βLg and βeq (0.734) with the effective charge distribution in the transition state shows that it has no positive character. The Leffler index presents bond formation being slightly ahead of bond rupture.

Sulfonamide as an Activating Group for the Synthesis of Poly(aryl ether sulfonamide)s by Nucleophilic Aromatic Substitution

Poly(aryl ether sulfonamide)s were produced utilizing the sulfonamide moiety as a new activating group for nucleophlic aromatic substitution polymerization. The activated monomer, 2,4-difluoro-N,N-dimethylbenzenesulfonamide, was synthesized in high yields through a simple substitution reaction between 2,4-difluorobenzenesulfonyl chloride and dimethyl amine. The reactivity of this monomer in a nucleophilic aromatic substitution mechanism was estimated using semiempirical calculations at the PM3 level, as well as by 1H, 13C and 19F NMR spectroscopy. The data support the sulfonamide as sufficiently electron-withdrawing to activate aryl fluorides for substitution by phenoxide nucleophiles. Model reactions with tert-butylphenol confirm that the aryl fluorides of 2,4-difluoro-N,N-dimethylbenzenesulfonamide can be displaced in quantitative yields and suggest the process is suitable for forming polymers. A variety of novel polymers were produced employing bisphenol A, 4,4′-biphenol, bisphenol AF and hydroquinone as comonomers. The polymers were characterized by gel permeation chromatography, solution viscometry, NMR spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. The high molecular weight poly(aryl ether sulfonamide)s exhibit moderate to high glass transition temperatures ranging from 163 to 199 °C. The polymers were shown to be thermally stable with 5% weight loss occurring from 398 to 442 °C in a nitrogen atmosphere.

Experimental and computational determination of Brønsted coefficients for equilibrium transfer of the O,O‐dimethyl phosphorothioyl group between oxyanion nucleophiles

An experimental determination of the βEq value for equilibrium transfer of the O,O‐dimethyl phosphorothioyl group between oxyanion nucleophiles in water and methanol at 25 °C is presented. The respective βEq values in the two solvents are experimentally the same at −1.45 ± 0.08 and −1.39 ± 0.12. Based on the observation that the Brønsted correlation for the nucleophilic reaction of phenoxides in water with substrate 1d (dimethyl 4‐nitrophenyl phosphorothioate, pKaHOAr of 7.14) is linear over the entire range of phenoxides employed (5.53 ≤ pKaNu ≤ 12.38), the reaction for phenoxide nucleophiles displacing phenoxide leaving groups is probably concerted. The obtained data allow one to calculate, for a symmetrical transition state involving 2,4,5‐trichlorophenoxide as a nucleophile and leaving group, an approximately 60% P–OAr cleavage and about 40% P–Nuc bond formation. A computational method is presented for the rapid prediction of the βEq values for such processes in water and methanol, and the results are compared with known values from the literature. Copyright © 2011 John Wiley & Sons, Ltd.

ChemInform Abstract: Studies on Ristocetin A. A Synthesis of Protected Ristomycinic Acid Using Organomanganese Chemistry.

Abstract Aryl ether formation by reaction of phenoxide nucleophiles with chloroarene-Mn(CO)3 cationic complexes, followed by reaction of the aryloxyarene-Mn(CO)3 complex with chiral glycine enolate equivalents, provides methodology for the synthesis of protected ristomycinic acid derivatives in a state of high optical purity.

Poly(aryl ether sulfide)s by sulfide-activated nucleophilic aromatic substitution polymerization

Poly(aryl ether sulfide)s have been produced by nucleophilic aromatic substitution with phenoxide nucleophiles bisphenol A and bisphenol AF, and the activated arylfluorides bis(4-fluorophenyl)sulfide and 2,7-difluorothianthrene. The resulting polymers are thermally stable, amorphous materials that have been characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and gel permeation chromatography (GPC). Moderate molecular weights have been achieved, representative of greater than 98% conversion of arylfluorides. The poly(aryl ether thianthrene)s are flame resistant and self extinguish within 0.2 s upon removal from a flame source. TGA of the poly(aryl ether thianthrene)s in an inert atmosphere result in a char yield greater than 50% at 750 °C. The flame resistant properties are more effectively modeled by TGA in an inert atmosphere as compared to TGA in an air atmosphere. The poly(aryl ether thianthrene)s are found to have high refractive index values, 1.61–1.70, depending on wavelength and bisphenol composition.

A Concerted Mechanism for the Transfer of the Thiophosphinoyl Group from Aryl Dimethylphosphinothioate Esters to Oxyanionic Nucleophiles in Aqueous Solution

Earlier work on the hydrolysis of aryl phosphinothioate esters has led to contradictory mechanistic conclusions. To resolve this mechanistic ambiguity, we have measured linear free energy relationships (beta(nuc) and beta(lg)) and kinetic isotope effects for the reactions of oxyanions with aryl dimethylphosphinothioates. For the attack of nucleophiles on 4-nitrophenyl dimethylphosphinothioate, beta(nuc) = 0.47 +/- 0.05 for phenoxide nucleophiles (pK(a) < 11) and beta(nuc) = 0.08 +/- 0.01 for hydroxide and alkoxide nucleophiles (pK(a) >or= 11). Linearity of the plot in the range that straddles the pK(a) of the leaving group (4-nitrophenoxide, pK(a) 7.14) is indicative of a concerted mechanism. The much lower value of beta(nuc) for the more basic nucleophiles reveals the importance of a desolvation step prior to rate-limiting nucleophilic attack. The reactions of a series of substituted aryl dimethylphosphinothioate esters give the same value of beta(lg) with the nucleophiles HO(-) (beta= -0.54 +/- 0.03) and PhO(-) (beta = -0.52 +/- 0.09). A significantly better Hammett correlation is obtained with sigma(-) than with sigma or sigma degrees , as expected for a transition state involving rate-limiting cleavage of the P-OAr bond. The (18)O KIE at the position of bond fission ((18)k = 1.0124 +/- 0.0008) indicates the P-O bond is approximately 40% broken, and the (15)N KIE in the leaving group ((15)k = 1.0009 +/- 0.0003) reveals the nucleofuge carries about a third of a negative charge in the transition state. Thus, both the LFER and KIE data are consistent with a concerted reaction and disfavor a stepwise mechanism.

On the regiochemistry of nucleophilic attack on 2-halo pi-allyl complexes. 4. The effect of silver acetate and nucleophile concentrations in competitive nucleophilic attack with malonate and phenoxide nucleophiles.

2,3-Dibromo-1-propene or its allyl carbonate analogue are ionized under Pd catalysis to generate the 2-bromo Pd-pi-allyl complex (triphenylphosphine ligand), which alkylates with malonate nucleophile at the terminal position. The presence of acetate ion in the reaction mixture results in some malonate attack being redirected to the central carbon. The acetate ion can come from the ionization of 1-acetoxy-2-bromo-2-propene or by the addition of silver acetate to the reaction mixture. The addition of phenoxide ion to the reaction also causes the same regiochemical phenomena, although harder anions such as methoxide exert no such effect.

On the regiochemistry of nucleophilic attack on 2-halo π-allyl complexes. Part 3: The electronic effect of phenoxide ion and the ligand

2,3-Dibromo-1-propene was subjected to competitive attack by malonate and different phenoxide nucleophiles in the presence of Pd substituted with monodentate or bidentate ligands. The presence of phenoxide promotes central carbon attack on the initially-formed 2-bromo Pd-π-allyl complex by malonate in the presence of mono or bidentate ligands on Pd. However, bidentate ligands on Pd disfavour the attack of phenoxide, either at the central position or the terminal position of either of the two π-ally complexes formed during the course of these di-additions.

Kinetics and mechanism of the phenolysis of asymmetric diaryl carbonates.

The reactions 4-methylphenyl 4-nitrophenyl carbonate (MPNPC), 4-chlorophenyl 4-nitrophenyl carbonate (CIPNPC), 4-methylphenyl 2,4-dinitrophenyl carbonate (MPDNPC), and 4-chlorophenyl 2,4-dinitrophenyl carbonate (CIPDNPC) with a homogeneous series of phenoxide anions are subjected to a kinetic investigation in aqueous solution (25.0 degrees C, ionic strength 0.2 M (KCI)). Under an excess of phenoxide with respect to the substrate, all of these reactions obey pseudo-first-order kinetics and are first order in phenoxide. The Brönsted-type plots for the nucleophilic rate constants (k(N)) are linear, with slopes beta = 0.48 (MPNPC), 0.67 (ClPNPC), 0.41 (MPDNPC), and 0.32 (ClPDNPC). The magnitude of these slopes and the absence of a curvature in the Brönsted plot at pK(a) = 7.1 for the CIPNPC reactions are consistent with concerted mechanisms (one step). The carbonates MPDNPC and ClPDNPC are more reactive than MPNPC and CIPNPC, respectively, toward phenoxide nucleophiles. This can be explained by the presence of a second nitro group in the nucleofuge of the dinitro derivatives, which (i) leaves their carbonyl carbon more positively charged, making them better electrophiles, and (ii) makes 2,4-dinitrophenoxide a better leaving group than 4-nitrophenoxide. The 4-chloro derivatives are more reactive than the corresponding 4-methyl derivatives. This should be due to the greater electron withdrawal of 4-chloro than 4-methyl, which makes the former carbonyl more electrophilic. Comparison of the concerted phenolysis of MPNPC with the stepwise reactions of secondary alicyclic amines with the same substrate indicates that substitution of a secondary alicyclic amine group in a zwitterionic tetrahedral intermediate by a phenoxy group greatly destabilizes the intermediate. An equation is deduced for log k(N) in terms of the basicity of the nucleophile, the nonleaving moiety, and the leaving group. This equation shows that for these reactions, the sensitivity of log k(N) to the basicity of the nonleaving moiety (beta(nlg) = -0.27) is very similar to that of the nucleofuge (beta(lg) = -0.25).

Kinetic investigation of the phenolysis of phenyl 4-nitrophenyl and phenyl 2,4-dinitrophenyl carbonates

The reactions of phenyl 4-nitrophenyl carbonate (PNPC) and phenyl 2,4-dinitrophenyl carbonate (PDNPC) with a homogeneous series of phenoxide anions are subjected to a kinetic investigation in water at 25.0 °C, ionic strength 0.2 mol dm−3 (KCl). Under phenoxide or total phenol excess over the substrate all these reactions obey pseudo first-order kinetics and are first order in phenoxide. The Bronsted-type plots for the nucleophilic rate constants are linear with slopes 0.61 and 0.49 for the phenolysis of PNPC and PDNPC, respectively. The magnitude of these slopes and the absence of curvature in the Bronsted plot at pKa = 7.1 for the PNPC reactions are consistent with concerted mechanisms (one step) for both reaction series. PDNPC is more reactive than PNPC toward phenoxide nucleophiles; this can be explained by the presence of a second nitro group in PDNPC, which (i) leaves its carbonyl carbon more positively charged than that of PNPC, making the former a better electrophile, and (ii) makes 2,4-dinitrophenoxide a better leaving group than 4-nitrophenoxide. The larger nucleophilic rate coefficients found in this work relative to those obtained in the concerted phenolysis of 4-nitrophenyl and 2,4-dinitrophenyl methyl carbonates is explained by a stronger electron withdrawal from PhO compared to MeO. Comparison of the concerted phenolysis of PNPC with the stepwise reactions of quinuclidines with the same substrate indicates that substitution of a quinuclidino group in a zwitterionic tetrahedral intermediate by a phenoxy group greatly destabilises the intermediate.

An Assessment of Desolvation on Rates of Acetyl Transfer: Insights into Enzyme Catalysis

Enzymes greatly enhance the rate of reactions by a variety of physical organic mechanisms. One of the more contentious of these has been desolvation. To get a quantitative assessment of this contribution, we examined acetyl transfer to oxydianions. This is a model reaction for enzymes in which a high-energy acyl phosphate is formed. The aqueous reaction of phosphate or phosphonates with p-nitrophenyl acetate (pNPA) shows a substantial negative deviation from the Bronsted correlation obtained with monoanionic nucleophiles and from the reactivity of other, larger, oxydianions (molybdate, arsenate and vanadate). This, and other data, suggests a significant contribution of desolvation to the activation energy. To further investigate this we studied the effect of various DMSO (dimethyl sulfoxide)/H_2O mixtures on the reaction of chloromethylphosphonate, and of molybdate, on the reaction with pNPA. Increasing the DMSO concentration from 1% to 90% (v/v) increases the second-order rate constant for each of these reactions by over a factor of 5000. This is over a 1000 times greater than the enhancing effect on the reaction of phenoxides and over 105 times the (inhibiting) effect on the reaction with neutral nucleophiles (imidazole). Extrapolation to pure DMSO yields a rate enhancement of ∼10^5, relative to the reaction in water, for the oxydianions. This enhancement is over 3 orders of magnitude greater than that seen with monoanionic phenoxide nucleophiles. This suggests a significant role for desolvation in the reactions in the enzyme-catalyzed nucleophilic reactions of inorganic phosphate but a modest role in reactions with less highly charged nucleophiles.

Solvent Effects on Acyl Transfers to Phosphonates

The nucleophilic reactivity of the phosphate dianion in aqueous solution is unusually low, relative to that of other nucleophiles of comparable pK4,s. For example, in the reaction with g-nitrophenyl acetate (pNPA), phosphate shows a negative deviation of over two orders of magnitude from the Bransted correlation (βnuc ≈ 0.7) obtained with other oxygen nucleophiles [l]. Since there are over 1 3 0 enzymatic reactions which catalyze nucleophilic reactions of phosphate, we were interested in exploring the possible sources of this catalytic efficiency. By using phosphonates (Rpo3 −2) as phosphate analogs we have shown an unusual insensitivity of the rate of acetyl transfer from E- nitrophenol to the phosphonate dianion (βnuc = 0.3). These observations, along with the more favorable entropy of activation for the reaction of pNPA with phosphonates (ΔS‡ ≈ −13 eu) than with most other nucleophiles (e.g., with imidazole or with acetate, δS‡ ≈ −30 eu) suggest a significant contribution of desolvation to the activation energy. To investigate this further we looked at the effect of DMSO/water mixtures on the reaction rate. The second-order rate constant for acetyl transfer from E-nitrophenol to chloromethylphosphonate increases over 5,000-fold as the DMSO concentration is increased to 90% (v/v). This sensitivity to DMSO concentration is greater than that reported for acetyl transfer to a variety of phenoxide nucleophiles [2] and is greater than can be accounted for simply from the increase in the effective pKa2 of the phosphonate nucleophile. This suggests a significant role for desolvation in the enzyme-catalyzed nucleophilic reactions of inorganic phosphate.

Synthesis of a Model Bicyclic CDE Ring System of Ristocetin A and Observation of a Facile Inversion of Configuration in a 16-Membered DE Ring Model

Areneruthenium chemistry was used to effect intramolecular SNAr reactions between phenoxide nucleophiles and chlorophenylalanine residues that are connected by a peptide chain, resulting in the construction of a bicyclic peptido aryl ether system that corresponds to the BCDF system of the glycopeptide antibiotics ristocetin A and teicoplanin. A facile and selective base-catalyzed complete inversion of configuration at the D ring arylglycine residue was observed when this unit is the carboxylate terminus on a 16-membered ring system corresponding to the DEF rings of the target molecules. The inversion appears to result from an overwhelming thermodynamic preference for the inverted system and is supported by molecular mechanics and semiempirical calculations on the minimized conformations of the epimeric molecules.

2,4,6‐trichloropyrimidine. Reaction with 4‐substituted phenolate ions

AbstractA systematic investigation of the reactivity of 2,4,6‐trichloropyrimidine with phenoxide nucleophiles has been conducted. Conditions have been described which lead to mono‐, di‐, and trisubstituted‐pyrimidines. Unexpected product distributions for mono‐ and disubstituted products were observed and explanations for these results are offered.

Conflicting evidence regarding the mechanism of the sulfonyl transfer reaction

Application of the novel solvent-dependent pKa method for the construction of Bronsted-type plots to the sulfonyl transfer reaction with phenoxide nucleophiles, finds the pKa's of aryloxides lower than those of the p-nitrophenoxide leaving group on separate lines, whereas nucleophiles of greater pKa fall on a common line, contrasting with the observed behaviour when using the traditional method.

ChemInform Abstract: Mitsunobu Reactions of Glycals with Phenoxide Nucleophiles are SN2′‐ Selective.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Mitsunobu reactions of glycals with phenoxide nucleophiles are S N2′-selective

The C 3-hydoxyl group of l-rhamnal ( 4) and d-glucal 7 underwent S N 2′-selective Mitsunobu displacements with substituted phenoxide nucleophiles. These reactions provide access to the corresponding α-arylglycoside.

A Formal Total Synthesis of the ACE Inhibitor K-13. An Application of Arene-Ruthenium Chemistry to Complex Chemical Synthesis

Stoichiometric ruthenium activation of 4-chlorophenylalanine derivatives toward nucleophilic substitution, using phenoxide nucleophiles that are derived from protected dipeptides, allowed the formation of isodityrosine derivatives that are synthetic precursors to the ACE inhibitor K-13. An evaluation of carboxyl blocking groups revealed that a 2-bromoethyl ester is the most useful in terms of its compatibility with ruthenium complexation and subsequent nucleophile addition but that its removal is problematic. Conversion to iodoethyl ester using Finkelstein reaction conditions, in the presence of the peptide and amino acid functionality, provided a solution to this problem, since the iodoethyl group was easily removed on treatment with samarium diiodide

Solvent independent transition-state structures. Part III. Sulfonyl transfer reactions

A kinetic spectrophotometric study has been performed on the reactions of p-nitrophenyl benzenesulfonate (PNPBS) with m-chlorophenoxide, p-chlorophenoxide, phenoxide, p-methylphenoxide and p-methoxyphenoxide ions in DMSO–H2O mixtures at 25.0 °C. Systematic variation of the DMSO content showed that the second-order rate constants (k2) changed only moderately upon addition of DMSO up to 20 mol% for reaction of p-chlorophenoxide, phenoxide and p-methylphenoxide. On the other hand, the rates of reaction for all of the phenoxide ions studied increased markedly in solvent compositions greater than 40 mol% DMSO. The nature of the transition state (TS) for these reactions was probed via Bronsted-type linear free energy relationships (LFERs). Traditional Bronsted-type plots (method ‘A’), in which the remote substituent on the aryloxide was varied and the solvent composition was held constant, were constructed for the reactions of the phenoxides with PNPBS in each of the following solvent compositions: 40%, 50%, 70% and 90% DMSO by mole. Novel Bronsted-type plots (method ‘B’), in which variation in phenoxide pKa, was imparted through solvent changes while the remote substituent was held constant, were also constructed for the reactions of each of the five phenoxide nucleophiles. Method A yielded a set of lines whose slopes (βnuc values) decreased steadily from 0.75 in 40 mol% DMSO to 0.60 in 90 mol% DMSO. Method B yielded a single straight line, βnuc= 0.60, with satisfactory linearity for all data points (r2= 0.995, 95% Cl =±0.021 ), although closer examination suggested slight curvature with βnuc varying from 0.54 for p-CH3O to 0.66 for m-Cl. These results point to a discrepancy in the traditional view that Bronsted-type LFERs can be directly translated into a TS structure. Considerations based on the Marcus equation suggest that linearity in a Bronsted-type plot may result for a set of reaction series with differing intrinsic barriers provided that ΔG#0 varies linearly with ΔG0.