Leaving Group Ability Research Articles

Investigation of the base promoted tandem syn-elimination–Favorskii rearrangement of levoglucosan sulfonates

The reaction of various 2,3,4-trisulfonated 1,6-anhydro-β-D-glucopyranoses with alkoxide was investigated. Upon treatment with methoxide the tritosylate5, tris(chlorosulfate) 20 and tris(trifluoromethanesulfonate) 21 all gave 1,5-anhydro-2,3-dideoxy-3-methoxycarbonyl-β-D-erythro-pentofuranose 6 in 41–57% yield with the yield increasing with improved leaving group ability. The trimesylate19 gave the 3,4-epoxide 23 and no rearranged product. Chloroform was found to be the best solvent for obtaining 6, while alcohol as the solvent only gave epoxide 2. A study of different bases showed that the yield of the Favorskii product was increased 10–20% by using ethoxide as base. Reaction of the corresponding chlorosulfonated 1,6-anhydrogalactopyranose or anhydromannopyranose gave the same product though in lower yield. The Favorskii product 6 rearranged in the presence of traces of acid to a l,5′:1′,5-dianhydride.

Folding disulfide-containing proteins faster with an aromatic thiol.

The traditional method for in vitro folding of disulfide-containing proteins is slow and involves a redox buffer of glutathione and glutathione disulfide. To increase the folding rate and to gain insight into the folding process, we replaced glutathione, an aliphatic thiol, with a commercially available aromatic thiol, 4-mercaptobenzeneacetate (1). Aromatic thiol 1 was selected due to its enhanced nucleophilicity and its enhanced leaving-group ability relative to glutathione at pH 7.7. To demonstrate the advantages of 1, the folding of reduced and scrambled RNase A at pH 7.0 and 7.7 in the presence of 1 and glutathione was investigated. For each set of folding conditions, the optimum concentration of each thiol was initially determined and then the folding rates in the presence of each thiol were measured concurrently. In all cases examined, the folding rate enhancement with the aromatic thiol was 5- 6-fold. Furthermore, under similar conditions folding rates were almost identical with either reduced or scrambled RNase A. In addition the 5-6-fold folding rate enhancement varied only slightly with pH, 7.0 vs 7.7.

A strategy for the construction of caged diols using a photolabile protecting group.

Caged analogues of biologically active compounds have received widespread attention as temporally and spatially controlled probes of cell-based processes. Recently, a coumarin-4-ylmethyl derivative has been used to cage carboxylates, sulfonates, carbamates, and phosphates. We describe herein a synthetic strategy that furnishes photosensitive caged diols and provides an entry into the protection/photodeprotection of functionality with modest leaving group abilities.

ChemInform Abstract: Nucleophilic Vinylic Substitutions of λ3-Vinyliodanes

Abstract Because of the excellent nucleofugality of the λ3-phenyliodanyl group, which shows a leaving group ability about 106 times greater than triflate, λ3-vinyl(phenyl)iodanes serve as highly reactive species in nucleophilic substitutions. This review summarizes the nucleophilic vinylic substitutions of λ3-vinyl(phenyl)iodanes. The reaction rates and mechanism of the nucleophilic vinylic substitutions change depending on the structure of λ3-vinyliodanes; the nature of the substituents at the β-vinylic carbons is especially important. β-Monoalkyl-λ3-vinyliodanes undergo bimolecular nucleophilic vinylic substitutions (SN2) with exclusive inversion of configuration under mild conditions, which, hitherto, has been considered to be impossible on the bases of experimental results and theoretical calculations. Vinylic SN1 reactions generating vinyl cations, ligand coupling reactions on hypervalent iodine(III), and addition–elimination and elimination–addition reactions, are also discussed.

ChemInform Abstract: Synthesis of Alkylidenecyclopentenones and Dialkylidenecyclopentenones via the Coupling of Propargylic Alcohol and 2-Alkyne-1,4-diol Derivatives with Cyclopropylcarbene-Chromium Complexes.

Abstract The coupling of propargylic alcohols and their derivatives with cyclopropylcarbene–chromium complexes has been investigated. The coupling reaction leads to alkylidenecyclopentenones or alkoxyalkyl-cyclopentenones, depending on the leaving group ability of the propargyl substituent. A mechanism involving formation of a cyclopentadienone, followed by reduction and β-elimination is proposed. Coupling of cyclopropylcarbene complexes with 2-alkyne-1,4-diol derivatives leads to dialkylidenecyclopentenone derivatives via a double elimination process.

Nucleophilic vinylic substitutions of λ 3-vinyliodanes

Because of the excellent nucleofugality of the λ 3-phenyliodanyl group, which shows a leaving group ability about 10 6 times greater than triflate, λ 3-vinyl(phenyl)iodanes serve as highly reactive species in nucleophilic substitutions. This review summarizes the nucleophilic vinylic substitutions of λ 3-vinyl(phenyl)iodanes. The reaction rates and mechanism of the nucleophilic vinylic substitutions change depending on the structure of λ 3-vinyliodanes; the nature of the substituents at the β-vinylic carbons is especially important. β-Monoalkyl-λ 3-vinyliodanes undergo bimolecular nucleophilic vinylic substitutions (S N2) with exclusive inversion of configuration under mild conditions, which, hitherto, has been considered to be impossible on the bases of experimental results and theoretical calculations. Vinylic S N1 reactions generating vinyl cations, ligand coupling reactions on hypervalent iodine(III), and addition–elimination and elimination–addition reactions, are also discussed.

3,4-Dihydro-3,4,6-trimethyl-2H,8H-pyrano-[3,2g]-1,3-benzoxazin-2,8-dione, a Potential Fluorogenic Reporter Group Reagent for Esterases—Synthesis and Interaction with Chymotrypsin

The synthesis of a novel “reporter group” reagent—3,4-dihydro-3,4,6-trimethyl-2H,8H-pyrano-[3,2g]-1,3-benzoxazin-2,8-dione (DTPBD)—is described. This compound has a cyclic carbamate functionality and thus, like the previously used 3,4-dihydro-3-methyl-6-nitro-2H-1,3-benzoxazin-2-one (DMNB), has the potential to label an esterase such as chymotrypsin. In so doing, DTPBD would incorporate into the protein a covalently linked 4-methylumbelliferone derivative, thus providing a sensitive reporter group that is both chromophoric and fluorescent. Experiments show that DTPBD reacts with chymotrypsin in the predicted manner, except that the labeling process is freely reversible (unlike the case with DMNB). 4-Methylumbelliferyl acetate (which is structurally closely related to DTPBD) is a good substrate for chymotrypsin. The rate of acylation of the enzyme is about an order of magnitude faster than with p-nitrophenyl acetate (which in turn is structurally related to DMNB), an unexpected observation in view of the relative leaving-group abilities of the groups concerned. The results suggest that these various modifiers and substrates show subtle but significant differences in the way they position themselves in chymotrypsin's binding site.

Synthesis of Alkylidenecyclopentenones and Dialkylidenecyclopentenones via the Coupling of Propargylic Alcohol and 2-Alkyne-1,4-diol Derivatives with Cyclopropylcarbene–Chromium Complexes

The coupling of propargylic alcohols and their derivatives with cyclopropylcarbene–chromium complexes has been investigated. The coupling reaction leads to alkylidenecyclopentenones or alkoxyalkyl-cyclopentenones, depending on the leaving group ability of the propargyl substituent. A mechanism involving formation of a cyclopentadienone, followed by reduction and β-elimination is proposed. Coupling of cyclopropylcarbene complexes with 2-alkyne-1,4-diol derivatives leads to dialkylidenecyclopentenone derivatives via a double elimination process.

Bifunctional Catalysis and Apparent Stereoelectronic Control in Hydrolysis of Cyclic Imidatonium Ions

To test stereoelectronic control in cleavage of tetrahedral intermediates, cyclic imidatonium ions were hydrolyzed in buffered aqueous media. In carbonate buffer >97% amino ester was observed, as previously reported. However, in borate buffers 65−91% hydroxy amide was observed from five-membered-ring imidatonium ions, except for a highly alkylated one. Selectivity is attributed to leaving-group ability. Stereoelectronic control does operate in six-membered rings but provides only 2 kcal/mol toward rate acceleration. Production of amino ester in carbonate buffers is due to the bifunctional nature of bicarbonate ion and thus cannot be used to support a large stereoelectronic contribution. The geometrical requirements for bifunctional catalysis further imply the intermediacy of conformations counter to stereoelectronic control.

Ring constructions by the use of fluorine substituent as activator and controller

Abstract By using the properties of fluorine such as electronic effects and leaving-group ability, two types of ring-forming reactions have been achieved starting from fluoroolefins: (i) fluorinated vinyl ketones with a vinyl and/or an aryl group, which undergo fluorine-directed and/or -activated Nazarov, Friedel-Crafts, and tandem cyclizations in their combination to construct highly functionalized and fused ring systems and (ii) gem-difluoroolefins bearing a nucleophilic center on the carbon δ to the flourines undergo intramolecular substitution for the fluorine via "anti-Baldwin" 5-endo-trig closures leading to ring-fluorinated heterocycles. Throughout these reactions, fluorines function as an activator of the substrates and a controller over the reaction pathways.

Deactivation Behavior and Excited-State Properties of (Coumarin-4-yl)methyl Derivatives. 1. Photocleavage of (7-Methoxycoumarin-4-yl)methyl-Caged Acids with Fluorescence Enhancement

The photochemistry of the (7-methoxycoumarin-4-yl)methyl (MCM) carboxylates 3a−d, the mesylate 4, and the phosphates 5a−e has been examined under near physiological conditions in acetonitrile or methanol/aqueous HEPES buffer solution, respectively. Analysis of photoproducts as well as measurements of photochemical quantum yields, fluorescence quantum yields, and lifetimes for the excited singlet state verified the similar photochemical and photophysical behavior of all the esters studied here. 4-(Hydroxymethyl)-7-methoxycoumarin (2) and the corresponding free acids were obtained as major products upon irradiation. The rates of deactivation of the excited MCM derivatives 3a−5e were found to be dependent on the leaving group ability of the anion concerned as well as on the solvent polarity. The polarity dependence and the exclusive formation of 18O-labeled 2 during irradiation of 5a in 18O-labeled water indicate that photocleavage of the excited singlet state of the MCM caged compounds 3a−5e proceeds via a photo SN1 mechanism (solvent-assisted photoheterolysis).

Asymmetric Synthesis of 2H-Azirine 2-Carboxylate Esters.

2H-Azirine 2-carboxylate esters (5), the smallest unsaturated nitrogen heterocycle, are readily prepared in enantiomerically pure form via the base-induced elimination of sulfenic acid (RSOH) from nonracemic N-sulfinylaziridine 2-carboxylate esters (4). Optimum yields were obtained when the aziridine was treated with TMSCl at -95 degrees C followed by LDA, which was attributed to the improved leaving group ability of an silicon-oxonium species. By using this new methodology the first asymmetric syntheses of the marine cytotoxic antibiotics (R)-(-)- and (S)-(+)-dysidazirine (2) were accomplished.

Palladium(0)-Catalyzed Synthesis of 2-Vinyl-2,3-dihydro-benzo[1,4]dioxins

The reaction of 1,4-bis(methoxycarbonyloxy)but-2-ene (2a–3a) or 3,4-bis(methoxycarbonyloxy)but-1-ene (4a) with various substituted benzene-1,2-diols was catalyzed by a palladium(0) complex to give substituted 2-vinyl-2,3-dihydro-benzo[1,4]dioxins in good yields via a tandem allylic substitution reaction. In the case of 4-substituted benzene-1,2-diols, the ratio of regioisomers is determined by the relative acidity of the two phenolic protons. For 3-substituted benzene-1,2-diols, this ratio is determined only by steric effects in the case of alkyl substituents, although it is determined mainly by the relative stabilities of the corresponding phenates for other substituents; however, for 3-nitrobenzene-1,2-diol, this ratio is determined by the relative leaving-group ability of 2-nitro- or 3-nitrophenate. When the cyclisation was performed in the presence of an optically active phosphane, chiral 2-vinyl-2,3-dihydro-benzo[1,4]dioxin (5) was obtained with enantioselectivity of up to 45% using BINAP as the chiral phosphane.

Synthesis of Alkylidenecyclopentenones via the Coupling of Propargyl Alcohol Derivatives with Cyclopropylcarbene−Chromium Complexes

The coupling of propargylic alcohols and their derivatives with cyclopropylcarbene−chromium complexes has been investigated. The coupling reaction leads to alkylidenecyclopentenones or alkoxyalkylcyclopentenones, depending on the leaving group ability of the propargyl substituent. A mechanism involving formation of a cyclopentadienone, followed by reduction and β-elimination, was proposed.

Axial ligand exchange of iron(III) tetramesitylporphyrin phenolate complexes

The axial ligand of a series of iron(III) 5,10,15,20-tetramesitylporphyrin phenolate complexes was found to exchange with added carboxylic acids and alcohols. The rates of axial ligand exchange with carboxylic acids were found to be dependent on acidity of the carboxylic acid, basicity of the phenolate, and the steric bulk of both the carboxylic acid and the phenolate axial ligand. The rates of axial ligand exchange with alcohols were found to be dependent on the nucleophilicity of the alcohol, leaving group ability of the phenolate, and the steric bulk of both the alcohol and the phenolate axial ligand. Different mechanisms for ligand exchange are proposed for carboxylic acids and alcohols.

Gas-phase negative ion chemistry of molecular fluorine. Synthesis of distonic radical anions and related species

The gas-phase negative ion chemistry of molecular fluorine is described, with an emphasis on its use in the regiospecific synthesis of distonic radical anions and related species. Sequential reaction of organic compounds containing two trimethylsilyl (TMS) substituents with F − followed by F 2 produces distonic radical anions with the negatively charged and odd-spin sites determined by the locations of the TMS groups. The mechanism of the F 2 reaction involves dissociative electron transfer from the TMS-substituted carbanion to F 2, yielding an F −/radical complex; subsequent attack by F − on the TMS group of the radical produces the distonic radical anion product. Experimental evidence in support of the proposed mechanism is presented, including the dependence of the efficiency of radical anion formation on both the electron binding energy of the reactant carbanion and the leaving-group ability of the radical anion product. Selected applications of the F 2 method for distonic anion synthesis are described, including formation of the negative ions of trimethylene methane, the benzynes, oxyallyl and acetoxyl biradicals and α,3-dehydrotoluene. Mechanistic variations in the F 2 reactions with carbanions are described in which the transient F − ion produced by dissociative electron transfer to F 2 reacts with the organic radical in the long-lived complex by proton transfer, nucleophilic substitution at carbon, and elimination. Formation of distonic biradical anions (ionized triradicals) from neutral precursors containing three TMS groups is described, along with the rational gas-phase synthesis using F 2 of distonic carbene and nitrene anions.

Phthalimidomethyl as a drug pro-moiety. Probing its reactivity.

Phthalimidomethyl derivatives 1, encompassing a wide range of leaving group abilities, are rapidly hydrolysed to the corresponding phthalamic acid via rate-determining attack at the phthalimide carbonyl group.

Hypervalent pyrrolidinium radicals by neutralization—reionization mass spectrometry: Metastability and radical leaving group abilities

Neutralization-reionization mass spectrometry was used to generate hypervalent radicals pyrrolidinium (1H·), N-methylpyrrolidinium (2H·), N-ethylpyrrolidinium (3H·), N-phenylpyrrolidinium (4H·), N,N-dimethylpyrrolidinium (5·), N-methyl-N-ethylpyrrolidinium (6·), and their deuterium-labeled derivatives and to study their dissociations in the gas phase. Isotopomers of pyrrolidinium and N-phenylpyrrolidinium showed small fractions of stable radicals of microsecond lifetimes that were detected following collisional reionization. The leaving group abilities in radical dissociations were established as H· » C2H5· ≈ C6H5·> CH3·. The hydrogen atom was the best leaving group in secondary and tertiary pyrrolidinium radicals 1H·–4H·, whereas losses of ethyl, phenyl, and ring openings by N-C bond cleavages were less facile. Methyl was the worst leaving group among those studied. Ring cleavages dominated the dissociations of quaternary pyrrolidinium radicals 5· and 6·, whereas losses of alkyl substituents were less efficient. The electronic properties of hypervalent ammonium radicals are discussed to rationalize the experimental leaving group abilities of hydrogen atom, alkyl, and phenyl radicals.

N,N-1,2-Benzenedisulfonylimide, a new cyclic leaving group for the stereoselective nucleophilic substitution of amines

We hereby report the preparation and nucleophilic substitutions of the N,N-1,2-benzenedisulfonylimide derivatives 1a and 2a of the chiral amines 1 and 2. The nucleophilic attack of KNO2 afforded the respective alcohols 3 and 4 with 84–90% inversion of configuration. Nucleophilic attack by the azide ion afforded the azide products 5 and 6 which were reduced to the corresponding inverted amines 1 and 2 (94–98.5% inversion). The improved leaving group ability of the N,N-1,2-benzenedisulfonylimides compared with previously reported N,N-disulfonylimides is discussed. Chiral GLC analysis of all products is summarized and the alternative chiral analysis of product 3 by 13C NMR using heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin as a chiral solvating agent (CSA) is discussed.

Reaction of Thiopivalophenones with Benzyne. Formation of 2H-Benzo[b]thietes

Abstract Reaction of thiopivalophenone with phenyl[2-(trimethylsilyl)phenyl]iodonium trifluoromethanesulfonate in the presence of tetrabutylammonium fluoride afforded the corresponding [2+2] cycloadduct, 2-tert-butyl-2-p-tolyl-2H-benzo[b]thiete, in 58% yield. On the other hand, reaction of thiopivalophenone with benzenediazonium 2-carboxylate gave 2-tert-butyl-2-p-tolyl-benzo[d][3,1]oxathiane-6-one in 82% yield. The difference in the reactivity might be owing to the leaving group ability.