Leaving Group Ability Research Articles

Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

Harnessing the anti-cancer potential of linamarin: A computational study on design and hydrolysis mechanisms of its derivatives

Cassava extracts containing cyanogenic compounds demonstrate anticancer properties. The cyanogenic glucoside linamarin found abundantly in cassava can release hydrogen cyanide (HCN) upon hydrolysis, a potent cytotoxin. However, linamarin's hydrolysis mechanism by human enzymes is poorly delineated and constitutes a bottleneck for therapeutic development. This study aimed to investigate linamarin's hydrolysis mechanism by human β-glucosidase and identify structural derivatives with enhanced hydrolytic potential using density functional theory calculations. Results revealed α-anomeric derivatives as promising, with leaving group ability and steric bulk strongly governing hydrolysability. We identified several linamarin analogs with predicted rapid hydrolysis kinetics that may enable swift cytotoxic HCN release against cancer cells. This investigation enriches understanding of cyanogenic glycoside reactivity to facilitate their development as targeted antineoplastic agents. The identified derivatives set the groundwork for experimental evaluation of enhanced linamarin-inspired compounds as innovative cancer therapeutics.

Dirigent isoflavene-forming PsPTS2: 3D structure, stereochemical, and kinetic characterization comparison with pterocarpan-forming PsPTS1 homolog in pea

Pea phytoalexins (-)-maackiain and (+)-pisatin have opposite C6a/C11a configurations, but biosynthetically how this occurs is unknown. Pea dirigent-protein (DP) PsPTS2 generates 7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene (DMDIF), and stereoselectivity toward four possible 7,2'-dihydroxy-4',5'-methylenedioxyisoflavan-4-ol (DMDI) stereoisomers was investigated. Stereoisomer configurations were determined using NMR spectroscopy, electronic circular dichroism, and molecular orbital analyses. PsPTS2 efficiently converted cis-(3R,4R)-DMDI into DMDIF 20-fold faster than the trans-(3R,4S)-isomer. The 4R-configured substrate's near β-axial OH orientation significantly enhanced its leaving group abilities in generating A-ring mono-quinone methide (QM), whereas 4S-isomer's α-equatorial-OH was a poorer leaving group. Docking simulations indicated that the 4R-configured β-axial OH was closest to Asp51, whereas 4S-isomer's α-equatorial OH was further away. Neither cis-(3S,4S)- nor trans-(3S,4R)-DMDIs were substrates, even with the former having C3/C4 stereochemistry as in (+)-pisatin. PsPTS2 used cis-(3R,4R)-7,2'-dihydroxy-4'-methoxyisoflavan-4-ol [cis-(3R,4R)-DMI] and C3/C4 stereoisomers to give 2',7-dihydroxy-4'-methoxyisoflav-3-ene (DMIF). DP homologs may exist in licorice (Glycyrrhiza pallidiflora) and tree legume Bolusanthus speciosus, as DMIF occurs in both species. PsPTS1 utilized cis-(3R,4R)-DMDI to give (-)-maackiain 2200-fold more efficiently than with cis-(3R,4R)-DMI to give (-)-medicarpin. PsPTS1 also slowly converted trans-(3S,4R)-DMDI into (+)-maackiain, reflecting the better 4R configured OH leaving group. PsPTS2 and PsPTS1 provisionally provide the means to enable differing C6a and C11a configurations in (+)-pisatin and (-)-maackiain, via identical DP-engendered mono-QM bound intermediate generation, which PsPTS2 either re-aromatizes to give DMDIF or PsPTS1 intramolecularly cyclizes to afford (-)-maackiain. Substrate docking simulations using PsPTS2 and PsPTS1 indicate cis-(3R,4R)-DMDI binds in the anti-configuration in PsPTS2 to afford DMDIF, and the syn-configuration in PsPTS1 to give maackiain.

Three-Component cine,ipso-Disubstitution of Nitrocoumarins.

The development of a three-component cine,ipso-disubstitution of nitrocoumarins is reported. The reaction leverages the electrophilicity of nitrocoumarins, the nucleophilicity of nitronates, and the leaving group ability of nitrite (NO2-) to yield complex polyfunctionalized biaryls that often display stable axial chirality.

Chiral 4-MeO-Pyridine (MOPY) Catalyst for Enantioselective Cyclopropanation: Attenuation of Lewis Basicity Leads to Improved Catalytic Efficiency.

The design of pyridine-derived organocatalysts aims at the increase of their Lewis basicity, however such an approach is not always efficient. For example, strongly Lewis basic DMAP is completely inefficient as catalyst in the cyclopropanation reaction. Herein we disclose an alternative approach that relies on attenuation of DMAP Lewis basicity. Specifically, the replacement of 4-dimethylamino substituent in DMAP for 4-MeO group delivered a highly efficient catalyst for cyclopropanation of electron-deficient olefins with α-bromoketones. Kinetic studies provide compelling evidence that the superior catalytic efficiency of 4-MeO pyridine (MOPY) is to be attributed to the favorable balance between Lewis basicity and leaving group ability. The use of chiral, enantiomerically pure MOPY catalyst has helped to achieve high enantioselectivities (up to 91 : 9 er) in the previously unreported pyridine-catalyzed cyclopropanation reaction.

An extended-gate-type organic transistor for monitoring the Menschutkin reaction of tetrazole at a solid-liquid interface.

We herein propose an approach to visualize the Menschutkin reaction at an interface between a self-assembled monolayer with nucleophilic properties and water containing alkyl halides. An organic field-effect transistor functionalized with a nucleophilic monolayer has detected in situ alkylation depending on differences in the leaving group ability and the bulkiness of electrophilic alkyls.

(Invited) Electrochemical Synthesis of Chelation-Stabilized Organo-Λ 3-Bromanes

The chemistry of hypervalent halogen species has made enormous progress over the last few decades, and hypervalent iodine(III) compounds have become common reagents in nowadays organic synthesis. The related isoelectronic hypervalent bromine(III) species feature superior reactivity to the I(III) counterparts due to the higher oxidizing ability, stronger electrophilicity and better leaving group ability (nucleofugality) of the bromanyl moiety. However, the hypervalent bromine chemistry appears to be significantly less developed than that of the iodine(III) compounds. This notable imbalance appears to be due to the relatively low stability and high oxidizing power of bromine(III) reagents, resulting in reactivity that is difficult to control. Furthermore, there is a clear shortage of simple method for the synthesis of bromine (III) species, but known methods often require handling of the highly toxic and corrosive BrF3 precursor. In this context, we have proposed the electrochemical generation of chelation-stabilized hypervalent bromine(III) compounds as a possible solution to the above problems. This presentation will give an overview of our current progress in this field.

Effects of Methyl Substitution and Leaving Group on E2/SN2 Competition for Reactions of F- with RY (R = CH3, C2H5, iC3H7, tC4H9; Y = Cl, I).

The competition between base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) is of significant importance in organic chemistry and is influenced by many factors. The electronic structure calculations for the gas-phase reactions of F- + RY (R = CH3, C2H5, iC3H7, tC4H9, and Y = Cl, I) are executed at the MP2 level with aug-cc-pVDZ or ECP/d basis set to investigate the α-methyl substitution effect. The variation in barrier height, reaction enthalpy, and competition of SN2/E2 as a function of methyl-substitution and leaving group ability has been emphasized. And the nature of these rules has been explored. As the degree of methyl substitution on α-carbon increases, the E2 channel becomes more competitive and dominant with R varying from C2H5, iC3H7, to tC4H9. Energy decomposition analysis offers new insights into the competition between E2 and SN2 processes, which suggests that the drop in interaction energy with an increasing degree of substitution cannot compensate for the rapid growth of preparation energy, leading to a rapid increase in the SN2 energy barrier. By altering the leaving group from Cl to I, the barriers of both SN2 and E2 monotonically decrease, and, with the increased number of substituents, they reduce more dramatically, which is attributed to the looser transition state structures with the stronger leaving group ability. Interestingly, ∆E0‡ exhibits a positive linear correlation with reaction enthalpy (∆H) and halogen electronegativity. With the added number of substituents, the differences in ∆E0‡ and ∆H between Y = Cl and I likewise exhibit good linearity.

Synthesis, Characterization, and Reaction of Hypervalent Organo-λ<sup>3</sup>-bromanes and Chloranes

Hypervalent organoiodine(III/V) reagents (λ3-/λ5-iodane) have enjoyed widespread application as oxidant/electrophile in synthetic organic chemistry. In contrast, the development of the chemistry of hypervalent organo-λ3-bromane and λ3-chlorane is still just beginning. We have developed a versatile, high-yield synthesis of λ3-chloranes and λ3-bromanes through the reaction of various haloarenes/chloroalkenes with readily prepared arenediazonium tetrakis(pentafluorophenyl)borate under mild conditions. The improved accessibility enabled us to investigate the unique physico-chemical characters and unprecedented reactivity of these hypervalent organo-λ3-haloganes (e.g. onium structure, enhanced electrophilicity, etc.). The leaving group ability of λ3-haloganyl groups was also evaluated as it governs the rate of a variety of chemical transformations.

Divergent Functionalization of Styrenes via Radical/Polar Crossover with CO2 and Sodium Sulfinates.

Sulfones and carboxylic acids are prominent motifs widely present in the chemical structure of agrochemicals, pharmaceuticals and many other highly valuable compounds. Herein, we describe a conjunctive strategy for the precise installation of these functionalities onto styrenes using sodium sulfinates and CO2 as coupling partners. The protocol allowed the preparation of carboxy-sulfonylated compounds in good yields and broad functional group tolerance. Additionally, taking advantage of the leaving group ability of the sulfone moiety, a one-pot photocatalytic carboxy-sulfonylation-elimination strategy was developed for the synthesis of α-aryl-acrylates.

Visible light-assisted chemistry of vinyl azides and its applications in organic synthesis.

Vinyl azides have emerged as highly versatile precursors in organic synthesis due to their rich reactivity driven by the excellent leaving-group ability of molecular nitrogen. Over the years, significant advancement has been achieved in the manipulation of vinyl azides for the construction of C-C and C-X bonds. Typical methods involve the application of transition metals and strong oxidants for the conversion of vinyl azides into useful compounds employing harsh reaction conditions coupled with intense product purification. In this regard, visible light chemistry has become one of the most exciting fields in organic synthesis for being mild, sustainable, and often orthogonal to conventional approaches. Visible light-induced reactions involving vinyl azides generate either 2H-azirines or iminyl radicals as key intermediates, which may undergo further useful transformations to form the desired cyclic or acyclic products. Herein, we provide the most significant transformations of vinyl azides as versatile synthetic precursors or transient intermediates for compounds of synthetic and biological significance under visible light photocatalysis. We have classified this review into two parts: (i) formation of an iminyl radical intermediate and (ii) formation of 2H-azirine intermediate-based reactions.

Reactions of Nitroarenes with Corey–Chaykovsky Reagents

AbstractElectrophilic and nucleophilic substitutions of aromatic substrates share common mechanistic pathways. In both scenarios reacting species attack rings at the unsubstituted (C–H) positions, giving cationic Wheland intermediates or anionic Meisenheimer complexes. However, the following step of rearomatization breaks the intrinsic symmetry, due to different leaving group ability of proton and hydride anion, respectively. In effect, electron-deficient arenes are prone to transformations unparalleled in electrophilic chemistry. In our article, we present transformations of anionic σH-adducts, formed between nitroarenes and carbanions of the Corey–Chaykovsky reagents. Depending on structure of the substrates and reaction conditions, the intermediates undergo cyclization to cyclopropanes (norcaradienes) or base-induced elimination to the alkylated products. Mechanistic studies reveal that order of the carbanions controls competition between the processes, due to steric hindrance developing at the β-elimination step.1 Introduction2 Cyclopropanation of Nitronaphthalenes3 Alkylation of Nitropyridines4 Mechanistic Studies5 Summary and Outlook

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.

Nucleofugality of diphenylphosphinate and kinetic stabilities of secondary and tertiary benzylic diphenylphosphinates in aqueous solvents

AbstractFirst‐order rate constants for solvolyses of variously substituted benzhydryl diphenylphosphinates in four aqueous solvents have been measured conductometrically in order to investigate leaving group ability of diphenylphosphinate (DPP), that is, to determine corresponding nucleofuge‐specific parameters (Nf and sf) according to the correlation equation log k (25°C) = sf(Ef + Nf). DPP is the first of phosphorus leaving groups included on the Nf nucleofugality scale which presently covers a reactivity range of 15 orders of magnitude. Application of log k (25°C) versus Ef plots has unequivocally shown that benzhydryl diphenylphosphinates solvolyze in hydroxylic solvents by the SN1 mechanism. As the abovementioned equation and corresponding reactivity parameters can also be employed for predicting heterolytic reactivity of substrates in various solvents, the range of kinetic stability of secondary and tertiary benzylic diphenylphosphinates toward heterolysis has been examined in terms of reaction half‐lives. Further, in order to investigate the origin of stability of the DPP anion and, consequently, the ability of the DPP leaving group, quantum mechanical calculations and the Natural Bond Orbital (NBO) analysis were performed at the M06‐2X/6‐311+G(3df,3pd) level of theory using the SMD solvation model. The NBO analysis has revealed that negative hyperconjugation plays a dominant role in delocalizing the anionic charge in disubstituted phosphinate leaving groups.

Enhancing the leaving group ability of alkyl fluorides: I/F exchange reactions mediated by LiI

The carbon–fluorine (C–F) bond is one of the strongest bonds in organic chemistry and generally inert toward nucleophilic substitution reactions. To overcome the relative inertness of the C–F bond, this work focused on the ability of simple lithium salts (Lewis acid) to activate alkyl fluorides (Lewis base) leading to F/I exchange in high yields and selectivity for displacement of fluoride versus chloride and bromide. The exchange of fluorine for iodine was effective on both activated and neutral alkyl fluorides leading to yields as high as 99%.

A Lewis Base Nucleofugality Parameter, NFB, and Its Application in an Analysis of MIDA-Boronate Hydrolysis Kinetics.

The kinetics of quinuclidine displacement of BH3 from a wide range of Lewis base borane adducts have been measured. Parameterization of these rates has enabled the development of a nucleofugality scale (NFB), shown to quantify and predict the leaving group ability of a range of other Lewis bases. Additivity observed across a number of series R'3-nRnX (X = P, N; R' = aryl, alkyl) has allowed the formulation of related substituent parameters (nfPB, nfAB), providing a means of calculating NFB values for a range of Lewis bases that extends far beyond those experimentally derived. The utility of the nucleofugality parameter is explored by the correlation of the substituent parameter nfPB with the hydrolyses rates of a series of alkyl and aryl MIDA boronates under neutral conditions. This has allowed the identification of MIDA boronates with heteroatoms proximal to the reacting center, showing unusual kinetic lability or stability to hydrolysis.

Intrinsic Nucleophilicity of Inverting and Retaining Glycoside Hydrolases Revealed Using Carbasugar Glyco-Tools

Hydrolyses of cyclohexenyl-based carbasugars that mimic either α-d-glucose or α-d-galactose were explored with two Bacteroides thetaiotaomicron enzymes from glycoside hydrolase family 97: an inverting α-glucosidase (BtGH97a) and a retaining α-galactosidase (BtGH97b). Both enzymes yield nucleophilic substitutions at the pseudo-anomeric center of the carbasugar substrates, giving significantly different linear energy relationships for the catalytic rate constant as a function of the leaving group ability. Specifically, the kinetic data for the inverting α-glucosidase is consistent with the reaction giving a hydrolyzed inverted carbaglucose product by a mechanism that proceeds with little nucleophilic participation by the bound water molecule at the reaction transition state. In contrast, the reaction of carbagalactose substrates with the retaining GH97 enzyme involves a rate-limiting nonchemical step, likely a conformational change, followed by rapid substitution involving a nucleophilic amino acid residue to give a covalently bound intermediate. Considering the structural similarities between these two GH97 enzymes, the kinetic data nonetheless reveal a significant (>106) difference in the rates of nucleophilic attack between the unique enzymatic nucleophiles─with the less nucleophilic species being H2O in the inverting α-glucosidase and the better nucleophile being a carboxylate in the retaining α-galactosidase. The enzymatic rate constant ratio for the phenyl carbasugars contrasts with the corresponding kinetic data obtained using natural substrate phenyl glycopyranosides. Last, for the galactocarbasugar with a phenol leaving group, the second-order rate constant for alkylation of the GH97 α-galactosidase is only ∼10-fold lower than that for glycosylation of this enzyme by the parent carbohydrate phenyl α-d-galactopyranoside. This modest difference in rate constants underscores our conclusion that retaining glycoside hydrolases may not have optimized the nucleophilicity of their active site nucleophiles with the result that the transition state free energies for formation and hydrolysis of the covalent enzyme intermediate are matched.

Front Cover Picture: Pyrazoleamides in Catalytic Asymmetric Reactions: Recent Advances (Adv. Synth. Catal. 14/2021)

The front cover picture, designed by Sara and Luca Meninno, illustrates poorly reactive carboxylic acids and their ester and amide derivatives transformed into pyrazoleamides super-molecules with superpowers. Where carboxylic acids, esters and amides fail pyrazoleamides succeed, allowing the transition from a world with limited possibilities to a rich and futuristic world, meeting the increasing needs of the society. The super-powers consist in: i) easy one-step synthesis from readily available carboxylic acids; ii) easy metal and H-bonding coordination with catalysts, unlocking otherwise inaccessible reactions on carboxylic acid derivatives; iii) exceptional leaving group ability which enables several post-functionalizations with different nucleophiles. Pyrazoleamides, unlike carboxylic acid derivatives have proven increasingly useful starting materials in a variety of diastereo- and enantioselective metal-, organocatalytic and photoinduced transformations, giving access to valuable intermediates, heterocycles and pharmaceuticals. Details can be found in the Review by Meninno, Franco, Benaglia, and Lattanzi. (S. Meninno, F. Franco, M. Benaglia, A. Lattanzi, Adv. Synth. Catal. 2021, 363, 3380–3410; DOI: 10.1002/adsc.202100006)

Prediction of the kinetic stability of N‐alkyl‐X‐pyridinium ions in dichloromethane

AbstractGeometries of 20 N‐[4,4′‐bis (dimethylamino)benzhydryl]‐X‐pyridinium ions (DMABh‐X‐pyridinium ions) and of corresponding heterolytic transition structures have been optimized at the M06‐2X/6‐311+G(2d,p) level of theory in the presence of the IEFPCM model with dichloromethane as a solvent. Using the optimized geometries, free energies of activation (∆G‡model) for the model heterolysis of the DMABh‐X‐pyridinium ions in dichloromethane at 20°C have been obtained. A very good correlation between ∆G‡model values for the model heterolysis of five reference DMABh‐X‐pyridinium ions and literature ∆G‡ values for the heterolysis of the same ions in dichloromethane (r = 0.992) validates the procedure for predicting experimental reactivities of the ions (∆G‡calc) in dichloromethane. Accordingly, the correlation has been employed to obtain predicted free energies of activation (∆G‡calc) for heterolyses of other 15 DMABh‐X‐pyridinium ions in dichloromethane from corresponding ∆G‡model values. The high quality of the whole set of the predicted reactivities is confirmed by a very good correlation plot of log kcalc (obtained from ∆G‡calc) versus σ (r = 0.995). Using the previously established correlation equation log k = sf (Ef + Nf), predicted nucleofugality parameters (Nfcalc), which quantitatively describe leaving group abilities, have been determined for various X‐pyridines in dichloromethane, and now can be used not only for comparing leaving group abilities of X‐pyridines with those of other leaving groups on the existing nucleofugality (Nf) scale but also for estimating the reactivity, that is, the kinetic stability, of diverse N‐alkyl‐X‐pyridinium ions in dichloromethane at 20°C.

Shelf-Stable (E)- and (Z)-Vinyl-λ3-chlorane: A Stereospecific Hyper-vinylating Agent

We report the first stereoselective synthesis of stable (E)- and (Z)-β-chlorovinyl-λ3-chlorane via direct mesitylation of 1,2-dichloroethylene with mesityldiazonium tetrakis(pentafluorophenyl)borate under mild reaction conditions. The structure of the (E)-vinyl-λ3-chlorane was established by single-crystal X-ray analysis. Because of the enormously high leaving group ability of the aryl-λ3-chloranyl group, vinyl-λ3-chloranes undergo not only SNVσ-type reaction with extremely weak nucleophiles such as perfluoroalkanesulfonate, iodobenzene, and aromatic hydrocarbons but also coupling with phenylcopper(I) species.