Internal Nucleophilic Substitution Research Articles

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an SN2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH4. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.

Ni(COD)2-Catalyzed ipso-Silylation of 2-Methoxynaphthalene: A Density Functional Theory Study

Density functional theory has been used for the systematic investigation of the mechanism involved in Ni(COD)2-catalyzed ipso-silylation of 2-methoxynaphthalene. The two fundamental mechanistic pathways, internal nucleophilic substitution and a nonclassical oxidative addition, have been studied. In both pathways, the first equivalent of KOtBu directly reacts with the silyl boronate (Et3SiBpin) to generate the silyl anion surrogate Et3SiK or silylborate [Et3Si-Bpin(OtBu)]K (IN3), which further reacts with Ni(COD)2 to form a substrate–catalyst complex, [(η2-COD)2NiSiEt3]K. The internal nucleophilic substitution reaction pathway proceeds through η2 complexation of nickel with the C(1)═C(2) bond of 2-methoxynaphthalene. Later, nickel connects to ═C(1) through σ-bond formation and coordinates with oxygen of the −OMe group. Simultaneously, the −SiEt3 group approaches ═C(2) possessing −OMe followed by rearomatization which is facilitated by coordination of K+ with nickel and methoxy oxygen. In a nonclassical oxi...

Reactions of 1‐Arylbenziodoxolones with Azide Anion: Experimental and Computational Study of Substituent Effects

New substituted 1‐arylbenziodoxolones were prepared and their reactivity with azide anion as a nucleophile was investigated. It was found that independent of the presence of substituents, all reactions of 1‐arylbenziodoxolones proceed as nucleophilic substitution of the iodonium leaving group in the electron‐deficient benziodoxolone benzene ring. The presence of bulky substituents in the ortho position of the aryl ring slows the reaction down, while the presence of a moderately electron‐withdrawing bromine substituent in para position to the iodine atom in the benziodoxolone ring moderately increases the rate of substitution. The presence of a strongly electron‐withdrawing nitro group in the para position to the iodine atom in the benziodoxolone ring dramatically increases the rate of substitution. These observations are in agreement with the electronic requirements for internal nucleophilic substitution in the benziodoxole ring. A quantum‐chemical computational study of the possible reaction paths is in agreement with the observed effects of substituents on the reactivity of arylbenziodoxolones in this reaction.

A new mechanism for internal nucleophilic substitution reactions.

A new mechanism for the classic internal nucleophilic substitution reactions SNi by means of computational studies in the gas-phase, DCM and acetonitrile is reported. Despite the importance of the SNi mechanism, since the mid-1990s this mechanism has remained unexplored. This study focused mainly on the comparison between the mechanisms postulated to date for the SNi reactions and a new mechanism suggested by us that fits better the experimental observations. This comparative study has been applied to the conversion of ethyl, neopentyl, isopropyl and tert-butyl chlorosulfites into the corresponding alkyl chlorides. This new mechanism occurs through two transition structures. For primary and secondary substrates, the first transition structure is a 6-center syn-rearrangement of the alkanesulfonyl chloride that produces the corresponding olefin by simultaneous expulsion of HCl and SO2. The olefin, HCl and SO2 form a molecular complex. The final syn-addition of HCl to the olefin leads to alkyl chloride with the retention of configuration. For tertiary substrates, a variation of the previous mechanism is postulated with the intervention of contact ion pairs. It is of great importance to emphasize that this new mechanism is able to explain some experimental observations such as the presence of olefins in these types of reactions and the low reactivity of some systems such as neopentyl chlorosulfite. Our results pave the way to a new mechanistic perspective in similar reactions which will need further studies and validation.

Mechanistic study of bismuth-catalyzed direct benzylation of 2,4-pentanediones: the case of BiCl3 and generalization

At present, we investigate the mechanisms for bismuth-catalyzed direct benzylation of 2,4-pentanediones using various density functional theories and post-Hartree–Fock ab initio methods. First, we deeply consider the role of BiCl3, where six scenarios are proposed. All of them start with the formation of a weakly bound complex between the BiCl3 catalyst and the alcohol or the dione. The most favorable one corresponds to the direct access to the products via a unique transition state (SN2-type mechanism). We also examined the effects of various nonpolar and polar solvents, which are viewed to slightly affect the energy profiles for SN2 and internal nucleophilic substitution (SNi) types of mechanism, whereas strong perturbations are observed for SN1 mechanism. For instance, the later one becomes the most thermodynamically favorable in DMSO solvent. In addition, several classes of benzyl alcohols and catalysts (BiX3, where X = Cl, Br, I, NO3, and OTf) were considered within the framework of SN2 and SNi mechanisms. The reactivity of these alcohols increases going from primary to secondary to tertiary. These findings are in line with the present available experimental results. Finally, our computations suggest that Bi(NO3)3 could be an excellent catalyst for the title reaction.

Deuterium-isotope study on the reductive ring opening of benzylidene acetals

Specific deuterated reference compounds were prepared to probe the stereoselectivity of the reductive ring opening of carbohydrate-based benzylidene-type acetals. AlD(3) revealed a retentive stereoselectivity probably through the rare S(N)i (internal nucleophilic substitution) mechanism. An S(N)1-like mechanism occurs in the acid-promoted regioselective BD(3)·THF- or Et(3)SiD-reductive ring opening.

Theoretical study of fluorination reaction by diethylaminosulfur trifluoride (DAST)

In this work, the mechanism of methanol fluorination by diethylaminosulfur trifluoride (DAST), was investigated in order to determine the thermodynamic, kinetic and structural parameters involved. The direct dynamics method was employed, where quantum mechanical calculations are used to study the reaction path and compute the rate coefficients of each step of the mechanism. The following ab initio and density functional methods have been used: RHF, B3LYP, with basis sets 6-31G** and 6-31+G**. First, the conformational analysis of DAST and a model compound, in the gas phase, were performed; the model compound was created to simplify the calculations, assuming that the behavior of the original molecule is preserved. Next, two different ways for the decomposition of the intermediate formed in the first step of the reaction were investigated: decomposition by internal nucleophilic substitution (Sni), and bimolecular nucleophilic substitution (Sn2). Finally, the inclusion of solvent effects in the mechanism was considered. The calculations show that the presence of the ethyl groups is not important to the formation of the intermediate of the reaction, but affect the decomposition of that species; furthermore, the formation of fluorinated product is favored by the Sn2 mechanism, once the fluoride ion is present.

An Experimental and Computational Study on the Effect of Al(OiPr)3 on Atom‐Transfer Radical Polymerization and on the Catalyst—Dormant‐Chain Halogen Exchange

Compound Al(OiPr)3 is shown to catalyze the halide-exchange process leading from [Mo(Cp)Cl2(iPrN=CH-CH=NiPr)] and CH3CH(X)COOEt (X=Br, I) to the mixed-halide complexes [Mo(Cp)ClX(iPrN=CH-CH=NiPr)]. On the other hand, no significant acceleration is observed for the related exchange between [MoX3(PMe3)3] (X=Cl, I) and PhCH(Br)CH3, by analogy to a previous report dealing with the Ru(II) complex [RuCl2(PPh3)3]. A DFT computation study, carried out on the model complexes [Mo(Cp)Cl2(PH3)2], [MoCl3(PH3)3], and [RuCl2(PH3)3], and on the model initiators CH3CH(Cl)COOCH3, CH3Cl, and CH3Br, reveals that the 16-electron Ru(II) complex is able to coordinate the organic halide RX in a slightly exothermic process to yield saturated, diamagnetic [RuCl2(PH3)3(RX)] adducts. The 15-electron [MoCl3(PH3)3] complex is equally capable of forming an adduct, that is, the 17-electron [MoCl3(PH3)3(CH3Cl)] complex with a spin doublet configuration, although the process is endothermic, because it requires an energetically costly electron-pairing process. The interaction between the 17-electron [Mo(Cp)Cl2(PH3)2] complex and CH3Cl, on the other hand, is repulsive and does not lead to a stable 19-electron adduct. The [RuCl2(PH3)3(CH3X)] system leads to an isomeric complex [RuClX(PH3)3(CH3Cl)] by internal nucleophilic substitution at the carbon atom. The transition state of this process for X=Cl (degenerate exchange) is located at lower energy than the transition state required for halogen-atom transfer leading to [RuCl3(PH3)3] and the free radical CH3. On the basis of these results, the uncatalyzed halide exchange is interpreted as the result of a competitive S(N)i process, whose feasibility depends on the electronic configuration of the transition-metal complex. The catalytic action of Al(OiPr)3 on atom-transfer radical polymerization (and on halide exchange for the 17-electron half-sandwich Mo(III) complex) results from a more favorable Lewis acid-base interaction with the oxidized metal complex, in which the transferred halogen atom is bound to a more electropositive element. This conclusion derives from DFT studies of the model [Al(OCH3)3]n (n=1,2,3,4) compounds, and on the interaction of Al(OCH3)3 with CH3Cl and with the [Mo(Cp)Cl3(PH3)2] and [RuCl3(PH3)3] complexes.

Thermochemistry and unimolecular reactivity of protonated α,ω-aminoalcohols in the gas phase

Competitive deamination and dehydration of protonated α,ω-aminoalcohols (1,2-aminoethanol ( 1), 1,3-aminopropanol ( 2), 1,4-aminobutanol ( 3) and 1,5-aminopentanol ( 4)) in the gas-phase has been examined by both tandem mass spectrometry experiments including metastable ions decompositions and collisional activation (CA) techniques and molecular orbital calculations. For all the precursor molecules 1– 4, CA experiments demonstrate that the low energy product ions are either a protonated cyclic amine or a protonated cyclic ether. The mechanisms of the internal nucleophilic substitution reactions leading to these products have been detailed at the MP2/6-31G ∗ level of theory. The thermochemistry associated with the initial protonation process of 1– 4 has been examined up to the G2(MP2,SVP) level.

Unimolecular Reactivity of Protonated α,ω-Alkanediamines in the Gas Phase

Unimolecular deamination of protonated α,ω-alkanediamines (1,2-ethanediamine (1), 1,3-propanediamine (2), 1,4-butanediamine (3), and 1,5-pentanediamine (4)) in the gas phase has been examined by tandem mass spectrometry experiments including metastable ions decompositions and collisional activation techniques and molecular orbital calculations up to the G2(MP2,SVP) level. For all the protonated molecules, only one unimolecular dissociation channel, leading to the formation of a protonated cyclic amine via an internal nucleophilic substitution, was detected. The hydride ion transfer from the α carbon to the ω position is not competitive with the internal nucleophilic substitution. This has been found to be the result of a large critical energy for this latter reaction.

A study of the electrospray ionisation and ion-trap fragmentation of [M - H](-) ions of new 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazin-2-thiones.

The electrospray ionisation (ESI) in negative mode of the pharmacologically significant 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazin-2-thiones, and their subsequent fragmentations using an ion-trap mass spectrometer, have been investigated. Experiments on sequential product ion fragmentations (MS(n)) were performed in order to elucidate the degradation pathways for these compounds. The data presented show that the fragmentation of the even-electron [M - H](-) ions could proceed through an internal nucleophilic substitution displacement. Decarboxylation and extrusion of carbon disulfide are other fragmentations observed.

Approach to synthesis of novel chiral 3-chloro-2(5H)-furanone and its application in asymmetric reactions

The synthetic method of the novel chiral synthon, 5-l-menthyloxy-3-chloro-2-(5H)-furanone 5a and its application in asymmetric reactions were investigated. 5a is easily obtained in highly optical purity, and acts as a stable acceptor of Michael addition with oxygen nucleophiles in tandem double Michael addition / internal nucleophilic substitution to offer the spiro-cyclopropane derivative containing four stereogenic centers 8, which it is difficult to obtain by routine methods. The synthetic methods for 5a and 8 are reported in detail and the new compounds are identified on the basis of their analytical data and spectroscopic data, such as UV, IR,1H NMR,13C NMR, MS and elementary analysis. The absolute configuration of the interesting spiro-cyclopropanes, spiro [1-chloro-4-(l-menthyloxy)-5-oxo-6-oxa-biscyclo[3.1.0]hexane-2,3′-(4′-/-menthyloxy-5′-l-menthyloxybutyrolactone)] 8 was established by X-ray crystallography. This result can provide important synthetic strategy in synthesis of some complex molecules containing spiro-cyclopropane skeleton with multiple chiral centers.

Electron capture of tetracyanoethylene oxide in the gas phase. Rearrangement of the parent radical anion to form [(NC) 3C] −. A joint experimental and ab initio study

Capture of an electron by tetracyanoethylene oxide can initiate a number of decomposition pathways. One of these decompositions yields [(NC) 3C] − as the ionic product. Ab initio calculations (at the B3LYP/6-31+G∗ level of theory) indicate that the formation of [(NC) 3C] − is initiated by capture of an electron into the LUMO of tetracyanoethylene oxide to yield the anion radical [(NC) 2C–O–C(CN) 2] −· that undergoes internal nucleophilic substitution to form intermediate [(NC) 3C–OCCN] −·. This intermediate dissociates to form [(NC) 3C] − ( m/z 90) as the ionic product. The radical (NC) 3C · has an electron affinity of 4.0 eV (385 kJ mol −1). Ab initio calculations show that [(NC) 3C] − is trigonal planar with the negative charge mainly on the nitrogens. A pictorial representation of this structure is the resonance structure formed from three degenerate contributing structures (NC) 2–CCN −. The other product of the reaction is nominally (NCCO) ·, but there is no definitive experimental evidence to indicate whether this radical survives intact, or decomposes to NC · and CO. The overall process [(NC) 2C–O–C(CN) 2] −· → [(NC) 3C] − + (NCCO) · is calculated to be endothermic by 21 kJ mol −1 with an overall barrier of 268 kJ mol −1.

Unimolecular Chemistry of Protonated Diols in the Gas Phase: Internal Cyclization and Hydride Ion Transfer

Unimolecular dehydration of protonated α,ω-diols in the gas phase has been examined by both tandem mass spectrometry experiments, including metastable ions decompositions, collisional activation, and neutralization−reionization techniques, and molecular orbital calculations up to the MP2/6-311G**//MP2/6-31G*+ZPE level. Two reaction mechanisms were found to explain the experimental observations: one leading to a protonated cyclic ether via an internal nucleophilic substitution and one giving a protonated carbonyl species after hydride ion transfer from the α-carbon to the ω-position. Our major findings are the following: (i) protonated 1,2-ethanediol exclusively leads to protonated acetaldehyde via a concerted pinacol rearrangement with the calculated critical energy equaling 99 kJ/mol; (ii) protonated 1,3-propanediol gives protonated oxetane at low internal energy and protonated propanal at high internal energy with the calculated critical energies of the reactions equaling 144 and 163 kJ/mol, respectively, and the competition between the two reactions being explained by the internal energy effect upon dissociation rate constants; (iii) for 1,4-butanediol and 1,5-pentanediol, the dehydration produces only the corresponding protonated cyclic ether with calculated critical energies equal to 110 and 107 kJ/mol, respectively.

Unusual cyclization and [formula omitted] displacement of carbazole sulfoxide under Pummerer reaction conditions

Trifluoroacetic anhydride induced Pummerer reactions of carbazole-sulfoxide 1 follow an unusual pathway, in which the initially formed acyloxysulfonium salt 3 undergoes not the usual abstract of α-proton but internal nucleophilic substitution with the indole nuclear followed by S n′-type reaction of an intermediate 4 with additive nucleophiles to give 1-substituted carbazole sulfides 2.

Fragmentation of conjugate bases of esters derived from multifunctional alcohols including triacylglycerols

Enolate anions of esters from 1,2 and 1,3 diols undergo an internal nucleophilic substitution reaction that produces a β-ketoester and an alkoxide ion within the molecular species. These intermediate ions undergo two competitive fragmentation pathways. The first pathway corresponds to a second nucleophilic substitution of the ketoester by the alkoxide that yields a neutral cyclic ether and the β-ketoacid carboxylate. The latter then loses carbon dioxide and produces the enolate anion of the corresponding ketone. The second proposed pathway is stepwise: it starts with a proton transfer from the methylene group between the two carbonyls to the alkoxide anion that produces an alcohol and the enolate ion of the β-ketoester inside the molecular species. The latter undergoes cleavage of the ester bond induced by the negative charge to yield an ion-dipole complex composed of a neutral acylketene and an alkoxide ion. The direct dissociation of this ion-dipole complex competes with an internal proton exchange to yield a new complex that consists of an alcohol molecule and the anion of the acylketene, which can also dissociate. The fragmentation pathway that leads to the ketone enolate is sensitive to the relative positions (1,2 or 1,3) of the esters on the molecular backbone. This position-sensitive reaction is useful for the assignment of the primary and secondary positions in triacylglycerols, even in mixtures, as shown by some examples.

Pseudoesters and derivatives. XXIII Reaction of 3-bromo-5-methoxyfuran-2(5 [formula omitted])-one with nucleophiles. Formation of cyclopropane derivatives

The reactions of 3-bromo-5-methoxyfuran-2 (5 H )-one ( 1 ) with nucleophiles in acetonitrile, in the presence of potassium carbonate and tetrabutylammonium bromide as a catalyst, are reported. The bromofuranone 1 reacts, with several carbon and oxygen nucleophiles to give the cyclopropane bis-lactones 7 , 8 , 11 or 12 . When 1 is reacted with diethylamine or propane-2-thiol in a 2:1 ratio, similar cyclopropane bis-lactones 16 or 21 , respectively, are formed. This behaviour is explained on the basis of a mechanism involving a double Michael addition, followed by ring closure via internal nucleophilic substitution of the halogen.