SN2-type Reactions Research Articles

Photoinduced Efficient Catalytic α-Alkylation Reactions of Active Methylene and Methine Compounds with Nonactivated Alkenes.

In catalytic α-alkylation reactions of carbonyl compounds, although SN2-type substitution reactions of enolates with alkyl halides are a conventional methodology, addition reactions with alkenes are more desirable because of their atom-economical character; however, reactions with nonactivated alkenes are challenging. Here, we developed highly efficient catalytic α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes such as 1-decene using an organophotocatalyst and lithium thiophenoxide as a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalyst under blue-light irradiation. The reaction was also performed with a higher degree of efficiency under a continuous-flow system to obtain the products in multigram scales. The present reaction system enables highly efficient and practical α-alkylation reactions of active methylene and methine compounds to be achieved.

One-Pot Consecutive Reductive Amination Synthesis of Pharmaceuticals: From Biobased Glycolaldehyde to Hydroxychloroquine

Reductive amination plays a paramount role in the synthesis of amines. It is often proposed as a more ecofriendly synthesis process than the traditional SN2-type reactions of amines as it avoids toxic alkylation reagents such as alkyl halides. This work demonstrates the versatility of the reductive amination reaction via the synthesis of hydroxychloroquine (HCQ), one of the most renowned pharmaceuticals during this coronavirus pandemic. The novel green synthesis strategy is based on three consecutive reductive amination reactions conducted in a one-pot system, avoiding intermediary purification steps. Furthermore, a biobased C2 platform molecule, glycolaldehyde, was selected as a starting reagent. The newly developed reductive amination pathway was appraised using the CHEM21 Green Metric toolkit and compared with the commercially operating method.

Topological description of complex patterns of bonding, charge transference and structural changes in chemical reactions: SN2 type reactions, a case study

In this report we deeply explore the electron rearrangements for a chemical reaction case study of the SN2 type OH- + CH3-CN ↔ HO-CH3 + CN-, within the topological formalism of QTAIM model in its local and the non-local or integrated form implementations. This is part of our main interest of a subtle description of the electron distribution at both, equilibrium and non-equilibrium conformations for the state function at correlated level of approximation. The emphasis is mainly placed on the determination of complex patterns of interaction of two or four electrons in three centers (2e-3c, 4e-3c). These results confirm them as a measure of electron excess or electron deficiency effects and revels their crucial importance in the charge transference process and its relationship with these complex patterns. All electronic magnitudes were followed along the configurations from reactants to products passing through the corresponding transition state TS. The results obtained throughout this case study reveals the high performance of the topological formalism of Bader type in the subtle description of electron rearrangements in a chemical transformation.

An Iron-Based Dehydration Catalyst for Selective Formation of Styrene

We report the synthesis and crystal structure of [Fe(OTf)2(FOX)] (A). This robust iron(II) complex was successfully applied as a homogeneous catalyst for the dehydration of 1-phenylethanol to styrene. Even at low catalyst loadings and moderate reaction temperatures, A showed a high catalytic efficiency. It was found to selectively activate the benzylic alcohol group of 1-phenylethanol. This is challenging since the vinyl system of styrene is highly reactive. In contrast to most of the other dehydration processes, the use of a Brønsted acid was not necessary. Furthermore, mechanistic insights into this E1-type transformation and its competing SN1-type side reactions are reported. [Fe(cHexOH)(OTf)(FOX)][OTf] (B), an alcohol adduct of A, [Fe(H2O)2(FOX)][OTf]2 (C), the completely hydrated derivative of A, and [μ-O{Fe(OTf)(FOX)}2][OTf]2 (D), a dinuclear oxidation product of A, were also characterized and are discussed.

Second Comes First: Switching Elementary Steps in Palladium-Catalyzed Cross-Coupling Reactions.

The electron‐poor palladium(0) complex L3Pd (L=tris[3,5‐bis(trifluoromethyl)phenyl]phosphine) reacts with Grignard reagents RMgX and organolithium compounds RLi via transmetalation to furnish the anionic organopalladates [L2PdR]−, as shown by negative‐ion mode electrospray‐ionization mass spectrometry. These palladates undergo oxidative additions of organyl halides R′X (or related SN2‐type reactions) followed by further transmetalation. Gas‐phase fragmentation of the resulting heteroleptic palladate(II) complexes results in the reductive elimination of the cross‐coupling products RR′. This reaction sequence corresponds to a catalytic cycle, in which the order of the elementary steps of transmetalation and oxidative addition is switched relative to that of palladium‐catalyzed cross‐coupling reactions proceeding via neutral intermediates. An attractive feature of the palladate‐based catalytic system is its ability to mediate challenging alkyl–alkyl coupling reactions. However, the poor stability of the phosphine ligand L against decomposition reactions has so far prevented its successful use in practical applications.

P-Methoxyphenol: A potent and effective scavenger for solid-phase peptide synthesis.

During the final step of t-Boc/Bzl, solid-phase peptide synthesis (SPPS)-protecting groups from amino acids (aa) side chains must be removed from the target peptides during cleavage from the solid support. These reaction steps involve hydrolysis with hydrogen fluoride (HF) in the presence of a nucleophile (scavenger), whose function is to trap the carbocations produced during SN 1-type reactions. Five peptide sequences were synthesised for evaluating p-methoxyphenol effectiveness as a potent scavenger. After the synthesis, the resin-peptide was then separated into two equal parts to be cleaved using two scavengers: conventional reactive p-cresol (reported in the literature as an effective acyl ion eliminator) and p-methoxyphenol (hypothesised as fulfilling the same functions as the routinely used scavenger). Detailed analysis of the electrostatic potential map (EPM) revealed similarities between these two nucleophiles, regarding net atomic charge, electron density distribution, and similar pKa values. Good scavenger efficacy was observed by chromatography and mass spectrometry results for the synthesised molecules, which revealed that p-methoxyphenol can be used as a potent scavenger during SPPS by t-Boc/Bzl strategy, as similar results were obtained using the conventional scavenger.

Impact of Oxidation State on Reactivity and Selectivity Differences between Nickel(III) and Nickel(IV) Alkyl Complexes.

Described is a systematic comparison of factors impacting the relative rates and selectivities of C(sp3 )-C and C(sp3 )-O bond-forming reactions at high-valent Ni as a function of oxidation state. Two Ni complexes are compared: a cationic octahedral NiIV complex ligated by tris(pyrazolyl)borate and a cationic octahedral NiIII complex ligated by tris(pyrazolyl)methane. Key features of reactivity/selectivity are revealed: 1) C(sp3 )-C(sp2 ) bond-forming reductive elimination occurs from both centers, but the NiIII complex reacts up to 300-fold faster than the NiIV , depending on the reaction conditions. The relative reactivity is proposed to derive from ligand dissociation kinetics, which vary as a function of oxidation state and the presence/absence of visible light. 2) Upon the addition of acetate (AcO- ), the NiIV complex exclusively undergoes C(sp3 )-OAc bond formation, while the NiIII analogue forms the C(sp3 )-C(sp2 ) coupled product selectively. This difference is rationalized based on the electrophilicity of the respective M-C(sp3 ) bonds, and thus their relative reactivity towards outer-sphere SN 2-type bond-forming reactions.

Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations.

The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.

Computational study of the C[sbnd]I bimetallic oxidative addition at Pt[sbnd]M (M = Ni, Pd and Pt) reaction centers

Three bimetallic complexes of the type [Me2Pt(μ-bipym)MMe2] (M = Ni, Pd, Pt) in which bipym = 2,2′-bipyrimidine, with a systematic variation in the metals, are chosen to investigate CI bond activation of MeI through SN2-type oxidative addition reactions by using the B3LYP levels of theory. The non-identical dual-core complexes (when M = Pd and Ni) containing two potential nucleophilic centers are theoretically studied to elucidate which center (M or Pt) is the stronger nucleophile toward MeI. The reasons for these two pathways (first attack on Pt, path A, or first attack on M, path B) are discussed based on the energy barrier needed for path A versus path B. On the basis of DFT calculations, in the reaction of complexes Pt–Ni and Pt–Pd with MeI, it is found that these complexes react through Pt(II) at the first step, following by M(II) attacking on carbon atom of MeI to give final Pt(IV)–M(IV) complexes. Also complex [Me2Pt(μ-bipym)NiMe2] is predicted reacting with MeI faster than the others with a lower free energy barrier. Qualitative frontier molecular orbitals for the complexes, energies and main compositions of the relevant frontier orbitals of complexes are also studied.

Making more efficient lithium carbenoid reagents for cyclopropanation by hetero-aggregation: A DFT prediction on a new factor to control the SN2-Type organometallic reaction

Lithium carbenoids are important reagents in organic synthesis. Systemic DFT calculations have been carried out to reveal the influence of hetero-aggregation states on the reactivity of lithium carbenoid reagents. The results indicate that the cyclopropanation reaction could be accelerated dramatically by hetero-aggregated lithium carbenoids with a halogen or oxygen as an α-heteroatom. The origin of the enhancement could attribute to the novel structural character of the hetero-aggregated lithium carbenoids. These intriguing finding predicts that it is practical to control a wide range of SN2-type organometallic reactions by using aggregated lithium carbenoids with other economical and convenient compounds.

Stereoselective SN1-Type Reaction of Enols and Enolates

Stereoselective alkylation of enolates represents a valuable and important procedure for accessing carbon–carbon-bond frameworks in natural and nonnatural product synthesis. Usually, activated electrophilic partners that react through an SN2 mechanism are employed. To overcome the limitations due to reduced reactivity and steric hindrance, SN1-type reactions can be considered a valid and practical alternative. Accessible enolates can be used in stereoselective (diastereo- or enantioselective) reactions with electrophilic carbenium ions, either used as stable reagents or generated in situ from suitable precursors. The results achieved in this active field are summarized in this review.1 Introduction2 Alcohols in SN1-Type Reactions with Enolates2.1 Enantioselective Reactions with Metal Complexes2.2 Organocatalytic Enantioselective Reactions3 Alcohols and Alcohol Derivatives in SN1-Type Reactions with Enolates­: Enantioselective Reactions with Metal Enolates4 Isolated Carbenium Ions in SN1-Type Reactions with Enolates: Enantioselective­ Reactions with Metal Enolates5 Miscellaneous6 Conclusion

Direct Substitution of Alcohols in Pure Water by Brønsted Acid Catalysis.

With the increasing concern for sustainability, the use of environmentally friendly media to perform chemical processes has attracted the attention of many research groups. Among them, the use of water, as the unique solvent for reactions, is currently an active area of research. One process of particular interest is the direct nucleophilic substitution of an alcohol avoiding its preliminary transformation into a good leaving group, since one of the by-products in this approach would be water. The direct substitution of allylic, benzylic, and tertiary alcohols has been achieved through SN1-type reactions with catalytic amounts of Brønsted or Lewis acids; however, organic solvents are often required. In this review, the pioneering SN1 approaches performed in pure water and in the absence of a metal based Lewis acid are compiled and discussed.

Concerning the Role of Supercritical Carbon Dioxide in SN 1 Reactions.

A series of SN 1-type reactions has been studied under various conditions to clarify the role of supercritical carbon dioxide (scCO2 ) as reaction medium for this kind of transformations. The application of scCO2 did not result in higher yields in any of the experiments in comparison to those under neat conditions or in the presence of other inert compressed gases. High-pressure UV/Vis spectroscopic measurements were carried out to quantify the degree of carbocation formation of a highly SN 1-active alkyl halide as a function of the applied solvent. No measureable concentration of carbocations could be detected in scCO2 , just like in other low polarity solvents. Taken together, these results do not support the previously claimed activating effect via enhanced SN 1 ionization due to the quadrupolar moment of the supercritical fluid.

Kinetic and Theoretical Insights into the Mechanism of Alkanol Dehydration on Solid Brønsted Acid Catalysts

Elementary steps that mediate ethanol dehydration to alkenes and ethers are determined here from rate and selectivity data on solid acids of diverse acid strength and known structure and free energies derived from density functional theory (DFT). Measured ethene and ether formation rates that differed from those expected from accepted monomolecular and bimolecular routes led to our systematic enumeration of plausible dehydration routes and to a rigorous assessment of their contributions to the products formed. H-bonded monomers, protonated alkanol dimers, and alkoxides are the prevalent bound intermediates at conditions relevant to the practice of dehydration catalysis. We conclude that direct and sequential (alkoxide-mediated) routes contribute to ether formation via SN2-type reactions; alkenes form preferentially from sequential routes via monomolecular and bimolecular syn-E2-type eliminations; and alkoxides form via bimolecular SN2-type substitutions. The prevalence of these elementary steps and their ...

Exploiting the σ-phylic properties of cationic gold(i) catalysts in the ring opening reactions of aziridines with indoles.

A study on the SN2-type ring opening reactions of aziridines with indoles as nucleophiles is reported. Under gold(i) catalysis a great variety of tryptamine derivatives were prepared in good to excellent yields with complete stereocontrol when chiral aziridines were used. We demonstrated that cationic gold(i) catalysts are superior Lewis acids to the previously reported group 3, 12 and 13 metals in terms of catalyst loading and reaction yields. Moreover, complete regioselectivity was observed for 2-phenyl-N-tosylaziridine; whereas, regioselectivity up to 10 : 1 ratio was observed with 2-methyl-N-tosylaziridine. Finally, a preliminary study on the dearomatization reactions giving rise to pyrroloindolines is also reported.

Hydrogen-bond promoted nucleophilic fluorination: concept, mechanism and applications in positron emission tomography.

Due to the tremendous interest in carbon-fluorine bond-forming reactions, research efforts in this area have been dedicated to the development of facile processes to synthesize small fluorine-containing organic molecules. Among others, PET (Positron Emission Tomography) is one of the most important applications of fluorine chemistry. Recognizing the specific requirements of PET processes, some groups have focused on fluorination reactions using alkali metal fluorides, particularly through SN2-type reactions. However, a common "misconception" about the role of protic solvents and hydrogen bonding interactions in this class of reactions has hampered the employment of these excellent promoters. Herein, we would like to review recent discoveries in this context, showing straightforward nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents. Simultaneous dual activation of reacting partners by intermolecular hydrogen bonding and the enhancement of the "effective fluoride nucleophilicity", which is Nature's biocatalytic approach with the fluorinase enzyme, are the key to this unprecedentedly successful nucleophilic fluorination.

ChemInform Abstract: A Practical and Stereoselective Organocatalytic Alkylation of Aldehydes with Benzodithiolylium Tetrafluoroborate

AbstractReview: 56 refs.

A convenient method for the synthesis of (prop-2-ynyloxy)benzene derivatives via reaction with propargyl bromide, their optimization, scope and biological evaluation.

A highly convenient method has been developed for the synthesis of (prop-2-ynyloxy) benzene and its derivatives. Differently substituted phenol and aniline derivatives were allowed to react with propargyl bromide in the presence of K2CO3 base and acetone as solvent. The compounds were synthesized in good yields (53–85%). Low cost, high yields and easy availability of compounds helped in the synthesis. Electron withdrawing groups favor the formation of stable phenoxide ion thus in turn favors the formation of product while electron donating groups do not favor the reaction. Phenol derivatives gave good yields as compared to that of aniline. As aprotic polar solvents favor SN2 type reactions so acetone provided best solvation for the reactions. K2CO3 was proved to be good for the synthesis. Antibacterial, Antiurease and NO scavenging activity of synthesized compounds were also examined. 4-bromo-2-chloro-1-(prop-2-ynyloxy)benzene 2a was found most active compound against urease enzyme with a percentage inhibition of 82.00±0.09 at 100 µg/mL with IC50 value of 60.2. 2-bromo-4-methyl-1-(prop-2-ynyloxy)benzene 2d was found potent antibacterial against Bacillus subtillus showing excellent inhibitory action with percentage inhibition of 55.67±0.26 at 100 µg/ml wih IC50 value of 79.9. Based on results, it can be concluded that some of the synthesized compounds may have potential antiurease and antibacterial effects against several harmful substances.

ChemInform Abstract: Recent Advances in the Direct Nucleophilic Substitution of Allylic Alcohols Through SN1‐Type Reactions

AbstractReview: 48 refs.

Synergistic Stereoselective Organocatalysis with Indium(III) Salts

The compatibility of indium(III) Lewis acids with water and amines allows their employment in synergistic and cooperative catalysis. Stereoselective organocatalytic SN1-type reactions, in which carbenium ions are generated, are promoted by the presence of indium salts. The peculiar properties of indium salts can be exploited in organocatalysis for the design of water-compatible, benign, green processes. The development of such indium(III)-promoted organocatalytic procedures is the focus of our recent research, a summary of which is presented in this article.