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This communication gives an overview of the relationships between four reactions that although related were not always perceived as such: S2, Walden, Finkelstein, and Menshutkin. Binary interactions (S2 & Walden, S2 & Menshutkin, S2 & Finkelstein, Walden & Menshutkin, Walden & Finkelstein, Menshutkin & Finkelstein) were reported. Carbon, silicon, nitrogen, and phosphorus as central atoms and fluorides, chlorides, bromides, and iodides as lateral atoms were considered. Theoretical calculations provide Gibbs free energies that were analyzed with linear models to obtain the halide contributions. The M06-2x DFT computational method and the 6-311++G(d,p) basis set have been used for all atoms except for iodine where the effective core potential def2-TZVP basis set was used. Concerning the central atom pairs, carbon/silicon vs. nitrogen/phosphorus, we reported here for the first time that the effect of valence expansion was known for Si but not for P. Concerning the lateral halogen atoms, some empirical models including the interaction between F and I as entering and leaving groups explain the Gibbs free energies., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Ministerio de Ciencia, Innovación y Universidades (PGC2018-094644-B-C22), and Comunidad Autónoma de Madrid (P2018/EMT-4329 AIRTEC-CM)

New eco-friendly conditions for Finkelstein reaction employing homogeneous media or alumina-supported reagents, both solventless, were utilized in the bromohydrins and iodohydrins synthesis from 1,3-dichlorohydrin (1,3-DCH), obtained from glycerol. Thus, the trans-halogenation of glycerol-1,3-dichlorohydrin (1) in homogeneous media, using NaI, NaBr salts and organic additives (TBAI, TBAB), led to the synthesis of four different glycerol halohydrins (2a, 2b, 3a, 3b) in regular to excellent conversions (43–96%) and good selectivities to 3a and 2b. Already, the alumina-supported reagents such as KI, KBr, NaBr were used for glycerol-1,3-dichlorohydrin trans-halogenation, in the absence of solvent, producing halohydrin mixtures in high conversions (77–99%) and very good selectivity (82%) to 1,3-diiodo-2-propanol (2b).

International audience; Non-symmetrical chiral 4,4′-bipyridines have recently found interest in organocatalysis and medicinal chemistry. In this regard, the development of efficient methods for their synthesis is highly desirable. Herein, a series of non-symmetrical atropisomeric polyhalogenated 4,4′-bipyridines were prepared and further functionalized by using cross-coupling reactions. The desymmetrization step is based on the N-oxidation of one of the two pyridine rings of the 4,4′-bipyridine skeleton. The main advantage of this methodology is the possible post-functionalization of the pyridine N-oxide, allowing selective introduction of chlorine, bromine or cyano groups in 2- and 2′-postions of the chiral atropisomeric 4,4′-bipyridines. The crystal packing in the solid state of some newly prepared derivatives was analyzed and revealed the importance of halogen bonds in intermolecular interactions

A simple continuous flow synthesis of alkenyl chlorides from the corresponding readily available alkenyl iodides in a copper reactor tubing is described. A variety of alkenyl chlorides were obtained in good to excellent yields with full retention of the double bond geometry. The reaction time was reduced by a factor of 24 to 48 compared to the batch process., SCOPUS: ar.j, info:eu-repo/semantics/published

The 3,3&prime, 5,5&prime, tetrachloro-2-iodo-4,4&prime, bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3&prime, tetrachloro-2-iodo-2&prime, substituted-4,4&prime, bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2&prime, substituent. The corresponding racemates, along with other five chiral 4,4&prime, bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4&prime, bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3&prime, tetrachloro-2&prime, (4-hydroxyphenyl)-2-iodo-4,4&prime, bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4&prime, bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4&prime, bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

An efficient total synthesis of the chlorinated thiazole-containing natural product conulothiazole A is reported. Key features of this synthesis include a novel rhodium-catalyzed enantioselective hydrogenation of a 2-enamido-thiazole and a vinylic Finkelstein reaction that could be implemented at all stages of the synthesis to install the chlorinated alkene., SCOPUS: ar.j, info:eu-repo/semantics/published

We thank the Engineering and Physical Sciences Research Council, UK, for a research grant. The fluorinase enzyme from Streptomyces cattleya is shown to catalyse a direct displacement of bromide and iodide by fluoride ion from 5′-bromodeoxyadenosine (5′-BrDA) and 5′-iododeoxyadenosine (5′-IDA) respectively to form 5′-fluorodeoxyadenosine (5′-FDA) in the absence of L-methionine (L-Met) or S-adenosyl-L-methionine (SAM). 5′-BrDA is the most efficient substrate for this enzyme catalysed Finkelstein reaction. Postprint

A pot-economical total synthesis of antifungal Sch-725674, 1, is reported. The approach takes advantage of a number of one-pot, sequential transformations, including a phosphate tether-mediated one-pot, sequential RCM/CM/chemoselective hydrogenation protocol, a one-pot tosylation/acrylation sequence, and a one-pot, sequential Finkelstein reaction/Boord olefination/acetonide deprotection procedure to streamline the synthesis route by reducing isolation and purification procedures, thus saving time. Overall, an asymmetric route has been developed that is efficiently accomplished in seven pots from phosphate (S,S)-triene and with minimal purification.

Dehalogenation of а series substituted 2-chloroquinoline-3-carbaldehydes was investigated. It was found that zinc dust in alkali ethanol practically do not react with 2-chloro-3-(1,3-dioxolan)-2-yl-7-methylquinolines for a 5 day at ambient temperature. Increase temperature to boiling point of reaction mixture lead to increase yield 7-methylquinoline-3-carbaldehyde to 12.5%. This reaction with 2-chloro-3-dimetoxymetyl-7-methylquinoline give 26.5 above aldehyde. Replacement of ethanol to methanol give only traces of desired aldehyde. Neither 2-chloro-7-methylquinoline-3-carbaldehyde, nor his acetals do not react with sodium dithionite. Furthermore for activation of halogen we replaced chloraldehydes to iodoaldehydes by Finkelstein reaction, then protect aldehyde function by formation of dimethylacetals and treatment his by sodium dithionite in mixture pyridine-water. Desired aldehydes was obtained with poor to moderate yields. Increasing yields of this reaction is goal our further investigations.

The facile iodination of aromatic compounds under mild conditions is a great challenge for both organic and medicinal chemistry. Particularly, the synthesis of functionalized aryl iodides by light has long been considered impossible due to their photo-lability, which actually makes aryl iodides popular starting materials in many photo-substitution reactions. Herein, a photo-induced halogen exchange in aryl or vinyl halides has been discovered for the first time. A broad scope of aryl iodides can be prepared in high yields at room temperature under exceptionally mild conditions without any metal or photo-redox catalysts. The presence of a catalytic amount of elemental iodine could promote the reaction significantly.

Glycinatocopper(II) complex 1, readily synthesized from copper chloride and glycine was characterized by various techniques including FTIR, XRD, TGA and SEM analysis. The as-synthesized copper complex was found to be a simple and efficient catalyst for the synthesis of aryl and heteroaryl chlorides via aromatic Finkelstein reaction of aryl and heteroaryl bromides in high to excellent yields. The developed glycinatocopper(II) catalyst could easily be recovered from the reaction mixture and reused successfully for several runs without any loss in catalytic efficiency. The developed methodology represents the first example of the use of heterogeneous catalyst for the synthesis of aryl and heteroaryl chlorides via aromatic Finkelstein reaction.

The preparation of 27 isomers of chiral hexahalogeno-4,4'-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4'-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4'-bipyridine-2,2'-diones. Iodine in 2,2'-positions of the 4,4'-bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2'-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4'-bipyridines were enantioseparated by High Performance Liquid Chromatography (HPLC) on chiral stationary phases and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction (XRD) analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.

This is the peer reviewed version of the following article: Fjellaksel, R., Dugalic, D., Demissie, T.B., Riss, P., Hjelstuen, O.-K., Sundset, R. & Hansen, J.H. (2018). An Acylation-Finkelstein Approach to Radioiodination of Bioactives: The Role of Amide Group Anchimeric Assistance. Journal of Physical Organic Chemistry. https://doi.org/10.1002/poc.3835, which has been published in final form at https://doi.org/10.1002/poc.3835. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Herein, we report a straightforward sequential acylation‐Finkelstein approach to achieve iodination of amine containing bioactives. The utility was demonstrated by successful radiolabelling with 123I in high radiochemical yield. Moreover, microwave‐assisted Finkelstein reaction can be employed to enhance conversion and reaction rates to obtain the desired iodides. The method is of interest for radioiodination of amine‐containing bioactives. The mechanistic details of the iodination process were studied by kinetics and density functional theory calculations, which revealed the mechanistic complexity of the reaction involving amide group anchimeric assistance. We disclose a number of fundamental aspects of amide group anchimeric assistance in substitution reactions.

International audience; The radical copolymerisation of electron-acceptor chlorotrifluoroethylene (CTFE) with electron-donorvinyl ethers (VEs) produced poly(CTFE-alt-VE) alternating fluorinated copolymers with a high content offunctional groups. This article describes methods to synthesise poly(CTFE-alt-VE) copolymers that bearammonium-groups insensitive to Hofmann degradation. Direct preparation and post-polymerisationfunctionalisation methods are presented. First, the radical copolymerisation of CTFE with a tertiaryamine-carrying vinyl ether led to low molecular weight-copolymers with an imperfect structure. Thatcopolymerisation and the quaternisation of the amino groups using methyl iodide were howeveraccompanied by side reactions, including transfer reactions and significant loss of functionality. Incontrast, the second strategy dealt with the post functionalisation of an alternated poly(CTFE-alt-2-chloroethyl vinyl ether) copolymer. Halogen exchange of poly(CTFE-alt-CEVE) copolymers was carriedout using the efficient Finkelstein reaction. Then, the nucleophilic substitution of the iodine atoms on theobtained poly(CTFE-alt-IEVE) copolymer led to a poor yield of functionalisation and was accompaniedby a substantial amount of side reactions. Then, the iodine atoms in poly(CTFE-alt-IEVE) copolymerswere chemically changed quantitatively into azides (especially from microwave activation) and theresulting azido-containing copolymer was reacted with 1-dimethylamino-2-propyne. An optimisation ofthis Huisgen's or thermal cycloaddition showed that (i) a copper catalyst led to cross-linked copolymers,(ii) whereas in the absence of the copper catalyst, the cycloaddition was slow and only converted ca.60% of the azides; (iii) then, microwave activation led to high yield in a few minutes. Dimethylaminogroups were inserted onto the copolymeric backbone and subsequently quaternised using iodomethaneefficiently. Such copolymers, potentially resistant to alkaline media and able to promote hydroxide anionconduction, may exhibit interesting properties as a component of solid alkaline fuel cell membranes.

Computational methods of organic reactions in solution are reviewed. The results of a series of molecular orbital calculations of the Wittig reaction are presented as an example which shows how the molecular orbital calculation is used to analyze the reaction and why computations of solvent effect are required. The theoretical bases of recently developed methods, including the supermolecule method, molecular simulation (Monte Carlo and molecular dynamics methods), QM/MM, RISM-SCF, and dielectric continuum model, are described with the stress on the applicability and limitation of the methods. The calculated results on several reactions such as solvolysis, the Finkelstein reaction and the Menschutkin reaction are presented.

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

Novel surfactants with specific functions were sinthesized from inexpensive, commercially available bulk chemicals by convenient synthetic methods. All were characterized by features such as chemical degradability, catalitic activity for a halide displacement reaction (Finkelstein reaction), ability to disperse lime soap and complex with alkali metal cations. Applications for emulsion polimerization, surface-active properties, stability constants of complexes with alkali metal ions, and solubilization of alkali metal picrates in organic solvents were studies.

Partition coefficients from water to organic solvents for phenoxide anions have been obtained using a method based on the variation of pK(a) of phenols with solvent. From these partition coefficients, the Abraham descriptors for phenoxide anions, on the same scale as descriptors for neutral molecules, have been obtained. Equations have been constructed for the prediction of descriptors, and values of the Abraham descriptors E, S, A (equal to zero for the phenoxide anions we have studied), B, V, and J(-) have been determined or estimated for some 60 substituted phenoxide anions. These anions are characterized by very large values of the dipolarity/polarizability descriptor S and the hydrogen bond basicity descriptor B. In order to show the utility of the obtained phenoxide descriptors, we demonstrate that they can be combined with descriptors for carboxylate anions and permanent anions to yield equations for the Finkelstein reaction of anions with iodomethane in methanol, N,N-dimethylformamide, and water.

A novel and efficient method of synthesis of 3-substituted derivatives of pentane-2,4-dione is proposed, wherein cheaper and easily accessible chloro derivatives are conversed into more reactive iodo derivatives. The method is based on the Finkelstein reaction for which the literature suggests highly polar organic solvents as ideal reaction media. In the presented work, the use of industrially used ketones, especially methyl isobutyl ketone, is proposed. The use of MIBK as a solvent additionally allows an azeotropic removal of water from the reaction mixture, enabling the application of moisture sensitive alkylating agents i.e. (3-chloropropyl)trimethoxysilane. The obtained products are isolated through distillation, which does however not allow the separation of C-alkylation products from O-alkylation ones. The products not containing water-sensitive substituents were isolated as copper complexes. The pure product of C-alkylation was obtained by decomposition of the copper complex with a hydrochloric acid solution and extraction of the formed ligand to an organic phase i.e. hexane. The obtained ligand can be further purified by distillation.

By quantitative evaluation of in situ recorded Br K-edge XAFS spectra we obtained kinetic parameters for the halogen exchange in 2-bromopropane with sodium iodide (‘Finkelstein reaction’). The results compare well with the classical data by Ingold and co-workers. Thus, XAFS is a suitable method to quantitatively monitor reactions in the liquid state.

A mild and general method for the conversion of aryl, heteroaryl, and vinyl bromides into the corresponding iodides was developed utilizing a catalyst system comprising 5 mol % of CuI and 10 mol % of a 1,2- or 1,3-diamine ligand. A variety of polar functional groups are tolerated, and even N−H containing substrates such as sulfonamides, amides, and indoles are compatible with the reaction conditions. Both the reaction rate and the equilibrium conversion of the aryl bromide depend on the choice of the halide salt and the solvent. The best results were obtained using NaI as the halide salt and dioxane, n-butanol, or n-pentanol as the solvents.

The rate constant of the reaction of methyl iodide with the bromide ion showed a characteristic dependence on the composition of solvent mixtures. In five solvent mixtures, i.e., acetonitrile–ethylene glycol, –1,2-propanediol, –1,3-butanediol, –1,4-butanediol, and –2,3-butanediol, its dependence was fairly well reproduced by the theoretical equations derived on the basis of the concept of the concurrent monodentate and bidentate solvation of the halide ion by glycol. In contrast, the rate constants in acetonitrile–diethylene glycol and –triethylene glycol mixtures were better reproduced by the modified theoretical equations allowing for a self-association of glycol.

橋かけポリ (4-ビニルビリジン) (P4VP) に臭化アルキル (C2～C16), 臭化アリール, 巣化アラルキルを反応し, 橋かけP4VP四級塩を得, これを触媒としてFinkelstein反応を有機溶煤-水系で, 反応温度102℃で行った. 四級化剤として臭化オクチルから得られた触媒 (四級化率70.7%) が臭化オクチルとヨウ化ナトリウムの反応において8時間後の収率は90%を示し, 概してアルキル鎖長の長いものが良好な触媒効果を有し, 65～91℃の間で測定した見掛けの活性化エネルギーは11kcal/molを示した. 臭化オクチルに対するヨウ化ナトリウムのモル比10がほぼ最適濃度と考えられる. 触媒量の増加に伴って反応速度定数も直線的に上昇している. 極性溶媒-水系では概してアルキル鎖長が長くなるにつれて触媒効果を促進する傾向にあるが, 非極性溶媒-水系では, アルキル鎖長がC8以上でなければあまり触媒効果は示さない. 触媒の対イオンの効果としてはBr>I>>Clの順序であった.

Chlorine isotopic exchange reactions of substituted chloromethanes [(arylsulfonyl)chloromethanes (1), (arylsulfinyl)chloromethanes (2), and 2-chloro-1-arylethanones (4)] with tetraethylammonium chloride-36Cl were studied in acetonitrile. This study enabled, for the first time, the accurate rate study of the former two classes of compounds (1 and 2) of extremely low reactivity. Both the large enthalpies of activation and the positive entropies of activation were the characteristics for these two substrates (1-p-NO2 and 2-p-NO2). High reactivity of 2-chloro-1-phenylethanone was substantiated, and was not associated with the significant secondary kinetic deuterium isotope effect. A nucleophile-substrate association that proceeds the reaction was suggested and the possible role of such an interaction was examined in the light of the intermediary of the nucleophile-substrate complex in the Finkelstein reaction.

The Finkelstein reaction has been studied in five dipolar aprotic–dipolar aprotic solvent mixtures and one protic-dipolar aprotic solvent mixture. The theoretical equations for the rate constant as a function of solvent composition derived previously have been reformulated in terms of the solvent exchange model on the solvation site, taking into account the two main features of solvation: the number of the solvation sites on the solvent molecule and the equilibrium constant for the solvent exchange process. The results obtained previously, together with present results, are comprehensively discussed and the solvent mixtures are classified into four groups from the viewpoint of solute-solvent interaction in the region near the ion, using derived theoretical equations.

A specific type of reaction should have a characteristic isokinetic temperature as long as the individual reactions are carried out in the same solvent and the reactions of substrates with bulky groups are excluded. Two kinds of reactions of tertiary amine with carboxylates, quaternization and aminolysis reactions, were distinguished by isokinetic temperatures of 430 and 256, respectively.

The rate constants were determined for both processes of the Finkelstein reaction in acetonitrile–alcohol mixtures at 30 °C:CH_3Br+I^-\oversetk_f\undersetk_r\ightleftarrowsCH_3I+Br^-Theoretical equations were derived describing the dependence of the rate constant on the composition changes in the solvent mixtures. These equations describe the change in the rate constant in terms of changes in the activity coefficient. The results were analyzed by means of the equations; they lead to the conclusion that anions have multiple solvation equilibria with alcohols. The relative magnitudes of the step-by-step association constants and of the solvation numbers thus determined agreed with the results determined spectrophotometrically.

Substrate-nucleophile association was found between substituted chloromethanes (ArXCH2Cl: X=NONE, S, SO, SO2, and CO) and halide ion (Cl−, Br−, and I−) in dipolar aprotic solvent. The equilibrium constant (K), limiting shift (Δc), the enthalpy of formation (ΔH°), and the entropy of formation (ΔS°), for complexing were determined by NMR measurement. The measurement of spin-lattice relaxation time (T1) gave an information on the conformation of this complex. Halide ion seems to locate closest to α-methylene protons at the site of potential SN2 reaction.