1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations,and Maybe Something More: A Review

N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In this context, 1-aminoalkyltriarylphosphonium derivatives deserve particular attention. The positively charged phosphonium moiety located in the immediate vicinity of the N-acyl group significantly facilitates C_α-P⁺ bond breaking, even without the use of catalyst. Moreover, minor structural modifications of 1-aminoalkyltriarylphosphonium derivatives make it possible to modulate their reactivity in a simple way. Therefore, these types of compounds can be considered as smart synthetic equivalents of N-acyliminium-type cations. This review intends to familiarize a wide audience with the unique properties of 1-aminoalkyltriarylphosphonium derivatives and encourage their wider use in organic synthesis. Hence, the most important methods for the preparation of 1-aminoalkyltriarylphosphonium salts, as well as the area of their potential synthetic utilization, are demonstrated. In particular, the structure–reactivity correlations for the phosphonium salts are discussed. It was shown that 1-aminoalkyltriarylphosphonium salts are not only an interesting alternative to other α-amidoalkylating agents but also can be used in such important transformations as the Wittig reaction or heterocyclizations. Finally, the prospects and limitations of their further applications in synthesis and medicinal chemistry were considered.     

N-Heterocyclic Iod(az)olium Salts – Potent Halogen-Bond Donors in Organocatalysis

This article describes the application of N-heterocyclic iod(az)olium salts (NHISs) as highly reactive organocatalysts. A variety of mono- and dicationic NHISs are described and utilized as potent XB-donors in halogen-bond catalysis. They were benchmarked in seven diverse test reactions in which the activation of carbon- and metal-chloride bonds as well as carbonyl and nitro groups was achieved. N-methylated dicationic NHISs rendered the highest reactivity in all investigated catalytic applications with reactivities even higher than all previously described monodentate XB-donors based on iodine(I) and (III) and the strong Lewis acid BF₃.     

Hydroxy-1-aminoindans and derivatives: preparation, stability, and reactivity

The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are strongly affected by the position of the OH group and its orientation relative to that of the amino moiety. Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to be inherently unstable as the free bases. The latter, having a para orientation between the OH and the amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and 7-hydroxy-1-propargylaminoindans represent an intermediate case; while sufficiently stable even as free bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the 5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.     

The crystal engineering of radiation-sensitive diacetylene cocrystals and salts

In this work we develop photoreactive cocrystals/salts of a commercially-important diacetylene, 10,12-pentacosadiynoic acid (PCDA, 1) and report the first X-ray crystal structures of PCDA based systems. The topochemical reactivity of the system is modified depending on the coformer used and correlates with the structural parameters. Crystallisation of 1 with 4,4′-azopyridine (2), 4,4′-bipyridyl (3), and trans-1,2-bis(4-pyridyl)ethylene (4) results in unreactive 2 : 1 cocrystals or a salt in the case of 4,4′-bipiperidine (5). However, salt formation with morpholine (6), diethylamine (7), and n-butylamine (8), results in highly photoreactive salts 12·7 and 1·8 whose reactivity can be explained using topochemical criteria. The salt 1·6 is also highly photoreactive and is compared to a model morpholinium butanoate salt. Resonance Raman spectroscopy reveals structural details of the photopolymer including its conformational disorder in comparison to less photoactive alkali metal salts and the extent of solid state conversion can be monitored by CP-MAS NMR spectroscopy. We also report an unusual catalysis in which amine evaporation from photopolymerised PCDA ammonium salts effectively acts as a catalyst for polymerisation of PCDA itself. The new photoreactive salts exhibit more reactivity but decreased conjugation compared to the commercial lithium salt and are of considerable practical potential in terms of tunable colours and greater range in UV, X-ray, and γ-ray dosimetry applications.

In this work we develop photoreactive cocrystals/salts of a commercially-important diacetylene, 10,12-pentacosadiynoic acid (PCDA, 1) and report the first X-ray crystal structures of PCDA based systems.     

Predicting the reactivity of ambidentate nucleophiles and electrophiles using a single, general-purpose, reactivity indicator

We recently proposed a new reactivity indicator, termed the "general-purpose reactivity indicator", Xi, which describes not only the classical reactivity paradigms, but also describes reactions that are neither frontier-orbital nor electrostatically controlled. This indicator was proposed to be especially useful for reactants with multiple reactive sites, especially if the nature of the reactivity at those sites was different. This suggests that this reactivity indicator is especially appropriate for ambidentate molecules; this paper confirms this hypothesis. The general-purpose reactivity indicator not only identifies the most reactive sites, it also identifies which substrates prefer which reactive sites. In particular, the reactivity indicator allows one to clearly distinguish which sites of an ambidentate molecule are most reactive when electron transfer from the attacking reagent is large (a soft reagent) and which sites are most reactive when the attacking reagent is hard and highly charged (so that electron transfer is relatively insignificant). To illustrate the efficacy of the indicator for nucleophiles we consider SCN(-), SeCN(-), NO(2)(-), SO(3)(2-). For electrophiles we consider dimethyl carbonate, N-methyl-N-nitrosotoluene-p-sulfonamide (MNTS), and 1-chloro-2,4,6-trinitrobenzene (CNB).     

Waste-free chemistry of diazonium salts and benign separation of coupling products in solid salt reactions

Gas-solid and solid-solid techniques allow for waste-free and quantitative syntheses in the chemistry of diazonium salts. Five techniques for diazotations with the reactive gases NO(2), NO and NOCl are studied. Two types are mechanistically investigated with atomic force microscopy (AFM) and are interpreted on the basis of known crystal packings. The same principles apply to the cascade reactions that had been derived from one-step reactions. Solid diazonium salts couple quantitatively with solid diphenylamine and anilines to give the triazenes. Azo couplings are achieved with quantitative yields by cautious co-grinding of solid diazonium salts with beta-naphthol and C-H acidic heterocycles, such as barbituric acids or pyrazolinones. Solid diazonium salts may be more easily applied in a stoichiometric ratio for couplings in solution. Co-grinding of solid diazonium salts with KI gives quantitative yields of various solid aryl iodides. The unavoidable coupling products in salt reactions are completely separated from the insoluble products in a highly benign manner. The solid-state reactions compare favourably with similar solution reactions that produce much waste. The structures of the products are elucidated with IR and NMR spectroscopy and mass spectrometry, while the tautomeric properties of the compounds are studied with density functional calculations at the B3LYP/6-31G* and BLYP/6-31G** levels.     

Green organic syntheses: organic carbonates as methylating agents

Dimethylcarbonate (DMC) is a valuable methylating reagent that can replace methyl halides and dimethylsulfate in the methylation of a variety of nucleophiles. It couples tunable reactivity and unprecedented selectivity towards mono-C- and mono-N-methylation. In addition, it is a prototype example of a green reagent, because it is nontoxic, is made by a clean process, is biodegradable, and reacts in the presence of a catalytic amount of base, thereby avoiding the formation of undesirable inorganic salts as by-products. Depending on the reaction conditions, DMC can be reacted under plug-flow, CSTR, or batch conditions. Other remarkable reactions are those where DMC behaves as an oxidant. The reactivity of other carbonates is reported as well.     

Participation of Alkoxy Groups in Reactions of Acetals: Violation of the Reactivity/Selectivity Principle in a Curtin–Hammett Kinetic Scenario

Nucleophilic substitution reactions of acetals having benzyloxy groups four carbon atoms away can be highly diastereoselective. The selectivity in several cases increased as the reactivity of the nucleophile increased, in violation of the reactivity/selectivity principle. The increase in selectivity with reactivity suggests that multiple conformational isomers of reactive intermediates can give rise to the products.     

Synthesis and polymerization of 2,5-dimethylene-2,5-dihydrothieno[3,2-b]thiophene derivatives: The structure and reactivity of quinonoid monomers

Novel 2,5-dimethylene-2,5-dihydrothieno[3,2-b]thiophene derivatives such as 2,5-bis[di(ethylthio)methylene]-2,5-dihydrothieno[3,2-b]thiophene ( 4b ) and 2,5-bis[cyano(ethylthio)methylene]-2,5-dihydrothieno[3,2-b]thiophene ( 4c ) were successfully synthesized as isolable crystals. Polymerization behavior of 2,5-bis(dicyanomethylene)-2,5-dihydrothieno[3,2-b]thiophene ( 4a ), 4b , and 4c was investigated. 4a , 4b , and 4c are not homopolymerizable with any initiators and also not copolymerizable with vinyl monomers such as styrene (St), methyl methacrylate, and acryronitrile except for an alternating copolymerization of 4a with St. 4a , 4b , and 4c did not copolymerize with 7,8-bis(butoxycarbonyl)-7,8-dicyanoquinodimethane (BCQ) as a highly conjugated comonomer and instead only homopolymer of BCQ was obtained, indicating that they are much less reactive than BCQ. To obtain the relative reactivity among 1c , 2c , and 4c , the rate of addition reaction of 2,2′-azobis(isobutyronitrile) (AIBN) with 4c was compared with those of AIBN with 7,8-bis(ethylthio)-7,8-dicyanoquinodimethane ( 1c ) and with 2,5-bis[cyano(ethylthio)methylene]-2,5-dihydrothiophene ( 2c ) by NMR spectroscopy and analyzed with the first-order kinetics. The relative reactivity among 1c , 2c , and 4c was found to be as follows: 1c > 4c > 2c . The relationship between structure and reactivity for the quinonoid compounds was discussed. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3027–3039, 1999     

Encrypting Chemical Reactivity in Protein Sequences toward Information‐Coded Reactions†

Controlling chemical reactivity has been the central theme in chemistry. Herein, we review the recent progress on the development of genetically encoded protein coupling reactions and their potential applications. The chemical reactivity is encoded in the protein sequences. The information is read out by folding and molecular recognition between two reactive components and subsequently translated into chemical bonding via autocatalysis. It has emerged as a unique way to tune the chemical reactivity and is regarded as one type of information‐coded reactions. Not only has it received many applications such as protein topology engineering, bioconjugation, biomaterials and synthetic biology, but also its principle may be extended beyond protein chemistry to enable new modes of supramolecular interactions that promote chemical bonding and that are simultaneously reinforced by covalent bonds.     

Regio- and diastereoselective cyclization reactions of free and masked 1,3-dicarbonyl dianions with 1,2-dielectrophiles

Despite their simplicity and synthetic usefulness, cyclisation reactions of 1,3-dicarbonyl dianions with 1,2-dielectrophiles are problematic, since both dianions and 1,2-dielectrophiles are highly reactive compounds (low reactivity matching). In addition, 1,2-dielectrophiles are often rather labile, and reactions with nucleophiles can result in polymerisation, decomposition, formation of open-chained products, elimination or SET-reactions. These intrinsic limitations can be overcome by a proper reactivity tuning and by the use of electroneutral dianion equivalents (masked dianions) in Lewis acid catalysed reactions. The cyclisations reported herein allow for an efficient, regio- and stereoselective one-pot synthesis of biologically relevant ring systems.     

Synthesis and Reactivity of Unsaturated Bisphosphonium Salts

Abstract

The synthesis of 1, 2 vinylene bisphosphonium salts 1 has now been enlarged to the vinylogous 1, 4-butadienylene bisphosphonium salts 2. The salts 2, a new class of unsaturated disalts, have also been prepared through a two-step isomerisation of acetylenic salts. New aspects of the reactivity of salts 1 and the comparative study of salts 2 (selective cleavage reactions of P-C bonds and reactions with nucleophiles having a mobile hydrogen) are described. This reactivity allows the preparation of new series of phosphonium salts substituted by heteroatomic groups.     

Thermal polymerizations of alkali 4-(1-bromoethyl)benzoates

Thermal reactions of alkali salts of 4-(1-bromoethyl)benzoic acid in bulk were investigated. These reactions were found to produce unexpectedly the graft copolymer, poly(4-vinylbenzoate)-graft-oligo(oxycarbonyl-1,4-phenylenethylidene) ( 1 ). The relative reactivity of the oligocondensation as well as the vinyl polymerization of the salts decreased in the following order: K > Na > Li. The reaction polymerization rate proceeded rapidly during the initial 15 min, and then slowed down.     

Reactivity analysis of ammonium dinitramide binary mixtures based on ab initio calculations and thermal analysis

Ammonium dinitramide (ADN) is a promising high energy oxidizer for rocket propellants because it offers a good oxygen balance and has a significant energy content. As a result, ADN-based energetic ionic liquid propellants (EILPs) have been studied, based on ADN combined with urea and monomethyl ammonium nitrate (MMAN). The thermal decomposition of ADN in the condensed phase affects the combustion of both pure ADN and ADN-based EILPs; thus, it is important to understand the reactions of EILPs in the condensed phase. The present study assessed the reactivity of ADN mixtures in the condensed phase, focussing on hydrogen abstraction reactions with NO₂· formed from the thermal decomposition of ADN. The potential energy surfaces of these reactions were obtained using ab initio calculations. The effects of functional groups and of carbon chain length on hydrogen abstraction by NO₂· were examined. Mixtures of ADN with urea and acetamide (AA) as amide compounds, and with MMAN and monoethanol amine nitrate (MEAN) as nitrate salts, were examined. Thermal analysis was conducted to investigate the properties of these mixtures, using differential scanning calorimetry (DSC). The calculation results shows that AA and MEAN are more reactive with ADN than urea and MMAN, which is supported by the DSC data. Hydrogen abstraction by NO₂· is evidently an important condensed phase reaction in ADN mixtures, and substances having alkyl groups and longer carbon chains are more highly reactive.

     

4-Dialkylaminopyridines as Highly Active Acylation Catalysts. [New synthetic method (25)]

The synthesis of 4-dialkylaminopyridines can be accomplished in two steps starting from pyridine. Compared to pyridine, these derivatives are approximately 10⁴ times more active when used as acylation catalysts. Dialkylaminopyridines are being used with ever-increasing frequency for acylation reactions which proceed either incompletely or not at all in pyridine. This article reviews the various possible applications of 4-dialkylaminopyridines in terpene, steroid, carbohydrate and nucleoside chemistry as well as in the transformation of amino acids into α-acyl aminoketones and polymerization of isocyanates. In addition, N-substituted 4-dialkylaminopyridinium salts can be used for the transfer of sensitive groups to nucleophiles in aqueous medium. The exceptional catalytic effect of these derivatives, even in non-polar solvents, is due, in part, to the formation of high concentrations of N-acylpyridinium salts which are present in solution as loosely-bound, highly reactive ion pairs.     

Multiple pathways for the oxygenation of a ruthenium(II) dithiocarbamate complex: S-oxygenation and S-extrusion

The reactions of Ru(bpy)(2)(N,N-dimethyldithiocarbamate)(+), 1, with O-atom-transfer reagents such as hydrogen peroxide, m-chloroperoxybenzoic acid, and oxone have been studied and several resulting derivatives isolated and structurally characterized. Both S-oxygenation and S-extrusion may occur depending upon reagent and conditions. Excess peroxygenation leads to a stable dioxygenate, Ru(bpy)(2)(N,N-dimethylthiocarbamatesulfinate-S,S)(+), 3. Stoichiometric oxygenation leads to mixtures of products from which two forms of monooxygenated species Ru(bpy)(2)(N,N-dimethylperoxydithiocarbamate-S,S), 2a, and Ru(bpy)(2)(N,N-dimethylperoxydithiocarbamate-O,S), 2b, and an S-extruded product, Ru(bpy)(2)(N,N-dimethylmonothiocarbamate)(+), 4, have been isolated as PF(6)(-) salts. The S,S-bound monooxygenate is unstable over time toward either O-atom-transfer reactions via disproportionation or reaction with phosphines or S-extrusion yielding complex 4 in which the thiocarbamate is bonded solely through the remaining S atom. All the complexes have been characterized by (1)H NMR, UV-vis, and mass spectroscopies, and all but the highly reactive 2a structurally determined by X-ray crystallography.     

Scope and mechanism of the C-H bond activation reactivity within a supramolecular host by an iridium guest: a stepwise ion pair guest dissociation mechanism

A chiral self-assembled supramolecular M(4)L(6) assembly has been shown to be a suitable host for a series of reactive monocationic half-sandwich iridium guests 1, 3, and 4 that are capable of activating C-H bonds. Upon encapsulation, selective C-H bond activation of organic substrates occurs. Precise size and shape selectivity are observed in the C-H bond activation of aldehydes and ether substrates. The reactions exhibit significant kinetic diastereoselectivities. Thermodynamic studies have shown that the iridium starting materials and products are bound strongly by the host assembly. The encapsulation process is largely entropy-driven. Kinetic investigations with water-soluble phosphine traps and added salts have provided evidence for a unique stepwise mechanism of guest dissociation for [4 subset Ga(4)L(6)]. Iridium guest 4 first dissociates from the host cavity to form an ion pair with the host exterior. This species then fully dissociates from the host exterior into the bulk solution. Model ion pair intermediates were characterized directly with (1)H NMR NOESY techniques. The rate of iridium guest dissociation is slower than the rate observed for the C-H bond activation processes, indicating that the selective C-H bond activation reactivity occurs within the cavity of the supramolecular host.     

Mononuclear Nonheme Iron(III)‐Iodosylarene and High‐Valent Iron‐Oxo Complexes in Olefin Epoxidation Reactions

High‐spin iron(III)‐iodosylarene complexes are highly reactive in the epoxidation of olefins, in which epoxides are formed as the major products with high stereospecificity and enantioselectivity. The reactivity of the iron(III)‐iodosylarene intermediates is much greater than that of the corresponding iron(IV)‐oxo complex in these reactions. The iron(III)‐iodosylarene species—not high‐valent iron(IV)‐oxo and iron(V)‐oxo species—are also shown to be the active oxidants in catalytic olefin epoxidation reactions. The present results are discussed in light of the long‐standing controversy on the one oxidant versus multiple oxidants hypothesis in oxidation reactions.     

Elucidation of the Alternating Copolymerization Mechanism of Epoxides or Aziridines with Cyclic Anhydrides in the Presence of Halide Salts

Organic halide salts in combination with metal or organic compound are the most common and essential catalysts in ring-opening copolymerizations (ROCOP). However, the role of organic halide salts was neglected. Here, we have uncovered the complex behavior of organic halides in ROCOP of epoxides or aziridine with cyclic anhydride. Coordination of the chain-ends to cations, electron-withdrawing effect, leaving ability of halide atoms, chain-end basicity/nucleophilicity, and terminal steric hindrance cause three types of side reactions: single-site transesterification, substitution, and elimination. Understanding the complex functions of organic halide salts in ROCOP led us to develop highly active and selective aminocyclopropenium chlorides as catalysts/initiators. Adjustable H-bonding interactions of aminocyclopropenium with propagating anions and epoxides create chain-end coordination process that generate highly reactive carboxylate and highly selective alkoxide chain-ends.     

Photochemical generation of a highly reactive iron-oxo intermediate. A true iron(V)-oxo species?

Laser flash photolysis of 5,10,15-tris(pentafluorophenyl)corrole-iron(IV) chlorate or nitrate, prepared from the corresponding chloride, gave a highly reactive iron-oxo transient identified as an iron(V)-oxo species on the basis of its UV-visible spectrum and high reactivity as well as by analogy to photochemical ligand cleavage reactions of related manganese species. The transient was shown to be an oxo transfer agent in a preparative reaction with cis-cyclooctene. Representative rate constants for oxidation reactions by the new transient at ambient temperature were k = 5900 M-1 s-1 for cyclooctene and k = 570 M-1 s-1 for ethylbenzene. The new transient is more than 6 orders of magnitude more reactive with typical organic reductants than expected for an iron(IV)-oxo corrole radical cation and 100 times more reactive than an analogous positively charged iron(IV)-oxo porphyrin radical cation. Slow electron transfer isomerization of ligand iron(V)-oxo species to iron(IV)-oxo ligand radical cations might be important in reactions of porphyrin-iron catalysts in the laboratory and in nature.