Amine Radical Cation Research Articles

The resonance energy of amides and their radical cations

The resonance energy of an amide can be calculated through comparison with a model amine and a model ketone (or aldehyde) with subtraction of the “residual” fragments. This classical approach, employing gas-phase experimental enthalpies of formation, corresponds to ca. 70 kJ mol−1 (≈ 16 kcal mol−1) for N,N-dimethylacetamide (DMA), a value close to that of the C(O)-N rotational barrier. Using a similar approach to explore the resonance energy of the DMA radical cation leads to the question of whether the amine radical cation or the ketone/aldehyde radical cation is the most appropriate model. An additional complication is whether the amide radical cation loses a π electron or an nO electron. These issues are analyzed. For DMA radical cation, the π orbital loses the electron and spin is mostly localized at nitrogen. A negative resonance energy of ca. 22 kJ mol−1 (5 kcal mol−1) is obtained. This somewhat surprising result can be attributed to reduced stabilization due to delocalization of a single electron relative to an electron pair and its significant localization on nitrogen which is exceeded by coulombic destabilization of the carbonyl carbon by the adjacent nitrogen.

Infrared Spectroscopic Study on Trimethyl Amine Radical Cation: Correlation between Proton-Donating Ability and Structural Deformation.

Barrierless intermolecular proton transfer from a CH bond has recently been reported in the vertical ionization of the trimethyl amine (TMA) dimer. This result indicates the remarkable enhancement of the proton-donating ability of the CH bond in its cationic state. In the present study, we have carried out an infrared spectroscopy of the neutral and cationic TMA in the CH stretch region and their theoretical calculations to investigate the mechanism of enhancement of the proton-donating ability in the cationic state. In the spectrum of the cation, the CH stretch band shows a long tail of up to 2600 cm-1. This tail component is attributed to the CH bond hyperconjugated with the nonbonding orbital at the nitrogen atom through geometry deformation (excitation of molecular vibrations) with the excess energy upon photoionization. This hyperconjugation causes the delocalization of the σ electron of the CH bond to the singly occupied nonbonding orbital so that the proton-donating ability of the CH is enhanced. It is shown that the excitation of the CN stretching vibration is especially effective in promoting the hyperconjugation.

Nitrogen gets radical.

The direct formation of C–N bonds onto arenes provides a simple route to synthesize a variety of important products. Now, formation of a highly polarized, aminium radical cation enables direct C–H amination, allowing the coupling of an exceptionally broad range of alkyl amines and arenes.

Succinimide-Promoted Malonylamination of Alkenes with Amines and Iodonium Ylides via Trapping of Transient Aminium Radical Cations.

A conceptually distinct strategy enabling malonylamination of alkenes with abundant amines and iodonium ylides without assistance of any transition metal was developed. Succinimide was identified as a proton shuttle that can not only largely accelerate the process of trapping highly unstable radical ion pairs with alkenes but also significantly improve the chemical yields.

Olefin Oxyamination with Unfunctionalized N‐Alkylanilines

AbstractN‐Alkylanilines have rarely been used in oxyamination reactions, due to the normally necessary pre‐functionalization of the N‐atom. Also, the formation of aminium radical cations (ARCs) of anilines bearing alkyl substituents is plagued by the ARC's tendency to instantaneously convert to α‐amino radicals or iminium ions. We present a readily available reagent combination that addresses both challenges, and thus allows for an oxyamination with N‐alkylanilines via ARCs as the crucial reactive intermediates and excellent diastereoselectivity.magnified image

Possible Intermediacy of Cyclopropane Complexes in the Isomerization of Aliphatic Amine Radical Cations.

The isomerization of aliphatic amine radical cations via intermediate [cyclopropane-NH3]+• and [cyclopropane-amine]+• ion-neutral complexes was studied experimentally with double-focusing mass spectrometers and computationally with composite ab initio methods. The results examine and extend Audier's suggestion that primary amine radical cations with alkyl substituents at the β- and/or γ-carbon atoms isomerize via transient complexes of NH3 and alkyl cyclopropanes; these are formed by ring closure of the easily accessible γ-distonic isomers. Ionized amines with substituents at the α-carbon may react analogously when trialkyl cyclopropane complexes can be formed. Isomerization via complex intermediates is a major reaction pathway when the internal energy of the amine radical cation is less than that required for simple CC-bond cleavage. Complexes of unsubstituted or monosubstituted ionized cyclopropanes rarely contribute to the isomerization reactions. Secondary and tertiary amine radical cations do not undergo isomerization via cyclopropane intermediates, whereas aliphatic ether radical cations do.

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3+2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional group tolerance (e.g. -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous flow processing allowed for efficient operation on gram-scale, providing promise for translation to industrially-relevant scales. This methodology only requires low loadings of a commercially-available, visible light-active photocatalyst and a simple salt, thus it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

Photochemical Co-Oxidation of Sulfides and Phosphines with Tris( p-bromophenyl)amine. A Mechanistic Study.

The photochemistry of tris( p-bromophenyl)amine was investigated in a nitrogen- and oxygen-flushed solution under laser flash photolysis conditions. The detected intermediates were the corresponding amine radical cation ("Magic Blue") and the N-phenyl-4a,4b-dihydrocarbazole radical cation that, under an oxygen atmosphere, is converted to the corresponding hydroperoxyl radical. The role of the last species was supported by the smooth co-oxidation of sulfides to sulfoxides. On the other hand, co-oxidation of nucleophilic triarylphosphines to triarylphosphine oxides arose from an electron transfer between the photogenerated "Magic Blue" and phosphine that prevented the amine cyclization. In this case, intermediate Ar3POO•+ was found to play a key role in phosphine oxide formation.

Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis.

We present a highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidation potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivatives and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.

C-H bond sulfonylation of anilines with the insertion of sulfur dioxide under metal-free conditions.

C-H bond sulfonylation of anilines with the insertion of sulfur dioxide under metal-free conditions is described. 2-Sulfonylanilines are generated in moderate to good yields through a three-component reaction of anilines, DABCO·(SO2)2, and aryldiazonium tetrafluoroborates under mild conditions. No metal catalysts or additives are needed for this transformation. This direct C-H functionalization is highly efficient, and broad functional group tolerance is observed. A radical process is believed to be involved. In the reaction process, the arylsulfonyl radical and the tertiary amine radical cation generated in situ from DABCO·(SO2)2, and aryldiazonium tetrafluoroborate are the key intermediates. Additionally, the tertiary amine radical cation acts as the electron carrier through a single electron transfer process.

Direct Aryl C−H Amination with Primary Amines Using Organic Photoredox Catalysis

AbstractThe direct catalytic C−H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C−H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C−N bonds, using primary amines, by direct C−H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron‐rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate.

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques.

Visible-light-mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and thus have generated significant interest from the organic chemistry community. Although the mechanisms of these reactions have been probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degrees of success has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate) because of the lack of structural information about the proposed and short-lived intermediates. Herein, we present the detection of transient amine radical cations involved in the intermolecular [3 + 2] annulation reaction of N-cyclopropylaniline (CPA, 1) and styrene 2 by electrospray ionization mass spectrometry (ESI-MS) in combination with online laser irradiation of the reaction mixture. In particular, the reactive CPA radical cation 1+•, the reduced photocatalyst Ru(I)(bpz)3+, and the [3 + 2] annulation product radical cation 3+• are all successfully detected and confirmed by high-resolution MS. More importantly, the post-irradiation reaction with an additional substrate, isotope-labeled CPA, following photolysis of 1, 2, and Ru catalyst provides strong evidence to support the chain mechanism in the [3 + 2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine radical cation 1+• by product radical cation 3+• (generated using online electrochemical oxidation of 3), is successfully established. Additionally, the coupling of ESI-MS with online laser irradiation has been successfully applied to probe the photostability of photocatalysts.

Metal-Free Oxidative C-C Coupling of Arylamines Using a Quinone-Based Organic Oxidant.

A variety of arylamines are shown to undergo oxidative C-C bond formation using quinone-based chloranil/H+ reagent as the recyclable organic (metal-free) oxidant system to afford benzidines/naphthidines. Arylamines (3°/2°) designed with various substituents were employed to understand the steric as well as electronic preferences of oxidative dimerization, and a mechanism involving amine radical cation has been proposed. The tetraphenylbenzidine derivative obtained via oxidative C-C coupling has been further converted to blue-emissive hole-transporting material via a simple chemical transformation. This study highlights the preparation of novel HTMs in a simple, economic, and efficient manner.

Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis.

Photocatalytic coupling of aldehydes and silicon amine protocol (SLAP) reagents enables the simple, scalable synthesis of substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes under continuous flow conditions. Key to the success of this process is the combination of an inexpensive organic photocatalyst (TPP) and a Lewis acid additive, which form an amine radical cation that is easily reduced to complete the catalytic cycle. Di- and trisubstituted SLAP reagents are formed in one step by an iron-catalyzed aminoetherification of olefins.

A Photocatalyzed Synthesis of Naphthalenes by Using Aniline as a Traceless Directing Group in [4 + 2] Annulation of Amino-benzocyclobutenes with Alkynes

We report a visible-light-promoted synthesis of substituted naphthalenes via [4 + 2] annulation of amino-benzocyclobutenes with alkynes. Amino-benzocyclobutenes, which are conveniently synthesized by [2 + 2] cycloaddition of arynes with ketenes followed by reductive amination, undergo regioselective opening of the cyclobutenyl ring to reveal a presumably distonic radical cation upon photooxidation by an excited iridium complex. The distonic radical cation undergoes the annulation with terminal and internal alkynes as well as diynes to afford structurally diverse naphthalenes. The regiochemistry of the annulation follows the pattern displayed in the addition of nucleophilic carbon radicals to alkynes. The aniline group plays a dual role in which it not only directs the initial photooxidation to generate the amine radical cation but also serves as a leaving group to complete aromatization.

Metal-Free α-C(sp³)-H Functionalized Oxidative Cyclization of Tertiary N,N-Diaryl Amino Alcohols: Theoretical Approach for Mechanistic Pathway.

The mechanistic pathway of TEMPO/I2-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, α-aminoalkyl radical 4, and iminium 5), four types of reactive species (radical TEMPO, cationic TEMPO, TEMPO-I, and iodo radical), and three types of pathways ((1) SET/PCET mechanism; (2) HAT/1,6-H transfer mechanism; (3) ionic mechanism) were assumed. Under the assumption, nine free energy diagrams were acquired through density functional theory calculations. From the comparison of solution-phase free energy, some possible mechanisms were excluded, and then the chosen plausible mechanisms were concretized using the more stable intermediate 7.

Photoredox‐Induced Radical 6‐exo‐trig Cyclizations onto the Indole Nucleus: Aromative versus Dearomative Pathways

The investigation of photoredox‐induced intra‐ and intermolecular radical [4+2] annulations of indoles confronted us with a puzzling dichotomous behavior of structurally closely related intermediate 3‐indolyl radicals, which either undergo exclusive oxidation to tricyclic tetrahydropyridoindoles or reduction to benzindolizidine products under identical reaction conditions. A combined experimental and computational study revealed that only very subtle structural changes in the substrate–reactant complexes of the key radical intermediates with amine radical cations steer the divergent product selectivities, instead of the usual reactivity parameters such as ionization potentials or partial charges.

Temperature Dependence of Hydrogen Bond in the Redox Process of Polyaniline

The in situ rapid-scan time-resolved IR spectroelectrochemistry (RS-TR-FTIRS) method was utilized to study the structures of hydrogen bond in the redox process of polyaniline for the first time. There are two types of hydrogen bond. The first was formed between the oxygen atom of water molecule and one hydrogen atom of amine cation radical according to the O-H stretching region (3200–2100 cm−1). Another was formed between the oxygen atom of water molecule and two hydrogen atoms of different amine cation radical according to the O-H stretching region (2700–1700 cm−1). It was found that the hydrogen bond strengthen with the increase of the quantity of amine cation radical in the redox process of polyaniline. The ordered hydrogen bond intensity increases as temperature decreases. The results may be important for understanding of chemical and electric structure and full use the chemical and electronic properties of PANI.

Nonaqueous electrochemical oxidation of tamoxifen

The electrochemical oxidation of the chemotherapeutic anti-cancer agent tamoxifen, 1, was studied by voltammetry and electrolysis. Three successive one-electron anodic reactions were observed for 1 in dichloromethane containing weakly-coordinating [B(C6F5)4]− as the supporting electrolyte anion. The first (totally irreversible) oxidation (ca 0.64V vs ferrocene) occurs at the tertiary amine, giving a putative amine radical cation 1+ that abstracts a hydrogen atom, most likely from solvent, to give the corresponding ammonium ion 1-H+. The latter is responsible for the two further one-electron oxidations, which take place at the triarylethenyl part of the molecule (E1/2 values of 0.94V and 1.33V vs ferrocene). Bulk oxidation of 1 at Eappl=0.6V produces the ammonium ion 1-H+, which can be cathodically reduced back to neutral tamoxifen in an overall chemically reversible process. The present findings are not consistent with the mechanism described in previous literature for the anodic oxidation of tamoxifen.

ChemInform Abstract: The Prowess of Photogenerated Amine Radical Cations in Cascade Reactions: From Carbocycles to Heterocycles

AbstractReview: 59 refs.