IPr*F - Highly Hindered, Fluorinated N-Heterocyclic Carbenes.

The introduction of fluorine atom has attracted considerable interest in molecular design owing to the high electronegativity and the resulting polarization of carbon-fluorine bonds. Simultaneously, sterically-hindered N-heterocyclic carbenes (NHCs) have received major interest due to high stabilization of the reactive metal centers, which has paved the way for the synthesis of stable and reactive organometallic compounds with broad applications in main group chemistry, inorganic synthesis and transition-metal-catalysis. Herein, we report the first class of sterically-hindered, fluorinated N-heterocyclic carbenes. These ligands feature variable fluorine substitution at the N-aromatic wingtip, permitting to rationally vary steric and electronic characteristics of the carbene center imparted by the fluorine atom. An efficient, one-pot synthesis of fluorinated IPr*F ligands is presented, enabling broad access of academic and industrial researchers to the fluorinated ligands. The evaluation of steric, electron-donating and π-accepting properties as well as coordination chemistry to Au(I), Rh(I) and Se is presented. Considering the unique properties of carbon-fluorine bonds, we anticipate that this novel class of fluorinated carbene ligands will find widespread application in stabilizing reactive metal centers.

Application of vibrational and fluorescence spectroscopy to the compositional analysis of colored-flesh potatoes.

BACKGROUND: Determination of composition and physicochemical parameters of natural products requires dedicated, often laborious and expensive, analytical protocols. Different spectroscopic techniques, in conjunction with chemometrics, seem to have a considerable potential in direct analysis of raw plant material and foods, without any chemical treatment. RESULTS: Fluorescence spectroscopy and three vibrational spectroscopy techniques were applied to determine total polyphenol content, antioxidant activity and macronutrient levels in red- and purple-fleshed potato varieties. Excitation-emission matrix fluorescence, Fourier transform Raman, attenuated total reflection Fourier transform infrared and near-infrared spectra were recorded for the freeze-dried samples. Combining spectral data and the results of reference analyses, partial least squares regression models were constructed for each parameter studied. For polyphenols and antioxidant activity, quantification errors found for validation samples amounted to 3.74-5.04% and 4.75-6.35%, respectively, whereas macronutrient analysis gave errors in the 3.45-4.55%, 3.09-5.30% and 5.10-8.58% ranges for starch, protein and sugar determinations, respectively. CONCLUSION: The obtained results demonstrate that different spectroscopic techniques in combination with multivariate modeling allow simultaneous determination of various parameters of plant samples based on a single sample spectrum. They can effectively replace commonly used protocols of food product analysis requiring sample dissolving and extraction of the compounds of interest. © 2023 Society of Chemical Industry.

Wingtip-Flexible N-Heterocyclic Carbenes: Unsymmetrical Connection between IMes and IPr.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed ß-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

[IPr#-PEPPSI]: A Well-Defined, Highly Hindered and Broadly Applicable Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalyst for Cross-Coupling Reactions.

In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr#-PEPPSI], a new, well-defined, highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#-PEPPSI] in cross-coupling reactions in a range of bond activations with C-N, C-O, C-Cl, C-Br, C-S and C-H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#-PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)-NHC precatalysts in chemistry research.

L-Shaped Heterobidentate Imidazo[1,5-a]pyridin-3-ylidene (N,C)-Ligands for Oxidant-Free AuI /AuIII Catalysis.

In the last decade, major advances have been made in homogeneous gold catalysis. However, AuI /AuIII catalytic cycle remains much less explored due to the reluctance of AuI to undergo oxidative addition and the stability of the AuIII intermediate. Herein, we report activation of aryl halides at gold(I) enabled by NHC (NHC=N-heterocyclic carbene) ligands through the development of a new class of L-shaped heterobidentate ImPy (ImPy=imidazo[1,5-a]pyridin-3-ylidene) N,C ligands that feature hemilabile character of the amino group in combination with strong σ-donation of the carbene center in a rigid conformation, imposed by the ligand architecture. Detailed characterization and control studies reveal key ligand features for AuI /AuIII redox cycle, wherein the hemilabile nitrogen is placed at the coordinating position of a rigid framework. Given the tremendous significance of homogeneous gold catalysis, we anticipate that this ligand platform will find widespread application.

Buchwald-Hartwig Amination of Coordinating Heterocycles Enabled by Large-but-Flexible Pd-BIAN-NHC Catalysts.

A new class of large-but-flexible Pd-BIAN-NHC catalysts (BIAN=acenaphthoimidazolylidene, NHC=N-heterocyclic carbene) has been rationally designed to enable the challenging Buchwald-Hartwig amination of coordinating heterocycles. This robust class of BIAN-NHC catalysts permits cross-coupling under practical aerobic conditions of a variety of heterocycles with aryl, alkyl, and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron-deficient heterocycles containing multiple heteroatoms with BIAN-INon (N,N'-bis(2,6-di(4-heptyl)phenyl)-7H-acenaphtho[1,2-d]imidazol-8-ylidene) as the most effective ligand. Studies on the ligand structure and electronic properties of the carbene center are reported. The study should facilitate the discovery of even more active catalyst systems based on the unique BIAN-NHC scaffold.

Quantitative Determination of Diosmin in Tablets by Infrared and Raman Spectroscopy.

Diosmin is widely used in the treatment of chronic venous diseases and hemorrhoids. Based on Raman and infrared reflection spectra of powdered tablets in the mid- and near-infrared regions and results of reference high-performance liquid chromatographic analysis, partial least squares models that enable fast and reliable quantification of the studied active ingredient in tablets, without the need for extraction, were elaborated. Eight commercial preparations containing diosmin in the 66-92% (w/w) range were analyzed. In order to assess and compare the quality of the developed chemometric models, the relative standard errors of prediction for calibration and validation sets were calculated. We found these errors to be in the 1.0-2.4% range for the three spectroscopic techniques used. Diosmin content in the analyzed preparations was obtained with recoveries in the 99.5-100.5% range.

Quantification of Salicylates and Flavonoids in Poplar Bark and Leaves Based on IR, NIR, and Raman Spectra.

Poplar bark and leaves can be an attractive source of salicylates and other biologically active compounds used in medicine. However, the biochemical variability of poplar material requires a standardization prior to processing. The official analytical protocols used in the pharmaceutical industry rely on the extraction of active compounds, which makes their determination long and costly. An analysis of plant materials in their native state can be performed using vibrational spectroscopy. This paper presents for the first time a comparison of diffuse reflectance in the near- and mid-infrared regions, attenuated total reflection, and Raman spectroscopy used for the simultaneous determination of salicylates and flavonoids in poplar bark and leaves. Based on 185 spectra of various poplar species and hybrid powdered samples, partial least squares regression models, characterized by the relative standard errors of prediction in the 4.5-9.9% range for both calibration and validation sets, were developed. These models allow for fast and precise quantification of the studied active compounds in poplar bark and leaves without any chemical sample treatment.

Structures of the Most Twisted Thioamide and Selenoamide: Effect of Higher Chalcogens of Twisted Amides on N-C(X) Resonance.

Amide bond replacement with planar isosteric chalcogen analogues has an important implication for the properties of the N-C(X) linkage in structural chemistry, biochemistry and organic synthesis. Herein, we report the first higher chalcogen derivatives of non-planar twisted amides. The synthesis of twisted thioamide in a versatile system has been accomplished by direct thionation without cleavage of the σ N-C bond. The synthesis of twisted selenoamide has been accomplished by selenation with Woollins' reagent. The structures of higher chalcogen analogues of non-planar amides were unambiguously confirmed by X-ray crystallography. Reactivity studies were conducted to determine the effect of isologous N-C(O) to N-C(X) replacement on the properties of the amide linkage. Computational studies were employed to evaluate structural and energetic parameters of amide bond alteration in higher chalcogen amides. The study provides the first experimental evidence on the effect of chalcogen isologues on the structural and electronic properties of the non-planar amide N-C(X) linkage.

[(NHC)PdCl2(Aniline)] Complexes: Easily Synthesized, Highly Active Pd(II)-NHC Precatalysts for Cross-Coupling Reactions.

We report the synthesis, characterization, and reactivity of [(NHC)PdCl2(aniline)] complexes. These well-defined, air- and moisture-stable catalysts are highly active in the Suzuki-Miyaura cross-coupling of amides by N-C(O) activation as well as in the Suzuki-Miyaura cross-coupling of esters, aryl chlorides, and Buchwald-Hartwig amination. Most crucially, this study introduces broadly available anilines as stabilizing ligands for well-defined Pd(II)-NHC catalysts. The availability of various aniline scaffolds, including structural and electronic diversity, has a significant potential in fine-tuning of challenging cross-couplings by Pd-NHCs. The parent catalyst in this class, [Pd(IPr)(AN)Cl2], has been commercialized in collaboration with Millipore Sigma, offering broad access for reaction screening and optimization.

Evaluation of Cyclic Amides as Activating Groups in N-C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions.

The development of efficient methods for facilitating N-C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N-C(O) bond cross-coupling. Evaluation of N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and six-membered rings using Pd(II)-NHC and Pd-phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki-Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O-C(O) and S-C(O) cross-coupling under the same reaction conditions. Most notably, the study reveals N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling. The X-ray structure of the model N-acyl-δ-valerolactam is characterized by an additive Winkler-Dunitz distortion parameter Σ(τ+χN) of 54.0°, placing this amide in a medium distortion range of twisted amides. Computational studies provide insight into the structural and energetic parameters of the amide bond, including amidic resonance, N/O-protonation aptitude, and the rotational barrier around the N-C(O) axis. This class of N-acyl-lactams will be a valuable addition to the growing portfolio of amide electrophiles for cross-coupling reactions by acyl-metal intermediates.

Conversion of esters to thioesters under mild conditions.

We report conversion of esters to thioesters via selective C-O bond cleavage/weak C-S bond formation under transition-metal-free conditions. The method is notable for a general and practical transition-metal-free system, broad substrate scope and excellent functional group tolerance. The strategy was successfully deployed in late-stage thioesterification, site-selective cross-coupling/thioesterification/decarbonylation and easy-to-handle gram scale thioesterification. Selectivity and computational studies were performed to gain insight into the formation of weak C-S bonds by C-O bond cleavage, which contrasts with the traditional trend of nucleophilic additions to carboxylic acid derivatives.

Electrophilicity Scale of Activated Amides: 17 O†NMR and 15 N†NMR Chemical Shifts of Acyclic Twisted Amides in N-C(O) Cross-Coupling.

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to nN →π*C=O conjugation. In this study, we report electrophilicity scale by exploiting 17 O NMR and 15 N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.

N-Acyl-glutarimides: Effect of Glutarimide Ring on the Structures of Fully Perpendicular Twisted Amides and N-C Bond Cross-Coupling.

N-Acyl-glutarimides have emerged as the most reactive precursors for N-C(O) bond cross-coupling reactions to date, wherein the reactivity is driven by ground-state destabilization of the amide bond. Herein, we report a full study on the effect of a glutarimide ring on the structures, electronic properties, and reactivity of fully perpendicular N-acyl-glutarimide amides. Most notably, this report demonstrates the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide bond, and results in the discovery of N-acyl-glutarimide amide with an almost perfect twist value, τ = 89.1°. X-ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in the Suzuki-Miyaura cross-coupling and transamidation reactions provide insight into the reactivity of N-acyl-glutarimides in metal-catalyzed and transition-metal-free reactions. The effect of distortion, structures, and rotational barriers around the N-C(O) axis is discussed. The ability to achieve full distortion of the amide bond significantly expands the range of reagents available for N-C(O) cross-coupling reactions.

Tröger's Base Twisted Amides: High Amide Bond Twist and N-/O-Protonation Aptitude.

Tröger's base twisted amides have emerged as attractive scaffolds to readily achieve substantial nonplanarity of the amide bond in a bicyclic lactam framework. Herein, we report structures and proton affinities of a diverse set of Tröger's base twisted amides and compare them with related nonplanar bridged lactams. The data demonstrate that Tröger's base twisted amides embedded in a [3.3.1] scaffold are among the most twisted bridged lactams prepared to date. Intriguingly, while these amides also favor N-protonation, our data show that the best model for probing N-protonation aptitude in the series of nonplanar amides are less twisted benzofused 1-azabicyclo[3.3.1]nonan-2-one derivatives. This work (1) provides the understanding for future design of nonplanar bridged lactams to directly access N-protonated amide bonds, (2) validates the use of the additive Winkler-Dunitz distortion parameter, and (3) emphasizes the importance of peripheral modification to modulate properties of nonplanar amides.

Chemistry of Bridged Lactams: Recent Developments.

Bridged lactams represent the most effective and wide-ranging method of constraining the amide bond in a non-planar conformation. A previous comprehensive review on this topic was published in 2013 (Chem. Rev. 2013, 113, 5701⁻5765). In the present review, which is published as a part of the Special Issue on Amide Bond Activation, we present an overview of the recent developments in the field of bridged lactams that have taken place in the last five years and present a critical assessment of the current status of bridged lactams in synthetic and physical organic chemistry. This review covers the period from 2014 until the end of 2018 and is intended as an update to Chem. Rev. 2013, 113, 5701⁻5765. In addition to bridged lactams, the review covers recent advances in the chemistry of bridged sultams, bridged enamines and related non-planar structures.

Reversible Twisting of Primary Amides via Ground State N-C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides.

Since the seminal studies by Pauling in 1930s, planarity has become the defining characteristic of the amide bond. Planarity of amides has central implications for the reactivity and chemical properties of amides of relevance to a range of chemical disciplines. While the vast majority of amides are planar, nonplanarity has a profound effect on the properties of the amide bond, with the most common method to restrict the amide bond relying on the incorporation of the amide function into a rigid cyclic ring system. In a major departure from this concept, here, we report the first class of acyclic twisted amides that can be prepared, reversibly, from common primary amides in a single, operationally trivial step. Di-tert-butoxycarbonylation of the amide nitrogen atom yields twisted amides in which the amide bond exhibits nearly perpendicular twist. Full structural characterization of a range of electronically diverse compounds from this new class of twisted amides is reported. Through reactivity studies we demonstrate unusual properties of the amide bond, wherein selective cleavage of the amide bond can be achieved by a judicious choice of the reaction conditions. Through computational studies we evaluate structural and energetic details pertaining to the amide bond deformation. The ability to selectively twist common primary amides, in a reversible manner, has important implications for the design and application of the amide bond nonplanarity in structural chemistry, biochemistry and organic synthesis.

Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides: Effect of Chloro-Substitution on Resonance and Distortion.

Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution in a class of benzamides that are important from the reactivity and medicinal chemistry perspective results in increased barriers to rotation around both the N-C(O) and C-C(O) axes. The effect of steric hindrance on structures, resonance energies, barriers to rotation, and proton affinities is discussed. The present study strongly supports the use of ortho-substitution in common benzamides to strengthen amidic resonance.

Twisted N-Acyl-hydantoins: Rotationally Inverted Urea-Imides of Relevance in N-C(O) Cross-coupling.

We report a combined structural and computational study on the properties of twisted acyclic hydantoins. These compounds feature cyclic urea-imide moiety that is widely found in bioactive compounds and is structurally related to the classic bridged hydantoins proposed by Smissman more than 50 years ago. We demonstrate that C to N-substitution of the imide moiety in the succinimide ring to give hydantoin results in one of the most distorted acyclic amide bonds reported to date. The energetic properties of twisted acyclic hydantoins with respect to structures, resonance energies, barriers to rotation, and proton affinities are discussed. The energetic and structural properties of twisted acyclic hydantoins described provide a benchmark to facilitate the development of twisted amides based on the biorelevant cyclic urea-imide scaffold.

Resonance Destabilization in N-Acylanilines (Anilides): Electronically-Activated Planar Amides of Relevance in N-C(O) Cross-Coupling.

Transition-metal-catalyzed activation of amide N-C(O) bonds proceeds via selective metal insertion into the carbon-nitrogen amide bond. Herein, we demonstrate that N-acylanilines (anilides), the first class of planar amides that have been shown to undergo selective amide N-C cross-coupling reactions, feature a significantly decreased barrier to rotation around the amide N-C(O) bond. Most significantly, we demonstrate that amide nN → π*C═O resonance in simple anilides can be varied by as much as 10 kcal/mol. The data have important implications for the design of N-C(O) amide cross-coupling reactions and control of the molecular conformation of anilides by resonance effects.