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The antioxidant capacity of β-carotene has been studied in terms of H-atom abstraction reactions using quantum chemical methods. These oxidation reactions are studied for the all-trans as well as 15,15'-cis isomers (15Z) of β-carotene, as the latter is only ~ 10 kJ/mol less stable than the all-trans isomer in the gas phase and about 9 kJ/mol less stable in aqueous solution. Hydrogen abstraction from the rotamers obtained through C-C single and double bond rotations has been shown to play an important role in determining the antioxidant capacity of β-carotene. Hydrogen abstraction from the C4 and C5-CH3 positions of the β-ionone rings and the C7 and C9 positions along the polyene chain of β-carotene by hydroxyl radical have been studied. In the all-trans form the most favorable H-atom abstraction reaction occurs at the C4 position of the terminal regions of the polyene -system of β-carotene, closely followed by hydrogen abstraction from the C5 methyl position. The H-atom abstraction reactions are more exothermic in water than in the gas phase due to solvation energies for the water product.

Relative rates for the Lewis base-catalyzed acylation of aryl-substituted 1,2-diols with anhydrides differing in size have been determined by turnover-limited competition experiments and absolute kinetics measurements. Depending on the structure of the anhydride reagent, the secondary hydroxyl group of the 1,2-diol reacts faster than the primary one. This preference towards the secondary hydroxyl group is boosted in the second acylation step from the monoesters to the diester through size and additional steric effects. In absolute terms the first acylation step is found to be up to 35 times faster than the second one for the primary alcohols due to neighboring group effects.

The monoalkylation of N-methoxypyridinium salts with alkyl radicals generated from alkenes (via hydroboration with catecholborane), alkyl iodides (via iodine atom transfer) and xanthates is reported. The reaction proceeds under neutral conditions since no acid is needed to activate the heterocycle and no external oxidant is required. A rate constant for the addition of a primary radical to N-methoxylepidinium >107 M−1 s−1 was experimentally determined. This rate constant is more than one order of magnitude larger than the one measured for the addition of primary alkyl radicals to protonated lepidine demonstrating the remarkable reactivity of methoxypyridinium salts towards radicals. The reaction has been used for the preparation of unique pyridinylated terpenoids and was extended to a three-component carbopyridinylation of electron-rich alkenes including enol esters, enol ethers and enamides., N-Methoxypyridinium salts are exceptionally reactive radical traps that can be used in efficient radical chain reactions with organoboranes.

The generation of carbon radicals by halogen-atom and group transfer reactions is generally achieved using tin and silicon reagents that maximize the interplay of enthalpic (thermodynamic) and polar (kinetic) effects. In this work, we demonstrate a distinct reactivity mode enabled by quantum mechanical tunneling that uses the cyclohexadiene derivative γ-terpinene as the abstractor under mild photochemical conditions. This protocol activates alkyl and aryl halides as well as several alcohol and thiol derivatives. Experimental and computational studies unveiled a noncanonical pathway whereby a cyclohexadienyl radical undergoes concerted aromatization and halogen-atom or group abstraction through the reactivity of an effective H atom. This activation mechanism is seemingly thermodynamically and kinetically unfavorable but is rendered feasible through quantum tunneling.

The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported., Enantiomerically enriched azabicyclic compounds found in several important families of alkaloids can be prepared by a remarkably stereospecific and stereoselective intramolecular Schmidt reaction. The initial asymmetric alcohol center controls the whole process, leading to the formation of one out of up to four possible diastereoisomers with inversion of the configuration at the original asymmetric center.

The Hofmann–Löffler–Freytag (HLF) reaction can be successfully used to synthesize saturated heterocyclic nitrogen-containing nature-derived pharmaceuticals such as nicotine and its derivatives. In this study the rate-determining hydrogen atom transfer (HAT) step in nicotine synthesis has been analyzed using quantum chemical methods. Through quantification of substituent effects in the HAT step of the reaction on both nitrogen and carbon atoms, optimized synthetic strategies are outlined for the racemic as well as the stereoselective synthesis of nicotine. This latter process can be achieved using common nitrogen protecting groups, such as Ac, TFAc, and Boc. The said protecting groups show superior nitrogen radical activation as compared to the commonly used Tosyl group. Computational results indicate that the 1, 5-HAT step is in this case likely to work even for the reaction with primary unactivated carbon centers.

DFT-calculations allow prediction of the reactivity of uncommon N-heterocyclic scaffolds of pyrazolo[1,5-a]pyrimidines and imidazo[1,2-b]pyridazines and considerably facilitate their functionalization. The derivatization of these N-heterocycles was realized using Grignard reagents for nucleophilic additions to 5-chloropyrazolo[1,5-a]pyrimidines and TMP

The factors responsible for the kinetic resolution of alcohols by chiral pyridine derivatives have been elucidated by measurements of relative rates for a set of substrates with systematically growing aromatic side chains using accurate competitive linear regression analysis. Increasing the side chain size from phenyl to pyrenyl results in a rate acceleration of more than 40 for the major enantiomer. Based on this observation a new catalyst with increased steric bulk has been designed that gives enantioselectivity values of up to s=250. Extensive conformational analysis of the relevant transition states indicates that alcohol attack to the more crowded side of the acyl‐catalyst intermediate is favoured due to stabilizing CH‐π‐stacking interactions. Experimental and theoretical results imply that enantioselectivity enhancements result from accelerating the transformation of the major enantiomer through attractive non‐covalent interactions (NCIs) rather than retarding the transformation of the minor isomer through repulsive steric forces., The kinetic resolution of secondary alcohols by fluxionally chiral pyridine catalysts is increasingly selective with increasingly bulky substrates. Detailed kinetic and computational studies show that this is mainly caused by a selective reaction rate acceleration for the major isomer through non‐covalent interactions. More bulky catalysts further increase reaction rate and selectivity.

We present the synthesis and the photochemical and catalytic switching properties of an azopyridine as a photoswitchable ligand, covalently attached to a Ni(II)-porphyrin. Upon irradiation with 530 nm (green light), the azopyridine switches to the cis configuration and coordinates with the Ni2+ ion. Light of 435 nm (violet) isomerizes the ligand back to the trans configuration, which decoordinates for steric reasons. This so-called record player design has been used previously to switch the spin state of Ni2+ between singlet and triplet. We now use the coordination/decoordination process to switch the catalytic activity of the dimethylaminopyridine (DMAP) unit. DMAP is a known catalyst in the nitroaldol (Henry) reaction. Upon coordination to the Ni2+ ion, the basicity of the pyridine lone pair is attenuated and hence the catalytic activity is reduced. Decoordination restores the catalytic activity. The rate constants in the two switching states differ by a factor of 2.2, and the catalytic switching is reversible.

The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pK a values of functionalized N‐, S‐, and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model., Metalation site prediction: The use of simple pK a calculations allowed a reliable prediction of metalation sites in various heterocycles, arenes, olefins, and alkanes, employing the mild base TMPZnCl⋅LiCl. Using this predictive model, also unexplored N‐heterocycles were investigated, and the obtained deprotonation sites rationalized readily.

Pyridinyl amide ion pairs carrying various electron-withdrawing substituents were synthesized with selected ammonium or phosphonium counterions. Compared to neutral pyridine-based organocatalysts, these new ion pair Lewis bases display superior catalytic reactivity in the reaction of isocyanates with alcohols and the

Sigmarene, which is a Kekule hydrocarbon with appreciable singlet biradical character originating from an o-quinodimethane scaffold, is isolated as a doubly σ-bonded dimer. The dimer dissociates into a monomeric sigmarene upon heating or photoirradiation. The monomeric species undergoes a rapid [4 + 4] cycloaddition reaction under dark conditions even at room temperature to produce the dimer. Contrarily, the monomeric sigmarene undergoes a [4 + 2] cycloaddition reaction in the presence of dienophile as an orbital symmetry allowed process. Therefore, the sigmarene shows high reactivity for both symmetry-forbidden and allowed processes in the framework of the orbital symmetry rule. This duality of reactivity of the sigmarene is consistent with the intermediate singlet biradical character (44%) estimated by a density functional theory (DFT) calculation.

A useful and convenient strategy for the synthesis of α,α‐disubstituted α‐amino acid (α‐AA) derivatives via aza‐Morita‐Baylis‐Hillman reaction of 2‐aminoacrylates with activated olefins has been developed. A variety of α‐AA derivatives containing an α‐amino tertiary center were synthesized in good to excellent yields. The kinetic profiles and calculated methyl anion affinity (MAA) values were employed to rationalize the reactivities of different Michael acceptors used in the reaction.

A convenient and efficient strategy for the synthesis of 3-pyrrolines containing an amino quaternary stereogenic center via phosphine-catalyzed formal [3 + 2] annulation of 2-aminoacrylates with allenoates is disclosed. A wide range of substrates underwent this reaction smoothly, affording a series of 3-pyrrolines in good to excellent yields, and it could be extended to a gram-scale reaction. The kinetic profiles and the calculated methyl anion affinity (MAA) values were employed to explain the reactivities of different allenoates used in the reaction, which provides deep understanding for the catalytic mechanism of this type of reaction.

The kinetics of the reactions of tributylphosphine with allenic and olefinic Michael acceptors in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. Combination with DFT-calculated methyl anion affinities revealed the relevance of retroaddition barriers in phosphine-catalysed reactions when mixtures of allenic and olefinic substrates are used.

The oxidized form of baicalein (BA) leads to covalent binding with human amyloid proteins. Such adducts hamper the aggregation and deposition of fibrils. A novel reaction of BA with pentylamine (PA) as a model for the lysine side chain is described. This is the first study addressing the atomistic details of a Schiff base reaction with the trihydroxylated moiety of BA. Nuclear magnetic resonance and mass spectrometry approaches clearly indicate the formation of dehydrobaicalein in solution as well as its condensation with PA under aerobic conditions, yielding regioselectively C6-substituted products. The combined results suggest initial ion pair formation between BA and PA, followed by a redox chain reaction: the initiation by oxygen/air; an o-quinone-based chain involving oxidation and reduction steps; and extra off-chain formation of a doubly oxidized product. These mechanistic details support the anti-amyloid activity of BA and endorse its trihydroxyphenyl moiety as a pharmacophore for drug-design studies.

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.

A modular and target-group oriented online video library with 48 videos was developed and produced in order to reduce the complexity of an introductory organic chemistry laboratory class. The library comprises three different types of videos: “Tutorials” explaining fundamental laboratory techniques, “Do nots” pointing students in a humorous way to typical mistakes, and videos demonstrating complete syntheses in a “Step-by-Step” fashion. This report describes the principles, development, production, and presentation of this video library.

An online video library comprising three different types of videos was used intensively by bachelor-level students before and throughout an introductory organic chemistry laboratory course, when presented and assigned to the experiments appropriately. An empirical study (N = 103) revealed that the utilization of videos and preferences for video types depend crucially on individual student characteristics, such as gender, study course, intrinsic motivation, and the self-perception of conscientiousness. Student assessment of the video library, a positive impact on students’ self-concept of ability, and an increase of knowledge in know-how tests on laboratory techniques of up to 100% indicate the benefits of the online video library on students’ cognitive, affective, and psychomotor learning in a laboratory course.

The epigenetic marker 5-methylcytosine (5mC) is an important factor in DNA modification and epigenetics. It can be modified through a three-step oxidation performed by ten-eleven-translocation (TET) enzymes and we have previously reported that the iron(IV)-oxo complex [Fe(O)(Py5 Me2 H)]2+ (1) can oxidize 5mC. Here, we report the reactivity of this iron(IV)-oxo complex towards a wider scope of methylated cytosine and uracil derivatives relevant for synthetic DNA applications, such as 1-methylcytosine (1mC), 5-methyl-iso-cytosine (5miC) and thymine (T/5mU). The observed kinetic parameters are corroborated by calculation of the C-H bond energies at the reactive sites which was found to be an efficient tool for reaction rate prediction of 1 towards methylated DNA bases. We identified oxidation products of methylated cytosine derivatives using HPLC-MS and GC-MS. Thereby, we shed light on the impact of the methyl group position and resulting C-H bond dissociation energies on reactivity towards TET-like oxidation.

The reaction profiles for the uni- and bimolecular decomposition of benzyl hydroperoxide have been studied in the context of initiation reactions for the (aut)oxidation of hydrocarbons. The unimolecular dissociation of benzyl hydroperoxide was found to proceed through the formation of a hydrogen-bonded radical-pair minimum located +181 kJ mol-1 above the hydroperoxide substrate and around 15 kJ mol-1 below the separated radical products. The reaction of toluene with benzyl hydroperoxide proceeds such that O-O bond homolysis is coupled with a C-H bond abstraction event in a single kinetic step. The enthalpic barrier of this molecule-induced radical formation (MIRF) process is significantly lower than that of the unimolecular O-O bond cleavage. The same type of reaction is also possible in the self-reaction between two benzyl hydroperoxide molecules forming benzyloxyl and hydroxyl radical pairs along with benzaldehyde and water as co-products. In the product complexes formed in these MIRF reactions, both radicals connect to a centrally placed water molecule through hydrogen-bonding interactions.

Mono- or bidentate boron Lewis acids trigger a regioselective magnesiation or zincation of pyridazine in position C3 (ortho product) or C4 (meta product). The regioselectivity of the metalation was rationalized with the help of calculated pKa values of both pyridazine and pyridazine/Lewis acid complexes.

Relative rates for the Lewis base-mediated acylation of secondary and primary alcohols carrying large aromatic side chains with anhydrides differing in size and electronic structure have been measured. While primary alcohols react faster than secondary ones in transformations with monosubstituted benzoic anhydride derivatives, relative reactivities are inverted in reactions with sterically biased 1-naphthyl anhydrides. Further analysis of reaction rates shows that increasing substrate size leads to an actual acceleration of the acylation process, the effect being larger for secondary as compared to primary alcohols. Computational results indicate that acylation rates are guided by noncovalent interactions (NCIs) between the catalyst ring system and the DED substituents in the alcohol and anhydride reactants. Thereby stronger NCIs are formed for secondary alcohols than for primary alcohols.

The development of single-component halogen-free organocatalysts in the highly investigated cyclo- addition of CO2 to epoxides is sought-after to enhance the sustainability of the process and reduce costs. In this context, the use of strongly nucleophilic single-component catalysts has been generally restricted to a limited selection of N-nucleophiles. In this study, predictive calculations of epoxide-specific carbon basicities suggested that highly nucleophilic 3,4-diaminopyridines possess suitable basicity to serve as active single-component catalysts for the cycloaddition of CO2 to epoxides. Indeed, experimentally, the most active compounds of this class performed efficiently for the conversion of epoxides to carbonates under atmospheric pressure outperforming the catalytic activity of traditional N-nucleophiles. Importantly, the 3,4-diaminopyridino scaffold could be easily supported on polystyrene and used as a recyclable heterogeneous catalyst under atmospheric CO2 pressure. Finally, the mechanism of the cyclo- addition reaction catalyzed by several N-nucleophiles was investigated highlighting the importance of the 3,4-diaminopyridine nucleophilicity in competently promoting the crucial initial step of epoxide ring- opening without the addition of nucleophiles or hydrogen bond donors A.P. and M.S. thank the Ministerio de Economía y Competitividad (MINECO) of Spain for projects CTQ2014-59832-JIN, PGC2018-097722-BI00 and CTQ2017-85341-P; Generalitat de Catalunya for project 2017SGR39, Xarxa de Referència en Química Teòrica i Computacional, and ICREA Academia prize 2014 to M.S. and 2019 to A.P

The stereoselectivity and stereospecificity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (–)-(cis)-3-propylindolizidine and (–)-(cis)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

We report a range of highly regioselective openings of [1.1.1]propellane with various allylic zinc halides, as well as zinc enolates of ketones, esters and nitriles. The resulting zincated bicyclopentanes (BCPs) were trapped with a range of electrophiles including acyl chlorides, sulfonothioates, hydroxylamino benzoates, tosyl cyanide as well as aryl and allyl halides, generating highly functionalized BCP‐derivatives. The unusually high regioselectivity of these reactions has been rationalized using DFT calculations. A bioisostere of the synthetic opioid pethidine was prepared in 95 % yield in one step using this method., A wide range of allylic zinc reagents as well as zinc enolates open [1.1.1]propellane to generate zincated bicyclopentanes (BCPs) in a highly regioselective manner. These intermediate zinc reagents are trapped with various electrophiles, giving access to fully functionalized BCPs including a BCP‐analogue of the synthetic opioid pethidine.

The stereoselectivity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity of is rationalized based on theoretical calculations.

Sigmarene, which is a Kekulé hydrocarbon with appreciable singlet biradical character originating from an

Relative rates for the silylation of C4-substituted 1-(naphthalen-1-yl)ethanol substrates with tert-butyldimethylsilyl chloride (TBSCl) in CDCl3 catalyzed by 9-azajulolidine (TCAP) have been measured. Hammett plot analysis of the resulting selectivity data yields two intersecting linear correlations. A small positive slope of rho = +0.09 is observed for donor-substituted alcohols, while silylation rates for acceptor-substituted alcohols correlate best with a slightly larger negative slope (rho = -0.48). The reaction of methanol with TBSCl catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP) has been studied at several different theoretical levels in chloroform solution. Silyl-group transfer between silylated DMAP and methanol occur over an exceedingly flat surface with barely defined minima and transition states. Reaction pathway calculations for the Lewis base and general base catalyzed mechanisms for reaction of TBSCl with C4-substituted 1-(naphthalen-1-yl)ethanol compounds predict a close competition of both pathways.

The mechanism of the oligomerization of aliphatic isocyanates catalyzed by trialkylphosphanes has been studied through low temperature 31 P and 15 N NMR spectroscopy combined with computational chemistry. A revised mechanism is proposed that contains several (spiro)cyclic pentacoordinate phosphorous intermediates. Previously reported spectroscopic data of a transient intermediate has been reevaluated and assigned to a cyclic intermediate containing a P-N bond by experiments with 15 N-labeled isocyanate. 13 C, 15 N, and 31 P NMR shifts that support this assignment have been calculated using quantum chemical methods.

Relative rates for the reaction of secondary alcohols carrying large aromatic moieties with silyl chlorides carrying equally large substituents have been determined in organic solvents., Relative rates for the reaction of secondary alcohols carrying large aromatic moieties with silyl chlorides carrying equally large substituents have been determined in organic solvents. Introducing thoroughly matching pairs of big dispersion energy donor (DED) groups enhanced rate constants up to four times, notably depending on the hydrogen bond donor ability of the solvent. A linear correlation between computed dispersion energy contributions to the stability of the silyl ether products and experimental relative rate constants was found. These results indicate a cooperation between solvophobic effects and DED-groups in the kinetic control of silylation reactions.

In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H2C═CH-Acc, 1) and styrenes (PhCH═CH-Acc, 2) with pyridinium ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloromethyl anion 5. Substitution of the 57 measured second-order rate constants (log k) and the previously reported nucleophile-specific parameters N and sN for 3–5 into the correlation log k = sN(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters sN, N, and E for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of 3–5 at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4 and 5), respectively. The electrophilicity parameters E th...

A set of successive regioselective metalations and functionalizations of the 1,5-naphthyridine scaffold are described. A combination of Zn-, Mg-, and Li-TMP (TMP = 2,2,6,6-tetramethylpiperidyl) bases and the presence or absence of a Lewis acid (BF3 center dot OEt2) allows the introduction of up to three substituents to the 1,5-naphthyridine core. Also, a novel "halogen dance" reaction was discovered upon metalation of an 8-iodo-2,4-trifunctionalized 1,5-naphthyridine allowing a fourth regioselective functionalization. Additionally, reactions leading to key 1,5-naphthyridines for the preparation of OLED materials and a potential antibacterial agent were performed.

The reaction of carboxylic acid chlorides with secondary alcohols carrying either flexible alkyl or rigid aryl substituents was studied through a series of competition experiments. Aliphatic acid chlorides react preferentially with the aryl-substituted alcohols, while acid chlorides derived from aromatic carboxylic acids react with very low selectivity. Catalysis by 9-azajulolidine (TCAP) increases the selectivity strongly, while solvent and temperature effects are only moderate. The size of the alcohol substituents seems to impact selectivities only for rigid aryl substituents, and highest selectivities have been found for 1-(1-pyrenyl)ethanol.

The structures of the covalent Lewis adducts and/or frustrated Lewis pairs derived from 2- and 2,6-substituted pyridines with diaryl (Ar2CH+) and with the more bulky triaryl (Ar3C+) carbenium ions were analyzed by UV-vis and NMR spectroscopy. Thermodynamics (equilibrium constants) and kinetics (rate constants) of the associations of the carbon-centered Lewis acids Ar2CH+ with a series of sterically hindered pyridines were investigated and used for the determination of the Lewis basicities and nucleophilicities, on the basis of the Mayr electrophilicity/nucleophilicity and Lewis acidity/basicity linear free energy relationships. In addition, methyl and benzhydryl cation affinities were computed to elucidate the respective steric and electronic contributions of the substituents to the nitrogen atom Lewis basicity. The influence of the size of the reference carbenium ion on the magnitude of the repulsion induced by the pyridine substituents (Me, tBu in 2- or 2,6-positions) was also analyzed. Cumulated steric repulsion was found to decrease the reactivity of the nitrogen atom by up to 10 orders of magnitude.

Radical chain reactions are commonly initiated through the thermal or photochemical activation of purpose‐built initiators, through photochemical activation of substrates, or through well‐designed redox processes. Where radicals come from in the absence of these initiation strategies is much less obvious and are often assumed to derive from unknown impurities. In this situation, molecule‐induced radical formation (MIRF) reactions should be considered as well‐defined alternative initiation modes. In the most general definition of MIRF reactions, two closed‐shell molecules react to give a radical pair or biradical. The exact nature of this transformation depends on the σ‐ or π‐bonds involved in the MIRF process, and this Minireview specifically focuses on reactions that transform two σ‐bonds into two radicals and a closed‐shell product molecule., Where radicals come from: Molecule‐induced radical formation (MIRF) processes, where one closed‐shell molecule helps another one dissociate, are viable alternatives for simple unimolecular homolytic bond breaking events.

Syntheses of very electron-rich dialkylamino-substituted 2,2':6',2''-terpyridines (TPYs) were adapted to moderate scale preparation without tedious purification of intermediates. The key 4'-bromo-6,6''-dimethyl-2,2':6',2''-terpyridine-4,4''-diyl bisnonaflate is now available in gram quantities. Its nucleophilic aromatic substitution with dimethylamine provided mixtures of 4'-bromo-substituted 4,4''-bis(dimethylamino)-TPY and the tris(dimethylamino)-TPY. The bromo compound was used in a Buchwald-Hartwig amination to provide the tris(dimethylamino)-TPY in excellent yield. The 4'-bromo substituent was reductively removed to furnish the bis(dimethylamino)-TPY. The same sequence of reactions with pyrrolidine as nucleophile leads to the hitherto unknown pyrrolidino-TPYs. Calculations at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level predict very high methyl cation affinities for compounds of this type, with the 4,4',4''-tri(pyrrolidin-1-yl)-TPY being the most Lewis basic TPY synthesized to date. The efficiently prepared electron-rich TPYs should be excellent ligands for many applications.

The accurate description of cis/trans peptide structures is of fundamental relevance for the field of protein modeling and protein structure determination. A comprehensive conformational analysis of dipeptide model Ace-Gly-NMe (1) has been carried out by using a combination of theoretical calculations and experimental ((1) H and (13) C NMR and NOESY) spectroscopic measurements to assess the relevance of cis-peptide conformers. NMR measurements in dimethyl sulfoxide (DMSO) solution and calculations employing a continuum solvation model both point to the extended trans,trans conformer C5_tt as the global minimum. The cis-peptide structures C5_ct and C5_tc, with the N- or C-terminal amide group in cis-conformation, are observed separately and located 13.0±2 kJ mol(-1) higher in energy. This is in close agreement with the theoretical prediction of around 12 kJ mol(-1) in DMSO. The ability of common protein force fields to reproduce the energies of the cis-amide conformers C5_ct and C5_tc in 1 is limited, making these methods unsuitable for the description of cis-peptide structures in protein simulations.