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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 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 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.

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.

Persulfurated arenes are a fascinating class of functional molecules with a wide range of potential applications. Ferrocenes are also a multifaceted class of aromatic compounds that can easily be finetuned for an enormous variety of desired properties. A combination of both substance classes might yield an even wider field of applications. Herein, we describe the synthesis of two ferrocenes with one persulfurated cyclopentadienyl ring [C5(SR)5], with R=Me or Ph, together with their crystal structures, optical, and electrochemical properties. Both crystal structures show significant intramolecular sulfur‐iron interactions as well as weak intermolecular sulfur– contacts. Cyclovoltammetry of the [C5(SPh)5] compound shows a high oxidation potential of 651 mV vs. FcH/FcH+., Metalation: Ferrocenes with one persulfurated cyclopentadienyl ring [C5(SR)5]FeCp have been prepared from monobromoferrocene by a sequence of deprotonations and electrophilic thiolations. In their crystal structures, all cyclopentadienyl rings have their thiolate substituents in axial positions away from the iron atom. Cyclovoltammetric studies show that the sulfur substituents lead to significantly enhanced oxidative stability (see figure).

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.

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...

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.

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.

Kinetics of the reactions of aryldiazomethanes (ArCHN2) with benzhydrylium ions (Ar2CH+) have been measured photometrically in dichloromethane. The resulting second-order rate constants correlate linearly with the electrophilicities E of the benzhydrylium ions which allowed us to use the correlation lg k = sN(N + E) (eq 1) for determining the nucleophile-specific parameters N and sN of the diazo compounds. UV–vis spectroscopy was analogously employed to measure the rates of the 1,3-dipolar cycloadditions of these aryldiazomethanes with acceptor-substituted ethylenes of known electrophilicities E. The measured rate constants for the reactions of the diazoalkanes with highly electrophilic Michael acceptors (E > −11, for example 2-benzylidene Meldrum’s acid or 1,1-bis(phenylsulfonyl)ethylene) agreed with those calculated by eq 1 from the one-bond nucleophilicities N and sN of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may al...

We explored the influence of external electric fields (EEFs) on the stability of a glycine dipeptide model radical using high-level quantum chemical methods. Remotely located ions (Cl-/Na+) are used to implement EEF effects. The effects of these ions are reproduced using background point charges and oriented EEFs. Remote charges as far as 900 pm from the C-alpha radical center can be significantly stabilizing or destabilizing as a function of their relative orientation. The magnitude of these effects is also strongly dependent on the distance between the radical center and the charge location. After examining the strengths and weaknesses of some frequently used quantum mechanics methods in describing these effects properly, a comparison is made on the stability of dipeptide radicals bearing protonable or deprotonable side chains. In this group, the stability of the respective C-alpha radicals mainly depends on the preferred orientation of the charge-carrying side chain.

Simple monocyclic diketopiperazine (DKP)-derived alkoxyamines exhibit unprecedented activation of a remote C-O bond for homolysis by amide distortion. The combination of strain-release-driven amide planarization and the persistent radical effect (PRE) enables a unique, irreversible, and quantitative trans→cis isomerization under much milder conditions than typically observed for such homolysis-limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both the amino acid side chains and the substituents at the DKP nitrogen atoms. Homolysis rate constants are determined, and they significantly differ for both the labile trans diastereomers and the stable cis diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans diastereomers and thermodynamic cis diastereomers are investigated in the solid state and in solution. X-ray crystallographic analysis and computational studies indicate substantial distortion of the amide bond from planarity in the trans-alkoxyamines, and this is believed to be the cause for the facile and quantitative isomerization. Thus, these amino-acid-derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, and this allows controlled switching of configurations and configurational cycling.

The kinetics of epoxide formation by Darzens condensation of aliphatic ketones 1 with arylsulfonyl-substituted chloromethyl anions 2 (ArSO2CHCl–) have been determined photometrically in DMSO solution at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions 4, which subsequently cyclize with formation of the oxiranes 3. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins 4-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins 4-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions 2, provided the relative rates of backward (k–CC) and ring closure (krc) reactions of the intermediates. Combination of the kinetic data (k2exptl) with the splitting ratio (k–CC/krc) gave the second-order rate constants kCC for the attack of the carbanions 2 at the ketones 1. T...

Protein-water interactions have widespread effects on protein structure and dynamics. As such, the function of many biomacromolecules can be directly related to the presence and exchange of water molecules. While the presence of structural water sites can be easily detected by X-ray crystallography, the dynamics within functional water-protein network architectures is largely elusive. Here we use solid-state NMR relaxation dispersion measurements with a focus on those active-site residues in the enzyme human carbonic anhydrase II (hCAII) that constitute the evolutionarily conserved water pocket, key for CAs' enzymatic catalysis. Together with chemical shifts, peak broadening, and results of molecular dynamics (MD) and DFT shift calculations, the relaxation dispersion data suggest the presence of a widespread fast μs-time-scale dynamics in the pocket throughout the protein-water network. This process is abrogated in the presence of an inhibitor which partially disrupts the network. The time scale of the protein-water pocket motion coincides both with the estimated residence time of Zn-bound water/OH- in the pocket showing the longest lifetimes in earlier magnetic relaxation dispersion experiments as well as with the rate-limiting step of catalytic turnover. As such, the reorganization of the water pocket:enzyme architecture might constitute an element of importance for enzymatic activity of this and possibly other proteins.