Radical fluorination has been known for a long time, but synthetic applications were severely limited by the hazardous nature of the first generation of reagents such as F
and the strongly ...electrophilic nature of the second generation of reagents such as N-fluorobenzenesulfonimide (NFSI) and Selecfluor
. Here, we report the preparation, use and properties of N-fluoro-N-arylsulfonamides (NFASs), a class of fluorinating reagents suitable for radical fluorination under mild conditions. Their N-F bond dissociation energies (BDE) are 30-45 kJ mol
lower than the N-F BDE of the reagents of the second generation. This favors clean radical fluorination processes over undesired side reactions. The utility of NFASs is demonstrated by a metal-free radical hydrofluorination of alkenes including an efficient remote C-H fluorination via a 1,5-hydrogen atom transfer. NFASs have the potential to become the reagents of choice in many radical fluorination processes.
In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H2CCH-Acc, 1) and styrenes ...(PhCHCH-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 s N for 3–5 into the correlation log k = s N(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters s N, 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 thus determined can be used to calculate the rates of the reactions of Michael acceptors 1 and 2 with any nucleophile of known N and s N. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with the LUMO energies and with Parr’s electrophilicity index ω, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities.
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.
The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to ...octahydro‐1H‐pyrrolo1,2‐aazepine, 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‐pyrrolo1,2‐aazepine. 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 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 (1H and 13C 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.
A twisted question: The conformational preferences of Ace‐Gly‐NMe is reported, with particular emphasis on the detection and characterization of sparsely populated cis‐peptide containing conformers by using advanced NMR techniques and theoretical calculations (see figure).
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 Cα 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 Cα radicals mainly depends on the preferred orientation of the charge-carrying side chain.
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.
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 = s N(N + E) (eq 1) for determining the nucleophile-specific parameters N and s N 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 s N of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may also be applied to predict the rates of highly asynchronous cycloadditions. Weaker electrophiles, e.g., methyl acrylate, react faster than calculated from E, N, and s N, and the ratio of experimental to calculated rate constants was suggested to be a measure for the energy of concert ΔG ‡ concert = RT ln(k 2 exptl/k 2 calcd). Quantum chemical calculations indicated that all products isolated from the reactions of the aryldiazomethanes with acceptor substituted ethylenes (Δ2-pyrazolines, cyclopropanes, and substituted ethylenes) arise from intermediate Δ1-pyrazolines, which are formed through concerted 1,3-dipolar cycloadditions with transition states, in which the C–N bond formation lags behind the C–C bond formation. The Gibbs activation energies for these cycloadditions calculated at the PCM(UA0,CH2Cl2)/(U)B3LYP-D3/6-31+G(d,p) level of theory agree within 5 kJ mol–1 with the experimental numbers showing the suitability of the applied polarizable continuum model (PCM) for considering solvation.
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.
Chelation is key: By chelating the diazine pyridazine with a bidentate diboroanthracene Lewis acid, a rare C4‐metalation has been achieved. Additionally, a highly regioselective ortho‐metalation was obtained when the monodentate Lewis acid BF3⋅OEt2 was employed. A rationalization of the regioselectivity was possible using the calculated pKa values of the pyridazine/Lewis acid complexes.
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.
Insights into the first step of R
3
P-catalysed Lu cycloadditions are given by the kinetics of phosphine additions to alkyl allenoates.
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