For the (aut)oxidation of toluene to benzyl hydroperoxide, benzyl alcohol, benzaldehyde, and benzoic acid, the thermochemical profiles for various radical-generating reactions have been compared. A key intermediate in all of these reactions is benzyl hydroperoxide, the heat of formation of which has been estimated by using results from CBS-QB3, G4, and G3B3 calculations. Homolytic OO bond cleavage in this hydroperoxide is strongly endothermic and thus unlikely to contribute significantly to initiation processes. In terms of reaction enthalpies the most favorable initiation process involves bimolecular reaction of benzyl hydroperoxide to yield hydroxy and benzyloxy radicals along with water and benzaldehyde. The reaction enthalpy and free energy of this process is significantly more favorable than those for the unimolecular dissociation of known radical initiators, such as dibenzoylperoxide or dibenzylhyponitrite.

Es wird eine vielseitig einsetzbare Methode zur Herstellung von funktionalisierten 2,2′:6′,2′′-Terpyridinen vorgestellt, bei der die äußeren Pyridinringe über Cyclisierungsreaktionen aufgebaut werden. Die Vorstufen – Bis-β-ketoenamide – werden aus in 4-Position substituierten 2,6-Pyridindicarbonsäuren und Acetylaceton oder dem entsprechenden Enaminoketon hergestellt. Ihre Cyclisierung erfolgt mithilfe von Trifluormethansulfonsäuretrimethylsilylester durch eine zweifache intramolekulare Kondensation. Die Methode bietet einen effizienten Zugang zu 4,4′′-di- und 4,4′,4′′-trifunktionalisierten 6,6′′-Dimethyl-2,2′:6′,2′′-terpyridinen und ermöglicht die Herstellung bislang unbekannter 4,4′′-Bis(dimethylamino)- und 4,4′,4′′-Tris(dimethylamino)terpyridine, für die extrem hohe Lewis-Basizitäten berechnet wurden.

A versatile method for the synthesis of functionalized 2,2′:6′,2′′-terpyridines by assembly of the terminal pyridine rings is presented. The cyclization precursors—bis-β-ketoenamides—are prepared from 4-substituted 2,6-pyridinedicarboxylic acids and acetylacetone or its corresponding enamino ketone. Treatment with trimethylsilyl trifluoromethanesulfonate induces a twofold intramolecular condensation providing an efficient access to 4,4′′-di- and 4,4′,4′′-trifunctionalized 6,6′′-dimethyl-2,2′:6′,2′′-terpyridines. Using this method, hitherto unknown 4,4′′-bis(dimethylamino)- and 4,4′,4′′-tris(dimethylamino)terpyridines have been prepared that show remarkably high calculated Lewis basicities.

The influence of the length of alkyl substituents on various kinetic, thermodynamic, and spectroscopic properties of 4-(dialkylamino)pyridines has been determined by using a combination of experimental and theoretical methods. The chain-length dependence of these properties has subsequently been analyzed by using a quantitative model for through-bond inductive effects.

New heterocyclic derivatives of 9-azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl-cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three-component quantitative structure–activity relationship (QSAR) model is, however, highly predictive.

The aza-Morita-Baylis–Hillman (aza-MBH) reaction has been studied in a variety of solvents, a selection of imine substrates and with various combinations of PPh₃ and para-nitrophenol as the catalyst system. The measured kinetic data indicates that the effects of solvent and protic co-catalyst are strongly interdependent. These results are most easily reconciled with a mechanistic model involving the reversible protonation of zwitterionic intermediates in the catalytic cycle, which is also supported by ³¹P NMR spectroscopy and quantum chemical studies.

We have developed a practical stereoretentive iodine/lithium-exchange process that allows the stereodefined preparation of cis- and trans-cycloalkyllithium compounds from their corresponding stereodefined iodides. Quenching with electrophiles offers stereospecific access to both cis- (up to 96 % cis) and trans-cycloalkyl derivatives (up to 99 % trans). A detailed study of the thermodynamic stabilities, stereochemical behavior, and reactivities of axially and equatorially substituted cyclohexyllithium reagents is reported. Ab initio calculations demonstrate that the formation of oligomeric cyclohexyllithium structures is pivotal for explaining the observed stereochemical preference.

A larger number of catalysts based on the 3,4-diaminopyridine motif have been synthesized and tested in the acetylation of tertiary alcohols. The rate data determined in these reactions together with results from previous studies were compared with theoretical data describing the ground and transition state properties of the respective catalysts. Surprisingly, it was found that the ground state data provided a better overall description of the catalytic activity than the transition state models. The latter approach clearly showed the presence of separate correlations for catalysts with small, but significant topological differences. Full analysis of the potential energy surface revealed that this owes to changes in the rate limiting step in the catalytic cycle.

S-Adenosylmethionine (SAM) plays an essential role in a variety of enzyme-mediated radical reactions. One-electron reduction of SAM is currently believed to generate the C5′-desoxyadenosyl radical, which subsequently abstracts a hydrogen atom from the actual substrate in a catalytic or a non-catalytic fashion. Using a combination of theoretical and experimental bond dissociation energy (BDE) data, the energetics of these radical processes have now been quantified. SAM-derived radicals are found to react with their respective substrates in an exothermic fashion in enzymes using SAM in a stoichiometric (non-catalytic) way. In contrast, the catalytic use of SAM appears to be linked to a sequence of moderately endothermic and exothermic reaction steps. The use of SAM in spore photoproduct lyase (SPL) appears to fit neither of these general categories and appears to constitute the first example of a SAM-initiated radical reaction propagated independently of the cofactor.

The copper-catalyzed Huisgen reaction between azides and alkynes was utilized to covalently attach derivatives of 4-(dimethylamino)pyridine (DMAP) to a polystyrene resin (PS) support. The catalytic potential of these constructs as determined in acylation and aza-Morita–Baylis–Hillman reactions far exceeds that of commercially available DMAP-PS resins and is fully competitive with DMAP in homogeneous solution.

The conformational space of dipeptide models derived from glycine, alanine, phenylalanine, proline, tyrosine, and cysteine has been searched extensively and compared with the corresponding C_α dipeptide radicals at the G3(MP2)-RAD level of theory. The results indicate that the (least-substituted) glycine dipeptide radical is the thermochemically most stable of these species. Analysis of the structural parameters indicates that this is due to repulsive interactions between the C_α substituents and peptide units in the radical. A comparison of the conformational preferences of dipeptide radicals and their closed-shell parents also indicates that radical stability is a strongly conformation-dependent property.

Methyl cation affinity (MCA) values have been calculated for a variety of phosphanes at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory. The analysis of MCA values for tri-alkyl phosphanes reveals that substituent effects are additive for unbranched and cyclic alkyl substituents, and (with some modification) also for most of the branched alkyl substituents. Copyright © 2010 John Wiley & Sons, Ltd.

Radical stabilization energies (RSE)s have been calculated for a variety of boryl radicals complexed to Lewis bases at the G3(MP2)-RAD level of theory. These are referenced to the BH bond dissociation energy (BDE) in BH₃ determined at W4.3 level. High RSE values (and thus low BDE(BH) values) have been found for borane complexes of a variety of five- and six-membered ring heterocycles. Variations of RSE values have been correlated with the strength of Lewis acid–Lewis base complex formation at the boryl radical stage. The analysis of charge- and spin-density distributions shows that spin delocalization in the boryl radical complexes constitutes one of the mechanisms of radical stabilization.

We have prepared trans- (1) and cis-octachloro-1,3,5-hexatriene (2) by known routes and studied their thermal behavior experimentally and theoretically by ab initio calculations. The three double bonds in 1 and 2 are completely decoupled due to steric hindrance by the eight Cls, as indicated by calculations as well as the single-crystal X-ray structure of 1. The cis isomer 2 can be isomerized to the trans isomer 1 by heating it to 220–250 °C either neat or dissolved in high-boiling solvents, leading to a roughly 2:1 mixture of trans and cis isomers. Calculations at several different levels of theory predict 1 and 2 to be isoenergetic within 2 kJ mol^–1. Unimolecular cis/trans isomerization is predicted to occur through an unusual vinylcyclobutene intermediate 7, whose formation faces a barrier of more than 150 kJ mol^–1, but whose stability is comparable to that of 1 and 2. The isomerization rate is strongly enhanced by the addition of small amounts of Br₂ or Cl₂ or by 3 and can be explained by a radical-induced isomerization mechanism. The heating of trienes 1 and 2 to 250 °C leads to cyclization, yielding 71 % of the cyclopentene isomer 3. Compound 3 can be dechlorinated by treatment with copper powder to give fulvene derivative 4. Using flash vacuum pyrolysis, the thermal conversion of trienes 1 and 2 to hexachlorobenzene (5) occurs at higher temperatures between 600–1000 °C, likely via perchlorinated 1,3-cyclohexadiene (6) as an intermediate. The elimination of molecular Cl₂ from 3 and 6 requires very high activitation energies in agreement with calculations.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The combined use of high concentration conditions, auxiliary bases, and new catalysts allows for the rapid synthesis of sterically hindered carboxylic acid esters at room temperature. Mechanistic analysis indicates the intermediate formation of acid anhydrides and subsequent rate-limiting transformation to the ester products.

The tautomers I–IV of the marine metabolite 3-amino-1-(2-aminoimidazol-4-yl)prop-1-ene (1) were previously suggested to have rather similar stabilities.1,2 Through a series of DFT and ab initio calculations, their relative stabilities were investigated in both the gas phase and in water, and also compared to their Z-isomers V–VIII. The tautomers I and III have almost identical stability in the gas phase and in water. The Z-isomer VII is more stable than other tautomers in the gas phase and quite competitive with I and III in water. The tautomers II and IV are much less stable and unlikely to coexist in equilibrium with I and III. The calculated pK_a of 1-H⁺ of +10.9 suggests that 1 is fully protonated even under mildly acidic conditions. Protonation decreases the stability difference between the most stable tautomer III and the less stable tautomer IV.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)