The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for more realistic solvation (RS) simulations, has been used for the direct prediction of pKa constants of a large variety of 64 organic and inorganic acids. A highly significant correlation of r(2) = 0.984 with a standard deviation of only 0.49 between the calculated values of the free energies of dissociation and the experimental pKa values was found, without any special adjustment of the method. Thus, we have a theoretical a priori prediction method for pKa, which has the regression constant and the slope as only adjusted parameters. Such a method can be of great value in many areas of physical chemistry, especially in pharmaceutical and agrochemical industry. To our surprise, the slope of pKa vs ΔGdiss is only 58% of the theoretically expected value of 1/RTln(10). A careful analysis with respect to different contributions as well as a comparison with the work of other authors excludes the possibility that the discrepancy is due to weaknesses of the calculation method. Hence, we must conclude that the experimental pKa scale depends differently on the free energy of dissociation than generally assumed.

BACKGROUNDThe development and commercialisation of new chemical classes of insecticides for efficient crop protection measures against destructive invertebrate pests is of utmost importance to overcome resistance issues and to secure sustainable crop yields. Flupyradifurone introduced here is the first representative of the novel butenolide class of insecticides active against various sucking pests and showing an excellent safety profile.RESULTSThe discovery of flupyradifurone was inspired by the butenolide scaffold in naturally occurring stemofoline. Flupyradifurone acts reversibly as an agonist on insect nicotinic acetylcholine receptors but is structurally different from known agonists, as shown by chemical similarity analysis. It shows a fast action on a broad range of sucking pests, as demonstrated in laboratory bioassays, and exhibits excellent field efficacy on a number of crops with different application methods, including foliar, soil, seed treatment and drip irrigation. It is readily taken up by plants and translocated in the xylem, as demonstrated by phosphor imaging analysis. Flupyradifurone is active on resistant pests, including cotton whiteflies, and is not metabolised by recombinantly expressed CYP6CM1, a cytochrome P450 conferring metabolic resistance to neonicotinoids and pymetrozine.CONCLUSIONThe novel butenolide insecticide flupyradifurone shows unique properties and will become a new tool for integrated pest management around the globe, as demonstrated by its insecticidal, ecotoxicological and safety profile. © 2014 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The COSMO-RS method, originally developed for the prediction of liquid-liquid and liquid-vapor equilibrium constants based on quantum chemical calculations, has been extended to solid compounds by addition of a heuristic expression for the Gibbs free energy of fusion. By this addition, COSMO-RS is now capable of a priori prediction of aqueous solubilities of a wide range of typical neutral drug and pesticide compounds. Only three parameters in the heuristic expression have been fitted on a data set of 150 drug-like compounds. On these data an rms deviation of 0.66 log-units was achieved. Later, the model was tested on a set of 107 pesticides, which have been critically selected based on two experimental data sources and by a crosscheck with an independent HQSAR model. On this data set an rms of 0.61 log-units was achieved, without any adjustments to the structurally extremely diverse pesticides. This result verifies the ability of this extended COSMO-RS to predict aqueous solubilities of drugs and pesticides of almost arbitrary structural classes. The new method is COSMO-RSol.

The graphical unitary group approach has been applied in an efficient implementation of a general multireference configuration interaction (MRCI) method for use with small active molecular orbital spaces in a semiempirical framework. Gradients can be computed analytically for molecular orbitals from a closed-shell or a half-electron open-shell Hartree-Fock calculation. CPU times for single point energy and gradient calculations are reported. The code allows MRCI geometry optimizations of large molecules, as illustrated for the singlet ground state and the four lowest triplet states of fullerene C(76).

The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world's most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery.

The PRINTS database of protein 'fingerprints' is described. Fingerprints comprise sets of motifs excised from conserved regions of sequence alignments, their diagnostic power or potency being refined by iterative database scanning (in this case the OWL composite sequence database). Generally, the motifs do not overlap, but are separated along a sequence, though they may be contiguous in 3-D space. The use of groups of independent, linearly or spatially separate motifs allows particular protein folds and functionalities to be characterized more flexibly and powerfully than conventional single-component patterns or regular expressions. The current version of the database (4.0) contains 150 entries (encoding > 700 motifs), covering a wide range of globular and membrane proteins, modular polypeptides and so on. The growth of the database is influenced by a number of factors, e.g. the use of multiple motifs, the maximization of sequence information through iterative database scanning and the fact that the database searched is a large composite. The information contained within PRINTS is distinct from but complementary to the single consensus expressions stored in the widely used PROSITE dictionary of patterns.

The term vinylogy, which describes a unique property of p systems where the electron density and reactivity is amplified along conjugated bonds, was proposed 75 years ago by Fuson.[1] The principle becomes particularly relevant in the context of the aldol reaction: While metal dienolates often furnish mixtures of a-and g-addition products, [2] the corresponding dienolsilanes react with high selectivity at the remote g position.[3] Asymmetric vinylogous Mukaiyama aldol reactions furnish structural subunits commonly occurring in natural products, as illustrated by the research groups of Carreira, Denmark, Kalesse, and others.[4] Several catalytic, asymmetric versions have been developed over the last few years.[5] However, general and highly stereoselective methods that tolerate a wide range of unactivated substrates are still needed. Moreover, bisvinylogous aldol additions, potentially furnishing a,b,g,d-unsaturated esters in a single step, have to our knowledge not been successfully developed to date.[6]Herein we report asymmetric vinylogous aldol additions, catalyzed by our recently introduced pre-Lewis acidic disulfonimide catalysts 1.[7] We also describe the unprecedented extension of the Mukaiyama aldol addition towards a bisvinylogous e-selective and highly enantioselective variant.Initial computational studies revealed the expected reactivity trends of the extended ketene acetals (Scheme 1). DFT calculations for attack by an electrophile (f À (r)) provided the corresponding condensed Fukui functions (CFF), and the electrostatic potentials (ESP).[8] The data obtained for nucleophiles of type 3 were in line with those previously reported, thus suggesting the reaction occurred preferentially in the g position (a = 0.09, g = 0.14).[3f] Interestingly for nucleophiles of type 4, compounds that have been obtained previously though never studied in terms of their application in aldol additions, [9] the calculations point to nucleophilic attack from the terminal position as well (a = 0.07, g = 0.07, e = 0.11). However, the values for the different positions vary less than for nucleophiles of type 3, possibly suggesting a less distinct selectivity. Furthermore, the nature of the aldehyde should also influence the outcome of the reaction.Despite the advancements in the asymmetric catalysis of vinylogous Mukaiyama aldol reactions, organocatalytic systems proved to be more challenging to establish. Probably the best system to date was reported by Denmark and co-workers, who described the Lewis base activation of Lewis acids by utilizing chiral hexamethylphosphoramide (HMPA) derivatives in combination with SiCl 4 .[10] However, even this method has its limitations, either in scope or reactivity, and requires stoichiometric amounts of the Lewis acid.As a starting point for our experimental work we explored our chiral disulfonimide catalyst 1 in the reaction of 2-naphthaldehyde with crotonate-derived nucleophile 3 a in different solvents at different temperatures. These studies revealed that Et 2 O at À78 8C was optimal ...

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