The weakly coordinated triflate complex [(P^P)Pd(OTf)](+)(OTf)(-) (1) (P^P = 1,3-bis(di-tert-butylphosphino)propane) is a suitable reactive precursor for mechanistic studies of the isomerizing alkoxcarbonylation of methyl oleate. Addition of CH(3)OH or CD(3)OD to 1 forms the hydride species [(P^P)PdH(CH(3)OH)](+)(OTf)(-) (2-CH(3)OH) or the deuteride [(P^P)PdD(CD(3)OD)](+)(OTf)(-) (2(D)-CD(3)OD), respectively. Further reaction with pyridine cleanly affords the stable and isolable hydride [(P^P)PdH(pyridine)](+)(OTf)(-) (2-pyr). This complex yields the hydride fragment free of methanol by abstraction of pyridine with BF(3)·OEt(2), and thus provides an entry to mechanistic observations including intermediates reactive toward methanol. Exposure of methyl oleate (100 equiv) to 2(D)-CD(3)OD resulted in rapid isomerization to the thermodynamic isomer distribution, 94.3% of internal olefins, 5.5% of α,β-unsaturated ester and <0.2% of terminal olefin. Reaction of 2-pyr/BF(3)·OEt(2) with a stoichiometric amount of 1-(13)C-labeled 1-octene at -80 °C yields a 50:50 mixture of the linear alkyls [(P^P)Pd(13)CH(2)(CH(2))(6)CH(3)](+) and [(P^P)PdCH(2)(CH(2))(6)(13)CH(3)](+) (4a and 4b). Further reaction with (13)CO yields the linear acyls [(P^P)Pd(13)C(═O)(12/13)CH(2)(CH(2))(6)(12/13)CH(3)(L)](+) (5-L; L = solvent or (13)CO). Reaction of 2-pyr/BF(3)·OEt(2) with a stoichiometric amount of methyl oleate at -80 °C also resulted in fast isomerization to form a linear alkyl species [(P^P)PdCH(2)(CH(2))(16)C(═O)OCH(3)](+) (6) and a branched alkyl stabilized by coordination of the ester carbonyl group as a four membered chelate [(P^P)PdCH{(CH(2))(15)CH(3)}C(═O)OCH(3)](+) (7). Addition of carbon monoxide (2.5 equiv) at -80 °C resulted in insertion to form the linear acyl carbonyl [(P^P)PdC(═O)(CH(2))(17)C(═O)OCH(3)(CO)](+) (8-CO) and the five-membered chelate [(P^P)PdC(═O)CH{(CH(2))(15)CH(3)}C(═O)OCH(3)](+) (9). Exposure of 8-CO and 9 to (13)CO at -50 °C results in gradual incorporation of the (13)C label. Reversibility of 7 + CO ⇄ 9 is also evidenced by ΔG = -2.9 kcal mol(-1) and ΔG(‡) = 12.5 kcal mol(-1) from DFT studies. Addition of methanol at -80 °C results in methanolysis of 8-L (L = solvent) to form the linear diester, 1,19-dimethylnonadecandioate, whereas 9 does not react and no branched diester is observed. DFT yields a barrier for methanolysis of ΔG(‡) = 29.7 kcal mol(-1) for the linear (8) vs ΔG(‡) = 37.7 kcal mol(-1) for the branched species (9).

It has been demonstrated that the fragmentation scheme of our adjustable density matrix assembler (ADMA) approach for the quantum chemical calculations of very large systems is well-suited to calculate NMR chemical shifts of proteins [Frank et al. Proteins 2011, 79, 2189–2202]. The systematic investigation performed here on the influences of the level of theory, basis set size, inclusion or exclusion of an implicit solvent model, and the use of partial charges to describe additional parts of the macromolecule on the accuracy of NMR chemical shifts demonstrates that using a valence triple-ζ basis set leads to large improvement compared to the results given in the previous publication. Additionally, moving from the B3LYP to the mPW1PW91 density functional and including partial charges and implicit solvents gave the best results with mean absolute errors of 0.44 ppm for hydrogen atoms excluding HN atoms and between 1.53 and 3.44 ppm for carbon atoms depending on the size and also on the accuracy of the protein structure. Polar hydrogen and nitrogen atoms are more difficult to predict. For the first, explicit hydrogen bonds to the solvents need to be included and, for the latter, going beyond DFT to post-Hartree–Fock methods like MP2 is probably required. Even if empirical methods like SHIFTX+ show similar performance, our calculations give for the first time very reliable chemical shifts that can also be used for complexes of proteins with small-molecule ligands or DNA/RNA. Therefore, taking advantage of its ab initio nature, our approach opens new fields of application that would otherwise be largely inaccessible due to insufficient availability of data for empirical parametrization.

Fragment-based quantum chemical calculations are able to accurately calculate NMR chemical shifts even for very large molecules like proteins. But even with systematic optimization of the level of theory and basis sets as well as the use of implicit solvents models, some nuclei like polar protons and nitrogens suffer from poor predictions. Two properties of the real system, strongly influencing the experimental chemical shifts but almost always neglected in the calculations, will be discussed here in great detail: (1) conformational averaging and (2) interactions with first-shell solvent molecules. Classical molecular dynamics simulations in explicit water were carried out for obtaining a representative ensemble including the arrangement of neighboring solvent molecules, which was then subjected to quantum chemical calculations. We could demonstrate with the small test system N-methyl acetamide (NMA) that the calculated chemical shifts show immense variations of up to 6 ppm and 50 ppm for protons and nitrogens, respectively, depending on the snapshot taken from a classical molecular dynamics simulation. Applying the same approach to the HA2 domain of the influenza virus glycoprotein hemagglutinin, a 32-amino-acid-long polypeptide, and comparing averaged values to the experiment, chemical shifts of nonpolar protons and carbon atoms in proteins were calculated with unprecedented accuracy. Additionally, the mean absolute error could be reduced by a factor of 2.43 for polar protons, and reasonable correlations were obtained for nitrogen and carbonyl carbon in contrast to all other studies published so far.

Despite the many protein structures solved successfully by nuclear magnetic resonance (NMR) spectroscopy, quality control of NMR structures is still by far not as well established and standardized as in crystallography. Therefore, there is still the need for new, independent, and unbiased evaluation tools to identify problematic parts and in the best case also to give guidelines that how to fix them. We present here, quantum chemical calculations of NMR chemical shifts for many proteins based on our fragment-based quantum chemical method: the adjustable density matrix assembler (ADMA). These results show that (13)C chemical shifts of reasonable accuracy can be obtained that can already provide a powerful measure for the structure validation. (1)H and even more (15)N chemical shifts deviate more strongly from experiment due to the insufficient treatment of solvent effects and conformational averaging.

The Ni(II) complexes [(N--O)Ni(H)(PMe(3))] (1) and [(N--O)Ni(CH(2)CH(3))(dmso)] (3) (NwedgeO = kappa(2)-{(2,6-(3,5-(F(3)C)(2)C(6)H(3))(2)C(6)H(3))-N=C(H)-(3,5-I(2)-2-O-C(6)H(2))}) were found to be well-defined model compounds to study the reactivity of polymerization active neutral Ni(II) species toward polar vinyl monomers. Methyl acrylate (MA) insertion into the Ni(II)-hydride bond of 1 was monitored at T >or= -40 degrees C by NMR spectroscopy. 2,1-Insertion yields the functionalized Ni(II) alkyl complex [(N--O)Ni(C(alpha)H(CH(3))C(beta)(O)OCH(3))(PMe(3))] (4). Low-temperature 2D ROESY data indicate a weak Ni(II)...O=C(beta) interaction in 4. This is supported by ab initio calculations at the gradient-corrected DFT (BP86/LACPV*) level of theory. Exposure of 1 to equal amounts of MA and ethylene afforded 4 and the Ni(II) ethyl complex 7 in a 9:1 ratio, which indicates that MA and ethylene effectively compete with each other for coordination and insertion. NMR spectroscopic monitoring revealed that 4 is stable in the absence of residual 1 at low temperatures but is subject to rapid bimolecular elimination of the functionalized alkyl moiety in the presence of free Ni(II) hydride species even at T = -40 degrees C. Isomerization into the 1,2-MA-insertion product was observed at T = 25 degrees C but occurred slowly compared to decomposition, which occurs at 0 degrees C by reaction of 4 with Ni(II) hydride formed by beta-elimination from 4 itself at this temperature. Exposure of the higher Ni(II) alkyl complex 3 to MA in the presence of excess ethylene results in the immediate formation of methyl pentanoate as the ultimate decomposition product. Functionalized Ni(II) alkyl species formed from 2,1-insertion of MA into the metal-carbon bond of higher Ni(II) alkyls are subject to rapid hydrolysis in the presence of trace amounts of water in the reaction medium, which contrasts the stability of nonfunctionalized Ni(II) alkyls toward water. Exposure of 1 to vinyl acetate (VA) affords the kinetic 1,2-insertion product [(NwedgeO)Ni(CH(2)CH(2)OC(gamma')(O)CH(3))(PMe(3))] (5) at temperatures T >or= -10 degrees C, which rearranges into the thermodynamically favored 2,1-insertion product [(N--O)Ni(CH(CH(3))OC(O)CH(3))(PMe(3))] (6). NMR data and ab initio calculations suggest a Ni(II)...O=C(gamma') interaction in 6. 5 decomposes via beta-acetate elimination to yield ethylene and Ni(II) acetate species. Notably, VA does not undergo observable nickel-carbon bond insertion with 3, but reacted with Ni(II) hydride species in equilibrium with 3 to yield 5* which is subject to rapid decomposition via beta-acetate elimination.