A DFT theoretical analysis of aldehyde condensation pathways onto methyllithium, lithium dimethylamide, and their aggregates

A DFT analysis of the condensation of monomeric methyllithium and lithium dimethylamide (LMA), as well as their homo and hetero dimers, on formaldehyde and acetaldehyde is reported. A stable complex, exhibiting a directional interaction between a lone pair of the oxygen on the aldehyde and a lithium, is first found. At this stage, the aldehyde carbonyl and the Li-X (X = C or N) bonds lie in the same plane. To proceed, the condensation reaction has to go through a transition state that mainly consists of a rotation of the aldehyde plane, placing it perpendicular to the C-C or C-N forming bond. The reaction then leads, in a strongly exothermic final step, to the addition product that is a lithium alcoholate or alpha-amino alcoholate, associating into an hetero-aggregate with the remaining moiety of the initial dimer. From the relative heights of the activation barriers, it appears that, for the heterodimer MeLi-LMA, the formation of the C-N bond should be kinetically favored over the C-C one, while the lithium ethylate resulting from the C-C binding is the thermodynamic product. A decomposition of the activation energy barriers has been carried out in order to determine the physicochemical forces responsible for the variation of the condensation activation barriers with the structure of the final species formed. The results obtained are discussed in relation with corresponding experimental data.

Theoretical Investigations of the Influence of Pressure on the Selectivity of the Michael Addition of Diphenylmethaneamine to Stereogenic Crotonates.

SIBFA (sum of interactions between fragments ab initio computed) molecular mechanics systematics has been modified to take into account the effect of pressure on intra- and intermolecular energies. The van der Waals radii are related to the pressure, using Bridgman results on the variation of crystal volume, on one hand, and the relation between the volume of an atom and its van der Waals radius on the other. This procedure produces a decrease of the volume of the systems considered. The modified systematics is used for the study of the conformation at 1 atm and 15 kbar of two stereogenic crotonates and of the complexes formed by these two molecules with the diphenylmethaneamine and the three solvent molecules present in the experiment. The results obtained show that in the case of NMECC 1a the diastereoselectivity induced by high pressure and by the presence of methanol proceeds from an important stabilization of the pro-R reactive complex in which the crotonate has a stacked-transoid conformation. This stabilization is mainly due to intermolecular interactions. In the case of the second crotonate considered, NMCC 1b, our results indicate that pressure induces a stabilization of the pro-R and pro-S complexes having the axial conformation for which the reaction exhibits little diastereoselectivity in qualitative agreement with experimental data. This study tends to show that it is possible to account theoretically for the influence of pressure on molecular conformation and/or complex structure, using a molecular mechanics method that is able to take into account the variation of volumes of the different entities present in the system studied.

Does the Mode of Dioxygen Binding to Dinuclear Copper Complexes Depend on the Spectator Nitrogen-Containing Ligands? An ab Initio Theoretical Study.

Ab initio two-determinants GVB computations (required to get the appropriate representation of the lowest singlet states of such systems) have been carried out for (Cu(+)(NH(3))(n)())(2)-O(2) (n = 0-3) and [Cu(2)(&mgr;-pydz)(2)(cnge)(2)](2+)-O(2). Different dioxygen binding modes (ranging from perpendicular to parallel with respect to the Cu-Cu direction) on these complexes have been examined. The results obtained show unambiguously that the parallel arrangements are always the less stable ones. In the especially important case of (Cu(+)(NH(3))(3))(2)-O(2) complexes, both staggered and eclipsed conformations have been considered. They are found almost isoenergetic, and the optimized geometrical parameters are, for a perpendicular O(2) binding onto a staggered complex, in fine agreement with corresponding experimental data obtained from either oxyhemocyanin or its synthetic models. In the case of a (Cu(+)(NH(3))(4))(2)-O(2) complex, taken as a model for Karlin's [{(TMPA)Cu}(2)-O(2)](2+) complex, the computations tend to show that the experimental end-on (trans &mgr;-1,2) O(2) binding is due to the presence of four nitrogens in the copper's coordination shell. Regarding the complexes with [Cu(2)(&mgr;-pydz)(2)(cnge)(2)](2+), the results indicate that the dioxygen binding mode remains perpendicular even if the fixation of a third pyridazine is known to occur in a parallel manner on this complex.

Theoretical study of oxyhemocyanin active site: a possible insight on the first step of phenol oxidation by tyrosinase.

Extended Huckel theory calculations have been carried out on a model of the oxyhemocyanin active site that includes six imidazoles, the two copper cations, and a dioxygen molecule. The results obtained for the very likely mu-eta 2:eta 2 arrangement of the dioxygen molecule show that the most favorable orientation of O2 is such that the two long Cu-N coordination bonds are perpendicular to the plane formed by the two metal atoms and O2. This arrangement leads to pentacoordinated coppers with a distorted square pyramidal geometry. The molecular electrostatic potential maps of the complexes exhibit a potential well located close to the peroxo anion midbond. The dependence of the energy and of the molecular electrostatic maps on the precise orientation and location of the imidazole rings has been investigated. These results, which show the important role played by the third remote imidazole ligand, are discussed in relation with the first step of tyrosinase-mediated phenol oxidation.

Theoretical variation of the H alpha chemical shift in acetyl-glycyl-N-methylamide and oligoglycines with molecular conformation and environment.

The sum of the magnetic anisotropy and polarization contributions to the magnetic shielding constants of the alpha protons is calculated as a function of the torsion angles about the NC alpha (phi) and C alpha C' (psi) bonds of the dipeptide. The results show that the polarization or electric field effect is several fold larger than the magnetic anisotropy contribution. The calculated variations are large enough to account for the spread of the values measured for these protons in peptides and proteins. The results obtained for polyglycine alpha helices and antiparallel beta sheets are discussed in relation with molecular conformation and environmental effects on the one hand and experimental data on the other.

A theoretical study of Zn++ interacting with models of ligands present at the thermolysin active site.

The binding energy and the geometrical arrangements of the complexes formed by the zinc dication with OH-, one, four, five or six water molecules, SH-, H2S, formic acid, the formate anion, imidazole, its anion and formamide are calculated using the MNDO method. The comparison of the results obtained with those of ab initio computations on the same complexes induced us to propose for Zn++ a set of parameters different from the one determined by Dewar for the neutral metal atom. Using the two MNDO parametrizations, similar calculations are carried out for Zn++ interacting with two molecules of 2-aminoethanethiol and with models of the four ligands which are present at the thermolysin active site, in order to evaluate the possibilities and limitations of this semiempirical method for theoretical studies concerning zinc metalloenzymes. In the last case, the results obtained suggest that, in the crystal state, the water molecule could be deprotonated. This finding is discussed in relation with the mechanism of action of the enzyme which has been proposed.

Nuclear magnetic spectra of self complementary decanucleotides in solution; base sequence effect on the chemical shifts of nonexchangeable protons.

The aim of this study was to attempt to determine the extent to which the chemical shifts of the nonexchangeable base protons of a DNA helix depend upon the base sequence. We measured the proton NMR spectra of twelve decadeoxynucleotides in order to carry out a "statistical" treatment. In the helices, the chemical shifts were found to be determined within +/- 0.04 ppm, largely by the nearest neighbor residues on the 5'-side, and to a smaller extent by the residue on the 3'-side. The theoretical chemical shift calculations reproduced very well the polymerization shifts measured for H2 protons of adenosines if the electrostatic field effect was taken into account. A fair agreement was also obtained for H8 protons of the adenosine and guanosine residues. However, theory underestimates the polarization effects of the base protons of cytidine. This discrepancy suggests that the conformation of this residue is different in the mononucleotides relative to double helices.

Ab initio quantum mechanical calculations of the variation of the 1H and 13C nuclear magnetic shielding constants in proline as a function of the angle psi.

The variation of the nuclear magnetic shielding constant of the different protons and carbons of trans HCO-L-Pro-NH2 with the value of the angle psi is calculated by a non-empirical method for three conformations of the proline ring. The results concerning the CH protons show that the chemical shift of the alpha, beta and gamma endo hydrogens can vary by more than 1 ppm when psi goes from -30 degrees to 180 degrees. The theoretical variation of the chemical shift difference between alpha and gamma or beta and gamma carbons is found to be sensitive to the puckering of the proline ring. For the second of these differences the theoretical results are in agreement with Siemion's relation only for a limited range of molecular conformations. Additional calculations show that the variations of the proton shifts with the value of psi are due to the magnetic anisotropy of the proline carbonyl group and to the polarization of the CH bonds by the multipolar charge distribution carried by this carbonyl. The results are discussed in relation to experiment and the possibility of using 1H and 13C chemical shifts for the determination of the value of the torsion angle about the C alpha C' bond.

Ab-initio quantum mechanical calculations of NMR chemical shifts in nucleic acids constituents. III. Chemical shift variations due to base stacking.

Ab inito computations of the different contributions to chemical shift variations due to intra and interstrand stacking are reported for the GC, CG, AT and TA sequences of a B DNA helix. The results obtained for the non hydrogen atoms of the GC stacks show that the chemical shift variations are mainly due to the polarization contribution, the term which decreases slowly with the intermolecular distance. Because of the weaker polarity of adenine and thymine the geometric and polarization contributions are of closer absolute magnitude for the non hydrogen atoms of the intrastrand stacks but the polarization term is the determining contribution in the corresponding interstrand stacks. For the protons which undergo smaller shifts due to the polarization (or electric field effects) the role of the geometric contribution is more important and is even the leading one for the hydrogens of cytosine and thymine in the case of intrastrand stacking. The charge transfer plus exchange term has a non negligeable value for a limited number of cases corresponding to the shortest intermolecular interatomic distances. These results are discussed in relation with the qualitative differences observed between the proton and carbon spectra of dinucleotides and B-DNA duplexes.

Ab-inito quantum mechanical calculations of NMR chemical shifts in nucleic acids constituents. II. Conformational dependence of the 1H and 13C chemical shifts in the ribose.

The magnetic shielding constant of the different 13C and 1H nuclei of a deoxyribose are calculated for the C2' endo and C3' endo puckerings of the furanose ring as a function of the conformation about the C4'C5' bond. For the carbons the calculated variations are of several ppm, the C3' endo puckering corresponding in most cases to a larger shielding than the C2' endo one. For the protons the calculated variations of chemical shifts are all smaller than 1.3 ppm, that is of the order of magnitude of the variation of the geometrical shielding produced on these protons by the other units of a DNA double helix, with a change of the overall structure of the helix. The computations carried out on the deoxyribose-3' and 5' phosphates for several conformations of the phosphate group tend to show that the changes of conformation of the charged group of atoms produce chemical shift variations smaller than the two conformational parameters of the deoxyribose itself. The calculations carried out for a ribose do give the general features of the differences between the carbon and proton spectra of deoxynucleosides and nucleosides. The comparison of the measured and calculated phosphorylation shifts tend to show that the counterion contributes significantly, for some nuclei of the deoxyribose, to the shifts measured. The calculated magnitude of this polarization effect on carbon shifts suggests a tentative qualitative interpretation of carbon spectra of the ribose part of DNA double helices.

Ab-initio quantum mechanical calculations of NMR chemical shifts in nucleic acid constituents. I. The Watson-Crick base pairs.

The magnetic shielding constants of the different nuclei of the four nucleic acid bases adenine, uracile, guanine and cytosine are calculated by a non empirical method using a minimal basis set and compared to the available corresponding experimental data. The same calculations carried out for AU and GC pairs give not only the values of the chemical shift variations due to the formation of the pairs but also the relative importance of the three different contributions (geometric, polarization and charge transfer plus exchange) to the total value of delta delta. Their analysis shows the importance of the polarization term. The magnitude of the charge transfer plus exchange term which is obtained for the nuclei belonging to the hydrogen bonding sites indicates that the hydrogen bond length is the major factor in the determination of the magnetic shielding constants of these atoms. On the other hand it appears that the pairing of the bases has a negligible effect on the "geometric" magnetic shielding due to the bases.

Proton NMR study of the B----Z transition of d(CGm5CG)2 and d(CGm5CGCG)2: theory and experiment.

The magnetic shielding produced by the double helix in a B-DNA and a Z-DNA conformation is calculated for each non exchangeable proton of the oligodeoxynucleotides d(CGm5CG)2 and d(CGm5CGCG)2. The differences between the values obtained for the two helical forms are in good agreement with the variations of chemical shift measured when the salt concentration of the solution is changed from 0.1 M to 2 or 4 M. The analysis of the theoretical chemical shift variations shows that the large upfield shift observed for some of the protons of the cytidine residues is due to the sum of the ring current and local magnetic anisotropy effects of the guanines of the two nearest neighbours residues.

Theoretical study of the geometrical arrangement of GT and GA wobble pairs in two short duplexes, Proton NMR chemical shifts and interaction energy calculations.

NMR shielding constants are calculated for the base protons of duplexes formed by the dodecamer d(CGTGAATTCGCG) and the decamer d(CCAAGATTGG). A good agreement with experimental data is obtained for B-DNA helices in which the wobble GT and GA pairs are in the plane of the corresponding GC pairs of the parent duplexes formed by d(CGCGAATTCGCG) and d(CCAAGCTTGG), if the glycosyl bonds of T and G or A and G are symmetrical with respect to the dyad axis of the Watson-Crick GC pair. Interaction energy calculations show that this type of geometrical arrangement, which implies a distortion of the ribonphosphate backbone of both strands of the duplexes are more stable than those in which only one strand has its conformation modified by the presence of the wobble pair. For the duplex containing the GA pair, NMR chemical shifts as well as interaction energy computations favour the Watson-Crick hydrogen bonding scheme. The variation of the different contributions (intrastrand, interstrand, pair-pair) to the interaction energy between the bases of the duplexes, with the geometrical arrangement of the wobble pairs, is reported.

Theoretical NMR study of the pre-melting transition in the d-(CGCGAATTCGCG) and d-(CGCGTATACGCG) self-complementary duplexes.

The difference between their shielding in a B-DNA duplex and in the single strand having the same conformation has been calculated for all base protons of the dodecamers d-(CGCGAATTCGCG) and d-(CGCGTATACGCG). The calculated chemical shift variations reproduce the qualitative features of the shifts which occur during the pre-melting of the helices. This agreement shows that the pre-melting mechanism consists mainly of a lengthening of the hydrogen bonds between the two strands (in line opening) and that the conformation of the ribophosphate backbone and the orientation of the bases do not undergo major modifications during the first step of the melting.

Computer programming for nucleic acid studies. II. Total chemical shifts calculation of all protons of double-stranded helices.

A FORTRAN computer program called SHIFTS is described. Through SHIFTS, one can calculate the NMR chemical shifts of the proton resonances of single and double-stranded nucleic acids of known sequences and of predetermined conformations. The program can handle RNA and DNA for an arbitrary sequence of a set of 4 out of the 6 base types A,U,G,C,I and T. Data files for the geometrical parameters are available for A-, A'-, B-, D- and S-conformations. The positions of all the atoms are calculated using a modified version of the SEQ program [1]. Then, based on this defined geometry three chemical shift effects exerted by the atoms of the neighboring nucleotides on the protons of each monomeric unit are calculated separately: the ring current shielding effect: the local atomic magnetic susceptibility effect (including both diamagnetic and paramagnetic terms); and the polarization or electric field effect. Results of the program are compared with experimental results for a gamma (ApApGpCpUpU) 2 helical duplex and with calculated results on this same helix based on model building of A'-form and B-form and on graphical procedure for evaluating the ring current effects.