Restricted rotation of the amino group and ring inversion in highly substituted anilines. A dynamic NMR and computational study

The reaction of cyclic ylidene malononitriles with acetylene (di)carboxylic acid esters led to the production of nine bicyclic systems incorporating highly substituted (5/6) anilines. The free energy of activation (ΔG^#) for the restricted rotation about the aniline-NH₂ bond was experimentally measured in each case and a correlation was evident between the increase in steric strain in the ground state, the electron withdrawing capabilities of the ring substituents, and a reduction in the rotational barrier. For four of the compounds, the slow ring interconversion (chair?chair) for the annelated saturated seven-membered ring that formed part of the bicyclic system was also evident. In these four compounds, both dynamic processes were also studied theoretically using ab initio methods whilst the ring interconversion was additionally studied using molecular dynamic simulations. The interconversion between the two stable chair forms was deemed to occur via a conformation series consisting of chair?boat?twist-boat?boat?chair.     

Parameterization and validation of Gromos force field to use in conformational analysis of epoxidic systems

In order to study the conformational space of new natural products derivatives using molecular mechanics (MM) and molecular dynamics (MD), the Gromos force field has been expanded to include epoxidic systems. The parameterization and validation of Gromos were done to simulate 22, 23 epoxides in brassinosteroids analogs. The parameters were derived with an emphasis on the dependence between energy and dihedral angle due to its relevance in the conformational analysis. Molecular dynamics simulations of two model systems similar to those of interest were performed to validate the force field with the proposed parameters. Excellent agreement has been obtained between the MD simulation and the results of a potential energy surface (PES) calculated at B3LYP/6-31G^** level.     

Derivation of class II force fields: V. Quantum force field for amides,peptides, and related compounds

As the field of biomolecular structure advances, there is an ever-growing need for accurate modeling of molecular energy surfaces to simulate and predict the properties of these important systems. To address this need, a second generation amide force field for use in simulations of small organics as well as proteins and peptides has been derived. The critical question of what accuracy can be expected from calculations in general, and with this class II force field in particular, is addressed for structural, dynamic, and energetic properties. The force field is derived from a recent methodology we have developed that involves the systematic use of quantum mechanical observables. Systematic ab initio calculations were carried out for numerous configurations of 17 amide and related compounds. Relative energies and first and second derivatives of the energy of 638 structures of these compounds resulted in 140,970 ab initio quantum mechanical observables. The class II peptide quantum mechanical force field (QMFF), containing 732 force constants and reference values, was parameterized against these observables. A major objective of this work is to help establish the role of anharmonicity and coupling in improving the accuracy of molecular force fields, as these terms have not yet become an agreed upon standard in the ever more extensive simulations being used to probe biomolecular properties. This has been addressed by deriving a class I harmonic diagonal force field (HDFF), which was fit to the same energy surface as the QMFF, thus providing an opportunity to quantify the effects of these coupling and anharmonic contributions. Both force field representations are assessed in terms of their ability to fit the observables. They have also been tested by calculating the properties of 11 stationary states of these amide molecules. Optimized structures, vibrational frequencies, and conformational energies obtained from the quantum calculations and from both the QMFF and the HDFF are compared. Several strained and derivatized compounds including urea, formylformamide, and butyrolactam are included in these tests to assess the range of applicability (transferability) of the force fields. It was found that the class II coupled anharmonic force field reproduced the structures, energies, and vibrational frequencies significantly more faithfully than the class I harmonic diagonal force field. An important measure, rms energy deviation, was found to be 1.06 kcal/mol with the class II force field, and 2.30 kcal/mol with the harmonic diagonal force field. These deviations represent the error in relative configurational energy differences for strained and distorted structures calculated with the force fields compared with quantum mechanics. This provides a measure of the accuracy that might be expected in applications where strain may be important such as calculating the energy of a system as it approaches a (rotational) barrier, in ligand binding to a protein, or effects of introducing substituents into a molecule that may induce strain. Similar results were found for structural properties. Protein dynamics is becoming of ever-increasing interest, and, to simulate dynamic properties accurately, the dynamic behavior of model compounds needs to be well accounted for. To this end, the ability of the class I and class II force fields to reproduce the vibrational frequencies obtained from the quantum energy surface was assessed. An rms deviation of 43 cm⁻¹ was achieved with the coupled anharmonic force field, as compared to 105 cm⁻¹ with the harmonic diagonal force field. Thus, the analysis presented here of the class II force field for the amide functional group demonstrates that the incorporation of anharmonicity and coupling terms in the force field significantly improves the accuracy and transferability with regard to the simulation of structural, energetic, and dynamic properties of amides. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 430–458, 1998     

Alcohols,ethers, carbohydrates,and related compounds. I. The MM4 force field for simple compounds

Simple alcohols and ethers have been studied with the MM4 force field. The structures of 13 molecules have been well fit using the MM4 force field. Moments of inertia have been fit with rms percentage errors as indicated: 18 moments for ethers, 0.28%; 21 moments for alcohols, 0.22%. Rotational barriers and conformational equilibria have also been examined, and the experimental and ab initio results are reproduced substantially better with MM4 than they were with MM3. Much of the improvement comes from the use of additional interaction terms in the force constant matrix, of which the torsion-bend and torsion-torsion are particularly important. Induced dipoles are included in the calculation, and dipole moments are reasonably well fit. It has been possible for the first time to fit conformational energetic data for both open chain and cyclic alcohols (e.g., propanol and cyclohexanol) with the same parameter set. For vibrational spectra, over a total of 82 frequencies, the rms error is 27 cm(-1), as opposed to 38 cm(-1) with MM3. Both the alpha and beta bond shortening resulting from the presence of the electronegative oxygen atom in the molecule are well reproduced. The electronegativity of the oxygen is sufficient that one must also include not only the alpha and beta electronegativity effects on bond lengths, but also on angle distortions, if structures are to be well reproduced. The heats of formation of 32 alcohols and ethers were fit overall to within experimental error (weighted standard deviation error 0.26 kcal/mol).     

Internal rotation in squaramide and related compounds. A theoretical ab initio study

The structural and energetic changes associated with C–N bond rotation in a squaric acid derivative as well as in formamide, 3-aminoacrolein and vinylamine have been studied theoretically using ab initio molecular orbital methods. Geometry optimizations at the MP2(full)/6-31+G* level confirmed an increase in the C–N bond length and a smaller decrease in the C=O length on going from the equilibrium geometry to the twisted transition state. Other geometrical changes are also discussed. Energies calculated at the QCISD(T)/6-311+G** level, including zero-point-energy correction, show barrier heights decreasing in the order formamide, squaric acid derivative, 3-aminoacrolein and vinylamine. The origin of the barriers were examined using the atoms-in-molecules approach of Bader and the natural bond orbital population analysis. The calculations agree with Pauling's resonance model, and the main contributing factor of the barrier is assigned to the loss of conjugation on rotating the C–N bond. Finally, molecular interaction potential calculations were used to study the changes in the nucleophilicity of N and O (carbonyl) atoms upon C–N rotation, and to obtain a picture of the abilities of the molecules to act in nonbonded interactions, in particular hydrogen bonds. The molecular interaction potential results confirm the suitability of squaramide units for acting as binding units in host–guest chemistry. Received: 13 March 2002 / Accepted: 23 June 2002 / Published online: 21 August 2002     

Effect of substituents in the cumulene and aryl fragments of aroylketenes on the stereoselectivity of diels-alder heteroreaction with mono-, Bi-, and polycyclic terpenoids containing a carbonyl group

Stereoisomeric adducts, substituted (R)-, (S)-spiro[6-aryldioxin-4-ones] have been obtained by thermolysis of 5-arylfuran-2,3-diones in the presence of menthone and allobetulone.     

Cooperative multimodal retention of IgG,fragments, and aggregates on hydroxyapatite

Retention mapping of chimeric monoclonal IgG₁, Fc, Fab, F(ab′)₂, and aggregated antibody was conducted on hydroxyapatite (HA) by systematically varying phosphate and chloride concentrations during gradient elution in order to characterize the interactions of each solute with calcium and phosphate residues on the solid phase. Lysozyme was used as a control to model cation exchange‐dominant interactions. Bovine serum albumin was used as a control for calcium affinity‐dominant interactions. Calcium affinity and phosphoryl cation exchange were positively cooperative for IgG‐related species. Fc retention was dominated by calcium affinity, while retention of Fab was dominated by cation exchange. F(ab′)₂ exhibited a curve shape similar to Fab, but stronger retention. The retention curve for intact IgG incorporated the distinctive elements of its fragments but stronger retention than that predicted by their addition to one another. Aggregate retention paralleled the curve for non‐aggregated antibody, with stronger retention by both binding mechanisms. Experimental data revealed evidence of charge repulsion between IgG carboxyls and HA phosphate at low conductivity values. Electrostatic repulsion of amino residues and attraction of carboxyls by HA calcium appeared to be blocked by strong complexation of calcium with mobile phase phosphate.     

The rotation of pentaphenylphenyl groups and their terminal phenyl groups: a variable-temperature H NMR study on an albatrossene and a three-bladed molecular propeller

Dynamic NMR of 1-phenylethynyl-3,5-bis(pentaphenylphenyl)benzene (1) and 1,3,5-tris(pentaphenylphenyl)benzene (2) allows us to determine two rotational barriers for each compound. For 1, a first process exhibits ΔG^‡ = 39.2 kJ/mol followed by a second one with a ΔG^‡ value of 69.9 kJ/mol. Two processes with similar rotational barriers are found for 2 (70.9 and 75.3 kJ/mol). Motional processes which can be related to these barriers are 60° and 180° rotations of the pentaphenylphenyl units about the single bond with the core benzene ring and rotation of the terminal phenyl rings of the pentaphenylphenyl units. The results are discussed considering the consequences of these processes on the NMR spectra.     

An Ab Initio Study of Conformational Energies in Dioxo-, Trioxo-, and Tetroxo-Dithianes

Ab initio Hartree–Fock calculations at the HF/6-31G* level of theory for geometry optimization and the MP2/6-31G*//HF/6-31G* and B3LYP/6-311G(2df,p)//HF/6-31G* levels for a single point total energy calculation are reported for the important energy-minimum conformations of 1,1-dioxo-thiane (2), 1,1-dioxo-1,2-dithiane (3), 1,1-dioxo-1,3-dithiane (4), 1,1-dioxo-1,4-dithiane (5), 1,1,2-trioxo-1,2-dithiane (6), 1,1,3-trioxo-1,3-dithiane (7), 1,1,4-trioxo-1,4-dithiane (8), 1,1,2,2-tetroxo-1,2-dithiane (9), 1,1,3,3-tetroxo-1,3-dithiane (10), and 1,1,4,4-tetroxo-1,4-dithiane (11). According to the MP2/6-31G*//HF/6-31G* calculations, compound 5 is more stable than 3 and 4 by 7.8 and 8.9 kJ mol^?1, respectively. The axial geometries of 6 and 8 are more stable than the equatorial forms by 21.4 and 19.1 kJ mol^?1, respectively, but the equatorial form of 7 is 4.1 kJ mol^?1 more stable than the axial geometry. Compound 11 is more stable than 9 and 10 by 49.3 and 31.0 kJ mol^?1, respectively.     

Effect of substituents and conformations on the optical rotations of cyclic oxides and related compounds. relationship between the anomeric effect and optical rotation

The effect of substituents on the specific rotation of substituted cyclic oxides (X = F, Cl, CN, and HCC) and related compounds was studied via geometry optimization at the B3LYP/6-311+G** level followed by calculations of the specific rotation with B3LYP/aug-cc-pVDZ and, when practical, also with B3LYP/aug-cc-pVTZ. In some cases chiral samples were prepared so that the calculated specific rotations could be compared with experimental data. With most compounds there was only a minor effect of the basis set on the specific rotations. With the oxiranes and oxetanes, the chloro derivative gave a different behavior than the other substituents, but all substituents behaved in the same fashion with trans-2-methyl-1-X-cyclopropanes. Therefore the unusual behavior of chlorooxirane probably results from an interaction between oxygen and chlorine rather than being due to the presence of a three-membered ring. Chlorine is also an unusual substituent for the tetrahydrofurans. The effect of conformation on the calculated specific rotations was examined with the axial and equatorial 2-substituted tetrahydropyrans, where the anomeric effect is operative with the axial substituent, and also the 3-substituted tetrahydropyrans that would not be subject to the anomeric effect. The unusual effect of chlorine was seen only when it is antiperiplanar with respect to the oxygen.     

An ab initio study of the influence of substituents and intramolecular hydrogen bonding on the carbonyl bond length and stretching force constant. I. Monosubstituted carbonyl compounds

The C?O bond length and f_C?O,C?O, the corresponding harmonic stretching force constant, are calculated ab initio using the 4-31G basis set (augmented by polarization functions on the sulfur and chlorine) with full geometry optimization for the monosubstituted carbonyl compounds RCHO, where R = H, CHO, CH?CH₂, CO₂H, CH?CHOH, OH, OC(?O)OH, OOH, S? H, Li, F, Cl, and NH₂. Straight-line relationships are found in plots of ln[f_C?O,C?O] vs. ln[r_C?O] for the series of compounds in which carbon atoms and oxygen atoms are bonded directly to the carbonyl carbon, in accordance with the empirical expression f = C′/rⁿ. The slopes and intercepts give n = 7.62 and 6.47, C′ = 62.6 and 48.6, for the lines with carbon and oxygen as the atom bonded directly to the carbonyl carbon, respectively. The point for formaldehyde lies very close to the C line, whereas the points for SH, Li, F, Cl, and NH₂ lie closer to the O line.     

Theoretical study of ketenimine: Geometry,electronic properties,force constants and barriers to inversion and rotation

Non-empirical calculations of the structure and properties of ketenimine have been performed using nine Gaussian basis sets. Values for the bond lengths and angles, HOMO and LUMO energies, atomic charges, overlap populations, dipole moments, bond energies, force constants and barriers to nitrogen inversion and internal rotation are predicted.     

Spectral, structural, and electrochemical properties of ruthenium porphyrin diaryl and aryl(alkoxycarbonyl) carbene complexes: influence of carbene substituents, porphyrin substituents, and trans-axial ligands

A wide variety of ruthenium porphyrin carbene complexes, including [Ru(tpfpp)(CR(1)R(2))] (CR(1)R(2) = C(p-C(6)H(4)Cl)(2) 1 b, C(p-C(6)H(4)Me)(2) 1 c, C(p-C(6)H(4)OMe)(2) 1 d, C(CO(2)Me)(2) 1 e, C(p-C(6)H(4)NO(2))CO(2)Me 1 f, C(p-C(6)H(4)OMe)CO(2)Me 1 g, C(CH==CHPh)CO(2)CH(2)(CH==CH)(2)CH(3) 1 h), [Ru(por)(CPh(2))] (por=tdcpp 2 a, 4-Br-tpp 2 b, 4-Cl-tpp 2 c, 4-F-tpp 2 d, tpp 2 e, ttp 2 f, 4-MeO-tpp 2 g, tmp 2 h, 3,4,5-MeO-tpp 2 i), [Ru(por)[C(Ph)CO(2)Et]] (por=tdcpp 2 j, tmp 2 k), [Ru(tpfpp)(CPh(2))(L)] (L = MeOH 3 a, EtSH 3 b, Et(2)S 3 c, MeIm 3 d, OPPh(3) 3 e, py 3 f), and [Ru(tpfpp)[C(Ph)CO(2)R](MeOH)] (R = CH(2)CH==CH(2) 4 a, Me 4 b, Et 4 c), were prepared from the reactions of [Ru(por)(CO)] with diazo compounds N(2)CR(1)R(2) in dichloromethane and, for 3 and 4, by further treatment with reagents L. A similar reaction of [Os(tpfpp)(CO)] with N(2)CPh(2) in dichloromethane followed by treatment with MeIm gave [Os(tpfpp)(CPh(2))(MeIm)] (3 d-Os). All these complexes were characterized by (1)H NMR, (13)C NMR, and UV/Vis spectroscopy, mass spectrometry, and elemental analyses. X-ray crystal structure determinations of 1 d, 2 a,i, 3 a, b, d, e, 4 a-c, and 3 d-Os revealed Ru==C distances of 1.806(3)-1.876(3) A and an Os==C distance of 1.902(3) A. The structure of 1 d in the solid state features a unique "bridging" carbene ligand, which results in the formation of a one-dimensional coordination polymer. Cyclic voltammograms of 1 a-c, g, 2 a-d, g-k, 3 b-d, 4 a, b, and 3 d-Os show a reversible oxidation couple with E(1/2) values in the range of 0.06-0.65 V (vs Cp(2)Fe(+/0)) that is attributable to a metal-centered oxidation. The influence of carbene substituents, porphyrin substituents, and trans-ligands on the Ru==C bond was examined through comparison of the chemical shifts of the pyrrolic protons in the porphyrin macrocycles ((1)H NMR) and the M==C carbon atoms ((13)C NMR), the potentials of the metal-centered oxidation couples, and the Ru==C distances among the various ruthenium porphyrin carbene complexes. A direct comparison among iron, ruthenium, and osmium porphyrin carbene complexes is made.     

A guide to Sonogashira cross-coupling reactions: the influence of substituents in aryl bromides, acetylenes, and phosphines

The conversion-time data for 168 different Pd/Cu-catalyzed Sonogashira cross-coupling reactions of five arylacetylenes (phenylacetylene; 1-ethynyl-2-ethylbenzene; 1-ethynyl-2,4,6-R(3)-benzene (R = Me, Et, i-Pr)) and Me(3)SiCCH with seven aryl bromides (three 2-R-bromobenzenes (R = Me, Et, i-Pr); 2,6-Me(2)-bromobenzene and three 2,4,6-R(3)-bromobenzenes (R = Me, Et, i-Pr)) with four different phosphines (P-t-Bu(3), t-Bu(2)PCy, t-BuPCy(2), PCy(3)) were determined using quantitative gas chromatography. The stereoelectronic properties of the substituents in the aryl bromides, acetylenes, and phosphines were correlated with the performance in Sonogashira reactions. It was found that the nature of the most active Pd/PR(3) complex for a Sonogashira transformation is primarily determined by the steric bulk of the acetylene; ideal catalysts are: Pd/P-t-Bu(3) or Pd/t-Bu(2)PCy for sterically undemanding phenylacetylene, Pd/t-BuPCy(2) for 2- and 2,6-substituted arylacetylenes or Me(3)SiCCH and Pd/PCy(3) for extremely bulky acetylenes and aryl bromides. Electron-rich and sterically demanding aryl bromides with substituents in the 2- or the 2,6-position require larger amounts of catalyst than 4-substituted aryl bromides. The synthesis of tolanes with bulky groups at one of the two aryl rings is best done by placing the steric bulk at the arylacetylene, which is also the best place for electron-withdrawing substituents.     

A theoretical study of the vibrational spectra,geometry and force field of thiourea

A theoretical force field for the molecular vibrations of thiourea has been determined from ab initio calculations at the Hartree-Fock level using the 3-21G* basis set. The reliability of the force field is analyzed by calculating the vibrational frequencies for the deuterated and ¹⁵N isotopomers. Frequencies calculated from the force field are utilized to critically examine the experimental assignments for thiourea and deuterated thiourea. Theoretical geometry, the calculated IR and Raman band intensifies are analyzed.     

Conformational rivalry of geminal substituents in silacyclohexane derivatives: 1-Phenyl vs. 1-OR,R=H or Me

Molecular structure and conformational equilibria of 1-methoxy- 1 and 1-hydroxy-1-phenylsilacyclohexanes 2 were studied by quantum chemical (QC) calculations and combined gas electron diffraction/mass spectrometry (GED/MS). Both molecules may exist in 5 or 6 forms, differing from each other by the substituents' position: (i) axial or equatorial and (ii) rotational orientation relative to the six-membered ring frame. The contribution of axial forms of both compounds varies from 35 to 60% depending on the theoretical method applied. From the GED data, the summarized molar fractions of the conformers were found to be Ph_ax:Ph_eq = 70(15):30(20) and 50(20):50(20)% which corresponds to ΔG = G_ax–G_eq = ?0.55(46) and 0.00(56) kcal/mol, for compound 1 and 2, respectively. The concentration of the Ph_ax forms of 1-phenyl-1-(X)-silacyclohexanes (X = H, HO, Me, MeO and Me₂N) increases with the size of the second substituent at the silicon atom: 38(10)<50(20)<58(15)<70(15) <80(15)%.