Transition-state structure of human 5'-methylthioadenosine phosphorylase

Kinetic isotope effects (KIEs) and computer modeling using density functional theory were used to approximate the transition state of human 5'-methylthioadenosine phosphorylase (MTAP). KIEs were measured on the arsenolysis of 5'-methylthioadenosine (MTA) catalyzed by MTAP and were corrected for the forward commitment to catalysis. Intrinsic KIEs were obtained for [1'-(3)H], [1'-(14)C], [2'-(3)H], [4'-(3)H], [5'-(3)H(2)], [9-(15)N], and [Me-(3)H(3)] MTAs. The primary intrinsic KIEs (1'-(14)C and 9-(15)N) suggest that MTAP has a dissociative S(N)1 transition state with its cationic center at the anomeric carbon and insignificant bond order to the leaving group. The 9-(15)N intrinsic KIE of 1.039 also establishes an anionic character for the adenine leaving group, whereas the alpha-primary 1'-(14)C KIE of 1.031 indicates significant nucleophilic participation at the transition state. Computational matching of the calculated EIEs to the intrinsic isotope effects places the oxygen nucleophile 2.0 Angstrom from the anomeric carbon. The 4'-(3)H KIE is sensitive to the polarization of the 3'-OH group. Calculations suggest that a 4'-(3)H KIE of 1.047 is consistent with ionization of the 3'-OH group, indicating formation of a zwitterion at the transition state. The transition state has cationic character at the anomeric carbon and is anionic at the 3'-OH oxygen, with an anionic leaving group. The isotope effects predicted a 3'-endo conformation for the ribosyl zwitterion, corresponding to a H1'-C1'-C2'-H2' torsional angle of 33 degrees. The [Me-(3)H(3)] and [5'-(3)H(2)] KIEs arise predominantly from the negative hyperconjugation of the lone pairs of sulfur with the sigma (C-H) antibonding orbitals. Human MTAP is characterized by a late S(N)1 transition state with significant participation of the phosphate nucleophile.     

The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar-Phosphate Backbone Torsions in Guanosine 3',5'-Bisphosphate

The intrinsic flexibility of the pentoses in RNA allows dynamic transmission of information on the electronic character of the nucleobase to modulate the sugar conformation by an interplay of gauche and anomeric effects. This modulation in turn steers the phosphate backbone conformation by tuning the 3'-O-P-O(ester) anomeric effect, as shown by conformational analysis of EtpGpMe as a function of pD. This tunable transmission is stereoelectronic in nature, and operates by appropriate overlap between donor and acceptor orbitals (see scheme), which causes single-stranded RNA to behave as a molecular wire.     

Substituent-dependent negative hyperconjugation in 2-aryl-1,3-N,N-heterocycles. fine-tuned anomeric effect?

The epimerization reactions of conformationally inflexible 2-aryl-1,3-N,N-heterocycles were used as model systems to study the role of the nitrogen lone pair-C2 associated antibonding orbital hyperconjugative interactions in the experimentally observed substituent-dependent generalized anomeric effect. The measured reaction free enthalpies were found to correlate well with the sum of the hyperconjugative stabilization energies of all the vicinal donor-acceptor orbital overlaps around C2, obtained from ab initio NBO analysis, and both quantities correlated linearly with the Hammett-Brown substituent constant. The individual stereoelectronic interactions (n(N)-sigma(C2)(-)(N), n(N)-sigma(C2)(-)(Ar), n(N)-sigma(C2)(-)(H)) were also observed to exhibit a substituent dependence, despite their distance from the 2-aryl substituent and their nonperiplanar arrangement. The higher the electron-withdrawing effect of the 2-aryl substituent, the larger was the stabilization for n(N)-sigma(C2)(-)(Ar), while the overlaps n(N)-sigma(C2)(-)(N) and n(N)-sigma(C2)(-)(H) changed in the opposite sense. The different polarization of the acceptor sigma orbitals, caused by the 2-aryl substituent, accounted for the observed propagation of the substituent effect. These results promote a detailed explanation of the useful tautomeric behavior of the 2-aryl-1,3-X,N-heterocycles, and reveal the nature of the connection between the anomeric effect and the Hammett-type linear free energy relationship.     

The Radical Cationic Repair Pathway of Cyclobutane Pyrimidine Dimer: The Effect of Sugar‐Phosphate Backbone

Radical cationic repair process of cis–syn thymine dimer has been investigated when (1) sugar‐phosphate backbones were substituted by hydrogen atoms, (2) phosphate group was substituted by two hydrogen atoms each on a sugar ring and (3) sugar‐phosphate backbone was taken into account. The effect of the interactions between N1 and N1′ lone pairs and the C6‐C6′ antibonding orbital are the most important evidences for the cleavage of the C6‐C6′ bond in the first step of radical cationic repair mechanism in the absence of the sugar‐phosphate backbone. The impact of the N1 and N1′ lone pairs on the C6‐C6′ bond cleavage decreases and the energy barrier of the cleavage of that bond significantly increases in the presence of the deoxynucleoside sugars and the sugar‐phosphate backbone.     

Interpretation of anomeric effect in the N-C-N unit with the quantum theory of atoms in molecules

The conformational preferences of six model compounds for the N-C-N anomeric unit (methanediamine, 2,2-propanediamine, N,N,N',N'-tetramethyl-methanediamine, 1,3-dizacyclohexane, 1,3,5-triazacyclohexane, and 2-aminopiperidine) were analyzed within the framework of the Quantum Theory of Atoms in Molecules. The relative stabilization of the conformers is related to two factors: (i) the reduction of the electron population experienced by the hydrogens of the central methylene when they display more gauche arrangements to lone pairs (lp) and (ii) the reduction of the electron population of aminic hydrogens when the corresponding N-H bond is in a parallel arrangement to the lone pair of another N. The former depletion takes place in lp-N-C-N antiperiplanar dispositions, whereas the latter is shown in lp-N-C-N gauche arrangements. Therefore, we can say that the electron density removed from the central hydrogens is moved to an aminic one on going from an antiperiplanar to a gauche disposition of a lp-N-C-N unit. The relative energies of aminic and central hydrogens in the conformer series is the main factor determining the conformational preference. In contrast to what happens in O-C-O containing compounds (where both N(H) depletions take place in the O-C-O-H gauche dispositions), the stabilization gained by N and C atoms plays a secondary role. This is in line with a general trend exhibited by hydrogens as the most available (less energy cost) atomic basins for receiving or providing electron density along a chemical change. It also explains why the anomeric conformational stabilization due to the N-C-N units is significantly less than that of the O-C-O- units. Moreover, the variations of electron population due to conformational changes are not in keeping with the stereoelectronic model of the anomeric effect, as was previously found for diverse molecules containing the O-C-O anomeric unit.     

Electronic delocalization contribution to the anomeric effect evaluated by computational methods

This study proposes the determination of the electronic delocalization contribution to the Anomeric Effect (EDCAE, Delta Delta E(deloc), eq 3) as a computational alternative in the evaluation of the excess of the axial preference shown by an electronegative substituent located at alpha position to the annular heteroatom of a heterocyclic compound (anomeric position) in both the presence and the absence of electronic delocalization retaining the same molecular geometry. The determination of the EDCAE is computationally accessible through the application of the natural bond orbital analysis (NBO). This type of analysis allows the comparison of hypothetical molecules lacking electronic delocalization (Lewis molecules, in which the electrons are strictly located in bonds and lone pairs) with the fully delocalized molecules retaining the same geometry and the evaluation of the anomeric effect in terms of eq 3. The role of the Lewis molecules is the same as the cyclohexane used experimentally to evaluate the anomeric effect. The advantage of doing this is that Lewis molecules are stereoelectronically inert. Applying this methology to cyclic and acyclic molecules at B3LYP/6-31G(d,p) and HF/6-31G(d,p)//B3LYP/6-31G(d,p) levels of theory, we found that the anomeric effect shown by Cl in 1,3-dioxane; F, Cl, SMe, PH(3), and CO(2)Me groups in 1,3-dithiane is of stereoelectronic nature while the preference of F, OMe, and NH(2) in 1,3-dioxane and the P(O)Me(2) group in 1,3-dithiane is not. Furthermore, this methodology shows that anomeric effects without stereoelectronic origin can modify the molecular geometry in agreement with the geometric pattern required by the double-bond no-bond model, as recently proposed by Perrin.     

Manifestation of the <Emphasis Type="Italic">gauche</Emphasis> effect in conformers of benzenesulfonic acid hydrazide

Conformational properties of a benzenesulfonic acid hydrazide molecule and its para-nitro and para-methyl derivatives, which have found wide application as porofors and biologically active compounds, are studied. It is found that the benzenesulfonic acid hydrazide molecule has six conformers with relative energies of 0//0 kcal/mol, 0.34//0.98 kcal/mol, 2.51//2.25 kcal/mol, 2.54//2.56 kcal/mol, 2.90//3.28 kcal/mol, 6.64//6.43 kcal/mol (MP2//DFT(B3LYP) with the cc-pVTZ basis set), each conformer has enantiomer. The conformers differ from each other in the relative orientation of the fragments of the–SO2NHNH2 group, the energies of the frontier orbitals, the direction and value of the dipole moments. It is shown that the introduction of a nitro or methyl group into the para-position practically does not affect the conformational properties of the sulfonyl hydrazide group. Change in the structure of benzenesulfonic acid hydrazide during the crystal–gas transition is considered and it is revealed that in the crystal the conformation similar in structure to one of the high-energy conformers of the free molecule is stabilized. The NBO analysis of the electron density distribution is performed and it is shown that the occurrence of the gauche effect in all conformers of the molecules under study can be interpreted by the manifestation of the total action of strong anomeric effects between the lone pairs of nitrogen atoms and antibonding orbitals of S=O, N–H, C–S, and N–S bonds.     

Quantum mechanical analysis of 1,2-ethanediol conformational energetics and hydrogen bonding

A proper understanding of the conformational energetics of 1,2-ethanediol (ethylene glycol) is important to the construction of molecular mechanics force fields for the treatment of carbohydrates since these biologically important molecules have a prevalence of vicinal hydroxyl groups. In the present study, quantum mechanical analysis of the 10 unique minimum-energy conformations of ethylene glycol is performed by using 10 model chemistries ranging from HF/6-311++G(d,p) up to a hybrid method that approximates CCSD(T)/cc-pVQZ. In addition, natural bond orbital (NBO) analysis of these conformations with deletion of pairings of CO bond/antibonding and lone pair/antibonding orbitals is used to investigate contributions from the "gauche" effect to ethylene glycol conformational energetics. MP2 with the "correlation consistent" basis sets and DFT/6-311++G(d,p) do the best job of matching the approximate CCSD(T)/cc-pVQZ energies while MP2/6-31G(d) and Hartree-Fock both fare poorly. NBO analysis shows the conformational energies to be independent of the deletion of matrix elements associated with (i) CO bonding and antibonding orbital interactions and (ii) lone pair and antibonding orbital interactions, whereas the energetic ordering correlates with geometric parameters consistent with internal hydrogen bonds. Thus, the present results suggest that standard molecular mechanics potential energy functional forms, which lack explicit terms to account for stereoelectronic effects, are appropriate for carbohydrates.     

Negative hyperconjugation in phosphorus stabilized carbanions

The electronic Fukui function is used to give qualitative electronic proof on the existence of back-bonding from the carbon lone pair toward the sigma* P-Y and P-O orbitals in phosphorus stabilized carbanions. NBO analyses are used to investigate the energetic, electronic, and structural impacts of this negative hyperconjugation interaction. The observed energetic stabilization can indeed be attributed to the electronic delocalization of the lone pair toward the antibonding orbitals. This delocalization is furthermore responsible for the shorter P-C bonds, longer P-Y (P-O) bonds, and wider Y-P-Y angles observed for the anionic compounds compared to their neutral counterparts. From the electronic NBO analysis it becomes clear that phosphorus containing functional groups are best described as sigma donor/pi acceptors.     

Electron-rich three-center bonding: role of s,p interactions across the p-block

This paper analyzes the importance of s,p mixing-a necessary addition to the simplest Rundle-Pimentel picture-and periodic and group trends in electron-rich three-center bonding. Our analysis proceeds through a detailed quantum chemical study of the stability of electron-rich three-center bonding in triatomic 22-valence electron anions. To provide interpretations, a perturbational molecular orbital (MO) analysis of s,p mixing is carried out. This analysis of the orbitals and the overlap populations is then tested by density functional calculations for a number of linear trihalides, trichalcogenides, and tripnictides. The most important effect of s,p mixing on the in-line bonding is in destabilization of the 3sigma(g) orbital and is determined by the overlap between the s orbital of the central atom and the p orbital of the terminal atom. Further destabilization arises from the repulsion of p(pi) lone pairs. Both of these antibonding effects increase with increasing negative charge of the system. The stability of isoelectronic X(3) systems thus decreases when moving from right to left in the periodic table. Interesting group trends are discerned; for instance, for the electron-rich tripnictides, the ability to accommodate a hypervalent electron count is the largest in the middle rather at the end of the group. Particularly strong s,p mixing can reverse the bonding/antibonding character of MOs: thus MO 2sigma(u) that is responsible for bonding for trihalides and trichalcogenides is actually antibonding in N(3)(7)(-).     

A photochemical activation scheme of inert dinitrogen by dinuclear Ru(II) and Fe(II) complexes

A general photochemical activation process of inert dinitrogen coordinated to two metal centers is presented on the basis of high-level DFT and ab initio calculations. The central feature of this activation process is the occupation of an antibonding pi* orbital upon electronic excitation from the singlet ground state S0 to the first excited singlet state S1. Populating the antibonding LUMO weakens the triple bond of dinitrogen. After a vertical excitation, the excited complex may structurally relax in the S1 state and approaches its minimum structure in the S1 state. This excited-state minimum structure features the dinitrogen bound in a diazenoid form, which exhibits a double bond and two lone pairs localized at the two nitrogen atoms, ready to be protonated. Reduction and de-excitation then yield the corresponding diazene complex; its generation represents the essential step in a nitrogen fixation and reduction protocol. The consecutive process of excitation, protonation, and reduction may be rearranged in any experimentally appropriate order. The protons needed for the reaction from dinitrogen to diazene can be provided by the ligand sphere of the complexes, which contains sulfur atoms acting as proton acceptors. These protonated thiolate functionalities bring protons close to the dinitrogen moiety. Because protonation does not change the pi*-antibonding character of the LUMO, the universal and well-directed character of the photochemical activation process makes it possible to protonate the dinitrogen complex before it is irradiated. The pi*-antibonding LUMO plays the central role in the activation process, since the diazenoid structure was obtained by excitation from various occupied orbitals as well as by a direct two-electron reduction (without photochemical activation) of the complex; that is, the important bending of N2 towards a diazenoid conformation can be achieved by populating the pi*-antibonding LUMO.     

On the origin of red and blue shifts of X-H and C-H stretching vibrations in formic acid (formate ion) and proton donor complexes.

Complexes between formic acid or formate anion and various proton donors (HF, H(2)O, NH(3), and CH(4)) are studied by the MP2 and B3LYP methods with the 6-311++G(3df,3pd) basis set. Formation of a complex is characterized by electron-density transfer from electron donor to ligands. This transfer is much larger with the formate anion, for which it exceeds 0.1 e. Electron-density transfer from electron lone pairs of the electron donor is directed into sigma* antibonding orbitals of X--H bonds of the electron acceptor and leads to elongation of the bond and a red shift of the X--H stretching frequency (standard H-bonding). However, pronounced electron-density transfer from electron lone pairs of the electron donor also leads to reorganization of the electron density in the electron donor, which results in changes in geometry and vibrational frequency. These changes are largest for the C--H bonds of formic acid and formate anion, which do not participate in H-bonding. The resulting blue shift of this stretching frequency is substantial and amounts to almost 35 and 170 cm(-1), respectively.     

The use of localized molecular orbitals and the polarization propagator to identify transmission mechanisms in nuclear spin-spin couplings

An extension of the IPPP (inner projections of the polarization propagator) method to theoretically analyze transmission mechanisms of indirect nuclear spin-spin couplings is presented. The localization technique used is modified so that all the canonical molecular orbitals of a compound may be localized to represent chemical bonds, lone pairs, and the corresponding antibonding molecular orbitals. These localized molecular orbitals, together with the polarization propagator, are used to obtain an intuitive picture of how a coupling is generated as a sum of terms, each one consisting of two particle-hole single excitations. This picture can be used to identify underlying transmission mechanisms and quantitatively evaluate their importance toward the total coupling. The paramagnetic spin-orbit and the spin-dipole interactions are studied in detail.     

SCF-Perturbational analysis of thetrans lone pair effect in methylamine and methanol

Thetrans lone pair effect on the C-H bonds in methylamine and methanol has been analysed by means of CNDO/2 SCF perturbation theory using localised orbitals. The lone pair electrons are partially delocalized into the antibonding C-H orbital beingtrans orientated to the lone pair. This finding supports Hamlow's intuitive rationalization of thetrans lone pair effect.     

Stereoelectronic control in the cleavage of tetrahedral intermediates in the hydrolysis of esters and amides

A new stereoelectronic theory for the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides is presented. In this new theory, the precise conformation of the intermediate hemi-orthoester or hemi-orthoamide controls the nature of the hydrolysis products. It is postulated that the breakdown of a conformer of a tetrahedral intermediate depends upon the orientation of the lone pair orbitals of the hetero-atoms. Specific cleavage of a carbon-oxygen or a carbon-nitrogen bond in any conformer is allowed only if the other two hetero-atoms (oxygen or nitrogen) each have an orbital oriented antiperiplanar to the leaving O-alkyl or N-alkyl group. Experimentally, the oxidation of acetals by ozone and the acid hydrolysis of a series of cyclic orthoesters demonstrates clearly that there is indeed a stereoelectronic control in the cleavage of hemiorthoesters. Similarly, a study of the basic hydrolysis of a variety of N,N-dialkylated imidate salts shows that the same stereoelectronic control is operating in the cleavage of hemiorthoamides.     

Is there stereoelectronic control in hydrolysis of cyclic guanidinium ions?

To assess stereoelectronic effects in the cleavage of tetrahedral intermediates, a series of five-, six-, and seven-membered cyclic guanidinium salts was synthesized. If stereoelectronic control by antiperiplanar lone pairs is operative, these are expected to hydrolyze with endocyclic C-N cleavage to acyclic ureas. However, hydrolysis in basic media produces mixtures of cyclic and acyclic products, as determined by 1H NMR analysis. The results show that in the six-membered ring antiperiplanar lone pairs provide a weak acceleration of the breakdown of the tetrahedral intermediate, but in five- and seven-membered rings there is no evidence for such acceleration, which instead can be provided by syn lone pairs.     

Theoretical study of the intermolecular hydrogen bond interaction for furan-HCl and furan-CHCl_3 complexes

The importance of intermolecular interactions in biology and material science has prompted chemists to explore the nature of the variety of such interactions. The strongest of these interac-tions are the hydrogen bonds, which play an important role in determining the molecular confor-mation, crystal packing, and the structure of biological systems such as nucleic acids. Extensive experimental and theoretical efforts[1—5] have been devoted to the studies of this type of interac-tions, such as …     

Ab initio studies of structural features not easily amenable to experiment: Part 6. Quantitative estimate of the effect of bond delocalization on structure and hyperconjugative interaction of the amide group

The structural changes, which occur in the amide unit when the NH₂-group is twisted out of plane by rotation about the NC bond, have been determined by comparing the completely relaxed ab initio geometries of planar and perpendicular formamide and acetamide. In the perpendicular conformation, in which the π-electron amide resonance is uncoupled, the NC bond distance is 0.080.09 Å longer than in the planar form; the CO bond distance is about 0.01 Å shorter; NH distances are about 0.01 Å longer; and HNC angles are 510° smaller, whereas the CNO angle is relatively constant. Because of the apparent invariance of CH₃-hyperconjugation effects in planar and perpendicular acetamide, it is tentatively postulated that anomeric orbital interactive effects (involving the lone pair on NH, the CO π-electron pair and antibonding π*-group-orbitals on C(α) in NHC(HR)C(O)), which should be an important factor in determining peptide chain conformation, do not vary significantly with small deviations from amide group planarity.     

The importance of lone pair delocalizations: theoretical investigations on the stability of cis and trans isomers in 1,2-halodiazenes

The relative and thermodynamic stabilities of cis and trans isomers of 1,2-dihalodiazenes (XN=NX; X = F, Cl, or Br) were examined using high level ab initio and density functional theory (DFT) calculations. For 1,2-dihalodiazenes, it was found that the cis isomers were more stable than the corresponding trans isomers, despite the existence of several cis destabilizing mechanisms, such as steric exchange between halogen lone pairs and dipole-dipole electrostatic repulsions (Delta(trans-cis) = 3.15, 7.04, and 8.19 kcal mol(-1), respectively, at BP86/6-311++G(3df,3pd)//B3LYP /6-311++G(3df,3pd) level). Their origin of the cis-preferred difference in energy was investigated with natural bond orbital (NBO) analysis to show that the "cis effect" came mainly from antiperiplanar interactions (AP effect) between the nitrogen lone pair and the neighboring antibonding orbital of the N-X bond (n(N) --> sigma(N'X'*)). The delocalization of halogen lone-pair into the antibonding orbital of the N=N bonds (the LP effects) was also found to enhance the cis preference by 1.20 to 6.58 kcal mol(-1), depending on the substituted halogen atom. The total amount of the AP effect increased as the halogen atom became larger, and the increased AP effect promoted the triple-bond-like nature of the N=N bond (shorter N=N bond length and wider NNX angle). The greater AP effect also made the N'-X' bond easier to cleave (longer N-X bond length), and a higher energy level than that of the nitrogen lone pair was found in the N-Br bonding orbital in 1,2-dibromodiazenes, thus indicating the significant instability of this molecule. The degradability of the N-Cl bond in 1,2-dichlorodiazenes and the fair stability of the N-F bond in 1,2-fluorodiazenes were also confirmed theoretically, and were found to be consistent with the previous experimental and theoretical reports. These results clearly indicate the dominance of lone-pair-related hyperconjugations on the basic electronic structure and energetic natures of 1,2-dihalodiazene systems.