Cooperative and competitive effects of substituents at C1 and C4 on the barriers to ring inversion of 5,5-difluorobicyclo[2.1.0]pentanes

To identify the reasons for the very low barrier that has been measured for ring inversion of 1,4,5,5-tetrafluorobicyclo[2.1.0]pentane (deltaG(double dagger) = 6.8 +/- 0.2 kcal/mol), CASSCF and CASPT2 calculations have been performed on ring inversion in this and other bicyclo[2.1.0]pentanes. The results of the calculations show that a cooperative interaction between the geminal fluorines at C2 and the fluorines at C1 and C3 in the singlet cyclopentane-1,3-diyl transition structure (TS) contributes 3.7 kcal/mol to lowering the barrier to ring inversion in the tetrafluoro compound. In contrast, a competitive substituent effect in the TS for ring inversion of 1,4-dicyano-5,5-difluorobicyclo[2.1.0]pentane is predicted to raise the barrier height by 6.1 kcal/mol. The origin of these cooperative and competitive substituent effects is discussed.     

NH tautomerism in the natural chlorin derivatives

The NH tautomerism of five Mg-free chlorophyll a and b derivatives 2-6 was studied utilizing NMR spectroscopy and molecular modeling. The results from the dynamic NMR measurements of the chlorins revealed that substituent effects contribute crucially to the free energy of activation (DeltaG(double dagger)) in the NH tautomeric processes. An intermediate tautomer for the total tautomeric NH exchange in a chlorin was observed for the first time, when the (1)H NMR spectra of chlorin e(6) TME (3) and rhodin g(7) TME (4) (TME = trimethyl ester) were measured at lower temperatures. The lower energy barriers (DeltaG(1)(double dagger)) obtained for the formation of the intermediate tautomers of 3 and 4, assigned to the N(22)-H, N(24)-H trans-tautomer, were 10.8 and 10.6 kcal/mol, respectively. The energy barrier (DeltaG(2)(double dagger) value) for the total tautomeric NH exchange in the five chlorins was found to vary from 13.6 kcal/mol to values higher than 18 kcal/mol. The lowest DeltaG(2)(double dagger) value (13.6 kcal/mol) was obtained for rhodochlorin XV dimethyl ester (2), which was the only chlorophyll derivative lacking the C(15) substituent. In the case of chlorins 4 and 5, the steric crowding around the methoxycarbonylmethyl group at C(15) raised the DeltaG(2)(double dagger) activation free-energy to 17.1 kcal/mol. However, the highest energy barrier with DeltaG(2)(double dagger) > 18 kcal/mol was observed for the NH exchange of pyropheophorbide a methyl ester (6), possessing the macrocycle rigidifying isocyclic ring E. Our results demonstrate that the steric strain, arising either from the steric crowding around the bulky substituent at C(15) or the macrocycle rigidifying isocyclic ring E, slows down the NH tautomeric process. We suggest that deformations in the chlorin skeleton are closely connected to the NH tautomeric exchange and that the exchange occurs by a stepwise proton-transfer mechanism via a hydrogen bridge.     

MINDO-SCF-MO-berechnung der cis-trans-isomerisierung von N-methyl- und N-phenylazomethin

MINDO/2-SCF-MO calculations for the ground state properties of N-methyl- and N-phenyl-azomethin have been carried out. The calculated rotation barrier for the methyl group in N-methyl-azomethin was 0·8 kcal/mol, the eclipsed conformation being most stable. The calculated rotation barrier about the CN bond in the protonated methylazomethin was 27·9 kcal/mol. MINDO/1-SCF-MO treatment for the N-inversion barrier of the unprotonated species yielded 13·00 kcal/mol. Similar MINDO/2 calculations for N-phenylazomethin yielded 4·0 kcal/mol for the rotation barrier of the phenyl ring around the CN= bond, the perpendicular conformation of the ring to the CNC plane being most stable. For the corresponding N protonated derivative the value 27·3 kcal/mol was calculated for the rotation barrier around the CN bond. MINDO/1 treatment yielded an inversion barrier of 14·0 kcal/mol for N-phenylazomethin.     

Reaction pathways and free energy barriers for alkaline hydrolysis of insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds: electrostatic and steric effects

Reaction pathways and free energy barriers for alkaline hydrolysis of the highly neurotoxic insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds were studied by performing first-principles electronic structure calculations on representative methylphosphonofluoridates, (RO)CH3P(O)F, in which R = CH2CH2N+(CH3)3, CH3, CH2CH2C(CH3)3, CH2CH2CH(CH3)2, CH(CH3)CH2N+(CH3)3, and CH(CH3)CH2N(CH3)2. The dominant reaction pathway was found to be associated with a transition state in which the attacking nucleophile OH- and the leaving group F- are positioned on opposite sides of the plane formed by the three remaining atoms attached to the phosphorus in order to minimize the electrostatic repulsion between these two groups. The free energy barriers calculated for the rate-determining step of the dominant pathway are 12.5 kcal/mol when R = CH2CH2N+(CH3)3, 15.5 kcal/mol when R = CH3, 17.9 kcal/mol when R = CH2CH2C(CH3)3, 16.5 kcal/mol when R = CH2CH2CH(CH3)2, 13.4 kcal/mol when R = CH(CH3)CH2N+(CH3)3, and 18.7 kcal/mol when R = CH(CH(3))CH(2)N(CH(3))(2). The calculated free energy barriers are in good agreement with available experimentally derived activation free energies, i.e. 14.7 kcal/mol when R = CH(3), 13.4 kcal/mol when R = CH2CH2N+(CH3)3, and 13.9 kcal/mol when R = CH(CH3)CH2N+(CH3)3. A detailed analysis of the calculated energetic results and available experimental data suggests that the net charge of the molecule (M) being hydrolyzed is a prominent factor affecting the free energy barrier (DeltaG) for the alkaline hydrolysis of phosphodiesters, phosphonofluoridates, and related organophosphorus compounds. The electrostatic interactions between the attacking nucleophile OH- and the molecule M being hydrolyzed favor such an order of the free energy barrier: DeltaG(M(+)+OH-) < DeltaG(M0+OH-) < DeltaG(M(-)+OH-), where M+, M0, and M- represent the cationic, neutral, and anionic molecules, respectively. The change of the substituent R in (RO)CH(3)P(O)F from CH3 to CH2CH2N+(CH3)3 is associated with both the electrostatic and steric effects on the free energy barrier, but the electrostatic effect dominates the substituent shift of the free energy barrier. This helps to better understand why the alkaline hydrolysis of (RO)CH3P(O)F with R = CH2CH2N+(CH3)3 and CH(CH3)CH2N+(CH3)3 is significantly faster than that with R = CH3. The effect of electrostatic interaction also helps to understand why the rate constants for the alkaline hydrolysis of phosphodiesters, such as intramolecular second messenger adenosine 3',5'-phosphate (cAMP), are generally smaller than those for the alkaline hydrolysis of the phosphonofluoridates and related phosphotriesters.     

Role of the somersault rearrangement in the oxidation step for flavin monooxygenases (FMO). A comparison between FMO and conventional xenobiotic oxidation with hydroperoxides

Model quantum mechanical calculations presented for C-4a-flavin hydroperoxide (FlHOOH) at the B3LYP/6-311+G(d,p) level suggest a new mechanism for flavoprotein monooxygenase (FMO) oxidation involving a concerted homolytic O-O bond cleavage in concert with hydroxyl radical transfer from the flavin hydroperoxide rather than an S(N)2-like displacement by the substrate on the C-4a-hydroperoxide OOH group. Homolytic O-O bond cleavage in a somersault-like rearrangement of hydroperoxide C-4a-flavinhydroperoxide (1) (FLHO-OH → FLHO···HO) produces an internally hydrogen-bonded HO(?) radical intermediate with a classical activation barrier of 27.0 kcal/mol. Model hydroperoxide 1 is used to describe the transition state for the key oxidation step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH). A comparison of the electron distribution in the transition structures for the PHBH hydroxylation of p-hydroxybenzoic acid (ΔE(?) = 23.0 kcal/mol) with that of oxidation of trimethylamine (ΔE(?) = 22.3 kcal/mol) and dimethyl sulfide (ΔE? = 14.1 kcal/mol) also suggests a mechanism involving a somersault mechanism in concert with transfer of an HO(?) radical to the nucleophilic heteroatom center with a hydrogen transfer back to the FLH-O residue after the barrier is crossed to produce the final product, FLH-OH. In each case the hydroxylation barrier was less than that of the O-O rearrangement barrier in the absence of a substrate supporting an overall concerted process. All three transition structures bear a resemblance to the TS for the comparable hydroxylation of isobutane (ΔE(?) = 29.2 kcal/mol) and for simple Fenton oxidation by aqueous iron(III) hydroperoxides. To our surprise the oxidation of N- and S-nucleophiles with conventional oxidants such as alkyl hydroperoxides and peracids also proceeds by HO(?) radical transfer in a manner quite similar to that for tricyclic hydroperoxide 1. Stabilization of the developing oxyradical produced by somersault rearrangement for concerted enzymatic oxidation with tricyclic hydroperoxide 1 results in a reduced overall activation barrier.     

Copper(I) chloride initiated decomposition of 7-phosphanorbornadiene. Evidence for a solvent-assisted catalytic mechanism

Density functional theory is used to explore the mechanism of the copper(I)-chloride-catalyzed decomposition of W(CO)(5)-complexed 7-phosphanorbornadiene and the subsequent olefin trapping of the terminal phosphinidene complex. CuCl lowers the activation barrier by interacting directly with the breaking P-C bond. Contrary to the prevailing notion that a free terminal phosphinidene complex (W(CO)(5)=PR) is generated in the CuCl-catalyzed cheletropic elimination of the 7-phosphanorbornadiene-W(CO)(5) complex, the present mechanism suggests that CuCl is attached to the terminal phosphinidene. Furthermore, a "chloride shuttle" takes place where the chloride first migrates to the phosphorus center and then is returned back to the copper center by the incoming olefin in an S(N)2 reaction step. When the substituent on phosphorus is a phenyl group (R = Ph), the uncatalyzed reaction has an activation barrier of 17.9 kcal/mol, which is reduced by 10.9 kcal/mol on including the CuCl catalyst. The CuCl-catalyzed decomposition of 7-phosphanorbornadiene followed by olefin trapping of the terminal phosphinidene complex has a close parallel with the Cu(I)-catalyzed cyclopropanation reaction of diazoalkane. In both catalyzed reactions, copper(I) is coordinated to the phosphinidene/carbene as a Lewis acid, while a Lewis base is displaced from the phosphorus/carbon center as the olefin is added.     

双哌啶基二硫化物的动态NMR的研究

双取代哌啶基二硫化物的动态^1H NMR谱的研究表明,分子内哌啶环的翻转活化自由能较哌啶有显著增加,△G值为71.43±0.25-73.27±0.46kJ.mol^-^1,同时观察到双哌啶基二硫化物分子内哌啶环的3,4,5-位所在平面的翻转,比1,2,6-位所有在平面约快四倍,△G值低3.62kJ.mol^-^1;这充分显示了分子中N原子上带有较大基团的影响.比较双哌啶基二硫化物与相应三硫化物的环翻转能垒,也显示出空间障碍的影响.     

Ab initio calculation of the electronic structure and the barrier to pyramidal inversion for H3S+

The electronic structure of H₃S⁺ is examined by ab initio MO calculations (STO 3G) and is compared with those of other XH₃ type molecules. The barrier to pyramidal inversion and the proton affinity of H₂S are calculated to be 34.8 and 225.05 kcal/mol respectively. Computations are made with respect to a model A₃S⁺ which is employed to discuss the barrier to pyramidal inversion of H₃S⁺, where A corresponds to an electromagnetive substituent or an electron donating one.     

Inversion vs retention of configuration in gas-phase ammonium ion/alcohol reactions

The potential energy surface for gas-phase reactions of ammonium ion with alcohols was examined by ab initio and DFT methods. Transition structures for inversion (S(N)2) and retention (S(N)F) mechanisms were located for 2-propanol and exo-2-norbornanol. The S(N)F (retention) process was found to be 6-8 kcal/mol higher in energy than the inversion S(N)2 counterpart for the 2-propanol system. The retention process in the 2-exo-norbornanol/ammonium ion system was favored by 1.3 kcal/mol.     

Influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine. A theoretical study

The influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine has been studied using density functional theory (DFT) methods. For the neutral system, two different pathways (with retention and inversion of configuration at the C1' anomeric carbon) have been found, both of them consisting of two steps and involving the formation of a dihydrofurane-like intermediate. The Gibbs free energy barrier for the first step is very high in both cases (53 and 46 kcal/mol for the process with inversion and with retention, respectively). However, the N7-protonated system shows a very different mechanism which consists of two steps. The first one leads to the formation of an oxacarbenium ion intermediate, with a Gibbs free energy barrier of 27 kcal/mol, and the second one corresponds to the nucleophilic attack of the water molecule to the oxacarbenium ion and takes place with a barrier of 1.3 kcal/mol. Thus, these results agree with a stepwise SN1 mechanism (DN*AN), with a discrete intermediate formed between the leaving group and the nucleophile approach, and show that N7 protonation strongly catalyzes the hydrolysis of the N-glycosidic bond, making the guanine a better leaving group. Finally, kinetic isotope effects have been calculated for the protonated system, and the results obtained are in very good agreement with experimental data for analogous systems.     

Internal rotation and pyramidal inversion in triacylphosphines

MO calculations predict a P-C rotation barrier in triformylphosphine of less than 6 kcal/mol, and an inversion barrier of ca 14 kcal/mol.     

Vibrational spectra and analysis of acetohydrazide CH3-CO-NH-NH2

The structural stability of acetohydrazide CH(3)-CO-NH-NH(2) was investigated by DFT-B3LYP and ab initio MP2 calculations with 6-311+G** basis set. The C-N rotational barrier in the molecule was calculated to be about 26 kcal/mol that suggested the planar sp(2) nature of the nitrogen atom of the central NH moiety. The N atom of the terminal NH(2) group was predicted to highly prefer the pyramidal sp(3) structure with an inversion barrier of about 7-8 kcal/mol. The molecule was predicted to have a trans-syn (N-H bond is trans with respect to CO bond and NH(2) moiety is syn to C-N bond) conformation as the lowest energy structure. The vibrational frequencies were computed at B3LYP level of theory and normal coordinate calculations were carried out for the trans-syn acetohydrazide. Complete vibrational assignments were made on the basis of normal coordinate analyses and experimental infrared and Raman data.     

Computational study of the aminolysis of 2-benzoxazolinone

Three possible mechanisms (zwitterionic, neutral stepwise, and neutral concerted) of the ring-opening reaction of 2-benzoxazolinone (BO) upon aminolysis with methylamine were studied at the B3LYP/6-31G* level. In the gas phase, the neutral concerted mechanism is shown to be most favorable, which proceeds via a rate-determining barrier of 28-29 kcal/mol. The transition state, CTS, associated with this barrier is a four-centered one, where 1,2-addition of the N[bond]H of methylamine to the C[bond]O of BO ring occurs. The rate-determining barrier of the neutral stepwise pathway is found to be ca. 42 kcal/mol. The inclusion of solvent effects by a polarizable continuum model (PCM) does not change the conclusions based on the gas-phase study; the barrier at CTS is reduced to 20, 20, and 22 kcal/mol in water, ethanol, and acetonitrile, respectively.     

Quantum and molecular mechanical study of the first proton transfer in the catalytic cycle of cytochrome P450cam and its mutant D251N

In the catalytic cycle of cytochrome P450cam, the hydroperoxo intermediate (Cpd 0) is formed by proton transfer from a reduced oxyheme complex (S5). This process is drastically slowed down when Asp251 is mutated to Asn (D251N). We report quantum mechanical/molecular mechanical (QM/MM) calculations that address this proton delivery in the doublet state through a hydrogen-bond network in the Asp251 channel, both for the wild-type enzyme and the D251N mutant, using four different active-site models. For the wild-type, we find a facile concerted mechanism for proton transfer from protonated Asp251 via Wat901 and Thr252 to the FeOO moiety, with a barrier of about 1 kcal/mol and a high exothermicity of more than 20 kcal/mol. In the D251N mutant with a neutral Asn251 residue, the proton transfer is almost thermoneutral or slightly exothermic in the three models considered. It is still very facile when the Asn251 residue adopts a conformation analogous to Asp251 in the wild-type enzyme, but the barrier increases significantly when the Asn251 side chain flips (as indicated by classical molecular dynamics simulations). This flip disrupts the hydrogen-bond network and hence the proton-transfer pathway, which causes a longer lifetime of S5 in the D251N mutant (consistent with experimental observations). The entry of an additional water molecule into the active site of D251N with flipped Asn251 regenerates the hydrogen-bond network and provides a viable mechanism for proton delivery in the mutant, with a moderate barrier of about 7 kcal/mol.     

DFT studies on the copolymerization of alpha-olefins with polar monomers: ethylene-methyl acrylate copolymerization catalyzed by a Pd-based diimine catalyst.

Gradient-corrected density functional theory has been used to study the elementary reactions for the copolymerization of ethylene with methyl acrylate catalyzed by Pd-based diimine catalysts, modeled by the generic complex N(wedge)N-Pd(n-C(3)H(7))(+), with N(wedge)N = -NHCHCHNH-. The steric effects in the real systems are discussed on the basis of the calculations for the catalyst with N(wedge)N = -NArCRCRNAr-, R = CH(3), and Ar = C(6)H(3)(i-Pr(2)) and the previous calculations on ethylene/propylene polymerization. Considerations have been given to the different possible acrylate complexes, as well as the transition states and the products (agostic complexes and the alternative chelates) for two acrylate insertion paths (1,2 and 2,1). The chelate-opening reactions have also been studied. The results revealed a strong electronic preference for the 2,1-insertion paths, with a barrier that is 4.5 kcal/mol lower than any other studied insertion pathway. In the real systems the 2,1-insertion of acrylate is preferred by 0.5 kcal/mol. The 2,1-insertion barrier calculated for the real system of 12.4 kcal/mol is in very good agreement with the experimental value of 12.1 kcal/mol. The six-member chelate is the most stable insertion product with an energy that is 21 kcal/mol lower than the kinetic insertion product. The reactions of the chelate opening by ethylene that start from the lowest energy complexes have the lowest barrier for the four-member ring (23 kcal/mol) and the highest for the six-member structure (30.4 kcal/mol). The high barrier for the opening of the six-member chelate suggests the possibility of a two-step chelate-opening mechanism. The internal barriers for the chelate-opening reactions starting from the higher energy complexes are lower then the one-step reaction that starts from the preferred complex and comparable to those of the ethylene insertion into the Pd-alkyl bond. While the chelate opening by a subsequent acrylate insertion seems to be facile for the generic catalyst, steric effects in the real catalyst are likely to decrease the acrylate pi-complexation energies and increase the insertion barriers to the extent where such a reaction becomes unfeasible.     

The microwave and infrared spectroscopy of benzaldehyde: conflict between theory and experimental deductions

Recently, it has been proposed that ab initio calculations cannot accurately treat molecules comprised of a benzene ring with a pi-conjugated substituent, for example, benzaldehyde. Theoretical predictions of the benzaldehyde barrier to internal rotation are typically a factor of 2 too high in comparison to the experimental values of 4.67 (infared) and 4.90 (microwave) kcal mol(-1). However, both experiments use Pitzer's 1946 model to compute the reduced moment of inertia and employ the experimentally observed torsional frequency to deduce benzaldehyde's rotational barrier. When Pitzer's model is applied to a system with a nonconjugated functional group, such as phenol, the model and theoretical values are in close agreement. Therefore, we conclude the model may not account for conjugation between the substituent and the pi-system of benzene. The experimental values of the benzaldehyde rotational barrier are therefore misleading. The true rotational barrier lies closer to the theoretically extrapolated limit of 7.7 kcal mol(-1), based on coupled cluster theory.     

A density functional theory study of the 5-exo cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals

Density functional theory computations were done to study the 5-exo radical cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals. The methoxy electron donor group substitution reduced the barrier to reaction by about 0.5 kcal/mol. On the other hand, the electron acceptor group substitutions (ethoxycarbonyl, carboxylic acid, carboxylate, and cyano) raised the barrier to reaction by varying amounts (0.5-2.1 kcal /mol). The entropic terms of these cyclization reactions are briefly discussed. Solvent effects on these reactions were explored by calculations that included a polarizable continuum model for the solvent. The density functional theory calculated results were found to be in good agreement with the experimental data available in the literature and help to explain some of the observed variation in these types of cyclization reactions with various substitutions. Our results also provide an explanation for why the rate constant for the carboxylate group substituted radical was found to be an order of magnitude smaller than the rate constant for those radicals with carboxylic acid and ethoxycarbonyl substitutions.     

QM/MM study of catalytic methyl transfer by the N5-glutamine SAM-dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme

The combined density functional quantum mechanical/molecular mechanical (QM/MM) approach has been used to investigate methyl-transfer reactions catalyzed by the N(5)-glutamine S-adenosyl-L-methionine (SAM)-dependent methyltransferase (HemK) and the coenzyme-modified HemK with the replacement of SAM by a nitrogen analogue. Calculations reveal that the catalytic methyl transfer by HemK is an energy-favored process with an activation barrier of 15.7 kcal/mol and an exothermicity of 12.0 kcal/mol, while the coenzyme-modified HemK is unable to catalyze the methyl transfer because of a substantial barrier of 20.6 kcal/mol and instability of the product intermediate. The results lend support to the experimental proposal that the nitrogen analogue of the SAM coenzyme should be a practicable inhibitor for the catalytic methyl transfer by HemK. Comparative QM/MM calculations show that the protein environment, especially the residues Asn197 and Pro198 in the active site, plays a pivotal role in stabilizing the transition state and regulating the positioning of reactive groups.     

1-Magnesiotetrahydroisoquinolyloxazolines as Chiral Nucleophiles in Stereoselective Additions to Aldehydes: Auxiliary Optimization, Asymmetric Synthesis of (+)-Corlumine, (+)-Bicuculline, (+)-Egenine, and (+)-Corytensine, and Preliminary (13)C NMR Studies of 1-Lithio- and 1-Magnesiotetrahydroisoquinolyloxazolines

Transmetalation of 1-lithiotetrahydroisoquinolyloxazolines with magnesium halides affords Grignard reagents that add to aldehydes with up to 80% selectivity for one of the four possible diastereomeric products. An oxazoline chiral auxiliary derived from camphor provides an optimal blend of diastereoselectivity and isomer separability. Synthetic applications of the optimal auxiliary, patterned after a literature approach in the racemic series, comprise an improved (formal) synthesis of bicuculline, egenine, and corytensine, as well as an efficient synthesis of corlumine. Preliminary NMR studies show that both 1-lithio- and 1-magnesiotetrahydroisoquinolyloxazolines are dynamic mixtures in THF solution at low temperatures. The barrier to pyramidal inversion of the secondary Grignard reagent is in the 9.8-10.1 kcal/mol range, while an upper limit of about 8.2 kcal/mol can be assigned to the barrier to the organolithium inversion.