Symmetry‐Enthalpy Correlations in Diels–Alder Reactions

Woodward–Hoffmann (WH) rules provide strict symmetry selection rules: when they are obeyed, a reaction proceeds; when they are not obeyed, there is no reaction. However, the voluminous experimental literature provides ample evidence that strict compliance to symmetry requirements is not an obstacle for a concerted reaction to proceed, and therefore the idea has developed that it is enough to have a certain degree of the required symmetry to have reactivity. Here we provide quantitative evidence of that link, and show that as one deviates from the desired symmetry, the enthalpy of activation increases, that is, we show that concerted reactions slow down the further they are from the ideal symmetry. Specifically, we study the deviation from mirror symmetry (evaluated with the continuous symmetry measure (CSM)) of the [4+2] carbon skeleton of the transition state of a series of twelve Diels–Alder reactions in seven different solvents (and in the gas phase), in which the dienes are butadiene, cyclopentadiene, cyclohexadiene, and cycloheptadiene; the dienophiles are the 1‐, 1,1‐, and 1,1,2‐cyanoethylene derivatives; the solvents were chosen to sample a range of dielectric constants from heptane to ethanol. These components provide twenty‐four symmetry–enthalpy DFT‐calculated correlation lines (out of which only one case is a relatively mild exception) that show the general trend of increase in enthalpy as symmetry decreases. The various combinations between the dienophiles, cyanoethylenes, and solvents provide all kinds of sources for symmetry deviations; it is therefore remarkable that although the enthalpy of activation is dictated by various parameters, symmetry emerges as a primary parameter. In our analysis we also bisected this overall picture into solvent effects and geometry variation effects to evaluate under which conditions the electronic effects are more dominant than symmetry effects.     

Symmetry-enthalpy correlations in diels-alder reactions

Woodward-Hoffmann (WH) rules provide strict symmetry selection rules: when they are obeyed, a reaction proceeds; when they are not obeyed, there is no reaction. However, the voluminous experimental literature provides ample evidence that strict compliance to symmetry requirements is not an obstacle for a concerted reaction to proceed, and therefore the idea has developed that it is enough to have a certain degree of the required symmetry to have reactivity. Here we provide quantitative evidence of that link, and show that as one deviates from the desired symmetry, the enthalpy of activation increases, that is, we show that concerted reactions slow down the further they are from the ideal symmetry. Specifically, we study the deviation from mirror symmetry (evaluated with the continuous symmetry measure (CSM)) of the [4+2] carbon skeleton of the transition state of a series of twelve Diels-Alder reactions in seven different solvents (and in the gas phase), in which the dienes are butadiene, cyclopentadiene, cyclohexadiene, and cycloheptadiene; the dienophiles are the 1-, 1,1-, and 1,1,2-cyanoethylene derivatives; the solvents were chosen to sample a range of dielectric constants from heptane to ethanol. These components provide twenty-four symmetry-enthalpy DFT-calculated correlation lines (out of which only one case is a relatively mild exception) that show the general trend of increase in enthalpy as symmetry decreases. The various combinations between the dienophiles, cyanoethylenes, and solvents provide all kinds of sources for symmetry deviations; it is therefore remarkable that although the enthalpy of activation is dictated by various parameters, symmetry emerges as a primary parameter. In our analysis we also bisected this overall picture into solvent effects and geometry variation effects to evaluate under which conditions the electronic effects are more dominant than symmetry effects.     

Influence of coulombic repulsion on the dissociation pathways and energetics of multiprotein complexes in the gas phase

Thermal dissociation experiments, implemented with blackbody infrared radiative dissociation and Fourier-transform ion cyclotron resonance mass spectrometry, are performed on gaseous protonated and deprotonated ions of the homopentameric B subunits of Shiga toxin 1 (Stx1 B5) and Shiga toxin 2 (Stx2 B5) and the homotetramer streptavidin (S4). Dissociation of the gaseous, multisubunit complexes proceeds predominantly by the loss of a single subunit. Notably, the fractional partitioning of charge between the product ions, i.e., the leaving subunit and the resulting multimer, for a given complex is, within error, constant over the range of charge states investigated. The Arrhenius activation parameters (E(a), A) measured for the loss of subunit decrease with increasing charge state of the complex. However, the parameters for the protonated and deprotonated ions, with the same number of charges, are indistinguishable. The influence of the complex charge state on the dissociation pathways and the magnitude of the dissociation E(a) are modeled theoretically with the discrete charge droplet model (DCDM) and the protein structure model (PSM), wherein the structure of the subunits is considered. Importantly, the major subunit charge states observed experimentally for the Stx1 B5(n+/-) ions correspond to the minimum energy charge distribution predicted by DCDM and PSM assuming a late dissociative transition-state (TS); while for structurally-related Stx2 B5(n+) ions, the experimental charge distribution corresponds to an early TS. It is proposed that the lateness of the TS is related, in part, to the degree of unfolding of the leaving subunit, with Stx1 B being more unfolded than Stx2 B. PSM, incorporating significant subunit unfolding is necessary to account for the product ions observed for the S4(n+) ions. The contribution of Coulombic repulsion to the dissociation E(a) is quantified and the intrinsic activation energy is estimated for the first time.     

Symmetry-broken reactant motion upon phase-related symmetrically modulated excitations: application to highly selective molecular sorting

This paper introduces a separation protocol relying on affinity chromatography that exhibits unprecedented selectivities. We submit the mixture contained in the separative medium to the simultaneous action of two symmetrically modulated excitations. The first is a uniform periodic field (e.g., electric field) with zero mean value, whereas the second is the periodic modulation of a thermodynamic parameter such as the temperature. Under appropriate tuning of the modulations with the dynamics of the discriminating chemical reaction, we predict a symmetry breaking of molecular motion: the mixture components that are addressed by their rate constants exhibit an oriented motion for a particular phase relation between the modulations of the field and the thermodynamic parameter. The resulting velocity of the mixture components depends on the rate constants and on a conjugated thermodynamic value such as the standard enthalpy of the discrimination process in the case of a temperature modulation. In particular, it may be possible to separate mixture components with identical rate constants. We use the present approach to design a protocol to sort nucleic acids by their sequence.     

一些热塑改性热固性树脂体系结构对反应诱导相分离时间/温度依赖性的影响

利用光学显微镜、DSC等手段研究了一些上临界共溶温度(UCST)类型的热塑性改性热固性树脂体系反应诱导相分离时间/温度依赖性随组分化学结构的变化规律.结果表明,分相活化能Ea(ps)受热塑性树脂的主链结构、热固性单体、交联剂结构、化学计量比等因素的影响.利用相互作用能密度解释了实验所研究的UCST体系的相分离活化能Ea(ps)随组分结构的变化规律.     

Aminolyses of aryl diphenylphosphinates and diphenylphosphinothioates: effect of modification of electrophilic center from P=O to P=S

A kinetic study is reported for aminolysis of aryl diphenylphosphinothioates (2a-i). The phosphinothioates 2a-i are less reactive than aryl diphenylphosphinates (1a-i), the oxygen analogues of 2a-i, regardless of the basicity of the leaving aryloxides or the attacking amines. The Yukawa-Tsuno plot for the reactions of 2b-i with piperidine exhibits good linearity with a small r value (r=0.28), indicating that the leaving group departs at the rate-determining step with a small degree of bond fission. Reactions of 2,4-dinitrophenyl diphenylphosphinothioate (2a) with alicyclic secondary amines result in a good linear Br?nsted-type plot with betanuc=0.52, implying that the reactions proceed through a concerted mechanism. The betanuc value determined for the reactions of 2a is slightly larger than that reported for the corresponding reactions of 2,4-dinitrophenyl diphenylphosphinate (1a, i.e., betanuc=0.38), suggesting that reactions of 2a proceed through a tighter transition state (TS) than that of 1a. The reaction of 2a with piperidine exhibits a ca. 0.4 kcal/mol more favorable enthalpy of activation (DeltaH) than that of 1a. On the contrary, the entropy of activation at 25.0 degrees C (TDeltaS) is ca. 1.5 kcal/mol more unfavorable for the reaction of 2a than for that of 1a. This result supports the proposal that the reaction of 2a proceeds through a tighter TS than that of 1a and explains why 2a-i are less reactive than 1a-i.     

Theoretical study on chlorine and hydrogen shift in cycloheptatriene and cyclopentadiene derivatives

The transition structures (TSs) for chlorine 1,7-shift and 1,5-shift in 1,7,7-trichlorocycloheptatriene (1) and those of chlorine 1,5-shifts in 1,5,5-trichlorocyclopentadiene (3) and 1,2,5-trichloro-1,3-pentadiene (5) derivatives have been located with density functional theory (DFT) at the Becke3LYP/6-311G [and Becke3LYP/6-311+G] level. The calculational results were compared with those for corresponding hydrogen shifts in nonsubstituted molecules (cycloheptatriene (2), cyclopentadiene (4), and 1,3-pentadiene (6)). The following points were clarified: (1) The activation energy (Delta E(++)) for chlorine 1,7-shift in 1 was evaluated to be only +50.1 [+49.2] kJ/mol, which is smaller than that (+69.9 [+68.3]) for a 1,5-shift, supporting the theory that the conversion between two equivalent A and A' proceeds through a TS for direct chlorine 1,7-shift (Figure 1), rather than through a TS for a 1,5-shift (Figure 2). (2) The considerable amount of charge separation between a migrating chlorine atom (Cl(m)) and a seven-membered ring (-0.53 and +0.47 for Merz-Singh-Kollman scheme) occurs in a chlorine 1,7-shift, which is in good contrast to the result that the migrating hydrogen atom (H(m)) for a 1,7-shift in cycloheptatriene (2) carries almost no charge (Figure 3). This large charge separation can stabilize the TS for the chlorine 1,7-shift pathway. (3) The Delta E(++) values for suprafacial hydrogen 1,7-shift in 2 are quite large (+288.0 [+284.8] kJ/mol), much larger than that (+166.8 [+167.0]) for a 1,5-shift in 4 which is orbital symmetrically allowed (Figure 3). The calculation suggests that the chlorine 1,7-shift in 1 occurs easily at room temperature (actually observed experimentally) by proceeding via concerted suprafacial 1,7-shift through the zwitterionic TS with the significant assistance of Coulomb interaction between charged fragments (negatively charged chlorine atom and positively charged tropylium ring), rather than via a suprafacial 1,5-sigmatropic pathway. Other cases studied in this paper showed usual results predicted by orbital symmetrical consideration.     

Transition-state energy and position along the reaction coordinate in an extended activation strain model.

We investigate palladium-induced activation of the C-H, C-C, C-F, and C-Cl bonds in methane, ethane, cyclopropane, fluoromethane, and chloromethane, using relativistic density functional theory (DFT) at ZORA-BLYP/TZ2P. Our purpose is to arrive at a qualitative understanding, based on accurate calculations, of the trends in activation barriers and transition state (TS) geometries (e.g. early or late along the reaction coordinate) in terms of the reactants' properties. To this end, we extend the activation strain model (in which the activation energy Delta E(not equal) is decomposed into the activation strain Delta E(not equal)(strain) of the reactants and the stabilizing TS interaction Delta E(not equal)(int) between the reactants) from a single-point analysis of the TS to an analysis along the reaction coordinate zeta, that is, Delta E(zeta)=Delta E(strain)(zeta)+Delta E(int)(zeta). This extension enables us to understand qualitatively, trends in the position of the TS along zeta and, therefore, the values of the activation strain Delta E(not equal)(strain)=Delta E(strain)(zeta(TS)) and TS interaction Delta E(not equal)(int)=Delta E(int)(zeta(TS)) and trends therein. An interesting insight that emerges is that the much higher barrier of metal-mediated C-C versus C-H activation originates from steric shielding of the C-C bond in ethane by C-H bonds. Thus, before a favorable stabilizing interaction with the C-C bond can occur, the C-H bonds must be bent away, which causes the metal-substrate interaction Delta E(int)(zeta) in C-C activation to lag behind. Such steric shielding is not present in the metal-mediated activation of the C-H bond, which is always accessible from the hydrogen side. Other phenomena that are addressed are anion assistance, competition between direct oxidative insertion (OxIn) versus the alternative S(N)2 pathway, and the effect of ring strain.     

On a possible invariance of a transition structure to the effects produced by ancillary H-bonding molecules: Modeling the effects of Ser-48 in the hydride-transfer step of liver alcohol dehydrogenase

The influence of a hydroxyl group simulating Ser-48 in the hydride-transfer step characteristic of liver alcohol dehydrogenase is studied on the hydride-transfer reaction as modeled by a methanolate anion interacting with a cyclo propenyl cation. It is shown first that this is an adequate model by comparing it to the methanolate-pyrydinium cation model transition structure, (TS ). The side-chain effect is modeled first by adding water and then with methanol located at the position that Ser-48 occupies in the enzyme; a supermolecule approach is used. It is found that (i) the normalized advance coordinate (NAC ) for the exchanged hydrogen has an invariant value at the TS and the reactant, while for the product, the NAC depends upon the external perturbation introduced by the ancillary molecule (the TS is reactant-like); (ii) the products are strongly destabilized, so the (activation) barrier with respect to the TS diminishes; (iii) the energy gap between reactants and products is sensibly diminished by the presence of methanol; (iv) the alcoholate moiety in the hydride transfer complex is not spontaneously protonated; and (v) there is a negligible charge transfer between the hydride-transfer system and models of Ser-48. In the present simplified model, methanol appears to have a catalytic effect via hydrogen bonding. © 1996 John Wiley & Sons, Inc.     

Zwitterionic Relatives of Cationic Platinum Group Metal Complexes: Applications in Stoichiometric and Catalytic σ‐Bond Activation

Zwitterionic platinum group metal complexes that feature formal charge separation between a cationic metal fragment and a negatively charged ancillary ligand combine the desirable reactivity profile of related cationic complexes with the broad solubility and solvent tolerance of neutral species. As such, zwitterionic complexes of this type have emerged as attractive candidates for a diversity of applications, most notably involving the breaking and/or forming of E? H and E? C σ bonds involving a main group element E. Important advances in ancillary ligand design are documented that have enabled the construction of platinum group metal zwitterions. Also summarized are the results of stoichiometric and catalytic investigations in which the reactivity of such zwitterions and their more traditionally employed cationic relatives in σ bond activation chemistry are compared and contrasted.     

Multivalent weak electrolytes - risky background electrolytes for capillary zone electrophoresis

Multivalent weak acids and bases are useful components of buffers in electrophoresis. The use of such buffers as background electrolytes (BGEs) in capillary zone electrophoresis (CZE) is, however, risky due to the existence of unsafe regions in the analytical window of the separation. This contribution discusses the problems and shows that multivalent weak species in BGEs bring about the same effects as mixtures of two independent co-ions, i.e., the presence of two centers of symmetry in the electropherograms and the existence of a migrating system zone with a mobility in between these two centers of symmetry. The system zone deteriorates the analytical separation and detection of the analytes in its neighborhood. Illustrative experimental examples for both cationic and anionic CZE are shown and related discussion is given. Finally, some basic rules are formulated to avoid the preparation of risky BGEs.     

Efficient Photoinduced Electron Transfer in a Rigid U-Shaped Tetrad Bearing Terminal Porphyrin and Viologen Units

Apparently solvent-mediated and not through-bond photoinduced electron transfer (ET) takes place from the porphyrin (P) unit to the methylviologen (MV²⁺) unit in the rigid U-shaped molecules 1 (i.e., k_TS^ET>k_TB^ET; TS=through-solvent, TB=through-bond). The ratio of the rates of charge separation to charge recombination is greater than 1400:1.     

Mayr electrophilicity predicts the dual Diels-Alder and sigma-adduct formation behaviour of heteroaromatic super-electrophiles

We report on the dual reactivity, i.e. anionic Meisenheimer sigma adduct formation and Diels-Alder adduct formation, of a series of heteroaromatic super-electrophiles, including 4,6-dinitro-benzofuroxan, -N-arylbenzotriazoles (4), -benzothiadiazole and -benzoselenadiazole. Measured pK(a)(H(2)O) values for sigma adduct formation provide a quantitative measure of super-electrophilic reactivity with a satisfactory correlation between the Mayr E electrophilicity parameter and pK(a)(H(2)O): E = -0.662 pK(a)(H(2)O) (or pK(R+) -3.20 (r(2) = 0.987). The most highly electrophilic, pre-eminent super-electrophile is 4,6-dinitrotetrazolopyridine (E = -4.67, pK(a)(H(2)O) = 0.4), which supercedes the reference Meisenheimer super-electrophile, 4,6-dinitrobenzofuroxan (E = -5.06, pK(a) = 3.75), having itself an E value superior by 8 orders of magnitude compared to 1,3,5-trinitrobenzene as the benchmark normal Meisenheimer electrophile (E = -13.19, pK(a)(H(2)O) = 13.43). (For relevant kinetic parameters as well as E and pK(a) values, see .) In a parallel study we have investigated Diels-Alder (normal and inverse electron demand) reactivity of this series of heteroaromatic electrophiles and have shown that Mayr E values are valid predictors of whether DA adducts will form and how rapidly. The observed order of pericyclic reactivity corresponds to E = -8.5 as the demarcation E value, in close agreement with sigma complexation; thus pointing to a common origin for the two processes, i.e. an inverse relationship between the degree of aromaticity of the carbocyclic ring and ease of sigma complexation, or DA reactivity, respectively.     

Elongated conformers of charge states +11 to +15 of bovine ubiquitin studied using ESI-FAIMS-MS

Recent advancements in high-field asymmetric waveform ion mobility spectrometry (FAIMS) have led to significant improvements in the application of this technology to the study of protein conformers. Compared with previous work, the maximum value of the separation voltage (i.e., the dispersion voltage) has increased, thereby enabling multiple, elongated conformers of individual charge states of bovine ubiquitin to be separated in the gas phase (e.g., four conformers of each of the +11 and +12 charge states were separated). The use of a carrier gas mixture of 40% nitrogen and 60% helium changed the separation selectivity compared with pure nitrogen and enhanced the signal intensity, especially for the +14 and +15 charge states (the latter was not detected in a nitrogen carrier gas). Conformer cross sections were determined using the FAIMS/energy-loss method and found to be similar within a given charge state. The cross sections for conformers of charge states +13, + 14, and +15 plateau at about 2000 A2 suggesting that the structure of bovine ubiquitin is essentially unfolded after the addition of the 13th proton.     

Blackbody infrared radiative dissociation of bradykinin and its analogues: energetics, dynamics, and evidence for salt-bridge structures in the gas phase

Blackbody infrared radiative dissociation (BIRD) spectra of singly and doubly protonated bradykinin and its analogues are measured in a Fourier-transform mass spectrometer. Rate constants for dissociation are measured as a function of temperature with reaction delays up to 600 s. From these data, Arrhenius activation parameters in the zero-pressure limit are obtained. The activation parameters and dissociation products for the singly protonated ions are highly sensitive to small changes in ion structure. The Arrhenius activation energy (E(a)) and pre-exponential (or frequency factor, A) of the singly protonated ions investigated here range from 0.6 to 1.4 eV and 10(5) to 10(12) s(-1), respectively. For bradykinin and its analogues differing by modification of the residues between the two arginine groups on either end of the molecule, the singly and doubly protonated ions have average activation energies of 1.2 and 0.8 eV, respectively, and average A values of 10(8) and 10(12) s(-1), respectively, i.e., the presence of a second charge reduces the activation energy by 0.4 eV and decreases the A value by a factor of 10(4). This demonstrates that the presence of a second charge can dramatically influence the dissociation dynamics of these ions. The doubly protonated methyl ester of bradykinin has an E(a) of 0.82 eV, comparable to the value of 0.84 eV for bradykinin itself. However, this value is 0.21 +/- 0.08 eV greater than that of singly protonated methyl ester of bradykinin, indicating that the Coulomb repulsion is not the most significant factor in the activation energy of this ion. Both singly and doubly protonated Lys-bradykinin ions have higher activation energies than the corresponding bradykinin ions indicating that the addition of a basic residue stabilizes these ions with respect to dissociation. Methylation of the carboxylic acid group of the C-terminus reduces the E(a) of bradykinin from 1.3 to 0.6 eV and the A factor from 1012 to 105 s(-1). This modification also dramatically changes the dissociation products. Similar results are observed for [Ala(6)]-bradykinin and its methyl ester. These results, in combination with others presented here, provide experimental evidence that the most stable form of singly protonated bradykinin is a salt-bridge structure.     

On the existence of a natural common gauge-origin for the calculation of magnetic properties of atoms and molecules via gaugeless basis sets

It is proven that, within the conventional approach using a common origin and gaugeless basis sets for the calculation of atomic magnetizability and Larmor current density induced by an external magnetic field, the natural gauge origin coincides with the nucleus. Recipes for defining an optimal gauge origin for the calculation of magnetizability and magnetic shielding at the nuclei of a molecule are given. Within the common origin approach, the paramagnetic contributions to the components of magnetic tensors of a molecule are represented by a minimum number of non-vanishing parameters if the gauge origin is chosen at a point characterized by the total molecular symmetry, e.g., the center of electronic charge for magnetizabilities. It is shown that total values of diagonal components of the magnetic shielding tensor σ(I) at a nucleus I in a molecule, as well as separate diamagnetic σ(dI) and paramagnetic σ(pI) contributions, calculated via the common origin method, are origin independent for a number of local point group symmetries. The diagonal components (and the average value) of σ(I) depend on the gauge origin only for nuclear site symmetries C(1), C(s), C(n), C(nv), n = 2, 3.... Group-theoretical methods show interesting features, e.g., for S(4) local symmetry, in a coordinate transformation, the paramagnetic contribution to the zz component and to the trace of the shielding tensor is origin independent, whereas the xx and yy components mix into one another, in such a way that their sum remains constant.     

Hydrolysis theory for cisplatin and its analogues based on density functional studies

Hydrolysis of cisplatin, the most widely used anticancer drug in the world, is believed to be the key activation step before the drug reaching its intracellular target DNA.To obtain an accurate hydrolysis theory for this important class of square-planar Pt(II) complexes, three typical reactions, i.e., the first and second hydrolyses of cisplatin and the hydrolysis of [Pt(dien)Cl](+) (dien = diethylenetriamine), were studied at the experimental temperature with the solvent effect using mPW1PW91/SDD from a comprehensive methodological study on the Hartree-Fock (HF) ab initio method, electron correlation methods, pure density functional theory (DFT) methods, and hybrid HF-DFT methods with several basis sets. The true five stationary states in the second-order nucleophilic substitution (S(N)2) pathway for the hydrolysis process, namely, reactant (R) --> intermediate 1 (I1) --> TS --> intermediate 2 (I2) --> product (P) were obtained and characterized theoretically for the first time. The most remarkable structural variations and the associated atomic charge variations in the hydrolysis process were found to occur in the equatorial plane of the five-coordinate trigonal-bipyramidal (TBP)-like structures of I1, TS, and I2. The reaction with the TS structure of smaller L-M-E angle and more lengthened M-L and M-E bonds was found to have a smaller Gibbs free energy change and accordingly the better hydrolysis yield. It is found that the sum of the three concentric angles in the TBP's equator is near 360 degrees in I1 and I2 and is almost 360 degrees in TS in each reaction. The associated energy profiles again demonstrated a typical S(N)2 reaction curve. The computed forward and backward reaction enthalpy (Delta H(++)) and reaction entropy (Delta S(++)) in the rate-determining step I1 --> TS --> I2 are in good agreement with the experiments. Natural bonding orbital population analysis shows that the charge-separating extent follows the same order of Delta G in studied reactions. Comparing with the computational results of gas-phase reactions, it can be concluded that the solvent effect should be considered to obtain an accurate hydrolysis picture. The most affected structural parameters after solvation are related to the equatorial plane of the TBP-like geometry. The results provide theoretical guidance on detailed understanding on the mechanism of the hydrolysis of cisplatin, which could be useful in the design of novel Pt-based anticancer agents.