Concerted Formation Research Articles

Understanding the molecular mechanism of the 1,3-dipolar cycloaddition between fulminic acid and acetylene in terms of the electron localization function and catastrophe theory.

The potential-energy profile of the 1,3-dipolar cycloaddition of fulminic acid and ethyne has been investigated theoretically within the framework provided by the electron localization function (ELF) analysis. This has been achieved by carrying out density functional theory (B3 LYP approach) calculations using the bonding evolution theory. Eight different domains of structural stability have been identified along the reaction path, as well as the bifurcation catastrophes responsible for the changes in the topology of the system. The analysis provides a chemical description of the reaction mechanism in terms of heterolytic concerted nonsynchronous bond formation: the first four catastrophes enable the simultaneous formation of the C-C bond and a lone pair on the nitrogen atom, whereas the remaining ones lead to the ring closure. The valence basin populations calculated along the reaction path do not support any mechanism involving pentavalent nitrogen. The simulation of the solvent effect, by means of a continuum model, does not indicate any significant difference of the mechanism of reaction between the gas phase and solution.

A concerted three-body formation X+Y+C2H4 in the photodissociation of CH2XCH2Y (X,Y=Br,Cl) at 193 nm.

The photodissociation of CH2XCH2Y (X,Y=Br,Cl) through absorption of 193 nm photons was investigated using product translational spectroscopy. No stable CH2BrCH2 or CH2ClCH2 was detected. The recorded time-of-flight spectra indicate that these internally excited radicals dissociated into Y+C2H4 in a concerted reaction with the first C-X bond rupture. Product anisotropy implies that the overall reaction time for three-body formation is in a fraction of rotational period. According to an asynchronous concerted reaction model, the measured spectra were simulated with product translational energy distributions coupled by asymmetric angular distributions. For the mixed halide, CH2BrCH2Cl, triple products Br+Cl+C2H4 can be originated from the cleavage of either the C-Br bond or the C-Cl bond. The results are discussed and where appropriate, comparisons with previous investigations of the related molecules are included.

Hydrogen-induced unzipping of single-walled carbon nanotubes

The chemisorption of atomic hydrogen on the single-walled armchair and zigzag carbon nanotubes is studied with ab initio calculations. The binding energy of H adsorption at the exterior of the nanotubes is much greater than that at the interior. We predict that two rows of H atoms chemisorbed on selective sites exterior to the smaller armchair nanotubes can break the nearest-neighbor $\mathrm{C}---\mathrm{C}$ bonds of the nanotubes through the concerted formation of $\mathrm{C}---\mathrm{H}$ bonds, leading to the unzipping of the nanotube wall. On the other hand, the larger armchair and zigzag nanotubes are stable against unzipping. We provide insights into the underlying electronic mechanism for the H-induced unzipping, lending strong support to the recent experimental observations for the coalescence of single-walled nanotubes in the presence of atomic hydrogen. Interestingly, H atoms chemisorbed inside the nanotubes do not break the $\mathrm{C}---\mathrm{C}$ bonds.

Thioformaldehyde S-methylide and thioacetone S-methylide: an ab initio MO study of structure and cycloaddition reactivity.

The mechanisms of cycloaddition of thioformaldehyde S-methylide and thioacetone S-methylide, as models for an alkyl-substituted ylide, to thioformaldehyde and thioacetone, as well as to ethene as a model for a C=C double bond have been studied by ab initio calculations. Restricted and unrestricted B3LYP/6-31G* calculations were performed for the geometries of ground states, transition structures, and intermediates. Although basis sets with more polarization functions were tested, the 6-31G* basis set was applied throughout. Single-point CASPT2 calculations are reported for analysis of the unsubstituted system. The stabilities of structures with high biradical character seem to be overestimated by DFT methods in comparison to CASPT2. The general trends of the results are independent of the level of theory. Thioformaldehyde adds to thioformaldehyde S-methylide without activation energy, and the activation energies for two-step biradical pathways to 1,3-dithiolane are low. C,S biradicals are more stable than C,C biradicals. The two-step cycloaddition is not competitive with the concerted cycloaddition. Methyl substitution in the 1,3-dipole and the dipolarophile does not change the mechanistic relationships. TSs for the concerted formation of the regioisomeric cycloadducts of thioacetone Smethylide and thioacetone were located. Concerted addition remains the preferred reaction. The reactivity of the C=S double bond is high relative to that of the C=C double bond.

A computational study on addition of Grignard reagents to carbonyl compounds.

The mechanism of stereoselective addition of Grignard reagents to carbonyl compounds has been investigated using B3LYP density functional theory calculations. The study of the reaction of methylmagnesium chloride and formaldehyde in dimethyl ether revealed a new reaction path involving carbonyl compound coordination to magnesium atoms in a dimeric Grignard reagent. The structure of the transition state for the addition step shows that an interaction between a vicinal-magnesium bonding alkyl group and C=O causes the C-C bond formation. The simplified mechanism shown by this model is in accord with the aggregation nature of Grignard reagents and their high reactivities toward carbonyl compounds. Concerted and four-centered formation of strong O-Mg and C-C bonds was suggested as a polar mechanism. When the alkyl group is bulky, C-C bond formation is blocked and the Mg-O bond formation takes precedence. A diradical is formed with the odd spins localized on the alkyl group and carbonyl moiety. Diradical formation and its recombination were suggested to be a single electron transfer (SET) process. The criteria for the concerted polar and stepwise SET processes were discussed in terms of precursor geometries and relative energies.

Dissection of the pathway of molecular recognition by calmodulin.

Amide hydrogen exchange has been used to examine the structural dynamics and energetics of the interaction of a peptide corresponding to the calmodulin-binding domain of smooth muscle myosin light chain kinase (smMLCKp) with calcium-saturated calmodulin. Heteronuclear NMR (15)N-(1)H correlation spectroscopy was used to quantify amide proton exchange rates of the uniformly (15)N-labeled domain bound to calmodulin. A key feature of a proposed model for molecular recognition by calmodulin [Ehrhardt et al. (1995) Biochemistry 34, 2731-2738] is tested by examination of the dependence of amide hydrogen exchange on applied hydrostatic pressure. Hydrogen exchange rates and corresponding protection factors (1/K(op)) for individual amide protons of the bound smMLCKp domain span 5 orders of magnitude at ambient pressure. Individual protection factors decrease significantly in a linear fashion with increasing hydrostatic pressure. A common pressure dependence is revealed by a constant large negative volume change across the residues comprising the core of the bound helical domain. The pattern of protection factors and their response to hydrostatic pressure is consistent with a structural reorganization that results in the concerted disruption of ion pairs between calmodulin and the bound domain. These observations reinforce a model for the molecular recognition pathway where formation of the initial encounter complex is followed by helix-coil transitions in the bound state and subsequent concerted formation of the extensive ion pair network defining the intermolecular contact surface between CaM and the target domain in the final, compact complex structure.

Trimethylenemethane Derivatives Stabilized by Conjugation II − Concerted or Nonconcerted Generation?

The concerted formation of the orthogonal trimethylene-type diradicals 3, 6, and 12 has been demonstrated for the three homofulvenes 2, 4, and 7 and shown to proceed preferentially in a disrotatory manner. The same type of orthogonal diradicals are formed, but in a nonconcerted fashion, from the bicyclic methylenecyclopropanes 26, 30, 33, and 40, through the planar diradicals 28, 31, 35, and 50, respectively. The different reaction modes are viewed as being caused by the different coupling probabilities of the underlying vibrations. The orthogonal or planar geometries of the diradicals were derived from stereochemical and kinetic arguments. Additional thermodynamic characterization was achieved for three diradicals [3c, (E)-19, and 41] by oxygen-trapping experiments.

The Photo-Nazarov Cyclization of 1-Cyclohexenyl(phenyl)methanone Revisited − Trapping of the 2-Oxyallyl Intermediates by Olefins

The photochemistry (> 300 nm) of 1-cyclohexenyl(phenyl)methanone (1) in the presence of various monoolefins and cyclopentadiene (9) has been investigated. While (Z)-cyclooctene and 1-pentene were unreactive, styrene, (E)-cyclooctene, and diene 9 co-reacted upon irradiation of 1. The reactions observed include [4 + 2] and [2 + 2] cycloadditions of the monoolefins to the primary photoproduct of 1 (which is the trans isomer 2), and trapping reactions of the 2-oxyallyl compound 4 formed thermally from 2 as a secondary intermediate. The trapping reactions of 4 are ene-type additions of the olefins, analogous to those observed with the prototypical 2-oxyallyl compound 18 in purely thermal reactions, and involving a hydrogen transfer from 4 to olefin to give adducts 10, 12, 13, 24, and 25. However, while 18 gives one single ene-type adduct with 9, intermediate 4 displays two regioisomeric ene-type addition modes with 9, both of which are concerted, albeit nonsynchronous. In the mode resulting in 10, it is suggested that hydrogen transfer lags behind C−C bond formation, whereas the reverse holds for the mode affording 12 and 13. For both major adducts, 10 and 12, concerted formation requires endo orientations of the two π systems.

1,3-Dipolar Cycloaddition Reactions of Stable Bicyclic and Monocyclic Azomethine Ylides: Kinetic Aspects

Kinetic data for 1,3-dipolar cycloadditions of stable azomethine ylides 1–3 with angle-strained, electron-poor and electron-rich 2π-components 4–10 prove that most reactions are LUMOdipole–HOMOdipolarophile-controlled. Small ρ-values and a minor solvent effect on the rate constants are in accord with a concerted bond formation in the transition state.

2++4] Cycloadditions of Iminium Ions − Concerted or Stepwise Mechanism of Aza Diels−Alder Reactions?

The N,N-dimethylmethyleneammonium ion 1 reacts regio- and stereoselectively with the 1,3-dienes 2a−2f to yield the 1,2,5,6-tetrahydropyridinium ions 3. The kinetics of these hetero Diels−Alder reactions, which have been followed by dilatometry and 1H-NMR spectroscopy, obey second-order rate laws. Since the observed rate constants are only 30−300 times larger than those calculated for the stepwise process by the linear free-enthalpy relationship lg k = s (E + N), it is concluded that these cycloadditions proceed in a stepwise manner or through pericyclic transition states that are not significantly stabilized by the concerted formation of two new σ-bonds. In contrast, the reaction of the iminium ion 1 with cyclopentadiene (2g) yields 2,2-dimethyl-2-azoniabicyclo[2.2.1]hept-5-ene (3g) 2×104 times more rapidly than predicted for the stepwise cycloaddition process, indicating a free enthalpy of concert of 27 kJ mol−1.

Definition and design of diagonalization reactions. Reactions of 1,2-heteraazetidine N-oxides

We have defined diagonalization reactions as a concerted bond formation between the diagonal saturated atoms in cyclic molecules and designed the reactions of 1,2-heteraazetidine N-oxides to produce heteracyclopropanes with the extrusion of HNO. Analysis of the bond interactions at the transition states suggested the reactivities of the diagonalization reactions are controlled by the strains of the incipient rings of the transition structures.

Theoretical and experimental investigation of the formation of E- and Z-Aldimines from the reaction of methylamine with acetaldehyde

The reaction of methylamine with acetaldehyde in pentane at 230 K leads to formation of both E- and Z- aldimines, the Z-isomer being the main product and generated upon kinetic control. The E- form is more stable than the Z- form by 3.3 kcal/mol (DG*). Ab initio calculations have indicated that a tetrahedral zwitterion intermediate is not formed, and the bimolecular process, forming the aminoalcohol intermediate, occurs through a four center transition state, with concerted formation of C-N bond and proton transfer. However, the predicted DG*¹ is very high, indicating that the true mechanism for this step is not bimolecular. A catalyzed pathway must be actuating. The following step, unimolecular elimination of water, also presents a very high activation free energy. Similarly, a catalyzed mechanism is needed. The isomerization from the Z- form to the E- form through inversion of the nitrogen atom has a predicted DG*¹ of 27.0 kcal/mol at 298.15 K, resulting in a lifetime of four months for the Z-isomer.

Photochemistry of Highly Alkylated Dienes: Computational Evidence for a Concerted Formation of Bicyclobutane

In this report, high-level ab initio quantum chemical computations (MC−SCF and multireference Møller−Plesset perturbation theory) are used to compute the composite S2 → S1 → S0 relaxation/reaction paths describing the photorearrangement of the highly alkylated diene 2,3-di-tert-butylbuta-1,3-diene (1) and of the parent compound s-cis-buta-1,3-diene. Reaction path computations require, typically, hundreds of energy and gradient evaluations. For this reason, we have defined, validated, and employed a simple hybrid method designed to simulate a tert-butyl group at the computational cost of a methyl group. Despite the fact that the method only treats specific substituents (e.g. tert-butyl groups) embedded in a specific environment (e.g. a hydrocarbon skeleton) we show that it can be successfully employed in mechanistic studies where steric factors dominate. The analysis of the computed relaxation coordinate provides a mechanistic explanation for the different strained photoproducts generated by photolysis of the parent and substituted dienes. In particular, we show that while s-cis-buta-1,3-diene produces cyclobut-1-ene via a disrotatory ring-closure path, the two bulky tert-butyl substituents in 1 greatly enhance the production of a highly strained bicyclo[1.1.0]butane derivative (which forms only in traces when the parent compound is photolyzed) by driving the excited-state relaxation along a concerted and synchronous path characterized by a conrotatory rotation of the two terminal methylenes.

Molecular mechanisms for cooperative folding of proteins

The folding of single-domain globular proteins exhibits the character of first-order or two-state thermodynamics. The origin of such high cooperativity in relatively small polymer systems is still not well understood. Recently, the statistical mechanics of protein folding has been studied extensively with simple protein models such as short cubic-lattice chains with contact-based interactions. While many valuable insights about protein folding were gained with such models, some concerns have also arisen, viz. that they lack the character of protein backbones whose interactions would limit the folding patterns of proteins. Here, a comparative study of the conventional cubic-lattice chain model and a fine-grained more realistic lattice protein model with both backbone and side-chain interactions is carried out. It is found that, even though both types of models exhibit a cooperative two-state folding transition to the native structure with optimized force fields, the character and origin of cooperativity of the two models are different. In the simple contact-based model, the free-energy barrier occurs at the low end of the energy scale, and the cooperativity arises from a concerted formation of native contacts among many residues in a compact state. In the other more complicated model, the free-energy barrier occurs in the intermediate energy region, and the folding cooperativity arises from collective orientational arrangements of locally structured units in semi-open conformational states. On the basis of these results, two limiting molecular mechanisms for protein folding emerge, which can be used for analyzing the folding process of real proteins.

Pentazole chemistry: the mechanism of the reaction of aryldiazonium chlorides with azide ion at −80 °C: concerted versus stepwise formation of arylpentazoles, detection of a pentazene intermediate, a combined 1H and 15N NMR experimental and ab initio theoretical study

The reaction of p-chlorophenyldiazonium chloride with azide ion at –80 °C has been examined by 1H and 15N NMR spectra. The main product, p-azidochlorobenzene, was present in the earliest spectra. Spectra were obtained before the appearance of the second product, p-chlorophenylpentazole and an intermediate was observed. Correlated ab initio calculations at the MP2/6-31G* level on 1H-pentazole and 1-phenylpentazole agree with the NMR spectra. An (E,Z)-arylpentazene 3 is the key intermediate leading to the 1-arylpentazole products. A (Z,E)-arylpentazene 2 leads directly to the aryl azide and is not convertible to the E-isomer. Three isomeric arylpentazenes, Z,E, E,E and E,Z are formed from initial azide ion attack at the diazonium β-atom.

Folding Dynamics of the src SH3 Domain

The thermodynamics and kinetics of folding of the chicken src SH3 domain were characterized using equilibrium and stopped-flow fluorescence, circular dichroism (CD), and nuclear magnetic resonance (NMR) hydrogen exchange experiments. As found for other SH3 domains, guanidinium chloride (GdmCl) denaturation melts followed by both fluorescence and circular dichroism were nearly superimposable, indicating the concerted formation of secondary and tertiary structure. Kinetic studies confirmed the two-state character of the folding reaction. Except for a very slow refolding phase due to proline isomerization, both folding and unfolding traces fit well to single exponentials over a wide range of GdmCl concentrations, and no burst phase in amplitude was observed during the dead time of the stopped-flow instrument. The entropy, enthalpy, and heat capacity changes upon unfolding were determined by global fitting of temperature melts at varying GdmCl concentrations (0.4-3.7 M). Estimates of the free energy of unfolding, DeltaGUH2O, from guanidine denaturation, thermal denaturation, and kinetic experiments were in good agreement. To complement these data on the global characteristics of src SH3 folding, individual hydrogen-deuterium (HD) exchange rates were measured for approximately half of the backbone amides in 0 and 0.7 M GdmCl. The calculated free energies of the opening reaction leading to exchange (DeltaGHD) indicated that unfolding is highly cooperative--slowly exchanging protons were distributed throughout the core of the protein. The slowly exchanging protons exhibited DeltaGHD values higher than the global DeltaGUH2O by approximately 1 kcal/mol, suggesting that the denatured state might be somewhat compact under native conditions. Comparison of the src SH3 with homologous SH3 domains as well as with other small well-characterized beta-sheet proteins provides insights into the determinants of folding kinetics and protein stability.

Water Catalyzed Hydrolysis ofp-Nitrotrifluoroacetanilide and Trifluoroacetanilide. Carbonyl18O-Exchange Does Not Accompany the Water Reaction

The water catalyzed hydrolyses of p-nitrotrifluoroacetanilide (3) and trifluoroacetanilide (8) were studied at various pH's and temperatures. The activation parameters for the water reactions of 3 and 8 are: ΔH⧧ = 14.4 ± 0.6 and 11.7 ± 0.3 kcal/mol and ΔS⧧ = −36.1 ± 1.8 and −52.3 ± 0.7 cal/mol·K, respectively. These are consistent with reactions that involve considerable restriction of degrees of freedom of the solvent/substrate in the transition state. A proton inventory analysis of the rate constants for hydrolysis of 3 in media of different mole fraction D2O indicates the process involves two or more protons in flight or undergoing loosening of their bonding in the transition state. 18O-Labeled amides were subjected to the hydrolytic conditions for various times up to 3 half-times of hydrolysis and recovered. Mass analysis showed that the 18O content in the recovered amide did not change during the course of the reaction. All the data support a process where the rate-limiting step for the water reaction involves a concerted or nearly concerted formation of a diol which undergoes subsequent C−N cleavage in preference to OH expulsion.

Solid-acid-catalyzed alkane cracking mechanisms: evidence from reactions of small probe molecules

This review is a summary of the mechanisms of catalytic cracking of small (C3-C6) alkanes. Most of the evidence has arisen from product distributions and kinetics of cracking of these alkanes, interpreted on the basis of solution carbocation chemistry and theoretical chemistry. Cracking of small alkanes catalyzed by solid acids such as the zeolite HZSM-5 proceeds by two mechanisms: (1) The unimolecular (protolytic cracking) mechanism, which proceeds via an alkanium ion formed by protonation of the alkane by the catalyst. This supposed transition state collapses to give either H2 and a carbenium ion or an alkane and a carbenium ion; the carbenium ions give up protons to the catalyst to form alkenes. The cracking products include methane and ethane as well as H2. (2) The classical (bimolecular) cracking mechanism, which involves carbenium ion chain carriers that react with the alkane reactant to abstract hydrides and generate carbenium ions that undergo β-scission. The products include alkanes and alkenes, but not methane, ethane, or H2. Because protolytic cracking gives alkene products, which are much stronger bases than alkanes, the alkenes become the predominant proton acceptors as conversions increase, and thus bimolecular cracking prevails at all but the lowest conversions. Protolytic cracking in the near absence of secondary reactions has been observed only for propane and n-butane at low conversions; secondary reactions appear to be generally significant for other alkanes. Although the product distributions are qualitatively understood, there are still inconsistencies in the literature of quantitative product distributions and kinetics, and more experimental work is needed with standard catalysts such as HZSM-5. Theoretical chemistry is leading to deeper understanding of the transition states, showing that cracking mechanisms involving bare carbocations are oversimplified. Rather, the catalyst surface must be included, and it has been simulated by clusters that are zeolite fragments. Surface alkoxides are more stable than surface carbenium ions, and cracking takes place by concerted bond breaking and formation. Theoretical activation energies for protolytic cracking of alkanes are close to experimental activation energies that have been corrected for the adsorption energy of the reactant, but it appears that more theoretical work (as well as better data) is required for satisfactory agreement of theory and experiment.

The chemistry of metallacyclic alkenylcarbene complexes, 3. CC bond formation with carbon nucleophiles. stereoselective dienylation of lithium enolates and cuprates and a novel cascade synthesis of highly substituted cyclopentenones from lithium acetylides

AbstractThe cationic ferracyclic carbene complexes 1 react with carbon nucleophiles like lithium enolates and organocuprates to give the corresponding 4‐substituted 1, (3E)‐diene tricarbonyl‐iron complexes 6 and 9. The reaction is thought to proceed by initial attack on the allyl terminus and subsequent ferra Claisen‐Ireland rearrangement of the intermediate (η2 alkene)carbene complex 4. This rationale is supported by the isolation and characterisation of analogous aminooxocarbene derivatives 8. With sterically demanding enolates products 6 are formed in diastereomeric ratios of up to 90:10, thus demonstrating the inductive power of the chiral metallacycle in 1. Lithium acetylides as carbon nucleophiles react with 1 according to a novel cascade to give regio‐ and stereospecifically 2,5,5‐trisubstituted‐cyclopentenones 10 suggesting a concerted formation of four CC bonds together with a CO insertion and a formal carbene transfer step.

Characterization of Transition States in Dichloro(1,4,7-triazacyclononane)copper(II)-Catalyzed Activated Phosphate Diester Hydrolysis

The reaction mechanism for Cu[9]aneN3Cl2-catalyzed hydrolysis of ethyl 4-nitrophenyl phosphate was probed using kinetic isotope effects and isotope exchange experiments. The solvent deuterium isotope effect (Dk = 1.14), combined with the absence of 18O incorporation into 4-nitrophenol, suggests that hydrolysis proceeds through intramolecular attack of the metal-coordinated hydroxide at the phosphorus center. The secondary 15N isotope effect (15k = 1.0013 ± 0.0002) implies that loss of the leaving group occurs at the rate-limiting step with approximately 50% bond cleavage in the transition state. This study is one of the first applications of the secondary 15N isotope effect to simple metal-promoted hydrolysis reactions, and the result is consistent with concerted bond formation and cleavage. A mechanism consistent with the isotope studies is presented.