Competitive Diels-Alder reactions: cyclopentadiene and phospholes with butadiene

Diene-dienophile competing Diels-Alder reaction pathways of cyclopentadiene, 1H-, 2H- and 3H-phospholes with butadiene were explored at the B3LYP level using 6-31G(d) and 6-311+G(d,p) basis sets, and at the CCSD(T)/6-31G(d)//B3LYP/6-31G(d) level. Activation barriers show that cyclopentadiene favors a diene rather than a dienophile conformation. Pathways 1 and 2 (A and B) corresponding to butadiene as the diene and dienophile are predicted to be highly competitive in the case of 1H-phosphole. Secondary orbital interactions and the preferable bispericyclic nature of transition states are responsible for the stability of endo transition states. The study indicates that some of the transition states are bispericyclic and most of them are highly asynchronous. The reactions require a lower activation energy when the conversion of weak C=P to C-P occurs in the case of 2H- and 3H-phospholes. The high stability of the products resulting via path 1 can be attributed to the less strain in the bicyclo[4.3.0]nonadiene skeleton compared to the norbornene derivatives obtained from path 2. Activation and reaction energy values for these Diels-Alder reaction pathways are compared with the values reported for the [4+2] cyclodimerizations of each of the reactants to examine the likelihood of cyclodimerizations along these pathways.     

Accurate prediction of rate constants of Diels-Alder reactions and application to design of Diels-Alder ligation

Bioorthogonal reactions are useful tools to gain insights into the structure, dynamics, and function of biomolecules in the field of chemical biology. Recently, the Diels-Alder reaction has become a promising and attractive procedure for ligation in bioorthogonal chemistry because of its higher rate and selectivity in water. However, a drawback of the previous Diels-Alder ligation is that the widely used maleimide moiety as a typical Michael acceptor can readily undergo Michael addition with nucleophiles in living systems. Thus, it is important to develop a nucleophile-tolerant Diels-Alder system in order to extend the scope of the application of Diels-Alder ligation. To solve this problem, we found that the theoretical protocol M06-2X/6-31+G(d)//B3LYP/6-31G(d) can accurately predict the activation free energies of Diels-Alder reactions with a precision of 1.4 kcal mol(-1) by benchmarking the calculations against the 72 available experimental data. Subsequently, the electronic effect and ring-strain effect on the Diels-Alder reaction were studied to guide the design of the new dienophiles. The criteria of the design is that the designed Diels-Alder reaction should have a lower barrier than the Michael addition, while at the same time it should show a similar (or even higher) reactivity as compared to the maleimide-involving Diels-Alder ligation. Among the designed dienophiles, three substituted cyclopropenes (i.e. 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes) meet our requirements. These substituted cyclopropene analogs could be synthesized and they are thermodynamically stable. As a result, we propose that 1,2-bis(trifluoromethyl)-, 1,2-bis(hydroxylmethyl)- and 1,2-bis(hydroxylmethyl)-3-carboxylcyclopropenes may be potential candidates for efficient and selective Diels-Alder ligation in living systems.     

On the origin of cis/trans stereoselectivity in intramolecular Diels-Alder reactions of substituted pentadienyl acrylates: a comprehensive density functional study

[structures: see text] A gas-phase B3LYP/6-31+G(d) study of substituent effects on the stereochemistry of both intramolecular Diels-Alder (IMDA) reactions of 9-E- and 9-Z-substituted pentadienyl acrylates and intermolecular Diels-Alder (DA) reactions between butadiene and monosubstituted alkenes and 3-substituted acrylates is reported and involves the calculation of 230 transition structures. It was found that, although exo ("anti-Alder") addition of monosubstituted ethenes to butadiene is the norm, Alder endo selectivity is more widely predicted for 3-substituted methyl acrylate dienophiles, and this was explained in terms of secondary orbital interactions (SOIs). Whereas cis/trans selectivity for IMDA reactions involving 9-E-substituted pentadienyl acrylates generally follows the normal pattern found for the corresponding intermolecular DA reactions, the 9-Z-substituted stereoisomers generally displayed trans selectivity that was much stronger than can be attributed to effects of the isolated substituent. This is strikingly so with unsaturated electron-withdrawing substituents whose endo selectivities, displayed in intermolecular DA reactions, are reversed in the IMDA reactions of pentadienyl acrylates. The origin of this anomalous Z-effect is explained in terms of the twist-mode asynchronicity concept of Brown and Houk. These ideas are used to explain the stereochemical outcomes of IMDA reactions of other triene systems.     

Origins of stereoselectivity in the Diels-Alder addition of chiral hydroxyalkyl vinyl ketones to cyclopentadiene: a quantitative computational study

Modest basis set level MP2/6-31G(d,p) calculations on the Diels-Alder addition of S-1-alkyl-1-hydroxy-but-3-en-2-ones (1-hydroxy-1-alkyl methyl vinyl ketones) to cyclopentadiene correctly reproduce the trends in known experimental endo/exo and diastereoface selectivity. B3LYP theoretical results at the same or significantly higher basis set level, on the other hand, do not satisfactorily model observed endo/exo selectivities and are thus unsuitable for quantitative studies. The same is valid also with regard to subtle effects originating from, for example, conformational distributions of reactants. The latter shortcomings are not alleviated by the fact that observed diastereoface selectivities are well-reproduced by DFT calculations. Quantitative computational studies of large cycloaddition systems would require higher basis sets and better account for electron correlation than MP2, such as, for example, CCSD. Presently, however, with 30 or more non-hydrogen atoms, these computations are hardly feasible. We present quantitatively correct stereochemical predictions using a hybrid layered ONIOM computational approach, including the chiral carbon atom and the intramolecular hydrogen bond into a higher level, MP2/6-311G(d,p) or CCSD/6-311G(d,p), layer. Significant computational economy is achieved by taking account of surrounding bulky (alkyl) residues at 6-31G(d) in a low HF theoretical level layer. We conclude that theoretical calculations based on explicit correlated MO treatment of the reaction site are sufficiently reliable for the prediction of both endo/exo and diastereoface selectivity of Diels-Alder addition reactions. This is in line with the understanding of endo/exo selectivity originating from dynamic electron correlation effects of interacting pi fragments and diastereofacial selectivity originating from steric interactions of fragments outside of the Diels-Alder reaction site.     

DFT-GIAO calculations of 19F NMR chemical shifts for perfluoro compounds

The (19)F NMR shieldings for 53 kinds of perfluoro compounds were calculated by the B3LYP-GIAO method using the 6-31G(d), 6-31+G(d), 6-31G(d,p), 6-31++G(d,p), 6-311G(d,p), 6-311++G(d,p), 6-311G(2d,2p), 6-311++G(2d,2p), 6-311++G(2df,2p), 6-311++G(3d,2p), and 6-311++G(3df,2p) basis sets. The diffuse functions markedly reduce the difference between the calculated and experimental chemical shifts. The calculations using the 6-31++G(d,p) basis set give the chemical shifts within 10 ppm deviations from experimental values except for the fluorine nuclei attached to an oxygen atom, a four- and a six-coordinated sulfur atom, and FC(CF(3))(2) attached to a sulfur atom.     

Allylic stereocontrol of the intramolecular Diels-Alder reaction

The stereochemical outcome of the intramolecular Diels-Alder reaction of ester-linked 1,3,8-nonatrienes can be controlled by substituents about a stereogenic center attached to C1. The scope and limitations of this approach have been investigated, with variation in substrate structure about the allylic stereocenter and the dienophile. The stereochemical outcomes of these reactions are explained by reference to B3 LYP/6-31G(d) transition structures. New insights into the conformational preferences of allylic alcohol derivatives are reported, results which allow an explanation of the differing levels of pi-diastereofacial selectivity and cis/trans (i.e. endo/exo) selectivity from the reaction.     

Hydrogen peroxide clusters: the role of open book motif in cage and helical structures

Hartree-Fock (HF) calculations using 6-31G*, 6-311++G(d,p), aug-cc-pVDZ, and aug-cc-pVTZ basis sets show that hydrogen peroxide molecular clusters tend to form hydrogen-bonded cyclic and cage structures along the lines expected of a molecule which can act as a proton donor as well as an acceptor. These results are reiterated by density functional theoretic (DFT) calculations with B3LYP parametrization and also by second-order M?ller-Plesset perturbation (MP2) theory using 6-31G* and 6-311++G(d,p) basis sets. Trends in stabilization energies and geometrical parameters obtained at the HF level using 6-311++G(d,p), aug-cc-pVDZ, and aug-cc-pVTZ basis sets are similar to those obtained from HF/6-31G* calculation. In addition, the HF calculations suggest the formation of stable helical structures for larger clusters, provided the neighbors form an open book structure.     

The reaction mechanism of the gas‐phase thermal decomposition kinetics of neopentyl halides: A DFT study

The kinetics and mechanisms of the gas‐phase elimination reactions of neopentyl chloride and neopentyl bromide have been studied by means of electronic structure calculations using density functional methods: B3LYP/6‐31G(d,p), B3LYP/ 6‐31++G(d,p), MPW1PW91/6‐31G(d,p), MPW1PW91/6‐31++G(d,p), PBEPBE/6‐31G(d,p), PBEPBE /6‐31++G(d,p). The reaction channels that account in products formation have a common first step involving a Wagner‐Meerwein rearrangement. The migration of the halide from the terminal carbon to the more substituted carbon is followed by beta‐elimination of HCl or HBr to give two olefins: the Sayzeff and Hoffmann products. Theoretical calculations demonstrated that these eliminations proceed through concerted asynchronous process. The transition state (TS) located for the rate‐determining step shows the halide detached and bridging between the terminal carbon and the quaternary carbon, while the methyl group is also migrating in a concerted fashion. The TS is described as an intimate ion‐pair with a large negative charge at the halide atom. The concerted migration of methyl group provides stabilization of the TS by delocalizing the electron density between the terminal carbon and the quaternary carbon. The B3LYP/6‐31++G(d,p) allows to obtain reasonable energies and enthalpies of activation. The nature of these reactions is examined in terms of geometrical parameters, electron distribution, and bond order analysis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

NMR spectra, GIAO and charge density calculations of five-membered aromatic heterocycles

The B3LYP/6-31+G(d) molecular geometry optimized structures of 17 five-membered heterocycles were employed together with the gauge including atomic orbitals (GIAO) density functional theory (DFT) method at the B3LYP/6-31+G(d,p), B3LYP/6-311++G(d,p) and B3LYP/6-311+G(2d,p) levels of theory for the calculation of proton and carbon chemicals shifts and coupling constants. The method of geometry optimization for pyrrole (1), N-methylpyrrole (2) and thiophene (7) using the larger 6-311++G(d,p) basis sets at the B3LYP/6-31+G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-31+G(2d,p) and B3LYP/cc-pVTZ levels of theory gave little difference between calculated and experimental values of coupling constants. In general, the (1)H and 13C chemical shifts for all compounds are in good agreement with theoretical calculations using the smaller 6-31 basis set. The values of nJHH(n=3, 4, 5) and rmnJ(CH)(n=1, 2, 3, 4) were predicted well using the larger 6-31+G(d,p) and 6-311++G(d,p) basis sets and at the B3LYP/6-31+G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-31+G(2d,2p) levels of theory. The computed atomic charges [Mülliken; Natural Bond Orbital Analysis (NBO); Merz-Kollman (MK); CHELP and CHELPG] for the B3LYP/6-311++G(d,p) geometry optimized structures of 1-17 were used to explore correlations with the experimental proton and carbon chemical shifts.     

A computational study of chlorocarbene additions to cyclooctyne

Dichloro- and phenylchlorocarbene (CCl2 and PhCCl) add to cyclooctyne via a barrierless process (MP2/6-311+G*, B3LYP/6-311+G*, B3LYP/6-31G*) to yield the expected corresponding cyclopropene adducts. A three-dimensional potential energy surface (PES) for CCl2 addition to cyclooctyne (B3LYP/6-31G*) shows the formation of the cyclopropene product and also possible formation of a vinylcarbene. Residing in a shallow energy well, the vinylcarbene easily rearranges to the cyclopropene product, or to an exocyclic vinyl bicyclo[3.3.0]octane. Although the calculated three-dimensional PES indicates possible dynamic control of the cyclooctyne-chlorocarbene system through the putative formation of a vinylcarbene (in addition to the expected cyclopropene), additional calculations and preliminary experimental work show paths through the vinylcarbene to be unlikely. If the additions of chlorocarbenes to cyclooctyne are controlled by reaction dynamics, we predict that the vast majority of the reactions proceed via traditional carbene cycloaddition with only a very minor amount of products formed from the alternative pathway.     

Modern valence-bond description of chemical reaction mechanisms: the 1,3-dipolar addition of diazomethane to ethene

The electronic mechanism for the gas-phase concerted 1,3-dipolar cycloaddition of diazomethane (CH2N2) to ethene (C2H4) is described through spin-coupled (SC) calculations at a sequence of geometries along the intrinsic reaction coordinate obtained at the MP2/6-31G(d) level of theory. It is shown that the bonding rearrangements occurring during the course of this reaction follow a heterolytic pattern, characterized by the movement of three well-identifiable orbital pairs, which are initially responsible for the pi bond in ethene and the C-N pi bond and one of the N-N pi bonds in diazomethane and are retained throughout the entire reaction path from reactants to product. Taken together with our previous SC study of the electronic mechanism of the 1,3-dipolar cycloaddition of fulminic acid (HCNO) to ethyne (C2H2) (Theor. Chim. Acc. 1998, 100, 222), the results of the present work suggest strongly that most gas-phase concerted 1,3-dipolar cycloaddition reactions can be expected to follow a heterolytic mechanism of this type, which does not involve an aromatic transition state. The more conventional aspects of the gas-phase concerted 1,3-dipolar cycloaddition of diazomethane to ethene, including optimized transition structure geometry, electronic activation energy, activation barrier corrected for zero-point energies, standard enthalpy, entropy and Gibbs free energy of activation, have been calculated at the HF/6-31G(d), B3LYP/6-31G(d), MP2/6-31G(d), MP2/6-31G(d,p), QCISD/6-31G(d) and CCD/6-31G(d) levels of theory. We also report the CCD/6-311++G(2d, 2p)//CCD/6-31G(d), MP4(SDTQ)/6-311++G(2d,2p)//CCD/6-31G(d) and CCSD(T)/6-311++G(2d, 2p)//CCD/6-31G(d) electronic activation energies.     

Clarification of the mechanism of the cascade reactions between amino-substituted heterocycles and 1,3,5-triazines

The mechanisms of the cascade reactions of amino-substituted imidazoles, pyrroles, and pyrazoles with 1,3,5-triazines have been studied using first principle MP2/6-311++G**//B3LYP/6-31G* calculations in both the gas phase and solution. Calculations indicate that these cascade reactions start with stepwise inverse-electron demand Diels-Alder (IDA) reactions, followed by elimination of ammonia from the IDA adducts, and retro Diels-Alder (RDA) reactions (referred as to the IER path). An alternative IRE path involving a reaction sequence of IDA, RDA, and elimination of ammonia is ruled out since the RDA transition states in this pathway are higher in energy than the reactants by as much as 50 kcal/mol. The preference of the IER over the IRE path is discussed.     

Ab Initio Study of Endo/Exo and Diastereofacial Selectivities in Diels-Alder Reactions between Chiral Butenolides and Cyclopentadiene

Diels-Alder reactions of cyclopentadiene with crotonolactone and beta-angelica lactone have been studied using ab initio methods at the MP3/6-31G//RHF/3-21G and MP2/6-31G//RHF/6-31G levels. The transition states corresponding to the formation of different stereoisomers and diastereoisomers have been located. The results obtained show that the correct endo/exo selectivity is only obtained when polarization functions are included in the basis set. However, syn/antiselectivity is correctly described at all levels of calculation.     

Theoretical calculations on the mechanisms of the gas‐phase elimination kinetics of 2‐chloro‐1‐phenylethane, 3‐chloro‐1‐phenylpropane, 4‐chloro‐1‐phenylbutane, 5‐chloro‐1‐phenylpentane,and their corresponding chloroalkanes: The effect of the phenyl ring

The kinetics and mechanisms of the dehydrochlorination of 2‐chloro‐1‐ phenylethane, 3‐chloro‐1‐phenylpropane, 4‐chloro‐1‐phenylbutane, 5‐chloro‐1‐phenylpentane, and their corresponding chloroalkanes were examined by means of electronic structure calculation using density functional theory methods B3LYP/6–31G(d,p), B3LYP/6–31++G(d,p), MPW1PW91/6–31G(d,p), MPW1PW91/6–31++G(d,p), PBEPBE/6–31G(d,p), and PBEPBE/6–31++G(d,p). The potential energy surface was investigated for the minimum energy path. Calculated enthalpies and energies of activation are in good agreement with experimental values using the MPW1PW91 and B3LYP methods. The transition state of these reactions is a four‐centered cyclic structure. The reported experimental results proposing neighboring group participation by the phenyl group was not supported by theoretical calculations. The rate‐determining process in these reactions is the breaking of Cl? C bond. The reactions are described as concerted moderately polar and nonsynchronous. © 2011 Wiley Peiodicals, Inc. Int J Chem Kinet 43: 292–302, 2011     

Theoretical studies on the intramolecular hydrogen bond and tautomerism of 8-mercaptoquinoline in the gaseous phase and in solution using modern DFT methods

A theoretical quantum chemical study of the intramolecular hydrogen bonding interactions in 8-mercaptoquinoline has been carried out. Special attention has been paid to the rotation of S-H bond and intramolecular proton-transfer reactions. Therewith, the B3LYP/6-311++G(d,p), B3LYP/6-31+G(2d,2p), MPW1K/6-311++G(d,p), MPW1K/6-31+G(2d,2p), BH&HLYP/6-311++G(d,p), and G96LYP/6-311++G(d,p) methods have been used. By means of the Onsager and PCM reaction field methods, the effects of solvent on hydrogen-bond energies, conformational equilibria, rotational barriers, and tautomerism in aqueous solution have been studied. These simulations were done at the MPW1K/6-311++G(d,p) and B3LYP/6-311++G(d,p) levels. Natural-bond orbital analysis has been performed to study the intramolecular hydrogen bond (IHB) in the gaseous phase and in aqueous medium. The stability of forms under consideration in solution does not coincide with that in the gaseous phase, underlining a great importance of the electrostatic influence of solvent. Double-proton transfer in the prototropic tautomerization of 8-mercaptoquinoline, one water molecule complex in the gaseous phase and in solution, has been systematically studied. The double-proton transfer occurs concertedly and synchronously. The water-assisted tautomerization is kinetically less, but thermodynamically more favorable, compared to that of the single-proton transfer. As in the case with single-proton transfer, for water-assisted reaction, the tautomerization energies and barrier heights decrease with the increase in dielectric constant, which implies faster and more complete tautomerization of 8-mercaptoquinoline in a polar solvent.     

Theoretical analysis of concerted and stepwise mechanisms of Diels-Alder reactions of butadiene with silaethylene and disilene

The concerted and the stepwise mechanisms of the Diels-Alder reactions of butadiene with silaethylene and disilene were studied by ab initio MO methods. For the reaction of butadiene and silaethylene, an asymmetric concerted process that is almost stepwise and two stepwise processes were located. For the first step of the stepwise process, the C-Si bond formation is more favorable than the C-C bond formation. The activation energy barrier of the concerted transition state is only 0.89 kcal/mol lower than that of the first-step transition state of the C-Si bond formation for the stepwise process by the CASPT2 calculation level. For the reaction of butadiene and disilene, the activation energy barrier of the concerted-type transition state constrained with Cs symmetry is about 9 kcal/mol higher than that of the stepwise transition state by the CASSCF method. The energy barrier of the first step of the stepwise reaction disappears at the CASPT2/6-311++G(d,p) calculation level including the nondynamical correlation energy, although the reaction of the butadiene with disilene occurs through the stepwise-like process.     

Reaction of ketenyl radical with acetylene: a promising route for cyclopropenyl radical

The reaction of the ketenyl radical (HCCO) with acetylene (C(2)H(2)) is very relevant to the oxygen-acetylene flames and fuel-rich combustion process for nitrogen-containing compounds. Unfortunately, except for several rate constant measurements, the mechanism is completely unknown for this reaction. In this paper, detailed theoretical investigations are performed for the HCCO + C(2)H(2) reaction at the G3B3 level using the B3LYP/6-31G(d), B3LYP/6-311++G(d,p), and QCISD/6-31G(d) geometries. The exclusive fragmentation channel is the formation of the cyclopropenyl radical (c-C(3)H(3)) and carbon monoxide (CO) via the chainlike OCCHCHCH and three-membered ring OC-cCHCHCH intermediates. Thus, the mass spectroscopic peak of C(3)H(3)(+) in a previous experiment can be explained. The calculated overall reaction barrier is 4.4, 4.4, and 5.3 kcal/mol at the G3B3//B3LYP/6-31G(d), G3B3//B3LYP/6-311++G(d,p), and G3B3//QCISD/6-31G(d) levels, respectively. The title reaction may provide an effective route for generating the long-sought cyclopropenyl radical in the laboratory, which has been the long-standing subject of numerous theoretical studies as the simplest cyclic conjugate radical, and its bulky derivatives were already known. Future experimental investigations for the HCCO + C(2)H(2) reaction are greatly desired to test the predicted fragmentation channel. The implication of the present study in combustion and interstellar processes is discussed.     

Theoretical study of Diels-Alder reaction: Role of substituent in regioselectivity and aromaticity

A comparative study on the influence of the substituents on the Diels-Alder reaction was performed. The energy profiles for 11 sets of Diels-Alder reaction between monosubstituted derivatives of butadiene and ethylene have been studied and the structures of all transition states were located at B3LYP/6-31+G* level. Four pathways were independently investigated; the reaction between substituted ethylene and 1-substituted butadiene leading to ortho (a ₁) and meta (a ₂) adducts, and in the same manner, the reaction between substituted ethylene and 2-substituted butadiene yields para (b ₁) and meta (b ₂) adducts. Inspection of both the activation barriers and the reaction energies for 44 reactions revealed that the pathway b ₁ is both thermodynamically and kinetically more favorable in all types of Diels-Alder reactions; while the pathway a ₁ can be labeled only as kinetic pathway. The aromaticity of all 44 transition state structures was measured using para delocalization index to study the effect of aromaticity on the reaction path. The calculations suggest that in normal and neutral DA reactions there is a gain in aromatic stabilization of the transition state which reduces slightly the activation barrier of the kinetic pathway a ₁.     

The molecular structure of fluoromalononitrile as determined by gas-phase electron diffraction and ab initio calculations

The molecular structure of fluoromalononitrile was studied by means of gas-phase electron diffraction and quantum mechanical methods using HF/6-31G(d), MP2/6-311++G(2df,2pd) and DFT/B3LYP/6-31G(d), B3PW91/6-31G(d), B3LYP/6-311++G(2df,2pd) and B3PW91/6-311++G(2df,2pd). The r(g) and angle(alpha) structural parameters we obtained from the present analysis are: CC=1.487(5) A, CN=1.157(3) A, CF=1.386(5) A, CH=1.096 A (ass.), angleCCC=106.7(1.0) degrees , angleCCF=108.0(0.7) degrees , angleCCN=177.6(2.0) degrees . Uncertainties in parenthesis are 3sigma.     

Synthesis of stable derivatives of cycloprop-2-ene carboxylic acid

Large-scale syntheses of 3-(cycloprop-2-en-1-oyl)oxazolidinones from acetylene and ethyl diazoacetate are described. Unlike other cyclopropenes that bear a single substitutent at C-3, these compounds are stable to long-term storage. Although the cyclopropene derivatives are unusually stable, they are reactive toward cyclic and acyclic dienes in stereoselective Diels-Alder reactions.