Cycloaddition Of Benzonitrile Oxide Research Articles

Regio‐, stereo‐, and site‐selectivities of 1,3‐dipolar Cycloaddition reaction of benzonitrile oxide with unsymmetrically substituted norbornenes and norbornadienes: A computational study

AbstractIn this computational study, density functional theory (DFT) calculations at the M06/6‐311G(d,p) level of theory were employed to study the regio‐, stereo‐, and site‐selectivities of 1,3‐dipolar cycloadditions of benzonitrile oxide (BNO) with unsymmetrically substituted norbornenes and norbornadienes. The reactions between BNO and unsymmetrically‐substituted 2‐norbornes and unsymmetrically‐substituted 2‐norbornadienes proceed with the oxygen of the BNO attacking the more hindered side of the double bond in all cases except when strong EWGs are introduced. For the reaction between BNO and unsymmetrically‐substituted 2‐norbornadienes, varying degrees of selectivities are observed depending on the substituent, indicating that site‐selectivity is largely influenced by nature of substituents. Generally, the regio‐isomers in which the oxygen of the BNO is bonded to the more hindered side of the double bond are favored except when strong EWGs are introduced, and exo stereo‐isomers are generally favored over the endo stereo‐isomers. Electrophilic (Pk+) and nucleophilic (Pk‐) Parr functions computations are in complete agreement with the selectivity predicted by the activation barrier trends.

Regioselectivity of 1,3‐Dipolar Cycloadditions of Benzonitrile Oxide to Alkenyl Boronic Esters: An Experimental and Computational Study

1,3‐Dipolar cycloaddition reactions of benzonitrile oxide to monosubstituted or 1,1‐disubstituted alkenyl boronic ester gave only 2‐isoxazolines, bearing the boronic ester group at the 5‐position of the ring. On the other hand, the cycloaddition reactions of benzonitrile oxide with trans‐1,2‐disubstituted alkenyl boronic esters produced 2‐isoxazolines, bearing the boronic ester group at the 4‐position of the ring. We used quantum mechanical calculations to investigate two regioisomeric channels that were associated with the formation of 2‐isoxazolines, bearing the boronic ester group at the 4‐position or 5‐position. The study revealed that the experimental results agreed well with the parameters based on the transition state energies in gas or solvent phase. The study also informed that all the cycloaddition reactions proceed in a spontaneous and exergonic fashion.

Pseudo-Interphase of Liposome Promotes 1,3-Dipolar Cycloaddition Reaction of Benzonitrile Oxide and N-Ethylmaleimide in Aqueous Solution.

The hydrophobic interior of a liposome membrane was used as a platform for the organic synthesis of hydrophobic compounds in water. The 1,3-dipolar cycloaddition of benzonitrile oxide (BNO) and N-ethylmaleimide (EMI) in liposome suspensions was carried out, and an increase in the reaction rate constant was observed depending on the liposome characteristics. While the reaction rate constant in 1,4-dioxane was 1.5 times higher than that in water, the reaction rate constant in an aqueous solution of cationic 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) liposome was 3 times higher than in water. The amount of substrate, BNO, accumulated in the DOTAP liposome was higher than that in 1,2-dipalmitoyl-3-trimethylammonium-propane (DPTAP), indicating that BNO prefers to be distributed in the liposome membrane in the liquid-disordered phase. The membrane polarity, GP340, as monitored by Laurdan, varied with the presence of BNO, while EMI slightly affected the membrane properties of the liposomes. These results suggest that the pseudo-interphase afforded by the liposome membrane can promote the 1,3-dipolar cycloaddition between BNO and EMI in water.

A DFT Study of 1,3-dipolar Cycloaddition Reaction of Benzonitrile Oxide and N-aryl-2,4,6-heptatrien-1-imine

A theoretical study of the effect of substitution on the 1,3-dipolar cycloaddition of benzonitrile oxide was performed using the DFT method at the B3LYP level of theory using 6–311G(d,p) basis sets. Equilibrium molecular geometries and harmonic vibrational frequencies of the reactants, transition state, and product were calculated. The corresponding rate constants and activation parameters were calculated. The results showed good agreement with experimental data. These calculations indicated that the reaction proceeds through an asynchronous mechanism.

A DFT Study on the 1,3-Dipolar Cycloaddition of Benzonitrile Oxide and N-Ethylmaleimide

A theoretical study of the kinetics and mechanism of the reaction between benzonitrile oxide and N-ethylmaleimide was performed using the DFT method at the B3LYP level of theory with the 6-311++G(d,p) basis set at 298.15 K. Equilibrium molecular geometries and harmonic vibrational frequencies of the reactants, transition state and product were calculated. The effect of solvent on the kinetic and thermodynamic parameters of the reaction was investigated. The calculated rate constants and activation thermodynamics parameters indicated very good agreement with experimental results, especially in water. These calculations indicated that the reaction proceeds through a synchronous concerted mechanism.

ChemInform Abstract: Synthesis of Aza Macrocycles from Polycyclic 5-Aminoisoxazoline Precursors.

A series of novel isoxazolo analogues 11 of the dibenzazonine alkaloid protostephanine (1) has been prepared. A new regiospecific and potentially general aza macrocyclic ring forming process was developed where the first step was the 1,3-dipolar cycloaddition of benzonitrile oxide to the readily available examine 6. The product, isoxazoline 9a, under solvolytic conditions that normally convert monocyclic 5-aminoisoxazolines to isoxazoles failed to give the desired aza macrocycle 14. Alternate sequences involving quaternization of 9a with methyl iodide followed by either solvolysis in polar solvents or base-induced elimination were successful and gave the target structure 11a in excellent overall yield. X-ray crystallographic analysis of the quaternized intermediate 10a corroborated the assignment of structure and defined the crystal-state conformation

Thermal fragmentation of 1,2,5- and 1,2,4-oxadiazoles

Thermolysis of 3,4-diphenyl-1,2,5-oxadiazole (diphenylfurazan) in tetradec-1-ene at 245 oC afforded 5-dodecyl-3-phenyl-2-isoxazoline resulting from cycloaddition of benzonitrile oxide to the alkene. Similarly, the tetramethylene and decamethylene furazans 13 and 15 in 4- methoxybenzonitrile at 240 oC fragmented to ω-cyanoalkanonitrile oxides, which were trapped as their 1,2,4-oxadiazole cycloadducts 17 and 19, respectively. The flash vacuum pyrolysis (FVP, 550-650 oC) technique was used to investigate the process in more detail using a range of mono and bicyclic furazans. In all cases the 1,2,5-oxadiazole ring cleaved cleanly at O(1)−N(2) and C(3)−C(4) to nitrile and nitrile oxide fragments. The nitrile oxides were trapped in high yield (81-100%) as their isoxazoline cycloadducts by reaction with hex-1-ene. The tetramethylene furazan 13 was converted into 4-cyanobutyl isocyanate by FVP and reaction of the condensate with sulfur dioxide. 3,5-Diphenyl-1,2,4-oxadiazole showed greater thermal stability under similar conditions (FVP, 600 oC), but at higher temperatures (700-800 oC) phenyl isocyanate was formed and trapped as its methyl urethane derivative. Attempts to trap the putative benzonitrile oxide intermediate were unsuccessful.

Flash vacuum pyrolysis of N-phenylbenzamide oxime and related compounds

Flash vacuum pyrolysis (FVP) of the benzamide oxime 1 at 650 °C leads to the imino-oxadiazole 10 as the major product. It is probably formed by intermolecular cycloaddition of benzonitrile oxide 11 and the diphenylcarbodiimide 12, an unexpected process to take place under FVP conditions. Intermediates 11 and 12 are themselves obtained by competitive dehydration and elimination of aniline from 1. Mixed products were obtained from FVP of the C- and N- p-tolyl analogues of 1 ( 5 and 6, respectively) probably owing to equilibration of the carbodiimide intermediate.

Investigation of NMR shielding tensors in 1,3 dipolar cycloadditions: solvents dielectric effect

In this article, NMR shielding is investigated in the reactions of 1,3 dipolar cycloaddition of benzonitrile oxide with acrylonitrile, which have been recently studied [E. Rajaeian, M. Monajjem, Cholami, J. Chem. Res., s, 279, (2002); E. Rajaeian, M. Monajjem, Cholami, J. Chem. Res., s, 91, (2003)]. We reported 15N and 17O tensors for benzonitrile oxide and two products in reactions in gas phase and several various solvents and compared the effect of dielectric constant on tensors of the materials mentioned above. Also diffuse and polarizable function effects in basis set are investigated.

Quantum-chemical study of the Lewis acid influence on the cycloaddition of benzonitrile oxide to acetonitrile, propyne and propene

Quantum chemical methods (MP2 and B3LYP) together with a topological analysis of the charge density have been used to study the BH 3- or BF 3-mediated reaction of benzonitrile oxide with acetonitrile, propyne and propene. In the reaction with propene or propyne, addition of Lewis acids has only little influence on the outcome of the reactions. The cycloaddition of nitrile oxides with nitriles, however, is generally promoted by strong Lewis acids. When the Lewis acid coordination takes place at the nitrile oxide the reactant is activated and the product binds weakly to the Lewis acid so that the reaction is expected to be catalytic. In the case of coordination to the nitrile the reaction is Lewis acid mediated. Here the reactant is not much influenced by addition of Lewis acid, but the transition state and the product are stabilised and consequently such processes require a stoichiometric amount of Lewis acid and form a stable Lewis acid–product complex. It has also been demonstrated that the different activation routes for these reactions involve different reaction mechanisms. Whereas the reaction of a Lewis acid coordinated nitrile oxide is of ‘inverse electron demand’, the Lewis acid coordinated nitrile reacts through a ‘normal electron demand’ cycloaddition.

AOT-Based Microemulsions Accelerate the 1,3-Cycloaddition of Benzonitrile Oxide to N-Ethylmaleimide

We studied the 1,3-dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide in AOT/isooctane/water microemulsions at 25.0 degrees C and found the reaction rate to be roughly 150 and 35 times greater than that in isooctane and pure water, respectively. The accelerating effect of the microemulsion is the combined result of an increase in the local concentrations of the reactants through incorporation into the interface and of the intrinsic rate of the process through electrostatic interactions with the headgroups in the surfactant.

Cycloadditions in mixed aqueous solvents: the role of the water concentration

AbstractWe examined the kinetics of a series of cycloaddition reactions in mixtures of water with methanol, acetonitrile and poly(ethylene glycol) (MW 1000). The reactions include the Diels–Alder (DA) reaction between cyclopentadiene and N‐n‐butylmaleimide or acridizinium bromide, the retro‐Diels‐Alder (RDA) reaction of 1,4,4a,9a‐tetrahydro‐4a‐methyl‐(1α,4α,4aα,9aα)‐1,4‐methaneanthracene‐9,10‐dione and the 1,3‐dipolar cycloaddition of benzonitrile oxide with N‐n‐butylmaleimide. Plots of logk vs the molar concentration or volume fraction of water are approximately linear, but with a characteristic break around 40 M water. This break, absent for the RDA reaction, is ascribed to hydrophobic effects. Comparison with aqueous mixtures of the more hydrophobic 1‐propanol shows that these mixtures induce qualitatively similar effects on the rate, but that preferential solvation effects cause the mixtures of 1‐propanol to exhibit a more complex behavior of logk on composition. The results are analyzed using the Abraham–Kamlett–Taft model. The solvent effects in aqueous mixtures are not satisfactorily described by this model. For some cycloadditions, small maxima in rate are observed in highly aqueous mixtures of alcohols. The origin of these maxima and the aforementioned breaks is most likely the same. Copyright © 2005 John Wiley & Sons, Ltd.

Kinetic solvent effects on 1,3‐dipolar cycloadditions of benzonitrile oxide

AbstractThe kinetics of 1,3‐dipolar cycloadditions of benzonitrile oxide with a series of N‐substituted maleimides and with cyclopentene are reported for water, a wide range of organic solvents and binary solvent mixtures. The results indicate the importance of both solvent polarity and specific hydrogen‐bond interactions in governing the rates of the reactions. The aforementioned reactions are examples for which these factors often counteract, leading to a complex dependence of rate constants on the nature of the solvent. For the reactions of N‐ethylmaleimide and N‐n‐butylmaleimide with benzonitrile oxide, isobaric activation parameters have been determined in several organic solvents, water, and water–1‐propanol mixtures. Interestingly, the activation parameters reveal significant differences in solvation in different solvents that are not clearly reflected in the rate constants. In highly aqueous mixtures, enforced hydrophobic interactions lead to an increase in rate constant, relative to organic solvents. However, the overall rate enhancement in water is modest, if present at all, because the solvent polarity diminishes the rate constant. This pattern contrasts with common Diels–Alder reactions, where polarity, hydrogen‐bond donor capacity and enforced hydrophobic interactions work together, which can result in impressive rate accelerations in water. Copyright © 2005 John Wiley & Sons, Ltd.

Cycloaddition of Benzonitrile Oxide to Acetonitrile, Propyne and Propene − A Comparative Theoretical Study of the Reaction Mechanism and Regioselectivity

AbstractQuantum chemical calculations (MP2/6‐31G* and B3LYP/6‐31G*) were used to compare the reactivity, regioselectivity and orbital involvement of the reaction of benzonitrile oxide with the dipolarophiles acetonitrile, propyne and propene. All reactions are thermodynamically favoured. The product stability decreases in an order propyne > acetonitrile > propene, and reflects the degree of aromatic stabilisation of the product. The activation barriers depend strongly on the computational method used and decrease in the expected order of increasing reactivity (acetonitrile > propyne > propene) in the MP2 calculations, but are similar to each other when B3LYP is applied. The regiochemistry is correctly predicted for all reactions and the experimentally observed regioisomer is both thermodynamically and kinetically favoured. The transition state geometries indicate that, in some of the reactions, the benzonitrile oxide does not interact through its frontier orbitals, as traditionally assumed. Instead, the FMO±2 are involved in the reaction, indicating that the classical FMO concept should be applied with care as it might lead to wrong conclusions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A DFT study for the regioselective 1,3-dipolar cycloadditions of nitrile N-oxides toward alkynylboronates

The mechanism for the 1,3-dipolar cycloaddition of benzonitrile oxide toward ethynyl and propynylboronate has been studied by using density functional theory (DFT) at B3LYP/6-31G* level. These cycloadditions are concerted [3+2] processes. The presence of the two oxygens on the boronic ester precludes the participation of the boron atom on [3+3] processes. The two regioisomeric channels associated to the formation of the isoxazoles bearing the boronic ester unit on the 4- or 5-positions have been characterized. The B3LYP/6-31G* activation parameters are in acceptable agreement with the experiments, allowing to explain the factors controlling these regioselective cycloadditions.

Highly Stereoselective [3+2] Cycloadditions of Nitrile Oxides to Methyl 4-O-Acryloyl-6-deoxy-2,3-O-(t-butyldimethylsilyl)-α-d-glucopyranoside

The [3+2] cycloadditions of benzonitrile oxide or pivalo­nitrile oxide to methyl 4-O-acryloyl-6-deoxy-2,3-di-O-(t-butyl­dimethylsilyl)-α-d-glucopyranoside provided the respective adducts, each as virtually a single diastereomer. By reductive remova­l of the carbohydrate template from each adduct, the respectiv­e (R)-enriched Δ2-isoxazoline derivative was obtained.

Ab Initio Calculation of Thermodynamic and Kinetic Quantities for 1,3-Dipolar Cycloadditions of Benzonitrile Oxide with Various Dipolarophiles

Ab initio molecular orbital calculations have been used to investigate the structures and transition states of 1,3-dipolar cycloadditions between benzonitrile oxide with ethylene, acrylonitrile, tetracyanoethylene and cyclopentene. Geometry optimisations and energy calculations were performed with RHF/6–31G*//RHF/6–31G* in each case. Calculation of vibrational frequencies permitted computation of the enthalpies, Gibbs free energies and rate constant of reactions. Cycloadditions of 1,3-dipolar benzonitrile oxide with electron-poor dipolarophiles have higher rates and lower thermodynamic stability than with other dipolarophiles.

Cycloaddition Reactions of Nitrile Oxides to 2,4-Silyl- and Germyl-Substituted Thiophene-1,1-dioxides

2,4-Silyl- and germyl-substituted thiophene-1,1-dioxides as well as 5,5‘- and 4,4‘-bis(trimethylsilyl)-2,2‘-bithiophene-1,1-dioxides were prepared from the corresponding thiophenes and bithiophenes by oxidation with m-CPBA in CH2Cl2 at room temperature. The [2+3] dipolar cycloaddition of nitrile oxides to the double CC bonds of thiophene-1,1-dioxides has been investigated. It was shown that in the series of 2,4-disubstituted thiophene-1,1-dioxides only the C(4)C(5) double bond interacts with acetonitrile oxide to give fused thienoisoxazolines. Addition of acetonitrile oxide to 5,5‘-bis(trimethylsilyl)-2,2‘-bithiophene-1,1-dioxide was accompanied by desilylation. Isomeric 4,4‘-bis(trimethylsilyl)-2,2‘-bithiophene-1,1-dioxide was inactive in the reaction with acetonitrile oxide. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structures of 2,4-bis(trimethylsilyl)thiophene-1,1-dioxide, 2-trimethylgermyl-4-trimethylsilylthiophene-1,1-dioxide, 2-trimethylsilyl-4-tri...

The intramolecular salt effect in chiral auxiliaries. Enhanced diastereoselectivity in a nitrile oxide cycloaddition via rational transition state stabilization

The use of ion pairs to control a nitrile oxide cycloaddition is demonstrated. A chiral phenylmaleimide derivative bearing an ionic group and an associated counterion provides enhanced selectivity in the cycloaddition of benzonitrile oxide. The intramolecular salt effect controls the orientation of the 1,3-dipolar reagent. The nature of the solvent is shown to be relevant in the selectivity of the reaction.

1,3-Dipolar Cycloadditions of Benzonitrile Oxide with Various Dipolarophiles in Aqueous Solutions. A Kinetic Study

The second-order rate constants for the 1,3-dipolar cycloaddition of benzonitrile oxide (1) with various dipolarophiles (2a-e) were determined in aqueous media and in organic solvents to gain more insight into the influence of an aqueous medium on pericyclic reactions. 1,3-Dipolar cycloadditions with electron-poor dipolarophiles are accelerated in water and protic solvents, whereas an aqueous medium has no special effect when electron-poor dipolarophiles are involved. These observations can be explained using frontier molecular orbital theory. In all cases, enforced hydrophobic interactions promote the reaction. These results are supported by kinetic experiments in water-ethanol mixtures. Sodium dodecyl sulfate micelles accelerate the cycloaddition of 1 with both electron-rich and electron-poor dipolarophiles. More than for other systems, the present results show that hydrogen bonding and hydrophobic interactions can either cooperate or counteract each other in determining the kinetic medium effects in aqueous solutions.