Substituent effects on the rate of formation of azomethine ylides. A computational investigation.

The effect of substituents on the rate of conrotatory thermal cleavage of aziridine has been studied at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level and also using SCS-MP2 methodology. While the parent compound has a high free energy of activation (194.6 kJ mol(-1)), this value could be drastically lowered by substituent effects. Anionic species were found to be particularly effective in increasing the calculated reaction rate. The potential utility of this approach in 1,3-dipolar cycloaddition is discussed.

Torquoselectivity studies in the generation of azomethine ylides from substituted aziridines.

Aziridines are useful precursors to the azomethine ylide family of 1,3-dipoles whose cycloaddition chemistry has been extensively exploited in the synthesis of heterocyclic targets. The torquoselectivity of aziridines that lack a plane of symmetry was investigated as an essential component of the calculation of the overall relative reaction rates and in prediction of the stereochemistry of the 2,3-trans compounds in 1,3-dipolar cycloaddition chemistry. It has been found at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level that outward rotation is preferred for electronegative or anionic substituents while electropositive and cationic substituents favor inward rotation. After consideration of frontier molecular orbital theory, inductive, resonance, and electrostatic effects, an explanation of the preferred direction of rotation during ring cleavage that is based on substituent electron-withdrawing ability by means of a polar effect is presented.

Is nucleophilic cleavage chemistry practical for 4-membered heterocycles?

A computational study at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level of the ammonolysis of halogen substituted azetidines, oxetanes and thietanes was performed in the gas phase and in the commonly used solvent, acetonitrile. Using the free energy of activation of a benchmark reaction for evaluation of synthetic viability, several haloazetidines and oxetanes that possessed the required reactivity were identified; however, no substituted thietane investigated herein was determined to be synthetically useful under the mild conditions selected for this study. In the case of the azetidines, the side reaction of displacement of halide ion was determined to be the preferred reaction course in acetonitrile; however, the amino product of the reactions of the 2-haloazetidines cleaved at an acceptable rate under mild conditions. For the oxetane derivatives investigated, 2-fluorooxetane proved to be a direct source of ring cleavage product. Nucleophilic cleavage of halogen-substituted azetidines and oxetanes is predicted to be a viable source of functionalized three-carbon moieties under mild conditions in organic synthesis.

Dramatic effects of halogen substitution and solvent on the rates and mechanisms of nucleophilic substitution reactions of aziridines.

In a previous study we reported that fluorine substitution at the carbon positions of aziridine results in profound enhancements of the rate of reaction with ammonia, a typical nucleophile, in the gas phase. In this study the investigation is extended to include chloro- and bromoaziridines. Because syntheses are largely performed in the condensed phase, the present computational investigation [(MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level] was conducted with three typical solvents that cover a wide range of polarity: THF, CH3CN, and H2O. Nucleophiles can react with haloaziridines 1 by displacing a substituted amide ion by means of an SN2 mechanism (pathway a), producing 1,2-diaminohaloethanes (from the initially formed dipolar species 2). Alternatively, a rearrangement mechanism involving rate-determining departure of a halide ion (pathway b) to form an imidoyl halide, 3, is possible. Transition-state theory was used to compute relative reaction rates of these mechanistic possibilities and to assess the role of the halogen substituents and the reaction solvent. Gas-phase results provided the basis of mechanistic insights that were more apparent in the absence of intermolecular interactions. Fluoroaziridines were found to react at accelerated rates relative to aziridine exclusively by means of the a Menshutkin-type mechanism (SN2) in each solvent tested, while the reactions of the chloro- and bromoaziridines could be directed toward 2 in the highly nonpolar solvent, cyclohexane, or toward 3 in the more polar solvents. An assessment is made of the feasibility of using this chemistry of the haloazirdines in the synthetic laboratory.

The profound effect of fluorine substitution on the reactivity and regioselectivity of nucleophilic substitution reactions of strained heterocycles. A study of aziridine and its derivatives.

Unlike the synthetically exploited oxiranes and thiiranes, aziridines that lack electron-withdrawing substituents, such as acyl or sulfonyl functionalities at nitrogen, are rather unreactive. As expected, three-membered aziridine 6 was calculated to be significantly more reactive than azetidine 7 in nucleophilic cleavage by ammonia, a typical nucleophile. The reactivity of 7 was about the same as that of an acyclic model compound, 8, when release of ring strain in the transition state was taken into account. Fluorine due to its similar size but vastly different electronegativity has been substituted for hydrogen as a means of modifying chemical properties for varied applications. In the present investigation, the effect of fluorine substitution at aziridine positions other than nitrogen was studied. Computations at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level found a vast preference for attack by ammonia at the 3-position of 2-fluoroaziridine in the gas phase at 298 K. When release of ring strain was taken into account, this compound reacted more than 10(11) times faster than 6. The reaction rate with trans-2,3-difluoroaziridine was about twice that of 2-fluoroaziridine, while its diastereomer reacted with ammonia considerably slower. Acyclic fluorinated amine model compounds were employed to assess the generality of the effects produced by fluorine substitution. The results were rationalized by the energy contributions of strain energy releases, stabilization of the leaving group, and the relative electrostatic energies of the heterocycles in the transition states. The more reactive fluoroaziridines underwent nucleophilic attack at rates comparable to those of N-acetylaziridine.

A computational study to elucidate the extraordinary reactivity of three-membered heterocycles in nucleophilic substitution reactions.

The accelerated rates of small-membered heterocycles relative to acyclic analogues are typically rationalized solely in terms of relief of ring strain. The relative rates of attack of ammonia on oxirane, oxetane, thiirane, and thietane were determined computationally in the gas phase at the MP2(Full)/6-31+G(d) level with respect to the model acyclic compounds methoxyethane and thiomethylethane. Because the cyclic ether and thioether pairs have very similar strain energies, they should react at similar rates by the S(N)2 mechanism if the degree of strain energy release in the transition state is approximately equal. The reactivity of the four-membered rings could be explained almost entirely by relief of strain. The three-membered rings reacted at rates at least 10(6) times faster than calculated from ring strain considerations alone. The electronic distribution of the transition states was determined using AIM methodology and found to indicate that bond cleavage was virtually complete, while bond formation was incomplete. Calculation of atomic charges by the Mulliken, AIM, CHELPG, and NBO methods indicated that positive charge at the reaction center was significantly lower for the three-membered rings than other members of the series. A simple electrostatic model identified differences in energy sufficient to account for the observed rate acceleration. The unique topological features of a three-membered ring make it possible for the partially negatively charged oxygen or sulfur to reduce the positive charge on the reaction center.

Glycoside-clustering round calixarenes toward the development of multivalent ligands. Synthesis and conformational analysis of Calix[4]arene O- and C-glycoconjugates.

Bis- and tetra-O- and C-glycosyl calixarenes (calixsugars) have been prepared by tethering carbohydrate moieties to a tetrapropoxycalix[4]arene scaffold through alkyl chains. Two methodologies have been employed. One consisted of the stereoselective multiple glycosylation of upper rim calix[4]arene polyols leading to calix-O-glycosides; the other involved a multiple Wittig olefination of upper rim calix[4]arene-derived polyaldehydes by the use of sugar phosphoranes and reduction of the alkene double bonds affording calix-C-glycosides. The NMR spectra and NOE experiments of bis-glycosylated products indicate that compounds bearing sugar-protected residues exist preferentially in solution in a flattened cone arrangement (far conformation) whereas deprotected derivatives adopt a close conformation. Calculations by molecular mechanics of the latter compounds point to a close conformation as well in gas phase.

Computational and experimental studies of di- and tetrasubstituted calix[4]arenes.

Calixarenes are molecular bowls or baskets that have been demonstrated to serve as hosts for cations, anions, and neutral molecules. The central cavity and scaffolding of various functionalities on the upper and lower rims establishes this class of compounds as extremely important in supramolecular chemistry studies. In earlier studies, calixsugars (molecules that have sugar molecules appended to the upper rim of the calix) were prepared. Among the potential advantages of these molecules are increased water solubility and enhanced possibilities that these chiral attachments can promote enantiomeric selection. Computational studies, however, have indicated that the chosen calixsugars had significantly encumbered upper rims, suggesting that host-guest associations would be limited. In an attempt to understand those factors responsible for the favored conformations of calixsugars, a number of 5,17-disubstituted and tetrasubstituted calix[4]arenes were prepared and studied experimentally as well as by molecular mechanics conformational searching techniques.