Zoran Zdravkovski

A SIMPLE PREPARATION OF AMIDES FROM ACIDS AND AMINES BY HEATING OF THEIR MIXTURE

Abstract Heating a mixture of an amine and an acid is demonstrated as the method of choice for the preparation of many amides. The yields depend on the physical properties and thermal stability of the reactants and range from good to excellent. The ideal reactants should have melting points below 200 °C, should not be highly volatile and should be thermally stable at that temperature for 30 minutes. Some of those disadvantages can be overcome by using acid esters instead of an acid in the reaction. The method stands out among the others by its simplicity, low cost and short reaction time. Also it can be performed in very large scale, does not require solvent and special purification of the reactants.

DFT study of the Diels–Alder reactions between ethylene with buta-1,3-diene and cyclopentadiene

A set of DFT methods (Xa, HFB, S-VWN, B–LYP; B–HandH and Becke3-LYP) has been used for the calculation of the transition states and energy barriers of the Diels–Alder reaction of ethylene with buta-1,3-diene and cyclopentadiene. The pure DFT methods overestimate the bond lengths, while the hybrid methods give values much closer to those obtained by conventional ab initio methods. The ratio of the σ-forming bonds to the π-breaking bonds is in excellent correlation to the predicted electronic energy barriers for these reactions. The local spin density approximation (S–VWN) fails completely giving a negative value for the classical energy barrier height for the addition of ethylene to buta-1,3-diene. On the other hand, the vibrational adiabatic barrier heights predicted by B-LYP/6-31G** and the hybrid Becke3-LYP/6-31G** theoretical models are in excellent agreement with available experimental data for both reactions.

Rates of hydrolysis of N-acetylazoles: semiempirical calculations compared to experimental values

Abstract An investigation of the reactivity of N -acetylazoles was performed by AM1 semiempirical method. The calculated electronic and geometry properties of N -acetylazoles and azolium anions were in good correlation with the reactivity of the azoles. The transition state geometries of hydrolysis for N -acetylazoles were located and optimized. The activation energies were calculated and were used for evaluation of the rate of the hydrolysis and were in good agreement with experimental values.

Molecular modeling methodology of β-cyclodextrin inclusion complexes

Abstract A docking approach for molecular mechanics optimization of β-cyclodextrin complexes is described. Because of the specific geometry of the cyclodextrins and the class of guests (relatives of tert-butyl benzene), the guest molecule is moved along a vector going through the middle of the cavity. This vector is perpendicular to the mean plane of the acetal oxygen atoms that link the glucose units. At each step along this vector, the geometry of the bimolecular assembly was optimized to give a minimum in the molecular mechanics steric energy. As expected, the energy decreases as the guest molecule enters the cyclodextrin cavity, and again increases as the guest exits from the other side of the cavity. Rotation of the guest within the cavity prior to energy minimization did not result in lower energies; the minimization process found the best rotational orientation of the guest. On the other hand, it was necessary to drive the guest along the vector; the energy minimization process did not pull the guest into an optimal depth of penetration into the cavity. The binding energies calculated at two different dielectric constants were almost identical, indicating that the complex formation is stabilized by dispersive or Van der Waals forces and not electrostatic (dipole-dipole or hydrogen bonding) forces.

Comparison of AM1 and PM3 semiempirical to ab initio methods in the study of Diels-Alder reactions of butadiene and cyclopentadiene with cyanoethylenes

Abstract Assuming a concerted synchronous mechanism with one transition state of the Diels-Alder reactions, the structures of the transition states and the activation energies for the reactions of butadiene and cyclopentadiene with cyanoethylenes were calculated by AM1 and PM3 semiempirical methods. The structural parameters were compared with those obtained by high level Gaussian calculations, whereas the activation energies were compared both with the ab initio calculations and those obtained experimentally. The structural properties calculated with PM3 methods are in general in better agreement with the ab initio calculations. The low level ab initio calculations are in many cases worse than the semiempirical methods. All predicted activation energies with both semiempirical methods are up to 300% higher than the experimental values. The predicted reactivity is also opposite to the experimental data. Only the very high level Gaussian calculations are in good correlation with experimental results. The predicted selectivity of the reaction is also opposite to the experimental facts. Two explanations are offered for this discrepancy: AM1 and PM3 methods cannot handle the calculation of the concerted Diels-Alder transition states and are not recommended to be used for that purpose, or this Diels-Alder reaction is not concerted but is stepwise.

Semiempirical and ab initio transition state calculations for the transformation of N-acetyltetrazoles into corresponding 1,3,4-oxadiazoles

Abstract The transformation of 2-acetyl-5-substituted-tetrazoles into the corresponding 1,3,4-oxadiazoles was studied with the mopac semiempirical and gaussian ab initio methods. Two mechanisms, one with two transition states and the other with three, were elucidated by mopac . The first mechanism supported by PM3 and MNDO has a two-step, almost concerted, mechanism for the elimination of a nitrogen molecule from the tetrazole ring and formation of the oxadiazole product from an open-chain intermediate through carbon C5 and acetyl oxygen bond formation. The second mechanism supported by AM1 and MINDO/3 breaks the elimination of the nitrogen molecule into two steps: first breaking the N4-C5 and then the N2-N3 bonds. Even when the AM1 and MINDO/3 transition state structures were optimized by PM3 and MNDO, the obtained transition states present only one bond breaking. The HF/STO-3G and HF/3-21G ab initio methods agree with the first mechanism where two bonds are breaking almost simultaneously. Despite the disagreement in the mechanism of the nitrogen elimination, the transition state that presents the product formation from open-chain intermediates is quite similar for all methods studied. The semiempirical calculation of this transition state is possible only if it is assumed that it has biradical character. The activation energies calculated by PM3 seem to be insensitive to the nature of the substituents.

PM3 study of the stereochemistry of heterodienophile cycloadditions to pyrrole: endo lone pair effect

Abstract A semiempirical PM3 theoretical study of heterodienophile addition to pyrrole, a heterocyclic aromatic diene is presented. The results are compared with the ethylene addition to pyrrole. Three approaches were used to determine the reactivity of the dienophiles: frontier orbital energy correlation, comparison of the calculated activation barriers, and comparison of the structural features of the transition state structures, all generated by PM3 calculations. On the basis of the frontier molecular orbital theory it was concluded that the reaction is LUMO dienophile controlled and that all studied heterodienophiles are more reactive than ethylene. Because pyrrole has a higher HOMO energy than cyclopentadiene, it was concluded that pyrrole is more reactive than cyclopentadiene as the diene in Diels-Alder reactions with normal electron demand. On the other hand, reaction energy barriers predict that almost all heterodienophiles except oxygen are less reactive than ethylene. Discrepancies in the frontier orbital and activation energy predictions are discussed in the light of repulsion interactions between the heteroatom endo lone pair and the π-system of pyrrole. In this way the stereoselectivity of the heterodienophile cycloadditions to pyrrole, as well as the geometries of the transition structures, can be explained.

Theoretical study of the Diels–Alder reaction between the S-methylthiophenium ion and ethene

The capability and activation of thiophene as a diene for the Diels–Alder reactions has been investigated by ab initio methods. The reactants and transition structures are optimized with RHF/3-21 + G*, RHF/6-31 + G* and MP2/6-31 + G*. Energies are evaluated with the same level of theory and by single point calculations employing MP2/6-31 + G*//RHF/6-31 + G* and MP3/6-31 + G*// MP2/6-31 + G* methods. The ab initio calculated geometries are compared with experimental data, where available. The relative reactivity of buta-1,3-diene, thiophene and the S-methylthiophenium ion were estimated by comparing their FMO energy gap with ethene as the dienophile. The predicted activation energies are in full agreement with the qualitative determination of reactivity and suggest that thiophene is not a suitable diene for the Diels–Alder reaction. For the S-methylthiophenium ion, the predicted activation energy may be reached under normal reaction conditions. Thus S-methylthiophenium should be a suitable diene for the Diels–Alder reactions.

Semiempirical and ab initio study of 1,3-dipolar addition of azide anion to organic cyanides

Abstract The 1,3-polar azide anion cyloaddition to nitriles was studied by semiempirical and ab initio methods. Two mechanisms were considered: a concerted and a two-step mechanism. AM1 strongly supports the two-step mechanism that involves a nucleophilic attack of the azide ion on the carbon of the nitrile group (formation of iminoazide intermediate) followed by tetrazole ring closure. The calculated activation energies are in good agreement with the experimentally obtained reactivity of the nitriles. The calculations agree with the fact that electron-withdrawing substituents on the nitrile group decrease the activation barrier and facilitate the reaction. Although RHF/3-21G was unable to locate the first transition state in all cases of the two-step mechanism, its concerted transition state structures are very unsymmetrical. The distortion depends much more on the polarity of the substituents than on their size.

Ab initio transition structures for hetero Diels-Alder cycloadditions to furan

Abstract Ab initio calculations at the RHF/3–21G and RHF/6–31G ∗ //RHF3–21G theory levels provide data on the reactivity and stereoselectivity of hetero dienophile additions to furan. The calculated activation energies for the hetero Diels-Alder reactions are usually small, and the newly formed bonds are shorter than in the corresponding all carbon Diels-Alder reactions. The formation of the endo isomer is predicted to be energetically more favorable due to n-π repulsion between the heteroatom lone pair and the π system of the furan ring. The activation energy for some hetero dienophiles is very low and the reaction is suggested to be of synthetic interest in the preparation of natural chiral compounds.