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It is possible to create novel synthetic routes for compounds using synthesis route design systems (SRDS). We have been investigating an in silico screening protocol, which makes it possible to reduce the number of SRDS experiments in developing new synthesis routes. However, there still remains the problem of how to rank synthesis routes for experiments. The experimental yield is considered to be one of the most important factors in determining which synthesis route is better. The present study describes an attempt toward predicting the trends of experimental yields for organic synthesis by fusing computational chemistry and chemoinformatics. We examined whether the prediction of experimental yields for Diels–Alder reactions is feasible using activation energies obtained from Density Functional Theory (DFT) calculations together with the experimental conditions. A partial least squares analysis using these values gave correlation equations for the experimental yields. If it is possible to construct similar correlation equations for other reactions, then SRDS synthetic routes could be ranked on the basis of their predicted yields, and an order can be determined before beginning the experiments.

In this paper we report on the asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides mediated by pybox/ytterbium triflates, -/magnesium bromide, and -/magnesium perchlorate. It was confirmed that the reactions proceed smoothly to give isoxazoline derivatives in high enantiomeric excesses with Mg2+ or Yb3+ complexes and acrylamide dipolarophiles bearing an oxazolidinone or imidazolidinone coordination auxiliary as well as a pybox ligand. In reactions with a dipolarophile bearing 4,4-dimethyloxazolidinone as the coordination auxiliary, an enantiomeric excess (59 % ee) of the corresponding cycloaddition product was achieved by using a slow addition technique to generate nitrile oxides in the presence of Yb(OTf)3/ph-pybox. The cycloaddition reaction of a dipolarophile with an unsubstituted oxazolidinone group in the presence of Yb(OTf)3/ph-pybox at a relatively high temperature (35 °C) produced a higher enantiomeric excess. A relatively low temperature (–78 °C) was required to obtain enantiomeric excesses such as 69 and 87 % ee in the reactions of a dipolarophile bearing an imidazolidinone group to afford cycloadducts in the presence of MgBr2/ip-pybox.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The mechanisms underlying the hydrolysis of methyl acetate and acetamide under acidic conditions were investigated using the MP2/6-311+G(d,p)//MP2/6-31+G(d,p) level of theory. It was necessary to include two water molecules as reactants to obtain a tetrahedral (TD) intermediate for the A AC 2 mechanism that Ingold classified for the hydrolysis of methyl acetate. This mechanism includes two TS structures, one for the formation of the TD intermediate and the other for its decomposition. Since the activation energies were calculated to be 15.7 and 18.3 kcal mol −1 , the second step determines the rate of hydrolysis. The calculated value was close to that observed at ∼16 kcal mol −1 . It was confirmed that the A AC 2 mechanism had a barrier lower by 9.9 kcal mol −1 than the A AL 2 mechanism. The A AC 2 mechanism is also applicable to the acid-catalyzed hydrolysis of acetamide. It is not the TD intermediate with which the NH 3 + moiety forms, but one further step is required to produce the final products, acetic acid and ammonium ion.

Molecular geometries of crown ether derivatives play an important role in capturing and transporting alkali metal ions such as Li + and Na + . As selectivity of the ions is observed in solution, it is necessary to know their molecular structures in solutions. Recently, we investigated stable conformations of 12-crown-O 3 N and its alkali ion complexes in aqueous and acetonitrile solutions. In the present study, we applied a procedure similar to that in previous papers to investigate the side arm effect of 12-crown-O 3 N with an amine arm for capturing Li + and Na + in the two solutions. It was confirmed that the stable structures of Li + and Na + complexes in solutions, especially the geometry of the amine side arm, are highly solvent-dependent. This conformational difference is the key to understanding the high Li + selectivity of 12-crown-O 3 N derivatives with an amine side arm in acetonitrile.

Molecular geometries of crown ether derivatives play an important role in capturing and transporting alkali metal ions such as Li+ and Na+. As the selectivity of ions is observed in solutions, it is necessary to know their molecular structures in solutions. Recently, we investigated stable conformations of 12-crown-O3N and its Li+ complex in aqueous solution by the combination of three programs, the CONFLEX, Gaussian 98, and BOSS programs. In the present study, we applied the same procedure to investigate stable structures of 12-crown-O3N complexes with an alkali ion in aqueous and acetonitrile solutions. It was confirmed that the stable structures of Li+ and Na+ complexes in solutions are highly dependent on the polarity of the solvents.

It is possible to synthesize poly(N-substituted maleimide) by using a chiral complex consisting of a zinc and N -diphenylmethyl-1-benzyl-2-pyrrolidinoethanamine (DPhBP). The optical specific rotations [ α ] 435 25 in obtained polymers depend on the chirality of ligands in the catalysts. In the present study, density functional theory (DFT) calculations were adopted to investigate the polymerization mechanism in detail. The bulky diphenylmethyl group in the chiral ligand is effective to enhance the formation of the product in the initiation reaction. The geometry related to the pyrrolidine ring of the chiral ligand in the Zn catalyst is responsible for determining the configuration of polymers. It was also confirmed that the bulky substituent on the N atom of the N-substituted maleimide is another factor for obtaining polymers with high [ α ] 435 25 .

Ab initio molecular orbital calculations at the MP4(SDTQ)/6-31G∗//RHF/6-31G∗ level of theory were used to obtain detailed insight into the reaction profile on the Mg controlled 1,3-cycloaddition of nitriles oxide with allylic alcohols. It was confirmed that the complex formation reduces the HOMO–LUMO energy gaps of the two reactants. The propensity correlates well to calculated activation energies of the cycloaddition. The syn-stereoselectivity depends on the steric repulsion between the vinyl fragment and the substituent at the α-position of the alcohol or alkoxide. THF or Et2O in the reaction mixture prevent the coordination of R1CNO from forming the Mg intermediate and result in deccelerating the cycloaddition. The results obtained in the present study well explain an important role of the Mg2+ ion in the 1,3-dipolar cycloadditions of nitrile oxides with allylic alcohols.

Photosolvolysis of 2-chloropropylbenzene in trifluoroethanol (TFE) produces propylbenzene, indane, 2-trifluoroethoxypropylbenzene and other solvolysis products. Propylbenzene clearly comes from 2-propylphenyl radical intermediate while the other products suggest existence of 2-propylphenyl cation as an intermediate. Density functional theory (DFT) calculations at the B3LYP/6-31G∗∗ level of theory were carried out to research reaction paths for the solvolysis products through the cationic intermediate. Three paths investigated in the present study well explain the products obtained in our experiments. The DFT calculations strongly suggest existence of the phenyl cation as an intermediate in the photosolvolysis of 2-chloropropylbenzene in TFE.

A substitution on 2,2-difluorovinylic carbon was investigated by using ab initio molecular orbital calculations. Three feasible mechanisms, which are the SN1-like, the SN2-type and the addition-elimination mechanisms, were ex- amined for a model borate, 2,2-difluoro-1-mesyloxyvinyl(trimethyl)borate. Four TSs were obtained depending on the position of Li+ around the vinylborate although activation energies in the gas phase are rather high (ca. 30–40 kcal mol−1) in comparison with that expected from the experimental conditions. It was confirmed at the SCRF-IPCM calculations that the solvent effect reduces the acti- vation energy of one SN2-type mechanism very much (4. l kcal mol−1 at the B3LYP/6-31+G∗//RHF/6-31+G/s* level of theory) while those for the other mechanisms do not change very much. Therefore, the SN2-type mechanism is applicable to the substitution reaction observed for the vinylborate.

In a previous paper (J. Am. Chem. Soc. 1991, 113, 4738), we reported that there was a linear relationship between the activation free energies ΔG⧧ of the Menshutkin reaction of CH3I and the proton ...

Ab initio molecular orbital (MO) study on the inversion process of six trimethylene bridges between two degenerate C 6h conformers of [3 6 ](1,2,3,4,5,6)cyclophane suggests that the inversion occurs in a stepwise manner rather than a synchronous mechanism.

1,4,7,10-Tetraazacyclododecane derivatives having ester- and amide-functionalized sidearms predominantly extracted Na+ ion from an aqueous mixture of Li+, Na+ and K+ ions into a CH2Cl2 via specific octadentate complexation.

The alkaline hydrolysis of amides, N-methyl acetamide 1, acetanilide 2, and N-acetyl imidazole 3, was investigated by use of ab initio molecular orbital calculations. A detailed analysis was performed for two possible mechanisms, Path 1 and 2. Path 1, similar to ester hydrolysis, releases CH3COOH and RNH whereas Path 2 contains the RNH group that extracts the H atom from the OH fragment in the tetrahedral intermediate. In this mechanism, carboxylate ion and an amine directly form. It was ascertained that Path 2 is a better route to decompose the TD intermediate than Path 1 for 1 and 2 in the gas phase. The stability of the leaving group RNH determines which route, Path 1 or 2, is preferred in the gas phase. The solvent effect was estimated for the two mechanisms by using the SCRF calculations of the IPCM model.

A variety of double armed crown ethers were prepared in which amine, amide, ester, nitrile and pyridine moieties were attached as cation-ligating sidearms to diaza-12-crown-4 ring. FAB-MS and 7Li/13C/23Na NMR binding and liquid membrane transport studies revealed that most of them exhibited Li+ cation selectivity, though corresponding single armed lariat ethers showed Na+ cation selectivity. Among them, amine-armed diaza-12-crown-4 derivative offered the highest Li+ ion-selective ionophoric property. Its transport efficiency and selectivity were particularly superior to those of commercially available Li+ ion-selective ionophores.

The density functional calculations were performed to investigate why Li + is selectively transported by the aza-12crown-4 with an amine pendant arm. Two type of complexes, + ] and [>M + ] with four or five donor atoms coordinating to a metal, were optimized where “ + , Na + , and K + ) as the fifth ligand in [>M + ]. This result is inconsistent with that observed, i.e., only the amine arm coordinates to Li + and form [>M + ] in the solution. In order to include solvent effect in the calculations, we optimized the geometries of Li + and Na + complexes with one or two waters, [>M + ](OH 2 ) and + ] (OH 2 ) 2 , which have a cation with the hexa-coordinated environment. Only the combination of an amine arm and Li + has similar stabilization energies for formation of such complexes. The + ](OH 2 ) 2 complex releases larger stabilization energies than those for the [>M + ](OH 2 ) in the other combination of the arms and the cations.

Experimental and theoretical investigations of the anti-selective nucleophilic addition induced by BF 3 to 3-formyl-Δ 2 -isoxazolines are described. Ab initio molecular orbital (MO) calculations show that the 3-formyl-Δ 2 -isoxazoline-BF 3 complex prefers s-trans conformation to s-cis conformation. Nucleophiles attack the stable s-trans conformer from the opposite side of C(4) substituent, giving anti-adducts selectively. The BO bond lengths and the stabilization energies suggest that the features of the complex resemble those of aliphatic aldehyde-BF 3 complexes. Introduction of substituent to allyl tin improves the anti-selectivity from 87/13 to 98/2. These results suggest that the reaction proceeds via anti-periplanar transition state.

A systematic investigation of the cyclic ethers and amines was conducted using molecular orbital calculations to assess their possibility as building blocks of novel functional molecules. A method was developed to quantitatively calculate the Free-O and Comp-O radii which correspond to the hole sizes of free and complexed crown compounds. These radii show the linear relationship with the number of atoms in crown ring for both calculated and observed coordinates. On the other hand, the Li-X (XO and N) lengths are not dependent on the number of atoms in the crown ring. While the ΔEstab's of the crown ethers show a clear dependence on the number of the crown ring atoms, the values does not vary significantly among the cyclic amines. The MNDO method gave reasonable results by chance.

The hitherto unknown stereochemistry concerning the formation of 2,3-disubstituted cycloheptanones by the Michael addition reaction was studied. The Michael addition of thiophenol to 3-substituted 2-methylene-cycloheptanones in the presence of triethylamine in THF at ambient temperature produced 3-substituted 2-[(phenylthio)methyl]cycloheptanones with high cis selectivity (>96/4), which was unequivocally established by 1 H NMR and X-rays analyses

Reversal of enantioface selectivity was observed by merely switching the solvent from CH2Cl2 (enantiomer ratio of the adduct = 91:9) to THF (14:86) in the asymmetric Diels-Alder reaction catalyzed by the aluminum complex of a newly prepared chiral methol derivative. Negative nonlinear effect on the relationship between enantiomeric excesses of the reaction product and optical purities of the ligand was observed for the reaction in CH2Cl2 whilst linear relationship for that in THF.

4,5-Disubstituted 3-formyl-Δ 2 -isoxazolines undergo the aldol, allylation, and carbonyl ene reactions in the presence of appropriate Lewis acid to give the adducts with an effective 1,3-asymmetric induction. The stereoselectivity of the reaction mainly depends on the nature of the Lewis acid and the relative configuration of the ring. It is remarkable that both diastereomers can be readily prepared stereoselectively

In the presence of magnesium perchlorate, 1,3-dipolar cycloaddition reactions of nitrile oxides to crotonamide bearing 4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one as the chiral auxiliary proceeded with a regio- and diastereo-selective manner to afford the corresponding chiral 2-isoxazoline. The mechanisms underlying the diastereoface selection in the cycloaddition reaction were investigated using the B3LYP/6-31G* level of theory.

The Michael addition of alkoxide anions to nitro olefins is studied in terms of ab initio and MNDO molecular orbital calculations. We have also done experiments using nitro olefins with the same substituents calculated here. It is proposed that the stereoselectivity of the reaction is due to the endo alkoxy effect, which is structural, and the electronic effect in nitronate anion intermediates. The effect does not exist in intermediates of conjugate addition of simple alkyl group to nitro olefines. The difference depends on whether the atom in the γ-position possesses lone pair orbitals or not. High stereoselectivity was observed in the Michael addition to nitro olefins with the bulky substituents of the α-carbon. This is due to the difficulty in rotating the alkoxy fragment about the Cα-Cβ axis

The reaction of nitro olefins with thiolate anions followed by protonation at −78 o C gives anti-β-nitro sulfides. This procedure can be applied to the anti-selective preparation of β-nitro ethers and β-nitro selenides. The reaction of cyclic nitro olefins with aryl thiol gives cis-β-nitro sulfide in excellent selectivity. The conjugate addition of alkylaluminum reagents to phenylthio β-nitro olefins followed by protonation at −78 o C also results in selective formation of anti-β-nitro sulfides. Theoretical calculations show that the methylthio group on the β-position covers the one side of the nitronate plane effectively to give the anti isomer in a stereoselective way

Cholesterol-armed cyclens worked as octadentate receptors for Na+, Ca2+, and Y3+ complexes in which four chiral cholesterol-functionalized sidearms were bundled and asymmetrically twisted above cyclen-metal complex platforms. Since the resulting helical metal complexes included chiral, hydrophobic cholesterol residues and charged, hydrophilic metal sites as well as asymmetric coordination geometries, they exhibited unique amphiphilic properties and provided chiral self-aggregates in aqueous solutions. Light scattering, fluorescence, and TEM characterizations demonstrated that Na+ complex with cholesterol-armed cyclen gave a particularly stable self-aggregate in aqueous solution and offered supramolecular environments effective for sensing and detection of amino acid anions. Various dansylamino acid derivatives (dansyl = 5-(dimethylamino)-1-naphthalenesulfonyl) were nicely accommodated in the helicate aggregates to give highly enhanced fluorescence signals, which could be detected by the naked eye at 10(-7) mol/L level. Their inclusion behaviors were analyzed by a Langmuir-type equation, indicating that enantiomer-selective inclusion occurred. MM/MD calculations and circular dichroism (CD) studies further suggested that cholesterol-armed cyclen helicates have chiral and hydrophobic cavities upon self-aggregation, in which the dansylamino acid anions were specifically accommodated. Since these helicates exhibited nonselective binding abilities in solvent extraction experiments of dansylamino acid anions, uncommon chiral recognition and sensing functions were generated by supramolecular alignments of the chiral metal helicates in the aqueous solutions.

This paper describes a new facial procedure to substitute a tosyloxy group in 2-(tosyloxy)alkanoate with SH(-) to yield 2-mercaptoalkanoate on the basis of ab initio MO calculations. Combination of substrate and solvent effects can control both reactivity and selectivity of reaction for 2-(tosyloxy)-3-alkoxycarboxylic acid which gave 2-mercapto-3-alkoxycarboxylic acid in good yield while its ethyl ester gave alpha,beta-unsaturated carboxylate ester as a main product. The difference of carboxylate moiety in the substrate causes remarkable change in reactivity and selectivity. To clarify origin of the difference, ab initio MO calculations in the gas phase and in DMF have been carried out. The solvent effect was considered at RHF/6-31+G with the IPCM-SCRF model. It was confirmed that the substrate with an ester fragment prefers the E1cB to the S(N)2 mechanism. In the transition state of the S(N)2 mechanism with a carboxylate ion fragment, the nucleophile SH(-) locates far from the reaction center due to the electrostatic repulsion between the COO(-) fragment and SH(-). This repulsion causes high activation barrier in the gas phase while polar solvent can reduce the barrier height. Therefore, reaction conditions can control reactivity of carboxylic acid. On the basis of analysis of the MO calculations, subsequent experiments were designed for a new dianion system to synthesize 2-pyrimidinylthio carboxylic acid from 2-tosyloxy carboxylate. We succeeded in developing a new facile method that the two reactions for thioether carried out in a one-pot procedure in excellent yield.

The S(N)i mechanism, which was previously proposed for the isomerization of 1-acylaziridines to the oxazolines, was reexamined theoretically by performing molecular orbital (MO) calculations of 1-formylaziridine and its derivatives as model compounds and experimentally by using 1(R)-[alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl]-2(S)-methylaziridine (5). At the MP2/6-31G//RHF/6-31G level, the activation energy was estimated to be 38.9 kcal mol(-1) for the S(N)i mechanism in which N-protonated 1-formylaziridine 8a(NH(+)) isomerizes to the N-protonated oxazoline 9a(NH(+)). Intrinsic reaction coordinate calculations showed that this reaction proceeds with retention of the ring carbon configuration. Methyl substitution in the aziridine ring reduces the activation energy by 10 kcal mol(-1). The ring closure of N-(2-chloroethyl)formamide (10a) to the oxazoline, which is a model reaction of the rate-determining step for the addition-elimination mechanism, was estimated to have an activation energy of 45.4 kcal mol(-1). The results of these MO calculations are consistent with the observation that the isomerization of the acylaziridine 5 to the oxazoline 6 is facilitated in the presence of weak nucleophiles such as with BF(3).OEt(2) while the formation of 6 is very slow in the presence of stronger nucleophiles such as p-toluenesulfonate. Both theoretical and experimental results suggest that the S(N)i mechanism explains well the isomerization of (R,S)-5 to the oxazoline with BF(3).OEt(2) in refluxing benzene.

Reversal of enantioface selectivity was observed by merely switching the solvent from CH2Cl2 (enantiomer ratio of the adduct = 91:9) to THF (14:86) in the asymmetric Diels-Alder reaction catalyzed by the aluminum complex of a newly prepared chiral methol derivative. Negative nonlinear effect on the relationship between enantiomeric excesses of the reaction product and optical purities of the ligand was observed for the reaction in CH2Cl2 whilst linear relationship for that in THF.

The characteristics of Ca2+-binding sites and of the structural reorganization induced by Ca2+-binding in storage proteins and ion carriers are being studied as models for molecular mechanisms in Ca2+ channels and in Ca2+-dependent modulatory proteins. A first step in the study was the development of energy parameters for Ca2+ compatible with those in the CHARMM package of computer simulation software. Such parameters were obtained from an analytical fit to the potential surface for [(Ca)(OCH2)4]2+ calculated with an ab initio molecular orbital method. The resulting parametrization was tested for the hexapeptide cyclo-(Pro-Gly)3, and a 75 residue long calcium binding protein from bovine intestine (ICaBP). The geometrical parameters calculated for the hexapeptide and its 2:1 complex with Ca2+ were in good agreement with experimental data from crystallography and nmr. Similarly, the structure of ICaBP optimized with CHARMM using the new Ca2+ parameters showed good agreement with the x-ray structure both in the local structures of the calcium-binding sites and in the overall shape of the protein.

The mechanism of the conversion of vinylazides into 2H-azirines is examined by use of ab initio MO calculations. It is ascertained that vinylnitrenes have very weak bonds between the vinylazides and nitrogen molecule parts. It seems to decompose readily into the two fragments. This is one of the most characteristic features of vinylazides. The reaction is shown to proceed with N2 at the tail of the vinylnitrene part. This mechanism accounts well for experimental results of the reaction.

Interaction energies between crown ethers and cations are discussed on the basis of ab-initio MO calculations of 12-crown-4, 18-crown-6, and their cation complexes. The field in cavities of these cyclic ethers are qualitatively discussed by use of the electrostatic potential calculated. The potential suggests that the relation between a hole size of crown ether and an ion radius does not always decide the selective complex formation with the special ion. The electrostatic interaction between Ione pair orbitals of crown ether and cation does not occupy the dominant part of the stabilization energy in complex formation. The charge transfer interaction from crown ether to cation also contributes to the formation of cation complex of crown ether.

Calculation using CNDO/2 method have been performed for the crown ethers and their cation complexes. The photoelectron spectra of 18-crown-6 and 12-crown-4 are well described by the present MO calculations. The orbital interactions between the crown ligand and the cation indicate the importance of the charge transfer interaction for the complex formation. The destabilization energy due to the ring-shrinking (~ 0.5 eV) is very small compared with the complexation energy (5–8 eV). The stability of the complex was reasonably explained by the considering the hydrated species of the cation and the complex, indicating the important role of the solvation effect in the selectivity of the crown ether to the cation.

Electronic structures of different d configurations have been studied in relation to the facility of protonation to dinitrogen ligand in Cr(0) and Co(I) complexes. The d6 Cr complex has much better MO's for protonation than the d8 Co complex. This difference largely affects the protonation energies and the reduction of nitrogen molecule in these complexes.

The hitherto unknown stereochemistry concerning the formation of 2,3-disubstituted cycloheptanones by the Michael addition reaction was studied. The Michael addition of thiophenol to 3-substituted 2-methylene-cycloheptanones in the presence of triethylamine in THF at ambient temperature produced 3-substituted 2-[(phenylthio)methyl]cycloheptanones with high cis selectivity (>96/4), which was unequivocally established by 1 H NMR and X-rays analyses