Bon-Su Lee

A theoretical study on keto-enol tautomerization involving simple carbonyl derivatives

The relative stabilities of the keto and enol forms [Δ E0 (enol‐keto)] and the energy barriers to enolization of the keto forms [Δ E≠ (transition state‐keto)] for CH3COR (R = CH3, H, F, and CN) and CH3CHY (Y = CH2, NH, and S) are investigated theoretically by Hartree‐Fock and Möoller‐Plesset second‐order calculations with 6–31G** basis sets. Specific and bulk solvent effects are considered by incorporating one water molecule and applying the self‐consistent reaction field (SCRF) method to the reaction system, respectively. The Δ E0MP2 values are all positive, in agreement with the lower stability of the enol form in the gas phase as well as in solution. In contrast to a relatively small effect of specific as well as bulk solvation on Δ E0, there is a large lowering of Δ E≠ (by ca. 30 kcal/mol) when solvent effects are accounted for. In general, both Δ E0 and Δ E≠ are depressed in solution and hence enolization is favored thermodynamically as well as kinetically. The keto form is strongly stabilized by a π donor, whereas the enol isomer is stabilized by a π as well as a σ‐acceptor substituent, R. As a result, substituent R = F is the most unfavorable whereas R = CN is the most favorable for the enolization. The water catalyzed enolization in the neutral water proceeds concertedly, but carbon deprotonation is more important than carbonyl‐oxygen protonation by water in the rate determining step.

Prediction of physicochemical properties of organic molecules using van der Waals surface electrostatic potentials

The generalized interaction properties function (GIPF) methodology developed by Politzer and coworkers, which calculated molecular surface electrostatic potential (MSESP) on a density envelope surface, was modified by calculating the MSESP on a much simpler van der Waals (vdW) surface of a molecule. In this work, vdW molecular surfaces were obtained from the fully optimized structures confirmed by frequency calculations at B3LYP/6‐31G(d) level of theory. Multiple linear regressions for normal boiling point, heats of vaporization, heats of sublimation, heats of fusion, liquid density, and solid density were performed using GIPF variables from vdW model surface. Results from our model are compared with those from Politzer and coworkers. The surface‐dependent β (and γ) values are dependent on the surface models but the surface‐independent α and regression coefficients (r) are constant when vdW surface and density surface with 0.001 a.u. contour value are compared. This interesting phenomenon is explained by linear dependencies of GIPF variables.

Ab initio molecular orbital studies of nonidentity allyl transfer reactions

Ab initio molecular orbital (MO) calculations are carried out on the nonidentity allyl transfer processes, X− + CH2CHCH2Y ⇌ CH2CHCH2 X + Y−, with X− = H, F, and Cl and Y = H, NH2, OH, F, PH2, SH, and Cl. The Marcus equation applies well to the allyl transfer reactions. The transition state (TS) position along the reaction coordinate and the TS structure are strongly influenced by the thermodynamic driving force, whereas the TS looseness is originated from the intrinsic barrier. The intrinsic barrier, ΔE  0‡ , looseness, %L‡, and absolute asymmetry, %AS‡, are well correlated with the percentage bond elongation, %CY‡ = [(d  CY‡ − d  CY0 )/d  CY0 ] × 100 and/or %CX‡. The %CY‡ and the bond orders indicate that a stronger nucleophile and/or a stronger nucleofuge (or a better leaving group) leads to an earlier TS on the reaction coordinate with a lesser degree of bond making as well as bond breaking. These are consistent with the Bell‐Evans‐Polanyi principle and the Leffler‐Hammond postulate.

Syntheses and binding affinities of 6-nitroquipazine analogues for serotonin transporter. Part 2: 4-substituted 6-nitroquipazines.

Eleven 4-substituted derivatives of 6-nitroquipazine were synthesized and evaluated for their abilities to displace [3H]citalopram binding to the rat cortical synaptic membranes. Among them, 4-chloro-6-nitroquipazine was shown to possess the highest binding affinity (K(i=)0.03 nM) which was approximately 6 times higher than that of 6-nitroquipazine (K(i)=0.17 nM) itself. In this paper, we describe the syntheses of 4-substituted 6-nitroquipazine derivatives, the results of corresponding biological evaluation and the SAR study.

DENSITY FUNCTIONAL THEORY STUDIES OF HETERO-DIELS-ALDER REACTIONS

Transition structures for hetero-Diels–Alder reactions involving the heteroatoms O, S and N in dienes as well as in dienophiles have been determined at the MP2 (MP2/6-31G*//MP2/6-31G*) and hybrid DFT (B3LYP/6-31G*//B3LYP/6-31G*) levels of theory. The transition structures are predicted to be relatively early, concerted and asynchronous in all cases, with the DFT transition structures being more asynchronous than the MP2 ones. The reactions of butadiene with formaldehyde, thioformaldehyde and formaldimine proceed by diene HOMO–dienophile LUMO interactions whereas those of ethylene with acrolein, 1-thiabutadiene and 1-azabutadiene proceed by reverse electron demand interactions. In all the hetero-Diels–Alder reactions, the C–C bond is more fully formed than the heteroatom–carbon bond in the transition structure with the exception of the reaction between formaldimine and butadiene for which C–N bond formation is ahead of C–C bond making. All the reactions are highly exothermic. The reactions are facilitated by heteroatoms in both the diene and dienophile, and bond formation between two heteroatoms is disfavored. The reaction of formaldimine shows an endo preference whereas that of 1-azabutadiene leads to an exo preference of the imino hydrogen; these preferences of ca. 4 kcal mol-1 are caused mostly by inter-hydrogen steric effects in the transition structures. We conclude that the DFT calculations provide an economical way of accounting for electron correlation effects at nearly the same level as the MP2 ones in the investigations of hetero-Diels–Alder reactions.

Nucleophilic substitution reactions of α-chloroacetanilides with benzylamines in dimethyl sulfoxide

Kinetic studies of the reactions of alpha-chloroacetanilides (YC6H4NRC(=O)CH2Cl; R = H (5) and CH3 (6)) with benzylamines (NH2CH2C6H4X) were carried out in dimethyl sulfoxide at 55.0 degrees C. The Brønsted betaX values were in the range from 0.6 to 0.9 and cross-interaction constants phoXY were positive: phoXY = +0.21 and +0.18 for 5 and 6, respectively. The rates were faster with 6 than with 5 and inverse secondary kinetic isotope effects involving deuterated benzylamine (ND2CH2C6H4X) nucleophiles, kH/kD < 1.0, were obtained. Based on these and other results, a stepwise mechanism with rate-limiting expulsion of the chloride leaving group from a zwitterionic tetrahedral intermediate, T+/-, is proposed. In this mechanism, a prior carbonyl addition to T+/- is followed by a bridged type transition state to expel the chloride. An enolate-like transition state in which the developing negative charge on C(alpha) delocalizes toward the carbonyl group (nC-->pi*(C=O) interaction) is not feasible for the present series of reactions due to a stronger charge transfer involving the lone pair on the anilino nitrogen (nAN-->pi*(C=O) interaction).

Downfield chemical shifts at α-protons and carbons of β-propiothiolactones

Both the α‐protons and carbons of β‐propiothiolactones exhibit atypical downfield chemical shifts. The α‐protons of β‐propiothiolactones with no heteroatom at the α‐position appear at 3.53–5.35 ppm, whereas the α‐carbons appear at 56.9–86.2 ppm. The major cause of the unexpected deshielding effect was rationalized by assuming a through‐space interaction between the occupied orbital of the α‐carbon and the vacant orbital of sulfur. Copyright

AB INITIO STUDIES OF THREE-MEMBERED RING FORMATION THROUGH INTRAMOLECULAR NUCLEOPHILIC SUBSTITUTION

Three‐membered ring (3MR) forming processes of −X(SINGLE BOND)CH2(SINGLE BOND)CH2(SINGLE BOND)F and −CH2(SINGLE BOND)C((SINGLE BOND)Y)(SINGLE BOND)CH2(SINGLE BOND)F (X(DOUBLE BOND)CH2, O, or S and Y(DOUBLE BOND)0 or S) through a gas phase neighboring group mechanism (SNi) are studied theoretically using the ab initio molecular orbital method with the 6–31+G* basis set. When electron correlation effects are considered, the activation (ΔG≠) and reaction energies (ΔG0) are lowered by ca. 10 kcal mol−1, indicating the importance of the electron correlation effect in these reactions. The contribution of entropy of activation (−TΔS≠) at 298 K to ΔG≠ is very small, and the reactions are enthalpy controlled. The ΔG≠ and ΔG0 values for these ring closure processes largely depend on the stabilities of the reactants and the heteroatom acting as a nucleophilic center. The Bell–Evans–Polanyi principle applies well to all these reaction series. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1773–1784, 1997

Nucleophilic substitution reactions of cinnamoyl chlorides with anilines in acetonitrile and acetonitrile–methanol mixtures

Kinetic studies on the solvolysis (in McOH–MeCN mixtures) and aminolysis (with anilines in McCN) of cinnamoyl chlorides have been carried out at 25.0 °C. The relatively large negative values of ρY+=–0.9 ∼–1.5 for the methanolysis are consistent with a dissociative SN2-like mechanism. For the aminolysis, the ρY values are positive (ρY= 0.52 ∼ 1.64) and ρX values range from –1.68 to –2.51 in acetonitrile. The positive values of βX= 0.6–0.9 and ρXY= 0.88 in acetonitrile, and isotope effect data suggest that the aminolysis proceeds by a stepwise mechanism with rate-limiting breakdown of the tetrahedral intermediate, T±. It is noted that in the acyl-transfer reactions proceeding by rate-limiting departure of the leaving group from the tetrahedral intermediate the signs of both ρY and ρXY are positive and the reactivity–selectivity principle (RSP) is valid in general.

Theoretical studies of substituent effects on SN1 reactivities of benzyl- and benzhydryl systems.

Abstract AM1MO theoretical calculations are carried out to investigate effects of substituents on the SN1 reactivities of cationic benzyl, I , mono-substituted benzhydryl, II , and di-substituted benzhydryl, III , systems with neutral leaving group of FH. The effects of para-substituents are markedly greater than those of meta-substituents in all systems due to a strong positive charge delocalization of electron donating substituents at para position. The enthalpies of activation, ΔH≠, are linearly correlated with the enthalpies of reaction, ΔH0, with slopes of 0.48 for I , and 0.39 for II and III , indicating that the transition state (TS) is reached at about half point along the reaction coordinate for I , but somewhat earlier for II and III . The linear correlations between ΔH≠ and Cα-leaving group bond length (d(CLG)) and between ΔH≠ and stretching of d(CLG) in the TS (Δd≠(CLG)) manifest that all reaction series conform to the Kirbys rule and the Bell-Evans-Polanyi principle, respectively. Satisfactory Hammett type plots, ΔH≠ vs σp+ , are obtained for the para substituents with the corresponding ϱ+ values of −3.0, −1.3 and −1.2 for the I , II and III series. For the meta substituted series, the difference in the substituent effects is small since the effects are solely due to polar effect.