Alkaloids and Selected Topics in Their Thermochemistry.

Alkaloid chemistry is varied and complex. Many alkaloids attract a great deal of interest because of their physiological activity, yet surprisingly little is known about the thermochemistry of these compounds, especially in the gas phase. In this paper, we investigate the thermochemical characteristics, specifically demethoxylation enthalpies rather than those derived from trans-methoxylation reactions, of a series of biologically relevant alkaloids in their condensed phase.

Photochemical Valence Isomerization to High Energy Products-Bicyclobutanes and Oxabicyclobutanes.

DFT calculations were used to determine the structures and energies of bicyclobutane and oxabicyclobutane as valence isomers derived from electronic excitation of their corresponding precursors, 1,3-butadiene and acrolein, respectively. Proton affinities of these strained compounds were determined and compared with their simple ring components, cyclopropane and ethylene oxide. The basicity as determined from proton affinities showed that bicyclobutane is the most basic saturated hydrocarbon, even more basic than oxabicyclobutane. Strain energies of these valence tautomers were computed which showed oxabicyclobutane to be significantly more strained than bicyclobutane. Qualitative reasons are provided to account for the difference in strain energies.

Predicted Reversal in N-Methylazepine/N-Methyl-7-azanorcaradiene Equilibrium Upon Formation of Their N-Oxides.

Density functional calculations and up to five different basis sets have been applied to the exploration of the structural, enthalpy and free energy changes upon conversion of the azepine to the corresponding N-oxide. Although it is well known that azepines are typically much more stable than their 7-azanorcaradiene valence isomers, the stabilities are reversed for the corresponding N-oxides. Structural, thermochemical as well as nucleus-independent chemical shift (NICS) criteria are employed to probe the potential aromaticity, antiaromaticity and nonaromaticity of N-methylazepine, its 7-azanorcaradiene valence isomer. For the sake of comparison, analogous studies are performed on N-methylpyrrole and its N-oxide.

Computational Study of Selected Amine and Lactam N-Oxides Including Comparisons of N-O Bond Dissociation Enthalpies with Those of Pyridine N-Oxides.

A computational study of the structures and energetics of amine N-oxides, including pyridine N-oxides, trimethylamine N-oxide, bridgehead bicyclic amine N-oxides, and lactam N-oxides, allowed comparisons with published experimental data. Most of the computations employed the B3LYP/6-31G* and M06/6-311G+(d,p) models and comparisons were also made between the results of the HF 6-31G*, B3LYP/6-31G**, B3PW91/6-31G*, B3PW91/6-31G**, and the B3PW91/6-311G+(d,p) models. The range of calculated N-O bond dissociation energies (BDE) (actually enthalpies) was about 40 kcal/mol. Of particular interest was the BDE difference between pyridine N-oxide (PNO) and trimethylamine N-oxide (TMAO). Published thermochemical and computational (HF 6-31G*) data suggest that the BDE of PNO was only about 2 kcal/mol greater than that of TMAO. The higher IR frequency for N-O stretch in PNO and its shorter N-O bond length suggest a greater difference in BDE values, predicted at 10-14 kcal/mol in the present work. Determination of the enthalpy of sublimation of TMAO, or at least the enthalpy of fusion and estimation of the enthalpy of vaporization might solve this dichotomy. The "extra" resonance stabilization in pyridine N-oxide relative to pyridine was consistent with the 10-14 kcal/mol increase in BDE, relative to TMAO, and was about half the "extra" stabilization in phenoxide, relative to phenol or benzene. Comparison of pyridine N-oxide with its acyclic model nitrone ("Dewar-Breslow model") indicated aromaticity slightly less than that of pyridine.

Why are the Elemental Nonmetals (F2 , Cl2 , Br2 , I2 , S8 , P4 ) of so Many Hues or of Any Hues and Where is the Chromophore? Insight into Intera-X-X Bonds.

A unique approach is used to relate the HOMO-LUMO energy difference to the difference between the ionization potential (IP) and electron affinity (EA) to assist in deducing not only the colors, but also chromophores in elemental nonmetals. Our analysis focuses on compounds with lone pair electrons and σ electrons, namely X2 (X = F, Cl, Br, I), S8 and P4 . For the dihalogens, the [IP - EA] energies are found to be: F2 (12.58 eV), Cl2 (8.98 eV), Br2 (7.90 eV), I2 (6.78 eV). We suggest that the interahalogen X-X bond itself is the chromophore for these dihalogens, in which the light absorbed by the F2 , Cl2 , Br2 , I2 leads to longer wavelengths in the visible by a π â†’ σ* transition. Trace impurities are a likely case of cyclic S8 which contains amounts of selenium leading to a yellow color, where the [IP - EA] energy of S8 is found to be 7.02 eV. Elemental P4 with an [IP - EA] energy of 9.09 eV contains a tetrahedral and σ aromatic structure. In future work, refinement of the analysis will be required for compounds with π electrons and σ electrons, such as polycyclic aromatic hydrocarbons (PAHs).

How Often are Orphan Drugs Orphaned by the Thermochemical Community?

Orphan drug products (e.g. drugs and biologics) in the United States are those that treat people with rare chronic diseases, often cancer or metabolic disease. The rare disease condition being treated by these orphan drugs must serve a patient population of less than 200,000 people in the U.S. in order to earn the orphan drug product title. Just as the disease conditions are seen as "orphans," so, we assert is the thermochemical understanding of the drugs themselves in terms of the chemical structures that define those drugs. This article illustrates this orphan thermochemical status for a recent series of orphan drugs.

Computed Regioselectivity and Conjectured Biological Activity of Ene Reactions of Singlet Oxygen with the Natural Product Hyperforin.

Hyperforin is a constituent of St. John's wort and coexists with the singlet oxygen sensitizer hypericin. Density functional theory, molecular mechanics and Connolly surface calculations show that accessibility in the singlet oxygen "ene" reaction favors the hyperforin "southwest" and "southeast" prenyl (2-methyl-2-butenyl) groups over the northern prenyl groups. While the southern part of hyperforin is initially more susceptible to oxidation, up to 4 "ene" reactions of singlet oxygen can take place. Computational results assist in predicting the fate of adjacent hydroperoxides in hyperforin, where the loss of hydrogen atoms may lead to the formation of a hydrotrioxide and a carbonyl instead of a Russell reaction.

Unique thermodynamic relationships for ΔfHo and ΔfGo for crystalline inorganic salts. I. Predicting the possible existence and synthesis of Na2SO2 and Na2SeO2. Addendum.

Addendum to Vegas et al. [(2012), Acta Cryst. B68, 511-527].

Energetic and structural study of bisphenols.

We have studied thermochemical, thermophysical and structural properties of bisphenols A, E, F, and AP. In particular, the standard enthalpies of sublimation and the standard enthalpies of formation in the gas phase at 298.15 K for all these species were experimentally determined. A computational study, through M05-2X density functional theory, of the various species shed light on structural effects and further confirmed, by means of the isodesmic reaction scheme, the excellent consistency of the experimental results. Our results reflect also the fact that energetic substituent effects are transferable from diphenylalkanes to bisphenols.

Theoretical study of the reaction formalhydrazone with singlet oxygen. Fragmentation of the C=N bond, ene reaction and other processes.

Photobiologic and synthetic versatility of hydrazones has not yet been established with (1)O2 as a route to commonly encountered nitrosamines. Thus, to determine whether the "parent" reaction of formalhydrazone and (1)O2 leads to facile C=N bond cleavage and resulting nitrosamine formation, we have carried out CCSD(T)//DFT calculations and analyzed the energetics of the oxidation pathways. A [2 + 2] pathway occurs via diradicals and formation of 3-amino-1,2,3-dioxazetidine in a 16 kcal/mol(-1) process. Reversible addition or physical quenching of (1)O2 occurs either on the formalhydrazone carbon for triplet diradicals at 2-3 kcal mol(-1), or on the nitrogen (N(3)) atom forming zwitterions at ~15 kcal/mol(-1), although the quenching channel by charge-transfer interaction was not computed. The computations also predict a facile conversion of formalhydrazone and (1)O2 to hydroperoxymethyl diazene in a low-barrier 'ene' process, but no 2-amino-oxaziridine-O-oxide (perepoxide-like) intermediate was found. A Benson-like analysis (group increment calculations) on the closed-shell species are in accord with the quantum chemical results.

An overview of the understanding of ions containing solely fluorine atoms.

We discuss in the current paper ions containing solely fluorine atoms, F-, F2- and F3-, their corresponding cationic and/or multiply charged counterparts. While the emphasis of the paper is on gas phase species, their energetics and reactions, aqueous solutions are also discussed. In particular, biomedical and analytical aspects of F- are also considered. The new trichotomy of convenience, anthropocentrism and folksonomy is also applied to the understanding of our fluorine-containing ions.

Amino, Ammonio and Aminioethenes: A Theoretical Study of their Structure and Energetics.

We have performed high level ab initio quantum mechanical calculations for aminoethene and the three isomeric 1,1- (Z)- or (E)-1,2-diaminoethenes as well as their singly and doubly charged cations derived by loss of electrons and/or upon protonation. Gas phase molecular structures were computed at the MP2/6-311+G(3df,2p) level. Standard molar enthalpies of formation in the gas phase, at T = 298.15 K were estimated using the G3 composite method and atomization, isodesmic and homodesmotic reactions. Other energetic parameters were also calculated at the G3 level: proton affinities, basicities and adiabatic ionization enthalpies. Theoretical and experimental data are compared. The reported experimental data refer only to aminoethene wherein the standard molar enthalpy of formation has a considerable uncertainty, although the molecular structure is well-established. There are no such data, neither structural nor thermochemical, for any of the three isomeric diaminoethenes. Isoelectronic comparisons are made. For example, the diprotonated diaminoethenes are isoelectronic to isobutene and (Z)- and (E)-butene, while the doubly ionized diaminoethenes are likewise related to trimethylenemethane and 1,3-butadiene.

Isoelectronic and isolobal O, CH2, CH3+ and BH3 as electron pairs; similarities between molecular and solid-state chemistry.

A topological analysis of the electron localization function (ELF) of a molecule of hexamethyldisiloxane, (H3C)3-Si-O-Si-(CH3)3, has been carried out, drawing a consistent picture of Si-O-Si bonding both in the linear and angular geometries. The ELF analysis confirms the idea that the O atom, in the linear geometry of (H3C)3-Si-O-Si-(CH3)3, is isolobal with the isoelectronic -CH3(+)- and -BH3- groups, the bonding in the Si-O-Si group being described as a two-electron, three-center (2e, 3c) bond. At the same time, the three oxygen lone pairs mirror the three C-H and B-H bonds, respectively. On the contrary, in the angular geometry the same O atoms form two Si-O bonds and its lone pairs mimic the geometry of the -CH2- group. In this model the O atoms would play the same role as the formally present O(2-) anions in the `so-called' ionic solids, such as in the skeletons of aluminate and silicate polyanions, thereby connecting molecular and solid-state chemistry as formulated by the `fragment formalism' or the `molecular unit-cell approach'. This unifying concept as well as the calculations we have carried out fully agree and also give support to earlier ideas developed by Bragg and Bent, among other authors. Bonding in the series of compounds P4, P4O6, P4O10, N4(CH2)6 (hexamethylenetetramine) and (CH)4(CH2)6 (adamantane) is discussed in the context of the isolobal model.

Thermochemistry of uracils. Experimental and computational enthalpies of formation of 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyluracils.

We describe in the current paper an experimental and computational study of three methylated uracils, in particular, the 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyl derivatives. The values of the standard (p(0) = 0.1 MPa) molar enthalpies of formation in the gas phase at T = 298.15 K have been determined. The energies of combustion were measured by static bomb combustion calorimetry, and from the results obtained, the standard molar enthalpies of formation in the crystalline state at T = 298.15 K were calculated. The enthalpies of sublimation were determined using the transpiration method in a saturated N(2) stream. Values of -(376.2 ± 2.6), -(355.9 ± 3.0), and -(381.7 ± 2.8) kJ·mol(-1) for the gas-phase enthalpies of formation at T = 298.15 K of 5,6-dimethyluracil, 1,3,5-trimethyluracil, and 1,3,5,6-tetramethyluracil, respectively, were obtained from the experimental thermochemical study. An extended theoretical study with the G3 and the G4 quantum-chemical methods has been carried out for all the possible methylated uracils. There is a very good agreement between experimental and calculated enthalpies of formation for the three derivatives studied. A Free-Wilson analysis on G4-calculated enthalpies of formation has been carried out, and the contribution of methylation in the different positions of the uracil ring has been estimated.

Unique thermodynamic relationships for ΔfHo and ΔfGo for crystalline inorganic salts. I. Predicting the possible existence and synthesis of Na2SO2 and Na2SeO2.

The concept that equates oxidation and pressure has been successfully utilized in explaining the structural changes observed in the M(2)S subnets of M(2)SO(x) (x = 3, 4) compounds (M = Na, K) when compared with the structures (room- and high-pressure phases) of their parent M(2)S `alloy' [Martínez-Cruz et al. (1994), J. Solid State Chem. 110, 397-398; Vegas (2000), Crystallogr. Rev. 7, 189-286; Vegas et al. (2002), Solid State Sci. 4, 1077-1081]. These structural changes suggest that if M(2)SO(2) would exist, its cation array might well have an anti-CaF(2) structure. On the other hand, in an analysis of the existing thermodynamic data for M(2)S, M(2)SO(3) and M(2)SO(4) we have identified, and report, a series of unique linear relationships between the known Δ(f)H(o) and Δ(f)G(o) values of the alkali metal (M) sulfide (x = 0) and their oxyanion salts M(2)SO(x) (x = 3 and 4), and the similarly between M(2)S(2) disulfide (x = 0) and disulfur oxyanion salts M(2)S(2)O(x) (x = 3, 4, 5, 6 and 7) and the number of O atoms in their anions x. These linear relationships appear to be unique to sulfur compounds and their inherent simplicity permits us to interpolate thermochemical data (Δ(f)H(o)) for as yet unprepared compounds, M(2)SO (x = 1) and M(2)SO(2) (x = 2). The excellent linearity indicates the reliability of the interpolated data. Making use of the volume-based thermodynamics, VBT [Jenkins et al. (1999), Inorg. Chem. 38, 3609-3620], the values of the absolute entropies were estimated and from them, the standard Δ(f)S(o) values, and then the Δ(f)G(o) values of the salts. A tentative proposal is made for the synthesis of Na(2)SO(2) which involves bubbling SO(2) through a solution of sodium in liquid ammonia. For this attractive thermodynamic route, we estimate ΔG(o) to be approximately -500 kJ mol(-1). However, examination of the stability of Na(2)SO(2) raises doubts and Na(2)SeO(2) emerges as a more attractive target material. Its synthesis is likely to be easier and it is stable to disproportionation into Na(2)S and Na(2)SeO(4). Like Na(2)SO(2), this compound is predicted to have an anti-CaF(2) Na(2)Se subnet.

Substituent effects on the thermochemistry of thiophenes. a theoretical (G3(MP2)//B3LYP and G3) study.

Very good linear correlations between experimental and calculated enthalpies of formation in the gas phase (G3(MP2)//B3LYP and G3) for 48 thiophene derivatives have been obtained. These correlations permit a correction of the calculated enthalpies of formation in order to estimate more reliable "experimental" values for the enthalpies of formation of substituted thiophenes, check the reliability of experimental measurements, and also predict the enthalpies of formation of new thiophenes that are not available in the literature. Moreover, the difference between the enthalpies of formation of isomeric thiophenes with the same substituent in positions 2 and 3 of the ring has been analyzed. Likewise, a comparison of the substituent effect in the thiophene and benzene rings has been established.

Large gallanes and the PSEPT theory: a theoretical study of Ga(n)H(n+2) clusters (n = 7-9).

Do alanes Al(n)H(n+2) and gallanes Ga(n)H(n+2) satisfy the polyhedral skeletal electron pair theory (PSEPT)? Taking into account previous work on this question, this paper provides a convincing answer and proposes the reformulation of the (n + 1) electron pairs rule of Wade and Mingos (W-M) for such systems. Following recent studies of tetra-, penta-, hexa-, hepta-, octa-, and nonaalanes as well as valence-isoelectronic/related gallanes, in this paper we present an analysis of the hydrides of aluminum and gallium A(n)H(n+2) (A = Al, Ga and n = 7-9). The aim is still to examine the applicability of PSEPT, especially the W-M rule, to these clusters. Exploration of the total potential energy surfaces (PESs) of hepta-, octa-, and nonagallanes shows that the absolute minima have a nido-like polyhedron arrangement. Unlike the smaller Ga(n)H(n+2) (n = 4, 5, 6), it seems that the size of the cluster largely dictates its preferred geometry. Although none of them have closed (totally triangular) cages, these clusters exhibit significant compactness, comparable to borane double anions, B(n)H(n) (2-), which are the archetypes for the PSEPT theory.

Study of energetics and structure of 1,2,3-benzotriazin-4(3H)-one and its 1H and enol tautomers.

This paper reports an experimental and computational study on the energetics of 1,2,3-benzotriazin-4(3H)-one. The standard (p° = 0.1 MPa) molar enthalpy of formation of solid 1,2,3-benzotriazin-4(3H)-one, at T = 298.15 K, was derived from its standard massic energy of combustion measured by static bomb combustion calorimetry in oxygen. The Calvet high-temperature vacuum sublimation technique was used to measure the respective standard molar enthalpy of sublimation at T = 298.15 K. From these two experimentally determined thermodynamic parameters, we have calculated the standard molar enthalpy of formation of 1,2,3-benzotriazin-4(3H)-one in the gas phase at T = 298.15 K, (200.9 ± 3.8) kJ·mol(-1). Interrelations between structure and energy for 1,2,3-benzotriazin-4(3H)-one, the tautomer 1,2,3-benzotriazin-4(1H)-one, and the enol tautomer 1,2,3-benzotriazin-4-ol were discussed based on density functional theory (DFT) calculations with the B3LYP hybrid functional and the 6-311++G(d,p) basis set. The gas-phase enthalpy of formation of 1,2,3-benzotriazin-4(3H)-one was estimated from quantum chemical calculations using the G3(MP2)//B3LYP composite method. Nucleus-independent chemical shifts (NICS) were also calculated with the purpose of analyzing the aromaticity of the benzenic and heterocyclic rings of the title molecule and others related tautomerically to it.

Energetics of the lighter chalcogen analogues of carboxylic acid esters.

In the current paper we present the results of our quantum chemical (G2, G2(MP2), and G3) study of the structure and energetics of carboxylic acids and their chalcogen analogues. In the particular, calculations and accompanying natural bond orbital (NBO) and atoms in molecules (AIM) analyses were performed on all species with the generic formula RC(═X)YR' (X, Y = O, S, Se and R = R' = CH(3)). Energies, enthalpies, and free energies of formation, resonance energies, interchalcogen methyl transfer energies and their energies of activation, and heavy atom bond lengths and angles are all discussed. A comparison of the calculated results with the sparse experimentally available data shows good agreement. Trends are also presented.