Ozonolysis can produce long-lived greenhouse gases from commercial refrigerants.

Hydrofluoroolefins are being adopted as sustainable alternatives to long-lived fluorine- and chlorine-containing gases and are finding current or potential mass-market applications as refrigerants, among a myriad of other uses. Their olefinic bond affords relatively rapid reaction with hydroxyl radicals present in the atmosphere, leading to short lifetimes and proportionally small global warming potentials. However, this type of functionality also allows reaction with ozone, and whilst these reactions are slow, we show that the products of these reactions can be extremely long-lived. Our chamber measurements show that several industrially important hydrofluoroolefins produce CHF3 (fluoroform, HFC-23), a potent, long-lived greenhouse gas. When this process is accounted for in atmospheric chemical and transport modeling simulations, we find that the total radiative effect of certain compounds can be several times that of the direct radiative effect currently recommended by the World Meteorological Organization. Our supporting quantum chemical calculations indicate that a large range of exothermicity is exhibited in the initial stages of ozonolysis, which has a powerful influence on the CHF3 yield. Furthermore, we identify certain molecular configurations that preclude the formation of long-lived greenhouse gases. This demonstrates the importance of product quantification and ozonolysis kinetics in determining the overall environmental impact of hydrofluoroolefin emissions.

Improved computational modeling of the kinetics of the acetylperoxy + HO2 reaction.

The acetylperoxy + HO2 reaction has multiple impacts on the troposphere, with a triplet pathway leading to peracetic acid + O2 (reaction (1a)) competing with singlet pathways leading to acetic acid + O3 (reaction (1b)) and acetoxy + OH + O2 (reaction (1c)). A recent experimental study has reported branching fractions for these three pathways (α1a, α1b, and α1c) from 229 K to 294 K. We constructed a theoretical model for predicting α1a, α1b, and α1c using quantum chemical and Rice-Ramsperger-Kassel-Marcus/master equation (RRKM/ME) simulations. Our main quantum chemical method was Weizmann-1 Brueckner Doubles (W1BD) theory; we combined W1BD and equation-of-motion spin-flip coupled cluster (SF) theory to treat open-shell singlet structures. Using RRKM/ME simulations that included all conformers of acetylperoxy-HO2 pre-reactive complexes led to a 298 K triplet rate constant, k1a = 5.11 × 10-12 cm3 per molecule per s, and values of α1a in excellent agreement with experiment. Increasing the energies of all singlet structures by 0.9 kcal mol-1 led to a combined singlet rate constant, k1b+1c = 1.20 × 10-11 cm3 per molecule per s, in good agreement with experiment. However, our predicted variations in α1b and α1c with temperature are not nearly as large as those measured, perhaps due to the inadequacy of SF theory in treating the transition structures controlling acetic acid + O3 formation vs. acetoxy + OH + O2 formation.

Drug-Excipient Interactions: Effect on Molecular Mobility and Physical Stability of Ketoconazole-Organic Acid Coamorphous Systems.

The use of excipients other than polymers for enhancing the physical stability of amorphous active pharmaceutical ingredients (APIs) has largely been unexplored. We investigated several organic acids (oxalic, tartaric, citric, and succinic acid) for the purpose of stabilizing a weakly basic API, ketoconazole (KTZ), in the amorphous state. Coamorphous systems with each acid, in 1:1 KTZ-acid molar ratio, were prepared by spray drying. The interaction of KTZ with each acid was investigated by FT-IR, solid-state NMR, and quantum chemical calculations. Each acid exhibited ionic and/or hydrogen-bonding interactions with KTZ, and quantum chemical calculations provided a measure of the strength of this interaction. The α-relaxation times, a measure of molecular mobility, were determined by dielectric spectroscopy, and their crystallization propensity by variable temperature X-ray powder diffractometry. Crystallization was observed only in two systems, KTZ-oxalic salt and KTZ-succinic as a cocrystal. An increase in the strength of KTZ-acid interaction translated to a decrease in molecular mobility. When the two systems prepared with structurally similar dicarboxylic acids (succinic and oxalic acid) were compared, the physical stability enhancement of KTZ-oxalic coamorphous system could be attributed to its lower mobility. However, the exceptional stability of KTZ-tartaric and KTZ-citric could not be explained by mobility alone, indicating that structural factors may also contribute to stabilization. The interaction between KTZ and acid may alter the system sufficiently so that the crystallization propensity of the KTZ-acid complex (salt or cocrystal) becomes relevant. We conclude that small molecule excipients have the potential to improve the physical stability of amorphous APIs.

Quantum Chemical and Statistical Rate Theory Studies of the Vinyl Hydroperoxides Formed in trans-2-Butene and 2,3-Dimethyl-2-butene Ozonolysis.

The vinyl hydroperoxide (VHP), the major isomerization product of the syn-alkyl Criegee intermediate (CI) formed in alkene ozonolysis, is a direct precursor of hydroxyl radical (OH), the most important oxidant in the troposphere. While simulations of CI reactivity have usually assumed the VHP to be a prompt and quantitative source of OH, recent quantum chemical studies have revealed subtleties in VHP reactivity such as a barrier to peroxy bond homolysis and a possible rearrangement to a hydroxycarbonyl. In this work, we use M06-L, Weizmann-1 Brueckner Doubles, and equation-of-motion spin-flip coupled-cluster theories to calculate a comprehensive reaction mechanism for the syn and anti conformers of the parent VHP formed in trans-2-butene ozonolysis and the 1-methyl VHP formed in 2,3-dimethyl-2-butene ozonolysis. We predict that for the parent VHP the anti homolysis transition structure (TS) is 3 kcal mol-1 lower in energy than the syn TS, but for the 1-methyl system, the syn TS is 2 kcal mol-1 lower in energy. Statistical rate theory simulations based on the quantum chemical data predict that the parent VHP preferentially decomposes to vinoxy and OH radicals under all tropospheric conditions, while the 1-methyl VHP preferentially decomposes to 1-methylvinoxy and OH radicals only close to 298 K; at 200 K, the 1-methyl VHP preferentially rearranges to hydroxyacetone. Lower temperatures and higher pressures favor the temporary accumulation of both the parent and the 1-methyl VHP.

Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals.

Although transfer of electrophilic alkoxyl ("RO+") from organic peroxides to organometallics offers a complement to traditional methods for etherification, application has been limited by constraints associated with peroxide reactivity and stability. We now demonstrate that readily prepared tetrahydropyranyl monoperoxyacetals react with sp(3) and sp(2) organolithium and organomagnesium reagents to furnish moderate to high yields of ethers. The method is successfully applied to the synthesis of alkyl, alkenyl, aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl peroxides, the displacements of monoperoxyacetals provide no evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an SN2 mechanism. Theoretical studies suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O-O bond.

Mechanism of the Intramolecular Hexadehydro-Diels-Alder Reaction.

Theoretical analysis of the mechanism of the intramolecular hexadehydro-Diels-Alder (HDDA) reaction, validated against prior and newly measured kinetic data for a number of different tethered yne-diynes, indicates that the reaction proceeds in a highly asynchronous fashion. The rate-determining step is bond formation at the alkyne termini nearest the tether, which involves a transition-state structure exhibiting substantial diradical character. Whether the reaction then continues to close the remaining bond in a concerted fashion or in a stepwise fashion (i.e., with an intervening intermediate) depends on the substituents at the remaining terminal alkyne positions. Computational modeling of the HDDA reaction is complicated by the significant diradical character that arises along the reaction coordinate, which leads to instabilities in both restricted singlet Kohn-Sham density functional theory (DFT) and coupled cluster theory based on a Hartree-Fock reference wave function. A consistent picture emerges, however, from comparison of broken-symmetry DFT calculations and second-order perturbation theory based on complete-active-space self-consistent-field (CASPT2) calculations.

A Computational Re-examination of the Criegee Intermediate-Sulfur Dioxide Reaction.

The atmospheric oxidation of sulfur dioxide by the parent and dimethyl Criegee intermediates (CIs) may be an important source of sulfuric acid aerosol, which has a large impact on radiative forcing and therefore upon climate. A number of computational studies have considered how the CH2OOS(O)O heteroozonide (HOZ) adduct formed in the CI + SO2 reaction converts SO2 to SO3. In this work we use the CBS-QB3 quantum chemical method along with equation-of-motion spin-flip CCSD(dT) and MCG3 theories to reveal new details regarding the formation and decomposition of the endo and exo conformers of the HOZ. Although ∼75% of the parent CI + SO2 reaction is initiated by formation of the exo HOZ, hyperconjugation preferentially stabilizes many of the endo intermediates and transition structures by 1-5 kcal mol(-1). Our quantum chemical calculations, in conjunction with statistical rate theory models, predict a rate coefficient for the parent CI + SO2 reaction of 3.68 × 10(-11) cm(3) molecule(-1) s(-1), in good agreement with recent experimental measurements. RRKM/master equation simulations based on our quantum chemical data predict a prompt carbonyl + SO3 yield of >95% for the reaction of both the parent and dimethyl CI with SO2. The existence of concerted cycloreversion transition structures 10-15 kcal mol(-1) higher in energy than the HOZ accounts for most of the predicted SO3 formation.

Generation of singlet oxygen from fragmentation of monoactivated 1,1-dihydroperoxides.

The first singlet excited state of molecular oxygen ((1)O(2)) is an important oxidant in chemistry, biology, and medicine. (1)O(2) is most often generated through photosensitized excitation of ground-state oxygen. (1)O(2) can also be generated chemically through the decomposition of hydrogen peroxide and other peroxides. However, most of these "dark oxygenations" require water-rich media associated with short (1)O(2) lifetimes, and there is a need for oxygenations able to be conducted in organic solvents. We now report that monoactivated derivatives of 1,1-dihydroperoxides undergo a previously unobserved fragmentation to generate high yields of singlet molecular oxygen ((1)O(2)). The fragmentations, which can be conducted in a variety of organic solvents, require a geminal relationship between a peroxyanion and a peroxide activated toward heterolytic cleavage. The reaction is general for a range of skeletal frameworks and activating groups and, via in situ activation, can be applied directly to 1,1-dihydroperoxides. Our investigation suggests the fragmentation involves rate-limiting formation of a peroxyanion that decomposes via a Grob-like process.

Computational studies of the isomerization and hydration reactions of acetaldehyde oxide and methyl vinyl carbonyl oxide.

Alkene ozonolysis is a major source of hydroxyl radical (*OH), the most important oxidant in the troposphere. Previous experimental and computational work suggests that for many alkenes the measured *OH yields should be attributed to the combined impact of both chemically activated and thermalized syn-alkyl Criegee intermediates (CIs), even though the thermalized CI should be susceptible to trapping by molecules such as water. We have used RRKM/master equation and variational transition state theory calculations to quantify the competition between unimolecular isomerization and bimolecular hydration reactions for the syn and anti acetaldehyde oxide formed in trans-2-butene ozonolysis and for the CIs formed in isoprene ozonolysis possessing syn-methyl groups. Statistical rate theory calculations were based on quantum chemical data provided by the B3LYP, QCISD, and multicoefficient G3 methods, and thermal rate constants were corrected for tunneling effects using the Eckart method. At tropospheric temperatures and pressures, all thermalized CIs with syn-methyl groups are predicted to undergo 1,4-hydrogen shifts from 2 to 8 orders of magnitude faster than they react with water monomer at its saturation number density. For thermalized anti acetaldehyde oxide, the rates of dioxirane formation and hydration should be comparable.

Infrared spectra of mass-selected Br(-)-(NH3)n and I(-)-NH3 clusters.

Infrared vibrational predissociation spectra are recorded for Br(-)-(NH(3))(n) (n = 1-4) and I(-)-NH(3) clusters in the N-H stretch region (3040-3460 cm(-1)). To aid spectral assignments and clarify structures of the Br(-)-(NH(3))(n) clusters, ab initio calculations are performed at the MP2/aug-cc-pVDZ and MP2/aug-cc-pVTZ levels of theory. The Br(-)-NH(3) and I(-)-NH(3) dimers are predicted to have structures in which the NH(3) molecule is attached to the halide anion by a single hydrogen-bond. The dominant infrared band for Br(-)-NH(3) at 3171 cm(-1) corresponds to a hydrogen-bonded N-H stretch vibrational mode, whereas two weaker bands are assigned to a symmetric stretch vibration of the nonbonded N-H groups (3347 cm(-1)) and to an ammonia-based bending overtone (3293 cm(-1)) deriving infrared intensity through Fermi interaction with the H-bonded N-H stretch mode. The corresponding I(-)-NH(3) spectrum is dominated by the H-bonded N-H stretch band at 3217 cm(-1), with three weaker bands at 3240, 3305, and 3360 cm(-1) assigned to two bending overtone vibrations and the nonbonded N-H symmetric stretch vibration, respectively. Spectra of the Br(-)-(NH(3))(n), n = 2-4, clusters are similar to the I(-)-NH(3) spectrum, exhibiting evidence for strong Fermi interactions between the H-bonded N-H stretch vibrational mode and ammonia-based bending overtones. On the basis of the infrared spectra and ab initio calculations, the larger Br(-)-(NH(3))(n) clusters are deduced to have structures in which the NH(3) molecules are attached to the Br(-) by single H-bonds, but not necessarily to one other.

Electronic spectrum of TaO and its hyperfine structure.

The B (2)Phi(5/2)-X(1) (2)Delta(3/2)(0,0) band at 778 nm and the C (2)Delta(3/2)-X(1) (2)Delta(3/2)(0,0) band at 737 nm of tantalum oxide (TaO) were recorded by laser excitation spectroscopy using a hollow cathode sputtering source to generate the molecules. The hyperfine structure arising from the (181)Ta (I=72) nucleus was measured at sub-Doppler resolution using the technique of intermodulated fluorescence spectroscopy. The hyperfine structure was assigned and fitted in order to derive accurate values for the magnetic dipole and electric quadrupole interactions. The magnetic hyperfine constant for the ground electronic state was also calculated using the density functional theory as h(3/2)=625 MHz, in good agreement with the experimental value of 647+/-10 MHz. This result suggests that the X (2)Delta ground state of TaO is well described by a pure deltasigma(2) electronic configuration, where the unpaired electron is located in a Ta 5ddelta orbital.

Computational studies of intramolecular hydrogen atom transfers in the beta-hydroxyethylperoxy and beta-hydroxyethoxy radicals.

The beta-hydroxyethylperoxy (I) and beta-hydroxyethoxy (III) radicals are prototypes of species that can undergo hydrogen atom transfer across their intramolecular hydrogen bonds. These reactions may play an important role in both the atmosphere and in combustion systems. We have used density functional theory and composite electronic structure methods to predict the energetics of these reactions, RRKM/master equation simulations to model the kinetics of chemically activated I, and variational transition state theory (TST) to predict thermal rate constants for the 1,5-hydrogen shift in I (Reaction 1) and the 1,4-hydrogen shift in III (Reaction 2). Our multi-coefficient Gaussian-3 calculations predict that Reaction 1 has a barrier of 23.59 kcal/mol, and that Reaction 2 has a barrier of 22.71 kcal/mol. These predictions agree rather well with the MPW1K and BB1K density functional theory predictions but disagree with predictions based on B3LYP energies or geometries. Our RRKM/master equation simulations suggest that almost 50% of I undergoes a prompt hydrogen shift reaction at pressures up to 10 Torr, but the extent to which I is chemically activated is uncertain. For Reaction 1 at 298 K, the variational TST rate constant is approximately 30% lower than the conventional TST result, and the microcanonical optimized multidimensional tunneling (muOMT) method predicts that tunneling accelerates the reaction by a factor of 3. TST calculations on Reaction 2 reveal no variational effect and a 298 K muOMT transmission coefficient of 10(5). The Eckart method overestimates transmission coefficients for both reactions.

Quantum chemical and master equation studies of the methyl vinyl carbonyl oxides formed in isoprene ozonolysis.

Methyl vinyl carbonyl oxide is an important intermediate in the reaction of isoprene and ozone and may be responsible for most of the (*)OH formed in isoprene ozonolysis. We use CBS-QB3 calculations and RRKM/master equation simulations to characterize all the pathways leading to the formation of this species, all the interconversions among its four possible conformers, and all of its irreversible isomerizations. Our calculations, like previous studies, predict (*)OH yields consistent with experiment if thermalized syn-methyl carbonyl oxides form (*)OH quantitatively. Natural bond order analysis reveals that the vinyl group weakens the C=O bond of the carbonyl oxide, making rotation about this bond accessible to this chemically activated intermediate. The vinyl group also allows one conformer of the carbonyl oxide to undergo electrocyclization to form a dioxole, a species not previously considered in the literature. Dioxole formation, which has a CBS-QB3 reaction barrier of 13.9 kcal/mol, is predicted to be favored over vinyl hydroperoxide formation, dioxirane formation, and collisional stabilization. Our calculations also predict that two dioxole derivatives, 1,2-epoxy-3-butanone and 3-oxobutanal, should be major products of isoprene ozonolysis.

Quantum chemical and master equation simulations of the oxidation and isomerization of vinoxy radicals.

The vinoxy radical, a common intermediate in gas-phase alkene ozonolysis, reacts with O2 to form a chemically activated alpha-oxoperoxy species. We report CBS-QB3 energetics for O2 addition to the parent (*CH2CHO, 1a), 1-methylvinoxy (*CH2COCH3, 1b), and 2-methylvinoxy (CH3*CHCHO, 1c) radicals. CBS-QB3 predictions for peroxy radical formation agree with experimental data, while the G2 method systematically overestimates peroxy radical stability. RRKM/master equation simulations based on CBS-QB3 data are used to estimate the competition between prompt isomerization and thermalization for the peroxy radicals derived from 1a, 1b, and 1c. The lowest energy isomerization pathway for radicals 4a and 4c (derived from 1a and 1c, respectively) is a 1,4-shift of the acyl hydrogen requiring 19-20 kcal/mol. The resulting hydroperoxyacyl radical decomposes quantitatively to form *OH. The lowest energy isomerization pathway for radical 4b (derived from 1b) is a 1,5-shift of a methyl hydrogen requiring 26 kcal/mol. About 25% of 4a, but only approximately 5% of 4c, isomerizes promptly at 1 atm pressure. Isomerization of 4b is negligible at all pressures studied.

Conformation-dependent state selectivity in O-O cleavage of ONOONO: an "inorganic cope rearrangement" helps explain the observed negative activation energy in the oxidation of nitric oxide by dioxygen.

ONOONO has been proposed as an intermediate in the oxidation of nitric oxide by dioxygen to yield nitrogen dioxide. The O-O bond breaking reactions of this unusual peroxide, and subsequent rearrangements, were evaluated using CBS-QB3 and B3LYP/6-311G hybrid density functional theory. The three stable conformers (cis,cis-, cis,trans-, and trans,trans-ONOONO, based on the O-N-O-O dihedral angles of either approximately 0 degrees or approximately 180 degrees ) are predicted to have very different O-O cleavage barriers: 2.4, 13.0, and 29.8 kcal/mol, respectively. These large differences arise because bond breaking leads to correlation of the nascent NO(2) fragments with either the ground (2)A(1) state or the excited (2)B(2) state of NO(2), depending on the starting ONOONO conformation. A cis-oriented NO(2) fragment correlates with the (2)A(1) state, whereas a trans-oriented NO(2) fragment correlates with the (2)B(2) state. Each NO(2) fragment that correlates with (2)A(1) lowers the O-O homolysis energy by approximately 15 kcal/mol, similar to the approximately 17-25 kcal/mol (2)A(1) --> (2)B(2) energy difference in NO(2). Hence, this provides an unusual example of conformation-dependent electronic state selectivity. The O-O bond homolysis of cis,cis-ONOONO is particularly interesting because it has a very low barrier and arises from the most stable ONOONO conformer, and also due to obvious similarities to the well-known [3,3]-sigmatropic shift of 1,5-hexadiene, i.e., the Cope rearrangement. As an additional proof of our state selectivity postulate, a comparison is also made to breakage of the O-O bond of cis,cis-formyl peroxide, where no significant stabilization of the transition state is available because the (2)A(1) and (2)B(2) states of formyloxy radical are near-degenerate in energy. In the case of trans,trans-ONOONO, the O-O bond breaking transition state is a concerted rearrangement yielding O(2)NNO(2), whereas for cis,cis- and cis,trans-ONOONO, the initially formed NO(2) radical pairs can undergo further rearrangement to yield ONONO(2). It is proposed that previous spectroscopic observations of certain N=O stretching frequencies in argon-matrix-isolated products from the reaction of NO with O(2) (or (18)O(2)) are likely from ONONO(2), not the OONO radical as reported.

Mechanism of ene reactions of singlet oxygen. A two-step no-intermediate mechanism.

The mechanism of the ene reaction of singlet ((1)delta(g)) oxygen with simple alkenes is investigated by a combination of experimental isotope effects and several levels of theoretical calculations. For the reaction of 2,4-dimethyl-3-isopropyl-2-pentene, the olefinic carbons exhibit small and nearly equal (13)C isotope effects of 1.005-1.007, while the reacting methyl groups exhibit (13)C isotope effects near unity. In a novel experiment, the (13)C composition of the product is analyzed to determine the intramolecular (13)C isotope effects in the ene reaction of tetramethylethylene. The new (13)C and literature (2)H isotope effects are then used to evaluate the accuracy of theoretical calculations. RHF, CASSCF(10e, 8o), and restricted and unrestricted B3LYP calculations are each applied to the ene reaction with tetramethylethylene. Each predicts a different mechanism, but none leads to reasonable predictions of the experimental isotope effects. It is concluded that none of these calculations accurately describe the reaction. A more successful approach was to use high-level, up to CCSD(T), single-point energy calculations on a grid of B3LYP geometries. The resulting energy surface is supported by its accurate predictions of the intermolecular (13)C and (2)H isotope effects and a very good prediction of the reaction barrier. This CCSD(T)//B3LYP surface features two adjacent transition states without an intervening intermediate. This is the first experimentally supported example of such a surface and the first example of a valley-ridge inflection with significant chemical consequences.