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The parasitic nematode Angiostrongylus cantonensis (rat lungworm) is the leading cause of human eosinophilic meningitis worldwide. Most human infections occur through the accidental consumption of A. cantonensis hidden within produce as infectious third-stage larvae (L3), yet little research has been published addressing possible methods to mitigate this means of transmission. Here, we describe our tests of ozone gas-an oxidizing agent-and ultrasound, both used for disinfection of food and municipal water supplies and in industrial cleaning. We found that exposure to ozone, produced using two different commercially available ozone generators over varying durations of time and concentrations, was capable of achieving 100% larval mortality. In addition, we evaluated the impact of different sound frequencies on A. cantonensis L3 survival using two different commercially available ultrasonic cleaners, and found that 60 s of 40 kHz produced 46% mortality within 2 h. The combined use of ultrasound and ozone gas simultaneously resulted in a minimum of 89% normalized mean percent mortality within 2 h of treatment. Our study suggests that both ozone and ultrasound show high larvicidal efficacy, both independently and together, and thus show promise as methods for reducing the risk of rat lungworm infection via accidental consumption.

A perspective on the development of mechanistic carbene chemistry is presented. The author will point out questions that have been answered, and a next generation of questions will be proposed.

Reinvestigation of the thermolysis of azido-meta-hemipinate (I) yielded, in addition to known II, unusual products III and IV. These products are formed via a rare intramolecular nitrene insertion into an adjacent methoxy C-H bond followed by an intermolecular reaction during a ring-expansion and a ring-extrusion reaction followed by a carbene insertion. The structures of the new compounds were confirmed using a battery of techniques, including HRMS (ESI-QTOF) and 2D NMR as well as X-ray crystallography for compound IV. Density functional theory methods were used to support the proposed mechanism of formation of the products.

The photochemistry of 4,5-carbomethoxy-1,2,3-thiadiazole in solution was studied at room temperature with use of UV-vis and IR transient absorption spectroscopies (λ(ex) = 266 nm). Ultrafast time-resolved techniques demonstrate that there is a very fast rise (<0.4 ps) of bis(carbomethoxy)thiirene in acetonitrile, and that it is the only intermediate formed. The lifetime of the thiirene is limited by dimerization to eventually form tetra(carbomethoxy)thiophene.

The photochemistry of diazocyclohexadienone (1), o-phenylene thioxocarbonate (2), and 2-chlorophenol (3) in solution was studied using time-resolved UV-vis and IR transient absorption spectroscopies. In these three cases, the same product cyclopentadienyl ketene (5) is formed, and two different mechanistic pathways leading to this product are discussed: (a) rearrangement in the excited state (RIES) and (b) a stepwise route involving the intermediacy of vibrationally excited or relaxed carbene. Femtosecond UV-vis detection allows observation of an absorption band assigned to singlet 2-oxocyclohexa-3,5-dienylidene (4), and this absorption feature decays with an ∼30 ps time constant in hexane and acetonitrile. The excess vibrational energy present in nascent carbenes results in the ultrafast Wolff rearrangement of the hot species. IR detection shows that photoexcited o-phenylene thioxocarbonate (2) and 2-chlorophenol (3) efficiently form the carbene species while diazocyclohexadienone (1) photochemistry proceeds mainly by a concerted process.

The photochemistry of 4-methoxycarbonylphenyl azide (2a), 2-methoxycarbonylphenyl azide (3a), and 2-methoxy-6-methoxycarbonylphenyl azide (4a) were studied by ultrafast time-resolved infrared (IR) and UV-vis spectroscopies in solution. Singlet nitrenes and ketenimines were observed and characterized for all three azides. Isoxazole species 3g and 4g are generated after photolysis of 3a and 4a, respectively, in acetonitrile. Triplet nitrene 4e formation correlated with the decay of singlet nitrene 4b. The presence of water does not change the chemistry or kinetics of singlet nitrenes 2b and 3b, but leads to protonation of 4b to produce nitrenium ion 4f. Singlet nitrenes 2b and 3b have lifetimes of 2 ns and 400 ps, respectively, in solution at ambient temperature. The singlet nitrene 4b in acetonitrile has a lifetime of about 800 ps, and reacts with water with a rate constant of 1.9 × 10(8) L·mol(-1)·s(-1) at room temperature. These results indicate that a methoxycarbonyl group at either the para or ortho positions has little influence on the ISC rate, but that the presence of a 2-methoxy group dramatically accelerates the ISC rate relative to the unsubstituted phenylnitrene. An ortho-methoxy group highly stabilizes the corresponding nitrenium ion and favors its formation in aqueous solvents. This substituent has little influence on the ring-expansion rate. These results are consistent with theoretical calculations for the various intermediates and their transition states. Cyclization from the nitrene to the azirine intermediate is favored to proceed toward the electron-deficient ester group; however, the higher energy barrier is the ring-opening process, that is, azirine to ketenimine formation, rendering the formation of the ester-ketenimine (4d') to be less favorable than the isomeric MeO-ketenimine (4d).

A time-resolved resonance Raman (TR(3)) and computational investigation of the photochemistry of 4-acetamidophenyl azide and 4-N-methylacetamidophenyl azide in acetonitrile is presented. Photolysis of 4-acetamidophenyl azide appears to initially produce singlet 4-acetamidophenylnitrene which undergoes fast intersystem crossing (ISC) to form triplet 4-acetamidophenylnitrene. The latter species formally produces 4,4'-bisacetamidoazobenzene. RI-CC2/TZVP and TD-B3LYP/TZVP calculations predict the formation of the singlet nitrene from the photogenerated S(1) surface of the azide excited state. The triplet 4-acetamidophenylnitrene and 4,4'-bisacetamidoazobenzene species are both clearly observed on the nanosecond to microsecond time-scale in TR(3) experiments. In contrast, only one species can be observed in analogous TR(3) experiments after photolysis of 4-N-methylacetamidophenyl azide in acetonitrile, and this species is tentatively assigned to the compound resulting from dimerization of a 1,2-didehydroazepine. The different photochemical reaction outcomes for the photolysis of 4-acetamidophenyl azide and 4-N-methylacetamidophenyl azide molecules indicate that the 4-acetamido group has a substantial influence on the ISC rate of the corresponding substituted singlet phenylnitrene, but the 4-N-methylacetamido group does not. CASSCF analyses predict that both singlet nitrenes have open-shell electronic configurations and concluded that the dissimilarity in the photochemistry is probably due to differential geometrical distortions between the states. We briefly discuss the probable implications of this intriguing substitution effect on the photochemistry of phenyl azides and the chemistry of the related nitrenes.

The photochemistry of two simple acyclic diazo carbonyl compounds, azibenzil and diazoacetone, were studied using the tools of ultrafast time-resolved spectroscopy. In the former case, UV-vis detection allows observation of an absorption band of singlet benzoylphenylcarbene, decaying with a 740 ± 150 ps time-constant in acetonitrile. IR detection shows that the ketene product of Wolff rearrangement (∼2100 cm(-1)) is formed by two parallel pathways: a stepwise mechanism with carbene intermediacy with a slow rise time-constant of 660 ± 100 ps, and directly in the diazo excited state as confirmed by the immediate formation of an IR band of a nascent hot ketene species. Photolysis (270 nm) of diazoacetone in chloroform leads mainly to the ketene species through a concerted process, consistent with the predominance of the syn conformation in the diazoacetone electronic ground state and a zero quantum yield of the internal conversion process.

Phenyldiazirine and phenyldiazomethane were studied at the B3LYP/6-31+G(d) and RI-CC2/TZVP levels of theory, and the three lowest singlet excited states of both compounds were optimized at the RI-CC2/TZVP level. The calculations predict that the S(1) state of phenyldiazirine is a sigma --> pi* state, with a quinoidal structure, and the C-N bonds of the diazirine group are slightly deformed from the C(s) symmetry of the ground state's geometry. Both the S(2) and S(3) states are predicted to be pi --> pi* states localized primarily on the phenyl group. The S(1) state was predicted to have an exceedingly large dipole moment with a strong and distinct aromatic C=C vibrational mode around approximately 1600 cm(-1), which is not present in any of the other electronic states examined in this study. The calculations are consistent with the assignment of the S(1) state of phenyldiazirine to the polar intermediate recently observed by ultrafast time-resolved UV-vis and IR spectroscopic studies of arylhalo- and arylalkyldiazirines. The excited states of phenyldiazomethane were also studied, and the implications of interconversion between phenyldiazirine and phenyldiazomethane are discussed. The calculations predict that the chemistry of the ground state and the S(1) excited state of phenyldiazirine are very different. Formation of phenylcarbene is favored on the ground state surface of phenyldiazirine, whereas the S(1) excited state favors isomerization to the first excited state of phenyldiazomethane, which rapidly extrudes nitrogen and forms carbene.

Ultrafast laser flash photolysis (310 nm) of methyl 2-napthyldiazoacetate (2-NpCN2CO2CH3) in acetonitrile or cyclohexane produces a diazo excited state which absorbs broadly in the visible region (tau = 300 fs). The decay of the excited diazo compound is accompanied by growth of the vibrationally excited singlet 2-naphthyl(carbomethoxy)carbene ((1)NpCCO2CH3). The singlet carbene absorbs at 360 and 470 nm. In acetonitrile these bands do not decay over 3 ns, but they do decay by approximately 50% of their original intensity in cyclohexane in 3 ns. It is concluded that (1)NpCCO2CH3 has a singlet ground state in acetonitrile but a triplet ground state in cyclohexane. Related experiments reveal a singlet ground state in Freon-113 and chloroform. This interpretation is supported by ultrafast IR spectroscopy, which confirms that only (1)NpCCO2CH3 is formed within 50 ps of the laser pulse rather than a singlet-triplet equilibrium mixture of carbene. The planar singlet relaxes to the preferred perpendicular singlet over a few tens of picoseconds, as evidenced by a red shift of the carbonyl stretching vibration. Although our data agrees with previous studies, its interpretation is somewhat altered.

The photochemistry of Diazo Meldrum's acid (DM) was investigated by fs time-resolved UV-vis and IR spectroscopic methods. UV (266 nm) excitation of DM pumps the molecule to the S 5 and S 7 excited states. After fast internal conversion (IC), the S 2 state is formed, which will undergo Wolff rearrangement to form vibrationally excited ketene, which relaxes in 9 ps. The S 2 state will also relax to the S 1 state, which isomerizes to diazirine, fragments to form carbene, and relaxes further to the ground state of DM. The singlet carbene absorbs at 305 nm, is formed within 300 fs of the laser pulse, and has a lifetime of 2.3 ps in acetonitrile. The lifetime of DM in the S 2 and S 1 states is less than 300 fs. The quantum efficiency of DM decomposition is approximately 50% in chloroform with 266 nm excitation.

Time-resolved resonance Raman (TR3) studies of the photochemistry of phenyl azide, 3-hyroxyphenyl azide, 3-methoxyphenyl azide and 3-nitrophenyl azide in acetonitrile:water solutions is reported. After photolysis of these four aryl azides in room temperature solutions, only one species was observed in the TR3 spectra for each azide, respectively at the probe wavelengths employed in the TR3 experiments. The species observed after photolysis of 3-nitrophenyl azide was assigned to 3,3'-dinitroazobenzene, an azo compound formed from the dimerization reaction of triplet 3-nitrophenylnitrene. In contrast, the species observed after photolysis of phenyl azide, 3-hydroxyphenyl azide and 3-methoxyphenyl azide were tentatively assigned to intermediates formed from the dimerization of didehydroazepines that are produced from the ring expansion reaction of the respective singlet arylnitrene. To our knowledge, this is the first time-resolved vibrational spectroscopic observation of the dimerization reaction of didehydroazepines in solution. In addition, these are the first resonance Raman spectra reported for dimers formed from didehydroazepines. We briefly discuss the structures, properties and chemical reactivity of the dimer species observed in the TR3 spectra and possible implications for the photochemistry of aryl azides.

The free energies of reaction (DeltaG) and activation (DeltaG) were determined for the Curtius-like rearrangement of dimethylphosphinoyl, dimethylphosphinyl, and dimethylphosphoryl azides as well as the corresponding singlet and triplet nitrenes by CBS-QB3 and B3LYP computational methods. From CASSCF calculations, it was established that the closed-shell configuration was the lower energy singlet state for each of these nitrenes. The triplet states of dimethylphosphinyl- and dimethylphosphorylnitrene are the preferred ground states. However, the closed-shell singlet state is the ground state for dimethylphosphinoylnitrene. The CBS-QB3 DeltaG values for the Curtius-like rearrangements of dimethylphosphinyl and dimethylphosphoryl azides were 45.4 and 47.0 kcal mol-1, respectively. For the closed-shell singlet dimethylphosphinyl- and dimethylphosphorylnitrene, the CBS-QB3 DeltaG values for the rate-limiting step of the Curtius-like rearrangement were 22.9 and 18.0 kcal mol-1, respectively. It is unlikely that the nitrenes will undergo a Curtius-like rearrangement because of competing bimolecular reactions that have lower activation barriers. The pharmacology of weaponized organophosphorus compounds can be investigated using phosphorylnitrenes as photoaffinity labels. Dominant bimolecular reactivity is a desirable quality for a photoaffinity label to possess, and thus, the resistance of phosphorylnitrenes to intramolecular Curtius-like rearrangements increases their usefulness as photoaffinity labels.

The primary photophysical and photochemical processes in the photochemistry of 1-acetoxy-2-methoxyanthraquinone (1a) were studied using femtosecond transient absorption spectroscopy. Excitation of 1a at 270 nm results in the population of a set of highly excited singlet states. Internal conversion to the lowest singlet npi* excited state, followed by an intramolecular vibrational energy redistribution (IVR) process, proceeds with a time constant of 150 +/- 90 fs. The 1npi* excited state undergoes very fast intersystem crossing (ISC, 11 +/- 1 ps) to form the lowest triplet pipi* excited state which contains excess vibrational energy. The vibrational cooling occurs somewhat faster (4 +/- 1 ps) than ISC. The primary photochemical process, migration of acetoxy group, proceeds on the triplet potential energy surface with a time constant of 220 +/- 30 ps. The transient absorption spectra of the lowest singlet and triplet excited states of 1a, as well as the triplet excited state of the product, 9-acetoxy-2-methoxy-1,10-anthraquinone (2a), were detected. The assignments of the transient absorption spectra were supported by time-dependent DFT calculations of the UV-vis spectra of the proposed intermediates. All of the stationary points for acyl group migration on the triplet and ground state singlet potential energy surfaces were localized, and the influence of the acyl group substitution on the rate constants of the photochemical and thermal processes was analyzed.

Exposure of 2-naphthyl azide in acetonitrile at ambient temperature to femtosecond pulses of 266 nm light produces a transient absorption with maxima at 350 and 420 nm. The carrier of the 350 nm band decays more rapidly than that of the 420 nm band which has a lifetime of 1.8 ps. Analogous experiments with 1-chloro-2-naphthyl azide in methanol allow the assignment of the 350 nm band to a singlet excited state of 2-naphthyl azide and the carrier of the 420 nm band to singlet 2-naphthylnitrene. This reactive intermediate has the shortest lifetime of any singlet nitrene observed to date and is a true reactive intermediate. Computational studies at the RI-CC2 level of theory support these conclusions and suggest that initial excitation populates the S2 state of 2-naphthyl azide. The S2 state, best characterized as a pi --> (pi*, aryl) transition, has a geometry similar to S0. S2 of 2-naphthyl azide can then populate the S1 state, a pi --> (in-plane, pi*, azide) excitation, and in the S1 state, electron density is depleted along the proximal N-N bond. S1 is dissociative along that N-N coordinate to form the singlet nitrene, and with a barrier of only approximately 5 kcal/mol for N2 extrusion.

p-Biphenylyldiazomethane was excited by femtosecond pulses of UV light in acetonitrile, in cyclohexane, and in methanol. Ultrafast photolysis produces a singlet excited state of p-biphenylyldiazomethane with lambdamax = 490 nm, and lifetimes of less than 300 fs in acetonitrile, in cyclohexane, and in methanol. The decay of the excited state is accompanied by the growth of transient absorption with lambdamax = 360 nm. The carrier of this transient absorption is attributed to singlet p-biphenylylcarbene, a result that is consistent with the predictions of TD-DFT calculations. The singlet carbene lifetimes are 200 and 77 ps in acetonitrile and cyclohexane, respectively, and are controlled by intersystem crossing to the lower energy triplet state. The transient absorption does not decay to baseline in acetonitrile, because of the formation of nitrile ylide. The equilibrium mixture of singlet and triplet p-biphenylylcarbene reacts with acetonitrile to form a nitrile ylide (lambdamax = 370 nm), and with cyclohexane by C-H insertion 1-20 ns after the laser pulse. The singlet carbene lifetime is only 7.9 ps in methanol, owing to a rapid reaction with the solvent. Reaction with the solvent gives rise, in part, to a p-biphenylylbenzyl cation (lambdamax = 450 nm, tau = 6.3 ps) in methanol.

Time-resolved infrared spectroscopy (TRIR) and density functional theory (DFT) calculations were used to directly observe and assign the vibrational spectra of the triplet states of visnagin and khellin, and to investigate their electron-transfer chemistry. The TRIR spectra of triplet visnagin and triplet khellin, and of their radical cations and anions, were obtained upon 266 nm laser flash photolysis in acetonitrile and in deuterated acetonitrile. The radical cations were observed in the presence of chloranil, and the radical anions were formed in the presence of NaI and KSCN. The TRIR spectra are in good agreement with the calculated vibrational spectra. We did not observe the related neutral radicals by TRIR spectroscopy upon laser flash photolysis (LFP) of khellin in the presence of hydroquinone, but we found evidence for the formation of semiquinone and neutral visnagin radicals upon LFP of visnagin and hydroquinone.

The solution-phase photochemistry of 2,6-difluorophenyl azide was studied by time-resolved infrared (TRIR) spectroscopy. A vibrational band of singlet 2,6-difluorophenyl nitrene (1N) was observed at 1404 cm(-1) between 243 and 283 K. At ambient temperature, it was not possible to detect this intermediate. At 298 K, only the decay products of the singlet nitrene, the isomerized products ketenimine (K) and triplet-2,6-difluorophenyl nitrene (3N), were observed at 1576 and 1444 cm(-1), respectively. The assignments are consistent with density functional theory calculations and previous studies of this system by laser flash photolysis techniques with UV-visible detection.

Laser flash photolysis (LFP) of acetonitrile solutions of N-hydroxypyridin-2-thione in the presence of trans-stilbene generates a transient absorbance at 392 nm, attributed to the addition of hydroxyl radical to stilbene. The observed transient absorbance was used in competitive LFP experiments to determine relative rates of reaction for hydroxyl radical with a range of aromatic hydrocarbons in acetonitrile. Structure-reactivity relationships for the reaction of hydroxyl radical with arenes are derived. With these aromatic hydrocarbons, we observe a good correlation between the rates of hydroxyl-radical reaction and the ionization potential of the arene. Kinetic isotope effects are consistent with hydroxyl-radical addition being the dominant reaction pathway with the arene.

Laser flash photolysis (LFP, 400 nm excitation) of the anti-cancer drug tirapazamine (TPZ) in acetonitrile produces the singlet excited-state S1 with lambda(max) = 544 nm. The lifetime of this state is 130 ps, in good agreement with the reported fluorescence lifetime. The excited state is reduced to the corresponding radical anion by KSCN or KI. The spectrum of the radical anion is in good agreement with previously reported pulse radiolysis studies and time-dependent density functional theory (TD-DFT) calculations. LFP of desoxytirapazamine (dTPZ) also produces the first excited singlet state, S1. The fluorescence quantum yield and lifetime (5.4 ns) of the dTPZ singlet excited state are both much greater than the corresponding values of TPZ. This is explained by DFT calculations that predict that cyclization of TPZ to form an oxaziridine is thermodynamically facile but that cyclization of dTPZ to form an oxadiaziridine is not. Thus, the S1 state of TPZ has a short lifetime and low fluorescence quantum yield due to ready cyclization whereas the cyclization of the S1 state of dTPZ is unimportant and does not limit either the fluorescence quantum yield or the fluorescence lifetime. This conclusion is confirmed by studies of dTPZ', an isomer of dTPZ containing the C=N-O moiety which has a low quantum yield and short fluorescence lifetime similar to that of TPZ.

Density functional theory (DFT), CCSD(T), and CBS-QB3 calculations were performed to understand the chemical and reactivity differences between acetylnitrene (CH(3)C(=O)N) and methoxycarbonylnitrene (CH(3)OC(=O)N) and related compounds. CBS-QB3 theory alone correctly predicts that acetylnitrene has a singlet ground state. We agree with previous studies that there is a substantial N-O interaction in singlet acetylnitrene and find a corresponding but weaker interaction in methoxycarbonylnitrene. Methoxycarbonylnitrene has a triplet ground state because the oxygen atom stabilizes the triplet state of the carbonyl nitrene more than the corresponding singlet state. The oxygen atom also stabilizes the transition state of the Curtius rearrangement and accelerates the isomerization of methoxycarbonylnitrene relative to acetylnitrene. Acetyl azide is calculated to decompose by concerted migration of the methyl group along with nitrogen extrusion; the free energy of activation for this concerted process is only 27 kcal/mol, and a free nitrene is not produced upon pyrolysis of acetyl azide. Methoxycarbonyl azide, on the other hand, does have a preference for stepwise Curtius rearrangement via the free nitrene. The bimolecular reactions of acetylnitrene and methoxycarbonylnitrene with propane, ethylene, and methanol were calculated and found to have enthalpic barriers that are near zero and free energy barriers that are controlled by entropy. These predictions were tested by laser flash photolysis studies of benzoyl azide. The absolute bimolecular reaction rate constants of benzoylnitrene were measured with the following substrates: acetonitrile (k = 3.4 x 10(5) M(-1) (s-1)), methanol (6.5 x 10(6) M(-1) s(-1)), water (4.0 x 10(6) M(-1) s(-1)), cyclohexane (1.8 x 10(5) M(-1) s(-1)), and several representative alkenes. The activation energy for the reaction of benzoylnitrene with 1-hexene is -0.06 +/- 0.001 kcal/mol. The activation energy for the decay of benzoylnitrene in pentane is -3.20 +/- 0.02 kcal/mol. The latter results indicate that the rates of reactions of benzoylnitrene are controlled by entropic factors in a manner reminiscent of singlet carbene processes.

Inactivation of viruses in blood products requires that the method employed display selectivity in its action for viral elements while not affecting the biological entity of interest. Several methods have been developed for the treatment of human plasma or products derived from human plasma. An effective technique for the treatment of the cellular components of blood has been lacking, in part due to the inability to develop agents capable of selectively targeting viral agents in the milieu of cellular material. In this paper, we examine the behavior of a group of viral sensitizers designed to be added to cellular samples and be activated upon exposure to UVA light. Upon activation, these agents are capable of disrupting nucleic acids of the virus in a manner that renders them inactive for proliferation. The selectivity observed in this inactivation is determined by the chemical structure of the sensitizer, which can be varied to increase viral killing capacity while diminishing collateral damage to cellular and protein constituents.