Investigation of Chain Extension Approaches for the Stereoselective Reagent-Controlled Synthesis of alpha-Heteroatom Substituted Alkyl Boronic Esters

Two distinct strategies were explored for the enantioselective synthesis of α-heteroatom substituted alkyl boronic esters by stereoselective reagent-controlled homologation using transient chiral carbenoid reagents CHYMX (Y = heteroatom, X = nucleofuge, M = electrofuge). In the first case, a stereospecific reagent-controlled homologation (sStReCH) approach to α-alkoxyalkylboronates using α-metalated S,O- and O,O-acetals was pursued that necessitated the development of methods to access these carbenoids in stereodefined form and study of their configurational and chemical stability (both classes of carbenoid are known to chain extend alkyl boronic esters). Sulfoxide-metal exchange from dithioorthoformate monooxides was evaluated as a means to access stereodefined α-metalated S,O-acetals. It was discovered that acyclic dithioorthoformate monooxides fragment spontaneously upon their oxidative generation from simple dithioorthoformates [(pTolS)₂CHOR, R = Me, Et]; however, two cyclic dithioorthoformate monooxides, trans and cis 2-isopentoxy-1,3-benzodithiolane-S-oxide (102), were obtained in 85% yield (trans:cis = 96:4) by 3-chloroperoxybenzoic acid mediated oxidation of 2-isopentoxy-1,3-benzodithiolane. Treatment of trans or cis-102 with EtMgCl (in THF at -78 °C) gave configurationally stable (≤ 2.5 h, at -78 °C) stereodefined α-magnesiated S,O-acetals 103 that incorporated D-atoms in a stereospecific manner upon reaction with CD3OD. Carbenoids 103 (M = MgCl) failed to react with all other electrophiles examined (allyl bromide, MeI, MeOTf), except benzaldehyde, and this low nucleophilicity precluded their use in boronic ester chain extension chemistry. α-Lithiated S,O-acetals 103 generated in the same fashion from 102 using PhLi were more reactive than their magnesiated congeners 103 but lacked sufficient configurational stability for applications in sStReCH (epimerization of 103 (M = Li) occurred within 1 min at -78 °C in THF). Direct metalation approaches to stereodefined lithiated S,O- and O,O-acetals were next explored, but ultimately, either acceptably high enantioselectivity was not realized or the organolithiums generated were found to be too chemically unstable for sStReCH applications. For example, kinetic enantioselective lithiation of methoxymethyl p-tolyl thioether (124) with s-butyllithium/(-)-sparteine (PhMe, -78 °C) followed by treatment of the resulting lithiated S,O-acetal [pTolSCH(Li)OMe] with benzaldehyde as a probe electrophile, led to addition products [pTolSCH(OMe)CH(OH)Ph] with low enantiomeric excess [55% yield, dr = 66:34, %ee (major isomer) = 24%, %ee (minor isomer) = 9%]. In another example, lithiation of a thiocarbamate of methoxymethyl mercaptan [i-Pr₂NC(=S)SCH₂OMe] with s-butyllithium and TMEDA (Et₂O, -110 °C) led to a chemically unstable carbenoid that spontaneously extruded methyl thioformate (MeOCHS) to yield putative a-lithio-N,N-diisopropylthioformamide [i-Pr₂NC(=S)Li]. The second strategy explored, and introduced here for the first time, ligand mediated stereoinductive reagent-controlled homologation (iStReCH), deliberately exploits the configurational lability of heteroatom substituted carbenoids and consequently it was more successful. In this case, dynamic kinetic resolution (DKR), or dynamic thermodynamic resolution (DTR), of a racemic configurationally labile carbenoid is effected by an exogenous chiral ligand as the carbenoid is trapped by the boronic ester electrophile. The iStReCH concept was demonstrated for an enantioselective synthesis of α-silylalkylboronates, as follows: (±)-lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate [TIBOCH(Li)SiMe₂Ph], obtained by lithiation of the corresponding silylmethyl TIB ester with t-butyllithium (cumene, -78 °C), was incubated with the chiral BOX ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl)propane (at -45 °C) before addition of B-phenethyl pinacol boronate at -95 °C. Warming to rt during 18 hours afforded the desired enantioenriched chain extended product (S)-2-[1-(dimethylphenylsilyl)-3-phenylpropyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (69% yield, 57% ee). Ligand mediated iStReCH of B-cyclohexyl (35% yield, 9% ee) and B-sec-butyl [43% yield, dr = 58:42, %ee (major) = 26%, %ee (minor) = 14%] pinacol boronates with the same silylated carbenoid was likewise demonstrated. Enantioselectivity was dependent on the temperature history of the organolithium/ligand complex indicating that the stereoinduction mechanism involves some aspect of DTR

Trace analysis of surfactants in Corexit oil dispersant formulations and seawater

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC–MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71 to 13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840 to 9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200 to 1900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater.Keywords: bis-(2-ethylhexyl) sulfosuccinate, LC-MS/MS Large-volume injection, DOSS, Corexit, Surfactants, Deepwater Horizon, Oil dispersan

Trace Analysis of Surfactants in Corexit Oil Dispersant Formulations and Seawater

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71–13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840–9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200–1,900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater

Stereocontrolled Generation of α-Metalated S,O-Acetals by Sulfoxide-Ligand Exchange from Cyclic Dithioorthoformate Monooxides

Treatment of trans or cis 2-isopentoxy-1,3-benzodithiolane-<i>S</i>-oxides with EtMgCl gave configurationally stable (≥2.5 h, at −78 °C) stereodefined α-magnesiated S,O-acetals that incorporated D atoms in a stereospecific manner upon reaction with CD₃OD. α-Lithiated S,O-acetals generated in the same fashion using PhLi were found to be less configurationally stable

Stereocontrolled Generation of α-Metalated S,O-Acetals by Sulfoxide-Ligand Exchange from Cyclic Dithioorthoformate Monooxides

Treatment of trans or cis 2-isopentoxy-1,3-benzodithiolane-<i>S</i>-oxides with EtMgCl gave configurationally stable (≥2.5 h, at −78 °C) stereodefined α-magnesiated S,O-acetals that incorporated D atoms in a stereospecific manner upon reaction with CD₃OD. α-Lithiated S,O-acetals generated in the same fashion using PhLi were found to be less configurationally stable

Trace Analysis of Surfactants in Corexit Oil Dispersant Formulations and Seawater

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71 – 13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840 – 9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200 – 1,900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater

PlaceTraceAnalysisofSurfactants.pdf

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC–MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71 to 13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840 to 9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200 to 1900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater.Keywords: LC-MS/MS, Surfactants, Oil dispersant, Corexit, Deepwater Horizon, DOSS, Large-volume injection, bis-(2-ethylhexyl) sulfosuccinat

PlaceBenjaminChemistryTraceAnalysisSurfactants_SupplementaryMaterials.pdf

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71–13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840–9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200–1,900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater

PlaceTraceAnalysisofSurfactantsAppendixA.pdf

After the April 2010 explosion on the Deepwater Horizon oil rig, and subsequent release of millions of barrels of oil, two Corexit oil dispersant formulations were used in unprecedented quantities both on the surface and sub-surface of the Gulf of Mexico. Although the dispersant formulations contain four classes of surfactants, current studies to date focus on the anionic surfactant, bis-(2-ethylhexyl) sulfosuccinate (DOSS). Factors affecting the integrity of environmental and laboratory samples for Corexit analysis have not been systematically investigated. For this reason, a quantitative analytical method was developed for the detection of all four classes of surfactants, as well as the hydrolysis products of DOSS, the enantiomeric mixture of α- and β-ethylhexyl sulfosuccinate (α-/β-EHSS). The analytical method was then used to evaluate which practices for sample collection, storage, and analysis resulted in high quality data. Large volume, direct injection of seawater followed by liquid chromatography tandem mass spectrometry (LC–MS/MS) minimized analytical artifacts, analysis time, and both chemical and solid waste. Concentrations of DOSS in the seawater samples ranged from 71 to 13,000 ng/L, while the nonionic surfactants including Span 80, Tween 80, Tween 85 were detected infrequently (26% of samples) at concentrations from 840 to 9100 ng/L. The enantiomers α-/β-EHSS were detected in seawater, at concentrations from 200 to 1900 ng/L, and in both Corexit dispersant formulations, indicating α-/β-EHSS were applied to the oil spill and may be not unambiguous indicator of DOSS degradation. Best practices are provided to ensure sample integrity and data quality for environmental monitoring studies and laboratory that require the detection and quantification of Corexit-based surfactants in seawater.Keywords: Surfactants, LC-MS/MS, DOSS, Deepwater Horizon, bis-(2-ethylhexyl) sulfosuccinate, Corexit, Oil dispersant, Large-volume injectio