Reaction Chemistry Of Epoxides With Fluorinated Carboxylic Acids

During measurements designed to develop a chiral tag rotational spectroscopy methodology for establishing the absolute configuration of a known persistent fluorinated carboxylic acid pollutant (FRD-903), an interesting reaction chemistry was observed. In several cases, highly fluorinated carboxylic acids participate in ring opening of epoxides under ambient conditions. Reactions of three fluorinated carboxylic acids, difluoroacetic acid, trifluoroacetic acid, and pentafluoropropionic acid, with propylene oxide (PO) were explored. The reactions were performed externally to the spectrometer and internally in the gas phase by flowing PO over the fluorinated acid samples. Reactions were performed by adding 4:1 molar equivalents of PO to carboxylic acid, and each reaction was highly exothermic. The reaction mixtures were analyzed by rotational spectroscopy using a chirped-pulsed Fourier transform rotational spectrometer. These measurements showed that the reaction products are created through epoxide ring-opening at both epoxide ring carbons. This reaction chemistry, in principle, offers a way to perform chiral analysis through covalent tagging, but this application would require retention of configuration in the reaction. The reaction products were subsequently chiral tagged to determine the extent of configuration retention. These experiments show that the products, both the ring-opening at the least- and most-substituted carbon on the epoxide ring, are racemized. While these results are not useful for obtaining the absolute configuration, these results further our understanding of the chemistry involved in these reactions. Covalently modifying fluorinated carboxylic acids can be achieved, and establishing absolute configuration could be possible with a more controlled reaction to prevent racemization of the chiral center on the epoxide

PRICE DISCOVERY MECHANISMS AND ALTERNATIVES FOR CANADIAN AGRICULTURE; Part I: A Review of Pricing Mechanisms in Agriculture

The purpose of this section is to review pricing mechanisms in agriculture and food. We started by constructing a taxonomy and system of classification for pricing mechanisms that is rooted in economic theory. This framework was applied to 26 pricing mechanisms observed from the following product categories: · Beef · Hogs · Grains and oilseeds · Dairy · Poultry and Eggs · Processed Food and HorticultureDemand and Price Analysis,

THE FEASIBILITY OF DETERMINING THE CARBON FRAMEWORK GEOMETRY OF A MOLECULE FROM ANALYSIS OF THE CARBON-13 ISOTOPOLOGUE ROTATIONAL SPECTRA IN NATURAL ABUNDANCE

One powerful feature of molecular rotational spectroscopy is the ability to obtain quantitative information for the positions of individual atoms in the structure through the analysis of singly-substituted isotopologue spectra. However, because the structural information comes from changes in the moments-of-inertia, the signs of the atom coordinates in the principal axis system are not available. This project explores the ability to obtain the carbon framework geometry of a molecule from isotopologue spectra. The first step of the analysis examines the distributions of carbon-carbon atom distances, C-C-C bond angles, and correlations between the bond angles and bond distances found in molecules. The “rules” for acceptable structures are obtained through the analysis of about 100 optimized structures from quantum chemistry that were available in lab. These rules are then used to find acceptable carbon framework geometries from the 8$^{N-1}$ possible carbon frameworks that come from the sign ambiguity of the substitution coordinates. In the test case of a molecule with 6 carbon atoms, cyclohexene oxide, these rules produced a single (and correct) carbon atom framework from the 32,768 possibilities. For molecules with 12 carbon atoms, a relatively large number of possible carbon atom frameworks are found to be consistent with the structure constraints: about 100,000 out of the 8.6 billion possible geometries. The results of the analysis as a function of molecular mass (number of carbon atoms) and structural characteristics (compact structures compared to structures with long alkyl tails, for example) will be presented. Approaches to assigning quality scores to candidate carbon atom frameworks that meet the structure conditions with the goal of ranking the most likely molecular structures will also be discussed

DETERMINATION OF ENANTIOMERIC EXCESS IN THE HIGH ENANTIOPURITY LIMIT USING CHIRAL TAGGING ROTATIONAL SPECTROSCOPY

Chiral tag rotational spectroscopy can be used for quantitative determination of the ratio of the two enantiomers of a chiral molecule. The strategy for chiral tag rotational spectroscopy is to convert the enantiomers of the analyte into diastereomers through non-covalent attachment of a small, chiral tag molecule. The analyte enantiomer ratio, which is used to determine the enantiomeric excess (EE), is determined by comparing the transition intensities of rotational transitions for the homochiral and heterochiral complexes when both a racemic and enantiopure tag sample is used. A calibration curve for EE determination of 3-methylcyclohexanone tagged with 3-butyn-2-ol will be presented. The role that intensity fluctuations in back-to-back measurements of the rotational spectra of the chiral tag complexes play in determining the EE measurement accuracy will be described. In applications to pharmaceutical chemistry the main need is the ability make quantitative EE determinations in the high enantiopurity limit of the analyte. This requirement poses challenges for chiral tag rotational spectroscopy from both the measurement sensitivity and the availability of high enantiopurity tag samples. Two analysis methods for high EE measurements will be discussed. In one case, the enantioimpurity detection limit is decreased by the co-adding of multiple rotational transitions of the homochiral and heterochiral tag complex. The second strategy uses a lower enantioimpurity tag to speed the EE determination of high enantioimpurity samples. In this case, the ability to accurately determine the tag EE is crucial and the functional dependence of EE measurement precision in chiral tag rotational spectroscopy provides the limit on measurement accuracy that can be achieved

ENANTIOMERIC EXCESS MEASUREMENTS OF ISOPULEGOL USING CHIRAL TAG SPECTROSCOPY

Chiral analysis was performed on samples of isopulegol and its isomers using chiral tag rotational spectroscopy. Isopulegol, with three chiral centers, has 8 stereoisomers. There are four diastereomers with distinct geometries and the diastereomer ratio can be determined using traditional rotational spectroscopy. To determine the enantiomeric ratio for each diastereomer the chiral tagging method was used to convert these enantiomers into distinguishable diastereomer complexes. Isopulegol was placed into the nozzles of a chirped-pulsed Fourier transform microwave spectrometer and was heated to 323K. The isopulegol was complexed with a 0.1\% mixture of propylene oxide in neon as the carrier gas. The measurement methodology for EE determinations is: 1) a 400K average spectrum is measured using the enantiopure S-propylene oxide, 2) the tag is purged by flowing pure neon over the sample and heating, and 3) a 400K average spectrum using racemic propylene oxide is measured. Enantiopure samples of (-)-isopulegol and (+)-isopuelgol were purchased from Sigma Aldrich and used to create standards of 0, 5, 10, 30, 55, 80, and 90 enantiomeric excess of (-)-isopulegol. The calibration curve was fit using a linear expression with zero offset giving a slope of 1.005 $\pm$ 0.007 (R$^{2}$ = 0.99935). These results demonstrate that the method has linear performance over the full EE scale. The reference solution with EE=80 was measured in six separate runs to assess reproducibility. The average of the measurements was 80.595\% with a standard deviation of 0.274. A sample of isopulegol provided as a mixture of isomers (Alfa Aesar) was analyzed using the chiral tag method. The enantiomeric excess for the two most abundant diastereomers were determined: isopulegol: EE=4.1(4) and neoisopulegol: EE=4.8(4). The similar enantiomeric excess values for these isomers is consistent with the usual production method for isopulegol where the EE of the reagent (citronellal) sets the EE for all four diastereomer products

CHIRAL TAGGING OF VERBENONE WITH 3-BUTYN-2-OL FOR ESTABLISHING ABSOLUTE CONFIGURATION AND DETERMINING ENANTIOMERIC EXCESS

Chiral analysis of a commercial sample of (1S)-(-)-verbenone has been performed using the chiral tag approach. The chirped-pulse Fourier transform microwave spectrum of the verbenone-butynol complex is measured in the 2-8 GHz frequency range. Verbenone is placed in a nozzle reservoir heated to 333K (about 1 Torr vapor pressure). The complex is formed by using a carrier gas of neon with approximately 0.1% butynol. The expansion pressure is about 2 atm. A measurement using racemic butynol is performed to identify isomers of both diastereomer complexes. Quantum chemistry calculations using the B3LYP-D3BJ method with the def2TZVP basis set provided estimated spectroscopic constants for the homochiral and heterochiral complexes. This analysis included 8 isomers for each diastereomer. Four rotational spectra are identified for isomers of the homochiral complex and correspond to the four lowest energy isomers from the theoretical study. Three heterochiral complexes are identified and also correspond to the lowest energy isomers from theory. Subsequent measurements were made with enantiopure tag (both (R)-(+)-3-buty-2-nol and (S)-(-)-3-butyn-2-ol) to establish the absolute configuration of verbenone. The sensitivity of the measurement was sufficient to perform $^{13}$C-isotopologue analysis of three of the homochiral complexes and two of the heterochiral complexes. These results provide definitive structures of verbenone with correct stereochemistry. The commercial sample has relatively low enantiomeric excess with the certificate of analysis reporting an EE of 53.6%. Using the intensities of assigned transitions of the chiral tag complexes, the enantiomeric excess was determined from the broadband rotational spectrum through the ratio of the intensities of pairs of transitions. A total of 2617 pairs of transitions were analyzed. The average EE was found to be 53.6% with a standard deviation of 2%

A COMPARATIVE STUDY OF CHIRAL ANALYSIS OF FENCHYL ALCOHOL USING NUCLEAR MAGNETIC RESONANCE, INFRARED, AND ROTATIONAL SPECTROSCOPY

The analysis of chiral molecules with multiple chiral centers is a challenging problem in analytical chemistry. The goal of the analysis is to determine the fractional composition for each unique stereoisomer. In the most general case, a molecule with N chiral centers will have 2$^{N}$ distinct stereoisomers. Half of these, 2$^{N-1}$, will be molecules with distinct molecular structures (the diastereomers). The diasteormer composition can be analyzed by normal spectroscopy methods because they have distinct spectra. For each diastereomer, there are the two non-superimposable mirror images (the enantiomers) and additional measurement methodology is required to determine the enantiomeric ratio using spectroscopy. Furthermore, in many applications the “unwanted” isomers (diastereomers and/or enantiomers) will be present as low-abundance impurities placing strong demands on the dynamic range of the spectroscopic technique. A commercial sample of (1R)-endo-(+)-Fenchyl alcohol (C10H18O, four stereoisomers) has been analyzed using nuclear magnetic resonance (NMR), infrared (IR), and rotational spectroscopy. The commercial sample has a small amount (~3\%) of the diastereomer as an impurity. The ability to quantitatively identify the diastereomer impurity using quantum chemistry estimates of the NMR, IR, and rotational spectrum parameters will be discussed. The enantiomer analysis uses chiral resolving agents for NMR spectroscopy, vibrational circular dichroism (VCD) for IR spectroscopy, and chiral tag rotational spectroscopy. The ability of these techniques to verify the stereochemistry of the dominant (1R)-endo-(+)-Fenchyl alcohol will be discussed. The ability to identify the enantiomeric excess of fenchyl alcohol and the possibility of performing enantiomer analysis on the low abundance diastereomer using the direct sample without purification will also be presented

Hybrid Lipids Inspired by Extremophiles and Eukaryotes Afford Serum‐Stable Membranes with Low Leakage

This paper presents a new hybrid lipid that fuses the ideas of molecular tethering of lipid tails used by archaea and the integration of cholesterol groups used by eukaryotes, thereby leveraging two strategies employed by nature to increase lipid packing in membranes. Liposomes comprised of pure hybrid lipids exhibited a 5–30‐fold decrease in membrane leakage of small ions and molecules compared to liposomes that used only one strategy (lipid tethering or cholesterol incorporation) to increase membrane integrity. Molecular dynamics simulations reveal that tethering of lipid tails and integration of cholesterol both reduce the disorder in lipid tails and time‐dependent variance in area per lipid within a membrane, leading to tighter lipid packing. These hybrid lipid membranes have exceptional stability in serum, yet can support functional ion channels, can serve as a substrate for phospholipase enzymes, and can be used for liposomal delivery of molecules into living cells.Hybrid synthetic lipids with dramatically reduced leakage properties incorporate many structural features used by Nature to generate stable membranes. Covalent attachment of cholesterol groups to membrane‐spanning tetraether lipids makes it possible to generate stable liposomes with low permeability, while retaining the possibility to support functional biomolecules and deliver liposome‐encapsulated molecules to living cells.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137415/1/chem201701378.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137415/2/chem201701378-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137415/3/chem201701378_am.pd

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study.

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing