Brian P. Mayer

Thermal Degradation Behavior and Product Speciation in Model Poly(dimethylsiloxane) Networks

The thermal degradation behavior of a series of well defined poly(dimethylsiloxane) (PDMS) model networks has been studied using a combination analytical thermal analysis techniques and multivariate statistical analysis in order to probe the influence of network architecture on degradation chemistry. The aim of this research has been to determine the effect differing network architectures: mono and bimodality, a range of crosslink density, inter-chain molar mass and percentage of free chain ends on the mechanisms of PDMS thermal degradation. A series of model PDMS networks have been formulated using of tin catalyzed condensation cure chemistry and a range of linear precursors to yield a matrix of model network systems. The thermal degradation chemistry of these model networks have been characterized in relation to their structure by means of pyrolysis gas chromatography mass spectrometry (Py-GCMS), thermal gravimetric analysis (TGA) and multivariate statistical analysis. The results clearly demonstrate that the structural architecture of (chemically similar) PDMS networks has a significant impact on the mechanisms of PDMS thermal degradation. Notability, with decreasing inter-crosslink chain length, larger cyclic siloxane species (>D5) become more abundant degradation products and that there is a relationship between inter-chain molar mass, degree of crosslinking and the thermal stability on the mechanisms of degradation. This work effectively demonstrates that quantifiable relationships exist between basic network architectures and the distributions of degradation derived species in PDMS networks.

An Efficient, Optimized Synthesis of Fentanyl and Related Analogs

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

Chemical Attribution of Fentanyl Using Multivariate Statistical Analysis of Orthogonal Mass Spectral Data

Attribution of the origin of an illicit drug relies on identification of compounds indicative of its clandestine production and is a key component of many modern forensic investigations. The results of these studies can yield detailed information on method of manufacture, starting material source, and final product, all critical forensic evidence. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic fentanyl, N-(1-phenylethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Six synthesis methods, all previously published fentanyl synthetic routes or hybrid versions thereof, were studied in an effort to identify and classify route-specific signatures. A total of 160 distinct compounds and inorganic species were identified using gas and liquid chromatographies combined with mass spectrometric methods (gas chromatography/mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry-time of-flight (LC-MS/MS-TOF)) in conjunction with inductively coupled plasma mass spectrometry (ICPMS). The complexity of the resultant data matrix urged the use of multivariate statistical analysis. Using partial least-squares-discriminant analysis (PLS-DA), 87 route-specific CAS were classified and a statistical model capable of predicting the method of fentanyl synthesis was validated and tested against CAS profiles from crude fentanyl products deposited and later extracted from two operationally relevant surfaces: stainless steel and vinyl tile. This work provides the most detailed fentanyl CAS investigation to date by using orthogonal mass spectral data to identify CAS of forensic significance for illicit drug detection, profiling, and attribution.

The Influence of Polyhedral Oligomeric Silsequioxanes on Domain Microstructure in Polyurethane Elastomers

The influence of polyhedral oligomeric silsequioxanes (POSS) as covalently bound hybrid physical property modifiers on the segmental dynamics and morphology of segmented polyurethane elastomers has been studied by solid-state magic sandwich echo nuclear magnetic resonance (MSE-NMR), differential scanning calorimetry (DSC) and atomic force microscopy (AFM). A model system has been synthesized which incorporates diol functionalized POSS over a range of loadings into the hard-block of a methylene di-isocyanate - butane diol - poly(tetramethylene glycol) (MDI-BDO-PTMG) segmented PU elastomer. MSE-NMR has been employed to probe the segmental dynamics of the PU system as a function of POSS loading and it has been demonstrated that low levels of POSS as a substitute chain extender, both rigidify the hard-block phase of the PU and significantly alter both the phase morphology, mixing and structure of the inter-phase domains. These observations are supported by more classical AFM and DSC morphological characterization of the POSS-PU hybrid systems which show significant re-structuring of the phase domain structure of the PU and ordering of the crystalline hard-block domains. This work demonstrates the application of a multi-scaled experimental approach towards understanding the effects of three-dimensional, nano-scale cage moieties on the already complex phase structure of segmented polyurethanes. Through these efforts, new insight has been gained into the mechanisms by which low levels of a nano-material such as a cubic sesquioxane, can impact the phase separation and segmental dynamics of block ter-polymer polyurethanes.

NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine

The binding stoichiometry, strength and structure of inclusion complexes formed between the neurotoxin tetramethylenedisulfotetramine (TETS) and both native and modified cyclodextrins (CyDs) were investigated using nuclear magnetic resonance (NMR) spectroscopy. Of all six examined cases, native β‐cyclodextrin (β‐CyD) and its chemically modified counterpart heptakis‐(2,3,6‐tris‐(2‐hydroxypropyl))‐β‐cyclodextrin (2HP‐β‐CyD) were found to associate most strongly with TETS as reflected in the magnitude of their binding constants (K = 537 ± 26 M−1 for β‐CyD and K = 514 ± 49 M−1 for 2HP‐β‐CyD). Two‐dimensional rotating‐frame Overhauser effect spectroscopy NMR experiments confirm close proximity of the TETS molecule to both β‐CyD and 2HP‐β‐CyD as intermolecular, through‐space interactions between the H3 and H5 protons located in the interior of the CyD cavity and the methylene protons of TETS were identified. Copyright

31P-Edited Diffusion-Ordered 1H NMR Spectroscopy for the Spectral Isolation and Identification of Organophosphorus Compounds Related to Chemical Weapons Agents and Their Degradation Products

Organophosphorus compounds represent a large class of molecules that include pesticides, flame-retardants, biologically relevant molecules, and chemical weapons agents (CWAs). The detection and identification of organophosphorus molecules, particularly in the cases of pesticides and CWAs, are paramount to the verification of international treaties by various organizations. To that end, novel analytical methodologies that can provide additional support to traditional analyses are important for unambiguous identification of these compounds. We have developed an NMR method that selectively edits for organophosphorus compounds via (31)P-(1)H heteronuclear single quantum correlation (HSQC) and provides an additional chromatographic-like separation based on self-diffusivities of the individual species via (1)H diffusion-ordered spectroscopy (DOSY): (1)H-(31)P HSQC-DOSY. The technique is first validated using the CWA VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate) by traditional two-dimensional DOSY spectra. We then extend this technique to a complex mixture of VX degradation products and identify all the main phosphorus-containing byproducts generated after exposure to a zinc-cyclen organometallic homogeneous catalyst.

Molecular weight distributions of irradiated siloxane-based elastomers: A complementary study by statistical modeling and multiple quantum nuclear magnetic resonance

The statistical methodology of population balance (PB) has been applied in order to predict the effects of cross-linking and chain-scissioning induced by ionizing radiation on the distribution of molecular weight between cross-links (MWBC) of a siloxane-based elastomer. Effective molecular weight distributions were extracted from the quantification of residual dipolar couplings via multiple quantum nuclear magnetic resonance (MQ-NMR) measurements and are taken to reflect actual MWBC distributions. The PB methodology is then applied to the unirradiated MWBC distribution and considers both chain-scissioning and the possibility of the formation of three types of cross-links: random recombination of scissioned-chain ends (end-linking), random covalent bonds of free radicals on scissioned-chain ends (Y-cross-linking), and the formation of random cross-links from free radicals on side groups (H-cross-linking). The qualitative agreement between the statistical modeling approach and the NMR data confirms that it is possible to predict trends for the evolution of the distribution of MWBC of polymers under irradiation. The approach described herein can also discern heterogeneities in radiation effects in different structural motifs in the polymer network.

Statistical analysis of the chemical attribution signatures of 3-methylfentanyl and its methods of production

Chemical attribution of the origin of an illegal drug is a key component of forensic efforts aimed at combating illicit and clandestine manufacture of drugs and pharmaceuticals. The results of these studies yield detailed information on synthesis byproducts, reagents, and precursors that can be used to identify the method of manufacture. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic 3-methylfentanyl, N-(3-methyl-1-phenethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Eighteen crude samples from six synthesis methods were generated, the analysis of which was used to identify signatures (i.e. chemical compounds) that were important in the discrimination of synthetic route. These methods were carefully selected to minimize the use of scheduled precursors, complicated laboratory equipment, number of steps, and extreme reaction conditions. Using gas and liquid chromatographies combined with time-of-flight mass spectrometry (GC-QTOF and LC-QTOF) over 160 distinct species were monitored. Analysis of this combined data set was performed using modern machine learning techniques capable of reducing the size of the data set, prioritizing key chemical attribution signatures, and identifying the method of production for blindly synthesized 3-methylfentanyl materials.

Solution-state structure and affinities of cyclodextrin: Fentanyl complexes by nuclear magnetic resonance spectroscopy and molecular dynamics simulation

Cyclodextrins (CDs) are investigated for their ability to form inclusion complexes with the analgesic fentanyl and three similar molecules: acetylfentanyl, thiofentanyl, and acetylthiofentanyl. Stoichiometry, binding strength, and complex structure are revealed through nuclear magnetic resonance (NMR) techniques and discussed in terms of molecular dynamics (MD) simulations. It was found that β-cyclodextrin is generally capable of forming the strongest complexes with the fentanyl panel. Two-dimensional NMR data and computational chemical calculations are used to derive solution-state structures of the complexes. Binding of the fentanyls to the CDs occurs at the amide phenyl ring, leaving the majority of the molecule solvated by water, an observation common to all four fentanyls. This finding suggests a universal binding behavior, as the vast majority of previously synthesized fentanyl analogues contain this structural moiety. This baseline study serves as the most complete work on CD:fentanyl complexes to date and provides the insights into strategies for producing future generations of designer cyclodextrins capable of stronger and more selective complexation of fentanyl and its analogues.

Part 3: Solid phase extraction of Russian VX and its chemical attribution signatures in food matrices and their detection by GC-MS and LC-MS

Chemical attribution signatures indicative of O-isobutyl S-(2-diethylaminoethyl) methylphosphonothioate (Russian VX) synthetic routes were investigated in spiked food samples. Attribution signatures were identified using a multifaceted approach: Russian VX was synthesized using six synthetic routes and the chemical attribution signatures identified by GC-MS and LC-MS. Three synthetic routes were then down selected and spiked into complex matrices: bottled water, baby food, milk, liquid eggs, and hot dogs. Sampling and extraction methodologies were developed for these materials and used to isolate the attribution signatures and Russian VX from each matrix. Recoveries greater than 60% were achieved for most signatures in all matrices; some signatures provided recoveries greater than 100%, indicating some degradation during sample preparation. A chemometric model was then developed and validated with the concatenated data from GC-MS and LC-MS analyses of the signatures; the classification results of the model were > 75% for all samples. This work is part three of a three-part series in this issue of the United States-Sweden collaborative efforts towards the understanding of the chemical attribution signatures of Russian VX in crude materials and in food matrices.