Non-deuterated Analogues Research Articles

PET Imaging of VMAT2 with the Novel Radioligand [18F]FE-DTBZ-d4 in Nonhuman Primates: Comparison with [11C]DTBZ and [18F]FE-DTBZ.

The vesicular monoamine transporter type 2 (VMAT2) is believed to be responsible for the uptake of monoamines into the vesicles of the synaptic terminals. Two VMAT2 radioligands [11C]DTBZ and [18F]FP-DTBZ have been used to assess the degree of nigrostriatal deficit in Parkinson’s disease (PD) using positron emission tomography (PET). [18F]FE-DTBZ-d4, the nondeuterated analogue of [18F]FE-DTBZ showed similar imaging properties with better stability against defluorination. Therefore, [18F]FE-DTBZ-d4 draws attention to be investigated as an imaging marker for VMAT2 in the brain. The aim of this study was to investigate the brain kinetics and quantification of [18F]FE-DTBZ-d4 in nonhuman primates (NHPs), with comparison to [11C]DTBZ and [18F]FE-DTBZ. Radiolabeling was successfully achieved either by one-step 11C-methylation or by a two-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield were analyzed with high-performance liquid chromatography (HPLC). Three female cynomolgus monkeys were included in the study and underwent a total of 12 positron emission tomography (PET) measurements. Each monkey was examined with each tracer. In addition, two pretreatment and one displacement PET measurements with tetrabenazine (2.0 mg/kg) were performed for [18F]FE-DTBZ-d4. All PET measurements were conducted using a high-resolution research tomograph (HRRT) system. Radiometabolites were measured in monkey plasma using gradient radio-HPLC. [18F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) displayed higher brain uptake compared to both [18F]FE-DTBZ (SUV: 3.43 ± 0.54) and [11C]DTBZ (SUV: 3.06 ± 0.32) and faster washout. Binding potential (BPND) values of [18F]FE-DTBZ-d4 in different brain regions (putamen: 5.5 ± 1.4; caudate: 4.4 ± 1.1; midbrain: 1.4 ± 0.4) were higher than those of [11C]DTBZ and [18F]FE-DTBZ. [18F]FE-DTBZ showed faster radiometabolism in plasma compared to [11C]DTBZ and [18F]FE-DTBZ-d4. [18F]FE-DTBZ-d4 is a suitable radioligand for quantification of VMAT2 in the nonhuman primate brain, with better imaging properties than [11C]DTBZ and [18F]FE-DTBZ. A preliminary comparison suggests that [18F]FE-DTBZ-d4 has increased stability against defluorination compared to the nondeuterated analogue.

Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer.

A series of deuterated curcuminoids (CUR) were synthesized, bearing two to six OCD3 groups, in some cases in combination with methoxy groups, and in others together with fluorine or chlorine atoms. A model ring-deuterated hexamethoxy-CUR-BF2 and its corresponding CUR compound were also synthesized from a 2,4,6-trimethoxybenzaldehyde-3,5-d2 precursor. As with their protio analogues, the deuterated compounds were found to remain exclusively in the enolic form. The antiproliferative activities of these compounds were studied by in vitro bioassays against a panel of 60 cancer cell lines, and more specifically in human colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) and in normal colon cells (CCD841CoN). The deuterated CUR-BF2 adducts exhibited better overall growth inhibition by NCI-60 assay, while for other CUR-BF2 adducts the non-deuterated analogues were more cytotoxic. Results of the more focused comparative cell viability assays followed the same trend, but with some variation depending on cell lines. The CUR-BF2 adducts exhibited significantly higher cytotoxicity than CURs. Structural studies (X-ray and DFT) and computational molecular docking calculations comparing their inhibitory efficacy with those of known anticancer agents used in chemotherapy are also reported.

A rapid MS/MS method to assess the deuterium kinetic isotope effect and associated improvement in the metabolic stability of deuterated biological and pharmacological molecules as applied to an imaging agent

The deuterium kinetic isotope effect has been known for a period of 40 years, but it is only relatively recently that new drug entities (NDEs) incorporating deuterium demonstrating beneficial pharmacokinetics, pharmacodynamics, and toxicology have arrived to market. Determination of the precise location to deuterate and subsequently any evaluation for a kinetic isotope effect (KIE) is challenging. Typically, such an evaluation would be performed in an in vitro metabolic assay (e.g. liver microsomes) in separate reaction media for both the deuterated and non-deuterated analogues. Here, we have devised an approach whereby we incubate a 1:1 ratio of both the deuterated and protio-form of an imaging agent together in the same liver microsomal assay and determine the relative rate of consumption of both moieties, based upon specific MS-MS transitions unique to both molecules without the need for liquid chromatography-mass spectrometry (LC-MS) separation and quantification. Any deviation of the ratio of the MS transitions from the initial starting point indicated an observable KIE.A site specific deuteration of PBR111, a neuroinflammation imaging agent, was chosen for a proof-of-concept study. Based upon prior mechanistic knowledge of PBR111, two locations were selected for deuteration; an active and inactive site, to corroborate that there was no significant KIE for the inactive site and confirm the efficacy of the developed methodology.

Diastereoselective Lithiation of N-Benzyl Pyrroloimidazolones Derived from l-Proline Hydantoin

An N-benzyl pyrroloimidazolone derived from l-proline hydantoin undergoes asymmetric lithiation with n-BuLi/TMEDA in toluene to give products of electrophile quench (E+) that range from 87:13 to 91:9 diastereomeric ratio (dr). All products appear to have the same relative stereochemistry as determined by transmetalation of benzylic stannanes, which gave identical major diastereomers for several products as to what was observed by direct lithiation–substitution of the starting material. X-Ray crystallography of the major diastereomer of the benzophenone adduct established (R)-configuration at the benzylic center, i.e., anti stereochemistry with respect to the imidazolone. Lithiation of a selectively deuterated analogue of the starting material according to the optimized conditions, followed by benzophenone quench, gave diastereomeric products with far lower selectivity (53:47 dr) than lithiation of the non-deuterated analogue (91:9 dr) owing to a large primary kinetic isotope effect. These preliminary results imply that metalation of the N-benzyl pyrroloimidazolone may follow an asymmetric deprotonation pathway to give a benzylic carbanion that retains its configuration during electrophile quench.

Addition reactions of Cp*Ru(1-5-η-CH2CHCRCHSO2) (R = H, Me) with carbon monoxide, phosphorus, sulfur and nitrogen ligands: Spectroscopic and structural characterization of Cp*Ru(1-2,5-η-butadienesulfonyl)(L)

A series of chiral compounds Cp*Ru(1-2,5-η-butadienesulfonyl)(L) (Cp* = C5Me5; butadienesulfonyl = CH2CHCRCHSO2) were prepared by treating Cp*Ru(1-5-η-CH2CHCRCHSO2) [R = H (1), Me (1Me)] with CO, P(OMe)3, a variety of phosphines, sulfur and nitrogen ligands. All addition reactions were selective, with the exception of PMe3 and P(OMe)3. Even in solution, NMR experiments show a rigid structure for the PPh3 adduct, while PPh2Me adduct shows dynamic behavior. 1H NMR demonstrates the formation and equilibrium reactions for both protio and deuterated adducts of the type Cp*Ru(1-2,5-η-CH2CHCRCHSO2)(L) [R = H, L = CH3CN; R = Me, L = CH3CN, DMSO and Py] in different deuterated solvents, such as C6D6, (CD3)2CO and CD3CN. Addition of deuterated donor ligands into 1 or 1Me occur at faster rate than non-deuterated analogues. X-ray crystal structure data are reported for Cp*Ru(1-2,5-η-CH2CHCRCHSO2)(L) [R = H, L = CO (2), PPh3 (3), PMe3 (6), P(OMe)3 (7), DMSO (8); R = Me, L = PPh3 (3Me), DMSO (8Me), Py (9Me), Py-d5 (9DMe)], as well as the side-product Cp*RuCl(P(CD3)2) (12D).

Neutron Powder Diffraction study of the Magnetic Ionic Liquid Emim[FeCL4] and its deuterated phase

A magnetic ionic liquid comprising 1-ethyl-3 methylimidazolium (Emim) cations and tetraclhoroferrate(III) (FeCl4) anions and its deuterated phase were synthetized and characterized magnetically. In both materials, the low temperature dependence of the magnetic susceptibility presents a maximum (around 4 K) related to an antiferromagnetic ordering, but the ordering temperatures are slightly shifted and the curves display different shapes. In addition, the magnetization of the deuterated phase tends to saturate at higher values than that corresponding to the non-deuterated analogue. A comparison of the neutron diffraction patterns above and below the magnetic transition clearly shows that the crystal and magnetic structures of these materials are different. Therefore, the present findings clearly prove that the magnetic exchange interactions that induce three-dimensional magnetic ordering are modified after the deuteration process.

Kinetic isotope effect in the oxidation of unsaturated fatty acids

The kinetic parameters of the oxidation of a series of polyunsaturated fatty acids (PUFAs), linoleic and linolenic acids and ethyl esters thereof are determined by measuring the rate R OX of the process in chlorobenzene at 310 K. The selective replacement of H atoms by deuterium atoms results in a dramatic decrease in R OX (the H/D kinetic isotope effect, KIE). Furthermore, the addition of a deuterated PUFA to its nondeuterated analogue decreases R OX for the latter. It looks as if the deuterated PUFA partially protects nondeuterated one from oxidation. The information on the KIE obtained under conditions of initiated liquid-phase oxidation is reported in the current work for the first time; all the numerous previous reports have dealt with enzymatic oxidation.

In Vivo Proton–Electron Double-Resonance Imaging of Extracellular Tumor pH Using an Advanced Nitroxide Probe

A variable radio frequency proton-electron double-resonance imaging (VRF PEDRI) approach for pH mapping of aqueous samples has been recently developed (Efimova et al. J. Magn. Reson. 2011, 209, 227-232). A pH map is extracted from two PEDRI acquisitions performed at electron paramagnetic resonance (EPR) frequencies of protonated and unprotonated forms of a pH-sensitive probe. To translate VRF PEDRI to an in vivo setting, an advanced pH probe was synthesized. Probe deuteration resulted in a narrow spectral line of 1.2 G compared to a nondeuterated analogue line width of 2.1 G allowing for an increase of Overhauser enhancements and reduction in rf power deposition. Binding of the probe to the cell-impermeable tripeptide, glutathione (GSH), allows for targeting to extracellular tissue space for monitoring extracellular tumor acidosis, a prognostic factor in tumor pathophysiology. The probe demonstrated pH sensitivity in the 5.8-7.8 range, optimum for measurement of acidic extracellular tumor pH (pH(e)). In vivo VRF PEDRI was performed on Met-1 tumor-bearing mice. Compared to normal mammary glands with a neutral mean pH(e) (7.1 ± 0.1), we observed broader pH distribution with acidic mean pH(e) (6.8 ± 0.1) in tumor tissue. In summary, VRF PEDRI in combination with a newly developed pH probe provides an analytical approach for spatially resolved noninvasive pHe monitoring, in vivo.

Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET

BackgroundFluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ.Methods[18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling.Results[18F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 ± 0.002 min-1), resulting in a six fold increase in half-life stability.Conclusions[18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.

18F]Fluoromethyl-[1,2-2H4]-Choline: A Novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography

Current radiotracers for positron emission tomography imaging of choline metabolism have poor systemic metabolic stability in vivo. We describe a novel radiotracer, [(18)F]fluoromethyl-[1,2-(2)H(4)]-choline (D4-FCH), that employs deuterium isotope effect to improve metabolic stability. D4-FCH proved more resistant to oxidation than its nondeuterated analogue, [(18)F]fluoromethylcholine, in plasma, kidneys, liver, and tumor, while retaining phosphorylation potential. Tumor radiotracer levels, a determinant of sensitivity in imaging studies, were improved by deuterium substitution; tumor uptake values expressed as percent injected dose per voxel at 60 min were 7.43 +/- 0.47 and 5.50 +/- 0.49 for D4-FCH and [(18)F]fluoromethylcholine, respectively (P = 0.04). D4-FCH was also found to be a useful response biomarker. Treatment with the mitogenic extracellular kinase inhibitor PD0325901 resulted in a reduction in tumor radiotracer uptake that occurred in parallel with reductions in choline kinase A expression. In conclusion, D4-FCH is a very promising metabolically stable radiotracer for imaging choline metabolism in tumors.

Direct monitoring of ochratoxin A in cheese with solid-phase microextraction coupled to liquid chromatography-tandem mass spectrometry

An in situ application of solid-phase microextraction (SPME) as a sampling and sample preparation method coupled to HPLC-MS/MS for direct monitoring of ochratoxin A (OTA) distribution at different locations in a single cheese piece is proposed. To be suited to the acidic analyte, the extraction phase (carbon-tape SPME fiber) was acidified with aqueous solution of HCl at pH 2, instead of the traditional sample pre-treatment with acids before SPME sampling. For calibration, kinetic on-fiber-standardization was used, which allowed the use of short sampling time (20 min) and accurate quantification of the OTA in the semi-solid cheese sample. In addition, the traditional kinetic calibration that used deuterated compounds as standards was extended to use a non-deuterated analogue ochratoxin B (OTB) as the standard of the analyte OTA, which was supported by both theoretical discussion and experimental verification. Finally, the miniaturized SPME fiber was adopted so that the concentration distribution of OTA in a small-sized cheese piece could be directly probed. The detection limit of the resulting SPME method in semi-solid gel was 1.5 ng/mL and the linear range was 3.5–500 ng/mL. The SPME–LC-MS/MS method showed good precision (RSD: ∼10%) and accuracy (relative recovery: 93%) in the gel model. The direct cheese analysis showed comparable accuracy and precision to the established liquid extraction. As a result, the developed in situ SPME–LC-MS/MS method was sensitive, simple, accurate and applicable for the analysis of complicated lipid-rich samples such as cheese.

Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Analysis of Multiple Hallucinogens, Chlorpheniramine, Ketamine, Ritalinic Acid, and Metabolites, in Urine

A validated method for the simultaneous analysis of multiple hallucinogens, chlorpheniramine, ketamine, ritalinic acid, and several metabolites is presented. The procedure comprises a sample clean-up step, using mixed-mode solid-phase extraction followed by liquid chromatography (LC)-tandem mass spectrometry analysis. Chromatographic separation was achieved using a Sunfire C(8) column eluted with a mixture of formate buffer, methanol, and acetonitrile. The applied LC gradient ensured the elution of all the drugs examined within 14 min and produced chromatographic peaks of acceptable symmetry. Selectivity of the method was achieved by a combination of retention time and two precursor-product ion transitions for the non-deuterated analogues. Validation of the method was performed using 500 microL of urine. The limits of quantification (LOQ) for LSD and 2-oxo-3-hydroxy-LSD were 0.05 and 1 ng/mL, respectively, and ranged, for the other hallucinogens, from 0.5 to 10 ng/mL. Linear and quadratic regression was observed from the LOQ of each compound to 12.5 ng/mL for LSD, 50 ng/mL for 2-oxo-3-hydroxy-LSD and 500 ng/mL for the others (r(2) > 0.99). Precision for the QC samples, spiked at a minimum of two concentrations, was calculated [%CV and %bias < 20% for most of the compounds, except for bufotenine and cathinone (%bias < 24%), and ibogaine (%bias < 30%)]. Extraction was found to be both reproducible and efficient with recoveries > 87% for all the analytes. Furthermore, the processed samples were demonstrated to be stable in the autosampler for at least 24 h. Finally, the validated method was applied to the determination of chlorpheniramine, ketamine, LSD, and psilocin in authentic urine samples.

Quantitative analysis of multiple illicit drugs in preserved oral fluid by solid-phase extraction and liquid chromatography–tandem mass spectrometry

We present a validated method for the simultaneous analysis of basic drugs which comprises a sample clean-up step, using mixed-mode solid-phase extraction (SPE), followed by LC–MS/MS analysis. Deuterated analogues for all of the analytes of interest were used for quantitation. The applied HPLC gradient ensured the elution of all the drugs examined within 14 min and produced chromatographic peaks of acceptable symmetry. Selectivity of the method was achieved by a combination of retention time, and two precursor-product ion transitions for the non-deuterated analogues. Oral fluid was collected with the Intercept ®, a FDA approved sampling device that is used on a large scale in the US for workplace drug testing. However, this collection system contains some ingredients (stabilizers and preservatives) that can cause substantial interferences, e.g. ion suppression or enhancement during LC–MS/MS analysis, in the absence of suitable sample pre-treatment. The use of the SPE was demonstrated to be highly effective and led to significant decreases in the interferences. Extraction was found to be both reproducible and efficient with recoveries >76% for all of the analytes. Furthermore, the processed samples were demonstrated to be stable for 48 h, except for cocaine and benzoylecgonine, where a slight negative trend was observed, but did not compromise the quantitation. In all cases the method was linear over the range investigated (2–200 μg/L) with an excellent intra-assay and inter-assay precision (coefficients of variation <10% in most cases) for QC samples spiked at a concentration of 4, 12 and 100 μg/L. Limits of quantitation were estimated to be at 2 μg/L with limits of detection ranging from 0.2 to 0.5 μg/L, which meets the requirements of SAMHSA for oral fluid testing in the workplace. The method was subsequently applied to the analysis of Intercept ® samples collected at the roadside by the police, and to determine MDMA and MDA levels in oral fluid samples from a controlled study.

Generation and Reactions of Diazo‐3,3‐dideuterio‐2‐methylidenecyclopropane and Isomerization of 3′,3′‐Dideuterio‐2′‐methylidenespiro [4,5‐dihydropyrazole‐5,1′‐cyclopropanes] into Isopropenylpyrazoles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Generation and reactions of diazo-3,3-dideuterio-2-methylidenecyclopropane and isomerization of 3",3"-dideuterio-2"-methylidenespiro[4,5-dihydropyrazole-5,1"-cyclopropanes] into isopropenylpyrazoles

N-(1,3,3-Trideuterio-2-methylidenecyclopropyl)-N-nitrosourea was synthesized and its decomposition on treatment with K2CO3 in the presence of acrylonitrile and ethyl acrylate or on treatment with MeONa in the absence of unsaturated substrates was studied. The rate of decomposition of the nitrosourea is much lower than that of the nondeuterated analog. The use of acrylates for trapping the intermediate 3,3-dideuterio-1-diazo-2-methylidenecyclopropane results in the corresponding 2"-methylidenespiro[4,5-dihydropyrazole-5,1"-cyclopropanes] containing two deuterium atoms in the cyclopropane fragment. The resulting dihydropyrazoles are isomerized almost entirely over a period of 1—3 days to give a mixture (∼1 : 1) of isopropenylpyrazoles in which both deuterium atoms occur either in the methyl or in the methylidene groups of the isopropenyl substituent. A possible mechanism of this transformation is considered.

The effect of deuterium and fluorine substitution upon the mutagenicity of N-hydroxy-2,6-dimethylaniline

2,6-Dimethylaniline (2,6-DMA) is an intermediate in the manufacture of several products, including pesticides, dyestuffs, and synthetic resins. It is also present in nanogram amounts in tobacco smoke, and is a major metabolite of the potent anesthetic and antiarrhythmic drug lidocaine, as well as a nasal carcinogen in rats. As with other aromatic amines, 2,6-DMA can undergo metabolic activation through cytochrome P450-mediated N-hydroxylation, followed by O-esterification to a reactive derivative capable of forming DNA adducts. We have recently characterized four DNA adducts resulting from this metabolic pathway. Three of the adducts arose from reaction of the exocyclic heteroatoms of deoxyadenosine and deoxyguanosine with the carbon para to the arylamine nitrogen. The fourth adduct resulted from reaction of the 2,6-DMA nitrogen with the C8 atom of deoxyguanosine. In order to investigate the relative contribution of the exocyclic heteroatom adducts as compared to the C8-deoxyguanosine adduct to the toxicities elicited by 2,6-DMA, we synthesized and compared the mutagenicity of N-hydroxy-2,6-DMA, N-hydroxy-4-deutero-2,6-DMA, 2,6-dimethylnitrosobenzene, 4-deutero-2,6-dimethylnitrosobenzene, and N-hydroxy-4-fluoro-2,6-DMA. In Salmonella typhimurium TA100, the two deuterated compounds and their non-deuterated analogues gave similar mutagenic responses (∼25 revertants/nmol). Likewise in S. typhimurium TA98, a similar mutant frequency (∼0.7 revertants/nmol) was obtained with the four compounds. With N-hydroxy-4-fluoro-2,6-DMA, the mutant frequency was reduced by ∼90% in S. typhimurium TA100 and ∼50% in S. typhimurium TA98. The results suggest that multiple adducts contribute to base substitution mutations detected by S. typhimurium TA100 while the C8-deoxyguanosine adduct is primarily responsible for the frameshift mutations detected by S. typhimurium TA98.

Hydrogen Isotope Effect on the Temperature Dependence of the 35Cl-NQR Frequency in (NH4)2IrCl6

The 35Cl-NQRfrequencies and spin-lattice relaxation times of (NH4)2IrCl6 and (ND4)2IrCl6 were measured in the temperature range 4.2 - 300 K. It was confirmed that no phase transition takes place down to 4.2 K. The observed frequency at 4.2 K in (ND4)2IrCl6 was higher by 18 kHz than that in the non-deuterated analogue. This discrepancy was attributed to a difference between the lowest rotational states of the ammonium ions in these compounds. The energy separation between the ground state and excited state of rotational motion, in which N-H of the ammonium ion rotates among the three directions slightly apart from the triad axis, was estimated by fitting analysis to be 31 cm-1 and 93 cm-1 for (ND4)2IrCl6 and (NH4)2IrCl6, respectively. The activation energy of the reorientation of the ammonium ion among the four directions of the triad axis was estimated to be 6.9 and 7.6 kJ mol-1, respectively

Resolution Enhancement and Band Assignments for the First Overtone of OH(D) Stretching Modes of Butanols by Two-Dimensional Near-Infrared Correlation Spectroscopy. 3. Thermal Dynamics of Hydrogen Bonding in Butan-1-(ol-d) and 2-Methylpropan-2-(ol-d) in the Pure Liquid States

Two-dimensional (2D) near-infrared (NIR) correlation spectroscopy was used to study the temperature-induced changes in the hydrogen bonding of butan-1-(ol-d) and 2-methylpropan-2-(ol-d) in the pure liquid phase. The similarity between the 2D correlation spectra of both studied butanols and their nondeuterated analogues proves that the isotopic substitution in the hydroxyl group affects little the dynamic properties of the hydrogen bonding. This conclusion also confirms the heterospectral analysis, performed for the spectra of the deuterated samples and their nondeuterated counterparts. In the asynchronous spectra of 2-methylpropan-2-ol and its deuterated analogue, we identified new bands at 7040 and 5226 cm-1, respectively, which are probably due to an intramolecular effect. Moreover, a heterospectral asynchronous plot develops a peak at (5286, 7085), not seen in the homospectral 2D plots of butan-1-(ol-d) and butan-1-ol, giving rise to an additional resolution enhancement. This new peak reveals different...

Selectively Deuterated Liquid Crystalline Cyanoazobenzene Side-Chain Polyesters. 2. Preparation and Characterization of Polyesters

Two sets of specifically deuterated cyanoazobenzene side-chain polyadipates and polytetrade-canedioates have been prepared by transesterification in the melt. Combinations of three different, selectively deuterium labeled 2-[6-[4-[(4-cyanophenyl)azo]phenoxy]hexyl]-1,3-propanediols or the non-deuterated analog and diphenyl adipate or tetradecanedioate in perdeuterated or non-deuterated versions were employed. The polyesters have weight average molecular masses in the range 21 000–183 000 as determined by SEC. The phase behaviour of the polyesters have been investigated in detail by differential scanning calorimetry. Whereas the polytetradecanedioates show a complex thermal behaviour with a number of different phases, the polyadipates are less complex and both nematic and smectic A phases have been identified by polarizing optical microscopy. Solution 1H, 13C and 2H NMR spectroscopy have been utilized for both polyester structural assessment and determination of deuterium distribution and content. FTIR spectroscopy has revealed suitable and characteristic vibrations which unequivocally represents the absorption behaviour of individual polyester segments or molecular structures in the different selectively deuterated polyesters.

Quantification of free ketene acetals and determination of cure kinetics of poly(ortho ester)s by a facile deuterium labeling method

AbstractA facile method was developed to quantify unreacted ketene acetals during polymerization of poly(ortho ester)s. The method was based on isotopic (deuterium) labeling of the unreacted ketene acetal groups arising from the diketene acetal monomer, 3,9‐diethylidene‐2,4,8,10‐tetraoxaspiro[5,5]undecane (DETOSU). In deuterium oxide, free ketene acetals are hydrolyzed to an α‐deuterated ester; ortho ester bonds are hydrolyzed to the nondeuterated analog. The relative abundance of the deuterated ester side chain can be quantified by gas chromatography‐mass spectrometry (GC‐MS). In the current method, aliquots of a diketene acetal/polyol(s) reaction mixture were dissolved (crosslinked polymers swollen) in methylene chloride and excess D2O. The diketene acetal/polyol(s) reaction mixture was hydrolyzed under mildly acidic conditions to yield pentaerythritol dipropionate (PDP; hydrolysis product of DETOSU). PDP was extracted into an organic phase, silylated, and analyzed by GC‐MS. Fragments corresponding to the C2H5CO+ ion (57 a.m.u.) and C2H4DCO+ ion (58 a. m. u.) were monitored and the quantity of free ketene acetal groups were calculated from the peak areas of the chromatograms. The precision of the method was ±0.1%. The accuracy, as compared to a parallel 1H‐NMR study, was within 5%. This method permits determination of the cure end‐point of a poly(ortho ester) polymerization reaction to within ±0.25%. The curing kinetics agreed well with DSC branching/crosslinking measurements. © 1994 John Wiley &amp; Sons, Inc.