Gerald W. Stockton

Method Performance and Validation for Quantitative Analysis by 1H and 31P NMR Spectroscopy. Applications to Analytical Standards and Agricultural Chemicals

Nuclear magnetic resonance (NMR) can be used to provide an independent and intrinsically reliable determination of chemical purity. Unlike chromatography, it is possible to employ a universal reference standard as an internal standard for the majority of chemical products assayed by quantitative NMR (QNMR). This is possible because the NMR response can be made the same for all chemical components, including the internal standard, by optimizing certain instrumental parameters. Experiments were performed to validate the quantitative NMR method described in this paper for the analysis of organic chemicals. Experimental precision, accuracy, specificity, linearity, limits of detection and quantitation, and ruggedness were systematically addressed, and system suitability criteria were established. The level of the major chemical ingredient can be determined with accuracy and precision significantly better than 1%, and impurities may be quantified at the 0.1% level or below. Thus, QNMR rivals chromatography in sensitivity, speed, precision, and accuracy, while avoiding the need for a reference standard for each analyte. Examples are given of (1)H and (31)P NMR used for quantitative analysis of agricultural chemicals, and a method for characterization of analytical standards is presented.

Versatile macroscale heat flow calorimeter for the study of chemical processes

A novel macroscale calorimeter has been designed and fabricated for the purpose of evaluating the thermodynamic and kinetic properties of chemical reactions, especially those associated with industrial manufacturing processes. This calorimeter includes provisions for isothermal and temperature‐programmed operation over a wide range of temperatures, simultaneous or sequential addition of several reagents, and variable‐rate agitation. The metal reaction vessel can be removed from the main housing of the calorimeter, permitting the use of vessels made from various materials for optimum corrosion resistance. Heat transfer takes place only through the base of the vessel, ensuring that the thermal efficiency remains independent of the sample volume. A novel computer control algorithm provides precise control of the reaction temperature, as well as low‐noise measurement of heat flux. The observed detection threshold is 50 mW and a heat flux of several hundred watts can be dissipated. Provisions for simultaneous ...

Crystal polymorphism in pendimethalin herbicide is driven by electronic delocalization and changes in intramolecular hydrogen bonding. A crystallographic, spectroscopic and computational study

Pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine, is a potent herbicide that exists in two differently coloured polymorphic crystal habits. Triclinic pendimethalin I (P) is the orange-coloured thermodynamically stable form, whereas monoclinic pendimethalin II (P21/c) is a bright-yellow metastable form. The latter is normally produced first upon cooling the molten chemical, whereas the orange form is formed by a polymorphic phase transition which occurs slowly upon long term storage of the yellow form at temperatures below its melting point. Such phase transitions are rapidly revealed by calorimetry. The crystal structures of the polymorphs have been determined using single crystal X-ray diffraction. Solid state NMR spectroscopy, vibrational spectroscopy and UV–VIS spectroscopy were applied to further study the nature of the polymorphism in terms of intra- and inter-molecular properties. Solid state CP-MAS 13C NMR spectroscopy was shown to be the method of choice for quantitative analysis of polymorphic mixtures. The differences in spectral properties and crystal habits were investigated by computational methods which included molecular exciton, molecular orbital and molecular mechanics calculations. The dramatic colour change from yellow to orange-red during the polymorphic transition is discussed in terms of competing inter- and intra-molecular electronic effects. The driving force for the yellow (II) to orange (I) polymorphic transition is attributed to the change in the electronic delocalization achieved from shortening, strengthening, and partially straightening the ‘bent’ hydrogen bond between the secondary amino hydrogen and an oxygen of the 6′-nitro group. This results in increased overlap between the amino nitrogen’s lone pair and the π-electron orbitals of the aromatic ring. The calculated lattice stabilization energy due to this process is 4 to 5 kcal mol–1, and the relative lattice energies are consistent with the observed stabilities of the polymorphs. The slow kinetics of the polymorphic transition are largely governed by the steric interaction of the 1-ethylpropyl side chain and the two nitro groups. During crystallization, the more compact side chain conformation required to form the energetically more stable orange (I) polymorph appears to be more difficult to achieve than that required for the yellow (II) polymorph.

DIRECT NMR DETERMINATION OF OPTICAL PURITY OF NICOTINIC AND QUINOLINIC CARBOXYLIC ACID COMPOUNDS USING 1, 2-DIPHENYLETHANE-1, 2-DIAMINE AS A CHIRAL SOLVATING AGENT

The use of the chiral solvating agent, (1R, 2R)- or (1S, 2S)-1, 2-diphenylethane-1, 2-diamine, in the NMR determination of the optical purity of α-chiral acids has been well documented. The amine forms soluble diastereoisomeric salts with the enantiomers of carboxylic acids, producing differences in chemical shifts between diastereoisomeric salts, thus permitting a direct measure of their enantiomeric composition. However, the acids that were studied principally were the α-chiral acids and, less frequently, β-chiral acids. We used this chiral solvating agent to determine the optical purity of ε-chiral acids of the imidazolinone herbicides imazapyr, imazethapyr, imazamox, imazapic, and imazaquin, in which the carboxylic acid group is attached to an aromatic ring and the chiral center in the imidazolinone ring is five bonds away from the acid group.The optical purity of these ε-chiral acids is readily determined in pyridine-d5 at room temperature with 1, 2-diphenyl- ethane-1, 2-diamine. In a 2:1 complex of the acid with the chiral solvating agent, the diastereomeric resonances in 1H NMR spectrum are typically non-equivalent by more than 0.05 ppm, thus allowing rapid and direct analysis of optical purity. The effect of stoichiometry, acid enantiomeric purity, concentration, and solvent on the observed non-equivalence is studied. The nature of the diastereomeric salt complex of these imidazolinones with 1, 2-diphenylethane-1, 2-diamine is also discussed.

Differential metal binding interactions of the imidazolinones revealed by NMR and UV spectroscopy

NMR and UV spectroscopy and molecular modeling methods were applied to probe the interaction of the two imidazolinones, imazethapyr (5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid) and its structural isomer CL 303,135 (5-ethyl-3-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)picolinic acid), with metal ions. Both the imidazolinones inhibit the enzyme acetohydroxyacid synthase (AHAS) in vitro. However, while imazethapyr is a herbicide that is used widely in agriculture, CL303,135 does not exhibit herbicidal activity. Imazethapyr and CL303,135 exhibited considerable differences in their interactions with metals. In the metal complex of imazethapyr, the carboxyl moiety binds strongly and the pyridine nitrogen binds weakly with metals. In the case of CL303,135, both the pyridine nitrogen and the carboxyl group that are positioned ortho to each other participated strongly in the binding and were found to act together as a strong bidentate ligand to a metal ion. Both of the imidazolinones form predominantly 2:1 complexes with multivalent metal ions. However, imazethapyr binds two orders-of-magnitude more weakly (1.0 x 10 9 M -2 ) with metal ions compared to CL303,135 (1.7 x 10 11 M -2 ). The interactions of the model compounds, nicotinic acid and picolinic acid, with metals were examined similarly. It was concluded that the strong affinity of CL303,135 for metals compared to imazethapyr may affect its absorption from soil into plants, or its translocation in plants, thereby explaining the differences in herbicidal activity of imazethapyr and CL303,135.