Quantitative High-Resolution Online NMR Spectroscopy in Pharmaceutical Reaction and Process Monitoring

Maiwald, Michael; Steinhof, Oliver; Sleigh, Chris J.; Bernstein, Michael A.; Hasse, Hans

doi:10.1016/b978-0-444-53173-5.00020-2

Cited by 20 publications

(15 citation statements)

References 29 publications

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“…The time between scans was set to 60 s. Hence, even the tertiary nitrogen centers relax almost completely. See Malz and Maiwald for further information on quantitative NMR spectroscopy. Inverse gated proton decoupling was applied to achieve a sufficient signal‐to‐noise ratio.…”

Section: Methodsmentioning

confidence: 79%

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Steinhof

Kibrik

Scherr

et al. 2014

Magnetic Reson in Chemistry

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Urea-formaldehyde resins are bulk products of the chemical industry. Their synthesis involves a complex reaction network. The present work contributes to its elucidation by presenting results from detailed NMR spectroscopic studies with different methods. Besides (1)H NMR and (13)C NMR, (15)N NMR spectroscopy is also applied. (15)N-enriched urea was used for the investigations. A detailed NMR signal assignment and a model of the reaction network of the hydroxymethylation step of the synthesis are presented. Because of its higher spectral dispersion and the fact that all key reactions directly involve the nitrogen centers, (15)N NMR provides a much larger amount of detail than do (1)H and (13)C NMR spectroscopy. Symmetric and asymmetric dimethylol urea can be clearly distinguished and separated from monomethylol urea, trimethylol urea, and methylene-bridged urea. The existence of hemiformals of methylol urea is confirmed. 1,3,5-Oxadiazinan-4-on (uron) and its derivatives were not found in the reaction mixtures investigated here but were prepared via alternative routes. The molar ratios of formaldehyde to urea were 1, 2, and 4, the pH values 7.5 and 8.5, and the reaction temperature 60 °C.

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Section: Methodsmentioning

confidence: 79%

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Steinhof

Kibrik

Scherr

et al. 2014

Magnetic Reson in Chemistry

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“…(25) The rate constants for the backward reactions k 6 14 are calculated using Eqn (9) with the equilibrium constants K 5 14 , which are estimated as well via empirical correlations reported by Hahnenstein et al as given by Eqn (26). (27) Hahnenstein et al assumed that methyleneglycol MG 1 is the reactive species. In the present work, formaldehyde CH 2 O is defined as reactive species.…”

Section: Determination Of Model Parametersmentioning

confidence: 99%

Investigation of the reaction of 1,3‐dimethylurea with formaldehyde by quantitative on‐line NMR spectroscopy: a model for the urea–formaldehyde system

Steinhof

Scherr

Hasse

2015

Magnetic Reson in Chemistry

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Quantitative on-line NMR spectroscopy is applied to study equilibria and reaction kinetics of the reaction of formaldehyde with 1,3-dimethylurea. This reaction system serves as a model system for the much more complex but industrially relevant urea-formaldehyde system. The aim is to study individual reactions and intermediates. The 1,3-dimethylurea-formaldehyde system undergoes only four reactions and, unlike urea-formaldehyde, does not form polymers. The following reactions are studied in detail: (1) the hydroxymethylation, (2) the formation of hemiformals of the hydroxymethylated intermediate, and (3) two condensation reactions of which the first leads to methylene bridges, the other to ether bridges. NMR spectroscopic chemical shift data of the reacting species are provided for the (1) H, (13) C, and (15) N domains. Equilibrium data of reactions (1), (2), and (3) are determined by quantitative (1) H and (13) C NMR spectroscopy at molar ratios of formaldehyde to 1,3-dimethylurea between 1:2 and 16:1 at a pH value of 8.5. Reaction kinetic experiments using an NMR spectrometer coupled to a batch reactor led to a reaction kinetic model parametrized with true species concentrations. The model takes into account reactions (1), (2), and (3). It describes the reaction system well for molar ratios of 1:1, 2:1, and 4:1, temperatures of 303 to 333K, and pH values from 5.0 to 9.5. Dilution experiments with a micro mixer coupled to the NMR spectrometer are conducted to estimate the time to equilibrium of reaction (2) of which the time constant is significantly lower than those of reactions (1) and (3). Copyright © 2015 John Wiley & Sons, Ltd.

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“…Quantitative high-resolution online nuclear magnetic resonance spectroscopy based on the application of online (flow) techniques for process applications is the method of choice for the investigation of complex fluid mixtures since it works online and without sample preparation [1,2]. A major advantage of NMR spectroscopy is that the method features linearity between absolute signal area according to the number of spins and sample concentration, which makes it an absolute analytical comparison method being independent on the matrix.…”

Section: Introductionmentioning

confidence: 99%

“…Thus it is a promising quantitative technique without elaborate calibration. Various theoretical and experimental papers have dealt with quantitative NMR spectroscopy, e.g., with respect to continuous flow [3,4], in agriculture [5], for trace components [6] or process engineering or pharmaceutical chemistry applications [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous 19F–1H medium resolution NMR spectroscopy for online reaction monitoring

Zientek

Laurain

Meyer

et al. 2014

Journal of Magnetic Resonance

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Quantitative High-Resolution Online NMR Spectroscopy in Pharmaceutical Reaction and Process Monitoring

Cited by 20 publications

References 29 publications

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Investigation of the reaction of 1,3‐dimethylurea with formaldehyde by quantitative on‐line NMR spectroscopy: a model for the urea–formaldehyde system

Simultaneous 19F–1H medium resolution NMR spectroscopy for online reaction monitoring

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Quantitative High-Resolution Online NMR Spectroscopy in Pharmaceutical Reaction and Process Monitoring

Cited by 20 publications

References 29 publications

Quantitative and qualitative 1H, 13C, and 15N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Quantitative and qualitative 1H, 13C, and 15N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Investigation of the reaction of 1,3‐dimethylurea with formaldehyde by quantitative on‐line NMR spectroscopy: a model for the urea–formaldehyde system

Simultaneous 19F–1H medium resolution NMR spectroscopy for online reaction monitoring

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Product

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About

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis

Quantitative and qualitative ¹H, ¹³C, and ¹⁵N NMR spectroscopic investigation of the urea–formaldehyde resin synthesis