Use of Standard Addition to Quantify In Situ FTIR Reaction Data

Hutchinson, G. H.; Welsh, Calum D. M.; Burés, Jordi

doi:10.1021/acs.joc.0c02684

Cited by 13 publications

(24 citation statements)

References 10 publications

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“…This requires multiple data points of concentration vs signal to acquire the slope. Instead, we took advantage of our in situ reaction monitoring technique and used standard addition 24 as an internal calibration method to transform signal (peak area) into concentrations (Figures S6 and S7 in the Supporting Information). However, the standard addition method requires accurate reaction volume measurements.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine

et al. 2021

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Solid–liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine

et al. 2021

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“…The time taken for the reaction to complete for a range of substrates is given ( Scheme 3 ). The use of the standard addition method (see the Supporting Information (SI): Section 1.3.3 ) 52 allowed for the quantification of the starting materials and products allowing rapid and accurate concentration analysis for the reactions. Off-line quantitative 19 F NMR analysis of the reactions confirmed the in situ measurements showing quantitative conversion of the benzoyl chloride starting material; a >99% contained 19 F NMR yield of acyl fluoride was calculated for all substrates.…”

Section: Resultsmentioning

confidence: 99%

Nucleophilic Fluorination Catalyzed by a Cyclometallated Rhodium Complex

et al. 2022

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Quantitative catalytic nucleophilic fluorination of a range of acyl chlorides to acyl fluorides was promoted by a cyclometallated rhodium complex [(η 5 ,κ 2 C-C 5 Me 4 CH 2 C 6 F 5 CH 2 NC 3 H 2 NMe)- RhCl] ( 1 ). 1 can be prepared in high yields from commercially available starting materials using a one-pot method. The catalyst could be separated, regenerated, and reused. Rapid quantitative fluorination generated the fluoride analogue of the active pharmaceutical ingredient probenecid. Infrared in situ monitoring verified the clean conversion of the substrates to products. VTNA graphical kinetic analysis and DFT calculations lead to a postulated reaction mechanism involving a nucleophilic Rh–F bond.

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“…To achieve this, internal calibration was performed via automated standard additions of starting materials before and after each reaction to account for matrix effects. [12,18] Concentrations of intermediates and products could then be calculated using mass balance (Section 1.5 in Supporting Information). This requires exact knowledge of the volume changes caused by each reagent's addition and/or aliquot removal, which were tracked by our system.…”

Section: Chemistry-methodsmentioning

confidence: 99%

“…After performing the reaction, our system converted the acquired peak area versus time data into concentration versus time data for species observed via HPLC (6). To achieve this, internal calibration was performed via automated standard additions of starting materials before and after each reaction to account for matrix effects [12,18] . Concentrations of intermediates and products could then be calculated using mass balance (Section 1.5 in Supporting Information).…”

Section: Instrumentation and Algorithmsmentioning

confidence: 99%

An Adaptive Auto‐Synthesizer using Online PAT Feedback to Flexibly Perform a Multistep Reaction

et al. 2022

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Automated chemical synthesizers have become more common in recent years but struggle to apply rigid procedures to broad substrate scopes. We have developed an adaptive auto‐synthesizer that uses online HPLC and FTIR measurements to adapt to the changing reactivities of different substrates, allowing precise control of reaction conditions. To do so, we designed a flexibly‐timed procedure consisting of specific actions performed by our platform when specific reaction‐monitoring checkpoints are met. Online HPLC allowed our system to autonomously separate, label and quantify most reaction components, with orthogonal FTIR enabling non‐UV active species to be additionally tracked. We tested our platform with CDI‐mediated multistep amidation reactions using a variety of different acid and amine substrates. To demonstrate the high reproducibility and control afforded by our system, we determined the relative rates of both acid activation and subsequent amidation, providing insight into substrate reactivities and the reaction mechanism.

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Use of Standard Addition to Quantify In Situ FTIR Reaction Data

Cited by 13 publications

References 10 publications

Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine

Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine

Nucleophilic Fluorination Catalyzed by a Cyclometallated Rhodium Complex

An Adaptive Auto‐Synthesizer using Online PAT Feedback to Flexibly Perform a Multistep Reaction

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