Real Time Analytics User s Forum 24 Optimization of a hazardous reaction with strong gas release - ReactIR in solution and gas phase - Kai Lovis Schering AG
Content Introduction Initial situation / Problems / Risks First experiments in solution Usage of the new gas cell for ReactIR Kinetic calculations / Reaction mechanism Summary
Introduction Overview of reaction HCOOH Cl-SO 2 -N C O Cl-SO 2 -NH 2 CH 2 Cl 2 + HO H 2 N R O chloro sulfonylisocyanate sulfamoylchloride Only the synthesis of the sulfamoyl chloride (1 st step) is critical
Supposed mechanism of the 1 st reaction step Initial Situation Cl-SO 2 -N C O Cl-SO 2 -NH 2 Chlorosulfonylisocyanate HCOOH Cl-SO 2 N H O O O intermediate IM H -CO,-CO 2 Sulfamoyl chloride yield quantitative high purity but: a lot of gas!! Previous assumptions of the reaction: fast formation of intermediate IM delayed cleavage of CO 2 and CO possibility of uncontrolled accumulation of IM risk of spontaneous release of the whole gas volume (Runaway) (approx. 7 m 3 gas in 25 L-vessel!) rigorous safety requirements for the manufacturing process
Hazard analysis in safety lab Initial Situation Conditions: Recipe based on optimization results Dosage of HCOOH over 1 h (Reflux) Dosage period of HCOOH gas volume [cm 3 ] IT [ C] bservations: delayed and apparently spontaneous gas release Runaway! Volume [ml] gas flow [cm 3 /h] T [ C] onsequences for the 1 st campaign: slow, batchwise dosage of HCOOH long breaks before dosage of next portion t [h]
First Experiments eproducing the manufacturing procedure at lab: conditions: charge of the total mass of CSI dosage of HCOOH in 8 portions duration of each dosage-phase: 2 min volumetric measurement of the gas (sum of CO 2 /CO) IR-signal IR-Signal 5 4 3 2 1 Gasfreisetzung release [ml/min] product SMC (amine) HCOOH Dosierung dosage 1 8 6 4 2 observations: partly delayed gas release at the outset strong subsequent release of gas at the outset nearly dosagecontrolled gas release at high conversions 1 2 3 4 5 6 t/min
ReactIR-Study in liquid phase (I) Simultaneous, fast addition of isocyanate und HCOOH (in 5 portions): 3D-series of IR-spectra in liquid phase (DiComp-probe) Solvent CH 2 Cl 2 is subtracted Isocyanat (-N=C=O) HCOOH (-C=O) Amidn (-NH 2 ) IM 1 (-C=O) IM 2
ReactIR-Study in liquid phase (II) Simultaneous, fast addition of CSI und HCOOH (in 5 portions): blue: start spectrum red: end spectrum Resulting concentration profiles: -N=C=O diamond (probe) IM 2 IM 1 anhydride HCOOH product (amine) IR-Signal 1.8.6.4.2 -N=C=O CSI amine SMC HCOOH IM1 IM2 Gas high increase of reaction rate by autocatalysis appearance of 2 intermediates: IM 1 corresponds to anhydride IM 1-kinetic like isocyanate or HCOOH IM 2 is formed after delay (IR-bands can not be assigned) 5 1 15 2 t Zeit/min [min]
Use of the ReactIR Gas Cell (I) Gas cell for ReactIR: qualitative and quantitative analysis of gas mixtures general information: diagram: IR-beam (from / to spektrometer) IR-window (ZnSe) Gas volume (optical path-length 2 x 5 cm) Gas mixture (from reactor) mirror (gold) suitable for: all compounds in gas phase (including solvents) except linear homonuclear (e.g. He, O 2, N 2, H 2, Cl 2 ) pressure: 1 mbar - 1 bar used at Schering for: CO/CO 2 CSI reaction ozone H 2 O/EtOH monitoring of an ozonolysis drying of a drug substance
Use of the ReactIR Gas Cell (II) ReactIR with gas cell RC 1
Use of the ReactIR Gas Cell (III) Parts from IR-spectra of the gas phase during the CSI reaction CO 2 CO CO 2 CO 2 υ sym. 2144 cm -1 CH 2 Cl 2 HCl υ Asym. 2349 cm -1 R-branch S-branch Q-branch excellent separation of the IR-bands in gas phase even rotational fine structure of CO can be recognized
Use of the ReactIR Gas Cell (IV) Simultaneous, fast addition of CSI und HCOOH (5 portions): 3D-series of IR-spectra in gas phase: resulting profiles: CO 2 CO Absorptionseinheiten 5 4 3 2 1 CO2 CO gas Gas overall gesamt increase of reaction rate delayed release of CO 2 compared with CO 6 12 18 24 3 Zeit t [min] decarbonylation takes place before decarboxylation!!
Use of the ReactIR Gas Cell (Ozonolysis) Calibration of an ozone generator at CChD ozone-signal at varied oxygen stream: n 3 (142 cm -1 ).2.15 Ozon-Anteil Ozone fraction Ozone Ozon-Anteil fraction.1.5 1 2 3 4 5 6 Oxygen Sauerstoffstrom flow [L/h](L/h) quantitative calibration of spectra: 1. with known molarabsorptivity (literature) 2. by titration
Use of the ReactIR Gas Cell (V) Rerun of the Standard Operation Procedure with gas cell: Profiles of released gas phase (by IR-spectroscopy) 5 Flowgesamt overall [ml/min] FlowCO2 [ml/min] Gasflow [ml/min] 4 3 2 1 FlowCO [ml/min] black: Sum of CO + CO 2 red: CO blue: CO 2 6 12 18 24 3 36 42 48 Zeit t [min] Sum of CO 2 and CO corresponds to previous results Decarbonylation (CO) is nearly dosage-controlled Decarboxylation (CO 2 ) increases (autocatalysis) A safety risk is only presented by CO 2 (half of the total gas volume)
Resulting reaction mechanism based on ReactIR-data : Reaction Mechanism O R O O N=C=O R R k 1 k 2 NH2 R NH OH k 3 + NH O H O CSI anhydride carbamid acid Sulfamoyl chloride OH 1. Resulting rate laws/-constants: k 1: autocatalyzed => k1 = f (conversion) k 2: much higher than k1 and k3 => k2 > k1, k3 k 3: strongly autocatalyzed => k3 = f (conversion) (acid- or base catalysis) 2. Determination of kinetic constants by software PRESTO: fitting the parameters to lab experiments C + + O O C O
Simulation of Standard Operation Procedure: dosage of HCOOH (5 x) to charged CSI kinetic calculations with PRESTO Verification of the kinetic model Simulation of the safety lab batch: continuous dosage of HCOOH (1 h) to CSI Signale CO2/CO.1.8.6.4.2 CO2 (berechnet) CO2 (gemessen) CO (berechnet) CO (gemessen) dosage phase Signale CO2/CO.2.15.1.5 CO2 (berechnet) CO (berechnet) dosage phase 6 12 18 24 3 36 42 48 Zeit [min] t [min] profiles of released gas components correspond closely to calculations.5 1 1.5 2 2.5 t Zeit [min] [min] simulation shows good agreement with safety lab Runaway no uncontrolled gas release, but calculable, autocatalyzed release of CO 2
Kinetic calculations Result of a PRESTO-simulation: all components were added quickly and simultaneously Set up: definition of real system (workshop): reactor (size, semibatch,...) gas cell reaction components (e.g. concentrations) operating mode recipe (Additiontime, -duration, -amount) reaction steps Parameters: k1 = 1.1e-3 L/(mol s) + autokatalysis-term k2 = 1.5e-2 L/(mol s) k3 = 3.e-3 L/(mol s) + autokatalysis-term
Optimization Experiments Rerun of the safty lab experiment by using ReactIR gas cell Dosage of HCOOH in 1 h at 5 C (IT)
Specific Optimization of Dosage-controlled Gas Release Situation after optimization: 16 12 Flow CO2 [ml/min] Flow CO [ml/min] Gasvolumen gesamt [ml] 6 45 Gasfluß [ml/min] 8 3 Gasvolumen/[mL] 4 15 5 1 15 2 25 3 35 t/min dosage-controlled CO 2 -release!! dosage breaks are not necessary!!
Optimization of sulfamoyl chloride formation achieved by using ReactIR: specific kinetic experiments in solution with DiComp-Probe Summary final determination of the reaction mechanism by IR-measurements in gas phase with ReactIR-Gas cell Specific search for new process variations was possible Simulation of process variations using softwaretool PRESTO
Who did the job? Christian Finke Monika Linnenlücke Kai Lovis
Ozonolysis Messung 117_4 Ozon MeCl 1 1 Ozon im Abgas/ % 8 6 4 2 Ozon im Abgas/ % Ozon-Zugabe /g Absorbiertes Ozon im Reaktor [g/h] 8 6 4 2 Absorbiertes Ozon im Reaktor [g/h] 1 2 3 4 5 Zeit/min
gas flow + heat flow Wärmeleistung + Gasfluss 8 2 Gasstrom 15 6 1 Leistung in Watt/kgERM 4 2 CO 2 CO 5-5 Gasfluss in l/mol/h Wärmestrom -1-2 -15 Dosierung -4-2 4 6 8 1 12 14 16 18 Zeit in s