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Similar to ReactIR as a Diagnostic Tool for Developing Robust, Scalable Synthetic Processes
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ReactIR as a Diagnostic Tool for Developing Robust, Scalable Synthetic Processes
- 1. David W. Place Scientific Update Basel, Switzerland ReactIR as a Diagnostic Tool for Developing Robust, Scalable Synthetic Processes 29-OCT-2007 InPACT
- 9. David Place ReactIR and Unit operations 10-APR-2007
- 11. Peak Selection
- 12. Depletion of Ethanol from 1:1 Ethanol/Ethyl Acetate Mixture GC Assay = 0.5 wt% EtOH ATR Assay (reflux)= 4.4 wt% EtOH ATR Assay (r.t.) = 1.4 wt% EtOH
- 13. Depletion of Ethyl Acetate from 1:1 Ethanol/ Ethyl Acetate mixture with 0.16M “API” “ API” 1513 cm -1 GC Endpoint Assay = 0.23 wt% EtOAc ATR Endpoint Assay (raw) = 2.1 wt% EtOAc ATR Endpoint Assay (ConcIRT) = 0.3 wt% EtOAc 1740 cm -1 EtOAc depletion 883 cm -1 EtOH enrichment ATR Spectra 1740 cm -1 (EtOAc)
- 19. Solvent Assisted Dehydration? Stable Hot Unstable Cold? C=O 1733 cm -1 C=O 1725 cm -1 C=O 1729, 1702 cm -1
- 20. ConcIRT Components Signal due to Toluene Signal due to Toluene Signal due to Toluene C=O str FMOC Glutamate
- 22. David Place Case Study #1: Vilsmeier Reaction 10-APR-2007
- 24. Vilsmeier Catalytic Cycle Me 2 NH 2 + Cl - + CO + HCl H 2 O H 2 O CO + CO 2 + 2HCl H 2 O H 2 O Thermal Barrier? Degradents Thermal Barrier? Solubility Solubility
- 29. LC/MS Data for Major Impurity = 193 amu Degradation via cyclic intermediate Acid Catalyzed cyclization Trace Impurity Detected in ReactIR Impurity identity Confirmed by NMR
- 30. Acid Catalyzed isomerization Isomers can be detected with the SiCOMP ConcIRT Component Spectra: IR “Footprint region” Cis- C=C-H 744, 667 cm -1
- 32. David Place Case Study #2: Unstable In-Situ Intermediates 10-APR-2007
- 38. Scaleup: Mixed anhydride Formation Stressed 3h (0.04 mole/h, 0.6 equiv/h) addition to avoid exotherm on scaleup (a) (b) (e) (f) (g) (d) (c) (a) To (b) IBCF Addition over 10 min (c) To (e) NMM addition over 3 h (f) To (g) RNH 2 addition over 3 h HPLC assay @ 220 nm Inflection at ~1 equiv NMM Incomplete reaction?
- 39. 3-D Contour Reveals More Info NMM.HCl is evident in solution R 3 N + -H Str. Vibrations Consumption Of IBCF Mixed anhydride Dissolved NMM.HCl was not observed with NMM Addition over 30 minutes
- 43. David Place Case Study #3: A Peek into Chiral Resolution 10-APR-2007
Editor's Notes
- Any spectra at any given point in time is a composite of all IR active components. Due to this, monitoring of a specific species in solution at a set wavenumber gives a kinetic profile that is a composite of all kinetic profiles of all species absorbing at that wavenumber. Best case scenario is when there is an isolated IR band to monitor. Then the kinetic profile obtained from monitoring that band is simply achieved by subtraction of a baseline in the system (usually solvent). In many cases however this scenario does not exist for all components of interest in a reaction mixture. Depending on the severity of spectral overlap certain information, such as endpoint determination and or establishing functional group assignments to specific components, may be skewed or difficult to pinpoint. As an analogy, the IR spectrum is the same as drawing the structures of all the components one on top of the other. You can see from the garbled mass that there are amine and carbonyl functional groups but you cannot with certainty assign them to any spectific component of the reaction. This is where deconvolution software is useful. By using statistics to analyze the changes in the IR spectrum over time, establishing component spectra that better describe the components and relating them to specific kinetic profiles eliminate some (but not all) of the uncertainty and make the technique more powerful and useful for mapping out reaction relationships and interdependencies.
- *ATR Raw intensity data correlation to GC is limited by Thermal Background and Baseline Absorption by EtOAc *Detection Limit for Ethanol in Ethyl Acetate is 1.36 wt% at room temperature. *Detection limits will depend on spectral overlap and band absorbativity
- Can we use ReactIR to help define the dependencies of the Vilsmeier catalytic cycle. First start with what is known: the suspected catalytic cycle. *Is there and operational window of temperatures that enables the control of the catalytic cycle and eliminates decomposition? How do we monitor this though? Conventional HPLC or GC techniques will give you almost no useful information. NMR techniques may provide useful information but we will have to operate in either special solvents or in a system that really does not simulate the reaction environment as it will be run. Can you really bring an NMR to the reactor? Some very distinct functional groups exist in all the anticipated components of the catalytic cycle, this gives us a hand hold onto following the fate of each species and defining the interconversions between reactive species. *Water contamination: We can infer certain decay pathways by derivatizing the acid chloride to its ester or amide, but this tells us limited information about what is actually happening in the reactor. Can use ReactIR to confirm or identify the most critical step that is responsible for inefficient conversions due to this parameter. *Solubility: Is a concern for using ReactIR. We need to understand the conversion process to acid chloride, but the starting material HCl salt is not soluable in the reaction solvent. Also solubility of acid chloride is not known.
- Example shows that there is a thermal operational window for this process. If heat ramp control is inadequate or uncontrolled could lead to less acid chloride. May be a reason why lab scale reactions work consistently and large batch reactions show variability.
- From Report on 07/13/2006. Initial temp was set to 0C during oxalyl chloride addition.
- Reaction mixture is a slurry at the start of the experiment. Almost no Product acid chloride is soluable at the point of quenching with water. The “sinusoidal” waves in the data are due to the partial immiscibility od water in THF. As a globual of water passes by the IR sensor the acid and acid chloride component concentrations increase indicating a higher conc of these components dissolved in the water phase. Eventually the mixture homogenized.
- Simplified display of ConcIRT deconvolution showing only major components: (a) Charge 10.53mL Isobutyl chloroformate (IBCF) over 10 minutes at Tr = -11.5C; (b) End IBCF charge; (c) Charge NMM over 3 h at Tr = -11.5C; (d) Sampled L34669-183-1#5; (e) End NMM charge sampled L34669-183-1#6; (f) Start FluoroPhenylDMPA Addition over 3 h at Tr = -8.5C; (g) End FluoroPhenylDMPA charge, Julabo Setpoint changed to –5C. NMM addition set to 1.8 equiv not enough when addition times are long. ~10% more NMM is required.
- Establishing the components in a reaction is the most important first step when using ConcIRT algorythm to analyze your data. This will usually require processing that data in multiple ways (all spectra collected vs. broken into logical unit operations, processing with and without solvent subtraction from the entire data set, using 1 of 4 baselining techniques, changing the spectral range to incorporate key vibrational bands or exclude large bands due to solvents) By doing this, certain characteristic Component spectra become evident and inefficiencies in the deconvolution of known and unknown components can be evaluated.
- Salt form A is produced immediately after mandelic acid is introduced (reaction <2 minutes) having featureless absorption at 1616 cm-1 and broad absorption at 2200-2800 cm-1 (indicative of a COO- NH+ salt). Salt form A converts to Salt Form B upon cooling to 50C or Form A crystallizes out and the rise in Form B is due to effective concentration in solution (the former is the more likely explanation). After point (e) the disappearance of form A can be attributed to crystallization out of solution.
- Critical observables should typically be kinetic profiles of reaction components like the product, starting material impurities of interest, solvents or any combination of those.