Appreciation of Chemical Engineering Principles · Attilio Citterio Chemical Engineers • An...
Transcript of Appreciation of Chemical Engineering Principles · Attilio Citterio Chemical Engineers • An...
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Appreciation of Chemical Engineering PrinciplesProf. Attilio CitterioDipartimento CMIC “Giulio Natta”http://iscamap.chem.polimi.it/citterio/dottorato//
PhDIN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)
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Attilio Citterio
Chemical Engineers
• An essential part of the development team• Approach problem from a different viewpoint• Should work alongside chemist from a early stage• Can propose solutions to seemingly intractable problems• Can ensure synthetic routes are not rejected for the wrong
reasons• Can teach chemists the vital importance of
- studying kinetics- heat transfer- mass transfer- Technology developments
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Heat Transfer (HT)
• Control of temperature with respect to time is one of the most important aspects of chemical engineering
• Reaction temperatures must be controlled in order to- Ensure the selectivity of the process- Reproduce results accurately- Prevent thermal runaways
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Heat Transfer (HT)
• HT is important not only in the reaction phase but also in work-up.
• For example- Control of exothermic neutralisation- Control of temperature during solvent-stripping- Control of temperature for crystallisation- Control of temperature during fractional distillation
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Heat Transfer Equation
Where:
q = heat flux (heat transfer per unit area)k = thermal conductivityT = temperaturey = distancedT/dy = temperature gradient across the reactor
dTq kdy
= −
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Heat Transfer (HT)
• In most chemical processes rate of external heating may not be important
• Rate of external cooling can be critical when exotherms take place
• Removal of heat is proportional to contact surface area as well as ∆T
• So reactions with low volume are most difficult to control
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Factors Affecting Heat Transfer
Rate of agitation Turbulent or laminar flow Viscosity of reaction medium
- Varies with temperature- May vary with distance from rector wall- Can change during reaction
Density Temperature Shape and surface area of vessel Exothermicity of reaction Phase changes (e.g. reflux)
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For Control of Heat Transfer
Correct vessel/batch size
Correct materials of construction- Stainless Steel, Glass, Hastelloy, etc.
Design of reactor and agitator
Design of process (compared to lab)- e.g. avoid low volumes when exotherms occurs
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Reactor HT AreaSize (L) m2 m2·L-1
Lab 0.5 0.02 0.0426
Pilot Plant 380 2.32 0.0061
Small Production 3,800 10.7 0.0028
Large Production 38,000 53.0 0.0014
Heat Transfer Areas
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Consequences
Increased cycle times
Increased rates of addition
Increased reaction times
Increased work-up times
Possible loss of control if accumulation occurs in an exothermic process
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Effect of Vessel Size on HT
Heat evolved proportional to number of moles of reactant(s)
Therefore proportional to volume of solution - therefore proportional to r3
Removal of heat proportional to surface area- therefore proportional to r3
Therefore as vessel size increases, volume-to-surface ratio also increases
Therefore control of heat transfer becomes more difficult
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To Improve Heat Transfer and Control Hexotherms
Increase temperature difference between coolant and reactor - Thus water not much good for controlling processes in 15-25°C
range
Increase flow of coolant - High flow rate for water-cooling may outweigh advantages of using
refrigerant below 0°C (because of its limited capacity)
Use refluxing solvent
Carry out reaction at higher temperature
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Incorporate coils in vessel
Use metal vessel
Use more dilute solutions- Reduces reaction rate and viscosity
Control rate of addition of one reagent
Ensure no accumulation of reactants
To Improve Heat Transfer and Control Hexotherms
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High Temperatures may be Safest!
If reaction temperature is too low - Rate of reaction is reduced
- Unreacted reagent may accumulate
When reaction proceeds it may go out of control - Accumulated reagent reacts all at once
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Heat Balance of a Stirred Tank Reactor
Influence of the coolant temperature
Rate of heat production
Rate of heat lossA
C
k
B1
2
Ta Taz Ta1
TC( )QR R Ar V H r= ⋅∆ −
dqdt
T
( )QW A Ar U T T= ⋅ −
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Influence of the HT parameter
Rate of heat production
Rate of heat lossAk
(UA) > (UA)cr
Ta
Tcr
Ta
(UA)cr
(UA) < (UA)cr
Heat Balance of a Stirred Tank Reactor
( )QR R Ar V H r= ⋅∆ −
( )QW A Ar U T T= ⋅ −
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No Accumulation Accumulation
Addition of reactant
Time
g
Time
qRHeat release rate
Heat of reaction
Time
gAddition of reactant
Time
qRAccumulate heat at the end of addition
Heatreleaserate
Thermal Accumulation
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Temperature
Time
Desired reaction
2∆Tad
Normal process
Coolingfailure
Reaction ofdecomposition
3
1
TMRad
Tend
Thermal Runaway
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Risk Assessment
Can process temperature be controlled by the cooling system?
What temperature can be attained after runaway of the desired reaction?
What temperature can be attained after runaway by decomposition?
At which moment does cooling failure have the worst case consequences?
How fast is the runaway of the desired reaction? How fast is the runaway of the decomposition starting at
MTSR?
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Grignard Reactions
• Charge magnesium and solvent
• Add alkyl halide (Max. 10%)
• Initiate reaction
• Once initiated, add alkyl halide to maintain reflux
• Problems- Low volume to start with- Reflux temperature- Initiation sometimes difficult- Reaction may stop
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Mass Transfer (MT)
Not the same as agitation
Important for reactions with more than one phase - Solid-liquid- Gas-liquid- Immiscible liquids- Gas/solid/liquid
Important in non-equilibrium processes- MT stops when equilibrium is reached
Also important in work-up, purification- distillation, extraction, filtration, crystallization, drying
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Grignard Requires THF Solvation for Stability
Reagent 4 kgMg 560 gTHF 3L + 1 L (reduced from 7.2 L in development work)
F Me
Br
THF
Mg
F Me
MgBr
Heat of decomposition 438 J·g-1 onset 140°CLow solvent 691 J·g-1 320°CHigh solvent no decomp. at 140°C
Aryl Grignard
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50 100 150 200 250 300 °C
20 m
W IntegrationDelta H 4192 mJ
437.6 J·g-1
Peak 210.0 °C8.8 mW
Integration (est.)Delta H 6624 mJ
691.4 J·g-1
Peak 339.7 °C32.6 mW
Grignard reaction. Sample 2. File: 05120.001 DSC METTLER 22-Sep-049.580 mg Rate: 5.0 °C·min-1 Ident: 2.0 Graphware TA72
DSC of a Grignard Reaction
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MT and Chemical Reactions
For substances to reach they must first come into contact - i.e. they must migrate to reaction zone
Before further molecules can react at the same site, products must migrate away
In a two-phase system, MT is affected by- Rate of diffusion to and across interfacial boundary- Rate of diffusion of products from reaction zone- Size of interfacial area or surface- Thus for solids, particle size affects reaction rate, increasing with
smaller particles
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MT and Scale-up
During scale-up, we wish to mimic lab reactions in the plant - to ensure consistency of yield and product
But agitation in the plant is completely different! - Laboratory glassware is usually spherical- Plant equipment is cylindrical
In process development, it is better to use cylindrical glassware
Plant vessels are usually baffled - Gives best mass transfer- Gives best heat transfer
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vortex
Swirl
Flow Pattern in an Unbaffled Tank
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baffles
Flow Pattern in an Baffled Tank
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Mass Transfer and Agitation
Mass Transfer varies with- Viscosity of the medium
may not be uniform if agitation poor varies remarkably with temperature e.g. for water by factor 7 from 0-100°C
- Density- Velocity (agitation rate)- Temperature (indirectly)
Therefore good agitation is vital
Type of agitation affects motion in solution and effectiveness of mass transfer
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Impeller
3 radial and curved blades
Assembled axially with 1-2 baffles
Axial suction and radial flow Application range peripheral
speed 0.5-10 m·s-1 - turbine flow
Service- homogenization- suspension of solids- liquid-liquid and solid-liquid
dispersion- heat transfer- chemical reaction
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Twin Agitator
Several 2-blades wheels 90°rotated
Assembled with or without baffle
Prevailing flow axial Application range peripheral
speed 0.5-12 m·s-1 - laminar or turbulent flow
Service- homogenization- liquid-liquid and solid-liquid
dispersion- heat transfer
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Anchor
Anchor agitation
Assembled axially without baffle or with one thermo-pocket
Axial suction and radial flow with rotation of product
Application range peripheral speed 0.5-5 m·s-1 - transitory or laminar flow
Service- homogenization- heat transfer- chemical reaction
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Loop Agitator
Tubular gate agitation
Assembled axially without baffle or with one thermo-pocket
Centripetal and centrifugal radial flow
Application range peripheral speed 3-5 m·s-1 - transitory or laminar flow
Service- homogenization of viscous
products- heat transfer- chemical reaction
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Uniflow Axial Turbine
Pitched blades to give high axial flow and low shear
Tapered blade to minimize radial flow and maintain constant mix velocity at blade tip
Shear mix minimized 3 blades give ease of installation
through canter opening Assembled with or without baffles Appl. range perif. speed 2-5 m·s-1
Service- homogenization- suspension of solids- solid-solid and gas-liquid dispersion- heat transfer- chemical reaction
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Piched Turbine
6-bladed propeller Assembled axially with 1-4
beaver-tail baffles or eccentrically without baffle
Prevailing flow axial Application range peripheral
speed 3-20 m·s-1 - turbulent flow
Service- homogenization - suspension of solids- liquid-liquid, solid-solid and
gas-liquid suspensions- heat transfer
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Radial Turbine
Flat blades to give high radial flow and high shear
Flat parallel blade to give high radial flow and obtain high mix shear
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Disc Turbine
Turbine wheel with 6 radial blades
Assembled axially with or without 1-4 beaver-tail baffles
Axial suction and radial flow Application range peripheral
speed 3-10 m·s-1 - transitory or turbulent flow
Service- homogenization - suspension of solids- liquid-liquid, solid-solid and gas-
liquid suspensions- emulsion- heat transfer- chemical reaction
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Effect of Scale-Up on MT
• Osborne Reynolds (1883) distinguished between two types of flow- laminar - pressure drop proportionally to v- turbulent - pressure drop proportional to v2
• The feature of turbulence is formation of lots of eddies of varying sizes, vital for good mixing
• Degree of turbulence can be characterized by a quantity called the “Reinolds number” Nre
• For scale-up, if pilot vessel designed so that NRe is the same as in the lab, then equivalent mixing is likely
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Reynold Number NRe
D = diameter of vesselv = average velocity of fluidρ = densityµ = viscosity
• NRe has NO dimensions
• Change from laminar to turbulent flow usually occurs around same values of NRe
- NRe < 2100 laminar- NRe > 2100 turbulent
ReD vN ρµ⋅ ⋅
=
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Viscosity and Mass Transfer
• For high viscosity applications (NRe up to 5000)- Large scale diameter agitator- Low speed- i.e. anchor stirrer
• For low viscosity fluid- Diameter of agitator may be as low as one third vessel diameter- High speed
• Propeller agitators induce axial flow Turbines induce radial flow
• Axial flow component increased by angling turbine blades
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Impeller Diameters
• Ratio of impeller to vessel diameter is an important factor in scale-up- To disperse a gas in a liquid, optimum ratio is approximately 0.25- To disperse 2 immiscible liquids, optimum ratio is approximately
0.40 - To blend, optimum ratio is > 0.60
• Where a gas is introduced to a solid-liquid dispersion a complex situation arises- Gas bubbling may lead to poor mass transfer, whereas in absence
of gas, mixing was good with the same agitator
• On scale-up, KEEP GEOMETRIC SIMILARITY!
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Reactions with Potential Mixing Problems
• Where reaction rate is comparable to rate of mixing and where a consecutive reaction can take place- Acidification or basification, when product may undergo a second reaction
such as hydrolysis- Halogenation - over-reaction always a problem - Nitration, under some circumstances- Organometallic reactions
• Where viscosity increases- Mixing rate decreases- e.g. polymerization
• Reactions which are sensitive to rate of addition of one reagent
• Where product ratio is sensitive to temperature
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Bulk Mixing
• Mixing times:- 500 ml flask 2 - 3 seconds- 40 m3 vessel 30 - 60 seconds
• Before complete mixing occurs there may be- “local” excesses of reagent- pH differences across mixture
• This may cause formation of by-products- particularly if rate of by-product formation is comparable to that of
main reaction
• Therefore, selectivity may change with scale
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Micromixing
• Mechanical agitation will not give completely homogeneous blend
• For two homogeneous fluids, there will be a residual eddy size below which no further blending takes place
• This is a function of- power input via agitator - viscosity of the medium
• For aqueous solutions, eddy size range is 10-2 - 10-3 cm • Time-scale for homogenization (by molecular diffusion) is
of the order of 0.1-1 sec
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k1/k2 = 104
NO2++
NO2++
NO2
NO2
O2N
k1
k2
P. Rys (ETH), Helv. Chim. Acta, 1977 (60), 2937Arc. Chem. Res., 1976 (9), 345
J.R. Bourne, J. Org. Chem., 1988 (53), 5166
Micromixing - Nitration of Durene
• With- equimolar reagents - slow rate of addition- good mixingwould expect little dinitration
• BUT- even at low concentrations of
nitronium salt, a high proportion of dinitration occurs
• Why? - Reaction is diffusion-controlled.
Mononitrodurene is nitrated again before it can diffuse away from nitronium salt
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A + B C
A + C D
kr
kdkr >> kd
t0 t1t2
Eddy size 10-2- 10-3 cmDiffusion time 0.01 - 1.0 sec
φ2 = R2 k2 B/D
Micromixing
A =B =C =D =
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Mixing Effects - Bromination
MeO OMeBr2
MeO OMe
BrOMe OMe
MeO OMe
BrOMe
Br+
Stirrer Starting mono diSpeed Material bromo bromo
0 22.2 57.9 19.9213 19.9 61.3 18.8425 18.3 64.5 17.2638 13.6 73.4 14.8
1063 13.5 73.4 13.1
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Attilio Citterio
O
O(H)
OH
O(H)
+ H+
1a
1b
O
O(H)2b
O
O(H)4b
O
O(H)6b
Br Br
Br
BrBr
Br
OH
O(H)3aBr
OH
O(H)5a
Br
Br
OH
O(H)6a
BrBr
Br
+ H+- H+- H+
Bromination of Resorcinol
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Attilio Citterio
J.Garcia-Rosas, Chimia, 1990, 368 Concentration of
NaOH is critical
Agitator Speed Mono Bis % ortho1000 94.5 5.5 9.72000 95.3 4.7 9.16000 96.7 3.3 8.78000 97.5 2.5 7.5
OH OHN
NPhPhN2
++
OH
NN
PhOH
NN
Ph
NN
Ph
NaOH
Influence of Mixing on Product Ratio
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Attilio Citterio
mono bispara ortho total
0.025 M NaOH 86.2 9.1 95.3 4.7At 600 rpm 0.05 M 94.0 4.5 98.5 1.5
0.10 M 94.5 5.4 99.9 0.1
mono bispara ortho total
0.025 M NaOH 88.0 8.7 96.7 3.3At 5000 rpm 0.05 M 94.8 4.3 99.1 0.9
0.10 M 96.5 3.1 99.6 0.4
mono bispara ortho total
0.025 M NaOH 90.0 7.5 97.5 2.5At 8000 rpm 0.05 M 95.6 3.9 99.5 0.5
0.10 M 95.6 3.9 99.5 0.5
Effect of pH - Constant Mixing Speed
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Attilio Citterio
Conclusions
At high mixing speed - good control Al low mixing speed - ortho isomer and bis- adduct
increase Rate of addition will be important As azo-dye precipitates, mixing worsens - viscosity
change Variation of local pH if mixing poor Variation of local temperature if mixing poor Diazotized solution should be added close to agitator tip
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Attilio Citterio
Mixing - Solid Reagents
NMe NH2
NBS
NMe NH2
Me Me
NMe NH2
BrMe
+Br
5-bromo 3-bromo
lab (solid plant (solid plant (solutionaddition) addition) addition
5-bromo 87 75 823-bromo 4 8 7dibromo 2 8.4 <1SM 7 11 7
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Attilio Citterio
Continuous processes often work when a batch process would lead to decomposition, e.g.
Answer -Continuous process
Continuous stirred tank reactor. Add Br2 and remove product at the same time, mix with ethanol and then quench.
• Lab process mix Br2/EtOAc and substrate, after 1 minute, add ethanol
• reaction autocatalytic, bromination requires H+
to start. 3rd order in substrate, Br2, HBr
• intermediate unstable in HBr; 10% loss in 2 min.
• product reacts further (CN hydrolysis) to Et ester
• if put EtOH in first, CN hydrolysis occurs
Continuous versus Batch
ArCONHCH2CN1) Br2/EtOAc
2) EtOHArCONHCH
OEt
CN
ArCONHCHBr
CN
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Attilio Citterio
Two-Phase Reactions
Rate of reaction will depend on- Interfacial area- Mass transfer rate per unit area
Mass transfer is governed by transport across thin layer adjacent to interface - diffusion
Therefore agitation may have little effect- other than on interfacial area
For good scale-up, rule-of-thumb is Ratio of INTERFACE AREA to VOLUME should be kept constant
CHEMICAL ENGINEERING ADVICE REQUIRED!
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Attilio Citterio
Main reactionAX + B AB (i)
Side reactionsAB + AX ABA (ii)AX + H2O AOH (iii)
Partition dataH2Oo / H2O w = 0.05Bo / Bw = 1AXo / Axw = ca. 104
Abo / Abw = ca. 10-4
H2O
H2O
B
B
AX
AX
AB
AB
AB (solid)
Aqueousphase
Alcoholphase
Two-Phase Reactions
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Attilio CitterioJ. Atherton, Trans. I. Chem. E., 1993 (71A), 111
Reaction in 2 Liquid Phase - Scale-up
1. Rate of (i) insensitive to agitation, provided layers are dispersed. Therefore reaction rate is slow relative to MT
2. All reaction tale place predominantly in upper (organic) phase
3. Reaction rate increased by adding saltIncrease conc. of B in upper layerLittle effect on partition of AB
4. Reaction (II) sensitive to agitationOver-agitation increases yield of productNeed just enough agitation to get good dispersion
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Attilio Citterio
Condensation Reaction
Main reactionArX + RY + M+Z- Ar-L-R + M+ + Y-
Side reactionRY + water hydrolysis product
ArX and RY are practically insoluble in water
M+Z- is an aqueous solution
QUESTION: WHETHER OR NOT TO USE A SOLVENT?
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Attilio Citterio
Scale-Up
Without solvent- After adding half reactant - phase inversion- Increase of viscosity from 5 cp to 1000 cp- Reaction rate becomes independent of agitation- Change in heat transfer coefficient
With solvent- None of the above problems- But reaction rate proportional to interfacial area
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Attilio Citterio
Change in HT Coefficient
Time (continuous reactant addition)
Hea
t tra
nsfe
r coe
ffici
ent
Phase inversion
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Attilio Citterio
Peptide Synthesis with N-Carboxyanhydrides (NCA)
Problem for Scale-up Reaction of amino-acid with NCA gives a carbamate
intermediate which can easily decarboxylate to give a new amino group
This amino group can then react with further NCA Need conditions which prevent decarboxylation of
carbamate pH control is crucial
“NCA and Related Heterocycles”H.R. Kricheddorf, Springer Verlag 1987pp. 78 onwards
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Attilio Citterio
k1 = ca. 100 l·mol-1 sec-1
k3/k1 = ca. 0.1
Peptide Synthesis with NCA
k1HN
OHO HN
O
O
O
H3C+ N
CO2
O
H3C
NH2
CO2H
k2 N CO2
O
H3C
NH2
CO2H
+
k3
HNO
O
O
H3C+
N
O
H3C
NH
CO2H
OH2N
H3C
A B R
S1
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Attilio Citterio
Selectivity vs. Stirrer Speed
% S
Speed (sec-1)
1 2 3 4
5
10
500 L GL Retread Blade5000 L GL Retread Blade
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Attilio Citterio
Selectivity vs. Stirrer Speed
% S
Speed (sec-1)
1 2 3 4
5
1060°60° Reversed90°
5000 L with variable pitch
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Attilio Citterio
Selectivity vs. Stirrer Speed
% S
Speed (sec-1)
1 2 3 4
5
10
500 Litres
5000 Litres - 1 Blade5000 Litres - 2 Blades
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Attilio Citterio
Mixing Configuration Semi-Batch Reactors
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Attilio Citterio
NH
O
O
OR
O O
CHO
NH
OH
O
OR
O O
Compound I Compound II(> 90 % pure)
• Dichloromethane solvent• Triphenylphosphine oxide• N,N’-diisopropylcarbonyl hydrazine• Formic acid
Case Study - Primaxin Intermediate
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CompoundI
TA-01
HydrolysisRE-01
HydrolysisCutsTA-02
Aq. CutsTA-03
DMCCutsTA-04
CompoundII
EvapEV-01
CompoundII
CrystCR-01
MLSTA-05
PODEX-01
CE01
HClMeOHwater
Hexane
SOLID COMPOUND II
Acid Hydrolysis Process
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Attilio Citterio
β-Ketoester Enolate salt
pH 12
pH 7
pKa = 10.5
Acidicproton
(C6H5)3PO
(CH3)2OCH-OCO-N=N-CO-O-CH(CH3)2
Methylene Chloride Aqueous
Conceptual Procedure
NO
H H
O
O
OH OR
NOO
-
O
OH OR
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Mixed Feeds, Single Stage with Solvent Backwash
POD
CE
Static Mixer
Organic Raffinate Fresh CH2Cl2
Aq. Enolate sol. Acid
SOLID COMPOUND II
AqueousMotherLiquorsAqueous NaOH
CH2Cl2Compound I
Final Design
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Attilio Citterio
Extractive vs. Acid Hydrolysis
Acid ExtractiveHydrolysis Hydrolysis
Productivity 1x 2.5xYield 81% 95%Solvent/RM HCl/MeOH NaOH
DichloromethaneHexane Phosphoric acid
Waste stream MeOH/HCl DichloromethaneWaterMeOH/water N/AVOC for DMC N/AHexane/DMC water
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CONTINUOUSDedicated processesSingle product usuallyHigh volume / low costHigh capital costSuitable for gas, liquid and solution reagents and products
Catalytic processesEquipment design criticalLong lead time for production
Good control of exotherms
BATCH/SEMIBATCHVariety of processes/Flexible
Low volume / high costRelatively low capital costSolid products easily handled
Solution phase processesQuick scale-upExothermic processes may have scale-up problemsFeedstock quality may vary
Continuous vs. (Semi)batch Processing
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Attilio Citterio
Continuous vs. Batch Process
Batch processes may be easier to scale up quickly
Scale up batch, simultaneously develop continuous
Kinetic differences (reversible reactions) can be used to advantage
Driving reactions to completion- by removal of product as it is formed (continuous)- by crystallisation from reaction solution (batch)
- by removal of byproduct as it is formed (both)
Once continuous process optimized, should remain at that level
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Attilio Citterio
Continuous vs. Batch Process
BASF: WITTIG PROCESSES
Ref. H. Pommer, Pure and Applied Chemistry, 1976, p. 527
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Attilio Citterio
Triphenylphosphine
3 PhCl + 6 Na + PCl3 Ph3P + 6 NaCl + 450 Kcal·mol-1
Very exothermic
Batch Process1. Suspend 200 Kg sodium in dry toluene and heat to pet
finely divided mixture2. Cool tp 40 °C3. Add PCl3 and PhCl, keeping temperature at 40-70°C4. Filter odd NaCl (centrifuge)5. Crystallise Ph3P by partial evaporation of toluene
OK for 100 tonnsWorry over safety for larger quantities
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Attilio Citterio
Triphenylphosphine Process
Toluene
Molten sodium
Chlorobenzene
Phosphorustrichloride
Toluene recycle
Separator
water
WaterSalt
High-boilingcompounds
Triphenyl-phosphine
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Attilio Citterio
Wittig Reaction
Ph3P+-CH2R + NaOMe Ph3P+--CHR + R’CHO RCH=CHR’
Batch Process1. Phosphonium salt in methanol or DMF2. Cool to - 30°C, add sodium methoxide
Strong exotherm, ylid unstable; viscous solutionDifficult to control and scale-up
3. Add aldehyde, exothermic reaction, viscous gelMixture; difficult to control
Overall VariableDifficult to controlWorry about safety
Therefore continuous process for large scale
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Attilio Citterio
Aqueous sulphuricacid
Phosphonium saltmethanol
AldehydeMethanol
Sodium methoxidesolution Extractant
PRODUCTWaste watertreatment
Wash liquidMixer
Mixer
Extraction column
Continuous Wittig Synthesis
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Attilio Citterio
Case Studies
The importance of mixing in scale-up will be addressed in some (or all, if time) following examples
1. Removal of by-products during the scale up of a process for the synthesis of the coccidiostat (Merk) 9-(2-chloro-6-fluorobenzyl)-adenine
S.H. Dan, I. Chem. E. Symp. Ser. 87, p.337L.H.Weinstock J. Org. Chem. 1980, 45, 5419
2. The formation and scale-up of a reaction to produce a dipeptide, L-alanyl-L-proline
E.L. Paul, Chem. Eng. Science 1988, 43, 1773
3. The selective hydrolysis of an ester intermediate in the synthesis of the β-lactam antibiotic primaxin. The use of a novel reactor to circumvent scale up problems will be discussed.
M.L. King, Chem. Eng. Progress, 1985, p.36