Appreciation of Chemical Engineering PrinciplesProf. Attilio CitterioDipartimento CMIC “Giulio Natta”http://iscamap.chem.polimi.it/citterio/dottorato//

PhDIN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

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

Attilio Citterio

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

Attilio Citterio

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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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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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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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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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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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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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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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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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

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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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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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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Change in HT Coefficient

Time (continuous reactant addition)

Hea

t tra

nsfe

r coe

ffici

ent

Phase inversion

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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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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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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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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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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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Mixing Configuration Semi-Batch Reactors

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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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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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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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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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Continuous vs. Batch Process

BASF: WITTIG PROCESSES

Ref. H. Pommer, Pure and Applied Chemistry, 1976, p. 527

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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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Triphenylphosphine Process

Toluene

Molten sodium

Chlorobenzene

Phosphorustrichloride

Toluene recycle

Separator

water

WaterSalt

High-boilingcompounds

Triphenyl-phosphine

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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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Aqueous sulphuricacid

Phosphonium saltmethanol

AldehydeMethanol

Sodium methoxidesolution Extractant

PRODUCTWaste watertreatment

Wash liquidMixer

Mixer

Extraction column

Continuous Wittig Synthesis

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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