CHEMICAL ENGINEERING (CII)

Appreciation of Chemical Engineering Principles

PhD

IN INDUSTRIAL CHEMISTRY AND

CHEMICAL ENGINEERING (CII)

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

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

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

Heat Transfer Equation

Where:

q = heat flux (heat transfer per unit area) k = thermal conductivity

T = temperature y = distance

dT/dy = temperature gradient across the reactor

q k dT

= − dy

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

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)

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

Reactor HT Area Size (L) m

m

·L

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

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

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 r

 Removal of heat proportional to surface area

- therefore proportional to r

 Therefore as vessel size increases, volume-to-surface ratio also increases

 Therefore control of heat transfer becomes more difficult

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

 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

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

Heat Balance of a Stirred Tank Reactor

Influence of the coolant temperature

Rate of heat production

Rate of heat loss A

C k

B

1

2

T

T

T

T

( )

QR R A

r = ⋅ ∆ V H − r dq

dt

T

( )

QW A A

r = U ⋅ T − T

Influence of the HT parameter

Rate of heat production

Rate of heat loss A

k

(U

) > (U

)

T

T

T

(U

)

(U

) < (U

)

Heat Balance of a Stirred Tank Reactor

( )

QR R A

r = ⋅ ∆ V H − r

( )

QW A A

r = U ⋅ T − T

No Accumulation Accumulation

Addition of reactant

Time g

q_R Heat release rate

Heat of reaction

Time g

Addition of reactant

q_R Accumulate heat

at the end of addition Heat

release rate

Thermal Accumulation

Temperature

Time Desired

reaction

2 ∆T

Normal process

Cooling failure

Reaction of decomposition

3

1 TMR

T

Thermal Runaway

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?

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

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

Grignard Requires THF Solvation for Stability

Reagent 4 kg

Mg 560 g

THF 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

onset 140°C

Low solvent 691 J·g

320°C

High solvent no decomp. at 140°C

Aryl Grignard

50 100 150 200 250 300 °C

20 m W

Delta H 4192 mJ 437.6 J·g^-1 Peak 210.0 °C

8.8 mW

Integration (est.) Delta H 6624 mJ

691.4 J·g^-1 Peak 339.7 °C

32.6 mW

Grignard reaction. Sample 2. File: 05120.001 DSC METTLER 22-Sep-04 9.580 mg Rate: 5.0 °C·min^-1 Ident: 2.0 Graphware TA72

DSC of a Grignard Reaction

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

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

vortex

Swirl

Flow Pattern in an Unbaffled Tank

baffles

Flow Pattern in an Baffled Tank

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

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

- turbine flow

 Service

- homogenization

- suspension of solids

- liquid-liquid and solid-liquid dispersion

- heat transfer

- chemical reaction

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

- laminar or turbulent flow

 Service

- homogenization

- liquid-liquid and solid-liquid dispersion

- heat transfer

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

- transitory or laminar flow

 Service

- homogenization - heat transfer

- chemical reaction

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

- transitory or laminar flow

 Service

- homogenization of viscous products

- heat transfer

- chemical reaction

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

 Service

- homogenization

- suspension of solids

- solid-solid and gas-liquid dispersion - heat transfer

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

- turbulent flow

 Service

- homogenization - suspension of solids

- liquid-liquid, solid-solid and

gas-liquid suspensions

- heat transfer

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

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

- transitory or turbulent flow

 Service

- homogenization - suspension of solids

- liquid-liquid, solid-solid and gas- liquid suspensions

- emulsion - heat transfer

- chemical reaction

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 v

• 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” N

• For scale-up, if pilot vessel designed so that N

is the same as in the

lab, then equivalent mixing is likely

Reynold Number N

D = diameter of vessel

v = average velocity of fluid ρ = density

µ = viscosity

• ^N

has NO dimensions

• Change from laminar to turbulent flow

usually occurs around same values of N

- N

< 2100 laminar - N

> 2100 turbulent

Re

N D v ρ µ

= ⋅ ⋅

Viscosity and Mass Transfer

• For high viscosity applications (N

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

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!

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

Bulk Mixing

• Mixing times:

- 500 ml flask 2 - 3 seconds - 40 m

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

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

- 10

cm

• Time-scale for homogenization (by molecular diffusion) is

of the order of 0.1-1 sec

k

/k

= 10

NO₂⁺ +

NO₂⁺ +

NO₂

NO₂

O₂N k₁

k₂

P. Rys (ETH), Helv. Chim. Acta, 1977 (60), 2937 Arc. Chem. Res., 1976 (9), 345

Micromixing - Nitration of Durene

• ^With

- equimolar reagents - slow rate of addition - good mixing

would 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

A + B C A + C D

k

k

k

>> k

t

t

t

Eddy size 10

- 10

cm Diffusion time 0.01 - 1.0 sec

φ

= R

k

B/D

Micromixing

A =

B =

C =

D =

Mixing Effects - Bromination

MeO OMe

Br₂

MeO OMe

Br

OMe OMe

MeO OMe

Br OMe + Br

Stirrer Starting mono di

Speed Material bromo bromo

0 22.2 57.9 19.9

213 19.9 61.3 18.8

425 18.3 64.5 17.2

638 13.6 73.4 14.8

1063 13.5 73.4 13.1

O

O(H)

OH

O(H) + H+

1a 1b

O

2bO(H)

O

4bO(H)

O

6bO(H)

Br Br

Br

Br Br

Br

OH

3aO(H) Br

OH

5aO(H) Br

Br

OH

6aO(H) Br Br

Br

- H⁺ - H⁺ + H+

Bromination of Resorcinol

J.Garcia-Rosas, Chimia,

1990, 368

Concentration of

NaOH is critical

Agitator Speed Mono Bis % ortho

1000 94.5 5.5 9.7

2000 95.3 4.7 9.1

6000 96.7 3.3 8.7

OH OH

N N Ph PhN₂⁺

+

OH

N N Ph OH

N N Ph

N N Ph NaOH

Influence of Mixing on Product Ratio

mono bis para ortho total

0.025 M NaOH 86.2 9.1 95.3 4.7

At 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 bis

para ortho total

0.025 M NaOH 88.0 8.7 96.7 3.3

At 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 bis

para ortho total

0.025 M NaOH 90.0 7.5 97.5 2.5

At 8000 rpm 0.05 M 95.6 3.9 99.5 0.5

Effect of pH - Constant Mixing Speed

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

Mixing - Solid Reagents

Me N NH

NBS

Me N NH

Me Me

Me N NH

Br Me

Br +

5-bromo 3-bromo

lab (solid plant (solid plant (solution addition) addition) addition

5-bromo 87 75 82

3-bromo 4 8 7

dibromo 2 8.4 <1

SM 7 11 7

Continuous processes often work when a batch process would lead to decomposition, e.g.

Answer -

Continuous process

Continuous stirred tank reactor. Add Br

and remove product at the same time, mix with ethanol and then quench.

• Lab process mix

Br

/EtOAc and substrate, after 1 minute, add

ethanol

• reaction autocatalytic, bromination requires H

to start. 3

order in substrate, Br

, 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

ArCONHCH₂CN 1) Br2/EtOAc 2) EtOH

ArCONHCH OEt CN

ArCONHCH Br CN

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!

Main reaction

AX + B AB (i) Side reactions

AB + AX ABA (ii) AX + H

O AOH (iii)

Partition data

H

O

/ H

O

= 0.05 B

/ B

= 1

AX

/ Ax

= ca. 10

Ab

/ Ab

= ca. 10

H

O H

O

B B

AX AX

AB

AB AB (solid)

Aqueous phase

Alcohol phase

Two-Phase Reactions

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 salt

Increase conc. of B in upper layer Little effect on partition of AB

4. Reaction (II) sensitive to agitation

Over-agitation increases yield of product

Need just enough agitation to get good dispersion

Condensation Reaction

 Main reaction

ArX + RY + M

Z

Ar-L-R + M

+ Y

 Side reaction

RY + 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?

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

Change in HT Coefficient

Time (continuous reactant addition)

He a t tr a n s fer c oe ff ic ie nt

Phase inversion

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 1987 pp. 78 onwards

k

= ca. 100 l·mol

sec

k

/k

= ca. 0.1

Peptide Synthesis with NCA

k

HN

O

HO HN

O O

O H

C

+ N

CO

O

H

C

NH

CO

H

k

N CO

O H

C

NH

CO

H +

k

HN

O O

O H

C

+

N O H

C

NH

CO

H

H

N O H

C

A B R

S

Selectivity vs. Stirrer Speed

% S

Speed (sec

)

1 2 3 4

5 10

500 L GL Retread Blade

5000 L GL Retread Blade

Selectivity vs. Stirrer Speed

% S

Speed (sec

)

1 2 3 4

5 10

60°

60° Reversed 90°

5000 L with variable pitch

Selectivity vs. Stirrer Speed

% S

Speed (sec

)

1 2 3 4

5 10

500 Litres

5000 Litres - 1 Blade

5000 Litres - 2 Blades

Mixing Configuration

Semi-Batch Reactors

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

Compound I

TA-01

Hydrolysis RE-01

Hydrolysis Cuts TA-02

Aq. Cuts TA-03

DMC Cuts TA-04

Compound II Evap EV-01 Compound

II Cryst CR-01 MLS

TA-05

POD EX-01

CE 01

HCl MeOH

water

Hexane

SOLID COMPOUND II

Acid Hydrolysis Process

β-Ketoester Enolate salt

pH 12 pH 7

pK_a = 10.5 Acidic proton

(C

H

)

PO

(CH ) OCH-OCO-N=N-CO-O-CH(CH )

Methylene Chloride Aqueous

Conceptual Procedure

N

O

H H

O O

OH OR

N

O

O

O

OH OR

Mixed Feeds, Single Stage with Solvent Backwash

POD

CE

Static Mixer Organic

Raffinate Fresh CH₂Cl₂ Aq. Enolate

sol. Acid

SOLID COMPOUND II Aqueous

Mother Liquors Aqueous NaOH

CH₂Cl₂

Compound I

Final Design

Extractive vs. Acid Hydrolysis

Acid Extractive

Hydrolysis Hydrolysis

Productivity 1x 2.5x

Yield 81% 95%

Solvent/RM HCl/MeOH NaOH

Dichloromethane

Hexane Phosphoric acid

Waste stream MeOH/HCl Dichloromethane Water

MeOH/water N/A

VOC for DMC N/A

Hexane/DMC water

CONTINUOUS

Dedicated processes Single product usually High volume / low cost High capital cost

Suitable for gas, liquid and

solution reagents and products Catalytic processes

Equipment design critical

Long lead time for production Good control of exotherms

BATCH/SEMIBATCH

Variety of processes/Flexible Low volume / high cost

Relatively low capital cost Solid products easily handled Solution phase processes Quick scale-up

Exothermic processes may have scale-up problems Feedstock quality may vary

Continuous vs. (Semi)batch

Processing

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

Continuous vs. Batch Process

BASF: WITTIG PROCESSES

Ref. H. Pommer, Pure and Applied

Chemistry, 1976, p. 527

Triphenylphosphine

3 PhCl + 6 Na + PCl

Ph

P + 6 NaCl + 450 Kcal·mol

Very exothermic

Batch Process

1. Suspend 200 Kg sodium in dry toluene and heat to pet finely divided mixture

2. Cool tp 40 °C

3. Add PCl

and PhCl, keeping temperature at 40-70°C 4. Filter odd NaCl (centrifuge)

5. Crystallise Ph

P by partial evaporation of toluene

OK for 100 tonns

Triphenylphosphine Process

Toluene

Molten sodium Chlorobenzene

Phosphorus trichloride

Toluene recycle

Separator water

Water Salt

High-boiling compounds

Triphenyl-

phosphine

Wittig Reaction

Ph

P

-CH

R + NaOMe Ph

P

-

CHR + R’CHO RCH=CHR’

Batch Process

1. Phosphonium salt in methanol or DMF 2. Cool to - 30°C, add sodium methoxide

Strong exotherm, ylid unstable; viscous solution Difficult to control and scale-up

3. Add aldehyde, exothermic reaction, viscous gel Mixture; difficult to control

Overall Variable

Difficult to control Worry about safety

Therefore continuous process for large scale

Aqueous sulphuric acid

Phosphonium salt methanol

Aldehyde Methanol

Sodium methoxide

solution Extractant

PRODUCT Waste water

treatment

Wash liquid Mixer

Mixer

Extraction column

Continuous Wittig Synthesis

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.337 L.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.