The Importance of Work-Up

The Importance of Work-Up

PhD

IN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

Causes of Accidents

• As important as the reaction

• ^Affects

- Yield - Cost

- Volume efficiency - Effluent

- Recovery

• Therefore work-up should be designed

Work-Up is a Variable

• Different work-up strategies required for

- 70% yield with 30% by-products - 90% yield with 10% by-products

• Better to optimise solution yield at the end of reaction

THEN

• Optimise work-up

HOWEVER

• This strategy requires good analytical methodology

Ideal Work-Up

• Cool reaction mixture until product crystallises

• Filter off product

• Wash if necessary

• Recover solvents at later stage

• Ideal because

- Simple and cheap to operate - Quick

- Little extra raw material required (wash solvent)

- Uses same vessel as reaction - no volume increase - Solvents easily recovered

- Little influent generated

Worst Work-Up

• Pour reaction mixture into volume of water

• Extract with another solvent

• Dry with drying agent

• ^Evaporate

• Crystallise from third solvent

• Typical research chemist laboratory method

- Slow - possibility of hydrolysis during work-up on plant - Wasteful of raw materials

- Volume inefficient - needs larger vessels

- Generate large volumes of aqueous and non-aqueous effluent

- Solvents recovery difficult

Comparison of Work-Up

REACTION

FILTRATION

DRYING

A B

C

REACTION

A B C

DILUTION EXTRACTION WASHING

DRYING SOLVENT/FILTRATION EVAPORATION

CRYSTALLISATION SOLVENT RECOVERY

Helpful to Know

 Solubility parameters of

- products - by-products

in a variety of solvents

 Choose solvent for work-up reasons as well as for selectivity

 Perhaps work-up solvent can be used as reaction solvent ad wee

- A quick and easy work-up may compensate for a relatively slow

reaction

Work-Up of Water-Reactive Agents

 Often the most difficult reactions to work up

 Strong acids

- nitric, sulfuric, oleum, chlorosulphonic

 Lewis acids

- aluminum chloride, boron trifluoride

 Chlorinating agents

- thionyl chloride, sulphuryl chloride, phosphorus oxychloride

 Hydrides and water-reactive bases

- sodium hydride, sodamide, lithium aluminum hydride

Work-Up of Aluminum Halides Process

 Exothermic quench

 Emulsions, finely-divided solids

 Filtration, difficult phase separation

 PRINCIPLE: try to precipitate aluminum salts as free- flowing solid

 Add alcohol or amine first, then minimum amount of water to form a solid

 Keep temperature as high as possible

 Products remain in solution

 May be able to use without further purification

Hydride Quenches

 Sodium hydride

- Add alcohol first, then water if necessary - consider combining stages

 Lithium aluminium hydride

- Use Chemetall methods, e.g. sodium sulfate

- Precipitate aluminium / lithium salts

Destruction of Excess Reagent

 Is excess necessary for good reaction?

 For volatile reagents (e.g. thionyl chloride) best to distill off prior to quench

- May not always be possible

 In laboratory reaction mixture poured into water

 On plant this may be difficult because:

- Viscosity too high for easy transfer - Transfer hazardous

- Reaction mixture heterogeneous (e.g. Friedel-Crafts reactions,

sodium hydride alkylations)

Accidents Caused by Layering

 Example - addition of POCl

to water

 Inadequate mixing - layering

 Rate of addition requires CAREFUL control

 Cooling may INCREASE the hazard

 Accumulation

 Increased viscosity - poor mixing

 Co-solvents may help

Toluene SOCl

CO

H

R

COCl R

PT catalyst NaN

CON

R

NCO steps R

NH

R

Combination of Steps - Unstable

Intermediates

CH

Cl

ClSO

H

X X

SO

Cl

X

SO

NH HN

NH

NH

NH

H

N

Combination of Steps - Unstable

Intermediates

Combination of Steps - Unstable Intermediates

HCO

Et

Base NH

NH

H

N

CH

CO

Et CH

CO

Et

CHO N NH

O

NHR solvent

• Quench reaction 1 with methanol, not water

• Reaction 2 proceeds well in methanol-solvent mixture

Control of Particle Size of Solid Products

 Filtration of finely-divided solids causes problems on scale-up

- Binding of filter cloths and centrifuge bags

 Resolve problem in laboratory prior to scale-up

 Finely-divided nature of solids often caused by lack of control of

- Rate of addition of acid, base, solvents, etc.

- Temperature / rate of cooling

- Water content of solid

To Control Particle Size and Avoid Problems

 Add co-solvent/acid/base at as high a temperature as possible, then cool slowly

 Seeding

 Azeotropic removal of water prior to crystallisation

 Avoid using water to precipitate

 Age solid suspension at moderate to high temperature

- May cause recrystallisation or crystal growth

Control of Particle Size

 Important for filtration on plant

- Affects filtration time

- Affects filtration efficiency - Affects washing

 Therefore impurity content can be higher

 Important for drying

- Affects drying time

- Affects drying efficiency - Causes lumping

- Causes discoloration of surface

- MAY cause decomposition!

Control of Particle Size

 Affects convenience of operation on large scale

 Larger particle size products will

- filter quickly - wash quickly

- be easier to dry because they retain low solvent content

Solvent Stripping

 As concentration increases, rate of reaction (decomposition?) increases

 At low volume, heat transfer poor

- May get baking on sides of vessel

 Do not evaporate to dryness

 “Put and take”

 Remove likely reactants before work-up

 Viscous oils difficult to remove from reactor

- must redissolve

 Crystallisation during stripping

 Energy / time inefficient

Miscellaneous Useful Ideas

 Salting out

- Products in aqueous solution may be isolated using common ion effect

- Add salt to aqueous phase and allow product to crystallise - May also assist in liquid-liquid extraction

- May avoid emulsions with ternary mixtures - Useful with partially-miscible solvents

 pH control to remove impurities

-

For isolation of basic or acidic products

- By-products may be removed by careful control of pH

- knowledge of pK

of product and by-products will help

Quality Control During Work-Up

 Test stability of products to work-up conditions prior to scale-up

 Extended reaction times required to control exotherms may cause decomposition during work-up

 Need analytical methods for quantitative determination of product in solution

 Check what is happening at each stage

 Ensure product extracted into appropriate phase

CH

Cl

. HCl

CH

(NMe

)

(BDAM) N

N N H N H

O S

O

N N

N H N H

O S

O

Me

NH

C

SK&F 93479 - Final Stage

N N

N H N

H HS

O

N N

NH NH

O S

O

Me₂NH₂C

CH₂NMe₂

N N

N S N

O

O

H₂C Me₂N⁺

MERCAPTAN

Bis-MANNICH

QUATERNARY

SK&F 93479 - Impurities

SK&F 93479 - Mechanism of Quaternary Salt Formation

CH

Cl

RH

C NMe

CH

Cl

Cl

(RCH

)

NMe

Cl RCH

NMe

RCH

NMe

 Reaction done at reflux without solvent (literature)

 Starts as two phase melt, gradually thickens

 Semisolid forms, lose agitation

 On cooling reaction mix forms a glass

 Therefore difficult to scale up safely

1) PCl

/H

PO

H

N(H

C)

C

PO

H

NH

(CH

)

CO

H

2) H

O

PO

H

OH

Work Up - Synthesis of

Bisphosphonates

GR Kieczykowski, J. 0rg. Chem, 1995, 60, 8310

Merck Modifications

 Increasing H

PO

, little effect on physical characteristics but reduced yield

 Increasing PCl

- no effect

 POCI

replacing PCl

- reaction goes solid

 PPA - no reaction

 Reaction homogeneous in ethereal solvents initially, but product oils out then sets solid, agitation difficult

 High speed agitation with various solvents not successful

Methanesulfonic Acid as Solvent

• Reaction mixture remains fluid

• MSA reacts with PCl

slowly - need to keep MSA to minimum

• Reaction parameters optimised

• Reaction becomes self heating at 85°C

- uncontrolled exotherms at > 140 °C

- max. 65 °C used on scale

- J. Org. Chem. 1995, 60, 8310

Methanesulfonic Acid as Solvent

 Work up by adding water, cool, adjust pH to 1.8 - bis acid crystallised out. (82% yield, 14 Kg scale)

 Adjust pH to 4.3 to get crystalline mono sodium salt

10

Scale-Up

Dottorato

in Chimica Industriale

e Ingegneria Chimica

Physical Organic Chemistry Approach

For good scale-up

 Understand mechanism

 Understand by-products formed

 Most reactions are several steps. Which is the rate- determining step?

 Expect changes on scale-up, if conditions change

Choose good processes / routes

Scale-Up - What Goes Wrong

 Control -or lack of!

 Attention to detail

 Changes in

- Raw materials / solvents - Conditions

 Kinetics

Important to keep everything the same

Keep geometric similarity

Stoichiometry is a Variable

Depend on

 Rate of addition

 Rate of reaction

 Good mixing

May be local differences on scale up

Control stoichiometry by rate of addition

Changes in Conditions

 Time

 Stoichiometry

 Rate of addition

 Temperature (gradient across reactor)

 Concentration (to improve efficiency?)

 Mixing

All affect kinetics

Low Temp Not Always Best for Selectivity on Scale-Up

 Low solubility of reactants / products

 High viscosity of solvents

 Poor heat transfer - Exotherms difficult to control

 Poor mixing, particularly on large scale

Often scale-up problems

Are there other ways of controlling selectivity?

20-25 L Glassware

 Agitation similar to smaller glassware

 Spherical vessels

 Physical handling problems

 Flammability hazard

 Difficulty to scrubbing toxics in laboratory environment

Therefore preferable to use small vessels in flameproof

pilot plant

Research Chemist Favorites

To be designed out before scale-up

 All reactants in, then heat!

 Ether extractions

 Evaporation to dryness (then trituration?)

- sometimes even before quench - concentrates reagents

 Add solids to refluxing reaction

 Pour into water

 Hot filtration

- sometimes even before quench - concentrates reagents

 Chromatography

 Add catalyst last!

Purpose of Scale-Up to Pilot Plant

The first run on plant are experiments

 To test the process and identify problems

 To find the best way to

- handle reactants, intermediates, waste-stream and off-gases - isolate products

- filter and dry product - distill and purify product

 To gather information which may be of value in chemical

 To make batches of chemicals for evaluation or for further

Pilot plant experiments are expensive Make maximum use of each experiment

Important Differences Between Lab and Plant

• Heat transfer

• ^Agitation

• Mass transfer - affects kinetics

• ^Visibility

- of reactions - in separations

- for cleanliness check

• Separation (stirring not shaking)

From a polythene-lined fibreboard drum to a chemical reactor

Electrostatic spark

Insulating gloves and

footwear

Flammable dust cloud and solvent vapour

Manual Additions of Powder

From a vacuum filter bed dryer

Explosible atmosphere

Powder cake Filter cloth

Metal support grill

Digging off Powder Cake

Important Differences Between Lab and Plant

• ^Time

- Slower addition rates - longer work up

- (try lab experiment with pilot plant times!)

• Hazards (Toxic, Exotherm and Electrostatic)

• Off-gas treatment

• Evaporation to low volume (temp.)

• Need for good sampling techniques

Planning for Scale-Up

• Decide on process

- As far as possible do not make major changes

• Decide on batch size

• Order raw materials

- Allow for at least 10% lower yield on plant

• Test process for safety

• Discuss plant requirements and process with plant manager / engineer

• Write out detailed procedure

Planning for Scale-Up

• Prepare safety data sheets and discuss ways of handling any hazardous reagents or

intermediates

• Ensure analytical procedures are available

• Contingency

Raw Materials

• Order well in advance so that there is time to use-test before pilot runs

• Specify grades

• Try to obtain buying sample, safety data sheet, technical data and analytical methods from suppliers

• Try to find out which impurities are present but not mentioned in the specification

• Analyse all raw materials except “reactives”

• Use-test raw materials prior to scale up

• Use-test in-house intermediates

Process

• Once decided to scale-up -fix process

• Concentrate effort on ensuring scale-up of process works well, modifying only for safety reasons or convenience on plant

• Only criterion is process must be safe to scale-up

• HAZOP - what if?

• Decide where to hold process if overnight working not

encouraged

Choosing Batch Size

• Depends on availability of vessel

• Depends on production requirements

• Work out maximum volume in reaction stage and in process as a whole

• Allow for frothing, gas evolution, possibly of adding extra reagents or solvents

• Ensure volumes compatible with good agitation at all times

• May be better to transfer to larger vessel for some processes

•

Safety Test of Process

 Better carried out independently (objectivity)

Find out limits

 Modify if necessary

Plant requirements and Safe Use of Plant

 Vessels

- Size

- Material of construction - Cooling capacity

- Temperature range (steam, oil) - Agitation

- Charging of reagents

 Filter / centrifuge

- Size

- Materials

- Easy of filtration (particle size)

Plant requirements and Safe Use of Plant

 Distillation

- Short-path - Fractionation - Column packing

- Compatibility with ceramic / steel

 Drying

- Vacuum or air

- Tray, rotary, fluid-bed - Hazards / limits

 Instrumentation

- Measurements (temp, pH, etc.)

- Safety cut-outs, pressure relief

Plant requirements and Safe Use of Plant

 Scrubbing

Effluent disposal

 Miscellaneous

- Gas addition

- Materials handling and transfer

Material of Construction

 Stainless steel

- Low temperature work - Good heat transfer

- Agitation better than glass-lined - Organometallics (Grignards, BuLi) - Unsuitable for strong acids

- Acetic acid OK

- Some compounds pick up iron (phenols, oximes)

 Hastelloy C

- Good heat transfer and agitation - Compatible with almost chemicals - Expensive

Material of Construction

 Glass-lined steel

- Suitable for most compounds - Easy to keep clean

- Strong alkali attacks glass - Attacked by fluoride

- Temperature limitation

- Need to check periodically for continuity of glass

 Fluoroshield

- Compatible with most chemicals - Poor heat transfer coefficient - Useful for fluorochemistry

 If in doubt about compatibility - check

Medium Concentration Temperature

Aluminium chloride 10% 20°

Formic acid 60 % boiling

Hydrazinium sulphate 10 % boiling

Nitration mixture 5% HNO₃, 30 % H₂SO₄ boiling Nitration mixture 50% HNO₃, 50 % H₂SO₄ 20°

Nitric acid 65 % boiling

Nitric acid 99% 20°

Oxalic acid 10% boiling

Phosphoric acid 80 % boiling

Potassium bisulphate 2 % 90°

Sulphuric acid 10 % 70°

Sulphuric acid 2.5% boiling

Tartaric acid 25 % boiling

P Hydrochloric ac!d 0.5 % 50°

P Hydrofluoric acid 10 % 20°

Media that Attack 316 Stainless Steel

Medium Concentration Temperature

Anilinium hydrochloride 5 % 20°

Caustic potash molten molten 380°

Caustic soda molten molten 318°

Chromium trioxide 50% boiling

Nitric acid 99% boiling

Phosphoric acid 80% boiling

Sulphuric acid 5% boiling

Trichloracetic acid any conc. 20°

P Aqua regia n/a 20°

P Chlorosulphonic acid 10% 20°

P Cupric chloride 1 % 75°

P Cupric chloride cold saturated 20°

P Ferric chloride 10% 20°

P Hydrochloric acid 10% 60°

P Hydrochloric acid 2% 20°

Media that Attack 316 Stainless Steel

Chemical Resistance of Hastelloid C-276

 Mineral acids

- Resistant to all concentrations below 50°C in the absence of oxygen or oxidising cations [Fe(III)]

 Halogens and halide

- Resist attack by elemental halogens incl. fluorine - Attacked by fluorinating agents like SbF

or SbCl

- Resists hydrogen halides

- Resists cupric and ferric chloride, but not in the presence of additional hydrochloric acid

 Oxidizing agents

- Oxidative attack requires presence of acids or Lewis acids

 Synergistic effects

Prepare Detailed Procedure / Record Sheet

List

Equipment / size

 Raw materials required

 Ancillary equipment / services

 Safety equipment

Write Out Detailed Procedure

 Cleaning check

 Preparative work (melting acetic acid)

- Preparation of scrubbers

 Charging and weighing

 Temperature control limits

 Acceptable times

 Sampling; in-process checks

 Transfers

 Work-up and isolation

 Drying

 Effluent

Prepare Idiot’s Guide

 Assume nothing!

 Leave space to record

- All measurements - Weights / volumes - Timings

- Results of in-process checks - Rates of addition (tabulate) - Unexpected events

 Specify and highlight

- Safety procedures

- What to do if spillage occurs

Prepare Safety Data Sheets

 Discuss handling of toxics and corrosives

 Literature search for compatibility of reagents

 Manufacturer’s data

- Some excellent, some useless

 Source books

 Common sense (comparison with known compounds)

 Example of data sheet

 Toxics

- Danger mainly from volatiles and dusts/powders - Inhalation

- LD (oral, rodent) may not give much guidance

Example of MSDS

Analytical Procedures

 For raw materials (buying spec?)

 Product

 In-process checks (quantitative methods)

- Always follow reaction in plant - check reaction has started

 Sampling - retain samples at as many points as possible

- To investigate when problems arise

 Criterion for completion of reaction (not time)

- Test for when to begin work-up

 Effluent analysis

- To decide disposal route

Contingency Plans

 Exotherms

 Reaction doesn’t proceed to completion

- Work-up?

- Add more reagents?

 Spare raw materials in stock?

 Overnight working!

 Spillage of toxics / corrosives

 Pressure build-up

 Gas release

Actual Run in Pilot Plant

 Observe

 Measure and analyse

 Record data and make notes

 If things start to go wrong

- change process?

- or accept low yield?

 BE THERE

Troubleshooting

1. Quality control and contamination issues

 Raw material quality has changed

 Reagent quality has changed

 Solvent contaminated / quality change

 Equipment contaminated

 Identify cause of problem by

- Use tests

- Retaining samples during batch for later evaluation

Troubleshooting

2. Scale-up issues

 Time change

 Rate of addition

 Mixing different

 Heat transfer different

 Need to identify by-products (if formed)

Troubleshooting

3. Equipment / control issues

 Temperature control (dual measurement)

 Instrumentation (calibrated?)

 Gas addition (dip pipe, sparging?)

 Liquid addition (dip pipe, metering?)

 Agitation (varies from vessel to vessel)

 Crystallisation / particle size