Chapter 4: Molecular and Mixture Design

10/4/2022
Outline of this Lecture

Chapter 4
Introduction & Overview
Molecular and Mixture Design: Framework for Computer-Aided Molecular-Mixture Design
• Molecular Structure Representation
Part 1 • Generation of Molecule-Mixture Candidates
• Property Prediction
• CAMD/CAMbD Problem Formulation
• Software for CAMD/CAMbD Problem Solution
• CAMD/CAMbD Solution Approaches
Case Studies – Solvent Substitution, Refrigerant Design etc.
Mohd Asmadi Bin Mohammed Yussuf

School of Chemical and Energy Engineering
Universiti Teknologi Malaysia, 81310 UTM
Johor Bahru, Johor, Malaysia
Overview
Overview Identical molecules in Molecular

2 classes of product products
and chemical products
Objectives Different molecules Mixture-blended
present as a liquid
solution/blend
product
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Important Questions Overview

MANY ways to design Framework based on
molecular & mixture products computer-aided methods
How to generate BUT we ONLY consider and software
How to represent chemically feasible
the structure of a candidate molecules and 1 2
molecule? mixtures?
Identify promising design LATER stage, verify experimentally
alternatives - model-based verify fine-tuned
How to estimate the How to formulate
computer-aided techniques
properties of and solve typical molecular
molecules and and mixture design
mixtures? problems?
Employed first to quickly & reliably Focused experiments performed on
reduce search space within which identified set of promising
optimal designs likely to be found. alternatives.
Learning Outcomes
Recognize characteristics of single molecules and liquid mixtures

1 as products.
Ability to convert the needs-functions of a product to the

2 properties of single molecules or liquid mixtures.
Familiar with computer-aided methods and software that are

Introduction
3 applicable for selection, design, and analysis of these products.
Able to select, design, and analyze products composed of the
4 same molecule throughout the product.
Ability to select, design, and analyze liquid products composed of

5 a mixture of different molecules.
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Molecular and Mixture Products Cont.

Molecular Molecular
products products
Molecular and
(liquid) mixture
products
B2B
Type
Molecular and
(liquid) mixture
products
B2B
Type
Applications Applications
In process Incorporated in other
industries
Molecules and/or chemicals-based
mixtures eventually products
incorporated in the final
help to manufacture a product and have a specified
Mixture-blended
desired chemicals-based function in the product.
products
product
Types of Molecular Products Solvents

B (B, C) Usually employed as the
main active ingredient of Good example
Three types of molecular chemicals-based products.
For both molecular and
products of varying size and mixture products
molecular structural
complexity (C) May be manipulated to obtain a
specific product function Process industries
A Feasibility of downstream product depends on successful performance of

solvent-based operation in a process manufacturing the product.
(A) Usually have process-
related applications or may be
C Mixture-blend design
part of a mixture-formulated
Examples - separations, cleaning operations, and organic synthesis – in
product each operations, desired solvents perform different functions.
Feasibility of the chemical product manufactured through the solvent-

Different chemicals are blended
to obtain a liquid solution
based process depends on the successful selection-design of the solvent
product with desired properties
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Cont. Single Molecular Products

Good example
For both molecular and mixture
products
Refrigerants and/or Heat-Pump Emulsifiers
Incorporated in Formulated Products
Fluids
Role: absorb and release energy in Surfactants that create
different states defined by changes in an emulsion
Example – in cosmetic products such as lotions
temperature and pressure in the
 function: deliver active ingredient to skin and then leave by refrigeration or heat-pump cycle.
evaporation.
Active Ingredients
Performance of the product depends on the function of the selected Chemicals performing the
solvent (molecular or mixture).
Important Issue main function of a chemicals-
Need to perform specific functions based product, as in drugs and
related to their properties as pure cosmetics
chemicals and/or as species in mixtures
of chemicals
Molecular Design Problem Mixture-Blend Design Problem
Important Issue
These properties differ based on their need-
functions in a processing operation or in a
Need to perform specific functions
related to their properties as pure
chemicals and/or as species in mixtures
Need-functions of
product =
X Properties of a
single molecule
Mixture of different
molecules are
considered
of chemicals
downstream product
Perform Operation
A typical molecular design problem is Examples - blends of solvents, lubricants, and process fluids,
defined as:
Perform Function
Given a set of building blocks and a specified set of target Examples - additives to fuels, solvent blends in paints,
properties, determine the molecule that matches these and aroma blends in cosmetic products.
properties.
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Cont. Needs-Function
Applications of Define their Define the set of properties
mixture need-functions the blend must provide to
products perform its functions.
Many types of mixture-blended products

A single-molecule solvent product must at least be a
 This chapter – only mixture-blends that are stable liquid
solutions are covered. liquid at the condition of application and must
The typical mixture-blend design problem is defined as: dissolve an assigned solute.
What should be the

Given a set of chemicals and a specified set of property
constraints, determine the optimal mixture and/or required properties of the
blend
solvent?
Property Values Molecular Structure

How to obtain?
• Property data or estimates only - insufficient
Measured experimentally
Retrieved from a database of measured data • Method needed to generate molecular structures - employing
appropriate building blocks - can be combined to form molecules
Calculated through the use of appropriate property models through a set of rules that ensure their molecular stability
• Some property models also require structural data -

advantageous to use these building blocks to predict
For a computer-aided technique molecular properties
• Must include a database of measured property values
complemented by a library of property models to predict property • Given these estimates, generated molecules can be
values not available in the database. checked for matches with target property values
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Molecular Structure for Mixture-Blended Essential Ingredients for Molecular Design

Products
• For mixture-blended products - molecules in mixture and their
compositions must be confirmed to satisfy liquid-phase stability Molecular Design
criterion at a specified temperature
1) Method to represent stable molecular structures
2) Method to generate chemically feasible molecules
• Appropriate property models - estimate needed property values -
generated mixtures to be tested for matches with target property 3) Methods to estimate the required properties.
values.
Mixture Design
1) Method to generate stable mixture-blend candidates

2) Methods to estimate the needed properties.
Cont. Framework for CAMD & CAMbD (Next Part)

• Framework for computer-aided molecular design (CAMD) and
mixture-blend design (CAMbD) is described
Because the number of generated, • Subsections :

chemically feasible molecules or mixtures 1. Molecular structure representation
can be very large, a systematic framework to
2. The generation of molecule-mixture candidates
generate the molecular structures and test
their properties, using the appropriate 3. Property prediction
computer-aided methods and software, is 4. CAMD/CAMbD problem formulation
needed. 5. Software for CAMD/CAMbD problem solution
6. CAMD/CAMbD solution approaches
• Case studies - solvent substitution, refrigerant design, active

ingredient design, tailor-made gasoline-blend design etc.
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Activity 1: Translating Needs-Function into

Properties (25 mins)
INSTRUCTIONS
• Given the list of needs-functions (application) of a molecular product
Chapter 4
(single type of molecules), translate it into a measurable properties.
• Provide 3 example molecules (existing organic chemicals) which can satisfy Molecular and Mixture Design:
the needs-function and provide the values of the properties.
• Post the answers in Jamboard.
Part 2
HERE ARE THE LIST OF GENERAL CASE STUDY APPLICATIONS:

1) A solvent must be in a liquid form at the extraction process of 25 °C
2) To avoid harmful condition, especially when a process is near to ignition
sources, the solvent used in the process must be non-flammable
3) Perfume is a mixture of fragrant oils in a solvent. When the perfume is Mohd Asmadi Bin Mohammed Yussuf
sprayed, the solvent needs to be evaporated right away, leaving the School of Chemical and Energy Engineering
fragrant compound in the perfume Universiti Teknologi Malaysia, 81310 UTM

Framework for Computer-Aided Molecular-Mixture Design
• Molecular Structure Representation Framework for Computer-
• Generation of Molecule-Mixture Candidates
• Property Prediction Aided Molecular-Mixture
• Software for CAMD/CAMbD Problem Solution Design
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Computer-Aided Framework for Molecular-Mixture Example: Application of the Framework for CAMD
Design
• OBJECTIVE - to find environmentally friendly substitute molecules for
Start benzene (only the concept is highlighted)
No suitable
solutions (due to
Step 1, 2 Step 3, 4
performance,
Candidate Selection
economic or safety Problem
(final verification/
concerns) formulation
comparison using
(identify the goals
rigorous simulation
of the design
& experimental Promising operation)
procedures) candidates have
been identified
Result analysis and Method and
constraint selection
Verification
(specify the design
Step 5
(analyze the
Finish suggested criteria based on
the problem
compounds using
external tools) formulation)
CAMD Solution
(identify compound
having the desired
properties)
GCA: Group Contribution Assembly
Problem Formulation and Pre-Design Phase Example of Goals of CAMD: Removal Phenols
• Description goals of CAMD can be of different types - few examples
• Design process - starts with definition of basic needs (or ultimate given
goals)
• Type of goal - influence design decisions need to be made in "Find a solvent suitable for removing phenol from a waste water
later phases stream by liquid-liquid extraction. The solvent should pose a low
• Should describe: health risk for the users, should be environmentally friendly and
1. Function of desired chemical product could be a single molecule or a mixture."
2. Environment/equipment where the function should be
performed
• Well-defined problem - almost all necessary details
3. Capabilities that are desirable/undesirable. are given.
• Example – for design of solvents • Properties needed - solubility, EH&S properties,
1) Must dissolve a specified solute(s)
liquid immiscibility, etc., can be identified.
2) Must be selective if other soluble solutes are also present • Goal values for properties are not given - but need to
3) Must not cause a negative environmental impact find best solvent - then must highest solubility and
4) Should be easy to recover. least environmental impact.
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Example of Goals of CAMD: Benzene Example of Goals of CAMD: Solvents Use for
Washing off an Equipment
"Identify a molecule(s) with the same pure component
properties as benzene, such as normal boiling point, "Find a solvent to be used for washing off an equipment
normal melting point, octanol-water partition (for example a printing press) which is environmentally
coefficient, solubility parameter as that of benzene but friendly and cheap."
with a much lower environmental impact in the work
place."
• Problem is not very well defined
• While some constraints are defined, one piece of
• Another well-defined problem important information is missing. What is it?
• What should be dissolved by the solvent?
• Goal values given because the • Definition of 'cheap' depends on the process
property values of benzene are involved as well as the current solution used
already known.
Example of Goals of CAMD: Solvents Use for Example of Goals of CAMD: Inhibition Activity
Washing off an Equipment
"Find a molecule that will have inhibition activity
"Find an additive (molecule or mixture) for a tape so that
the tape will stick to a painted surface for a year and then against Alzheimer's disease."
can be removed without pulling off the paint."
• Very well defined in terms of property – but
difficult to solve - because of potential search
• Another example of a not very well-defined space.
problem
• Because we need more information on the • If add -"search only among isomers of X” where
glue that will be added to the tape "XX" is a particular molecular type
• As well as the various compositions of paints  Then - well-defined problem, even though
where the tape will stick. number of possible isomers may be large &
• The main question here is which properties are prediction of inhibition activity as function of
we looking for and what are their goal values? molecular structure may be quite difficult.
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Example of Goals of CAMD: Azeotrope Problem Formulation and Pre-Design Phase
Find all molecules that form an azeotrope with ethanol at • Examples (previous slides) highlight need for a knowledge-
based system
a pressure of 1 atm.
 to identify needed properties from general problem
specifications presented
• Not a typical product design problem
• CAMD can also solve problems like this
• Then, their goal values need to be specified & methods for
• Not well defined – large search space obtaining the necessary property values need to be selected.
• If we select a molecule type (for example, acyclic hydrocarbons
of molecular weight less than 100) - becomes well defined.
• Qualitative problem specification needs to be transformed
into a quantitative problem specification.
Translate Properties/ Constraints

Needs/goals/
Qualitative Convert Quantitative
Methods and Constraint Selection

Activity 2: Problem Formulation (15 mins)
• Objective - transform qualitative problem specification to quantitative
- suitable for CAMD problem solution during design phase. INSTRUCTIONS
• Given the list of products to be designed, write problem
formulations which are considered well-defined.
• The quantitative problem specification consists of:
1. Identify needed properties
 This matches the qualitative specification with behavior (properties) of the • Write in a paper, take a picture of it and submit in the Jamboard.
chemical product. Write “Activity 2” and your name.
2. Identify goal values of needed properties
 Matches actual goal of product with respect to its function & behavior.
HERE ARE THE LIST OF PRODUCTS TO BE DESIGNED:
3. Identify methods for obtaining property values
1) Hand sanitizer
 Determines how property (behavior) of product are obtained.
4. Identify building blocks for generation of molecular 2) Air freshener
structures or candidate chemicals for mixture design 3) Hair cream
 Determines search space and scale of molecular structural model. Example: Water purifier-Target to find the water filter that can remove both organic and metal ions from water (just
like examples from previous slides)
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Methods and Constraint Selection
Translate Properties/ Constraints

Needs/goals/
Qualitative Convert Quantitative
Methods and Constraint The quantitative problem specification consists of the following:
Selection Identify needed properties (behaviour) of product
Identify goal values of needed properties
Identify methods for obtaining the property values
Identify building blocks for generation of molecular structures or

candidate chemicals for mixture design
Translation of Product Need to Target Properties Translation of Product Need to Target Properties
Need to have a knowledge base • Another option, collect necessary data from:
• To assist transformation of general qualitative Published expert-insights

problem specifications into quantitative,
suitable for CAMD problem solution Open source database
• A lot of work need to be done to prepare a knowledge base (and
time consuming) Patents
 Necessary to gather information from consumers in terms of
basic needs - main functions of products & additional needs – to Published articles etc.
improve product quality)
 Know-how to translate the consumer needs into target
properties.
• To prepare the translation of needs to properties
• Expert would be able to provide this knowledge if necessary data is
available.
tables
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Knowledge Base Examples Translation of Product Need to Target Properties

Need Target Properties Gasoline Jet Fuels Diesel Gasoline based products:
Ability to be Reid vapour pressure (RVP) √ √ √ • High Reid vapour pressure to ensure fuel is sufficiently
burned ASTM distillation temperature (T) √ √ √
vaporized to be burned & engine can start at operating
Safety Flash-point (Tf) √ √ √
temperature;
Engine Higher heating value (HHV) √ √ √
efficiency Density (ρ) √ √ √
Research octane number (RON) √ • Low viscosity - fuel can flows smoothly from fuel tank to
Cetane Index (CI) √ combustion chamber.
Consistency of Dynamic viscosity (η) √
fuel flow Kinematic viscosity (V) √ √
Melting point (Tm) √ • Must be stable:
Stability Miscibility √ √ √
o Should not evaporate easily;
Environmental Oxygen weight content (WtO2) √
effects
o Do not oxidize to form unwanted by-products
Human toxicity (Lethal √ √ √
concentration) (-logLC50) (gums/sludge/deposits during storage;
√
CO2 emission in the combustion o Must not split into two liquid phases.
engine (CO2e)
Translation of Product Need to Target Properties Translation of Product Need to Target Properties
Diesel based products: Jet fuel based products:

• Surrogate blends of diesel must have: • Operated at low temperature above ground - blends
1. Low Reid vapour pressure; of jet-fuel should have:
2. High flash-point temperature; 1. Low Reid vapour pressure to prevent evaporative

losses & fuel system vapour lock;
3. Low viscosity;
2. High flash-point temperature;
4. Low environmental impacts as well as human toxicity
3. High HHV to maximize energy that can be stored in
a fixed volume & provide longest flight range;
4. Low melting point to prevent formation of wax
crystals - difficult to pump into turbine engines;
5. Low greenhouse gas emissions
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Knowledge Base Examples Translation of Product Need to Target Properties

Lubricant blends:
Lubricant Blends • Principal function - reduce resistance
Need Target Properties & prevent wear between two moving
Ability to lubricate and prevent wear Kinematic viscosity (V)
surfaces.
• Needs - obtained through knowledge
Friction coefficient (μtot)
base, literature search & legislation
details.
Ability to flow at the ambient temperature Pour point (PP)
• Must able to resist a high temperature, flow continuously at
Non-flammable Flash-point (Tf)
a low temperature & non-flammable.
Handling purpose Density (ρ)
• Density of base oils is also considered for handling purposes.
Liquid at ambient temperature Melting point (Tm)
• Different upper & lower bounds of target properties listed
Heavy component Molecular weight (Mw) may be specified to obtain different varieties of blended
Not easily vaporize Normal boiling point (Tb) products.
Knowledge Base Examples Knowledge Base Examples
Root
Solvent Design: Solvent Design – Property Classification

Unit
Process Fluid Essential Desirable EH&S
Operation
• Hierarchical system • Function of desired • Performance or efficiency of a product in a • Associated with performance of product in
product specified application. a specific operation or function & its effect
LLE VLE SLE
• Application types of on surroundings as result of their use &
• Related to phase • Sill acceptable if these properties are not emission.
solvent-based process at Not Solvent-
behavior or driving matched.
Solvent-Based forces for separation • May be specified as essential, desirable
the top Based
operation • Important during selection of feasible and/or undesirable.
candidates & during performance evaluation -
• Properties & property Homogenous Heterogeneous
Extractive
Distillation Absorption
Supercritical
Fluid
• Example - molecule must to determine optimal design. • Placed as separate class - methods for
in liquid state at their direct estimations are usually not
values at the bottom Extraction
temperatures of process • Fixed lower or upper limits cannot usually be available.
EH&S Desirable Essential
set for these desirable properties.
Properties Properties Properties • Requirements - boiling • May be considered in post-design phase
point of molecule > • To have highest or lowest possible value for through database search or even through
temperature while identified desirable properties direct or indirect experiments.
Pure Pure Pure melting point is below.
Properties Properties Properties • Example - selectivity towards a specified solute • Potentially expensive analysis is reserved
• If molecule is to be used that must be extracted from a mixture through only for those candidates that satisfy all
Mixture Mixture Mixture as a solvent for L-L a solvent-based extraction process such as LLE other product criteria.
Properties Properties Properties extraction - it must
cause a phase split & • For convenience, the undesirable properties are • Some essential and desired products may
have density different also be included in this class of properties. implicitly also satisfy the EH&S & special
from solutes. property constraints - smell, colour and
taste.
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Knowledge Base Examples Knowledge Base Examples

Solvent Design – Property Classification
• Some mixture properties - solubility may be calculated as function of primary
properties
• Example - estimation of solute solubility through solubility parameters (SP).
Solvent Design:
• SP is both a functional (temperature dependence) & secondary property • For functional properties, the CAMD problem specification
(function of molar volume & ∆Hv needs to specify range of conditions where these properties
• SP becomes primary if T is fixed to 298 K & if it directly correlated as function of must be matched
molecular structure
Essential,
Desirable, EH&S • Intervals of conditions of operation as a function of
temperature, pressure and/or composition.
Pure
Mixture
Component
Functional Functional Secondary Primary
Knowledge Base Examples Essential & Desirable Properties as Function of

Application Type
• May also include tabular data
Separation Technique Class Phases Involved L-L Extractive Azeotropic Solid Gas
Properties
Extraction Distillation Distillation Separation Absorption
Crystallization Property difference Solid-Liquid
Pure E D E D E D E D E D
Distillation Property difference Vapour-Liquid
∂ √ √ √ √ √ √ √ √
Extractive Distillation Solvent-Based Vapour-Liquid
τ √ √
Azeotropic Distillation Solvent-Based Vapour-Liquid-Liquid μ √ √
Liquid-Liquid Extraction Solvent-Based Liquid-Liquid Tb √ √ √ √ √
Supercritical Extraction Solvent-Based Fluid-Vapour-Liquid Tm
ρ √ √ √ √
Pv √
• Properties important to function in a particular application
listed along relative property differences needed to perform Hvap √ √
function & associated phases involved in particular
application
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Essential & Desirable Properties as Function of

Application Type • EH&S properties given as general guidelines based on phases involved
applications listed in previous table
L-L Extractive Azeotropic Environmental Concern
Properties Solid Separation Gas Absorption
Extraction Distillation Distillation Properties Health Safety Environment
Mixture E D E D E D E D E D Toxicity √ √
Selectivity √ √ √ √ √ Biological Persistence
Implicit
Chemical Stability √ √
SL √ √ √
Reactivity √
SP √ √ √ √ √ Biodegrability √ √
DC √ √ √ Pv √ √ √
H (in water) √
Phase Split √ √ √ √
Log P √ √
Azeotrope √ √ Log Ws √ √
Explicit
ρm √ Flash Point √
BOD √
μm √ ρ (vapour) √ √
H √ LD 50 √ √
ODP √
References Activity 3 (In-class and continue outside class) :

Mini Knowledge Base (20 mins+)
1. Harper, P. M., M. Hostrup, and R. Gani, A Hybrid CAMD INSTRUCTIONS
Method, Computer-Aided Chemical Engineering, 12, 129 • In your team, prepare a preliminary or mini knowledge base (tables
(2002). with needs, properties and values if possible), based on the
products that have been assigned to you during the “problem
formulation” activity.
2. Kalakul S, Zhang L, Fang Z, Choudhury HA, Intikhab S,
Elbashir N, Eden MR, Gani R: Computer Aided Chemical
Product Design – ProCAPD and Tailor-Made Blended • Here are the product assignment for each team:
Products, Comput Chem Eng 2018, 116:37-55. 1. Teams 1-5 – Hand sanitizer
2. Team 5-8 – Air freshener
3. Lei Zhang, Habitat Mao, Qilei Liu and Rafiqul Gani, Chemical 3. Team 9-14 – Hair cream
Product Design – Recent Advances and Perspectives,
Current Opinion in Chemical Engineering 2020, 27:22–34
• Submit through the link provided (padlets)
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Chapter 4

What’s Next? – Problem Formulation What’s Next? – Problem Formulation

Algorithm Algorithm
• Database - type of molecules vs building Molecule Building
• To transform qualitative problem specification into a quantitative blocks vs EH&S properties helps in Type Blocks
one through a combination of knowledge base, insights and problem formulation
Acyclic
experience hydrocarbons
CH3, CH2, CH, C
• Alcohols & acids - linked to automatic
Aromatic CH3, CH2, CH, C, ACH, AC,
selection of OH & COOH groups in the hydrocarbons ACCH3, ACCH2, ACCH
• Multi-step process - different levels of information set of building blocks
Alcohols CH3, CH2, CH, C, OH
• Aromatic compounds - carcinogenic, Ketones
CH3, CH2, CH, C, CH3CO,
chlorides - cause corrosion & have CH2CO
• Summary:
negative impact on environmental CH3, CH2, CH, C, CH3COO,
Esters
Identify known properties of Obtain system temperature Identify important pure and indicators. CH2COO, HCOO, COO
compounds to be used with pressure, composition mixture properties for the Acids CH3, CH2, CH, C, COOH
designed compound ranges in system system
• Choice of EH&S properties as constraints
Identify property models List the molecule types that Create list of building blocks - automatic exclusion of corresponding
available for estimation of can be handled by the used to assemble molecules compounds & building blocks.
the properties. property models in design phase.
• Next – design phase of CAMD method
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Design Phase-Molecular Representation

• Design phase – objective: to apply a suitable method for
generating feasible candidates
• Feasible candidates - set of molecules (or mixtures) that satisfy

all property constraints and reflect optimal performance
Molecular Structure
• Representations of molecules:
Representation
• Simplest form
A C5H10O2 • Based on chemical formula
• Compound represented by types of atoms
• it contains and number of occurrences
• But - no information on the bonds in compound.
Molecular Representation Molecular Representation
• A group vector, contains some of this

2 CH3 C
BHC C O • Collection of functional groups or
1 CH2 connectivity information, but does not
fragments define it completely.
2 1 CH2COO
O • Molecular fragment or substructure
• Defined by number and types of atoms

• A group vector can represent isomers
• Showing how atoms are connected
D
• Illustrates the different compounds
• How many free bond connections and its location
that can be represented using the
group vector in C.
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Adjacency Matrix Fragment-Based Matrix
• Knowing the valence of the different atom types in the molecule, it • Can be expressed using fragments or atoms
is possible to generate the bond configurations.
• Conversion from a fragment-based matrix to an atom-

• The compounds depicted in D have the connectivity defined. based matrix is achieved by replacing the entry for each
fragment with the atom adjacency matrix representing the
• Simple & flexible way to define connectivity - ADJACENCY MATRIX fragment
CH3 CH3 CH2 CH2COO

• Square symmetrical matrix with rows & columns representing
each atom (or fragment) in the molecule and containing
E CH3 0 0 0 1
CH3 0 0 1 0
1. Nonzeroes indicating the number of bonds
CH2 0 1 0 1
2. Zeroes indicating the number absence of bonds CH2COO 1 0 1 0
Atom-Based Matrix Molecular Representation

H H H H H H H H H H C C C C C O O • To distinguish between isomers - need to have 3D information
F H 0 1
• Adjacency matrix expressed
using atoms for the compound
about atom placements.
H 0 1
H 0 1
D
• 3D - adjacency matrices with a list of x, y, z Cartesian coordinates
H 0 1
for atoms are possible.
H 0 1
H 0 1 • 2D relations between atoms -
H 0 1 no steric information to • Internal coordinate system - atom positions defined using bond
H 0 1 distinguish isomers. length & angle & torsion angle, is used.
H 0 1
H 0 1 • Choice of representation depends on computations to be
C 1 1 1 0 1 performed involving 3D representation.
C 1 1 1 0 1
C 1 1 1 0 1
• Examples (3D) - structures of compounds (molecules) developed
C 1 1 1 0 1
using appropriate descriptors together with an algorithm to
C 1 0 1 2
construct 3D structures of compounds & estimate their physical
O 1 1 0
properties.
O 2 0
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Molecular Structures & Estimation of Activity 4: Molecular Structure Representation

Properties at 4 Levels (20 mins) (For tutorial)
3 4
2 • For these two chemicals: 1) Propylamine 2) Ethyl benzoate,
provide the molecule representation using the following:
1
1) Chemical formula
2) Group vector (refer group list in Table 4.2 in text book)
Just representation of molecules by functional groups (Level 2) is
employed for our class ! 3) Fragment-based adjacency matric
4) Atomic-based adjacency matric
• Write the answers in a piece of paper. Submit a scanned copy

through the provided link.
Generation of Molecular Structures

Objective – given functional groups as building blocks & a set of rules
to combine them into chemically feasible molecules – generate
candidate structures
• Rules - limit combinations of groups to those in chemically feasible

Generation of Molecule- molecules, fewer than total number of unrestricted combinations.
Mixture Candidates Example:

Given the groups CH3, CH2 and OH, how many chemically stable molecules
can be generated with a minimum of two groups, a maximum of three
groups, and the condition that the OH functional group appears no more
than once?
Answers:
CH3-CH3, CH3-OH,
CH3-CH2-CH3, CH3-CH2-OH
OH-OH, OH-CH3-OH,
CH2-CH2-CH3
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Generation of Molecular Structures Recall Example

• To ensure molecules are chemically feasible, the following rules must Given the groups CH3, CH2 and OH, how many chemically stable
be satisfied - Odele & Macchietto (1993) molecules can be generated with a minimum of two groups, a
maximum of three groups, and the condition that the OH functional
• m = number of distinct groups in basis set; group appears no more than once?
2− =2 (1)
• q = [−1, 0, 1] for [bicyclic, monocyclic, acyclic];
• nj and ni = number of groups j and i present in Groups (i, j) uj n jl n ju
≥ −2 +2 ∀ (2) molecule; CH3 1 0 2
≤ ≤ ∀ (3)
• uj is the valence of group j i.e., the number of free CH2 2 0 2
bond connections)
OH 1 0 1
2≤ ≤ (4) • nmax = maximum number of groups allowed
(specified) in molecule;
• m=3
• n = number of groups present in a specific molecule; • q = -1(bicyclic), q = 0 (monocyclic), q = 1 (acyclic)
= (5)
• njl and nju = lower and upper bounds (specified) on • nmax = 3
number of allowed groups of type j, respectively.
Cont. Cont.
=
[1] for acyclic
2≤ ≤
Number of groups present
in a specific molecule Rules
Chemically
2− =2 ≥ −2 +2 ∀ ≤ ≤ ∀ Possible Molecules
Feasible
(1) (2) (3) (4) (5)
Possible Group Rules
n q CH3-CH3 ✔ N/A ✔ ✔ ✔ ✔
Molecules Vector (1) (=2q) (2) (3) (4) (5)
CH3-CH3 2 CH3 2 1 (2-1)2 = 2 N/A CH3: 0 ≤ 2 ≤ 2 2≤2≤3 2
CH3-OH ✔ ✔ ✔ ✔ ✔ ✔
1 CH3 CH3 (j): 1 ≥ 1(1-2)+2 CH3: 0 ≤ 1 ≤ 2
CH3-OH 1 OH 2 1 (2-1)1 +(2-1)1 = 2 2≤2≤3 2
OH (j): 1 ≥ 1(1-2)+2 OH: 0 ≤ 1 ≤ 1
2 CH3
CH3-CH2-CH3 ✔ ✔ ✔ ✔ ✔ ✔
CH3 (j): 1 ≥ 2(1-2)+2 CH3: 0 ≤ 2 ≤ 2
CH3-CH2-CH3 1 CH2 3 1 (2-1)2+(2-2)1= 2 2≤3≤3 3
CH2 (j): 2 ≥ 1(2-2)+2 CH2: 0 ≤ 1 ≤ 2
1 CH3 CH3 (j): (1+1) ≥ 1(1-2)+2 CH3: 0 ≤ 1 ≤ 2
CH3-CH2-OH ✔ ✔ ✔ ✔ ✔ ✔
1 CH2 (2-1)1+(2-2)1+(2-1)1
CH3-CH2-OH 3 1 CH2 (j): (1+1) ≥ 1(2-2)+2 CH2: 0 ≤ 1 ≤ 2 2≤3≤3 3
1 OH =2
OH (j): (1+1) ≥ 1(1-2)+2 OH: 0 ≤ 1 ≤ 1 OH-OH ✔ N/A ✘ ✔ ✔ ✘
OH-OH 2 OH 2 1 (2-1)2 = 2 N/A OH: 0 ≤ 2 ≤ 1 2≤2≤3 2
1 CH2 CH2 (j): 2 ≥ 1(2-2)+2 CH2: 0 ≤ 1 ≤ 2 OH-CH2-OH ✔ ✔ ✘ ✔ ✔ ✘
OH-CH2-OH 2 OH 3 1 (2-1)2+(2-2)1 = 2 2≤3≤3 3
OH (j): 1 ≥ 2(1-2)+2 OH: 0 ≤ 2 ≤ 1
2 CH2 CH3 (j): 2 ≥ 1(1-2)+2 CH3: 0 ≤ 2 ≤ 2 CH2-CH2-CH3 ✘ ✘ ✔ ✔ ✔ ✘
CH2-CH2-CH3 1 CH3 3 1 (2-2)2+(2-1)1 = 1 2≤3≤3 3
CH2 (j): 1 ≥ 2(2-2)+2 CH2: 0 ≤ 1 ≤ 2
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Activity 5: Molecular Structure Generation

Generation of Molecular Structures
(20 mins)
• Number of molecules generated for a larger set of functional • Given the basis set of groups: (CH3, CH2, CH2O, CH3O). The last two
groups is enormous. groups are common in ethers.
Group Valence Group Valence
• Even with the basis set in the (uj) (uj)
1. List down 10 possible combinations (without checking its available
table, millions of chemically CH3 1 COOH 1
valence electron) with a minimum of two groups and a maximum
CH2 2 CH3COO 1
feasible molecular structures of three groups
CH 3 CH2COO 2
can be generated C 4 CH3O 1
ACH 2 CH2O 2 2. From the list, how many are chemically feasible molecules
AC 3 COO 3 (satisfying Eqs. 1–5 by Odele and Macchietto)?
OH 1 CH3N 2
CH3CO 1 CH3NH 1
CH2CO 2 CONH2 1 • Discuss in your team and show your calculations and answer clearly
CHO 1 CONHCH3 1 using Excel. You can use the free version of Zoom or Webex to discuss.
Submit the Excel files through the provided link below
Generation of Mixture-Blend Structures Generation of Mixture-Blend Structures

Given a basis set of n molecules, determine mixtures containing mmax ≥ m ≥ Example:
2 that are stable liquid solutions at given conditions of temperature and Given the molecules, methanol [OC; 000067-56-1], ethanol [OCC; 000064-17-
pressure, where mmax = maximum no. of molecules and m is the actual 5], benzene [C1CCCCC1; 000071-43-2], and water, find stable liquid binary and
number in the solution. ternary mixtures at 298 K and 1 atm
Example: • Solution
Given the molecules, methanol [OC; 000067-56-1], ethanol [OCC; 000064-17-
5], benzene [C1CCCCC1; 000071-43-2], and water, find stable liquid binary • For each mixture, to ensure liquid-phase stability, the following criterion
and ternary mixtures at 298 K and 1 atm. must be satisfied for all mixture compositions:
For stable liquid solutions
Answers: ∆
= + < 0 (7) ∆G = Gibbs energy of mixing;
Methanol-ethanol, GE = excess Gibbs energy due to mixing
Methanol-benzene, xi = mole fraction of compound i
where
Ethanol-benzene, (8) NC = number of compounds
=
Methanol-water, γi = liquid-phase activity coefficient of compound i
Ethanol-water, and
Methanol-ethanol-benzene
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∆
= + < 0 (7)
Example:
where Which binary pairs in a mixture of methanol, ethanol, benzene, and
= (8)
water are unstable at temperature = 298 K and pressure = 1 atm?
• The equation is easily checked for binary mixtures to establish miscibility
(stability) • There are six binary pairs:
1. Methanol-ethanol,
• Multicomponent mixtures - each binary pair is checked first for 2. Methanol-benzene,
miscibility
3. Methanol-water,
• If any pair is found to be unstable, then corresponding multicomponent
4. Ethanol-benzene,
mixture is likely to be unstable 5. Ethanol-water, and
6. Benzene-water
• Equation - not a sufficient condition - only a necessary condition for
stability • For each pair, an equimolar mixture is tested for stability – results
shown in table
• Checks at equimolar binary composition are usually sufficient to identify
phase instability when it arises

• Benzene-water pair = unstable
• Since, benzene-water is unstable
• Multicomponent mixtures containing
• Solution this pair – unstable • Solution
• Therefore, only 7 liquid solutions are
• Size of mixture-blend design problems
potentially stable, with only 4
depends on n and mmax
potentially unstable.
• For n molecules, total number of
binary mixtures is given by Σj (n–j) • In general, total number of mixtures
may be very large.
• Similarly – no. of ternary mixtures
(mmax = 3), quaternary mixtures (mmax
= 4) can be calculated • However, when instability is detected
in binary mixtures, the number of
• This example - 6 binary pairs, 4 ternary feasible multicomponent mixtures
mixtures, and 1 quaternary mixture; a may be reduced dramatically.
total of 11 mixtures
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Chapter 4

Target and Selection Properties

• Target properties - pure compound & mixture properties
• Selection of property estimation models to predict –

issues: application ranges, availability of parameters & and
uncertainties
Property Prediction • Application range - limits size of search space
• If parameters not available – related molecules/mixtures

must be removed from list of candidates - eliminate
potential optimal products
• Estimation models with fewer parameters & larger

application ranges are needed.
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Property Arrangement Task Classification of Properties
• Estimation task -
arranged hierarchically Properties can be classified as:
based on computational
Primary
effort & cost
• Single-value properties - calculated using structural information only
• Computationally Secondary
intensive calculations - • In addition to structural information, usually a function of other
for candidates satisfied properties
all targets using simpler
property models. Functional
• Pure-compound properties that depend on the intensive variables,
temperature, and/or pressure
Mixture
• In addition to structural information, depend on the intensive
variables, temperature, pressure, and composition
Relationships Among Properties, Property

Models for Primary Properties
Models, Solvers, & Calculation Algorithms
• Property models that employ structural variables are
• To estimate properties - first
appropriate
property model is selected
• Group-contribution (GC) approach based on MG method –
o Simple,
• For phase-equilibrium-related
mixture properties - solution
o Accurate, and
algorithms employed that require o Extensive group-parameter tables for broad arrays of
estimates of other properties. properties & molecules.
• Required property estimates

• These property prediction models have the form:
ordered & calculated according to
hierarchy
• where f( ) is a function of primary properties
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Property Prediction Model List of the Primary Properties
• Partial list of the primary properties for MG model
• Ci - contribution of first-order group of type i that has Ni occurrences,

• Dj - contribution of second-order group of type j that has Mj
occurrences
• Ek - contribution of a third-order group of type k that has Ok
occurrences, in molecular structures of pure compounds.
Steps to Use Primary Property Models Example

Example: Estimate Normal Boiling Points
Application - four steps: Estimate the normal boiling point of butanoic acid, di-
Identify functional groups (first, and if necessary, second, and third- isopropyl ester [CCCOC(=O)CCC(=O)OCCC; 000925-15-5]
1 order groups) using the M-G method and group-contribution
Determine how many groups of each type are needed to represent parameters
2 molecule
Solution
Retrieve parameters from model parameter tables for properties of
3 interest. Identify functional groups (first, and if necessary, second, and
third-order groups)
Sum the contributions and use the corresponding property model
4 functions.
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Solution Polymer Repeat Units Primary Properties

• For primary properties of polymer repeat units, GC-based methods
1. Identify functional groups (first, and if
such as by van Krevelen and MG method adapted for polymers can used
necessary, second, and third-order
groups)
Example: Estimate Glass-Transition Temperatures
Estimate the glass-transition temperature for the polymer repeat unit
[—(CH2CH2CHCl)—].
Solution
Activity 6: Primary Property Prediction

Cont.
(20 mins)
[—(CH2CH2CHCl)—]
The experimental data for 2-ethylpentanoic acid is hardly available in
any database, therefore we need to predict it using available models.
Estimate the
a) normal boiling point,
b) normal melting point,
c) heat of fusion
for 2-ethylpentanoic acid, CCCC(CC)C(=O)O; CAS: 020225-24-5, using the
Marrero-Gani model
• Refer to the given Marrero-Gani 2021 paper, to extract the group

contribution parameters
• In your solution, show clearly the steps that need to be followed in

predicting primary properties
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Chapter 4

Models for Secondary Properties Example 4.11 (Text Book)

• Secondary properties are functions of other properties.
• Three steps needed
Select an estimation method and property model for specific

1 property.
Identify the properties data needed to use model and verify

2 the application range of estimation method for chemical
species of specific types.
Retrieve from a database or predict the necessary properties

3 (to be used as input).
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Example 4.12 (Text Book) Example 4.13 (Text Book)
Step in Functional Property Models Example 4.14 (Text Book)
Models for Functional Properties

For properties of interest, following steps are recommended:
1 Check a database(s) for availability of correlation coefficients.
2 If available, use the corresponding correlation.
3 Else, use models based on the principle of corresponding states, if

available for necessary properties.
4 Otherwise, collect experimental data and regress parameters for a

preferred correlation.
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Cont. Models for Functional Properties
When correlations are employed, follow this guidelines:
1 Always check the correlation limits and extrapolations beyond the

limits.
Always try to check whether sufficient accuracy is provided within
2 these limits.
When correlations are not available, try to check the estimates
3 with experimental data, when available.
4 Perform cross-validation, if possible.
Models for Mixture Properties 1. Functional Mixture Properties
• Compounds & their composition in mixture – known, with phase

• Commonly encountered in chemicals-based product design:
identity
1) Functional properties for mixture in specified phase (e.g., • At known temp., pure-compound property, i, for each compound
bulk density & enthalpy of mixture) needs to be estimated.
2) Phase equilibrium–related properties of compounds in • Using a mixing rule, bulk property of mixture, M, is calculated:
mixture (e.g., liquid-phase activity coefficients for species in 0 E 0 E
mixture, saturation temperatures - bubble- and dew-point • M= + where and are ideal & excess mixing terms.
temperatures) • When excess mixing term can be neglected, bulk mixture property is
simply the molal average of the pure-compound properties:
• M = Σi ( ixi)
• To calculate mixture properties, pure-component properties are
needed with calculation algorithms & equation solvers • Models for excess property terms vary with property & specific phase
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2. Equilibrium-Based Mixture Properties Cont.

• i - liquid-phase activity coefficient
• Estimated when two or more phases are of compound i;
in equilibrium. • i - fugacity coefficient of
compound i in vapour phase; Pisat -
• Iso-fugacity criteria for pure-compound vapour pressure at
1. vapour-liquid equilibrium (VLE), temperature,
2. liquid-liquid equilibrium (LLE), and
3. solid-liquid equilibrium (SLE) are: • T; xi, yi - liquid & vapor mole fractions of compound i;
• Tm - melting point of solid solute;
• ΔHfus - heat of fusion of solid solute;
• R - universal gas constant.
• Superscripts I and II - first and second liquid phases,
• Superscript V - vapor phase
• NC - number of compounds in the mixture.
The Needed of Specifications, Properties, &

Cont.
Property Model Parameters
• Appropriate iso-fugacity equation is selected
• Together with mass balances (involving a feed stream and two • Examples of needed specifications, properties, property model
effluent streams), along with mole fraction summations (equal unity parameters for two-phase equilibrium calculations.
for each stream) - solved by appropriate solver.
1. Solution of VLE
 Bubble-points, dew-points, VLE phase diagrams.
2. Solutions of LLE
 Amount & composition of each liquid phase
3. Solution of SLE
 Saturation temperature-composition curves,
solubility of solid solute in the solvent.
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Chapter 4

Mathematical Formulations of Molecular

and/or Mixture Design Problems
• Molecular & mixture design problems - described in context of a

generic mathematical representation:
CAMD/CAMbD–Mathematical o x - vector of continuous
variables such as
Formulations of Molecular and/or  flow rates, conditions of
Mixture Design Problems operation, design variables
o y - vector of measured-
controlled variables
 composition, temperature,
pressure, etc.
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Mathematical Formulations of Molecular Mathematical Formulations of Molecular

and/or Mixture Design Problems and/or Mixture Design Problems
• C - vector of constant coefficients

• Eqs. (4.22)–(4.25) bound the four
classes of property models
• Y - vector of binary integer (primary, secondary, functional, and
variables (such as unit operation mixture)
identity, descriptor identity,
• - vector of molecular structural
compound identity)
parameters
• - vector of properties
• Eq. (4.21) - process model • Eqs. (4.26) & (4.27) - molecular and
equations with u, d, and , flowsheet feasibility rules,
vectors of input variables, respectively
manipulated-design variables, and
property values, • B - matrix of constant coefficients

• Many variations of this mathematical formulation may be

derived to represent different molecular-mixture design
problems. Examples:
• D - vector of constant coefficients
• f(x) - linear or nonlinear portion of The Selection Problem

objective function
• Find molecules that satisfy a set of target properties; that is,
satisfy only Eqs. (4.22)–(4.25).
• For process optimization, f(x) is
usually a nonlinear function.
• Molecular structure generation is not necessary. Problem solved
by simply searching within an appropriate database.
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The Selection-Design Problem The Process-Product Design Problem
• Molecular structures are generated • Feasible molecules need to satisfy process-related
• Eq. (4.26) ensures chemical feasibility of generated molecule specifications in Eqs. (4.21) and (4.27), in addition to
and tested for matches with desired properties - Eqs. (4.22)– satisfying Eqs. (4.22)–(4.26).
(4.25).
• Most common CAMD/CAMbD problem. • Involves simultaneous design of product & process that
produces it
The Optimal Design Problem

The Optimal Process-Product Design Problem
• In addition to satisfying Eqs. (4.26) and (4.22)–(4.25),
molecular structure that maximizes the profit function - Eq. • All of Eqs. (4.20)–(4.27) apply.
(4.20) is desired.
Mixture Design Algorithm Level 1: Pure-component Constraints.
• Employs decomposition method - design problem is decomposed

into four sub-problems
Level 1: Pure-component Constraints.
• Pure-component properties of chemicals in
database and main ingredients (MI)
compared with respect to target values
• Initial screening is performed to remove
compounds unlikely to be present in the
blend.
• This step is applied only for linear target
properties.
• For remaining compounds, all feasible
binary mixtures are generated.
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Level 2: Stability Analysis Level 3: Linear Constraints
Level 2: Stability Analysis.

• The stability test [Eqs. (4.7)–(4.8)] is
performed for binary mixtures. Level 3: Linear Constraints.
• The result indicates the miscibility of the • Mixture compositions are adjusted
binary pairs, either totally miscible,
partially miscible, or immiscible.
giving the desired mixture
properties using ideal mixing rules
• Only total and partially miscible mixtures
are retained.
[Eq. (4.16)].
Mathematical Formulations of Molecular

Level 4: Nonlinear Constraints
and/or Mixture Design Problems
• Mixture Design Algorithm Level 4: Nonlinear Constraints.

• The nonlinear property models
are included and an NLP problem
is formulated and solved.
• The resulting mixtures satisfy all

linear and nonlinear constraints
(property models).
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• g3 - vector of linear constraints

in Table 4.8, g4 - vector of
mole, weight, or volume
fractions.
• Solution of this problem is a range of compositions for each blend within which
all linear property constraints are satisfied.
• Stability test performed for all feasible mixtures - those not found to be
miscible rejected.
• Because a reliable model to calculate the extent of oxidation is not available,
compound selection is made without knowledge of the ability of compounds to
oxidize into unwanted by-products.
Product-Design Problems Solved Using CAMbD Minimum Cost Additive (Solvent Mixture)
• A very wide range of chemical (formulation) product-design
• Paints and coatings need additives (usually solvent mixtures) - target
problems is solved using CAMbD. Examples:
properties - include time as a variable (example: solvent evaporation
rate).
Solvent Mixture: • When not possible to satisfy product needs

• Consider adding additional chemicals to the original solvent with a single solvent, a solvent mixture is
sought.
• When cost (of process and/or solvent) can be reduced
without having a negative effect on the solvent functional • Optimal solvent mixture must satisfy property
properties constraints and be the lowest-cost solvent
mixture.
• Or when multifunctional properties are desired (example:
solvent for one solute & anti-solvent for another solute). • Important design steps - product formulation
• Important design steps - product formulation and testing, and testing, product manufacturing - not an
product manufacturing - not an important issue. important issue
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Polymer Formulations Oil Blends

• Mixing of crude oils from different locations to obtain specified
• Properties and performance of polymer formulations (such as characteristics is a routine operation in refineries.
blends, composites, reactive systems, lubricants, plasticizers) -
critically dependent on structure or morphology
• Such operations often provide well defined mixture design
problems.
• But a specific combination of raw
materials and processing is
required to obtain superior • Good property models are usually available, with the design
performance. step (defining the optimal quantities of each oil in the blend)
being most important.
• In addition to product formulation

& testing, processing is also an
important issue.
Specific Examples:
Additives in Specialty Chemical Products
Pesticide Delivery and Uptake
• Many complex mixtures (such as dispersions, flavours, perfumes)
used in the paper, food, cosmetics, agrochemicals, textiles, and • Problem involves formulating an additive to a pesticide
health-care industries are first manufactured as liquid (complex) product that increases its uptake into plants.
products but delivered as emulsions, liposomes, or dry granules
with well-defined properties.
• Also, to control release of pesticide, problem involves
formulating a polymer-based membrane that achieves a
• Here, multiscale models may be needed, with the formulation desired rate of release.
and testing steps being most important.
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Specific Examples:
Drug Delivery and/or Application
• Formulating an additive to a drug, permitting it to form an

emulsion that can be applied on surface (skin) and that
evaporates at a desired rate.
Software for
• Additive compounds should be miscible with each other, should
evaporate when exposed & form an emulsion with drug CAMD/CAMbD
(product) - solid.
Software for CAMD/CAMbD 1. The CAPEC Database

• The database contains a large collection of pure compound and mixture
• Several software packages are used to solve various types properties organized with a specially developed ontology for efficient data
of CAMD/CAMbD problems, a few of which are briefly management.
described here.
• These are not commercially available, but readers can
obtain an education license for noncommercial research
and education.
1. The CAPEC Database

2. CAPEC Property-Prediction Software
3. ProCAMD Software
4. VPPD-Lab Software
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2. CAPEC Property-Prediction Software 3. ProCAMD Software

• CAPEC property-prediction software integrates the CAPEC database • This software implements the work-flow shown below.
together with a large collection of pure-compound and mixture property • It has built-in solvers for CAMD, and has links to other software (for the
models. CAPEC database and CAPEC Property Prediction).
Start
No suitable
solutions (due to
performance,
Candidate Selection
economic or safety Problem
(final verification/
concerns) formulation
comparison using
(identify the goals
rigorous simulation
of the design
& experimental Promising operation)
procedures) candidates have
been identified
Result analysis and Method and
Verification constraint selection
(analyze the (specify the design
Finish suggested criteria based on
the problem
compounds using
external tools) formulation)
CAMD Solution
(identify compound
having the desired
properties)
4. VPPD-Lab Software Cont.
• Implements the so-called Virtual Product-Process Design

laboratory
• Incorporates all software mentioned above, together with

tools for formulation design modeling, and simulation of
product performance (that is, how the product performs when
applied).
• For mixture design, VPPD-Lab allows the user to perform

virtual experiments to rapidly identify the most promising
candidates for future verification and selection using
experimental measurements.
38
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Chapter 4
Molecular and Mixture Design:
Part 7
ICAS

Outline
Molecular
• and Mixture Framework for Computer-Aided Molecular-Mixture Design
Molecular Structure Representation
Design Generation of Molecule-Mixture Candidates
Property Prediction
Instructor: CAMD/CAMbD Problem Formulation
Dr. Azizul Azri Mustaffa Software for CAMD/CAMbD Problem Solution

School of Chemical & Energy Engineering CAMD/CAMbD Solution Approaches
Universiti Teknologi Malaysia
1 2
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Outline ICAS Software Version 18

• Developed by the Computer-Aided Process-Product Engineering Center
Software for CAMD/CAMbD Problem Solution - ICAS (CAPEC), Technical University Denmark
CAPEC Database
• ICAS – Integrated Computer Aided System
ProPred
• Integration of tools
Utility – SLE, VLE, LLE
• Not a commercial software, not quite
ProCAMD stable and can be not very user friendly
Covered by Dr. Alafiza
ICAS Software Version 18 ICAS Software Version 18

• Main interface • User may decide to use the tools in a stand-alone
mode or in an integrated mode.
• The tools listed under task manager may be used on
a stand-alone mode
• Tools list in the second menu-bar on the top of the
screen may be used in an integrated manner.
40
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ICAS Software Version 18 CAPEC Database

• CAPEC database: Static database of pure component properties, mixture • To investigate the database for compound information
properties and model parameters. • To add a compound using ProPred
• ProPred: Pure component property estimation and analysis. Can also be • Edit the created compound
connected to external molecular modeling programs such as CHEM3D.
• Create a compound by cloning an
• Utility: Phase diagrams, phase equilibrium calculations and functional pure existing compound.
component properties
• ProCAMD: Design/selection of compounds (such as solvents) with desired
properties through computer aided molecular design.
• Manuals: (C:) > CAPEC > ICAS > docs > manuals
CAPEC Database CAPEC Database

To search database • Select “Add/Edit compound using ProPred” Draw Cumene in the ProPred
• Launch the CAPEC DB Manager interface.
• Select “Basic Search” and enter “Cumene” • Close the ProPred window and return to the CAPEC DB Manager.
as search criteria. Search the base by clicking “Search CAPEC DB” • Inspect/alter the data in the property pages.
• Select “View Compound” to examine the data. • Commit the changes by clicking “Add/Update Data”
To add new compound • Return to the “Basic Search” feature and redo the search for “Cumene” –
• From the Menu > Database > Select Change base to user.mdb now the new added compound appears as well.
• Select “Add new compound” and enter the “Cumene – special version” as To clone existing compound
name. • As an alternative to adding a compound by using ProPred one can “Clone” a
compound instead.
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CAPEC Database ProPred

• To estimate properties of a molecule: 1) draw the
• Select “Change Compound Data” molecular structure using the drawing tools OR 2) import
• Find “Cumene” in the databank the SMILES description of the molecular structure.
• Select “Clone Compound” – the compound will be cloned into a new • Working area in ProPred is divided into two parts – a
compound ready for editing. properties area and a drawing area.
• Then prompted give the “new” compound a name.
• Select a target database where the compound will be cloned. This should
always be the USER database.
• The data are automatically written.
ProPred ProPred
• For any structure present in the drawing area, the corresponding property values • Right click in the drawing area, select “Import” →
will be shown in the properties area. “SMILES” and then write or paste the SMILES description.
• Properties are calculated with 4 methods – Marrero & Gani (2001), Constantinou
& Gani (1994), Joback & Reid, and, Wilson.
• Properties ordered in terms of primary properties, secondary properties and
functional properties.
• Importing the SMILES description of the molecule can also draw the same molecular • Press OK and ProPred will now draw the molecule and show the calculated
structure. properties.
• SMILES - simplified molecular-input line-entry system – another way to • Example, predict properties for: 1) Salicylic Acid, 2) Ibuprofen, 3) Diphenylamine
represent molecular structures
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Organic SLE Organic

SLE
• Use of the SLE tool-box to calculate solid solubilities as Step 1: Problem set-up –
well as binary SLE phase diagrams (temperature versus draw stream, select
compounds, and double
composition) click on the stream to
define stream conditions
Example system:
Benzene & Phenol
Organic Organic Step 3.1: From the

“property” menu, first
SLE SLE click on “selection of
Step 2: The menu for “mixture thermodynamic model”
specifications” comes up. Give
estimates of temperature,
pressure and component flows
(or mole fraction) & then click
on “property”
Step 3.2: In the “selection of thermodynamic

model” menu, select the appropriate models –
in this case, the “gamma-phi” option
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Organic Organic
SLE SLE
Step 3.2: Select the liquid phase model & leave every Step 4: From the “property” menu, click on “organic SLE” to
thing else on their default values. enter the SLE tool-box
The parameters for the selected model is shown.
Press OK to return to the “selection of
thermodynamic model”
Set all other options to through the “default” button
and then click OK to return to the “property” menu
Organic Organic
SLE SLE
Step 6: Follow the directions in order to

calculate a binary SLE phase diagram
Step 5: Follow the directions in order to calculate
the solubility at a specified temperature
44
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Organic • Raw output file: ICAS1.sle Organic

SLE (open with a notepad)
• (C:) > CAPEC > ICAS > work
LLE
The calculated SLE phase diagram (temperature • Use of the LLE tool-box to calculate liquid solubilities as well as binary LLE
versus composition) is shown
phase diagrams (temperature versus composition)
• Acetone-Water-Methyl Isobutyl Ketone ternary mixture is used as an
example.
• Define components and mixture just like for SLE. For the thermodynamic model
selection, choose UNIFAC LLE.
Organic Organic
LLE LLE
• Click on Organic LLE • From the “LLE organic”
window, click on
“Calculate & Plot” to
enter the “Plot Ternary
LLE Curves”
• Make sure component

#1 and #3 is the
partially miscible pair
45
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Organic
LLE
• Click in OK in order to
calculate a ternary LLE phase
diagram:
• Raw output file: PLOTTRI

Case Studies
(open with a notepad)
• (C:) > CAPEC > ICAS > work
Problem: Azeotrope Formation
• Find all of the binary mixtures that form an azeotrope

with ethanol at 1 atm where the other compound is an
acyclic compound, having 300 < Tb < 400 K.
46
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Problem: Dichloromethane (DCM) Replacement in

Organic Synthesis
• The objective here is to find replacements for

dichloromethane [ClCCl; 000075-09-2], which is a very
well-known solvent used in organic synthesis.
• Note that DCM is a hazardous chemical whose release

into the atmosphere needs to be strictly regulated. It is
not only carcinogenic but also, when inhaled, can affect
the central nervous system.
47

Chapter 4: Molecular and Mixture Design

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Chapter 4: Molecular and Mixture Design

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10/4/2022

Outline of this Lecture

Mohd Asmadi Bin Mohammed Yussuf

Overview Identical molecules in Molecular

Important Questions Overview

Recognize characteristics of single molecules and liquid mixtures

Ability to convert the needs-functions of a product to the

Familiar with computer-aided methods and software that are

Ability to select, design, and analyze liquid products composed of

Molecular and Mixture Products Cont.

Types of Molecular Products Solvents

A Feasibility of downstream product depends on successful performance of

Feasibility of the chemical product manufactured through the solvent-

Cont. Single Molecular Products

Molecular Design Problem Mixture-Blend Design Problem

Many types of mixture-blended products

What should be the

Property Values Molecular Structure

• Some property models also require structural data -

Molecular Structure for Mixture-Blended Essential Ingredients for Molecular Design

1) Method to generate stable mixture-blend candidates

Cont. Framework for CAMD & CAMbD (Next Part)

Because the number of generated, • Subsections :

• Case studies - solvent substitution, refrigerant design, active

Activity 1: Translating Needs-Function into

HERE ARE THE LIST OF GENERAL CASE STUDY APPLICATIONS:

Outline of this Lecture

Example of Goals of CAMD: Azeotrope Problem Formulation and Pre-Design Phase

Translate Properties/ Constraints

Methods and Constraint Selection

Methods and Constraint Selection

Translate Properties/ Constraints

Selection Identify needed properties (behaviour) of product

Identify goal values of needed properties

Identify methods for obtaining the property values

Identify building blocks for generation of molecular structures or

• To assist transformation of general qualitative Published expert-insights

Knowledge Base Examples Translation of Product Need to Target Properties

Diesel based products: Jet fuel based products:

2. High flash-point temperature; 1. Low Reid vapour pressure to prevent evaporative

Knowledge Base Examples Translation of Product Need to Target Properties

Knowledge Base Examples Knowledge Base Examples

Solvent Design: Solvent Design – Property Classification

Knowledge Base Examples Knowledge Base Examples

Functional Functional Secondary Primary

Knowledge Base Examples Essential & Desirable Properties as Function of

Essential & Desirable Properties as Function of

References Activity 3 (In-class and continue outside class) :

Outline of this Lecture

Mohd Asmadi Bin Mohammed Yussuf

What’s Next? – Problem Formulation What’s Next? – Problem Formulation

• Next – design phase of CAMD method

Design Phase-Molecular Representation

• Feasible candidates - set of molecules (or mixtures) that satisfy

Molecular Representation Molecular Representation

• A group vector, contains some of this

• Defined by number and types of atoms

Adjacency Matrix Fragment-Based Matrix

• Conversion from a fragment-based matrix to an atom-

CH3 CH3 CH2 CH2COO

Atom-Based Matrix Molecular Representation

Molecular Structures & Estimation of Activity 4: Molecular Structure Representation

• Write the answers in a piece of paper. Submit a scanned copy