Molecular

and Mixture
Design PART 1A

Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical and Energy Engineering
Universiti Teknologi Malaysia

1
 Outline
Introduction & Overview
Framework for Computer-Aided Molecular-Mixture Design
Molecular Structure Representation

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.

2
 Overview

Identical Molecular
2 classes of
chemical products
molecules in
product
products

Different molecules Mixture-blended

present as a liquid products
solution/blend

3
Important Questions

How to generate
How to represent chemically feasible
the structure of a candidate molecules
molecule? and mixtures?

How to estimate How to formulate

the properties of and solve typical
molecules and molecular and mixture
mixtures? design problems?
4
 Overview
Framework based on
MANY ways to design
computer-aided
molecular & mixture products
methods and software
BUT we ONLY consider
1 2
Identify promising design LATER stage, verify
alternatives - model-based experimentally
computer-aided techniques verify fine-tuned

Employed first to quickly & reliably Focused experiments performed on

reduce search space within which identified set of promising alternatives.
optimal designs likely to be found. 5
Objectives
Recognize characteristics of single molecules and liquid
1 mixtures as products.
Ability to convert the needs-functions of a product to the properties of
2 single molecules or liquid mixtures.

Familiar with computer-aided methods and software that are

3 applicable for selection, design, and analysis of these products.
Able to select, design, and analyze products composed of the same
4 molecule throughout the product.
Ability to select, design, and analyze liquid products composed of a
5 mixture of different molecules. 6
Introduction Molecular
products
Molecular and
(liquid) mixture
products
B2B
Type
Applications
In process industries
Molecules and/or
mixtures eventually Mixture-blended
help to manufacture products
a desired chemicals-
based product

7
Introduction Molecular
products
Molecular and
(liquid) mixture
products
B2B
Type
Applications
Incorporated in other
chemicals-based products
incorporated in the final Mixture-blended
product and have a products
specified function in the
product.
8
Introduction B (B, C) Usually employed as
the main active ingredient of
chemicals-based products.
Three types of molecular
products of varying size and (C) May be manipulated to
molecular structural complexity obtain a specific product
function

A Mixture-blend design

(A) Usually have process-

related applications or
may be part of a mixture-
C
formulated product Different chemicals are
blended to obtain a liquid
solution product with
desired properties 9
 Solvents Good example
For both molecular and
mixture products
Process industries
Feasibility of downstream product depends on
successful performance of solvent-based operation
in a process manufacturing the product.
Examples - separations, cleaning operations, and organic synthesis - in each
operations, desired solvents perform different functions.

Feasibility of the chemical product manufactured through the solvent-based

process depends on the successful selection-design of the solvent
10
 Solvents Good example
For both molecular and mixture products

Incorporated in Formulated Products

Example – in cosmetic products such as lotions – function: deliver active

ingredient to skin and then leave by evaporation.
Performance of the product depends on the function of the selected solvent
(molecular or mixture).

11
 Other Examples - Molecular
Refrigerants and/or Heat-Pump Fluids
Role: absorb and release energy in
different states defined by changes in
temperature and pressure in the
refrigeration or heat-pump cycle.
Important Issue
Need to perform specific functions
related to their properties as pure
chemicals and/or as species in
mixtures of chemicals
Emulsifiers
Surfactants that
create an emulsion
Active Ingredients
Chemicals performing
the main function of a
chemicals-based product,
as in drugs and cosmetics
12
Molecular Design Problem Important Issue
Need to perform specific functions
related to their properties as pure
These properties differ based on their need- chemicals and/or as species in
functions in a processing operation or in a mixtures of chemicals
downstream product
A typical molecular design problem is defined as:

Given a set of building blocks and a specified

set of target properties, determine the molecule
that matches these properties.
13
 Mixture Design Problem
Mixture of
X
=
Need-functions Properties of a
of product different molecules
single molecule
are considered
Perform Operation
Examples - blends of solvents, lubricants, and process fluids,

Perform Function
Examples - additives to fuels, solvent blends in paints,
and aroma blends in cosmetic products.
14
 Mixture Design Problem
Applications of Define their Define the set of properties
the blend must provide to
mixture products need-functions
perform its functions.
Many types of mixture-blended products - this chapter - only mixture-
blends that are stable liquid solutions are covered.
The typical mixture-blend design problem is defined as:

Given a set of chemicals and a specified set of

property constraints, determine the optimal
mixture and/or blend
15
 Needs-Function

A single-molecule solvent product must at

least be a liquid at the condition of application
and must dissolve an assigned solute.

What should be the required

properties of the solvent?
16
Molecular
and Mixture
Design PART 1B

Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical and Energy Engineering
Universiti Teknologi Malaysia

17
 Property Values How to obtain?
Measured experimentally
Retrieved from a database of measured data
Calculated through the use of appropriate property models

For a computer-aided technique

• Must include a database of measured property values complemented
by a library of property models to predict property values not
available in the database.
18
Molecular Structure

Property data or estimates only - insufficient

Method needed to generate molecular structures - employing

appropriate building blocks - can be combined to form molecules 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
molecular properties
Given these estimates, generated molecules can be
checked for matches with target property values
19
Molecular Structure

For mixture-blended products - molecules in mixture and their

compositions must be confirmed to satisfy liquid-phase stability criterion
at a specified temperature
Appropriate property models - estimate needed property values -
generated mixtures to be tested for matches with target property values.

20
Essential Ingredients

Molecular Design
• (1) a method to represent stable molecular structures,
• (2) a method to generate chemically feasible molecules, and
• (3) methods to estimate the required properties.

Mixture Design
• (1) a method to generate stable mixture-blend candidates, and
• (2) methods to estimate the needed properties.

21
Molecular and Mixture Design

Because the number of generated,

chemically feasible molecules or
mixtures can be very large, a
systematic framework to generate
the molecular structures and test
their properties, using the appropriate
computer-aided methods and
software, is needed.

22
 Next
Molecular
and Mixture
• Framework for computer-aided molecular design (CAMD) and mixture-blend
Design
design (CAM D) is described b
Lecturer:
• Subsections
Dr. Azizul Azri Mustaffa
- molecular
structure representation, the generation of molecule-
Universiti Teknologi Malaysia

mixture candidates, property prediction, CAMD/CAMbD problem formulation,

software for CAMD/CAMbD problem solution, and CAMD/CAMbD solution
1

approaches.
• Case studies - solvent substitution, refrigerant design,
active ingredient design, tailor-made gasoline-blend
design etc.

23
Molecular
and Mixture
Design
Lecturer:
Dr. Azizul Azri Mustaffa
Universiti Teknologi Malaysia

24
 Outline
Introduction & Overview
Framework for Computer-Aided Molecular-Mixture Design
Molecular Structure Representation

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.

25
Framework for Computer-Aided
Molecular-Mixture Design
START
• Solution of CAMD/CAMbD problems – 5
hierarchical steps:
Problem 1) Problem Formulation: CAMD/CAMbD
Formulation
problem defined in terms of product
Method & needs & functions.
Constraint
Selection
2) Method & Constraint Selection: Needs &
functions of product converted into
specific set of properties together with
their target values.

26
Framework for Computer-Aided
Molecular-Mixture Design
START
• Solution of CAMD/CAMbD problems – 5
hierarchical steps:
Problem 3) CAMD/CAMbD Solution: Any technique
Formulation
(e.g. C-based) to automatically
Method & generate & test candidates is used.
Constraint
Selection
Selected technique should able to
generate molecular-structure mixtures &
evaluate their properties with respect to
target properties.
CAMD
Solution

27
Framework for Computer-Aided
Molecular-Mixture Design
START
• Solution of CAMD/CAMbD problems – 5
hierarchical steps:
Problem 4) Result Analysis & Verification: Selected
Formulation
candidates further analysed to confirm
Method & their desired performance.
Constraint
Selection
Models capable of simulating product
Results
Analysis &
performance during application are
Verification needed - process simulation, product
application (e.g. to confirm delivery of
CAMD an active ingredient).
Solution

28
 Framework for Computer-Aided
Molecular-Mixture Design
START
• Solution of CAMD/CAMbD problems – 5
No suitable
solutions
hierarchical steps:
Candidate Problem
Selection
5) Final Selection: Through detailed
Formulation
Promising
verification using a combination of
candidates have
been identified Method & experiments and/or rigorous model-
FINISH Constraint based tests.
Results Selection
Analysis &
Verification

CAMD
Solution

29
 Framework for Computer-Aided Molecular-Mixture Design
• Example application: Objective - to find environmentally friendly substitute
molecules for benzene (only the concept is highlighted)
Pre-design Design (Start)
Interpretation
“I want acyclic to input/ A set of building blocks: A collection of group
constraits
alcohols, ketones, CH3, CH2, CH, C, OH, vectors like:
aldehydes and ethers CH3CO, CH2CO, CHO, 3 CH3, 1 CH2, 1 CH,
with solvent properties CH3O, CH2O, CH-O 1 CH2O
similar to Benzene.” + A set of numerical All group vectors
constraints. satisfy constraints.
Design (Higher Levels) Start of Post Design
2nd order
group
Refined property estimation.
Ability to estimate
additional properties or use
alternative methods.
Group from Rescreening against
other GCA
method constraints.
Molecular
and Mixture
Design
Lecturer:
Dr. Azizul Azri Mustaffa
Universiti Teknologi Malaysia

31
 Problem Formulation/Pre-Design Phase
• Design process - starts with definition of basic needs (or ultimate goals)
• Type of goal - influence design decisions need to be made in later phases
• Should describe:
Function of desired chemical product
Environment/equipment where the function should be performed
Capabilities that are desirable/undesirable.
• Example – for design of solvents
1) Must dissolve a specified solute(s)
2) Must be selective if other soluble solutes are also present
3) Must not cause a negative environmental impact
4) Should be easy to recover.
 Problem Formulation/Pre-Design Phase
• Description goals of CAMD can be of different types - few examples given

"Find a solvent suitable for removing phenol from a waste water

stream by liquid-liquid extraction. The solvent should pose a low
health risk for the users, should be environmentally friendly and
could be a single molecule or a mixture."

• Well-defined problem - almost all necessary details are given.

• Properties needed - solubility, EH&S properties, liquid
immiscibility, etc., can be identified.
• Goal values for properties are not given - but need to
find best solvent - then must highest solubility and least
environmental impact.
 Problem Formulation/Pre-Design Phase

"Identify a molecule(s) with the same pure component

properties as benzene, such as normal boiling point, normal
melting point, octanol-water partition coefficient, solubility
parameter as that of benzene but with a much lower
environmental impact in the work place."

• Another well-defined problem

• Goal values given because the property
values of benzene are already known.
 Problem Formulation/Pre-Design Phase

"Find a solvent to be used for washing off an

equipment (for example a printing press)
which is environmentally friendly and cheap."

• Problem is not very well defined

• While some constraints are defined, one piece of important
information is missing. What is it?
• What should be dissolved by the solvent?
• Definition of 'cheap' depends on the process involved as well as the current
solution used
 Problem Formulation/Pre-Design Phase

"Find an additive (molecule or mixture) for a tape so that

the tape will stick to a painted surface for a year and
then can be removed without pulling off the paint."

• Another example of a not very well-defined problem

• Because we need more information on the glue that will
be added to the tape
• As well as the various compositions of paints where the
tape will stick.
• The main question here is which properties are we looking for and what are
their goal values?
 Problem Formulation/Pre-Design Phase

"Find a molecule that will have inhibition activity

against Alzheimer's disease."

• Very well defined in terms of property – but difficult to

solve - because of potential search space.
• If add -"search only among isomers of X” where "XX" is a
particular molecular type
• Then - well-defined problem, even though number of possible isomers may be
large & prediction of inhibition activity as function of molecular structure may
be quite difficult.
 Problem Formulation/Pre-Design Phase

Find all molecules that form an azeotrope

with ethanol at a pressure of 1 atm.

• Not a typical product design problem

• CAMD can also solve problems like this
• Not well defined – large search space
• If we select a molecule type (for example, acyclic
hydrocarbons of molecular weight less than 100)
- becomes well defined.
 Problem Formulation/Pre-Design Phase
• Examples highlight need for a knowledge-based system - to identify needed
properties from general problem specifications presented
• Then, their goal values need to be specified & methods for obtaining the
necessary property values need to be selected.
• Qualitative problem specification needs to be transformed into a quantitative
problem specification.

Properties/
Needs/goals/ Translate
Constraints
Qualitative Convert
Quantitative
Molecular
and Mixture
Design
Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical and Energy Engineering
Universiti Teknologi Malaysia

40
 Outline
Introduction & Overview
Framework for Computer-Aided Molecular-Mixture Design
Molecular Structure Representation

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.

41
 Methods & Constraint Selection
Objective
Needs/goals/ Translate Properties/ Constraints
Qualitative Quantitative
Convert
The quantitative problem specification consists of the following:
Identify needed properties (behaviour) of product that matches qualitative
specification
Identify goal values of needed properties - matches product function and
behavior

Identify methods for obtaining the property values

Identify building blocks for generation of molecular structures or candidate

chemicals for mixture design
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
Need to have a knowledge base
• To assist transformation of general qualitative problem
specifications into quantitative, suitable for CAMD
problem solution.
• A lot of work need to be done to prepare a knowledge base (and time
consuming)
• Necessary to gather information from consumers in terms of basic needs - main
functions of products & additional needs – to improve product quality)
• Know-how to translate the consumer needs into target properties.
• Expert would be able to provide this knowledge if necessary data is available.
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
Another option, collect necessary data from:

Published expert-insights
Open source database
Patents
Published articles etc.

To prepare the translation of needs to properties tables

 Methods & Constraint Selection
Knowledge Base Examples
Need Target Properties Gasoline Jet Fuels Diesel
Ability to be burned Reid vapour pressure (RVP) √ √ √
ASTM distillation temperature (T) √ √ √
Safety Flash-point (Tf) √ √ √
Engine efficiency Higher heating value (HHV) √ √ √
Density (ρ) √ √ √
Research octane number (RON) √
Cetane Index (CI) √
Consistency of fuel Dynamic viscosity (η) √
flow Kinematic viscosity (V) √ √
Melting point (Tm) √
Stability Miscibility √ √ √
Environmental effects Oxygen weight content (WtO2) √
Human toxicity (Lethal concentration) (-logLC50) √ √ √
CO2 emission in the combustion engine (CO2e) √
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
• Gasoline based products:
• High Reid vapour pressure to ensure fuel is sufficiently vaporized to be
burned & engine can start at operating temperature;
• Low viscosity - fuel can flows smoothly from fuel tank to
combustion chamber.
• Must be stable:
o Should not evaporate easily;
o Do not oxidize to form unwanted by-products
(gums/sludge/deposits during storage;
o Must not split into two liquid phases.
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
• Diesel based products:
• Surrogate blends of diesel must have:
o Low Reid vapour pressure;
o High flash-point temperature;
o Low viscosity;
o Low environmental impacts as well as
human toxicity
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
• Jet fuel based products:
• Operated at low temperature above ground - blends of jet-fuel should have:
o Low Reid vapour pressure to prevent evaporative losses & fuel system
vapour lock;
o High flash-point temperature;
o High HHV to maximize energy that can be stored in a fixed volume &
provide longest flight range;
o Low melting point to prevent formation of wax crystals -
difficult to pump into turbine engines;
o Low greenhouse gas emissions
 Methods & Constraint Selection
Knowledge Base Examples
Lubricant Blends
Need Target Properties
Ability to lubricate and prevent wear Kinematic viscosity (V)
Friction coefficient (μtot)
Ability to flow at the ambient temperature Pour point (PP)
Non-flammable Flash-point (Tf)
Handling purpose Density (ρ)
Liquid at ambient temperature Melting point (Tm)
Heavy component Molecular weight (Mw)
Not easily vaporize Normal boiling point (Tb)
 Methods & Constraint Selection
Translation of Product Needs to Target Properties
• Lubricant blends:
• Principal function - reduce resistance & prevent
wear between two moving surfaces
• Needs - obtained through knowledge base,
literature search & legislation details
• Must able to resist a high temperature, flow continuously at a low
temperature & non-flammable.
• Density of base oils is also considered for handling purposes.
• Different upper & lower bounds of target properties listed may be
specified to obtain different varieties of blended products.
Molecular
and Mixture
Design
Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical and Energy Engineering
Universiti Teknologi Malaysia

51
Methods & Constraint Selection
Knowledge Base Examples
• Solvent Design:
• Hierarchical system
• Application types of solvent-based
process at the top
• Properties & property values
at the bottom
 Methods & Constraint Selection
Solvent Design – Property Classification
Essential
• Function of desired product
• Related to phase behavior
or driving forces for
separation operation
• Example - molecule must in •
liquid state at temperatures
of process
• Requirements - boiling
point of molecule >
temperature while melting
point is below.
• If molecule is to be used as
a solvent for L-L extraction
- it must
cause a phase split & have
density different from
solutes.
Knowledge Base Examples
Desirable
• Performance or efficiency of a product in a
specified application.
• Sill acceptable if these properties are not
matched.
Important during selection of feasible candidates
& during performance evaluation - to determine •
optimal design.
• Fixed lower or upper limits cannot usually be set
for these desirable properties.
• To have highest or lowest possible value for
identified desirable properties
• Example - selectivity towards a specified solute
that must be extracted from a mixture through a
solvent-based extraction process such as LLE
• For convenience, the undesirable properties are
also be included in this class of properties.
EH&S
• Associated with performance of product in a
specific operation or function & its effect on
surroundings as result of their use & emission.
• May be specified as essential, desirable
and/or undesirable.
Placed as separate class - methods for their
direct estimations are usually not available.
• May be considered in post-design phase
through database search or even through
direct or indirect experiments.
• Potentially expensive analysis is reserved
only for those candidates that satisfy all
other product criteria.
• Some essential and desired products may
implicitly also satisfy the EH&S & special
property constraints - smell, colour and taste.
Methods & Constraint Selection
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).

Essential, • SP is both a functional (temperature

Desirable, EH&S dependence) & secondary property (function
of molar volume & ∆Hv
• SP becomes primary if T is fixed to 298 K &
Mixture Pure Component if it directly correlated as function of
molecular structure

Functional Functional Secondary Primary

Methods & Constraint Selection
Knowledge Base Examples
• Solvent Design:
• For functional properties, the CAMD problem specification needs to specify
range of conditions where these properties must be matched
• Intervals of conditions of operation as a function of temperature, pressure
and/or composition.
 Methods & Constraint Selection
Knowledge Base Examples
• May also include tabular data
Separation Technique Class Phases Involved
Crystallization Property difference Solid-Liquid
Distillation Property difference Vapour-Liquid
Extractive Distillation Solvent-Based Vapour-Liquid
Azeotropic Distillation Solvent-Based Vapour-Liquid-Liquid
Liquid-Liquid Extraction Solvent-Based Liquid-Liquid
Supercritical Extraction Solvent-Based Fluid-Vapour-Liquid

• Properties important to function in a particular application listed along relative

property differences needed to perform function & associated phases involved in
particular application
Methods & Constraint Selection
• Essential & desirable properties as function of application type
Extractive Azeotropic
Properties L-L Extraction Solid Separation Gas Absorption
Distillation Distillation
Pure E D E D E D E D E D
∂ √ √ √ √ √ √ √ √
τ √ √
μ √ √
Tb √ √ √ √ √
Tm
ρ √ √ √ √
Pv √
Hvap √ √
Methods & Constraint Selection
• Essential & desirable properties as function of application type
Extractive Azeotropic
Properties L-L Extraction Solid Separation Gas Absorption
Distillation Distillation
Mixture E D E D E D E D E D
Selectivity √ √ √ √ √
SL √ √ √
SP √ √ √ √ √
DC √ √ √
Phase Split √ √ √ √
Azeotrope √ √
ρm √
μm √
H √
Methods & Constraint Selection
Environmental Concern
Properties
Health Safety Environment
• EH&S properties given as
Toxicity √ √ general guidelines based
Biological Persistence on phases involved
Implicit
Chemical Stability √ √ applications listed in
Reactivity √
previous table
Biodegrability √ √
Pv √ √ √
H (in water) √
Log P √ √
Log Ws √ √
Explicit
Flash Point √
BOD √
ρ (vapour) √ √
LD 50 √ √
ODP √
 References
• Harper, P. M., M. Hostrup, and R. Gani, A Hybrid CAMD Method, Computer-
Aided Chemical Engineering, 12, 129 (2002).
• 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 Products, Comput Chem Eng 2018, 116:37-55.
• Lei Zhang, Habitat Mao, Qilei Liu and Rafiqul Gani, Chemical Product
Design – Recent Advances and Perspectives, Current Opinion in Chemical
Engineering 2020, 27:22–34
Molecular
and Mixture
Design Part 3a

Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical & Energy Engineering
Universiti Teknologi Malaysia

1
 Outline
Introduction & Overview

Framework for Computer-Aided Molecular-Mixture Design

Molecular Structure Representation

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.

2
What’s Next? – Problem Formulation Algorithm
• To transform qualitative problem specification into a quantitative one through
a combination of knowledge base, insights and experience
• Multi-step process - different levels of information
• Summary:
Identify known properties Obtain system temperature Identify important pure
of compounds to be used pressure, composition and mixture properties
with designed compound ranges in system for the system

Identify property models List the molecule types that Create list of building blocks
available for estimation of can be handled by the used to assemble molecules
the properties. property models in design phase.
What’s Next? – Problem Formulation Algorithm
Molecule Type Building Blocks
• Database - type of molecules vs building
Acyclic CH3, CH2, CH, C
blocks vs EH&S properties helps in problem hydrocarbons
formulation Aromatic CH3, CH2, CH, C, ACH, AC,
hydrocarbons ACCH3, ACCH2, ACCH
• Alcohols & acids - linked to automatic
Alcohols CH3, CH2, CH, C, OH
selection of OH & COOH groups in the set of
Ketones CH3, CH2, CH, C, CH3CO,
building blocks CH2CO
• Aromatic compounds - carcinogenic, chlorides Esters CH3, CH2, CH, C, CH3COO,
CH2COO, HCOO, COO
- cause corrosion & have negative impact on
Acids CH3, CH2, CH, C, COOH
environmental indicators.
• Choice of EH&S properties as constraints -
automatic exclusion of corresponding
compounds & building blocks.
• Next – design phase of CAMD method
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
• Representations of molecules:

Simplest form
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
O Collection of functional groups or fragments
H2C C Molecular fragment or substructure
defined by number and types of atoms
O
Showing how atoms are connected,
how many free bond connections and
its location
Can represent isomers
Different compounds that
can be represented Group vector 2 CH3
Contains some 1 CH2
connectivity information,
but not completely 1 CH2COO
Molecular Representation
Simple & flexible way to define connectivity - adjacency matrix
Square symmetrical matrix with rows & columns representing
atom (or fragment) in molecule
CH3 CH3 CH2 CH2COO Containing non-zeroes & zeroes =
CH3 0 0 0 1
number of bonds or absence of bonds
CH3 0 0 1 0
CH2 0 1 0 1
Can be expressed using
CH2COO 1 0 1 0
fragments or atoms
Conversion from fragment-based to an atom-based matrix = replacing entry
for each fragment with atom adjacency matrix representing fragment.
Molecular Representation
H H H H H H H H H H C C C C C O O
H 0 1
Adjacency matrix
H 0 1 expressed using atoms
H 0 1
H 0 1 2D relations between
H 0 1
H 0 1
atoms - no steric
H 0 1 information to
H 0 1 distinguish isomers.
H 0 1
H 0 1
C 1 1 1 0 1
C 1 1 1 0 1
C 1 1 1 0 1
C 1 1 1 0 1
C 1 0 1 2
O 1 1 0
O 2 0
Molecular Representation
• To distinguish between isomers - need to have 3D information about atom
placements.
• 3D - adjacency matrices with a list of x, y, z Cartesian coordinates for
atoms are possible.
• Internal coordinate system - atom positions defined using bond length &
angle & torsion angle, is used.
• Choice of representation depends on computations to be performed
involving 3D representation.
• Examples (3D) - structures of compounds (molecules) developed using
appropriate descriptors together with an algorithm to construct 3D structures
of compounds & estimate their physical properties.
 Molecular Representation
• Representation of molecular structures and estimation of properties at 4 levels are summarized

Just representation
of molecules by
functional groups is
employed for our
class !
Molecular
and Mixture
Design Part 3b

Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical & Energy Engineering
Universiti Teknologi Malaysia

11
 Generation of Molecule-Mixture Candidates
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
molecules, fewer than total number of unrestricted combinations.
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
 Generation of Molecule-Mixture Candidates
Generation of Molecular Structures
• To ensure molecules are chemically feasible, the following rules must be
satisfied - Odele & Macchietto (1993)
𝑚
෍ 2 − 𝑢𝑗 𝑛𝑗 = 2𝑞 (1) • m = number of distinct groups in basis set;
𝑗=1 • q = [−1, 0, 1] for [bicyclic, monocyclic, acyclic];
𝑚
• nj and ni = number of groups j and i present in molecule;
෍ 𝑛𝑖 ≥ 𝑛𝑗 𝑢𝑗 − 2 + 2 ∀𝑗 (2)
𝑖≠𝑗 • uj is the valence of group j
𝑛𝑗𝑙 ≤ 𝑛𝑗 ≤ 𝑛𝑗𝑢 ∀𝑗 (3) • nmax = maximum number of groups allowed (specified) in
𝑚 molecule;
2 ≤ ෍ 𝑛𝑗 ≤ 𝑛𝑚𝑎𝑥 (4) • n = number of groups present in a specific molecule;
𝑗=1
• njl and nju = lower and upper bounds (specified) on number
𝑚
of allowed groups of type j, respectively.
𝑛 = ෍ 𝑛𝑗 (5)
𝑗=1
Generation of Molecule-Mixture Candidates
Generation of Molecular Structures
Recall 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?
• Solution
Groups (i, j) uj n jl n ju
CH3 1 0 2
CH2 2 0 2
OH 1 0 1

• m = 3, q = -1(bicyclic), q = 0 (monocyclic), q = 1 (acyclic), nmax = 3

Generation of Molecule-Mixture Candidates
Generation of Molecular Structures
• Solution
Rules
Possible Group
n q
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

1 CH3 CH3 (j): 1 ≥ 1(1-2)+2 CH3: 0 ≤ 1 ≤ 2
CH3-OH 2 1 (2-1)1 +(2-1)1 = 2 2≤2≤3 2
1 OH OH (j): 1 ≥ 1(1-2)+2 OH: 0 ≤ 1 ≤ 1
2 CH3 CH3 (j): 1 ≥ 2(1-2)+2 CH3: 0 ≤ 2 ≤ 2
CH3-CH2-CH3 3 1 (2-1)2+(2-2)1= 2 2≤3≤3 3
1 CH2 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
(2-1)1+(2-2)1+(2-1)1 =
CH3-CH2-OH 1 CH2 3 1 CH2 (j): (1+1) ≥ 1(2-2)+2 CH2: 0 ≤ 1 ≤ 2 2≤3≤3 3
2
1 OH OH (j): (1+1) ≥ 1(1-2)+2 OH: 0 ≤ 1 ≤ 1
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 3 1 (2-1)2+(2-2)1 = 2 2≤3≤3 3
2 OH 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 3 1 (2-2)2+(2-1)1 = 1 2≤3≤3 3
1 CH3 CH2 (j): 1 ≥ 2(2-2)+2 CH2: 0 ≤ 1 ≤ 2
Generation of Molecule-Mixture Candidates
Generation of Molecular Structures
• Solution
Possible Molecules Rules Chemically
(1) (2) (3) (4) (5) Feasible
CH3-CH3 ✔ N/A ✔ ✔ ✔ ✔
CH3-OH ✔ ✔ ✔ ✔ ✔ ✔
CH3-CH2-CH3 ✔ ✔ ✔ ✔ ✔ ✔
CH3-CH2-OH ✔ ✔ ✔ ✔ ✔ ✔
OH-OH ✔ N/A ✘ ✔ ✔ ✘
OH-CH2-OH ✔ ✔ ✘ ✔ ✔ ✘
CH2-CH2-CH3 ✘ ✘ ✔ ✔ ✔ ✘
 Generation of Molecule-Mixture Candidates
Generation of Molecular Structures
• Number of molecules generated for a larger set of functional groups is
enormous.
Group Valence (uj ) Group Valence (uj )
• Even with the basis set in the table, CH3 1 COOH 1
millions of chemically feasible CH2 2 CH3COO 1
molecular structures can be generated CH 3 CH2COO 2
C 4 CH3O 1
ACH 2 CH2O 2
AC 3 COO 3
OH 1 CH3N 2
CH3CO 1 CH3NH 1
CH2CO 2 CONH2 1
CHO 1 CONHCH3 1
Generation of Molecule-Mixture Candidates
Generation of Mixture-Blend Candidates

Given a basis set of n molecules, determine mixtures containing

mmax ≥ m ≥ 2 that are stable liquid solutions at given conditions of
temperature and pressure, where mmax = maximum no. of molecules
and m is the actual number in the solution.

Example:
Given the molecules, methanol [OC; 000067-56-1], ethanol [OCC; 000064-17-5], benzene
[C1CCCCC1; 000071-43-2], and water, find stable liquid binary and ternary mixtures at
298 K and 1 atm.

Answers: methanol-ethanol, methanol-benzene, ethanol-benzene, methanol-water,

ethanol-water, and methanol-ethanol-benzene
Generation of Molecule-Mixture Candidates
Generation of Mixture-Blend Candidates
Example:
Given the molecules, methanol [OC; 000067-56-1], ethanol [OCC; 000064-17-5], benzene
[C1CCCCC1; 000071-43-2], and water, find stable liquid binary and ternary mixtures at
298 K and 1 atm
• Solution
• For each mixture, to ensure liquid-phase stability, the following criterion must
be satisfied for all mixture compositions:
∆𝐺 𝐺𝐸
𝑁𝐶 For stable liquid solutions
= + ෍ 𝑥𝑖 ∙ 𝑙𝑛 𝑥𝑖 < 0
𝑅𝑇 𝑅𝑇
𝑖
∆G = Gibbs energy of mixing;
GE = excess Gibbs energy due to mixing
where 𝑁𝐶
𝐺𝐸 xi = mole fraction of compound i
= ෍ 𝑥𝑖 ∙ 𝑙𝑛 𝛾𝑖
𝑅𝑇 NC = number of compounds
𝑖
γi = liquid-phase activity coefficient of compound i
Generation of Molecule-Mixture Candidates
Generation of Mixture-Blend Candidates
∆𝐺 𝐺𝐸
𝑁𝐶 where
= + ෍ 𝑥𝑖 ∙ 𝑙𝑛 𝑥𝑖 < 0 𝐺𝐸 𝑁𝐶
𝑅𝑇 𝑅𝑇
𝑖 = ෍ 𝑥𝑖 ∙ 𝑙𝑛 𝛾𝑖
𝑅𝑇
𝑖

• The equation is easily checked for binary mixtures to establish miscibility (stability)
• Multicomponent mixtures - each binary pair is checked first for miscibility
• If any pair is found to be unstable, then corresponding multicomponent mixture is
likely to be unstable
• Equation - not a sufficient condition - only a necessary condition for stability
• Checks at equimolar binary composition are usually sufficient to identify phase
instability when it arises
Generation of Molecule-Mixture Candidates
Generation of Mixture-Blend Candidates
Example:
Which binary pairs in a mixture of methanol, ethanol, benzene, and water are unstable at
temperature = 298 K and pressure = 1 atm?

• Solution
• There are six binary pairs: methanol-ethanol, methanol-benzene, methanol-
water, ethanol-benzene, ethanol-water, and benzene-water
• For each pair, an equimolar mixture is tested for stability – results shown in
table
Generation of Molecule-Mixture Candidates
Generation of Mixture-Blend Candidates
• Benzene-water pair = unstable
• Solution
• Multicomponent mixtures containing
this pair - unstable
• Size of mixture-blend design
problems depends on n and mmax
• This example - 6 binary pairs, 4
ternary mixtures, and 1 quaternary
mixture; a total of 11 mixtures
• Therefore, only 7 liquid solutions are
potentially stable, with only 4
potentially unstable.
• However, when instability is detected in binary
mixtures, the number of feasible multicomponent • In general, total number of mixtures
mixtures may be reduced dramatically. may be very large.
Molecular
and Mixture
Design Part 4

Lecturer:
Dr. Azizul Azri Mustaffa
School of Chemical & Energy Engineering
Universiti Teknologi Malaysia

23
 Outline
Introduction & Overview

Framework for Computer-Aided Molecular-Mixture Design

Molecular Structure Representation

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.

24
 Property Prediction
• Target properties - pure compound & mixture properties
• Selection of property estimation models to predict –
issues: application ranges, availability of parameters & and
uncertainties
• 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.
 Property Prediction
• Estimation task -
arranged hierarchically
based on computational
effort & cost
• Computationally
intensive calculations -
for candidates satisfied
all targets using simpler
property models.
 Property Prediction
Properties can be classified as:
Primary
• Single-value properties - calculated using structural information only
Secondary
• In addition to structural information, usually a function of other properties
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
 Property Prediction Relationships among properties, property
models, solvers & calculation algorithms
• To estimate properties - first
property model is selected
• For phase-equilibrium-related
mixture properties - solution
algorithms employed that require
estimates of other properties.
• Required property estimates
ordered &
calculated
according to
hierarchy
 Property Prediction
Models for Primary Properties
• Property models that employ structural variables are appropriate
• Group-contribution (GC) approach based on MG method - simple, accurate
• Extensive group-parameter tables for broad arrays of properties & molecules.
• These property prediction models have the form:

• where f(𝜃) is a function of primary properties 𝜃

Property Prediction

• 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.
 Property Prediction
• Partial list of the primary properties for MG model
 Property Prediction
Application - four steps:
Identify functional groups (first, and if necessary, second, and third-order
1 groups)

Determine how many groups of each type are needed to represent

2 molecule

Retrieve parameters from model parameter tables for properties of

3 interest.

Sum the contributions and use the corresponding property model

4 functions.
Property Prediction
Example: Estimate Normal Boiling Points
Estimate the normal boiling point of butanoic acid, di-isopropyl ester
[CCCOC(=O)CCC(=O)OCCC; 000925-15-5] using the M-G method
and group-contribution parameters
Solution
Identify functional groups (first, and if necessary, second, and third-order
groups)
 Property Prediction
Solution
Identify functional groups (first, and if necessary, second, and third-order
groups)
 Property Prediction
• For primary properties of polymer repeat units, GC-based methods
such as by van Krevelen and MG method adapted for polymers can
used

Example: Estimate Glass-Transition Temperatures

Estimate the glass-transition temperature for the polymer repeat unit
[—(CH2CH2CHCl)—].
Property Prediction [—(CH2CH2CHCl)—]
 Property Prediction
Models for Secondary Properties
Three steps needed:

1 Select an estimation method and property model for specific property.

Identify the properties data needed to use model and verify the
2 application range of estimation method for chemical species of specific
types.

Retrieve from a database or predict the necessary properties (to be

3 used as input).
Property Prediction
Property Prediction
 Property Prediction
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.

Else, use models based on the principle of corresponding states, if

3 available for necessary properties.
Otherwise, collect experimental data and regress parameters for a
4 preferred correlation.
Property Prediction
Property Prediction
 Property Prediction
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 these
2 limits.
When correlations are not available, try to check the estimates with
3 experimental data, when available.

4 Perform cross-validation, if possible.

 Property Prediction
Models for Mixture Properties
Commonly encountered in chemicals-based product design:
• (1) Functional properties for mixture in specified phase (e.g., bulk
density & enthalpy of mixture)
• (2) Phase equilibrium–related properties of compounds in mixture (e.g.,
liquid-phase activity coefficients for species in mixture, saturation
temperatures - bubble- and dew-point temperatures)
• To calculate mixture properties, pure-component properties are needed
with calculation algorithms & equation solvers
 Property Prediction
Functional Mixture Properties.
• Compounds & their composition in mixture – known, with phase identity
• At known temp., pure-compound property, 𝜃i, for each compound needs
to be estimated.
• Using a mixing rule, bulk property of mixture, 𝜃M, is calculated:
• 𝜃M = 𝜃0 + 𝜃E where 𝜃0 and 𝜃E are ideal & excess mixing terms.
• When excess mixing term can be neglected, bulk mixture property is
simply the molal average of the pure-compound properties:
• 𝜃M = Σi (𝜃ixi)
• Models for excess property terms vary with property & specific phase
 Property Prediction
• Equilibrium-Based Mixture Properties.
• Estimated when two or more phases are in equilibrium.
• Iso-fugacity criteria for vapour-liquid equilibrium (VLE), liquid-liquid
equilibrium (LLE), and solid-liquid equilibrium (SLE) are:
 Property Prediction
• Equilibrium-Based Mixture Properties.
• 𝛾i - liquid-phase activity coefficient of
compound i;
• 𝜑i - fugacity coefficient of compound i in
vapour phase; Pisat - pure-compound vapour
pressure at temperature,
• 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.
 Property Prediction
• Appropriate iso-fugacity equation is selected
• Together with mass balances (involving a feed stream and two effluent
streams), along with mole fraction summations (equal unity for each
stream) - solved by appropriate solver.
• Solution of VLE  bubble-points, dew-points, VLE phase
diagrams.
• Solutions of LLE  amount & composition of each liquid
phase
• Solution of SLE  saturation temperature-composition
curves, solubility of solid solute in the solvent.
 Property Prediction
• Examples of needed specifications, properties, property model
parameters for two-phase equilibrium calculations.