Computational Chemistry

Introduction
A mathematical method that is sufficiently well developed that it can be automated for
implementation on a computer. The theoretical chemistry may be defined as the mathematical
description of chemistry. Currently, there are two ways to approach theoretical chemistry
problems: computational chemistry and non-computational chemistry.
Computational chemistry is primarily concerned with the numerical computation of
molecular electronic structures, molecular interactions and non-computational quantum
chemistry deals with the formulation of analytical expressions for the properties of molecules and
their reactions.

What is it?
Computational chemistry is the study of the structures and characteristics of molecules and
materials using computer modelling and simulation, including ab initio methodologies based on
quantum chemistry and empirical approaches.
Computational chemistry is the application of chemical, mathematical and computing skills to
the solution of interesting chemical problems. It uses computers to generate information such as
properties of molecules or simulated experimental results. Very few aspects of chemistry can be
computed exactly, but almost every aspect of chemistry has been described in a qualitative or
approximate quantitative computational scheme. For spectral data of molecules are resolved, often a
qualitative or approximate computation can give useful insight into chemistry if you understand what
it tells you and what it doesn't.
Computational chemistry has become a useful way to investigate materials that are too
difficult to find or too expensive to purchase. It also helps chemists make predictions before running
the actual experiments so that they can be better prepared for making observations.
The quantum and classical mechanics as well as statistical physics and thermodynamics are the
foundation for most of the computational chemistry theory and computer programs. This is because
they model the atoms and molecules with mathematics. Using computational chemistry software one
can perform:
 electronic structure determinations,
 geometry optimizations,
  frequency calculations,
 definition of transition structures and reaction paths,
 protein calculations, i.e. docking,
 electron and charge distributions calculations,
 calculations of potential energy surfaces (PES),
 calculations of rate constants for chemical reactions (kinetics)
 thermodynamic calculations- heat of reactions, energy of activation, etc.,

The most important numerical techniques are ab-initio, semi-empirical and molecular mechanics.
Definitions of these terms are helpful in understanding the use of computational techniques for
chemistry:

 ab-initio, (Latin for "from scratch") a group of methods in which molecular structures can be
calculated using nothing but the Schrödinger equation, the values of the fundamental
constants and the atomic numbers of the atoms present.
 Semi-empirical techniques use approximations from empirical (experimental) data to provide
the input into the mathematical models.
 Molecular mechanics uses classical physics and empirical or semi-empirical (predetermined)
force fields to explain and interpret the behaviour of atoms and molecules.
Various methods:
Ab-initio methods for electronic structure calculations:
The most common type of ab-initio calculation is called Hartree-Fock calculation
(abbreviated HF), in which the primary approximation is called the mean field approximation. This
means that the Columbic electron-electron repulsion is not explicitly taken into account, however, its
average effect is included in the calculation. This is a variational calculation, which implies that the
approximate energies calculated are all equal to or greater than the exact energy. The accuracy of the
calculation depends on the size of the basis set used, however because of the mean field
approximation, the energies from HF calculations are always greater than the exact energy and tend,
with increasing basis size, to a limiting value called the Hartree-Fock limit.
The good side of ab-initio methods is that they eventually converge to the exact solution, once
all of the approximations are made sufficiently small in magnitude. However, this convergence is not
monotonic. Sometimes, more approximate calculation gives better result for a given property, than a
more elaborate calculation.
The limitation of ab-initio methods is that they are expensive. These methods often take
enormous amounts of computer CPU time, memory and disk space.
In general, ab-initio calculations give very good qualitative results and can give increasingly
accurate quantitative results as the molecules in question become smaller.

Semiempirical calculations:
 Semiempirical calculations are set up with the same general structure as a HF
calculation. Within this framework, certain pieces of information, such as two electron
integrals, are approximated or completely omitted.
The good side of semiempirical calculations is that they are much faster than the ab-
initio calculations.
The limitation of semiempirical calculations is that the results can be erratic. If the
molecule under study is similar to molecules in the database used to parameterize the method,
then the results may be very good. If this molecule is significantly different from anything in
the parameterization set, the answers may be poor.
Semiempirical calculations have been very successful in computational organic
chemistry, where there are only a few elements used extensively and the molecules are of
moderate size. However, semiempirical methods have been devised specifically for the
description of inorganic chemistry as well.
Molecular Mechanics approach:
If a molecule is too big to effectively use a semiempirical treatment, it is still possible
to model it's behaviour by avoiding quantum mechanics. This is done by constructing a
simple expression for “molecular force field”, i.e. the potential energy as function of all
atomic positions, and using it study molecular properties without the need to compute a wave
function or total electron density.
The good side of molecular mechanics is that it allows the modelling of enormous
molecules, such as proteins and segments of DNA, making it the primary tool of
computational biochemists.
The bad side is that there are many chemical properties that are not even defined
within the method, such as electronic excited states. In order to work with extremely large
and complicated systems, often molecular mechanics software packages have the most
powerful and easiest to use graphical interfaces.
When using computational chemistry to answer a chemical question, the obvious
problem is that you need to know how to use the software.
Often computational chemistry calculations (especially ab-initio ones) are so time
consuming that it would take a decade to do a single calculation, even if you had a very
power machine with enough memory and disk space. However, a number of methods exist
because each is best for different situations. The trick is to determine which one is best for
your project. Again, concerning the time consumption, the answer is to look into the literature
and see how long each calculation takes, when particular soft- and hardware is used.
 The common computer software used in computational chemistry are
(i) Gaussian 03, Gaussian 09, Gaussian 16 versions – for Gas Phase Calculations
(ii) Vienna ab initio Simulation Package (VASP) – for Gas Surface Calculations
(iii) Schrodinger Software for Molecular Docking and Molecular Dynamics
Simulation
(iv) To draw the 2D structure of the molecules Chemkdraw could be used.
The above mentioned software are commercial and a few free version of alternative to
commercial are;
(i) Hyperchem
(ii) Avagadro
(iii) Autodock for Molecular Docking
(iv) Gromacs for Molecular Dynamics Simulation
(v) Chemsketch (To draw 2D structures)

Data Visualization:
Data visualization is the process of displaying information in any sort of pictorial or graphical
representation using Gaussview, MolDen, gOpenMol software.

HOW COMPUTATIONAL CHEMISTRY IS USED?

Computational chemistry is used in a number of different ways. One particularly
important way is to model a molecular system prior to synthesizing that molecule in the
laboratory. Although computational models may not be perfect, they are often good enough
to rule out 90% of possible compounds as being unsuitable for their intended use. This is very
useful information because synthesizing a single compound could require months of labour
and raw materials, and generate toxic waste.
Computational chemistry methods for calculating various thermodynamic and
electronic properties of molecules and helps to understand the chemical or physical problems
more completely than experiment do. Using computational chemistry, one can predict values
like activation energy, site reactivity, other thermodynamic properties, significant
contributions to the mechanistic understanding of the origin of enantioselectivity in transition
metal-catalysed asymmetric synthesis.
In Computational Chemistry several terms will be used in calculation which will be
discussed below;
ENERGY:
Energy is one of the most useful concepts in science. The analysis of energetics can
predict what molecular processes are likely to occur, or able to occur. All computational
chemistry techniques define energy such that the system with the lowest energy is the most
stable. Thus, finding the shape of a molecule corresponds to finding the shape with the lowest
energy.
The amount of energy in a system is often broken down into kinetic energy and
potential energy. The kinetic energy may be further separated into vibrational, translational
and rotational motion. A distinction is also made between the kinetic energy due to nuclear
motion versus that due to electron motion. The potential energy may be expressed purely as
Coulomb's law, or it might be broken down into energies of bond stretching, bond bending,
conformational energy, hydrogen bonds, and so on.
Chemical processes, such as bond stretching or reactions, can be divided into
adiabatic and diabatic processes. Adiabatic processes are those in which the system does not
change state throughout the process. Diabatic, or non-adiabatic, processes are those in which
a change in the electronic state is part of the process. Diabatic processes usually follow the
lowest energy path, changing state as necessary.

ELECTROSTATICS
Electrostatics is the study of interactions between charged objects. Electro- statics
alone will not describe molecular systems, but it is very important to the understanding of
interactions of electrons, which is described by a wave function or electron density. The
central pillar of electrostatics is Coulombs law, which is the mathematical description of how
like charges repel and unlike charges attract. The Coulombs law equations for energy and the
force of interaction between two particles with charges q1 and q2 at a distance r12 are
q1 q2
E= ………….(1.1)
r 12
q1 q2
F= …………(1.2)
r 12

ATOMIC UNITS
The system of atomic units was developed to simplify mathematical equations by setting
many fundamental constants. It reduces the amount of computer time necessary to perform
chemical computations, which can be considerable. Scientist work entirely in atomic units,
but many researchers convert the theoretical results into more familiar unit systems.

THERMODYNAMICS
Thermodynamics is one of the most well-developed mathematical descriptions of
chemistry. It is the field of thermodynamics that defines many of the concepts of energy, free
energy and entropy. Computational results can be related to thermodynamics. The result of
computations might be internal energies, free energies, and so on, depending on the
computation done.

Ab initio Methods:
The term ab initio is Latin for ‘‘from the beginning.'' This name is given to
computations that are derived directly from theoretical principles with no inclusion of
experimental data. This is an approximate quantum mechanical calculation. The
approximations made are usually mathematical approximations, such as using a simpler
functional form for a function or finding an approximate solution to a differential equation.

HARTREE–FOCK APPROXIMATION:
The most common type of ab initio calculation is called a Hartree-Fock calculation
(abbreviated HF), in which the primary approximation is the central field approximation. This
means that the Coulombic electron–electron repulsion is taken into account by integrating the
repulsion term. This gives the average effect of the repulsion, but not the explicit repulsion
interaction. This is a variational calculation, meaning that the approximate energies
calculated are all equal to or greater than the exact energy. The energies are calculated in
units called Hartrees (1 Hartree 27.2116 eV).

CORRELATION

One of the limitations of HF calculations is that they do not include electron

correlation. This means that HF takes into account the average effect of electron repulsion,
but not the explicit electron–electron interaction. Within HF theory the probability of finding
an electron at some location around an atom is determined by the distance from the nucleus
but not the distance to the other electrons. This is not physically true, but it is the con-
sequence of the central field approximation, which defines the HF method. A number of
types of calculations begin with a HF calculation and then correct for correlation. Some of
these methods are Møller–Plesset perturbation theory (MPn, where n is the order of
correction), the generalized valence bond (GVB) method etc.,
MØLLER–PLESSET PERTURBATION THEORY
Correlation can be added as a perturbation from the Hartree–Fock wave function is
called Møller–Plesset perturbation theory. In mapping the HF wave function onto a
perturbation theory formulation, HF becomes a first-order perturbation. Thus, a minimal
amount of correlation is added by using the second- order MP2 method. Third-order
(MP3) and fourth-order (MP4) calculations are also common. The accuracy of an MP4
calculation is roughly equivalent to the accuracy of a higher level calculation. The
higher calculations are seldom done due to the high computational cost (N 10 time
complexity or worse).
Overall, ab initio calculations give very good qualitative results and can yield
increasingly accurate quantitative results as the molecules in question become smaller. The
advantage of ab initio methods is that they eventually converge to the exact solution once all
the approximations are made sufficiently small in magnitude.

Density Functional Theory (DFT)

The DFT is that the energy of a molecule can be determined from the electron density
instead of a wave function. This theory originated with a theorem by Hohenburg and Kohn
that stated this was possible. The original theorem applied only to finding the ground-state
electronic energy of a molecule. A practical application of this theory was developed by
Kohn and Sham who formulated a method similar in structure to the Hartree–Fock method.
In this formulation, the electron density is expressed as a linear combination of basis
functions similar in mathematical form to HF orbitals. A determinant is then formed from
these functions, called Kohn–Sham orbitals. It is the electron density from this determinant of
orbitals that is used to compute the energy.
The advantage of using electron density is that the integrals for Coulomb repulsion
need be done only over the electron density, which is a three-dimensional function, thus
scaling as N3. Furthermore, at least some electron correlation can be included in the
calculation. This results in faster calculations than HF calculations (which scale as N 4) and
computations that are a bit more accurate as well. The better DFT functionals give results
with an accuracy similar to that of an MP2 calculation.
 A few DFT methods or functionals are BLYP, B3LYP, PW91, G96, P86, B3P86,
B3PW91, Minnesota functionals etc.,

Application of Computational Chemistry:

This is a powerful tool for solving complex problems in the fields of chemistry and
physics. It’s revolutionized the way researchers approach and solve many challenging tasks,
allowing them to explore areas that may have been difficult to access using traditional
methods.

Accuracy: Computational chemistry allows for precise calculations that yield highly accurate
results. That’s because we can consider a wider range of variables than what’s possible with
traditional experimental techniques. It can also simulate complex chemical processes,
allowing scientists to gain insights into how molecules interact in various environments.

Cost Savings: This approach can save money by eliminating the need for expensive
experiments and equipment. Furthermore, the computational chemistry algorithms used can
be developed and used again for different tasks, reducing the need for multiple expensive
runs.

Speed: One of the biggest benefits of computational chemistry is its speed. Complex
chemical reactions and processes can be simulated quickly and with on-demand, pay-as-you-
go resources. This makes it an ideal tool for doing rapid testing and prototyping. you can also
use it to analyse large datasets to develop new insights and technologies.

 Computational chemistry provides insights into the behaviour of various chemicals,

materials, and products. This allows us to evaluate new materials, analyse existing
processes and products, optimize them for circularity, and develop more sustainable
alternatives.

 For example, we can use computational chemistry to identify and understand

materials to recycle or reuse. We can identify molecules to use as energy sources. We
can also determine the best use of resources or find new materials to reduce our
carbon footprint.
 Computational chemistry models and simulations decrease the development timeline
and costs by allowing for fast screening, design and testing of new materials.

 Recently, acceleration of the lead optimization process was made by using a broad
search algorithm and cloud computing to explore a huge chemical space–more than 1
billion molecules computationally characterized–towards the goal of designing new
inhibitors of d-amino acid oxidase (DAO). DAO is a target for the treatment of
schizophrenia. This work shows the application of chemical enumeration, property
filtering, machine learning and rigorous free energy perturbation calculations to
design new small-molecule drugs and tackle the multiparameter optimization
problem.

 One of the most exciting areas of the circular economy opened by computational
chemistry is in new materials science. We can identify areas where a given material
might be most appropriate for re-use by analysing its properties and behaviour, to
determine whether it can replace or reduce use of other resources.

 In recent years, number of investigations on the design and synthesis of low-band gap
electrochromic polymers have been the major attractive area and a most successful
and flexible strategy to design small band gap polymers involves the alternation of
electron-rich and electron deficient units along the polymer chain.

 Identifying relationships between chemical structures and properties (also known as

quantitative structure-property relationships (QSPR) and quantitative structure-
activity relationships (QSAR)).

 Data storage and retrieval for chemical entities (see chemical databases).

 Computational spectroscopy plays a crucial role in the interpretation and

understanding of spectral observables of complex systems.

 For water splitting, in the search for new electrocatalysts / photocatalysts based on
lower bandgap and H2 dissociation energy on the catalyst enabling the predictions of
electrocatalyst performance.

 Helps to predict the structure of unknown molecules using calculated NMR, IR, UV,
Geometry parameters, hardness, softness etc.,