Computational chemistry

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Computational chemistry is a branch of chemistry that uses computers to assist in solving chemical problems. It uses the results of theoretical chemistry, incorporated into efficient computer programs, to calculate the structures and properties of molecules and solids. While its results normally complement the information obtained by chemical experiments, it can in some cases predict hitherto unobserved chemical phenomena. It is widely used in the design of new drugs and materials.

Examples of such properties are structure (i.e. the expected positions of the constituent atoms), absolute and relative (interaction) energies, electronic charge distributions, dipoles and higher multipole moments, vibrational frequencies, reactivity or other spectroscopic quantities, and cross sections for collision with other particles.

The methods employed cover both static and dynamic situations. In all cases the computer time increases rapidly with the size of the system being studied. That system can be a single molecule, a group of molecules or a solid. The methods are thus based on theories which range from highly accurate, but are suitable only for small systems, to very approximate, but suitable for very large systems. The accurate methods are used called ab initio methods, as they are based entirely on theory from first principles. The less accurate methods are called empirical or semi-empirical because some experimental results, often from atoms or related molecules, are used along with the theory.

[edit] History

Building on the founding discoveries and theories in the history of quantum mechanics, the first theoretical calculations in chemistry were those of Walter Heitler and Fritz London in 1927. The books that were influential in the early development of computational quantum chemistry include: Linus Pauling and E. Bright Wilson’s 1935 Introduction to Quantum Mechanics – with Applications to Chemistry, Eyring, Walter and Kimball's 1944 Quantum Chemistry, Heitler’s 1945 Elementary Wave Mechanics – with Applications to Quantum Chemistry, and later Coulson's 1952 textbook Valence, each of which served as primary references for chemists in the decades to follow.

With the development of efficient computer technology in the 1940s the solutions of elaborate wave equations for complex atomic systems began to be a realizable objective. In the early 1950s, the first semi-empirical atomic orbital calculations were carried out. Theoretical chemists became extensive users of the early digital computers. A very detailed account of such use in the United Kingdom is given by Smith and Sutcliffe.^[1] The first ab initio Hartree-Fock calculations on diatomic molecules were carried out in 1956 at MIT using a basis set of Slater orbitals. For diatomic molecules a systematic study using a minimum basis set and the first calculation with a larger basis set were published by Ransil and Nesbet respectively in 1960.^[2] The first polyatomic calculations using Gaussian orbitals were carried out in the late 1950s. The first configuration interaction calculations were carried out in Cambridge on the EDSAC computer in the 1950s using Gaussian orbitals by Boys and coworkers.^[3] By 1971, when a bibliography of ab initio calculations was published,^[4] the largest molecules included were naphthalene and azulene.^{[5] [6]} Abstracts of many earlier developments in ab initio theory have been published by Schaefer.^[7]

In 1964, Hückel method calculations, which are a simple LCAO method for the determination of electron energies of molecular orbitals of π electrons in conjugated hydrocarbon systems, ranging from simple systems such as butadiene and benzene to ovalene with 10 fused six-membered rings , were generated on computers at Berkeley and Oxford.^[8] These empirical methods were replaced in the 1960s by semi-empirical methods such as CNDO.^[9]

In the early 1970s, efficient ab initio computer programs such as ATMOL, GAUSSIAN, IBMOL, and POLYAYTOM, began to be used to speed up ab initio calculations of molecular orbitals. Of these four programs only GAUSSIAN, massively expanded, is still in use, but many other programs are now in use. At the same time, the methods of molecular mechanics, such as MM2, were developed, primarily by Norman Allinger.^[10]

One of the first mentions of the term “computational chemistry” can be found in the 1970 book Computers and Their Role in the Physical Sciences by Sidney Fernbach and Abraham Haskell Taub, where they state “It seems, therefore, that 'computational chemistry' can finally be more and more of a reality.”^[11] During the 1970s, widely different methods began to be seen as part of a new emerging discipline of computational chemistry.^[12] The Journal of Computational Chemistry was first published in 1980.

[edit] Concepts

The term theoretical chemistry may be defined as a mathematical description of chemistry, whereas computational chemistry is usually used when a mathematical method is sufficiently well developed that it can be automated for implementation on a computer. Note that the words exact and perfect do not appear here, as very few aspects of chemistry can be computed exactly. Almost every aspect of chemistry, however, can be described in a qualitative or approximate quantitative computational scheme.

Molecules consist of nuclei and electrons, so the methods of quantum mechanics apply. Computational chemists often attempt to solve the non-relativistic Schrödinger equation, with relativistic corrections added, although some progress has been made in solving the fully relativistic Schrödinger equation. It is, in principle, possible to solve the Schrödinger equation, in either its time-dependent form or time-independent form as appropriate for the problem in hand, but this in practice is not possible except for very small systems. Therefore, a great number of approximate methods strive to achieve the best trade-off between accuracy and computational cost. Accuracy can always be improved with greater computational cost. Present computational chemistry can routinely accurately calculate the properties of molecules that contain up to about 40 electrons. Errors for energies can be less than 1 kcal/mol. For geometries, bond lengths can be predicted within a few picometres and bond angles within 0.5^o. The treatment of larger molecules that contain a few dozen electrons is computationally tractable by approximate methods such as density functional theory (DFT). There is some dispute within the field whether the latter methods are sufficient to describe complex chemical reactions, such as those in biochemistry. Large molecules can be studied by semi-empirical approximate methods. Even larger molecules are treated by classical mechanics methods that are called molecular mechanics.

In theoretical chemistry, chemists, physicists and mathematicians develop algorithms and computer programs to predict atomic and molecular properties and reaction paths for chemical reactions. Computational chemists, in contrast, may simply apply existing computer programs and methodologies to specific chemical questions. There are two different aspects to computational chemistry:

• Computational studies can be carried out in order to find a starting point for a laboratory synthesis, or to assist in understanding experimental data, such as the position and source of spectroscopic peaks.
• Computational studies can be used to predict the possibility of so far entirely unknown molecules or to explore reaction mechanisms that are not readily studied by experimental means.

Thus computational chemistry can assist the experimental chemist or it can challenge the experimental chemist to find entirely new chemical objects.

Several major areas may be distinguished within computational chemistry:

• The prediction of the molecular structure of molecules by the use of the simulation of forces, or more accurate quantum chemical methods, to find stationary points on the energy hypersurface as the position of the nuclei is varied.
• Storing and searching for data on chemical entities (see chemical databases).
• Identifying correlations between chemical structures and properties (see QSPR and QSAR).
• Computational approaches to help in the efficient synthesis of compounds.
• Computational approaches to design molecules that interact in specific ways with other molecules (e.g. drug design).

[edit] Methods

A given molecular formula can represent a number of molecular isomers. Each isomer is a local minimum on the energy surface (called the potential energy surface) created from the total energy (electronic energy plus repulsion energy between the nuclei) as a function of the coordinates of all the nuclei. A stationary point is a geometry such that the derivative of the energy with respect to all displacements of the nuclei is zero. A local (energy) minimum is a stationary point where all such displacements lead to an increase in energy. The local minimum that is lowest is called the global minimum and corresponds to the most stable isomer. If there is one particular coordinate change that leads to a decrease in the total energy in both directions, the stationary point is a transition structure and the coordinate is the reaction coordinate. This process of determining stationary points is called geometry optimization.

The determination of molecular structure by geometry optimization became routine only when efficient methods for calculating the first derivatives of the energy with respect to all atomic coordinates became available. Evaluation of the related second derivatives allows the prediction of vibrational frequencies if harmonic motion is assumed. In some ways more importantly it allows the characterisation of stationary points. The frequencies are related to the eigenvalues of the matrix of second derivatives (the Hessian matrix). If the eigenvalues are all positive, then the frequencies are all real and the stationary point is a local minimum. If one eigenvalue is negative (an imaginary frequency), the stationary point is a transition structure. If more than one eigenvalue is negative the stationary point is a more complex one, and usually of little interest. When found, it is necessary to move the search away from it, if we are looking for local minima and transition structures.

The total energy is determined by approximate solutions of the time-dependent Schrödinger equation, usually with no relativistic terms included, and making use of the Born-Oppenheimer approximation which, based on the much higher velocity of the electrons in comparison with the nuclei, allows the separation of electronic and nuclear motions, and simplifies the Schrödinger equation. This leads to evaluating the total energy as a sum of the electronic energy at fixed nuclei positions plus the repulsion energy of the nuclei. A notable exception are certain approaches called direct quantum chemistry, which treat electrons and nuclei on a common footing. Density functional methods and semi-empirical methods are variants on the major theme. For very large systems the relative total energies can be compared using molecular mechanics. The ways of determining the total energy to predict molecular structures are:

[edit] Ab initio methods

Main article: Ab initio quantum chemistry methods

The programs used in computational chemistry are based on many different quantum-chemical methods that solve the molecular Schrödinger equation associated with the molecular Hamiltonian. Methods that do not include any empirical or semi-empirical parameters in their equations - being derived directly from theoretical principles, with no inclusion of experimental data - are called ab initio methods. This does not imply that the solution is an exact one; they are all approximate quantum mechanical calculations. It means that a particular approximation is rigorously defined on first principles (quantum theory) and then solved within an error margin that is qualitatively known beforehand. If numerical iterative methods have to be employed, the aim is to iterate until full machine accuracy is obtained (the best that is possible with a finite word length on the computer, and within the mathematical and/or physical approximations made).

The simplest type of ab initio electronic structure calculation is the Hartree-Fock (HF) scheme, an extension of molecular orbital theory, in which the correlated electron-electron repulsion is not specifically taken into account; only its average effect is included in the calculation. As the basis set size is increased the energy and wave function tend to a limit called the Hartree-Fock limit. Many types of calculations, known as post-Hartree-Fock methods, begin with a Hartree-Fock calculation and subsequently correct for electron-electron repulsion, referred to also as electronic correlation. As these methods are pushed to the limit, they approach the exact solution of the non-relativistic Schrödinger equation. In order to obtain exact agreement with experiment, it is necessary to include relativistic and spin orbit terms, both of which are only really important for heavy atoms. In all of these approaches, in addition to the choice of method, it is necessary to choose a basis set. This is a set of functions, usually centered on the different atoms in the molecule, which are used to expand the molecular orbitals with the LCAO ansatz. Ab initio methods need to define a level of theory (the method) and a basis set.

The Hartree-Fock wave function is a single configuration or determinant. In some cases, particularly for bond breaking processes, this is quite inadequate and several configurations need to be used. Here the coefficients of the configurations and the coefficients of the basis functions are optimized together.

The total molecular energy can be evaluated as a function of the molecular geometry, in other words the potential energy surface. Such a surface can be used for reaction dynamics. The stationary points of the surface lead to predictions of different isomers and the transition structures for conversion between isomers, but these can be determined without a full knowledge of the complete surface.

A particularly important objective, called computational thermochemistry, is to calculate thermochemical quantities such as the enthalpy of formation to chemical accuracy. Chemical accuracy is the accuracy required to make realistic chemical predictions and is generally considered to be 1 kcal/mol or 4 kJ/mol. To reach that accuracy in an economic way it is necessary to use a series of post-Hartree-Fock methods and combine the results. These methods are called quantum chemistry composite methods.

[edit] Density Functional methods

Main article: Density functional theory

Density functional theory (DFT) methods are often considered to be ab initio methods for determining the molecular electronic structure, even though many of the most common functionals use parameters derived from empirical data, or from more complex calculations. This means that they could also be called semi-empirical methods. It is best to treat them as a class on their own. In DFT, the total energy is expressed in terms of the total electron density rather than the wave function. In this type of calculation, there is an approximate Hamiltonian and an approximate expression for the total electron density. DFT methods can be very accurate for little computational cost. The drawback is, that unlike ab initio methods, there is no systematic way to improve the methods by improving the form of the functional. Some methods combine the density functional exchange functional with the Hartree-Fock exchange term and are known as hybrid functional methods.

[edit] Semi-empirical and empirical methods

Main article: Semi-empirical quantum chemistry methods

Semi-empirical quantum chemistry methods are based on the Hartree-Fock formalism, but make many approximations and obtain some parameters from empirical data. They are very important in computational chemistry for treating large molecules where the full Hartree-Fock method without the approximations is too expensive. The use of empirical parameters appears to allow some inclusion of correlation effects into the methods.

Semi-empirical methods follow what are often called empirical methods where the two-electron part of the Hamiltonian is not explicitly included. For π-electron systems, this was the Hückel method proposed by Erich Hückel, and for all valence electron systems, the Extended Hückel method proposed by Roald Hoffmann.

[edit] Molecular mechanics

Main article: Molecular mechanics

In many cases, large molecular systems can be modeled successfully while avoiding quantum mechanical calculations entirely. Molecular mechanics simulations, for example, use a single classical expression for the energy of a compound, for instance the harmonic oscillator. All constants appearing in the equations must be obtained beforehand from experimental data or ab initio calculations.

The database of compounds used for parameterization - (the resulting set of parameters and functions is called the force field) - is crucial to the success of molecular mechanics calculations. A force field parameterized against a specific class of molecules, for instance proteins, would be expected to only have any relevance when describing other molecules of the same class.

These methods can be applied to proteins and other large biological molecules, and allow studies of the approach and interaction (docking) of potential drug molecules.

[edit] Methods for solids

Main article: Computational chemical methods in solid state physics

Computational chemical methods can be applied to solid state physics problems. The electronic structure of a crystal is in general described by a band structure, which defines the energies of electron orbitals for each point in the Brillouin zone. Ab initio and semi-empirical calculations yield orbital energies, therefore they can be applied to band structure calculations. Since it is time-consuming to calculate the energy for a molecule, it is even more time-consuming to calculate them for the entire list of points in the Brillouin zone.

[edit] Chemical dynamics

Once the electronic and nuclear variables are separated (within the Born-Oppenheimer representation), in the time-dependent approach, the wave packet corresponding to the nuclear degrees of freedom is propagated via the time evolution operator (physics) associated to the time-dependent Schrödinger equation (for the full molecular Hamiltonian). In the complementary energy-dependent approach, the time-independent Schrödinger equation is solved using the scattering theory formalism. The potential representing the interatomic interaction is given by the potential energy surfaces. In general, the potential energy surfaces are coupled via the vibronic coupling terms.

The most popular methods for propagating the wave packet associated to the molecular geometry are

• the split operator technique,
• the Multi-Configuration Time-Dependent Hartree method (MCTDH),
• the semiclassical method.

Molecular dynamics (MD) examines (using Newton's laws of motion) the time-dependent behavior of systems, including vibrations or Brownian motion, using a classical mechanical description. MD combined with density functional theory leads to the Car-Parrinello method.

[edit] Interpreting molecular wave functions

The Atoms in Molecules model developed by Richard Bader was developed in order to effectively link the quantum mechanical picture of a molecule, as an electronic wavefunction, to chemically useful older models such as the theory of Lewis pairs and the valence bond model. Bader has demonstrated that these empirically useful models are connected with the topology of the quantum charge density. This method improves on the use of Mulliken population analysis.

[edit] Software packages

There are many self-sufficient software packages used by computational chemists. Some include many methods covering a wide range, while others concentrating on a very specific range or even a single method. Details of most of them can be found in:-

• Quantum chemistry computer programs supporting several methods.
• Density functional theory programs.
• Molecular mechanics programs.
• Semi-empirical programs.
• Solid state system programs with periodic boundary conditions.
• Valence Bond programs.