Simplifying inverse material design problems for fixed lattices with alchemical chirality

Massive brute-force compute campaigns relying on demanding ab initio calculations routinely search for novel materials in chemical compound space, the vast virtual set of all conceivable stable combinations of elements and structural configurations which form matter. Here we demonstrate that 4-dimensional chirality, arising from anti-symmetry of alchemical perturbations, dissects that space and defines approximate ranks which effectively reduce its formal dimensionality, and enable us to break down its combinatorial scaling. The resulting distinct `alchemical' enantiomers must share the exact same electronic energy up to third order -- independent of respective covalent bond topology, and imposing relevant constraints on chemical bonding. Alchemical chirality deepens our understanding of chemical compound space and enables the `on-the-fly' establishment of new trends without empiricism for any materials with fixed lattices. We demonstrate its efficacy for three such cases: i) new formulas for estimating electronic energy contributions to chemical bonding; ii) analysis of the perturbed electron density of BN doped benzene; and iii) ranking stability estimates for BN doping in over 2,000 naphthalene and over 400 million picene derivatives

Simplifying inverse materials design problems for fixed lattices with alchemical chirality

Brute-force compute campaigns relying on demanding ab initio calculations routinely search for previously un- known materials in chemical compound space (CCS), the vast set of all conceivable stable combinations of elements and structural configurations. Here, we demonstrate that four-dimensional chirality arising from antisymmetry of alchemical perturbations dissects CCS and defines approximate ranks, which reduce its formal dimensionality and break down its combinatorial scaling. The resulting "alchemical" enantiomers have the same electronic energy up to the third order, independent of respective covalent bond topology, imposing relevant constraints on chemical bonding. Alchemical chirality deepens our understanding of CCS and enables the establishment of trends without empiricism for any materials with fixed lattices. We demonstrate the efficacy for three cases: (i) new rules for elec- tronic energy contributions to chemical bonding; (ii) analysis of the electron density of BN-doped benzene; and (iii) ranking over 2000 and 4 million BN-doped naphthalene and picene derivatives, respectively

A treatment of stereochemistry in computer aided organic synthesis

This thesis describes the author’s contributions to a new stereochemical processing module constructed for the ARChem retrosynthesis program. The purpose of the module is to add the ability to perform enantioselective and diastereoselective retrosynthetic disconnections and generate appropriate precursor molecules. The module uses evidence based rules generated from a large database of literature reactions. Chapter 1 provides an introduction and critical review of the published body of work for computer aided synthesis design. The role of computer perception of key structural features (rings, functions groups etc.) and the construction and use of reaction transforms for generating precursors is discussed. Emphasis is also given to the application of strategies in retrosynthetic analysis. The availability of large reaction databases has enabled a new generation of retrosynthesis design programs to be developed that use automatically generated transforms assembled from published reactions. A brief description of the transform generation method employed by ARChem is given. Chapter 2 describes the algorithms devised by the author for handling the computer recognition and representation of the stereochemical features found in molecule and reaction scheme diagrams. The approach is generalised and uses flexible recognition patterns to transform information found in chemical diagrams into concise stereo descriptors for computer processing. An algorithm for efficiently comparing and classifying pairs of stereo descriptors is described. This algorithm is central for solving the stereochemical constraints in a variety of substructure matching problems addressed in chapter 3. The concise representation of reactions and transform rules as hyperstructure graphs is described. Chapter 3 is concerned with the efficient and reliable detection of stereochemical symmetry in both molecules, reactions and rules. A novel symmetry perception algorithm, based on a constraints satisfaction problem (CSP) solver, is described. The use of a CSP solver to implement an isomorph‐free matching algorithm for stereochemical substructure matching is detailed. The prime function of this algorithm is to seek out unique retron locations in target molecules and then to generate precursor molecules without duplications due to symmetry. Novel algorithms for classifying asymmetric, pseudo‐asymmetric and symmetric stereocentres; meso, centro, and C2 symmetric molecules; and the stereotopicity of trigonal (sp2) centres are described. Chapter 4 introduces and formalises the annotated structural language used to create both retrosynthetic rules and the patterns used for functional group recognition. A novel functional group recognition package is described along with its use to detect important electronic features such as electron‐withdrawing or donating groups and leaving groups. The functional groups and electronic features are used as constraints in retron rules to improve transform relevance. Chapter 5 details the approach taken to design detailed stereoselective and substrate controlled transforms from organised hierarchies of rules. The rules employ a rich set of constraints annotations that concisely describe the keying retrons. The application of the transforms for collating evidence based scoring parameters from published reaction examples is described. A survey of available reaction databases and the techniques for mining stereoselective reactions is demonstrated. A data mining tool was developed for finding the best reputable stereoselective reaction types for coding as transforms. For various reasons it was not possible during the research period to fully integrate this work with the ARChem program. Instead, Chapter 6 introduces a novel one‐step retrosynthesis module to test the developed transforms. The retrosynthesis algorithms use the organisation of the transform rule hierarchy to efficiently locate the best retron matches using all applicable stereoselective transforms. This module was tested using a small set of selected target molecules and the generated routes were ranked using a series of measured parameters including: stereocentre clearance and bond cleavage; example reputation; estimated stereoselectivity with reliability; and evidence of tolerated functional groups. In addition a method for detecting regioselectivity issues is presented. This work presents a number of algorithms using common set and graph theory operations and notations. Appendix A lists the set theory symbols and meanings. Appendix B summarises and defines the common graph theory terminology used throughout this thesis

Kinetic model construction using chemoinformatics

Kinetic models of chemical processes not only provide an alternative to costly experiments; they also have the potential to accelerate the pace of innovation in developing new chemical processes or in improving existing ones. Kinetic models are most powerful when they reflect the underlying chemistry by incorporating elementary pathways between individual molecules. The downside of this high level of detail is that the complexity and size of the models also steadily increase, such that the models eventually become too difficult to be manually constructed. Instead, computers are programmed to automate the construction of these models, and make use of graph theory to translate chemical entities such as molecules and reactions into computer-understandable representations. This work studies the use of automated methods to construct kinetic models. More particularly, the need to account for the three-dimensional arrangement of atoms in molecules and reactions of kinetic models is investigated and illustrated by two case studies. First of all, the thermal rearrangement of two monoterpenoids, cis- and trans-2-pinanol, is studied. A kinetic model that accounts for the differences in reactivity and selectivity of both pinanol diastereomers is proposed. Secondly, a kinetic model for the pyrolysis of the fuel “JP-10” is constructed and highlights the use of state-of-the-art techniques for the automated estimation of thermochemistry of polycyclic molecules. A new code is developed for the automated construction of kinetic models and takes advantage of the advances made in the field of chemo-informatics to tackle fundamental issues of previous approaches. Novel algorithms are developed for three important aspects of automated construction of kinetic models: the estimation of symmetry of molecules and reactions, the incorporation of stereochemistry in kinetic models, and the estimation of thermochemical and kinetic data using scalable structure-property methods. Finally, the application of the code is illustrated by the automated construction of a kinetic model for alkylsulfide pyrolysis

A general computational tool for structure synthesis

Synthesis of structures is a very difficult task even with only a small number of components that form a system; yet it is the catalyst of innovation. Molecular structures and nanostructures typically have a large number of similar components but different connections, which manifests a more challenging task for their synthesis. This thesis presents a novel method and its related algorithms and computer programs for the synthesis of structures. This novel method is based on several concepts: (1) the structure is represented by a graph and further by the adjacency matrix; and (2) instead of only exploiting the eigenvalue of the adjacency matrix, both the eigenvalue and the eigenvector are exploited; specifically the components of the eigenvector have been found very useful in algorithm development. This novel method is called the Eigensystem method. The complexity of the Eigensystem method is equal to that of the famous program called Nauty in the combinatorial world. However, the Eigensystem method can work for the weighted and both directed and undirected graph, while the Nauty program can only work for the non-weighted and both directed and undirected graph. The cause for this is the different philosophies underlying these two methods. The Nauty program is based on the recursive component decomposition strategy, which could involve some unmanageable complexities when dealing with the weighted graph, albeit no such an attempt has been reported in the literature. It is noted that in practical applications of structure synthesis, weighted graphs are more useful than non-weighted graphs for representing physical systems. Pivoted at the Eigensystem method, this thesis presents the algorithms and computer programs for the three fundamental problems in structure synthesis, namely the isomorphism/automorphism, the unique labeling, and the enumeration of the structures or graphs

The Polytope Formalism: isomerism and associated unimolecular isomerisation

This thesis concerns the ontology of isomerism, this encompassing the conceptual frameworks and relationships that comprise the subject matter; the necessary formal definitions, nomenclature, and representations that have impacts reaching into unexpected areas such as drug registration and patent specifications; the requisite controlled and precise vocabulary that facilitates nuanced communication; and the digital/computational formalisms that underpin the chemistry software and database tools that empower chemists to perform much of their work. Using conceptual tools taken from Combinatorics, and Graph Theory, means are presented to provide a unified description of isomerism and associated unimolecular isomerisation spanning both constitutional isomerism and stereoisomerism called the Polytope Formalism. This includes unification of the varying approaches historically taken to describe and understand stereoisomerism in organic and inorganic compounds. Work for this Thesis began with the synthesis, isolation, and characterisation of compounds not adequately describable using existing IUPAC recommendations. Generalisation of the polytopal-rearrangements model of stereoisomerisation used for inorganic chemistry led to the prescriptions that could deal with the synthesised compounds, revealing an unrecognised fundamental form of isomerism called akamptisomerism. Following on, this Thesis describes how in attempting to place akamptisomerism within the context of existing stereoisomerism reveals significant systematic deficiencies in the IUPAC recommendations. These shortcomings have limited the conceptualisation of broad classes of compounds and hindered development of molecules for medicinal and technological applications. It is shown how the Polytope Formalism can be applied to the description of constitutional isomerism in a practical manner. Finally, a radically different medicinal chemistry design strategy with broad application, based upon the principles, is describe

Prospects in computational molecular medicine: a millennial mega-project on peptide folding

During the second half of the 20th century, Molecular Computations have reached to a level that can revolutionize chemistry. The next target will be structural biology, which will be followed soon by Molecular Medicine. The present paper outlines where we are at, in this field, at the end of the 20th century, and in what direction the development may take in the new millennium. In view of the gigantic nature of the problem, it is suggested that a suitably designed cooperative Millennial Mega-project might accelerate our schedule. (C) 2000 Elsevier Science B.V. All rights reserved