Structure-based classification and ontology in chemistry

<p>Abstract</p> <p>Background</p> <p>Recent years have seen an explosion in the availability of data in the chemistry domain. With this information explosion, however, retrieving <it>relevant </it>results from the available information, and <it>organising </it>those results, become even harder problems. Computational processing is essential to filter and organise the available resources so as to better facilitate the work of scientists. Ontologies encode expert domain knowledge in a hierarchically organised machine-processable format. One such ontology for the chemical domain is ChEBI. ChEBI provides a classification of chemicals based on their structural features and a role or activity-based classification. An example of a structure-based class is 'pentacyclic compound' (compounds containing five-ring structures), while an example of a role-based class is 'analgesic', since many different chemicals can act as analgesics without sharing structural features. Structure-based classification in chemistry exploits elegant regularities and symmetries in the underlying chemical domain. As yet, there has been neither a systematic analysis of the types of structural classification in use in chemistry nor a comparison to the capabilities of available technologies.</p> <p>Results</p> <p>We analyze the different categories of structural classes in chemistry, presenting a list of patterns for features found in class definitions. We compare these patterns of class definition to tools which allow for automation of hierarchy construction within cheminformatics and within logic-based ontology technology, going into detail in the latter case with respect to the expressive capabilities of the Web Ontology Language and recent extensions for modelling structured objects. Finally we discuss the relationships and interactions between cheminformatics approaches and logic-based approaches.</p> <p>Conclusion</p> <p>Systems that perform intelligent reasoning tasks on chemistry data require a diverse set of underlying computational utilities including algorithmic, statistical and logic-based tools. For the task of automatic structure-based classification of chemical entities, essential to managing the vast swathes of chemical data being brought online, systems which are capable of hybrid reasoning combining several different approaches are crucial. We provide a thorough review of the available tools and methodologies, and identify areas of open research.</p

The concept of protobranching and its many paradigm shifting implications for energy evaluations

Branched alkanes like isobutane and neopentane are more stable than their straight chain isomers, n-butane and n-pentane (by 2 and 5 kcal mol(-1), respectively). Electron correlation is largely responsible. Branched alkanes have a greater number of net attractive 1,3-alkyl-alkyl group interactions, there are three such stabilizing 1,3 "protobranching" dispositions in isobutane, but only two in n-butane. Neopentane has six protobranches but n-pentane only three. Propane has one protobranch and is stabilized appreciably, by 2.8 kcal mol(-1), relative to methane and ethane. This value per protobranch also applies to the n-alkanes and cyclohexane. Consequently, energy evaluations employing alkane reference standards, for example, of small ring strain and stabilizations due to conjugation, hyperconjugation, and aromaticity, should be corrected for protobranching, for example, by employing Pople’s isodesmic bond separation reaction method. This reduces the ring strain of cyclopropane to 19.2 from the conventional 27.7 kcal mol(-1), while the stabilization energies of alkenes and alkynes due to hyperconjugation (5.5 and 7.7 kcal mol(-1) for propene and propyne) and conjugation (14.8 and 27.1 kcal mol(-1) for butadiene and butadiyne) are considerably larger than the traditional estimates. Widely diverging literature evaluations of benzene resonance energy all give approximate to 65kcal mol(-1) after adjusting for conjugation, hyperconjugation, and protobranching "contaminations." The BLW (block localized wavefunction) method, which localizes pi bonds and precludes their interactions, largely confirms these stabilization estimates for hyperconjugation, conjugation, and aromaticity. Protobranching is seriously underestimated by theoretical computations at the HF and most DFT levels, which do not account for electron correlation satisfactorily. Such levels give bond separation energies, which can differ greatly from experimental values

Strain and reactivity: Electrophilic addition of bromine and tribromide salts to cyclic allenes

The kinetics and the products of the bromination of several cyclic allenes, from C-9 to C-13 (1a-e), with tetrabutylammonium tribromide (TBAT) and Br-2 have been investigated in 1,2-dichloroethane (DCE) and methanol. The first product of the interaction between the allene and Br-2 is a 1:1 pi complex. The stability constant of this complex, determined at 25degreesC for allene 1a, is 7.4m(-1). The comparison of this value with those reported for several alkenes and alkynes further support the hypothesis of the existence of sizeable structural effects on the stability of these complexes. The negative values of the apparent activation energy for the reaction of allenes 1a-e with Br-2 in DCE demonstrate the involvement of these complexes as essential intermediates along the reaction coordinate. Different stereochemical behavior was observed in the bromine addition on going from the strained 1,2-cyclononadiene to the larger compounds. Furthermore, a solvent-dependent stereochemistry has been observed for each compound. The kinetic and product distribution data have been interpreted in terms of the influence of the strain on the nature of the intermediate and by considering the competition between pre-association and ion-pair pathways on going from aprotic to nuclophilic solvents or when nucleophilic bromide ions are added. Ab initio (MP2/6-311 + G**) and density functional (B3LYP/6-311 + G**) computations of 1:1 Br-2 complexes showed that the association energies of allene Br-2 and ethene Br-2 complexes are nearly the same but are greater than that of acetylene Br-2 complexes. Allene 2Br(2) complexes are more stable than their ethene 2Br(2) counterparts. Br-2 allene Br-2 structures, in which the bromine molecules interact either with a single allene double bond or individually with both double bonds, are not preferred significantly over alternatives with (Br2Br2)-Br-... interactions. As a result of the entropy, the association of bromine with unsaturated hydrocarbons is usually unfavorable in the gas phase (except at extremely low temperatures); complexes are observed in solution (under ambient conditions), since the entropy loss is reduced as a result of restricted translation and rotation and possible association to the solvent. The 1,2-cycloheptadiene Br-2 > 1,2-cyclononadiene Br-2 > 1,3-dimethylallene Br-2 association energies increase with ring strain