SCIENCE & TECHNOLOGY
H-BONDS PROVIDE STRUCTURAL EDGE New constants will aid in designing compounds for drug and agrochemical applications
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ETS OF NUMERICAL STRUCTURAL
constants derived from the hydrogen-bonding ability of functional groups now can be used to correlate, analyze, and predict solute properties of compounds being screened for drug and agrochemical applications. The new constants are analogous to the widely used Hammett-Taft substituent constants and were developed by senior research fellow Michael H. Abraham of the department of chemistry at University College London and former postdoctoral researcher James A. Platts, who is now a chemistry lecturer at Cardiff University in Wales [J. Org. Chem., 66,3484 (2001)]. Substituent constants are calculated values that serve as indicators of the chemical properties of a substrate molecule when different functional groups are attached. Chemists have used these constants for many years in organic chemistry to deduce reaction mechanisms and to predict reaction rates. "The real usefulness of hydrogen-bond scales and the new structural group constants is to enable chemists to take account of hydrogen bonding quantitatively in a relatively simple way," Abraham says. There no longer will be a need to rely on estimated solute descriptors, he suggests, such as counting the number of hydrogen-bond acidic or basic groups on a molecule without consideration of their strengths. "Chemists will be able to look up values in tables of structural constants in the same way that they look up values in tables of Hammett constants."
THE FIRST SETS of substituent constants were calculated in the 1930s by Louis P. Hammett of Columbia University from an equation based on the ionization equilibria of substituted benzoic acids in water at 2 9 8 K. T h e H a m m e t t constants were extended in the 1950s by Robert W. Taft Jr., then at Pennsylvania State University, to include steric effects of functional groups in close proximity to one another. There are now many sets of substituent constants for aromatic and aliphatic compounds that are derived from linear freeHTTP://PUBS.ACS.ORG/CEN
energy relationships (LFERs) involving equilibrium constants and rate constants. The new constants established by Abraham and Platts are the first based on the ability of functional groups to act as acids or bases during hydrogen-bonding interactions. Preliminary work leading to the constants began in the late 1980s when Abraham and coworkers published the first general scales of functional group hydrogen-bond acidity and basicity THESE SCALES were derived from a set of equations based on the 1:1 complexation ! constants (log K at 298 K) between various compounds in tetrachloromethane. The 1:1 scales included some 190 hydrogen-bond acids and 500 hydrogen-bond bases, which were later expanded upon by other groups. Although these first scales are useful predictive tools, they're not additive if a compound has more than one ABRAHAM functional group. Nor do they take into account solvation effects, such I as dipole-dipole or dipole-induced dipole interactions with the functional group. Over time, a number of so-called solute descriptors—variables determined from chromatography methods and solubility data—have been devised by Abraham and coworkers to take solvation effects into account. These descriptors include overall hydrogen-bond acidity and basicity that apply to solutes that are surrounded by solvent molecules. The overall hydrogen-bond descriptors, Abraham notes, are the most useful for calculating the new structural constants, which can effectively be used as substituent constants. The term structural constant rather than substituent constant is used, Abraham says, because the Hammett-Taft substituent constants refer to the effect of a group in a molecule on a reaction center within that molecule, whereas the new hydrogen-bond structural constants refer to the effect of a group on the hydrogenbond properties of the whole molecule. From a practical standpoint, the struc- I
tural constants can be applied to physicochemical properties as LFERs and to biological properties as quantitative structureactivity relationships (QSARs), according to Abraham. Properties that can be investigated by LFERs include the solubility of gases, liquids, and solids in water; partitioning of various compounds between solvent phases; and chromatographic processes. QSARs have been set up for skin permeation by chemicals, blood-brain distribution and intestinal permeability of drugs, and the toxicity of gases and vapors to mice and humans. Chemistry professor Colin F. Poole of Wayne State University, Detroit, a past collaborator with Abraham, has used the hydrogen-bond acidity and basicity scales for a number of years in chromatography, sample preparation, and biopartitioning. The hydrogen-bond model has made an important contribution to understanding the retention process in chromatography and in the development of structuredriven, computer-aided method development, Poole says. T h e structural constants laid out in the new paper make a further important contribution to the field by helping to determine the required solute descriptors, Poole notes. "This is usually the stumbling block for most scientists using the model for the first time who require solute descriptors for compounds that lack experimental values," he says. "Thus a simple estimation method based on the summation of molecular fragments will have a great impact." T h e hydrogen-bond model is still young enough to be considered new to many scientists, Poole observes, "while sufficiently proven to suggest that a rapid expansion in its use is just around the corner." One company that has found Abraham's work useful is Syngenta. 'A key aspect of our work designing compounds with optimal bioavailability profiles is the determination of solute descriptors for the diverse chemical classes represented in agrochemicals," notes Eric D. Clarke, a Syngenta chemistry design consultant. The type of parameters established by Abraham and Platts and being further developed by other groups, including those at Syngenta, Clarke says, "will lead directly to improvements in predictive methods and significantly enhance our ability to reliably assess diverse mobility-related properties for agrochemical target structures."—STEVE RITTER C&EN
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