The nucleophilicity N index (J. Org. Chem.2008, 73, 4615), the inverse of the electrophilicity, , and the recently proposed inverse of the electrodonating power, , (J. Org. Chem.2010, 75, 4957) have been checked toward (i) a series of single 5-substituted indoles for which rate constants are available, (ii) a series of para-substituted phenols, and for (iii) a series of 2,5-disubstituted bicyclic[2.2.1]hepta-2,5-dienes which display concurrently electrophilic and nucleophilic behaviors. While all considered indices account well for the nucleophilic behavior of organic molecules having a single substitution, the nucleophilicity N index works better for more complex molecules. Unlike, the inverse of the electrophilicity, , (R2 = 0.71), and the inverse of the electrodonating power, (R2 = 0.83), a very good correlation of the nucleophilicity N index of twelve 2-substituted-6-methoxy-bicyclic[2.2.1]hepta-2,5-dienes versus the activation energy associated with the nucleophilic attack on 1,1-dicyanoethylene is found (R2 = 0.99). This comparative study allows to assert that the nucleophilicity N index is a measure of the nucleophilicity of complex organic molecules displaying concurrently electrophilic and nucleophilic behaviors.

The nucleophilicity N index in organic chemistry

This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.

Predicting and tuning physicochemical properties in lead optimization: amine basicities.

In line with the charge transfer (ΔNmax = −μ/η) proposed by Parr et al (Parr, R G; Szentpaly, L V; Liu, S J Am Chem Soc 1999, 121, 1922), we propose an electrophilicity-based charge transfer (ECT) descriptor in this paper and validate it through the interaction between a series of chlorophenols and DNA bases Application of ECT can be extended to the interaction of any toxin with the biosystem

Electrophilicity-based charge transfer descriptor.

Update 1 of: Electrophilicity Index

An empirical nucleophilicity index based on the gas-phase ionization potentials has been recently shown to be useful categorizing and settling the nucleophilicity power of a series of captodative ethylenes reacting in cycloaddition reactions (L.R. Domingo, E. Chamorro, P. Perez, Journal of Organic Chemistry 73 (2008) 4615–4624). In the present work, the applicability of such model is tested within a broader series of substituted alkenes, substituted aromatic compounds and simple nucleophilic molecules. This index obtained within a Koopman’s theorem framework has been evaluated here in both gas and solution phases for several well-known nucleophiles. These results are found to be linearly correlated. Finally, the feasibility of the predictive character of this index has been discussed in comparison to the available experimental nucleophilicities of some amines in water. These results further support and validate the usefulness of such approximation in the modeling of the global nucleophilicity.

A further exploration of a nucleophilicity index based on the gas-phase ionization potentials

Global reactivity and local selectivity profiles such as electronegativity, hardness, polarizability, electrophilicity index, condensed Fukui function, and local electrophilic power of a selected polychlorinated biphenyl, viz., 2,2‘,5,5‘-tetrachlorobiphenyl have been calculated using the B3LYP/6-31G* method in gas and solution phases in order to gain insight into the toxic nature of this compound and a comparison is also made with 3,3‘,4,4‘,5-pentachlorobiphenyl. It is seen that both global and local electrophilicity helps in understanding the overall toxic nature of the system. The significance of the planarity and electron affinity in determining the toxic nature of the polychlorinated biphenyls is now better understood.

Chemical Reactivity Profiles of Two Selected Polychlorinated Biphenyls

In line with the local philicity concept proposed by Chattaraj et al. (Chattaraj, P. K.; Maiti, B.; Sarkar, U. J. Phys. Chem. A. 2003, 107, 4973) and a dual descriptor derived by Morell, Grand and Toro-Labbe, (J. Phys. Chem. A 2005, 109, 205), we propose a multiphilic descriptor. It is defined as the difference between nucleophilic (omega(k)+) and electrophilic (omega(k)-) condensed philicity functions. This descriptor is capable of simultaneously explaining the nucleophilicity and electrophilicity of the given atomic sites in the molecule. Variation of these quantities along the path of a soft reaction is also analyzed. Predictive ability of this descriptor has been successfully tested on the selected systems and reactions. Corresponding force profiles are also analyzed in some representative cases. Also, to study the intra- and intermolecular reactivities another related descriptor, namely, the nucleophilicity excess (Deltaomega(g)-/+) for a nucleophile over the electrophilicity in it, has been defined and tested on all-metal aromatic compounds.

Multiphilic descriptor for chemical reactivity and selectivity.

The philicity concept [J. Phys. Chem. A 2003, 107, 4973] is put in proper perspective. In the present work we analyze different physicochemical problems using philicity. It provides satisfactory results in all such cases. We also compare the relative electro(nucleo)philicity with philicity to show that philicity is better than relative electro(nucleo)philicity when the intermolecular reactivity trends are considered and there is hardly any preference of one above the other as far as the intramolecular reactivities are concerned. On the contrary, the philicity concept has some advantages over the other concept.

Careful scrutiny of the philicity concept.

Acid-base dissociation constants (pK a values) are important in understanding the chemical, environmental and toxicological properties of molecules. Though various methods have been developed to predict pK a by experimental and theoretical models, prediction of pK a is still complicated. Hence, a new approach for predicting pK a using the group philicity concept has been attempted. Presence of known functional groups in a molecule is utilized as the most important indicator to predict pK a . The power of this descriptor in describing pK a for the series of carboxylic acids, various substituted phenols, anilines, phosphoric acids, and alcohols is probed. Results reveal that the group electrophilicity is suitable for effectively predicting the pK a values.

J. Padmanabhan

Papers

Electrophilicity-based charge transfer descriptor.

Chemical Reactivity Profiles of Two Selected Polychlorinated Biphenyls

Multiphilic descriptor for chemical reactivity and selectivity.

Careful scrutiny of the philicity concept.

pKa prediction using group philicity.