Intrinsic Nucleofugality Scale within the Framework of Density Functional Reactivity Theory

Abstract

Nucleofugality is a measure of the quality of a leaving group in substitution and elimination reactions. In a conceptual DFT context, the nucleofugality is calculated for an elaborate set of common organic leaving groups, both in the gas phase and in two organic solvents (dichloromethane and methanol). An intrinsic nucleofugality scale is constructed showing fair agreement with the classical trends in leaving group capacity in organic chemistry. The correlation of the results with acidities (tabulated pK(a) values) on one hand and experimental solvolysis reaction rate constants (kinetic parameters) on the other hand is discussed. Finally, a conceptual DFT based formula is derived, describing the influence of the solvation energy on the nucleofugality; excellent correlations were found with explicit calculations for the studied leaving groups.

Bisubstrate Adenylation Inhibitors of Biotin Protein Ligase from Mycobacterium tuberculosis

“…We immediately observed that it is chemically unstable and decomposes through cyclonucleoside formation to afford N -biotinylsulfamic acid 7 (Figure 1C) and 3,5′-cyclo-5′-deoxyadenosine 8 (experimental details and complete characterization are found in the Supplemental Information). We hypothesized that a more stable compound would result if the 5′-oxygen atom in sulfamate 5 were replaced with a nitrogen atom of sulfamide 6 as a result of the decreased nucleofugality of the sulfamide (Broeckaert et al, 2008). Compound 6 (Bio-AMS) was synthesized, and as predicted, it did not undergo cyclonucleoside formation.…”

Effect of the Leaving Group and Solvent Combination on the LFER Reaction Constants

“…Reasonably good correlation has recently been found between the electrofugality paramameters ( E f ) and the theoretical electrofugality indexes ( ν − ) for the referent benzhydrylium ions [35]. In addition, intrinsic nucleofugalities for numerous leaving groups have been calculated by using theoretical background that has not included heterolytic transition states [36]. …”

Predicting the quality of leaving groups in organic chemistry: Tests against experimental data

“…This delocalization of the negative charge will change the free energy of solvation of the ions and, in addition, change the hydrogen-bonding pattern around the nucleofuge. Hydrogen bonding is something that cannot be captured accurately in continuum solvation models, which perhaps explains why sulphonates were problematic in earlier computational studies using continuum solvation models also [33]. One may note that the two most problematic phosphinates (molecule P5 and P6) should be better at forming hydrogen bonds (and thus more stabilised) in solution than the other molecules in this family.…”