Heterocyclic Ambident Nucleophiles. V. Alkylation of Benzimidazoles

1993 ◽  
Vol 46 (8) ◽  
pp. 1177 ◽  
Author(s):  
JR Howell ◽  
M Rasmussen
Keyword(s):  
Transition State ◽  
Electrostatic Field ◽  
Alkyl Halides ◽  
Proximity Effects ◽  
Aprotic Solvents ◽  
Control Factors ◽  
Transition State Structures

Alkylation of 5-substituted benzimidazole anions with a variety of primary alkyl halides in both protic and aprotic solvents showed only small regioselectivity , with a slight preference for reaction at N1 for 5-nitro and N3 for 5-methoxy systems. With 4-substituted benzimidazole anions, alkylation gave more divergent results with the N1 to N3 regioselectivity varying between 100:0 and 29:71. These alkylation patterns are interpreted as deriving from an interplay of electrostatic, thermodynamic, steric and associative control factors within the variable SN2 transition state structures involved. In the 4-substituted series, proximity effects, both electrostatic field and steric non-bonded, are clearly dominant.

Ambident Heterocyclic Reactivity: Alkylation of 4-Substituted and 2,4-Disubstituted Benzimidazoles

1994 ◽  
Vol 47 (8) ◽  
pp. 1523 ◽  
Author(s):  
MR Haque ◽  
M Rasmussen
Keyword(s):  
Hydrogen Bonding ◽  
Transition State ◽  
Electrostatic Field ◽  
Transition States ◽  
Alkyl Halides ◽  
Methyl Group ◽  
Site Selectivity ◽  
Leaving Group ◽  
Standard Set ◽  
Specific Association

The N1/N3-alkylation patterns of 4-amino-, 4-methyl- and 4-nitro-benzimidazole anions, and their 2-methyl analogues, with a standard set of primary alkyl halides (in dimethylformamide, 30°) have been determined and compared. The observed regioselectivities are dominated by proximal effects-electrostatic field, non-bonded steric and in some cases specific association (hydrogen bonding)-the interplay of which is critically dependent on the (variable) geometries of the SN2 transition states involved, in particular on the N---C distance of the developing N-alkyl bonds. The presence of a symmetrically placed 2-methyl group produces an enhanced N1/N3 site selectivity, very sensitive to the loose-tight nature of the transition state. Halide leaving group effects on butylation regioselectivities of 2-unsubstituted, 2-ethoxy-, 2-methyl- and 2-chloro-4-methylbenzimidazole anions, whilst small, are consistent with a Bell-Evans-Polanyi analysis of SN2 transition state variations, with the earlier transition states of CH3(CH2)3I leading to reduced regioselectivities.

Heterocyclic ambident nucleophiles. II. The alkylation of adenine

1981 ◽  
Vol 34 (5) ◽  
pp. 1107 ◽  
Author(s):  
AE Beasley ◽  
M Rasmussen
Keyword(s):  
Transition State ◽  
Alkylating Agent ◽  
Alkyl Halides ◽  
Transition State Structures

The alkylation of un-ionized adenine by a variety of primary alkyl halides under standardized, common conditions (HCONMe2, 100�) was investigated. The alkylation pattern (N 1 : N 3 : N 7 : N 9) was found to be relatively insensitive to changes in the nature of the alkylating agent, except for cases involving benzyl chloromethyl ether and chloromethyl pivalate. An interpretation of these patterns in terms of modern ambient nucleophile reactivity concepts and variable SN2 transition state structures is presented.

scholarly journals Popular Integration Grids Can Result in Large Errors in DFT-Computed Free Energies

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Steven Wheeler
Keyword(s):  
Transition State ◽  
Molecular Orientation ◽  
Density Functional ◽  
Basis Sets ◽  
Free Energies ◽  
Functional Theory ◽  
Metal Free ◽  
Stereoselective Reactions ◽  
Functionalization Reaction ◽  
Transition State Structures

<div>Density functional theory (DFT) has emerged as a powerful tool for analyzing organic and organometallic systems and proved remarkably accurate in computing the small free energy differences that underpin many chemical phenomena (e.g. regio- and stereoselective reactions). We show that the lack of rotational invariance of popular DFT integration grids reveals large uncertainties in computed free energies for isomerizations, torsional barriers, and regio- and stereoselective reactions. The result is that predictions based on DFT-computed free energies for many systems can change qualitatively depending on molecular orientation. For example, for a metal-free propargylation of benzaldehyde, predicted enantioselectivities based on B97-D/def2-TZVP free energies using the popular (75,302) integration grid can vary from 62:38 to 99:1 by simply rotating the transition state structures. Relative free energies for the regiocontrolling transition state structures for an Ir-catalyzed C–H functionalization reaction computed using M06/6-31G(d,p)/LANL2DZ and the same grid can vary by more than 5 kcal mol–1, resulting in predicted regioselectivities that range anywhere from 14:86 to >99:1. Errors of these magnitudes occur for different functionals and basis sets, are widespread among modern applications of DFT, and can be reduced by using much denser integration grids than commonly employed.</div>

Evaluating transition state structures of vanadium–phosphatase protein complexes using shape analysis

2015 ◽  
Vol 147 ◽  
pp. 153-164 ◽  
Author(s):  
Irma Sánchez-Lombardo ◽  
Santiago Alvarez ◽  
Craig C. McLauchlan ◽  
Debbie C. Crans
Keyword(s):  
Transition State ◽  
Shape Analysis ◽  
Protein Complexes ◽  
Transition State Structures
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