Theoretical Bond Dissociation Energies of Halo-Heterocycles: Trends and Relationships to Regioselectivity in Palladium-Catalyzed Cross-Coupling Reactions

Abstract

Selectivity of the palladium-catalyzed cross-coupling reactions of heterocycles bearing multiple identical halogens is mainly determined by the relative ease of oxidative addition. This is related to both the energy to distort the carbon halogen bond to the transition-state geometry (related to the CX bond-dissociation energy) and to the interaction between the heterocycle π* (LUMO) and PdL 2 HOMO (J. Am. Chem. Soc. 2007, 129, 12664). The computed bond dissociation energies of a larger series of halo-heterocycles have been explored with B3LYP and higher accuracy G3B3 calculations. Quantitative trends in bond dissociation energies have been identified for five-and six-membered chloro and bromo substituted heterocycles with N, O, and S heteroatoms.

Synthesis and Photophysical Property Studies of the 2,6,8-Triaryl-4-(phenylethynyl)quinazolines

“…This observation was found to compare with previous literature results for the Suzuki-Miyaura cross-coupling reactions of the analogous 2-arylquinolines bearing two bromine atoms on the fused benzo ring [9] and 3,6,8-tribromoquinoline which occur without selectivity [24]. Computed bond dissociation energies at B3LYP and G3B3 levels reveal that all of the positions on the fused benzo ring of various heterocycles bearing identical halogen atoms have comparable C-X bond dissociation energies [3]. This presumably accounts for the observed lack of selectivity.…”

“…The 2-substituted quinazolin-4(3H)-ones have also been synthesized directly from anthranilamide and aldehydes using NaHSO 3 [14], DDQ [15], CuCl 2 (3 equiv.) [16], FeCl 3 .6H 2 O [17] or I 2 [18]. In this investigation, we exploited the combined electrophilic (cyclocondensation) and oxidative (dehydrogenation) properties of iodine on 3,5-dibromobenzamide 1 and benzaldehyde derivatives 2a-d in ethanol under reflux for 7 h to afford products 3a-d in a single-pot operation (Scheme 1).…”

“…The electronic absorption spectra of compounds 6a-l (Figures 1-3) were acquired in CHCl 3 and are characterized by intense broad bands in the ultraviolet region λ 270-295 nm. These bands are attributed to the π-π* transition and the intramolecular donor-acceptor charge transfer absorption, respectively [25].…”

“…It has been established that the order of reactivity of carbon-halogen bonds, C-I > C-Br >> C-Cl, in transition metal-mediated cross-coupling of aryl/heteroaryl halides allows selective coupling with iodides or bromides in the presence of chlorides [1,2]. Although the bond dissociation energy (BDE) of the C-Cl bond at the 4-position (84.8 kcal/mol at B3LYP) of 6-bromo-2,4-dichloroquinazoline is larger than that of the weaker C-Br bond (83 kcal/mol at B3LYP) [3], the selectivity of Pd-catalyzed cross-coupling favours C-4 substitution due to α-nitrogen effect [4,5]. For cross-coupling reactions employing 2,4-dichloroquinazoline, for example, exclusive selectivity for the most electrophilic C-4 position is favoured [3,4,6].…”

“…Although the bond dissociation energy (BDE) of the C-Cl bond at the 4-position (84.8 kcal/mol at B3LYP) of 6-bromo-2,4-dichloroquinazoline is larger than that of the weaker C-Br bond (83 kcal/mol at B3LYP) [3], the selectivity of Pd-catalyzed cross-coupling favours C-4 substitution due to α-nitrogen effect [4,5]. For cross-coupling reactions employing 2,4-dichloroquinazoline, for example, exclusive selectivity for the most electrophilic C-4 position is favoured [3,4,6]. Likewise, regioselective Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of 2,4,7-trichloroquinazoline with aryl-and heteroarylboronic acids favours coupling at C-4 position albeit in low yield due to competitive hydrolysis at this site [7].…”