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 pi* (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.

Scheme 1

Regioselective cross-coupling reactions in the total synthesis of (+)-Dragmacidin F.

Figure 1

FMO interactions between PdLL' and Ar-X in an oxidative addition.

Figure 2

Comparison of BDEs computed using UB3LYP/6-31G(d) and G3B3 (kcal/mol). The correlation coefficint is R² = 0.975 ± 0.007.

Figure 3

Comparison of C-Cl and C-Br BDEs using UB3LYP/6-31G(d); BDEs in kcal/mol. The correlation coefficint is R² = 0.992 ± 0.002.

Figure 4

Bond angles of G3B3 calculated structures of 3-chlorothiophene and 3-chloropyrrole and the corresponding radicals.

Figure 5

Bond angles of mono and dichlorothiophene and of the corresponding radicals.

Figure 6

Bond angle and bond length analysis of G3B3 calculated structures of chloroisothiophene and its radicals.

Figure 7

C-Cl BDEs of 5-membered heterocycles with 3 or 4 heteroatoms using G3B3 (bold) and B3LYP (in parentheses), in kcal/mol.

Figure 8

C-Cl BDEs (kcal/mol) of mono and dichloropyrimidine, pyrazine and pyridazine using G3B3 (bold) and B3LYP (in parentheses).

Figure 9

C-Cl BDEs of 6-membered heterocycles using G3B3 (bold) and B3LYP (parentheses); energies in kcal/mol.

Figure 10

C-Cl BDEs of 6,5 fused- heterocycles using estimated G3B3 values (bold) and B3LYP values (parentheses); energies in kcal/mol. G3B3 BDEs were estimated using a linear regression model.

Figure 10

C-Cl BDEs of 6,5 fused- heterocycles using estimated G3B3 values (bold) and B3LYP values (parentheses); energies in kcal/mol. G3B3 BDEs were estimated using a linear regression model.

Figure 11

C-Cl BDEs of 6,6 fused heterocycles using G3B3 (bold) and B3LYP (parentheses); energies in kcal/mol. G3B3 BDEs were estimated using a linear regression model.

Scheme 2

Sonogashira cross-coupling reaction of 6-bromo 2,4-dichloroquinazoline 7.

Scheme 3

Definition of bond angle X-C-Y.

Figure 12

Bond angle vs. C-Cl BDE of chloro heterocycles and C-H BDE of heterocycles using G3B3. (Results for C-H BDEs from Feng et al.18)

Figure 13

Summary of C-Cl BDEs.