Toward Rational Understandings of α-C-H Functionalization: Energetic Studies of Representative Tertiary Amines

Abstract

Functionalization of α-C-H bonds of tertiary amines to build various α-C-X bonds has become a mainstream in synthetic chemistry nowadays. However, due to lack of fundamental knowledge on α-C-H bond strength as an energetic guideline, rational exploration of new synthetic methodologies remains a far-reaching anticipation. Herein, we report a unique hydricity-based approach to establish the first integrated energetic scale covering both the homolytic and heterolytic energies of α-C-H bonds for 45 representative tertiary amines and their radical cations. As showcased from the studies on tetrahydroisoquinolines (THIQs) by virtue of their thermodynamic criteria, the feasibility and mechanisms of THIQ oxidation were deduced, which, indeed, were found to correspond well with experimental observations. This integrated scale provides a good example to relate bond energetics with mechanisms and thermodynamic reactivity of amine α-C-H functionalization and hence, may be referenced for analyzing similar structure-property problems for various substrates.

Keywords: Organic Chemistry; Organic Synthesis; Physical Organic Chemistry.

Graphical abstract

Scheme 1

CDC Process of Tertiary Amines in Organic Synthesis

Scheme 2

Representative Reactivity Trends for THIQ-Involved Processes in Organic Synthesis (A) Substituent effects; (B) Effects of oxidants; (C) Mechanism diversities.

Scheme 3

Possible Pathways for Generation of Iminium Ions from Tertiary Amines

Scheme 4

Thermodynamic Cycles for Derivation of ΔH_HD(H), ΔH_HD(HD^•+), and ΔH_PD(HD^•+)

Figure 1

Hydricity Scale (ΔH_H-_D) of Amines (Colored Bars) and Hydride Affinity (ΔH_H-_A) for Common Hydride Acceptors in Acetonitrile (Data on Top) Note: p-BQ: p-benzoquinone; AcrH⁺: acridinium; T⁺: tropylium; PhXn⁺: 9-phenylxanthylium, also see Table S1 (Zhu et al., 2008a, Zhu et al., 2008b, Zhu et al., 2007).

Figure 2

Hydrogen-Atom-Donating Abilities (ΔH_HD) of Amines (Blue Bar) and Hydrogen Atom Affinities (ΔH_HA) of Common Acceptors Also see Table S1 (Cheng et al., 2016).

Scheme 5

Thermodynamic Analysis of Possible Pathways in the Oxidation of N-Ph-THIQ by DDQ (kcal mol⁻¹) Also see Table S1.

Scheme 6

Thermodynamic Rationalization of Possible Pathways for Oxidization of N-Ph-THIQ by Dual-Component Oxidants (A) the oxidatants are CuCl₂/O₂; (B) the oxidatants are CuBr/TBHP. Also see Table S2.