Tuning hydrogen atom abstraction from the aliphatic C–H bonds of basic substrates by protonation. Control over selectivity by C–H deactivation

Abstract

A kinetic study on the effect of acetic (AcOH) and trifluoroacetic acid (TFA) on hydrogen abstractions from the C-H bonds of basic substrates by the cumyloxyl radical (CumOc) was carried out in acetonitrile. With tetrahydropyran no significant effect on k H was observed after acid addition. With the more basic tertiary amines acid addition led to greater than 4-orders of magnitude decreases in k H . Protonation at nitrogen decreases the degree of overlap between the a-C-H s* orbital and the lone-pair leading to an increase in the strength of the C-H bond and a destabilization of the radical formed after abstraction.Evidence that C-H deactivation extends up to the g-C-H bonds and for the reversibility of this approach was also provided. With TFA no reaction was observed up to [amine] ¼ [TFA], pointing towards stoichiometric protonation. At [amine] > [TFA], k H values that are very similar to those measured in the absence of added acid were obtained. With the weaker acid, AcOH, no reaction was observed up to[AcOH]/[amine] $4, and a curved plot was observed with increasing [amine], as a result of the acidbase equilibrium between AcOH and the amine. With 1,4-dimethylpiperazine, a quantitative evaluation of the C-H deactivation determined by sequential protonation of one or both nitrogen centers was obtained. These observations show that protonation provides an extremely efficient, precise and tunable method for the deactivation of the C-H bonds of basic substrates allowing moreover for careful control over the hydrogen abstraction selectivity. The implications of this approach are discussed.

Optimization of reaction parameters for the electrochemical oxidation of lidocaine with a Design of Experiments approach

“…Salamone et al proposed that hydrogen abstraction from the aliphatic C-H group adjacent to a basic group can be tuned depending on the strength of the added acid [34]. If lidocaine N-dealkylation is indeed initiated in this way, then acidic conditions should prevent Ndealkylation, whereas basic conditions should favor this reaction, as observed in our study.…”

“…The results can, however, be reconciled with the mechanistic view that abstraction of a hydrogen atom from the CH group adjacent to the tertiary amine is critical to initiate the N-dealkylation reaction [34]. This proposed mechanism was confirmed by blocking the reaction completely at pH 0.5, well below the pH range initially used.…”

Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at Remote Benzylic C–H Sites

“…10 This should deactivate proximal C–H sites, thereby enabling selective oxidation remote to nitrogen. 11,12 …”

Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C−H Bond Functionalization

“…[51] This behavior was explained in terms of the stoichiometric protonation of the amine substrate by TFA( Scheme 23). Them easured k H value for [substrate] > [TFA] was essentially identical to the value measured in MeCN in the absence of added TFA.…”