Direct Reversible Decarboxylation from Stable Organic Acids in Solution

Abstract

Many classical and emerging methodologies in organic chemistry rely on carbon dioxide extrusion to generate reactive intermediates for subsequent bond-­forming events. Synthetic reactions that involve the microscopic reverse, the carboxylation of reactive intermediates such as organometallic nucleophiles, occur under vastly different reaction conditions. We found that under appropriate conditions chemically stable C(sp3) carboxylates undergo rapid, uncatalyzed reversible decarboxylation in solution. The decarboxylation/carboxylation process occurs through the generation and trapping of otherwise undetectable carbanion intermediates that are largely resistant to protodecarboxylation in the presence of Brønsted acids or to trapping by external electrophiles. Isotopically labelled carboxylic acids, including drug molecules and valuable synthetic intermediates, can be prepared in high chemical and isotopic yield by simply supplying an atmosphere of 13CO2 to carboxylate salts in polar aprotic solvents. Our results indicate that the reversibility of decarboxylation from organic acids should be taken into consideration when designing and executing decarboxylative functionalization processes.

Origin of Free Energy Barriers of Decarboxylation and the Reverse Process of CO2 Capture in Dimethylformamide and in Water

“…In Nature, the equilibrium of decarboxylation and carboxylation is established through CO 2 release by respiring organisms and CO 2 fixation in photosynthesis on a mammoth scale of billions of tons per year. 3 Although the change from water to aprotic solvents can accelerate decarboxylation reactions, 4 we were intrigued by reports 5,6 that exchange between the carboxylate of ringsubstituted arylacetates (R−CO 2 − , Scheme 1) and labeled 13…”

“…− among recombination to form the reactant (k −1 ), protonation to form a ring-substituted toluene (k′ p ), and diffusional separation (k −d ) to form a free carbanion, which then partitions between protonation (k p ) and addition of isotope-labeled *CO 2 . Other competing pathways include a nucleophilic addition to the solvent DMF and a disproportionation process of arylacetates; 5,6 they have high reaction barriers (SI) and are not further discussed in this study. The observation of exchange of *CO 2 requires a large kinetic barrier to protonation of ring-substituted benzyl carbanions, compared to the barrier for addition of CO 2 : k d [*CO 2 ]≫ k′ p , k p .…”

Nickel-Catalyzed Deaminative Alkyl–Alkyl Cross-Coupling of Katritzky Salts with Cyclopropanols: Merging C–N and C–C Bond Activation

“…3 In this scenario, the pyridinium salts, which are readily prepared from aliphatic primary amines and pyrylium salt, acted as single-electron acceptors to promote the cleavage of the inert C(sp 3 )−N bonds and as alkyl radical reservoirs to facilitate the occurrence of the targeted cross-couplings. Since this elegant discovery, a variety of impressive deaminative functionalizations based on the utilization of these redox-active amines, 4 including arylations, 5 vinylations, 6 allenylation, 7 alkynylations, 8 borylations, 9 and other C−X bond-forming reactions, 10 have been well established. Nevertheless, the corresponding deaminative alkylation processes are still relatively scarce, and the existing approaches are mainly limited to photomediated radical addition to olefin partners or coupling with specific substrates.…”