Carboxylic acids are prevalent functional groups found in numerous biologically active molecules and natural compounds^[1,2]. Beyond their significance in bioactive compounds, carboxylic acids also serve as valuable synthetic linchpins in organic chemistry, providing functional handles for a wide range of useful transformations^[3,4]. Compared to traditional synthetic methods for carboxylic acid formation^[5-7], the use of CO₂ as a carboxyl source has attracted considerable interest due to its low toxicity, affordability, and renewability^[8,9]. Many strategies for converting CO₂ into carboxylic acids rely on excess CO₂ gas or high-pressure conditions to drive the reaction forward^[10,11]. Additionally, the high thermodynamic stability and low reactivity of CO₂ often necessitate sensitive organometallic reagents (e.g., organolithium and Grignard reagents) or other preactivated substrates to form C–CO₂H bonds^[12,13]. However, as carboxylic acid derivatives become increasingly complex for applications in materials science, biomedicine, and drug discovery^[14], new synthetic routes must be developed to minimize both the length and cost of synthesis.

Recently, the ready availability of carboxylic acids has led to the development of decarboxylative coupling reactions, in which carboxylic acids function as user-friendly cross-coupling partners^[15]. In these reactions, the released CO₂ is typically considered as a waste. Catalytic reversible transfer reactions, such as alkene metathesis^[16,17] and transfer hydrogenation^[18,19], are key transformations in modern organic chemistry. Building on these foundational techniques, researchers have developed shuttle catalysis processes that transfer functional groups between donor and acceptor molecules^[20]. In this context, CO₂ shuttling, where CO₂ is transferred from a readily available carboxylic acid or its derivative to an acceptor molecule, has emerged as a promising method for generating new molecules. Several CO₂ shuttling systems have recently been reported, utilizing carboxylic acids (R₁CO₂H) or their derivatives (R₁CO₂R₂) as CO₂ donors instead of excess CO₂ gas [Figure 1]^[21-35].

Notably, formate salts (R₁CO₂M, R₁ = H; M = Na, K, Cs) have recently gained prominence in organic chemistry as CO₂^•- sources for accessing valuable carboxylic acids. For example, Hendy et al. and Alektiar et al. developed alkene hydrocarboxylation reactions mediated by CO₂^•-, which was generated via hydrogen atom transfer (HAT) from formate salts^[21,22]. Since then, numerous studies and reviews have summarized carboxylation reactions involving HAT of formate salts^[23], so further discussion will not be provided here. Additionally, amino acids (AAs) and organic acids have proven to be attractive reactants in CO₂ shuttling reactions, serving multiple roles as reaction substrates, bases, and CO₂ donors^[24-35]. This approach circumvents the need for excess CO₂ or pressurized vessels, offering a more versatile and safer method for functional group interconversion.

This Perspective summarizes recent advances in CO₂ shuttling that exploit carboxylic acids and their derivatives (R₁CO₂R₂, R₁ ≠ H) as potential CO₂ donors, including carbonates, α-amino acids (α-AAs), and organic carboxylates. We also explore potential future developments in CO₂ shuttling strategies.

Carbonates (e.g., OCO₂Me or OCO₂^tBu) are among the most commonly used leaving groups in substitution reactions, where their cleavage releases CO₂ gas while simultaneously generating an alkoxide anion^[24-31]. Efficient re-fixation of the resulting CO₂ into organic molecules aligns with the principle of carbon economy, making the development of such methods highly desirable. In 2001, Yoshida et al. introduced the concept of CO₂ recycling to develop a novel approach for synthesizing cyclic carbonates. As shown in Figure 2, their proposed mechanism involved sequential CO₂ elimination and fixation. In this process, a palladium catalyst promoted the decarboxylation of a propargylic carbonate, generating allenylpalladium methoxide intermediate (Int-1) and CO₂. Deprotonated phenols then underwent nucleophilic attack on Int-1, forming the π-allylpalladium complex (Int-3), which subsequently re-fixed CO₂ to yield carbonate species Int-4. Cyclization of this intermediate produced aryloxy-substituted cyclic carbonates^[24]. This is the first reported example of efficient CO₂ re-fixation from carbonate decarboxylation reactions. Since then, numerous reactions based on the CO₂ elimination-fixation process have been developed, enabling the synthesis of chiral cyclic carbonates, vinyl-substituted cyclic carbonates, 1,3-dienyl-substituted cyclic carbonates, oxazolidinones, allenic oxazolidin-2-ones, and branched allyl carbamates [Figure 3]^[25-30].

In 2024, Li et al. introduced Cu-catalyzed stereoselective propargylation and alkynylallylic substitution strategies that integrate CO₂ shuttling and fixation. In these reactions, a variety of alkynyl carbonates underwent decarboxylation and then asymmetric propargylation or alkynylallylic substitution with primary amines in sequence. The resulting propargyl amines then captured CO₂ released from decarboxylation. Experimental and computational mechanistic studies indicated that the reaction proceeded via a CO₂ shuttling pathway as depicted in Figure 4. Additionally, DABCO was proposed to facilitate the capture of low-concentration CO₂, while the cyclization process likely involved a rate-limiting step^[31].

AAs, particularly the readily available and inexpensive α-AAs, are essential and widely occurring carboxylic acids that play a crucial role in nature. Recently, Liao et al. reported an elegant approach to alkene carboxylation using α-AAs as CO₂ surrogates. The proposed photocatalytic radical mechanism, which incorporated CO₂ shuttling, was depicted in Figure 5. Upon irradiation, single-electron transfer (SET) occurred between the photoexcited Ir(III) catalyst and the α-AA salt, which formed in situ upon deprotonation of the α-AA in the presence of a base. Cyclic voltammetry (CV) experiments revealed that the carboxylate form is more readily oxidized than the corresponding carboxylic acid during the SET process, highlighting the critical role of the base. For example, when N-Cbz-Pro-OH was tested in the presence of CsF, a distinct oxidative peak was observed at +1.37 V. In contrast, no oxidative peak appeared in the absence of CsF. This SET process generated the α-amino alkyl radical (Int-5) and CO₂. The radical then added to the alkene, forming intermediate Int-6, which underwent another SET with the Ir(II) photocatalyst to yield the key carbanion intermediate (Int-7). In this system, the CO₂ produced in situ at low concentration was efficiently recaptured by Int-7, leading to the desired carboxylated product^[32]. Luminescence quenching experiments demonstrated that the quenching rate for product is much slower than that of substrate in presence of CsF, which might be the reason for more facile decarboxylation of substrate than product under the reaction conditions^[32]. In stark contrast to conventional carboxylation methods that require high pressure and/or excess CO₂ gas, this strategy offers an efficient and sustainable alternative by utilizing CO₂ shuttling with near-stoichiometric amounts of α-AAs as CO₂ donors.

Wang et al. recently demonstrated the carboxylation of heteroarenes, electron-deficient arenes and terminal alkynes using triphenylacetic acid potassium salt as a bifunctional reagent, acting as both a base and a CO₂ donor. The proposed mechanism was outlined in Figure 6. This strategy relied on the decarboxylation of triphenylacetic acid potassium salt to generate CO₂ and the trityl anion (Int-8). Due to its high basicity (pKa of Ph₃CH = 30.6 in DMSO)^[36], the trityl anion could efficiently deprotonate substrates, forming alkyl carbanion (Int-9), which subsequently recaptured the in situ generated CO₂ to yield the desired carboxylated product. Notably, this reaction system enables CO₂ shuttling carboxylation of certain acidic C–H bonds and provides a convenient route for synthesizing ¹³C-labeled molecules^[34].

Similarly, in 2024, Liu et al. reported a sequential approach for synthesizing α-keto acids by integrating umpolung reactivity with CO₂ shuttling, utilizing triphenylacetic acid potassium salt as a formal CO₂ donor. The reaction began with the umpolung activation of carbonyl compounds using thiol, facilitating the carboxylation of aldehydes. The subsequent CO₂ shuttling process was key to obtaining α-keto acids. This transition-metal-free shuttle carboxylation method effectively transfers CO₂ from triphenylacetic acid potassium salt to dithioacetals, eliminating the need for pressurized CO₂ gas or specialized equipment. Moreover, this approach has been extended to achieve complete ¹³C labeling of α-keto acid derivatives with biological and pharmacological relevance [Figure 7]^[35].

CO₂ shuttling has emerged as a promising strategy for sustainable carboxylation reactions, enabling efficient CO₂ utilization without requiring excess gaseous CO₂ or high-pressure conditions. In recent years, significant progress has been made in this field through the development of diverse carboxylic acid derivatives - such as carbonates, AAs, and triphenylacetic acids - as CO₂ donors within various reaction models. These advances underscore the potential of CO₂ shuttling as a carbon-economical and sustainable synthetic tool, offering new opportunities for functional group interconversion and isotope labeling in organic chemistry. Despite these achievements, key challenges remain. While CO₂ shuttling strategies have enabled the carboxylation of heteroarenes and electron-deficient arenes, the direct carboxylation of electron-rich arenes remains unresolved. Additionally, the selective C(sp³)-H carboxylation of simple linear alkanes via CO₂ shuttling remains elusive. Another critical frontier is the design of novel and stereoselective carboxylating agents for constructing chiral carboxylic acid derivatives. Advancing these methodologies could significantly expand the synthetic utility of CO₂ shuttling and warrants further intensive research.

Beyond synthetic applications, CO₂ shuttling holds particular promise for carbon isotope labeling, which is essential in nuclear medicine and drug discovery. The high cost of carbon isotope-labeled building blocks makes efficient synthetic methods highly valuable. Carbon isotopic CO₂ has recently emerged as an attractive primary isotope source; however, the need for large excesses and high-pressure conditions presents economic and safety concerns. An ideal approach would involve stoichiometric isotopic CO₂ precursors that release CO₂ gradually, enabling more controlled and efficient labeling. This CO₂ shuttling paradigm could pave the way for the complete ¹³C labeling of carboxylic acids, further broadening its applicability in synthetic and pharmaceutical chemistry.