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. 2026 Jan 7;17:1510. doi: 10.1038/s41467-025-68224-z

Tetrachloromethane as an editable all-carbon quaternary source

Tingrui Li 1,2,3,4, Zhi Liu 1,2,3,4, Yulong Fu 1,2,3,4, Hongliang Chen 1,2,3,4, Jun Huang 1,2,3,4, Yongxing Tang 5,✉, Jin Xie 1,2,3,4,6,✉
PMCID: PMC12891700  PMID: 41501045

Abstract

Despite the widespread presence of all-carbon quaternary centers in natural products and bioactive compounds, a concise construction strategy remains very challenging. Herein, we introduce a highly controllable sequential dechlorination strategy of tetrachloromethane by means of relay catalysis with different photocatalysts of eosin Y, 1,2,3,5-tetrakis(carbazol-9-yl)−4,6-dicyanobenzene and Au2(µ-dcpm)2Cl2. Four C-Cl bonds in CCl4 can undergo sequential, highly selective cleavage by combination of outer-sphere and inner-sphere crossover single electron transfer mechanism, enabling radical-addition reactions with a wide range of terminal alkenes to construct all-carbon quaternary centers in four steps with 17-38% yields. Furthermore, using 1,1-disubstituted styrene as the substrates, cyclopropanes bearing with challenging vicinal all-carbon quaternary centers are also successfully constructed from CCl4 in two-pots three steps with moderate yields of 10-50%. This work suggests the possibility of tetrachloromethane as an editable C1 synthon to facilitate the construction of all-carbon quaternary centers.

Subject terms: Photocatalysis, Synthetic chemistry methodology

All-carbon quaternary centers are ubiquitous in natural products and bioactive molecules, yet strategies for their streamlined construction remain scarce. Here, the authors report a sequential dechlorination strategy of tetrachloromethane, offering a concise route to quaternary carbon frameworks.

Introduction

The properties of organic molecules are intrinsically linked to their structures. C(sp3)-hybridized atoms, particularly all-carbon quaternary centers, serve as an important scaffold in pharmaceuticals, functionalized materials, and natural products (Fig. 1a)1–5, providing a promising platform to escape flatland6. Consequently, the development of practical synthetic methodologies to construct quaternary carbon centers has gained increasing momentum in recent years7–10. While significant progress11–17 has been achieved, the assembly of a general method for all-carbon quaternary centers, especially those with four distinct carbon substituents, still represents the state-of-the-art in organic synthesis. Very recently, atomic carbon strategy has been proven to be a valuable strategy which can facilitate the formation of four covalent bonds using a C1 synthon (Fig. 1b)18–21. For example, in 2023, Tobisu22 reported a N-heterocyclic carbenes facilitated atomic carbon transfer reaction, which could construct γ-lactams from acrylamides. In 2025, Hansmann23 reported a C(sp3)-atom transfer reaction to construct highly strained spiro[2.2]pentanes structures in a three steps manner.

Fig. 1. The importance of alkanes with all-carbon quaternary centers and our work design.

Fig. 1

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a All-carbon quaternary centers in biologically important compounds. b Recent advances in atomic carbon chemistry. c Our design: photocatalyst-controlled relay activation of CCl4. d This work: relay dechlorinative alkylation of CCl4 to access multiple alkyl quaternary centers.

Considering the highly functionalized C1 synthon needed in most atomic carbon strategies, as well as with our continuing interest in photocatalytic activation of C-Cl bonds24–38, we questioned if the commercially available carbon tetrachloride, one of the functionalized C1 sources, would serve as an editable carbon center by photocatalyst-controlled relay dechlorinative functionalization. Generally, both carbon tetrachloride and alkyl carbon trichloride have a moderate reduction potential (Ered = −1.6 ~ −2.0 V versus saturated calomel electrode (SCE))39 and could be actively involved in radical C(sp³)–C(sp³) bond formation by using a redox-matched photocatalyst40. However, the gem-dichloroalkanes and tertiary alkyl chlorides (Ered = ~ −2.8 V versus SCE)41 in such an outer-sphere single-electron transfer mechanism are limited by the inherent redox potentials of the photocatalysts.

A pioneering but in non-catalytic approach was described by Wang and co-workers in 202242,43, who successfully used Lewis base–boryl radicals as promoters and selectively alkylated the three C–Cl bonds of activated trichloromethyl groups. Despite this impressive advance, significant challenges remain in the development of a new catalytic strategy to realize selective relay activation of four C–Cl bonds in CCl4, accessing all-carbon quaternary carbon centers. As part of our ongoing efforts, we sought to combine different kinds of commercially available photocatalysts bearing different redox potential44 with dinuclear gold-complex developed in our group45–53, which would precisely control the dechlorination selectivity through outer-sphere and inner-sphere crossover single electron transfer (SET) mechanism (Fig. 1c).

Herein, we report a photocatalytic relay strategy that enables construct all-carbon quaternary centers from carbon tetrachloride (Fig. 1d). Four C−Cl bonds in CCl4 have been selectively and sequentially activated by eosin Y, 1,2,3,5-tetrakis(carbazol-9-yl)−4,6-dicyanobenzene (4CzlPN), and Au2(μ-dcpm)2Cl2, generating corresponding alkyl radical intermediates, which can subsequently add to alkenes to introduce four different alkyl substituted quaternary carbon center compounds in moderate yields. Interestingly, cyclopropanes bearing with challenging vicinal all-carbon quaternary centers have been successfully constructed for CCl4 with relay dechlorinative strategy.

Results and discussion

Reaction development

We initiated our investigations by reacting CCl4 with 4-methoxystyrene using various photocatalysts under visible light irradiation (λmax = 460 nm). After a preliminary screening, it was found that the organic dye eosin Y (1/2E = −1.01 V vs. SCE)44 could successfully activate only one C–Cl bond of CCl4 (Ep = −1.51 V vs. SCE, Fig. 2a) in acetonitrile, yielding the desired trichloroalkane (4) in 81% yield without over dechlorination. Additional experiments demonstrated that γ-terpinene, acting as an H-donor, and N,N’-dimethyl-1,3-propanediamine, serving as a base, are crucial for a productive outcome. During the optimization process, it is interesting to find that employing photoredox catalyst 4CzIPN (1/2E = −1.21 V vs. SCE)44, enables the second dechlorination process of trichloroalkane (4) (Ep = −1.75 V vs. SCE), yielding the gem-dichloroalkanes as byproduct. This finding suggests that continuous dechlorinative process can be controlled via relay photocatalysis. Inspired by this, we successfully obtained the desired two different alkyl-substituted gem-dichloroalkane (5) with an overall yield of 69% in a one-pot process (Fig. 2b). Light irradiation, triethanolamine, and the photocatalyst 4CzIPN were essential for the success of the transformation.

Fig. 2. Reaction development.

Fig. 2

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a Cyclic voltammetry studies of alkyl chlorides. The Ag/Ag+ (Ag wire in 0.01 M AgNO3 with 0.1 M nBu4Cl in MeCN) was used as the reference electrode at a scan rate of 100 mV s−1, Ep, peak potential. b Activation of CCl4 and RCCl3 via outer-sphere SET (redox potential matched with PC). c Activation of gem-dichloroalkanes via inner-sphere SET (condition C).

It is notable that commonly used strong reducing photocatalysts, such as fac-Ir(ppy)3, remain challenging to activate the unactivated C-Cl bonds in gem-dichloroalkanes and tertiary alkyl chlorides (Ered = ~ −2.8 V vs. SCE)54. In light of our recent work on light-mediated inner-sphere SET mechanisms29,30,32,35,55, we examined the reaction of gem-dichloroalkanes (5) with alkenes in the presence of Au2(µ-dcpm)2Cl2 in MeCN under blue light irradiation (λmax = 460 nm) (Fig. 2c). The reaction successfully produced the expected tertiary alkyl chlorides (6-8) in 65-75% yields using Hantzsch ester as the reductant and 1,1,3,3-tetramethylguanidine (TMG) as the base additive (conditions C).

Significantly, as shown in Fig. 3, we successfully obtained the product 9 that bears four different alkyl substituents on a quaternary carbon center, from tertiary alkyl chlorides (6) in 62% yield (conditions D) by changing the light wavelength from 460 nm to 390 nm, replacing Hantzsch ester with γ-terpinene, and TMG with 1,4-diazabicyclo[2.2.2]octane (DABCO). This would imply that the activation of both C-Cl bonds in gem-dichloroalkanes would be tuned by different wavelength LEDs and additives. Different from our previous work29,32, unactivated monochlorinated alkanes, which typically require harsh reductive reaction conditions56, can react smoothly in this process, further demonstrating the advances of inner-sphere SET mechanism of Au2(µ-dcpm)2Cl2 photocatalyst. With these standard conditions, we next turned our attention to explore the generality of dechlorinative alkylation reaction with tertiary alkyl chlorides. It is found that they underwent this transformation readily to, result in the formation of the corresponding all-carbon quaternary center products (9-16) in 40-68% yields. Substrates containing ether, ester, amide (9-11), chlorine (12), fluorine (13) and trifluoromethyl (16) groups all successfully yielded the desired products in moderate yields. Additionally, the bulky substituents, such as 2-naphthyl (14), were successfully incorporated under standard reaction conditions.

Fig. 3. Scope of alkane with four alkyl substituents quaternary centers.

Fig. 3

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Conditions D: PC 3 (2 mol%), monochlorinated alkanes (0.1 mmol), alkene 4 (0.5 mmol), DABCO (0.25 mmol), γ-terpinene (0.4 mmol), LiF (0.2 mmol), DMAc: 1,4-dioxane (v/v = 2: 1, 1 mL), LEDs (λmax = 390 nm), 24 h.

Compounds containing vicinal all-carbon quaternary centers are commonly found in secondary metabolites and are known to exhibit significant biological and pharmacological activities57–59. With the successful implementation of photocatalyzed sequential dechlorination of CCl4 to generate an editable all-carbon quaternary center, we employed CCl4 to construct vicinal all-carbon quaternary centers through the homolysis of another C–Cl bond (Fig. 4). Intriguingly, we found that the 1,1-disubstituted styrenes could undergo gold-catalyzed cyclopropanation smoothly with gem-dichloroalkanes60,61, furnishing the desired highly substituted cyclopropanes in 23–64% yields from gem-dichloroalkanes. It is important to point out that the resulting unsymmetrical gem-dichloroalkanes in this protocol are challenging to prepare by classical synthetic methods owing to the unavailability of corresponding starting materials62. This strategy allows for facile construction of structurally diverse cyclopropanes in moderate yields.

Fig. 4. Scope of cyclopropanes bearing with vicinal all-carbon quaternary centers.

Fig. 4

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Conditions E: PC 3 (2 mol%), gem-dichloroalkanes (0.1 mmol), alkene 5 (0.2 mmol), Hantzsch ester (1.2 mmol), BTMG (0.2 mmol), MeCN (1 mL), LEDs (λmax = 460 nm), 24 h. The first step yield is for the synthesis of gem-dichloroalkanes and the second step yield is for the target products.

The 1-vinylnaphthalene and 2-vinylnaphthalene were also applicable in the reaction, producing the products in 50–53% yields (31, 33). To our delight, unactivated olefins such as 4-phenyl-1-butene and allylbenzene tolerated the reaction conditions well (35, 37). Electron-deficient olefins besides ethyl acrylate were also studied and it was found that they could participate in this transformation to afford the products (41, 43, 47) in moderate yields. Substrates containing nitrile group seem to lead to a decrease in the reaction efficiency, and only 23% yield in the cycloaddition reaction (45) was obtained. Styrene with electron-withdrawing substituents such as methyl 4-vinylbenzoate could also replace ethyl acrylate, giving rise to the desired products (50, 52, 53) in moderate yields. Moreover, derivatives of 1,1-diphenylethylene could be used, affording the desired product (48) in moderate yield. It is important to find that the neutral terminal olefins and styrene with electron-donating groups behaved well in the first dechlorinative alkylation reaction, while the election-deficient olefins behaved well in the second step. Overall, the above cases successfully demonstrate the proof-of-concept for concise construction of challenging cyclopropanes bearing with vicinal all-carbon quaternary centers from CCl4, with an overall yield ranging from 10 to–50% in two-pots three-step procedure.

Mechanism studies

To verify if the relay radical dechlorination is involved in this strategy, electron paramagnetic resonance (EPR) experiments were carried out (Fig. 5). Two equivalents of N-tert-butyl-α-phenylnitrone (PBN) were added into each model reaction. Interestingly, in all four independent reactions, we detected signal of alkyl radicals, which would suggest the alkyl radicals were involved in all reactions. In the first and second dechlorinative alkylation process, for eosin Y and 4CzIPN, oxidative quenching of the photoexcited photocatalyst via outer-sphere SET process can readily occur with alkyl chloride owing to the matched redox potential, followed by the cleavage of C-Cl bond to generate corresponding alkyl radicals. In addition, a signal of H-radical in the first step was observed, which may originate from terpinene within the system63 (see Supplementary Fig. 5 for details). For the third and fourth reaction steps, the reactions became more difficult due to the reduced number of electron-negative chlorine atoms directly bonded to the central carbon atom. The use of dinuclear gold catalyst will lead to an inner-sphere SET mechanism to break the unactivated C-Cl bonds and furnish the corresponding alkyl radicals64. It is interesting to disclose that the use of different wavelength LEDs together with additives would tune the C-Cl cleavage sequence in gem-dichloroalkanes. The selectivity of first two steps is probably controlled by outer-sphere SET mechanism with different reductive potentials while the last two steps may be tuned by inner-sphere SET mechanism.

Fig. 5. EPR studies.

Fig. 5

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a The EPR spectra of 1st dechlorination reaction. C-centered radical [g = 2.006, aH = 1.9 G, aN = 14.6 G]. b The EPR spectra of 2nd dechlorination reaction. C-centered radical [g = 2.006, aH = 2.4 G, aN = 14.7 G]. c The EPR spectra of 3rd dechlorination reaction. C-centered radical [g = 2.006, aH = 2.4 G, aN = 14.9 G]. d The EPR spectra of 4th dechlorination reaction. C-centered radical [g = 2.006, aH = 2.6 G, aN = 14.6 G].

Discussion

In summary, we have developed a straightforward method to assemble all-carbon quaternary centers from commercially available CCl4 and alkenes. This method allows for flexible modification of the alkyl substituent in the quaternary carbon centers. Remarkably, the sequential dechlorinative process can be tuned by the combination of different kinds of photosensitizers with outer-sphere SET and inner-sphere SET crossover mechanisms, avoiding over-dechlorination side reactions. Furthermore, synthetically challenging cyclopropanes bearing with vicinal all-carbon quaternary centers have been successfully constructed directly from CCl4 in two-pots three steps. With photocatalytic relay dechlorinative protocol, tetrachloromethane can be utilized as an editable C1 synthon to construct all-carbon quaternary centers. This protocol offers a new method to facilitate the synthesis of all-carbon quaternary homologues, which holds the potential value for the development of novel and valuable organic molecules. Further application in this strategy for the synthesis of natural products is ongoing in our labs.

Methods

General methods for one-pot two steps synthesis of two different alkyl-substituted gem-dichloroalkanes (conditions A and B)

General procedure A

In a 10 mL transparent glass bottle equipped with a stirrer, eosin Y (2 mol%) is added, then the tube is moved into glove box. Alkenes 1 (0.1 mmol), CCl4 (5 equiv.) Me2PDA (2.5 equiv.), γ-terpinene (3 equiv.), MeCN (1 mL) are added successively under nitrogen atmosphere. The bottle is sealed and putted under blue LEDs (λmax = 460 nm) irradiation with vigorous stirring. Upon reaction completion judged by TLC, the reaction mixture is concentrated under reduced pressure and directly used for subsequent procedure.

General procedure B

The crude product obtained from General procedure A is added 4CzIPN (2 mol%), then this tube is moved into glove box. Alkene 2 (0.4 mmol), TEOA (0.2 mmol) and DCM (1 mL) are added successively under nitrogen atmosphere. The bottle is sealed and putted under blue LEDs (λmax = 460 nm) irradiation with vigorous stirring. Upon reaction completion judged by TLC, the reaction mixture is concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent =PE/EA).

General methods for synthesis of three different alkyl-substituted chloroalkanes (conditions C)

In a 10 mL transparent glass bottle equipped with a stirrer, Au2(μ-dcpm)2Cl2 (2 mol%), Hantzsch ester (2 equiv.) and gem-dichloroalkanes (0.1 mmol) are added successively. Then the tube is moved into glove box. Alkene 3 (2 equiv.), TMG (2 equiv.), MeCN (1 mL) are added successively under nitrogen atmosphere. The bottle is sealed and putted under blue LEDs (λmax = 460 nm) irradiation with vigorous stirring. Upon reaction completion judged by TLC, the reaction mixture is concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent =PE/EA).

General methods for synthesis of all-carbon quaternary centers (conditions D)

In a 10 mL transparent glass bottle equipped with a stirrer, Au2(μ-dcpm)2Cl2 (2 mol%), monochlorinated alkanes (0.1 mmol) and DABCO (2.5 equiv.)is added. Then the tube is moved into glove box. Alkene 4 (5 equiv.), γ-terpinene (4 equiv.), LiF (2 equiv.), DMAc: 1,4-dioxane =2: 1 mix solvent (1 mL) are added successively under nitrogen atmosphere. The bottle is sealed and putted under 390 nm LEDs irradiation with vigorous stirring. Upon reaction completion judged by TLC, the reaction mixture is concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent =PE/EA).

General methods for synthesis of cyclopropanes (conditions E)

In a 10 mL transparent glass bottle equipped with a stirrer, Au2(μ-dcpm)2Cl2 (2 mol%), Hantzsch ester (1.2 equiv.) and gem-dichloroalkanes (0.1 mmol) is added successively. Then the tube is moved into glove box. Alkene 5 (2 equiv.), BTMG (2 equiv.), MeCN (1 mL) are added successively under nitrogen atmosphere. The bottle is sealed and putted under blue LEDs (λmax = 460 nm) irradiation with vigorous stirring. Upon reaction completion judged by TLC, the reaction mixture is concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent =PE/EA).

Supplementary information

Supplementary Information (9.8MB, pdf)
Transparent Peer Review file (332.3KB, pdf)

Acknowledgements

We thank the National Natural Science Foundation of China (Grant No. 22471121), Fundamental Research Funds for the Central Universities (Grant No.0020514380327), and the Open Project of State Key Laboratory of Natural Medicines (No. SKLNMKF202401) for financial support. We also acknowledge Hongliang Chen, Gaofeng Yang, and Jun-Heng Liu at Nanjing University for reproduction of the experimental procedures for products 11, 21, and 41.

Author contributions

J.X. and Y.T. conceived the work and designed the experiments. T.L., Z.L., Y.F., H.C. and J.H. performed the experiments and analyzed the experimental data. T.L. and Z.L. discussed the results with H.C. Y.T. and T.L., Z.L. and J.X. co-wrote the manuscript with the input from all the other authors.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Data availability

Data related to materials and methods, optimization of conditions, experimental procedures, mechanistic experiments, and spectra are provided within the paper and its Supplementary information. All data are available from the corresponding authors upon request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Yongxing Tang, Email: yongxing@njust.edu.cn.

Jin Xie, Email: xie@nju.edu.cn.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-025-68224-z.

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Data Availability Statement

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