Copper- and copper–N-heterocyclic carbene-catalyzedC─H activating carboxylation of terminal alkyneswith CO2 at ambient conditionsDingyi Yu and Yugen Zhang1

Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved October 4, 2010 (received for review July 26, 2010)

The use of carbon dioxide as a renewable and environmentallyfriendly source of carbon in organic synthesis is a highly attractiveapproach, but its real world applications remain a great challenge.The major obstacles for commercialization of most current proto-cols are their low catalytic performances, harsh reaction conditions,and limited substrate scope. It is important to develop new reac-tions and new protocols for CO2 transformations at mild conditionsand in cost-efficient ways. Herein, a copper-catalyzed and copper–N-heterocyclic carbene-cocatalyzed transformation of CO2 to car-boxylic acids via C─H bond activation of terminal alkynes withor without base additives is reported. Various propiolic acids weresynthesized in good to excellent yields under ambient conditionswithout consumption of any organometallic or organic reagent ad-ditives. This system has a wide scope of substrates and functionalgroup tolerances and provides a powerful tool for the synthesisof highly functionalized propiolic acids. This catalytic system is asimple and economically viable protocol with great potential inpractical applications.

The chemical fixation and transformation of carbon dioxide(CO2) has attracted much attention in view of environmental,

legal, and social issues in the past few decades (1–7). Carbondioxide is an attractive C1 building block in organic synthesisbecause it is an abundant, renewable carbon source and anenvironmentally friendly chemical reagent (8–13). The utiliza-tion, as opposed to the storage of CO2, is indeed more attractiveespecially if the conversion process to useful bulk products is aneconomical one. Significant efforts have been devoted towardexploring technologies for CO2 transformation, whereby harshand severe reaction conditions are one of the major limitationsfor their practical applications (1–15). Therefore, the develop-ment of efficient catalyst systems for CO2 utilization under mildconditions is highly desired, especially for real world applications.

Carboxylic acids are one of the most important types of com-pounds in medicinal chemistry and also in fine-chemicals synth-esis (16, 17). Although there are many well-established protocolsfor the preparation of carboxylic acids, the direct carboxylation ofcarbon nucleophiles using CO2 as the electrophile is the mostattractive and straightforward method (16, 17). The formationof a stable C─C bond is desired for CO2 fixation and remainsthe most challenging aspect thus far. Typically, this type of reac-tion is facilitated by the insertion of CO2 into a metal-carbonbond (16–26). Widespread use of these methods is limited bythe synthesis organometallic reagents as precursors and therestricted substrate scope.

R M CO2catalyst

R-COOM (M=Li, Mg, Cu, Mn, Sn, Zn, Al, B)

In the past decades, several interesting systems have beenreported for metal-mediated reductive carboxylation of alkynes(27, 28), allenes (29, 30), and alkyenes (31) with CO2 to formcarboxylic acids or esters. However, most of those systems needeither a stoichiometric amount of transition metals as reactants

or an excess amount of organometallic reagents for transmetalla-tion processes. An alternative possibility to achieve the catalyticsynthesis of carboxylic acid from CO2 is by direct C─H bond ac-tivation and carboxylation. Very recently, Nolan’s group reporteda gold-catalyzed CO2 carboxylation of C─H bonds of highlyactivated arenes and heterocycles (32). Herein, we reported acopper- and copper–N-heterocyclic carbene (NHC)-catalyzedtransformation of CO2 to carboxylic acid through C─H bond ac-tivation and carboxylation of terminal alkynes. Various propiolicacids were synthesized in good to excellent yields under ambientconditions. This catalytic system is a simple and economicallyviable protocol with great potential in practical applications.

Results and DiscussionThe ubiquity of alkynyl carboxylic acids in a vast array of medic-inally important compounds as well as its tremendous utility as asynthon in organic synthesis makes them particularly attractivetargets for pharmaceutical and fine-chemical as well as conduc-tive polymer synthesis (16, 17, 33, 34). A plethora of well-estab-lished methods for the preparation of alkynyl carboxylic acidsincludes CO2 insertion into the metal-carbon bond of organome-tallic reagents, the well-known hydrolysis of bromide and relatedderivatives, and the oxidation of preoxidized substrates, such asalcohols or aldehydes (Fig. 1 A–C) (35). Despite the efficiency ofthese conventional procedures, their major drawback includessevere reaction conditions and restrictions of organometallicreagents that dramatically limit the synthesis of a wide scope offunctionalized propiolic acids. Therefore, a functional group tol-erant and straightforward method for accessing alkynyl carboxylicacids (Fig. 1D) is highly desired and will provide opportunities inorganic, pharmaceutical, and materials synthesis.

Organocopper reagents are very unique because the metal-car-bon bond is of moderate polarity and is ready for CO2 insertionunder ambient conditions, and they are also tolerant to mostfunctional groups (18). Copper catalysts can also catalyze variousC─H and C-halogen activation reactions, and many of them in-volve intermediates with a Cu─C bond (36–38). These facts makecopper catalysts a very promising choice for CO2 transformation,especially with the formation of new C─C bonds. Hay (39) devel-oped oxidative homocoupling of terminal alkynes via C─H acti-vation and copper acetylide intermediate. After that, carbondioxide was successfully introduced into the copper–terminalalkyne system, and the insertion of CO2 into the copper acetylideintermediate was observed by Inoue’s group (40). However, thecopper propynoate intermediate is unstable under the appliedreaction conditions (100 °C, 1 atm CO2). Propiolic acid products

Author contributions: Y.Z. designed research; D.Y. and Y.Z. performed research; D.Y. andY.Z. analyzed data; and D.Y. and Y.Z. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.1To whom correspondence should be addressed. E-mail: ygzhang@ibn.a-star.edu.sg.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1010962107/-/DCSupplemental.

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could not be isolated (40). We assumed that the copper propyno-ate intermediate should be stable under milder conditions, suchas room temperature, and the carboxylate end product could bedissociated from the copper catalyst under normal basic condi-tions. On the basis of this hypothesis, the initial proof of conceptexperiment was conducted by using 2 mol% of CuCl, 1.5 mol% ofTMEDA (N;N;N 0;N 0-tetramethylethylenediamine) ligand (L1),and K2CO3 as the base for the carboxylation of 1-ethynylbenzene1a at ambient temperature and atmospheric pressure (Table 1,entry 1). Remarkably, phenylpropiolic acid 1b was produced inexcellent yield after acid workup. The isolated pure productwas characterized by NMR and elemental analysis. Phenylpropio-lic acid was further converted into the methyl ester and charac-terized by NMR and GC/MS. Interestingly, the catalytic reactioncould be performed without any base additives to give 55% of 1b(Tables S1 and S2). Further studies indicated that a catalyticamount of base is important to activate the CuCl catalyst. Mean-while, a weak basic environment is necessary to stabilize the acidproduct and to ensure that the reaction is completed. In a catalystsystem with basic ligands (Table S2, entries 1–3) or a catalyticamount of base (Table S2, entry 13), a moderate yield of 1bwas obtained when the reaction was conducted in dimethylforma-mide (DMF) (a weak Lewis base) but not in THF, CH3CN, orDMSO (Table S2). Stoichiometric amounts of base additivesfurther promote the reaction, and a good yield of 1b could beobtained in DMF as well as in THF, CH3CN, and DMSO(Tables S1 and S3). This result demonstrated a valuable exampleof a base free C─C coupling reaction system.

When the reaction was conducted with 2.0 mol% CuCl catalystin the absence of ligands, the yield of 1b dropped to 50%(Table S4, entry 8). This result indicates that σ donor ligand canincrease the catalyst activity (41). Other σ donor ligands, such asN;N 0-dimethylethanediamine, 1,3-dimesitylimidazol-2-ylidene,and 1,8-diazabicyclo[5.4.0]undec-7-ene, also work well for thiscatalytic system (Table S4). For the carboxylation of 1-ethynyl-benzene 1a, when the catalyst loadings was reduced from2 mol% to 0.5 mol%, good to excellent yields were still obtainedafter prolonged reaction time (24 h) (Table S4). The yield of 1bdecreased sharply to 8% when the catalyst loading was furtherreduced to 0.1 mol%. No reaction was observed for the controlexperiments with K2CO3 or Cs2CO3 as the base and withoutcopper catalyst (Table S4, entries 1 and 14) (42).

Kinetics studies of this reaction showed that 1b was formedrapidly in the first 4 h, reaching a yield of 70%, before the gradualincreased to the final yield of 90% in 16 h. The yield remainedconstant around 90% even with further increasing the reactiontime from 16 to 24 h (Fig. S1).

With the optimized reaction conditions of 2.0 mol% CuCl,1.5 mol% TMEDA, and 120 mol% K2CO3 in DMF for 16 h,the substrate scope of the reaction was studied. For aromaticalkynes with or without electron donation functional groups,the corresponding alkynyl carboxylic acids were obtained in80–91% yields (isolated) under standard conditions (Table 1, en-tries 1–11). The catalytic system is not sensitive to the position ofsubstituents on the benzene ring. The related acid yields of p-,m-,o-substituted 1-ethylbenzene are approximately in the samerange. The transformations proceeded smoothly without any sideproduct formation. The initial trials for the carboxylation of thealkyl-substituted alkynes were unsatisfactory with a low yield ofthe corresponding acids (∼20%). The low reactivity of alkyl-substituted alkynes is probably because of the weak acidity ofthe alkyne proton. The conjugation system between the benzenering and alkyne C≡C bond in aryl alkynes imposes more negativecharge on C1 carbon and makes it a stronger nucleophile thanalkyl alkynes. A density functional theory calculation [B3LYP/6-31G(d,p) level] indicated that the negative charge on C1 carbonof 1-ethynylbenzene is −0.534 and that of 1-hexyne is −0.461.After investigating further, a stronger base Cs2CO3 was used in-stead of K2CO3, and the yield of corresponding alkyl-substitutedpropiolic acids was raised to 80–91% (Table 1, entries 12–16).

In general, terminal aromatic alkynes with an electron with-drawing group are deactivated and often inert to many transfor-mations (43, 44). With the electron withdrawing group on thephenyl ring, the nucleophilicity of the C1 carbon of alkynesdropped dramatically. The carboxylation of 4-nitro-1-ethynylben-zene 19a was unsatisfactory with a very low yield of the corre-sponding acids 19b (0 ∼ 8%) under standard conditions evenwith a very strong base, such as KOtBu (Table S5). The low yields(∼2%) were also observed as the reaction temperature wasadjusted to 0 °C and 50 °C. This result may be because of thelow reaction rate at low temperature and instability of the reac-tion intermediate at high temperature (Table S5). The key stepfor this transformation is CO2 insertion into the copper acetylideintermediate. Increasing the nucleophilicity of the carbanionic

Fig. 1. Protocols for synthesis of substituted propiolic acids.

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intermediate may increase the yield of the carboxylic acid pro-duct. Various ligands (L1–L12, Table 2) (45) were screened inthe reaction with 4-nitro-1-ethynylbenzene 19a and the yieldsof the acid product ranged from 3% to 47%. The catalyst withthe strongest electron donation ligand phenanthroline L10 gavethe highest yield. It is well known that NHCs can activate CO2

in various catalytic transformations (5, 7). With that, a uniqueNHC-Cu cocatalyst was designed by using poly-N-heterocycliccarbene (PNHC) as both ligand and catalyst. PNHC has a three-dimensional network structure, and the carbene units are locatedand fixed in the backbone of the network (Fig. 2) (46, 47).PðNHCÞ0.5ðNHC─CuÞ0.5 (P1) catalyst was prepared by the reac-tion of one equivalent of CuCl with two equivalents of PNHC.In the structure of this catalyst, only half of the carbene speciescoordinated with copper, and the other half remained as free car-benes (46). The initial experiment was conducted by using 5 mol% of P1 and Cs2CO3 as a base for the carboxylation of 4-nitro-1-ethynylbenzene 19a with CO2 at ambient conditions. Remark-ably, 4-nitro-phenylpropiolic acid 19b was produced in 70% yieldafter acid workup. Good yields were also achieved for terminalaromatic alkynes with different electron withdrawing groups in

36–48 h (Table 2). The longer reaction time may be becauseof the heterogeneous reaction behavior in this solid catalystsystem. The mechanism of this unique process is intriguing, andrelated control experiments were conducted. We used 4-nitro-1-ethynylbenzene as a model substrate. No reaction was observed ina system with PNHC only. When an additional two portions ofCuCl were added into the P1 catalyst reaction system, the yieldof the desired product dropped dramatically to 18% (Table 2,entry 15). This result indicated that free carbene species in thecatalyst play an important role for high activity. Furthermore,a reaction intermediate PðNHC─CO2Þ0.5ðNHC─CuÞ0.5 wassynthesized by the reaction of PðNHCÞ0.5ðNHC─CuÞ0.5 (P1) withCO2. This intermediate was directly used to react with a stoichio-metric amount of 1-ethynylbenzene (equivalent to NHC─CO2)under standard conditions without an additional CO2 source.A 52% yield of phenylpropiolic acid was obtained in 24 h. Withthese experiment results, it is believed that the unique structureof P1 catalyst is the key to the high activities. The free carbene

Table 1. Copper-catalyzed carboxylation of terminal alkyneswith CO2

R H CO2 R

OH

ODMF, R.T., 1 atm

Base, 2-5 mol% CuCl, Ligand HClNN

L1 L13

Poly-NHC+

Isolatedyields,%

Entry Alkynes Time, h Base L1 L13

1 16 K2CO3 90 95

2O

18 K2CO3 81 85

3 O 18 K2CO3 86 90

4O

18 K2CO3 89 92

5 F 16 K2CO3 80 82

6 F 16 K2CO3 85 86

7F

16 K2CO3 88 86

8 Cl 16 K2CO3 84 90

9 Cl 16 K2CO3 86 88

10Cl

16 K2CO3 86 90

11S

24 K2CO3 89 93

12HO

24 Cs2CO3 80 83

13 NC 24 Cs2CO3 82 88

14 H3COOC 24 Cs2CO3 82 90

15 n-C4H9 24 Cs2CO3 85 85

16 24 Cs2CO3 83 85

Reaction conditions: for L1, CuCl (2.0 mol%), TMEDA, 1.5 mol%; for L13,PðNHCÞ0.5ðNHC─CuÞ0.5, 5 mol%; alkynes (2.0 mmol), base (2.4 mmol), CO2

(1 atm), DMF (4 mL), room temperature (25 °C).

Table 2. Cu-NHC–catalyzed carboxylation of deactivated terminalalkynes with CO2

H CO2DMF, R.T., 1 atm

Cs2CO3, CuCl, Ligand HCl+EW EW

OH

O

NNN

N N

N NN N

N

NN

NNN N

L11

L8 L9

L12

L10

L13

N

N

NN

N

N

N

N

N

N

N

N

NN

L7

NNNNNHHN

N

NNNP

L1 4L2L L3 L5 L6

Entry AlkyneLigand(mol%)

CuCl(mol%)

Timeh

Yields%

1O2N

L1 (10) 5 24 <5

2 L2 (10) 5 60 23 L3 (10) 5 60 34 L4 (10) 5 60 85 L5 (10) 5 60 56 L6 (10) 5 60 97 L7 (10) 5 60 98 L8 (10) 5 48 219 L9 (10) 5 48 4010 L10 (10) 5 48 4711 L11 (10) 5 48 3012 L12 (20) 5 48 3213 L12 (10) 5 48 2514 L13 (10)* 5 48 7015 L13 (10)* 15 48 1816

OHCL13 (10)* 5 36 68

17 NC L13 (10)* 5 24 72

18

HO

L13 (10)* 5 36 73

19

HO

L13 (10)* 5 36 79

Reaction conditions: alkynes (2.0 mmol), CuCl, Cs2CO3 (2.4 mmol), ligand,CO2 (1 atm), DMF (4 mL), RT.*10 mol% of NHC.

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species in the structure are randomly located around the coppercenter and act as an organocatalyst to activate CO2. This essentialstep may reduce the activation energy barrier for CO2 insertion.

PhCCCOOH (52% of yield)0.5 eq. P(NHC-CO2)2(NHC-Cu)

PhCCHCs2CO3, DMF, r.t., 24 hrs

Finally, with this unique P1 catalyst, different terminal alkyneswith various functional groups were all successfully convertedinto the related carboxylic acids in good to excellent yield withcarbon dioxide under very mild reaction conditions (2) (Table 1).The most remarkable advantage of this copper or copper–NHCcatalyst system is its wide scope of substrate and functional groupstolerance. The catalytic system is not sensitive to a variety of func-tional groups, such as ─COOR, ─OH, ─CHO, ─CN, ─NO2, etc.It provides a powerful tool for the synthesis of highly functiona-lized propiolic acids.

It is known that copper acetylide is the key intermediate forcopper-catalyzed C─H activation of terminal alkynes and theCu─C bond is active for CO2 insertion (18, 39–41, 48). A catalyticcycle for copper-catalyzed carboxylation of terminal alkynes withCO2 is proposed as shown in Fig. 3. The copper acetylide inter-mediate A was formed from the reaction of the terminal alkyneand L2CuCl in the presence of a base. Subsequent CO2 insertioninto the polar Cu─C bond will form propynoate intermediate B,in which it will undergo metathesis with the terminal alkyne underbasic conditions. This step would release propiolic acid and re-generate intermediate A (Fig. 3A). However, it must be notedthat the copper propynoate intermediate B is not stable at ele-vated temperatures (40). In this reaction, intermediate B maydecompose over heat to reform A through a decarboxylation

process (Fig. 3B). As the temperature was raised from ambienttemperature (25 °C) to 60 °C for the reaction of 1a, the yield of 1bdropped from 90% to 42%. Instead, some homocoupling by-pro-duct c was observed. Under room temperature condition, becauseof the quick insertion of CO2 into intermediate A and the absenceof an oxidant, production of c is prohibited. On heating, inter-mediate B decomposes to A, and CO2 may also act as an oxidantin the production of c. The same reaction conducted at 0 °Cshowed lower activity but high selectivity. This observation is wellin agreement with the proposed hypothesis.

In the P1 catalyst system, it is proposed that the copper centeractivates the terminal alkyne with a base to form the copper acet-ylide intermediate, whereas the free carbene activates CO2 toform NHC carboxylate (Fig. 4). The NHC carboxylate will coor-dinate to a nearby copper center, which will induce the nucleo-philic carbanion of the alkyne into attacking the carboxyliccarbon. Following the formation of the new C─C bond, theCO2 unit is transferred from the carbene center to the coppercenter, which will be regenerated by metathesis with the alkyne.This system demonstrated an interesting synergistic effect of anorganocatalyst and an organometallic catalyst in one system.

In summary, we have successfully developed a process wherecopper and copper–NHC catalyzed the transformation of CO2

to carboxylic acids through C─H bond activation of terminalalkynes. Various propiolic acids were synthesized in good toexcellent yields under ambient conditions. The most remarkableadvantage of this mild reaction system is its tolerance toward awide substrate scope. This protocol opens up access to a pool ofhighly functionalized propiolic acids from CO2. In addition, thepoly─NHC─Cu system demonstrated a concept for the coeffectof organo and organometallic catalysts.

Fig. 2. Structures of poly─NHC and PðNHCÞ0.5ðNHC─CuÞ0.5 catalyst.

Fig. 3. Proposed catalytic cycle (A) and decomposition pathway (B).

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Materials and MethodsAll solvents were anhydrous and bought from Sigma-Aldrich (99.8%). Thealkynes were used without purification from commercial suppliers, unlessotherwise indicated. The carbonates were all dried under vacuum withheating before use. Poly─NHC and poly─NHC─Cu were synthesized onthe basis of the literature (46). All reactions were performed in oven-dried(140 °C) or flame-dried glassware under an inert atmosphere of dry N2

or Ar.

Preparation of PðNHCÞ0.5ðNHC─CuÞ0.5. NaOtBu (60 mg, 0.6 mmol) was addedto a DMF (10 ml) suspension of poly-imidazolium (46) (250 mg) in a re-action flask. The reaction mixture was stirred for 1 h, and then CuCl(25 mg, 0.25 mmol) was added. The resulting mixture was stirred at80 °C for 6 h. The solid product was filtered and dried to obtain a paleyellow powder PðNHCÞ0.5ðNHC─CuÞ0.5. The catalyst is directly used for re-action. The coexistence of a metal center and free carbene was studiedin ref. 46.

General Procedure for Carboxylation of the Terminal Alkynes (1b as an Exam-ple). CuCl (4.0 mg, 0.04 mmol, 2.0 mol%), TMEDA (3.5 mg, 0.03 mmol, 1.5 mol%), and K2CO3 or Cs2CO3 (2.4 mmol) were added to DMF (4 mL) in the reac-tion tube (10 mL). CO2 (balloon) and 2 mmol of terminal alkynes (1a, 204 mg)were introduced into the reaction mixture under stirring. The reaction mix-ture was stirred at room temperature (about 24 °C) for 16 h. After completionof the reaction, the reaction mixture was transferred to potassium carbonatesolution (2 N, 5 mL) and the mixture was stirred for 30 min. The mixture wasextracted with dichloromethane (3 × 5 mL), and the aqueous layer was acid-ified with concentrated HCl to pH ¼ 1 and then extracted with diethyl ether(3 × 5 mL) again. The combined organic layers were dried with anhydrousNa2SO4 and filtered and the solution was concentrated in vacuum, affordingpure product 1b.

ACKNOWLEDGMENTS. This work was supported by the Institute of Bioengi-neering and Nanotechnology (Biomedical Research Council, Agency forScience, Technology and Research, Singapore).

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Yu and Zhang PNAS ∣ November 23, 2010 ∣ vol. 107 ∣ no. 47 ∣ 20189

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