Catalytic Sonogashira couplings mediated by an amido pincer complex of palladium

Abstract

This work describes the efficacy of [PNP]PdCl (1a), where [PNP]⁻ = bis(2-diphenylphosphinophenyl)amide, as a catalyst precursor for C_sp–C_sp2 bond-forming cross-coupling reactions of terminal alkynes with aryl halides in the presence of copper bromide and aliphatic amines in ethereal solutions under mild conditions. This catalysis is compatible with acetylenes that are alkyl, alkenyl, (hetero)aryl, or silyl substituted and aryl iodides or bromides that are electronically activated, neutral, or deactivated. The low reaction constants of 0.82(6) and 0.97(7) obtained from Hammett plots of competitive reactions employing electronically distinct aryl iodides and terminal alkynes, respectively, are likely suggestive of irrelevance of the rate-determining step in these catalytic transformations to oxidative addition of aryl halides or generation of mono-substituted acetylides. In sharp contrast, reactions employing a phosphorus-bound isopropyl derived 1b gave rather unsatisfactory results, highlighting a profound phosphorus substituent effect on this aryl alkynylation catalysis.

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Introduction

The palladium-catalyzed C_sp–C_sp2 bond-forming reactions of terminal alkynes with aryl or alkenyl (pseudo)halides, generally referred to as the Sonogashira coupling,^1,2 are among the most versatile and valuable methods for the preparation of arylated alkynes and conjugated enynes. These compounds are important precursors or key intermediates for natural products, bioactive compounds, pharmaceuticals, liquid crystalline materials, conducting polymers, etc.^3–12 To develop effective methods for these specific chemical transformations and to elucidate the reaction mechanisms involved therein are tasks of fundamental and practical importance.^13–15

It has been demonstrated that palladium complexes of amido phosphine ligands, e.g., 1a and 2 in Fig. 1, are highly active catalyst precursors for Heck and Suzuki couplings.^16,17 These compounds may be regarded as electronic modifications of phosphine palladacycles, e.g., 3 and 4,^18–21 which are popular constitutional motifs as pre-catalysts for cross-coupling reactions.²² Interestingly, while 3a is highly active for catalytic Heck reactions of aryl iodides and bromides but is almost inactive for chlorides,¹⁸ the oxygen-incorporated 3b is an efficient pre-catalyst for the olefination of these inherently inert yet industrially important substrates.¹⁹ The discrepancy in reactivity of 3b and 3a was ascribed to electronic factors. In a separate study, 3b was also found to be active for catalytic Sonogashira couplings of aryl chlorides with phenyl acetylene, though relatively high temperatures (160 °C) and participation of the co-catalyst ZnCl₂ were required.²³ Other precedents of pincer complexes active for catalytic Sonogashira couplings are also known.^22,24–29 The high thermal stability of the palladium pincer complexes 1a and 3a–b is believed to be one of the keys to the success of these catalytic transformations.^16,18,19,23 Though palladium complex 1b is unprecedented, nickel analogues of 1a–b have been known to facilitate catalytic Kumada couplings.³⁰ In an effort to expand the reaction scope of these amido pincer complexes in cross-coupling catalysis,^31–35 we became interested in the efficacy of 1 with respect to Sonogashira couplings. In this contribution, we aim to demonstrate that 1 is also a competent catalyst precursor for efficient alkynylation of aryl halides under relatively mild conditions. Mechanistic insights implied by reactivity discrepancy ascribed to distinct substituents at phosphorus in 1 and by competitive alkynylation of aryl iodides are discussed. To the best of our knowledge, this study represents the first report on Sonogashira couplings catalyzed by PNP complexes.

Fig. 1 Representative examples of phosphine palladacycles.

Results and discussion

Complex 1b could be readily prepared in high yield by treating a THF solution of bis(2-diisopropylphosphinophenyl)amine³⁰ with either PdCl₂ upon heating or PdCl₂(PhCN)₂ at room temperature. Similar to 1a,¹⁶1b is a brick red crystalline solid that is not sensitive to oxygen or moisture and can be conveniently manipulated under aerobic conditions for subsequent reactions. The solution NMR data of 1b are all consistent with a structure having a square planar geometry, as evidenced by virtual triplet resonances ascribed to the o-phenylene carbon atoms in the ¹³C{¹H} NMR spectrum. Complex 1a has previously been proved to be remarkably thermally stable even at temperatures as high as 200 °C (>100 hours).¹⁶ Similarly, 1b is also thermally stable; no decomposition was found when a toluene-d₈ solution of 1b (63 mM) was heated to 110 °C for 4 days as indicated by ¹H and ³¹P{¹H} NMR studies. The high thermal stability of both 1a and 1b leads us to preclude their thermal degradation^36,37 in catalysis under conditions milder than these prescribed examination parameters.

Our initial Sonogashira studies focused on the survey of reaction parameters of 1 employing iodobenzene and trimethylsilyl acetylene as building blocks under various conditions. Table 1 summarizes the effects of phosphorus substituents in 1 and possible co-catalysts, bases, and solvents that are frequently employed in Sonogashira couplings. Notably, these building blocks may be effectively cross-coupled with a catalytic amount of 1a in the presence of CuBr as the co-catalyst and triethylamine as the base in 1,4-dioxane solutions under ambient conditions. This reaction proceeds smoothly and selectively, affording in an hour the desired cross-coupled product 5a in quantitative yield (entry 1); no Glaser coupling product³⁸ was detectable. In contrast, the employment of catalytic 1b (entries 2 and 3) or other co-catalysts (entries 4–9) under otherwise identical conditions gave rather unsatisfactory results, highlighting the significance of the distinctive phosphorus substituents in PNP ligands^39–41 and the identity of the co-catalysts employed, respectively. In particular, 1b hardly gave the desired cross-coupled product (entry 2) under the standard model reaction conditions. The reactivity of 1b, however, may be accelerated at elevated temperatures, e.g., 55 °C at entry 3. Though unsatisfactory, the turnover number (entry 3) of complex 1b is unambiguously indicative of its catalytic characteristics. The phenyl substituted 1a thus markedly outperforms the isopropyl derived 1b in terms of catalytic turnover frequencies in Sonogashira couplings under the conditions investigated. Such a discrepancy in catalytic activities is likely reflective of their inherent electronic nature, as ascribed to what was found for 3a and 3b.^18,19 Herrmann and Beller et al.²⁰ and Gibson and Cole-Hamilton et al.²¹ also independently demonstrated that phosphine palladacycles 4 that are P-arylated are superior catalyst precursors for Heck reactions to those containing ethyl or tert-butyl substituents at the phosphorus donors. The lower reactivity of 1b is tentatively attributed, at least in part, to its lesser electrophilicity that induces higher activation barriers for substrates, presumably the in situ generated nucleophilic acetylide, to coordinate and catalysis to proceed, in view of the established reactivity discrepancy found in nickel chemistry wherein these ligands are involved.^40,41 In contrast to 3b,²³ the participation of ZnCl₂ did not promote the activities of 1 at all (entry 8). A number of aliphatic amines were surveyed as the base; triethylamine appears to be superior to the others (entries 10–13). Among the solvents investigated (entries 14–21), both polar and non-polar solvents are compatible, though THF and 1,4-dioxane solutions facilitate this catalysis most efficiently. Without the pre-catalyst 1a or the co-catalyst CuBr (entries 22–24), the cross-coupling reactions hardly proceed even with extended reaction time (entry 22), thereby underscoring clearly the synergistic role of these transition metal complexes in this catalysis. No induction period was found, as corroborated by a reaction profile established by product yields as a function of time (see ESI†).

Table 1 Effects of co-catalyst, base, and solvent on the Sonogashira coupling of iodobenzene with trimethylsilyl acetylene^a

Entry	Co-catalyst	Base	Solvent	Yield^b (%)
a Reaction conditions unless otherwise noted: 1.0 equiv. of iodobenzene, 1.1 equiv. of trimethylsilyl acetylene, 1.0 mol% of 1a (24 mM in specified solvent), 2.0 mol% of co-catalyst, 15 equiv. of base, 25 °C, 1 hour. b Determined by GC, based on iodobenzene using icosane as an internal standard; average of two runs. c Catalytic 1b instead of 1a was employed. d Reaction run at 55 °C for 36 hours. e DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. f Reaction run for 24 hours. g Reaction run without 1a.
1	CuBr	NEt3	1,4-Dioxane	>99
2^c	CuBr	NEt3	1,4-Dioxane	<1
3^c	CuBr	NEt3	1,4-Dioxane	17^d
4	CuCl	NEt3	1,4-Dioxane	15
5	CuI	NEt3	1,4-Dioxane	10
6	CuOTf	NEt3	1,4-Dioxane	12
7	FeCl3	NEt3	1,4-Dioxane	<1
8	ZnCl2	NEt3	1,4-Dioxane	<1
9	AlCl3	NEt3	1,4-Dioxane	<1
10	CuBr	HNEt2	1,4-Dioxane	19
11	CuBr	HN^iPr2	1,4-Dioxane	66
12	CuBr	MeNCy2	1,4-Dioxane	<1
13	CuBr	DBU^e	1,4-Dioxane	2
14	CuBr	NEt3	THF	>99
15	CuBr	NEt3	DMSO	74
16	CuBr	NEt3	DMF	64
17	CuBr	NEt3	DMA	38
18	CuBr	NEt3	MeCN	93
19	CuBr	NEt3	CH2Cl2	94
20	CuBr	NEt3	PhMe	78
21	CuBr	NEt3	PhH	92
22	None	NEt3	1,4-Dioxane	2^f
23^g	CuBr	NEt3	1,4-Dioxane	0
24^g	None	NEt3	1,4-Dioxane	0

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In spite of the established virtually equal efficacy of catalysis run in both 1,4-dioxane and THF, we chose to investigate the reaction scope in the former due to its higher boiling point that offers the possibility of catalysis run at higher temperatures if necessary. As shown in Table 2 (accumulating 35 examples of products), a variety of functional groups are compatible, including (fluoro)alkyl, alkenyl, (hetero)aryl, silyl, fluoro, alkoxy, ketone, nitro, etc. Both aryl iodides and bromides are reactive, though the couplings involving the latter electrophiles require mild heating. Notably, aryl iodides may be effectively coupled in high yields with terminal alkynes at room temperature. Both ortho- and para-substituted substrates are suitable building blocks, though a slower rate is generally found for the former (entries 3 and 4, 17 and 18, 22 and 23, 27 and 28, 34 and 35), likely due to the steric congestion imposed by the 2-substituent and the amido pincer ligand. Nevertheless, an extension of the reaction time is sufficient to afford the cross-coupled products in reasonable yields (e.g., entry 4 versus 5). The reaction rates are also a function of the electronic characteristics of the halogenated electrophiles, following the order: electron-deficient > electron-neutral > electron-rich substituents. Consistent with what was found in Table 1, 1a is a superior pre-catalyst to 1b (entry 12 versus 13). In all attempts, no palladium black was observed, reflecting the robust nature of these palladium complexes even at elevated temperatures. In particular, catalysis runs in the presence of liquid mercury gave virtually identical results (e.g., entry 10 in Table 2), indicating that this catalysis is homogeneous and not a consequence of bulk or colloidal palladium(0).^42–44 Whether a soluble palladium(0) species is produced from chemical degradation of the Pd[PNP] entity, however, is not clear at this stage. Attempts to identify possible intermediates in this regard by ³¹P{¹H} NMR spectroscopy were inconclusive. It is worth noting that catalysis runs employing crude 1 without further purification generally led to significantly lower turnover frequencies, strongly implying the presence of some unidentified impurities and their incapability or poisoning effect in this catalysis. In contrast, purified 1, even with different synthetic batches, gave consistent catalysis results.

Table 2 Catalytic Sonogashira couplings of aryl halides with terminal alkynes^a

Entry	X	Temp (°C)	Time (h)	Product		Yield^b (%)
a Reaction conditions unless otherwise noted: 1.0 equiv. of aryl halides (2.4 M in 1,4-dioxane), 1.1 equiv. of alkynes, 15 equiv. of NEt3. b Determined by GC, based on aryl halides using icosane as an internal standard; average of two runs. c Catalytic 1b instead of 1a was employed.
1	I	25	1		5a	>99
2	I	25	2		5b	92
3	I	25	2		5c	76
4	I	25	2		5d	28
5	I	25	6		5d	77
6	I	25	2		5e	>99
7	Br	50	74		5e	60
8	Br	50	74		5f	98
9	Br	50	74		5g	>99
10	I	25	17		6a	>99
11	I	25	17		6b	99
12	Br	110	24		6b	72
13^c	Br	110	24		6b	13
14	I	25	17		6d	97
15	I	25	17		6e	>99
16	I	25	24		7a	94
17	I	25	24		7c	92
18	I	25	24		7d	83
19	I	25	24		7e	98
20	I	25	20		8a	98
21	I	25	20		8b	89
22	I	25	20		8c	57
23	I	25	20		8d	68
24	I	25	20		8e	>99
25	I	25	24		9a	90
26	I	25	24		9b	>99
27	I	25	24		9c	92
28	I	25	24		9d	82
29	I	25	24		9e	>99
30	Br	110	24		9e	96
31	Br	110	24		9f	93
32	Br	110	24		9g	>99
33	I	25	17		10a	96
34	I	25	17		10c	75
35	I	25	17		10d	30
36	I	25	17		10e	87
37	I	25	17		11b	73
38	I	25	17		11c	53
39	I	25	17		11e	94
40	Br	60	96		11f	90

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In addition to electronic reasons (vide supra), the steric discrepancy of 1a and 1b was also considered to correlate with their reactivity differences as implied by the slightly higher reactivity of 4c than that of 4b in Heck reactions.²⁰ To this end, we pursued evidence with crystallographic data of both 1a and 1b. Complex 1a has previously been structurally characterized.¹⁶ Red crystals of 1b suitable for X-ray diffraction analysis were grown from a concentrated diethyl ether solution at −35 °C. Fig. 2 depicts the solid state structure of 1b. These structures, however, resemble closely each other in view of their similar bond distances, angles, and dihedral angles about the palladium center (Table 3). The only notable difference is a slightly larger dihedral angle between two o-phenylene rings in 1b. The origin of such a discrepancy is tentatively attributed to the sterically distinct P-substituents incorporated. Other structural parameters are not exceptional.

Fig. 2 Molecular structure of 1b with thermal ellipsoids drawn at the 35% probability level.

Table 3 Selected bond distances (Å), bond angles (°), and dihedral angles (°) for 1a and 1b

Compound	1a	1b
a Data selected from ref. 16.
Pd–N	2.056(11)	2.029(3)
Pd–P	2.3010(18), 2.3010(18)	2.2860(12), 2.2898(11)
Pd–Cl	2.313(5)	2.3119(12)
P–Pd–P	165.27(11)	165.33(4)
N–Pd–Cl	180.0000(10)	177.39(11)
P–Pd–N	82.63(6), 82.63(6)	83.45(10), 82.87(10)
P–Pd–Cl	97.37(6), 97.37(6)	96.30(5), 97.60(5)
o-Phenylene/o-phenylene	36.87	42.16
P–N–P–Cl/C–N–C	24.07	23.48

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Structural resemblance of 1b to 1a does not necessarily lead us to conclude that sterics plays a negligible role in the reactivity discrepancy of these complexes, particularly taking into account the possibility of an increase in coordination number of palladium intermediates produced in the catalytic cycles. It is generally accepted that the catalytic cycle of Sonogashira couplings comprises successive oxidative additions of aryl/alkenyl halides, transmetallation of copper acetylides to palladium, and reductive elimination of the desired cross-coupled products.⁹ If this or similar mechanisms are operative in the current study, 1b might in principle outperform 1a in view of its more electron-releasing nature to facilitate oxidative addition and its sterically more demanding nature to accelerate reductive elimination, assuming that either one of these elementary steps is rate-determining. On the other hand, 1a that is phenyl instead of isopropyl substituted may sterically favor oxidative addition and electronically encourage reductive elimination. We have recently demonstrated that complexes with a phenyl substituted PNP ligand have much higher propensity to undergo reductive elimination than those containing isopropyl substituents.⁴¹ It has also been shown that phosphine dissociation from the metal center of group 10 PNP complexes is rather unlikely as deduced by their marked thermal stability.^30,40,45,46 As a result, an increase in coordination number for palladium intermediates is highly possible in this catalysis, thereby sterically discouraging oxidative addition to occur for 1b or its subsequent derivatives.

Mechanistic possibilities involving radical pathways were considered. Addition of typical radical inhibitors⁴⁷ such as 2,2,6,6-tetramethyl-1-piperidinyloxy or 2,6-di-tert-butyl-4-hydroxytoluene (1 equiv. to pre-catalyst) to the model reaction (entry 1, Table 1) appears not to affect much the activity and selectivity of 1a, thus implying that the radical participation is rather unlikely.

To gain more insights into the reaction mechanism, competitive experiments employing electronically deactivated, unactivated, and activated aryl iodides with 3-ethynylthiophene were conducted, leading to a Hammett plot (fitted with Hammett σ_p substituent constants) with a reaction constant ρ of 0.82(6) (Fig. 3). Similar reactions involving electronically distinct aryl acetylenes with phenyl iodide were also attempted, yielding ρ = 0.97(7) (Fig. 4). These results are unambiguously indicative of an increase in reaction rates with electron-withdrawing substituents at both aryl iodides and acetylenes, consistent with the development of a negative charge at the reaction center in the transition state. At first glance, the positive sign of these reaction constants appear to imply that the aryl iodide and acetylene building blocks are both electrophilic in character. This result is peculiar given the established concepts⁹ that acetylenes are typically regarded as nucleophiles in traditional Sonogashira couplings though aryl halides are indeed electrophilic. Lei et al. have recently demonstrated an elegant mechanistic study on traditional Sonogashira couplings, wherein the corresponding ρ values of 1.29 and −1.65 were found for electronically distinct aryl iodides and acetylenes, respectively.¹⁵ We reason that the positive ρ value (Fig. 4), in contrast to the negative value reported by Lei et al., highlights the ease of deprotonation of terminal acetylenes to generate mono-substituted acetylides in the presence of electron-withdrawing substituents. In this particular elementary step, acetylenes indeed act as electrophiles, in which the negative charge built in the transition state is more readily stabilized with electron-withdrawing groups. As a result, the opposite signs of ρ values corresponding to substituent constants in aryl acetylenes in the present and Lei's¹⁵ studies are likely suggestive of either inherently different reaction mechanisms or similar pathways with different rate-determining factors for these Sonogashira couplings, a discrepancy that is ascribed to the participation and the non-dissociative characteristic of the PNP ligand employed.

Fig. 3 Hammett plot for the competitive couplings of 4-substituted phenyl iodides with 3-ethynylthiophene catalyzed by 1a in 1,4-dioxane at 25 °C.

Fig. 4 Hammett plot for the competitive couplings of 4-substituted phenyl acetylenes with phenyl iodide catalyzed by 1a in 1,4-dioxane at 25 °C.

In contrast to the small ρ value derived in Fig. 3, several studies on oxidative addition of aryl halides to phosphine ligated zero-valent palladium have disclosed consistently larger reaction constants.^48–51 For instance, Buchwald et al. demonstrated ρ = 2.3 for oxidative addition of aryl chlorides to Pd(XPhos)⁴⁸ whereas Fauvarque et al. determined ρ = 2 for aryl iodides to Pd(PPh₃)₂.⁵¹ The notably smaller value found in the present study thus suggests that the involvement of oxidative addition of aryl halides in the rate-determining step is unlikely. This result is also consistent with the fact that the electronically more releasing 1b is an inferior pre-catalyst compared to 1a for this catalysis. Similar conclusions were also deduced in other studies with low reaction constants involving electronically distinct aryl halides in Heck olefination (e.g., ρ = 0.60 for 1a¹⁶ and 1.39 for 3a)¹⁸ or Suzuki couplings (e.g., ρ = 0.48 for 2),¹⁷ wherein either olefin coordination/insertion⁵² or transmetallation,^53,54 respectively, is suggested to be slowest. In particular, Lei et al. demonstrated in their Sonogashira study with quantitative kinetic data that the transmetallation step is indeed rate-limiting.¹⁵ Given the facile reductive elimination rate found for phenyl substituted PNP complexes,⁴¹ we suggest that reductive elimination of the cross-coupled products is not rate-determining, either. We are currently conducting systematic, controlled experiments employing selected combinations of starting materials (in stoichiometric amount) of the model reaction, in an attempt to elucidate any possible reaction intermediates, particularly those informative to potentially distinguish Pd(0)/Pd(II),^55,56 Pd(I)/Pd(III),^57–60 or Pd(II)/Pd(IV)^61,62 redox cycles.

Conclusions

We have demonstrated that the amido pincer complex 1a is a competent catalyst precursor for the Sonogashira couplings of aryl halides with terminal alkynes under mild conditions. This catalysis is compatible with a variety of functional groups incorporated into these building blocks, including (fluoro)alkyl, alkenyl, (hetero)aryl, silyl, fluoro, alkoxy, ketone, nitro, etc. The fact that 1a outperforms 1b in catalytic activities and low reaction constants obtained from Hammett plots suggests that oxidative addition of aryl halides, in this case aryl iodides, is not rate-determining. Studies directed to identify reaction intermediates and to elucidate the reaction mechanism of this catalysis are currently under way.

Experimental section

General procedures

Unless otherwise specified, all experiments were performed under nitrogen using standard Schlenk or glovebox techniques. All solvents were reagent grade or better and purified by standard methods. Compound 1a was prepared following the procedures reported previously.¹⁶ All other chemicals were used as received from commercial vendors. All NMR spectra were recorded at room temperature in specified solvents using Varian Unity or Bruker AV instruments. Chemical shifts (δ) are listed as parts per million downfield from tetramethylsilane and coupling constants (J) are in hertz. Routine coupling constants are not listed. ¹H NMR spectra are referenced using the residual solvent peak at δ 7.16 for C₆D₆ and δ 7.27 for CDCl₃. ¹³C NMR spectra are referenced using the internal solvent peak at δ 128.39 for C₆D₆ and δ 77.23 for CDCl₃. The assignment of the carbon atoms for all compounds is based on the DEPT ¹³C NMR spectroscopy. ³¹P and ¹⁹F NMR spectra are referenced externally using 85% H₃PO₄ at δ 0 and CFCl₃ in CHCl₃ at δ 0, respectively. The Sonogashira coupling reactions were analyzed by GC on a Varian chrompack CP-3800 instrument equipped with a CP-Sil 5 CB chrompack capillary column or by GC/MS on a Varian 450-GC/240-MS instrument equipped with a Restek MXT-5 column. The identity of the cross-coupling products was confirmed by comparison with authentic samples. GC yields were quantified by signal integral relative to those of prescribed amounts of icosane as an internal standard. MALDI mass spectra were recorded with an α-cyano-4-hydroxycinnamic acid (generally abbreviated as CHCA) matrix on a Bruker Autoflex Mass Spectrometer. Elemental analysis was performed on a Heraeus CHN-O Rapid analyzer.

X-ray crystallography

Crystallographic data for 1b (CCDC reference number 956287) are available in ESI.† Data were collected on a diffractometer with graphite monochromated Mo-Kα radiation (λ = 0.7107 Å). Structures were solved by direct methods and refined by full matrix least squares procedures against F² using SHELXL-97.⁶³ All full-weight non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in calculated positions.

Synthesis of 1b

Method 1: To a suspension of PdCl₂ (77 mg, 0.44 mmol) in THF (6 mL) was added a THF solution (4 mL) of bis(2-diisopropylphosphinophenyl)amine (175 mg, 0.44 mmol). The reaction mixture was transferred to a Teflon-capped vessel and heated in an oil bath to 110 °C for 1 h. All volatiles were removed in vacuo. Diethyl ether (10 mL) was added. The diethyl ether solution was filtered through a pad of Celite and evaporated to dryness under reduced pressure to afford the product as a red solid; yield 223 mg (94%).

Method 2: To a solid mixture of bis(2-diisopropylphosphinophenyl)amine (150 mg, 0.37 mmol) and PdCl₂(PhCN)₂ (144 mg, 0.37 mmol) was added THF (5 mL) at room temperature. The solution was stirred at room temperature for 10 min and evaporated to dryness under reduced pressure. Diethyl ether (8 mL) was added. The ether solution was filtered through a pad of Celite and evaporated to dryness under reduced pressure. The solid residue thus obtained was washed with pentane (2 mL × 2) and dried in vacuo to afford the product as a red solid; yield 187 mg (92%). ¹H NMR (C₆D₆, 500 MHz) δ 7.69 (d, 2, Ar), 6.93 (m, 4, Ar), 6.48 (m, 2, Ar), 2.28 (br m, 4, CHMe₂), 1.40 (dd, 12, CHMe₂), 1.09 (dd, 12, CHMe₂). ³¹P{¹H} NMR (C₆D₆, 202.3 MHz) δ 49.0. ¹³C{¹H} NMR (C₆D₆, 125.5 MHz) δ 164.3 (t, J_CP = 11.0, C), 133.4 (s, CH), 131.9 (s, CH), 120.2 (t, J_CP = 18.3, C), 117.8 (t, CH), 117.0 (t, J_CP = 5.9, CH), 25.3 (t, CHMe₂), 18.9 (s, CHMe₂), 18.2 (s, CHMe₂). Anal. Calcd for C₂₄H₃₆ClNP₂Pd: C, 53.13; H, 6.69; N, 2.58. Found: C, 53.18; H, 6.29; N, 2.16.

General procedures for the Sonogashira couplings outlined in Table 2

A Schlenk flask was sequentially charged with 1a (24 mM in 1,4-dioxane for each single experiment, corresponding to 1.0 mol%) along with an appropriate amount of CuBr (2.0 mol%), aryl halide (1.0 equiv.), alkyne (1.1 equiv.), NEt₃ (15 equiv.), and a magnetic stir bar. The flask was capped with a stopper and the solution was stirred either at 25 °C or heated in an oil bath at prescribed temperatures for a specified period of time. After the reaction mixture was cooled to room temperature, aqueous hydrochloric acid (1 M, 6 mL) was added and the product was extracted with diethyl ether (15 mL × 3). The aqueous solution was separated from the organic layer. The diethyl ether solution was washed with deionized water (15 mL × 3), dried over MgSO₄, and evaporated to dryness under reduced pressure to afford the desired product, which, if necessary, was subjected to flash column chromatography on silica gel using hexane or diethyl ether as the eluent.

4-(Phenylethynyl)acetophenone (6e)⁶⁴

¹H NMR (CDCl₃, 300 MHz) δ 7.94 (d, 2, J = 8.4, Ar), 7.61 (d, 2, J = 8.4, Ar), 7.55 (d, 2, J = 3.9, Ar), 7.37 (m, 3, Ar), 2.60 (s, 3, C(O)Me). ¹³C NMR (CDCl₃, 75 MHz) δ 197.4 (C(O)Me), 136.3 (Ar), 132.6 (Ar), 131.9 (ArH), 131.8 (ArH), 129.3 (ArH), 128.6 (ArH), 128.4 (ArH), 122.8 (Ar), 92.8 (C≡C), 88.7 (C≡C), 26.7 (C(O)Me). MS (MALDI) Calcd for C₁₆H₁₂O m/z 220.089 ([M]⁺), found m/z 220.877 ([M + H]⁺).

4-(4-Fluorophenylethynyl)acetophenone (7e)⁶⁴

¹H NMR (CDCl₃, 300 MHz) δ 7.92 (d, 2, J = 7.8, Ar), 7.58 (d, 2, J = 7.5, Ar), 7.52 (m, 2, Ar), 7.05 (m, 2, Ar), 2.60 (s, 3, C(O)Me). ¹³C NMR (CDCl₃, 75 MHz) δ 197.3 (C(O)Me), 162.9 (J_CF = 248.5, CF), 136.4 (Ar), 133.8 (J_CF = 8.6, ArH), 131.7 (ArH), 128.4 (ArH), 128.1 (Ar), 118.9 (Ar), 115.9 (J_CF = 21.8, ArH), 91.7 (C≡C), 88.4 (C≡C), 26.7 (C(O)Me). ¹⁹F NMR (CDCl₃, 282 MHz) δ −109.9. MS (MALDI) Calcd for C₁₆H₁₁FO m/z 238.079 ([M]⁺), found m/z 238.887 ([M + H]⁺).

1-(Phenylethynyl)-4-(trifluoromethyl)benzene (8a)^64,65

¹H NMR (CDCl₃, 300 MHz) δ 7.64 (m, 4, Ar), 7.55 (m, 2, Ar), 7.38 (m, 3, Ar). ¹³C NMR (CDCl₃, 75 MHz) δ 132.0 (ArH), 131.9 (ArH), 129.0 (ArH), 128.6 (ArH), 127.3 (Ar), 125.9 (Ar), 125.4 (ArH), 122.7 (Ar), 91.9 (C≡C), 88.1 (C≡C). ¹⁹F NMR (CDCl₃, 282 MHz) δ −62.8. MS (MALDI) Calcd for C₁₅H₉F₃m/z 246.066 ([M]⁺), found m/z 247.077 ([M + H]⁺).

4-(4-Trifluoromethylphenylethynyl)acetophenone (8e)⁶⁶

¹H NMR (CDCl₃, 300 MHz) δ 7.95 (d, 2, J = 6, Ar), 7.62 (m, 6, Ar), 2.61 (s, 3, C(O)Me). ¹³C NMR (CDCl₃, 75 MHz) δ 197.3 (C(O)Me), 136.8 (Ar), 132.3 (ArH), 131.9 (ArH), 128.4 (ArH), 127.5 (Ar), 126.6 (Ar), 125.5 (ArH), 122.2 (Ar), 91.1 (C≡C), 90.9 (C≡C), 26.7 (C(O)Me). ¹⁹F NMR (CDCl₃, 282 MHz) δ −62.9. MS (MALDI) Calcd for C₁₇H₁₁F₃O m/z 288.076 ([M]⁺), found m/z 289.051 ([M + H]⁺).

3-(4-Acetylphenylethynyl)thiophene (9e)⁶⁶

¹H NMR (CDCl₃, 300 MHz) δ 7.93 (d, 2, Ar), 7.59 (m, 3, Ar), 7.32 (dd, 1, Ar), 7.21 (m, 1, Ar), 2.60 (s, C(O)Me). ¹³C NMR (CDCl₃, 75 MHz) δ 197.4 (C(O)Me), 136.3 (Ar), 131.7 (ArH), 130.1 (Ar), 129.9 (ArH), 129.6 (ArH), 128.4 (ArH), 125.7 (ArH), 121.9 (Ar), 88.3 (C≡C), 88.0 (C≡C), 26.7 (C(O)Me). MS (MALDI) Calcd for C₁₄H₁₀OS m/z 226.045 ([M]⁺), found m/z 226.858 ([M + H]⁺).

3-(2-Pyridylethynyl)thiophene (9g)⁶⁷

¹H NMR (CDCl₃, 300 MHz) δ 8.59 (d, 1, J = 4.5, Ar), 7.64 (m, 2, Ar), 7.48 (d, 1, J = 7.8, Ar), 7.29 (m, 1, Ar), 7.24 (m, 2, Ar). ¹³C NMR (CDCl₃, 75 MHz) δ 150.1 (ArH), 143.6 (Ar), 136.2 (ArH), 130.3 (ArH), 130.1 (ArH), 127.1 (ArH), 125.6 (ArH), 122.8 (ArH), 121.5 (Ar), 88.4 (C≡C), 84.6 (C≡C). MS (MALDI) Calcd for C₁₁H₇NS m/z 185.030 ([M]⁺), found m/z 185.804 ([M + H]⁺).

4-(Isobutylethynyl)acetophenone (11e)

¹H NMR (CDCl₃, 300 MHz) δ 7.86 (d, 2, J = 8.1, Ar), 7.45 (d, 2, J = 8.1, Ar), 2.56 (s, 3, C(O)Me), 2.32 (d, 2, J = 6.6, CH₂), 1.93 (m, 1, CH), 1.04 (d, 6, J = 6.6, (CH₃)₂). ¹³C NMR (CDCl₃, 75 MHz) δ 197.4 (C(O)Me), 135.9 (Ar), 131.7 (ArH), 129.3 (Ar), 128.3 (ArH), 93.4 (C≡C), 81.1 (C≡C), 28.8 (CH₂), 28.2(CH), 26.6 (C(O)Me), 22.1 (CH(CH₃)₂). MS (MALDI) Calcd for C₁₄H₁₆O m/z 200.120 ([M]⁺), found m/z 200.992 ([M + H]⁺).

Representative procedures for the competition reactions (Fig. 3)

A vial was charged with 1a (3 μmol), CuBr (6 μmol), aryl iodides (0.13 mmol each), 3-ethynylthiophene (0.58 mmol), NEt₃ (7.8 mmol), 1,4-dioxane (4 mL), and a magnetic stir bar. The reaction mixture was stirred at 25 °C for 12 h. An aliquot was taken and quenched with aqueous hydrochloric acid as described above. The product identity and yield were analyzed by GC/MS, from which the relative rate constants were derived and employed for the Hammett plot (see ESI†).

Mercury drop experiment

The catalytic solutions were generated using the procedures described above and mercury (0.35 g) was added. The reaction temperature, time, and work-up procedures were all identical to those conducted without mercury. The product's identity and yield were examined by GC/MS.

Acknowledgements

We thank the Ministry of Science and Technology of Taiwan for financial support (NSC 99-2113-M-110-003-MY3 and NSC 102-2113-M-110-002-MY3), Mr Ting-Shen Kuo (NTNU) for assistance with X-ray crystallography, and the National Center for High-performance Computing (NCHC) for access to chemical databases.

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Footnotes

† Electronic supplementary information (ESI) available: X-ray crystallographic data for 1b, a catalytic reaction profile, details of competition reactions to construct Hammett plots, and NMR spectra of products isolated. CCDC 956287. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3qi00086a

‡ Current address: Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA.

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