DOI: 10.1002/chem.201403860
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& Synthetic Methods
C(sp3) H Activation without a Directing Group: Regioselective Synthesis of N-Ylide or N-Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand Warren B. Cross,*[a] Sunnah Razak,[b] Kuldip Singh,[b] and Andrew J. Warner[b] and NaOAc, C(sp3) H activation gave the N-ylide complex 4; in contrast, with Ag2O followed by [Cp*IrCl2]2, C(sp2) H activation gave the N-heterocyclic carbene complex 5. DFT calculations revealed that the N-ylide complex 4 was the kinetic product of an ambiphilic C H activation. Examination of the computed transition state for the reaction to give 4 indicated that unlike in related reactions, the acetate ligand appears to play the dominant role in C H bond cleavage.
Abstract: N-Ylide complexes of Ir have been generated by C(sp3) H activation of a-pyridinium or a-imidazolium esters in reactions with [Cp*IrCl2]2 and NaOAc. These reactions are rare examples of C(sp3) H activation without a covalent directing group, which—even more unusually—occur a to a carbonyl group. For the reaction of the a-imidazolium ester [3H]Cl, the site selectivity of C H activation could be controlled by the choice of metal and ligand: with [Cp*IrCl2]2
Introduction
rely on the innate reactivity of the C H bond with the metal complex, yet there is almost no information on the factors that influence this reactivity. Herein, we report the undirected C(sp3) H activation of a-pyridinium esters and a-imidazolium esters by [Cp*IrCl2]2 and NaOAc. For the C H activation of aimidazolium esters, we demonstrate that the regioselectivity can be controlled by the choice of the metal and ligand and report the results of DFT calculations that rationalise this selectivity. We also highlight the implications for catalyst-controlled selectivity in C H functionalization.
Over the past decade, a number of highly efficient synthetic strategies have been developed that involve the activation of C H bonds by a transition-metal catalyst.[1] Much of this progress has arisen from an understanding that the dual action of an electrophilic metal and a basic ligand enables low-energy pathways for C H activation: a mechanism that has been labelled concerted metalation–deprotonation (CMD) and ambiphilic metal–ligand activation (AMLA).[2] The overwhelming majority of reactions of this type involve the activation of C(sp2) H bonds and, in contrast, C(sp3) H activation has received much less attention.[3] Performing C(sp3) H activation in the presence of usually more reactive C(sp2) H bonds has been achieved by using an appropriate directing group.[4] However, the use of a chelating directing group introduces an intrinsic limitation to the reaction and strategies are required that avoid a directing group to functionalize alternative C H bonds.[5] Examples of C(sp3) H activation without a directing group are relatively uncommon and most undirected C(sp3) H activations occur at either allylic or benzylic C H bonds.[6, 7] Well-defined examples of undirected C(sp3) H activation a to a carbonyl group are remarkably scarce, and those that have been reported tend to involve oxidative addition rather than an AMLA or CMD mechanism.[8, 9] These undirected reactions
Results and Discussion Experimental investigations We started by investigating the reaction of the a-pyridinium ester [1 aH]Cl, which was stirred with 0.5 equivalents of [Cp*IrCl2]2 and three equivalents of NaOAc in CH2Cl2 at room temperature for 45 min. The 1H NMR spectrum for the product contained a 1H singlet at d = 6.75 ppm for an a-proton and two doublets of quartets at 4.11 and 4.35 ppm for the now diastereotopic protons of the methylene group at the ethyl ester; these signals indicated that activation of an a-C(sp3) H bond had occurred, giving a N-ylide coordinated to iridium through a stereogenic carbon atom, that is, rac-[Cp*Ir(1 a)Cl2] (2 a; Scheme 1). To the best of our knowledge, this C(sp3) H activation is the first report of the synthesis of a monodentate Nylide complex by C H activation.[10, 11] Complex 2 a was isolated in 69 % yield. Similarly, the reaction of [1 bH]Cl with [Cp*IrCl2]2 and NaOAc gave the N-ylide complex rac-[Cp*Ir(1 b)Cl2] (2 b) in 73 % yield. In the 13C NMR spectra, signals for the ylide carbon were observed at d = 55.5 and 54.2 ppm for 2 a and 2 b, respectively. The identity of 2 b was further confirmed by single crystal X-ray diffraction (Figure 1).
[a] Dr. W. B. Cross School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS (UK) E-mail: [email protected] [b] S. Razak, K. Singh, A. J. Warner Department of Chemistry University of Leicester, Leicester, LE1 7RH (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403860. Chem. Eur. J. 2014, 20, 1 – 8
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Scheme 1. C(sp3) H Activation to give N-ylide complexes rac-[Cp*Ir(1)Cl2] (2).
Scheme 2. Regioselective C H activation to give the complexes rac-[Cp*Ir(3ylide)Cl2] (4) and [Cp*Ir(3NHC)Cl2] (5; Mes = 2,4,6-Me3C6H2).
Complex 4 was isolated as an analytically pure solid in 41 % yield, and its identity was confirmed by X-ray crystallography (Figure 2 a). In the solid state, the geometry of 4 is similar to that of 2 b. The most notable difference is the length of the Ir C(ylide) bond, which is approximately 0.03 shorter in 4 than in 2 b (4: 2.135(6) ; 2 b: 2.162(6) ); indeed, in 4 the Ir C(ylide) bond is now the shortest Ir C distance, but this distance is not significantly shorter than the shortest Ir C(Cp*) distances. It is likely that the nature of the adjacent cation affects the Ir C(ylide) distance: in 4, this positive charge is stabilised over two nitrogen atoms, whereas in 2 b, it is localised on one. Evidence for the greater negative charge on the ylide carbon in 4 than in 2 b is provided by the 13C NMR spectra for the two complexes: in 4, the signal for the ylide carbon (d = 42.8 ppm) is approximately 12 ppm further upfield than in 2 b. Monitoring the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc by 1H NMR spectroscopy revealed no evidence for the formation of an NHC isomer of 4. Other researchers have reported difficulty preparing carbonyl-functionalised NHC complexes when using a strong base to deprotonate an imidazolium
Figure 1. Solid-state structure of rac-[Cp*Ir(1 b)Cl2] (2 b) with ellipsoids drawn at 50 % probability. Only selected H atoms are shown for clarity. Selected bond lengths []: Ir C6 2.162(6); Ir1 C(Cp*) 2.134(7) to 2.205(7).
In the piano-stool complex, there is a tilt in the Cp* ring relative to the metal centre: the two Ir C(Cp*) bonds trans to the N-ylide ligand are the longest (2.200(6) and 2.205(7) ), whereas the three Ir C(Cp*) bonds trans to the two chloride ligands are shortest (2.134(7) to 2.159(6) ). The Ir C(ylide) distance of 2.162(6) is comparable with the Ir C(sp3) distances reported in iridium(III)–enolate complexes.[12] To examine the relative reactivity of the a-C(sp3) H bonds, we next investigated the reaction of an a-imidazolium ester, which also contained a reactive C(sp2) H bond. Indeed, we have previously reported the synthesis of N-heterocyclic carbene (NHC) complexes of Cp*Ir from the reaction of imidazolium salts with [Cp*IrCl2]2 and NaOAc.[13] Hence, [3H]Cl was reacted with [Cp*IrCl2]2 and NaOAc at room temperature. A 1H NMR spectrum of the crude reaction mixture after 2 h showed two new compounds in a 3:1 ratio, but remarkably neither of the products was an NHC complex. The major compound was the product of C(sp3) H activation: that is, N-ylide complex rac-[Cp*Ir(3ylide)Cl2] (4; Scheme 2). Complex 4 was easily identified from its 1H NMR spectrum, which contained a 1H singlet at d = 6.33 ppm and two doublets of quartets for the now diastereotopic protons Figure 2. Solid-state structures of a) rac-[Cp*Ir(3ylide)Cl2] (4) and b) [Cp*Ir(3NHC)Cl2] (5) with of the methylene group at the ethyl ester at d = 4.03 ellipsoids at 50 % probability. Only selected hydrogen atoms are shown for clarity. Selectand 4.22 ppm. ed bond lengths [], 4: Ir1 C1 2.135(6), Ir1 C(Cp*) 2.138(6) to 2.205(7); 5: Ir1 C1 2.072(6), Ir1 C(Cp*) 2.156(7) to 2.239(7).
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Full Paper group, which they have attributed to deprotonation of an aC(sp3) H bond.[14] In contrast, NaOAc is not sufficiently basic to deprotonate an a-C(sp3) H bond of [3H]Cl, but herein can cleave an a-C(sp3) H bond in conjunction with [(Cp*IrCl2)2], presumably in a CMD or AMLA reaction. Site-selective C H activation controlled by the choice of metal and ligand is an uncommon but highly useful strategy for synthesis.[15] Hence, we wanted to see if the alternative iridium NHC complex could be isolated under different conditions. This turned out to be the case and the reaction of imidazolium salt [3H]Cl with Ag2O followed by [Cp*IrCl2]2 gave the NHC complex [Cp*Ir(3NHC)Cl2] (5) as the only product (Scheme 2), with no evidence for the formation of the N-ylide complex 4. The solid-state structure of 5 was also determined by X-ray crystallography (Figure 2 b). Comparison of the structures of 4 and 5 enables a direct comparison of the isomeric ligands 3ylide and 3NHC. For ligand 3NHC, the Ir C distance (2.072(6) ) is approximately 0.06 shorter than the Ir C distance for 3ylide. In addition, 3NHC has the greater trans influence: the two Ir C(Cp*) distances trans to 3NHC in 5 (2.215(7) and 2.239(7) ) are approximately 0.03 longer than the corresponding bonds that are trans to 3ylide in 4.
solid-state structures obtained from single-crystal X-ray diffraction data, and they replicate the longer Ir C(ylide) distance in 4 compared with the Ir C(NHC) distance in 5. The computed solution energy (ESCF + ZPE in CH2Cl2) of the NHC complex 5 was 6.5 kcal mol 1 lower than that of the N-ylide complex 4, suggesting that the experimentally observed product of the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc, that is, 4, may be the kinetic product of the reaction. Hence, we investigated the barriers to the C(sp3) H activation and the C(sp2) H activation of [3H] + through an AMLA-6 pathway (Figure 3).[2, 17] The starting point for our study was the complex [Cp*Ir(OAc)2], containing one k1-acetate ligand and one k2-acetate ligand. The complex [Cp*Ir(OAc)2] has been isolated previously and been shown to participate in C H activation.[18, 19] In addition, from experimental observations involving analogous rhodium(III) complexes, [Cp*Ir(OAc)2] has been implicated as an intermediate in C H activation reactions involving [Cp*IrCl2] and NaOAc.[20] Furthermore, [Cp*Ir(OAc)2] has been used as the reference structure in previously reported DFT studies of C H activation.[21] Previous computational studies of C H activation by [Cp*Ir(OAc)2] have involved covalent directing groups and, hence, the substitution of one of the acetate ligands by a heteroatom donor atom of the substrate.[17, 21] Imidazolium ion [3H] + lacks a competent covalent directing group, so instead, a hydrogenbonded complex was considered. The complex A (DE = 12.6 kcal mol 1) involving two H-bonding interactions between [Cp*Ir(k2-OAc)(k1-OAc)] and [3H] + was located: one of the H bonds in A involved the k2-OAc ligand and the a-C(sp3) H bond; the other H bond involved the k1-OAc ligand and the N2C(sp2) H bond. An alternative complex involving H bonding between of the k1-OAc ligand with the aC(sp3) H bond and the k2-OAc ligand with the N2C(sp2) H bond could not be located as a local minimum on the potential energy surface. From A, two possibilities exist for activation of the a-C(sp3) H bond via an AMLA-6 mechanism: either k2 to k1 displacement of an acetate ligand can occur with concurrent
Computational investigations DFT calculations were used to determine the origin of the regioselectivity in the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc. Geometries and thermal contributions were computed in the gas phase at the B3LYP/LANL2DZ/6-31G(d,p) level; SCF energies were computed in CH2Cl2 solution (PCM approach) at the M06/def2-TZVP level. Due to the difficulties associated with assessing Gibbs free energies in solution, especially for charged species and in associative reactions,[16] the energies discussed in the main text are SCF energies corrected with the zero point energy (ESCF + ZPE). However, both ESCF + ZPE and Gibbs energies are presented in Figure 3. First, we computed the structures of the two isomeric products 4 and 5. The computed structures are in accord with the
Figure 3. Computed energy-profile diagram for the C H activation of [3H] + with [Cp*Ir(OAc)2]. Relative energies (ESCF + ZPE) and Gibbs energies (parentheses) in CH2Cl2 are shown in kcal mol 1. Chem. Eur. J. 2014, 20, 1 – 8
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Full Paper C H activation,[17] or k2 to k1 displacement of the acetate ligand could give rise to an intermediate prior to C H activation.[21] Direct activation of the N2C(sp2) H bond from A does not appear to be possible, because the metal lacks a vacant coordination site. A relaxed potential-energy surface scan was employed to follow the reaction coordinate corresponding with k2 to k1 displacement of the acetate ligand; these computations indicated that activation of the a-C(sp3) H bond did not occur concurrently with the change in coordination mode of the acetate ligand. However, the complex [Cp*Ir(k1-OAc)2] [3H] + (B), involving k1-coordination of both acetate ligands, was located as a minimum on the potential energy surface (DE = 4.7 kcal mol 1). From B, activation of the a-C(sp3) H bond proceeds via TS(B-C) (DE° = + 24.1 kcal mol 1) to give the N-ylide complex C (DE = + 0.8 kcal mol 1); exchange of the acetate and acetic acid ligands in C with two chloride ligands gives the experimentally observed product 4. Alternatively from B, activation of the N2C(sp2) H bond via TS(B-D) (DE° = + 27.6 kcal mol 1) would give the NHC complex D (DE = 6.9 kcal mol 1); subsequent ligand exchange would lead to the computed thermodynamic product 5, which was not observed experimentally from the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc. Given the difference in energy of the two transition states TS(B-C) and TS(B-D) (DDE° = 3.5 kcal mol 1), these computations suggest that for C H activation of the imidazolium ion [3H] + by [Cp*Ir(OAc)2], the experimentally observed N-ylide complex 4 is the kinetic product of the reaction. Experimentally, we attempted to isolate the computed thermodynamic product 5 under more forcing conditions, heating [3H]Cl with [Cp*IrCl2]2 and NaOAc in 1,2-dichloroethane at 80 8C. The reaction under these conditions gave an unidentifiable mixture of products; however, it was apparent from a 1H NMR spectrum of the crude reaction mixture that neither 4 or 5 were products of the reaction at elevated temperature. In addition to having different energies, the two transition states TS(B-C) and TS(B-D) have very different geometries
Table 1. Computed distances and bond orders for the breaking and forming bonds in TS(B-C) and TS(B-D).
C O Ir Ir
H H C H
TS(B-C) Distance []
Bond order[a]
TS(B-D) Distance []
Bond order[a]
1.81 1.04 3.31 2.77
0.16 0.53 0.15 0.02
1.38 2.89 2.20 1.66
0.45 0.02 0.51 0.34
[a] Wiberg bond index from NBO analysis calculation.
(Figure 4 and Table 1). Analysis of the computed bond orders for the breaking C H bond and the forming O H and Ir C bonds, revealed that in TS(B-C) C(sp3) H cleavage is almost complete, but the Ir C distance is still very long. In contrast, in TS(B-D) there is a strong interaction of the breaking C(sp2) H bond with the electrophilic iridium(III) centre, but a much weaker interaction with the basic acetate ligand. A similar analysis of transition states for the reactions of aromatic and heteroaromatic compounds with [Pd(C6H5)(PMe3)(OAc)] revealed a much narrower distribution of bond orders for the breaking C H bonds and the forming O H and Pd C(sp2) bonds.[22] Hence, in contrast to the transition states analysed for [Pd(C6H5)(PMe3)(OAc)], our findings suggest that a mechanistic spectrum of AMLA or CMD reactions does exist: at one extreme of this spectrum, for example TS(B-D), the electrophilic metal plays the major role in C H activation and at the other extreme of the spectrum, for example TS(B-C), the basic ligand plays the major role in C H activation. As further evidence for the significant role played by the base in the reaction of [3H]Cl with [Cp*IrCl2]2, experimentally we observed no reaction when sodium acetate was replaced with sodium fluoroacetate. To the best of our knowledge, TS(B-C) is the first demonstration of an AMLA reaction in which the basic ligand plays the dominant role in C H cleavage. The ability of the basic ligand to play this dominant role may have significant implications for the development of catalyst controlled, site-selective C H functionalization.
Conclusion
Figure 4. Computed structures for the isomeric transition states a) TS(B-C) and b) TS(B-D), with selected bond lengths []. Only selected hydrogen atoms are shown for clarity.
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We have demonstrated C(sp3) H activation without a directing group to give N-ylide complexes of iridium. Moreover, the regioselective C H activation of the a-imidazolium ester [3H]Cl can be controlled by the choice of metal and ligand: C(sp3) H activation with [Cp*IrCl2]2 and NaOAc gave the N-ylide complex 4, whereas C(sp2) H activation with Ag2O followed by [Cp*IrCl2]2 gave the NHC complex 5. By using DFT calculations, we have demonstrated that the C H activation of [3H]Cl with [Cp*IrCl2]2 and NaOAc operates under kinetic control. To the best of our knowledge, these are the first well-defined examples of undirected a-C(sp3) H activation involving the cooperative action of a metal and a weakly basic ligand in a CMD or AMLA reaction. Analysis of the comput 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper ed transition state for the conversion of [3H]Cl to 5 revealed that, unlike CMD or AMLA reactions of (hetero)arenes involving Pd acetate complexes, the acetate ligand plays the dominant role in this a-C(sp3) H activation. This C(sp3) H activation is a direct and exceptionally mild method for the formation of metal ylide complexes; we are currently pursuing applications of this reaction in (asymmetric) catalysis.
Synthesis of rac-[Cp*Ir(1 a)Cl2] (2 a) Sodium acetate (62 mg, 0.75 mmol) was added to a solution of [Cp*IrCl2]2 (100 mg, 0.126 mmol) in CH2Cl2 (14 mL), which was then stirred at RT for 20 min. After this time, pyridiniumium salt [1 aH]Cl (51 mg, 0.25 mmol) was added to the reaction mixture, which was stirred for a further 45 min. After this time, the volatiles were removed in vacuo to give an orange/yellow solid. The solid was scraped from the sides of the flask and washed with Et2O (12 10 mL). The solid was extracted in MeCN (3 mL), and the solution was dried by passing it through a pipette containing K2CO3 ; this extraction was repeated twice. Finally, the volatiles were removed in vacuo to give 2 a as a yellow solid (98 mg, 69 %). 1H NMR (400 MHz, CDCl3): d = 1.31 (3 H, t, J = 7.1, OCH2CH3), 1.61 (15 H, s, C5Me5), 4.11 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 4.35 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 6.75 (1 H, s, HC Ir), 7.58 (2 H, app t, J = 6.9, PyCH), 7.85 (1 H, tt, 3J = 7.7, 4J = 1.3, PyCH), 8.66 (2 H, d, J = 6.7, PyCH); 13C{1H} NMR (100.6 MHz, CDCl3): d = 8.7 (C5Me5), 14.7 (OCH2CH3), 55.5 (HC Ir), 60.8 (OCH2CH3), 86.4 (C5Me5), 124.5 (PyC3,5), 139.8 (Py-C4), 145.1 (Py-C2,6), 175.05 ppm (C=O); IR (solid): u˜ = 1709 cm 1 (C=O); MS (FAB): m/z (%): 563 (16) [M] + , 528 (100) [M Cl] + ; elemental analysis calcd (%) for C19H26NO2IrCl2 (563.54): C 40.49, H 4.65, N 2.49; found: C 40.52, H 4.60, N 2.52.
Experimental Section All manipulations were performed under dry, oxygen-free nitrogen by using standard Schlenk techniques, unless otherwise stated. CH2Cl2 was dried by passing through a column of activated alumina and then degassed. [Cp*IrCl2]2 and 1-mesityl imidazole were prepared as reported in the literature.[23, 24] NaOAc was dried in an oven at 80 8C overnight before use. All other reagents were obtained from Sigma–Aldrich, Johnson Matthey or Alfa Aesar and used as supplied. NMR spectra were recorded on a Bruker DRX400 spectrometer at 298 K; chemical shifts have been referenced to the residual protonated solvent peak, and J values are given in Hz. For some compounds, assignments for 1H and 13C NMR peaks were aided by 1H–1H COSY, 1H–1H NOESY and 1H–13C HMQC 2D NMR experiments. FTIR spectra were run in a diamond ATR cell by using a Perkin–Elmer Spectrum 1 instrument. ESI mass spectra were recorded on a micromass Quattra LC spectrometer in MeCN/MeOH with a cone voltage of + 25 V; FAB mass spectra were obtained on a Kratos concept spectrometer by using NBA as the matrix. Elemental analyses were performed at London Metropolitan University.
Synthesis of rac-[Cp*Ir(1 b)Cl2] (2 b) Sodium acetate (52 mg, 0.64 mmol) was added to a solution of [Cp*IrCl2]2 (85 mg, 0.106 mmol) in CH2Cl2 (12 mL), which was then stirred at RT for 20 min. After this time, pyridinium chloride salt [1 aH]Cl (50 mg, 0.21 mmol) was added to the reaction mixture, which was stirred for a further 45 min. After this time, the volatiles were removed in vacuo to give an orange yellow solid. The solid was scraped from the sides of the flask and washed with Et2O (10 10 mL). The solid was extracted in MeCN (2 9 mL), and the solution was dried by passing it through a pipette containing K2CO3 ; this extraction was then repeated once. Finally, the volatiles were removed in vacuo to give 2 b as an orange solid (92 mg, 73 %). Crystals of 2 b suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 2 b. 1H NMR (400 MHz, CDCl3): d = 1.31 (3 H, t, J = 7.2, OCH2CH3), 1.61 (15 H, s, C5Me5), 4.12 (1 H, dq, J = 10.7, J = 7.2, OCH2CH3), 4.35 (1 H, dq, J = 10.7, J = 7.2, OCH2CH3), 6.72 (1 H, s, HC-Ir), 7.53 (1 H, dd, J = 8.3, J = 6.3, Py-5-CH), 7.80 (1 H, ddd, J = 8.3, J = 2.0, 1.1, Py-4-CH), 8.61 (1 H, app dt, J = 6.3, J = 1.1, Py-6-CH), 8.65 ppm (1 H, app t, Py2-CH); 13C{1H} NMR (100.6 MHz, CDCl3): d = 7.1 (C5Me5), 13.1 (OCH2CH3), 54.2 (HC Ir), 59.1 (OCH2CH3),84.8 (C5Me5), 123.0 (Py C5), 130.5 (Py C3), 137.6 (Py C4), 141.1 (Py C6), 142.4 (Py C2), 172.9 ppm (C=O); IR (solid): u˜ = 1712 cm 1 (C=O); MS (ESI): m/z (%): 562 (100) [M Cl] + ; elemental analysis calcd (%) for C19H25IrNO2Cl3 : C 38.16, H 4.21, N 2.34; found: C 38.15, H 3.95, N 2.29.
Synthesis of [1 aH]Cl A solution of pyridine (1.50 mL, 18.6 mmol) and ethyl chloroacetate (2 mL, 18.6 mmol) in Et2O (5 mL) was heated at 40 8C for 16 h. The resulting brown precipitate was isolated by filtration and washed with Et2O (2 5 mL), giving [1 aH]Cl as a brown solid (2.16 g, 58 %). 1 H NMR (400 MHz, CDCl3): d = 1.33 (3 H, t, J = 7.1, CH2CH3), 4.29 (2 H, q, J = 7.1, CH2CH3), 6.50 (2 H, s, CH2CO2Et), 8.07 (2 H, app t, J = 7.1, PyCH), 8.50 (1 H, t, J = 7.8, PyCH), 9.59 ppm (2 H, d, J = 5.4, PyCH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 14.04 (OCH2CH3), 61.0 (CH2), 63.3 (CH2), 127.5 (Py-C3,5), 145.6 (Py-C4), 147.1 (Py-C2,6), 166.20 (C=O); MS (ESI) m/z (%): 166 (50) [M Cl] + , 138 (100) [M Cl Et + H] + .
Synthesis of [1 bH]Cl A mixture of 3-chloropyridine (0.44 mL, 4.7 mmol) and ethyl chloroacetate (0.50 mL, 4.7 mmol) was heated at 90 8C for 64 h. The resulting brown residue was extracted with CHCl3 (3 10 mL). The volatiles were then removed in vacuo, and the oily residue washed with Et2O (3 5 mL). The residue was dried in vacuo to give [1 bH]Cl as a brown solid (0.687 g, 62 %). 1H NMR (400 MHz, CDCl3): d = 1.30 (3 H, t, J = 7.2, CH2CH3), 4.27 (2 H, q, J = 7.2, CH2CH3), 6.51 (2 H, s, CH2CO2Et), 8.13 (1 H, dd, J = 8.4, 6.1, PyCH), 8.47 (1 H, dd, J = 8.4, 0.7, PyCH), 9.71 (1 H, d, J = 6.1, PyCH), 9.76 ppm (1 H, s, PyCH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 13.9 (OCH2CH3), 60.7 (CH2), 63.2 (CH2), 128.2 (Py-CH), 125.0 (Py CCl), 145.6, 145.8, 145.9, (Py CH), 166.20 (C=O); MS (ESI) m/z (%): 200 (88) [M Cl] + , 172 (100) [M Cl Et + H] + . Chem. Eur. J. 2014, 20, 1 – 8
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Synthesis of [3 H]Cl A solution of 1-mesityl imidazole (0.97 g, 5.3 mmol) and ethyl chloroacetate (0.70 mL, 6.4 mmol) in MeCN (8 mL) was heated at 90 8C for 12 h. The solution was cooled to RT, and the volatiles were removed in vacuo. The resulting solid was washed with Et2O (3 5 mL) to give [3H]Cl as a white solid (1.59 g, 96 %). 1H NMR (400 MHz, CDCl3): d = 1.26 (3 H, t, J = 7.2, CH2CH3), 2.03 (6 H, s, oCH3), 2.28 (3 H, s, p-CH3), 4.21 (2 H, q, J = 7.2, CH2CH3), 5.88 (2 H, s, NCH2CO2Et), 6.94 (2 H, s, Mes-CH), 7.08 (1 H, t, J = 1.7, NCHCHN), 7.80 (1 H, t, J = 1.7, NCHCHN), 10.45 ppm (1 H, t, J = 1.4, N2CH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 14.0 (CH2CH3), 17.5 (o-CH3), 21.1 (p-CH3), 50.6 (CH2), 62.7 (CH2), 122.4 (NCHCHN), 124.7
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Full Paper (NCHCHN), 129.8 (Ar CH), 130.7, 134.3, 139.7 (Ar C), 141.3 (N2CH), 166.6 ppm (C=O); MS (ESI): m/z (%) 273 (100) [M Cl] + .
data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of rac-[Cp*Ir(3ylide)Cl2] (4) Sodium acetate (62 mg, 0.75 mmol) was added to a solution of [Cp*IrCl2]2 (100 mg, 0.126 mmol) in CH2Cl2 (14 mL), which was then stirred at RT for 20 min. After this time, imidazolium salt [3H]Cl (78 mg, 0.25 mmol) was added to the reaction mixture, which was stirred for a further 2 h. A crude-mixture 1H NMR spectrum obtained at this stage revealed two products in a 3:1 ratio. The minor product was subsequently identified as [IrCl3][3H] by single-crystal X-ray diffraction. To isolate the major product, the volatiles were removed in vacuo to give an orange yellow solid, which was extracted with 50 % hexanes/Et2O (6 10 mL). The volatiles were then removed in vacuo, and the extraction was repeated, again with 50 % hexanes/Et2O (6 10 mL). The volatiles were again removed in vacuo to give 4 as a deep orange solid (69 mg, 41 %). Crystals of 4 suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 4. 1 H NMR (400 MHz, CDCl3): d = 1.23 (3 H, t, J = 7.1, OCH2CH3), 1.59 (15 H, s, C5Me5), 1.98 (3 H, s, o-CH3), 2.24 (3 H, s, o-CH3), 2.28 (3 H, s, p-CH3), 4.03 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 4.22 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 6.33 (1 H, s, HC Ir), 6.74 (1 H, t, J = 1.5, NCHCHN), 6.90 (2 H, s, Mes-CH), 7.03 (1 H, t, J = 1.5, NCHCHN), 9.08 ppm (1 H, t, J = 1.5, N2CH); 13C{1H} NMR (100.6 MHz, CDCl3): d 8.6 (C5Me5), 14.8 (OCH2CH3), 17.3 (o-CH3), 18.2 (o-CH3), 21.1 (p-CH3), 42.8 (HC Ir), 60.2 (OCH2CH3), 86.1 (C5Me5), 118.5 (NCHCHN), 123.2 (NCHCHN), 129.0 (Ar CH), 129.8 (Ar CH), 131.7, 134.8, 136.3, 140.3 (Ar C), 140.5 (N2CH), 175.0 ppm (C=O); IR (solid): u˜ = 1704 cm 1 (C=O); MS (ESI): m/z (%): 635 (100) [M-Cl] + ; elemental analysis calcd (%) for C26H35Cl2IrN2O2 (670.69): C 46.56, H 5.26, N 4.18; found: C 46.47, H 5.16, N 4.09.
Computational methods
Synthesis of [Cp*Ir(3NHC)Cl2] (5)
The authors would like to acknowledge the use of the EPSRC UK National Service for Computational Chemistry Software (NSCCS) at Imperial College London in carrying out this work. We thank the University of Leicester for financial support and Johnson Matthey for a loan of iridium trichloride. We are grateful to Prof. Dai Davies (University of Leicester) for useful discussions and the reviewers for their suggestions.
Calculations were performed with Gaussian 09, Revision C.01.[25] Geometry optimizations and thermal contributions to energies were computed in the gas phase with the B3LYP hybrid functional and employed the LANL2DZ basis set for Ir with a 60 electron ECP;[26] the 6–31G(d,p) basis set was used for all other atoms. Stationary points were identified as minima or transition states through analytical frequency calculations; transition states were further characterised through IRC calculations and subsequent geometry optimisations. More accurate SCF energies were then computed by employing single-point calculations with the M06 hybrid functional;[27] in these calculations, the flexible def2-TZVP basis set was employed for all atoms, including the associated 60 electron ECP for Ir.[28] The effects of CH2Cl2 solvent were computed by using the PCM approach. Energies reported in the main text (ESCF + ZPE) were determined from the sum of the SCF energy (MO6, CH2Cl2) and the zero-point correction (B3LYP, gas phase). Wiberg bond orders were determined from NBO analysis calculations (B3LYP/LANL2DZ/6– 31G(d,p)). There are two diastereomers of C and D. The diastereomers reported for C and D were found to have SCF energies 1.1 and 2.6 kcal mol 1 lower in energy than the alternative diastereomers. Computed Cartesian coordinates and energies for all species computed are available in the Supporting Information.
Acknowledgements
A suspension of imidazolium salt [3H]Cl (39 mg, 0.13 mmol) and Ag2O (16 mg, 0.069 mmol) in CH2Cl2 (4 mL) was stirred at 35 8C in the dark. After 24 h, [Cp*IrCl2]2 (50 mg, 0.063 mmol) was added to the reaction mixture, which was again stirred for a further 24 h in the dark. After this time, the solution was filtered through Celite, and the volatiles were removed in vacuo to give 5 as an orange solid (136 mg, 73 %). Crystals of 5 suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 5. 1H NMR (400 MHz, CDCl3): d = 1.34 (3 H, t, J = 7.1, OCH2CH3), 1.49 (15 H, s, C5Me5), 2.07 (6 H, s, o-CH3), 2.29 (3 H, s, p-CH3), 4.31 (2 H, q, J = 7.1, OCH2CH3), 5.38 (2 H, br s, NCH2CO2Et), 6.70 (1 H, d, J = 2.0, NCHCHN), 6.84 ((2 H, s, Mes-CH), 7.15 ppm (1 H, d, J = 2.0, NCHCHN); 13C{1H} NMR (100.6 MHz, CDCl3): d = 8.9 (C5Me5),14.2 (OCH2CH3), 19.2 (o-CH3), 21.2 (p-CH3), 53.5 (NCH2CO2Et), 61.8 (OCH2CH3), 89.2 (C5Me5), 123.1 (NCHCHN), 125.4 (NCHCHN), 128.2, 129.0 (Ar CH), 136.6, 138.4 (Ar C), 156.1 (N2C Ir), 169.4 ppm (C=O); IR (solid): u˜ = 1746 cm 1 (C=O); MS (ESI): m/z (%): 635 (100) [M Cl] + ; elemental analysis calcd (%) for C26H35Cl2IrN2O2 (670.69): C 46.56, H 5.26, N, 4.18; found: C 46.39, H, 5.17, N 4.36. 1 H and 13C NMR spectra for all compounds are available in the Supporting Information.
Keywords: C H activation · cooperative effects · iridium · synthetic methods · ylides [1] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345, and references therein. [2] a) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848 – 10849; b) Y. Boutadla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Bahamonde, Dalton Trans. 2009, 5820 – 5831. [3] O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902 – 4911. [4] a) R. Giri, J. Liang, J.-G. Lei, J.-J. Li, D.-H. Wang, X. Chen, I. C. Naggar, C. Guo, B. M. Foxman, J.-Q. Yu, Angew. Chem. 2005, 117, 7586 – 7590; Angew. Chem. Int. Ed. 2005, 44, 7420 – 7424; b) M. Chaumontet, R. Piccardi, N. Audic, J. Hitce, J.-L. Peglion, E. Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130, 15157 – 15166; c) M. Wasa, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 9886 – 9887; d) S. Rousseaux, S. I. Gorelsky, B. K. W. Chung, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 10692 – 10705; e) D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965 – 3972; f) Y. Nakao, E. Morita, H. Idei, T. Hiyama, J. Am. Chem. Soc. 2011, 133, 3264 – 3267; g) K. J. Stowers, A. Kubota, M. S. Sanford, Chem. Sci. 2012, 3, 3192 – 3195. [5] N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem. Int. Ed. 2012, 51, 10236 – 10254.
X-Ray crystallographic studies The solid-state structures of the compounds 2 b, 4, 5 and [IrCl3] [3H] were determined by single-crystal X-ray diffraction. CCDC945376 (2 b), CCDC-945377 (4), CCDC-945378 (5), and CCDC945379 ([IrCl3][3H]) contain the supplementary crystallographic
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Full Paper [6] For examples of allylic C-H activation, see: a) C. Engelin, T. Jensen, S. Rodriguez-Rodriguez, P. Fristrup, ACS Catal. 2013, 3, 294 – 302; b) B. M. Trost, E. Iglesias-Sigenza, D. A. Thaisrivongs, E. J. Donckele, Angew. Chem. 2012, 124, 1553 – 1555; Angew. Chem. Int. Ed. 2012, 51, 1523 – 1524; c) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9585 – 9587; d) T. Jensen, P. Fristrup, Chem. Eur. J. 2009, 15, 9632 – 9636. [7] For examples of benzylic C-H activation, see: a) J.-J. Jin, H.-Y. Niu, G.-R. Qu, H.-M. Guo, J. S. Fossey, RSC Adv. 2012, 2, 5968 – 5971; b) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am. Chem. Soc. 2010, 132, 3650 – 3651; c) L.-C. Campeau, D. Schipper, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266 – 3267; d) K. Chan, P. Chiu, K. Choi, Organometallics 2007, 26, 1117 – 1119; e) A. F. Heyduk, T. G. Driver, J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc. 2004, 126, 15034 – 15035. [8] Herein, we use the term C H activation to refer to a reaction in which the transition metal is intimately involved in the cleavage of the C H bond. Although transition-metal catalysed functionalizations of aC(sp3) H bonds in carbonyl compounds are well established, these reactions typically differ from our definition by employing a strong base, such as an alkali metal amide or alkoxide, to generate a stoichiometric alkali metal enolate; for relevant reviews, see: a) F. Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082 – 1146; b) C. C. C. Johansson, T. J. Colacot, Angew. Chem. 2010, 122, 686 – 718; Angew. Chem. Int. Ed. 2010, 49, 676 – 707; c) G. C. Lloyd-Jones, Angew. Chem. 2002, 114, 995 – 998; Angew. Chem. Int. Ed. 2002, 41, 953 – 956. [9] For examples a-C H activation via oxidative addition, see: a) Y. Guo, X. Zhao, D. Zhang, S.-I. Murahashi, Angew. Chem. 2009, 121, 2081 – 2083; Angew. Chem. Int. Ed. 2009, 48, 2047 – 2049; b) S.-I. Murahashi, T. Naota, H. Taki, M. Mizuno, H. Takaya, S. Komiya, Y. Mizuho, N. Oyasato, M. Hiraoka, J. Am. Chem. Soc. 1995, 117, 12436 – 12451; c) M. Feller, A. Karton, G. Leitus, J. M. L. Martin, D. Milstein, J. Am. Chem. Soc. 2006, 128, 12400 – 12401. [10] For bidentate bis(N-ylide) complexes from reactions with [Pd(OAc)2] at elevated temperatures, see: a) A. Lleds, J. J. Carb, R. Navarro, E. Serrano, E. P. Urriolabeitia, Inorg. Chem. 2004, 43, 7622 – 7635; b) D. J. Nielsen, K. J. Cavell, B. W. Skelton, A. H. White, Organometallics 2001, 20, 995 – 1000. [11] For bidentate carbene/N-ylide complexes, see: a) R. Lalrempuia, N. McDaniel, H. Mller-Bunz, S. Bernhard, M. Albrecht, Angew. Chem. 2010, 122, 9959 – 9962; Angew. Chem. Int. Ed. 2010, 49, 9765 – 9768; b) M. Viciano, M. Feliz, R. Corberan, J. A. Mata, E. Clot, E. Peris, Organometallics 2007, 26, 5304 – 5314. [12] a) H. Kanemitsu, K. Uehara, S. Fukuzumi, S. Ogo, J. Am. Chem. Soc. 2008, 130, 17141 – 17147; b) Q. W. Chang, M. J. Xie, W. P. Liu, X. Z. Chen, Q. S. Ye, Acta Cryst. E 2009, 65, 1264 – 1264. [13] W. B. Cross, C. G. Daly, Y. Boutadla, K. Singh, Dalton Trans. 2011, 40, 9722 – 9730. [14] a) B. R. M. Lake, E. K. Bullough, T. J. Williams, A. C. Whitwood, M. A. Little, C. E. Willans, Chem. Commun. 2012, 48, 4887 – 4889; b) K. S. Coleman, H. T. Chamberlayne, S. Turberville, M. L. H. Green, A. R. Cowley, Dalton
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Trans. 2003, 2917 – 2922; c) D. S. McGuinness, K. J. Cavell, Organometallics 2000, 19, 741 – 748; d) W. A. Herrmann, L. J. Gooßen, M. Spiegler, J. Organomet. Chem. 1997, 547, 357 – 366. For examples of metal or ligand control of selectivity in C H activation, see: a) S. Yanagisawa, K. Ueda, H. Sekizawa, K. Itami, J. Am. Chem. Soc. 2009, 131, 14622 – 14623; b) A. N. Campbell, E. B. Meyer, S. S. Stahl, Chem. Commun. 2011, 47, 10257 – 10259; c) J. D. Dooley, S. Reddy Chidipudi, H. W. Lam, J. Am. Chem. Soc. 2013, 135, 10829 – 10836; d) K. J. T. Carr, D. L. Davies, S. A. Macgregor, K. Singh, B. Villa-Marcos, Chem. Sci. 2014, 5, 2340 – 2346, and references therein. a) P. Winget, C. J. Cramer, D. G. Truhlar, Theor. Chem. Acc. 2004, 112, 217 – 227; b) B. O. Leung, D. L. Reid, D. A. Armstrong, A. Rauk, J. Phys. Chem. A 2004, 108, 2720 – 2725; c) D. Ardura, R. Lpez, T. L. Sordo, J. Phys. Chem. B 2005, 109, 23618 – 23623; d) P. A. Dub, R. Poli, J. Mol. Catal. A 2010, 324, 89 – 96. D. L. Davies, S. M. A. Donald, O. Al-Duaij, S. A. Macgregor, M. Pçlleth, J. Am. Chem. Soc. 2006, 128, 4210 – 4211. J. Kang, P. M. Maitlis, J. Organomet. Chem. 1971, 30, 127 – 133. S. Arita, T. Koike, Y. Kayaki, T. Ikariya, Organometallics 2008, 27, 2795 – 2802. L. Li, W. W. Brennessel, W. D. Jones, Organometallics 2009, 28, 3492 – 3500. D. A. Frasco, C. P. Lilly, P. D. Boyle, E. A. Ison, ACS Catal. 2013, 3, 2421 – 2429. S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Org. Chem. 2012, 77, 658 – 668. C. White, A. Yates, P. M. Maitlis, D. M. Heinekey, Inorg. Synth. 1992, 29, 228 – 234. T. Strassner, Y. Unger, A. Zeller (BASF SE), US 2009/0326237 A1, 2007. Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, . Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2009. P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 299 – 310. Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215 – 241. F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297 – 3305.
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FULL PAPER & Synthetic Methods W. B. Cross,* S. Razak, K. Singh, A. J. Warner && – && C(sp3) H Activation without a Directing Group: Regioselective Synthesis of N-Ylide or N-Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand
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Which C H bond reacts? N-Ylide complexes of Ir were generated by a-C(sp3 -H activation with [Cp*IrCl2]2 and NaOAc. The reaction of an a-imidazolium ester is a rare example of a C H activation where the site selectivity can
be controlled by the choice of metal and ligand; DFT calculations revealed that the N-ylide complex is the kinetic product of an ambiphilic C H activation, in which the acetate ligand plays the dominant role (see scheme).
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& Synthetic Methods
C(sp3) H Activation without a Directing Group: Regioselective Synthesis of N-Ylide or N-Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand Warren B. Cross,*[a] Sunnah Razak,[b] Kuldip Singh,[b] and Andrew J. Warner[b] and NaOAc, C(sp3) H activation gave the N-ylide complex 4; in contrast, with Ag2O followed by [Cp*IrCl2]2, C(sp2) H activation gave the N-heterocyclic carbene complex 5. DFT calculations revealed that the N-ylide complex 4 was the kinetic product of an ambiphilic C H activation. Examination of the computed transition state for the reaction to give 4 indicated that unlike in related reactions, the acetate ligand appears to play the dominant role in C H bond cleavage.
Abstract: N-Ylide complexes of Ir have been generated by C(sp3) H activation of a-pyridinium or a-imidazolium esters in reactions with [Cp*IrCl2]2 and NaOAc. These reactions are rare examples of C(sp3) H activation without a covalent directing group, which—even more unusually—occur a to a carbonyl group. For the reaction of the a-imidazolium ester [3H]Cl, the site selectivity of C H activation could be controlled by the choice of metal and ligand: with [Cp*IrCl2]2
Introduction
rely on the innate reactivity of the C H bond with the metal complex, yet there is almost no information on the factors that influence this reactivity. Herein, we report the undirected C(sp3) H activation of a-pyridinium esters and a-imidazolium esters by [Cp*IrCl2]2 and NaOAc. For the C H activation of aimidazolium esters, we demonstrate that the regioselectivity can be controlled by the choice of the metal and ligand and report the results of DFT calculations that rationalise this selectivity. We also highlight the implications for catalyst-controlled selectivity in C H functionalization.
Over the past decade, a number of highly efficient synthetic strategies have been developed that involve the activation of C H bonds by a transition-metal catalyst.[1] Much of this progress has arisen from an understanding that the dual action of an electrophilic metal and a basic ligand enables low-energy pathways for C H activation: a mechanism that has been labelled concerted metalation–deprotonation (CMD) and ambiphilic metal–ligand activation (AMLA).[2] The overwhelming majority of reactions of this type involve the activation of C(sp2) H bonds and, in contrast, C(sp3) H activation has received much less attention.[3] Performing C(sp3) H activation in the presence of usually more reactive C(sp2) H bonds has been achieved by using an appropriate directing group.[4] However, the use of a chelating directing group introduces an intrinsic limitation to the reaction and strategies are required that avoid a directing group to functionalize alternative C H bonds.[5] Examples of C(sp3) H activation without a directing group are relatively uncommon and most undirected C(sp3) H activations occur at either allylic or benzylic C H bonds.[6, 7] Well-defined examples of undirected C(sp3) H activation a to a carbonyl group are remarkably scarce, and those that have been reported tend to involve oxidative addition rather than an AMLA or CMD mechanism.[8, 9] These undirected reactions
Results and Discussion Experimental investigations We started by investigating the reaction of the a-pyridinium ester [1 aH]Cl, which was stirred with 0.5 equivalents of [Cp*IrCl2]2 and three equivalents of NaOAc in CH2Cl2 at room temperature for 45 min. The 1H NMR spectrum for the product contained a 1H singlet at d = 6.75 ppm for an a-proton and two doublets of quartets at 4.11 and 4.35 ppm for the now diastereotopic protons of the methylene group at the ethyl ester; these signals indicated that activation of an a-C(sp3) H bond had occurred, giving a N-ylide coordinated to iridium through a stereogenic carbon atom, that is, rac-[Cp*Ir(1 a)Cl2] (2 a; Scheme 1). To the best of our knowledge, this C(sp3) H activation is the first report of the synthesis of a monodentate Nylide complex by C H activation.[10, 11] Complex 2 a was isolated in 69 % yield. Similarly, the reaction of [1 bH]Cl with [Cp*IrCl2]2 and NaOAc gave the N-ylide complex rac-[Cp*Ir(1 b)Cl2] (2 b) in 73 % yield. In the 13C NMR spectra, signals for the ylide carbon were observed at d = 55.5 and 54.2 ppm for 2 a and 2 b, respectively. The identity of 2 b was further confirmed by single crystal X-ray diffraction (Figure 1).
[a] Dr. W. B. Cross School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS (UK) E-mail: [email protected] [b] S. Razak, K. Singh, A. J. Warner Department of Chemistry University of Leicester, Leicester, LE1 7RH (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403860. Chem. Eur. J. 2014, 20, 1 – 8
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Scheme 1. C(sp3) H Activation to give N-ylide complexes rac-[Cp*Ir(1)Cl2] (2).
Scheme 2. Regioselective C H activation to give the complexes rac-[Cp*Ir(3ylide)Cl2] (4) and [Cp*Ir(3NHC)Cl2] (5; Mes = 2,4,6-Me3C6H2).
Complex 4 was isolated as an analytically pure solid in 41 % yield, and its identity was confirmed by X-ray crystallography (Figure 2 a). In the solid state, the geometry of 4 is similar to that of 2 b. The most notable difference is the length of the Ir C(ylide) bond, which is approximately 0.03 shorter in 4 than in 2 b (4: 2.135(6) ; 2 b: 2.162(6) ); indeed, in 4 the Ir C(ylide) bond is now the shortest Ir C distance, but this distance is not significantly shorter than the shortest Ir C(Cp*) distances. It is likely that the nature of the adjacent cation affects the Ir C(ylide) distance: in 4, this positive charge is stabilised over two nitrogen atoms, whereas in 2 b, it is localised on one. Evidence for the greater negative charge on the ylide carbon in 4 than in 2 b is provided by the 13C NMR spectra for the two complexes: in 4, the signal for the ylide carbon (d = 42.8 ppm) is approximately 12 ppm further upfield than in 2 b. Monitoring the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc by 1H NMR spectroscopy revealed no evidence for the formation of an NHC isomer of 4. Other researchers have reported difficulty preparing carbonyl-functionalised NHC complexes when using a strong base to deprotonate an imidazolium
Figure 1. Solid-state structure of rac-[Cp*Ir(1 b)Cl2] (2 b) with ellipsoids drawn at 50 % probability. Only selected H atoms are shown for clarity. Selected bond lengths []: Ir C6 2.162(6); Ir1 C(Cp*) 2.134(7) to 2.205(7).
In the piano-stool complex, there is a tilt in the Cp* ring relative to the metal centre: the two Ir C(Cp*) bonds trans to the N-ylide ligand are the longest (2.200(6) and 2.205(7) ), whereas the three Ir C(Cp*) bonds trans to the two chloride ligands are shortest (2.134(7) to 2.159(6) ). The Ir C(ylide) distance of 2.162(6) is comparable with the Ir C(sp3) distances reported in iridium(III)–enolate complexes.[12] To examine the relative reactivity of the a-C(sp3) H bonds, we next investigated the reaction of an a-imidazolium ester, which also contained a reactive C(sp2) H bond. Indeed, we have previously reported the synthesis of N-heterocyclic carbene (NHC) complexes of Cp*Ir from the reaction of imidazolium salts with [Cp*IrCl2]2 and NaOAc.[13] Hence, [3H]Cl was reacted with [Cp*IrCl2]2 and NaOAc at room temperature. A 1H NMR spectrum of the crude reaction mixture after 2 h showed two new compounds in a 3:1 ratio, but remarkably neither of the products was an NHC complex. The major compound was the product of C(sp3) H activation: that is, N-ylide complex rac-[Cp*Ir(3ylide)Cl2] (4; Scheme 2). Complex 4 was easily identified from its 1H NMR spectrum, which contained a 1H singlet at d = 6.33 ppm and two doublets of quartets for the now diastereotopic protons Figure 2. Solid-state structures of a) rac-[Cp*Ir(3ylide)Cl2] (4) and b) [Cp*Ir(3NHC)Cl2] (5) with of the methylene group at the ethyl ester at d = 4.03 ellipsoids at 50 % probability. Only selected hydrogen atoms are shown for clarity. Selectand 4.22 ppm. ed bond lengths [], 4: Ir1 C1 2.135(6), Ir1 C(Cp*) 2.138(6) to 2.205(7); 5: Ir1 C1 2.072(6), Ir1 C(Cp*) 2.156(7) to 2.239(7).
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Full Paper group, which they have attributed to deprotonation of an aC(sp3) H bond.[14] In contrast, NaOAc is not sufficiently basic to deprotonate an a-C(sp3) H bond of [3H]Cl, but herein can cleave an a-C(sp3) H bond in conjunction with [(Cp*IrCl2)2], presumably in a CMD or AMLA reaction. Site-selective C H activation controlled by the choice of metal and ligand is an uncommon but highly useful strategy for synthesis.[15] Hence, we wanted to see if the alternative iridium NHC complex could be isolated under different conditions. This turned out to be the case and the reaction of imidazolium salt [3H]Cl with Ag2O followed by [Cp*IrCl2]2 gave the NHC complex [Cp*Ir(3NHC)Cl2] (5) as the only product (Scheme 2), with no evidence for the formation of the N-ylide complex 4. The solid-state structure of 5 was also determined by X-ray crystallography (Figure 2 b). Comparison of the structures of 4 and 5 enables a direct comparison of the isomeric ligands 3ylide and 3NHC. For ligand 3NHC, the Ir C distance (2.072(6) ) is approximately 0.06 shorter than the Ir C distance for 3ylide. In addition, 3NHC has the greater trans influence: the two Ir C(Cp*) distances trans to 3NHC in 5 (2.215(7) and 2.239(7) ) are approximately 0.03 longer than the corresponding bonds that are trans to 3ylide in 4.
solid-state structures obtained from single-crystal X-ray diffraction data, and they replicate the longer Ir C(ylide) distance in 4 compared with the Ir C(NHC) distance in 5. The computed solution energy (ESCF + ZPE in CH2Cl2) of the NHC complex 5 was 6.5 kcal mol 1 lower than that of the N-ylide complex 4, suggesting that the experimentally observed product of the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc, that is, 4, may be the kinetic product of the reaction. Hence, we investigated the barriers to the C(sp3) H activation and the C(sp2) H activation of [3H] + through an AMLA-6 pathway (Figure 3).[2, 17] The starting point for our study was the complex [Cp*Ir(OAc)2], containing one k1-acetate ligand and one k2-acetate ligand. The complex [Cp*Ir(OAc)2] has been isolated previously and been shown to participate in C H activation.[18, 19] In addition, from experimental observations involving analogous rhodium(III) complexes, [Cp*Ir(OAc)2] has been implicated as an intermediate in C H activation reactions involving [Cp*IrCl2] and NaOAc.[20] Furthermore, [Cp*Ir(OAc)2] has been used as the reference structure in previously reported DFT studies of C H activation.[21] Previous computational studies of C H activation by [Cp*Ir(OAc)2] have involved covalent directing groups and, hence, the substitution of one of the acetate ligands by a heteroatom donor atom of the substrate.[17, 21] Imidazolium ion [3H] + lacks a competent covalent directing group, so instead, a hydrogenbonded complex was considered. The complex A (DE = 12.6 kcal mol 1) involving two H-bonding interactions between [Cp*Ir(k2-OAc)(k1-OAc)] and [3H] + was located: one of the H bonds in A involved the k2-OAc ligand and the a-C(sp3) H bond; the other H bond involved the k1-OAc ligand and the N2C(sp2) H bond. An alternative complex involving H bonding between of the k1-OAc ligand with the aC(sp3) H bond and the k2-OAc ligand with the N2C(sp2) H bond could not be located as a local minimum on the potential energy surface. From A, two possibilities exist for activation of the a-C(sp3) H bond via an AMLA-6 mechanism: either k2 to k1 displacement of an acetate ligand can occur with concurrent
Computational investigations DFT calculations were used to determine the origin of the regioselectivity in the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc. Geometries and thermal contributions were computed in the gas phase at the B3LYP/LANL2DZ/6-31G(d,p) level; SCF energies were computed in CH2Cl2 solution (PCM approach) at the M06/def2-TZVP level. Due to the difficulties associated with assessing Gibbs free energies in solution, especially for charged species and in associative reactions,[16] the energies discussed in the main text are SCF energies corrected with the zero point energy (ESCF + ZPE). However, both ESCF + ZPE and Gibbs energies are presented in Figure 3. First, we computed the structures of the two isomeric products 4 and 5. The computed structures are in accord with the
Figure 3. Computed energy-profile diagram for the C H activation of [3H] + with [Cp*Ir(OAc)2]. Relative energies (ESCF + ZPE) and Gibbs energies (parentheses) in CH2Cl2 are shown in kcal mol 1. Chem. Eur. J. 2014, 20, 1 – 8
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Full Paper C H activation,[17] or k2 to k1 displacement of the acetate ligand could give rise to an intermediate prior to C H activation.[21] Direct activation of the N2C(sp2) H bond from A does not appear to be possible, because the metal lacks a vacant coordination site. A relaxed potential-energy surface scan was employed to follow the reaction coordinate corresponding with k2 to k1 displacement of the acetate ligand; these computations indicated that activation of the a-C(sp3) H bond did not occur concurrently with the change in coordination mode of the acetate ligand. However, the complex [Cp*Ir(k1-OAc)2] [3H] + (B), involving k1-coordination of both acetate ligands, was located as a minimum on the potential energy surface (DE = 4.7 kcal mol 1). From B, activation of the a-C(sp3) H bond proceeds via TS(B-C) (DE° = + 24.1 kcal mol 1) to give the N-ylide complex C (DE = + 0.8 kcal mol 1); exchange of the acetate and acetic acid ligands in C with two chloride ligands gives the experimentally observed product 4. Alternatively from B, activation of the N2C(sp2) H bond via TS(B-D) (DE° = + 27.6 kcal mol 1) would give the NHC complex D (DE = 6.9 kcal mol 1); subsequent ligand exchange would lead to the computed thermodynamic product 5, which was not observed experimentally from the reaction of [3H]Cl with [Cp*IrCl2]2 and NaOAc. Given the difference in energy of the two transition states TS(B-C) and TS(B-D) (DDE° = 3.5 kcal mol 1), these computations suggest that for C H activation of the imidazolium ion [3H] + by [Cp*Ir(OAc)2], the experimentally observed N-ylide complex 4 is the kinetic product of the reaction. Experimentally, we attempted to isolate the computed thermodynamic product 5 under more forcing conditions, heating [3H]Cl with [Cp*IrCl2]2 and NaOAc in 1,2-dichloroethane at 80 8C. The reaction under these conditions gave an unidentifiable mixture of products; however, it was apparent from a 1H NMR spectrum of the crude reaction mixture that neither 4 or 5 were products of the reaction at elevated temperature. In addition to having different energies, the two transition states TS(B-C) and TS(B-D) have very different geometries
Table 1. Computed distances and bond orders for the breaking and forming bonds in TS(B-C) and TS(B-D).
C O Ir Ir
H H C H
TS(B-C) Distance []
Bond order[a]
TS(B-D) Distance []
Bond order[a]
1.81 1.04 3.31 2.77
0.16 0.53 0.15 0.02
1.38 2.89 2.20 1.66
0.45 0.02 0.51 0.34
[a] Wiberg bond index from NBO analysis calculation.
(Figure 4 and Table 1). Analysis of the computed bond orders for the breaking C H bond and the forming O H and Ir C bonds, revealed that in TS(B-C) C(sp3) H cleavage is almost complete, but the Ir C distance is still very long. In contrast, in TS(B-D) there is a strong interaction of the breaking C(sp2) H bond with the electrophilic iridium(III) centre, but a much weaker interaction with the basic acetate ligand. A similar analysis of transition states for the reactions of aromatic and heteroaromatic compounds with [Pd(C6H5)(PMe3)(OAc)] revealed a much narrower distribution of bond orders for the breaking C H bonds and the forming O H and Pd C(sp2) bonds.[22] Hence, in contrast to the transition states analysed for [Pd(C6H5)(PMe3)(OAc)], our findings suggest that a mechanistic spectrum of AMLA or CMD reactions does exist: at one extreme of this spectrum, for example TS(B-D), the electrophilic metal plays the major role in C H activation and at the other extreme of the spectrum, for example TS(B-C), the basic ligand plays the major role in C H activation. As further evidence for the significant role played by the base in the reaction of [3H]Cl with [Cp*IrCl2]2, experimentally we observed no reaction when sodium acetate was replaced with sodium fluoroacetate. To the best of our knowledge, TS(B-C) is the first demonstration of an AMLA reaction in which the basic ligand plays the dominant role in C H cleavage. The ability of the basic ligand to play this dominant role may have significant implications for the development of catalyst controlled, site-selective C H functionalization.
Conclusion
Figure 4. Computed structures for the isomeric transition states a) TS(B-C) and b) TS(B-D), with selected bond lengths []. Only selected hydrogen atoms are shown for clarity.
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We have demonstrated C(sp3) H activation without a directing group to give N-ylide complexes of iridium. Moreover, the regioselective C H activation of the a-imidazolium ester [3H]Cl can be controlled by the choice of metal and ligand: C(sp3) H activation with [Cp*IrCl2]2 and NaOAc gave the N-ylide complex 4, whereas C(sp2) H activation with Ag2O followed by [Cp*IrCl2]2 gave the NHC complex 5. By using DFT calculations, we have demonstrated that the C H activation of [3H]Cl with [Cp*IrCl2]2 and NaOAc operates under kinetic control. To the best of our knowledge, these are the first well-defined examples of undirected a-C(sp3) H activation involving the cooperative action of a metal and a weakly basic ligand in a CMD or AMLA reaction. Analysis of the comput 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper ed transition state for the conversion of [3H]Cl to 5 revealed that, unlike CMD or AMLA reactions of (hetero)arenes involving Pd acetate complexes, the acetate ligand plays the dominant role in this a-C(sp3) H activation. This C(sp3) H activation is a direct and exceptionally mild method for the formation of metal ylide complexes; we are currently pursuing applications of this reaction in (asymmetric) catalysis.
Synthesis of rac-[Cp*Ir(1 a)Cl2] (2 a) Sodium acetate (62 mg, 0.75 mmol) was added to a solution of [Cp*IrCl2]2 (100 mg, 0.126 mmol) in CH2Cl2 (14 mL), which was then stirred at RT for 20 min. After this time, pyridiniumium salt [1 aH]Cl (51 mg, 0.25 mmol) was added to the reaction mixture, which was stirred for a further 45 min. After this time, the volatiles were removed in vacuo to give an orange/yellow solid. The solid was scraped from the sides of the flask and washed with Et2O (12 10 mL). The solid was extracted in MeCN (3 mL), and the solution was dried by passing it through a pipette containing K2CO3 ; this extraction was repeated twice. Finally, the volatiles were removed in vacuo to give 2 a as a yellow solid (98 mg, 69 %). 1H NMR (400 MHz, CDCl3): d = 1.31 (3 H, t, J = 7.1, OCH2CH3), 1.61 (15 H, s, C5Me5), 4.11 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 4.35 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 6.75 (1 H, s, HC Ir), 7.58 (2 H, app t, J = 6.9, PyCH), 7.85 (1 H, tt, 3J = 7.7, 4J = 1.3, PyCH), 8.66 (2 H, d, J = 6.7, PyCH); 13C{1H} NMR (100.6 MHz, CDCl3): d = 8.7 (C5Me5), 14.7 (OCH2CH3), 55.5 (HC Ir), 60.8 (OCH2CH3), 86.4 (C5Me5), 124.5 (PyC3,5), 139.8 (Py-C4), 145.1 (Py-C2,6), 175.05 ppm (C=O); IR (solid): u˜ = 1709 cm 1 (C=O); MS (FAB): m/z (%): 563 (16) [M] + , 528 (100) [M Cl] + ; elemental analysis calcd (%) for C19H26NO2IrCl2 (563.54): C 40.49, H 4.65, N 2.49; found: C 40.52, H 4.60, N 2.52.
Experimental Section All manipulations were performed under dry, oxygen-free nitrogen by using standard Schlenk techniques, unless otherwise stated. CH2Cl2 was dried by passing through a column of activated alumina and then degassed. [Cp*IrCl2]2 and 1-mesityl imidazole were prepared as reported in the literature.[23, 24] NaOAc was dried in an oven at 80 8C overnight before use. All other reagents were obtained from Sigma–Aldrich, Johnson Matthey or Alfa Aesar and used as supplied. NMR spectra were recorded on a Bruker DRX400 spectrometer at 298 K; chemical shifts have been referenced to the residual protonated solvent peak, and J values are given in Hz. For some compounds, assignments for 1H and 13C NMR peaks were aided by 1H–1H COSY, 1H–1H NOESY and 1H–13C HMQC 2D NMR experiments. FTIR spectra were run in a diamond ATR cell by using a Perkin–Elmer Spectrum 1 instrument. ESI mass spectra were recorded on a micromass Quattra LC spectrometer in MeCN/MeOH with a cone voltage of + 25 V; FAB mass spectra were obtained on a Kratos concept spectrometer by using NBA as the matrix. Elemental analyses were performed at London Metropolitan University.
Synthesis of rac-[Cp*Ir(1 b)Cl2] (2 b) Sodium acetate (52 mg, 0.64 mmol) was added to a solution of [Cp*IrCl2]2 (85 mg, 0.106 mmol) in CH2Cl2 (12 mL), which was then stirred at RT for 20 min. After this time, pyridinium chloride salt [1 aH]Cl (50 mg, 0.21 mmol) was added to the reaction mixture, which was stirred for a further 45 min. After this time, the volatiles were removed in vacuo to give an orange yellow solid. The solid was scraped from the sides of the flask and washed with Et2O (10 10 mL). The solid was extracted in MeCN (2 9 mL), and the solution was dried by passing it through a pipette containing K2CO3 ; this extraction was then repeated once. Finally, the volatiles were removed in vacuo to give 2 b as an orange solid (92 mg, 73 %). Crystals of 2 b suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 2 b. 1H NMR (400 MHz, CDCl3): d = 1.31 (3 H, t, J = 7.2, OCH2CH3), 1.61 (15 H, s, C5Me5), 4.12 (1 H, dq, J = 10.7, J = 7.2, OCH2CH3), 4.35 (1 H, dq, J = 10.7, J = 7.2, OCH2CH3), 6.72 (1 H, s, HC-Ir), 7.53 (1 H, dd, J = 8.3, J = 6.3, Py-5-CH), 7.80 (1 H, ddd, J = 8.3, J = 2.0, 1.1, Py-4-CH), 8.61 (1 H, app dt, J = 6.3, J = 1.1, Py-6-CH), 8.65 ppm (1 H, app t, Py2-CH); 13C{1H} NMR (100.6 MHz, CDCl3): d = 7.1 (C5Me5), 13.1 (OCH2CH3), 54.2 (HC Ir), 59.1 (OCH2CH3),84.8 (C5Me5), 123.0 (Py C5), 130.5 (Py C3), 137.6 (Py C4), 141.1 (Py C6), 142.4 (Py C2), 172.9 ppm (C=O); IR (solid): u˜ = 1712 cm 1 (C=O); MS (ESI): m/z (%): 562 (100) [M Cl] + ; elemental analysis calcd (%) for C19H25IrNO2Cl3 : C 38.16, H 4.21, N 2.34; found: C 38.15, H 3.95, N 2.29.
Synthesis of [1 aH]Cl A solution of pyridine (1.50 mL, 18.6 mmol) and ethyl chloroacetate (2 mL, 18.6 mmol) in Et2O (5 mL) was heated at 40 8C for 16 h. The resulting brown precipitate was isolated by filtration and washed with Et2O (2 5 mL), giving [1 aH]Cl as a brown solid (2.16 g, 58 %). 1 H NMR (400 MHz, CDCl3): d = 1.33 (3 H, t, J = 7.1, CH2CH3), 4.29 (2 H, q, J = 7.1, CH2CH3), 6.50 (2 H, s, CH2CO2Et), 8.07 (2 H, app t, J = 7.1, PyCH), 8.50 (1 H, t, J = 7.8, PyCH), 9.59 ppm (2 H, d, J = 5.4, PyCH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 14.04 (OCH2CH3), 61.0 (CH2), 63.3 (CH2), 127.5 (Py-C3,5), 145.6 (Py-C4), 147.1 (Py-C2,6), 166.20 (C=O); MS (ESI) m/z (%): 166 (50) [M Cl] + , 138 (100) [M Cl Et + H] + .
Synthesis of [1 bH]Cl A mixture of 3-chloropyridine (0.44 mL, 4.7 mmol) and ethyl chloroacetate (0.50 mL, 4.7 mmol) was heated at 90 8C for 64 h. The resulting brown residue was extracted with CHCl3 (3 10 mL). The volatiles were then removed in vacuo, and the oily residue washed with Et2O (3 5 mL). The residue was dried in vacuo to give [1 bH]Cl as a brown solid (0.687 g, 62 %). 1H NMR (400 MHz, CDCl3): d = 1.30 (3 H, t, J = 7.2, CH2CH3), 4.27 (2 H, q, J = 7.2, CH2CH3), 6.51 (2 H, s, CH2CO2Et), 8.13 (1 H, dd, J = 8.4, 6.1, PyCH), 8.47 (1 H, dd, J = 8.4, 0.7, PyCH), 9.71 (1 H, d, J = 6.1, PyCH), 9.76 ppm (1 H, s, PyCH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 13.9 (OCH2CH3), 60.7 (CH2), 63.2 (CH2), 128.2 (Py-CH), 125.0 (Py CCl), 145.6, 145.8, 145.9, (Py CH), 166.20 (C=O); MS (ESI) m/z (%): 200 (88) [M Cl] + , 172 (100) [M Cl Et + H] + . Chem. Eur. J. 2014, 20, 1 – 8
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Synthesis of [3 H]Cl A solution of 1-mesityl imidazole (0.97 g, 5.3 mmol) and ethyl chloroacetate (0.70 mL, 6.4 mmol) in MeCN (8 mL) was heated at 90 8C for 12 h. The solution was cooled to RT, and the volatiles were removed in vacuo. The resulting solid was washed with Et2O (3 5 mL) to give [3H]Cl as a white solid (1.59 g, 96 %). 1H NMR (400 MHz, CDCl3): d = 1.26 (3 H, t, J = 7.2, CH2CH3), 2.03 (6 H, s, oCH3), 2.28 (3 H, s, p-CH3), 4.21 (2 H, q, J = 7.2, CH2CH3), 5.88 (2 H, s, NCH2CO2Et), 6.94 (2 H, s, Mes-CH), 7.08 (1 H, t, J = 1.7, NCHCHN), 7.80 (1 H, t, J = 1.7, NCHCHN), 10.45 ppm (1 H, t, J = 1.4, N2CH); 13 1 C{ H} NMR (100.6 MHz, CDCl3): d = 14.0 (CH2CH3), 17.5 (o-CH3), 21.1 (p-CH3), 50.6 (CH2), 62.7 (CH2), 122.4 (NCHCHN), 124.7
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data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of rac-[Cp*Ir(3ylide)Cl2] (4) Sodium acetate (62 mg, 0.75 mmol) was added to a solution of [Cp*IrCl2]2 (100 mg, 0.126 mmol) in CH2Cl2 (14 mL), which was then stirred at RT for 20 min. After this time, imidazolium salt [3H]Cl (78 mg, 0.25 mmol) was added to the reaction mixture, which was stirred for a further 2 h. A crude-mixture 1H NMR spectrum obtained at this stage revealed two products in a 3:1 ratio. The minor product was subsequently identified as [IrCl3][3H] by single-crystal X-ray diffraction. To isolate the major product, the volatiles were removed in vacuo to give an orange yellow solid, which was extracted with 50 % hexanes/Et2O (6 10 mL). The volatiles were then removed in vacuo, and the extraction was repeated, again with 50 % hexanes/Et2O (6 10 mL). The volatiles were again removed in vacuo to give 4 as a deep orange solid (69 mg, 41 %). Crystals of 4 suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 4. 1 H NMR (400 MHz, CDCl3): d = 1.23 (3 H, t, J = 7.1, OCH2CH3), 1.59 (15 H, s, C5Me5), 1.98 (3 H, s, o-CH3), 2.24 (3 H, s, o-CH3), 2.28 (3 H, s, p-CH3), 4.03 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 4.22 (1 H, dq, 2J = 10.8, 3J = 7.1, OCH2CH3), 6.33 (1 H, s, HC Ir), 6.74 (1 H, t, J = 1.5, NCHCHN), 6.90 (2 H, s, Mes-CH), 7.03 (1 H, t, J = 1.5, NCHCHN), 9.08 ppm (1 H, t, J = 1.5, N2CH); 13C{1H} NMR (100.6 MHz, CDCl3): d 8.6 (C5Me5), 14.8 (OCH2CH3), 17.3 (o-CH3), 18.2 (o-CH3), 21.1 (p-CH3), 42.8 (HC Ir), 60.2 (OCH2CH3), 86.1 (C5Me5), 118.5 (NCHCHN), 123.2 (NCHCHN), 129.0 (Ar CH), 129.8 (Ar CH), 131.7, 134.8, 136.3, 140.3 (Ar C), 140.5 (N2CH), 175.0 ppm (C=O); IR (solid): u˜ = 1704 cm 1 (C=O); MS (ESI): m/z (%): 635 (100) [M-Cl] + ; elemental analysis calcd (%) for C26H35Cl2IrN2O2 (670.69): C 46.56, H 5.26, N 4.18; found: C 46.47, H 5.16, N 4.09.
Computational methods
Synthesis of [Cp*Ir(3NHC)Cl2] (5)
The authors would like to acknowledge the use of the EPSRC UK National Service for Computational Chemistry Software (NSCCS) at Imperial College London in carrying out this work. We thank the University of Leicester for financial support and Johnson Matthey for a loan of iridium trichloride. We are grateful to Prof. Dai Davies (University of Leicester) for useful discussions and the reviewers for their suggestions.
Calculations were performed with Gaussian 09, Revision C.01.[25] Geometry optimizations and thermal contributions to energies were computed in the gas phase with the B3LYP hybrid functional and employed the LANL2DZ basis set for Ir with a 60 electron ECP;[26] the 6–31G(d,p) basis set was used for all other atoms. Stationary points were identified as minima or transition states through analytical frequency calculations; transition states were further characterised through IRC calculations and subsequent geometry optimisations. More accurate SCF energies were then computed by employing single-point calculations with the M06 hybrid functional;[27] in these calculations, the flexible def2-TZVP basis set was employed for all atoms, including the associated 60 electron ECP for Ir.[28] The effects of CH2Cl2 solvent were computed by using the PCM approach. Energies reported in the main text (ESCF + ZPE) were determined from the sum of the SCF energy (MO6, CH2Cl2) and the zero-point correction (B3LYP, gas phase). Wiberg bond orders were determined from NBO analysis calculations (B3LYP/LANL2DZ/6– 31G(d,p)). There are two diastereomers of C and D. The diastereomers reported for C and D were found to have SCF energies 1.1 and 2.6 kcal mol 1 lower in energy than the alternative diastereomers. Computed Cartesian coordinates and energies for all species computed are available in the Supporting Information.
Acknowledgements
A suspension of imidazolium salt [3H]Cl (39 mg, 0.13 mmol) and Ag2O (16 mg, 0.069 mmol) in CH2Cl2 (4 mL) was stirred at 35 8C in the dark. After 24 h, [Cp*IrCl2]2 (50 mg, 0.063 mmol) was added to the reaction mixture, which was again stirred for a further 24 h in the dark. After this time, the solution was filtered through Celite, and the volatiles were removed in vacuo to give 5 as an orange solid (136 mg, 73 %). Crystals of 5 suitable for structure determination by X-ray diffraction were obtained by diffusion of n-pentane into a CH2Cl2 solution of 5. 1H NMR (400 MHz, CDCl3): d = 1.34 (3 H, t, J = 7.1, OCH2CH3), 1.49 (15 H, s, C5Me5), 2.07 (6 H, s, o-CH3), 2.29 (3 H, s, p-CH3), 4.31 (2 H, q, J = 7.1, OCH2CH3), 5.38 (2 H, br s, NCH2CO2Et), 6.70 (1 H, d, J = 2.0, NCHCHN), 6.84 ((2 H, s, Mes-CH), 7.15 ppm (1 H, d, J = 2.0, NCHCHN); 13C{1H} NMR (100.6 MHz, CDCl3): d = 8.9 (C5Me5),14.2 (OCH2CH3), 19.2 (o-CH3), 21.2 (p-CH3), 53.5 (NCH2CO2Et), 61.8 (OCH2CH3), 89.2 (C5Me5), 123.1 (NCHCHN), 125.4 (NCHCHN), 128.2, 129.0 (Ar CH), 136.6, 138.4 (Ar C), 156.1 (N2C Ir), 169.4 ppm (C=O); IR (solid): u˜ = 1746 cm 1 (C=O); MS (ESI): m/z (%): 635 (100) [M Cl] + ; elemental analysis calcd (%) for C26H35Cl2IrN2O2 (670.69): C 46.56, H 5.26, N, 4.18; found: C 46.39, H, 5.17, N 4.36. 1 H and 13C NMR spectra for all compounds are available in the Supporting Information.
Keywords: C H activation · cooperative effects · iridium · synthetic methods · ylides [1] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345, and references therein. [2] a) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848 – 10849; b) Y. Boutadla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Bahamonde, Dalton Trans. 2009, 5820 – 5831. [3] O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902 – 4911. [4] a) R. Giri, J. Liang, J.-G. Lei, J.-J. Li, D.-H. Wang, X. Chen, I. C. Naggar, C. Guo, B. M. Foxman, J.-Q. Yu, Angew. Chem. 2005, 117, 7586 – 7590; Angew. Chem. Int. Ed. 2005, 44, 7420 – 7424; b) M. Chaumontet, R. Piccardi, N. Audic, J. Hitce, J.-L. Peglion, E. Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130, 15157 – 15166; c) M. Wasa, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 9886 – 9887; d) S. Rousseaux, S. I. Gorelsky, B. K. W. Chung, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 10692 – 10705; e) D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965 – 3972; f) Y. Nakao, E. Morita, H. Idei, T. Hiyama, J. Am. Chem. Soc. 2011, 133, 3264 – 3267; g) K. J. Stowers, A. Kubota, M. S. Sanford, Chem. Sci. 2012, 3, 3192 – 3195. [5] N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem. Int. Ed. 2012, 51, 10236 – 10254.
X-Ray crystallographic studies The solid-state structures of the compounds 2 b, 4, 5 and [IrCl3] [3H] were determined by single-crystal X-ray diffraction. CCDC945376 (2 b), CCDC-945377 (4), CCDC-945378 (5), and CCDC945379 ([IrCl3][3H]) contain the supplementary crystallographic
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Full Paper [6] For examples of allylic C-H activation, see: a) C. Engelin, T. Jensen, S. Rodriguez-Rodriguez, P. Fristrup, ACS Catal. 2013, 3, 294 – 302; b) B. M. Trost, E. Iglesias-Sigenza, D. A. Thaisrivongs, E. J. Donckele, Angew. Chem. 2012, 124, 1553 – 1555; Angew. Chem. Int. Ed. 2012, 51, 1523 – 1524; c) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132, 9585 – 9587; d) T. Jensen, P. Fristrup, Chem. Eur. J. 2009, 15, 9632 – 9636. [7] For examples of benzylic C-H activation, see: a) J.-J. Jin, H.-Y. Niu, G.-R. Qu, H.-M. Guo, J. S. Fossey, RSC Adv. 2012, 2, 5968 – 5971; b) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am. Chem. Soc. 2010, 132, 3650 – 3651; c) L.-C. Campeau, D. Schipper, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266 – 3267; d) K. Chan, P. Chiu, K. Choi, Organometallics 2007, 26, 1117 – 1119; e) A. F. Heyduk, T. G. Driver, J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc. 2004, 126, 15034 – 15035. [8] Herein, we use the term C H activation to refer to a reaction in which the transition metal is intimately involved in the cleavage of the C H bond. Although transition-metal catalysed functionalizations of aC(sp3) H bonds in carbonyl compounds are well established, these reactions typically differ from our definition by employing a strong base, such as an alkali metal amide or alkoxide, to generate a stoichiometric alkali metal enolate; for relevant reviews, see: a) F. Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082 – 1146; b) C. C. C. Johansson, T. J. Colacot, Angew. Chem. 2010, 122, 686 – 718; Angew. Chem. Int. Ed. 2010, 49, 676 – 707; c) G. C. Lloyd-Jones, Angew. Chem. 2002, 114, 995 – 998; Angew. Chem. Int. Ed. 2002, 41, 953 – 956. [9] For examples a-C H activation via oxidative addition, see: a) Y. Guo, X. Zhao, D. Zhang, S.-I. Murahashi, Angew. Chem. 2009, 121, 2081 – 2083; Angew. Chem. Int. Ed. 2009, 48, 2047 – 2049; b) S.-I. Murahashi, T. Naota, H. Taki, M. Mizuno, H. Takaya, S. Komiya, Y. Mizuho, N. Oyasato, M. Hiraoka, J. Am. Chem. Soc. 1995, 117, 12436 – 12451; c) M. Feller, A. Karton, G. Leitus, J. M. L. Martin, D. Milstein, J. Am. Chem. Soc. 2006, 128, 12400 – 12401. [10] For bidentate bis(N-ylide) complexes from reactions with [Pd(OAc)2] at elevated temperatures, see: a) A. Lleds, J. J. Carb, R. Navarro, E. Serrano, E. P. Urriolabeitia, Inorg. Chem. 2004, 43, 7622 – 7635; b) D. J. Nielsen, K. J. Cavell, B. W. Skelton, A. H. White, Organometallics 2001, 20, 995 – 1000. [11] For bidentate carbene/N-ylide complexes, see: a) R. Lalrempuia, N. McDaniel, H. Mller-Bunz, S. Bernhard, M. Albrecht, Angew. Chem. 2010, 122, 9959 – 9962; Angew. Chem. Int. Ed. 2010, 49, 9765 – 9768; b) M. Viciano, M. Feliz, R. Corberan, J. A. Mata, E. Clot, E. Peris, Organometallics 2007, 26, 5304 – 5314. [12] a) H. Kanemitsu, K. Uehara, S. Fukuzumi, S. Ogo, J. Am. Chem. Soc. 2008, 130, 17141 – 17147; b) Q. W. Chang, M. J. Xie, W. P. Liu, X. Z. Chen, Q. S. Ye, Acta Cryst. E 2009, 65, 1264 – 1264. [13] W. B. Cross, C. G. Daly, Y. Boutadla, K. Singh, Dalton Trans. 2011, 40, 9722 – 9730. [14] a) B. R. M. Lake, E. K. Bullough, T. J. Williams, A. C. Whitwood, M. A. Little, C. E. Willans, Chem. Commun. 2012, 48, 4887 – 4889; b) K. S. Coleman, H. T. Chamberlayne, S. Turberville, M. L. H. Green, A. R. Cowley, Dalton
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Received: June 6, 2014 Published online on && &&, 0000
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FULL PAPER & Synthetic Methods W. B. Cross,* S. Razak, K. Singh, A. J. Warner && – && C(sp3) H Activation without a Directing Group: Regioselective Synthesis of N-Ylide or N-Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand
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Which C H bond reacts? N-Ylide complexes of Ir were generated by a-C(sp3 -H activation with [Cp*IrCl2]2 and NaOAc. The reaction of an a-imidazolium ester is a rare example of a C H activation where the site selectivity can
be controlled by the choice of metal and ligand; DFT calculations revealed that the N-ylide complex is the kinetic product of an ambiphilic C H activation, in which the acetate ligand plays the dominant role (see scheme).
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