Computational Mechanistic Study of C–C Coupling of Methanol and

Feb 13, 2012 - Density functional theory calculations have been performed to understand the mechanism of the C–C couplings of methanol with allenes ...
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Computational Mechanistic Study of C−C Coupling of Methanol and Allenes Catalyzed by an Iridium Complex Haixia Li and Zhi-Xiang Wang* College of Chemistry and Chemical Engineering, Graduate University of the Chinese Academy of Sciences, Beijing 100049, People’s Republic of China S Supporting Information *

ABSTRACT: Density functional theory calculations have been performed to understand the mechanism of the C−C couplings of methanol with allenes (e.g., 1,1-dimethylallene (2all)) catalyzed by an iridium complex (1cat). The study leads us to propose the following mechanism for the reaction. The iridium complex first needs to be activated via methanolysis to generate the active catalyst (an iridium alkoxide complex). Starting from the active catalyst, the catalytic cycle for the C−C coupling includes four steps: β-hydrogen elimination to give formaldehyde and an iridium hydride complex, allene hydrometalation to afford a (η3-πallyl)iridium intermediate, addition of formaldehyde to the (η3-π-allyl)iridium intermediate to produce a homoallylic iridium alkoxide complex, and methanolysis of the formed homoallylic iridium alkoxide complex to deliver the final coupling product 3alc and regenerate the active catalyst. The regioselectivity exclusively producing the alcohol 3alc with an all-carbon quaternary center is due to the Ir−CMe2 bond being weaker than the Ir−CH2 bond and the steric effect between the methyl groups of the allene substrate and the C,O-benzoate ligand of the catalyst. The replacement of the middle hydrogen of the η3-π-allyl moiety of 1cat with a F, Cl, Me, or OMe group (F and OMe groups in particular) can benefit the catalyst activation both kinetically and thermodynamically. The possibility of using 1cat for the coupling of allene (2all) with amine (CH3NH2) was also explored. The allene coupling with amine is energetically less favorable than the coupling with methanol but could be experimentally achievable. Because the barrier for the activation of 1cat by amine (34.0 kcal/mol) could be too high, we proposed to lower the barrier by replacing the middle hydrogen atom of the η3-π-allyl moiety in 1cat with a F or OMe group. very recently.2 They have prepared a novel iridium catalyst (termed as 1cat hereafter) that can perform C−C couplings between methanol and 1,1-disubstituted allenes, regioselectively affording homoallylic neopentyl alcohols with all-carbon quaternary centers (eq 1).

1. INTRODUCTION Methanol is an abundant and renewable chemical feedstock.1 Development of efficient reactions using methanol to synthesize value-added chemicals is of great importance in terms of green and sustainable chemistry. The catalytic C−C couplings of methanol with allenes developed by Krische’s group represent a remarkable progress in realizing this chemistry.2 In 2007, the group developed catalytic C−C couplings between carbonyl and π-unsaturated allenes.3 Subsequently, they advanced the strategy to use alcohols as coupling partners and further extended the π-unsaturated compounds to others such as dienes and allylic acetates.4−7 In these reactions, alcohols served dually as precursors of carbonyl compounds and hydrogen donors, but the alcohols were limited to ethanol or higher alcohols.4−7 To broaden the applications of the protocol, it is desirable to extend the alcohol substrates to the readily available methanol. However, the extension is challenging because methanol dehydrogenation (ΔH = +84 kJ/mol) is thermodynamically less favorable than the dehydrogenation of higher alcohols such as ethanol (ΔH = +68 kJ/mol).8 Nevertheless, the group has succeeded in reaching the goal © 2012 American Chemical Society

In their experimental study,2 Krische et al. have postulated a mechanism for their C−C coupling reactions, but the detailed mechanism is still unknown. An in-depth understanding of the reaction mechanism on the basis of energetics and structures of intermediates and transition states may help the further Received: January 19, 2012 Published: February 13, 2012 2066

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development of the protocol. Herein we report a density functional theory (DFT) study to account for the coupling mechanism in detail. On the basis of the mechanistic understanding, we explored how to tailor the catalyst to improve its catalytic performance and whether the protocol can be applied to C−C couplings of amines with allenes. In relation to the present study, we call attention to the elegant studies conducted by Houk and Krische on the mechanisms of Rhand Ni-catalyzed C−C couplings between diynes or alkyne and carbonyl compounds.9

2. COMPUTATIONAL DETAILS All the structures were optimized and characterized as minima or transition states at the B3LYP10/BSI level (BSI designates the basis set combination of LanL2DZ11 for Ir and Fe and 6-31G(d,p) for all nonmetal atoms). When necessary, IRC (intrinsic reaction coordinate) calculations12 at this level were conducted to confirm the right connection of a transition state to its forward and backward minima. At the B3LYP/BSI structures, the energetic results were further refined by single-point calculations at the B3LYP/BSII level with solvation effects accounted for (BSII denotes the basis set combination of LanL2DZ for Ir and Fe and 6-31++G(d,p) for all nonmetal atoms). The bulky solvation effects of toluene (experimentally used solvent) were simulated by the PCM solvent model.13 The gas-phase B3LYP/ BSI harmonic frequencies were used for the thermal and entropic corrections to the enthalpies and free energies at 298.15 K and 1 atm. The basis set superposition errors (BSSE)14 in estimating the nonbonding interactions involved in the addition or dissociation of ligands were computed at the B3LYP/BSII level by using the standard BSSE procedure.14 For some important stationary points, we also conducted the single-point calculations at the level of B3LYP/BSIII with solvent effects accounted for (BSIII denotes the basis set combination of SDD15 for Ir and Fe and 6-311++G(d,p) for all nonmetal atoms). To estimate the dispersion effect, a final correction term was based on single-point energy calculations using the dispersion-corrected B3LYP-D3 approach.16 All calculations were carried out by using the Gaussian 0317 and Gaussian 0918 programs.

Figure 1. Optimized and X-ray structures of 1cat (the parameters of the optimized structure are given in parentheses) and the optimized structure of 1cat′, along with the key bond lengths in Å. Trivial hydrogen atoms are omitted for clarity.

catalyst precursor, requiring activation to perform catalysis. Interestingly, the activation does not require any additional/external activator, and the methanol substrate activates the precursor via methanolysis. On the basis of the structure of 1cat, two possible activation pathways were considered. As illustrated in Figure 2A, the activation proceeds by initial formation of a complex (i.e., CP1 or CP1′) between methanol and 1cat. Subsequently, a transition state (TS1 or TS1′) transfers the methanol hydroxyl hydrogen to the terminal carbon of the allyl ligand, which changes the η3 coordination of allyl ligand to η2 coordination and leads to another complex (CP2 or CP2′). After release of propylene (4pro), the active catalyst 5 is generated. Note that the geometric optimizations starting from different initial structures related to CP2 and CP2′ converged to the same active catalyst 5. As compared in Figure 2A, the pathway in which methanol attacks 1cat at the site below the allyl ligand is slightly more favorable than at the site above; the barrier (TS1) for the former, 30.7 kcal/mol relative to CH3OH + 1cat, is 1.3 kcal/mol lower than the transition state (TS1′) for the latter. The preference is probably due to the the steric effect between the −OCH3 group and C,O-benzoate ligand in TS1 being less than that between the −OCH3 group and the phosphine ligand in TS1′ (see Figure 2B). The activation is slightly exergonic by 1.7 kcal/mol. For the more favorable pathway (black path), the BSSE corrections to the energies of the complexes CP1 and CP2 were estimated to be 2.9 and 2.2 kcal/mol. The small corrections should not change the activation mechanism and reverse the relative favorability of the two pathways. 3.1.2. Catalytic Cycle. The catalyst activation generates the active catalyst (5) that participates in the catalytic cycle. Our computed mechanism is schematically consistent with the mechanism proposed by Krische et al.,2 in spite of some differences in details (see below). As shown in Scheme 1, the active catalyst 5 (i.e., A) is generated via the catalyst activation which has been discussed in section 3.1.1. The catalytic cycle can be characterized by the following four steps: (I) β-hydrogen (β-H) elimination from A (i.e., 5) by passing through B to give formaldehyde and C, (II) allene hydrometalation to deliver the (η3-π-allyl)iridium intermediate D, (III) isomerization of the η3 coordination complex D to the (η1-π-allyl)iridium complex E and the addition of formaldehyde to the (η1-π-allyl)iridium complex E, producing the homoallylic iridium alkoxide complex F,

3. RESULTS AND DISCUSSION Experimentally, the catalyst 1cat was applied to promote the C−C couplings of methanol with various allenes.2 We chose the eq 2 reaction for our mechanistic study, where the allene

substrate is exemplified by 1,1-dimethylallene (2all) and the experimental catalyst was used. Figure 1 shows the good agreement between the optimized structure and the X-ray structure of 1cat.2 Importantly, the η3 coordination adopted by the π-allyl ligand in 1cat is well maintained in the optimized structure, as demonstrated by the Ir−C1, Ir−C2, and Ir−C3 distances in 1cat close to those in the X-ray structure. The isomer (1cat′ shown in Figure 1) of 1cat is 3.6 kcal/mol less stable than 1cat, in agreement with the X-ray experiment, which gave 1cat rather than 1cat′. The π-allyl ligand in 1cat may adopt η1 coordination, resulting in another possible isomer. However, the geometric optimizations for such an isomer repeatedly converged to 1cat. Thus, the more stable 1cat was used for a mechanistic study. 3 Catalytic Mechanism of Eq 2 Reaction. 3.1.1. 3.1.1. Catalyst Activation. The saturated 18e complex 1cat is just a 2067

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Figure 2. (A) Two pathways for the catalyst activation. (B) Optimized geometries of the key stationary points, together with the key bond lengths in Å (similarly henceforth). Trivial hydrogen atoms are omitted for clarity. Geometries not shown in (B) are included in SI1 in the Supporting Information.

Scheme 1. Mechanism Proposed by Krische et al.2

and (IV) the methanolysis of the formed homoallylic iridium alkoxide (F) to close the catalytic cycle. In the following, we will discuss the mechanism in terms of the four steps. Step I: β-H Elimination of 5. The active catalyst (5) is a 16e iridium alkoxide complex possessing a vacant coordination site for undergoing β-H elimination. The β-H elimination can take

place along two pathways to release CH2O (Figure 3A). The path in black uses the equatorial coordination site of the Ir center to accept the methanol Hβ, and the other path in red uses the axial coordination site to adopt the methanol Hβ. The energetic results indicate both pathways are feasible with a barrier of 11.6 (TS2) and 15.1 kcal/mol (TS2′), respectively. 2068

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Figure 3. (A) Two pathways for the β-H elimination of 5. (B) Optimized geometries of the key stationary points. Geometries not shown in (B) are included in SI2 in the Supporting Information.

The methanol dehydrogenation discussed above takes place through a β-H elimination mechanism. Our recent study on the alcohol dehydrogenation catalyzed by an Ir complex indicated that dehydrogenation via bifunctional hydrogen transfer might be preferred,20,21 which called our attention to such a mechanism. Two transition states corresponding to using the bifunctional sites constructed by the Ir center and the π-allyl moiety or carboxyl group of the C,O-benzoate ligand have been located (see SI3 in the Supporting Information for the optimized structures). The barriers, 49.9 and 55.1 kcal/mol measured from 1cat + CH3OH, respectively, are too high for the mechanism. The disfavor of the dehydrogenation mechanism in the present case is due to the weak Lewis basicity of the π-allyl moiety and the carboxyl group. Step II: Allene Hydrometalation To Form the (η3-π-Allyl) iridium Intermediate. Subsequent to the β-H elimination giving 6 + CH2O, allene hydrometalation takes place by transferring the hydridic hydrogen in 6 to the middle carbon of the allene substrate (2all), giving the (η3-π-allyl)iridium intermediate (i.e., D in Scheme 1). Depending on the orientation of 2all, two pathways could be located (Figure 4A). Apparently, the black pathway is more favorable, because the orientation of 2all in this pathway causes less steric effect between 2all and the phosphine ligands. The complex CP4 and transition state

The transition states TS2 and TS2′ lead to complexes CP3 and CP3′, respectively. The release of CH2O from the complexes then leads to 6 and 6′, respectively. However, complex 6, produced from the kinetically more favorable pathway (black), is 12.1 kcal/mol less stable than 6′ from the less favorable pathway. As the vacant coordination site and the hydridic hydrogen of iridium center in 6 are cis to each other, the complex 6′ has a structure with the coordination site trans to the hydridic hydrogen atom. Attempts to optimize another structure for 6′ with the vacant coordination site cis to the hydridic hydrogen (i.e., starting from CP3′ by removing CH2O) repeatedly converged to 6′. We will elucidate separately that it is 6 rather than 6′ that, as the active intermediate, directly involves the next step after completing the discussion of the catalytic cycle. In the following step II, we consider 6 to be the active intermediate to continue the reaction. Previously, it has been reported that CH2O can be released from a transition-metal complex via η 2−η 1 slippage after crossing a barrier.19 A similar mechanism for the release of CH2O from CP3 was considered. The located η1 complex is 4.6 kcal/mol lower than CP3, and the barrier is only 2.8 kcal/mol higher than CP3. Therefore, CH2O can be released from the complex CP3 easily. 2069

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Figure 4. (A) Two pathways for allene hydrometalation to form the (η3-π-allyl)iridium intermediate. (B) Optimized geometries of the key stationary points. Geometries not shown in (B) are included in SI4 in the Supporting Information.

surface (PES) for the addition step of CH2O to 7, choosing the distance of forming a C−C bond as a reaction coordinate varying from 2.5 to 1.5 Å at an interval of 0.1 Å. The monotonously decreasing PES (see SI5 in the Supporting Information) confirmed that the transition state cannot be optimized. However, it should be emphasized that the automatic geometric optimization for the transition state and the PES scanning were conducted on the surface of electronic energy, rather than on the surface of free energy. Therefore, the nonexistence of a transition state on the surface of electronic energy does not mean there is no transition state on the free energy surface. Addition is an entropically unfavorable process, but the entropic penalty cannot be taken into account in the geometric optimization or PES scanning. This is nicely demonstrated by the case of the addition of CH2O to 7′; the transition state (TS4′) is only 3.6 kcal/mol higher than 7′ + CH2O in terms of enthalpy, but the barrier increases to 18.3 kcal/mol in terms of free energy, indicating a significant entropic contribution. For the addition of CH2O to 7, because no transition state could be located on the surface of electronic energy, the free energy barrier could not be calculated. However, it could be reasonable to assume that the barrier should not be higher than TS4′. We reasoned that the “barrierless” addition of CH2O to 7 on the surface of electronic energy is due to the small size of CH2O, and more steric aldehyde could result in a barrier even on the surface of electronic energy. To verify this, CH2O was replaced with a large aldehyde (PhCHO) to study the addition of PhCHO to 7. Indeed, two transition states (TS5R and TS5S in Figure 6B) could be optimized successfully. The barrier for the addition of PhCHO to 7 via TS5R, leading to an R alcohol Ir alkoxide complex (9R), is 29.9 kcal/mol, which is 0.7 kcal/mol smaller than TS5S (30.6 kcal/mol) leading to the S alcohol Ir alkoxide complex 9S. The energy difference between the two

TS3 are 16.4 and 18.2 kcal/mol lower than CP4′ and TS3′ in the red pathway, respectively. However, the product 7 given by the kinetically favorable pathway is 4.7 kcal/mol higher than 7′. We rationalize this inconsistency as follows. In the complexes (CP4/CP4′) and transition states (TS3/TS3′), because the hydridic hydrogen is still bonded to the Ir center, the substrate (2all) prefers coordinating to the top of the Ir center, which results in the steric effect between the methyl groups of 2all and the phosphine ligands in CP4′ and TS3′. After the hydridic hydrogen is transferred to the middle carbon of 2all, the allylic moiety in 7′ tilts, which weakens the steric effect between methyl groups and phosphine ligands, but a similar change tends to increases the steric effect between methyl groups and the C,O-benzoate ligand in 7. Step III: C−C Coupling via the Addition of Formaldehyde to (η3-π-Allyl)iridium. The C−C coupling step adds formaldehyde (CH2O) to the (η3-π-allyl)iridium intermediate 7 or 7′. Note that 7′ is kinetically much less favorably generated than 7 (see Figure 4), and we considered 7′ for comparison purposes. To produce 3alc product, the CH2O carbon should couple with the methyl-substituted carbon of the η3-π-allyl moiety. The regioselective formation of 3alc will be discussed in section 3.1.3. Under Krische et al.’s mechanism (see Scheme 1),2 the (η3-π-allyl)iridium intermediate (D) first converts to a (η1-π-allyl)iridium complex (E), and then CH2O adds to E to give F after passing a chairlike six-membered transition state (not shown in Scheme 1). For the addition of CH2O to 7′, the proposed pathway could be located unambiguously; the complex CP5′ and the transition state TS4′ in the red pathway in Figure 5 correspond to E and the proposed chairlike sixmembered transition state, respectively. However, for the addition of CH2O to 7, geometric optimizations to locate E repeatedly converged back to 7 and the chairlike transition state could not be found. We further scanned the potential energy 2070

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Figure 5. (A) Two pathways for the C−C coupling process via the addition of formaldehyde to (η3-π-allyl)iridium intermediates. (B) Optimized geometries of the key stationary points. Geometries not shown in (B) are included in SI6 in the Supporting Information.

types of transition states could account for the general enantioselective coupling between allene and higher aldehydes/ alcohols catalyzed by some transition-metal complexes.4 The resulting 18e homoallylic Ir alkoxide complexes (9R and 9S) are 21.3 and 20.5 kcal/mol less stable than 7 + PhCHO, respectively. When Figures 6 and 5 are compared, it can be observed that the addition of CH2O to 7 is energetically much more favorable than the addition of PhCHO to 7. When the two C−C coupling pathways are compared, although 7′ is more stable than 7 and both C−C coupling pathways can occur with an accessible barrier, we reasoned 8 would be the predominant intermediate for this step, because the formation of 7 is also kinetically more favorable (by 18.2 kcal/mol; see Figure 4A) than the formation of 7′. The resultant 8, an 18e homoallylic Ir alkoxide complex, corresponds to F in Scheme 1. Note that 8 is 1.7 kcal/mol higher in free energy but 11.7 kcal/mol lower in enthalpy than 7 + CH2O. Step IV: Methanolysis of the Homoallylic Iridium Alkoxide. The homoallylic Ir alkoxide 8 undergoes methanolysis to deliver the final product (3alc) and regenerate the active catalyst (5), closing the catalytic cycle. As illustrated in Figure 7A, the Ir alkoxide 8 first lost the η2-π coordination between the CC double bond and the Ir center to reach a more stable (by 5.6 kcal/mol) intermediate (10). Similar to the methanolysis occurring in the catalyst activation, there exist two pathways (colored in black in Figure 7A) for the process. The energies given in Figure 7A indicate that both pathways are kinetically

feasible, competitive, and thermodynamically favorable to lead to the same products (5 + 3alc). In parallel to the methanolysis, the Ir alkoxide complex 8 may also undergo β-H elimination to form aldehyde 11ald via the two pathways colored in red (see Figure 7A). Relative to 10, the two barriers for β-H elimination (13.0 (TS7) and 16.9 kcal/mol (TS7′), respectively) are not high but are higher than those for methanolysis (10.8 (TS6) and 12.1 kcal/mol (TS6′)); therefore, the β-H elimination can be ruled out. Consistently, no aldehyde was observed in experiment.2 Experimentalists rationalized that the β-H elimination can be avoided because the vacant site required for β-H elimination is occupied by the CC bond of 3alc. Our calculations show that this is because the β-H elimination is less competitive than the methanolysis. To show the catalytic cycle concisely, Scheme 2 assembles the four steps together by following the most favorable pathway to produce 3alc via coupling CH3OH with 2all, using 5 + CH3OH + 2all as the energy reference. Along the cycle, the highest energy point is TS3 + CH2O, which is only 16.8 kcal/mol higher than the energy reference, and the whole reaction is exergonic by 10.0 kcal/mol. Thus, the catalytic coupling is favorable in terms of both kinetics and thermodynamics. With regard to the catalytic cycle, we need to explain why 6′ from step I that is 12.1 kcal/mol more stable than its isomer 6 is not directly involved in step II. First, as shown in Figure 3, the pathway leading to 6′ is kinetically less favorable than the pathway to 6; the free energy difference (3.5 kcal/mol) between TS2 and TS2′ prefer the production of 6 over 6′ by a ratio of 99.5%. Second, even if 6′ could be produced, it could be 2071

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Figure 6. (A) Two pathways for the addition of PhCHO to 7. (B) Optimized geometries of the transition states TS5R and TS5S. Geometries not shown in (B) are included in SI7 in the Supporting Information.

Alternative to the stepwise mechanism, we further considered a concerted coupling mechanism after step I. The mechanism involves three components (i.e., CH2O, 6, and 2all) simultaneously and does not contradict the experimental deuteriumlabeling results. As illustrated by the transition state TS8 in Figure 8, the mechanism occurs by transferring the hydridic hydrogen of 6 (iridium hydride) to the middle carbon atom of 2all and simultaneously coupling the CH2O carbon and the carbon (the one with two methyl substituents) of 2all. Relative to 6 + CH2O + 2all, the barrier for TS8 is 42.6 kcal/mol, which is much higher (by 27.6 kcal/mol) than the highest stationary point (TS3) in the stepwise pathway. Therefore, a concerted mechanism can be excluded. To verify the reliability of our calculations, we performed single-point energy calculations on some important stationary points at the B3LYP/BSIII level in the solvent with the larger basis set BSIII (SDD19 for Ir and Fe and 6-311++G(d,p) for all nonmetal atoms) and with the dispersion effect corrected by using the B3LYP-D3 method.23 As compared in Table 1, the B3LYP/BSIII values are close to the B3LYP/BSII values with a deviation of less than 3.2 kcal/mol. Because the B3LYP-D3 method takes dispersion effects into account explicitly, understandably, the B3LYP-D3/BSIII values are smaller than the B3LYP/BSIII values except for 6 (the unfavorable dispersion effect is due to the release of CH2O when 6 is formed). In spite of the numerical differences, the energetic changing trend remains unchanged. Note that the conclusion that the

isomerized into 6 by passing a barrier of 27.2 kcal/mol to complete the cycle, due to the thermodynamic driving force of the whole reaction. At first glance, the predicted energetics seem not to support the argument, because the formation of 6′ is exergonic by 10.3 kcal/mol, while the whole reaction producing 3alc is only exergonic by 10.0 kcal/mol. However, this is an artifact attributable to the well-recognized overestimation of entropic contributions in solution, when ideal gas phase computational methods are employed.22 An experimental study has shown that this inherent overestimation could be 50− 60% of the total entropic contribution.22e Accurate entropy estimations in solution are still a challenge for theoretical chemistry.23 The step from 5 to 6′ + CH2O is entropically favorable with an entropic contribution of −13.3 kcal/mol, while the whole reaction from 5 + 2all + CH3OH to 5 + 3alc is entropically unfavorable with an entropic penalty of 13.4 kcal/mol. If the experimentally derived scaling factor (0.5) is applied to the entropic contributions,22e 6′ + CH2O is 3.6 kcal/mol lower than 5, while 5 + 3alc is 16.7 kcal/mol lower than 5 + 2all + CH3OH. Therefore, 5 + 3alc is actually much more stable than 6′ + CH2O + 2all, providing the driving force for the isomerization of 6′ into 6. Furthermore, as shown by the optimized structure of 6′, its vacant coordination site is cis to the hydridic hydrogen atom, which is not geometrically preferable for the allene hydrometalation step (step II). In fact, the transition state for the hydrometalation between 2all and 6′ could not be located. 2072

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Scheme 2. Complete Catalytic Cycle of the C−C Coupling of Methanol with Allene (2all) Starting from the Active Catalyst (5)a

a

Note that 5 + CH3OH + 2all is used as energy reference and the values in kcal/mol are the free energies and entropies (in brackets).

formation of 7 via TS3 is more kinetically favorable than the formation of 7′ via TS3′ holds true at the three levels of calculations. 3.1.3. Rationalization of the Regioselectiviy. The C−C coupling reactions also feature phenomenal regioselectivity; all experimental reactions exclusively afford the product corresponding to 3alc in eq 2.2 For the eq 2 reaction, we have located the energetically feasible pathway leading to 3alc, but the pathway is not able to explain why 3alc is preferred over its regioisomer (3alc′), which can be formed by coupling the CH2O carbon with the CH2 carbon of the 2all moiety in step III. On the other hand, because the CH2 carbon is more nucleophilic than the CMe2 carbon and the CH2 group is less sterically demanding than the CMe2 group, one can expect the production of 3alc′ could be more favorable. In agreement with these expectations, 3alc′ is predicted to be 6.4 kcal/mol more stable than 3alc. To understand the regioselectivity, the transition state (TS9 in Figure 9) for the C−C coupling between the CH2O carbon and the CH2 carbon of the 2all moiety in 7 was located. The transition state (TS9) is 34.9 kcal/mol higher than 7 + CH2O, in comparison with the “barrierless” C−C coupling leading to 3alc (see Figure 5A), rationalizing why the CH2O carbon selectively couples to the CMe2 carbon of the 2all moiety in 7. Qualitatively, the regioselectivity can be attributed to the following factors. First, as indicated by the Ir−CH2 bond length (2.338 Å) being shorter than the Ir−CMe2 (2.370 Å) bond in 7, the Ir−CH2 bonding is stronger than Ir−CMe2 bonding; thus, the Ir−CH2 bond breaks more difficultly than the Ir−CMe2 bond when coupling with CH2O. Second, the C−C coupling at the CH2

carbon leads to the enhanced steric effect between the methyl groups and C,O-benzoate ligand (see TS9 in Figure 9). 3.1.4. Side Reactions Related to 1cat and (η3-π-Allyl) iridium Intermediate 7. Interestingly, the catalyst precursor 1cat and the (η3-π-allyl)iridium intermediate 7 (Figure 4A) involved in the catalytic cycle are similar except for the difference in their allyl ligands. We have discussed the reaction of 1cat with CH3OH in catalyst activation and 7 with CH2O in step III. The similarity between the two complexes intrigued us to investigate the side reactions of 7 with CH3OH and 1cat with CH2O. For the reaction of 7 with CH3OH, the two transition states (TS10 and TS10′) shown in Figure 10 correspond to TS1 and TS1′ for the reaction of 1cat with CH3OH, respectively. In comparison with the reaction of 1cat with CH3OH (Figure 2), the reaction of 7 with CH3OH is kinetically and thermodynamically more favorable. Relative to 7 + CH3OH, the barriers are 23.2 (TS10) and 36.6 kcal/mol (TS10′), respectively, which are comparable with the 30.7 kcal/mol (TS1) and 32.0 kcal/mol (TS1′) for the 1cat + CH3OH reaction. The products (5 + 12 or 5 + 13) along the two pathways are 11.1 and 16.9 kcal/mol lower than 7 + CH3OH. The values are compared with the value (−1.7 kcal/mol) in the 1cat + CH3OH reaction. In comparison with the “barrierless” reaction of 7 with CH2O (see Figure 5A), the reaction of 7 + CH3OH is much less favoable. However, because of the much greater availability of CH3OH than of CH2O in the system, the side reaction may occur and transfers partial allene substrates to the byproducts (12 or 13). We think this could be one of the reasons responsible for the experimental yields being less than 70%.2 2073

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Figure 7. (A) Pathways for the methanolysis (in black) and β-H elimination (in red) of the homoallylic iridium alkoxide. (B) Optimized geometries of the stationary points. Geometries not involved in (B) are included in SI8 in the Supporting Information.

Table 1. Relative Energies (in kcal/mol) of Some Stationary Points at Different Levels TS1a TS2b TS2′b 6b TS3b TS3′ b 7b 8b 10b TS6b 3alcb

B3LYP/BSII

B3LYP/BSIII

B3LYP-D3/BSIII

30.7 [18.1] 11.6 [10.7] 15.1 [13.2] 1.8 [14.6] 16.8 [14.6] 35.0 [29.9] −0.4 [−5.8] 1.3 [−17.5] −4.3 [−18.1] 6.5 [−21.8] −10.0 [−23.4]

31.2 [18.6] 9.8 [8.9] 13.4 [11.5] 0.7 [13.6] 13.6 [11.4] 31.4 [26.3] −2.2 [−7.5] 0.8 [−18.0] −5.3 [−19.1] 5.3 [−23.0] −8.9 [−22.2]

20.4 [7.8] 6.8 [5.9] 10.5 [8.6] 8.4 [21.3] 4.3 [2.1] 15.8 [10.7] −17.7 [−23.0] −20.4 [−39.2] −16.1 [−29.9] −17.2 [−45.5] −15.1 [−28.4]

a

Values in kcal/mol are the free energies and entropies (in brackets) relative to 1cat and CH3OH. bValues are relative to 5 + CH3OH + 2all.

Figure 8. Optimized structure of the transition state for the concerted three-component coupling (6, CH2O, and 2all). The barrier in kcal/mol is relative to 6 + CH2O + 2all.

that TS11 should lie below TS11′. Although the side reaction (1cat + CH2O) can take place with feasible energetics, it cannot influence the catalytic system significantly because (i) the reaction of 1cat + CH2O is thermodynamically more unfavorable than the reaction of 7 and CH2O (the former is endothermic by 8.6 kcal/mol and the latter is endothermic by 1.7 kcal/mol) and so the CH2O would prefer to react with 7 and (ii) if the side reaction does take place, the product (14 or 14′)

The mechanism for the reaction of 1cat with CH2O (Figure 11) is similar to that for the reaction of 7 with CH2O (Figure 5A). Similarly, the transition state TS11 for the pathway where CH2O attacks 1cat at the equatorial site could not be located, while the pathway where CH2O attacks 1cat at the axial site has a barrier of 25.7 kcal/mol (TS11′). According to the above discussion about the “barrierless” transition state, we propose 2074

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Figure 9. Optimized geometry corresponding to the unfavorable transition state TS9 for the C−C coupling. The barrier in kcal/mol is relative to 7 + CH2O.

Figure 11. Energy profiles for the C−C coupling of 1cat and CH2O. Optimized geometries are included in SI10 in the Supporting Information.

Table 2. Energetic Results of the Activation Step for the Catalysts (1catR) Tailored by Replacing the H on the Middle Carbon of the η3-π-Allyl Ligand of 1cat with F, Cl, Me, or MeOa R

TS1Rb

5 + 4proRb

H F Cl Me OMe

30.7 [18.1] 25.4 [12.9] 28.9 [15.4] 29.2 [16.6] 23.5 [11.2]

−1.7 [2.1] −8.1 [−4.6] −11.7 [−8.3] −9.3 [−5.5] −10.3 [−6.6]

a

Optimized geometries involved in the table are given in the Supporting Information (SI11). bRelative to 1catR + CH3OH.

Figure 10. Pathways for the reaction of 7 with CH3OH. Optimized geometries are included in SI9 in the Supporting Information.

following to denote the stationary points along the C−C coupling pathway of CH3NH2 and 2all. For the catalyst step, the barrier (TS1am) for catalyst activation is 34.0 kcal/mol, 3.3 kcal/mol higher than the barrier (TS1) via methanolysis. The high activation barrier can be attributed to the amino N−H bond being less polar than the alcohol O−H bond. Therefore, the catalyst 1cat may not catalyze the couplings of amines and allenes effectively. To lower the activation barrier, we suggest applying modifications similar to those in Table 2 to 1cat. The energies of TS2am, TS3, and TS6am, involved in the catalytic cycle, relative to 5am are also larger than those of the corresponding TS2, TS3, and TS6 relative to 5. Furthermore, while the coupling of CH2O with 7 is “barrierless” in the case of methanol coupling, the transition state (TS4am) for coupling H2CNH with 7 could be located and the barrier is 11.2 kcal/mol measured from 7 and H2CNH. The comparisons imply that the C−C coupling of CH3NH2 and 2all is somewhat less favorable than that of CH3OH and 2all. Note that the predicted barriers for the C−C coupling of CH3NH2 and 2all are not too high for experimental realization. It seems to be promising that the protocol could be used for the C−C coupling of amines and allenes after slightly modifying the catalyst, e.g. replacing the middle hydrogen of the η3-π-allyl ligand in 1cat with an F or OMe group.

of the reaction can further undergo methanolysis to generate the active species 5. 3.2. Further Exploration. 3.2.1. Catalyst Modification. The mechanistic study indicates that the catalyst activation has the highest barrier. Therefore, lowering the activation barrier may benefit the performance of the catalyst. We substituted the hydrogen atom on the middle carbon of the η3-π-allyl ligand with F, Cl, Me, and OMe groups. The energetic results for the activation step are given in Table 2. Because the substitutions can lower the activation barriers and stabilize the activation products, we expect the substitutions could benefit the C−C coupling reaction by facilitating the production of the active catalyst. Recall that the predicted activation barrier (30.7 kcal/mol) for the 1cat system is somewhat high. 3.2.1. Extension of Methanol to Amine. Krische et al. prospected that the protocol could be extended for C−C couplings between amines and allenes.4 While the extension waits for experimental realization, we explored the possibility from an energetic point of view. By mimicking the most favorable pathway of the 1cat-catalyzed coupling of CH3OH with 2all, we calculated the energies for the 1cat-catalyzed C−C coupling of amine (CH3NH2) with 2all leading to 15am (Figure 12). Note that the subscript “am” is used in the 2075

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Figure 12. Energy profiles of the C−C coupling of amine (CH3NH2) and 2all to afford the amine 15am. Optimized geometries are included in SI12 in the Supporting Information. Results for the 1cat-catalyzed reaction of CH3OH and 2all are given in blue for comparison purposes.

4. CONCLUSIONS The mechanism of the C−C coupling of CH3OH and allene (2all, 1,1-dimethylallene) catalyzed by the iridium complex 1cat has been investigated by means of DFT calculations. The reaction starts with the catalyst activation via methanolysis to generate the active catalyst (alkoxide complex 5), which participates in the catalytic C−C coupling cycle. The cycle includes four steps: (I) β-hydrogen elimination to give formaldehyde and an iridium hydride complex, (II) allene hydrometalation to deliver a (η3-π-allyl)iridium intermediate, (III) addition of formaldehyde to the (η3-π-allyl)iridium complex to produce the homoallylic iridium alkoxide complex, and (IV) methanolysis of the formed homoallylic iridium alkoxide to afford the final product 3alc and regenerate the active catalyst (5). The regioselectivity affording the alcohol 3alc with an all-carbon quaternary center can be attributed to the Ir−CMe2 bond being weaker than the Ir−CH2 bond and the steric effects between the methyl groups of 2all and the C,O-benzoate ligand of 1cat. The side reaction of 7 with CH3OH could open to result in byproducts (12 or 13), which could be one of the reasons for the experimental yield not being high (