Computational Study on the Catalytic Role of Pincer Ruthenium(II

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Computational Study on the Catalytic Role of Pincer Ruthenium(II)PNN Complex in Directly Synthesizing Amide from Alcohol and Amine: The Origin of Selectivity of Amide over Ester and Imine Haixia Li,† Xiaotai Wang,†,‡ Fang Huang,† Guang Lu,† Jinliang Jiang,† 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 ‡ Department of Chemistry, University of Colorado, Denver Campus, Denver, Colorado 80217-3364, United States

bS Supporting Information ABSTRACT: Density functional theory calculations have been performed to investigate the mechanism of the reactions of amines with primary alcohols to produce amides, catalyzed by the pincer complex Ru(II)-PNN (PNN = 2-(di-tertbutylphosphinomethyl)-6-diethylaminomethyl)pyridine). The results lead us to propose a catalytic cycle that includes four stages: (stage I) alcohol dehydrogenation to aldehyde, (stage II) coupling of aldehyde with amine to form hemiaminal, (stage III) hemiaminal dehydrogenation to amide, and (stage IV) catalyst regeneration via H2 elimination of the trans Ru dihydride complex produced in the two dehydrogenation stages. Both of the dehydrogenation reactions proceed via the bifunctional double hydrogen transfer mechanism rather than the β-H elimination mechanism. The selectivity of amide over ester is determined by the coupling stage in which the aldehyde∧amine coupling to give hemiaminal is more favorable than aldehyde∧alcohol coupling to give hemiacetal. The competition between dehydrogenation and dehydration of hemiaminal governs the selectivity of amide over imine. Three alternative mechanisms without involving hemiaminal or hemiacetal have also been taken into consideration. One of them is less favorable than the pathway involving hemiaminal, and the other two are unlikely, although they have been shown to operate in other catalytic systems. The mechanistic difference is that alcohol dehydrogenation in the present system takes place via bifunctional double hydrogen transfer, whereas it prefers the β-H elimination mechanism in the other systems. The different dehydrogenation mechanisms are attributed to the different ways in which the catalytically active species are generated. In the current system, the catalyst is the catalytically active species itself, requiring no further activation, and its bifunctional active site makes the dehydrogenation follow the double hydrogen transfer mechanism. By contrast, the catalysts in the other systems need to be activated in situ to generate the active species that have vacant coordinate sites suitable for the β-H elimination dehydrogenation.

1. INTRODUCTION The amide bond occurs widely in biological molecules and natural products. It is also a useful linkage in the synthesis of pharmaceutical molecules.1
4 The traditional methods for synthesizing amide do not meet the standards of green chemistry because they require harsh conditions and produce chemical wastes.5
10 Thus, chemists are seeking better ways of synthesizing amides, and a promising approach involves using readily available amines and alcohols to synthesize amides directly.11
14 Specifically, Milstein and co-workers have recently reported the direct synthesis of amides from various amines and primary alcohols catalyzed by the pincer complex Ru(II)-PNN (1cat).15 These reactions occur under mild conditions, require no stoichiometric activating agents, and generate only H2 as byproduct. Subsequent to this work, there have been several reports of similar amide-forming reactions catalyzed by different transition metal complexes.16
20 Most recently, Zeng and Guan have reported the synthesis of polyamides from diols and diamines, using the same catalyst (1cat).21 r 2011 American Chemical Society

It is worth noting that 1cat and its analogues are also effective catalysts for other reactions involving X
H (X = H, C, N, or O) σ bond activation.22
25 Using 1cat or its analogues, the Milstein group has realized a variety of other reactions,26 including amide synthesis from ester and amine,27 dehydrogenative coupling of primary alcohol to produce ester,28 hydrogenation of esters and amides to afford respectively alcohols29 and a mixture of alcohols and amines,30 dehydrogenation of secondary alcohol to ketone,31 and acylation of secondary alcohol with ester.32 Intriguingly, the dehydrogenative coupling of amine with primary alcohol, catalyzed by Ru(II)-PNP (PNP = 2,6-bis(di-tert-butylphosphinomethyl)pyridine), an analogue of 1cat (pincer complex), generates imine rather than amide as the major product.33 Remarkably, 1cat is able to catalyze the direct synthesis of amines from alcohols and ammonia.34 The high catalytic power of such catalysts Received: July 11, 2011 Published: September 14, 2011 5233

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Organometallics originates from their novel electronic structures.35,36 By mimicking the electronic structure of the catalyst, we have recently designed metal-free counterparts of the catalyst that can reversibly activate H2.37 In this computational study, we present a thorough account of how 1cat catalyzes the dehydrogenative coupling of primary alcohols and amines to produce amides. A deep understanding of this remarkable catalytic reaction could provide guidance for practicing chemists to improve the existing catalysts and develop new catalysts, with an aim to broaden the scope of green chemical synthesis.

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Scheme 1. Mechanism Proposed by Milstein et al.

2. COMPUTATIONAL DETAILS All the structures involved in this study were optimized and characterized as minima or transition states at the TPSSTPSS/BSI level in the gas phase,38 BSI designating the basis set combination of LanL2DZ39 for Ru and 6-31G(d,p) for all nonmetal atoms. The choice of TPSSTPSS was based on Hall and co-workers’ success in applying the method to study the light-induced water splitting reaction catalyzed by 1cat.36a When necessary, IRC (intrinsic reaction coordinate) calculations were conducted to verify the right connections among a transition state and its forward and backward minima.40 The energies of the TPSSTPSS/BSI geometries were further improved by single-point calculations at the TPSSTPSS/BSII level with solvation effects included, BSII denoting the basis set combination of LanL2DZ for Ru and 6-31++G(d,p) for all nonmetal atoms. The bulk solvation effects of toluene, including the polarization effect and nonelectrostatic contributions, were simulated by using the integral equation formalism polarizable continuum model (IEFPCM).41 The gas phase TPSSTPSS/BSI harmonic frequencies were employed for the thermal and entropic corrections to the enthalpies and free energies at 298.15 K and 1 atm. It should be emphasized that the ideal gas model inevitably overestimates the entropic contributions because the model ignores the suppressing effect of solvent on the rotational and transitional degrees of freedoms of reactants.42,43 Accurate prediction of enthalpies and entropies in solution is still a challenge for computational chemistry, and no standard approach is currently available.44 Nevertheless, Martin, Hay, and Pratt have proposed a correction for the overestimation of entropic contribution, that is, artificially raising the reaction pressure from 1 to 1354 atm (called the MHP scheme hereafter).45 According to their approach, an additional 4.3 kcal/mol free energy correction applies to one unit change in stoichiometric coefficient for a reaction at 298.15 K and 1 atm; that is, for mR fnP, the correction = (n
m)  4.3 kcal/mol. Experimentally, Yu and coworkers have demonstrated that the ideal gas model could overestimate the entropic contribution by 50
60% in their cyclization reactions.43 On the basis of the experimental results, we apply a scaling factor of 0.5 to the gas phase entropic contributions (called the Yu scheme hereafter). The uncorrected TPSSTPSS (IEFPCM, toluene)/BSII//TPSSTPSS/ BSI free energies are generally used in the discussion of the mechanistic details, aided by the free energies corrected by the MHP and Yu schemes where necessary. It must be noted that neither of the correction schemes, when applied, invalidates our proposed reaction mechanism. Furthermore, we give the enthalpy results in square brackets following the free energy data for comparison purposes. All the calculations are performed using Gaussian 03 and Gaussian 09 packages.46,47

3. RESULTS AND DISCUSSION A homogeneous catalyst combines proper electronic and geometric structures. The electronic and geometric structures of substrates also have a significant influence on the performance of a catalyst. To better account for both the electronic and

geometric effects of both substrates and catalyst, it is desirable to use experimental catalyst and substrates for the mechanistic study, as shown by our recent work on the catalyst design48 and mechanistic study of dehydrogenation or hydrogenation.49,50 Equation 1 represents a catalytic reaction recently reported by Milstein et al., which we have identified as well-suited for computational study. First, the substrates (2alc and 3ami) are structurally simple, thereby reducing computational cost. Second, the high amide yield (99%) should facilitate identifying the major factors responsible for catalysis.

Milstein et al. have proposed a mechanism for their reactions (Scheme 1). The catalytic cycle has four stages: (1) alcohol dehydrogenation to the reactive aldehyde (1cat + RCH2OH f A f RCHO), (2) coupling of aldehyde with amine to give hemiaminal (RCHO + R0 NH2 f B), (3) dehydrogenation of the hemiaminal B to amide (B f RCONHR0 + 5dih), and (4) catalyst liberation via H2 elimination from the trans Ru dihydride complex (5dih) produced in the two dehydrogenation stages. Our extensive computational study lends support to this mechanism, and we wish to discuss the computational details about the four stages with emphasis on the selectivity of amide over ester and imine that are also possible products. 3.1. Alcohol Dehydrogenation (Stage I). Alcohol dehydrogenation, which activates alcohol to more reactive ketone/aldehyde, is a key step in the dehydrogenative coupling reaction.12,13,17,51 β-H elimination is a widely accepted mechanism for alcohol dehydrogenation. As indicated by the intermediates A and C in Scheme 1, Milstein et al. adopt β-H elimination in their proposed mechanism. However, our previous study on the acceptorless alcohol dehydrogenation catalyzed by an iridium complex suggests that alcohol dehydrogenation may occur via 5234

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Figure 1. (A) Alcohol dehydrogenation pathways via β-H elimination (in red) and bifunctional double hydrogen transfer (in green). (B) Energy profiles corresponding to the two pathways. Values in the square brackets are enthalpies. All values are in kcal/mol.

a bifunctional double hydrogen transfer (BDHT) mechanism.50 Thus, we took both mechanisms into consideration in the present study. Dehydrogenation via β-H Elimination. The β-H elimination dehydrogenation pathway, along with the energy profile, is shown in red in Figure 1. The optimized structures of the stationary points in the pathway are displayed in Figure 2. The pathway can be divided into three steps: the cleavage of the alcohol (2alc) O
H bond to give complex 7, the formation of the alkoxide (8) following the opening of the
NEt2 arm, and the release of aldehyde (10ald) after β-H transfer. The alkoxide 8 corresponds to A in Scheme 1 and is a key intermediate for β-H elimination. Another possible pathway, in which the
NEt2 arm opens before the O
H bond cleaves, has also been examined and found to be less favorable (SI1). The binding of 2alc to 1cat initiates β-H elimination dehydrogenation, which is favorable by 3.6 kcal/mol in terms of

enthalpy, but unfavorable by 8.3 kcal/mol in terms of free energy due to entropic penalty. After passing through a transition state (TS1) with a relative energy of 24.8[11.6] kcal/mol to 1cat + 2alc, the O
H bond breaks and the H atom transfers to the sp2-C of the C
P(t-Bu)2 moiety. Note that we hereafter present the energetic results in the form of ΔG[ΔH]. The sixmembered C5N ring in 1cat is nonaromatic, exhibiting bond length alternations (see 1cat in Figure 1). The alcohol activation turns the ring to an aromatic pyridine ring in 7. Relative to 1cat + 2alc, the energy of 7 is 2.3[
11.2] kcal/mol. To undergo β-H elimination, the
NEt2 arm of 7 must open to afford a vacant coordination site for the activation of the C
Hβ bond of alcohol. The transition state (TS2) for opening the
NEt2 arm is 19.2[8.5] kcal/mol higher than 1cat + 2alc. Because of losing NfRu coordination, the alkoxide 8 is 12.7[17.0] kcal/mol less stable than 7. As an alternative to the arm opening (7 f TS2 f 8), complex 7 could also undergo H2 elimination (i.e., removing the 5235

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Figure 2. Optimized structures of the stationary points in the β-H elimination pathway in Figure 1, along with the key bond lengths (in Å). Trivial hydrogen atoms are omitted for clarity.

hydridic hydrogen on Ru and one of hydrogen atoms on sp3 C of the
PtBu2 arm), but the transition state (not shown in Figure 1) having a relative energy of 33.7[19.5] kcal/mol to 1cat + 2alc is higher than TS2 and other transition states in the β-H elimination pathway (see below). We exclude the possibility. The barrier (TS3) to transfer β-H to the Ru center is not high (11.3[8.3] kcal/mol relative to 8), but because the dissociation of the
NEt2 arm raises the energy of the system, TS3 is 26.3[14.1] kcal/mol higher than 1cat + 2alc. The C
Hβ (1.584 Å) and Ru
Hβ (1.707 Å) bond lengths in TS3 validate the Hβ transfer process. TS3 leads to complex 9, in which the CdO π bond coordinates to the Ru center, as characterized by the close Ru
O and Ru
C distances (2.208 and 2.218 Å), respectively. After releasing aldehyde (10ald) from 9, the catalyst becomes a syn Ru dihydride complex (11). The transition state (TS4) closes the
NEt2 arm and turns the syn Ru complex (11) into the trans Ru dihydride complex (5dih). The trans Ru dihydride (5dih) needs to undergo H2 elimination to regenerate the catalyst (1cat). The same process also occurs in stage III (hemiaminal or hemiacetal dehydrogenation). We will discuss the process, separately (see below). Dehydrogenation via Bifunctional Double Hydrogen Transfer. The BDHT dehydrogenation is mediated by the bifunctional active site of 1cat consisting of the Lewis acidic Ru center and

Lewis basic sp2C center on the C
P(t-Bu)2 moiety, which is similar to the hydrogen transfer step in the hydrogenation catalyzed by metal
ligand bifunctional hydrogenation catalysts (MLBHCs)52
54 and our designed metal-free hydrogenation catalysts.48 The energy profile for the BDHT dehydrogenation pathway is shown in green in Figure 1B, and the optimized structures of stationary points are included in Figure 3. In comparison with the β-H elimination pathway, the BDHT pathway is straightforward, in which the Ru center and the sp2C center serve as hydrogen acceptors. The double hydrogen transfer occurs stepwise and is characterized by the bond lengths labeled in TS5, 12, and TS6 (Figure 3). The pathway leads to the reactive 10ald and the trans Ru dihydride 5dih. Comparing the two dehydrogenation pathways in Figure 1B, one can find that the BDHT pathway is more favorable than the β-H elimination one, which is similar to the case of acceptorless alcohol dehydrogenation catalyzed by the iridium complex.50 The highest transition state (TS5) in the BDHT pathway is lower than three (TS1, TS3, and TS4) of the four transition states in the β-H elimination pathway. If the Yu scheme is applied (see Computational Details), the energetic differences between the two pathways would be more significant. The preference of the BDHT mechanism over β-H elimination can be rationalized as follow. To undergo β-H elimination, the
NEt2 arm of the catalyst 5236

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Figure 3. Optimized geometries of the stationary points in the BDHT pathway in Figure 1, together with the key bond lengths in Å. Trivial hydrogen atoms are omitted for clarity.

Table 1. Relative Energies (in kcal/mol) of TS3 and TS5 at the Different DFT Levelsa

TS3 TS5

TPSSTPSS/BSII

TPSSTPSS/BSIIIb

B3LYP/BSIII

WB97XD/BSIII

M06/BSIII

B97D/BSIII

26.3[14.1] 24.8[9.6]

24.2[11.0] 23.2[8.9]

31.5[17.0] 30.4[15.6]

21.4[8.6] 14.8[0.2]

23.1[11.5] 21.1[6.1]

26.1[13.1] 16.0[0.9]

a

Relative to 1cat + 2alc. Values were obtained by the single-point calculations in the solvent at the DFT/BSIII level at the TPSSTPSS/BSI optimized geometries. b BSIII denotes the basis set combination of SDD for Ru and 6-31++G(d, p) for all nonmetal atoms.

Figure 4. Energetic and geometric results for the indirect 10ald∧3ami and 10ald∧2alc coupling mediated by alcohol (values in square brackets are enthalpies in kcal/mol). Key bond lengths are given in Å. Trivial hydrogen atoms are omitted for clarity. Optimized structures of the intermediates (15
18) are given in SI2.

must open to create a vacant coordination site. Although β-H elimination can occur easily if the alkoxide 8 is available, the
NEt2 arm opening destabilizes the catalytic system. Note that complex 8 with the
NEt2 arm opened is 12.7[17.0] kcal/mol less stable than 7 with the
NEt2 arm closed. In addition, the formation of the alkoxide 8 requires 2alc to enter the inner coordination sphere of the catalyst, which results in relatively large steric repulsion between catalyst and substrate. By contrast, the bifunctional double hydrogen transfer takes place in the outer coordination sphere, the
NEt2 arm stays closed, and the substrate (2alc) need not approach the Ru center as closely as in the β-H elimination pathway. To verify the reliability of the TPSSTPSS

density functional theory (DFT) calculations, the relative energies of the two important transition states involved in the two pathways (TS3 in BDHT pathway and TS5 in β-H elimination pathway) to 1cat + 2alc were recalculated using different DFT functionals (B3LYP,55 WB97XD,56 M06,57 and B97D58) and basis set (SDD59). As compared in Table 1, in spite of the numerical differences, all the DFT calculations consistently predicted TS5 to be lower than TS3, validating the conclusion that the BDHT mechanism is more favorable than the β-H elimination in this stage. In Figure 1B, the two dehydrogenation pathways are separated. There is a possibility that the two pathways could be connected via a transition state between 7 and 12 that transfers 5237

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Figure 5. Energetic and geometric results for the indirect 10ald∧3ami and 10ald∧2alc couplings mediated by amine (values in square brackets are enthalpies in kcal/mol), together with the important bond lengths (in Å). Trivial hydrogen atoms are omitted for clarity. Optimized structures of intermediates (19
22) are given in SI3.

Figure 6. (A) Pathways for the formations of hemiaminal/hemiacetal mediated by catalyst 1cat. (B) Free energy (in kcal/mol) profiles corresponding to the pathways (values in square brackets are enthalpies in kcal/mol). 5238

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Table 2. Comparison of the Barriers (in kcal/mol) for the Hemiaminal Formation with Those for the Hemiacetal Formation, Catalyzed by Various Mediators mediator

a

Figure 7. Optimized structures of the key stationary points shown in Figure 6. Some trivial hydrogen atoms are omitted for clarity, and important bond length is given in Å. Those not included in Figure 6 are shown in SI4.

the H-bridging complex 12 to the O-coordinated complex 7. Although we were not able to locate the transition state, we reason whether the transformation between 7 and 12 occurs or does not should not have essential influence on the dehydrogenation stage. If the presumed transition state is much higher than TS6, the transformation from 7 to 12 would not compete with the forward reaction to reach 5dih + 10ald. If the presumed transition state is comparable with TS6 in energy, complex 7 can be transformed to 5dih + 10ald via a microscopic equilibrium between them. Note that, although 5dih + 10ald is less stable than 7, the coupling reaction that uses 10ald as coupling component is overall thermodynamically favorable, which provides the driving force to shift the microscopic equilibrium toward the side of 5dih + 10ald. 3.2. Formations of Hemiaminal and Hemiacetal Intermediates (Stage II). Because 2alc (an alcohol) and 3ami (an amine) coexist in the reaction system, aldehyde 10ald from stage I can couple either with 3ami to give hemiaminal (13heam) or with 2alc to give hemiacetal (14heac), which can be further dehydrogenated to generate amide and ester, respectively (see below). To understand why amide is preferred over ester, we have considered the energetics of both scenarios. The net effect of coupling aldehyde with amine or alcohol is the transfer of the hydrogen atom of the amino or hydroxyl group to aldehyde oxygen and the formation of the C
N or C
O bond. The coupling can take place directly or indirectly. The direct 10ald∧3ami coupling has a somewhat high energy barrier at 32.5[19.3] kcal/mol but cannot be ruled out absolutely. The barrier for the direct 10ald∧2alc coupling, 42.0[30.2] kcal/mol, is too high to be accessible. As far as indirect coupling is concerned,

hemiaminal ΔGq[ΔH]q

hemiacetal ΔGq[ΔH]q

no mediator

32.5[19.3]

42.0[30.2]

alcohol (2alc)

21.0[
4.3]

34.7[10.7]

amine (3ami)

28.2[2.8]

29.4[4.0]

catalyst (1cat)a

28.0[12.3]

25.5[10.5]

29.2[
2.0]

31.5[1.6]

There are two barriers for the coupling reactions.

the hydrogen transfer can be mediated by 2alc, 3ami, or the catalyst 1cat. In the following section, we will examine the catalytic effects of the three mediators. Alcohol Used As the Mediator. Figure 4 shows the energetic and geometric results of the indirect 10ald∧3ami and 10ald∧2alc coupling mediated by 2alc. As illustrated by TS7, 2alc donates the hydrogen atom of the hydroxyl group to aldehyde (10ald) and accepts a hydrogen atom from 3ami, which promotes the C
N bond formation simultaneously. The energy barrier (TS7) for the indirect coupling, 21.0[
4.3] kcal/mol, is much less than that (32.5[19.3] kcal/mol) for the direct coupling, demonstrating the significant catalytic effect of alcohol. Relative to the direct 10ald∧2alc coupling, the mediator alcohol also exhibits a catalytic effect: the coupling barrier (TS8), 34.7[10.7] kcal/mol, is much less than that (42.0[30.2] kcal/mol) for direct coupling. Nevertheless, the indirect 10ald ∧2alc coupling is less favorable than the indirect 10ald∧3ami coupling both in kinetics and in thermodynamics. The transition state (TS8) is 13.7[15.0] kcal/mol higher than TS7, and the hemiacetal (14heac) is 1.4[2.4] kcal/mol above the hemiaminal (13heam). The more favorable 2alc-mediated 10ald∧3ami coupling over the 10ald∧2alc coupling can be attributed to two factors: (1) The amine nitrogen is more nucleophilic than the alcohol oxygen in attacking the electrophilic aldehyde; (2) TS7 has a hydrogen bond between the other amino hydrogen and the chain oxygen of 2alc, which is lacking in TS8. Amine Used As the Mediator. Similar to alcohol 2alc, amine (i.e., 3ami) also mediates 10ald∧3ami and 10ald∧2alc couplings. Because the N
H bond in amine is less polar than the O
H bond in alcohol, we can expect 3ami to be less catalytically effective than 2alc. This holds true for the 10ald∧3ami coupling: the barrier (TS9 in Figure 5) is 7.2[7.1] kcal/mol higher than TS7 in Figure 4. However, for the 10ald∧2alc coupling, the barrier (TS10) is 5.3[6.7] kcal/mol lower than the related TS8 in Figure 4. The discrepancy can be attributed to the stronger hydrogen bonding involved in TS10 than in TS8. 1cat Used As a Mediator. The energetic and geometric results for the 10ald∧3ami and 10ald∧2alc couplings mediated by 1cat are shown in Figure 6, and the optimized geometries of the key stationary points are displayed in Figure 7. Using the 10ald∧3ami coupling as an example, we depict the coupling mechanism. The amine (3ami) first binds to 1cat, forming complex 23, which has a relative energy of 3.3[
9.4] kcal/mol to 1cat + 3ami. Subsequently, one of the amino hydrogen atoms transfers to the sp2C of the C
P(t-Bu)2 moiety after passing through the transition state (TS11). The hydrogen transfer affords complex 24, in which the N center of the 3ami moiety is ready to couple with 10ald. Subsequently, aldehyde 10ald binds to 24 to form a weak complex (25). By overcoming the transition state TS12, the 5239

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Figure 8. (A) Pathways for the dehydrogenations of the intermediate 13heam (in green) and 14heam (in red) via a bifunctional double hydrogen transfer pathway. (B) Corresponding energy profiles (in kcal/mol).

C
N bond is formed while one of the hydrogen atoms on the sp3 C in the C
P(t-Bu)2 moiety moves back to the aldehyde moiety, affording intermediate 26. Complex 26 then dissociates to the catalyst (1cat) and hemiaminal (13heam). Note that, while 1cat mediates the coupling stepwise, alcohol and amine mediate the coupling concertedly. The two energy barriers for the 1catmediated 10ald∧3ami coupling are 28.0[12.3] kcal/mol (TS11) and 29.2 [
2.0] kcal/mol (TS12), respectively. The values are higher than the 21.0[
4.3] kcal/mol (TS7 for alcohol-mediated 10ald∧3ami coupling in Figure 4) and 28.2[2.8] kcal/mol (TS9 for amine-mediated 10ald∧3ami coupling in Figure 5), but still experimentally accessible. This is desirable because the alcohol or amine will gradually deplete as the reaction progresses. As compared in Figure 7, the pathway for the 1cat-mediated 10ald∧2alc coupling is similar to that for the 1cat-mediated 10ald∧3ami coupling except that the former is less favorable than the latter. Note that Gr€utzmacher et al. have reported a similar pathway in their study of dehydrogenative coupling of ethanol.18,60 In the above-discussed mechanism for the 1cat-mediated 10ald∧3ami and 10ald∧2alc couplings, amine (3ami) and alcohol (2alc) are assumed to bind to 1cat first, giving complexes

(i.e., 23 and 6 in Figure 6, respectively), followed by the attack of 10ald. We have further considered the scenario where aldehyde (10ald) first binds to 1cat to form a complex and 3ami or 2alc then attacks the complex. As detailed in SI5, the couplings are less favorable than the reported one (Figure 6). Table 2 summarizes the energy barriers for the coupling reactions mediated by the three mediators. One can find that the 10ald∧3ami coupling is consistently more favorable than the 10ald∧2alc coupling in terms of kinetics. In addition, the formation of 13heam is also thermodynamically more favorable than the formation of 14heac (see above). Taking both kinetics and thermodynamics into account, we conclude that the hemiaminal 13heam is preferred in comparison with the hemiacetal. This is in agreement with the experimental fact that amide is the major product. 3.3. Dehydrogenations of Hemiaminal and Hemiacetal (Stage III). Hemiaminal (13heam) and hemiacetal (14heac) intermediates can be dehydrogenated to give amide (4amd) and ester (29est), respectively. To further understand why 4amd was preferred over 29est in the experiments, we have studied both dehydrogenation reactions. In addition, we have considered two mechanisms (BDHT and β-H elimination) for both dehydrogenations. We 5240

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Figure 9. Optimized geometries of the transition states shown in Figure 8. Some trivial hydrogen atoms are omitted for clarity, and key bond lengths are given in Å. Those not included in Figure 8 are shown in SI7.

discuss the favorable BDHT pathway here and leave the results for the β-H elimination pathway in SI6. The BDHT pathways for 13heam and 14heac dehydrogenations, together with the energetic results, are shown in Figure 8. The optimized geometries of the transition states are given in Figure 9. We wish to emphasize the following points: (1) Similar to the alcohol dehydrogenation, both 13heam and 14heac dehydrogenations occur stepwise. (2) The key barrier (TS14) for the 13heam dehydrogenation, 27.3[11.6] kcal/mol measured from 1cat + 13heam, is comparable to the key barrier (TS16) for the 14heac dehydrogenation, 27.3[12.4] kcal/mol measured from 1cat + 14heac. This seems to contradict the experimental fact that amide is the preferred product. However, we argue that this is because the coupling (stage II), which controls the formation of 13heam and 14heac, determines the selectivity of amide over ester. Recall that the formation of 13heam is more favorable than that of 14heac in terms of both kinetics and thermodynamics. Amide Selectivity over Imine. In the above discussions, we have attributed the amide selectivity over ester to the more favorable production of 13heam over 14heac. Alternatively, 13heam can also undergo dehydration to give imine (i.e., 32imi). Recently, Milstein et al.33 have reported that the reactions of alcohols with amines, catalyzed by an analogue of 1cat (the pincer complex Ru(II)-PNP), produce imines rather than amides as the major product. In the following section, we will rationalize why amide is preferred over imine in our chosen system of study. Figure 10 examines three dehydration pathways of 13heam, including the direct dehydration via TS18, indirect dehydration mediated by 2alc via TS19, and indirect dehydration mediated by 1cat via TS20. The dehydration barriers of the three pathways are 53.1[40.9] (TS18), 38.3[12.6] (TS19), and 40.4[11.4] kcal/ mol (TS20), respectively, which are substantially larger than the dehydrogenation barrier of 27.3[11.6] kcal/mol (TS14, measured from 1cat + 13heam). Furthermore, the dehydration is less thermodynamically favorable than dehydrogenation: 32imi + H2O

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Figure 10. (A) Three pathways for 13heam dehydration, together with the energetic (in kcal/mol) and geometric results. Trivial hydrogen atoms are omitted for clarity, and the important bond lengths are given in Å.

is 12.5[14.3] kcal/mol less stable than 4amd + H2. The energy results are consistent with the observed experimental results that amide is preferred over imine. 3.4. Catalyst Regeneration via H2 Elimination (Stage IV). Dehydrogenations of alcohol (stage I) and hemiaminal (stage III) lead to the trans Ru dihydride (5dih), which needs to undergo H2 elimination to regenerate the catalyst. The mechanism has been studied by Hall and co-workers in their study of the 1cat-catalyzed water splitting reaction.36a They have found that the pathway via eliminating hydrogen atoms on the Ru center and sp3C of the C
P(t-Bu)2 moiety is more favorable than that through eliminating hydrogen atoms on the Ru center and sp3C of the C
NEt2 moiety.36a Therefore, we considered only the favorable scenario in the present study. Figure 11A shows the two possible pathways for the H2 elimination of 5dih. In the pathway 5dih f TS21 f 33 f 1cat0 , the H2 elimination removes the downside hydrogen on Ru and the axial hydrogen on sp3C of the
P(t-Bu)2 arm by crossing the transition state TS21, affording the complex 33, which then twists to 1cat0 . In the pathway 5dih f 34 f TS22 f 330 f 1cat, the complex 5dih first twists to a conformation with the
P (t-Bu)2 arm down and
NEt2 arm up (i.e., 34 in Figure 11). Subsequently, the transition state (TS22) removes the upside hydrogen on Ru and the axial hydrogen on sp3C of the
P (t-Bu)2. The resultant complex 330 then twists to 1cat. The H2 elimination of 5dih via both pathways is endothermic (see Figure 11A). Because of the endothermic H2 release and the somewhat high barriers (23.9[23.5] kcal/mol for TS21 and 25.3[24.7] kcal/mol for TS22), the H2 elimination is unfavorable under our defined conditions (298.15 K, 1 atm), and experimentally it is assisted by removing H2 gas from the system.15 In agreement with the predicted energetics for the H2 elimination, it has been demonstrated that H2 addition to 1cat is facile, but H2 elimination proceeds more slowly under mild conditions. Using 5241

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Figure 11. (A) Two pathways for H2 elimination of 5dih to generate 1cat0 or 1cat. (B) Optimized geometries corresponding to (A). Trivial hydrogen atoms are omitted for clarity, and the important bond lengths are given in Å.

the 5dih f TS21 f 33 f 1cat0 pathway as a representative, we further explored if alcohol can facilitate the H2 elimination. The transition state (TS210 ) for the alcohol-mediated H2 elimination is 31.6[20.7] kcal/mol higher than 5dih + 2alc. Although the alcohol mediator lowers the enthalpy barrier by 2.8 kcal/mol, the involvement of the additional alcohol component brings in an entropic penalty; the free energy barrier becomes even larger (31.6 kcal/mol versus 23.9 kcal/mol). After taking the entropic overestimation by the ideal gas phase model into consideration, the corrected free energy barriers are 26.1 (Yu scheme) and 27.3 kcal/mol (MHP scheme), respectively, which are still larger than the corresponding values (23.7 and 23.9 kcal/mol) for the direct H2 elimination. Thus, the alcohol is unlikely to facilitate the H2 elimination. Because the two H2 elimination pathways are kinetically comparable and thermodynamically the same (note that 33 and 1cat0 are the mirror isomers of 330 and 1cat, respectively) and because the arm twists are facile, the species 33, 330 , 1cat, and 1cat should coexist as catalytically active species in the catalytic system. Recently, Sandhya and Suresh have reported an alternative pathway through a dihydrogen complex for hydrogen production from water splitting promoted by 1cat.36b Under their mechanism, the rate-determining step is the hydrogen evolution via the transition state TSss_H2O (see below). We also located a similar transition state TSss_alc (see below) for hydrogen evolution from 1cat and 2alc. The calculated barrier of TSss_alc is 40.9[26.7] kcal/mol higher than 1cat + 2alc, 15.6[2.0] kcal/mol higher than

that of TS21, implying that the pathway is unlikely in the present system.

3.5. Additional Remarks. Pathways without Passing Hemiaminal or Hemiacetal. Our mechanistic study supports Milstein

et al.’s mechanism (Scheme 1), which involves the hemiaminal intermediate. However, there was no direct experimental observation of the involvement of hemiaminal or hemiacetal. On the basis of the mechanisms proposed for the reactions relevant to the present study, we have further explored whether amide (4amd) or ester (29est) could be produced without involving 13heam or 14heac. On the basis of the mechanism proposed by Milstein et al. in their study of amide hydrogenation catalyzed by a catalyst somewhat similar to 1cat,30 we located the pathways (Figure 12) that can lead to 4amd and 29est, respectively. On the pathway (the green one) giving 4amd, the highest transition state (TS25) is 32.5[6.3] kcal/mol higher than 1cat + 10ald + 3ami. The value is 1.3[4.1] kcal/mol larger than the energy of TS14 (31.2[2.2] kcal/ mol) relative to 1cat + 10ald + 3ami. Note that TS14 is the highest transition state on the pathway. If the Yu scheme is applied to 5242

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Figure 12. (A) Pathways for the formation of 4amd and 29est via the 1cat
aldehyde complex. (B) Corresponding energy profiles (in kcal/mol). The optimized structures involved in the pathway are given in SI8.

Scheme 2. Transition States for Amide or Ester Formations without Passing Intermediates (13heam and 14heac), Which Are Similar to the Mechanism Proposed by the Eisenstein
Carbtree Groups for the eq 2 Reactiona

Scheme 3. Amide Formation via a Similar Mechanism Proposed by Gr€utzmacher and Co-workers in Their Dehydrogenative Ethanol Coupling Reactiona

a

a

The optimized geometries of two transition states are given in SI9.

correct the entropy penalty overestimation, the free energy difference between TS25 and TS14 is 2.7 kcal/mol. Therefore, the pathway without involving hemiaminal (13heam) is slightly less favorable. On the pathway (red one in Figure 12) leading to ester (29est), the highest transition state (TS28) is

The optimized geometries are given in SI10.

38.7[14.6] kcal/mol higher than 1cat + 10ald + 2alc. In comparison, the highest transition state (TS16) in the pathway involving the hemiacetal intermediate is 32.6[5.4] kcal/mol higher than 1cat + 10ald + 2alc. Therefore, the pathway without involving hemiacetal (14heac) cannot contribute to the reaction. 5243

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Table 3. Energetic Differences (in kcal/mol) between Hemiaminal (heam) and Hemiacetal (heac) Formationsabcd

a Values are the kinetic barrier differences between the hemiacetal and hemiaminal formations. b Values are the thermodynamic differences between the hemiacetal and hemiaminal formations. c Values are the thermodynamic differences between the amide and ester productions. d Values for R-enantiomer. No significant differences were found for S-enantiomers. Because alcohol-mediated coupling is most favorable, except the reactions of entries 1
3, values are calculated by using alcohols as mediators. For the reaction of entries 1
3, because of the hydrogen-bonding interaction between the alcohol chain oxygen and the amino hydrogen, the amine is catalytically more effective than alcohol. The barriers for aldehyde^alcohol couplings in entries 1
3 were predicted by using amine as mediator.

Recently, the groups of Eisenstein
Crabtree have reported the Ru-catalyzed intramolecular dehydrogenative amide synthesis (eq 2)17 and proposed that the reaction follows the β-H elimination mechanism via complex 42 and transition state TS29 in Scheme 2. We have examined a similar mechanism for amide or ester production in the present study. Under this mechanism, 3ami or 2alc first attacks the aldehyde
catalyst complex 9 (Figure 1) and then passes through the transition state (TS30 or TS31) to give 4amd or 29est. We did not locate the full pathways, but the relative energies of TS30 (47.4[21.1] kcal/mol relative to 1cat + 3ami + 2alc) and TS31 (55.4[30.2] kcal/mol relative to 1cat + 2alc + 2alc) are high enough for us to rule out the reaction pathways. The mechanistic differences between the two systems can be rationalized as follows. In the

Eisenstein
Crabtree system, the catalytically active species, generated in situ by KOH, possesses a vacant coordination site for β-H elimination, which the catalyst 1cat does not have. To undergo β-H elimination, the
NEt2 arm of 1cat must open, which raises the energy of the catalytic system, making the reaction pathway unfavorable (see Section 3.1). On the basis of that interpretation, we envision that β-H elimination should operate in other similar catalytic systems in which the catalysts have no bifunctional active sites, and the catalytically active species were generated in situ by catalyst activators such as strong bases.16,51 For the β-H elimination-based dehydrogenative coupling reactions, because aldehyde binds to the catalyst to form a robust complex such as 42, no free aldehyde could be detected, which was often used as experimental support for the β-H 5244

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Organometallics elimination mechanism. In the present reaction, if the BDHT mechanism is followed, because the complexes between aldehyde and the Ru center (i.e., 9 in Figure 2 and 35 in Figure 12) are labile, one may reason that free aldehyde could be detected. However, Milstein et al. did not report the detection of free aldehyde in their experiments, although they reported a trace of free aldehyde in other experiments (ester production from alcohols catalyzed by 1cat).28 According to our calculation, it may not be easy to detect free aldehyde because the coupling of 10ald with 3ami mediated by 2alc is very fast (see Section 3.3). Consistently, we attribute the detection of trace aldehyde in ester production from alcohol to the fact that the aldehyde∧alcohol coupling is much less favorable than the aldehyde∧amine coupling (see Table 2).

Gr€utzmacher et al. have recently reported the production of ethyl acetate (MeCOOEt) via dehydrogenative coupling of ethanol, using a Rh catalyst.60 They have proposed two pathways for the reaction. One has been mentioned in Section 3.2, and the other involves simultaneous coupling of three components, as shown by TS32. The transition states shown in Scheme 3, TS33 for 10ald∧3ami coupling and TS34 for 10ald∧2alc coupling, are similar to TS32. However, the energy of TS33 is 49.8[21.5] kcal/mol relative to 1cat + 3ami + 2alc, and that of TS34 is 42.7[15.7] kcal/mol relative to 1cat + 2alc + 2alc, both of which are too high for the present reaction. Selectivity of Amide over Ester. Of particular importance in the reactions is the amide selectivity among the possible products (amide, imine, and ester). In their reported 10 reactions, the amide yields vary from zero to 99%. Remarkably, we have found that the mechanism derived for eq 1 can be used to qualitatively elucidate the varying amide yield in these reactions. On the basis of the study on the reaction represented by eq 1, the coupling stage (Section 3.2) to give either hemiaminal or hemiacetal is crucial for selective production of amide or ester. Thus, the kinetics and thermodynamics for that step determine the selectivity. Table 3 lists the energetic results of the coupling step for all reactions reported in ref 15, and the optimized structures of the transition states are given in SI11. For the reactions (entries 1
3) where alcohols have chain oxygen atoms, the yields of amide are 99%. Consistently, the aldehyde^∧amine coupling reactions are 5.2[5.8]
11.2[13.4] kcal/mol more favorable kinetically than aldehyde∧^alcohol couplings. Similarly, the aldehyde∧amine couplings are thermodynamically more favorable than the aldehyde∧alcohol couplings except for entry 3. For the reactions (entries 4 and 5) where alcohols have no chain oxygen atoms, the barrier differences between the two competitive couplings decrease to 4.3[5.0]
4.0[5.2] kcal/mol. Meanwhile, the formation of hemiaminal becomes 1.4[1.0]
1.7[1.3] kcal/mol less favorable thermodynamically than the hemiacetal formation. Both factors work against the formation of hemiaminal, which is consistent with the reduced amide yields for entry 4 and entry 5. The effect of the oxygen atom in the alcohol chain is more apparent when comparing the energetic results of entries 4 and 5 with those of entry 2. Note that the three reactions use the same amine substrates (see Table 3).

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As to the reactions (entries 6
8) that have amide yields in the range 70
78%, the barrier differences between the two types of couplings become further smaller (3.2[2.9]
3.7[5.0] kcal/mol) in comparison with those for entries 1
5. In addition, compared with entries 4 and 5 reactions, the aldehyde∧amine coupling becomes much less favorable thermodynamically than aldehyde∧alcohol coupling. Therefore, the amide yields of entries 6
8 decrease further. In entry 9, the barrier to form hemiaminal is nearly equal to that to form hemiacetal, and the formation of hemiaminal thermodynamically is slightly more favorable than the formation of hemiacetal. The changes in kinetics and thermodynamics are consistent with the further reduced amide yield (58%). In entry 10, which uses secondary amine, the aldehyde∧amine coupling is 3.2[
0.1] kcal/mol less favorable than the aldehyde∧alcohol coupling. Furthermore, the aldehyde∧amine coupling is thermodynamically (8.5[6.2] kcal/mol) less favorable than the aldehyde∧alcohol coupling. Therefore, the unfavorable aldehyde∧amine coupling in kinetics and thermodynamics results in 0% amide yield. This property allows direct synthesis of the compound with a functional amino group without protecting the secondary amine, which has been used to synthesize bis-amide15 and polyamides.21 It is worth noting that the amide yields correlate well with the thermodynamics to produce amide and ester. For the reactions with high amide yields (70
99%, entries 1
8), the amide production is thermodynamically more favorable than the ester production (see the values in column 9 of Table 3), whereas for the reactions of entries 9 and 10 with low yields of amide (58% and 0%, respectively), the thermodynamics for amide production is less favorable than that for ester production.

4. CONCLUSIONS In conclusion, we have presented a thorough computational study of the role of the pincer complex Ru(II)-PNN in catalyzing the direct synthesis of amides using amines and primary alcohols as feedstock. The catalytic cycle includes four steps: alcohol dehydrogenation to form aldehyde, coupling of aldehyde with amine to form hemiaminal, hemiaminal dehydrogenation to form amide, and the catalyst regeneration via H2 elimination of the trans Ru dihydride complex produced in the two dehydrogenation stages. Our results suggest that the two dehydrogenation reactions occur via the bifunctional double hydrogen transfer mechanism, which is more favorable than the β-H elimination mechanism proposed by the experimentalists. The unfavorable β-H elimination can be attributed to the high-energy state of the catalytic system caused by the
NEt2 arm opening and the greater steric repulsion between catalysts and substrates. The second stage, which can lead to either hemiaminal via aldehyde∧amine coupling or hemiacetal via aldehyde∧alcohol coupling, determines the selectivity of amide over ester. For the targeted reaction, the formation of hemiaminal is both kinetically and thermodynamically favorable over the formation of hemiacetal. The changes in the kinetics and thermodynamics are consistent with the changes of amide yields in other reactions. The coupling stages require mediators, which could be alcohol, amine, or the catalyst (1cat). The competition between dehydrogenation and dehydration of hemiaminal determines the selectivity of amide over imine, because the dehydrogenation is both kinetically and thermodynamically favorable over the dehydration. Three alternative pathways leading to the amides 5245

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Organometallics or esters without involving the hemiaminal or hemiacetal are unfavorable in the present systems. Unlike our proposed mechanism, the dehydrogenation in the other systems prefers the β-H elimination mechanism, because the catalysts therein need to be activated in situ to generate the catalytically active species. By contrast, in the present system, the catalyst is active by itself, requiring no further activation, and its bifunctional active site makes the dehydrogenation follow the double hydrogen transfer mechanism.

’ ASSOCIATED CONTENT

bS

Supporting Information. Computational details for the pathway leading to the alkoxide complex 8 from 1cat + 2alc with the N-arm opening first and then the O
H bond breaking (SI1); optimized geometries shown in Figure 4, but not given in the main text (SI2); optimized geometries shown in Figure 5, but not given in the main text (SI3); optimized geometries shown in Figure 6, but not given in the main text (SI4); 1cat-mediated intermediate formation via the reverse order shown in Figure 6 (SI5); results for the dehydrogenations of 13heam and 14heac via β-H elimination (SI6); optimized geometries shown in Figure 8, but not given in the main text (SI7); optimized geometries shown in Figure 12 (SI8); optimized geometries of transition states TS30 and TS31 (SI9); optimized geometries of transition states TS33 and TS34 (SI10); optimized geometries involved in Table 3 (SI11); complete information for refs 46 and 47 (SI12); and the total energies and Cartesian coordinates of all the structures involved in this study (SI13). This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT This work is supported financially by the Chinese Academy of Science and the National Science Foundation of China (Grant Nos. 20973197 and 21173263). ’ REFERENCES (1) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. (2) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York, 1999. (b) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and Materials Science; Wiley-Interscience: New York, 2000. (c) Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology; WileyVCH: Weinheim, Germany, 2002. (3) Bray, B. L. Nat. Rev. Drug Discovery 2003, 2, 587. (4) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. (5) Smith, M. B. Compendium of Organic Synthetic Methods; Wiley: New York, 2001; Vol. 9, pp 100
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