An ExperimentalâTheoretical Study of the Factors That Affect the

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Organometallics 2010, 29, 6548–6558 DOI: 10.1021/om101015u

An Experimental-Theoretical Study of the Factors That Affect the Switch between Ruthenium-Catalyzed Dehydrogenative Amide Formation versus Amine Alkylation Ainara Nova,† David Balcells,‡ Nathan D. Schley,§ Graham E. Dobereiner,§ Robert H. Crabtree,*,§ and Odile Eisenstein*,† †

Universit e Montpellier 2, Institut Charles Gerhardt, CNRS 5253, cc 1501, Place Eug ene Bataillon 34095, Montpellier, France, ‡Departament de Quimica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain, and §Chemistry Department, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520, United States. Received October 26, 2010

A ruthenium(II) diamine complex can catalyze the intramolecular cyclization of amino alcohols H2N(CH2)nOH via two pathways: (i) one yields the cyclic secondary amine by a redox-neutral hydrogen-borrowing route with loss of water; and (ii) the second gives the corresponding cyclic amide by a net oxidation involving loss of H2. The reaction is most efficient in cases where the product has a six-membered ring. The amide and amine pathways are closely related: DFT calculations show that both amine and amide formations start with the oxidation of the amino alcohol, 5-amino-1-pentanol, to the corresponding amino aldehyde, accompanied by reduction of the catalyst. The intramolecular condensation of the amino aldehyde takes place either in the coordination sphere of the metal (path I) or after dissociation from the metal (path II). Path I yields the Ru-bound zwitterionic form of the hemiaminal protonated at nitrogen, which eliminates H2, forming the amide product. In path II, the free hemiaminal dehydrates, giving an imine, which yields the amine product by hydrogenation with the reduced form of the catalyst generated in the initial amino alcohol oxidation. For amide to be formed, the hemiaminal must remain metal-bound in the key intermediate and the elimination of H2 must occur from the same intermediate to provide a vacant site for β-elimination. The elimination of H2 is affected by an intramolecular H-bond in the key intermediate. For amine to be formed, the hemiaminal must be liberated for dehydration to imine and the H2 must be retained on the metal for reduction of the imine intermediate.

Introduction Amines and amides are key classes of organic materials for which traditional syntheses have low atom economy. Alkylating agents for standard amine alkylation are typically mutagenic and thus pose toxicity problems for large-scale commercial syntheses.1 Pharmaceutical production is particularly affected in view of the tight regulatory climate that penalizes the presence of mutagenic impurities in the final product, even in trace amounts. Coupling agents for amide synthesis from a carboxylic acid and an amine generate waste; for example, dicyclohexylcarbodiimide (DCC) gives the corresponding urea, a material that is hard to recycle. In recent years, green routes have been developed for secondary amine and amide synthesis that do not involve traditional *To whom correspondence should be addressed. E-mail: odile. [email protected]; [email protected]. (1) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, England, NY, 1998. (2) Selected reviews: (a) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681–703. (b) Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611–1641. (c) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009, 753–762. (d) Hamid, M.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555–1575. pubs.acs.org/Organometallics

Published on Web 11/12/2010

alkylating or coupling agents but instead involve the transition metal-catalyzed coupling of primary amines and alcohols.2 Because they have a low intrinsic reactivity, these substrates require catalysis for activation. A rich chemistry of metal-catalyzed C-N bond-forming reactions between amines and alcohols has developed from initial metalmediated oxidation of alcohols to aldehydes and ketones.2 In the most common scheme, the initial alcohol oxidation provides aldehyde and reducing equivalents stored in the form of a metal hydride and a proton (MH- þ Hþ). If the (MH- þ Hþ) subsequently reduces the imine formed on condensation of the aldehyde with the amine co-reactant, a secondary amine product results, along with H2O in a formally redox-neutral overall reaction (Scheme 1, right). If (MH- þ Hþ) loses H2 (Scheme 1, left), the result is a net oxidation of the substrate to give amide. The presence of a hydrogen acceptor can facilitate the process, however.3-5 While acceptorless dehydrogenative oxidations of alcohols (3) Naota, T.; Murahashi, S. I. Synlett. 1991, 693–694. (4) Zweifel, T.; Naubron, J. V.; Gr€ utzmacher, H. Angew. Chem., Int. Ed. 2009, 48, 559–563. (5) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004, 6, 2785–2788. r 2010 American Chemical Society

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Organometallics, Vol. 29, No. 23, 2010

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Scheme 1. Pathways Proposed for Amide (left) and Amine (right) Formation from Alcohols and Amines

to homocoupled esters and lactones6 have long been known, very few examples of the acceptorless dehydrogenative synthesis of amides from primary alcohols and amines are known,7-10 the most notable being the Milstein catalyst.7 We now report a case where the same catalyst operates under similar conditions on similar reactants to produce two entirely different products. The switch between the two reactions is therefore of particular interest, and our computational work now identifies the key steps that differentiate the two pathways. Our proposed pathways for catalytic amine alkylation and amide formation shown in Scheme 1 illustrate the close relationship between these two reactions. Both require initial catalytic oxidation of the alcohol to aldehyde and the formation of a hemiaminal by condensation of the aldehyde and amine. The two pathways diverge after the formation of this unstable intermediate. If the heminaminal eliminates H2O, the resulting imine is catalytically reduced by (MH- þ Hþ) to form the secondary amine. If the hemiaminal eliminates H2, it forms the amide. The role of the catalyst is thus to abstract (MH- þ Hþ) and either release it as H2 or use it to reduce the intermediate imine. In the first case, amide is formed, whereas in the second, amine is formed. The release or retention of hydrogen is thus a key choice that determines the product ratio. The purpose of this work is to better understand the factors that favor one path over the other. The experimental catalyst reported here has the unusual characteristic of giving both amide and amine in significant amounts and thus allows both pathways to be usefully compared. It only operates efficiently on substrates, such as 5-amino-1-pentanol, that give cyclic products. This means that the system is well adapted for studying the factors that favor either amine or amide product. Prior computational studies of related reaction pathways have been carried out for the alkylation of amines with

alcohols catalyzed by a d6 Ir(III) catalyst,11 for the oxidation of methanol catalyzed by d6 Ru(II) catalyst,12 and for the reduction of ketones and imines by alcohols or H2 with various catalysts.13-15 In each case, the transfer of the two hydrogen atoms occurs by formally transferring a proton and a hydride by either an inner- or an outer-sphere mechanism. The inner-sphere mechanism involves coordination of the substrate to the metal fragment, followed by deprotonation with a Lewis base, which can be either coordinated or not. The hydride is then transferred to the metal by β-H elimination from the resulting alkoxo intermediate. The outer-sphere mechanism, originally proposed by Noyori,14a involves a concerted transfer of (H- þ Hþ) between two substrate molecules. Gr€ utzmacher et al. have published an experimental study of the dehydrogenative coupling of alcohol and water, methanol, and amine with a rhodium(I) amido complex and a hydrogen acceptor, typically cyclohexanone.4 The reaction pathway with water has been also studied computationally, naturally without considering the key step in the process reported here, hydrogen loss from the catalyst, which does not occur in the acceptor-driven systems.

We needed to identify a suitable catalyst for study, since it is rare to have a catalyst that gives both redox-neutral amine formation and dehydrogenative amide formation. In looking at (p-cymene)ruthenium(II) chloride dimer and 1,10 -bis(diphenylphosphino)ferrocene as catalysts for the N-alkylation of amines with alcohols, Hamid et al. found that 2-aminopyridine was inefficiently alkylated because of the formation of an amide byproduct.16 We thought that 2-aminopyridine could be functioning both as a ligand and as a substrate for amide formation. This led us to investigate cis-RuCl2(dppb)(2-aminomethylpyridine) (I), a complex previously reported to have an

(6) Selected references utilizing ruthenium catalysts: (a) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 10840–10841. (b) Zhang, J.; Gandelman, M.; Shimon, L. J. W.; Milstein, D. Dalton Trans. 2007, 107–113. (c) Zhao, J.; Hartwig, J. F. Organometallics 2005, 24, 2441–2446. (d) Murahashi, S.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52, 4319–4327. (e) Murahashi, S. I.; Ito, K. I.; Naota, T.; Maeda, Y. Tetrahedron Lett. 1981, 22, 5327–5330. (f ) Blum, Y.; Shvo, Y. J. Organomet. Chem. 1985, 282, C7–C10. (7) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790–792. (8) (a) Ghosh, S. C.; Muthaiah, S.; Zhang, Y.; Xu, X. Y.; Hong, S. H. Adv. Synth. Catal. 2009, 351, 2643–2649. (b) Muthaiah, S.; Ghosh, S. C.; Jee, J.-E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002– 3006. (9) (a) Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672–17673. (b) Dam, J. H.; Osztrovszky, G; Nordstrøm, L. U.; Madsen, R. Chem.—Eur. J. 2010, 16, 6820–6827. (10) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y. X.; Hong, S. H. Organometallics 2010, 29, 1374–1378.

(11) Balcells, D.; Nova, A.; Clot, E.; Gnanamgari, D.; Crabtree, R. H.; Eisenstein, O. Organometallics 2008, 27, 2529–2535. (12) Sieffert, N.; B€ uhl, M. J. Am. Chem. Soc. 2010, 132, 8056–8070. (13) Samec, J. S. M.; B€ackvall, J. E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237–248. (14) (a) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478. (b) Leyssens, T.; Peeters, D.; Harvey, J. N. Organometallics 2008, 27, 1514–1523. (c) Wu, X.; Liu, J.; DiTommaso, D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J. Chem.—Eur. J. 2008, 14, 7699–7715. (d) Chen, Y; Tang, Y. H.; Lei, M. Dalton Trans. 2009, 2359–2364. (15) (a) Casey, C. P.; Johnson, J. B.; Singer, S. W.; Cui., Q. J. Am. Chem. Soc. 2005, 127, 3100–3109. (b) Privalov, T.; Samec, J. S. M.; B€ackvall, J.-E. Organometallics 2007, 26, 2840–2848. (c) Comas-Vives, A; Ujaque, G.; Lledos, A. J. Mol. Struct. (THEOCHEM) 2009, 903, 123– 132. (d) Comas-Vives, A.; Ujaque, G.; Lledos, A. Organometallics 2008, 27, 4854–4863. (16) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766–1774.

Experimental Results

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Table 1. Ring Size Dependence: Cyclization of H2N(CH2)nOHa b

n

amide

amine

imine

6 5 4

70% 80% 25%

20% 8% 15%

43%

a

Conditions: 0.025 mmol of catalyst I, 1.0 mmol of substrate, 0.07 mmol of KOH in 1 mL of toluene. Reactions heated to reflux under a slow flow of N2 for 16 h. Yields by 1H NMR with respect to an internal standard. b On a monomer basis (see ref 18).

Table 2. Influence of Basea entry

catalyst

base

substrate

1 2 3 4 5

I I I I I

none NaOOCH K2CO3 NaOiPr KOH

5-amino-1-pentanol 5-amino-1-pentanol 5-amino-1-pentanol 5-amino-1-pentanol 5-amino-1-pentanol

lactamb

amineb

no reaction 77% 23% 81% 19% 85% 15% 7%c 93%c

a Conditions: 0.025 mmol of catalyst, 1.0 mmol of substrate, 0.07 mmol of base in 1 mL of toluene. Reactions heated to reflux under a slow flow of N2 for 16 h. No starting material remained for entries 2-5. b Conversion by 1H NMR. c Average of two runs.

Scheme 2. Conversion of 5-Amino-1-pentanol to δ-Valerolactam and Piperidine

exceptional turnover frequency in standard catalytic transfer hydrogenation.17 We now find that complex I catalyzes the conversion of 5-amino-1-pentanol to a mixture of δ-valerolactam (amide product) and piperidine (amine product) in refluxing toluene in the presence of added base (Scheme 2). At 2.5% catalyst loading, the amino alcohol is completely consumed within 4 h, giving 85% lactam and 8% piperidine by 1H NMR. Similar amide to amine ratios are found for reactions run for 1 and 16 h. Other amino alcohols could also be used as substrates, with 6-amino1-heptanol giving caprolactam and azepane, and 4-amino-1butanol giving 2-pyrrolidinone, pyrrolidine, and the cyclic imine 1-pyrroline and its byproducts (Table 1).18 The presence of base in these reactions is critical to reactivity, a feature common for dehydrogenative amidation catalysts that lack a metal hydride.8,9 The nature of the base also influences the selectivity, with potassium hydroxide providing the highest fraction of amide in the product distribution (Table 2). The efficiency of the catalyst for amide formation is highly substrate dependent. While 5-aminopentanol proceeds to full conversion in under four hours, after 16 h neither 4-amino-1-butanol nor 6-amino-1-hexanol reaches 90% conversion. Attempts to extend the intramolecular reaction to the corresponding intermolecular case between primary alcohols and amines gave both poor selectivity and yield (Table 3). In contrast to the efficient formation of amides as major products from amino alcohols, intermolecular reactions largely give imine in preference to (17) Baratta, W.; Rigo, P. Eur. J. Inorg. Chem. 2008, 4041–4053. (18) 1-Pyrroline, the imine formed by self-condensation of 4-aminobutanal, is in equilibrium with its trimer. See: Poisel, H. Monatsh. Chem. 1978, 109, 925–928.

amine or amide. In the case of benzyl alcohol, small quantities of homocoupled ester are also seen. In the expectation that we could divert the reaction into giving amide rather than amine, we prepared a number of RHN(CH2)5OH substrates containing a secondary amine. Because formation of an imine was no longer possible in such cases, the amine pathway was expected to be forbidden. These substrates were prepared in an operationally simple two-step procedure by the reaction of 3,4-dihydropyran with RNH2, followed by reduction.19 The catalyst converted secondary amino alcohols, having n-butyl, benzyl, and isobutyl substituents, to the corresponding N-substituted valerolactams in high yield in less than 4 h (Table 4). Branching at the R position led to reduced yield, even at longer reaction times, as in the cases of N-isopropyl5-aminopentanol and N-(R-methylbenzyl)-5-amino-1-pentanol. The secondary amine substrates also reacted faster than their primary amine analogues. When reactions were stopped and analyzed at short reaction times, N-butyl-5-amino-1-pentanol was found to be completely converted to the corresponding lactam in the first 20 min at reflux (Table 4, entry 1), while a similar analysis on N-isopropyl-5-aminopentanol found that two-thirds of the total amide product obtained (Table 4, entry 5) had been formed in the first hour. Amide formation implies H2 generation, and this point was verified by heating a sealed NMR tube containing 0.2 mmol of 5-amino-1-pentanol, 0.05 equiv of potassium hydroxide, and 0.02 equiv of catalyst I in toluene-d8 for 30 min in a 115 °C oil bath. A signal corresponding to dissolved H2 gas20 was observed at 4.50 ppm, but disappeared when the sample was subsequently sparged with nitrogen. In view of the computational proposal, discussed below, that monohydride intermediates of a specific geometry should be favored, we looked for evidence for the presence of hydrides in the same catalytic mixture, discussed above, that gave evidence of H2 formation. From the NMR data, we were indeed able to detect the presence of two hydride species, which, however, could not be isolated. In the region upfield of 0 ppm, two signals in an approximate 2:1 ratio could be seen at -15.24 and -22.02 ppm. Both signals are doublets of doublets with coupling constants of 23.2, 35.3 Hz and 26.9, 35.8 Hz, respectively. These patterns are consistent with the presence of two different ruthenium monohydride species in which the hydride is cis to two inequivalent phosphines. While observable species in a catalytic mixture may not lie on the catalytic cycle itself, these observations nevertheless substantiate the computational result that this geometry is favored in the system.

Computational Results Models. The catalyst I of Scheme 2 is modeled by replacing the ligand PPh2 groups with PH2. The experimental X-ray structure21 is used as the initial guess for geometry optimization. In the presence of an excess of KOH, we assume that the chloride ligands are initially replaced by hydroxide. In addition, an empty coordination site is needed to initiate the reaction. Complex 1 is therefore postulated as the active species. The mechanism for the formation of 1 from reactants is beyond the scope of this study. 5-Amino-1pentanol is selected as substrate. The substrate has many conformations and orientations with respect to the catalyst. A systematic search of all the possibilities in the intermediates and transition states is not carried out because they are not expected to significantly influence the energy profiles. Likewise, unless mentioned, we (19) Hoffman, R. V.; Salvador, J. M. J. Chem. Soc., Perkin Trans. 1 1989, 1375–1380. (20) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176–2179. (21) Baratta, W.; Herdtweck, E.; Siega, K.; Toniutti, M.; Rigo, P. Organometallics 2005, 24, 1660–1669.

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Table 3. Selected Intermolecular Reactionsa

entry

catalyst

cat. loading

base loading

alcohol

solvent

amide

imine

ester

1 2 3 4 5

I I I I I

2.5% 5.0% 2.5% 2.4% 2.5%

8% 20% 10% 11% 13%

benzyl alcohol benzyl alcohol 1-butanol 1-butanol 1-butanol

toluene toluene toluene tert-amyl alcohol p-xylene

22% 42% 10% 10% 7%

10% 2% 48% 20% 38%

9% 9%

a Conditions: 1.0 mmol of alcohol, 1.0 mmol of 1-hexylamine, catalytic KOH in 2 mL of solvent. Reactions heated to reflux under a slow flow of N2 for 16 h. Stated yields are by 1H NMR with respect to an internal standard.

Table 4. Secondary Amino Alcoholsa

a

Conditions: 0.025 mmol of catalyst, 1.0 mmol of substrate, 0.07 mmol of base in 1 mL of toluene. Reactions heated to reflux under a slow flow of N2 for 4 h. Products purified by flash chromatography on silica gel. b Reactions run for 16 h.

used a fully staggered conformation of the substrate and a chair conformation of the six-membered cyclic product. The Gibbs energy origin for all the profiles is that of separated 1 and two molecules of 5-amino-1-pentanol. All co-reactants have not been included in the figures, but they are mentioned in the captions. Throughout the article, an activation barrier is defined as the difference in Gibbs energy between a transition state and its associated reactants. Solvent effects from the toluene have been shown not to modify the gas phase results to any great extent (see Computational Details). Oxidation of Amino Alcohol to Amino Aldehyde. The oxidation of the amino alcohol is the initial step for the formation of the alkylamine, piperidine, and the amide, δ-valerolactam (Scheme 1). In a previous study, we showed that the oxidation of the alcohol could occur by an inner-sphere mechanism with deprotonation of the coordinated alcohol and β-H elimination of the resulting alkoxy group.11 The base for the deprotonation could be either free or metal-bound. Furthermore, an empty coordination site is needed cis to the alkoxide group. A simple way of studying these processes is by using a Ru hydroxo complex as model active species. The Ru-OH moiety may deprotonate the coordinated amino alcohol, yielding an aqua ligand, which is decoordinated to open a vacant site. The Gibbs energy profiles for these steps show that the proton transfer occurs without any activation barrier and that the amino alkoxy complex 4 and water products are marginally higher in energy than the Ru-OH complex 1 and amino alcohol

Figure 1. Gibbs energy profiles, in kcal mol-1, for the deprotonation of the 5-amino-1-pentanol and the opening of a vacant site. The starting point is the species shown and an additional molecule of 5-amino-1-pentanol. reactants (Figure 1). The most stable form of 4 has the amine alkoxy group trans to the NH2 group of the aminomethyl pyridine, so the first step is simply a replacement of Ru-OH by Ru-OR. The associative ligand exchange goes via hexacordinate intermediates (2 and 3), which are ca. 10 kcal mol-1 more stable than the 16e species. Once the active species, 1, has initiated the reaction, the resulting complex, 4, is regenerated by the following steps, yielding the amide and amine products (vide infra); therefore, 4 is regarded as the catalyst in this study. The activation of one of the β C-H bonds of the amino alkoxo ligand in complex 4 yields the amino aldehyde via either an inner-sphere or an outer-sphere mechanism (Figure 2). In the inner-sphere mechanism, the alkoxo ligand yields a hydride by undergoing intramolecular β-elimination. In the outer-sphere mechanism, the hydride is formed by intermolecular reaction with an external molecule of amino alcohol, which transfers a hydride to the metal vacant site and a proton to the oxygen atom of the amino alkoxo ligand. In either pathway, the hydride group can be either trans to NH2 (ΔG = -10.8 kcal mol-1, Figure 2) or trans to P (ΔG = -0.4 kcal mol-1, Figure S2), but the hydride is trans to NH2 in the more stable isomer, consistent with the experimental observation of hydrides in

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Nova et al. coordinated to Ru via an oxygen lone pair. The oxidation of the amino alcohol to the coordinated amino aldehyde 6 is calculated to be exergonic by -10.8 kcal mol-1. In the transition state for the outer-sphere mechanism, TS4-7, an external molecule of the substrate reacts with 4 by transferring a hydrogen from one of the β C-H0 bonds to the vacant site at the metal, with d(C 3 3 3 H0 ) = 1.35 A˚ and d(Ru 3 3 3 H0 ) = 1.74 A˚, and a proton from the Ο0 -H00 group to the oxygen of the amino alkoxo ligand, with d(O0 3 3 3 H00 ) = 1.33 A˚ and d(O 3 3 3 H00 ) = 1.10 A˚, respectively. This reaction yields 7, which has an uncoordinated aldehyde and a coordinated amino alcohol. Exchange between these two ligands gives the more stable product 6, previously described. The activation barrier of 6.5 kcal mol-1 for the outer-sphere formation of the aldehyde is low and similar to that for the inner-sphere mechanism (ΔGq = 8.8 kcal mol-1). One or both of these two paths may thus contribute to the oxidation of the amino alcohol to the coordinated amino aldehyde 6. Amide Formation. The formation of the amide from complex 6 starts with the intramolecular cyclization of the amino aldehyde ligand in the coordination sphere of the metal (Figure 3). This reaction involves the nucleophilic addition of the amino group to the carbonyl group, the latter being activated by coordination to the metal. This step yields complex 8, containing a zwitterionic tautomer of the hemiaminal ligand having a cationic ammonium group and a Ru-bound alkoxide group, d(Ru-O) = 2.16 A˚. One of the two N-H protons of the ammonium group makes a dihydrogen bond with the cis hydride, as shown by the short H 3 3 3 H distance of 1.66 A˚ (Figure 4). This interaction helps the N-H proton transfer to the hydride via TS8-9, d(N 3 3 3 H) = 1.63 A˚ and d(H 3 3 3 H) = 0.95 A˚, leading by eq 1 to the dihydrogen intermediate 9.

Figure 2. Gibbs energy profiles, in kcal mol-1, for the inner (top) and outer (bottom) sphere mechanisms of C-H cleavage. The starting point is, for the top profile, the complex shown, 5-amino-1-pentanol, and H2O; for the bottom profile, the species shown and H2O. the catalytic mixture (vide supra). Calculations show that the other isomer behaves similarly, and the corresponding results are given in the Supporting Information. At the transition state TS4-5 for β-elimination in the innersphere mechanism, the amino alkoxo ligand is trans to P and the C-H and Ru 3 3 3 H distances are still similar (1.11 and 2.93 A˚, respectively) to those in the reactant 4 (1.11 and 3.08 A˚, respectively). The origin of the difference in energy between 4 and TS4-5 comes mainly from the change in the position of the amino alkoxo ligand. This reaction, 4 f TS4-5 f 5, involves an activation barrier of 8.8 kcal mol-1 and is exergonic by 8.3 kcal mol-1. In the product complex, 5, the hydride ligand is trans to NH2 and the amino aldehyde is coordinated to Ru in an η2-CdO structure with d(C 3 3 3 O) = 1.28 A˚. This η2-CdO complex undergoes isomerization via TS5-6 with a very low activation barrier to the more stable κ1-O amino aldehyde complex 6,22 with d(C 3 3 3 O) = 1.24 A˚, where the aldehyde is (22) This intermediate was obtained from TS6-8 so the amino aldehyde does not have a staggered conformation.

In this species, the transferred H is only 1.86 A˚ from the nitrogen and thus takes part in an N 3 3 3 H-H H-bond. Intermediate 9 has a significantly stretched dihydrogen ligand with an H-H distance of 0.91 A˚. In addition, the H2 is canted as shown by the unequal Ru-H distances of 1.68 and 1.75 A˚, the longer distance being associated with the central, H-bonded, H of the N 3 3 3 H-H unit. Electron donation from the hemiaminal N lone pair into the σ* orbital of the coordinated H2 adds to the back-donation from the metal, leading to a long H-H distance. Furthermore, the weak trans influence of the methylenamine NH2 ligand allows a strong Ru-H2 interaction, which also contributes to the elongation of the H-H bond. The strong Ru-H2 bond makes H2 loss from 9 challenging, as shown by the associated transition state, TS9-10, which, at 14.7 kcal mol-1, is the highest energy point along the amide formation pathway (Figure 3). A key point in allowing liberation of H2 is the easy accessibility of another isomer of 9 lacking the N 3 3 3 H-H hydrogen bond and thus having a labile H2. This isomerization is possible because the coordinated H2 is not the only source of acidic hydrogen since one acidic N-H bond of the coordinated aminopyridine group is perfectly placed to act as an alternative site for hydrogen bond formation. The bound hemiaminal can thus detach its nitrogen lone pair from the H2 ligand and rotate through 180°, as shown in eq 2,

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Figure 3. Gibbs energy profile, in kcal mol-1, for amide formation. The starting point is the complex shown, 5-amino-1-pentanol, and H2O.

Figure 4. Optimized structures of 8, TS8-9, 9, and 90 with selected N-H and H-H distances in A˚. to become hydrogen bonded to the aminomethyl NH. This rotation transition state (TS9-90 ) has a Gibbs energy of 6.6 kcal mol-1.

This rotamer, 90 , has been located as a minimum, with a Gibbs energy of only 1.7 kcal mol-1 above 9 (Figure 3). In 90 , the methylenamine NH2 ligand makes a H-bond with the N lone

pair of the hemiaminal, d(N 3 3 3 H) = 1.69 A˚ (Figure 4). This rotamer has a much more labile H2, as reflected in the Ru-H2 structural parameters. The H-H distance of the dihydrogen ligand now shortens to 0.86 A˚ and the H2 is no longer canted, as shown by the equal Ru-H distances of 1.70 A˚. These changes result from the absence of the N 3 3 3 H-H hydrogen bond in 90 , perhaps aided by an increase in the trans influence of the methylenamino NH2 ligand by the H-bond. The structural changes in the Ru-H2 moiety prompted by the 9 f 90 transformation lead to a significant lowering of the energy required for H2 release, from 14.7 kcal mol-1, TS9-10, to only 7.8 kcal-mol-1, TS9-100 (Figure 3). The release of dihydrogen, needed for amide formation, is thus strongly promoted by the rotation of the heminaminal and rearrangement of the hydrogen-bonding pattern. The best transition state for β-H elimination from the hemiaminal has the relevant C-H trans to the phosphine ligand. Thus 100 needs to isomerize to 12 for the β-H elimination step.

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Figure 5. Gibbs energy profile, in kcal mol-1, for the regeneration of the catalyst, 4. The starting point is the complex shown, H2O, H2, and the amide. In 12, the oxygen of the hemiaminal is trans to NH2 and the nitrogen is trans to phosphine. The isomerization from 100 to 12 goes via a succession of five-coordinate square pyramids where the hemiaminal is bonded only to Ru via the oxygen atom since isomerization is difficult in six-coordination. The transition states for these isomerizations could not be identified, but their energy can be estimated by calculating the energy of 11, which has a decoordinated hemiaminal. This isomer is found at a Gibbs energy of 1.2 kcal mol-1, which shows that it costs around 15 kcal mol-1 to decoordinate the hemiaminal amine group to open up a vacant site. The Gibbs energy of the transition state TS12-13 for the β-H migration is 9.8 kcal mol-1. This energy is required to create the empty coordination site by decoordination of the nitrogen of the hemiaminal and to bring the C-H bond in the proximity of the metal. This is achieved only by significantly bending the Ru-O-C angle from 126° in 11 to 106° at the transition state. TS12-13 connects to the final product, 14, via a very shallow minimum, 13, having a very strong agostic C-H bond with a long d(C-H) of 1.24 A˚ and a short d(Ru 3 3 3 H) of 1.87 A˚. This rearranges via the low barrier TS13-14 to cleave the C-H bond to give a hydrido complex containing the coordinated product amide, 14. The catalyst, 4, is recovered from 14 in three steps: substitution of the product amide ligand by the amino alcohol substrate, dihydrogen complex formation, and H2 release. The first step yields the free amide product and hydride complex 7, previously discussed, with a ΔG of -2.1 kcal mol-1. From 7, the proton of the OH group is transferred to the hydride ligand via a transition state, TS7-15, with d(O 3 3 3 H) = 1.50 A˚ and d(H 3 3 3 H) = 1.00 A˚ (Figure 5). The high activation barrier associated with this step, 23.7 kcal mol-1, is most likely significantly lowered in the real experimental situation by participation of an additional proton transfer carrier, substrate amino alcohol, or a (23) (a) Sandoval, C. A.; Ohkuma, T.; Mu~ niz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490–13503. (b) Casey, C. P.; Johnson, J. B.; Singer, S. W.; Cui, Q. J. Am. Chem. Soc. 2005, 127, 3100–3109. (c) Comas-Vives, A.; Gonzalez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F.; Ujaque, G. J. Am. Chem. Soc. 2006, 128, 4756–4765. (d) Shi, F. Q.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503–15512. (e) Kennedy, D. F.; Nova, A.; Willis, A. C.; Eisenstein, O.; Messerle, B. A. Dalton Trans. 2009, 10296–10304. (f) Friedrich, A.; Drees, M.; Schmedt auf der G€unne, J.; Schneider, S. J. Am. Chem. Soc. 2009, 131, 17552–17553. (g) Kovacs, G.; Lledos, A.; Ujaque, G. Organometallics 2010, 29, 3252–3260.

Figure 6. Metal-assisted (blue) and metal-free (red) pathways for imine formation. Gibbs energies are given in kcal mol-1. The starting point is the complex shown, H2O, and 5-amino-1pentanol. water molecule.23 The release of H2 on going from 15 to 4 is endoergic by 5.9 kcal mol-1. The high-energy transition state obtained in this case, 32.1 kcal mol-1 above 7, will be lowered by the hydrogen bond with the NH2 group trans to H2, similar to that found for TS9-100 . From complex 4, the catalytic cycle can restart as shown in Figure 2. Amine Alkylation. The pathway for amine alkylation has been previously described by us for a Cp*Ir fragment and related substrates.11 To avoid duplication, we concentrate on the new points here: the factors that differentiate the two pathways. In amine alkylation, the metal catalyzes the oxidation of the amino alcohol to the amino aldehyde and the reduction of the cyclic imine to the amine product.11 The imine comes from the dehydratation of a hemiaminal formed by condensation of the aldehyde with the amine group. This is a well-documented acid- or base-catalyzed reaction where the metal catalyst may or may not be involved (Figure 6). In the former case, the hemiaminal is formed by proton migration from nitrogen to oxygen in 8 or from the H2 ligand to the oxygen in 9. The transition states for forming the neutral hemiaminal from either 8 or 9 are high in energy (TS8-17 = 6.5 and TS9-17 = 14.0 kcal mol-1) compared to that for the proton migration from N to hydride to form the dihydrogen complex (TS8-9 = -7.7 kcal mol-1). This means that, in the absence of an outersphere assistance for the proton transfer with significant influence on the energy of the transition state, intermediate 8 would prefer to form the dihydrogen complex rather than the neutral hemiaminal. We did not study hemiaminal dehydration, a well-known reaction, but instead focused on the hydrogenation of the resulting imine. As was the case for the oxidation of the amino alcohol, hydrogenation of the imine by 16 may follow either an inner- or an outer-sphere mechanism (Figure 7). In the inner-sphere mechanism, the imine coordinates to the vacant site of 16 and undergoes intramolecular hydrogenation by insertion into the Ru-H bond. In the outer-sphere mechanism, the imine can undergo intermolecular hydrogenation by hydride and proton transfer

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with d(Ru 3 3 3 H) = 1.70 A˚ and d(H 3 3 3 C) = 1.68 A˚, the transfer of the hydride H from Ru to the β-C of the imine is concerted with the transfer of the proton H from the amino alcohol to the N of the imine, with d(O 3 3 3 H) = 1.61 A˚ and d(H 3 3 3 N) = 1.07 A˚ in TS7-4. The products, 4 þ amine, are 7.6 kcal mol-1 below the initial reactants, whereas the transition state, TS7-4, is 7.8 kcal mol-1 above. The hydrogenation of the imine by an outer-sphere hydrogen transfer mechanism has a transition state at lower energy than the insertion mechanism and may therefore be preferred.

Discussion

Figure 7. Gibbs energy profiles, in kcal mol-1, for the formation of the amine product through the inner (top) and outer (bottom) sphere mechanisms. The starting point is, for the top profile, the species shown, 5-amino-1-pentanol, and H2O and, for the bottom profile, the species shown and H2O. from the hydrido alcohol complex 7. The energy profiles associated with both mechanisms are shown in Figure 7. In the inner-sphere mechanism, the coordination of the imine to Ru yields complex 18, which is less stable than 16 by 13.4 kcal mol-1, clearly showing that the imine is a poor ligand for this intermediate. In the following step, the imine inserts into the Ru-H bond, yielding the agostic complex 18. In the transition state, TS18-19, with d(Ru 3 3 3 H) = 1.94 A˚ and d(H 3 3 3 C) = 1.18 A˚, the hydride is transferred from the Ru to the β-C of the imine ligand. TS18-19, 18.9 kcal mol-1 above the initial reactants, is the highest energy point along the reaction pathway. The amido complex 19 has a Gibbs energy of 12.4 kcal mol-1, which is well above the reactants despite the presence of an agostic interaction with the β-hydrogen of the cyclic amine. However, protonation by amino alcohol and decoordination of the resulting amine regenerating 4 (19 þ amino alcohol f 4 þ amine) is thermodynamically favored by 20.0 kcal mol-1. In the outer-sphere mechanism, the hydrogenation of the amine could be carried out by any complex having a hydride bound to the metal and an adjacent acidic hydrogen. Species 7, which can be generated by any of several routes (see Figures 2 and 3), would be suitable, for example. In transition state TS7-4,

Catalytic systems that produce two different products from the same reactants by divergent pathways under the same conditions are inherently interesting to study computationally to examine the factors that affect the branching ratio between the products.24 The interest is further enhanced in this case by the intrinsic importance of each of the two reactions. In the case of complex I, the amine formation pathway could be disfavored by employing amino alcohol substrates containing secondary amines because of the inability, under the conditions used, to give the iminium ion that would have to form for the amine pathway to be possible. As a result of this modification, the unbranched N-butyl5-amino-1-pentanol even proved to be a superior substrate to the unsubstituted 5-amino-1-pentanol, proceeding to completion in less than a third of the time required for the primary amino alcohol. Unfortunately, no such improvement was observed in the intermolecular reaction when a secondary amine was employed, however. In general, the superior selectivity obtained with amino alcohols versus the intermolecular reaction can be attributed to the rapid formation of a metal-bound hemiaminal and the reactivity of the resulting organometallic species. This one-step, atom economic reaction provides a much greener pathway to these cyclic amides than the standard route involving oxidation followed by amide formation with a coupling reagent. The central feature of the study is the remarkable effect of hydrogen bonding on modulating reactivity. Figure 8 shows the mechanistic information deduced from the calculations of the reaction of I with 5-amino-1-pentanol. The formation of the amide and amine follow different pathways, but only after the oxidation of the alcohol to the aldehyde yielding intermediate 6. Since free hemiaminal, formed on cyclization of the amino aldehyde, eliminates water, liberation of free aldehyde leads to the free hemiaminal and from there to imine and finally to amine. In contrast, intramolecular cyclization of the amino aldehyde within the coordination sphere of the metal leads to a zwitterionic form of a metal-bound hemiaminal in 8 that leads to amide. Species 8 may also undergo intramolecular proton transfer yielding the neutral hemiaminal bound to the metal (17), which would decoordinate more easily to give amine formation. Calculations show that 8 can form an H2 complex, 9, by a low activation barrier proton transfer from the ammonium group to the metal hydride. The dihydrogen bond that connects the ammonium and the hydride in 8 is transformed into a H-bond between the H2 ligand and the proximal amine lone pair in 9. This H-bond strongly stabilizes the H2 ligand and prevents easy H2 dissociation, a step (24) Hull, J. F.; Balcells, D.; Sauer, E. L. O.; Raynaud, C.; Brudvig, G. W.; Crabtree, R. H.; Eisenstein, O. J. Am. Chem. Soc. 2010, 132, 7605–7616.

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Figure 8. Mechanistic model for the switch between the amide and amine formation reactions.

that is needed if amide is to be formed. In a remarkable feature of these complexes, it is possible to make H2 release much easier by dissociating the N 3 3 3 (H2)-Ru H-bond, allowing the O-bound hemiaminal to rotate 180°, and engaging the hemiaminal N in a N 3 3 3 H-N-Ru hydrogen bond with the methylenamino NH2 ligand, 9 f 90 . This significantly lowers the activation barrier for H2 release, showing the cooperative character of the key H-bond formation and dissociation steps: the H-bond pattern that initially facilitates H2 formation has to be rearranged in order to facilitate the critical loss of H2 needed for amide formation. This requires the presence of an acidic proton at an appropriate distance from the nitrogen of the hemiaminal and may explain the activity of both complex I and related ruthenium diamines6c in dehydrogenation chemistry. The H-bond between the hemiaminal nitrogen and the methylenamino NH2 ligand may also have another effect on the Ru-H2 bond energy. NH2 has a weak trans influence, but when it is H-bonded, the resulting incipient deprotonation gives it some NH(-) anionic character, enhancing its trans influence and thus also contributing to the weakening of the Ru-H2 bond. While we focus here on the intramolecular pattern of H bonds, we cannot exclude the possibility that outer-sphere anions such as OH- could also contribute, with the same results. Indeed, the catalysts that give amide formation by release of H2 all have ligands with strong trans effects, such as carbenes, hydrides, or CO, in agreement with our results.7-10 The large number of processes that participate in the formation of amine and amide and the complexity of these reactions, such as dissociation of ligands or H-transfer processes, make difficult if not impossible at present to give a quantitative comparison of the amine and amide pathways because the elimination of water from the free hemiaminal has not been studied. In general this last reaction is considered to be easy, although a computational study on a related catalytic system shows that it is not always the case.25 However, our work suggests that H2 formation and release, which requires the (25) Marcelli, T. Angew. Chem., Int. Ed. 2010, 49, 6840–6843.

presence of the metal fragment, is the switch between amide and amine formation. If H2 is formed and released easily, the amino alcohol substrate is oxidized to the amide product, whereas, if retained by the metal as H- þ Hþ, the amino alcohol leads to imine via hemiaminal, and the imine is reduced by the metal to the amine product. The metal plays an important role in this switch reaction: H2 formation is more favored with a second-row metal than with a third row one. For instance, the Cp*Ir complexes that we studied earlier give only amine and no amide,11 in contrast with the present Ru catalysts. In the Supporting Information, we show how the protonation of an iridium hydride is more endergonic than that of a ruthenium hydride. The calculations have shown that outer-sphere hydrogen transfer can be achieved with low activation barriers in an H-Ru-(HOR) moiety. This shows that this reaction is not exclusive to the H-M-(NH2R) systems widely studied following the seminal discovery by Noyori.14a Some O-containing ligands have also been shown to be efficient in ketone hydrogenation.26 The analogy between the oxygen- and nitrogen-containing complexes in hydrogen transfer reactions is related to the similar polarity and proton donor power of their OH and NH bonds. The reaction requires a relatively high temperature of 110 °C. This is probably needed to open the vacant site of the five-coordinated 16-electron reactive intermediate (1 or 4), from the more stable six-coordinated 18-electron catalyst precursor, where the sixth ligand can be the amino alcohol, the hemiaminal, the imine, the amine and amide products, or even H2. Therefore, the coordination of the N of the amine or hemiaminal is more difficult with bulky secondary amines than with primary amines, which accounts for the faster reaction observed with the former amines. The β-H elimination from the metalated hemiaminal also requires a relatively high barrier. This is attributed to the need for the C-O-Ru angle of the bound hemiaminal ligand to bend at oxygen in order to bring the β-C-H bond into close (26) Phillips, S. D.; Fuentes, J. A.; Clarke, M. L. Chem.—Eur. J. 2010, 16, 8002–8005.

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proximity to Ru for β-elimination. The high temperature would also help in surmounting this high energy barrier.

Conclusions This study highlights some of the factors that are important in favoring formation of amide versus alkylated amine in the Ru-catalyzed reaction of alcohol with amine. The relatively high temperature of 110° that is needed for the reaction is proposed to be required to access an empty coordination site in the presence of such good coordinating agents as the reactant amine. High temperatures are also needed for βhydrogen elimination, especially the one involved in the formation of the amide. For amide to be formed, the amine must add to a metal-bound aldehyde to form a zwitterionic hemiaminal. This key intermediate must then eliminate H2 to provide a vacant site for β-elimination. The NMR observation of ruthenium monohydride species under conditions close to those of the catalytic reaction is consistent with the suggestion from calculation that ruthenium monohydrides are implicated in catalysis; there is also good agreement between experiment and theory concerning the geometry of these intermediates. We have shown that in the calculated pathway a redirection of the intermolecular hydrogen bond associated with the formation of the H2 ligand is of crucial importance in lowering the energy barrier for dihydrogen release. For amine to be formed, the neutral hemiaminal must be liberated and the H2 must be retained on the metal, in the form of H- þ Hþ, for reduction of the imine intermediate. If the hemiaminal is liberated and the H2 is lost from the system, imine is necessarily formed, but this is a significant pathway only in the intermolecular amine/alcohol reactions. On this basis, the rarity of amide formation in experimental systems is a result of the rarity of catalysts that can retain the aldehyde before the nucleophile addition of the amine but release H2 from the O-metalated hemiaminal.

Experimental Section Complex I was prepared according to the literature procedure.21 NMR spectra were recorded at room temperature in CDCl3 or CD2Cl2 on a 400 or 500 MHz Bruker spectrometer and referenced to the residual protio solvent signal. The identities of the δ-valerolactam and piperidine products were confirmed by GC-MS and by comparison to the NMR spectra of commercially available samples. Representative Procedure for Catalytic Amidation/Alkylation. The catalyst (0.025 mmol) and a catalytic amount of potassium hydroxide (0.07 mmol) were loaded into a flame-dried 10 mL round-bottom flask attached to a straight-walled reflux condenser (27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03 (Revision E.01); Gaussian, Inc.: Wallingford, CT, 2004.

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and placed under nitrogen. At the top of the condenser, a septum cap was fitted with a nitrogen inlet needle and an outlet needle leading to an oil bubbler. 5-Aminopentanol (1.0 mmol) and dry, degassed toluene (1 mL) were then added via syringe. The reaction was heated to a vigorous reflux in a 125 °C oil bath. During the reaction, a nitrogen flow rate of approximately 10 mL/min was maintained at the top of the reflux condenser. At the end of the reaction the mixture of products was analyzed by 1 H NMR. NMR yields were calculated with respect to a known quantity of internal standard (1,3,5-trimethoxybenzene) added at the end of the reaction. Computational Details. All calculations were performed with Gaussian0327 at the DFT(B3PW91) level.28 The basis set was the ECP-adapted SDDALL29 with a set of polarization functions for Ru30 and P31 and the all-electron 6-31G(d,p)32 for N, O, C, and H. All structures were fully optimized without any geometry or symmetry constraint. Each stationary point was classified as minimum or transition state by analytical calculation of the frequencies. The connection between reactant and product through a given transition state was checked by optimization of slightly altered geometries of the transition state along the two directions of the transition-state vector associated with the imaginary frequency. Entropy effects calculated in the gas phase from harmonic approximation of frequencies were included in order to compare the inner- and outer-sphere mechanisms, since the former is unimolecular whereas the latter is bimolecular. The effect of toluene solvent, which is weakly coordinating and of low polarity (ε = 2.379), was evaluated by using the continuum PCM model33 with single-point 6-311þG** calculations and the methodology proposed by Maseras et al.34 for the Gibbs energy in solution. It was verified that the solvent does not modify significantly the results found in the gas phase. Therefore, we present the results in the gas phase in the article and report the results in solution in the Supporting Information.

Acknowledgment. O.E. thanks the CNRS and Ministere de l’Enseignement Superieur et de la Recherche for funding. A.N. thanks the Spanish MICINN for a MEC postdoctoral fellowship. D.B. thanks Sanofi-Aventis for a postdoctoral fellowship (2007-2009) and the Spanish MICINN for his current Juan de la Cierva position. R.H.C. thanks the ACS-GCI Pharmaceutical Round Table for funding, and N.S and G.D. thank the U.S. Department of Energy, Office of Basic Energy Sciences catalysis grant DE-FG02-84ER13297 and the ACS GCI Pharmaceutical Roundtable. We would also like to thank Miriam Bowring for her early work on dehydrogenative imine formation at Yale. (28) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5662. (b) Perdew, J. P.; Wang, Y. Phys. Rev. B 1992, 45, 13244–13249. (29) (a) Andrae, D.; H€aussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Theor. Chim. Acta 1990, 77, 123–141. (b) Bergner, A.; Dolg, M.; K€uchle, W.; Stoll, H.; Preuss, H. Mol. Phys. 1993, 80, 1431–1441. (30) Ehlers, A. W.; B€ ohme, M.; Dapprich, S.; Gobbi, A.; H€ ollwarth, A.; Jonas, V.; K€ ohler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 208, 111–114. (31) H€ ollwarth, A.; B€ ohme, H.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.; Jonas, V.; K€ ohler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 203, 237–240. (32) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222. (33) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032–3041. (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett. 1998, 286, 253–260. (c) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151–5158. (34) (a) Balcells, D.; Ujaque, G.; Fernandez, I.; Khiar, N.; Maseras, F. J. Org. Chem. 2006, 71, 6388–6396. (b) Braga, A. A. C.; Ujaque, G.; Maseras, F. Organometallics 2006, 25, 3647–3658.

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Supporting Information Available: The synthesis, purification, MS, and observed 1H and 13C NMR shifts of secondary amino alcohol substrates and their product lactams. The computed Gibbs energy profiles for alcohol oxidation with hydride trans to the phosphine ligand. The computed energy profiles for the protonation

Nova et al. of the hydride for Ru and Ir complexes. Computed Gibbs energy profile including solvent effects. List of the coordinates of all optimized structures with potential energy (E), Gibbs energy (G), and Gibbs energy in solvent (Gs). This material is available free of charge via the Internet at http://pubs.acs.org.

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