Ruthenium-Catalyzed Deuteration of Alcohols with Deuterium Oxide

Article pubs.acs.org/Organometallics

Ruthenium-Catalyzed Deuteration of Alcohols with Deuterium Oxide Wei Bai, Ka-Ho Lee, Sunny Kai San Tse, Ka Wing Chan, Zhenyang Lin,* and Guochen Jia* Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People’s Republic of China S Supporting Information *

ABSTRACT: The catalytic properties of a series of ruthenium complexes for H/D exchange between D2O and alcohols were studied. The catalytic activity of the ruthenium complexes and the regioselectivity of the H/D exchange reactions were found to be dependent on the auxiliary ligands. While ruthenium η6-cymene complexes such as [(η6cymene)RuCl(NH2CH2CH2NTs)]Cl, (η6-cymene)RuCl2/ NH2CH2CH2OH, and (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} catalyzed regioselective deuteration of alcohols with D2O at the β-carbon positions only, octahedral ruthenium complexes such as RuCl2(2-NH2CH2Py)(PPh3)2 (2-NH2CH2Py = 2aminomethylpyridine) and RuCl2(NH2CH2CH2NH2)(PPh3)2 catalyzed regioselective H/D exchange reactions of D2O with alcohols at both the α- and β-carbon positions of alcohols. The H/D exchange reactions proceed through reversible dehydrogenation of alcohols and hydrogenation of carbonyl compounds involving hydride species and H/D exchange among D2O and carbonyl and hydride species. The different regioselectivities of the H/D exchange reactions can be related to the relative ease of H/D exchange of ruthenium hydride intermediates with D2O.

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INTRODUCTION Deuterium-labeled compounds are highly useful compounds that can be used for a wide range of applications, including solvents for NMR spectroscopy, labeled drugs, probes for mechanistic studies in chemical and biochemical processes, probes in mass spectrometry, and raw materials for labeled compounds and polymers. There has been much interest in the development of methodologies for the production of such species.1,2 The preparation of regioselectively deuterium-labeled alcohols is desirable because many biologically active compounds contain hydroxyl functional group(s) and because alcohols can be used for a variety of organic syntheses. While regioselectively deuterium labeled alcohols can be made by conventional methods, for example, by multistep organic synthesis from deuterium-labeled synthons3 and by reduction of carbonyl compounds with reagents such as NaBD4,4 LiAlD4,5 and SiDR3,6 metal-catalyzed direct H/D exchange between alcohols and an appropriate deuterium source represents a more cost effective approach to deuterium-labeled alcohols. For example, deuterium-labeled alcohols could be obtained from H/D exchange reactions of alcohols with C6D6 catalyzed by [Cp*Ir(H)3(PMe3)][OTf] (5 mol %, 135 °C)7 and from H/ D exchange reactions of alcohols with deuterated isopropyl alcohol catalyzed by osmium or ruthenium pincer catalysts (1 mol %, 30−50 °C).8 Transition-metal-catalyzed direct H/D exchange between deuterium oxide (D2O) and alcohols is a very attractive synthetic method for the preparation of deuterium-labeled alcohols, because deuterium oxide (D2O) is relatively cheap and safe. However, only a few studies have been carried out in this direction, and highly efficient systems that work for a wide range of substrates with high regioselectivity under mild © XXXX American Chemical Society

conditions are still rare. In the area of heterogeneous catalysis, the catalytic activities of Ru/C−H2 and Pd/C−H2 for the transformation have been reported. Ru/C−H2 (20 wt %, 50− 80 °C)9 was found to be able to catalyze regioselective H/D exchange reactions between alcohols and D2O at the α-carbon positions. Pd/C−H2 (10 wt %) was found to be able to catalyze H/D exchange reactions between aryl-substituted alkyl alcohols Ph(CH2)nOH and D2O at the aliphatic carbon positions (except the α-carbon position) at 110 °C (e.g., Ph(CH2)4OH is converted to Ph(CD2)3CH2OH)10 or at the benzylic carbon positions at room temperature (e.g., Ph(CH2)3OH is converted to PhCD2(CH2)2OH)11 and H/D exchange reactions of D2O with secondary alcohols to give a mixture of labeled alcohols and ketones.12 In the area of homogeneous catalysis, it has been demonstrated that RuCl2(PPh3)3 (5 mol %, microwave, 150 °C, 10 atm)13 and a β-D-glucopyranoside-incorporated NHC iridium complex (100 °C)14 can catalyze regioselective H/D exchange reactions between alcohols and D2O at the α-carbon positions. The complex [(η5-C5H4Me)2Mo(OH)(OH2)]OTs (0.9−6.5 mmol %, 80−102 °C) can effect regioselective H/D exchange between D2O and alcohols at the α-carbon positions for primary alcohols and at both α- and β-carbon positions for secondary alcohols such as 2-propanol and 2-butanol.15 Other systems that can effect H/D exchange between D2O and alcohols at both α- and β-carbon positions include the ruthenium CNN-pincer complex RuCl{(2-(3-MeC6H3)-6(NH2CH2)-C5H3N)} (1 mmol %, 50 °C) and the PNN-pincer complex RuHCl(CO){(2-(Bu2PCH2)-6-(2-C5H4N)-C5H3N)}) (0.1 mmol %, 120 °C).16 The iridium complex Cp*Ir(PMe3)Received: February 21, 2015

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DOI: 10.1021/acs.organomet.5b00134 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Cl2 (5 mol %) was reported to induce deuteration of the alkyl chains of n- and 2-propanol with D2O at 135 °C.17 We have been interested in preparing deuterated compounds using D2O as the deuterium source. We have previously reported that the ruthenium complex (η6-cymene)RuCl2 in combination with NH2CH2CH2OH can catalyze regioselective deuteration of a variety of alcohols at β-carbon positions with deuterium oxide.18 In this work, we report (i) a comparative study on the catalytic properties of a series of ruthenium complexes for the H/D exchange reactions of alcohols with D2O, (ii) regioselective deuteration of alcohols at both α- and β-carbon positions with deuterium oxide catalyzed by RuCl2(2NH2CH2Py)(PPh3)2 (2-NH2CH2Py = 2-aminomethylpyridine), and (iii) a plausible explanation why the (η6-cymene) Ru systems supported by amine ligand and octahedral ruthenium complexes supported by amine ligand induced different selectivities in the catalytic H/D exchange reactions.

Table 1. H/D Exchange Reaction of 2-Phenylethyl Alcohol with D2O Catalyzed by Ruthenium Complexesa %Dinc entry

complex

α position

β position

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

CpRuCl(PPh3)2 Cp*RuCl(PPh3)2 (η5-indenyl)RuCl(PPh3)2 RuCl2(DMSO)4 RuHCl(CO)(PPh3)3 RuCl2(PPh3)3 RuCl2(2-H2NCH2Py)(dppf) RuCl2(NH2CH2CH2NH2)(PPh3)2 RuHCl{(R,R)-dach}(PPh3)2 RuCl2(2-H2NCH2Py)(PPh3)2 RuHCl(2-H2NCH2Py)(PPh3)2 RuH2(2-H2NCH2Py)(PPh3)2 [(η6-cymene)RuCl2]2 (η6-cymene)RuCl2(PPh3) (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} (η6-cymene)RuCl(NH2CH2CH2NTs) [(η6-cymene)RuCl(H2NCH2CH2NH2)]Cl

n.d. n.d. n.d. n.d n.d. 8 25 24 26 88 85.5 89 n.d n.d. n.d. n.d. n.d.

n.d n.d. n.d n.d. n.d. 23.5 37.5 42.5 45 85.5 84.5 84 n.d. n.d. 80 84.5b 22.5b

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RESULTS AND DISCUSSION Ligand Effect on the Catalytic Activity and Regioselectivity. It is well established that catalytic properties of metal complexes vary with ligands. In our effort to search for active catalysts for H/D exchange reactions between alcohols and D2O and to study ligand effects on the catalytic activity of ruthenium complexes on the regioselectivity of the catalytic reactions, we have investigated catalytic properties of a series of ruthenium complexes for the H/D exchange reaction between 2-phenylethanol and D2O (eq 1). In a typical experiment, a

a

The reactions were carried out with 2 mol % of a ruthenium complex and 10 mol % of KOH under N2 at 80 °C in a Schlenk tube for 3.5 h, unless specified otherwise. The molar ratio of substrate and D2O was chosen such that the expected percentage of deuterium incorporated at the α- and β-carbon positions is about 90% (expected percentage of deuterium is the statistical percentage of D when we consider the exchangeable hydrogen atoms associated with H2O, KOH, catalysts, and alcohols). %Dinc is the percentage of deuterium incorporation determined experimentally by 1H NMR. The abbreviation n.d. indicates that the percentage of deuterium incorporated is less than 5% or is too small to be detected by 1H NMR spectroscopy. bThe reactions were carried out with 3 mol % of a ruthenium complex and 15 mol % of KOH under N2 at 80 °C in a Schlenk tube for 4.5 h.

mixture of D2O and 2-phenylethanol (in a ca. 22.5:1 molar ratio) was heated at 80 °C for 3.5 h in the presence of 2 mol % of a ruthenium complex and 10 mol % of KOH. Assuming that the protons of the −CH2CH2OH group of 2-phenylethanol can undergo complete H/D exchange with D2O, it is expected that about 90% of the protons can be replaced with deuterium. The results of the catalytic reactions mediated by selected ruthenium complexes are summarized in Table 1. Ruthenium cyclopentadienyl complexes such as CpRuCl(PPh3)2, Cp*RuCl(PPh3)2, and (η5-indenyl)RuCl(PPh3)2 are ineffective for the reaction (Table 1, entries 1−3). Octahedral complexes not supported by a primary or secondary amine ligand, for example, RuCl2(DMSO)4 and RuHCl(CO)(PPh3)2 are also ineffective for the reaction (entries 4 and 5). The complex RuCl2(PPh3)3 is marginally effective for the reaction, giving partially deuterated 2-phenylethanol with 8.0% and 23.5% D at the α- and β-carbon positions, respectively (entry 6). Octahedral complexes supported by an amine ligand are more active in promoting the H/D exchange reaction. The complexes RuCl2(2-H2NCH2Py)(dppf), RuCl2(NH2CH2CH2NH2)(PPh3)2, and RuHCl{(R,R)-dach}(PPh3)2 (dach = 1,2-diaminocyclohexane) are moderately active for the reaction, giving partially deuterated 2-phenylethanol with 24−26% and 37.5−45% D at the α- and β-carbon positions, respectively (entries 7−9). The complex RuCl2(2H2NCH2Py)(PPh3)2 is a better catalyst for the reaction, giving partially deuterated 2-phenylethanol with 88% and 85.5% D at the α- and β-carbon positions, respectively (entry 10). RuHCl(2-H2NCH2Py)(PPh3)2 and c,t-RuH2(2-H2NCH2Py)(PPh3)2 give similar results (entries 11 and 12).

We have monitored the reaction mediated by CpRuCl(PPh3)2 and RuCl2(PPh3)3 by in situ 31P{1H} and 1H NMR in order to see why these complexes are less effective for the catalytic reaction. In these experiments, a mixture of the complex (2 mol %) and PhCH2CH2OH in water in the presence of KOH (10 mol %) was heated at 80 °C for 1 h. The mixture was extracted with CDCl3, and then 31P{1H} and 1H NMR spectra were recorded. In the case of CpRuCl(PPh3)2, the in situ NMR suggests that the majority of CpRuCl(PPh3) was unreacted, and small amounts of CpRu(CH2Ph)(CO)(PPh3),19 CpRuCl(CO)(PPh3),19 and unidentified phosphorus-containing species with 31P signals at 66.9, 42.4, 41.9, and 30.9 ppm were formed. In the case of RuCl2(PPh3)3, the in situ NMR suggests that almost all RuCl2(PPh3)3 has been consumed and the major product is the hydrido carboxylate complex RuH(O2CCH2Ph)(PPh3)3, which can be obtained alternatively by the reaction of RuCl3 with PhCH2CO2H/PPh3 in the presence of KOH in ethanol (see the Supporting Information for details). Minor signals of RuH2(CO)(PPh3)3 were also observed. A subsequent study confirmed that RuH(O2CCH2Ph)(PPh3)3 is also an ineffective catalytic precursor for the H/D exchange reaction. The poor catalytic activity of CpRuCl(PPh3)2 and RuCl2(PPh3)3 for the H/D exchange reaction could be related to side reactions with alcohols in water. We previously reported that the ruthenium complex (η6-pcymene)RuCl2 in combination with NH2CH2CH2OH induced regioselective deuteration of a variety of alcohols at the βB


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Organometallics Table 2. H/D Exchange Reactions of Alcohols with D2O Catalyzed by RuCl2(2-H2NCH2Py)(PPh3)2a

a The reactions were carried out with 2 mol % of RuCl2(2-H2NCH2Py)(PPh3)2 and 10 mol % of KOH under N2 at 80 °C in a Schlenk tube. %Dex. is the statistical percentage of D when we consider the exchangeable hydrogen atoms associated with water, KOH, catalyst, and substrates. %Dinc is the percentage of deuterium incorporated and determined experimentally by 1H and 2D NMR. Alcohols are shown as ROH rather than ROD, since the OD group is changed back to OH in the process of isolation and purification of the deuterated products, where the crude products have been washed with water and subjected to chromatogrphy. b%Dinc is the percentage of deuterium incorporated and determined experimentally by in situ 1H NMR.

with other amine ligands can effect deuteration of 2phenylethanol at the β-carbon position only, although the activity varies with the ligand. The complex [(η6-cymene)RuCl(NH2CH2CH2NH2)]Cl is moderately active for the reaction, giving partially deuterated 2-phenylethanol with 22.5% D at the β-carbon position (entry 17). The complex (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} is more efficient, giving partially deuterated 2-phenylethanol with 80% D at βcarbon position (entry 15). The ability of (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} to induce deuteration only at the β-carbon positions of alcohols was further confirmed by the observation that PhCH(OH)CH3 reacted with D2O to give

carbon positions with deuterium oxide and that the related complex (η6-cymene)RuCl(NH2CH2CH2NTs) similarly induced regioselective H/D exchange between D2O and PhCH2CH2OH also at the β-carbon positions. It is interesting to note that the regioselectivity in the catalytic reactions promoted by the (η6-cymene)Ru systems is different from those in entries 6−12 given in Table 1. To find out if other (η6cymene)Ru systems behave similarly, we have tested their catalytic properties. [(η6-cymene)RuCl2]2 and (η6-cymene)RuCl2(PPh3) were found to be inactive (entries 13 and 14). Like (η6-cymene)RuCl(NH2CH2CH2NTs) and (η6-cymene)RuCl2/NH2CH2CH2OH, (η6-cymene)Ru complexes supported C


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Organometallics

Scheme 1. Proposed Mechanism for the H/D Exchange Reaction of PhCH2CH2OD with D2O To Give PhCD2CH2OD Catalyzed by (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs}

PhCH(OD)CD3 in the presence of (η6-cymene)Ru{(S,S)NHCHPhCHPhNTs}, while PhCH2OH did not undergo a similar H/D exchange reaction under the same conditions. It has been reported that complexes such as RuCl2(PPh3)2(NH2CH2CH2NH2), RuCl2(PPh3)3, CpRuCl(PPh 3 ) 2 , (η 5 -indenyl)RuCl(PPh 3 ) 2 , [(η 6 -cymene)RuCl(dppp))]Cl, [(η6-cymene)RuCl(bipy)]Cl, (η6-cymene)Ru(NHCH2CH2NH), and (η6-cymene)Ru(H2NCHPhCHPhNTs} are catalytically active for transfer hydrogenation from (S)-PhCD(OH)Me to PhC(O)Me to give rac-PhCD(OH)Me. It was also noted that the catalytic

properties of the (η6-cymene)Ru complexes for the reaction are also different from those of RuCl2(PPh3)2(NH2CH2CH2NH2) and RuCl2(PPh3)3. The reaction using RuCl 2 (PPh 3 ) 2 (NH 2 CH 2 CH 2 NH 2 ), or RuCl2(PPh3)3 gives rac-PhCD(OH)Me with a deuterium content of 37 or 40%, respectively, in the α-position, while the reaction using the (η6-cymene)Ru complexes gives racPhCD(OH)Me gives a deuterium content of over 90% in the α-position.20 Scope of RuCl2(2-H2NCH2Py)(PPh3)2-Catalyzed Reactions. The observation that RuCl2(2-NH2CH2Py)(PPh3)2 can D


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for reactions catalyzed by these complexes to give alcohols with deuterium at the β-carbon positions only, as illustrated in Scheme 1 using the H/D exchange reaction of PhCH2CH2OH with D2O catalyzed by (η6-cymene)Ru{(S,S)NHCHPhCHPhNTs} to give PhCD2CH2OD. PhCH2CH2OH can undergo rapid H/D exchange with D 2O to give PhCH2CH2OD. Thus, the alcohol is mainly in the form of PhCH2CH2OD before the H/D exchange occurs, involving the C−H protons at the β-carbon. (η 6 -cymene)Ru{(S,S)NHCHPhCHPhNTs} (1) can be hydrogenated by PhCH2CH2OD to give the monohydride complex 2d1, which can undergo H/D exchange with D2O to give the dideuterated hydride complex 2d2. 2d2 can react with the aldehyde PhCH2CHO to give the monodeuterated complex 1d1. 1d1 can react with PhCH2CH2OD to give the dideuterated monohydride complex 2d2 and aldehyde PhCH2CHO via the six-membered cyclic transition state 3. A similar transition state has been proposed previously for hydrogen transfer reactions catalyzed by (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs}.22 The aldehyde then undergoes H/D exchange with D2O in the presence of KOH via keto−enol tautomerization to give the partially deuterated aldehyde PhCD2CHO. The partially deuterated aldehyde is then reduced by the hydride complex 2d2 via the transition state 4 to give the deuterated alcohol PhCD2CH2OD, and the active species 1d1 is regenerated for the next catalytic cycle. It should be noted that amide complexes such as MH(NHCMe2CMe2NH2)(PPh3)2 (M = Ru, Os) and RuH((R)BINAP)((R,R)-NHCHPhCHPh2NH2)) are known to react with H2O to give the corresponding amine hydroxide complexes by protonation of the amide nitrogen.24 Thus, (η6cymene)Ru{(S,S)-NHCHPhCHPhNTs} (1) may also react with water to give the hydroxide complex 1·D2O as a side product. Our theoretical calculations show that the addition reaction of the model complex (η6-C6H6)Ru(NHCH2CH2NSO2Me) with H2O to give (η6-C6H6)Ru(OH)(NH2CH2CH2NSO2Me) is thermodynamically favored by 6.0 kcal/mol (see the Supporting Information), suggesting that the hydroxide complex 1·D2O could be in equilibrium with 1 in water, although this process does not contribute to the H/D exchange described in this work. Scheme 2 shows a plausible pathway for the H/D exchange reactions of alcohols with D2O to give alcohols with deuterium at both the α- and β-carbon positions catalyzed by RuCl2(2H2NCH2Py)(PPh3)2, using the reaction of PhCH2CH2OD to give PhCD2CHDOD as an illustration. In the presence of the base KOH, RuCl2(2-H2NCH2Py)(PPh 3 ) 2 (5) can react with PhCH 2 CH 2 OD to give PhCH2CHO and the dihydride complex c,t-RuH2(2H2NCH2Py)(PPh3)2 (6), which could undergo H/D exchange with D2O to give the deuteride complex c,t-RuD2(2D2NCH2Py)(PPh3)2 (7). Complex 7 can isomerize to t,cRuD2(2-D2NCH2Py)(PPh3)2 (8), which can react with aldehyde PhCH2CHO to generate the five-coordinated amido complex 9. Complex 9 can react with PhCH2CH2OD via the transition state 10 to give the hydrido deuteride complex t,c-RuH(D)(2-D2NCH2Py)(PPh3)2 (11) and aldehyde PhCH2CHO. PhCH2CHO then undergoes H/D exchange with D2O in the presence of KOH via keto−enol tautomerization to give PhCD2CHO. The hydrido deuteride complex t,c-RuH(D)(2-D2NCH2Py)(PPh3)2 (11) can undergo H/D exchange with D2O either directly or via c,c-RuH(D)(2D2NCH2Py)(PPh3)2 (12) to give the deuteride complex t,c-

effectively catalyze regioselective H/D exchange between D2O and 2-phenylethanol at both the α- and β-carbon positions is interesting, as reported systems that can induce similar transformation are still rare. Therefore, we have explored the scope of substrates in the H/D exchange reactions catalyzed by RuCl2(2-H2 NCH2Py)(PPh3) 2. In most cases, the H/D exchange reactions were performed in the presence of 2 mol % of RuCl2(2-H2NCH2Py)(PPh3)2 and 10 mol % of KOH. The molar ratio of substrate and D2O was chosen such that the expected percentage of deuterium incorporation at the α- and β-carbon positions is about 90%. After the reaction was completed, the product was extracted with diethyl ether, washed with water, and purified by column chromatography. The product was analyzed by 1H and 2D NMR. The results of the catalytic reactions are given in Table 2. As shown in Table 2, secondary benzylic alcohols were readily deuterated at the α- and β-carbon positions in the presence of the ruthenium catalyst (entries 1−5). For example, the reaction of 1-phenylethanol for 3.5 h gave deuterated 1phenylethanol with 87% and 86% deuterium, respectively, at the α- and β-carbon positions (ca. 90% expected deuteration can be achieved; entry 2). Under similar conditions, primary alkyl alcohols mainly undergo H/D exchange at the α-carbon positions (entries 6 and 7). Secondary alkyl alcohols are less reactive than primary alcohols. When the reaction was carried out for 3.5 h, the H/D exchange reaction mainly occurred at the β-carbon positions (entry 8). Higher contents of deuterium could be achieved by increasing the reaction time. For example, the reaction of cyclohexanol for 3.5 h produced partially deuterated cyclohexanol with 14% and 32% deuterium, respectively, at the α- and β-carbon positions (entry 8), and that for 10.5 h produced partially deuterated cyclohexanol with 71% and 72% deuterium, respectively, at the α- and β-carbon positions (entry 9). The reaction involving 1-(4-pyridinyl)ethanol gives an unsatisfactory result (entry 10). The lower reactivity is likely due to the coordination of pyridine to ruthenium, which deactivates the catalyst. Further support for the capability of RuCl2(2-H2NCH2Py)(PPh3)2 to induce deuteration of alcohols with D2O at α-carbon positions comes from the reaction of benzyl alcohol (PhCH2OH) with D2O under similar reaction conditions, which produced partially deuterated benzyl alcohol (PhCD2OH) with 89% deuterium at the α-carbon positions (entry 12). Proposed Reaction Mechanisms. It is interesting to note that (η6-cymene)Ru systems such as (η6-cymene)RuCl2/ NH2CH2CH2OH, (η6-cymene)RuCl(NH2CH2CH2NTs) and (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} induced regioselective deuteration of alcohols with deuterium oxide only at the β-carbon positions, whereas octahedral complexes such as RuCl2(2-NH2CH2Py)(PPh3)2 and RuCl2(NH2CH2CH2NH2)(PPh3)2 catalyzed regioselective deuteration of alcohols with deuterium oxide at both the α- and β-carbon positions. C o n s i d e r i n g t h e f a c t t h a t ( η 6 -c y m e n e) R uC l 2 / NH2CH2CH2OH is an efficient catalyst for transfer hydrogenation reactions,21 we have proposed previously that the reaction catalyzed by (p-cymene)RuCl2/NH2CH2CH2OH may proceed through reversible dehydrogenation of alcohols and hydrogenation of carbonyl compounds and H/D exchange reactions between D2O and carbonyl compounds generated in situ in an alkaline medium. Since both (η6-cymene)RuCl(NH2CH2CH2NTs)22 and (η6-cymene)Ru{(S,S)NHCHPhCHPhNTs}23 are also good catalysts for transfer hydrogenation reactions, a similar mechanism can be proposed E


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either the presence or absence of a base25a and catalytically active for hydrogenation of PhC(O)Me.25b We have shown that the dihydride complex c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6) has activity similar to that of RuCl2(2-NH2CH2Py)(PPh3)2 in inducing H/D exchange reactions between alcohols and D2O. Thus, it is reasonable to assume that the dihydride complex RuH2(2-NH2CH2Py)(PPh3)2 is the active species in the present H/D exchange reactions. In a hydrogenation reaction, the thermodynamically less stable isomer of the hydride complex t,c-RuH2(PPh3)2(2-NH2CH2Py) was proposed to be the active species, which can reduce carbonyl compounds via an outer-sphere mechanism. Our computational work confirms that the reaction of t,c-RuH2(2-NH2CH2Py)(PMe3)2 with acetone is indeed kinetically more favorable than that of c,t-RuH2(2-NH2CH2Py)(PMe3)2 (see below). Thus, we propose that the dihydride complex t,c-RuH2(2-NH2CH2Py)(PPh3)2 is involved in the transfer hydrogenation reaction. Since c,t-RuH2(2-H2NCH2Py)(PPh3)2 (6) is thermodynamically more stable than t,c-RuH2(2-H2NCH2Py)(PPh3)2, it is also possible that the H/D exchange reaction of the hydride species may involve isomerization of t,c-RuH(D)(2-D2NCH2Py)(PPh3)2 (11) to c,t-RuH(D)(2-D2NCH2Py)(PPh3)2 (12), which undergoes H/D exchange with D2O to give c,t-RuD2(2D2NCH2Py)(PPh3)2 (7), followed by isomerization of 7 to give t,c-RuH(D)(2-HDNCH2Py)(PPh3) (8). H/D Exchange Reactions of Hydride Complexes with D2O. The key difference in the proposed mechanisms for reactions catalyzed by the η6-cymene complex (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} (Scheme 1) and the octahedral amine complex RuCl2(2-NH2CH2Py)(PPh3)2 (Scheme 2) is that the hydride ligand of the complex (η6-cymene)RuH((S,S)NH2CHPhCHPhNTs) (13) undergoes an H/D exchange reaction with D2O less readily than does c,t-RuH2(2NH2CH2Py)(PPh3)2. To confirm this hypothesis, we have studied H/D exchange reactions of the complexes (η6cymene)RuH{(S,S)-NH2 CHPhCHPhNTs} (13) and c,tRuH2(2-NH2CH2Py)(PPh3)2 (6) with D2O or CH3OD. The 1 H NMR spectrum of a C6D6 solution of the ruthenium complex c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6) mixed with 200 equiv of D2O collected immediately (ca. 2 min) after the reagents were mixed indicated that the NH2 proton signal disappeared completely and the intensity of the RuH signal was decreased by more than 90%. After the solution stood at room temperature for 20 min, nearly no RuH signal could be observed. The observation clearly suggests that the NH2 group and the hydride ligands of c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6) can undergo rapid H/D exchange with D2O to give the deuterated complex RuD2(2-D2NCH2Py)(PPh3)2 (7) (Scheme 3). On the other hand, while the NH2 group of (η6cymene)RuH{(S,S)-NH2CHPhCHPhNTs} (13) underwent rapid H/D exchange with D2O or CD3OD, the hydride ligand of the complex 13 did not undergo H/D exchange reactions under similar conditions. For example, the NH2 proton signals disappeared completely, while the intensity of the hydride signal of 13 did not change appreciably after its C6D6 solution containing ca. 200 equiv of CD3OD stood at room temperature for 3 h or was heated at 80 °C for 3 h (Scheme 3). Computational Studies on H/D Exchange Reactions of Hydride Complexes with D2O. To understand why the hydride ligand of the complex (η6-cymene)RuH{(S,S)NH2CHPhCHPhNTs} (13) undergoes H/D exchange less readily than those of c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6), a computational study was carried out. In our computational

Scheme 2. Proposed Mechanism for the H/D Exchange Reaction of PhCH2CH2OD with D2O To Give PhCD2CHDOD Catalyzed by RuCl2(2-NH2CH2Py)(PPh3)2

RuD2(2-D2NCH2Py)(PPh3)2 (8). The partially deuterated aldehyde PhCD2CHO is then reduced by the deuteride complex 8 via the transition state 10′ to give the deuterated alcohol PhCD2CHDOD and regenerate the active species 9. The mechanism was proposed based on the following reasons. It is known that the dichloro complex RuCl2(2NH2CH2Py) (PPh3)2 (5) can be used as a catalytic precursor for transfer hydrogenation of PhC(O)Me with 2-propanol in the presence of NaOH.25a It has also been reported that the related monohydride complex RuHCl(2-NH2CH2Py)(PPh3)2 can react with NaOCHMe2 to give the dihydride complex c,tRuH2(2-NH2CH2Py)(PPh3)2 (6), which is catalytically active for transfer hydrogenation of PhC(O)Me with 2-propanol in F


Article

Organometallics

substantially high barrier of 35.2 kcal/mol, although the interconversion of 17 and 17′ via transition states TS17‑18 and TS18‑17′ (responsible for switching the positions of H of Ru−H and D of D2O) involves small barriers. From 16, the H/D exchange reaction of Ru−H with D2O could proceed through transition state TS16‑16′ or the η2-HD complex 19. The H/D exchange reaction involving TS16‑16′ has a very high barrier of 52.4 kcal/mol from 16. Switching the positions of H/D in 19 can proceed through dissociation and association of HD via complex 20 and transition states TS19‑20 and TS20‑19′. However, complex 19 is 28.1 kcal/mol in free energy above 16 (or 33.4 kcal/mol in free energy above 15). Formation of 19 from 16 also has a high barrier of 31.2 kcal/mol. In addition, our calculations show that 20 can evolve to the thermodynamically more stable (by 5.8 kcal/mol) hydroxyl complex (η6-C6H6)Ru(OH)(NH2CH2CH2NSO2Me) (see Figure S3 in the Supporting Information), which will make the H/D exchange reaction involving 20 more difficult. The high energies of the intermediates and transition states as well as the high overall reaction barriers indicate that the H/D exchange reaction of the Ru−H of 14 with D2O cannot proceed easily, in agreement with our experimental observations. It has been reported that protonation of [(η6-cymene)RuH(dmbpy)]+ by H+ (solvated with three water molecules) to give a dihydrogen complex is slightly endergonic by 4.6 kcal/mol with a barrier of 7.6 kcal/mol.2t The protonation reaction of 14 was not considered in our present system because our reaction medium is not acidic.

Scheme 3. H/D Exchange Reactions of Hydride Complexes 6 and 13

studies, (η6-cymene)RuH{(S,S)-NH2CHPhCHPhNTs} (13) and c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6) were modeled by (η6-C6H6)RuH(NH2CH2CH2NMs) (14; Ms = SO2Me) and c,t-RuH2(2-NH2CH2Py)(PMe3)2 (21), respectively. The calculated energy profile for the H/D exchange reaction of the model complex (η6-C6H6)RuH(NH2CH2CH2NMs) (14) with D2O is shown in Figure 1. Two hydrogen-bonded species, namely 15 and 16, were found from the initial interaction of (η6-C6H6)RuH(NH2CH2CH2NSO2Me) (14) with D2O. The hydrogen-bonded species 15 and 16 are 7.2 and 1.9 kcal/mol in free energy below 14 + D2O. From 15, the H/D exchange reaction of Ru−H with D2O could proceed through complex 17. Complex 17 is 27.1 kcal/mol in free energy above 15. The transformation of 15 to 17 has a

Figure 1. Energy profile calculated for the H/D exchange reaction of (η6-C6H6)RuH(NH2CH2CH2NMs) (14) with D2O. The relative free energies and electronic energies (in parentheses) are given in kcal/mol. G


Article

Organometallics

Figure 2. Energy profile calculated for the H/D exchange reaction of c,t-RuH2(2-NH2CH2Py)(PMe3)2 (21) with D2O. The relative free energies and electronic energies (in parentheses) are given in kcal/mol.

very small barrier of 3.3 kcal/mol. The reverse process starting from 25′ instead of 25 will generate a partially deuterated 21 with a deuteride cis to the pyridine nitrogen. The low overall barrier (24.1 kcal/mol) for H/D exchange involving η2-HD intermediates indicates that H/D exchange reaction of c,tRuH2(2-NH2CH2Py)(PMe3)2 (21) with D2O can proceed easily through intermediates 23−25, consistent with experimental observations. We have also calculated the reaction energy profile for the H/D exchange reaction of D2O with the complex t,c-RuH2(2NH2CH2Py)(PMe3)2 (21-trans), a model complex for t,cRuH2(2-NH2CH2Py)(PPh3)2. As expected, the complex can also undergo H/D exchange reaction with a reaction barrier similar to that of 21 (see the Supporting Information). The above computational results confirm that the hydride ligand of RuH2(2-NH2CH2Py)(PPh3)2 can undergo H/D exchange with D2O more readily than that of (η6-cymene)RuH{(S,S)-NH2CHPhCHPhNTs} (13). The difference can be related to the relative ease of the hydride complexes to react with water to generate dihydrogen complexes. The octahedral complex RuH2(2-NH2CH2Py)(PPh3)2 can easily undergo H/D exchange with D2O, because it can be protonated by D2O to give a Ru(η2-HD) intermediate. (η6-cymene)RuH{(S,S)NH2CHPhCHPhNTs} (13) undergoes an H/D exchange reaction with D2O less readily, as the Ru(η2-HD) intermediates are not easily accessible. In a related study, Jalón, Lledós, and their co-workers recently reported that the hydride complex [(η6-cymene)RuH(dmbpy)]+ undergoes H/D exchange readily with D2O in acidic medium to give [(η6-cymene)RuD-

The calculated energy profile for the reaction of the model complex c,t-RuH2(2-NH2CH2Py)(PMe3)2 (21) with D2O is shown in Figure 2. Reaction of c,t-RuH2(2-NH2CH2Py)(PMe3)2 with D2O initially produces the two hydrogen-bonded species 22 and 23. The hydrogen-bonded species 22 and 23 are 3.9 and 7.5 kcal/mol in free energy below 21 + D2O. From 22, the H/D exchange reaction of Ru−H with D2O could proceed through the transition state TS22‑22′. Calculations show that the H/D exchange reaction involving TS22‑22′ has a very high barrier of 43.2 kcal/mol. The high barrier suggests that the H/ D exchange reaction is unlikely to occur through this pathway. From 23, the H/D exchange reaction could proceed through 23′ via the transition state TS23‑23′ or through generation of the η2-HD complexes 24 and 25. The H/D exchange reaction through TS23‑23′ also has a very high barrier (50.5 kcal/mol). On the other hand, the process through the η2-HD complexes was found to have much lower barriers. The η2-HD complex 24, which is 14.7 kcal/mol in free energy above complex 23, can be generated via the transition state TS23‑24 with a barrier of 24.1 kcal/mol. The H and D atoms of the η2-HD ligand in 24 can easily exchange their positions to give 24′ by rotation of HD about the M−(HD) bond through the transition state TS24‑24′ with a barrier of 5.2 kcal/mol. The reverse process starting from 24′ instead of 24 will generate a partially deuterated 21 with a deuteride trans to the pyridine nitrogen. The η2-HD intermediate 25, which is 12.5 kcal/mol in energy above complex 23, can be generated from 24′ via the transition state TS24′‑25 barrierlessly. Again, the barrier for conversion of 25 to 25′ by rotation of HD about the M−(HD) bond has a H


Article

Organometallics (dmbpy)]+.2t It was found that the H/D exchange reaction also proceeds through Ru(η2-HD) species and the reaction played an key role in alcohol deuteration at the α-carbon positions by transfer hydrogenation of ketones using HCOOH/HCOONa in D2O. Computational Studies on Hydrogen Transfer Reactions. Dehydrogenation of alcohols and hydrogenation of carbonyl compounds are also important steps in the proposed mechanisms. It is therefore of interest to compare the relative ease of these processes with H/D exchange reactions of hydride species with D2O. Figure 3 shows the reaction energy profile calculated for the hydrogenation of acetone by the model complex (η6-C6H6)-

reactions are 22.9 kcal/mol (from 26) and 16.7 kcal/mol (from 28), respectively. It is noted that the energy (29.0 kcal/mol) of the ratedetermining transition state for the hydrogenation/dehydrogenation/dehydrogenation reaction (TS26‑27, Figure 3) mediated by 14 is substantially lower than those (>35 kcal/mol) for the H/D exchange reaction (TS15‑17, TS16‑16′, TS16‑19 in Figure 1) of 14 with D2O. The results suggest that hydrogenation of carbonyl compounds and dehydrogenation of alcohol mediated by 14 will proceed more easily than the H/D exchange of the hydride complex 14 with D2O. The computational results are in good agreement with our experimental observations that the α protons of alcohols do not undergo H/D exchange with D2O in the reactions catalyzed by (η 6 -cymene)RuH{(S,S)NH2CHPhCHPhNTs}. The hydride complex RuH2(2-NH2CH2Py)(PPh3)2 has cis and trans isomers. The most stable isomer is c,t-RuH2(2NH2CH2Py)(PPh3)2 (6), and the least stable isomer is t,cRuH2(2-NH2CH2Py)(PPh3)2, which has not been observed experimentally but was suggested as the active species for hydrogenation of carbonyl compounds.25b Our computational study suggests that c,t-RuH2(2-NH2CH2Py)(PMe3)2 (21), a model complex for c,t-RuH2(2-NH2CH2Py)(PPh3)2 (6), is 7.2 kcal/mol more stable than t,c-RuH2(2-NH2CH2Py)(PMe3)2 (21_trans), a model complex for t,c-RuH2(2-NH2CH2Py)(PPh3)2, which can be obtained from isomerization of 21 with an overall barrier of 22.8 cal/mol (see the Supporting Information for details). In principle, the hydrogenation can involve any of the isomers of RuH2(2-NH2CH2Py)(PPh3)2. Our computational study reveals that hydrogenation of acetone by the model complex t,c-RuH2(2-NH2CH2Py)(PH3)2 (21_trans) is both thermodynamically and kinetically more favorable than that involving c,t-RuH2(2-NH2CH2Py)(PH3)2 (21), supporting Morris’s proposal that t,c-RuH2(2-NH2CH2Py)(PPh3)2 is the active species for hydrogenation of carbonyl compounds.25b Figure 4 shows the reaction energy profile calculated for hydrogenation of acetone by the model complex RuH2(2NH2CH2Py)(PMe3)2. The hydrogenation of acetone by the

Figure 3. Energy profile calculated for the hydrogenation reaction of (η6-C6H6)RuH(NHCH2CH2NHSO2Me) (14) with acetone. The relative free energies and electronic energies (in parentheses) are given in kcal/mol.

RuH(NHCH2CH2NHSO2Me) (14) to give amide complex 28 and (CH3)2CHOH. The reaction is slightly endergonic by 5.1 kcal/mol. The activation barriers for the forward and reverse

Figure 4. Energy profile calculated for the hydrogenation reaction of RuH2(2-NH2CH2Py)(PMe3)2 with acetone. The relative free energies and electronic energies (in parentheses) are given in kcal/mol. I


Organometallics

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model complex c,t-RuH2(2-NH2CH2Py)(PMe3)2 (21) to give 2-propanol and the amido complex 32 (via TS30‑31 and intermediates 30 and 31) is endergonic by 30.2 kcal/mol. On the other hand, the hydrogenation of acetone by the model complex t,c-RuH2(2-NH2CH2Py)(PMe3)2 (21-trans) to give 2propanol and the five-coordinate amido complex 35 is exergonic by 5.7 kcal/mol. The barrier for the forward reaction is 9.6 kcal/mol from 21-trans or 16.8 kcal/mol from 21. The barrier for the reverse reaction is 15.3 kcal/mol from 35. The results are in good agreement with those reported by Morris et al. for the reaction of acetone with the model complex c,tRuH2(2-NH2CH2Py)(PH3)2.25c It is noted that the energy of the rate-determining transition state (TS33‑34) for the hydrogenation/dehydrogenation reaction (24.3 kcal/mol; Figure 4) is comparable to that of TS23‑24 for the H/D exchange reaction (24.1 kcal/mol; Figure 2). The results suggest that hydrogenation of carbonyl compounds and dehydrogenation of alcohol mediated by the hydride complex 21 could proceed at a rate similar to that of the H/D exchange reaction of the hydride complex 21 with D2O, consistent with our experimental observations that that the α protons of alcohols can also undergo H/D exchange with D2O in reactions catalyzed by RuCl2(2-NH2CH2Py)(PPh3)2.

Article

EXPERIMENTAL SECTION

All manipulations were carried out under a nitrogen atmosphere using standard Schlenk techniques unless otherwise stated. Solvents were distilled under nitrogen from sodium/benzophenone (n-hexane, diethyl ether, THF), or calcium hydride (dichloromethane). Other solvents were purged with nitrogen for 10 min before use. The complexes CpRuCl(PPh3)2,26 Cp*RuCl(PPh3)2,27 (η5-indenyl)RuCl(PPh3)2,28 RuCl2(DMSO)4,29 RuHCl(CO)(PPh3)3,30 RuCl2(PPh3)3,31 RuCl2(2-PyCH2NH2)(dppf),32 RuCl2(NH2CH2CH2NH2)(PPh3)2,33 RuHCl{(R,R)-dach}(PPh 3 ) 2 , 34 RuCl2 (2-H2 NCH 2 Py)(PPh 3 ) 2 , 25a RuHCl(2-H2NCH2Py)(PPh3)2,25a RuH2(2-H2NCH2Py)(PPh3)2,25a (p-cymene)RuCl2(PPh3),35 and (η6-cymene)Ru{(S,S)NHCHPhCHPhNTs}23a were synthesized according to reported procedures. Deuterium oxide, 99.9 atom % D, was purchased from Aldrich Chemical Co. and used as received. All other reagents were used as purchased from Aldrich Chemical Co., Acros Organics, International Laboratory, or Kodak. 1H and 13C{1H} NMR spectra were collected on a Bruker ARX 300 MHz spectrometer or a Bruker AV 400 MHz spectrometer. 2D NMR spectra were collected on a Bruker AV 400 MHz spectrometer. General Procedure for the H/D Exchange Reactions between PhCH2CH2OH and D2O in the Screening Experiments (for Entries in Table 1). A mixture of a ruthenium complex (0.04 mmol), KOH in D2O (1.84 M solution, 110 μL, 0.20 mmol), 2phenylethanol (240 μL, 2.0 mmol), and D2O (720 μL, totally 830 μL, 45.87 mmol) was heated at 80 °C for 3.5 h. The resulting solution was analyzed by 1H NMR. The percentage of deuterium incorporated was estimated on the bsis of 1H NMR integrations. General Procedure for H/D Exchange Reactions between Alcohols and D2O Catalyzed by RuCl2(PPh3)2(2-NH2CH2Py) (for Entries in Table 2). In a Schlenk tube charged with RuCl2(2NH2CH2Py)(PPh3)2 (32 mg, 0.04 mmol) and alcohol (2 mmol) were placed KOH in D2O (110 μL, 1.84 M, 0.2 mmol) and D2O. The molar ratio of substrate and D2O was chosen such that the expected percentage of deuterium incorporation at the α- and β-carbon positions is about 90%. The mixture was heated at 80 °C for a period of time. The progress of the reaction was monitored by 1H NMR. After the reaction was completed, the product was extracted with diethyl ether, washed with water, and purified by column chromatography. The product was analyzed by 1H and 2D NMR. The percentage of deuterium incorporated was estimated on the basis of 1H NMR integrations. General Procedure for H/D Exchange Reactions between Alcohols and D2O Catalyzed by (η6-cymene)Ru{(S,S)-NHCH(Ph)CH(Ph)NTs}. In a Schlenk tube charged with (η6-cymene)Ru{(S,S)-NHCH(Ph)CH(Ph)NTs} (8 mg, 0.013 mmol) and an alcohol (0.66 mmol) were placed KOH in D2O (36 mL, 1.84 M, 0.066 mmol) and D2O. The molar ratio of the substrate and D2O was chosen such that the expected percentage of deuterium incorporated at the α- and β-carbon positions is about 90%. The mixture was heated at 80 °C for 3.5 h. The resulting solution was analyzed by 1H NMR, and the percentage of deuterium incorporated was estimated on the basis of 1 H NMR integrations. H/D Exchange between (p-cymene)RuH{(S,S)H2NCHPhCHPhNTs} and D2O. About 0.02 mL of 2-propanol (0.262 mmol) was placed in an NMR tube containing (p-cymene)Ru{(S,S)-HNCHPhCHPhNTs} (8 mg, 0.013 mmol) and 0.4 mL of C6D6. The purple solution turned red in 20 min, indicating the formation of (p-cymene)RuH{(S,S)-H2NCHPhCHPhNTs}.23a Then 0.1 mL of MeOD-d4 (2.462 mmol) was added. 1H NMR spectra of the solution were collected after the solution stood at room temperature for 30 min and 3 h and heated for 30 min, 3 h, and overnight. The 1H NMR spectra displayed no NH2 peak at 2.79 and 5.29 ppm, suggesting that the NH2 protons undergo rapid exchange with MeOD-d4. The relative intensities of the RuH signal (at −5.25 ppm) in comparison to that of CH on p-cymene at 4.62 ppm did not change appreciably. H/D Exchange between RuH2(2-NH2CH2Py)(PPh3)2 and D2O. About 0.05 mL of D2O (2.763 mmol) was placed in an NMR tube containing RuH2(2-NH2CH2Py)(PPh3)2 (10 mg, 0.0136 mmol) and 0.4 mL of C6D6. 1H NMR spectra of the solution were collected after

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CONCLUSION We have studied the catalytic properties of a series of ruthenium complexes for H/D exchange between D2O and alcohols. The catalytic activity of the ruthenium complexes and the regioselectivity of the H/D exchange reactions between D2O and alcohols are dependent on the auxiliary ligands. Ruthenium p-cymene complexes supported by an amine ligand such as [(p-cymene)RuCl(NH2CH2CH2NTs)]Cl and (η6cymene)Ru{(S,S)-NHCHPhCHPhNTs} were found to be able to catalyze regioselective deuteration of alcohols with deuterium oxide at the β-carbon positions only. In contrast, octahedral ruthenium complexes supported by an amine ligand such as RuCl2(2-NH2CH2Py)(PPh3)2 (2-NH2CH2Py = 2aminomethylpyridine) and RuCl2(NH2CH2CH2NH2)(PPh3)2 catalyzed regioselective H/D exchange reactions between D2O and alcohols at both the α- and β-carbon positions of alcohols. The H/D exchange reactions proceed through reversible dehydrogenation of alcohols and hydrogenation of carbonyl compounds involving hydride species and H/D exchange among D2O and carbonyl and hydride species. Experimental and computational studies suggest that the different regioselectivities of the H/D exchange reactions can be related to the relative ease of exchange reactions of ruthenium hydride intermediates with D2O. In the case of octahedral ruthenium complexes supported by an amine ligand, ruthenium hydride intermediates can undergo H/D exchange with D2O via Ru(η2-HD) intermediates with a barrier similar to that of hydrogenation. Thus, H/D exchange can take place at both α- and β-carbon positions. In the case of ruthenium pcymene complexes supported by an amine ligand, Ru(η2-HD) intermediates are not easily accessible and the barrier for H/D exchange between ruthenium hydride intermediates with D2O is substantially higher than that of hydrogenation. Thus, H/D exchange can only take place at β-carbon positions. It is noted that Jalón, Lledós, and their co-workers recently reported that Ru(η2-HD) species also play an key role in alcohol deuteration by transfer hydrogenation of ketones using HCOOH/ HCOONa in D2O.2t J


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the solution stood at room temperature for a period of time. The relative intensities of the RuH (at −18.12 and −16.20 ppm) and NH2 signals (at 2.86 ppm) were measured relative to that of CH2. The relative intensities of the NMR signals are as follows: 2 min after mixing with D2O, CH2 2.0 H, NH2 0 H, RuH 0.05 H; 20 min after mixing with D2O, CH2 2.0 H, NH2 0 H, RuH 0 H. Computational Details. All structures were optimized without any constraint at the B3LYP level of density functional theory.36 Frequency calculations were also performed to identify all the stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency) and to provide free energies at 298.15 K. In the calculations, all of the deuterium atoms were replaced by hydrogen atoms on the basis of the fact that H and D share the same electronic and chemical properties. The standard 6-31G* basis set was used for C, N, O, and H atoms. The effective core potentials (ECPs) of Lanl2dz were used to describe Ru, S, and P atoms,37 with polarization functions for Ru (ζ(f) = 1.235), S (ζ(d) = 0.503), and P (ζ(d) = 0.387) being added.38 To reduce the overestimation of the entropy contribution in the gas-phase results, corrections of −2.6 kcal/ mol in free energies were made for 2:1 transformations.39 This correction was employed in a number of earlier expected studies.40 All of the calculations were performed with the Gaussian 03 software package.41 To verify that the relative free energies do not change significantly when the calculations are done with solvation and dispersion effects included, we carried out single-point energy calculations in solvent at the B3LYP-D3 level with the same basis set on the selected optimized structures TS15‑17, TS16‑19, and TS23‑24.42 The conductor-like polarizable continuum model (CPCM) was used in the single-point energy calculations, where water was employed as the solvent according to the reaction conditions, and the solute surface was defined by UAKS radii.43−46 These additional calculations were performed with the Gaussian 09 (rev. D.01) package.47 The solvation and dispersion corrected free energies of the selected structures with respect to the energy reference point are approximately the same as the free energies obtained in the gas-phase calculations. For example, the free energies calculated for TS15‑17, TS16‑19, and TS23‑24 in the gas phase with respect to the reference point are 35.2, 36.5, and 24.1 kcal/mol, respectively, while the solvation and dispersion-corrected free energies are 37.0, 36.1, and 26.1 kcal/mol, respectively. The small differences in the free energies obtained between the two methods do not change the whole picture and conclusions. In other words, the effects of solvation and dispersion on the relative free energies are small. Thus, the free energies obtained in gas-phase calculations were used in this article.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

Text, figures, and XYZ files givng experimental details and spectroscopic data, supplementary computational results, and Cartesian coordinates and electronic energies for all of the calculated structures. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00134.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for Z.L.: [email protected]. *E-mail for G.J.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Hong Kong Research Grants Council (Project No.: 602611, 601812, 602113, CUHK7/ CRF/12G-2). K


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