Mechanistic Studies on the pH-Controllable Hydrogenation of NAD+

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Mechanistic Studies on the pH-Controllable Hydrogenation of NAD+ by H2 and Generation of H2 from NADH by a Water-Soluble Biomimetic Iridium Complex J. Vijaya Sundar and V. Subramanian* Chemical Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India S Supporting Information *

ABSTRACT: Functional biomimicking of hydrogenases at ambient conditions is challenging. Recently an Ir(III)-cyclometalated complex (J. Am. Chem. Soc. 2012, 134, 367) has been shown to catalyze the pHdependent reversible reduction of NAD+ (nicotinamide adenine dinucleotide) by dihydrogen in water medium. Yet, the reaction mechanism for the catalysis has not been unravelled comprehensively. Hence in this work, mechanisms for catalytic hydrogenation of NAD+ to the reduced form of NAD+ (NADH) and the reverse reaction catalyzed by the Ir(III)-cyclometalated complex have been proposed using the results obtained from density functional theory based calculations. The mechanism suggests that the carboxylate group of the Ir(III) complex can act as a proton relay between hydrogen and water molecules. As a consequence, the direction of the reaction is controlled by the pH of the medium. Splitting of H2 and generation of H2 are the rate-determining steps in the two directions with the same activation barrier height of 34.6 kcal/mol. Also, the mechanism supports that the σ-bond metathesis is preferred over oxidative addition of hydrogen. Results show that NADH may act as an inhibitor of the substrate at high basic pH.

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INTRODUCTION Hydrogen is considered to be one of the cleanest fuels with high energy content for future energy needs. Hydrogen production, storage, and utilization have been the major concerns of the research community today. It can be produced by the electrolysis or photocatalytic splitting of water. But major production of hydrogen worldwide comes through the steam reforming of coal gas.1−5 The H2 produced is then oxidized to water in fuel cells to generate electricity. The catalysts used for this process are derived from high-cost noble metals such as Pt. Hence there is a need to develop environmentally friendly techniques for efficient production and activation of hydrogen with low cost.6,7 One of the means to unravel the various bottlenecks in the production and utilization of H2 is to understand the corresponding biological processes carried out by Mother Nature. A wide variety of organisms such as methanogenic, acetogenic, and nitrate- and sulfate-reducing bacteria; anaerobic archaea, rhizobia, protozoa, and fungi; and anaerobically adapted algae metabolize molecular dihydrogen. Anaerobic organisms perform fermentation of carbohydrates, lipids, etc., and generate dihydrogen. On the other hand, organisms such as methanogenic archaea utilize hydrogen as an energy source. The enzyme responsible for this uptake and generation of hydrogen is known as hydrogenases.8−11 Hydrogenases catalyze the reversible conversion of dihydrogen into protons and electrons. They utilize NAD+ as its cofactor for coupling the © XXXX American Chemical Society

electrons. These are multisite redox enzymes utilizing Fe and Ni ions as their redox centers.12−15 Especially, Fe−Fe hydrogenase and Ni−Fe hydrogenase have been studied by both experimental16−22 and theoretical methods.23−31 These enzymes could be used to couple the protons and electrons generated from artificial photosynthetic systems to form dihydrogen and also to oxidize hydrogen into protons for the production of energy. These enzymes are already used for the production of hydrogen from biomass32−34 and also employed in the field of chemoenzymatic reactions.35,36 Attempts have been made to design and develop metal complexes that can carry out functions of hydrogenases.37−39 The biomimics of H2-ases are of two types: (i) structural mimics and (ii) functional mimics. Numerous experimental studies have been performed on biomimetics of H2-ases.40−44 Theoretical calculations on such structural mimics have also been made to understand the catalysis.45−51 It is found from previous studies that only a few systems have a catalytic performance comparable to that of hydrogenases.40,41 Therefore compounds containing different metals with different ligands have been studied for H2-ase activity.52 Various metal complexes have been found to have H2-ase activity. But they work either at high temperature or in organic solvents.53−56 Received: August 22, 2012

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dx.doi.org/10.1021/om300812k | Organometallics XXXX, XXX, XXX−XXX

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Figure 1. Optimized structure of compound 1 at the level of M06-2X/6-31G* (SDD for Ir) and important geometrical parameters from calculated and experimental results for comparison.

Figure 2. Acid−base equilibria for compound 1. calculation of barrier heights. Geometries on the minimum energy reaction path were then reoptimized with M06-2X/6-311G** (SDD for Ir atom). The intermediates and transition states were characterized by zero imaginary frequency and single imaginary frequency criterion. Single-point calculations were also performed at the level of M06-2X/6-311G** (SDD for Ir atom) with the PCM model68 (ε = 80) to understand the effect of solvent environment on the reaction mechanism. All energies were corrected for zero-point energy. NBO analysis was also carried out to characterize the differences between the various associative pathways.69,70 All calculations were carried out using the Gaussian 09 suite of program.71

Hence, the design and development of functional mimics at ambient conditions in water medium are necessary. In this regard, Fukuzumi et al. reported a functional mimic of hydrogenases, a water-soluble iridium aqua complex, [Ir III (Cp*)-(4-(1H-pyrazol-1-yl-κN 2 )benzoic acid-κC 3 )(H2O)]2SO4 (compound 1).57−59 It contains both Cp* and a [C,N] cyclometalated ligand. A variety of reactions have been catalyzed by compound 1 including reduction of carbon dioxide with dihydrogen and hydrogen evolution from alcohols. This complex also catalyzes both the hydrogenation of NAD+ by H2 to produce protons and NADH and generation of H2 from NADH and protons, under atmospheric pressure at room temperature.57 One of the interesting features of this catalytic reaction is that the direction of the reaction is controlled by the pH of the medium. When the pH of the medium is slightly basic, compound 1 catalyzes the formation of NADH from H2 and NAD+. When the medium is neutral or slightly acidic, the reverse of the above reaction takes place.57 As this reaction could be useful for generating H2 in biobased hydrogen fuel cells, a systematic understanding of the reaction mechanism is necessary. Hence, in this investigation an attempt has been made to (i) explore different competing pathways for the above reactions in acidic and basic conditions, (ii) understand the role of the carboxylic acid group in the catalysis, (iii) unravel the minimum energy path for the activation of H2, and (iv) delineate the effect of the solvent environment on the forward and backward reactions.

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RESULTS AND DISCUSSION As mentioned, Fukuzumi et al. have determined the structure of compound 1 by using X-ray diffraction techniques.57 It is found that compound 1 contains one bound water molecule. The optimized structure of compound 1 at the M06-2X/6-31G* (SDD for Ir atom) level of calculation is given in Figure 1. The comparison of important geometrical parameters obtained from experimental study57 with those of calculated values reveals that the predicted values are in good agreement with the experimental geometrical parameters. This evidence reveals that the level of calculation is sufficient to understand the above-mentioned reactions. Fukuzumi and co-workers have reported the acid−base equilibria of compound 1.57 The details of the acid−base equilibria of compound 1 are represented in Figure 2. In basic pH, the carboxylic acid group is deprotonated to give neutral species 2. Under high basic conditions, the bound water in compound 2 is deprotonated to form compound 3. It is found from the work of Fukuzumi et al. that compound 3 has low catalytic activity.57 The general mechanism for the catalysis under basic and neutral conditions is shown in Scheme 1. When hydrogen is added to compound 2 ([M − H2O]0) in basic medium, a Ir(III)−monohydride species is obtained ([M − H]−). Upon addition of NAD+ to the solution, the hydride is transferred to NAD+ to form NADH and compound 2 is restored. In neutral

COMPUTATIONAL DETAILS

The initial model for the complex was taken from the Cambridge Crystallographic Data Center (CCDC) (ID No. 814147).57 The M062X60−62 functional was used for all geometry optimizations, frequency and IRC calculations with the Stuttgart relativistic effective core potential, ECP60MWB, for Ir atom,63,64 and the 6-31G* basis set65−67 for all other atoms. The minimum energy structures on the IRC path were again optimized to their respective reactants and products for the B


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theoretically studied a similar kind of mechanism for the homolytic and heterolytic bond cleavage of dihydrogen by Niand Pd-based complexes.51 The competing pathways (pathways 1−5) of H2 splitting are displayed in Schemes 3−7. The optimized geometries of all transition states are represented in Figure 3. 1.1.1. Pathway 1. In pathway 1, we have interacted H2 directly with the Ir(III) center to unravel the possibility of oxidative addition. The detailed mechanism is presented in Scheme 3. The encounter complex, transition state, and product for pathway 1 are denoted as P1(E), P1(T), and P1(Pr), respectively. The optimized structures of P1(E), P1(T), and P1(Pr) along with geometrical parameters are given in the Supporting Information (Figure S1). It involves elimination of a bound water molecule from compound 2 followed by insertion of H2 to form P1(E). Then H2 splitting occurs through transition state P1(T) to form dihydride P1(Pr), where Ir(III) is oxidized to Ir(V). It can be seen from Figure 3a that in P1(T) the distance between hydrogen atoms (H−H) is 0.75 Å and the Ir−H distance is 2.42 Å. Figure 4a shows the energy profile for pathway 1. It can be noted that the activation barrier of H2 splitting is 40.5 kcal/mol and the product P1(Pr) is higher in energy than the encounter complex by 30.8 kcal/mol. The entropy changes accompanying H2 binding and H2 splitting along the reaction path were calculated. The results are listed in Table 2. The binding of H2 with compound 2 and H2 splitting results in an entropy loss of 90.2 and 44.9 J K−1 mol−1, respectively. 1.1.2. Pathway 2. In pathway 1, a dihydride complex is formed, which is not experimentally observed. Also, the above pathway does not take into account the pH of the medium. Hence, in pathway 2, one water molecule (W1) is added to study the same oxidative addition mechanism. The encounter complex, transition states, intermediate, and product are represented as P2(E), P2(T1), P2(T2), P2(I), and P2(Pr) for pathway 2. From Scheme 4, it could be visualized that the metal is oxidized from the +3 to the +5 oxidation state, upon H2 insertion, through the transition state P(T1) to form the intermediate P(I). Next the dihydride undergoes a dissociation in which one of the hydrogen atoms is transferred to the carboxylate group as a proton through W1. The transfer results in reduction of the metal from the +5 to the +3 oxidation state by the hydride bond. The optimized structures with geometrical parameters are shown in the Supporting Information (Figure S2). From Figure 3b, it can be noted that in P2(T1) the H−H distance is 0.97 Å, which indicates that cleavage of H2 takes place. The energy profile for pathway 2 (Figure 4b) indicates that the activation barriers for H2 splitting and proton transfer are 51.5 and 1.4 kcal/mol, respectively. As the

Scheme 1

conditions, compound 1 ([M − H2O]+) reacts with NADH to form Ir(III)−monohydride species with neutral charge ([M − H]0). After acidification, [M − H]0 releases H2 to form compound 1. To explore the molecular details of these reactions, various schemes are proposed in this investigation and illustrated in the following sections. 1. Catalytic Hydrogenation of NAD+. In basic medium, catalytic hydrogenation of NAD+ takes place via two steps: (i) H2 activation by compound 2 to form [M − H]− (step 1) and (ii) hydride transfer to NAD+ (reduction) to form NADH (step 2). 1.1. Step 1 (H2 Activation). Hydrogen could be activated by metal complexes by two different mechanism: (i) oxidative addition and (ii) σ-bond metathesis. These are illustrated in Scheme 2. In oxidative addition, H2 interacts directly with the metal through its σ-bond, and it is reduced to dihydride. During this reaction, oxidation of metal atom takes place. The σ-bond metathesis mechanism occurs by a concerted transfer of hydride to the metal and the proton to the metal ligand. Both of these mechanisms are taken onto account for studying the H2 splitting step. De Gioia et al. have proposed and Scheme 2

C


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Scheme 3

Scheme 4

geometrical parameters for pathway 3 are given in the Supporting Information (Figure S3). The inserted water molecule (W2) bridges the bound water molecule and carboxylate group through a H-bond. It can be observed that the hydrogen bond network paves the way for the activation of the bound water molecule. Unexpectedly, one of the hydrogen atoms in the bound water molecule is transferred to the carboxylate group through a H-bonded network without any activation barrier to form M−OH. All attempts to optimize P3(S1) failed, indicating the actual structure (P3(S2)) of compound 2 in water medium. P3(S2) upon addition of H2 forms an encounter complex P3(E), wherein H−H interacts with the O atom of M−OH through its antibonding (σ*)

oxidation state of Ir is restored in pathway 2, the product P2(Pr) is more stabilized when compared to P1(Pr). Table 2 shows that H2 binding with the substrate results in a change in entropy of −135.1 J K−1 mol−1. This indicates that there is a decrease in entropy upon binding with the metal compound. 1.1.3. Pathway 3. Pathway 3 follows a σ-bond metathesis mechanism in which H2 is activated by a metal−ligand bond. The metal ligand should be a proton acceptor. For this purpose a water molecule is inserted between the bound water molecule and carboxylate group of compound 2, as shown in Scheme 5. The substrates, encounter complex, transition state, and products are represented as P3(S1), P3(S2), P3(E), P3(T), and P3(Pr), respectively. The optimized geometries with D


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Scheme 5

Scheme 6

splitting is 89.6 and 10.1 J K−1 mol−1, respectively. This indicates that this pathway is entropically favored compared to oxidative addition. 1.1.4. Pathway 4. Based on the findings from the calculations in pathway 3, the role of solvent water molecules in activating the bound water molecule can be easily understood. Hence, the critical number of water molecules in H-bond network has to be investigated, which could lead to the lowest activation barrier. To study this problem, another water

orbital. It can be realized from the geometrical parameters of P3(T) that H2 splits into a proton and a hydride in which the metal accepts the hydride and the metal ligand (OH−) accepts the proton. This leads to the formation of Ir(III)− monohydride. The H−H and Ir−H distances in P3(T) are 2.42 and 1.14 Å, respectively. From Figure 4c, it can be noted that the activation barrier for P3(T) is 39.9 kcal/mol and the product is stabilized by −16.6 kcal/mol more than P3(E). The entropy loss accompanying H2 binding with P3(S2) and H2 E


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Scheme 7

represented in Scheme 8. The substrate, encounter complex, transition state, and product are represented as R(S), R(E), R(T), and R(Pr) in NAD+ reduction. The optimized structures with geometrical parameters are shown in the Supporting Information (Figure S6). When MNA is added to Ir(III)− monohydride (R(S)), the hydride interacts with the C−H bond present in the fourth position of the pyridine ring. Then hydride transfer occurs via a transition state (R(T)) with an activation barrier of 11.1 kcal/mol (Figure 5). The Ir−H and C−H distances in R(T) are 1.76 and 1.09 Å, respectively. The product (R(Pr)) energy is 9.7 kcal/mol higher than R(E). The entropy of activation for the formation of R(T) is −54.4 J K−1 mol−1, indicating that the hydride transfer is entropically less favored. 1.3. Salient Features of Hydrogenation of NAD+. It can be seen that various competing pathways exist for H2 splitting. The energies of all the structures are tabulated in Table 1. It can be noted that pathway 5 has the lowest activation barrier and higher stabilization of product. But experimentally it has been proved that the substrate for pathway 5 (compound 3) exists in highly basic medium and the rate of reaction drops at such pH. To explore this anomaly, various substrates (H2, MNA, reduced MNA) were made to interact with compound 3. It is found from interaction energy calculation that reduced MNA binds with compound 3 more than H2. The interaction energy for reduced MNA is −19.4 kcal/mol, whereas for H2 it is −3.6 kcal/mol. This indicates that reduced MNA can replace H2 and binds with compound 3, hence inhibiting the substrate of pathway 5. The optimized structure of P5(S1) complexed with MNA is given in the Supporting Information (Figure S8a). A similar type of inhibition can also occur by the interaction of P3(S2) with NADH. The possible interaction between P3(S2) and NADH was taken into account for the calculation of interaction energies. Figure S8b in the Supporting Information represents the interaction between P3(S2) and NADH. It could be noted that the amide group of NADH interacts with the carboxylate group of the Ir complex, and the conformation indicates that there is still a vacant site for the dihydrogen to

molecule is inserted into P3(S2) to form P4(S2). The same mechanism of pathway 3 has been studied (Scheme 6). The substrates, encounter complex, transition states, and products in pathway 4 are represented as P4(S1), P4(S2), P4(E), P4(T), and P4(Pr). The optimized structures with geometrical parameters are shown in the Supporting Information (Figure S4). Interestingly, addition of excess water molecules increases the barrier height to 42.8 kcal/mol (Figure 4d). This result indicates that increasing the number of water molecules in the network may tend to increase the barrier height. Hence, the optimal number of water molecules could be two including one bound water molecule. Table 2 shows that the entropy changes by −105 J K−1 mol−1 upon H2 binding with P4(S2). 1.1.5. Pathway 5. As the H-bonded metal−hydroxide ion (M−OH−) is the H2-activating ligand, it is desirable to study the effect of the metal-bonded OH− ion without any H-bond network. This type of metal−hydroxide (compound 3) is already shown in the acid−base equilibria of compound 1 (Figure 1). The mechanism of H2 activation by compound 3 is represented in Scheme 7. The encounter complex, transition state, and product in pathway 5 are represented as P5(E), P5(T), and P5(Pr). The optimized structures with geometrical parameters are shown in the Supporting Information (Figure S5). Upon insertion of H2, encounter complex P5(E) is formed, which undergoes a σ-bond metathesis reaction through transition state P5(T). The H−H bond dissociation distance is 1.35 Å, and formation of the Ir−H bond takes place at a distance of 2.32 Å. The activation barrier for the reaction is 34.3 kcal/mol (Figure 4e). The product P5(Pr) is highly stabilized by −25.5 kcal/mol. The entropy loss upon H2 binding with P5(S) is 111.9 J K−1 mol−1. From Table 2, it can be noted that the entropy of reaction highly favors pathway 5. 1.2. Step 2 (NAD+ Reduction). After the formation of Ir(III)−monohydride, the reduction of NAD+ takes place via a hydride transfer mechanism. Experiments showed that NAD+ has a high binding affinity toward [M − H]−. The model taken for mimicking NAD+ is 1-methylnicotinamide and is abbreviated as MNA. The hydride transfer is schematically F


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Figure 3. Optimized geometries of the transition states of all the pathways considered in this study.

pathway were optimized at the M06-2X/6-311G** (SDD for Ir) level of theory, and single-point PCM calculations were carried out at the same level with water as the medium. 2. Catalytic Dehydrogenation of NADH. In acidic medium, catalytic dehydrogenation of NADH takes place. This implies that the active substrate for the reaction is compound 1. This reaction takes place in two steps: (i) hydride transfer from NADH to form Ir(III)−monohydride and (ii) generation of H2.

bind with the H-bonded hydroxyl group. Therefore P3(S2) and NADH complex structure was interacted with dihydrogen. The optimized geometry is shown in Figure S8c. The calculated interaction energy for binding of H2 is −2.7 kcal/mol, whereas that for binding of P3(S2) with H2 is −3.7 kcal/mol. This reveals that the binding affinity of dihydrogen is lowered by the interaction of NADH with P3(S2). However, it is not inhibited. These findings imply that pathway 3 combined with NAD+ reduction is the most favorable one for the reaction in basic medium. Therefore geometries of the minimum energy G


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Figure 4. Relative energy profile for H2 splitting reaction.

Table 1. Relative Energies (kcal/mol) of All the Optimized Structures Calculated at the Level of M06-2X/6-31G* (SDD for Ir)a pathway 1 pathway 2 pathway 3 pathway 4 pathway 5 reduction of NAD+ oxidation of NADH

SUB

EC

TS1

IM1

TS2

Pr

b

0 0 0.3 (0.5) 0.5 0.1 0 0

40.5 51.5 39.9 (34.2) 42.8 34.3 11.1 (11.0) 4.7 (2.1)

b

b

48.6

49.9

b

b

b

b

b

b

b

b

b

b

30.8 5.2 −16.5 (−18.6) −9.9 −25.3 9.7 (9.6) 3.1 (−6.2)

b

0 0 0 b b

a

SUB, EC, TS1, IM1, TS2, and Pr represent the substrate, encounter complex, transition state 1, intermediate 1, transition state 2, and product, respectively. Values in parentheses are those calculated at M06-2X/6-311G** (SDD for Ir) with the PCM model. bIndicates the absence of structures in the proposed pathway.

H


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Table 2. Entropy Change (J K−1 mol−1) Accompanying H2 Binding with the Substrate, Barrier Crossing, and Conversion of Encounter Complex to Product Calculated at the Level of M06-2X/6-31G* (SDD for Ir)a

pathway 1 pathway 2 pathway 3 pathway 4 pathway 5 reduction of NAD+ oxidation of NADH

ΔSE = S(E) − (SUB + H2)

ΔS‡T1 = S(T1) − S(E)

−90.2 −135.1 −89.6 −105.4 −111.9 −209.9

−44.9 −4.2 −10.1 −5.2 −7.3 −54.4

−53.6

−8.5

ΔS‡T2 = S(T2) − S(I) b

−45.5 b b b b

b

ΔSR = S(Pr) − S(E) −65.9 8.6 −5.7 5.7 9.9 −39.7 −11.2

ΔS represents entropy change in J K−1 mol−1. SUB, E, T, I, and Pr represent the substrate, encounter complex, transition state, intermediate, and product for all pathways. bIndicates the absence of structures in the proposed pathway.

a

Figure 5. Energy profile for NADH formation.

distances are 1.67 and 1.09 Å, respectively. The product energy lies above that of O(E) by 3.1 kcal/mol. It can be noted from Table 2 that the entropy of activation for hydride transfer is −8.5 J K−1 mol−1. 2.2. Step 2 (H2 Generation). As the medium is acidic, the combination of acidic protons in the water and Ir(III)− monohydride is favored. But the carboxylic acid group can act as a better proton donor than water, because of the more ordered arrangement of water molecules required for the transfer of proton to the hydride. Since the proton of the carboxylic acid group cannot be transferred over a large space to the hydride, a water molecule is added in between, to connect them through a hydrogen-bonded network. The structure represents the geometry of the product obtained in pathway 3. Hence, it can be assumed that the H2 generation is

2.1. Step 1 (Oxidation Of NADH). The hydride transfer from 1-methyl-1,4-dihydronicotinamide (HMNA, model for NADH) to compound 1 takes place by the removal of a bound water molecule and addition of HMNA. The mechanism is shown in Scheme 9. The encounter complex, transition state, and product are denoted as O(E), O(T), and O(Pr) for the oxidation of NADH. The optimized structures with geometrical parameters are shown in the Supporting Information (Figure S7). It is the backward process of NAD+ reduction, except that in this case the carboxylate group is protonated. The encounter complex O(E) leads to the product O(Pr) by hydride transfer through the transition state O(T) with an activation energy of 4.7 kcal/mol (Figure 6). In O(T), the Ir−H and C−H Scheme 8

I


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Scheme 9

11.1 kcal/mol and the product lies above the encounter complex by 9.7 kcal/mol. For the dehydrogenation of NADH, the activation barrier decreases to 2.1 kcal/mol and stabilizes the product by −6.2 kcal/mol. In both cases, as H2 splitting and H2 generation are the rate-limiting steps, the aqueous environment decreases the barrier height of the overall reaction by 4.6 kcal/mol.

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CONCLUSION The mechanisms for the catalytic hydrogenation of NAD+ and H2 generation from NADH were proposed and studied using the M06-2X/6-311G**(PCM)//6-31G* (SDD for Ir) method. The results show that the direction of the reaction is controlled by the pH of the solution, wherein the carboxylate group acts as a proton relay. Both H2 splitting and H2 generation follow the same mechanism. The rate-determining steps for catalytic hydrogenation of NAD+ and catalytic dehydrogenation of NADH are H2 splitting and H2 generation, respectively, which are supported by experimental evidence.57 The mechanism indicates that the σ-bond metathesis mechanism is more favorable for H2 splitting than oxidative addition. Moreover, the lower catalytic activity at high basic pH can be explained through the inhibition of substrate by NADH. As the mechanism of proton relay is very important in controlling the reactions (pH dependent), these findings are useful in designing proton relays and metal ligand activation of H2.

Figure 6. Energy profile for oxidation of NADH.

the reversal of the H2 splitting mechanism, and it follows the same reaction pathway 3. 3. NBO Analysis. NBO charges were calculated for all pathways to characterize the difference between homolytic and heterolytic bond cleavage of dihydrogen. Tables S12−S18 in the Supporting Information show the NBO charge for Ir and first coordination sphere atoms. It can be noted from Tables S12−S13 that the charge on Ir decreases when it changes from the +3 to the +5 oxidation state. It may be due to the higher electronegativity of Ir(V). Hence the charges on hydrogen are taken into account to describe the oxidative addition and metathesis reaction. In pathway 1, the charge on dihydrogen at the transition state is positive and nearly zero (0.07, 0.03). This implies that the splitting occurs by homolytic cleavage of dihydrogen. From Table S13, it can be seen that the charge of H1 in the transition state P2(T2) becomes more positive compared to H2, which indicates the transfer of H1 as a proton. In pathways 3−5, the charges on H1 and H2 are equal and opposite in the transition state. This shows the heterolytic cleavage of dihydrogen. Hence, NBO analysis of charges illustrates that pathways 3−5 follow a metathesis mechanism and pathways 1 and 2 follow an oxidative addition mechanism. 4. Effect of Solvent Environment. Single-point energies of the minimum energy pathway for catalytic hydrogenation of NAD+ and catalytic dehydrogenation of NADH were calculated employing the PCM model at the M06-2X/6-311G** (SDD for Ir) level. The relative energy values are given in parentheses in Table 1. The values reveal that the water decreases the barrier height of H2 splitting to 34.1 kcal/mol and stabilizes the product by −18.7 kcal/mol. The same trend is obtained for hydrogenation of MNA, wherein the barrier height decreases to

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ASSOCIATED CONTENT

S Supporting Information *

Figures S1, S2, S3, S4, and S5 represent the optimized geometries described in pathways 1, 2, 3, 4, and 5, respectively. Figures S6 and S7 show the optimized geometries of reduction of NAD+ and oxidation of NADH, respectively. The optimized geometries of P5(S) and P3(S2) inhibited by NADH are presented in Figure S8. IRC paths for the minimum energy pathways are shown in Figures S9−S11. Tables S13−S18 show the NBO charges on Ir and first coordination sphere atoms for the entire pathway. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +91 44 24411630. Fax: +91 44 24911589. E-mail: [email protected]; [email protected]. Notes

The authors declare no competing financial interest. J


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ACKNOWLEDGMENTS The authors acknowledge the Multi-Scale Simulation and Modeling Project (MSM) funded by CSIR. J.V.S. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, for financial support.

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