Density functional theory calculations of novel Rh(I) diphosphinite catalysts

Polyhedron 27 (2008) 2529–2538

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Density functional theory calculations of novel Rh(I) diphosphinite catalysts Graeme J. Gainsford a,*, Andrew Falshaw a, Cornelis Lensink a, Michael Seth b a b

Industrial Research Limited, P.O. Box 31-310, Lower Hutt, New Zealand Chemistry Department, University of Calgary, Calgary, Alberta, Canada T2N 1N4

a r t i c l e

i n f o

Article history: Received 17 March 2008 Accepted 1 May 2008 Available online 13 June 2008 Keywords: Asymmetric catalysis DFT calculations Enantiomeric excess Rh(I) catalyzed asymmetric hydrogenation Diphosphinite ligands Transition state energies

a b s t r a c t Novel Rh(I) diphosphinite catalysts [Rh((R,R)-3,4-(bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methylchiro-inositol)]+ ([Rh-CANDYPHOS]+) and [Rh((R,R)-3,4-(bis(O-diphenylphosphino)-1,2,5,6-tetra-Oethyl-chiro-inositol)]+ ([Rh-EtCP]+) have been prepared utilizing naturally-occurring resources. Potential energy surfaces for the catalyzed asymmetric hydrogenation of the prochiral enamides methyl-(Z)-aacetamido cinnamate, methyl-(Z)-a-acetamido cinnamic acid and dimethyl itaconate have been surveyed using density function theory (DFT) methods. Key transition states were identified from previous [Rh((R,R)-DUPHOS)]+ studies for the two diastereoisomeric manifolds [1,2]. Transition state energies were found starting from models based on (1) the X-ray structure of the active complex (CANDYPHOS)(g4-(Z,Z)-cyclo-octa-1,5-diene)-rhodium(I) tetrafluoroborate CHCl3 solvate [3] and (2) models in which the complex (without substrate) started with C2 molecular symmetry. The difficulties encountered in calculations of the transition state energies of large cations are outlined and limitations noted. Transition state enthalpy values are compared with the observed experimental free energy differences results and previous studies [1,2]. The predictive aspects of the calculations appear to be limited with the starting models playing an important part in the absolute value of the final energies. Ó 2008 Elsevier Ltd. All rights reserved.

1. Introduction Interest in highly selective asymmetric catalysis continues at a significant level [4] both from synthetic [3] and computational modelling perspectives [2,5–7,20]. In particular we observe that research into asymmetric hydrogenation involving new metal diphosphine/diphosphinite-based compounds [8–13], mono-phosphine/phosphite metal catalysts [9,14–22], including mixtures of chiral and achiral species [23,24], and more recently self-assembled cyclic monophosphanes [25] as well as improved methods for testing their efficiency [26,27] is intense. This is undoubtedly spurred on by the need to produce high value chiral products economically as noted by Knowles [28] and reviewed recently [4]. In passing we note also the considerable interest in ‘‘heterogenized”-homogeneous catalysts, where the active catalyst is attached to a heterogeneous framework [4,27,29], reactions involving biphasic [30,31] and continuous hydrogenation membrane systems [32]. An alternative to the quadrant rule [33] used in prediction has also been recently proposed [7] and we note the multiple model calculations of BINOL-based monophosphite Rh catalysts [20]. Finally, for completeness, we record a recent publication which noted that even for the well-studied [Rh(I)-bin-

* Corresponding author. Tel.: +64 4 931 3518; fax: +64 4 931 3142. E-mail address: [email protected] (G.J. Gainsford). 0277-5387/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2008.05.011

ap]+ catalyzed reactions the mechanism ‘‘is still controversial” [34] as to whether it goes via the dihydride pathway (initial formation of dihydride) [35] or the ‘‘alkene” or ‘‘unsaturated” route [36,37] via an initial Rh-substrate complex (as shown in Scheme 1). Along with the synthesis of novel homogeneous chiral bis- and mono-phosphinite catalysts, for which both enantiomeric sources were readily available, we were interested to ascertain whether the density functional calculations (DFT) could provide timely and accurate predictions of the enantiomeric excess (ee) for a general reaction with a specific, and with an homologous catalyst. The difficulty of this task was known: DFT energies are usually accurate to a few kcal/mol while ee’s require accuracy of 1 kcal/mol. We began with the advantage of previous mechanistic studies providing knowledge of the mechanism of the reaction and of the enantiodetermining steps (see full Refs. 2 and 3 in [2]). Although previous papers noted some energy resolution concerns [6], we anticipated that these would be ameliorated through the subtraction of systematic errors in the difference energy calculations for the (two) energy states. In order to expedite the process, and take advantage of the previous modelling and kinetically-derived mechanisms [2,38], we chose our initial models from those reported for [Rh((R,R)-DUPHOS)]+ by Feldgus and Landis [1], (hereafter DUPHOS, see Fig. 1) noting that their more comprehensive report [39] suggested different enantiomeric results could result when the substituent at the alpha-carbon site of the enamide was changed.

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2.1. A. Finding the transition states The refinement of any model to a transition state (for which the Hessian matrix has a negative eigenvalue) [42] for these molecules is a difficult exercise. A potential energy surface of this dimension will include numerous saddle points and probably several of them in the neighborhood of the saddle point of interest. Ensuring that a transition state search finds the correct saddle point can be a challenge, especially if one or more of the nearby saddle points are lower in energy. In the DUPHOS models [1], there are 4 transition states of significance as recently confirmed in the study by Donoghue et al. [2]. We use the same labels here for the minor and major manifolds (min/MAJ: the major manifolds are labelled in capitals): these are sqpl(SQPL) {the square planar starting complex plus hydrogen molecule}, iid-aà (IIDAà), molh(MOLH), molhà(MOLHà) and dihy(DIHY) for the A (approach) series. The highest, and rate determining transition state is the third (MOLHà) with a typical dihydride H–H distance 1.28 Å, Rh–H distances  1.6 Å, and H– Rh–H angle 45° (Table 2; for full description see text and Fig. 6 in Ref. [1]). For our DUPHOS ‘‘proofing” calculations (Table 2), convergence from the provided coordinates was straightforward to the expected values, although the energy differences were rather smaller than previous studies (see Fig. 3 drawn in the Donoghue style [2]). We elected to concentrate on the central transition state (MOLHà) and the two adjacent states. 2.2. B. Establishing the transition state energies

Scheme 1. Overall reaction and model names. Scheme Key: Dihydride transition states for the substrate models; for DUPHOS see Ref. [1]. In data tables below, the EtCP-based catalysts are distinguished from the CANDYPHOS ones by the prefix Et (e.g. Mpac and EtMpac).

Our initial calculations with the electron withdrawing cyano group [as in [1]] gave us confidence that we were reproducing both similar energies and geometries (Table 1). Reference to the compositions shown in Scheme 1 and Fig. 1 show that this work incorporates a new level of detail particularly for the substrate molecule compared with the earlier DUPHOS[1] simplifications. The evaluation involved using a standard Kohn– Sham density functional theory programme suite [40,41] in full DFT mode on two homologous catalysts: [Rh-CANDYPHOS]+ and [Rh-EtCP]+ and three substrates: methyl(Z)-a-acetamido cinnamate, methyl(Z)-a-acetamido cinnamic acid and dimethyl itaconate (Fig. 1a–c). 2. Results and discussion We begin this report with an examination of the critical elements of the methodology.

2.2.1. Reproducibility In the process of building models from a combination of the Xray structural parameters for 1L-Rh(CANDYPHOS)+ [3] and the published transition states in DUPHOS, we came to the first decision point: was the reproducibility of electronic energy (and geometry) in the gas-phase calculations for these larger molecules (>100 atoms including Rh) sufficient? Our overall conclusion from a variety of model compounds (the variants of the substrate as we built intermediate models from the CN-bound simplified DUPHOS substrate model to the full methyl(Z)-a-acetamido cinnamate (see Fig. 1)) was that the reproducibility was only just adequate (±0.3 kcal/mol). Our worst agreement of 0.45 kcal/mol occurred when we started from significantly different starting models, using the default integration accuracy parameter of 4.0. In ADF this parameter approximately corresponds to the number of significant figures in the calculated numbers. For all our final calculations therefore we used the more accurate integration accuracy parameter of 5.0. 2.2.2. Convergence parameters The next decision point concerned the need to establish termination limits for the converging parameters; for any non-linear problem, both the significance level of the calculations and the criteria for three differently determined factors in the ADF package (energy gradient slope, energy differences and distance movement

Fig. 1. The target substrates as bound to Rh(I).

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G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538 Table 1 Initial energies for the key transition state (MOLHà) Compound

E-internal

E-electronic

MAJ MIN Ref. [1]

327.85 327.92 all E’s in kcal/mol

S-Entropy

8333.57 8329.67

Total

0.18409 0.18645

8060.61 8057.34

DE (total)

DE (electronic)

– 3.27 3.61

– 3.90 4.60

Table 2 Selected minor manifold path A transition state dataa Transition state

Relative free energy

Relative electronic energy

Ha


Hb (Å)

Rh–H (Å) (average)

Ha–Rh–Hb (a) °

molh molhà dihy

12.5 16.0 13.5

0.1 4.4 1.2

0.82 1.23 1.88

1.80 1.60 1.56

30 45 73

a

Key: from [1], see Fig. 2 for definition; all energies kcal/mol.

or expected saddle points. Using empirical trials we came up with a compromise set of 0.0002 (tolE), 0.01 (tolG) and 0.012 (tolCART) for ADF [40]. It was sometimes necessary to reduce the maximum step size to values as low as 0.005 Å to ensure that the search converged on the saddle point of interest. In a few cases which were consistent with the rather flattened saddle point profiles (see below) these convergence parameters gave final cycles with oscillating enthalpy values, within a range of 0.2 kcal/mol.

Fig. 2. Mpac1 transition state parameters (Table 2).

for the atoms) must be set to obtain accurate results within a practical refinement time (assuming of course that the refinement does not involve untoward oscillation in energies). The recommended minimum integration limit (of 5 significant figures) in the ADF [40] package was used for final calculations, although a limit of 4 (4.0) was frequently applied for QM/MM runs. A series of trials were run with variations of the limiting ratio for energy, gradient and Cartesian coordinates. Reducing the default parameters to one-tenth of the standard values (i.e. to 0.0001, 0.001 and 0.001) prolonged stable refinements unnecessarily with no significant change in total energy (<0.05 kcal/mol). At the same time, less stable refinements (see saddle point location below) frequently bypassed the requested (using a dihydride H–H distance restraint)

2.2.3. Saddle point location: strategy Our initial success in locating saddle points based on the DUPHOS models was not always repeated for the various models built on the same frameworks in which the DUPHOS ligand was replaced with CANDYPHOS or EtCP and/or the simplified substrates were progressively converted to the actual (experimental) substrates. It is our contention that this reflects different shaped energy surfaces as determined by examining (and plotting) these using the internal reaction coordinate (IRC) feature of the ADF package. An example plot, the XMpof2 MOLHà transition state, is given in Fig. 4 to illustrate the commonly observed flat gradients, width and asymmetry. 2.2.4. Starting models The X-ray structural study result for the CANDYPHOS ligand both bound to Rhodium(I) [3] and free [10] represent ground (and solid) state results. We became concerned that this might not be close enough to the real solution (in situ) situation when the CANDYPHOS ligand would (at least initially on release of the

Electronic E kcal/mol

20 15.2

15 12.6 10 5

12.4 8.7

11

9.9 6.9

5.7

5.2

4.6 2.8

2.8 0 0.1 DIHY MOLH‡

0.6 MOLH

0 SQPL

sqpl

4.4 0.1 -0.1 molh molh‡ -3.2

1.2 dihy-1.9

-5 Dono

FL

ADF

Fig. 3. Calculated enthalpies for DUPHOS models: FL [1], Dono [2], ADF this work.

G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538

Energy change kcal/mol

2532

-5

0.5 0 -0.5 0 -1 -1.5 -2 -2.5 -3 -3.5

IRC run XEtMpof2(MOLH*)

5

10

15

Step number (0=saddle point) Fig. 4. Enthalpy energy change over the XEtMpof2 saddle point from internal reaction coordinate calculation.

Rh-bound cyclo-octadiene ligand) start from a state with approximate C2-symmetry. Consequently we transformed the X-ray structure-based starting models to a C2-symmetrical state and began a new series of transition state searches. As summarized (Table 3), the transition state attained from this new C2-symmetric start did not convert to the (X) ground-state ‘‘non-symmetrical state” found in the crystal structure (Fig. 5) and energies were significantly different: in this case the difference was 6.8 kcal/mol (entries Xmpac2 and C2Mpac2, Table 4). This dramatically emphasizes the requirement that both enantiomers in the two manifolds must be as similar in conformation for a comparative energy to have any meaning. To ensure this point is clear, we have included results for both sets in Tables 3–5 (complex names are prefixed by X or C2 accordingly).

Table 3 Major structural differences (Å,°) in Mpac2 transition state models (Fig. 5A and B) Atoms

XMpac2

C2Mpac2

Rh–P10 Rh–P11 Rh–O2 Rh–C6 P10–Rh–P11 P11–Rh–O2 O–P11–Rh–P10 C–O–P11–Rh P10–Rh–P11–C40 P10–Rh–P11–C39 P11–Rh–P10–C38 P11–Rh–P10–C37

2.264 2.388 2.164 2.172 90.4 89.3 4.8 72.9 107.9 132.6 61.9 172.8

2.243 2.402 2.190 2.134 96.5 80.9 33.3 68.8 140.5 102.4 74.5 161.0

Having recognized that conversion from different conformations of the phenyl rings in the Mpac series was unlikely, we noted that (at least) two different conformations were obvious for the dimethyl itaconate models as shown in Fig. 6. We labelled these Cdmit and CdMeS, respectively (Table 5). 2.2.5. Electronic energies and Gibbs free energies Our initial trials using DUPHOS suggested that entropy contributions to the transition state energies were small and that zero point energies were not significantly different for the same transition states: room temperature difference of the TS term was 0.7 kcal/ mol (Table 1). Although this difference approaches a significant energy, it was anticipated that a cancellation effect would prevail, meaning that electronic energies alone could be used for comparative purposes. The calculation time for the entropy energies is essentially six times the number of atoms longer: so a typical calculation in this 112 atom structure is 672 times one equivalent electronic energy calculation. At present with our 4-cpu cluster, the latter takes around 75 cpu minutes . . . the entropy calculation 36 days! In a recent check calculation using our most studied molecule (Fig. 1a), we found that the difference in vibrational entropy contribution was around 9.4 cal/mol K (cf. 2.4 for DUPHOS) corresponding to a different number of contributing vibrational frequencies leading to an ‘‘apparent” entropy difference between the two transition states of 2.5 kcal/mol at room temperature (in this case the total difference between MAJOR and minor energies widened from 4.2 to 6.7 kcal/mol). Moreover, the zero point energies of these two transition states were different by 0.5 kcal/mol (again increasing the overall difference). We therefore note that the difference in total energy, including the entropy contribution and the

Fig. 5A. XMpac2 (left) and C2Mpac2 (right) final transition state models: only the dihydride and C6 hydrogen atoms are shown. All phenyl groups in stick form; CANDYPHOS with thick bonds. Atom colors: O, red; Rh, pink; P, orange; N, blue; C, gray; H, black. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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Fig. 5B. Overlap plot of XMpac2 (atoms colored) and C2Mpac2 (in purple) final transition state models (see text). Only the dihydride hydrogens are shown for clarity. All phenyl groups in stick form; CANDYPHOS with thick bonds. Atom colors: as for Fig. 5A. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 4 Calculated transition state electronic energiesa and MOLHà geometryb for Cinnamate complexes (see Fig. 1 a and b) Complex DUPHOS MAJ DUPHOS min XMpac1 XMpac2 C2Mpac1 C2Mpac2 XMpof1 XMpof2 C2Mpof1 C2Mpof2 XEtMpac1 XEtMpac2 XEtMpof1 XEtMpof2 a b c

SQPL (0.0) kcal/mol 8088.8 8084.2 15522.8 15528.2 15525.7 15524.4 15156.8 15160.2 15159.5 15156.4 17026.1 17030.2 16657.6 16663.3

MOLH kcal/mol

MOLHà kcal/mol

0.6 7.8 0.4 2.0 1.4 2.4 1.7 1.4 2.3 5.8 0.7 4.7 1.6 0.0

2.8 4.7 0.8 0.4 8.6 3.4 10 0.6c 7.4 6.2 0.1 2.2 2.3 2.4

Ha


Hb Å

Ha–Rh–Hb °

Ha


C6 Å

DIHY kcal/mol

1.24 1.21 1.33 1.28 1.28 1.24 1.37 1.22c 1.40 1.39 1.38 1.29 1.31 1.17

44.9 43.9 49.1 46.4 47.4 45.1 50.9 46.1 52.1 51.6 51.6 47.2 48.1 42.1

2.60 2.52 2.51 2.52 2.61 2.47 2.48 2.54 2.58 2.22 2.41 2.55 2.53 2.52

15.8 6.5 3.5 1.5 3.5 1.7 3.5 0.1 8.9 2.8 5.8 2.9 5.8 1.8

Ha


Hb Å

Ha–Rh–Hb°

Ha


C6 Å

DIHY kcal/mol

1.61 1.52 1.35 1.54 1.77 1.54 1.60 1.51

61.3 56.8 50.2 58.0 68.2 58.0 61.0 56.4

2.33 2.34 2.21 2.32 2.36 2.32 2.42 2.34

Transition model names Scheme 1[1] & text; Energies are relative to the listed SQPL entries of each row. For geometry parameters, see Fig. 2 (atom C6 is the alpha carbon atom). Averaged values.

Table 5 Calculated transition state electronic energies and MOLHà geometry for dimethyl itaconate complexesa Complex XCdmit1 XCdmit2 XCdMeS1 XCdMeS2 C2CdMeS1 C2CdMeS2 XEtCdMeS1 XEtCdMeS2 a b c

SQPL (0.0) kcal/mol 14217.9 14219.5 14223.3 14224.1 14226.9 14223.2 15727.2 15731.8

MOLH kcal/mol

MOLHà kcal/mol

4.5 2.0 0.8 2.9 10.9 0.7 2.7 0.7

3.6 6.3 0.8b 2.0 8.1 2.2 0.2b 1.9

2.6 0.7 1.1c 1.2 7.9 2.2 5.1 6.5

See Table 4 for label and layout information. Obtained using step radius of 0.005 Å. An alternative adjacent state with energy 5.5 kcal/mol was observed.

zero point correction terms might well be significant at the 1 kcal/ mol level: a reduction in the computation time, and removal of ex-

tra vibrating atoms which contribute to the entropy sum, are two features that would be useful in future studies.

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G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538

Fig. 8. Energy change vs. H–H dihydride distance (XMpac2 model) (see text).

the energy changes between the DIHY and MOLH models for XMpac2: the energy change compared with the H–H distance is small around the MOLHà model region (steps 9–12, Fig. 8). 3. Overall results Fig. 6. Superposition of final methyl itaconate transition state models XCdmit1 (in purple) and XCdMes1 (thick bonds with atom colors: O, red; Rh, pink; C, gray; H, blue). Labels indicate the different methyl substrate conformations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

2.2.6. Comparing like models (the predictive quandary) We have confirmed that the stereochemistry of the minor and major manifold transition states must be closely aligned also with respect to the dihydride hydrogen geometries. In one case (XMpof2) it was possible to locate transition states with differing H–H distances (1.19 and 1.39 Å) which gave electronic energies differing by 2.5 kcal/mol. On further refinement of both with lower convergence parameters, the energies came closer (within 1 kcal/ mol) but with one model not converging in a realistic timeframe: final H–H distances of 1.22 (converged) [quoted in Table 4] and 1.16 Å (oscillating). The models are essentially superimposable (Fig. 7) and serve to warn that care must be taken in comparing similar transition states from the two manifolds. We present a simplified view of this issue in Fig. 8, which maps (using a linear step)

We present difference enthalpy results in Tables 4 and 5 and emphasize that the magnitude of the difference between the minor and major manifold transition states is of the order of 0.02% of the total energies by listing the numerical values for the SQPL/sqpl models. Given the notes above about the need to compare similar dihydride geometries, these tables also include the relevant (MOLHà) dihydride geometric parameters. For comparative purposes, Figs. 9–11 follow the summary format suggested by Donoghue et al. [2] and align with Table 6 which contains the comparative experimental data. Overall the results indicate that the predicted ee% values are cinnamate > cinnamic acid > itaconate, as observed experimentally. In general, the overall difference magnitudes are much lower than those recently calculated using DFT/ONIOM calculations [2] for the X-ray based starting set, but somewhat similar for the C2symmetry starting models. Given a choice of model, we would normally take the lowest energy models as being correct but note that the parallel reaction curves suggest the same conclusions. The prediction for the homologous EtCP versus CANDYPHOS based catalysts is mixed with the itaconate and cinnamic acid giving the correct trend, while the cinnamate results are in reverse to the measured value (averaged values 4.1 and 6.4 kcal/mol, respectively). The latter result may well be influenced by other factors, including solvent choice, possibly significant entropy affects and the significance of the DIHYà transition state [2]. Another noteworthy aspect of the computations is the relative energy of the square planar starting-complex (the calculations include a non-bound molecule of hydrogen) relative to the transition state energies. This aspect is best shown in the following Figs. 9–11 where the plotted difference values given are relative to the lowest square planar complex in either major or minor manifold (i.e. either sqpl or SQPL models). 3.1. Hydrogenation of methyl-(Z)-a-acetamido-cinnamic acid (Mpof series)

Fig. 7. Overlap of XMof2 transition state models (see text): only the dihydride hydrogen atoms are shown. Converged model with atom colors: O, red; Rh, pink; N, blue; C, gray; H, black. Other model: purple. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Relative MOLHà transition state energies (Fig. 9) are not consistent for the 3 models (see molhà & MOLHà points), but the relative energies of the square planar starting complexes are quite similar for both manifolds as might be expected. The notable difference is the reversal of chirality predicted from the C2 symmetry-based starting model. Unfortunately no experimental value is available for the EtCP experiment to confirm the lower predicted ee%, though this would be consistent with the Mpac series.

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G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538

Electronic E (kcal/mole)

10 8 6 4 2 0 DIHY -2

MOLH‡

MOLH

SQPL

sqpl

molh

molh‡

dihy

-4 XMpof

C2Mpof

XEtMpof

Fig. 9. Calculated enthalpies for substrate methyl(Z)-a-acetamido cinnamic acid over pathway A [2] relative to sqpl model.

10 8.6

8

Kcal/mole

6 4 2

5.8

5.4

4.6

4.6

3.5

3

1.9

1.3 0

0 DIHY

MOLH‡

MOLH

-1.4

-2

SQPL

0.4

0 sqpl

molh-1.1

molh‡

-2

dihy

-1.5

-4 -6 XMpac

C2Mpac

XEtMpac (see Text)

Fig. 10. Calculated enthalpies for substrate methyl(Z)-a-acetamido cinnamate over pathway A [2] relative to sqpl model.

12 10

Kcal/mol

8 6

5.2 4

6.3

6.1

4.2

2 0 0 -0.3 DIHY MOLH‡ -2

1.6 0.8

0 MOLH

SQPL

2 0.7

0 sqpl

molh

-2 -2.9

molh‡

dihy-1.2

-4

XCdmit

XCdMeS

C2CdMeS

XEtCdMeS (see Text)

Fig. 11. Calculated enthalpies for substrate dimethyl itaconate over pathway A [2] relative to the sqpl/SQPL model.

3.2. Methyl-(Z)-a-acetamido-cinnamate (Mpac) For this larger substrate, there is a consistent ee% prediction over the three models (see Fig. 10), with the minor manifold square planar model (sqpl) less stable for both X-ray starting models but

not for the C2 model. The relative energies of the molhà and molh minor manifold transition states are lower than the starting square-planar complexes, but this comparison is not considered significant given that the starting catalyst is a cyclo-octadiene 6coordinate complex.

2536 G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538 Table 6 a b Enantiomeric excess: experimental and calculation results Target

Codename

Experimental (CANDYPHOS)

Calc(X)

Mpof

76% 1.20 7.6:1

3.0

95% 2.15 41:1

4.2

1.1, ( 2.0)c

Mpac

Cdmit/CdMeS

a b c

29% 0.35 1.8:1

Calc (C2)

Exptal (EtCP)

Calc(X)

–

1.0

4.0

92% 1.90 25:1

6.4

2.2

51% 0.65 3:1

2.5

1.9

Energies are in kcal/mol. Experimental values listed in three ways: ee (%), DDG°, ratio of enantiomers. Enthalpy energies (DH). For the Cdmit (CdMeS) models (see Table 5).

Table 7 QM/MM calculated D(molhà–MOLHà) enthalpy electronic difference energies (kcal/mol) Model

DE* (X) (Cp)

DE* (C2) (Cp)

DG Measured

DE* (X)(EtCP)

DE* (C2)(EtCP)

DG Measured

Mpof Mpac Cdmit CdMeS

10.1 6.6 7.6 7.6

4.6 5.4 – 4.4

1.2 2.15 0.35 0.35

14.0 3.0 2.0 2.5

– 9.1 –

– 1.90 0.65 0.65

3.3. Hydrogenation of dimethyl itaconate (Cdmit, CdMes) The low ee% values observed for this substrate (Table 5) would suggest potential resolution difficulties in the calculation, for the reasons noted above (Fig. 11). The results are surprisingly good in relation to the Mpac and Mpof series. Nevertheless, the transi-

tion state geometries were difficult to locate, and show wide variation particularly with respect to the Ha–Hb geometries (Table 5). 3.4. The QM/MM results Limitations of QM/MM methods have been identified previously [43]. The QM/MM approach does allow the full system to be treated and ‘‘breakout” from starting symmetric geometries to occur, as well as having the bonus of substantial gains in computation time. We present here (Table 7) a summary of our QM/MM trials. Partly as expected from the approximate force constants covering a large part of the molecule (using SYBYL Force Field parameters, 2-layer; see Fig. 12 below), the final energy differences were a poor guide to the ee% values reflecting that the errors involved in this approach are too large. 4. Experimental 4.1. Computational details

Fig. 12. The division of QM and MM regions in the molecules (Mpac example).

DFT calculations were carried out using ADF 2006.01 [40,41] on a cluster of four 3.2 GHz Intel Pentium 4 CPUs with hyperthreading. Each node ran under Redhat 9 Linux configured with OSCAR software from the Open Cluster Group, http://www.openclustergroup. org/. That included the PVM and MPI parallel libraries and PBS (Portable Batch System) used for the queuing and scheduling of batch jobs. The calculations were carried out within the framework of the generalized gradient approximation (GGA) by using the local den-

G.J. Gainsford et al. / Polyhedron 27 (2008) 2529–2538

sity functional of Voska et al. [44], the exchange correction of Becke [45] and the correlation correction of Perdew [46,47]. Frozen core orbitals were used for all atoms, with the core orbitals for rhodium defined as 1s, 2s, 2p, 3s, 3p and 3d shells. All calculations were spin restricted and relativistic effects were included using the ZORA method [48–50]. Model structures were built from [Rh(CandyPhos)(COD)]+ [3] and the DUPHOS transition state models [1] or locally-programmed C2-symmetric conversions. Substituents were added when required using standard structural data in VEGAZZ[51] and locally written software [52]. The structures were then optimized with respect to their energies using the transition state search algorithm [42] by using double-zeta polarized STO basis sets on all non Rh atoms, and triple-zeta polarized sets for Rh. The division of the atomic coordinates between the QM and MM regions is shown in Fig. 12: the P–C and O–C a link parameters [41] used were 1.28 and 1.44, respectively. A typical sequence involved using a distance restraint on the hydride hydrogens (e.g. H. . .H 1.28 Å) and, in QM/MM runs, the molecular dynamics search using conjugate gradient optimization with a 100 ps for 101 sampled structures heated to a temperature 100–700 K. This final model was then refined under full QM (DFT) calculations with our compromise set of convergent values of 0.0002 (tolE), 0.01 (tolG) and 0.012 (tolCART) with integration limits of 5.0. 4.2. Preparative details 4.2.1. General methods Manipulations of air sensitive materials were conducted in an argon atmosphere by using either Schlenk techniques or an Innovative Technology dry box. Tetrahydrofuran, ether and toluene were distilled from sodium benzophenone ketal under nitrogen and stored over activated 4 Å molecular sieves. NMR spectra were recorded on an AC300 Bruker spectrometer. Flash column chromatography [53] was carried out on 230–400 silica (Scharlau). Gas chromatographic analysis was performed on a Hewlett–Packard Model 6890. Chiral gas chromatographic separations were accomplished using a Chirasil L-Val (50 m  0.25 mm, 0.12 lm film thickness) capillary column (Chrompack). Elemental analyses were performed by the Campbell Analytical Laboratory, University of Otago, Dunedin, New Zealand. L-Quebrachitol was obtained from the Rubber Research Institute of Malaysia, Kuala Lumpur, Malaysia. D-Pinitol was obtained from New Zealand Pharmaceuticals Ltd., Palmerston North, New Zealand. Acetamidoacrylate derivatives were synthesized according to literature procedures [54]. (CODRhCl)2 was purchased from Aldrich. All NMR spectra were recorded in CDCl3 unless noted otherwise. The synthetic pathway that was employed to obtain the diphosphinite ligand was described previously (see ligand D-10 [10]).

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H (CDCl3) 1.22 ppm (m, 12H), 3.2–3.8 (m, 14H). C (CDCl3) 15.8 (CH3), 16.0 (CH3), 66.1 (CH3), 67.4 (CH2), 72.2 (CH), 75.1 (CH), 79.8 (CH).

13

4.4. 1D-3,4-Bis(O-diphenylphosphino)-1,2,5,6-tetra-O-ethyl-chiroinositol The 1,2,5,6-tetra-O-ethyl-chiro-inositol (2.28 g, 7.8 mmol), which had been pre-dried azeotropically with dry toluene (2  5 mL) and dry pyridine (excess, 4 mL), was added to dry THF (20 mL). The resulting solution was transferred by cannula into a Schlenk tube containing freshly distilled chlorodiphenyl phosphine (3.49, 15.6 mmol) in dry THF (10 mL) under argon. The resulting suspension was stirred at room temperature overnight. The solution was filtered under argon and the solvent removed from the filtrate under vacuum. The remaining solid was washed with dry toluene and filtered. The filtrate was collected and the solvent removed under vacuum to give the diphosphinite as a white solid (5.02 g, 97%). Anal. Calc. for C38H46O6P: C, 68.86; H, 6.88. Found: C, 69.08; H, 7.02%. 4.5. 1D-3,4-Bis(O-diphenylphosphino)-1,2,5,6-tetra-O-ethyl-chiroinositol rhodium cyclooctadiene BF4 [RhCODCl]2 (123 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL). The ligand (330 mg, 0.5 mmol) dissolved in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. AgBF4 (97 mg, 0.5 mmol) was added and the reaction mixture stirred for 2 h. The mixture was filtered through CeliteÒ and the solvent removed in vacuo to yield the title compound (480 mg, 100%) as a bright yellow solid. Anal. Calc. for C46H59BF4O6P2Rh: C, 57.63; H, 6.10. Found: C, 57.40.; H, 6.14%. 31P NMR: 137.6 ppm, JRh–P 180.7 Hz. 4.6. 1D-3,4-Bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiroinositol rhodium cyclooctadiene BF4 A solution of 1L-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-Omethyl-chiro-inositol (122 mg, O.20 mmol) in THF (5 mL) was added dropwise to a solution of (RhCODCl)2 (49 mg, 0.10 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 17 h. AgBF4 (0.039 g, 0.2 mmol) was added and the reaction mixture stirred for 2 h. Filtration and removal of the solvent yielded an orange solid. Crystallization from CHCl3/ pentane yielded pure title compound as a CHCl3 solvate (0.078 g, 76%). 31 P NMR 134.8, JRh–P = 178 Hz. Anal. Calc. for C43H51BCl3F4O6P2Rh: C, 50.54; H, 5.03. Found: C, 50.44; H, 5.00%. 4.7. Hydrogenations

4.3. 1,2,5,6-Tetraethyl-chiro-inositol 3,4-Dibenzyl-chiro-inositol [10] (5.0 g, 13.9 mmol) dissolved in dry DMF (150 mL) was treated at 0 °C with NaH (1.5 g, 62.5 mmol) and ethyl bromide (8.76 g, 80.4 mmol). Reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water and extracted with toluene. Removal of the toluene and purification by flash-chromatography (Si-60, hexanes:ethylacetate 4:1) yielded 3,4-dibenzyl1,2,5,6-tetraethyl-chiro-inositol as a clear oil (4.52 g, yield 69%). This oil was dissolved in ethanol (90 mL), TFA (10 lL) and Pd/C (100 mg) were added, and hydrogenated at 1 atm hydrogen pressure for 4 h. Purification by flash-chromatography (Si-60, hexanes:ethylacetate 3:2) yielded 1,2,5,6-tetraethyl-chiro-inositol (2.97, yield 100%) as a light orange oil and was committed to the next step without further purification.

Hydrogenations were carried in 12 mL glass vials equipped with magnetic stirrer bars. The vials were charged with catalyst (0.005 mmol), substrate (1.0 mmol) and solvent (3 mL) inside an inert atmosphere glove box (Innovative Technologies) and placed inside a 300 mL Parr autoclave made from Hastelloy C. In this way several hydrogenation experiments could be carried out at the same time. The autoclave was sealed, taken outside the glovebox and heated to the required temperature using a thermostatic heating mantel. The autoclave was flushed with hydrogen three times before being filled to the required pressure. After the required reaction time the autoclave pressure was reduced to atmospheric pressure and samples of the crude reaction mixture were analyzed by GC. The GC analysis to obtain conversion and enantiomeric excess were performed on a HP 6890 Series gas chromatography apparatus

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using a capillary Supelco GAMMA-DEX 225 (30 m  0.25 mm  0.25 lm) column or a SGE CYDEX-B (2 m  0.32 mm  0.25 lm) column.

5. Conclusions Overall, our gas phase calculations (without counterions) supported the observed enantiomeric excess for the catalytic hydrogenation of the prochiral enamides (methyl-(Z)-a-acetamido cinnamate, methyl-(Z)-a-acetamido cinnamic acid and dimethyl itaconate) using the two homologous Rh(I) bisphosphinite catalysts. The calculations for dimethyl itaconate were not consistent, but the ee% values experimentally observed corresponded to energy differences of <1 kcal/mol. We found that starting models can determine which transition state energies are determined: this raises issues of confidence in predictions as the comparable (other pathway) transition states must represent both the same conformations and comparable ‘‘internal” geometries. The observed enthalpy differences are rather smaller than those reported by Feldgus and Landis[1] and Donoghue et al. [2] for the Rh(I)DUPHOS systems. We have established straightforward chemical routes to two new Rh(I) hydrogenation catalysts based on readily available starting materials. Our experience in searching for transition state saddle points suggests that a ‘‘more intimate” QM/MM relationship would enhance this process, given the difficulty of moving across the energy surface using QM methods alone observed here. Obstacles to the use of DFT calculations for the prediction of enantiomeric excess on larger molecular systems have been identified. Our original intent was to consider other factors, such as solvent effects, but our results suggest that, at the state of current knowledge (mechanism and modeling) such an extension was not justified. Acknowledgments This study would not have been possible without the close support of Professor Tom Ziegler (University of Calgary, Calgary, Alberta, Canada). Contributions to the synthetic programme were made by Chris Enright and Joanne Hart. We thank the NZ Foundation for Research Science and Technology for funding (Contract No. CO8X0411). Appendix A. Supplementary data The Cartesian coordinates (in XYZ format) for the calculated models in Tables 4 and 5. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.poly. 2008.05.011. References [1] [2] [3] [4]

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