A Dihydride Mechanism Can Explain the. Intriguing Substrate Selectivity of Iron-PNP-

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1 SUPPORTING INFORMATION A Dihydride Mechanism Can Explain the Intriguing Substrate Selectivity of Iron-PNP- Mediated Hydrogenation Glenn R. Morello, Kathrin H. Hopmann* Centre for Theoretical and Computational Chemistry and Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø Norway *kathrin.hopmann@uit.no CONTENTS 1. Mechanism A, FePNP CH2 2. Mechanism B, FePNP CH2 3. Mechanism C, FePNP CH2 4. Direct H 2 cleavage versus shuttling, FePNP CH2 and FePNP NH 5. Mechanism D with stepwise proton transfer, FePNP CH2 6. Computed hydride affinities 7. Mechanism B, FePNP NH 8. Mechanism C, FePNP NH 9. Conversion of experimental yields to approximate barrier differences 10. Mechanism B, FePNP NCH3 11. Mechanism C, FePNP NCH3 12. Mechanism E, FePNP NCH3 13. Iron-dihydride geometries for FePNP NCH3

2 1. Mechanism A, FePNP CH2 Figure S1. Results computed here for FePNP CH2 -mediated hydrogenation with mechanism A (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. Although the irondihydride is drawn as an off-cycle species, it is accessible through TS shuttle (see Figure S6) and constitutes the resting state of the system. Attempts to locate the concerted TS for hydrogenation (TS concertedh+andh-_redox) failed and only a proton for hydrogen transfer from the linker to the substrate was found (with a barrier of 48.1 kcal/mol). However, the barrier for TS redox_aromatization is very high (regardless if referenced relative to the iron-dihydride or to the dearomatized monohydride), implying that mechanism A can be excluded for FePNP CH2.

3 2. Mechanism B, FePNP CH2 Figure S2. Results computed here for FePNP CH2 -mediated hydrogenation of acetophenone with mechanism B (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. Although the iron-dihydride is drawn as an off-cycle species, it is accessible through TS shuttle (see Figure S6) and constitutes the resting state of the system. We also evaluated the barrier and reaction energy for insertion of a solvent molecule (as first proposed by Yang i ), and find that the formed Fe-etoxy species is not lower in energy than the iron-dihydride.

4 3. Mechanism C, FePNP CH2 Figure S3. Results computed here for FePNP CH2 -mediated hydrogenation of acetophenone with mechanism C (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. The energy of TS H+ could only be approximated, but is not expected to be ratelimiting for this system (results by Yang indicate that the barrier for TS H+ will be similar to that of TS H-). i Figure S4. Results computed here for FePNP CH2 -mediated hydrogenation of benzophenone with mechanism C (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. The energy of TS H+ could only be approximated, but is not expected to be ratelimiting for this system.

5 4. Direct H 2 cleavage versus shuttling, FePNP CH2 and FePNP NH Figure S5. Evaluated pathways for H 2 cleavage in Mechanism D for FePNP CH2 and FePNP NH (P = P i Pr 2). Energies (ΔG 298K, sol, kcal/mol) are given relative to the Fe-dihydride species (Fig. S3). From left: Shuttling of a proton through the product alcohol formed from acetophenone, shuttling of a proton through EtOH, direct proton transfer from H 2 to the linker (* = geometry optimized in vacuum, see computational details). We evaluated if the difference between TS shuttle and TS shuttle_etoh might be due to an artefact arising from differences in the model (e.g. different number of atoms might leading to different solvation effects). We thefore made two extended models of the FePNP NH transition states, adding either an EtOH molecule to TS shuttle (= TS shuttle_extended) or an 1-phenyl-ethanol molecule to TS shuttle_etoh (= TS shuttle_etoh_extended), so that the two extended molecules have the same number of atoms. Note that the added molecule has a large conformational freedom, and we would generally not advocate using such a model. It is only employed here to evaluate if the barrier differences are consistent. The raw Gibbs free energies predict a difference of 4.2 kcal/mol between TS shuttle and TS shuttle_etoh, compared to 4.4. kcal/mol between TS shuttle_extended and TS shuttle_etoh_extended, indicating that the energy difference is consistent and not due to an artefact. Table S1. Optimized geometries and energies for proton shuttling through the product alcohol formed from acetophenone (top) or through EtOH (bottom), without (left side) or with an additional molecule of alcohol hydrogen bonded to the ligand NH group (right side). TS shuttle TS shuttle_extended 79 atoms ΔGraw = 22.1 kcal/mol ΔGraw + SS+ CP = ΔG298K,sol = 20.2 kcal/mol 88 atoms ΔGraw = 25.1 kcal/mol ΔGraw + SS+ CP = ΔG298K,sol = 21.0 kcal/mol

6 TS shuttle_etoh TS shuttle_etoh_extended 69 atoms ΔGraw = 26.3 kcal/mol ΔGraw + SS+ CP = ΔG298K,sol = 22.5 kcal/mol 88 atoms (for clarity, one ipr group is drawn without H atoms) ΔGraw = 29.6 kcal/mol ΔGraw + SS+ CP = ΔG298K,sol = 25.5 kcal/mol 5. Mechanism D with stepwise proton transfer, FePNP CH2 Figure S6. Results computed here for FePNP CH2 -mediated hydrogenation of acetophenone with Mechanism D (P = P i Pr 2), comparing a step-wise proton transfer (red colouring) to a concerted proton transfer (green). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the Fe-dihydride species. Following formation of the dearomatized species and H 2 coordination, H 2 cleavage and regeneration of the backbone might occur stepwise (red): First a proton is transferred to the linker (TS H+back) with a barrier of 20.3 kcal/mol for acetophenone and then the formed alkoxide takes a proton from H 2, occurring as in Mechanism C, TS H+_aromatized.. Thus, TS H+back provides a link between Mechanism D and C. The energy of TS H+_aromatized could only be approximated, but is not expected to be ratelimiting. The barrier for TS H+back and TS shuttle are comparable, implying that proton transfer might occur stepwise or concerted.

7 6. Computed hydride affinities Figure S7. The hydride affinity of different substrates was computed relative to the same reference point, as illustrated. The formed alkoxide was stabilized with a solvent molecule. The ΔG values were referenced to the hydride affinity of benzaldehyde to obtain the relative hydride affinity (ΔΔG = ΔG given_substrate ΔG benzaldehyde, Table S2). The relative hydride affinities are independent of the hydride donor employed in calculations. Note: A positive value implies less hydride affinity than benzaldehyde, a negative value implies more hydride affinity than benzaldehyde Table S2. Computed intrinsic hydride affinities, relative to benzaldehyde (ΔΔG 298,sol) See Figure S7 for illustration of computation and further explanations. Substrate Relative hydride affinity (kcal/mol) Benzaldehyde 0.0 Acetophenone CH 3-acetophenone +5.4 Benzophenone NO 2-acetophenone Cl-acetophenone OMe-acetophenone +6.2

8 7. Mechanism B, FePNP NH Figure S8. Results computed here for FePNP NH -mediated hydrogenation of acetophenone with mechanism B (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. Although the iron-dihydride is drawn as an off-cycle species, it is accessible through TS shuttle (see main text, Figure 5 and 6) and constitutes the resting state of the system. We also evaluated the barrier and reaction energy for insertion of a solvent molecule (as first proposed for FePNP CH2 by Yang i ), and find that the formed Fe-etoxy species is not lower in energy than the irondihydride.

9 8. Mechanism C, FePNP NH Figure S9. Results computed here for FePNP NH -mediated hydrogenation of acetophenone with mechanism C (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. An optimized structure of TS H+ could not be computed. Approximate results indicate that this step might be ratelimiting. It is therefore not possible to clearly conclude if mechanism C might be operative.

10 9. Conversion of experimental yields to approximate barrier differences Table S3. Experimental yields reported in the literature (for each catalyst, the substrates given here were hydrogenated under identical conditions), and estimated barrier differences (ΔΔG) using Equation 2. Substrate Yield in experiment ΔΔG experiment (kcal/mol) FePNP CH2 - mediated hydrogenation ii (313 K) a Acetophenone 89 % CH 3-acetophenone 53 % +0.3 Benzophenone 72 % +0.1 FePNP NH -mediated hydrogenation iii (298 K) Acetophenone 99 % 0.0 Benzaldehyde 23 % NO 2-acetophenone 47 % Cl-acetophenone 99 % OMe-acetophenone 34 % +0.6 FePNP NCH3 -mediated hydrogenation iv (313 K) 4-F-benzaldehyde > 99 % 0.0 Acetophenone < 1 % >2.9 Ethyl benzoate < 1 % >2.9 a) Benzaldehyde is not included in the comparison, as it is suspected to form benzoic acid, resulting in catalyst inactivation. ii With additives that might suppress the formation of benzoic acid or its deactivating properties, FePNP CH2 is able to convert aldehydes in large yields. v We have assumed that a difference in yield can be related to a difference in hydrogenation rate (provided the evaluated substrates do not show full conversion). If during the same amount of time, Sub1 shows 99% conversion and Sub2 shows 34% conversion, then one may assume that Sub1 was converted approximately 2.9 times as fast as Sub2 (k SUB1/k SUB2 = 2.9). This ratio can be converted to a barrier difference. For this we use transition state theory, vi which is applied to convert a rate to a barrier (eq 1): (eq 1) k r k B T h ΔG exp RT k r = rate constant in s -1, h= Planck s constant, J s, R = gas constant, JK -1 mol -1, k B = Boltzmann s constant, JK 1 Using (eq 1) applied to two different substrates (Sub1 and Sub2), a rate ratio can be related to a barrier difference (ΔΔG): (eq 2) RT*ln(k SUB1/k SUB2) = ΔG SUB2-ΔG SUB1 = ΔΔG If k SUB1/k SUB2 = 2.9, then ΔΔG = 0.6 kcal/mol. We emphasize that this approach, converting differences in partial yields to barrier differences, should be considered a rough approximation.

11 10. Mechanism B, FePNP NCH3 Figure S10. Results computed here for FePNP NCH3 -mediated hydrogenation of benzaldehyde with mechanism B (P = P i Pr 2). Energies (ΔG 313K, sol values in kcal/mol) are given relative to an iron-ethanol monohydride species. In contrast to FePNP CH2 and FePNP NH, the linker of FePNP NCH3 cannot be deprotonated by base and FePNP NCH3 therefore has a charge of +1 throughout mechanism B. In mechanism B, both the hydride and the proton transfer steps have significantly larger barriers than the overall barrier for Mechanism D (18.5 kcal/mol for benzaldehyde, Figure S11). Mechanism B is therefore considered highly unlikely for FePNP NCH3.

12 11. Mechanism C, FePNP NCH3 Figure S11. Results computed here for FePNP NCH3 -mediated hydrogenation of benzaldehyde with mechanism C (P = P i Pr 2). Energies (ΔG 298K, sol values in kcal/mol) are given relative to the iron-dihydride species. A fully optimized structure of TS H+ could not be computed and could only be estimated. Results by Gorgas et al. indicate that TS H+ should not be ratelimiting. iv

13 12. Mechanism E, FePNP NCH3 Figure S12. Results computed here for FePNP NCH3 -mediated hydrogenation of benzaldehyde with an alternative new mechanism E (P = P i Pr 2). Energies (ΔG 313K, sol values in kcal/mol) are given relative to an ironethanol monohydride species. In contrast to FePNP CH2 and FePNP NH, the linker of FePNP NCH3 cannot be deprotonated by base and FePNP NCH3 therefore has a charge of +1 throughout mechanism E. In mechanism E, a concerted proton and hydride transfer to the substrate occurs, followed by regeneration of the active species. Both TS concerted and TS regeneration have a larger barrier than the overall barrier for mechanism D (18.5 kcal/mol for benzaldehyde, Figure S11), making mechanism E highly unlikely.

14 13. Iron-dihydride geometries for FePNP NCH3 A) B) Figure S13. A) Iron-dihydride geometry of FePNP NCH3 as reported by Kirchner and coworkers. iv B) Irondihydride geometry of FePNP NCH3 as optimized here. In structure B, all ipr groups are rotated such that the hydrogens point outwards. When reoptimized with our computational protocol, A is 5 kcal/mol higher in energy than B. References (i) Yang, X. Inorg. Chem. 2011, 50, (ii) Langer, R.; Iron, M. A.; Konstantinovski, L.; Diskin-Posner, Y.; Leitus, G.; Ben-David, Y.; Milstein, D. Chem. - Eur. J. 2012, 18, (iii) Gorgas, N.; Sto ger, B.; Veiros, L. F.; Pittenauer, E.; Allmaier, G. N.; Kirchner, K. Organometallics 2014, 33, (iv) Gorgas, N.; Sto ger, B.; Veiros, L. F.; Kirchner, K. ACS Catal. 2016, 6, (v) Zell, T.; Ben-David, Y.; Milstein, D. Catal. Sci. Technol. 2015, 5, (vi) Cramer, C. J. Essentials of Computational Chemistry: Theories and Models, John Wiley & Sons Ltd, 2002, page 527.