Supporting Information

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1 Supporting Information Ligand-Substrate Dispersion Facilitates the Copper-Catalyzed Hydroamination of Unactivated Olefins Gang Lu 1, Richard Y. Liu 2, Yang Yang 2, Cheng Fang 1, Daniel S. Lambrecht 1 *, Stephen L. Buchwald 2 * and Peng Liu 1 * 1 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA *Correspondence to: lambrecht@pitt.edu, sbuchwal@mit.edu, pengliu@pitt.edu Table of Contents Comparison of Hydrocupration Barriers Using Different Levels of Theories... S2 Comparison of ΔE int-space Using Different Levels of Theories... S4 Comparison of Dispersion Energies Calculated Using Different Methods... S7 Effects of Solvent... S9 Effects of Ligand s Methoxy and tert-butyl Substituents... S10 Correlations of ΔE with ΔE int-bond, ΔE dist, and ΔE int... S11 Contribution of Each Component in the Ligand-Substrate Interaction Model Analysis... S13 Dispersion Interaction Energies Between Pr and t-bu Substituents in TS2... S16 Correlations of ΔE rep, ΔE pol and ΔE ct with ΔE int-space and ΔE... S17 General Information for Kinetic Experiments... S19 Additional Computational Results... S24 Cartesian Coordinates (Å) and Energies of the Optimized Structures... S29 References... S249 S1

2 Comparison of Hydrocupration Barriers Using Different Levels of Theories The barriers of the hydrocupration of trans-2-butene with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)) were calculated using a few popular modern density functionals and solvation models (Table S1). Although the absolute activation energies differ by a few kcal mol -1 among the methods tested, the trend of ligand effects on the reactivity, i.e. the relative free energies of the two transition states of hydrocupration of trans-2-butene with SEGPHOS and DTBM-SEGPHOS (TS1a vs. TS2a), is only minimally affected by the choice of the density functional and the solvation model in the single-point energy calculations. Since dispersion is critical for the hydrocupration reactivity as demonstrated in the manuscript, we also used the dispersion-corrected functional B3LYP-D3 in place of B3LYP for geometry optimization. The results also indicate the CuH catalyst based on DTBM-SEGPHOS is more reactive towards trans-2-butene than that based on SEGPHOS, regardless of the level of theory used in the calculations. Thus, a more commonly used combination of computational methods, M06 with the SMD solvation model for single point calculations and B3LYP for geometry optimization, was chosen in the present study. Table S1. Comparison of activation free energies (ΔG sol) of hydrocupration of trans-2-butene with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)) using different levels of theories. Method for Single Point Energy Calculation a M06/SDD G(d,p)/SMD b ωb97xd/sdd G(d,p)/SMD TPSS-D3/SDD G(d,p)/SMD B3LYP-D3/SDD G(d,p)/SMD M06/SDD G(d,p)/CPCM M06/SDD G(d,p)/SMD ωb97xd/sdd G(d,p)/SMD TPSS-D3/SDD G(d,p)/SMD B3LYP-D3/SDD G(d,p)/SMD M06/SDD G(d,p)/CPCM Method for Geometry Optimization B3LYP/ SDD 6-31G(d) b B3LYP-D3/ SDD 6-31G(d) trans-2-butene + L1CuH TS1a (ΔG sol) trans-2-butene + L2CuH TS2a (ΔG sol) ΔΔG sol (TS1a TS2a) a All free energies are in kcal mol -1. The calculated ΔG sol are with respect to the separated olefin and LCuH. THF was used as solvent in all solvation energy calculations. b The level of theory used in the present study. S2

3 To confirm the nature of the stationary points, vibrational frequency calculations were performed for all optimized structures. All optimized transition state structures have only one imaginary (negative) frequency, and all minima (reactants, products, and intermediates) have no imaginary frequencies. The imaginary frequencies of all transition states and three lowest vibrational frequencies for each optimized structure are provided in the Cartesian coordinates (Å) and energies of the optimized structures section below. The reported Gibbs free energies and enthalpies include zero-point vibrational energies and thermal corrections at 298 K calculated using a harmonic-oscillator model. Since the harmonic-oscillator approximation may lead to spurious results for the computed entropies in molecules with low-frequency vibrational modes, 1 the quasiharmonic approximation from Cramer and Truhlar 2 was applied to compute the thermal corrections for a few key transition state structures. In the quasiharmonic approximation, vibrational frequencies lower than 100 cm -1 were raised to 100 cm -1 as a way to avoid spurious results associated with the harmonic-oscillator model for very low-frequency vibrations. The computed relative Gibbs free energies of the hydrocupration transition states of trans-2-butene and propene with SEGPHOS (L1) and DTBM-SEGPHOS (L2) based CuH catalysts (TS1a, TS2a, TS3, TS4) using the harmonicoscillator approximation (the method used in this manuscript) and the quasiharmonic approximation are shown in Table S2. The computed Gibbs free energies are only slightly affected by using the quasiharmonic approximation. More importantly, the key conclusion about the ligand effect on the hydrocupration reactivity is not affected by the choice of method. Table S2. Comparison of activation free energies of hydrocupration transition states computed with harmonic and quasiharmonic approximations. Hydrocupration Transition ΔG sol (harmonic) ΔG sol (quasiharmonic) State a trans-2-butene + L1CuH (TS1a) trans-2-butene + L2CuH (TS2a) propene + L1CuH (TS3) propene + L2CuH (TS4) a All free energies are in kcal mol -1. The calculated ΔG sol are with respect to the separated substrate and LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). THF was used as solvent in all solvation energy calculations. S3

4 Comparison of ΔE int-space Using Different Levels of Theories The ligand-substrate through-space interaction energy (ΔE int-space ) in the hydrocupration transition states (TS1a and TS2a) of trans-2-butene with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)) were calculated using different levels of theories (Table S3). ΔE int-space in these two transition states and the relative energy difference (ΔΔE int-space ) are marginally affected by the choice of the dispersioncorrected density functionals (M06, ωb97xd, TPSS-D3, and B3LYP-D3). Furthermore, the ΔE int-space calculated using the SOS(MI)-MP2/db-cc-pVTZ method are comparable to those from the dispersioncorrected DFT methods. All these methods show the through-space interaction energies are negative, indicating stabilizing interaction. In contrast, B3LYP and HF give positive interaction energies due to their inefficiencies in describing the dispersion effects. Table S3. Comparison of the ΔE int-space in the hydrocupration transition states of trans-2-butene with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)) using different levels of theories. Method for Single Point Energy Calculation a ΔE int-space in TS1a (trans-2-butene + L1CuH) ΔE int-space in TS2a (trans-2-butene + L2CuH ) ΔΔE int-space (TS1a TS2a) M06/6-311+G(d,p) b ωb97xd/6-311+g(d,p) TPSS-D3/6-311+G(d,p) B3LYP-D3/6-311+G(d,p) SOS(MI)-MP2/db-cc-pVTZ B3LYP/6-311+G(d,p) HF/6-311+G(d,p) a All energies are in gas phase and kcal mol -1. The geometries were optimized at the B3LYP/SDD 6-31G(d) level. b The level of theory used in the present study. S4

5 Next, we chose eight dispersion-stabilized complexes from the S22 database, 3,4 and compared their interaction energies calculated at M06/6-311+G(d,p), SOS(MI)-MP2/db-cc-pVTZ, and CCSD(T)/CBS levels. As shown in Table S4, both the M06 and SOS(MI)-MP2 methods show good agreement with the CCSD(T)/CBS results. Table S4. Comparison of interaction energies of eight dispersion-stabilized complexes in the S22 database at M06/6-311+G(d,p), RIMP2/db-cc-pVTZ and CCSD(T)/CBS levels. a Complex a M06/6-311+G(d,p) SOS(MI)-MP2/ db-cc-pvtz CCSD(T)/CBS methane dimer methane-benzene parallel benzene dimer ethene dimer stacked indole-benzene stacked pyrazine dimer stacked uracil dimer stacked adenine-thymine MSE b MUE c a All energies (kcal mol -1 ) are in gas phase. The geometries and the interaction energies at CCSD(T)/CBS level were taken from the S22 database. See ref. 3. b MSE denotes mean signed error. c MUE denotes mean unsigned error. S5

6 Furthermore, we compared the ligand-substrate interaction energy calculated at M06/6-311+G(d,p) and SOS(MI)-MP2/db-cc-pVTZ levels for the hydrocupration transition sates of internal olefins with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). A good linear correlation was obtained for these two methods (Figure S1). Taken together, these benchmark calculations suggest that M06/6-311+G(d,p) and SOS(MI)-MP2 methods provide comparable results for the calculation of ligandsubstrate interaction energies. Figure S1. Linear correlation of ΔE int-space calculated at M06/6-311+G(d,p) and SOS(MI)-MP2/db-ccpVTZ levels for the hydrocupration transition states of internal olefins with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). S6

7 Comparison of Dispersion Energies Calculated Using Different Methods The dispersion energies between the ligand and the substrate were calculated by using three different methods: a) the energy difference between MP2 and HF (denoted as MP2 HF), b) Grimme s HF-D3 dispersion correction, and c) the symmetry-adapted perturbation theory (SAPT). The MP2 HF dispersion energy was used in the manuscript. Here we compared the MP2 HF dispersion energy with those calculated from Grimme s HF-D3 and SAPT. Excellent linear correlations were obtained (Figures S2 and S3). This indicates the MP2 HF dispersion energy is in good agreement with those from Grimme s HF-D3 and SAPT methods. Computational details for dispersion calculations: 1) The MP2 HF method. Since most complexes in the present study have more than 200 atoms, efficient SOS(MI)-MP2 calculations with dual-basis set of db-cc-pvtz were performed in a development version of Q-Chem. The frozen core approximation with the default setting was used to speed up the calculations. The counterpoise correction (CP) was used to reduce the basis set superposition error (BSSE) in the calculation of binding energies. The MP2 energy was calculated by the sum of the HF energy and the scaled Total OS-MP2 correlation energy with a factor of The dispersion energy was obtained from the energy difference of MP2 with HF. 2) Grimme s HF-D3 method. Version 3.1 of Grimme s DFT-D3 was used to calculate the dispersion energy. 6 The HF-D3 with zero-damping was used to calculate the dispersion energy. 3) The SAPT method. Density-fitted SAPT calculations were performed at the SAPT0 level using the SAPT module 7,8 in the PSI4 software package. 9 A truncated aug-cc-pvdz basis 10 (i.e. jun-cc-pvdz) was used, which was optimal with the SAPT0 level due to the good performance in error cancellation. 7 The frozen core approximation with the default setting was also used. Due to the high computational demand, only the hydrocupration transition states of internal olefins with SEGPHOS were selected to calculate the dispersion using SAPT. S7

8 Figure S2. Linear correlation of the ΔE disp calculated using the MP2 HF and HF-D3 methods. Figure S3. Linear correlation of the ΔE disp calculated using the MP2 HF and SAPT methods. S8

9 Effects of Solvent In the hydrocupration of trans-4-octene with SEGPHOS- and DTBM-SEGPHOS-based CuH catalysts (TS1 and TS2, Figure S4), solvent is not expected to have a significant impact due to the small difference of the change in solvent-accessible area between these two reactions. Figure S4. Changes in the solvent-accessible area of TS1 and TS2. S9

10 Effects of Ligand s Methoxy and tert-butyl Substituents As discussed in the manuscript, the CuH catalyst based on DTBM-SEGPHOS (L2) displays a higher level of reactivity in olefin hydrocupration than that based on SEGPHOS (L1) due to more favorable dispersion interactions with the 3,5-di-tert-butyl-4-methoxyphenyl substituents on the DTBM- SEGPHOS ligand. To investigate whether the reactivity is sensitive to the electronic effects of the ligands, we calculated the activation free energies of hydrocupration of trans-2-butene using CuH catalysts based on two additional SEGPHOS-derived ligands. Replacing the t-bu substituents on L2 with H atoms, L14 is expected to have comparable electronic properties while considerably reduced dispersion interactions with the olefin substrate in the hydrocupration transition state (Figure S5). Replacing the MeO groups on L2 with H atoms, L5 is expected to be much less electron-rich while have comparable dispersion interactions as L2. The computations show that the catalysts based on the ligands with a stronger electrondonating para-meo group do not enhance the reactivity of hydrocupration (L1 vs L14, L2 vs L5). In contrast, the meta-t-bu substitution is critical for the enhanced reactivity (L1 vs L5, L2 vs L14). These results suggest the enhanced reactivity of the DTBM-SEGPHOS (L2)-based catalyst is not due to the electron-donating property of the ligand. Instead, bulky t-bu substituents play a much more important role in promoting the reactivity of hydrocupration. These computationally predicted activation energies were consistent with the experimentally measured initial rates with these ligands (see Figure 6 of the main manuscript). Figure S5. Comparison of the activation free energies of the hydrocupration of trans-2-butene with CuH catalysts based on different ligands. Energies are with respect to the separated trans-2-butene and LCuH. S10

11 Correlations of ΔE with ΔE int-bond, ΔE dist, and ΔE int We dissected the activation energy (ΔE ) of hydrocupration of terminal and internal olefins into through-space interaction energy (ΔE int-space ), through-bond interaction energy (ΔE int-bond ) and distortion energy of catalysts and substrate (ΔE dist ) (equation 1 in the manuscript). Great linear correlations were obtained for the relationships of ΔE with ΔE int-space, which are shown in Figure 3b in the manuscript (R 2 = 0.97 for terminal olefins and R 2 = 0.95 for internal olefins). In contrast, poor correlations were observed between ΔE and ΔE int-bond (Figure S6), and between ΔE and ΔE dist (Figure S7) for both terminal and internal olefins. These results indicate that the reactivity of hydrocupration (ΔE ) is predominantly controlled by the through-space ligand-substrate interaction (ΔE int-space ). While there is no clear trend to distinguish ΔE int-bond of the two types of substrates (internal and terminal olefins, Figure S6), the ΔE dist of terminal olefins are generally lower than that of internal olefins (Figure S7). In addition, we studied the correlation between ΔE and the total interaction energy (ΔE int ) that is the sum of through-bond (ΔE intbond) and through-space (ΔE int-space ) interactions. This total interaction energy can be derived from the classical distortion/interaction model (i.e. ΔE = ΔE int + ΔE dist ). Poor correlations between ΔE and ΔE int were observed for both terminal and internal olefins (Figure S8). This highlights the advantage of the ligand-substrate interaction model described in the present study. Figure S6. Correlations between ΔE and ΔE int-bond in the hydrocupration transition states of terminal (in blue) and internal olefins (in black) (R = Me, Et, Pr, i-pr, t-bu, Cy, Bn, CHEt 2 and Ph) with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). S11

12 Figure S7. Correlations between ΔE and ΔE dist in the hydrocupration transition states of terminal (in blue) and internal olefins (in black) (R = Me, Et, Pr, i-pr, t-bu, Cy, Bn, CHEt 2 and Ph) with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). Figure S8. Correlations between ΔE and ΔE int in the hydrocupration transition states of terminal (in blue) and internal olefins (in black) (R = Me, Et, Pr, i-pr, t-bu, Cy, Bn, CHEt 2 and Ph) with LCuH (L = SEGPHOS (L1) and DTBM-SEGPHOS (L2)). S12

13 Contribution of Each Component in the Ligand-Substrate Interaction Model Analysis Table S5. Energies (in kcal mol -1 ) of different components derived from the ligand-substrate interaction model and the activation free energies (ΔG sol) of the hydrocupration transition states. Energy R = Me (TS1a) R = Et (TS1b) R = Pr (TS1) R = i-pr (TS1c) L1CuH (L1 = SEGPHOS) + internal olefin R = t-bu (TS1d) S13 R = Cy (TS1e) R = Bn (TS1f) R = CHEt 2 (TS1g) R = Ph (TS1h) R = CEt 3 (TS1i) ΔG sol ΔE ΔE dist ΔE int-bond ΔE int-space ΔE rep ΔE pol ΔE ct ΔE disp L2CuH (L2 = DTBM-SEGPHOS) + internal olefin Energy R = Me R = Et R = Pr R = i-pr R = t-bu R = Cy R = Bn R = CHEt 2 R = Ph R = CEt 3 (TS2a) (TS2b) (TS2) (TS2c) (TS2d) (TS2e) (TS2f) (TS2g) (TS2h) (TS2i) ΔG sol ΔE ΔE dist ΔE int-bond ΔE int-space ΔE rep ΔE pol ΔE ct ΔE disp L1CuH (L1 = SEGPHOS) + terminal olefin Energy R = Me R = Et R = Pr R = i-pr R = t-bu R = Cy R = Bn R = CHEt 2 R = Ph R = COMe (TS3) (TS3a) (TS3b) (TS3c) (TS3d) (TS3e) (TS3f) (TS3g) (TS3h) (TS3i) ΔG sol ΔE ΔE dist ΔE int-bond ΔE int-space ΔE rep ΔE pol ΔE ct ΔE disp L2CuH (L2 = DTBM-SEGPHOS) + terminal olefin Energy R = Me R = Et R = Pr R = i-pr R = t-bu R = Cy R = Bn R = CHEt 2 R = Ph R = COMe (TS4) (TS4a) (TS4b) (TS4c) (TS4d) (TS4e) (TS4f) (TS4g) (TS4h) (TS4i) ΔG sol ΔE ΔE dist ΔE int-bond ΔE int-space

14 ΔE rep ΔE pol ΔE ct ΔE disp S14

15 Based on the data shown in Table S5, we used pie charts to show the percentage contribution of each energy component to the reactivities of hydrocupration of internal and terminal olefins using SEGPHOS and DTBM-SEGPHOS based CuH catalysts. Here, only the energy components that positively contribute to the stability of TS2x and TS4x compared to that of TS1x and TS3x were considered. The results clearly indicate that the enhanced reactivity of the CuH catalyst with DTBM-SEGPHOS is mostly attributed to the dispersion interaction energy for both internal and terminal olefins (Figure S9). Figure S9. Pie chart analysis based on the ligand-substrate interaction model. S15

16 Dispersion Interaction Energies Between Pr and t-bu Substituents in TS2 To study the origin of the dispersion interaction in TS2, we separately calculated the dispersion interactions between the Pr substituents in trans-4-octene and the t-bu substituents in DTBM-SEGPHOS using the MP2 HF method (see Method section in the main text). The geometry of each pairwise Pr and t-bu was taken from the geometry of TS2. An additional H atom was added to the dangling carbon atom in the Pr and t-bu groups along the direction of previous C C bonds and the C H distance was set to 1.07 Å (Figure S10a). The dispersion interaction energies of the Pr group with the t-bu group at adjacent quadrants are shown in Figure S10b. The total dispersion energy of the eight pairwise interactions shown in Figure S10b is 4.5 kcal mol -1, which is comparable to the difference of ligand-substrate dispersion energy between TS1 with SEGPHOS and TS2 with DTBM-SEGPHOS (ΔΔE disp = 6.4 kcal mol -1, Figure 4a in the manuscript). This indicates that the dispersion interactions between the t-bu groups on the ligand and the alkyl substituents on the olefin substrate dominant the enhanced reactivity of hydrocupration with the bulky DTBM-SEGPHOS ligand. Figure S10. Dispersion interaction energies between the Pr and the t-bu substituents in TS2. S16

17 Correlations of ΔE rep, ΔE pol and ΔE ct with ΔE int-space and ΔE To investigate the nature of the through-space ligand-substrate interaction, we dissected ΔE int-space into four chemically meaningful energy components: dispersion (ΔE disp ), Pauli and electrostatic repulsion (ΔE rep ), intrafragment polarization (ΔE pol ) and ligand-substrate charge transfer (ΔE ct ). The ΔE disp term correlates well with ΔE int-space and ΔE (Figure 5 in the manuscript). The correlations of the rest of three components (ΔE rep, ΔE pol and ΔE ct ) with ΔE int-space and ΔE are shown in Figures S11-S13. Poor correlations were observed between ΔE rep and ΔE int-space and between ΔE rep and ΔE in Figure S11. Although ΔE pol and ΔE ct show relatively good correlations with ΔE int-space and ΔE (Figures S12 and S13), the energy differences for ΔE pol and ΔE ct in different reactions are quite small (less than 1.0 kcal mol -1 ). This suggests these two components only have marginal influence on the activation energy of hydrocupration. In contrast, ΔE disp not only shows good linear correlations with ΔE int-space and ΔE, but also has large variations in different reactions (Figure 5 in the manuscript). Therefore, the dispersion term is the dominating factor that controls the ligand-substrate interactions and the hydrocupration reactivity. Figure S11. a, Relationship between ΔE rep and ΔE int-space (including terminal and internal olefins). b, Relationships between ΔE rep and ΔE (terminal olefins in blue and internal olefins in black). S17

18 Figure S12. a, Relationship between ΔE pol and ΔE int-space (including terminal and internal olefins). b, Relationships between ΔE pol and ΔE (terminal olefins in blue and internal olefins in black). Figure S13. a, Relationship between ΔE ct and ΔE int-space (including terminal and internal olefins). b, Relationships between ΔE ct and ΔE (terminal olefins in blue and internal olefins in black). S18

19 General Information for Kinetic Experiments Caution: Dimethoxy(methyl)silane (DMMS, CAS # ) DMMS is listed by several vendors' SDS or MSDS as a H318, a category 1 Causes Serious Eye Damage. Other vendors list DMMS as a H319, a category II Eye Irritant. DMMS should be handled in a well-ventilated fumehood using proper precaution as outlined for the handling of hazardous materials in prudent practices in the laboratory. At the end of the reaction either ammonium fluoride in methanol, aqueous sodium hydroxide (1 M) or aqueous hydrochloric acid (1 M) should be carefully added to the reaction mixture. This should be allowed to stir for at least 30 minutes or the time indicated in the detailed reaction procedure. All reactions were carried out under a dry nitrogen atmosphere. THF was purchased from J.T. Baker in CYCLE-TAINER solvent delivery kegs and purified by passage under argon pressure through two packed columns of neutral alumina and copper(ii) oxide. Copper(II) acetate was purchased from Strem and was used as received. Dimethoxymethylsilane was purchased from TCI-America and stored under nitrogen at 20 C. DTBM-SEGPHOS was obtained from Takasago and was used without further purification. O-benzoyl-N,N-dibenzylhydroxylamine was synthesized according to a previously reported procedure. 11 All other ligands and reagents were purchased from Sigma-Aldrich, Strem, Alfa Aesar, TCI- America, Combi-Blocks, Matrix Scientific, or Enamine Chemicals and were used as received. NMR experiments were performed on a Varian 300 MHz, Bruker 400 MHz, or Varian 500 MHz instrument. Chemical shifts are reported in parts per million (ppm) relative to residual chloroform (7.26 ppm for 1 H, ppm for 13 C). A recycle delay of 1.0 s was employed, and 8 initial steady state scans were discarded to ensure accurate integration. O + O Bn N Bn 5.1 mol% Ligand 5 mol% Cu(OAc) 2 3 equiv (MeO) 2 MeSiH THF (0.5 M), 40 C NBn 2 General Procedure for Measuring Relative Rates of Catalytic Anti-Markonikov Hydroamination: In a nitrogen-filled glove box, a stock solution of 4-phenyl-1-butene (79 mg, 0.6 mmol, 1 equiv), O- benzoyl-n,n-dibenzylhydroxylamine (229 mg, 0.72 mmol, 1.2 equiv), copper(ii) acetate (5.5 mg, 0.03 mmol, 0.05 equiv), and ligand ( mmol, equiv) in THF (1.20 ml) was loaded into a dry 20 ml scintillation vial. This mixture was stirred vigorously for 5 minutes, until a homogeneous solution was obtained. Meanwhile, 6 to 12 oven-dried screw-cap reaction tubes (13 x 100 mm, Fisher part # C) were equipped with a magnetic stirring bar inside the glove box. Mesitylene ( ml, 0.6 mmol, 1 equiv) was added to the stock solution as an internal standard, and the stock solution was evenly distributed into the reaction tubes (0.05 or 0.1 mmol olefin each). The tubes were capped tightly with a screw cap equipped with a rubber septum insert (National part #C A) and removed from the glove box. The reaction mixtures were submerged roughly 1 cm into the center of an oil bath, which was preheated to and maintained at 40 C using a thermocouple. Under rapid stirring, dimethoxymethylsilane (37.5 µl, 0.3 mmol, 3 equiv) was added in one portion to each tube using a syringe, which led to an immediate color change of the solution to yellow or orange. A timer was started at this point, and after S19

20 the appropriate amount of time had passed (see results below for quenching schedule), a reaction tube was removed from the oil bath and uncapped. Then, 1.0 ml of a saturated ammonium fluoride solution in methanol was quickly added (CAUTION: vigorous hydrogen evolution!). After 20 minutes, the solvent was removed in vacuo. The residue was suspended in CDCl 3, and filtered through a cotton plug, washing with additional CDCl 3. This crude solution was analyzed by 1 H NMR to determine the yield of N,N-dibenzyl-4-phenylbutan-1-amine, which has been previously characterized. 12 Table S6. Yield measurements for copper-catalyzed anti-markovnikov hydroamination using bisphosphine ligands. Ligand DTBM- SEGPHOS DTB- SEGPHOS DMM- SEGPHOS DM- SEGPHOS SEGPHOS DM-MeO- BIPHEP Cy-MeO- BIPHEP DPPBz DTB- DPPBz MeO- DTBM- DTBM-MeO- BINAP BIPHEP BINAP BIPHEP Time (min) Product (%) S20

21 Yield (%) DTBM-SEGPHOS DM-SEGPHOS SEGPHOS DTBM-MeO- BIPHEP DM-MeO-BIPHEP MeO-BIPHEP Cy-MeO-BIPHEP DTB-DPPBz DPPBz DTBM-BINAP BINAP Time (min) Figure S14. Kinetic profiles of anti-markovnikov hydroamination with variation of the phosphine ligand. S21

22 Determination of Relative Initial Rate: For each ligand, the measured yield of product as a function of time was fitted using simple least-squares regression to a third- or fourth-order polynomial with no y- intercept. The ratios of the initial rates (k/k 0 and log(k/k 0 )) were calculated relative to the reference ligand (SEGPHOS). Table S7. Initial and relative rates for copper-catalyzed anti-markovnikov hydroamination using bisphosphine ligands. DTBM- SEGPHOS DTB- SEGPHOS DMM- SEGPHOS DM- SEGPHOS SEGPHOS DM-MeO- BIPHEP Cy-MeO- BIPHEP Initial Rate (M/hr) 3.63E E E E E E E-03 k/k E E E E E E E-02 log(k/k 0 ) DPPBz DTB- DPPBz MeO- BIPHEP BINAP DTBM- BINAP DTBM-MeO- BIPHEP Initial Rate (M/hr) 8.40E E E E E E-01 k/k E E E E E E+00 log(k/k 0 ) Assessment of Kinetic Order in Olefin: Using representative ligands DTBM-SEGPHOS (a fast ligand), MeO-BIPHEP (an intermediate ligand), and DPPBz (a slow ligand), the general procedure for measuring relative rates was followed, except the starting concentration of olefin was varied. The initial rates were calculated and displayed below. We concluded that the order in olefin in all cases is non-zero, and thus the hydrocupration step was likely contained in the rate-determining energetic span. Initial Rate (M/hr) A. DTBM-SEGPHOS Initial [Olefin] (M) S22

23 B. MeO-BIPHEP Initial Rate (M/hr) Initial [Olefin] (M) Initial Rate (M/hr) C. DPPBz Initial [Olefin] (M) Figure S15. Rates determined while varying initial [Olefin]. S23

24 Additional Computational Results NCI plot of the ligand-substrate non-covalent interaction in the hydrocupration transition state NCI (non-covalent interactions) plot was obtained for the supramolecular complex of the DTBM- SEGPHOS ligand and the trans-4-octene substrate in the hydrocupration transition state (TS2). The NCI plot shows weakly attractive interaction (the green slice) between the bisphosphine ligand (e.g. DTBM- SEGPHOS, in blue) and the olefin substrate (e.g. trans-4-octene, in red) in the hydrocupration transition state. This is consistent with the dispersion energy calculations in the main manuscript that show attractive interactions between the ligand and the substrate. Figure S16. The NCI plot between DTBM-SEGPHOS (in blue) and trans-4-octane (in red) in the hydrocupration transition state. Ligand effects on the stability of the alkyl copper(i) intermediate after the hydrocupration transition state We calculated the energies of the alkyl copper(i) intermediates after the hydrocupration transition state. As shown in Figure S17, the alkyl copper intermediate with the DTBM-SEGPHOS ligand (S4) is also more stable than that with SEGPHOS (S3). This suggests that dispersion interactions with the bulkier DTBM-SEGPHOS ligand also stabilize the intermediate. S24

25 Figure S17. Energy profile of hydrocupration of trans-2-butene with the CuH catalysts supported by SEGPHOS (L1) and DTBM-SEGPHOS (L2). Energies are with respect to the separated LCuH and olefin. Effects of CuH binding on the dispersion interactions between the P atoms on the ligand and the substrate The binding with Cu could affect the polarizability of P atoms, and influence the dispersion interactions between P atoms and the substrate. To examine the magnitude of this effect, we performed second-generation energy decomposition analysis ( EDA2 ) in Q-CHEM, 13 which identifies dispersion contributions by calculating the difference between non-local dispersion-corrected density functionals and dispersion-free functionals. Our calculations used the wb97m-v functional 14 for predicting dispersion interactions and the revpbe and PBE functionals 15,16 for the dispersion-free exchange and correlation energies, respectively. We employed the def2-tzvp basis 17 for copper and 6-311G(d,p) for all other atoms. The dispersion energies between the ligand (L) and the substrate (S) were calculated using two approaches, without CuH (ΔE disp, i.e. from the hypothetical ligand-substrate complex as employed in the EDA calculations in the main manuscript), and with CuH. In the second approach (with CuH), the dispersion energy between the ligand and the substrate (ΔE disp-3 ) was calculated from the difference between the total three-fragment dispersion (E disp-tot ) in the transition state and the ligand-cuh dispersion interaction (E disp-1 ) in the absence of the substrate and the substrate-cuh dispersion interaction (E disp-2 ) in the absence of the ligand. For the hydrocupration transition state with SEGPHOS and trans-4-octene (TS1), as shown in Table S8, the L-S dispersion interactions without and with CuH are 11.1 and 8.5 kcal/mol, respectively. It should be noted that the second approach (with CuH) is expected to overestimate the ligand-cuh (E disp-1 ) and the substrate-cuh dispersion (E disp-2 ), because the CuH in the hypothetical complexes used in these calculations is expected to be more polarizable than that in the real transition state. Therefore, the ligand-substrate dispersion interaction in the presence of CuH should be more S25

26 negative than 8.5 kcal/mol. Overall, these results suggest the binding of CuH reduces the L-S dispersion by no more than 2.6 kcal/mol, relatively small compared to the overall ligand-substrate dispersion. Furthermore, the effect of CuH on the L-S dispersion is expected to much smaller when studying the difference among bisphosphine ligands. Table S8. The Effect of Cu on the Ligand-Substrate Dispersion Interaction. L-S a (ΔE disp ) L-CuH-S b (E disp-tot ) L-CuH c (E disp-1 ) CuH-S d (E disp-2 ) L-S ΔE disp-3 = (E disp-tot ) (E disp-1 ) (E disp-2 ) ΔE disp-3 ΔE disp Energy (kcal/mol) a L = SEGPHOS; S = trans-4-octene. The dispersion energy (ΔE disp ) was calculated based on a supramolecular ligand-substrate complex at the transition state geometry in the absence of the CuH moiety. b The dispersion energy (ΔE disp-tot ) was calculated from a three-fragment EDA2 calculation of TS1 in Q-CHEM. c The dispersion energy (ΔE disp-1 ) was calculated from a hypothetical L-CuH complex at the transition state geometry in the absence of the substrate. d The dispersion energy (ΔE disp- 2) was calculated from a hypothetical CuH-S complex at the transition state geometry in the absence of the ligand. EDA calculations using the B3LYP-D3 optimized geometries EDA calculations were performed using both B3LYP and B3LYP-D3 geometries to investigate whether using the dispersion-corrected method for geometry optimization will affect the energy values of the different components in the EDA. As shown in Table S9, EDA calculations using the two sets of geometries provide similar energy values for each component. In both cases, the ligand-substrate dispersion interaction (ΔE disp ) is the major factor that contributes to the higher reactivity of the CuH catalyst with DTBM-SEGPHOS than that with SEGPHOS. Table S9. Comparison of EDA Based on B3LYP and B3LYP-D3 Optimized Hydrocupration Transition States. Energy (kcal/mol) L1CuH + trans-2-butene (TS1a) B3LYP optimized geometry L2CuH + trans-2-butene (TS2a) ΔΔG or ΔΔE (TS1a TS2a) L1CuH + trans-2-butene (TS1a ) B3LYP-D3 optimized geometry L2CuH + trans-2-butene (TS2a ) ΔΔG or ΔΔE (TS1a TS2a ) ΔG sol ΔE ΔE dist ΔE int-bond ΔE int-space ΔE rep ΔE pol ΔE ct ΔE disp L1 = SEGPHOS, L2 = DTBM-SEGPHOS S26

27 Correlation between activation free energy and through-space ligand-substrate interaction energy We also studied the relationship between the activation free energy (ΔG ) and through-space ligand-substrate interaction energy (ΔE int-space ). Good linear correlations were observed for most terminal and internal olefins (Figure S18). This is consistent with the linear correlations between ΔE int-space and ΔE shown in Figure 3b in the manuscript. Figure S18. Energy profile of hydrocupration of trans-2-butene with the CuH catalysts supported by SEGPHOS (L1) and DTBM-SEGPHOS (L2). Energies are with respect to the separated LCuH and olefin. Through-space ligand-substrate interaction and dispersion in the reactions with other bisphosphine ligands We studied the relationships between the activation energy (ΔE ) and the through-space ligandsubstrate interaction (ΔE int-space, Figure S19a), and between the activation energy (ΔE ) and the ligandsubstrate dispersion (ΔE int-space, Figure S19b) for the thirteen bisphosphine ligands shown in Figure 6 in the manuscript. In general, good correlations were observed in these relationships, which indicate that the enhanced reactivity with the di-tert-butyl substituted ligands (L2, L5, L9, and L11) is primarily due to the more stabilizing dispersion and through-space interactions. Deviations from the linear relationships also shed light on other factors that affect the reactivity. For example, the reaction using the Cy-MeO- BIPHEP ligand suffers greater steric repulsions with this ligand. Reactions with the DPPBz family of ligands have smaller dispersion and through-space interactions because the P-bound aryl substituents S27

28 point slightly further away from olefins in the hydrocupration transition sates. However, similar to the promotion effects of bulkier ligands in the SEGPHOS, MeO-BIPHEP, and BINAP families, DTB-DPPBz (L13) with di-t-bu substituents is more effective than DPPBz (L12). Figure S19. a, Linear correlation between the activation energy (ΔE ) and the through-space ligandsubstrate interaction (ΔEint-space). b, Linear correlation between ligand-substrate dispersion (ΔEdisp) and activation energy (ΔE ). S28

29 Cartesian Coordinates (Å) and Energies of the Optimized Structures SEGPHOS-CuH B3LYP SCF energy: a.u. B3LYP enthalpy: a.u. B3LYP free energy: a.u. M06 SCF energy in solution: a.u. M06 enthalpy in solution: a.u. M06 free energy in solution: a.u. Three lowest frequencies (cm-1): Cartesian coordinates ATOM X Y Z C C C C C C C C C C O C O C O O P P H H H H H H Cu C C C C H C H C H H H C C C S29

30 C H C H C H H H C C C C H C H C H H H C C C C H C H C H H H H C C H H DTBM-SEGPHOS-CuH B3LYP SCF energy: a.u. B3LYP enthalpy: a.u. B3LYP free energy: a.u. M06 SCF energy in solution: a.u. M06 enthalpy in solution: a.u. M06 free energy in solution: a.u. Three lowest frequencies (cm-1): Cartesian coordinates ATOM X Y Z C C S30

31 C C C C C C C C O C O C O O P P H H H H H H Cu C C C C H C H C C C C C H C H C C C C C H C H C C C C C S31

32 H C H C H C C H H C C H H H C H H H C H H H C C H H H C H H H C H H H C C C H H H C H H H C H H H C H S32

33 H H C H H H C H H H C C C H H H C H H H C H H H C H H H C H H H C H H H C C C H H H C H H H C H H H C S33

34 H H H C H H H C H H H O C H H H O O O C H H H C H H H C H H H TS1 B3LYP SCF energy: a.u. B3LYP enthalpy: a.u. B3LYP free energy: a.u. M06 SCF energy in solution: a.u. M06 enthalpy in solution: a.u. M06 free energy in solution: a.u. Three lowest frequencies (cm-1): Imaginary frequency: cm-1 Cartesian coordinates ATOM X Y Z Cu H C C H S34

35 P C C C C C C C C C C C C H C H C H C H C H C O C C H C C O C C O C P H H C O C H C C H H H C C C C C S35

36 H C H C H C H C C C H H C H C H H C H H H H C H H H C H H H H H H H H H H H H H H H TS1a B3LYP SCF energy: B3LYP enthalpy: B3LYP free energy: M06 SCF energy in solution: M06 enthalpy in solution: a.u a.u a.u a.u a.u. S36