S1

Supporting Information to

Hydration of Nitriles using a Metal-Ligand Cooperative Ruthenium Pincer Catalyst

Beibei Guo, Johannes G. de Vries and Edwin Otten

Table of ContentsGeneral considerations .................................................................................................................................2

Optimization of reaction conditions..............................................................................................................3

Synthetic procedures.....................................................................................................................................5

Preparation of stock solutions of catalysts and reagents..........................................................................5

General procedure for catalytic nitrile hydration experiments.................................................................6

Reactions performed on larger scale.........................................................................................................7

Reactions performed at 70 C ...................................................................................................................8

Characterization of amide products ..............................................................................................................9

Stoichiometric NMR scale reactions for PNP complexes ............................................................................11

Reaction of APNP with 4-fluorobenzonitrile (1b) ......................................................................................11

Reaction of APNP with 4-fluorobenzonitrile (1b) and water .....................................................................13

Characterization of DPNP ..........................................................................................................................15

Stoichiometric NMR scale reactions for PNN complexes............................................................................21

Reaction of APNN with 4-fluorobenzonitrile (1b)......................................................................................21

Reaction of APNN with 4-fluorobenzonitrile (1b) and water.....................................................................24

Characterization of DPNN ..........................................................................................................................26

Stoichiometric reaction of DPNN with 4-fluorobenzonitrile (1b)...............................................................29

Catalyst inhibition........................................................................................................................................31

Preliminary DFT calculations .......................................................................................................................34

References...................................................................................................................................................44

NMR spectra of products (2a-2ag) ..............................................................................................................46

Electronic Supplementary Material (ESI) for Chemical Science.This journal is © The Royal Society of Chemistry 2019

S2

General considerations

The chemicals 2,6-bis(di-tert-butylphosphinomethyl)pyridine (Strem Chemicals, 99%), carbonylchlorohydridotris(triphenylphosphine)ruthenium(II) (Strem Chemicals, 99%), [2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride (precatPNN, Sigma-Aldrich, 99%), potassium tert-butoxide (Sigma-Aldrich, ≥98%), 2-fluorobiphenyl (Sigma-Aldrich, 96%), 4-fluorobenzonitrile (1b, Sigma-Aldrich, 99%), 4-chlorobenzonitrile (1c, Sigma-Aldrich, 99%), bromobenzonitrile (1d-f, Sigma-Aldrich, 99%), 4-(trifluoromethyl)benzonitrile (1g, Sigma-Aldrich, 99%), 4-formylbenzonitrile (1h, TCI, >98%), tert-butyl 4-cyanobenzoate (1i, Enamine Ltd, 95%), 1-naphthonitrile (1j, TCI, >95%), 2-naphthonitrile (1k, TCI, >98%), 4-methylbenzonitrile (1l, Sigma-Aldrich, 98%), 4-methoxybenzonitrile (1m, Sigma-Aldrich, 99%), 4-(dimethylamino)benzonitrile (1n, TCI, >98%), 4-aminobenzonitrile (1o, Sigma-Aldrich, 98%), pyridinecarbonitrile (1p-r, Sigma-Aldrich, 98%), 2-furonitrile (1v,TCI, >98%), 3-furonitrile (1w, Sigma-Aldrich, >97%), terephthalonitrile (1ag, Sigma-Aldrich, 98%), 4-acetoxybenzonitrile (Fisher Scientific, 97%), 4-nitrobenzonitrile (Sigma-Aldrich, 97%), 4-hydroxybenzonitrile (Fluka, 98%) and ethyl 4-cyanobenzoate (TCI, >98%) were obtained commercially and used without further purification. The substrates benzonitrile (1a, Sigma-Aldrich, 99%), pyrazinecarbonitrile (1s, Sigma-Aldrich, 99%), 2-thiophenecarbonitrile (1t, Sigma-Aldrich, 99%), 3-thiophenecarbonitrile (1u, TCI, >98%), benzyl cyanide (1x, Sigma-Aldrich, 98%), 2-phenylpropanitrile (1y, Sigma-Aldrich, 96%), 3-phenylpropanitrile (1z, Sigma-Aldrich, 99%), cinnamonitrile (1aa, Sigma-Aldrich, 97%), n-pentanenitrile (1ac, Sigma-Aldrich, 99.5%), cyclohexanecarbonitrile (1ad, Sigma-Aldrich, 98%), pivalonitrile (1ae, Sigma-Aldrich, 98%), adiponitrile (1af, TCI, >98%), were obtained commercially, degassed and passed over columns of Al2O3 prior to use. The complex [2,6-Bis(di-tert-butylphosphinomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride (precatPNP) was prepared according to a literature procedure.[1][2] Toluene was passed over columns of Al2O3 (Fluka), BASF R3-11-supported Cu oxygen scavenger, and molecular sieves (Aldrich, 4 Å). THF (Aldrich, anhydrous, 99.8%) was dried by percolation over columns of Al2O3 (Fluka). Tert butanol (Boom, >99%), isopropanol (Boom, >99%), 1,4-dioxane (Boom, >99%) and acetonitrile (1ab, Boom, >99%) were dried with calcium hydride and distilled under N2 atmosphere prior to use. Doubly distilled water was obtained from the Microanalytical Department of the University of Groningen and degassed prior to use. d8-THF and d8-toluene (Aldrich) were vacuum transferred from Na/K alloy and stored in the glovebox. NMR spectra were recorded on Varian 400, Agilent 400 or Varian Inova 500 spectrometers and referenced using the residual solvent resonance. Gas chromatography measurements were performed on HP6890 series equipped with a Rxi-5Sil column for GC/MS and HP5890 series II equipped with Rtx-1701 column for GC-MS/FID. Enantiomeric excess (ee) was determined by chiral HPLC analysis using a Shimadzu LC-20AD HPLC equipped with a Shimadzu SPD-M20A diode array detector. Elemental analysis and high resolution mass spectra (HRMS) were performed at the Microanalytical Department of the University of Groningen.

S3

Optimization of reaction conditions

Table S1: Solvent screening for hydration of acetonitrile. Conditions: 3 mol% of catalyst APNP at room temperature in the presence of 5 equiv. of water.

Me CN + H2O APNP (3mol%)solvent (0.5 ml) Me

C0.25 mmol

O

NH224h, rt

5 eq.

entry solvent conversion (%)a

1 toluene -

2 THF 37

3 Isopropanol <10

4 dioxane -

5 tBuOH 63(82b)

a) Conversions were detected by 1H NMR. b) Reactionfor 2.5 days.

Table S2: Effect of the amount of added water on the hydration of acetonitrile

Me CN + H2O APNP(3 mol%)tBuOH (0.5 ml) Me

C0.25 mmol

O

NH224h, rt

entry water (eq.) conversion (%)a

5 5 63(82b)

6 1 25

7 2 44

8 3 56

9 8 42

10 20 4

a) Conversions were detected by 1H NMR. b) Reactionfor 2.5 days.

S4

Table S3: Influence of catalyst structure and reaction temperature on the hydration of acetonitrile

Me CN + H2O catsolvent (0.5 ml) Me

C0.25 mmol

O

NH224h

5 eq.

entry solvent cat (mol%) temperature conversion (%)a

5 tBuOH APNP (3) rt 63(82b)

11 tBuOH APNN (3) rt 56

12 tBuOH APNP (3) 50 oC >99

13 tBuOH precatPNP (3) rt 0

14 tBuOH tBuOK (3) rt 0

a) Conversions were determined by 1H NMR.

N

PtBu2

PtBu2

RuH

CO

APNP

N

NEt2

PtBu2

RuH

CO

APNN

N

PtBu2

PtBu2

RuH

COCl

precatPNP

S5

Synthetic procedures

Preparation of stock solutions of catalysts and reagents

APNP catalyst (stock solution 1): In the glovebox, the catalyst precursor (PNP)Ru(Cl)(H)(CO)[2][1] (precatPNP, 28.0 mg, 0.050 mmol) was dissolved in 5 mL of toluene in a 20 ml vial, and then cooled in the freezer to -32 oC. Subsequently, tBuOK (5.6 mg, 0.050 mmol, 1 eq.) was added and the vial was stored at -32 oC for 1 hour, after which it was allowed to warm to room temperature and stirred for another 3 hours. The solution was filtered and toluene was added to achieve a total volume of 10 mL. This stock solution (0.0050 mol/L) was stored at -32 oC for later use.

APNP catalyst (stock solution 2, used for reactions on larger scale): In the glovebox, the catalyst precursor (PNP)Ru(Cl)(H)(CO)[2][1] (precatPNP, 0.375 mmol, 213.0 mg) was dissolved in 25 mL of toluene in a 25 ml vial, and then cooled in the freezer to -32 oC. Subsequently, tBuOK (42.0 mg, 0.375 mmol, 1 eq.) was added and the vial was stored at -32 oC for 1 hour, after which it was allowed to warm to room temperature and stirred for another 3 hours. The solution was filtered and the filtrate was dried under vacuum for 1 hours. Then the green solid was dissolved in 25 ml tBuOH and the stock solution (0.0150 mol/L) was used immediately.

APNN catalyst stock solution: In the glovebox, the catalyst precursor (PNN)Ru(Cl)(H)(CO) (precatPNN, 14.7 mg, 0.030 mmol) was dissolved in 4 mL of toluene in a 20 ml vial, and then cooled in the freezer to -32 oC. Subsequently, tBuOK (3.4 mg, 0.030 mmol, 1 eq.) was added and the vial was stored at -32 oC for 1 hour, after which it was allowed to warm to room temperature and stirred for another 3 hours. This stock solution (0.0075 mol/L) was stored at -32 oC for later use.

4-fluorobenzonitrile stock solution: A stock solution (0.30 mol/L) was prepared by dissolving 18.2 mg of 4-fluorobenzonitrile in 0.5 ml d8-THF.

4-fluorobenzamide stock solution: A stock solution (0.24 mol/L) was prepared by dissolving 16.7 mg of 4-fluorobenzamide in 0. 5ml d8-THF.

Water stock solution: A stock solution (1.70 mol/L) was prepared by dissolving 9.2 μl of H2O in 300 μl of anhydrous d8-THF.

S6

General procedure for catalytic nitrile hydration experiments

In the glovebox, 1.5 mL of a 0.0050 mol/L stock solution of APNP catalyst (0.0075 mmol) was added to a 20 mL vial. After removal of all volatiles under vacuum, 0.5 ml tBuOH was added to dissolve catalyst again. After ca. 2 min, water (22.5 μl, 1.25 mmol) was added to the catalyst solution, and then the mixture was transferred into a 2 mL GC vial (equipped with a Teflon-lined screw cap and additionally sealed with parafilm) containing the nitrile (0.25 mmol). The reaction mixture was taken out of glovebox and stirred for 16 h to 1 day at rt or 50/80oC. After this time, the reaction mixture was exposed to air to deactivate the catalyst. The procedure for subsequent workup depended on the nature of the reaction mixture:

Procedure a) If precipitated solid product was precipitated during the reaction, 3 mL of ether was added into the vial and the solid product was isolated by filtration and washed with ether. The filtrate was concentrated under vacuum to a viscous oil, then washed with ether/pentane (5:1, 3x2 ml) precipitating the second portion; collecting all the white solid and drying under vacuum gave >99% yield;

Procedure b) If no solid was precipitated during the reaction, the solvent was removed under vacuum to give a viscous oil and the residue was washed with ether/pentane (5:1 or 10:1) to precipitate a solid product; collecting all the white solid and drying under vacuum gave 90-99% yields.

S7

Reactions performed on larger scale

Catalytic hydration reactions for a series of representative nitriles were performed on 2.5 mmol scale. For nitriles 1a, 1b, 1i and 1ad, 5 mL of a 0.0150 M stock solution of APNP catalyst (0.0750 mmol, 3 mol%) was added to a 20 mL vial containing the nitrile. For nitrile 1r, 0.8 mL of a 0.0150 M stock solution of APNP catalyst (0.0120 mmol, 0.5 mol%) was diluted with 4.2 mL of tBuOH and added to a 20 mL vial containing the nitrile. Water (225 μl, 5 equiv relative to nitrile) was added to each of the vials and the mixtures were stirred at 50oC (1ad) or rt (1a, 1b, 1i and 1r) inside the glovebox. To monitor reaction progress, samples for GC analysis were taken at regular time intervals from each of these reaction mixtures. After the reaction went to completion, workup was carried out as described above.

benzonitrile (1a): 257.5 mg (2.5 mmol) of 1a afforded 287.4 mg (2.38 mmol, 95%) of benzamide (2a). Elemental analysis for C7H7NO: Calculated: C, 69.41; H, 5.82; N, 11.56; Found: C, 69.44; H, 5.75; N, 11.42.

4-fluorobenzonitrile (1b): 302.5 mg (2.5 mmol) of 1b afforded 336 mg (2.42 mmol, 97%) of 4-fluorobenzamide (2b). Elemental analysis for C7H6FNO: Calculated: C, 60.43; H, 4.35; N, 10.07; Found: C, 60.64; H, 4.44; N, 9.97.

4-methylbenzonitrile (1i): 292.5 mg (2.5 mmol) of 1i afforded 335.8 mg (2.49 mmol, 99%) of 4-methylbenzamide (2i). Elemental Analysis for C8H9NO: Calculated: C, 71.09; H, 6.71; N, 10.36; Found: C, 71.26; H, 6.67; N, 10.24.

Cyclohexanecarbonitrile (1ad): 272.5 mg (2.5 mmol) of 1ad afforded 305.0 mg (2.40 mmol, 96%) of cyclohexanecarboxamide (2ad). Elemental Analysis for C7H13NO: Calculated: C, 66.11; H, 10.30; N, 11.01; Found: C, 66.09; H, 10.18; N, 10.83.

4-pyridinecarbonitrile (1r): 260.0 mg (2.5 mmol) of 1r afforded 304.0 mg (2.49 mmol, 99%) of 4-pyridinecarboxamide (2r). Elemental Analysis for C6H6N2O: Calculated: C, 59.01; H, 4.95; N, 22.94; Found: C, 58.87; H, 4.84; N, 22.93.

Figure S1. Conversion vs. time plot for hydrdation of nitriles using APNP as catalyst in tBuOH (3 mol%, 5 eq of H2O). Reaction progress monitored at room temperature, except for cyclohexane carbonitrile (Cy), which was monitored at 50 oC.

S8

Reactions performed at 70 C

Reactions were carried out using the standard procedure described above, but the reaction mixture was heated to 70 C for 24 h.

O

NH2

F

N O

NH2

> 99%

x mol%24 h, 70 C

APNP(CH2)4

O

NH2O

H2N

(CH2)4 CNO

H2N +

98% > 99%

TON

conversion

307 196 1000

0.1 mol%x 0.5 mol%0.5 mol%

S9

Characterization of amide products

All isolated amide products were characterized by 1H and 13C NMR spectroscopy as well as high-resolution mass spectrometry. For the following compounds, these data are in agreement with the literature: 2a-2c[3], 2e[3], 2f [4], 2g[3], 2h[3], 2i[4], 2j[3], 2k[3], 2I[3], 2m[3], 2n[3], 2o[5], 2p-2r[7], 2s[8], 2t[3], 2u[9], 2v[3], 2x[3], 2y[10], 2z[11], 2aa[12], 2ac[3], 2ad[13], 2aec, 2af[15], 2ag[3].

Spectral assignment of amide products for which no NMR data in DMSO-d6 has been reported in the literature are provided below.

4-bromobenzamide (2d) [4]

O

NH2

Br

1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H, NH), 7.81 (d, J = 8.2 Hz, 2H, Ph), 7.66 (d, J = 8.2 Hz, 2H, Ph), 7.45 (s, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ 166.9(CONH2), 133.4 (1-Ph), 131.2 and 129.6 (o, m-Ph), 125.0 (p-Ph). HRMS (ESI) calcd. for C7H6BrNO [M+H+] 199.97055, found 199.97005.

4-formylbenzamide (2h) [16]

CHO

O

NH21H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H, CHO), 8.17 (s, 1H, NH), 8.05 (d, J = 8.0 Hz, 2H, Ph), 7.98 (d, J = 8.0 Hz, 2H, Ph), 7.60 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ 192.9 (CHO), 167.1 (CONH2), 139.3 and 137.8 (Ph, quaternary C), 129.4 and 128.2 (o, m-Ph). HRMS (ESI) calcd. for C8H7NO2 [M+H+] 150.05496, found 150.05477.

tert-butyl 4-cyanobenzoate (2i)

COOtBu

CONH2

1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H, NH), 7.97(d, J = 9.1 Hz, 2H, Ph), 7.95(d, J = 9.1 Hz, 2H, Ph), 7.55 (s, 1H, NH), 1.55 (s, 9H, tBu); 13C NMR (101 MHz, DMSO-d6) δ 167.1(CONH2), 164.4(COOtBu), 138.0 and 133.5 (Ph, quaternary C), 128.9 and 127.7 (o, m-Ph), 81.2 (C(CH3)3), 27.7 (C(CH3)3). HRMS (ESI) calcd. for C12H15NO3 [M+H+] 222.11247, found 222.11229.

S10

4-(dimethylamino)benzamide (2n)[17]

O

NH2

N

1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.7 Hz, 2H,o-Ph ), 7.63 (s, 1H, NH), 6.93 (s, 1H, NH), 6.67 (d, J = 8.7 Hz, 2H, m-Ph), 2.95 (s, 6H, N(CH3)2); 13C NMR (101 MHz, DMSO-d6) δ 168.0 (CONH2), 152.1 (p-Ph), 128.9 (o-Ph), 121.0 (1-Ph), 110.7 (m-Ph), 39.7(CH3). HRMS (ESI) calcd. for C9H12N2O [M+H+] 165.10224, found 165.10172.

3-furanamide (2w)[5]

O

NH2O

1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H, 1-furan), 7.69 (dd, J = 1.7 Hz, 1H, 4-furan), 7.64 (s, 1H, NH), 7.18 (s, 1H, NH), 6.80 (d, J = 1.9 Hz, 1H, 3-furan); 13C NMR (101 MHz, DMSO-d6) δ 163.4 (CONH2), 145.3 (1-furan), 143.9 (4-furan), 122.9 (2-furan), 109.3 (3-furan). HRMS (ESI) calcd. for C5H5NO2 [M+H+] 112.03930, found 112.03902.

Acetamide (2ab)[15]

O

NH21H NMR (400 MHz, D2O) δ 2.01 (s, 1H, CH3); 13C NMR (101 MHz, D2O) δ 180.0(CO), 23.9(CH3).

S11

Stoichiometric NMR scale reactions for PNP complexes

Reaction of APNP with 4-fluorobenzonitrile (1b)

N

PtBu2

PtBu2

Ru COH

RCNN

PtBu2

PtBu2

Ru COH

N

R

APNPBPNP

A solution of APNP was prepared as described above from precatPNP (15.6 mg, 0.028 mmol) and tBuOK (3.1 mg, 0.028 mmol, 1 eq.) in 5 mL of toluene. After the toluene was evaporated, 0.5 mL of THF-d8 was added to the catalyst, followed by 93 μl of 0.30 mol/L 4-fluorobenzonitrile stock solution (0.028 mmol, 1 eq.), and the solution was transferred into a J. Young NMR tube. Analysis of the NMR spectral data shows the formation of an equilibrium mixture of BPNP in rapid exchange with the starting materials APNP + 4-fluorobenzonitrile.[18]

NMR data for the equilibrium mixture [APNP + 1b ⇄ BPNP]:19F NMR (376 MHz, THF-d8) δ -102.8;31P NMR (162 MHz, THF-d8) δ 84.8 (d, J = 219.9 Hz), 78.7 (d, J = 219.9 Hz).;1H NMR (500 MHz, THF-d8) δ 7.73 (dd, J = 8.8, 5.0 Hz, 2H, o-Ph), 7.29 (dd, J = 8.3 Hz, 2H, m-Ph), 6.23 (t, J = 7.7 Hz, 1H, Py-4H), 6.01 (d, J = 8.8 Hz, 1H, Py-5H), 5.39 (d, J = 6.4 Hz, 1H, Py-3H), 3.43 (d, J = 4.0 Hz, 1H, Py-2-CH), 3.16 (d, J = 8.7 Hz, 2H, Py-5-CH2), 1.37 – 1.27 (m, 36H, tBu), -19.06 (s, 1H, RuH).

-21.0-20.0-19.0-18.0-17.0-0.50.51.52.53.54.55.56.57.58.5

f1 (ppm)

1.11

28.5

98.

84

2.29

1.23

0.99

0.97

1.00

2.01

2.01

-19.

06

1.27

1.29

1.30

1.31

1.32

1.36

1.38

3.16

3.17

3.43

3.44

5.39

5.40

6.00

6.02

6.21

6.23

6.24

7.27

7.29

7.31

7.71

7.72

7.73

7.74

Figure S2A. 1H NMR spectrum of reaction mixture APNP + 4-fluorobenzonitrile (1b) in THF-d8.

S12

-190-170-150-130-110-90-70-50-30-101030f1 (ppm)

-102

.84

Figure S2B. 19F NMR spectrum of reaction mixture APNP + 4-fluorobenzonitrile (1b) in THF-d8.

0102030405060708090100110120130140150160170f1 (ppm)

78.0

579

.41

84.1

385

.49

Figure S2C. 31P NMR spectrum of reaction mixture APNP + 4-fluorobenzonitrile (1b) in THF-d8.

S13

Reaction of APNP with 4-fluorobenzonitrile (1b) and water

N

PtBu2

PtBu2

Ru COH

RCNN

PtBu2

PtBu2

Ru COH

N

R

H2O

OH

N

PtBu2

PtBu2

Ru CO

H

NC

R

DPNPAPNPBPNP

R=4-F-Ph

Subsequent addition of 16.4 μl of H2O stock solution (1.70 mol/L, 0.028 mmol, 1 eq.) to the mixture described above resulted in the slow appearance of a new set of NMR signals that is attributed to the Ru-carboxamide species DPNP as the major product.

NMR data for DPNP: 19F NMR (376 MHz, THF-d8) -118.3 (DPNP);31P NMR (162 MHz, THF-d8) 82.3(DPNP);1H NMR (500 MHz, THF-d8) δ -13.05 (t, J = 19.8 Hz, 8H, RuH of DPNP).

-27-26-25-24-23-22-21-20-19-18-17-16-15-14-13-12123456789f1 (ppm)

1

2

3

4

5

RuH of DPNP

py-H ofAPNP

Apnp

Apnp+ nitrile

Apnp+ nitrile+water(2 hour)

Apnp+ nitrile+water(30hour)

Apnp+ nitrile+water(3day)

RuH ofAPNP

RuH of APNP+nitrile

Figure S3A. 1H NMR spectra for the stoichiometric reaction of APNP with 4-fluorobenzonitrile (1b) and water

S14

-145-140-135-130-125-120-115-110-105-100-95-90-85-80f1 (ppm)

1

2

3

4

4-fluorobenzonitrile

4-fluorobenzamide

DPNP

Apnp+ nitrile

Apnp+ nitrile+water(2 hour)

Apnp+ nitrile+water(30hour)

Apnp+ nitrile+water(3day)

Figure S3B. 19F NMR spectra for the stoichiometric reaction of APNP with 4-fluorobenzonitrile (1b) and water.

0102030405060708090100110120130140150160170180f1 (ppm)

82.3

0

Apnp+ nitrile+water(3day)

DPNP

Figure S3C. 31P NMR spectrum for the stoichiometric reaction of APNP with 4-fluorobenzonitrile (1b) and water, recorded after standing at room temperature for 3 days.

S15

Characterization of DPNP

Assignment of the major product from the above NMR scale reaction (APNP+ 1b + H2O) as compound DPNP was corroborated by an independent synthesis as described below.

N

PtBu2

PtBu2

Ru COH

RCONH2

OH

N

PtBu2

PtBu2

Ru CO

H

NC

R

DPNPAPNP R=4-F-Ph

In a glovebox, 1 ml of APNP stock solution (0.017 mol/L, 0.017 mmol) was added to a vial. After removal of all volatiles, 0.5 mL of d8-THF was added to dissolve the catalyst. Then 70 μl of 4-fluorobenzamide (2b) stock solution (0.24 mol/L, 0.017 mmol) was added. The solution was transferred into a J. Young NMR tube and taken out of the glovebox. NMR characterization data are consistent with formation of DPNP as the major species (> 90%). In addition to compound DPNP, the Ru-H resonance of APNP as well as amide 2b are visible, which shows that these are in equilibrium.

NMR data for DPNP: 19F NMR (376 MHz, THF-d8) δ -118.3. 31P NMR (162 MHz, THF-d8) δ 82.3.1H NMR (400 MHz, THF-d8) δ 7.56 (dd, J = 8.8, 5.9 Hz, 2H, o-Ph), 7.51 (t, J = 7.7 Hz, 1H, Py-4H), 7.21 (d, J = 7.7 Hz, 2H, Py-3,5H), 6.82 (dd, J = 8.8 Hz, 2H, m-Ph), 4.66 (s, 1H, NH), 4.16 (d, J = 16.3 Hz, 2H, py-2,6-CH2), 3.52 (dt, J = 16.3, 3.9 Hz, 2H, py-2,6-CH2), 1.35 (dd, J = 6.4 Hz, 18H, PtBu2), 1.29 (t, J = 6.4 Hz, 18H, PtBu2), -13.04 (t, J = 19.9 Hz, 1H, RuH).

13C NMR (101 MHz, THF-d8) δ 209.8 (RuCO), 172.3 (CONH), 165.3 (py-2,6C), 163.45 (d, J = 243.7 Hz, p-F-ph-4C), 140.9 (p-F-ph-1C), 137.7 (py-4C), 129.32 (d, J = 8.1 Hz, p-F-ph-oC), 120.1 (py-3,5C), 114.17 (d, J = 21.0 Hz, p-F-ph-pC), 39.4 (py-2,6-CH2), 37.50 (dd, J = 5.3 Hz, C(CH3)3), 36.56 (dd, J = 10.6 Hz, C(CH3)3), 30.5 and 30.0 C(CH3)3).

S16

-27-25-23-21-19-17-15-13-11-9-7-5-3-113579

f1 (ppm)

1.00

20.3

117

.83

2.00

1.88

0.87

1.86

1.95

0.95

1.93

-13.

09-1

3.04

-12.

991.

271.

291.

301.

331.

351.

363.

493.

503.

513.

533.

543.

554.

144.

184.

666.

796.

826.

847.

207.

227.

497.

517.

537.

547.

547.

557.

567.

567.

58

Figure S4A. 1H NMR spectrum of DPNP in THF-d8

0102030405060708090100110120130140150160170180190200210220230f1 (ppm)

30.0

330

.46

36.4

536

.56

36.6

637

.44

37.5

037

.55

39.3

8

114.

0711

4.28

120.

1212

9.28

129.

3613

7.68

140.

92

162.

2416

4.66

165.

2917

2.28

209.

82

Figure S4B. 13C NMR spectrum of DPNP in THF-d8

O

H

N

PtBu2

PtBu2

Ru COH

NCF

O

H

N

PtBu2

PtBu2

Ru COH

NCF

S17

-165-155-145-135-125-115-105-95-85-75-65-55f1 (ppm)

-118

.27

Figure S4C. 19F NMR spectrum of DPNP in THF-d8

-20-100102030405060708090100110120130140150160170180190f1 (ppm)

82.3

2

Figure S4D. 31P NMR spectrum of DPNP in THF-d8

S18

Reaction of DPNP with water

N

PtBu2

PtBu2

Ru COHRCONH2

OH

N

PtBu2

PtBu2

Ru CO

H

NC

R

DPNP APNP

R=4-F-Ph

H2ON

PtBu2

PtBu2

Ru CO

H

HO

+ RCONH2

RuOH

An NMR solution of DPNP, prepared as described above, was treated with increasing amounts of water by sequential addition of a 1.70 mol/L stock solution (0.5, 1, 2, 5, 10, 20 eq). After each addition, NMR spectra were recorded.

Before addition of water, the mixture of APNP + amide 2b shows the formation of DPNP as the major product, with a small amount of APNP left in the equilibrium mixture. Addition of water results in broadening and ultimately disappearance (> 10 equiv H2O) of the signals due to APNP, with concomitant appearance of a new Ru-H triplet at -14.68 ppm. In the 31P NMR spectrum, a new resonance at 86.3 ppm appears. These signals are attributed to the Ru-hydroxide species shown in the scheme (RuOH) by comparison to the literature values reported this compound.[19][20] The changes in the 19F NMR spectrum upon addition of increasing amounts of water show that the amount of free amide 2b in solution (relative to that bound in DPNP) increases ca. twofold upon addition of 20 equiv of water, and the data indicate that the deromatized species APNP is involved in dynamic equilibria with nitrile, amide and water.

S19

-26.5-25.5-15.0-14.0-13.00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

1

2

3

4

5

6

7

py4-H ofA PNP

freeamide RuH of Ru-OH species

0 eq water

1 eq water

0.5 eq water

2 eq water

5 eq water

10 eq water

20 eq water

RuH ofA PNPRuH ofD PNP

Figure S5A. Effect of water amount on the equilibrium of DPNP with APNP and 4-fluorobenzamide (2b) followed by 1H NMR

-118.7-118.5-118.3-118.1-117.9-117.7-117.5-112.2-112.0-111.8-111.6-111.4-111.2f1 (ppm)

0.5eq5eq

20eq water10eq

2eq 1eq no water

S20

Figure S5B. Effect of water amount on the equilibrium of DPNP with APNP and 4-fluorobenzamide (2b) followed by 19F NMR

75767778798081828384858687888990919293

f1 (ppm)

1

2

3

4

5

6

7

bg296-20eq-h2o_20190214141735

bg296-10eq-h2o_20190213193135

bg296-5eqh2o_20190213141245

bg296-cat_2eqh2o_20190212223700

bg296-1eqh2o_20190212174525

bg296_cat_sm_h2o_20190212145229

bg296-cat_sm_20190211221515

Ru-OH species

D PNP

Figure S5C. Effect of water amount on the equilibrium of DPNP with APNP and 4-fluorobenzamide (2b) followed by 31P NMR

S21

Stoichiometric NMR scale reactions for PNN complexes

Reaction of APNN with 4-fluorobenzonitrile (1b)

N

PtBu2

NEt2Ru CO

H

RCNN

PtBu2

NEt2Ru CO

H

N

R

APNN BPNNR=4-F-Ph

N

PtBu2

NEt2Ru CO

H

NC

R

N

PtBu2

NEt2Ru CO

H

NC

RH

+

CPNN C'PNN

In a glovebox, 2 ml of APNN stock solution (0.0075 mol/L, 0.015 mmol) was added to a vial. After removal of all volatiles, 0.5 mL of d8-THF was added to dissolve the catalyst. Then 50 μl of 4-fluorobenzonitrile stock solution (0.30 mol/L, 0.015 mmol) was added. The solution was transferred into a J. Young NMR tube and taken out of glovebox. NMR characterization data are consistent with formation of an equilibrium mixture of CPNN and C’PNN in a ratio of 1 : 3.84. In addition, resonances due to the equilibrium [APNN + 1b ⇄ BPNN] were observed (e.g., Ru-H at -25.24) that account for ca. 7% of the total Ru-H concentration.

selected NMR data for CPNN and C’PNN:19F NMR (376 MHz, THF-d8) δ -109.6(C’ PNN), -118.0(CPNN).31P NMR (162 MHz, THF-d8) δ 117.6 (CPNN), 102.1 (C’PNN).1H NMR (500 MHz, THF-d8) δ 11.65 (s, 3.2H, NH of C’PNN), -10.47 (d, J = 25.7 Hz, 1H, RuH of CPNN), -13.75 (d, J = 32.8 Hz, 3.8H, RuH of C’PNN).

S22

-30-28-26-24-22-20-18-16-14-12-10-8-6-4-2024681012

f1 (ppm)

0.33

3.84

1.00

3.17

-25.

24

-13.

79-1

3.72

-10.

49-1

0.44

11.6

5

Figure S6A. 1H NMR spectrum of reaction mixture APNN + 4-fluorobenzonitrile (1b) in THF-d8.

-119-118-117-116-115-114-113-112-111-110-109-108-107-106-105-104-103f1 (ppm)

-118

.03

-109

.63

-104

.97

CPNN

C'PNN

4-fluorobenzonitrile

Figure S6B. 19F NMR spectrum of reaction mixture APNN + 4-fluorobenzonitrile (1b) in THF-d8.

S23

-55152535455565758595105115125135145155165175185195

102.

09

117.

56

Figure S6C. 31P NMR spectrum of reaction mixture APNN + 4-fluorobenzonitrile (1b) in THF-d8.

S24

Reaction of APNN with 4-fluorobenzonitrile (1b) and water

H2O

OH

N

PtBu2

NEt2Ru CO

H

NC

R

DPNNR=4-F-Ph

N

PtBu2

NEt2Ru CO

H

NC

R

N

PtBu2

NEt2Ru CO

H

NC

RH

+

CPNN C'PNN

Subsequent addition of 8.8 μl of a H2O stock solution (1.7 mol/L, 0.015 mmol) to the mixture described above resulted in the slow appearance of a new set of NMR signals that is attributed to the Ru-carboxamide species DPNN as the major Ru-containing product.

NMR data for DPNN:19F NMR (376 MHz, THF-d8) δ -117.731P NMR (162 MHz, THF-d8) δ 105.31H NMR (400 MHz, THF-d8) δ -13.06 (d, J = 26.9 Hz, RuH)

-30-28-26-24-22-20-18-16-14-12-10-8-6-4-202468101214f1 (ppm)

1

2

3

6

9

APNN

APNN+ nitrile

APNN+ nitrile+water(4 hour)

APNN+ nitrile+water(27 hour)

APNN+ nitrile+water(4 weeks)RuH of DPNN

RuH ofA PNN

RuH ofCPNN

RuH ofC' PNN

NH ofC'PNN

Figure S7A. 1H NMR spectra for the stoichiometric reaction of APNN with 4-fluorobenzonitrile (1b) and water.

S25

-123-121-119-117-115-113-111-109-107-105-103-101f1 (ppm)

1

2

5

8

4-fluorobenzonitrile

4-fluorobenzamide

C'PNNCPNN

APNN+ nitrile

APNN+ nitrile+water(4 hour)

APNN+ nitrile+water(27 hour)

APNN+ nitrile+water(4 weeks)

DPNN

Figure S7B. 19F NMR spectra for the stoichiometric reaction of APNN with 4-fluorobenzonitrile (1b) and water.

8084889296100104108112116120124128f1 (ppm)

1

2

5

8

C'PNPCPNP

APNN+ nitrile

APNN+ nitrile+water(4 hour)

APNN+ nitrile+water(27 hour)

DPNP APNN+ nitrile+water(4 weeks)

Figure S7C. 31P NMR spectra for the stoichiometric reaction of APNN with 4-fluorobenzonitrile (1b) and water.

S26

Characterization of DPNN

Assignment of the major product from the above NMR scale reaction (APNN + 1b + H2O) as compound DPNN was corroborated by an independent synthesis as described below.

N

PtBu2

NEt2Ru CO

H

RCONH2

OH

N

PtBu2

NEt2Ru CO

H

NC

R

DPNNAPNN R=4-F-Ph

In glovebox, a small vial was added with 2 ml of 0.0075 mol/L APNN stock solution (0.0150 mmol, 1 eq.). After under vacuum for 0.5 hour, 0.5 ml d8-THF was added to dissolve the catalyst (dark red). Then 63 μl of 0.24 mol/L 4-fluorobenzamide (0.0150 mmol, 1 eq.) was added forming amide adduct DPNN (light yellow). The solution was then transferred into a J. Young NMR tube and taken out of glovebox to characterize by NMR spectroscopy, which shows full conversion to DPNN.

19F NMR (376 MHz, THF-d8) δ -117.7.

31P NMR (162 MHz, THF-d8) δ 105.3.1H NMR (400 MHz, THF-d8) δ 7.70 – 7.64 (m, 2H,p-F-Ph-oH ), 7.61 (t, J = 7.7 Hz, 1H,Py-4H), 7.32 (d, J = 7.8 Hz, 1H, py-3H), 7.14 (d, J = 7.2 Hz, 1H, py-5H), 6.92 – 6.81 (m, 2H, p-F-Ph-mH), 5.21 (s, 1H, NH), 4.75 (d, J = 14.3 Hz, 1H,py-6-CH2), 3.87 (dd, J = 14.4, 2.6 Hz, 1H, py-6-CH2), 3.81 (dd, J = 16.8, 9.5 Hz, 1H, py-2-CH2), 3.41 – 3.19 (m, 3H, py-2-CH2 and N(CH2CH3)2), 2.96 – 2.85 (m, 2H, N(CH2CH3)2 ), 1.29 (d, J = 12.9 Hz, 9H,PtBu2), 1.28 (t, J = 7.0 Hz, 3H, N(CH2CH3)2), 1.23 (d, J = 12.9 Hz, 9H, PtBu2), 1.06 (t, J = 7.2 Hz, 3H, N(CH2CH3)2), -13.06 (d, J = 26.9 Hz, 1H, RuH). 13C NMR (101 MHz, THF-d8) δ 209.2 (d, J = 16.3 Hz, RuCO), 172.3 (CONH), 163.3 (d, J = 244.1 Hz, p-F-ph-4C), 162.4 (d, J = 3.9 Hz, py-2C), 161.6 (py-6C), 140.2 (d, J = 2.9 Hz, p-F-ph-1C), 137.0 (py-4C), 129.2 (d, J = 8.0 Hz, p-F-ph-oC ), 120.3 (d, J = 9.7 Hz, py-3C), 119.1 (py-4C), 114.0(d, J = 21.1 Hz, p-F-ph-mC), 66.5 (py-6-CH2), 55.6 and 50.6 (N(CH2CH3)2), 38.1 (d, J = 20.1 Hz, py-2-CH2), 36.7 (d, J = 12.6 Hz, C(CH3)3), 36.4 (d, J = 25.5 Hz, C(CH3)3), 29.9 (d, J = 3.1 Hz, C(CH3)3), 29.5 (d, J = 4.5 Hz, C(CH3)3), 11.6 and 8.6 (N(CH2CH3)2).

S27

-16-15-14-13-12-11-10-9-8-7-6-5-4-3-2-1012345678910f1 (ppm)

1.00

3.18

9.25

16.8

4

2.00

3.21

2.02

0.98

0.96

1.86

1.24

0.89

0.98

1.92

-13.

09-1

3.03

1.05

1.06

1.08

1.22

1.25

1.26

1.28

1.30

2.88

2.88

2.90

2.90

3.30

3.32

3.32

3.32

3.34

3.36

3.85

3.89

3.89

4.73

4.76

5.21

6.84

6.87

6.87

6.89

7.13

7.15

7.31

7.33

7.59

7.61

7.65

7.65

7.66

7.67

7.69

toluene

Figure S8A. 1H NMR spectrum of DPNN

102030405060708090100110120130140150160170180190200210220f1 (ppm)

8.6

11.6

29.5

29.5

29.9

29.9

36.3

36.4

36.6

36.7

38.0

38.1

50.6

55.6

66.5

113.

911

4.0

119.

112

0.3

120.

412

9.1

129.

213

7.0

140.

214

0.3

161.

616

2.4

162.

416

2.5

164.

117

2.3

209.

120

9.2

toluene

Figure S8B. 13C NMR spectrum of DPNN

O

H

N

PtBu2

NEt2Ru CO

H

NCF

S28

-200-180-160-140-120-100-80-60-40-20020f1 (ppm)

-117

.71

Figure S8C. 19F NMR spectrum of DPNN in THF-d8

-20-100102030405060708090100110120130140150160170180190f1 (ppm)

105.

29

Figure S8D. 31P NMR spectrum of DPNN in THF-d8

S29

Stoichiometric reaction of DPNN with 4-fluorobenzonitrile (1b)

RCN

R=4-F-Ph

RCONH2

OH

N

PtBu2

NEt2Ru CO

H

NC

R

DPNN

N

PtBu2

NEt2Ru CO

H

NC

R

N

PtBu2

NEt2Ru CO

H

NC

RH

+

CPNN C'PNN

+

To a NMR solution of DPNN, prepared as described above, was added 50 μl of a 0.30 mol/L stock solution of 4-fluorobenzonitrile (0.015 mmol, 1 eq.), resulting in a color change to light brown. Analysis of the NMR spectral data showed immediate conversion (ca. 13%) of DPNN to the CN addition products CPNN and C’PNN. This demonstrates that compounds CPNN are kinetically accessible from DPNN and nitrile.

19F NMR (376 MHz, THF-d8) δ-109.7(C’PNN), -117.7(DPNN), -118.0(CPNN);31P NMR (162 MHz, THF-d8) δ 117.6(CPNN), 105.3(DPNN), 102.1(C’ PNN);1H NMR (400 MHz, THF-d8) δ 11.65 (s, 1H, NH of C’PNN), -10.47 (d, J = 25.8 Hz, 0.22H, RuH of CPNN), -13.06 (d, J = 26.9 Hz, 8H, RuH of DPNN), -13.76 (d, J = 32.8 Hz, 1H, RuH of C’PNN).

-18-16-14-12-10-8-6-4-202468101214f1 (ppm)

4.99

39.1

0

1.00

4.97

-13.

80-1

3.72

-13.

09-1

3.03

-10.

50-1

0.44

11.6

5

RuH of DPNN

RuH ofCPNNRuH ofC' PNN

NH ofC'PNN

Figure S9A. 1H NMR spectra for the stoichiometric reaction of DPNN with 4-fluorobenzonitrile (2b).

S30

-122-121-120-119-118-117-116-115-114-113-112-111-110-109-108-107-106-105-104-103-102

f1 (ppm)

-118

.03

-117

.67

-111

.57

-109

.65

-105

.02

DPNP

C'PNP CPNP

4-fluorobenzonitrile

4-fluorobenzamide

Figure S9B. 19F NMR spectra for the stoichiometric reaction of DPNN with 4-fluorobenzonitrile (2b).

9092949698100102104106108110112114116118120122124126128f1 (ppm)

102.

11

105.

29

117.

57

DPNP

C'PNPCPNP

Figure S9C. 31P NMR spectra for the stoichiometric reaction of DPNN with 4-fluorobenzonitrile (2b).

S31

Catalyst inhibition

a) Hydration of 4-fluorobenzonitrile (1b) under standard conditions, with addition of a new batch of substrate after completion

In a glovebox, 0.5 mL of a stock solution of APNP (0.0015 mol/L, 0.0075 mmol, 3 mol%) was added to a vial. After removal of volatiles under vacuum for 0.5 hour, 0.5 mL of tBuOH and 22.5 ul of water (5 eq.) were added to dissolve the catalyst. The solution was then transferred into another vial containing 4-fluorobenzonitrile (30.3 mg, 121, 0.25 mmol) and an internal standard (2-fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10h. After this time, 19F NMR spectroscopy indicated > 98% conversion of nitrile 1b to the corresponding amide 2b. The tube was taken into the glovebox and another batch of 4-benzonitrile (30.3 mg, 1 eq.) and water (5.4 ul, 1eq.) were added into the J. Young NMR tube. The reaction was monitored by 19F NMR again for another 15h. Figure S10 shows the conversion vs. time plot of the two sequential nitrile hydration reactions, indicating that a second batch of substrate is converted with a somewhat lower reaction rate.

0 5 10 15 20 250

10

20

30

40

50

60

70

80

90

100

standard condition

second batch

t/h

conv

/%

Figure S10. Conversion vs. time plot for hydration of 4-fluorobenzonitrile (3mol% APNP catalyst), followed by addition of a second batch of nitrile substrate.

b) Catalysis with additional amide present from the start.

To test whether the decreased rate in experiment (a) above is due to decomposition of the catalyst, or due to product inhibition, we subsequently carried out a catalytic nitrile hydration reaction under identical conditions, but now with 0.075 mmol amide 2b present at the start (0.3 equiv. with respect to nitrile 1b).

S32

The catalyst solution in tBuOH (prepared as described above, 3 mol% APNP + 5 eq. of water) was transferred into a vial containing a mixture of 4-fluorobenzonitrile (30.3 mg, 121, 0.25 mmol), 4-fluorobenzamide (10.4 mg, 139, 0.075 mmol, 0.3 eq.) and internal standard (2-Fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10 h. A comparison of the data with and without amide 2b added at the start (Figure S11) shows that product inhibition takes place.

0 100 200 300 400 500 6000

10

20

30

40

50

60

70

80

90

100

standard condition

inhibition by product

t/min

conv

/%

Figure S11. Conversion vs. time plot for hydrdation of 4-fluorobenzonitrile (1b) inhibited by 4-fluorobenzamide (2b)

S33

c) Effect of nitro group on hydration of nitrile

To test whether the catalyst is deactivated by nitro-groups (as suggested by the lack of catalytic turnover for p-nitrobenzonitrile), the hydration of 1b was carried out in the presence of an equimolar amount of nitrobenzene.In a glovebox, a small vial was charged with 0.0015 mol/L APNP stock solution (0.5 ml, 0.0075 mmol, 3 mol%). After removal of the volatiles under vacuum for 0.5 hour, 0.5 ml of tBuOH and 22.5 ul of water (5 eq.,) were added to dissolve the catalyst. The solution was transferred into another vial containing a mixture of 4-fluorobenzonitrile (30.3 mg, 0.25 mmol), nitrobenzene (30.8 mg, 0.25 mmol, 1 eq.) and internal standard (2-Fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10 h. A comparison of the data collected in the presence/absence of nitrobenzene is shown in Figure S12, indicating that the catalyst is not deactivated by the -NO2 functional group.

0 100 200 300 400 500 6000

10

20

30

40

50

60

70

80

90

100

standard condition

nitrobenzene

t/min

conv

/%

Figure S12. Conversion vs. time plot for hydration of 4-fluorobenzonitrile (1b) with additive of nitrobenzene

S34

Preliminary DFT calculations

Geometry optimizations were carried out using density functional theory with the TPSSTPSS functional[21] and def2-TZVP basis set[22] on all atoms. The W06 density fitting set was employed. Calculations were carried out with a SMD solvation model[23] with isopropanol, and an empirical dispersion correction using Grimme’s D3 damping function.[24] The calculations converged on minima on the potential energy surface, as confirmed by a frequency analysis (no imaginary frequencies). Gibss free energies of the nitrile-MLC activation products C (all with PhCN bound) shown below are relative to the dearomatized precursors A and PhCN computed at the same level of theory.

APNP APNN

S35

CPNP CPNN (addition to P-arm) CPNN (addition to N-arm)

G 7.2 kcal/mol 9.4 kcal/mol -2.7 kcal/mol

S36

Absolute Gibbs free energies and Cartesian coordinates for PhCN and complexes A and C.

PhCN (-324.616336)C -0.088550000 -1.221607000 0.000000000C 0.608429000 0.000062000 0.000026000C -0.088621000 1.221638000 -0.000014000C -1.480458000 1.212361000 0.000002000C -2.175380000 -0.000040000 0.000014000C -1.480356000 -1.212426000 -0.000015000H 0.462143000 -2.156812000 -0.000018000H 0.461952000 2.156914000 -0.000033000H -2.023695000 2.152773000 -0.000005000H -3.261895000 -0.000110000 -0.000002000H -2.023587000 -2.152842000 -0.000012000C 2.036220000 0.000058000 0.000003000N 3.199627000 -0.000029000 -0.000004000

APNP (-1848.385245)Ru 0.027747000 -0.411262000 -0.012131000H -0.023565000 -0.208646000 -1.558932000P 2.347252000 -0.015652000 -0.055708000O 0.068403000 -3.357532000 -0.623169000N -0.014270000 1.723316000 0.247051000C 2.383016000 1.747094000 -0.095318000C 1.186451000 2.437592000 0.082905000C 1.121488000 3.872758000 0.109014000H 2.045274000 4.428343000 -0.028002000C -0.071467000 4.522451000 0.291403000H -0.104599000 5.610073000 0.299874000C -1.259773000 3.779272000 0.481083000H -2.212358000 4.267085000 0.658359000C -1.181585000 2.396880000 0.465902000C -2.405585000 1.570133000 0.774038000H -2.454749000 1.427768000 1.861744000H -3.320733000 2.094003000 0.481137000C 0.059445000 -2.210121000 -0.352957000C 3.066126000 -0.565910000 1.624970000C 3.026146000 -2.093001000 1.811309000H 3.228050000 -2.329212000 2.865464000H 2.042439000 -2.503568000 1.557839000H 3.778700000 -2.608464000 1.210775000C 4.479593000 -0.035701000 1.900909000H 4.741905000 -0.219612000 2.952536000H 5.228924000 -0.539167000 1.282293000H 4.547023000 1.043646000 1.722809000C 2.078860000 0.058283000 2.636579000H 2.046397000 1.149360000 2.552516000H 1.059287000 -0.328371000 2.485238000H 2.386237000 -0.203244000 3.658109000C 3.407029000 -0.592387000 -1.516043000C 3.695810000 -2.101712000 -1.464917000H 4.443220000 -2.347580000 -0.705390000

S37

H 2.790261000 -2.685622000 -1.268277000H 4.096806000 -2.421612000 -2.436286000C 4.732948000 0.186711000 -1.609058000H 5.287910000 -0.162760000 -2.490506000H 4.560313000 1.260981000 -1.730660000H 5.370232000 0.034431000 -0.733884000C 2.579137000 -0.289561000 -2.782473000H 1.697549000 -0.934559000 -2.847791000H 2.245545000 0.754462000 -2.802954000H 3.204116000 -0.468224000 -3.667998000C -3.175764000 -0.011988000 -1.611549000C -2.851983000 -1.263591000 -2.450463000H -3.232349000 -2.182033000 -1.995563000H -3.320265000 -1.158858000 -3.438124000H -1.772122000 -1.372512000 -2.594147000C -3.239750000 -1.193591000 1.302306000C -4.538264000 -0.556060000 1.829347000H -4.971240000 -1.221238000 2.588773000H -4.355193000 0.411313000 2.308508000H -5.286163000 -0.417737000 1.046089000H 3.303801000 2.318047000 -0.175523000P -2.290079000 -0.132155000 0.053857000C -2.266214000 -1.381292000 2.487192000H -1.366667000 -1.927576000 2.180403000H -1.960299000 -0.425654000 2.929382000H -2.766417000 -1.964344000 3.271843000C -3.540847000 -2.576455000 0.697842000H -3.912156000 -3.238735000 1.491164000H -4.309927000 -2.523152000 -0.078264000H -2.642839000 -3.035884000 0.270866000C -2.588312000 1.220880000 -2.331768000H -2.868053000 2.157990000 -1.839505000H -1.495923000 1.172471000 -2.392593000H -2.986067000 1.248738000 -3.354603000C -4.698055000 0.165291000 -1.492116000H -5.110899000 0.354432000 -2.492224000H -5.186368000 -0.730148000 -1.097538000H -4.961539000 1.019193000 -0.858243000

APNN (-1404.493034)Ru -0.438089000 -0.548063000 0.039221000H -0.419397000 -0.634083000 -1.520355000P 1.746354000 0.136155000 -0.059029000O 0.123345000 -3.509744000 0.007573000N -2.680430000 -0.461628000 0.106724000N -0.769736000 1.506591000 -0.099235000C 1.555986000 1.835960000 -0.536698000C 0.271796000 2.367697000 -0.456672000C -0.081172000 3.739418000 -0.697246000H 0.703915000 4.433978000 -0.983751000C -1.382421000 4.162676000 -0.571813000H -1.630942000 5.203604000 -0.768144000

S38

C -2.404748000 3.261642000 -0.178134000H -3.432519000 3.583675000 -0.048769000C -2.038604000 1.949956000 0.058921000C -2.979654000 0.917088000 0.624461000H -2.838441000 0.885704000 1.712119000H -4.023149000 1.189641000 0.427829000C -0.102177000 -2.350982000 0.048977000C 2.442783000 0.130392000 1.724750000C 2.543932000 -1.288805000 2.314580000H 2.733545000 -1.211909000 3.394548000H 1.611723000 -1.847959000 2.176445000H 3.359343000 -1.870256000 1.879902000C 3.784635000 0.860639000 1.872802000H 4.020748000 0.980792000 2.939865000H 4.605505000 0.298813000 1.416004000H 3.751384000 1.859957000 1.423840000C 1.360175000 0.887476000 2.525550000H 1.233823000 1.915237000 2.170855000H 0.388197000 0.377999000 2.447957000H 1.643137000 0.917003000 3.586328000C 2.985114000 -0.612583000 -1.280103000C 3.562586000 -1.944566000 -0.773364000H 4.276215000 -1.793417000 0.041963000H 2.778347000 -2.628354000 -0.432351000H 4.101108000 -2.435066000 -1.595534000C 4.138299000 0.361282000 -1.593097000H 4.828833000 -0.124605000 -2.295903000H 3.772038000 1.277397000 -2.066900000H 4.710258000 0.636339000 -0.702934000C 2.209143000 -0.874315000 -2.586971000H 1.470644000 -1.671973000 -2.461998000H 1.689553000 0.027123000 -2.932146000H 2.919446000 -1.180246000 -3.367262000C -3.285712000 -0.578037000 -1.265201000H -2.792662000 0.183646000 -1.876107000H -4.350034000 -0.309559000 -1.201180000C -3.135018000 -1.948879000 -1.908565000H -3.720791000 -2.715179000 -1.390725000H -3.501346000 -1.891739000 -2.939781000H -2.087610000 -2.264032000 -1.933243000C -3.216439000 -1.492580000 1.058949000H -2.898134000 -2.467260000 0.683163000H -2.697005000 -1.324076000 2.008356000C -4.730113000 -1.479710000 1.279754000H -4.980952000 -2.261780000 2.005245000H -5.081877000 -0.524763000 1.683219000H -5.281190000 -1.692860000 0.358263000H 2.392979000 2.491243000 -0.757398000

S39

CPNP (-2172.990129)C 1.674569000 1.126584000 -0.267468000C 2.029515000 -0.003032000 0.764435000C 1.059271000 0.214996000 1.881805000N -0.244263000 0.033426000 1.528764000C -1.241510000 0.344941000 2.393795000C -0.948742000 0.801533000 3.676269000C 0.385237000 0.952929000 4.064081000C 1.400274000 0.672130000 3.156042000Ru -0.634305000 -0.658668000 -0.452907000C -1.030108000 -1.140777000 -2.179681000O -1.313173000 -1.425225000 -3.287423000C -2.643740000 0.188055000 1.879488000C -2.809276000 2.222228000 -0.306565000C 2.663156000 -1.900012000 -1.580134000C 4.104235000 -2.260138000 -1.177983000N 0.592549000 1.052210000 -0.930945000C -4.311031000 -0.507476000 -0.447927000C 1.757843000 -2.952475000 1.220931000C 1.764204000 -4.348111000 0.567750000C -4.102738000 -2.034499000 -0.405710000C -4.154352000 2.875807000 0.048302000H -1.384633000 -1.993793000 0.151717000H -3.327160000 0.872788000 2.390562000H -2.985565000 -0.836377000 2.079254000H -4.059454000 3.961835000 -0.089033000H -4.431044000 2.699046000 1.093493000H -4.970056000 2.534753000 -0.594835000H -3.757559000 -2.381269000 0.573791000H -3.382205000 -2.367567000 -1.156376000H -5.068875000 -2.514325000 -0.613719000H 2.445017000 0.802478000 3.418309000H 3.063299000 0.008420000 1.113686000H 0.626417000 1.301870000 5.064333000H 0.868649000 -4.513958000 -0.040701000H 1.769238000 -5.100255000 1.367380000H 2.649474000 -4.521110000 -0.048480000H -1.759627000 1.041698000 4.356201000H 4.710755000 -2.329617000 -2.090986000H 4.171367000 -3.223843000 -0.667348000H 4.552426000 -1.490470000 -0.540620000C 2.617454000 2.278190000 -0.381368000C 3.531301000 2.618736000 0.630020000C 2.584415000 3.073291000 -1.541927000C 4.374679000 3.723867000 0.491239000H 3.575329000 2.034207000 1.544111000C 3.432792000 4.167138000 -1.685698000H 1.880891000 2.808986000 -2.326631000C 4.332472000 4.501315000 -0.666696000H 5.065232000 3.976413000 1.292459000H 3.397836000 4.761302000 -2.595961000H 4.993576000 5.357140000 -0.777167000P 1.495804000 -1.589724000 -0.105272000

S40

C 2.724608000 -0.643959000 -2.473825000H 1.730517000 -0.291850000 -2.761326000H 3.260393000 0.179900000 -1.996175000H 3.274530000 -0.917050000 -3.384362000C 2.051454000 -3.025023000 -2.445557000H 2.648411000 -3.111589000 -3.362826000H 2.056735000 -3.998920000 -1.955192000H 1.023103000 -2.788720000 -2.734996000C 0.588260000 -2.942580000 2.230475000H 0.581148000 -2.048329000 2.857442000H -0.380793000 -3.027896000 1.731846000H 0.715827000 -3.807494000 2.894931000C 3.060619000 -2.741387000 2.019018000H 3.164026000 -3.566660000 2.736444000H 3.953978000 -2.734189000 1.391920000H 3.031839000 -1.809577000 2.592868000P -2.679340000 0.353437000 0.019394000C -5.462729000 -0.169927000 0.521765000H -5.692834000 0.895567000 0.561111000H -6.366056000 -0.691785000 0.178629000H -5.251330000 -0.517608000 1.538295000C -4.705763000 -0.127042000 -1.887930000H -3.884569000 -0.302134000 -2.590879000H -5.551864000 -0.754887000 -2.196969000H -5.021600000 0.916177000 -1.970982000C -1.712450000 2.892759000 0.547971000H -0.732006000 2.445022000 0.363994000H -1.658948000 3.953718000 0.269210000H -1.938291000 2.843410000 1.618675000C -2.469910000 2.465720000 -1.791480000H -3.228534000 2.059400000 -2.465667000H -2.411389000 3.548412000 -1.968050000H -1.499831000 2.024084000 -2.041265000

CPNN (addition to P-arm; -1729.094415)C -2.087735000 -0.245503000 -0.393910000C -2.087676000 0.898333000 0.675429000C -1.322277000 0.337637000 1.835936000N -0.012815000 0.153817000 1.546331000C 0.819688000 -0.493347000 2.393620000C 0.334630000 -0.967750000 3.609782000C -1.009597000 -0.760873000 3.938640000C -1.854475000 -0.105581000 3.045494000Ru 0.553566000 0.854590000 -0.338304000C 1.117951000 1.435636000 -1.986289000O 1.506005000 1.811155000 -3.034416000C 2.233836000 -0.650313000 1.911694000P 2.295377000 -0.570300000 0.039552000C 2.029928000 -2.373752000 -0.510830000C 0.794645000 -2.888646000 0.258832000N -1.287599000 2.025684000 0.050647000C -1.938886000 2.524363000 -1.212962000C -3.331432000 3.132911000 -1.047999000

S41

N -1.000642000 -0.459339000 -1.021576000C 4.090983000 -0.041382000 -0.302779000C 4.441545000 -0.320438000 -1.776956000C -1.143646000 3.131701000 1.059145000C -0.428696000 4.364971000 0.524377000C 5.111950000 -0.737875000 0.620845000C 4.213377000 1.477367000 -0.066727000C 3.196975000 -3.335062000 -0.233826000C 1.686470000 -2.370317000 -2.014356000H 1.480830000 1.990311000 0.415450000H -0.582390000 2.713746000 1.898037000H -2.142126000 3.401956000 1.430158000H 5.112002000 -1.823638000 0.519122000H 4.945035000 -0.487878000 1.673698000H 6.115570000 -0.379868000 0.354969000H 2.697804000 -1.552605000 2.321455000H 2.819594000 0.211988000 2.257698000H 2.876973000 -4.353347000 -0.494523000H 3.481270000 -3.340026000 0.824154000H 4.081147000 -3.106108000 -0.834778000H -1.977240000 1.678605000 -1.899806000H -1.248785000 3.255512000 -1.638507000H 3.919161000 1.764831000 0.948159000H 3.603907000 2.048717000 -0.771134000H 5.265732000 1.759490000 -0.207628000H 4.518504000 -1.390028000 -1.989491000H 5.416854000 0.132970000 -1.998034000H 3.706022000 0.120190000 -2.457865000H -2.903244000 0.055217000 3.272495000H -3.077889000 1.246295000 0.980522000H -1.395104000 -1.118249000 4.889384000H 0.515348000 4.087442000 0.044185000H -0.204768000 5.030797000 1.365363000H -1.039861000 4.925252000 -0.190005000H 1.428802000 -3.393587000 -2.320271000H 2.524166000 -2.038911000 -2.634048000H 0.823684000 -1.725886000 -2.208714000H 1.000036000 -1.493269000 4.287008000H 0.522737000 -3.873591000 -0.143745000H -0.063982000 -2.223362000 0.129254000H 0.997976000 -3.013824000 1.327935000H -3.679290000 3.461986000 -2.033774000H -3.333867000 4.005394000 -0.386657000H -4.056719000 2.405410000 -0.669212000C -3.332100000 -1.043453000 -0.589073000C -4.439351000 -0.958657000 0.273020000C -3.405058000 -1.939088000 -1.673123000C -5.577630000 -1.739772000 0.058113000H -4.421049000 -0.290276000 1.128534000C -4.541124000 -2.711495000 -1.891236000H -2.549287000 -2.011472000 -2.338862000C -5.636595000 -2.617135000 -1.024706000H -6.419332000 -1.660632000 0.742014000

S42

H -4.576592000 -3.390600000 -2.739971000H -6.524045000 -3.221648000 -1.193884000

CPNN (addition to N-arm; -1729.113682) C -1.463286000 -0.846914000 -0.297718000C -1.394339000 0.181396000 0.895967000C -0.410065000 -0.461007000 1.822333000N 0.835659000 -0.542231000 1.288305000C 1.802239000 -1.296484000 1.848668000C 1.578061000 -1.947369000 3.054978000C 0.327354000 -1.805383000 3.670478000C -0.682253000 -1.075775000 3.046463000Ru 1.195606000 0.328951000 -0.570172000C 1.532074000 0.959160000 -2.262712000O 1.781335000 1.310738000 -3.359893000C 3.062882000 -1.336183000 1.033344000C 2.018780000 -2.637356000 -0.797281000C -1.703902000 2.480415000 -1.139289000C -2.945007000 3.129651000 -0.501248000N -0.467881000 -0.955903000 -1.081362000C 3.963183000 -1.233380000 -1.262674000C -0.260125000 2.860925000 1.605159000C 0.069403000 4.284046000 1.115300000C 4.748133000 0.066096000 -1.144326000C 2.807460000 -3.934852000 -0.606239000H 2.375782000 1.318013000 0.043332000H 3.688605000 -2.193892000 1.304128000H 3.629893000 -0.418803000 1.219979000H 2.141665000 -4.766984000 -0.863252000H 3.128101000 -4.081616000 0.430495000H 3.684381000 -4.001713000 -1.256863000H 5.093693000 0.256876000 -0.123326000H 4.166736000 0.927102000 -1.479563000H 5.636940000 -0.024328000 -1.780684000H -1.669936000 -0.992786000 3.487719000H -2.349480000 0.394782000 1.377517000H 0.135044000 -2.291134000 4.623039000H 0.910041000 4.285044000 0.413060000H 0.359177000 4.888216000 1.984970000H -0.785604000 4.776751000 0.646595000H 2.359162000 -2.553934000 3.501637000H -3.607701000 3.472114000 -1.307250000H -2.696801000 4.001271000 0.109334000H -3.508393000 2.417066000 0.110608000C -2.697913000 -1.677074000 -0.418006000C -3.575287000 -1.897703000 0.657116000C -2.999546000 -2.276741000 -1.654853000C -4.708310000 -2.700507000 0.504445000H -3.368061000 -1.458576000 1.628528000C -4.134316000 -3.067429000 -1.810435000H -2.325650000 -2.102519000 -2.489217000C -4.995558000 -3.286416000 -0.728994000

S43

H -5.367150000 -2.867015000 1.353434000H -4.353683000 -3.512158000 -2.778385000H -5.881248000 -3.905058000 -0.849438000N 2.715596000 -1.348050000 -0.431186000H 1.100231000 -2.673776000 -0.208653000H 1.719754000 -2.523263000 -1.841779000H 4.624501000 -2.069814000 -1.000170000H 3.639092000 -1.376094000 -2.298151000P -0.519497000 1.671405000 0.116508000C -2.194178000 1.425199000 -2.152078000H -1.367844000 0.874299000 -2.608345000H -2.883971000 0.707006000 -1.702246000H -2.737167000 1.958569000 -2.943633000C -0.911217000 3.533311000 -1.946249000H -1.557573000 3.897464000 -2.755550000H -0.611176000 4.395724000 -1.350472000H -0.016701000 3.099165000 -2.401558000C 0.940459000 2.396119000 2.459146000H 0.753733000 1.446220000 2.964871000H 1.853109000 2.302310000 1.865908000H 1.105940000 3.153898000 3.236622000C -1.491206000 2.895844000 2.534392000H -1.290674000 3.609969000 3.344484000H -2.405248000 3.215088000 2.031318000H -1.671169000 1.919459000 2.995655000

S44

References

[1] X. J. Dai, C. J. Li, J. Am. Chem. Soc. 2016, 138, 5433–5440.

[2] B. Gnanaprakasam, J. Zhang, D. Milstein, Angew. Chem. Int. Ed. 2010, 49, 1468–1471.

[3] S. Zhang, H. Xu, C. Lou, A. M. Senan, Z. Chen, G. Yin, Eur. J. Org. Chem. 2017, 2017, 1870–1875.

[4] J. Lee, M. Kim, S. Chang, H. Y. Lee, Org. Lett. 2009, 11, 5598–5601.

[5] R. S. Ramón, J. Bosson, S. Díez-González, N. Marion, S. P. Nolan, J. Org. Chem. 2010, 75, 1197–1202.

[6] M. Takasaki, Y. Motoyama, K. Higashi, S. H. Yoon, I. Mochida, H. Nagashima, Org. Lett. 2008, 10, 1601–1604.

[7] C. Crisóstomo, M. G. Crestani, J. J. García, Inorganica Chim. Acta 2010, 363, 1092–1096.

[8] K. Singh, A. Sarbajna, I. Dutta, P. Pandey, J. K. Bera, Chem. A Eur. J. 2017, 23, 7761–7771.

[9] W. Ren, M. Yamane, J. Org. Chem. 2010, 75, 8410–8415.

[10] C. Liu, C. He, W. Shi, M. Chen, A. Lei, Org. Lett. 2007, 9, 5601–5604.

[11] J. M. ConcelloÂn, R.-S. Humberto, Chem. Eur. J. 2001, 4266–4271.

[12] A. Schnyder, M. Beller, G. Mehltretter, T. Nsenda, M. Studer, A. F. Indolese, J. Org. Chem. 2001, 66, 4311–4315.

[13] G. E. Veitch, K. L. Bridgwood, K. Rands-Trevor, S. V. Ley, Org. Lett. 2008, 3623–3625.

[14] D. Kaufmann, M. Bialer, J. A. Shimshoni, M. Devor, B. Yagen, J. Med. Chem. 2009, 52, 7236–7248.

[15] M. G. Crestani, J. J. García, J. Mol. Catal. A Chem. 2009, 299, 26–36.

[16] D. U. Nielsen, R. H. Taaning, A. T. Lindhardt, T. M. Gøgsig, T. Skrydstrup, Org. Lett. 2011, 13, 4454–4457.

[17] R. R. Gowda, D. Chakraborty, European J. Org. Chem. 2011, 2226–2229.

[18] L. E. Eijsink, S. C. P. Perdriau, J. G. de Vries, E. Otten, Dalt. Trans. 2016, 45, 16033–16039.

[19] S. W. Kohl, L. Weiner, L. Schwartsburd, L. Konstantinovski, L. J. W. Shimon, Y. Ben-David, M. A. Iron, D. Milstein, Science 2009, 324, 74--77.

[20] R. Zeng, M. Feller, Y. Ben-David, D. Milstein, J. Am. Chem. Soc. 2017, 139, 5720–5723.

[21] J. Tao, J. P. Perdew, V. N. Staroverov, G. E. Scuseria, Phys. Rev. Lett. 2003, 91, 146401.

[22] F. Weigend, R. Ahlrichs, PCCP 2005, 7, 3297-3305

[23] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113, 6378-6396

[24] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104.

S45

S46

NMR spectra of products (2a-2ag)

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

B (d)7.87

C (t)7.44

D (t)7.52

E (s)7.35

A (s)7.97

0.95

2.08

1.04

2.06

0.95

7.35

7.43

7.44

7.46

7.50

7.52

7.53

7.86

7.88

7.97

O

NH2

102030405060708090100110120130140150160170180190f1 (ppm)

127.

4412

8.19

131.

1913

4.26

167.

87

O

NH2

Figure S13. NMR spectra of benzamide (2a): 1H NMR(top) and 13C NMR(bottom)

S47

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (s)7.39

B (m)7.28

D (m)7.94

C (s)7.99

1.98

1.00

2.11

0.74

7.25

7.26

7.27

7.27

7.28

7.29

7.30

7.39

7.92

7.93

7.94

7.94

7.95

7.96

7.99

O

NH2

F

-160-155-150-145-140-135-130-125-120-115-110-105-100-95-90-85-80-75-70-65-60f1 (ppm)

-109

.65

O

NH2

F

S48

102030405060708090100110120130140150160170180190f1 (ppm)

114.

9811

5.19

130.

0613

0.15

130.

7313

0.76

162.

6816

5.14

166.

78O

NH2

F

Figure S14. NMR spectra of 4-fluorobenzamide (2b): 1H NMR(top), 19F NMR(middle) and 13C NMR(bottom)

S49

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

B (d)7.89

C (d)7.52

D (s)7.45

A (s)8.04

0.91

2.00

2.09

0.92

7.45

7.51

7.53

7.88

7.90

8.04

O

NH2

Cl

102030405060708090100110120130140150160170180f1 (ppm)

128.

2812

9.39

133.

0313

6.06

166.

78

O

NH2

Cl

Figure S15. NMR spectra of 4-chlorobenzamide (2c): 1H NMR(top) and 13C NMR(bottom)

S50

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

B (d)7.81

C (d)7.66

A (s)8.04

D (s)7.45

0.95

1.90

2.00

1.01

7.45

7.65

7.67

7.80

7.82

8.04

O

NH2

Br

102030405060708090100110120130140150160170180190f1 (ppm)

125.

0112

9.60

131.

2313

3.40

166.

92

O

NH2

Br

Figure S16. NMR spectra of 4-bromobenzamide (2d): 1H NMR(top) and 13C NMR(bottom)

S51

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (s)8.08

B (s)8.05

C (d)7.87

E (s)7.51

F (t)7.42

D (d)7.72

1.12

0.96

0.88

1.08

1.26

0.95

7.40

7.42

7.44

7.51

7.71

7.73

7.86

7.88

8.05

8.08

Br

NH2

O

102030405060708090100110120130140150160170180f1 (ppm)

121.

6312

6.55

130.

1813

0.51

133.

9613

6.49

166.

32

Br

NH2

O

Figure S17. NMR spectra of 3-bromobenzamide (2e): 1H NMR(top) and 13C NMR(bottom)

S52

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

A (s)7.85

B (d)7.63

C (s)7.55

D (m)7.41

E (m)7.33

1.04

2.14

0.94

1.01

1.00

7.31

7.32

7.32

7.33

7.34

7.34

7.35

7.39

7.40

7.41

7.42

7.44

7.55

7.62

7.64

7.85

O

NH2Br

30405060708090100110120130140150160170180f1 (ppm)

118.

59

127.

4712

8.53

130.

6213

2.68

139.

35

169.

03

O

NH2Br

Figure S18. NMR spectra of 2-bromobenzamide (2f): 1H NMR(top) and 13C NMR(bottom)

S53

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

f1 (ppm)

A (s)8.20

B (d)8.06

C (d)7.83

D (s)7.63

0.97

2.02

2.11

0.95

7.63

7.82

7.85

8.05

8.08

8.20

O

NH2

FF

F

-140-130-120-110-100-90-80-70-60-50-40-30

f1 (ppm)

-61.

36

O

NH2

FF

F

S54

102030405060708090100110120130140150160170f1 (ppm)

119.

9012

2.61

125.

1912

5.23

125.

2712

5.31

128.

0312

8.32

130.

6713

0.98

131.

3013

1.62

138.

10

166.

67O

NH2

FF

F

Figure S19. NMR spectra of 4-(trifluoromethyl)benzamide (2g): 1H NMR(top), 19F NMR(middle) and 13C NMR(bottom)

S55

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0f1 (ppm)

A (s)10.08

B (s)8.17

C (s)7.60

D (d)8.05

E (d)7.98

1.07

2.05

2.06

1.02

1.00

7.60

7.97

7.99

8.04

8.06

8.17

10.0

8

O

NH2

O

102030405060708090100110120130140150160170180190200210f1 (ppm)

128.

1512

9.35

137.

8113

9.34

167.

05

192.

93

O

NH2

O

Figure S20. NMR spectra of 4-formylbenzamide (2h): 1H NMR(top) and 13C NMR(bottom)

S56

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

A (s)8.12

C (s)7.55

B (m)7.96

D (s)1.55

8.93

0.95

3.84

1.00

1.55

7.55

7.93

7.93

7.94

7.95

7.96

7.98

7.98

7.98

8.12

OO

CH3CH3

CH3

O NH2

0102030405060708090100110120130140150160170180f1 (ppm)

27.7

3

81.1

5

127.

6612

8.88

133.

5113

8.05

164.

4216

7.08

OO

CH3CH3

CH3

O NH2

Figure S21. NMR spectra of tert-butyl 4-carbamoylbenzoate (2i): 1H NMR(top) and 13C NMR(bottom)

S57

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

A (m)8.32

C (m)7.59

B (m)7.98

5.36

2.91

0.90

7.50

7.51

7.53

7.53

7.55

7.55

7.56

7.57

7.57

7.58

7.59

7.60

7.60

7.61

7.63

7.64

7.64

7.66

7.66

7.67

7.94

7.95

7.96

7.97

7.98

7.99

8.01

8.02

8.30

8.32

8.33

8.33

O NH2

30405060708090100110120130140150160170180f1 (ppm)

124.

9212

5.12

125.

5812

6.11

126.

5912

8.16

129.

7112

9.75

133.

1913

4.65

170.

58

O NH2

Figure S22. NMR spectra of 1-naphthamide (2j): 1H NMR(top) and 13C NMR(bottom)

S58

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

B (s)8.14

C (m)7.98

D (m)7.59

E (s)7.47

A (s)8.49

0.92

2.01

4.05

0.98

0.99

7.47

7.56

7.56

7.58

7.58

7.59

7.59

7.60

7.61

7.61

7.62

7.63

7.94

7.96

7.97

7.97

7.98

7.99

8.00

8.01

8.02

8.14

8.49

O

NH2

2030405060708090100110120130140150160170180190f1 (ppm)

124.

3912

6.64

127.

5512

7.58

127.

7512

7.80

128.

8513

1.64

132.

1513

4.16

167.

95

O

NH2

Figure S23. NMR spectra of 2-naphthamide (2k): 1H NMR(top) and 13C NMR(bottom)

S59

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (s)7.88

B (d)7.77

C (d)7.24

D (s)2.34

3.17

2.95

2.13

0.95

2.34

7.23

7.25

7.76

7.78

7.88

O

NH2

CH3

102030405060708090100110120130140150160170180f1 (ppm)

20.9

3

127.

5012

8.71

131.

49

141.

03

167.

78

O

NH2

CH3

Figure S24. NMR spectra of 4-methylbenzamide (2l): 1H NMR(top) and 13C NMR(bottom)

S60

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (s)7.17

B (d)7.85

C (d)6.97

D (s)3.80

3.16

2.01

1.00

2.99

3.80

6.96

6.98

7.17

7.84

7.86

O

NH2

OCH3

35455565758595105115125135145155165175f1 (ppm)

55.3

0

113.

37

126.

5112

9.33

161.

57

167.

41

O

NH2

OCH3

Figure S25. NMR spectra of 4-methoxybenzamide (2m): 1H NMR(top) and 13C NMR(bottom)

S61

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (d)7.74

B (s)7.63

D (d)6.67

E (s)2.95

C (s)6.93

6.36

2.04

0.90

1.00

2.09

2.95

6.66

6.68

6.93

7.63

7.73

7.75

O

NH2

N

CH3

CH3

102030405060708090100110120130140150160170180190f1 (ppm)

39.7

2

110.

70

120.

96

128.

92

152.

12

167.

97

O

NH2

N

CH3

CH3

Figure S26. NMR spectra of 4-(dimethylamino)benzamide (2n): 1H NMR(top) and 13C NMR(bottom)

S62

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (d)7.57

B (s)7.50

D (d)6.51

E (s)5.58

C (s)6.81

2.00

2.02

0.90

0.70

2.12

5.58

6.50

6.53

6.81

7.50

7.56

7.58

O

NH2

NH2

0102030405060708090100110120130140150160170180190f1 (ppm)

112.

5112

0.96

129.

15

151.

70

168.

12

O

NH2

NH2

Figure S27. NMR spectra of 4-aminobenzamide (2o): 1H NMR(top) and 13C NMR(bottom)

S63

2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

A (dt)8.63

C (dd)8.04

D (td)7.98

F (ddd)7.58

E (s)7.64

B (s)8.11

1.16

0.89

1.13

1.06

0.95

1.00

7.57

7.57

7.58

7.58

7.59

7.59

7.60

7.60

7.64

7.96

7.96

7.98

7.98

7.99

8.00

8.03

8.03

8.03

8.05

8.05

8.05

8.11

8.62

8.62

8.62

8.63

8.63

8.64

N

O

NH2

30405060708090100110120130140150160170180f1 (ppm)

121.

87

126.

42

137.

62

148.

4315

0.30

166.

00

N

O

NH2

Figure S28. NMR spectra of picolinamide (2p): 1H NMR(top) and 13C NMR(bottom)

S64

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

B (d)8.69

C (d)8.20

D (s)8.16

E (s)7.59

F (dd)7.49

A (s)9.03

1.10

1.00

0.80

1.50

0.89

0.93

7.47

7.49

7.49

7.51

7.59

8.16

8.19

8.21

8.69

8.70

9.03

N

O

NH2

102030405060708090100110120130140150160170180f1 (ppm)

123.

6112

9.77

135.

35

148.

7515

2.04

166.

71

N

O

NH2

Figure S29. NMR spectra of nicotinamide (2q): 1H NMR(top) and 13C NMR(bottom)

S65

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

A (m)8.71

B (s)8.24

D (s)7.72

C (m)7.76

0.81

2.26

1.00

1.89

7.72

7.76

7.76

7.77

7.77

8.24

8.71

8.71

8.72

8.72

N

O

NH2

102030405060708090100110120130140150160170180190f1 (ppm)

121.

40

141.

28

150.

22

166.

32

N

O

NH2

Figure S30. NMR spectra of isonicotinamide (2r): 1H NMR(top) and 13C NMR(bottom)

S66

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

A (d)9.18

B (d)8.85

C (dd)8.72

D (s)8.25

E (s)7.86

1.05

1.10

1.00

1.00

0.91

7.86

8.25

8.71

8.71

8.72

8.72

8.85

8.86

9.18

9.18

N

N

O

NH2

30405060708090100110120130140150160170180f1 (ppm)

143.

3714

3.61

145.

1014

7.37

165.

05

N

N

O

NH2

Figure S31. NMR spectra of pyrazine-2-carboxamide (2s): 1H NMR(top) and 13C NMR(bottom)

S67

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (dd)7.12

B (s)7.37

C (ddd)7.73

D (s)7.96

1.00

0.93

1.92

0.96

7.11

7.12

7.12

7.13

7.37

7.72

7.72

7.73

7.73

7.74

7.74

7.75

7.75

7.96

O

NH2

S

2030405060708090100110120130140150160170f1 (ppm)

127.

8912

8.69

130.

98

140.

32

162.

92

O

NH2

S

Figure S32. NMR spectra of 2-thiophenecarboxamide (2t): 1H NMR(top) and 13C NMR(bottom)

S68

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (dd)8.12

B (s)7.77

C (dd)7.55

D (dd)7.48

E (s)7.22

1.09

1.10

0.99

1.05

1.00

7.22

7.47

7.47

7.48

7.48

7.54

7.55

7.56

7.56

7.77

8.12

8.12

8.12

8.13

O

NH2S

30405060708090100110120130140150160170180f1 (ppm)

126.

5212

7.15

128.

97

138.

00

163.

66

O

NH2S

Figure S33. NMR spectra of 3-thiophenecarboxamide (2u): 1H NMR(top) and 13C NMR(bottom)

S69

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

B (s)7.75

D (d)7.09

E (dd)6.59

A (d)7.80

C (s)7.35

1.00

1.01

0.98

0.82

0.96

6.59

6.59

6.59

6.60

7.08

7.09

7.35

7.75

7.79

7.80

O

NH2

O

2030405060708090100110120130140150160170180f1 (ppm)

111.

7511

3.56

144.

9914

8.06

159.

37

O

NH2

O

Figure S34. NMR spectra of 2-furamide (2v): 1H NMR(top) and 13C NMR(bottom)

S70

1.82.22.63.03.43.84.24.65.05.45.86.26.67.07.47.88.2f1 (ppm)

A (s)8.15

B (dd)7.69

C (s)7.64

D (s)7.18

E (d)6.80

1.07

0.98

0.91

1.05

1.00

6.80

6.81

7.18

7.64

7.69

7.69

7.70

8.15

O

NH2O

2030405060708090100110120130140150160170f1 (ppm)

109.

29

122.

90

143.

9214

5.30

163.

37

O

NH2O

Figure S35. NMR spectra of 3-furamide (2w): 1H NMR(top) and 13C NMR(bottom)

S71

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5

f1 (ppm)

A (s)7.45

B (m)7.27

C (s)6.86

D (s)3.36

2.09

1.13

4.87

1.00

3.36

6.86

7.19

7.19

7.20

7.20

7.21

7.22

7.22

7.23

7.23

7.24

7.25

7.26

7.27

7.27

7.28

7.29

7.29

7.30

7.31

7.31

7.31

7.45

O

NH2

30405060708090100110120130140150160170180190f1 (ppm)

42.2

5

126.

2312

8.12

129.

0413

6.50

172.

18

O

NH2

Figure S36. NMR spectra of 2-phenylacetamide (2x): 1H NMR(top) and 13C NMR(bottom)

S72

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

A (s)5.87

B (s)5.38

C (q)3.58

D (dd)1.51

E (m)7.30

2.98

0.91

0.98

1.00

4.44

1.49

1.50

1.51

1.52

3.55

3.57

3.59

3.61

5.38

7.24

7.24

7.25

7.26

7.26

7.28

7.28

7.30

7.30

7.32

7.32

7.33

7.35

7.35

O

NH2

CH3

0102030405060708090100110120130140150160170180190200f1 (ppm)

18.4

3

46.7

3

127.

4612

7.70

127.

9112

9.06

141.

40

176.

94

O

NH2

CH3

Figure S37. NMR spectra of 2-phenylpropanamide (2y): 1H NMR(top) and 13C NMR(bottom)

S73

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

f1 (ppm)

A (s)6.00

B (s)5.59

C (t)2.95

D (t)2.51

E (t)7.28

F (dd)7.20

1.98

1.96

1.01

1.00

2.66

1.84

2.49

2.51

2.53

2.93

2.95

2.97

5.59

6.00

7.18

7.19

7.19

7.21

7.21

7.26

7.28

7.30

O

NH2

102030405060708090100110120130140150160170180190f1 (ppm)

31.4

7

37.5

8

126.

3612

8.38

128.

64

140.

78

175.

02

O

NH2

Figure S38. NMR spectra of 3-phenylpropanamide (2z): 1H NMR(top) and 13C NMR(bottom)

S74

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

A (d)6.62

B (m)7.55

C (m)7.40

D (s)7.11

1.00

0.86

3.91

2.83

6.60

6.64

7.36

7.38

7.38

7.39

7.40

7.41

7.44

7.54

7.55

7.55

7.56

7.57

O

NH2

30405060708090100110120130140150160170f1 (ppm)

122.

3412

7.52

128.

9112

9.43

134.

8813

9.14

166.

66

O

NH2

Figure S39. NMR spectra of cinnamamide (2aa): 1H NMR(top) and 13C NMR(bottom)

S75

1.01.41.82.22.63.03.43.84.24.65.05.45.86.26.67.07.4f1 (ppm)

A (s)2.01

1.00

2.01

O

NH2CH3

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

22.1

1

178.

24

Figure S40. NMR spectra of acetamide (2ab): 1H NMR(top) and 13C NMR(bottom)

S76

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

A (s)7.20

B (s)6.66

C (t)2.02

D (p)1.45

E (h)1.26

F (t)0.86

3.13

2.37

2.19

2.19

0.97

1.00

0.84

0.86

0.86

0.88

1.21

1.23

1.25

1.27

1.28

1.30

1.41

1.43

1.45

1.47

1.49

2.00

2.02

2.04

6.66

7.20

O

NH2

CH3

0102030405060708090100110120130140150160170180190f1 (ppm)

13.7

221

.83

27.2

534

.81

174.

28

O

NH2

CH3

Figure S41. NMR spectra of pentanamide (2ac): 1H NMR(top) and 13C NMR(bottom)

S77

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

A (tt)2.14

B (dd)1.90

C (m)1.78

D (dd)1.67

E (qd)1.42

F (dtd)1.26

G (s)5.60

H (s)5.47

3.56

2.21

1.10

2.54

2.18

1.00

1.00

0.97

1.19

1.21

1.22

1.24

1.24

1.25

1.26

1.27

1.28

1.29

1.30

1.32

1.37

1.38

1.40

1.41

1.43

1.44

1.46

1.47

1.65

1.66

1.68

1.69

1.74

1.77

1.77

1.78

1.79

1.80

1.81

1.81

1.88

1.89

1.91

1.92

2.11

2.13

2.14

2.15

2.17

O

NH2

102030405060708090100110120130140150160170180190200f1 (ppm)

25.8

225

.86

29.8

3

44.9

3

178.

83

O

NH2

Figure S42. NMR spectra of cyclohexanecarboxamide (2ad): 1H NMR(top) and 13C NMR(bottom)

S78

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

A (s)5.70

B (s)1.21

9.00

2.04

1.21

5.70

O

NH2

CH3

CH3CH3

102030405060708090100110120130140150160170180190200f1 (ppm)

27.7

5

38.7

3

181.

58

O

NH2

CH3

CH3CH3

Figure S43. NMR spectra of pivalamide (2ae): 1H NMR(top) and 13C NMR(bottom)

S79

-2.0-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)

A (t)2.00

C (s)6.65

D (s)7.19

B (m)1.43

4.09

4.08

2.00

2.03

1.41

1.41

1.42

1.43

1.44

1.98

2.00

2.01

6.65

7.19

O

NH2

O

NH2

102030405060708090100110120130140150160170180190f1 (ppm)

25.1

9

35.1

8

175.

41

O

NH2

O

NH2

Figure S44. NMR spectra of adipamide (2af): 1H NMR(top) and 13C NMR(bottom)

S80

2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

A (s)7.47

B (s)7.92

C (s)8.06

2.00

4.07

1.89

7.47

7.92

8.06

O NH2

ONH2

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

127.

35

136.

56

167.

24

O NH2

ONH2

Figure S45. NMR spectra of terephthalamide (2ag): 1H NMR(top) and 13C NMR(bottom)

S81

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

B (h)2.19

C (m)1.66

E (d)1.16

F (t)0.94

A (s)5.45

D (m)1.46

3.002.971.071.620.932.28

0.92

0.94

0.96

1.15

1.17

1.40

1.42

1.44

1.44

1.46

1.47

1.47

1.49

1.51

1.62

1.63

1.65

1.66

1.67

1.67

1.69

1.71

1.72

2.15

2.17

2.18

2.20

2.22

2.24

5.45

CH3

CH3

O

NH2

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

11.9

517

.54

27.4

1

42.5

8

179.

09

Figure S46. NMR spectra of 2-methylbutanamide: 1H NMR(top) and 13C NMR(bottom)