A Versatile Palladium-Triphosphane System for Direct

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N‐Directed Palladium C−H Halogenation: Unsymmetrical Polyhalogenated and Biphenyl s‐ ... 0. 0. 5. Pd(OAc)2. NBS (1.0). CH3NO2. 76. 61 (52). 9 (6). 6. 0. 6[c]. Pd(dba)2 ... instead of 100 °C. [f] 80 °C instead of 100 °C. [g] 30 mn instead of 10 min. ... 38 (32). 4. Pd(OAc)2. NBS (8.0). AcOH. 100. 0. 0. 0. 40 (35). 60 (44). 5[c].
Building

Diversity

in

ortho-Substituted

s–Aryltetrazines

By

Tuning

N‑Directed Palladium C−H Halogenation: Unsymmetrical Polyhalogenated and Biphenyl s‑Aryltetrazines Clève D. Mboyi, Christelle Testa, Sarah Reeb, Semra Genc, Hélène Cattey, Paul Fleurat-Lessard, Julien Roger,* and Jean-Cyrille Hierso*,†

Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB - UMR CNRS 6302), Université de Bourgogne Franche-Comté (UBFC), 9 Avenue Alain Savary, 21078 CEDEX Dijon, France



Institut Universitaire de France (IUF), 103 Boulevard Saint Michel, 75005 Paris Cedex, France

Table of contents

General conditions

2

Screening of the conditions

2

Synthesis of s-tetrazine derivatives (1) and (3d)

5

General procedure of functionalization of 3,6-diaryl-1,2,4,5-tetrazine

6

General procedure for Suzuki-Miyaura cross-coupling

17

Detailed C–H halogenation selectivity

21

Crystal data

24

Computational details

34

1

43

H, 13C and 19F NMR copy of new products.

1

General conditions All reagents were purchased from commercial suppliers and used without purifications. All reactions were performed in Schlenk tubes or in a microwave reaction vessel. Microwave heating was carried out using a CEM Discover microwave reactor. The microwave reactions were run in closed reaction vessels with magnetic stirring and with the temperature controlled via IR detection. 1H (300 MHz), 13C (75 or 125 MHz), 19F (282 MHz) spectra were recorded on Brucker AVANCE III instrument in CDCl3 solutions. Chemical shifts are reported in ppm relative to CDCl 3 (1H: 7.26 and 13C: 77.16) and coupling constants J are given in Hz. High resolution mass spectra (HRMS) were obtained on a Thermo LTQ-Orbitrap XL with ESI source. Flash chromatography was performed on silica gel (230-400 mesh). Elemental analysis experiments were performed Thermo Electron Flash EA 1112 Series.

Screening of the conditions Table S1. Screening of mono-bromination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Oxidant

Entry

[Pd]

1

X

NBS (1.0)

CH3NO2

[b]

2

(equiv)

2a (%)

3a (%)

3a’ (%)

4a (%)

0

0

0

0

0

(%)

Pd(dba)2

NBS (1.0)

CH3NO2

44

41 (25)

3

0

0

3

Pd(dba)2

NBS (1.0)

CH3NO2

53

47 (47)

7

0

0

4

Pd2(dba)3

NBS (1.0)

CH3NO2

51

46 (38)

5

0

0

5

Pd(OAc)2

NBS (1.0)

CH3NO2

76

61 (52)

9 (6)

6

0

[c]

6

Pd(dba)2

NBS (1.0)

CH3NO2

53

49 (30)

4

0

0

7

Pd(dba)2

TBATB (1.0)

CH3NO2

0

0

0

0

0

8

Pd(dba)2

PTB (1.0)

CH3NO2

0

0

0

0

0

9

Pd(dba)2

NBS (2.0)

CH3NO2

69

53 (46)

9

7

0

10

Pd(dba)2

NBS (3.0)

CH3NO2

87

54 (46)

22 (20)

8

3

11

Pd(dba)2

NBS (1.0)

PhCF3

47

42

5

0

0

12[d]

Pd(dba)2

NBS (1.0)

HOAc

55

48

6

1

0

[e]

13

Pd(dba)2

NBS (1.0)

DCE

26

25

1

0

0

14[f]

Pd(dba)2

NBS (1.0)

CH3NO2

28

27

1

0

0

[g]

15

Pd(dba)2

NBS (1.0)

CH3NO2

60

49

8

3

0

16[d]

Pd(OAc)2

NBS (1.0)

AcOH

81

61 (53)

15 (13)

5

0

[d]

Pd(OAc)2

NBS (2.0)

AcOH

100

28

51 (45)

11

10 (5)

17 [a]

Conv.

Solvent

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), [X] (1-3.0 equiv), solvent (0.125 M), 100 °C, microwave 200

W, under air, 10 min. 1H NMR yield and isolated yield under bracket. dba: dibenzylidene acetone. TBATB = tetrabutylammonium tribromide. PTB = pyridinium tribromide. DCE: dichloroethane. instead of 100 °C.

[f]

80 °C instead of 100 °C.

[g]

[b]

Under argon. [c] [Pd] (20 mol%).

30 mn instead of 10 min.

2

[d]

110 °C instead of 100 °C.

[e]

90 °C

Table S2. Screening of mono-iodination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Entry

[Pd]

Oxidant (equiv)

Conv.

Solvent

(%)

2b (%)

3b (%)

3b’ (%)

4b (%)

1

Pd(dba)2

NIS (1.0)

CH3NO2

10

10

0

0

0

2

Pd(dba)2

NIS (1.0)

AcOH

66

54 (47)

9 (4)

3

0

Pd(OAc)2

NIS (1.0)

AcOH

82

56 (34)

19 (11)

7

0

[b]

3

[a]

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), NIS (1 equiv), solvent (0.125 M), 100 °C, microwave 200 W,

under air, 10 min. 1H NMR yield and isolated yield under bracket. [b] 110 °C instead of 100 °C.

Table S3. Screening of mono-chlorination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Entry

[Pd]

Oxidant (equiv)

Conv.

Solvent

(%)

2c (%)

3c (%)

3c’ (%)

4c (%) 0

1

Pd(dba)2

NCS (1.0)

CH3NO2

0

0

0

0

2[b]

Pd(dba)2

NCS (1.0)

AcOH

47

43 (33)

4

0

0

3[b]

Pd(OAc)2

NCS (1.0)

AcOH

45

41 (37)

4

0

45

4[b]

Pd(dba)2

NCS (3.0)

AcOH

79

56 (54)

15 (9)

8

0

[a]

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), NCS (1-2.5 equiv), solvent (0.125 M), 100 °C, microwave 200

W, under air, 45 min. 1H NMR yield and isolated yield under bracket. [b] 110 °C instead 100 °C. [d] PivOH (30% mol.).

3

Table S4. Screening of tetra-bromination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Entry

[Pd]

Oxidant (equiv)

Conv.

Solvent

(%)

2a (%)

3a (%)

3a' (%)

4a (%)

4a' (%)

1

Pd(OAc)2

NBS (2.0)

AcOH

100

28

51 (45)

11

10 (5)

0

2

Pd(OAc)2

NBS (3.0)

AcOH

100

0

43 (37)

6

48 (41)

3

3

Pd(OAc)2

NBS (5.0)

AcOH

100

0

0

0

62 (60)

38 (32)

4

Pd(OAc)2

NBS (8.0)

AcOH

100

0

0

0

40 (35)

60 (44)

[c]

5

Pd(OAc)2

NBS (8.0)

AcOH

100

0

0

0

44

56

6[d]

Pd(OAc)2

NBS (8.0)

AcOH

100

0

0

0

59

41

7

Pd(OAc)2

NBS (8.0)

PivOH

52

45 (36)

7

0

0

0

8[e]

Pd(OAc)2

NBS (8.0)

AcOH

100

0

0

0

10 (6)

90 (79)

9[f]

Pd(OAc)2

NBS (8.0)

AcOH

100

0

0

0

0

99 (89)

[a]

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), NBS (3-8 equiv), solvent (0.125 M), 110 °C, microwave 200 W, under

air, 10 min. 1H NMR yield and isolated yield under bracket. [b] TFA = trifluoroacetic acid (30% mol.). min.

[f]

[c]

PivOH (30% mol.).

[d]

30 min instead 10

45 min instead 10 min.

Table S5. Screening of tetra-iodination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Entry

[Pd]

Oxidant (equiv)

Conv.

Solvent

(%)

2b (%)

3b (%)

3b' (%)

4b (%)

4b' (%)

1[b]

Pd(OAc)2

NIS (2.0)

AcOH

100

13

38 (17)

22 (13)

27

0

2

Pd(OAc)2

NIS (8.0)

AcOH

100

0

0

0

67 (7)

33 (31)

3

Pd(OAc)2

NIS (10.0)

AcOH

100

0

0

0

52

38[c]

4

Pd(OAc)2

NIS (12.0)

AcOH

100

0

0

0

0

26[c]

[d]

Pd(OAc)2

NIS (12.0)

CH3NO2

100

0

0

0

58 (9)

42 (42)

[d,e]

Pd(OAc)2

NIS (12.0)

CH3NO2

100

0

0

0

78 (15)

22 (20)

5 6

[a]

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), NIS (8-12 equiv), solvent (0.125 M), 110 °C, microwave 200 W, under

air, 10 min. 1H NMR yield and isolated yield under bracket. 1

1,2,4,5-tetrazine was detected by H NMR et GC-MS.

[d]

[b]

120 °C instead of 110 °C.

100 °C instead of 110 °C.

4

[e]

[c]

3-(2-acetoxy-6-iodophenyl)-6-(2,6-diiodophenyl)-

PivOH (30% mol.).

Table S6. Screening of tetra-chlorination with 3,6-diphenyl-1,2,4,5-tetrazine (1)[a]

Entry 1[b]

[Pd]

Oxidant

Solvent

(equiv)

Conv. (%)

2c (%)

3c (%)

3c' (%)

4c (%)

4c' (%)

4

0

Pd(OAc)2

NCS (4.0)

AcOH

93

53 (38)

25 (19)

11

2

Pd(OAc)2

NCS (4.0)

AcOH

100

37 (33)

38 (37)

14 (11)

10 (8)

0

3

Pd(OAc)2

NCS (8.0)

AcOH

100

0

6 (3)

0

48 (35)

46 (20)

4

Pd(OAc)2

NCS (10.0)

AcOH

100

0

7 (1)

0

47 (30)

46 (10)

5

Pd(OAc)2

NCS (12.0)

AcOH

100

0

7 (2)

0

46 (22)

47 (8)

[c]

6

Pd(OAc)2

NCS (12.0)

AcOH

100

0

0

0

23 (18)

77 (34)

7[c,d]

Pd(OAc)2

NCS (12.0)

AcOH

100

0

0

0

17 (8)

83 (40)

8[c]

Pd(OAc)2

NCS (12.0)

PivOH

45

43 (28)

2

0

0

0

[c]

9

Pd(OAc)2

NCS (12.0)

PrCOOH

100

0

20 (14)

7

53 (34)

20

10

PdCl2

NCS (10.0)

AcOH

100

11

42 (37)

11

31

5

[b,c]

[a]

Conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd] (10 mol%), NCS (4-12 equiv), solvent (0.125 M), 110 °C, microwave 200 W, under

air, 45 min. 1H NMR yield and isolated yield under bracket. [c] 10 min instead 45 min. [d] 120 °C instead 110 °C. [e] PivOH (30% mol.).

Synthesis of s-tetrazine derivatives (1) and (3d)

3,6-diphenyl-1,2,4,5-tetrazine (1): CAS 6830-78-0

To a mixture of benzonitrile (1 ml, 9.70 mmol) and hydrazine monohydrate (2.4 ml, 48.50 mmol) in absolute ethanol (10 ml) was added Sulfur (311 mg, 9.70 mmol). The resulting suspension was placed under nitrogen atmosphere, magnetically stirred and heated at 60°C for 3 h. Upon cooling, the solvent was removed under reduced pressure to afford a yellowish solid. The crude mixture was dissolved in dichloromethane (2.9 ml), a solution of was NaNO2 added (195.0 ml, 0.3 mM in distilled water), followed by addition of acetic acid (2.8 ml) at 0°C. A pink color develops that is characteristic of the tetrazine (labs = 550 nm). The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (Dichloromethane-Heptane = 1:1) to afford 1 (purple solid) in 30% (348.4 mg) yield. Rf = 0.50 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.67 (dd, J = 7.85, 1.45 Hz, 4H), 7.67-7.61 (m, 6H).

5

3,6-bis(2-fluorophenyl)-1,2,4,5-tetrazine (3d): CAS 108350-48-7

To a mixture of 2-fluorobenzonitrile (0.88 ml, 8.26 mmol) and hydrazine monohydrate (2 ml, 41.30 mmol) in absolute ethanol (10 ml) was added Sulfur (265 mg, 8.26 mmol). The resulting suspension was placed under nitrogen atmosphere, magnetically stirred and heated at 60°C for 4 h. Upon cooling, the solvent was removed under reduced pressure to afford a yellowish solid. The crude mixture was dissolved in dichloromethane (2.5 ml), a solution of was NaNO2 added (166 ml, 0.3 mM in distilled water), followed by addition of acetic acid (2.4 ml) at 0°C. A pink color develops that is characteristic of the tetrazine (labs = 540 nm). The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (Dichloromethane-Heptane = 1:1) to afford 1 (purple solid) in 10% (107.8 mg) yield. Rf = 0.31 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.38 (td, J = 7.64, 1.77 Hz, 2H), 7.67-7.60 (m, 2H), 7.41 (td, J = 7.74, 1.06 Hz, 2H), 7.34 (ddd, J = 10.85,

8.34, 0.94 Hz, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -111.6.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 163.4 (d, J = 260.1 Hz), 163.2 (d, J = 5.6 Hz), 134.3 (d, J = 8.8 Hz), 131.5 (d, J = 0.8 Hz), 124.9 (d, J = 3.9

Hz), 120.6 (d, J = 9.8 Hz), 117.6 (d, J = 21.5 Hz). Elemental analysis: Calcd (%) for C14H8F2N4: C 62.22, H 2.98, N 20.73. Found: C 61.10, H 2.84, N 20.77. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8F2N4: 293.061. Found: m/z = 293.060. For alternative synthesis of fluorinated tetrazine by microwaves, see: Angew. Chem. Int. Ed. 2016, 55, 5555−5559. 3-(2-fluorophenyl)-6-phenyl-1,2,4,5-tetrazine (2d): Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.43 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.70-8.66 (m, 2H), 8.34 (td, J = 7.63, 1.77 Hz, 1H), 7.68-7.58 (m, 4H), 7.40 (td, J

= 7.70, 1.14 Hz, 1H), 7.33 (ddd, J = 10.87, 8.31, 0.96 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -112.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 164.0 (d, J = 5.9 Hz), 163.4 (d, J = 5.6 Hz), 159.9, 134.1 (d, J = 8.7 Hz), 133.0,

131.7, 131.4 (d, J = 0.9 Hz), 129.5, 128.4, 124.9 (d, J = 3.9 Hz), 120.9 (d, J = 9.9 Hz), 117.7 (d, J = 21.8 Hz). Elemental analysis: Calcd (%) for C14H9FN4: C 66.66, H 3.60, N 22.21. Found: C 66.49, H 3.53, N 21.16. HRMS + p ESI (m/z) [M+H+] Calcd for C14H9FN4: 253.088. Found: m/z = 253.088.

General procedure of functionalization of 3,6-diaryl-1,2,4,5-tetrazine

As a typical experiment, the tetrazine (1.0 eq., 0.25 mmol), halogenated source (X eq.), and palladium source (10 mol%) were introduced in a 10 mL microwave reaction vessel, equipped with a magnetic stirring bar. The solvent (mL, 0.125 M) was added, and the reaction mixture was heated in the microwave at T °C for corresponding reaction time (200 W, 2 min ramp). After cooling down to room temperature, the reaction mixture was diluted with dichloromethane, and was washed three times with water + 3% of TEA (or Na2S2O3 when NIS was involved). The combined organic layer was washed with water and dried over MgSO 4. The solvent was removed in vacuo and the residue was analyzed by NMR to determine the conversion of the halogenated product. Then, the crude product was purified by silica gel column chromatography using an appropriate ratio of the eluent. For elemental analysis, the product was recrystallized with a slow diffusion of dichloromethane into heptane (RPE quality).

6

3-(2-bromophenyl)-6-phenyl-1,2,4,5-tetrazine (2a) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.43 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.73-8.69 (m, 2H), 8.02 (ddd, J = 7.49, 1.93, 0.23 Hz, 1H), 7.82 (ddd, J = 7.94,

0.99, 0.30 Hz, 1H), 7.70-7.60 (m, 3H), 7.57 (td, J = 8.06, 0.52 Hz, 1H), 7.47 (ddd, J = 7.96, 7.54, 1.80 Hz, 1H).

3,6-bis(2-bromophenyl)-1,2,4,5-tetrazine (3a): CAS 108350-48-7 Rf = 0.34 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.07 (dd, J = 7.68, 1.76 Hz, 2H), 7.84 (dd, J = 7.96, 1.13 Hz, 2H), 7.58 (td, J =

7.52, 1.23 Hz, 2H), 7.49 (td, J = 7.90, 1.81 Hz, 2H).

3-(2,6-dibromophenyl)-6-(2-bromophenyl)-1,2,4,5-tetrazine (4a) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.42 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.09 (ddd, J = 7.72, 1.68, 0.11 Hz, 1H), 7.85 (ddd, J = 7.92, 1.27, 0.28 Hz, 1H),

7.77 (d, J = 8.10 Hz, 2H), 7.60 (td, J = 7.52, 1.24 Hz, 1H), 7.53-7.47 (m, 1H), 7.35 (dd, J = 8.33, 7.89 Hz, 1H).

3,6-bis(2,6-dibromophenyl)-1,2,4,5-tetrazine (4a’) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.42 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (sppm) = 7.77 (d, J = 8.10 Hz, 4H), 7.36 (t, J = 8.20 Hz, 2H).

3-(2-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (2b) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.44 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.74-8.70 (m, 2H), 8.12 (dd, J = 7.97, 0.95 Hz, 1H), 7.99 (dd, J = 7.74, 1.60 Hz,

1H), 7.70-7.58 (m, 4H), 7.31-7.26 (m, 1H).

7

3,6-bis(2-iodophenyl)-1,2,4,5-tetrazine (3b) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.38 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.12 (dd, J = 7.99, 0.93 Hz, 2H), 8.07 (dd, J = 7.75, 1.61 Hz, 2H), 7.62 (td, J =

7.58, 1.15 Hz, 2H), 7.33-7.28 (m, 2H).

3-(2,6-diiodophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (4b) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.44 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.14 (dd, J = 7.88, 0.96 Hz, 1H), 8.13 (dd, J = 7.75, 1.71 Hz, 1H), 8.05 (d, J =

7.97 Hz, 2H), 7.64 (td, J = 7.58, 1.14 Hz, 1H), 7.32 (td, J = 7.63, 1.66 Hz, 1H), 6.98 (t, J = 7.96 Hz, 1H).

3,6-bis(2,6-diiodophenyl)-1,2,4,5-tetrazine (4b’) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.44 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.06 (d, J = 7.97 Hz, 4H), 7.00 (t, J = 7.96 Hz, 2H).

3-(2-chlorophenyl)-6-phenyl-1,2,4,5-tetrazine (2c): CAS 74115-26-7 Rf = 0.45 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.72-8.69 (m, 2H), 8.08-8.05 (m, 1H), 7.70-7.60 (m, 4H), 7.56-7.49 (m, 2H).

3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine (3c): CAS 74115-24-5 Rf = 0.38 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.13-8.10 (m, 2H), 7.66-7.63 (m, 2H), 7.60-7.50 (m, 4H).

8

3-(2,6-dichlorophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (4c) Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.45 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.15-8.11 (m, 1H), 7.67-7.61 (m, 1H), 7.59-7.49 (m, 5H).

3,6-bis(2,6-dichlorophenyl)-1,2,4,5-tetrazine (4c’): CAS 162320-76-5 Angew. Chem. Int. Ed. 2016, 55, 5555−5559. Rf = 0.52 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.58-7.48 (m, 6H).

3-(2-bromo-6-fluorophenyl)-6-(2,6-dibromophenyl)-1,2,4,5-tetrazine (5a) Rf = 0.59 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.78 (d, J = 8.10 Hz, 2H), 7.63 (dt, J = 8.10, 0.92 Hz, 1H), 7.54-7.47 (m, 1H),

7.39-7.30 (m, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –109.9.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 167.4, 163.9 (d, J = 1.3 Hz), 162.6 (d, J = 256.3 Hz), 135.6, 133.4 (d, J = 9.0 Hz),

133.0, 132.0, 129.0 (d, J = 3.6 Hz), 123.7 (d, J = 17.8 Hz), 123.6, 123.5 (d, J = 2.6 Hz), 115.6 (d, J = 21.3 Hz). Elemental analysis: Calcd (%) for C14H6Br3FN4: C 34.39, H 1.24, N 11.46. Found: C 34.62, H 1.47, N 11.15. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Br3FN4: 486.820. Found: m/z = 486.821. 3-(2-iodo-6-fluorophenyl)-6-(2,6-diiodophenyl)-1,2,4,5-tetrazine (5b) Rf = 047 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.05 (d, J = 8.00 Hz, 2H), 7.91-7.85 (m, 1H), 7.37-7.33 (m, 2H), 6.99 (t, J = 8.00

Hz, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –108.6.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 170.7, 165.3 (d, J = 1.4 Hz), 162.0 (d, J = 256.9 Hz), 142.3, 139.1, 135.4 (d, J =

3.6 Hz), 133.8 (d, J = 9.0 Hz), 133.2, 127.11 (d, J = 17.3 Hz), 116.4 (d, J = 21.3 Hz), 97.1 (d, J = 0.9 Hz), 96.0. Elemental analysis: Calcd (%) for C14H6FI3N4: C 26.69, H 0.96, N 8.89. Found: C 26.86, H 1.09, N 8.43. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H6FI3N4: 652.760. Found: m/z = 652.760. 3-(2-bromo-6-fluorophenyl)-6-(2,6-dichlorophenyl)-1,2,4,5-tetrazine (5c) Rf = 0.57 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.54-7.42 (m, 4H), 7.39 (td, J = 8.10, 0.92 Hz, 1H), 7.22 (dt, J = 8.10, 0.92 Hz,

1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.3, 163.2 (d, J = 1.4 Hz), 162.8 (d, J = 256.9 Hz), 135.1, 134.8 (d, J = 3.6 Hz),

133.1 (d, J = 9.0 Hz), 132.4, 132.0, 128.4, 126.0 (d, J = 3.6 Hz), 121.8 (d, J = 17.3 Hz), 115.0 (d, J = 21.3 Hz). Elemental analysis: Calcd (%) for C14H6Cl3FN4: C 47.29, H 1.70, N 15.76. Found: C 47.58, H 1.32, N 15.45. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Cl3FN4: 354.971. Found: m/z = 354.970.

9

3-(2-bromo-6-chlorophenyl)-6-(2,6-dibromophenyl)-1,2,4,5-tetrazine (6a) Rf = 0.68 (Dichloromethane-Heptane = 2:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.78 (d, J = 8.10 Hz, 2H), 7.73 (dd, J = 8.10, 0.90 Hz, 1H), 7.61 (dd, J = 8.10,

0.90 Hz, 1H), 7.44 (t, J = 8.10 Hz, 1H), 7.39 (t, J = 8.10 Hz, 1H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 167.4, 166.3, 135.6, 134.8, 133.9, 132.9, 132.7, 132.0, 131.5, 128.9, 123.7,

123.5. Elemental analysis: Calcd (%) for C14H6Br3ClN4: C 33.27, H 1.20, N 11.09. Found: C 33.78, H 1.54, N 10.69. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Br3ClN4: 502.790. Found: m/z = 502.792.

3,6-bis(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (7a) Rf = 0.61 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.62 (dt, J = 8.10, 0.92 Hz, 2H), 7.51 (t, J = 8.31 Hz, 2H), 7.48 (t, J = 8.33 Hz,

2H), 7.35-7.29 (m, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –109.9.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 164.2 (d, J = 1.3 Hz), 162.9 (d, J = 256.3 Hz), 133.6 (d, J = 9.1 Hz), 129.3 (d, J =

3.6 Hz), 123.8 (d, J = 17.3 Hz), 123.7 (d, J = 2.6 Hz), 115.8 (d, J = 21.3 Hz). Elemental analysis: Calcd (%) for C14H6Br2F2N4: C 39.29, H 1.41, N 13.09. Found: C 39.24, H 1.75, N 11.95. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Br2F2N4: 426.900. Found: m/z = 426.900. 3,6-bis(2-iodo-6-fluorophenyl)-1,2,4,5-tetrazine (7b) Rf = 0.58 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.90-7.84 (m, 2H), 7.38-7.32 (m, 4H).

19

F NMR (282 MHz, CDCl3): δ (ppm) = –108.6.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.5 (d, J = 1.4 Hz), 162.2 (d, J = 256.9 Hz), 135.6 (d, J = 3.7 Hz), 133.9 (d, J =

8.7 Hz), 127.2 (d, J = 16.6 Hz), 116.6 (d, J = 21.3 Hz), 97.2 (d, J = 0.9 Hz). Elemental analysis: Calcd (%) for C14H6I2F2N4: C 32.21, H 1.16, N 10.73. Found: C 33.79, H 1.58, N 10.38. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6F2I2N4: 522.872. Found: m/z = 522.871.

3,6-bis(2-chloro-6-fluorophenyl)-1,2,4,5-tetrazine (7c) Rf = 0.59 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.58 (t, J = 8.27 Hz, 1H), 7.56 (t, J = 8.23 Hz, 1H), 7.45 (dt, J = 8.17, 1.03 Hz,

2H), 7.31-7.25 (m, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 163.3 (d, J = 1.3 Hz), 163.0 (d, J = 255.7 Hz), 135.1 (d, J = 3.5 Hz), 133.3 (d, J =

9.5 Hz), 126.2 (d, J = 3.6 Hz), 121.9 (d, J = 17.3 Hz), 115.2 (d, J = 21.3 Hz). Elemental analysis: Calcd (%) for C14H6Cl2F2N4: C 49.58, H 1.78, N 16.52. Found: C 46.04, H 2.08, N 14.68 (hygroscopic product). HRMS + p ESI (m/z) [M+Na+] Calcd for C14H6Cl2F2N4: 360.982. Found: m/z =360.982. 3,6-bis(2-bromo-6-chlorophenyl)-1,2,4,5-tetrazine (8a) Rf = 0.49 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.75 (dd, J = 8.08, 1.03 Hz, 2H), 7.60 (dd, J = 8.16, 1.03 Hz, 2H), 7.44 (t, J =

8.11 Hz, 2H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.5, 135.1, 134.1, 132.8, 131.6, 129.1, 123.9.

Elemental analysis: Calcd (%) for C14H6Br2Cl2N4: C 36.48, H 1.31, N 12.16. Found: C 35.61, H 1.71, N 10.90 (hygroscopic product). HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Br2Cl2N4: 458.840. Found: m/z = 458.840.

10

3,6-bis(2-chloro-6-iodophenyl)-1,2,4,5-tetrazine (8b) Rf = 0.37 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.77 (dd, J = 8.00, 0.98 Hz, 2H), 7.64 (dd, J = 8.14, 0.97 Hz, 2H), 7.27 (t, J =

8.06 Hz, 2H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 168.2, 137.9, 137.6, 134.1, 133.0, 129.9, 97.4.

Elemental analysis: Calcd (%) for C14H6Cl2I2N4: C 30.30, H 1.09, N 10.10. Found: C 30.09, H 1.06, N 10.05. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Cl2I2N4: 554.813. Found: m/z = 554.812.

3-(2-chloro-6-bromophenyl)-6-(2,6-chlorophenyl)-1,2,4,5-tetrazine (10a) The separation between 4c and 10a was found troublesome. Rf = 0.22 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (500 MHz, CDCl3): δ (ppm) = 7.72 (dd, J = 8.10, 1.03 Hz, 1H), 7.60 (dd, J = 8.10, 1.03 Hz, 1H), 7.58-7.50 (m,

3H), 7.47-7.41 (m, 1H). 13

C NMR (125 MHz, CDCl3): δ (ppm) = 166.6, 165.5, 135.1, 135.1, 134.0, 132.8, 132.6, 132.2, 131.6, 129.1, 128.6,

123.8. Elemental analysis: Calcd (%) for C14H6Cl3BrN4: C 40.37, H 1.45, N 13.45. Found: C 40.74, H 1.71, N 12.76. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H6Cl3BrN4: 438.87. Found: m/z = 438.87. 3-(2-bromophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (11a) Rf = 0.33 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.40 (td, J = 7.9, 1.8 Hz, 1H), 8.05 (dd, J = 7.7, 1.7 Hz, 1H), 7.83 (dd, J = 7.9,

1.8 Hz, 1H), 7.69-7.61 (m, 1H), 7.58 (td, J = 7.6, 1.2 Hz, 1H), 7.49 (dd, J = 7.9, 1.8 Hz, 1H), 7.43 (dd, J = 8.0, 1.1 Hz, 1H), 7.40-7.32 (m, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -111.5.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.7, 163.4 (d, J = 260.0 Hz), 163.1 (d, J = 5.8 Hz), 134.4, 134.4 (d, J = 8.8 Hz),

133.5, 132.6, 132.3, 131.6 (d, J = 0.9 Hz), 127.9, 124.9 (d, J = 3.9 Hz), 122.4, 120.4 (d, J = 9.8 Hz), 117.6 (d, J = 21.6 Hz). Elemental analysis: Calcd (%) for C14H8BrFN4: C 50.78, H 2.44, N 16.92. Found: C 50.56, H 3.04, N 16.51. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8BrFN4: 352.980. Found: m/z = 352.980. 3-(2-bromo-6-fluorophenyl)-6-phenyl-1,2,4,5-tetrazine (11a’) 11a' was isolated as a side product of 11a in a few amount with a ratio 11a/11a' of 82/18 (2d/11a/11a'/16a/16a': 9/59/8/15/8). Figure S1 Rf = 0.46 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.75-8.72 (m, 2H), 7.69-7.60 (m, 4H), 7.51-7.44 (m, 1H), 7.30 (td, J = 8.10, 0.90

Hz). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –110.1.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 164.3 (d, J = 1.5 Hz), 163.9, 163.0 (d, J = 256.0 Hz), 133.4, 133.3 (d, J = 9.1 Hz),

131.5, 129.6, 129.2 (d, J = 3.6 Hz), 128.7, 124.1 (d, J = 18.0 Hz), 123.8 (d, J = 2.6 Hz), 115.7 (d, J = 21.5 Hz). Elemental analysis: Calcd (%) for C14H8BrFN4: C 50.78, H 2.44, N 16.92. Found: C 50.56, H 3.04, N 16.51. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8BrFN4: 352.980. Found: m/z = 352.980. 3-(2-fluorophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (11b) Rf = 0.36 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.41 (td, J = 1.80, 7.63.Hz, 1H), 8.13 (dd, J = 1.01, 8.00 Hz, 1H), 8.03 (dd, J =

1.63, 7.75 Hz, 1H), 7.69-7.58 (m, 2H), 7.42 (td, J = 1.13, 7.72 Hz, 1H), 7.36-7.27 (m, 2H). 9

F NMR (282 MHz, CDCl3): δ (ppm) = –111.5.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.4, 163.4 (d, J = 260.1 Hz), 163.2 (d, J = 5.9 Hz), 141.2, 136.8, 134.4 (d, J =

8.8 Hz), 132.4, 131.7, 131.6 (d, J = 1.0 Hz), 128.7, 124.9 (d, J = 3.9 Hz), 120.5 (d, J = 9.8 Hz), 117.6 (d, J = 21.6 Hz), 95.6. Elemental analysis: Calcd (%) for C14H8FIN4: C 44.47, H 2.13, N 14.82. Found: C 44.74, H 2.84, N 14.23. HRMS + p ESI (m/z) [M+H+] Calcd for C14H8FIN4: 378.985. Found: m/z = 378.985.

11

3-(2-fluoro-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (11b') 11b' was isolated as a side product of 11b in a very few amount with a ratio 10b/10b' of 82/18 (2d/11b/11b'/16c/16c': 21/51/11/10/8). Figure S1 Rf = 0.42 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.76-8.72 (m, 2H), 7.90-7.84 (m, 1H), 7.70-7.61 (m, 3H), 7.34-7.30 (m, 2H).

9

F NMR (282 MHz, CDCl3): δ (ppm) = -108.9.

3-(2-chlorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (11c) Rf = 0.35 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.40 (td, J = 7.65, 1.80 Hz, 1H), 8.10 (td, J = 7.00, 1.80 Hz, 1H), 7.69-7.50 (m,

4H), 7.43 (td, J = 7.65, 1.80 Hz, 1H), 7.36 (ddd, J = 10.8, 7.65, 1.10 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.5.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.0, 163.4 (d, J = 260.0 Hz), 163.1 (d, J = 5.8 Hz), 134.4 (d, J = 9.9 Hz), 133.8,

132.6, 132.2, 131.6 (d, J = 0.9 Hz), 131.2, 127.4, 124.9 (d, J = 3.9 Hz), 120.5 (d, J = 9.8 Hz), 117.6 (d, J = 21.6 Hz). Elemental analysis: Calcd (%) for C14H8ClFN4: C 58.65, H 2.81, N 19.54. Found: C 58.41, H 2.68, N 19.32. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8ClFN4: 309.031. Found: m/z = 309.031. 3-(2-chloro-6-fluorophenyl)-6-phenyl-1,2,4,5-tetrazine (11c') 11c' was isolated as a side product of 11c in a very few amount with a ratio 11c/11c' of 84/16 (2d/11c/11c’/16b/16b': 16/53/10/13/7). Figure S1 Rf = 0.48 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.74-8.71 (m, 2H), 7.69-7.61 (m, 3H), 7.58-7.50 (m, 1H), 7.44 (td, J = 7.00, 1.80

Hz, 1H), 7.26 (td, J = 7.00, 1.80 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.2.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 163.9, 163.3 (d, J = 1.5 Hz), 163.0 (d, J = 255.0 Hz), 135.1 (d, J = 3.5 Hz), 133.4,

132.9 (d, J = 9.5 Hz), 131.5, 129.5, 128.7, 126.2 (d, J = 3.6 Hz), 122.2 (d, J = 17.4 Hz), 115.7 (d, J = 21.5 Hz). Elemental analysis: Calcd (%) for C14H8ClFN4: C 58.65, H 2.81, N 19.54. Found: C 58.41, H 2.68, N 19.32. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8ClFN4: 309.031. Found: m/z = 309.031. 3-(2-bromophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (12a) Rf = 0.33 (Dichloromethane-Heptane = 2:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.13-8.05 (m, 2H), 7.84 (dd, J = 7.00, 1.80 Hz, 1H), 7.67-7.46 (m, 5H).

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.6, 164.9, 134.4, 133.9, 133.4, 132.7, 132.6, 132.3, 132.3, 131.5, 131.2,

127.9, 127.4, 122.5. Elemental analysis: Calcd (%) for C14H8BrClN4: C 48.38, H 2.32, N 16.12. Found: C 48.59, H 2.53, N 15.88. HRMS + p ESI (m/z) [M+H+] Calcd for C14H8BrClN4: 346.969. Found: m/z = 346.970.

3-(2-bromo-6-chlorophenyl)-6-phenyl-1,2,4,5-tetrazine (12a') 12a' was isolated as a side product of 12a in a very few amount with the ratio 12a/12a' of 85/15 (2c/12a/12a'/16d/16d': 16/67/12/5/0). Figure S1 Rf = 0.28 (Dichloromethane-Heptane = 2:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.76-8.73 (m, 2H), 7.71 (dd, J = 8.10, 1.00 Hz, 1H), 7.70-7.62 (m, 3H), 7.59 (dd,

J = 8.10, 1.00 Hz, 1H), 7.41 (t, J = 8.12 Hz, 1 H).

12

3-(2-chlorophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (12b) Rf = 0.36 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.15-8.11 (m, 2H), 8.06 (dd, J = 7.75, 1.60 Hz, 1H), 7.67-7.51 (m, 4H), 7.30 (td,

J = 7.75, 1.60 Hz, 1H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.3, 164.9, 141.2, 136.7, 133.9, 132.7, 132.5, 132.3, 131.7, 131.5, 131.2,

128.7, 127.36, 95.7. Elemental analysis: Calcd (%) for C14H8ClIN4: C 42.61, H 2.04, N 14.20. Found: C 42.98, H 2.57, N 11.86. HRMS + p ESI (m/z) [M+H+] Calcd for C14H8ClIN4: 394.955. Found: m/z = 394.955.

3-(2-chloro-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (12b') 12b' was isolated as a side product of 12b in a few amount with traces of starting material 2c and a ratio 12b/12b'of 85/15 (2c/12b/12b'/16e/16e': 18/61/11/10/0). Figure S1 Rf = 0.47 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.77-8.74 (m, 2H); 7.96 (dd, J = 8.00, 1.00 Hz, 1H), 7.70-7.63 (m, 3H), 7.61 (dd,

J = 8.00, 1.00 Hz, 1H), 7.24 (t, J = 8.00 Hz, 1H).

3-(2-bromophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (13b) Rf = 0.36 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.13 (dd, J = 7.98, 1.04 Hz, 1H), 8.10-8.05 (m, 2H), 7.84 (dd, J = 7.95, 1.16 Hz,

1H), 7.65-7.56 (m, 2H), 7.49 (td, J = 7.54, 1.77 Hz, 1H) 7.30 (dd, J = 7.58, 1.70 Hz, 1H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.3, 165.5, 141.0, 136.7, 134.4, 133.4, 123.6, 132.5, 132.3, 131.6, 128.7,

127.9, 122.5, 95.7. Elemental analysis: Calcd (%) for C14H8BrIN4: C 38.30, H 1.84, N 12.76. Found: C 38.86, H 2.42, N 12.14. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H8BrIN4: 460.887. Found: m/z = 460.887.

3-(2-bromo-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (13b') 13b' was isolated as a side product of 3b in a few amounts with a ratio 13b/13b' of 84/16 (2b/13b/13b': 26/62/12). Figure S1 Rf = 0.47 (Dichloromethane-Heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.77-8.74 (m, 2H), 7.01 (dd, J = 8.00, 1.00 Hz, 1H), 7.79 (dd, J = 8.10, 1.00 Hz,

1H), 7.70-7.62 (m, 3H), 7.16 (t, J = 8.04 Hz, 1H).

3-(2-bromo-6-fluorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14a) Rf = 0.52 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.42 (td, J = 7.53, 1.69 Hz, 1H), 7.70-7.64 (m, 1H), 7.62 (dt, J = 8.14, 0.98 Hz,

1H), 7.52-7.27 (m, 4H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –110.1, –111.1.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 164.0 (d, J = 5.9 Hz), 163.5 (d, J = 260.6 Hz), 163.5 (d, J = 1.3 Hz), 163.0 (d, J =

256.0 Hz), 134.6 (d, J = 8.8 Hz), 133.3 (d, J = 9.2 Hz), 131.8 (d, J = 0.8 Hz), 129.1 (d, J = 3.6 Hz), 124.9 (d, J = 3.9 Hz), 124.0 (d, J = 17.2 Hz), 123.8 (d, J = 2.6 Hz), 120.4 (d, J = 9.7 Hz), 117.7 (d, J = 21.6 Hz), 115.6 (d, J = 21.4 Hz). Elemental analysis was unsatisfactory. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7BrF2N4: 348.989. Found: m/z =348.988.

13

3-(2-fluoro-6-iodophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14b) Rf = 0.51 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.46-8.40 (m, 1H), 7.88-7.84 (m, 1H), 7.71-7.63 (m, 1H), 7.46-7.30 (m, 4H).

19

F NMR (282 MHz, CDCl3): δ (ppm) = –108.8, –111.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.1 (bs), 163.9 (d, J = 5.9 Hz), 163.6 (d, J = 260.7 Hz), 162.3 (d, J = 256.6

Hz), 135.7 (d, J = 3.7 Hz), 134.8 (d, J = 8.8 Hz), 133.8 (d, J = 8.8 Hz), 131.9 (d, J = 0.8 Hz), 127.3 (d, J = 16.4 Hz), 125.1 (d, J = 3.9 Hz), 120.5 (d, J = 9.8 Hz), 117.8 (d, J = 21.6 Hz), 116.6 (d, J = 21.5 Hz), 97.4 (d, J = 0.9 Hz). Elemental analysis: Calcd (%) for C14H7F2IN4: C 42.45, H 1.78, N 14.14. Found: C 42.23, H 2.29, N 13.38. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7F2IN4: 396.975. Found: m/z = 396.974. 3-(2-chloro-6-fluorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14c) Rf = 0.55 (dichloromethane-heptane = 7:3 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.42 (td, J = 7.62, 1.78 Hz, 1H), 7.70-7.63 (m, 1H), 7.59-7.51 (m, 1H), 7.46-7.43

(m, 2H), 7.41-7.23 (m, 2H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.1, –111.1.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 163.9 (d, J = 5.9 Hz), 163.6 (d, J = 260.6 Hz), 163.1 (d, J = 255.3 Hz), 162.7

(bs), 135.1 (d, J = 3.5 Hz), 134.8 (d, J = 8.8 Hz), 133.1 (d, J = 9.5 Hz), 131.9 (d, J = 0.8 Hz), 126.2 (d, J = 3.6 Hz), 125.0 (d, J = 3.9 Hz), 122.1 (d, J = 17.3 Hz), 120.5 (d, J = 9.7 Hz), 117.8 (d, J = 21.6 Hz), 115.2 (d, J = 21.4 Hz). Elemental analysis: Calcd (%) for C14H7ClF2N4: C 55.19, H 2.32, N 18.39. Found: C 55.59, H 3.20, N 16.61. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7ClF2N4: 305.040. Found: m/z = 305.039. 3-(2-bromo-6-chlorophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (15a) Rf = 0.41 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.15-8.12 (m, 1H), 7.72 (dd, J = 8.08, 1.05 Hz, 1H), 7.67-7.52 (m, 4H), 7.43 (t, J

= 8.11 Hz, 1H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.9, 165.7, 135.2, 134.1, 134.0, 132.9, 132.7, 132.5, 131.7, 131.6, 131.3,

129.2, 127.5, 124.1. Elemental analysis: Calcd (%) for C14H6BrCl2N4: C 44.01, H 1.85, N 14.67. Found: C 44.62, H 1.98, N 14.45. HRMS + p ESI (m/z) [M+Na+] Calcd for C14H6BrCl2N4: 402.912. Found: m/z = 402.913.

3-(2-chloro-6-iodophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (15b) Rf = 0.31 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.16-8.13 (m, 1H), 7.76 (dd, J = 7.99, 0.97 Hz, 2H), 7.67-7.52 (m, 4H), 7.25 (t, J

= 8.06 Hz, 1H). 13

C NMR (75 MHz, CDCl3): δ (ppm) = 167.5, 165.6, 137.9, 137.5, 134.3, 134.1, 133.0, 132.9, 132.5, 131.7, 131.3,

129.9, 127.5, 97.6. Elemental analysis: Calcd (%) for C14H7Cl2IN4: C 39.19, H 1.64, N 13.06. Found: C 38.80, H 1.73, N 12.78 . HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Cl2IN4: 428.916. Found: m/z = 428.916.

3-(2-bromo-6-fluorophenyl)-6-(2-bromophenyl)-1,2,4,5-tetrazine (16a) Starting with 2d and 3 equiv of NBS, 16a and 16a' were obtained with a ratio 62/38 (11a/11a'/16a/16a'/5a: 4/0/43/26/27%). Figure S3 Starting with 11a and 1 equiv of NBS, 16a and 16a' were obtained with a ratio 51/49 (11a/16a/16a'/5a: 17/36/34/13%). Figure S2 The separation between 16a and 16a' was found troublesome. Rf = 0.50 (dichloromethane-heptane = 1:1 (v/v)). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -110.0.

14

3-(2,6-dibromophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (16a') Rf = 0.50 (dichloromethane-heptane = 1:1 (v/v)). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -110.9.

3-(2-chloro-6-fluorophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (16c) Starting with 2d and 3 equiv of NCS, 16c and 16c' were obtained with a ratio 67/33 (11c/11c'/16c/16c'/5b: 9/2/42/21/26%). Figure S3 Starting with 11c and 1 equiv of NCS, 16c and 16c' were obtained with a ratio 53/47 (11c/16c/16c'/5b: 48/25/22/5%). Figure S2 The separation between 16c and 16c' was found troublesome. Starting with 11c' and 3 equiv of NCS, 16c was obtained in 65% (49). Rf = 0.39 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.14-8.10 (m, 1H), 7.67-7.64 (m, 1H), 7.62-7.52 (m, 3H), 7.45 (dt, J = 8.1, 1.0

Hz, 1H), 7.27 (td, J = 8.1, 1.0 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -111.1.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.7, 163.1 (d, J = 255.5 Hz), 162.7 (d, J = 1.56 Hz), 135.1 (d, J = 3.5 Hz),

134.1, 133.2 (d, J = 9.6 Hz), 133.0, 132.6, 131.5, 131.4, 127.5, 126.2 (d, J = 3.6 Hz), 122.0 (d, J = 7.3 Hz), 115.2 (d, J = 21.4 Hz). Elemental analysis: Calcd (%) for C14H7Cl2FN4: C 52.36, H 2.20, N 17.45. Found: C 52.13, H 2.74, N 16.97. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7Cl2FN4: 321.010. Found: m/z = 321.010. 3-(2,6-dichlorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine 16c' Rf = 0.39 (dichloromethane-heptane = 1:1 (v/v)). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -111.0.

3-(2-bromo-6-fluorophenyl)-6-(2-chloro-6-fluorophenyl)-1,2,4,5-tetrazine (17a) Rf = 0.59 (dichloromethane-heptane = 3:2 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.64-7.44 (m, 4H), 7.35-7.26 (m, 2H).

19

F NMR (282 MHz, CDCl3): δ (ppm) = -109.9, -111.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 164.2 (d, J = 1.3 Hz), 163.2 (d, J = 1.3 Hz), 163.0 (d, J = 255.6 Hz), 162.9 (d, J =

256.3 Hz), 135.1 (d, J = 3.5 Hz), 133.6 (d, J = 9.2 Hz), 133.3 (d, J = 9.5 Hz), 129.3 (d, J = 3.6 Hz), 126.2 (d, J = 3.6 Hz), 123.7 (sb), 123.7 (d, J = 13.7 Hz), 121.9 (d, J = 17.3 Hz), 115.8 (d, J = 21.2 Hz), 115.2 (d, J = 21.2 Hz). Elemental analysis: Calcd (%) for C14H6BrClF2N4: C 43.84, H 1.58, N 14.61. Found: C 44.15, H 2.02, N 14.25. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6BrClF2N4: 382.951. Found: m/z = 382.951.

15

3-(2-chloro-6-fluorophenyl)-6-(2-fluoro-6-iodophenyl)-1,2,4,5-tetrazine (17b) Rf = 0.59 (dichloromethane-heptane = 3:2 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.90-7.84 (m, 1H), 7.61-7.54 (m, 1H), 7.46 (dt, J = 8.2, 1.0 Hz, 1H), 7.36-7.26

(m, 3H). 19

F NMR (282 MHz, CDCl3): δ (ppm) =-108.7, -111.0.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 165.6 (d, J = 1.4 Hz), 163.1 (d, J = 1.4 Hz), 163.0 (d, J = 255.7 Hz), 162.2 (d, J =

256.9 Hz), 135.6 (d, J = 3.7 Hz), 135.0 (d, J = 3.5 Hz), 134.0 (d, J = 8.7 Hz), 133.3 (d, J = 9.5 Hz), 127.1 (d, J = 16.6 Hz), 126.2 (d, J = 3.6 Hz), 121.9 (d, J = 17.4 Hz), 116.6 (d, J = 21.2 Hz), 115.2 (d, J = 21.2 Hz), 97.2 (d, J = 1.0 Hz). Elemental analysis: Calcd (%) for C14H6ClF2IN4: C 39.05, H 1.40, N 13.01. Found: C 39.07, H 1.91, N 12.55. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6ClF2IN4: 430.937. Found: m/z = 430.937.

3-(2-bromo-6-chlorophenyl)-6-(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (18a) Rf = 0.54 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.73 (dd, J = 8.08, 1.05 Hz, 1H), 7.64-7.59 (m, 2H), 7.54-7.41 (m, 2H), 7.33 (td,

J = 8.80, 1.05 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = -109.9.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.5, 164.2 (d, J = 1.3 Hz), 162.8 (d, J = 256.2 Hz), 135.1, 134.0, 133.6 (d, J =

9.1 Hz), 132.8, 131.7, 129.2 (d, J = 3.7 Hz), 129.1, 123.9, 123.8 (d, J = 17.4 Hz), 123.7 (d, J = 2.7 Hz), 115.8 (d, J = 21.2 Hz). Elemental analysis was unsatisfactory. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6Br2ClFN4: 442.870. Found: m/z = 442.871. 3-(2-chloro-6-iodophenyl)-6-(2-fluoro-6-iodophenyl)-1,2,4,5-tetrazine (18b) Rf = 0.57 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 7.97 (dd, J = 8.0, 1.0 Hz, 1H), 7.89-7.86 (m, 1H), 7.63 (dd, J = 8.0, 1.0 Hz, 1H),

7.37-7.33 (m, 2H), 7.27 (t, J = 8.10 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –108.62.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 168.1, 165.6 (d, J = 1.4 Hz), 158.8 (d, J = 256.9 Hz), 137.9, 137.4, 135.6 (d, J =

3.7 Hz), 134.2, 134.0 (d, J = 9.7 Hz), 133.1, 129.9, 127.2 (d, J = 16.7 Hz), 116.6 (d, J = 21.2 Hz), 97.4, 97.3 (d, J = 0.9 Hz). Elemental analysis: Calcd (%) for C14H6ClFI2N4: C 31.23, H 1.12, N 10.40. Found: C 31.76, H 1.78, N 9.63. HRMS + p ESI (m/z) [M+H+] Calcd for C14H6ClFI2N4: 538.843. Found: m/z = 538.844.

3-(2-chlorophenyl)-6-(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (19a) Rf = 0.38 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (300 MHz, CDCl3): δ (ppm) = 8.08 (dd, J = 8.0, 1.0 Hz, 1H), 7.85 (dd, J = 8.0, 1.0 Hz, 1H), 7.62-7.43 (m, 4H),

7.27 (td, J = 8.10, 1.0 Hz, 1H). 19

F NMR (282 MHz, CDCl3): δ (ppm) = –111.1.

13

C NMR (75 MHz, CDCl3): δ (ppm) = 166.4, 163.0 (d, J = 255.5 Hz), 162.6 (d, J = 1.4 Hz), 135.1 (d, J = 3.5 Hz), 135.0,

133.5, 133.2 (d, J = 9.7 Hz), 132.9, 132.5, 128.1, 126.2 (d, J = 3.6 Hz), 122.7, 122.0 (d, J = 7.3 Hz), 115.2 (d, J = 21.3 Hz). Elemental analysis: Calcd (%) for C14H7BrClFN4: C 46.00, H 1.93, N 15.33. Found: C 46.05, H 2.05, N 14.51. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7BrClFN4: 364.960. Found: m/z = 364.960.

16

3-(2-chlorophenyl)-6-(2,6-bromohenyl)-1,2,4,5-tetrazine (19a') 19'a was isolated as a side product of 19. Figure S5 Rf = 0.20 (dichloromethane-heptane = 1:1 (v/v)). 1

H NMR (500 MHz, CDCl3): δ (ppm) = 7.59-749 (m, 4H), 7.45 (dt, J = 8.10, 1.0 Hz, 1H), 7.28 (td, J = 8.10, 1.0 Hz, 1H).

19

F NMR (302 MHz, CDCl3): δ (ppm) = -111.0.

13

C NMR (125 MHz, CDCl3): δ (ppm) = 165.5, 163.3 (d, J = 1.1 Hz), 162.7 (d, J = 255.5 Hz), 135.3, 135.0 (d, J = 3.5

Hz), 133.3 (d, J = 9.5 Hz), 132.6, 132.2, 128.6, 126.5 (d, J = 3.6 Hz), 121.8 (d, J = 17.4 Hz), 115.2 (d, J = 21.1 Hz). Elemental analysis was unsatisfactory.

3-(2-chloro-6-fluoro phenyl)-6-(2-iodo-6-bromophenyl)-1,2,4,5-tetrazine (20) Rf = 0.18 (dichloromethane-heptane = 1:1 (v/v)). Figure S5 1

H NMR (500 MHz, CDCl3): δ (ppm) = 8.01 (dd, J = 8.0, 0.9 Hz, 1H), 7.80 (dd, J = 8.0, 0.9 Hz, 1H), 7.59-7.55 (m, 1H),

7.46 (dt, J = 8.67, 0.9 Hz, 1H), 7.29 (td, J = 8.67, 0.9 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H). 19

F NMR (302 MHz, CDCl3): δ (ppm) = –110.9.

13

C NMR (125 MHz, CDCl3): δ (ppm) = 169.2, 163.0, 162.2 (d, J = 255.6 Hz), 139.1, 138.5, 135.0 (d, J = 3.4 Hz), 133.3

133.2 (d, J = 9.5 Hz), 133.0, 126.1 (d, J = 3.6 Hz), 122.8, 122.0 (d, J = 17.6 Hz), 115.1 (d, J = 21.2 Hz), 97.2. Elemental analysis: Calcd (%) for C14H6BrClFIN4: C 34.21, H 1.23, N 11.40. Found: C 35.84, H 1.84, N 10.80. HRMS + p ESI (m/z) [M+H+] Calcd for C14H7BrClFN4: 514.834. Found: m/z = 514.835.

General procedure for Suzuki-Miyaura cross-coupling

As a typical experiment, 3-(2-bromophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (23.0 mg, 0.07 mmol), phenylboronic acid (17.1 mg, 0.14 mmol), Pd(dba)2 (4.0 mg, 0.007 mmol) and K2CO3 (19.3 mg, 0.14 mmol) were introduced in a Schlenk tube, equipped with a magnetic stirring bar. Dry toluene (0.7 mL) was added, and the Schlenk tube purged several times with argon. The Schlenk tube was placed in a pre-heated oil bath at 110 °C and reactants stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, and was washed three times with water. The combined organic layers were washed with water and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography to afford 21 in 59% yield (13.6 mg).

3-(phenyl)-6-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (21) Rf = 0.66 (dichloromethane-heptane = 3/7 (v/v)). 1

H NMR (500 MHz, CDCl3): δ (ppm) = 8.62-8.60 (m, 2H), 8.11 (dd, J = 3.0 Hz, 6.0 Hz, 1H), 7.71 (td, J = 3.0 Hz, 6.0

Hz, 1H), 7.66-7.58 (m, 5H), 7.32-7.29 (m, 3H), 7.19-7.17 (m, 2H). Traces of dehalogenated 1 ( 2(I)).

Figure S7: Molecular structure of 10a showing 50% probability

ellipsoids and the crystallographic numbering scheme (ORTEP view in Olex2) [Br red, Cl green, N blue, C grey, H white]. Sym. Op.: (i) 1x, -y, 2-z ; (ii) 1-x, 2-y, 1-z. The bromide and chloride atoms are disordered on occupied the same positions with occupation factors equal respectively to 0.27 :0.73 for Br1/Cl1, 0.23 :0.77 for Br2/Cl2, 0.31 :0.69 for Br3/Cl3 and 0.19 :0.81 for Br4/Cl4. Experimental. A single red prism-shaped crystal of 10a (0.25×0.20×0.15) mm3 was mounted on a mylar loop with oil on a Bruker D8 Venture triumph Mo diffractometer. The crystal was kept at T = 100 K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the ShelXT structure solution program, using the intrinsic phasing solution method. The model was refined with version 2014/7 of XL (Sheldrick, 2008) using Least Squares minimisation. Crystal Data. C14H6BrCl3N4, Mr = 416.49, triclinic, P-1 (No. 2), a = 7.9396(5) Å, b = 8.9312(6) Å, c = 11.4076(7) Å,  = 73.749(2)°,  = 87.753(3)°,  = 86.227(3)°, V = 774.73(9) Å3, T = 100 K, Z = 2, Z' = 1, (MoK) = 3.169, 27309 reflections measured, 3554 unique (Rint =

29

CCDC

1558815

Formula Dcalc./ g cm-3 /mm-1 Formula Weight Colour Shape Size/mm3 T/K Crystal System Space Group a/Å b/Å c/Å /° /° /° V/Å3 Z Z' Wavelength/Å Radiation type min/° max/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1

C14H6BrCl3N4 1.785 3.169 416.49 red prism 0.25×0.20×0.15 100 triclinic P-1 7.9396(5) 8.9312(6) 11.4076(7) 73.749(2) 87.753(3) 86.227(3) 774.73(9) 2 1 0.71073 MoK 3.141 27.534 27309 3554 2924 0.0405 230 0 0.331 -0.370 1.084 0.0544 0.0504 0.0404 0.0264

A red prism-shaped crystal with dimensions 0.25×0.20×0.15 mm3 was mounted on a mylar loop with oil. X-ray diffraction data were collected using a Bruker D8 Venture triumph Mo diffractometer equipped with a Oxford Cryosystems low-temperature device, operating at T = 100 K. Data were measured using  and  scans using MoK radiation (X-ray tube, 50 kV, 30 mA). The total number of runs and images was based on the strategy calculation from the program APEX2 (Bruker, V2, n/a).The maximum resolution achieved was  = 27.534°. Cell parameters were retrieved using the SAINT (Bruker, V8.37A, after 2013) software and refined using SAINT (Bruker, V8.37A, after 2013) on 9955 reflections, 36 % of the observed reflections. Data reduction was performed using the SAINT (Bruker, V8.37A, after 2013) software which corrects for Lorentz polarisation. The final completeness is 99.80 out to 27.534 in . The absorption coefficient  of this material is 3.169 at this wavelength ( = 0.71073) and the minimum and maximum transmissions are 0.6440 and 0.7456. The structure was solved in the space group P-1 (# 2) by ShelXT methods using the intrinsic phasing structure solution program and refined by Least Squares using version 2014/7 of XL (Sheldrick, 2008). All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model. Table S13: Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å 2×103) for 10a. Ueq is defined as 1/3 of the trace of the orthogonalised Uij. Atom C1 N1 Br1 Cl1 C2 N2 Br2 Cl2 C3 C4 C5 C6 C7 N3 Br3 Cl3 N4 Br4 Cl4 C8 C9 C10 C11 C12 C13 C14

x 6376(2) 5270.2(18) 8883(14) 8851(13) 7982(2) 3828.7(18) 6569(12) 6839(9) 9218(2) 10720(2) 11005(2) 9803(2) 8307(2) 5501(2) 873(4) 885(5) 5985(2) 7274(17) 7173(10) 4535(2) 3992(2) 2345(2) 1812(2) 2953(2) 4608(2) 5106(2)

y -474.9(19) 365.4(18) 2109(12) 1980(11) -1043(2) 861.6(17) -4005(13) -3967(9) -23(2) -549(2) -2128(2) -3179(2) -2621(2) 8979.0(18) 8172(4) 8177(5) 10438.2(17) 6304(15) 6135(8) 8605(2) 6976.8(19) 6623(2) 5119(2) 3942(2) 4245(2) 5760(2)

z 9579.8(16) 8765.2(14) 8441(10) 8374(9) 9093.2(15) 9203.8(13) 9857(11) 9884(8) 8531.8(15) 8086.6(16) 8205.2(16) 8749.8(16) 9187.7(16) 4343.2(15) 4861(3) 4857(4) 3969.0(15) 6651(12) 6583(7) 5356.5(16) 5794.4(15) 5656.5(15) 6114.4(16) 6706.8(16) 6845.7(16) 6394.9(15)

30

Ueq 16.5(4) 20.1(3) 17.6(7) 21.5(10) 16.5(3) 19.6(3) 22.9(10) 23.1(7) 17.2(4) 19.6(4) 21.2(4) 21.1(4) 19.3(4) 27.2(4) 18.5(9) 33.7(14) 27.6(4) 23.2(12) 22.2(6) 18.9(4) 15.9(3) 16.7(3) 18.6(4) 21.3(4) 20.5(4) 17.4(4)

Table S14: Anisotropic Displacement Parameters (×104) 10a. The anisotropic displacement factor exponent takes the form: 22[h2a*2 × U11+ ... +2hka* × b* × U12] Atom C1 N1 Br1 Cl1 C2 N2 Br2 Cl2 C3 C4 C5 C6 C7 N3 Cl3 N4 Br4 Cl4 C8 C9 C10 C11 C12 C13 C14

U11 14.4(9) 14.5(8) 18.2(10) 20.3(10) 14.0(8) 14.8(8) 14(2) 14.3(17) 18.6(9) 15.9(9) 16.9(9) 22.5(10) 16.3(9) 39.3(10) 27.9(13) 40.3(10) 12.3(13) 13.2(10) 21.6(9) 21.4(9) 20.3(9) 18.1(9) 29.7(11) 25(1) 16.9(9)

U22 16.9(8) 27.0(8) 14.5(11) 20.6(17) 21.8(9) 24.3(8) 23.3(9) 21.3(8) 18.0(8) 26.6(10) 30(1) 21.5(9) 22.0(9) 16.1(7) 29.1(13) 16.4(8) 33(2) 30.3(13) 16.1(8) 14.2(8) 15.5(8) 18.9(9) 13.3(8) 16.9(8) 21.4(9)

U33 16.6(9) 15.7(7) 20.1(12) 24.1(13) 12.1(8) 17.3(8) 32.5(10) 31.3(8) 13.4(8) 15.8(9) 17.4(9) 19.7(9) 18.1(9) 27.2(9) 35.2(15) 27.5(9) 30.4(16) 26.3(9) 19.8(9) 12.8(8) 13.6(8) 20.4(9) 20.6(9) 17.2(9) 15.5(9)

U23 -1.6(7) -1.3(6) -4.0(11) -6.5(9) -2.0(7) -2.0(6) -7.8(7) -3.0(6) -1.7(7) -4.5(7) -8.4(8) -6.7(7) -2.4(7) -8.2(7) 3.9(3) -8.6(7) -16.9(12) -11.6(9) -6.0(7) -5.0(7) -3.7(7) -7.5(7) -4.2(7) -1.9(7) -7.6(7)

U13 0.5(7) 1.0(6) -0.2(8) 3.0(8) -0.4(7) 1.3(6) 6.7(15) 5.9(11) -1.3(7) 1.5(7) 3.7(7) 0.6(7) 1.9(7) 16.5(7) -8.2(4) 17.4(8) -1.8(10) -2.9(6) 6.7(7) 5.4(7) 1.9(7) 3.5(7) 5.7(8) 1.3(7) 2.9(7)

U12 -4.5(7) 1.4(6) -3.7(8) -5.6(9) -2.2(7) -0.3(6) -10.7(13) -7.2(10) -1.0(7) -5.1(7) -0.5(8) -0.4(7) -4.5(7) -10.0(7) 11.2(4) -12.0(7) -8.8(12) -5.2(9) -5.2(7) -4.3(7) 1.1(7) -6.5(7) -5.6(7) 2.6(7) -3.4(7)

Table S15: Bond Lengths in Å for 10a. Atom C1 C1 C1 N1 Br1 Cl1 C2 C2 N2 Br2 Cl2 C3 C4 C5 C6 N3

Atom N1 C2 N21 N2 C3 C3 C3 C7 C11 C7 C7 C4 C5 C6 C7 N4

Length/Å 1.336(2) 1.486(2) 1.339(2) 1.330(2) 1.879(11) 1.753(10) 1.394(2) 1.390(2) 1.339(2) 1.905(10) 1.735(7) 1.383(2) 1.383(3) 1.387(3) 1.388(2) 1.330(2)

Atom Atom N3 C8 Br3 C10 Cl3 C10 N4 C82 Br4 C14 Cl4 C14 C8 N42 C8 C9 C9 C10 C9 C14 C10 C11 C11 C12 C12 C13 C13 C14 –––– 1 1-X,-Y,2-Z; 21-X,2-Y,1-Z

31

Length/Å 1.336(2) 1.809(4) 1.807(5) 1.338(2) 1.874(13) 1.729(8) 1.338(2) 1.486(2) 1.390(2) 1.392(2) 1.385(2) 1.381(3) 1.382(3) 1.385(2)

Table S16: Bond Angles in ° for 10a Atom N1 N1 N21 N2 C3 C7 C7 N1 Cl1 C2 C2 C4 C4 C4 C5 C4 C5 C2 C2 Cl2 C6 C6 C6 N4 N3

Atom C1 C1 C1 N1 C2 C2 C2 N2 C3 C3 C3 C3 C3 C3 C4 C5 C6 C7 C7 C7 C7 C7 C7 N3 N4

Angle/° 117.10(15) 126.13(16) 116.77(15) 116.93(14) 121.51(15) 120.87(15) 117.62(16) 116.94(15) 3.0(7) 119.3(4) 119.2(4) 118.9(4) 119.1(4) 121.68(16) 119.13(16) 120.97(17) 118.75(17) 117.9(4) 120.4(3) 4.6(6) 121.86(16) 120.1(4) 117.7(3) 116.98(15) 117.07(15)

Atom C2 N21 C2 C1 C1 C1 C3 C11 Br1 Br1 Cl1 Br1 Cl1 C2 C3 C6 C7 Br2 Cl2 Br2 C2 Br2 Cl2 C8 C82

Atom Atom Atom N3 C8 N42 N3 C8 C9 N42 C8 C9 C10 C9 C8 C10 C9 C14 C14 C9 C8 Cl3 C10 Br3 C9 C10 Br3 C9 C10 Cl3 C11 C10 Br3 C11 C10 Cl3 C11 C10 C9 C12 C11 C10 C11 C12 C13 C12 C13 C14 Cl4 C14 Br4 C9 C14 Br4 C9 C14 Cl4 C13 C14 Br4 C13 C14 Cl4 C13 C14 C9 –––– 1 1-X,-Y,2-Z; 21-X,2-Y,1-Z

Angle/° 125.94(15) 117.79(15) 116.26(15) 121.38(16) 117.71(15) 120.87(16) 0.3(3) 118.81(16) 118.50(18) 119.63(17) 119.94(19) 121.56(17) 119.10(17) 120.99(16) 118.93(17) 4.8(7) 116.4(4) 119.6(3) 121.7(4) 118.7(3) 121.70(16)

Table S17: Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 10a. Ueq is defined as 1/3 of the trace of the orthogonalised Uij. Atom H4 H5 H6 H11 H12 H13

x 11544 12040 10001 678 2596 5390

y 166 -2498 -4262 4901 2909 3427

z

Ueq

7704 7909 8822 6022 7024 7244

23 25 25 22 26 25

Table S18: Atomic Occupancies for all atoms that are not fully occupied in 10a. Atom Br1 Cl1 Br2 Cl2 Br3 Cl3 Br4 Cl4

Occupancy 0.269 0.731 0.232 0.768 0.305 0.695 0.194 0.806

32

Software APEX2 suite for crystallographic software: Bruker V8.34A : SADABS, SAINT, APEX2. Bruker AXS Inc Bruker axs, Madison, WI (2014).

33

Computational details Quantum mechanics calculations were performed with the Gaussian09 software package. 1 Energy and forces were computed by density functional theory with the range separated wB97X-D2 exchange-correlation functional. This range separated functional was selected because it properly describes charge transfer, and dispersion effect (such as -stacking) are taken into account. The acetic acid solvent was modelled using a micro-solvation approach: all molecules were complexed with one explicit solvent molecules while the bulk effects were described using a continuum. A polarizable continuum model3 (PCM) of acetic acid was used as implemented in Gaussian09 to describe the bulk medium. Transition states were localized using the string theory as implemented in Opt’n Path.4 Geometries were optimized and characterized with the LANL2DZ(f) basis set and associated pseudo potentials for the palladium atom and the 6-31+G(d,p) basis sets for all other atoms. All structures were optimized and frequency calculations were performed to ensure the absence of any imaginary frequencies on local minima, and the presence of only one imaginary frequency on transition states. Reactants and products were re-localized starting from the transition states (IRC calculations followed by optimizations) to ensure that no TS were forgotten. It is worth noting that for all complexes, many conformers and isomers are possible (as illustrated below): as a consequence, for each stationary structure (reactant, intermediate, product or transition state), we have tested between 3 and 6 different conformers. Only the most stable one is described here. Ratio computation The full reaction network for the formation of the palladacycles is shown in Scheme S1. For clarity’s sake, the explicit AcOH solvating molecule is not shown in this scheme and in the following ones.

Scheme S1: Full kinetic network describing the formation of palladacycles by C–H activation.

34

The activation enthalpies found for the C–H activation are much higher than those involved in the isomerization of the palladium-bis-tetrazine complexes A11, A12 and A22. Therefore, A11, A12 and A22 are at equilibrium and the kinetic of this system can be analyzed by considering the simplified but exact system shown on Scheme S2.

Scheme S2: Simple kinetic network describing the formation of palladacycles by C–H activation. In these, all energies are measured with respect to A11. The kinetic equations can be written: 𝑑[𝐴11 ] = −(𝑘11 + 𝑘12 + 𝑘21 + 𝑘22 )[𝐴11 ] 𝑑𝑡 𝑑[𝐵1−1 ] = 𝑘11 [𝐴11 ] 𝑑𝑡 𝑑[𝐵1−2 ] = 𝑘12 [𝐴11 ] 𝑑𝑡 𝑑[𝐵2−1 ] = 𝑘21 [𝐴11 ] 𝑑𝑡 𝑑[𝐵2−2 ] = 𝑘22 [𝐴11 ] 𝑑𝑡 We assume that the formation of B1-1, B1-2, B2-1 and B2-2 is irreversible as the palladacycles will then evolve into other products, much more stable. When is introduced 𝑘 = 𝑘11 + 𝑘12 + 𝑘21 + 𝑘22. Concentrations are then: [𝐴11 ] = [𝐴11 ]0 × 𝑒 −𝑘𝑡 𝑘11 [𝐴11 ]0 × (1 − 𝑒 −𝑘𝑡 ) 𝑘 𝑘12 [𝐵1−2 ] = [𝐴11 ]0 × (1 − 𝑒 −𝑘𝑡 ) 𝑘 𝑘21 [𝐵2−1 ] = [𝐴11 ]0 × (1 − 𝑒 −𝑘𝑡 ) 𝑘 𝑘22 [𝐵2−2 ] = [𝐴11 ]0 × (1 − 𝑒 −𝑘𝑡 ) 𝑘 [𝐵1−1 ] =

35

And thus, under kinetic control, [𝐵1−1 ] + [𝐵1−2 ] 𝑘11 + 𝑘12 %𝐵1 = = [𝐵2−1 ] + [𝐵2−2 ] 𝑘21 + 𝑘22 %𝐵2 In which %B1 refers to all palladacycles in which the palladium is linked to a N1 nitrogen atom, and %B2 refers to all palladacycles in which the palladium is linked to a N2 nitrogen atom. Using %B1+%B2 = 100%, one finally gets: 𝑘11 + 𝑘12 𝑘 𝑘21 + 𝑘22 %𝐵2 = 100 𝑘 %𝐵1 = 100

Using the Eyring equation to link ki to ΔG#(i) gives: ‡

𝑘𝑖 =

𝑘𝐵 𝑇 −Δ𝑟 𝐺𝑖 𝑒 𝑅𝑇 ℎ

When the C–H activation takes place on the unsubstituted aryl fragment, two C –H bonds can be activated so that the effective kinetic rate constant has to be multiplied by two (Scheme S3).5

Scheme S3: C–H activation of the unsubstituted fragment can take place at two equivalent positions. Results obtained our computational level are given in Table S19.

Table S19: Activation free enthalpies, rate constants and theoretical ratio for the position of the second halogenation. *

Activation Free Enthalpies for TS1-1, TS1-2, TS2-1, TS2-2 (kcal/mol)

X=F

X = Cl

X = Br

‡ Δ𝐺11

33.2

32.1

34.5

‡ Δ𝐺12

34.9

34.7

39.7

‡ Δ𝐺21

32.4

31.7

32.7

‡ Δ𝐺22

34.8

33.6

35.2

2.9189E-06

1.1923E-05

5.5328E-07

3.3167E-07

4.2837E-07

7.1425E-10

1.6245E-05

3.9777E-05

1.1067E-05

7.5386E-07

3.4995E-06

4.5191E-07

%B1-1

14.4

21.4

4.6

%B1-2

1.6

0.8

0.0

%B2-1

80.2

71.5

91.7

%B2-2

3.8

6.3

3.7

%B1

16.0

22.2

4.6

%B2

84.0

77.8

95.4

Rate constants (s-1) ‡

𝑘11 =

𝑘𝐵 𝑇 −Δ𝑟 𝐺11 𝑒 𝑅𝑇 ℎ ‡

𝑘12

𝑘𝐵 𝑇 −Δ𝑟 𝐺12 = 𝑒 𝑅𝑇 ℎ

𝑘21 = 2 × 𝑘22 = 2 ×

𝑘𝐵 𝑇 𝑒 ℎ

Δ𝑟 𝐺 ‡ − 𝑅𝑇21

𝑘𝐵 𝑇 𝑒 ℎ

Δ 𝐺‡ − 𝑟 22 𝑅𝑇

Percentages

*From Scheme S2

36

Interconversions between A11, A12 and A22 Three mechanisms were tested for the interconversions of the initial complexes with fluorine substituents. Main intermediates and transitions states are shown in Scheme S4. Free energies are indicated in red for X = F with respect to A11.

Scheme S4: Main path for interconversion of the reactants. The highest barrier for interconversion is 25.4 kcal.mol-1, and the most favorable path proceeds with a barrier of only 21.9 kcal.mol-1. The activation free energies for the interconversion between the reactants are thus much lower than those estimated fort the C–H activation step. This means that all isomers are in equilibrium at experiment temperature.

37

Energies and free enthalpies of the main minima and transition states Table S20: Relative Free Enthalpies (in kcal/mol) for the reactants, the transition states and the products for the C –H activation (Scheme S1) Relative Free Enthalpies (kcal/mol)

X=F

X = Cl

X = Br

A11

0

0

0

A12

1.6

2.1

4.8

A22

4.9

2.2

4.4

‡ Δ𝐺11

33.2

32.1

34.5

‡ Δ𝐺12

34.9

34.7

39.7

‡ Δ𝐺21

32.4

31.7

32.7

‡ Δ𝐺22

34.8

33.6

35.2

B1-1+2 AcOH

-9.7

-8.7

-4.0

B1-2+2 AcOH

-8.0

-7.0

-2.1

B2-1+2 AcOH

-9.1

-8.7

-6.6

B2-2+2 AcOH

-7.0

-6.5

-2.5

Table S21: Absolute electronic energies (in Hatrees) for the reactants, the transition states and the products for the C-H activation (Scheme S1). (a) The full system includes 2 solvent molecules (acetic acid). E(AcOH)= -229.037216 au. X=F

X = Cl

X = Br

A11

-2527.594090

-3248.317783

-7470.839423

A12

-2527.592619

-3248.315759

-7470.832905

A22

-2527.586743

-3248.315832

-7470.832468

TS1-1

-2527.536161

-3248.259965

-7470.776974

TS1-2

-2527.534378

-3248.265607

-7470.770493

TS2-1

-2527.539029

-3248.256941

-7470.783266

TS2-2

-2527.534224

-3248.257951

-7470.777935

B1-1(a)

-2069.489265

-2790.211786

-7012.726752

B1-2(a)

-2069.486944

-2790.208621

-7012.721703

B2-1(a)

-2069.489669

-2790.213655

-7012.730317

B2-2(a)

-2069.486267

-2790.209442

-7012.723908

38

Table S22: Absolute Gibbs free energies (in Hatrees) for the reactants, the transition states and the products for the C –H activation (Scheme S1). (a) The full system includes 2 solvent molecules (acetic acid). G(AcOH)= -229.002176 au. X=F

X = Cl

X = Br

A11

-2527.094682

-3247.822714

-7470.346442

A12

-2527.092077

-3247.819430

-7470.338777

A22

-2527.086815

-3247.819233

-7470.33949

TS1-1

-2527.041037

-3247.771629

-7470.291438

TS1-2

-2527.039047

-3247.772189

-7470.283237

TS2-1

-2527.042996

-3247.767395

-7470.294388

TS2-2

-2527.039179

-3247.769102

-7470.290402

B1-1(a)

-2069.105769

-2789.832233

-7012.348534

B1-2(a)

-2069.103137

-2789.829454

-7012.345411

B2-1(a)

-2069.104851

-2789.832161

-7012.352585

B2-2(a)

-2069.101490

-2789.828779

-7012.346128

39

Geometries of the main stationary points The optimized structures for the main intermediates and transition states are given in Table S23. They have been drawn with the Cylview.6

Table S23: Optimized geometries for the main intermediates. Carbon atoms are in gray, Nitrogen atoms in blue, Oxygen atoms in red, Palladium atom in light blue, Hydrogen atoms in white, Fluorine atoms in light green, Chlorine atoms are in lime and Bromine atoms in dark purple. X=F

X = Cl

A11

A12

A22

TS1-1

40

X = Br

TS1-2

TS2-1

TS2-2

B1-1

B1-2

41

B2-1

B2-2

References 1

Frisch, M. J. et al., Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT, 2009.

2

Chai, J. D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615-6620.

3

a) S. Mierts et al., J. Chem. Phys. 1981, 55, 117-129; b) M. Cossi, et al. Chem. Phys. Letters 1994, 228, 165-170; c) B. Mennucci et al. J.

Phys. Chem. B 1997, 101, 10506-10517. 4

a) Ren, W.; Vanden-Eijnden, E. Phys. Rev. B 2002, 66, 052301-1/4; b) Opt’n Path v1.50; Fleurat-Lessard, P.; Dayal, P. Freely available at:

http://perso.ens-lyon.fr/paul.fleurat-lessard/ReactionPath.html. 5

Fernández-Ramos, A.; Ellingson, B. A.; Meana-Pañeda, R.; Marques, J. M. C.; Truhlar, D. G. Theor. Chem. Acc. 2007, 118, 813-826.

6

CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org).

42

1

H,

13

C and

19

F NMR copy of new products.

3-(2-bromo-6-fluorophenyl)-6-(2,6-dibromophenyl)-1,2,4,5-tetrazine (5a)

43

3-(2-iodo-6-fluorophenyl)-6-(2,6-diiodophenyl)-1,2,4,5-tetrazine (5b)

44

45

3-(2-bromo-6-fluorophenyl)-6-(2,6-dichlorophenyl)-1,2,4,5-tetrazine (5c)

46

3-(2-bromo-6-chlorophenyl)-6-(2,6-dibromophenyl)-1,2,4,5-tetrazine (6a)

47

3,6-bis(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (7a)

48

49

3,6-bis(2-iodo-6-fluorophenyl)-1,2,4,5-tetrazine (7b)

50

3,6-bis(2-chloro-6-fluorophenyl)-1,2,4,5-tetrazine (7c)

51

52

3,6-bis(2-bromo-6-chlorophenyl)-1,2,4,5-tetrazine (8a)

53

3,6-bis(2-chloro-6-iodophenyl)-1,2,4,5-tetrazine (8b)

54

3-(2-chloro-6-bromophenyl)-6-(2,6-chlorophenyl)-1,2,4,5-tetrazine (10a)

55

3-(2-bromophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (11a)

56

3-(2-bromo-6-fluorophenyl)-6-phenyl-1,2,4,5-tetrazine (11a’)

57

58

3-(2-fluorophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (11b)

59

3-(2-fluoro-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (11b’)

60

3-(2-chlorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (11c)

61

62

3-(2-chloro-6-fluorophenyl)-6-phenyl-1,2,4,5-tetrazine (11c’)

63

3-(2-bromophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (12a)

64

3-(2-bromo-6-chlorophenyl)-6-phenyl-1,2,4,5-tetrazine (12a’)

65

3-(2-chlorophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (12b)

66

3-(2-chloro-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (12b’)

3-(2-bromophenyl)-6-(2-iodophenyl)-1,2,4,5-tetrazine (13b)

67

3-(2-bromo-6-iodophenyl)-6-phenyl-1,2,4,5-tetrazine (13b’)

68

3-(2-bromo-6-fluorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14a)

69

3-(2-fluoro-6-iodophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14b)

70

71

3-(2-chloro-6-fluorophenyl)-6-(2-fluorophenyl)-1,2,4,5-tetrazine (14c)

72

3-(2-bromo-6-chlorophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (15a)

73

3-(2-chloro-6-iodophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (15b)

74

3-(2-chloro-6-fluorophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine (16c)

75

76

3-(2-bromo-6-fluorophenyl)-6-(2-chloro-6-fluorophenyl)-1,2,4,5-tetrazine (17a)

77

3-(2-chloro-6-fluorophenyl)-6-(2-fluoro-6-iodophenyl)-1,2,4,5-tetrazine (17b)

78

79

3-(2-bromo-6-chlorophenyl)-6-(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (18a)

80

3-(2-chloro-6-iodophenyl)-6-(2-fluoro-6-iodophenyl)-1,2,4,5-tetrazine (18b)

81

82

3-(2-chlorophenyl)-6-(2-bromo-6-fluorophenyl)-1,2,4,5-tetrazine (19a)

83

3-(2-chlorophenyl)-6-(2,6-bromohenyl)-1,2,4,5-tetrazine (19a’)

84

85

3-(2-chloro-6-fluorophenyl)-6-(2-iodo-6-bromophenyl)-1,2,4,5-tetrazine (20)

86

3-(phenyl)-6-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (21)

87

3-phenyl-6-(4’-trifluoromethyl)- [(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (22)

88

89

3-(4’-fluoro-[(1,1’-biphenyl)-2-yl]-6-phenyl-1,2,4,5-tetrazine (23)

90

3-(4’-(tert-butyl)-[(1,1’-biphenyl)-2-yl]-6-phenyl-1,2,4,5-tetrazine (24)

91

3-(4’methoxy-[(1,1’-biphenyl)-2-yl]-6-phenyl-1,2,4,5-tetrazine (25)

92

3-(2-fluorophenyl)-6-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (26)

93

3-(2-chlorophenyl)-6-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (27)

94

3-(4’-tert-butyl)-3-chloro-[1,1’-biphenyl]-2’-yl)-6-phenyl-1,2,4,5-tetrazine (28)

95

3-(4,4’’-tert-butyl)-[1,1’:3’,1’’-terphenyl]-2’-yl)-6-phenyl-1,2,4,5-tetrazine (28’)

96

3-(4’-tert-butyl)-3-chloro-[1,1’-biphenyl]-2’-yl)-6-(2,6-dichlorophenyl)-1,2,4,5-tetrazine (29)

97

3,6-bis-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (30)

98

3,6-bis(4’-trifluoromethyl)-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (31)

99

3,6-bis(4’-(tert-butyl)-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (32)

100

3-(4’-( tert-butyl)-[(1,1’-biphenyl)-2-yl]-6-(4’-(methoxy-[(1,1’-biphenyl)-2-yl]-1,2,4,5-tetrazine (33)

101

3-(4’-tert-butyl)-4’’-methoxy-[1,1’:3’,1’’-terphenyl]-2’-yl)-6-phenyl-1,2,4,5-tetrazine (34)

102

103