S1

Supporting Information

Two-component assembly of recognition-encoded oligomers that form stable H-bonded duplexes

Luca Gabrielli, Diego Nűñez-Villanueva and Christopher A. Hunter*

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

Table of Contents

1. Experimental procedures .................................................................................................. S2

2. Synthesis and characterization of monomer D’ ................................................................ S3

3. Synthesis and characterization of monomer D ............................................................... S17

4. Synthesis and characterization of monomer A’ .............................................................. S20

5. Synthesis and characterization of monomer A ............................................................... S26

6. Synthesis and characterization of dimer DD ................................................................... S30

7. Synthesis and characterization of dimer AA ................................................................... S35

8. Synthesis and characterization of Aniline 7 ................................................................ S40

9. Synthesis and characterization of trimer DDD ............................................................... S45

10. Synthesis and characterization of trimer AAA ................................................................ S54

11. NMR binding studies ....................................................................................................... S64

12. References ...................................................................................................................... S74

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

S2

1. Experimental Procedures

General: The reagents and materials used in the synthesis of the compounds described below

were bought from commercial sources, without prior purification. UV irradiations were performed

using an UVP lamp model UVGL-58 (1x365 nm tube, 6 watt) and an UVP lamp model UVL-28 (2x365

nm tubes, 8 watt). Thin layer chromatography was carried out using with silica gel 60F (Merck) on

aluminium. Flash chromatography was carried out on an automated system (Combiflash

Companion, Combiflash Rf+ or Combiflash Rf Lumen) using prepacked cartridges of silica (25μ or

50μ PuriFlash® Columns). All NMR spectroscopy was carried out on a Bruker AVI250, AVI400,

DPX400, AVIII400 spectrometer using the residual solvent as the internal standard. All chemical

shifts (δ) are quoted in ppm and coupling constants given in Hz. Splitting patterns are given as

follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet). FT-IR spectra were

measured on a PerkinElmer Spectrum 100 or One spectrometer equipped with an ATR cell. Melting

points were measured in a Mettler Toledo MP50 Melting Point System. Optical activity was

measured in an AA-10 or an Anton Paar (MCP 100) at 589 nm. ES+ was carried out on a Waters LCT-

TOF spectrometer or a Waters Xevo G2-S bench top QTOF machine.

S3

2. Synthesis of monomer D’

Monomer D’ was prepared as reported in the following scheme:

2.1 Synthesis of 1.

1 5-bromo-2-hydroxybenzaldehyde (1 g, 4.975 mmol, 1 equiv) and 3-(bromomethyl)heptane (3.54 mL, 19.899 mmol, 4 equiv) were dissolved in dry DMF (30 mL); K2CO3 (2.75 g, 19.899 mmol, 4 equiv) anhydrous was added and the mixture was stirred at 120°C for 5 hours. Then the reaction mixture was extracted 3 times with EtOAc and LiCl 5% solution. The organic layers were collected, dried over MgSO4, concentrated under vacuum and purified by combiflash, giving 1.5 g of a colourless oil (98% yield).

Br

OH

RBr, DMF, K2CO3, 120°C

98%

O

Br

O O

OHOHCF3

Br B

CF3

O O

B2pin2, KOAc,Pd(dppf)2Cl2Dioxane, MW 101°C, 50 min

75%

KF, HP(tBu)3BF4, Pd(dba)3, H2O, THF, 80°C, MW 1h

OH

O

CF3

O85%

1

2

D’

Br

O

O

S4

1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 3.97 (d, J = 6.5 Hz, 2H), 1.87 – 1.74 (m, 1H), 1.56 – 1.41 (m, 4H), 1.38 – 1.27 (m, 4H), 0.96 (t, J = 7.5 Hz, 3H), 0.94 – 0.88 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 188.31, 160.60, 138.26, 130.73, 126.21, 114.53, 113.18, 71.26, 39.35, 30.55, 29.05, 23.94, 22.97, 14.04, 11.14. HRMS (ES+): Calculated for C15H22

79BrO2 313.0798 a.m.u., found 313.0785 a.m.u. FT-IR (ATR): νmax / cm-1 2958, 2928, 2859, 1725, 1682, 1590, 1482, 1461, 1384, 1268, 1240, 1176, 1122.

1H-NMR spectrum

S5

13C-NMR spectrum

S6

2.2 Synthesis of 2.

2 4-bromo-2-(trifluoromethyl)phenol (0.5 g, 2.075 mmol, 1 equiv), KOAc (0.611 g, 6.225 mmol, 3 equiv) and Bis(pinacolato)diboron (1.05 g, 4.149 mmol, 2 equiv) were added to dioxane (7 mL); the reaction mixture was degassed bubbling N2 for 30 min, then Pd(dppf)2Cl2 (0.152 g, 0.2075 mmol, 0.1 equiv) was added and the reaction was refluxed under stirring in N2 atmosphere overnight. Then the solution was extracted in H2O/EtOAc, the organic layers were collected, dried over MgSO4, concentrated under vacuum and purified by combiflash, giving 0.450 g of a white solid (75% yield). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H, H3), 7.82 (d, J = 7.9 Hz, 1H, H5), 7.39 (bs, 1H, OH), 6.92 (d, J = 8.1 Hz, 1H, H6), 1.36 (s, 12H, 4CH3). 13C NMR (101 MHz, CDCl3) δ 156.84 (q, J3

CF = 1.9 Hz, C1), 139.89 (1C, C5), 133.86 (q, J3CF = 4.7 Hz,

C3), 124,98 (1C, C4) 124.02 (q, J1CF = 272.3 Hz, CF3), 116.46 (q, J2

CF = 30.6 Hz, C2), 116.72 (1C, C6), 84.26 (2C, Cquat), 24.72 (8C, CH3). 11B NMR (128 MHz, CDCl3) δ 30.42. 19F NMR (376 MHz, CDCl3) δ -61.81. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C13H17O311BF3, 289,1223; found 289,1213. FT-IR (ATR): νmax 2958, 2930, 2872, 1474, 1458, 1389, 1360, 1326, 1272, 1215, 1164, 1144, 1119, 1098, 1079, 1020, 857, 675 cm-1.

OHCF3

BO O

S7

1H-NMR spectrum

13C-NMR spectrum

S8

11B-NMR spectrum

19F-NMR spectrum

S9

2.3 Synthesis of D’.

D’

Modifying a reported procedure,1 in a sealed vial compound 1 (400 mg, 1.277 mmol, 1.2 equiv), compound 2 (306 mg, 1.064 mmol, 1 equiv), KF (250 mg, 4.256 mmol, 4 equiv) and HP(tBu)3BF4 (10 mg, 0.035 mmol, 0.03 equiv) were suspended in freshly degassed (3 freeze pump thaw cycles) THF (3 mL) and H2O (1 mL). Then Pd2(dba)3 (16 mg, 0.0175 mmol, 0.016 equiv) was added and the reaction was stirred under N2 atmosphere at 80°C under MW irradiation (normal absorbance) for 1 hour and 7 minutes. Then it was extracted in H2O/EtOAc, the organic phases were collected, dried with MgSO4, concentrated under vacuum and purified by combiflash chromatography with PE:EtOAc (from 9:1 to 8:2). Fractions containing the product were concentrated and then purified again via combiflash chromatography, eluting with 100% DCM, giving the pure desired monomer D’ (355 mg, 85% yields).

1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H, OH), 8.03 (d, J = 2.6 Hz, 1H Ph), 7.74 (dd, J = 8.6, 2.6 Hz, 1H Ph), 7.71 (d, J = 2.3 Hz, 1H Ph), 7.63 (dd, J = 8.5, 2.3 Hz, 1H Ph), 7.13 – 7.03 (m, 2H Ph), 4.05 (dd, J = 5.5, 1.1 Hz, 2H, CH2), 1.89 – 1.76 (m, 1H), 1.64 – 1.09 (m, 8), 1.03 – 0.82 (m, 9H). 13C NMR (126 MHz, CDCl3) δ 193.0, 161.4, 154.4, 134.6, 130.8, 125.95, 124.8 (q, J3

CF = 4.9Hz, 1C), 124.51, 123,9 (q, J1

CF = 272.3 Hz, CF3), 122.79, 118.62, 117.1 (q, J2CF = 30.6 Hz, 1C), 116.9, 110.7,

71.13, 38.3, 30.5, 29,0, 23.8, 20.5, 15.5, 8.9. 19F NMR (376 MHz, CDCl3) δ -61.17. m.p.: 110.1-111.7 °C HRMS (ES+): Calculated for C22H25F3O3 394.1756 a.m.u., found 394.1747 a.m.u. FT-IR (ATR): νmax / cm-1 3162, 2944, 2874, 1665, 1610, 1493, 1437, 1335, 1291, 1261, 1237, 1180, 1120, 1051, 814.

O

O

OHCF3

S10

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.5

3.0

3.0

5.8

4.1

1.0

2.0

2.0

1.1

1.0

1.0

1.2

1.0

0102030405060708090100110120130140150160170180190200

8.92

15.48

20.48

23.84

28.96

30.46

38.29

71.13

75.57

110.67

116.95

117.19

118.62

122.79

124.51

124.70

124.74

124.78

124.82

124.96

125.95

128.55

130.75

132.00

134.59

154.37

161.42

193.01

S11

19F-NMR spectrum

-125-120-115-110-105-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25-20-15-10-5

S12

HSQC-NMR spectrum

COSY-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

S13

3. Synthesis of monomer D

Monomer D was prepared as reported in the following scheme:

3.1 Synthesis of 3.

3

According to a reported procedure,2 hexamethylenetetramine (16 g, 115.60 mmol, 4 equiv) was dissolved in TFA (50 mL) under stirring. 4- Bromophenol (3 g, 17.34 mmol, 1 equiv) was added in one portion and the solution was stirred at 120°C under N2 for 24 hours. Then other 4- Bromophenol (8 g, 57.80 mmol, 2 equiv) was added and the solution was stirred at 120°C for 48 hours. Then 1N HCl solution (400 mL) was added and the solution stirred at 80°C for 4 hours. Then the solution was cooled to room temperature and the resulting precipitate was collected on a Büchner funnel and washed with HCl 1N. The obtained orange precipitate was purified via combiflash (PE:EtOAc 8:2) giving the desired product as a yellow solid (2.3 g, 60% yield). Spectroscopic data are in agreement with those reported in literature.5

1H NMR (400 MHz, Chloroform-d) δ 11.56 (s, 1H, OH), 10.20 (s, 2H, CHO), 8.07 (s, 2H, CH). 13C NMR (101 MHz, CDCl3) δ 190.63, 162.27, 139.76, 124.61, 112.16.

Br

OH

TFA, Urotropine,120°C, 48h

60%

Br

OH

RBr, DMF, K2CO3 120°C, 48h

97%

OO

Br

O OO

OH

O

CF3

OO

82%3

4

D

2, KF, HP(tBu)3BF4, Pd(dba)3, H2O, THF, 80°C, MW 1h

Br

OHO O

S14

1H-NMR spectrum

13C-NMR spectrum

S15

3.2 Synthesis of 4.

4 Compound 3 (300 mg, 1.310 mmol, 1 equiv) and 3-(bromomethyl)heptane (932 µL, 5.240 mmol, 4 equiv) were dissolved in dry DMF (5 mL); K2CO3 anhydrous (724 mg, 5.240 mmol, 4 equiv) was added and the mixture was stirred at 120°C for 48 hours. Then the reaction mixture was extracted 3 times with EtOAc and LiCl 5% solution. The organic layers were collected, dried over MgSO4, concentrated under vacuum and purified by combiflash chromatography, giving 433 mg of a colourless oil (97% yield).

1H NMR (400 MHz, CDCl3) δ 10.31 (s, 2H, CHO), 8.13 (s, 2H, CH Ph), 4.00 (d, J = 5.9 Hz, 2H, CH2O), 1.91 – 1.80 (m, 1H), 1.63 – 1.41 (m, 4H), 1.36 – 1.22 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H), 0.91 – 0.86 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 186.98, 163.60, 137.11, 131.62, 118.11, 83.80, 40.66, 30.04, 28.96, 23.50, 22.94, 14.00, 11.03. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H21O3

79Br1, 340,0674; found 340,0661. FT-IR (ATR): νmax 2959, 2928, 2861, 1741, 1689, 1573, 1441, 1404, 1375, 1259, 1236, 1212, 1147, 963, 945, 897, 872, 713, 623, 544 cm-1.

Br

OO O

S16

1H-NMR spectrum

13C-NMR spectrum

S17

3.3 Synthesis of D.

D

Modifying a reported procedure,3 in a sealed vial compound 4 (500 mg, 1.736 mmol, 1 equiv), compound 2 (711 mg, 2.783 mmol, 1.2 equiv), KF (303 mg, 5.208 mmol, 3 equiv) and HP(tBu)3BF4 (10 mg, 0.035 mmol, 0.02 equiv) were suspended in freshly degassed (3 freeze pump thaw cycles) THF (2.8 mL) and H2O (1 mL). Then Pd2(dba)3 (16 mg, 0.018 mmol, 0.016 equiv) was added and the reaction was stirred under N2 atmosphere at 80°C under MW irradiation (normal absorbance) for 1 hour and 5 minutes. Then it was extracted in H2O/EtOAc, the organic phases were collected, dried with MgSO4, concentrated under vacuum and purified by combiflash chromatography with PE:EtOAc (from 9:1 to 8:2). Fractions containing the product were concentrated and then purified again via combiflash chromatography, eluting with 100% DCM, giving the pure desired monomer D (605 mg, 82% yields).

1H NMR (400 MHz, CDCl3) δ 10.49 (s, 2H), 8.29 (s, 2H), 7.77 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.5, 2.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.05 (s, 1H), 4.08 (d, J = 5.9 Hz, 2H), 1.99 – 1.85 (m, 1H), 1.69 – 1.45 (m, 5H), 1.37 (h, J = 3.5 Hz, 4H), 1.00 (t, J = 7.5 Hz, 3H), 0.98 – 0.91 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 189.4, 164.8, 154.0, 136.1, 132.4, 131.6, 130.5, 130.3, 125,3 (q, J3

CF = 4.9Hz, 1C), 123,7 (q, J1

CF = 272.3 Hz, CF3), 118.4, 117,2 (q, J2CF = 30.6 Hz, 1C), 83.8, 40.6, 30.0, 28.9,

23.5, 22.9, 13.9, 10.9. 19F NMR (471 MHz, CDCl3) δ -61.55. HRMS (ASAP+) (m/z): [M + H]+ calcd for C23H26O4F3, 423,1783; found 423,1773. FT-IR (ATR): νmax / cm-1 3054, 2929, 2872, 2307, 1688, 1622, 1575, 1519, 1461, 1443, 1401, 1381, 1338, 1295, 1264, 1235, 1189, 1135, 1072, 1055, 896, 731, 703.

OH

O

CF3

OO

S18

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

3.0

3.0

4.0

5.0

1.0

2.0

1.0

1.0

1.0

1.0

2.0

2.0

0102030405060708090100110120130140150160170180190200

10.96

13.91

22.87

23.46

28.91

30.02

40.64

83.82

116.87

117.11

117.35

117.60

118.38

119.99

122.60

124.76

125.20

125.24

125.28

127.23

130.29

130.52

131.66

132.41

136.06

154.00

164.80

189.38

S19

19F-NMR spectrum

HSQC-NMR spectrum

-125-115-105-95-85-75-65-55-45-35-25-15-5

-61.55

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

S20

4. Synthesis of monomer A’

Monomer A’ was prepared as reported in the following scheme:

4.1 Synthesis of 5.

Compound 5 was synthesized following a reported procedure.4 A flask, evacuated/N2 filled (3x), was

charged with n-BuMgCl (2 M in Et2O, 38.78 mL, 77.57 mmol) and the solution cooled to 0°C. A

solution of diethylphosphite (3.331 mL, 25.86 mmol) in 50 mL THF was then added dropwise over

15 minutes. The mixture was aged 15 minutes at 0°C, then the bath was removed, and the mixture

stirred two hours at room temperature, then cooled again to 0°C. 0.1 M HCl solution (50 mL) was

added dropwise over 20 minutes. To the obtained gel was added CH2Cl2 (50 mL), and the mixture

agitated well for 5 minutes. The resultant mixture was then filtered through a Celite pad, washing

the pad with CH2Cl2. The filtrate phases were separated, and the organic phase combined with the

first organic phase, dried (MgSO4), and the solvents removed in vacuum. The residue was

I

OH

1) RBr, DMF, K2CO3 120°C, 3,5h

O

P

O

O

O

2) 5, Pd2dba3, TEA, Xantphos, Dioxane, 45 min, MW 101°C65% over 2 steps

A’

5

PHO O

OHPO

BuMgBr, THF

98%

I

OH

1) RBr, DMF, K2CO3 120°C, 3,5h

O

P

O

O

O

2) 5, Pd2dba3, TEA, Xantphos, Dioxane, 45 min, MW 101°C65% over 2 steps

A’

5

PHO O

OHPO

BuMgBr, THF

98%

5

HPO

S21

azeotroped with hexane (2x30 mL) causing a precipitate that correspond to dibutylphosphine oxide

(4.195 g, quantitative). Spectroscopic data were in agreement with the reported,4 and this

compound was used in the following step without further purification.

1H NMR (400.0 MHz, CDCl3): δH = 7.49 – 6.25 (dm, J = 446 Hz, 1H), 1.94 – 1.50 (m, 8H), 1.50 – 1.34 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H). 13C NMR (100.6 MHz, CDCl3): δC = 28.25, 27.60, 23.78 (dd, J = 9.1, 5.2 Hz), 13.56. 31P NMR (162.0 MHz, CDCl3): δP = 35.03 HRMS (ES+): Calculated for C8H20OP 163.1252 a.m.u., found 163.1258 a.m.u.

1H-NMR spectrum

S22

13C-NMR spectrum

4.2 Synthesis of A’.

2-hydroxy-5-iodobenzaldehyde (1.5 g, 6.048 mmol, 1 equiv) and 3-(bromomethyl)heptane (4.3 mL,

24.192 mmol, 4 equiv) were dissolved in dry DMF (15 mL); K2CO3 anhydrous (3.3 g, 24.192 mmol, 4

equiv) was added and the mixture was stirred at 120°C for 3.5 hours. Then the reaction mixture was

extracted 3 times with EtOAc and LiCl 5% solution. The organic layers were collected, dried over

P

O

O

O

S23

MgSO4, concentrated under vacuum and purified by combiflash chromatography (PE:EtOAc) , giving

1.5 g of a colorless oil, which is freshly used for the next synthetic step, because of its instability.

Thus, the obtained alkylated iodobenzaldehyde (1.5 g, 4.164 mmol, 1 equiv) was mixed with

phosphine oxide 5 (1 g, 6.246 mmol, 1.5 equiv), Xantphos (241 mg, 0.416 mmol, 0.1 equiv) and

Pd2dba3 (241 mg, 0.416 mmol, 0.1 equiv); finally, previously degassed dioxane (30 mL, 3 freeze

pump thaw cycles) and trimethylamine (1.7 mL, 12.492 mmol, 3 equiv) were added, and the solution

was stirred under nitrogen atmosphere, in dark conditions, for 45 minutes. Then the mixture was

filtered through Celite, washing the pad with EtOAc. The filtrate was collected, the solvent

evaporated, and the obtained residue was purified using combiflash chromatography EtOAc: MeOH

(from 0% to 3%) and then DCM: MeOH (from 0% to 3%), affording 1.1 g of the desired monomer A’

(67% yield over 2 steps).

1H NMR (500 MHz, CDCl3) δ 10.36 (s, 1H), 7.92 (t, J = 10.5 Hz, 1H), 7.79 (dd, J = 10.3, 2.4 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.90 (d, J = 5.5 Hz, 2H), 1.88 – 1.76 (m, 2H), 1.75 – 1.61 (m, 3H), 1.49 – 1.11 (m, 16H), 0.79 (t, J = 7.4 Hz, 3H), 0.72 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 188.65, 163.48 (d, J = 2.6 Hz), 138.86 (d, J = 8.3 Hz), 129.42 (d, J = 12.0 Hz), 124.43 (d, J = 10.9 Hz), 123.94 (d, J = 95.5 Hz), 112.70 (d, J = 10.7 Hz), 70.95, 39.08, 30.30, 29.77, 29.22, 28.79, 23.85, 23.73, 23.69, 23.24, 23.21, 22.70, 13.76, 13.31, 10.90. 31P NMR (202 MHz, CDCl3) δ 40.41. HRMS (ES+): Calculated for C23H40O3P 395.2715 a.m.u., found 395.2696 a.m.u. FT-IR (ATR): νmax / cm-1 2957, 2929, 2861, 1684, 1594, 1489, 1463, 1385, 1280, 1242, 1193, 1168, 1087, 1007, 918.

S24

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

9.1

3.1

16.4

3.0

2.0

2.0

1.0

1.0

1.0

1.0

0102030405060708090100110120130140150160170180190200

10.90

13.31

13.76

22.70

23.21

23.24

23.69

23.73

23.85

28.79

29.22

29.77

30.30

39.08

70.95

112.66

112.75

123.56

124.32

124.38

124.47

129.37

129.47

138.82

138.89

163.47

163.49

188.65

S25

31P-NMR spectrum

COSY-NMR spectrum

-120-100-80-60-40-20020406080100120140160180200

40.41

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1

2

3

4

5

6

7

8

9

10

S26

5. Synthesis of monomer A

Monomer A’ was prepared as reported in the following scheme:

5.1 Synthesis of A.

Acceptor monomer A was synthesized in one step, dissolving 5-bromoisophthalaldehyde (500 mg,

2.347 mmol, 1 equiv), phosphine oxide 5 (420 mg, 2.589 mmol, 1.1 equiv), Xantphos (163 mg, 0.282

mmol, 0.1 equiv), K2PO3 (550 mg, 2.589 mmol, 1.1 equiv) and Pd(OAc)2 (53 mg, 0.235 mmol, 0.1

equiv) in freshly degassed DMF (4 mL, 3 freeze pump thaw cycles). Then the mixture was stirred

under N2 atmosphere, in a sealed vial, under MW irradiation (high absorption), at 150°C for 25

minutes (30 sec of pre-stirring). Then the mixture was extracted (3x) with EtOAc / LiCl 5%; the

organic layers were dried with MgSO4, concentrated under reduced pressure and then purified via

combiflash chromatography (EtOAc:MeOH, from 0 to 10%), affording the desired monomer A (510

mg, 75% yield).

1H NMR (500 MHz, Chloroform-d) δ 10.16 (s, 2H), 8.50 (s, 1H), 8.45 (dd, J = 9.9, 1.7 Hz, 2H), 2.12 – 2.00 (m, 2H), 1.96 – 1.84 (m, 2H), 1.67 – 1.57 (m, 2H), 1.39 – 1.30 (m, 6H), 0.85 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, Chloroform-d) δ 190.2, 137.04 (d, J = 9.6 Hz), 136.38 (d, J = 86.4 Hz), 136.22 (d, J = 9.1 Hz), 132.67 (d, J = 2.6 Hz), 29.50 (d, J = 68.8 Hz), 23.89 (d, J = 14.5 Hz), 23.33 (d, J = 4.4 Hz), 13.4. 31P NMR (202 MHz, CDCl3) δ 40.06. HRMS (ASAP+): Calculated for C16H24O3P 295,1463 a.m.u., found 295,1450 a.m.u.

O O

Br

O O

PO

HPOBu2, Pd(OAc)2, K2PO3, Xantphos, DMF, 150°C, 25 min

75%

A

O O

PO

S27

FT-IR (ATR): νmax / cm-1 3401, 2958, 2932, 2871, 2734, 2715, 1702, 1590, 1542, 1466, 1405, 1378, 1345, 1313, 1258, 1221, 1169, 1141, 1122, 1095, 1053, 987, 964, 907, 882, 860, 798, 683, 650.

1H-NMR spectrum

-0.50.51.52.53.54.55.56.57.58.59.510.511.512.5

6.0

6.0

2.1

2.0

2.1

1.9

1.0

1.9

0.82

0.83

0.85

0.86

0.88

0.89

0.91

0.92

1.30

1.31

1.32

1.33

1.34

1.34

1.35

1.36

1.37

1.37

1.38

1.39

1.57

1.58

1.59

1.59

1.60

1.61

1.62

1.62

1.63

1.63

1.64

1.64

1.66

1.66

1.67

1.86

1.87

1.88

1.89

1.90

1.90

1.91

1.92

1.92

1.93

1.94

1.95

2.02

2.03

2.04

2.05

2.06

2.06

2.07

2.07

2.08

2.09

2.10

S28

13C-NMR spectrum

31P-NMR spectrum

0102030405060708090100110120130140150160170180190200

13.41

23.31

23.34

23.83

23.95

29.23

29.78

132.66

132.68

136.04

136.19

136.26

136.72

137.01

137.08

190.23

-110-90-70-50-30-101030507090110130150170190

40.06

S29

HSQC-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

S30

6. Synthesis of dimer DD

Monomer DD was prepared as reported in the following scheme:

6.1 Synthesis of DD.

Donor dimer DD was synthesized via one step reductive amination. Monomer D’ (100 mg, 0.237

mmol, 1 equiv) and 5-(trifluoromethyl)benzene-1,3-diamine (20 mg, 0.237 mmol, 0.5 equiv) were

dissolved in dry dichloroethane (2 mL). Then molecular sieves (3 A) are added and the reaction is

shaken on an orbital oscillator for 6 hours, under N2 atmosphere. Subsequently, NaBH(OAc)3 (50

mg, 0.237 mmol, 1 equiv) was added and the mixture was shaken for 12 hours. Then, in order to be

sure that the reduction is fully complete (since imine impurities co-eluate with desired dimer) NaBH4

OH

O

CF3

O

Aniline, DCE, MSNaBH(OAc)3,

75%HN

HN

CF3

OH

O

CF3 F3C

O

OH

DDD’

HN

HN

CF3

OH

O

CF3 F3C

O

OH

DD

S31

(9 mg, 0.237 mmol, 1 equiv) and MeOH (0.5 mL) are added and the mixture is shaken for one hour.

Then the solution is filtered, MS are washed with DCM and a saturated solution of NaHCO3 is added.

The mixture is stirred until complete solubilisation, then the organic phase is extracted and the

aqueous phase is washed (3x) with EtOAc. The organic layers are collected and dried over MgSO4,

the solvent is evaporated and the residue is purified via combiflash chromatography (PE:EtOAc),

giving the desired dimer DD (163 mg, 75% yield).

1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 2.3 Hz, 2H), 7.49 (dd, J = 8.5, 2.3 Hz, 2H), 7.42 (d, J = 2.4 Hz, 2H), 7.36 (dd, J = 8.4, 2.4 Hz, 2H), 6.92 (dd, J = 8.5, 1.7 Hz, 4H), 6.30 (d, J = 1.9 Hz, 2H), 6.05 (s, 2H), 4.34 (s, 4H), 3.93 (dd, J = 5.5, 1.8 Hz, 4H), 1.80 – 1.72 (m, 2H), 1.69 (s, 2H), 1.53 – 1.36 (m, 8H), 1.36 – 1.22 (m, 9H), 0.92 (t, J = 7.5 Hz, 6H), 0.91 – 0.84 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 156.56, 152.27, 149.47, 133.58, 132.15 (dd, J = 62.6, 31.2 Hz),131.49, 127.37, 126.58, 124.36 (d, J = 272.6 Hz), 124.00 (d, J = 272.3 Hz), 118.00, 116.53 (q, J = 30.3 Hz), 111.36, 99.87, 99.69 (dd, J = 7.6, 3.6 Hz), 70.33, 43.75, 39.31, 30.62, 29.00, 23.96, 22.90, 13.93, 11.04. 19F NMR (471 MHz, CDCl3) δ -61.33, -63.38. HRMS (ES+): Calculated for C51H58N2O4F9 933.4253 a.m.u., found 933.4263 a.m.u. FT-IR (ATR): νmax / cm-1 3448, 2959, 2928, 2874, 2862, 1612, 1494, 1463, 1440, 1381, 1335, 1284, 1247, 1165, 1053, 899, 891812, 695.

S32

COSY-NMR spectrum

HSQC-NMR spectrum

1.01.52.02.53.03.54.04.55.05.56.06.57.07.5

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

S33

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

5.9

5.9

9.2

8.1

2.6

4.0

4.1

1.1

2.1

4.0

2.0

2.0

2.0

2.1

0102030405060708090100110120130140150160170180190200

11.04

13.93

22.90

23.96

29.00

30.62

39.31

43.75

70.33

99.67

99.87

111.36

116.17

116.41

116.65

116.89

118.00

120.68

122.92

123.27

124.68

124.72

124.76

124.80

125.09

125.44

126.58

127.37

131.49

131.56

132.03

133.58

149.47

152.27

156.56

S34

19F-NMR spectrum

-120-115-110-105-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25-20-15-10-50

-63.38

-61.33

S35

7. Synthesis of dimer AA

Monomer AA was prepared as reported in the following scheme:

7.1 Synthesis of AA.

Acceptor dimer AA was synthesized via one step reductive amination. Monomer A’ (108 mg, 0.275

mmol, 1 equiv) and 5-(trifluoromethyl)benzene-1,3-diamine (24 mg, 0.275 mmol, 0.5 equiv) were

dissolved in dry dichloroethane (2 mL). Then molecular sieves (3 A) are added and the reaction is

shaken on an orbital oscillator for 6 hours, under N2 atmosphere. After imine formation NaBH(OAc)3

(58 mg, 0.275 mmol, 1 equiv) was added and the mixture was shaken for 12 hours. Then, in order

to be sure that the reduction is fully complete (since imine impurities co-eluate with desired dimer)

NaBH4 (10 mg, 0.275 mmol, 1 equiv) and MeOH (0.5 mL) are added and the mixture is shaken for

one hour. Then the solution is filtered, MS are washed with DCM and a saturated solution of NaHCO3

P

O

O

O

Aniline, NaBH(OAc)3,DCE, MS

70%

HN

HN

CF3

P

O

O O

O

P

AAA’

HN

HN

CF3

P

O

O O

O

P

S36

is added. The mixture is stirred until complete solubilisation, then the organic phase is extracted

and the aqueous phase is washed (3x) with EtOAc. The organic layers are collected and dried over

MgSO4, the solvent is evaporated and the residue is purified via combiflash chromatography

(EtOAc:MeOH), giving the desired dimer AA (179 mg, 70% yield).

1H NMR (500 MHz, Chloroform-d) δ 7.65 – 7.54 (m, 2H), 7.49 (d, J = 10.3 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.17 (s, 2H), 6.00 (s, 1H), 4.30 (s, 7H), 3.99 – 3.85 (m, 5H), 2.38 (s, 4H), 1.87 (ddq, J = 15.5, 11.9, 4.9 Hz, 5H), 1.74 (qd, J = 14.5, 12.7, 4.1 Hz, 7H), 1.57 – 1.22 (m, 33H), 0.91 (t, J = 7.5 Hz, 7H), 0.89 – 0.84 (m, 5H), 0.81 (t, J = 7.1 Hz, 14H). 13C NMR (126 MHz, CDCl3) δ 159.44, 159.42, 149.21, 131.57 (d, J = 9.2 Hz), 130.29 (d, J = 10.9 Hz), 127.53 (d, J = 186.5 Hz), 127.34 (d, J = 11.4 Hz), 124.29 (q, J = 272.5 Hz), 122.91 (d, J = 97.3 Hz), 110.95, 110.85, 100.01, 99.26, 99.24, 99.20, 99.17, 70.36, 43.29, 39.24, 30.57, 29.90, 29.36, 28.97, 23.36 (d, J = 4.0 Hz), 22.87, 13.91, 13.41, 11.04. 31P NMR (202 MHz, CDCl3) δ 41.17. 19F NMR (471 MHz, CDCl3) δ -63.44. HRMS (ES+): Calculated for C53H86N2O4F3P2 933,6015 a.m.u., found 933,5975 a.m.u. FT-IR (ATR): νmax / cm-1 3280, 2959, 2931, 2872, 1598, 1552, 1510, 1492, 1466, 1394, 1380, 1347, 1324, 1275, 1246, 1223, 1187, 1159, 1116, 1084, 1029, 909, 815, 762, 713, 698.

1H-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

11.8

6.2

5.9

32.1

5.9

3.9

2.0

4.0

5.8

1.0

2.0

2.0

2.0

2.0

0.77

0.80

0.81

0.82

0.85

0.86

0.88

0.90

0.91

0.93

1.241.261.271.271.281.291.30

1.30

1.31

1.33

1.34

1.35

1.36

1.37

1.38

1.40

1.41

1.42

1.43

1.45

1.46

1.47

1.49

1.49

1.50

1.51

1.52

1.52

1.53

1.55

1.701.711.721.731.731.751.761.771.781.83

1.84

1.85

1.86

1.88

1.88

1.89

1.91

1.91

2.38

3.90

3.92

3.93

3.94

3.96

4.30

6.00

6.17

6.91

6.95

6.97

7.48

7.50

7.58

7.58

7.60

7.61

7.62

S37

13C-NMR spectrum

31P-NMR spectrum

0102030405060708090100110120130140150160170180190200

ppm

11.040

13.406

13.910

22.871

23.339

23.340

23.371

23.371

23.870

23.930

23.986

28.968

29.357

29.904

30.574

39.236

43.289

70.358

77.198

99.202

99.235

100.009

110.853

110.949

121.042

122.524

123.208

123.298

125.374

126.785

127.295

127.386

127.542

128.268

130.249

130.335

131.529

131.602

131.724

131.972

132.221

132.468

149.211

159.422

159.444

-140-120-100-80-60-40-20020406080100120140160180200

41.17

S38

19F-NMR spectrum

-120-115-110-105-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25-20-15-10-50

-63.44

S39

HSQC-NMR spectrum

COSY-NMR spectrum

1.01.52.02.53.03.54.04.55.05.56.06.57.07.5

10

20

30

40

50

60

70

80

90

100

110

120

130

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

S40

8. Synthesis of aniline 7

Aniline 7 was prepared as reported in the following scheme:

8.1 Synthesis of 6.

1-(chloromethyl)-3,5-dinitrobenzene (3 g, 13.851 mmol, 1 equiv) was dissolved in dry THF (45 mL)

and trimethylamine (2.3 mL, 16.621, 1.2 equiv). Then, 2-ethylhexane-1-thiol was added, and the

reaction was stirred under N2 atmosphere. A pink precipitate was formed, and after 15 minutes

the solvent was evaporated and the residue was firstly extracted (3x) with DCM / NaOH 2N. The

organic layers were collected, dried over MgSO4 and purified via combiflash chromatography

(PE:EtOAc), giving 4.3 g of compound 6 (95% yield).

1H NMR (500 MHz, CDCl3-d) δ 8.94 (t, J = 2.1 Hz, 1H), 8.56 (d, J = 2.2 Hz, 2H), 3.88 (s, 2H), 2.45 (d, J

= 6.2 Hz, 2H), 1.51 – 1.14 (m, 9H), 0.88 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 149.11, 143.97, 128.91, 117.47, 38.95, 36.45, 36.09, 32.33, 28.85,

25.54, 22.91, 14.04, 10.77.

HRMS (ES+): Calculated for C15 H23 N2 O4 S 327,1379 a.m.u., found 327,1371 a.m.u.

FT-IR (ATR): νmax / cm-1 3107, 3084, 2958, 2927, 2872, 2858, 1594, 1538, 1459, 1358, 1341, 1235,

1115, 1075, 909, 809, 729, 661.

O2N NO2

Cl

O2N NO2

S

H2N NH2

S

RSH, TEA

THF, 95% SnCl2, 90%

EtOH

6 7

O2N NO2

S

6

S41

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0

3.0

3.0

9.3

2.0

2.0

1.7

0.7

0102030405060708090100110120130140150160170180190200

10.77

14.04

22.91

25.54

28.85

32.33

36.09

36.45

38.95

117.47

128.91

143.97

149.11

S42

8.2 Synthesis of 6.

Compound 6 (4.3 g, 13.185 mmol, 1 equiv) was dissolved in EtOH 96% (75 mL) then SnCl2 (20 g,

105.48 mmol, 8 equiv) was added, and the reaction was refluxed for 10 minutes. Then, solvent

was evaporated the residue was firstly extracted (3x) with DCM / NaOH 2N. The organic layers

were collected, dried over MgSO4 and purified via combiflash chromatography (PE:EtOAc), giving

3.6 g of compound 7 (90% yield).

1H NMR (500 MHz, CDCl3-d) δ 6.11 (d, J = 2.1 Hz, 2H), 5.92 (t, J = 2.1 Hz, 1H), 3.53 (s, 4H), 3.51 (s, 2H), 2.44 (d, J = 6.2 Hz, 2H), 1.51 – 1.19 (m, 9H), 0.91 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 147.52, 140.33, 106.64, 100.25, 39.00, 37.00, 36.09, 32.46, 28.91, 25.61, 23.01, 14.16, 10.85. HRMS (ES+): Calculated for C15 H27 N2 S 267, 1884 a.m.u., found 267,1895 a.m.u. FT-IR (ATR): νmax / cm-1 3424, 3342, 3216, 3024, 2956, 2924, 2871, 2856, 1596, 1514, 1466, 1378, 1357, 1295, 1232, 1191, 1158, 1004, 992, 834, 725, 686, 630.

H2N NH2

S

7

S43

1H-NMR spectrum

13C-NMR spectrum

0102030405060708090100110120130140150160170180190200

10.85

14.16

23.01

25.61

28.91

32.46

36.09

37.00

39.00

100.25

106.64

140.33

147.52

S44

HSQC-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.5

10

20

30

40

50

60

70

80

90

100

110

S45

9. Synthesis of trimer DDD

Trimer DDD was prepared as reported in the following scheme:

9.1 Synthesis of 8.

Monomer D (123 mg, 0.302 mmol, 1 equiv) and aniline 7 (722 mg, 2.718, 9 equiv) were dissolved in

dry DCE (2.5 mL). Molecular sieves (3A) were added and the mixture was mixed overnight on an

orbital shaker, under N2 atmosphere. Then, NaBH4 (114 mg, 3.020 mmol, 10 equiv) and MeOH (2.5

mL) were added and the mixture was shaken for 2 hours (1H-NMR was used to confirm fully imine

OH

O

CF3

OOHN

HNH2N NH2

1) 7, DCE, MS2) NaBH4, MeOH

70%

OHCF3

S S

O

HN

HNH2N NH2

OHCF3

S S

HN

HN

HN

HN

70%

OHCF3

S S

OH

O

CF3 F3C

O

OH

OO

8

DDD

D

8

1) D’, DCE, MS2) NaBH4, MeOH

HN

HNH2N NH2

OHCF3

S S

O

8

S46

reduction). Then the solution was filtered, MS were washed with DCM and a saturated solution of

NaHCO3 was added. The mixture was stirred until complete solubilisation, then the organic phase

was extracted and the aqueous phase was washed (3x) with EtOAc. The organic layers were

collected and dried over MgSO4, the solvent was evaporated and the residue was purified via

combiflash chromatography (PE:EtOAc), giving the desired compound 8 (195 mg, 70% yield).

1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 2.3 Hz, 1H), 7.41 – 7.31 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H), 6.10 (s, 2H), 5.91 (s, 2H), 4.35 (s, 4H), 3.79 (d, J = 5.9 Hz, 2H), 3.51 (s, 4H), 2.41 (d, J = 6.2 Hz, 4H), 1.80 – 1.70 (m, 1H), 1.62 – 1.13 (m, 26H), 0.92 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.1 Hz, 9H), 0.81 (t, J = 7.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 171.47, 154.77, 153.43, 149.16, 145.78, 140.19, 135.22, 132.91, 132.09, 131.40, 126.68, 124.95, 123.87 (d, J = 272.5 Hz), 117.59, 116.73 (q, J = 30.3 Hz), 107.01, 106.34, 103.67, 98.32, 60.49, 43.41, 40.67, 38.90, 37.06, 36.04, 32.32, 30.27, 29.15, 28.78, 25.47, 23.63, 22.97, 22.89, 13.61, 11.17, 10.71. 19F NMR (471 MHz, CDCl3) δ -61.76. HRMS (ASAP+): Calculated for C53H78N4O2F3S2 923.5518 a.m.u., found 923.5536 a.m.u. FT-IR (ATR): νmax / cm-1 3383, 3043, 2958, 2926, 2871, 2858, 2724, 1715, 1599, 1515, 1445, 1407, 1379, 1338, 1266, 1201, 1103, 1078, 1052, 956, 907, 882, 767, 687, 600.

S47

1H-NMR spectrum

13C-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

6.0

9.0

3.0

26.2

0.9

4.0

4.0

2.0

4.0

1.9

2.0

1.8

0.9

0.8

1.9

0.9

0.77

0.78

0.80

0.81

0.83

0.84

0.86

0.87

0.87

0.89

0.90

0.92

0.93

1.161.171.181.181.191.201.211.231.241.251.261.271.271.281.30

1.31

1.32

1.33

1.35

1.36

1.38

1.39

1.40

1.42

1.43

1.44

1.45

1.46

1.47

1.48

1.49

1.51

1.52

1.53

1.55

1.56

1.58

1.59

1.731.741.751.762.40

2.41

3.51

3.793.80

4.35

5.91

6.10

6.16

6.53

6.55

7.237.247.35

7.37

7.51

7.51

0102030405060708090100110120130140150160170180190200

10.71

11.17

13.61

22.89

22.97

23.63

25.47

28.78

29.15

30.27

32.32

36.04

37.06

38.90

40.67

43.41

60.49

98.32

103.67

106.34

107.01

117.59

124.95

126.68

131.40

132.09

132.91

135.22

140.19

145.78

149.16

153.43

154.77

171.47

S48

19F-NMR spectrum

HSQC-NMR spectrum

-125-115-105-95-85-75-65-55-45-35-25-15-5

-61.76

1.01.52.02.53.03.54.04.55.05.56.06.57.07.5

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

S49

COSY-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

S50

9.2 Synthesis of DDD.

Compound 8 (120 mg, 0.164 mmol, 1 equiv) and donor monomer D’ (260 mg, 0.657, 4 equiv) were

dissolved in dry DCE (2 mL). Molecular sieves (3A) were added and the mixture was mixed overnight

on an orbital shaker, under N2 atmosphere. Then, NaBH4 (70 mg, 1.640 mmol, 10 equiv) and MeOH

(2.5 mL) were added and the mixture was shaken for 2 hours (1H-NMR was used to confirm fully

imine reduction). Then the solution was filtered, MS were washed with DCM and a saturated

solution of NaHCO3 was added. The mixture was stirred until complete solubilisation, then the

organic phase was extracted and the aqueous phase was washed (3x) with EtOAc. The organic layers

were collected and dried over MgSO4, the solvent was evaporated and the residue was purified via

combiflash chromatography (PE:EtOAc), giving the desired compound DDD (192 mg, 70% yield).

1H NMR (500 MHz, CDCl3-d) δ 7.56 (s, 2H), 7.50 (s, 1H), 7.44 – 7.28 (m, 9H), 7.26 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.80 – 6.71 (m, 3H), 6.12 (s, 4H), 5.95 (s, 2H), 4.34 (s, 8H), 3.92 (t, J = 4.8 Hz, 4H), 3.76 (d, J = 5.9 Hz, 2H), 3.52 (s, 4H), 2.38 (d, J = 6.3 Hz, 4H), 1.80 – 1.64 (m, 3H), 1.57 – 1.13 (m, 46H), 0.93 (t, J = 7.5 Hz, 6H), 0.91 – 0.87 (m, 6H), 0.86 – 0.82 (m, 9H), 0.81 – 0.74 (m, 9H). 13C NMR (126 MHz, CDCl3) δ 156.54, 154.96, 152.47, 151.98, 149.25, 148.15, 140.51, 135.52, 133.28, 132.97, 132.82, 131.58, 131.52, 131.37, 127.80, 127.38, 126.90, 126.29, 124.91 (d, J = 4.9 Hz), 124.65 (d, J = 4.7 Hz), 123.99 (d, J = 272.4 Hz), 117.86, 111.25, 104.92, 104.39, 97.07, 70.29, 44.15, 43.58, 40.62, 39.31, 38.90, 37.29, 35.54, 32.28, 30.62, 30.20, 29.08, 29.01, 28.76, 25.42, 23.98, 23.54, 22.95, 22.89, 22.86, 13.99, 13.94, 11.07, 10.67. 19F NMR (471 MHz, CDCl3) δ -61.56, -61.59. HRMS (ASAP+): Calculated for C97H128F9N4O6S2 1679,9126 a.m.u., found 1679,9118 a.m.u. FT-IR (ATR): νmax / cm-1 3408, 2957, 2926, 2871, 2859, 1601, 1495, 1441, 1407, 1380, 1334, 1292, 1247, 1160, 1130, 1052.

HN

HN

HN

HN

OHCF3

S S

OH

O

CF3 F3C

O

OH

O

DDD

S51

1H-NMR spectrum

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0

9.6

9.2

6.5

6.2

46.0

3.2

4.0

4.0

2.0

4.0

8.0

2.0

4.0

2.9

2.0

0.9

9.0

1.0

1.9

0.76

0.77

0.79

0.80

0.82

0.83

0.84

0.84

0.85

0.86

0.87

0.89

0.90

0.92

0.93

0.95

1.151.161.171.171.181.201.201.211.231.241.241.251.261.261.281.281.291.30

1.30

1.31

1.32

1.33

1.33

1.34

1.35

1.37

1.38

1.39

1.41

1.42

1.43

1.44

1.45

1.47

1.48

1.49

1.50

1.50

1.52

1.53

1.64

1.65

1.67

1.68

1.69

1.701.721.721.741.751.761.771.781.80

2.37

2.38

3.52

3.753.763.91

3.92

3.93

4.34

5.95

6.12

6.73

6.75

6.76

6.77

6.78

6.89

6.91

7.267.30

7.31

7.32

7.33

7.33

7.34

7.35

7.35

7.37

7.39

7.39

7.41

7.41

7.50

7.56

S52

13C-NMR spectrum

19F-NMR spectrum

0102030405060708090100110120130140150160170180190200

10.67

11.07

13.94

13.99

22.86

22.89

22.95

23.54

23.98

25.42

28.76

29.01

29.08

30.20

30.62

32.28

35.54

37.29

38.90

39.31

40.62

43.58

44.15

70.29

97.07

104.39

104.92

111.25

116.22

116.46

116.70

116.88

117.86

122.91

124.64

124.67

124.89

124.93

125.07

126.29

126.90

127.38

127.80

131.37

131.52

131.58

132.82

132.97

133.28

135.52

140.51

148.15

149.25

151.98

152.47

154.96

156.54

-120-115-110-105-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25-20-15-10-50

-61.59

-61.56

-61.9-61.7-61.5-61.3

-61.59

-61.56

S53

COSY-NMR spectrum

HSQC-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

S54

10. Synthesis of trimer AAA

Trimer AAA was prepared as reported in the following scheme:

10.1 Synthesis of 9.

Monomer A (105 mg, 0.357 mmol, 1 equiv) and aniline 7 (565 mg, 3.210, 9 equiv) were dissolved in

dry DCE (2.5 mL). Molecular sieves (3A) were added and the mixture was mixed overnight on an

orbital shaker, under N2 atmosphere. Then, NaBH4 (114 mg, 3.570 mmol, 10 equiv) and MeOH (1

mL) were added and the mixture was shaken for 2 hours (1H-NMR was used to confirm fully imine

reduction). Then the solution was filtered, MS were carefully washed with DCM and a saturated

solution of NaHCO3 was added. The mixture was stirred until complete solubilisation, then the

organic phase was extracted and the aqueous phase was washed (3x) with EtOAc. The organic layers

HN

HN

PO

H2N NH2

CF3 CF3

HN

HN

PO

HN

HN

CF3 CF3

65%

P

O

O O

O

P

O O

PO

HN

HN

PO

H2N NH2

CF3 CF3

1) Aniline, DCE, MS2) NaBH4, MeOH

65%

9

AAA9

A

1) A’, DCE, MS2) NaBH4, MeOH

HN

HN

PO

H2N NH2

CF3 CF39

S55

were collected and dried over MgSO4, the solvent was evaporated and the residue was purified via

combiflash chromatography (PE:EtOAc), giving the desired compound 9 (142 mg, 65% yield).

1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 10.8 Hz, 2H), 7.46 (s, 1H), 6.25 (s, 2H), 6.22 (s, 2H), 5.96 (s, 2H), 4.33 (s, 6H), 3.77 (bs, 4H), 1.99 – 1.86 (m, 2H), 1.84 – 1.76 (m, 2H), 1.57 – 1.50 (m, 2H), 1.38 – 1.21 (m, 6H), 0.83 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, Chloroform-d) δ 148.36 (d, J = 137.6 Hz), 140.18 (d, J = 10.9 Hz), 133.60 (d, J = 90.3 Hz), 132.31 (q, J = 31.5 Hz), 129.01 (d, J = 2.6 Hz), 127.95 (d, J = 9.1 Hz), 124.11 (q, J = 272.4 Hz), 101.40, 100.29 (q, J = 4.2 Hz), 47.50, 29.40 (d, J = 68.4 Hz), 23.91 (d, J = 14.6 Hz), 23.36 (d, J = 4.2 Hz), 13.37. 19F NMR (471 MHz, CDCl3) δ -63.47. 31P NMR (202 MHz, CDCl3) δ 41.32. HRMS (ES+): Calculated for C30H38N4OF6P 615,2687 a.m.u., found 615,2674 a.m.u. FT-IR (ATR): νmax / cm-1 3428, 3327, 3219, 3071, 3040, 2961, 2933, 2873, 1608, 1519, 1487, 1455, 1427, 1385, 1330, 1269, 1210, 1157, 1112, 1085, 989, 995, 904, 888, 829, 735, 695.

1H-NMR spectrum

S56

13C-NMR spectrum

31P-NMR spectrum

0102030405060708090100110120130140150160170180190200

13.37

23.35

23.38

23.85

23.96

29.13

29.68

47.50

100.24

100.27

100.30

100.34

101.40

120.86

123.02

125.19

127.36

127.91

127.98

129.00

129.02

131.94

132.19

132.44

132.69

133.24

133.95

140.13

140.22

147.81

148.91

-60-50-40-30-20-100102030405060708090100110

41.32

S57

19F-NMR spectrum

-96-94-92-90-88-86-84-82-80-78-76-74-72-70-68-66-64-62-60-58-56-54-52-50-48-46-44-42-40-38-36-34

-63.47

S58

COSY-NMR spectrum

HSQC-NMR spectrum

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

0

10

20

30

40

50

60

70

80

90

100

110

120

130

S59

10.2 Synthesis of AAA.

Compound 9 (40 mg, 0.065 mmol, 1 equiv) and donor monomer A’ (102 mg, 0.260, 4 equiv) were

dissolved in dry DCE (1 mL). Molecular sieves (3A) were added and the mixture was mixed overnight

on an orbital shaker, under N2 atmosphere. Then, NaBH4 (50 mg, 1.300 mmol, 10 equiv) and MeOH

: DCE (2.5 mL, 7:3) were added and the mixture was shaken for 2 hours (1H-NMR was used to confirm

fully imine reduction). Then the solution was filtered, MS were carefully washed with DCM and a

saturated solution of NaHCO3 was added. The mixture was stirred until complete solubilisation, then

the organic phase was extracted and the aqueous phase was washed (3x) with EtOAc. The organic

layers were collected and dried over MgSO4, the solvent was evaporated and the residue was

purified via combiflash chromatography (PE:EtOAc), giving the desired compound AAA (59 mg, 65%

yield).

1H NMR (500 MHz, CDCl3-d) δ 7.59 – 7.51 (m, 7H), 6.95 (d, J = 8.7 Hz, 2H), 6.15 (d, J = 4.8 Hz, 4H), 6.00 (s, 2H), 4.32 (s, 4H), 4.29 (s, 4H), 3.93 (d, J = 5.5 Hz, 4H), 2.43 (bs, 4H), 1.98 – 1.68 (m, 14H), 1.58 – 1.19 (m, 42H), 0.92 (t, J = 7.5 Hz, 6H), 0.89 – 0.85 (m, 6H), 0.84 – 0.76 (m, 18H). 13C NMR (126 MHz, CDCl3-d) δ 159.53, 149.08 (d, J = 17.7 Hz), 140.26 (d, J = 10.9 Hz), 133.34 (d, J = 90.5 Hz), 132.08 (q, J = 31.5 Hz), 131.22 (d, J = 9.6 Hz), 130.66 (d, J = 10.1 Hz), 129.37, 128.07 (d, J = 8.8 Hz), 127.37 (d, J = 11.2 Hz), 124.26 (q, J = 272.6 Hz), 110.95 (d, J = 12.5 Hz),123,1, 122,4, 99.46 (d, J = 3.5 Hz), 99.71, 99.07 (d, J = 3.9 Hz), 70.36, 47.59, 42.43, 39.25, 30.60, 29.88, 29.68, 29.33, 29.14, 28.97, 23.97, 23.95, 23.86, 23.37, 23.33, 22.88, 13.92, 13.40, 11.05. 19F NMR (471 MHz, CDCl3) δ -63.43. 31P NMR (202 MHz, CDCl3) δ 41.46. HRMS (ASAP+): Calculated for C76H116N4O5F6P3 1371,8063 a.m.u., found 1371,8041 a.m.u.

HN

HN

PO

HN

HN

CF3 CF3

P

O

O O

O

P

AAA

S60

FT-IR (ATR): νmax / cm-13286, 2959, 2930, 2872, 1608, 1546, 1513, 1494, 1466, 1396, 1381, 1346, 1324, 1276, 1247, 1218, 1188, 1117, 1085, 908, 820, 805, 709, 696.

1H-NMR spectrum

-0.50.51.52.53.54.55.56.57.58.59.510.511.512.5

18.1

6.3

6.1

42.2

14.1

3.8

4.0

8.0

1.9

3.9

2.0

7.0

S61

13C-NMR spectrum

19F-NMR spectrum

0102030405060708090100110120130140150160170180190200

11.05

13.40

13.92

22.88

23.33

23.37

23.86

23.95

23.97

28.97

29.14

29.33

29.68

29.88

30.60

39.25

42.43

47.59

70.36

99.06

99.09

99.45

99.47

99.71

110.90

111.00

122.37

123.15

123.18

125.35

127.33

127.42

128.04

128.11

130.62

130.70

131.18

131.26

131.96

132.21

132.98

133.70

140.22

140.31

149.01

149.15

159.53

-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25-20

-63.43

S62

31P-NMR spectrum

1015202530354045505560657075

41.46

S63

HSQC-NMR spectrum

COSY-NMR spectrum

1.01.52.02.53.03.54.04.55.05.56.06.57.07.5

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

S64

11. NMR spectroscopy studies

All binding constants were measured by 19F and 1H NMR titrations in a Bruker 500

MHz AVIII HD Smart Probe spectrometers. The host (H, phenol derivatives D, DD,

DDD) was dissolved in toluene-d8 or chloroform-d3 at a known concentration. The

guest (G, phosphine oxide derivatives A, AA, AAA) was dissolved in the host solution

and made to a known concentration. A known volume of host was added to an NMR

tube and the spectrum was recorded. Known volumes of guest in host solution were

added to the NMR tube, and the spectra were recorded after each addition. The

chemical shifts of the host spectra were monitored as a function of guest

concentration and analysed using a purpose written software in Microsoft Excel.

Errors were calculated as two times the standard deviation from the average value

(95% confidence limit).

19F and 1H (donor CF3 and OH) NMR chemical shifts and limiting complexation-induced

changes in chemical shifts of the free host (ppm) obtained by fitting titration data

measured in toluene-d8 and chloroform-d3 at 298 K to a 1:1 binding isotherm.

11.1 Titration D vs A in chloroform (1H and 19F-NMR).

19F-NMR 1H-NMR

Solvent Complex d free d bound Dd d free d bound Dd

CDCl3

D•A -61,1 -62,8 -1,7 5,7 11,3 5,6

DD•AA -61,0 -62,3 -1,2 5,5 10,3 4,8

DDD•AAA -61,0 -62,2 -1,2

-61,1 -62,2 -1,0

Toluene D•A -61,8 -62,3 -0,5 4,9 11,6 6,6 DD•AA -61,5 -61,8 -0,3

DD•AAIMINE -61,5 -61,9 -0,4

S65

Titration of A (40.59 mM) into D (2.27 mM) in CDCl3 (1H and 19F-NMR).

Plot of the change in chemical shift of the D 1H signal as a function of [A] (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [A].

4.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

0.000.501.001.502.002.503.003.504.004.505.00

0 5 10 15 20 25

∆∂

[A] / mM

1H-NMR D Signals

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

pop

ula

tion

/ %

[A] / mM

Speciation

H

G

HG

S66

Plot of the change in chemical shift of the D 19F signal as a function of [A] (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [A].

-62.6-62.5-62.4-62.3-62.2-62.1-62.0-61.9-61.8-61.7-61.6-61.5-61.4-61.3-61.2-61.1-61.0-60.9-60.8-60.7-60.6

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

-1.60

-1.40

-1.20

-1.00

-0.80

-0.60

-0.40

-0.20

0.000 5 10 15 20 25 30

∆∂

[A] / mM

19F-NMR D Signals

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30

pop

ula

tion

/ %

[A] / mM

Speciation

H

G

HG

S67

11.2 Titration DD vs AA in chloroform (1H and 19F-NMR).

Titration of AA (10.08 mM) into DD (2.28 mM) in CDCl3 (1H and 19F-NMR)

Plot of the change in chemical shift of the DD 1H signal as a function of [AA] (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [AA].

4.04.55.05.56.06.57.07.58.08.59.09.510.010.5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

S68

Plot of the change in chemical shift of the DD 19F signal as a function of [AA] (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [AA].

-63.5-63.3-63.1-62.9-62.7-62.5-62.3-62.1-61.9-61.7-61.5-61.3-61.1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

-1.20

-1.00

-0.80

-0.60

-0.40

-0.20

0.00

0.20

0 2 4 6 8

∆∂

[AA] / mM

19F-NMR DD Signals

0102030405060708090100

0 2 4 6 8

pop

ula

tion

/ %

[AA] / mM

Speciation

H

G

HG

S69

11.3 Titration DDD vs AAA in chloroform (19F-NMR).

Titration of AAA (1 mM) into DDD (0.1 mM) in CDCl3 (19F-NMR)

Plot of the change in chemical shift of the DDD 19F signals as a function of [AAA]: red for the internal D monomer, black for the two external D monomers (the lines represent the best fit to a 1:1 binding isotherm) and speciation as a function of [AAA].

-63.9-63.7-63.5-63.3-63.1-62.9-62.7-62.5-62.3-62.1-61.9-61.7-61.5-61.3-61.1-60.9-60.7

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

S70

11.4 Titration D vs A in toluene (1H and 19F-NMR).

Titration of A (6.70 mM) into D (2.31 mM) in Toluene (1H and 19F-NMR).

Plot of the change in chemical shift of the D 1H signal as a function of [A] in toluene (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [A].

3.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

S71

Plot of the change in chemical shift of the D 19F signal as a function of [A] in toluene (the line represents the best fit to a 1:1 binding isotherm) and speciation as a function of [A].

-62.32-62.28-62.24-62.20-62.16-62.12-62.08-62.04-62.00-61.96-61.92-61.88-61.84-61.80-61.76-61.72

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

S72

11.5 Titration DD vs AA in toluene (1H and 19F-NMR).

Titration of AA (1.00 mM) into DD (0.10 mM) in Toluene (19F-NMR).

Plot of the change in chemical shift of the DD 19F signals as a function of [AA]: red for the aniline backbone CF3, black for the D monomers CF3 (the lines represent the best fit to a 1:1 binding isotherm) and speciation as a function of [AA].

-63.0-62.9-62.8-62.7-62.6-62.5-62.4-62.3-62.2-62.1-62.0-61.9-61.8-61.7-61.6-61.5

1

2

3

4

5

6

7

8

9

S73

11.6 Titration DD vs dimer imine AAIMINE in toluene (1H and 19F-NMR).

Titration of AAIMINE (1.00 mM) into DD (0.099 mM) in Toluene (19F-NMR).

Plot of the change in chemical shift of the DD 19F signals as a function of [AAIMINE]: black for the D monomers CF3 (the lines represent the best fit to a 1:1 binding isotherm – K = 7,43 E+04) and speciation as a function of [AAIMINE].

-63.7-63.5-63.3-63.1-62.9-62.7-62.5-62.3-62.1-61.9-61.7-61.5-61.3-61.1-60.9

1

2

3

4

5

6

7

8

9

10

-0.45-0.40-0.35-0.30-0.25-0.20-0.15-0.10-0.050.000.05

0.00 0.20 0.40 0.60 0.80

∆∂

[AAIMINE ] / mM

DD Signals

0102030405060708090100

0.00 0.20 0.40 0.60 0.80

pop

ula

tion

/ %

[AAIMINE ] / mM

Speciation

H

G

HG

S74

12. References

1 D. Reinhard, L. Schöttner, V. Brosius, F. Rominger, M. Mastalerz, Eur. J. Org. Chem. 2015, 3274. 2 L. Gonzalez-Bulnes, I. Ibanez, L. M. Bedoya, M. Beltran, S. Catalμn, J. Alcamí, S. Fustero, J. Gallego Angew. Chem. Int. Ed., 2013, 52, 13405. 3 D. Reinhard, L. Schöttner, V. Brosius, F. Rominger, M. Mastalerz, Eur. J. Org. Chem. 2015, 3274. 4 D. Nűñez-Villanueva and C. A. Hunter, Chem. Sci., 2017, 8, 206.