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.