Dual nucleophilic substitution reactions of O,O-diethyl 2,4dinitrophenyl phosphate and thionophosphate triesters
Raul Aguayo, Felipe Arias, Alvaro Cañete, Carolina Zuñiga, Enrique A. Castro,
Paulina Pavez* and José G. Santos
*Correspondence to: P. Pavez, Facultad de Química. Pontificia Universidad Católica de Chile. Casilla 306,
Santiago 6094411, Chile.
E-mail: ppavezg@uc.cl
Raul Aguayo, Felipe Arias, Alvaro Cañete, Enrique A. Castro, Paulina Pavez* and José G. Santos
Facultad de Química. Pontificia Universidad Católica de Chile. Casilla 306, Santiago 6094411,
Chile.
Carolina Zuñiga
Department of Chemical and Bioprocess Engineering, School of Engineering. Pontificia
Universidad Católica de Chile
ppavezg@uc.cl
SUPPORTING INFORMATION
S1
Table of contents
Figure S1.
HPLC analysis of reaction of 1 with morpholine
S6
Figure S2.
HPLC analysis of reaction of 1 with 4-Oxypyridine
S6
Figure S3.
HPLC analysis of reaction of 1 with phenol
S7
Figure S4.
HPLC analysis of reaction of 2 with Morpholine
S7
Figure S5.
HPLC analysis of reaction of 2 with 4-Oxypyridine
S8
Figure S6.
HPLC analysis of reaction of 2 with phenol
S8
Figure S7
Progressive spectra obtained for the reaction of 1 (0.01 M) with 4-
S11
oxypyridine (0.1M) at 25ºC and pH 11.5 in D2O-ACN (60:40 v/v).
(A) 1H-NMR spectra. (B)
31
P-NMR spectra. Chemical shifts are
given in Table S1
Figure S8:
Progressive 1H-NMR spectra obtained for the reaction of 2 (0.01 M)
with 3,4-dimethylpyridine (0.1M) at 25ºC and pH 5.7 in D2O-ACN
(60:40 v/v).
S12
Table S1:
Chemical shifts and signal attributed to the reagent and product of the
reaction of 1 and 2 with the nucleophiles used.
S13
Figure S9.
Brønsted-type plot (log k NAr vs pKa of the nucleophile) for the
phenolysis (a) and SA aminolysis (b) of 1 in 44 wt% ethanol-water, at
25.0 °C, ionic strength 0.2 M (KCl).
S14
Figure S10
Brønsted-type plots for the pyridinolysis of 1 in 44wt % ethanolwater, at 25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa
of the nucleophile for attack at the phosphoryl center. (b) Plot of log
k NAr vs pKa of the nucleophile for attack at the C-1 aromatic carbon.
Brønsted-type plots for the SA aminolysis of 2 in 44wt % ethanolwater, at 25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa
of the nucleophile for attack at the phosphoryl center. (b) Plot of log
k NAr vs pKa of the nucleophile for attack at the C-1 aromatic carbon.
S14
Brønsted-type plots for the phenolysis of 2 in 44wt % ethanol-water,
at 25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa of the
S15
Figure S11.
Figure S12.
nucleophile for attack at the phosphoryl center. (b) Plot of log k NAr vs
S2
S15
pKa of the nucleophile for attack at the C-1 aromatic carbon.
Figure S13
Brønsted-type plots for the pyridinolysis of 2 in 44wt % ethanolwater, at 25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa
S16
of the nucleophile for attack at the phosphoryl center. (b) Plot of log
k NAr vs pKa of the nucleophile for attack at the C-1 aromatic carbon.
Table S2.
Pseudo-first-order rate coefficients (kobsd) for the reactions between
piperidine and 1 at different pH values.
S17
Table S3
Pseudo-first-order rate coefficients (kobsd) for the reactions between
piperazine and 1 at different pH values.
S17
Table S4
Pseudo-first-order rate coefficients (kobsd) for the reactions between 1(2-hydroxyethyl)piperazine and 1 at different pH values.
S18
Table S5
Pseudo-first-order rate coefficients (kobsd) for the reactions between
morpholine and 1 at different pH values.
S18
Table S6
Pseudo-first-order rate coefficients (kobsd) for the reactions between 1formylpiperazine and 1 at different pH values.
S19
Table S7
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4oxypyridine and 1 at different pH values.
S19
Table S8
Pseudo-first-order rate coefficients (kobsd) for the reactions between
3,4-diaminopyridine and 1 at different pH values.
S20
Table S9
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4dimethylaminopyridine and 1 at different pH values.
S20
Table S10
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4aminopyridine and 1 at different pH values.
S21
Table S11
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4amino-3-bromopyridine and 1 at different pH values.
S21
Table S12
Pseudo-first-order rate coefficients (kobsd) for the reactions between
3,4-dimethylpyridine and 1 at different pH values.
S22
Table S13
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4methoxyphenol and 1 at different pH values.
S22
Table S14
Pseudo-first-order rate coefficients (kobsd) for the reactions between
phenol and 1 at different pH values.
S23
Table S15
Pseudo-first-order rate coefficients (kobsd) for the reactions between
4chlorophenol and 1 at different pH values.
S23
Table S16
Pseudo-first-order rate coefficients (kobsd) for the reactions between 3-
S24
S3
cyanophenol and 1 at different pH values.
Table S17
Pseudo-first-order rate coefficients (kobsd) for the reactions between
2,6-difluorophenol and 1 at different pH values.
S24
Table S18
Pseudo-first-order rate coefficients (kobsd) for the reactions between
2,3,4,5,6-pentafluorophenol and 1 at different pH values.
S25
Table S19
Pseudo-first-order rate coefficients (kobsd) for the reactions between
piperidine and 2 at different pH value
S25
Table S20
Pseudo-first-order rate coefficients (kobsd) for the reactions between
piperazine and 2 at different pH values.
S26
Table S21
Pseudo-first-order rate coefficients (kobsd) for the reactions between 1(2-hydroxyethyl)piperazine and 2 at different pH values
S27
Table S22
Pseudo-first-order rate coefficients (kobsd) for the reactions between
morpholine and 2 at different pH values.
S27
Table S23
Pseudo-first-order rate coefficients (kobsd) for the reactions between 1formylpiperazine and 2 at different pH values.
S28
Table S24
Pseudo-first-order rate coefficients (kobsd) for the reactions between
piperazinium ion and 2 at different pH values.
S29
Table S25
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4oxypyridine and 2 at different pH values.
S30
Table S26
Pseudo-first-order rate coefficients (kobsd) for the reactions between
3,4-diaminopyridine and 2 at different pH values.
S31
Table S27
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4dimethylaminopyridine and 2 at different pH values.
S32
Table S28
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4aminopyridine and 2 at different pH values.
S33
Table S29
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4amino-3-bromopyridine and 2 at different pH values.
S34
Table S30
Pseudo-first-order rate coefficients (kobsd) for the reactions between
3,4-dimethylpyridine and 2 at different pH values.
S34
Table S31
Pseudo-first-order rate coefficients (kobsd) for the reactions between 4methoxyphenol and 2 at different pH values.
S35
Table S32
Pseudo-first-order rate coefficients (kobsd) for the reactions between
phenol and 2 at different pH values.
S35
Table S33
Pseudo-first-order rate coefficients (kobsd) for the reactions between
S36
S4
4chlorophenol and 2 at different pH values.
Table S34
Pseudo-first-order rate coefficients (kobsd) for the reactions between 3cyanophenol and 2 at different pH values.
S36
Table S35
Pseudo-first-order rate coefficients (kobsd) for the reactions between
2,6-difluorophenol and 2 at different pH values.
S37
Table S36
Pseudo-first-order rate coefficients (kobsd) for the reactions between
2,3,4,5,6-pentafluorophenol and 2 at different pH values.
S37
Figure S14
(A) 1H NMR spectrum of 2 and (B) 13C NMR spectrum of 2.
S38
Figure S15
(A) 1H NMR spectrum of 1 and (B) 13C NMR spectrum of 1.
S39
Scheme S1
(a) Concerted mechanism for the SA aminolysis and pyridinolysis of
the substrates. (b) Concerted mechanism for the phenolysis of the
substrates.
(a) SNAr process leads to the formation of the Meisenheimer complex
(MC) for the aminolysis of substrate 1 (b) SNAr process leads to the
formation of the Meisenheimer complex (MC) for the pyridinolysis
of substrates 1 and 2 (c) SNAr process leads to the formation of the
Meisenheimer complex (MC) for the phenolysis of substrate 1
S40
Scheme S2
S5
S41
Figure S1. HPLC analysis of reaction of 1 with morpholine
Figure S2. HPLC analysis of reaction of 1 with 4-oxypyridine
S6
Figure S3. HPLC analysis of reaction of 1 with phenol
Figure S4. HPLC analysis of reaction of 2 with morpholine, the insert is the zoom of the
signals of 2,4-dinitrophenol.
S7
Figure S5. HPLC analysis of reaction of 2 with 4-oxypyridine
Figure S6. HPLC analysis of reaction of 2 with phenol
S8
Reaction 1 with nucleophiles: In order to determine the products formed in these reactions,
the chromatographic signals of these reactions were compared with those obtained by
reactions
of
1-chloro-2,4-dinitrobenzene
with
the
same
nucleophiles.
Other
chromatographic signals were compared with an authentic sample of 2,4-dinitrophenol in
the same experimental conditions.
a) Reaction with morpholine: The HPLC analysis shows one signal (tr = 5.71 min, 244nm),
attributed to 1-morpholino-2,4-dinitrobenzene, and the absence of signal due to 2,4dinitrophenol (tr =1.61 min and 366nm), see Figure S1. These results are consistent with
the exclusive reaction on the C-1 aromatic center of substrate 1.
b) Reaction with 4-oxypiridine: The HPLC analysis shows signals (tr =8.25 min, 420nm),
attributed to 1-(4-oxypiridino)-2,4-dinitrobenzene, and (tr=1.86 min, 366nm) due to 2,4dinitrophenol, see Figure S2 These results are consistent with the dual reaction on the C-1
aromatic center and on the P=S group of substrate 1.
c) Reaction with phenol: The HPLC analysis shows one signal at (tr=6.96 min, 244 nm),
attributed to phenyl 2,4-dinitrophenyl ether, and the absence of signal due to 2,4dinitrophenol (tr=1.60 min and 366nm), see Figure S3. These results are consistent with the
exclusive reaction on the C-1 aromatic center of substrate 1.
Reaction of 2 with nucleophiles: In order to determine the products formed in these
reactions, the chromatographic signals of these reactions were compared with those
obtained by reactions of 1-choloro-2,4-dinitrobenzene with the same nucleophiles. Other
chromatographic signals were compared with an authentic sample of 2,4-dinitrophenol in
the same experimental conditions.
S9
a) Reaction with morpholine: The HPLC analysis shows signals at (tr = 5.80 min, 244nm),
attributed to 1-morpholino-2,4-dinitrobenzene, and (tr=1.70 min, 366nm) due to 2,4dinitrophenol, see Figure S4. These results are consistent with the dual reaction on the C-1
aromatic center and on the P=O group of substrate 2.
b) Reaction with 4-oxypyridine: The HPLC analysis shows signals at (tr = 7.69 min,
300nm), attributed to 1-(4-oxypiridino)-2,4-dinitrobenzene, and (tr=1.65min, 366nm) due
to 2,4-dinitrophenol, see Figure S5. These results are consistent with the dual reaction on
the C-1 aromatic center and on the P=O group of substrate 2.
c) Reaction with phenol: The HPLC analysis shows signals at (tr=7.10 min, 310 nm),
attributed to phenyl 2,4-dinitrophenyl ether, and (tr=1.66min and 366nm) due to 2,4dinitrophenol, see Figure S6. These results are consistent with the dual reaction on the C-1
aromatic center and on the P=O group of substrate 2.
S10
Figure S7: Progressive spectra obtained for the reaction of 1 (0.01 M) with 4-oxypyridine
(0.1M) at 25ºC and pH 11.5 in D2O-ACN (60:40 v/v). (A) 1H-NMR spectra. (B) 31P-NMR
spectra. Chemical shifts are given in Table S1
The spectra for the reaction of 1 with 4-oxypyridine show the increase of the signals
corresponding
to
2,4-dinitrophenol
and
4-oxypyridinothiophosphate
(evidencing
nucleophilic attack to the thiophosphoryl group) and that of 1-(4-oxypyridino)-2,4dinitrobenzene, attributed to the product derived from attack to the C-1 aromatic atom. This
was also confirmed by 31P-NMR, where was observed the disappearance of the signal due
to 1 (62.18 ppm) and the increase of two new signals, due to OO-diethyl thiophosphoric
acid (55.25 ppm) and to O,O-diethyl 4-oxypyridine thiophosphate (61.74 ppm).
S11
Figure S8: Progressive 1H-NMR spectra obtained for the reaction of 2 (0.01 M) with 3,4dimethylpyridine (0.1M) at 25ºC and pH 5.7 in D2O-ACN (60:40 v/v).
Reaction of 2 with 3,4-dimethylpyridine. Figure S7 shows a sequence of 1H-NMR spectra
(in the aromatic region) at different times. It can be observed the decrease of the signal of 2
and the increase of several other signals, corresponding to 2,4-dinitrophenol and to 1-(3,4dimethylpyridino)-2,4-dinitrobenzene. This experiment evidences the dual character of this
reaction.
S12
Table S1: Chemical shifts and signal attributed to the reagent and product of the reaction of
1 and 2 with the nucleophiles used
NMR-1H δ (ppm)
Compound
NMR-31P
δ (ppm)
1
8.11 (d, J=9.2 Hz, 1H), 8.90 (dd, J1= 9.2 Hz ,
62.18
J2= 2.8 Hz, 1H), 9.17 (d, J= 2.8 Hz, 1H)
2
8.11 (d, J= 9.2 Hz, 1H), 8.90 (dd, J1= 9.2 Hz,
-7.52
J2= 2.8 Hz, 1H), 9.19 (d, J=2.8 Hz, 1H)
2,4-dinitrophenol
7.01 (d, J=9.6 Hz, 1H-Ar), 8.35 (dd, J1=9,6 Hz,
J2=3.2 Hz, 1H), 9.08 (d, J=2.8 Hz, 1H)
1-chloro-2,4-dinitrobenzene
8.34 (d, J=8.8 Hz, 1H), 8.83 (dd, J1=8.8 Hz, J2
=2.8 Hz, 1H), 9.16 (d, J= 2.4 Hz, 1H)
1-morpholino-2,4-dinitrobenzene
7.66 (d, J=18.8 Hz, 1H), 8.65 (dd, J1=18.8 Hz,
J2 =5.6 Hz, 1H), 9.00 (d, J=5.6 Hz, 1H)
1-(4-oxypyridino)-2,4-dinitrobenzene
6.98 (d, J=7.6 Hz, 2H), 8.24 (d, J=7.6, 2H), 8.38
(d, J=8.8 Hz, 1H), 9.10 (dd, J1=8.8, J2=2.4,
1H), 9.42 (d, J=2.4 Hz, 1H)
1-(3,4-dimethylpyridino)-2,4-dinitrobenzene
8.40 (d, J= 6.4 Hz, 1H), 8.50 (d, J=8.4 Hz, 1H),
9.08 (d, J=6.4 Hz, 1H), 9.11 (s, 1H), 9.23 (dd,
J1=2.4Hz, J2=8.8Hz, 1H), 9.58 (d, J=2.4 1H)
diethylthiophosphoric acid
55.25
diethylphosphoric acid
0.81
diethyl morpholino-thiophosphate
73.51
diethyl morpholino-phosphate
8.84
diethyl 4-0xypyridino-thiophosphate
61.74
diethyl 3,4-dimethylpyridino-phosphate
0.66
diethyl chlorophosphate
-13.05
diethyl chlorothiophosphate
65.75
S13
-1
-1
-1
log kN q /s M
-1
-2
(a)
-3
-4
2
0,40; r =0,84
6
-0,8
-1,2
-1,6
-2,0
-2,4
8
10
12
(b)
2
0,51; r =0,92
6
8
10
12
pKa + log (p/q)
Figure S9. Brønsted-type plot (log k NAr vs pKa of the nucleophile) for the phenolysis (a) and
SA aminolysis (b) of 1 in 44 wt% ethanol-water, at 25.0 °C, ionic strength 0.2 M (KCl).
-2
(a)
-6
2
0,71; r =0,95
-1
-1
log kN q /s M
-1
-4
6
-2
8
10
12
(b)
-3
-4
-5
2
0,58; r =0,89
6
8
10
12
pKa + log (p/q)
FIGURE S10. Brønsted-type plots for the pyridinolysis of 1 in 44wt % ethanol-water, at
25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa of the nucleophile for attack at
the phosphoryl center. (b) Plot of log k NAr vs pKa of the nucleophile for attack at the C-1
aromatic carbon.
S14
-1 -1 -1
logNkq /s M
-1 (a)
-2
-3
-4
-1
0.8; r2=0.89
8
9
10
11
(b)
-2
0.71; r2=0.86
-3
8
9
10
pKa + log (p/q)
11
FIGURE S11. Brønsted-type plots for the SA aminolysis of 2 in 44wt % ethanol-water,
at 25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa of the nucleophile for attack at
the phosphoryl center. (b) Plot of log k NAr vs pKa of the nucleophile for attack at the C-1
aromatic carbon.
(a)
-1
-1
log kN q /s M
-1
-2
2
0,23; r =0,90
-3
-1
6
8
10
12
(b)
-2
-3
-4
2
0,48; r =0,86
6
8
10
12
pKa + log (p/q)
FIGURE S12. Brønsted-type plots for the phenolysis of 2 in 44wt % ethanol-water, at
25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa of the nucleophile for attack at
the phosphoryl center. (b) Plot of log k NAr vs pKa of the nucleophile for attack at the C-1
aromatic carbon.
S15
-1
-1
-1
log kN q /s M
-1
-2
-3

0,58; r 0
-4
6
8
10
12
-2,0
-2,5
-3,0
-3,5

0; r 08
6
8
10
12
X Axis Title
FIGURE S13. Brønsted-type plots for the pyridinolysis of 2 in 44wt % ethanol-water, at
25ºC, ionic strength 0.2 M (KCl). (a) Plot of log k NP vs pKa of the nucleophile for attack at
the phosphoryl center. (b) Plot of log k NAr vs pKa of the nucleophile for attack at the C-1
aromatic carbon.
S16
Table S2. Pseudo-first-order rate coefficients (kobsd) for the reaction between piperidine
and 1 at different pH values. a
pH=10.52
pH=10.82 pH=11.12
b
FN=0.33
FN=0.50b
FN=0.67b
103[N]tot/M c
104kobsd/s-1
104kobsd/s-1
104kobsd/s-1
3.0
0.33
2.83
7.0
5.60
6.37
11
6.13
10.1
12.2
15
8.06
13.9
19.3
19
9.80
16.6
21.1
23
13.8
20.9
25.1
30
15.1
24.1
29.8
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
Table S3. Pseudo-first-order rate coefficients (kobsd) for the reaction between piperazine
and 1 at different pH values. a
pH=9.41
pH=10.01
b
FN=0.33
FN=0.67 b
103[N]tot/M c
104 kobsd/s-1
104 kobsd/s-1
5.0
1.46
2.24
13
3.02
5.56
21
5.03
8.87
30
8.50
12.9
37
10.5
16.3
45
10.9
19.8
50
12.6
25.2
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
S17
Table S4. Pseudo-first-order rate coefficients (kobsd) for the reaction between 1-(2hydroxyethyl)piperazine and 1 at different pH values.a
pH=8.79
pH=9.09
pH=9.39
b
b
FN=0.33
FN=0.50
FN=0.67 b
103[N]tot/M c
104 kobsd /s-1
104 kobsd/s-1
104 kobsd/s-1
5.0
0.32
0.47
0.60
13
0.85
1.49
1.52
21
1.38
2.46
2.50
30
2.04
3.82
3.63
37
2.49
4.54
4.47
45
3.07
5.68
5.44
50
3.74
6.68
6.64
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
Table S5. Pseudo-first-order rate coefficients (kobsd) for the reaction between morpholine
and 1 at different pH values.a
pH=8.18
pH=8.48
pH=8.78
b
b
FN=0.33
FN=0.50
FN=0.67 b
103[N]tot/M c
104 kobsd /s-1
104 kobsd/s-1
104kobsd/s-1
8.0
0.38
0.47
20
0.97
1.24
1.51
32
1.53
1.55
2.50
45
2.21
2.72
3.55
56
2.66
3.33
4.52
68
3.23
4.21
5.46
80
4.80
6.60
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
S18
Table S6. Pseudo-first-order rate coefficients (kobsd) for the reaction between 1formylpiperazine and 1 at different pH values. a
pH=9.00
pH=9.50
b
FN=1.00
FN=1.00b
103[N]tot/M c
105 kobsd/s-1
105 kobsd/s-1
5.0
0.35
0.85
13
2.75
3.36
21
4.82
5.86
30
6.99
8.23
37
8.72
10.1
45
10.6
12.3
50
12.6
14.4
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M. bFree amine fraction. cConcentration of total amine (free base plus
protonated forms).
Table S7. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4-oxypyridine
and 1 at different pH values. a
pH=11.2
pH=11.5
pH=11.8
b
b
FN=0.33
FN=0.50
FN=0.67 b
103[N]tot/M c 104 kobsd/s-1 103[N]tot/M c 104 kobsd/s-1 103[N]tot/M c
104 kobsd/s-1
8.0
0.48
4.0
0.63
7.0
0.87
21
1.41
11
1.59
11
1.45
35
2.50
18
2.56
15
2.00
48
3.35
26
3.66
19
2.48
61
4.35
31
4.48
23
2.98
80
5.23
38
5.60
30
3.34
50
6.72
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
S19
Table S8. Pseudo-first-order rate coefficients (kobsd) for the reaction between 3,4diaminopyridine and 1 at different pH values. a
pH=9.15
pH=9.45
pH=9.75
b
b
FN=0.33
FN=0.50
FN=0.67 b
103[N]tot/M c
105 kobsd/s-1
105 kobsd/s-1
105 kobsd/s-1
5.0
0.87
13
2.39
2.79
0.11
21
4.08
4.98
4.37
30
5.92
7.61
7.00
37
7.22
10.2
9.53
45
8.73
12.6
12.3
50
10.5
14.3
15.1
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
Table S9. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4dimethylaminopyridine and 1 at different pH values. a
pH=8.84
pH=9.14
pH=9.44
b
b
FN=0.33
FN=0.50
FN=0.67 b
102[N]tot/M c
104 kobsd/s-1
104 kobsd/s-1 104 kobsd/s-1
2.50
0.43
0.64
6.50
6.50
1.15
1.76
10.5
10.5
1.87
2.93
15.0
15.0
2.84
4.24
18.5
18.5
3.58
5.11
22.5
22.5
4.28
6.06
27.0
27.0
5.18
7.16
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
S20
Table S10. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4aminopyridine and 1 at different pH values. a
pH=8.68
pH=8.98
pH=9.28
b
b
FN=0.33
FN=0.50
FN=0.67 b
102[N]tot/M c
105 kobsd/s-1
105 kobsd/s-1
105kobsd/s-1
1.3
0.08
1.05
1.3
3.3
2.75
5.17
3.3
5.3
4.56
8.34
5.3
7.5
6.60
1.26
7.5
9.3
8.72
15.5
9.3
11.3
9.98
18.8
11.3
13
12.1
22.8
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. b Free amine
fraction. cConcentration of total amine (free base plus protonated forms).
Table S11. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4-amino-3bromopyridine and 1 at different pH values. a
pH=9.00
pH=9.50
b
FN=1.00
FN=1.00b
102[N]tot/M c
106 kobsd/s-1
106 kobsd/s-1
1.3
1.39
1.83
2.1
2.22
3.22
3.0
3.25
4.38
3.7
4.23
5.43
4.5
6.47
5.0
7.75
5.3
6.35
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M. bFree amine fraction. cConcentration of total amine (free base plus
protonated forms).
S21
Table S12. Pseudo-first-order rate coefficients (kobsd) for the reaction between 3,4dimethylpyridine and 1 at different pH values. a
pH=9.00
pH=9.50
b
FN=1.00
FN=1.00b
102[N]tot/M c
106kobsd/s-1
106kobsd/s-1
13
0.02
1.08
21
0.29
1.51
30
0.89
2.28
37
1.13
2.86
45
1.80
3.81
53
1.94
4.17
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M. bFree amine fraction. cConcentration of total amine (free base plus
protonated forms).
Table S13. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4metoxyphenol and 1 at different pH values. a
pH=11.25
pH=11.55 pH=11.85
b
FN=0.33
FN=0.50 b
FN=0.67 b
103[N]tot/M c
105kobsd/s-1
105kobsd/s-1
1.98
4.27
3.96
6.30
5.94
8.80
7.92
11.9
9.90
11.9
16.4
13.9
18.3
15.8
20.7
17.8
23.4
19.8
26.6
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and
fraction of free base (phenoxide). cConcentration of
acid).
S22
105kobsd/s-1
3.91
8.27
6.62
12.3
9.89
16.8
14.3
22.9
17.9
29.4
20.0
32.4
25.0
37.3
28.9
41.7
32.0
46.4
35.0
51.6
an ionic strength of 0.2 M. bMolar
total phenol (phenoxide + conjugate
Table S14. Pseudo-first-order rate coefficients (kobsd) for the reaction between phenol and 1
at different pH values. a
pH=10.86
pH=11.16 pH=11.46
b
FN=0.33
FN=0.50 b
FN=0.67 b
102[N]tot/M c
104kobsd/s-1
104kobsd/s-1
4.95
1.11
9.90
1.86
14.9
2.52
19.8
2.89
24.8
3.45
29.7
3.76
34.7
4.60
39.6
5.16
44.6
5.86
49.5
6.60
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and
fraction of free base (phenoxide). cConcentration of
acid).
104kobsd/s-1
3.02
3.33
4.10
4.70
5.50
6.45
6.43
7.55
6.71
9.43
7.75
9.91
8.42
11.3
9.47
12.1
10.0
12.5
11.0
14.0
an ionic strength of 0.2 M. bMolar
total phenol (phenoxide + conjugate
Table S15. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4chlorophenol and 1 at different pH values. a
pH=10.47 pH=10.77
FN=0.50 b
FN=0.67 b
103[N]tot/M c
105kobsd/s-1
105kobsd/s-1
14.9
1.99
19.8
1.70
24.8
1.95
2.70
29.7
2.26
3.35
34.7
2.53
3.69
39.6
2.97
3.98
44.6
3.21
4.52
49.5
3.48
4.82
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
S23
Table S16. Pseudo-first-order rate coefficients (kobsd) for the reaction between 3cyanophenol and 1 at different pH values. a
pH=9.23
pH=9.53
b
FN=0.50
FN=0.67 b
103[N]tot/M c
105kobsd/s-1
105kobsd/s-1
9.90
0.99
0.95
19.8
1.37
1.55
39.6
2.47
2.94
59.4
3.25
4.16
69.3
3.71
4.65
79.2
4.21
5.29
99.0
5.07
6.54
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
Table S17. Pseudo-first-order rate coefficients (kobsd) for the reaction between 2,6difluorophenol and 1 at different pH values. a
pH=8.21
pH=8.51
b
FN=0.50
FN=0.67b
103[N]tot/M c
105kobsd/s-1
105kobsd/s-1
9.90
0.09
19.8
0.51
0.51
29.7
0.93
39.6
1.02
1.34
59.4
1.80
2.12
69.3
2.06
79.2
2.43
99.0
3.15
3.67
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
S24
Table 18. Pseudo-first-order rate coefficients (kobsd) for the reaction between 2,3,4,5,6pentafluorophenol and 1 at different pH values. a
pH=5.45
pH=5.75
b
FN=0.50
FN=0.67 b
103[N]tot/M c
107kobsd/s-1
107kobsd/s-1
9.90
0.41
19.8
3.86
2.21
39.6
5.78
8.24
49.5
6.37
69.3
7.95
16.1
89.1
10.2
21.0
99.0
11.5
a
In 44 wt% ethanol-water, at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
Table S19. Pseudo-first-order rate coefficients (kobsd) for the reaction between piperidine
and 2 at different pH values.a
103 kobsd /s-1
1
pH = 10.52
pH = 10.82
pH = 11.12
102[N]tot / M c
b
b
FN = 0.33
FN = 0.50
FN = 0.67b
1.19
1.86
2.03
0.700
1.50
2.12
3.89
4.74
2.20
3.03
5.07
6.54
3.00
4.13
6.83
9.90
3.70
4.81
8.29
11.4
4.80
5.52
9.24
15.4
6.00
7.34
13.1
17.5
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S25
Table S20. Pseudo-first-order rate coefficients (kobsd) for the reaction between piperazine
and 2 at different pH values.a
103 kobsd /s-1
1
pH = 9.41
pH = 9.71
pH = 10.01
102[N]tot / M c
FN = 0.33b
FN = 0.50b
FN = 0.67b
0.468
0.924
0.800
1.50
0.874
1.07
2.20
1.45
2.30
2.40
2.28
1.54
2.90
2.37
3.00
3.10
3.02
1.85
3.70
2.90
3.80
3.90
3.41
2.08
4.70
4.42
4.80
5.00
4.26
2.81
5.90
5.49
6.00
6.30
1.46
4.85
3.60
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S26
Table S21. Pseudo-first-order rate coefficients (kobsd) for the reaction between 1-(2hydroxyethyl)piperazine and 2 at different pH values.a
1 103 kobsd /s-1
pH = 9.10
pH = 9.40
102[N]tot / M c
FN = 0.50b
FN =0.67b
0.283
1.60
3.20
0.320
0.473
3.80
0.498
0.642
4.70
1.00
6.30
1.10
1.12
7.90
1.23
1.60
9.50
1.71
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
Table S22. Pseudo-first-order rate coefficients (kobsd) for the reaction between morpholine
and 2 at different pH values.a
1 103 kobsd /s-1
pH = 8.18
pH = 8.48
102[N]tot / M c
b
FN = 0.33
FN =0.50b
0.535
0.656
4.00
8.10
0.845
9.70
1.18
1.40
12.1
1.32
1.67
16.2
1.69
2.28
20.2
1.98
3.15
24.2
2.36
3.63
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S27
Table S23. Pseudo-first-order rate coefficients (kobsd) for the reaction between 1formylpiperazine and 2 at different pH values.a
1 104 kobsd /s-1
pH = 9.00
pH = 9.50
102[N]tot / M c
FN = 0.96b
FN =0.99b
0.765
4.70
5.70
0.694
7.60
1.15
9.10
1.30
9.50
1.21
11.3
14.2
1.50
1.73
15.1
2.02
18.9
2.50
19.0
2.25
22.7
23.7
2.77
2.77
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M bFree amine fraction. cConcentration of total amine (free and
protonated forms).
S28
Table S24. Pseudo-first-order rate coefficients (kobsd) for the reaction between piperazinium
ion and 2 at different pH values.a
106 1kobsd /s-1
pH = 5.40
102[N]tot / M c
FN = 0.52b
6.60
9.90
19.9
7.17
23.9
8.92
29.8
9.94
39.8
10.8
49.7
14.0
59.7
15.2
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S29
Table S25. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4oxypyridine and 2 at different pH values.a
103 kobsd /s-1
1
pH = 11.3
pH = 11.8
102[N]tot / M c
b
FN = 0.33
FN =0.67b
2.28
2.10
2.60
2.34
2.90
5.16
3.00
2.58
3.40
2.95
4.00
4.30
5.75
3.36
4.60
5.10
7.89
4.46
5.80
9.08
6.90
11.9
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S30
Table S26. Pseudo-first-order rate coefficients (kobsd) for the reaction between 3.4diaminopyridine and 2 at different pH values.a
103 kobsd /s-1
1
pH = 9.45
pH = 9.75
102[N]tot / M c
b
FN = 0.50
FN =0.67b
0.317
0.375
1.80
2.80
1.10
0.690
3.70
1.22
0.960
4.60
1.18
7.40
1.99
2.45
9.20
2.23
2.89
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S31
Table S27. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4(dimethylamino)pyridine and 2 at different pH values.a
103 kobsd /s-1
1
pH = 9.14
pH = 9.44
102[N]tot / M c
b
FN = 0.50
FN =0.67b
1.89
5.00
7.50
2.06
10.0
10.1
2.94
2.50
12.5
12.6
3.82
3.44
16.0
16.1
4.79
4.70
20.0
20.1
6.90
5.68
25.0
25.2
2.17
9.13
6.85
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S32
Table S28. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4aminopyridine and 2 at different pH values.a
1 103 kobsd /s-1
2
c
10 [N]tot / M
pH = 8.68
pH = 8.98
pH = 9.28
b
b
FN = 0.33
FN = 0.50
FN = 1.00b
6.10
1.49
6.20
0.651
6.30
1.14
9.20
9.40
2.41
1.12
1.76
12.3
12.5
3.31
1.21
2.41
15.3
15.6
3.95
1.79
15.7
2.80
19.6
20.0
5.06
2.22
20.1
2.99
24.5
6.44
25.1
3.95
30.6
31.2
7.87
3.63
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bFree amine
fraction. cConcentration of total amine (free and protonated forms).
S33
Table S29. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4-amine-3bromopyridine and 2 at different pH values.a
104 kobsd /s-1
1
pH = 9.50
2
c
10 [N]tot / M
FN = 1.00b
0.546
3.50
4.60
0.641
5.80
0.779
6.90
0.969
9.20
1.23
11.6
1.52
13.9
1.79
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M bFree amine fraction. cConcentration of total amine (free and
protonated forms).
Table S30. Pseudo-first-order rate coefficients (kobsd) for the reaction between 3.4dimethylpyridine and 2 at different pH values.a
104 kobsd /s-1
1
pH = 7.50
pH = 8.00
101[N]tot / M c
b
FN = 0.99
FN =1.00b
0.915
1.34
1.78
1.36
2.23
1.75
2.68
2.12
1.29
3.57
2.33
1.89
4.46
2.59
1.92
5.35
2.69
2.12
a
0.834
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. in the presence
of borate buffer 0.05M bFree amine fraction. cConcentration of total amine (free and
protonated forms).
S34
Table S31. Pseudo-first-order rate coefficients (kobsd) for the reaction between
4-metoxyphenol and 2 at different pH values.a
pH=11.25
pH=11.55
FN=0.33b
FN=0.50b
103[N]tot/M c
103kobsd/s-1
103[N]tot/M c
103kobsd/s-1
30.0
1.76
25.6
2.09
50.0
2.45
51.2
4.31
100
4.16
102
5.86
150
6.17
128
6.20
160
6.99
153
7.51
164
8.32
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
Table S32. Pseudo-first-order rate coefficients (kobsd) for the reaction between phenol and 2
at different pH values. a
3
-1
1 10 kobsd /s
pH = 11.16
pH = 11.46
103[N]tot / M c
b
FN = 0.50
FN =0.66b
1.23
1.20
22.0
44.0
1.96
89.0
3.11
111
3.61
6.03
133
4.33
6.52
142
4.52
177
4.99
a
2.50
9.87
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
S35
Table S33. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4chlorophenol and 2 at different pH values. a
103kobsd /s-1
1
pH = 10.17
pH = 10.47
pH = 10.77
103[N]tot/ M c
b
b
FN = 0.33
FN = 0.50
FN = 0.66b
0.387
1.09
0.939
30.0
50.0
0.528
1.44
1.60
100
1.17
2.04
2.99
130
1.96
2.29
3.31
150
2.28
2.79
3.28
160
2.18
2.39
3.70
200
4.82
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
Table S34. Pseudo-first-order rate coefficients (kobsd) for the reaction between 4cyanophenol and 2 at different pH values. a
pH=8.12
pH=8.42
pH=8.72
b
b
FN=0.33
FN=0.5
FN=0.66b
3
c
4
-1
3
c
4
-1
3
10 [N]tot/M
10 kobsd/s
10 [N]tot/M
10 kobsd/s
10 [N]tot/M c
104kobsd/s-1
30.0
0.444
30.0
1.52
30.0
1.12
50.0
1.16
50.0
3.26
50.0
3.30
126
3.92
100
4.95
70.0
6.70
150
5.05
130
5.69
200
11.5
160
5.23
150
6.45
200
5.55
170
6.80
200
7.78
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M. bMolar
fraction of free base (phenoxide). cConcentration of total phenol (phenoxide + conjugate
acid).
S36
Table S35. Pseudo-first-order rate coefficients (kobsd) for the reaction between 2.6difluorophenol and 2 at different pH values. a
4
-1
1 10 kobsd /s
pH = 9.00
pH = 9.50
pH = 10.0
103[N]tot/ M c
b
b
FN = 0.757
FN = 0.837
FN = 0.895b
1.88
2.16
2.43
26.0
51.0
3.97
3.44
3.95
102
6.53
6.05
5.19
127
7.56
6.91
5.39
153
8.66
7.35
6.47
163
8.71
8.15
6.84
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M. bMolar fraction of free base (phenoxide). cConcentration of total
phenol (phenoxide + conjugate acid).
Table S36. Pseudo-first-order rate coefficients (kobsd) for the reaction between 2.3.4.5.6pentafluorophenol and 2 at different pH values. a
4
-1
1 10 kobsd /s
pH = 9.00
pH = 9.50
103[N]tot / M c
FN = 0.958b
FN =0.974b
25.1
0.500
0.630
50.3
0.837
1.24
126
2.44
1.95
151
2.38
2.65
161
2.49
a
In 44 wt% ethanol-water. at 25.0 ± 0.1° C and an ionic strength of 0.2 M, in the presence
of borate buffer 0.05M. bMolar fraction of free base (phenoxide). cConcentration of total
phenol (phenoxide + conjugate acid).
S37
2500
1.411
4.321
7.864
7.885
8.464
8.493
8.816
(A)
2000
NO 2
O
1500
O
P
O Et
O Et
O 2N
1000
15.0
10.0
0
6.00
-0.00
3.78
0.92
0.88
0.98
500
5.0
0.0
ppm (f1)
16.359
16.425
66.444
66.509
122.040
123.770
129.241
141.283
143.996
148.589
(B)
1500
NO2
O
O
1000
P
OEt
OEt
O2N
500
0
200
150
100
50
0
ppm (f1)
Figure S14: (A) 1H NMR spectrum of 2 and (B) 13C NMR spectrum of 2.
S38
5000
1.409
4.309
7.708
7.734
8.464
8.480
8.825
(A)
4000
NO 2
3000
O
S
P
OEt
OEt
2000
O2N
1000
15.0
10.0
5.80
3.85
0.69
0.67
0.82
0
5.0
0.0
ppm (f1)
3000
16.215
16.290
66.678
66.741
122.033
125.000
128.911
142.144
144.247
148.573
(B)
2500
NO2
2000
O
S
P
OEt
OEt
1500
O2N
1000
500
0
-500
200
150
100
50
0
ppm (f1)
Figure S15: (A) 1H NMR spectrum of 1 and (B) 13C NMR spectrum of 1.
S39
Scheme S1:
 X
EtO
X
EtO
P
ODNP

EtO
ODNP +
 -
P
+
X
Nu
Nu
EtO
OEt
P
Nu+
+
DNPO-
OEt
Nu: SA amines,pyridines
X: O; S
(a) Concerted mechanism for the SA aminolysis and pyridinolysis of the substrates
 X
EtO
X
EtO
P
EtO
ODNP +
 -
P
OAr

-
O
ODNP
ArO-
EtO
OEt
P
OEt
Nu: phenols
X: O; S
(b) Concerted mechanism for the phenolysis of the substrates
S40
OAr
+
DNPO-
Scheme S2:
EtO
S
P
EtO
R
O
+ HN
NO2
R
R´
k2
+ NH
(EtO)2PO
k-1
R´
R
S
k1
+ NH
-
NO2
R´
S
NO2
(EtO)2PONO2
NO2
NO2
(MC)
-H+
R
N
R´
NO2
NO2
(a) SNAr process leads to the formation of the Meisenheimer complex (MC) for the SA
aminolysis of substrate 1
EtO
P
X
R
O
N
X
k1
+
NO2
R
R
EtO
k-1
k2
(EtO)2PO
N
N
+
NO2
-
X
+
NO2
(EtO)2PONO2
NO2
NO2
(MC)
X: O; S
(b) SNAr process leads to the formation of the Meisenheimer complex (MC) for the
pyridinolysis of substrates 1 and 2
S41
EtO
P
S
EtO
S
k1
O
+
NO2
ArOk-1
(EtO)2PO
k2
OAr
NO2
-
OAr
S
NO2
(EtO)2PONO2
NO2
NO2
(MC)
(c) SNAr process leads to the formation of the Meisenheimer complex (MC) for the
phenolysis of substrate 1
S42