Structure and Reactivity of Indolylmethylium Ions: Scope and Limitations in Synthetic Applications

Article abstract of DOI:10.1021/acs.joc.5b01298

Eight substituted aryl(indol-3-yl)methylium tetrafluoroborates 3(a-h)-BF₄ and three bis(indol-3-yl)methylium tetrafluoroborates 3(i-k)-BF₄ have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their reactions with π-nucleophiles 8(a-j) (silylated enol ethers and ketene acetals) were studied kinetically using photometric monitoring at 20 °C. The resulting second-order rate constants were found to follow the correlation log k(20 °C) = s_N(N + E), in which nucleophiles are characterized by the two solvent-dependent parameters N and s_N, and electrophiles are characterized by one parameter, E. From the previously reported N and s_N parameters of the employed nucleophiles and the measured rate constants, the electrophilicities of the indol-3-ylmethylium ions 3(a-k) were derived and used to predict potential nucleophilic reaction partners. A discrepancy between published rate constants for the reactions of morpholine and piperidine with the (2-methylindol-3-yl)phenylmethylium ion 3h and those calculated from E, N, and s_N was analyzed and demonstrated to be due to a mistake of the value reported in the literature.

Full text of DOI:10.1021/acs.joc.5b01298

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Structure and Reactivity of Indolylmethylium Ions: Scope and
Limitations in Synthetic Applications
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Elsa Follet, Guillaume Berionni, Peter Mayer, and Herbert Mayr*
Department Chemie,
Ludwig-Maximilians-Universität München,
Butenandtstrasse 5–13, Haus F, 81377 München (Germany).
Fax: (+49) 089 2180 77717
Phone: (+49) 089 2180 77719
E-mail: herbert.mayr@cup.uni-muenchen.de
ABSTRACT
Eight substituted aryl(indol-3-yl)methylium

- and N-
Nu-
nucleophiles
tetrafluoroborates 3(a-h)-BF
bis(indol-3-yl)methylium tetrafluoroborates 3(i-
k)-BF have been synthesized and
characterized by NMR spectroscopy and X-ray
4
and three
Ar
Nu
N
Ar
kinetics
CH Cl ,
2
2
4
N
CH CN
3
crystallography. Their reactions with -nucleophiles 8(a-j) (silylated enol ethers, and
ketene acetals) were studied kinetically using photometric monitoring at 20 C. The
resulting second-order rate constants were found to follow the correlation log k (20 C) =
N
s (N + E), in which nucleophiles are characterized by the two solvent-dependent
parameters N and s , and electrophiles are characterized by one parameter, E. From
N
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the previously reported N and s parameters of the employed nucleophiles, and the
N
measured rate constants, the electrophilicities of the indol-3-ylmethylium ions 3(a-k)
were derived and used to predict potential nucleophilic reaction partners. A discrepancy
between published rate constants for the reactions of morpholine and piperidine with the
0
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0
1
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0
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0
1
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9
0
1
2
3
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9
0
N
(2-methylindol-3-yl)phenylmethylium ion 3h and that calculated from E, N and s was
analyzed and demonstrated to be due to a mistake of the value reported in the literature.
INTRODUCTION
Indolyl-substituted carbenium ions have recently been employed as prochiral
1
2,3a
intermediates in asymmetric Diels-Alder reactions, Friedel-Crafts reactions,
additions
3
4
to aliphatic -systems, -alkylations of aldehydes and other CH acidic compounds,
5
6
hydrogenation reactions, and other asymmetric syntheses. They are commonly
generated by treatment of readily available precursors with Brønsted or Lewis acids
(Scheme 1), and subsequently trapped by hydride donors, organometallic reagents, and
1
-6
other nucleophiles to give a wide variety of functionalized indole derivatives.
Scheme 1. In situ Generation and Trapping of Aryl(indol-3-yl)methylium Ions with
Nucleophiles
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While some electron-donor substituted aryl(indol-3-yl)methylium ions (Scheme 1, R =
7
Ar) have previously been characterized in solution and in the solid-state and have been
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c-g
used as dyes,
quantitative information about their electrophilic reactivity is rare. Apart
8
a-c
from investigations of their Lewis acidities (pKR+),
we are aware of only one kinetic
8d
investigation of their reactions with amines and hydride nucleophiles.
In order to evaluate the scope and limitations of their reactions with nucleophiles we
have now quantified the electrophilicities of aryl(indol-3-yl)methylium ions using a
method analogous to that which we have used previously for quantifying the
electrophilicity of a large number of iminium and carbenium ions. These results have
9a-f,10
then been integrated into a comprehensive electrophilicity scale.
RESULTS AND DISCUSSION
Synthesis of Aryl(indol-3-yl)methylium Ions. Substituted aryl(indol-3-yl)methylium
tetrafluoroborates 3(a-e)-BF were obtained in good yields in a one-pot procedure by
4
adding 1.5 equivalent of HBF ·OEt to 1:1-mixtures of N-methylindole 1a and one of the
4
2
benzaldehydes 2a-e in CH
Cl
2 2
solution (Table 1). An optimization of these reaction
conditions has recently been reported and used to synthetise a large variety of
7b
diarylmethylium tetrafluoroborates, including several indolyl-substituted systems. The
6
c
mechanism of the formation of 3 has been reported previously. Whereas the less
stabilized aryl(indol-3-yl)methylium tetrafluoroborates 3(a-c)-BF decomposed within few
4
hours at ambient temperature, 3(d-e)-BF did not change when stored in ordinary
4
atmosphere for a year.
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Table 1. Syntheses, Structures, Yields, Visible-Absorption Maxima max, and Molar
Absorbances ε of the Aryl(N-methylindol-3-yl)methylium Tetrafluoroborates 3(a-e)-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
3
4
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7
8
9
0
BF
4
R
1
6
17
R15
CHO
R
11
10
4
7
14
13
3
–
5
6
4
7
3
BF
4
.
9
8
Z
E
HBF OEt
2
5
6
12
2
4
+
–
2
BF
4
N 1
CH Cl , 0 °C
2
5
2
N 1
min
N
1
a
2a R = H
2b R = Me
2c R = OMe
2d R = NMe2
2e R = Jul
R
R
BF4–
Jul =
N
BF4–
N
N
R = H Me OMe NMe2 Jul
a 3b 3c 3d 3e
3
-
1

max
 (L mol
2 2
Z:E ratio in CD Cl
Indolylmethylium Isolated
-1
R
Aldehyde
(nm) in
CH Cl
cm ) in
CH Cl
a
b
ions
yields (%)
exp.
calcd.
2
2
2
2
4
4
4
4
4
c
c
c
H
2a
2b
2c
2d
2e
3a
36
79
60
57
68
425
431
492
580
589
2.34 × 10
2.81 × 10
2.84 × 10
8.88 × 10
9.22 × 10
75:25
77:23
78:22
73:27
82:18
88:12
97:3
Me
3b
3c
OMe
NMe
2
3d
3e
> 99:1
Jul
> 99:1 99.8:0.2
a
1
b
Determined by H NMR at 27 C. Calculated at the B3LYP/6-31G(d) DFT level in CH
2
Cl
2
for
c
the tetrafluoroborate salts see details in the Supporting Information. The Z/E ratio in CD
for 3a: 83/17, for 3b: 85/15, and for 3c: 87/13.
3
CN was
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Most known aryl(indol-3-yl)methylium ions are substituted at C2; because of the steric
repulsion between the C2 substituent and the aryl ring, they generally adopted the (E)-
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a-b,d-e
configuration as revealed by NMR spectroscopy and X-ray crystallography.
In
contrast, the carbenium ions 3a-c, which are unsubstituted at C2, give a ≈ 3:1 (Z:E)
diastereomeric mixture in CD Cl and a ≈ 5:1 mixture in CD CN at 27 C. The
2
2
3
predominant (Z)-configuration of 3c was derived from a NOE effect observed between 2-
H and 12-H and 17-H (Table 1). The (Z):(E) ratio of 3c is almost independent of
temperature. Between +27 C and -80 C in CD
78:22 to 86:14 and between +27 C to+60 C in CD
7:13 to 83:17 (see SI S39-41).
DFT calculations of the tetrafluoroborate salts showed that the (Z)-isomers have smaller
2
Cl
2
, the (Z):(E) ratio changes from
3
CN, the (Z):(E) ratio changes from
8
-
1
dipole moments than the (E)-isomers, and are more stable by several kJ mol (see SI
S33). As the (Z):(E) ratio increases with increasing electron-donating substituents in the
1
phenyl ring (Table 1), only the (Z)-isomers of 3d-e were observed by H NMR in CD
2
Cl
2
.
The (Z)-isomers crystallized preferentially as shown by the X-ray structures of the
1
1
aryl(indol-3-yl)methylium ions 3b, 3c, and 3e (Figure 1).
3c
3b
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0
3
e
Figure 1. ORTEP drawings (50% probability ellipsoids) of the (Z)-aryl(indol-3-
yl)methylium tetrafluoroborates 3b-BF , 3c-BF , 3e-BF . Selected interatomic distances
Å) and angles () for 3b: N1–C2 = 1.311(3), C2–C3 = 1.432(3), C3-C10 = 1.365(3),
C10–C11 = 1.439(3) and N1–C2–C3 = 110.0(2), C2–C3–C10 = 130.7(2), C3–C10–C11
133.2(2), C2–C3–C10–C11 = 2.9(4), C3–C10–C11–C12 = 5.7(3). For 3c: N1-C2 =
.319(3), C2-C3 = 1.430(3), C3-C10 = 1.373(3), C10-C11 = 1.430(3), N1-C2-C3 =
110.19(18), C2-C3-C10 = 130.64(19), C3-C10-C11 = 132.8(2), C2–C3–C10–C11 = -
.1(4), C3–C10–C11–C12 = -6.2(4). For 3e: N1-C2 = 1.339(3), C2-C3 = 1.408(3), C3-
C10 = 1.395(3), C10-C11 = 1.404(3), N1-C2-C3 = 110.53(17), C2-C3-C10 = 130.58(18),
4
4
4
(
=
1
3
1
1
C3-C10-C11 = 132.77(19), C2–C3–C10–C11 = 1.0(4), C3–C10–C11–C17 = -179.7(2).
According to the X-ray structures shown in Figure 1, the molecules are almost planar,
with dihedral angles between the aryl ring and the indole ring of less than 10 degrees.
The considerably shorter bond length C3-C10 (1.37 Å) compared to C10-C11 (1.43 -
1
.44 Å) shows that the positive charge is more stabilized by the indole ring than the aryl
ring in the case of 3b and 3c, as represented by the upper resonance structures in Table
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. However, in the case of the -Jul substituted indolylmethylium ion 3e, the increasing
stabilizing effect of the anilino ring is indicated by the similar C3-C10 and C10-C11 bond
lengths (1.400 ± 0.005 Å) (Figure 1c). As a consequence of the increased double-bond
character between C10 and C11, the rotation around this bond is restricted, as revealed
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1
by a distinct resonances for the 12-H and 17-H signals in the 400 MHz H NMR spectra
below -20 C (3d) and +25 C (3e) (see Supporting Information pp S40 and S43).
1
Analogous dynamic effects were not observed in the H NMR spectra of 3a-c and there
was no evidence for the interconversion of the (Z)- and (E)-isomers on the NMR time
scale.
7a-b
In agreement with a recently published X-ray structure by Barbero et al.,
and
7b
subsequent NMR investigations of related compounds, the aryl(indol-3-yl)methylium
ions 3f-h with a methyl group at C2 of the indole ring were formed exclusively as the (E)-
isomers (Table 2) from the 2-methyl substituted indoles 1b-c. DFT calculations showed
that even in case of the julolidyl substituted analogue (2-methyl derivative of 3e) the (E)-
-1
isomer is more stable than the (Z)-isomer by 18.7 kJ mol , i.e. the steric repulsion by the
2-methyl group is so large that now the isomer with the larger dipole moment is
preferred.
Table 2. Syntheses, Structures, Yields, Visible-Absorption Maxima max and Molar
Absorbances ε of the Aryl(indol-3-yl)methylium Tetrafluoroborates 3(f-h)-BF
4
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2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
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5
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5
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0
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9
0
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0
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9
0
-1
-1
1
Indolylmethylium Isolated

max (nm)
 (L mol cm )
R
Indole
R
Aldehyde
ions
yields (%) in CH Cl
in CH Cl
2
2
2
2
4
H
1b
Me
2b
3f
71
88
84
417
425
405
2.15 × 10
2.28 × 10
-
4
Me
Me
1c
1c
Me
H
2b
2a
3g
3h
4
The bis(indol-3-yl)methylium tetrafluoroborates 3(i-k)-BF were synthesized from the
1
2
indoles 1 and triethyl orthoformate 4 following the procedure of Pindur et al. as shown
in Table 3.
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Table 3. Syntheses, Structures, Yields, Visible-Absorption Maxima max and Molar
Absorbances  of the Symmetrical Bis(indol-3-yl)methylium Tetrafluoroborates 3(i-
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k)-BF
4
R2
N
(
EtO) CH 4
R2
3
.
R2
HBF OEt
R1
4
2
10
E, E 10
N
or
N
0 to 20 °C
2 h, CH Cl
Z, Z
2
2
2
2
N
–
N
BF4
BF4–
1
a, c, d
3 i, j
3k
-
1
-1
1
2
Indolylmethylium
ions
Isolated

max (nm)
 (L mol cm )
R
R
Indole
yields (%) in CH Cl
in CH Cl
2
2
2
2
a
4a
H
H
H
1a
1d
1c
3i
86
69
74
540
4.87 × 10
a
4a
OMe
H
3j
540
2.39 × 10
5.33 × 10
4
Me
3k
497
a
3
5% (v/v) of CH CN was added for full solubilization of 3i and 3j.
The X-ray structures of the bis(indol-3-yl)methylium ions 3i and 3k depicted in Figure 2
illustrate that a methyl group at C2 of the indole rings induces a change of configuration.
Whereas the 2-unsubstituted indole-derivative 3i is almost planar with a twist angle of
7.21° between the two indole planes and adopts the (Z,Z)-configuration, the bis-
methylated derivative 3k adopts the (E,E)-configuration and has an indole-indole twist
angle of 42.57°.
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9
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i
3k
Figure 2. ORTEP drawing (50% probability ellipsoids) of the bis(indol-3-yl)methylium
11
tetrafluoroborates 3i-BF
4
and 3k-BF
4
.
Selected interatomic distances (Å) and angles
(
) for 3i: N1-C2 = 1.329(2), C2-C3 = 1.410(2), C3-C10 = 1.391(2), C10-C11 = 1.392(2),
N1-C2-C3 = 110.39(13), C2-C3-C10 = 130.09(14), C3-C10-C11 = 131.49(14), C2–C3–
C10–C11 = 2.6(3), C3–C10–C11–C12 = 2.1(3). For 3k: N1-C2 = 1.343(2), C2-C3 =
1
.425(2), C3-C10 = 1.397(2), C10-C11 = 1.394(2), N1-C2-C3 = 109.02(14), C2-C3-C10
= 121.82(15), C3-C10-C11 = 130.37(14), C2–C3–C10–C11 = -162.78(16), C3–C10–
C11–C12 = -160.44(16).
We also attempted to synthesize the indol-2-yl(p-methoxyphenyl)methylium ion 3l from
the alcohol 5, as shown in Scheme 2. Dropwise addition of HBF
4 2
·OEt to a solution of
the p-anisyl(indol-2-yl)methanol 5 in CH Cl at 0 C produced a deep violet solution,
2
2
attributed to 3l, which faded spontaneously. After 5 min the pentacyclic compound 6
precipitated as a colorless solid. The inverse addition of a CH Cl solution of 5 to an
2
2
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equimolar amount of HBF ·OEt dissolved in CH Cl also produced a transient violet
4
2
2
2
species which yielded 6, and we did not succeed to isolate 3l.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Only one diastereoisomer of 6 was formed and we were not able to assign its
configuration. The acid-catalyzed cyclization of aryl(indol-2-yl)methanols has been
13
previously reported by Santoso et al.
to give pentacyclic dihydro-indolo[3,2-
b]carbazoles analogous to 6 with cis configuration (X-ray analysis). We, therefore,
assume that the phenyl groups in product 6 also are in cis configuration.
Scheme 2. Attempted Synthesis of the p-Anisyl(indol-2-yl)methylium
Tetrafluoroborate 3l-BF
4
and Formation of the Dihydro-indolo[3,2-b]carbazole 6
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
Product Studies. For the quantification of the electrophilic reactivities of
indolylmethylium ions 3a-k we have studied their reactions with representative -
nucleophiles of known nucleophilicity (Table 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. -Nucleophiles 8 Employed as Reference Compounds for the
Determination of the Electrophilicity of the indolylmethylium Ions 3a-k
a
Nu
Structure
N (s
N
) in CH
2
Cl
2
OSiMe3
8
a
b
12.56 (0.70)
0.61 (0.86)
O
O
1
OSiMe
3
8
b
10.52 (0.78)
OSiMe3
9.00 (0.98)
8
c
d
b
9.11 (0.88)
OMe
8
8.57 (0.84)
8e
7.48 (0.89)
7.22 (1.00)
SnBu3
OSiMe3
8f
O
8
g
h
OSiMe3
6.57 (0.93)
5.21 (1.00)
8
OSiMe3
OSiMe3
SiMe3
8
i
4.60 (0.90)
4.41 (0.96)
1.68 (1.00)
8
j
8
k
SiMe
3
a
Nucleophilicity parameters N and nucleophile-specific sensitivity
b
parameters s
N
for 8a-k from ref. 9f. In CH
3
CN.
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As depicted in Scheme 3 for a series of representative combinations of aryl(indol-3-
yl)methylium ions 3 with -nucleophiles 8, all reactions occurred regioselectively at the
10 position of 3, but were not diastereoselective when prochiral -nucleophiles 8b,h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14
were used. Reactions of aryl(indol-3-yl)methylium ions 3 with electron-rich dienes,
such as Danishefsky´s diene 8d and 1-(trimethylsiloxy)buta-1,3-diene 8i, yielded the

,-unsaturated compounds 11 and 12, respectively.
Scheme 3. Reactions of Representative -Nucleophiles 8 with Aryl(indol-3-yl)-
methylium Tetrafluoroborates 3-BF (in CH Cl at 20 C)
4
2
2
OSiMe3
O
1
0
SiMe3
8j
8h
10 min
in CH CN
3
N
N
1
h
9
87% from 3b
10 61% from 3a dr = 1:1
O
MeO
R
O
OSiMe3
10
NMe2
OMe
MeO
OSiMe3
R2
BF4–
8d
8i
N
overnight
1 h
N
N
3a R = H, R = H
2
12 40% from 3c
11 56% from 3d
3b R = Me, R = H
2
3c R = OMe, R = H
OSiMe3
O
2
3d R = NMe , R = H
O
O
2
2
3
g R = Me, R = Me
2
SiMe3
8k
8b
1 h
15 min
N
N
1
3 57% from 3a
14 95% from 3g dr = 1:1
The reactions of -nucleophiles with the bis(indol-3-yl)methylium ions 3i,k sometimes
12
followed a different pattern, as shown for the silyl enol ethers 8a-c (Scheme 4).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Reactions of Bis(indol-3-yl)methylium Ions 3i,k with Silyl Enol Ethers
8a-c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Whereas the reaction of the bis(indol-3-yl)methylium ion 3i with the ketene acetal 8c
gave the expected product 15 in high yield, the reactions of 3i,k with the cyclic ketene
acetals 8a-b gave a mixture of the analogously formed products (16-19)a, accompanied
by the alkylidene lactones (16-19)b and the indoles 1a,c. Single crystals of 19b were
obtained, and the X-ray diffraction analysis confirmed its (E)-configuration in the solid-
1
1
state with a dihedral angle C3–C10–C11–C12 of 178.8° (Figure 3).
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10
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19
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43
44
45
46
47
48
49
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52
53
54
55
56
57
58
59
60
1
1
Figure 3. ORTEP drawing (50% probability ellipsoids) of the alkylidene lactone 19b.
Selected interatomic distances (Å) and angles (°): N1-C2 = 1.375(2), C2-C3 = 1.383(2),
C3-C10 = 1.452(2), C10-C11 = 1.347(2), C11-C12 = 1.488(2), C12-O2 = 1.209(2), N1-
C2-C3 = 109.64(13), C2-C3-C10 = 123.78(14), C3-C10-C11 = 128.00(14), C10-C11-
C12 = 116.08(14), C11-C12-O2 = 124.11(14), C2–C3–C10–C11 = -139.90(17), C3–
C10–C11–C12 = 178.80(14).
The formation of the latter product may occur via two different pathways. As shown in
Scheme 5 for the reaction of 3i,k with 8a-b, the cleavage of one indole ring may in
principle occur before or after desilylation. As fragmentation of the isolated compound
1
1
7a observed by H NMR takes days in CDCl
3
solution, we can conclude that the
elimination of an indole ring occurs before desilylation (left pathway in Scheme 5) or via
BF induced cleavage of the initial adducts (16-19)a. This type of -elimination of indole
3
1
5
was previously observed in other cases. Compound 15, obtained by the reaction with
c cannot undergo this cleavage because there are no hydrogens in -position which
are needed for the 1,2-elimination of indole.
8
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Possible Mechanisms for the Formation of (16-19)b
F
F
F
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
B
F
SiMe3
OSiMe3
O
O
H
O
3i, k
n
n
N
n = 0, 1
R = H, CH3
8a,b
R
R
N
-
-
BF3
H+
~
FSiMe3
F
B
F
F
F
O
O
SiMe3
H
O
O
n
N
R
R
n
N
N
R
BF4-
R
Isolated compounds
16-19)a
N
(
- BF3
H+
CDCl3
-
1a,c
slow
-
FSiMe3
O
O
O
O
n
H H
n
- 1a,c
N
R
N
R
R
N
Isolated compounds
(16-19)b
X-ray
Kinetic Investigations. The kinetics of these reactions were determined in CH
2 2
Cl by
following the disappearance of the absorbances of 3a-k at their maximum wavelengths

max (Tables 1-3). In the presence of an excess (10−200 equivalents) of the nucleophiles
a-j (Table 4), pseudo first-order conditions were achieved, as indicated by the mono-
8
exponential decays of the absorbances of 3a-k, which is illustrated in Figure 4 for the
-1
reaction of the ketene acetal 8j with the indolylmethylium ion 3b. Plots of kobs (s )
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against the concentrations of the nucleophiles were linear with negligible intercepts as
2
illustrated in Figure 4. The second-order rate constants k for the reactions of 3a-k with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the nucleophiles 8a-j were derived from the slopes of these linear plots (see Supprting
Information pp S2-S14) and are reported in Table 5.
3.5
1
1
.2
.0
2
kobs = 1.14 × 10 [8j] - 0.0766
3
2
2
.0
.5
.0
2
R = 0.9968
0.8
1.5
.0
1
A
0
0
0
.6
.4
.2
0.5
0.0
431 nm
0.00
0.005
0.010
[8j] / M
0.015
0.020
0.025
0.0
0
1
2
3
4
5
6
7
8
9
10
t / s
Figure 4. Exponential decay of the absorption of 3b (9.28 × 10 M) during the reaction
-5
-3
-1 -1
with 8j (5.09 × 10 M) (kobs = 5.23 × 10 s ) in CH
2 2
Cl . Inset: plot of the first-order rate
2
-1 -1
constants kobs versus the nucleophile concentrations [8j] k
2
= 1.14 × 10 M s .
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5. Second-Order Rate Constants k for the Reactions of the Nucleophiles 8a-
2
j with the Indolylmethylium Tetrafluoroborates 3(a-k)-BF in CH Cl at 20 C
4
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 -1
a
-1 -1
b
Electrophile
Nucleophile k / M s
kcalc / M s
2.73 × 10
2.57 × 10
3.20 × 10
1.18 × 10
1.05 × 10
1.35 × 10
2.00 × 10
1.55 × 10
2.16 × 10
8.72 × 10
1.22 × 10
1.94
E
2
4
3
2
4
3
2
3
2
1
2
4
3
2
4
3
2
3
2
1
1
1
3a
8g
8h
3.07 × 10
2.22 × 10
3.42 × 10
1.35 × 10
-1.80
-2.19
-3.02
-6.26
-7.79
(
R = H)
8j
3b
8g
8h
(
R = Me)
1.08 × 10
1.14 × 10
1.91 × 10
1.48 × 10
2.34 × 10
1.36 × 10
9.19
8j
3c
8g
8h
(
R = OMe)
8j
3d
8d
8e
(
2
R = NMe )
8g
1.71
2
2
3e
8b
3.62 × 10
3.65 × 10
2.66 × 10
2.66 × 10
1.35 × 10
1.53 × 10
1.53 × 10
1.45 × 10
5.30 × 10
7.33 × 10
2c
2
(R = Jul)
2d
2
1
.78 × 10
1
8c
9.35
c
1
9.02
d
1
6.70
-1
-2
-1
-2
8e
8.78 × 10
5.56 × 10
8g
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Table 5. (continued)
-
1
-1
a
-1 -1
b
Electrophile
Nucleophile
k
2
/ M s
k
calc / M s
7.46 × 10
1.18 × 10
2.09 × 10
1.15
E
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
59
60
2
2
2
1
3f
8d
6.32 × 10
1.67 × 10
1.72 × 10
1.13
-5.15
2
1
8e
8
g
h
8
4
3
1
4
2
1
3g
8b
3.50 × 10
1.43 × 10
2.62 × 10
1.54
6.05 × 10
9.05 × 10
2.59 × 10
1.45
-5.05
8d
8g
8h
1
1
3h
8g
3.30 × 10
3.14 × 10
-4.96
-5.99
8h
1.70
1.78
4
2
1
3
2
1
3i
8b
1.32 × 10
5.21 × 10
2.39 × 10
3.07
9.40 × 10
8.91 × 10
1.70 × 10
3.46
8c
8f
8g
3
3
3j
8b
2.23 × 10
5.92 × 10
7.15 × 10
2.96 × 10
1.57
1.55 × 10
1.14 × 10
4.93 × 10
4.28 × 10
2.12
-6.90
1
2
8c
-
1
-1
1
8g
1
3k
8a
-10.23
8
b
d
-
2
-2
8
7.49 × 10
4.03 × 10
a
Calculated by using Equation (1), N and s
N
from Table 4 and E from this
b
c
table. For the determination of E, see Figure 5 and accompanying text.
–
d
6 3
Counterion PF ; In CH CN.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
As shown in Table 5, the second-order rate-constants k
acetals 8b and 8c with the aryl(indol-3-yl)methylium ion 3e differ by less than a factor of
in CH CN and in CH Cl , illustrating that the solvent has little effect on the reaction
kinetics, as previously reported for analogous reactions of benzhydrylium and iminium
2
for the reactions of the ketene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
2
2
9
–
–
ions with neutral -nucleophiles. Variation of the counterion (BF
4
vs. PF
Cl
% indicating that the counterion effects on the kinetics of these reactions are
6
) of aryl(indol-
3-yl)methylium ion 3e affected the second-order rate constants in CH
2
2
by less than
5
16
negligible.
Determination of the electrophilicity of 3a-k. Since the pioneering work of Swain and
1
0a
Scott
numerous attempts have been made to quantify nucleophilicity and
1
0b-j
10h,i
electrophilicity,
among which Ritchie’s constant selectivity relationship
and its
10j
extensions by Kane-Maguire and Sweigart are the most prominent ones. In 1994 we
have introduced Equation (1) which characterizes electrophiles by one parameter, E,
and nucleophiles by the solvent-dependent nucleophilicity parameter N and the
9
d
N
sensitivity parameter s .
log k
2
(20 C) = s
N
(N + E)
(1)
Figure 5 shows that plots of (log k )/s vs. the nucleophilicity N of 8a-j are linear with
2
N
slopes close to 1, which indicates the applicability of Equation (1). By enforcing a slope
of 1.0 for the least-squares minimization it was possible to evaluate the electrophilicities
E of 3a-k which are listed in Table 5. Only the correlation lines for cations 3e, 3i and 3j,
which include reactions with the sterically most demanding -nucleophile 8c, showed
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some scatter presumably because the steric crowding at the disubstituted nucleophilic
site of 8c affected the transition states of the reactions with 3e,i,j more than those of the
reactions with benzhydrylium ions, which were used for the calibration of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
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56
57
58
59
60
nucleophile-specific parameters N and s for 8a-k.
N
6
3
g y = N – 5.05
5
4
3
2
1
0
1
3a y = N – 1.80
3i y = N – 5.99
3j y = N – 6.60
3e y = N – 7.79
3
3
b y = N – 2.19
c y = N – 3.02
3
k y = N – 10.23
log k2
sN
3
h y = N – 4.96
3d
3f y = N – 5.15
y = N – 6.26
-
-2
3
4
5
6
7
8
9
10
11
12
13
14
N
Figure 5. Plots of (log k
the nucleophiles 8a-j in CH
a-j from Table 4.
Figure 6 shows a linear correlation of the electrophilicity E of the four para-substituted
aryl(indol-3-yl)methylium ions 3a-d with Hammett’s  constants of the substituents of
the phenyl ring, which is of higher quality than the corresponding correlation with p+
The slope of this correlation (5.59) corresponds to the Hammett reaction constant ρ for
reactions with nucleophiles of s = 1. It is considerably larger than the corresponding
slopes of E vs  correlations for substituted benzylidene malonates (3.45), quinone
2
)/s
N
vs. N for the reactions of indolylmethylium ions 3a-k with
2
Cl
2
at 20 C. k values from Table 5 and N and s values for
2
N
8
p
.
N
p
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
methides (1.79) and trans-β-nitrostyrenes (2.08), comparable to that of aryl-para-
methoxyphenylmethylium ions (7.38), which can be explained by the more efficient
ground-state effects of the substituents in the more electron-deficient aryl-indolyl and
benzhydryl cations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
H
Me
OMe
E = 7.38 σ + 2.28
p
MeO
X
1
E = 5.59 σ - 1.54
p
N
X = NMe2
X
-
4
NOO
2
NO2
CN
~
Br
X
X
E
E = 2.08 σ - 13.95
p
tBu
-
-
-
14
19
24
O
tBu
E = 1.79 σ - 15.68
p
CO Et
2
E = 3.45 σ - 20.42
p
CO Et
2
X
-
1.0
-0.5
0.0
0.5
1.0
σp
Figure 6. Correlation of the E values of aryl(indol-3-yl)methylium ions 3a-d,
benzhydrylium ions, benzylidene malonates, quinone methides and trans-β-
nitrostyrenes with Hammett’s 
Me), -0.27 (OMe), -0.83 (NMe
p
p 2
constants ( = 0.78 (NO ), 0.66 (CN), 0.23 (Br), -0.17
1
7
(
2
)).
From the electrophilicity parameter of 3h given in Table 5 (E = -4.96) and the previously
reported reactivity parameters for the Hantzsch ester 8o (N = 9.00, s = 0.90 in
N
9
g
3
-1 -1
CH
Cl
2 2
)
one can calculate the rate constant for hydride transfer of 4.33 × 10 M s
(CH
2
2
Cl , 20 °C) by Equation (1). This value agrees within the confidence limit of
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8
4
-1 -1
Equation (1) (factor 10-100) with the experimental rate constant of 1.32 × 10 M s
8d
(
3
CH CN, 30 °C) for this reaction reported by Huffman et al. (Table 6, entry 4). While
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
calculated (Equation 1) and reported experimental rate constants also agree nicely for
the reaction of 3h with imidazole (8l, Table 6, entry 1), the calculated values for the
reactions of the indolylmethylium ion 3h with morpholine (8m) and piperidine (8n) were
8
d
approximately 3 orders of magnitude larger than those reported by Huffman et al.
(Table 6, entries 2 and 3). Apart from the discrepancy with the rate constants predicted
by eq. (1), Huffman´s report that morpholine (8m) and piperidine (8n) reacted more
slowly than imidazole (8l) appeared surprising to us, since in all reactions of
carbocations and Michael acceptors studied so far, the reactivity order was always the
other way around. In order to clarify the origin of this discrepancy, we have repeated the
reactions of the N-nucleophiles 8l-n with the aryl(indol-3-yl)methylium ion 3h using
different counterions.
The kinetic investigations, which were performed under pseudo-first-order conditions as
5
-1 -1
described above, gave a rate constant of 2.65 × 10 M s for the reaction of imidazole
8
d
(
8l) with 3h, close to Huffman’s value and to the rate constant calculated by Equation
(1). As expected from the calculations based on Equation (1), the reactions of 3h with
morpholine (8m) and piperidine (8n) were much faster than reported by Huffman, and
were too fast to be followed with our stopped-flow equipment.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Experimental and Calculated Second-Order Rate-Constants k for the
2
Reactions of the Nucleophiles 8l-o with the indolylmethylium ions 3h,k
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
exp
-1 -1
exp
-1 -1
k
2
/ M s
3
CN, 20°C
calcd
-1 -1
N, s
(CH CN)
N
k
2
/ M s
CN, 30°C
k
2
/ M s
a
Indolylmethylium
CH
4
BF , this
Entry
1
N-Nucleophiles
3
CH
3
-
3
CH CN, 20°C
from Eq(1)
b
ions / (E)
-
c
pKaH (H
2
O)
HSO
4
, Huffman
work
5
d
5
5
N
11.47, 0.79
pKaH = 6.9
3h / -4.96
3h / -4.96
4.26  10
2.65  10
1.39  10
NH
8
l
5
6
7
2
15.65, 0.74
pKaH = 8.4
1.15  10
>> 10
8.14  10
O
NH
NH
8
m
n
4
4
3k / -10.23
3h / -4.96
Not studied
2.90  10
1.03  10
5
6
8
3
4
17.35, 0.68
pKaH = 11.2
2.30  10
>> 10
2.66  10
8
4
3
9.00, 0.90
3h / -4.96
1.32 x 10
Not studied
4.33 x 10
(CH
Cl
2 2
)
2 2
(in CH Cl )
8o
a
b
c
d
8d
From Ref. 9; From Ref. 18a; From Ref. 8d; Average of two kinetic measurements at 30 °C .
For that reason, we measured the rate constant for the reaction of morpholine 8m with
the less electrophilic bis(indol-3-yl)methylium ion 3k, which proceeded selectively at C10
according to NMR of the crude material (Scheme 6, the poor yield of isolated adduct 20
is due to losses during recrystallization). Since the measured rate constant is in accord
with that calculated by equation (1), we can conclude that equation (1) is also applicable
to reactions of the carbenium ions 3 with amines and that the rate constants for the
reactions of 3h with 8m and 8n reported by Huffman cannot refer to the attack of the
amines at the carbenium ions. Unfortunately, the experimental part of Huffman’s article
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does not give detailed information about the concentrations used for the different kinetic
experiments. Possibly the amines 8m and 8n were not used in high excess over the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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49
50
51
52
53
54
55
56
57
58
59
60
-
indolylmethylium hydrogen sulfate, that protonation of the amines by the HSO
counterion accounts for the incorrect rate constants reported for these reactions.
4
Scheme 6. Reaction of Bis(indol-3-yl)methylium Tetrafluoroborate 3k-BF
Morpholine (8m)
4
with
Structure-reactivities relationships. The right column of Figure 7 compares the
reactivities of the aryl(indol-3-yl)methylium ions 3a-k with those of structurally related
benzhydrylium ions. One can see that replacement of the NH group of the aryl(N-
methylindol-3-yl)methylium ion 3f (E = -5.15) by NMe to give 3g (E = -5.05) has a
negligible effect on electrophilicity, analogous to the small N-methyl effect on the relative
1
9
nucleophilicities of indole and N-methylindole. The indol-3-ylmethylium ion 3d (E = -
6
.26) has a similar electrophilicity as the bis(p-dimethylamino)benzhydrylium ion (E = -
.02) and the bis(N-methylindol-3-yl)methylium ion 3i (E = -5.99), indicating that the
7
N,N-dimethylaminophenyl group and the N-methyl-indole ring stabilize carbenium ions to
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1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
a similar extent, in agreement with the similar magnitudes of the Hammett  constants
+
p
20a
+
20b
for the N,N-dimethylamino group (
= -1.70) and N-methylindole ( arene = -1.93).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In order to demonstrate the practical use of the electrophilicity parameters of the
indolylmethylium ions determined in this work, we have complemented the
electrophilicity scale on the right of Figure 7 with a nucleophilicity scale on the left side.
By arranging the reactivities of electrophiles and nucleophiles in opposite order,
electrophiles and nucleophiles which are placed on the same level react with a rate
-1
-1
9b
constant of 1 M s . Using the rule of thumb
that electrophile-nucleophile
combinations may take place at room temperature if E + N > -5, one can derive that the
indolylmethylium ions will react with those nucleophiles which are positioned below them
or not more than 5 units above them in Figure 7.
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60
Figure 7. Ranking of the indolylmethylium ions 3a-g,i,k in the electrophilicity scale and
scope of their reaction with nucleophiles.
One can, thus, expect that indoles, furans, thiophenes, and pyrroles which have N
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
4
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5
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5
5
5
5
5
5
5
6
parameters from 1 to 8, undergo Friedel-Crafts reactions with most aryl(indol-3-
yl)methylium ions to give tris(heteroaryl)methanes. Organocatalytic reactions of
indolylmethylium ions with enamines and enamides, which are good nucleophiles (5 < N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
f
4a-c, 6a
<
19) have been reported to proceed smoothly even at low temperature.
3
Trialkylsilanes HSiR are not sufficiently nucleophilic to react with the least reactive
indolylmethylium ions 3e,k (E + N < -5), but stronger hydride donors such as the
Hantzsch ester (8o, N = 9.00) can be used to reduce all 3a-k with formation of bis-
indolyl-methanes or aryl(indolyl)methanes. Allylsilane, stannane and organoboron
9
f
nucleophiles, which have been calibrated in our scale, are also suitable reaction
2c, 3a
partners for indolylmethylium ions.
The data reported in this work can thus be
employed for designing syntheses of bis(indol-3-yl)methane derivatives, which have
21
been identified as building blocks of several alkaloids.
CONCLUSION
The second-order rate constants for the reactions of the indolylmethylium ions 3(a-k)
with -nucleophiles follow Equation (1), which allowed us to derive the electrophilicitiy
parameters -10.2 < E < -1.8 for these substituted indolylmethylium ions and to predict
+
potential mucleophilic reaction partners. In line with the similar values of 
p 2
(NMe ) and
+

arene (1-methylindol-3-yl), the bis(4-dimethylamino)-substituted benzhydrylium ion and
the substituted indol-3-ylmethylium ion 3d and 3i were found to have similar electrophilic
reactivities (Scheme 7).
Scheme 7. Comparison of the Electrophilic Reactivities of Benzhydrylium Ions
and Indol-3-ylmethylium Ions
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Earlier attempts in our group to generate benzhydrylium ions in the reactivity range -6 <
E < -2 by combining strong (NMe
2
) and weak (Me, OMe) electron donating substituents
group
protonation?) could not be avoided. Since 1-methylindole is a considerably weaker
at the two phenyl rings failed, because electrophilic attack at the NMe
2
(
1
8b
18c
Bronsted base (pKaH = -2.32 in H
2
O) than N,N-dimethylaniline (pKaH = 5.15 in H
2
O)
,
the strong electron-donating indolyl group can be combined with weaker electron
donating groups as phenyl, tolyl, and anisyl to give the stable diarylcarbenium ions 3(a-
c) which may be used as readily accessible reference electrophiles in future mechanistic
investigations.
EXPERIMENTAL SECTION
2 2
Materials. Dichloromethane was freshly distilled over CaH prior to use, and Et O was
distilled over sodium/benzophenone. Commercially available acetonitrile (99.9%, extra
dry) and dimethyl sulfoxide (99.7%, extra dry) were used as received. Indoles (1), 4-
4 2 6 2
(dimethylamino)benzaldehyde (2d), HBF ·OEt , HPF (65 wt % in H O), triethyl
orthoformate (4), nucleophiles (8c-e, g-i, k-l, n) were purchased and used without
further purification. Aldehydes (2a-c) and nucleophile 8m were purchased and distilled
9
a
prior to use. 1,2,3,5,6,7-Hexahydropyrido[3,2,1-ij]quinoline-9-carbaldehyde (2e),
2
2
22
23
24
nucleophiles (8a , 8b , 8f , 8j ) were synthesized as described in the literature.
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
19
31
Analytics. The H, C, F, and P NMR chemical shifts are in ppm and recorded in
CDCl ( = 7.26,  = 77.16), CD CN ( = 1.94,  = 118.69), (CD ) SO ( = 2.50, 
3
H
C
3
H
C
3 2
H
C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
= 39.52), and in CD
2
Cl
2
(
H
C
= 5.32,  = 53.84). The following abbreviations were used
for signal multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad, sept = septet. NMR signal assignments were based on additional 2D-NMR
experiments (COSY, HSQC, HMBC and NOESY). HRMS in EI and ESI mode were
performed on a LTQ mass spectrometer. Melting points were determined in capillary
tubes with a standard melting point device and were not corrected. An IR spectrometer
with an ATR unit (attenuated total reflection) was used to record the IR spectra of neat
compounds. The composition of the compounds was determined with a conventional C-,
H-, N- , S- elemental analyzer. All yields refer to non-optimized procedures.
Synthesis of aryl(indol-3-yl)methylium tetrafluoroborates 3(a-g)-BF
General procedure: Benzaldehyde 2 was dissolved in a mixture of CH
Et
g, 1.00 equiv.) was added to the mixture and the solution was stirred until complete
homogenization (2 min). The solution was cooled to 0 C, and HBF ·Et O (1.50 equiv.)
4
.
2
2
Cl (5 mL) and
2
O (5 mL) in a flame-dried Schlenk-flask; flushed with nitrogen. Then an indole 1 (1.00
4
2
was added dropwise at this temperature. After 10 min, the solution was allowed to warm
at room temperature whilst a strongly colored solid precipitated (see Tables 1 and 2).
After 10 min the solid was filtered and washed thoroughly with Et
crystallized in CH CN/Et O (1/1) to give the aryl(indol-3-yl)methylium tetrafluoroborates
3-BF as colored crystals of high purity.
2
O (4 x 25 mL) and was
3
2
4
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