Nucleophilicity parameters of pyridinium ylides and their use in mechanistic analyses

Article abstract of DOI:10.1021/ja407885h

Kinetics of the reactions of pyridinium, isoquinolinium, and quinolinium ylides with diarylcarbenium ions, quinone methides, and arylidene malonates (reference electrophiles) have been studied in dimethylsulfoxide solution by UV-vis spectroscopy. The seco

Full text of DOI:10.1021/ja407885h

Subscriber access provided by Georgetown University | Lauinger and Blommer Libraries
Article
Nucleophilicity Parameters of Pyridinium
Ylides and Their Use in Mechanistic Analyses
Dominik S. Allgäuer, Peter Mayer, and Herbert Mayr
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja407885h • Publication Date (Web): 10 Sep 2013
Downloaded from http://pubs.acs.org on September 14, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Nucleophilicity Parameters of Pyridinium Ylides and Their Use
in Mechanistic Analyses
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
Dominik S. Allgäuer, Peter Mayer, and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
ABSTRACT: Kinetics of the reactions of pyridinium, isoquinolinium, and quinolinium ylides
with diarylcarbenium ions, quinone methides, and arylidene malonates (reference electrophiles)
have been studied in DMSO solution by UV–Vis spectroscopy. The second-order rate constants
(
log k
electrophiles, as required by the linear free-energy relationship log k20 °C = s
Chem. Soc. 2001, 123, 9500), which allowed us to derive the nucleophile-specific parameters N
and s for these ylides. Pyridinium-substitution is found to have a similar effect on the reactivity
2
) were found to correlate linearly with the electrophilicities E of the reference
N
(N + E) (J. Am.
N
of carbanionic reaction centers as alkoxycarbonyl substitution. Agreement between the rate
constants measured for the 1,3-dipolar cycloadditions of pyridinium, isoquinolinium, and
quinolinium ylides with acceptor substituted dipolarophiles (arylidenemalononitrile and
N
substituted chalcone) and those calculated from E, N, and s shows that the above correlation can
also be employed for predicting absolute rate constants of stepwise or highly unsymmetrical
concerted cycloadditions. Deviations between calculated and experimental rate constants by a
6
factor of 10 were demonstrated to indicate a change of reaction mechanism.
Introduction
Pyridinium ylides are readily accessible nucleophiles and their chemistry has been studied
1-6
7-9
intensively. They undergo various reactions, e. g., 1,3-dipolar cycloadditions Michael
1
0
11
additions, or cyclopropanations depending on the nature of the employed electrophile. The
nucleophilic reactivities of pyridinium ylides have mostly been rationalized by the pK values of
a
2
a,c
the corresponding pyridinium ions,
although it is known that pK
a
values are not a reliable
1
2
13
gauge of relative reactivities of nucleophiles, even when the reaction center is kept constant.
3
4
While some kinetic studies on the formation and reactions of pyridinium ylides have been
performed, their reactivities have, to our knowledge, not been analyzed in relationship with other
nucleophiles, such as carbanions.
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 26
1
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
In previous work we have shown that the rates of the reactions of carbocations and Michael
14
acceptors with n-, π-, and σ-nucleophiles, including various ylides, can be described by eq 1,
–
1
–1
where k20°C is the second-order rate constant in M s , s
N
is a nucleophile-specific sensitivity
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
15,16
parameter, N is a nucleophilicity parameter, and E is an electrophilicity parameter.
The
reactivity parameters N and E were used to develop comprehensive reactivity scales, which
provide direct comparisons of many different classes of nucleophiles and electrophiles.
log k20 °C = s
N
(N + E)
(1)
We recently reported that the [3+2]-cycloaddition reactions of pyridinium ylides with
9
benzylidene malonates proceed stepwise. This observation encouraged us to analyze the kinetics
of reactions of pyridinium ylides with various electrophiles, including electron-deficient
ethylenes, by eq 1, in order to include the ylides 1 (Table 1) into our comprehensive
nucleophilicity scale. We now report on the kinetics of the reactions of the pyridinium ylides
1a−g, the isoquinolinium ylide 1h, and the quinolinium ylide 1i with the benzhydrylium ions 2,
the quinone methides 3, and the benzylidene malonates 4, which were commonly used as
1
4-16
reference electrophiles (Chart 1).
of pyridinium ylides with benzylidene malononitrile 5a and chalcone 5b to examine whether the
N and s parameters for pyridinium ylides derived from the reactions of 1a−i with reference
Subsequently we investigated the kinetics of the reactions
N
electrophiles can also be employed for predicting the rates of the reactions of pyridinium ylides
with other types of Michael acceptors, which undergo diverse subsequent reactions after a
common initial rate-determining CC-bond-forming step.
Results and Discussion
Products
+
−
+
−
The pyridinium (1(a−g)H X ), the isoquinolinium (1hH Br ), and the quinolinium salts
+
−
(1iH Br ) were obtained by nucleophilic substitution from the corresponding pyridines,
9
isoquinoline, or quinoline in THF as described previously (Table 1). As most ylides (1a−i) are
unstable compounds, we made no attempts to isolate them but generated them in solution by
+
–
−
−
−
treating their conjugate acids 1H X (X = Cl , Br ) with a base.
2
ACS Paragon Plus Environment

Page 3 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
+
–
Table 1. Synthesis and pK
1 and Visible Absorption Maxima of the Ylides 1.
a
-Values of the Pyridinium Salts 1H X Employed as Precursors for the Pyridinium Ylides
R
N
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
1
EWG
a
Pyr
EWG
CO Et
X
Salt
Yield/% pK
a
(DMSO) Ylide λmax(DMSO) /nm
+
−
−
b
c
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
2
Br
Br
Br
Cl
Br
Br
Br
Br
Br
1aH Br
82
83
14.1
1a
1b
1c
1d
1e
1f
425
425
433
425
443
425
453
479
516
+
b
d
CONEt
CN
2
1bH Br
~20
16.5
11.8
10.7
13.2
-
+
−
b
c
c
c
e
1cH Br
quant
+
−
b
COMe
COPh
1dH Cl
45
+
−
b
1eH Br
94
+
−
4-Me
2
N-Pyridine COPh
1fH Br
98
88
+
−
3-Cl-Pyridine
Isoquinoline
Quinoline
COPh
COPh
COPh
1gH Br
1g
1h
1i
+
−
b
f
1hH Br
93
~10
+
−
1iH Br
85
-
a
b
Absorption maximum in the visible range; full UV–Vis spectra are given in the Supporting Information. From ref.
c
2c
d
9
. From ref. . Estimated from the average difference of ΔpK
a
~ 4.5 between pyridinium and analogously
O; from ref. 2d; Estimated from the difference of ΔpK ~ 3 between
of the analogously substituted isoquinolinium salt
2c e
f
substituted trimethylammonium salts. In H
2
a
+
−
+
−
the pK
a
(1eH Br ) and pK
a
(1aH Br ), and pK
a
+
−
2c
Isoquin CH
2
CO
2
Et Br (pK
a
= 13.5 in DMSO).
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 26
1
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
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
Chart 1. Electrophiles employed in this work (electrophilicities E from ref. 15b,c, 16).
4
The benzhydrylium tetrafluoroborate 2a-BF was chosen as representative to study the products
of the reactions of the ylides 1 with the benzhydrylium ions 2. Slow addition of a solution of
t
potassium tert-butoxide (KO Bu) in THF to a suspension of equimolar amounts of benzhydrylium
+
–
tetrafluoroborate 2a-BF
temperature gave rise to the formation of the pyridinium salts 6(a−i)-BF
crystallization and isolated in 39% to quantitative yields (Table 2). The structures of the products
4
and 1(a−i)H X in acetonitrile/dichloromethane (5:1) at room
4
, which were purified by
1
13
were identified by NMR spectroscopy ( H and C) and HRMS, as well as by the crystal structure
of 6e-BF (Figure 1).
4
4
ACS Paragon Plus Environment

Page 5 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
4
Table 2. Reactions of the Ylides 1 with the Benzhydrylium Tetrafluoroborate 2a-BF .
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
Salt
Pyr
Pyridine
EWG
CO Et
Product Yield/%
+
−
1
aH Br
2
6a-BF
6b-BF
6c-BF
6d-BF
6e-BF
6f-BF
4
39
+
−
1bH Br
Pyridine
Pyridine
Pyridine
Pyridine
CONEt
CN
2
4
98
+
−
1
1
1
1
1
1
cH Br
4
88
+
−
dH Cl
COMe
COPh
4
69
+
−
b
eH Br
4
quant.
quant.
+
−
fH Br
2
4-NMe -Pyridine COPh
4
+
−
c
gH Br
3-Cl-Pyridine
Isoquinoline
Quinoline
COPh
COPh
COPh
6g-BF
4
(quant.)
57
+
−
hH Br
6h-BF
4
+
−
1iH Br
6i-BF
4
63
a
b
+
−
2
After recrystallization from Et O/MeCN or MeCN. 1eH Br was dissolved in aq. KOH (0.1 M), and the resulting
ylide 1e was extracted with CHCl
the CHCl
Et
3
4 2 2
. The benzhydrylium tetrafluoroborate 2a-BF (1 equiv) in CH Cl was added to
c
3
solution of 1e at room temperature. Yield of the crude product; purification by crystallization from
2
4
O/MeCN failed due to decomposition of 6g-BF .
4
Figure 1. ORTEP-drawing of the crystal structure of 6e-BF .
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 26
1
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
Electrophile 3b was chosen as a representative example for investigating the course of the
+
−
reactions of the ylides 1 with the quinone methides 3. The salts 1(a−i)H X and quinone methide
b were suspended in acetonitrile at room temperature and treated with triethylamine (2.2
3
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
equiv.). This procedure afforded the Michael adducts 7a−h in excellent yields and modest
diastereoselectivities (Table 3). The quinolinium derivative 7i could not be isolated from the
reaction of ylide 1i with quinone methide 3b, and only decomposition was observed.
Table 3. Synthesis of the Michael Adducts 7a−h.
a
Salt
Pyr
EWG
CO Et
Product Yield/% dr
+
−
1
aH Br Pyridine
2
7a
7b
7c
7d
7e
7f
94
1:2
1:2
1:2
2:3
1:7
1:5
1:5
1:3
-
+
−
1
bH Br Pyridine
CONEt
2
quant.
quant.
quant.
quant.
quant.
quant.
quant.
0
+
−
1cH Br Pyridine
CN
+
−
1
1
1
dH Cl Pyridine
COMe
+
−
eH Br Pyridine
COPh
+
−
fH Br 4-NMe
2
-Pyridine COPh
+
−
1gH Br 3-Cl-Pyridine
COPh
COPh
COPh
7g
7h
7i
+
−
1
hH Br Isoquinoline
+
−
1
iH Br Quinoline
a
1
Determined by H-NMR of the isolated product.
As already mentioned above, we recently reported on the reactions of the ylides 1 with
9
benzylidene malonates 4 (Scheme 1). We observed that in polar solvents, such as DMSO,
addition of ylide 1a to benzylidene malonate 4d gave the Michael adduct 9a via the intermediate
9
betaine 8a. Carrying out the reaction of 1a with 4d in a non-polar solvent, such as CH
Cl
2 2
, led to
9
the formation of the [3+2]-cycloadduct 10a, which was subsequently oxidized to the indolizine
11a. The scope of this indolizine formation was tested for a broad variety of differently
9
substituted pyridinium ylides (including 1a−e) and Michael acceptors (including 4a−d). The
6
ACS Paragon Plus Environment

Page 7 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
reaction of isoquinolinium ylide 1h with benzylidene malonate 4a did not give a Michael adduct
9
in DMSO but the [3+2]-cycloadduct, which was isolated in 75% yield.
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
9
Scheme 1. Solvent Dependence of the Reaction of the Ylide 1a with Benzylidene Malonate 4d.
Kinetic Investigations
The kinetics of the reactions of the ylides 1 with the electrophiles 2−4 in DMSO at 20 °C were
monitored photometrically by following the disappearance of one of the two reagents at or close
to their absorption maxima (see Supporting Information). Because of the low stabilities of the
ylides 1, they were generated in solution by combining freshly prepared solutions of the salts
+
–
t
1
(a−i)H X and KO Bu (typically 1.05 equiv.) in DMSO directly before the kinetic experiments.
The formation of the ylides 1a−i was confirmed by their UV–Vis spectra (see Table 1 and
+
Supporting Information). In order to assure that the pyridinium ions 1(a−i)H were quantitatively
+
deprotonated, the pyridinium ion with the highest pK
a
value in the series (1bH , Table 1) was
t
titrated with a solution of KO Bu in DMSO, while the absorbance of the ylide 1b was monitored
t
by UV–Vis spectroscopy at 425 nm. After the addition of one equivalent of KO Bu, addition of
t
further portions of KO Bu did not lead to an increase of the absorbance of ylide 1b, indicating the
+
t
complete deprotonation of 1bH by one equivalent of KO Bu (see Supporting Information). To
simplify the kinetics, one of the two components, nucleophile or electrophile, was used in high
excess (≥10 equivalents), which resulted in monoexponential decays of the UV–Vis absorbances
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 26
1
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
of the minor component. From the decays of the UV–Vis absorbances, the first-order rate
–
1
constants kobs (s ) were derived by least-squares fitting of the exponential function A
exp(−kobst) to the time-dependent absorbances A
of the minor component (Figure 2). Plots of kobs
against the concentrations of the excess compound were linear, mostly with negligible intercepts
Figure 2, Insert). From the slopes of these plots, the second order rate constants k for the
t 0
= A
t
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
reactions of the ylides 1 with the reference electrophiles 2−4 could be derived as listed in Table 4.
Errors given refer to standard deviations of the correlations kobs vs. concentration of the
compounds used in excess.
1
0
0
0
.0
.8
.6
.4
2.4
3
kobs = 2.00 × 10 [1e] - 0.01
1
1
.8
.2
0.6
0
.0
0
0.0004
0.0008
0.0012
[
1e]/M
0.2
0.0
0.0
1.0
2.0
3.0
t/s
−5
−3
Figure 2. Decay of the absorbance of 3a (2.00 × 10 M) at 533 nm during its reaction with 1e (1.00 × 10 M) in
DMSO at 20 °C. Insert: Linear correlation of kobs with increasing concentration of 1e.
8
ACS Paragon Plus Environment

Page 9 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Table 4. Second-Order Rate Constants k
2
for the Reactions of the Ylides 1 with the Reference Electrophiles 2(b−c)-
BF , 3, and 4 in DMSO at 20 °C.
4
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
a
−1 −1
Nucleophile
N/s
Electro-
phile
Excess λ/nm
k
2
(20 °C)/M
s
N
of
4
3a
1a
1a
1a
1a
4b
4c
4d
1b
1b
1b
1b
4a
4c
1c
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
4a
1e
1e
1e
1e
1e
533
371
521
302
445
445
445
533
371
486
521
425
425
533
371
486
521
302
277
283
295
533
533
371
393
486
425
635
630
533
371
521
(9.00 ± 0.30) × 10
(9.68 ± 0.37) × 10
(1.09 ± 0.04) × 10
(1.37 ± 0.09) × 10
(1.08 ± 0.02) × 10
(1.97 ± 0.03) × 10
(1.13 ± 0.01) × 10
(2.99 ± 0.26) × 10
(3.21 ± 0.23) × 10
(7.94 ± 0.64) × 10
(3.79 ± 0.26) × 10
(4.23 ± 0.30) × 10
(6.10 ± 0.50) × 10
(2.34 ± 0.10) × 10
(2.03 ± 0.11) × 10
(2.67 ± 0.09) × 10
(2.13 ± 0.12) × 10
(2.08 ± 0.11) × 10
(6.26 ± 0.49) × 10
(1.77 ± 0.14) × 10
(1.77 ± 0.05) × 10
(1.09 ± 0.07) × 10
(1.07 ± 0.08) × 10
(5.02 ± 0.30) × 10
(4.13 ± 0.22) × 10
(7.18 ± 0.51) × 10
(2.26 ± 0.01) × 10
(7.08 ± 0.31) × 10
(3.85 ± 0.14) × 10
(2.00 ± 0.08) × 10
(1.29 ± 0.10) × 10
(1.03 ± 0.03) × 10
3
3b
3
3e
3
26.71/0.37
4a
3
4b
2
4c
2
4d
5 b
3a
4
b
3b
3 b
b
3d
3
3
2
5
4
3
3
3
2
2
2
4
4
2
2
1
1
5
5
3
2
1
27.45/0.38
3e
4a
4c
3a
3
b
d
3
25.94/0.42
3e
4a
4b
4c
4d
3
a
a
c
3
3b
20.24/0.60
3c
3d
4a
2b-BF
4
N
2c-BF
3a
4
1e
COPh
19.46/0.58
3b
3e
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 26
1
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
Table 4. continued.
a
−1 −1
Nucleophile
Electro-
phile
3a
Excess λ/nm
k
2
(20 °C)/M
s
N/s
N
of
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
4
1f
4a
4b
533
425
425
(5.51 ± 0.32) × 10
(1.77 ± 0.09) × 10
(3.39 ± 0.24) × 10
2
1
4a
4b
21.61/0.58
5
2
2
2
2
b-BF
4
4
4
1g
1g
4a
630
533
476
(2.49 ± 0.13) × 10
(5.73 ± 0.31) × 10
1.78 ± 0.16
3a
4a
17.98/0.63
6
3
1
b-BF
3a
1h
1h
4a
630
533
482
(1.51 ± 0.11) × 10
(3.88 ± 0.28) × 10
(3.05 ± 0.12) × 10
N
1h
COPh
4a
20.08/0.57
5
b-BF
1i
1i
630
533
530
(1.17 ± 0.08) × 10
2
3
a
a
(7.54 ± 0.31) ×10
8.48 ± 0.43
4
4a
19.38/0.50
a
b
+
−
t
c
Monitored wavelength. Excess of pyridinium salt, that is, 1bH Cl : KO Bu = 1.9 : 1.0. Reproduction with excess
+
−
t
of pyridinium salt (1dH Cl : KO Bu = 1.9 : 1.0).
2
Plots of log k for the reactions of the pyridinium ylides 1a,b and 1d,e with the reference
electrophiles 2−4 against the corresponding electrophilicity parameters E are linear, as depicted
for some representative examples in Figure 3 (for ylides 1c,f−i see Supporting Information).
From the linearity of these correlations one can deduce that the additions of pyridinium ylides to
benzhydrylium ions 2, quinone methides 3, and benzylidene malonates 4 in DMSO have
analogous rate-limiting steps despite leading to different reaction products. Since the E
parameters for 2−4 were derived from reactions of benzhydrylium ions with πCC-nucleophiles
and from reactions of quinone methides and benzylidene malonates with carbanions, i.e.,
reactions in which one new CC-bond is formed in the rate-determining step, we conclude that the
rate constants listed in Table 4 also correspond to the formation of one CC-bond by attack of the
ylides 1 at one carbon of the benzhydrylium ions 2 or the Michael acceptors 3,4. From the slopes
N
of the linear correlations the nucleophile-specific slope parameters s can be derived, and the
10
ACS Paragon Plus Environment

Page 11 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
negative intercepts on the abscissa give the nucleophilicity parameter N of the pyridinium ylides
1 (Figure 3; Table 4).
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
4
3
2
4d 4c 4b 3e 4a 3d 3c 3b 3a
2c 2b
EWG =
6
5
4
3
2
1
0
1
b CONEt
2
2
1a CO Et
1
d COMe
log k
2
1e COPh
1
-
22
-20
-18
-16
-14
-12
-10
-8
Electrophilicity E
2
Figure 3. Plots of log k (DMSO, 20°C) for the reactions of the pyridinium ylides 1a,b,d,e with the reference
electrophiles 2–4 versus their electrophilicity parameters E. For the sake of clarity, the correlation lines for 1c and
1f–i are not shown (see Supporting Information).
N
The different sensitivities s of the various ylides 1a−i imply that their relative reactivities are
significantly affected by the nature of the electrophilic reaction partner. As shown in Figure 4 for
3a as reference electrophile, the reactivities of the ylides 1a−i toward the quinone methide 3a
differ by almost a factor of 500. While the pyridinium ylides 1a−c with CO
substituents are the most reactive nucleophiles, the acetyl and benzoyl substituted ylides 1d,e are
to 2 orders of magnitude less reactive. Comparison of the benzoyl substituted ylides 1e, 1h, and
2 2
Et, CONEt , and CN
1
1i shows that variation of the heterocyclic ring has little influence on the nucleophilicity.
Nevertheless, one can see that the isoquinolinium ylide 1h is more reactive than the pyridinium
ylide 1e and the quinolinium ylide 1i. An interpretation of this ranking will not be attempted
because of the small differences in reactivity that can even be inverted when other electrophiles
are used as references.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 26
1
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
log k (towards 3a)
2
5
5
.47
.37
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
1b
4
.95
5
1
c
Me N
2
4
.74
N
COPh
COPh
1a
1f
4
.04
4
3
1
d
3.59
2.88
1
h
3.30
N
1
e
1
i
2
.76
1g
2
Figure 4. Reactivities (log k towards 3a) for the reactions of ylides 1a−i with the quinone methide 3a in DMSO at
20 °C
Applications to Mechanistic Analyses
N
To investigate the applicability of the N and s parameters in Table 4 to reactions with other
types of electrophiles, the kinetics of the reactions of the ylides 1 with the benzylidene
malononitrile 5a and chalcone 5b were studied.
Benzylidene malononitrile 5a. Table 5 lists the experimental (kexp) and calculated (kcalcd by eq 1)
second-order rate constants for the reactions of the ylides 1d−i with 5a, which were determined
by following the consumption of the ylides in DMSO at 20 °C. While the experimental and
calculated second-order rate constants for the reactions of ylides 1d,f,h,i with 5a agree within a
6
factor of 7 (i. e. within the confidence limit of eq 1), 1e and 1g react 10 times more slowly than
calculated (Table 5). This behavior prompted us to investigate the reactions of pyridinium ylides
1a−i with the benzylidene malononitrile 5a more closely.
12
ACS Paragon Plus Environment

Page 13 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Table 5. Experimentally determined (kexp) and Calculated (kcalcd) Second-Order Rate Constants for the Reactions of
the Ylides 1d−i with the Electrophile 5a in DMSO at 20 °C.
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
−
1
−1
−1 −1, a
Ylide
kexp/M
s
kcalcd/M
s
k
exp/kcalcd
exp
k =
5
−
5
−
4
3
5
1d
(2.14 ± 0.07) × 10
(2.19 ± 0.15) × 10
(4.27 ± 0.25) × 10
(2.02 ± 0.08) × 10
(2.95 ± 0.06) × 10
(5.73 ± 0.13) × 10
4.86 × 10
1.05 × 10
1.70 × 10
3.11 × 10
1.96 × 10
2.07 × 10
0.44
k
2
1
1
5
6
4
5
4
−6
1e
2.09 × 10
0.25
Kkrc
1f
k
2
−6
1g
6.50 × 10
0.15
Kkrc
1h
k
2
2
1i
0.28
k
a
Calculated by eq 1 from E (Chart 1) and N, s
N
from Table 4.
The reactions of the ylides 1 with benzylidene malononitrile 5a may either give the betaines 12,
the cyclopropanes 13, or the tetrahydroindolizines 14, as summarized in Scheme 2.
Scheme 2. Reactions of Ylides 1 with Benzylidene Malonate 5a in DMSO.
+
−
When an equimolar solution of the 4-dimethylamino-substituted pyridinium salt 1fH Br and
benzylidene malononitrile 5a in DMSO-d was treated with 1,5,7-triazabicyclo[4.4.0]dec-5-ene
TBD) as base, quantitative formation of the betaine 12f was observed with moderate
diastereoselectivity (Scheme 3). The structure of betaine 12f could be assigned by 2D-NMR, but
6
(
1
3
attempts to isolate 12f failed. The C-NMR signal at δ = 16.0 ppm was assigned to a carbanionic
center, in agreement with published data for betaines derived from carboxamido-substituted
11a
pyridinium ylides and benzylidene malononitriles. As the pyridinium ring is stabilized by the
dimethylamino group in 4-position, 12f does not undergo subsequent cyclizations, and the
2
measured rate constant corresponds to k .
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 26
1
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
6
Scheme 3. Reaction of the Ylide 1f with Benzylidene Malononitrile 5a in DMSO-d .
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
As expected from the large rate constant for the reaction of 1d with 5a reported in Table 5,
1
complete consumption of the reactants was observed in the H-NMR-spectrum taken immediately
+
−
t
6
after mixing 1dH Cl with benzylidene malononitrile 5a and KO Bu in DMSO-d at ambient
1
temperature. H-NMR spectra taken after 5, 30, and 60 min showed 40/60, 21/79, and 0/100
mixtures of betaine 12d and cyclopropane 13d, respectively, indicating that the fast formation of
the betaine 12d is followed by a slow cyclization step. The cyclopropane 13d was isolated in
+
−
t
5
3% yield when the mixture obtained from 1dH Cl , 5a, and KO Bu was worked up after a
reaction time of 60 min (Table 6). The exclusive formation of trans-13d was derived from a
1
7
NOESY-experiment.
+
−
A different behavior was observed for the ylides 1e and 1g. When the reaction of 1eH Br with
1
5
a and 1.8 equivalents triethylamine was monitored by H-NMR spectroscopy in DMSO-d
6
, the
intermediate betaine 12e was not observable, and the reaction mixture showed signals of the
+
−
reactants 1eH Br and 5a, the ylide 1e, and the cyclopropane 13e, the yield of which increased
+
−
from 41% after 5 min to 81% after 30 min. Combination of 1eH Br with benzylidene
malononitrile 5a and triethylamine in DMSO at ambient temperature yielded cyclopropane 13e
with complete trans-selectivity within 30 min (Table 6), as confirmed by the crystal structure of
3e (Figure 5). Analogously, combination of the 3-chloro substituted ylide 1g with 5a afforded
1
cyclopropane 13g (= 13e) with complete trans-selectivity within 30 min.
The non-observance of the intermediate betaines 12e,g in the reactions of 1e,g with 5a implies
that in the reactions of these less Lewis-basic ylides (pK
a
in Table 1), the equilibrium depicted on
top of Scheme 2 is completely shifted to the left side, with the consequence that the
14
ACS Paragon Plus Environment

Page 15 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
experimentally determined rate constants kexp correspond to Kkrc, which explains the large
deviation of kexp from kcalcd for these two combinations in Table 5.
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
Table 6. Formation of the Cyclopropanes 13 in DMSO.
Salt
R
H
H
EWG
Base
Betaine Cyclopropane
Yield/%
+
−
−
−
t
a
1
dH Cl
COMe KO Bu
12d
12e
12g
13d
13e
53
+
b
1
eH Br
COPh
NEt
3
3
67
+
b
1
gH Br
3-Cl COPh
NEt
13g (= 13e)
95
a
b
After column chromatography over silica (n-pentane : EtOAc = 5 : 1). After recrystallization from EtOH.
Figure 5. ORTEP-drawing of the crystal structure of 13e. The asymmetric unit contains two formula units.
The reactions of the ylides 1h,i with benzylidene malononitrile 5a in DMSO yielded 88% and
68% of the [3+2]-cycloadducts 14h,i, respectively (Scheme 4). The stereochemistry of 14h,i was
assigned on the basis of NOESY correlations between the protons and the substituents of the
pyrrolidine rings. From the stereochemistry of the [3+2]-cycloadducts one can deduce that the
depicted major diastereoisomers of 14h,i were formed via an endo-approach of electrophiles to
the anti-ylides (Scheme 4), in agreement with literature reports for similar [3+2]-cycloadducts
15
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 26
1
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
7
b, c
obtained from isoquinolinium ylides and benzylidene malononitriles.
the minor diastereoisomers could not be assigned unambiguously.
The stereochemistry of
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
The formation of the [3+2]-cycloadducts 14h,i from isoquinolinium and quinolinium ylides,
instead of betaines or cyclopropanes as obtained with pyridinium ylides (see above), can be
explained by the lower aromaticity of the heterocyclic ring of the bicyclic compounds, which
5
b
facilitates the cyclization of the intermediate betaine.
Scheme 4. Formation of the Tetrahydroindolizines 14h,i in DMSO.
In line with quantum chemical calculations by Matsumura, which indicated a barrier of only
2
.9 kJ/mol for the cyclization of a betaine generated from an isoquinolinium ylide and 1,1-
5b
dicyanoethylene, one can conclude that the betaines formed from 5a and 1h,i undergo fast
subsequent ring closures with formation of the [3+2]-adducts 14h,i (Scheme 4), with the
2
consequence that in these cases kexp corresponds to k . The observation kexp ≈ kcalcd also excludes
concerted 1,3-dipolar cycloadditions 5a + 1h,i with a high energy of concert, because in this case
18
kexp should be considerably larger than kcalcd.
19
Chalcone 5b underwent [3+2]-cycloadditions with all ylides 1, as evidenced by the isolation of
the indolizines 16a−i, obtained by oxidation of the initially generated tetrahydroindolizines 15a−i
with tetrakispyridinocobalto(II)dichromate (TPCD; Table 7).
16
ACS Paragon Plus Environment

Page 17 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Table 7. Synthesis of the Indolizines 16.
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
Salt
R
EWG
CO Et
Product Yield/%
+
−
−
1aH Br
H
2
16a
16b
16c
16d
16e
16g
16h
16i
54
63
95
50
93
85
91
77
+
a
1bH Br
H
CONEt
2
+
−
1cH Br
H
CN
+
−
−
−
1dH Cl
H
COMe
COPh
COPh
+
1eH Br
H
+
b
a
1gH Br
3-Cl
+
−
1hH Br
Isoquinoline COPh
Quinoline COPh
+
−
1
iH Br
a
b
2 2 2 2
1. CH Cl /aq. NaOH (32%), 20°C; 2. Chloranil (2 equiv.), CH Cl , 20°C. Mixture of isomers; 16g-(8-Cl) : 16g-(6-
Cl) = 4 : 1.
Because of the low stabilities of the initially formed tetrahydroindolizines 15a−i, which was
7b
already reported in the literature, their isolation was generally not attempted. Only the
tetrahydroindolizine 15i was obtained in low yield by the reaction of ylide 1i with chalcone 5b,
1
analyzed by H-NMR spectroscopy, and identified as a 5 : 27 : 68 mixture of diastereoisomers.
The stereochemistry of the depicted major diastereoisomer of 15i (Scheme 5) was derived from
the NOESY correlations between the protons and substituents at the pyrrolidine ring. Its
formation can be explained by the 1-endo-2-exo approach of the electrophile 5b to the anti-
configuration of ylide 1i, in agreement with Tsuge’s interpretation of the stereoselectivities of the
7b
reactions of isoquinolinium ylides with several different chalcones. The stereochemistry of the
other diastereoisomers could not be assigned unambiguously. The purification of the [3+2]-
17
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 26
1
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
cycloadduct 15i failed due to its decomposition during work-up, which may also explain the low
yield.
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
+
−
Scheme 5. Reaction of Salt 1iH Br with Chalcone 5b in DMSO.
For the [3+2]-cycloadditions of the ylides 1 with the chalcone 5b concerted or stepwise
mechanisms have to be considered (Scheme 6). In case of a stepwise mechanism with rate-
determining formation of the intermediate betaine 18, the experimentally determined rate
2
constant kexp should correspond to k and agree with the calculated rate constant kcalcd within the
1
5a,b
general confidence limit of equation 1 (one to two orders of magnitude).
18
ACS Paragon Plus Environment

Page 19 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Scheme 6. Concerted and Stepwise 1,3-Dipolar Cycloaddition of Ylides 1 with Chalcone 5b.
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 kinetics of the reactions of the ylides 1 with chalcone 5b were studied by monitoring the
consumption of the ylides 1a−i. Table 8 lists the experimental (kexp) and calculated second-order
rate (kcalcd by eq 1) for these reactions in DMSO at 20 °C. For 7 of the 8 reactions of the ylides 1
with chalcone 5b experimental and calculated second-order rate constants agree within a factor of
2
.5, indicating a stepwise mechanism with rate-determining formation of the betaine 18 (Table
8). Only the reaction of ylide 1e with chalcone 5b proceeds 20 times more slowly than calculated
by equation 1. This deviation might be due to a partial reversibility of the betaine formation
followed by rate-determining cyclization, but since the deviation is within the confidence limit of
equation 1, we do not want to speculate.
In case of concerted cycloadditions kexp/kcalcd should be greater than 1, depending on the degree of
18
concertedness. Because of the large error limits of eq 1, the kinetic data do not allow us to
differentiate stepwise cycloadditions from concerted processes with highly unsymmetrical
transition states and a small energy of concert. As none of the experimental rate constants kexp in
Table 8 is considerably faster than kcalcd, we conclude that none of these cycloadditions proceeds
with a high energy of concert, which implies that eq 1, which has been derived for one-bond-
forming reactions of electrophiles with nucleophiles, can also be employed for predicting
absolute rate constants for stepwise cycloadditions or concerted cycloadditions with highly
unsymmetrical transition states. As the E parameters used for these calculations have previously
19
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 26
1
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
1
6a
been derived from the rate constants of carbanion additions (E for 5a) or from stepwise
1
6c
cyclopropanations with sulfonium ylides (E for 5b) the general power of this approach has thus
been corroborated.
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 8. Experimentally Determined (kexp) and Calculated (kcalcd) Second-Order Rate Constants for the [3+2]-
2
Cycloadditions of the Ylides 1a−i with the p-NO -Chalcone 5b in DMSO at 20 °C.
−
1
−1
−1 −1 a
Ylide
kexp/M
s
kcalcd/M
s
k
exp/kcalcd
1.80
0.78
1.92
0.45
0.05
1.43
0.96
1.52
3
3
3
1
3
1a
(4.82 ± 0.10) × 10
(6.12 ± 0.28) × 10
(7.92 ± 0.37) × 10
(2.55 ± 0.09) × 10
2.68 × 10
7.80 × 10
4.13 × 10
5.61 × 10
1.72 × 10
2.56
3
3
1
1
1b
1c
1d
-
1
1e
(8.54 ± 0.45) × 10
3.67 ± 0.12
1g
1
1
1
1h
(3.56 ± 0.22) × 10
(1.64 ± 0.05) × 10
3.70 × 10
1.08 × 10
1
1i
a
N
Calculated by eq 1 from E (Chart 1) and N, s from Table 4.
Conclusion
The rates of the reactions of the pyridinium ylides 1 with benzhydrylium ions 2, quinone
methides 3, and arylidenemalonates 4 follow the linear free-energy relationship (eq 1), which
allows us to characterize the synthetically important pyridinium ylides by the reactivity
1
5h
N
parameters N and s and to include them in our comprehensive nucleophilicity scale. Figure 6
compares the reactivities of the ethoxycarbonyl-substituted pyridinium ylide 1a (left) and of the
cyano-substituted pyridinium ylide 1c (right) with those of analogously substituted carbanions, as
well as with those of phosphorus and sulfur ylides. Both columns show that pyridinium ylides are
approximately a million times more reactive than analogously substituted triphenylphosphonium
ylides and about thousand times more reactive than the corresponding dimethylsulfonium ylides.
The close similarity of the reactivities of the pyridinium ylides and of diethyl malonate and ethyl
cyanoacetate anions shows that pyridinium substitution affects the reactivities of nucleophilic
reaction centers to a similar extent as ethoxycarbonyl- and cyano-substitution. Because of the
smaller sensitivities s
N
of the pyridinium ylides compared to the other C-nucleophiles, the
relative reactivities of the pyridinium ylides with respect to the other nucleophiles of Figure 6
20
ACS Paragon Plus Environment

Page 21 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
will depend on the nature of the electrophilic reaction partner. Pyridinium ylides will show a
lower relative reactivity toward reaction partners which are more electrophilic than 3a (E > −13),
while they will show an even higher relative reactivity toward less reactive electrophiles (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
54
55
56
57
58
59
60
−
13).
1
4a,c
15c
Figure 6. Comparison of the log k
2
-values (towards 3a) of analogously substituted ylides
and carbanions
towards electrophile 3a. N and s -values are given below each nucleophile (reactivities refer to DMSO as solvent).
N
As correlation eq 1 allows one to calculate the rate constants for the formation of the zwitterions
betaines) from pyridinium ylides 1 and Michael acceptors, it can be employed for the analysis of
(
reaction mechanisms. From the agreement between calculated (eq 1) and experimental rate
constants for the 1,3-dipolar cycloadditions of the isoquinolinium (1h) and quinolinium ylide (1i)
with the benzylidenemalononitrile 5a and of all investigated ylides 1 with the chalcone 5b we
have concluded that these cycloadditions proceed stepwise or in a concerted way with negligible
energy of concert.
21
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 22 of 26
1
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
In two cases, i. e., in the reactions of the benzylidenemalononitrile 5a with the pyridinium ylides
1e and 1g, the experimental rate constants were found to be a million times smaller than
calculated by eq 1. NMR-spectroscopic monitoring of these reactions showed that they proceed
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
with reversible formation of the intermediate betaines, which undergo subsequent slow, rate-
determining ring-closure with formation of cyclopropanes. The large deviation between
experimental and calculated rate constants thus was indicative of a change of the reaction
mechanism, illustrating the value of eq 1 for mechanistic analyses.
2
0
The differentiation of concerted and stepwise 1,3-dipolar cycloadditions has been a challenge
21
for mechanistic chemistry for many decades. While mechanistic investigations indicate a
2
2
concerted pathway for most 1,3-dipolar cycloadditions, stepwise processes via zwitterionic
intermediates have been observed in reactions of thiocarbonyl ylides (electron-rich 1,3-dipoles)
2
3
with electron-deficient dipolarophiles.
Our observation that eq 1 allows one to predict absolute rate constants for 1,3-dipolar
cycloadditions of pyridinium, isoquinolinium and quinolinium ylides with the electron-poor
dipolarophiles 4a−d and 5a,b implies a remarkable extension of the validity range of eq 1. It now
appears feasible that eq 1 can generally be employed for predicting absolute rate constants of
cycloadditions of highly nucleophilic 1,3-dipoles with highly electrophilic dipolarophiles as well
as of electrophilic 1,3-dipoles with electron-rich dipolarophiles. In view of the great recent
interest in the mechanisms of 1,3-dipolar cycloadditions using the distortion/interaction energy
24
25
model or activation strain model, we expect that these data will significantly broaden the
experimental basis of these models and assist the further development of this theoretical
approach.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, product characterization, kinetic
experiments, copies of all NMR spectra and crystallographic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
22
ACS Paragon Plus Environment

Page 23 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Corresponding Author
Herbert Mayr
Present Address
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
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13 (Haus F), 81377 München
(Germany),
Fax:
(+49)89-2180-77717,
E-mail:
Herbert.mayr@cup.uni-muenchen.de,
Homepage:
http://www.cup.uni-muenchen.de/oc/mayr
Funding Source
Deutsche Forschungsgemeinschaft (SFB 749, Project B1).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
th
Dedicated to Professor Manfred Reetz on the occasion of his 70 birthday. We thank the
Deutsche Forschungsgemeinschaft (SFB 749, Project B1) for the financial support, and Dr. A. R.
Ofial and Dr. J. Bartl for their help during the preparation of this manuscript.
ABBREVIATIONS
DMSO, dimethylsulfoxide; MeCN, acetonitrile; THF, tetrahydrofuran.
REFERENCES
(
1)
For reviews see: (a) Zugravescu, I.; Petrovanu, M. N-Ylid Chemistry; McGraw-Hill, New
York: 1976; (b) Mikhailovskii, A. G.; Shklyaev, V. S. Chem. Heterocycl. Compd. 1997,
3
3, 243−265; (c) Jacobs, J.; Van Hende, E.; Claessens, S.; De Kimpe, N. Curr. Org.
Chem. 2011, 15, 1340−1362; (d) Kakehi, A. Heterocycles 2012, 85, 1529-1577.
For pK -studies see: (a) Phillips, W. G.; Ratts, K. W. J. Org. Chem. 1970, 35, 3144-3147;
(
2)
a
(b) Carey, A. R. E.; Al-Quatami, S.; More O'Ferrall, R. A.; Murray, B. A. J. Chem. Soc.,
Chem. Commun. 1988, 1097−1098; (c) Zhang, X.-M.; Bordwell, F. G.; Van Der Puy, M.;
Fried, H. E. J. Org. Chem. 1993, 58, 3060−3066; (d) Carey, A. R. E.; More O'Ferrall, R.
A.; Murray, B. A. J. Chem. Soc., Perkin Trans. 2 1993, 2297−2302; (e) Fu, Y.; Wang, H.-
J.; Chong, S.-S.; Guo, Q.-X.; Liu, L. J. Org. Chem. 2009, 74, 810−819.
(
3)
4)
For deprotonation studies see: (a) Dega-Szafran, Z.; Schroeder, G.; Szafran, M. J. Phys.
Org. Chem. 1999, 12, 39−46; (b) Dega-Szafran, Z.; Schroeder, G.; Szafran, M.; Szwajca,
A.; Łeska, B.; Lewandowska, M. J. Mol. Struct. 2000, 555, 31−42; (c) Szafran, M.;
Szwajca, A.; Łęska, B.; Schroeder, G.; Dega-Szafran, Z. J. Mol. Struct. 2002, 643, 55−68;
(
d) Szwajca, A.; Łęska, B.; Schroeder, G.; Szafran, M. J. Mol. Struct. 2004, 708, 87−95.
(
For kinetic studies see: (a) Jackson, J. E.; Soundararajan, N.; Platz, M. S.; Liu, M. T. H. J.
Am. Chem. Soc. 1988, 110, 5595−5596; (b) Bonneau, R.; Liu, M. T. H.; Lapouyade, R. J.
Chem. Soc., Perkin Trans. 1 1989, 1547−1548.
23
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 26
1
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
(
(
5)
6)
For computational studies see: (a) Karafiloglou, P.; Surpateanu, G. Int. J. Quantum Chem.
2004, 98, 456−464; (b) Matsumura, S.; Takagi, R.; Kojima, S.; Ohkata, K.; Abe, M.
Heterocycles 2010, 81, 2479−2495.
Examples of dihydrofuran synthesis: (a) Rajesh, S. M.; Perumal, S.; Menendez, J. C.;
Pandian, S.; Murugesan, R. Tetrahedron 2012, 68, 5631−5636; (b) Gunasekaran, P.;
Balamurugan, K.; Sivakumar, S.; Perumal, S.; Menéndez, J. C.; Almansour, A. I. Green
Chem. 2012, 14, 750−757; (c) Osyanin, V. A.; Osipov, D. V.; Klimochkin, Y. N. J. Org.
Chem. 2013, 78, 5505−5520.
Examples for [3+2]-cycloadduct synthesis: (a) Tsuge, O.; Kanemasa, S.; Takenaka, S.
Bull. Chem. Soc. Jpn. 1985, 58, 3137−3157; (b) Tsuge, O.; Kanemasa, S.; Takenaka, S.
Bull. Chem. Soc. Jpn. 1985, 58, 3320−3336; (c) Shestopalov, A. M.; Sharanin, Y. A.;
Nesterov, V. N.; Rodinovskaya, L. A.; Shklover, V. E.; Struchkov, Y. T.; Litvinov, V. P.
Chem. Heterocycl. Compd. 1991, 27, 1006−1011; (d) Fernández, N.; Carrillo, L.; Vicario,
J. L.; Badía, D.; Reyes, E. Chem. Commun. 2011, 47, 12313−12315.
Examples of indolizine synthesis: (a) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J.
Org. Chem. 1999, 64, 7618−7621; (b) Kim, E.; Koh, M.; Ryu, J.; Park, S. B. J. Am.
Chem. Soc. 2008, 130, 12206–12207; (c) Kim, E.; Koh, M.; Lim, B. J.; Park, S. B. J. Am.
Chem. Soc. 2011, 133, 6642–6649; (d) Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Org. Lett.
2012, 14, 957−959; (e) Kucukdisli, M.; Opatz, T. Eur. J. Org. Chem. 2012, 4555–4564.
Allgäuer, D. S.; Mayr, H. Eur. J. Org. Chem. 2013, DOI 10.1002/ejoc.201300784.
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
(
(
7)
8)
(9)
(
10) Examples for the synthesis of stable betaines: (a) Han, Y.; Chen, J.; Hui, L.; Yan, C.-G.
Tetrahedron 2010, 66, 7743−7748; (b) Wang, Q.-F.; Hui, L.; Hou, H.; Yan, C.-G. J.
Comb. Chem. 2010, 12, 260–265; (c) Kumar, A.; Gupta, G.; Srivastava, S. Org. Lett.
2011, 13, 6366−6369.
(
11) Examples for cyclopropanations: (a) Shestopalov, A. M.; Litvinov, V. P.; Rodinovskaya,
L. A.; Sharanin, Y. A. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1991, 40,
1
7
29−138; (b) Vo, N. H.; Eyermann, C. J.; Hodge, C. N. Tetrahedron Lett. 1997, 38,
951−7954; (c) Kojima, S.; Fujitomo, K.; Shinohara, Y.; Shimizu, M.; Ohkata, K.
Tetrahedron Lett. 2000, 41, 9847–9851; (d) Yamada, S.; Yamamoto, J.; Ohta, E.
Tetrahedron Lett. 2007, 48, 855–858; (e) Wang, Q.-F.; Song, X.-K.; Chen, J.; Yan, C.-G.
J. Comb. Chem. 2009, 11, 1007−1010; (f) Kanomata, N.; Sakaguchi, R.; Sekine, K.;
Yamashita, S.; Tanaka, H. Adv. Synth. Catal. 2010, 352, 2966–2978.
(12) (a) Bordwell, F. G.; Cripe, A.; Hughes, D. L. In Nucleophilicity; Harris, J. M.; McManus,
S. P., Eds.; American Chemical Society: Washington, DC, 1987, p 137−154; (b) Jencks,
W. P. In Nucleophilicity; Harris, J. M.; McManus, S. P., Eds.; American Chemical
Society: Washington, DC, 1987; p 155−168.
(
13) (a) Berger, S. T. A.; Ofial, A. R.; Mayr, H. J. Am. Chem. Soc. 2007, 129, 9753–9761; (b)
Nigst, T. A.; Antipova, A.; Mayr, H. J. Org. Chem 2012, 77, 8142−8155.
(14) (a) Appel, R.; Loos, R.; Mayr, H. J. Am. Chem. Soc. 2009, 131, 704−714; (b) Lakhdar, S.;
Appel, R.; Mayr, H. Angew. Chem., Int. Ed. 2009, 48, 5034−5037; (c) Appel, R.; Mayr,
H. Chem. Eur. J. 2010, 16, 8610−8614; (d) Appel, R.; Hartmann, N.; Mayr, H. J. Am.
Chem. Soc. 2010, 132, 17894−17900.
(
15) For reviews see: (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938−957;
b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos,
(
R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123,
9500−9512; (c) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91−95;
(
d) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−77; (e) Mayr, H.;
24
ACS Paragon Plus Environment

Page 25 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Ofial, A. R. Pure Appl. Chem. 2005, 1807−1821; (f) Mayr, H.; Ofial, A. R. J. Phys. Org.
Chem. 2008, 21, 584−595; (g) Mayr, H.; Lakhdar, S.; Maji, B.; Ofial, A. R. Beilstein J.
Org. Chem. 2012, 8, 1458−1478; (h) For a comprehensive database of nucleophilicity
N
parameters N, s and electrophilicity parameters E, see http://www.cup.lmu.de/oc/mayr/.
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
(
(
(
(
16) (a) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880−6886; (b) Kaumanns, O.; Lucius,
R.; Mayr, H. Chem. Eur. J. 2008, 14, 9675−9682; (c) Appel, R.; Mayr, H. J. Am. Chem.
Soc. 2011, 113, 8240−8251.
17) The trans-selectivity of pyridinium ylide mediated cyclopropanations of a broad variety
of benzylidene malononitriles and related Michael acceptors was already reported in
11
different solvents, e.g in MeCN or EtOH.
18) (a) Hartnagel, M.; Grimm, K.; Mayr, H. Liebigs Ann. 1997, 71–80; (b) Mayr, H.; Ofial, A.
R.; Sauer, J.; Schmied, B. Eur. J. Org. Chem. 2000, 2013−2020; (c) Fichtner, C.; Mayr,
H. J. Chem. Soc., Perkin Trans. 2 2002, 1441−1444.
2
19) In case of the reaction of chalcone 5b with the 4-NMe substituted pyridinium ylide 1f
complicated kinetics were observed, which may be caused by a reversible formation of
the intermediate betaine (compare Scheme 3). As it is unclear, which reaction step was
observed in the kinetic measurement, we excluded 1f from the studies with chalcone 5b.
20) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565−598; (b) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1963, 2, 633−645.
(
(21) (a) Firestone, R. A. J. Org. Chem. 1968, 33, 2285−2290; (b) Huisgen, R. J. Org. Chem.
968, 33, 2291−2297.
22) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
984; Vol. 1; p. 1−176.
1
(
(
1
23) (a) Huisgen, R.; Mloston, G.; Langhals, E. J. Am. Chem. Soc. 1986, 108, 6401−6402; (b)
Huisgen, R.; Mloston, G.; Langhals, E. Helv. Chim. Acta 2001, 84, 1805−1820; (c)
Huisgen, R.; Mloston, G.; Giera, H.; Langhals, E. Tetrahedron 2002, 58, 507−519; (d)
Mloston, G.; Huisgen, R.; Giera, H. Tetrahedron 2002, 58, 4185−4193; (e) Huisgen, R.;
Giera, H.; Polborn, K. Tetrahedron 2005, 61, 6143−6153; (f) Huisgen, R.; Pöchlauer, P.;
Mloston, G.; Polborn, K. Helv. Chim. Acta 2007, 90, 983−998.
(
(
24) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646−10647; (b) Ess, D. H.;
Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187−10198; (c) Xu, L.; Doubleday, C. E.;
Houk, K. N. J. Am. Chem. Soc. 2010, 132, 3029−3037; (d) Lan, Y.; Zou, L.; Cao, Y.;
Houk, K. N. J. Phys. Chem. A 2011, 115, 13906–13920; (e) Lopez, S. A.; Munk, M. E.;
Houk, K. N. J. Org. Chem. 2013, 78, 1576−1582.
25) (a) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118−3127; (b)
Fernández, I.; Cossío, F. P.; Bickelhaupt, F. M. J. Org. Chem. 2011, 76, 2310−2314.
25
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 26 of 26
1
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
Table of Content Graphics
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
26
ACS Paragon Plus Environment