SUPPLEMENTARY MATERIAL (11 pages)
1,3-Dipolar cycloaddition of diazo compounds to
electron-deficient alkenes. Kinetics and mechanism
of formation of dimethyl-4,5-dihydro-1Hpyrazol-3,5-dicarboxylate
Mikhail Yu. Ovchinnikov*, Tagir A. Yangirov, Alexander N. Lobov, Rimma M. Sultanova, Sergey
L. Khursan
Institution of Russian Academy of Sciences Institute of Organic Chemistry Ufa Scientific Centre
of the RAS, 71 Prospect Oktyabrya, 450054 Ufa, Russian Federation. Fax: +7 (347) 235-60-66.
*
Corresponding author. Tel.: +7 (347) 235-61-11; Fax: +7 (347) 235-60-66.
E-mail address: myuovchinnikov@gmail.com (Mikhail Yu. Ovchinnikov).
IR spectra were recorded on the instrument Shimadzu «Prestige21» in capillary film between
KBr windows or in vaseline oil. High-resolution electron ionization mass spectra were recorded
using an Thermo Finnigan «MAT95XP» mass spectrometer (EI, 70 eV, temperature of ionizing
chamber 523°K, the temperature of the direct input 323-543°K, heating rate 10 K·min-1).
NMR spectra were recorded in C6D6 on a Bruker AvanceIII spectrometer (5mm z-gradient
PABBI probe) operating at 500.30 MHz (1H) and 125.75 MHz (13C), at 298 K. Chemical shifts
are expressed in parts per million (ppm) from tetramethylsilane as internal standard. The 1H
NMR spectra were acquired with a spectral width of 6.0 kHz and 64k data points and 1 scans.
Conditions for proton composite pulse decoupled (WALTZ-16)
13
C NMR experiments were as
follows: spectral width 29.76 kHz, number of data points 64K, number of scans 512, acquisition
time 1.1 s, relaxation delay 2.0 s and 3.2 μs 30° 13C pulse width.
Gradient selected HSQC spectra were recorded using the standard Bruker sequence (hsqcetgp).
These data were collected with 4096 x 256 data points with 2 scans for each increment. The
delay d4 was set to 1.72 ms. Gradient selected HMBC spectra (hmbcgpndqf) were collected with
4096 x 256 data points with 4 scans for each increment. The delay d6 was set to 71.4 ms.
Spectral widths of 5.6 and 29.7 kHz were used in the F2 (1H) and F1 (13C) domains,
respectively. HSQC and HMBC data were processed using a sine window in the F2 and F1
dimensions. Gs-COSY data were collected with 2K x 2K data points with 2 scans for each
increment. For the 2D NOESY (noesygpph) NMR following parameters and procedures are
commonly employed: spectral width 5.6 kHz, 2Kx2K data matrix and 256 time increments of 2
transients each. Fourier transformations were carried out with zero-filling only in and using the
shifted sine-bell F1, apodization function in both dimensions.
Kinetics experiments were carried out in C6D6 on a Bruker AMX-300 spectrometer (5mm
QNP direct detection probe) operating at 300.13 MHz (1H) and 75.47 MHz (13C), at 298 K. 1H
kinetics spectra were recorded using proton 30° excitation pulse (pulse length 2.4 μs), acquisition
time 2.3s, relaxation delay 5s and 8 scans. 1H NMR spectra were recorded consecutively with an
interval of 5 minutes during the first hour and 15 minutes in the remaining time by using AUmacros. In order to increase the digital resolution FID’s were multiplied by exponential function
(lb = 0.1 Hz 1H), spectra were subjected to automatic phase correction and baseline correction.
The dependence of the concentration of substances from time to time constructed by measuring
the signal intensity: С(3)Н and С(5)H signals of trans-3H-pyrazole (δH 5.30 ppm) and cis-3Hpyrazole (δH 4.86 ppm); C(5)H signal of 1Н-pyrazole (δH 4.15 ppm); СН signal of methyl
diazoacetate (δH 4.45 ppm), olefinic proton of methyl acrylate (δH 5.43, 5.99 and 6.28 ppm), and
olefinic proton of acrylic acid (δH 5.49 ppm).
In order to avoid overlap of integration ranges and possible errors, previously we studied the
drift of the characteristic signals in the whole time range. Automatic integration of a series of 1D
spectra with calibration of the integral values were performed using AU-macro. As a reference
integral for calibration used by sum of the integrated intensities of all signals of the spectrum.
Dimethyl cys-4,5-dihydro-3H-pyrazol-3,5-dicarboxylate (cys-pyrazoline). 1H NMR (C6D6),
δ (ppm): 1.78 (dt, 1H, HaC(4), 2J = 12.8 Hz, 3J =8.8 Hz); 2.05 (dt, 1H, HbC(4), 2J = 12.8 Hz,
3
J = 8.8 Hz); 3.47 (s, 6H, OMe); 4.86 (t, 2H, HC(3), HC(5), 3J = 8.8 Hz).
13
C NMR (C6D6), δ
(ppm): 23.70 (C(4)), 52.51 (OMe), 91.54 (C(3), C(5)), 168.50 (CO).
Dimethyl trans-4,5-dihydro-3H-pyrazol-3,5-dicarboxylate (trans-pyrazoline).
1
H NMR
(C6D6), δ (ppm): 1.86 (t, 2H, HC(4), 3J = 7.5 Hz); 3.51 (s, 6H, OMe); 5.30 (t, 2H, НC(3), НC(5),
3
J =7.7 Hz). 13C NMR (C6D6), δ (ppm): 24.06 (C(4)), 52.55 (OMe), 92.24 (C(3), C(5)), 168.44
(CO).
Dimethyl 4,5-dihydro-1H-pyrazol-3,5-dicarboxylate (1H-pyrazoline) IR, /cm-1: 744,
1045, 1122, 1199, 1251, 1371, 1438, 1571, 1693, 1739, 2954, 3109, 3346 (NH). Found: m/z
186.066 [M]+.. C7H10N2O4. Calc.: M = 186.064. 1H NMR (C6D6), δ (ppm): 2.90 (dd, 1H, HaC(4),
2
J = 17.4 Hz, 3J = 12.6 Hz); 3.16 (dd, 1H, HbC(4), 2J = 17.4 Hz, 3J = 5.4 Hz); 3.37 (s, 3H, OMe);
3.45 (s, 3H, OMe); 4.15 (dd, 1H, HC(5), 3J = 5.7 Hz, and 6.2 Hz); 7.10 (br. s, 1H, NH).
13
C
NMR (C6D6), δ (ppm): 35.11 (C(4)), 51.63 (CO2Me), 52.31 (CO2Me), 61.91 (C(5)), 141.81
(C(3)), 162.82 (CO2Me), 172.23 (CO2Me).
Acrylic acid (AA). 1H NMR (CDCl3), δ (ppm): 6.00 (dd, 1H, Hcis-C(3), 2J = 1.1 Hz, 3J
=10.4 Hz); 6.17 (dd, 1H, H-C(2), 3J = 10.4 Hz, 3J = 17.1 Hz, H); 6.55 (dd, 1H, Htrans-C(3), 2J =
1.0 Hz, 3J =17.2 Hz); 11.98 (br.s, 1H, COOH).
C NMR (CDCl3), δ (ppm): 127.99 (C(2));
13
133.20 (C(3)); 171.88 (C(1)).
Some details of 1,3-dipolar cycloaddtion of MDA to MA in presence of acrylic acid. One of
the reviewers has suggested that the isomerization of 3Н-pyrazolines can pass faster under action
of a trace amount of acrylic acid (AA) which can be present in the reaction mixture. First
question we ask is “what amount of acrylic acids (AA) should consider as ‘trace admixture’?”. In
our regular experiments we do not observed signals of AA protons by NMR 1H spectroscopy.
Using this amount of AA will prevent elucidation of mechanism of AA action supposed by the
reviewer. So, we have chosen the following tactics: to study a reaction system with observable
amount of AA and then to extrapolate our results to a lesser content of acid. Additional
experiments have been done: kinetics of the interaction of MDA with MA without and with
admixture of acrylic acid (AA) (0.02 M) was investigated. This concentration cannot be “a
trace”. However, this amount of AA made it possible to follow the acrylic acid concentration by
kinetic NMR 1H spectroscopy (in addition to other reaction participants).
From the blank experiment ([MDA]0 = 1.77 M, [MA]0 = 0.96 M) the reaction rate constants of
the process were determined (k1 ÷ k3, cis and trans): they are in reasonable accordance with that
of the table 1 of the article. Then the system with AA was examined. Following results were
obtained in these experiments (see Figure 3SM). First, it was found that acid is consumed with
the reaction rate constant kAA which is very close to that of MA, kAA  k1c + k1t, i.e. AA reacts as
electron-deficient alkene and takes part in the cyclization with MDA. Since [MA] >> [AA], the
rate of MDA consuming remains almost the same as in the blank experiment. Second, we have
observed a slight acceleration of 3H → 1H-isomerization. Actually, the fact is well expected by
us, because labile protons of AA should accelerate proton exchange in pyrazolines. Fixing the
reaction rate constants k1 ÷ k3, we have determined the reaction rate constants of isomerization
k4c and k4t, which are attributed to AA catalytic effect. When the concentration of AA is 10 times
lower, the signals of AA protons remain detectable by NMR 1H, i.e. AA concentration in our
regular experiments is definitely less than 0.002 M. Solution of differential equations system
with appropriate set of the kinetic constants and initial conditions (k1 ÷ k3, k4c, k4t, the same
[MDA]0 and [MA]0, whereas [AA]0 = 0.002 M) was shown (see Figure 4SM) that catalytic effect
of AA under this concentration is negligible, i.e. presence of AA trace in the reaction mixture
does not distort kinetics of the MDA-MA reaction.
OCH3 groups of reagents
HC(3) and HC(5)
of trans-pyrazoline
HC(3) and HC(5)
of cis-pyrazoline
CH of
MDA
double bond
hydrogens of MA
HC(5) of
1H-pyrazoline
H2C(4) of
trans-pyrazoline
H2C(4) of
cis-pyrazoline
H2C(4) of
1H-pyrazoline
Figure 1SM. NMR 1H spectrum of the reaction mixture registered after 12 hours 7 minutes 50 seconds (benzene-d6, 298 К).

C, M
1,8
1,6
8
7
MDA, MA
MA
1,4
6
MDA
1,2
5
1,0
1H-pyrazoline
4
0,8
trans-pyrazoline
0,6
3
2
0,4
cis-pyrazoline
0,2
1
0,0
0
0
20
40
60
80
t, h
(a)

C, M
1,8
4
MA
1,6
MA
1,4
3
MDA
1,2
1,0
2
MDA
1H-pyrazoline
0,8
0,6
1
0,4
0,2
0,0
0
0
5
10
15
t, h
(b)
20
25
30

C, M
2,0
5
MDA
MA
1,6
4
MDA
1,2
3
MA
0,8
2
1H-pyrazoline
trans-pyrazoline 1
0,4
cis-pyrazoline
0,0
0
0
10
20
30
40
50
60
70
t, h
(c)

C, M
2,0
3,0
MDA
2,5
MA
1,5
2,0
1,0
1,5
MDA
0,5
1,0
MA
trans-pyrazoline
0,5
cis-pyrazoline
1H-pyrazoline
0,0
0,0
0
10
20
30
t, h
(d)
40
50
60

C, M
1,8
2,0
MDA, MA
MA
1,6
MDA
1,4
1,5
1,2
1,0
1,0
0,8
trans-pyrazoline
0,6
cis-pyrazoline
0,5
0,4
1H-pyrazoline
0,2
0,0
0,0
0
2
4
6
8
10
12
14
16
t, h
(e)
Figure 2SM. Kinetic curves of the reaction compounds MDA, MA, trans-pyrazoline,
cis-pyrazoline and 1H-pyrazoline according to the data of NMR 1H (benzene-d6, 298 К): (a)
[MDA]0 = 1.74 M, [MA]0 = 1.72 M, (b) [MDA]0 = 0.84 M, [MA]0 = 1.75 M, (c) [MDA]0 =
1.82 M, [MA]0 = 0.96 M, (d) [MDA]0 = 1.94 M, [MA]0 = 0.53 M, (e) [MDA]0 = 1.74 M,
[MA]0 = 1.8 M, [1H-pyrazoline]0 = 0.11 M. Solid line is solution of IKP of RSHNDE. Dash
line is fitting by equations (2, 3) (linearization in β – t coordinates) and equations (10, 11).
C(AA).102, M
2
1
C, M
1,8
C, M
0,5
MDA
0
1,5
0
5
0,4
10
t, h
1,2
0,3
0,9
MA
0,2
0,6
0,1
0,3
0,0
0,0
0
2
4
t, h
6
8
10
Figure 3SM. Experimental kinetic curves of MDA, MA and the pyrazolines without (black
points) and with acrylic acid ([AA]0 = 0.02 M, white points) according to the data of NMR 1H
([MDA]0 = 1.77 M, [MA]0 = 0.96 M, benzene-d6, 298 К): triangle – trans-pyrazoline,
diamond – cis-pyrazoline, hexagon – 1H-pyrazoline.
C, M
0,4
trans-pyrazoline
0,3
cis-pyrazoline
0,2
0,1
1H-pyrazoline
0,0
0
2
4
t, h
6
8
10
Figure 4SM. Kinetic curves of the pyrazolines according to the data of NMR 1H ([MDA]0 =
1.77 M, [MA]0 = 0.96 M, benzene-d6, 298 К). Solid line is solution for reaction with acrylic
acids (0.002 M).