Thermodynamics and Kinetics of Click Reaction between Benzyl Azide and Different Alkynes by Microcalorimetry

Article abstract of DOI:10.1021/acs.oprd.9b00435

The copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes provides diverse building blocks for chemical synthesis, biochemistry, pharmaceutical industries, and materials science. To provide a good theoretical support for industrial amplifica

Full text of DOI:10.1021/acs.oprd.9b00435

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Full Paper
Thermodynamics and Kinetics of Click Reaction between
Benzyl Azide and Different Alkynes by Microcalorimetry
Xiaoyi Li, Bo Jin, Zhicheng Guo, Shijin Chu, and Rufang Peng
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00435 • Publication Date (Web): 30 Dec 2019
Downloaded from pubs.acs.org on January 3, 2020
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Thermodynamics and Kinetics of Click Reaction between Benzyl
Azide and Different Alkynes by Microcalorimetry
a
a,
a,
Xiaoyi Li , Bo Jin *, Zhicheng Guo, Shijin Chu, Rufang Peng *
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aState Key Laboratory of Environmental-friendly Energy Materials, Southwest University of Science and
Technology, Sichuan Mianyang 621010, China
* Corresponding author.
E-mail address: jinbo0428@163.com (B. Jin), rfpeng2006@163.com (R. Peng).
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Abstract: The copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes provides
diverse building blocks for chemical synthesis, biochemistry, pharmaceutical industries, and
materials science. In order to provide a good theoretical support for industrial amplification reaction,
it is significant to study the catalytic properties and the corresponding kinetics of a given reaction.
In this article the reaction kinetics and thermodynamics of “Click reaction” between benzyl azide
and different alkynes were investigated by microcalorimetry. Benzyl azide and ethyl propiolate were
used as model reactions. The effects of a variety of parameters were studied in a calorimeter to
establish the kinetics and mechanism of the reaction under isothermal conditions. The activation
energies for the reaction of benzyl azide with 4-nitrophenylacetylene, ethyl propiolate, and 3-
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butyyne-2-one were 22.99 ± 0.13, 55.81 ± 0.74, and 56.75 ± 0.65 kJ mol , respectively. The
difference of reaction kinetics of different alkynes was explained by the reaction mechanism
combined with theoretical calculations, and the reaction is intrinsically kinetically controlled.
Keywords: Azide, Alkyne, Microcalorimetry, Kinetics, Thermodynamics
1. Introduction
1
2
Since the groups of Sharpless and Meldal independently reported the "click chemistry" of
copper-catalyzed azide and alkyne cycloaddition (CuAAC) in 2002, it has become an area of interest
3
for scientists. The 1,3-dipolar cycloaddition of azides and alkynes is an effective way to form
4
connections between structures that bear various functional groups. The discovery of copper(ɪ)
2
catalysis of this process has been widely used in bioconjugation,5-10 organic synthesis,11-14 materials
and surface science,15-17 and combinatorial chemistry. In the field of fine chemical industry, in order
to prevent accidents in batch and semi-batch reactors, especially in the case of highly exothermic
reaction or thermal unstable compounds, the selection of safe operating conditions plays an
important role in the chemical production process. In the past few decades, a lot of research has
been carried out on this issue, and most of which are based on the knowledge of reaction kinetics
and thermodynamics.18 Unfortunately, due to its expensive, time-consuming and equipment
limitations, there are few reports on the reaction kinetics and thermodynamics.19-20
Binauld et al. successfully synthesized oligomers and polymers containing triazole units by the
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copper(I)-catalyzed 1,3-dipolar cycloaddition reaction. H NMR was used to monitor the step-
-1 21
growth click polymerization, and the activation energy of the reaction was 45 ± 5 kJ mol . Sheng
et al. studied the kinetics of Cu(I)-catalyzed polymerization by differential scanning calorimetry
2
2
(
DSC). Wu et al. used the real-time infrared analysis technology based on ATR-FTIR principle to
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monitor the designed ligand-accelerated CuAAC reaction. The experiment also determined that the
rate-determining step of the CuAAC reaction was the transition of azide-alkyne 1:1 complex to the
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preproduct 1,2,3-triazole. However, it is difficult to determine the detailed kinetic model of the
reaction because of the influence of the reaction mixture system composition on the activity of the
reagents and products. Therefore, it is particularly important to find an optimal method to obtain
accurate kinetic parameters of these reactions.
The microcalorimeter (MC) is an experimental device for detecting the change of micro-heat
level. Compared with differential scanning calorimeter (DSC), microcalorimeter offer a specific
sensitivity that is approximately 1000 higher. For a long time, it has been used to study biological
processes24-26 and molecular interactions27,28 in life sciences. As an essential thermal analysis method,
microcalorimetry was used to study the kinetics and thermodynamics of curing reaction.29-32
Compared with the traditional method, the advantage of microcalorimetry is that it can determine
the thermodynamic and kinetic parameters simultaneously. In this work, we investigated the
thermochemical process of the “Click reaction’’ between benzyl azide with different alkynes, such
as ethyl propiolate, 4-nitrophenylacetylene, and 3-butyne-2-one, by using microcalorimetry, and
obtained the kinetics and thermodynamics data for the reaction of benzyl azide with different
alkynes. Moreover, the difference in reaction kinetics between benzyl azide and different alkynes
was explained from the perspective of reaction mechanism and theoretical calculation. Meanwhile,
the mechanism function of the title reaction was obtained by the model-fitting method. At 295.15 -
3
07.15 K, all the models conform to the Jander equation, with n = 1/2 described as 3D diffusion,
which indicates that the reaction interface advances at a constant velocity in three dimensions.33
2
. Experimental
2.1. Materials
Benzyl azide (Aladdin, China), ethyl propiolate (Aladdin, China), DIPEA (Aladdin, China), 4-
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nitrophenylacetylene (Shanghai Macklin Biochemical, China), 3-butyne-2-one (Shanghai Macklin
Biochemical, China), dichloromethane (Xinjie Trade Company, China), acetic acid (Xinjie Trade
Company, China), and all of reagents were used as supplied without further purification.
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2.2. Measurements
RD496-2000 Calvet microcalorimeter (MC) (Mianyang CAEP Thermal Analysis Instrument
Company, China) was used to measure the thermokinetics of the title reaction. At 298.15K, the
-1 34-36
sensitivity of the instrument is 64.53 μV mW .
Before each experiment, the microcalorimeter
was calibrated based on the Joule effect. RD496-2000 Calvet microcalorimeter was used to measure
-1
the standard molar enthalpy of dissolution of KCl (spectral purity) is 17.237 ± 0.028 kJ mol ,
-1 37
compared with the literature value of 17.241 ± 0.018 kJ mol , the relative error is less than 0.02%,
which indicates the reliability of the measuring device.
2.3 Experimental Details
Before the experiment, we designed the glass casing for the reaction. Fig. 1. shows the structural
schematic of glass tube. The outer tube has a length of 67 mm and a diameter of 15 mm; the inner
tube has a length of 43 mm and a diameter of 13 mm. The bottom of the inner tube is very thin,
which makes it very easy to be broken by a platinum pushrod. The heat generated during the process
of smashing the inner tube is about 200 mJ, which is eliminated by the differential method.
The reaction system was composed of alkyne and azide with a molar ratio of 1:1. Benzyl azide
(
0.5 mmol), DIPEA (0.02 mmol, 0.04 equiv), HOAc (0.02 mmol, 0.04 equiv), CuI (1.9 mg, 0.02
equiv) were added to the outer glass tube and were diluted to 2 mL CH Cl . Alkyne (0.5 mmol) was
added to the inner glass bubble and was diluted to 2 mL CH Cl . In each experiment, the glass tube
with the reactants was placed in a calorimeter measuring cell. Another glass tube containing the
same volume of CH Cl was placed in the reference cell. After the temperature and baseline were
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stabilized, the inner glass tubes in the measuring cell and the reference cell were simultaneously
ruptured and the reaction enthalpy was detected.
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Fig. 1. The structural schematic of glass reaction tube.
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Results and Discussion
3.1 Mechanism
In recent years, people have focused on the research of CuAAC reaction mechanism. Sharplees
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and his colleagues have proposed a widely accepted three-step catalytic cycle mechanism. As
shown in Fig. 2., first, the π-electron complexing of Cu(I) with acetylenic bonds reduces the pKa of
the terminal alkyne and is further converted to Cu(I) acetylide (2). Then the Cu(I) acetylide (2) is
coordinated to the azide (3) to form a 5-Cu-substituted 1,2,3-triazole (4) which is rearranged to form
a Cu-substituted triazole intermediate. Finally, the triazole product (5) is obtained by protonation.
Catalysts are considered to be one of the main factors affecting the efficiency of organic reactions.
CuI is the most commonly used catalyst in CuAAC reactions. In this paper, the combination of
CuI/DIPEA (N,N-diisopropylethylamine)/HOAc was considered as a highly efficient catalytic
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system. In the reaction system, the functions of DIPEA and HOAc were assigned, HOAc not only
accelerated the conversions of the intermediates, but also buffered the basicity of DIPEA.
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Fig. 2. Three-step mechanism of CuAAC reaction.
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.2. Effect of Temperature
The reaction between benzyl azide and ethyl propiolate is chosen as a model system to determine
the behavior of azide-alkyne systems. The reaction between benzyl azide and ethyl propiolate is
given in Scheme 1, as follows:
Scheme. 1. The reaction equation of benzyl azide and propiolate.
The reactions were studied at different temperatures under otherwise similar conditions. The
isothermal temperatures set as 295.15, 299.15, 303.15, and 307.15 K because the CuAAC reaction
can take place at room temperature. Fig. 3(a). shows the corresponding heat flow curves for the
reaction of the benzyl azide and ethyl propiolate at four different temperatures. Each curve is a
smooth and single exothermic peak. According to the heat flow curve, it can be seen that the increase
of the reaction temperature leads to the acceleration of the reaction rate. As the temperature
increased, the exothermic peak moved towards the higher peak of heat flow and reached a certain
value at the end of the reaction. As shown in Fig. 3(b), the reaction was completed after 17300,
1
0800, 9300, and 8100 s at 295.15, 299.15, 303.15, and 307.15 K, respectively. Changes in reaction
temperature had a greater impact on reaction rates. By integrating the heat flow curves, the total
heat can be obtained. The total reaction heat at 295.15, 299.15, 303.15, and 307.15 K were 176959.1,
175776.5, 172980.0, and 167969.7 mJ, respectively.
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The degree of the reaction, α, can be calculated using Eq. (1), where Ho is the total heat of the
reaction when α=1, and H is the partial heat at a certain time.
t
Ht
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The reaction degree and reaction rate versus time obtained at four different isothermal
temperatures are shown in (Figs. 3(c) and3(d)). The conversion was found to increase with
temperature. The curves displayed in Fig. 3(d) indicate that the reaction occurs rapidly at the initial
stage, this phenomenon was attributed to more azide and alkyne molecules involved in the reaction.
Alkynes can be rapidly converted into Cu-intermediates, thus accelerating the formation of triazole
products. At the late stage of the reaction, the reactants were consumed, so the reaction rate
decreased gradually. There was no significant change in the time required to reach the maximum
reaction rate at different temperatures.
Fig. 3. (a) Heat flow curves of the reaction between benzyl azide and ethyl propiolate at different
temperatures; (b)The histogram describing the heat and time at different temperatures; (c) Degree of
reaction (α) vs. time (t) of the reaction between benzyl azide and ethyl propiolate at different
temperatures; (d) Reaction rate vs. time (t) of the reaction between benzyl azide and ethyl propiolate at
different temperatures.
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The model-fitting method was used to calculate the rate constants. In the isothermal method, the
rate constant k(T) is a constant; thus, k is separated with the reaction model G(α). Hence, the kinetic
parameters can be evaluated by using the model-fitting method as follows:
G() = kt
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The isothermal kinetics processing software presents 41 kinds of line of G(α) vs. time by least-
square method. the most proper form of G(α) is selected on the basis of the fitting line with the
maximum correlation coefficient and the minimum intercept.33 The reaction rate constant k is
obtained through the slope. The plots of G(α) against t are fitted as shown in Fig. 4(a). At 295.15 -
307.15 K, all the models conform to the Jander equation, with n = 1/2 described as 3D diffusion.
1/3 1/2
The mechanism function No.5 is G(α)= [1-(1-α) ] . The Arrhenius equation (Eq. (3)) can be
employed to calculate the activation energy and the pre-exponential factor of the reaction of between
benzyl and alkynes. By plotting ln k versus 1/T, the values of activation energy, E , and pre-
a
exponential factor, A, can be estimated by calculating the slope of the linear fit and the y-intercept,
as shown in Fig. 4(b), which exhibits a fine linear relationship. Thus, the reaction is kinetically
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≠
≠
controlled. The value of (ΔG ) is obtained by Eq. (4) and the values of (ΔH ) and (ΔS ) are obtained
by Eq. (5).39
Ea
ln k = ln A−
(3)
(4)
RT
RT
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
G = RT ln
Nhk
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
k
H
S
R
kB
h
ln = −
+
+ ln
(5)
T
RT
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constant (6.626 × 10-34 J s ), N is the Avogadro number (6.024 × 10 mol ), and k
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is the
B
Boltzmann’s constant (1.3807 × 10-23 J K ). The original data of the reaction of benzyl azide and
-1
ethyl propiolate with different temperatures are shown in Table S1 and the kinetic parameters are
≠
≠
≠
listed in Table 1, and the ΔH , ΔS , and ΔG values for the reaction between benzyl azide and ethyl
-1
propiolate in the temperature range of 295.15 - 307.15 K were 54.24 ± 0.82 kJ mol , -141.22 ±
-1
-1
-1
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.25J mol K , and 96.77 ± 0.73 kJ mol , respectively.
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Table 1. Values of ln k, A, E, ΔG , ΔH , ΔS , and r for the reaction between azide and ethyl propiolate
at different temperatures
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ΔH /kJ mol
ΔS /J mol K
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0.996
0.998
0.999
0.999
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0.997
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96.43±1.62
97.05±1.70
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96.77±0.73
54.24±0.82
-141.22±1.25
0.996
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Fig. 4. (a) Plots of G(α) vs. time (t) at different temperatures; (b) Plots of ln k vs. T for the benzyl
azide and ethyl propiolate system.
3.3. Effect of Catalyst
To research the influence of catalyst on the reaction rate, the reaction systems with different
contents of CuI were studied at 303.15 K. Fig. 5(a) shows the corresponding heat flow curves. The
exothermic peak value of the heat flow curve increased while the content of CuI increased. The
increased content of CuI caused a decreased time to reach the maximum reaction rate. As seen in
Fig. 5(b), the reaction was completed after 9300, 7200, 6600, and 5100 s and the total reaction heat
values were 172980, 170204, 175635.6 and 175569.8 mJ, whereas the contents of CuI were 2 mol%,
3
mol%, 4 mol%, and 5 mol%, respectively, which demonstrated that the contents of catalyst do not
affect the total heat of the reaction and only the reaction rate. The conversion is plotted against time
for different contents of the catalyst under otherwise similar conditions (Figure 5(c)). As the content
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of the catalyst is increased, there is an increase in conversion. In the presence of a large contents of
CuI, the formation of the C-Cu bond-containing intermediates can be accelerated. Analogously, the
reaction rate gradually slowed down as the reaction progressed. The relationship between ln k and
the contents of CuI is shown in Fig. 5(d). Higher contents of catalyst can enhance the rate constant.
Original data of the reaction of benzyl azide and ethyl propiolate at 303.15 K with different contents
of CuI are shown in Table S2, the ln k values are -9.04±0.01, -8.72±0.02, -8.60±0.01, and -8.34±0.02
at the contents of CuI were 2 mol%, 3 mol%, 4 mol%, and 5 mol%, respectively.
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Fig. 5. (a) Heat flow curves of the reaction between benzyl azide and ethyl propiolate at different
contents of CuI; (b) The histogram describing the heat and time at different contents of CuI; (c) Degree
of reaction (α) vs. time (t) of the reaction between benzyl azide and ethyl propiolate at different
contents of CuI; (d) The histogram describing the relationship between ln k and CuI contents.
3.4. Effect of Concentration of Ethyl propiolate
The reaction rate constant was studied by varying the content of ethyl propiolate at 303.15 K. The
effect of reactant concentration was studied at five levels of -C≡C/-N
.8). The curves at five different concentrations are shown in Fig. 6 and the original data are
displayed in Table S3. From Fig. 6(a), with the increase of ethyl propiolate content, the peak value
3
ratio (0.4, 0.8, 1.0, 1.4, and
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of heat flow curve increased. The total reaction heat values were 67899, 138689.6, 172980,
1
67771.8, and 178485.6 mJ whereas the -C≡C/-N molar ratios were 0.4, 0.8, 1.0, 1.4, and 1.8,
3
respectively. The heat of reaction increased as the ethyl propiolate content increased at the same
temperature, with the exception of the ratio of 1.4, and this finding may be due to the influence of
intermediate in the reaction. As exhibited in Fig. 6(b), the degrees of reaction at different proportions
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are similar. Fig. 7 shown the relationship between ln k and the molar ratio of the -C≡C and -N
groups. As listed in Table S3, the ln k values are - 8.97 ± 0.01, - 8.99 ± 0.02, - 9.04 ± 0.02, - 8.89 ±
.01, and - 8.79 ± 0.02 at -C≡C/-N molar ratios of 0.4, 0.8, 1.0, 1.4, and 1.8, respectively. The
time to complete the reaction are 7500, 8500, 9300,7900, and 7300s at -C≡C/-N molar ratios of 0.4,
.8, 1.0, 1.4, and 1.8, respectively. The results show that ln k has an inverse relationship with the
3
0
3
3
0
reaction time. The reason is that when one of the reactants is excessive, the other reactant will be
rapidly consumed and the reaction rate is fast, thus, the reaction time is shortened with the decrease
of reactant content.
Fig. 6. (a) Heat flow curves of the reaction between benzyl azide and different contents of ethyl
propiolate at 303.15 K; (b) Degree of reaction (α) vs time (t) of the reaction between benzyl azide and
different contents of ethyl propiolate at 303.15 K.
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Fig. 7. The histogram describing the relationship between ln k and the molar ratio of -C≡C to -N .
3
.5. Effect of different alkynes
The stereoelectronic effect of substituents has a significant effect on the rate of CuAAC click
reaction. Matyjaszewski studied the effects of electronic and steric effects on the reaction rate. They
found that for reactants with electron-withdrawal capacities and less sterically congested, the
40
reaction rate was fastest. Alkynes with α-carbonyl groups are more reactive than alkynes for the
Huisgen reaction. Moreover, the solubility of the substrates is also a key factor for a successful
4
1
outcome. To study the effect of different groups on the reaction rate, we selected the other two
different alkynes to react with benzyl azide and obtained their thermodynamics and kinetics
parameters.
Tables S4 and S5 listed the original data of the reactions between benzyl azide and 4-
nitrophenylacetylene, 3-butyne-2-one at four temperatures. Fig. 8(a) shown the heat flow of the
reactions between benzyl azide and different alkynes at 303.15 K, and Fig. 8(b) shown the heat and
time of three different reaction systems. At 303.15 K, the reaction process of benzyl azide with 4-
nitrophenylacetylene is the fastest growing reaction, followed by 3-butyne-2-one and ethyl
propiolate with almost similar behavior. The thermokinetic parameters of the reaction between
benzyl azide and 4-nitrophenylacetylene, 3-butyne-2-one at four temperatures were derived from
the Arrhenius equation, as shown in (Figs. 8(c) and (8d)), respectively. Tables 2 and 3 showed the
≠
≠
≠
values of ln k, A, E , ΔG , ΔH , and ΔS , and the correlative coefficient r values for the reaction
a
between azide and 4-nitrophenylacetylene, 3-butyne-2-one at different temperatures. As shown in
Tables 1, 2, and 3, the activation energies of the reaction of benzyl azide with 4-nitrophenylacetylene,
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ethyl propionate, and 3-butyne-2-one are 22.99 ± 0.13, 55.81 ± 0.74, and 56.75 ± 0.65 kJ mol ,
respectively, which indicate that the order of reaction rate of the three different alkynes with benzyl
azide is 4-nitrophenylacetylene > 3-butyne-2-one > ethyl propiolate.
To understand the difference in reaction kinetics between different alkynes, the click reaction
mechanism combined with theoretical calculations was used to study the difference in reactivity
between benzyl azide and different alkynes. The CuAAC reaction catalytic cycle proposed by
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Sharpless is widely accepted. Generally, copper-catalyzed azide-alkyne cycloaddition is 7 to 8
orders of magnitude faster than non-catalytic thermal cycloaddition.42 Therefore, the step of the
copper catalyst acting on the alkyne to form the intermediate (2) is highly critical and directly affects
the rate of the azide-alkyne cycloaddition reaction. By reducing the electron density on the sp carbon
atom, the activity of alkynyl ligand was increased, and the π-complexation of the δ-alkynyl-CuI
species was invoked.43-46 To verify our results, the compound structure was optimized by using
density functional theory with B3LYP method and 6-311G(d,p) basis set. Subsequently, the atomic
dipole moment-corrected Hirshfeld charge (ADCH)47 was calculated to study atomic charge
distribution. Additionally, the electrostatic potential (ESP) on molecular van der Waals (vdW)
surface was implemented via Multiwfn soft 48 to predicate the reaction site. Based on the Bader 49
3
point of view, vdW surface denotes the isosurface of electron density ρ=0.001 e/bohr . As presented
in Figs. 9 and 10 the charge density of 4-nitrophenylacetylene is -0.24, and the electrostatic potential
is -0.40, indicating that a more negative charge facilitates interaction with the copper ion. The
conjugate electron effect of aromatic ring structure enhances the reaction activity of the terminal
alkynes and facilitates the formation of the corresponding intermediates with the copper ion, which
is beneficial to the reaction. Therefore, the activation energy of p-nitrophenylene acetylene is the
lowest and its reaction rate is the fastest. Furthermore, ethyl propiolate and 3-butyn-2-one have a
similar behavior. From the above, the calculated results are in good agreement with our experimental
results.
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Fig. 8. (a) Heat flow curves of the reaction between benzyl azide and different alkynes at 303.15 K; (b)
The histogram describing the heat and time of the reaction benzyl azide with different alkynes at
-
1
303.15 K; (c) Plot of ln k vs. T for the benzyl azide and 4-nitrophenylacetylene system at different
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1
temperatures; (d) Plot of ln k vs. T for the benzyl azide and 3-butyne-2-one system at different
temperatures.
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≠
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≠
Table 2. Values of ln k, A, E, ΔG , ΔH , ΔS , and r for the reaction between azide and 4-nitrophenylacetylene at different temperatures
≠
≠
≠
/kJ mol-1
ln A
r
-1
-1
-1 -1
r
T/K
ln k
r
E
a
ΔG /kJ mol
ΔH /kJ mol
ΔS /J mol K
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95.15
-8.43±0.01
-8.34±0.01
-8.17±0.01
-8.08±0.01
0.999
0.997
0.994
0.985
22.99±0.13
0.93±0.28
0.974
92.95±1.95
94.02±2.40
94.88±1.27
95.93±2.05
94.45±1.27
20.48±0.79
-245.60±1.63
0.968
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99.15
03.15
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mean
≠
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Table 3. Values of ln k, A, E, ΔG , ΔH , ΔS , and r for the reaction between azide and 3-butyne-2-one at different temperatures
≠
≠
≠
/kJ mol-1
-1
-1
-1 -1
T/K
ln k
r
E
a
ln A
r
ΔG /kJ mol
ΔH /kJ mol
ΔS /J mol K
r
295.15
-9.42±0.01
-9.04±0.02
-8.80±0.01
0.994
0.988
0.995
55.81±0.74
13.34±0.21
0.994
95.38±1.98
95.81±1.86
96.47±1.84
53.31±2.03
-142.36±1.26
0.993
2
3
99.15
03.15
307.15
-8.52±0.02
0.993
97.06±1.57
96.18±0.74
mean
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Fig. 9. Charge distribution of compound (a)3-butyne-2-one; (b)ethyl propiolate; (c)4-
nitrophenylacetylene.
Fig. 10. Electrostatic potential (ESP) on molecular vdW surface of compound (a) 3-butyne-2-one; (b)
ethyl propiolate; (c) 4-nitrophenylacetylene; Surface local minima and maxima of ESP are represented
as cyan and orange spheres, respectively
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. Conclusions
The protocol based on microcalorimetry which is described in this paper offers a kinetic and
thermodynamic model in CuAAC reactions. Microcalorimetry can accurately measure the heat
change in the reaction process. This method facilitates the rapid screening of catalytic process steps,
as well as the study of the thermodynamics and kinetics of organic reactions. In this paper, the
thermodynamic properties of the reaction were investigated by changing the reaction conditions.
Temperature and catalyst content have great influence on the reaction rate. The experimental results
also show that CuI/DIPEA/HOAc system is an efficient catalytic system, which has the advantages
of short reaction time and mild reaction conditions.
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Acknowledgments
We are grateful for financial support from the Science Challenge Project (project no. TZ2018004),
Natural Science Foundation of China (21875192), Outstanding Youth Science and Technology
Talents Program of Sichuan (No. 19JCQN0085), National Defense Technology Foundation Project
(project no. JSJL2016404B002), Key Projects of the Pre-research Fund of the General Armament
Department (No. 6140720020101) and the Institute of Chemical Materials, China Academy of
Engineering Physics (project no. 18zh0043).
Supporting Information
Original data of the reaction of benzyl azide and different alkynes under different conditions (PDF)
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