AgN3-Catalyzed Hydroazidation of Terminal Alkynes and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.0c00836

The hydroazidation of alkynes is the most straightforward way to access vinyl azides-versatile building blocks in organic synthesis. We previously realized such a fundamental reaction of terminal alkynes using Ag₂CO₃ as a catalyst. H

Full text of DOI:10.1021/jacs.0c00836

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Article
AgN3-Catalyzed Hydroazidation of Terminal Alkynes and Mechanistic Studies
Shanshan Cao, Qinghe Ji, Huaizhi Li, Maolin Pang, Haiyan Yuan, Jingping Zhang, and Xihe Bi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00836 • Publication Date (Web): 26 Mar 2020
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AgN3-Catalyzed Hydroazidation of Terminal Alkynes and
Mechanistic Studies
Shanshan Cao,a Qinghe Ji,a Huaizhi Li,a Maolin Pang,*c Haiyan Yuan a Jingping Zhang*a and Xihe
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Bi*a,b
a
b
Department of Chemistry, Northeast Normal University, Changchun 130024, China. State Key Laboratory of
c
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
Chemistry Chinese Academy of Sciences, Changchun 130022, China.
Changchun Institute of Applied
ABSTRACT: The hydroazidation of alkynes is the most straightforward way to access vinyl azides – versatile building
blocks in organic synthesis. We previously realized such a fundamental reaction of terminal alkynes using Ag2CO3 as a
catalyst. However, the high catalyst loading seriously limits its practicality, and moreover the exact reaction mechanism
remains unclear. Here, on the basis of X-ray diffraction studies on the conversion of silver salts, we report the
identification of AgN3 as the real catalytic species in this reaction, and therefore developed a AgN3-catalyzed
hydroazidation of terminal alkynes. AgN3 proved to be a highly robust catalyst, as the loading of AgN3 could be as low as 5
mol%, and such a small proportion of AgN3 is still highly efficient even at a 50 mmol reaction scale. Further, the
combination of experimental investigations and theoretical calculations disclosed that the concerted addition mechanism
via a six-membered transition state is more favored than the classical silver acetylide mechanism.
challenging for silver-catalyzed reactions, because in situ-
formed organosilver intermediates readily undergo
■ INTRODUCTION
Alkynes are versatile building blocks for organic synthesis,
and the development of catalytic reactions to convert
carbon-carbon triple bonds (C≡C) into other
functionalities is of great value to a synthetic chemist.1
demetallation–protonation. In such situations,
a
technique capable of identifying the silver intermediate in
a reaction process would be highly desirable. X-ray
diffraction (XRD) is useful for identifying metal catalysts
and their activation and/or deactivation behavior during
reaction.9 Herein, for the first time, we applied XRD to
study a silver-catalyzed organic reaction and found that
Ag2CO3 underwent a rapid conversion to AgN3, thus
identifying AgN3 as the actual catalytic species (Figure 1b).
The hydrofunctionalization of alkynes is
a highly
appealing strategy for accessing functionalized alkenes in
an atom-economical manner.2 In this context, the
hydroazidation of alkynes is the most straightforward
approach to access α-vinyl azides,3 a class of synthetically
useful functionalized alkenes, that have been widely
exploited as versatile building blocks in organic
synthesis.4 However, the hydroazidation of alkynes is
primarily dependent on the Michael addition of azide
anions to the activated alkynes.5 In terms of more general
unactivated alkynes, no efficient method was available6
until we reported a Ag2CO3-catalyzed hydroazidation
reaction of terminal alkynes in 2014 (Figure 1a).7 Since
then, our group and others have further demonstrated the
power of this method by developing a wide variety of
Although AgN3 has been proposed as
a plausible
intermediate in some silver-catalyzed nitrogenation
reactions,10-13 no spectroscopic evidence was available to
support its existence. AgN3 itself proved to be a highly
robust catalyst for the hydroazidation of alkynes, with low
catalyst loading (5 mol%) and efficiency at large scale
reaction (up to 50 mmol). Finally, experimental
investigations and theoretical calculations clarified the
catalytic mechanism by AgN3.
a.
Ag2CO3-catalyzed hydroazidation of terminal alkynes (2014)
tandem reactions involving such
a silver-catalyzed
reaction as a critical step.4a,4b,8 However, this fundamental
reaction has not yet been well developed because of the
following significant issues: 1) the reaction mechanism is
unclear; 2) the loading of silver salt is high (equal to 20
mol% Ag), which has seriously limited the practicality of
this method. Hence, addressing these issues is essential
for eventually establishing this fundamental reaction.
Ag2CO
N3
3 (10 mol%)
TMSN3
R
H
+
R
 Chemo- and regioselective  Atom- and step-economy
 High catalyst loading  Unclear mechanism
b.
R
AgN3-catalyzed hydroazidation of terminal alkynes (this work)
AgN3
(5 mol%)
H
Ag
N3
N
N3 Ag
TMSN3
+
H
H2O, DMSO
R
N
The isolation and identification of organometallic
intermediates in a transition-metal-catalyzed reaction
would provide most usefull information of their possible
involvement in a reaction mechanism. However, this is
R
N
 AgN3 identified by XRD  Ag as an azido group shuttle  AgN3 as catalyst and reactant
 Low AgN3 catalyst loading  Unusual concerted addition mechanism
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Figure 1. Silver-catalyzed hydroazidation of terminal alkynes.
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■ COMPUTATIONAL METHODS
All of the DFT calculations were performed with the
Gaussian 09 package.14 The B3LYP15 functional with the
standard 6-31G(d,p) basis set (SDD16 basis set for Ag) was
used for geometry optimizations. The vibrational
frequencies were computed at the same level of theory to
check whether each optimized structure is an energy
minimum or a transition state and to evaluate its zero-
point vibrational energy (ZPVE). Intrinsic reaction
coordinate (IRC)17 calculations were carried out to
ascertain the true nature transition states. M06 functional
proposed by Truhlar et al.18 with the 6-31++G(d, p) basis
set (SDD basis set for Ag) was used to calculate the single-
point energies, because it has been widely used in recent
literature to account for noncovalent interactions in
transition metal system,19 including silver.20 Solvent
effects (solvent = Dimethylsulfoxide) was evaluated by
single-point energy calculations of the solution-phase
stationary points with SMD solvation model.21 Unless
other noted, all the discussions in the text are presented
using the SMD(DMSO)/M06/6-31++G(d,p)-SDD(Ag) level of
theory.
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■ RESULTS AND DISCUSSION
Figure 2. Reaction monitoring by powder XRD. Patterns at
Identification of AgN3 as the real catalyst. We initially
conducted an XRD study on the Ag2CO3-catalyzed
different times of the solid material generated from the
Ag2CO3-catalyzed hydroazidation reaction, the prepared
AgN3 (blue line) and β-Ag2CO3 (orange line). Safety Notice:
AgN3 should be avoided to be subjected to stimuli, such as
impact, heat (> 273 °C), friction using metal spoon, or
discharge. The explosion temperature generally needs to
reach 273 °C.
hydroazidation reaction (Figures
2
and S1). p-
Tolylacetylene (1a) was chosen as a model reactant. XRD
analysis of the crude insoluble reaction mixture clearly
showed a rapid and complete conversion of Ag2CO3 to
AgN3 within 5 min. Notably, vinyl azide 2a was not
observed in that time, but was after 20 min, as evidenced
by 1H NMR analysis (see SI, Figure S2). Several
experiments were conducted in parallel under the same
reaction conditions, and the insoluble catalytic mixture
was removed at different times from each reaction and
analyzed by XRD. For comparison, pure AgN3 was
separately prepared by the reaction of AgNO3 with
NaN3.22 The diffraction peaks of these solids were
consistent with those of pure AgN3 (Figure 2), indicating
that the catalytic species in this reaction is AgN3 rather
than Ag2CO3. To our knowledge, this is the first time XRD
To further confirm the unexpected conversion of
Ag2CO3 to AgN3, treatment of Ag2CO3 with trimethylsilyl
azide (TMSN3) was performed in the absence of alkyne
and water (Figure 3a). To our surprise, a rapid and
complete transformation from Ag2CO3 to AgN3 was
observed, as indicated by XRD analysis of the reaction
mixture (See SI, Figure S3). The side product
hexamethyldisiloxane
[(CH3)3Si-O-Si(CH3)3]
was
confirmed by H, C, and 29Si NMR spectroscopy and MS
analysis. To the best of our knowledge, the conversion of
Ag2CO3 with TMSN3 to yield AgN3 represents a new
inorganic reaction of silver salts. To rationalize the
reaction process, DFT calculations were performed
(Figure 3b). Three sequential reaction steps were
disclosed, including first Si–O bond formation,
decarboxylation, and second Si–O bond formation, for
which the energy barriers are 4.6, 9.5, and 11.7 kcal/mol,
respectively, suggesting that the conversion from Ag2CO3
to AgN3 proceeds quickly and smoothly under standard
conditions.
1
13
was used to study
a silver salt-catalyzed organic
reaction.23
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a)
b)
O
N3
Si
Si
Ag2CO3
+
TMSN3
AgN3
+
+
CO2
AgN3 x mol%
( )
1
2
3
4
80 C, DMSO
5 min
TMSN3
a)
Tol
+
Tol
H2O (2.0 equiv), 80 ºC, 90 min
DMSO
1a
2a
2.0 equiv
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N3
AgN
3 (5 mol%)
TMSN3
Tol
b)
+
Tol
H2O (2.0 equiv), 80 ºC, 90 min
Varied solvent
1a
2a
2.0 equiv
DMF
CH3CN
DMSO
THF
89%
65%
0%
1,4-Dioxane
trace
0%
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Figure 3. a) The reaction of Ag2CO3 with TMSN3 in absence
of alkyne and water. b) M06/6-31++G(d,p)-SDD (Ag)
computed free energy profile for the conversion of Ag2CO3 to
AgN3. DMSO acts as ligands.
Figure 4. a) Effect of the amount of AgN3 on the reaction
efficiency: 1a (0.5 mmol), TMSN3 (1.0 mmol), AgN3 (0~5
mol%), DMSO, 80 °C, 90 min. b) Effect of solvent: 1a (0.5
mmol), TMSN3 (1.0 mmol), AgN3 (5 mol%) in different
solvents, 80 ºC, 90 min. Yields refer to isolated products.
On the basis of this conversion, we envisage AgN3
should be the real catalyst for the hydroazidation of
terminal alkynes. To confirm this, AgN3 was prepared
separately and examined in the hydroazidation reaction
of p-tolylacetylene (1a) and TMSN3 in the presence of
water at 80 ºC (Figure 4a). Encouragingly, the
transformation efficiency increased with increasing AgN3
loading amount, and even as little as 5 mol% of AgN3
could catalyze a complete transformation affording the
desired vinyl azide 2a in 89% NMR yield. These results
clearly suggested that AgN3 was the real catalytic species
with high catalytic activity. Furthermore, the effect of
solvent on this AgN3-catalyzed reaction was examined
(Figure 4b). The solvent appeared to have significant
influence: use of DMSO gave an 86% yield of isolated
vinyl azide 2a, and, with the exception of DMF (54%
yield), other solvent such as CH3CN, THF, and 1,4-dioxane
were all ineffective.
AgN3 is a robust catalyst for the hydroazidation of
terminal alkynes. We then investigated the scope of the
AgN3-catalyzed hydroazidation reaction at a small scale. A
variety of aryl alkynes, bearing either electron-donating
or electron-withdrawing substituents at either the para or
meta positions of the phenyl ring, all smoothly reacted to
give corresponding vinyl azides 2a–2k in good-to-
excellent yields (82–93%, Scheme 1). Likewise, two
heteroaryl alkynes, 2-pyridyl and 2-thienyl acetylenes,
were reactive and converted into expected heteroaryl-
vinyl azides 2l and 2m in 81% and 70% yields, respectively.
The scope of this hydroazidation reaction was not limited
to aryl alkynes, as alkyl-substituted alkynes were also
viable substrates. For example, n-hexyl-, phenylethyl-,
and benzyl-substituted alkynes furnished expected
products 2aa–2ac in 82%, 86%, and 83% yields,
respectively. Moreover, alkyl alkynes bearing potentially
sensitive functional groups, such as hydroxy, chloro,
carboxyl, ether, thioether, and amino groups, all smoothly
underwent this reaction, delivering target products 2ad–
2aj in good-to-excellent yield (75–94%). In addition,
cyclohexylacetylene was suitable for this reaction,
affording 2ak in 73% yield. Notably, this strategy was also
applied to the direct postmodification of bioactive
compounds, clodinafop-propargyl (1al) and ethisterone
(1am), which afforded the corresponding vinyl azides 2al
and 2am in 85% and 78% yields, respectively. Overall,
these results clearly demonstrate the excellent catalytic
activity of AgN3 in the hydroazidation of terminal alkynes.
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To our knowledge, this is the first time to exploit AgN3 in
a low catalyst-loading Ag2CO3-catalyzed hydroazidation
an organic reaction.22
reaction in a one-pot two-step operation. The reaction
scope is quite broad and afforded the corresponding vinyl
azides in 70–81% yield.
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8
Encouraged by the above results, we further evaluated
the practicality of the AgN3-catalyzed hydroazidation
reaction on a multigram scale (Scheme 2). We were
pleased to find that the reactions of aryl alkynes 1a, 1b,
and 1g could be performed on an approximate 30~50
mmol scale, affording the corresponding products 2a, 2b,
and 2g in 89%, 77%, and 79% yield, respectively.
Additionally, functionalized aliphatic alkynes having
ether (2ag), thioether (2ah), hydroxy (2aj), protected
amino (2an), or cyclohexenyl (2ao) groups were
amenable to large-scale reactions, giving the desired vinyl
azides with good-to-high yields. Note that 5 mol% AgN3
was used in these reactions, thus further demonstrating
AgN3 is a robust catalyst for the hydroazidation reaction
of terminal alkynes.
Scheme 2. Multigram-scale synthesis of vinyl azides
AgN
N3
2
3 (5 mol%)
TMSN3
R
+
H2O (2 equiv)
DMSO, 80 ºC, 80-100 min
R
1
30~50 mmol
1.5 equiv
9
N3
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2a
2b
2g
, R' = Me, 50 mmol, 100 min, 89%
, R' = H, 50 mmol, 100 min, 77%
, R' = Cl, 40 mmol, 80 min, 79%
R'
N3
2ag
2ah
, X = O, 40 mmol, 90 min, 74%
, X = S, 40 mmol, 90 min, 76%
X
Ph
2a
N3
N3
N3
H
Ph
N
Ts
OH
Scheme 1. Scope of AgN3-catalyzed hydroazidation of
terminal alkynes on a small scale
2aj
2an
, 40 mmol
90 min, 84%
2ao
, 30 mmol
150 min, 77%
, 40 mmol
90 min, 82%
N3
Scheme 3. Ag2CO3-catalyzed hydroazidation of
alkynes in a one-pot two-step protocol
AgN
3 (5 mol%)
R
TMSN3
+
R
H2O (2.0 equiv)
DMSO, 80 oC, 90-120 min
1
2
2.0 equiv
N3
i) DMSO, 80 °C, 5 min
(het)Aryl alkynes
N3
Ag2CO3
TMSN3
+
R
Alkynes
ii)
(1.0 equiv)
2i
2j
2k
, R' = F, 82%
, R' = Cl, 89%
, R' = Me, 88%
2a
2b
2c
2d
2e
, R' = Me, 89%
, R' = H, 86%
, R' = Et, 92%
, R' = t-Bu, 93%
, R' = Ph, 88%
, R' = F, 85%
R'
2.5 mol%
H2O (2.0 equiv)
80 °C, 90 min
2
2.0 equiv
N3
N3
N3
N3
N3
N3
N3
N3
2f
Cl
R'
2g
2h
, R' = Cl, 90%
, R' = Br, 83%
N
S
tBu
Br
2l
2m
, 70%
, 81%
2a
2k
2b
2d
2h
2j
, 79%
N3
, 77%
, 80%
, 72%
, 72%
N3
Aliphatic alkynes
N3
( )4
N3
N3
N3
N3
N3
N3
N3
Ph
2aj
Ph
( )3
HO
Cl
2ae
Ph
( )4
( )4
( )4
( )4
HO
2ad
Cl
2ae
OH
, 78%
2aa
O
2ab
2ac
2ad
, 93%
, 82%
N3
( )4
, 86%
, 83%
, 88%
2aa
, 75%
, 70%
, 81%
, 76%
N3
N3
N3
N3
H
Ph
O
S
N
Ph
Ph
Ph
HO
2af
Experimental investigations and DFT studies on the
AgN3-catalyzed reaction mechanism. To gain
mechanistic insights into the AgN3-catalyzed reaction,
control experiments were designed and performed. As
summarized in Scheme 4, in the presence of two
equivalents of deuterium oxide (D2O), the reaction of 1b
with TMSN3 afforded a deuterated product [D]-2b in 85%
yield, and we identified that the di-deuterated, two kinds
of mono-deuterated and non-deuterated [D]-2b products
were forming in 36%, 36%, 14% and 14% of overall mixture
(Eq. 1). When starting from deuterated substrate [D]-1b,
[D]-2b was obtained in a similar yield (86%), albeit with a
low 10% and 6% mono-deuterated products (Eq. 2). These
two results implied that a silver-acetylide intermediate
formed from the alkyne by cleavage of the Csp–H bond
during the reaction. Then, using silver acetylide [Ag]-1b
as a reactant under reaction conditions, albeit in the
absence of AgN3, which resulted in a mixture of vinyl
azide 2b and alkyne 1b with a ratio of 1:2.8, thus silver
acetylide could be converted to alkyne in turn (Eq. 3). The
results support that there exists a fast equilibrium
between alkyne and silver-acetylide, which was also
verified by the DFT calculations. In contrast, no reaction
OH
2ag
2ah
2ai
2aj
, 94%
, 91%
, 76%
, 75%
, 76%
Structural modification of bioactive compounds
N3
HO
O
N3
Cl
F
O
H
O
N3
H
N
O
H
O
2ak
VA-Clodinafop-propargyl
2al
VA-Ethisterone
2am
, 73%
, 85%
, 78%
To avoid the direct operation of potentially explosive
AgN3, we try to develop a one-pot two-step protocol to
achieve similar high catalytic efficiency starting from the
employment of Ag2CO3 as catalyst (Scheme 3). Through
extensive investigations on the factors that could
influence the reaction outcome in such a one-pot two-
step protocol (See SI, Schemes S1-S2), we found that water
should be added after the in situ formation of AgN3,
otherwise the catalytic activity would be significantly
inhibited due to some kind of silicon-containing floc
simultaneously formed during the conversion from
Ag2CO3 to AgN3 and covered on the surface of AgN3
particles (See SI, Figures S5-6). Eventually, we established
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occurred if internal alkyne 1b-Me was used as the
substrate under the same conditions (Eq. 4).
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3
4
5
6
Scheme 4. Control experiments
7
8
9
Terminal alkyne
Ph
1b
N3
N3
N3
N3
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AgN
3 (5 mol%)
D
D
H
+
H
1
)
+
+
+
Ph
Ph
Ph
Ph
D O
(2.0 equiv)
2
TMSN3
D
H
D
H
80 ºC, DMSO
2.0 equiv
36%
36%
14%
14%
The ratio detected by 1H NMR
93%
Ph
D
1b
[D]-
N3
N3
N3
AgN
3 (5 mol%)
H
D
H
2
3
)
+
+
+
Ph
Ph
Ph
H O
(2.0 equiv)
80 ºC, DMSO
2
TMSN3
H
H
D
2.0 equiv
84%
10%
6%
The ratio detected by 1H NMR
N3
TMSN
3 (1.5 equiv)
)
Ph
Ag
Ph
H
+
Ph
H O
(2.0 equiv)
80 °C, DMSO
2
1b
[Ag]-
2b 1b
: , 1:2.8
(The ratio detected by 1H NMR)
Internal alkyne
AgN3 (5 mol%)
H2O (2.0 equiv)
DMSO, 80 o
Me
TMSN3
+
no reaction
4
)
Ph
C
1a
-Me
With the above experimental results in hand, density
functional theory (DFT) calculations were conducted to
gain more insights into the reaction mechanism. Initially,
the alkynes must coordinate with the AgN3 catalyst to
form an active complex. It was found that A1, the complex
representing double AgN3 activation, is more stable than
A1 by 16.9 kcal/mol. Gibbs free energies of the formation
of different likely active species (A1', A1, and A1-Me)
computed with respect to the separated reactants
(substrates, AgN3, and DMSO).24 Two activation models,
A1' and A1, were considered for the coordination of
terminal alkyne 1b with 1 or 2 molecules of AgN3 (Scheme
5a). Furthermore, natural population analysis (NPA)
charge analysis showed that the charge on the terminal
C2 in A1 (–0.438) is more negative than that in A1' (–0.314),
indicating that the C≡C triple bond of A1 is more
polarized and activated than that of A1'; therefore, the
silver ion preferentially attacks at C2 of A1, which is an
important driving force for the reaction. The C≡C triple
bond of the internal alkyne A1-Me is not polarized by
AgN3, as supported by the similar NPA charge on the C1
and C2 atoms. Therefore, the electrophilic attack of silver
ion at the C2 atom of A1-Me is unfavorable and therefore
does not occur, which is consistent with the experimental
observation (Scheme 4, Eq. 4).
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Figure 5. M06/6-31++G(d,p)-SDD (Ag) computed free energy profiles of two possible pathways for the AgN3-catalyzed
hydroazidation of terminal alkynes and the computed structures of the key transition sates (distances in Å).
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Scheme 5. Computed skeletons of three types of considered, but it could be excluded due to the high
1
2
3
4
5
6
7
8
silver-alkyne complexes and two types of reaction
modesa
energy barrier (TSA2-1, 26.3 kcal/mol). Intermediate A3
then undergoes proto-demetallation assisted by HN3
(TSA3, 5.2 kcal/mol) to provide vinyl azide product 2b. In
addition to the pathway of the reaction between terminal
alkyne and AgN3, HN3 can also be generated by the silver-
catalyzed reaction of water with TMSN3, which has a low
energy barrier (4.8 kcal/mol) (see SI, Figures S13-14). In
Path A, TSA2 is the highest stationary point and overall
kinetic barrier with 11.9 kcal/mol. Thus the silver acetylide
pathway is energetically feasible under the experimental
conditions.
a) NPA charges on Ag-alkyne complexes
b) Two reaction modes
N
N
N
N
N
N
N N N
N
N N
Ag
Ag
Ag
Ag
I
1
2
1
2
1
2
1
2
Ph
-0.08
Me
-0.03
Ph
H
Ph
H
Ph
H
-0.05 -0.31
0.01
-0.44
Ag
II
9
Ag
Ag
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N
N
N
N
N
N
N
N
N
Two possible pathways:
Mode I and Mode II
from A1
A1' (
)
A1 (
)
A1
-10.4
-27.3
-Me (-26.9)
Concerted addition mechanism. one of the bound
molecules of AgN3 (labeled 1 in Figure 5) undergoes
concerted addition across the triple bond of 1b via a six-
membered-ring transition state TSB1 (8.1 kcal/mol), in
which another molecule of AgN3 (labeled 2 in Figure 5) is
π-coordinated to 1b (Figure 5, Path B). This could
significantly reduce the energy barrier, thereby resulting
in alkenylsilver intermediate B1. This is the rate-
determining step in Path B (TSB1, 8.1 kcal/mol). In TSB1,
the attack of silver ions (Ag1) to terminal carbon atom C2
leads to further polarization of the C≡C triple bond, thus
favoring the addition of azido ion to the internal carbon
atom C1. In contrast, the concerted addition of internal
alkyne 1b-Me (TSB1-Me, 23.1 kcal/mol) is energetically
disfavored (see SI, Figure S15), which is also consistent
with the experimental results and NPA charge analysis
(Schemes 4 and 5a). Then, the demetallation–protonation
of alkenylsilver B1 with HN3 occurs via transition state
TSB2 (7.4 kcal/mol), affording product 2b, with the
regeneration of two molecules of AgN3 and three
molecules of DMSO. Note that the possibilities of
demetallation–protonation process assisted by water,
instead of HN3, were also considered: TSB2-2w is
calculated to be the most favored one among the
transition states assisted by different numbers of water,
but the energy barrier is too high (21.9 kcal/mol) to
proceed under this reaction conditions (see SI, Figures
S16-S17).
Taken together, the overall energy barrier in Path B is
3.8 kcal/mol more favored than that in Path A. In both
pathways, silver serves as an azido group shuttle to
transfer the azido functional group from TMSN3 to α-
vinyl azide products. In the meantime, DFT methods
M06-2X and ωB97XD with the same basis set 6-31++G(d,p)-
SDD(Ag) were employed to calculate the solvation single
point energies of the two Paths A and B for comparison
(Figures S18-19 and Table S1 in Supporting Information).
Our computational results indicated that M06, M06-2X
and ωB97XD functionals give the same trend in the
relative energies of transition states and intermediates.
The relative energies of transition states and
intermediates on the potential energy surfaces in Paths A
and B at M06/6-31++G(d,p)-SDD(Ag) level are much
lower than those at M06-2X(ωB97XD)/6-31++G(d,p)-
SDD(Ag) levels, the differences of Gibbs free energy
values between TSA2 and TSB1 using these three methods
are 3.8 (M06), 2.1 (M06-2X) and 4.5 (ωB97XD). Note that
e = 0.26
e = 0.45
e = 0.05



less activated
activated
unactivated
a The relative free energies in parentheses are given in
kcal/mol and the solvent ligand (DMSO) is omitted for
clarity.
Furthermore, based on the double activation mode A1,
two possible reaction pathways were proposed (Scheme
5b). One proceeds through the classical silver acetylide
intermediate (Mode I). As suggested by the results of the
deuteration studies (Scheme 4), silver acetylide is formed
during the reaction, which could react with the HN3
generated in situ to achieve hydroazidation. This is a
stepwise procedure involving Csp–H bond cleavage. In
another possible pathway (Mode II), the Ag ion activates
the terminal carbon atom (C2) and leads to the
polarization of the C≡C triple bond, which might induce a
concerted addition, that is, the azide anion of coordinated
AgN3 simultaneously attacks the internal carbon atom
(C1), resulting in the formation of the crucial alkenylsilver
intermediate. Based on the results of these experimental
studies and theoretical calculations, we carried out
further DFT calculations on these two possible reaction
pathways.
Silver acetylide mechanism. Silver acetylides are
commonly proposed as intermediates in silver-catalyzed
reactions of terminal alkynes.25,4b Therefore, we first
investigated the classical silver acetylide mechanism
(Figure 5, Path A). From the stable complex A1, one
molecule of AgN3 first activates the C–H bond of 1b via
the six-membered ring transition state TSA1 (6.2 kcal/mol)
to form a AgN3–silver-acetylide–HN3 complex A2. Notably,
the free energy of complex A2 is 0.9 kcal/mol higher than
that of complex A1, which indicates that the C(sp)–H
bond activation is an endergonic and reversible process. It
is feasible that the alkyne complex A1 and silver-
acetylide–HN3 complex A2 are in a fast equilibrium, due
to similar energies and small activation barriers between
these two species, which is consistent with experimental
observations (Scheme 4). Note that similar behavior has
been reported for copper-catalyzed Csp–H activation of
terminal alkynes by the formation of a copper acetylide.26
Next, the nucleophilic addition of HN3 to the triple bond
of the silver acetylide (TSA2, 11.9 kcal/mol relative to A1)
produces alkenylsilver intermediate A3. The nucleophilic
addition of AgN3 to the silver acetylide was also
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R
H
the activation of alkyne by one molecule of AgN3 in Mode
I and Mode II were considered, but finally was excluded
due to the high energy demands (See SI, Figures S20-22).
AgN3
N3
2
1
1
2
R
3
4
AgN3
H
R
5
6
7
8
AgN3
TMSN3
Ag
A1
N3
HN3
+
H2O
Path A
Path B
N3
Ag
TMSOH
R
AgN3
Ag
AgN3
A3/B1
9
R
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HN3
A2
■ CONCLUSION
highly efficient AgN3-catalyzed hydroazidation of
A
terminal alkynes is reported. The reaction mechanism has
been elucidated by the combined use of experimental
investigations and theoretical calculations. XRD studies
revealed AgN3 is the real and robust catalyst in the
Ag2CO3-catalyzed protocol. Furthermore, a new inorganic
reaction between Ag2CO3 and TMSN3 to yield AgN3 was
demonstrated and further rationalized by DFT calculation.
The AgN3-catalyzed hydroazidation of terminal alkynes
was efficient and practical because of the low catalyst
loading (5 mol%) and scalable reaction (up to 30~50
mmol). DFT calculations disclosed an unusual concerted
addition mechanism is more favorable than the stepwise
silver-acetylide mechanism. We therefore have developed
a fundamental AgN3-catalyzed hydroazidation reaction of
terminal alkynes and further clarified the catalytic
mechanism. Moreover, AgN3 was for the first time
exploited in organic synthesis, thus opening an avenue to
the exploration of its synthetic potency as a promising
azido reagent. Taken together, the significance of these
findings would not be only restricted to the specific
hydroazidation of alkynes, but also have important
inspiration on other silver-catalyzed reactions.
Figure 6. Noncovalent interaction (NCI) plots for TSA2 and
TSB1.
To get more information about the differences between
these two pathways, we carried out noncovalent
interaction (NCI) analysis27 for the critical transition
states, TSA2 and TSB1. NCI analysis shows that the
coordination of the C≡C triple bond (a2) and one
molecule of solvent (b2) to silver center Ag2 and two
molecules of solvent to Ag1 (c2, d2), as well as the
electrostatic interactions between the Ag1 and the azide
ion (e), effectively stabilize the structure of TSB1, thereby
promoting this step (Figure 6). However, in TSA2, the
strong electrostatic interaction e is absent. Overall, the
calculation results revealed that this concerted addition
mechanism (Path B) is favored over the silver acetylide
mechanism (Path A).
On the basis of the experimental and calculation results,
we propose two plausible reaction pathways A and B
(Scheme 6). A silver–π complex A1 with two molecules of
AgN3 is first formed from alkyne 1 in the presence of the
AgN3 catalyst. A1 may undergo cleavage of the Csp–H bond
of alkyne to get a AgN3–silver-acetylide–HN3 complex A2,
and this process was proved to be in a fast equilibrium
during the reaction. Then, the nucleophilic addition step
produces alkenylsilver intermediate A3 (Path A).
Alternatively, from A1, the slightly more favorable
concerted addition of cationic silver and azido anion to
the triple bond of alkyne 1 could also produce an
alkenylsilver intermediate B1 (A3 and B1 are isomers, Path
B). Subsequently, protonation of A3 or B1 by HN3 formed
in situ occurs and delivers the vinyl azide product 2, in
which the generation of HN3 proceeds through the
reaction of water with TMSN3 catalyzed by AgN3.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, additional figures, details of DFT
calculations, and NMR spectra are available free of charge via
the
Internet
at
(http://pubs.acs.org/page/jacsat/submission/authors.html).
AUTHOR INFORMATION
Corresponding Author
E-Mail: bixh507@nenu.edu.cn
jpzhang@nenu.edu.cn
mlpang@ciac.ac.cn
Scheme 6. Proposed mechanism for the AgN3-
catalyzed hydroazidation of terminal alkynes
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by NSFC (21871043,
21961130376, 21873018, and 21471145), Department of Science
and Technology of Jilin Province (20180101185JC and
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