Mechanism of Copper(I)-Catalyzed 5-Iodo-1,2,3-triazole Formation from Azide and Terminal Alkyne

Article abstract of DOI:10.1021/acs.joc.5b01536

5-Iodo-1,2,3-triazole (iodotriazole) can be prepared from a copper(I)-catalyzed reaction between azide and terminal alkyne in the presence of an iodinating agent, with 5-protio-1,2,3-triazole (protiotriazole) as the side product. The increasing utilities of iodotriazoles in synthetic and supramolecular chemistry drive the efforts in improving their selective syntheses based on a sound mechanistic understanding. A routinely proposed mechanism takes the cue from the copper(I)-catalyzed azide-alkyne cycloaddition, which includes copper(I) acetylide and triazolide as the early and the late intermediates, respectively. Instead of being protonated to afford protiotriazole, an iodinating agent presumably intercepts the copper(I) triazolide to give iodotriazole. The current work shows that copper(I) triazolide can be iodinated to afford iodotriazoles. However, when the reaction starts from a terminal alkyne as under the practical circumstances, 1-iodoalkyne (iodoalkyne) is an intermediate while copper(I) triazolide is bypassed on the reaction coordinate. The production of protiotriazole commences after almost all of the iodoalkyne is consumed. Using ¹H NMR to follow a homogeneous iodotriazole forming reaction, the rapid formation of an iodoalkyne is shown to dictate the selectivity of an iodotriazole over a protiotriazole. To ensure the exclusive production of iodotriazole, the complete conversion of an alkyne to an iodoalkyne has to, and can be, achieved at the early stage of the reaction.

Full text of DOI:10.1021/acs.joc.5b01536

Subscriber access provided by Stockholm University Library
Article
Mechanism of Copper(I)-Catalyzed 5-Iodo-1,2,3-
triazole Formation from Azide and Terminal Alkyne
David N. Barsoum, Najeah Okashah, Xiaoguang Zhang, and Lei Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01536 • Publication Date (Web): 09 Sep 2015
Downloaded from http://pubs.acs.org on September 9, 2015
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.
The Journal of Organic Chemistry 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 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Mechanism of Copper(I)ꢀCatalyzed 5ꢀIodoꢀ1,2,3ꢀ
triazole Formation from Azide and Terminal Alkyne
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
David N. Barsoum,1 Najeah Okashah,1 Xiaoguang Zhang, Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way,
Tallahassee, FL 32306ꢀ4390, United States
ABSTRACT. 5ꢀIodoꢀ1,2,3ꢀtriazole (iodotriazole) can be prepared from a copper(I)ꢀcatalyzed
reaction between azide and terminal alkyne in the presence of an iodinating agent, with 5ꢀprotioꢀ
1,2,3ꢀtriazole (protiotriazole) as the side product. The increasing utilities of iodotriazoles in
synthetic and supramolecular chemistry drive the efforts in improving their selective syntheses
based on a sound mechanistic understanding. A routinely proposed mechanism takes the cue
from the copper(I)ꢀcatalyzed azideꢀalkyne cycloaddition, which includes copper(I) acetylide and
triazolide as the early and the late intermediates, respectively. Instead of being protonated to
afford protiotriazole, an iodinating agent presumably intercepts the copper(I) triazolide to give
iodotriazole. The current work shows that copper(I) triazolide can be iodinated to afford
iodotriazoles. However, when the reaction starts from a terminal alkyne as under the practical
1 These authors contributed equally.
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
9
circumstances, 1ꢀiodoalkyne (iodoalkyne) is an intermediate while copper(I) triazolide is
bypassed on the reaction coordinate. The production of protiotriazole commences after almost all
iodoalkyne is consumed. Using 1H NMR to follow a homogenous iodotriazole forming reaction,
the rapid formation of iodoalkyne is shown to dictate the selectivity of iodotriazole over
protiotriazole. To ensure the exclusive production of iodotriazole, the complete conversion of
alkyne to iodoalkyne has to, and can be achieved at the early stage of the reaction.
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
Introduction
5ꢀIodoꢀ1,2,3ꢀtriazoles (iodotriazoles) have found increasing utilities in multicomponent
synthesis,1ꢀ9 halogen bondingꢀbased anion recognition,10ꢀ13 and radiolabeling of probes and drugs
in biomedical research.14,15 An iodotriazole can be synthesized from a copper(I)ꢀcatalyzed
cycloaddition between an organic azide with either a terminal alkyne in the presence of an
electrophilic iodinating agent (Figures 1aꢀc),16ꢀ20 or a 1ꢀiodoalkyne (iodoalkyne, Figure 1d).21,22
The method that our group reported (Figure 1c)19 is initialized by the reaction between an alkali
metal iodide and Cu(ClO4)2·6H2O, which quickly affords the CuI catalyst for the subsequent
ꢀ
cycloaddition, and the electrophilic I2 or I3 as the source of the iodo substituent.23 This method
avoids the preformation of iodoalkyne and the direct use of the often corrosive electrophilic
iodinating agents in the earlier methods, and has since been applied in producing iodotriazoles as
synthetic intermediates24 or anion receptors.11ꢀ13 In these iodotriazoleꢀforming reactions, 5ꢀ
protioꢀ1,2,3ꢀtriazole (protiotriazole) resulting from the more conventional copper(I)ꢀcatalyzed
azideꢀalkyne cycloaddition is the somewhat persistent side product. This mechanistic study was
ACS Paragon Plus Environment
2

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
motivated in part by the need of increasing iodo/protio selectivity in the synthesis of
iodotriazoles.
7
8
9
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
Figure 1. Selective methods for preparing iodotriazoles.
The postulated mechanisms of iodotriazole formation from either iodoalkyne or terminal
alkyne are summarized in Figure 2. One unclarified issue is whether a copper(I) triazolide (E)
intermediate is involved. Hein, Fokin, and coworkers described two possible routes starting from
iodoalkyne.21,25 One entails a cycloaddition between iodoalkyne and azide without breaking the
CꢀI bond (B/C→D, red route in Figure 2); the other requires a copper(I) triazolide intermediate
(B/C→E→D blue route). Most reports on reactions starting from a terminal alkyne accepted the
electrophilic iodination of a copper(I) triazolide intermediate as a necessary step (A/C→E→D,
blue route),15ꢀ18,26,27 including our own initial work.19 Mechanisms including similar steps of
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
electrophilic addition to a copper(I) triazolide have been proposed to explain the formations of 5ꢀ
chloroꢀ,28 5ꢀphosphonate,29 and 5ꢀaminoꢀ1,2,3ꢀtriazoles.30
7
8
9
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
Figure 2. Postulated paths to take terminal alkyne A and azide C to iodotriazole D, and related
products F and G. E+ = electrophile; I+ = potential iodinating agent, in this work I2 or iodoalkyne.
Some discussions on the mechanistic aspects of the iodotriazole formation have appeared in
literature26,31ꢀ33 in the context of the two proposals (either including or excluding copper(I)
triazolide) depicted in Figure 2.21,25 However, evidence that could unambiguously distinguish the
two mechanisms has yet to emerge. We previously reported that (a) the addition of allyl iodide in
the reaction mixture affords the 5ꢀallylated product 2 (Figure 3a), which supports the
involvement of a copper(I) triazolide,19 and (b) 19F NMR shows the formation of iodoalkyne (4)
from alkyne prior to the appearance of iodotriazole 5 (Figure 3b).20,34 The principal purpose of
this paper is to piece together these observations and to provide a coherent mechanistic picture of
copper(I)ꢀcatalyzed iodotriazole formation. The key question to ask is whether the copper(I)
triazolide is a required intermediate in the mechanistic sequence, or is an offꢀcycle species that
ACS Paragon Plus Environment
4

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
forms only under suboptimal conditions. The dependence of the reaction efficiency, in terms of
conversion and iodo/protio selectivity, on the reaction variables will also be characterized.
7
8
9
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
Figure 3. Observations supporting (a) copper(I) triazolide,19 and (b) iodoalkyne intermediates.20
Results and Discussion
1
1. Using H NMR to Monitor the Reaction in Real Time.35 In our previous study, aliquots of
the mixture from the heterogeneous reaction starting from 1ꢀethynylꢀ4ꢀfluorobenzene were
quenched before subjecting to 19F NMR analysis (Figure 3b).20 While this method provided
evidence of the iodoalkyne intermediate, revelations on other aspects of the reaction, in
1
particular the changes of nonꢀfluorinated species, were limited. In the current work, H NMR
spectroscopy was used to follow the changes of all organic components in an iodotriazoleꢀ
forming homogenous reaction. The conditions listed in the caption of Figure 4 were adapted
from our previously reported method19,20 and were modified appropriately to answer specific
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
questions regarding (a) reaction conversion, (b) iodo/protio selectivity, and (c) how to distinguish
two mechanistic pathways.
7
8
9
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
See
caption
N
N
N
N
N
N3
F
+
F
F
I
R
3
1
4
6: R = I; 7: R = H
Figure 4. A homogeneous reaction between azide 1 and alkyne 3 to afford iodotriazole 6 was
1
monitored by H NMR in real time. Protiotriazole 7 is the side product. Reagents: azide 1 (10
mM), alkyne 3 (10 mM), TEA (0ꢀ60 mM), LiI (20ꢀ45 mM), Cu(ClO4)2·6H2O (0ꢀ30 mM), in
CD3CN (0.5 mL).
Stock solutions of each reaction component were prepared in CD3CN. Metalꢀchelating 2ꢀ
picolyl azide36ꢀ38 1 was used due to its fast reaction rate under ligandꢀfree conditions, so that
millimolar concentrations of substrates could afford a significant conversion39 in a homogenous,
therefore, H NMR manageable environment (Figure 5).40 1ꢀEthynylꢀ4ꢀfluorobenzene 3 was the
1
alkyne of choice, whereas LiI was the iodide source owning to its excellent reactivity and
1
solubility in CD3CN. The timeꢀevolved H NMR spectra of an example reaction are shown in
Figure 5a. The relative conversion (disappearance of reactants and appearance of products) of
each species over time was calculated using the formulas listed in the caption of Figure 5. The
conversion values over time are plotted in Figure 5b.
ACS Paragon Plus Environment
6

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
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
Figure 5. (a) Timeꢀevolution of the H NMR spectrum of a reaction shown in Figure 4. The
reactants were dissolved in CD3CN (0.5 mL) in the following order: TEA (20 mM), DCM (2.5
mM, internal standard), LiI (40 mM), alkyne 3 (10 mM, blue), and Cu(ClO4)2·6H2O (20 mM).
Azide 1 (10 mM, gold) was added after the first spectrum was taken. Iodoalkyne 4: green;
iodotriazole 6: garnet. All other peaks in black were not used to determine conversions. (b)
Reaction profile showing the relative changes of different reaction participants over time,
calculated from the raw integration values based on the following formulas: azide (gold squares)
= [1]/([1] + [6] + [7]); alkyne (blue diamonds) = [3]/([3] + [4] + [6] + [7]); iodoalkyne (green
open circles) = [4]/([3] + [4] + [6] + [7]); iodotriazole (garnet filled circles) = [6]/([3] + [4] + [6]
+ [7]); and protiotriazole (not observed in this example) = [7]/([3] + [4] + [6] + [7]).
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
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
Figure 6. The effect of TEA on the outcome of the reaction. Blue open diamonds ꢀ alkyne 3,
green open circles – iodoalkyne 4, garnet filled circles – iodotriazole 6, and gold filled diamonds
– protiotriazole 7. Initial concentrations: alkyne 3 (10 mM), LiI (40 mM), TEA (4.0 mM), and
Cu(ClO4)2·6H2O (10 mM). Azide 1 (10 mM) was added after the first datum point was taken.
[TEA] was increased to 10, 13, 17 mM at the end of sections I, II, and III, respectively.
2. TEA Accelerates the Formation of Iodotriazole, Which Precedes that of Protiotriazole. In an
experiment designed for studying the role of TEA, alkyne 3 (10 mM), LiI (40 mM),
Cu(ClO4)2·6H2O (10 mM), and TEA (4 mM) were dissolved in CD3CN. The amount of
Cu(ClO4)2·6H2O as the stoichiometric oxidant is enough to convert 50% alkyne to iodotriazole,
leaving the other half to afford protiotriazole. Therefore, the information on the competitive
formation of iodoꢀ and protiotriazoles could be acquired. 1H NMR revealed that 18% iodoalkyne
4 (green open circles, Figure 6) formed after mixing the reaction components except the azide.
The addition of 2ꢀpicolyl azide 1 (10 mM, not shown) led to the formation of iodotriazole 6
(garnet filled circles) at the expense of iodoalkyne 4, while the concentration of alkyne 3 (blue
ACS Paragon Plus Environment
8

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
open diamonds) was unaltered. The effect of TEA on the reaction was studied by periodic
introduction of TEA aliquots into the reaction. At the 16ꢀmin mark, the concentration of TEA
was brought up to 10 mM (section II), which prompted an immediate conversion from alkyne 3
to iodoalkyne 4, and further on to iodotriazole 6 with a higher rate than the first leg of the
reaction. The next addition of TEA took place at the 43ꢀmin mark (section III), which caused a
similarly steep drop in alkyne 3. However, the jump in iodoalkyne 4 was not close in magnitude
to that of the previous segment, because the conversion rate of the incipiently formed iodoalkyne
4 to iodotriazole 6 was much greater than that in the last period.
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 observations up to this point suggest that the rate of iodotriazole formation from
iodoalkyne is sensitively dependent on [TEA]. The conversion of alkyne to iodoalkyne, but not
necessarily the rate, also depends on [TEA]. As soon as iodoalkyne 4 was fully consumed at ~
50ꢀmin mark, 50% of alkyne 3 had been converted to iodotriazole 6, which is the maximum
possible amount of iodotriazole production under the given conditions. At this point, the
formation of protiotriazole 7 commenced, which was significantly accelerated by the last
addition of TEA aliquot at the 58ꢀmin mark (section IV). The delayed formation of protiotriazole
7 suggests that the productions of iodoꢀ and protiotriazoles are governed by two independent
processes, rather than competing in the same catalytic cycle.
The kinetic dependence on [TEA] of both iodotriazole and protiotriazole formation can be
understood by the necessity of alkyne deprotonation in the early stages of the reactions. Beyond
the function of a base, TEA may act as a supporting ligand for solvating copper catalyst and may
accelerate ligand exchange in the catalytic cycle to assist in the cycloaddition step. The
significant beneficial effect of TEA on the formation of iodoalkyne will be elaborated in
Subsection 4.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
9
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
Figure 7. The effect of LiI on the outcome of the reaction. Spectrum ‘0’: the mixture of alkyne 3
(10 mM, blue), LiI (20 mM), Cu(ClO4)2·6H2O (20 mM), and TEA (20 mM). Spectrum ‘1’:
Azide 1 (10 mM, gold) was added in the reaction mixture. Spectra ‘2’ – ‘4’: [LiI] was increased
to 36, 50, 62 mM, respectively. Spectrum ‘5’: the reaction 18 min after spectrum ‘4’ was taken.
Iodoalkyne 4: green; iodotriazole 6: garnet.
3. Excess LiI is Needed to Maintain High Reactivity of the Copper(I) Catalyst. The effect of
LiI on the efficiency of iodotriazole formation was studied by increasing [LiI] over the course of
a reaction. The initial [LiI] was equal to [Cu(ClO4)2·6H2O], which was the minimum amount of
1
LiI to fully reduce copper(II) (equation 1). The H NMR of the mixture excluding azide 1 is
spectrum ‘0’ in Figure 7. In addition to the peaks of TEA, alkyne 3 (blue), and a small amount of
iodoalkyne 4 (green), there was a broad triplet at 6.7ꢀ6.9 ppm (pointed to by an arrow). The
addition of azide 1 (10 mM) did not alter the spectrum (Figure 7, spectrum ‘1’). The azide
ACS Paragon Plus Environment
10

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
signals were completely unseen, suggesting that the chelating azide 1 formed paramagnetic
copper(II) complexes36,38 that are likely in a rapid equilibrium with its copper(I) counterparts,
thus broadening the proton peaks of azide 1 down to the baseline. The addition of LiI eliminated
the broad triplet at 6.7ꢀ6.9 ppm; and simultaneously the azide signals appeared (spectrum ‘2’).
This observation suggests that added LiI reduced the remaining copper(II), thus restoring the
azide signals in the spectrum. In this case, the reaction depicted in equation 1 is an equilibrium
with a substantial amount of copper in +2 oxidation state, rather than a complete irreversible
reaction as we had presumed.23 The broad triplet is attributed to a copper(II) complex of TEA
(equation 2, Figure S2), and the observation of which marks a condition unsuitable for
iodotriazole formation.
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
ꢂ
ꢆ
2ꢀꢁ ꢀꢃꢄꢅ ꢇ + 2ꢈꢉꢊ ⇌ 2ꢀꢁꢀꢃꢄꢅ + 2ꢈꢉꢀꢃꢄꢅ + ꢊꢇ
(1)
(2)
ꢂ
ꢆ
ꢂ
ꢆ
ꢎ
ꢀꢁ ꢀꢃꢄꢅ ꢇ + nꢋꢌꢍ ⇌ [ꢀꢁ ꢋꢌꢍ ]ꢂꢀꢃꢄꢅꢆꢇ
The second addition of LiI narrowed the bandwidths of the azide peaks, and appeared to have
initiated the formation of iodotriazole 6 (garnet in spectrum ‘3’, Figure 7). The last addition of
LiI, which favors the formation of CuI from the acetonitrileꢀsolvated CuClO4 (equation 3),
further increased the rate of iodotriazole formation (spectrum ‘4’). The conversion values of
various components as a function of time is shown in Figure S3. These observations suggest that
in order to have a meaningful production of iodotriazole, the amount of LiI needs to be more
than enough to reduce all copper(II) to CuI (equation 3). Therefore, CuI, rather than acetonitrileꢀ
solvated copper(I), presumably catalyzes the iodotriazole formation.
ꢀꢁꢀꢃꢄꢅ + ꢈꢉꢊ ⇌ ꢀꢁꢊ + ꢈꢉꢀꢃꢄꢅ
(3)
At fixed concentrations of LiI and TEA, the incremental addition of Cu(ClO4)2·6H2O over the
course of a reaction led to the ultimate inhibition of the cycloaddition that affords iodotriazole
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
8
9
(Figure S4), due to the growth of inactive copper species including copper(II). Therefore,
[Cu(ClO4)2·6H2O] needs to be adequate to produce enough iodoalkyne for selective iodotriazole
formation, yet not too high that the formation of inactive copper complexes is favored.
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 results in this subsection provided guidance for improving the efficiency and selectivity of
iodotriazole formation. (a) Adequate amounts of TEA and LiI are needed to maintain copper in
its catalytically active form; (b) the inhibitory effect of Cu(ClO4)2·6H2O suggests that its
concentration should be scaled back if a more convenient stoichiometric oxidant could be
included; (c) because protiotriazole formation starts after all iodoalkyne is consumed, the
iodoalkyne formation needs to be maximized in order to achieve a high iodo/protio selectivity.
Figure 8. (a) Iodoalkyne 4 formation from alkyne 3 (10 mM) in the presence LiI (40 mM), Et3N
(10 or 20 mM), and Cu(ClO4)2 6H2O (0ꢀ25 mM). (b) [TEA] = 10 mM and [Cu(ClO4)2 6H2O] at
0’, ‘1’, ’2’, ‘3’, and ‘4’ were 0, 5, 10, 15, and 19 mM, respectively. (c) [TEA] = 20 mM and
[Cu(ClO4)2 6H2O] at 0’, ‘1’, ’2’, ‘3’, ‘4’, and ‘5’ were 0, 4, 10, 16, 21, 25 mM, respectively.
ACS Paragon Plus Environment
12

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4. Iodo/Protio Selectivity Depends on the Efficiency of Iodoalkyne Formation. The conversion
from iodoalkyne to iodotriazole precedes that of alkyne to protiotriazole (Figure 6). Therefore,
the efficient iodoalkyne formation appears to be the prerequisite for a selective synthesis of
iodotriazole over protiotriazole. The factors that contribute to the iodoalkyne formation were
studied (Figure 8a). In the absence of azide 1, mixing alkyne 3 (10 mM), LiI (40 mM),
Cu(ClO4)2·6H2O (5 mM), and TEA (10 mM) in CD3CN resulted in the instantaneous formation
of iodoalkyne 4 (Figure 8b, spectrum ‘1’) at 40% level.41 The addition of more Cu(ClO4)2·6H2O
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
(Figure 8b, spectra ‘2’ꢀ‘4’) failed to result in further increase in iodoalkyne production. The H
NMR spectra acquired when [Cu(ClO4)2·6H2O] was higher than 10 mM showed the broad triplet
in 6.7ꢀ6.9 ppm (Figure 8b, spectra ‘3’ and ‘4’), revealing the presence of the inhibitive
Cu(II)/TEA complex (Figure S2).42
When [TEA] was increased to 20 mM (Figure 8c), or higher up to 0.1 M (Figure S5),
increasing [Cu(ClO4)2·6H2O] facilitated the iodoalkyne formation linearly to completion. Under
such conditions, the selectivity of iodotriazole formation was expected to be maximized as the
terminal alkyne was no longer present. As shown in Figure 9, at 25 mM TEA, full conversion
from alkyne 3 to iodoalkyne 4 was reached (green open circle at time ‘0’). The addition of 2ꢀ
picolyl azide 1 at this point led to the rapid production of iodotriazole 6 (garnet filled circles).
Over 50% of iodoalkyne 4 (green open circles) was converted to iodotriazole 6 even before the
1
first H NMR spectrum was taken after the addition of azide 1. The complete conversion to
iodotriazole 6 was over within 30 min. No protiotriazole 7 was observed.
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
9
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
Figure 9. Full conversion to iodoalkyne 4 (green open circles) leads to the complete selectivity
for iodotriazole 5 (garnet filled circles). Concentrations: alkyne 3 (10 mM), LiI (40 mM),
Cu(ClO4)2·6H2O (25 mM), and TEA (25 mM). Azide 1 (10 mM) was added after the first
spectrum was taken. Inset: alkyne 3 (10 mM), Cu(ClO4)2·6H2O (2 mM), LiI (15 mM), I2 (8
mM), and TEA (30 mM). Azide 1 (10 mM) was added after the first spectrum was taken.
The initial iodoalkyne formation appears to proceed through deprotonation of terminal alkyne
followed by electrophilic iodination (equation 4). The deprotonation step is depicted in equation
5. In addition to being a base, TEA also activates I2 via the TEAI+ intermediate (equation 6).19,26
In conjunction with the accelerating effect of TEA on the cycloaddition step as described in the
previous subsection, we believe that TEA has three functions in this reaction: (a) deprotonating
the alkyne as a base; (b) activating I2 as a nucleophilic catalyst to enhancing the efficiency of
iodoalkyne formation; and (c) protecting CuI from aggregating during the reaction, thus
maintaining the catalytic potency of the copper(I) catalyst.
[
]
ꢏ ꢐ ꢀ ≡ ꢀ ꢐ ꢑ + ꢊꢇ + ꢌꢒꢓꢔ ⇌ ꢏ ꢐ ꢀ ≡ ꢀ ꢐ ꢊ + ꢌꢒꢓꢔꢑ ꢊ
(4)
ACS Paragon Plus Environment
14

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
ꢕ
ꢖ
[
]
ꢏ ꢐ ꢀ ≡ ꢀ ꢐ ꢑ + ꢌꢒꢓꢔ ⇌ ꢏ ꢐ ꢀ ≡ ꢀ + ꢌꢒꢓꢔꢑ
(5)
(6)
ꢊꢇ + ꢌꢒꢓꢔ ⇌ ꢌꢒꢓꢔꢊ ꢖ + ꢊꢕ
[
]
7
8
9
In our iodotriazole synthesis Cu(ClO4)2·6H2O has been used as the stoichiometric oxidant that
converts iodide to iodine (or triiodide), which reacts with alkyne to afford iodoalkyne. If iodine
(I2) was offered as the stoichiometric oxidant, then the reaction could be rendered catalytic in
Cu(ClO4)2·6H2O. The reaction shown in the inset of Figure 9 indeed proceeded smoothly in the
presence of 20 mol% Cu(ClO4)2·6H2O and 0.8 molar equivalent of I2, which is the first example
of copperꢀcatalyzed iodotriazole formation from terminal alkyne.43 TEA and LiI were added at
3.0 and 1.5 molar equivalents, respectively, which ensured that the iodoalkyne formation was
complete and the copper(I) catalyst for the cycloaddition was competent. A lower amount of
either component would have decreased either the conversion or the iodo/protio selectivity, or
both, of the catalytic reaction significantly.
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
5. More Electron-Deficient Alkyne Reacts Faster. The kinetic profiles of two reactions
involving fluorinated alkyne 3 or methoxylated alkyne 8 were compared to show the electronic
effect on the reactivity and iodo/protio selectivity (Figures 10a,b). The reaction conditions were
modified by reducing the copper loading so that both iodoꢀ and protiotriazole products could
form. In the experiments, all reaction components other than Cu(ClO4)2·6H2O were dissolved in
CD3CN in an NMR tube, and an initial NMR spectrum was taken before Cu(ClO4)2·6H2O was
added to start the reaction. Therefore, unlike the data presented in previous sections, no in situ
preformation of iodoalkyne was deliberately done.
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
7
8
9
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
Figure 10. Reaction progress monitored by 1H NMR. Alkyne = 3 in (a), 4ꢀethynylanisole (8) in
(b); and 3 in (c). Allyl iodide (10 mM) was also included in (c). Concentrations: azide 1 (10
mM), alkyne (10 mM), LiI (40 mM), Cu(ClO4)2·6H2O (10 mM), and TEA (20 mM) in CD3CN.
ACS Paragon Plus Environment
16

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Alkyne 3 was quickly converted to iodoalkyne 4, the consumption of which (green open
circles, Figure 10a) coincided with the production of iodotriazole 6 (garnet filled circles). The
appearance of protiotriazole 7 (gold filled diamonds) lagged behind, but took over the latter half
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
of the reaction after iodoalkyne 4 was consumed. The timeꢀevolved H NMR spectra of this
reaction are shown in Figure S6a. Starting with alkyne 8 with the electronꢀricher methoxy
substituent (Figure 10b), the rapid production of iodoalkyne was not affected. Rather, the initial
rate of iodotriazole formation dropped by 4 folds. Protiotriazole was not observed during the
allotted time.
Preliminary conclusions could be drawn based on the dependence of the reaction on the
electronic property of the alkyne. The production of iodoalkyne appears insensitive to the
substituent on the alkyne. Therefore, the iodoalkyne formation step is not turnꢀover limiting in
this reaction. The electronꢀdeficient iodoalkyne reacts faster with azide 1 in the cycloaddition
step than its electronꢀricher, methoxylated counterpart, to afford iodotriazole 6 and protiotriazole
7 sequentially. This observation suggests that the cycloaddition step is turnꢀover limiting, and is
favored by an electronꢀdeficient iodoalkyne. Presumably, backbonding of copper(I) to
iodoalkyne,33,44,45 which should be favored by an electronꢀwithdrawing substituent, accelerates
the cycloaddition step.46
6. Allyltriazole Forms after Iodotriazole, Simultaneously with Protiotriazole. To provide more
details in the allylation reaction depicted in Figure 3a, allyl iodide was introduced into the
reaction mixture that produced the data in Figure 10a. Comparing to the reaction progress data in
Figure 10a, iodotriazole 6 reached a similar conversion in 20 min (Figure 10c; the spectra are
shown in Figure S6b). The production of protiotriazole 7 (gold filled diamonds) picked up at this
point. Allyltriazole 11 (purple crosses in Figure 10c) appeared together with protiotriazole 7. The
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
6
7
8
9
delayed coꢀproduction of protiotriazole 7 and allyltriazole 11 supports the mechanism that both
compounds are formed via a copper(I) triazolide intermediate, after the reaction to produce
iodotriazole is (almost) over in a separate reaction pathway.
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 1. Electrophile trapping of [CuI(NHC)(triazolide)] 12a
a. Conditions: Compound 12 (10 mM) and electrophile (10 mM each) in CD3CN with 12.5%
(v/v) THF at rt. The yields were calculated from the 1H NMR spectra of the reaction mixtures.
7. Copper(I) Triazolide is a Viable Substrate to be Iodinated. The reactivity of a copper(I)
triazolide in iodination to afford iodotriazole was also investigated. Following a modified
synthesis (see Scheme 1 in the Experimental Section) by Straub and coworkers,47 an Nꢀ
heterocyclic carbene (NHC) supported copper(I) triazolide 12 was prepared (Table 1). In the
presence of iodoalkyne 4,48 copper(I) triazolide 12 was slowly converted to iodotriazole 13
(Table 1, entries 1 and 2), while the alkynylated triazole 15 was observed as the minor product.
This reaction demonstrated that an iodoalkyne could be an (surprisingly reluctant) electrophilic
iodination source for the NHCꢀsupported copper(I) triazolide 12 to afford an iodotriazole – part
ACS Paragon Plus Environment
18

Page 19 of 33
The Journal of Organic Chemistry
1
2
of the less favored of the two mechanistic models proposed by Hein, Fokin, and coworkers.21
Allyl iodide turned out to be a more competent electrophile in the reaction with copper(I)
3
4
5
6
7
8
9
1
triazolide 12, reaching 58% yield (based on H NMR) of allyltriazole 14 after 3 h (entry 3). The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
low reactivity of iodoalkyne in the reaction with copper(I) triazolide 12 was further demonstrated
in the experiment while both iodoalkyne 4 and allyl iodide competed for coupling with the
triazolide (entry 4). The timeꢀcourse experiment showed that both iodotriazole 13 and
allyltriazole 14 formed simultaneously with the latter having a higher rate (Figure 11).49 This
kinetic profile is in stark contrast to that in Figure 10c, in which allyltriazole did not appear until
the iodotriazole formation phase was almost over. Therefore, the comparison between kinetic
profiles in Figures 10c and 11 further supports the conclusion that when the iodotriazole
formation reaction starts from terminal alkyne and azide in the presence of an iodinating agent,
the copper(I) tirazolide becomes an incompetent intermediate that is bypassed on the reaction
coordinate altogether. In the last experiment (entry 5), the strongly electrophilic molecular iodine
easily outcompeted allyl iodide to deliver iodotriazole 13 within minutes.
1
Figure 11. Reaction progress of entry #4 in Table 1 monitored by H NMR. Concentrations:
[CuI(NHC)(triazolide)] (12, 10 mM), iodoalkyne 4 (10 mM), and allyl iodide (10 mM) in
CD3CN with 12.5% (v/v) THF at rt.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
8. Mechanistic Proposal. The iodotriazole formation mechanism as shown in Figure 12 starts
from the rapid reduction of Cu(ClO4)2·6H2O by an alkali metal iodide (e.g., LiI). With an
adequate amount of iodide, the resulting CuI is the catalyst for the subsequent cycloaddition
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
ꢀ
reaction, while molecular iodine (I2) or triiodide ions (I3 as shown) act as the iodinating agent.
The rapid, TEAꢀaided conversion of alkyne to iodoalkyne (depicted in the grey box), which is
completed within the time of preparing an NMR sample, sends iodoalkyne into the catalytic
cycle on right to produce iodotriazole. Based on our previous work, an accelerating ligand such
as tris[(1ꢀbenzylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)methyl]amine (TBTA)50 might be needed for the
cycloaddition step,20 if the azide is not selfꢀaccelerating via chelating copper. The cycloaddition
between a terminal alkyne and an azide – the typical ‘click’ reaction to produce protiotriazole,
occurs much slower and operates through a separate catalytic cycle that involves a copper(I)
triazolide intermediate (left, Figure 12). Electrophiles such as allyl iodide may compete with the
proton source to react with copper(I) triazolide to afford 5ꢀsubstituted triazoles. Therefore, both
mechanistic pathways proposed by Hein et al.,21 which include either the cycloaddition between
iodoalkyne and azide, or the iodination of a copper(I) triazolide intermediate, are verifiable.
However, under various reported experimental conditions in which the reaction starts from either
terminal alkyne or iodoalkyne, the reaction bypasses the copper(I) triazolide intermediate by
proceeding in a separate pathway via a rapid formation of iodoalkyne followed by the copper(I)ꢀ
catalyzed cycloaddition with an azide.
ACS Paragon Plus Environment
20

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
N
N
R1
R1
N
N
N
N
H
R2
R2
CuI
R2
H
5 I- + 2 Cu2+
CuII
I
CuI
R1 N3
8
R2
I
9
H
I
R2
N
R1
-
2 CuII
2 CuII
I3
+
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
N
N
CuI
CuIII
I
R1
TEA
R2
2 I-
I
(TEA)H+ TEA
+ I-
CuI
R2
R2
N
CuII
CuI
N
N
CuII
TEA I+
R1
R2
I
(TEA)H+
R1 N3
N
N
N
CuI
I
CuI
N
R1
N
R1
R2
N
N
N
N
CuIII
I
R2
I
R2
I
Figure 12. Proposed mechanism of iodotriazole formation under the conditions shown in the
caption of Figure 4. Copper in oxidation states +1, +2, and +3 are colorꢀcoded orange, blue, and
green, respectively.
Conclusions
Azide and alkyne undergo copper(I)ꢀcatalyzed cycloaddition in the presence of an electrophilic
iodinating agent to afford iodotriazole, while protiotriazole is the undesired but sometimes
persistent side product. Two mechanisms have been proposed for the iodotriazole formation, in
which iodination occurs either on the alkyne outside of the catalytic cycle to afford iodoalkyne,
or on the copper(I) triazolide intermediate within the catalytic cycle to afford iodotriazole. This
work provides evidence to support the former scenario, in which the iodoalkyne forms rapidly
from alkyne in the presence of an iodinating agent. Iodoalkyne then undergoes cycloaddition
with an azide to afford iodotriazole. The protiotriazole side product is produced via a different
pathway that operates after the iodotriazole formation is almost completed. This information
leads to the recommendation that in order to achieve exclusive selectivity of iodotriazole in a
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
reaction starting from a terminal alkyne, conditions need to be applied to ensure full in situ
conversion of alkyne to iodoalkyne. Specific to our reported method, the optimized conditions
shall include adequate quantities of the nucleophilic base TEA and the iodide source LiI.
Copper(I) triazolide is confirmed to be reactive towards certain electrophiles, including I2 to
afford iodotriazole. However, in reality it is bypassed on the reaction coordinate that starts from
terminal alkyne.
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
Experimental Section
1. Materials and General Methods. Reagents and solvents were purchased from various
commercial sources and were used without further purification unless otherwise stated.
Cu(ClO4)2⋅6H2O was dried in a vacuum oven at 40 °C before use. Stock solutions of each
reaction component were prepared in advance except Cu(ClO4)2⋅6H2O, which was prepared
1
13
immediately prior to mixing because of its tendency to lose efficacy in acetonitrile. H and C
NMR spectra were recorded at 500 and 125 MHz respectively. All chemical shifts were reported
in δ units relative to tetramethylsilane. High resolution mass spectra (HRMS) were obtained
using a timeꢀofꢀflight analyzer. The identity of compounds 1,36 4,20 6,19 7,47 9,19 10,37 13,19 14,16
16,19 17,51 and 1852 were verified by comparing with reported data. These compounds were
prepared when needed by following reported procedures.
2. Synthesis and Characterization of New Compounds. Compound 11 was prepared by
following a reported procedure.19 2ꢀPicolyl azide (27 mg, 0.20 mmol) was dissolved in THF (1
mL). To this solution were added NaI (30 mg, 0.20 mmol), Na2S2O3 (158 mg, 1.0 mmol), and
Cu(ClO4)2·6H2O (37 mg, 0.10 mmol). The reaction mixture was stirred for ∼5 min before DBU
(30 ꢁL, 0.20 mmol), allyl iodide (30 ꢁL, 0.33 mmol), and 1ꢀethynylꢀ4ꢀfluorobenzene (28 mg,
ACS Paragon Plus Environment
22

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
0.23 mmol) were added. The stirring was continued at rt for 12 h. Upon completion, the reaction
mixture was eluted through a short silica column using CH2Cl2 to remove the inorganic
materials. Solvent removal followed by purification on a silica column eluted with CH2Cl2
containing an increasing amount of ethyl acetate up to 50% (v/v) afforded a pale yellow oil in
12% yield (7.0 mg). 1H NMR (500 MHz, CD3CN) δ/ppm 8.52 (bs, 1H), 7.75 (td, J = 7.5 Hz, 2.0
Hz, 1H), 7.73ꢀ7.69 (m, 2H), 7.29 (t, J = 6.5 Hz, 1H), 7.22ꢀ7.18 (m, 3H), 5.88ꢀ5.80 (m, 1H), 5.62
(s, 2H), 5.04 (dt, J = 10.5 Hz, 1.0 Hz, 1H), 4.86 (dt, J = 17.5 Hz, 1.5 Hz, 1H), 3.62 (dt, J = 5.5
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
13
1
Hz, 2 Hz, 2H); C NMR (125 MHz, CD3CN) δ/ppm. 163.7 (d, JCF = 242 Hz), 156.4, 150.8,
3
2
138.6, 134.1, 132.7, 130.2 (d, JCF = 7.5 Hz), 129.5, 124.5, 123.4, 118.1, 116.9 (d, JCF = 21.2
Hz), 54.5, 28.0; HRMS (ESI): m/z [M+H]+ calcd for C17H16FN4: 295.1359; found 295.1359.
iPr
iPr
iPr
iPr
N
N
Cu Powder
N
N
iPr
iPr
iPr
iPr
ACN, air
rt, 24 h
Cl
Cu
Cl
16
17, 97%
Li
Ph
in THF,
-78 oC to rt
iPr
iPr
iPr
iPr
N
N
N
N
BnN3
iPr
iPr
iPr
iPr
Cu
Ph
Cu
Cu(PPh3)3Br
THF
35 oC, 1 h
18, 93%
N
N
N
12, 63%
Scheme 1. Synthesis of [CuI(NHC)(triazolide)] 12.
[CuI(NHC)Cl] (17).51 To a flameꢀdried roundꢀbottom flask equipped with a magnetic stirring
bar, compound 16 (2.0 g, 4.68 mmol) was added followed by Cu powder (1.5 g, 23.4 mmol) and
acetonitrile (50 mL). The reaction was stirred vigorously at rt for 10 min, then at 55 °C for 24 h.
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
The hot reaction mixture was filtered through a silica pad to remove excess copper powder and
the solvent was removed under vacuum to provide a white solid. The yield was 2.2 g (97%, 4.5
7
8
9
1
mmol). H NMR (500 MHz, CDCl3) δ/ppm 7.40 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 7.7 Hz, 4H),
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
4.02 (s, 4H), 3.10ꢀ3.02 (m, 4H), 1.37 (d, J = 6.5 Hz, 12H), 1.34 (t, J = 6.5 Hz, 12H).
[CuI(NHC)(PhꢀC≡C)] (18).52 To a dry Schlenk flask charged with argon and equipped with a
magnetic stirring bar, compound 17 (2.21 g, 4.52 mmol) was suspended in dry THF (50 mL) and
cooled to ꢀ78 °C in a dry ice/acetone bath. To this, a lithium phenylacetylide solution in THF
(6.2 mL, 1.0 M in THF, 6.2 mmol) was added dropwise over 5 min. The cold bath was then
removed and the reaction mixture was stirred vigorously for 2 h as it slowly warmed to rt. The
solvent was removed in vacuo on the Schlenk line to provide a gummy yellow solid. DCM (40
mL) was added to the crude product, and the solution was filtered through a Celite plug (slurry
packed in DCM) then washed with additional DCM (3 × 25 mL). The filtrate was concentrated
under vacuum on the Schlenk line to give a yellow solid, which was reꢀdissolved in a minimal
amount of DCM and combined with hexanes (100 mL). The flask was capped and placed in a
freezer for approximately 1 h. The precipitate was filtered, washed with hexanes and dried under
1
high vacuum to afford a pale yellow powder. The yield was 2.32 g (93%, 4.18 mmol). H NMR
(500 MHz, C6D6) δ/ppm 7.42 (d, J = 7.0 Hz, 2H), 7.17ꢀ7.14 (m, 2H), 7.04 (d, J = 8.0 Hz, 4H),
6.82 (t, J = 7.5 Hz, 2H), 6.76 (t, J = 7.5 Hz, 1H), 3.12 (s, 4H), 2.99ꢀ2.94 (m, 4H), 1.48 (d, J = 6.1
Hz, 12H), 1.17 (d, J = 6.9 Hz, 12H).
[CuI(NHC)(triazolide)] (12). This procedure is modified from that reported in reference #47.
To a dry Schlenk flask charged with argon and equipped with a magnetic stirring bar, compound
18 (0.43 g, 0.77 mmol) and Cu(PPh3)3Br (36 mg, 0.04 mmol) was suspended in dry THF (10
mL). Benzyl azide (145 ꢀL, 1.16 mmol) was added and the reaction mixture was stirred
ACS Paragon Plus Environment
24

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
vigorously for 3 h. The solvent was removed in vacuo and the crude product was triturated with
toluene. The solid was dissolved in DCM and filtered through a Celite plug (slurry in DCM).
Hexanes were added to the filtrate and the solution was placed in a freezer for approximately 1 h.
The precipitate was collected and dried in vacuo, to afford a white amorphous solid. The yield
was 340 mg (64%). 1H NMR (500 MHz, CD2Cl2) δ/ppm 7.44 (t, J = 7.8 Hz, 4H), 7.25 (d, J = 8.0
Hz, 4H), 7.18ꢀ7.17 (m, 3H), 6.97 (tt, J = 8.0, 1.5 Hz, 1H), 6.90 (t, J = 8.0 Hz, 2H), 6.64 (dd, J =
3.9, 1.6 Hz, 2H), 4.50 (s, 2H), 4.05 (s, 4H), 3.16–3.07 (m, 4H), 1.32 (d, J = 6.9 Hz, 12H), 1.19
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
(d, J = 6.9 Hz, 12H). C NMR (125 MHz, CD2Cl2) δ/ppm 205.2, 155.2, 152.8, 147.5, 139.2,
136.4, 135.2, 130.5, 128.7, 128.4, 127.2, 127.1, 125.4, 125.3, 125.2, 55.9, 29.4, 25.6, 24.1.
HRMS (ESI): m/z [M+H]+ calcd for C42H51N5Cu: 688.3440; found 688.3425.
3. Procedures of Using 1H NMR to Monitor Reaction Progress. A Representative Procedure of
1
the in situ H NMR Assay (azide was added last). Stock solutions in CD3CN were prepared in
advance for all reaction components except Cu(ClO4)2·6H2O, because of its tendency to lose
efficacy in acetonitrile. The Cu(ClO4)2·6H2O solution was prepared immediately prior to the
experiment to limit this effect. TEA (50 ꢁL, 200 mM), DCM (25 ꢁL, 50 mM, internal standard),
1ꢀethynylꢀ4ꢀfluorobenzene (25 µL, 200 mM), and LiI (100 ꢁL, 200 mM) were added to the NMR
tube sealed with a rubber septum sequentially using airtight glass syringes. The mixture was
diluted with 225 µL of CD3CN before adding Cu(ClO4)2·6H2O (50 ꢁL, 200 mM). The first NMR
spectrum taken was marked as time “0”. After collecting the initial scan, 2ꢀpicolyl azide (25 µL,
200 mM) was injected into the sample. This injection served as the start time for the reaction. All
the concentrations listed in the procedure are stock solution concentrations of individual reaction
participants. The final concentrations of all reaction components after mixing of this experiment
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
6
are listed in the caption of Figure 5. NMR spectra were collected every 3 min over the course of
the reaction for 1.5 h on average.
7
8
9
1
A Representative Procedure of the in situ H NMR Assay (copper(II) perchlorate was added
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
last). TEA (25 ꢁL, 200 mM), DCM (25 ꢁL, 50 mM), 1ꢀethynylꢀ4ꢀfluorobenzene (25 ꢁL, 200
mM), LiI (100 ꢁL, 200 mM), and 2ꢀpicolyl azide (25 ꢁL, 200 mM) were added to a rubber
septumꢀsealed NMR tube sequentially using glass syringes. Then 250 ꢁL of CD3CN was injected
into the NMR tube. An initial scan of the mixture was taken which served as time “0”.
Immediately prior to the spectral acquisition, Cu(ClO4)2·6H2O (50 ꢁL, 200 mM) was injected
into the sample. This injection served as the start time for the reaction. The final concentrations
of all the reaction components are listed in the caption of Figure 10. NMR spectra were collected
every 3 min over the course of the reaction for 1.5 on average.
The Procedure to Study the Effect of TEA on the Outcome of the Reaction. TEA (10 ꢁL, 200
mM), DCM (25 ꢁL, 50 mM, internal standard), 1ꢀethynylꢀ4ꢀfluorobenzene (25 µL, 200 mM),
and LiI (100 ꢁL, 200 mM) were added to a rubber septumꢀsealed NMR tube sequentially using
glass syringes. The mixture was diluted with 265 µL of CD3CN before adding Cu(ClO4)2·6H2O
(25 ꢁL, 200 mM). An initial NMR was taken, which marked as time “0”. After collecting the
initial scan, 2ꢀpicolyl azide (25 µL, 200 mM) was injected into the sample. This injection served
as the start time for the reaction. The concentrations of all reaction components at the start of the
reaction are listed in the caption of Figure 6. Six NMR scans were then collected from the
sample every 3 min. Immediately after the sixth scan, TEA (15 µL, 200 mM) was injected into
the NMR tube and the reaction was again scanned six times. The process was repeated two more
cycles with sequential additions of TEA (10 µL × 2 at 200 mM). The NMR experiments to study
the effects of LiI and Cu(ClO4)2·6H2O were conducted similarly.
ACS Paragon Plus Environment
26

Page 27 of 33
The Journal of Organic Chemistry
1
2
Supporting Information. Additional figures and 1H/13C NMR spectra of new compounds. This
3
4
5
6
material is available free of charge via the Internet at http://pubs.acs.org.
7
8
9
AUTHOR INFORMATION
Corresponding Author
lzhu@chem.fsu.edu
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
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation (CHE1213574). N.O. was a
recipient of the Bess H. Ward Honors Thesis Award and the Mentored Research and Creative
Endeavors Award. D.N.B was supported by Delos F. and Frances L. Detar Undergraduate
Research Award.
REFERENCES
(1) Deng, J.; Wu, Y.ꢀM.; Chen, Q.ꢀY. Synthesis 2005, 16, 2730.
(2) Schwartz, E.; Breitenkamp, K.; Fokin, V. V. Macromolecules 2011, 44, 4735.
(3) Bogdan, A. R.; James, K. Org. Lett. 2011, 13, 4060.
(4) Morris, J. C.; Chiche, J.; Grellier, C.; Lopez, M.; Bornaghi, L. F.; Maresca, A.; Supuran,
C. T.; Pouysségur, J.; Poulsen, S.ꢀA. J. Med. Chem. 2011, 54, 6905.
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
(5) Worrell, B. T.; Hein, J. E.; Fokin, V. V. Angew. Chem. Int. Ed. 2012, 51, 11791.
5
6
7
8
9
(6) Carcenac, Y.; DavidꢀQuillot, F.; Abarbri, M.; Duchêne, A.; Thibonnet, J. Synthesis 2013,
45, 633.
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
(7) Bédard, A.ꢀC.; Collins, S. K. Org. Lett. 2014, 16, 5286.
(8) Wang, D.; Chen, S.; Chen, B. Tetrahedron Lett. 2014, 55, 7026.
(9) Hassan, S.; Müller, T. J. J. Adv. Synth. Catal. 2015, 357, 617.
(10) Schulze, B.; Schubert, U. S. Chem. Soc. Rev. 2014, 43, 2522.
(11) Mullaney, B. R.; Thompson, A. L.; Beer, P. D. Angew. Chem. Int. Ed. 2014, 126, 11642.
(12) Mullaney, B. R.; Partridge, B. E.; Beer, P. D. Chem. Eur. J. 2015, 21, 1660.
(13) Robinson, S. W.; Mustoe, C. L.; White, N. G.; Brown, A.; Thompson, A. L.; Kennepohl,
P.; Beer, P. D. J. Am. Chem. Soc. 2015, 137, 499.
(14) Yan, R.; ElꢀEmir, E.; Rajkumar, V.; Robson, M.; Jathoul, A. P.; Pedley, R. B.; Årstad, E.
Angew. Chem. Int. Ed. 2011, 50, 6793.
(15) Yan, R.; Sander, K.; Galante, E.; Rajkumar, V.; Badar, A.; Robson, M.; ElꢀEmir, E.;
Lythgoe, M. F.; Pedley, R. B.; Årstad, E. J. Am. Chem. Soc. 2013, 135, 703.
(16) Wu, Y.ꢀM.; Deng, J.; Li, Y.; Chen, Q.ꢀY. Synthesis 2005, 1314.
(17) Li, L.; Zhang, G.; Zhu, A.; Zhang, L. J. Org. Chem. 2008, 73, 3630.
(18) Smith, N. W.; Polenz, B. P.; Johnson, S. B.; Dzyuba, S. V. Tetrahedron Lett. 2010, 51,
550.
ACS Paragon Plus Environment
28

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
(19) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77, 6443.
5
6
7
(20) Barsoum, D. N.; Brassard, C. J.; Deeb, J. H. A.; Okashah, N.; Sreenath, K.; Simmons, J.
8
9
T.; Zhu, L. Synthesis 2013, 45, 2372.
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
(21) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem.
Int. Ed. 2009, 48, 8018.
(22) GarcíaꢀÁlvarez, J.; Díez, J.; Gimeno, J. Green Chem. 2010, 12, 2127.
(23) The KauffmanꢀPinnell procedure for preparing CuI from CuSO4 and KI requires more
than twice as much KI to produce CuI as a precipitate in water in a quantitative yield. See:
Kauffman, G. B.; Pinnell, R. P. Inorg. Synth. 1960, 6, 3.
(24) Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Zhu, L. J. Org. Chem. 2013, 78, 5038.
(25) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(26) Buckley, B. R.; Dann, S. E.; Heaney, H. Chem. Eur. J. 2010, 16, 6278.
(27) Li, L.; Hao, G.; Zhu, A.; Liu, S.; Zhang, G. Tetrahedron Lett. 2013, 54, 6057.
(28) Wang, B.; Zhang, J.; Wang, X.; Liu, N.; Chen, W.; Hu, Y. J. Org. Chem. 2013, 78,
10519−10523.
(29) Li, L.; Hao, G.; Zhu, A.; Fan, X.; Zhang, G.; Zhang, L. Chem. Eur. J. 2013, 19, 14403.
(30) Wang, B.; Liu, N.; Chen, W.; Huang, D.; Wang, X.; Hu, Y. Adv. Synth. Catal. 2015, 357,
401.
(31) Spiteri, C.; Moses, J. E. Angew. Chem. Int. Ed. 2010, 49, 31.
ACS Paragon Plus Environment
29