Effect of resonance on the clickability of alkenyl azides in the strain-promoted cycloaddition with dibenzo-fused cyclooctynes

Article abstract of DOI:10.1246/cl.190400

The clickabilities of various alkenyl and alkyl azides in the strain-promoted cycloaddition with dibenzo-fused cyclooctynes were investigated. Although alkenyl azides generally exhibited lower clickabilities than those of alkyl azides, a sterically-hindered alkenyl azide showed high reactivity comparable with those of alkyl azides. Theoretical analyses indicated that these unique reactivities are derived from the frontier molecular orbital interactions and distortability of the azido groups.

Full text of DOI:10.1246/cl.190400

Advance Publication Cover Page
Effect of Resonance on the Clickability ofAlkenyl Azides
in the Strain-promoted Cycloaddition with Dibenzo-fused Cyclooctynes
Suguru Yoshida,* Sayuri Goto, Yoshitake Nishiyama, Yuki Hazama,
Masakazu Kondo, Takeshi Matsushita, and Takamitsu Hosoya*
Advance Publication on the web June 5, 2019
doi:10.1246/cl.190400
© 2019 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
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Publication manuscripts.

Effect of Resonance on the Clickability of AlkenylAzides
in the Strain-promoted Cycloaddition with Dibenzo-fused Cyclooctynes
Suguru Yoshida,*1 Sayuri Goto,1 Yoshitake Nishiyama,1,† Yuki Hazama,1 Masakazu Kondo,2 Takeshi Matsushita,2
and Takamitsu Hosoya*1
1Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
2Ichihara Research Center, JNC Petrochemical Corporation, 5-1 Goikaigan, Ichihara, Chiba 290-8551, Japan
E-mail: s-yoshida.cb@tmd.ac.jp (S. Yoshida), thosoya.cb@tmd.ac.jp (T. Hosoya)
1
2
3
4
5
6
7
8
9
The clickabilities of various alkenyl and alkyl azides in
the strain-promoted cycloaddition with dibenzo-fused
cyclooctynes were investigated. Although alkenyl azides
generally exhibited lower clickabilities than those of alkyl
azides, a sterically-hindered alkenyl azide showed high
reactivity comparable with those of alkyl azides. Theoretical
analyses indicated that these unique reactivities are derived
from the frontier molecular orbital interactions and
distortability of the azido groups.
A
Previous work
N
R
N
N
N
N
2
R–N3
+ isomer
MeOH
25 °C
1
cis-3
R
N
trans-3
i-Pr
N3
N3
10 Keywords: Click chemistry, Azide, Resonance effect
N3
i-Pr
1a
1b
1c
11 The rise of click reactions such as the copper-catalyzed
98%
62/38
0.063
94%
95%
96/4
0.67
yield
12 azide–alkyne cycloaddition (CuAAC) and the strain-
13 promoted azide–alkyne cycloaddition (SPAAC) have
14 improved the utility of organic azides in a broad range of
15 disciplines, including materials chemistry, medicinal
16 chemistry, and chemical biology.1–6 Particularly, the
17 clickabilities of various azides have gained increasing
18 attention as a means to improve the efficiency of click
19 conjugation and to achieve sequential click reactions.7,8
trans/cis
43/57
k/M–1s–1
0.0088
krel
7.2
1
76
B
1b
1c
20
Previously, we discovered a unique enhancement of the
21 clickability of aromatic azides, i.e., that the double SPAAC
22 reaction of 2,6-diisopropylphenyl azide (1c) with
23 Sondheimer diyne (2) is significantly more accelerated than
24 that of unsubstituted phenyl azide (1b) with 2 (Figure 1A).8d
25 We surmised that the enhanced reactivity of doubly
26 sterically-hindered aromatic azide 1c is due to the increased
27 distortability of the azido group induced by the steric
28 inhibition of resonance. Several analyses, including
29 absorption spectroscopy and theoretical studies based on a
30 density functional theory (DFT) (B3LYP/6-31G(d)) method,
31 indicated that azide 1c is predisposed to adopt a twisted
32 structure, whereas azide 1b rather prefers the planar state due
33 to the resonance between its phenyl and azido groups (Figure
34 1B). Interestingly, 2,6-diisopropylphenyl azide (1c) showed
35 almost ten-times higher reactivity than benzyl azide (1a)
36 (Figure 1A). We speculated that the lower clickability of 1a
37 than that of 1c is caused by stabilization of the azido group
38 by hyper-conjugation with carbon–hydrogen bonds, which
39 decreases the distortability of the azido group. However, the
40 effect of the resonance remains unclear. Herein, we report the
41 significant effects of resonance and its inhibition by steric
42 hindrance in the clickability of various alkyl and alkenyl
43 azides from experimental and theoretical aspects (Figure 1C).
44
C
R1
This work
R1
✔ Hyperconjugation in aliphatic azides
✔ Resonance in alkenyl azides
✔ Steric inhibition of resonance
in sterically-hindered alkenyl azide
N
N
N
N
N
N
R2
R2
45
46 Figure 1. Clickability of various azides. (A) Double-click reactions of
47 benzyl azide (1a), phenyl azide (1b), and 2,6-diisopropylphenyl azide
48 (1c) with diyne 2. (B) Overhead and side views of the ground state
49 structures of 1b and 1c.8d (C) Alkyl and alkenyl azides.
50
51
We at first examined the clickability of alkyl and
52 alkenyl azides 1 in the double-click reactions with
53 Sondheimer diyne (2) (Table 1).9,10 All reactions proceeded
54 smoothly to afford
a
regioisomeric mixture of
55 biscycloadducts 3 in excellent yields. The second-order rate

1
2
3
4
5
6
7
8
9
constants (k) for the first cycloadditions between azides 1 and
diyne 2 clearly showed that the clickabilities of alkenyl azides
1e and 1g are lower than those of the corresponding saturated
alkyl azides 1d and 1f. The reaction of 2-phenylethyl azide
(1d) with diyne 2 was slightly faster than that of benzyl azide
(1a) (entry 1 vs entry 2). Unsaturation from 1d to trans-styryl
azide (1e) decreased the clickability, indicating that the
resonance between the azido and alkenyl groups retarded the
cycloaddition (entry 2 vs entry 3). The reaction of secondary
38 middle). The base-catalyzed triazole formation11 with 1,3-
39 diketone 10 provided an almost 1:1 mixture of triazoles 11
40 and 12 (Scheme 1, bottom). These results indicate that
41 concerted triazole formation reactions between alkenyl
42 azides and dibenzo-fused cyclooctynes are accelerated by
43 increasing the steric hindrance of the azido group. This is
44 similar to the enhanced clickability observed for aromatic
45 azides upon introduction of two bulky ortho-substituents.
46
10 alkyl azide 1f proceeded more slowly than those of primary
11 alkyl azides 1a and 1d (entry 4 vs entries 1 and 2).
12 Unsaturated azides such as 2-styryl azide (1g) and 4-phenyl-
13 1-buten-2-yl azide (1h) also exhibited lower reactivities than
14 that of 1f, indicating that the alkenyl moiety decreased the
15 clickability of azides (entries 5 and 6 vs entry 4). In contrast
16 to the low reactivity of alkenyl azide 1g, trans-1,2-
17 diphenylvinyl azide (1i) showed similar reactivity to that of
18 alkyl azide 1d, despite the presence of an alkenyl and two
19 bulky phenyl groups (entry 7). Thus, the introduction of a
20 phenyl group to alkenyl azide 1g significantly accelerates its
21 click reaction with diyne 2.
N
N
N
N
N
N
Ph
4
(1.0 equiv)
+
MeOH
rt, 1 h
Ph
Ph
5
6
83%a
16%a
Ph
(1.0 equiv)
7
(MeCN)4CuBF4
(5 mol %)
TBTA (5 mol %)
N
N
N
Ph
Ph
N
N3
Ph
Ph
N3
+
N
N
+
Ph
CH2Cl2
rt, 24 h
Ph
Ph
Ph
8
9
1g
69%b
30%b
1i
(1.2 equiv)
(1.2 equiv)
O
O
22
Me
Me 10
(1.0 equiv)
K2CO3
(20 mol %)
23 Table 1. Double-click reactions of diyne 2 with various alkyl and alkenyl
24 azides 1
O
O
N
N
N
Ph
N
N
N
+
Me
Me
DMF
rt, 24 h
Me
Me
12
Ph
Ph
N
R
N
N
11
42%b
48%b
2
47
(1.0 equiv)
R–N3
1
(2.4 equiv)
+ isomer
48 Scheme 1. Competitive triazole formation reactions. TBTA = tris[(1-
MeOH
rt, 1 h
49 benzyl-1H-1,2,3-triazol-4-yl)methyl]amine. Isolated yields. b 1H NMR
cis-3
a
N
N
50 yields.
51
R
N
trans-3
25
52
To gain more insight into the clickability between alkyl
Entry
1a
R–N3
1
3
Yield/% trans:cis k/M−1s−1 c
krel
53 and alkenyl azides in the SPAAC reaction with dibenzo-fused
54 cyclooctynes, a DFT study was conducted for several azides
55 1 (Table 2). Although only slight differences were observed
56 in the natural bond orbital analyses,12 the frontier molecular
57 orbital calculations clearly indicated the hyper-conjugation
58 characteristics of azides 1. For example, hyper-conjugation
59 between the azido group and the neighboring C–H bonds was
60 observed in the highest occupied molecular orbitals
61 (HOMOs) of alkyl azides 1a and 1d. Comparisons of energy
62 gaps between the lowest unoccupied molecular orbital
63 (LUMO) and HOMO levels of azides 1 and diyne 2 suggest
64 more favorable interactions between the frontier orbitals of
65 alkenyl azides (1e, 1g, and 1i) and diyne 2 than those between
66 alkyl azides (1a and 1d) and 2. Notably, the energy gap
67 between the HOMO of the highly reactive azide 1i and the
68 LUMO of diyne 2 was the lowest (2.47 eV) among the azides
69 examined.
2
Ph
Ph
Ph
Me
N3
1a 3a
98
99
62/38
57/43
6.3 ´ 10−
9.6 ´ 10−
16
N3
2
2
3
1d 3d
25
11
N3
N3
4.1 ´ 10−
2.1 ´ 10−
2
2
1e
1f
3e
3f
98
98
53/47
n.d.b
4
5
5.4
1
Ph
N3
3.9 ´ 10−
6.1 ´ 10−
3
3
1g 3g
1h 3h
98
97
49/51
54/46
Ph
N3
6
1.6
23
Ph
Ph
N3
8.9 ´ 10−
2
7
1i
3i
quant.
75/25
Ph
26 aFrom ref. 10. bNot determined. cSee the Supporting Information for
27 details.
28
29
We also performed competition experiments using an
70
The distortability of the azido groups in 1d, 1e, 1g, and
71 1i was theoretically evaluated by calculation of the rotation
72 energy of the azido group (Figure 2). The low rotation energy
73 of the azido group in alkyl azide 1d indicates its higher
74 distortability than those of the azido groups in alkenyl azides
75 1e, 1g, and 1i (Figure 2A vs Figures 2B–2D). Azides 1e and
76 1g are most stable when the azido group lies in the same plane
77 with the alkenyl group (Figures 2B and 2C). This causes the
78 low distortability of the azido groups in these azides,
30 equimolar mixture of alkenyl azides 1i and 1g in three types
31 of triazole formation reactions (Scheme 1). The SPAAC
32 reaction with cyclooctyne 44e resulted in a preferential
33 consumption of the bulkier alkenyl azide 1i to afford
34 cycloadduct 5 with good selectivity along with a small
35 amount of cycloadduct 6 obtained from 1g (Scheme 1, top).
36 The CuAAC reaction2 with terminal alkyne 7 afforded
37 triazoles 8 and 9 without significant selectivity (Scheme 1,

1
2
3
4
5
6
resulting in their low reactivities in the concerted click
reactions. In contrast, alkenyl azide 1i is stable as a partially-
twisted structure, which renders the azido group slightly more
distortable than those in alkenyl azides 1e and 1g (Figure 2D
vs Figures 2B and 2C).
18
19
Detailed theoretical analysis of the cycloaddition of
20 alkenyl azides 1g and 1i with diyne 2 provided further insight
21 into the enhancement of the clickability of 1i. The potential
22 energy profiles for the reactions of 1g and 1i with 2 are shown
23 in Table 3. The order of calculated activation energies was in
24 good agreement with that of the second-order rate constants
25 shown in Table 1 (entries 5 and 7). Further analysis based on
26 the distortion/interaction model13 showed that the difference
27 in the activation energies consists largely of the difference
28 between the distortion energies of azides 1g and 1i. The lower
29 distortion energy of 1i than that of 1g would be derived by
30 the steric inhibition of resonance between the azido and
31 alkenyl groups. This result and the analysis based on the
32 frontier molecular orbitals show that the higher clickability
33 of 1i than that of 1g is attributable to the enhanced
34 distortability of the azido group induced by the inhibition of
35 resonance with the additional bulky phenyl group, which
36 surpassed the deceleration caused by the steric hindrance.
37
7
8
Table 2. Selected molecular orbitals contributing to the SPAAC
reactions between azides 1 and diyne 2.
1
Optimized structurea
Frontier orbitalsa
1a
HOMO (−6.33 eV)
LUMO (−1.63 eV)
1d
1e
LUMO (−1.61 eV)
LUMO (−2.16 eV)
HOMO (−6.35 eV)
HOMO (−5.48 eV)
38
Table 3. DFT analysis of the cycloaddition of 1g and 1i with 2a
1g
LUMO (−2.15 eV)
HOMO (−5.83 eV)
39
1i
2
Reactants
1g
+
2
1i
+
2
Distorted reactantsb
+18.8
+3.3
+16.3
+3.2
LUMO (−2.27 eV)
LUMO (−2.86 eV)
HOMO (−5.33 eV)
HOMO (−5.24 eV)
Distortion energyb (DEd )
Interaction energyc (DEi‡)
Activation energyd (DE‡)
‡
+22.1
−11.6
+10.5
+19.5
−12.7
+6.8
40 aDistortion, interaction, and activation energies for the first cycloaddition
41 from the most stable conformations obtained at the M11-L/6-31G(d)
42 level are shown in kcal mol−1. bEnergy required to distort the geometry
43 of each reactant to the transition state (TS). cInteraction energy between
44 the distorted fragments at the TS. dEnergy differences for each fragment
45 between the optimized and the TS geometries.
9
aOptimized structures, molecular orbitals, and charge distributions were
10 obtained by the theoretical analyses at the M11-L/6-31G(d) level. See
11 the Supporting Information for details.
12
46
47
In summary, we found that alkenyl azides generally
48 exhibit lower clickabilities than those of alkyl azides in the
49 SPAAC reactions with dibenzo-fused cyclooctynes, though a
50 sterically-hindered alkenyl azide shows high reactivity
51 comparable with those of alkyl azides. DFT analysis revealed
52 that the frontier molecular orbital interactions between azides
53 and cyclooctynes and the distortion energy of the azido group
54 determine the clickabilities of alkenyl and alkyl azides. The
55 development of a new convergent synthetic method for
56 multifunctional molecular probes and construction of a
57 chemical library by sequential click conjugations based on
58 the diverse clickabilities of various azides are now underway
59 in our group.
13
14 Figure 2. Rotation energy of the azido groups in 1d (A), 1e (B), 1g (C),
15 and 1i (D) calculated at the M11-L/6-31G(d) level, where zero energies
16 are set at the local minima. Rotation barrier (green) and dihedral angles
17 in local minima (red) are shown.
60
61
This work was supported by AMED under Grant
62 Numbers JP19am0101098 (Platform Project for Supporting

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Drug Discovery and Life Science Research, BINDS) and
JP18am0301024 (the Basic Science and Platform
Technology Program for Innovative Biological Medicine);
JSPS KAKENHI Grant Numbers JP15H03118 and
JP18H02104 (B; T. H.), JP16H01133 and JP18H04386
(Middle Molecular Strategy; T. H.), JP17H06414 (Organelle
Zone; T. H.), JP26350971 (C; S. Y.), and JP17K13266
(Young Scientist B; Y. N.); the Cooperative Research Project
of Research Center for Biomedical Engineering; and the
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10 Naito Foundation (S. Y.).
11
12
13 10.1246/cl.xxxxxx.
14
Supporting Information is available on http://dx.doi.org/
15 References and Notes
16 † Present address: Laboratory of Natural Products Chemistry, Graduate
17 School of Pharmaceutical Sciences, Nagoya University, Furo-cho,
18 Chikusa-ku, Nagoya, 464-8601, Japan.
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