1,3-Dipolar cycloaddition reactivities of perfluorinated aryl azides with enamines and strained dipolarophiles

Article abstract of DOI:10.1021/ja511457g

The reactivities of enamines and predistorted (strained) dipolarophiles toward perfluoroaryl azides (PFAAs) were explored experimentally and computationally. Kinetic analyses indicate that PFAAs undergo (3 + 2) cycloadditions with enamines up to 4 orders of magnitude faster than phenyl azide reacts with these dipolarophiles. DFT calculations were used to identify the origin of this rate acceleration. Orbital interactions between the cycloaddends are larger due to the relatively low-lying LUMO of PFAAs. The triazolines resulting from PFAA-enamine cycloadditions rearrange to amidines at room temperature, while (3 + 2) cycloadditions of enamines and phenyl azide yield stable, isolable triazolines. The 1,3-dipolar cycloadditions of norbornene and DIBAC also show increased reactivity toward PFAAs over phenyl azide but are slower than enamine-azide cycloadditions.

Full text of DOI:10.1021/ja511457g

Subscriber access provided by GAZI UNIV
Article
1,3-Dipolar Cycloaddition Reactivities of Perfluorinated
Aryl Azides with Enamines and Strained Dipolarophiles
Sheng Xie, Steven A Lopez, Olof Ramstrom, Mingdi Yan, and K. N. Houk
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja511457g • Publication Date (Web): 30 Dec 2014
Downloaded from http://pubs.acs.org on January 6, 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.
Journal of the American Chemical Society 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 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1,3-Dipolar Cycloaddition Reactivities of Perfluorinated Aryl
Azides with Enamines and Strained Dipolarophiles
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
Sheng Xie,†a Steven A. Lopez,§a Olof Ramström,† Mingdi Yan,*†,‡ and K. N. Houk *§
†Department of Chemistry, KTH - Royal Institute of Technology, Teknikringen 36, Stockholm, Sweden.
‡Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854, USA.
§Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA.
aThese authors contributed equally to this paper
ABSTRACT: The reactivities of enamines and pre-distorted (strained) dipolarophiles towards perfluoroaryl azides (PFAAs) were
explored experimentally and computationally. Kinetic analyses indicate that PFAAs undergo 3+2 cycloadditions with enamines up
to four orders of magnitude faster than phenyl azide reacts with these dipolarophiles. DFT calculations were used to identify the
origin of this rate acceleration. Orbital interactions between the cycloaddends are larger due to the relatively low-lying LUMO of
PFAAs. The triazolines resulting from PFAA-enamine cycloadditions rearrange to amidines at room temperature, while 3+2 cy-
cloadditions of enamines and phenyl azide yield stable, isolable triazolines. The 1,3-dipolar cycloadditions of norbornene and
DIBAC also show increased reactivity towards PFAAs over phenyl azide, but are slower than enamine-azide cycloadditions
Introduction
Scheme 1. Azide and dipolarophile scope for the (3+2) cy-
cloadditions studied here.
Perfluorinated aryl azides (PFAAs) have been extensively
utilized for the functionalization materials and surfaces1 and
for photoaffinity labeling.2 PFAAs are easily converted to
nitrenes by photolysis or thermolysis. They are also relatively
electrophilic due to the presence of strongly electronegative
fluorine atoms. PFAAs have been further used as photocou-
pling agents, primarily by the Yan group, to functionalize
surfaces and nanomaterials3 and are relatively stable to elevat-
ed temperatures (Table S1). Here we report a theoretical and
experimental exploration of the 1,3-dipolar cycloadditions of
PFAAs to expand the reagents that can be used for surface
functionalization. of to enamines and strained dipolarophiles
such as norbornene and dibenzoazacyclooctyne (DIBAC).
N3
N3
N3
F
F
F
F
F
F
F
F
a. R=CO2Me
b. R=F
c. R=CN
d. R=NO2
e. R=CHO
N
R
(a–e)
g
f
N3
Ph
N
Ph
N
X
1. X=CH2
2. X=O
Huisgen discovered 1,3-dipolar cycloadditions of azides in the
1960s.4 Meldal and Sharpless independently developed the
click reaction of azides and terminal alkynes that requires Cu-
h
1–2
3
,
catalysis, to form triazoles efficiently and regioselectively,5 6
resulting in renewed interest in the cycloaddition.7 Azide-
alkyne cycloadditions, particularly those involving strained
alkynes, now constitute a key bioorthogonal reaction used to
label biomolecules in vivo.8 Initial calculations on 1,3-dipolar
cycloadditions of PFAAs predicted that these electron-
deficient aryl azides would undergo rapid cycloadditions with
electron-rich dipolarophiles such as enamines. We explored
substituent effects on several aryl azides with various p-
electron withdrawing groups (EWGs) (a–f) in cycloadditions
to enamines (1–8), norbornene (9), and DIBAC (10) (Scheme
1). The rates for these cycloadditions are compared to those
for ambiphilic azides g and h.
Ph
Ph
Ph
N
N
N
X
5. X=CH2
6. X=O
4
7
5–6
Ph
N
N
O
8
9
10
NH2
Results and Discussion
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
The rate constants for these 1,3-dipolar cycloadditions were
Table 1. Rate constants (kc) for the (3+2) cycloadditions of (a–
d, g, and h) to 1.a
1
2
3
4
5
6
7
8
determined in CDCl3 at 25 °C with a 2:1 ratio of azide to dipo-
1
larophile. Most reactions were monitored by H-NMR or 19F-
ΔG‡
(kcal mol–1)
c
b
exp
Azide
kc
krel
NMR spectroscopy, and the second order rate constants (kc)
were found based on the triazoline or triazole formation rate.
Detailed information about the kinetic studies we performed
can be found in the experimental section and in the supporting
information.
(10–2 M–1 s–1)
F
F
F
MeO2C
N3
N3
N3
N3
1.41 ± 0.04
0.126 ± 0.05
11.8 ± 0.06
15.9 ± 0.4
16,300
1,450
20.0 ± 0.1
21.0 ± 0.1
18.4 ± 0.1
18.2 ± 0.1
9
F
Acetophenone-Derived Enamine Cycloadditions
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
F
F
The reaction of acetophenone enamines and PFAAs gave
perfluoroanilines as the major products (60–90% isolated
1
yields) on the basis of 19F- and H-NMR spectroscopy (Figure
F
S1A). These triazolines decomposed to perfluoroanilines by a
mechanism for which the mechanism is not known with cer-
tainty (Scheme 2).9
F
F
F
F
Scheme 2. Cycloadditions of PFAAs and acetophenone
enamines.
NC
135,000
185,000
N
F
F
NH2
Ph
N
F
F
F
F
F
F
N
N
F
Ph
N
+
N
F
ArN3
F
F
R
F
F
R
[(a–d)-(1–4)]
[(a–d)-aniline
a–d
1–4
N3
0.867 ± 0.04 x 10–4
1
–
25.3 ± 0.1
–
The kc for the cycloadditions of azides to enamine 1 were
1
determined using 19F-NMR (a-c, f) or H-NMR (g and h) and
CH2N3
n.d.
are shown in Table 1. These data are presented as a plot of
triazoline concentration vs. time in the Supporting Infor-
mation.
aConditions: [Azide]:[Enamine] 2:1, 1H- and 19F-NMR in CDCl3, 293.0 K,
Figure S2-S6. bkrel = kc(a–h)/kc(g). cCalculated from Eyring equation . d No
cycloaddition detected by NMR.
Phenylacetaldehyde-Derived Enamine Cycloadditions
Scheme 3 shows the 1,3-dipolar cycloadditions of (a–f), to
enamines (5–8) under ambient conditions. Intermediate tria-
zolines bearing a perfluoroaryl group underwent a room tem-
perature rearrangement (observed by H-NMR) to afford ami-
dines (Scheme 3).
1
Scheme 3. Reaction of PFAAs (a–f) and phenylacetaldehyde
enamines (5–8) result in triazolines [(a–c)-(1–4)] that lose N2
to form amidines.
Ph
Ph
Ph
N
N
(3+2)
N
ArN3
+
N
Ar
N
N
N
Ar
[(a–f)-(5–8)]
(a–f)
(5–8)
[(a–f)-(5–8)]'
Figure 1 shows the scope of these reactions, and the experi-
mental yields. The triazolines were only transiently observed
as intermediates by 1H-NMR.
2
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
Ph
O
Ph
the yield was calculated against the conversion of the enamine
reactant.
F
N
F
F
N
1
2
3
4
5
6
7
8
N
N
N
N
F
F
F
F
We show the first example of fluorinated aryl azides that un-
dergo (3+2) cycloadditions at room temperature to afford
amidines. Triazolines bearing electron-deficient aryl groups
are known to decompose, and several mechanisms have been
proposed for this rearrangement10. Erba and coworkers recent-
ly performed DFT calculations on the rearrangement mecha-
nism.11 We are currently exploring in more detail how N2 is
extruded from triazolines to afford amidines.
O
O
F
O
O
> 95%
(a-6)'
> 95%
(a-5)'
Ph
Ph
F
N
F
F
N
F
9
N
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
F
F
F
O
Table 2 gives kc and the corresponding experimental activation
free energies (ΔG‡exp). Rate constants for cycloadditions were
found in the same manner as for reactions of acetophenone-
derived enamines. However, triazolines [(a–g)-(5–8)] decom-
pose to form amidines [(a–g)-(5–8)]’.
O
F
O
O
> 90%
(a-7)'
> 90%
(a-8)'
Ph
O
Ph
O
F
N
F
F
F
N
F
F
Table 2. Rate constants (kc) for the (3+2) cycloadditions of
azides (a–h) and phenylacetaldehyde piperidine enamine 5.a
N
F
F
F
CN
b
ΔG‡
c
Azide
kc
krel
exp
88%
(c-6)'
89%a
(b-6)'
(kcal mol–1)
(10–2 M–1 s–1)
Ph
Ph
F
F
F
F
N
N
F
F
7.22 ± 0.04
9,080
18.7 ± 0.1
N
N
MeO2C
N3
F
F
F
F
F
F
F
F
F
F
> 90%a
(b-5)'
79%
(b-7)'a
1.05 ± 0.03
97.2 ± 2.4
1,320
19.8 ± 0.1
17.2 ± 0.1
F
N3
Ph
Ph
O
F
F
F
F
N
N
F
F
N
F
F
N
F
F
F
F
122,000
N
NC
N3
N3
N3
F
F
F
66%a
(b-8)'
90%
(f-6)'
F
F
121.6 ± 3.2
35.9 ± 0.6
153,000
45,000
17.0 ± 0.1
17.7 ± 0.1
O2N
Ph
Ph
F
N
N
F
F
N
F
F
F
F
N
F
F
F
F
N
O
OHC
CN
F
90%
(f-1)'
F
F
88%
(c-2)'
F
F
80.8 ± 0.2
102,000
17.3 ± 0.1
Ph
Ph
N
F
N3
F
N
N
F
F
N
F
F
N
F
F
F
O2N
1.85 x 10–3 ± 0.02
< 10–5 (f)
1
–
24.0 ± 0.1d
–
N3
O
CHO
F
92%
(d-1)'
85%
(e-1)'
CH2N3
aConditions: [Azide]:[Enamine] 2:1, 1H- and 19F-NMR in CDCl3, 293.0 K,
Figure S7-S13 in SI. bkrel = kc(a–h)/kc(g), at 293.0 K. cCalculated from the
Eyring equation (kB = 1) . dAt 298.0 K.
Figure 1. Amidines isolated experimentally. Reaction condi-
tions: enamine (1.0 mmol), azide (1.1 mmol), THF or
MeOH(2 mL), room temperature. isolated yields after 12
56
57
58
59
60
a
hours. after 72 hours, When decomposition was incomplete,
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
The rate constants for the cycloadditions of 5–8 and aryl az-
Page 4 of 13
1
2
3
4
5
6
7
8
ides (a and b) are summarized in Table 3. The reactivities of
PFAAs with phenylacetaldehyde-derived enamines follow the
same trend as that of acetophenone-derived enamines, but
have kc that are 5 to 10 fold greater. Likely due to of the great-
er steric bulk associated with ketonic enamines. The reaction
between a and 5 is nearly four orders of magnitude faster than
that of phenyl azide. The rate constant for the cycloaddition of
4-nitroperfluorophenyl azide (d) and 5 is 1.216 ± 0.032 M–1 s–
1, which is the fastest for the cycloaddition of an azide with an
unstrained dipolarophile. The mechanism of 1,3-dipolar cy-
cloadditions involving enamines and phenyl azide has been
explored experimentally by Munk12 and computationally by
Houk.13 The rate constants of the cycloaddition between PFAA
(a, b) and enamine (5-8) were subsequently measured and are
summarized in Table 3.
9
TS-a5!
21.0!
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
27.4!
Table 3. Rate constants of the cycloadditions of a and b with
5–8.a Relative rate constants are given in parentheses.
Enamine
kc (a)
(10–2 M–1 s–1)
kc (b)
(10–2 M–1 s–1)
TS-b5!
21.7!
Ph
27.3!
7.22 ± 0.04 (11)
0.639 ± 0.001 (1)
1.05 ± 0.03 (11)
0.098 ± 0.002 (1)
N
Ph
N
O
Ph
17.6 ± 0.2 (27)
10.1 ± 0.1 (16)
2.29 ± 0.06 (23)
1.35 ± 0.03 (14)
N
TS-g5!
25.3!
Ph
32.1!
N
Figure 2. The concerted transition structures for the (3+2)
cycloaddition of PFAAs (a and b) and phenyl azide (g) to 5
are in the left column. The stepwise transition structures are in
aRates were determined by 1H- and 19F-NMR in CDCl3, [Az-
ide]:[Enamine] 2:1, 293.0 K, Figure S14-S19.
the
right
column.
Computed
using
M06-2X/6-
.
The reactivities of enamines towards PFAAs de-
crease in the following order: 7, 5, 6. Munk et al. observed the
same trend experimentally for the reactions of phenyl azide
with the same substrates.13a Lopez and Houk showed that the
reactions of PhN3 and enamines are concerted and proceed
through relatively asynchronous transition structures.13 The
asynchronicity of the reactions arises from a strong orbital
interaction of the high-lying enamine HOMO with the LU-
MOs of phenyl azide and to a greater extent with the PFAAs
studied here. Computationally, both concerted and stepwise
mechanisms were considered; the transitions structures for
both modes of cycloaddition are shown in Figure 2.
CHCl3
311+G(d,p)/IEFPCMCHCl //M06-2X/6-31G(d)/IEFPCM
3
Bond lengths are reported in Å, and reported energies, are
Gibbs free energies in kcal mol–1 determined assuming a
standard state of 1 M and 298.15 K.
The activation free energies for the stepwise cy-
cloadditions are greater than the ΔG‡ of the corresponding
concerted reaction by 5–7 kcal mol–1 and will not be consid-
ered further. In comparison to experimental ΔG‡ (Table 2),
computed activation free energies for concerted cycloaddition
are greater by 1–3 kcal mol–1
However, the qualitative reac-
.
tivity trends observed experimentally are reproduced computa-
tionally.
4
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
Figure 2 shows that the activation free energies decrease for
the transition structures involving increasingly electron-
1
2
3
4
5
6
7
8
9
deficient aryl azides along the series TS-g5, TS-b5, TS-a5
(ΔG‡ = 25.3, 21.7, 21.0, respectively). These transition struc-
tures are concerted but asynchronous. The transition structures
have bond lengths between the β-carbon and terminal azide
nitrogen (Cβ-N) that are more developed than the other form-
ing bond (Cα-N). The (Cα-N) forming bond lengths (ca. 2.6 Å)
are nearly unchanged in these transition structures. The Cβ-N
forming bond lengths are also similar in TS-a5 and TS-b5 (ca.
2.1 Å). This forming bond is notably shorter in TS-g5, 2.04 Å.
a, 3.01
b, 3.06
g, 3.68
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
We utilized the Distortion/Interaction model14 to understand
the origins of the reactivity difference of PFAAs studied ex-
perimentally with enamines and strained dipolarophiles. The
activation energy (ΔE‡) is dissected into distortion energy
(ΔE‡ ) and interaction energy (ΔE‡ ). Distortion energy is the
5, –7.16 eV!
Figure 4. Computed LUMOs of azides a, b, g and the HOMO
of enamine 5. Orbital energies are reported in eV and calculat-
ed using HF/6-31G(d)//M06-2X/6-31G(d)/IEF-PCMCHCl
.
3
d
i
energy required to distort each of the reactants into their re-
spective transition state geometries, without allowing the
fragments to interact. The interaction energy is the energy of
interaction between the distorted cycloaddends. It is often a
net stabilizing quantity that results from charge transfer of
occupied-vacant orbital interactions, electrostatic interactions,
polarization, and closed-shell (steric) repulsions. Figure 3
The major stabilizing orbital interaction is between the HOMO
of enamine 5 and the LUMO of a, b, and g. Perfluorination of
the phenyl ring substantially lowers the azide LUMO energies
of a and b, resulting in smaller HOMO-LUMO gaps and
stronger FMO interactions.
‡
summarizes our findings as a graph of ∆E‡, ∆Ed (enamine),
1,3-Dipolar Cycloadditions of Norbornene and PFAAs
‡
∆Ed (azide), and ∆Ei‡ for TS-a5, TS-b5, and TS-g5.
Motivated by the use of strained alkenes in bioorthogonal
reactions, we explored the reactivity of norbornene towards
PFAAs, (a–c, f), phenyl azide (g) and benzyl azide (h)
(Scheme 4). Additions to norbornene are fast and exo stere-
oselective. At 25 °C, PFAAs react with norbornene faster than
does phenyl azide. Rate constants for these reactions are sum-
marized in Table 4.
–17.6!
12.2!
–18.7!
7.4!
–18.2!
6.6!
20.2!
4.6!
21.2!
5.0!
23.7!
6.1!
Scheme 4. (3+2) cycloadditions of phenyl and benzyl azides
to norbornene
Ph
a5!
b5!
g5!
(3+2)
N3
N
N
+
+
Figure 3. Graph of activation, distortion, and interaction ener-
gies for TS-a5, TS-b5, and TS-g5. (black: activation energies,
green: distortion energies of dipolarophile, blue: distortion
energies of azides, red: interaction energies). Calculated using
r.t.
CHCl3
N
Ph
N
M06-2X/6-311+G(d,p)/IEFPCMCHCl //M06-2X/6-
N3
3
(3+2)
31G(d)/IEFPCMCHCl
.
3
N
r.t.
CHCl3
N
The graph in Figure 3 suggests that TS-g5 has the highest
activation energy because of increased total cylcoaddend
distortion and reduced interaction between the dipole and
dipolarophile. Both components of distortion energy (green
and blue) increase from left to right in Figure 3. TS-g5 occurs
latest, which means that the cycloaddends are most distorted
from their reactant geometries. A Frontier Molecular Orbital
(FMO) analysis can be used to understand how interaction
energies contribute to the activation energies of these reac-
tions. Figure 4 shows the computed molecular orbitals of
enamine 5 and azides a, b, and g.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
Table 4. Azide-norbornene (3+2) cycloaddition rate constants
Figure 5. The transition structures for the (3+2) cycloaddi-
tions of norbornene (9) and a, b, and g. Computed using M06-
and corresponding activation free energies. a
1
2
CHCl3
2X/6311+G(d,p)/IEFPCMCHCl //M06-2X/31G(d)/IEFPCM
.
3
b
ΔG‡c
Azide
kc
krel
3
4
5
(kcal mol–1)
(10–4 M–1 s–1)
–9.2!
–10.6!
–10.7!
F
F
9.13 ± 0.06
60
21.3 ± 0.1
18.7!
3.5!
18.6!
3.7!
19.5!
4.1!
6
7
8
9
MeO2C
N3
F
F
14.4!
F
F
4.08 ± 0.03
27
21.8 ± 0.1
11.5!
11.7!
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
F
N3
a9!
b9!
g9!
F
F
F
F
28.0 ± 0.2
30.9 ± 0.2
185
205
20.7 ± 0.1
20.6 ± 0.1
Figure 6. Graph of activation, distortion, and interaction ener-
gies for TS-a9, TS-b9, TS-g9. (black: activation energies,
green: distortion energies of dipolarophile, blue: distortion
energies of azides, red: interaction energies). Calculated using
NC
N3
F
F
F
N
F
F
M06-2X/6-311+G(d,p)/IEFPCMCHCl //M06-2X/6-31G(d)/ IEF-
3
PCMCHCl
.
3
N3
The ∆E‡ of TS-a9 and TS-b9 are lower in energy (11.5 and
11.7 kcal mol–1, respectively) than TS-9g (14.4 kcal mol–1).
The higher ∆E‡ for PhN3 cycloadditions arise from increased
distortion energies and less favorable interaction energies. The
F
0.151 ± 0.022
0.0184 ± 0.002
1
23.7 ± 0.1
25.0 ± 0.1
N3
0.12
CH2N3
‡
∆Ed of TS-a9 and TS-b9 are nearly identical (22.2 and 22.3
kcal mol–1) and increase to 23.6 kcal mol–1 in TS-g9. The new-
ly-forming bonds in TS-g9 are more developed than TS-a9 or
TS-b9, which requires additional distortion of the cycload-
dends to reach the geometries of the transition structures. The
interaction energies are more favorable for TS-a9 and TS-b9
(–10.7 and –10.6, respectively) than TS-g9 (–9.2 kcal mol–1).
The dominant FMO interaction is that of the LUMO of dipole
and the relatively high-lying HOMO (ca. –7.79 eV) of nor-
bornene. The reactions with the greatest interaction energies
involve the most electrophilic dipole, azide a.
aConditions: [Azide]:[Norbornene] 2:1, 1H- and 19F-NMR in CDCl3,
b
294.7 K, Figure S20-S25. krel = kc(a–h)/kc(g)
equation (kB = 1) .
.
cCalculated from Eyring
Representative transition structures TS-a9, TS-b9, and TS-g9
are shown in Figure 5. The transition structures are concerted,
but slightly asynchronous. The bond length between the car-
bon and terminal azide nitrogen (C–Nterm) is slightly shorter
than that of the carbon and internal nitrogen (C–Nint) for each
of these transition structures.
Reactivity enhancement by predistortion vs. orbital effects
Perfluorophenyl azide reacts with enamine 5 25-fold faster
than norbornene (9) (kc = 1.05 x 10–2 and 4.08 x 10–4 M–1 s–1,
respectively). The distortion/interaction model was used to
understand why orbital effects outweigh norbornene predistor-
tion. The ∆E‡ for TS-b5 and TS-b9 are 7.4 and 11.7 kcal mol–
1, respectively; the distortion energies are 26.1 and 22.3 kcal
mol–1, respectively. The double bond of norbornene is pyrami-
dalized and resembles the exo transition structure (i.e., the
reaction is distortion accelerated).13a The interaction energies
for TS-b5 and TS-b9 are –18.7 and –10.6 kcal mol–1, respec-
tively. The HOMO of norbornene is not as high-lying as 5
does not interact strongly with the LUMO of b. The enhanced
interaction energy component overrides norbornene predistor-
tion.
!
TS-a9
TS-b9
!
Cycloadditions of DIBAC
In addition to examining norbornene as a dipolarophile in
these cycloadditions, the cycloaddition of PFAAs with other
pre-distorted dipolarophiles, including benzocyclooctynes
bioorthogonal reagents like DIBAC,15 DIBO,16 DIFO,17 and
BARAC were explored. These strained alkynes are used as
bioorthogonal probes to label cell-surface azido glycans
(Scheme 5).
!
TS-g9
6
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
Scheme 5. Some cyclooctynes DIBO, DIBAC, DIFO, and
DIBO known to participate in bioorthogonal reactions.
Table 5. Azide-DIBAC (10) cycloaddition rate constantsa and
corresponding activation free energies. a
1
2
3
4
5
b
ΔG‡c
(kcal mol–1)
Azide
kc
krel
+
(10–2 M–1 s–1)
N
N
6
7
8
9
R
O
F
F
F
DIBAC
O
BARAC
H2N
4.88 ± 0.11
11.1 ± 0.4
4.28 ± 0.1
1.96
4.45
1.72
1.03
19.0 ± 0.1
18.5 ± 0.1
19.1 ± 0.1
19.4 ± 0.1
MeO2C
N3
F
F
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
F
F
F
F
N3
DIBO
DIFO
F
F
BARAC shows the greatest reactivity towards benzyl azide
cycloadditions (0.96 M–1 s–1).18 Computations by the Houk
group have explained how predistortion and substituent effects
control the reactivities of BARAC and its derivatives.19 Here
we performed cycloadditions of PFAAs, phenyl, and benzyl
F
F
NC
N3
F
F
1
azide to DIBAC (10). Experimental observations using H-
F
N
F
F
and 19F-NMR for product a-10 (Figure. S32) indicated a mix-
ture of regioisomers in a ratio of 1:0.4. Attempts to assign the
identity of the isomers however proved inconclusive. Rate
constants were measured and are shown in Table 5.
2.58 ± 0.05
2.49 ± 0.03
N3
F
1
19.4 ± 0.1
18.1 ± 0.1
N3
Scheme 6. The regioisomeric products resulting from the
reaction of 10 with azides (a, b, or g).
21.9 ± 0.3
8.8
CH2N3
N
N
Ar
Ar
N
N
N
N
a
1
Conditions: [Azide]:[DIBAC] 2:1, H- or 19F-NMR in CDCl3, 294.7 K.
b
Figure S26-S31. krel: relative rate kc/kc(g). Calculated from Eyring equa-
c
tion (kB = 1).
N
N
DIBAC is more reactive with PFAAs than with PhN3 and
show poor regioselectivity. We use the M06-2X density func-
tional to understand the differences in reactivity of aryl azides
with 10 used model dibenzoazacyclooctyne, 11. The global
minimum of 11 is shown in Figure 7.
O
O
H2N
H2N
[(a–h)-10-anti]
[(a–h)-10-syn]
N
N
O
O
H2N
11
10
153°% 155°%
Figure 7. The lowest energy conformer of dibenzocyclooctyne
11. The alkyne bond angles are reported in degrees.
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
As expected, the amide isomerization is facile at room temper-
Page 8 of 13
1
2
3
4
5
6
7
8
ature. We computed twelve possible transition structures (dif-
fering in syn/anti orientation of azide and s-trans/s-cis amide
conformation, and three conformations of the aryl ring for the
reaction of a, b, and g with 11 (See SI for higher energy tran-
sition structures). Table 6 shows the activation free energies
for the regioisomeric transition structures for the reactions of
azides a, b, and g to 11. The lowest energy transition struc-
tures for the syn and anti approaches of the azide [TS(g11-
syn) and TS(g11-anti)] are shown in Figure 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
Table 6. The activation free energies for the cycloadditions
involving a, b, and g to 11. Activation free energies are re-
ported in kcal mol–1. Computed free energies in solution are
for the standard state of 1 M and 298.15 K.
TS(g11-syn)!
‡
‡
Azide
∆Gsyn
∆Ganti
F
F
23.4
24.1
MeO2C
N3
F
F
F
F
22.2
24.0
22.8
24.0
F
N3
TS(g11-anti)
F
F
Figure 8. Lowest energy syn and anti transition structures for
the cycloadditions of g to 11. Bond lengths are reported in Å
and energies in kcal mol–1. Computed free energies in solution
are for the standard state of 1 M and 298.15 K using M06-
N3
2X/6-311+G(d,p)/IEFPCMCHCl //M06-2X/6-
3
31G(d)/IEFPCMCHCl
.
3
These transition structures are almost perfectly synchronous.
The C-N bond lengths range only from 2.19–2.24 Å. While
computations do not quantitatively reproduce experimental
activation free energies, the experimental reactivity trends are
reproduced by theory. Our calculations show that the ∆G‡ for
TS(a11-syn) and TS(b11-syn) are lower in energy than the
corresponding anti transition states by 0.7 and 0.6 kcal mol–1,
respectively. These results suggest that there should be a small
preference for the syn regioisomers for PFAAs. The ∆G‡ for
TS(g11-syn) and TS(g11-anti) are identical, which should
result in a 1:1 mixture of syn and anti regioisomers.
To understand why PFAAs are more reactive than phenyl
azide in cycloadditions involving DIBAC, distor-
tion/interaction analyses were performed on TS(a11-syn),
TS(b11-syn), and TS(g11-syn) (Figure 9).
–11.0!
–11.3!
–11.4!
16.9!
2.6!
16.1!
17.8!
3.2!
10.1!
8.2!
7.2!
2.5!
a11!
b11!
g11!
8
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
room temperature without stirring until a white solid started to
Figure 9. Graph of activation, distortion, and interaction ener-
1
gies for TS-a11, TS-b11, and TS-g11. (black: activation ener-
form. When TLC indicated full conversion of the azide, the
mixture was cooled to -20 oC, filtered, and the solid was
washed with a small amount of hexanes to afford the product
as a white solid (270 mg, 87%).
2
gies, green: distortion energies of dipolarophile, blue: distor-
tion energies of azides, red: interaction energies). Calculated
3
4
5
M06-2X/6-311+G(d,p)/IEFPCMCHCl //M06-2X/6-
3
using
31G(d)/IEFPCMCHCl
.
3
6
7
8
9
Cycloaddition reaction between azide and DIBAC. In a
typical reaction, a solution of DIBAC in CDCl3 (9.0 mM) was
added into a solution of azide (18 mM). The reactions were
followed by NMR. The products were not isolated, and only
characterized by NMR as presented in the kinetic studies.
The interaction energies are nearly constant, and the distortion
energies control the small difference in reactivities.
Conclusion
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
We have experimentally and computationally explored the
1,3-dipolar cycloaddition of PFAAs to enamines and strained
dipolarophiles (norbornene and DIBAC). Perfluorination of
phenyl group of these aryl azides accelerates cycloadditions to
all of the substrates studied here. This is due to improved
orbital interactions with the relatively low-lying LUMO of
PFAAs. Despite the predistortion of norbornene, PFAAs pre-
fer to react with enamines because of the much more favorable
interaction energies. These cycloadditions give triazolines as
intermediates that rearrange at room temperature to give ami-
dines, while cycloadditions involving enamines and phenyl
azide yield isolable triazolines. The mechanism of triazoline
decomposition is currently being investigated.
Kinetic studies. Kinetic experiments were conducted using
NMR following similar protocols reported in the litera-
ture.12,15,19 In a typical experiment, a solution of azide in deu-
terated solvent was mixed with an equal volume of the dipo-
1
larophile in an NMR tube at a mole ratio of 2:1. The H- or
19F-NMR spectra of the sample were recorded on a Bruker
AVANCE (400 MHz or 500 MHz) spectrometer every 1.5-5
minutes. The acquisition time for a typical experiment was 30
1
1
seconds for H-NMR and 18 seconds for 19F-NMR. In the H-
NMR studies, the peaks of the dipolarophile were monitored,
which decreased as the reaction proceeded. In the 19F-NMR
studies, the F signals in PFPAs and the cycloaddition products
were followed. Each reaction was allowed to proceed to 10% -
90% conversion. Every experiment was repeated at least three
times.
Experimental Methods
To calculate the rate constant of the cycloaddition reaction, the
conversion-time curve was constructed. The curves were then
fit to the standard second-order kinetic model using the statis-
tic software GraphPad prism (see SI for detailed calculations).
The characteristic peaks of the intermediates and products can
be found in corresponding datasheets in the supporting infor-
mation.
Materials. Azides, ketonic enamines, and aldehydic enamines
,
were synthesized using reported procedures.20 21 All com-
o
pounds were stored at –20 C and compound purity was as-
1
sessed by H-NMR before performing kinetic studies. Nor-
bornene (bicyclo[2.2.1]hept-2-ene, 99%) and DIBAC (diben-
zocyclooctyneamine, >94.5%) were purchased from Sigma-
Aldrich, and were used as received. In kinetic studies, CDCl3
was filtered through K2CO3 and treated over molecular sieves.
The amount of water in the purified CDCl3 was 0.3 ppm meas-
ured by 756 KF Coulometer, which was <1 mole% enamines
used in all kinetic studies.
Computational Methods
All computations were carried out with Gaussian09.22 Reac-
tants, transition states, and products were optimized with the
density functional M06-2X23 using the 6-31G(d) basis set with
an ultrafine grid, consisting of 590 radial shell and 99 grid
points per shell.24 M06-2X has been found to give reliable
energetics for cycloadditions involving main group elements.25
Normal vibrational mode analysis confirmed all stationary
points to be minima (no imaginary frequencies) or transition
states (one imaginary frequency). Zero point energy and ther-
mal corrections were computed from unscaled frequencies for
the standard state of 1 M and 298.15 K. Truhlar’s quasi-
harmonic correction was applied for entropy calculations by
setting all frequencies less than 100 cm-1 to 100 cm–1.26,27 Input
structures for these computations were generated using
Gaussview.
Cycloaddition reaction between azide and enamine
(Schemes 2 and 3). The following describes the reaction
between PFPA a and enamine 5. Other reactions were carried
out using the same protocols. To a solution of 5 (1.0 mmol) in
THF (1.0 mL), a solution of a (1.1 mmol) in THF (1.0 mL)
was added dropwise while stirring at room temperature. Reac-
tion progress was monitored by NMR spectroscopy. Upon a
reaction’s completion (8-12 hours), the solvent was removed
under reduced pressure and the residual mixture was purified
by flash column chromatography (hexanes/EtOAc= 9:1, Rf=
0.27) yielding (a-5)’ as a white powder (390 mg, 95%). Alter-
natively, the reactions could be carried out in methanol (1.5-3
mL) using a slight excess of enamines (1.1 eq). In this case,
the amidine product precipitated out from the solution within
12 hours and the product was separated by filtration (isolated
yields > 70% for all amidines).
ACKNOWLEDGMENT
We thank the National Science Foundation (NSF CHE-
1059084 to KNH and CHE-1112436 to MY), and KTH for
financial support of this research. SL thanks Dr. Colin Lam,
Rob Giacometti, and Ashay Patel for helpful discussions. SX
thanks the China Scholarship Council for a special scholarship
award. Calculations were performed on the Hoffman2 cluster
at UCLA and the Extreme Science and Engineering Discovery
Cycloaddition between azide and norbornene (Scheme 4).
The following describes the reaction of azide c with nor-
bornene 9. Reactions of other azides followed the same proto-
col. To a solution of norbornene 9 (1.25 mmol) in hexanes (2-
4 mL), azide c (1.00 mmol) was added. The solution was set at
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
Environment (XSEDE), which is supported by National Sci-
houk@chem.ucla.edu, mingdi_yan@unl.edu
1
2
ence Foundation grant number OCI-10535. Figures 2, 5, 7,
and 8 were generated using CYLview.28
SUPPORTING INFORMATION
Experimental information, calculated geometries and corre-
sponding energies are available free of charge via the Internet
at http://pubs.acs.org.
3
4
5
6
7
8
AUTHOR INFORMATION
SX and SAL contributed equally to this paper.
Corresponding Authors
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
10
ACS Paragon Plus Environment

Page 11 of 13
References
Journal of the American Chemical Society
1
2
3
4
5
6
1
(a) Cai, S.; Nabity, J. C.; Wybourne, M. N.; Keana, J. F. W. Chem. Mater. 1990, 2, 631. (b) Yan, M.; Cai, S.; Wybourne,
7
8
9
M. N.; Keana, J. F. W., 1994, 5 , 151. (c) Yan, M.; Cai, S.; Keana, J. F. W. J. Org. Chem. 1994, 59, 5951. (d) Yan, M.; Ren,
J. Chem. Mater.2004, 16 , 1627. (e) Joester, D.; Klein, E.; Geiger, B.; Addadi, L. J. Am. Chem. Soc. 2006, 128, 1119.
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
2
(a) Schnapp, K. A.; Poe, R.; Leyva, E.; Soundararajan, N.; Platz, M. S., Bioconjug. Chem. 1993, 4, 172. (b) Kapfer, I.;
Jacques, P.; Toubal, H.; Goeldner, M. P., Bioconjug. Chem. 1995, 6, 109. (c) Tate, J. J.; Persinger, J.; Bartholomew, B., Nu-
cleic. Acids. Res. 1998, 26, 1421. (d) Baruah, H.; Puthenveetil, S.; Choi, Y. A.; Shah, S.; Ting, A. Y., Angew. Chem., Int. Ed.
2008, 47, 7018. (e) Jung, M. E.; Chamberlain, B. T.; Ho, C. L.; Gillespie, E. J.; Bradley, K. A., ACS. Med. Chem. Lett. 2014,
5, 363.
3
(a) Liu, L. H.; Yan, M. Acc. Chem. Res. 2010, 43, 1434. (b) Pastine, S. J.; Okawa, D.; Kessler, B.; Rolandi, M.; Llorente,
M.; Zettl, A.; Frechet, J. M. J. Am. Chem. Soc. 2008, 130, 4238. (c) Park, J.; Yan, M. Acc. Chem. Res. 2013, 46, 181. (d)
Chen, X.; Ramström, O.; Yan, M., Nano. Res. 2014, 7, 1381.
4 Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565.
5 (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Agnew, H.
D.; Rohde, R. D.; Millward, S. W.; Nag, A.; Yeo, W. S.; Hein, J. E.; Pitram, S. M.; Tariq, A. A.; Burns, V. M.; Krom, R. J.;
Fokin, V. V.; Sharpless, K. B.; Heath, J. R. Angew. Chem., Int. Ed. 2009, 48, 4944.
6 Tornøe, C. W.; Christensen, C. and Meldal, M. J. Org. Chem. 2002, 67, 3057.
7 Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
(a) Sletten, E. M.; Bertozzi, C. R. Angew. Chem., Int. Ed. 2009, 48, 6974. (b) Bertozzi, C. R. Acc. Chem. Res. 2011, 44,
8
651.
9 The decomposition of the triazolines was furthermore accompanied by a rapid color change from light yellow to dark red as
well as the evolution of gas after 20-60 minutes reaction time.
10
(a) Fusco, R.; Bianchetti, G.; Pocar, D. Gazz. Chim. Ital. 1961, 91, 933. (b)Fusco, R.; Bianchetti, G.; Pocar, D.; Ugo, R.
Chem. Ber. 1963, 96, 802. (c) Shea, K. J.; Kim, J-S. J. Am. Chem. Soc. 1992, 114, 4846.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
1
2
3
4
5
11 Contini, A.; Erba, E. RSC. Adv. 2012, 2, 10652.
6
7
12 Meilahn, M. K.; Cox, B.; Munk, M. E. J. Org. Chem. 1975, 40, 819.
8
9
13 (a) Lopez, S. A.; Munk, M. E.; Houk, K. N. J. Org. Chem. 2013, 78, 1576. (b) Jones, G. O.; Houk, K. N. J. Org. Chem.
2008, 73, 1333.
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
14 Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646.
15
Debets, M. F.; van Berkel, S. S.; Schoffelen, S.; Rutjes, F. P.; van Hest, J. C.; van Delft, F. L. Chem. Commun. 2010, 46,
97.
16 Ning, X.; Guo, J.; Wolfert, M. A.; Boons, G.-J.; Angew. Chem., Int. Ed. 2008, 47, 2253.
17 Baskin, J. M.;Prescher, J. A.;Laughlin, S. T.; Agard, N. J.; Chang, P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C.
R. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16793.
18 Jewett, J. C.; Sletten, E. M.; Bertozzi, C. R. J. Am. Chem. Soc. 2010, 132, 3688.
19 Gordon, C. G.; Mackey, J. L.; Jewett, J. C.; Sletten, E. M.; Houk, K. N.; Bertozzi, C. R.; J. Am. Chem. Soc. 2012, 134,
9199.
20 (a) Keana, J. F. W.; Cai, S. X. J. Org. Chem. 1990, 55, 3640. (b) Chapyshev, S. V. Chem. Heterocycl Compd. 2001, 37. (c)
Berger, O.; Kaniti, A.; van Ba, C.; Vial, H.; Ward, S.; Biagini, G.; Bray, P.; O'Neill, P. ChemMedChem 2011, 6, 2094. (d)
Serwinski, P.; Esat, B.; Lahti, P.; Liao, Y.; Walton, R.; Lan, J. J. Org. Chem. 2004, 69, 5247. (e) Jin, L. M.; Xu, X.; Lu, H.;
Cui, X.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int. Ed. 2013, 52, 5309.
21
(a) Carlson, R.; Nilsson, Å.; Carlström, K.; Sköldefors, H.; Wilking, N.; Theve, N. Acta Chem Scand. B 1984 38, 49. (b)
Amat, M.; Cantó, M.; Llor, N.; Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343.
22 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
12
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi,
J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09, revision C.01; Gaussian Inc.: Wallingford, CT, 2010
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
23 Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
24 Wheeler, S. E.; Houk, K. N. J. Chem. Theory Comput. 2010, 6, 395.
25 Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
26 Zhao, Y.; Truhlar, D. G. Phys. Chem. Chem. Phys. 2008, 10, 2813.
27 Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B. 2011, 115, 14556.
28 Legault, C. Y. CYLview 1.0b; Université de Sherbrooke; 2014 (www.cylview.org)
F
MeO2C
F
NAr
F
N3
F
Ph
R2N
Ph
r.t. CHCl3
krel = ~104
R2N
N
Ph
N
N
N3
Ph
Ph
R2N
r.t. CHCl3
krel = 1
R2N
13
ACS Paragon Plus Environment