Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N3 Charge-Transfer Complex

Article abstract of DOI:10.1021/jacs.8b06744

We report a mild and efficient electrochemical protocol to access a variety of vicinally C-O and C-N difunctionalized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reported for TEMPO-mediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation of azidyl radical via a charge-transfer complex with azide, TEMPO-N₃. DFT calculations together with spectroscopic characterization provided a tentative structural assignment of this charge-transfer complex. Kinetic and kinetic isotopic effect studies revealed that reversible dissociation of TEMPO-N₃ into TEMPO^- and azidyl precedes the addition of these radicals across the alkene in the rate-determining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations. The discovery of this new reaction pathway mediated by the TEMPO⁺/TEMPO^- redox couple may expand the scope of aminoxyl radical chemistry in synthetic contexts.

Full text of DOI:10.1021/jacs.8b06744

Subscriber access provided by ST FRANCIS XAVIER UNIV
Article
Electrochemical Azidooxygenation of Alkenes
Mediated by a TEMPO–N3 Charge-Transfer Complex
Juno C. Siu, Gregory S. Sauer, Ambarneil Saha, Reed L. Macey,
Niankai Fu, Timothee Chauvire, Kyle M. Lancaster, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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 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 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.
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 12
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Electrochemical Azidooxygenation of Alkenes Mediated by a
TEMPO–N3 ChargeꢀTransfer Complex
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
Juno C. Siu, Gregory S. Sauer, Ambarneil Saha, Reed L. Macey, Niankai Fu, Timothée Chauviré, Kyle
M. Lancaster*, Song Lin*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca 14853, USA
ABSTRACT: We report a mild and efficient electrochemical protocol to access a variety of vicinally C–O and C–N difunctionalꢀ
ized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reꢀ
ported for TEMPOꢀmediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation
of azidyl radical via a chargeꢀtransfer complex with azide, TEMPO–N3. DFT calculations together with spectroscopic characterizaꢀ
tion provided a tentative structural assignment of this chargeꢀtransfer complex. Kinetic and kinetic isotopic effect studies revealed
that reversible dissociation of TEMPO–N3 into TEMPO• and azidyl precedes the addition of these radicals across the alkene in the
rateꢀdetermining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations.
The discovery of this new reaction pathway mediated by the TEMPO+/TEMPO• redox couple may expand the scope of aminoxyl
radical
chemistry
in
synthetic
contexts.
INTRODUCTION
lic compounds11 (Scheme 2D) and hypervalent iodine speꢀ
cies,12 respectively, to the corresponding radicals.
Since its discovery in 1959,1 tetramethylpiperidineꢀ1ꢀoxyl
(TEMPO), a stable aminoxyl radical, has shown broad utility
in the fields of chemistry and biochemistry research.2 TEMPO
can undergo 1ꢀelectron redox processes granting access to
three discrete oxidation states (Scheme 1). This behavior
makes TEMPO and related aminoxyls highly versatile agents
in the organic synthesis of small molecules and polymers.3
Scheme 2. Existing and new reaction modes of TEMPO.
Scheme 1. Accessible oxidation states of TEMPO via singleꢀ
a
electron oxidation and reduction processes. This value was reꢀ
ported in ref. 4 and measured in an aqueous buffer.
TEMPO–
TEMPO
TEMPO+
–e–
+e–
–e–
+e–
N
O
N
O
N
O
–0.04 V
0.24 V
(vs SCE)a
(vs Fc/Fc+)
The mechanism of action of TEMPO and related aminoxyl
radicals in organic transformations primarily relies on four key
attributes. In one scenario, the electrophilic nature of
TEMPO+, the oxidized form of TEMPO, is used in the activaꢀ
,
tion of nucleophilies such as alcohols5 6 and amines7 toward
oxidation (Scheme 2A). Alternatively, the free radical characꢀ
ter of TEMPO is exploited in the abstraction of H atoms in
weak C–H bonds8 (Scheme 2B) and the reversible trapping
and liberation of transient carbonꢀcentered radicals9 (Scheme
2C). In particular, the latter mode of action serves as the basis
of nitroxideꢀmediated radical polymerizations (NMP).10 Finalꢀ
ly, TEMPO can serve as a mild singleꢀelectron oxidant while
TEMPO– reacts as a strong singleꢀelectron reductant—these
features have been exploited in the conversion of organometalꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 12
and NaN3 led to the regioselective formation of a vicinally
1
2
3
4
5
6
7
8
azidooxygenated product (2a) (Scheme 3). Herein, we deꢀ
scribe our effort to elucidate the mechanism responsible for
the observed reactivity using electrochemical, experimental
physical organic, and computational methods. The aggregate
data obtained accord with a new reaction pathway for the forꢀ
mation of C–N bonds mediated by the TEMPO+/TEMPO•
redox couple. Analysis of the computational and spectroscopic
data support the formation of an unprecedented chargeꢀ
–
transfer complex from TEMPO+ and N3 that serves as a key
9
reaction intermediate. The mechanistic insights may guide the
design of new radical reactions promoted by TEMPO and
related aminoxyl radicals.
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
Scheme 3. Electrochemical azidooxygenation of alkenes.
OTMP
NaN3 (3.0 equiv), TEMPO (1.5 equiv)
LiClO4 (0.1 M), H2O/MeCN (1:5)
N3
t-Bu
1a (1 equiv)
t-Bu
C(+)/Pt(-), Ecell = 2.6 V
2a (94%)
RESULTS and DISCUSSION
A. Reaction Development
From a synthetic point of view, vicinal aminoalcoholꢀtype
structures frequently exist in bioactive natural products and
synthetic pharmaceuticals.17 As such, we investigated the subꢀ
strate scope and found that our electrochemical azidooxygenaꢀ
tion protocol is applicable to a wide variety of alkenes beyond
styrenes (Scheme 4A). Aliphatic alkenes with different substiꢀ
tution patterns are all compatible with the described method.
Common functional groups including ketones, aldehydes, carꢀ
boxylic acids, amides, and alkyl bromides remain intact under
the electrochemical conditions. Cyclic alkenes were converted
to the corresponding difunctionalized products in moderate to
high stereoselectivity favoring the trans configuration. Stilꢀ
bene was transformed to a mixture of diastereomeric comꢀ
pounds in ca. 1:1 ratio; the two products were readily separatꢀ
ed via column chromatography and the structure of the syn
isomer was confirmed via Xꢀray crystallography.
Given our research interests in synthetic electrochemistry
and the attractive electrochemical features of aminoxyls, we
aim to develop new synthetically useful transformations mediꢀ
ated by these persistent radicals. In particular, we are interestꢀ
ed in exploring the chemical space of the TEMPO+/TEMPO•
redox couple because its application in synthetic contexts reꢀ
mains rare 13 when compared with TEMPO+/TEMPO– and
TEMPO•/TEMPO– redox couples. Based on the reduction
potential, TEMPO+ is a stronger oxidant than TEMPO• itself
(see Scheme 1) and can in principle engage nucleophiles that
are less potent than main group organometallic compounds.
This hypothesis is evident from the alcohol oxidation activity
(see Scheme 2A) but is currently limited to the twoꢀelectron
oxidation regime (i.e., use of the TEMPO+/TEMPO– couple).6
In principle, by exploring the capability of TEMPO+ as a sinꢀ
gleꢀelectron oxidant, we could expand the scope of this amiꢀ
noxyl radical’s redox chemistry and advances its limits beyond
C–C and C–O bond forming processes (Scheme 2E).
Furthermore, the mechanistic insights into TEMPOꢀ
mediated reactions has lagged behind their development. Eleꢀ
gant and thorough mechanistic investigations exist but are
largely limited to systems such as catalytic alcohol oxidation5
and NMP. 14 Detailed studies on TEMPOꢀmediated radical
transformations will aid in the development of new and better
reagents, enrich the reaction chemistry of aminoxyl radicals,
and advance fundamental knowledge in radical chemistry.
,
Whilst studying electrochemical diazidation reactions,15 16
we uncovered a new electrochemical transformation in which
the electrolysis of a mixture of tertꢀbutylstyrene (1a), TEMPO,
ACS Paragon Plus Environment

Page 3 of 12
Journal of the American Chemical Society
reagents, proceeds under milder conditions, and offers a subꢀ
1
2
3
4
5
6
7
8
stantially broader substrate scope. For example, our protocol
features the use of functional groups including ketone (2e),
carboxylic acid (2g), aldehyde (2i), alkyl bromide (2j), alcohol
(2x; see Scheme 9), and sulfide (2y) groups, which represents
an important synthetic advancement. In addition, the previous
method requires 3 equiv each of NaTEMPO and the azidoꢀ
hypervalent iodine. In contrast, while our substrate scope studꢀ
ies were conducted using 1.5 equiv TEMPO and 3 equiv
NaN3, we demonstrated that the amount of the reagents can be
reduced to 1 equiv each without significantly affecting the
efficiency of the reaction (76% yield with 2m).
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
We further expanded the scope of the reaction to feature a
completely aqueous buffer medium (Scheme 4c). By replacing
LiClO4 and MeCN with a pH 7 phosphate buffer solution, we
were able to observe the same reactivity with a select number
of substrates, albeit with diminished yields. This feature is
likely difficult with the chemical conditions reported previousꢀ
ly, as NaTEMPO is reportedly sensitive to moisture. These
promising results, taken together with the broad use of organic
azides and TEMPO in biological labelling studies, indicate
that our reaction may provide a new chemical tool for studying
biological processes.
When compared to other existing catalytic reactions that
converts alkenes to vicinal amino alcohols,19 our new method
displays complementary scope, regioselectivity, and stereoseꢀ
lectivity. For instance, the classical Osꢀcatalyzed aminohyꢀ
droxylation encounters problematic regioselectivity with cerꢀ
tain types of alkenes, while sterically hindered substrates freꢀ
quently undergo undesirable dihydroxylation.20 Another eleꢀ
gant example is the Feꢀcatalyzed aminooxygenation using
oxaziridines.19c However, this protocol has primarily been
applied to activated alkenes (e.g., styrenes and conjugate
dienes) and shows decreased efficiency with unactivated alꢀ
kenes. It is also noteworthy that both aforementioned methods
are stereospecific with both O and N groups added to the same
side of the C=C bond. In contrast, our reaction is applicable to
a wide range of activated and unactivated alkenes and proꢀ
vides exclusive regioselectivity with all substrates studied; the
latter of which can be explained by the intrinsic relative stabilꢀ
ity of carbonꢀcentered radicals. Our electrochemical method is
also nonꢀstereospecific and gives moderate to high dr with
cyclic alkenes favoring the antiꢀaddition products.
An attractive feature of the products from this transforꢀ
mation lies in the versatile and often orthogonal reactivity of
the azido and aminooxy groups, which leads to a diverse array
of vicinally difunctionalized organic structures upon additional
synthetic elaborations (for examples, see Scheme 4B and ref.
18).
Scheme 4. Substrate scope of the azidooxygenation reaction.
aReaction condition: alkene (0.2 mmol, 1 eq), TEMPO (0.3 mmol,
1.5 eq), NaN3 (0.6 mmol, 3 eq), MeCN (3.5 ml), H2O (0.3 ml) at
22 °C, cell voltage (Ecell) = 2.6 V, under N2. bUnder air. cReaction
B. Radical clock experiments
d
was conducted at 40 °C. Ecell = 2.2 V with 2 equiv of NaN3.
The mild reaction conditions and potential synthetic utility
of this methodology prompted us to undertake a detailed
mechanistic investigation. Radical clock experiments using
cyclopropylꢀsubstituted alkenes 1s and 1t confirmed our hyꢀ
pothesis that radical intermediates are involved in the observed
reactivity (Scheme 5). Upon formation of the C–N3 bond, the
vicinal carbonꢀcentered radical induces the rupture of the
threeꢀmembered ring prior to capture by the aminoxyl radical.
However, when diallyl ether was subjected to the standard
reaction conditions, no cyclization product was observed,
whereas the monoꢀazidooxygenated product was isolated in
f
eWith 1 eq TEMPO and 1 eq NaN3. CuSO4, phenylacetylene,
t
sodium ascorbate, BuOH and water. gmCPBA and DCM. h1)
Pd/C and H2; 2) Boc2O; 3) Zn and HOAc.
The sole existing method available for obtaining the same
types of products emerged from an elegant seminal work by
Studer and coworker.18 However, this protocol requires the use
of a hypervalent iodineꢀderived azide source and a highly reꢀ
ducing NaTEMPO complex, which limits the functional group
compatibility and the broad use of this method in organic synꢀ
thesis. In comparison, our reaction employs readily available
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 12
–
42% yield. These findings suggest that the radical cross couꢀ
Pathway 1a: Direct anodic oxidation of N3
1
2
3
4
5
6
7
8
pling between the carbonꢀcentered radical intermediate and
TEMPO• happens at a rate between 106 and 1011 sꢀ1, consistent
with previous reports (109 Mꢀ1 sꢀ1).21 Further supporting the
stepwise radical mechanism, cisꢀstilbene underwent nonꢀ
stereospecific addition to produce a pair of diastereomeric
products with the same dr.
–
N3
–e–
OTMP
N3
R
TEMPO
N3
N3
R
R
Scheme 5. Radical clock experimental results.
Ep/2 = 0.45 V (vs. Fc/Fc+)
ring opening:
k ≈ 1011 s–1
standard
conditions
OTMP
–
Pathway 1b: TEMPO-mediated oxidation of N3
N3
9
Ph
N3
Ph
Ph
2u (88%, E/Z = >19:1)
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
1u
OBn
standard
conditions
TEMPO
BnO2C CO2Bn
OTMP
BnO2C CO2Bn
N3
O
outersphere
–e–
N3
N3
BnO
O
O
1v
–
2v (13%, E/Z = >19:1)
OTMP
N3
R
N3
N
radical annihilation:
OTMP
R
k ≈ 109 M–1s–1
O
N3
TEMPO N3
E
1/2 = 0.25 V (vs. Fc/Fc+)
standard
conditions
innersphere
I
2w (42%)
N3
O
O
N3
OTMP
In pathway 1b, the outerꢀsphere oxidation of N3– by TEMPO+ is
unlikely due to the highly unfavorable energetics of this electron
transfer process, indicated by the 200 mV potential difference
1w
cyclization:
k ≈ 105 s–1
O
2w’ (< 5%)
Ph
Ph
(E)ꢀ1o
between the donor (N3 ) and acceptor (TEMPO+). Experimental
–
standard
conditions
Ph
N3
TMPO
Ph
evidence detailed in the follow section strongly support an innerꢀ
sphere mechanism involving the formation of a TEMPO–N3 adꢀ
duct (I).
Ph
Ph
Ph
N3
Ph
(Z)ꢀ1o
2o [dr 1.4:1 for both (Z) and (E) 1o]
We considered two plausible mechanistic scenarios for the
electrochemical generation of N3 or its equivalent before alꢀ
kene addition (Scheme 6). Pathway 1a involves the direct anꢀ
•
120
–
0.85 mM TEMPO
10 mM TBA azide
0.85 mM TEMPO + 10 mM TBA azide
odic oxidation of N3 [Ep/2 = 0.45 V vs ferrocenium/ferrocene
(Fc/Fc+);22 Figure 1] to N3·. Alternatively, in pathway 1b,
100
80
60
40
20
0
TEMPO• with its significantly lower reduction potential (E1/2
=
0.25 V) will first lose an electron on the anode to form the
corresponding oxoammonium ion (TEMPO+).23 TEMPO+ will
then oxidize NaN3 either through the formation of a TEMPO–
azide adduct (I; innersphere mechanism) or through direct
electronꢀtransfer from N3– to form free N3· (outersphere mechꢀ
anism).24
Data from chemical and electrochemical experiments exꢀ
cludes pathway 1a and supports pathway 1b as a possible reacꢀ
-20
tion mechanism. First, reaction of TEMPO+ClO4 (indeꢀ
–
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
pendently synthesized), NaN3, and indene (1m) in the absence
of applied potential afforded 66% of the vicinally difunctionalꢀ
ized product 2m. In addition, controlled potential electrolysis
revealed that the reaction occurs smoothly at 0.35 V (vs
Fc/Fc+), which is sufficient to oxidize TEMPO• to TEMPO+,
Potential vs Fc/Fc+ (V)
–
Figure 1. Cyclic voltammograms of TEMPO, N3 , and their mixꢀ
ture.
–
but insufficient to drive direct oxidation of N3 (see Figure 1).
–
•
C. Identification of a chargeꢀtransfer complex
Both results indicate that direct oxidation of N3 to N3 is unꢀ
necessary and unlikely to account for the observed reactivity.
Voltammetric and spectroscopic data revealed the forꢀ
mation of a new TEMPO–N3 adduct upon oxidation of
Scheme 6. Plausible mechanistic pathways for the formation of
,
TEMPO.25 26 The TEMPO+/TEMPO• redox couple appeared
the azidyl radical or its equivalent.
on the cyclic voltammogram as a highly reversible wave at
0.25 V in MeCN, but the addition of TBAN3 resulted in a sigꢀ
nificant cathodic shift of the redox wave (Figure 1). This shift
likely arose from the reversible formation of a discrete and
stable complex between TEMPO+ and N3 . The magnitude of
–
–
the potential shift follows a Nernstian dependence on [N3 ]
with a slope of 62 mV/dec (Figure 2), indicating a 1:1 stoichiꢀ
ometry of the complex.
ACS Paragon Plus Environment

Page 5 of 12
Journal of the American Chemical Society
45
40
35
30
25
20
15
10
5
1
2
3
4
5
6
7
8
1.5
1.4
1.3
TEMPO-N3
TEMPO+ClO4
TEMPO
-
1.2
1mM
2mM
3mM
4mM
5mM
6mM
7mM
8mM
9mM
10mM
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
-5
-10
-15
-20
-25
-30
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
-0.2
0.0
0.2
0.4
0.6
Potential vs Fc/Fc+ (V)
200
400
600
220
200
180
160
140
Wavelength (nm)
Figure 3. UVꢀvis absorption spectra of TEMPO• (8.6 mM),
TEMPO+ClO4– (8.6 mM), and the TEMPO–N3 complex (0.2 mM)
in MeCN at room temperature (ca. 22 °C).
0.0
0.2
0.4
0.6
0.8
1.0
-
log[N3
]
Figure 2. Cyclic voltammograms of TEMPO in the presꢀ
ence of N3 (top), showing a Nernstian dependence of the redox
–
–
potential on [N3 ] (bottom). The curve depicts a leastꢀsquares
fit to the function f(x) = ax + b: a = –62 ± 2; b = 210 ± 2; R2 =
Figure 4. Color of the MeCN solution of TEMPO–N3 adduct
(right) in comparison to TEMPO• (left) and TEMPO+ (center).
0.990.
The TEMPO–N3 adduct proved sufficiently stable for variꢀ
ous voltammetric and spectroscopic analyses. However, it
slowly decomposes at room temperature to form TEMPO•, as
detected by electron spin resonance spectroscopy (ESR; see
UVꢀvis absorption experiments provide further evidence
for the formation of the TEMPO–N3 adduct (I). TEMPO• and
TEMPO+ display UVꢀvis features with
λmax at 446 nm and 465
nm, respectively (Figure 3).27 The addition of NaN3 to the
TEMPO+ solution led to the appearance of a new, intense abꢀ
sorption peak at 380 nm.28 The resulting solution exhibited a
dark brown color at high concentrations and orange at low
concentrations (Figure 4), the latter of which was also obꢀ
served under electrochemical reaction conditions immediately
upon application of an anodic potential.
•
Figure S30), and presumably N3 . This nitrogenꢀcentered radiꢀ
cal is known to undergo rapid dimerization followed by fragꢀ
mentation to form N2 (vide infra).29 The halfꢀlife of I is ca. 7
min as measured by the disappearance of the UV absorbance
at 380 nm.30
The identity of this new TEMPO–N3 adduct was further
analyzed using a variety of experimental and computational
techniques. A UVꢀvis absorption titration of a solution of
TBAN3 with TEMPO+ClO4 resulted in a linear correlation
–
between the absorbance and molar ratio. Upon reaching 1:1
stoichiometry, the addition of more TEMPO+ salt to the mixꢀ
ture resulted in a rapid decrease of the absorbance at 380 nm
because TEMPO+ catalytically decomposes the TEMPO–N3
adduct through a currently unknown mechanism. To complete
the titration, we added additional TBAN3 to the 1:1 mixture of
TBAN3 and TEMPO+ClO4 and observed no further change in
–
the absorption intensity at 380 nm. These data confirmed the
1:1 stoichiometry of the complexation event and further indiꢀ
cated that the formation of I, although reversible, is effectively
quantitative.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 12
1
2
3
4
5
6
7
8
2.0
1.5
1.0
0.5
0.0
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
0
1
2
3
4
5
[N3 ]/TEMPO+]
-
[TEMPO+]/[N3 ]
-
Figure 5. Titration experiments, showing the 1:1 stoichiometry of
the TEMPO–N3 adduct.
DFT calculations were then carried out to predict the strucꢀ
ture of adduct I. Previous studies showed that TEMPO+ can
form complexes by reacting at either O or N of the oxoammoꢀ
nium group31 depending on the identity of the reacting partner
and the reaction medium. We computed the structure and enꢀ
–
ergy of the corresponding Oꢀ and Nꢀadducts of N3 using
Figure 6. Energetically viable structures of the TEMPO–N3 comꢀ
B3LYP/def2ꢀTZVP 32 with polarizable continuum solvation
model in MeCN (I1 and I2, respectively; Figure 6). Intriguingꢀ
ly, we also found two additional energetically viable structures
(I3 and I4), both displaying a 5ꢀmembered cyclic scaffold reꢀ
sulting from a complexation event akin to a [3+2] cycloaddiꢀ
plex predicted by DFT calculation. All energies are reported in
terms of the ground state energy corrected for zeroꢀpoint energy
(E+ZPE).
To further confirm our structural assignment, we predicted
the UVꢀvis spectrum for each structure (I1–I4) using timeꢀ
dependence DFT (TDDFT). To assess the accuracy of our
computational method in predicting the spectroscopic data of
structurally related compounds, we used TEMPO• and
TEMPO+ as references. The maximum absorbance predicted
for TEMPO• and TEMPO+ were at 439 nm and 466 nm, reꢀ
spectively. These data are consistent with experimental measꢀ
urements (446 nm and 465 nm, respectively; see Figure 3).
When comparing the experimentally measured absorbance
maximum of 380 nm to the predicted value for each viable
structure, we found that I4 is again the most likely structure.
DFT also estimated a high molar extinction coefficient of I4 of
13,100 Mꢀ1 cmꢀ1, which is on par with the experimental value
(5174 Mꢀ1 cmꢀ1)34 and substantially more intense than that of
either free TEMPO (~2 Mꢀ1 cmꢀ1) or the oxoammonium (~1 Mꢀ
–
tion between N=O and N3 . The terminal N–N and N–O disꢀ
tances are both about 2.5 Å, substantially longer than that of a
typical chemical bond, indicating that this adduct is more of a
chargeꢀtransfer complex than a covalent adduct. I4 appeared
most energetically favorable among all plausible structures
examined. Structural and energetic agreement across a series
of DFT methods (see table in Figure 6), including methods
consistent with previous studies of metalꢀfree chargeꢀtransfer
complexes,33 offers strong evidence for the validity of these
models.
1
cmꢀ1).35 We also computed structures with H+ or Na+ bound
to various forms of the adduct but none appears energetic viaꢀ
ble or predicts spectroscopic features consistent with the exꢀ
perimental data.
The structure of adduct I was also supported by NMR data.
When formed with azide labelled at a terminal position
[(15N=N=N)–], adduct I showed a 15N resonance of 244.66
ppm in MeCNꢀd3; a dramatic chemical shift change from
99.34 ppm for the free azide in D2O (Figure 7). Computationꢀ
ally, the complex in MeCN has a chemical shift of 255.71 ppm
(when 15N is bound to the N terminus of the oxoammonium)
and 233.85 ppm (when 15N is bound to the O terminus of the
oxoammonium), while the free sodium azide has a chemical
shift of 88.15 ppm.36 The observed chemical shift of the comꢀ
plex is in between the two predicted values, suggesting that
there is rapid scrambling of the two terminal azides. This findꢀ
ACS Paragon Plus Environment

Page 7 of 12
Journal of the American Chemical Society
ing is consistent with the reversible formation of the adduct
state at room temperature. Further, we conducted an experiꢀ
ment under standard electrochemical conditions with the exꢀ
clusion of light and observed minimal changes in efficiency in
the azidooxygenation reaction. This finding indicates that phoꢀ
toexcitation is not necessary for the observed reactivity. Taken
together, pathway 2b is an unlikely mechanism for the radical
addition of complex I to the alkene.
–
from TEMPO+ and N3 .
1
2
3
4
5
6
Kinetics experiments were carried out to further distinꢀ
guish between pathways 2b and 2c. The TEMPO–N3 adduct
alone is metastable under ambient conditions with a decompoꢀ
sition halfꢀlife of ca. 7 minutes. This decomposition results in
the formation of TEMPO•, as detected by ESR (see SI), and
presumably N2 from the dimerization of N3·.25 Notably, upon
the addition of an excess of indene (1m) at room temperature,
the UV absorbance peak at 380 nm disappears instantaneously
(< 5 s).
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. NMR spectra of TEMPO–N3 complex in MeCN (top)
and NaN3 in D2O (bottom).
D. Mechanism of reaction between TEMPO–N3 and alkenes
We then investigated the reaction between this TEMPO–
N3 adduct and the alkene substrate. Three plausible mechaꢀ
nisms are proposed for this reaction (Scheme 7). In pathway
2a, TEMPO–N3 undergoes polar addition across the C=C
bond in either a concerted or a stepwise fashion to yield the
difunctionalized product. Alternatively, in pathway 2b,
TEMPO–N3 directly delivers the N3 group onto the alkene in a
manner akin to metalꢀmediated radical group transfer.37 This
process results in the formation of TEMPO and carbonꢀ
centered radical II, which subsequently cross couple to furnish
the desired product. Finally, in pathway 2c, TEMPO–N3 first
decomposes into TEMPO• and azidyl radical (N3·), upon
which the sequential addition of these two openꢀshell species
across the alkene yields the desired azidooxygenated product.
Based on the information from the radical clock experiments
(see Scheme 5), pathway 2a can be conclusively ruled out.
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0.0
0.5
1.0
1.5
[alkene] (mM)
Scheme 7. Plausible mechanistic pathways for the reaction
between TEMPO–N3 and alkenes.
Figure 8. Plot of initial rates versus concentration of alkene 1l for
the reaction between adduct I (TEMPO+ClO4 + TBAN3) and
–
Pathway 2a: Polar addition
alkene 1l, showing first order rate dependence on [1l]. The data
point corresponding to [1l] = 0 represents the rate of decomposiꢀ
tion of I in the absence of 1l. Error bars represent the standard
deviation of three independent measurements. The curve depicts
an unweighted leastꢀsquares fit to the function f(x) = ax + b: a =
2.09 ± 0.08; b = 0.73 ± 0.04; R2 = 0.993.
N
N
N
R
OTMP
N3
O
N
R
Pathway 2b: Direct azidyl transfer
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
TEMPO–N3
R
N3
OTMP
N3
+
R
TEMPO
R
Pathway 2c: Dissociation–radical addition
k1
OTMPH2
N3
TEMPO
R
N3
TEMPO–N3
N3
+
TEMPO
R
R
k–1
k2
k3
Pathway 2b requires transition of adduct I from a closedꢀ
shell ground state to an openꢀshell excited state (singlet or
triplet) prior to transferring N3· to the alkene. However, the
first singlet excited state of complex I is predicted by DFT
calculation to be 3.56 eV more expensive than the ground
state. Therefore, this spinꢀunpaired singlet state is thermally
inaccessible. The triplet state, which requires intersystem
crossing from the singlet state, is thus also inaccessible. Analꢀ
ysis of other plausible isomers of I in Figure 6 revealed that
none of these structures possess a thermally available excited
0.0
0.5
1.0
1.5
2.0
2.5
[azide] (mM)
–
Figure 9. Plot of initial rates versus concentration of N3 for the
–
reaction between adduct I (TEMPO+ClO4 + TBAN3) and alkene
–
1l, showing zero order rate dependence on [N3 ]. Error bars repreꢀ
sent the standard deviation of three independent measurements.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 12
The curve depicts an unweighted leastꢀsquares fit to the function
f(x) = ax + b: a = –0.04 ± 0.01; b = 0.78 ± 0.02; R2 = 0.63.
1
2
3
4
5
6
7
8
18
16
14
12
10
8
0.5
0.4
0.3
0.2
0.1
0.0
6
9
4
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
0
0
1
2
3
4
5
6
7
1/ [TEMPO] (mM-1)
0
2
4
6
8
10
12
14
1/[TEMPO] (mM-1)
Figure 11. Plot of initial rates versus concentration of TEMPO for
the reaction between adduct I (TEMPO+ClO4 + TBAN3) and
–
alkene 1l (50 mM). Saturation kinetics were observed when
Figure 10. Plot of initial rates versus concentration of TEMPO for
TEMPO• concentration is less than 0.25 mM.
–
the reaction between adduct I (TEMPO+ClO4 + TBAN3) and
alkene 1l, showing inverse first order rate dependence on
[TEMPO•]. Error bars represent the standard deviation of three
independent measurements. The curve depicts an unweighted
leastꢀsquares fit to the function f(x) = ax–1 + b: a = 0.0345 ±
0.0008; b = 0.057 ± 0.002; R2 = 0.998.
These kinetic data are summarized in the following rate
equation:
rate = kobs[alkene]1[N3 ] [TEMPO•]–1, at synthetically releꢀ
– 0
vant [TEMPO•] (eq 1)
The rate equation is fully consistent with the proposed
pathway 2c (Scheme 7). Using steadyꢀstate approximation, the
following rate equation can be constructed for this mechanistic
scenario.
Using a less reactive alkene, 2ꢀmethylꢀ4ꢀphenylbutene (1l),
we studied the kinetics of the radical addition of TEMPO–N3
(I) to 1l using UVꢀvis spectroscopy. The experiment was carꢀ
ried out by mixing TEMPO+ClO4– and TBAN3 (used in lieu of
NaN3 to ensure full solubility in the reaction medium) in
MeCN followed by immediate addition of 1l prior to spectrum
collection at 380 nm. This reaction shows a firstꢀorder deꢀ
ꢄ ꢄ ꢇꢈꢉꢊꢋꢌ–ꢍ ꢏ[ꢐꢑꢒꢓꢔꢓ]
ꢅ
ꢆ
[
ꢎ
ꢀꢁꢂꢃ =
(eq 2)
•
]
ꢄ
ꢈꢉꢊꢋꢌ ꢕꢄ [ꢐꢑꢒꢓꢔꢓ]
ꢆ
–ꢅ
–
In eq 1, the zeroꢀorder rate dependence on [N3 ] indicates
that the formation of TEMPO–N3 is quantitative, in agreement
with our previous titration experiment (see Figure 5). The inꢀ
verse firstꢀorder rate dependence on [TEMPO•] at syntheticalꢀ
ly relevant [TEMPO•] suggests that the homolysis of TEMPO–
N3 is reversible and that the subsequent addition of N3· to alꢀ
kene 1l is rateꢀdetermining (k–1[TEMPO•] >> k2[alkene]). The
saturation kinetics at very low [TEMPO•] and high [alkene] (k–
1[TEMPO•] << k2[alkene]) is also consistent with the proposed
mechanism.
–
pendence on [1l] (Figure 8) and zero order on [N3 ] (Figure 9).
The rate vs [1l] plot shows a nonꢀzero intercept due to the
competing, alkeneꢀindependent decomposition of I (vide inꢀ
fra). When the amount of 1l is greater than 6 equiv with reꢀ
spect to TEMPO+, saturation kinetics behavior was observed
(see SI). Exogenous TEMPO• inhibits this reaction and an
inverse first order rate dependence was observed on
[TEMPO•] (Figure 10). The rate vs 1/[TEMPO•] plot exhibits a
small, nonꢀzero intercept, which likely also arises from the
competing decomposition pathway that unproductively conꢀ
sumes TEMPO–N3 adduct.
The inhibition effect of TEMPO• on the reaction rate was
also studied under conditions that resemble the electrochemiꢀ
cal reaction (Figure 11). At high [alkene] ([1l] = 50 mM), two
kinetic regimes were observed when altering the concentration
of exogenous [TEMPO•]. At very low [TEMPO•] ([TEMPO•]
< 0.25 mM, or 1/[TEMPO•] > 4), the lack of rate dependence
on [TEMPO•] was evident. At higher [TEMPO•] ([TEMPO•] >
0.25 mM, or 1/[TEMPO•] < 4), which is the case under synꢀ
thetic electrochemical conditions, 38 inverse firstꢀorder rate
dependence was again observed.
E. Mechanism of the decomposition of TEMPO–N3 in the
absence of an alkene
As previously discussed, adduct I undergoes slow decomꢀ
position in the absence of an alkene. We hypothesize that this
process also occurs through the reversible homolytic fragmenꢀ
tation of I into TEMPO• and N3 . Based on previous reports,
•
•
the resultant N3 will undergo facile dimerization followed by
irreversible decomposition to form N2.27 Kinetic data reveal
that this process is inhibited by exogenous TEMPO• (see SI),
which is consistent with our hypothesis. However, the reaction
rate does not follow a simple inverse firstꢀorder dependence
on [TEMPO•], likely as a result of the complex mechanism
• 26,27
underlying the decomposition of N3 .
decomposition side reaction is significantly slower than the
desired alkene addition presumably as a result of the low conꢀ
This dimerizationꢀ
•
centration of N3 in the reaction medium.
F. Full mechanism of the electrochemical azidooxygenation
ACS Paragon Plus Environment

Page 9 of 12
Journal of the American Chemical Society
The voltammetric, kinetic, spectroscopic, and computaꢀ
1
2
3
4
5
6
7
8
tional data presented above lead to a full understanding of the
mechanism for the electrochemical azidooxygenation reaction
(Scheme 8). Upon oxidation of TEMPO• to TEMPO+, the
G. Mechanismꢀguided expansion of substrate scope
The quantitative formation of the TEMPO–N3 adduct as a
–
result of the strong association between N3 and the oxoamꢀ
–
complexation of N3 with TEMPO+ takes place to furnish the
monium suggests that functional groups that are typically inꢀ
compatible with TEMPOꢀmediated oxidation conditions may
be tolerated in our electrochemical azidooxygenation reaction.
For instance, alcohols and sulfides have been shown to underꢀ
go oxidation to carbonyl compounds and sulfoxides, respecꢀ
tively, in the presence of TEMPO+.5,41 However, owing to the
lower nucleophilicity of alcohols and sulfides compared with
chargeꢀtransfer adduct I. This complexation event is reversible
but quantitative (association constant Ka >> 1). This metastaꢀ
ble intermediate will then undergo uphill and reversible fragꢀ
mentation, resulting in the formation of TEMPO• and azidyl
radical. The transient Nꢀcentered radical can dimerize to form
N2 as an undesired side reaction. In the presence of an alkene,
however, the addition of N3· to the C=C πꢀbond outcompetes
the decomposition pathway to yield carbonꢀcentered radical
II.39 Finally, the capture of II by TEMPO generates the diꢀ
functionalized product to complete the reaction.
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
–
N3 , the formation of adduct I will result in a very low concenꢀ
tration of TEMPO+ when N3– is in excess.
Indeed, alkenes with pendant hydroxyl or sulfide groups
proved suitable substrates and were transformed to the azꢀ
idooxygenated products in high yield (Scheme 9). In the case
with alcohol 1w, monitoring the reaction progress and controlꢀ
ling the reaction time are crucial to preventing the side reacꢀ
tion that oxidizes the hydroxyl group. Currently, amines and
thiols are not compatible with the azidooxygenation condiꢀ
tions.
The addition of N3· to the alkene is the slowest chemical
step postꢀelectron transfer. Natural abundance 13C kinetic isoꢀ
tope effects (KIE) further support the assignment of the rateꢀ
determining step (RDS) (see Scheme 8). A significant primary
KIE (3%) was observed at the terminal carbon connected to
the azide moiety. The computationally predicted value (1.033)
of an azidyl addition to the terminal position of tertꢀ
butylstyrene is consistent with the experimentally measured
value of 1.032(6). In addition, using cisꢀstilbene as a substrate,
upon 50% conversion, the alkene was recovered in complete
cis conformation, thereby showing that the N3· addition to the
alkene is irreversible and thus the RDS.
Scheme 9. Expanded substrate scope to include oxidatively labile
functional groups
Scheme 8. Mechanism of the electrochemical azidooxygenation
reaction.
N2
CONCLUSIONS
TEMPO
We described the development of an electrochemical proꢀ
tocol for the regioselective synthesis of vicinal azidooxygenatꢀ
ed products from alkenes. Through detailed mechanistic studꢀ
ies, we uncovered a new mode of reactivity of TEMPO in
which the TEMPO+/TEMPO• redox couple promotes the sinꢀ
–e–
kdec
N
N
N
O
N
N
–
k1
+ N3
+
N3
TEMPO
O
k–1
Ka >> 1
I
E1/2 = 0.25 V (vs. Fc/Fc+)
k2
(RDS)
R
–
•
13C KIE (see SI for full data set)
gleꢀelectron oxidation of N3 to N3 toward C–N bond forꢀ
mation with an alkene. This oxidation event is mediated by
TEMPO–N3, a newly observed chargeꢀtransfer complex
N3
1.011(9)
1.006 calc.
R
1.001(4)
1.001 calc.
II
TEMPO
formed from TEMPO+ and N3 . Although the direct structural
–
1.032(6)
1.033 calc.
elucidation of this complex proved challenging, DFT calculaꢀ
tions combined with NMR and UVꢀvis spectroscopic data
provided a tentative structural assignment. The most viable
structure displays an intriguing molecular scaffold resulting
OTMP
N3
1.008(6)
1.002 calc.
R
An alternative mechanistic scenario includes the formation
of N3· and TEMPO· through an endergonic outersphere elecꢀ
–
from the cycloaddition between N3 and the N=O motif of
–
tron transfer (+4.6 kcal/mol) from N3 to TEMPO+. In this
TEMPO+. Kinetic and computational studies depict a detailed
mechanistic scheme and energy diagram of the electrochemiꢀ
cal reaction. The mechanism involving the formation and subꢀ
sequent reaction of the TEMPO–N3 adduct guided the further
expansion of the reaction scope to include alkenes with oxidaꢀ
tively sensitive functional groups. This charge transfer comꢀ
plex exhibits a new class of reactivity not reported for
TEMPO+. Current work is focused on applying this new
mechanistic pathway enabled by the TEMPO+/TEMPO• redox
cycle for the development of new transformations mediated by
aminoxyl radicals.
scenario, TEMPO–N3 complex serves as an offꢀcycle reservoir
of azidyl radical. This mechanism is in principle plausible and
cannot be kinetically differentiated from the proposed scenario
in Scheme 8. However, this outersphere electron transfer is
unlikely the predominant pathway. As is evident from the UVꢀ
vis titration (see Figure 5) and CV data (see Figure 1), the
–
formation of TEMPO–N3 from TEMPO+ and N3 is instantaꢀ
neous and quantitative; this process is essentially barrierꢀless
–
and outcompetes the outersphere electron transfer from N3 to
TEMPO+. From the TEMPO–N3 resting state, it is highly unꢀ
likely that TEMPO–N3 completely dissociates into discrete
ions before electron transfer. In fact, outersphere electron
transfer between two molecules frequently occurs when the
redox pair are within a few Å.40 Taken together, we propose a
concerted innersphere mechanism for the generation of
ASSOCIATED CONTENT
Supporting Information
•
TEMPO• and N3 that comprises simultaneous dissociation of I
and electron transfer from N3– to TEMPO+.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 12
The Supporting Information is available free of charge on the
ACS Publications website.
1
2
3
4
5
Experimental procedures and characterization data (PDF)
Crystallographic data for compound 2o (deposited in the Camꢀ
bridge Structural Database: CCDC1843443) (CIF)
lan, S. N.; Stahl, S. S.; Lancaster, K. M. J. Am. Chem. Soc. 2017, 139,
13507.
(7) For examples of enamine addition to a TEMPO+ equivalent (Lewꢀ
is acidꢀactivated TEMPO), see: (a) Van Humbeck, J.; Simonovich,
S.; Knowles, R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
10012. (b) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166. (c) Sibi, M.
P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124. For examples
of amine oxidation, see: (d) Semmelhack, M. F.; Schmid, C. R. J. Am.
Chem. Soc. 1983, 105, 6732. (e) Sonobe, T.; Oisaki, K.; Kanai, M.
Chem. Sci. 2012, 3, 3249. (f) Wu, Y.; Yi, H.; Lei, A. ACS Catal. 2018,
8, 1192.
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
Song Lin: songlin@cornell.edu
Kyle Lancaster: kml236@cornell.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
Notes
(8) (a) Babiarz, J. E.; Cunkle, G. T.; DeBellis, A. D.; Eveland, D.;
Pastor, S. D.; Shum, S. P. J. Org. Chem. 2002, 67, 6831. (b) Coseri,
S.; Ingold, K. U. Org. Lett. 2004, 6, 1641.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(9)(a) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U. J. Am. Chem.
Soc. 1992, 114, 4983. (b) Sobek, J.; Martschke, R.; Fischer, H. J. Am.
Chem. Soc., 2001, 123, 2849. (c) Gentry, E. C.; Rono, L. J.; Hale, M.
E.; Matsuura, R.; Knowles, R. R. J. Am. Chem. Soc. 2018, 140, 3394.
(d) Xu, F.; Zhu, L.; Zhu, S.; Yan, X.; Xu, H.ꢀC. Chem. Eur. J. 2014,
20, 12740. (e) Fuller, P. H.; Kim, J.ꢀW.; Chemler, S. R. J. Am. Chem.
Soc. 2008, 130, 17638. For a related work on reversible Ti radical
capture by TEMPO, see: (f) Huang, K.ꢀW.; Han, J. H.; Musgrave, C.
B.; Waymouth, R. M. Organometallics 2006, 25, 3317.
Financial support to S.L. was provided by Cornell University, the
Atkinson Center for a Sustainable Future, and NSF (CHEꢀ
1751839). K.M.L. gratefully acknowledges the Alfred P. Sloan
Foundation and NIGMS (R35 GM124908) for support. This study
made use of the Cornell Center for Materials Research Shared
Facilities supported from NSF MRSEC (DMRꢀ1719875), NMR
facility supported by the NSF (CHEꢀ1531632), and National Biꢀ
omedical Research Center for AdvanCed ESR Technology
(ACERT) laboratory supported by the NIGMS (P41GM103521).
G.S.S. is grateful for an NSF Graduate Fellowship (DGEꢀ
1650441); A.S. is grateful for an ACS SURF Award. We thank
Dr. Ivan Keresztes for help with NMR spectral analysis, Dr. Saꢀ
mantha MacMillan for help with Xꢀray crystallography analysis,
Dr. Bo Chen for discussions on the DFT calculation, and Dr. Keꢀ
Yin Ye for experimental assistance.
( 10 ) Nicolas, J.; Guillaneuf, Y.; Lefay, C.; Bertin, D.; Gigmes,
D.; Charleux, B. Prog. Polym. Sci. 2013, 38, 63.
(11) (a) Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem. Int. Ed.
2008, 47, 9547. (b) Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129. (c)
Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415. (d) Liwosz, T.; Chemler, S. R.
Synlett 2014, 26, 335.
(12) Li, Y.; Studer, A. Angew. Chem. Int. Ed. 2012, 51, 8221.
(13) TEMPO+/TEMPO has been used for the singleꢀelectron oxidaꢀ
tion of superoxide and reduction of peroxyl. See: (a) Krishna,
M.; Grahame, D.; Samuni, A.; Mitchell, J.; Russo A. Proc. Natl. Acad.
Sci. 1992, 89, 5537. (b) Griesser, M.; Shah, R.; Van Kessel, A. T.;
Zilka, O.; Haidasz, E. A.; Pratt, D. A. J. Am. Chem. Soc. 2018, 140,
3798. TEMPO+ has also been proposed to mediated a radical cyclizaꢀ
tion reaction (ref. 9d) via a singleꢀelectron pathway, although little
evidence was provided to support such a mechanism.
REFERENCES
(1) Lebedev, O. L.; Kazarnovsky, S. N. Tr. Khim. Khim. Tekhnol.
1959, 3, 649.
(14) For examples, see: (a) Knoop, C. A.; Studer, A. J. Am. Chem.
Soc. 2003, 125, 16327. (b) Hawker, C. J.; Bosman, A. W.; Harth, E.
Chem. Rev. 2001, 101, 3661. (c) Puts, R. D.; Sogah, D. Y. Macromol-
ecules 1996, 29, 3323. (d) Moad, G.; Rizzardo, E. Macromole-
cules 1995, 28 , 8722.
(2) For representative recent reviews, see: (a) Tebben, L.; Studer, A.
Angew. Chem. Int. Ed. 2011, 50, 5034. (b) Wertz, S.; Studer A. Green
Chem. 2013, 15, 3116. (c) Nutting, J. E.; Rafiee, M. R.; Stahl, S.
S. Chem. Rev. 2018, 118, 4834. (d) Leadbeater, N. E.; Bobbitt, J.
Aldrichimica Acta 2014, 47, 65.
(3) Greszta, D.; Matyjaszewski, K. Macromol. 1996, 29, 7661.
(4) Kato, Y.; Shimizu, Y.; Yijing, L.; Unoura, K.; Utsumi, H.; Ogata,
T. Electrochim. Acta. 1995, 40, 2799.
(5) For some examples, see: (a) Anelli P. L.; Biffi, C.; Montanari,
F.; Quici, S. J. Org. Chem. 1987, 52, 2559; (b) Hoover, J.; Stahl, S. S.
J. Am. Chem. Soc., 2011, 133, 16901; (c) Hoover, J. M.; Ryland, B.
L.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357; (d) Bailey, W.
F.; Bobbitt, J. M. J. Org. Chem. 2007, 72, 4504. (e) Ganem, B. J. Org.
Chem. 1975, 40, 1998. (f) Hickey, D.; Milton, R.; Chen, D.; Sigman
M.; Minteer, S. ACS Catal., 2015, 5, 5519. (g) Semmelhack, M. F.;
Chou, C. S.; Cortes, D. A. J. Am. Chem. Soc. 1983, 105, 4492. (h) de
Nooy, A. E. J.; Besemer, A. C. Tetrahedron 1995, 51, 8023. (i) Bobꢀ
bitt, J. M.; Brückner, C.; Merbouch, N. Org. React. 2009, 74, 103.
(6) The oxidation of alcohol can also go through a singleꢀelectron
pathway relying on the TEMPO/TEMPO– redox cycle in the presence
of a copper catalyst. See: Badalyan, A.; Shannon, S. S. Nature 2016,
535, 406. A mechanistic study shows that this reaction is mediated by
a [Cu]–TEMPO complex in which the bound TEMPO behaves like
TEMPO+. See: Walroth, R. C.; Miles, K. C.; Lukens, J. T.; MacMilꢀ
(15) Fu, N.; Sauer, G.; Saha, A.; Loo, A.; Lin S. Science 2017, 357,
575.
(16) For representative reviews on synthetic electrochemistry, see: (a)
Moeller, K. D. Tetrahedron 2000, 56, 9527. (b) Yoshida, J.; Kataoka,
K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265. (c)
Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492. (d) Yan,
M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230. (e)
Möhle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.; Waldvoꢀ
gel, S. R. Angew. Chem. Int. Ed. 2018, 57, 6018. (f) Mitsudo, K.;
Kurimoto, Y.; Yoshioka, K.; Suga, S. Chem. Rev. 2018, 118, 5985–
5999. (g) Tang, S.; Liu, Y.; Lei, A. Chem 2018, 4, 27.
(17) For a review, see: (a) Bergmeier, S. C. Tetrahedron 2000, 56,
2561. For recent examples of aminooxygenation of alkenes, see: (b)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179. (c) Lu, D.ꢀF.;
Zhu, C.ꢀL.; Jia, Z.ꢀX.; Xu, H. J. Am. Chem. Soc. 2014, 136, 13186. (d)
Hemric, B. N.; Shen, K.; Wang, Q. J. Am. Chem. Soc. 2016, 138,
5813. (e) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.ꢀF.; Jiao, N. J.
Am. Chem. Soc. 2015, 137, 6059. Also see ref. 9e.
(18) Zhang, B.; Studer, A. Org. Lett. 2013, 15, 4548.
(19) For examples, see: (a) Bruncko, M.; Schlingloff, G.; Sharpless,
K. B. Angew. Chem. Int. Ed. 1997, 36, 1483. (b) Michaelis, D. J.;
Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc. 2007, 129, 1866. (c)
ACS Paragon Plus Environment

Page 11 of 12
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 4570.
Türkyilmaz, F.; Kehr, G.; Li, J.; Daniliuc, C.; Tesch, M.; Studer,
A.; Erker, G. Angew. Chem. Int. Ed. 2016, 55, 1470. Also see refs. 5
and 12.
Intramolecular examples: (d) Hemric, B. N.; Shen, K.; Wang, Q. J.
Am. Chem. Soc. 2016, 138, 5813. (e) Fuller, P. H.; Kim, J. W.; Chemꢀ
ler, S. R. J. Am. Chem. Soc. 130, 17638.
(32) For examples of B3LYP/def2ꢀTZVP being used in the study of
charge transfer complexes, see: (a) Marsh, B. M.; Zhao, J.; Garand, E.
Phys. Chem. Chem. Phys. 2015, 17, 25786. (b) Baumeier, B.; Andriꢀ
enꢀko, D.; Rohlfing, M. J. Chem. Theory Comput. 2012, 8, 2790.
(33) (a) Steinmann, S. N.; Piemontesi, C.; Delachat, A.; Corminꢀ
boeuf, C. J. Chem. Theory Comput. 2012, 8, 1629. (b) Bauzá, A.;
Ramis, R.; Frontera, A. J. Phys. Chem. A. 2014, 118, 2827.
(34) The extinction coefficient is highly dependent on the medium. As
such, the computational data with PCM solvation model can only
provide an approximation for this value. It is further known that exꢀ
tinction coefficients are poorly predicted by default TDDFT methods.
However, the ratio between experimental:experimental and calculatꢀ
ed:calculated molar extinction coefficients for different UV peaks
exhibiting a difference of less than a factor of 2 has been used as
evidence supporting the accuracy of TDDFT UVꢀVis prediction. This
is true of the results presented herein. For a relevant reference, see:
Sundholm, D. Chem. Phys. Lett. 1999, 302, 480.
(20) Muñiz, K. Chem. Soc. Rev. 2004, 33, 166–174
(21) Newcomb, M. Tetrahedron 1993, 49, 1151. Comparison of these
firstꢀorder and secondꢀorder rate constants can be made at a given
reaction concentration (ca. 0.06 M).
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
–
•
(22) The potential of N3 /N3 has been measured in aqueous media.
See: (a) Ram, S.; Stanbury, D. M. J. Phys. Chem. 1986, 90, 3691. (b)
Alfassi, Z. B.; Harriman, A.; Huie, R. E.; Mosseri, S.; Neta, P. J. Phys.
Chem. 1987, 91, 2120.
(23) For examples, see: (a) Hickey, D. P.; McCammant, M. S.;
Giroud, F.; Sigman, M. S.; Minteer, S. D. J. Am. Chem. Soc. 2014,
136, 15917. (b) Rafiee, M.; Miles, K. C.; Stahl, S. S. J. Am. Chem.
Soc. 2015, 137, 14751.
(24) TEMPO has been used for the generation of azidyl radical via
different mechanisms. See: (a) Wang, T.; Jiao, N. J. Am. Chem. Soc.
2013, 135, 11692. (b) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M.
B.; Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406. Also see ref. 18.
(25) The formation of an adduct between TEMPO and azidyl was
postulated as a side reaction of the alkene functionalization in ref. 18.
(35) DFTꢀpredicted values are 8 Mꢀ1 cmꢀ1 for TEMPO and 4 Mꢀ1 cmꢀ1
for TEMPO+. See ref. 25 for experimental data on the extinction coefꢀ
ficients of TEMPO and TEMPO+.
(36) The NMR prediction was made using GaugeꢀIndependent Atomꢀ
ic Orbital (GIAO) method with TaoꢀPerdewꢀStaroverovꢀScuseria
hybrid functional and a polarization continuum model. See SI for
details.
(37) For some recent examples of metalꢀmediated azidyl transfer, see:
(a) Huang, X.; Bergsten, T.; Groves, J. J. Am. Chem. Soc., 2015, 137,
5300; (b) Sharma, A.; Hartwig, J. Nature 2015, 517, 600; (c) Yuan,
Y.ꢀA.; Lu, D.ꢀF.; Chen, Y.ꢀR.; Xu, H. Angew. Chem. Int. Ed. 2015, 2,
534. Also see ref. 15.
(38) Under synthetic conditions, TEMPO–N3 is generated electroꢀ
chemically in small doses whereas TEMPO is in large access in comꢀ
parison.
(39) The kinetics of azidyl addition to alkenes has been studied using
timeꢀresolved UVꢀvis and laser flash photolysis. See: Workentin,
M.; Wagner, B.; Lusztyk, J.; Wayner, D. J. Am. Chem. Soc. 1995, 117,
119.
(40) Hupp, J. T.; Weaver, M. J. J. Phys. Chem. 1984, 88, 1463.
(41) (a) Siedlecka, R.; Skarzewski, J. Synlett. 1996, 8, 757. (b) Veꢀ
lusamy, S.; Kumar, A.; Saini, R.; Punniyamurthy, T. Tetrahedron Lett.
2005, 46, 3819. (c) Huang, J.; Li, S.; Wang, Y. Tetrahedron Lett.
2006, 47, 5637.
–
(26) A charge transfer complex between TEMPO+ and ClO2 was
reported in the context of alcohol oxidation: (a) Furukawa,
K.; Shibuya, M.; Yamamoto Y. Org. Lett., 2015, 17, 2282; charge
transfer complexes between TEMPO and quinone derivatives have
also been described: (b) Nakatsuji, S.; Takai, A.; Nishikawa, K.;
Morimoto, Y.; Yasuoka, N.; Suzuki, K.; Enokid, T.; Anzai, H. Chem.
Commun. 1997, 275.
(27) These experimentally measured values are consistent with literaꢀ
ture report. See: Hase, Y.; Ito, E.; Shiga, T.; Mizuno, F.; Nishikoori
H.; Iba, H.; Takechi, K. Chem. Commun. 2013, 49, 8389.
(28) This spectroscopic feature at 380 nm was observed in a previous
study when azidyl generated from pulse radiolysis was mixed with
TEMPO, although the speciation was not discussed in this previous
study. See: Samuni, A.; Goldstein, S.; Russo, A.; Mitchell, J.; Krishna,
M. Neta, P. J. Am. Chem. Soc. 2002, 124, 8719.
(29) (a) Hayon, E.; Simic, M. J. Am. Chem. Soc. 1970, 92, 7486. (b)
Workentin, M.; Wagner, B.; Negri, F.; Zgierski, M.; Lusztyk,
J.; Siebrand, W.; Wayner, D. J. Phys. Chem. 1995, 99, 94.
(30) Although the decay of adduct I should in theory follow the firstꢀ
order behavior, the generation of TEMPO, which inhibits the reaction
(see section below), results in deviation from firstꢀorder reaction kiꢀ
netics. The halfꢀlife reported here gives a rough estimate of the stabilꢀ
ity of the complex.
(31) For examples, see: (a) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu,
Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410. (b)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 12
1
2
3
4
5
R1
N
TEMPO, NaN3
O
R3
R1
R2
R2
R3
N3
LiClO4 in MeCN/H2O or
pH 7 phosphate buffer
(23 examples, 37%–99% yield)
R4
R4
6
7
Mechanism: TEMPO-mediated azide oxidation
(CV, kinetics, KIE, UV-vis, ESR, 15N NMR, DFT)
8
9
TEMPO
N
O
–
N
via:
N3
N
N
–e–
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
N3
TEMPO+
charge-transfer
complex
anode
12
ACS Paragon Plus Environment