Catalyst-Controlled and Tunable, Chemoselective Silver-Catalyzed Intermolecular Nitrene Transfer: Experimental and Computational Studies

Article abstract of DOI:10.1021/jacs.6b07981

The development of new catalysts for selective nitrene transfer is a continuing area of interest. In particular, the ability to control the chemoselectivity of intermolecular reactions in the presence of multiple reactive sites has been a long-standing ch

Full text of DOI:10.1021/jacs.6b07981

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Catalyst-Controlled and Tunable, Chemoselective Silver-Catalyzed
Intermolecular Nitrene Transfer: Experimental and Computational Studies
Nicholas Dolan, Ryan J Scamp, Tzuhsiung Yang, John F. Berry, and Jennifer M Schomaker
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07981 • Publication Date (Web): 11 Oct 2016
Downloaded from http://pubs.acs.org on October 11, 2016
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 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Catalyst-controlled and tunable, chemoselective silver-catalyzed in-
termolecular nitrene transfer: Experimental and computational
studies
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
Nicholas S. Dolan,† Ryan J. Scamp,† Tzuhsiung Yang,† John F. Berry* and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
ABSTRACT: The development of new catalysts for selective nitrene transfer is a continuing area of interest. In particular, the ability to
control the chemoselectivity of intermolecular reactions in the presence of multiple reactive sites has been a longꢀstanding challenge in the
field. In this paper, we demonstrate examples of silverꢀcatalyzed, nonꢀdirected, intermolecular nitrene transfer reactions that are both
chemoselective and flexible for aziridination or C–H insertion, depending on the choice of ligand. Experimental probes present a puzzling
picture of the mechanistic details of the pathways mediated by [(tBu3tpy)AgOTf]2 and (tpa)AgOTf. Computational studies elucidate these
subtleties and provide guidance for the future development of new catalysts exhibiting improved tunability in group transfer reactions.
site-selective nitrene transfer reactions, a longꢀstanding goal in
the field.
Introduction
We have demonstrated that silver(I) catalysis offers unique opꢀ
portunities to tune the chemoꢀ and siteꢀselectivity of intramolecuꢀ
lar nitrene transfer (Scheme 1AꢀB).13,14,15 Changes to the ligand,
the AgOTf:ligand ratio, and the nitrene precursor all influence the
coordination geometry and reactivity of the putative nitrene. For
example, preference for aziridination or C–H bond insertion in a
homoallylic carbamate can be controlled by simply changing the
ratio of 1,10ꢀphenanthroline (phen) to AgOTf (Scheme 1A).13
Enforcing different coordination geometries at Ag(I) using diverse
ligands, including 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine (tBubpy) and
tris(2ꢀpyridylꢀmethyl)amine (tpa), enables siteꢀselective amination
of chemically distinct C—H bonds (Scheme 1B).14,15 Expanding
Ag(I) catalysis to tunable, intermolecular nitrene transfer reacꢀ
tions has been challenging; in this work, we describe initial experꢀ
imental and computational studies to better understand these reacꢀ
tions (Scheme 1C).
Amines are important functional groups occurring in a diverse
array of molecules with significant biological and therapeutic
value. One effective strategy for streamlining the synthesis of
amines involves the selective introduction of a new C—N bond at
a specific site in a hydrocarbon precursor. Diverse transition metꢀ
als1ꢀ8 are known to catalyze the insertion of metal nitrenes into
either a C–H or C=C bond to yield amines or aziridines, respecꢀ
tively. Substrate control has traditionally been the primary factor
dictating the chemoselectivity of the amination event; for examꢀ
ple, intramolecular aminations of homoallylic sulfamates tend to
yield the aziridination product using popular dinuclear Rh(II)
tetracarboxylate catalysts.2 One notable exception is the dinuclear,
chiral carboxamidate complex Rh2(Sꢀnap)4, which can favor inꢀ
tramolecular C–H bond insertion over aziridination.9 More recentꢀ
ly, it has been shown that the chemoselectivity of nitrene transfer
can be altered to favor C–H insertion by changing the metal idenꢀ
tity to Ru, Co, Mn or Fe, which results in a change from a conꢀ
certed to a stepꢀwise nitrene transfer event.3,4b,5,8
Scheme 1. Agꢀcatalyzed chemoꢀ and siteꢀselective aminations.
Achieving catalyst control over the chemoselectivity of intermo-
lecular nitrene transfer using a single metal is even more chalꢀ
lenging, particularly when compared to metalꢀcatalyzed carbene
transfer reactions.10 A rare example of a Rhꢀbased system selecꢀ
tive for intermolecular nitrene insertion into allylic C–H bonds
employs Rh2((S)ꢀnta)4 (nta = (S)ꢀNꢀ1,8ꢀnaphthoylalanine) in the
presence of chiral sulfonimidamides 11
however, this behavior
;
relies on a strong match between the chiral Rh catalyst and the
optically pure nitrene precursor. In general, most dinuclear Rh
catalysts that are successful for intramolecular nitrene transfer
perform poorly in intermolecular reactions.12 Two major factors
impeding the development of more modular and less expensive
catalysts for nitrene transfer include a poor understanding of how
reactivity differs in intraꢀ vs. intermolecular processes, as well as
how the mechanism and selectivity of the nitrene transfer reꢀ
sponds to modifications to the supporting ligands for a particular
metal. A better understanding of these issues is necessary to spur
further progress towards our ultimate goal of developing new,
inexpensive catalysts for predictable, tunable and intermolecular
Results and Discussion
Initial experimental studies. The reaction of cyclohexene (1),
2,2',2''ꢀtrichloroethylsulfamate (TcesNH2, 2) and iodosobenzene
(PhIO) with Ag catalysts supported by a variety of readily availaꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
ble Nꢀdonor ligands (see the Supporting Information for further
(Table 3). Fiveꢀ and sixꢀmembered rings (entries 1ꢀ4) give cheꢀ
1
2
3
4
5
6
7
8
details) was carried out (Table 1). We found that AgOTf ligated
by tert-butylterpyridine 4 (entry 1) gave good selectivity for proꢀ
duction of the aziridine 3a over the allylic amine 3b.7dꢀf Xꢀray
crystallographic and DOSY NMR studies showed that the silver
catalyst supported by 4 exists in both the solid and solution states
as the dimer [(tBu3tpy)AgOTf]2 (hereafter called catalyst A), conꢀ
sisting of two threeꢀcoordinate Ag centers.7e,13 Interestingly, emꢀ
ploying the tpa ligand 5 (entry 2) resulted in a preference for alꢀ
lylic C–H amination to 3b over aziridination. A crystal structure
of a silver(I) complex bearing a ligand similar to 5 has been reꢀ
ported, suggesting the formula (tpa)Ag(OTf) for catalyst B.16
modivergent amination. However, as the size of the ring increases
(entries 5ꢀ6), chemoselectivity for the aziridine product also inꢀ
creases with both catalysts A and B. The lesser selectivity for C–
H amination with B in this case may be attributed to poor stabiliꢀ
zation of an allylic radical via conjugation with the double bond in
the 7ꢀmembered ring due to competing transannular interactions,
providing indirect evidence that B may operate via a stepꢀwise
nitreneꢀtransfer pathway. Reaction of transꢀhexꢀ2ꢀene 8 (entries
7ꢀ8) gave no isomerization in either aziridination or C–H aminaꢀ
tion reactions, but did show a rearranged product using B (entry
8), also indicative of a potential stepwise pathway. A is not overly
sensitive to steric effects, giving excellent selectivity for aziridinaꢀ
tion of both triꢀ and tetrasubstituted alkenes 9 and 10 (entries 9,
11). However, achieving selectivity for C–H insertion in acyclic
substrates employing B is challenging, as aziridination becomes
competitive (entries 10, 12). In order to rationalize these observaꢀ
tions and achieve a better understanding of the reasons for the
lack of chemocontrol, extensive computational studies were carꢀ
ried out as described later in this report.
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 1. Impact of the ligand on silverꢀcatalyzed nitrene transfer.
Table 3. Tunable, catalystꢀcontrolled amination.
R2
NSO3R
AgOTf
ligand
R2
R1
R1
O
O
R2
R1
+
+
S
RO
NH2
R3
PhIO
NHSO3R
R3
R3
H
3, 6-10
3a,b 6-10a,b
3c,d 6-10c,d
Having demonstrated the ability to control the chemoselectivity
of Agꢀcatalyzed amination by changing the nature of the ligand,
the identity of the nitrene precursor was varied in an attempt to
further improve selectivity (Table 2). While the 3a:3b selectivity
for aziridination catalyzed by A was not improved with alkylꢀ
sulfamate 2c as compared to 2a, the yield did increase to 97%.
Other nitrene precursors resulted in either lower yields or deꢀ
creased selectivity for the aziridine 3a. When B was employed,
the C–H amination product was favored to a greater extent emꢀ
ploying arylsulfamates 2eꢀ2g, with 2f displaying the highest
3b:3a ratio of 5.8:1. It is worth noting that in the majority of exꢀ
amples, the overall preference of A for aziridination and that of B
for C–H amination is independent of the identity of the nitrene
precursor, supporting catalystꢀcontrol of nitrene transfer. The one
exception is the chiral sulfonimidamide 2d previously employed
by Dauban in Rhꢀcatalyzed nitrene transfer; in this case, aziridinaꢀ
tion was preferred using both A and B.11
Aa
Ia
substrate
entry
ligand
tBu3tpy
A : I
1
2
61% 6a
13% 6b
11% 6c
35% 6d
5.5 : 1
1 : 2.7
H
H
6
3
tpa
tBu3tpy
tpa
3
4
84% 3a
8% 3b
13% 3c
46% 3d
6.5 : 1
1 : 5.8
tBu3tpy
tpa
5
6
59% 7a
20% 7b
2% 7c
30 : 1
7
H
H
24% 7d
1 : 1.2
tBu3tpy
tpa
58%
b 8a
4%
b 8c
c 8d
15 : 1
1: 3.1
7
8
8
9
8% 8b
25%
H
H
tBu3tpy
tpa
72%b 9a
29% 9b
2%b 9c
25%d 9d
36 : 1
9
1.2 : 1
10
tBu3tpy
tpa
97% 10a
25% 10b
0% 10c
0% 10d
>19 : 1
>19 : 1
11
12
10
A: HfsNH2 (0.25 mmol), 10 mol% AgOTf, 12 mol% tBu3tpy, 3.5 equiv PhIO,
CH2Cl2, 4 A MS, 4 h, rt. I: DfsNH2 (0.25 mmol), 10 mol% AgOTf, 12 mol%
tpa, 1.2 equiv PhIO, CH2Cl2, 4 A MS, 1 h, rt. aIsolated yield. bNMR yield,
Cl3CCH2Cl internal standard. ctrans only, 6% rearranged. d3% rearranged.
A series of substituted cyclohexenes of varying complexity were
investigated further in tunable silverꢀcatalyzed amination (Table
4). Addition of a Me group to the alkene of 11 increases selectiviꢀ
ty for aziridination with A (entry 1), and improves the preference
for C–H amination with B; amination of the less hindered allylic
C–Ha bond is favored over C–Hb by a ratio of 3.0:1 (entry 2).
Arylꢀsubstituted alkenes 12 and 14 (entries 3 and 7) resulted in
good selectivity using A, but competing epoxidation occurs with
electronꢀrich 13 (entry 5). Excellent selectivity for C–H amination
is observed for 12ꢀ14 using B (entries 4, 6, 8). Catalyst B shows
sensitivity to steric effects, as amination of the less congested Ha
in 12ꢀ14 is preferred over the more hindered Hb by a ratio of apꢀ
proximately 6:1 in all three cases. Conjugation of an alkyne with
the cyclohexene of 15 gives good chemoselectivity with both
catalysts (entries 9ꢀ10); however, the aziridine is not stable to
chromatography, undergoing rearrangement and hydrolysis to
aldehyde 15a.17 Good siteꢀselectivity for the amination of Ha over
Hb was also noted using 15 (entry 10). Moving the Me group from
the vinyl carbon of 11 to the allylic position in 16 (entries 11ꢀ12)
decreases selectivity for aziridination with A. In contrast, the seꢀ
lectivity of C–H amination was improved with B; however, allylic
transposition occurs to give 11d and 16d. The addition of an alꢀ
lylic Ph group in 17 further decreases selectivity in aziridination
Table 2. Influence of the nitrene precursor on chemoselectivity.
The scope of tunable nitrene transfer was briefly explored with
selected substrates containing both C=C and C–H functionalities
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
Table 4. Tunable amination of C=C and C–H bonds.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(entry 13), but showed increased preference for insertion to 12d
crease in yield in the presence of TEMPO, indicating the possibilꢀ
ity of a radical intermediate. These results suggest that catalysts A
and B operate under mechanistically distinct pathways. However,
we note that the C–H amination products of 16 and 17 employing
either catalyst A or B contain a transposed double bond (Table 4,
(entry 14). These experiments provide insights into the mechanisꢀ
tic details of Agꢀcatalyzed intermolecular nitrene transfer that will
be further discussed in the context of our computational studies
(vide infra).
Scheme 2. Influence of TEMPO on the amination of 11 and 16.
A series of natural productꢀderived substrates 18ꢀ20, containing
multiple alkene and allylic C–H functionalities, were explored.
Alkene 18 gives good selectivity for aziridination and a high 11:1
anti:syn ratio (entry 15). The sensitivity of B to steric effects is
illustrated in entry 16, where activation of Ha is now preferred
over Hb by a ratio of 4.4:1 (compare to entry 2). The αꢀionone
derivative 19 shows poorer selectivity for aziridination (entry 17),
perhaps due to the increased steric demand of the more electronꢀ
rich alkene a. Both chemoꢀ and siteꢀselectivity for C–H insertion
(entry 18) are excellent. Finally, only aziridination of bisabolyl
methyl ether 20 is observed with A (entry 19), with the exocyclic
alkene preferred over the endocyclic alkene by a ratio of 2.4:1.
The presence of two electronꢀrich alkenes in 20 results in poor
selectivity for C–H amination (entry 20); however, siteꢀselectivity
for the less hindered Ha is excellent, favoring Ha over Hb by a
ratio of > 19:1.
Mechanistic studies. Further experimental studies were carried
out to better understand the mechanistic details of amination
pathways promoted by A and B with both cyclic and acyclic subꢀ
strates. In Scheme 2A, subjecting 11 to aziridination conditions in
the absence and presence of TEMPO as a radical inhibitor showed
a modest 10% decrease in yield, which is not a definitive indicaꢀ
tion that radical intermediates are involved. In contrast, subjecting
11 to C–H amination conditions did result in a substantial deꢀ
entries 11ꢀ14). This suggests both silver catalysts are capable of
promoting stepꢀwise nitrene transfer pathways involving radical
intermediates. Surprisingly, TEMPO inhibition studies with 16
(Scheme 2B) show decreased yields of the insertion product, but
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
have little effect on the aziridination yield. Explaining these puzꢀ
zling results is important for developing better Ag(I) catalysts and
catalyst A follows a singleꢀstep mechanism similar to that deꢀ
1
scribed by Pérez and coworkers, and catalyst B follows a stepwise
pathway.7a However, our experimental probes of the mechanism
(Schemes 2ꢀ4) yield puzzling results. Experiments in Scheme 2 on
cyclic alkenes appear to support our hypothesis, as the use of
TEMPO as a radical inhibitor did not impact the aziridination
pathways involving catalyst A. The same is true for the acyclic
alkene 21 in Scheme 3; however, the data in Scheme 4 suggest
that even catalyst A is capable of promoting stepꢀwise nitrene
transfer, as allylic C=C double bond transposition is observed. To
find a mechanistic explanation for these seemingly contradictory
observations, as well as to investigate the reasons for the
chemoselectivity differences between A and B, we decided to
employ quantum chemical methods to study the reactivity of these
two catalysts at the level of density functional theory. Here,
B3LYPꢀD3 is used for the structures of critical points along the
reaction coordinates and we employ complete active space selfꢀ
consistent field (CASSCF) for the electronic structure of the
nitrene complexes. The validity of our choice of B3LYPꢀD3 is
demonstrated by benchmarking various functionals against the
crystal structure of catalyst A and B3LYPꢀD3 was found to be one
of the most robust functional in reproducing the observed molecuꢀ
lar geometry (see Table S1ꢀ4 for quantitative assessments of the
functionals).
were addressed using computational studies (vide infra).
2
3
4
5
6
7
8
9
Further mechanistic studies with acyclic alkenes (Schemes 3ꢀ4)
reveal that catalyst A generates 21a exclusively as the cis isomer
(Scheme 3), while B gives 21b as a 13:1 mixture of cis:trans isoꢀ
mers. Both catalysts favor aziridination, although the selectivity
with B (2.9:1) is much lower than that observed with A (>20:1).
Slight isomerization of the alkene from >20:1 cis:trans to 13:1
cis:trans in the C–H amination product 21b occurs in both the
absence and presence of TEMPO.
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. Influence of the radical inhibitor TEMPO on the amiꢀ
nation of acyclic alkene 21.
Dfs
Hfs
N
N
Ag(tBu3tpy)OTfa
Hfs-NH2
Ag(tpa)OTf b
Dfs-NH2
H
8b
8a
21
NHHfs
NHDfs
21a
21b
aziridination predominates
42% yield 2.9 : 1
13 : 1 cis/trans
> 99:1 cis:trans
63% yield >20 : 1
>20 : 1 cis/trans
no inhibitor
>20 : 1
>20 : 1
57% yield
>20 : 1 cis/trans
10% yield
20 mol% TEMPO
Structural features of nitrene intermediates. To begin our compuꢀ
tational studies, the nitrene complex of B, (tpa)Ag(OTf)(NSO3R)
B(N), was optimized with the nitrene ligand bound in the equatoꢀ
rial site (cis to the tertiary amine) and the OTf– ion bound in the
axial site. This nitrene complex of catalyst B was chosen for comꢀ
putational studies of its reactivity owing to the fact that the
chemoselectivity of B is affected by the identity of the Ag salt
employed supporting the hypothesis that the anionic OTf ligand
remains bound to B(N) during catalysis (See the Supporting Inꢀ
formation for the discussion of other potential structure of B(N)).
Catalyst A has been shown to exist as a dimer with one of the two
OTf ions dissociated in its crystal structure, leaving two inequivaꢀ
lent Ag sites.7e AgN has a coordination sphere composed entirely
of tBu3tpy N atoms, while AgO also has a coordinated OTf ion. To
improve computational efficiency, the tertꢀbutyl groups on the
13 : 1 cis/trans
aA: HfsNH2 (0.25 mmol), 10 mol % AgOTf, 12 mol % tBu3tpy, 3.5 equiv PhIO,
bI
CH2Cl2, 4 A MS, 4 h, rt. : DfsNH2 (0.25 mmol), 10 mol % AgOTf, 12 mol % tpa,
1.2 equiv PhIO, CH2Cl2, 4 A MS, 1 h, rt.
While the addition of TEMPO using catalyst B supported the
presence of radical intermediates in the nitrene transfer pathway,
the minimal isomerization of 21 (Scheme 3) with both A and B
was unexpected. To shed more insight into this question, a steriꢀ
cally congested alkene 22 was subjected to both aziridination and
C–H amination conditions (Scheme 4). These experiments sugꢀ
gest the presence of radical intermediates in both pathways, as
transposition of the alkene double was noted using both catalysts.
The question was why catalyst A appeared in many cases to give
concerted nitrene transfer, as opposed to the clearꢀcut evidence
that B proceeded through a stepwise nitrene transfer pathway.
+
tBu3tpy ligand were replaced by H atoms ([(tpy)AgOTf]2 , called
Aʹ). The nitrene complex of A' was optimized with the nitrene
ligand bound to the AgN, denoted as Aʹ(N). This coordination
isomer was chosen due to the fact that catalyst A displays minimal
counteranion effects. The effect of the truncation on the structures
of A and A(N) is also assessed in Figures S1ꢀ3 and S1ꢀ4 in the SI
(see Tables S1ꢀ9, S1ꢀ20 and S1ꢀ22 for a quantitative comparison
and Aʹ(N) and Aʹ(NO),nitrene binding to the AgO atom of catalyst
A, between A and Aʹ, and A(N) and Aʹ(N), respectively). The
optimized structures of B(N) and AʹN are shown in Figure 1.
Scheme 4. Allylic isomerization studies.
H
Hfs
N
H
a
b
NHfs
NHfs
22
23a
23c
16%
23b
5%
Dfs
6%
H
DfsN
N
NHDfs
22
24a
24b
24c
3%
15%
19%
a
b
t
22
a: 5 equiv
, 1 equiv HfsNH2, 10 mol % AgOTf, 12 mol % Bu3tpy, 3.5 equiv
PhIO, 0.05 M CH2Cl2, 4 A MS, 4 h, rt. b: 5 equiv 22, 1 equiv DfsNH2, 10 mol
% AgOTf, 12 mol % tpa, 1.2 equiv PhIO, 0.05 M CH2Cl2, 4 A MS, 1 h, rt.
Computational studies
The only previously reported, extensive computational study on
Agꢀcatalyzed nitrene transfer explores aziridination using a trisꢀ
pyrazolyl borate complex (catalyst C).7a Aziridination was found
to proceed through an initial C–N bond formation step, but a minꢀ
imum energy crossing point (MECP) between the triplet and
closedꢀshell singlet surface induces direct formation of the aziriꢀ
dine from the C–N bond formation transition state, resulting in
retention of the stereochemistry of the alkene. The reactivity obꢀ
served with our ligands on Ag(I) led to an initial hypothesis that
Figure 1. The optimized structures of the Agꢀnitrene intermediꢀ
ates investigated. B(N) and A'(N) are shown on the left (a) and
right (b), respectively.
Electronic features of nitrene intermediates. The electronic strucꢀ
tures of B(N) and A'(N) have been investigated both at the density
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
functional (DFT) and complete active space selfꢀconsistent field
hibitors. This finding is consistent with our experimental observaꢀ
1
2
3
4
5
6
7
8
(CASSCF) levels of theory. For both B(N) and A'(N), the lowest
energy state was found by DFT to be a triplet state, in which a
Ag(II) ion is ferromagnetically coupled to a doublet nitrene anion
radical (Ag(II)↑–↑{NSO3R}–). The ferromagnetic alignment of
spins in this complex is due to the orthogonality of the Ag–N σ*
and N pπ magnetic orbitals. Analysis of the KohnꢀSham orbitals
shows that the Ag–N bond is composed of a 3ꢀelectron σ compoꢀ
nent and a 3ꢀelectron π component, with an overall calculated
Mayer bond order of 0.56 and 0.57 for the (antiferromagnetically
coupled) openꢀshell (OS) singlet and triplet B(N), respectively,
and 0.63 and 0.55 for OS singlet and triplet A'(N), respectively.
The σ* orbital in both complexes is strongly covalent with ~20%
polarization toward Ag, whereas the π* orbital is strongly polarꢀ
ized towards the nitrene N atom by 85–90%. The OS singlet exꢀ
cited state is lowꢀlying, at 4.13 and 8.27 kcal·molꢀ1 above the
triplet ground state for B(N) and A'(N), respectively. The frontier
orbitals are shown in Figure S1ꢀ5. Analysis of the CASSCF wave
function indicates that there is only one configuration that conꢀ
tributes strongly to the electronic structure of both complexes in
their triplet state. This configuration can be described as
(σ)2(π'*)2(π''*)1(σ*)1. On the other hand, the OS singlet has multiꢀ
configurational character with a major configuration (~70%) of
tions that a radical quencher lowers the yield of the C–H inserted
product of B(N) in the reactions of 11 and 21 (Schemes 2ꢀ3). In
contrast, substrate aziridination by B(N) occurs on the triplet PES
3
via TStpa,A,1; no OS1TStpa,A,1 was located. Complete formation of
3
the C–N bond gives Inttpa,A,1; a reorganization of the electronic
structure is presumed to occur to give OS1Inttpa,A,1 (kcal·molꢀ1 in
terms of vertical excitation energy), which then leads to the forꢀ
1
mation of the aziridine product, PCA,tpa,1. Similar to the case for
3
C–H insertion, the presence of Inttpa,A,1, along with the absence
9
of a fast recombination OS1TStpa,A,1, suggest that trapping by radiꢀ
cal inhibitors is possible (vide infra), a hypothesis that is conꢀ
sistent with our experimental observations.
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
(σ)2(π'*)2(π''*)2(σ*)0 and
a minor configuration (~30%) of
(σ)2(π'*)2(π''*)0(σ*)2. A second closedꢀshell (CS) singlet excited
state, discussed previously in the literature,7a was located 7.23 and
12.1 kcal·molꢀ1 above the triplet ground state for B(N) and A'(N),
respectively. This particular excited state, which could be deꢀ
scribed as either a Ag(I) ion bound to a singlet nitrene or a
Ag(III)ꢀimido complex, is not discussed due to its high energy.
We recently discussed the necessity for a metalꢀnitrene intermeꢀ
diate to have a pair of empty α and β molecular orbitals with N
character in order to be able to undergo concerted nitrene transꢀ
fer.18 Given this constraint, we would expect nitrene transfer from
these silver complexes with triplet ground states (i.e., having two
empty β molecular orbitals with N character) to occur via a stepꢀ
wise mechanism. However, Pérez and coworkers found in their
computational study that it is possible for intersystem crossing to
occur directly following an initial singleꢀelectron transition state
in such a way as to avoid radicalꢀcontaining intermediate speꢀ
cies.7a Thus, an examination of the nitrene transfer potential enerꢀ
gy surface (PES) for both A'(N) and B(N) is warranted.
Figure 2. Reaction coordinate of nitrene transfer from B(N) to 1
to give either the C–H amination (blue) or aziridine product
(brown). R = reactant, TS = transition state, Int = intermediate,
and PC = product complex. Subscript I = C–H insertion and A =
aziridination; superscript OS1 and 3 denote openꢀshell singlet and
triplet spin states, respectively. Solid lines denote the triplet poꢀ
tential energy surface (PES) and dashed lines denote the openꢀ
shell singlet PES. Arrows and the size of the arrows represent α or
β spin populations for the electrons on Ag (silver), blue for N
(blue), and black (organic substrate). Black arrows inside the ring
indicate that electron density is delocalized over the allylic radical
and arrows outside the ring represent electron density localized on
the carbon proximal to the arrow. Numbers shown are Gibbs free
energies; numbers enclosed in parentheses are enthalpies, both
taking into account the solvent (CH2Cl2). Note: the energy for the
blue dashed line enclosed by quotation marks was obtained from
converging the single point energy at the OS singlet state based on
the geometry of the solid blue line below it.
Reactivity landscape for nitrene transfer. PESs for nitrene transfer
from B(N) to substrate 1 modeling experimental chemoselectivity.
Two distinct transition states (TSs) have been located as substrate
1 approaches B(N). The first involves partial formation of an N–H
bond (C–H bond amination (I), TStpa,I,1, the numerical subscript
denotes the substrate identity) on either the triplet (3TS) or OS
singlet (OS1TS) potential energy surface (PES). The second TS
involves partial formation of a C–N bond (aziridination (A),
3
TStpa,A,1) on the triplet (3TS) PES. Both OS1TStpa,I,1 and TStpa,I,1
PESs for nitrene transfer from A'(N) to substrate 1 modeling ex-
perimental chemoselectivity. Four distinct TSs are located as 1
approaches A'(N). Partial formation of the N–H bond (TStpy,I,1) or
C–N bond (TStpy,A,1) occurs on either the triplet or OS singlet
were found to be lower in energy than the 3TStpa,A,1 (10.1 and 10.2
vs 10.7 kcal·molꢀ1, respectively), consistent with the experimenꢀ
tally observed chemoselectivity. After HAT is complete, intermeꢀ
diates (Int) were found on both the OS singlet (OS1Inttpa,I,1) and
triplet (3Inttpa,I,1) PES (–19.2 and –19.7 kcal·molꢀ1, respectively),
with a slight favoring of the triplet state. Radical rebound occurs
without an energetic barrier after the complete formation of
OS1Inttpa,I,1 on the OS singlet surface to give the aminated product
and regenerate catalyst B (–71.4 kcal·molꢀ1). The complete reacꢀ
tion coordinate for both reactions catalyzed by B(N) is shown in
Figure 2. The presence of an intermediate after hydrogenꢀatom
abstraction on both the OS singlet and triplet PESs and the fact
that the two intermediates are close in energy suggest that the
3Inttpa,I,1 could be longꢀlived enough to be trapped by radical inꢀ
3
3
PES. TStpy,I,1 and TStpy,A,1 are lower in energy than OS1TStpy,I,1
and OS1TStpy,A,1 by 5.60 and 7.62 kcal·molꢀ1, respectively.
3TStpy,A,1 was found to be lower in energy than TStpy,I,1 (9.38 vs
3
11.4 kcal·molꢀ1) in agreement with the experimental selectivity.
3
3
Both TStpy,I,1 and TStpy,A,1 lead to the formation of triplet state
intermediates, 3Inttpy,I,1 and 3Inttpy,A,1 (–16.0 and –8.32 kcal·molꢀ1,
respectively). However, these intermediates do not evolve to form
products on the triplet surface. Instead, it was found that
OS1TStpy,I,1 and OS1TStpy,A,1 lead to the direct formation of product
complexes, 1PCtpy,I,1 and PCtpy,A,1, respectively (–81.7 and –62.5
1
kcal·molꢀ1, respectively) without accessing an intermediate. The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
complete reaction coordinate for both reactions by A'(N) is shown
triplet states are similar to that of C(N) (1.26 on N and 0.74 on
1
2
3
4
5
6
7
8
in Figure 3. The experimental observation that A is resistant to
(tpa)Ag for B(N) and 1.27 on N and 0.64 on (tpy)2Ag2 for A'(N)).
inhibition by TEMPO (Schemes 2 and 3) suggests that direct acꢀ
3
Unlike either Aʹ(N) or C(N), B(N) performs nitrene transfer via
a mechanism that generates Inttpa on both the triplet and OS sinꢀ
glet PESs. This allows radical inhibition of the reaction, in conꢀ
trast to the tolerance towards TEMPO exhibited by Aʹ(N) and
C(N) (Scheme 5). Importantly, the divergence in mechanism beꢀ
tween these three catalysts occurs after the initial transition state.
Therefore, the differences in the mechanism for nitrene transfer
from B(N), A'(N), and C(N) are not likely due to their different
ground state electronic structures. Instead, the nature of the transiꢀ
tion states needs to be examined along with the thermodynamic
driving forces en route to product formation.
cess of the OS PES after Inttpy (the crosses in Figure 3) to yield
products is the major reaction pathway (vide infra).
The shape of the PES and the experimentally observed tolerance
of the aziridination pathway towards radical inhibition are strongꢀ
ly reminiscent of the system described by Pérez and coworkers for
Ag complexes supported by tripodal ligands.7a These resemꢀ
blances prompted us to perform a comparison between B(N),
A'(N), and the Pérez (TpMe2)Ag(NTs) (C(N); TpMe2 = hydro(3,5ꢀ
dimethylꢀ1ꢀpyrazolylborate)) system in order to achieve a deeper
understanding of reactivity in our silverꢀcatalyzed intermolecular
nitrene transfer reactions.
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
Scheme 5. Comparisons among A'(N), B(N), and C(N).
Nature of the C–H amination transition states from A(N), B(N),
and C(N). It is useful to examine the general geometrical features
of nitrene transfer transition states. For simplicity, we will analyze
in detail only the C–H amination transition states. In concerted
insertions of nitrenes into C–H bonds, as is seen in Rh2ꢀcatalyzed
reactions, the transition state involves simultaneous (though asynꢀ
chronous) C–N and N–H bond formation and C–H cleavage.18
These three interactions take place within a triangular, threeꢀ
membered ring transition state (left, Scheme 6). Stepwise reacꢀ
tions proceed first through a hydrogen atom transfer (HAT) transiꢀ
tion state leading to radical intermediates. The transition state
involves a linear NꢀꢀꢀHꢀꢀꢀC geometry (right, Scheme 6). These
geometries are electronically dictated: the threeꢀmembered ring
transition state requires a stabilizing pair of electrons and thereꢀ
fore an empty N orbital (or a pair of α/β holes with N characters to
accept the electrons of the C–H bond. The linear NꢀꢀꢀHꢀꢀꢀC strucꢀ
tures result from threeꢀcenter/threeꢀelectron or threeꢀcenter/fourꢀ
electron bonds and are
Figure 3. Reaction coordinate of nitrene transfer from A'(N) to 1
to give either C–H insertion (blue) or aziridine products (brown).
R = reactant, TS = transition state, Int = intermediate, and PC =
product complex. Subscript I = C–H insertion and A = aziridinaꢀ
tion and superscript OS1 and 3 denote openꢀshell singlet and triꢀ
plet spin states, respectively. Solid lines denote the triplet potenꢀ
tial energy surface (PES) and dashed lines denote the openꢀshell
singlet PES. Arrows and the size of the arrows represent α or β
spin populations for the electrons on Ag (silver), N (blue), and
organic substrate (black). Black arrows inside the ring represent
electron density delocalized over the allylic radical and arrows
outside the ring represent electron density localized on the carbon
proximal to the arrow. Numbers shown are Gibbs free energies
and numbers enclosed in parentheses are enthalpies, both taking
into account the solvent (CH2Cl2).
Differential mechanisms for nitrene transfer from B(N), A'(N),
and C(N) to organic substrates. Results for the reaction coordiꢀ
nates of nitrene transfer from B(N) and A'(N) to substrate 1 (vide
supra) contrast with those recently reported for Agꢀnitrene interꢀ
mediates supported by tripodal Tp ligands.7a,19 In previously reꢀ
ported examples, only a triplet and CS singlet state were located,
with the triplet favored in energy by 7.6 kcal·molꢀ1.7a The large
spin population of 1.32 on the N atom, along with the inability to
locate an OS singlet state, led to the description of C(N) as a
Ag(I) complex with a coordinated triplet nitrene ligand. In conꢀ
trast, we located OS singlet states for B(N) and A'(N) with spin
populations (–0.78 on N and 0.78 on (tpa)Ag for B(N) and –0.74
on N and 0.74 on (tpy)2Ag2 for A'(N)), which prompt us to deꢀ
scribe these silver nitrene complexes as Ag(II) ions coupled to
nitrene anion radicals, despite the fact that spin densities on the
Scheme 6. Diagrams of concerted and HAT transition state geꢀ
ometries for C–H amination, including the features of stepwise
transition states vs those leading to barrierless rebound.
seen for the more electronꢀrich systems. All silverꢀnitrene comꢀ
plexes are electron rich and will therefore use HAT transition
states for C–H amination (and corresponding singleꢀelectron tranꢀ
sition states for aziridination). The major question of this work,
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
however, is to explain when the HAT transition state leads to the
formation of radical intermediates vs when it is followed by a
barrierless rebound.
from the substrate (∆(Ag–N)TS–R = +0.062 Å for OS1TStpy,A,1 and
∆(Ag–N)TS–R = +0.077 Å for OS1TStpy,I,1 vs ∆(Ag–N)TS–R = ꢀ0.01
Å for OS1TStpa,I). Once past OS1TStpy, the Ag–N bond has elongatꢀ
1
2
1
ed enough to form PCtpy in a barrierless radical recombination
3
4
5
6
7
8
9
Geometric details of the C–H amination transition states of cataꢀ
lysts A', B, and C are given in Table 5 (a more complete set of
data for catalyst A' and B is given in Tables S1ꢀ23, S1ꢀ24 and
Tables S1ꢀ27, S1ꢀ28, respectively, in the SI). Since catalyst A
performs C–H amination via a barrierless recombination pathway
and B via a stepwise pathway, it is useful to compare their geoꢀ
metric differences. Both catalysts feature typical HAT transition
states with NꢀꢀꢀHꢀꢀꢀC angles very close to linearity. However, the
lowestꢀenergy transition state (triplet) for catalyst Aʹ also clearly
shows signs of Ag–N bond cleavage, since its Ag–N bond length
is increased by 0.05 Å from the geometry of Aʹ(N). The Ag–N
bond length for B is unchanged (0.01 Å). The observation that
transition states leading to barrierless recombination involve Ag–
N bond cleavage is also true of aziridination transition states.
Catalysts A and C undergo aziridination via barrierless rebound,
and their Ag–N bond distances are elongated by 0.06 and 0.04 Å,
respectively, in their transition state geometries.
step. The transient process leading to the formation of 1PCtpy
means that the A'(N)ꢀsubstrate complex must cross from 3TStpy to
1PCtpy through an MECP (where dashed and solid lines cross in
Figures 2 and 3). Through this analysis, we observe that nitrene
complexes with a semiꢀchelating coordination mode to Ag lead to
nitrene transfer transition states having significant Ag–N bond
cleavage character, which results in barrierless recombination and
an absence of radical intermediates.
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
Interplay of enthalpy and entropy of activation on the differential
chemoselectivity of nitrene transfer from B(N) and A'(N) to sub-
strate 1. The differential chemoselectivity of nitrene transfer from
B(N) and A'(N) to substrate 1 is satisfactorily reproduced by DFT
studies of the reaction coordinates on both the triplet and OS sinꢀ
glet PESs ( ꢊ : ꢊ
≈ ꢓꢋ: ꢓꢌ
= 2.60: 1 using OS1TStpa,1,I
ꢍꢗꢘꢙꢗ
ꢆꢔꢕꢖ
ꢉ
ꢍꢑꢒꢃꢑ
ꢌ
ꢆꢎꢏꢐ
ꢉ
ꢋ
3
ꢉ
ꢍꢗꢘꢙꢗ
ꢉ
ꢍꢚꢛꢜ
ꢌ
ꢆꢎꢏꢐ
or ꢓꢋ: ꢓꢌ
= 2.3: 1 using TStpa,1,I vs ꢊ : ꢊ
= 5.8: 1;
ꢋ
ꢆꢔꢕꢖ
ꢉ
ꢍꢗꢘꢙꢗ
ꢉ
ꢍꢗꢘꢙꢗ
≈ ꢓꢋ: ꢓꢌ
ꢝ′ꢎ
ꢉ
ꢍꢚꢛꢜꢞ
= 1: 30.7 vs ꢊ : ꢊ
ꢌ
ꢝ
ꢊ : ꢊ
= 1: 5.2 ;
′ꢎ
ꢋ
ꢌ
ꢋ
ꢝ
′
ꢎ
Table 5. Geometrical features of optimized transition states.
see below for the origin of the approximately equal signs). The
agreement with experiment justifies a further analysis of thermoꢀ
dynamic parameters, namely enthalpy, entropy, and Gibbs free
energy of activation/formation. Activation of the C=C bond on the
triplet PES is the most exothermic step among all TSs for both
B(N) and A'(N) (Table 6). This is sensible, as breaking the C=C
πꢀbond in an alkene is less energetically costly than breaking the
C–H σꢀbond at an allylic position.20 However, when the entropy
of activation is taken into account, B(N) suffers more than A'(N)
for both C–N bond formation and HAT. The fact that B(N) is
C–C Amination Transition States
Δ d(Ag–N)b,
Catalyst
Spin Statea
∠NꢀꢀꢀHꢀꢀꢀC, °
Å
Singlet
Triplet
Singlet
Triplet
171
172
173
176
0.03
0.05
–0.03
0.01
Aʹ
B
Aziridination Transition States
Catalyst
Spin Statea
Δ d(N – C)c, Δd(Ag–N)b,
‡
more negatively impacted by ∆SA is due to steric hindrance
Å
Å
around the nitrene site, which restricts the flexibility of the incomꢀ
ing substrate, as can be seen from spaceꢀfilling models of B(N)
and A'(N) (Figure 4). This larger negative entropic contribution of
Singlet
Triplet
Triplet
Singlet
Triplet
0.627
0.736
0.626
0.335
0.625
0.01
0.06
0.03
–0.06
0.04
Aʹ
3
3
3TStpa,1 in general, and of TStpa,A,1 compared to TStpa,I,1, is the
major thermodynamic factor in the differential chemoselectivity
of B(N) and A'(N). Hence, the chemoselectivity of A'(N) towards
aziridination of 1 is enthalpyꢀdriven while that of B(N) towards
amination of 1 is entropyꢀdriven.
B
C
a The singlet spin states are all optimized openꢀshell singlets.
b
Δd(Ag–N) is defined as the difference in Ag–N(nitrene) bond
distance between the transition state geometry and the reactant
complex geometry.
Table 6. Enthalpy (kcal·molꢀ1), entropy (cal·molꢀ1·Kꢀ1), and Gibbs
free energy (kcal·molꢀ1) of activation for nitrene transfer from
B(N) to 1 and 21 on either the triplet or OS singlet surface.
c
Δd(N–C) is defined as the difference between the two NꢀꢀꢀC
distances in the transition state.
ꢟꢠꢡ‡ꢠ
ꢟꢥ‡ꢡꢠ
ꢡꢣ
ꢢ
TS
substrate
ꢟꢤ‡
ꢡꢣ
ꢢ
ꢢ
ꢢ
OS1TStpa,I
3TStpa,I
3TStpa,A
3TStpy,I
3TStpy,A
OS1TStpa,I
3TStpa,I
3TStpa,A
1
1
1
1
1
21
21
21
–4.30
–4.53
–4.75
–3.00
–5.58
–4.89
–0.51
–4.69
10.1
10.2
10.7
11.0
9.38
12.1
13.7
11.2
This geometrical observation is also supported by an energetic
analysis. First, we compare ∆H‡ of the singlet and triplet transiꢀ
tion states. In contrast to B(N), which has a similar enthalpic drivꢀ
–48.3
–49.5
–51.7
–48.3
–50.2
–57.0
–47.5
–53.4
‡,ꢄꢅꢆꢇꢈ
ing force at both OS1TStpa,I,1 and 3TStpa,I,1 (ΔΔH
= 0.23
ꢀꢁꢂꢀꢃꢂ
kcal·molꢀ1), OS1TStpy,1 for Aʹ(N) is much less exothermic than
‡,ꢄꢅꢆꢇꢈ
3TStpy,1 ( ΔΔH
ꢀꢁꢂꢀꢃꢂ
=
3.08 kcal·molꢀ1 for TStpy,A,1 and
ΔΔH
= 3.34 kcal·molꢀ1 for TStpy,I,1). Since the ꢁH‡
for
CH2Cl2
‡,ꢄꢅꢆꢇꢈ
ꢀꢁꢂꢀꢃꢂ
the formation of the first C–N bond in aziridination and the N–H
bond in C–H insertion should be very similar on both PESs, the
difference in ꢁH‡CH Cl between 3TStpy and OS1TStpy must result
Fine-tuning the chemoselectivity of nitrene transfer from B(N) to
cyclic vs acyclic alkenes. To further examine our hypothesis that
the interplay of ∆H‡ and ∆S‡ fineꢀtunes the chemoselectivity of
Agꢀnitrene complexes, the reaction coordinate for nitreneꢀtransfer
from B(N) to acyclic substrate 21 was studied. Replacing cyclic
alkenes by acyclic alkenes (i.e., 1 by 21) changes the experimental
2
2
mainly from the breaking of the Ag–N bond during OS1TStpy
.
Comparing the Ag–N bond lengths in B(N) and A'(N), they differ
by ~ 0.07 Å, a difference that may be attributed to partial chelatꢀ
ing character of the nitrene ligand in Aʹ(N), which contains a
weak Ag···O interaction of 2.7 Å, reminiscent of the quasiꢀ
bidentate nitrene coordination mode in C(N). This implies that the
bond between Ag and N is stronger in the OS singlet A'(N) than
in the triplet A'(N); thus, it takes more energy to break the Ag–N
bond during OS1TStpy to form the bond with the incoming atom
chemoselectivity of B(N). Correspondingly, we found that the
3
lowest energy TS is the aziridination transition state TStpa,A,21
,
which is 0.89 kcal·molꢀ1 more stable than the lowest energy C–H
amination transition states TStpa,I,21
OS1TStpa,I,21. This gives
,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
ꢓꢌ/ꢓꢋ = 4.52 ≈ ꢊ /ꢊ , assuming that the productꢀdetermining
ꢌ
ꢋ
a)
b)
1
2
3
4
steps are the rateꢀdetermining steps. Note that there are only two
internal secondary allylic C–H bonds in 21, compared to four
accessible C=C sites comprised of C2ꢀre, C2ꢀsi, C3ꢀre and C3ꢀsi.
This could potentially increase the ꢊ /ꢊ to 9.04. The calculated
ꢌ
ꢋ
5
6
7
H
R
H
H
R
CR2
R2C
H
H
8
H
9
Figure 5. Structure of OS1TStpa,I,1 (a) and OS1TStpa,I,21 (b). The
allylic group, nitrene N atom, and the Ag atom are shown in
spheres for emphasis. Insets: Neumann projections of substrate
looking down along C2–C3 bond (a) or C3–C4 bond (b).
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 4. Spaceꢀfilling models of B(N) a) viewed from the top of
the nitrene and b) viewed from the side. Spaceꢀfilling models of
A'(N) c) viewed from the top of the nitrene and d) viewed from
the side. Color code: silver:grey, sulfur:yellow, fluorine:green,
oxygen:red, nitrogen:blue, carbon:black, and hydrogen:white.
Figure 6. a) Overlay of 3 ꢦꢧꢨꢨꢩꢪ,ꢬ,ꢢꢫ (mostly in beige) and
3ꢦꢧꢨꢨꢩꢪ,ꢬ,ꢫ (mostly in blue). Ag, the nitrene N, the pyridyl group
closest to substrates, and substrates are shown in spheres for clariꢀ
ty. b) Overlay of 3 ꢦꢧꢨꢨꢩꢪ,ꢦ,ꢢꢫ (mostly in beige) and 3 ꢦꢧꢨꢨꢩꢪ,ꢦ,ꢫ
(mostly in blue). Ag, the aryl sulfamate, and substrates are shown
in spheres for clarity.
product ratios match the experimental product ratio of 2.9:1 well
and, more importantly, the observed chemoselectivity. To underꢀ
stand the influence of ∆H‡ and ∆S‡ on the change of chemoselecꢀ
tivity from 1 to 21, their contributions to the TStpa are summaꢀ
rized in Table 6. ꢁH‡CH Cl is more favorable for HAT than C–N
2
2
bond formation for 21 as compared to 1, because the migrating
allylic C–H bond can adopt a nearly coplanar alignment with the π
orbitals of the C=C bond to allow some degree of resonance stabiꢀ
lization as the C–H bond starts to break. This stabilization is less
prominent in 1 due to the constraint imposed by the cyclic strucꢀ
ture (Figure 5). However, the staggered conformation of 21 forces
the propyl substituent to impose steric hindrance on B(N), a feaꢀ
ture that is absent in 1. The reason for this is the constraint imꢀ
posed by the cyclic structure of 1 that forces C4 to stay in a pseuꢀ
doꢀgauche conformation with respect to the C=C bond (Figure 6).
depends on the kinetic barrier of the isomerization, which, in turn,
depends on the specific steric constraints of the substrate and the
degree of C=C bond character in Inttpa,21, i.e. the C=C bond is
completely broken in Inttpa,A,1 to give a carbon radical at C3 while
the C=C bond is half broken in Inttpa,I,1 to stabilize the carbon
radical at C4 after HAT through resonance (Figure 7). This can be
seen structurally in Figure 7a where the methyl group on C2 and
3
the propyl group on C3 are no longer coplanar in Inttpa,A,21 and
This steric effect reflects heavily on ꢁS‡, hence making 3TStpa,A,21
3Int
.
iso
tpa,A,21
more energetically accessible than OS1TStpa,I,21
.
The C=C cis/trans isomerization of acyclic alkene 21 during
nitrene transfer from B(N). Radical intermediates are found on
3
both triplet and OS singlet surfaces for B, with Inttpa,I lower in
3
energy by only 0.6 kcal·molꢀ1. However, Inttpa,I cannot lead to
the formation of products without first accessing OS1Inttpa,I via a
minimum energy crossing point (MECP: where crosses are locatꢀ
ed in Figure 3) to allow the conservation of spin symmetry. The
3
presence of an MECP after the initial formation of Inttpa,I sugꢀ
gest that this species will be relatively longꢀlived. In turn, this
increased lifetime allows cis/trans isomerization of the allylic
C=C bond via C–C rotation of the diradical 3Inttpa,I species to
occur. This also explains why TEMPO inhibition is observed
(Scheme 3). Similar arguments apply to Inttpa,A,. To further supꢀ
port this hypothesis, the transꢀisomer of ꢦꢧꢨꢨꢩꢪ,ꢢꢫ (Intitspoa,21) was
Figure 7. a) Overlay of 3 ꢦꢧꢨꢨꢩꢪ,ꢢꢫ,ꢬ (mostly in beige) and
3Inttispoa,21,A (mostly in blue). The rest of the molecule except Ag,
nitrene N, the pyridyl group closed to 21, and substrate 21 is omitꢀ
ted for clarity. b) Overlay of 3ꢦꢧꢨꢨꢩꢪ,ꢦ,ꢢꢫ (mostly in beige) and
considered. Indeed, 3Int
and 3Int
were located and
tpa,I,21
iso
iso
3Int
(mostly in blue), the rest of the molecule except Ag, the
iso
tpa,I,21
tpa,A,21
found to be more stable than their cisꢀisomers (–7.02 kcal·molꢀ1
sulfamate, and substrate 21 is omitted for clarity.
for 3Int
and –3.55 kcal·molꢀ1 for 3Int
). This result
tpa,A,21
iso
iso
tpa,I,21
implies that a preꢀequilibrium between the two isomers occurs
before radical recombination to yield the trans isomer as the maꢀ
jor product. However, the distribution of different isomers also
Timing of intersystem crossing and C=C bond transposition.
MECPs are required to be present after the transition states in the
reaction trajectories from both A'(N) and B(N). Yet, the two Agꢀ
nitrene complexes display dissimilar reactivity. As discussed
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
above, for catalyst B, the MECP must occur after intermediate
NMR facilities at UWꢀMadison are funded by the NSF (CHEꢀ
1
2
3
4
5
6
7
8
formation and this feature “delays” the formation of products
allowing a byꢀproduct shunt to occur through bimolecular colliꢀ
sion of Inttpa with TEMPO. On the other hand, for catalyst A, the
MECP must occur before the formation of intermediates, because
no radical byproducts are observed, with the exception of C=C
bond transposition products seen with substrate 16. Thus, the
potential energy surface for this substrate was examined more
closely. For this substrate, as the allylic C–H bond on 16 breaks in
the (triplet) transition state, electronic reorganization occurs alꢀ
most instantaneously, as compared to the nuclear movement to
form the C–N bond giving products. The HAT nature of the tranꢀ
sition state yields an allylic radical with spin population on both
C1 and C3. Bond formation between C1 and N occurs immediateꢀ
ly on the OS singlet PES to give 16d. The driving force favoring
C1 over C3, which is mostly steric, is due to ∆S‡ (vide infra),
hence giving the thermodynamic product. Indeed, 16d is formed
9208463, CHEꢀ9629688) and NIH (RR08389ꢀ01). The National
Magnetic Resonance Facility at Madison is supported by the NIH
(P41GM103399, S10RR08438, S10RR029220) and the NSF
(BIRꢀ0214394). JFB thanks the Center for Selective C–H Funcꢀ
tionalization supported by the National Science Foundation
(CHE01205646). The computational facility at Madison is supꢀ
ported in part by National Science Foundation Grant CHEꢀ
0840494 and at the UWꢀMadison Center For High Throughput
Computing (CHTC) in the Department of Computer Sciences.
The CHTC is supported by UWꢀMadison, the Advanced Compuꢀ
ting Initiative, the Wisconsin Alumni Research Foundation, the
Wisconsin Institutes for Discovery, and the National Science
Foundation, and is an active member of the Open Science Grid,
which is supported by the National Science Foundation and the
U.S. Department of Energy's Office of Science. U.S. Chimera is
developed by the Resource for Biocomputing, Visualization, and
Informatics at the University of California, San Francisco (supꢀ
ported by NIGMS P41ꢀGM103311).
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
directly (with no intermediates) as the product after OS1TStpy
,
consistent with experimental observations (Table 1 and Scheme 2).
Thus, although C=C double bond transposition in this case was
initially suggestive of a stepwise mechanism with radical interꢀ
mediates, we find computationally that this transposition can ocꢀ
cur via a barrierless recombination and does not necessitate a
longꢀlived diradical intermediate. This reactivity is therefore conꢀ
sistent with an HAT mechanism with barrierless rebound from
A'(N).
REFERENCES
1. For selected reviews on nitrene transfer, see: a) Müller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905. b) Collet, F.; Lescot, C.; Dauban, P. Chem.
Soc. Rev. 2011, 40, 1926. c) DíazꢀRequejo, M. M.; Pérez, P. J. Chem. Rev.
2008, 108, 3379. d) Collet, F.; Dodd, R.; Dauban, P. Chem. Commun.
2009, 5061.
2. For selected examples of Rhꢀcatalyzed nitrene transfers, see: a) Roizen,
J. L.; Harvey, M. E.; Du Bois, J. Accts. Chem. Res. 2012, 45, 911. b)
Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2010, 292, 347. c) Dequirez,
G.; Pons, V.; Dauban, P. Angew. Chem. Int. Ed. 2012, 51, 7384. d) Esꢀ
pino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598. e) Fiori, K.
W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562. f) Collet, F.; Lescot,
C.; Liang, C. G.; Dauban, P. Dalton Trans. 2010, 39. 10401. g) Espino, C.
G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126,
15378. h) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220.
i) Liang, C.; RobertꢀPeillard, F.; Fruit, C.; Muller, P.; Dodd, R. H.;
Dauban, P. Angew. Chem. Int. Ed. 2006, 45, 4641. j) Lescot, C.; Darses,
B.; Collet, F.; Retailleau, P.; Dauban, P. J. Org. Chem. 2012, 77, 7232. k)
Lebel, H.; Spitz, C.; Leogane, O.; Trudel, C.; Parmentier, M. Org.
Lett. 2011, 13, 5460.
Conclusions
In conclusion, we have reported the first examples of simple
silver catalysts capable of tunable, non-directed and intermolecu-
lar chemoselective amination. We have found catalyst systems
that demonstrate complementary chemoselectivities in alkenes
containing sites for both aziridination and C–H amination in
nitrene transfer, largely independent of substrate identities. Comꢀ
putational studies showed that the tunable chemoselectivity beꢀ
t
tween tpa and bu3tpy ligands is a result of the steric profile
around the Agꢀnitrene intermediates. The means to tune the steric
bulk around the nitrene site without changing the electronic strucꢀ
ture of the silverꢀnitrene intermediates, such as the size of the
bound counteranion, could potentially afford an additional tunaꢀ
bility within the same ligand system. Furthermore, two distinct
nitreneꢀtransfer mechanisms are observed in the computational
results, the first involving a very late transitionꢀstate from catalyst
A, followed by a barrierless recombination step that preserves
stereochemistry and the second having a very early transition state
from catalyst B to yield radical intermediates. The major distincꢀ
tion between these two mechanisms appears to be the extent to
which the Ag–N bond breaks during the HAT transition state.
Future studies are focused on the development of increasingly
selective amination catalysts using a broader array of supporting
ligands and counteranions. The ability to correlate the coordinaꢀ
tion geometry of the catalyst with both reaction mechanism pathꢀ
ways and selectivity are goals currently under investigation.
3. Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc. 2011,
133, 17207.
4. For selected references of Feꢀcatalyzed nitrene transfer: a) Halfen, J. A.
Curr. Org. Chem. 2005, 9, 657. b) Paradine, S. M.; White, M. C. J. Am.
Chem. Soc. 2012, 134, 2036. c) Cramer, S. A.; Jenkins, D. M. J. Am.
Chem. Soc. 2011, 133, 19342. d) Hennessy, E. T.; Liu, R. Y.; Iovan, D.
A.; Duncan, R. A.; Betley, T. A. Chem. Sci. 2014, 5, 1526. e) Fantauzzi,
S.; Caselli, A.; Gallo, E. Dalton Trans. 2009, 5434. f) Nakanishi, M.;
Salit, A.; Bolm, C. Adv. Synth. Catal. 2008, 350, 1835.
5. For selected examples of Coꢀcatalyzed nitrene transfer: a) Lu, H. J.;
Subbarayan, V.; Tao, J. R.; Zhang, X. P. Organometallics 2010, 29, 389.
b) Lu, H.; Zhang, X. P. Chem. Soc. Rev. 2011, 40, 1899. c) Ruppel, J. V.;
Kamble, R. M.; Zhang, X. P. Org. Lett. 2007, 9, 4889.
6. Cuꢀcatalyzed nitrene transfer: a) Bagchi, V.; Paraskevopoulou, P.; Das,
P.; Chi, L.; Wang, Q.; Choudhury, A.; Mathieson, J. S.; Cronin, L.; Parꢀ
due, D. B.; Cundari, T. R.; Mitrikas, G.; Sanakis, Y.; Stavropoulos, P. J.
Am. Chem. Soc. 2014, 136, 11362. b) Duran, F.; Leman, L.; Ghini, A.;
Burton, G.; Dauban, P.; Dodd, R. H. Org. Lett. 2002, 4, 2481. c) Lebel,
H.; Lectard, S.; Parmentier, M. Org. Lett. 2007, 9, 4797. d) Dauban, P.;
Sanière, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707.
e) Srivastava, R. S.; Tarver, N. R.; Nicholas, K. M. J. Am. Chem. Soc.
2007, 129, 15250. f) Barman, D. N.; Nicholas, K. M. Eur. J. Org. Chem.
2011, 5, 908. g) Fructos, M. R.; Trofimenko, S.; DiazꢀRequejo, M. M.;
Perez, P. J. J. Am. Chem. Soc. 2006, 128, 11784.
Supporting Information
Experimental procedures and characterization for all new comꢀ
pounds is included in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
Corresponding Authors
schomakerj@chem.wisc.edu, berry@chem.wisc.edu
7. For selected recent examples describing Agꢀcatalyzed nitrene transfer:
a) Maestre, L.; Sameera, W. M. C.; DiaꢀRequejo, M. M.; Maseras, F.;
Perez, P. J. J. Am. Chem. Soc. 2013, 135, 1338. b) Li, Z.; Capretto, D. A.;
Rahaman, R.; He, C. Angew. Chem. Int. Ed. 2007, 46, 5184. c) Gómezꢀ
Emeterio, B. P.; Urbano, J.; DíazꢀRequejo, M. M.; Pérez, P. J. Organome-
tallics 2008, 27, 4126. d) Li, Z. G.; He, C. Eur. J. Org. Chem. 2006, 19,
ACKNOWLEDGMENT
This work was funded through an NSFꢀCAREER Award 1254397
and the Wisconsin Alumni Research Foundation to JMS. The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
4313. e) Cui, Y.; He, C. J. Am. Chem. Soc. 2003, 125, 16202. f) Cui, Y.;
He, C. Angew. Chem. Int. Ed. 2004, 43, 4210. g) Llaveria, J.; Beltrán, A.;
Sameera, W. M. C.; Locati, A.; DíazꢀRequejo, M. M.; Matheu, M. I.;
Castillón, S.; Maseras, F.; Pérez, P. J. J. Am. Chem. Soc. 2014, 136, 5342.
g) Yang, M.; Su, B.; Wang, Y.; Chen, K.; Jiang, X.; Zhang, Y.ꢀF.; Zhang,
X.ꢀS.; Chen, G.; Cheng, Y.; Cao, Z.; Guo, Q.ꢀY.; Wang, L.; Shi, Z.ꢀJ.
Nature Comm. 2014, 5, 4707. h) Zheng, Q.ꢀZ.; Jiao, N. Chem. Soc. Rev.
2016, 45, 4627.
1
2
3
4
5
6
7
8
8. Paradine, S.M.; Griffin, J.R.; Zhao, J.; Petronico, A.L.; Miller, S.M.;
White, M.C. Nature Chem. 2015, 7, 987.
9. Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220.
9
10. For selected references, see: a) Padwa, A.; Austin, D. J.; Price, A. T.;
Semones, M. A.; Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.;
Tran, A. J. Am. Chem. Soc. 1993, 115, 8669. b) Doyle, M. P.; Phillips, I.
M. Tetrahedron Lett. 2001, 42, 3155. c) Davies, H. M. L.; Beckwith, R.
E. J. Chem. Rev. 2003, 103, 2861. d) Doyle, M. P.; Duffy, R.; Ratnikov,
M.; Zhou, L. Chem. Rev. 2010, 110, 704. e) Davies, H. M. L.; Dick, A. R.
Top. Curr. Chem. 2010, 292, 303.
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
11. a) Liang, C.; Collet, F.; RobertꢀPeillard, F.; Muller, P.; Dodd, R. H.;
Dauban, P. J. Am. Chem. Soc. 2008, 130, 343. b) Lescot, C.; Darses, B.;
Collet, F.; Retailleau, P.; Dauban, P. J. Org. Chem. 2012, 77, 7232.
12. a) Progress in Inorganic Chemistry Vol. 58, Karlin, K. D., ed.; John
Wiley & Sons, Inc.: Hoboken, 2014, p. 225ꢀ302. b) Kornecki, K. P.; Berꢀ
ry, J. F. Chem. Eur. J. 2011, 17, 5827. c) Kornecki, K. P.; Berry, J. F.
Eur. J. Inorg. Chem. 2012, 562. d) Kornecki, K. P.; Berry, J. F. Chem.
Commun. 2012, 48, 12097.
13. Rigoli, J. W.; Weatherly, C. D.; Alderson, J. M.; Vo, B. T.; Schomakꢀ
er, J. M. J. Am. Chem. Soc. 2013, 135, 17238.
14. Alderson, J. M.; Phelps, A. M.; Scamp, R. J.; Dolan, N. S.; Schomakꢀ
er, J. M. J. Am. Chem. Soc. 2014, 136, 16720.
15. Scamp, R. J.; Jirak, J. G.; Dolan, N. S.; Guzei, I. A.; Schomaker, J. M.
Org. Lett., 2016, 18 , 3014–3017.
16. Willams, N. J.; Gan, W.; Reibenspies, J. H.; Hancock, R. D. Inorg.
Chem. 2009, 48, 1407.
17. a) Li, D. R.; X, W. J.; Tu, Y. Q.; Zhang, F. M., Shi, L. Chem. Com-
mun. 2003, 798. b) Li, X.; Wu, B.; Zhao, X. Z.; Jia, Y. X.; Tu, Y. Q.; Li,
D. R. Synlett 2003, 5, 623.
18. VarelaꢀÁlvarez; Yang, T.; Jennings, H.; Kornecki, K. P.; Macmillan,
S. N.; Lancaster, K. M.; Mack, J. B. C.; Du Bois, J.; Berry, J. F.; Musaev,
D. G. J. Am. Chem. Soc. 2016, 138, 2327.
19. Besora, M.; Braga, A.C.; Sameera, W.M.C.; Urbano, J.; Fructos, M.;
Pérez, P.J.; Maseras, F. J. Organometallic Chem. 2015, 784, 2.
20. a) Blanksby, S.J.; Ellison, G.B. Accts. Chem. Res. 2003, 36, 255. b)
Luo, Y.ꢀR. Comprehensive Handbook of Chemical Bond Energies CRC
Press: Boca Raton, FL, 2007.
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11
ACS Paragon Plus Environment