Enantioselective Intermolecular Excited-State Photoreactions Using a Chiral Ir Triplet Sensitizer: Separating Association from Energy Transfer in Asymmetric Photocatalysis

Article abstract of DOI:10.1021/jacs.9b06244

Enantioselective catalysis of excited-state photoreactions remains a substantial challenge in synthetic chemistry, and intermolecular photoreactions have proven especially difficult to conduct in a stereocontrolled fashion. Herein, we report a highly enantioselective intermolecular [2 + 2] cycloaddition of 3-alkoxyquinolones catalyzed by a chiral hydrogen-bonding iridium photosensitizer. Enantioselectivities as high as 99% ee were measured in reactions with a range of maleimides and other electron-deficient alkene reaction partners. An array of kinetic, spectroscopic, and computational studies supports a mechanism in which the photocatalyst and quinolone form a hydrogen-bonded complex to control selectivity, yet upon photoexcitation of this complex, energy transfer sensitization of maleimide is preferred. The sensitized maleimide then reacts with the hydrogen-bonded quinolone-photocatalyst complex to afford a highly enantioenriched cycloadduct. This finding contradicts a long-standing tenet of enantioselective photochemistry that held that stereoselective photoreactions require strong preassociation to the sensitized substrate in order to overcome the short lifetimes of electronically excited organic molecules. This system therefore suggests that a broader range of alternate design strategies for asymmetric photocatalysis might be possible.

Full text of DOI:10.1021/jacs.9b06244

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Article
Enantioselective Intermolecular Excited-State Photoreactions
Using a Chiral Ir Triplet Sensitizer: Separating Association
from Energy Transfer in Asymmetric Photocatalysis
Jian Zheng, Wesley B. Swords, Hoimin Jung, Kazimer L Skubi,
Jesse B Kidd, Gerald J. Meyer, Mu-Hyun Baik, and Tehshik P. Yoon
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Jul 2019
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Enantioselective Intermolecular Excited-State Photoreactions Using a
Chiral Ir Triplet Sensitizer: Separating Association from Energy Transfer
in Asymmetric Photocatalysis
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Jian Zheng,† Wesley B. Swords,†,‡ Hoimin Jung,§,¶ Kazimer L. Skubi,† Jesse B. Kidd,† Gerald J. Meyer,‡ Mu-Hyun
Baik,¶,§,* Tehshik P. Yoon†,*
† Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
‡ Department of Chemistry, University of North Carolina at Chapel Hill, Murray Hall 2202B, Chapel Hill, North Carolina 27599-
3290, United States
§ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
¶ Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea
ABSTRACT: Enantioselective catalysis of excited-state photoreactions remains a substantial challenge in synthetic chemistry, and intermolec-
ular photoreactions have proven especially difficult to conduct in a stereocontrolled fashion. Herein, we report a highly enantioselective inter-
molecular [2+2] cycloaddition of 3-alkoxyquinolones catalyzed by a chiral hydrogen-bonding iridium photosensitizer. Enantioselectivities as
high as 99% ee were measured in reactions with a range of maleimides and other electron-deficient alkene reaction partners. An array of kinetic,
spectroscopic, and computational studies supports a mechanism in which the photocatalyst and quinolone form a hydrogen-bound complex to
control selectivity yet upon photoexcitation of this complex, energy transfer sensitization of maleimide is preferred. The sensitized maleimide
then reacts with the hydrogen-bound quinolone-photocatalyst complex to afford a highly enantioenriched cycloadduct. This finding contra-
dicts a long-standing tenet of enantioselective photochemistry that held that stereoselective photoreactions require strong preassociation to the
sensitized substrate in order to overcome the short lifetimes of electronically excited organic molecules. This system therefore suggests that a
broader range of alternate design strategies for asymmetric photocatalysis might be possible.
the stereodifferentiating environment of the chiral catalyst. This ap-
proach obviates the need to intercept a fleeting excited-state inter-
mediate with a low-concentration chiral catalyst, thereby circum-
Introduction
Asymmetric catalysis has been a central theme in synthetic or-
ganic chemistry for many decades. However, enantioselective catal-
ysis of photochemical reactions has only recently been proven to be
venting one underlying limitation of excited-state photoreactions.1b,
6
However, this requirement imposes a significant constraint on the
catalyst designs that have thus far been utilized in asymmetric pho-
tochemistry.
1
feasible. The central challenges in asymmetric excited-state photo-
chemistry derive from the existence of unimolecular relaxation path-
ways that provide a rapid mechanism for deactivation of the key re-
active intermediates in photochemical reactions. The intrinsic life-
times of these electronically excited intermediates are generally
quite short (ps to ns), and thus their ability to engage in bimolecular
interactions, either with chiral enantiocontrolling catalysts or with
Recently, we and others have been interested in the ability of tran-
sition metal complexes to serve as triplet sensitizers in organic pho-
7
toreactions. We have argued that these complexes feature several
key advantages over organic chromophores: they possess superior
chemical stability and longer excited-state lifetimes, and they can tol-
erate substantial structural modifications that facilitate the tuning of
the structural and photophysical properties necessary for effective
photocatalysis. Meggers has developed a family of enantiopure, hel-
ically chiral Ir and Rh organometallic complexes that serve as photo-
catalysts in a remarkable variety of highly stereoselective transfor-
2
other reaction partners, is usually limited. The literature of asym-
metric excited-state photoreactions has consequently been domi-
nated by intramolecular transformations, where local proximity ef-
fects enable product-forming reactions to compete with unproduc-
tive relaxation. Only a handful of known asymmetric catalytic pho-
3
tocycloaddition reactions are effective in an intermolecular context.
8
9
mations. While most of these have been photoredox reactions, in
which the key bond-forming steps are ground-state radical reactions,
three recent papers have also demonstrated that chiral-at-metal Rh
Lewis acids offer exceptional chiral environments for photoreactions
of electronically excited organic intermediates as well.3e,f,h We re-
cently reported that an Ir complex bearing a pyridylpyrazole hydro-
gen-bonding domain can be used as an asymmetric triplet sensitizer,
enabling the exceptionally efficient and highly enantioselective ca-
More fundamentally, all examples of highly enantioselective ex-
cited-state photoreactions reported to date rely upon strong ground-
state preassociation between the organic substrate and a chiral cata-
lyst prior to its excitation. Arguably, the most successful general
strategies to date have involved chiral photosensitizers functional-
ized with a hydrogen-bonding domain that organizes the substrate
proximal to a sensitizing organic chromophore such as an aromatic
4
5
ketone or binaphthyl unit. This design principle ensures that the
electronically excited intermediate is generated exclusively within
10
talysis of [2+2] photocycloadditions of quinolones (Scheme 1).
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However, the scope of the reaction was limited to intramolecular cy-
cloaddition reactions.
10). Finally, control experiments revealed that product formation re-
1
2
3
4
5
6
7
8
quired both light and photocatalyst, validating the photocatalytic na-
ture of this reaction (entries 11 and 12). Under these optimized con-
ditions we measured a quantum yield of 1.3% for the optimized re-
action between 1c and 2.
Scheme 1: Intramolecular vs. intermolecular enantioselective [2+2]
photoreactions using enantiopure chiral Ir sensitizers.
Table 1. Optimization studies for intermolecular [2+2] photocy-
cloadditionsa
n Previous work (ref 10)
n This work:
CF3
OMe
CF3
F
O
F
NH
O
N
H
1.5 mol% [Ir(A)2(B)]+BArF–
N
EnT
OR
O
F
N
N
9
O
F
N
N
F
H
O
Ir
NH
+
Ir
H
F
10
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CH2Cl2, blue LED
24 h
F
F
N
N
OR
O
N
H
i-PrO
N
+
NH
N
H
O
O
H
N
EnT
F
1a R = n-Bu
1b R = Me
1c R = i-Pr
H
F
H
CF3
O
O
CF3
N
O
2
3a–c
NH
O
F
F
X
F
CF3
CF3
N
N
N
Herein, we describe studies that led to the development of a
highly enantioselective intermolecular [2+2] photocycloaddition
reaction using a structurally modified chiral Ir sensitizer (Scheme 1).
The structure of the Ir complex can be tuned for optimal reactivity
without deleteriously impacting its ability to act as a triplet sensitizer,
which suggests that this family of hydrogen-bonding organometallic
photosensitizers might offer an important complement to conceptu-
ally similar chiral organic photosensitizers. More interestingly, pho-
toluminescence quenching and transient absorption studies suggest
that, in contrast to prior work from our group and others, the ex-
cited-state reactant is generated outside of the binding domain of the
chiral sensitizer. The identification of this novel mechanism contra-
dicts a long-standing principle that has informed previous ap-
proaches to enantioselective catalysis of excited-state photoreac-
tions and suggests a new and potentially more general strategy for
asymmetric photocatalysis.
F
F
A1
A3
A2
N
F
F
HN
CF3
F3C
CF3
B1 X = H
B2 X = CF3
B3 X = OMe
N
N
F
A4
entry quinolone photocatalyst
T
yield ee
1
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
4a [Ir(A1)2(B1)]+
4a [Ir(A1)2(B1)]+
4b [Ir(A2)2(B1)]+ 23 °C
4c [Ir(A3)2(B1)]+
23 °C
4d [Ir(A4)2(B1)]+ 23 °C
4e [Ir(A4)2(B2)]+
4f [Ir(A4)2(B3)]+
4f [Ir(A4)2(B3)]+
4f [Ir(A4)2(B3)]+
4f [Ir(A4)2(B3)]+
4f [Ir(A4)2(B3)]+
none
–78 °C 14% --
23 °C 60% 2%
2
3
74% 12%
63% 1%
60% 19%
55% 10%
54% 21%
52% 44%
72% 51%
4
5
6
23 °C
23 °C
23 °C
23 °C
7
Results and Discussion
8
Our studies began by screening the reaction of 3-n-butoxyquino-
lone (1a) and 5 equiv of maleimide (2) upon visible light irradiation
at –78 °C in the presence of Ir complex 4a, which had proven to be
the optimal photocatalyst for the intramolecular cycloaddition (Ta-
ble 1, entry 1). However, the rate of this probe reaction was prohib-
itively slow, consistent with the general trend that intermolecular
photocycloadditions are substantially less efficient than intramolec-
ular reactions. The rate could be improved by conducting the reac-
tion at ambient temperature; however, the product was formed with
negligible ee (entry 2). Because the iridium center defines the stere-
ogenic unit of this photocatalyst, we speculated that the identity of
both the cyclometalating phenylpyridine (ppy) and hydrogen-
bonding ligands would have a substantial impact on enantioinduc-
tion. Indeed, alterations to the ppy ligand had a pronounced impact
on ee, with ligand A4 providing the cycloadduct in 19% ee (entry 5).
The structure of the hydrogen-bonding ligand had less of an effect,
although methoxy-substituted ligand B3 afforded a modest im-
provement in ee (entry 7). The identity of the 3-alkoxy group on the
quinolone substrate had a much larger impact on stereoselectivity.
Methoxy quinolone 1b provided significantly higher ee without loss
of reactivity (entry 8), and isopropoxy-substituted analogue 1c of-
fered both higher yield and ee (entry 9). Because of this increased
reactivity, we were able to lower the temperature to –78°C and
achieve complete conversion to cycloadduct 3c in 97% ee (entry
9
10
11b
12
a
–78 °C 85% 97%
–78 °C 0%
–78 °C 0%
--
--
Reactions conducted using 1 equiv quinolone and 5 equiv malei-
b
mide with a 15 W LED lamp unless otherwise noted. Reaction con-
ducted in the dark.
Experiments probing the scope of this reaction are summarized in
Table 2. First, we verified that the identity of the 3-alkoxy substituent
is critical for the success of the enantioselective photocycloaddition.
Both 3-n-butoxy and 3-methoxy quinolones reacted with lower ee
(3a and 3b), and quinolones lacking this 3-substituent failed to react
at all (3d). The reaction, however, proved less sensitive to substitu-
tions at other positions on the quinolone ring. We examined the ef-
fect of substitution at the 6-position of the quinolone and found that
substrates bearing alkyl, halogen, and alkoxy groups all reacted to af-
ford [2+2] cycloadducts in high enantioselectivity and good dia-
stereoselectivity (3g–3i), although electron-rich 6-methoxyquino-
lone reacted sluggishly and required longer reaction times to afford
reasonable yields of the cycloadduct (3i). The product of cycloaddi-
tion with 6-iodoquinoline (3f) was highly crystalline, and X-ray anal-
ysis of this compound enabled us to assign the absolute and relative
2
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Journal of the American Chemical Society
Table 2. Scope of quinolones in asymmetric intermolecular [2+2] cycloadditionsa
1
2
3
4
5
6
7
8
BArF–
CF3
OMe
O
NH
O
F
H
N
Ir
Oi-Pr
1.5 mol% 4f
O
F
H
N
NH
+
H
F
N
O
CH2Cl2, –78 °C
blue LED
24 h
Oi-Pr
N
HN
H
O
N
N
O
H
F
cat
4f
1c
2
3c, 82% yield
97% ee
CF3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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O
O
O
O
O
NH
NH
NH
NH
NH
3a (R = On-Bu)
O
H
H
H
H
H
14% yield,b 7% ee
NH
O
O
O
O
O
H
H
H
H
H
H
O
Me
I
Br
F
MeO
H
H
H
H
H
3b (R = OMe)
30% yield,b 70% ee
H
H
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
R
O
N
O
N
O
N
O
N
O
N
O
3d (R = H)
0% yieldb
H
H
H
H
H
N
H
3i, 60% yieldc
94% ee
3f, 67% yield
99% ee (9:1 d.r.)
3g, 71% yield
95% ee (9:1 d.r.)
3e, 99% yield
96% ee
3h, 77% yield
90% ee
O
NH
H
O
NH
H
O
O
NH
H
O
O
O
NH
H
NH
NH
NH
H
H
H
O
O
Cl
O
O
O
O
O
H
H
H
H
H
H
Me
H
Oi-Pr
H
Oi-Pr
F
F
H
H
H
H
H
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
N
O
N
O
Br
N
O
Cl
N
O
N
O
N
O
N
O
H
H
H
H
H
H
H
Cl
F
3m, 99% yield
99% ee (6:1 d.r.)
3n, 78% yield
87% ee (5:1 d.r.)
3p, 79% yield
14% ee (8:1 d.r.)
3j, 92% yield
93% ee
3k, 85% yield
97% ee
3l, 54% yield
93% ee
3o, 74% yield
51% ee
O
Bn
O
NH
H
O
O
O
NH
H
OMe
MeO2C
O
O
N
N
N
N
H
H
CO2Me
H
H
O
H
O
O
O
H
H
H
O
H
O
H
H
H
Oi-Pr
H
H
H
H
Oi-Pr
H
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
N
O
N
O
H
N
O
N
O
O
O
Me
N
O
N
O
H
H
H
H
3r, 96% yield
72% ee (3:1 d.r.)
3w, 60% yield
61% ee (7:1 d.r.)
3q, 87% yield
7% ee
3s, 63% yield
88% ee
3t, 61% yield
97% ee
3u, 44% yield
84% ee
3v, 76% yield
99% ee
aIsolated yields are reported except where noted. Diastereomer ratios were determined by 1H NMR analysis and are >10:1 unless noted. Reac-
tions conducted using 1 equiv quinolone, 5 equiv maleimide, and 1.5 mol% 4f in CH2Cl2, irradiating for 24 h with a blue LED unless otherwise
noted. b Yield determined by 1H NMR. Reaction conducted for 48 h.
c
11
configuration of the product. Substitution at the 7-position of the
quinolone had minimal effect on the success of the cycloaddition
(3j–3l). Substitutions proximal to the reacting C=C bond of the
quinolone, either at the 5-position (3m) or directly on the alkene
(3n) did not significantly impact the enantioselectivity of the reac-
tion, although the diastereoselectivity of these reactions was some-
what diminished.
Most of these observations were consistent with the analogous in-
vestigations of scope in the intramolecular photocycloaddition.10
There were, however, some surprising discrepancies. For instance,
we had previously observed that modification of the 8-position,
which is proximal to the catalyst-binding amide motif, had a pro-
nounced deleterious effect on ee (3o). In the present system, how-
ever, the enantioselectivity was not rescued upon incorporation of a
small fluorine substituent at this position (3p), as it was in the intra-
molecular reaction Most notably, N-methylquinolone, which re-
acted without stereoselectivity in the intramolecular reaction, never-
theless provided good ee in this intermolecular context (3r). In our
previous work, we had proposed that the quinolone N-H was neces-
sary to ensure the proper orientation of the reactant with the Ir pho-
tocatalyst. The observation that N-methylated quinolone reacts to
afford 3r in 72% ee suggests that the product-forming catalyst–sub-
strate complex must possess some differences compared to the intra-
molecular system we reported previously.
We first considered the possibility that the catalyst might bind
principally to the other reaction partner, maleimide, and not the
quinolone. However, an NMR titration study indicates that the
ground-state hydrogen-bonding interaction of catalyst 4f with ma-
leimide is negligible (Ka = 24) at room temperature compared to its
interaction with quinolone 1c (Ka = 603). These results suggest that
a catalyst–maleimide interaction is likely not critical for this reaction
to occur. Indeed, the ee remained high in reactions between 1c and
a range of alternate reaction partners, N-alkyl, proparyl, allyl, and
carbamoyl maleimides (3s–3v), that could not participate in H–
bonding interactions similar to 1c. Moreover, an experiment using
dimethyl fumarate as a reaction partner also afforded cycloadduct
with substantial ee (3w), supporting the contention that there is a
specific binding interaction between the catalyst and the quinolone
but not with its reaction partner in the product-forming complex.
An analysis of the kinetics of this photoreaction are also consistent
with this hypothesis. We observe a first-order dependence on the
photocatalyst and maleimide 2 but a zero-order dependence on
quinolone 1c. Thus, we concluded from these collected data that
the principle binding interaction was between the Ir photocatalyst
and the quinolone substrate, similar to the intramolecular reaction,
and that the differences in reaction scope likely arise from subtle
changes in the geometry of the hydrogen-bound complex.
3
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Luminescence measurements, on the other hand, suggested that and thereafter react with maleimide in a product-forming step (eq
1
2
3
4
5
6
7
8
the maleimide might play a critical role in the photoactivation mech-
anism. Stern–Volmer quenching studies were conducted to measure
the rate of energy transfer from triplet-state photocatalyst 4f to both
reaction partners. These studies indicated that 1c is a modest
quencher of 4f* with a calculated Stern–Volmer constant of KSV = 47
M . This value is substantially lower than both KSV for quenching
of 4f* by maleimide (1900 M–1) and for the optimal intramolecular
catalyst–substrate pair of 4a + 1x (KSV = 4700 M–1).10 This observa-
tion encouraged us to wonder whether the role of the photocatalyst
might not be to activate the bound quinolone, which is a poor ex-
cited-state quencher, but rather to sensitize the maleimide, which ex-
hibits much faster quenching dynamics.
C). This process would be analogous to the “triplex mechanism”
proposed by Schuster for enantioselective [4+2] cycloadditions cat-
alyzed by dicyanobinapthyl chromophores as chiral photocata-
13
lysts. However, the luminescence spectrum of the photocatalyst
does not change significantly upon addition of increasing quantities
of quinolone 1c. There is, therefore, no spectroscopic evidence to
support the formation of a new triplet state with any significant ex-
cited-state delocalization onto the quinolone unit.
–1
12
9
10
11
12
13
14
15
16
17
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19
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22
23
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Scheme 3. Limiting scenarios considered to explain observed rate
law, quenching, and competition studies.
As a test of this hypothesis, we examined the reaction of alkene-
functionalized quinolone 1x using photocatalyst 4f (Scheme 2). In
the absence of added maleimide, we observe the formation of intra-
molecular cyclization product 5 in 13% yield after 24 h of irradiation.
Thus, 4f is a competent catalyst for the intramolecular photocy-
cloaddition, albeit a relatively inefficient one. When the reaction is
conducted in the presence of maleimide, however, the formation of
5 is suppressed, and we exclusively observe formation of intermolec-
ular maleimide adduct 3x in 24% yield.
A - Bimolecular energy transfer to maleimide
O
*
O
3
O
+ 2
NH
[Ir]
3[Ir*]
3x
O
N
H
O
N
H
O
B - Intra-complex energy transfer to quinolone
3
*
O
O
+ 2
[Ir]
3[Ir*]
3x
Scheme 2. Control experiments show intermolecular cycloaddition
of 1x with maleimide out-competes intramolecular cyclization.
O
N
H
O
N
H
C - Exciton delocalization across Ir-Q complex
H
1.5 mol% 4f
3
O
*
CH2Cl2, blue LED
–78 °C, 24 h
O
O
O
N
O
hν
+ 2
N
H
O
H
[Ir]
[Ir]
3x
O
N
H
O
N
H
5, 13% yield
1x
O
NH
H
maleimide (2)
1.5 mol% 4f
O
O
O
H
In order to differentiate among these possibilities, we next per-
formed transient absorption spectroscopic experiments. Photoexci-
H
CH2Cl2, blue LED
–78 °C, 24 h
O
O
N
H
N
H
tation of a 150 µM solution of the iridium photocatalyst in CH2Cl2
by a 532 nm laser (7 ns full-width at half-max) produced the long-
lived iridium triplet excited state (3[Ir*]), which showed absorption
from 350–550 nm (see Supporting Information). The feature at 370
nm decayed with first-order kinetics, and a single exponential fit pro-
vided an excited-state lifetime of 4.4 µs. This lifetime was in good
agreement with the decay of the photoluminescence monitored at
580 nm. Cooling the sample to –78 °C produced minor changes in
the absorption difference spectrum and a negligible change in the
photoluminescence lifetime (t–78 = 4.3 µs.) This lifetime was insen-
sitive to the addition of up to 10 mM of quinolone 1c, indicating that
dynamic energy transfer to quinolone cannot compete kinetically
with excited-state decay. In contrast, the addition of maleimide 2 to
the iridium photocatalyst at –78 °C produced a significant decrease
in the lifetime of the 3[Ir*] excited state (500 ns with 10 mM 2, Fig-
ure 1A).
These results are fully consistent with the conclusions of the lumi-
nescence experiments conducted at room temperature: (1) binding
of quinolone does not significantly perturb the photophysics of the
Ir triplet, which is inconsistent with formation of a triplet exciplex
required in Scheme 3C; (2) the quinolone substrate does not un-
dergo energy transfer with the iridium photocatalyst which is incon-
sistent with the model depicted in Scheme 3B; and (3) only the ma-
1x
3x, 24% yield
49% ee
We considered three limiting scenarios to explain the overall rate
law derived for this reaction, the Stern–Volmer studies, and the out-
come of the competition study. These hypotheses are outlined in
Scheme 3. First, we believe that the collective data are most con-
sistent with a scenario in which the exciton is initially localized on
the Ir component of the complex and then transferred to maleimide
via an intermolecular energy-transfer process (eq A). This would be
a surprising and, to the best of our knowledge, unprecedented exam-
ple of a highly enantioselective triplet-state photoreaction that does
not involve photosensitization of a catalyst-bound substrate. Next,
we also considered an alternate model in which the initially formed
Ir-localized triplet state undergoes intramolecular energy transfer to
generate a quinolone-localized triplet state (eq B). In order to ex-
plain the competition experiments in Scheme 2, this scenario would
require a preference for triplet quinolone to react with an electron-
deficient maleimide over a tethered aliphatic alkene and that the in-
termolecular process out-competes an intramolecular one.
Finally, we considered a third possibility in which the excited-state
Ir–quinolone complex might form a charge-transfer complex, in
which the exciton is distributed over both the Ir and quinolone units,
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3
leimide is a competent quencher of the 3[Ir*] excited state, in agree-
At lower concentrations of quinolone 1c, the [Ir*] absorbance
decayed with biexponential kinetics in the presence of 10 mM ma-
leimide. The two lifetimes were independent of the quinolone con-
centration, with the short lifetime, τ1 ~ 680 ns, consistent with the
previously obtained lifetime for energy transfer quenching of a free
iridium photocatalyst by maleimide, and the long decay, τ2 ~ 3.4 μs,
aligning with the expected lifetime for maleimide quenching of the
[3Ir*-Q] complex. The presence of these two decays at –78 °C can
be rationalized as a consequence of a slow rate of association and dis-
sociation of the quinolone-iridium complex at lower temperatures.
In order to measure the strength of this binding interaction, a solu-
tion of the iridium photocatalyst and 10 mM concentration of ma-
leimide 2 was titrated with increasing concentrations of quinolone
1c. An analysis of the preexponential factors from biexponential fits
to the single wavelength kinetics allowed us to estimate the equilib-
rium constant for the hydrogen bound [Ir-Q] complex at –78 °C
(Keq,-78 = 3,400 ± 900). The free energy of association for hydrogen-
bonding interactions typically increases with decreasing tempera-
ture, which agrees with the increased binding constant at –78°C ver-
sus room temperature.
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ment with the model proposed in Scheme 3A. However, transient
absorption experiments also provided us with an opportunity to in-
terrogate the decay of the triplet excited-state photocatalyst in the
presence of both reaction partners. Based on the equilibrium con-
stant for the formation of the hydrogen-bound catalyst–quinolone
complex [Ir-Q], a solution of iridium photocatalyst 4f and quino-
lone 1c was prepared with quinolone concentrations large enough
to ensure that > 95% of the iridium photocatalyst was bound to quin-
olone. As noted above, the lifetime of the iridium excited state was
unaffected by the bound quinolone. The addition of maleimide 2 did
quench the 3[Ir*-Q] excited-state, but the rate of quenching was sig-
nificantly attenuated compared to the free iridium: we observed only
a 2-fold decrease in the excited-state lifetime (4.3 → 2.2 µs) after the
addition of 14 mM 2. A Stern–Volmer analysis was linear and pro-
vided a KSV of 130 M–1, which corresponds to a bimolecular quench-
ing rate constant of kq = 3.0 x 107 M–1 s–1. We note that there was no
evidence for static quenching by the quinolone within the [Ir-Q]
complex. Any small, unmeasurable static quenching by quinolone
would not be kinetically competitive with the maleimide quenching,
and thus not be a significant mechanistic pathway for the reported
reaction.
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The combination of transient absorption and photoluminescence
quenching experiments, however, does not establish exactly which
species are involved in C–C bond-forming process. The triplet ma-
leimide may react with the quinolone present within the same [Ir-
Q] complex that was quenched, or the maleimide could escape the
solvent cage and undergo a bimolecular reaction with a different [Ir-
Q] complex. Attempts to observe the triplet maleimide complex by
transient absorption spectroscopy were unsuccessful. However, two
details support the proposed caged reaction mechanism. First, the
concentration of free quinolone is nearly two orders of magnitude
larger than that of hydrogen bound quinolone. Thus, if triplet malei-
mide escapes the solvent cage, one would expect it to react readily
with free quinolone and produce a racemic mixture. This expecta-
tion is inconsistent with the highly enantioselective transformation
observed. Second, triplet maleimide has a lifetime of 170 ns and un-
dergoes rapid self-reaction near the diffusion limit, 109–1010 M–1 s–
1
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.
Under the initial reaction conditions, the concentration of malei-
mide is 5-fold higher than quinolone and more than 100-fold higher
than the [Ir-Q] complex. Thus, any triplet maleimide that escapes
the solvent cage would be expected to rapidly dimerize before en-
countering an [Ir-Q] complex. The maleimide dimers are difficult to
unambiguously identify in the reaction mixtures of most of the ex-
periments summarized in Table 2. We were, however, able to quan-
tify the formation of 8% of N-benzyl maleimide dimer along with in-
termolecular cycloadduct 3s. Thus, it is clear that triplet maleimide
is being generated during the course of these photoreactions, but
that the rate of dimerization is relatively slow compared to the rate
of the reaction with [Ir-Q]. This would be consistent with a scenario
in which maleimide is formed via triplet energy transfer, but the ma-
jority of [2+2] cycloaddition occurs before the triplet maleimide can
escape the solvent cage.
The transient absorption data therefore show that energy transfer
occurs exclusively through an intermolecular interaction with malei-
mide. These results rule out the mechanistic proposal depicted in
Scheme 3B: there is essentially no population of triplet quinolone
under the reaction conditions. Instead, the conclusion from these
studies support the mechanism shown in Scheme 3A, in which a bi-
molecular, collisional energy transfer process is substantially faster than
an analogous intramolecular event. This is a surprising result. It is well
Figure 1. A) Normalized change in absorbance at 370 nm of iridium
photocatalyst 4f (150 μM) after excitation with a 7 ns, 532 nm laser in
dichloromethane (gray) and in the presence of maleimide 2 (blue) or
quinolone 1c (red). B) Titration of a solution of iridium photocatalyst
4f (150 μM) and maleimide 2 (10 mM) with increasing concentra-
tions of quinolone 1c. Black lines are fits to a biexponential decay
model. Both experiments were performed at –78 °C with a laser power
of 3 mJ/pulse.
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Figure 2. Computationally optimized structures for possible hydrogen-bonding complexes of Ir catalyst 4f with A) quinolone 1c and B) malei-
mide 2. (Bond lengths in Å.) C) Gibbs free energy changes during the energy-transfer process. Energies are evaluated based on the two separated,
ground-state components.
1
appreciated that Dexter energy transfer exhibits a strong distance de-
pendence, which seems incongruous to the finding that the Ir pho-
tocatalyst binds quinolone but sensitizes unbound maleimide. On
the other hand, investigations of intramolecular energy transfer pro-
cesses conducted by Speiser demonstrated that the rate of Dexter
energy transfer can also exhibit a strong dependence on the relative
quinolone substrate. Among these four possible adducts, [Ir-QC]
was most stable at a relative binding energy of –6.1 kcal/mol, which
is in good agreement with the experimentally observed sense of the
stereoinduction, although the absolute value of the binding energy
estimate is not consistent with the measured association constant.
Given the many approximations about the unbound state and the
crude way solvation is treated, we cannot expect a quantitatively re-
liable prediction of the binding energy. Moreover, because the en-
tropic penalty is temperature-dependent, this inconsistency might
also be due to an overestimation of the entropy correction at the re-
action temperature. Nonetheless, these computed energies are use-
ful for comparing the stabilities of different geometries, as significant
error-cancellation is expected.
We find notable differences in the optimal binding structure, 1[Ir-
QC], compared to the optimal complex involved in the intramolecu-
lar [2+2] cycloaddition.10 Previously, we had found that the quino-
line N–H moiety engages in a non-classical hydrogen bond to the
pyrazole nitrogen, which aligns Q to maximize the orbital overlap
with the cyclometalating ligand. In the present case, the encounter
complex adopts a different geometry because the tether carrying the
olefin fragment is not present and the main hydrogen-bonding fea-
ture is between the pyrazole N–H and the oxygen atoms of Q, as
shown in Figure 2. Importantly, this quinolone binding mode mini-
mizes the potential for orbital overlap between it and the photocata-
lyst ligands and thus suggests that energy transfer within the complex
might not be facile. The calculated optimal binding geometry, how-
ever, is in good agreement with the unexpected experimental obser-
vation that the photoreaction of N-methyl quinolone substrate (3r)
shows good ee, implying that the quinolone N–H bond is no longer
critical. Compared to this intermediate, the binding of maleimide is
15
orientations of the interacting chromophores We wondered
whether a similar explanation could be invoked to rationalize these
findings.
We therefore further interrogated this reaction using density func-
tional theory (DFT) to model the parent reaction between quino-
lone 1c and maleimide. In our previous computational studies of the
intramolecular version of this cycloaddition,10 we found that key to
engineering an efficient triplet energy-transfer event is maximizing
the overlap between orbitals that are involved in the double electron
transfer on the cyclometalating ligand and the coordinated sub-
strate. For the present intermolecular reaction system, however,
Stern–Volmer quenching experiments and transient absorption data
showed that the energy transfer to the bound quinolone substrate is
not facile. Instead, the intermolecular activation of maleimide is
more effective. Figure 2 summarizes the DFT-calculated energy dif-
ferences of all plausible donor-acceptor pairs. Extensive sampling of
possible donor-acceptor geometries revealed four relevant struc-
tures for the [Ir-Q] complex and two structures for the [Ir-2] adduct,
shown in Figure 2.
In analogy to our previous work,10 encounter complexes 1[Ir-QA],
and 1[Ir-QB] feature non-classical hydrogen bonds between the py-
razole N–H group and the oxygen and N–H functionalities of the
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predicted to be much less favored: the two lowest energy structures
1
1
1
2
3
4
being [Ir-2A] and [Ir-2B] have binding energies of 0.2 and 2.2
kcal/mol, respectively. Thus, our calculations predict that the [Ir–2]
encounter complexes should be much harder to detect experimen-
tally, which is also in good agreement with the NMR titration exper-
iments.
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Using the singlet ground state structures of the encounter com-
plexes, the energies of two triplet states denoted [3Ir-1Q] and [1Ir-
3Q] can be calculated, which in turn allows for estimating the energy
of the triplet energy transfer from the photocatalyst to the bound
substrates (Figure 2c). Interestingly, these calculations reveal that
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1
the triplet energy transfer in [Ir-2B] is easiest at –1.0 kcal/mol. In
contrast, the energy transfer to the quinolone substrate is slightly up-
hill with energy requirement of +1.4 to +2.3 kcal/mol for the triplet
energy transfer. These results agree with the Stern–Volmer quench-
ing experiments and offers a rationale for the relatively low rate of
triplet energy transfer to the quinolone compared to maleimide, as
the rate of triplet energy transfer is generally dependent on the ther-
modynamic driving force.
Under the employed experimental conditions, however, the con-
centration of the quinolone compared to the photocatalyst is high,
and practically all of the Ir complexes will be bound to a quinolone
16
substrate. Thus, the direct triplet sensitization from a free Ir cata-
lyst to maleimide as outlined above is unlikely to be kinetically rele-
vant. We wondered if a transient three-component complex [Ir-Q-
2] might be responsible for the triplet energy transfer. We located a
3-component adduct with maleimide bound to [3Ir-1QC]. Notably,
this arrangement exhibits a π-π stacking interaction between malei-
mide and the cyclometalating phenylpyridine ligand of the Ir-cata-
lyst. Such a favorable non-covalent interaction was not possible with
the free photocatalyst. We speculate that this arrangement allows for
the appropriate orbital overlap necessary that would enable rapid
Dexter energy transfer between the triplet Ir complex and malei-
mide.
Figure 3. Computationally optimized structures of 3[Ir-Q-2] hydrogen
bond complex. For triplet-state structures, molecules with high Mulli-
ken spin density are colored in blue. Bond lengths are in Å. Energies are
calculated based on the two separated species, [3Ir-1QC] and maleimide
2.
Using the calculated structure of the singlet ground state [Ir-Q-
2], three triplet states denoted [3Ir-1Q-12], [1Ir-3Q-12] and [1Ir-1Q-
32] were optimized, and their structures and energies are shown in
Figure 3. The Mulliken spin density values are helpful in identifying
which state corresponds to which conceptual triplet and are given in
the supporting information. Interestingly, the quinolone in the [1Ir-
3Q-12] state shows an elongated C=C double bond of 1.472 Å, which
is 0.103 Å longer than in [3Ir-1Q-12]. Similarly, the C=C double
bond of maleimide was elongated to 1.472 Å from 1.349 Å in [3Ir-
1Q-12]. These structural features are indicative of triplet formation
in the respective substrates, as a result of the Dexter energy transfer
event. These calculations strongly suggest that the fully delocalized
exciplex, as shown in Scheme 3C, is unlikely to exist. The metal and
ligand based orbitals do not mix strongly enough justify such a delo-
calized state and our calculations show significant preference for the
localized states, consistent with the experimental observations dis-
cussed above.
Our calculations suggest that the energy required to access the
two possible reactive triplet species is 3.7 kcal/mol for quinolone
and 4.6 kcal/mol for maleimide. However, the rate of Dexter energy
transfer depends upon the degree of orbital overlap between the
1
photocatalyst and the triplet acceptors. The arrangement that [Ir-
QC] possesses does not show a strong π-π interaction between the
quinolone and the cyclometalating ligand of the photocatalyst,
which is a notably different feature from what we had found in the
intramolecular [2+2] case. As illustrated in Figure 3, the position of
the quinolone does not change significantly upon maleimide attach-
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ment. Therefore, we expect the Dexter energy transfer to the quino-
Page 8 of 11
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lone unit to be still inefficient. The maleimide, on the other hand,
can approach the excited-state photocatalyst from many different
trajectories, and in the optimized ternary encounter complex [3Ir-
1Q-12] the maleimide interacts directly with the cyclometalating lig-
and, appropriately positioning these components to participate in
the Dexter energy transfer and become the triplet state that triggers
the intermolecular [2+2] cycloaddition. Note that this geometry is
only one reasonable arrangement for the energy transfer; there may
exist many other binding modes that can remotely activate the ma-
leimide into its triplet state.
These studies suggest that highly enantioselective excited-state
photoreactions are feasible even when there is no strong ground-
state preassociation between the chiral catalyst and the sensitized or-
ganic substrate. This conclusion contradicts a central axiom of asym-
metric photochemistry, which has long posited that such preassoci-
ations are necessary to ensure that highly reactive excited-state inter-
mediates remain closely associated with the chiral catalyst through-
out the photoexcitation and bond-forming processes. The potential
implications of this work are highly significant for a variety of rea-
sons. First, the discovery of this unexpected mechanism of substrate
activation suggests that a similar principle might be utilized in the
development of other highly enantioselective excited-state photore-
actions. The sequestration of the excited-state intermediate within
a well-defined chiral environment need not be considered a strict re-
quirement in the design of asymmetric photochemical reactions.
More broadly, this work highlights that subtly different photocata-
lytic methodologies have multiple reactivity pathways available to
them and can proceed via entirely different mechanisms. The results
of our comprehensive kinetic, spectroscopic, and computational
studies underscore the importance of mechanistic investigations in
the field of synthetic organic photochemistry.
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Thus, computational evidence provides a model that explains the
differences in substrate scope between this newly discovered inter-
molecular reaction and the analogous intermolecular system previ-
ously reported by our group: the reactive binding conformation of
the quinolone substrate is quite different and involves a different set
of hydrogen-bonding interactions with the photocatalyst pyridylpy-
razole unit. More importantly, this binding mode also minimizes p
overlap between the photocatalyst and the quinolone that would be
necessary for efficient Dexter energy transfer, leaving maleimide sen-
sitization as the dominant reaction pathway in this cycloaddition.
Conclusion
ASSOCIATED CONTENT
In conclusion, we have developed a highly enantioselective inter-
molecular [2+2] photocycloaddition using a chiral hydrogen-bond-
ing Ir complex as a triplet sensitizer. A combination of synthetic, ki-
netic, spectroscopic, and computational studies suggest an unusual
mode of asymmetric photocatalysis, outlined in Scheme 4. The
quinolone substrate associates to the pyrazole moiety of iridium
complex 4f to produce the resting state of the photocatalytic cycle.
The bidentate hydrogen-bonding interaction enforces a geometry
that prevents overlap between the π molecular orbitals of the catalyst
and quinolone that would enable Dexter energy transfer to occur.
Thus upon excitation, the photocatalyst preferentially undergoes bi-
molecular energy transfer with maleimide 2. The resulting triplet
state maleimide reacts with the quinolone within the stereodifferen-
tiating influence of the Ir stereocenter, affording cycloadduct 3c in
high ee.
Supporting Information. The Supporting Information is available free of
charge on the ACS Publications website.
Experimental procedures; characterization data; spectra for all new
compounds; crystallographic data; Cartesian coordinates of all com-
puted structures; binding and photoluminescence quenching studies
(PDF)
AUTHOR INFORMATION
Corresponding Author
* Email: tyoon@chem.wisc.edu, mbaik2805@kaist.ac.kr
Notes
ORCID:
Jian Zheng: 0000-0002-4698-3407
Scheme 4. Proposed mechanism for enantioselective intermolecu-
lar [2+2] photocycloaddition
Wesley B. Swords: 0000-0002-2986-326X
Hoimin Jung: 0000-0002-3026-6577
Kazimer L. Skubi: 0000-0002-9689-1842
Jesse B. Kidd: 0000-0003-2225-8021
Gerald J. Meyer: 0000-0002-4227-6393
Mu-Hyun Baik: 0000-0002-8832-8187
Tehshik P. Yoon: 0000-0002-3934-4973
[Ir]
1c
+
3c
i-Pr
O
[Ir]
O
N
H
hν
1c
ACKNOWLEDGMENT
O
We thank Dr. Ilia A. Guzei for determining the crystal structure of 3f and
3w. T.P.Y. is grateful to the NSF for a research grant (CHE 1665109).
J.Z. thanks the Shanghai Institute of Organic Chemistry for a postdoc-
toral fellowship. M.B. acknowledges support from the Institute for Basic
Science (IBS-R10-A1) in Korea. Analytical instrumentation at UW–
Madison is supported in part by the NIH (S10 OD020022, S10
OD012245) and by a generous gift from the Paul J. Bender fund.
NH
i-Pr
H
O
O
H
3[Ir*]
H
Oi-Pr
O
N
H
[Ir]
N
O
H
2
O
*
i-Pr
O
3
[Ir]
NH
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O
N
H
O
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4
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CCDC-1897932 and CCDC-1897933 contain the supplementary
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free of charge from the Cambridge Crystallographic Data Centre.
12 See Supporting Information for details.
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cloadditions by energy transfer”, Angew. Chem. Int. Ed. 2012, 51, 10329–
10332. (b) Zou, Y. Q.; Duan, S. W.; Meng, X. G.; Hu, X. Q.; Gao, S.; Chen,
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tion of vinyl azides by transition-metal photocatalysis”, Angew. Chem. Int. Ed.
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The experimentally determined association constant at suggests that
99% of the Ir photocatalysts are bound to quinolone under initial reaction
concentrations at –78 °C.
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+
+
OMe
OMe
O
*
N
Ir
N
Ir
C
C
C
N
N
NH
N
N
O
HN
H
H
C
O
O
H
N
H
N
H
N
N
O
*
iPrO
O
iPrO
iPrO
O
O
HN
N
H
NH
NH
O
97% ee
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unconventional energy flow in asymmetric photocatalysis
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