Realizing the Photoene Reaction with Alkenes under Visible Light Irradiation and Bypassing the Favored [2 + 2]-Photocycloaddition

Article abstract of DOI:10.1021/jacs.8b08100

The textbook photoreaction between two alkenes is the [2 + 2]-photocycloaddition resulting in functionalized cyclobutanes. Herein, we disclose an unusual reactivity of alkenes that favor photoene reaction over the [2 + 2]-photocycloaddition.

Full text of DOI:10.1021/jacs.8b08100

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Communication
Realizing the Photo-Ene Reaction with alkenes under visible light
irradiation and bypassing the favored [2+2]-photocycloaddition
Sapna Ahuja, Ramya Raghunathan, Elango Kumarasamy, Steffen Jockusch, and Jayaraman Sivaguru
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Sep 2018
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Realizing the Photo-Ene Reaction with alkenes under visible light ir-
radiation and bypassing the favored [2+2]-photocycloaddition
Sapna Ahuja,§ Ramya Raghunathan,† Elango Kumarasamy,† Steffen Jockusch,†
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§
,
*
Jayaraman Sivaguru
§ Center for Photochemical Sciences and Department of Chemistry, Bowling Green State University, Bowling
Green, OH 43403, USA.
† Department of Chemistry Columbia University, New York, NY 10027, USA.
Supporting Information Placeholder
ABSTRACT: The text book photoreaction between two
alkenes is the [2+2]-photocycloaddition resulting in func-
tionalized cyclobutanes. Herein, we disclose an unusual
reactivity of alkenes that favor photo-ene reaction over the
[2+2]-photocycloaddition.
The synthetic utility of ene reaction lies in the fact that
simple thermal reorganization affords C-C bond for-
Figure 1: Preferred [2+2]-photocycloaddition of alkenes vs.
mation to access complex carbocycles and heterocycles.
photo-ene reaction.
(Figure 1).1-4 Thermally, different variants of ene reaction
Scheme 1: Photoreactivity of citraconicimide 1 with substi-
tuted alkenes 2a-d.
exist depending upon the nature of enophile such as
alkene, alkyne, azo and carbonyl functionality.5-6 Photo-
chemical routes to access ene reactions are rare as pho-
to-excited alkene undergo the preferred / photochemical-
ly-allowed [2+2]-photocycloaddition leading to cyclobu-
tanes .7-9 A well-known variant of photo-ene reaction is
the formation of hydroperoxide upon reaction of alkene
with singlet oxygen.10-14 Weedon and coworkers have
reported photo-ene reaction involving an alkene where
the photo-ene adduct was observed as a minor side
product (1-2% yield).15 To the best of our knowledge,
directing the photoreactivity of an excited alkene exclu-
sively towards ene-reaction i.e., the photochemical
equivalent of the thermal ene-reaction, is not reported in
literature. In this report, we present our observation
wherein the excited state reactivity of alkenes is exclu-
sively directed towards photo-ene reaction and com-
pletely evading the preferred [2+2]-photocycloaddition
(Figure 1-bottom). An important highlight of our finding is
that the photo-ene reaction proceeds at ambient tem-
perature with visible-light compared to thermal ene trans-
formations that typically require elevated temperatures.
leads to biradicaloid intermediate(s), its excited state
lifetime can be tuned by appropriately substituting the
reactants. In this idealized scenario, a long-lived triplet
biradical will likely open other competing pathways or at
the very least make the other pathways competitive lead-
ing to new reactivity.16 We have been successful in alter-
ing excited state pathways thereby uncovering new reac-
tivity by employing restricted bond rotations in photoac-
tive chromophores in unimolecular transformations.17-20
To highlight the influence of restricted bond rotations in
bimolecular photoreactions, we selected N-tert-butyl-
phenyl citraconicimide 1 as model system and evaluated
its reactivity with different alkenes 2a-d (Scheme 1).20
Citraconicimide 1 was synthesized using established
literature procedures.20 An added advantage of the
[2+2]-Photocycloaddition involving alkenes is a con-
certed process when it occurs from a pp* singlet excited
state.16 Hence directing the excited state of the reactant
to a different reaction pathway requires changing its
characteristic and the associated dynamics which is
quite challenging. However, [2+2]-photocycloaddition is
also known to occur efficiently from a triplet pp* excited
state (3pp*) in a stepwise mechanism. We believed this
will present an opportunity to alter reactivity pathways.
The stepwise pathway in a 3pp* excited state typically
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TABLE 1. Reaction optimization for photoreactivity of
citraconicimide 1 with tetramethylethylene 2d.a
design is the restricted N-CAryl bond rotation which could
21-24
be employed for atropselective transformations.17,
1
2
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Citraconicimide 1 exist as atropisomers and its energy
barrier for N-CAryl bond rotation was evaluated25 through
kinetics measurements of racemization at 70 oC in
MeCN. As expected, 1 featured a high activation energy
barrier of ~29.6 kcal/mol with a half-life for racemization
(t1/2) of 8.3 days corresponding to the racemization rate
constant (krac) of 9.6x10-7 s-1. Such high racemization
barrier allows 1 to maintain its absolute configuration
during reaction with alkene under ambient conditions.
We evaluated the photochemical reactivity of 1 with vari-
ous alkenes 2a-d. The reactions were performed under
both direct and sensitized irradiation conditions (Tables
1-2). After the photoreaction, the reaction mixture was
purified by column chromatography and analyzed by
NMR spectroscopy and mass spectrometry. Unambigu-
ous characterization of the photoproducts was estab-
lished using single crystal XRD.26 Table 1 displays the
optimization of reaction conditions for reactivity of 1 with
tetramethylethylene 2d.
Entry
Irradiation conditions b
bb/Pyrex cutoff, Acetone, 2 h
bb/Pyrex cutoff, MeCN, 8 h
350 nm, X, MeCN, 2 h
420 nm, TX, MeCN, 2 h
420 nm, TX, DCM, 2 h
420 nm, TX, CHCl3, 2 h
420 nm, TX, MeOH, 2 h
420 nm, TX, EtOAc, 2 h
% Yield (5d)
1
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8
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a [1]=3.3 mM at room temperature under N2 atmosphere.
30 mol% xanthone (X) or thioxanthone, (TX) and 10 eq.
of 2d. Yield based on H-NMR spectroscopy using tri-
phenylmethane as internal standard (error ±5%).
bb/Pyrex cutoff broadband irradiation using a medium
pressure 450 W mercury lamp with Pyrex cutoff; c ~350
nm/~420 nm irradiations performed in a Rayonet reactor.
1
b
Table 2. Intermolecular photochemical reaction of citraconicimide with alkenesa
a Irradiation with 30 mol% TX and 10 equiv of 2. ee values from chiral stationary phase HPLC with A and B representing
the order of eluting enantiomers; dr values from H NMR spectroscopy ( ±3% error). Based on crude NMR (<5%) of
1
side products (photo-ene product for 2b; [2+2]-product for 2c) were observed. In addition, there were also trace
amounts of uncharacterized side products.
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Figure 2: (A) Determination of bimolecular rate constant (kq) for quenching of xanthone and thioxanthone triplet states by 1 using
laser flash photolysis (λex=355 nm, 7 ns pulse width). Inverse xanthone and thioxanthone triplet lifetimes determined from triplet ab-
sorption decay traces monitored at 620 nm vs. varying concentration of 1 in argon saturated MeCN solutions. (B) Transient absorp-
tion spectrum of 1 monitored at the end of the laser pulse (λex=308 nm, 20 ns pulse width) of argon saturated MeCN solutions. Inset:
decay trace monitored at 350 nm. (C) Determination of kq of 31* by alkenes 2a-2d using LFP (λex=308 nm, 20 ns pulse width). Inverse
triplet lifetime of 1 determined from triplet absorption decay traces monitored at 350 nm vs. varying concentration of 2 in argon satu-
rated MeCN solutions.
Based on this observation, optimized reaction conditions
were developed (Table 2) to probe the reactivity of 1 with
various alkenes 2a-d. Irradiation was carried out at ~420
nm (Rayonet reactor) using thioxanthone as sensitizer.
Inspection of Table 2 reveals that [2+2]-photo-adducts 3
and 4 were observed as the major/isolated products up-
on employing mono and di-substituted alkenes 2a-2b
and 2e. However, photo-ene product 5 was observed as
the major product with tri- and tetrasubstituted 2c-2d. It
was interesting to observe that the chemoselectivity is
based on the substitution pattern on the alkene em-
ployed. To further understand the chemoselectivity lead-
ing to photo-ene reaction, we evaluated the photoreac-
tivity of 1 with tetra-substituted alkene 2d under varying
reaction conditions. While the photo-ene product 5d was
observed under both direct and sensitized irradiations,
the reaction efficiency and the product yield was evident-
ly much higher under triplet sensitized irradiation condi-
tions (Table 1; compare entries 2 and 4). Based on this
observation, we believe that 1 reacts from the triplet ex-
cited state and triplet sensitizer thioxanthone accelerates
the reaction by populating the triplet states of 1 through
energy transfer. Thus in the absence of sensitizer, the
reaction is less efficient due to poor intersystem crossing
rates of 1.20
Based on our previous investigations on atropselective
intramolecular photoreactions, we believed that the axial
chirality would influence the stereochemical outcome of
the reaction.17 To establish the role of axial chirality, we
performed photoreactions on enantiopure atropisomeric
citraconicimide 1 with monosubstituted alkene 2a and
analyzed the stereoselectivity in the product. Since al-
kene 2a is unsymmetric, two regioisomeric products 3a
and 4a were isolated. The atropselectivity in the products
were >97% suggesting that the axial chirality played a
critical role by facially biasing the approach of the alkene
leading to excellent stereoselectivity in the products.
Inspection of the stereoselectivity and the crystal struc-
ture of photo-ene 5d shows that the enantiomer (M)-1
gave (M,S)-5d, while the opposite enantiomer (P)-1 gave
the enantiomeric (P,R)-5d with atropselectivity >99%.26
Irrespective of chemoselectivity in the reaction, the enan-
tiomeric excess (atropselectivity) in the products is de-
termined by the axial chirality of the citraconicimide 1.
To rationalize the above observations and to under-
stand the mechanistic details for this chemoselectivity,
we performed detailed photophysical experiments. As
we have previously shown that maleimides feature only
weak luminescence both at room temperature and at 77
K,20 we turned to laser flash photolysis (LFP; λex = 355
nm, 7 ns pulse width) to understand the excited state
reactivity of 1 with alkenes 2. As the reaction occurred
efficiently through triplet sensitization under both UV and
visible light, we determined the bimolecular quenching
rate constant kq (Figure 2A) of excited sensitizers xan-
thone (X) and thioxanthone (TX) triplet states by 1. The
excited sensitizers were efficiently quenched by 1 (for
Inspection of Table 2 shows that the alkene substitu-
tion has a profound effect on the reaction outcome. Pho-
toreaction of 1 (thioxanthone sensitization) with mono-
substituted alkene 2a afforded the 1,2-substituted cyclo-
butane 3a and 1,3-substituted cyclobutane 4a in 41%
and 23% isolated yields, respectively. We confirmed
these products unambiguously from the single crystal
XRD of the major and minor regioisomers 3b and 4b
respectively. The absolute configurations were deter-
mined to be (P,R,R)-3b, (M,S,S)-3b and (P,S,R)-4b,
(M,R,S) 4b.26 On the other hand, under identical condi-
tions, photoreaction of 1 with tri-substituted alkene 2c
and tetra-substituted alkene 2d gave the respective pho-
to-ene product 5c (45% isolated yield) and 5d respec-
tively (41% isolated yield). When the reaction was car-
X
xanthone kq = 6.6±0.1 x 109 M-1s-1 and for thioxanthone
kqTX = 4.6±0.1 x 109 M-1s-1). The high kq indicated that the
energy of the triplet state of 1 is below that of thioxan-
thone (~63 kcal/mol). Direct excitation of 1 with laser
pulses at 308 nm (20 ns pulse width) generated a weak
transient absorption spectrum which decayed with a life-
time of 8.7 µs (Figure 2B). The transient signal was as-
signed to the triplet state of 1 based on the high rate
constant of quenching by molecular oxygen (~2 × 109 M-
1s-1) and similarities with a previously reported triplet
spectrum of maleimides.27 This enabled us to determine
o
ried out at -78 C, the isolated yield of the photo-ene
adduct 5d increased to 83%. Unambiguous characteriza-
tion of 5d was established through single crystal XRD.
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the quenching rate constants of 1* by various alkenes
2a-2d (Figure 2C). All the alkenes screened quenched
31* efficiently with kq ranging from 1 × 108 M-1s-1 (for 2a)
to 11 × 108 M-1s-1 (for 2c). This shows that the nature of
the alkene played a significant role in quenching the ex-
cited state of the citraconicimide. We believe the chemi-
cal quenching of the triplet excited state of 1 by alkenes
results in the formation of the triplet biradicals (vide in-
fra).
the ortho-tert-butyl substituent on the N-aryl ring leading
to t-1,4-BR-2d. This fixed the stereochemistry of the
point chiral stereocenter at the allylic position as the “S”
configuration leading to the photo-ene (M,S)-2d. In
mono- or di-substituted alkenes, the initially formed tri-
plet 1,4-biradical is a primary radical center that will react
at a faster rate leading to ring closure resulting in [2+2]-
photocycloaddition. In tri-and tetra- substituted alkene,
the triplet biradical is relatively long lived enabling allylic
hydrogen abstraction leading to photo-ene reaction.
Thus, the nature of the biradical in the reaction pathway,
its lifetime and stability that are dictated by the substitu-
ents on the alkenes determine the course of the photo-
reaction i.e., [2+2]-cycloaddition vs. photo-ene reaction.
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Scheme 2: Mechanistic rationale for the observed photo-
ene reaction
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To conclude, our study has uncovered that by tuning
the substitution on alkene, the photochemical reaction
pathway between citraconicimide and alkenes can be
entirely directed towards either [2+2]-photocycloaddition
or photo-ene reaction. Additionally, irrespective of the
chemoselectivity, the incorporation of axial chirality in the
system leads to the stereo-enriched photoproduct where
the steric handle in the axial chirality influence the ap-
proach of alkene towards the excited maleimide chro-
mophore. Thus, our study has showcased the effective-
ness of employing restricted bond rotations to open new
avenues to perform light initiated reactions and uncover
new reaction pathways. In the present case, our investi-
gation has showcased the utility of light to promote one
of the useful thermal transformations viz., ene-reaction at
room temperature.
ASSOCIATED CONTENT
Supporting Information. Supporting Information is available
free of charge on the ACS Publications website. Single-crystal
XRD data (CIF),ꢀExperimental procedures, characterization
data, analytical conditions, and photophysical studies (PDF).
To rationalize the formation of photo-ene product, we
propose a mechanistic model from the excited state 1
that involves zwitterionic or radical pathway as detailed
in Scheme 2. In radical pathway, we postulate that citra-
conicimide 1 react from the triplet excited state with al-
kene 2d to form triplet 1,4-biradical t-1,4-BR-2d. This t-
1,4-BR-2d abstracts the allylic hydrogen of citracon-
icimide through a cyclic 6-memembered transition state
to form triplet 1,2-biradical t-1,2-BR-2d. Subsequent in-
tersystem crossing and recombination results in photo-
ene product 5d. In ionic pathway, the triplet excited 1
could form an exciplex with the alkene which after addi-
tion leads to a zwitterionic intermediate ZW-2d. Hydride
migration from this intermediate lead to the desired
product 5d. Based on the oxidation potential of alkene
(1.59 eV for 2c and 1.31 eV for 2d) and the reduction
potential of 1 (1.66 eV),26 we believe that the exciplex
formation from the triplet excited state of 1 (estimated ET
~ 62 kcal/mol)20 and the ionic pathway is not very likely
due to endergonic nature of electron transfer. Hence, in
the present case, it is very likely that the reaction occurs
through a radical mechanism. Based on the atropselec-
tive reaction of enantiopure 1 with 2d, the approach of
the alkene towards the excited citraconicimide was dic-
tated by the ortho-tert-butyl substituent on the N-aryl
ring. In the case of triplet excited (M)-1 undergoing pho-
to-ene reaction with 2d, the alkene approached the
citraconicimide from the side opposite (Si-face) to that of
AUTHOR INFORMATION
Corresponding Author
* E-Mail: sivagj@bgsu.edu
ORCID
J. Sivaguru: 0000-0002-0446-6903
Steffen Jockusch: 0000-0002-4592-5280
Elango Kumarasamy: 0000-0002-7995-6894
Sapna Ahuja: 0000-0002-3060-9699
Author Contributions
Manuscript was written through contributions of all authors. All
authors have given approval to the final version of the manu-
script.
Funding Sources
The authors thank the National Science Foundation for gener-
ous support for their research (CHE-1465075 and CHE-
1811795).
Notes
Part of the work was conducted during SA, RR, EK and JS
affiliation with North Dakota State University, Fargo, ND.
Acknowledgment
The authors thank Dr. Angel Ugrinov for solving the single crys-
tal XRD structures.
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16. Turro, N. J.; Ramamurthy, V.; Scaiano, J. C., Modern
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